Transdermal Drug Delivery

PRESENTED BY:GANDHI SONAM MUKESHCHANDRAM.PHARM [INDUSTRIAL PHARMACY]

Transdermal Drug Delivery

The structure of Human Skin Theoretical advantages of the

transdermal route Optimization of percutaneous absorption Development of the transdermal

therapeutic system Examples of transdermal applications Other transdermal systems Recent advances

I. Introduction Transdermal permeation (percutaneous absorption)

The passage of substance from the outside of the skin through its various layers into the bloodstream

Advantages of transdermal delivery system The system avoids the chemically hostile GI environment No Gi distress or other physiological contraindications of

the oral route Can provide adequate absorption of certain drugs Increased patient compliance 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 Drug input can be promptly interrupted when toxicity

occurs

Disadvantages of TDS Drug that require high blood levels cannot be

administered Adhesive may not adhere well to all types of skin Drug or drug formulation may cause skin irritation or

sensitization Uncomfortable to wear May not be economical

Consideration of TDS development Bioactivity of drug Skin characteristics Formulation Adhesion System design

Factors influence the permeation of drugs Skin structure and its properties The penetrating molecule and its physical-chemical

relationship to skin and the delivery platform The platform or delivery system carrying the penetrant The combination of skin, penetrant, and delivery system

II. The Structure of Human Skin

Human skin The stratified avascular cellular epidermis An underlying dermis of connective tissue

Stratum corneum or horny layer Rate-limiting or slowest step in the penetration

process Transport mechanism

Transepidermal pathway across the horny layer either intra- or intercellularly

Via hair folicles and sweat glands (the appendageal route)

Fig. 1 Basic diagram of skin structure.

Factor influence the transdermal route Time scale of permeation (steady-state vs.

transient diffusion) 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

Stable preparation of TDS Correct partition coefficient relative to the drug

reservoir, device membrane and skin layers Rate-controlling membrane : low flux (skin act as a

sink) Impermeability of stratum corneum : individual

patient’s skin control drug input and significant biological variability

Partition into skin Prodrugs with low melting points Penetration-enhancing substances

Microenviornment of the skin surface Light, oxygen, bacteria Change in skin flora with maceration and irritation

of the skin – sweat gland ineffective Enzyme (80 to 90% as efficient as in the liver)

Hydrolytic, oxidative, reductive and conjugative reaction

Incorporate enzyme inhibitors

III. Theoretical Advantages of the Transdermal Route

Variables associated with GI absorption First-pass effect Changes in pH Gastric emptying, intestinal motility and transit time Activity of human and bacterial enzymes Influence of food

Percutaneous administration Control administration and limit pharmacological

action Minimize pulse entry of a drug into the bloodstream Not deliberately provide a control on/off action

Skin membranes : slow-response system with prolonged lag time

Fig. 2. Process of transdermal permeation.

IV. Optimization of Percutaneous Absorption

Formulation of dermatological preparations Vehicle or device to maximize drug partition into the skin Incorporate penetration enhancer into formulation

Enhancers Phamacologically inert, not interacting with receptors Neither toxic, irritating nor allergenic The onset of enhancer activity and the duration of effect :

predictable and controllable Skin : immediate and full recovery Promote penetration without problems of loss of body

fluids, electrolytes or other endogeneous materials Compatible with drug and adjuvants A suitable solvent for drug Spread well on the skin Formulate into cream, ointment, gel, lotion, suspension,

aerosol, etc Odorless, tasteless, colorless, inexpensive

V. The Theory for Penetration-Enhancer Activity

Activity of penetration enhancers Interaction with the polar head groups of

lipid via hydrogen and ionic bonding Change in hydration sphere of lipids and affect

the packing at the head region 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 DMSO, propylene glycol, ethanol Partition coefficient elevate drug concentration in

the skin 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 Interaction mechanism of solvents and

surfactants with proteins Interaction with polar groups Relaxation of binding forces and alterations in helix

conformations Pore route formation

VI. Development of the Transdermal Therapeutic System

A. Transdermal Penetration of Drugs

Percutaneous absorption via diffusion Transcellular penetration through stratum

corneum Intercellular penetration through stratum

corneum Transappendageal penetration including

the subaceous pathway and aqueous pathway of the salty sweat glands

B. Formulation

Platform for the drug A liquid : well-constrained A semisolid : ointment, semisolid gel A non-flowing material

Polymeric film or rubbery gels Solid-state platform

Combination Types of platform

Monolith, slabs, reservoirs, vehicles, films, polymer matrix

Films : nature (natural or synthetic), structure (porous or nonporous)

C. Adhesion

Adhesion Good skin contact Good bonding between laminating layers

Properties of pressure-sensitive adhesives Adhesive-cohesive properties Peel strength Tack and creep quality of adhesive Occlusive (serve as barrier such as vinyl, PE,

polyester film) Nonocclusive (allow water and gases to flow

through films)

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

definition : viscoelastic material which remains permanently tacky

Remove from a surface without leaving a residue Natural or synthetic rubbers, polyacrylates, silicone

Release liner (release paper, peel-away strip) Sheet that serve as a protectant or carrier for an

adhesive film (easily removed) Paper, polystyrene or polyester films with coating

of silicone, long-chain branched polymers, chromium complex, fluorochemicals or various hard polymers

D. Bioactivity

Trandermal drug delivery Minimize the fluctuating levels of drug in

the blood Provide drug level within the limits of the

therapeutic windows Pharmacokinetic view

Prolonged steady-state blood levels by adjusting drug loading, vehicle components, and surface area

VII. Examples of Transdermal Applications

Monolithic systems Nitrodur and Nitrodisc Manufacture drug reservoir with polymer

with subsequent casting and drying Punch from sheet or sliced cylinder Assembled with the system backing,

peripheral adhesive and protective liner Membrane-controlled transdermal

system Transderm-Nitro, Transderm-Scop Form-fill-seal from lamination process

Fig. 3. Types of transdermal delivery devices.

Hormones Estradiol and progesterone Avoid hepatic metabolism

Cardiovascular drugs Hypertension and angina

Betablockers : timolol, propranolol Hepatic metabolism of propranolol

Analgesics Control of chronic pain by transdermal therapy

Antihistamines Treatment of allergy Chlorpheniramine Maintain histamine-receptor antagonism while reducing

CNS side effects such as drowsiness Central nervous system drugs

Physostigmine : cholinesterase inhibitors To inhibit breakdown of acetylcholine by 30 to 40% over

4d

Table 1 Transdermal Controlled-Release Products and Devices

Drug Trade Name Type of Devices

Indication

Scopolamine Transderm-Scop

Reservoir Motion sickness

Nitroglycerine Transderm-Nitro

Reservoir Angina

Nitro-Dur Monolithic

Nitrodisc Monolithic

Estradiol Estraderm Reservoir and ethanol enhancer

Hormone treatment

Table 2 Transdermal Products under Development

Drug Trade name Producer-Marketer

Minocycline Sunstar American Cyanamide, Takeda

Estradiol+Norethisterone

Estracombi TIS

Ciba-Geigy, Alza

DHEA Pharmedic

Fentanyl

Triamcinolone acetonide

Whitby Pharm.

Drug development using TTS Ketoprofen, 5-Fu, metoprolol, terodiline,

primaquine, ibuprofen, piconol, nitrendipine, diclofenac, corticosteroids, sandimune (cyclosporine A), fluazifopbutyl, glyceryl trinitrate, azo-profen esters, methotrexate, medroxyprogesterone acetate, levonorgestrel, mepindolol, oxycodone, prostaglandins, 9--D-arabinofuranosyladenine (Ara-A)

Iontophoresis Built-in battery layer Comparable in size to a normal transdermal patch The Lectro Patch, General Medical Co. Treatment time : 20 min Recommended maximum current : 4mA Lidocaine (local anesthesia), dexamethasone

(arthritis), hydrocortisone (arthritis), acetic acid (calcified tendinitis) etc.

Fig. 4. Schematic diagram illustrating the principles of iontophoresis.

VIII. Other Transdermal Systems

Lectec Co. A solid-state, hydrophilic reservoir system

Health-Chem Co. Transdermal laminar system

Elan Co. Absorbed from bracelets by electrical

impulses Molecular Biotech Co.

Proplastic membrane (molecular sponge)

IX. 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) Path with no drug as occlusive dressing Placed over topically applied corticosterids to

enhance efficacy by promoting hydration of the stratum corneum

Laminated reservoir system by Hercon 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

Ketobemidone and carbonate ester prodrug Prodrug with isopropyl myristate, ethanol and

ethanol-water readily penetrate the skin Enzymatic conversion, high solubility of prodrug in

polar and apolar solvents

X. Conclusion

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

Two mechanism that manipulate the diffusion of a drug across the skin Change the degree of interaction between drug and

vehicle (drug’s 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

delivered 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

Peptide delivery biotechnology Penetration enhancer and iontophoresis

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