Jul.  3, 2003  20  US 2003/0124176 Al  antimicrobial agents, to prevent spoilage upon storage, i.e.,  to inhibit growth of microbes such as yeasts and molds.  Suitable antimicrobial agents are typically selected from the  group consisting of the methyl and propyl esters of p-hy› droxybenzoic acid (i.e., methyl and propyl paraben), sodium  benzoate, sorbic acid, imidurea, and combinations thereof.  [0244]  For those drugs having an unusually low rate of  permeation through the skin or mucosal tissue, it may be  desirable to include a second permeation enhancer in the  formulation in addition to the inorganic or organic base  enhancer, although in a preferred embodiment the base  enhancer is administered without any other permeation  enhancers. Any other enhancers should, like the base  enhancer, minimize the possibility of skin damage, irritation,  and systemic toxicity. Examples of classes of suitable sec› ondary enhancers (or "co-enhancers") include, but are not  limited to, fatty acids, both saturated and unsaturated; fatty  alcohols; bile acids; nonionic surfactants, including esters of  fatty acids, fatty (long-chain alkyl or alkenyl) esters of  monohydric alcohols, dials, and polyols, dials and polyols  that are both esterified with a fatty acid and substituted with  a polyoxyalkylene, polyoxyalkylene fatty acid esters, poly› oxyalkylene fatty ethers, polyoxyalkylene fatty ethers, and  polyglyceryl fatty acid esters; amines; amides; N-alkyl› azacycloalkanones and N-alkyl-azacycloalkenones; hydro› carbon solvents; terpenes; lower alkyl esters; cyclodextrin  enhancers; nitrogen-containing heterocycles; sulfoxides;  and urea and its derivatives.  [0245]  Specific examples of suitable co-enhancers include  ethers such as diethylene glycol monoethyl ether (available  commercially as Transcutolfi, Gattefosse  SA)  and diethyl› ene glycol monomethyl ether; surfactants such as sodium  laurate, sodium lauryl sulfate, cetyltrimethylammonium bro› mide, benzalkonium chloride, Poloxamer (231, 182, 184),  Tween (20, 40, 60, 80) and lecithin; alcohols such as ethanol,  propanol, octanol, benzyl alcohol, and the like; fatty acids  such as lauric acid, oleic acid and valeric acid; fatty acid  esters such as isopropyl myristate, isopropyl palmitate,  methylpropionate, and ethyl oleate; polyols and esters  thereof such as polyethylene glycol, and polyethylene glycol  monolaurate; amides and other nitrogenous compounds such  as urea, dimethylacetamide, dimethylformamide, 2-pyrroli› done, l-methyl-2-pyrrolidone, ethanolamine, diethanola› mine and triethanolamine; terpenes; alkanones; and organic  acids, particularly citric acid and succinic acid. Azonefi and  sulfoxides such as dimethylsulfoxide and decylmethylsul› foxide may also be used, but are less preferred.  Percutane› ous Penetration Enhancers,  eds. Smith et al. (CRC Press,  1995) provides an excellent overview of the field and further  information concerning possible secondary enhancers for  use in conjunction with the present invention.  [0246]  The formulation may also contain irritation-miti› gating 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-tocopherol; monoamine oxidase inhibitors, particularly  phenyl alcohols such as 2-phenyl-1-ethanol; glycerin; sali› cylic acids and salicylates; ascorbic acids and ascorbates;  ionophores such as monensin; amphiphilic amines; ammo› nium chloride; N-acetylcysteine; cis-urocanic acid; capsai› cin; and chloroquine. 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.  [0247]  The concentration of the active agent in the for› mulation will typically depend upon a variety of factors,  including 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  particular knowledge of the patient and physician. Preferred  formulations will typically contain on the order of about  0.5-50 wt %, preferably about 5-30 wt %, active agent.  [0248]  V.  Drug Delivery Systems  [0249]  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  laminated 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.  [0250]  Accordingly, another embodiment of the invention  is a system for the enhanced topical or transdermal admin› istration 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  backing 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.  [0251]  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› sensitive 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;  polyisobutylenes; polyacrylates; polyacrylamides; polyure› thanes; plasticized ethylene-vinyl acetate copolymers; and  tacky rubbers such as polyisobutene, polybutadiene, poly› styrene-isoprene  copolymers,  polystyrene-butadiene  copolymers, and neoprene (polychloroprene ). Preferred  adhesives are polyisobutylenes.  [0252]  The backing layer functions as the primary struc› tural element of the transdermal system and provides the  device with flexibility and, preferably, occlusivity. The  material 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 elasto› meric material that serves as a protective covering to prevent 