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TRANS MUCOSAL (BUCCAL)DRUG DELIVERY SYSTEMS By : Mr.Kailash Vilegave Lecturer in Pharmacy S.S.Jhondle college of pharmacy, Asangaon

Traditional Routes : 

Traditional Routes Enteral Oral First Pass Metabolism Pre-systemic Metabolism Rectal Slow drug absorption Patient compliance issues Parenteral Intravenous Localized pain Not for sustained release Intramuscular Painful Unpredictable release rates

Alternative Routes : 

Alternative Routes Transdermal (TD) Permeability issues Potent drugs Oral Transmucosal (TM) Bioadhesion issues Better permeability

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Advantages of TM Drug Delivery Avoids first-pass effect Avoids chemically hostile GI environment Avoids GI Distress Allows use of drugs with short t1/2s Controls plasma levels of potent drugs Can interrupt drug input quickly if toxicity Reduces multiple dosing Improvement in patient compliance Fast cellular recovery following stress (TM)

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Disadvantages Expensive Multi-layering--uncomfortable to wear (i.e. Oral) Processing methods (for cast films) Generally not applicable for drugs that require high blood levels or large Doses Limited absorption of high MW drugs Relatively low surface area (TM)

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Comparison of Routes of Delivery TM vs. Intravenous route Oral vs. TD and TM Routes Oral CR formulation (0.76 mg); TDD patch (8.0 mg); TMD patch (0.5 mg)

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Therapeutic Applications Angina – Organic and nitrate compounds Acute seizures; asthma & allergy Chronic severe pain Migraine; hypertension Smoking cessation; alcohol abuse Hormonal treatments Diabetes – Emerging indication for TM delivery TM delivery of traditional drugs; proteins, peptides, vaccines

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Basic Facts & Considerations Structure of mucosa Factors affecting TM delivery Permeation Enhancement Devices & Formulations Models for TM absorption testing

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The Mucosa

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Mucosa Characteristics(Oral, Nasal, Rectal, Vaginal, Pulmonary) High cellular turn-over rate Very Robust Avoids First Pass Effect Routinely exposed to exogenous compounds Areas of relatively “immobile” tissue—Bioadhesion Issues (Oral—Buccal or more appropriately “Labial” mucosa)

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Comparison of Routes for Systemic Drug Delivery  = Not Favorable;  = Intermediate;  = Very Favorable

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Drug/Mucosa Considerations Barriers are in the outer layer of the mucosa No Stratum Corneum—However is Lipophilic Transport is Intercellular for both Polar and Non-Polar Penetrants Drugs exposed to Enzymatic Degradation Barrier Areas composed of “Membrane-Coating Granules”—Discharged into Intercellular Space Contain glycoproteins and glycolipids in an amorphous arrangement Keratinized tissue’s MCGs contain glycolipids organized as stacks of lamellar discs

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Regional Variation in the Oral Mucosa Masticatory Mucosa Keratinized epithelium 25% of total surface area of oral cavity Lining mucosa Non-keratinized epithelium 60% of total surface area Specialized mucosa Both keratinized and nonkeratinized 15% of total surface area

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Oral Cavity Schematic Hard palate Gingival Sublingual Soft palate Buccal Tongue Keratinized Layer Epithelium Lamina Propria Basal Lamina Mucus Layer Basal Lamina Epithelium Lamina Propria Mucus Layer Stratum Basale Repka et al. Matrix and Reservoir-Based Transmucosal Systems: Tailoring Delivery Solutions. American Journal of Drug Delivery, 2004.

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Pathways of Drug Penetration (TM) Drugs follow route of least resistance Intercellular: Hydrophilic compounds Transcellular: Lipophilic compounds

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Mechanisms of Drug Transport Intercellular flux, J = DEC Transcellular flux, J = (1-E)DCK h h D=Diffusion Coefficient of the Memb. E=Fraction of Surface Area C=Donor Drug Conc. K=Partition Coefficient h=Path Length

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Factors Affecting Drug Delivery

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Factors Affecting Drug Delivery Physicochemical factors Biological factors Formulation factors

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Physicochemical Factors Partition coefficient Solubility Ionization / pKa Molecular size and weight Stability or Half – life

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Biological Factors Salivation (TM) pH of environment Area Condition of the Mucosa Hydration Metabolism

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Salivation Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996. Substances that reduce salivary secretion would be expected to increase drug concentrations in the oral cavity.

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Formulation Factors Daily dose Adhesion use of bioadhesives Permeability use of enhancers

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Daily Dose Delivery The total amount of drug that could be systematically delivered across the buccal mucosa from 2-cm2 system in one day has been estimated to be 10-20 mg.* *J. R. Robinson, M. A. Longer, and M. Veillard. Bioadhesive polymers for controlled drug delivery. Biological Approaches to the Controlled Delivery of Drugs (R. L. Juliano, ed.). Annals of the New York Academy of Sciences 507: p.307 (1987). *Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996.

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Adhesion and Use of Bioadhesives Hemant H. Alur, S. Indiran Pather, Ashim K. Mitra, Thomas P. Johnston. Transmucosal sustained-delivery of chlorpheniramine maleate in rabbits using a novel, natural mucoadhesive gum as an excipient in buccal tablets. Int. J. Pharm. 188: 1-10 (1999). Bioadhesive used – Hakea  40 mg CPM and 22 mg Hakea  25 mg CPM and 22 mg Hakea  40 mg CPM and 32 mg Hakea

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Penetration Enhancement

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Permeability Barrier: Lipid Nature LIPID SKIN KERATINIZED NONKERATINIZED ORAL EPITHELIUM ORAL EPITHELIUM Ceramides X X Cholesterol X X X Fatty acids X X Phospholipids X X Glycosylceramides X X (high)

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Penetration Enhancement Chemical Methods (TM): Chemical Penetration Enhancers (CPE) Pro-drugs

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Chemical Penetration Enhancers (CPEs) A substance that will increase the permeability of the epithelial barrier by modifying its structure Ideal Penetration Enhancer: Non-toxic, non-irritating, non-allergenic Immediate onset of increased permeability Immediate recovery of normal barrier properties upon removal Physically and Chemically compatible with a wide range of drugs

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“Trans” Absorption Enhancing Mechanism of Action of CPEs Drug Flux can be “Enhanced” by: Disruption of the highly ordered structure of permeability barrier lipids (modifying D) Fluidizing Intercellular Lipids (DMSO, Azone) Interaction with intracellular protein Alter Protein Conformation Improved partitioning of a drug, co-enhancer or solvent into the membrane Modify Drug Solubility Parameters (Ethanol,Lactose) J = D•Kp•Cv/h

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Use of Permeation Enhancers  Buccal delivery of FD4 without GDC.  Buccal delivery of FD4 with 10 mM GDC. A. J. Hoogstraate et al. In-vivo buccal delivery of Fluorescein Isothiocyanate-Dextran 4400 with Glycodeoxycholate as an absorption enhancer in pigs. J. Pharm. Sci. 85: 457-460 (1996).

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TM Delivery System Requirements Local drug delivery to superficial tissues or systemic delivery Systems must make drug available for permeation through the substrate at a specific rate Must adhere to mucosa Must easily be removed & Non-irritating For systemic use, must permeate series of barriers to reach systemic circulation The drug must partition from the vehicle into the epithelial barrier and the drug must diffuse through the epithelial barrier (rate-limiting step)

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Devices & Formulations Passive transdermal systems: Driven by concentration gradient Typical Design: Rectangular or round therapeutic system (TS) or ‘patch’ Core: Drug, polymeric carrier (HPC, Eudragits) and adhesive (Polybutylacrylate, polyisobutylene, karaya gum) Inert backing (transparent or pigmented): Attach the TS to the mucosa. E.g. Polypropylene, polyethylene Inert release liner: Remove prior to use so that drug-containing area and adhesive is exposed to mucosa

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Basic Types of TM Patches Drug-in-Adhesive Systems: Incorporates the active ingredient directly into the adhesive Works best if the drug is highly potent (adhesive performance may deteriorate as conc. of drug ) Matrix Systems: Semi-solid drug containing mixture encapsulated into a self-contained core; adhesive incorporated into the release liner Reservoir Systems: Drug delivery mixture and adhesive separate Easy to design; incorporate much higher volumes of drug and additives Allow semi-solid suspensions and alcoholic solutions

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Models for TM absorption testing In vitro methodology: Access to human membranes Comparative studies using patches, ointments and creams Distribution of drug in various membrane layers Determination of membrane biotransformation Prediction of local tolerance and enhancing techniques Animal Studies: Toxicokinetic studies in small and large animals Assessment of local tolerance Studies in Volunteers: Kinetics of parent compound and metabolites

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Production of TM Systems

Formulation of Compressed Disks : 

Formulation of Compressed Disks Drug (20 mg Omeprazole) + Polymer (200 mg) Ratio: 1: 10 Polymers used: HPC, PVP, HPMC, Carbopol, Na. CMC Formulation with various polymer combinations Drug content fixed – Polymer ratio changed HPC + HPMC – 2:1, 3:1, 4:1 PVP +HPMC – 2:1, 3:1, 4:1


OPTIMIZATION OF PATCHES Optimizing the polymer content –Uniformity and Flexibility of film, Drug release Optimizing the plasticizer content - Flexibility Optimizing the solvent volume – Swelling, air entrapment etc Formulation of patches Polymer: HPMC E 5 cps(3.8 gm, 4.0 gm, 4.2 gm, 4.4 gm, 4.6 gm, 4.8 gm, 5.0 gm)Drug: Diltiazem hydrochloride (1 gm)Solvent mixture: Alcohol + Dichloromethane (50:50)Plasticizer: 20% v/w propylene glycol

Quality control tests AssayWeight variationThickness variation : 

Quality control tests AssayWeight variationThickness variation In vitro Release studies Moisture absorption studies % Moisture absorbed = Final weight – Initial weight __________________________________________________________ Initial weight × 100

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Cast Films vs. HME Films Cast Films Processing Methods Environmental Concerns  Organic Solvents Aqueous Solvents  P-M Stability Reproducibility Time Consuming Process Labor Intensive Multi-step Process HME Films Environmental No organic solvents or water Recycling of material Less labor and equipment demands Shorter and more efficient processing times Favorable cost Potential “Continuous Process” Can Produce “Solid Solutions or Dispersions”

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List of marketed buccal preparations under various stages of development

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Some buccal –adhesive matrix tablet formulations

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Related research on mucoadhesive polymers and delivery systems

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Mucosal penetration enhancers and mechanisms of action

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List of macromolecular drugs delivered through buccal route

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Oral Controlled Drug Delivery System Thank you !!! 50 NKV

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