http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, 2014; 40(5): 591–598 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.892959
REVIEW ARTICLE
Mucoadhesive polymers for buccal drug delivery Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria Abstract
Keywords
Raising the concept of mucoadhesion in the 1980s, the use of mucoadhesive polymers for buccal drug delivery has been the subject of interest. Buccal route is one of the non-invasive routes comprising several advantages such as targeting the specific tissue (I), bypassing the first-pass effect (II) as well as higher patient compliance (III) and higher bioavailability (IV) have rendered administration route feasible for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. An overview of the oral mucosa’s anatomy, theories of mucoadhesion as well as mucoadhesive polymers is given within this review. Furthermore, recent advantages in mucoadhesive polymers according to the variety of drug delivery forms are presented.
Buccal drug delivery, buccal mucosa, mucoadhesion, mucoadhesive polymers, PAT generation
Introduction Pharmaceutical scientists face challenges of a suitable delivery route. Although invasive administration has been the common route for peptide and protein drug delivery, it is associated with infections and pain on repeated administration leading to poor patient compliance. Being administered by the gastrointestinal route, protein and peptide exhibit poor oral bioavailability owing to gastric acid hydrolysis and first-pass metabolism. Furthermore, non-invasive routes have been investigated for systemic delivery. The mucosal delivery bears many advantages such as targeting a specific tissue (I), avoiding the first-pass metabolism (II) and protection toward enzymatic degradation (III)1. The buccal administration is convenient and easy to access. This route appears to be an alternative for both systemic and local drug delivery2. Since the concept of mucoadhesion raised in the early 1980s, various attempts have been made to improve adhesive properties of polymers for drug delivery3,4. In the late 1990s, a new generation of mucoadhesive polymers was introduced to the pharmaceutical segment5. Thiolated polymers – designated thiomers – were able to form covalent mucus bridging leading to improved mucoadhesion6. Nowadays, the second generation of thiomers, namely preactivated thiomers, have been established in buccal delivery with enhanced mucoadhesion as well as permeation properties where prolonged drug retention time is desired7. In this review, an overview of buccal mucosa, mucoadhesion as well as mucoadhesive theories and recent advantages in
Address for correspondence: Flavia Laffleur, Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/ 82, 6020 Innsbruck, Austria. Tel: +43-512-507-58608. Fax: +43-512507-58699. E-mail: [email protected]
History Received 2 December 2013 Accepted 5 February 2014 Published online 27 February 2014
mucoadhesive polymers for protein and peptide delivery to buccal mucosa will be provided.
Buccal mucosa In several publications, the anatomy and physiology of the oral mucosa have been extensively reviewed8–11. The oral mucosa exhibits the epithelium, basement membrane and connective tissues building up the three distinctive layers of the buccal mucosa. The oral cavity is lined with the epithelium. The basement membrane is supported by connective tissues as depicted in Figure 1. The epithelium being a protective layer for the tissues beneath is divided into (I) non-keratinized surface in the mucosal lining of the soft palate, the ventral surface of the tongue, the floor of the mouth, alveolar mucosa, vestibule, lips and cheeks and (II) keratinized epithelium being found in the hard palate and non-flexible regions of the oral cavity12. The epithelial cells, originating from the basal cells, mature and change their shape as well as increase in size during their movement toward the surface. In the literature, thickness of buccal epithelium in humans, dogs and rabbits has been determined to be approximately 500–800 mm9. The basement membrane shows a distinctive layer between the connective tissues and the epithelium providing the required adherence between the epithelium and the underlying connective tissues and functions as a mechanical support for the epithelium. The connective tissues, which are also stated to as the lamina propria, consist of collagen fibers, a supporting layer of connective tissues, blood vessels and smooth muscles8. The rich arterial blood supply to the oral mucosa is resulting from the external carotid artery. The buccal artery, some terminal branches of the facial artery, the posterior alveolar artery and the infraorbital artery are the main sources of blood supply to the lining of the cheek in the buccal cavity12,13. A gel-like secretion identified as mucus encompassing mostly water-insoluble glycoproteins shelters the entire oral cavity. Acting as protecting layer to the cells below mucus is bound to
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Flavia Laffleur
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Drug Dev Ind Pharm, 2014; 40(5): 591–598
Figure 1. Overview of the buccal mucosa anatomy.
Figure 2. Synopsis of the passive diffusion via paracellular and transcellular route. Figure 3. Mucoadhesion concept.
the apical cell surface14 being a viscoelastic hydrogel and primarily consisting of 1–5% of the above-mentioned water insoluble glycoproteins, 95–99% water and several other components in small quantities, such as proteins, enzymes, electrolytes and nucleic acids15.
Absorption routes through the buccal mucosa Passive diffusion, carrier-mediated transport or endocytosis can be reasons for the absorption through the buccal mucosa. The physicochemical properties of the permeating compound predominates these routes16. Passive diffusion can take place on the one hand via intracellular gaps (paracellular)17 and on the other hand via cell membrane (transcellular)18. In Figure 2, the two routes of drug permeation, i.e. paracellular and transcellular, are depicted. Carrier-mediated transport in the buccal mucosa has been reported19. The translocation from oral mucosa into systemic circulation is related to monocarboxylate residues of benzoic and lactic acids20. The last route, namely endocytosis, takes place rarely. Within endocytosis, the molecules are surrounded by cells. Fluorescent dyes8, confocal laser microscopy21 or autoradiography9 give information about absorption behavior.
Principle of mucoadhesion Theories of mucoadhesion A variety of theories subsists to explain the bioadhesion process as depicted in Figure 3. However, each theoretical model can only elucidate a restricted number of the diversity of interactions constituting bioadhesive bonds22. Wetting theory of mucoadhesion One of the oldest theories related to adhesion is the wetting theory22. Herein, adhesion is expounded as an embedding process.
During this embedding mechanism, adhesives penetrate into surface irregularities of substrates and locate by producing several adhesive anchors. Calculations of the contact angle and the thermodynamic work of adhesion are tools of the wetting theory. The work is related to the surface tension of both the adhesive and the substrate calculating by Dupre’s equation: wA ¼ yb þ yt ybt where wA is the specific thermodynamic work of adhesion and yb, yt and ybt represent the surface tensions of the bioadhesive polymer, the substrate and the interfacial tension, respectively. The adhesive work is described as sum of the surface tensions of the two adherent phases, less the interfacial tensions apparent between both phases. Diffusion theory of mucoadhesion The key element of the diffusion theory is the interpenetration of polymeric chains from the bioadhesive into glycoprotein mucin chains. Reaching sufficient depth within the opposite matrix, formation of a semi-permanent bond occurs. Visualization of the process starts from the point of initial contact. Concentration gradient is the driving force for equilibrium of penetration depth of polymer chains into the mucus network, and the glycoprotein mucin chains into the bioadhesive matrix as shown in Figure 4. Once having established an intimate contact, the substrate and adhesive chains move along their respective concentration gradients into the opposite phases. For effective bioadhesive bonds, an estimated depth of 0.2–0.5 mm is necessary. Depth of diffusion is dependent on the diffusion coefficient of both phases. Shaikh et al. reported diffusion coefficient to be depended on the molecular weight of the polymer as well as decrease with increasing cross-linking density23.
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Figure 4. Diffusion theory.
Electrostatic theory of mucoadhesion Within the electrostatic theory, transfer of electrons are explained along the adhesive interface and adhering surface. By these electrons, an electrical double layer is established at the interface. In addition, a series of attractive forces maintain the contact between the two layers23. Adsorption theory of mucoadhesion Following the adsorption theory, the adhesion between two surfaces is incurred because of surface forces acting between the chemical structures at the two surfaces after an initial contact. Chemisorption can result when adhesion is particularly strong. The theory postulates adherence to tissue emerges due to one or more secondary forces such as van der Waal’s forces, hydrogen bonding and hydrophobic bonding24. Fracture theory of adhesion By this theory, a description of the force required for the separation of two surfaces after adhesion is given23. With this theory, investigations by tensile apparatus can be conducted in order to study bioadhesion. The following equation is necessary; fracture strength is equivalent adhesive strength. ¼ ðE "=LÞ1=2 where describes the fracture strength, " fracture energy, E young modulus of elasticity and L the critical crack length.
Mucoadhesive polymers A system for mucoadhesive polymers can be classified due to their origin (e.g. natural/synthetic), the kind of mucosa being applied to (e.g. buccal/ocular) or depending their chemical structure (e.g. cellulose/polyacrylates). Nevertheless, mucoadhesive polymers can be categorized based on their binding mechanism to the mucosa14. Non-covalent binding polymers The surface charge of polymers plays an important key role in the mechanism of adhesion. In case of the anionic polymers, their carboxylic moiety (–COOH) is mainly responsible for mucoadhesion25. Due to the –COOH groups, a formation of hydrogen bonds
Figure 5. Overview of anionic mucoadhesive polymers.
arise with the hydroxyl groups of the oligosaccharide side chains on mucus proteins. Figure 5 represents the important anionic polymers. The most effective anionic polymers seem to be polyacrylates and carboxymethlcellulose (NaCMC)26. Both display a high buffer capacity and a high charge density. Anionic polymers exhibit the drawback of being incompatible with multivalent cations like Mg2+ and Ca2+. Once in contact with these cations, anionic polymers turn to precipitate and express reduced adhesive properties. In the case of cationic polymers, mucoadhesion results due to ionic interactions between the polymers and anionic substructures such as sialic acid groups of the mucus gel layer27. Among all cationic polymers, chitosan seems to be a potential representative with high mucoadhesive properties7. In Figure 6, the most important cationic polymers are listed. The non-ionic polymers are independent from pH value of surrounding fluids. Poly(ethylene oxides) are able to build up hydrogen bonds28. In their case, mucoadhesion can be explained by an entanglement of polymer chains. This group of polymers is less adhesive than anionic or cationic ones. The last group of non-covalent binding polymers are ambiphilic polymers. This kind of polymers reveals both anionic and cationic substructures. The mucoadhesion of cationic ones is told to occur due to interaction with negatively charged substructures of mucus7. The mechanism of anionic ones is reported to take place due to hydrogen bond forming. However, both groups simultaneously show a reduced effect on the mucoadhesive properties.
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Covalent binding polymers
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A new generation of polymer is described in the literature being able to form covalent bonds with the mucus gel layer29. Thiolated
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polymers, so-called thiomers, show thiol-bearing groups on their polymeric backbones30. Based on thiol/disulfide exchange reactions, and/or simple oxidation process, disulfides are built up between polymeric excipients and cysteine-rich substructures of mucus gel layer31. Various anionic and cationic thiolated polymers have been synthesized as listed in Figure 7. Mucoadhesive test according to the rotating cylinder revealed improved mucoadhesion of thiomers showing a more pronounced mucoadhesive effect in comparison with unmodified polymers32. Recently, a completely novel class of polymers, the preactivated thiomers namely the PAT generation exhibiting more pronounced mucoadhesive properties as well as higher stability toward oxidation compared to corresponding polymers, were synthesized1. In Figure 8, all so far synthesized preactivated thiomers for buccal delivery are mentioned.
Proteins and peptides
Figure 6. Overview of cationic mucoadhesive polymers. Figure 7. Overview of anionic and cationic thiolated mucoadhesive polymers.
Biomacromolecules, i.e. proteins and peptides, exhibit less than 5% bioavailability when delivered to the buccal mucosa. Controlled and sustained delivery of large peptides and proteins are challenging through buccal mucosa. Nevertheless, advantages associated with buccal mucosa are avoidance of acid- and enzyme-directed degradation33 as well as bypassing the firstpass metabolism34. Biomacromolecules are low lipid soluble and exhibit large molecular weight in comparison with conventional small molecules. Furthermore, most peptides and proteins are susceptible toward enzymatic degradation such as esterases, aminopeptidases, carboxypeptidases and several endopeptidases. Transcellular permeation through the buccal epithelium by passive diffusion is affected by the molecular weight and size
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Table 1. Overview of buccal-adhesive dosage forms for peptide/protein delivery.
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Protein/peptide drug Buserelin Calcitonin Captopril LH releasing hormone Octreotide acetate Oxytocin Oxytocin Pituitary adenylate cyclase-activating polypeptide Pitocin Protirelin Thyrotropin releasing hormone
Figure 8. Overview of preactivated mucoadhesive thiomers.
of the peptide drug itself35. Generally, the higher the molecular weight of a biomacromolecule, the lesser the bioavailability. Peptides and proteins being hydrophilic and globular in nature show transport via paracellular route. Besides passive diffusion as the key absorption pathway for peptides and proteins, carriermediated processes affect the transport of certain drugs through the buccal mucosa36,37. Table 1 gives an overview about proteins and peptides being investigated for buccal delivery. Furthermore, amino acids such as glutamic acid and lysine were reported to be transported via carrier-mediated processes. However, endocytotic processes are not apparent in buccal epithelium.
Buccal drug delivery systems Buccal tablets The most commonly investigated dosage forms for buccal drug delivery to date are buccal tablets. Buccal tablets are
Dosage form
References
Patch Tablet Tablet Tablet Patch Tablet Patch Patch
62
Tablet Patch Patch
69
63 64 65 66 67 68 41
70 71
small, flat and oval with a diameter of approximately 5–8 mm38. Buccal mucoadhesive tablets permit drinking and speaking without major discomfort unlike conventional tablets. Adhesion to the mucosa is given until dissolution and/or release is completed. Different areas of the oral cavity can be chosen for application such as palate, mucosa lining the cheek, also between the gum and the lip. Application to alternate sides of the oral cavity can be conducted for successive tablets. Buccal bioadhesive tablets exhibit as major drawback the lack of physical flexibility. Bioadhesive tablets are usually directly compressed; other techniques as wet granulation can also be used. Tablets designed for buccal administration in order to be inserted into the buccal pouch should dissolve or erode slowly. Therefore, sufficient pressure is required to keep the hardness of the tablets. Furthermore, each site of the tablet, except the one in contact with the mucosa, can exhibit a coating with water impermeable materials, such as ethylcellulose, hydrogenated castor oil, etc., using either compression or spray coating. Drugs may be formulated in certain physical states, such as microspheres, prior to direct compression achieving desirable features, e.g. enhanced activity and prolonged drug release39. Some recent approaches use tablets melting at body temperatures40. Furthermore Langoth et al. performed bioavailability studies in pigs by buccal administration pituitary adenylate cyclaseactivating polypeptide (PACAP). The resulting mucoadhesive chitosan-4-thiobutylamidine conjugate was homogenized with the enzyme inhibitor and permeation mediator glutathione (gamma-Glu-Cys-Gly), Brij 35 and PACAP (formulation A) and compressed into flat-faced discs. One formulation was additionally coated on one side with palm wax (formulation B). Moreover, in the case of formulations A and B, a continuously raised plasma level of the peptide drug being in the therapeutic range could be maintained over the whole period of application (6 h)41. Buccal patches Patches are laminates, which consist of three compartments: first, an impermeable backing layer; second, a drug-containing reservoir layer where the drug is released from in a controlled manner and third, a bioadhesive surface for mucosal attachment42,43. Two methods are decisive for the preparations of adhesive patches comprising solvent casting and direct milling. For the first method, 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 evaporate44. For the second method, the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired
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thickness. Thereafter, patches of predetermined size and shape are cut or punched out45. The application of an impermeable backing layer leads to control the direction of drug release, prevent drug loss and minimize deformation and disintegration of the device during the application period.
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Buccal films The most recently developed dosage forms for buccal administration are films. In terms of flexibility and comfort, buccal films are preferred over adhesive tablets46. In addition, they can overwhelm the relatively short residence time of oral gels on the mucosa, being easily washed away and removed by saliva. Furthermore, concerning local delivery for oral diseases, the films holds the advantage to protect the wound surface, thus leading to reduce pain and treat the disease more effectively47. Flexibility, elasticity, softness as well as strength to withstand breakage due to oral movements should be features of an ideal film. Key factor as possessing good bioadhesive strength in order to be retained in the mouth for the desired duration of action are indispensable48. In order to prevent discomfort, swelling should not be too extensive. Bioadhesive films being usually manufactured by a solvent-casting method are similar to laminated patches in terms of their flexibility and manufacturing process49. First of all, drug and polymer(s) are dissolved in a casting solvent or solvent mixture. Then, the solution is cast into films, dried and finally laminated with a backing layer or a release liner. The backing layer helps retard the diffusion of saliva into the drug layer by improving the adhesion time and reducing drug loss into the oral cavity. The solvent-casting method is a simple method suffering from some disadvantages, including long processing time, high cost and environmental concerns due to the solvents used50. These hindrances can be overwhelmed by the hot-melt extrusion method recently reported by Repka and McGinity51. Buccal gels and ointments Bioadhesive ointments have not been described in the literature as extensively as other dosage forms, especially when compared to tablets and patches52. Advantages associated with semisolid dosage forms, such as gels and ointments, are the easy dispersion throughout the oral mucosa. Disadvantages related on semisolid dosage forms are the not accurate drug dosing from these dosage form in comparison with drug dosing from tablets, patches or films. In order to overwhelm the poor retention of the gels at the site of application bioadhesive formulations are used. Certain bioadhesive polymers, e.g. poloxamer 40753, sodium carboxymethylcellulose54, Carbopol55, hyaluronic acid56 and xanthan gum57, undergo a phase change from a liquid to a semisolid. This change improves the viscosity resulting in sustained and controlled release of drugs. Hydrogels are also a promising dosage form for buccal drug delivery. They are formed from polymers being hydrated in an aqueous environment and physically entrap drug molecules for subsequent slow release by diffusion or erosion58. The application of bioadhesive gels provides an extended retention time in the oral cavity, adequate drug penetration, as well as high efficacy and patient acceptability. The treatment of periodontitis, being an inflammatory and infectious disease causing formation of pockets between the gum and the tooth, leads eventually to loss of teeth. The major application of adhesive gels could be the local delivery of medicinal agents. Mucoadhesive polymers are reported to be useful for periodontitis therapy when incorporated in antimicrobial-containing formulations being easily introduced into the periodontal pocket with a syringe59–61. Mucoadhesion provides retention of the formulation within the pocket.
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Conclusion Buccal drug delivery is a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. The buccal mucosa offers a variety of advantages such as avoiding first-pass metabolism for drug delivery for extended periods of time. The area is well suited for retentive device and show high acceptance of the patients. Developing the distinctive formulation and dosage form, the permeability and bioavailability of biomacromolecules will be tremendously improved. A promising approach to overcome the challenges of contemporary macromolecular drug delivery might be the use of multifunctional auxiliary agents. By introducing the PAT generation, the susceptibility of first-generation mucoadhesive thiomers in semisolid formulations toward oxidation could be suppressed as well as a more pronounced mucoadhesiveness could be reported. These features approve preactivated thiomers promising for delivery where prolonged residence time is in need. Buccal drug delivery is an auspicious area for further research aiming systemic delivery of orally inefficient drugs in the not-too far future. Once available, macromolecular drugs will revolutionize the treatment of various diseases as well as provide novel diagnostic tools to the benefit for the patient.
Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. The author reports no declaration of interest.
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43. Palem CR, Gannu R, Doodipala N, et al. Transmucosal delivery of domperidone from bilayered buccal patches: in vitro, ex vivo and in vivo characterization. Arch Pharm Res 2011;34: 1701–10. 44. Semalty M, Semalty A, Kumar G. Formulation and characterization of mucoadhesive buccal films of glipizide. Indian J Pharm Sci 2008; 70:43–8. 45. Boddupalli BM, Mohammed ZN, Nath RA, Banji D. Mucoadhesive drug delivery system: an overview. J Adv Pharm Technol Res 2010; 1:381–7. 46. Semalty A, Semalty M, Nautiyal U. Formulation and evaluation of mucoadhesive buccal films of enalapril maleate. Indian J Pharm Sci 2010;72:571–5. 47. Nappinnai M, Chandanbala R, Balaijirajan R. Formulation and evaluation of nitrendipine buccal films. Indian J Pharm Sci 2008;70: 631–5. 48. Padula C, Pozzetti L, Traversone V, et al. In vitro evaluation of mucoadhesive films for gingival administration of lidocaine. AAPS PharmSciTech 2013;14:1279–83. 49. Kumria R, Gupta V, Bansal S, et al. Oral buccoadhesive films of ondansetron: development and evaluation. Int J Pharm Investig 2013;3:112–18. 50. Muzib YI, Kumari KS. Mucoadhesive buccal films of glibenclamide: development and evaluation. Int J Pharm Investig 2011;1: 42–7. 51. Repka MA, McGinity JW. Bioadhesive properties of hydroxypropylcellulose topical films produced by hot-melt extrusion. J Control Release 2001;70:341–51. 52. Ishida M, Nambu N, Nagai T. Ointment-type oral mucosal dosage form of Carbopol containing prednisolone for treatment of aphtha. Chem Pharm Bull (Tokyo) 1983;31:1010–14. 53. Miller SC, Donovan MD. Effect of poloxamer 407 gel on the miotic activity of pilocarpine nitrate in rabbits. Int J Pharm 1982;12: 147–52. 54. Wong CF, Yuen KH, Peh KK. Formulation and evaluation of controlled release Eudragit buccal patches. Int J Pharm 1999;178: 11–22. 55. Kumar S, Haglund BO, Himmelstein KJ. In situ-forming gels for ophthalmic drug-delivery. J Ocul Pharmacol 1994;10:47–56. 56. Gurny R, Ryser JE, Tabatabay C, et al. Precorneal residence time in humans of sodium hyaluronate as measured by gamma-scintigraphy. Graef Arch Clin Exp 1990;228:510–12. 57. Meseguer G, Gurny R, Buri P, et al. Gamma-scintigraphic study of precorneal drainage and assessment of miotic response in rabbits of various ophthalmic formulations containing pilocarpine. Int J Pharm 1993;95:229–34. 58. Martin L, Wilson CG, Koosha F, Uchegbu IF. Sustained buccal delivery of the hydrophobic drug denbufylline using physically cross-linked palmitoyl glycol chitosan hydrogels. Eur J Pharm Biopharm 2003;55:35–45. 59. Jones DS, Woolfson AD, Brown AF, et al. Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J Control Release 2000;67:357–68. 60. Vinholis AH, Figueiredo LC, Marcantonio Junior E, et al. Subgingival utilization of a 1% chlorhexidine collagen gel for the treatment of periodontal pockets. A clinical and microbiological study. Braz Dent J 2001;12:209–13. 61. Ikinci G, Senel S, Akincibay H, et al. Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis. Int J Pharm 2002; 235:121–7. 62. Hoogstraate AJ, Verhoef JC, Tuk B, et al. In-vivo buccal delivery of fluorescein isothiocyanate-dextran 4400 with glycodeoxycholate as an absorption enhancer in pigs. J Pharm Sci-Us 1996; 85:457–60. 63. Alur HH, Beal JD, Pather SI, et al. Evaluation of a novel, natural oligosaccharide gum as a sustained-release and mucoadhesive component of calcitonin buccal tablets. J Pharm Sci-Us 1999;88: 1313–19. 64. Iscan YY, Capan Y, Senel S, et al. Formulation and in vitro in vivo evaluation of buccal bioadhesive captopril tablets. Stp Pharma Sci 1998;8:357–63. 65. Nakane S, Kakumoto M, Yukimatsu K, Chien YW. Oramucosal delivery of LHRH: pharmacokinetic studies of controlled and enhanced transmucosal permeation. Pharm Dev Technol 1996;1: 251–9.
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66. Merkle HP, Wolany G. Buccal delivery for peptide drugs. J Control Release 1992;21:155–64. 67. Metia PK, Bandyopadhyay AK. In vitro and in vivo evaluation of a novel mucoadhesive buccal oxytocin tablet prepared with Dillenia indica fruit mucilage. Pharmazie 2008; 63:270–4. 68. Li C, Bhatt PP, Johnston TP. Transmucosal delivery of oxytocin to rabbits using a mucoadhesive buccal patch. Pharm Dev Technol 1997;2:265–74.
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69. Dillon TF, Douglas RG, Duvigneaud V, Barber ML. Transbuccal administration of pitocin for induction and stimulation of labor. Obstet Gynecol 1960;15:587–92. 70. Anders R, Merkle HP, Schurr W, Ziegler R. Buccal absorption of protirelin – an effective way to stimulate thyrotropin and prolactin. J Pharm Sci-Us 1983;72:1481–3. 71. Li C, Koch RL, Raul VA, et al. Absorption of thyrotropin-releasing hormone in rats using a mucoadhesive buccal patch. Drug Dev Ind Pharm 1997;23:239–46.
REVIEW ARTICLE
Mucoadhesive polymers for buccal drug delivery Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria Abstract
Keywords
Raising the concept of mucoadhesion in the 1980s, the use of mucoadhesive polymers for buccal drug delivery has been the subject of interest. Buccal route is one of the non-invasive routes comprising several advantages such as targeting the specific tissue (I), bypassing the first-pass effect (II) as well as higher patient compliance (III) and higher bioavailability (IV) have rendered administration route feasible for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. An overview of the oral mucosa’s anatomy, theories of mucoadhesion as well as mucoadhesive polymers is given within this review. Furthermore, recent advantages in mucoadhesive polymers according to the variety of drug delivery forms are presented.
Buccal drug delivery, buccal mucosa, mucoadhesion, mucoadhesive polymers, PAT generation
Introduction Pharmaceutical scientists face challenges of a suitable delivery route. Although invasive administration has been the common route for peptide and protein drug delivery, it is associated with infections and pain on repeated administration leading to poor patient compliance. Being administered by the gastrointestinal route, protein and peptide exhibit poor oral bioavailability owing to gastric acid hydrolysis and first-pass metabolism. Furthermore, non-invasive routes have been investigated for systemic delivery. The mucosal delivery bears many advantages such as targeting a specific tissue (I), avoiding the first-pass metabolism (II) and protection toward enzymatic degradation (III)1. The buccal administration is convenient and easy to access. This route appears to be an alternative for both systemic and local drug delivery2. Since the concept of mucoadhesion raised in the early 1980s, various attempts have been made to improve adhesive properties of polymers for drug delivery3,4. In the late 1990s, a new generation of mucoadhesive polymers was introduced to the pharmaceutical segment5. Thiolated polymers – designated thiomers – were able to form covalent mucus bridging leading to improved mucoadhesion6. Nowadays, the second generation of thiomers, namely preactivated thiomers, have been established in buccal delivery with enhanced mucoadhesion as well as permeation properties where prolonged drug retention time is desired7. In this review, an overview of buccal mucosa, mucoadhesion as well as mucoadhesive theories and recent advantages in
Address for correspondence: Flavia Laffleur, Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innrain 80/ 82, 6020 Innsbruck, Austria. Tel: +43-512-507-58608. Fax: +43-512507-58699. E-mail: [email protected]
History Received 2 December 2013 Accepted 5 February 2014 Published online 27 February 2014
mucoadhesive polymers for protein and peptide delivery to buccal mucosa will be provided.
Buccal mucosa In several publications, the anatomy and physiology of the oral mucosa have been extensively reviewed8–11. The oral mucosa exhibits the epithelium, basement membrane and connective tissues building up the three distinctive layers of the buccal mucosa. The oral cavity is lined with the epithelium. The basement membrane is supported by connective tissues as depicted in Figure 1. The epithelium being a protective layer for the tissues beneath is divided into (I) non-keratinized surface in the mucosal lining of the soft palate, the ventral surface of the tongue, the floor of the mouth, alveolar mucosa, vestibule, lips and cheeks and (II) keratinized epithelium being found in the hard palate and non-flexible regions of the oral cavity12. The epithelial cells, originating from the basal cells, mature and change their shape as well as increase in size during their movement toward the surface. In the literature, thickness of buccal epithelium in humans, dogs and rabbits has been determined to be approximately 500–800 mm9. The basement membrane shows a distinctive layer between the connective tissues and the epithelium providing the required adherence between the epithelium and the underlying connective tissues and functions as a mechanical support for the epithelium. The connective tissues, which are also stated to as the lamina propria, consist of collagen fibers, a supporting layer of connective tissues, blood vessels and smooth muscles8. The rich arterial blood supply to the oral mucosa is resulting from the external carotid artery. The buccal artery, some terminal branches of the facial artery, the posterior alveolar artery and the infraorbital artery are the main sources of blood supply to the lining of the cheek in the buccal cavity12,13. A gel-like secretion identified as mucus encompassing mostly water-insoluble glycoproteins shelters the entire oral cavity. Acting as protecting layer to the cells below mucus is bound to
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Figure 1. Overview of the buccal mucosa anatomy.
Figure 2. Synopsis of the passive diffusion via paracellular and transcellular route. Figure 3. Mucoadhesion concept.
the apical cell surface14 being a viscoelastic hydrogel and primarily consisting of 1–5% of the above-mentioned water insoluble glycoproteins, 95–99% water and several other components in small quantities, such as proteins, enzymes, electrolytes and nucleic acids15.
Absorption routes through the buccal mucosa Passive diffusion, carrier-mediated transport or endocytosis can be reasons for the absorption through the buccal mucosa. The physicochemical properties of the permeating compound predominates these routes16. Passive diffusion can take place on the one hand via intracellular gaps (paracellular)17 and on the other hand via cell membrane (transcellular)18. In Figure 2, the two routes of drug permeation, i.e. paracellular and transcellular, are depicted. Carrier-mediated transport in the buccal mucosa has been reported19. The translocation from oral mucosa into systemic circulation is related to monocarboxylate residues of benzoic and lactic acids20. The last route, namely endocytosis, takes place rarely. Within endocytosis, the molecules are surrounded by cells. Fluorescent dyes8, confocal laser microscopy21 or autoradiography9 give information about absorption behavior.
Principle of mucoadhesion Theories of mucoadhesion A variety of theories subsists to explain the bioadhesion process as depicted in Figure 3. However, each theoretical model can only elucidate a restricted number of the diversity of interactions constituting bioadhesive bonds22. Wetting theory of mucoadhesion One of the oldest theories related to adhesion is the wetting theory22. Herein, adhesion is expounded as an embedding process.
During this embedding mechanism, adhesives penetrate into surface irregularities of substrates and locate by producing several adhesive anchors. Calculations of the contact angle and the thermodynamic work of adhesion are tools of the wetting theory. The work is related to the surface tension of both the adhesive and the substrate calculating by Dupre’s equation: wA ¼ yb þ yt ybt where wA is the specific thermodynamic work of adhesion and yb, yt and ybt represent the surface tensions of the bioadhesive polymer, the substrate and the interfacial tension, respectively. The adhesive work is described as sum of the surface tensions of the two adherent phases, less the interfacial tensions apparent between both phases. Diffusion theory of mucoadhesion The key element of the diffusion theory is the interpenetration of polymeric chains from the bioadhesive into glycoprotein mucin chains. Reaching sufficient depth within the opposite matrix, formation of a semi-permanent bond occurs. Visualization of the process starts from the point of initial contact. Concentration gradient is the driving force for equilibrium of penetration depth of polymer chains into the mucus network, and the glycoprotein mucin chains into the bioadhesive matrix as shown in Figure 4. Once having established an intimate contact, the substrate and adhesive chains move along their respective concentration gradients into the opposite phases. For effective bioadhesive bonds, an estimated depth of 0.2–0.5 mm is necessary. Depth of diffusion is dependent on the diffusion coefficient of both phases. Shaikh et al. reported diffusion coefficient to be depended on the molecular weight of the polymer as well as decrease with increasing cross-linking density23.
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Figure 4. Diffusion theory.
Electrostatic theory of mucoadhesion Within the electrostatic theory, transfer of electrons are explained along the adhesive interface and adhering surface. By these electrons, an electrical double layer is established at the interface. In addition, a series of attractive forces maintain the contact between the two layers23. Adsorption theory of mucoadhesion Following the adsorption theory, the adhesion between two surfaces is incurred because of surface forces acting between the chemical structures at the two surfaces after an initial contact. Chemisorption can result when adhesion is particularly strong. The theory postulates adherence to tissue emerges due to one or more secondary forces such as van der Waal’s forces, hydrogen bonding and hydrophobic bonding24. Fracture theory of adhesion By this theory, a description of the force required for the separation of two surfaces after adhesion is given23. With this theory, investigations by tensile apparatus can be conducted in order to study bioadhesion. The following equation is necessary; fracture strength is equivalent adhesive strength. ¼ ðE "=LÞ1=2 where describes the fracture strength, " fracture energy, E young modulus of elasticity and L the critical crack length.
Mucoadhesive polymers A system for mucoadhesive polymers can be classified due to their origin (e.g. natural/synthetic), the kind of mucosa being applied to (e.g. buccal/ocular) or depending their chemical structure (e.g. cellulose/polyacrylates). Nevertheless, mucoadhesive polymers can be categorized based on their binding mechanism to the mucosa14. Non-covalent binding polymers The surface charge of polymers plays an important key role in the mechanism of adhesion. In case of the anionic polymers, their carboxylic moiety (–COOH) is mainly responsible for mucoadhesion25. Due to the –COOH groups, a formation of hydrogen bonds
Figure 5. Overview of anionic mucoadhesive polymers.
arise with the hydroxyl groups of the oligosaccharide side chains on mucus proteins. Figure 5 represents the important anionic polymers. The most effective anionic polymers seem to be polyacrylates and carboxymethlcellulose (NaCMC)26. Both display a high buffer capacity and a high charge density. Anionic polymers exhibit the drawback of being incompatible with multivalent cations like Mg2+ and Ca2+. Once in contact with these cations, anionic polymers turn to precipitate and express reduced adhesive properties. In the case of cationic polymers, mucoadhesion results due to ionic interactions between the polymers and anionic substructures such as sialic acid groups of the mucus gel layer27. Among all cationic polymers, chitosan seems to be a potential representative with high mucoadhesive properties7. In Figure 6, the most important cationic polymers are listed. The non-ionic polymers are independent from pH value of surrounding fluids. Poly(ethylene oxides) are able to build up hydrogen bonds28. In their case, mucoadhesion can be explained by an entanglement of polymer chains. This group of polymers is less adhesive than anionic or cationic ones. The last group of non-covalent binding polymers are ambiphilic polymers. This kind of polymers reveals both anionic and cationic substructures. The mucoadhesion of cationic ones is told to occur due to interaction with negatively charged substructures of mucus7. The mechanism of anionic ones is reported to take place due to hydrogen bond forming. However, both groups simultaneously show a reduced effect on the mucoadhesive properties.
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Covalent binding polymers
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A new generation of polymer is described in the literature being able to form covalent bonds with the mucus gel layer29. Thiolated
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polymers, so-called thiomers, show thiol-bearing groups on their polymeric backbones30. Based on thiol/disulfide exchange reactions, and/or simple oxidation process, disulfides are built up between polymeric excipients and cysteine-rich substructures of mucus gel layer31. Various anionic and cationic thiolated polymers have been synthesized as listed in Figure 7. Mucoadhesive test according to the rotating cylinder revealed improved mucoadhesion of thiomers showing a more pronounced mucoadhesive effect in comparison with unmodified polymers32. Recently, a completely novel class of polymers, the preactivated thiomers namely the PAT generation exhibiting more pronounced mucoadhesive properties as well as higher stability toward oxidation compared to corresponding polymers, were synthesized1. In Figure 8, all so far synthesized preactivated thiomers for buccal delivery are mentioned.
Proteins and peptides
Figure 6. Overview of cationic mucoadhesive polymers. Figure 7. Overview of anionic and cationic thiolated mucoadhesive polymers.
Biomacromolecules, i.e. proteins and peptides, exhibit less than 5% bioavailability when delivered to the buccal mucosa. Controlled and sustained delivery of large peptides and proteins are challenging through buccal mucosa. Nevertheless, advantages associated with buccal mucosa are avoidance of acid- and enzyme-directed degradation33 as well as bypassing the firstpass metabolism34. Biomacromolecules are low lipid soluble and exhibit large molecular weight in comparison with conventional small molecules. Furthermore, most peptides and proteins are susceptible toward enzymatic degradation such as esterases, aminopeptidases, carboxypeptidases and several endopeptidases. Transcellular permeation through the buccal epithelium by passive diffusion is affected by the molecular weight and size
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Table 1. Overview of buccal-adhesive dosage forms for peptide/protein delivery.
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Protein/peptide drug Buserelin Calcitonin Captopril LH releasing hormone Octreotide acetate Oxytocin Oxytocin Pituitary adenylate cyclase-activating polypeptide Pitocin Protirelin Thyrotropin releasing hormone
Figure 8. Overview of preactivated mucoadhesive thiomers.
of the peptide drug itself35. Generally, the higher the molecular weight of a biomacromolecule, the lesser the bioavailability. Peptides and proteins being hydrophilic and globular in nature show transport via paracellular route. Besides passive diffusion as the key absorption pathway for peptides and proteins, carriermediated processes affect the transport of certain drugs through the buccal mucosa36,37. Table 1 gives an overview about proteins and peptides being investigated for buccal delivery. Furthermore, amino acids such as glutamic acid and lysine were reported to be transported via carrier-mediated processes. However, endocytotic processes are not apparent in buccal epithelium.
Buccal drug delivery systems Buccal tablets The most commonly investigated dosage forms for buccal drug delivery to date are buccal tablets. Buccal tablets are
Dosage form
References
Patch Tablet Tablet Tablet Patch Tablet Patch Patch
62
Tablet Patch Patch
69
63 64 65 66 67 68 41
70 71
small, flat and oval with a diameter of approximately 5–8 mm38. Buccal mucoadhesive tablets permit drinking and speaking without major discomfort unlike conventional tablets. Adhesion to the mucosa is given until dissolution and/or release is completed. Different areas of the oral cavity can be chosen for application such as palate, mucosa lining the cheek, also between the gum and the lip. Application to alternate sides of the oral cavity can be conducted for successive tablets. Buccal bioadhesive tablets exhibit as major drawback the lack of physical flexibility. Bioadhesive tablets are usually directly compressed; other techniques as wet granulation can also be used. Tablets designed for buccal administration in order to be inserted into the buccal pouch should dissolve or erode slowly. Therefore, sufficient pressure is required to keep the hardness of the tablets. Furthermore, each site of the tablet, except the one in contact with the mucosa, can exhibit a coating with water impermeable materials, such as ethylcellulose, hydrogenated castor oil, etc., using either compression or spray coating. Drugs may be formulated in certain physical states, such as microspheres, prior to direct compression achieving desirable features, e.g. enhanced activity and prolonged drug release39. Some recent approaches use tablets melting at body temperatures40. Furthermore Langoth et al. performed bioavailability studies in pigs by buccal administration pituitary adenylate cyclaseactivating polypeptide (PACAP). The resulting mucoadhesive chitosan-4-thiobutylamidine conjugate was homogenized with the enzyme inhibitor and permeation mediator glutathione (gamma-Glu-Cys-Gly), Brij 35 and PACAP (formulation A) and compressed into flat-faced discs. One formulation was additionally coated on one side with palm wax (formulation B). Moreover, in the case of formulations A and B, a continuously raised plasma level of the peptide drug being in the therapeutic range could be maintained over the whole period of application (6 h)41. Buccal patches Patches are laminates, which consist of three compartments: first, an impermeable backing layer; second, a drug-containing reservoir layer where the drug is released from in a controlled manner and third, a bioadhesive surface for mucosal attachment42,43. Two methods are decisive for the preparations of adhesive patches comprising solvent casting and direct milling. For the first method, 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 evaporate44. For the second method, the direct milling method, formulation constituents are homogeneously mixed and compressed to the desired
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thickness. Thereafter, patches of predetermined size and shape are cut or punched out45. The application of an impermeable backing layer leads to control the direction of drug release, prevent drug loss and minimize deformation and disintegration of the device during the application period.
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Buccal films The most recently developed dosage forms for buccal administration are films. In terms of flexibility and comfort, buccal films are preferred over adhesive tablets46. In addition, they can overwhelm the relatively short residence time of oral gels on the mucosa, being easily washed away and removed by saliva. Furthermore, concerning local delivery for oral diseases, the films holds the advantage to protect the wound surface, thus leading to reduce pain and treat the disease more effectively47. Flexibility, elasticity, softness as well as strength to withstand breakage due to oral movements should be features of an ideal film. Key factor as possessing good bioadhesive strength in order to be retained in the mouth for the desired duration of action are indispensable48. In order to prevent discomfort, swelling should not be too extensive. Bioadhesive films being usually manufactured by a solvent-casting method are similar to laminated patches in terms of their flexibility and manufacturing process49. First of all, drug and polymer(s) are dissolved in a casting solvent or solvent mixture. Then, the solution is cast into films, dried and finally laminated with a backing layer or a release liner. The backing layer helps retard the diffusion of saliva into the drug layer by improving the adhesion time and reducing drug loss into the oral cavity. The solvent-casting method is a simple method suffering from some disadvantages, including long processing time, high cost and environmental concerns due to the solvents used50. These hindrances can be overwhelmed by the hot-melt extrusion method recently reported by Repka and McGinity51. Buccal gels and ointments Bioadhesive ointments have not been described in the literature as extensively as other dosage forms, especially when compared to tablets and patches52. Advantages associated with semisolid dosage forms, such as gels and ointments, are the easy dispersion throughout the oral mucosa. Disadvantages related on semisolid dosage forms are the not accurate drug dosing from these dosage form in comparison with drug dosing from tablets, patches or films. In order to overwhelm the poor retention of the gels at the site of application bioadhesive formulations are used. Certain bioadhesive polymers, e.g. poloxamer 40753, sodium carboxymethylcellulose54, Carbopol55, hyaluronic acid56 and xanthan gum57, undergo a phase change from a liquid to a semisolid. This change improves the viscosity resulting in sustained and controlled release of drugs. Hydrogels are also a promising dosage form for buccal drug delivery. They are formed from polymers being hydrated in an aqueous environment and physically entrap drug molecules for subsequent slow release by diffusion or erosion58. The application of bioadhesive gels provides an extended retention time in the oral cavity, adequate drug penetration, as well as high efficacy and patient acceptability. The treatment of periodontitis, being an inflammatory and infectious disease causing formation of pockets between the gum and the tooth, leads eventually to loss of teeth. The major application of adhesive gels could be the local delivery of medicinal agents. Mucoadhesive polymers are reported to be useful for periodontitis therapy when incorporated in antimicrobial-containing formulations being easily introduced into the periodontal pocket with a syringe59–61. Mucoadhesion provides retention of the formulation within the pocket.
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Conclusion Buccal drug delivery is a feasible and attractive alternative for non-invasive delivery of potent peptide and protein drug molecules. The buccal mucosa offers a variety of advantages such as avoiding first-pass metabolism for drug delivery for extended periods of time. The area is well suited for retentive device and show high acceptance of the patients. Developing the distinctive formulation and dosage form, the permeability and bioavailability of biomacromolecules will be tremendously improved. A promising approach to overcome the challenges of contemporary macromolecular drug delivery might be the use of multifunctional auxiliary agents. By introducing the PAT generation, the susceptibility of first-generation mucoadhesive thiomers in semisolid formulations toward oxidation could be suppressed as well as a more pronounced mucoadhesiveness could be reported. These features approve preactivated thiomers promising for delivery where prolonged residence time is in need. Buccal drug delivery is an auspicious area for further research aiming systemic delivery of orally inefficient drugs in the not-too far future. Once available, macromolecular drugs will revolutionize the treatment of various diseases as well as provide novel diagnostic tools to the benefit for the patient.
Declaration of interest The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript. The author reports no declaration of interest.
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DOI: 10.3109/03639045.2014.892959
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