Patent Publication Number: US-4221783-A

Title: Composition and method for the treatment of duodenal ulcers, gastritis and gastro-duodenitis

Description:
This application is a continuation-in-part of copending application, Ser. No. 906,202 filed May 15, 1978 now abandoned. 
    
    
     This invention relates to medicinal compositions, more particularly, the present invention relates to compositions suitable for use in the treatment of gastritis; gastro-duodenitis and gastro-duodenal ulcers. 
     Heretofore, both medicinal techniques and surgical procedures have been commonly used in the treatment of gastro-duodenal ulcers. The medicinal methods employed typically have focused upon the pathogenetic links which intervene in ulcerogenesis and may involve neutralization of gastric acid secretion, dressings of the gastric mucous membrane, the use of substances which enhance the factors protecting the gastric mucous membrane, anticholinergics (vagolitics), tranquilizers, and the like. Medications employed for such purposes include sodium bicarbonate, compositions containing colloidal aluminum hydroxide, belladone extract, salts of calcium, magnesium, and bismuth, various silicates, scopalamine derivatives and combinations thereof with tranquilizers or flavoring substances which enhance digestion. 
     The surgical procedures employed for treatment of gastro-duodenal ulcers are directed to the elimination of those zones which play a role in the secretion of gastric acids. These procedures include gastric resection, antrectomy, vagatomy, and variations thereof. 
     Each of these noted techniques is primarily directed to precluding the formation of hydrochloric acid in the parietal cell and migration thereof to the fundic zone of the stomach. Although these medicinal and surgical techniques have been employed with varying degrees of success, research efforts have continued with the goal of developing improved medications designed to obviate the necessity of surgery. 
     In accordance with the present invention, this end is attained by the use of a composition which is capable of inhibiting the carbonic anydrase enzyme (carboanhydrase) which, when present in the renal tubules, erythrocytes, and other tissues, catalyzes the reversible hydration of carbon dioxide as shown by the following equation: 
     
         CO.sub.2 +H.sub.2 O⃡H.sup.+ +HCO.sub.3.sup.- 
    
     During the course of this reaction, the liberated hydrogen ion is replaced by the sodium ion of the tubal urine which then combines with the HCO 3   -  ion and reappears as sodium in extracellular fluid. The hydrogen ion is eliminated either in the form of NH 4   +  ions or as an acid salt such as disodium phosphate. Inhibition of enzyme formation pursuant to the invention results in diminution of carbonic acid formation as well as a lessening in the rate of formation of hydrogen ions. 
     The compositions described herein include a carbonic anhydrase inhibitor as an active component which comprises a sulfonamide including an SO 2  NH 2  group linked either to a thiazolic or benzothiazolic ring together with an alkali metal bicarbonate (e.g., sodium and/or potassium), an alkali metal citrate (e.g., sodium or potassium), the oxide or carbonate of magnesium, and aluminum hydroxide. 
     The sulfonamides described herein are of the general formula 
     
         R-SO.sub.2 NH.sub.2 
    
     wherein R is selected from the group consisting of 
     (a) 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide, 
     (b) 5-acetylamino-4,methyl-Δ 2  -1,3,4-thiadiazoline-2-sulfonamide, 
     (c) 6-ethoxy-2-benzothiazole-sulfonamide, and 
     (d) 5-benzosulfonamide-1,3,4-thiadiazole-2-sulfonamide. 
     The described compositions may conveniently be prepared in tablet or powder form together with adjuvants commonly employed for the rapid disintegration of tablets. The constituent, components of the described composition may be employed in amounts falling within the broad ranges set forth in the following table, the quantities being expressed in weight percentages: 
     
                       TABLE                                                       
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Compound          Amount Present (weight %)                               
______________________________________                                    
linked sulfonamide                                                        
                   5-40                                                   
bicarbonates of alkali metals                                             
                  15-30                                                   
alkali metal citrate                                                      
                  10-40                                                   
magnesium compound                                                        
                  14-30                                                   
(oxide or carbonate)                                                      
aluminum hydroxide                                                        
                   0-15                                                   
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     The noted compositions may be effectively employed in treating gastro-duodenal ulcers in adults and children and is particularly effective in treating cases with chronic and gigantic recesses or those evidencing an ususually high degree of gastric acid secretion. This end is attained by use of the noted sulfonamides which act to diminish gastric secretion. Electrolytic losses are compensated by means of adjuvants. 
     Administration of the described medication may be effected orally, after meals, with a frequency ranging from 2-4 times per day for a time period ranging from 2-5 weeks. In administering the drug, it is important to avoid exceeding the daily permissible therapeutic doses, which are determined on the basis of the body weight of the patient the doses falling within the following ranges: 200-3000 mg acetazolamide, 60-1500 mg methazolamide, 30-800 mg benzolamide, 100-3000 mg ethoxolamide, 100-3500 mg alkali metal bicarbonate, 100-4000 mg alkali metal citrate, 100-3000 mg magnesium oxide or carbonate and 50-1500 mg aluminum hydroxide. During treatment, the patient does not require a strict hygieno-dietic diet. 
    
    
     Several examples of medicinal compositions in accordance with the present invention are set forth below. It will be understood by those skilled in the art that these exemplary embodiments are for purposes of exposition and are not be contrued as limiting. 
     
         ______________________________________                                    
                  I           II                                          
Examples I and II % by weight % by weight                                 
______________________________________                                    
Ethoxolamide      15.38       20.00                                       
Potassium bicarbonate                                                     
                  23.08       23.33                                       
Sodium citrate    30.77       26.67                                       
Magnesium oxide   23.08       20.00                                       
aluminum hydroxide                                                        
                  7.69        10.00                                       
______________________________________                                    
                  III         IV                                          
Examples III and IV                                                       
                  % by weight % by weight                                 
______________________________________                                    
Benzolamide       5.17        6.25                                        
Sodium bicarbonate                                                        
                  25.86       27.34                                       
Potassium citrate 34.48       31.25                                       
Magnesium carbonate/oxide                                                 
                  25.86       23.44                                       
aluminum hydroxide                                                        
                  8.63        11.72                                       
______________________________________                                    
                  V           VI                                          
Examples V and VI % by weight % by weight                                 
______________________________________                                    
Methazolamide     11.77       12.50                                       
Potassium bicarbonate                                                     
                  29.41       29.17                                       
Sodium citrate    39.21       33.33                                       
Magnesium carbonate                                                       
                  19.61       25.00                                       
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                  VII         VIII                                        
Exampls VII and VIII                                                      
                  % by weight % by weight                                 
______________________________________                                    
Acetazolamide     38.30       36.36                                       
Potassium citrate 21.28       --                                          
Sodium citrate    --          13.64                                       
Sodium bicarbonate                                                        
                  17.02       4.54                                        
Potassium bicarbonate                                                     
                  --          13.64                                       
Magnesium oxide   14.89       18.18                                       
Aluminum hydroxide                                                        
                  8.51        13.64                                       
______________________________________                                    
                  IX          X                                           
Examples IX and X % by weight % by weight                                 
______________________________________                                    
Acetazolamide     38.10       40.00                                       
Potassium bicarbonate                                                     
                  11.43       14.00                                       
Sodium bicarbonate                                                        
                  11.43       5.00                                        
Sodium citrate    13.34       15.00                                       
Magnesium oxide   19.04       18.00                                       
Aluminum hydroxide                                                        
                  6.66        8.00                                        
______________________________________                                    
 
    
     Adjuvants employed in preparing tablets of the above-described compositions may be selected from among sodium carboxymethylcellulose, polyvinyl pyrolidone, magnesium steorate, talc, and the like. 
     Evaluation of patients treated with compositions of the invention reveal that closure of gastric recess is effected within a time period ranging from 10-18 days, such being for superior to that attainable with known prior art medications. Furthermore, surgery was avoided in each case. Additionally, closure of recesses in a duodenal ulcer was attained in all cases within 3 to 5 days after treatment. And lastly, in peptic post-operative ulcers and pyloric stenosis, use of the described composition limited further surgical intervention.