How Does the Drug Enter the Human Body Through the Skin?

Transdermal drug delivery systems in a broad sense include topical drug delivery systems and transdermal drug delivery systems (TDDS). The former acts on the skin or subcutaneous tissue; the latter is the absorption of drugs into the blood through the skin. Compared with oral or injection administration, the advantages of the transdermal drug delivery system include: 1. No gastrointestinal irritation; 2. Avoid the first pass effect of the liver 3. Get a controlled release effect; 4. Easy to use, good patient compliance; 5. High safety , Easy to remove; 6. less skin tissue degrading enzymes, can be used for the administration of macromolecular drugs. Global sales of transdermal drug delivery preparations reached US$12.7 billion in 2005, US$21.5 billion in 2010, and US$31.5 billion in 2015, with an average annual growth rate of 17.8%, far exceeding the average growth rate of the pharmaceutical industry. The market prospect of transdermal drug delivery system is broad, and the three pillars of oral, injection and transdermal drug delivery system have been formed.

The skin is the largest organ and the outermost barrier of the human body, which mainly prevents the invasion of microorganisms. The skin not only plays a physical defense role, but also has immune, metabolic and ultraviolet protection functions. The skin includes the epidermis (including the stratum corneum and the active epidermis), the dermis and the subcutaneous fat layer. The stratum corneum (SC) is a layered structure composed of stratum corneum cells embedded in the lipids between the cells, similar to “bricks” and “cement”. The stratum corneum barrier is the most important obstacle to drug penetration. Only drugs that meet certain conditions are suitable for transdermal administration, but most drugs cannot. How to make drugs break through the stratum corneum for transdermal absorption is the focus of research on transdermal drug delivery systems.

Skin Structure and Drug Absorption

The skin is the largest organ and outermost tissue of the human body. It has a barrier function. On the one hand, it can prevent the invasion of harmful factors such as mechanical, chemical, physical or biological in the external environment, and protect various organs and tissues from damage; on the other hand, it can prevent Loss of nutrients, electrolytes and water in the body. Normal skin is composed of epidermis, dermis and subcutaneous tissue, and the permeability and absorption capacity of each layer of tissue are different. The outermost layer of the epidermis is the stratum corneum. The stratum corneum is composed of 12-20 layers of keratinocytes. The cells rely on denatured connective tissue adhesion. The outermost 2~3 layers are loose and easy to peel off, and the inner layer is dense, which restricts the penetration of chemicals through the skin. The drug enters the dermis and subcutaneous fat tissue through the intact epidermis, and is absorbed by capillaries and lymphatic vessels into the systemic circulation. There are two ways of drug absorption through the skin: one way is to enter the dermis through the stratum corneum and epidermis, and is absorbed by capillaries into the systemic circulation, that is, the epidermal route. This is the main way for the drug to be absorbed through the skin. In this way, the drug can pass through the stratum corneum cells to reach the active epidermis, or through the interstitial spaces of the stratum corneum to reach the active epidermis. Due to the large diffusion resistance of stratum corneum cells, drug molecules diffuse through the stratum corneum mainly from the intercellular space. Between the stratum corneum cells is a multilayer lipid bilayer formed by lipid molecules. The hydrophilic part of the lipid molecule combines with water molecules to form an aqueous zone, while the hydrocarbon chain part of the lipid molecule forms a hydrophobic zone. Polar drug molecules penetrate through the aqueous zone between stratum corneum cells, while non-polar drug molecules penetrate through the hydrophobic zone. The other way is absorption through skin appendages, namely through hair follicles, sebaceous glands and sweat glands. The penetration rate of drugs through the skin appendages is faster than through the stratum corneum, but the skin appendages occupies only about 0.1% of the skin surface area, so it is generally considered that it is not the main way of drug absorption through the skin. When transdermal penetration begins, the drug is first absorbed through the skin adnexal pathway. When the drug reaches the blood circulation through the epidermal route, the percutaneous penetration reaches a steady state, and the effect of the adnexal route can be ignored. Some ionic drugs and water-soluble macromolecules are difficult to pass through the lipid-rich stratum corneum, and the adnexal pathway becomes very important. In addition, during iontophoresis, the skin appendages are the main channels for ionized drugs to pass through the skin. When the drug formulation is applied to the skin, the drug is released from the formulation to the skin surface. The drug dissolved on the skin surface is distributed into the stratum corneum, diffuses through the stratum corneum to reach the aqueous active epidermis, continues to diffuse to the dermis, and is absorbed by capillaries into the human circulation. The lipid-rich stratum corneum is the main barrier during the entire diffusion process. When the skin is damaged, the drug is easily absorbed through the active epidermis. The permeability coefficients of water, ethanol, glycerol, and amphetamine in non-stratum corneum skin are 20-100 times, 20 times, 15 times and 6600 times that of intact skin, respectively.