Aug. 6, 2009  4  US 2009/0197849 Al  [0032]  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.  [0033]  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 mini› mized 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-mitigat› ing additive. Alternatively, the patient can be advised to  change the location of application with each subsequent  administration.  [0034]  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 administered and  whether there are any acidic species present in the formula- [0037]  Inorganic hydroxides include, for example, ammo› nium hydroxide, alkali metal hydroxide and alkaline earth  metal hydroxides, and mixtures thereof. Preferred inorganic  hydroxides include animonium 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 combina› tions thereof.  [0038]  The amount of inorganic hydroxide included in the  compositions and systems of the invention, will typically  $^{1 }$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  [0036]  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 pre› ferred 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.  [0035]  A. Inorganic Base  tion 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.  Inorganic base  Ammoniwn hydroxide 1 , 2 , 3  Sodium hydroxide 1 • 2 3  Potassiwn hydroxide 1 , 2 , 3  Calcium hydroxide 1 • 3  Magnesium hydroxide 1 • 3  Magnesium oxide 1 , 2 , 3  Calciwn 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 1  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  Potassiwn carbonate 1 , 3  Potassiwn bicarbonate 3  Potassiwn citrate 1 ’ 2 ’ 3  Potassiwn citrate monohydrate  Potassiwn acetate 1 , 3  Potassiwn phosphate, dibasic 1 ’ 2  Potassiwn phosphate, tribasic 3  Ammoniwn 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)o  ~8.9 (0.1  N)  8.9 (0.1  N)  ~8.9 (0.1  N)  ~8.8-9.4, 9.15 to 9.2 (0.01M)  8.8-9.4, 9.15 to 9.2 (0.01M)  Strongly alkaline  ~11.6  ~11.6  ~11.6  8.3 (0.1 M fresh)  ~11.5 (0.1%),~ll.7 (0.5%),~ll.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  Inorganic Hydroxides 