Transdermal Drug Delivery System Project Report - Part 1
INTRODUCTION
Continuous intravenous infusion is recognized as a superior mode of drug administration not only to bypass hepatic "first-pass" metabolism, but also to maintain a constant and prolonged drug level in the body. A closely monitored intravenous infusion can provide the advantages of both direct entry of drug into the systemic circulation and control of circulating drug levels. However, such mode of drug administration entails certain risks and, therefore, necessitates hospitalization of the patients and close medical supervision of administration.
Recently, it is becoming evident that the benefits of intravenous drug infusion can be closely duplicated, without its hazards, by using the skin as the port of drug administration to provide continuous transdermal drug infusion into the systemic circulation1.
To provide continuous drug infusion through an intact skin, several transdermal therapeutic systems have been developed for topical application onto the intact skin surface to control the delivery of drug and its subsequent permeation through the skin tissue. It is exemplified by the development and marketing of scopolamine-releasing transdermal therapeutic system for 72-hr prophylaxis or treatment of motion-induced nausea2, of nitroglycerin and isosorbide dinitrate-releasing trans-dermal therapeutic systems for once-a-day medication of angina pectoris3, and of clonidine-releasing transdermal therapeutic system for weekly treatment of hypertension4. The intensity of interests in the potential biomedical applications of transdermal controlled drug administration is demonstrated in the increasing research activities in a number of health care institutions in the development of various types of transdermal therapeutic systems for long term continuous infusion of therapeutic agents, including antihypertensive, anti-anginal, anti-histamine, anti-inflammatory, analgesic, anti-arthritic, steroidal, and contraceptive drugs.
Skin and drug permeation
For understanding the concept of transdermal drug delivery systems, it is important to review the structural and biochemical features of human skin and those characteristics which contribute to the barrier function and the rate of drug access into the body via skin.
The Skin
The skin is one the most extensive organs of the human body covering an area of about 2m2 in an average human adult. The skin separates the underlying blood circulation network from the outside environment, serves as a barrier against physical, chemical and microbial attacks, acts as a thermostat in maintaining body temperature, protects against harmful ultraviolet rays of the sun and plays a role in the regulation of blood pressure.Anatomically, the skin has many histologic layers but in general, it is described in terms of three major tissue layers: the epidermis, the dermis and the hypodermis.The epidermis results from an active epithelial basal cell population and is approximately 150 micrometers thick. It is the outermost layer of the skin and the process of differentiation results in migration of cells from the basallayer towards the skin surface.5The end result of this process is the formation of a thin, stratified and extremely resilient layer at the skin surface. Below this layer are the other layers of the epidermis - the stratum lucidum, stratum granulosum, stratumspinosum and stratum germinativum. Together, these other layers constitute the viable epidermis.The stratum corneum or the horny layer is the rate-limiting barrier that restricts the inward and outward movement of chemical substances. The interior of the cells is crisscrossed with densely packed bundles of keratin fibres. Due to this, the dry composition of the horny layer is 75-85% protein, most of which is the intracellular keratin and a part being associated with a network of cell membranes. The bulk of the remainder of the substance of the stratum corneum is a complicated mixture of lipids which lies between regions, the mass of intracellular protein and the intercellular lipoidalmedium.The epidermis rests on the much thicker dermis. The dermis essentially consists of about 80% of protein in a matrix of muco-polysaccharide "ground substance".
KINETICS OF TRANSDERMAL PERMEATION
Trans-dermal permeation of a drug involves the following steps
1. Sorption by stratum corneum
2. Penetration of drug through viable epidermis
3. Uptake of the drug by the capillary network in the dermal papillary layer.
The rate of permeation across the skin is given by
dq/dt = Ps ( Cd – Cr ) (1)
where Cd and Cr are the concentrations of skin penetrant in the donor compartment and in the receptor compartment. Ps is the overall permeability coefficient of the skin tissues to the penetrant. This permeability coefficient is given by the relationship:
DssPs= Ks/hs (2)
where Ks is the partition coefficient for the interfacial partitioning of the penetrant molecule from a solution medium or a transdermal therapeutic system on to the stratum corneum, Dss is the apparent diffusivity for the steady state diffusion of the penetrant molecule through a thickness of skin tissues and hs is the overall thickness of skin tissues.6 As Ks, Dss and hs are constant under given conditions, the permeability coefficient (Ps) for a skin penetrant can be considered to be constant.From equation (1) it is clear that a constant rate of drug permeation can be obtained only when Cd>> Cr, ie., the drug concentration at the surface of the stratum corneum (Cd) is consistently and substantially greater than the drug concentration in the body (Cr). Then the equation (1) becomes:
dq/dt = Ps Cd
and the rate of skin permeation (dQ/dt) is constant provided the magnitude of Cd remains fairly constant throughout the course of skin permeation. For keeping Cd constant, the drug should be released from the device at a rate (Rr) that is either constant or greater than the rate of skin uptake (Ra). Since Rr is greater than Ra, the drug concentration on the skin surface (Cd) is maintained at a level equal to or greater than the equilibrium solubility of the drug in the stratum corneum (Cs). Therefore, a maximum rate of skin permeation is obtained and is given by the equation:
(dQ/dt)m = Ps Cs
from the above equation, it can be seen that the maximum rate of skin permeation depends on the skin permeability coefficient (Ps) and its equilibrium solubility int eh stratum corneum (Cs).
APPROACHES USED IN DEVELOPMENT OF TRANSDERMAL DRUG DELIVERY SYSTEMS
Four different approaches have been utilized to obtain trans-dermal drug delivery systems:
a. MEMBRANE PERMEATION CONTROLLED SYSTEMS
In this type of system, the drug reservoir is totally encapsulated in a shallow compartment moulded from a drug-impermeable metallic plastic laminate and a rate controlling polymeric membrane which may be micro-porous or non-porous e.g., ethylene vinyl acetate (EVA) copolymer, with a defined drug permeability property. A cross-sectional view of this system is shown in figure. The drug molecules are permitted to release only through the rate-controlling membrane.7In the drug reservoir compartment, the drug solids are either dispersed in a solid polymer matrix or suspended in an unleachable, viscous liquid medium such as silicone fluid to form a paste like suspension. A thin layer of drug compatible, hypoallergenic adhesive polymer e.g. silicone or polyacrylate adhesive may be applied to the external surface of the rate controlling membrane to achieve an intimate contact of the trans-dermal system and the skin surface the rate of drug release from this type of trans-dermal drug delivery system can be tailored by varying the polymer composition, permeability coefficient and thickness of the rate limiting membrane and adhesive.
The constant release rate of the drug is the major advantage of membrane permeation controlled trans-dermal system. However, a rare risk also exist when an accidental breakage of the rate controlling membrane can result in dose dumping or a rapid release of the entire drug content. Examples of this system are:
• Nitroglycerin-releasing trans-dermal system for once a day medicatin in angina pectoris.
• Scopolamine-releasing trans-dermal system prophylaxis of motion sickness
• Estradiol-releasing trans-dermal system for treatment of menopausal syndrome for 3-4 days
The intrinsic rate of drug release from this type of drug delivery system is defined bywhere CR is the drug concentration in the reservoir compartment and Pa and Pm are the permeability coefficients of the adhesive layer and the rate controlling membrane, respectively. For a micro-porous membrane, Pm is the sum of permeability coefficients for simulations penetration across the pores and the polymeric material Pm and Pa respectively, where km/r and ka/m are the partition coefficients for the interfacial partitioning of drug from the reservoir to the membrane and from the membrane to the adhesive respectively; Dm and Da are the diffusion coefficients in the rate controlling membrane and adhesive layer respectively; and hm and ha are the membrane, the porosity and tortuosity of the membrane should be taken into the calculation of the Dm and hm values. Substituting equations for Pm and Pa which defines the intrinsic rate of drug release from a membrane moderated drug delivery system.
b. ADHESIVE DISPERSION TYPE SYSTEMS
This is a simplified form of the membrane permeation controlled system. As represented in figure the drug reservoir is formulated by directly dispersing the drug in an adhesive polymer eg. Poly (isobutylene) or poly (acrylate) adhesive and then spreading the medicated adhesive, by solvent casting or hot melt, on to the flat sheet of drug impermeable metallic plastic backing to form a thin drug reservoir layer.
On top of the drug reservoir layer, thin layers of non-medicated, rate controlling adhesive polymer of a specific permeability and constant thickness are applied to produce an adhesive diffusion-controlled delivery system. An example of this type of system is isosorbide dinitrate releasing trans-dermal therapeutic system for once a day medication of angina pectoris. This adhesive diffusion controlled drug delivery system is also applicable to the trans-dermal controlled administration of verapamil.8
The rate of drug release in this system is defined by:
where Ka/r is the partition coefficient for the interfacial portioning of the drug from the reservoir layer to adhesive layer.
c. MATRIX DIFFUSION CONTROLLED SYSTEMS
In this approach, the drug reservoir is prepared by homogeneously dispersing drug particles in a hydrophilic or lipophilic polymer matrix. The resultant medicated polymer is then moulded into a medicated disc with a defined surface area and controlled thickness. The dispersion of drug particles in the polymer matrix can be accomplished by either homogeneously mixing the finely ground drug particles with a liquid polymer or a highly viscous base polymer followed by cross linking of the polymer chains or homogeneously blending drug solids with a rubbery polymer at an elevated temperature. The drug reservoir can also be formed by dissolving the drug and polymer in a common solvent followed by solvent evaporation in a mould at an elevated temperature and/or under vacuum. This drug reservoir containing polymer disc is then pasted on to an occlusive polymer is then spread along the circumference to form a strip of adhesive rim around the medicated disc.
This type of trans-dermal system is exemplified by the nitroglycerin releasing trans-dermal therapeutic systems. These are designed to be applied to the intact skin to provide a continuous trans-dermal infusion of nitroglycerin at a daily dose of 0.5 mg/cm2 for therapy of angina pectoris. It is a modified version of NitroDur in which the drug is dispersed in an acrylic based polymer adhesive with a resinous cross linking agent which results in a much thinner and more elegant patch. Patent disclosures have also been filed for applying this drug delivery system for trans-dermal controlled administration of estradiol discetyate and verapamil. The rate of drug release from this type of system is defined as:where A is the initial drug loading dose dispersed in the polymer matrix and Cp and Dp are the solubility and diffusivity of the drug in the polymer respectively.
