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Journal of Drug Delivery and Therapeutics
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Open Access Full Text Article Review Article
Bioadhesive polymers, permeation enhancers and types of dosage forms for buccal drug delivery
Kumara Swamy Samanthula1*, Shobha Rani Satla2, Agaiah Goud Bairi3
1 Vaagdevi Pharmacy College, Bollikunta, Warangal, India
2 Centre for Pharmaceutical Sciences, IST, JNTU, Kukatpally, Hyderabad, India
3 SRR College of Pharmaceutical Sciences, Valbhapur, Warangal, India
Article Info: ___________________________________________________ Article History: Received 06 Oct 2020; Review Completed 19 Dec 2020 Accepted 27 Dec 2020; Available online 15 Jan 2021 ________________________________ Cite this article as: Samanthula KS, Satla SR, Bairi AG, Bioadhesive polymers, permeation enhancers and types of dosage forms for buccal drug delivery, Journal of Drug Delivery and Therapeutics. 2021; 11(1):138-145 DOI: http://dx.doi.org/10.22270/jddt.v11i1.4495 ___________________________________________________ *Address for Correspondence: Kumara Swamy Samanthula, Vaagdevi Pharmacy College, Bollikunta, Warangal, India |
Abstract _______________________________________________________________________________________________ The buccal delivery is defined as the drug administration through the mucosal membranes lining the cheeks (buccal mucosa). The main impediment to the use of many hydrophilic macromolecular drugs as potential therapeutic agents is their inadequate and erratic oral absorption. Based on our current understanding of biochemical and physiological aspects of absorption and metabolism of many biotechnologically produced drugs, they cannot be delivered effectively through the conventional oral route. Because after oral administration many drugs are subjected to pre-systemic clearance extensive in the liver, which often leads to a lack of significant correlation between membrane permeability, absorption and bioavailability. Difficulties associated with the parenteral delivery and poor oral bioavailability provided the impetus for exploring alternative routes for the delivery of such drugs. This review covers the advantages, disadvantages of buccal delivery, drug and excipient selection especially bioadhesive polymers and permeation enhancers, and further a list of drugs developed as various dosage forms for buccal route of administration. Keywords: Buccal delivery, bioadhesive/mucoadhesive, permeation enhancer, dosage forms. |
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Introduction
Conventional oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes1, 2. It remains the preferred route of administration in the discovery and development of new drug candidates and formulation. The popularity of the oral route is attributed to patient acceptance, ease of administration accurate dosing, cost effective manufacturing methods, and generally improve the shelf-life of the product3-5. In recent years, the interest in novel routes of drug administration occurs from their ability to enhance the bioavailability of drugs6-9.
The concept of mucosal-adhesive or mucoadhesive was introduced into the controlled drug delivery in the early 1980's. Bioadhesive polyacrylic acid nanoparticles are an example of a novel drug delivery system designed for mucosal and topical drug delivery10,11. Mucoadhesive polymers are synthetic or natural polymers, which interact with the mucus layer covering the mucosal epithelial surface and mucin molecules constituting a major part of mucus12. They render the treatment more effective and safe, not only for topical disorders but also for systemic problems13,14. These dosage forms are self-administrable, cheap and have superior patient compliance. With the right dosage form design, the local environment of the mucosa can be controlled and manipulated in order to optimize the rate of drug dissolution and permeation15.
Drugs can be absorbed from the oral cavity through the oral mucosa either sublingually or buccal. Buccal drug delivery was introduced by Orabase in 1947, when gum tragacanth was mixed with dental adhesive powder to supply penicillin to the oral mucosa16. In recent years, delivery of therapeutic agents through various transmucosal routes has gained significant attention. Buccal delivery of drugs provides an attractive alternative to the oral route of drug administration, particularly in overcoming deficiencies associated with the latter mode of dosing17. Extensive first-pass metabolism and drug degradation in the harsh gastro intestinal environment can be circumvented by administering the drug via buccal route and also other lipid carrier systems18, 19.
The buccal delivery is defined as the drug administration through the mucosal membranes lining the cheeks (buccal mucosa). The main impediment to the use of many hydrophilic macromolecular drugs as potential therapeutic agents is their inadequate and erratic oral absorption20. Based on our current understanding of biochemical and physiological aspects of absorption and metabolism of many biotechnologically- produced drugs, they cannot be delivered effectively through the conventional oral route. Because after oral administration many drugs are subjected to pre-systemic clearance extensive in liver, which often leads to a lack of significant correlation between membrane permeability, absorption and bioavailability21-23. Difficulties associated with the parenteral delivery and poor oral bioavailability provided the impetus for exploring alternative routes for the delivery of such drugs24 (Rathbone et al., 1996).
Advantages
Disadvantages
Mucoadhesive drug delivery systems:
The oral cavity is an attractive site for drug delivery due to ease of administration, avoidance of possible drug degradation in the gastrointestinal tract, and first-pass metabolism. Within the oral mucosal cavity, delivery of drugs is classified into three categories:
Buccal mucoadhesive dosage forms
Buccal mucoadhesive dosage forms can be categorized into 3 types based on their geometry.
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 rate25. 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 general, dosage forms designed for buccal drug delivery should be small and flexible enough to be acceptable for patients, and should not cause irritation. Other desired characteristics of a buccal mucoadhesive dosage form include high drug loading capacity, controlled drug release (preferably unidirectional release), good bioadhesive properties, smooth surface, tastelessness, and convenient application. Erodible formulations can be beneficial because they do not require system retrieval at the end of desired dosing interval. A number of relevant buccal mucoadhesive dosage forms have been developed for a variety of drugs. Several peptides, including thyrotropin-releasing hormone, insulin, octreotide, leuprolide, and oxytocin, have been delivered via the buccal route. Buccal dosage forms can be used to treat both local and systemic conditions. Mainly the following types of buccal dosage forms are available in the market.
General criteria for candidate’s drug:
One of the drug properties required for the practical buccal formulation will be high pharmacological activity or a low dose requirement. There is a limit to the size of a dosage form. The size of the dosage form should not exceed 12 cm2 for buccal application or 3cm2 for sublingual or gingival application. In general, any drug with a daily requirement of 25 mg or less would make a good candidate.
Other than dose considerations, the following properties will make the drug suitable candidate for buccal delivery:
Formulation design
An ideal buccal adhesive system must have the following properties:
Bioadhesive polymers
The concept of biomucoadhesive polymers has been introduced into the pharmaceutical literature more than 40 years ago and nowadays it has been accepted as a promising strategy to prolong the residence time and to improve the specific localization of drug delivery systems on various membranes. Polymer is a generic term used to describe a very long molecule consisting of structural units and repeating units connected by covalent chemical bonds. The term is derived from the Greek words: polys meaning many, and meros meaning parts26. Bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in the oral drug delivery (Table 1). The first step in the development of mucoadhesive dosage forms is the selection and characterization of appropriate bioadhesive polymers in the formulation27,28.
Bioadhesive polymers should possess certain physicochemical features including hydrophilicity, numerous hydrogen bond-forming groups, flexibility for interpenetration with mucus and epithelial tissue, and visco-elastic properties29. Bioadhesive polymers also used for development of other delivery systems such as microspheres30 (Vasir et al., 2003), peptide delivery31 (Harris and Robinson, 1994), floating and floating-mucoadhesive32-34, transfersomes system35-37.
Ideal characteristics
Table 1: Mucoadhesive Polymers used in Buccal drug delivery
Criteria |
Categories |
Examples |
Source |
Semi-natural /natural |
Agarose, chitosan, gelatin, Hyaluronic acid Various gums (guar, hakea, xanthan, gellan, carragenan, pectin, and sodium alginate) |
Synthetic |
Cellulose derivatives [CMC, sodium CMC, HEC, HPC, HPMC, MC, hydroxyl ethyl cellulose] |
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Poly(acrylic acid)-based polymers [CP, PC, PAA, polyacrylates, poly (methylvinylether-co-methacrylic acid), poly (2-hydroxyethyl methacrylate), poly (alkylcyanoacrylate), copolymer of acrylic acid and PEG] |
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Others Poly(N-2-hydroxypropyl methacrylamide) (PHPMAm) PVA, PVP, thiolated polymers |
||
Aqueous Solubility |
Water-soluble |
CP, HEC, HPC, HPMC (cold water) |
Water-insoluble |
Chitosan (soluble in dilute aqueous acids), EC, PC |
|
Charge |
Cationic |
Aminodextran, chitosan, trimethylated chitosan |
Anionic |
Chitosan-EDTA, CP, CMC, pectin, PAA, PC |
|
Non-ionic |
Hydroxyethyl starch, HPC, poly(ethylene oxide), PVA, PVP |
|
Potential bioadhesive forces |
Covalent |
Cyanoacrylate |
Hydrogen bond |
Acrylates [hydroxylatedmethacrylate, poly (methacrylic acid)], CP, PC, PVA |
|
Electrostatic force |
Chitosan |
Permeation enhancers
Membrane permeation is the limiting factor for many drugs in the development of buccal adhesive delivery devices. The epithelium that lines the buccal mucosa is a very effective barrier to the absorption of drugs. It is estimated that the permeability of the buccal mucosa is 4-4000 times greater than that of the skin. Substances that facilitate the permeation through buccal mucosa are referred to as permeation enhancer38. Permeation enhancers are substances added to pharmaceutical formulation in order to increases the membrane permeation rate or absorption rate of a co-administered drug. They are used to improve bioavailability of drugs with normally poor membrane permeation properties without damaging the membrane and causing toxicity39-42.
The goal of designing penetration enhancers, with improved efficacy and reduced toxicity profile is possible by understanding the relationship between enhancer structure and the effect induced in the membrane and of course, the mechanism of action. However, the selection of enhancer and its efficacy depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other excipients43,44. In some cases, usage of enhancers in combination has shown synergistic effect than the individual enhancers. The efficacy of enhancer in one site is not same in the other site because of differences in cellular morphology, membrane thickness, enzymatic activity, lipid composition and potential protein interactions are structural and functional properties45-49.
Penetration enhancement to the buccal membrane is drug specific. Penetration enhancement to the buccal membrane is drug specific50,51. Effective penetration enhancers for transdermal or intestinal drug delivery may not have similar effects on buccal drug delivery because of structural differences; however, enhancers used to improve drug permeation in other absorptive mucosa improve drug penetration through buccal mucosa. These permeation enhancers should be safe and non-toxic, pharmacologically and chemically inert, non-irritant, and non-allergenic50.
However, an examination of the penetration route for transbuccal delivery is important because it is fundamental to select the proper penetration enhancer to improve the drug permeability52 (Table 2).
Table 2: Mucosal penetration enhancers and mechanisms of action
Classification |
Examples |
Mechanism |
Surfactants |
Anionic: Sodium lauryl sulphate Cationic:Cetylpyridinium Chloride, cetyltrimethyl ammonium bromide Nonionic:Poloxamer, Brij, Span, Myrj, Tween Bile salts: Sodium glycodeoxycholate, Sodiumglycocholate, Sodium taurodeoxycholate, Sodium taurocholate, Azone |
Perturbation of intercellular lipids, protein domain integrity |
Fatty acids |
Oleic acid, Caprylic acid,Lauric acid, Propylene glycol, Methyloleate, Phosphatidylcholine |
Increase fluidity of phospholipid domain |
Cyclodetrin |
a, b, g, Cyclodextrin, methylated b-cyclodextrins |
Inlusion of membrane compounds |
Chelators |
EDTA, Citric acid, Sodium salicylate, Methoxy salicylates. |
Interfere with Ca2+ Polyacrylates |
Positively charged polymers |
Chitosan, Trimethyl chitosan |
Ionic interaction with negative charge on the mucosal surface |
Cationic compounds |
Poly-L-arginine, L-lysine |
Ionic interaction with negative charge on the mucosal surface |
Research on buccal adhesive drug delivery systems:
Several buccal adhesive delivery devices were developed at the laboratory scale by many researchers either for local or systemic actions. They are broadly classified in to
Solid buccal adhesive formulations
Dry formulations achieve bio adhesion via dehydration of the local mucosal surface.
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 mm53. 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 use54,55.
Bioadhesive tablets are usually prepared by direct compression, wet granulation techniques can also be used. Tablets intended for buccal administration by insertion into the buccal pouch may dissolve or erode slowly; therefore, they are formulated and compressed with sufficient pressure only to give a hard tablet. To achieve unidirectional release, every face of the tablet, except the one that is in contact with the buccal mucosa, can be coated with water impermeable materials, such as ethyl cellulose, hydrogenated castor oil, etc., using either compression or spray coating. Multilayered tablets may be prepared by sequentially adding and compressing the ingredients layer by layer. Monolithic and two-layered matrix tablets are designed for buccal delivery of drugs. Monolithic tablets consist of a mixture of drugs with a swelling bioadhesive or sustained release polymer with a bi-directional release. They can be coated on the outer or on all sides but one face with water impermeable hydrophobic substances to allow the unidirectional drug release for systemic delivery56.
Two layered tablets consist of an inner layer based on a bioadhesive polymer and an outer non-bioadhesive layer containing the drug for a bi-directional release but mainly a local action. Examples of drugs that loaded with matrix tablets are Propranolol, Timolol, Metronidazole, Metoclopramide, Nitroglycerin and Calcitonin (Table 3).
Table 3: List of investigated mucoadhesive buccal tablets
Active ingredient |
Polymers used |
Ref |
Propranolol HCl |
HPMC and PC |
57 |
Promethazine |
Sodium CMC and Carbopol 934P |
58 |
Theophylline |
CP 974P |
59 |
Curcumin |
Anacardium occidentale |
60 |
Nifedipine |
CMC and CP |
61 |
Duloxetine Hydrochloride |
HPMC K4M, Carbopol 934P and PEO WSR 303 |
62 |
Miconazole nitrate |
Mixtures of HPMC, sodium CMC, CP 934P, and sodium alginate |
63 |
Metronidazole |
HEC, HPC, HPMC, or NaCMC combined with CP 940, |
64 |
Semi-solid dosage forms
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 milling65 (GUO, 1994).
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 period66 (Shirvan et al., 2019). The drugs and polymers that have been used to develop buccal mucoadhesive patches are listed in Table 4.
Table 4: List of investigated buccal mucoadhesive patches
Active ingredient |
Polymers used |
Ref |
Domperidone |
hydroxy propyl methyl cellulose, PVPK30, Eudragit RLPO, PEO |
67 |
miconazole nitrate |
Sodium CMC, chitosan, PVA, HEC, HPMC |
68 |
Sumatriptan succinate |
Gelatin, PVP |
69 |
Carvedilol |
HPMC E 15 |
70 |
Pioglitazone and felodipine |
PEON80, HMCK4M |
15 |
Zolmitriptan |
PVA and HPMC E-15 |
71 |
Buccal films:
Buccal films are preferred over tablets because of their flexibility and comfort. The films protect the wound surface, which reduces the pain and treats the disease more effectively. Flexible films may be used to deliver drugs directly to a mucosal membrane. They also offer advantages over creams and ointments in that they provide a measured dose of drug to the site. 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. An ideal film should be flexible, elastic and soft and adequately strong to withstand breakage due to stress from mouth movements. Swelling of film, if occurs, should not be too extensive to prevent discomfort72.
Bioadhesive films are similar to laminated patches in terms of their flexibility and manufacturing process. They are usually manufactured by a solvent casting method. The drug and polymer(s) are first dissolved in a casting solvent or solvent mixture. The solution is then 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, thus enhancing the adhesion time and reducing drug loss into the oral cavity. The solvent casting method is simple, but suffers from some disadvantages, including long processing time, high cost, and environmental concerns due to the solvents used73. Some of developed buccal films reported in Table 5.
Table 5: List of investigated buccal mucoadhesive films
Active ingredient |
Polymers used |
Ref |
Domperidone |
PEO N750 (X1) and HPMC E5 LV |
74 |
Insulin |
Gelatin and CP 934P |
75 |
Fluconazole |
HPMC, HEC, chitosan, Eudragit and sodium alginate |
76 |
Prednisolone |
HPMC, Carbopol 940 and/or Eudragit® NE 40 D. |
77 |
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 formulations78 (Hua, 2019). A major application of adhesive gels is the local delivery of medicinal agents for the treatment of periodontitis, which is an inflammatory and infectious disease that causes formation of pockets between the gum and the tooth, and can eventually cause loss of teeth (Table 6).
Bioadhesive ointments have not been described in the literature as extensively as other dosage forms, especially when compared to tablets and patches. HPMC has been used as an adhesive ointment ingredient79 (Smart, 2005).
Table 6: List of investigated buccal mucoadhesive gels
Active ingredient |
Polymers used |
Ref |
Ibuprofen |
Carbopol® 980 and polycarbophil |
80 |
Ergotamine tartrate |
PVA |
81 |
Diclofenac sodium |
Hydroxyethyl methacrylate |
82 |
triamcinolone acetonide |
HEC, PVP, and PC |
83 |
Lidocaine |
PEG, CP 934P, |
84 |
Celecoxib |
Chitosan |
85 |
Buccal hydrogels:
They are formed from polymers that are hydrated in an aqueous environment and entrap drug molecules for slow release by diffusion or erosion. The advantages of these buccal hydrogels include extended retention time in the oral cavity, adequate drug penetration, high efficacy and patient acceptability86,87. Major application is a medicinal agent for the treatment of periodontitis, which is an inflammatory and infectious disease that causes formation of pockets between the gum and the tooth and leads to loss of teeth88.
Conclusion:
Buccal drug delivery specifically refers to the delivery of drugs within/through buccal mucosa to affect local/systemic pharmacological actions. This review briefly describes advantages and limitations of buccal drug delivery, selection criteria of drugs and mucoadhesive and bioadhesive polymers, mechanism of permeation enhancers and various types of buccal delivery formulations.
References: