Aug. 30, 2012  1  US 2012/0220962 Al  TRANSDERMAL AND TOPICAL  ADMINISTRATION OF VITAMINS USING  BASIC PERMEATION ENHANCERS  CROSS-REFERENCE TO RELATED  APPLICATIONS  FIELD OF THE INVENTION  SUMMARY OF THE INVENTION  BACKGROUND OF THE INVENTION  [0001]  This application is a continuation of U.S. Ser. No.  12/343,000 filed on Dec. 23, 2008. U.S. Ser. No. 12/343,000  is a continuation of Ser. No. 10/860,887, filed on Jun. 3, 2004.  Ser. No. 10/860,887 is a divisional of U.S. Ser. No. 10/177,  436 filed on Jun. 20, 2002. U.S. Ser. No. 10/177,436 is a  continuation in part ofU.S. Ser. No. 09/972,008 filed on Oct.  4, 2001 and now issued as U.S. Pat. No. 6,582,724, which is  a continuation in part of U.S. Ser. No. 09/738,410 filed on  Dec. 14, 2000 and now issued as U.S. Pat. No. 6,586,000,  which is a continuation in part of U.S. Ser. No. 09/569,889  filed on May 11, 2000 and now abandoned, which is a con› tinuation in part of U.S. Ser. No. 09/465,098 filed on Dec. 16,  1999 and now abandoned; and is a continuation in part ofU.S.  Ser. No. 09/738,395 filed on Dec. 14, 2000, which is a con› tinuation in part of U.S. Ser. No. 09/607,892 filed on Jun. 30,  2000, now abandoned, the disclosures of which are incorpo› rated herein by reference.  [0002]  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 pharma› cologically active agents through a body surface by treatment  with a basic permeation enhancer.  [0003]  The delivery of drugs through the skin provides  many advantages; primarily, such a means of delivery is a  comfortable, convenient and noninvasive way of administer› ing drugs. The variable rates of absorption and metabolism  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.  [0004]  Skin is a structurally complex, relatively thick mem› brane. Molecules moving from the environment into and  through intact skin must first penetrate the stratum comeum  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 resistance to penetra› tion in each type of tissue. Transport across the skin mem› brane is thus a complex phenomenon. However, it is the cells  of the stratum comeum, which present the primary barrier to  absorption of topical compositions or transdermally admin› istered 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 substantially impermeable bar› rier to drug penetration. With many drugs, the rate of perme› ation through the skin is extremely low without the use of  some means to enhance the permeability of the skin.  [0005]  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 pre› treated with a chemical enhancer) in order to increase the  permeability of the stratum comeum, and thereby provide for  enhanced penetration of the drug through the skin. Ideally,  such chemical penetration enhancers or "permeation enhanc› ers," 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 physicochemical char› acteristics may be enhanced using these chemical enhance› ment means. However, there are skin irritation and sensitiza› tion problems associated with high levels of certain  enhancers.  [0006]  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 per› meation enhancers. Furthermore, in contrast to many conven› tional enhancers, transdermal administration of drugs with  basic permeation enhancers, employed at the appropriate lev› els, does not result in systemic toxicity.  [0007]  One aspect of the invention pertains to a method for  enhancing the flux of a drug through a body surface, compris› ing: (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.  [0008]  Another aspect of the invention relates to a compo› sition 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 adminis› tration 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 inven› tion 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.  [0009]  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 