Aug. 30, 2012  22  US 2012/0220962 Al  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.  EXAMPLES  [0274]  DI Deionized  [0275]  HPMC Hydroxypropylmethylcellulose  [0276]  late  HPMCP Hydroxypropylmethylcellulose phtha- [0277]  PG Propylene glycol  [0278]  PIB Polyisobutylene  Abbreviations 