Overview Of Transdermal Drug Administration

Transdermal drug delivery system is defined as the topically administered medications in the form of patches which when applied to the skin deliver the drug, through the skin at a predetermined and controlled rate. This increases the therapeutic efficacy of the drug and reduces the side effects of the drug. Skin is an effective medium from which absorption of the drug takes place and enters the circulatory system. Transdermal formulation maintains drug concentration within the therapeutic window for a prolonged period of time ensuring that drug levels neither fall below the minimum effective concentration nor exceed the maximum effective concentration.

Transdermal

Anatomy Of The Skin

There are two important layers to the human skin: (1) the Epidermis and (2) the Dermis. For transdermal delivery, drugs must pass through the two sublayers of the epidermis to reach the microcirculation of the dermis.

Read Also: Types Of Topical Medication

The skin’s outermost layer called stratum corneum, which is 10 to 20 µm thick. Underneath this layer is the viable epidermis, which measures 50 to 100 µm and is avascular. Deeper still is the dermis, which is 1–2 mm thick and contains a rich capillary bed for systemic drug absorption just below the dermal–epidermal junction. Closer examination of the stratum corneum barrier reveals a brick and mortar structure, where the bricks represent non-living corneocyte cells composed primarily of cross-linked keratin and the intercellular mortar is a mixture of lipids organized largely in bilayers. Drug transport across the stratum corneum typically involves diffusion through the intercellular lipids via a path that winds tortuously around corneocytes, where hydrophilic molecules travel through the lipid head group regions and lipophilic molecules travel through the lipid tails. This transport pathway is highly constrained by the structural and solubility requirements for solution and diffusion within stratum corneum lipid bilayers.

Transdermal Pathways

There are two main pathways by which drugs can cross the skin and reach the systemic circulation. The more direct route is known as the transcellular pathway.

Transcellular Pathway

By this route, drugs cross the skin by directly passing through both the phospholipid membranes and the cytoplasm of the dead keratinocytes that constitute the stratum corneum.

Although this is the path of shortest distance, the drugs encounter significant resistance to permeation. This resistance is caused because the drugs must cross the lipophilic membrane of each cell, then the hydrophilic cellular contents containing keratin, and then the phospholipid bilayer of the cell one more time. This series of steps is repeated numerous times to traverse the full thickness of the stratum corneum.

Intracellular Pathway

The other more common pathway through the skin is via the intercellular route. Drugs crossing the skin by this route must pass through the small spaces between the cells of the skin, making the route more tortuous. Although the thickness of the stratum corneum is only about 20 µm, the actual diffusional path of most molecules crossing the skin is on the order of 400 µm. The 20-fold increase in the actual path of permeating molecules greatly reduces the rate of drug penetration.

Microneedles

A third pathway to breach the Stratum Corneum layer is via tiny microchannels created by a medical micro-needling device. The microneedles can be hollow, solid, coated, dissolving, or hydrogel-forming. Microneedle devices/patches can be used to deliver nanoparticle medicines. In general, microneedles (i) increase skin permeability by creating micron-scale pathways into the skin, (ii) can actively drive drugs into the skin either as coated or encapsulated cargo introduced during microneedle insertion or via convective flow through hollow microneedles and (iii) target their effects to the stratum corneum, although microneedles typically pierce across the epidermis and into the superficial dermis too.

Generation Of Transdermal Delivery Systems

First Generation Delivery Systems

A variation on the traditional transdermal patch of first-generation delivery systems involves no patch at all, but applies a metered liquid spray, gel or other topical formulation to the skin that, upon evaporation or absorption, can drive small lipophilic drugs into the stratum corneum, which in turn serves as the drug reservoir for extended release into the viable epidermis over hours.

Second Generation Transdermal Delivery Systems

The second generation of transdermal delivery systems recognizes that skin permeability enhancement is needed to expand the scope of transdermal drugs. The ideal enhancer should (i) increase skin permeability by reversibly disrupting stratum corneum structure, (ii) provide an added driving force for transport into the skin and (iii) avoid injury to deeper, living tissues. However, enhancement methods developed in this generation, such as conventional chemical enhancers, iontophoresis and non-cavitational ultrasound, have struggled with the balance between achieving increased delivery across stratum corneum, while protecting deeper tissues from damage. As a result, this second generation of delivery systems has advanced clinical practice primarily by improving small molecule delivery for localized, dermatological, cosmetic and some systemic applications, but has made little impact on delivery of macromolecules.

Third Generation Transdermal Delivery Systems

The third generation of transdermal delivery systems is poised to make significant impact on drug delivery because it targets its effects to the stratum corneum. This targeting enables stronger disruption of the stratum corneum barrier, and thereby more effective transdermal delivery, while still protecting deeper tissues. In this way, novel chemical enhancers, electroporation, cavitational ultrasound and more recently microneedles, thermal ablation and microdermabrasion have been shown to deliver macromolecules, including therapeutic proteins and vaccines, across the skin in human clinical trials. These advances were made possible in part by the emergence of technologies to localize effects to the stratum corneum combined with recognition that the safety afforded by localization should make these more aggressive approaches medically acceptable.

Suitably designed combinations of chemical enhancers can balance trade-offs between enhancement and irritation based on the hypothesis that certain enhancer combinations are especially potent when present at specific, narrow compositions. This approach enables a strategy to target effects that enhance skin permeability in the stratum corneum, but avoids irritation in deeper tissues where the formulation composition becomes diluted or otherwise altered.

Enhancers Of Transdermal Drug Delivery System

Enhancers increase the penetration of permeants by disrupting the structure of skin’s outer layer i.e stratum corneum and increasing penetrant solubility. Disruption, either by the means of chemical or physical means, may affect both the intracellular and extracellular structure. Disruption may be due to protein denaturation, fluidization and randomization of intercellular lipids or intercellular delamination and expansion.

Enhancers of transdermal drug delivery system are:

1. Physical enhancers

2. Particulate systems

3. Chemical enhancers

Physical Enhancers

The enhancers of the transdermal drug delivery system are the iontophoresis, thermal ablation, microdermabrasion, electroporation, magnetophoresis, microneedle and ultrasound (also known as phonophoresis or sonophoresis). Useful in enhancing percutaneous penetration (and absorption) of various types of therapeutic agents. The expected mechanism of cavitational ultrasound is that bubbles oscillate and collapse at the skin surface, which generates localized shock waves and liquid microjets directed at the stratum corneum. This disrupts stratum corneum lipid structure and thereby increases skin permeability for up to many hours without damaging deeper tissues.

In thermal ablation, transiently heating the skin’s surface to hundreds of degrees for microseconds to milliseconds localizes heat transfer to the skin surface without allowing heat to propagate to the viable tissues below. Volumetric expansion ablates micron-scale craters in the skin’s surface due to the high temperature and allow medication to pass through. Microdermabrasion is another way to remove the stratum corneum barrier employs abrasion by microdermabrasion or simply using sandpaper. It is related to sand blasting on the microscopic scale to deliver drug.

Particulate System

The enhancers of the transdermal drug delivery system are liposomes, microemulsion, transfersome, niosomes and nanoparticles are examples of particulate means of enhancement.

Chemical Enhancers

The enhancers of the transdermal drug delivery system by means of chemicals are sulfoxides, glycols, alkanols, terpenes, azones etc. Chemicals that promote the penetration of topically applied drugs are commonly referred to as accelerants, absorption promoters, or penetration enhancers. Chemical enhancers act by increasing the drug permeability through the skin by causing reversible damage to the stratum corneum and by increasing the partition coefficient of the drug to promote its release from the vehicle into the skin. Some can be combine.

Transdermal Patch

Transdermal patch or skin patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and directly into the bloodstream. Skin patch uses a special membrane to control the rate at which the liquid drug contained in the reservoir within the patch can pass through the skin and into the bloodstream. Some drugs must be combined with substances, such as alcohol because alcohol increases their ability to penetrate the skin in order to be used in a skin patch. Various types of transdermal patches are used that deliver the specific dose of medication directly into the bloodstream.

When To Use Transdermal Patch

1. When the patient has intolerable side effects including constipation and dysphagia .

2. Where the pain control might be improved by reliable administration.

3. It can be used in combination with other enhancement strategies to produce synergistic effects.

Transdermal Patch Design

In almost all transdermal patch designs, the drug is stored in a reservoir that is enclosed on one side with an impermeable backing and has an adhesive that contacts the skin on the other side. Some designs employ drug dissolved in a liquid or gel-based reservoir, which can simplify formulations and permit the use of liquid chemical enhancers, such as ethanol. These designs characteristically are composed of four layers: an impermeable backing membrane; a drug reservoir; a semi-permeable membrane that may serve as a rate-limiting barrier; and an adhesive layer. Other designs incorporate the drug into a solid polymer matrix, which simplifies manufacturing. Matrix systems can have three layers, by eliminating the semi-permeable membrane, or just two layers, by incorporating the drug directly into the adhesive.

Types Of Transdermal Patches

a) Single layer drug in adhesive: adhesive layer contains the drug. The adhesive layer is surrounded by a temporary liner and a backing.

b) Multi -layer drug in adhesive: made up of two or three layers. The adhesive layer and another layer for sustain release. The sustain release layer may be made up of just a layer or two. An immediate release and control release layer.

c) Vapor patch: In this type of patch the role of adhesive layer not only serves to adhere the various layers together but also serves the market, commonly used for releasing essential oils in decongestion.

d) Reservoir system: In this system the drug reservoir is embedded between the two layers; an impervious backing layer and a rate controlling membrane. The drug releases only through the rate controlling membrane. In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix.

Transdermal Gels

Gels as a semisolid system consisting of dispersion made up of either small inorganic particles or large organic molecules enclosing and interpenetrated by liquid. Gels consists of two phase system in which inorganic particles are not dissolved but merely dispersed throughout the continuous phase and large organic particles are dissolved in the continuous phase, randomly coiled in the flexible chains. A gel is colloid that is typically 99% weight liquid, which is immobilized by surface tension between it and a macromolecular network of fibers built from a small amount of a chelating substance present. Topical drug administration a localized drug delivery system anywhere in the body through ophthalmic, rectal, vaginal and skin as topical routes.

Gel Forming Substances

Polymers are used to give the structural network, which is essential for the preparation of gels. Gel forming polymers are classified as follows:

1. Natural polymers

i. Proteins – Collagen, Gelatin

ii. Polysaccharides – Agar, Alginate acid, etc

2. Semisynthetic polymers cellulose derivatives: Carboxymethyl cellulose, Methylcellulose, etc

3. Synthetic polymers

i. Carbomer – Carbopol 940, Carbopol 934

ii. Poloxamer

iii. Polyacrylamide

iv. Polyvinyl alcohol

v. Polyethylene and its co-polymers

4. Inorganic substances

i. Aluminium hydroxide

ii. Bentonite

5. Surfactants

i. Cetostearyl alcohol

ii. Brij

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