Apr. 7, 2005  22  US 2005/0074487 Al  overlayer is sized such that it extends beyond the drug  reservoir so that adhesive on the overlayer comes into  contact with the body surface. The overlayer is useful  because the adhesive/drug reservoir layer may lose its  adhesion a few hours after application due to hydration. By  incorporating an adhesive overlayer, the delivery system  will remain in place for the required period of time.  [0266]  Other types and configurations of transdermal drug  delivery systems may also be used in conjunction with the  method of the present invention, as will be appreciated by  those skilled in the art of transdermal drug delivery. See, for  example, Ghosh,  Transdermal and Topical Drug Delivery  Systems  (Interpharm Press, 1997), particularly Chapters 2  and 8.  [0267]  As  with the topically applied formulations of the  invention, the drug and enhancer composition contained  within the drug reservoir(s) of these laminated systems may  comprise a number of additional components. In some cases,  the drug and enhancer may be delivered neat, i.e., in the  absence of additional liquid. In most cases, however, the  drug will be dissolved, dispersed or suspended in a suitable  pharmaceutically acceptable vehicle, typically a solvent or  gel. Other components that may be present include preser› vatives, stabilizers, surfactants, solubilizers, additional  enhancers, and the like.  [0268]  The invention accordingly provides a novel and  highly effective means for increasing the flux of an active  agent through the body surface (skin or mucosal tissue) of a  human or animal. The base enhancers discussed herein,  employed in specific amounts relative to a formulation or  drug reservoir, may be used as permeation enhancers with a  wide variety of drugs and drug types, including free acids,  free bases, acid addition salts of basic drugs, basic addition  salts of acidic drugs, nonionizable drugs, peptides and  proteins. Surprisingly, the increase in permeation is not  accompanied by any noticeable tissue damage, irritation, or  sensitization. The invention thus represents an important  advance in the field of drug delivery.  [0269]  It is to be understood that while the invention has  been described in conjunction with the preferred specific  embodiments thereof, the foregoing description is intended  to illustrate and not limit the scope of the invention. Other  aspects, advantages and modifications will be apparent to  those skilled in the art to which the invention pertains.  Furthermore, the practice of the present invention will  employ, unless otherwise indicated, conventional techniques  of drug formulation, particularly topical and transdermal  drug formulation, which are within the skill of the art. Such  techniques are fully explained in the literature. See  Reming› ton: The Science and Practice of Pharmacy,  cited supra, as  well as Goodman & Gilman’s  The Pharmacological Basis of  Therapeutics,  10$^{th }$Ed.(2001).  [0270]  The following examples are put forth so as to  provide those of ordinary skill in the art with a complete  disclosure and description of how to practice the methods as  well as make and use the compositions of the invention, and  are not intended to limit the scope of what the inventors  regard as their invention. Efforts have been made to ensure  accuracy with respect to numbers (e.g., amounts, tempera› ture, etc.) but some errors and deviations should be  accounted for. Unless indicated otherwise, parts are parts by  weight, temperature is in °  C. and pressure is at or near  atmospheric. The following abbreviations will be used in  accordance with the definitions set out below.  [0272]  Each formulation was coated onto a release liner  and dried in an oven at 55°  C. for two hours to remove water  and other solvents. The dried drug-in-adhesive/release liner  film was laminated to a backing film. The backing/drug-in› adhesive/release liner laminate was then cut into round discs  with a diameter of  1 ‰6 inch.  [0273]  The in vitro permeation of drugs through human  cadaver skin was performed using Franz-type diffusion cells  with a diffusion area of 1 cm 2  .  The volume of receiver  solution was 8 ml. Human cadaver skin was cut to a proper  size and placed on a flat surface with the stratum corneum  side facing up. The release liner was peeled away from the  disc laminate. The backing/drug-in-adhesive film was  placed and pressed on the skin with the adhesive side facing  the stratum corneum. The skin/adhesive/backing laminate  was clamped between the donor and receiver chambers of  the diffusion cell with the skin side facing the receiver  solution.  [0274]  The pH of the patches was measured using the  following procedures. A 2.5 cm $^{2 }$circular patch was punched  out. Ten ml purified water was pipetted into a glass vial, and  a stir bar was added. The liner was removed from the patch  and placed in the vial along with the patch. The vial was then  placed on a stir plate and the water/patch/liner mixture was  stirred for 5 minutes, at which point the liner was removed  from the vial and discarded. The vial was again placed on a  stir plate and stirring continued for an additional 18 hours.  After 18 hours, the stir bar was removed from the vial and  the  pH  of the solution determined using a calibrated  pH  meter.  [0275]  An in vitro skin permeation study was conducted  using three estradiol transdermal systems, designated Est-1,  Est-2, and Est-3, the compositions of which are set forth in  Table  1.  Round disc samples were prepared as described in  Example 1  Measurement of pH  Measurement of Permeation of Drugs through  Human Cadaver Skin  Preparation of Round Disc Samples  Methods  EXAMPLES  [0271]  DI  HPMC  HPMCP  PG  PIE  ABBREVIATIONS  Deionized  Hydroxypropylmethylcellulose  Hydroxypropylmethylcellulose phthalate  Propylene glycol  Polyisobutylene 