Aug. 6, 2009  5  US 2009/0197849 Al  represent 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.  [0039]  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.  [0040]  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%, 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.  [  0041]  Still greater amounts ofinorganic hydroxide may be  used by controlling the rate and/or quantity ofrelease of the  base, preferably during the drug delivery period itself.  [0042]  Inorganic oxides include, for example, magnesium  oxide, calcium oxide, and the like.  [0043]  The amount of inorganic 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  about 2-20 wt%. These amounts may be adjusted to take into  consideration the presence of any base-neutralizable species.  [0044]  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 ( di basic), potassium carbonate, potassium  bicarbonate, potassium citrate, potassium acetate, potassium  phosphate ( dibasic ), potassium phosphate (tribasic ); alkaline  earth metal salts of weak acids such as magnesium phosphate  and calcium phosphate; and the like, and combinations  thereof.  [0045]  Preferred inorganic salts of weak acids include,  ammonium phosphate ( dibasic) and alkali metal salts of weak  acids.  [0046]  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.  [0047]  B. Organic Bases  [0048]  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-contain› ing heterocycle, a urea group, and combinations thereof.  More specifically, examples of suitable organic bases are  nitrogenous bases, which include, but are not limited to, pri› mary amines, secondary amines, tertiary amines, amides,  oximes, cyano (-CN) containing groups, aromatic and non› aromatic nitrogen-containing heterocycles, urea, and mix› tures thereof. Preferred organic bases are primary amines,  secondary amines, tertiary amines, aromatic and non-aro› matic  nitrogen-containing  heterocycles,  and mixtures  thereof.  [0049]  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.  [0050]  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.  [0051]  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 values).  [0052]  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 ofWeakAcids  $^{1}$listed in the "Handbook of Pharmaceutical Additives"  $^{2}$1isted in the FDA’s food additive database  Inorganic Oxides  Organic base  2-amino-2-methyl-1,3-propanediol  1  2-amino-2-methyl-1-propanol 1  Diethanolarnine 1  Triethanolarnine 1  Butylamine 2  Dimethylamine 2  Cyclohexylamine 2  Ethylenediamine 2  Isopentylamine 2  Monoethanolarnine 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 