Inhibition of LP (%) in Fe2+/ascorbate system of induction by essential oil of balm leaves and BHT (as a positive control) in the TBA assay.
\\n\\n
More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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He also works as a Honorary Senior Research Fellow at Birmingham University, UK, Lecturer at the Postgraduate European Institute, and has worked as Senior Manager in Accenture (2013-2014). He obtained his European PhD with a maximum distinction. He is a holder of the Runner Prize for Management Science and Engineering Management Nominated Prize (2020), Advancement Prize (2018), First International Business Ideas Competition 2017 Award (2017), Runner (2015), Advancement (2013) and Silver (2012) by the International Society of Management Science and Engineering Management (ICMSEM), and Best Paper Award in the international journal of Renewable Energy (Impact Factor 3.5) (2015). He has published more than 150 papers (65 % ISI, 30% JCR, and 92% internationals), some recognized as follows: “Applied Energy” (Q1, as “Best Paper 2020”), “Renewable Energy” (Q1, as “Best Paper 2014”), “ICMSEM” (as “excellent”), “International Journal of Automation and Computing” and “IMechE Part F: Journal of Rail and Rapid Transit” (most downloaded), etc. He is an author and editor of 25 books (Elsevier, Springer, Pearson, Mc-GrawHill, IntechOpen, IGI, Marcombo, AlfaOmega, etc.), and 5 patents. He is also an Editor of 5 International Journals and Committee Member of more than 40 International Conferences. He has been a Principal Investigator in 4 European Projects, 6 National Projects, and more than 150 projects for universities, companies, etc. He is an European Union expert in AI4People (EISMD) and ESF. He is Director of www.ingeniumgroup.eu. His main interest are: artificial intelligence, maintenance, management, renewable energy, transport, advanced analytics, and data science.",institutionString:"University of Castile-La Mancha",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"10",totalChapterViews:"0",totalEditedBooks:"10",institution:{name:"University of Castile-La Mancha",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:{id:"155714",title:"Dr.",name:"Noor",middleName:null,surname:"Zaman",slug:"noor-zaman",fullName:"Noor Zaman",profilePictureURL:"https://mts.intechopen.com/storage/users/155714/images/5120_n.png",biography:"Dr. Noor Zaman acquired his degree in Engineering in 1998, and Master’s in Computer Science at the University of Agriculture at Faisalabad in 2000. His academic achievements further extended with Ph.D. in Information Technology at University Technology Petronas (UTP) Malaysia. He has vast experience of 16 years in the field of teaching and research. He is currently working as an Assistant Professor at the College of Computer Science and Information Technology, King Faisal University, in Saudi Arabia since 2008. He has contributed well in King Faisal University for achieving ABET Accreditation, by working as a member and Secretary for Accreditation and Quality cell for more than 08 years. He takes care of versatile operations including teaching, research activities, leading ERP projects, IT consultancy and IT management. He headed the department of IT, and administered the Prometric center in the Institute of Business and Technology (BIZTEK), in Karachi Pakistan. He has worked as a consultant for Network and Server Management remotely in Apex Canada USA base Software house and call center.\n\nDr. Noor Zaman has authored several research papers in indexed journals\\\\international conferences, and edited six international reputed Computer Science area books, has many publications to his credit. He is an associate Editor, Regional Editor and reviewer for reputed international journals and conferences around the world. He has completed several international research grants\\\\funded projects and currently involved in different courtiers. His areas of interest include Wireless Sensor Network (WSN), Internet of Things IoT, Mobile Application Programming, Ad hoc Networks, Cloud Computing, Big Data, Mobile Computing, and Software Engineering.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"King Faisal University",institutionURL:null,country:{name:"Saudi Arabia"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"759",title:"System Modeling and Analysis",slug:"system-modeling-and-analysis"}],chapters:[{id:"40445",title:"Maintenance Management Based on Signal Processing",slug:"maintenance-management-based-on-signal-processing",totalDownloads:2773,totalCrossrefCites:0,authors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"},{id:"155699",title:"Dr.",name:"Raul",surname:"Ruiz De La 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This requires extensive analysis of developing trends in scientific research in order to offer our readers relevant content. Creating the book catalogue is also based on keeping track of the most read, downloaded and highly cited chapters and books and relaunching similar topics. I am also responsible for consulting with our Scientific Advisors on which book topics to add to our catalogue and sending possible book proposal topics to them for evaluation. Once the catalogue is complete, I contact leading researchers in their respective fields and ask them to become possible Academic Editors for each book project. Once an editor is appointed, I prepare all necessary information required for them to begin their work, as well as guide them through the editorship process. I also assist editors in inviting suitable authors to contribute to a specific book project and each year, I identify and invite exceptional editors to join IntechOpen as Scientific Advisors. I am responsible for developing and maintaining strong relationships with all collaborators to ensure an effective and efficient publishing process and support other departments in developing and maintaining such relationships."}},relatedBooks:[{type:"book",id:"120",title:"Digital Filters",subtitle:null,isOpenForSubmission:!1,hash:"10692f498575728ddac136b0b327a83d",slug:"digital-filters",bookSignature:"Fausto Pedro García Márquez",coverURL:"https://cdn.intechopen.com/books/images_new/120.jpg",editedByType:"Edited by",editors:[{id:"22844",title:"Prof.",name:"Fausto Pedro",surname:"García Márquez",slug:"fausto-pedro-garcia-marquez",fullName:"Fausto Pedro García Márquez"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"5223",title:"Non-Destructive Testing",subtitle:null,isOpenForSubmission:!1,hash:"1cd0602adf345e3f19f63dfbf81651d0",slug:"non-destructive-testing",bookSignature:"Fausto Pedro Garcia Marquez, Mayorkinos Papaelias and Noor 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Lipid peroxidation is used as a marker of cellular oxidative stress and contributes to the oxidative damage that occurs as a result of xenobiotics metabolism, inflammatory processes, ischemia, reperfusion injuries and chronic diseases such as atherosclerosis and cancer [1,2].
Cell membrane lipids (phospholipids, glycolipids and cholesterol) are the most common substrates of oxidative attack. Once initiated reaction autocatalytic continues, it has pro-gradient flow, and the ultimate consequence is the structural-functional changes of the substrate. Lipid peroxidation is one of the best studied processes of cell damage under conditions of oxidative stress [3-5]. In 1960s Hochstein et al. [6] found that the initiation of lipid peroxidation require the presence of iron ions. From that moment the mechanism of lipid peroxidation process has been studied in many in vitro systems. However, accurate and precise mechanism is still not fully understood. Peroxidation in liposomes is usually studied after adding iron ions (Fe2+ plus ascorbic acid). Although the mechanism is not fully understood, it is known that redox chemistry of iron plays an important role in the occurrence and the rate of lipid peroxidation. Many studies have shown that the iron-dependent lipid peroxidation in systems comprised initially of Fe2+ and liposomes requires Fe2+ oxidation. In their research work, Minotti and Aust [7] assumed that the complex is formed between Fe2+ and Fe3+ ions could be initiator of iron-dependet lipid peroxidation. However, the existence of this complex has never been proven. In contrast, Aruoma et al. [8] argue against the participation of a Fe2+-Fe3+-O2 complex, or a critical 1:1 ratio of Fe2+ to Fe3+, in the initiation of lipid peroxidation in liposomes. Study of Tang et al. [9] showed that whether adding 100 or 150 mM Fe2+ initially or adding 100 mM Fe2+ initially and then 50 mM Fe2+ later at various times during the latent period in the liposomal system, the concentration of the remaining Fe2+ at the end of the latent period was almost the same every time.
Since lipid peroxidation causes oxidative damage to cell membranes and all other systems that contain lipids, in investigation of total antioxidative activity of plant extracts it is necessary to investigate their effects on lipid peroxidation. However, the impact of various natural products (isolated compounds and extracts) on the intensity of lipid peroxidation is studied in a number of substrate (linoleic acid, liposomes, various fatty oils, liver homogenates or hepatocytes isolated from it). Some substrates (liposomes and linolenic acids) are used more frequently than others mainly because of the simpler ways of performing the method. Also, due to the complex composition, examining the process of lipid peroxidation in fatty oils and liver homogenates makes research more difficult.
Liposomes are microscopic structure consisting of the one or more lipid bilayer enclosing the same number of water compartments. First, they were produced in Great Britain in 1961 by Alex D. Bangham while he was studying blood clotting. It was discovered that when phospholipids were combined with water they immediately formed a sphere. This is due to the fact that one end of each molecule is water soluble, while the oposite end is water insoluble. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends; fat-soluble medications were incorporated into phospholipids layer and then – an important delivery system was born! Generally, such a structure formed polar lipids (such as phospholipids) [10]. Liposomes could be characterized as particles, similar to the structure and composition of cell membrane (Figure 1.). They occur in nature and could be artificially prepared [11].
Example of a) empty liposome; b) liposome (2007 Encyclopadeia Britannica, Inc.)
The behaviour of liposomes in physical and biological systems is governed by the factors such as physical size, membrane permeability, percent entrapped solutes, chemical composition (estimation of phospholipids, phospholipids oxidation, and analysis of cholesterol), and quantity and purity of the starting material. Therefore, liposomes are characterized for physical attributes: shape, size, and its distribution; percentage drug capture; entrapped volume; lameliarity; percentage drug release. Based on the structure and size, we distinguish between different types of liposomes: Multilamellar Vesicles (MLV, size >0.5μm), Oligolamellar Vesicles (OLV, size 0.1-1μm), Unilamellar Vesicles (UV, all size ranges), Multivesicular Vesicle (MVV/MV, size >1μm). Unilamellar Vesicles are further divided into Small Unilamellar Vesicles (SUV, size 20-50nm), Medium Unilamellar Vesicles (MUV, size 50-100nm), Large Unilamellar Vesicles (LUV, size >100nm) and Giant Unilamellar Vesicles (GUV) (Figure 2.).
Example of a) unilamellar liposome; b) multilamellar liposome
Based on composition and applications, liposomes are divided into conventional liposomes (CL), fusogenic liposomes, pH sensitive liposomes, cationic liposomes, long circulatory (stealth) liposomes (LCL) and immuno-liposomes [12]. It is very difficult to measure dirrectly the phospholipid concentration, since dried lipids can often contain considerable quantities of residual solvent. Because of that, the method most widely used is an indirect one in which the phosphate content of the sample is first measured. The phospholipid concentration is measured using two methods - Bartlett and Stewart. In the Bartlett method the phospholipid phosphorous in the sample is first hydrolyzed to inorganic phosphate. This is converted to phospho-molybdic acid by the addition of ammonium molybdate and phospho-molybdic acid is quantitatively reduced to a blue colored compound by amino-naphthyl-sulfonic acid. The intensity of the blue color is measured spectrophotometrically and is compared with the curve of standards to give phosphorous and hence phospholipid content. This method is very sensitive. The problem is that test is easily upset by trace contamination with inorganic phosphate. In the other test, Stewart test, the phospholipid forms a complex with ammonium ferrothiocyanate in organic solution. The advantage of this method is that the presence of inorganic phosphate does not interfere with the test.
Until recently, liposomes are used as inert particles, carries of active principles, mostly for cosmetic purposes [13]. Today liposomes are used as very useful models, reagents and tools in various scientific disciplines, including biophysics (properties of cell membranes and channels), chemistry (catalysis, energy conversion, photosynthesis), biochemistry (the function of membrane proteins) and biology (excretion, cellular functions, transports and signaling, the transfer of genes and their functions). Liposomal formulation of several active molecules are currently in pre-clinical and clinical trials in different fields, with promising results. Two of the key problems in drug therapy (biodistribution throught the body and targeting to specific receptors) can be overcome by using liposomal formulations – liposomes protect encapsulated molecules from degradation and can passively target tissues or organs that have a discontinuous endothelium, such as liver, spleen, and bone marrow [14]. Comercial use of liposome was based on their colloidal, chemical and surface and microcapsuled proporties. These products include dosage formes of drugs (anti-cancer and antifugal agents, vaccines), cosmetic formulation (skin care products, shampoos), diagnostic products, a variety of applications in the food chemistry, as well as oral nutrient transport (liposomal vitamins, minerals and plants extracts for oral use). Liposome stability is an importrant aspect that must be met to be able to apply. By selecting the optimal value and size, pH and ionic strenght and the addition of complexing agents, liquid liposomical formulations could be stable for years.
Liposomal models have helped us to better understand the structure and dynamics of natural biomembrane systems. The concepts of structure and function of biomembranes, such as membrane fluidity, phase transition, the movement of lipids and proteins, triggering prosesses that affect metal ions or pH, have been very developed in this way. Modulatind effect of internal molecules (such as cholesterol) and insight into the mechanisms of membrane permeabillity for non-electrolytes and ions, are obtained by testing the model membranes. Liposomes that contains proteins as a components of membrane (reconstructes liposomes) were used in testing lipid-protein interactions in biological membranes, in examining the activities of active components such as membrane ionophores, anesthetics and divalent cations and mechanisms of antybody-antigen interactions [10].
Liposomes are very good models because they show the selectivity of the membrane to ions, osmotic swelling and response of range to agents that speed up or slow down the loss of ions and molecules from the particles in a way that at least, qualitatively mimic their activity in the natural membrane systems. Liposomes have also been successfully applied to „exclude the role“ of membranes lipids and other components in biomembranes interact with the physical or chemical agents. Nevertheless, liposomal systems are useful because they allow the manipulation of membrane lipid composition, pH, temperature, content of different compounds in a limited way and provide the ability to determine the individual effect of the investigation product [15].
An example of the advantages of liposome in investigation of lipid peroxidation is that the influence of free radicals can be explored in the absence of chemical systems that produce free radicals, which may affect the test reaction. It is also possible to control the chemical composition of the liposome. This is particularly useful for the determination of lipid peroxidation induced by different systems for the generation of free radicals, and monitoring the overall effect of the combined system, or synergistic effects of combined systems that may arise. In addition to this it is possible to determine the antioxidant activity of tested compounds and determine which system works the best, by simple monitoring of lipid peroxidation. The tests used to determine the power of antioxidants to exert suppression of lipid peroxidation based on an assessment of the strength of oxidation of lipid substrate in the presence or absence of potential antioxidant molecules of plant extracts. There are four different strategies for assessing antioxidant capacity of molecules to the lipid substrate. They include the determination of oxygen consumed, the loss of substrate and formation of primary and secondary oxidation products [16]. The first method for determining the degree of lipid peroxidation, which includes the determination of oxygen consumed, based on following of initiation phase and its extension in the absence of antioxidants. The second method is based on measuring the loss of substrate in systems such as samples of food or biological samples and is very complicated, because they are full of potential oxiable substrates that are difficult to identify and characterize. The third method is based on monitoring the formation of primary oxidation products. It is a method that is well adapted to study such complex model systems and often involves the spectrophotometric determination of hydroperoxide, the dominant primary products of lipid peroxidation. Monitoring of secondary products of oxidation is the most commonly used method for the study of lipid model systems and lipid isolated from their natural environment. Both the in vitro and in vivo conditions are very often used TBA (thiobarbituric acid) test for detection of MDA (malondialdehyde), a secondary product of oxidation. This test is based on the reaction between TBA and MDA, which produces red chromophore with maximum of absorbance at 532 nm. This reaction is widely used and is performed by means of determination of many oxiable substrates (free fatty acids, LDL, body fluids). However, this method has some drawbacks. One is that the MDA is formed from free fatty acids which contain at least three double bonds. The next disadvantage is that the TBA is not specific for MDA because it can react with other aldehydes, such as occurs brown color that comes from the reactions of decomposition of sugar, amino acids, proteins and nucleic acids. Finally, MDA is not generated during the oxidation of many lipids and is often less important secondary oxidation product, and therefore not representative enough for the individual measurements. However, the TBA test was held for examination of lipid peroxidation, due to the simplicity of the method.
Despite all these advantage, liposomal systems remain different from the natural cellular systems. For this reason, regardless of the results obtained by testing the liposomes, they could not be reproduced on the natural membrane system, but they can provide useful information.
Therefore, the liposomes are still mostly used as a model system of biological membrane for testing the LP, especially when testing extracts and essential oils from plants on the intensity of LP. These studies are important because free radical oxidation of lipid components of food is a major strategic problem of food producers. The degree of oxidation of fatty acids and their esters in foods depends on the chemical structure of fatty acids, food processing technology, the temperature at which food is stored or prepared for eating and the presence of antioxidants. Synthetic antioxidants are widely used in many foods to retard undesirable changes as a result of oxidation. Chemicals, like tert-butyl-4-hydroxyanisole (BHA) and tert-butyl hydroxytoluene (BHT), can be used as antimicrobial and antioxidants agents. However, the use of some of these chemicals is restricted in several countries, as they may be dangerous to human health [17]. Therefore, the search for new natural antioxidant sources has been greatly intensified. For this reason, there is a growing interest in the studies of natural additives as potential antioxidants. The antioxidant properties of many herbs and spices are reported to be effective in retarding the process of lipid peroxidation in oils and fatty foods and have gained the interest of many research groups. A number of studies on the antioxidant activities of various aromatic plants have been reported over the last 20 years [18,19]. Their aroma is associated with essential oils, complex mixtures of volatile compounds, dominated by mono- and sesquiterpenes. It is known that essential oils exhibit significant biological and pharmacological activities such as anti-inflammatory, antimicrobial, spasmolytic, stimulant effect on the CNS and the like. New research shows that they possess significant antitumor activity [20], and act as inhibitors of growth of breast tumors [21]. It was confirmed that essential oils of some aromatic plants possess a high antioxidant potential [22]. Widely used in the food industry to improve the flavor of foods.
In addition to essential oils, aromatic plants and characterized by the presence of plant phenolic compounds, primarily phenylpropanoids and coumarins which are proven to have multiple pharmacological activities. Studies of these secondary biomolecules have become intensified when some commercial synthetic antioxidants found to be expressed toxic, mutagenic and carcinogenic activities [23]. In addition, it was found that excessive production of oxygen radicals in the body initiates oxidation and degradation of polyunsaturated fatty acids. It is known that free radicals attack the highly unsaturated fatty acid of membrane system and induce lipid peroxidation, which is a key process in many pathological conditions, and one of the reactions caused by oxidative stress. Particularly vulnerable are the biological membrane lipids in the spinal cord and brain because they contain high oxiable polyunsaturated fatty acids. These features facilitate the formation of oxygen radicals involved in the processes of aging, Alzheimer\'s and Parkinson\'s disease, ischemic damage, arthritis, myocardial infarction, arteriosclerosis and cancer. Phenolic antioxidants "stop" oxygen free radicals and free radicals formed from the substrate by giving hydrogen atom or an electron. Some flavonoids have strong inhibitory effect on lipid peroxidation processes. This action is based on their ability to chelate transition metal ions, thereby preventing the formation of radicals (initiators of LP), caught radicals initiators of LP (ROS), scavenge lipid-alkoxyl and lipid-peroxyl radicals and regenerate α-tocopherol by reduction of α-tocopheryl radicals. Flavonoids have the following characteristics: 3 \', 4\'-dihydroxy group in ring B, or 4-keto and 3-hydroxy group in C ring, or 4\'-keto group in C ring and 5-hydroxy group in A ring have the metal chelated properties (Figure 3.).
Possible places on flavonoids for chelating the transition metal ions in the process of lipid peroxidation.
Different metals have different binding affinity of the flavonoids [24]. Thus, for example, iron has the highest binding affinity for 3-OH group of ring C, then catechol group ring B and at the end of 5-OH group of ring A, while the copper ions bind to the first ring catechol group B [25]. Solubility of flavonoids in the lipid phase and the ability to penetrate the lipid membrane is small, since flavonoids in nature are mostly in the form of polar glycosides. Numerous tests of the inhibitory effects of flavonoids on lipid peroxidation were carried out on models of cell membranes. Based on these studies, it is assumed that quercetin and other flavonoids probably located on the surface membrane could easily capture radicals from the aqueous phase and thus prevent the initiation of LP. Thus located, flavonoids faster capture radicals initiators LP than α-tocopherol, which is located within phospholipid bilayer and that the switch is a typical chain reaction. Prevention of initial attacks radicals from the aqueous phase to membrane phospholipids is essential in the antioxidant protection of biomembranes because free radicals are constantly generated in the aqueous phase of cellular and sub cellular structure [25,26].
In the present chapter, lipid peroxidation in a liposomal system was initiated by Fe2+-ascorbic acid system and the effects of four different Lamiaceae species (Melittis melissophyllum, Marrubium peregrinum, Ocimum basilicum, and Origanum vulgare) extracts and essential oils were investigated. Particular attention was paid to the chemical composition of extracts and essential oils and their capability to reduce lipid peroxidation. The plant leaves were dried in air and ground in a mixer. Finely powdered material (200 g) was macerated three times in 70% methanol (MeOH) with 4 L during a 24-h period. The macerates were collected, filtered, and evaporated to dryness under vacuum. The residues were dissolved in water and successively extracted with four solvents of increasing polarity: ether (Et2O), chloroform (CHCl3), ethyl acetate (EtOAc), and n-butanol (n-BuOH). The extraction was carried out until a colorless extract was obtained. The residue was the aqueous extract. All of five extracts (Et2O, CHCl3, EtOAc, n-BuOH, and H2O) were evaporated to dryness and then dissolved in 50% ethanol to make 10% (w=v) solutions. Both, these and the diluted solutions, were further used for examination. Essential oil was made when air-dried plant material was submitted to hydrodistillation according to Eur. Pharm. 4 [27], using n-hexane as a collecting solvent. The solvent was removed under vacuum. The oils were dried over anhydrous sodium sulphate and kept at +4 ºC. The inhibition of LP was determined by measuring the formation of secondary components (malondialdehyde) of the oxidative process, using liposomes as an oxidizable substrate [28-30]. However, because the thiobarbituric acid test is not specific for MDA, other non-lipid substances present in plant extracts, or peroxidation products other then malondialdehyde, could react positevely with TBA. These interfering compounds distort the results and therefore all the final results of investigated extracts have been corrected using the absorbances of the investigated extracts after the TBA-test (without liposomes) [31]. The commercial preparation of liposomes ‘PRO-LIPO S’ (Lucas-Meyer) pH = 5–7 was used as a model system of biological membranes. The liposomes, 225–250 nm in diameter, were obtained by dissolving the commercial preparation in demineralized water (1:10), in an ultrasonic bath.
The Lamiaceae family is one of the largest and most distinctive families of flowering plants, with about 220 genera and almost 4000 species worldwide [32]. Lamiaceae are best known for the essential oils common to many members of the family [33]. The family was established by De Jussieu in 1789 as the order Labiatae. This was the original family name, so given because the flowers typically have petals fused into an upper lip and a lower lip, the flower thus having an open mouth. Although this is still considered an acceptable alternative name, most botanists now use the name "Lamiaceae" in referring to this family. The main centre of diversity is the Mediterranean region to central Asia. Members are found in tropical and temperature regions [34]. All Lamiaceae are aromatic plants. The essential oil contains mainly monoterpenes, sesquiterpenes and phenylpropanoid compounds. Also, the plant species of Lamiaceae have been shown as rich sources of phenolic compounds mostly flavonoids and phenolic acids.
The name melittis of the genus derives from a Greek words Melissa or Melitta, meaning "honey bee" and refers to the properties of flowers of attracting these insects. The name melissophyllum of the species simply means "with leaves similar to melissa". This is a tall plant which likes shady places and is ideal for a sunny woodland edge or scrubby border, where it will be attractive to bees and other insects. Bastard balm is a strongly aromatic plant that smells like fresh mowed grass and has erect hairy stems. It blooms white with a large pinkish purple blotch on the lower lip. The flowers are hermaphrodite and get pollinated by bees and moths. It has oval, bluntly-toothed, leaves in opposite pairs up the stems. Bastard balm is a herb native to the Mediterranean region.
Main flavonoids in balm are glycosides of apigenin and luteolin. However, presence of some other flavonoids as kaempherol, quercetin (Figure 4.) and ramnocitrin have been also reported [35].
Structures of two flavonoids present in M. melissophyllum
Balm is characterized by the presence of the other important plant phenolic substances such as phenolic acids (caffeic, rosmarinic and chlorogenic acid) (Figure 5.).
Also, balm leaf is characterized by the presence of pentacyclic triterpenes (ursolic, pomolic and oleanolic acid) (Figure 6.). The main biopharmacological effects shared by ursolic and oleanolic acid are anti-inflammatory, hepatoprotective, antitumor, and antioxidative [36-39].
Essential oil is present in all parts of the plant. The largest amount of oil obtained from aerial parts of plants, harvested in late summer. Balm leaves contain no more than 0.13% of essential oil which is of complex and variable composition. Among the more than 50 compounds identified to date, citronellal (dominantly the (R) enantiomer), β-caryophyllene, -caryophyllene oxide, germacrene-D, nerol, geranial, citronellol, and geraniol amount to about 70% of the oil (Figure 7.) [40]. The composition is similar to that of lemongrass, but balm oil can be identified by its typical pattern of chiral compounds; for example, almost enantiomerically pure (R)-(+)-methyl citronellate is a good indicator of true balm oil. For distinguish between two oils there is used the carbon isotopic ratio (IRMS-isotope ratio mass spectrometry) [41]. The essential oil exhibits spasmolitic action and acts as a muscle relaxant, sedative, narcotic, antibacterial, and antifungal [42,43].
Structures of phenolic acids in M. Melissophyllum
Structures of triterpenoids compounds present in M. melissophyllum leaves.
Sesquiterpenes in M.melissophyllum leaves
Beneficial effects of plants introduced by ancient Greeks and Romans.There is overlap with the use of plants in folk medicine and science. In relation to its complex composition it has multiple medicinal effects. Its herb has wide applications in the folk medicine. Due to the soothing action balm leaves enters into the composition of tea for calming, which is recommended for hysteria and neuralgia. Balm leaves mixed with bitter herbs are a great tool to enhance appetite. Various preparations containing extract or essential oil balm leaves are used as an addition to baths against rheumatism. In the folk medicine of Belarus alcoholic extract is drunk for stomach ulcer and duodenum, to calm the pain in the stomach, intestines, the liver, heart, and women’s diseases. Terpenes found in essential oil of balm leaves, have a relaxing and antiviral effects. Eugenol calms muscle spasms and destroy bacteria [44]. It is also used as a carminative and sedative. Recent results indicate that the balm extract acts as depressants and have sedative effect on central nervous system of mice [45]. In the folk medicine of central Italy inflorescences of this plant, called “Erba Lupa”, were used under infusion as antispasmodic, against insomnia and eyes inflammations [46,47].
Our research on balm was recently extended to the comprehensive in vitro and in vivo studies of antioxidant properties of balm essential oil and extracts measuring their capability to reduce lipid peroxidation in liposomes and effect on some enzymes of antioxidant defense systems [48]. Investigation of balm essential oil showed that with increasing concentration of essential oil reduces the intensity of lipid peroxidation compared to hexane-control (Table 1). Also, only the most diluted solution of essential oil of balm (0.213 and 0.535 μg/mL) has a weaker protective effect than the synthetic antioxidant BHT. The capability to reduce lipid peroxidation of essential oil was dose-dependent. This high inhibitory effect of balm essential oil was found to be in correlation with the content of monoterpene alcohols and ketones.
Concentration (μg/mL) | |||||||
BHT | 0.213 | 0.535 | 1.065 | 1.598 | 2.130 | ||
LP | 26.15 | 13.05 | 21.03 | 39.62 | 46.09 | 56.81 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by essential oil of balm leaves and BHT (as a positive control) in the TBA assay.
The protective effects on lipid peroxidation of balm extracts have been evaluated using the Fe2+/ascorbate system of induction, by the TBA-assay (Table 2.). In general, all of the examined extracts (except n-BuOH extract) expressed strong antioxidant capacity and ability to reduce lipid peroxidation in liposomes. The largest inhibitory activity was exhibited by EtOAc and H2O extracts because the 5% solutions show better protective effect than BHT. All extracts of the highest concentrations (10%) exhibited a better inhibitory effect than BHT. Protective activity of these extracts and its components towards Fe2+-dependent LP of liposomes can be explained by present of phenolic acids and flavonoids and their influence on antioxidative capacity of ascorbic acid, which doesn`t show a strong antioxidative effect in lipid phase, but different phenolic compounds can result increase of its antioxidant activity [49].
Extracts | ||||||
Concentration | BHT | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
1% | 26.15 | 17.52 | 16.15 | 22.87 | -10.59 | 24.24 |
5% | 26.15 | 20.82 | 20.59 | 27.88 | -13.19 | 39.36 |
10% | 26.15 | 26.40 | 28.40 | 38.47 | -18.52 | 41.32 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by extracts of balm leaves and BHT (as a positive control) in the TBA assay.
It is known that quercetin, like many other flavonoids, prevents oxidation of LDL cholesterol, and its anti-inflammatory activity comes from inhibition of the enzyme lipooxigenase and inhibition of inflammatory mediators [50]. Kaempferol acts synergistically with quercetin to reduce the proliferation of malignant cells, and treatments are a combination of quercetin and kaempherol efficient than their single use [51]. It is, also, known that rutin has strong antioxidant effects, as well as a feature to built chelates with metal ions (e.g. iron) and reduces the Fenton reaction in which the resulting harmful oxygen radicals. It is supposed to stabilize vitamin C. If rutin is taken together with vitamin C, increases the activity of ascorbic acid [52]. In addition, HPLC-DAD analysis showed that the aqueous extract, in large quantities, present phenolic acids (rosmarinic, chlorogenic and caffeic acid), which are known antioxidants. It was determined that rosmarinic acid has stronger antioxidant activity than vitamin E. Rosmarinic acid prevents cell damage caused by free radicals and reduce the risk of cancer and atherosclerosis. In contrast to the histamines, rosmarinic acid prevents activation of the immune system cells that cause swelling and fluid collection. Also, it is known that the caffeic acid by far surpassing other antioxidants because it reduces the production of α-toxin for more than 95% [35]. Furthermore, it can be supposed that the reduction process of lipid peroxidation is caused, besides flavonoids, also by triterpenoids acids (especially ursolic, oleanolic, and pomolic acid) since non-polar extracts (Et2O and CHCl3) also exhibited high antioxidant potential [39]. The n-BuOH extract shows a prooxidative effect that is increased by increasing concentration of added extract. It can be supposed that compounds with polar groups were extracted by n-BuOH, and are present in high concentration in the extract. It is notable that molecules which show antioxidant activity, when they are present in high concentration, might behave as prooxidants [53], so n-BuOH extract of balm leaves probably have this kind of activity. The antioxidant activities of all extracts of balm leaves were dose dependent.
The represented antioxidant activity results show that extracts of examined plant species, especially EtOAc and H2O extracts are efficient in the protection of tissues and cells from oxidative stress. Anyway, according to variations in regard to antioxidant activity of tested by different in vitro models, there are also requiste in vivo test that would confirm the capability of extracts to reduce the lipid peroxidation. In vivo tests are also necessary because a lot of plant phenols are biotransformed during their active metabolism. In vivo effects are evaluated on LP in the mice liver (Table 3.) and blood hemolysate (Table 4.) after treatment with examined balm extracts, or in combination with carbon tetrachloride (CCl4).
Parameter | Control | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
LP | 7.19±0.23 | 7.36±0.21 | 7.91±0.19 | 6.71±0.16 | 7.12±0.23 | 6.19±0.27 |
LP + CCl4 | 8.91±0.29 | 7.12±0.21 | 7.06±0.24 | 6.92±0.17 | 6.98±0.24 | 6.81±0.24 |
Effect of extracts of balm leaves on intensity of lipid peroxidation (nmol malondialdehyde/mg of proteines) in liver homogenate before and after treatment with CCl4
As compared with control, intensity of LP is statistically significant reduced during the treatment with ethylacetate and water extracts of balm leaves. The result derived by treatment with ethylacetate and water extracts is in according with amounts got in vitro experiment. Using CHCl3 extract leads to a significant increase of LP intensity, whereas the other two extracts had no effect on this parameter. All extracts of balm leaves combine with CCl4 have showed a statistically significant decrease of LP intensity, and this behavior of the extract probably results from the presence of secondary biomolecules like flavonoids and phenolic acids. Handa et al. [54] determined that secondary biomolecules such as flavonoids, xanthones and tannins in combination with CCl4 have protective effects on liver. Phenolic components present in balm leaves (rutin, luteolin, kaempherol) are known as strong inhibitors of CCl4-induced LP [55]. Flavonoids could affect the initiation phase of lipid peroxidation, where they influence the metabolism of CCl4, they scavenge the free radicals, or they decrease the microsomal enzyme systems that are claimed for CCl4 metabolism [56]. In continuation of this process, flavonoids can scavenge lipoperoxides and their radicals or they can act as chelating agents for Fe2+ ion, and in this way can stop Fenton reactions [57]. Furthermore, Afanas′ev et al. [28] found that quercetin and rutin exhibited a high inhibitory effect on the Fe2+-induced liposomal LPx and NADPH-dependent CCl4-induction LPx in liver microsomes. Luteolin, one of the main active component in the balm, is responsible for the inhibitory effect on the former reaction. In addition to the above-mentioned mechanism (chelate formation with Fe2+) it is possible that these compounds (of flavonoid type) act as scavengers of OH radicals, whereby they are transformed in the corresponding radical form which is stabilized by resonance. On the basis of these results, it can be concluded that all of extracts of balm leaves showed protection effect in relation to the CCl4-induced lipid peroxidation.
Similar results were obtained during examining the effects of extracts of bastard balm on LP in blood hemolysate in mice (Table 4.). Three extracts, CHCl3, EtOAc and H2O, induced a significant decrease of LP intensity, while Et2O and n-BuOH ones decreased the level of this enzyme insignificantly.
Parameter | Control | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
LP | 4.81±0.24 | 4.59±0.28 | 3.78±0.17 | 2.96±0.13 | 4.74±0.19 | 4.07±0.24 |
LP + CCl4 | 5.11±0.24 | 5.31±0.17 | 4.92±0.21 | 3.02±0.24 | 5.17±0.25 | 2.98±0.12 |
Effect of extracts of balm leaves on intensity of lipid peroxidation (nmol malondialdehyde/mL erythrocytes) in blood hemolysate before and after treatment with CCl4
The LP value showed a statistically insignificant increase with CCl4-treated animals compared with the untreated ones. A clear protective effect was seen in experimental animals administered H2O extract and CCl4 compared with untreated animals. Furthermore, EtOAc extract also significantly decreased the activity of LP, while Et2O, CHCl3 and n-BuOH extracts did not change notably the levels of lipid peroxidation. These results suggest that these two extracts (EtOAc and H2O) had a protective effect. According to the literature data [58], the reduction of the serum LP might be the result of antioxidant activity of several classes of plant phenolic constituents, such as cinnamic acids (ferulic, caffeic, and chlorogenic), flavonoids and biflavonoids, 1,3,6,7-tetrahydroxyxynthones, and acylphoroglycinols such as hyperforin and adhyperforin. Cock and Samman [59] showed that quercetin and rutin and their glycosides show strong inhibitory effect in respect of LP. The observed differences in the action of particular balm extracts are probably due to the different contents of flavonoids, but the potential protective effects of some other groups of compounds can not be ruled out.
Marrubium genus includes about 40 species. Species of this genus growing in dry pastures, abandoned the places along the roads in central and southern Europe, but also in North Africa, in parts of Asia and the Americas. Horehound is a perennial plant with a rectangular stem, branched in the upper part. Rhizomes of this species are ligneous, leaves oblong, flowers grouped in loose inflorescence [60]. A common plant blooms from July to September and harvested in that period. It has a bitter and pungent taste and smell. It is the drug of Herba Marrubii albi. This plant doesn`t require special conditions for growth.
In previous phytochemical investigations on M. peregrinum, different groups of chemicals were isolated: flavones (apigenin and luteolin) [61] (Figure 8.), flavonols (kaempferol) [62], glycosylated flavonoids (quercetin-3-O-β-D-rutinoside, naringenin-7-O-β-D-glucoside, kaempferol-3-O-β-D-rutinoside, quercetin-3-O-β-D-glucoside) [63], caffeic acid derivatives [64], and four diterpenoids (peregrinin, peregrinol, marrubiin and premarrubiin) [65]. T. Hennebelle et al. [66] have established the presence of acteoside, forsythoside B, arenarioside and terniflorine (apigenin-7-O-[6″-E-p-coumaroyl]β-D-glucopyranoside) in the MeOH extract of M. peregrinum.
Marrubium peregrinum essential oil yield between 0.02-0.07% [67]. Dominant monoterpenes are: α-pinene, sabinene, limonene, camphene and α-terpinolene. In a Greek sample, β-phellandrene, epi-bicyclosesquiphellandrene and bicyclogermacrene proved to be the major compounds [68], whereas the essential oil of a sample from Central Europe was rich in β-caryophyllene and its oxide, bicyclogermacrene and germacrene D [69]. The main sesquiterpene compounds are Z- and E- β-farnesene (~12%), β-caryophyllene (~8.5%), heksahidrofarnesil acetone (~ 6.5%), spathullenol (~5%) i germacrene D (~4.5%) (Figure 9.) [68].
Figure 8. Structures of two main flavonoids in M. peregrinum.
Main constituents of M. peregrinum essential oil
Some species of Marrubium are used in traditional and modern medicine. Many studies have shown various activities in this genus, such as hypoglycemic effect, anti-schistosoma, antioxidant, calcium channel blocker and hypotensive activity [70]. As a medicinal plant, M. peregrinum have been employed against vascular diseases (antihypertensive, antispasmolitic) [61].
In our comprehensive study of chemical and biochemical investigation of M. peregrinum from three different locations (Backo Gradiste-Rimski Sanac (No 1.); Novi Knezevac (No 2.) and Senta (No 3.)), we have identified more than 40 compounds in essential oil of M. peregrinum (44 for M. peregrinum from Senta locality, 42 for M. peregrinum from Novi Knezevac locality and 41 for M. peregrinum from Rimski Sanac locality, representing 96.15%, 87.60% and 83.66% of the total oil contents, respectively), in which dominant compounds were β-caryophyllene (13.20-17.99%), bicyclogermacrene (6.42-9.80%) and germacrene-D (6.79-9.05%). Besides sesquiterpene hydrocarbons, oxygenated sesquiterpenes, spathulenol (3.76-5.78%) and caryophyllene oxide (3.73-4.78%) are also present in relevant quantities. However, we must point out that the amounts of these components in essential oil from different localities are very different. Essential oil obtain from plant collected in Senta is the richest of sesquiterpene hydrocarbons (62.71%), while oxygenated sesquiterpenes are most represented (11.84%) in essential oil from plants collected in the Rimski Sanac area.
Concentration(μg/mL) | ||||||||
BHT | 0.213 | 0.535 | 1.065 | 1.598 | 2.130 | |||
M. peregrinum (No 1.) | 26.15 | 12.24 | 26.00 | 35.36 | 44.26 | 56.18 | ||
M. peregrinum (No 2.) | 26.15 | 19.15 | 20.05 | 39.37 | 52.14 | 61.18 | ||
M. peregrinum (No 3.) | 26.15 | 21.17 | 37.02 | 55.81 | 65.16 | 71.32 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by essential oil of M. peregrinum from three different location, and BHT (as a positive control) in the TBA assay.
Also, our study showed that all of the examined essential oils express strong antioxidant activity and capability to reduce lipid peroxidation (Table 5.). The largest inhibitory activity was exhibited by essential oil from plant collected at Senta locality (No. 3.). Solution of all concentrations, except the most diluted (0.213 μg/mL), have exhibited a stronger protective effect (from 37.02 to 71.32% of inhibition of LP) than BHT (26.15%). The other two essential oils (from Rimski sanac and Novi Knezevac), at higher concentration (from 1.065 to 2.130 μg/mL), have also exhibited more intense protective effect than BHT [71].
The effect of crude MeOH extracts of M. peregrinum was preliminarily determined from the three localities. There were taken three concentrations of MeOH extracts (1, 5, and 10% extracts). All of the examined extracts expressed stronger antioxidant capacity as compared to the 50% solution of MeOH. In particular, the largest inhibitory activity was established by the MeOH extracts of M. peregrinum collected from Senta locality. Also, the best results were obtained using solutions of the highest concentrations [72]. Because of all this there was carried out successive extractions of M. peregrinum from all three localities, and for further work 10% extracts are prepared. Successive extraction was performed as the extraction of antioxidant substances of different chemical structure, was achieved using solvents of different polarity. Numerous investigations of qualitative composition of plant extracts revealed the presence of high concentration of phenols in the extracts obtained using polar solvents [73]. The extracts that perform the highest antioxidant activity have the highest concentration of phenols. Phenols are very important plant constituents because of their scavenging ability on free radicals due to their antioxidant action [74]. The examination of capability to reduce intensity of lipid peroxidation of plant extracts from M. peregrinum showed different values (Table 6.). The first two extracts (Et2O and CHCl3) obtained from plants from all three locality are exhibited weaker protective effect than BHT, while the other three extracts (EtOAc, n-BuOH and H2O) showed better protective properties than synthetic antioxidant.The largest inhibitory activity, again, was exhibited by the EtOAc and H2O extracts of M. peregrinum collected from Senta locality.
Obtained results can be related to the experiments in which the total amount of flavonoids was determined, which show that EtOAc and H2O extracts from Senta locality contains the largest amounts of total flavonoids, namely of luteolin, either being present as free or in the form of its glucosides. The suggested mechanism of flavonoid antioxidative action is as follows: the double bond in position 2, 3 is conjugated with C4-carbonyl group, and free OH groups (C5, C3 and C7) can form chelates with ions of d-elements. Once formed, complex with Fe2+ ion prevents formation of OH• radicals in Fenton’s reaction [59]. Also, luteolin is thought to play an important role in the human body as an antioxidant, a free radical scavenger, an agent in the prevention of inflammation, a promoter of carbohydrate metabolism, and an immune system modulator. These characteristics of luteolin are also believed to play an important part in the prevention of cancer. Multiple research experiments describe luteolin as a biochemical agent that can dramatically reduce inflammation and the symptoms of septic shock [75]. Furthermore, it is well known that some other flavonoids isolated from M. peregrinum possess certain biological and pharmacological activity. For example, apigenin, one of the flavonoids present in M. peregrinum, was shown to express strong antioxidant effects, increasing the activities of antioxidant enzymes and, related to that, decreasing the oxidative damage to tissues [61].
Extracts | ||||||
BHT | Et2O | CHCl3 | EtOAc | n-BuOH | H2O | |
M. peregrinum (No 1.) | 26.15 | 9.38 | 14.22 | 29.41 | 27.39 | 32.35 |
M. peregrinum (No 2.) | 26.15 | 14.27 | 21.19 | 29.54 | 26.83 | 37.55 |
M. peregrinum (No 3.) | 26.15 | 17.11 | 23.52 | 38.83 | 28.73 | 41.18 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by extracts of M. peregrinum and BHT (as a positive control) in the TBA assay.
Basil is originally native to India and other tropical regions of Asia, having been cultivated there for more then 5.000 years. Ocimum genus includes about 150 species [76]. There are many varieties of Ocimum basilicum, as well as several related species or species hybrids also called basil. These varieties differ in morphological and general structure, and also in the content and composition of essential oil. The chemotype is determined by chemical composition of essential oil and it is basic for chemotaxonomy within the genus Ocimum and species Ocimum basilicum [77].
The word market has several types of essential oils that differ in chemical structure, composition and fragrance. The dominant compounds of basil essential oil occur in two different biochemical pathways: phenylpropanoids (methyl chavicole, eugenol, methyl eugenol, and methyl cinnamate) through shicimic acid, and terpenoids (linalool and geraniol) through mevalonic acid. Based on chemical content, basils can be divided into four groups: European (French) O. basilicum (contains lower amounts of phenols); Exotic (contains methyl chavicol (40-80%)); Reunion and Javanean. European type of essential oil is the finest quality, has the finest fragrance and the highest price in the market. Other components that can be found in higher concentrations in this type of oil are: linalool, methyl chavicol (estragole) (Figure 10.), 1,8-cineole, eugenol, geraniol, germacrene D, α-terpinolene, β-caryophyllene, ocimene, sabinene, thujone, and γ-terpinene [78].
Among phenolic constituents flavonoids and their glucosides are dominant. The major flavonoids are: quercetin, kaempferol, apigenin, luteolin and rutin. Quercetin-3-O-diglucoside and kaempferol-3-O-β-rutinoside have been also identified. Beside, basil is rich in triterpenoid acids (ursolic and oleanolic), cinnamic acid (caffeic and rosmarinic), vitamin C and β-carotene, as well with calcium, copper, magnesium, sodium and potassium [79].
Main constituents of O. basilicum essential oil
Basilici herba has been used in traditional and homeopathic medicine to treat number of diseases. Essential oil (Basilici aetheroleum) extracted from fresh leaves and flowers can be used as aroma additives in foods, pharmaceuticals, and cosmetics [80]. Traditionally, basil has been used as a medicinal plant in the treatment of headaches, coughs, diarrhea, constipation, warts, worms, and kidney malfunction. Major aroma compounds from volatile extracts of basil present anti-oxidative activity [81]. Among the many studies to determine the antioxidant activities of basil, most have focused mainly on the antioxidant activities of crude extracts, using methanol, acetone, or water as a solvent [82,83].
Concentration (μg/mL) | ||||||||
BHT | 0.213 | 0.535 | 1.065 | 1.598 | 2.130 | |||
LP | 26.15 | 24.12 | 35.17 | 48.41 | 64.13 | 79.14 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by essential oil of basil leaves and BHT (as a positive control) in the TBA assay.
In our investigation, the examined essential oil expressed strong antioxidant activity (Table 7.). Solutions of all concentrations, except the most diluted (0.213 μg/mL), have exhibited a stronger protective effect (from 35.17 to 79.14% of inhibition of LP) than BHT (26.15%). The largest inhibitory activity was achieved by using the solution of the highest concentration. For the inhibition of LP, the most responsible compounds were the oxygenated phenolic monoterpens (methyl chavicole) and the mixture of mono- and sesquiterpene hydrocarbons. These findings are in correlation with the earlier published data on the antioxidant activities of the investigated essential oil and selected oil components [84,85].
Extracts | ||||||
Concentration | BHT | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
1% | 26.15 | -0.87 | -0.86 | 37.42 | 26.31 | 31.74 |
5% | 26.15 | -0.94 | -0.89 | 38.91 | 27.06 | 35.29 |
10% | 26.15 | -1.01 | -1.04 | 41.56 | 28.83 | 36.54 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by extracts of basil leaves and BHT (as a positive control) in the TBA assay.
The data presented in Table 8. show that the last three extracts of O. basilicum (EtOAc, n-BuOH and H2O) reduced the intensity of lipid peroxidation, while the first two extracts (Et2O and CHCl3) increased the intensity of LP, but statistically insignificant. The largest inhibitory activity was exhibited by ethyl acetate extract. High inhibitory effect of this three extracts can be related to the presence of the amount of total phenolic compounds and content of total flavonoids in the extracts, because a considerably content of total phenolic compounds and total flavonoids was determined in EtOAc and H2O extract of O. basilicum. Preliminary 2D-TLC (Two Dimensional - Thin Layer Chromatography) analysis showed that the dominant flavonoid in the EtOAc extract of O. basilicum is derivative of quercetin. It is known that quercetin shows high antioxidant activity because of present OH groups in position 3\' ring B (includes a 3\', 4\'-dihydroxy group). In the same experiment we established the presence of caffeic acid and its derivatives in the H2O extract, which has two hydroxyl groups in ortho position. This was confirmed once again that the antioxidant capacity depends not only on quantity, but also depends on of the type of phenols and flavonoids present in the extracts. However, in extracts of O. basilicum higher content of total phenols and flavonoids from the EtOAc extract had an H2O extract. From all this it can be assumed that the polarity of flavonoid components affects their ability to inhibit the process of LP. Specifically, in this test we used liposomes as a model system of biological membranes, and the least polar flavonoids present in the EtOAc extract could help to approach the scene and engage in the process of defense from the LP, compared to more polar compounds that are found in H2O extract. A little less of total flavonoids was determined in n-BuOH extracts, while the smallest quantity of these compounds was found in Et2O and CHCl3 extracts. Differences in the amount of total phenolic compounds and flavonoid content between extracts can be explained by different number of secretory structures in various plant tissues [86]. Furthermore, the obtained results could be related to the protective role of phenolics, especially the flavonoid aglycones, in plants collected on the outskirts of big cities. One of the functions of these biomolecules, which are produced in response to ecological stress factors like pollution, is to serve as UV-B filters in plants [87]. It was established that flavonoids act as mighty scavengers of free radicals [88]. Different flavonoids inhibit LP in vitro and the most pronounced effect is exhibited by quercetin whose presence is found in extracts of O. basilicum using 2D-TLC [89]. More investigation is required to explain the enhanced production of phenolics in certain geographic areas [90]. Also, from the presented results we can conclude that the increase in concentration of the extracts does not significantly affect the inhibition of lipid peroxidation.
Origanum is one of the most variable genera of Lamiaceae family. Originates from Europe, but is now cultivated throughout the world including USA, India and South America. This is an extremely variable species with several subspecies and named cultivars grown for ornamental, culinary and medicinal uses. Oregano is a bushy, semi-woody sub-shrub with upright or spreading stems and branches. Some varieties grow in mound like mats, spreading by underground stems (called rhizomes), and others with a more upright habit. The aromatic leaves are oval-shaped. Oregano will grow in a pH range between 6.0 (mildly acid) and 9.0 (strongly alkaline) with a preferred range between 6.0 and 8.0. The flowers are purple, 3–4 mm long, produced in erect spikes.
As the other three Lamiaceae species oregano is characterized by the presence of essential oil, flavonoids, phenolic acids (caffeic, chlorogenic and rosmarinic), triterpenoid acids (oleanolic and ursolic) and tannins. The oregano essential oil yield between 0.35-0.55% [91]. According to Arnold et al. [92], the content of essential oil in Origanum ssp. may come up even to 8.8%. Essential oils obtained from different parts of plant have a similar chemical profile. The dominant components are oxygenated phenolic monoterpenes thymol and carvacrol (Figure 11.), as well as sabinene, linalool, terpine-4-ol, α-pinene, caryophyllene, caryophyllene-oxide and 1,8-cineole.
Oxygenated phenolic monoterpens from O. vulgare essential oil
According to Duke [93], flavonoids are found in the leaves and whole plant, mostly as kaempferol, quercetin, apigenin, luteolin and rutin. Beside, oregano is rich in apigenin-7-O-β-D-glucoside and luteolin-7-O-β-D-glucuronide. In oregano flavanon naringenin and flavanon glucoside (naringin), have also been identified (Figure 12.).
Most of the healing properties are attributed to the essential oil and flavonoids. It has been widely used in agricultural, pharmaceutical and cosmetic industries as a culinary herb, flavoring substances in food products, alcoholic beverages and perfumery for its spicy fragrance [94]. Regarding the nonvolatile components, the extracts of oregano have the most effective antioxidant activity among aromatic herbs [95]. Oregano family, is widely known as possessing therapeutic properties (diaphoretic, carminative, antispasmodic, antiseptic, tonic) being used in traditional medicine systems in many countries. Different groups of researchers [96,97] studied oregano alcohol extracts. The antioxidant effect of the mentioned extracts is generally due to the presence of rosmarinic and caffeic acid [98].
Structures of main flavonoids of O. vulgare
Concentration (μg/mL) | ||||||||
BHT | 0.213 | 0.535 | 1.065 | 1.598 | 2.130 | |||
LP | 26.15 | 17.31 | 24.35 | 37.17 | 49.58 | 51.13 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by essential oil of oregano leaves and BHT (as a positive control) in the TBA assay.
Our tests showed that only concentrated solutions of essential oil exhibit a greater ability to inhibit LP in liposomes of synthetic antioxidant BHT. The antioxidant activities were dose dependent, but it is noticeable that the values obtained using two most concentrated solution of essential oils (1.598 and 2.130 μg/mL) are very close (49.58 and 51.13% of inhibition of LP). For the inhibition of LP, the most responsible compounds were the oxygenated phenolic monoterpens (thymol and carvacrol) and the mixture of mono- and sesquiterpene hydrocarbons [98].
Extracts | ||||||
Concentration | BHT | Et2O | CHCl3 | EtOAc | n-BuOH | H2O |
1% | 26.15 | -0.46 | -0.92 | 24.17 | 11.31 | 13.58 |
5% | 26.15 | -0.77 | -0.94 | 26.04 | 14.57 | 16.49 |
10% | 26.15 | -0.91 | -0.97 | 30.28 | 19.78 | 23.24 |
Inhibition of LP (%) in Fe2+/ascorbate system of induction by extracts of oregano leaves and BHT (as a positive control) in the TBA assay.
The data presented in Table 10. show that the last three extracts of O. vulgare (EtOAc, n-BuOH and H2O) reduced the intensity of lipid peroxidation while the first two extracts (Et2O and CHCl3) have prooxidative effect (but not statistically significant). The largest inhibitory activity was exhibited by ethyl acetate extract. High inhibitory effect of this extract and its components towards Fe2+-dependent LP of liposomes can be related to the presence of flavonoids in the extract. It was established that flavonoids that antiradical potential of flavonoids are the most pronounced towards OH, peroxy- and alkoxy radicals, which are formed in the process of lipid peroxidation [99]. Also, these results are consistent with 2D-TLC analysis which showed that the dominant component of the EtOAc extract was kaempferol monoglycoside, while the H2O extract contains multiple kaempferol diglycosides. From the literature it is known that additional glycosylation reduces the antioxidant activity and capability to reduce lipid peroxidation [100].The antioxidant and prooxidant activities of all extracts of oregano leaves were dose dependent.
It was found that excessive production of oxygen radicals in the body initiates oxidation and degradation of polyunsaturated fatty acids. It is known that free radicals attack the highly unsaturated fatty acid of membrane system and induce lipid peroxidation. Since lipid peroxidation causes oxidative damage to cell membranes and all other systems that contain lipids, in any investigation of total antioxidative activity of extracts and essential oils it is necessary to investigate their effects on lipid peroxidation. Some substrates (for example liposomes) are used more frequently than others, mainly because of the simplicity of the methods involved. In this way we get very useful information to direct future research. The results of our in vitro assays of examined four different Lamiaceae species extracts expressed significant protective effects on LP, which was found to be correlated to different compounds. It can be concluded that ethyl acetate and water proved to be the best solvent for extraction of plant material. Also, a very strong protective activity of the EtOAc and H2O extracts in lipid peroxidation processes was recorded, which means that they may have a protective role in oxidative stress. Experimental results indicate that the essential oil of M. peregrinum collected from the Senta locality (No.3) exhibited the strongest inhibitory effect on lipid peroxidation. Furthermore, the present chapter on the chemistry and biological activity of four well known Lamiaceae species explicitly prove that these plants may be an important sources of pharmalogically active substances, and thus can be used in the preparation of various herbal medicine.
This work was supported by the Ministry of Science and Environmental Protection of the Republic of Serbia (Project No. 172058) and by the Provincial Secretariat for Science and Technological Development, Autonomous Province of Vojvodina, Republic of Serbia.
Cellulose, a fibrous carbohydrate found in all plants, is the most abundant natural polymer with biomass production of 50 billion tons per year [1]. Cellulose is a linear polymer of glucose. Based on solubility in alkaline, cellulose is divided into three groups which are alpha, beta, and gamma celluloses. Microcrystalline cellulose (MCC) is a purified, partially depolymerized cellulose having the formula (C6H10O5)n. It is prepared by treating alpha cellulose with mineral acids (type Ib). This polysaccharide polymer consists of a linear chain of several hundred to over ten thousand β(1 → 4) linked D-glucose units, consisting of linear chains of β-1,4-
Non-woody lignocellulosic materials have also been developed as source of MCC such as cotton linters [5], cotton stalks [6], cotton rags [5], cotton fabric waste [7], cotton wool [8], soybean husk [9], corn cob [10], water hyacinth [11], coconut shells [12], oil palm biomass residue [13, 14], oil palm fronds [15], rice husk [6, 16], sugar cane bagasse [6, 16, 17, 18, 19, 20], jute [21, 22], ramie [23], fibers and straw of flax [24], wheat straw [25], sorghum stalks [26], sisal fibers [27] and mangosteen [28], alfa grass fibers [29, 30], soybean hulls [31], orange mesocarp [32], Indian bamboo [33], roselle fiber [34], and alfa fiber [35]. Seed flosses from milkweed pods (Calotropis procera), shrubs, and kapok (Ceiba pentandra) trees are also known as cellulosic resources. Due to its high purity of alpha cellulose, most seed flosses must be treated to remove impurities including lignin, pectin, and wax [36].
Wooden sources contain cellulose chains which are packed as layers held by cross-linking hydrogen bonds [37]. Chemically it consists of polymeric matrix of lignin, hemicelluloses, and pectin [38]. Different woods considerably possessed different chemical composition of cellulose (including allocations of cellulose, hemicelluloses, and lignin in cell wall) and structural organization as well. Relatively different crystallinity in particular regions is observed as more amorphous according to softwoods (evergreen conifer) and hardwoods which are termed as deciduous broadleaf [4, 37]. The amorphous regions of cellulose provide a more susceptible property for depolymerization by acid hydrolysis. At optimum acid concentration, the process gave shorter and more crystalline fragments such as the MCC [2, 37].
The MCC can be synthesized by different processes including extrusion and enzyme-mediated process [25]. Other studies reported that it can also be synthesized by steam explosion and acid hydrolysis process [5, 6]. The acid hydrolysis process is more preferable due to shorter duration than others. It also offered the possibility to be applied as a continuous process rather than a batch-type process. Limited quantity of consumed acid is also the advantage of the process, while, despite the lower unit cost from less chemicals used, this process offered more fine particles of the MCC as the final product [5]. Fibrous plant pulp is hydrolyzed by mineral acid under heat and pressure. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which soluble components of cellulose such as beta and gamma celluloses, hemicelluloses, and lignin are dissolved with acid and water, are separated out during washing process by water which continued by filtration. The obtained pure alpha cellulose has then been neutralized and given the slurry final product [3]. This suspension is dried to obtain the insoluble white, odorless, tasteless powder, which has later been characterized as MCC [39]. MCC is hygroscopic in nature, and insoluble in water, but swells when in contact with water.
Another synthesis procedure of the MCC reported by Ohwoavworhua et al. [40] can be concluded as follows: the α-cellulose was hydrolyzed with hydrochloric acid at a boiling temperature of 105° for 15 min. The neutralized slurry obtained from the hydrolysis process was washed, and the fraction passing through 710 μm sieve was stored at room temperature in a desiccator. MCC is commonly dried from the slurry by spray-drying method. By varying spray-drying conditions, the degree of agglomeration and moisture content can be manipulated. In order to obtain smaller particle sizes (below 50 μm), further milling MCC can be performed [1].
Other drying techniques may be used, which may require additional screening steps postdrying in order to control particle size distribution [41, 42]. Higher bulk density grades are also available by using specific cellulose pulps (raw material), and median particle sizes below 50 mm can be obtained by further milling MCC [1].
Several studies have compared microcrystalline cellulose with various sources, including different manufacturers and different sites [4, 43, 44, 45, 46, 47]. MCC produced by various manufacturers or in various manufacturing sites may have different properties due to the kinds of pulp used as raw materials and their respective manufacturing conditions [2, 4]. A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and viscoelastic properties [48].
It was generally recognized that batch-to-batch variability from a sole manufacturing site was less important than differences observed between multiple sources. Only a few studies have tried to correlate the manufacturing conditions of microcrystalline cellulose with its physicochemical properties and its performance in tableting applications [2, 49, 50]. The effect of some parameters on hydrolysis process on yield value of production is shown in Tables 1 and 2.
Type | Conc. | Hydrolysis condition | MCC-Y (%) | Duration (minute) | References | |
---|---|---|---|---|---|---|
L/C (vol./wt) | Temperature (°C) | |||||
HCl | 2 N | 10:1 | 105 | 15 | n.a | [5] |
HCl | 2 N | 10:1 | 45 | 15 | n.a | [6] |
HCl | 2.5 N | 20:1 | 85 | 90 | 80 | [5] |
HCl | 2.5 N | 62.5:1 | 105 | 15 | 19 | [6] |
HCl | 2 N | 10:1 | n.a | 45–60 | n.a | [7] |
Hydrolysis reagents (acid type and concentration), liquor to cellulose ratio (L/C), hydrolysis conditions, and yield of microcrystalline cellulose (MCC-Y) hydrolysis reagent.
MCC Type | Particle size (micron) | Utilization |
---|---|---|
PH 101 | 50 | It is most widely used for direct compression tableting, for wet granulation, for spheronization, and in capsule filling processes |
PH 102 | 100 | It is used as the PH-101, but its larger particle size improves the flow of fine powders |
PH 103 | 50 | It has the same particle size as PH-101 with lower moisture content (3%), so it is used for moisture-sensitive pharmaceutical active ingredients |
PH 105 | Less than 50 | It is the most compressible of the PH products owing the smallest particle size. Well known as excipient for direct compression for granular or crystalline materials. When mixed with PH-101 or PH-102, specific flow and compression characteristics will be obtained. It has applications in roller compaction |
PH 112 | 100 | It has the same particle size as PH-102. It has lower moisture content (1.5%). It is used for high moisture-sensitive pharmaceutical active ingredients |
PH 113 | 50 | It has the same particle size as PH-101. It has lower moisture content (1.5%). It is used for high moisture-sensitive pharmaceutical active ingredients |
PH 200 | 180 | It has a large particle size with increased flowability. It is used to reduce weight variation and to improve content uniformity in direct compression formulations and in wet granulation formulations |
PH 301 | 50 | It has the same particle size as PH-101 but is denser providing more flowability and tablet weight uniformity. Useful for making smaller tablets and in capsule filling excipient |
A number of studies have confirmed that the moisture content of MCC influences compaction properties, tensile strength, and viscoelastic properties [48, 52, 53]. Moisture within the pores of MCC may act as an internal lubricant, reduce frictional forces, and facilitate slippage and plastic flow within the individual microcrystals [54, 55]. The lubricating properties of water may also reduce tablet density variation by providing a better transmission of the compression force through the compact and by decreasing the adhesion of the tablet to the die wall [55, 56]. Compressibility of MCC depends on moisture content, which means that when MCC having different moisture content is compressed with the same pressure, it may not result in the same compact porosity. It is very well known that compaction pressure required to produce certain porosity (or solid fraction) decreases with increasing moisture content. Sun reported that below 3% water content, the compaction properties of MCC were insensitive to variation of moisture [53]. However up to an optimum level, an increase of moisture will increase the tablet strength of most excipients. This can be explained by the fact that molecular binding in water vapor layers reduces interparticular surface distances, hence increasing intermolecular attraction forces [56].
The storage conditions of the MCC compacts also play an important role, as an increase in relative humidity will negatively impact tablet strength [47]. However this softening is often reversible when tablets are removed from the humid environment [1]. Fundamental forces affecting powder flow are cohesion and friction [55]. Frictional forces and electrostatic charges between particles during the compression process will decrease as moisture content increases. Moisture may also play a role in increasing cohesion forces inside particles due to the creation of liquid or even solid bridges. In the case of MCC as excipient, significant changes in flowability were observed when increasing moisture contents were applied which resulted in changes in powder cohesiveness. This phenomenon was described by the increase in compressibility index and the shear cell [48].
Particle size has a very little effect on the tabletability of neat MCC, i.e., not lubricated nor blended with other excipients or active pharmaceutical ingredients (APIs) [57, 58, 59, 60]. MCC particle size and moisture content are often considered as the most important CMAs for tableting performance [61]. Considering that the brittle-ductile transition diameter (Dcrit) of MCC is 1949 mm, standard MCC grades, having particle sizes below Dcrit, should all deform plastically when compression pressure exceeds yield pressure. Coarser grades of MCC, characterized by a smaller envelope surface area, have been reported to be more lubricant sensitive than finer MCC [52, 58, 62, 63]. In complete formulations finer MCCs would therefore promote tablet (compact) strength [64, 65]. Reducing the particle size of MCC will increase cohesiveness and hence as a consequence surely affect its flowability. Kushner et al. reported that different particle sizes of excipient may impact tablet characteristics including hardness, friability, disintegration, and content uniformity [66]. Improved flowability will be obtained when coarser MCCs are employed as well as reduction in tablet weight variation [67]. Hlinak et al. suggested that particle size may also impact wetting properties, dissolution of the API, and stability of drug products [68].
Albers et al. evaluated the tableting properties of three batches from five different brands MCC type 101 [43]. Batches using single manufacturer source produced more similar tablet characteristic than those using samples from various sources. Statistically significant differences were also observed within single brands of MCC. From a different batch of MCC studied, the greatest differences in powder properties were observed in the median particle size and specific surface area. Despite the lower median particle size of Avicel PH-101 (FMC), this MCC was described as easy flowing powder compared to other brands as illustrated by its low compressibility index and high values of shear cell flow functions (FFc) which exceed 4.
Williams et al. used tableting indices to investigate the compaction properties of MCC types 101 and 102 (median particle size of about 50 and 100 mm, respectively), each type being represented by two batches from five different sources [47]. The lubricant sensitivity of MCC expressed as its compressibility decreased when this excipient was mixed with other materials such as magnesium stearate. Another factor affecting lubricant sensitivity of MCC is the particle size. A higher particle size of MCC, Avicel PH-200 (180 microns), is more sensitive to lubricant than Avicel PH-101 (50 microns). At the same concentration, the lubricant covers more efficiently a larger particle size of MCC (PH-200) than that of the smaller particle size of MCC (PH-101) due to a larger particle surface area of smaller particles of MCC [51].
Compactability of the MCC particles is affected by the porosity. Avicel PH-101, Avicel PH-102, and Avicel PH-200 as marketed products of MCC owing almost the same density showed the same compressibility despite their mean particle size which varies from 50 to 180 microns. Avicel PH-301 (50 microns) and Avicel PH-302 (90 microns) which physically are more dense revealed less compressible or compactable properties [51].
Obae et al. suggested that MCC morphology, described by the length of particles (L) and their width (D), was one of the most important factors influencing tabletability [69]. Rod-shaped particles which are fibrous and having higher L/D ratios resulted in higher tablet strengths than round-shaped particles. Other physicochemical properties of MCC including moisture content, bulk density, and specific surface area did not correlate well with tensile strength of obtained tablet. Obae et al. illustrated the reduction of bulk density and flowability and the increase of specific surface area when the L/D ratio increased. This may be due to the property of the particles which is more fibrous. MCC morphology was found to be affecting the drug dissolution which may due to porosity [70].
Modifying the hydrolysis conditions, including temperature, time, and acid concentration, also has a very little impact on the degree of crystallinity, i.e., the regularity of the arrangement of the cellulose polymer chains [2, 50]. This observation indicates that crystallinity cannot be controlled at the hydrolysis stage. Crystallinity appears to be more dependent on pulp source rather than on processing conditions [4], which is consistent with the method of MCC manufacture where the acid preferentially attacks the (pulp dependent) amorphous regions.
The total amount of sorbed water in MCC is proportional to the fraction of amorphous material [48, 54, 55]. Therefore MCC powders with a lower degree of crystallinity may contain more water than their counterparts with a higher degree. If low-crystallinity MCC preferentially binds more water, moisture-sensitive APIs may exhibit lower rates of degradation [71]. Despite the controversial impact of crystallinity, it may influence the adsorption of water on cellulose microfibrils, which may in turn influence flowability, tabletability, and stability of the drug product.
Mostly, direct compression excipients are spray-dried; therefore porous structure was produced as a result. This property is characterized by a relatively low bulk density. Increase in porosity (lower density) facilitates higher compressibility, i.e., the densification of a powder bed due to the application of a stress [56]. The improved compressibility of plastically deforming materials, such as MCC, might then result in improved tabletability as a result of the increased bonding surface area [72]. The higher roughness of low density MCC particles may also contribute to particle interlocking [73]. Low bulk density MCC will provide higher dilution potential and hence better counteract the poor tableting properties of APIs. Granulation or drying as preprocesses of tablet formulation will densify MCC hence less tabletable than the original porous MCC [74, 75]. It can therefore be generalized that a decrease in bulk density improves tabletability; however, it will often hinder flowability [62].
The degree of polymerization (DP) expresses the number of glucose units (C6H10O5) in the cellulose chain. It decreases exponentially as a function of hydrolysis conditions, including temperature, acid concentration, and time of reaction. The rate of hydrolysis slows down to a certain value which is stated as level-off degree of polymerization (LODP). The LODP value is specific for a particular pulp, and it is usually between the range of 200 and 300 [44, 61], e.g., 180–210 range for hardwood pulps and 210–250 for softwood pulps. Theoretically, to obtain a certain degree of polymerization which is higher than the LODP value, hydrolysis process could be terminated at any time. However, due to the exponential decay of DP, this termination is neither a robust nor a reproducible approach. The degree of polymerization is used as an identity test, as pharmacopoeial MCC is defined by a DP below 350 glucose units, compared to DPs in the order of 10,000 units for the original native cellulose [1].
The correlation between the degree of polymerization (DP) of MCC and its tabletability has not been explored yet. Therefore, it is merely an identity test to distinguish the tabletability of MCC (DP < 350) compared with powdered cellulose (DP > 440). Dybowski showed that the origin of the raw materials and the production method of MCC more decisively influence the physical characteristics than DP. DP value is a criterion used to guide the manufacturer about hydrolysis of MCC, whereas for the user it is a characteristic to distinguish between properties of MCC and powdered cellulose.
Wood pulps with high bulk density grades which can be characterized by lower level-off DP should not be directly compared with standard grades. This parameter reflects the lack of distinction between the degree of polymerization (DP) and level-off degree of polymerization (LODP). LODP is typical of a particular raw material, with a common value between the range of 200 and 300 [44]. Cellulose having LODP value at this range usually difficult for further hydrolysis. In contrast, cellulose materials with DP values higher than the level-off degree of polymerization plateau are more difficult to control due to their greater sensitivity to hydrolysis. Owing LODP above 200–300, the MCC remains to be more fibrous, which would result in a lower bulk density, with improved tabletability, but would hinder powder flow [49, 50]. Below the LODP MCC is less fibrous, denser, and less tabletable. Tabletability is not related to a particular DP value; as an example powdered cellulose has a higher DP than MCC but is not as tabletable [1].
Landín et al. compared four brands of MCC [45]. Different woods used as raw materials, i.e., hardwood versus softwood, suggested differences in lignin and hemicelluloses composition. The non-cellulose component has also significantly different manufacturing process intensities which resulted in variable suggestive composition and potentially varying qualities of product. Landín et al. found that lignin content increased the dissolution rate of prednisone [46]. Lignin being hydrophobic may alter cellulose–cellulose and/or cellulose–API interactions and hence drug release rate.
Thoorens et al. [37] studied that differences in packing and flow properties which are shown by scanning electron micrographs from Avicel PH-101 and Avicel PH-102 were attributed to differences in moisture content, particle shape, and particle size distribution. Tabletability which also varied among the MCC samples were attributed to the differences in moisture content and the internal structure of the particles. These are mostly caused by different processing conditions which are specific to each manufacturer. However, the impacts of crystallinity and particle morphology are negligible. Significant differences in lubricant sensitivity, compressibility, and tablet disintegration were also noted between MCCs due to various manufacturing processes by different manufacturers. Variability between lots from the same manufacturer was found to give a smaller effect on properties of MCC product. A current study from Doelker concluded that even if all of various MCCs comply with compendial specifications, large differences still exist among them [44].
According to the International Pharmaceutical Excipient Council (IPEC), excipients are the process aids or any substances other than the active pharmaceutical ingredient that are included in pharmaceutical dosage forms. The functionalities of excipient are to impart weight, consistency, and volume which allow accuracy of dose, improve solubility, and in the end increase stability. It can also be proposed to enhance bioavailability, modifying drug release and used in product quick identification, increase patient acceptability, and facilitate dosage form design.
Excipients classified as:
Primary excipients: diluents (filler), binders (adhesives), disintegrants, lubricants, antiadhesives, glidants
Secondary excipients: coloring agents, flavors, sweeteners, coating agents, plasticizers wetting agents, buffers, and adsorbents
Diluents are incorporated into tablet or capsule dosage forms to increase dosage form volume or weight and can also be referred as fillers. Direct compression binders are functional even at low use levels and offer superior tabletability [1]. Some diluents, such as microcrystalline cellulose, can also be considered as dry binders since they improve the compactibility or tabletability of the compression mix.
Microcrystalline cellulose, according to many publications, is an excipient of outstanding merit and remains the most widely used direct compression excipient serving as a strong dry binder, tablet disintegrant, an absorbent, filler or diluent, a lubricant, and anti-adherent.
MCC is generally considered as the diluent having the best binding properties and is recognized as one of the preferred DC binders [44, 76]. It is used as a binder/diluent in oral tablet and capsule formulations including both wet granulation and direct compression processes. It also has some lubricant and disintegrant properties which is useful in direct tableting. Small amounts of MCCs are able to efficiently bind other materials, especially poorly tabletable active pharmaceutical ingredients. MCC exhibits a high dilution potential, whereas the broad particle size range provides optimum packing density and coverage of other materials [44, 54].
MCC has been the most favorite diluent among others due to its low bulk density. Excipient having low bulk density and large particle size distribution will exhibit a high dilution potential on a weight basis, optimum packing density, and coverage of drug and other excipient materials [77].
MCC is commercially available in different particle sizes, density, and moisture grades that have different properties and applications. The most widely pronounced grades are Avicel PH 101 and Avicel PH 102 (FMC Corporation, Princeton, NJ, USA). PH stands for the pharmaceutical grade of MCC. Avicel PH 101 is the original grade of MCC, while PH 102 is available as a partially agglomerated product with a larger particle size distribution and slightly better fluidity. Both grades show no significant difference in the compressibility [78].
MCC has been very well known as the most compressible of all direct compression fillers which has the highest dilution potential and capacity. It is defined as the amount of active ingredient that a diluent can successfully carry in the direct compression method. This property can be explained by the basis of the physicochemical nature of MCC particles, which are held together by hydrogen bonds. MCC particles are deformed plastically under compaction forces to yield an extremely large number of clean surfaces brought in contact during this deformation, forming a strong compact even under low compression forces [78].
Direct compression (DC) is the tableting process of a blend of ingredients without a preliminary granulation or agglomeration process. Despite involving only few process steps, product design in DC can be challenging because of the numerous competing objectives [79]. Direct compression requires increased performance, quality, and consistency from the starting ingredients including excipients [44, 56, 80, 81]. The use of poorly controlled or inadequately specified raw materials may lead to several challenges in DC, such as poor flowability and inconsistent tablet weight, unsatisfactory tablet strength, lack of content uniformity or segregation, and dissolution failure [56, 82, 83]. Among several requirements, the compression mix has to flow to ensure a consistent tablet weight; it has to compress and compact into robust tablets. Overall, as a direct compression filler, Avicel promotes efficient dry blending of ingredients and produces tablets with high hardness levels and low friability levels with excellent compression. It produces tablets of superior whiteness and color stability.
Lately, MCC can be considered as the most widely used diluent in the direct compression and wet granulated tablet making procedures. MCC type 102, having a median particle size of about 100 mm (D50 value measured by laser diffraction), presents acceptable flow properties required for successful high-speed tableting [2, 84]. However due to the low bulk density of MCC, its mass flow is less than that of other common and denser excipients such as direct compression grades of lactose or dibasic calcium phosphates [43, 44, 59, 82]. Avicel grades (Avicel PH-102 SCG, Avicel HFE-102, Avicel PH-200, Avicel PH-302) provide excipient solutions to many challenges of direct compression formulations including improved flow, better compressibility, and accommodation of moisture-sensitive actives [78]. The larger particle size grades generally provide better flow properties, while low-moisture grades are used for moisture-sensitive materials. Higher-density grades have improved flowability. Flowability may be improved by selecting coarser grades of MCC with a larger number of aggregates, such as MCC type 200 with a median particle size approximating 200 mm [58, 85].
The difference between these common excipients is less pronounced on a volumetric basis [86], which determines die fill. Another approach may be to combine MCC with other free flowing excipients or glidants [59, 62, 87]. Gamble et al. observed that the particle size distributions of coarser grades of MCC do not scale up proportionally [58]. MCC types 101, 102, and 200 all have primary particles of about 50 mm but differ in the number of larger aggregated particles. These aggregates, accounting for a large volume/mass fraction but a low number fraction, enable improved flow.
During compression, MCC plastically deforms and therefore maximizes the area of interparticle bonding [88]. Mechanical interlocking of irregularly shaped and elongated MCC particles has also been suggested to enhance tabletability [44, 60, 75]. The plasticity of MCC is the main reason of its exceptional binding properties. However, compared to brittle excipients, MCC is more lubricant sensitive. For a constant number of revolutions, tabletability may also decrease with increasing blender sizes and decreasing loadings in the blender [89]. The viscoelastic behavior of MCC also explains its strain rate sensitivity (SRS), which refers to the greater elastic effects at higher tableting speeds where there is insufficient compaction time for plastic deformation [90]. The strain rate sensitivity of viscoelastic excipients has to be taken into account by the formulation scientists in order to design robust formulations.
MCC is one of the types of filler which is water insoluble having swelling tendencies and excellent water imbibing or wicking action. Other filler examples with the same property are calcium pectinate and sodium alginate. This property makes MCC as also an excipient of choice for wet granulation. Both Avicel PH 101 and Avicel PH 102 can be used advantageously as fillers in wet granulation in a concentration of 5.15%. When used as filler in wet granulation method, the wicking action of MCC promotes rapid wetting of the powder mix. Another advantage offfered by using MCC as wet granulation filler is the ability to retain water, which makes the wet mass less sensitive to overwetting due to an excess of granulating fluid. The milling of the wet mass will be much easier due to less clogging of the screen; hence it will produce a more uniform granules. Drying process also will be more homogeneous, and the case of hardening can be reduced. Case hardening is a phenomenon which is observed in incompletely dried granules. This case happened when the granules are dried at a high temperature, from which the inside part of the granules remains wet, while the surface seems dried. The granules are often hard and resist disintegration. When coming to compaction process, the compression forces will break the granules and deform plastically to form soft tablets due to the moisture coming out of the incompletely dried granules. The use of Avicel PH 101 or Avicel PH 302 as filler in wet granulation promotes rapid wetting as a result of the wicking action of MCC. They reduce sensitivity of the wet mass to overwetting and increase the drying process speed. Since there is fewer excess of granulating fluid, screen blockages and case hardenings can be reduced. Homogeneous and uniform granule when MCC is used as wet granulation filler will reduce dye migration. When MCC is employed, faster disintegration from granules and tablets will be obtained.
Basically, using MCC in wet granulation included wetting MCC with water followed by drying and compression. The process resulted in lower hardness tablets than that with dry compression. The wet granulation reduces the density of agglomerated particles thereby decreasing their internal surface area. In contrast, it can also cause adhesion between particle agglomerates, reducing external surface area resulting in less particle interlocking and hydrogen bonding. In general, using Avicel PH-101 or Avicel PH-102 in wet granulation formulations with concentration between 5 and 20% offers the following benefits [51]:
Rapid adsorption of water by MCC and distribution through the mixture
Decrease of sensitivity to water content, wet screening, and localized overwetting due to the large surface area of MCC, hence high adsorptive capacity
Increased drying efficiency
Decreased color mottling
Better drug content uniformity
Higher tablet hardness at the same compression force with less friability
Roller compaction is a dry process involving compaction of materials that are then milled to generate a granulation. This granulation is then lubricated and compressed on a tablet machine. This process can be used for moisture-sensitive active pharmaceutical ingredients. The use of Avicel PH grades in roller compaction includes improvement of compaction in the ribbon phase, enhancement of flow of the granules, and preserving of the content uniformity of the Þ nal granulation.
MCC is a self-disintegrating binder [91] with low lubricant requirement with regard to its dry binding properties due to the extreme low coefficient of friction and its very low residual die wall pressure [56, 62, 92]. However these properties do not replace the need for true disintegrants and lubricants as an addition when MCC is used in a tablet formulation. In fact combination of MCC and superdisintegrants may be complementary to promote fast disintegration [93, 94]. Other advantages of MCC include broad compatibility with various APIs, physiological inertness, ease of handling, and ease of supply for manufacturer [54].
Study on the use of MCC with spray-dried lactose as the poorest compressibility among all directly compressible fillers showed that a blend of 200 mg of spray-dried lactose with appropriate lubricants may not be able to compress unless a correct amount of dry binder is incorporated inside the blend. Incorporation of 2.5% of Avicel to the formulation proved that MCC has served the purpose. A number of Avicel such as PH-113 can act as a dry binder [95]. However, it will also function as a disintegrant when dry compression is employed.
MCC can also be used as a secondary binder in wet granulation tablet preparation either to granulate both soluble and insoluble APIs. This formulation will produce less hard tablets than that without MCC. The fast wicking action of MCC promotes rapid wetting of the powder mix. This is particularly useful in high moisture granulations as it binds the excess moisture and keeps the granules dry and free flowing.
Disintegrants expand and dissolve once it is in contact with water causing the tablet to break apart in the GI tract and release the active ingredients for absorption. It will break a tablet into smaller fragments therefore increasing the surface area of the active drug in the dosage form; hence it will also increase the rate of drug absorption. The mechanism of disintegrants in the tablet disintegration could be as either water uptake facilitators or tablet rupture promoters. MCC has been widely used as a disintegrant in dry compressions and wet granulation method for tablet manufacturing. It enhances drug dissolution by increasing the rate of tablet disintegration. Basically a disintegrant should provide the highest level of disintegration force at low use levels and utilizes dual disintegration mechanisms either in wicking or swelling for faster tablet disintegration.
The Avicel derivate showed the nature in a fast wicking rate of water with small elastic deformation. These properties provide the ability for tablet disintegration. However, Avicel has a tendency to develop static charges with increased moisture content. Sometimes it even can cause striation or separation in the granules. This occurs when the moisture content in Avicel is above 3%, in which the static charges during mixing and compression become more pronounced. The problem can be overcome by drying the Avicel prior the formulation process to reduce the moisture to lower level. Wet granulated Avicel will lose some of its disintegration properties when performing drying and compression during formulation [4]. In contrast with starch, it cannot be wet granulated without losing some of its disintegration properties. Normally, to overcome this problem, Avicel and starch are used in combination in order to facilitate effective and rapid disintegration of tablets.
MCC has a very high intraparticle porosity with approximately 90–95% of the surface area being internal [44]. Therefore the surface area is not directly influenced by the nominal particle size [58]. High porosity of MCC promotes swelling and disintegration of formulated tablets, which is attributed to either by the penetration of water into the hydrophilic tablet matrix by means of capillary action of the pores or even by a disruption of the hydrogen bonds. By increasing compaction pressure, water penetration into the tablets will decrease; therefore disintegration time will increase [54, 85].
In intramolecular view, water is only sorbed in the amorphous regions of MCC, which are more hydrophilic than the crystalline regions [3, 54]. Therefore the total amount of sorbed water is proportional to the fraction of amorphous material in the MCC crystallinity and is independent of the surface area [48]. The crystallinity of MCC determined by X-ray diffraction and infrared measurement was found to be in the range of 60–80% [53].
Recently, Avicel has been used as a disintegrant in orally disintegrating tablets. Besides being a disintegrant, it also acts as a dissolution enhancer. US Patent No 6350470 explains the use of Avicel as a disintegrating agent in effervescent drug delivery system for oral administration. In this system, by performing dry granulation, Avicel acts as disintegrant in a concentration of 5.20% [96]. Avicel acts as an effervescent penetration enhancer.
Lubricants ensure that tablet formation and ejection can occur with low friction between the solid and die wall.
Avicel has an extremely low coefficient of friction, both static and dynamic, so that it has no lubricant requirement itself. However, when more than 20% of the drug and other excipients are added, lubrication is necessary.
In tablet formulation, glidant is used to promote powder flow by reducing interparticle friction and cohesion. Glidants can be used in combination with lubricants as they have no ability to reduce die wall friction. Normally, silica-based glidants like silicon dioxide, hydrated sodium silicoaluminate, silica hydrogel, etc. are used in tablet compression to promote good flow property. Proslov as a marketed product of coprocess excipient containing MCC is available which imparts superior flow, good compactibility, and dispersion to tablet formulation [97].
When used as excipient in direct compression, Prosolv SMCC® (JRS Pharma, Patterson, NY) can replace granulation step and significantly reduce excipient numbers and levels. Prosolv SMCC® formulations produce distinctive, uniform, and cost-effective tablets. It is available in three grades: Prosolv SMCC 50, Prosolv SMCC 90, and Prosolv SMCC HD 90. The products differ in average of particle size and bulk density [98]. They offer many benefits including enhanced mixing characteristics, enhanced flow properties, lower unit cost of production due to less excipients needed, and shorter disintegration time. Due to improvement in powder compactibility and dust-free handling during production, Prosolv facilitates less loss in production hence a higher manufacturing efficiency.
In a more recent study, it is reported that silicified MCC and MCC were found to be good plug formers in hard gelatin capsule shells. The study was conducted in a compaction simulator at tamping forces and piston speeds similar to those found in some filling machines. Several grades of silicified MCC and a particular grade of MCC having particle size of 90 μm produced plugs with a higher maximum breaking force than anhydrous lactose and Starch 1500 under similar compression conditions [99].
MCC is an excipient of choice in a multiparticulate delivery of pellets prepared by extrusion spheronization. The extrusion-spheronization process aims to produce drugs into sphere-shaped tablets. Extrusion-spheronization process offers an alternative to traditional drug layering on pellets. This highly specialized process results in unique spherical, drug-loaded spherical pellets. Higher drug loading can be employed with this approach over that which looks impossible with conventional drug layering. The product, initially called as extrudates, is plastic without rigidity, which tends to agglomerate into very large spherical balls. The formulation mixture which will be manufactured by extrusion method must fulfill the requirements:
Cohesive and deformable in order to have good flow through the die without sticking and able to retain its shape after extrusion process
Plastic, so that it can proceed rolling process into spheres in the spheronizer but possesses non-cohesive property so that the final sphere form can remain discrete
MCC, especially Avicel PH-101, can act as an excellent extrusion-spheronization aid excipient that absorbs the water added to the formulation more as a molecular sponge. This ability alters the rheological properties of the wet mass, therefore enhancing the tensile strength of the wet mass during spheronization process through autoadhesion.
Avicel® PH-101 or Avicel PH-102 is highly recommended to be used for this method because it can reduce spheroid friability, prevent overwetting of spheres, and improve sphericity of pellets. Process sensitivity during the whole manufacture can be lessened to the lower level.
Recently, MCC has been widely used in the formulation of multiparticulate and matrix tablet dosage forms for sustained release drug delivery system. In general, hydrophilic polymers in matrix tablet formulation are included to form a viscous, gelling layer which can retard water penetration and acts as a barrier to drug release. Drug release is accomplished by diffusion through the gel layer and at the same time through erosion of this layer. Some studies proved that zero-order release profiles can be achieved by selection of appropriate polymers in addition of Avicel as fillers/binders.
Microcrystalline cellulose is a pure partially depolymerized cellulose synthesized from α-cellulose precursor with hydrolysis by mineral acids, usually in forms of a pulp from a fibrous plant. In the presence of water and acid, hydrolysis process breaks cellulose polymers into smaller chain polymers or microcrystals. Other celluloses, to which more soluble, such as beta and gamma celluloses, hemicelluloses and lignin are dissolved with acid and water, are separated out during washing. MCC is commonly dried from the slurry by spray-drying method. By varying spray-drying conditions, the degree of agglomeration and moisture content can be manipulated, in order to obtain particular particle sizes.
Mostly, a raw material for MMC is a cellulose pulp from fibrous plant such as conifer wood. Another source is from cotton either its linters, stalks, rags, fabric waste, or wool. Another study reported a potential source for MCC such as soybean, corn cob, water hyacinth, coconut shells, oil palm biomass residue, oil palm fronds, rice husk, sugar cane bagasse, jute, ramie, fibers and straw of flax, wheat straw, sorghum stalks, sisal fibers, mangosteen, alfa grass fibers, soybean hulls, orange mesocarp, Indian bamboo, roselle fiber, and alfa fiber. Seed flosses from milkweed pods, shrubs, and kapok (Ceiba pentandra) trees are also known as sources of cellulose.
A different manufacture will produce variability in properties of MCC due to the kinds of pulp used as raw materials and applied process parameters. This can be characterized from the physicochemical properties of product including moisture content, particle size, particle morphology, crystallinity, bulk density, and degree of polymerization.
Microcrystalline cellulose, according to many publications, is an excipient most widely used for direct compression. Besides, it also serves as a strong dry binder, tablet disintegrant, absorbent, filler or diluent, a lubricant, and anti-adherent.
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