Patent Publication Number: US-7914803-B2

Title: Ophthalmic compositions containing a synergistic combination of three polymers

Description:
This application is a continuation-in-part of U.S. Ser. No. 10/863,172, filed Jun. 8, 2004, which claims priority to U.S. Provisional Application, U.S. Ser. No. 60/478,713, filed Jun. 13, 2003. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Field of the Invention 
     The present invention relates to pharmaceutical compositions. In particular, this invention relates to topically administrable ophthalmic compositions that contain three polymeric components. 
     2. Description of Related Art 
     The use of polymeric ingredients in topically administrable ophthalmic compositions is well known. Polymeric ingredients are typically used in suspension compositions as physical stability aids, helping to keep the insoluble ingredients suspended or easily redispersible. In solution compositions, polymeric ingredients are typically used to increase the composition&#39;s viscosity. 
     Many polymers have been used in topically administrable ophthalmic compositions. Included among these are cellulosic polymers, such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, and ethylhydroxyethyl cellulose. Also included are synthetic polymers, such as carboxyvinyl polymers and polyvinyl alcohol. Still others include polysaccharides such as xanthan gum, guar gum, and dextran. 
     Combinations of polymers have also been used in ophthalmic compositions. Certain combinations of polymers are known to provide synergistic effects on viscosity and, in some cases, even a phase transition from a liquid to a gel. For example, U.S. Pat. No. 4,136,173 discloses ophthalmic compositions containing a combination of xanthan gum and locust bean gum. 
     One approach to achieving a target viscosity in a topically administrable ophthalmic composition might involve simply adding a sufficient amount of one polymeric ingredient. Often, however, it is desirable to minimize the total amount of polymeric additives in topically administrable ophthalmic compositions. A mixed polymer system containing more than one polymer can significantly enhance the viscosity and lubrication property of a composition while minimizing total polymer concentration and cost of materials. 
     SUMMARY OF THE INVENTION 
     The present invention is directed toward ophthalmic compositions that contain three polymeric components. The compositions contain hydroxypropyl methylcellulose and a combination of two polymers selected from the group of combinations consisting of guar gum and a carboxyvinyl polymer; guar gum and hydroxyethyl cellulose; guar gum and dextran; hydroxyethyl cellulose and a carboxyvinyl polymer; and dextran and a carboxyvinyl polymer. The compositions are useful as artificial tear products, but can also serve as vehicles for delivering ophthalmic drugs. 
     The present invention is based upon the finding that the specified combinations of three polymers have a synergistic effect on viscosity. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWING 
         FIG. 1  shows the viscosity for each of Compositions 1-8 (Example 2), demonstrating the remarkable synergy among the three polymer system: hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer. 
         FIG. 2  shows the effect of total polymer concentration on viscosity for the three polymer system of hydroxypropyl methylcellulose, guar gum and carboxyvinyl polymer for a concentration ratio of 3:1:1 (hydroxypropyl methylcellulose:guar gum:carboxyvinyl polymer) at pH 7.0. 
     
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Unless otherwise indicated, all ingredient concentrations are listed as a weight/volume percentage basis (% w/v). 
     The ophthalmic compositions of the present invention are aqueous compositions that include a combination of three polymeric ingredients: hydroxypropyl methylcellulose (“HPMC”) and a combination of two polymers selected from the group of combinations consisting of guar gum (“Guar”) and a carboxyvinyl polymer (“carbomer”); Guar and hydroxyethyl cellulose (“HEC”); Guar and dextran; HEC and carbomer; and dextran and carbomer. All of these types of polymers are known and have been used in ophthalmic compositions. All of these types of polymers are also commercially available. 
     HPMC is commercially available from the Dow Chemical Company under the brand name Methocel®. HPMC is available in a variety of grades. Most preferred for use in the compositions of the present invention is Methocel E4M, (HPMC 2910), which has a number average molecular weight of approximately 86,000 dalton. The concentration of HPMC in the compositions of the present invention will generally range from 0.05-0.5%, and will preferably be 0.3%. 
     Guar includes guar gum and guar gum derivatives, such as the hydroxypropyl or hydroxypropyltrimonium chloride derivatives of guar gum. Guar and its derivatives are described in U.S. Pat. No. 6,316,506, the entire contents of which are hereby incorporated by reference. For purposes of the present application, guar includes unsubstituted guar gum and its substituted derivatives. Guar gum and many of its derivatives are commercially available from Rhone-Poulenc (Cranbury, N.J.), Hercules, Inc. (Wilmington, Del.) and TIC Gum, Inc. (Belcamp, Md.). A preferred derivative for use in the compositions of the present invention is hydroxypropyl guar (“HP-Guar”). The concentration of guar in the compositions of the present invention will generally range from 0.01-0.2%, and will preferably be 0.1%. 
     Carboxyvinyl polymers suitable for use in the present invention are also known as “carbomers” or carboxypolymethylene. They are commercially available from sources such as Noveon, Inc. (Cleveland, Ohio), which distributes them under the trade name Carbopol®. Carbopol polymers are crosslinked, acrylic acid-based polymers. They are cross-linked with allyl sucrose or allylpentaerythritol. Carbopol copolymers are polymers of acrylic acid, modified by C 10-30  alkyl acrylates, and crosslinked with allylpentaerythritol. A preferred carbomer for use in the compositions of the present invention is a polymer of acrylic acid cross-linked with allyl sucrose or allylpentaerythritol, which is commercially available as Carbopol® 974P. The concentration of carbomer in the compositions of the present invention will generally range from 0.01-0.2%, and will preferably be 0.1%. 
     HEC is commercially available from Hercules Inc. (Aqualon Division) in a variety of grades, including Natrasol 250 LR, Natrasol 250 MR and Natrasol 250 HR. A preferred HEC for use in the compositions of the present invention is the NF grade material, which is commercially available as Natrasol 250HR. The concentration of HEC in the compositions of the present invention will generally range from 0.05-0.5%, and will preferably range from 0.1-0.2%. 
     Dextran is commercially available from Amresco in a variety of grades, including Dextran 5, 10, 20, 40, 70, 110, 500, and 2000. A preferred dextran for use in the compositions of the present invention is Dextran 70 (NOC grade; dry powder). The concentration of dextran in the compositions of the present invention will generally range from 0.01-0.2%, and will preferably be 0.1%. 
     The aqueous compositions of the present invention contain the three specified polymeric ingredients in a ratio ranging from 1:1:1 to 3:3:3, with a ratio of 3:1:1 being most preferred, where the amount of HPMC is listed first and the amounts of the other two polymers are listed second and third, respectively. The total concentration of the three polymeric ingredients should range from 0.1-1%, preferably 0.3-0.9%, and most preferably, 0.4-0.7%. 
     In addition to the three required polymeric ingredients, the aqueous compositions of the present invention may contain other ingredients as excipients. For example, the compositions may include one or more pharmaceutically acceptable buffering agents, preservatives (including preservative adjuncts), tonicity-adjusting agents, surfactants, solubilizing agents, stabilizing agents, comfort-enhancing agents, emollients, pH-adjusting agents and/or lubricants. Preferably, the aqueous composition does not contain any polymeric ingredients, other than the synergistic combination of the three polymeric ingredients specified above, with the exception of polymeric preservatives for compositions that contain a preservative. If the compositions contain a carbomer as one of the three polymers, then the compositions of the present invention do not contain any ionic tonicity-adjusting agents, such as sodium chloride, or other ionic excipients, such as boric acid, as these ingredients have a significant, detrimental effect on the composition&#39;s viscosity. 
     The compositions of the invention have a pH in the range of 4-9, preferably 6-8, and most preferably 6.5-7.5. If the compositions contain a carbomer as one of the three polymers, it is critical that the compositions are formulated so that the target pH is not exceeded. Once a target pH has been exceeded in compositions containing a carbomer, adding an acid such as hydrochloric acid to adjust the pH downward can compromise the synergistic viscosity. Even relatively small amounts of acid or salts, on the order of 0.005%, can have a significant effect on the viscosity of compositions containing a carbomer. 
     The compositions of the present invention generally have an osmolality in the range of 220-340 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg. 
     The aqueous compositions of the present invention are suitable for use as artificial tear products to relieve symptoms of dry eye. Alternatively, the compositions of the present invention may act as a vehicle for an ophthalmic drug. Ophthalmic drugs suitable for use in the compositions of the present invention include, but are not limited to: anti-glaucoma agents, such as beta-blockers including timolol, betaxolol, levobetaxolol, carteolol, miotics including pilocarpine, carbonic anhydrase inhibitors, prostaglandins, seretonergics, muscarinics, dopaminergic agonists, adrenergic agonists including apraclonidine and brimonidine; anti-angiogenesis agents; anti-infective agents including quinolones such as ciprofloxacin, and aminoglycosides such as tobramycin and gentamicin; non-steroidal and steroidal anti-inflammatory agents, such as suprofen, diclofenac, ketorolac, rimexolone and tetrahydrocortisol; growth factors, such as EGF; immunosuppressant agents; and anti-allergic agents including olopatadine. The ophthalmic drug may be present in the form of a pharmaceutically acceptable salt, such as timolol maleate, brimonidine tartrate or sodium diclofenac. Compositions of the present invention may also include combinations of ophthalmic drugs, such as combinations of (i) a beta-blocker selected from the group consisting of betaxolol and timolol, and (ii) a prostaglandin selected from the group consisting of latanoprost; 15-keto latanoprost; travoprost; and unoprostone isopropyl. In the case of a cationic drug, the amount of drug and/or the amount of carboxyvinyl polymer and/or the identity and amount of other formulation ingredients may need to be adjusted to minimize or eliminate interactions between the carboxyvinyl polymer and the cationic drug. Preferably, the ophthalmic drug is a neutral or negatively-charged drug. 
     Although the amount of drug included in the compositions of the present invention will be whatever amount is therapeutically effective and will depend upon a number of factors, including the identity and potency of the chosen drug, the total concentration of drug will generally be about 5% or less. 
     The compositions of the present invention are preferably not formulated as solutions that undergo a phase transition to a gel upon administration to the eye. The compositions illustrated in the Examples below do not gel upon administration to the eye. 
     The compositions of the present invention may be topically applied to the eye or injected into the eye, depending upon the target site and disease or condition to be treated. To treat diseases or conditions inside the eye rather than at the surface of the eye, the compositions of the present invention may, for example, be administered by intravitreal injection, subconjunctival injection, sub-tenon injection, retrobulbar injection, suprachoroidal injection, or periocular injection. A syringe apparatus including an appropriately sized needle, for example, a 27 gauge needle or a 30 gauge needle, can be effectively used to inject the composition into the posterior segment of an eye of a human or animal. The combination of polymers may be particularly advantageous for injections into the eye for the following reasons: prevention of reflux, prolonged duration of action so as to increase the period of time between repeat injections, and reduction in the total amount of polymer required to achieve a target viscosity, thereby reducing the polymer disposition from back of the eye. 
     The following examples are presented to illustrate further various aspects of the present invention, but are not intended to limit the scope of the invention in any respect. 
     EXAMPLES 
     Example 1 
     Artificial Tear Composition 
     A representative formulation for an artificial tear product according to the present invention is shown in Table 1. 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Ingredients 
                 Concentration (% w/w) 
               
               
                   
                   
               
             
            
               
                   
                 HPMC 2910 
                 0.3 
               
               
                   
                 HP-Guar 
                 0.1 
               
               
                   
                 Carbopol 974P 
                 0.1 
               
               
                   
                 Mannitol 
                 4.0 
               
               
                   
                 NaOH/HCl 
                 qs to pH 7.0 
               
               
                   
                 Purified water 
                 qs to 100 
               
               
                   
                   
               
            
           
         
       
     
     The composition shown in Table 1 can be prepared by at least two methods. One method involves adding the following ingredients slowly and in the following order to heated purified water (70-80° C.) (approximately 80% of the desired batch volume) with mixing: mannitol, HPMC 2910, Carbopol 974P, and HP-Guar (waiting until each ingredient is mixed well before adding the next). pH is then adjusted with 1N NaOH, and the remaining amount of purified water is added. The composition is then autoclaved at 121° C. for thirty minutes and subsequently cooled to room temperature with constant stirring. 
     An alternative method of preparing the composition shown in Table 1 is as follows. In a first container, add heated purified water (70-80° C.) (approximately 60% of the desired batch volume), then mix in mannitol, then HPMC 2910, and then Carbopol 974P, waiting until each ingredient is mixed well before adding the next. Autoclave the resulting composition at 121° C. for thirty minutes, then allow the composition to cool to room temperature with constant stirring (“the HPMC/Carbopol composition”). In a separate container, add purified water (approximately 30% of the desired batch volume), then mix in HP-Guar. Adjust the pH of the HP-Guar composition with 1N NaOH to pH 9. Autoclave the HP-Guar composition at 121° C. for thirty minutes, then allow it to cool to room temperature with constant stirring (“the HP-Guar composition”), then aseptically combine the HP-Guar composition with the HPMC/Carbopol composition, and aseptically adjust the final pH to 7.0, if necessary, with 1N NaOH and/or 1N HCl. 
     Example 2 
     Synergistic Effect on Viscosity (HPMC+Guar+Carbomer) 
     The compositions shown in Table 2 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) for more viscous samples (viscosity more than 20 cps). Two people independently prepared the indicated samples and measured their viscosity values (n=1) for each person. The averages of each set of results are shown in Table 2 and in  FIG. 1 . 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Ingredient 
                 1 
                 2 
                 3 
                 4 
                 5 
                 6 
                 7 
                 8 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 
                 — 
                 0.3 
                 — 
                 — 
                 0.3 
                 0.3 
                 — 
                 0.3 
               
               
                 2910 
               
               
                 Carbopol 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
                 — 
                 0.1 
                 0.1 
               
               
                 974P 
               
               
                 HP-Guar 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
                 0.1 
                 0.1 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
               
               
                   
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
               
               
                 Purified 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Water 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                 Viscosity 
                 1.1 
                 8.2 
                 488.1  
                 5.3 
                 1339.5   
                 32.3  
                 1273.0   
                 2477.0   
               
               
                 (cps) 
               
               
                 Subst. 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 Yes 
               
               
                 Synergy @   
               
               
                   
               
               
                   @ Subst. Synergy = substantial synergy: greater than 150% of the simple sum of the three respective single polymer solutions 
               
            
           
         
       
     
     Example 3 
     Synergistic Effect on Viscosity (HPMC+HEC+Guar; HPMC+HEC+Carbomer) 
     The compositions shown in Table 3 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) for more viscous samples (viscosity more than 20 cps). Two people independently prepared the indicated samples and measured their viscosity values (n=1) for each person. The averages of each set of results are shown in Table 3. 
     
       
         
           
               
             
               
                 TABLE 3 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Ingredient 
                 9 
                 10 
                 11 
                 12 
                 13 
                 14 
                 15 
                 16 
                 17 
                 18 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 
                 — 
                 0.3 
                 — 
                 — 
                 — 
                 0.3 
                 — 
                 — 
                 0.3 
                 0.3 
               
               
                 2910 
               
               
                 HP-Guar 
                 — 
                 — 
                 0.1 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
                 — 
               
               
                 Carbopol 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
               
               
                 974P 
               
               
                 Natrasol 
                 — 
                 — 
                 — 
                 — 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 250HR 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
               
               
                   
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
               
               
                 Purified 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Water 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                 Viscosity 
                 1.0 
                 8.0 
                 5.2 
                 465.9  
                 3.0 
                 27.7  
                 10.9  
                 642.0  
                 62.8  
                 1300.5   
               
               
                 (cps) 
               
               
                 Subst. 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 Yes 
                 Yes 
               
               
                 Synergy @   
               
               
                   
               
               
                   @ Subst. Synergy = substantial synergy: greater than 150% of the simple sum of the three respective single polymer solutions 
               
            
           
         
       
     
     Example 4 
     Lack of Synergistic Effect on Viscosity (Polyvinyl Alcohol+Chondroitin Sulfate+Polyvinylpyrrolidone) 
     The compositions shown in Table 4 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) for more viscous samples (viscosity more than 20 cps). Two people independently prepared the indicated samples and measured their viscosity values (n=1) for each person. The averages of each set of results are shown in Table 4. Airvol 523S is a commercially available polyvinyl alcohol polymer. Chondroitin sulfate is a commercially available polymer. K90 is a commercially available polyvinylpyrrolidone polymer. 
     
       
         
           
               
             
               
                 TABLE 4 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
               
               
               
            
               
                 Ingredient 
                 19 
                 20 
                 21 
                 22 
                 23 
                 24 
                 25 
                 26 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 PVA (Airvol 
                 — 
                 0.2 
                 — 
                 — 
                 0.2 
                 0.2 
                 — 
                 0.2 
               
               
                 523S) 
               
               
                 Chondroitin 
                 — 
                 — 
                 0.2 
                 — 
                 0.2 
                 — 
                 0.2 
                 0.2 
               
               
                 Sulfate 
               
               
                 PVP (K90) 
                 — 
                 — 
                 — 
                 0.2 
                 — 
                 0.2 
                 0.2 
                 0.2 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
               
               
                   
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
               
               
                 Purified Water 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                 Viscosity (cps) 
                 1.0 
                 1.5 
                 1.3 
                 1.4 
                 1.7 
                 1.9 
                 1.8 
                  2.3* 
               
               
                 Subst. 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 No 
               
               
                 Synergy @   
               
               
                   
               
               
                 *slight, transparent precipitate observed 
               
               
                   @ Subst. Synergy = substantial synergy: greater than 150% of the simple sum of the three respective single polymer solutions 
               
            
           
         
       
     
     Example 5 
     Lack of Synergistic Effect on Viscosity (Polyvinyl Alcohol+Chondroitin Sulfate+Carbomer; Polyvinyl Alcohol+Polyvinylpyrrolidone+Carbomer; Chondroitin Sulfate+Polyvinylpyrrolidone+Carbomer) 
     The compositions shown in Table 5 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) for more viscous samples (viscosity more than 20 cps). Two people independently prepared the indicated samples and measured their viscosity values (n=1) for each person. The averages of each set of results are shown in Table 5. Airvol 523S is a commercially available polyvinyl alcohol polymer. Chondroitin sulfate is a commercially available polymer. K90 is a commercially available polyvinylpyrrolidone polymer. The viscosities of the single polymer solutions for polyvinyl alcohol, chondroitin sulfate and polyvinylpyrrolidone can be found in Table 4—Examples 20-22. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
               
               
            
               
                 Ingredient 
                 27 
                 28 
                 29 
                 30 
                 31 
                 32 
                 33 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 PVA 
                 — 
                 0.2 
                 — 
                 — 
                 — 
                 0.2 
                 0.2 
               
               
                 (Airvol 523S) 
               
               
                 Chondroitin 
                 — 
                 — 
                 0.2 
                 — 
                 0.2 
                 0.2 
                 — 
               
               
                 Sulfate 
               
               
                 PVP 
                 — 
                 — 
                 — 
                 0.2 
                 0.2 
                 — 
                 0.2 
               
               
                 (K90) 
               
               
                 Carbopol 974P 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
               
               
                   
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
               
               
                 Purified Water 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                 Viscosity (cps) 
                 441.6  
                 323.8  
                 12.7  
                 N/A* 
                  16.7** 
                 14.2  
                 N/A* 
               
               
                 Subst. 
                 — 
                 — 
                 — 
                 — 
                 — 
                 No 
                 No 
               
               
                 Synergy @   
               
               
                   
               
               
                 *PVP was incompatible with Carbopol 974P - it formed a precipitate. 
               
               
                 **Solution obtained only by specific order of mixing: mannitol, then chondroitin sulfate, then PVP, then carbomer. 
               
               
                   @ Subst. Synergy = substantial synergy: greater than 150% of the simple sum of the three respective single polymer solutions 
               
            
           
         
       
     
     Example 6 
     Synergistic Effect on Viscosity (HPMC+HEC+Guar; HPMC+HEC+Carbomer) 
     The compositions shown in Table 6 were prepared and their viscosity determined using a Brookfield cone/plate viscometer with number 42 cone/plate set (30 rpm, at 25° C.) for less viscous samples (viscosity less than 20 cps) and number 52 cone/plate set (3 rpm, at 25° C.) for more viscous samples (viscosity more than 20 cps). Two people independently prepared the indicated samples and measured their viscosity values (n=1) for each person. The averages of each set of results are shown in Table 6. 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
               
               
               
               
               
            
               
                 Ingredient 
                 34 
                 35 
                 36 
                 37 
                 38 
                 39 
                 40 
                 41 
                 42 
                 43 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 
                 — 
                 0.3 
                 — 
                 — 
                 — 
                 0.3 
                 — 
                 — 
                 0.3 
                 0.3 
               
               
                 2910 
               
               
                 HP-Guar 
                 — 
                 — 
                 0.1 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
                 — 
               
               
                 Carbopol 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 — 
                 — 
                 0.1 
                 — 
                 0.1 
               
               
                 974P 
               
               
                 Dextran 
                 — 
                 — 
                 — 
                 — 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 70 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
                 pH 
               
               
                   
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
                 7.0 
               
               
                 Purified 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                 Water 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                 Viscosity 
                 1.1 
                 7.9 
                 5.2 
                 461.6  
                 1.4 
                 8.4 
                 5.2 
                 379.3  
                 46.1  
                 829.2  
               
               
                 (cps) 
               
               
                 Subst. 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 — 
                 Yes 
                 Yes 
               
               
                 Synergy @   
               
               
                   
               
               
                   @ Subst. Synergy = substantial synergy: greater than 150% of the simple sum of the three respective single polymer solutions 
               
            
           
         
       
     
     Example 7 
     The Effect of Polymer Ratio on Viscosity 
     The effect of polymer ratio on viscosity was determined by preparing compositions containing a ratio of the three designated polymers that varied from 1:1:1 to 3:3:3. The compositions are shown in Table 5. The viscosity was determined using a Bohlin Rheometer Model CS-10 at 25° C. (shear rate: 0.8 1/s). Two people independently prepared the indicated compositions and determined viscosity values (n=10 for each person). The averages of the results are shown in Table 7. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
            
               
                 Ingredient 
                 44 
                 45 
                 46 
                 47 
                 48 
               
               
                   
               
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 2910 
                 0.1 
                 0.1 
                 0.1 
                 0.3 
                 0.3 
               
               
                 Carbopol 
                 0.1 
                 0.1 
                 0.3 
                 0.1 
                 0.3 
               
               
                 974P 
               
               
                 HP-Guar 
                 0.1 
                 0.3 
                 0.1 
                 0.1 
                 0.3 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
               
               
                 Purified 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
               
               
                 Water 
               
               
                 Polymer ratio 
                 1:1:1 
                 1:1:3 
                 1:3:1 
                 3:1:1 
                 3:3:3 
               
               
                 HPMC:Carbopol:HP- 
               
               
                 Guar 
               
               
                 Viscosity 
                 2865 
                 8450 
                 101950 
                 3660 
                 145000 
               
               
                 (cps) 
                 [700] 
                 [1655] 
                 [2899] 
                 [141] 
                 [1414] 
               
               
                 [Stnd. 
               
               
                 Deviation] 
               
               
                   
               
            
           
         
       
     
     Example 8 
     Effect of Salt on Viscosity for a Polymer Combination that Contains Carbomer 
     The compositions shown below in Table 8 were prepared to determine the effect of the addition of salt (NaCl) on viscosity. The viscosity of each sample was determined using a Brookfield cone/plate viscometer (52 cone, 3 rpm). The results are shown in Table 8. 
     
       
         
           
               
             
               
                 TABLE 8 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
            
               
                 INGREDIENT 
                 Ex. 1 
                 X 
                 Y 
                 Z 
                 AA 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 29.0 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
               
               
                 Carbopol 974P 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 HP Guar 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 NaCl 
                 0 
                 0.001 
                 0.005 
                 0.01 
                 0.05 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
                 q.s. 
               
               
                   
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
                 pH 7.0 
               
               
                 Purified Water 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
               
               
                 Viscosity (cps) 
                 1569 
                 1382 
                 774 
                 608 
                 202 
               
               
                   
               
            
           
         
       
     
     Example 9 
     Effect of Boric Acid on Viscosity for a Polymer Combination that Contains Carbomer 
     The compositions shown below in Table 9 were prepared to determine the effect of the addition of boric acid on viscosity. The viscosity of each sample was determined using a Brookfield cone/plate viscometer (52 cone, 3 rpm). The results are shown in Table 9. 
     
       
         
           
               
             
               
                 TABLE 9 
               
             
            
               
                   
               
               
                 Composition (% w/v) 
               
            
           
           
               
               
               
               
               
               
            
               
                 INGREDIENT 
                 Ex. 1 
                 X 
                 Y 
                 Z 
                 AA 
               
               
                   
               
            
           
           
               
               
               
               
               
               
            
               
                 Mannitol 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
                 4.0 
               
               
                 HPMC 2910 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
                 0.3 
               
               
                 Carbopol 974P 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 HP Guar 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
                 0.1 
               
               
                 Boric acid 
                 0 
                 0.001 
                 0.005 
                 0.01 
                 0.05 
               
               
                 NaOH/HCl 
                 q.s. 
                 q.s. pH 7 
                 q.s. pH 7 
                 q.s. pH 7 
                 q.s. pH 7 
               
               
                   
                 pH 7 
               
               
                 Purified Water 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
                 q.s. 100 
               
               
                 Viscosity (cps) 
                 1250 
                 1035 
                 682 
                 531 
                 172 
               
               
                   
               
            
           
         
       
     
     Example 10 
     Effect of Total Polymer Concentration on Viscosity 
     The effect of total polymer concentration on the viscosity of compositions containing a combination of HPMC 2910, HP-Guar and Carbopol 974P was evaluated using 5 compositions containing only the three designated polymers, mannitol and purified water. In each case, the composition contained 4.0% (w/w) of mannitol and had an adjusted pH of 7.0. The total polymer concentrations ranged from 0.1 to 1.0, with the ratio of polymers held constant at 3:1:1 (HPMC:HP-Guar:Carbopol). The viscosity was determined using a Bohlin Rheometer Model CS-10 at 25° C. (shear rate: 0.8 1/s). The results (average of 10 measurements, n=10) are shown in Table 10 and  FIG. 2 . 
     
       
         
           
               
               
               
             
               
                   
                 TABLE 10 
               
               
                   
                   
               
               
                   
                 Total Polymer 
                   
               
               
                   
                 Concentration (% w/v) 
                 Viscosity (cps) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 0.1 
                 48 
               
               
                   
                 0.25 
                 83 
               
               
                   
                 0.5 
                 3087 
               
               
                   
                 0.75 
                 21,099 
               
               
                   
                 1.0 
                 44,064 
               
               
                   
                   
               
            
           
         
       
     
     The invention has been described by reference to certain preferred embodiments; however, it should be understood that it may be embodied in other specific forms or variations thereof without departing from its spirit or essential characteristics. The embodiments described above are therefore considered to be illustrative in all respects and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description.