any of these drug delivery systems. Fabric layers may be used to facilitate fabrication of the device, while a rate-controlling membrane may be used to control the rate at which a compo› nent permeates out of the device. The component may be a drug, a base enhancer, an additional enhancer, or some other component contained in the drug delivery system. 

[0265] A rate-controlling membrane, if present, will be included in the system on the skin side of one or more of the drug reservoirs. The material used to form such a membrane is selected so as to limit the flux of one or more components contained in the drug formulation. Representative materials useful for forming rate-controlling membranes include poly› olefins such as polyethylene and polypropylene, polyamides, polyesters, ethylene-ethacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene-vinyl methylacetate copolymer, ethylene-vinyl ethylacetate copolymer, ethylene-vinyl pro› pylacetate copolymer, polyisoprene, polyacrylonitrile, ethyl› ene-propylene copolymer, and the like. 

[0266] Generally, the underlying surface of the transdermal device, i.e., the skin contact area, has an area in the range of about 5-200 cm 2 , preferably 5-100 cm 2 , more preferably 20-60 cm 2 . That area will vary, of course, with the amount of drug to be delivered and the flux of the drug through the body surface. Larger patches can be used to accommodate larger quantities of drug, while smaller patches can be used for smaller quantities of drug and/or drugs that exhibit a rela› tively high permeation rate. 

[0267] Such drug delivery systems may be fabricated using conventional coating and laminating techniques known in the art. For example, adhesive matrix systems can be prepared by casting a fluid admixture of adhesive, drug and vehicle onto the backing layer, followed by lamination of the release liner. Similarly, the adhesive mixture may be cast onto the release liner, followed by lamination of the backing layer. Alterna› tively, the drug reservoir may be prepared in the absence of drug or excipient, and then loaded by soaking in a drug/ vehicle mixture. In general, transdermal systems of the inven› tion are fabricated by solvent evaporation, film casting, melt extrusion, thin film lamination, die cutting, or the like. The inorganic or organic base permeation enhancer will generally be incorporated into the device during patch manufacture rather than subsequent to preparation of the device. Thus, for acid addition salts of basic drugs ( e.g., hydrochloride salts of amine drugs), the enhancer will neutralize the drug during manufacture of the drug delivery system, resulting in a final drug delivery system in which the drug is present in nonion› ized, neutral form along with an excess of base to serve as a permeation enhancer. For nonionized acidic drugs, the base will neutralize such drugs by converting them to the ionized drug in salt form. 

[0268] In a preferred delivery system, an adhesive over› layer that also serves as a backing for the delivery system is used to better secure the patch to the body surface. This overlayer is sized such that it extends beyond the drug reser› voir so that adhesive on the overlay er comes into contact with the body surface. The overlayer is useful because the adhe› sive/drug reservoir layer may lose its adhesion a few hours after application due to hydration. By incorporating an adhe› sive overlay er, the delivery system will remain in place for the required period of time. 

[0269] Other types and configurations oftransdermal drug delivery systems may also be used in conjunction with the method of the present invention, as will be appreciated by those skilled in the art oftransdermal drug delivery. See, for 

example, Ghosh, Transdermal and Topical Drug Delivery Systems (Interpharm Press, 1997), particularly Chapters 2 and 8. 

[0270] As with the topically applied formulations of the invention, the drug and enhancer composition contained within the drug reservoir(s) of these laminated systems may comprise a number of additional components. In some cases, the drug and enhancer may be delivered neat, i.e., in the absence of additional liquid. In most cases, however, the drug will be dissolved, dispersed or suspended in a suitable phar› maceutically acceptable vehicle, typically a solvent or gel. Other components that may be present include preservatives, stabilizers, surfactants, solubilizers, additional enhancers, and the like. 

[0271] The invention accordingly provides a novel and highly effective means for increasing the flux of an active agent through the body surface (skin or mucosa! tissue) of a human or animal. The base enhancers discussed herein, employed in specific amounts relative to a formulation or drug reservoir, may be used as permeation enhancers with a wide variety of drugs and drug types, including free acids, free bases, acid addition salts of basic drugs, basic addition salts of acidic drugs, nonionizable drugs, peptides and pro› teins. Surprisingly, the increase in permeation is not accom› panied by any noticeable tissue damage, irritation, or sensi› tization. The invention thus represents an important advance in the field of drug delivery. 

[0272] It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. Fur› thermore, the practice of the present invention will employ, unless otherwise indicated, conventional techniques of drug formulation, particularly topical and transdermal drug formu› lation, which are within the skill of the art. Such techniques are fully explained in the literature. See Remington: The Science and Practice of Pharmacy, cited supra, as well as Goodman & Gilman’s The Pharmacological Basis of Thera› peutics, 10 $^{th }$Ed. (2001). 

[0273] The following examples are put forth so as to pro› vide those of ordinary skill in the art with a complete disclo› sure and description of how to practice the methods as well as make and use the compositions of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers ( e.g., amounts, temperature, etc.) but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in° C. and pressure is at or near atmospheric. The following abbreviations will be used in accordance with the definitions set out below. 

[0274] DI Deionized 

[0275] HPMC Hydroxypropylmethylcellulose 

[0276] late HPMCP Hydroxypropylmethylcellulose phtha- 

[0277] PG Propylene glycol 

[0278] PIB Polyisobutylene 

## EXAMPLES 

## Abbreviations 

