Apr. 7, 2005  4  US 2005/0074487 Al  composition is preferred. In addition, when using aqueous  formulations, the pH of the formulation may change over  time after it is applied on the skin. For example, gels,  solutions, ointments, etc., may experience a net loss of  moisture after being applied to the body surface, i.e., the  amount of water lost is greater than the amount of water  received from the body surface. In that case, the  pH  of the  formulation may be different than its  pH  when manufac› tured. This problem can be easily remedied by designing the  aqueous formulations to provide a target pH at the interface.  [0033]  In other embodiments of the invention, the pH of  the formulation or the drug composition contained within a  delivery system will be in the range of approximately  8.0-13.0, preferably about 8.5-11.5, more preferably about  9.5-11.5 and most preferably about 10.0 to 11.5.  [0034]  In one embodiment of the invention the pH of the  formulation is higher than the pH at the interface. For  example, if an aqueous formulation is used, moisture from  the body surface can dilute the formulation, and thus provide  for a different pH at the interface, which will typically be  lower than that of the formulation itself.  [0035]  In one preferred embodiment, the body surface is  exposed to a base or basic solution for a sufficient period of  time so as to provide a high pH at the skin surface, thus  creating channels in the skin or mucosa for the drug to go  through.  It is expected that drug flux is proportional to the  strength of the solution and the duration of exposure. How› ever, it is desirable to balance the maximization of drug flux  with the minimization of skin damage. This can be done in  numerous ways. For example, the skin damage may be  minimized by selecting a lower  pH  within the 8.0-13.0  range, by exposing the skin to the formulation or system for  a shorter period of time, or by including at least one  irritation-mitigating additive. Alternatively, the patient can  be advised to change the location of application with each  subsequent administration.  [0036]  While certain preferred amounts are set forth  below, it is understood that, for all of the inorganic and  organic bases described herein, the optimum amount of any  such base will depend on the strength or weakness of the  base and its molecular weight, and other factors such as the  number of ionizable sites in the active agent being admin› istered and whether there are any acidic species present in  the formulation or patch. One skilled in the art may readily  determine the optimum amount for any particular base such  that the degree of enhancement is optimized while the  possibility of damage to the body surface is eliminated or at  least substantially minimized.  [0037]  A Inorganic Base  [0038]  Exemplary inorganic bases are inorganic hydrox› ides, inorganic oxides, inorganic salts of weak acids, and  combinations thereof. Preferred inorganic bases are those  whose aqueous solutions have a high  pH,  and are acceptable  as food or pharmaceutical additives. Examples of such  preferred inorganic bases are those listed below, along with  their respective pHs. Some of the bases are identified by  their hydrate forms, and it is understood that when referring  to a "base", both the hydrated and non-hydrated forms are  intended to be included.  [0039]  Inorganic hydroxides include, for example, ammo› nium hydroxide, alkali metal hydroxide and alkaline earth  metal hydroxides, and mixtures thereof. Preferred inorganic  hydroxides include  ammonium hydroxide; monovalent  alkali metal hydroxides such as sodium hydroxide and  potassium hydroxide; divalent alkali earth metal hydroxides  such as calcium hydroxide and magnesium hydroxide; and  combinations thereof.  $^{1}$listed in the "Chemicals in Compliance with Pharmaceutical Standards:  Inactive Ingredient Guide"  $^{2}$listed in the "Handbook of Pharmaceutical Additives"  $^{3}$listed in the FDA’ s food additive database  Inorganic Hydroxides  Inorganic base  Ammonium hydroxide 1 , 2 , 3  Sodium hydroxide 1 • 2 3  Potassium hydroxide 1 , 2 , 3  Calcium hydroxide 1 • 3  Magnesium hydroxide 1 ’ 3  Magnesium oxide 1 ’ 2 ’ 3  Calcium oxide 3  Sodium acetate 1 ’ 3  Sodium acetate,  trihydrate 1 • 2  Sodium acetate,  anhydrous 1 ’ 2  Sodium borate  decahydrate 1 • 2  Sodium borate 1 ’ 2 ’ 3  Sodium metaborate  Sodium carbonate 1 ’ 2 ’ 3  Sodium carbonate  hydrate’  Sodium carbonate  anhydrous  Sodium bicarbonate 1 , 2 , 3  Sodium phosphate,  tribasic 1 ’ 3  Sodium phosphate,  tribasic dodecahydrate  Sodium phosphate,  dibasic, anhydrous 1 ’ 2  Sodium phosphate,  dibasic, heptahydrate 1 • 2  Sodium phosphate,  dibasic 1 ’ 3  Sodium phosphate,  dibasic, dihydrate 1  Sodium phosphate,  dibasic, dodecahydrate  Potassium carbonate 1 , 3  Potassium bicarbonate 3  Potassium citrate 1 ’ 2 ’ 3  Potassium citrate  monohydrate  Potassium acetate 1 ’ 3  Potassium phosphate,  dibasic 1 ’ 2  Potassium phosphate,  tribasic 3  Ammonium phosphate,  dibasic 1 ’ 2 ’ 3  pH of Aqueous Solution  (concentration)  11.27 (1  N),  10.27  (0.001  N)  14 (5%), 13 (0.5%),  12 (0.05%)  13.5 (0.1 M)  12.4 (saturated  solution in water)  9.5 to 10.5 slurry  10.3 (saturated  aqueous solution)  Soluble in water,  Form Ca(OH)$_{2 }$ -8.9 (0.1  N)  8.9 (0.1  N)  -8.9 (0.1  N)  -8.8-9.4, 9.15  to 9.2 (0.01 M)  8.8-9.4, 9.15  to 9.2 (0.01 M)  Strongly alkaline  -11.6  -11.6  -11.6  8.3 (0.1 M fresh)  -11.5 (0.1 %), -11.7 (0.5%),  -11.9 (1.0%)  11.5 (0.1 %), 11.7 (0.5%),  11.9 (1.0%)  9.1 (1%)  -9.5  -9.5  -9.5  -9.5  -11.6  8.2 (0.1 M)  -8.5  -8.5  9.7 (0.1 M)  Aqueous solution is  slightly alkaline  Aqueous solution is  strongly alkaline  -8 