Topical Preparations One of the functions of the skin is to protect the internal body components against the external environment and thus to control the passage of chemicals into and out of the body. The skin is the most common site of administration for dermatological drugs to achieve local action and recently it has been used for delivery of systemically acting drugs. Skin Structure: The human skin is divided histologically into: 1-Epidermis: Thin, dry and tough outer layer. 2-Dermis: containing blood vessels, nerves, hair follicles, sebum and sweat glands. 3-The subcutaneous fat layer. The epidermis is made of two layers: 1-Basal layer (Viable). 2-Outer layer (Non-viable). The outer layer is called the stratum corneum (S.C.), it is a thick layer of dead epidermal cell and composed of 40% proteins (keratin), water and lipids. The high content of keratin in S.C. makes it an efficient barrier for percutaneous absorption. 1
-Routes of Drug Penetration: -Drug may penetrate intact skin after topical application through: 1-S.C. 2-Skin appendages. -Drug could permeate though the S.C. either by: A-Transcellular (Through the keratinized cells of S.C.). B-Intercellular (Between the keratinized cells of S.C.). After the drug molecules pass the S.C., these molecules may pass through the deeper epidermal tissues and into the dermis. When the drug reaches the vascularized dermal layer, it becomes available for absorption into the general circulation. On the other hand, drug could bypass S.C. and permeates the skin appendages which include hair follicles, sebaceous and sweat glands and pass into the general circulation. In general, if the skin is intact, the main route for the penetration of the drug is through the epidermis layers (S.C.), rather than the skin appendages where the effect of the appendageal diffusion is usually minimized due to the relatively small fractional area on the skin. -Percutaneous Absorption: Percutaneous absorption, that is the passage of the drug through the skin into the blood circulation, involves: a-dissolution of a drug in its vehicle. b-diffusion of solubilized drug from the vehicle to the surface of the skin. c-penetration of the drug through the layers of the skin, principally the S.C. Generally, drug absorption into the skin occurs by passive diffusion. The rate of drug transport across the S.C. follows Fick's law of diffusion which states that: 2
-Factors Affecting Percutaneous Absorption: They can be classified into: Factors related to the drug: 1-Drug concentration: The amount of the drug absorbed increased as the concentration of the drug in the vehicle is increased. 2-More drug is absorbed when it applied to a large surface area. 3-Partition coefficient: The drug substances should have a greater physicochemical attraction to the skin than to the vehicles in which it is presented (high p.c.) in order for the drug to leave the vehicle in favor of the skin. 4-Diffusion coefficient of the drug. Factors related to the vehicle: 1-Drug absorption appears to be enhanced from vehicles that easily cover the skin surface, mix readily with the sebum and bring the drug into contact with the tissue cell for absorption. 2-Vehicles that increase the hydration of the skin generally favor the percutaneous absorption of drugs. 3-Vehicles that increase the temperature of the skin like occlusive vehicles may affect on the absorption. 3
Factors related to the skin: 1-Skin age: The skin of the fetus, young and elderly are more permeable than adult. 2-Skin condition: Diseases commonly alter the skin condition e.g. inflamed skin with the loss of the S.C. increase the skin permeability. 3-Skin site: Variation in cutaneous permeability depends on the thickness and nature of the S.C. and the density of skin appendages e.g. Hyoscine Transdermal system employs at the post auricular skin (i.e. behind the ear) to insert the drug into the blood stream where the layer of the S.C. are thinner and less dense and there are more sweat and sebaceous glands. 4-Skin metabolism: the skin metabolizes some drugs e.g. steroid hormones. 5-Circulatory Effect (Blood flow). -Penetration Enhancers: They can be defined as substances used to increase the penetration of the drug through the skin. Substances reported to render the S.C. more permeable i.e. penetration enhancers include: organic solvents (like for ex. alcohol and dimethylsulphoxide (DMSO)), fatty acids (like oleic acid), Terpenes (like polysorbates and sodium lauryl sulphate). The proposed mechanisms of action include: Alteration in the hydration state of the S.C., alteration in the structure of the lipid in the intercellular channel of the S.C. and through the solvent action and carrier mechanism in the transport of ionizable drug. -Transdermal Therapeutic Systems (TTSs): They are non-conventional dosage form intended to deliver the drug across the skin for systemic activity. TTSs are drug loaded patches which deliver the therapeutic agents, at controlled rate, through the skin to the systemic circulation. 4
-Advantages of TTSs: 1-Avoid the G.I.T drug absorption difficulties caused by G.I.T ph, enzymatic activity, drug interaction with food...etc 2-Substitutes for oral administration of medication when that route is unsuitable, as 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 G.I.T absorption (thereby possibly avoiding the drug's deactivation by the liver enzymes). 4-Avoids the risks and inconveniences of parenteral therapy and the variable absorption and metabolism associated with oral therapy. 5-TTSs provide a sustained plasma profile over several days and consequently improve patient's compliance. 6-Extends the activity of drugs having short half-lives through the reservoir of drug present in the therapeutic delivery system and its controlled release characteristics. 7- TTSs Provide capacity to terminate drug effect rapidly (if clinically desired) by removal of drug application from the surface of the skin. -Disadvantages of TTSs: 1-It is unsuitable route for drugs that irritate or sensitize the skin. 2-Only relatively potent drugs are suitable candidate for transdermal delivery due to the natural limits of drug entry imposed by the skin's impermeability. 5
-TTSs Design: The patches are design into two main types: 1-Monolithic or matrix system: It consists of: 1-An occlusive backing layer protect the drug matrix. 2-A drug matrix layer which comprises a suspension of drug in equilibrium with its saturated solution. 3-An adhesive layer contains dissolved drug in equilibrium with that in the matrix and attaches to the skin. 4- A protective strippable film ( removed prior to application). 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. The matrix may be of two types: 1-Matrix without an excess of drug, in this type, drug is available to maintain the saturation of the stratum corneum as long as the level of drug in the device exceeds the solubility limit of the stratum corneum. As the conc. of drug in the device diminishes below the skin's saturation limit the transport of drug from device to skin gradually declines. 2-Matrix have an excess amount of drug, a drug reserve is present to assure continued drug saturation at the stratum corneum. In these instances, the rate of drug decline is less than in the type designed with no drug reserve. 6
Most transdermal drug delivery systems are designed to contain an excess of drug due to the advantage of assurance continuous drug availability and absorption used patches are replaced on schedule with fresh ones. 2-Rate-limiting membrane system: A typical patch in this system consists of backing layer, a reservoir containing the drug, the membrane, a skin adhesive and protective layer Membrane-controlled system have the advantage over monolithic systems in that as long as the drug solution in the reservoir remains saturated, the release rate of the drug through the controlling membrane remains constant. In membrane system, a small quantity of drug is frequently placed in the adhesive layer to prompt drug absorption and therapeutic effects upon skin placement. In summary, either the drug delivery device or the skin may serve as the rate controlling mechanism in drug delivery. For ex., if the drug is delivered to the stratum corneum at a rate less than the absorption capacity, the device is the controlling factor. If, on the other hand, the drug is delivered to the skin area in saturation, the skin is the controlling factor to the rate of drug transport. 7