Jun.5,2003  1  US 2003/0104041 Al  TRANSDERMAL AND TOPICAL  ADMINISTRATION OF DRUGS USING BASIC  PERMEATION ENHANCERS  FIELD OF THE INVENTION  BACKGROUND OF THE INVENTION  SUMMARY OF THE INVENTION  [0001]  CROSS-REFERENCE TO RELATED APPLICA› TIONS  [0002]  This application is a continuation in part of U.S.  Ser. No. 09/972,008 filed on Oct. 4, 2001, which is a  continuation in part of U.S. Ser. No. 09/738,410 filed on  Dec. 14, 2000, which is a continuation in part of U.S. Ser.  No. 09/569,889 filed on May 11, 2000, which is a continu› ation in part of U.S. Ser. No. 09/465,098 filed on Dec. 16,  1999; and is a continuation in part of U.S. Ser. No. 09/738,  395 filed on Dec. 14, 2000, which is a continuation in part  of U.S. Ser. No. 09/607,892 filed Jun. 30, 2000, now  abandoned.  [0003]  This invention relates generally to the topical and  transdermal administration of pharmacologically or cosme› ceutically active agents, and more particularly relates to  methods and compositions for enhancing the flux of phar› macologically active agents through a body surface by  treatment with a basic permeation enhancer.  [0004]  The delivery of drugs through the skin provides  many advantages; primarily, such a means of delivery is a  comfortable, convenient and noninvasive way of adminis› tering drugs. The variable rates of absorption and metabo› lism encountered in oral treatment are avoided, and other  inherent inconveniences, e.g., gastrointestinal irritation and  the like, are eliminated as well. Transdermal drug delivery  also makes possible a high degree of control over blood  concentrations of any particular drug.  [0005]  Skin is a structurally complex, relatively thick  membrane. Molecules moving from the environment into  and through intact skin must first penetrate the stratum  corneum and any material on its surface. They must then  penetrate the viable epidermis, the papillary dermis, and the  capillary walls into the blood stream or lymph channels. To  be so absorbed, molecules must overcome a different resis› tance to penetration in each type of tissue. Transport across  the skin membrane is thus a complex phenomenon. How› ever, it is the cells of the stratum corneum, which present the  primary barrier to absorption of topical compositions or  transdermally administered drugs. The stratum corneum is a  thin layer of dense, highly keratinized cells approximately  10-15 microns thick over most of the body.  It  is believed to  be the high degree of keratinization within these cells as well  as their dense packing which creates in most cases a sub› stantially impermeable barrier to drug penetration. With  many drugs, the rate of permeation through the skin is  extremely low without the use of some means to enhance the  permeability of the skin.  [0006]  Numerous chemical agents have been studied as a  means of increasing the rate at which a drug penetrates  through the skin.  As  will be appreciated by those in the field,  chemical enhancers are compounds that are administered  along with the drug ( or in some cases the skin may be  pretreated with a chemical enhancer) in order to increase the  permeability of the stratum corneum, and thereby provide  for enhanced penetration of the drug through the skin.  Ideally, such chemical penetration enhancers or "permeation  enhancers," as the compounds are referred to herein, are  compounds that are innocuous and serve merely to facilitate  diffusion of the drug through the stratum corneum. The  permeability of many therapeutic agents with diverse physi› cochemical characteristics may be enhanced using these  chemical enhancement means. However, there are skin  irritation and sensitization problems associated with high  levels of certain enhancers.  [0007]  Accordingly, although there are many chemical  methods of enhancing permeation, there remains an ongoing  need for a method that is highly effective in increasing the  rate at which a drug permeates the skin, does not result in  skin damage, irritation, sensitization, or the like, and can be  used to effect transdermal delivery of even high molecular  weight drugs such as peptides, proteins, and nucleic acids.  It  has now been discovered that basic permeation enhancers as  described herein are highly effective permeation enhancers,  and provide all of the aforementioned advantages relative to  known permeation enhancers. Furthermore, in contrast to  many conventional enhancers, transdermal administration of  drugs with basic permeation enhancers, employed at the  appropriate levels, does not result in systemic toxicity.  [0008]  One aspect of the invention pertains to a method  for enhancing the flux of a drug through a body surface,  comprising: (a) administering the drug to a localized region  of a human patient’s body surface; and (b) administering a  basic permeation enhancer to the localized region, the  enhancer comprising a pharmaceutically acceptable base  and being present in an amount effective to provide a  pH  within the range of about 8.0-13.0 at the localized region of  the body surface during administration of the drug and to  enhance the flux of the drug through the body surface  without causing damage thereto. The pharmaceutically  acceptable base can be an inorganic or an organic base.  [0009]  Another aspect of the invention relates to a com› position for the enhanced delivery of a drug through a body  surface, comprising a formulation of: (a) a therapeutically  effective amount of the drug; (b) a pharmaceutically accept› able base, in an amount effective to provide a  pH  within the  range of about 8.0-13.0 at the body surface during admin› istration of the drug and to enhance the flux of the drug  through the body surface without causing damage thereto;  and ( c) a pharmaceutically acceptable carrier suitable for  topical or transdermal drug administration. In one aspect of  the invention the  pH is  about 8.0-11.5 and in another aspect,  the pH is about 8.5-10.5. The formulation is typically  aqueous. The pharmaceutically acceptable base can be an  inorganic or an organic base.  [0010]  Yet another aspect of the invention pertains to a  system for the enhanced topical or transdermal administra› tion of a drug, comprising: ( a) at least one drug reservoir  containing the drug and a pharmaceutically acceptable 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 