Aug. 6, 2009  20  US 2009/0197849 Al  containing the drug and a pharmaceutically acceptable inor› ganic or organic base in an amount effective to enhance the  flux of the drug through the body surface without causing  damage thereto; (b) a means for maintaining the system in  drug and base transmitting relationship to the body surface  and forming a body surface-system interface; and ( c) a back› ing layer that serves as the outer surface of the device during  use, wherein the base is effective to provide a pH within the  range of about 8.0-13 .0 at the body surface-system interface  during administration of the drug. The pH is more preferably  about 8.5-11.5, more preferably about 9.5-11.5 and most  preferably about 10.0 to 11.5.  [0252]  In one embodiment, the drug reservoir comprises a  polymeric matrix of a pharmaceutically acceptable adhesive  material that serves to affix the system to the skin during drug  delivery; typically, the adhesive material is a pressure-sensi› tive adhesive (PSA) that is suitable for long-term skin contact,  and which should be physically and chemically compatible  with the active agent, inorganic or organic base, and any  carriers, vehicles or other additives that are present. Examples  of suitable adhesive materials include, but are not limited to,  the following: polyethylenes; polysiloxanes; polyisobuty› lenes; polyacrylates; polyacrylamides; polyurethanes; plasti› cized ethylene-vinyl acetate copolymers; and tacky rubbers  such as polyisobutene, polybutadiene, polystyrene-isoprene  copolymers, polystyrene-butadiene copolymers, and neo› prene (polychloroprene). Preferred adhesives are polyisobu› tylenes.  [0253]  The backing layer functions as the primary struc› tural element of the transdermal system and provides the  device with flexibility and, preferably, occlusivity. The mate› rial used for the backing layer should be inert and incapable of  absorbing the drug, the base enhancer, or other components of  the formulation contained within the device. The backing is  preferably comprised of a flexible elastomeric material that  serves as a protective covering to prevent loss of drug and/or  vehicle via transmission through the upper surface of the  patch, and will preferably impart a degree of occlusivity to the  system, such that the area of the body surface covered by the  patch becomes hydrated during use. The material used for the  backing layer should permit the device to follow the contours  of the skin and be worn comfortably on areas of skin such as  at joints or other points of flexure, that are normally subjected  to mechanical strain with little or no likelihood of the device  disengaging from the skin due to differences in the flexibility  or resiliency of the skin and the device. The materials used as  the backing layer are either occlusive or permeable, as noted  above, although occlusive backings are preferred, and are  generally derived from synthetic polymers (e.g., polyester,  polyethylene, polypropylene, polyurethane, polyvinylidine  chloride, and polyether amide), natural polymers ( e.g., cellu› losic materials), or macroporous woven and nonwoven mate› rials.  [0254]  During storage and prior to use, the laminated struc› ture preferably includes a release liner. Immediately prior to  use, this layer is removed from the device so that the system  may be affixed to the skin. The release liner should be made  from a drug/vehicle impermeable material, and is a dispos› able element, which serves only to protect the device prior to  application. Typically, the release liner is formed from a  material impermeable to the pharmacologically active agent  and the base enhancer, and is easily stripped from the trans› dermal patch prior to use.  [0255]  In an alternative embodiment, the drug-containing  reservoir and skin contact adhesive are present as separate and  distinct layers, with the adhesive underlying the reservoir. In  such a case, the reservoir may be a polymeric matrix as  described above. Alternatively, the reservoir may be com› prised of a liquid or semisolid formulation contained in a  closed compartment or pouch, or it may be a hydrogel reser› voir, or may take some other form. Hydrogel reservoirs are  particularly preferred herein. As will be appreciated by those  skilled in the art, hydrogels are macromolecular networks that  absorb water and thus swell but do not dissolve in water. That  is, hydrogels contain hydrophilic functional groups that pro› vide for water absorption, but the hydro gels are comprised of  crosslinked polymers that give rise to aqueous insolubility.  Generally, then, hydrogels are comprised of crosslinked  hydrophilic polymers such as a polyurethane, a polyvinyl  alcohol, a polyacrylic acid, a polyoxyethylene, a polyvi› nylpyrrolidone, a poly(hydroxyethyl methacrylate) (poly  (HEMA)), or a copolymer or mixture thereof. Particularly  preferred hydrophilic polymers are copolymers of HEMA  and polyvinylpyrrolidone.  [0256]  Additional layers, e.g., intermediate fabric layers  and/or rate-controlling membranes, may also be present in  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.  [0257]  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.  [0258]  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.  [0259]  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 