BUCCAL DRUG DELIVERY SYSTEM: AN OVERVIEW ABOUT
DOSAGE FORMS AND RECENT STUDIES
Meliha GÜNEŞ1, Sinem Yaprak KARAVANA1, Evren ALGIN YAPAR2*
1Department of Pharmaceutical Technology, Faculty of Pharmacy, Ege University, 35100 Bornova, Izmir, Turkey.
2Department of Analysis and Control Laboratories, Turkish Medicines and Medical Devices Agency, Sıhhiye, Ankara, Turkey.
Management of illness through medication is entering a new era in which growing number of novel drug delivery systems are being employed and are available for therapeutic use. Pharmaceutical research and development is currently focused on the development of drug delivery systems to target a drug to the desired organ or site with the aim of minimizing its overall distribution in the body. The oral mucosa has many properties which make it an attractive site for drug delivery but simultaneously provide several problems for researchers for effective and efficient delivery of therapeutic active agents. However, with the development of novel delivery techniques overcome several challenges. Oral mucosa delivery has many advantages like high blood flow, rapid recovery, prevention of hepatic first-pass effect and pre-systemic elimation in gastrointestinal tract. On the other hand relatively small surface area and significant loss of drug due to swallowing and salivary flow are main limitations of buccal delivery. Different formulations including sprays, tablets, mouthwashes, gels, pastes and patches are presently used for delivery into and/or across the oral mucosa. Over the last 20 years, a wide range of formulations has been developed for buccal drug delivery systems but unfortunately few have been accomplished to be a medicine. One of the main reasons of this unsuccessful result could be the lack of the standardized methods which evaluate in vitro performance of buccal dosage forms. Thus aim of this review, to discuss the potential of buccal drug delivery and buccal dosage forms and also explore recent studies and in vitro analyses methodology of buccal dosage forms.
Keywords: Buccal dosage forms, buccal mucosa, drug delivery, mucoadhesion.
INTRODUCTION
Drug research and development has been progressing in improving the quality of life of patients as well as contributing to the treatment of diseases1,2. Development of new a drug molecule is expensive and time consuming. Because of this, the scientist and researchers in the drug development industries are focusing on alternative routes of administration to add to the potential of approved drugs or to overcome the drawbacks of the oral route. Buccal drug administration has remarkable advantages such as prevention and elimination of first-pass effect in the gastrointestinal tract, having a more favorable enzymatic environment for the absorption of certain drugs, having low cost, easy administration to pediatric and geriatric patients and also patients with intellectual disabilities2–4. The oral mucosa is highly vascularized, drugs absorbed through the mucosa and enter the systemic circulation directly. Furthermore, the high blood flow and permeability of the oral mucosa makes it an ideal site of administration for the rapid systemic delivery of a drug in the treatment of pain, seizures and angina pectoris5,6. When transmucosal drug administration routes such as rectal, vaginal, nasal and buccal routes are compared, buccal route is prominent with patient compliance. For example rectal and vaginal delivery systems are in part less acceptable ways for patients. In terms of drug administration, rectal and vaginal administration may sometimes lead to slow and sometimes incomplete drug absorption and may vary in the same person or between individuals7. For nasal application; the limited area of the nasal cavity, the rapid removal of the administered drug, and the variable physiological functions of the nasal cavity are among the disadvantages of this application6. With the development of mucoadhesive formulations, the local and systemic effects of drug delivery systems have increased. The likelihood of using biological agents such as genes, peptides and antibodies that can be reduced by the administration of oral mucosa may increase6,8. Pharmaceutical researchers are conducting further research on the development of novel drug delivery systems to enhance the therapeutic effects of existing molecules relative to novel drug molecules. At this point, buccal drug systems are thought to have great potential, and this review summarizes general information about buccal drug delivery systems and provides information about recent studies.
Anatomical structure of oral cavity
The oral cavity consists of the lips, cheeks, tongue, hard palate, soft palate and the base of the mouth, and its surface consists of oral mucosa. Oral mucosa; buccal, sublingual, gingival, palatal and labial mucosa, buccal mucosal tissues (buccal), the bottom of the mouth (sublingual) and the ventral surface of the tongue accounts for about 60% of the oral mucosal surface area. The buccal cavity has a very limited surface area of around 50 cm2 but the accessibility of the site makes it a preferred location for delivering therapeutic agents. Buccal and sublingual tissues are suitable site for buccal administration and these are the regions with the highest permeability in the oral mucosa9. The sublingual mucosa is relatively more permeable than the buccal mucosa; hence, formulations for sublingual delivery are formulated to release the active agent immediately. The mucoadhesive formulation is of importance for the delivery of active agents to the buccal mucosa where the active agent has to be released in a controlled manner. Hence, the buccal cavity is more suitable for mucoadhesive drug delivery. The epithelium of the oral cavity resembles the skin epithelium, but exhibits distinct characteristics from the skin in terms of keratinization, protective and lubricating mucus. Mucus is a translucent and viscous secretion that forms a thin and continuous gel layer that adheres to the mucosal epithelial surface. Mean thickness of mucus varies from about 50-450 µm in humans,and it secreted by the globet cells lining the epithelia. Generally, mucus components; water (95%), glycoproteins and lipids (0.5-5%), mineral salts (1%) and free protein (0.5-1%). The saliva produced by the salivary glands in the oral cavity and as part of the saliva, mucus secreted from the major and minor salivary glands are present, allowing the adhesion of mucoadhesive drug delivery systems during drug administration10,11. The pH of saliva is 5.5 to 7.0 and viscosity value is 1.09±0.11 mPa.s. Saliva is composed of 99% water and is complex fluid containing organic and inorganic material. Secretion of saliva is highest during working hours. Continuous available volume of it 696±312 µl. Protective fluid for all tissues of the oral cavity, continuous mineralization/demineralization of the tooth enamel and moisten the oral cavity are main functions of saliva12.
The Advantages and Disadvantages of Buccal Drug Administration
The buccal area has a highly vascularized tissue and a neutral environment. The route of drugs through the buccal mucosa is like a slow i.v. infusion. Thus higher bioavailability of some medicines may be achieved with fewer doses compared to conventional oral dosage forms. Absorption, the size of the drug molecule, its sensitivity to hydrophilicity, its enzymatic degradation, and its application to the oral cavity need to be taken into consideration to accomplish the above mentioned achievement13,14,15.
Buccal dosage forms and applications
Numerous dosage forms are available for buccal administration, such as tablets, films, lozenges, sprays, gels, lollipops, gums and powders. In addition, new formulations such as sponges can be used for buccal drug administration17,18,19.
Buccal dosage forms include dry dosage forms that need to be moistened before buccal tablets are administered11. In recent years, various mucoadhesive buccal tablet formulations have been prepared by direct compression for local or systemic effect. Buccal tablets can be developed to release the active ingredient into the saliva either unidirectionally or multidirectionally by targeting the buccal mucosa18. The buccal films/patches comprise an impermeable layer of the active substance/formulation, a reservoir layer containing the formulation in which the active substance is released in a controlled manner, and a mucoadhesive surface for attachment to the mucosa. Compared to creams and ointments, they are more advantageous in delivering a certain dose of the drug to the site20. Buccal films are more preferred than buccal tablets. Because buccal tablets are more flexible and can be applied more easily. In addition, they can reduce pain by protecting the wound surfaces and improve treatment efficacy21. Buccal films are particularly designed for pediatric patients22.
Buccal gels and ointments are semi-solid dosage forms and have the advantage of easy administration to the buccal mucosa. The problem of low adhesion of the gels in the field of application was overcome by the preparation of mucoadhesive formulations2. Buccal gels or ointments are less preferred by patients than buccal tablets and films, but are generally administered for local effect11.
Buccal dosage forms may be developed for systemic effect or for local treatment of the oral mucosa. When selecting the dosage form, the target site of action and the properties of the active substance should be considered23. For mucosal and transmucosal administration, conventional dosage forms cannot provide therapeutic drug levels in the mucosa and circulation due to the physiological nature of the oral cavity (the presence of saliva and the effect of mechanical stress). The constant flow of saliva and the mobility of tissues within the mouth makes it difficult to keep the dosage form in the oral cavity. The residence time of medications administered to the oral cavity is generally between 5 and 10 minutes. Since the dosage form remains in the absorption area for a very short time, an unpredictable distribution is observed. In order to achieve the desired therapeutic effect, it is important to increase the contact time between the formulation and the mucosa. For this purpose, mucoadhesive buccal formulations are developed using mucoadhesive polymers. To develop an ideal mucoadhesive buccal drug delivery system, it is important to identify and understand the forces responsible for adhesive bond formation24.There are three sites that are effective for the formation of adhesive bonds between the polymer and mucus:
Mucoadhesion is a complex process and adhesion mechanisms of polymers to mucosal surfaces have not yet been fully understood. However, numerous theories such as adsorption theory, wetting theory, electrical theory, diffusion theory and fracture theory have been proposed10, 25;
In particular, buccal systems are needed to treat local diseases of the mucosa24,26. In order to provide therapeutic requirements, buccal dosage forms include; penetration enhancers to increase the permeability of the active substance by transmucosal administration or mucosal administration; enzyme inhibitors to protect the active substance from degradation by mucosal enzymes. Due to the limited absorption area with respect to the site of administration of the buccal dosage form, they are generally preferred for a buccal delivery system of 1-3 cm2 and for active ingredients with a daily dose of 25 mg or less. The ellipsoidal shape is most preferred in films/patches and the thickness of buccal drug delivery systems is generally limited to a few millimeters27. Many diseases can affect the thickness of the buccal epithelium and ultimately alter the barrier property of the mucosa. Some diseases or treatments may also affect mucus secretion and properties10. Due to these physiopathological conditions, changes in the mucosal surface may make it difficult to administer and retain a buccal delivery system. Therefore, it is necessary to evaluate the structure of the mucosa under the relevant disease conditions in order to develop an effective buccal release system. In addition, it should be noted that active substances that have the potential to alter the physiological conditions of the oral cavity may not be suitable for buccal administration27.
In vitro evaluation of buccal dosage forms
Several dosage forms have been developed and evaluated to suitability applying oral mucosa. Regardless of the properties of dosage forms different methods are required for quality control studies and evaluation of release, permeation and mucoadhesion properties12. Some test like uniformity of content, permeability study, buccal absorption test and residence time should be performed for all dosage forms. On the other hand, the test like weight variation, friability, tensile strength or viscosity are necessary for some dosage forms. In vitro disintegration tests are generally performed for solid dosage forms like films and tablets to determine the disintegration rate when the dosage form come in contact with the mucus and saliva. Disintegration of these dosage forms can also be examined visually while dissolution studies. Between all the buccal mucosal products listed in USP 35, the monograph of isosorbide dinitrate sublingual tablets has specific information about dissolution test. Hence, comparison of different products or evaluation of newly developed formulations is problematic because of the lack of standardized methods available in the pharmacopeia.
In this monograph, the USP dissolution apparatus II is used at a paddle speed of 50 rpm with 900 ml water dissolution medium which does not correlate with in vivo conditions of buccal mucosa and the result couldn`t reflect in vivo dissolution. Several studies have been performed to dissolution studies in smaller volumes or with different devices for mimic in vivo conditions. Fabregas and Garcia used apparatus III for the dissolution of hydrocortisone hemisuccinate buccal mucoadhesive tablets28.
Ikinci et al. used a Franz diffusion cell method as an alternative for the release of nicotine from buccal tablets. The in vitro residence time test is specifically useful to evaluate the time to remain at the buccal mucosa for mucoadhesive drug delivery systems29. Nafee et al.used modified disintegration test apparatus for determination of residence time30. The disintegration medium was 800 ml of pH 6.75 isotonic phosphate buffer and rabbit intestinal mucosa was used for the test. The hydrated mucoadhesive tablet was brought into contact with the membrane. The time necessary for erosion or detachment of the tablet was determined. Kockisch et al. proposed a dynamic in vitro retention testing system31. The porcine esophageal mucosa was held flat by application of a moderate vacuum through small openings at the base plate of the cell. The tissue was kept 37°C; 90% RH and was allowed to equilibrate for a period of 1 h. To ensure that the tissue was sufficiently hydrated, artificial saliva was circulated over the tissue at a rate of 1 ml/min using a peristaltic pump. Polymer microparticles were placed onto the center of the mucosal surface with a small glass funnel. The time taken for the particles to travel along mucosa was used as a measure of particle retention31. Mucoadhesion tests have been performed in the literature based on different method such as modified Wilhelmy plate surface, modified dual tensiometry, texture analysis and rotating cylinder methods. Between all the methods the texture analyzer is generally usedliterature in the recent years because of the varied experimental setups, precision and reproducibility of results.
Buccal permeation studies must be conducted to determine the feasibility of this route of a drug candidate and the type of enhancer during the pre-formulation studies. These studies are usually enforced to determine the barrier properties of different mucosal tissues. Similar like transdermal drug delivery, different types of diffusion cells with modifications are suitable to performed permeation studies for buccal dosage forms. Human buccal tissues may be the most suitable to mimic in vivo conditions researchers usually use animal tissue because it is not easy to reach human tissues. Permeation studies involve methods that would examine in vitro, ex vivo and/or in vivo buccal permeation profile and kinetics of absorption of the drug12,20.
Recent studies and on buccal drug delivery and future approaches
Pather et al. summarized challenges for the development and approval of buccal dosage forms as; including low dose drugs, biology and permeability issues and the complexity of them, need a special mechanism to enhance the absorption of the drug without causing undue side effects, the taste of the drug, patient acceptability, dose titration for in vivo studies may prove to be difficult and difficulties related with regulations, authorities and economical circumstances32. Very few innovative dosage forms for buccal drug delivery have reached the clinical development phase. The main strategies have been the incorporation of permeation enhancers or mucoadhesive constituents to conventional dosage forms. For example, surfactants, bile salts, fatty acids, cyclodextrins and chelators have been shown to enhance mucosal permeability and absorption of various compounds33 by changing mucus rheology, increasing the fluidity of the lipid bilayer membrane, acting on the components at tight junctions, inhibiting mucosal enzymes; and increasing the thermodynamic activity of drugs20. In addition, the incorporation of mucoadhesive constituents has been demonstrated to enhance formulation retention time with the sublingual or buccal mucosa34.
The major obstacle to the use of many hydrophilic macromolecules is inadequate and irregular oral absorption. With the development of recombinant DNA technology, buccal administration is thought to be important in order to develop protein and peptide formulations in the future and deliver them to the systemic circulation by a non-parenteral administration26. In line with recent developments in buccal drug delivery systems such as lipophilic gel, buccal spray and phospholipid vesicles, numerous studies have been conducted on the buccal administration of peptides. In particular, some researchers have proposed the use of glyceryl monooleate phases of cubic and lamellar liquid crystals as buccal drug delivery systems for peptide-structured drugs35. Some researchers have developed liquid crystal systems for the buccal administration of KSL-W, an antimicrobial decapeptide to treat multispecific oral biofilms36. In addition, a new insulin liquid aerosol formulation has been developed. This formulation has been shown to allow metered dose insulin administration in the form of aerosolized droplets for buccal administration. Compared to conventional dosage forms, a significant increase in the level of the active ingredient has been shown in the buccal dosage form. Studies have shown that this oral aerosol formulation is rapidly absorbed from the buccal mucosa and provides the necessary postprandial plasma insulin levels in diabetic patients. This new, painless, oral insulin formulation; rapid absorption, an application technique with high patient compliance and full dosing have been reported to have many advantages37. Another interesting novel buccal formulation used gold nanoparticle technology to form a film soluble in buccal mucosa. Clinical trials have been reached in two approaches to insulin buccal administration: oromucose sprays of the peptide, a permeability enhancing film, and gold nanoparticles embedded in a soluble film38,39.
In another study, soy lecithin and propanediol were used for insulin buccal spray formulation. Soy lecithin has a high affinity for biological membranes, but its solubility is low and the solubility of propandiol and soy lecithin could be increased. Insulin buccal spray was applied to diabetic rabbits and the hypoglycemic effect of the formulation was investigated. When the results were examined, it was shown that there was a significant decrease in blood glucose levels of rabbits treated with insulin buccal spray compared to the control group. To investigate insulin delivery from the buccal mucosa, the distribution of fluorescence probe in the epithelium using confocal laser scanning microscopy and fluorescence probe isothiocyanate-labeled insulin penetration were examined. The results demonstrated that the fluorescent probe isothiocyanate-labeled insulin can pass through the buccal mucosa, and that insulin passes through the epithelium, which includes both intracellular and paracellular pathways40. The world's first approved transbuccal release system for testosterone replacement therapy in men is a mono-convex, tablet-like mucoadhesive buccal system, with a recommended dose of 30 mg at a 12-hour interval. This transbuccal delivery system is presented as an alternative to patches, gels or injectable testosterone formulations21,41. Biodegradable mucoadhesive drug technology has been developed to provide both local and systemic effects of drugs in mucosal tissues, and includes a small disc with biodegradable layers that enable rapid release of the active ingredient over a period of time. This disc adheres to the buccal mucosa and transmits the active ingredient to the mucosa while eroding in the mouth42. Transmucosal administration is also thought to provide significant benefit in the application of new classes of biological drugs, such as nucleic acids, antibodies, and proteins26. A recent study was showed succeded results which wereaimed to design and evaluate zolpidem nanoparticle-impregnated buccal films for the treatment of insomnia with a prolong drug action. Zolpidem-loaded PLGA nanospheres were succeded in vitro and in vivo tests43. In another recent study it was shown that nabumetone, nonsteroidal anti-inflammatory drug, including buccal films were prepared using polymers like HPMC, Eudragit, sodium alginate, and sodium CMC in varying proportions were subjected to in vitro quality control parameters ex-vivo permeation and stability studies and the formulations showed optimum results and good control over dug release along with correlation between in vitro and ex vivo studies44. Somayaji et al. used an ethylcellulose strip as delivery medium for tetracycline and metronidazole to reduce microorganisms in periodontal pockets45. Patients were given supragingival scalingand then divided into 5 groups, depending on thelength of time the medication was in place. Sites weremarked for tetracycline, metronidazole, and placebo. Results showed that tetracycline and metronidazole could both be applied locally to periodontal sites using ethyl cellulose strips and markedly suppress the subgingival bacteria over a periodof several days45. A novel saliva activated bioadhesive drug delivery system was developed by Taware et al,for lidocaine hydrochloride and compared its effect with topical gel preparation in dentistry. Aim of this study, was determining the feasibility of the system as a viable alternative to infiltration anesthesia in dentistry. It was found that drug delivery system adhered to gingival within a minute and produced peak effect in 15 minutes and produced greater depth of anesthesia than the marketed topical gel46.
Although there are many formulation studies have been reported in the literature, particularly to improve retention and absorption in the buccal and sublingual regions, very few of them have translated to the clinical phase. This is because it needs to be a clear benefit of efficacy and/or safety with any new drug formulation compared to clinically available dosage forms47. In addition, comprehensive evaluations of the pharmacokinetics, stability, efficacy, and safety of the formulations are required in appropriate animal models as well as in clinical studies, based on regulatory standards and protocols48.
Gilhotra et al. has overviewed mucoadhesive buccal drug delivery systems in terms of a clinical perspective and studies have shown that buccal drug delivery will be increase for the treatment of cardiovascular diseases, migraine, epilepsy and antimicrobial, anti-inflammatory, hypoglycaemia, muscle relaxation, emesis concomitant chemotherapy, smoking deterrent therapies and also for protein and hormone delivery49. An ongoing clinical study of a buccal film has begun on April 13 2019 for the treatment of epilepsy as diazepam containing buccal film
Nanoparticulate systems have been incorporated into various dosage forms for buccal drug delivery, including gels, sprays, tablets, films and patches.
These nanoparticulate formulations have been shown to:
These factors all aim to promote higher sublingual or buccal bioavailability of drugs for subsequent systemic absorption39,47.
In the development process of buccal delivery systems, research and invention has been fairly active in this area, especially during the last. The ongoing research and development is expected to yield at least a few successes in the form of products approved for marketing in a short time. Especially the products contain peptides and protein based active substance seems to be a high potential to be in the drug market. Initial development successes by established companies with the collaboration of universities, may encourage researchers by new entrants into the field and stimulate more vigorous development. Further successes are likely to lead to some opportunistic entrants into buccal dosage forms development.
CONCLUSION
The buccal mucosa provides many advantages for local and systemic drug administration. Buccal drug administration is an important field of research as it allows for systemic administration of drugs with low oral bioavailability. It is also a suitable alternative in the delivery of peptides and protein-structured drugs. Pediatric population still great need of developing flexible and appropriate drug dosage forms, it is expected to develop new and more buccal dosage forms especially designed for pediatric applications that can improve transepithelial drug permeability and improve existing therapies and allow new forms of treatment.
REFERENCES