Transdermal Drug Delivery System

Prepared By:Maksud Al- Hasan MahimB.Pharm, M.Pharm

The skin plays an important role in the transdermal drug delivery system. The skin of an average adult body covers a surface area of approximately 2 sq.m. and receives about one third of the blood circulating through the body and serves as a permeability barrier against the transdermal absorption of various chemical and biological agents.

Human Skin

Figure: Various routes of drug absorption.

Different Levels of Drug Effect Seen after Percutaneous Drug Delivery

A Drug applied to the skin may elicit effect at any one of four different levels:1. skin surface effect2. stratum corneum effect3. A more deep seated effect requiring penetration into the living epidermis4. A systemic effect resulting from sufficient delivery of drug across the layers of skin into the vascular system

1. Surface effectsAn effect on the skin surface may be

any one of the following types:

i. Film formation: The film may either be protective (e.g. a zinc oxide cream or a sunscreen) or occlusive (giving a moisturizing effect)

ii. Antimicrobial effect

iii. A cleansing effect (e.g. effect of soaps or surfactants)

2. Stratum corneum effects i. Effect of certain sunscreens e.g. p -aminobenzoic acid ii. Effect of surface films causing moisturization and consequent softening of skiniii. Effect of keratolytic agents, such as salicylic acid, causing breakup of stratum corneum cell aggregates seen in conditions like psoriasis (a disease characterized by thickened scaly plaques)iv. The stratum corneum may serve as a reservoir or depot for certain drugs that accumulate to a significant extent in the skin on topical application (e.g. benzocaine, scopolamine and corticosteroids).

3&4. Epidermal, Dermal, Local & Systemic effectsPenetration of a drug into the viable epidermis and

dermis may be difficult to achieve. But once transepidermal penetration has occurred, the continued diffusion of drug into the dermis may cause transfer of the drug into the microcirculation of the dermis and then into the general circulation.

Nevertheless, it is possible to formulate a drug delivery system which provides substantial localized drug delivery without achieving corresponding high systemic concentrations.

Percutaneous Absorption (Sometimes referred as Transdermal absorption)

The absorption of substances from outside the skin to positions beneath the skin including entrance into the blood stream is referred to as percutaneous absorption.

In O the r Wo rds - Percutaneous absorption involves the transfer of drug from the skin surface into the stratum corneum and its subsequent diffusion through the underlying epidermis & the dermis and into the microcirculation.

Although the skin has been divided histologically into the stratum corneum, the living epidermis and the dermis collectively, it can be considered as a laminate of barriers. Passage through this laminate of barriers can occur by diffusion via: -

1. Transcellular penetration (across the cells)2. Intercellular penetration (between the cells)3. Transappendageal penetration (via hair follicles, sweat and sebum glands and pilosebaceous apparatus)

The major routes of penetration is through the intercellular channels. The role of transappendageal penetration is very minor because the areas of the skin occupied by these appendages is relatively small.

The skin behaves as a passive barrier to diffusing molecules. The diffusional resistances are encountered against penetrations of molecules through various regions of skin.

The total diffusional resistance (Rskin) can be given by:

Rskin = Rsc + Re + Rpd

Where R is the diffusional resistance and the subscripts sc, e and pd refers to the stratum corneum, epidermis and papillary layer of the dermis respectively.

By and large, the greatest resistance to penetration is met in the stratum corneum, i.e. diffusion through the stratum corneum tends to be rate limiting step. Once through the stratum corneum, the molecules may then pass through the deeper epidermal tissues and into the dermis. When the drug reaches the vascularized dermal layer it is available for absorption into general circulation.

Factors Affecting Percutaneous Absorption

1. Drug Concentration2. Surface area of the application site3. Aqueous solubility and partition coefficient of

drug4. Vehicle characteristics5. Occlusion of the skin6. The degree of rubbing or inunctions7. Thickness of the stratum corneum in the

application site8. The length of the application period9. Number/frequency of application per day10. Percutaneous absorption/penetration enhancer

Transdermal Drug Delivery SystemsTransdermal drug delivery systems are designed to

support the passage of drug substances from the surface of the skin, through its various layers, into the systemic circulation. Physically, these systems are sophisticated patches.

There are two basic types of transdermal dosing systems:1. Those that allow the skin to control the rate of drug absorption.2. Those that control the rate of drug delivery to the skin.

The first type is useful for drugs for which a wide range of plasma concentration is effective, but not toxic. For these drugs, transdermal dosage forms may be developed of various size and concentrations, with physician increasing the dose or transdermal application until the desired effect is obtained.

However, for many drugs, it is important to control the predictable rate of drug delivery and percutaneous absorption. In these instances, effective transdermal drug delivery systems deliver uniform quantities of drug to the skin over a period of time. The amount of drug delivered per unit of time may varied with different types of skin and thus, the drug d e live ry s y s te m , and not the skin, controls the amount of drug entering the circulation.

Design features and objectives

Included among the designed features and objectives of rate-controlling transdermal drug delivery systems are the followings:

1. Deliver the drug substances at a controlled rate, to the intact skin of patients, for absorption into the systemic circulation.

2. The system should possess the proper physico-chemical characteristics to permit the ready release of the drug substance and facilitate its partition from the delivery system into the stratum corneum.

3. The system should occlude the skin to ensure the one–way flux of the drug substance.

4. The transdermal system should have a therapeutic advantage over other dosage forms and drug delivery systems.

5. The system's adhesive, vehicle and active agent should be non–irritating and non–sensitizing to the skin of the patient.

6. The patch should adhere well to the patient’s skin and its physical size and appearance and placement on the body should not be deterrent to use.

7. The system should not permit the proliferation of skin bacteria beneath the occlusion.

TYPES OF TRANSDERMAL PATCHES

There are various types of Transdermal Patches:

1. Single layer drug in adhesiveIn this type, the adhesive layer contains the drug. The adhesive layer not only serves to adhere the various layers together but also responsible for releasing the drug to the skin.

The adhesive layer is surrounded by a temporary liner and a backing.

2. Multi-layer drug in adhesiveThis type is also similar to the single layer but it contains an immediate drug release layer and other layer will be a controlled release along with the adhesive layer.

The adhesive layer is responsible for the releasing of drug.

This patch also has a temporary liner-layer and a permanent backing.

3. Vapour patchIn this type of patch, the role of adhesive layer not only serves to adhere the various layers together but also serves as release vapour.

These are new to the market, commonly used for releasing of essential oils in decongestion. Various other types of vapor patches are also available in the market which are used to improve the quality of sleep and reduces the cigarette smoking conditions.

4. Reservoir systemIn this system the drug reservoir is embedded between an impervious backing layer and rate controlling membrane. The drug releases only through the rate controlling membrane, which can be micro porous or non porous.

In the drug reservoir compartment, the drug can be in the form of a solution, suspension, gel or dispersed in a solid polymer matrix.

Hypoallergenic adhesive polymer can be applied as outer surface polymeric membrane which is compatible with drug.

Figure: Representative designs of transdermal drug delivery systems.

5. Matrix systemi. Drug-in-adhesive systemii. Matrix-dispersion system

6. Micro-reservoir systemIn this type, the drug delivery system is a combination of reservoir and matrix-dispersion system. The drug reservoir is formed by first suspending the drug in an aqueous solution of water soluble polymer and then dispersing the solution homogeneously in a lipophilic polymer to form thousands of unreachable, microscopic spheres of drug reservoirs. This thermodynamically unstable dispersion is stabilized quickly by immediately cross-linking the polymer in situ by using cross linking agents.

BASIC COMPONENTS OF TDDS1.Polymer matrix 2. Drug substance Following are some of the desirable properties of a drug suitable for transdermal delivery:

i. Physicochemical propertiesii. Biological properties

3. Penetration enhancers a. Solventsb. Surfactantsc. Miscellaneous chemicals

4. Drug reservoir components

Figure: Different layers of TDDS.

5. Backing laminates The primary function of the backing laminate is to provide support. They should be able to prevent drug from leaving the dosage form through top. They must be impermeable to drugs and permeation enhancers; should have a low moisture vapor transmission rate; must have optimal elasticity, flexibility, and tensile strength; must be chemically compatible with the drug, enhancer, adhesive and other excipients; must be relatively inexpensive and allow printing and adhesive lamination. Type backing membranes are composed of a pigmented layers, an aluminum vapor coated layer, a plastic film (polyethylene, polyvinyl chloride, polyester) and a heat seal layer.

6. Rate controlling membrane Rate controlling membranes in transdermal devices govern drug release from the dosage form.

Membranes made from natural polymeric material such as chitosan show great promise for use as rate controlling membranes. Recently composite polyhydroxyethyl methacrylate membranes have been evaluated as rate controlling barriers for transdermal application.

7. Adhesive layer The fasting of all transdermal devices to the skin using a pressure sensitive adhesive that can be positioned on the face or in the back of device is necessary. It should not cause irritation, sensitization or imbalance in the normal skin flora during its contact with the skin. It should adhere to the skin aggressively.

The three major classes of polymers evaluated for potential medical applications in TDDS include:

•Polyisobutylene type pressure sensitive adhesives. •Acrylic type pressure sensitive adhesives.•Silicone type pressure sensitive adhesives.

8. Release liners The release liner has to be removed before the application of transdermal system, and it prevents the loss of the drug that has migrated into the adhesive layer during storage. It also helps to prevent contamination.

It is composed of a base layer, which may be non-occlusive or occlusive, and a release coating layer made of silicon or Teflon. Other materials include polyesters, foil and metallized laminates.

Technology of Transdermal Drug Delivery System (Basic manufacturing Designs)

Technically, transdermal drug delivery systems may be categorized into two types:1. Monolithic systems2. Membrane controlled systems

1. Monolithic system: Monolithic systems incorporate a drug matrix layer between backing and frontal layers. The drug matrix layer is composed of a polymeric material in which the drug is dispersed. The polymer matrix controls the rate at which the drug is released for percutaneous absorption. Nitro-Dur (Key) and Nitrodisc (Searle) are the examples of monolithic systems.

In the preparation of monolithic systems, the drug and the polymer are dissolved or blended together, cast as the matrix and dried.

The gelled matrix may be produced in sheet or cylindrical form, with individual dosage units cut and assembled between the backing and frontal layers.

Most transdermal drug delivery systems are designed to contain an excess of drug and thus have drug releasing capacity beyond the time-frame recommended for replacement. This ensures continued drug availability and absorption as used patches are replaced on schedule with fresh ones.

2. Membrane Controlled Transdermal Systems: Membrane-controlled transdermal systems are designed to contain a drug reservoir, usually in liquid or gel form, a rate controlling membrane and adhesive or protective backing.

In membrane-controlled systems, a small quantity of drug is frequently placed in the adhesive layer to initiate prompt drug absorption and therapeutic effects upon placement into the skin. Transderm – Nitro (Sumit) and Transderm – Scop (CIBA) are the examples of this technology.

Membrane controlled systems have the advantage over monolithic systems in that, as long as the drug solution in the reservoir remains saturated, the release rate of drug through the controlling membrane remains constant.

Membrane controlled systems may be prepared by preconstructing the delivery unit, filling the drug reservoir and sealing or lamination with controlling membrane.

Examples of Transdermal Systems in Use1. Transdermal Scopolamine Systems2. Transdermal Nitroglycerine Systems3. Transdermal Clonidine Systems 4. Transdermal Estradiol Systems 5. Other Transdermal Therapeutic Systems:

i. A Testosterone Transdermal Systems [Testoderm (Alza)]

ii. A Salicylic Acid Transdermal System [Trans-Ver-Sal (Tsumura Medical)]

6. Others TDDSs under study: i. Isosorbide Nitrate, propranolol and mepindolol and cardiovascular drugs

ii. Levonorgestrel / estradiol for contraception.

Advantages of TDDSAmong the advantages of TDDSs are the followings:

1. Avoid gastrointestinal drug absorption difficulties caused by gastrointestinal pH, enzymatic activity and drug interactions with food, drink or other orally administered drugs.

2. Substitute for oral administration of medication when that route is unsuitable, as in instances of vomiting and / or diarrhea.

3. Avoid the first pass effect, that is, the initial pass of a drug substance through the systemic and portal circulation following gastrointestinal absorption, thereby possibly avoiding the drug deactivation by digestive and liver enzymes.

4. Avoid the risks and inconveniences of parenteral therapy and the variable absorption and metabolism associated with oral therapy.

5. Provide the capacity for multi–day therapy with a single application therapy improving patient compliance over use of other dosage forms requiring more frequent dose administration.

6. Extend the activity of drugs having short half-lives through the reservoir of the drug present in the therapeutic delivery system and its controlled release characteristics.

7. Provide capacity to terminate the effect rapidly (if clinically desired) by removal of drug application from the surface of the skin.

8. Provide ease of rapid identification of the medication in emergencies (e . g . nonresponsive, unconscious, or comatose patients).

Disadvantages of TDDSAmong the disadvantages of TDDSs are the

followings:

1. The transdermal route of administration is unsuitable for drugs that irritate or sensitize the skin.

2. Only relatively potent drugs are suitable candidates for transdermal delivery due to natural limits of drug entry imposed by skin’s impermeability.

3. Technical difficulties are associated with the adhesion of systems to different skin types and under various environmental conditions.

4. The development of rate-controlling drug delivery features which are not economically feasible and therapeutically effective for many drug substances.

General considerations in the use of TDDSSome general points applicable to the use of transdermal

patches include the following:1. The site selected for the application should be clear, dry

and hairless (but not shaved). [Nitroglycerin patches are generally applied to the chest, estradiol to the buttocks or the abdomen, scopolamine behind the ear and nicotine to the upper trunk or upper outer arm.] Because of the possible occurrence of skin irritation, the site of application for replacement patches is rotated. Skin sites generally are not reused for a week.

2. The transdermal patch should not be applied to skin that is oily, irritated, cut or abraded. (This is to assure the intended amount and rate of transdermal drug delivery and absorption.)

3. The patch should be removed from its protective package, being careful not to tear or cut it. The patch's protective backing should be removed to expose the adhesive layer, and it should be applied firmly with the palm or heel of the hand until securely in place (about 10 seconds).

4. The patches should be worn for the period of time stated in the product's instructions. Following that period the patch should be removed and a fresh patch applied as directed. The used patch should be folded in half with the adhesive layer together so that it cannot be reused.

5. Patches generally may be left on when showering, bathing or swimming. Should a patch prematurely dislodge, an attempt may be made to reapply it, or it may be replaced with a fresh patch.

6. The patient should be instructed to clean the hands thoroughly before and after applying the patch. Care should be taken not to rub the eyes or touch the mouth during handling the patch.

7. As with all medications, if the patient exhibits sensitivity or intolerance to the drug, or if undue skin irritation results, the patient should seek re-evaluation.