109 Transdermal Drug Delivery Systems 109.1 Introduction 109-1 109.2 Attributes of a Transdermal System 109.2 Developing a Ranudermal Selecting Drug Candidate Gary W. Cleary 108.3 Future Approaches to Transdermal Delivery CGyynos Research Corporation Systems 109.4 109.1 Introduction A “transdermal approach of technology” can be defined as any method that allows a drug or biologic: marker to transit skin in either direction, A transdermal drug delivery system allows the drug oF molecule to transit from the outside of skin, through its various layers, and finally into the circulatory system to exert a pharmacological action. There may be some exceptions to this definition — for example, a system ‘may concentrate the drug in the skin layers or near the surface ofthe skin to exert a localized effect, such as wound dressings for antisepsis or improved healing processes. ‘The transdermal drug delivery approach offers new opportunities for old drugs and new avenues to ‘medical therapy. Developing these new products isa complex task. Primarily, today’s transdermal designs. lude not only drugs, pharmaceutical vehicles, and other excipients but also polymeric fils, specialty coatings, pressure-sensitive adhesives, and release substrates, They involve many different scientific and. ‘manufacturing disciplines that are unfamiliar to both the pharmaceutical industry and the pressure sensitive adhesive industry. New technology that can be brought to bear will expand future opportunities In the 1870s, physicians and their associates were not only exploring new materials and adhesives for binding surgical wounds, but were also including medicaments in these adhesive tapes to treat conditior that respond to drugs in the systemic circulation, Medicated plasters have been used to treat back pai and iodine-impregnated gauze pads were quite popular at one time, but these devices gained dislavor because of such problems as irritation, side effects, and changes in the drug regulatory environment. Although, physicians have long been prescribing topical products for treatment of localized diseases, it was not until the 1950s in the United States that a drug was made commercially available for systemic circulation by means of a topical application. Topical delivery of nitroglycerin was achieved by ‘means of an ointment that was rubbed into the skin and overwrapped with Saran film, which was secured to the skin by means of surgical tape. This was the forerunner of the current transdermal device that has pressure-sensitive adhesives as part of the product. It was not until 30 years later, in the early 1980s, that ‘a more sophisticated transdermal product appeared on the market. Several transdermal delivery systems had reached the U.S. market as of 1988, They ranged in design from the amorphous ointments to solid state laminates. A review of the patent literature indicates a furry of activity in developing many different designs. Scopolamine (1980), nitroglycerin (1981), clonidine (1985), and estradiol (1986) are drugs that have reached the U.S. transdermal market. Drugs that are 109-1109-2 Coatings Technology Handbook, Third Edition sold outside the United States include isosorbide dinitrate and progesterone. The market to the pharma- ceutical companies reached close to $500 million in 1987. The products have been accepted by physicians and by patients asa viable dosage form, 109.2 Attributes of a Transdermal System “To begin a program of developing a transdermal, one should consider what itis that the product isto achieve; tha is, one should develop a "product profile” that describes the essential attributes ofthe desired. transdermal. Once the criteria have been determined, a list of attributes of the delivery system can be made to develop a product profile to provide direction to the formulator or “system designer” These autributes will describe the following: + Physical characteristics (system size and shape, thickness, construction, amount of drug, color, flexibility, ete.) + Functionality (necessary rate of release through skin, rate of release from the system, degree of adhesion to skin, ength of time to adhere on skin site, method of applying system to skin, ete:) + Patient demography + Degree of iritation tolerance by patient Cost to patient and to third-party payers + Medical rationale and intended indications + Required margins by pharmaceutical company + Availability of raw materials + Patentability + Effect of regulatory environment For example, Key Pharmaceutical Company’ first transdermal nitroglycerin product delivered 10 mg/ day over a20 cm! area (equal to 0.5 mg/cm:/day). This transdermal, which has been accepted by patients, was actually a 90 em: system because of the peripheral adhesive (see below, Type III design). Cosmetic appearance and size of the system will affect patient acceptance. Depending on the size that patients ddeem to be acceptable, the maximum total amount of drug that can be delivered may be as high as 50 ‘mg/day. The sizeof the system will then depend on how much the skin will allow through, what blood. level is needed to be achieved to elicit the desired pharmacological effec, and perhaps the patient’ well being. Skin irritation and sensitization are issues that must be addressed in the ealy stages of develop: ‘ment. A skin reaction may be caused by the drug, or by any vehicles, enhancers, or polymer that may be present. The cost/benefit ratio ofthe transdermal compared to other dosage forms must be weighed, as well ‘There are various ways to view the design of these transdermals. One way is to stat by considering the design of the transdermal without regatd to the mechanism of how the drug is released or controlled. Figure 109.1, a schematic side view of the laminate construction that is found in transdermal products, facilitates a visual conception of the actual product, its components, and how it might be formulated fabricated. There are four types of designs on the market: + Type I: amorphous ointment, cream, lotion, oF viscous dispersion that is applied directly to the skin — Nitrobid (Kremers-Urban) + Type Il: amorphous liquid dispersion that is sealed between two laminate structures on all sides — Transderm Nitro and Estraderm (Ciba) + Type IIL solid state polymer matrix attached to a peripheral adhesive tape — Nitrodise (Searle); Nitro TDS (Bolar) + Type 1V: solid state polymer film structures laminated together — Transderm Scop V (Ciba); ‘Transderm-clonidine (Bochringer-Ingelheim); Nitro-Dur I (Key); Deponit (Wyeth) jtro-Dur I (Key); ‘These four types are not all-inclusive, as new approaches and combinations of each are always possible. All these designs have the potential to deliver a drug to the skin so that the drug can migrate through‘Transdermal Drug Delivery Systems 109.3 | semisquid 7 liquid ited laminate structure Backing Liquid Drug Reservoir Modulating ot Nonmodulating Rate Layer ‘Skin Contact Adhesive I peripheral adhesive laminate stucture Backing Peripheral ‘Skin Contact achesive Release Paper Protective Fol Poel Sip Drug Reservoir Layer 1V cold etate laminate structure Backing Drug ReservotrLayor Modulating ot "Nonmodulating Rate Layer ‘Skin Contact Adhesive FIGURE 109.1, Schematic diagrams of four types of transdermal drug delivery system designs. the skin, Types Il, Il, and IV have the adhesive and film laminate structure built into the final product. By understanding these basic designs, their advantages and disadvantages, one can incorporate the most suitable diffusional mechanism, using the appropriate plasticizers or vehicles, polymers, branes, and adhesives, and matching the diffusivity of the drug through skin to achieve the desired. delivery rate and plasma profile of the drug. The types of material that have been used in transdermal products that have reached the marketplace include the following: + Pressure-senstive adhesives: acrylates, silicone, and rubber-based adhesives + Release liners: silicone and fluorocarbon coats on paper, polyester, or polycarbonate films + Backings and membranes: ethylene-vinyl acetate, polypropylene, polyester, polyethylene, polyvinyl chloride, and aluminum films + Specialty films: foams, nonwovens, croporous films, vapor-deposited aluminum films