Aug. 30, 2012  5  US 2012/0220962 Al  Inorganic base  pH of Aqueous Solution (concentration)  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  11.27 (lN), 10.27 (0.001N)  14 (5%), 13 (0.5%), 12 (0.05%)  13.5 (0.lM)  12.4 (saturated solution in water)  9.5 to 10.5 slurry  Sodium acetate 1 ’ 3  10.3 (saturated aqueous solution)  Soluble in water, Form Ca(OH)o  ~8.9 (0.lN)  8.9 (0.lN)  Sodium acetate, trihydrate 1 ,2.  Sodium acetate, anhydrous 1 ’ 2  Sodium borate decahydrate 1 ’ 2  Sodium borate 1 , 2 , 3  ~8.9 (0.lN)  ~8.8-9.4, 9.15 to 9.2 (0.0lM)  8.8-9.4, 9.15 to 9.2 (0.0lM)  Sodium metaborate  Strongly alkaline  ~11.6  ~11.6  ~11.6  8.3 (0.lM fresh)  Sodium carbonate 1 ’ 2 ’ 3  Sodium carbonate hydrate 1  Sodium carbonate anhydrous  Sodium bicarbonate 1 , 2 , 3  Sodium phosphate, tribasic 1 ’ 3  ~11.5 (0.1%), ~11.7 (0.5%), ~11.9 (1.0%)  Sodium phosphate, tribasic dodecahydrate  Sodium phosphate, dibasic, anhydrous  1 , 2  Sodium phosphate, dibasic, heptahydrate 1 , 2  Sodium phosphate, dibasic 1 ’ 3  11.5 (0.1%), 11.7 (0.5%), 11.9 (1.0%)  9.1 (1%)  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  ~9.5  ~9.5  ~9.5  ~9.5  ~11.6  8.2 (0.lM)  ~8.5  ~8.5  9.7 (0.lM)  Potassiwn phosphate, dibasic 1 ’ 2  Potassiwn phosphate, tribasic 3  Ammoniwn phosphate, dibasic 1 , 2 , 3  Aqueous solution is slightly alkaline  Aqueous solution is strongly alkaline  ~8  2 1isted in the "Handbook of Pharmaceutical Additives"  $^{1}$1isted in the "Chemicals in Compliance with Pharmaceutical Standards: Inactive Ingredient Guide"  3 1isted in the FDA’s food additive database  Inorganic Hydroxides  Inorganic Oxides  [0041]  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 combina› tions thereof.  [0042]  The amount of inorganic hydroxide included in the  compositions and systems of the invention will typically rep› resent about 0.3-7.0 wt %, preferably 0.5-4.0 wt %, more  preferably about 0.5-3.0 wt%, most preferably about 0.75- 2.0 wt %, of a topically applied formulation or of a drug  reservoir of a drug delivery system, or patch.  [0043]  The aforementioned amounts are particularly appli› cable to those formulations and patches in which the active  agent is (1) an uncharged molecule, e.g., wherein a basic drug  is in nonionized, free-base form, (2) a basic salt of an acidic  drug, or (3) there are no additional species in the formulation  or patch that could react with or be neutralized by the inor› ganic hydroxide, to any significant degree.  [0044]  For formulations and patches in which the drug is in  the form of an acid addition salt, and/or wherein there are  additional species in the formulations or systems that can be  neutralized by or react with the inorganic base (i.e., acidic  inactive ingredients), the amount of inorganic hydroxide is  preferably the total of (1) the amount necessary to neutralize  the acid addition salt and/or other base-neutralizable species  [0046]  Inorganic oxides include, for example, magnesium  oxide, calcium oxide, and the like.  [0047]  The amount ofinorganic oxide included in the com› positions and systems of the invention may be substantially  higher than the numbers set forth above for the inorganic  hydroxide, and may be as high as 20 wt %, in some cases as  high as 25 wt% or higher, but will generally be in the range of  [0045]  Still greater amounts of inorganic hydroxide may be  used by controlling the rate and/or quantity ofrelease of the  base, preferably during the drug delivery period itself.  (i.e., the "acidic species"), plus (2) about 0.3-7.0 wt%, pref› erably 0.5-4.0 wt %, more preferably about 0.5-3.0 wt %,  most preferably about 0.75-2.0 wt%, of the formulation or  drug reservoir. That is, for an acid addition salt, the enhancer  is preferably present in an amount just sufficient to neutralize  the salt, plus an additional amount (i.e., about 0.3-7.0 wt%,  preferably 0.5-4.0 wt%, more preferably about 0.5-3.0 wt%,  most preferably about 0.75-2.0 wt%) to enhance the flux of  the drug through the skin or mucosa! tissue. Basic drugs in the  form of a neutral, free base or basic salt of acidic drug are  usually not affected by a base, and thus for these drugs, the  amount in (1) is usually the amount necessary to neutralize  inactive components that are acidic. For patches, the afore› mentioned percentages are given relative to the total weight of  the formulation components and the adhesive, gel or liquid  reservmr. 