Buccal Drug Delivery System

Formulation and evaluation of buccal drug delivery system.

1. Methods of Formulation and Evaluations of Buccal Drug Delivery Systems By- Mohammad Asim 20/MPH/DIPSAR/2019 Department of Pharmaceutics DIPSAR

2. Structure and Design of Buccal Dosage Form Buccal Dosage form can be of 1. Matrix type : The buccal patch designed in a matrix configuration contains drug, adhesive, and additives mixed together. 2. Reservoir type: The buccal patch designed in a reservoir system contains a cavity for the drug and additives separate from the adhesive. An impermeable backing is applied to control the direction of drug delivery; to reduce patch deformation and disintegration while in the mouth; and to prevent drug loss.

3. FORMULATION DESIGN- 1. Pharmaceutical considerations: Great care needs to be exercised while developing a safe and effective buccal adhesive drug delivery device. Factors influencing drug release and penetration through buccal mucosa are organoleptic factors and effects of additives used to improve drug release pattern and absorption, the effects of local drug irritation caused at the site of application are to be considered while designing a formulation 2. Physiological considerations- Physiological considerations such as texture of buccal mucosa, thickness of the mucus layer, its turn over time, effect of saliva and other environmental factors are to be considered in designing the dosage forms Eg. Saliva contains moderate levels of esterase's, carbohydrates, and phosphatase that may degrade certain drugs. Although saliva secretion facilitates the dissolution of drug, involuntary swallowing of saliva also affects its bioavailability

4. 3. Pharmacological considerations- Drug absorption depends on the partition coefficient of the drugs. Generally lipophilic drugs absorb through the transcellular route, where as hydrophilic drugs absorb through the paracellular route. Chemical modification may increase drug penetration through buccal mucosa. Residence time and local concentration of the drug in the mucosa, the amount of drug transported across the mucosa into the blood are the responsible factors for local or systemic drug delivery. Optimization by a suitable formulation design fastens drug release from the dosage form and taken up by the oral mucosa.

5. BASIC COMPONENTS The basic components of buccal drug delivery system are 1. Drug substance 2. Bio adhesive polymers 3. Backing membrane 4. Permeation enhancers 1. DRUG SUBSTANCE: Before formulating mucoadhesive drug delivery systems, one has to decide whether the intended action is for rapid release/prolonged release and for local/systemic effect. The selection of suitable drug for the design of buccoadhesive drug delivery systems should be based on pharmacokinetic properties. The drug should have following characteristics :- The conventional single dose of the drug should be small. The drugs having biological half-life between 2-8 hrs are good candidates for controlled drug delivery. MW should be less than 1000dalton. It should be having both nature i.e. hydro- lipophilic type. Should be potent . Non-irritant to mucosa . Drugs that degrades in GIT.

6. 2. BIOADHESIVE POLYMER: The first step in the development of buccoadhesive dosage forms is the selection and Characterization of appropriate bio adhesive polymers in the formulation. Bio adhesive polymers play a major role in buccoadhesive drug delivery systems of drugs. Polymers are also used in matrix devices in which the drug is embedded in the polymer matrix, which control the duration of release of drugs . The drug is released into the mucous membrane by means of rate controlling layer or core layer. Bio adhesive polymers which adhere to the mucin/ epithelial surface are effective and lead to significant improvement in the oral drug delivery An ideal polymer for buccoadhesive drug delivery systems should have following Characteristic s :- It should be inert and compatible with the environment The polymer and its degradation products should be non-toxic, absorbable from the mucous layer. It should adhere quickly to moist tissue surface and should possess some site specificity. The polymer must not decompose on storage or during the shelf life of the dosage form. The polymer should be easily available in the market and economical. It should allow easy incorporation of drug in to the formulation.

7. Criteria followed in polymer selection It should form a strong non covalent bond with the mucine/epithelial surface It must have high molecular weight and narrow distribution. It should be compatible with the biological membrane. Mucoadhesive Polymers used in the Oral Cavity Criteria Categories Examples Source Semi natural/ Natural Agarose, chitosan, gelatin, Hyaluronic acid, Various gums (guar gum, xanthan, gellan, carragenan, pectin and sodium alginate) Synthetic Cellulose derivatives: [CMC, thiolated CMC, NaCMC, HEC, HPC, HPMC,MC.] Poly(acrylic acid)-based polymers: [CP, PC, PAA, polyacrylates, poly(methyl vinyl ether-co methacrylic acid), poly(2- hydroxy ethyl methacrylate),poly(acrylic acid co-ethyl hexyl acrylate), poly(methacrylate), poly( isobutylcyanoacrylate), copolymer of acrylic acid and PEG Others: polyoxyethylene, PVA, PVP, thiolated Polymers

8. Criteria Categories Examples Aqueous solubility Water soluble CP, HEC, HPC, HPMC (cold water), PAA, NaCMC, sodium alginate Water insoluble Chitosan (soluble in dilute aqueous acids), EC, PC Charge Cationic Amino dextran, Chitosan, (DEAE)- dextran, TMC Anionic Chitosan-EDTA, CP, CMC, pectin, PAA, PC, sodium alginate, NaCMC, xanthan gum Non-ionic Hydroxy ethyl starch, HPC, poly(ethylene oxide), PVA, Potential Covalent PVP, scleroglucan Hydrogen bond Cyanoacrylate

9. 3. BACKING MEMBRANE: Backing membrane plays a major role in the attachment of bioadhesive devices to the mucus membrane. The materials used as backing membrane should be inert, and impermeable to the drug and penetration enhancer. Such impermeable membrane on buccal bioadhesive patches prevents the drug loss and offers better patient compliance. The commonly used materials in backing membrane include carbopol, magnesium stearate, HPMC, HPC, CMC, polycarbophil etc. 4. PERMEATION ENHANCERS: Substances that facilitate the permeation through buccal mucosa are referred as permeation enhancers. Selection of enhancer and its efficacy depends on the physicochemical properties of the drug, site of administration, nature of the vehicle and other Excipients. Mechanisms of action of permeation :- 1) Changing mucus rheology By reducing the viscosity of the mucus and saliva overcomes this barrier. 2) Increasing the fluidity of lipid bilayer membrane Disturb the intracellular lipid packing by interaction with either lipid packing by interaction with either lipid or protein components. 3) Acting on the components at tight junctions: By inhibiting the various peptidases and proteases present within buccal mucosa, thereby overcoming the enzymatic barrier. In addition, changes in membrane fluidity also alter the enzymatic activity indirectly. 4) Increasing the thermodynamic activity of drugs: Some enhancers increase the solubility of drug there by alters the partition coefficient.

10. EXAMPLES OF PERMEATION ENHANCERS WITH MECHANISM Category Examples Mechanism(s) Surfactants and Bile Salts Surfactants and Bile Salts Sodium dodecyl sulphate Sodium lauryl sulphate Polysorbate 80 Acting on the components at tight junctions ,Increasing the fluidity of lipid bilayer membrane Fatty Acids Oleic acid, Cod liver oil, Capric acid, Lauric acid Increasing the fluidity of lipid bilayer membrane Polymers and Polymer Derivatives Chitosan Trimethyl chitosan Chitosan-4- thiobutylamide Increasing the fluidity of lipid bilayer membrane; Increased retention of drug at mucosal surface Others Ethanol, Azone, Octisalate, Padimate, Menthol Acting on the components at tight junctions; Increasing the fluidity of lipid bilayer membrane

11. FORMULATIONS: Buccal adhesive dosage forms are broadly classified in following dosage forms: Solid buccal adhesive dosage forms - Tablets , Patches/films , Wafers ,Lozenges , Powders Semi-solid buccal adhesive dosage forms - Gels , Ointments Liquid buccal adhesive dosage forms - Sprays Solid buccal adhesive dosage forms 1. Tablets: Buccal tablets are small, flat, and oval, with a diameter of approximately 5–8 mm. Tablets are placed directly onto the mucosal surface tablets adhere to the buccal mucosa in presence of saliva. Tablets are usually prepared by direct compression, but wet granulation techniques can also be used. Designed to release the drug either unidirectionally targeting buccal mucosa or mutidirectionally in to the saliva. However, size is a limitation for tablets due to the requirement for the dosage form to have intimate contact with the mucosal surface.

12. Eg: prochlorperazine maleate buccal tablet glyceryl trinitrate buccal tablet Fentanyl buccal tablet Miconazole buccal tablet

13. 2. Patches and Films Buccal patches consists of two laminates, with an aqueous solution of the adhesive polymer being cast onto an impermeable backing sheet, which is then cut into the required oval shape. A novel mucosal adhesive film called “Zilactin” – consisting of an alcoholic solution of hydroxyl Propyl cellulose and three organic acids. The film which is applied to the oral mucosal can be retained in place for at least 12 hours even when it is challenged with fluids. Composition of buccal patches: A. Active ingredient. B. Polymers (adhesive layer): HEC, HPC, polyvinyl pyrrolidone(PVP), polyvinyl alcohol (PVA), carbopol and other mucoadhesive polymers. C. Diluents: Lactose DC is selected as diluents for its high aqueous solubility, its flavouring characteristics, and its physico-mechanical properties, which make it suitable for direct compression. other example : microcrystalline starch and starch. D. Sweetening agents: Sucralose, aspartame, Mannitol, etc. E. Flavouring agents: Menthol, vanillin, clove oil, etc. F. Backing layer: EC etc. G. Penetration enhancer: Cyano acrylate, etc H. Plasticizers: PEG-100, 400, propylene glycol, etc

14. 3. Buccal wafers: Bromberg et al. described a conceptually novel periodontal drug delivery system that is intended for the treatment of microbial infections associated with peridontitis The delivery system is a composite wafer with surface layers possessing adhesive properties, while the bulk layer consists of antimicrobial agents, biodegradable polymers and matrix polymers. Oral wafer medication systems can vary between 2cm² and 8cm² in area, and 20µm and 500µm in thickness. Eg : Nimodepine 4. Lozenges: Used for the delivery of drugs that act topically within the mouth including antimicrobials, corticosteroids, local anaesthetics, antibiotics and antifungals. A slow release bioadhesive lozenge offers the potential for prolonged drug release with improved patient compliance. Eg: fenatyl lozenges

15. Semi-solid buccal adhesive dosage forms Bioadhesive gels or ointments have less patient acceptability than solid Bioadhesive dosage forms, and most of the dosage forms are used only for localized drug therapy within the oral cavity. One of the original oral mucoadhesive delivery systems –“ orabase ”– consists of finely ground pectin, gelatin and sodium carboxy methyl cellulose dispersed in a poly (ethylene) and a mineral oil gel base, which can be maintained at its site of application for 15- 150 minutes. A high-viscosity "gel ointment" containing Carbopol (12.5%), poly(ethylene glycol) or glycerol and an aqueous solution containing sodium salicylate, sustained drug absorption for 5 hours. Eg: Antifungal Antibiotics such as Ofloxacin, T retinoin Liquid dosage forms Viscous liquids may be used to coat buccal surface either as protectants or as drug vehicles for delivery to the mucosal surface. Polymers were used to enhance the viscosity of products to aid their retention in the oral cavity. These solutions contain sodium CMC as bioadhesive polymer. Eg: sodium alginate suspension

16. Manufacturing methods of buccal patches/ films: Solvent casting Hot melt extrusion Direct milling. 1. Hot melt extrusion of films: In hot melt extrusion ,blend of pharmaceutical ingredients is molten and then forced through an orifice to yield a more homogeneous material in different shapes such as granules, tablets, or films. Hot melt extrusion has been used for the manufacture of controlled release matrix tablets, pellets and granules, as well as oral disintegrating films.

17. 2. Solvent casting: In this method, all patch excipients including the drug co-dispersed in an organic solvent and coated onto a sheet of release liner. After solvent evaporation a thin layer of the protective backing material is laminated onto the sheet of coated release liner to form a laminate that is die-cut to form patches of the desired size and geometry Flow chart of Solvent casting Method Water soluble ingredient is dissolve in water (H2O) and API and other agent are dissolving in suitable solvent so as to form a clear solution Followed by both the solution are mixed Resulting solution in cast as a film is and allowed to dry Film is coated

18. 3. Direct milling: In this, patches are manufactured without the use of solvents. Drug and excipients are mechanically mixed by direct milling or by kneading, usually without the presence of any liquids. After the mixing process, the resultant material is rolled on a release liner until the desired thickness is achieved. The backing material is then laminated as previously described. While there are only minor or even no differences in patch performance between patches fabricated by the two processes, the solvent-free process is preferred because there is no possibility of residual solvents and no associated solvent-related health issues Flow chart of Direct Milling API and excipient are blended by direct milling Blended mixture is rolled with the help of roller Followed material is laminated Finally film is collected

19. Evaluation of buccal dosage forms:

20. 1. Weight variation: Collect 10 tablets from each formulation of varying concentration of natural polymer. Weigh the tablets individually from all the selected formulations; calculate the average weight and comparing the individual tablet weights to the average. 2 . Thickness: Collect 3 tablets/patch from each batch of formulation and the thickness of the tablets were measured with the help of vernier caliper. The average thickness is calculated. 3 . Friability :Friability of the tablets was determined by using Roche friabilator. From each batch, 6 tablets were weighed accurately which was W1 then placed in the friabilator and rotated at 25 rpm for 4 min. After completing the rotation weight of tablets were weighed which is W2. The percentage friability was determined. 4. Hardness: Monsanto hardness tester was used for this purpose. The hardness of five tablets in each batch was measured and the average hardness was calculated 5. In-vitro swelling studies : The swelling rate of buccoadhesive tablets/patches are evaluated using 2% w/v agar gel plate. For each formulation, 3 tablets are weighed and average weight of each 3 tablets are calculated (W1). The tablets are placed with the core facing the gel surface in Petri dishes which are placed in an incubator at 37±0.1°c. The tablets are removed at time intervals of 0.5, 1, 2, 3, 4, 5and 6 hours, excess water on surface is absorbed using filter paper and swollen tablets are weighed. In case of patches, they were left to dry for 7 days in a desiccators over anhydrous calcium chloride at room temperature then the final constant weights are recorded The average weight (W2) is determined and then swelling index is calculated using the formula. % Swelling index = ((W2-W1)/W1) ×100 Were, W 1 = weight of natural mucoadhesive agent before swelling W 2 =weight of natural mucoadhesive agent after swelling

21. 6. In-vitro mucoadhesion studies: Mucoadhesive strength of the buccal tablets was measured on the “Modified Physical Balance method” which is shown in figure. The method used porcinebuccal membrane as the model mucosal membrane. The fresh porcine buccal mucosa was cut into pieces and washed with phosphate buffer pH 6.8. The both pans were balanced by adding an appropriate weight on the left- hand pan. A piece of mucosa was tied to the surface of the beaker and placed below the left pan which was moistened with phosphate buffer pH 6.8. The tablet was stuck to the lower side of left pan with glue. Previously weighed beaker was placed on the right hand pan and water (equivalent to weight) was added slowly to it until the tablet detach from the mucosal surface. The both pans were balanced by adding an appropriate weight on the left- hand pan. The weight required to detach the tablet from the mucosal surface gave the bioadhesive strength. The experiment was performed in triplicate and average value was calculated. Force of adhesion = (mucoadhesive strength/100)×9.81.

22. 7. In-vivo residence time : The in-vivo residence time was examined in human volunteers. The placebo buccal tablets were prepared and given to the human volunteers and advised to administer the tablet in the buccal region. The time required for the tablet to detach from the buccal region is determined as residence time 8. In-vitro release studies : The United pharmacopoeia (USP) type 2 dissolution apparatus was used to study the release of drug from buccal tablets. Tablets were supposed to release the drug from one side only; therefore an impermeable backing membrane was placed on the other side of the tablet. The tablet was further fixed to a 2×2 cm glass slide with a solution of cyanoacrylate adhesive. In vitro drug release studies were carried out in 500 ml of phosphate buffer solution pH 6.6 for 8h using TDT 08L dissolution apparatus at 50 rpm and 37±0.5oc. At predetermined time intervals samples were withdrawn and replaced with fresh medium. The samples were filtered, diluted suitably then analyzed spectrometrically. All dissolutions were performed in triplicate. The in-vitro buccal permeation through the buccal mucosa (sheep and rabbit) is performed using Keshary-Chien /Franz type glass diffusion cell at 37°C± 0.2°C. Fresh buccal mucosa is mounted between the donor and receptor compartments. The buccal patch is placed with the core facing the mucosa and the compartments clamped together. 9. Folding endurance : The folding endurance of patches is determined by repeatedly folding 1 patch at the times without breaking 10. Determination of surface pH of tablets : Buccoadhesive tablets/patch are left to swell for 2hrs on surface of agar plate. The surface pH is measured using pH paper placed on core surface of the swollen tablet/patch

23. 11. Permeation study of buccal patch : The receptor compartment is filled with phosphate buffer pH 6.8, and the hydrodynamics in the receptor compartment is maintained by stirring with a magnetic bead at 50 rpm. Samples are withdrawn at predetermined time intervals and analyzed for drug content 12. Ex-vivo mucoadhesion time : The ex-vivo mucoadhesion time performed after application of the buccal patch on freshly cut buccal mucosa (sheep and rabbit). The fresh buccal mucosa is tied on the glass slide, and a mucoadhesive patch is wetted with 1 drop of phosphate buffer pH 6.8 and pasted to the buccal mucosa by applying a light force with a fingertip for 30 secs. The glass slide is then put in the beaker, which is filled with 200 ml of the phosphate buffer pH 6.8, is kept at 37°C ± 1°C. After 2 minutes, a 50-rpm stirring rate is applied to simulate the buccal cavity environment, and patch adhesion is monitored for 12 hrs. The time for changes in color, shape, collapsing of the patch, and drug content is noted. 12. Measurement of mechanical properties : Mechanical properties of the films (patches) include tensile strength and elongation at break is evaluated using a tensile tester. Film strip with the dimensions of 60 x 10 mm and without any visual defects cut and positioned between two clamps separated by a distance of 3 cm. Clamps designed to secure the patch without crushing it during the test, the lower clamp held stationary and the strips are pulled apart by the upper clamp moving at a rate of 2 mm/sec until the strip break. The force and elongation of the film at the point when the strip break is recorded. The tensile strength and elongation at break values are calculated using the formula. T = m x g/ b x t Kg/mm2 Where, M - is the mass in gm, g - is the acceleration due to gravity 980 cm/sec 2 , B - is the breadth of the specimen in cm, T - is the thickness of specimen in cm Tensile strength (kg/mm2 ) is the force at break (kg) per initial cross- sectional area of the specimen (mm2 ).