Pharmaceutical composition having synergistic analgesic activity and containing azidomorphine or azidocodeine
The present invention relates to pharmaceutical compositions having synergetic analgetic activity and a process for the preparation thereof. For the relief of postoperational pain and in the case of cancer patients in an advanced stage of the disease morphine and its derivatives are the most frequently used efficient analgesics. It is a wellknown fact, however, that in patients treated with morphine, the harmful side-effects, e.g. respiratory depression, tolerance and dependence develop in a relatively short time. The patient gets used to morphine and rapidly rising doses are required to obtain an equinanalgetic effect; tolerance or dependence develops and the patient is in permanent need of the euphorizing effect of morphine. Another disadvantage of morphine is the fact that it is practically ineffective on oral application. All the analgesics suited for the treatment of unbearable pain (e.g. cancer, postoperative, infraction, lithiases, etc.) are likely to induce the development of tolerance on chronic administration and their withdrawal produces severe -- often fatal -- somatic and psychic symptoms (physical and psychic dependence). It is generally accepted (Martin, 1967, Pharm. Rev. 19, 463) that the apperance of tolerance and dependence necessarilly accompany the action of the morphine type drugs on the analgesic receptors. An analgesic equipotent to morphine, but devoid of its narcotic side-effects, has for long been needed in clinical practice. For the replacement of morphine 6-desoxy-6-azido14-hydroxy-dihydro-isomorphine, prepared by Bognar and Makleit seems to be suitable. According to the present invention there are provided pharmaceutical compositions having synergestic analygesic effect comprising at least one compound of the formula I or a salt thereof (wherein R is hydrogen or methyl) and at least one compound of the formula II (wherein R 1  and R 2  are lower alkyl and R 3  is hydrogen or lower alkyl) in admixture with pharmaceutically acceptable inert solid or liquid carriers or diluents. 
     The present invention is based on the recognition that the compounds of the formula II and their salts and quaternary salts potentiate the analgesic action of the azido compounds of the formula I to a significant extent and also have an advantageous influence on their other properties. Thus, a well-expressed potentiation takes place and the effect of the combination surpasses the additive effect of the components when used alone. A further advantage resides in the fact that the combinations according to the present invention are devoid of narcotic side effects. 
     In the compositions of the present invention a compound of the formula I preferably 14-hydroxy-azido-morphine may be used, but 14-hydroxy-axido-codeine may be applied with similar results too. The compound of the formula I may be used as the free base or in the form of an acid addition salt thereof. The salts may be those formed with inorganic or organic acids; the acid component used must be pharmaceutically acceptable and should provide preferably solubility properties to the salt obtained. The bitartarate salts of the compounds of the formula I possess particularly advantageous solubility characteristics. 
     In the compounds of the formula II the alkyl groups may be straight or branched chained and contain 1-6, preferably 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isobutyl, etc.). The salts and quaternary salts of the compounds of the formula II may contain any pharmaceutically acceptable anion (e.g. inorganic anions, such as nitrate, chloride, bromide or sulphate anion; and organic anions, e.g. methylsulphate, ethylsulphate, etc.). A particularly preferred representative of the compounds of the formula II is the 1,6-dimethyl-3-carbethoxy-4-oxo- 6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate. 
     Synergistic analgesic effect is measured on the one hand by means of the analgesis tests (Knoll et al: Animal and Clinical Pharm. Techn. in Drug Ev. (1967) 305-321). This is a model test for surgical pains and demonstrates exclusively a major analgesic effect. The essence of the test is that under the effect of a 10 mg/kg i.v. dose of morphine, rats can be subjected to laparatomia without the slightest signs of pain. For each dose 10 rats each were used. 
     It has been found that the homopyrimidazole derivatives of the formula II and salts and quaternary salts thereof on the one hand, and the 14-hydroxy-azido-morphine and 14-hydroxy-azido-codeine on the other, potentiate the analgesic effect of each other to a significant extent without influencing the toxicity or other side effects. The present invention is based on the recognition that a mutual effect exists between the representatives or both compound-groups. The synergistic effect is shown on the examples of a composition cobtaining 14-hydroxy-azido-morphine and 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate by using the algolytic test discussed above. The results are summarized in the following table: 
     
                       Table I                                                     
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Compound A                                                                
         Route of ad-                                                     
                    Compound  Route of ad-                                
                                       Algo-                              
         ministration                                                     
                    B         ministration                                
                                       lytic                              
                                       test                               
                                       anal-                              
                                       getic                              
                                       effect                             
                                       in %                               
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0.050    i.v.       --        --       15                                 
--       --          75       i.v.      2                                 
0.050    i.v.        75       i.v.     81                                 
10       p.o.       --        --       18                                 
--       --         250       p.o.      9                                 
10       p.o.       250       p.o.     69                                 
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     It appears from the data of the above table that both on intravenous and oral administration the combination containing doses of the components being ineffective per se (0.050 mg/kg) of compound A i.v. and 75 mg/kg i.v. of compound B, or 10 mg/kg p.o. of compound A and 250 mg/kg p.o. of compound B respectively produces a very strong analgesic effect being 81% in intravenous and 69% in oral administration. The algolytic test is a measure exclusively of the analgesic effect of narcotics. For this reason, the said composition of the present invention may be very valuable in the relief of surgical pains. The synergistic effect of the pharmaceutical composition of the present invention is also proved by the hot-plate test, described by Woolfe and McDonald (J. Pharm. 80, 300) and modified by Porszasz and Herr (Kiserl. Orvostud 2, 292). This method is based on the measurement of radiating heat. The essence of the test is that rats without preliminary training are placed on plates having a temperature of 56°C and after a certain period, the time of appearance of certain pain reactions (blowing and licking of the paws) is measured. The analgesic effect is expressed in the percental prolongation of the reaction time of the control. 
     
                       Table II                                                    
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Compound                                                                  
        Route of Compound  Route of                                       
                                  Hot plate test                          
A       adminis- B         adminis-                                       
                                  analgesic effect                        
        tration            tration                                        
                                  in %                                    
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0.025   i.v.     --        --     29                                      
--      --       50        i.v.   14                                      
--      --       75        i.v.   49                                      
0.025   i.v.     50        i.v.   68                                      
0.025   i.v.     75        i.v.   97                                      
10.0    p.os     --        --     21                                      
--      --       250       p.os   32                                      
10.0    p.os     250       p.os   92                                      
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     It may be seen from the above table that the homopyrimidazole-derivative increases analgesic effect of compound A to a significant extent. This is well proved by the experiment in which the two compounds are added simultaneously intravenously (0.025 mg/kg and 50 mg/kg respectively) or orally (10 mg/kg and 250 mg/kg respectively). From the point of view of practical therapy the latter may be of great importance, since it is well-known the derivatives of morphine when administered orally, show low activity and the strong peroral assuaging of pain is an undissolved problem. The effective intravenous combinations may be used in operation narcosis and the introduction thereof. The mutual effect between azidomorphine derivatives and homopyrimidazole derivatives has been demonstrated in several pharmocological tests. In pain relief, a potentiating synergism has been proved. Furtheron, it has been shown that the synergism of the analgesic effect is not accompanied by a synergism of undesired side-effects (e.g. central nerval depressive effect). 
     The central nerval depressive effect is tested on the modified spring test (J. Knoll: Publications of the Hungarian Academy of Sciences 14, 223). In earlier publications (Knoll, 1967; Screening and grouping of psycho-pharmacologic agents in: Animal and Clinical Pharm.Techn. in Drug Ev. 2, Ed.s.: Siegler, P. E. and Moyer, J. H. Year Book Medical Publ. Chicago, 1967. pp. 305-321.: Knoll et al: 1967, Arzneimittelforschung 21, (1971) 717-738) we have pointed out that while in the modified spring test morphine derivatives inhibit the defence reaction and escape of the animals when administered already in therapeutical doses exerting analgesic effect, the homopyrimidazoles exhibit said effect but in sub-toxical doses. The synergistic combinations were tested under subcutaneous and oral administration. The mutuality and many-sidedness of the synergism was determined too. The results are summarized in the following table: 
     
                       Table III                                                   
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         Route of            Route of                                     
Compound A                                                                
         adminis- Compound B adminis-                                     
                                    Activity                              
mg/kg    tration  mg/kg      tration                                      
                                    % index                               
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0.025    s.c.     --         --     0    8                                
--       --       50         s.c.   0    7.6                              
0.025    s.c.     50         s.c.   20   6.2                              
5        p.os     --         --     0    8.8                              
--       --       150        p.os   0    8.8                              
5        p.os     150        p.os   40   5.0                              
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     Thus in the modified spring test the combination of 14-hydroxy-azido-morphine and 1,6-dimethyl-4-oxo-3-ethoxycarbonyl-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate results a simple addition of the effect of the components in the place of the synergistic effect potentiating observed in the analgesic effect. 
     Similarly to 14-hydroxy-azido-morphine, a synergism has been demonstrated with the combination of 14-hydroxy-azido-codeine and 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate too. The results are summarized in the following table: 
     
                                           Table IV                                
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Com- Route of                                                             
           Com- Route of                                                  
                      Hot plate                                           
                            Modified                                      
                                 spring                                   
pound C                                                                   
     administ-                                                            
           pound B                                                        
                administ-                                                 
                      test %                                              
                            test                                          
mg/kg                                                                     
     ration                                                               
           mg/kg                                                          
                ration      %    index                                    
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 0.25                                                                     
     s.c.                   20   6.2                                      
0.5  s.c.  --   --    17    --   --                                       
1.0  s.c.  --   --    35    --   --                                       
           50   s.c.  13    --   --                                       
           75   s.c.  49    20   5.6                                      
0.5  s.c.  50   s.c.  86         --                                       
 0.125                                                                    
     s.c.  75   s.c.  --    20   6.2                                      
 0.125                                                                    
     s.c.  100  s.c.  --    40   4.6                                      
2.5  p.os  --   --    --     0   8.2                                      
 3.75                                                                     
     p.os  --   --    --     0   6.8                                      
5.0  p.os  --   --    --    40   5.2                                      
2.5  p.os  50   p.os  --     0   8.2                                      
2.5  p.os  100  p.os  --    50   4.4                                      
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     The values of the above table show a synergism of analgesic effect similar to 14-hydroxy-azido-morphine (14-hydroxy-azido-codeine, 0.5 mg/kg s.c. and 50 mg/kg of compound B s.c.), while the central depressive effect of the combination does not exceed the additive effect of the components. 
     In the following test compound B has been replaced by the following representative derivatives of the homopyrimidazole compounds of the formula II. 
     
         ______________________________________                                    
Compound A =                                                              
           14-hydroxy-azido-morphine                                      
Compound B =                                                              
           1,6-dimethyl-3-ethoxycarbonyl-4-oxo-6,7,8,9-                   
           tetrahydro-homopyrimidazolium-methosulphate                    
Compound C =                                                              
           14-hydroxy-azido-codeine                                       
Compound D =                                                              
           1,6-dimethyl-3-ethoxycarbonyl-4-oxo-                           
           1,6,7,8,9,10-hexahydro-homopyrimidazole                        
Compound E =                                                              
           6-methyl-3-ethoxycarbonyl-4-oxo-6,7,8,9-                       
           tetrahydro-homopyrimidazole                                    
Compound F =                                                              
           1,6-dimethyl-3-ethoxycarbonyl-4-oxo-6,7,8,9-                   
           tetrahydro-homopyrimidazole.                                   
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     The results obtained are summarized in the following table. 
     
                       Table V                                                     
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Compound A                                                                
         Compound B Homopyrimidazole                                      
                                   Hot plate                              
mg/kg    mg/kg      Compound  Dose   Test %                               
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0.025 i.v.                                                                
         --         --        --     29                                   
--       --         E         200 i.v.                                    
                                     20                                   
--       --         --        300 i.v.                                    
                                     72                                   
0.025 i.v.                                                                
         --         E         200 i.v.                                    
                                     39                                   
--       --         F         300 i.v.                                    
                                     24                                   
--       --         --        400 i.v.                                    
                                     61                                   
0.025 i.v.                                                                
         --         F         300 i.v.                                    
                                     48                                   
--       --         D          50 i.v.                                    
                                     39                                   
0.025 i.v.                                                                
         --         D          50 i.v.                                    
                                     52                                   
--       0.5 s.c.   --        --     17                                   
--       --         E         200 s.c.                                    
                                     27                                   
--       0.5 s.c.   E         200 s.c.                                    
                                     26                                   
--       --         D          50 s.c.                                    
                                     22                                   
--       0.5 s.c.   D          50 s.c.                                    
                                     55                                   
--       --         F         300 s.c.                                    
                                     28                                   
--       0.5 s.c.   F         300 s.c.                                    
                                     27                                   
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     The above data show that synergism is also present in combinations comprising a compound of the formula I and a compound of the formula II other, than compound B, but the best results were achieved when using compositions containing a compound of the formula I and 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate. A further advantage of the composition of the present invention is that the central depressive effect of the composition does not surpass the additive effect of the components. The homopyrimidazole derivatives of the formula II and salts and quaternary salts thereof and also the preparation of these compounds is described in our British Pat. No. 1,209,946. The relative amount of the active ingredients in the combination according to the present invention may vary between wide ranges. It may be stated that the composition may contain about 20-1000, preferably 100-1000, particularly 300-1000 parts by weight of a compound of the formula II related to 1 part by weight of an azidocompound of the formula I. In oral parenteral compositions the said ratio may be about 100:1-1000:1, while in oral compositions about 20:1-100:1. The pharmaceutical compositions of the formula I may be finished in dosage forms suitable for oral or parenteral administration. The oral forms may be tablets, capsules, pills, coated pills, etc., while the parenteral dosage forms may be injectable preparations, powder ampouls, etc. The pharmaceutical compositions of the present invention comprising 14-hydroxy azido-codeine or a salt thereof as compound of the formula I are suitable for oral administration (tablets, capsules too. This oral dosage form is particularly advantageous, since in the clinical practice of analgesics of morphine type it enables the elimination of the injection treatment, being very uncomfortable and painful, for the first time. The said oral composition comprises preferably about 20-100 parts by weight, particularly preferably 30 parts by weight of a compound of the formula II calculated on 1 part by weight of azido-compound or the bitartarate thereof. A highly preferred embodiment of the present invention is a tablet or capsule comprising about 100-250 mg. particularly 150 mg., of 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate and 2,5-10 mg., preferably 5 mg of 14-hydroxy-azido-codeine on the bitartarate thereof. 
     The parenteral compositions according to the present invention contain preferably 100-1000 parts by weight of a compound of the formula II related to 1 part by weight of an azido-compound of the formula I. A very preferred embodiment of the present invention is a parenteral composition (injectable solution, powder ampouls/ comprising about 75-500 mg of 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate and about 0.2-0.5 mg of azido-derivative. 
     The synergistic compositions of the present invention may be prepared by methods of the pharmaceutical industry known per se. The compositions for oral administration may be prepared by admixing the active ingredient with inert non-toxic carriers or diluents (e.g. cellulose, silicic acid, stearine, polyvinylpyrrolidone, talk, starch, etc.). The said compositions may also contain the well-known additives/e.g. emulsifying, suspending agents, dyes, salts for controlling the osmotic pressure, buffers, etc.). 
     The parenteral compositions of the present invention may be prepared in aqueous or non-aqueous medium. The non-aqueous preparations may be prepared in propylene glycol, polyethylene glycol or any other suitable solvents. Powder ampoules may be prepared preferably by introducing a homopyrimidazole derivative of the formula II into a powder ampoule, dissolving an azido-compound of the formula I in distilled water or in a suitable non-aqueous medium, in a solvent ampoule and dissolving a homopyrimid-azole derivative of the powder ampoule before use in the content of the solvent ampoule. 
     The preferred dosage in human therapy amounts to 1 capsule or one injection described above. The total daily dosage may consist of three or four single doses as defined above. These data are, however, mainly of informative character, and the dosage used may be lower or higher, than the said data depending on the circumstances of the given case, the condition of the patient and the prescription of the physician. 
    
    
     Further details of our invention are to be found in the Examples, without limiting the scope of our invention to the Examples. 
     EXAMPLES 
     1. 500 mg of 1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazolium-methosulphate are filled into a powder ampoule. 0.5 mg. of 14-hydroxy-azido-morphine bitartarate are dissolved in 5 ml of distilled water. Before use, the homopyrimidazole derivative being present in the powder ampoule is dissolved in the contents of the solvent ampoule. The composition is suitable for intravenous administration. In use at surgical intervention the proposed dose is one ampoule. 
     
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2.   1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-                  
     homopyrimidazolium-methosulphate                                     
                                 75 mg                                    
     14-hydroxy-azido-morphine-bitartarate                                
                                 0.5 mg                                   
Distilled water  ad  q.s.        2 ml.                                    
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 3. A parenteral preparation having the following composition is prepared:
 
    
     
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3.   A parenteral preparation having the following                        
     composition is prepared:                                             
     1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-                             
     tetrahydro-homopyrimidazolium-methosulphate                          
                                150    mg                                 
     14-hydroxy-azido-morphine-bitartarate                                
                                0.5    mg                                 
     Propylene glycol           0.66   ml                                 
     Polyethylene glycol        0.66   ml                                 
     Cellosolve                 0.66   ml                                 
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     The injectable solution thus obtained is filled into ampoules. The solution thus obtained is very stable; during storage at 20°C for 5 years, the decomposition is but a few per cent. 
     
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4.   According to known methods of pharmaceutical in-                     
     dustry, capsules having the following composition                    
     are prepared:                                                        
14-hydroxy-azido-codeine   5      mg                                      
1,6-dimethyl-3-carbethoxy-4-oxo-6,7,8,9-                                  
tetrahydro-homopyrimidazolium-metho-                                      
sulphate                   150    mg                                      
Colorant (dye)             1      mg                                      
Titanium dioxide           3      mg                                      
Betaine hydrochloride      3      mg                                      
Colloidal silicic acid     13     mg                                      
Polyvinylpyrrolidone       15     mg                                      
Stearine                   26     mg                                      
Crystalline cellulose      76     mg.                                     
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