Lipids in Transdermal and Topical Drug Delivery | American Pharmaceutical Review - The Review of American Pharmaceutical Business & Technology

Lipid formulations, while gaining increasing importance in parenteral and oral drug delivery, are also important in transdermal and topical drug delivery. Examples and mechanisms by which lipids enhance the transport of drugs transdermally (through the skin) and topically (into the skin) will be discussed. Lipid formulations can form structures such as micelles, reverse micelles, emulsions, microemulsions, and liposomes that can aid delivery into and through the skin. A case study will be presented of a topical immunosuppressant investigated for the treatment of atopic dermatitis and psoriasis. A lipid-based polymeric ointment formulation gave superior skin uptake in vitro and in an in vivo swine efficacy model. Lipid formulations have become increasingly important in parenteral and oral drug delivery, and are also important in transdermal and topical drug delivery. There are a number of processes by which lipids facilitate delivery of drugs into and through the skin. Lipids can form unique phase structures such as micelles, emulsions, liposomes, and similar systems that can aid delivery. This article will review these processes, as well as highlight examples of transdermal and topical products that use lipids, including a case study of a lipid formulation of a topical immunosuppressant. Transdermal products are designed to deliver a given dose of a drug through the skin into the systemic circulation. Thus, in order to control the dose and rate of administration, these products are generally patches with a defined amount of drug and a defined area that is applied to the skin with an adhesive. Topical products are designed to deliver a drug into the skin to treat skin conditions such as atopic dermatitis and psoriasis, which generally reside in the lower regions of the skin (ie, the dermis and epidermis). Therefore, topical formulations are creams, lotions, ointments, or gels that the patient can apply to the affected areas at a relatively constant thickness. Despite these differences, the rate-limiting barrier of drug delivery for both transdermal and topical delivery is the stratum corneum, the upper layer of the skin (Figure 1). The stratum corneum is composed of proteinaceous dead cells (corneocytes), with a lipid domain between the cells; it thus can be visualized as protein “bricks” held together by lipid “mortar”; the lipids are about 78% neutral lipids and 18% sphingolipids.1 Figure 1. Structure of the skin, with applied topical formulation and transdermal patch Skin permeation through the stratum corneum is governed by the permeability coefficient, Kp, of Fick’s laws of diffusion as shown in the equations below. The permeability coefficient is comprised of the drug’s effective diffusion coefficient in the stratum corneum (D), the skin vehicle partition coefficient (Ps/v), and the effective diffusion path length (h) through the skin barrier. Flux (J) is the Kp multiplied by the drug concentration (c) in the donor vehicle 2: Kp is defined as being in an aqueous vehicle. The vehicle, in fact, may contain a solvent which solubilizes the drug to a greater extent than water. If the solvent does not penetrate the skin, however, the partition coefficient Ps/v will decrease by roughly the same proportion that the concentration is increased so that there is no net change in the flux, J. If, however, the solvent does penetrate the skin, Ps/v will not decrease as much, so that there will be an increase in flux. Furthermore, such a vehicle may also increase the diffusion coefficient D, providing an additional increase in flux.3 A compound that acts in such a way to increase the flux of a drug may accurately be called a penetration enhancer. Enhancers can exert their effect by influencing either D or Ps/v, or possibly both. 4 Many lipids solubilize a variety of poorly water-soluble drugs and penetrate the skin, and thus can act as penetration enhancers. A number of these interact with the lipid domains of the stratum corneum, increasing their fluidity and rendering the stratum corneum more permeable. Lipids will also act as a hydrophobic occlusive barrier to prevent water loss from the underlying skin; the resulting increased hydration of the stratum corneum leads to increased permeation.2 Lipids are classically defined as biological materials that are insoluble in water but soluble in organic solvents such as methylene chloride/methanol. This definition thus encompasses a diverse group such as fatty acids, triglycerides, phospholipids, steroids, terpenes, waxes, and even fat-soluble vitamins. An alternative definition, sometimes preferred by pharmaceutical scientists, is that lipids are fatty acids and the derivatives of those fatty acids, and substances related biosynthetically or functionally to these compounds. This definition would thus include synthetic substances such as propylene glycol fatty acid esters and ethyl laurate, as well as fatty alcohols such as cetyl alcohol (1-hexadecanol) and stearyl alcohol (1-octadecanol). Figure 2A shows the structures of some of these lipids used in topical and transdermal products. Figure 2. A) Structures of some lipids used in topical and transdermal formulations. B) Structures of solvents examined for topical immunosuppressant Oleic acid (OA) has been known to be a penetration enhancer for several decades. The polar head group of OA interacts with the head groups of the stratum corneum lipids; the cis-double bond near the middle of the tail group leads to a “kink” in the chain, thus leading to increased fluidity of the stratum corneum lipids when OA intercalates with them.4 Using 2-photon scanning fluorescence microscopy, Yu et al. have shown that OA’s effects as an enhancer result from both an increase in the vehicle/skin partition coefficient and an increase in the skin diffusion coefficient.5 Fatty acids can form ion pairs with amine-containing drugs, facilitating the diffusion of this more hydrophobic species into the stratum corneum.6 While 18 carbons appear to be the optimal chain length for enhancement among unsaturated fatty acids (viz, oleic acid), 10 to 12 carbons are optimal for saturated fatty acid chains.2 Propylene glycol monolaurate (PGML) and propylene glycol monocaprate (the 10-carbon analog) are examples of enhancers in this class found in some topical and transdermal products; they are also good solvents for a variety of drugs. Glycerol monoesters (such as glycerol monolaurate, glycerol monocaprate, glycerol monocaprylate, and glycerol monooleate) are another class of enhancer lipids used topically. The 14-carbon fatty acid ester, isopropyl myristate (IPM), is found in a number of topical products and at least one transdermal patch. IPM enhances permeation primarily by increasing the fluidity of the stratum corneum lipids and reducing the diffusional resistance.7 Lipid enhancers can act synergistically with one another, as was shown with IPM and glycerol monocaprylate in permeation of pentazocine.8 Other fatty acid derivatives used in topical and transdermal products are ethyl oleate, methyl laurate, isopropyl palmitate, and oleyl alcohol. Table 1 provides a representative list of lipids used in transdermal and topical products. Some of these lipids confer desirable formulation properties on the products such as stability, viscosity, improved consistency, or spreadability, and thus may not necessarily be included to enhance drug penetration. Table 1. Transdermal and topical products that contain lipid excipients