Abstract:
Novel pharmaceutical compositions are disclosed which comprise a hypotensive agent and a phenyl hydrazino substituted propionic acid decarboxylase inhibitor. The compositions have enhanced anti-hypertensive activity.

Description:
BACKGROUND OF THE INVENTION 
     The present invention is directed to novel pharmaceutical compositions containing a hypotensive agent and a decarboxylase inhibitor. 
     The hypotensive agents of the present invention comprise agents, other than phenylalanine and reserpine type compounds, which are known to be effective in treating hypertension in humans. The decarboxylase inhibitor is encompassed in the class of hydrazino phenyl propionic acid compounds disclosed in U.S. Pat. No. 3,462,536; 3,830,827 and 3,781,415. Combinations of this hydrazino phenylpropionic acid type decarboxylase inhibitor with reserpine or phenylalanine type hypertensive agents are disclosed in Canadian Pat. No. 737,907 and U.S. Pat. No. 3,839,585. 
     It has now been discovered that the combination of the aforesaid non-phenylalanine, non-reserpine hypotensive agents with the hydrazino-phenyl propionic acid type decarboxylase inhibitors affords enhanced anti-hypertensive activity. 
     SUMMARY OF THE INVENTION 
     Novel pharmaceutical compositions comprising (a) a non-phenylalanine, non-reserpine hypotensive agent and (b) a D,L- or L-hydrazino-phenyl propionic acid decarboxylase inhibitor and a method of treating hypertensive animals. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     An embodiment of this invention is a hypotensive pharmaceutical composition comprising 
     A. a non-phenylalanine, non-reserpine hypotensive agent and 
     B. the L-isomer or racemic mixture (D,L-) of a hydrazino phenylpropionic acid decarboxylase inhibitor. 
     Preferred hypotensive agents are selected from the group consisting of (1) spironolacetone, hydralazine, trimethaphan camsylate, clonidine, guanethidine, thiazide diuretics, cryptenamine, pharmaceutically acceptable salts thereof and (2) sodium nitroprusside. A more preferred group of hypotensive agents includes hydralazine, clonidine, guanethidine, the thiazide diuretics and pharmaceutically acceptable salts thereof. A most preferred group of hypotensive agents is clonidine, hydralazine, guanethidine and their pharmaceutically acceptable salts. 
     The thiazide diuretics include the benzothiadiazine class of compounds having the basic ring structure ##STR1## Representative compounds are disclosed in U.S. Pat. No. 2,809,184; 2,937,169; 3,025,292; 3,164,588 and 3,043,840, and are incorporated herein by references. 
     The preferred thiazide compounds are chlorothiazide, hydrochlorothiazide, trichlormethizide, bendroflumethiazide, polythiazide, flumethiazide, and their pharmaceutically acceptable salts. Hydrochlorothiazide is a most preferred thiazide hypotensive agent. 
     Preferred decarboxylase inhibitors include the D,L-racemic mixture and the individual L-isomer of compounds having the formula: ##STR2## wherein R, R 1 , R 2  and R 3  are independently selected from hydrogen and C 1  -C 4  alkyl such as methyl, t-butyl, isopropyl and the like. A more preferred decarboxylase inhibitor is the L-isomer and most preferred is the L-isomer of ##STR3## and its pharmaceutically acceptable salts. The monohydrate of IV is known as carbidopa. 
     Pharmaceutically acceptable salts include the salts of the various compounds with suitable organic or inorganic acids. Suitable organic acids are C 2  -C 24  carboxylic acids such as acetic acid, maleic acid, pamoic acid, succinic acid, citric acid, propionic acid, isethionic acid, oxalic acid, pivalic acid and the like. Suitable inorganic acids include the hydrohalides, e.g., HCl, HI, HBr, sulfuric acid, phosphoric acid and the like. The salts may also be alkali metal salts such as the sodium or potassium salt or the ammonium salt. 
     The compositions of the present invention may contain varying amounts of the hypotensive agent and decarboxylase inhibitor. In general, the weight ratio of hypotensive agent (a) to decarboxylase inhibitor (b) will be from about 4:1 to about 1:9000. A preferred weight ratio of (a):(b) is about 1:1 to about 1:1000 and a most preferred weight ratio is about 1:5 to about 1:500. 
     In treating hypertension, a sufficient amount of the present composition is administered to the hypertensive animal to produce the desired hypotensive effect, i.e., reduction in blood pressure. Effective dosages may vary and can range from about 0.2 mg/kg to about 1000 mg/kg per day. The composition may be given as a single daily dose or divided into several smaller doses during the course of the day. 
     The composition may be administered parenterally or orally. The dosage form used will depend on the mode of administration. The oral form may be a tablet, a liquid solution, dispersion, or emulsion, a capsule, or an encapsulated composition--while the parenteral dosage form will generally be a liquid solution, suspension or emulsion. The dosage forms generally will include conventional carriers, diluents, either solid or liquid, dyes etc. and will be prepared using applicable formulation procedures. 
     The compositions of the present invention are administered to hypertensive animals to effect reduction in blood pressure. The decarboxylase inhibitors are known to have no appreciable anti-hypertensive effect. When combined with the present hypotensive agents, however, the anti-hypertensive effect of the hypotensive agent is unexpectedly enhanced. 
     This enhancement of anti-hypertensive activity is demonstrated in vivo in spontaneously hypertensive (SH) rats. The procedure used is as follows: 
     The test animals used were conscious, male, SH rats weighing about 290 to about 340 grams. The arterial blood pressure was measured by a direct technique involving cannulation of the caudal artery. Initial blood pressure reading was recorded. The decarboxylase inhibitor was then administered intraperitoneally (i.p.) and about 5 minutes later the hypotensive agent was given, (i.p.). The blood pressure was then continuously recorded at 1/2 hour intervals for 24 hours. 
     The effect on blood pressure of the decarboxylase inhibitor and the hypotensive agent alone was also obtained by this method. The results of these tests for representative compositions of the present invention are in the following tables: 
     
                                           Table 1__________________________________________________________________________Effects of guanethidine and hydrochlorothiazide, alone and in combinationwith carbidopa, on themean arterial pressure of conscious SH rats.__________________________________________________________________________         Dose    No.  Mean Arterial Pressure, mm Hg,Group         mg/kg   of   at hours after treatment__________________________________________________________________________No.  Treatment         i.p.    Rats 0   1/2 1   2   4   8   12  18  24__________________________________________________________________________1    Saline   2 mg/kg 9    168 170 170 170 166 164 166 166 1642    Carbidopa.sup.1         25      6    167 166 164 166 158 167 172 172 1623    Guanethidine.sup.2         0.078   6    179 178 177 177 174 180 180 177 1784    Guanethidine         0.312   5    174 167 168 171 171 174 170 170 1665    Guanethidine         0.625   4    176 180 180 178 172 179 173 174 1766    Guanethidine         1.25    4    171 143 163 150 150 154 147 155 1627    Guanethidine         5       4    174 131 133 132 140 157 155 163 1628    Carbidopa &amp;         25      4    173 161 162 173 166 172 171 172 170Guanethidine         0.3129    Carbidopa &amp;         25      6    173 157 140 137 137 144 152 147 149Guanethidine         0.62510   Carbidopa &amp;         25      4    166 126 133 129 126 141 147 158 157Guanethidine         1.2511   Hydrochloro-         5       4    170 179 177 176 165 170 174 171 171thiazide.sup.312   Hydrochloro-         20      4    164 161 159 161 159 163 152 151 149thiazide13   Hydrochloro-         40      5    168 167 167 164 163 161 159 155 155thiazide14   Hydrochloro-         80      5    169 152 160 142 145 145 141 141 140thiazide15   Carbidopa &amp;         25      4    170 169 161 159 156 158 152 154 152Hydrochloro-         5thiazide16   Carbidopa &amp;         25      4    170 164 164 163 155 162 158 158 153Hydrochloro-         20thiazide17   Carbidopa &amp;         25      5    179 181 170 162 148 160 158 162 161Hydrochloro-         40thiazide18   Carbidopa &amp;         25      6    176 153 146 146 128 135 133 138 146Hydrochloro-         80thiazide__________________________________________________________________________ .sup.1 Dissolved in 1N HCl .sup.2 As Guanethidine sulfate dissolved in water .sup.3 Dissolved in 1N NaOH 
    
     
                                           Table 2__________________________________________________________________________Effect of hydralazine and clonidine, alone and in combination withcarbidopa, on the mean arterialpressure of conscious SH rats.__________________________________________________________________________         Dose    No.  Mean Arterial Pressure, mm Hg,Group         mg/kg   of   at hours after treatment__________________________________________________________________________No.  Treatment         i.p.    Rats 0   1/2 1   2   4   8   12  18  24__________________________________________________________________________1    Saline   2 ml/kg 9    168 170 170 170 166 164 166 166 1642    Carbidopa.sup.1         25      6    167 166 164 166 158 167 172 172 1623    Hydralazine.sup.2         0.03    3    167 169 165 173 172 166 168 171 1734    Hydralazine         0.125   4    170 166 165 166 171 174 168 168 1675    Hydralazine         0.25    4    180 159 166 172 170 172 175 176 1696    Hydralazine         0.5     9    164 128 138 146 152 161 160 160 1597    Hydralazine         1       4    180 120 127 157 157 178 176 177 1768    Hydralazine         2       5    169 120 126 135 144 152 156 154 1629    Carbidopa &amp;         0.312   4    166 158 146 154 153 166 164 163 157Hydralazine         0.12510   Carbidopa &amp;         1.25    4    163 155 142 145 151 156 147 147 151Hydralazine         0.12511   Carbidopa &amp;         5       4    168 187 175 166 163 135 133 130 152Hydralazine         0.12512   Carbidopa &amp;         25      4    174 163 157 144 138 152 160 163 160Hydralazine         0.0313   Carbidopa &amp;         25      5    177 137 132 149 140 149 151 155 158Hydralazine         0.12514   Carbidopa &amp;         25      4    173 146 147 158 158 159 164 164 170Hydralazine         0.2515   Carbidopa &amp;         1.25    6    169 143 149 156 159 161 157 165 166Hydralazine         0.516   Carbidopa &amp;         5       6    172 134 129 143 150 152 152 149 154Hydralazine         0.517   Carbidopa &amp;         25      8    175 117 115 130 141 149 153 153 153Hydralazine         0.518   Clonidine.sup.3         0.00075 4    170 171 171 170 169 166 172 161 17019   Clonidine         0.003   4    169 166 156 165 163 165 168 177 17920   Clonidine         0.0125  4    167 159 167 163 163 169 169 167 17221   Clonidine         0.025   6    168 148 147 149 151 154 151 149 15022   Clonidine         0.05    7    180 164 159 149 146 154 159 164 16623   Clonidine         0.2     3    173 164 147 152 150 148 152 157 16224   Carbidopa &amp;         25      6    169 153 157 158 162 175 169 163 171Clonidine         0.0007525   Carbidopa &amp;         25      6    168 134 141 146 150 148 151 152 162Clonidine         0.00326   Carbidopa &amp;         25      5    166 144 139 143 154 161 167 170 164Clonidine         0.012527   Carbidopa &amp;         25      4    170 149 121 114 116 127 135 136 142Clonidine         0.0528   Carbidopa &amp;         1.25    4    180 156 149 148 151 159 171 170 175Clonidine         0.0529   Carbidopa &amp;         5       5    175 142 129 128 132 149 153 156 164Clonidine         0.05__________________________________________________________________________ .sup.1 Dissolved in 1N HCl .sup.2 As hydralazine . HCl Dissolved in water .sup.3 As clonidine . HCl Dissolved in 1N HCl 
    
     The above data clearly shows the enhancement of antihypertensive properties of the non-reserpine, non-phenylalanine agent by the decarboxylase inhibitor. 
     Following are formulations of some representative dosage forms: 
     
         ______________________________________Tablet FormulationClonidine hydrochloride                 0.1      mgCarbidopa             5.0      mgCalcium phosphate     50.0     mgLactose               20.0     mgStarch                10.0     mgMagnesium sulfate     0.5      mgLiquid SuspensionGuanethidine sulfate  2.5      gCarbidopa             2.5      gVeegum HV             3.0      gMethylparaben         1.0      gKaolin                10.0     gGlycerin              250.0    g ##STR4##Injectable SolutionHydralazine hydrochloride                 20       mgCarbidopa .HCl        100      mg ##STR5##Capsule Formulation - IHydrochlorothiazide   50       mgCarbidopa             15       mgLactose               50       mgTalc                  3        mgCapsule Formulation - IIClonidine HCl         0.2      mgCarbidopa             100.0    mgMannitol              98.0     mgStearic acid          1.0      mg______________________________________ 
    
     While the test results were obtained by i.p. administration of the two drugs of the present composition separately, the effect is demonstrative of the anti-hypertensive effect which would be obtained on administration, orally or parenterally, of the hypotensive agent and decarboxylase inhibitor either as a combination or individually and simultaneously. Another embodiment of this invention is a method of treating hypertensive animals by thus administering an anti-hypertensive amount of the aforesaid composition comprising the hypotensive agent and the decarboxylase inhibitor. 
     The term animals includes humans. 
     Claims to the invention follow.