New uses of 3-tetrazolo -5,6,7,8- substituted-pyrido (1,2-a) pyrimidin-4-ones
This application is a continuation of application Ser. No. 955,532, filed Oct. 1, 1992 now abandoned. 
    
    
     BACKGROUND 
     Perimolast, i.e., optionally substituted 3(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one and pharmaceutically acceptable derivatives thereof have been taught for use as inhibitors of allergic reactions. U.S. Pat. No. 4,122,274 describes these compounds and their use in oral and parenteral formulations. 
     U.S. Pat. No. 4,457,932 teaches the use of this same family of drugs in formulations to treat peptic ulcers and a variety of other gastrointestinal disorders generally characterized by inflammation and necrosis. Oral and parenteral routes of administration are discussed. 
     European Patent Application Publication 316,174 (Tokyo Tanabe Co. Ltd., assignee) discloses aqueous preparations containing the potassium salt of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (i.e., pemirolast potassium). The preparations contain 0.05 to 0.5% of the salt, 0.1 to 0.1% of dibasic potassium phosphate and 0.005 to 0.2% of monobasic potassium phosphate. They are used in nasal and ophthalmic compositions and in part for allergic dermatitis. The patent cites the induction of crystallization of pemirolast potassium by antiseptic benzalkonium chloride and a preference for the addition of antiseptic, such as potassium sorbate and sodium dehydroacetate. However, these antiseptics are not effective as micropreservatives in the pH range 7.0-9.0, that is, at the pH range at which pemirolast is most preferentially formulated. 
     U.S. Pat. No. 5,034,230 (Santen Pharmaceutical Co., Ltd., assignee) shows antiallergic eye drops which contain 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (i.e., pemirolast) and its salts. The eye drops must contain specific pairs of buffers and generally include preservatives, such as benzalkonium chloride, and chelating agents, such as disodium ethylene diaminetetraacetic acid (Na 2  EDTA). 
     THE INVENTION 
     It has been discovered that optically clear, stable aqueous solutions of optionally substituted 3(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one and their derivatives can be prepared. The solutions contain up to 2.0% drug(s) and from about 0.004 to about 0.02% of certain benzalkonium chlorides. 
     In a preferred embodiment, 2% of potassium salt of 9-methyl-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one (i.e., potassium pemirolast) is put into aqueous solution with 0.02% of C 12  benzalkonium chloride to yield a clear solution useful for ophthalmic, nasal or topical use. The solution is stable for up to two years when stored at room temperature. 
     OBJECTS OF THE INVENTION 
     It is one object of the invention to provide clear, well preserved stable solutions of certain derivatives of substituted pyrido[1,2-a]pyrimidine-4-ones, i.e., pemirolast. 
     It is another to provide compositions and methods for the treatment of allergic conditions of the eye, nose and skin. 
     DESCRIPTION OF THE INVENTION 
     Unless otherwise indicated, all percentages recited herein are weight percentages, based on total composition weight. 
     All publications referred to herein are hereby incorporated by reference. 
     The preparations and the methods are based upon novel aqueous solutions which contain: 
     (a) an anti-allergic amount of a compound of formula I: ##STR1##  wherein R 1 , R 2  and R 3 , which may be the same or different, are each hydrogen, halogen, alkyl, cyclo alkyl, alkoxy, alkenyl, alkynyl, alkoxy, alkyl, --O--alkenyl, ##STR2##  (in which m is 0 or an integer from 1 to 6 and n is an integer from 2 to 7), --OCH 2  (CH 2 ) x  O(CH 2 ) y  CH 3 , in which x and y are each independently 0 or an integer from 1 to 6, CF 3 , hydroxy, hydroxymethyl, alkylthio, amino, nitro, ##STR3##  in which r is 4 or 5, alkylamino, dialkylamino, carboxyl, --CO 2  -- alkyl, phenyl, phenyl substituted by one or two alkyl, alkoxy or halogen radicals, benzyl, alkylsulfinyl, R&#39;--CO-- in which R&#39; is alkyl, R&#39;--COO-- in which R&#39; is alkyl, --O(CH 2 ) k  OH in which k is an integer from 2 to 6, or ##STR4##  --OCH 2  C 6  H 5 , or a pharmaceutically acceptable salt thereof, with the provisos that (1) when two or more of R 1 , R 2  and R 3  are tertiary alkyl groups, they are located on non-adjacent positions and (2) no more than two of R 1 , R 2  and R 3  may be nitro groups and all alkyl and alkenyl moieties contain from 1 to 4 C atoms. 
     (b) at least one mixture of C 8  to C 18  benzalkonium chlorides; and 
     (c) water. 
     The Antiallergic Compounds 
     The active ingredient(s) in the systems of the invention is at least one compound of formula I above, or at least one pharmaceutically acceptable derivative thereof. 
     One preferred group of compounds are pemirolast, i.e., the compound of formula II, ##STR5## and its pharmaceutically acceptable derivatives. 
     By &#34;pharmaceutically acceptable derivatives&#34;, applicant means salts, amides, esters, and the like. 
     Salts can be produced by contacting the appropriate hydroxides, oxides or organic amines with the acid form of the drug. Examples of pemirolast salts are metal salts, such as potassium, sodium, calcium and magnesium and organic amine salts. A highly preferred salt of pemirolast is the potassium salt. 
     The Benzalkonium Chloride Preservative 
     The phrase &#34;benzalkonium chloride&#34; refers to a mixture of compounds of formula III: ##STR6## wherein R 4  represents a mixture of alkyl groups. R 4  is a normal alkyl group which contains from about 8 to about 18 carbon atoms. 
     In the benzalkonium chloride (BKC) mixtures, it is preferred that R 4  be 90% or more of a mixture of C 8  to C 12  homologs and most preferably be 90% or more of C 12 . C 12  benzalkonium chloride alone is highly preferred. 
     Applicant has found that of 90% or more, and preferably more than 95%, of the C 8  to C 12  benzalkonium chloride fraction present in a C 8-18  mix gives remarkable clarity and stability when aqueous solutions of the drugs described herein are prepared. In fact, when a substantially pure C 12  benzalkonium chloride is used (i.e., ≦5% of homologs other than the C 12  species are present), 2.0% of pemirolast potassium can be dissolved in the presence of about 0.004 to about 0.02% of the C 12  benzalkonium chloride to yield aqueous solutions which are stable for up to ten weeks when stored at 5° C., and a minimum of two years when stored at room temperature. 
     It should be noted that not all benzalkonium chlorides are operable in the invention. Those containing 10% or more of C 14  to C 18  homologs yield unstable solutions. 
     Water 
     The water used in the invention is deionized distilled water. No other treatment need be carried out. 
     In general, distilled water or other pharmaceutically acceptable water can be added. 
     pH 
     It is preferred that the pH of the aqueous solutions used herein be between 7.5 and 9.0, and preferably between 8.0 and 8.5. pH adjustment with such agents as potassium hydroxide and sodium hydroxide is contemplated. 
     Compositions 
     The aqueous compositions of the invention will generally contain active ingredient, benzalkonium chloride and water in the amounts given below. 
     
         ______________________________________                                    
Typical Compositions                                                      
                                   Highly                                 
               Broad     Preferred Preferred                              
Ingredient     Range (%) Range (%) Range (%)                              
______________________________________                                    
A.  Active Ingredient                                                     
                   0.001-2   0.001-1 0.1-1                                
B.  Benzalkonium   0.001-0.05                                             
                             0.004-0.02                                   
                                     0.01-0.02                            
    Chloride                                                              
C.  pH             7.0-9.0   7.8-8.7   8-8.7                              
D.  Excipients and Other                                                  
                    0-99      0-10   0-3                                  
    Additives                                                             
E.  Water          q.s. to   q.s. to q.s. to                              
                   100%      100%    100%                                 
______________________________________                                    
 
    
     The compositions of the invention may include suitable amounts of one or more chelating agents such as sodium ethylenediaminetetraacetic acid (EDTA), preferably disodium EDTA, dipotassium EDTA and the like. 0.05 to 0.01 wt % of such agents are operable. Mixtures can be used. 
     Preferably disodium EDTA, in amounts of about 0.05 to about 0.001 wt %, and preferable about 0.01 to about 0.005 wt %, is employed. 
     In addition, buffers, such as mono- or dipotassium phosphate, can be added. Monobasic potassium phosphate buffer is preferred. In such embodiments, the concentration of monobasic potassium phosphate is between about 0.002 and about 0.3 wt %, with about 0.009 to about 0.045 wt % preferred. Similarly, the concentration of dibasic potassium phosphate is between about 0.1 and about 2 wt %, with 0.392 to about 1.2 wt % preferred. 
     In some preferred embodiments, monobasic and dibasic sodium phosphates are employed together. In those embodiments, the concentration of monobasic sodium phosphate is between about 0.002 and about 1.0 wt % with about 0.005 to about 0.02 wt % preferred; and the concentration of dibasic sodium phosphate is between about 0 1 and about 2.0% wt %, with 0.39 to about 0.6 wt % preferred. In such double buffered systems, the pH will generally lie between about 7.0 and about 9.0, with pH&#39;s of about 8.0 to about 8.7 preferred. 
     In addition to buffers, the compositions and methods of the invention may advantageously include chelating agents. 
     Other useful additives include tonicity agents, solvents, perfumes, humectants, preservatives, surfactants, colorants, viscosity modifiers and the like. 
     It is contemplated that active ingredients other than those of formula I and their derivatives be used. If present, additional active ingredients should constitute no more than 5 wt % of the compositions. 
     While ophthalmic, nasal and paintable skin formulations are described herein, it should be noted that other types of topical delivery systems are contemplated. Thus, creams, gels, ointments, powders and sprayable formulations are also operable. 
    
    
     EXAMPLES 
     The following examples illustrate the invention. In all cases, the concentration levels of the buffering agents was as specified in the tables. 0.1 to 2% of potassium pemirolast was used. 
     The typical method used to prepare the formulation of this invention is illustrated in Example I. 
     Example I 
     
         ______________________________________                                    
Potassium pemirolast 2.00       g                                         
Potassium dihydrogen phosphate                                            
                     0.009      g                                         
Dipotassium hydrogen phosphate                                            
                     0.392      g                                         
C.sub.12 BKC         0.01       g                                         
Na.sub.2 EDTA        0.01       g                                         
Glycerin             1.80       g                                         
Deionized distilled water                                                 
                     q.s.                                                 
Total                100        ml                                        
______________________________________                                    
 
    
     Preparation method: 
     1. The beakers, pipettes and magnetic stirrers used in the preparation of solution were washed with deionized distilled water. 
     2. Potassium dihydrogen phosphate and dipotassium hydrogen phosphate were dissolved in 90 ml of deionized distilled water. 
     3. C 12  BKC, Na 2  EDTA and glycerin were then added to the solution and mixed to dissolve. 
     4. Potassium pemirolast was finally added to the solution and was dissolved by mixing for a minimum of 30 minutes. 
     5. The volume of the solution was then adjusted to 100 ml with deionized distilled water. 
     6. The solution was then filtered by passing through Millex GB 0.22 micron filter. The solution was stored in the previously washed and sterilized scintillation vials. Scintillation vials were free of dust and fibers. 
     In reading the tables, note that BKC means benzalkonium chloride, &#34;NC&#34; indicates no change, i.e., the solution was stable. The presence of (*) indicates that pemirolast crystals formed. 
     
                       TABLE I                                                     
______________________________________                                    
MONOBASIC SODIUM PHOSPHATE (0.008%) AND                                   
DIBASIC SODIUM PHOSPHATE (0.32%) BUFFER, pH 8.0                           
Sample        Ia     Ib      Ic    Id    Ie                               
______________________________________                                    
% C.sub.18 BKC                                                            
              0.01   --      --    --    --                               
% C.sub.14 BKC                                                            
              --     0.01    --    --    --                               
% C.sub.12 BKC                                                            
              --     --      0.01  --    --                               
% C.sub.8 BKC --     --      --    0.01  --                               
% BKC USP     --     --      --    --    0.01                             
% Potassium pemirolast                                                    
              0.1    0.1     0.1   0.1   0.1                              
Stability                                                                 
1 day, 5° C.                                                       
              *      *       NC    NC    *                                
4 weeks, 5° C.                                                     
              *      *       NC    NC    *                                
10 weeks, 5° C.                                                    
              *      *       NC    NC    *                                
1 day, RT (25° C.)                                                 
              *      *       NC    NC    *                                
10 month, RT (25° C.)                                              
              *      *       NC    NC    *                                
______________________________________                                    
 BKC = benzalkonium chloride                                              
 * = crystals                                                             
 
    
     
                                           TABLE II                                
__________________________________________________________________________
MONOBASIC POTASSIUM PHOSPHATE/DIBASIC POTASSIUM PHOSPHATE                 
+0.01% c.sub.12 BKC, pH 8.0                                               
Potassium Phosphate Buffer                                                
              0.023M                                                      
                  0.023M                                                  
                      0.023M                                              
                          0.023M                                          
                              0.023M                                      
                                  0.046M                                  
                                      0.046M                              
                                          0.069M                          
__________________________________________________________________________
% NA.sub.2 EDTA                                                           
              0.01                                                        
                  0.01                                                    
                      0.01                                                
                          0.025                                           
                              0.025                                       
                                  0.025                                   
                                      0.025                               
                                          0.05                            
% Potassium Pemirolast                                                    
              0.5 1.0 2.0 0.5 1.0 0.5 1.0 1.0                             
Stability:                                                                
1 week, 5° C.                                                      
              NC  NC  NC  NC  *   NC  NC  NC                              
2 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
4 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
5 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
6 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
7 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
8 weeks, 5° C.                                                     
              NC  NC  NC  NC  *   NC  NC  NC                              
18 months RT (25° C.)                                              
              NC  NC  NC  NC  *   NC  NC  NC                              
__________________________________________________________________________
 
    
     
                       TABLE III                                                   
______________________________________                                    
BORIC ACID 1.8%/ETHANOL AMINE 0.6% BUFFER                                 
(pH 8.66)                                                                 
Sample         IIIa   IIIb   IIIc IIId IIIe IIIf                          
______________________________________                                    
% C.sub.12 /BKC                                                           
               .005   .005   .005 0.01 0.01 0.01                          
% Potassium Pemirolast                                                    
               1.0    0.5    0.1  1.0  0.5  0.1                           
Stability:                                                                
3 days, 5° C.                                                      
               NC     NC     NC   NC   NC   NC                            
2 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
4 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
6 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
8 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
10 weeks, 5° C.                                                    
               NC     NC     NC   NC   NC   NC                            
10 months RT (25° C.)                                              
               NC     NC     NC   NC   NC   NC                            
______________________________________                                    
 BKC = benzalkonium chloride                                              
 
    
     
                       TABLE IV                                                    
______________________________________                                    
MONOPOTASSIUM PHOSPHATE 0.6%/DISODIUM                                     
PHOSPHATE 0.3% BUFFER (adjusted pH to 8.54 with                           
potassium hydroxide)                                                      
Sample         IVa    IVb    IVc  IVd  IVe  IVf                           
______________________________________                                    
% C.sub.12 /BKC                                                           
               .005   .005   .005 0.01 0.01 0.01                          
% Potassium Pemirolast                                                    
               1.0    0.5    0.1  1.0  0.5  0.1                           
Stability:                                                                
3 days, 5° C.                                                      
               NC     NC     NC   NC   NC   NC                            
2 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
4 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
6 weeks, 5° C.                                                     
               NC     NC     NC   NC   NC   NC                            
8 weeks, 5° C.                                                     
               NC     NC     NC   *    NC   NC                            
10 weeks, 5° C.                                                    
               NC     NC     NC   *    NC   NC                            
10 months RT (25° C.)                                              
               NC     NC     NC   NC   NC   NC                            
______________________________________                                    
 BKC = benzalkonium chloride                                              
 
    
     
                       TABLE V                                                     
______________________________________                                    
BORIC ACID 0.81%/SODIUM BORATE 0.67% BUFFER                               
(contains 0.24% potassium chloride, pH 8.2)                               
Sample         Va     Vb     Vc   Vd   Ve   Vf                            
______________________________________                                    
% C.sub.12 /BKC                                                           
               .005   .005   .005 0.01 0.01 0.01                          
% Potassium Pemirolast                                                    
               1.0    0.5    0.1  1.0  0.5  0.1                           
Stability:                                                                
3 days, 5° C.                                                      
               NC     NC     NC   NC   NC   NC                            
2 weeks, 5° C.                                                     
               NC     *      NC   *    NC   NC                            
4 weeks, 5° C.                                                     
               *      *      NC   *    *    NC                            
6 weeks, 5° C.                                                     
               *      *      NC   *    *    NC                            
8 weeks, 5° C.                                                     
               *      *      NC   *    *    NC                            
10 weeks, 5° C.                                                    
               *      *      NC   *    *    NC                            
10 months RT (25° C.)                                              
               NC     NC     NC   NC   NC   NC                            
______________________________________                                    
 BKC = benzalkonium chloride                                              
 
    
     
                       TABLE VI                                                    
______________________________________                                    
MONO (0.3%) &amp; DISODIUM PHOSPHATE (0.15%) BUFFER                           
(adjusted pH to 8.54 with potassium hydroxide)                            
Sample         VIa    VIb    VIc  VId  VIe  VIf                           
______________________________________                                    
% C.sub.12 /BKC                                                           
               .005   .005   .005 0.01 0.01 0.01                          
% Potassium Pemirolast                                                    
               1.0    0.5    0.1  1.0  0.5  0.1                           
Stability:                                                                
3 days, 5° C.                                                      
               NC     NC     NC   NC   NC   NC                            
2 weeks, 5° C.                                                     
               *      *      NC   NC   NC   NC                            
4 weeks, 5° C.                                                     
               *      *      NC   *    NC   NC                            
6 weeks, 5° C.                                                     
               *      *      NC   *    NC   NC                            
8 weeks, 5° C.                                                     
               *      *      NC   *    *    NC                            
10 weeks, 5° C.                                                    
               *      *      NC   *    *    NC                            
10 months RT (25° C.)                                              
               NC     NC     NC   NC   NC   NC                            
______________________________________                                    
 BKC = benzalkonium chloride                                              
 
    
     Table I illustrates the stability of potassium pemirolast with different homologs of benzalkonium chloride. It is observed that C 14  and C 18  homologs of banzalkonium chloride and benzalkonium chloride USP are incompatible with potassium pemirolast, as they formed crystals or turbid solutions at room temperature and 5° C. Benzalkonium chloride USP is a mixture of C 8  to C 16  homologs of benzalkonium chloride. The amount of C 14  to C 16  homologs of benzalkonium is greater than 20% in benzalkonium chloride USP and, hence, causes crystallization of potassium pemirolast solution. The C 8  to C 12  homologs of benzalkonium chloride are compatible with potassium pemirolast. The solutions can be stored at 5° C. and room temperature for a long time without crystallization. 
     Table II illustrates the stability of various strengths of potassium pemirolast solution at 5° C. and room temperature in different molar strengths of monobasic-and dibasic potassium phosphate buffers containing different concentrations of Na 2  -EDTA. It is observed that a stable solution of 0.1 to 2% potassium pemirolast can be prepared with C 12  benzalkonium chloride in potassium phosphate buffer. The incompatibility caused by Na 2  EDTA can be overcome by using higher molar strengths of potassium phosphate buffer. 
     Tables III through Table VI illustrate the stability of potassium pemirolast solution containing 0,005% to 0.01% of C 12  benzalkonium chloride and a variety of buffer systems at 5° C. and room temperature. 
     Tables III through Table VI show that, at 0,005 to 0.01 wt % C 12  benzalkonium chloride levels, the stability of 0.1% potassium pemirolast solution in boric and sodium borate and monosodium phosphate and disodium phosphate combination buffers is at least 10 weeks at 5° C. When boric acid/ethanolamine and monopotassium/disodium phosphate combination buffers are used, the solutions are stable for at least 10 weeks and 6 to 10 weeks at 5° C., respectively. Only at low temperature (5° C.) is crystallization observed in boric acid/sodium borate, monosodium phosphate and disodium phosphate buffer. In all systems given in Tables III to VI, the potassium pemirolast solutions are stable for a minimum of 10 months at room temperature. 
     Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.