Transdermal Drug Delivery Systems

TRANSDERMAL DRUG DELIVERY SYSTEMS

Transdermal delivery systems are topically administered medicaments in the form of patches that deliver drugs for systemic effects at a predetermined and controlled rate. Some of the advantages of these systems over other controlled-release formulations are:

1. Drugs with very short half-lives e.g. nitroglycerine when administered as transdermal patches, release medicaments at a constant rate for a time period more than that obtainable with oral formulations.

2. Drugs with narrow therapeutic indices can be safely administered since better control of release is possible.

3. The noninvasive nature of these systems permits easy removal and termination of drug action in situations of toxicity.

4. Problems encountered with oral administration like degradation, gastric irritation, first-pass effect, etc. are avoided.

The route is unsuitable when —

4. Drug dose is large

5. Drug has large molecular size (makes absorption difficult; should ideally be below 800-1000)

6. Drug is skin sensitising and irritating

7. Drug is metabolized in skin

8. Drug undergoes protein binding in skin

9. Drug is highly lipophilic or hydrophilic (should be moderately soluble in both oil and water).

Other disadvantages of such systems include variation in absorption efficiency at different sites of skin, difficulty of adhesion to certain skin types and length of time for which a patch can be left on any area due to permeability changes (usually not more than 7 to 10 days).

Several types of transdermal drug delivery devices are available but they can be basically divided into two broad categories based on the mechanism by which drug release is controlled:

1. Monolithic (or matrix) systems.

2. Reservoir (or membrane) systems.

All such devices are fabricated as multilayer laminate structures in which the drug-polymer matrix or a drug reservoir is sandwiched between two polymeric layers. The outer layer, called as backing layer, is impermeable and meant to prevent drug loss through it. It is generally composed of metallized plastic. The other layer which contacts the device with the skin is adhesive layer. It is permeable and in some cases, may act as rate-limiting membrane. It is generally made of pressure sensitive adhesive materials like acrylic copolymers, polyisobutylene and polysiloxane or contact adhesives.

The choice of monolithic or reservoir type of system for controlling drug release depends upon the major rate-limiting step in the absorption of drug from such devices. The two rate-limiting steps are:

1. Rate of drug diffusion from the device, R₁, and

2. Rate of drug permeation through the stratum corneum, R₂.

The overall rate of drug transport is proportional to the sum (R₁ + R₂).

Monolithic (or Matrix) Devices

These devices are used when R₂ is the rate-controlling step (R₂ < R₁) and the drug has a large therapeutic index so that overdosing does not precipitate toxic reactions. The two categories of matrix devices are—one in which the drug is dissolved (usually below saturation levels) in the polymer matrix and the other in which the drug is dispersed (generally much above saturation levels). The polymers employed for matrix systems may be hydrophilic or lipophilic and includes PVC, PVP, polysaccharides, polyesters, microporous polypropylene and ethylene vinyl acetate copolymers. The drug release rate from matrix systems is rapid

Rate Controlling Factors :

Drug concentration in

olymer matrix

Chemical nature of

polymer matrix

Geometry of device

Fig. 14.18 Schematic representation of a monolith (matrix) transdermal drug delivery system

initially and falls as the matrix gets depleted of drug. The rate is thus proportional to the square root of time. Fig. 14.18. shows a typical matrix system.

Reservoir (or Membrane) Devices

These devices are used when drug permeation rate is rapid and absorption should therefore be controlled by controlling drug release (R₁ < R₂). It is also suitable for potent drugs with low therapeutic indices where monitoring drug levels in a narrow range is essential. The drug is usually

Rate Controlling Factors :

Membrane thickness

Membrane permeability

Fig. 14.19 Schematic representation of reservoir (membrane) type of transdermal drug delivery system

contained within the reservoir as a suspension in a liquid (such as silicone) or gel carrier. The rate-controlling thin polymeric membrane is made of olefinic polymers and copolymers, cellulosic esters, polyamides or PVC. When applied on skin, the device shows a rapid release at first (initial burst effect) followed by a constant zero-order release as long as the solution inside the reservoir is saturated. Fig. 14.19 shows such a device.

Mixed Monolithic-Reservoir Devices

A third type of system, it is basically a device having drug release kinetics intermediate between monolithic and reservoir systems. Here the drug-polymer matrix is layered by a rate-controlling membrane. Release is controlled initially by the membrane but as the drug gets depleted, the rate is controlled by diffusion of drug through a thicker layer of polymer matrix.

A major limitation of transdermal therapy is poor skin penetrability of several drugs. This problem can be overcome by use of penetration enhancers such as glycerol, propylene glycol, DMSO, SLS, etc.

Drugs commonly presented in such systems are nitroglycerine, clonidine, scopolamine and estradiol.