INTRODUCTION:

One of the most valuable methods of administration for systemic and local drugs actions is ‘Buccal administration’ of drugs¹. The natural or synthetic polymer adhesion tissues are titled as bio-adhesion and are integrated among mucus membrane and polymer labelled as mucoadhesion. Goblet cells are present in mucus membrane comprised of glycoprotein mucin for secretion of mucus. Buccal mucosa exhibits a rationally flat and steady surface for the settlement of Mucoadhesive dosage form².

The extent of drug that can be integrated is restricted by the size inadequacy of the buccal dosage form³. The appropriate dose for buccal dosage forms suggested for daily necessity is 25mg or less, considered valuable for patients. Drug with small half-life, needing sustained or organized release demonstrating poor aqueous solubility and may be efficaciously distributed through the buccal mucosa⁴.

Losartan potassium (LP), an antagonist of the angiotensin II type 1 receptor, has a potent and extremely selective antihypertensive effect. When used orally as 25mg tablets once or twice daily, the drug dosage ranges from 25 to 100mg per day⁵. After oral administration, it is promptly absorbed from the GI tract, with a 33% oral bioavailability and a 1.5–2.5hour plasma elimination half-life⁶. The administration of LP in a controlled release dosage form with burst release and extended release would be ideal, as these features would enable rapid onset and sustained anti-hypertensive effects by maintaining the drug's plasma concentrations well above the therapeutic concentration⁷.

Response surface methodology (RSM) is one of the methods that is commonly used in the development and enhancement of drug delivery systems⁷. It is founded on the principles of design of experiments and employs a range of experimental designs, generates polynomial mathematical equations, and maps the response over the experimental domain to select the optimal formulation or formulations⁸. The technology is substantially more cost-effective and efficient than the conventional methods of preparing dosage forms because it requires less time and experimentation. Central composite design, three-level factorial design, and Box-Behnken design are some of the different RSM designs that are available for statistical formulation optimization⁹.

Buccal distribution of medications is an alternative for the traditional oral route of drug administration in order to overcome shortcomings such as high first pass metabolism and drug degradation in the harsh gastrointestinal environment¹⁰. Buccal medications produce the most beneficial effects because the mouth mucosa receives a enough supply of blood. Drug transmission in saliva is caused by concentration gradients. Flexible and having strong bioadhesive qualities are essential for an effective buccal medication delivery system. The medication is released in a predictable and controlled manner in order to have the necessary therapeutic effect. The type of polymer used to prepare buccal patches affects how well mucoadhesive preparation works¹¹. Buccal patches have the advantages of easy exclusion, low enzymatic activity, straightforward application, and the capacity to include permeability enhancers, enzyme inhibitors or pH changer.

Food ingestion, loss of dissolved or suspended medication, saliva ingestion, and a risk of choking from accidentally ingesting buccal dosage forms are all issues that might arise with buccal drug delivery. The disadvantages of buccal dose forms include a smaller surface area and limited buccal membrane penetrability.

FIG 1: Buccal patch

The goal of the current work was to create and refine a mucoadhesive, bilayered LP buccal patch. The patch's bilayered design was chosen to achieve the medication's unidirectional release. Ethyl cellulose (EC) was utilized as a backing layer polymer due to its characteristics, which included moderate flexibility, low water permeability, drug impermeability, and hydrophobicity. Three level factorial design, a computer-aided optimization technique, was utilized. The amount of release retardant polymers, hydroxypropyl methylcellulose (HPMC) K4M (X1) and HPMC K100M (X2), was the independent variable for this investigation. The swelling index (Y3), cumulative percentage medication release after eight hours (Y2), and burst release in thirty minutes (Y1) were the dependent variables under investigation¹².

BUCCAL DRUG ABSORPTION AND DELIVERY SYSTEMS:

The mucosal membranes of the mouth serve as a permeable barrier against diseases and germs. It does, however, permit the flow of gasses, water, nutrients, and tiny molecules. Drugs must permeate through a variety of layers in the oral mucosa during the drug absorption process, including hydrophilic mucus, basement membrane, keratinized layers, if relevant, and layers of densely packed epithelial cells. The drug's absorption may be hampered by any of these layers. The primary medication delivery methods¹³.

BUCCAL MUCOADHESIVE PATCH:

The most popular kind of oral drug delivery systems are buccal patches, which are typically made by pouring a solution containing a polymer, medication, and any necessary excipients onto a surface. Many factors, which have been reviewed in some literature, may influence mucoadhesion in buccal patches¹⁴. These factors include hydrophilicity, molecular weight, cross-linking, swelling, spatial conformation, pH, concentration of the active polymer, drug concentration, initial force of application, and rate of mucus turnover¹⁵.

ORAL MUCOSA:

The squamous epithelium of the oral mucosa is stratified, making up its outermost layer. A lamina propria and a basement membrane can be found underneath the squamous epithelium. The submucosa is the oral mucosa's innermost layer. The epithelium resembles the rest of the body's stratified squamous epithelia¹⁶. Approximately 40–50 cell layers make up the buccal mucosa epithelium, whereas the sublingual epithelium has fewer cell layers. The thickness varies depending on the location. The gingival, floor of the mouth, ventral tongue, and hard and soft palates all have mucosal thicknesses of 100–200μm, whereas the buccal mucosa measures 500–800μm¹⁷.

ENVIRONMENT OF BUCCAL MUCOSA:

Role of Saliva:

1. Saliva offers a moisturizing quality for buccal dosage forms.

2. It contains a protective fluid for all of the oral cavity's muscles.

3. Another characteristic of saliva is continuous mineralization.

Role of Mucus:

Human mucus is made up of protein and carbs. They provide a lubricating effect and are in charge of the dosage forms' adherence to the buccal mucosa.

Permeability of Drugs through Buccal Mucosa:

The following are some pathways via which drugs could enter the oral mucosa:

(i) Trans-cellular

(ii) Para-cellular

Buccal adhesive polymers:

Materials used to adhere items are called adhesives, hydrogen bond-forming groups, elasticity for inter-permeation with mucus and epithelial muscle, and visco-elasticity are only a few of the many physiochemical characteristics of bioadhesive polymers¹⁸.

Perfect Polymer Features For Bucco- adhesive Drug Delivery System:

1. It is simple to include into many dosage forms.

2. It should be unaffected by various circumstances, such as diet and pH changes.

3. It ought to be inert and in tune with the surroundings.

4. It should have some site specificity and stick readily to the surface of moist tissue.

5. The polymer and the byproducts of its breakdown ought to be non-toxic and able to be absorbed from the mucosal layer.

6. Neither during storage nor the dosage form's shelf life may the polymer degrade.

7. The polymer must to be reasonably priced and easily obtainable in the market¹⁹.

Table 1: Categories of mucoadhesive polymers used in buccal patches:

Natural polymers	Synthetic polymers
Tragacanth	Cellulose derivatives(MC,EC,HEC etc)
Sodium alginate	Poly (Acrylic acid) polymers (Carbomers, Polycarbophil).
Guar Gum	Poly hydroxyl ethyl methylacrylate
Xanthan gum	Polyethylene oxide
Soluble starch	Polyvinylpyrrolidone
Gelatin	Polyvinyl alcohol
Chitosan	--

Polymer Selection Criteria for Buccal Patches:

(1) It must be compatible with the mucosal membrane of the mouth.

(2) The polymer should have a larger molecular weight because they have a restricted transport via tissues²⁰.

Benefits of Buccal Drug Delivery System:

1. Drugs delivered through the buccal mucosa offer a wide range of advantageous effects.

2. The oral cavity receives an increased blood supply by buccal administration.

3. Drugs directly absorbed from the oral mucosa prevent the first pass effect.

4. Using buccal dose forms is simpler than using other dosage forms. If harmful consequences develop, they can be stopped.

5. The negative effects diminished, and patient compliance increased.

6. The buccal mucosa provides an easy way to distribute peptide molecules that are not appropriate for oral delivery. Drug delivery can be continued thanks to the buccal delivery system's ability to endure environmental conditions²¹.

Drawbacks:

The following are the drawbacks of the buccal medication delivery system:

(1) The medicine is diluted by the continuous evacuation of saliva.

(2) It is difficult to administer medications by buccal route when the dosage is high.

(3) Constantly swallowing saliva can result in the accidental removal of the dosage form and possible medication loss.

(4) A smaller portion of the mouth cavity is accessible for the absorption of drugs.

(5) Inappropriate drugs are those that irritate the mucosa or taste harsh.

(6) Mucosal barrier characteristics.

(7) It is not possible to deliver medications that are unstable at buccal Ph^22.

MANUFACTURING METHODS OF BUCCAL PATCHES:

Mucoadhesive buccal patches and films are produced using the hot melt extrusion, solvent casting, direct milling, semisolid casting, and rolling processes.

1. Solvent casting: Mucoadhesive polymers in the necessary amount are treated with solvent in the solvent casting method, and the polymers expand after being vortexed. The determined amount of plasticizer was added to the polymer mixture and vortexed once more. The required amount of medication is liquefied in a small volume solvent system, added to the polymer solution, and well mixed. Entrapped air is then released, and the mixture is then put into a dried petri dish. The created patches are kept in a desiccator till the assessment tests are carried out²³.

2. Direct milling: Solvents are not used in the fabrication of patches during this technique. For motorized mixing of medicine and excipients without the presence of any liquid solution, direct milling or kneading procedures are used. The resultant material is rolled to get the required thickness. After that, the backing material is laminated. Because there is no chance of residual solvents or health problems brought on by solvents, the solvent-free technique is preferred²⁴.

3. Hot melt extrusion: A blend of medicinal components is melted and given various shapes by pushing the mixture through an aperture in the hot melt extrusion process. Oral disintegrating films, pellets, granules, and controlled release matrix tablets have all been produced via hot melt extrusion. Drug-extruding immiscible components are used to create solid dispersions after they are prepared. Ultimately, dies are used to form the solid dispersions into films²⁵.

4. Semisolid casting:An initial solution of a water-soluble film-forming polymer is arranged in the semisolid casting method. The final solution is mixed with an acid-insoluble polymer solution made with sodium or ammonium hydroxide. The right amount of plasticizer is then added, resulting in the formation of a gel mass. Finally, using heat-controlled drums, the gel mass is molded into films or ribbons²⁶.

5. Rolling method: A drug-containing solution or suspension is rolled onto a carrier using this technique. The primary solvents are alcohol and water mixtures. After being dried on rollers, the film is sliced into the required dimensions²⁷.

Types of Buccal Patches:

1. In matrix type: The medication is regularly mixed with a hydrophilic or lipophilic polymer matrix to create matrix type buccal patches. By molding medicated polymer, a therapeutic disc with a specific surface area is created.

2. Reservoir type: The reservoir system consists of a cavity that is separate from the adhesive and holds the medicine and additives. The addition of a water-resistant backing prevents medication loss²⁸.

The Buccal patches Composition:

1. Active Pharmaceutical Ingredient (API): A wide range of active pharmaceutical ingredients are delivered using the buccal patches delivery technique. However, there is a size restriction on the amount of active component that may be added to buccal patches, making it difficult to include large-sized medications.

2. Polymers (adhesive layer): Polymer swelling and hydration properties may be the key factors. The polymers that are utilized are carbopol, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxyethyl cellulose, and hydroxypropyl cellulose.

3. Diluents: Lactose, microcrystalline starch, and starch are the diluents utilized in buccal patches.

4. Sweetening agents: Mannitol, aspartame, and sucrose are utilized as sweeteners.

5. Flavoring agents: Menthol, vanillin, clove oil, peppermint oil, cinnamon oil, spearmint oil, vanilla, cocoa, coffee, and chocolate are among the flavoring agents utilized in formulations.

6. Backing layer: Polyvinyl alcohol and ethyl cellulose are employed as the backing layer in patches.

7. Penetration enhancer: Materials including cyanoacrylate, EDTA, citric acid, PEG-100, 400, and propylene glycol are employed as penetration enhancers^29.

PERMEATION ENHANCERS:

These are compounds that are added to pharmaceutical formulations to increase the bioavailability of medications that typically have poor membrane penetration qualities without compromising the integrity of the membrane or producing toxicity. Enhancer efficacy is influenced by the drug's physiochemical characteristics, the route of administration, and the kind of vehicle³⁰.

Mechanism of Penetration Enhancers:

The mechanisms of penetration enhancers are as follows:

· Modifying mucus rheology: Saliva solves the issue caused by permeation enhancers reducing the mucus's viscosity. Increasing the lipid bilayer membrane's fluidity: Lipid or protein components interacting with the lipid packing, which typically prevents penetration, eventually causes the fluidity of the membrane to rise.

· Components of a tight junction: Penetration enhancers working on junctions improve drug absorption.

· By breaking through the enzymatic barrier Incidentally, changes in membrane fluidity caused differences in enzymatic activity. They work by blocking different peptidases, which breaks down the enzymatic barrier.

· By improving the way that medications work thermodynamically: The partition coefficient is altered by the drug's increased solubility. The increased thermodynamic activity led to better absorption after that. Drug permeability is increased by chelators that interfere with calcium ions and fatty acids by increasing the aggregate fluidity of phospholipids and surfactants³¹.

EVALUATION PARAMETERS OF BUCCAL PATCH:

1. Surface pH: Buccal patches were put to the surface of the previously prepared agar media plates for one hour, and the pH of the swelled patch was measured using pH paper³².

2. Thickness measurements: Measurement is done with a screw gauge whose thickness has a minimum count of 0.01. Five distinct locations were used to assess thickness, and an average value was found³³.

3. Swelling study: The buccal patch is weighed, then it is incubated at 37±1ºC in a 1.5% agar gel plate. The patch is taken out of the petri dish and any extra surface water is gently dried with the filter paper after one to three hours of time intervals. The swelling index is then estimated after reweighing the swollen patch.

4. Folding endurance: The folding endurance test is conducted by doubling the number of times a patch can be folded until it breaks. This process contributes to the folding endurance score³⁴.

5. Thermal analysis study: The process of differential scanning calorimeter is used to perform thermal analysis.

6. Buccal patches morphological characterization: Using a scanning electron microscope, one can examine the morphological features of patches³⁵.

7. Water absorption study: On the surface of agar plates, patches are allowed to swell. The pH is adjusted with phosphoric acid to pH 6.7. Samples are kept in an incubator maintained at 37°C±0.5°C. After the allotted time intervals, samples are weighed (wet weight) and desiccated for 7 days at room temperature. Following drying, final constant weights are noted. The following equation is used to calculate the water uptake (%):

Water uptake (%) = (Ww – Wi)/Wf x 100.

In this case, Ww is the wet weight and Wf is the final weight³⁶.

8. In-vitro drug release studies: Paddle device is used for in-vitro patch release. The dissolution medium, phosphate buffer pH 6.8, is kept at 37°C±0.5°C, using a rotating paddle at 50rpm. The adhesive substance applied to the backing layer of the patch. The disintegration vessel's bottom receives the disk. Fresh medium was swapped with the previously collected sample after predefined time intervals. The samples were diluted appropriately before being examined for drug content.

9. Permeation evaluation of buccal patch: The hydrodynamics in the receptor compartment are maintained by mixing with a magnetic bead at 50 rpm, and the receptor compartment is filled with phosphate buffer pH 6.8 for the permeation investigation. At predefined intervals, samples are taken out and their drug content is assessed³⁷.

10. Ex-vivo bioadhesion method: A section of gingival mucosa was knotted using an open mouth glass vial after being degraded with phosphate buffer (pH 6.8)³⁸. This glass vial fits snugly into a beaker that has phosphate buffer inside of it. The apparatus's temperature was kept at 37±1ºC when it was in contact with the mucosal surface³⁹. The cyanoacrylate adhesive that is used to balance and set patches is properly calibrated to have a five-gram weight. The patch covering the mucosa was removed before fastening the weight was loaded into the pan on the left. The patch's contact time is five minutes. Water is progressively added to the right-side pan at a rate of one hundred drops per minute until the patch is removed from the mucosal surface. The mucoadhesive strength measured in grams was the amount needed to remove the patch from the mucosal surface.

11. In-vivo techniques for buccal patches:

· Utilizing radioisotopes is one of the methods used to determine buccal patches in vivo.

· Use of gamma scintigraphy, second.

· Pharmacoscintigraphy Utilization

· The application of electron paramagnetic resonance oximetry (EPR).

· Studies using X-rays.

· The isolated loop method⁴⁰.

CONCLUSION:

It was determined that buccal patches are superior to traditional medication delivery systems in several ways. The mucosa avoids first-pass metabolism and has good vascular and lymphatic drainage. Research on buccal drug administration is encouraging in terms of systemic delivery of ineffective oral medications. Patients can safely use buccal drug delivery because the medication is withdrawn if any side effects arise. Therefore, it is expected that buccal patches will continue to be an essential dosage form in the pharmaceutical and healthcare industries in the years to come.

REFERENCES:

1. S. Pushpakom, F. Iorio, P.A. Eyers, K.J. Escott, S. Hopper, A. Wells, et al. Drug repurposing: progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019; 18(1): 41–58.

2. S. Jacob, A.B. Nair, S.H.S. Boddu, B. Gorain, N. Sreeharsha, J. Shah, An updated overview of the emerging role of patch and film-based buccal delivery systems. Pharmaceutics. 2021; 13(8): 1206.

3. M.S. Alqahtani, M. Kazi, M.A. Alsenaidy, M.Z. Ahmad, Advances in oral drug delivery. Front. Pharmacol. 2021; 12.

4. I. Speer, M. Preis, J. Breitkreutz, Dissolution testing of oral film preparations: experimental comparison of compendial and non-compendial methods, Int. J. Pharm. 2019; 561: 124–134.

5. J. Ali, J. Bong Lee, S. Gittings, A. Iachelini, J. Bennett, A. Cram, et al. Development and optimisation of simulated salivary fluid for biorelevant oral cavity dissolution, Eur. J. Pharm. Biopharm. 2021; 160: 125–133.

6. V.F. Patel, F. Liu, M.B. Brown. Advances in oral transmucosal drug delivery. J. Control. Release. 2011; 153(2): 106–116.

7. L. Shipp et al. Journal of Controlled Release. 2022; 352: 1071–1092.

8. D. Abouhussein, M.A. el Nabarawi, S.H. Shalaby, A.A. El-Bary, Cetylpyridinium chloride chitosan blended mucoadhesive buccal films for treatment of pediatric oral diseases, J. Drug Deliv. Sci. Technol. 2020; 57; 101676.

9. J.G. Meher, M. Tarai, N.P. Yadav, A. Patnaik, P. Mishra, K.S. Yadav. Development and characterization of cellulose–polymethacrylate mucoadhesive film for buccal delivery of carvedilol. Carbohydr. Polym. 2013; 96(1): 172–180.

10. S. Khan, J.S. Boateng, J. Mitchell, V. Trivedi, Formulation, characterisation and stabilisation of buccal films for paediatric drug delivery of omeprazole, AAPS PharmSciTech. 2015; 16(4): 800–810.

11. F. Laffleur, J. Krouska, J. Tkacz, M. Pekar, F. Aghai, K. Netsomboon. Buccal adhesive films with moisturizer- the next level for dry mouth syndrome? Int. J. Pharm. 2018; 550(1–2): 309–315.

12. Harris D, Robinson JR. Drug delivery via the mucous membranes of the oral cavity. Journal of Pharmaceutical Sciences. 1992; 81: 1-10.

13. Gupta J, Md. Mohiuddin and Md. Shah F. A comprehensive review on Buccal Drug Delivery System. International Journal of Pharmaceutical Research and Development. 2012; 3(11): 59- 57.

14. Mamatha Y, Prasanth VV and Kumar S A. Buccal drug delivery a technical approach. Journal of Drug Delivery and Therapeutics. 2012; 2(2): 26-33.

15. Reddy C, Chatanya KSC and Madhusudan RY. A review on bioadhesive drug delivery system: current status of formulation and evaluation method. DARU Journal of Pharmaceutical Sciences. 2011; 19(6): 385-403.

16. Mujorruya R, Dhamande K, Wankhede UR, A review on study of buccal drug delivery system: Innovative System Design and Engineering. online 2(3).

17. Gandhi PA, Patel M.R. and Patel K.R. A review article on mucoadhesive buccal drug delivery system. International Journal of Pharmaceutical Research and Development. 2011; 3(5): 159-173.

18. Roychowdhary S, Gupta R and Saha S. A Review on Buccal Mucoadhesive Drug Delivery System. Indo-Global Journal of Pharmaceutical Sciences. 2011; 1(3): 223-233.

19. Tangri P. Recent advances in oral mucoadhesive drug delivery system: A review. International Journal of Pharmaceutical Research and Development. 2011; 3(2): 151- 161.

20. Murali krishna K, Nagaraju T, Gowthami R, Rajashekar M and Yamsani SK. Comprehensive Review on Buccal Delivery, International Journal of Pharmacy. 2012; 2(1): 205-217.

21. Gandhi SD, Pandya PR and Umbarkar R. Mucoadhesive drug delivery system-an unusual maneuver for site specific drug delivery system. IJPSR. 2011; 2(3): 132-152.

22. Tangri P, Khurana S and Mandav S. Mucoadhesive drug delivery: Mechanism and methods of evaluation. International Journal of Pharmaceutical and Biomedical Sciences. 2011; 2(1): 458-467.

23. Khairnar GA, Sayyad FG. Development of Buccal Drug Delivery System Based on Mucoadhesive Polymers. Int J PharmTech Res. 2010; 2(1): 719-735.

24. Patel KV, Patel ND and Dodiya HD. Buccal bioadhesive drug delivery system: A review. International Journal of Pharmaceutical and Biological Archives. 2011; 2(2): 600-609.

25. Khanna R, Agarwal SP, Ahuja A. Mucoadhesive Buccal Drug Delivery: A Potential Alternative to Conventional Therapy, International Journal of Pharmaceutical Sciences. 1998; 60(1): 1-11.

26. Senel S, Hincal A. Drug permeation enhancement via buccal route: possibilities and limitations. Journal of Controlled Release. 2001; 72: 133-144.

27. Squier CA and Wertz PW. Structure and function of the oral mucosa and implications for drug delivery, in eds. Rathbone MJ, Oral Mucosal Drug Delivery. Marcel Dekker, Inc., New York, 1996: 1-26.

28. Wani MS, SR Parakh and MH Dehghan. Current status in buccal drug delivery system. http://www.pharmanfo.net. 2007; 5(2).

29. Bhalodia R, Basu B and Garala K. Buccoadhesive drug delivery system: A review. International Journal of Pharmaceutical and Biological Sciences. 2010; 2(2): 1-32.

30. Kumria R, Goomber G. Emerging trends in insulin delivery: Buccal route. Journal of Diabetology. 2011; 2(1): 4.

31. Venkatalakshmi R and Sudhakar Y. Buccal Drug Delivery Using Adhesive Polymeric Patches. IJPSR. 2012; 3(1): 35-41

32. Galey WR, Lonsdale HK and Nacht S. The in vitro permeability of skin and buccal mucosa to selected drugs and tritiated water. Journal of Investigative Dermatology. 1976; 67: 713-717.

33. Gandhi RB and Robinson JR. Oral cavity as a site for bioadhesive drug delivery. Advanced Drug Delivery Reviews. 1994; 13: 43-74.

34. Tayal S, Jain N. Buccal Control Drug Delivery System: A Review. International Journal of Pharmaceutical Sciences and Research, 2011; 2(1): 27-38.

35. Bruschi ML, Osvaldo F. Oral bioadhesive drug delivery systems, Drug Development and Industrial Pharmacy. 2005; 31(3): 293-310.

36. Bhaskara J, Gary C. Recent advances in mucoadhesive drug delivery systems. Business Briefing, Pharmtech. 2004: 194- 196.

37. Mujoriya R, Dhamande K, Wankhede UR and Angure S, A. Review on study of Buccal Drug Delivery System. Innovative Systems Design and Enginnering. 2011; 2(3): 24-35.

38. Shojaei AH. Buccal Mucosa as a Route for Systemic Drug Delivery: A Review, Journal of Pharmacy and Pharmaceutical Sciences. 1998; 1(1): 15-30.

39. Pramodkumar TM, et al. Oral transmucosal drug delivery systems. Indian Drug. 2004; 41(2): 63-1.

40. Edsman K, et al. Pharmaceutical applications of mucoadhesion for the non-oral routes. Journal of Pharmacy and Pharmacology. 2005; 57: 3-19.

41. Steward A, et al, The Effect of Enhancers on the Buccal Absorption of Hybrid (BDBB) Alpha Interferon. International Journal of Pharmacy. 1994; 145–149.

Received on 24.01.2024 Modified on 26.02.2024

Asian J. Pharm. Tech. 2024; 14(2):157-162.

DOI: 10.52711/2231-5713.2024.00028