STIMULI TO THE REVISION PROCESS Stimuli articles do not necessarily reflect the policies Pharmacopeial Forum 750 of the USPC or the USP Council of Experts Vol. 35(3) [May–June 2009] Topical and Transdermal Drug Products The Topical/Transdermal Ad Hoc Advisory Panel for the USP Performance Tests of Topical and Transdermal Dosage Forms: Clarence T. Ueda (Chair), Vinod P. Shah (USP Scientific Liaison), Kris Derdzinski, Gary Ewing, Gordon Flynn, Howard Maibach, Margareth Marques (USP Scientific Liaison),a Howard Rytting,b Steve Shaw, Kailas Thakker, and Avi Yacobi. ABSTRACT This Stimuli article provides general information about the test methods that should be employed to ensure the quality and performance of topical and transdermal drug products. The term topical drug products refers to all formulations applied to the skin except transdermal delivery systems (TDS) or transdermal patches that will be addressed separately. INTRODUCTION Therefore, the in vitro release test for those products also may differ significantly and may require different Drug products topically administered via the skin fall types of apparatus. At present, a product performance into two general categories, those applied for local action test exists only for semisolid formulations, specifically and those for systemic effects. Local actions include creams, ointments, and gels. That test employs the ver- those at or on the surface of the skin, those that exert tical diffusion cell (VDC) system. The VDC system is sim- their actions on the stratum corneum, and those that ple to operate and yields reliable and reproducible results modulate the function of the epidermis and/or the der- when employed by properly trained laboratory person- mis. Common products in the former category include nel. creams, gels, ointments, pastes, suspensions, lotions, TDS or transdermal patches are physical devices ap- foams, sprays, aerosols, and solutions. Creams, oint- plied to the skin and vary in their composition and meth- ments, and gels generally are referred to as semisolid od of fabrication. Therefore, they release their active Stimuli to the Revision Process dosage forms. The most common drug products applied ingredients by different mechanisms. to the skin for systemic effects are referred to as self- adhering transdermal drug delivery systems (TDS) or GLOSSARY OF TERMS transdermal patches. Two categories of tests, product quality tests and prod- Definitions of topical drug products, some aspects re- uct performance tests, are performed with drug products lated to the manufacture of these products, and a glos- to provide assurances of batch-to-batch quality, reprodu- sary of dosage form names commonly used can be found cibility, reliability, and performance. Product quality tests in General Information Chapter Pharmaceutical Dosage are performed to assess attributes such as assay, identifi- Forms h1151i. cation, content uniformity, pH, microbial limits, and minimum fill and are part of the compendial mono- Collodion graph. Product performance tests are conducted to as- sess drug release from the finished dosage form. Collodion (pyroxylin solution; see USP monograph), is This Stimuli article provides general information about a solution of nitrocellulose in ether and acetone, some- the test methods that should be employed to ensure the times with the addition of alcohol. As the volatile solvents quality and performance of topical and transdermal drug evaporate, a dry celluloid-like film is left on the skin. Be- products. The term topical drug products refers to all for- cause the medicinal use of a collodion depends on the mulations applied to the skin except transdermal delivery formation of a protective film, the film should be durable, systems (TDS) or transdermal patches that will be ad- tenacious in adherence, flexible, and occlusive. dressed separately. Topical dosage forms include solutions (for which re- Creams lease testing is not indicated), collodion, suspensions, emulsions (e.g., lotions), semisolids (e.g., foams, oint- Creams are semisolid dosage forms that contain one or ments, pastes, creams, and gels), solids (e.g., powders more drug substances dissolved or dispersed in a suitable and aerosols), and sprays. The physical characteristics base. This term traditionally has been applied to semi- of these dosage forms vary widely. solids that possess a relatively soft, spreadable consis- tency formulated as either water-in-oil or oil-in-water emulsions. However, more recently the term has been re- stricted to products consisting of oil-in-water emulsions a Correspondence should be addressed to: Margareth Marques, PhD, or aqueous microcrystalline dispersions of long-chain Senior Scientist, Documentary Standards Division, US Pharmacopeial fatty acids or alcohols that are water washable and more Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790; cosmetically and aesthetically acceptable. tel. 301.816.8106; e-mail [email protected]. b Deceased. # 2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved. STIMULI TO THE REVISION PROCESS Pharmacopeial Forum Stimuli articles do not necessarily reflect the policies Vol. 35(3) [May–June 2009] of the USPC or the USP Council of Experts 751 Emulsions 50% hydrocarbons, waxes, or polyols as the vehicle. Ointment bases recognized for use as vehicles fall into Emulsions are viscid, multiphase systems in which one four general classes: hydrocarbon bases, absorption or more liquids are dispersed throughout another immis- bases, water-removable bases, and water-soluble bases. cible liquid in the form of small droplets. When oil is the Each therapeutic ointment possesses as its base one of dispersed phase and an aqueous solution is the continu- these four general classes. ous phase, the system is designated as an oil-in-water emulsion. Conversely, when water or an aqueous solu- Hydrocarbon Bases—Hydrocarbon bases, known also tion is the dispersed phase and oil or oleaginous material as ‘‘oleaginous ointment bases,’’ are represented by is the continuous phase, the system is designated as a White Petrolatum and White Ointment (both USP). Only water-in-oil emulsion. Emulsions are stabilized by emulsi- small amounts of an aqueous component can be incor- fying agents that prevent coalescence, the merging of porated into these bases. Hydrocarbon bases serve to small droplets into larger droplets, and, ultimately, into keep medicaments in prolonged contact with the skin a single separated phase. Emulsifying agents (surfac- and act as occlusive dressings. These bases are used tants) act by concentrating at the interface between chiefly for their emollient effects and are difficult to wash the immiscible liquids, thereby providing a physical bar- off. They do not ‘‘dry out’’ or change noticeably on rier that reduces the tendency for coalescence. Surfac- aging. tants also reduce the interfacial tension between the phases, facilitating the formation of small droplets upon Absorption Bases—This class of bases may be divided mixing. The term emulsion is not used if a more specific into two groups: the first consists of bases that permit Stimuli to the Revision Process term is applicable, e.g., cream or ointment. the incorporation of aqueous solutions with the forma- tion of a water-in-oil emulsion (e.g., Hydrophilic Petrola- Foams tum and Lanolin, both USP), and the second group consists of water-in-oil emulsions that permit the incor- Foams are emulsified systems packaged in pressurized poration of additional quantities of aqueous solutions containers or special dispensing devices that contain dis- (Lanolin, USP). Absorption bases also are useful as persed gas bubbles, usually in a liquid continuous phase, emollients. that when dispensed has a fluffy, semisolid consistency. Water-removable Bases—Water-removable bases are Gels oil-in-water emulsions (e.g., Hydrophilic Ointment, USP), and are more correctly called ‘‘creams’’ (see Gels (sometimes called Jellies) are semisolid systems Creams, above). They also are described as ‘‘water-wash- consisting of either suspensions composed of small inor- able’’ because they may be readily washed from the skin ganic particles or large organic molecules interpene- or clothing with water, an attribute that makes them trated by a liquid. When the gel mass consists of a more acceptable for cosmetic purposes. Some medica- network of small discrete particles, the gel is classified ments may be more effective in these bases than in hy- as a two-phase system (e.g., Aluminum Hydroxide Gel, drocarbon bases. Other advantages of the water- USP). In a two-phase system if the particle size of the dis- removable bases are that they may be diluted with water persed phase is relatively large, the gel mass is sometimes and that they favor the absorption of serous discharges in referred to as a magma (e.g., Bentonite Magma, NF). dermatological conditions. Both gels and magmas may be thixotropic, forming semisolids after standing and becoming liquid when agi- Water-soluble Bases—This group of so-called ‘‘grease- tated. They should be shaken before use to ensure homo- less ointment bases’’ comprises water-soluble constitu- geneity and should be labeled to that effect (see Topical ents. Polyethylene Glycol Ointment, NF is the only Suspensions, below). Single-phase gels consist of organic pharmacopeial preparation in this group. Bases of this macromolecules uniformly distributed throughout a liq- type offer many of the advantages of the water-remova- uid with no apparent boundary between the dispersed ble bases and, in