Draw Attention Towards Mucoadhesive Buccal Drug Delivery System
1. Introduction
Considerable attention has been focused in recent years on the delivery through the oral mucosa of drugs which have a high first pass metabolism (i.e., metabolized to a large extent by the liver during the first pass there through and therefore do not enter the blood stream) or degrade in the gastrointestinal tract. Transmucosal delivery has also been considered for treatment of oral disorders and as a local anesthetic1.
Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, which presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption2. Other routes, such as nasal, ocular, pulmonary, rectal, and vaginal drug administration, have provided excellent opportunities for the delivery of a variety of compounds. However, the mucosal lining of the oral cavity offers some distinct advantages.
Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site.3
2. Advantages of Buccal Drug Delivery Systems
Advantages of buccal administration are currently recognized commercially or in the medical literature. The first known advantage is rapidity of action. Medications administered buccally enter the blood stream immediately after passage through the buccal mucosa instead of first having to be swallowed and then having to pass through a portion of the gastrointestinal tract before being absorbed. This rapidity of action is one of the reasons that one commercially available and one experimental product for pain relief have been administered via the buccal route. The first of these products contains nitroglyerin, and is available as a buccal pill that adheres to the mucosa, sold under the trademark Nitrogard. The second product contains the non-steroidal anti-inflammatory analgesic diclofenac which has been used in an experimental buccal pill that adheres to the mucosa. The second known advantage of the buccal route is to allow administration of medications which cannot normally be administered orally. Additional unique advantages of the buccal route and the medications that exploit these advantages are described below, as well as additional medications that could be administered buccally to exploit the two previously mentioned advantages of the buccal route4.
As far as the first advantage, rapidity of action, is concerned several classes of medications would have improved efficacy if administered via the buccal route. One class of medications for which rapidity of action is important and which could be placed in buccal tablets in general and the inventive buccal tablet in particular are analgesics which include aspirin, ibuprofen, fenoprofen, sulindac, salsalate, diflunisal, mecleofenamate, naproxen, nabumetone, tolmetin, diclofenac, oxaprozin, indomethacin ketoprofen, choline salicylate, piroxicam, mefenamic acid, etodolac and ketorolac.
As far as the second advantage of buccal administration, the ability to administer drugs that cannot be ingested because of drug destruction, there are several drugs which are potentially in this category. Testosterone could be placed in a buccal tablet and could then be administered via the oral route to avoid destruction via first pass metabolism. Normally such metabolism necessitates the administration of testosterone via injection or a large skin patch worn on the scrotum. However, the scrotal patch has an important potential disadvantage since scrotal skin generates an increased amount of a testosterone metabolite, 5 alpha-dihydrotestosterone that can potentially stimulate prostate hypertrophy.5
Similarly, many drugs affect liver metabolism of other drugs. This affect would be greatly attenuated by administering such drugs in buccal form. One class of drugs in this category are medications that inhibit metabolizing enzymes in the liver resulting in increased concentrations of other drugs. Another class of drugs increases metabolizing enzymes in the liver resulting in decreased concentrations of other drugs. By administering both classes of these drugs using a buccal tablet there would be less effect on the concentration of other drugs and thus the avoidance of toxic as well as sub-therapeutic drug levels. Drugs in the category of liver enzyme inhibitors which could be administered via a buccal tablet include allopurinol, ketoconazole. Drugs in the category of liver enzyme inducers which could be administered via a buccal tablet include cabamazepine, phenytoin, glutethimide, primidone, rifampin and barbiturates such as phenobarbital, pentobarbital, secobarbital,
The third of these advantages of buccal administration is that it results in much less exposure of the GI tract to a drug as opposed to oral ingestions. One of the side effects of many antibiotics is the destruction of normal GI flora resulting in diarrhea and overgrowth with dangerous organisms such as C. difficile. Antibiotics that could be incorporated in a buccal tablet, which would then have enhanced safety because of reduction in the toxic effect on gut flora, include cephlosporins such as cephalexin, cefadroxil, cefaclor, cefamandone, cefuroxime, cefprozil, cefpodoxime, loracarbef and cefixime; also penicillins including penicillin G, penicillin V, cloxacillin, dicloxacillin
The fourth of these advantages of buccal administration is that it allows drugs to be administered which would otherwise interfere with the absorption of other drugs. In particular iron supplements can be administered via a buccal tablet with the avoidance of many adverse effects on the absorption of other medications such as thyroid hormone.
The fifth of these advantages of buccal administration is that it increases the practicality of administering drugs whose absorption is adversely affected by the presence of food. Tetracyclines, in particular, could be administered buccally thus avoiding the effects of food on tetracycline administration which otherwise complicates the administration of this class of antibiotics via the oral route.
The sixth of these advantages of buccal administration is that it allows blood lipids such as cholesterol to be lowered and modified in ways not possible through the oral ingestion of medications. Lipids can be incorporated into a buccal tablet. Lipids absorbed via the buccal mucosa bypass liver metabolism and can directly interact with endogenous lipoproteins thus influencing blood lipid levels. Recently an acute lowering of cholesterol has been demonstrated by applying lecithin to the skin.6
Compared with the oral, nasal, and rectal routes for drug delivery, the buccal route presents advantages such as an efficient blood supply and relatively low enzymatic activity. Moreover, the buccal mucosa is easily accessible and acceptable to patients; it allows the patient to interrupt drug administration by simply removing the drug delivery system. On the other hand, the buccal route is characterized by some intrinsic limitations (barrier properties of the mucosa, small area available for drug absorption, short residence time of the formulation caused by physiologic-removal mechanisms), which have to be considered in the design of buccal drug delivery systems.7
3.3. Factors affecting mucoadhesion in the oral cavity
Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. A variety of factors affect the mucoadhesive properties of polymers, such as molecular weight, flexibility, hydrogen bonding capacity, cross-linking density, charge, concentration, and hydration (swelling) of a polymer, which are briefly addressed below.
3.3.1. Polymer-related factors
3.3.1.1. Molecular weight
In general, it has been shown that the bioadhesive strength of a polymer increases with molecular weights above 100,000 8. As one example, the direct correlation between the bioadhesive strength of polyoxyethylene polymers and their molecular weights, in the range of 200,000 to 7,000,000, has been shown by Tiwari et al. 9
3.3.1.2. Flexibility
Bioadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore, it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. A recent publication demonstrated the use of tethered poly(ethylene glycol)–poly(acrylic acid) hydrogels and their copolymers with improved mucoadhesive properties 10. The increased chain interpenetration was attributed to the increased structural flexibility of the polymer upon incorporation of poly(ethylene glycol). In general, mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network 11.
3.3.1.3. Hydrogen bonding capacity
Hydrogen bonding is another important factor in mucoadhesion of a polymer. Park and Robinson found that in order for mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds 12. They have also confirmed that flexibility of the polymer is important to improve this hydrogen bonding potential. Polymers such as poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid), as well as all their copolymers, are polymers with good hydrogen bonding capacity 13.
3.3.1.4. Cross-linking density
The average pore size, the number average molecular weight of the cross-linked polymers, and the density of cross-linking are three important and interrelated structural parameters of a polymer network 11. Therefore, it seems reasonable that with increasing density of cross-linking, diffusion of water into the polymer network occurs at a lower rate which, in turn, causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin 11. Flory 14 has reported this general property of polymers, in which the degree of swelling at equilibrium has an inverse relationship with the degree of cross-linking of a polymer.
3.3.1.5. Charge
Some generalizations about the charge of bioadhesive polymers have been made previously, where nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers. Peppas and Buri have demonstrated that strong anionic charge on the polymer is one of the required characteristics for mucoadhesion 13. It has been shown that some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium 15. Additionally, some cationic high-molecular-weight polymers, such as chitosan, have shown to possess good adhesive properties.
3.3.1.6. Concentration
The importance of this factor lies in the development of a strong adhesive bond with the mucus, and can be explained by the polymer chain length available for penetration into the mucus layer. When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable 13. In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which the polymer produces an "unperturbed" state due to a significantly coiled structure. As a result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in some cases, actually diminish mucoadhesive properties. One of the studies addressing this factor demonstrated that high concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl alcohol) as film-forming polymers did not further enhance the mucoadhesive properties of the polymer 16. On the contrary, it decreased the desired strength of mucoadhesion 16.
3.3.1.7. Hydration (swelling)
Hydration is required for a mucoadhesive polymer to expand and create a proper "macromolecular mesh" 11 of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin. Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network 11. However, a critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and bioadhesion occurs 13.
3.3.2. Environmental factors
The mucoadhesion of a polymer not only depends on its molecular properties, but also on the environmental factors adjacent to the polymer. Saliva, as a dissolution medium, affects the behavior of the polymer. Depending on the saliva flow rate and method of determination, the pH of this medium has been estimated to be between 6.5 and 7.5 17. The residence time of dosage forms is limited by the mucin turnover time, which has been calculated to range between 47 and 270 min in rats 18 and 12–24 h in humans 19.
Movement of the buccal tissues while eating, drinking, and talking, is another concern which should be considered when designing a dosage form for the oral cavity. Movements within the oral cavity continue even during sleep, and can potentially lead to the detachment of the dosage form. Therefore, an optimum time span for the administration of the dosage form is necessary in order to avoid many of these interfering factors 20.
4. Buccal drug delivery systems
Bioadhesive polymers have been used extensively in buccal drug delivery systems to provide dosage form retention. Bioadhesive polymers are defined as polymers that can adhere to a biological substrate. The term mucoadhesion is applied when the substrate is mucosal tissue 21. Diverse classes of polymers have been investigated for their potential use as mucoadhesives. These include synthetic polymers such as monomeric _ cyanoacrylate 22, polyacrylic acid 23, hydroxyl propyl methylcellulose 24, and polymethacrylate derivatives 25as well as naturally occurring polymers such as hyaluronic acid 26and chitosan 27. Other synthetic polymers such as polyurethanes, epoxy resins, polystyrene, and natural-product cement also have been extensively investigated 28. In general, dosage forms designed for buccal administration should not cause irritation and should be small and flexible enough to be accepted by the patient. These requirements can be met by using hydrogels. Hydrogels are hydrophilic matrices that are capable of swelling when placed in aqueous media. Normally, hydrogels are cross-linked so that they will not dissolve in the medium and will absorb only water. When drugs are loaded into these hydrogels, as water is absorbed into the matrix, polymer chain relaxation occurs and drug molecules are released through the spaces or channels within the hydrogel network. In a broader meaning of the term, hydrogels also would include water-soluble matrices that are capable of swelling in aqueous media; these include natural gums and cellulose derivatives.
Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging29.
5. Buccal mucoadhesive dosage forms
Buccal mucoadhesive dosage forms can be categorized into three types based on their geometry. Type I is a single layer device with multidirectional drug release. This type of dosage form suffers from significant drug loss due to swallowing. In type II devices, an impermeable backing layer is superimposed on top of the drug-loaded bioadhesive layer, creating a double-layered device and preventing drug loss from the top surface of the dosage form into the oral cavity. Type III is a unidirectional release device, from which drug loss is minimal, since the drug is released only from the side adjacent to the buccal mucosa. This can be achieved by coating every face of the dosage form, except the one that is in contact with the buccal mucosa.
Buccal dosage forms can also be classified as either a "reservoir" or "matrix" type. In the reservoir type, an excessive amount of the drug is present in the reservoir surrounded by a polymeric membrane, which controls the drug's release rate. In the matrix-type systems, the drug is uniformly dispersed in the polymer matrix, and drug release is controlled by diffusion through the polymer network.
In addition, the mucoadhesive tablet was generally well-tolerated and caused fewer incidences of gastrointestinal disorders and drug-related adverse events than those observed when ketoconazole was administered systemically. The authors suggested that this particular dosage form is the first and only once-daily topical treatment option for this condition 30.
5.1 Buccal tablets
Tablets have been the most commonly investigated dosage form for buccal drug delivery to date. Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm 31. Unlike conventional tablets, buccal mucoadhesive tablets allow for drinking and speaking without major discomfort. They soften, adhere to the mucosa, and are retained in position until dissolution and/or release is complete. These tablets can be applied to different sites in the oral cavity, including the palate, the mucosa lining the cheek, as well as between the lip and the gum. Successive tablets can be applied to alternate sides of the mouth. The major drawback of buccal bioadhesive tablets is their lack of physical flexibility, leading to poor patient compliance for long-term and repeated use.
5.2 Buccal patches
Patches are laminates consisting of an impermeable backing layer, a drug-containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment. Buccal patch systems are similar to those used in transdermal drug delivery. Two methods used to prepare adhesive patches include solvent casting and direct milling. In the solvent casting method, the intermediate sheet from which patches are punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer sheet, and subsequently allowing the solvent(s) to evaporate. In the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired thickness, and patches of predetermined size and shape are then cut or punched out. An impermeable backing layer may also be applied to control the direction of drug release, prevent drug loss, and minimize deformation and disintegration of the device during the application period.
5.3 Buccal films
Films are the most recently developed dosage form for buccal administration .Buccal films may be preferred over adhesive tablets in terms of flexibility and comfort. In addition, they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva. Moreover, in the case of local delivery for oral diseases, the films also help protect the wound surface, thus helping to reduce pain and treat the disease more effectively. An ideal film should be flexible, elastic, and soft, yet adequately strong to withstand breakage due to stress from mouth movements. It must also possess good bioadhesive strength in order to be retained in the mouth for the desired duration of action. Swelling of film, if it occurs, should not be too extensive in order to prevent discomfort.
5.4 Buccal gels and ointments
Semisolid dosage forms, such as gels and ointments, have the advantage of easy dispersion throughout the oral mucosa. However, drug dosing from semisolid dosage forms may not be as accurate as from tablets, patches, or films. Poor retention of the gels at the site of application has been overcome by using bioadhesive formulations .Certain bioadhesive polymers, e.g. poloxamer 407 32, sodium carboxy methylcellulose 33, carbopol, hyaluronic acid, and xanthan gum, undergo a phase change from a liquid to a semisolid. This change enhances the viscosity, which results in sustained and controlled release of drugs. However, these polymers have been investigated for this purpose primarily in ocular drug delivery.
Conclusion
The buccal mucosa offers several advantages for controlled drug delivery. The mucosa is well supplied with both vascular and lymphatic drainage; first-pass metabolism in the liver and presystemic elimination in the GI tract is avoided. The area is well suited for a retentive device and appears to be acceptable to patients. With the proper formulation and dosage form design, the permeability and the local environment of the mucosa can be controlled and manipulated to accommodate drug permeation. Buccal drug delivery is a promising area for systemic delivery of orally inefficient drugs as well as an attractive alternative for noninvasive delivery of potent peptide and perhaps protein drug molecules. However, the need for safe and effective buccal permeation and absorption enhancers is a crucial component for a promising future in the area of buccal drug delivery. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug and excipients. Advances in experimental and computational methodologies will be helpful in shortening the processing time from formulation design to clinical use.
References
1. de Vries, M.E., Bodde, H.E., Verhoef, J.C., Junginger, H.E., "Developments in Buccal Drug Delivery," Critical Reviews in Therapeutic Drug Delivery Systems, CRC Press, Inc., 1991, 8(3), pp. 271-303.
2. The use of mucoadhesive polymers in buccal drug delivery Nazila Salamat-Miller, Montakarn Chittchang1, Thomas P. Johnston* Advanced Drug Delivery Reviews 57 (2005) 1666– 1691
3. Molecular aspects of muco- and bioadhesion : Tethered structures and site-specific surfaces Journal of controlled release YANBIN HUANG (1) ; LEOBANDUNG W. (1) ; FOSS A. (1) ; PEPPAS N. A. (1) ; 2000, vol. 65, no 1-2 (23 ref.), pp. 63-71
4. Cassidy, J. et al., "Human Transbuccal Absorption of Diclofenac Sodium from a Prototype Hydrogel Delivery Device," Pharmaceutical Research, vol. 10, No. 1, 1993, pp. 126-129.
5. Geller, J. et al., "Therapeutic Controversies: Clinical Treatment of Benign Prostatic Hyperplasia," Journal of Cinical Endocrinology & Metabolism, vol. 80, No. 3, pp. 745-756.
6. Oral transmucosal delivery tablet and method of making it US Patent Issued on August 12, 1997Michael S. Balkin
7. Buccal Delivery Systems for Peptides: Recent Advances. Healthcare Technology ReviewAmerican Journal of Drug Delivery. 3(4):215-225, 2005.
Rossi, Silvia; Sandri, Giuseppina; Caramella, Carla
8. J.L. Chen and G.N. Cyr, Compositions producing adhesion through hydration. In: R.S. Manly, Editor, Adhesion in Biological Systems, Academic Press, New York (1970), pp. 163–180.
9. D. Tiwari, D. Goldman, R. Sause and P.L. Madan, Evaluation of polyoxyethylene homopolymers for buccal bioadhesive drug delivery device formulations, AAPS PharmSci 1 (1999), p. E13.
10. Y. Huang, W. Leobandung, A. Foss and N.A. Peppas, Molecular aspects of muco- and bioadhesion: tethered structures and site-specific surfaces, J. Control. Release 65 (2000), pp. 63–71.
11. J.-M. Gu, J.R. Robinson and S.-H.S. Leung, Binding of acrylic polymers to mucin/epithelial surfaces: structure–property relationships, Crit. Rev. Ther. Drug Carr. Syst. 5 (1998), pp. 21–67.
12. H. Park and J.R. Robinson, Mechanisms of mucoadhesion of poly(acrylic acid) hydrogels, Pharm. Res. 4 (1987), pp. 457–464.
13. N.A. Peppas and P.A. Buri, Surface, interfacial and molecular aspects of polymer bioadhesion on soft tissues, J. Control. Release 2 (1985), pp. 257–275.
14. P.J. Flory, Principle of Polymer Chemistry, Cornell University Press, Ithaca, New York (1953), p. 541.
15. C.-M. Lehr, J.A. Bouwstra, E.H. Schacht and H.E. Junginger, In vitro evaluation of mucoadhesive properties of chitosan and some other natural polymers, Int. J. Pharm. 78 (1992), pp. 43–48.
16. D. Solomonidou, K. Cremer, M. Krumme and J. Kreuter, Effect of carbomer concentration and degree of neutralization on the mucoadhesive properties of polymer films, J. Biomater. Sci., Polym. Ed. 12 (2001), pp. 1191–1205.
17. M.J. Rathbone, B.K. Drummond and I.G. Tucker, The oral cavity as a site for systemic drug delivery, Adv. Drug Deliv. Rev. 13 (1994), pp. 1–22.
18. C.-M. Lehr, F.G.J. Poelma, H.E. Junginger and J.J. Tukker, An estimate of turnover time of intestinal mucus gel layer in the rat in situ loop, Int. J. Pharm. 70 (1991), pp. 235–240.
19. J.F. Forstner, Intestinal mucins in health and disease, Digestion 17 (1978), pp. 234–263.
20. N.F.H. Ho, C.L. Barsuhn, P.S. Burton and H.P. Merkle, (D) Routes of delivery: case studies. (3) Mechanistic insights to buccal delivery of proteinaceous substances, Adv. Drug Deliv. Rev. 8 (1992), pp. 197–235.
21. N.A. Peppas and P.A. Buri, "Surface, Interfacial and Molecular Aspects of Polymer Bioadhesion on Soft Tissues," J. Contr. Rel. 2, 257–275(1985).
22. H.S. Ch'ng et al., "Bioadhesive Polymers as Platforms for Oral Controlled Drug Delivery II: Synthesis and Evaluation of Some Swelling, Water-Insoluble Bioadhesive Polymers," J. Pharm. Sci. 74 (4), 399–405 (1985).
23. R.E. Gandhi and J.R. Robinson, "Bioadhesion in Drug Delivery," Indian J. Pharm. Sci. 50 (May/June), 145–152 (1988).
24. S.S. Leung and J.R. Robinson,"Polymer Structure Features Contributing to Mucoadhesion: II," J. Contr. Rel. 12, 187–194 (1990).
25. Y.D. Sanzgiri et al., "Evaluation of Mucoadhesive Properties of Hyaluronic Acid Benzyl Esters," Int. J. Pharm. 107, 91–97 (1994).
26. C.M. Lehr et al., "In Vitro Evaluation of Mucoadhesive Properties of Chitosan and Some Other Natural Polymers," Int. J. Pharm. 78, 43–48 (1992).
27. K. Park and J.R. Robinson, "Bioadhesive Polymers as Platforms for Oral Controlled Drug Delivery: Method to Study Bioadhesion," Int. J. Pharm. 19, 107–127 (1984).
28. T.Nagai and Y.Machida,"Buccal Delivery Systems Using Hydrogels," Adv. Drug Del. Rev. 11, 179–191 (1993).
29. J Control Release. 2006 Aug 10;114(1):15-40. Buccal bioadhesive drug delivery - A promising option for orally less efficient drugs. Sudhakar Y, Kuotsu K, Bandyopadhyay AK
30. J. Van Roey, M. Haxaire, M. Kamya, I. Lwanga and E. Katabira, Comparative efficacy of topical therapy with a slow-release mucoadhesive buccal tablet containing miconazole nitrate versus systemic therapy with ketoconazole in HIV-positive patients with oropharyngeal candidiasis, J. Acquir. Immune Defic. Syndr. 35 (2004), pp. 144–150.
31. M.J. Rathbone, B.K. Drummond and I.G. Tucker, The oral cavity as a site for systemic drug delivery, Adv. Drug Deliv. Rev. 13 (1994), pp. 1–22.
32. S.C. Miller and M.D. Donovan, Effect of poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits, Int. J. Pharm. 12 (1982), pp. 147–152.
33. C.F. Wong, K.H. Yuen and K.K. Peh, Formulation and evaluation of controlled release Eudragit buccal patches, Int. J. Pharm. 178 (1999), pp. 11–22.
Considerable attention has been focused in recent years on the delivery through the oral mucosa of drugs which have a high first pass metabolism (i.e., metabolized to a large extent by the liver during the first pass there through and therefore do not enter the blood stream) or degrade in the gastrointestinal tract. Transmucosal delivery has also been considered for treatment of oral disorders and as a local anesthetic1.
Buccal delivery involves the administration of the desired drug through the buccal mucosal membrane lining of the oral cavity. Unlike oral drug delivery, which presents a hostile environment for drugs, especially proteins and polypeptides, due to acid hydrolysis and the hepatic first-pass effect, the mucosal lining of buccal tissues provides a much milder environment for drug absorption2. Other routes, such as nasal, ocular, pulmonary, rectal, and vaginal drug administration, have provided excellent opportunities for the delivery of a variety of compounds. However, the mucosal lining of the oral cavity offers some distinct advantages.
Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site.3
2. Advantages of Buccal Drug Delivery Systems
Advantages of buccal administration are currently recognized commercially or in the medical literature. The first known advantage is rapidity of action. Medications administered buccally enter the blood stream immediately after passage through the buccal mucosa instead of first having to be swallowed and then having to pass through a portion of the gastrointestinal tract before being absorbed. This rapidity of action is one of the reasons that one commercially available and one experimental product for pain relief have been administered via the buccal route. The first of these products contains nitroglyerin, and is available as a buccal pill that adheres to the mucosa, sold under the trademark Nitrogard. The second product contains the non-steroidal anti-inflammatory analgesic diclofenac which has been used in an experimental buccal pill that adheres to the mucosa. The second known advantage of the buccal route is to allow administration of medications which cannot normally be administered orally. Additional unique advantages of the buccal route and the medications that exploit these advantages are described below, as well as additional medications that could be administered buccally to exploit the two previously mentioned advantages of the buccal route4.
As far as the first advantage, rapidity of action, is concerned several classes of medications would have improved efficacy if administered via the buccal route. One class of medications for which rapidity of action is important and which could be placed in buccal tablets in general and the inventive buccal tablet in particular are analgesics which include aspirin, ibuprofen, fenoprofen, sulindac, salsalate, diflunisal, mecleofenamate, naproxen, nabumetone, tolmetin, diclofenac, oxaprozin, indomethacin ketoprofen, choline salicylate, piroxicam, mefenamic acid, etodolac and ketorolac.
As far as the second advantage of buccal administration, the ability to administer drugs that cannot be ingested because of drug destruction, there are several drugs which are potentially in this category. Testosterone could be placed in a buccal tablet and could then be administered via the oral route to avoid destruction via first pass metabolism. Normally such metabolism necessitates the administration of testosterone via injection or a large skin patch worn on the scrotum. However, the scrotal patch has an important potential disadvantage since scrotal skin generates an increased amount of a testosterone metabolite, 5 alpha-dihydrotestosterone that can potentially stimulate prostate hypertrophy.5
Similarly, many drugs affect liver metabolism of other drugs. This affect would be greatly attenuated by administering such drugs in buccal form. One class of drugs in this category are medications that inhibit metabolizing enzymes in the liver resulting in increased concentrations of other drugs. Another class of drugs increases metabolizing enzymes in the liver resulting in decreased concentrations of other drugs. By administering both classes of these drugs using a buccal tablet there would be less effect on the concentration of other drugs and thus the avoidance of toxic as well as sub-therapeutic drug levels. Drugs in the category of liver enzyme inhibitors which could be administered via a buccal tablet include allopurinol, ketoconazole. Drugs in the category of liver enzyme inducers which could be administered via a buccal tablet include cabamazepine, phenytoin, glutethimide, primidone, rifampin and barbiturates such as phenobarbital, pentobarbital, secobarbital,
The third of these advantages of buccal administration is that it results in much less exposure of the GI tract to a drug as opposed to oral ingestions. One of the side effects of many antibiotics is the destruction of normal GI flora resulting in diarrhea and overgrowth with dangerous organisms such as C. difficile. Antibiotics that could be incorporated in a buccal tablet, which would then have enhanced safety because of reduction in the toxic effect on gut flora, include cephlosporins such as cephalexin, cefadroxil, cefaclor, cefamandone, cefuroxime, cefprozil, cefpodoxime, loracarbef and cefixime; also penicillins including penicillin G, penicillin V, cloxacillin, dicloxacillin
The fourth of these advantages of buccal administration is that it allows drugs to be administered which would otherwise interfere with the absorption of other drugs. In particular iron supplements can be administered via a buccal tablet with the avoidance of many adverse effects on the absorption of other medications such as thyroid hormone.
The fifth of these advantages of buccal administration is that it increases the practicality of administering drugs whose absorption is adversely affected by the presence of food. Tetracyclines, in particular, could be administered buccally thus avoiding the effects of food on tetracycline administration which otherwise complicates the administration of this class of antibiotics via the oral route.
The sixth of these advantages of buccal administration is that it allows blood lipids such as cholesterol to be lowered and modified in ways not possible through the oral ingestion of medications. Lipids can be incorporated into a buccal tablet. Lipids absorbed via the buccal mucosa bypass liver metabolism and can directly interact with endogenous lipoproteins thus influencing blood lipid levels. Recently an acute lowering of cholesterol has been demonstrated by applying lecithin to the skin.6
Compared with the oral, nasal, and rectal routes for drug delivery, the buccal route presents advantages such as an efficient blood supply and relatively low enzymatic activity. Moreover, the buccal mucosa is easily accessible and acceptable to patients; it allows the patient to interrupt drug administration by simply removing the drug delivery system. On the other hand, the buccal route is characterized by some intrinsic limitations (barrier properties of the mucosa, small area available for drug absorption, short residence time of the formulation caused by physiologic-removal mechanisms), which have to be considered in the design of buccal drug delivery systems.7
3.3. Factors affecting mucoadhesion in the oral cavity
Mucoadhesive characteristics are a factor of both the bioadhesive polymer and the medium in which the polymer will reside. A variety of factors affect the mucoadhesive properties of polymers, such as molecular weight, flexibility, hydrogen bonding capacity, cross-linking density, charge, concentration, and hydration (swelling) of a polymer, which are briefly addressed below.
3.3.1. Polymer-related factors
3.3.1.1. Molecular weight
In general, it has been shown that the bioadhesive strength of a polymer increases with molecular weights above 100,000 8. As one example, the direct correlation between the bioadhesive strength of polyoxyethylene polymers and their molecular weights, in the range of 200,000 to 7,000,000, has been shown by Tiwari et al. 9
3.3.1.2. Flexibility
Bioadhesion starts with the diffusion of the polymer chains in the interfacial region. Therefore, it is important that the polymer chains contain a substantial degree of flexibility in order to achieve the desired entanglement with the mucus. A recent publication demonstrated the use of tethered poly(ethylene glycol)–poly(acrylic acid) hydrogels and their copolymers with improved mucoadhesive properties 10. The increased chain interpenetration was attributed to the increased structural flexibility of the polymer upon incorporation of poly(ethylene glycol). In general, mobility and flexibility of polymers can be related to their viscosities and diffusion coefficients, where higher flexibility of a polymer causes greater diffusion into the mucus network 11.
3.3.1.3. Hydrogen bonding capacity
Hydrogen bonding is another important factor in mucoadhesion of a polymer. Park and Robinson found that in order for mucoadhesion to occur, desired polymers must have functional groups that are able to form hydrogen bonds 12. They have also confirmed that flexibility of the polymer is important to improve this hydrogen bonding potential. Polymers such as poly(vinyl alcohol), hydroxylated methacrylate, and poly(methacrylic acid), as well as all their copolymers, are polymers with good hydrogen bonding capacity 13.
3.3.1.4. Cross-linking density
The average pore size, the number average molecular weight of the cross-linked polymers, and the density of cross-linking are three important and interrelated structural parameters of a polymer network 11. Therefore, it seems reasonable that with increasing density of cross-linking, diffusion of water into the polymer network occurs at a lower rate which, in turn, causes an insufficient swelling of the polymer and a decreased rate of interpenetration between polymer and mucin 11. Flory 14 has reported this general property of polymers, in which the degree of swelling at equilibrium has an inverse relationship with the degree of cross-linking of a polymer.
3.3.1.5. Charge
Some generalizations about the charge of bioadhesive polymers have been made previously, where nonionic polymers appear to undergo a smaller degree of adhesion compared to anionic polymers. Peppas and Buri have demonstrated that strong anionic charge on the polymer is one of the required characteristics for mucoadhesion 13. It has been shown that some cationic polymers are likely to demonstrate superior mucoadhesive properties, especially in a neutral or slightly alkaline medium 15. Additionally, some cationic high-molecular-weight polymers, such as chitosan, have shown to possess good adhesive properties.
3.3.1.6. Concentration
The importance of this factor lies in the development of a strong adhesive bond with the mucus, and can be explained by the polymer chain length available for penetration into the mucus layer. When the concentration of the polymer is too low, the number of penetrating polymer chains per unit volume of the mucus is small, and the interaction between polymer and mucus is unstable 13. In general, the more concentrated polymer would result in a longer penetrating chain length and better adhesion. However, for each polymer, there is a critical concentration, above which the polymer produces an "unperturbed" state due to a significantly coiled structure. As a result, the accessibility of the solvent to the polymer decreases, and chain penetration of the polymer is drastically reduced. Therefore, higher concentrations of polymers do not necessarily improve and, in some cases, actually diminish mucoadhesive properties. One of the studies addressing this factor demonstrated that high concentrations of flexible polymeric films based on polyvinylpyrrolidone or poly(vinyl alcohol) as film-forming polymers did not further enhance the mucoadhesive properties of the polymer 16. On the contrary, it decreased the desired strength of mucoadhesion 16.
3.3.1.7. Hydration (swelling)
Hydration is required for a mucoadhesive polymer to expand and create a proper "macromolecular mesh" 11 of sufficient size, and also to induce mobility in the polymer chains in order to enhance the interpenetration process between polymer and mucin. Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network 11. However, a critical degree of hydration of the mucoadhesive polymer exists where optimum swelling and bioadhesion occurs 13.
3.3.2. Environmental factors
The mucoadhesion of a polymer not only depends on its molecular properties, but also on the environmental factors adjacent to the polymer. Saliva, as a dissolution medium, affects the behavior of the polymer. Depending on the saliva flow rate and method of determination, the pH of this medium has been estimated to be between 6.5 and 7.5 17. The residence time of dosage forms is limited by the mucin turnover time, which has been calculated to range between 47 and 270 min in rats 18 and 12–24 h in humans 19.
Movement of the buccal tissues while eating, drinking, and talking, is another concern which should be considered when designing a dosage form for the oral cavity. Movements within the oral cavity continue even during sleep, and can potentially lead to the detachment of the dosage form. Therefore, an optimum time span for the administration of the dosage form is necessary in order to avoid many of these interfering factors 20.
4. Buccal drug delivery systems
Bioadhesive polymers have been used extensively in buccal drug delivery systems to provide dosage form retention. Bioadhesive polymers are defined as polymers that can adhere to a biological substrate. The term mucoadhesion is applied when the substrate is mucosal tissue 21. Diverse classes of polymers have been investigated for their potential use as mucoadhesives. These include synthetic polymers such as monomeric _ cyanoacrylate 22, polyacrylic acid 23, hydroxyl propyl methylcellulose 24, and polymethacrylate derivatives 25as well as naturally occurring polymers such as hyaluronic acid 26and chitosan 27. Other synthetic polymers such as polyurethanes, epoxy resins, polystyrene, and natural-product cement also have been extensively investigated 28. In general, dosage forms designed for buccal administration should not cause irritation and should be small and flexible enough to be accepted by the patient. These requirements can be met by using hydrogels. Hydrogels are hydrophilic matrices that are capable of swelling when placed in aqueous media. Normally, hydrogels are cross-linked so that they will not dissolve in the medium and will absorb only water. When drugs are loaded into these hydrogels, as water is absorbed into the matrix, polymer chain relaxation occurs and drug molecules are released through the spaces or channels within the hydrogel network. In a broader meaning of the term, hydrogels also would include water-soluble matrices that are capable of swelling in aqueous media; these include natural gums and cellulose derivatives.
Over the last few decades' pharmaceutical scientists throughout the world are trying to explore transdermal and transmucosal routes as an alternative to injections. Among the various transmucosal sites available, mucosa of the buccal cavity was found to be the most convenient and easily accessible site for the delivery of therapeutic agents for both local and systemic delivery as retentive dosage forms, because it has expanse of smooth muscle which is relatively immobile, abundant vascularization, rapid recovery time after exposure to stress and the near absence of langerhans cells. Direct access to the systemic circulation through the internal jugular vein bypasses drugs from the hepatic first pass metabolism leading to high bioavailability. Further, these dosage forms are self-administrable, cheap and have superior patient compliance. Developing a dosage form with the optimum pharmacokinetics is a promising area for continued research as it is enormously important and intellectually challenging29.
5. Buccal mucoadhesive dosage forms
Buccal mucoadhesive dosage forms can be categorized into three types based on their geometry. Type I is a single layer device with multidirectional drug release. This type of dosage form suffers from significant drug loss due to swallowing. In type II devices, an impermeable backing layer is superimposed on top of the drug-loaded bioadhesive layer, creating a double-layered device and preventing drug loss from the top surface of the dosage form into the oral cavity. Type III is a unidirectional release device, from which drug loss is minimal, since the drug is released only from the side adjacent to the buccal mucosa. This can be achieved by coating every face of the dosage form, except the one that is in contact with the buccal mucosa.
Buccal dosage forms can also be classified as either a "reservoir" or "matrix" type. In the reservoir type, an excessive amount of the drug is present in the reservoir surrounded by a polymeric membrane, which controls the drug's release rate. In the matrix-type systems, the drug is uniformly dispersed in the polymer matrix, and drug release is controlled by diffusion through the polymer network.
In addition, the mucoadhesive tablet was generally well-tolerated and caused fewer incidences of gastrointestinal disorders and drug-related adverse events than those observed when ketoconazole was administered systemically. The authors suggested that this particular dosage form is the first and only once-daily topical treatment option for this condition 30.
5.1 Buccal tablets
Tablets have been the most commonly investigated dosage form for buccal drug delivery to date. Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm 31. Unlike conventional tablets, buccal mucoadhesive tablets allow for drinking and speaking without major discomfort. They soften, adhere to the mucosa, and are retained in position until dissolution and/or release is complete. These tablets can be applied to different sites in the oral cavity, including the palate, the mucosa lining the cheek, as well as between the lip and the gum. Successive tablets can be applied to alternate sides of the mouth. The major drawback of buccal bioadhesive tablets is their lack of physical flexibility, leading to poor patient compliance for long-term and repeated use.
5.2 Buccal patches
Patches are laminates consisting of an impermeable backing layer, a drug-containing reservoir layer from which the drug is released in a controlled manner, and a bioadhesive surface for mucosal attachment. Buccal patch systems are similar to those used in transdermal drug delivery. Two methods used to prepare adhesive patches include solvent casting and direct milling. In the solvent casting method, the intermediate sheet from which patches are punched is prepared by casting the solution of the drug and polymer(s) onto a backing layer sheet, and subsequently allowing the solvent(s) to evaporate. In the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired thickness, and patches of predetermined size and shape are then cut or punched out. An impermeable backing layer may also be applied to control the direction of drug release, prevent drug loss, and minimize deformation and disintegration of the device during the application period.
5.3 Buccal films
Films are the most recently developed dosage form for buccal administration .Buccal films may be preferred over adhesive tablets in terms of flexibility and comfort. In addition, they can circumvent the relatively short residence time of oral gels on the mucosa, which are easily washed away and removed by saliva. Moreover, in the case of local delivery for oral diseases, the films also help protect the wound surface, thus helping to reduce pain and treat the disease more effectively. An ideal film should be flexible, elastic, and soft, yet adequately strong to withstand breakage due to stress from mouth movements. It must also possess good bioadhesive strength in order to be retained in the mouth for the desired duration of action. Swelling of film, if it occurs, should not be too extensive in order to prevent discomfort.
5.4 Buccal gels and ointments
Semisolid dosage forms, such as gels and ointments, have the advantage of easy dispersion throughout the oral mucosa. However, drug dosing from semisolid dosage forms may not be as accurate as from tablets, patches, or films. Poor retention of the gels at the site of application has been overcome by using bioadhesive formulations .Certain bioadhesive polymers, e.g. poloxamer 407 32, sodium carboxy methylcellulose 33, carbopol, hyaluronic acid, and xanthan gum, undergo a phase change from a liquid to a semisolid. This change enhances the viscosity, which results in sustained and controlled release of drugs. However, these polymers have been investigated for this purpose primarily in ocular drug delivery.
Conclusion
The buccal mucosa offers several advantages for controlled drug delivery. The mucosa is well supplied with both vascular and lymphatic drainage; first-pass metabolism in the liver and presystemic elimination in the GI tract is avoided. The area is well suited for a retentive device and appears to be acceptable to patients. With the proper formulation and dosage form design, the permeability and the local environment of the mucosa can be controlled and manipulated to accommodate drug permeation. Buccal drug delivery is a promising area for systemic delivery of orally inefficient drugs as well as an attractive alternative for noninvasive delivery of potent peptide and perhaps protein drug molecules. However, the need for safe and effective buccal permeation and absorption enhancers is a crucial component for a promising future in the area of buccal drug delivery. A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug and excipients. Advances in experimental and computational methodologies will be helpful in shortening the processing time from formulation design to clinical use.
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