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Transdermal Drug Delivery System- A Total View


Factors affecting transdermal permeability:

The factors influencing transdermal permeability of stratum corneum can be classified into 3 major categories:

1. Physicochemical properties of the penetrants

2. Physicochemical properties of the drug delivery systems

3. Physiological and pathological conditions of the skin

 (A) Physicochemical properties of the penetrants:

1. Partition coefficient- Drugs possessing both water and lipid solubilities are favorably absorbed through skin. Transdermal permeability coefficient shows in linear dependency on partition coefficient. A lipid/water partition coefficient of 1 or greater is generally required for optimal transdermal permeability.

2. pH conditions- pH conditions of skin surface and in drug delivery systems affect the extent of dissociation of ionogenic drug molecules and their transdermal permeability.

3. Penetrant concentration- Transdermal permeability across mammalian skin is a passive diffusion process thus depends on the concentration of penetrant molecules on the surface layers of the skin.

(B) Physicochemical properties of drug delivery systems:

1.Release characteristics- Generally, the more easily the drug is released from the delivery system, the higher the rate of transdermal permeation .The mechanism of drug release depends on whethere the drug molecules are dissolved or suspended in the delivery system and on interfacial partition coefficient of the drug from delivery system to the skin tissue.

2. Composition of drug delivery systems-The composition of drug delivery system has a great influence on percutaneous absorption of a drug molecule. It may affect not only the rate of drug release but also the permeability of stratum corneum by means of hydration, mixing with skin lipids or other sorption promoting effects.

3. Enhancement of transdermal permeation- Transdermal permeation of drugs can be improved by the addition of a sorption or permeation promoter in the drug delivery system

(a)     Organic solvents as permeation promotor-
e.g. Dimethylsulfoxide(DMSO), Dimethylacetamide, Dimethylformide, Ethylene glycol, Polyethylene glycol, Ethanol
(b) Surface active agent as permeation promoter- The anionic surfactants are most effective permeation promoters. e.g. Sodium lauryl sulfate, Sodium dioctyl  sulfosuccinate.

(C) Physiological and pathological conditions of the skin:

1. Reservoir effect of horny layer- The horny layer especially its deeper layer can act as a depot or reservoir and modify transdermal permeation characteristics of some drug.

2. Lipid film- Lipid film on skin surface, formed by product of the excretion of sebaceous gland and epidermal cell lipid maintains the barrier function of stratum corneum.

3. Skin hydration- Hydration of stratum corneum can enhance the permeability of the skin by as much as eight fold.

4. Skin temperature- A ten fold in the skin permeation was raised from 100 to 370 C of acetyl salicylic acid and glucosteroids was noticed when the environmental temperature7.

Classification of transdermal drug delivery systems:
Transdermal drug delivery systems generally fall into the following subcategories:   
(1) Polymer membrane permeation-controlled
(2) Polymer matrix diffusion-controlled
(3) Drug reservoir gradient-controlled
(4) Micro reservoir dissolution-controlled
           - Liquid-filled laminate structure
           - Peripheral-adhesive laminate structure
           - Solid-state laminate structure
           - Sub-classes of the above

In terms of the drug release mechanisms, TDDS can be divided into six categories:
(1) Solution in matrix
(2) Suspension in continuous matrix
(3) Suspension in porous matrix
(4) Solution upstream of membrane
(5) Suspension upstream of membrane
(6) Laminated membrane downstream

However, TDDS are most commonly classified into two groups:
(A) Matrix patches-
In the matrix system, the inert polymer matrix binds with the drug and controls its release from the device (e.g., Nitro-Dur® Patch, Nicotrol® Patch [OTC], and Vivelle® Transdermal).
(B) Liquid reservoir patches-
In the reservoir system, the polymer matrix does not control drug release. Instead, a rate-controlling membrane present between the drug matrix and the adhesive layer provides the rate-limiting barrier for drug release from the device. (e.g. Transderm-Nitro® Patch, Transderm Scop® Patch, Catapres-TTS® Transdermal, Estraderm® Transdermal, Duragesic® Transdermal, Nicoderm® CQ Patch, and Androderm® Transdermal System).4,8

Basic Components of TDDS:
Both matrix patches and liquid reservoir patches consist of several components. Some of these are similar in both classes, while others are class-specific. Those common to both include:
(1) Backing films
(2) Release liners
(3) Pressure-sensitive adhesives
(4) Active ingredient(s)
(5) Permeation enhancers
(6) Other additives
(7) Micro porous or semi-permeable membranes
(8) Pouching materials
Although the pouching materials do not represent a direct component of patches, it is included because, firstly, a patch is never fully isolated from its pouching material. Secondly, it plays a critical role in the patch's stability, and finally, it protects children (in cases of Nicotine and Fentanyl) from a very strong and dangerous active.

(1) Backing Films-
Backing films play a critical role in the TDDS (as long as they are packaged in their pouch), as well as during the use of the system. The role of such a film is to protect the active layer and safeguard the stability of the system, and to affect skin permeation and tolerance, depending on occlusion or breathability. Because of the huge variety of ingredients, the release liner must be fully inert to the ingredients in order to avoid any type of incompatibility. It must also be flexible, comfortable and must present good affinity with the adhesive, as well as excellent printability. The most common materials used as release liners are polypropylene, polyethylene (both high and low density), saran, polyesters, PVC and nylon.

(2)  Release Liners-
Generally, a release liner is a film covered with an anti-adherent coating. The role of the release liner is to protect the system as long as it is in the package, and it is removed just before the adhesion of the TDDS to the skin. Release liners play a crucial role in the stability of the product and in its safe and functional use. The release liner must therefore be chosen very carefully.
An incorrect release liner does not permit the easy release of the patch, and can interfere with the active(s) or other components, thereby reducing its shelf life. The most common films used as release liners are paper-based, plastic film-based and composite films. The two major classes of coating are silicones and fluoro-polymers.

(3) Pressure-Sensitive Adhesives-
For both classes of TDDS, pressure-sensitive adhesives (PSAs) play a major role, serving as the matrix that carries everything active (such as additives and permeation enhancers) and the means for making the patch stick to the skin. There are three major families of PSAs: rubber-based PSAs, acrylic PSAs in the formof acrylic solutions, emulsion polymers or hot melts, and silicon PSAs.  For each family of adhesives there are several sub-categories that give the required flexibility to the formulator.
Each active is different and the choice of adhesives is critical for the success of the final product. There are several examples (Table 1), such as:
Acrylics:

1. With or without functional groups
2. Cross-linked or not
Solutions, hot melts or emulsions
Silicon-Based Adhesives:

1. Standard
2. Amine-compatible
Rubbers with different:

1. Tackifiers
2. Cross-linkers
3. Stabilisers and   plasticizers

(4) Penetration Enhancers-

This term refers to an entire family of chemically different substances that all share a common characteristic - they facilitate the permeation of the actives through the skin, increasing the permeation rate by several times. This is very important with respect to the feasibility of a system, because most of the actives do not enter the skin in the required dosage from a relatively small area. Sometimes a combination of ingredients is needed to create the correct enhancement effect.

                            Table 1: Pressure-Sensitive Adhesives in TDDS


                Advantages

          Disadvantages





   Rubber Adhesives

Good adherence to low and high energy surfaces

Poor ageing

Relatively inert adhesives

Low shear and irradiation resistance

High initial adhesion

M.W. variability

Useful in broad temperature range


Low tack and adhesion without additives

Flexibility


Low cost





   Acrylic Adhesives

Good UV, solvent and hydrolysis resistance

Moderate cost

Excellent adhesion build-up


Fair initial adhesion

Good shear strength

Poor creep

Easy to apply


Good service life






Silicon-Based                  PSAs

Chemical and biological inertness

Highest cost

Extremely low toxicity, sensitisation and irritation


The need for expensive release liners


Retaining of mechanical and physiochemical properties on the skin

No aggressive behaviour

 (5) Micro porous or Semi-Permeable Membranes-
The porous membrane is a special kind of plastic film which is used in all liquid reservoir patches and in some matrix patches. Its role is to limit the flow of the semi-solid content from the liquid reservoir, and/or to act as a rate-limiting membrane for both liquid reservoir and matrix systems. The function depends on the design of the specific system, the size of the active component and the need to have a rate-limiting factor in order to satisfy the release and absorption characteristics of the system. The chemical composition of these membranes is a key factor in their permeability.

There are two types of porous membranes-

A. Ethylene Vinyl Acetate Membranes (EVA)
B. Micro porous Polyethylene Membranes

(6) Pouching Materials-
Most patches for use in a TDDS are packaged as unit doses in sealed pouches. The pouching material is therefore critical to the stability and integrity of the product. When there are two films with similar positive characteristics, the one with the lower cost, better machinability and better printability will be chosen.
There are three main layers in the composite materials used for pouches: the internal plastic heat sealable layer, the aluminium foil layer and the external printable layer. If the film is a lamination, an adhesive is used to keep the layers together. Alternatively, an extrusion method can be used if it is suitable.
a. Heat Sealable Layer:

This layer plays an important role in the machinability, stability and  protection of the product. Several plastic films or coatings can be used for its formation, including polyethylene, surlyn and other similar heat sealable materials.
b. Aluminium Foil Layer:

This layer plays an important role in protecting the product from light and oxygen. In 'ideal' conditions the foil needs to have a thickness of more than 1mil or 25 micrometers to be a real barrier. If any less than this thickness level is used, there will always be pinholes reducing the barrier properties.
c. External Layer:

The external layer of a composite film or laminate is used to achieve a better 'finishing' and printing quality. It can also compensate for a lack of stability as it acts synergistically with the aluminium foil. Paper or polyester film is used for this role, but the polyester film creates a better-looking pouch and a better barrier.6,8

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