Jun.5,2003  5  US 2003/0104041 Al  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.  [0041]  The  aforementioned  amounts  are  particularly  applicable 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 inorganic hydroxide, to any significant degree.  [0042]  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  (i.e., the "acidic species"), plus (2) 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 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 mucosal  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 aforementioned percentages are given rela› tive to the total weight of the formulation components and  the adhesive, gel or liquid reservoir.  [0043]  Still greater amounts of inorganic hydroxide may  be used by controlling the rate and/or quantity of release of  the base, preferably during the drug delivery period itself.  [0044]  Inorganic oxides include, for example, magnesium  oxide, calcium oxide, and the like.  [0045]  The amount of inorganic oxide included in the  compositions and systems of the invention may be substan› tially 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 about 2-20 wt %. These amounts may be  adjusted to take into consideration the presence of any  base-neutralizable species.  [0046]  Inorganic salts of weak acids include, ammonium  phosphate ( dibasic ); alkali metal salts of weak acids such as  sodium acetate, sodium borate, sodium metaborate, sodium  carbonate, sodium bicarbonate, sodium phosphate (tribasic),  sodium phosphate ( dibasic ), potassium carbonate, potassium  bicarbonate, potassium citrate, potassium acetate, potassium  phosphate (dibasic), potassium phosphate (tribasic); alkaline  earth metal salts of weak acids such as magnesium phos› phate and calcium phosphate; and the like, and combinations  thereof.  [0047]  Preferred inorganic salts of weak acids include,  ammonium phosphate (dibasic) and alkali metal salts of  weak acids.  [0048]  The amount of inorganic salts of weak acids  included in the compositions 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 approximately 2-20 wt%. These  amounts may be adjusted to take into consideration the  presence of any base-neutralizable species.  [0049]  B.  Organic Bases  [0050]  Organic bases suitable for use in the invention are  compounds having an amino group, amido group, an oxime,  a cyano group, an aromatic or non-aromatic nitrogen-con› taining heterocycle, a urea group, and combinations thereof.  More specifically, examples of suitable organic bases are  nitrogenous bases, which include, but are not limited to,  primary amines, secondary amines, tertiary amines, amides,  oximes, cyano  (-CN)  containing groups, aromatic and  non-aromatic nitrogen-containing heterocycles, urea, and  mixtures thereof. Preferred organic bases are primary  amines, secondary amines, tertiary amines, aromatic and  non-aromatic nitrogen-containing heterocycles, and mix› tures thereof.  [0051]  For nitrogenous bases, the amount of enhancing  agent will typically represent about 0.5-4.0 wt%, preferably  about 0.5-3.0 wt%, more preferably about 0.75-2.0 wt%, of  a topically applied formulation or of a drug reservoir of a  drug delivery system or a patch. These amounts may be  adjusted to take into consideration the presence of any  base-neutralizable species.  [0052]  Still greater amounts of the nitrogenous base may  be used depending on the strength of the base and the rate  and/or quantity of release of the nitrogenous base preferably  during the drug delivery period itself.  [0053]  Preferred organic bases are those whose aqueous  solutions have a high  pH  or a high pKa (more preferably a  pKa>9), and are acceptable as food or pharmaceutical addi› tives. Examples of such preferred organic bases are those  listed below, along with their respective pHs (or pKa val› ues).  ’listed in the "Handbook of Pharmaceutical Additives"  $^{2}$listed in the FDA’ s food additive database  [0054]  Amines are compounds that include at least one  primary amino  (-NH$_{2}$ )  group, mono-substituted (second› ary) amino group or di-substituted (tertiary) amino group.  Amines  Inorganic Salts of Weak Acids  Inorganic Oxides  Organic base  2-amino-2-methyl-1,3-propanediol 1  2-amino-2-methyl-1-propanol 1  Diethanolamine 1  Triethanolamine 1  Butylamine 2  Dimethylamine 2  Cyclohexylamine 2  Ethylenediamine 2  Isopentylamine 2  Monoethanolamine 2  Phenethylamine 2  Piperidine 2  Pyrrolidine 2  Trimethylamine 2  pH of Aqueous Solution  (concentration)  10.8 (0.1 m)  11.3 (0.1 m)  11.0 (0.1  N)  10.5 (0.1  N)  pKa - 10.56  Strong base, pKa - 10. 73  Strong base, pKa - 10.64  Strong base, pKa - 10. 71  pKa - 10.6  12.1 (25%), 12.05 (0.1  N),  pKa - 9.4  Strong base, pKa - 9.83  Strong base, pKa - 11.12  Strong base, pKa - 11.27  Strong base, pKa - 9.81 