Patent Publication Number: US-4731384-A

Title: Etofenamate formulation

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     The present application is a continuation-in-part application of application Ser. No. 622,429, filed June 20, 1984, now abandoned and application Ser. No. 622,424, filed June 20, 1984, now abandoned. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to an antiinflammatory medicament formulation which has an analgesic action and is to be applied topically, and which contains 2-(2-hydroxyethoxy)-ethyl N-(α,α,α-trifluoro-m-tolyl)anthranilate, called Etofenamate below, as the essential active compound. Etofenamate has the following structure: ##STR1## 
     Etofenamate is already known as a non-steroid medicament with a good antiinflammatory action and outstanding tolerance, compare Arzneimittelforschung 27 (I) Special Edition 6 b, 1299-1364, 1977. Etofenamate has hitherto been used in the form of alcohol-containing gels. Because of the alcohol, the gel has a cooling action when applied, and this has not been found pleasant by all patients. Furthermore, such a gel can be applied only to intact skin, and a desirable application in cases of trauma with open wounds is thus not possible. In addition, such a formulation is of only limited suitability for patients with an exceptionally dry skin. 
     An object of the present invention is thus to overcome the disadvantages described by providing a new formulation which, however, has the antiinflammatory and analgesic action to the same degree as the gel form. 
     Surprisingly, it has been possible to discover cream and ointment formulations which have the required properties. 
     The present invention thus relates to cream and ointment formulations containing Etofenamate and an adjuvant. 
     Etofenamate is a highly viscous oil, only traces of which dissolve in water. In a large number of galenical auxiliaries, it has only inadequate solubility, interactions, such as, for example, hydrolysis, transesterification, esterification and the like, take place, or demixing, phase separation and the like occurs. Although some formulations containing Etofenamate have proved homogeneous and stable, their absorption is inadequate in comparison with the known Etofenamate-containing gel. These disadvantages do not arise in the formulation according to the invention. In the formulation according to the invention, the absorption of Etofenamate by the skin is outstanding. 
     BACKGROUND OF THE INVENTION 
     The cream and ointment formulations according to the present invention thus also contain, in addition to Etofenamate, an adjuvant and, if appropriate, agents which give the formulation consistency and/or emulsifiers and other auxiliaries, such as additives which promote circulation or have a warming effect or which have a pleasant odor. 
     According to the invention, one or more compounds from the groups: triglycerides, and/or esters of monohydric and/or polyhydric alcohols, and/or higher alcohols, are used as the adjuvant. 
     Adjuvants which are preferably used from the triglyceride group are one or more triglycerides of medium-chain carboxylic acids of C 6  to C 14  chain length in saturated or unsaturated, preferably mono-unsaturated and branched or straight-chain form, particularly preferably, neutral oils, such as, for example, Miglyol 810® or Miglyol 812® or Viscoleo®. 
     Viscoleo® is understood as meaning a mixture of saturated triglycerides of medium chain length and a fatty acid distribution of 45-60% of caprylic acid, 35-50% of capric acid and 2-10% of lauric acid, and Miglyol® is understood as meaning a caprylic/capric acid triglyceride. 
     An adjuvant from the group of esters of monohydric and/or polyhydric alcohols is preferably understood as meaning one or more esters of monohydric and/or polyhydric alcohols of C 1  -C 18  (preferably C 2  to C 18 ) chain length with carboxylic acid components of C 6  -C 18  chain length, especially where the alcohols are alkanols or alkenols and the carboxylic acids are alkane or alkene - carboxylic acids, particularly preferably are propylene glycol diesters, ethyl oleate, isopropyl myristate, stearate or palmitate, diisopropyl adipate, diethyl sebacate, oleyl oleate, hexyl laurate and isooctyl stearate, and very particularly preferably diisopropyl adipate and/or isopropyl myristate. 
     Adjuvants from the group of C 8  -C 20  alcohols are used to accomplish the objections of the invention. 
     An adjuvant from the group of higher alcohols is preferably understood as meaning oleyl alcohol and/or 2-octyl-dodecanol, particularly preferably 2-octyl-dodecanol, by itself. 
     According to the invention, Etofenamate can be present in the formulations as a mixture with one or more adjuvants of all three groups or of only two groups or only one group. 
     Starting from these Etofenamate/adjuvant mixtures or solutions, various creams of a liquid to semi-solid consistency can be prepared: 1. Oil-in-water emulsions, 2. Water-in-oil emulsions and 3. Microemulsions. 
     According to the invention, it is necessary for the cream consisting of the active compound and adjuvant to contain about 2 to about 30% by weight of Etofenamate as the active compound and about 5 to about 80% by weight of adjuvant or adjuvant mixtures as described above. 
     According to the invention, it is necessary for the ointment consisting of the active compound and adjuvant to contain about 5 to about 40% by weight of Etofenamate as the active compound and about 3 to about 95% by weight of adjuvant or adjuvant mixtures as described above. The mixture particularly preferably contains 5-15% by weight of Etofenamate, and particularly preferably 6-12% by weight. 
     The formulation can furthermore also contain one or more agents to give it consistency and/or one or more emulsifiers and/or additives which promote circulation or have a warming effect and/or other auxiliaries, such as, for example, substances which have a pleasant odor, and/or also other active compounds. 
     In many cases, agents which give the formulation consistency and emulsifiers are also identical, and strict separation is thus not possible. 
     As agents which give the formulation consistency, there may be used one or more of the group of fatty alcohols (especially alkanols or alkenols), of C 10  to C 30  chain length, such as for example, stearyl alcohol, hydrocarbons, such as petroleum jelly,paraffins, hard paraffins and waxes, such as beeswax or carnauba wax. It is furthermore also possible to use monoglycerides, diglycerides and triglycerides, such as glycerol monostearate and glycerol distearate, and metal soaps, such as Al stearate, Aerosol® (silicon dioxide colloid) and polyglycols, such as polyalkylene glycols, such as polyethylene glycols and polypropylene glycols. 
     The consistency of the aqueous phase of water-containing formulations can be adjusted by means of hydrogel-forming agents, such as Veegum®, cellulose derivatives (for example methylcellulose, hydroxyethylcellulose or carboxymethylcellulose), carboxyvinyl polymers such as polyacrylates and especially Carbopol 940®, 938® and 941®, alginic acid derivatives, gum arabicum and the like. 
     As the emulsifier there may be used one or more from the group of ionic or non-ionic water-in-oil and oil-in-water emulsifiers. 
     Compounds which are preferably used are slats of higher fatty acids and bile acids, such as triethanolamine stearate, alkyl sulphates, such as Na lauryl sulphate, alkylsulphonates, such as Na cetylsulphonate, higher fatty alcohols, such as cetyl alcohol, lauryl alcohol and stearyl alcohol, sterol alcohols, such as cholesterol, fatty acid esters of polyhydric alcohols and polyols, such as ethylene monostearate, glycerol monooleate, sorbitan monolaurate, sorbitan trioleate, polyoxyethylene-(20) sorbitan monolaurate and polyoxyethylene sorbitol hexaoleate, fatty alcohol ethers, such as polyoxyethylene lauryl ether and polyoxyethylene oleyl ether, fatty acid esters of sucrose, such as sucrose distearate, lecithin and derivatives, betaines and sulphobetaines, such as fatty acid amidoalkylbetaine and/or polyoxyethylene/polyoxypropylene polymers, such as pluronics. 
     Examples of additives which may be used which promote circulation or have a warming effect are benzyl nicotinate, salicylic acid esters, for example methylsalicylate, ethereal oils, capsaicin, capsicum extract or nonylic acid vanillyamide. 
     The customary pharmacologically acceptable substances can be used as the odor substances, as long as they are compatible with the active compound and adjuvant. 
     The amount of agents which give the formulation consistency and/or emulsifiers in the formulation, besides the Etofenamate and adjuvant, is up to about 70% by weight, and is preferably 5 to 25% by weight. 
     Furthermore, the cream formulation also contains up to 85% by weight, preferably 40 to 60% by weight, of water. 
     Cream formulations containing 2 to 30% by weight of Etofenamate, 5-80% by weight of adjuvant and 40 to 60% by weight of water are particularly preferred. 
     A preferred cream formulation contains 50 to 100 mg of Etofenamate, 400 to 650 mg of water, 100 to 150 mg of an adjuvant of an emulsifier selected from the group consisting of isopropylmyristate, diisopropyl adipate, Miglyol 810® and Miglyol 840®, 40 to 60 of Myrj. 59®, 0 to 10 mg of Tylose MH 400 (methylcellulose), 30 to 180 mg of Cutina MD® or Cutina GMS®, 10 to 50 mg of a citrate buffer, 0 to 15 mg benzyl nicotinate, 0 to 20 mg of cetyl alcohol and 0 to 20 mg of Veegum®. 
     Preferred ointment formulations contain up to 250 mg of Etofenamate, 50 to 100 mg of an adjuvant selected from the group consisting of diisopropyl adipate, isopropyl myristate, Miglyol 840®, Miglyol 812®, oleyl alcohol and diisopropyl stearate, 20 to 60 mg of an emulsifier selected from the group consisting of Cremophor EL®, Tween 40®, Tween 60® and Myrj. 59®, 0 to 1000 mg of an agent which gives consistency selected from the group consisting of wool wax alcohol ointment DAB 8, Softisan®, PEG 4000 and Cutina MD®, 0 to 100 mg of Aerosil®, 0 to 50 mg of cetyl alcohol, 0 to 500 mg of PEG 400 and 0 to 20 mg of benzyl nicotate. 
     The formulations, the composition of which can be seen from the examples, are furthermore particularly preferred. 
     According to the invention, the antiinflammatory, analgesic cream formulations according to the invention are prepared by mixing the Etofenamate, dissolved in a suitable solvent, with any other molten fat/wax emulsifier constituents and then adding, with intensive mixing of the constituents, the aqueous phase, which has been brought to about the same temperature and contains preservatives, buffer and the like. Homogenization is then carried out, for example, by means of a rotor-stator device. 
     According to the invention, the antinflammatory, analgesic ointment formulations according to the invention are prepared by mixing the Etofenamate, dissolved in a suitable solvent, with any other molten fat/wax emulsifier constituents and then subjecting the mixture to homogenization. 
     The homogenization temperature depends on the particular formulation and is generally between about 40° and about 60° C. 
     The Etofenamate formulation according to the invention contains the active compound in stable form and is capable of penetrating the skin without having the entraining function of isopropanol, which is contained in the gel. Comparison studies with Etofenamate gel showed a bioequivalent absorption, which it was possible to demonstrate by an approximately equal absorption rate, timed to the maximum plasma level, maximum plasma level concentration, elimination from the plasma, area under the plasma level curves (AUC) and renal elimination in humans. The present invention may be illustrated in more detail by the following examples. 
     The Etofenamate formulation according to the invention contains the active compound in stable form and is capable of penetrating the skin without having the entraining function, for example, of isopropanol. Comparison studies with Etofenamate gel showed a bioequivalent absorption, which it was possible to demonstrate by an approximately equal absorption rate, timed to the maximum plasma level, maximum plasma level concentration, elimination from the plasma, area under the plasma level curfves (AUC) and renal elimination in warm-blooded animals. 
     The equivalence of the absorption is also shown by clinical trials, in which the activity was compared in a double-blind cross-over study against ointment containing 1-(p-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid and against salicylic-containing ointments, and in which the formulation according to the invention had a significantly (p&lt;0.05) better action, for example in Lumbago cases in respect of the Schober distance and the spontaneous, movement and pressure pain, compared with the first comparison product, and proved significantly more effective, for example in cases of acute gonathrosis in respect of the target parameters of joint mobility, joint range and spontaneous and movement pain, compared with the second comparison product. 
    
    
     The present invention may be illustrated in more detail by the following examples. 
     
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Example  1       2       3       4       5     6                          
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Etofenamate                                                               
         100     100     100     100     100   50                         
(mg)                                                                      
H.sub.2 O                                                                 
         522.5   512.5   509     522.5   613   679                        
(mg)                                                                      
Adjuvant Isopropyl                                                        
                 Isopropyl                                                
                         Diisopropyl                                      
                                 Miglyol 840 ®                        
                                         Diisopropyl                      
                                               Diisopropyl                
(mg)     myristate                                                        
                 myristate                                                
                         adipate 100                                      
                                 100     adipate                          
                                               adipate                    
         100     100                     130   110                        
Emulsifier                                                                
         Myrj. 59 ®                                                   
                 Myrj. 59 ®                                           
                         Myrj. 59 ®                                   
                                 Myrj. 59 ®                           
                                         Myrj. 59 ®                   
                                               Myrj. 59 ®             
(mg)     50      50      50      50      50    50                         
Benzyl alcohol                                                            
         15      15      15      15      15    15                         
(mg)                                                                      
Tylose MH 4000                                                            
         7.5     7.5     7.5     7.5     --    --                         
(mg)                                                                      
Agent which                                                               
         Cutina MD ®                                                  
                 Cutina MD ®                                          
                         Cutina MD ®                                  
                                 Cutina MD ®                          
                                         Cutina  ®                    
                                               Cutina  ®              
gives con-                                                                
         175     175     175     175     GMS 37                           
                                               GMS 41                     
sistency                                                                  
(mg)                                                                      
Citrate  30      30      30      30      30    30                         
buffer solu-                                                              
tion (mg)                                                                 
Benzyl   --      10      --      --      --    10                         
nicotinate                                                                
Cetyl alcohol                            10    10                         
Veegum                                   15    15                         
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Example   7      8        9        10        11                           
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Etofenamate                                                               
          100    100      200      50       200                           
(mg)                                                                      
H.sub.2 O 603    605      442      582      442                           
(mg)                                                                      
Adjuvant  Diisopropyl                                                     
                 Miglyol 810 ®                                        
                          Isopropyl-                                      
                                   Isopropyl-                             
                                            Diisopropyl-                  
(mg)      adipate 130                                                     
                 130      myristate                                       
                                   myristate                              
                                            adipate 100                   
                          100      100                                    
Emulsifier                                                                
          Myrj. 59 ®                                                  
                 Myrj. 59 ®                                           
                          Myrj. 59 ®                                  
                                   Myrj. 59 ®                         
                                            Myrj. 59 ®                
(mg)      50     50       50       50       50                            
Benzyl alcohol                                                            
          15     15       15       15       15                            
(mg)                                                                      
Tylose MH 4000                                                            
          --     --       8.0      8.0      8.0                           
(mg)                                                                      
Agent which                                                               
          Cutina ®                                                    
                 Cutina ®                                             
                          Cutina MD ®                                 
                                   Cutina MD ®                        
                                            Cutina MD ®               
gives con-                                                                
          GMS 37 GMS 45   155      165      155                           
sistency                                                                  
(mg)                                                                      
Citrate   30     30       30       30       30                            
buffer solu-                                                              
tion (mg)                                                                 
Benzyl    --     --       --       --       --                            
nicotinate                                                                
Cetyl alcohol                                                             
          10     10                                                       
Veegum    15     15                                                       
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                                           TABLE                                   
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                                   Agent which     Cetyl                  
Exam-                                                                     
    Etofenamate                                                           
           Adjuvant I                                                     
                   Adjuvant II                                            
                          Emulisifier I                                   
                                   gives con-                             
                                             Aerosil ®                
                                                   alco-                  
                                                       PEG                
                                                          Benzyl          
ple (mg)   (mg)    (mg)   (mg)     sistency (mg)                          
                                             (mg)  hol 400                
                                                          nicotinate      
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12  50     Diisopropyl                                                    
                   --     Cremophor EL ®                              
                                   --        80                           
           adipate 820    50                                              
13  200    Diisopropyl                                                    
                   --     Cremophor EL ®                              
                                   --        80                           
           adipate 670    50                                              
14  50     Isopropyl                                                      
                   --     Cremophor EL ®                              
                                   --        --                           
           myristate 900  50                                              
15  200    Isopropyl                                                      
                   --     Cremophor EL ®                              
                                   --        --                           
           myristate 750  50                                              
16  50     Myglyol 840 ®                                              
                   --     Tween 40 ®                                  
                                   --        --                           
           900            50                                              
17  200    Myglyol 670 ®                                              
                   --     Tween 40 ®                                  
                                   --        80                           
           900            50                                              
18  50     Miglyol 812 ®                                              
                   --     Tween 60 ®                                  
                                   --        80                           
           820            50                                              
19  200    Miglyol 750 ®                                              
                   --     Tween 60 ®                                  
                                   --        --                           
           820            50                                              
20  50     Oleyl alcohol                                                  
                   Diisopropyl                                            
                          Cremophor EL ®                              
                                   --        --                           
           450     stearate 450                                           
                          50                                              
21  100    Isopropyl                                                      
                   --     Tween 40 ®                                  
                                   --        80                           
           myristate 770  50                                              
22  100    Isopropyl                                                      
                   Diisopropyl                                            
                          Tween 60 ®                                  
                                   --        80                           
           myristate 500                                                  
                   adipate 260                                            
                          50                                              
23  50     Diisopropyl                                                    
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             --    20  -- --              
           adipate 100    50       ointment DAB 8 780                     
24  200    Diisopropyl                                                    
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             --    30  -- --              
           adipate 150    50       ointment DAB 8 570                     
25  50     Isopropyl                                                      
                   --     Myrj 59 ®                                   
                                   Softisan 378 ®                     
                                             30    --  -- --              
           myristate 100  50       770                                    
26  200    Isopropyl                                                      
                   --     Myrj 59 ®                                   
                                   Softisan 378 ®                     
                                             35    --  -- --              
           myristate 110  50       615                                    
27  200    Isopropyl                                                      
                   --     Myrj 59 ®                                   
                                   PEG 4000 ®                         
                                             --    --  230                
                                                          --              
           myristate 120  50       400                                    
28  50     Miglyol 810 ®                                              
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             --    20  -- --              
           100            50       ointment DAB 8 780                     
29  200    Miglyol 810 ®                                              
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             25    30  -- --              
           150            50       ointment DAB 8 545                     
30  50     Miglyol 840 ®                                              
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             --    20  -- --              
           100            50       ointment DAB 8 780                     
31  200    Miglyol 840 ®                                              
                   --     Myrj 59 ®                                   
                                   Wool wax alcohol                       
                                             25    30  -- --              
           150            50       ointment DAB 8 545                     
32  50     Isopropyl                                                      
                   --     Myrj 59 ®                                   
                                   Cutina MD ®                        
                                             --    --  -- --              
           myristate 520  50       380                                    
33  200    Isopropyl                                                      
                   --     Myrj 59  ®                                  
                                   Cutina MD ®                        
                                             --    --  -- --              
           myristate 450  50       300                                    
34  100    Diisopropyl                                                    
                   --     Myrj 59 ®                                   
                                   --        --    --  -- 10              
           adipate 840                                                    
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     Miglyol 840®=propylene glycol diester of caprylic/capric acid 
     Myrj 59®=polyoxyethylene fatty acid ester 
     Tween 40®=polyoxyethylene-20 sorbitan monopalmitate 
     Tween 60®=polyoxyethylene-20 sorbitan monopalmitate 
     Cremophor E®=glycerol polyethylene glycol castor oil ester 
     Cutina MD/GMS®=mixture of monoglycerides and diglycerides of palmitic acid and stearic acid 
     Softisan 378®=triglycerides of stearic acid, gapric acid and caprylic acid. 
     Veegum®=magnesium aluminum silicate 
     Miglyol 810®=triester of caprylic/capric acid glycol 
     It will be appreciated that the instant specification and claims are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.