Abstract:
A novel class of lubricious ophthalmic solutions is formulated to permit the use of a recognized class of demulcents; namely, anionic polymeric demulcents in the presence of a cationic quaternary germicide wherein no precipitation of said germicide occurs.

Description:
RELATED APPLICATIONS  
       [0001]     This application is a continuation in part of applicant&#39;s application Ser. No. 10/835,449 filed Apr. 29, 2004 
     
    
     FIELD OF THE INVENTION  
       [0002]     Discussion of the Prior Art  
         [0003]     The use of ophthalmic solutions for the relief of many eye conditions is well known in the art. The problem with many of these solutions is that while they are pH compatible with tears, their level of lubricity or slipperiness is less than would be desirable. Thus many advantages of such solutions and the pharmacologically active substances which they may carry are not optimized. A further legal issue which must be met, at least in the United States of America is that the Food and Drug administration has set forth a list of substances which can be used in such non-prescription solutions and no others are permissible. Thus any invention in this art must be limited to the use of “monographed” components.  
         [0004]     In order to provide lubricity to ophthalmic solutions, a demulcent must be added. A number of these have been “monographed” by the FDA. Unfortunately, some exhibit incompatibility with quaternary preservatives. Thus solutions containing them must be marketed in a single dose applicator to avoid the possibility of infection by an already opened container. This increases the expense and inconvenience to the consumer. Thus the ability to incorporate preservatives into solutions of such demulcents meets a long felt need.  
       SUMMARY OF THE INVENTION  
       [0005]     There is provided a novel class of lubricious ophthalmic solutions which is formulated to permit the use of a recognized class of demulcents; namely, anionic polymeric demulcents in the presence of a cationic quaternary germicide wherein no precipitation of said germicide occurs.  
         [0006]     This class of solutions is used at a pH between 7 and 8 and consists essentially of from about 0.1 to about 4.0% by weight of an anionic polymeric demulcent; from about 0.005 to about 1.0% by weight of a quaternary germicide and from about 0.1 to about 1.0% by weight of a polysorbate surfactant.  
         [0007]     Suitably, said anionic polymeric component is selected from the group consisting of anionic cellulose derivatives, anionic polymers derived from acrylic acid, anionic polymers derived from methacrylic acid, anionic polymers derived from alginic acid, anionic polymers derived from amino acids and mixtures thereof. Preferably it is carboxymethyl cellulose and most preferably sodium carboxymethylcellulose (hereinafter CMC).  
         [0008]     The most suitable quaternary germicide is benzalkonium chloride, preferably used at a concentration of 0.10 to 0.010%. Heretofore this germicide could not be used with CMC as their reaction caused precipitate formation. It is the surprising finding of this invention that the presence of a polysorbate surfactant in the solution prior to the addition of the germicide prevents such precipitation. In addition to preventing the precipitation of the cationic quaternary germicide, the polysorbate acts as an ameliorating agent to lessen the irritation potential of the cationic quaternary germicide.  
         [0009]     It will be understood by those skilled in the art that to the foregoing groups and subgroups of components there may be added monographed pharmacologically inactive substances such as colorants and other nonionic demulcents.  
         [0010]     The invention also includes the process of preparing the novel solutions of the present invention. The process comprises the steps of: 
        a.) dissolving the anionic polymeric demulcent in water;     b.) adding the polysorbate;     c.) adding the quaternary germicide;     d.) adjusting the pH to the desired range with various buffers and     e.) adding water to adjust the concentration to the desired range. 
 
 This process is to be carried out in the foregoing sequence but is not limited thereto. The sequence of steps (b), (a), (c), (d) and (e) is also within the scope of the invention since the results obtained are similar.
       
 
     
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0016]     Suitably there are employed about 0.1 to about 4.0% by weight of an anionic polymeric demulcent; from about 0.005 to about 0.1% by weight of a quaternary germicide and from about 0.1 to about 1.0% by weight of a polysorbate surfactant. Preferably it is a carboxymethyl cellulose, most preferably sodium carboxymethylcellulose, USP (hereinafter CMC).  
         [0017]     Useful polysorbates include Polysorbate 20 (polyethylene 20 sorbitan monolaurate), Polysorbate 40 (polyethylene 20 sorbitan monopalmitate), Polysorbate 60 (polyethylene 20 sorbitan monostearate), and Polysorbate 80 (polyethylene 20 sorbitan monooleate). The preferred polysorbates are Polysorbate 20 and Polysorbate 80 at 0.10 to 1.00% by weight of the total solution and most preferably 0.20 to 0.60% by weight.  
         [0018]     Buffers useful in adjusting and maintaining pH include acetic acid, hydrochloric acid, phosphoric acid, potassium bicarbonate, potassium tetraborate, potassium hydroxide, potassium carbonate, potassium citrate, potassium phosphate, sodium acetate, sodium bicarbonate, sodium biphosphate, sodium borate, sodium carbonate, sodium citrate, sodium hydroxide and sodium phosphate.  
         [0019]     Any monographed active which is soluble in the solutions may be used. These include ophthalmic vasoconstrictors such as ephedrine HCI, naphazoline HCI, phenylephrine HCI, tetrahydrozoline HCI, oxymetazoline HCI, xylometazoline HCI and the like as well as other monographed actives such as antihistamines.  
         [0020]     The CMC can be used in combination with other monographed polymers such as povidone, hydroxymethyl cellulose, hydroxypropyl cellulose and the like. In addition, other polyols that may be used are polyvinyl alcohol, glycerin, propylene glycol, polyethylene glycol and the like.  
         [0021]     As stated above, benzalkonium chloride, suitably about 0.01 to about 0.10% but preferably about 0.01 to about 0.015% by weight of the total solution, may be used as a preservative which may be potentiated by EDTA.  
         [0022]     The natural pH of ophthalmic tears is 7.4. It is important that the pH of the solutions of the system be held at a pH of between 7.0 and 8.0 in order to avoid damage to the eye.  
         [0023]     The system is also very useful in products for contact lens wearers. It will refresh and moisten the lenses and help to remove particulate matter that may cause irritation and discomfort.  
       EXAMPLES  
     Example # 1 
       [0024]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                 Eye Care Lubricant 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1. CMC, USP 
                 1.00 
               
               
                   
                 2. Polysorbate 20 
                 0.50 
               
               
                   
                 3. Benzalkonium Chloride 
                 0.01 
               
               
                   
                 4. Disodium EDTA 
                 0.10 
               
               
                   
                 5. Boric Acid 
                 0.30 
               
               
                   
                 6. Sodium Borate 
                 0.20 
               
               
                   
                 7. PEG 400 
                 1.00 
               
               
                   
                 8. Deionized Water 
                 96.89 
               
               
                   
                   
                 100.00 
               
               
                   
                   
               
             
          
         
       
     
         [0025]     Adjust the pH to 7.4 with hydrochloric acid or sodium hydroxide.  
         [0000]     Procedure:  
         [0000]    
       
         
           
              1.) Mix #1 and #8 and heat to 70° C. until dissolved.  
              2.) Add #2 to the batch and mix.  
              3.) Add #&#39;s 4, 5, 6 and 7 to the batch and mix.  
              4.) Cool the batch to 50° C.; add #3 and cool the batch to room temperature.  
              5.) Adjust the pH to 7.4 with sodium hydroxide or hydrochloric acid.  
           
         
       
     
       Example #2 
       [0031]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                 Eye Care Lubricant with 
                   
               
               
                   
                 Tetrahydrozoline HCl 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1. CMC, USP 
                 0.50 
               
               
                   
                 2. Polysorbate 20 
                 0.50 
               
               
                   
                 3. Benzalkonium chloride 
                 0.01 
               
               
                   
                 4. Disodium EDTA 
                 0.10 
               
               
                   
                 5. Boric Acid 
                 0.30 
               
               
                   
                 6. Sodium Borate 
                 0.20 
               
               
                   
                 7. PEG 400 
                 1.00 
               
               
                   
                 8. Tetrahydrozoline HCl 
                 0.05 
               
               
                   
                 9. Deionized Water 
                 97.34 
               
               
                   
                   
                 100.00 
               
               
                   
                   
               
             
          
         
       
     
         [0032]     Adjust the pH to 7.4 with hydrochloric acid or sodium hydroxide.  
         [0000]     Procedure:  
         [0000]    
       
         
           
              1.) Mix #1 and #9 and heat to 70° C. until dissolved.  
              2.) Add #2 to the batch and mix.  
              3.) Add #&#39;s 4, 5, 6 and 7 to the batch and mix.  
              4.) Cool the batch to 50° C.; add #8 and mix until dissolved.  
              5.) Add #3 to the batch and cool the batch to room temperature.  
              6.) Adjust the pH to 7.4 with sodium hydroxide or hydrochloric acid.  
           
         
       
     
       Example #3 
       [0039]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                   
               
               
                   
                 Eye Care Lubricant with 
                   
               
               
                   
                 Oxymetazoline HCl 
                 % 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1. CMC, USP 
                 0.50 
               
               
                   
                 2. Polysorbate 80 
                 0.50 
               
               
                   
                 3. Benzalkonium chloride 
                 0.01 
               
               
                   
                 4. Disodium EDTA 
                 0.10 
               
               
                   
                 5. Boric Acid 
                 0.30 
               
               
                   
                 6. Sodium Borate 
                 0.20 
               
               
                   
                 7. PEG 400 
                 1.00 
               
               
                   
                 8. Oxymetazoline HCl 
                 0.05 
               
               
                   
                 9. Deionized Water 
                 97.34 
               
               
                   
                   
                 100.00 
               
               
                   
                   
               
             
          
         
       
     
         [0040]     Adjust the pH to 7.4 with hydrochloric acid or sodium hydroxide.  
         [0000]     Procedure:  
         [0041]     See the procedure used in Example #2.