Summary of the Sterilization Techniques Applied on Liposomal Preparations.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"stanford-university-identifies-top-2-scientists-over-1-000-are-intechopen-authors-and-editors-20210122",title:"Stanford University Identifies Top 2% Scientists, Over 1,000 are IntechOpen Authors and Editors"},{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"}]},book:{item:{type:"book",id:"8290",leadTitle:null,fullTitle:"Pharmacognosy - Medicinal Plants",title:"Pharmacognosy",subtitle:"Medicinal Plants",reviewType:"peer-reviewed",abstract:"Pharmacognosy is a term derived from the Greek words for drug (pharmakon) and knowledge (gnosis). It is a field of study within Chemistry focused on natural products isolated from different sources and their biological activities. Research on natural products began more than a hundred years ago and has continued up to now with a plethora of research groups discovering new ideas and novel active constituents. This book compiles the latest research in the field and will be of interest to scientists, researchers, and students.",isbn:"978-1-83880-611-8",printIsbn:"978-1-83880-610-1",pdfIsbn:"978-1-83880-874-7",doi:"10.5772/intechopen.78419",price:139,priceEur:155,priceUsd:179,slug:"pharmacognosy-medicinal-plants",numberOfPages:320,isOpenForSubmission:!1,isInWos:1,hash:"0288b7ddce8b6d3ff07a3d78db289282",bookSignature:"Shagufta Perveen and Areej Al-Taweel",publishedDate:"June 19th 2019",coverURL:"https://cdn.intechopen.com/books/images_new/8290.jpg",numberOfDownloads:20593,numberOfWosCitations:30,numberOfCrossrefCitations:16,numberOfDimensionsCitations:43,hasAltmetrics:1,numberOfTotalCitations:89,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"July 13th 2018",dateEndSecondStepPublish:"August 3rd 2018",dateEndThirdStepPublish:"October 2nd 2018",dateEndFourthStepPublish:"December 21st 2018",dateEndFifthStepPublish:"February 19th 2019",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,editors:[{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Dr. Shagufta Perveen is a Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University. She has completed her Undergraduate, Postgraduate and Doctorate Education from the University of Karachi, Pakistan and University of Southampton UK. Dr. Perveen has acted as the Principal Investigator of major research projects funded by the research unit of King Saud University. She is a Ph.D. and MS supervisor of the different students in Natural Product Chemistry. She has to her credit, more than 75 original research papers in peer-reviewed journals of International repute. She has also edited two books bearing ISBN numbers. Besides attending several National and International Seminars and Conferences, she has delivered several plenary/invited talks and chaired various sessions. She is a fellow member of Royal Society of Chemistry UK and Member American Chemical Society of USA.",institutionString:"King Saud University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:{id:"192994",title:"Dr.",name:"Areej",middleName:null,surname:"Al-Taweel",slug:"areej-al-taweel",fullName:"Areej Al-Taweel",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Areej Al-Taweel is a Professor at King Saud University in Saudi Arabia. She obtained her Ph.D. from the King Saud University in 2007. She is an expert in Natural Product Isolation and structure. She has published more than forty research papers and two chapters one book in different ISI listed journals.",institutionString:"King Saud University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:null},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1200",title:"Pharmacognosy",slug:"pharmacognosy"}],chapters:[{id:"66977",title:"Introductory Chapter: Pharmacognosy",doi:"10.5772/intechopen.86019",slug:"introductory-chapter-pharmacognosy",totalDownloads:808,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Shagufta Perveen and Areej Mohammad Al-Taweel",downloadPdfUrl:"/chapter/pdf-download/66977",previewPdfUrl:"/chapter/pdf-preview/66977",authors:[{id:"192992",title:"Prof.",name:"Shagufta",surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"}],corrections:null},{id:"65477",title:"Role of Medicinal and Aromatic Plants: Past, Present, and Future",doi:"10.5772/intechopen.82497",slug:"role-of-medicinal-and-aromatic-plants-past-present-and-future",totalDownloads:2280,totalCrossrefCites:5,totalDimensionsCites:15,signatures:"Maiko Inoue, Shinichiro Hayashi and Lyle E. Craker",downloadPdfUrl:"/chapter/pdf-download/65477",previewPdfUrl:"/chapter/pdf-preview/65477",authors:[{id:"193395",title:"Ph.D.",name:"Maiko",surname:"Inoue",slug:"maiko-inoue",fullName:"Maiko Inoue"},{id:"196850",title:"BSc.",name:"Shinichiro",surname:"Hayashi",slug:"shinichiro-hayashi",fullName:"Shinichiro Hayashi"},{id:"196853",title:"Prof.",name:"Lyle",surname:"Craker",slug:"lyle-craker",fullName:"Lyle Craker"}],corrections:null},{id:"64821",title:"Medicinal Plants of the Peruvian Amazon: Bioactive Phytochemicals, Mechanisms of Action, and Biosynthetic Pathways",doi:"10.5772/intechopen.82461",slug:"medicinal-plants-of-the-peruvian-amazon-bioactive-phytochemicals-mechanisms-of-action-and-biosynthet",totalDownloads:831,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Juan Carlos Castro, Joseph Dylan Maddox, Marianela Cobos, Jae Diana Paredes, Anthony Jhoao Fasabi, Gabriel Vargas-Arana, Jorge Luis Marapara, Pedro Marcelino Adrianzen, María Zadith Casuso and Segundo Levi Estela",downloadPdfUrl:"/chapter/pdf-download/64821",previewPdfUrl:"/chapter/pdf-preview/64821",authors:[{id:"212751",title:"Dr.",name:"Juan C.",surname:"Castro",slug:"juan-c.-castro",fullName:"Juan C. Castro"},{id:"212757",title:"Dr.",name:"J. Dylan",surname:"Maddox",slug:"j.-dylan-maddox",fullName:"J. Dylan Maddox"},{id:"212758",title:"Dr.",name:"Marianela",surname:"Cobos",slug:"marianela-cobos",fullName:"Marianela Cobos"},{id:"271012",title:"Dr.",name:"Gabriel",surname:"Vargas-Arana",slug:"gabriel-vargas-arana",fullName:"Gabriel Vargas-Arana"},{id:"271963",title:"MSc.",name:"Jae D.",surname:"Paredes",slug:"jae-d.-paredes",fullName:"Jae D. Paredes"},{id:"271964",title:"Dr.",name:"Jorge L.",surname:"Marapara",slug:"jorge-l.-marapara",fullName:"Jorge L. Marapara"},{id:"283391",title:"BSc.",name:"Anthony J.",surname:"Fasabi",slug:"anthony-j.-fasabi",fullName:"Anthony J. Fasabi"},{id:"283393",title:"MSc.",name:"Pedro M.",surname:"Adrianzén",slug:"pedro-m.-adrianzen",fullName:"Pedro M. Adrianzén"},{id:"283394",title:"BSc.",name:"María Z.",surname:"Casuso",slug:"maria-z.-casuso",fullName:"María Z. Casuso"},{id:"283395",title:"BSc.",name:"Segundo L.",surname:"Estela",slug:"segundo-l.-estela",fullName:"Segundo L. Estela"}],corrections:null},{id:"64667",title:"Medicinal Plants Used as Galactagogues",doi:"10.5772/intechopen.82199",slug:"medicinal-plants-used-as-galactagogues",totalDownloads:1057,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Emelia Oppong Bekoe, Cindy Kitcher, Nana Ama Mireku Gyima, Gladys Schwinger and Mark Frempong",downloadPdfUrl:"/chapter/pdf-download/64667",previewPdfUrl:"/chapter/pdf-preview/64667",authors:[{id:"186992",title:"Dr.",name:"Emelia Oppong",surname:"Bekoe",slug:"emelia-oppong-bekoe",fullName:"Emelia Oppong Bekoe"},{id:"280851",title:"Dr.",name:"Cindy",surname:"Kitcher",slug:"cindy-kitcher",fullName:"Cindy Kitcher"},{id:"280852",title:"Dr.",name:"Nana Ama",surname:"Mireku-Gyimah",slug:"nana-ama-mireku-gyimah",fullName:"Nana Ama Mireku-Gyimah"},{id:"280854",title:"Dr.",name:"Mark",surname:"Frimpong",slug:"mark-frimpong",fullName:"Mark Frimpong"},{id:"280855",title:"Dr.",name:"Gladys",surname:"Schwinger",slug:"gladys-schwinger",fullName:"Gladys Schwinger"}],corrections:null},{id:"64792",title:"Medicinal Plants Used by Indigenous Communities of Oaxaca, Mexico, to Treat Gastrointestinal Disorders",doi:"10.5772/intechopen.82182",slug:"medicinal-plants-used-by-indigenous-communities-of-oaxaca-mexico-to-treat-gastrointestinal-disorders",totalDownloads:525,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Mónica Lilian Pérez-Ochoa, José Luis Chávez-Servia, Araceli Minerva Vera-Guzmán, Elia Nora Aquino-Bolaños and José Cruz Carrillo-Rodríguez",downloadPdfUrl:"/chapter/pdf-download/64792",previewPdfUrl:"/chapter/pdf-preview/64792",authors:[{id:"177908",title:"Prof.",name:"Jose Luis",surname:"Chavez-Servia",slug:"jose-luis-chavez-servia",fullName:"Jose Luis Chavez-Servia"},{id:"178517",title:"Dr.",name:"Elia N.",surname:"Aquino-Bolaños",slug:"elia-n.-aquino-bolanos",fullName:"Elia N. Aquino-Bolaños"},{id:"178519",title:"Dr.",name:"José C.",surname:"Carrillo-Rodríguez",slug:"jose-c.-carrillo-rodriguez",fullName:"José C. Carrillo-Rodríguez"},{id:"270332",title:"MSc.",name:"Mónica Lilian",surname:"Pérez-Ochoa",slug:"monica-lilian-perez-ochoa",fullName:"Mónica Lilian Pérez-Ochoa"},{id:"270333",title:"Dr.",name:"Araceli Minerva",surname:"Vera-Guzmán",slug:"araceli-minerva-vera-guzman",fullName:"Araceli Minerva Vera-Guzmán"}],corrections:null},{id:"64529",title:"Anticancer Activity of Uncommon Medicinal Plants from the Republic of Suriname: Traditional Claims, Preclinical Findings, and Potential Clinical Applicability against Cancer",doi:"10.5772/intechopen.82280",slug:"anticancer-activity-of-uncommon-medicinal-plants-from-the-republic-of-suriname-traditional-claims-pr",totalDownloads:1534,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Dennis R.A. Mans and Euridice R. Irving",downloadPdfUrl:"/chapter/pdf-download/64529",previewPdfUrl:"/chapter/pdf-preview/64529",authors:[{id:"193905",title:"Dr.",name:"Dennis",surname:"Mans",slug:"dennis-mans",fullName:"Dennis Mans"},{id:"281592",title:"Dr.",name:"Euridice",surname:"Irving",slug:"euridice-irving",fullName:"Euridice Irving"}],corrections:null},{id:"64833",title:"Therapeutic Use of Some Romanian Medicinal Plants",doi:"10.5772/intechopen.82477",slug:"therapeutic-use-of-some-romanian-medicinal-plants",totalDownloads:643,totalCrossrefCites:2,totalDimensionsCites:2,signatures:"Adina-Elena Segneanu, Claudiu Cepan, Ioan Grozescu, Florentina Cziple, Sorin Olariu, Sonia Ratiu, Viorica Lazar, Sorin Marius Murariu, Silvia Maria Velciov and Teodora Daniela Marti",downloadPdfUrl:"/chapter/pdf-download/64833",previewPdfUrl:"/chapter/pdf-preview/64833",authors:[{id:"25269",title:"Dr.",name:"Adina-Elena",surname:"Segneanu",slug:"adina-elena-segneanu",fullName:"Adina-Elena Segneanu"},{id:"156334",title:"Prof.",name:"Ioan",surname:"Grozescu",slug:"ioan-grozescu",fullName:"Ioan Grozescu"},{id:"205722",title:"Dr.",name:"Silvia",surname:"Velciov",slug:"silvia-velciov",fullName:"Silvia Velciov"},{id:"205723",title:"Prof.",name:"Sorin",surname:"Olariu",slug:"sorin-olariu",fullName:"Sorin Olariu"},{id:"205724",title:"Dr.",name:"Florentina",surname:"Cziple",slug:"florentina-cziple",fullName:"Florentina Cziple"},{id:"282836",title:"MSc.",name:"Claudiu",surname:"Cepan",slug:"claudiu-cepan",fullName:"Claudiu Cepan"},{id:"282837",title:"Dr.",name:"Sonia",surname:"Ratiu",slug:"sonia-ratiu",fullName:"Sonia Ratiu"},{id:"282839",title:"Dr.",name:"Viorica",surname:"Lazar",slug:"viorica-lazar",fullName:"Viorica Lazar"},{id:"287216",title:"Dr.",name:"Teodora Daniela",surname:"Marti",slug:"teodora-daniela-marti",fullName:"Teodora Daniela Marti"}],corrections:[{id:"66684",title:"Corrigendum to: Therapeutic Use of Some Romanian Medicinal Plants",doi:null,slug:"corrigendum-to-therapeutic-use-of-some-romanian-medicinal-plants",totalDownloads:null,totalCrossrefCites:null,correctionPdfUrl:null}]},{id:"64288",title:"Medicinal Properties of Bamboos",doi:"10.5772/intechopen.82005",slug:"medicinal-properties-of-bamboos",totalDownloads:908,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Katarzyna B. Wróblewska, Danielle C.S. de Oliveira, Maria Tereza Grombone-Guaratini and Paulo Roberto H. Moreno",downloadPdfUrl:"/chapter/pdf-download/64288",previewPdfUrl:"/chapter/pdf-preview/64288",authors:[{id:"270231",title:"Dr.",name:"Paulo Roberto H",surname:"Moreno",slug:"paulo-roberto-h-moreno",fullName:"Paulo Roberto H Moreno"},{id:"270245",title:"Dr.",name:"Katarzyna Barbara",surname:"Wroblewska",slug:"katarzyna-barbara-wroblewska",fullName:"Katarzyna Barbara Wroblewska"},{id:"270246",title:"MSc.",name:"Danielle C. S,",surname:"Oliveira",slug:"danielle-c.-s-oliveira",fullName:"Danielle C. S, Oliveira"},{id:"270247",title:"Dr.",name:"Maria Tereza",surname:"Grombone-Guratini",slug:"maria-tereza-grombone-guratini",fullName:"Maria Tereza Grombone-Guratini"}],corrections:null},{id:"64420",title:"Medicinal Plants for Treatment of Prevalent Diseases",doi:"10.5772/intechopen.82049",slug:"medicinal-plants-for-treatment-of-prevalent-diseases",totalDownloads:3284,totalCrossrefCites:1,totalDimensionsCites:5,signatures:"Susana Oteng Mintah, Tonny Asafo-Agyei, Mary-Ann Archer, Peter Atta-Adjei Junior, Daniel Boamah, Doris Kumadoh, Alfred Appiah, Augustine Ocloo, Yaw Duah Boakye and Christian Agyare",downloadPdfUrl:"/chapter/pdf-download/64420",previewPdfUrl:"/chapter/pdf-preview/64420",authors:[{id:"182058",title:"Dr.",name:"Christian",surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"186987",title:"Dr.",name:"Yaw Duah",surname:"Boakye",slug:"yaw-duah-boakye",fullName:"Yaw Duah Boakye"},{id:"268666",title:"Ms.",name:"Susana",surname:"Oteng Mintah",slug:"susana-oteng-mintah",fullName:"Susana Oteng Mintah"},{id:"282286",title:"Ms.",name:"Mary-Ann",surname:"Archer",slug:"mary-ann-archer",fullName:"Mary-Ann Archer"},{id:"282288",title:"Mr.",name:"Tonny",surname:"Asafo-Agyei",slug:"tonny-asafo-agyei",fullName:"Tonny Asafo-Agyei"},{id:"282290",title:"Mr.",name:"Peter",surname:"Atta-Adjei Junior",slug:"peter-atta-adjei-junior",fullName:"Peter Atta-Adjei Junior"},{id:"282291",title:"Dr.",name:"Daniel",surname:"Boamah",slug:"daniel-boamah",fullName:"Daniel Boamah"},{id:"282293",title:"MSc.",name:"Newman",surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"282294",title:"Dr.",name:"Alfred",surname:"Appiah",slug:"alfred-appiah",fullName:"Alfred Appiah"},{id:"282297",title:"Prof.",name:"Augustine",surname:"Ocloo",slug:"augustine-ocloo",fullName:"Augustine Ocloo"}],corrections:null},{id:"64726",title:"Cytotoxic and Antitumoral Activities of Compounds Isolated from Cucurbitaceae Plants",doi:"10.5772/intechopen.82213",slug:"cytotoxic-and-antitumoral-activities-of-compounds-isolated-from-cucurbitaceae-plants",totalDownloads:610,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Carlos Alberto Méndez-Cuesta, Ana Laura Esquivel Campos, David Salinas Sánchez, Cuauhtemoc Pérez González and Salud Pérez Gutiérrez",downloadPdfUrl:"/chapter/pdf-download/64726",previewPdfUrl:"/chapter/pdf-preview/64726",authors:[{id:"224593",title:"Dr.",name:"Salud",surname:"Perez",slug:"salud-perez",fullName:"Salud Perez"}],corrections:null},{id:"64699",title:"Natural Polymers as Potential Antiaging Constituents",doi:"10.5772/intechopen.80808",slug:"natural-polymers-as-potential-antiaging-constituents",totalDownloads:681,totalCrossrefCites:1,totalDimensionsCites:1,signatures:"Pranati Srivastava and Syed Abul Kalam",downloadPdfUrl:"/chapter/pdf-download/64699",previewPdfUrl:"/chapter/pdf-preview/64699",authors:[{id:"267695",title:"Ms.",name:"Pranati",surname:"Srivastava",slug:"pranati-srivastava",fullName:"Pranati Srivastava"},{id:"270702",title:"Mr.",name:"Syed",surname:"Abul Kalam",slug:"syed-abul-kalam",fullName:"Syed Abul Kalam"}],corrections:null},{id:"64577",title:"Pharmacology Evaluation of Bioactive Compounds that Regulate Cervical Cancer Cells",doi:"10.5772/intechopen.82258",slug:"pharmacology-evaluation-of-bioactive-compounds-that-regulate-cervical-cancer-cells",totalDownloads:607,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Mauricio Salinas-Santander, Patricia Alvarez-Ortiz, Juan Alberto-Ascacio Valdes, Raul Rodriguez-Herrera, Alejandro Zugasti-Cruz, Ricardo Rangel-Zertuche, Victor de Jesus Suarez Valencia and Antonio Morlett-Chavez",downloadPdfUrl:"/chapter/pdf-download/64577",previewPdfUrl:"/chapter/pdf-preview/64577",authors:[{id:"183439",title:"Dr.",name:"Raul",surname:"Rodriguez-Herrera",slug:"raul-rodriguez-herrera",fullName:"Raul Rodriguez-Herrera"},{id:"193767",title:"Dr.",name:"Jesus",surname:"Morlett",slug:"jesus-morlett",fullName:"Jesus Morlett"},{id:"197592",title:"Dr.",name:"Alberto",surname:"Ascacio-Valdes",slug:"alberto-ascacio-valdes",fullName:"Alberto Ascacio-Valdes"},{id:"270341",title:"Dr.",name:"Mauricio",surname:"Salinas-Santander",slug:"mauricio-salinas-santander",fullName:"Mauricio Salinas-Santander"},{id:"280655",title:"Ms.",name:"Patricia",surname:"Alvarez-Ortiz",slug:"patricia-alvarez-ortiz",fullName:"Patricia Alvarez-Ortiz"},{id:"280658",title:"Dr.",name:"Alejandro",surname:"Zugasti-Cruz",slug:"alejandro-zugasti-cruz",fullName:"Alejandro Zugasti-Cruz"},{id:"280659",title:"Dr.",name:"Ricardo",surname:"Rangel-Zertuche",slug:"ricardo-rangel-zertuche",fullName:"Ricardo Rangel-Zertuche"},{id:"280660",title:"MSc.",name:"Victor",surname:"Suarez-Valencia",slug:"victor-suarez-valencia",fullName:"Victor Suarez-Valencia"}],corrections:null},{id:"65186",title:"Pharmacognostic Study of a Plant Seed Extract",doi:"10.5772/intechopen.81860",slug:"pharmacognostic-study-of-a-plant-seed-extract",totalDownloads:653,totalCrossrefCites:0,totalDimensionsCites:0,signatures:"Maxwell Osaronowen Egua",downloadPdfUrl:"/chapter/pdf-download/65186",previewPdfUrl:"/chapter/pdf-preview/65186",authors:[{id:"268715",title:"Dr.",name:"Maxwell",surname:"Egua",slug:"maxwell-egua",fullName:"Maxwell Egua"}],corrections:null},{id:"65128",title:"Natural Products in Drug Discovery",doi:"10.5772/intechopen.82860",slug:"natural-products-in-drug-discovery",totalDownloads:4935,totalCrossrefCites:5,totalDimensionsCites:15,signatures:"Akshada Amit Koparde, Rajendra Chandrashekar Doijad and Chandrakant Shripal Magdum",downloadPdfUrl:"/chapter/pdf-download/65128",previewPdfUrl:"/chapter/pdf-preview/65128",authors:[{id:"268668",title:"Mrs.",name:"Akshada",surname:"Koparde",slug:"akshada-koparde",fullName:"Akshada Koparde"}],corrections:null},{id:"64600",title:"Pharmacognosy: Importance and Drawbacks",doi:"10.5772/intechopen.82396",slug:"pharmacognosy-importance-and-drawbacks",totalDownloads:1253,totalCrossrefCites:0,totalDimensionsCites:1,signatures:"Fatai Oladunni Balogun, Anofi Omotayo Tom Ashafa, Saheed Sabiu, Abdulwakeel Ayokun-nun Ajao, Chella Palanisamy Perumal, Mutiu Idowu Kazeem and Ahmed Adebowale Adedeji",downloadPdfUrl:"/chapter/pdf-download/64600",previewPdfUrl:"/chapter/pdf-preview/64600",authors:[{id:"200124",title:"Dr.",name:"Fatai Oladunni",surname:"Balogun",slug:"fatai-oladunni-balogun",fullName:"Fatai Oladunni Balogun"},{id:"248272",title:"Dr.",name:"Abdulwakeel",surname:"Ayokun-nun Ajao",slug:"abdulwakeel-ayokun-nun-ajao",fullName:"Abdulwakeel Ayokun-nun Ajao"},{id:"267697",title:"Prof.",name:"Ahmed",surname:"Adedeji",slug:"ahmed-adedeji",fullName:"Ahmed Adedeji"},{id:"267699",title:"Dr.",name:"Mutiu Idowu",surname:"Kazeem",slug:"mutiu-idowu-kazeem",fullName:"Mutiu Idowu Kazeem"},{id:"267700",title:"Dr.",name:"Anofi",surname:"Ashafa",slug:"anofi-ashafa",fullName:"Anofi Ashafa"},{id:"267978",title:"Dr.",name:"Chella",surname:"Perumal",slug:"chella-perumal",fullName:"Chella Perumal"},{id:"300406",title:"Dr.",name:"Saheed",surname:"Sabiu",slug:"saheed-sabiu",fullName:"Saheed Sabiu"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},relatedBooks:[{type:"book",id:"6530",title:"Terpenes and Terpenoids",subtitle:null,isOpenForSubmission:!1,hash:"104f235908f326361a3ab16891949b70",slug:"terpenes-and-terpenoids",bookSignature:"Shagufta Perveen and Areej Al-Taweel",coverURL:"https://cdn.intechopen.com/books/images_new/6530.jpg",editedByType:"Edited by",editors:[{id:"192992",title:"Prof.",name:"Shagufta",surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1444",title:"Drug Discovery",subtitle:"Research in Pharmacognosy",isOpenForSubmission:!1,hash:"8bc52e1d2e327b804916b93037881500",slug:"drug-discovery-research-in-pharmacognosy",bookSignature:"Omboon Vallisuta and Suleiman M. Olimat",coverURL:"https://cdn.intechopen.com/books/images_new/1444.jpg",editedByType:"Edited by",editors:[{id:"73943",title:"Prof.",name:"Omboon",surname:"Vallisuta",slug:"omboon-vallisuta",fullName:"Omboon Vallisuta"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7855",title:"Essential Oils",subtitle:"Oils of Nature",isOpenForSubmission:!1,hash:"4cbe4fd4ef95d61934405026e1702d4c",slug:"essential-oils-oils-of-nature",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/7855.jpg",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6828",title:"Alkaloids",subtitle:"Their Importance in Nature and Human Life",isOpenForSubmission:!1,hash:"50b0f252045663a75760f2915a330575",slug:"alkaloids-their-importance-in-nature-and-human-life",bookSignature:"Joanna Kurek",coverURL:"https://cdn.intechopen.com/books/images_new/6828.jpg",editedByType:"Edited by",editors:[{id:"214632",title:"Dr.",name:"Joanna",surname:"Kurek",slug:"joanna-kurek",fullName:"Joanna Kurek"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6553",title:"Seaweed Biomaterials",subtitle:null,isOpenForSubmission:!1,hash:"60cbd38f47d2f3d95f9fc80bf226200e",slug:"seaweed-biomaterials",bookSignature:"Sabyasachi Maiti",coverURL:"https://cdn.intechopen.com/books/images_new/6553.jpg",editedByType:"Edited by",editors:[{id:"180971",title:"Dr.",name:"Sabyasachi",surname:"Maiti",slug:"sabyasachi-maiti",fullName:"Sabyasachi Maiti"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],ofsBooks:[]},correction:{item:{id:"67322",slug:"corrigendum-to-sexual-dysfunction-in-patients-with-systemic-sclerosis",title:"Corrigendum to: Sexual Dysfunction in Patients with Systemic Sclerosis",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/67322.pdf",downloadPdfUrl:"/chapter/pdf-download/67322",previewPdfUrl:"/chapter/pdf-preview/67322",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/67322",risUrl:"/chapter/ris/67322",chapter:{id:"66966",slug:"sexual-dysfunction-in-patients-with-systemic-sclerosis",signatures:"Barbora Heřmánková",dateSubmitted:"July 16th 2018",dateReviewed:"April 5th 2019",datePrePublished:"May 3rd 2019",datePublished:null,book:{id:"8269",title:"New Insights into Systemic Sclerosis",subtitle:null,fullTitle:"New Insights into Systemic Sclerosis",slug:"new-insights-into-systemic-sclerosis",publishedDate:"September 18th 2019",bookSignature:"Michal Tomcik",coverURL:"https://cdn.intechopen.com/books/images_new/8269.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193284",title:"Dr.",name:"Michal",middleName:null,surname:"Tomcik",slug:"michal-tomcik",fullName:"Michal Tomcik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null}},chapter:{id:"66966",slug:"sexual-dysfunction-in-patients-with-systemic-sclerosis",signatures:"Barbora Heřmánková",dateSubmitted:"July 16th 2018",dateReviewed:"April 5th 2019",datePrePublished:"May 3rd 2019",datePublished:null,book:{id:"8269",title:"New Insights into Systemic Sclerosis",subtitle:null,fullTitle:"New Insights into Systemic Sclerosis",slug:"new-insights-into-systemic-sclerosis",publishedDate:"September 18th 2019",bookSignature:"Michal Tomcik",coverURL:"https://cdn.intechopen.com/books/images_new/8269.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193284",title:"Dr.",name:"Michal",middleName:null,surname:"Tomcik",slug:"michal-tomcik",fullName:"Michal Tomcik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null},book:{id:"8269",title:"New Insights into Systemic Sclerosis",subtitle:null,fullTitle:"New Insights into Systemic Sclerosis",slug:"new-insights-into-systemic-sclerosis",publishedDate:"September 18th 2019",bookSignature:"Michal Tomcik",coverURL:"https://cdn.intechopen.com/books/images_new/8269.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"193284",title:"Dr.",name:"Michal",middleName:null,surname:"Tomcik",slug:"michal-tomcik",fullName:"Michal Tomcik"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"9833",leadTitle:null,title:"Pharmacoepidemiology and Drug Safety",subtitle:null,reviewType:"peer-reviewed",abstract:"This book will be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, PhD students and other scientists. The contents of the book will be written by multiple authors and edited by experts in the field.",isbn:null,printIsbn:null,pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"a517ca4362c1a1ab66459dbb6c846fdb",bookSignature:"",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9833.jpg",keywords:null,numberOfDownloads:132,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 6th 2019",dateEndSecondStepPublish:"June 27th 2019",dateEndThirdStepPublish:"August 26th 2019",dateEndFourthStepPublish:"November 14th 2019",dateEndFifthStepPublish:"January 13th 2020",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:1,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"19",title:"Pharmacology, Toxicology and Pharmaceutical Science",slug:"pharmacology-toxicology-and-pharmaceutical-science"}],chapters:[{id:"74576",title:"Drug-Induced Delirium among Older People",slug:"drug-induced-delirium-among-older-people",totalDownloads:132,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:null},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3621",title:"Silver Nanoparticles",subtitle:null,isOpenForSubmission:!1,hash:null,slug:"silver-nanoparticles",bookSignature:"David Pozo Perez",coverURL:"https://cdn.intechopen.com/books/images_new/3621.jpg",editedByType:"Edited by",editors:[{id:"6667",title:"Dr.",name:"David",surname:"Pozo",slug:"david-pozo",fullName:"David Pozo"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"46983",title:"Liposomes as Potential Drug Carrier Systems for Drug Delivery",doi:"10.5772/58459",slug:"liposomes-as-potential-drug-carrier-systems-for-drug-delivery",body:'Lipids are amphiphilic molecules, where one part of the molecule is water-loving (hydrophilic) and the other water-hating (hydrophobic). When lipids are placed in contact with water, the unfavorable interactions of the hydrophobic segments of the molecule with the solvent result in the self assembly of lipids, often in the form of liposomes. Liposomes consist of an aqueous core surrounded by a lipid bilayer, much like a membrane, separating the inner aqueous core from the bulk outside. They were first discovered by Bangham and his co-workers in 1961 [1] and described as swollen phospholipid systems [2]. In the following years, a variety of enclosed phospholipid bilayer structures were defined which were initially called bangosomes and then liposomes, which was derived by the combination of two Greek words, “lipos” meaning fat and “soma” meaning body.
Liposomes have been used to improve the therapeutic index of new or established drugs by modifying drug absorption, reducing metabolism, prolonging biological half-life or reducing toxicity. Drug distribution is then controlled primarily by properties of the carrier and no longer by physico-chemical characteristics of the drug substance only.
Lipids forming liposomes may be natural or synthetic, and liposome constituents are not exclusive of lipids, new generation liposomes can also be formed from polymers (sometimes referred to as polymersomes). Whether composed of natural or synthetic lipids or polymers, liposomes are biocompatible and biodegradable which make them suitable for biomedical research. The unique feature of liposomes is their ability to compartmentalize and solubilize both hydrophilic and hydrophobic materials by nature. This unique feature, coupled with biocompatibility and biodegradability make liposomes very attractive as drug delivery vehicles.
Hydrophobic drugs place themselves inside the bilayer of the liposome and hydrophilic drugs are entrapped within the aqueous core or at the bilayer interface. Liposomal formulations enhance the therapeutic efficiency of drugs in preclinical models and in humans compared to conventional formulations due to the alteration of biodistribution. Liposome binding drugs, into or onto their membranes, are expected to be transported without rapid degradation and minimum side effects to the recipient because generally liposomes are composed of biodegradable, biologically inert and non-immunogenic lipids. Moreover, they produce no pyrogenic or antigenic reactions and possess limited toxicity [3-5]. Consequently, all these properties as well as the ease of surface modification to bear the targetable properties make liposomes more attractive candidates for use as drug-delivery vehicles than other drug carrying systems such as nanoparticles [6, 7] and microemulsions [8, 9]. In the 1970s [1, 10-13], liposomes were introduced as drug delivery vehicles but the initial clinical results were not satisfactory due to their colloidal and biological instability and their inefficient encapsulation of drug molecules.
Subsequent research on their stability and drug interactions resulted in several commercial liposome products in the market in the 1980s and early 1990s [14]. A schematic representation of liposomal drug delivery is given in Figure 1.
Structural and design considerations for liposomal drug delivery. Liposomes can be surface functionalized to endow stealth through PEGylation and to promote receptor-mediated endocytosis by using targeting ligands such as antibodies, peptides, proteins, carbohydrates, and various other small molecules. PEGylation extends liposomal circulation half-life in vivo by reducing clearance, immune recognition, and the non-specific absorption of serum proteins. Polyethylene glycol (PEG) density determines its structure at the liposome surface, with densities below 9% adopting a mushroom-like globular structure and those above 9% adopting a more rigid, extended, brush-like morphology. Chemotherapeutics or diagnostics can be encapsulated into the aqueous lumen, incorporated into the lipid bilayer, or conjugated to the liposome surface. Abbreviation: siRNA, small interfering RNA [15].
Liposomes represent versatile and advanced nanodelivery systems for a wide range of biologically active compounds [16]. The final amount of the encapsulated drug is affected by a selection of an appropriate preparation method providing a preparation of liposomes of various size, lamellarity and physicochemical properties [17]. The entrapment of the drugs, both hydrophilic and hydrophobic, into the liposomes is used to bypass the frequent generic toxicity associated with the drug as often seen in cancer drugs [18]. Thus, it represents a very effective route that enhances the drug therapeutic effect. The modification of liposomes permits a passive or active targeting of the tumor site. This effect enables an efficient drug payload into the malignant cell of tumors, while the non-malignant cells become minimally impacted.
In some of the first demonstrations of the improved in vivo activity of liposome-encapsulated drugs in animal models, the anti-cancer drug cytosine arabinoside used which showed a significant increase in the survival times of the mice bearing leukemia [19, 20] which became a popular model for testing the effects of a wide range of liposome characteristics on therapeutic outcomes. Following experiments include liposomal amphotericin B [21] and liposomal doxorubicin [22] that finally led to the first clinical trials of liposomal drugs. Nowadays; the liposomal products (as a suspension, as an aerosol or in a semi-solid form such as a gel, cream, or powder) in the market still include mostly anticancer preparations as well as antifungal and antibacterial preparations and cosmetics. In addition, liposomes are recently used as therapeutic agents to treat a disease because increased gene transfer efficiencies have been obtained via liposomal gene vectors in gene therapy.
The benefits and limitations of liposome drug carriers critically depend and based on physicochemical and colloidal characteristics such as size, composition, loading efficiency and stability, as well as their biological interaction with the cell membranes. There are four major interactions between liposomes and cells [23]. The predominant interaction among them is either simple adsorption or subsequent endocytosis. Adsorption occurs when the attractive forces exceed the repulsive ones and obviously this type of interaction depends on the surface properties of liposomes. In the delivery through endocytosis, liposome and its contents indirectly place themselves in the cytoplasm. Fusion with cell membranes, delivery of the liposomal content directly into the cell through the merge of liposome lipids into the membrane, is much rarer. The last possible interaction is the lipid exchange which is a long-range interaction that involves the exchange of bilayer constituents, such as lipids, cholesterol, and membrane bound molecules with components of cell membranes. Upon entering into the body, the delivered liposomes via one of these interaction types trigger the response of the immune system and the encapsulated material may become inactive. Therefore; substantial researches have been carried out in the development of the biocompatible and nonrecognizable liposomal surfaces.
Various types of liposomes can be prepared by different preparation methods, depending on the required application. In this chapter, these methods are summarized to give a general understanding of the relationship between structure and functionality of liposomes. As one of the advantages of liposomal formulations is the encapsulation ability of both hydrophobic and hydrophilic drugs, incorporation methods are shortly visited. Physical properties of liposomes such as stability, storage and sterilization are discussed along with the characterization techniques for size, charge, etc. Clinical applications of liposomes are a vast area of research where cancer therapy is the area of highest impact. Different clinical applications of liposomes and most recent advances in cancer therapy are summarized. New generation involving constituents other than conventional ones such as phospholipids prove to be a growing field in nanotechnology. A brief list of different types of new generation liposomes are given with short descriptions at the end of this chapter.
The manufactured liposome features are directly related to the preparation method. Although liposome formation may be spontaneous, often some mechanical agitation is required. In order to have control over the size and structure of the liposomes that are formed, increase the efficiency of entrapment of the desired molecules, and prevent subsequent leakage from the liposomes, different preparation methods have been devised.
There are a few parameters that should be considered during the method selection: 1) the physicochemical characteristics of the material to be entrapped and those of the liposomal ingredients, 2) the nature of the medium in which the liposomes are dispersed, 3) the effective concentration of the encapsulated material and its potential toxicity, 4) additional processes involved during application (delivery of the liposomes), 5) optimum size, polydispersity and shelf-life of the liposomes for the intended application and 6) batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products [24-26].
Liposome size is a crucial parameter in determining the circulation half-life of liposomes in drug delivery. The amount of encapsulated drug is also related with the size and the number of bilayers of the prepared liposome. According to the desired formulation, different liposome preparation methods can be employed. The main difference in these methods is their approach to overcome the low solubility of lipids in water. Accordingly, these methods can be classified as mechanical agitation, solvent evaporation, solvent injection, and detergent solubilization. In all the above mentioned methods, drug loading is passive.
In this method, lipids are directly solubilized in water upon application of high mechanical agitation, through the use of probe sonication. It is one of the simplest methods of liposome preparation, however, yields small liposomes that are highly unstable in terms of their size and suffers from the drawback that it is impossible to remove completely the risk of lipid degradation by contact with the hot probe, and contamination with titanium from the probe. Its advantage is the exclusion of use of organic solvents as described in the following methods. However, for drug delivery applications, liposomes prepared with mechanical agitation are not suitable due to their size instability and high leakage of encapsulated drugs [27].
In general this method consists of four major steps; first is the solubilization of the lipid (and a hydrophobic compound) in an organic solvent; second is solvent evaporation; third is hydration with a buffer (and the hydrophilic compound) and if need the fourth often involves obtaining unilamellar liposomes from the obtained multilamellar ones.
The aqueous volume enclosed within these lipid membranes is very small proportion of total volume used for preparation (5-10%). Consequently, large amount of water soluble drug is wasted during the preparation. On the other hand, lipid soluble drug can be encapsulated with 100% efficiency, providing that they are not present in quantities which overwhelm the structural components of the membrane [28]. The volume of entrapment can be significantly increased by the usage of negatively charged lipids in the membrane which tend to push the bilayers apart from each other. The same effect can also be achieved in the presence of neutral lipids by freezing and thawing repeatedly the obtained liposomes. 30% volume of entrapment can be achieved, which can further be increased at higher lipid concentrations [29]. The freeze-thaw protocol results in a dramatic change in liposome morphology followed by freeze-fracture electron micrographs. Before freeze-thawing, the samples exhibit the tightly packed “onions skin” arrangements of concentric bilayers normally associated with liposomal systems. After a few freeze-thaw steps, however, new structures are observed where the interlamellar spaces are much increased, and where closed lamellar systems can be intercalated between bilayers [30].
The starting point of this liposome preparation method is to prepare an organic solution of membrane lipids in order to ensure complete and homogenous mixing of all the components as they are required in the final membrane preparation. Compounds to be incorporated which are lipid soluble will be added to the organic solution, while compounds to be entrapped in the aqueous compartment of liposomes will be dissolved in the aqueous environment. In this method, phospholipids are first dissolved in an organic solvent along with lipid soluble compounds (if any) to be incorporated in the liposome to ensure complete and homogenous mixing.
The next step is the evaporation of the organic solvent. The simplest is to allow the solvent to evaporate in a glass container. A better method is evaporating the solvent using a rotary evaporator connected to a vacuum pump to obtain a thin film of the lipid on the walls of a round bottom flask. In order to increase encapsulation, it is recommended to start with a large volume round bottom flask so that the lipids will be dried down onto a large surface area possible to form a very thin film. The evaporator is detached from vacuum pump and introduced to nitrogen. The container is then removed from the evaporator and fixed to a lyophilizer or exposed to high vacuum overnight to remove the residual solvent.
An alternative method of dispersing the lipids in a finely-divided form before the addition of aqueous media is to freeze-dry the dissolved lipids in an organic solvent [31]. The important concept in this method is the choice of the organic solvent which should have a freezing point above the temperature of the condenser of the freeze-drying and also be inert with regard to rubber seals of commercial lyophilizers. When these restrictions are concerned, the most suitable organic solvent happens to be tertiary buthanol.
Evaporation (or freeze-drying) of the solvent is followed by hydration of lipids with the aqueous medium. Often for hydration, a suitable buffer at a temperature above the phase transition temperature of the phospholipid is employed. The solution is swirled manually or mechanically (either with a bath sonicator or vortex mixer) until all the lipids have been incorporated into the solution. The resulting product is a milky suspension of lipids which is allowed to stand for a while for the complete swelling to give MLVs [28]. Further treatment is required for the preparation of ULVs, which will be discussed later in the text.
It is possible to obtain LUVs instead of MLVs during hydration by introducing an aqueous sucrose solution down the side of the flask by inclining the flask to one side and slowly returning the flask to the upright orientation, allowing the fluid to run gently over the lipid layer on the bottom of the flask. The swelling is carried out as usual without any shaking or agitation. The suspension is then centrifuged and the layer of MLVs floating on the surface is removed, leaving LUVs in solution.
After preparation of MLVs by hydration of dried lipid, it is possible to continue processing the liposomes in order to modify their size and other characteristics. For many purposes, MLVs are too large of too heterogeneous population to work with. There are several methods devised to reduce their size. These include techniques such as micro-emulsification, extrusion, and ultrasonication. A second set of methods is designed to increase the entrapment volume of hydrated lipids, and/or reduce the lamellarity of the liposomes formed, and involves procedures such as freeze-drying, freeze-thawing or induction of vesiculation by ions or pH change.
Microemulsification of liposomes is performed with an equipment called micro fluidizer to prepare small vesicles from concentrated lipid suspension. This method can produce liposomes in 50-200 nm size range with the encapsulation efficiency of up to 75% [32].
Sonication [33] disrupts MLV suspensions by using sonic energy to produce SUVs with diameters in the range of 15-50 nm. There are two methods of sonication; bath sonication and probe sonication. The former method is used for large volumes of dilute lipids whereas the latter one is used for suspensions which require high energy, such as high concentration of lipid suspensions. The disadvantage of probe sonication is the contamination of preparation with metal from the tip of the probe which should be removed by centrifugation prior to use. Also, as a result of high energy, probe sonication suffers from overheating the lipid suspension causing degradation. For these reasons, bath sonicators are the most widely used instrumentation for SUV preparation.
An even gentler method of reducing the size of the liposomes is to pass through a membrane filter of defined pore size [34]. This can be at much more lower pressure and can give populations in which one can choose the upper size limit depending on the exact pore size of the filter used. This membrane extrusion technique can be used to process both LUVs and MLVs in which liposome contents are exchanged with the suspending medium during breaking and resealing of the phospholipid bilayers as they pass through the polycarbonate membrane. In order to achieve as high an entrapment as possible of water-soluble compounds, it is crucial to have these compounds present in the suspending medium during the extrusion. An almost completely unilamellar population can be produced after 5-10 repeated extrusions through two stacked membranes.
In freezing-thawing method, SUVs are rapidly frozen and thawed slowly. The short-lived sonication disperses aggregated materials to LUV. The creation of unilamellar vesicles is as a result of the fusion of SUV throughout the processes of freezing and thawing [35-37].
In this type of preparation methods, lipids are first dissolved in an organic solvent and then brought into contact with the aqueous phase containing the materials to be encapsulated within the liposome. The lipids align themselves into a monolayer at the interface between the organic and aqueous phase which is an important step to form the bilayer of the liposome [29]. There are three categories in solvent dispersion method including; (i) a miscible organic solvent with the aqueous phase, (ii) an immiscible organic solvent with the aqueous phase that is used in excess, and (iii) an immiscible organic solvent used in excess with the aqueous phase.
In this method an ethanol solution of lipids is injected rapidly into an excess saline or other aqueous medium by a fine needle [38]. The injection force is usually sufficient to achieve complete mixing, so that ethanol is diluted in water, and lipids are dispersed evenly throughout the medium. This method yields a high proportion of SUVs. This method is extremely simple and it has a very low risk of degradation for sensitive lipids. Its major disadvantages are the limitation of solubility of lipids in ethanol and the volume of ethanol that can be introduced into the medium, which in turn limits the quantity of lipid dispersed, so that the resulting liposome solution is generally dilute. As a result, the percentage encapsulation for hydrophilic materials is very low. One last disadvantage for this method is the difficulty of the removal of ethanol from the lipid membranes.
This method [39, 40] involves injecting the immiscible organic solution very slowly into an aqueous phase through a narrow needle at a temperature that the organic solvent is removed by vaporization during the process. In this method, large vesicles are formed which might be due to the slow vaporization of solvent giving rise to an ether: water gradient extending on both sides of the interfacial lipid monolayer, resulting in the eventual formation of a bilayer sheet which folds in on to itself to form a sealed vesicle [29]. Ether injection treats sensitive lipids very gently and runs very little risk of causing oxidative degradation. Since the solvent is removed at the same rate as it is introduced, there is no limit to the final concentration of lipid which can be achieved, since the process can be run continuously for a long period of time, giving rise to a high percentage of the aqueous medium encapsulated within the liposomes. The major drawbacks of this method are the long time taken to produce a batch of liposomes and the need of careful control for the introduction of lipid solution.
In this method, the phospholipids are brought into contact with the aqueous phase via the intermediary of surfactants. Phospholipid molecules associate with surfactants and form mixed micelles. The basic feature of this method is the removal of the surfactant from pre-formed mixed micelles containing phospholipids, whereupon unilamellar liposomes form spontaneously. However, removal of surfactants is carried out using techniques such as, dialysis and column chromatography, inevitably remove other small water-soluble molecules, making this method not very efficient in terms of percentage encapsulation values attainable for water soluble compounds. On the other hand, surfactant solubilization method has the ability to vary the size of the liposomes by precise control of the conditions of surfactant removal and to obtain liposomes of very high size homogeneity [29].
The transfer from laboratory to industry was very important for liposomes, as it is for any biotechnological discipline. The first liposomal drug delivery experiments in humans were carried out by freshly prepared liposomes but in order to be a commercial product the liposome-drug formulation must have well-defined stability and a shelf life over a year. Of the several preparation methods described in the literature, only a few of them have the potential to be used in the large scale liposome manufacturing. The crucial problem is the presence of organic solvent residues, pyrogen control, stability, sterility, size and size distribution as well as batch to batch reproducibility.
In the parental administration the liposomes two important conditions involve being sterile and pyrogen free. In the case of animal experiments, the sufficient sterility can be obtained by the passage of the liposome preparations through the 400 nm pore size Millipore filters. In human experiments the sterilization depyrogenation techniques should be taken much more seriously starting from the raw materials, containers and working areas [41].
Once lipids are hydrated in the presence of hydrophilic drugs, a portion of the drug gets entrapped inside the liposome and another portion remains in the bulk, outside the aqueous core of the liposome. As only the entrapped drug is of interest, drug in the bulk should be removed. This purification is generally done by gel filtration column chromatography (Sephadex G-50, Pharmacia LKB) and dialysis (hollow fiber dialysis cartridge) on the basis of size differences between the liposomes and the non-encapsulated material. In the cases where DNA or proteins are being encapsulated, or where there is concern that non-encapsulated material may form large aggregates, techniques such as centrifugation can be employed due to the differences in the buoyant densities of liposomes and non-encapsulated material [42, 43].
A hydrophilic drug may not be encapsulated with high efficiency because the drug molecules can diffuse in and out of the lipid membrane. Thus, the drug would be difficult to retain inside the liposomes. However, compounds with ionizable groups and those that are both water and lipid soluble can be encapsulated with high efficiency (up to 90%) by the liposomes after the formation of membranes [44] by active loading. In this technique, the pH of the interior part of the liposome is such that the unionized drug which enters the liposome by passive loading is ionized inside the liposome, and ionized drug molecules lose their ability to diffuse through the lipid membrane. Therefore, high concentration of the ionized drug is obtained inside the liposome. For example, doxorubicin and epirubicin can be entrapped in preformed SUV with high efficiency through active loading [45, 46].
The pH difference can be brought about by encapsulating a non-permeating buffer ion such as glutamate inside the liposomes at low pH and replacing the extra-liposomal buffer with one which is iso-osmolar at pH 7.0. Alternatively, charged lipids may be incorporated into the membrane at low pH, followed by adjustment of the suspending medium to neutrality. A similar approach may be adopted by using a potassium gradient, in which the membrane is made selectively permeable to potassium ions entrapped inside the liposome by incorporation of valinomycin into the lipid membrane [47, 48].
Hydrophobic drugs are solubilized in the phospholipid bilayer of the liposomes that mainly provide a hydrophobic environment. Once trapped, they remain in the liposome bilayer as they have very low affinity towards the inner or outer aqueous regions of the liposomes. During the preparation of liposomes, hydrophobic drugs are solubilized in the organic solvent along with the phospholipids and during the subsequent hydration phase, they remain entrapped in the hydrophobic bilayer region. For example, the liposomal photosensitizer verteporfin (Visudyne) contains a hydrophobic drug that is rapidly transferred to blood proteins in vivo. Activation of the drug by targeting laser light to blood flowing though the eye causes its site-specific activity in the treatment of wet macular degeneration [49]. Amphotericin B and paclitaxel are the other most commonly investigated hydrophobic drugs in liposome formulations.
Liposome stability can be explained by physical, chemical and biological means which are all interrelated. Generally, chemical (degradation of phospholipids structures) and physical (uniformity of size distribution and encapsulation efficiency) stability determine the shelf-life of liposomes. Once the liposomal formulations have been obtained, maintenance of the physical properties of these preparations can be difficult. Leakage of the encapsulated material due to the permeability of the membrane, change in the size distribution and stability problems due to the hydrolytic and oxidative degradation are the general problems upon storage. Methods are devised to overcome these instability problems, those designed to minimize the degradation processes and those which help liposomes to survive in the face of conditions which encourages these processes.
Two different types of chemical degradation can affect the performance of the phospholipids bilayers; hydrolysis of the ester bonds linking the fatty acids to the glycerol backbone and oxidation of the unsaturated acyl chains, if present. The level of oxidation can be kept to a minimum by taking some precautions like starting with freshly purified lipids and freshly distilled solvents, avoiding procedures involving high temperatures, carrying out the manufacturing process in the absence of oxygen, deoxygenating the aqueous solutions by passing nitrogen, storing all liposome suspensions in an inert atmosphere and including an anti-oxidant, e.g. α-tocopherol [50], a common non-toxic dietary lipid, as a component of the lipids membrane. An alternative solution to the oxidation problem is to reduce the level of oxidizable lipids in the membrane by using saturated lipids instead of the unsaturated ones. Also, the mono-unsaturated ones have much less tendency of oxidation than the polyunsaturated ones. Thus; sphingomyelins, usually having only one double bond, are expected to degrade more slowly than other mammalian origin lipids. Entirely synthetic and saturated phospholipids; DMPC, DPPC and DSPC, can also be considered as a solution for the oxidative degradation of liposomes.
Hydrolysis type of chemical degradation of the ester linkages in the phospholipid structure occurs most slowly at pH values close to neutral. In general, the rate of hydrolysis has a “V-shaped” dependence, with a minimum at pH 6.5 and an increased rate at both higher and lower pH. In the active loading of drugs, as it is mentioned before, low pH levels are required which triggers the hydrolysis. This hydrolysis kind of chemical degradation is also very effective on the aqueous solutions of liposome due to the presence of water. Temperature also triggers the hydrolysis of the lipids which creates the need for refrigeration. In order to keep hydrolysis to a minimum during active loading, attention must be paid for the removal of residual solvent from the dried lipids. To avoid hydrolysis, instead of ester linked lipids, the usage of ether linkage containing lipids (e.g. found in the membrane of halophilic bacteria) would be an absolute solution [51]. Another chemical degradation, oxidation of the lipids in the liposome structures can be prevented by the addition of small amounts of antioxidants during the manufacturing steps.
The problems related to the lipid oxidation and hydrolysis during the shelf-life of the liposomal product can be reduced by the storage of liposomal dispersion in the dry state by freeze-drying (lyophilization), without compromising their physical state or encapsulation capacity [52]. However, freeze-drying of liposome systems without appropriate stabilizers will lead to fusion of vesicles, i.e. physical instability. To promote vesicle stability during the freeze-drying process, cycloprotectants [53-55], including saccharides (e.g. sucrose, trehalose, and lactose) and their derivatives are employed [56]. Cycloprotectants, especially sucrose because of its high glass transition temperature, are believed to be effective to protect the liposome membranes against possible fracture and rapture that might cause a change in size distribution and a loss of the encapsulated material presumably by forming glasses under the typical freezing conditions used for lyophilization [57]. Lyophilization increases the shelf-life of the finished product by preserving in a relatively more stable dry state. Some liposome products on market or clinical trials are provided as lyophilized powder. For example, AmBisomeTM, a liposomal amphotericin, is the first liposome product to be marketed in several countries is supplied as a lyophilized powder to be reconstituted with sterile water injection. Additionally, paclitaxel-liposome formulations have been developed which show good stability [58, 59]. These formulations once lyophilized can be stored at room temperature for extended time. On the other hand, once the preparation is reconstituted, it is not stable for more than a day in terms of size.
The physical degradation, leakage and fusion of liposomes, can occur as a result of the lattice defects in the membrane introduced during the manufacture, particularly in SUVs that are prepared below the membrane phase transition temperature. Annealing process, incubating the liposomes at a higher temperature than the phase transition temperature, can wipe out these defects by equalizing the differences in packing density between opposite sides of the bilayers. Even in annealed vesicles, aggregation and fusion can occur over a long period of time. In neutral liposomes, aggregation takes place because of the van der Waals interactions and because of the increased surface area it tends to be more pronounced in large liposomes. The simplest solution to overcome this aggregation is to add a small amount of negatively charged phospholipid (e.g. 10% PA or PG) to the liposome composition [29]
SUVs have much more tendency to fusion when compared to large liposomes due to the presence of stress arising from the high curvature of the membrane. Since this can occur specifically at the transition temperature of the membrane, it would be better to store these liposomes at a temperature much lower than the transition temperature of the lipids. For example, SUVs should be stored above their transition temperature for no longer than 24 hours but LUVs can be stored for a longer period of time if the temperature of the solution is kept in a range of 4-8 0C for approximately 1 week before the leakage of the encapsulated material starts due to the hydrolytic degradation on the membrane structure [60]. Also, addition of cholesterol to the phospholipid mixture would be a solution to reduce or eliminate the transition. The presence of cholesterol prevents packing and aggregation by inducing orientation and more rigidity to the phospholipids. Other than cholesterol, peptide incorporation to the lipid membrane also enables the lipid membrane to be more rigid at physiological temperature [61-63].
Permeability of liposome membranes depends highly on the membrane lipid composition, as well as on the encapsulated material. Large polar or ionic molecules will be retained much more efficiently than low molecular weight lipophilic compounds. Generally, for both type of encapsulated material, a rigid, more saturated membrane with a higher ratio of cholesterol forms the most stable lipid membrane concerning the leakage of the encapsulated material.
Many attempts have been made to enhance the physical stability of liposomes. Among these, surface modification of liposomes is an attractive method to improve liposomal stability both in vitro and in vivo. Some improvements in chemical and physical stability of polymer coated liposomes prepared with polysaccharide derivatives, such as mannan or amylopectin, have been demonstrated [64]. Several other substances also have been used for preparation of polymer coated liposomes such as poloxamer, polysorbate 80, carboxymethyl chitosan, and dextran derivatives [65-69]. While the possibility of coating liposomes with these polymers has been reported, few papers have dealt with the systematic evaluation of the physical stability of polymer coated liposomes. Moreover, contravening results have been also reported such as that polymer coated liposomes showed less stability than non-coated ones [65, 70].
In vivo stability of liposomes is also dependent on their charge. In serum, there are several proteins that are both positively and negatively charged. Liposomes with neutral charge are found to be more stable as they have much less electrostatic affinity towards proteins. [71].
Biological liposome stability plays important roles at various stages of drug delivery. However, liposomes are somewhat biologically unstable as a parenteral drug delivery system owing to their rapid uptake and clearance from circulation by cells of the mononuclear phagocytic system (MPS) located mainly in the liver and spleen [72, 73]. Biological stability of liposomes is dependent on the presence of agents such as proteins that interact with liposomes upon application to the subject and the administration route. There have been many strategies to enhance the biological stability of liposomes that improve the liposomal drug delivery in vivo and increase the circulation time in blood stream [74]. The complexation between polymers and liposomes has been studied as a way to increase the long-term stability of liposomes. Grafting hydrophilic polymers onto the head groups of phospholipids, or the addition of water soluble polymers containing several hydrophobic groups has been shown to increase the circulation time in vivo, as well as to inhibit liposome fusion [75-77]. These kinds of liposomes are called stealth liposome [78] or sterically stabilized liposomes [79]. The steric repulsion of these liposomes stabilizes the liposomes against aggregation. One of the most popular and successful methods to obtain long-circulating biologically stable liposomes is to coat the surface of the liposome with poly(ethylene glycol), PEG [80-84]. Although the PEG chemistry is successful in coating the liposome surface, alternative sterically protecting polymers are also under research. The candidate polymers should be biocompatible, soluble, hydrophilic and have highly flexible main chain for drug delivery. Some of these polymers given in the literature are synthetic polymers of vinyl series i.e. poly(vinyl pyrrolidone) (PVP) and poly(acrylamide) (PAA) [85, 86]. PVP has a similar history on pharmaceutical application to PEG [87, 88]. It shows high degree of biocompatibility and also acts as efficient steric protector for liposomes. It was found that the liposomal bilayers containing lipids with covalently attached to polyethylene glycol by which the membrane surface steric inhibits protein and cellular interactions with liposomes drastically prolonging the blood circulation time when injected in animals [89]. Doxil® is the liposomal doxorubicin available in the market which is stable for more than 18 months in the liquid state due to being stabilized by the usage of polyethylene glycol.
Pharmaceutical industry in general differentiates between two principally different approaches to ensure sterility of a parental product: terminal sterilization of the final product in its container (steam sterilization) and aseptical manufacturing. Terminal sterilization is the commonly used one because of its higher sterility assurance level achieved when compared with the aseptical methods. However, terminal sterilization is not applicable to many liposomal drug carrier formulations.
There are several sterilization methods; such as filtration, gamma irradiation, final steam sterilization, dry heat sterilization, ethylene oxide sterilization, and ultraviolet sterilization. Bearing in mind the susceptibility of liposomes to the previously mentioned physical and chemical degradation mechanisms, the conditions required in conventional sterilization techniques (except filtration) are rather concerning since they involve the usage of heat, radiation and/or chemical sterilizing agents. Therefore, identification of a suitable method for sterilization of liposome formulations is a major challenge.
\n\t\t\t\tSterilization Technique\n\t\t\t | \n\t\t\t\n\t\t\t\tAdvantage(s)\n\t\t\t | \n\t\t\t\n\t\t\t\tDisadvantage(s)\n\t\t\t | \n\t\t\t\n\t\t\t\tConvenience\n\t\t\t | \n\t\t
Filtration | \n\t\t\tLow operation temperature | \n\t\t\tApplicable to liposomes lower than 200 nm in diameter Operation under aseptic conditions | \n\t\t\tLow | \n\t\t
γ-irradiation | \n\t\t\tModerate operation temperature Highest microbial death reliability | \n\t\t\tLarge scale operation Risk of degradation of liposomes | \n\t\t\tHigh | \n\t\t
Final steam sterilization | \n\t\t\tLow cost and convenient | \n\t\t\tRisk of degradation of liposomes | \n\t\t\tHigh | \n\t\t
Dry heat | \n\t\t\tLow cost and convenient | \n\t\t\tRisk of degradation of liposomes | \n\t\t\tHigh | \n\t\t
Ethylene oxide | \n\t\t\tLow operation temperature | \n\t\t\tPossible carcinogenic residues | \n\t\t\tLow | \n\t\t
UV-sterilization | \n\t\t\tLow cost and convenient | \n\t\t\tPoor penetration into products Risk of degradation of liposomes | \n\t\t\tHigh | \n\t\t
Summary of the Sterilization Techniques Applied on Liposomal Preparations.
Filtration is the most suitable sterilization technique for the thermolabile liposomes since it does not include any form of heat or condition that can result in the degradation of liposomes or leakage of the encapsulated material. However, filtration has some drawbacks such as; being only applicable to the liposomes that are smaller than 200 nm in diameter and being an expensive method due to the equipment requiring to work under high pressure (25 kg/cm2 and above). Additionally, this technique must be performed under aseptic conditions [90].
Filtration sterilization is relatively time-consuming and not efficient for the removal of viruses [91]. Studies have shown that polycarbonate membranes are less effective than hydrophobic Fluoropore membrane and cellulose acetate/surfactant-free membrane filtration units [91]. Although the limitations of filtration provoked researches on other sterilization methods, all resulted in the formation of degradation products via the previously mentioned degradation pathways. Filtration and the other methods are summarized according to their applicability on liposomal preparations in Table 1 [92], given above.
After preparation and before application, liposomes have to be characterized in order to ensure their in vitro and in vivo performance. Liposomal properties that are commonly discussed include lamellarity (the number of bilayers present in liposomes), diameter and size distribution, lipid composition and concentration determination, the encapsulant concentration and its encapsulation efficiency.
For the characterization of chemical properties, phospholipids can be quantitatively in terms of concentration either by Bartlett Assay or Stewart Assay. The phospholipid hydrolysis might be followed by HPLC where the column outflow can be monitored continuously by UV absorbance to obtain a quantitative record of the eluted components. Moreover, the phospholipid oxidation can also be followed by a number of techniques i.e., UV absorbance method, TBA method (2-thiobarbutiric acid) (for endoperoxides), iodometric method (for hydroperoxides) and GLC (gas-liquid chromatography) method [93].
The most direct method for determination of liposome size is the electron microscopy due to the possibility of viewing the liposomes individually and obtaining the exact information about the liposome population over the whole range of sizes [94]. As liposomes do not naturally create a contrast to be visible by electron microscopy, either cryo-TEM (Figure 2) should be used or staining of the liposome sample is required. Either way, it is a very time-consuming method and it requires equipments that may not always be immediately accessible. The other method for the determination of liposome size, dynamic light scattering [95, 96], is very simple and rapid to perform but it measures an average size of liposome bulk. More recently, atomic force microscopy is also used to determine the morphology, size and stability of liposomal structures. All these size determination methods are very expensive. If only an approximate size range is required, gel exclusion chromatography might be suitable.
Cryo-TEM pictures of Size Exclusion Chromatography fractions eluted at 90 minutes and prepared from egg-phosphatidylcholine.
Electrostatic stabilization of liposomes may be a desirable feature to prevent fusion. The surface charge on the liposomes is measured by zeta-potential measurements [98]. These measurements are useful in determination of the in vivo behavior of liposomes. Often zeta potential values <-25 mV or >+25 mV are considered stable [99]. However, as mentioned earlier, charged liposomes have the disadvantage of being unstable in biological conditions.
Residual solvent is very unacceptable for drug delivery applications, therefore residual solvent should be kept at a minimum in the formulations. Quantification of residual solvents as a result of preparation methods is done through gas chromatography (GC) [100-101] This is a very rapid and reliable method and most analytical and organic laboratories are equipped with a GC.
An important feature of liposomes is the existence of a temperature dependant, reversible phase transition, where the hydrocarbon chains of the phospholipid structures undergo a transformation from an ordered gel state to a more disordered fluid, liquid crystalline, state. This transition temperature is important in optimizing the storage conditions (i.e Temperature) to minimize fusion and drug leakage. These changes have been monitored by freeze fracture electron microscopy and much more easily by differential scanning calorimetry (DSC) [102-104, 93].
Entrapped volume is a crucial parameter that governs the morphology of liposomes. This internal volume is defined as the aqueous entrapped volume per unit quantity of lipids. The most promising way to determine the internal volume is to measure the quantity of water by replacing external medium (water) with a spectrophotometrically inert fluid (i.e. deuterium oxide) and then measuring water signal by NMR [93].
It is essential to measure the quantity of the encapsulated material inside liposomal structures before studying the behavior of this encapsulated material physically and biologically since the effects observed experimentally will be dose related. After the removal of the non-encapsulated material by the separation techniques the quantity of material remained can be assumed as 100% encapsulated. Minicolumn centrifugation and protamine aggregation methods are the general separation procedures that are commonly used [93].
Methods for determining the amount of material encapsulated within the liposomes typically rely on the destruction of the lipid bilayer and subsequent quantification of the released material [105]. In these measurements, the signal due to intact liposomes is typically monitored prior to bilayer disruption. The techniques used for this quantification depend on the nature of the encapsulant and include spectrophotometry [106, 107], fluorescence spectroscopy [108], enzyme-based methods [109] and electrochemical techniques. If a separation technique such as HPLC of field-flow fractionation (FFF) is applied, the percent encapsulation can be expressed as the ratio of the unencapsulated peak area to that of a reference standard of the same initial concentration [110, 111]. This method can be applied if the liposomes do not undergo any purification following preparation. Either technique serves to separate liposome encapsulated materials from those that remain in the extravesicular solution and hence can also be used to monitor the storage stability in terms of leakage or the effect of various disruptive conditions o the retention of encapsulants. Some authors have combined the size distribution and encapsulation efficiency determination in one assay by using FFF-MALS (multi angled light scattering) coupled to a concentration detector suitable for the encapsulant [112].
Since techniques used to separate free materials from liposome-encapsulated contents can potentially cause leakage of contents and, in some cases, ambiguity in the extent of separation, research using methods that do not rely on separation are of interest. Reported methods have included 1H NMR where free markers exhibited pH sensitive resonance shifts in the external medium versus encapsulated markers [113]; diffusion ordered 2D NMR which relied on differences in diffusion coefficients of entrapped and free marker molecules [114]; fluorescence methods where the signal from unencapsulated fluorophores was quenched by substances present in the external solution [115]; electron pin resonance (ESR) methods which rely on the signal broadening of unencapsulated markers by the addition of a membrane-impermeable agent [116, 117].
The drug release from liposomes can be followed by the usage of a well calibrated in vitro diffusion cell in order to predict pharmacokinetics and bioavailability of drug before expensive and time-consuming in vivo studies. For the determination of pharmacokinetic performance of liposomal formulations, dilution-induced drug release in buffer and plasma was employed and for the determination of drug bioavailability, another procedure is followed which involves the liposome degradation in the presence of mouse-liver lysosome lysate [93].
New drug delivery systems such as liposomes are developed when the existing formulations are not satisfactory. Among all the nanomedicine platforms, liposomes have demonstrated one of the most established nanoplatforms with several FDA-approved formulations for cancer treatment, and had the greatest impact on oncology to date, because of their size, biocompatibility, biodegradability, hydrophobic and hydrophilic character, low toxicity and immunogenicity [118]. A vast of literature describes the feasibility of encapsulation of a wide range of drugs, including anti-cancer and antimicrobial agents, peptide hormones, enzymes, other proteins, vaccines and genetic materials, in the aqueous or lipid phases of liposomes which showed enhanced therapeutic activity and/or reduced toxicity in preclinical models and in humans when compared to their non-liposomal formulations.
Liposome applications in drug delivery depend, and are based on, physicochemical and colloidal characteristics such as composition, size, loading efficiency and the stability of the carrier, as well as their biological interactions between liposomes and cells. Based on these liposome properties, several modes of drug delivery can be listed: the major ones are enhanced drug solubilization (e.g. amphotericin B, minoxidil), protection of sensitive drug molecules (e.g. cytosine arabinose, DNA, RNA, antisense olgionucleotides, ribozymes), enhanced intracellular uptake (all agents, including antineoplastic agents, antibiotics and antivirals) and altered pharmacokinetics and biodistribution of the encapsulated drug.
Although lipid based formulations have advantages as drug carriers, drug-delivery systems based on unmodified liposomes are limited by their short blood circulation time, instability in vivo and lack of target selectivity [119, 120]. To increase accumulation of liposomal formulations in the desired cells and tissues, the use of targeted liposomes including surface-attached ligands such as; antibodies, folates, peptides and transferrin that are capable of recognizing and binding to the desired cells. Despite of some improvements in targeting efficiency by these immunoliposomes, the majority of these modified liposomes were still eliminated rapidly by the reticulo endothelial system, primarily in the liver [120]. Better target accumulations are expected if liposomes can be made to remain in the circulation long enough.
Schematic drawing of cytosolic delivery and organelle-specific targeting of drug loaded nanoparticles (i.e. most frequently liposomes) via receptor-mediated endocytosis is shown in Figure 3.
Schematic drawing of the cytosolic delivery and organelle-specific targeting of drug loaded nanoparticles via receptor-mediated endocytosis. After receptor mediated cell association with nanoparticles, the nanoparticles are engulfed in a vesicle known as an early endosome. Nanoparticles formulated with an endosome disrupting property disrupt the endosomes followed by cytoplasmic delivery. On the other hand, if nanoparticles are captured in early endosomes, theymaymake theirway to lysosomes as late endosomes where their degradation takes place. Only fraction of non-degraded drug released in the cytoplasm interacts with cellular organelles in a random fashion. However, cytosolic delivery of a fraction of organelle-targeted nanoparticles via endosomal escape or from lysosomes travel to the targeting organelles to deliver their therapeutic cargo [121].
Different methods have been suggested to achieve liposomes with high stability and long circulation times in vivo, including the surface coating of the liposomes with inert, biocompatible polymers such as PEG (stealth liposomes), which forms a protective layer over the liposome surface and slow down liposome recognition by opsonins and therefore subsequent clearance of liposomes [80, 84]. Long circulating liposomes are now being investigated in detail and are widely used in vitro and in vivo studies due their flexibility and also they found their place in the clinical applications. The flexibility allows a relatively small number of surface-grafted polymer molecules to create an impermeable layer over the liposome surface [122, 123]. Long-circulating liposomes demonstrate dose-dependent, non-saturable, log-linear kinetics and increased bioavailability [124].
The studies that attempt to combine the properties of long-circulating liposomes and immunoliposomes in one preparation place themselves in the literature as the further development in the liposomal formulations as drug carriers [125, 126]. In the early experiments, simple co-immobilization of an antibody and PEG on the surface of the same liposome has been performed despite the possibility of PEG creating steric hindrance for target recognition with the targeting moiety [125]. To achieve better selectivity of PEG-coated liposomes, it is advantageous to attach the targeting ligand via a PEG spacer arm, so that the ligand is extended outside the dense PEG brush which reduces steric hindrance of binding to the target [127]. The use of PEG-conjugated immunoliposomes for increasing drug carrying capacity of monoclonal antibody has been demonstrated [128]. In addition to costly monoclonal antibodies, common molecules such as folic acid, trensferrin and RGD peptides have also been studied for tumor targeting with enhanced selective uptakes [120].
Encouraging results of liposomal drugs in the treatment or prevention of a wide spectrum of diseases in experimental animals and in human, indicate that more liposome-based products for clinical and veterinary applications may be forthcoming. These could include treatment of eye and skin diseases in therapeutic applications, antimicrobial and anticancer therapy in clinical applications, metal chelation, enzyme and hormone replacement therapy, vaccine and diagnostic imaging, etc. Some of the liposome applications in terms of drug delivery are discussed below.
The eye is protected by three highly efficient mechanisms (a) an epithelial layer which is the barrier to penetration (b) tear flow (c) the blinking reflex. All these mechanisms are responsible for the poor drug penetration into the deeper layers of the cornea and the aqueous humor and for the rapid wash out of drugs from the corneal surface. Initially, in 1981 the enhanced efficiency of liposomes encapsulated idoxuridine in herpes simplex infected corneal lesions in rabbits was reported [129]. In 1985, it was concluded that ocular delivery of drugs can be either promoted or impeded by the use of liposome carriers, depending on the physicochemical properties of the drugs and the lipid mixture employed [130]. The use of mucoadhesive polymers, carbopol 934P and carbopol 1342 to retain liposomes at the cornea was proposed [131]. While precorneal retention times were indeed significantly enhanced under appropriate conditions, liposomes even in the presence of the mucoadhesive had migrated toward the conjuctival sac with very little activity remaining at the corneal surface.
Lung is a natural target for the delivery of therapeutic and prophylactic agents such as peptides and proteins. The past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local therapy but also for systemic therapy as well as diagnostic purposes, primarily due to the several advantages the pulmonary route offers over other routes of drug administration. Drugs that undergo gastrointestinal degradation (such as proteins and peptides) are ideal candidates for pulmonary delivery.
Targeted drug delivery to the lungs has evolved to be one of the most widely investigated systemic or local drug delivery approaches. The use of drug delivery systems for the treatment of pulmonary diseases is increasing because of their potential for localized topical therapy in the lungs. This route also makes it possible to deposit drugs more site-specific at high concentrations within the diseased lung thereby reducing the overall amount of drug activity while reducing systemic side effects. To further exploit the other advantages presented by the lungs, as well as to overcome some challenges, scientists developed interests in particulate drug delivery systems for pulmonary administration, such as liposomes, micelles, nano-and micro-particles based on polymers.
The use of liposomes as drug carriers for pulmonary delivery has been reported for different kinds of therapeutics such as anti-microbial agents, cytotoxic drugs, antioxidants, anti-asthma compounds and recombinant genes for gene therapy in the treatment of cystic fibrosis.
Liposomes as carrier systems for pulmonary delivery offer several advantages over aerosol delivery of the corresponding non-encapsulated drug. Liposomes might be used to solubilize poorly soluble drugs, provide a pulmonary sustained release reservoir prolonging local and systemic therapeutic drug levels, facilitate intracellular delivery of drugs especially to alveolar macrophages, tumor cells or epithelial cells, prevent local irritation of lung tissue and reduce the drug’s toxicity, target specific cell populations using surface bound ligands or antibodies and be absorbed across the epithelium to reach the systemic circulation intact [132].
Local delivery of medication to the lungs is highly desirable, especially in patients with specific pulmonary diseases such as cystic fibrosis, asthma, chronic pulmonary infections or lung cancer. The principal advantages include reduction of systemic side effects and application of higher doses of the medication at the site of drug action. Although simple inhalation devices and aerosols containing various drugs have been used since the early 19th century for the treatment of respiratory disorders, the past 15 years have been marked by intensive research efforts on pulmonary drug delivery not only for local therapy but also for systemic therapy as well as diagnostic purposes due to the several advantages the pulmonary route offers over other routes of drug administration. Lung is a natural target for the delivery of therapeutic and prophylactic agents such as peptides and proteins due to the large surface area available for absorption, the very thin absorption membrane and the elevated blood flow which rapidly distributes molecules throughout the body. Moreover, the lungs exhibit relatively low local metabolic activity, and unlike the oral route of drug administration, pulmonary inhalation is not subject to first pass metabolism [133].
Inhaled drug delivery devices can be divided into three principal categories: nebulizers, pressurized metered-dose inhalers and dry powder inhalers; each class presents unique strengths and weaknesses. A good delivery device has to generate an aerosol of suitable size and provide reproducible drug dosing. It must also protect the physical and chemical stability of the drug formulation.
For controlled delivery of drug to the lung, liposomes are one of the most extensively investigated systems in recent studies given that they can be prepared with phospholipids such as egg phosphatidylcholine (PC), distearoyl phosphatidylcholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC) endogenous to the lung.
A significant disadvantage of many existing inhaled drugs is the relatively short duration of resultant clinical effects, which requires most medications to be inhaled at least twice daily. This often leads to poor patient compliance. A reduction in the frequency of dosing would be convenient, particularly for chronic diseases such as asthma. The advantages of such an approach include reduced dosing, increased effectiveness of rapidly cleared medicine and enhanced residence time at the target site for the treatment of infection. Many challenges exist in developing controlled release inhalation medicine, which is reflected in the fact that no commercial product exists. Cytotoxic agents, bronchodilators, anti-asthma drugs, antimicrobial and antiviral agents and drugs for systemic action, such as insulin and proteins are being investigated.
The numerous anti-cancer agents that have a high cytotoxic effect on the tumor cells in vitro exhibit a remarkable decrease of the selective ant-tumor effect for in vivo procedures applicable in the clinical treatment. One of the significant limitations of the anti-cancer drugs is their low therapeutic index meaning that the dose required to produce an anti-tumor effect is toxic to normal tissues. The low therapeutic index of these drugs results from the inability to achieve therapeutic concentrations at the specific target sites, tumors. Further, it results from the non-specific toxicity to normal tissues such as bone marrow, renal, gastrointestinal tract, and cardiac tissue and also from the problems associated with a preparation of a suitable formulation of the drugs [134].
Many different liposome formulations of various anticancer agents were shown to be less toxic than the free drug so that most of the medical applications of liposomes that have reached the preclinical stage are in cancer treatment [135-137]. Entrapment of these drugs into liposomes resulted in increased circulation lifetime, enhanced deposition in the infected tissues, and protection from the drug metabolic degradation, altered tissue distribution of the drug, with its enhanced uptake in organs rich in mononuclear phagocytic cells (liver, spleen and bone marrow) and decreased uptake in the kidney, myocardium and brain. To target tumors, liposomes must be capable of leaving the blood and accessing the tumor. However, because of their size liposomes cannot normally undergo transcapillary passage. In spite of this, various studies have demonstrated the accumulation of liposomes in certain tumors in a higher concentration than found in normal tissues [138, 139]. Anthracyclines are drugs which stop the growth of dividing cells by intercalating into the DNA and therefore kill predominantly quickly dividing cells. These cells are not only in tumors but are also in hair, gastrointestinal mucosa, and blood cells; therefore, this class of drugs is very toxic. Many research efforts have been directed towards improving the safety profile of the anthracyclines cytotoxics, doxorubicin and daunorubicin, along with vincristine. Encapsulation of these drugs into the liposomes showed reduced cardiotoxicity, dermal toxicity and better survival of the experimental animals compared to the controls receiving free drugs [138]. Such beneficial effects of liposomal anthracyclines have been observed with a variety of liposome formulations regardless of their lipid composition and provided that lipids used high cholesterol concentration of phospholipids with high phase transition temperature are conducive to drug retention by the vesicles in the systemic circulation [45].
Active targeting of cancer drugs to the tumors is shown schematically in Figure 4.
Representation of active targeting via receptors [121].
Currently several liposomal formulations are in the clinical practice containing different chemotherapeutics such as doxorubicin (Doxil1/Caelyx1), doxorubicin (Myocet1), daunorubicin (DaunoXome1) and cytarabine (DepoCyte1) for treating the ovarian cancer, AIDS related Kaposi’s sarcoma, multiple myeloma, lymphomas, leukemia with meningeal spread. Several other liposomal chemotherapeutic drugs containing doxorubicin, annamycin, mitoxantrone, cisplatin, oxaliplatin, camptothecine, 9-nitro-20 (S)-camptothecin, irinotecan, lurtotecan, topotecan, paclitaxel, vincristine, vinorelbine and floxuridine are at the various stages of clinical trials [140].
Two liposomal formulations have been approved by the US Food and Drug Administration (FDA) and are commercially available for the treatment of AIDS-related Kaposi’s sarcoma. Doxil, first liposomal drug approved by FDA and has been on the market since 1995, is a formulation of doxorubicin precipitated in sterically stabilized liposomes and has been on the market since 1995 [141], while DaunoXome, approved six months later than Doxil, is daunorubicin encapsulated in small liposomes with very strong and cohesive bilayers, which can be referred as mechanical stabilization [142].
DaunoXome is composed of small unilamellar vesicles containing distearoylphosphatidylcholine-cholesterol (2:1) with daunorubicin loaded by a pH gradient [137]. These liposomes are selectively stable in the circulation because they are small and their membrane is electrically neutral and mechanically very strong [142]. This reduces the charge-induced and hydrophobic binding of plasma components but does not protect against van der Waals adsorption. Also, uncharged liposomes are colloidally less stable than charged ones.
Doxil is a liquid suspension of 80-100 nm liposomes (2000PEG-distearoylphosphatidylethanolamine-hydrogenated-soya-bean phosphatidylcholine-cholesterol, 20 mM) loaded with doxorubicin HCl by ammonium sulfate gradient technique and additionally precipitation with encapsulated sulfate anions. These liposomes circulate in patients for several days, which increase their chances of extravasating at sites with a leaky vascular system. Their stability is due to their surface PEG coating as well as to their mechanically very stable bilayers [141, 142].
Cytarabine (Ara-C) is an effective hydrophilic chemotherapeutic agent used widely for the treatment of acute myelogenous leukaemia and lymphocytic leukeamia [143]. It has often been utilized in the combination chemotherapy, against solid tumors and leukaemias. Cytarabine is a cell cycle-dependent drug; hence, prolonged exposure of cells to cytotoxic concentrations is critical to achieve maximum cytotoxic activity. The toxicity of cytarabine is reduced if it is able to maintain an effective therapeutic level for a long period of time and, thus, it is a suitable candidate for administration in a controlled-release dosage form. Liposome encapsulated liposomes (DepoCytTM) are now commercially available.
Etoposide (VP-16-213) is another successful chemotherapeutic agents used for the treatment of human cancers. The drug is currently in its third decade of clinical use and is a front line therapy for a variety of malignancies, including leukaemias, lymphomas and several solid tumors [144]. It has a short biological half-life (3.6 h) with a terminal half-life of 1.5 h intravenously and a variable oral bioavailability ranging from 24% to 74%. Although intraperitoneal injection would result in initial high local tumor concentrations, prolonged exposure of tumor cells may not be possible [145].
The harmful and even destructive effect of cytotoxic drugs on healthy body cells makes it necessary to search for new delivery methods for drugs like cytarabine and etoposide. There are many articles describing the results of investigations of incorporation of cytarabine [146] and etoposide [147] into liposome. However, there is no information about their simultaneous incorporation, in spite of the fact that these two drugs have been used for more than 30 years.
Taxanes are complexes of diterpenoid natural products and semisynthetic analogs. Presently, these drugs belong to prominent anticancer agents used for combined chemotherapy [148]. Paclitaxel (PTX), the prototype of this class, emerges from a natural source [149]. This drug have been used for various cancers including ovarian, breast, head and neck, and non-small cell lung cancers [150].
The commercial PTX preparation (Taxol®) is formulated in the vehicle composed of Cremophor EL® (polyethoxylated castor oil used as a solubilizing surfactant) and dehydrated ethanol, which provides a homogenous preparation. However, some drawbacks have been reported for its clinical applications of this formulation such as severe hypersensitivity reactions, neurotoxicity and neutropenia [151, 152]. It was reported that these adverse effects associated with this formlation would be due to Cremophor EL rather than PTX itself [153]. PTX solubilized in Cremophor EL shows also an incompatibility with the polyvinyl chloride of the administration sets [152]. Furthermore, the short-term stability of PTX upon dilution with aqueous media can result in possible drug precipitation [154].
Special requirements regarding a proper filter device as well as appropriate containers and infusion bags for the storage and administration of the drug have to be fulfilled in order to overcome the problems of incompatibility and instability during the clinical application of Taxol®. Hence, the development of an improved delivery system for PTX is of high importance. Current approaches are focused mainly on the development of formulations that are devoid of Cremophor EL, investigation of the possibility of a large-scale preparation and a request for a longer-term stability. There are some promising possibilities to replace Taxol® by a less irritable preparation such as micelle formulations, water-soluble prodrug preparations, enzyme-activatable prodrug preparations conjugated with antibodies or albumin, parenteral emulsions, microspheres, cyclodextrins, and nanocrytals [155-162].
The preparation of an optimal PTX formulation requires important considerations such as the optimization of the liposomal composition, the balance of the PTX amount encapsulated in the liposomes and the stability of the prepared PTX liposomes during storage in aqueous media [163]. The main characteristics of PTX molecule are asymmetry, bulkiness, hydrophobicity, low solubility and tendency to crystallization in aqueous media. All these factors affect the final design and preparation of a suitable drug formulation.
Liposomes provide suitable environment enhancing the solubility of the hydrophobic nature PTX by associating the molecule within the membrane bilayers. Commonly prepared formulations of PTX with liposomes were able to encapsulate the highest achievable content of PTX, 3-4 mol% with stability for weeks to months whereas 4-5 mol% paclitaxel was stable in the time range of just several hours to a day, and 8% paclitaxel loading only resulted in 15 minutes of liposome stability. Generally, increasing the encapsulated amount of PTX causes a reduction in the stability of the liposomal-PTX formulation due to the crystallization of the drug molecule. Thereby, to achieve a high drug/lipid ratio while retaining the long-term physical-chemical stability, a freeze-drying method is employed to obtain a dry drug-lipid powder, which is rehydrated in an aqueous solution immediately before use [58]. The encapsulation of PTX into liposomes enhances the drug therapeutic efficacy, thus, the same therapeutic effect could be reached by a decreased PTX-dose. On the other hand, the maximum tolerated dose (MTD) of liposome-encapsulated PTX increased compared with the Taxol® [Straubinger, R.M. and S.V. Balasubramanian, Preparation and Characterization of Taxane-containing Liposomes, Methods Enzymol. 391 (2005) 97-117.]. [163].
Taxane liposomes have shown slower elimination, higher antitumor activity against various murine and human tumors and lower systemic toxic effect compared to Taxol® [58]. They have also shown antitumor effect in Taxol-resistant tumor models [164]. Abraxane®, the only nonliposomal preparation of PTX, (albumin nanoparticle-based PTX preparation) and Lipusu® (liposomal PTX approved by State FDA of China) have entered the field of clinical applications. LEP-ETU (NeoPharm) and EndoTAG®-1 (Medigene) have reached the phase II of the clinical trials. Generally, liposomes and protein nanoparticles represent a promising approach to the optimization of PTX delivery. Their commercialization is at the doorstep of modern drug delivery market.
Liposomes made up of commonly used ester phospholipids such as phosphatidylcholine are referred as conventional liposomes. These structures are very attractive for encapsulation and drug delivery applications to entrap both hydrophilic and hydrophobic materials due to the presence of aqueous core part as well as the lipid bilayer. Up to this date, there are many formulations in the market and also in the clinical trials. However, none of them truly overcome their chemical and physical instability problems especially during the transfer to the site of action [120]. Various attempts like modification of the liposome surface with i.e. hydrophilic polyethylene glycol polymers, using cryoprotectants or incorporation of high amount of cholesterol into the bilayer have led to only limited success. Other than instability problems, liposomal drug vehicles show extensive leakage of water-soluble drugs during the passage through the gastrointestinal tract and they are heterogeneous in terms of size distribution. Therefore, scientists have been looking for new drug delivery formulations that could address these issues about liposomes, which lead to the so-called new generation of liposomes which will be summarized in this section.
Archaeosomes are liposomal formulations that are prepared with one or more lipids, mainly containing diether and/or tetraether linkages, found in archaeobacterial membrane [165]. These archaeobacterial lipids present unique features and higher stabilities to several conditions (high or low temperatures, high salinity, acidic media, anaerobic atmosphere, high pressure) over conventional liposomes [166]. The definition of archaeosomes also includes the use of synthetically derived lipids that have the properties of archaeobacterial ether lipids, that is, regularly branched phytanyl chains attached via ether bonds at sn-2,3 glycerol carbons [167]. The surprising stability of archaeosomes can be attributed to some properties brought by the archaeobacterial lipids’ structure: (i) the ether linkages that are more stable than esters over a wide range of pH, and the branching methyl groups help both to reduce crystallization and permeability; (2) the stability towards oxidative degradation of these lipid membranes are provided by the fully saturated alkyl chains in the archaeobacterial lipids; (3) the unusual stereochemistry of the glycerol backbone ensures the resistance of the membrane to enzymatic attack; (4) the bipolar lipids span the membranes and enhance their stability properties [167, 168].
Archaeosomes can be prepared by using conventional procedures (hydration of a thin film followed by sonication or extrusion, detergent dialysis) at any temperature in the physiological range or lower, thus making it possible to encapsulate thermally labile compounds. Additionally, they can be prepared and stored in the presence oxygen without any degradation. According to the clinical experiments, in vivo and in vitro, these new drug delivery vehicles are not toxic. Thus, the biocompatibility and better stability of archaeosomes in numerous conditions offer advantages over conventional liposomes for their usage in biotechnology including vaccine and drug/gene delivery [167]. Consequently, they can be considered as better carriers than conventional liposomes, especially for protein and peptide delivery due to their high stability. Li et al. showed the superiority of archaeosomes over conventional liposomes in their study in which they used insulin as a model peptide for its oral delivery [169].
Another development aiming to enhance tissue targeting is virosomes in which the liposome surface is modified with fusogenic viral envelope proteins [170]. Virosomes have been used for the intracellular delivery of drugs and DNA [171, 172] as well as the basis of the newly developed vaccines which are very effective in the delivery of protein antigens to the immune system [173]. As a result, a whole set of virosomes-based vaccines have been developed for human and animal use. Special attention has been paid to the delivery of influenza vaccine using virosomes containing the spike proteins of influenza virus. Virosome-based vaccines were found to be highly immunogenic and well tolerated in children. A similar approach was used to prepare virosomal hepatitis A vaccine that elicited high antibody titres after primary and booster vaccination of infants and young children which was also confirmed for the healthy adults and elderly patients [174-176]. In general, virosomes can provide an excellent opportunity for the efficient delivery of both various antigens and many drugs, including nucleic acids, cytotoxic drugs and toxoids [177, 178], although they might present certain problems associated with their stability, leakiness and immunogenicity.
Niosomes, exhibiting a similar behavior to liposomes, are the vesicles that are made up of nonionic surfactants (e.g. alkyl ethers and alkyl esters) and cholesterol. These structures are stable on their own and they increase the stability of the encapsulated drugs. No special conditions are needed for handling and storage of these surfactants. Niosomes improve the oral bioavailability of poorly absorbed drugs, and enhance skin penetration of drug. When compared with liposomes, their oral absorption is better due to the replacement of phospholipids with nonionic surfactants which are less susceptible to the action of bile salts, parenteral, as well as topical routes. These delivery systems are biodegradable, biocompatible and non-immunogenic. Niosomes improve the therapeutic performance of drug molecules by delaying the clearance from the circulation and protecting the drug from biological environment [179].
The transdermal delivery is one of the most important routes of drug administration. The main factor which limits the application of transdermal route for drug delivery is the permeation of drugs through the skin. Human skin has selective permeability for drugs. Lipophilic drugs can pass through the skin but the drugs which are hydrophilic in nature can not pass through. Water soluble drugs either show less or no permeation. To improve the permeation of drugs through the skin various mechanisms have been investigated, including use of chemical or physical enhancers, such as iontophoresis, sonophoresis, etc. Liposomes and niosomes are not suitable for transdermal delivery due to poor skin permeability, breaking of the system, aggregation, drug leakage, and fusion of vesicles [180].
A new type of carrier system, suitable for transdermal delivery, called transfersome has been proposed for the delivery of proteins and peptides like insulin, bovin, serum albumin, vaccines, etc. These systems are soft and malleable carriers that offer noninvasive delivery of drug into or across the deeper skin layers and/or the systemic circulation [181]. Transfersomes improve the site specificity while providing the safety of the drug. Transfersomes are the lipid supramolecular aggregates which make them very flexible. This flexibility as well as their good penetration ability causes them to be used in the effective delivery of non-steroidal anti-inflammatory agents like ibuprofen and diclofenac [182].
Alternatively, unlike classic liposomes [183, 184], that are known mainly to deliver drugs to the outer layers of skin, ethosomes can enhance permeation through the stratum corneum barrier [185-187]. Ethosomes, developed by Touitou in 1997, are the slight modification of well established drug carrier liposome, containing phospholipids, alcohol (ethanol or isopropyl alcohol) in relatively high concentration and water [188]. The size of these soft vesicles can vary from nanometers to microns [189-193]. The high concentration of ethanol makes the ethosomes unique. The ethanol in ethosomes causes disturbance in the skin lipid bilayer organization, hence when incorporated into a vesicle membrane, it enhances the vesicle’s ability to penetrate the stratum corneum. Also, because of the high concentration of ethanol the lipid membrane is packed less tightly than conventional vesicles but has equivalent stability, allowing a more malleable structure and improves drug distribution ability in stratum corneum lipids. Ethosomes can be used for many purposes in drug delivery for the treatment of many diseases such as Minoxidil for baldness, testosterone as steroidal hormone, Trihexyphenidyl hydrochloride for Parkinson’s disease, Zidovudine and Lamivudine as anti-HIV, Bacitracin as antibacterial, Erythromycin as antimicrobial, DNA for genetic disorders, Cannabidol in the treatment of rheumatoid arthiritis and many others [190, 192, 194-201].
Novasomes are the modified forms of liposomes [202] or a type of niosomes prepared from the mixture of monoester of polyoxyethylene fatty acids, cholesterol and free fatty acids with the diameter of 0.1-1.0 microns. They consist of two to seven bilayer shells that surround an unstructured space occupied by a large amorphous core of hydrophilic or hydrophobic materials [203]. The inner amorphous core can be loaded up to 80-85% with a medical drug and the surfaces of novasomes can be positive, negative or neutral.
Novasomes offer several advantages to the owners of the product such as: Both hydrophilic and hydrophobic products can be incorporated in the same formulation, drugs showing interactions can be incorporated in between bilayers to prevent incompatibility, they can be made site specific due to their surface charge characteristics, they can deliver a large volume of active ingredient, thus also reducing the frequency of application, and they have the ability of adhering skin or hair shafts which makes novasomes applicable in the cosmetic formulations [204].
Novasomes have extensive utilization in fields of foods, cosmetics, personal care, chemical, agrochemical and pharmaceuticals. The technology enhances absorption rate via topical delivery of pharmaceuticals and cosmeceuticals by utilizing non-phospholipid structures. Various FDA-regulated products such as human pharmaceuticals and vaccines can be developed by this technology [205, 206]. These nonionic vesicles composed of glyceryl dilaurate with cholesterol and polyoxyethylene-10-stearyl ether have been known to deliver greater amounts of cyclosporine into and through hairless mouse skin than phosphatidyl choline or ceramide based vesicles [206]. Among various liposomal formulations, novasomes appeared more effective when delivered under non-occluded conditions from a finite dose [206]. Various vaccines based on novasomes have been licensed for the immunization of fowl against Newcastle disease virus and avian rheovirus [135]. Some of the novasome-based vaccines against bacterial and viral infections have been developed such as small pox vaccine while still many are under development [207]. Novasomes inactivate viruses such as orthomyxoviruses, paramyxoviruses, coronaviruses and retroviruses, etc., by fusing with enveloped virus and that the nucleic acid of the virus denatures shortly after the fusion [208].
Although liposomes are like biomembranes, they are still foreign objects of the body. Therefore, liposomes are known by the mononuclear phagocytic system (MPS) after contact with plasma proteins. Accordingly, liposomes are cleared from the blood stream. For more than two decades, various PEG derivatives have been used to stabilize for increasing efficiency in drug or gene delivery. Most ‘stabilized’ liposomes, the so-called stealth liposomes [78], or cryptosomes [84], contain a certain percentage of PEG-derivatized phospholipids, which reduce the uptake by MPS, thereof prolonging the circulation times and making available abundant time for these liposomes to leak from the circulation through the leaky endothelium. Unlike, conventional liposomes, PEG-liposomes do not show dose dependent blood clearance kinetics [209]. Vesicles containing PEG-conjugated lipids at various concentrations, molecular weights, or various sizes of PEG-containing vesicles were reported to have different circulation times [81, 84, 210-212]. These kind of liposomal systems are generally used in the ligand-mediated drug targeting [213]. This stealth principle has been used to develop the successful doxorubicin-loaded liposome product that is presently available in the market as Doxil (Janssen Biotech, Inc., Horsham, USA) or Caelyx (Schering-Plough Corporation, Kenilworth, USA) for the treatment of solid tumors.
Cryptosomes is a liposomal composition for targeted delivery of drugs. The composition comprises poloxamer molecules and liposomes encapsulating one or more delivery agents. Poloxamers are polyethylene oxide (PEO)-polypropylene oxide (PPO)-polyethylene oxide tri-block co-polymers of different molecular weights. The hydrophobic PPO group in the middle links the two hydrophilic PEO groups. The hydrophilic PEO groups of a poloxamer, on either side of the central PPO unit, can provide steric protection to a bilayer surface. The amphiphilic nature of the poloxamers makes them extremely useful in various applications as emulsifiers and stabilizers. It is considered that the central PPO unit, being hydrophobic, would tend to push into the bilayer interior serving as an anchor. Dislodging the poloxamer molecule from the bilayer is achieved by reducing its hydrophobicity which is achieved by decreasing the temperature. In an aqueous medium, poloxamers stay as individual molecules at temperatures below their critical micelle temperature (CMT), but at temperatures above the CMT, they form micelles due to their amphiphilic nature. In the presence of lipid bilayers, some poloxamer molecules would partition into the bilayers as well as forming micelles with other poloxamer units. If the temperature again goes below the CMT, the poloxamer molecules lose their amphiphilic nature and disassociate from the lipid bilayer or micelle [179].
Emulsome, having the characteristics of both liposomes and emulsions, is a novel lipoidal vesicular system with an internal solid fat core surrounded by phospholipid bilayer. Emulsomes comprise a hydrophobic core (composed of solid fates instead of oils) as in standard oil-in-water emulsions, but the core is surrounded and stabilized by one or more envelopes of phospholipid bilayers as in liposomes allowing water insoluble drugs in the solution form without requiring any surface active agent or co-solvent. Emulsomes differ from liposomes since their internal core is a lipid, whereas the internal core in liposomes is an aqueous compartment. The drug loading is generally followed by sonication to produce emulsomes of smaller size [214]. These systems are often prepared by melt expression or emulsion solvent diffusive extraction. The lipid assembly of emulsomes, stabilized by cholesterol and soya lecithin (5-10% by weight), has features that are intermediate between liposomes and oil-in-water emulsions droplets. Emulsomes provide the advantages of improved hydrophobic drug loading in the internal solid lipid core and the ability of encapsulating water-soluble medicaments in the aqueous compartments of surrounding phospholipid layers.
Beside the other vesicular formulations, emulsomes are much stabilized and nano range vesicles. It is a new emerging delivery system and therefore could play a fundamental function in the effective treatment of life-threatening viral infections and fungal infections such as hepatitis, HIV, Epstein-Barr virus, leishmaniasis, etc. appear promising for the treatment of visceral leishmaniasis specifically and hepato-splenic candidiasis [214-216]. Emulsomes could be utilized in order to improve oral controlled delivery of drug, vaccine, and biomacromolecules. It is due to the fact that they are nano sized in range and could be utilized for the intravenous route. The common application areas of emulsomes are drug targeting, anti-neoplastic treatment, leishmaniasis (a disease in which a parasite of the genus Leishmania invades the cells of the liver and spleen) treatment, and biotechnology. Moreover, emulsomes could represent a more economical alternative to current commercial lipid formulations for the treatment of viral infections and fungal infections. Emulsomes provide a controlled and sustain release of drug. In comparison to the liposomes, emulsomes provide a prolong release of drug up to 24 hours, whereas liposomes have shown release up to 6 hours [217-219]. Emulsomes are nano size range in comparison to other vesicular delivery system such as niosomes and ethosomes. Due to the reduced size (10-250 nm) they can be used to enhance bioavailability to drug and as the best carrier for the intravenous drug delivery as well as oral drug delivery.
The lipid core of emulsomes may contain one or more anti-oxidants which are generally α-tocopherol or its derivatives that are the members of Vitamin-E family. The presence of anti-oxidants reduces the formation of oxidative degradation products of unsaturated lipids such as peroxides. The need of anti-oxidant can be prevented by the usage of saturated fatty acids during the preparation of the lipid core [220]. In the formation of emulsomes, like in the case of liposomes, cholesterol is essential component for the system that influences the stability of emulsomal systems and plays an important role in the drug encapsulation [221-224].
The most important advantage of emulsomes is their ability to protect the encapsulated drug from harsh gastric environment of stomach before oral administration because the drug is inside the triglyceride lipid core which can be supported that the gastric pH and the gastric enzymes are unable to hydrolyze triglycerides. Also, they resist development of multi drug resistance, often associated with over expression of a cell membrane glycoprotein, which cause efflux of the drug from the cytoplasm and results in an ineffective drug concentration inside the cellular compartment [225].
The development of emulsomes, however, is still largely empirical, and in vitro models that are predictive of oral bioavailability enhancement are lacking. There is a need for in vitro methods for predicting the dynamic changes involving the drug in the gut in order to monitor the solubilization state of the drug in vivo. Attention also needs to be paid to the interactions between lipid systems and the pharmacologically active substance. The characteristics of various lipid formulations also need to be understood, so that guidelines can be established that allow identification of suitable candidate formulations at an early stage. Future research should involve human bioavailability studies as well as more basic studies on the mechanisms of action of this fascinating and diverse group of formulations.
Unilamellar vesicles or liposomes are commonly used as simple cell models and as drug delivery vehicles to follow the release kinetics of lipophilic drugs that require compartmental models in its therapeutics and triggers. The localization of the drug at the site of action, rate of achieving the therapeutic index and circulation lifetime are the key parameters for a liposome. Lately, their arises a need for a multi-compartment structure consisting of drug-loaded liposomes encapsulated within another bilayer, is a promising drug carrier with better retention and stability due to prevention enzymes or proteins reaching the interior bilayers. A vesosome is a more or less heterogeneous, aggregated, large lipid bilayer enclosing multiple, smaller liposomes that offer a second barrier of protection for interior compartments and can also serve as the anchor for active targeting components [226, 76]. The multi-compartment structure of vesosome can also allow for independent optimization of the interior compartments and exterior bilayer; however, just the bilayer-within-a-bilayer structure of the vesosome is sufficient to increase drug retention from minutes to hours [227, 228].
In nature, eukaryotes increased their ability to optimize their response to their surroundings by developing multiple compartments, each of which has a distinct bilayer membrane, usually of quite varied composition and physical structure. Mimicking this natural progression to nested bilayer compartments led to the development of the vesosome, or vesicles deliberately trapped within another vesicle. The vesosome has distinct inner compartments separated from the external membrane; each compartment can encapsulate different materials and have different bilayer compositions. In addition, while it has proven difficult to encapsulate anything larger than molecular solutions within lipid bilayers by conventional vesicle self-assembly, the vesosome construction process lends itself to trapping colloidal particles and biological macromolecules relatively efficiently [229, 230]. The nested bilayer compartments of the vesosome provide a degree of freedom for optimization not possible with a single membrane enclosed compartment and a more realistic approximation of higher order biological organization.
The vesosome structure could be used to deliver a cocktail of antibiotics or antimicrobials to sites at a fixed ratio; such mixtures have been shown to act synergistically when delivered in a single liposome [231]. Such multi-drug formulations may be useful to avoid inducing pathogen resistance to a single drug.
As vesosomes are simply liposomes within liposomes, it should be possible to directly translate the extensive body of research on liposome drug delivery to the vesosome with only minor changes, and perhaps significant major improvements. The vesosome is created by simply self-assembly steps very similar to those used in making conventional unilamellar liposomes [229]. An important question is whether such additional effort in developing new structures will provide a therapeutic benefit over direct injection of the free drug or drug delivery by conventional unilamellar liposomes. The most obvious potential application for the vesosome is for drugs that have already shown increased efficacy by delivery with conventional liposomes. As an example, ciprofloxacin (cipro), a synthetic bactericidal fluoroquinolone antibiotic with broad spectrum efficacy, is released much more quickly from unilamellar liposomes in serum relative to saline [232, 233]. Conventional pH-loaded liposomes can retain essentially all encapsulated ciprofloxacin when stored in buffer for 12 weeks at 21 0C and 8 weeks at 37 0C [234, 235]. Although liposomal cipro has shown increased efficacy due to prolonged residence of cipro in the blood (free cipro is cleared in minutes), the half-life of release from the liposomes was only 1 hour, yet the liposomes themselves circulated for more than 24 hours [232, 235]. A second example is vincristine, a naturally occurring dimeric catharanthus alkaloid that has been used extensively as an antitumor agent since 1960’s. The therapeutic activity of vincristine is dictated by the duration of therapeutic concentrations at the tumor site [236, 238, 239]. However, conventional liposomes, while offering improved bioavailability, also cannot encapsulate vincristine for sufficient time to give optimal results [234, 236, 237]. Future work will determine if multiple compartment structures like vesosome give sufficient enhancement of small drug entrapment to lead to new therapeutics.
Genetics play an increasingly important role in medicine and is used routinely to diagnose diseases and to understand malfunctions at the molecular level. The active approach of trying to amend genetic defects or insufficiencies is a logical next step. Major elements in the successful advance of gene therapy are identification of the disease and target cells, tissues and organs as well as construction of appropriate gene vectors, effective gene transfer and expression in the targeted cells. Many inherited diseases follow the Mendelian inheritance pattern in which the cause is due to a single genetic defect. Because the existing therapeutic treatments of such diseases are in most cases very limited, it is hoped that by transfecting appropriate cells with the correct gene or by adding a missing one, the disease could be alleviated. Examples of such potential treatments are for cystic fibrosis, hemophilia, sickle cell anemia or hypercholesterimia and mutant tumor suppressor genes.
The aim of gene therapy is to deliver DNA, RNA or antisense sequences to appropriate cells in order to alleviate symptoms or prevent the occurrence of a particular disease, i.e. repair the defect and also its cause. The major approaches to gene therapy include gene replacement, addition of genes for production of natural toxins, stimulation of the immune system or over expression of highly immunogenenic genes for immune self-attack and sensitization of cells to other treatments.
Recently, the studies on gene delivery into eukaryotic cells by the use of non-viral-lipid-based macromolecular delivery systems have been experiencing a growing interest owing to the appearance of clinical protocols for gene therapy. Although the efficiency and specificity of such non-viral delivery systems are not yet very high, some of the problems concerning transfection methods are being successfully solved. To date, the transfection mediators that ensure effective and directed gene delivery into various cells have been created. Transfection of plasmid DNA is closely connected to the problem of condensation of its molecule since the plasmid is too large (13-15 kb) to effectively overcome the cellular membrane barrier. Besides, free DNA has to be protected from destruction by endogenous nucleases. Lastly, it is necessary to neutralize the negative charge on DNA.
Genosomes are the artificial functional complexes for functional gene or DNA delivery to cell [238]. For the production of genosomes, cationic phospholipids were found to be more suitable because they possess high biodegradability and stability in the blood stream. Gene delivery is a vast area of research and a detailed summary of work in that field is beyond the scope of this chapter.
New generation liposomes and their features are summarized in Table 2.
\n\t\t\t\tType\n\t\t\t | \n\t\t\t\n\t\t\t\tMain constituent\n\t\t\t | \n\t\t\t\n\t\t\t\tAdvantage\n\t\t\t | \n\t\t
Liposomes | \n\t\t\tPhospholipids | \n\t\t\t\n\t\t |
Archaesomes | \n\t\t\tOne or more lipids containing diether linkages | \n\t\t\tHigh stability at several conditions | \n\t\t
Niosomes | \n\t\t\tNon-ionic surfactant and cholesterol | \n\t\t\tLess prone to action of bile salts | \n\t\t
Novasomes | \n\t\t\tMonoester of polyoxyethylene fatty acids, cholesterol and free fatty acids. Two to seven bilayer shells | \n\t\t\tHigh loading of drugs | \n\t\t
Transfersomes | \n\t\t\tLipid supramolecular aggregates | \n\t\t\tMore flexible hence better transdermal delivery | \n\t\t
Ethosomes | \n\t\t\tPhospholipids and alcohol in relatively high concentration | \n\t\t\tMore distruptive in the skin lipid bilayer organization hence better transdermal delivery | \n\t\t
Virosomes | \n\t\t\tLipids surface modified with fusogenic viral envelope proteins | \n\t\t\tIntracellular delivery of antigens, drugs and DNA | \n\t\t
Cryptosomes | \n\t\t\tPhospholipids and polaxamers or PEG | \n\t\t\tMore stable | \n\t\t
Emulsomes | \n\t\t\tInternal solid fat core surrounded by phospholipid bilayer | \n\t\t\tBetter for encapsulation of hydrophobic drugs | \n\t\t
Vesesomes | \n\t\t\tMultilamellar liposomes | \n\t\t\tMultidrug formulations are possible | \n\t\t
Genosomes | \n\t\t\tComplex of cationic phospholipids and a functional gene or DNA | \n\t\t\tSuitable for gene delivery | \n\t\t
New generation liposomes and their features.
Extensively motivated by the need to increase the stability and bioavailability of drugs, and to reduce their side effects by targeting to the site of action, research in new drug delivery vehicles has taken giant steps. Liposomes and their derivatives, so called new generation liposomes, present a vast area in this field where several advances have already been achieved as summarized in this chapter. However, still further research is required to overcome the limitations faced today in terms of prolonged stability, drug loading and active targeting.
In the last decade from the concept of clinical utility of liposomes to their recognized position in mainstream of drug delivery systems, the path has been long and winding. The liposome systems have been explored in the clinic for applications as diverse as sites of infection and imaging, for vaccine, gene delivery and small molecular drugs, for treatment of infections and for cancer treatment, for lung disease and for skin conditions etc. Several liposomal formulations are already on the market, while quite a few are still in the pipeline for treatment of diseases. Conventional techniques for liposome preparation and size reduction remain popular as these are simple to implement and do not require sophisticated equipment. However, not all laboratory scale techniques are easy to scale-up for industrial liposome production. Many conventional methods, for preparing small and large unilamellar vesicles, involve use of either water miscible/immiscible organic solvents or detergent molecules. The need for improvements in the design and stability of liposomal diagnostic and therapeutic systems will continue to motivate innovative and efficient routes to their production.
Malnutrition is a universal public health problem in both children and adults globally [1]. It is not only a public health concern but it is an impediment to global poverty eradication, productivity and economic growth. By eliminating malnutrition, it is estimated that 32% of the global disease burden would be removed [2]. As a widespread serious problem affecting children in developing countries, progress towards tackling the different forms of malnutrition remains relatively slow [3]. Malnutrition occurs due to an imbalance in the body, whereby the nutrients required by the body and the amount used by the body do not balance [1]. There are several forms of malnutrition and these include two broad categories namely undernutrition and over nutrition. Undernutrition manifests as wasting or low weight for height (acute malnutrition), stunting or low height for age (chronic malnutrition), underweight or low weight for age, and mineral and vitamin deficiencies or excessiveness. Over nutrition includes overweight, obesity and diet-related non-communicable diseases (NCDs) such as diabetes mellitus, heart disease, some forms of cancer and stroke [1]. Malnutrition is an important global issue currently, as it affects all people despite the geography, socio-economic status, sex and gender, overlapping households, communities and countries. Anyone can experience malnutrition but the most vulnerable groups affected are children, adolescents, women, as well as people who are immune-compromised, or facing the challenges of poverty [3].
\nAccording to the World Health Organization (WHO), 462 million adults are underweight, while 1.9 billion adults are overweight and/or obese. In children under 5 years of age, 155 million are stunted, 52 million are wasted, 17 million are severely wasted and 41 million are overweight and/or obese [1]. The manifestation of malnutrition is multifold, but the paths to addressing prevention are key and include exclusive breastfeeding for the first 2 years of life, diverse and nutritious foods during childhood, healthy environments, access to basic services such as water, hygiene, health and sanitation, as well as pregnant and lactating women having proper maternal nutrition before, during and after the respective phases (levels and trends) [3].
\nIt is vital that malnutrition is addressed in children as malnutrition manifestations and symptoms begin to appear in the first 2 years of life [4]. Coinciding with the mental development and growth periods in children, protein energy malnutrition (PEM) is said to be a problem at ages 6 months to 2 years. Thus, this age period is considered a window period during which it is essential to prevent and/or manage acute and chronic malnutrition manifestations [4, 5, 6]. Child and maternal malnutrition together have contributed to 3.5 million annual deaths. Furthermore, children less than 5 years of age have a disease burden of 35% [7]. In 2008, 8.8 million global deaths in children less than 5 years old were due to underweight, of which 93% occurred in Africa and Asia. Approximately one in every seven children faces mortality before their fifth birthday in sub Saharan Africa (SSA) due to malnutrition [8].
\nYoung malnourished children are affected by compromised immune systems by succumbing to infectious diseases and are prone to cognitive development delays, damaging long term psychological and intellectual development effects, as well as mental and physical development that is compromised due to stunting [7, 9, 10, 11]. A malnutrition cycle exists in populations experiencing chronic undernutrition and in this cycle, the nutritional requirements are not met in pregnant women. Thus, infants born to these mothers are of low birth weight, are unable to reach their full growth potential and may therefore be stunted, susceptible to infections, illness, and mortality early in life. The cycle is aggravated when low birth weight females grow into malnourished children and adults, and are therefore more likely to give birth to infants of low birth weight as well [9]. Malnutrition is not just a health issue but also affects the global burden of malnutrition socially, economically, developmentally and medically, affecting individuals, their families and communities with serious and long lasting consequences [1].
\nStudies in Sudan, Ethiopia, Bangladesh, and Haiti have indicated that the causes of malnutrition are multi-faceted, with both environmental and dietary factors contributing to malnutrition risk in young children [12]. Diet and disease have been identified as primary immediate determinants; with household food security, access to health facilities, healthy environment, and childcare practices influenced by socio-economic conditions [13]. Mother’s antenatal visit and body mass index were also identified as risk factors for malnutrition [14]. In children under 3 years of age some of the main factors included poor nutrition, feeding practices, education and occupation of parent/caregiver, residence, household income, nutrition knowledge of mother [15]. These studies have suggested that nutrition education for the mother is important, as it is a resource that mothers can utilize for better care of their children. It can also provide the necessary skills required for childcare, improvement of her feeding practices, enable her to make choices and have preference of health facilities available, increase her nutritional needs awareness, and give her the chance of changing her beliefs regarding medicine and disease [16]. Some of the nutritional interventions that have had some success in addressing malnutrition include exclusive breastfeeding for the first 6 months of life, vitamin A supplementation, deworming, zinc treatment and rehydration salts for diarrhea, food fortification, and folic acid/iron for lactating and pregnant women, improvement of access to piped water and hygiene [17]. These interventions have positively influenced the development, growth and survival of children [18]. Malnutrition is not a uniform condition and therefore groups and areas that experience high risk of malnutrition must be identified and targeted interventions available to assist [17].
\nTo determine both over and undernutrition, assessment of the nutritional status is important. This identifies those individuals who are vulnerable and at risk, and how to guide a response [19]. In determining the nutritional status of a child, it must be referenced in comparison to a healthy child [20]. Most of the anthropometric indices are used with reference tables such as that of the National Center for Health Statistics (NCHS) and the currently widely recommended and used 2006 WHO child growth standards [21]. In expressing anthropometric indices relative to a reference population, the measurements are developed using the median and standard deviations of the reference populations, which are known as Z scores [22, 23, 24]. The Z score classification system interprets weight for age (W/A), weight for height (W/H) and height for age (H/A). Z scores describe a child’s mid upper arm circumference (MUAC)/weight/height in comparison to the median and the mid upper arm circumference (MUAC)/weight/height of the child relative to the reference population [25]. The anthropometric value is expressed by the two score system as “a number of standard deviations or Z scores below or above the reference mean or median value” [26]. Thus, the Z score is calculated as follows:
\nAs previously mentioned malnutrition consists of both over and undernutrition (Table 1).
\nUndernutrition does not only affect the health of individuals but impacts greatly on the growth of the economy and productivity, as well as the eradication of poverty. To support their growth and development, infants and young children have increased nutritional needs and therefore are most affected by undernutrition [27, 28]. Prolonged malnourished status in children can lead to the development of motor function and physical growth delays, lack of social skills, and low infection resistance, thus making them susceptible to common ailments and infections [28, 29]. Additionally, due to frequent infection, susceptible children become engaged in a negative cycle whereby infections lead to growth delays and their learning abilities are hindered, and infections in malnourished children may lead to childhood mortality [30].
\nUndernutrition is subdivided into two categories that include micronutrient malnutrition and growth failure. To differentiate between acute or chronic malnutrition, the nutritional status of an individual is assessed by using anthropometry [27]. According to Zere and McIntyre [31], anthropometry is advantageous over biochemical evaluation, as it is less invasive and cost effective; hence, in addressing child survival nutritional status anthropometry is one of the favored predictors [32]. To assess the growth status of children the most common indices used in anthropometry include low weight for height or wasting, stunting or low height for age, underweight or a low weight for age and waist/arm circumference.
\nIn PEM the condition is characterized by the individual being susceptible to infection due to long-term consumption of protein and energy that is insufficient to meet the body’s needs. While the body may first attempt to utilize the nutrients to meet the energy demands, if there is insufficient intake of energy then the consumed protein is used to meet the energy demands and does not address the functions of the protein in the body, hence leading to PEM. While PEM requires the measuring of growth parameters such as height and weight as it is not immediately obvious, in severe PEM children present with marasmus and kwashiorkor [33, 34]. Marasmus is characterized by a lack of protein and energy in the diet, while an inadequate intake of protein causes kwashiorkor. Marasmus or severe wasting (below −3SD) presents with a MUAC less than 115 mm in children under age five. Children with marasmus present with an “old man” appearance and are very thin [33]. In kwashiorkor, a child does not necessarily appear as undernourished but there is the presence of oedema. The children present with hair that is discolored and skin that is shiny and very tight. The weight for height is greater than or equal to −2SD. In marasmic-kwashiorkor bilateral oedema is present, with a weight for height less than −2SD [33, 34, 35].
\nA common presentation of PEM in children is underweight. Underweight is seen as children having a weight for age with a Z score of −2SD, with severe underweight at −3SD [36, 37]. Since proteins and/or energy are insufficient in a diet, there is weight loss or failure to gain weight. This can be accompanied by a decline in linear height [38]. While the children may present with normal body proportions such as weight to height ratios, they will be undersized and underweight [39]. Through regular monitoring of growth indices such as height and weight, underweight can be identified at an early stage [26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39]. In 2013, 99 million children less than 5 years of age were underweight. Of this figure, one third of the children were from Africa and two-thirds present in Asia. An estimated 14.6% of newborns were with low birth weight in 2015, and approximately nine out of 10 of the newborns were from low and middle income countries (LMICs). Approximately 45% of deaths in LMICs in children under age five is due to underweight. In adolescent girls the underweight prevalence increased from 5.5% in 2000 to 5.7% in 2016 [40].
\nStunting is a major public health concern that begins in intrauterine life although children are only classified as stunted at approximately age 2 years. The detrimental effects of stunting include intrauterine growth retardation, as well as inadequate nutrition required for growth and development of children [41]. High frequency of infection and decreased disease resistance such as diarrhea and pneumonia are influenced by stunting. Childhood stunting may also lead to increased mortality, poor recovery from disease and is also an obesity risk factor in adulthood [41, 42]. Stunting causes growth impairment during childhood that is associated with increased cardio-metabolic disease and obesity risk and cognitive development delay in adulthood [43]. This creates both short and long term effects that indicate the importance of stunting being identified and monitored in early life [42].
\nIn children the initial 1000 days of life are an important window period for intervention implementation and tracking for the improvement of child growth and development [7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44]. Often stunting is correlated with poor socio-economic status, as well as environmental conditions surveys in South Africa (SA) have identified an increased stunting prevalence in black people compared to their Indian or white counterparts [31]. Some surveys looked at a wider age range of children (0–14 years) and higher stunting prevalence was found in children living informal settlements within urban and rural areas [36, 37, 38, 39, 40, 41, 42, 43, 44, 45].
\nIn stunting or low height for age the Z score is below 2 standard deviations [21]. It is prevalent usually in infants and children younger than 5 years [36], who are susceptible to infection and have an insufficient intake of nutrients over the long term. Low height for age is seen as the failure of an individual to reach full linear growth and if stunting occurs before age two then irreversible poor cognitive and motor developments may occur [41]. Severe stunting is indicated by a height for age that is lesser than the median by 85% to represent a standard deviation of −3SD [46]. In 2013 in children under 5 years of age, 161 million were identified as stunted globally. The trend of global decrease were evident from the period 2000–2013, during which figures declined from 199 million to 161 million (33–25%). However, one third of stunted children were still found in Africa [47]. During 2000–2018 the number and proportion of stunted children under age five rose by 6.5 million in Central and Western Africa and by 1.4 million in Southern and Eastern Africa. Thus, the stunting burden continues to escalate in Africa, creating serious human capital development complications [40].
\nIn the last five decades overweight and obesity appears to be reaching epidemic levels in both developing and developed countries [48, 49]. Eclipsing infectious disease and under-nutrition as a significant mortality and ill-health contributor, overweight and obesity have presented as the most prevalent global nutritional problem over the last two decades. Globally an estimated 1 billion adults are overweight, with 300 million of them being obese [49]. An estimated 155 million obese children contribute to this epidemic [50]. Obese children tend to become obese adults. Obesity-related health problems occur in early years of life and progress into adulthood [51]. Several chronic disease conditions in later life are associated with childhood obesity. These chronic diseases include diabetes, stroke, high blood pressure, cancers and heart disease [52]. Despite the increased prevalence of overweight and obesity in children, research evaluating treatment in these age groups is minimal. Middle-income countries such as South Africa (SA), Brazil and China have increased overweight and obesity rates across all age groups and economic levels [49]. However, over the last few years overweight has increased in every continent. It has been postulated that the number of overweight children under age five will rise from over 40 million to approximately 43 million by 2025 [53]. As of 2018, approximately half of the overweight under five children were in Asia, with a quarter in Africa. Between 2000 and 2018 in Africa, the number of overweight under five children rose by just under 44%. In children and adolescents aged 5–19 years old, the proportion of overweight in 2000 rose from one in 10 (10.3%) to just under one in five (18.4%) in 2016 [40].
\nSome developing countries such as SA are currently facing a nutrition transition with the dual burden of over and undernutrition. This nutrition transition is the replacement of traditional home cooked balanced diet meals by energy-dense foods, as well as sedentary lifestyles due to technology and urbanization. A review study highlighted the dual burden in SA in children aged 0–20 years. The prevalence of wasting and stunting was higher in younger male children and predominant in rural areas, whereas overweight/obesity prevalence was highest in females and children in urban settings. It is important for tracking of over and undernutrition in children at a district level that can also be used to prioritize, monitor and evaluate government policies regarding malnutrition [54]. More recent years have seen the double burden of malnutrition being accompanied by a triple burden of malnutrition, affecting families, communities and countries. In countries such as India and Egypt, the problem is increasing and therefore highlights the urgent need to consider child malnutrition in the greater familial and household contexts [40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55]. A study in Ghana addressed the concurrent occurrence of obesity and stunting in children aged under 5 years, providing data for the first time on such an occurrence. The study reported a stunting prevalence of 27.5%, overweight prevalence of 2.4% and an overall concurrent stunting and overweight prevalence of 1.2% [56]. A study in South Africa, with children aged 6–12 years old, reported that 9.1% were stunted, while 14.9% were overweight/obese [57]. This highlights the need for urgent targeted interventions in children to address this double burden to prevent these malnutrition issues as they transition into adulthood.
\nIn wasting or low weight for height the Z score is below 2 standard deviations [21]. Wasting is reflective of a body mass that is low in comparison to the age and may be due to disease or starvation. Weight loss and retardation of growth occur due to inadequate intake of food and long term it leads to wasting and becomes more severe with emaciation [58]. A child falls behind another child who is growing actively when his/her own growth is affected acutely [38], and the body height and weight become less than ideal for the age of the child [59]. Severe wasting occurs when the weight for height is less than the median by 70% to represent a standard deviation of −3SD [46]. According to the national Department of Health (DoH) height measurements in all children should be conducted at least every 3 months [60]. In measuring overall growth to compare growth standards, both height and weight measurements are essential. Globally, in 2013, in children less than 5 years of age, 51 million were wasted and 17 million severely wasted. Global wasting prevalence in 2013 approximated 8%, of which 3% accounted for severe wasting. A postulated third of wasted children were present in Africa and an estimate of the children severely wasted in Africa followed the same trend [61]. As of 2018–2019 52 million children are wasted, with an estimated 16.6 suffering from severe wasting in 2018 [62]. Children left untreated with severe acute malnutrition (SAM) are at least 12 times more likely to die than healthy children [63]. South Asia is the global wasting epicenter as 15.2% of children under five are wasted. Together with other hotspots such as Oceania, Southeast Asia and SSA, improvements regarding wasting are minimal [64] (Table 2).
\n\nClassification | \nZ score values | \n
---|---|
Adequately nourished | \n−2 < Z-score < +1 | \n
Moderately malnourished | \n−3 < Z-score < −2 | \n
Severely malnourished | \nZ-score < −3 | \n
Malnutrition classification of children based on Z scores [20].
Country | \nYear of last survey | \nWasting | \nOverweight | \nStunting | \nUnderweight | \n
---|---|---|---|---|---|
Angola | \n2015–2016 | \n4.9 | \n3.4 | \n37.6 | \n19.0 | \n
Benin | \n2017–2018 | \n5.0 | \n1.9 | \n32.2 | \n16.8 | \n
Botswana | \n2007–2008 | \n7.2 | \n11.2 | \n31.4 | \n11.2 | \n
Burkina Faso | \n2017 | \n8.6 | \n1.7 | \n21.1 | \n16.2 | \n
Burundi | \n2016–2017 | \n5.1 | \n1.4 | \n55.9 | \n29.3 | \n
Cabo Verde | \n1994 | \n6.9 | \n— | \n21.4 | \n11.8 | \n
Cameroon | \n2014 | \n5.2 | \n6.7 | \n31.7 | \n14.8 | \n
Central African Republic | \n2012 | \n7.6 | \n1.9 | \n39.6 | \n24.6 | \n
Chad | \n2014–2015 | \n13.3 | \n2.8 | \n39.8 | \n29.4 | \n
Comoros | \n2012 | \n11.3 | \n10.6 | \n31.1 | \n16.9 | \n
The Congo | \n2014–2015 | \n8.2 | \n5.9 | \n21.2 | \n12.3 | \n
Cote d’Ivoire | \n2016 | \n6.1 | \n1.5 | \n21.6 | \n12.8 | \n
Democratic Republic of Congo | \n2013–2014 | \n8.1 | \n4.4 | \n42.7 | \n23.4 | \n
Djibouti | \n2012 | \n21.6 | \n8.1 | \n33.5 | \n29.9 | \n
Equatorial Guinea | \n2011 | \n3.1 | \n9.7 | \n26.2 | \n5.6 | \n
Eritrea | \n2010 | \n15.3 | \n2.0 | \n52.0 | \n39.4 | \n
Eswatini (former Swaziland) | \n2014 | \n2.0 | \n9.0 | \n25.5 | \n5.8 | \n
Ethiopia | \n2016 | \n10.0 | \n2.9 | \n38.4 | \n23.6 | \n
Gabon | \n2012 | \n3.4 | \n7.7 | \n17.0 | \n6.4 | \n
The Gambia | \n2013 | \n11.0 | \n3.2 | \n24.6 | \n16.5 | \n
Ghana | \n2014 | \n4.7 | \n2.6 | \n18.8 | \n11.2 | \n
Guinea | \n2016 | \n8.1 | \n4.0 | \n32.4 | \n18.3 | \n
Guinea—Bissau | \n2014 | \n6.0 | \n2.3 | \n27.6 | \n17.0 | \n
Kenya | \n2014 | \n4.2 | \n4.1 | \n26.2 | \n11.2 | \n
Lesotho | \n2014 | \n2.8 | \n7.5 | \n33.4 | \n10.5 | \n
Liberia | \n2013 | \n5.6 | \n3.2 | \n32.1 | \n15.3 | \n
Madagascar | \n2012–2013 | \n7.9 | \n1.1 | \n48.9 | \n32.9 | \n
Malawi | \n2015–2016 | \n2.8 | \n4.6 | \n37.4 | \n11.8 | \n
Mali | \n2015 | \n13.5 | \n1.9 | \n30.4 | \n25.0 | \n
Mauritania | \n2015 | \n14.8 | \n1.3 | \n27.9 | \n24.9 | \n
Mauritius | \n1995 | \n15.7 | \n6.5 | \n13.6 | \n13.0 | \n
Mozambique | \n2011 | \n6.1 | \n7.8 | \n42.9 | \n15.6 | \n
Namibia | \n2013 | \n7.1 | \n4.0 | \n22.7 | \n13.2 | \n
Niger | \n2016 | \n10.1 | \n1.1 | \n40.6 | \n31.4 | \n
Nigeria | \n2016–2017 | \n10.8 | \n1.5 | \n43.6 | \n31.5 | \n
Rwanda | \n2014–2015 | \n2.3 | \n7.9 | \n38.2 | \n9.6 | \n
Sao Tome and Principe | \n2014 | \n4.0 | \n2.4 | \n17.2 | \n8.8 | \n
Senegal | \n2017 | \n9.0 | \n0.9 | \n16.5 | \n14.4 | \n
Seychelles | \n2012 | \n4.3 | \n10.2 | \n7.9 | \n3.6 | \n
Sierra Leone | \n2013 | \n9.5 | \n8.8 | \n37.8 | \n18.2 | \n
Somalia | \n2009 | \n15.0 | \n3.0 | \n25.3 | \n23.0 | \n
South Africa | \n2016 | \n2.5 | \n13.3 | \n27.4 | \n5.9 | \n
South Sudan | \n2010 | \n24.3 | \n5.8 | \n31.3 | \n29.1 | \n
Togo | \n2013–2014 | \n6.6 | \n2.0 | \n27.6 | \n16.1 | \n
Uganda | \n2016 | \n3.5 | \n3.7 | \n28.9 | \n10.4 | \n
United Republic of Tanzania | \n2015–16 | \n4.5 | \n3.7 | \n34.5 | \n13.7 | \n
Zambia | \n2013–14 | \n6.2 | \n6.2 | \n40.0 | \n14.9 | \n
Zimbabwe | \n2015 | \n3.3 | \n5.6 | \n27.1 | \n8.5 | \n
Joint malnutrition country estimates of anthropometric indicators in children aged 0–59 months [65].
As a developing or middle-income country, SA is still undergoing major transitions socially, economically and in the population’s health. The country is currently facing a quadruple disease burden, with non-communicable diseases linked to diet and lifestyle; the burden of Human Immunodeficiency Virus/Acquired immunodeficiency syndrome (HIV/AIDS); infectious diseases and poverty linked to under nutrition; and deaths due to injuries [66]. As a developing country SA is in a nutrition transition where both over and undernutrition coexist [67]. The first 2 years of life are a vulnerable time frame as it is during this period that malnutrition begins. According to Faber and Wenhold [68], chronic malnutrition or stunting is more prevalent in children in SA compared to wasting. Since the post-apartheid era in 1994, SA has faced great challenges in addressing the nutritional status of infants, young children and adults [69]. However, large-scale nationwide surveys were conducted to trace the progress, failures and successes in addressing malnutrition. In 1994 the South African Vitamin A Consultative Group (SAVACG) conducted a national survey on the nutritional status of children aged 6–71 months [70]. Anthropometric results revealed that approximately 10% or 660,000 children were underweight, with one in every four children (1.5 million) affected by stunting. Severe wasting was only recorded in 0.4% of children. KwaZulu-Natal (KZN), Eastern Cape and Northern Province revealed the greatest prevalence of malnutrition [70]. In 1999 the National Food Consumption Survey (NFCS) was conducted in children aged 1–9 years [71], collecting a larger set of data in comparison to the SAVACG survey. The NFCS reported 10% underweight in children, with 20% affected by stunting and 17.1% as overweight and/or obese. The NFCS secondary analysis, focusing on children aged 1–5 years, reported underweight at 6.8%, stunting at 20.1%, overweight at 20.6% and obesity at 9.5% [69]. In 2005, the National Food Consumption Survey-Fortification Baseline (NFCS-FB) reported that of children aged 1–9 years old, 20% were affected by stunting, 9.3% were underweight, wasting was found in 4.5%, and 14% were overweight or obese [72]. The South African National Health and Nutrition Examination Survey (SANHANES) conducted in 2012 reported that in children aged 0–14 years stunting prevalence was 15.4%, with 3.8% having severe stunting. Wasting was reported at 2.9%, with severe wasting at 0.8%. Underweight was reported at 5.8%, with severe underweight at 1.1%. Regarding over nutrition, SANHANES identified 18.1% of children as overweight and 4.6% as obese [36]. The prevalence of overweight and obesity was significantly greater in females (25% and 40.1%) compared to males (19.6% and 11.6%) respectively. Underweight was significantly higher in males (13.1%) in comparison to females (4.0%) [36]. Thus, it is evident that SA is facing the malnutrition epidemic at a young age and context-specific and targeted interventions are required to prevent child malnutrition before it progresses into adulthood.
\nDuring 2012–2013, WHO member states recognized the seriousness of malnutrition and its effect on global health [3]. Thus, at the United Nation’s General Assembly in 2016, the United Nations Decade of Action on Nutrition 2016–2025 was announced. This set a time frame for all forms of malnutrition to be addressed and for diet-related and nutrition targets to be met by 2025. This also set the time frame for the Sustainable Development Goals (SGDs) to be achieved before 2030, particularly SDG 2 that aims to improve nutrition, achieve food security and end hunger, as well as SDG 3 that aims to ensure healthy living and promote well-being for all [1]. To tackle the malnutrition epidemic food fortification is important to ensure that children with good weight do not risk becoming overweight or obese [73]. All malnutrition indicators must be included in interventions, and more importantly treated together rather than stand-alone issues [74]. As part of the health system strengthening and with the goal of combatting malnutrition, existing policies on child malnutrition must be evaluated. The coexistence of stunting and overweight/obesity remains a challenge in LMICs that requires multi-sectoral action. During infancy and early childhood optimal nutrition is vital to ensure that, development and rapid growth demands are met. In the efforts to tackle the nutrition disparities, the first 1000 days of life are an important window period, presenting the opportunity to prevent both stunting and overweight/obesity [75]. Interventions must be inclusive of both linear growth and appropriate weight, beginning in early life and preferably during this important window period. To further tackle the double and triple burdens of malnutrition, early screening and identification of at risk children, including those already with malnutrition, is essential at healthcare facilities [76]. Thus, a more holistic, context-specific approach is required, whereby interventions not only take into consideration the risk factors, but also consider the inclusion of nutritionists and educating mothers on self and childcare regarding nutrition [77]. Furthermore, child malnutrition research and interventions must be up-scaled from community level to provincial and national levels so that it informs policy on the intervention strategies that can address the burden of child malnutrition. This is vital as children left untreated transition into malnourished adulthood, increasing the healthcare costs and needs, weakening the healthcare systems, and perpetuating the vicious malnutrition cycle.
\nAs this section deals with legal issues pertaining to the rights of individual Authors and IntechOpen, for the avoidance of doubt, each category of publication is dealt with separately. Consequently, much of the information, for example definition of terms used, is repeated to ensure that there can be no misunderstanding of the policies that apply to each category.
",metaTitle:"Copyright Policy",metaDescription:"Copyright is the term used to describe the rights related to the publication and distribution of original works. Most importantly from a publisher's perspective, copyright governs how authors, publishers and the general public can use, publish and distribute publications.",metaKeywords:null,canonicalURL:"/page/copyright-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\\n\\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\\n\\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\\n\\nAgreement samples are listed here for the convenience of prospective Authors:
\\n\\n\\n\\nDEFINITIONS
\\n\\nThe following definitions apply in this Copyright Policy:
\\n\\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\\n\\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\\n\\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\\n\\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\\n\\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\\n\\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\\n\\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\\n\\nTERMS
\\n\\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\\n\\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\\n\\nAnd for any purpose, provided the following conditions are met:
\\n\\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\\n\\n\\n\\n
LICENSE | \\n\\t\\t\\tUSED FROM - | \\n\\t\\t\\tUP TO - | \\n\\t\\t
\\n\\t\\t\\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \\n\\t\\t\\t | \\n\\t\\t\\t\\n\\t\\t\\t 1 July 2005 (2005-07-01) \\n\\t\\t\\t | \\n\\t\\t\\t\\n\\t\\t\\t 3 October 2011 (2011-10-03) \\n\\t\\t\\t | \\n\\t\\t
Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \\n\\t\\t\\t\\n\\t\\t\\t 5 October 2011 (2011-10-05) \\n\\t\\t\\t | \\n\\t\\t\\tCurrently | \\n\\t\\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\\n\\nContent reuse:
\\n\\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\\n\\nContent adaptation & reuse:
\\n\\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\\n\\nReposting & sharing:
\\n\\nOriginally published in {full citation}. Available from: {DOI}
\\n\\nRepublishing – More about Attribution Policy can be found here.
\\n\\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\\n\\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\\n\\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\\n\\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\\n\\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\\n\\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\\n\\nUnder the following terms:
\\n\\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\\n\\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\\n\\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\\n\\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\\n\\nContent reuse:
\\n\\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\\n\\nContent adaptation & reuse:
\\n\\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\\n\\nReposting & sharing:
\\n\\nOriginally published in {full citation}. Available from: {DOI}
\\n\\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\\n\\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\\n\\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\\n\\nShare — copy and redistribute the material in any medium or format
\\n\\nUnder the following terms:
\\n\\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\\n\\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\\n\\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\\n\\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\\n\\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\\n\\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\\n\\nPolicy last updated: 2016-06-08
\\n"}]'},components:[{type:"htmlEditorComponent",content:'Copyright is the term used to describe the rights related to the publication and distribution of original Works. Most importantly from a publisher's perspective, copyright governs how Authors, publishers and the general public can use, publish, and distribute publications.
\n\nIntechOpen only publishes manuscripts for which it has publishing rights. This is governed by a publication agreement between the Author and IntechOpen. This agreement is accepted by the Author when the manuscript is submitted and deals with both the rights of the publisher and Author, as well as any obligations concerning a particular manuscript. However, in accepting this agreement, Authors continue to retain significant rights to use and share their publications.
\n\nHOW COPYRIGHT WORKS WITH OPEN ACCESS LICENSES?
\n\nAgreement samples are listed here for the convenience of prospective Authors:
\n\n\n\nDEFINITIONS
\n\nThe following definitions apply in this Copyright Policy:
\n\nAuthor - in order to be identified as an Author, three criteria must be met: (i) Substantial contribution to the conception or design of the Work, or the acquisition, analysis, or interpretation of data for the Work; (ii) Participation in drafting or revising the Work; (iii) Approval of the final version of the Work to be published.
\n\nWork - a Chapter, including Conference Papers, and any and all text, graphics, images and/or other materials forming part of or accompanying the Chapter/Conference Paper.
\n\nMonograph/Compacts - a full manuscript usually written by a single Author, including any and all text, graphics, images and/or other materials.
\n\nCompilation - a collection of Works distributed in a Book that IntechOpen has selected, and for which the coordination of the preparation, arrangement and publication has been the responsibility of IntechOpen. Any Work included is accepted in its entirety in unmodified form and is published with one or more other contributions, each constituting a separate and independent Work, but which together are assembled into a collective whole.
\n\nIntechOpen - Registered publisher with office at 5 Princes Gate Court, London, SW7 2QJ - UNITED KINGDOM
\n\nIntechOpen platform - IntechOpen website www.intechopen.com whose main purpose is to host Monographs in the format of Book Chapters, Long Form Monographs, Compacts, Conference Proceedings and Videos.
\n\nVideo Lecture – an audiovisual recording of a lecture or a speech given by a Lecturer, recorded, edited, owned and published by IntechOpen.
\n\nTERMS
\n\nAll Works published on the IntechOpen platform and in print are licensed under a Creative Commons Attribution 3.0 Unported License, a license which allows for the broadest possible reuse of published material.
\n\nCopyright on the individual Works belongs to the specific Author, subject to an agreement with IntechOpen. The Creative Common license is granted to all others to:
\n\nAnd for any purpose, provided the following conditions are met:
\n\nAll Works are published under the CC BY 3.0 license. However, please note that book Chapters may fall under a different CC license, depending on their publication date as indicated in the table below:
\n\n\n\n
LICENSE | \n\t\t\tUSED FROM - | \n\t\t\tUP TO - | \n\t\t
\n\t\t\t Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) \n\t\t\t | \n\t\t\t\n\t\t\t 1 July 2005 (2005-07-01) \n\t\t\t | \n\t\t\t\n\t\t\t 3 October 2011 (2011-10-03) \n\t\t\t | \n\t\t
Creative Commons Attribution 3.0 Unported (CC BY 3.0) | \n\t\t\t\n\t\t\t 5 October 2011 (2011-10-05) \n\t\t\t | \n\t\t\tCurrently | \n\t\t
The CC BY 3.0 license permits Works to be freely shared in any medium or format, as well as the reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as the source Work is cited and its Authors are acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nRepublishing – More about Attribution Policy can be found here.
\n\nThe same principles apply to Works published under the CC BY-NC-SA 3.0 license, with the caveats that (1) the content may not be used for commercial purposes, and (2) derivative works building on this content must be distributed under the same license. The restrictions contained in these license terms may, however, be waived by the copyright holder(s). Users wishing to circumvent any of the license terms are required to obtain explicit permission to do so from the copyright holder(s).
\n\nDISCLAIMER: Neither the CC BY 3.0 license, nor any other license IntechOpen currently uses or has used before, applies to figures and tables reproduced from other works, as they may be subject to different terms of reuse. In such cases, if the copyright holder is not noted in the source of a figure or table, it is the responsibility of the User to investigate and determine the exact copyright status of any information utilised. Users requiring assistance in that regard are welcome to send an inquiry to permissions@intechopen.com.
\n\nAll rights to Books and all other compilations published on the IntechOpen platform and in print are reserved by IntechOpen.
\n\nThe copyright to Books and other compilations is subject to separate copyright from those that exist in the included Works.
\n\nAll Long Form Monographs/Compacts are licensed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) license granted to all others.
\n\nCopyright to the individual Works (Chapters) belongs to their specific Authors, subject to an agreement with IntechOpen and the Creative Common license granted to all others to:
\n\nUnder the following terms:
\n\nThere must be an Attribution, giving appropriate credit, provision of a link to the license, and indication if any changes were made.
\n\nNonCommercial - The use of the material for commercial purposes is prohibited. Commercial rights are reserved to IntechOpen or its licensees.
\n\nNo additional restrictions that apply legal terms or technological measures that restrict others from doing anything the license permits are allowed.
\n\nThe CC BY-NC 4.0 license permits Works to be freely shared in any medium or format, as well as reuse and adaptation of the original contents of Works (e.g. figures and tables created by the Authors), as long as it is not used for commercial purposes. The source Work must be cited and its Authors acknowledged in the following manner:
\n\nContent reuse:
\n\n© {year} {authors' full names}. Originally published in {short citation} under {license version} license. Available from: {DOI}
\n\nContent adaptation & reuse:
\n\n© {year} {authors' full names}. Adapted from {short citation}; originally published under {license version} license. Available from: {DOI}
\n\nReposting & sharing:
\n\nOriginally published in {full citation}. Available from: {DOI}
\n\nAll Book cover design elements, as well as Video image graphics are subject to copyright by IntechOpen.
\n\nEvery reproduction of a front cover image must be accompanied by an appropriate Copyright Notice displayed adjacent to the image. The exact Copyright Notice depends on who the Author of a particular cover image is. Users wishing to reproduce cover images should contact permissions@intechopen.com.
\n\nAll Video Lectures under IntechOpen's production are subject to copyright and are property of IntechOpen, unless defined otherwise, and are licensed under the Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. This grants all others the right to:
\n\nShare — copy and redistribute the material in any medium or format
\n\nUnder the following terms:
\n\nUsers wishing to repost and share the Video Lectures are welcome to do so as long as they acknowledge the source in the following manner:
\n\n© {year} IntechOpen. Published under CC BY-NC-ND 4.0 license. Available from: {DOI}
\n\nUsers wishing to reuse, modify, or adapt the Video Lectures in a way not permitted by the license are welcome to contact us at permissions@intechopen.com to discuss waiving particular license terms.
\n\nAll software used on the IntechOpen platform, any used during the publishing process, and the copyright in the code constituting such software, is the property of IntechOpen or its software suppliers. As such, it may not be downloaded or copied without permission.
\n\nUnless otherwise indicated, all IntechOpen websites are the property of IntechOpen.
\n\nAll content included on IntechOpen Websites not forming part of contributed materials (such as text, images, logos, graphics, design elements, videos, sounds, pictures, trademarks, etc.), are subject to copyright and are property of, or licensed to, IntechOpen. Any other use, including the reproduction, modification, distribution, transmission, republication, display, or performance of the content on this site is strictly prohibited.
\n\nPolicy last updated: 2016-06-08
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5774},{group:"region",caption:"Middle and South America",value:2,count:5239},{group:"region",caption:"Africa",value:3,count:1721},{group:"region",caption:"Asia",value:4,count:10411},{group:"region",caption:"Australia and Oceania",value:5,count:897},{group:"region",caption:"Europe",value:6,count:15810}],offset:12,limit:12,total:118377},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"1",sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"10231",title:"Proton Therapy",subtitle:null,isOpenForSubmission:!0,hash:"f4a9009287953c8d1d89f0fa9b7597b0",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10231.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10652",title:"Visual Object Tracking",subtitle:null,isOpenForSubmission:!0,hash:"96f3ee634a7ba49fa195e50475412af4",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10652.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10653",title:"Optimization Algorithms",subtitle:null,isOpenForSubmission:!0,hash:"753812dbb9a6f6b57645431063114f6c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10653.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10655",title:"Motion Planning",subtitle:null,isOpenForSubmission:!0,hash:"809b5e290cf2dade9e7e0a5ae0ef3df0",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10655.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10657",title:"Service Robots",subtitle:null,isOpenForSubmission:!0,hash:"5f81b9eea6eb3f9af984031b7af35588",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10657.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10662",title:"Pedagogy",subtitle:null,isOpenForSubmission:!0,hash:"c858e1c6fb878d3b895acbacec624576",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10662.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10673",title:"The Psychology of Trust",subtitle:null,isOpenForSubmission:!0,hash:"1f6cac41fd145f718ac0866264499cc8",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10673.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10675",title:"Hydrostatics",subtitle:null,isOpenForSubmission:!0,hash:"c86c2fa9f835d4ad5e7efd8b01921866",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10675.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10677",title:"Topology",subtitle:null,isOpenForSubmission:!0,hash:"85eac84b173d785f989522397616124e",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10677.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10678",title:"Biostatistics",subtitle:null,isOpenForSubmission:!0,hash:"f63db439474a574454a66894db8b394c",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10678.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10679",title:"Mass Production",subtitle:null,isOpenForSubmission:!0,hash:"2dae91102099b1a07be1a36a68852829",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10679.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10689",title:"Risk Management in Construction",subtitle:null,isOpenForSubmission:!0,hash:"e3805b3d2fceb9d33e1fa805687cd296",slug:null,bookSignature:"",coverURL:"https://cdn.intechopen.com/books/images_new/10689.jpg",editedByType:null,editors:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:6},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:6},{group:"topic",caption:"Business, Management and Economics",value:7,count:4},{group:"topic",caption:"Chemistry",value:8,count:1},{group:"topic",caption:"Computer and Information Science",value:9,count:5},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:3},{group:"topic",caption:"Engineering",value:11,count:4},{group:"topic",caption:"Environmental Sciences",value:12,count:4},{group:"topic",caption:"Immunology and Microbiology",value:13,count:2},{group:"topic",caption:"Mathematics",value:15,count:2},{group:"topic",caption:"Medicine",value:16,count:26},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:3},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:3},{group:"topic",caption:"Robotics",value:22,count:4},{group:"topic",caption:"Social Sciences",value:23,count:3},{group:"topic",caption:"Technology",value:24,count:1}],offset:12,limit:12,total:81},popularBooks:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5249},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.jpg",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9644",title:"Glaciers and the Polar Environment",subtitle:null,isOpenForSubmission:!1,hash:"e8cfdc161794e3753ced54e6ff30873b",slug:"glaciers-and-the-polar-environment",bookSignature:"Masaki Kanao, Danilo Godone and Niccolò Dematteis",coverURL:"https://cdn.intechopen.com/books/images_new/9644.jpg",editors:[{id:"51959",title:"Dr.",name:"Masaki",middleName:null,surname:"Kanao",slug:"masaki-kanao",fullName:"Masaki Kanao"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9243",title:"Coastal Environments",subtitle:null,isOpenForSubmission:!1,hash:"8e05e5f631e935eef366980f2e28295d",slug:"coastal-environments",bookSignature:"Yuanzhi Zhang and X. San Liang",coverURL:"https://cdn.intechopen.com/books/images_new/9243.jpg",editedByType:"Edited by",editors:[{id:"77597",title:"Prof.",name:"Yuanzhi",middleName:null,surname:"Zhang",slug:"yuanzhi-zhang",fullName:"Yuanzhi Zhang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10020",title:"Operations Management",subtitle:"Emerging Trend in the Digital Era",isOpenForSubmission:!1,hash:"526f0dbdc7e4d85b82ce8383ab894b4c",slug:"operations-management-emerging-trend-in-the-digital-era",bookSignature:"Antonella Petrillo, Fabio De Felice, Germano Lambert-Torres and Erik Bonaldi",coverURL:"https://cdn.intechopen.com/books/images_new/10020.jpg",editedByType:"Edited by",editors:[{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9521",title:"Antimicrobial Resistance",subtitle:"A One Health Perspective",isOpenForSubmission:!1,hash:"30949e78832e1afba5606634b52056ab",slug:"antimicrobial-resistance-a-one-health-perspective",bookSignature:"Mihai Mareș, Swee Hua Erin Lim, Kok-Song Lai and Romeo-Teodor Cristina",coverURL:"https://cdn.intechopen.com/books/images_new/9521.jpg",editedByType:"Edited by",editors:[{id:"88785",title:"Prof.",name:"Mihai",middleName:null,surname:"Mares",slug:"mihai-mares",fullName:"Mihai Mares"}],equalEditorOne:{id:"190224",title:"Dr.",name:"Swee Hua Erin",middleName:null,surname:"Lim",slug:"swee-hua-erin-lim",fullName:"Swee Hua Erin Lim",profilePictureURL:"https://mts.intechopen.com/storage/users/190224/images/system/190224.png",biography:"Dr. Erin Lim is presently working as an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates and is affiliated as an Associate Professor to Perdana University-Royal College of Surgeons in Ireland, Selangor, Malaysia. She obtained her Ph.D. from Universiti Putra Malaysia in 2010 with a National Science Fellowship awarded from the Ministry of Science, Technology and Innovation Malaysia and has been actively involved in research ever since. Her main research interests include analysis of carriage and transmission of multidrug resistant bacteria in non-conventional settings, besides an interest in natural products for antimicrobial testing. She is heavily involved in the elucidation of mechanisms of reversal of resistance in bacteria in addition to investigating the immunological analyses of diseases, development of vaccination and treatment models in animals. She hopes her work will support the discovery of therapeutics in the clinical setting and assist in the combat against the burden of antibiotic resistance.",institutionString:"Abu Dhabi Women’s College",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Perdana University",institutionURL:null,country:{name:"Malaysia"}}},equalEditorTwo:{id:"221544",title:"Dr.",name:"Kok-Song",middleName:null,surname:"Lai",slug:"kok-song-lai",fullName:"Kok-Song Lai",profilePictureURL:"https://mts.intechopen.com/storage/users/221544/images/system/221544.jpeg",biography:"Dr. Lai Kok Song is an Assistant Professor in the Division of Health Sciences, Abu Dhabi Women\\'s College, Higher Colleges of Technology in Abu Dhabi, United Arab Emirates. He obtained his Ph.D. in Biological Sciences from Nara Institute of Science and Technology, Japan in 2012. Prior to his academic appointment, Dr. Lai worked as a Senior Scientist at the Ministry of Science, Technology and Innovation, Malaysia. His current research areas include antimicrobial resistance and plant-pathogen interaction. His particular interest lies in the study of the antimicrobial mechanism via membrane disruption of essential oils against multi-drug resistance bacteria through various biochemical, molecular and proteomic approaches. Ultimately, he hopes to uncover and determine novel biomarkers related to antibiotic resistance that can be developed into new therapeutic strategies.",institutionString:"Higher Colleges of Technology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"8",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Higher Colleges of Technology",institutionURL:null,country:{name:"United Arab Emirates"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9560",title:"Creativity",subtitle:"A Force to Innovation",isOpenForSubmission:!1,hash:"58f740bc17807d5d88d647c525857b11",slug:"creativity-a-force-to-innovation",bookSignature:"Pooja Jain",coverURL:"https://cdn.intechopen.com/books/images_new/9560.jpg",editedByType:"Edited by",editors:[{id:"316765",title:"Dr.",name:"Pooja",middleName:null,surname:"Jain",slug:"pooja-jain",fullName:"Pooja Jain"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9669",title:"Recent Advances in Rice Research",subtitle:null,isOpenForSubmission:!1,hash:"12b06cc73e89af1e104399321cc16a75",slug:"recent-advances-in-rice-research",bookSignature:"Mahmood-ur- Rahman Ansari",coverURL:"https://cdn.intechopen.com/books/images_new/9669.jpg",editedByType:"Edited by",editors:[{id:"185476",title:"Dr.",name:"Mahmood-Ur-",middleName:null,surname:"Rahman Ansari",slug:"mahmood-ur-rahman-ansari",fullName:"Mahmood-Ur- Rahman Ansari"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10192",title:"Background and Management of Muscular Atrophy",subtitle:null,isOpenForSubmission:!1,hash:"eca24028d89912b5efea56e179dff089",slug:"background-and-management-of-muscular-atrophy",bookSignature:"Julianna Cseri",coverURL:"https://cdn.intechopen.com/books/images_new/10192.jpg",editedByType:"Edited by",editors:[{id:"135579",title:"Dr.",name:"Julianna",middleName:null,surname:"Cseri",slug:"julianna-cseri",fullName:"Julianna Cseri"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9550",title:"Entrepreneurship",subtitle:"Contemporary Issues",isOpenForSubmission:!1,hash:"9b4ac1ee5b743abf6f88495452b1e5e7",slug:"entrepreneurship-contemporary-issues",bookSignature:"Mladen Turuk",coverURL:"https://cdn.intechopen.com/books/images_new/9550.jpg",editedByType:"Edited by",editors:[{id:"319755",title:"Prof.",name:"Mladen",middleName:null,surname:"Turuk",slug:"mladen-turuk",fullName:"Mladen Turuk"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10065",title:"Wavelet Theory",subtitle:null,isOpenForSubmission:!1,hash:"d8868e332169597ba2182d9b004d60de",slug:"wavelet-theory",bookSignature:"Somayeh Mohammady",coverURL:"https://cdn.intechopen.com/books/images_new/10065.jpg",editedByType:"Edited by",editors:[{id:"109280",title:"Dr.",name:"Somayeh",middleName:null,surname:"Mohammady",slug:"somayeh-mohammady",fullName:"Somayeh Mohammady"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9313",title:"Clay Science and Technology",subtitle:null,isOpenForSubmission:!1,hash:"6fa7e70396ff10620e032bb6cfa6fb72",slug:"clay-science-and-technology",bookSignature:"Gustavo Morari Do Nascimento",coverURL:"https://cdn.intechopen.com/books/images_new/9313.jpg",editedByType:"Edited by",editors:[{id:"7153",title:"Prof.",name:"Gustavo",middleName:null,surname:"Morari Do Nascimento",slug:"gustavo-morari-do-nascimento",fullName:"Gustavo Morari Do Nascimento"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",isOpenForSubmission:!1,hash:"c2c8773e586f62155ab8221ebb72a849",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"166",title:"Statistics",slug:"mathematics-statistics",parent:{title:"Mathematics",slug:"mathematics"},numberOfBooks:10,numberOfAuthorsAndEditors:148,numberOfWosCitations:86,numberOfCrossrefCitations:93,numberOfDimensionsCitations:161,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"mathematics-statistics",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"9218",title:"Bayesian Inference on Complicated Data",subtitle:null,isOpenForSubmission:!1,hash:"5cf83c23db5b0ae47192d34ec8091162",slug:"bayesian-inference-on-complicated-data",bookSignature:"Niansheng Tang",coverURL:"https://cdn.intechopen.com/books/images_new/9218.jpg",editedByType:"Edited by",editors:[{id:"221831",title:"Prof.",name:"Niansheng",middleName:null,surname:"Tang",slug:"niansheng-tang",fullName:"Niansheng Tang"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7680",title:"Statistical Methodologies",subtitle:null,isOpenForSubmission:!1,hash:"b9ba6b053350f5e59925bce32b1d692d",slug:"statistical-methodologies",bookSignature:"Jan Peter Hessling",coverURL:"https://cdn.intechopen.com/books/images_new/7680.jpg",editedByType:"Edited by",editors:[{id:"20815",title:"Dr.",name:"Jan Peter",middleName:null,surname:"Hessling",slug:"jan-peter-hessling",fullName:"Jan Peter Hessling"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7372",title:"Bayesian Networks",subtitle:"Advances and Novel Applications",isOpenForSubmission:!1,hash:"ee81401d110a5f6bca2997a28e8d169b",slug:"bayesian-networks-advances-and-novel-applications",bookSignature:"Douglas McNair",coverURL:"https://cdn.intechopen.com/books/images_new/7372.jpg",editedByType:"Edited by",editors:[{id:"219757",title:"Dr.",name:"Douglas",middleName:null,surname:"McNair",slug:"douglas-mcnair",fullName:"Douglas McNair"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8362",title:"Time Series Analysis",subtitle:"Data, Methods, and Applications",isOpenForSubmission:!1,hash:"7e98dd03d921c19cc2324e91845d5160",slug:"time-series-analysis-data-methods-and-applications",bookSignature:"Chun-Kit Ngan",coverURL:"https://cdn.intechopen.com/books/images_new/8362.jpg",editedByType:"Edited by",editors:[{id:"227503",title:"Dr.",name:"Chun-Kit",middleName:null,surname:"Ngan",slug:"chun-kit-ngan",fullName:"Chun-Kit Ngan"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6703",title:"Statistics",subtitle:"Growing Data Sets and Growing Demand for Statistics",isOpenForSubmission:!1,hash:"f67636870f28cdf080018abaddd953d2",slug:"statistics-growing-data-sets-and-growing-demand-for-statistics",bookSignature:"Türkmen Göksel",coverURL:"https://cdn.intechopen.com/books/images_new/6703.jpg",editedByType:"Edited by",editors:[{id:"190299",title:"Dr.",name:"Türkmen",middleName:null,surname:"Göksel",slug:"turkmen-goksel",fullName:"Türkmen Göksel"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5856",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",subtitle:null,isOpenForSubmission:!1,hash:"950e8a681056d4b6bdc024121529d1ce",slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",bookSignature:"Valter Silva",coverURL:"https://cdn.intechopen.com/books/images_new/5856.jpg",editedByType:"Edited by",editors:[{id:"187136",title:"Dr.",name:"Valter",middleName:null,surname:"Silva",slug:"valter-silva",fullName:"Valter Silva"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5964",title:"Bayesian Inference",subtitle:null,isOpenForSubmission:!1,hash:"b05b9b63cb02573c7e0cc5e877e35c61",slug:"bayesian-inference",bookSignature:"Javier Prieto Tejedor",coverURL:"https://cdn.intechopen.com/books/images_new/5964.jpg",editedByType:"Edited by",editors:[{id:"177972",title:"Dr.",name:"Javier Prieto",middleName:null,surname:"Tejedor",slug:"javier-prieto-tejedor",fullName:"Javier Prieto Tejedor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5446",title:"Advances in Statistical Methodologies and Their Application to Real Problems",subtitle:null,isOpenForSubmission:!1,hash:"93e5e8e7a09c351b3e0377d6ac6ccc35",slug:"advances-in-statistical-methodologies-and-their-application-to-real-problems",bookSignature:"Tsukasa Hokimoto",coverURL:"https://cdn.intechopen.com/books/images_new/5446.jpg",editedByType:"Edited by",editors:[{id:"69561",title:"Dr.",name:"Tsukasa",middleName:null,surname:"Hokimoto",slug:"tsukasa-hokimoto",fullName:"Tsukasa Hokimoto"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3812",title:"Dynamic Programming and Bayesian Inference",subtitle:"Concepts and Applications",isOpenForSubmission:!1,hash:"f507023ddf3414519592ec0f0d6b25e3",slug:"dynamic-programming-and-bayesian-inference-concepts-and-applications",bookSignature:"Mohammad Saber Fallah Nezhad",coverURL:"https://cdn.intechopen.com/books/images_new/3812.jpg",editedByType:"Edited by",editors:[{id:"150393",title:"Dr.",name:"Mohammad Saber Fallah",middleName:null,surname:"Nezhad",slug:"mohammad-saber-fallah-nezhad",fullName:"Mohammad Saber Fallah Nezhad"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2155",title:"Bayesian Networks",subtitle:null,isOpenForSubmission:!1,hash:"2c08ecbb5580e47a9c16cdaec48c2adc",slug:"bayesian-networks",bookSignature:"Wichian Premchaiswadi",coverURL:"https://cdn.intechopen.com/books/images_new/2155.jpg",editedByType:"Edited by",editors:[{id:"10820",title:"Dr.",name:"Wichian",middleName:null,surname:"Premchaiswadi",slug:"wichian-premchaiswadi",fullName:"Wichian Premchaiswadi"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:10,mostCitedChapters:[{id:"59209",doi:"10.5772/intechopen.73690",title:"Utilization of Response Surface Methodology in Optimization of Extraction of Plant Materials",slug:"utilization-of-response-surface-methodology-in-optimization-of-extraction-of-plant-materials",totalDownloads:3648,totalCrossrefCites:20,totalDimensionsCites:28,book:{slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Alev Yüksel Aydar",authors:[{id:"218870",title:"Dr.",name:"Alev Yüksel",middleName:null,surname:"Aydar",slug:"alev-yuksel-aydar",fullName:"Alev Yüksel Aydar"}]},{id:"56460",doi:"10.5772/intechopen.69501",title:"Application of Taguchi-Based Design of Experiments for Industrial Chemical Processes",slug:"application-of-taguchi-based-design-of-experiments-for-industrial-chemical-processes",totalDownloads:2134,totalCrossrefCites:9,totalDimensionsCites:21,book:{slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Rahul Davis and Pretesh John",authors:[{id:"199438",title:"Mr.",name:"Rahul",middleName:null,surname:"Davis",slug:"rahul-davis",fullName:"Rahul Davis"}]},{id:"64216",doi:"10.5772/intechopen.81170",title:"CNN Approaches for Time Series Classification",slug:"cnn-approaches-for-time-series-classification",totalDownloads:2607,totalCrossrefCites:8,totalDimensionsCites:12,book:{slug:"time-series-analysis-data-methods-and-applications",title:"Time Series Analysis",fullTitle:"Time Series Analysis - Data, Methods, and Applications"},signatures:"Lamyaa Sadouk",authors:[{id:"257943",title:"Ph.D.",name:"Lamyaa",middleName:null,surname:"Sadouk",slug:"lamyaa-sadouk",fullName:"Lamyaa Sadouk"}]}],mostDownloadedChaptersLast30Days:[{id:"59209",title:"Utilization of Response Surface Methodology in Optimization of Extraction of Plant Materials",slug:"utilization-of-response-surface-methodology-in-optimization-of-extraction-of-plant-materials",totalDownloads:3659,totalCrossrefCites:20,totalDimensionsCites:28,book:{slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Alev Yüksel Aydar",authors:[{id:"218870",title:"Dr.",name:"Alev Yüksel",middleName:null,surname:"Aydar",slug:"alev-yuksel-aydar",fullName:"Alev Yüksel Aydar"}]},{id:"56460",title:"Application of Taguchi-Based Design of Experiments for Industrial Chemical Processes",slug:"application-of-taguchi-based-design-of-experiments-for-industrial-chemical-processes",totalDownloads:2142,totalCrossrefCites:9,totalDimensionsCites:21,book:{slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Rahul Davis and Pretesh John",authors:[{id:"199438",title:"Mr.",name:"Rahul",middleName:null,surname:"Davis",slug:"rahul-davis",fullName:"Rahul Davis"}]},{id:"56653",title:"Bayesian Hypothesis Testing: An Alternative to Null Hypothesis Significance Testing (NHST) in Psychology and Social Sciences",slug:"bayesian-hypothesis-testing-an-alternative-to-null-hypothesis-significance-testing-nhst-in-psycholog",totalDownloads:2607,totalCrossrefCites:7,totalDimensionsCites:8,book:{slug:"bayesian-inference",title:"Bayesian Inference",fullTitle:"Bayesian Inference"},signatures:"Alonso Ortega and Gorka Navarrete",authors:[{id:"203438",title:"Dr.",name:"Alonso",middleName:null,surname:"Ortega",slug:"alonso-ortega",fullName:"Alonso Ortega"},{id:"208842",title:"Dr.",name:"Gorka",middleName:null,surname:"Navarrete",slug:"gorka-navarrete",fullName:"Gorka Navarrete"}]},{id:"61268",title:"The Application of Discrete Choice Models in Transport",slug:"the-application-of-discrete-choice-models-in-transport",totalDownloads:995,totalCrossrefCites:1,totalDimensionsCites:0,book:{slug:"statistics-growing-data-sets-and-growing-demand-for-statistics",title:"Statistics",fullTitle:"Statistics - Growing Data Sets and Growing Demand for Statistics"},signatures:"Foued Aloulou",authors:null},{id:"71603",title:"A Brief Tour of Bayesian Sampling Methods",slug:"a-brief-tour-of-bayesian-sampling-methods",totalDownloads:376,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"bayesian-inference-on-complicated-data",title:"Bayesian Inference on Complicated Data",fullTitle:"Bayesian Inference on Complicated Data"},signatures:"Michelle Y. Wang and Trevor Park",authors:null},{id:"56066",title:"Development of Falling Film Heat Transfer Coefficient for Industrial Chemical Processes Evaporator Design",slug:"development-of-falling-film-heat-transfer-coefficient-for-industrial-chemical-processes-evaporator-d",totalDownloads:1400,totalCrossrefCites:0,totalDimensionsCites:1,book:{slug:"statistical-approaches-with-emphasis-on-design-of-experiments-applied-to-chemical-processes",title:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes",fullTitle:"Statistical Approaches With Emphasis on Design of Experiments Applied to Chemical Processes"},signatures:"Muhammad Wakil Shahzad, Muhammad Burhan and Kim Choon\nNg",authors:[{id:"174208",title:"Dr.",name:"Muhammad Wakil",middleName:null,surname:"Shahzad",slug:"muhammad-wakil-shahzad",fullName:"Muhammad Wakil Shahzad"}]},{id:"35660",title:"Making a Predictive Diagnostic Model for Rangeland Management by Implementing a State and Transition Model Within a Bayesian Belief Network (Case Study: Ghom- Iran)",slug:"making-a-predictive-diagnostic-model-for-rangeland-management-by-implementing-a-state-and-transition",totalDownloads:1992,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"bayesian-networks",title:"Bayesian Networks",fullTitle:"Bayesian Networks"},signatures:"Hossein Bashari",authors:[{id:"10124",title:"Dr.",name:"Hossein",middleName:null,surname:"Bashari",slug:"hossein-bashari",fullName:"Hossein Bashari"}]},{id:"64216",title:"CNN Approaches for Time Series Classification",slug:"cnn-approaches-for-time-series-classification",totalDownloads:2611,totalCrossrefCites:8,totalDimensionsCites:12,book:{slug:"time-series-analysis-data-methods-and-applications",title:"Time Series Analysis",fullTitle:"Time Series Analysis - Data, Methods, and Applications"},signatures:"Lamyaa Sadouk",authors:[{id:"257943",title:"Ph.D.",name:"Lamyaa",middleName:null,surname:"Sadouk",slug:"lamyaa-sadouk",fullName:"Lamyaa Sadouk"}]},{id:"54071",title:"Validation of Instrument Measuring Continuous Variable in Medicine",slug:"validation-of-instrument-measuring-continuous-variable-in-medicine",totalDownloads:1402,totalCrossrefCites:1,totalDimensionsCites:2,book:{slug:"advances-in-statistical-methodologies-and-their-application-to-real-problems",title:"Advances in Statistical Methodologies and Their Application to Real Problems",fullTitle:"Advances in Statistical Methodologies and Their Application to Real Problems"},signatures:"Rafdzah Zaki",authors:[{id:"190238",title:"Dr.",name:"Rafdzah",middleName:null,surname:"Zaki",slug:"rafdzah-zaki",fullName:"Rafdzah Zaki"}]},{id:"68138",title:"Bayesian Graphical Model Application for Monetary Policy and Macroeconomic Performance in Nigeria",slug:"bayesian-graphical-model-application-for-monetary-policy-and-macroeconomic-performance-in-nigeria",totalDownloads:490,totalCrossrefCites:0,totalDimensionsCites:0,book:{slug:"bayesian-networks-advances-and-novel-applications",title:"Bayesian Networks",fullTitle:"Bayesian Networks - Advances and Novel Applications"},signatures:"David Oluseun Olayungbo",authors:null}],onlineFirstChaptersFilter:{topicSlug:"mathematics-statistics",limit:3,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[{type:"book",id:"10176",title:"Microgrids and Local Energy Systems",subtitle:null,isOpenForSubmission:!0,hash:"c32b4a5351a88f263074b0d0ca813a9c",slug:null,bookSignature:"Prof. Nick Jenkins",coverURL:"https://cdn.intechopen.com/books/images_new/10176.jpg",editedByType:null,editors:[{id:"55219",title:"Prof.",name:"Nick",middleName:null,surname:"Jenkins",slug:"nick-jenkins",fullName:"Nick Jenkins"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:8,limit:8,total:1},route:{name:"profile.detail",path:"/profiles/191356/alejandro-sousa-escandon",hash:"",query:{},params:{id:"191356",slug:"alejandro-sousa-escandon"},fullPath:"/profiles/191356/alejandro-sousa-escandon",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()