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Transmucosal drug delivery by Kailash Vilegave

This document discusses trans mucosal drug delivery systems. It begins by comparing traditional drug delivery routes like oral and parenteral and their limitations. It then introduces trans mucosal delivery as an alternative that avoids first pass metabolism and provides controlled release. The document discusses the anatomy and characteristics of different mucosal sites. It also examines factors that influence trans mucosal delivery such as drug properties, biological factors, and formulation techniques. Finally, it reviews various trans mucosal delivery devices, methods for optimizing formulations, and quality control testing.

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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  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  Transdermal (TD)  Permeability issues  Potent drugs  OralTransmucosal (TM)  Bioadhesion issues  Better permeability
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)
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)
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)
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
Basic Facts & Considerations • Structure of mucosa • Factors affecting TM delivery • Permeation Enhancement • Devices & Formulations • Models for TM absorption testing
The Mucosa
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)
Comparison of Routes for Systemic Drug Delivery Issues Nasal Oral Mucosal Vaginal/ Rectal Gastro- Intestinal Dermal Accessibility      First-pass Clearance      Acceptability      Surface Area      Onset of Action      Robustness      Duration      Permeability      Vascular Drainage      Surface Environment       = Not Favorable;  = Intermediate;  = Very Favorable
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
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
Oral Cavity Schematic Hard palate Gingival Sublingual Soft palate Buccal Tongue Keratinized LayerEpithelium 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.
Pathways of Drug Penetration (TM) • Drugs follow route of least resistance – Intercellular: Hydrophilic compounds – Transcellular: Lipophilic compounds
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
Factors Affecting Drug Delivery
Factors Affecting Drug Delivery • Physicochemical factors • Biological factors • Formulation factors
Physicochemical Factors • Partition coefficient • Solubility • Ionization / pKa • Molecular size and weight • Stability or Half – life
Biological Factors • Salivation (TM) • pH of environment • Area • Condition of the Mucosa • Hydration • Metabolism
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.
Formulation Factors • Daily dose • Adhesion – use of bioadhesives • Permeability – use of enhancers
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.
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
Penetration Enhancement
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)
Penetration Enhancement • Chemical Methods (TM): – Chemical Penetration Enhancers (CPE) – Pro-drugs
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
“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
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).
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)
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
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
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
Production of TM Systems
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 Assay Weight variation Thickness variation In vitro Release studies Moisture absorption studies % Moisture absorbed = Final weight – Initial weight __________________________________________________________ Initial weight × 100
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”
ORGANIZATION PRODUCT PRESENT STATUS Generex Biotechnology Corporation Insulin Buccal Spray ORALGEN (US) ORALIN (Canada) Heparin Buccal Delivery System Fentanyl Buccal Delivery Systems In Market Clinical Trials Completed Clinical Trials Completed Columbia Laboratories Inc. Testosterone Buccal Tablet (Straint) Desmopressin Buccal Tablet In Market In Market Ergo Pharm Androdiol Buccal Tablets (Cyclo-Diol SR) Norandrodiol Buccal Tablets (Cyclo- Nordiol SR) In Market In Market Cytokine Pharma Sciences Inc. Pilocarpine Buccal Tablet (PIOLOBUC) In Market Britannia Pharmaceuticals Limited Prochlorperazine Buccal Tablet (Buccastem) In Market Pharmax Limited Glyceryl Trinitrate (Suscard Buccal Tablet) In Market Cephalon, Inc. Oral Transmucosal Fentanyl Citrate Solid Dosage Form (ACTIQ) In Market List of marketed buccal preparations under various stages of development
Wyeth Pharma Ceuticals Lorazepam Buccal Tablets (Temesta Expidet) Oxazepam Buccal Tablets (Seresta Expidet) In Market In Market GW Pharmaceuticals Mucosal Spray and Buccal Tablets (Cannabis-Based Medicines) Under Development NovaDel Pharma Inc. Buccal Aerosol Spray for Clemastine,Nicotine, Testosterone,Estradiol, Progestorone,Fluoxetine, Piroxicam Under Development IVAX Corporation Estrogen Buccal Tablet Under Phase III clinical trials Regency Medical research Vitamins Trans Buccal Spray In Market Leo Pharmaceuticals Nicotine Mucoadhesive Tablet (Nicorette) Nicotine Chewing Gum (Nicotinell) In Market In Market Teijin Ltd. Triamcinolone acetonmide(Aftach) In Market Rhone-Poulenc Rorer Prochlorperazine Bioadhesive Buccal Tablet (Tementil) In Market Ciba-Geigy Methyltestosterone Buccal Tablets (Metandren) In Market
Some buccal –adhesive matrix tablet formulations Formulation components Active ingredient References Hydroxypropyl cellulose, Cetostearyl alcohol and Hydroxyethyl cellulose Several suggested e.g., Morphine Jenkins et al., (1986) Chitosan and Sodium hyaluronate Brilliant blue used as model drug Takayama et al., (1991) Modified maize starch with either Poly(acrylic acid) or poly(ethylene Oxide) Fluoride Bottenberg at al., (1991) Hydroxypropyl cellulose and Carboxyvinyl polymer Triamcinolone acetonide Kubo et al., (1989) Sodium carboxymethylcellulose and Hydroxypropyl methylcellulose Codeine Phosphate Ranga rao et al., (1989) Hydroxypropyl methylcellulose and Poly(acrylic acid) Fluoride Bottenberg et al.¸(1989)
Bioadhesive Polymer(s) Studied Investigation objectives Reference HPC and CP Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination Ishida et al., 1981 HPC and CP Measured Bioadhesive property using mouse peritoneal membrane Satoh et al., 1989 CP, HPC, PVP, CMC Studied inter polymer complexation and its effects on bioadhesive strength Gupta et al., 1994 CP and HPMC Formulation and evaluation of buccoadhesive controlled release delivery systems Anlar et al., 1994 HPC, HEC, PVP, and PVA Tested mucosal adhesion on patches with two-ply laminates with an impermeable backing layer and hydrocolloid polymer layer Anders, R. and Merkle, H., 1989 HPC and CP Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base Ishida et al., 1982 CP, PIP, and PIB Used a two roll milling method to prepare a new bioadhesive patch formulation Guo,J.-H., 1994 Xanthum gum and Locust bean gum Hydrogel formation by combination of natural gums Watanabe et al., 1991 Related research on mucoadhesive polymers and delivery systems
Chitosan, HPC, CMC, Pectin, Xanthum gum, and Polycarbophil Evaluate mucoadhesive properties by routinely measuring the detachment force from pig intestinal mucosa Lehr et al., 1992 Hyaluronic acid benzyl esters, Polycarbophil, and HPMC Evaluate mucoadhesive properties Sanzgiri et al., 1994 Hydroxyethyl cellulose Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis Anders et al., 1983 Polycarbophil Design of a unidirectional buccal patch for oral mucosal delivery of peptide drugs Veillard et al., 1987 Poly(acrylic acid) and Poly(methacrylic acid) Synthesized and evaluated cross-linked polymers differing in charge densities and hydrophobicity Ch’ng et al., 1985 Number of Polymers including HPC, HPMC, CP, CMC. Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion Park, k. and Robinson, J.R., 1984
Poly(acrylic acid-co- acrylamide) Adhesion strength to the gastric mucus layer as a function of crosslinking agent, degree of swelling, and carboxyl group density Park, H. and Robinson, J.R., 1987 Poly(acrylic acid) Effects of PAA molecular weight and crosslinking concentration on swelling and drug release characteristics Garcia- Gonzalez et al., 1993 Poly(acrylic acid-co-methyl methacrylate) Effects of polymer structural features on mucoadhesion Leung, S and Robinson, J.R., 1988 Leung, S and Robinson, J.R., 1990 Poly(acrylic acid-co- butylacrylate) Relationships between structure and adhesion for mucoadhesive polymers Bodde et al., 1990 HEMA copolymerized with Polymeg® (polytetramethylene glycol) Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine Cassidy et al., 1993 Cydot® by 3M (bioadhesive polymeric blend of CP and PIB) Patch system for buccal mucoadhesive drug delivery Benes et al., 1997 DeGrande, et al., 1996 Formulation consisting of PVP, CP, and cetylpyridinium chloride (as stabilizer) Device for oral mucosal delivery of LHRH - device containing a fast release and a slow release layer Nakane et al., 1996
CMC, Carbopol 974P, Carbopol EX-55, Pectin (low viscosity), Chitosan chloride, Mucoadhesive gels for intraoral delivery Nguyen-Xuan et al., 1996 HPMC and Polycarbophil (PC) Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC yielding the highest force of adhesion Taylan et al., 1996 PVP, Poly(acrylic acid) Transmucosal controlled delivery of isosorbide dinitrate Yukimatsu et al., 1994 Nozaki et al., 1997 Poly(acrylic acid-co-poly ethyleneglycol) copolymer of acrylic acid and polyethylene glycol monomethylether monomethacrylate To enhance the mucoadhesive properties of PAA for buccal mucoadhesive drug delivery Shojaei, A. H and Li, X., 1995 Shojaei, A. H and Li, X., 1997 Poly acrylic acid and polyethylene glycol To enhance mucoadhesive properties of PAA by interpolymer complexation through template polymerization Choi et al., 1997 Drum dried waxy maize starch (DDWM), Carbopol 974P, and sodium stearylfumarate Bioadhesive erodible buccal tablet for progesterone delivery Voorspoels et al., 1997 Natural oligosaccharide gum, hakea Evaluation of mucoadhesive buccal tablets for sustained release of salmon calcitonin (SCT) Alur et al., 1999 Poly(acrylic acid-co-ethylhexyl acrylate), P(AA-co-EHA) Evaluation of P (AA-co-EHA) films for buccal mucoadhesive drug delivery. Shojeai et al., 2000
Classification Examples Mechanism Surfactants Anionic Cationic Non-ionic Bile salts Sodium lauryl sulfate, Sodium laurate Cetylpyridinium chloride Polaxamer, Brij, Span, Myrj, Polysorbate Sodium glycodeoxycholate, Sodium glycocholate, Sodium taurodeoxycholate, Sodium taurocholate. Perturbation of intercellular lipids, protein domain integrity Fatty acids Oleic acid, Caprylic acid. Increase fluidity of phospholipid domains. Cyclodextrins -,-, γ- cyclodextrins, Methylated -cyclodextrins Inclusion of membrane compounds Chelators EDTA, Sodium citrate, Polyacrylates Interfere with Ca+2 Positively charged polymers Chitosan, Trimethyl chitosan Ionic interaction with negative charge on the mucosal surface Cationic compounds Poly-L-arginine, L-lysine Miscellaneous Azone Mucosal penetration enhancers and mechanisms of action
List of macromolecular drugs delivered through buccal route Drug Enhancer Results Method (Ref) Insulin 5% Sodium glycocholate ↑ F sublingual from 0.3% to 12%, ↑ F buccal from 0.7% to 26% Rat in vivo ( Aungust et al., 1988) Insulin Sodium glycocholate Absorption only in presence of enhancer (F=0.5%) Dog in vivo (Ishida et al., 1981) Insulin 5% laureth-9, 5% Sodium salicylate, 5% Sodium EDTA, Aprotinin ↑ F from 0.7-3.6% to 27% with laureth-9. Others had no effect Rat in vivo (Aungst et al., 1988) Calcitonin Various saponins, Bile salts, Fatty acids, Sucrose esters, Sodium lauryl sulfate ↑ pharmacologic effect Rat in vivo (Nakada et al., 1988) Calcitonin Various bile salts ↑ pharmacologic effect, ↑ stability in mucosal homogenate Rat in vivo (Nakada et al., 1989)
Insulin Sodium lauryl sulfate, Sodium taurocholate, EDTA, POE 23 lauryl ether, Methoxysalicylate, Dextran sulfate Maximum F~12% Rabbit in vivo (Oh et al., 1990) Octreotide 3% Azone, 4% Sodium glycocholate, Sodium taurocholate, Sodium taurocholate + EDTA Azone ↑ F from 1.5% to 6%, sodium glycocholate ↑ F from ~ 0.4% -4.2% Dog in vivo (Wolany et al., 1990) Interferon 1-4% sodiumtaurocholate, 5% polysorbate 80, 1% sodium lauryl sulphate, 5% cyclodextrins ↑ F from 0.014% to 0.25% with sodium taurocholate. Others less effective Rat in vivo (Steward et al., 1994) Insulin Various alkyl glycosides (0.1- 0.2M) ↑ F from 0.8% to ~ 30% maximum Rat in vivo (Aungst et al., 1994)
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Transmucosal drug delivery by Kailash Vilegave

  • 1.
    TRANS MUCOSAL (BUCCAL) DRUGDELIVERY SYSTEMS By : Mr.Kailash Vilegave Lecturer in Pharmacy S.S.Jhondle college of pharmacy, Asangaon
  • 2.
    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
  • 3.
    Alternative Routes  Transdermal(TD)  Permeability issues  Potent drugs  OralTransmucosal (TM)  Bioadhesion issues  Better permeability
  • 4.
    Advantages of TMDrug 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)
  • 5.
    Disadvantages • Expensive • Multi-layering--uncomfortableto 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)
  • 6.
    Comparison of Routesof 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)
  • 7.
    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
  • 8.
    Basic Facts &Considerations • Structure of mucosa • Factors affecting TM delivery • Permeation Enhancement • Devices & Formulations • Models for TM absorption testing
  • 9.
  • 10.
    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)
  • 11.
    Comparison of Routesfor Systemic Drug Delivery Issues Nasal Oral Mucosal Vaginal/ Rectal Gastro- Intestinal Dermal Accessibility      First-pass Clearance      Acceptability      Surface Area      Onset of Action      Robustness      Duration      Permeability      Vascular Drainage      Surface Environment       = Not Favorable;  = Intermediate;  = Very Favorable
  • 12.
    Drug/Mucosa Considerations • Barriersare 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
  • 13.
    Regional Variation inthe 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
  • 14.
    Oral Cavity Schematic Hard palate Gingival Sublingual Softpalate Buccal Tongue Keratinized LayerEpithelium 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.
  • 15.
    Pathways of DrugPenetration (TM) • Drugs follow route of least resistance – Intercellular: Hydrophilic compounds – Transcellular: Lipophilic compounds
  • 16.
    Mechanisms of DrugTransport • 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
  • 17.
  • 18.
    Factors Affecting DrugDelivery • Physicochemical factors • Biological factors • Formulation factors
  • 19.
    Physicochemical Factors • Partitioncoefficient • Solubility • Ionization / pKa • Molecular size and weight • Stability or Half – life
  • 20.
    Biological Factors • Salivation(TM) • pH of environment • Area • Condition of the Mucosa • Hydration • Metabolism
  • 21.
    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.
  • 22.
    Formulation Factors • Dailydose • Adhesion – use of bioadhesives • Permeability – use of enhancers
  • 23.
    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.
  • 24.
    Adhesion and Useof 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
  • 25.
  • 26.
    Permeability Barrier: LipidNature 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)
  • 27.
    Penetration Enhancement • ChemicalMethods (TM): – Chemical Penetration Enhancers (CPE) – Pro-drugs
  • 28.
    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
  • 29.
    “Trans” Absorption Enhancing Mechanismof 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
  • 30.
    Use of PermeationEnhancers  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).
  • 31.
    TM Delivery SystemRequirements • 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)
  • 32.
    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
  • 33.
    Basic Types ofTM 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
  • 34.
    Models for TMabsorption 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
  • 35.
  • 36.
    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
  • 37.
    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
  • 38.
    Quality control tests Assay Weightvariation Thickness variation In vitro Release studies Moisture absorption studies % Moisture absorbed = Final weight – Initial weight __________________________________________________________ Initial weight × 100
  • 39.
    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”
  • 40.
    ORGANIZATION PRODUCT PRESENTSTATUS Generex Biotechnology Corporation Insulin Buccal Spray ORALGEN (US) ORALIN (Canada) Heparin Buccal Delivery System Fentanyl Buccal Delivery Systems In Market Clinical Trials Completed Clinical Trials Completed Columbia Laboratories Inc. Testosterone Buccal Tablet (Straint) Desmopressin Buccal Tablet In Market In Market Ergo Pharm Androdiol Buccal Tablets (Cyclo-Diol SR) Norandrodiol Buccal Tablets (Cyclo- Nordiol SR) In Market In Market Cytokine Pharma Sciences Inc. Pilocarpine Buccal Tablet (PIOLOBUC) In Market Britannia Pharmaceuticals Limited Prochlorperazine Buccal Tablet (Buccastem) In Market Pharmax Limited Glyceryl Trinitrate (Suscard Buccal Tablet) In Market Cephalon, Inc. Oral Transmucosal Fentanyl Citrate Solid Dosage Form (ACTIQ) In Market List of marketed buccal preparations under various stages of development
  • 41.
    Wyeth Pharma Ceuticals Lorazepam BuccalTablets (Temesta Expidet) Oxazepam Buccal Tablets (Seresta Expidet) In Market In Market GW Pharmaceuticals Mucosal Spray and Buccal Tablets (Cannabis-Based Medicines) Under Development NovaDel Pharma Inc. Buccal Aerosol Spray for Clemastine,Nicotine, Testosterone,Estradiol, Progestorone,Fluoxetine, Piroxicam Under Development IVAX Corporation Estrogen Buccal Tablet Under Phase III clinical trials Regency Medical research Vitamins Trans Buccal Spray In Market Leo Pharmaceuticals Nicotine Mucoadhesive Tablet (Nicorette) Nicotine Chewing Gum (Nicotinell) In Market In Market Teijin Ltd. Triamcinolone acetonmide(Aftach) In Market Rhone-Poulenc Rorer Prochlorperazine Bioadhesive Buccal Tablet (Tementil) In Market Ciba-Geigy Methyltestosterone Buccal Tablets (Metandren) In Market
  • 42.
    Some buccal –adhesivematrix tablet formulations Formulation components Active ingredient References Hydroxypropyl cellulose, Cetostearyl alcohol and Hydroxyethyl cellulose Several suggested e.g., Morphine Jenkins et al., (1986) Chitosan and Sodium hyaluronate Brilliant blue used as model drug Takayama et al., (1991) Modified maize starch with either Poly(acrylic acid) or poly(ethylene Oxide) Fluoride Bottenberg at al., (1991) Hydroxypropyl cellulose and Carboxyvinyl polymer Triamcinolone acetonide Kubo et al., (1989) Sodium carboxymethylcellulose and Hydroxypropyl methylcellulose Codeine Phosphate Ranga rao et al., (1989) Hydroxypropyl methylcellulose and Poly(acrylic acid) Fluoride Bottenberg et al.¸(1989)
  • 43.
    Bioadhesive Polymer(s) Studied Investigation objectivesReference HPC and CP Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination Ishida et al., 1981 HPC and CP Measured Bioadhesive property using mouse peritoneal membrane Satoh et al., 1989 CP, HPC, PVP, CMC Studied inter polymer complexation and its effects on bioadhesive strength Gupta et al., 1994 CP and HPMC Formulation and evaluation of buccoadhesive controlled release delivery systems Anlar et al., 1994 HPC, HEC, PVP, and PVA Tested mucosal adhesion on patches with two-ply laminates with an impermeable backing layer and hydrocolloid polymer layer Anders, R. and Merkle, H., 1989 HPC and CP Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base Ishida et al., 1982 CP, PIP, and PIB Used a two roll milling method to prepare a new bioadhesive patch formulation Guo,J.-H., 1994 Xanthum gum and Locust bean gum Hydrogel formation by combination of natural gums Watanabe et al., 1991 Related research on mucoadhesive polymers and delivery systems
  • 44.
    Chitosan, HPC, CMC,Pectin, Xanthum gum, and Polycarbophil Evaluate mucoadhesive properties by routinely measuring the detachment force from pig intestinal mucosa Lehr et al., 1992 Hyaluronic acid benzyl esters, Polycarbophil, and HPMC Evaluate mucoadhesive properties Sanzgiri et al., 1994 Hydroxyethyl cellulose Design and synthesis of a bilayer patch (polytef-disk) for thyroid gland diagnosis Anders et al., 1983 Polycarbophil Design of a unidirectional buccal patch for oral mucosal delivery of peptide drugs Veillard et al., 1987 Poly(acrylic acid) and Poly(methacrylic acid) Synthesized and evaluated cross-linked polymers differing in charge densities and hydrophobicity Ch’ng et al., 1985 Number of Polymers including HPC, HPMC, CP, CMC. Measurement of bioadhesive potential and to derive meaningful information on the structural requirement for bioadhesion Park, k. and Robinson, J.R., 1984
  • 45.
    Poly(acrylic acid-co- acrylamide) Adhesion strengthto the gastric mucus layer as a function of crosslinking agent, degree of swelling, and carboxyl group density Park, H. and Robinson, J.R., 1987 Poly(acrylic acid) Effects of PAA molecular weight and crosslinking concentration on swelling and drug release characteristics Garcia- Gonzalez et al., 1993 Poly(acrylic acid-co-methyl methacrylate) Effects of polymer structural features on mucoadhesion Leung, S and Robinson, J.R., 1988 Leung, S and Robinson, J.R., 1990 Poly(acrylic acid-co- butylacrylate) Relationships between structure and adhesion for mucoadhesive polymers Bodde et al., 1990 HEMA copolymerized with Polymeg® (polytetramethylene glycol) Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine Cassidy et al., 1993 Cydot® by 3M (bioadhesive polymeric blend of CP and PIB) Patch system for buccal mucoadhesive drug delivery Benes et al., 1997 DeGrande, et al., 1996 Formulation consisting of PVP, CP, and cetylpyridinium chloride (as stabilizer) Device for oral mucosal delivery of LHRH - device containing a fast release and a slow release layer Nakane et al., 1996
  • 46.
    CMC, Carbopol 974P,Carbopol EX-55, Pectin (low viscosity), Chitosan chloride, Mucoadhesive gels for intraoral delivery Nguyen-Xuan et al., 1996 HPMC and Polycarbophil (PC) Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC yielding the highest force of adhesion Taylan et al., 1996 PVP, Poly(acrylic acid) Transmucosal controlled delivery of isosorbide dinitrate Yukimatsu et al., 1994 Nozaki et al., 1997 Poly(acrylic acid-co-poly ethyleneglycol) copolymer of acrylic acid and polyethylene glycol monomethylether monomethacrylate To enhance the mucoadhesive properties of PAA for buccal mucoadhesive drug delivery Shojaei, A. H and Li, X., 1995 Shojaei, A. H and Li, X., 1997 Poly acrylic acid and polyethylene glycol To enhance mucoadhesive properties of PAA by interpolymer complexation through template polymerization Choi et al., 1997 Drum dried waxy maize starch (DDWM), Carbopol 974P, and sodium stearylfumarate Bioadhesive erodible buccal tablet for progesterone delivery Voorspoels et al., 1997 Natural oligosaccharide gum, hakea Evaluation of mucoadhesive buccal tablets for sustained release of salmon calcitonin (SCT) Alur et al., 1999 Poly(acrylic acid-co-ethylhexyl acrylate), P(AA-co-EHA) Evaluation of P (AA-co-EHA) films for buccal mucoadhesive drug delivery. Shojeai et al., 2000
  • 47.
    Classification Examples Mechanism Surfactants Anionic Cationic Non-ionic Bilesalts Sodium lauryl sulfate, Sodium laurate Cetylpyridinium chloride Polaxamer, Brij, Span, Myrj, Polysorbate Sodium glycodeoxycholate, Sodium glycocholate, Sodium taurodeoxycholate, Sodium taurocholate. Perturbation of intercellular lipids, protein domain integrity Fatty acids Oleic acid, Caprylic acid. Increase fluidity of phospholipid domains. Cyclodextrins -,-, γ- cyclodextrins, Methylated -cyclodextrins Inclusion of membrane compounds Chelators EDTA, Sodium citrate, Polyacrylates Interfere with Ca+2 Positively charged polymers Chitosan, Trimethyl chitosan Ionic interaction with negative charge on the mucosal surface Cationic compounds Poly-L-arginine, L-lysine Miscellaneous Azone Mucosal penetration enhancers and mechanisms of action
  • 48.
    List of macromoleculardrugs delivered through buccal route Drug Enhancer Results Method (Ref) Insulin 5% Sodium glycocholate ↑ F sublingual from 0.3% to 12%, ↑ F buccal from 0.7% to 26% Rat in vivo ( Aungust et al., 1988) Insulin Sodium glycocholate Absorption only in presence of enhancer (F=0.5%) Dog in vivo (Ishida et al., 1981) Insulin 5% laureth-9, 5% Sodium salicylate, 5% Sodium EDTA, Aprotinin ↑ F from 0.7-3.6% to 27% with laureth-9. Others had no effect Rat in vivo (Aungst et al., 1988) Calcitonin Various saponins, Bile salts, Fatty acids, Sucrose esters, Sodium lauryl sulfate ↑ pharmacologic effect Rat in vivo (Nakada et al., 1988) Calcitonin Various bile salts ↑ pharmacologic effect, ↑ stability in mucosal homogenate Rat in vivo (Nakada et al., 1989)
  • 49.
    Insulin Sodium laurylsulfate, Sodium taurocholate, EDTA, POE 23 lauryl ether, Methoxysalicylate, Dextran sulfate Maximum F~12% Rabbit in vivo (Oh et al., 1990) Octreotide 3% Azone, 4% Sodium glycocholate, Sodium taurocholate, Sodium taurocholate + EDTA Azone ↑ F from 1.5% to 6%, sodium glycocholate ↑ F from ~ 0.4% -4.2% Dog in vivo (Wolany et al., 1990) Interferon 1-4% sodiumtaurocholate, 5% polysorbate 80, 1% sodium lauryl sulphate, 5% cyclodextrins ↑ F from 0.014% to 0.25% with sodium taurocholate. Others less effective Rat in vivo (Steward et al., 1994) Insulin Various alkyl glycosides (0.1- 0.2M) ↑ F from 0.8% to ~ 30% maximum Rat in vivo (Aungst et al., 1994)
  • 50.
    Oral Controlled DrugDelivery System Thank you !!! 50NKV