Aug. 30, 2012  21  US 2012/0220962 Al  used, but are less preferred.  Percutaneous Penetration  Enhancers,  eds. Smith et al. (CRC Press, 1995) provides an  excellent overview of the field and further information con› cerning possible secondary enhancers for use in conjunction  with the present invention.  [0256]  The formulation may also contain irritation-mitigat› ing additives to minimize or eliminate the possibility of skin  irritation or skin damage resulting from the drug, the base  enhancer, or other components of the formulation. Suitable  irritation-mitigating additives include, for example: a-toco› pherol; monoamine oxidase inhibitors, particularly phenyl  alcohols such as 2-phenyl-1-ethanol; glycerin; salicylic acids  and salicylates; ascorbic acids and ascorbates; ionophores  such as monensin; amphiphilic amines; ammonium chloride;  N-acetylcysteine; cis-urocanic acid; capsaicin; and chloro› quine. The irritant-mitigating additive, if present, may be  incorporated into the formulation at a concentration effective  to mitigate irritation or skin damage, typically representing  not more than about 20 wt %, more typically not more than  about 5 wt%, of the formulation.  [0257]  The concentration of the active agent in the formu› lation will typically depend upon a variety of factors, includ› ing the disease or condition to be treated, the nature and  activity of the active agent, the desired effect, possible  adverse reactions, the ability and speed of the active agent to  reach its intended target, and other factors within the particu› lar knowledge of the patient and physician. Preferred formu› lations will typically contain on the order of about 0.5-50 wt  %, preferably about 5-30 wt%, active agent.  V.  DRUG DELIVERY SYSTEM  [0258]  An alternative and preferred method involves the  use of a drug delivery system, e.g., a topical or transdermal  "patch," wherein the active agent is contained within a lami› nated structure that is to be affixed to the skin. In such a  structure, the drug composition is contained in a layer, or  "reservoir," underlying an upper backing layer that serves as  the outer surface of the device during use. The laminated  structure may contain a single reservoir, or it may contain  multiple reservoirs.  [0259]  Accordingly, another embodiment of the invention  is a system for the enhanced topical or transdermal adminis› tration of a drug, comprising: (a) at least one drug reservoir  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 8.0-11.5, and most preferably about 8.5-10.5.  [0260]  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.  [0261]  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.  [0262]  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.  [0263]  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.  [0264]  Additional layers, e.g., intermediate fabric layers  and/or rate-controlling membranes, may also be present in 