TRANSDERMAL DRUG DELIVERY: FORMULATION & EVALUATION

SUBMITTED BY : Pandya Sanket M. Roll no. 50/09 MS (PHARMACEUTICS) NIPER, Raebareli

GUIDED BY : Mr. Md. Sajid Ali Lecturer NIPER, Raebareli

Introduction Potential benefits Factors affecting TD route Mechanism of skin permeation Basic components Different types of transdermal patches Evaluation (physicochemical, invitro, invivo) Recent advancements Conclusion

Potential benefits of transdermal routes

The system avoids the chemically hostile GI environment No GI distress or other physiological contraindications of the oral route Avoids first-pass effect Allows effective use of drugs with short biological half-life Allow administration of drugs with narrow therapeutic windows Provides controlled plasma levels of very potent drugs Increased patient compliance Painless Simple application and removal Flexibility of terminating drug administration by simply removing the patch

 Controlled drug delivery Maintain efficacious plasma drug levels for over 1-7 days Drug input can be promptly interrupted when toxicity occurs

Disadvantages

Drug that require high blood levels cannot be administered Drug or drug formulation may cause skin irritation or sensitization Adhesive may not adhere well to all types of skin Expensive

Factors influencing TD route

Physicochemical properties of penetrant (pKa, molecular size, stability, binding affinity, solubility, partition coefficient) Integrity and thickness of stratum corneum Density of sweat glands and folicles Skin hydration Metabolism Vehicle effects Time scale of permeation (steady-state vs. transient diffusion) Microenvironment of skin surface

Basic Components Of TDDS

Polymer matrix / Drug reservoir Drug Permeation enhancers Pressure sensitive adhesive (PSA) Backing laminates Release liner Other excipients like plasticizers and solvents

Polymer matrix / Drug reservoir:

Backbone of TDDS Control the release of the drug from the device. Prepared by dispersion of drug in liquid or solid state

synthetic polymer base.

Natural Polymers: e.g. cellulose derivatives, zein, gelatin,

shellac, waxes, gums, natural rubber and chitosan etc. Synthetic Elastomers: e.g. polybutadiene, hydrin rubber, polyisobutylene, silicon rubber, nitrile, acrylonitrile, neoprene, butylrubber etc. Synthetic Polymers: e.g. polyvinyl alcohol, polyvinylchloride, polyethylene, polypropylene, polyacrylate, polyamide, polyurea, polyvinylpyrrolidone, polymethylmethacrylate etc

Drug Properties
Potency of the drug <=20 mg
Lipophilicity log P = 1-3 Molecular weight < 500 daltons

Non irritant
Melting point <200oc No immunogenicity

 Activity of penetration enhancers Interaction with the polar head groups of lipid via hydrogen and ionic bonding Increase volume of the aqueous layer : swelling and hydration Alter the packing of the lipid tails disorder and traverse by a lipid-like penetrant Solvents
Cosolvent Azone (1-dodecylazacycloheptane-2-one) Cis-unsaturated oleic acid Additive : PG increase solubilizing ability for lipid-like materials Flip over to insert between the hydrophobic groups of the membrane lipids increasing fluidity of lipid
DMSO, propylene glycol, ethanol

Penetration Enhancers

 Pressure-sensitive adhesive
ASTM (American Society for Testing and Materials) definition :

Release liner (release paper, peel-away strip)

Sheet that serve as a protectant or carrier for an adhesive film

viscoelastic material which remains permanently tacky Remove from a surface without leaving a residue Natural or synthetic rubbers, polyacrylates, silicone

(easily removed) Paper, polystyrene or polyester films with coating of silicone, longchain branched polymers, chromium complex, fluorochemicals or various hard polymers

Rate controlling membranes

Ethyl vinyl (EVA) copolymers

Microporous polyethylene or polypropylene

Backing Laminate: High flexibility Good oxygen transmission High moisture vapor transmission rate EG. vinyl, polyethylene and polyester films Other excipients: Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir. In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch

Figure 1: Design of matrix type transdermal patch

Figure 2: Design of reservoir type transdermal patch

Figure 3: Design of micro reservoir type transdermal patch

Figure 4: Design of drug in adhesive type transdermal patch

Evaluation
Physicochemical evaluation.

Invitro studies
Invivo studies

Physicochemical evaluation
UNIFORMITY OF WEIGHT CONTENT UNIFORMITY THICKNESS

MOISTURE CONTENT

FOLDING ENDURANCE

TENSILE STRENGTH

TACK PROPERTIES

PEEL ADHESION PROPERTIES

WATER VAPOUR TRANSMISSION STUDIES

Invitro Release studies

The Paddle over Disc: (USP apparatus 5 ) The Cylinder modified USP Basket: (USP apparatus 6 ) The reciprocating disc: (USP apparatus 7) Diffusion Cells e.g. Franz Diffusion Cell and its modification Keshary- Chien Cell

pH of the dissolution medium= 1-5 Temp = 320 C ( physiological skin temp. ) 100 rpm Concn of drug determined

Invivo studies :
Animal

models

mouse,

hairless rat, hairless dog, hairless rhesus monkey, rabbit, guinea pig etc

Human

volunteers

collection

Skin irritation studies

White

of pharmacokinetic and pharmacodynamic data following application of the patch to human volunteers. Phase I,II.III.IV clinical trials

Stability studies

albino rats, mice or white rabbits are used to study any hypersensitivity reaction on the skin.

 RECENT ADVANCES

Rolf

Amphoteric enhancers : SLS, lauryl amine oxide, Azone decylmethylsulfoxide, lauryl ethoxylate, octanol

PSA (pressure sensitive adhesives)

Adhesive matrix, multilaminated PSA matrix Adverse interaction between the drug, exicipents, cosolvents and permeation enhancers in reservoir and matrix-type system Silicone PSA : tack, adhesion, cohesive strength Polydimethylsioxane PSA : biocompatibility and high permeability

Actiderm (Bristol Myers Squibb)

Laminated reservoir system by Hercon

Path with no drug as occlusive dressing Placed over topically applied corticosterids to enhance efficacy by promoting hydration of the stratum corneum

Ketobemidone and carbonate ester prodrug

Steady-state blood levels for extended periods Two or four layers, including a backing membrane, the drug reservoir, a rate-controlling membrane, and an adhesive

Prodrug with isopropyl myristate, ethanol and ethanolwater readily penetrate the skin Enzymatic conversion, high solubility of prodrug in polar and apolar solvents

EXAMPLES OF TRANSDERMAL APPLICATIONS

Drug
Scopolamine

Trade Name
TransdermScop

Type of Devices
Reservoir Reservoir Monolithic Monolithic Reservoir and ethanol enhancer

Indication
Motion sickness Angina

Nitroglycerine TransdermNitro Nitro-Dur Nitrodisc Estradiol Estraderm

Hormone treatment

TABLE 2 TRANSDERMAL PRODUCTS UNDER DEVELOPMENT

Drug Minocycline Estradiol+Nor ethisterone DHEA Trade name Sunstar Estracombi TIS Producer-Marketer American Cyanamide, Takeda Ciba-Geigy, Alza Pharmedic Alza pharmaceuticals Whitby Pharm.

Fentanyl Triamcinolon e acetonide

Duragesic

 Critical parameter in designing a TDS

Drug stability, physical stability of the formulation, irritation and sensitization properties, preservation and esthetic acceptability Vehicle affect drug bioavailability Maximizing drug penetration into skin

Conclusion

Two mechanism that manipulate the diffusion of a drug across the skin
Change the degree of interaction between drug and vehicle (drugs thermodynamic activity) Changes in the stratum corneum that will affect its diffusional resistance (vehicle-barrier interaction)

 Transdermal therapy
70% or more of all drugs : potentially delive.red by TDS Limitation : drug potency, skin permeability, topical reaction, cutaneous metabolism, delivery by small volume of skin Further TTS : use of prodrug, penetration enhancer and specific nontoxic enzyme inhibitors, Iontophoresis