Comparison of mean (
\r\n\tThe book also covers the more specialized areas of energy consumption, riding comfort, noise and vibration.
\r\n\tEscalators and passengers conveyors should also be addressed, as these devices complement elevator system in moving passenger around the building.
\r\n\tModern developments are hope to be covered within the relevant chapters, some of which are listed as follows: Modern electrical safety systems,Modern shaft and motor feedback devices, Modern electrical drive system, Two elevator cars in the same shaft, Multiple elevator car systems in the same shaft, Evacuation systems using elevators, Modern calculation and simulation tools and software packages, Ropeless elevator systems.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8d5766ef86475867198610aeb050233c",bookSignature:"Dr. Lutfi Al-Sharif",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10040.jpg",keywords:"Elevator Traffic Engineering, Simulation, Elevator Mechanical Engineering, Safety Gear System, Drive Systems, Control Systems, Energy Consumption, Power, Riding Comfort, Noise and Vibration, Escalators, Passenger Conveyors",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:1,numberOfDimensionsCitations:1,numberOfTotalCitations:2,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 14th 2019",dateEndSecondStepPublish:"February 28th 2020",dateEndThirdStepPublish:"April 28th 2020",dateEndFourthStepPublish:"July 17th 2020",dateEndFifthStepPublish:"September 15th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"314726",title:"Dr.",name:"Lutfi",middleName:null,surname:"Al-Sharif",slug:"lutfi-al-sharif",fullName:"Lutfi Al-Sharif",profilePictureURL:"https://mts.intechopen.com/storage/users/314726/images/system/314726.jpg",biography:"Lutfi Al-Sharif is currently Professor of Building Transportation Systems at of the Department of Mechatronics Engineering, The University of Jordan. He received his Ph.D. in lift traffic analysis in 1992 from UMIST (Manchester, U.K.). He worked for 9 years for London Underground, London, United Kingdom in the area of lifts and escalators.\r\nIn 2002, he formed Al-Sharif VTC Ltd, a vertical transportation consultancy based in London, United Kingdom. He has over 30 papers published in peer reviewed journals the area of vertical transportation systems and is co-inventor of four patents and co-author of the 2nd edition of the Elevator Traffic Handbook.\r\nHe is also a visiting professor at the University of Northampton (UK), member of the scientific committee of the annual Symposium on Lift & Escalator Technologies and a member of the editorial board of the journal Transportation Systems in Buildings. \r\nHe is a passionate believer in making higher education simple and accessible for engineering students and has a You Tube channel on engineering that has around 50 000 subscribers and around 7 million views. He has also been working as a member of the METHODS Project that aims to improve teaching methods in higher education in Jordan and Palestine. He is also the author of the Mechatronics Engineering Module on Saylor.org.",institutionString:"University of Jordan",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Jordan",institutionURL:null,country:{name:"Jordan"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"11",title:"Engineering",slug:"engineering"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"194667",firstName:"Marijana",lastName:"Francetic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/194667/images/4752_n.jpg",email:"marijana@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},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:"64646",title:"Nanofibers in Mucosal Drug and Vaccine Delivery",doi:"10.5772/intechopen.82279",slug:"nanofibers-in-mucosal-drug-and-vaccine-delivery",body:'\nMucosal drug delivery is an alternative method of systemic drug delivery that offers numerous benefits over/parenteral and oral administration. Mucosal surfaces, particularly oral, nasal, and vaginal, have been widely explored for systemic delivery of drugs. Drugs that are absorbed via mucosal surfaces directly enter the systemic circulation and bypass the gastrointestinal tract including first-pass metabolism in the liver. Rapid onset of drug action is another advantage of oral, nasal, and vaginal mucosae drug administration. A lot of efforts have been devoted to the discovery of efficient delivery of vaccine antigens to mucosal sites that enhance uptake by local antigen-presenting cells in order to generate protective mucosal immune responses. Potent mucosal adjuvants and suitable mucosal vaccine delivery systems are crucial steps on the way to effective mucosal vaccines.
\nOn the other hand, several challenges need to be overcome to successfully deliver drug molecules. Poor water solubility of numerous drugs, macromolecular nature of newly developed biologically active molecules, including therapeutic peptides, proteins, and nucleic acids, are some examples of challenging features that need to be overcome by developing new delivery approaches, devices, and dosage forms. Mucoadhesive drug formulations, rapidly disintegrating formulations, and formulations with mucus penetration properties enabling mucosal delivery of such therapeutic molecules have made great progress over the last decade.
\nAnatomical and physiological functions of different types of mucosa need to be taken into consideration when formulating new drug delivery systems. These need to respect the flexibility of mucosal surfaces, the flow of body fluids such as saliva or vaginal fluid, ciliary movement on the nasal mucosa, presence of mucosal absorption barriers, including the mucus layer and keratinization of some surfaces, etc.
\nNanofibers represent an interesting opportunity to tackle some of the difficulties in mucosal drug delivery. Nanofibers represent an almost universal platform the properties of which can be tailored according to specific demands in terms of their composition as well as surface modifications. Advanced features of nanofibers include possible mucoadhesive properties, fast disintegration, controlled drug release, formulation of small drugs of different nature, and formulation of therapeutic macromolecules. These properties can help solve problems with mucosal delivery of poorly water-soluble drugs, drugs with fast liver metabolism, therapeutic proteins, and antigens for mucosal immunization. Taken together, formulations based on nanofibers intended for mucosal applications represent a new trend in drug delivery.
\nHistology, physiology, and barrier functions of mucosal surfaces play a critical role in mucosal drug and vaccine delivery. All aspects have to be taken into consideration when designing a mucosal drug delivery system. Also, appropriate drug candidates for mucosal delivery have to be selected, not only with respect to physical-chemical properties of drug molecule, but also anatomical and physiological aspects of the intended site of administration and their deep knowledge are essential for successful delivery of drugs and vaccines.
\nThe mucosa of oral cavity is divided into the buccal, sublingual, gingival, palatal, and labial regions. The mucosa of each region is of specific histological and functional characteristics. Oral mucosa consists of three layers: a stratified squamous epithelium, composed of several cell layers, below which lies the basement membrane, and finally the connective tissue divided into the lamina propria and submucosa, which comprise a number of vascular capillaries [1]. Drugs absorbed via the oromucosal route of administration are absorbed through these capillaries and gain access to the systemic circulation [2, 3].
\nThree major types of epithelium located in different regions of the oral cavity differ in the degree of keratinization, namely masticatory, specialized, and lining mucosa. The masticatory epithelium is keratinized (100–200-μm thick) and covers the gingival region and the hard palate. The specialized epithelium is stratified, keratinized, and covers the dorsal surface of the tongue. The lining mucosa covers buccal and sublingual regions of the oral cavity. The epithelial layer of the buccal and sublingual mucosa is non-keratinized, with variation in thickness [4]. The lining mucosa exhibits high permeability for different drugs, and thus is an interesting site for drug administration.
\nThe oral epithelium is covered by a 70–100-μm thick film of saliva, the secretion from salivary glands. The daily production of saliva secreted into the oral cavity is between 0.5 and 2 L. Continuous production of saliva significantly impacts drug residence time after administration within the oral cavity, a phenomenon known as saliva washout [5].
\nMucus is the intercellular ground matrix secreted by the sublingual and salivary glands, which is bound to the apical cell surface and acts as a protective layer for the cells below [6]. It is also a viscoelastic hydrogel consisting of the water-insoluble glycoproteins, water, and small quantities of different proteins, enzymes, electrolytes, and nucleic acids. The mucus layer carries a negative charge due to a high content of sialic acid and forms a strongly cohesive gel structure that binds to the epithelial cells.
\nThe mucus layer varies in thickness from 40 to 300 μm. The mucus layer plays a critical role in the function of different mucoadhesive drug delivery systems which work on the principle of mucoadhesion, and thus prolong the dosage form retention time at the site of administration [7].
\nThe total surface area available in the human nasal mucosa is estimated to be about 180 cm2. Most of the surface is covered with highly vascularized respiratory mucosa and only a small surface area of the nasal cavity is covered by olfactory mucosa. Due to the presence of microvilli on the apical cell surface, the effective surface area for drug absorption is relatively high [8]. The nasal vestibule is lined by stratified squamous epithelium which gradually transitions in the valve region with a ciliated, pseudostratified, columnar epithelium characterized by presence of mucus-secreting goblet cells. Mucus lies over the epithelium as a protective layer and the mucociliary apparatus filters the air. Mucus is secreted at a flow rate of 5 mm/min and this fast renewal rate means that particles are eliminated from the nasal cavity in less than 20 min. The nasal mucosa is about 2–4-mm thick and composed of two distinct layers: periciliary layer and superficial layer [5, 9].
\nEnzymes and peptidases contained in the mucus, its constant secretion, and nasal clearance mechanisms significantly reduce the ability of drugs to penetrate through the epithelium [10]. Studies have shown that rapid systemic delivery of topically applied drugs can be achieved after intranasal administration due to the permeable properties of the respiratory epithelia and highly vascularized nature of the adjacent submucosa.
\nImmunologically specialized region localized at the gateway of the respiratory and alimentary tract consists of the palatine tonsils, nasopharyngeal tonsils (adenoid), lingual tonsils, and tubal tonsils and is designated as Waldeyer’s ring or nasal-associated lymphoid tissue (NALT). It represents a site of intimate contact between exogenous antigens and the host aerodigestive tract. With exception of adenoids and tubal tonsils covered by pseudostratified ciliated columnar epithelium (respiratory epithelium) the palatine and lingual tonsil are covered by stratified non-keratinized squamous epithelium with many invaginations allowing the enhanced exposure of foreign antigens to the underlying cryptal lymphatic tissue. Therefore, nasal mucosa is one of intensively explored sites for vaccine administration.
\nThe vaginal mucosa is composed of four histological layers: the stratified squamous epithelium (with underlying basement membrane), the elastic lamina propria (a dense connective tissue layer which projects papillae into the overlying epithelium), the fibromuscular layer comprising two layers of smooth muscle, and the tunica adventitia, consisting of areolar connective tissue [5].
\nThe vaginal epithelium is composed of non-cornified, stratified squamous cells. Several layers of cuboidal cells are close to the basement membrane and become flattened as they move toward the luminal surface. The thickness of vaginal epithelium is around 200–300 μm, and is influenced by physiological factors, e.g., variability in estrogen concentration [11].
\nVaginal surface is coated with a layer of cervicovaginal fluid. The fluid contains secretions from the cervix in the form of mucins and secretions from the Bartholin’s and Skene’s glands, endometrial fluid, and fluid transuded from the vascular bed of the vaginal tissue. It also contains a large number of squamous epithelial cells, enzymes, proteins, carbohydrates, and amino acids. The acidic vaginal environment is maintained by production of lactic acid by lactobacilli but the exact pH value is influenced by the presence of cervical mucus, the amount of vaginal fluid, infections, and other factors. Cervical mucus forms a semipermeable viscoelastic barrier at the vaginal surface. High constant production of cervicovaginal fluid influences the properties of different drug delivery systems, the residence time after administration as well as the rate of drug release and absorption [12].
\nThe rate of drug absorption following oromucosal administration is influenced by the permeability of the buccal and sublingual mucosa, physical-chemical properties of the delivered drug, and other factors, namely the presence and properties of mucus, saliva production, movement of the oral tissues during speaking, food and drink intake, etc. The mucus layer is the main natural barrier of mucosa against penetration of different pathogens and foreign particles. One the other hand, mucus layer is one of the main absorption barriers to a variety of drugs, including nanoparticle-based drugs and vaccine formulations [5].
\nDrug permeability through the oral cavity mucosa represents a major limiting factor in transmucosal drug delivery. Mechanically stressed areas are keratinized and impermeable to water, which makes such areas unfavorable for drug delivery. On the other hand, more permeable non-keratinized buccal and sublingual epithelia make such regions of the oral cavity attractive sites for drug delivery and a great number of active ingredients are currently being explored in terms of transmucosal drug delivery [13].
\nOne of the main permeability barriers of oral mucosa is represented by the presence of a layer of extracellular lipidic material coming from membrane-coating granules (MCGs). They are present in both keratinized and non-keratinized epithelia, but the composition of lipidic material is different between the two types [14].
\nPassive diffusion of drugs and drug carriers through mucosal surfaces is generally considered the primary mechanism responsible for the transport of drugs across the oral mucosa [15]. However, active transport mechanisms are connected to the activity of different types of immune cells widely present in oral mucosal tissues, especially in sublingual and buccal regions. Such immune cells, mainly different types of dendritic cells, act as an immunological barrier between the body and foreign stimuli (including pathogens and potential allergens), mainly coming to the body with food and drink. These cells are responsible for tolerogenic, or opposite reaction to such stimuli.
\nAnother barrier to drug permeability across oromucosal surfaces is enzymatic degradation. Saliva contains some enzymes that are able to metabolize some peptide and protein therapeutics. This fact leads to reduced bioavailability of protein-based therapeutics after oromucosal administration.
\nThe flow of saliva makes it difficult for a drug delivery system to retain the released drug at the site of administration and, therefore, mucoadhesive drug formulations are the preferred dosage form for oromucosal drug delivery [5].
\nThe main barrier functions of nasal mucosa include the role of the mucus layer and the process of mucociliary clearance. For systemically acting drugs, the mucus layer acts as a diffusion barrier. The rate of the diffusion through the mucus layer is dependent on several factors involving thickness and viscosity of the mucus, and drug physical-chemical properties. The thickness of the layer of mucus in the nasal cavity is a few microns and, therefore, in contrast to other mucosal surfaces, it does not represent a substantial diffusion barrier. The rate of mucociliary clearance influences the contact time of epithelia and a drug delivery formulation and also the drug molecules themselves [9].
\nTransport across epithelial barriers with respect to the nasal route, and drug permeation via the paracellular route are limited because of the presence of tight junctions. Therefore, passive diffusion via the transcellular route is the main transport pathway across the nasal epithelium [16].
\nPhysical-chemical factors that influence nasal drug absorption are the molecular weight and lipophilicity. Polar and ionized molecules show poor permeability. On the other hand, drugs with systemic action currently administered by the intranasal route are of low molecular weight and lipophilic nature. Moreover, some therapeutic peptides, e.g., salmon calcitonin and oxytocin, also exhibit some level of systemic nasal absorption [5].
\nProperties of the vaginal epithelium such as thickness and barrier functions are depending on several factors, including age and hormonal activity [12]. The above mentioned factors affect both vaginal fluid production and the amount of enzymes contained in the fluid. The surface of vaginal epithelium contains a variety of enzymes which can metabolize the delivered drugs, especially therapeutic peptides and proteins. The present proteases are the main barrier for absorption of such drugs into the blood as they are degraded before they cross the epithelium and can reach systemic circulation. Cervicovaginal fluid acts as a dissolution medium that enables transfer of drugs from the dosage form into the tissue. It has also been claimed that drugs can directly be transferred from dosage form to epithelial tissues. This means that a portion of the released drug molecules can overcome the fluid compartment. The pH in the vagina is around 4, thus strongly acidic under normal conditions. These conditions can lead to rapid drug degradation.
\nSystemic mucosal delivery through vaginal epithelium has several advantages, including ease of administration, avoidance of drug liver first-pass metabolism, relatively low metabolic activity, high permeability, prolonged retention, and the potential for sustained release from drug delivery formulations with controlled release properties. Important physical-chemical properties of drugs delivered through vaginal mucosa include drug solubility in the vaginal fluid, tissue permeability, chemical stability of drugs under certain pH conditions, and drug lipophilicity [5].
\nMucosal surfaces, such as those of the respiratory, gastrointestinal, and genital tracts, act as the first line of defense against environmental pathogens. Although immunization by mucosally applied vaccines has had a long history with numerous micro-organisms and a variety of administration routes, only a few such vaccines are currently used in human medicine. Nevertheless, these examples (e.g., poliomyelitis, influenza, cholera, Salmonella typhi) clearly demonstrate the validity of this strategy. There are many reasons for the development of mucosal vaccines as an attractive alternative to those administered by systemic routes. Most importantly, protective immune responses can be induced at the relevant mucosal sites of pathogen entry by mucosal delivery of vaccines, and thus the enormous potential of immunity in mucosal tissues and their associated secretory glands remains to be exploited in vaccinology. Better understanding of mucosal immune system together with new nanomaterials, including nanofibers and engineering of recombinant antigens, enhanced a long-lasting effort to develop mucosal vaccines capable of effectively inducing both mucosal and systemic immune responses, thereby resulting in two layers of host protection.
\nMucosal vaccination, in contrast to other routes of vaccine administration, is of particular interest since it can enhance immune responses, mainly secretory IgA, which defends the portal of entry of various infectious pathogens [17]. Since the route of vaccine administration has a significant effect on the resultant immune response, much effort has been made to explore novel mucosal vaccine delivery routes, briefly described in this chapter.
\nThe noninvasive needle-free vaccine delivery mode (nonparenteral routes of application) has become a global priority, both to eliminate the risk of improper and unsafe needle use and to simplify vaccination procedures. Development of alternative vaccine delivery methods, including mucosal routes, becomes a prominent field of vaccine research and represents a challenge for new biocompatible materials, especially nanomaterials. The vaccine administration route significantly affects immune responses regarding the intensity and quality (class-specified Ig, TH1/TH2 balance, anergy).
\nFurthermore, for vaccination campaigns organized to stop epidemics of mucosally transmitted infections, mass immunization by mucosal routes is likely to be more practicable and less expensive than immunization by systemic routes. In addition, many parents already hesitate to subject their young children to repeated needle sticks. The factors like reduced cost of mucosal vaccines must be taken into consideration. Economy of mucosal vaccines is based on both production/distribution and application levels. The purity of mucosally delivered vaccines, including endotoxin contamination, is less critical than for injectable vaccines. Finally, mucosal vaccine delivery does not require sterile syringes and needles or personnel trained in their use and disposal, although spray devices or other applicators may be needed for intranasal and other routes of administration. From this point of view, sublingual application of vaccines represents the easiest and the most favorable modes.
\nNevertheless, there are some drawbacks in terms of mucosal vaccination, particularly the uncertainty of the amount of effectively delivered antigen following its mucosal administration. Another problem is the limited uptake of intact protein and polysaccharide antigens at mucosal surfaces. Moreover, potential for degradation of antigens, especially in the gastrointestinal tract following oral administration is another issue. Therefore, as compared to oromucosal administration, significantly higher doses of vaccine antigens must be administered orally to induce measurable immune responses. To overcome such difficulties, various particulate antigen delivery systems have been designed.
\nSuccessful development of future mucosal vaccines is based on three basic pillars critical for inducing the effective immune response. These pillars are adjuvants, application/delivery systems, and antigens.
\nAdjuvants represent one of the key issues in all vaccine development. The identification and development of appropriate mucosal adjuvants to enhance the desired aspects of the immune response against the antigens represent a special challenge because adjuvants for mucosal application involve requirements different from those for parenteral use. On the other hand, this affords greater opportunities for discovery by exploiting the growing understanding of the mechanisms whereby mucosal pathogens and commensals interact with the immune system. Cholera toxin (CT) and related heat-labile enterotoxins such as Escherichia coli labile toxin (LT) are classic examples of mucosal adjuvants for their ability to break immune tolerance [18]. A major concern for human application has been to separate the toxicity of these molecules from their adjuvant properties. Different approaches were used based on targeted mutations in the enzymatically active site of the A subunit, the selection of various types of toxins including mutants that have different ganglioside (receptor)-binding B subunits and the use of nontoxic B subunits alone or coupled to vaccine antigens. Intranasal administration has generated interest and concern with the finding that CT and LT can undergo retrograde migration along neurons, potentially reaching the brain via the olfactory nerve, and thus leading to neurological pathology. An intranasal influenza vaccine which contained a low dose of LT as an adjuvant was introduced in Switzerland, but it was withdrawn due to suspicion of causing Bell’s palsy in some recipients [19]. Facial nerve palsy was another side effect demonstrated after intranasal application of a flu vaccine. As an alternative route, sublingual vaccination has been demonstrated to achieve similar immune responses but without the risk of retrograde transmission to the brain [20].
\nOther molecules derived from microorganisms and falling into the category of pathogen associated molecular pattern (PAMP) have also been shown to have immunomodulatory properties. Ligand for Toll-like receptors, NOD1/2 receptors, and inductors of inflammasomes are examples of such molecules (e.g., monophosphoryl lipid A, “CpG” oligodeoxynucleotides, muramyl glycopeptides, flagellin). Nevertheless, none of these has been investigated as extensively as the heat-labile enterotoxins.
\nDelivery systems for mucosal immunization are functionally related to adjuvants for mucosal vaccines as well as to antigen formulations. The principal task for delivery systems is to keep antigen on mucosal surface and to enhance its penetration into submucosal tissue to be accessible in sufficient amount to immune cells, especially to dendritic cells. Various gels and films are available for buccal application of drugs, while sprays or droplets are used for intranasal application of influenza vaccines. Oral application of vaccines is achieved mainly by various capsules containing antigens or simply by administration of the vaccine on a spoon (polio).
\nWhile some formulations for nasal and oral delivery of vaccines are available, suitable delivery systems for sublingual vaccination are at their door step of development. In this chapter, we describe the mucoadhesive nanofiber-based film fulfilling the role of delivery system for sublingual immunization. This system is compatible with antigens formulated as proteoliposomes and immunostimulating complexes (ISCOMs), virus and virus-like particles, bacteria and bacterial ghosts, plasmid DNA, polymeric nanoparticles, and a simple free antigen. Such formulations also allow the sustained release of vaccine antigens and provide some protection against removal from the site of application by saliva flow and tongue movement. Also, enhancers of mucosal penetration can be combined with antigens and mucosal adjuvants, which make the mucoadhesive nanofiber-based films a universal platform for mucosal sublingual vaccination. The important aspect of the mucoadhesive nanofiber-based film is its suitability for industrial production as the crucial factor of pharmacoeconomy [21].
\nIn conclusion, sublingual immunization represents the route of a big hidden potential for development of effective, cheap, and safe vaccines for prevention of infectious diseases as well as the treatment of allergy.
\nPenetration enhancers, sometimes also referred to as chemical enhancers, are functional pharmaceutical excipients that possess the ability to modify the physical-chemical properties of mucosal barriers. The reason for co-administration of penetration enhancers is to enhance penetration of drugs through different barriers of mucosa including mucus layer, extracellular lipid layer originating from MCGs, enzymatic barrier, and others. The target compartment of the delivered drug can differ according to the mode of its action, e.g., blood circulation in systemic drug delivery, specialized immune cells present in epithelium or submucosal tissue in vaccine delivery and local cell therapy, etc. Penetration enhancers can potentially facilitate the systemic absorption of a wide range of drugs, including large therapeutic molecules such as polypeptides, proteins, nucleic acids [22], and therapeutic nanoparticles.
\nDifferent surfactants, bile salts (deoxycholic, ursocholic, and taurocholic acids), ethylenediaminetetraacetic acid (EDTA), fatty acids, and amino acids are the most frequently explored chemicals used in mucosal enhancing of drug permeability, and thus its bioavailability [23, 24]. An important concern related to penetration enhancers is the capacity of adjacent tissues to tolerate the effects of penetration enhancers.
\nPenetration enhancers act usually by a combination of different mechanisms. Some penetration enhancers are amphipathic in nature, and thus associate and influence bilayers of the cell membranes, increase the fluidity and permeability of membranes and finally promote transcellular transport. Penetration enhancers can interact with tight junctions between epithelial cells that cause facilitation of paracellular drug transport. Another group of penetration enhancers, known as mucolytic agents (e.g., acetylcysteine) influence the integrity of the mucus layer.
\nFormulation of drugs into nanofibers, especially nanofibers with mucoadhesive properties, enhances drug absorption via mucosal surfaces in general. Moreover, combination of nanofiber-based formulations and chemical enhancers can increase penetration of drug molecules, or nanoparticle-based drug and vaccine delivery systems. Nanofibers themselves have extraordinary capacity to combine different types of chemicals including combination of drugs and penetration enhancers, whether using electrospinning technique for nanofiber production, or another technique. As an example, mucosal penetration of model mucus penetration poly(lactic-co-glycolic) acid (PLGA) nanoparticles from nanofiber-based mucoadhesive film into porcine sublingual and buccal mucosa was enhanced using sodium deoxycholate as penetration enhancer [21].
\nDifferent parts of the human body are covered by mucosa with different features and barrier properties for drug delivery. Some areas are more accessible than others. In principle, there are two ways of mucosal drug delivery—local delivery, e.g., antimicrobials, anti-inflammatory drugs, etc., and systemic drug delivery. Whereas many indications for drugs intended for local treatment exist and include all mucosal surfaces, systemic drug delivery is a completely different task and only a few parts of mucosa are suitable sites for systemic drug administration and absorption. Moreover, only several drugs with suitable physical-chemical properties have been administered via transmucosal delivery. On the other hand, mucosal drug absorption has enormous potential, and different strategies including penetration enhancers, nanoparticle-based drugs, and mucoadhesive drug formulations have been employed.
\nBecause of easy accessibility, high vascularization and a relatively low thickness, oral mucosa, especially its sublingual and buccal parts, is a preferred site of systemic drug administration. Transmucosal delivery of certain drugs can result in a rapid onset of their action, thus having the potential to replace the injection administration of some specific drug molecules [25]. Oromucosal delivery of nitroglycerin brings many benefits for patients, and today, nitroglycerin is one of the most frequent drug molecules delivered via oral mucosa. Exploration of cardiovascular drugs (e.g., captopril, verapamil) has shown promising results. Oral transmucosal delivery of analgesics has attracted substantial attention. As an example, oromucosally administered fentanyl is designed for rapid noninvasive delivery of analgesia for severe pain treatment.
\nOromucosal delivery of sedatives and hypnotics has shown favorable results with clinical advantages over other routes of administration. Another example is drugs for erectile dysfunction and transmucosal formulations of hormones, e.g., testosterone and estrogen. Transmucosal spray formulation of insulin (Oral-lyn®, Generex) is a great example of the potential of oral mucosa for systemic macromolecular drug delivery.
\nTransmucosal nasal drug delivery is another interesting site for systemic drug delivery. The considerable blood supply of nasal mucosa provides efficient systemic drug absorption and enables direct access to the systemic circulation for drugs. In nasal drug delivery, limited nasal capacity often results in partial swallowing of the instilled drug as the instilled volumes exceed the limited capacity of the nasal mucosa. Therefore, the administered dose of the drug is partially swallowed, and drug absorption is in part transmucosal, in part gastrointestinal. Formulation of drugs into different mucoadhesive dosage forms and nasal inserts can be beneficial in this regard. Several drugs have been successfully administered including active ingredients with hormonal activity (salmon calcitonin, oxytocin, desmopressin) and small drugs (e.g., sumatriptan, zolmitriptan, dihydroergotamine).
\nAs nasal mucosa is the first barrier which must be conquered by pathogens, nasal mucosa is very immunocompetent. Many studies have shown that even small amounts of antigen can elicit a strong protective response. Intranasal administration, similarly to oromucosal, seems to be the best strategy for barrier vaccinations following the outbreak of highly infectious diseases, because less erudite persons (e.g., nurses) can provide mass vaccination. FluMist® (US) and Fluenz® (Europe) are examples of live attenuated influenza vaccines.
\nThe vaginal mucosa offers many advantages as a site for drug delivery, including easy access, prolonged residence time interval of drug availability, avoidance of first-pass metabolism, and relatively low activity of proteases and other enzymes. The vagina has a rich vascularization and a large surface area due to the folds in the mucosa (rugae) making it ideal for high absorption of drug molecules. Administration of drugs through vaginal mucosa represents an interesting alternative to oral administration for drugs treating osteoporosis, hormone replacement therapy, contraception, infections, and others. Mucoadhesive polymers are often used in formulations for vaginal drug delivery systems to prolong retention time of drug delivery systems [26].
\nMucosal immune responses in the genital tract can be induced by the administration of antigen to mucosal surfaces. IgA antibodies in the vaginal tract are essential as a first line defense against pathogens that enter the body through vaginal mucosa. Immune responses of various types of vaginally administered vaccines have been investigated. Both vaginal and serum IgA and IgG levels have been enhanced following vaginal vaccine administration [27].
\nThe nasal mucosa vaccination induces preferentially mucosa-associated immune responses. There are several vaccination approaches to induce both mucosal and systemic immune responses (antibodies and cell-mediated immunity), for example by heterologous immunization by systemic followed by mucosal routes. Combining of parenteral and mucosal administration of antigen is required because parenteral vaccines are notoriously inefficient for stimulating immune responses in mucosal tissues; and on the other hand, mucosal vaccination, particularly that administered by oral route to subjects without antecedent contact with vaccination antigen leads to induction of the “oral tolerance” phenomenon consisting in induction of IgA-mediated immune responses in mucosal compartments but dominantly cell-mediated antigen-specific tolerance in systemic compartment. In contrast, sublingual (SL) vaccination represents a route effectively stimulating both systemic and mucosal antibody- and cell-mediated immune responses. Sublingual mucosa is the place of vaccine administration which in contrast to other mucosally effective intranasal routes does not elicit neurotoxic effects as demonstrated for example with inactivated influenza virus administered SL together with a mucosal adjuvant which did not migrate to or replicate in the nerve system [28]. Furthermore, sublingual mucosa may be useful as a delivery site for mucosal vaccines because the sublingual epithelium harbors a dense lattice of dendritic cells (DC), and that using mucosal adjuvants mobilizes DCs within the sublingual epithelium. These cells migrate to the above mentioned proximal draining lymph nodes (submaxillary and superficial cervical lymph nodes), on uptake of the sublingual vaccine antigens. It is important that sublingual immunization induces antigen-specific immune responses in the female reproductive tract in addition to the respiratory tract and oral/nasal cavity [29]. Another mucosal administration route, orogastric route, can induce strong mucosal responses, especially secretory IgA in the small intestine, proximal colon, and mammary and salivary glands but it is poorly efficient for disseminating these responses to the distal segments of the gut and to the respiratory and reproductive tracts. Moreover, orogastric immunization requires substantially more antigen application because of intensive degradation. In addition to orogastric, nasal, and sublingual vaccines, transcutaneous immunizations are now part of a new generation of mucosal vaccines [30].
\nMucoadhesion is defined as adhesion between a mucosal surface and a surface of another material. Mucoadhesive dosage forms have recently attracted much attention from pharmaceutical research as well as from pharmaceutical industry due to substantial improvements in mucosal drug delivery. Increasing the residence time of drug formulations at the site of administration automatically leads to much more effective transmucosal drug delivery, drug bioavailability, and results in increased therapeutic efficiency, thus lowering the drug dose needed [13]. Instead of small drug molecules, mucoadhesive formulations enable delivery of therapeutic biologicals such as peptides, proteins, antibodies, and nucleic acids through a variety of routes of administration such as oromucosal, ocular, nasal, and vaginal. Moreover, mucosal delivery of nanoparticle-based therapeutic formulations can be achieved by materials with mucoadhesive properties, mucus penetration formulations, and their combinations. Taste masking properties are of importance for mucoadhesive formulations intended for oromucosal administration.
\nNanofibers made up of mucoadhesive polymers exhibit one of new trends in mucosal drug delivery. Due to their extremely large surface area, unique surface topology, and porosity, nanofibers are known to significantly improve the adhesiveness of the mucoadhesive drug delivery systems utilizing nanofibers for their construction. Architecture of nanofibers significantly intensifies the intimate contact between the nanofiber-based products and mucosal surface, and high drug concentration at the site of administration is achieved (Figure 1). Moreover, their ability to enhance drug solubility makes nanofibers an almost ideal platform for transmucosal drug delivery.
\nSchematic representation of drug and vaccine delivery after mucosal administration of nanofiber-based drug delivery system.
The use of mucoadhesive polymers is conditioned by their ability to form nanofibers. A variety of factors affect the ability of polymers to form nanofibers as well as the mucoadhesive properties of polymers, including molecular weight, chain flexibility, hydrogen bonding capacity, cross-linking density, charge and degree of ionization of a polymer, concentration, and hydration (swelling) of a polymer [3].
\nThese are reasons why only a few mucoadhesive polymers have been tested for nanofiber-based drug delivery system formulations. Chitosan (cationic polymer), hyaluronic acid, sodium alginate, sodium carboxymehylcellulose (anionic polymers), different cellulose derivatives, poly(ethylene oxide), and polyvinylpyrrolidone (nonionic polymers) are excellent examples of conventional mucoadhesive materials utilized for construction of nanofiber-based mucoadhesive drug delivery systems. A group of thiolated polymers, e.g., thiolated chitosan, are representatives of next-generation mucoadhesive materials [3, 13]. Mucoadhesive nanofibrous membrane made of chitosan/PEO is visualized in Figure 2 as an example.
\nElectrospun nanofibrous membrane fabricated using Nanospider technology (A) and detail of mucoadhesive chitosan/PEO nanofibers (B).
Chitosan is a linear polysaccharide composed of randomly distributed D-glucosamine and N-acetyl-D-glucosamine obtained by deacetylation of chitin (Figure 3). Because of the broad chemistry of chitosan, which covers different degrees of deacetylation, a range of molecular weights and different distribution of the acetyl groups along the polymeric chain, chitosans can provide a number of physical-chemical as well as biological properties. Mucoadhesion of chitosan occurs due to the electrostatic interactions of amino groups of chitosan and the sialic groups of mucin in the mucus layer.
\nStructural formula of chitosan.
Several studies have explored mucoadhesive properties of chitosan-based nanofibers. As an example, Lancina et al. have produced chitosan-based nanofiber mats capable of delivering insulin via the buccal mucosa. Chitosan was electrospun into nanofibers using poly(ethylene oxide) (PEO) as a carrier molecule. Insulin release rates were determined and showed no reduction in bioactivity due to electrospinning. Buccal permeation of insulin was significantly facilitated as compared to free insulin. Taken together, this work demonstrates that chitosan-based nanofibers have the potential to serve as a transbuccal insulin delivery vehicle [31]. In another study, mucoadhesive fibers of zein/chitosan have been prepared by electrospinning to study the encapsulation efficiency and release of tocopherol. The addition of the acidic chitosan solution to the zein containing tocopherol has improved the mucoadhesive properties of the final composite nanofibers [32]. Mucoadhesive hybrid electrospun chitosan/phospholipid nanofibers intended for drug-delivery applications were produced by Mendes et al. [33]. Nanofibrous membranes intended for local delivery of an antimicrobial agent in combination with poly(hexamethylene biguanide) hydrochloride were produced by electrospinning of chitosan/PEO solution. Inhibition of bacterial growth for both Escherichia coli and Staphylococcus aureus were achieved using nanofiberous membranes [34].
\nCellulose (Figure 4) mucoadhesive derivatives are a wide group of pharmaceutical excipients and cover both nonionic polymers, including hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), methylcellulose (MC), and anionic derivatives, e.g., carboxymethylcellulose (CMC).
\nStructural formula of cellulose.
The aim of the study exploring carboxymethylcellulose as a mucoadhesive agent for nanofiber formation was to develop a progesterone-loaded mucoadhesive system for vaginal application with sustained release. Presently, two dosage form options are being considered: direct compression of nanofibers into tablets for vaginal insertion and winding bundles of the fiber into a miniature tampon [35, 36].
\nIn another work, nanofiber-based indomethacin films were prepared using different grades of methylcellulose, polyvinylpyrrolidone, and Tween® 80 by electrospinning. The addition of Tween® 80 to polyvinylpyrrolidone formulations significantly improved their wettability. Moreover, nanofiber-based patches containing methylcellulose and Tween® 80 were found to exhibit the highest permeation of indomethacin across porcine mucosa without significantly affecting the ultrastructure of the oral mucosa [37].
\nEl-Newehy et al. demonstrated the preparation of HPC-based nanofibers. They found that the thermal stability and mechanical properties of nanofiber mats were dramatically enhanced with the addition of HPC to polyvinyl acetate or polyvinylpyrrolidone. The in vitro sustained release of an incorporated model drug, diclofenac sodium, was controlled when loaded into electrospun nanofibers of HPC with either PVA or PVP [38].
\nMucoadhesive glutamine-loaded poly(ethylene oxide) (Figure 5) electrospun nanofibers were prepared by Tort et al. The effect of different polyelectrolytes on resultant properties of nanofibers was observed. 85% of the drug was released from the nanofibers after 4 h in simulated saliva solution suggesting that glutamine-loaded nanofibers have potential as an oromucosal drug delivery system [39].
\nStructural formula of poly(ethylene oxide).
Nanofiber-based local drug delivery system may be suitable for the treatment of cervical cancer. A pilot study by Zong et al. was carried out to examine the efficacy of cisplatin-loaded poly(ethylene oxide)/polylactide composite electrospun nanofibers as a local chemotherapy system against cervical cancer in mice via vaginal implantation. They have shown that a better balance between antitumor efficacy and systemic safety was achieved in a group of animals treated with nanofiber formulation as compared to i.v. injection group using an equal drug dose. Therefore, electrospun nanofibers present a promising approach to the local drug delivery via vaginal mucosa against cervical cancer [40].
\nThiolated polymers are obtained by the addition of conjugated sulfhydryl groups. Thiolation of chitosan increases their mucoadhesive properties due to formation of disulfide bridges with cysteine domains of glycoproteins of the mucus. Moreover, chitosan and thiolated chitosan possess antiprotease activity due to their affinity to divalent cations, which are co-factors for proteases. All these characteristics make thiolated chitosan a promising material for mucosal administration of drugs, peptides, and proteins [13].
\nLeila Behbood et al. developed mucoadhesive nanofibers made up of thiolated chitosan as a drug delivery system for tetracycline and triamcinolone. Chitosan was modified via the immobilization of thiol groups from L-cysteine as a mucoadhesive reagent. Maximal mucoadhesion of nanofibers was observed at the pH value of 6. Release studies demonstrated that a sustained release of both drugs continued up to 48 h. The drug delivery system represented a novel tool for the improvement of therapeutic efficacy of various drugs that are poorly absorbed from different parts of the gastrointestinal tract. It was also shown to be an efficient system for treatment of oral ulceration [41].
\nThe aim of the study performed by Samprasit et al. [42] was to fabricate mucoadhesive electrospun nanofiber mats containing α-mangostin for the maintenance of oral hygiene and reduction of the bacterial growth. Thiolated chitosan blended with polyvinyl alcohol was selected as the mucoadhesive polymer. The results of this study suggest that α-mangostin-loaded mucoadhesive electrospun nanofiber mats may be a promising material for the prevention of dental caries.
\nMany drugs are highly hydrophobic with poor water solubility and the number of poorly water-soluble drug candidates selected for development is rapidly increasing. It results in low oral absorption of these drugs as the absorption and bioavailability are limited by their poor solubility or slow dissolution in the gastrointestinal tract. This represents a major challenge for the pharmaceutical industry and novel formulation approaches are required. Several strategies including particle size reduction, micellization, salt formation, complexation, and solid dispersions have been developed to increase the oral absorption of such drugs. Solid dispersion is defined as the dispersion of one or more drugs in an inert matrix in the solid state. Simple eutectic mixtures, solid solutions, glass solutions of suspensions, and amorphous precipitates of a drug in a crystalline carrier are examples of solid dispersions [43]. Due to difficulties occurring during conventional methods of drug formulation, the applicability of solid dispersion systems has remained limited. Electrospun nanofibers provide a novel approach to improve the dissolution rate of even poorly water-soluble drugs, and thus might minimize the limitations of oral and oromucosal drug bioavailability [44].
\nAs an example, maraviroc, an anti-HIV drug intended for intravaginal administration, was electrospun as solid dispersion made from either polyvinylpyrrolidone or poly(ethylene oxide) nanofibers or microfibers. In the study, the role of drug loading, distribution and crystallinity in determining drug release rates into aqueous media was investigated. It was shown that water-soluble electrospun materials can rapidly release maraviroc upon contact with moisture and that drug delivery is fast [45].
\nSalt formation improves drug solubility. However, drugs administered onto mucosal surfaces are effectively absorbed through mucosal surfaces if they are in the unionized form. Therefore, this strategy of enhanced drug dissolution is not advantageous for mucosal drug delivery.
\nThe rate of dissolution of drugs formulated into particles is increased with their increasing surface area and decreasing particle size. Technologies used to decrease drug particle size to sub-micrometer range are being frequently applied to poorly water-soluble drug product development. Electrospinning is one of the technologies that can produce uniform nanosized polymeric nanofibers with drugs loaded into their structure. The release rates, and thus bioavailability of nanofiber-formulated drugs, are enhanced compared to those from the original drug substance [46].
\nOral mucosa provides an interesting site of drug administration and absorption including poorly water-soluble drugs. However, they are not usually suitable for the formulation into classical oromucosal drug delivery systems. The formulation of nanofibers represents one possible route to achieve effective drug absorption via mucosal surfaces. Potrč et al. formulated polycaprolactone (PCL) nanofibers intended for oromucosal delivery of poorly water-soluble drugs. In this study, two model drugs, ibuprofen and carvedilol, with similar lipophilic properties, but differing in their molecular weights were chosen, and their influence on the nanofiber’s physical properties and drug release profiles were investigated. The aim of the study was to establish a correlation between the drug’s properties and the release characteristics of a PCL nanofiber-based delivery system. The results obtained in this study have shown that electrospinning can be used for the fabrication of drug-loaded PCL nanofibers with a high percentage of API embedded in them. The formulation of poorly water-soluble drugs into polycaprolactone-based nanofibers significantly increases their dissolution rate. However, the release rate of drugs from nanofibers is drug-dependent. Electrospinning was shown to be a very promising approach to the formulation of poorly water-soluble drugs in order to enhance their release and enable oromucosal administration [46].
\nMucosal surfaces are the most convenient routes for drug delivery to systemic circulation. However, transmucosal transport of macromolecular drugs such as peptides and proteins is much less effective as compared to low molecular weight drugs. Several strategies exploiting permeation enhancers, nanoparticulate carriers, nanofibers, and their combinations represent a promising strategy to facilitate transmucosal transport of macromolecules.
\nRecently, nanofiber-based mucoadhesive films have been invented for oromucosal administration of nanocarriers used for delivery of drugs and vaccines (Figure 6). The mucoadhesive film consists of an electrospun nanofibrous reservoir layer, a mucoadhesive film layer, and a protective backing layer. The mucoadhesive layer made of HPMC and Carbopol 934P polymers is responsible for tight adhesion of the whole system to the oral mucosa after application. The electrospun nanofibrous reservoir layer is intended to act as a reservoir for polymeric and lipid-based nanoparticles, liposomes, virosomes, virus-like particles, dendrimers and the like, plus macromolecular drugs, antigens and/or allergens. The extremely large surface area of nanofibrous reservoir layers allows high levels of nanoparticle loading. Nanoparticles can either be reversibly adsorbed to the surface of nanofibers or they can be deposited in the pores between the nanofibers. After mucosal application, nanofibrous reservoir layers are intended to promote prolonged release of nanoparticles into the submucosal tissue. Reversible adsorption of model nanoparticles as well as sufficient mucoadhesive properties was demonstrated. This novel system appears appropriate for the use in oral mucosa, especially for sublingual and buccal tissues [21].
\nTransmucosal penetration of model fluorescently labeled PLGA-PEG nanoparticles after ex vivo porcine mucosal administration using nanofibers. (A) PLGA-PEG nanoparticles (red) and (B) PLGA-PEG nanoparticles (red) plus nuclei (blue).
Another example of novel multi-layered fibrous mucoadhesive film is based on self-assembled liposomes that are formed directly from nanofibrous layer after contacting with water. The idea came from a method of liposome preparation based on electrospinning technology. PVP was used as a nanofiber-forming matrix and phospholipid as liposome-forming molecules [47]. The membrane has been developed to improve the bioavailability of carvedilol. The whole system consists of an electrospun layer, an adhesive layer made of mucoadhesive film and a backing layer, similarly as previously described by Masek et al. [21]. Mucoadhesive film was formed using HPMC and CMC polymers and the standard solvent casting method. In general, this drug delivery system offered a novel platform for potential buccal delivery of drugs with a high first-pass effect.
\nOne example for all macromolecular drugs is insulin. Insulin is a protein which is made of two polypeptide chains and it is not completely soluble in water. Many efforts have been made to find appropriate noninvasive routes of administration, including oral, pulmonary, rectal, oromucosal, and nasal. Although a certain degree of success exploiting all routes of mucosal administration of insulin was achieved, oromucosal, namely buccal and sublingual, delivery of insulin brings several advantages. A number of attempts have been made to improve buccal insulin absorption by adding absorption enhancers or to modify the lipophilicity of insulin.
\nIt is important to note that buccal and sublingual delivery of macromolecules including insulin using rodents as an animal model are of no value, because oral mucosa of rodents is highly keratinized. Therefore, the permeability for macromolecules and nanoparticles is negligible, while that of humans is quite high in the non-keratinized areas (sublingual and buccal). It means that the only animal models that can be of use when studying the human permeability of oral mucosa for macromolecules is pigs or dogs.
\nSeveral drug delivery systems have been tested for oromucosal insulin delivery, including sprays, mucoadhesive gels, and mucoadhesive films.
\nTransmucosal delivery of insulin via oral mucosa represents a novel approach. As an example, Sharma et al. have prepared an electrospun nanofiber-based membrane containing insulin molecules within the nanofiber structure. The solubility of insulin increases have been enhanced after formulation into polyvinyl alcohol (PVA) nanofibers as PVA itself is a surfactant and hence increases the solubility of insulin in the polymer solution. The release of insulin from a nanofiber membrane followed controlled release, and in vivo experiments confirmed high transmucosal delivery effectivity. Insulin release exhibits first order kinetics followed by an initial burst release necessary to produce the desired therapeutic activity. Furthermore, extremely high encapsulation efficacy of 99% of insulin indicates that nanofiber-based delivery system serves as an ideal carrier for the delivery of insulin via the sublingual route [48].
\nFast-dissolving drug delivery systems (FDDS) represent advanced formulations intended for oromucosal administration. FDDS are characterized by excellent flexibility and comfort for patients. The efficacy of drugs and rapid onset of their action are improved as FDDS dissolve within a minute in the oral cavity after the contact with saliva without the need of water for administration. FDDS are beneficial especially in pediatric and geriatric patients. It is also useful for delivery of drugs with local action.
\nLi et al. have fabricated nanofiber-based FDDS by electrospinning using PVA as the nanofiber-forming polymer and drug carrier. Caffeine and riboflavin were used as the model drugs. They found that drug release was completed in a burst manner. 100% of caffeine and 40% of riboflavin was dissolved within 60 s from the PVA nanofibrous matrices [49].
\nIsosorbide dinitrate-polyvinylpyrrolidone electrospun nanofibers were formulated and explored as a potentially sublingual membrane by Chen et al. The composition was favorable for the fabrication of the sublingual membrane as the dissolution was completed at 120 s. The pharmacokinetic study in rats demonstrated that the electrospinning fiber membrane had a higher Cmax and lower Tmax compared to the reference preparation [50].
\nQuan et al. demonstrated the concept of nanofiber-based FDDS also for poorly water-soluble drugs. In the study, feruloyl-oleyl-glycerol was used as a model drug and polyvinylpyrrolidone (PVP) K90 as a filament-forming polymer [51].
\nDifferent mucosal sites of administration are a suitable target for nanofiber-based drug delivery systems, including oromucosal, nasal, vaginal, and ocular mucosa. Nanofiber-based drug delivery systems are used for both systemic and local drug administration.
\nNanofiber membranes intended for oromucosal administration possess different properties according to the need of the desired indication and drug administered. The oromucosal site of administration, especially sublingual and buccal regions, are the most explored mucosal surfaces for drug delivery using the nanofiber-based system (Figure 7). The applications include fast-dissolving nanofiber-based formulations, mucoadhesive nanofibers, nanofiber-based formulations of poorly water-soluble drugs and, finally, nanofibers for delivery of different mucosal vaccines. Small drug molecules, macromolecules as therapeutic proteins, peptides, nucleic acids, and antigens are examples of the explored nanofiber-based systems intended for oromucosal administration. As description of these applications is broad, they are divided into relevant subchapters.
\nApplication of multi-layered mucoadhesive film with nanofibrous reservoir layer to sublingual (A) and buccal (B) mucosa.
Mucoadhesive nanofiber-based drug delivery systems are investigated for vaginal drug delivery. A wide range of materials have been explored for their fabrication into nanofibers. However, the local environment of vaginal surface has to be taken into the account when designing nanofiber-based vaginal drug delivery systems. Especially, the low pH values around pH 4.0 ± 0.5 make the difference as compared to other mucosal surfaces. As an example, progesterone-loaded drug delivery nanofiber constructs are described in Chapter 4.1.2.
\nSupramolecular peptide nanofibers have been explored as nasal formulation for vaccines and immunotherapy. Si et al. performed a study eliciting the immune response without the use of adjuvants and without measurable inflammation. Peptides comprise an epitope from influenza polymerase and the Q11 self-assembly domain formed nanofibers which were taken up by dendritic cells in lung-draining mediastinal lymph nodes after intranasal immunization. Nanofibers administered onto nasal mucosa elicited higher antigen-specific CD8+ T cell responses in the lung-draining lymph nodes as compared to subcutaneous immunizations, while retaining the noninflammatory character of the materials as opposed to other delivery sites. Influenza vaccines that can be administered intranasally or by other needle-free delivery routes have potential advantages over injected formulations in terms of patient compliance, cost, and ease of global distribution. It means that peptide nanofibers represent an interesting strategy for noninvasive influenza vaccines [52].
\nOcular inserts are drug-impregnated formulations which can be placed onto ocular mucosa. Ocular inserts have been frequently used for reducing the frequency of administration, and, therefore, a controlled release profile is desired.
\nThe objective of the study made by Mirzaeei et al. was to produce the electrospun nanofibers used as ophthalmic inserts. Triamcinolone acetonide was incorporated into a chitosan nanofiber-based ocular insert. This formulation increased the contact time between the drug and the conjunctival tissue, and thus decreased the number of administrations needed. This work showed that the concept of nanofibers in ophthalmic drug delivery is feasible [53].
\nNanofibers can be fabricated by several different techniques including drawing [54], phase separation [55], nanofiber seeding [56], template synthesis [57], self-assembly [58], etc. These techniques, on the other hand, allow neither control of nanofiber diameter nor continuous nanofiber production. Moreover, such techniques can only be used with specific polymers. On the contrary, electrospinning [59] is a resourceful and cost-effective technique that can be used to synthesize continuous nanofibers from numerous polymers and efficiently control their diameter.
\nSpecifically, nanofibers produced by electrospinning (electrospun nanofibers) may be prepared from soluble polymers or from polymer solutions modified with additives such as particles, antimicrobial agents, or enzymes. Thanks to these additives, electrospun nanofibers may have desired properties. Therefore, electrospinning has gained a remarkable popularity in various disciplines boosting a recent steep rise in numbers of scientific publications.
\nTechnically, electrospinning is a process that uses a strong electrical field to draw a polymer fluid into fine filaments. A typical electrospinning setup only requires a high voltage power supply, a syringe, a flat tip needle, and a conducting collector. When a polymer solution is charged with a high voltage, electrostatic force draws the fluid into a liquid jet (Figure 8A). Finally, solvent evaporation from the filaments results in solid nanofibers. In most cases, as-spun fibers deposit randomly on the electrode collector forming a nonwoven nanofiber mat. The basic equipment can be modified for various applications such as dual needle syringe (to make blended fibers), rotating collectors, etc.
\nSchematic representation of an electrospinning process (A): (1) a high voltage supply, (2) a grounded collector of nanofibers, (3) a polymer solution, and (4) a positive electrode. Schematic representation of Nanospider technology (B): (1) a polymer solution, (2) a rotating electrode with a high voltage supply, (3) created nanofibers, and (4) a grounded collector of nanofibers.
Nanospider technology is a modern electrospinning technology for industrial-scale production of nanofibrous material without nozzles, needles, or spinnerets. Nanospider technology uses simply shaped electrodes covered by polymer solution (Figure 8B). It results in a mechanically simple technology with no parts that can be easily clogged (in comparison to needle-type electrospinning). Proven by an industrial operation, Nanospider technology provides high efficiency, outstanding fiber diameter, and web uniformity.
\nBy electrospinning process it is possible to produce continuous nanofibers from a wide range of polymers. However, there are several parameters affecting the fiber morphology and properties of electrospun nanofibers. The whole process can be controlled by four important characteristics: (i) process parameters such as voltage, spinning distance, flow rate, or collecting plate, (ii) systemic and (iii) solution parameters which affected concentration, conductivity, or surface tension of a polymer solution, and (iv) physical parameters such as humidity, temperature, or air velocity. All mentioned parameters are major factors affecting the fiber morphology and web properties. Because these variables interrelate, a small change in either of these variables can have a significant impact on nanofiber morphology or even the electrospinning process altogether. Solvents or their mixtures used for dissolving of polymer have a direct impact on the electrospinning process and morphology of the resulting nanofibers. Laboratory experience has shown that a solvent that creates mostly 80–99 wt% of polymer solution has a dominant impact. Solvents primarily determine (i) conformation of dissolved macromolecular chains, (ii) easiness of charging the surface layer, (iii) cohesion of the polymer solution due to the surface tension forces, and (iv) the rate of solidification of the liquid jet during evaporation of the solvent.
\nNanofiber-based mucosal drug delivery systems cannot be in general electrospun from any polymer as they require specific properties. As examples of very interesting materials for nanofiber-based mucosal drug delivery systems, the following can be mentioned: biopolymers such as gelatin [60], chitosan [31], collagen [61], cellulose [62], silk fibroin [63], hyaluronic acid [64], polylactic acid [65], or polycaprolactone [46].
\nIn addition to specific materials used for production of nanofiber mucosal drug delivery systems they also require surface modification of nanofibers. After the functionalization of a nanofiber surface, drugs might be bound or conjugated to nanofiber surfaces. In such a way, the release of drugs would be attenuated, and the functionality of the surface-immobilized biomolecules could be preserved. This strategy is usually applied in order to overcome the issue of initial burst release as well as short release time. The most used surface modifications are: (i) plasma treatment, (ii) wet chemical method, or (iii) co-electrospinning of active agents.
\nDifferent sources of plasma (e.g., oxygen, argon, ammonia, air) used for treatment of nanofibers can create different functional groups (such as carboxyl or amine groups) on the nanofiber surface. This kind of chemical groups may interact with particular drugs and create covalent bonds. However, if a target biomolecule is chemically bound onto the nanofiber surface, it would hardly be released. Therefore, this technique is more suitable for drugs, where a slow and prolonged release of the agent is required. Plasma treatment can also change hydrophilicity and hydrophobicity of nanofibers.
\nWet chemical method allows changing the wettability of nanofibers under acidic or basic conditions. Surface of nanofibers deep in mesh can also be modified by the wet chemical method. Plasma treatment is, on the contrary, more suitable for flat materials.
\nBy co-electrospinning of active agents, it is possible to directly expose biological functional agents on the surface of nanofibers. Conjugating the biomolecules (DNA, growth factors, or enzymes) to the fiber surfaces allows their slow release into a nearby tissue significantly preserving the functionality of biomolecules.
\nFunctionalization of the nanofiber surface enables loading of drugs. There are many methods how to load them. The most popular and used techniques are: (i) physical adsorption, (ii) nanoparticle assembly method, (iii) layer by layer method, and (iv) chemical immobilization.
\nIn the case of physical adsorption, there is no need for nanofiber functionalization after electrospinning. The fiber web is simply immersed into a solution containing drugs and dried afterward. The same method can be used in the case of nanoparticles containing biological agents. Chemical immobilization requires functionalized surface of nanofibers by the plasma treatment or chemical wet method. Afterward, functional groups on the surface of nanofibers chemically react with added drugs and create covalent bonds. By the multilayer method, it is possible to produce a nanofiber sandwich with different properties on both surfaces. After electrospinning of one layer with drugs added during the electrospinning process, a sandwich with another nanofiber layer without drugs can be created.
\nBiomedical applications of nanofibers such as the mucosal drug delivery system put special requirements on the three-dimensional electrospun materials. Besides the biocompatibility, the morphology of nanofibers is one of the most important attributes. The specific surface area, volume, and the size of the pores have considerable effect on the loading capacity of drugs. The following methods are used to characterize electrospun materials for mucosal drug delivery systems.
\nImaging methods are used for evaluation of nanofiber structure. Imaging methods involve scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM). By SEM and TEM, it is possible to evaluate the nanofiber orientation, nanofiber diameter, and the morphology of nanofibers, which do not only affect the mechanical properties of electrospun materials, but also play a key role in the loading capacity of drugs in the mucosal drug delivery systems. Imaging methods also allow visualization of the morphology of nanofibers at various points of an electrospun material.
\nLoading of drugs must be controlled during the assessment of biological properties and this ability is significantly affected by the physical properties such as pore size and volume of electrospun material. The surface area and the porosity could be measured by mercury porosimetry or by Brunauer-Emmett-Teller (BET) surface area analysis. A pore size distribution is one of the most often presented results of mercury porosimetry. However, the mercury porosimetry can produce a misleading result due to the mechanical deformation of the nanofibers [66]. To overcome this issue, BET measurements are used to measure the specific surface area value and distribution of pores.
\nBesides the morphology of nanofibers, the chemical composition is an important attribute for materials applicable in the mucosal drug delivery systems. The Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) [67], and differential thermal analysis (DTA) are essential methods for measuring the chemical composition. These methods allow detection of abundance of each polymer in the final product. FTIR indicates degradation of nanofibers (for biodegradable materials) as well as it may show their bioactivity. The bioactivity is detected by infrared spectra obtained via FTIR that identifies the functional chemical groups. The hydrophilic/hydrophobic character of electrospun materials influences the loading capacity of nanofibers as well. To determine the degree of hydrophilicity, contact angle measurement is one of the most used methods.
\nThe last most important and crucial characteristic of nanofibers is the release of drugs from electrospun materials [68]. As it was mentioned above, slow or fast release of target drugs might be changed by a different surface functionalization of nanofibers. For this purpose, a dissolution testing apparatus with UV-Vis spectrophotometer is essential to control the release profile.
\nDifferent parts of the human body are covered by mucosa with different features, barrier properties for drug delivery, and also with different accessibility. Formulation of drugs into nanofibers represents one of the new trends in mucosal drug delivery. Due to their extremely large surface area, unique surface topology and porosity, nanofiber-based drug delivery systems enable transmucosal delivery of poorly water-soluble drugs, macromolecules, nanoparticles, and vaccine delivery carriers.
\nExtraordinary flexibility of nanofibers enables us to follow unique anatomical specialities of mucosal surfaces, and hence helps to overcome different absorption barriers of mucosal sites. Moreover, the flexibility of nanofibers helps to significantly increase the comfort of nanofiber-based drug delivery formulations for patients.
\nMucoadhesive nanofibers with drug-controlled release properties and nanofibers with extremely fast-dissolving properties are examples of a great variety of nanofiber-based materials and also examples of a variety of drug delivery system properties advantageous for mucosal administration. Different mucosal sites of administration, including sublingual, buccal, nasal, vaginal, and ocular mucosa, are suitable targets for nanofiber-based drug delivery systems. Mucosal surfaces, as a portal of entry of various infectious pathogens, naturally possess great potential for induction of defensive immune responses against such pathogens. Nanofiber-based delivery platforms, owning their unique properties, may play an important role in formulation of antigens into next-generation vaccine delivery systems intended for mucosal administration.
\nTechnologies of electrospinning, such as Nanospider technology, are modern electrospinning technologies enabling cost-effective industrial-scale production of nanofibrous materials, among others, suitable for mucosal drug delivery applications.
\nCombinations of nanofiber-based formulations and chemical enhancers have a great potential to increase penetration of drug molecules and nanoparticle-based drug and vaccine delivery systems. In conclusion, nanofibers represent a new emerging trend in formulation of drug and vaccine delivery systems for mucosal administration.
\nThis work was supported by the Ministry of Education, Youth, and Sports OPVVV project “CEREBIT” CZ.02.1.01/0.0/0.0/16_025/0007397 (MR,JT); OPVVV project “FIT” CZ.02.1.01/0.0/0.0/15_003/0000495 (JT); the Ministry of Health CZ AZV-ČR 15-32198A (MR, JT), the project MZE0002716202, RO0518 of the Czech Ministry of Agriculture (JT).
\nThere are no conflicts to declare.
In recent years, 68Ga-radiopharmaceuticals gained more and more attention due to their steadily growing clinical application. Facilitated is this development by increasing interest in the application of its “theranostic twin” lutetium-177. Combining both, gallium-68 and lutetium-177, enables diagnostic molecular imaging followed by personalized treatment based on the diagnostic scan [1].
This concept is well established for treatment of neuroendocrine tumors (NETs) using peptide receptor radionuclide therapy (PRRT). This approach allows the targeted treatment of inoperable or metastatic NETs already proven in multiple clinical trials employing radiolabeled somatostatin analogs [2, 3, 4, 5, 6, 7, 8, 9]. Based on the data received, the U.S. Food and Drug Administration (FDA) recently approved 177Lu-labeled DOTA-TATE for PRRT treatment. However, not only for NETs, but also for other types of cancer (e.g. prostate cancer (PC)), lutetium-177 is of interest, reflected in numerous clinical trials registered at
Although, gallium-68 was already proposed for medical use by Gleason [10] its way to clinical application was not possible without the advancement of the primary generator design. Providing [68Ga]GaCl3 and containing only trace levels of the long-living mother radionuclide germanium-68 regarding 68Ga-activity, the commercially availability of generator simplified research and motivated developments with a view to a broad routine application. The launch of this new type of 68Ga-generator together with decades of research in chelation chemistry and drug discovery resulted in the design of 68Ga-radiopharmaceuticals of high affinity/selectivity for their biological targets [11, 12, 13].
The advantages of the generator availability and the easy one-step chelation chemistry ensured the relatively fast and broad application of the 68Ga-radiopharmaceuticals even in smaller institutions. However, exactly these advantages lead to problems in the supply today and require new developments in order to meet the growing demands.
What is the advantage of radiometals for an application in nuclear medicine? With carbon-11 and mostly fluor-18, two radionuclides for positron emission tomography (PET) are available, which can be used for radiolabeling without appreciably altering the biological properties of the compounds in addition to their favorable decay characteristics. However, the disadvantage of radiometals, the need for a chelator is also their advantage over fluor-18 and carbon-11.
Due to this, radiolabeling with radiometals is very easy, can be conducted in aqueous solution and with the right choice of chelator possible under mild conditions. That enables radiolabeling of temperature or organic solvent sensitive compounds (e.g. antibodies). Additionally, the choice of chelator provides the possibility of radiolabeling one compound with different radiometals. Thus, widespread application (PET, single photon emission computed tomography (SPECT), magnet resonance tomography (MRT) and therapy) of the compound only by exchange of the radiometal with minimum changes in biological behavior is possible. This facilitates patient-centered care from diagnosis via molecular imaging, over treatment planning, prognosis and monitoring utilizing one compound (Figure 1).
Depiction of the theranostic concept: utilizing one compound for a variety of applications in patient-centered care radiolabeled with different radionuclide.
Advantages in favor of gallium-68 compared with other appropriate radiometals are its favorable decay characteristics, its (commercial) availability and the possible combination with lutetium-177 as theranostic pair (Figure 2). Also gallium-68 possibly provides patient care in places where cyclotron-produced fluor-18 is not obtainable.
PET-images (A; C) and SPECT-images (B) of a patient with metastatic castrate-resistant prostate cancer (mCRPC) undergoing therapy with [177Lu]Lu-PSMA-617 with pre- and posttherapeutic 68Ga-PET-imaging using the diagnostic counterpart [68Ga]Ga-PSMA-11.
Currently gallium-68 is most widely used in the diagnosis of prostate cancer in the form of [68Ga]Ga-PSMA-11, respectively. [68Ga]Ga-PSMA-617 together with [177Lu]Lu-DOTA-PSMA-617 forms a theranostic couple, which is very well suited for the diagnosis or treatment of prostate cancer as the 68Ga/177Lu-radiolabelled tracers show a very similar biological behavior. Due to similarities in chemical behavior, identical (in case of PSMA-617) precursors can be radiolabelled using the same or similar equipment, synthesis and quality control methods [14].
The second, but longest known and best evaluated, 68Ga theranostic pair is used for neuroendocrine tumors in combination with various somatostatin analogs. The three most widely used analogs of somatostatin with gallium-68 are [68Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TATE, [68Ga]Ga-DOTA-LAN or [68Ga]Ga-DOTA-NOC [15]. As a therapeutic counterpart, yttrium-90 and lutetium-177 are used.
Besides these two main applications of gallium-68, a variety of studies work on the extension of the application scope.
For imaging of insulinoma pancreatic islets, several versions of 68Ga-radiopharmaceuticals based on Exendin-4, a glucagon-like protein-1 receptor agonist, exist and it was demonstrated that [68Ga]Ga-DOTA-exendin-4 localizes insulinoma significantly better than 111In-radiolabelled radiopharmaceuticals [16].
Integrin αvβ3 and gastrin-releasing peptide receptor (GRPR) are usually overexpressed in human breast cancer, prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, glioma, lung cancer, ovarian cancers, endometrial cancers, renal cell cancer and gastrointestinal stromal tumors. An amphibian homolog of the mammalian gastrin-releasing peptide bombesin was intensively investigated, also radiolabelled with gallium-68, for imaging of GRPR. For integrin αvβ3, specific imaging probes usually use the peptide arginine-glycine-aspartic acid (RGD). For imagine of GRPR, several radiopharmaceuticals based on gallium-68 were proposed, in particular [68Ga]Ga-BBN-RGD for breast cancer imagine [17], [68Ga]Ga-NOTA-Aca-BBN for glioma imagine [18], [68Ga]-NOTA-DUPA-RM26 for prostate cancer imagine.
Another promising area of application of 68Ga-based radiopharmaceuticals is the labeling of human epidermal growth factor receptor family (HER2) [19] and carcinoembryonic antigen (CEA) [20].
Even though gallium-68 is a very convenient radionuclide for use in radiopharmacy, it is widespread in radiopharmaceuticals in comparison with other diagnostic isotopes. But usability and the commercially availability of generator simplified research and motivated developments with a view to a broad routine application.
Radiolabeling with radiometals is in some ways challenging. Due to the very low amount of substance, other metals present in the reaction mixture can be serious problem and noticeably effect the radiolabeling. These metallic impurities can compete with gallium-68 for the chelating function of the precursor and are compared with gallium-68 (1 GBq equals to 9.73×10−12 mol) even when present at low levels (<ppm) clearly in excess number. They are result of external influences (e.g. production of starting materials) or are an intrinsic generator property (e.g. matrix; decay product). To avoid additional or larger impurities than necessary, the following is recommended by the IAEA [21]:
Use plastic disposables/contact materials
Avoid contact with metals of your working equipment during preparation of reagents (e.g. pipettes, spatulas, vials, etc.)
Protect your working materials from direct contact with metals (e.g. surfaces, etc.)
Use chemicals and water with lowest metal content as possible (e.g. ultra-pure grade)
Do not use standard laboratory glassware (e.g. beakers, etc.)
Consider coating of your fume hood.
Gallium is located in group 13 in the 4th period. It has 31 known isotopes and 11 metastable isomers including the two natural occurring stable isotopes gallium-69 (60.11%) and gallium-71 (39.89%). Two gallium isotopes are applied in nuclear medicine for PET-imaging: gallium-67, which has the longest half-life (T1/2 = 3.26 d) of the instable 68Ga-isotopes, and gallium-68 (T1/2 = 67.71 min).
Ga(III) is a hard Lewis acid forming complexes coordinating four, five or six ligands. The most stable complexes are the last-mentioned with a octahedral coordination sphere in which oxygen, nitrogen and sulfur donor atoms form coordination bonds with Ga(III). To ensure the complex formation thorough pH, control is required to ensure deprotonation of the electron donor and to protect Ga(III) from forming Ga(OH)3 precipitating at pH 3–7 [22].
Gallium-68 is a positron emitter that decays with a half-life of 67.71 min and 89% positron branching to stable zinc-68. The transition is accompanied by low-abundant photon emission (1077 keV, 3.22%) [23]. Table 1 shows the mean and maximum energies of the positrons emitted in comparison to fluorine-18.
Positron emitter | Half-life | Eβ, max | |
---|---|---|---|
[MeV] | |||
Gallium-68 | 67.71 min | 0.829 | 1.899 |
Flourine-18 | 109.77 min | 0.250 | 0.634 |
Comparison of mean (
One of the reasons of the emerging application of gallium-68 in nuclear medicine is its cyclotron-independency and availability via radionuclide generator. Since the application of gallium-68 was a long time limited to research, advancements in generator design facilitated research on new 68Ga-radiopharmaceuticals as well as clinical use of the known.
Physical basis for radionuclide generators is the existence of the radioactive equilibria. The differentiation between radionuclide generations is based on the half-lives of the parent (1) and its daughter (2). Depending on the ratio between the two half-lives, three principal cases can be distinguished:
Transient equilibrium. Longer living parent but not more than factor 100: T1/2, 2 < T1/2,1 < 100.
Secular equilibrium. Much longer living parent: T1/2, 2 < < T1/2,1.
No equilibrium. Shorter living parent.
The basis for the 68Ge/68Ga-generator is the secular equilibrium between the parent radionuclide germanium-68 and its daughter gallium-68. Germanium-68 decays with T1/2 = 270.95 days via electron capture to gallium-68. This transition is subsequently followed by decay of gallium-68 to stable zinc-68. At equilibrium, the quantity of gallium-68 produced is equal to the quantity of gallium-68 decaying, while the parent activity does not significantly decrease over many half-lives of the daughter. The theoretical maximum activity or equilibrium state for a certain generator system can be obtained at the time t (Figure 3):
Build-up kinetics of gallium-68 on the generator column after initial elution.
For the 68Ge/68Ga system, equilibrium is reached after 14.1 h, representing maximum obtainable activity. Even if idle times of 12.5 half-lives are necessary to obtain maximum activities, the generators can be used more frequently. Within two half-lives of gallium-68 already 75% of the maximum value is build-up and could be used.
The 68Ge/68Ga-generator system introduced in the 1960s by Gleason [10] underwent a lot of changes until today. From the first gallium cow providing gallium-68 after liquid–liquid extraction [10], nowadays the generators, based on a solid matrix (inorganic or organic) providing “ionic” 68Ga3+ eluates. The first commercially available generator of this type was developed by Cyclotron Ltd., Obninsk, Russian Federation [25] eluting gallium-68 with 0.1 M HCl with initial elution yields of ~80% and 68Ge breakthrough of 0.001% [26]. Since the introduction of this generator in 1996 [26], a lot has happened on the market. Today several manufacturers produce 68Ge/68Ga-generators, including ones with GMP grade (e.g. Isotopen Technologien Garching (ITG)) or with approval (e.g. GalliPharm® Eckert & Ziegler in the EU with marketing authorization, in the USA with type II drug master file (DMF) on file with FDA).
Even though these generators represent considerable improvements in 68Ga-production, there are still some obstacles to direct radiolabeling with gallium-68. Beside the low radioactive and high [H+] concentration and 68Ge breakthrough, especially the presence of other trivalent metal ions is an inconvenience. As 1 GBq gallium-68 is equal to 9.73 pmol (9.73×10−12 mol), these metallic impurities, even present at low levels (<ppm), can be a serious problem as they can compete with gallium-68 for the chelating function of the precursor. In addition to the IAEA recommendations on externally introduced metallic contaminations [21], several procedures are available to reduce those metallic impurities, either intrinsic or externally introduced. These post-elution purification methods, so called post-processing’s, aim to improve the radioactive and [H+] concentration and the radionuclidic as well as chemical purity of the 68Ga-eluate. Beside fractionation of the eluate [11], anion-exchange (AEX) [13], cation-exchange (CEX) [27, 28, 29] and a combination thereof [30, 31] found to be suitable but only for fractionation but also are commercially used for cation-exchange.
Although 68Ge/68Ga-generators represent a convenient possibility for persistent patient care with 68Ga-radiopharmaceuticals, their 68Ga-activity available for radiolabeling underlies several restrictions resulting from generator design and physics. In conjunction with the sharp increase in demand in recent years, alternative production routes, preferably realizable with existing medical cyclotrons, moved into the focus.
Small to medium energy medical cyclotrons are suitable for 68Ga-production via the 68Zn(p,n)68Ga reaction using either a solid or a liquid target. Among the possible nuclear reactions [32, 33], it is the most reasonable leading to large production yields. For optimal results, the starting material zinc-68 as well as the proton energy needs to be selected with care to reduce co-production of long-living radioisotopes of gallium. Nevertheless, co-production of gallium-66 and gallium-67 is unavoidable due to the starting material and the excitation function of the 68Zn(p,2n)67Ga reaction [32, 33]. This has to be taken into account when producing gallium-68 via cyclotron for radiopharmaceutical application as both radioisotopes cannot be separated from the desired gallium-68.
For production of gallium-68 via cyclotron, either a solid or a liquid target can be used. For both target types, a lot of options exist leading to a several considerations to be made. Solid targets, for example, can be pressed, electroplated, foil or fused, all types having their advantages and disadvantages which are not mentioned here. In a first instance, the choice of target will mostly be done due to the actual conditions of the site. An existing production site for 18F-compounds which want to implement gallium-68 would probably choose the liquid target route, as the preconditions for a solid target (target holder, cooling, target transfer and target processing) are expensive and likely not available. Compared with that, the liquid target is a quick and inexpensive option to obtain gallium-68 when a generator is not reasonable. A detailed overview about all possible alternatives and their advantages/disadvantages is given by the IAEA [21].
After irradiation, the gallium-68 needs to be purified from target material either if a solid or liquid target was used. The quantity of zinc necessary for the target need to be removed as it and all other metal impurities may perturb the radiolabeling reaction of gallium-68. Intense research on this topic lead to several purification methods based on solvent extraction [34, 35], precipitation [36] and solid phase separation [37, 38, 39, 40, 41, 42, 43, 44] and suitable for automation.
Solid-phase extraction using a cation exchange resin or hydroxamate resin is most appropriate for an effective separation of gallium-68 from unwanted metals and can be easily combined with a second resin. This second purification step allows an additional reduction of [H+] concentration to facilitate further processing of the final product [21]:
Local conditions (expertise and equipment)
Separation time (should be as short as possible)
Acids (concentration and volume)
Availability of materials
Robustness of technique
Ease of automation
Possibility to recycle zinc-68 from target solution
The manual radiolabeling approach is a leftover from times, where gallium-68 was mainly used for research purpose, with lower 68Ga-activities and not in a clinical setting for patient care. It is widely used in research and development of new tracers [11, 12, 13, 29, 30, 45, 46, 47, 48, 49, 50, 51]. Its main advantage is full control over the complete process (pH, time and temperature) and the possibility to easily access radiolabeling kinetics.
Due to its general setup, this method is not suitable and indented for clinical use. Nevertheless, before the introduction of module systems or the cold kits, it was a long time, the only available method.
In general (Figure 4), the first step is the preparation of the reaction mixture by mixing [68Ga]GaCl3 with a suitable buffer in the required pH range and the radiolabeling precursor. Here, the purified cyclotron-produced, generator eluate or post-processed gallium-68 can be used.
Schematic description of the 68Ga-radiolabeling procedure (I) preparation of the reaction mixture by adding gallium-68 eluted from a generator or after post-processing to a mixture of a suitable buffer and precursor, (II) incubation of the reaction mixture for a certain time. If elevated temperatures are needed or not depends on the chelator, (III) purification step using solid phase extraction (SPE). For example, the 68Ga-radiopharmaceutical is trapped on a SPE C18-cartridge where it is washed with water to remove free gallium-68, germanium-68 and buffer, (IV) the purified product is finally eluted with diluted ethanol solution and formulated after sterile filtration in the product vial.
Then, the reaction vial is incubated to form the 68Ga-complex. Reaction period and reaction temperature are selected in accordance to the kinetics of the complex formation of gallium with the used chelator.
After the reaction, the reaction mixture can be purified using, for example, solid phase extraction from, for example, free gallium-68 and residual germanium-68 impurities.
In the final step, the 68Ga-radiopharmaceutical is sterile filtrated and formulated in the product vial (Table 2).
With the growing interest for gallium-68 not only for research but also for clinical routine and patient care the need for pharmacopeia compliant preparation of 68Ga-radiopharmaceuticals. This led to promotion of the automation of the traditional manual synthesis from which numerous semi- and fully automated devices have emerged. Today, those systems are designed with respect to Good Manufacturing Practice (GMP) Guidelines provided, for example, by the FDA, EU/EMA, ICH, WHO or others [55]. They use software and methods designed to minimize user interventions and utilize single-use consumables produced under GMP standard.
While the module production requires a fully equipped laboratory and quality control, it reduces radiation exposure of the operator the production process in terms of higher reliability and reduced variability [56, 57, 58].
Accordingly, the amount of contaminated waste materials is higher due to the procedure as well the complete quality control. Nevertheless, these systems are suitable for a variety of tracers and in most cases for more radionuclides not only for gallium-68 (e.g. Scintomics GRP series; Eckert & Ziegler Modular-Lab PharmTracer; Trasis AllInOne).
Recently, cold kits for radiolabeling entered the scene enable production of 68Ga-radiopharmaceuticals as easy as that of 99mTc-radiopharmaceuticals. This method allows the reconstitution of the pre-formulated cold kit with no previous post-processing of the eluate or subsequent purification of the final product. They are available in GMP quality and leaves only minimum quality control tests to the final user responsibility to verify the reconstitution procedure.
For example, the European Pharmacopeia (Ph. Eur.) states the marketing authorization (MA) holder of a licensed kit is responsible to ensure compliance of the kit with the requirements of its MA, while the final user carries the responsibility for the quality of the preparation and the handling. If the given instructions are not strictly followed or if one or more components used for the reconstitution do not have MA, it is the responsibility of the final user to demonstrate that the quality of the final preparation is suitable for the intended, use [26].
Therefore, preparation as well as quality control requires at least the equipment according to the instructions provided by the manufacturer. In addition, minimum contaminated waste materials remain. It has to be noted, according to the Ph. Eur. that applies only for licensed kits in combination with the generator mentioned in the instructions from the manufacturer. In contrast, unlicensed kits or a licensed kit used with an unlicensed generator or cyclotron produced gallium-68 also require full quality control according to the monograph. Additionally, local authorities may require more detailed quality control even for licensed kits.
Indeed, these cold kits contain relatively high amounts of precursor and additional filler materials. They still require manual handling and are only commercially available as single-dose kits for radiolabeling PSMA-11 (e.g. illumet™) and DOTA-TOC (e.g. NETSPOT®). In addition, the use of unpurified generator eluates requires very strict specifications for the generators in terms of 68Ge-breakthrough to ensure the quality of the final product. Nevertheless, there is a possibility for small sites to offer 68Ga-radiopharmaceuticals to their patients without great expense.
Quality defects of pharmaceutical can lead to serious consequences when they are applied. Consequently, the regulatory framework for production and quality control is very strict. In general, one main requirement in the production of pharmaceuticals is a comprehensive, integrated system of quality assurance. Its purpose is the monitoring and documentation of all processes as well as their functionality with respect to the rules of GMP.
Because radiopharmaceuticals are pharmaceutical preparations containing minimum one radionuclide for diagnostic or therapeutic purpose, in principle the same rules apply. Their quality control is intended to ensure that the quality meets the predefined specifications for the radiopharmaceutical. These specifications take into account the radionuclide, the precursor, the preparation process, the formulation and the intended administration route. Due to the nature of the contained radionuclides, not all necessary quality control tests can be performed before release for administration and require retrospective examination. In the available monographs, it is indicated if a test need not to be completed before release of the batch.
In the case of gallium-68, the short half-live and the limited available activities lead to further challenges. Here are sophisticated logistics for preparation and quality control essential.
In general, quality control of 68Ga-radiopharmaceuticals should include the following tests and information [59, 60, 61]:
Characters/appearance. Should discover any visible container defects. The quality of the final product in terms of absence of particular matter [62] and/or turbidity should be ensured as well as its correct appearance. Typically performed by visual inspection.
pH determination. Should ensure that the pH of the final product is in the necessary range for its purpose. For the final injectable formulation of a radiopharmaceutical, the pH should be closed to the physiologic value of 7.4. With regard to the relatively low volume of radiopharmaceuticals and depending on the injected volume and rate, a wider range (3.5–8.5) is applicable. Contrary to this, the pH of the radionuclide precursor gallium-68 should not exceed 2 to prevent the formation of unwanted 68Ga-colloids.
Radionuclidic identification. Identification of a radionuclide is generally conducted by determination of its half-life and/the nature and energy of its radiation emitted. For positron emitters like gallium-68 instead of energy and nature of the radiation, the identification is based on a γ-spectrum additional to their half-life determination (e.g. with dose calibrator).
Radiochemical identification. Identification of the desired radiochemical species via HPLC and/or TLC exploiting different chemical behavior of the different radiochemical species.
Radionuclidic purity. Due to the contribution or formation of other radionuclides during the production of gallium-68, their amount present in the final radiopharmaceutical must be determined. Depending on the production route of gallium-68, different limits for radionuclidic impurities may apply. The test for those long-living radionuclides need to be performed after complete decay of the sample using γ-spectrometry, representing a test performed after release of the batch.
Radiochemical purity. Should discover all chemical forms containing the radionuclide and determine their percentage of the total radioactivity of the product. These radiochemical impurities arise from the synthesis method, radiolysis or the radionuclide production and can lower the quality of the final diagnostic examination. Principally be determined by any suitable analytical method but with respect to the short half-life and radiation TLC and HPLC are normally used for quality control of 68Ga-radiopharmaceuticals.
Chemical purity. The chemical purity refers to the amount of the specified chemical form of a preparation if radioactivity is present or not [61]. Purity assessment is of special importance when diagnostic or therapeutic properties are directly linked to chemistry [63]. Therefore, particular attention is necessary for pharmacologically active impurities as they can affect the diagnostic value of the examination. The chemical purity of 68Ga-radiopharmaceuticals is normally ascertained with TLC and/or HPLC.
Residual solvents. Ph. Eur. as well as US pharmacopeia defines residual solvents as organic volatile chemicals used in the manufacture of drug substances/active substances, excipients or in the preparation of medicinal products (Eur. Ph. 5.4.; USP 467). As they represent a risk of health, they should be determined. Determination can be performed using gas chromatography (GC)
It has to be noted that the texts about residual solvents not cover solvents added by purpose or solvates. For those other limits and regulations may apply.
Microbiological contamination. Parenteral administered radiopharmaceuticals need to be compliant in terms of bacterial endotoxins or pyrogens as well as sterility
Bacterial endotoxins are known to cause a wide spectrum of nonspecific pathophysiological reactions (fever, changes in white blood cell counts, hypotension, disseminated intravascular coagulation, shock and death) leading to death when injected in most mammals [64]. Thanks to the development of more and more efficient systems today tests (LAL-test) for bacterial endotoxins (BET) can be completed before release of the batch of the 68Ga-radiopharmaceuticals.
In contrary, the test for sterility of 68Ga-radiopharmaceuticals via direct inoculation is necessarily retrospective nevertheless indispensable. Additionally, to the direct inoculation test the integrity of the sterile filter used for sterile filtration of the final product is performed. Due to the need for sterilization to obtain a sterile parenteral solution and the not applicability of autoclaving for short-living radiopharmaceuticals membrane filtration is normally the method of choice. The tests for the filter integrity (e.g. bubble point, diffusion rate, pressure hold) have the advantage that they can be completed before batch release.
Radioactivity content/concentration. Defines the activity, measured with a dose calibrator, within the volume of the final preparation.
Specific radioactivity. The specific radioactivity (activity of the radionuclide per unit mass either of the element or the desired chemical form) is calculated using the concentrations of radioactivity and the chemical form. Referring to the consensus nomenclature rules for radiopharmaceutical chemistry [65], the specific activity is expressed as measured activity per gram of compound (e.g. MBq/μg), while it is called molar activity when expressing the measured activity per mole of compound (MBq/nmol) [65]. As gallium-68 requires a complex ligand which is normally not fully removed during the final product purification, the measured specific or molar activity is lower than actual. Then the correct terms are apparent specific or molar activity [65].
The specific or molar activity is always given with reference date and time.
For gallium-68 obtained from a 68Ge/68Ga-generator, the Ph. Eur. contains a distinct monograph (#2464). This monograph specifies the quality characteristics of 68Ga chloride solutions for radiolabeling independently if obtained directly from a generator or after post-processing the generator eluate. If a further purification of the generator eluate is performed, this has to be stated on the label.
Use of generator-produced gallium-68 in the USA is regulated under 10 CFR 35. 1000 and 10 CFR 30.33 [66] (Table 3).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of generator produced gallium-68 as defined by the Ph. Eur. (monograph #2464) [59].
For incoming starting materials, the GMP guidelines prescribe certain handling procedures to ensure their quality and suitability. For material acceptance of an incoming new 68Ge/68Ga-generator, minimum controls are needed. This include the conformation of the radionuclide identity, 68Ge-breakthrough and of activity stated in the Certificate of Analysis (CoA) all verified by activity measurement if possible [60]. Establishment of additional acceptance criteria may be required.
Nevertheless, the 68Ga-eluate used for radiolabeling should meet those specifications (Table 4), their verification is in clinical routine not possible for every production. This results from the different production routes of 68Ga-radiopharmaceuticals, which do not intend or allow an intervention for sampling of the eluate. Thus, the quality control of the starting material gallium-68 or of the final radiopharmaceuticals is allowed. This should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
Manufacturer | Type | Maximum nominal activity |
---|---|---|
Eckert & Ziegler (Germany) | GalliaPharm® | 2.4 GBq |
IGG100 | 2.4 GBq | |
Obninsk Cyclotron Ltd. (Russia) | 3.7 GBq | |
IRE Elit (Belgium) | Galio Eo® | 1.85 GBq |
Galli Ad® | 1.85 GBq | |
ITG (Germany) | 2 GBq | |
iThemba Labs (South Africa) | 1.85 GBq | |
Pars Isotopes (Iran) | Pars-GalluGEN | 2.59 GBq |
In all conscience a list of 68Ge/68Ga-generators available.
When produced via accelerator, the presence of the radioisotopes gallium-66 and gallium-67 is difficult to avoid due to zinc-66 and zinc-67 contaminating the target material. In return, germanium-68 is absent. Therefore, quality control and specifications for radionuclidic impurities are different to generator-produced gallium-68.
For gallium-68 obtained from a cyclotron, a new monograph (#3109) is already submitted for adoption to the Ph. Eur. [67]. This monograph specifies the quality characteristics of 68Ga-chloride solutions for radiolabeling obtained by irradiation of enriched zinc-68 in an accelerator with subsequent isolation of gallium-68 in acidic solution (Table 5).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | <2 |
Radionuclide identity | Half-life determination | 62–74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<2% gallium-66 & gallium-67 | ||
Radiochemical purity | TLC | >95% 68Ga(III) |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
Bacterial Endotoxins | LAL test | ≤175 EU/total volume |
Quality control specifications for diluted hydrochloric solutions of accelerator-produced gallium-68 as defined by a draft of a monograph for the Ph. Eur. Submitted for adoption (#3109) [67].
Similar to generator-produced gallium-68, quality control can be performed of the starting material obtained via cyclotron or on the final radiopharmaceutical. If quality control of the final radiopharmaceuticals performed, it should include at least tests for 68Ge-breakthrough, radionuclidic purity, radiochemical purity and chemical purity.
As an example for the specifications and limitations for a 68Ga-radiopharmaceutical quality control as requested by the monograph #2464 of the Ph. Eur. [68Ga]Ga-DOTA-TOC is provided [59]. It has to be noted, that monograph #2464 is currently under revision which can lead to different limits in feature (Table 6).
WHAT? | HOW? | LIMITS |
---|---|---|
Appearance | Visual inspection | Clear, colorless solution |
pH | pH indicator strips | < 2 |
Radionuclide identity | Half-life determination | 62 to 74 min |
γ-spectrometry | 511, (1022), 1077, (18,839 keV | |
Radionuclidic purity | γ-spectrometry | <0.1% long living impurities |
<0.001% germanium-68 | ||
Radiochemical purity | TLC | >91% |
TLC | <3% [68Ga]Ga in colloidal form | |
HPLC | <2% [68Ga]Ga3+ | |
Chemical purity | ICP-AES/ICP-MS | <10 μg/GBq Fe |
<10 μg/GBq Zn | ||
HPLC | <50 μg/V DOTA-TOC and metal complexes of DOTA-TOC | |
TLC | <200 μg/V HEPES | |
GC | <10% V/V and <2.5 g per administration | |
Bacterial endotoxins | LAL test | ≤175 EU/total volume |
Sterility | Direct inoculation | sterile |
Quality control specifications [68Ga]Ga-DOTA-TOC as given by the Ph. Eur. For generator-produced gallium-68 (monograph #2464) [59].
The quality control for a certain 68Ga-radiopharmaceutical depends on the production route of gallium-68, the synthesis route of the radiopharmaceutical as well as of the relevant legislation.
As descripted in Section 7.2, the respective production route leads to different radionuclidic impurities (germanium-68 vs. gallium-66 & gallium-67) that need to take into account for the final product specifications. However, this is not yet implemented in the pharmacopeias but is in part already in progress. For example, the monograph for [68Ga]Ga-DOTA-TOC (#2464) of the Ph. Eur. is currently in revision to take into account the cyclotron production of gallium-68 [68].
In general, the quality of the final radiopharmaceutical needs to fulfill all specifications given by the relevant legislation or pharmacopeia independent from the synthesis route. Nevertheless, it may be possible to dispense individual tests given, for example, for licensed kit preparations. For example, the Ph. Eur. states in its general notices “An article is not of Pharmacopoeia quality unless it complies with all the requirements stated in the monograph. This does not imply that performance of all the tests in a monograph is necessarily a prerequisite for a manufacturer in assessing compliance with the Pharmacopoeia before release of a product. The manufacturer may obtain assurance that a product is of Pharmacopoeia quality on the basis of its design, together with its control strategy and data derived, for example, from validation studies of the manufacturing process” [59]. Further details can be found in the general chapter on extemporaneous preparation of radiopharmaceuticals (5.19) and the general monograph radiopharmaceutical preparations (#0125) [59].
Nevertheless, the competent authorities may request further quality control testing. Therefore, it is strongly recommended, especially in case of doubt, to consult the competent authorities.
The implementation of a new radiopharmaceutical into the certain pharmacopeias is a protracted process. Therefore, several commonly used 68Ga-radiopharmaceuticals are not yet represented with own monographs in the pharmacopeias (e.g. [68Ga]Ga-PSMA-11). Nevertheless, such radiopharmaceuticals can be produced with consideration of the general notices, texts, monographs and along the lines of, for example, the monograph for [68Ga]Ga-DOTA-TOC. Again, in case of doubt, the competent authorities should be consulted.
Gallium-68 is a well-researched radionuclide with growing importance for clinical practice triggered by the development of new tracers expanding its application and the increasing demand for theranostic patient care.
Its availability via radionuclide generator in combination with comparably easy coordination chemistry enables a patient care even in places where the cyclotron-produced PET-radionuclides are unavailable and, in the case of NETs, enables patient care where no 18F-alternative exists.
This work was supported by the Ministry of Science and Higher Education of the Russian Federation project RFMEFI60719X0301.
The authors declare no conflict of interest.
AEX | anion-exchange |
API | active pharmaceutical ingredient |
BET | bacterial endotoxin test |
CEX | cation-exchange |
DMF | drug master file |
EU | European Union |
FDA | U.S. Food and Drug Administration |
GC | gas chromatography |
GMP | good manufacturing practice |
HCl | hydrochloric acid |
HPLC | high pressure liquid chromatography |
ICP-AES | inductively coupled plasma atomic emission spectroscopy |
ICP-MS | inductively coupled plasma mass spectrometry |
ITG | Isotopen Technologien Garching |
LAL-test | limulus amebocyte lysate test |
M | molarity (mol/liter) |
MA | marketing authorization |
mCRPC | metastatic castrate-resistant prostate cancer |
NET | neuroendocrine tumor |
PC | prostate cancer |
PET | positron emission tomography |
Ph. Eur. | European pharmacopeia |
pmol | picomol (10−12 mol). |
QC | quality control |
PRRT | peptide receptor radionuclide therapy |
SPE | solid phase extraction |
T1/2 | half-life |
TLC | thin layer chromatography |
USA | United States of America |
U.S. | United States |
USP | United States Pharmacopeia |
IntechOpen implements a robust policy to minimize and deal with instances of fraud or misconduct. As part of our general commitment to transparency and openness, and in order to maintain high scientific standards, we have a well-defined editorial policy regarding Retractions and Corrections.
",metaTitle:"Retraction and Correction Policy",metaDescription:"Retraction and Correction Policy",metaKeywords:null,canonicalURL:"/page/retraction-and-correction-policy",contentRaw:'[{"type":"htmlEditorComponent","content":"IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\\n\\n1. RETRACTIONS
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\\n\\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\\n\\nPublishing of a Retraction Notice will adhere to the following guidelines:
\\n\\n1.2. REMOVALS AND CANCELLATIONS
\\n\\n2. STATEMENTS OF CONCERN
\\n\\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\\n\\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\\n\\n3. CORRECTIONS
\\n\\nA Correction will be issued by the Academic Editor when:
\\n\\n3.1. ERRATUM
\\n\\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\\n\\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n3.2. CORRIGENDUM
\\n\\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\\n\\n4. FINAL REMARKS
\\n\\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\\n\\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\\n\\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\\n\\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\\n\\nPolicy last updated: 2017-09-11
\\n"}]'},components:[{type:"htmlEditorComponent",content:'IntechOpen’s Retraction and Correction Policy has been developed in accordance with the Committee on Publication Ethics (COPE) publication guidelines relating to scientific misconduct and research ethics:
\n\n1. RETRACTIONS
\n\nA Retraction of a Chapter will be issued by the Academic Editor, either following an Author’s request to do so or when there is a 3rd party report of scientific misconduct. Upon receipt of a report by a 3rd party, the Academic Editor will investigate any allegations of scientific misconduct, working in cooperation with the Author(s) and their institution(s).
\n\nA formal Retraction will be issued when there is clear and conclusive evidence of any of the following:
\n\nPublishing of a Retraction Notice will adhere to the following guidelines:
\n\n1.2. REMOVALS AND CANCELLATIONS
\n\n2. STATEMENTS OF CONCERN
\n\nA Statement of Concern detailing alleged misconduct will be issued by the Academic Editor or publisher following a 3rd party report of scientific misconduct when:
\n\nIntechOpen believes that the number of occasions on which a Statement of Concern is issued will be very few in number. In all cases when such a decision has been taken by the Academic Editor the decision will be reviewed by another editor to whom the author can make representations.
\n\n3. CORRECTIONS
\n\nA Correction will be issued by the Academic Editor when:
\n\n3.1. ERRATUM
\n\nAn Erratum will be issued by the Academic Editor when it is determined that a mistake in a Chapter originates from the production process handled by the publisher.
\n\nA published Erratum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n3.2. CORRIGENDUM
\n\nA Corrigendum will be issued by the Academic Editor when it is determined that a mistake in a Chapter is a result of an Author’s miscalculation or oversight. A published Corrigendum will adhere to the Retraction Notice publishing guidelines outlined above.
\n\n4. FINAL REMARKS
\n\nIntechOpen wishes to emphasize that the final decision on whether a Retraction, Statement of Concern, or a Correction will be issued rests with the Academic Editor. The publisher is obliged to act upon any reports of scientific misconduct in its publications and to make a reasonable effort to facilitate any subsequent investigation of such claims.
\n\nIn the case of Retraction or removal of the Work, the publisher will be under no obligation to refund the APC.
\n\nThe general principles set out above apply to Retractions and Corrections issued in all IntechOpen publications.
\n\nAny suggestions or comments on this Policy are welcome and may be sent to permissions@intechopen.com.
\n\nPolicy last updated: 2017-09-11
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