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

Oral Transmucosal

(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
(OralBuccal or more appropriately Labial mucosa)

Comparison of Routes for Systemic Drug Delivery

Issues
Accessibility First-pass Clearance Acceptability

Nasal

Oral Mucosal

Vaginal/ Rectal

GastroIntestinal

Dermal

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 CorneumHowever is Lipophilic

Transport is Intercellular for both Polar and NonPolar Penetrants

Drugs exposed to Enzymatic Degradation

Barrier Areas composed of Membrane-Coating GranulesDischarged into Intercellular Space
Contain glycoproteins and glycolipids in an amorphous arrangement Keratinized tissues 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

Epithelium

Mucus Layer Keratinized Layer

Hard palate

Basal Lamina Lamina Propria

Soft palate Gingival Buccal Mucus Layer Epithelium Sublingual Stratum Basale Basal Lamina Lamina Propria

Tongue

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
h

Transcellular
flux, J = (1-E)DCK
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

Substances that reduce salivary secretion would be expected to increase drug concentrations in the oral cavity.

Michael J. Rathbone. Oral mucosal drug delivery. Marcel Dekker, Inc. 1996.

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

Bioadhesive used Hakea

40 mg CPM and 22 mg Hakea 25 mg CPM and 22 mg Hakea 40 mg CPM and 32 mg Hakea

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).

Penetration Enhancement

Permeability Barrier: Lipid Nature

LIPID SKIN KERATINIZED NONKERATINIZED ORAL EPITHELIUM ORAL EPITHELIUM X X X X X X X (high) X

Ceramides Cholesterol Fatty acids Phospholipids Glycosylceramides

X X X

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 removal properties upon

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 = DKpCv/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 drugcontaining 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 ) Semi-solid drug containing mixture encapsulated into a self-contained core; adhesive incorporated into the release liner Drug delivery mixture and adhesive separate Easy to design; incorporate much higher volumes of drug and additives Allow semi-solid suspensions and alcoholic solutions

Matrix Systems:

Reservoir Systems:

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

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

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

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

HME Films
Environmental
No organic solvents or water Recycling of material

Time Consuming Process Labor Intensive Multi-step Process

Less labor and equipment demands Shorter and more efficient processing times Favorable cost Potential Continuous Process Can Produce Solid Solutions or Dispersions

List of marketed buccal preparations under various stages of development

ORGANIZATION PRODUCT
Insulin Buccal Spray ORALGEN (US) ORALIN (Canada) Heparin Buccal Delivery System Fentanyl Buccal Delivery Systems Testosterone Buccal Tablet (Straint) Desmopressin Buccal Tablet Androdiol Buccal Tablets (Cyclo-Diol SR) Norandrodiol Buccal Tablets (CycloNordiol SR) Pilocarpine Buccal Tablet (PIOLOBUC) Prochlorperazine Buccal Tablet (Buccastem) Glyceryl Trinitrate (Suscard Buccal Tablet) Oral Transmucosal Fentanyl Citrate Solid Dosage Form (ACTIQ)

PRESENT STATUS
In Market Clinical Trials Completed Clinical Trials Completed

Generex Biotechnology Corporation

Columbia Laboratories Inc.

In Market In Market

Ergo Pharm
Cytokine Pharma Sciences Inc. Britannia Pharmaceuticals Limited Pharmax Limited

In Market In Market

In Market

In Market
In Market

Cephalon, Inc.

In Market

Wyeth Pharma Ceuticals

Lorazepam Buccal Tablets (Temesta Expidet) Oxazepam Buccal Tablets (Seresta Expidet) Mucosal Spray and Buccal Tablets (Cannabis-Based Medicines) Buccal Aerosol Spray for Clemastine,Nicotine, Testosterone,Estradiol, Progestorone,Fluoxetine, Piroxicam Estrogen Buccal Tablet Vitamins Trans Buccal Spray Nicotine Mucoadhesive Tablet (Nicorette) Nicotine Chewing Gum (Nicotinell) Triamcinolone acetonmide(Aftach) Prochlorperazine Bioadhesive Buccal Tablet (Tementil) Methyltestosterone Buccal Tablets (Metandren)

In Market In Market

GW Pharmaceuticals

Under Development

NovaDel Pharma Inc.

Under Development

IVAX Corporation Regency Medical research Leo Pharmaceuticals

Under Phase III clinical trials In Market In Market In Market

Teijin Ltd. Rhone-Poulenc Rorer

Ciba-Geigy

In Market In Market

In Market

Some buccal adhesive matrix tablet formulations

Formulation components
Hydroxypropyl cellulose, Cetostearyl alcohol and Hydroxyethyl cellulose Chitosan and Sodium hyaluronate

Active ingredient
Several suggested e.g., Morphine

References
Jenkins et al., (1986)

Brilliant blue used as model drug

Takayama et al., (1991)

Modified maize starch with either Poly(acrylic acid) or poly(ethylene Oxide)

Hydroxypropyl cellulose Carboxyvinyl polymer and

Fluoride

Bottenberg at al., (1991)

Triamcinolone acetonide Codeine Phosphate

Kubo et al., (1989)

Sodium carboxymethylcellulose and Hydroxypropyl methylcellulose Hydroxypropyl methylcellulose and Poly(acrylic acid)

Ranga rao et al., (1989) Bottenberg et al.(1989)

Fluoride

Related research on mucoadhesive polymers and delivery systems

Bioadhesive Polymer(s) Studied
HPC and CP HPC and CP

Investigation objectives
Preferred mucoadhesive strength on CP, HPC, and HPC-CP combination Measured Bioadhesive property using mouse peritoneal membrane Studied inter polymer complexation and its effects on bioadhesive strength Formulation and evaluation of buccoadhesive controlled release delivery systems Tested mucosal adhesion on patches with two-ply laminates with an impermeable backing layer and hydrocolloid polymer layer Used HPC-CP powder mixture as peripheral base for strong adhesion and HPC-CP freeze dried mixture as core base Used a two roll milling method to prepare a new bioadhesive patch formulation Hydrogel formation by combination of natural gums

Reference
Ishida et al., 1981

Satoh et al., 1989

CP, HPC, PVP, CMC

CP and HPMC

Gupta et al., 1994

Anlar et al., 1994

HPC, HEC, PVP, and PVA

Anders, R. and Merkle, H., 1989

HPC and CP

Ishida et al., 1982

CP, PIP, and PIB Xanthum gum and Locust bean gum

Guo,J.-H., 1994

Watanabe et al., 1991

Chitosan, HPC, CMC, Pectin, Xanthum gum, and Polycarbophil Hyaluronic acid benzyl esters, Polycarbophil, and HPMC Hydroxyethyl cellulose

Evaluate mucoadhesive properties by routinely measuring the detachment force from pig intestinal mucosa

Lehr et al., 1992

Evaluate mucoadhesive properties

Sanzgiri et al., 1994

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

Chng 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-coacrylamide)

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) Poly(acrylic acid-co-methyl methacrylate) Poly(acrylic acid-cobutylacrylate) HEMA copolymerized with Polymeg (polytetramethylene glycol) Cydot by 3M (bioadhesive polymeric blend of CP and PIB) Formulation consisting of PVP, CP, and cetylpyridinium chloride (as stabilizer)

Effects of PAA molecular weight and crosslinking concentration on swelling and drug release characteristics Effects of polymer structural features on mucoadhesion Relationships between structure and adhesion for mucoadhesive polymers Bioadhesive buccal hydrogel for controlled release delivery of buprenorphine

Garcia- Gonzalez et al., 1993

Leung, S and Robinson, J.R., 1988 Leung, S and Robinson, J.R., 1990

Bodde et al., 1990

Cassidy et al., 1993

Patch system for buccal mucoadhesive drug delivery

Benes et al., 1997 DeGrande, et al., 1996

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, HPMC and Polycarbophil (PC)

Mucoadhesive gels for intraoral delivery

Nguyen-Xuan et al., 1996

Buccal mucoadhesive tablets with optimum blend ratio of 80:20 PC to HPMC yielding the highest force of adhesion Transmucosal controlled delivery of isosorbide dinitrate

Taylan et al., 1996

PVP, Poly(acrylic acid)

Poly(acrylic acid-co-poly ethyleneglycol) copolymer of acrylic acid and polyethylene glycol monomethylether monomethacrylate Poly acrylic acid and polyethylene glycol Drum dried waxy maize starch (DDWM), Carbopol 974P, and sodium stearylfumarate Natural oligosaccharide gum, hakea Poly(acrylic acid-co-ethylhexyl acrylate), P(AA-co-EHA)

Yukimatsu et al., 1994 Nozaki et al., 1997

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

To enhance mucoadhesive properties of PAA by interpolymer complexation through template polymerization Bioadhesive erodible buccal tablet for progesterone delivery Evaluation of mucoadhesive buccal tablets for sustained release of salmon calcitonin (SCT) Evaluation of P (AA-co-EHA) films for buccal mucoadhesive drug delivery.

Choi et al., 1997

Voorspoels et al., 1997

Alur et al., 1999

Shojeai et al., 2000

Mucosal penetration enhancers and mechanisms of action

Classification
Surfactants Anionic Cationic Non-ionic Bile salts

Examples
Sodium lauryl sulfate, Sodium laurate Cetylpyridinium chloride Polaxamer, Brij, Span, Myrj, Polysorbate Sodium glycodeoxycholate, Sodium glycocholate, Sodium taurodeoxycholate, Sodium taurocholate. Oleic acid, Caprylic acid. -,-, - cyclodextrins, Methylated -cyclodextrins EDTA, Sodium citrate, Polyacrylates Chitosan, Trimethyl chitosan

Mechanism
Perturbation of intercellular lipids, protein domain integrity

Fatty acids Cyclodextrins Chelators Positively charged polymers

Increase fluidity of phospholipid domains. Inclusion of membrane compounds Interfere with Ca+2 Ionic interaction with negative charge on the mucosal surface

Cationic compounds
Miscellaneous

Poly-L-arginine, L-lysine
Azone

List of macromolecular drugs delivered through buccal route

Drug
Insulin

Enhancer
5% Sodium glycocholate

Results
F sublingual from 0.3% to 12%, F buccal from 0.7% to 26% Absorption only in presence of enhancer (F=0.5%)

Method (Ref)
Rat in vivo ( Aungust et al., 1988)

Insulin

Sodium glycocholate

Dog in vivo (Ishida et al., 1981)

Insulin

5% laureth-9, 5% Sodium salicylate, 5% Sodium EDTA, Aprotinin

Various saponins, Bile salts, Fatty acids, Sucrose esters, Sodium lauryl sulfate Various bile salts

F from 0.7-3.6% to 27% with laureth-9. Others had no effect

pharmacologic effect

Rat in vivo (Aungst et al., 1988)

Calcitonin

Rat in vivo (Nakada et al., 1988)

Calcitonin

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 (0.10.2M)

F from 0.8% to ~ 30% maximum

Rat in vivo (Aungst et al., 1994)

Thank you !!!

NKV

Oral Controlled Drug Delivery System

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