Aug. 6,  2009  19  US 2009/0197849 Al  pyl]-N,N,N-triethylammonium (DOTMA) in appropriate  ratios. Methods for making liposomes using these materials  are well known in the art.  [0243]  Micelles are known in the art and are comprised of  surfactant molecules arranged so that their polar headgroups  form an outer spherical shell, while the hydrophobic, hydro› carbon chains are oriented towards the center of the sphere,  forming a core. Micelles form in an aqueous solution con› taining surfactant at a high enough concentration so that  micelles naturally result. Surfactants useful for forming  micelles include, but are not limited to, potassium laurate,  sodium octane sulfonate, sodium decane sulfonate, sodium  dodecane sulfonate, sodium lauryl sulfate, docusate sodium,  decyltrimethylammonium bromide, dodecyltrimethylammo› nium bromide, tetradecyltrimethylammonium bromide, tet› radecyltrimethyl-ammonium chloride, dodecylammonium  chloride, polyoxyl 8 dodecyl ether, polyoxyl 12 dodecyl  ether, nonoxynol 10 andnonoxynol 30. Micelle formulations  can be used in conjunction with the present invention either  by incorporation into the reservoir of a topical or transdermal  delivery system, or into a formulation to be applied to the  body surface.  [0244]  Microspheres, similarly, may be incorporated into  the present formulations and drug delivery systems. Like  liposomes and micelles, microspheres essentially encapsu› late a drug or drug-containing formulation. They are gener› ally, although not necessarily, formed from lipids, preferably  charged lipids such as phospholipids. Preparation of lipidic  microspheres is well known in the art and described in the  pertinent texts and literature.  [0245]  Various additives, known to those skilled in the art,  may be included in the topical formulations. For example,  solvents, including relatively small amounts of alcohol, may  be used to solubilize certain drug substances. Other optional  additives include opacifiers, antioxidants, fragrance, colo› rant, gelling agents, thickening agents, stabilizers, surfactants  and the like. Other agents may also be added, such as antimi› crobial agents, to prevent spoilage upon storage, i.e., to inhibit  growth of microbes such as yeasts and molds. Suitable anti› microbial agents are typically selected from the group con› sisting of the methyl and propyl esters of p-hydroxybenzoic  acid (i.e., methyl and propyl paraben), sodium benzoate, sor› bic acid, imidurea, and combinations thereof.  [0246]  For those drugs having an unusually low rate of  permeation through the skin or mucosa! 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 mono› hydric alcohols, dials, and polyols, dials and polyols that are  both esterified with a fatty acid and substituted with a poly› oxyalkylene, polyoxyalkylene fatty acid esters, polyoxyalky› lene fatty ethers, polyoxyalkylene fatty ethers, and polyglyc› eryl  fatty  acid  esters;  amines;  amides;  N-alkyl› azacycloalkanones  and  N-alkyl-azacycloalkenones;  hydrocarbon solvents; terpenes; lower alkyl esters; cyclodex› trin enhancers; nitrogen-containing heterocycles; sulfoxides;  and urea and its derivatives.  [0247]  Specific examples of suitable co-enhancers include  ethers such as diethylene glycol monoethyl ether (available  commercially as Transcutolfi, Gattefosse SA) and di ethylene  glycol monomethyl ether; surfactants such as sodium laurate,  sodium lauryl sulfate, cetyltrimethylammonium bromide,  benzalkonium chloride, Poloxamer (231, 182, 184), Tween  (20, 40, 60, 80) and lecithin; alcohols such as ethanol, pro› panol, octanol, benzyl alcohol, and the like; fatty acids such as  !auric 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 polyeth› ylene glycol, and polyethylene glycol monolaurate; amides  and other nitrogenous compounds such as urea, dimethylac› etamide, dimethylformamide, 2-pyrrolidone, l-methyl-2- pyrrolidone, ethanolamine, diethanolamine and triethanola› mine; terpenes; alkanones; and organic acids, particularly  citric acid and succinic acid. Azonefi and sulfoxides such as  dimethylsulfoxide and decylmethylsulfoxide may also be  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.  [0248]  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.  [0249]  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 Systems  [0250]  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.  [0251]  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 