Abstract:
Topical formulations of olopatadine for treatment of allergic or inflammatory disorders of the nose are disclosed. The aqueous formulations contain approximately 0.6% (w/v) of olopatadine.

Description:
[0001]     This application is a continuation-in-part of Ser. No. 11/079,996, filed Mar. 15, 2005, which is a continuation of Ser. No. 10/175,106, filed Jun. 19, 2002, which claims priority to U.S. Provisional Application Ser. No. 60/301,315, filed Jun. 27, 2001, all of which are incorporated herein by reference. 
     
    
     BACKGROUND OF THE INVENTION  
       [0002]     1. Field of the Invention  
         [0003]     The present invention relates to topical formulations used for treating allergic and inflammatory diseases. More particularly, the present invention relates to formulations of olopatadine and their use for treating and/or preventing allergic or inflammatory disorders of the nose.  
         [0004]     2. Description of the Related Art  
         [0005]     As taught in U.S. Pat. Nos. 4,871,865 and 4,923,892, both assigned to Burroughs Wellcome Co. (“the Burroughs Wellcome Patents”), certain carboxylic acid derivatives of doxepin, including olopatadine (chemical name: Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine-2-acetic acid), have antihistamine and antiasthmatic activity. These two patents classify the carboxylic acid derivatives of doxepin as mast cell stabilizers with antihistaminic action because they are believed to inhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast cells and to inhibit directly histamine&#39;s effects on target tissues. The Burroughs Wellcome Patents teach various pharmaceutical formulations containing the carboxylic acid derivatives of doxepin, including nasal spray and ophthalmic formulations. See, for example, Col. 7, lines 7-26, and Examples 8 (H) and 8 (I) of the &#39;865 patent.  
         [0006]     U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko Kogyo Co., Ltd., (“the Kyowa patent”), teaches that acetic acid derivatives of doxepin and, in particular, olopatadine, have anti-allergic and anti-inflammatory activity. Olopatadine is the cis form of the compound having the formula:  
                         
 
 Medicament forms taught by the Kyowa patent for the acetic acid derivatives of doxepin include a wide range of acceptable carriers; however, only oral and injection administration forms are mentioned. 
 
         [0007]     U.S. Pat. No. 5,641,805, assigned to Alcon Laboratories, Inc. and Kyowa Hakko Kogyo Co., Ltd., teaches topical ophthalmic formulations containing olopatadine for treating allergic eye diseases. According to the &#39;805 patent, the topical formulations may be solutions, suspensions or gels. The formulations contain olopatadine, an isotonic agent, and “if required, a preservative, a buffering agent, a stabilizer, a viscous vehicle and the like.” See Col. 6, lines 30-43. “[P]olyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid or the like” are mentioned as the viscous vehicle. See Col. 6, lines 55-57.  
         [0008]     PATANOL® (olopatadine hydrochloride ophthalmic solution) 0.1% is currently the only commercially available olopatadine product for ophthalmic use. According to its labelling information, it contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01% benzalkonium chloride, and unspecified amounts of sodium chloride, dibasic sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust pH) and purified water.  
         [0009]     Topical olopatadine formulations that are effective as products for treating allergic or inflammatory conditions in the nose are desirable.  
       SUMMARY OF THE INVENTION  
       [0010]     The present invention provides topical olopatadine formulations that are effective as products for treating allergic or inflammatory disorders of the nose. The formulations of the present invention are aqueous solutions that comprise approximately 0.6% olopatadine. Despite their relatively high concentration of olopatadine, they do not contain any polymeric ingredient as a physical stability enhancing ingredient. The formulations contain a phosphate salt that permits the pH of the formulations to be maintained within the range 3.5-3.95 and that also aids in solubilizing the olopatadine drug in the presence of sodium chloride.  
         [0011]     Among other factors, the present invention is based on the finding that stable, nasal spray, solution formulations of olopatadine can be prepared within a pH range of 3.5-3.95 using a phosphate buffer without the need for any polymeric ingredient to enhance the solubility or physical stability of the formulation. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0012]      FIGS. 1A and 1B  show the pH-solubility profile of olopatadine.  
         [0013]      FIG. 2  shows the effect of NaCl and Na 2 HPO 4  on the dissolution of olopatadine in water.  
         [0014]      FIG. 3  shows the effect of NaCl and Na 2 HPO 4  on the dissolution of olopatadine in a nasal vehicle.  
         [0015]      FIG. 4  shows the effect of NaCl and Na 2 HPO 4  concentrations on the dissolution rate of olopatadine in a nasal vehicle.  
         [0016]      FIG. 5  shows the buffer capacity of an olopatadine nasal spray composition.  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0017]     Unless indicated otherwise, all component amounts are presented on a % (w/v) basis and all references to amounts of olopatadine are to olopatadine free base.  
         [0018]     Olopatadine is a known compound that can be obtained by the methods disclosed in U.S. Pat. No. 5,116,863, the entire contents of which are hereby incorporated by reference in the present specification. The solution formulations of the present invention contain 0.54-0.62% olopatadine. Preferably, the solution formulations contain 0.6% olopatadine.  
         [0019]     Olopatadine has both a carboxylic functional group (pKa 1 =4.18) and a tertiary amino group (pKa 2 =9.79). It exists in different ionic forms depending upon the pH of the solution. Olopatadine exists predominantly as a zwitterion in the pH range between the two pKa values with a negatively-charged carboxylic group and a positively-charged tertiary amino group. The iso-electric point of the olopatadine zwitterion is at pH 6.99. At a pH lower than pKa 1 , cationic olopatadine (with ionized tertiary amino group) is dominant. At a pH higher than pKa 2 , anionic olopatadine (with ionized carboxylic group) is dominant.  
                         
 
         [0020]     In many zwitterionic molecules, such as various amino acids, intra-molecular ionic interactions are not significant or do not exist. But the structure of olopatadine is such that intra-molecular interactions exist and are significant, possibly due to the distance and bonding angle between the oppositely charged functional groups. This interaction effectively reduces the ionic and dipole character of the molecule. The net effect of the intra-molecular interactions between the oppositely charged functional groups is the reduction of aqueous solubility of olopatadine. Olopatadine has the pH-solubility profile shown in  FIGS. 1A  (theoretical) and  1 B (obtained using phosphate buffer).  
         [0021]     Generally, olopatadine will be added in the form of a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salts of olopatadine include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; metal salts such as aluminum salt and zinc salt; and organic amine addition salts such as triethylamine addition salt (also known as tromethamine), morpholine addition salt and piperidine addition salt. The most preferred form of olopatadine for use in the solution compositions of the present invention is the hydrochloride salt of (Z)-11-(3-dimethylaminopropylidene)-6,11-dihydro-dibenz-[b,e]oxepin-2-acetic acid. When olopatadine is added to the compositions of the present invention in this salt form, 0.665% olopatadine hydrochloride is equivalent to 0.6% olopatadine free base. Preferably the compositions of the present invention comprise approximately 0.665% olopatadine hydrochloride.  
         [0022]     In addition to olopatadine, the aqueous solution compositions of the present invention comprise a phosphate salt. The phosphate salt not only helps maintain the pH of the compositions within the targeted pH range of 3.5-3.95 by contributing to the buffer capacity of the compositions, but also helps solubilize olopatadine. Suitable phosphate salts for use in the compositions of the present invention include monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate, and tribasic potassium phosphate. The most preferred phosphate salt is dibasic sodium phosphate. The compositions of the present invention comprise an amount of phosphate salt equivalent (on an osmolality contribution basis) to 0.2-0.8%, preferably 0.3-0.7%, and most preferably 0.4-0.6% of dibasic sodium phosphate. In a preferred embodiment, the phosphate salt is dibasic sodium phosphate at a concentration of 0.4-0.6% (w/v). In a most preferred embodiment, the compositions contain 0.5% (w/v) dibasic sodium phosphate.  
         [0023]     Phosphate buffer is commonly used in aqueous pharmaceutical compositions formulated near neutral pH. Phosphate buffer (pKa 1 =2.12, pKa 2 =7.1, pKa 3 =12.67) would not normally be chosen for an aqueous composition with a target pH range of 3.5-3.95 because it has low buffer capacity in that region. Other buffering agents are commonly used in aqueous pharmaceutical compositions, including acetate, citrate and borate buffers, but are not suitable for use in the topical nasal compositions of the present invention. Borate buffers are not suitable because they do not have any significant buffer capacity in the pH range 3.5-3.95. Though acetate and citrate buffers have buffer capacity in this region, they are not preferred because they have the potential to cause irritation to nasal mucosal tissues and undesirable taste and/or smell.  
         [0024]     In addition to olopatadine and phosphate salt, the compositions of the present invention comprise sodium chloride as a tonicity-adjusting agent. The compositions contain sodium chloride in an amount sufficient to cause the final composition to have a nasally acceptable osmolality, preferably 240-350 mOsm/kg. Most preferably, the amount of sodium chloride in the compositions of the present invention is an amount sufficient to cause the compositions to have an osmolality of 260-330 mOsm/kg. In a preferred embodiment, the compositions contain 0.3-0.6% sodium chloride. In a more preferred embodiment, the compositions contain 0.35-0.55% sodium chloride, and in a most preferred embodiment, the compositions contain 0.35-0.45% sodium chloride.  
         [0025]     The compositions of the present invention also contain a pharmaceutically acceptable pH-adjusting agent. Such pH-adjusting agents are known and include, but are not limited to, hydrochloric acid (HCl) and sodium hydroxide (NaOH). The compositions of the present invention preferably contain an amount of pH-adjusting agent sufficient to obtain a composition pH of 3.5-3.95, and more preferably, a pH of 3.6-3.8.  
         [0026]     In one embodiment, the aqueous compositions of the present invention consist essentially of olopatadine, phosphate buffer, sodium chloride, a pH-adjusting agent, and water, and have a pH from 3.5-3.95. These compositions can be manufactured as sterile compositions and packaged in multi-dose, pressurized aerosol containers to avoid microbial contamination. In another embodiment, the aqueous compositions of the present invention contain a preservative and a chelating agent such that the compositions pass United States Pharmacopeia/National Formulary XXX criteria for antimicrobial effectiveness, and more preferably the Pharm. Eur. 5 th  Edition criteria for antimicrobial preservation (Pharm. Eur. B preservative effectiveness standard). Suitable preservatives include p-hydroxybenzoic acid ester, benzalkonium chloride, benzododecinium bromide, and the like. Suitable chelating agents include sodium edetate and the like. The most preferred preservative ingredient for use in the compositions of the present invention is benzalkonium chloride (“BAC”). The amount of benzalkonium chloride is preferably 0.005-0.015%, and more preferably 0.01%. The most preferred chelating agent is edetate disodium (“EDTA”). The amount of edetate disodium in the compositions of the present invention is preferably 0.005-0.015%, and more preferably 0.01%.  
         [0027]     The aqueous solution compositions of the present invention do not contain a polymeric ingredient intended to enhance the solubility of olopatadine or the physical stability of the solution. For example, the compositions of the present invention do not contain polyvinylpyrrolidone, polystyrene sulfonic acid, polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose or xanthan gum.  
         [0028]     The compositions of the present invention are preferably packaged in opaque plastic containers. A preferred container is a high-density polyethylene container equipped with a nasal spray pump. Preferably, the package is designed to provide the spray characteristics described in commonly-assigned, co-pending, U.S. Patent Application Publication No. 2006/0110328, which is incorporated herein by reference.  
         [0029]     The present invention also relates to a method of treating allergic rhinitis comprising topically administering to the nasal cavities a composition containing 0.6% olopatadine, phosphate buffer, sodium chloride, a pH-adjusting agent, and water. The compositions optionally contain one or more preservative ingredients. Preferably, the compositions are administered such that 1200 mcg of olopatadine (e.g., 600/mcg per 100 microliter spray×two sprays) is delivered to each nostril twice per day.  
         [0030]     Certain embodiments of the invention are illustrated in the following examples.  
       EXAMPLE 1  
     Topically Administrable Nasal Solution  
       [0031]                                TABLE 1                                   Ingredient   Amount (%, w/v)                           Olopatadine Hydrochloride   0.665 a             Benzalkonium Chloride   0.01           Edetate Disodium, Dihydrate   0.01           Sodium Chloride   0.41           Dibasic Sodium Phosphate, Anhydrous   0.5           Hydrochloric Acid   Adjust to pH 3.7 ± 0.1           and/or           Sodium Hydroxide           Purified Water   qs to 100                           a 0.665% w/v olopatadine hydrochloride (665 mcg/100 microliter spray) is equivalent to 0.6% w/v olopatadine as base (600 mcg/100 microliter spray).               
 An exemplary compounding procedure for the nasal composition shown in Table 1 is described as below. 
    1. Tare a suitable compounding vessel with magnetic stir bar. Add approximately 80% of the batch weight of purified water.     2. While stirring, add dibasic sodium phosphate (anhydrous), sodium chloride, edetate disodium, benzalkonium chloride and olopatadine HCl.     3. Add equivalent to approximately 0.55 g, 6N hydrochloric acid per 100 ml batch.     4. Allow adequate time between each addition for dissolution of each ingredient     5. Add purified water to approximately 90% of final batch weight.     6. Measure pH and adjust, if necessary, to 3.7 with 6N (and/or 1N) hydrochloric acid and 1N sodium hydroxide.     7. Adjust to final batch weight with purified water (QS).     8. Measure final pH.     9. Filter through 0.2 μm filtration membrane.      
       EXAMPLE 2  
     Effect of NaCl and Phosphate Buffer on Dissolution of Olopatadine Hydrochloride  
       [0041]     The effect of NaCl on the dissolution rate of olopatadine hydrochloride in water was determined. NaCl caused a significant reduction in the rate of dissolution of olopatadine. With addition of Na 2 HPO 4 , however, the dissolution of olopatadine was dramatically improved. The complete dissolution of 0.6% olopatadine solution without Na 2 HPO 4  would take at least several hours assuming that the entire amount of olopatadine would eventually dissolve, but with Na 2 HPO 4  it takes less than one minute. The results are shown in  FIG. 2 .  
       EXAMPLE 3  
     Effect of NaCl and Na 2 HPO 4  on the Dissolution Olopatadine Hydrochloride in a Nasal Vehicle  
       [0042]     The effect of NaCl, Na2HPO4, and mannitol on the dissolution rate of olopatadine hydrochloride in a nasal formulation containing 0.01% EDTA and 0.01% BAC was determined. The results are shown in  FIG. 3 . The effect of phosphate salt in this vehicle is the same as that shown in water in Example 2.  
       EXAMPLE 4  
     Effect of NaCl and Na 2 HPO 4  Concentrations on Dissolution  
       [0043]     The effect of NaCl and Na 2 HPO 4  concentrations on the dissolution rate of olopatadine hydrochloride in a nasal formulation containing 0.01% EDTA and 0.01% BAC was determined. The results are shown in  FIG. 4 . The aqueous solubility of olopatadine HCl decreases with increasing concentration of NaCl. However, increasing phosphate buffer correlates with increased aqueous solubility of olopatadine HCl in the presence of NaCl.  
       EXAMPLE 5  
     Effect of Phosphate Buffer on Olopatadine Nasal Spray Composition  
       [0044]     The two compositions shown in Table 2 below were prepared using the procedure described in Example 1 and visual observations of the compositions clarity were made at different points during the compounding procedure. The results are shown in Table 2.  
                                     TABLE 2                           Formulation 2A   Formulation 2B       Component   % w/v   % w/v                                Olopatadine HCl   0.665   0.665       Benzalkonium Chloride   0.01 + 3% xs   0.01 + 3% xs       Disodium EDTA   0.01   0.01       Sodium Chloride   0.37   0.7       Dibasic Sodium Phosphate   0.5   absent       Sodium Hydroxide   pH to 3.7   pH to 3.7       Hydrochloric Acid   pH to 3.7   pH to 3.7       Purified Water   qs 100   qs 100       Batch Size   2000 mL   2000 mL       Osmolality   266   250       Initial pH   6.704   3.189       Final pH   3.699   3.618       Visual Observations:       Upon addition of HCl   Solution appeared clear with   Solution appeared cloudy           a few particles   with many particles               suspended       After overnight stirring   Solution became cloudy with   Solution remained cloudy           many particles   with many particles       Final pH adjustment   Solution began to clear   Solution remained cloudy           during pH adjust down to 3.7   even after pH adjust down               to 3.6       Add final batch quantity of water   Solution remained clear   Solution was still cloudy       (approximately 10%)       with many particles                  
 
 The results for Formulation A show that it is a clear solution. The results for Formulation B show that despite the pH-solubility profile indicating 0.6% olopatadine should dissolve at pH 3.189, the olopatadine did not go into solution. These results demonstrate that, without phosphate buffer, 0.665% olopatadine hydrochloride did not completely dissolve in water in the presence of 0.7% NaCl at a pH as low as 3.6 using the compounding procedure described in Example 1. 
 
       EXAMPLE 6  
     Effect of Phosphate Buffer Added to Cloudy 0.6% Olopatadine Nasal Spray Composition  
       [0045]     Formulations 3A, 3B, and 3C shown in Table 3 were prepared without phosphate buffer and, despite extensive stirring, the olopatadine HCl was not completely solubilized. A portion of Formulation 3C was removed and phosphate buffer was added to form Formulation 3D. The results, summarized in Table 3, demonstrate that 0.665% olopatadine hydrochloride is not soluble in the tested nasal vehicle without a phosphate salt.  
                                                         TABLE 3                                   Formulation 3A   Formulation 3B   Formulation 3C   Formulation 3D                                    Olopatadine HCl   0.665   0.665   0.665   0.665       Benzalkonium   0.01 + 3% xs   0.01 + 3% xs   0.01 + 3% xs   0.01 + 3% xs       Chloride       Disodium EDTA   0.01   0.01   0.01   0.01       Sodium Chloride   0.33   0.7   0.7   0.7       Sodium   pH to 3.7   pH to 3.7   pH to 3.7   pH to 3.7       Hydroxide       Hydrochloric   pH to 3.7   pH to 3.7   pH to 3.7   pH to 3.7       Acid       Purified Water   qs 100%   qs 100%   qs 100%   qs 100%       Batch Size   300 mL   800 mL   2000 mL   100 mL       Osmolality   137   246   250   —       Initial pH   3.002   3.176   3.189   6.908       Final pH   3.002   3.664   3.618   3.7       Visual       Observations:   Upon addition of Olopatadine HCl,   Upon addition of Olopatadine HCl,   Upon addition of   Used dibasic sodium phosphate           solution appeared cloudy, batch   solution appeared cloudy, batch was   Olopatadine HCl,   (0.5%) in attempts to clarify a           was qs to 100% and   qs to 90% and pH adjusted, solution   solution appeared   portion of the cloudy solution           still cloudy   still cloudy   cloudy   (Formulation 3C)           After 2.5 hours of stirring, solution   After 7 hours of stirring, the   After overnight   Within a minute of stirring, the           began to clear   solution was still cloudy.   stirring, the solution   solution became clear with a few           but still many particles*       remained cloudy with   particles** in solution (mostly           in solution       many particles*   fibrous in appearance)           After 3.5 hours of stirring, solution   After 7 days of stirring, the solution   After final qs to 100%   After qs to 100% (using solution           appeared clear with particles*   was still cloudy with many particles*   and pH adjust, the   from the original batch), the                   solution was still   solution remained clear with                   cloudy with   a few fibrous particles**                   many particles*           After overnight stirring, solution   The batch was qs to 100% and still   After approx. 7 hours           appeared clear with several   cloudy with   of stirring, the solution           particles*   many particles*   was cloudy with                   many particles*                 *Insoluble drug related            **Extraneous fibrous particles             
 
       EXAMPLE 7  
     Effect of Compounding Sequence on 0.6% Olopatadine Nasal Spray Composition  
       [0046]     The composition of Example 1 above was prepared using four different sequences for the addition of ingredients. The four sequences are indicated in Table 4 in the “OA” (order of addition) columns. In each case, visual observations relating to the composition&#39;s clarity were recorded. The results are shown in Table 4. In all four cases (Formulations 4A-4D), at the end of the compounding procedure, the solutions were clear. (The solutions contained some extraneous fibrous particles that did not appear to be related to the drug or the formulation excipients and were likely attributable to laboratory equipment and glassware.)  
                                                                                                                                     TABLE 4                                       4A   4B   4C   4D            Component   % w/v   OA a     % w/v   OA a,c     % w/v   OA a     % w/v   OA a                      Olopatadine HCl   0.665   3   0.665   5   0.665   2   0.665   2       Benzalkonium Chloride   0.01   4   0.01   4   0.01   3   0.01   4       Disodium EDTA   0.01   5   0.01   3   0.01   4   0.01   5       Sodium Chloride   0.41   6   0.41   2   0.41   5   0.41   6       Dibasic Sodium   0.5   1   0.5   1   0.5   6   0.5   1       Phosphate (Anhydrous)       Sodium Hydroxide   pH to 3.7   NA b     pH to 3.7   NA b     pH to 3.7   NA b     pH to 3.7   NA b         Hydrochloric Acid   pH to 3.7   2   pH to 3.7   6   pH to 3.7   1   pH to 3.7   3       Purified Water   qs 100%   NA   qs 100%   NA   qs 100%   NA   qs 100%   NA            Batch Size   100 mL   100 mL   100 mL   100 mL       Sodium Hydroxide added   0.238 g (1N)   None   None   None       Hydrochloric Acid added   0.576 g (6N)   0.550 g (6N)   0.550 g (6N)   0.550 g (6N)       Initial Observations   Cloudy, many suspended   Cloudy, many suspended   Cloudy, many suspended   Cloudy, many suspended           particles   particles   particles   particles       Additional observations   After 10 minutes - solution   After 1 minute - clear with   After 2 minutes - clear with a   After 5 minutes - clear with a           began to clear, many   several suspended particles   few suspended particles   few suspended particles           suspended particles           After 30 minutes - clear with   After 6 minutes - clear with a   After 7 minutes - clear with a   After 20 minutes - clear with           several suspended particles   few suspended particles   few suspended particles   a few suspended particles           After 1 hour - clear with many   After 1 hour - clear with a few   After 1 hour - clear with   After 1 hour - clear with           suspended particles*   suspended particles*   several suspended particles*   several suspended particles*           Next day (approx 16 hours) -   Next day (approx 16 hours) -   Next day (approx 16 hours) -   Next day (approx 16 hours) -           clear with several particles*   clear with a few particles*   clear with a few particles*   clear with a few particles*       pH   3.698   3.692   3.718   3.724       Osmolality   274   283   279   280                   b NA = not applicable              c Preferred method of manufacturing            *Extraneous fibrous particles             
 
       EXAMPLE 8  
     Effect of Various Buffer Systems  
       [0047]     The composition of Example 1 above was prepared but acetate, borate and citrate buffers, respectively, were substituted in place of the phosphate buffer. Visual observations regarding the clarity of each of the compositions were recorded and are shown in Table 5.  
                                                           TABLE 5                                       5A   5B   5C            Component   % w/v                    Olopatadine HCl   0.665   0.665   0.665       Benzalkonium   0.01   0.01   0.01       Chloride       Disodium EDTA   0.01   0.01   0.01       Sodium Chloride   0.41   0.41   0.41       Sodium Acetate   0.5   —   —       Sodium Borate   —   —   0.5       Sodium Citrate   —   0.5   —       Sodium Hydroxide   pH to 3.7   pH to 3.7   pH to 3.7       Hydrochloric Acid a     pH to 3.7   pH to 3.7   pH to 3.7       Purified Water   qs 100%   qs 100%   qs 100%       Batch Size   100 mL   100 mL   100 mL       Sodium Hydroxide   0.332 g (1N)   0.244 g (1N)   0.963 g (1N)       added       Hydrochloric Acid   0.550 g (6N)   0.550 g (6N)   0.550 g (6N)       added       pH   3.711   3.710   3.716       Osmolality   257   246   270       Visual Observations:       Observations: Initial   Upon addition of   Upon addition of   Upon addition of           Olopatadine, batch   Olopatadine, batch   Olopatadine, batch           appeared cloudy but   appeared cloudy but   appeared cloudy but           began to clear within a   began to clear within   began to clear with in a           few seconds   one minute   few seconds       Additional   After 3 minutes of   After 17 minutes of   After 16 minutes of       observations:   stirring, solution   stirring, solution   stirring, solution           appeared clear with a   appeared clear with   appeared clear with a           few extraneous particles   several large flakey   few large flakey               particles   particles           After 20 additional   After 20 additional   After 20 additional           minutes of stirring,   minutes of stirring,   minutes of stirring,           solution appeared clear   solution appeared clear   solution appeared clear           with very few   with very few   with very few           extraneous particles   extraneous particles   extraneous particles           The pH was adjusted,   The pH was adjusted,   The pH was adjusted,           solution was brought to   solution was brought to   solution was brought to           100% of batch weight   100% of batch weight   100% of batch weight           and remained clear (with   and remained clear (with   and remained clear (with           very few extraneous   very few extraneous   very few extraneous           particles)   particles)   particles)                  
 
       EXAMPLE 9  
     Effect of Phosphate Buffer, NaCl, and Hot Water  
       [0048]     The compositions shown in Table 6 were prepared to examine (1) the effect of adding phosphate buffer to a composition containing olopatadine hydrochloride, BAC, EDTA, NaOH/HCl, and NaCl, (2) the effect of adding NaCl to a composition containing olopatadine, BAC, EDTA, NaOH/HCl, and (3) the effect of hot water on the dissolution of olopatadine in a composition comprising olopatadine, BAC, EDTA, NaCl and NaOH/HCl. In each case, visual observations concerning the clarity of the composition were recorded. The results are shown in Table 6.  
                                   TABLE 6                       Component   6A1   6A2   6B1   6B2   6C*                   Olopatadine HCl   0.665 (3)    Same   0.665 (3)    Same   0.665 (4)        Benzalkonium   0.01 (5)   Same   0.01 (2)   Same   0.01 (3)       Chloride       Disodium EDTA   0.01 (4)   Same   0.01 (1)   Same   0.01 (2)       Sodium Chloride    0.8 (1)   Same   —   Added 0.8% to existing    0.8 (1)                       solution       Dibasic Sodium   —   Added 0.5% to existing   —   —   —       Phosphate       solution       Sodium   2 drops added (2)   Same   —   Same   pH to 3.7       Hydroxide   qs pH to 3.7 (6)       Purified Water   qs 100%   Same   qs 100%   Same   qs 100%       Batch Size   50 mL   25 mL   50 mL   25 mL   50 mL       Initial pH   3.329   —   2.838   —   2.873       1N NaOH added   0.087 g   —   0.343 g   —   0.318 g       Final pH   3.667   —   3.730   —   3.714       Observations:   Upon addition of   25 mL portion of batch   Upon addition of   25 mL portion of batch   Upon addition of           olopatadine HCl, solution   1 - phosphate added and   olopatadine HCl, solution   2 - NaCl added and   olopatadine HCl, the           appeared cloudy with   allowed to stir. Within 10   appeared cloudy with   allowed to stir. After   solution appeared cloudy           many small white   minutes, the solution   many small white   10 minutes of stirring,   with many white           suspended particles   appeared clear   suspended particles   the solution remained   suspended particles                       clear           After addition of EDTA   After one day without   After 2 minutes of   After one day without   After 5 minutes of           and BAC, the solution   stirring, solution   stirring, the solution   stirring, solution   stirring, the solution           appeared the same   appeared clear with a   began to clear, still with   appeared clear with 2   began to clear, still with               few extraneous fibers   few many white particles   small white flakey   many small white               (7:30 am)       particles and a few   suspended particles                       extraneous fibers                       (7:30 am)           pH was adjusted to 3.7   Later that day (2:45 pm)   After 5 additional   Later that day (2:45 pm)   After 20 minutes of           and allowed to stir for 30   batch was observed to be   of stirring, the solution   the batch appeared clear   stirring, the solution           minutes, appearance was   clear with many crystals   was clear   with very few (˜3-4)   remained clear with           the same   formed at the bottom of       small white flakey   many small white               the beaker       particles and a few   suspended particles                       extraneous fibers           After one day without   Next day (8:00 am),   After pH adjust and qs to   Next day (8:00 am), the   After 30 additional           stirring, the solution   batch remained the same   100%, the batch   batch remained the same   minutes of stirring, the           appeared clear with many       remained clear       solution remained the           small white particles at               same           the bottom of the beaker           (7:30 am)           Next day (8:00 am),       After one day without       After pH adjust and qs to           batch remained the       stirring, the solution       100%, the solution was           same.       remained clear (7:30 am)       allowed to stir and                           appeared the same                   Next day (8:00 am) batch       After one day without                   remained the same       stirring, the solution                           appeared clear with many                           small white particles                           settled at the bottom of                           the beaker                 Note:            Number in parenthesis refers to order of addition of components.            *Hot purified water (˜70° C.) was used.             
 
       EXAMPLE 10  
     Buffer Capacity of Phosphate Buffer  
       [0049]     The contribution of phosphate buffer to the buffer capacity of the composition of Example 1 was determined in a classical acid-base titration experiment. The results are shown in  FIG. 5 . The buffer capacity of the composition of Example 1 (without phosphate buffer) was 2.66 from pH 3.5-3.8 and 2.7 from pH 3.5-3.9. The buffer capacity of the composition of Example 1 (i.e., including phosphate buffer) was 2.93 from pH 3.5-3.8 and 3.1 from pH 3.5-3.8.  
       EXAMPLE 11  
     Stability of Olopatadine Nasal Spray Compositions Lacking Phosphate Buffer  
       [0050]     The compositions (without phosphate buffer) shown below in Table 7A were prepared. Visual observations of the clarity of each composition were recorded as each composition was prepared. The results are shown in Table 7A.  
                                                           TABLE 7A                                       7A   7B   7C            Component   % w/v                    Olopatadine HCl   0.665 (2)   0.665 (4)    0.665 (5)        Benzalkonium   —   0.01 (3)   0.01 (4)       Chloride       Disodium EDTA   —   0.01 (2)   0.01 (3)       Sodium Chloride    0.8 (3)    0.8 (5)    0.8 (2)       Sodium Hydroxide   Adjust pH to 3.95   Adjust pH to 3.95   Adjust pH to 3.95       Hydrochloric Acid   Adjust pH to 3.95   Adjust pH to 3.95   Adjust pH to 3.95       Purified Water   qs 100% (1)   qs 100% (1)   qs 100% (1)       Batch Size   200 ml   200 mL   200 mL       Osmolality   286   286   n/a       Initial pH   2.898   2.930   3.098       Final pH   3.947   3.952   3.957       Observations:   Upon addition of drug, the solution   Upon addition of drug, solution appeared   Upon addition of drug, the solution           appeared cloudy with many large flakey   cloudy with many large flakey particles;   appeared cloudy with many large flakey           particles, after approx 20 minutes, the   within approx 25 minutes, solution   particles. After 3 hours of stirring the           solution appeared clear with very few   appeared clear with very few fibrous/small   solution remained cloudy with many           fibrous/small white particles (pH 2.845)   white particles (pH 2.880)   suspended particles           Upon addition of NaCl, solution remained   Upon addition of NaCl, solution remained   After pH adjust and final qs, the solution           the same (pH 2.898)   the same (pH 2.930)   remained cloudy with many suspended           After pH adjust, final qs and several   After pH adjust, final qs and several   particles (while stirring)           minutes of stirring, the final solution   minutes of stirring, the final solution           appeared clear with some fibrous   appeared clear with some fibrous           particles and a few small white   particles and a few small white           particles   particles                 Note:            Numbers in parenthesis next to the components represents the order of addition.             
 
         [0051]     Each of the compositions was then split. One portion of each was split again into three storage batches (“pre-filtration”) and the other portion was filtered through a 0.2 μM filter and then split into three storage batches (“post-filtration”). One of the storage batches of each set was stored at room temperature (˜22° C.), one in the refrigerator (˜4° C.), and one subjected to freeze-thaw cycling (one day in the freezer (˜−20° C.) and one day at room temperature, except over the weekends). Visual observations of the clarity of each sample of Formulation 7A (lacking BAC and EDTA) were recorded on the indicated days and the results were recorded. The results are shown in Tables 7B (pre-filtration) and 7C (post-filtration).  
                                         TABLE 7B                                       7A Pre-Filtration            Observations:   Bottle 1 (at RT)   Bottle 2 (at 4° C.)   Bottle 3 (at FTC a )               Initial   Clear, many fibrous particles, a few   Clear, many fibrous particles, a few   Clear, many fibrous particles, a few           small white particles   small white particles   small white particles       Day 1   Clear, some fibrous particles, a few   Same   FT Cycle 1 - same           small white particles       Day 2   Same   Same   FT Cycle 2 - same       Day 5   Clear, many fibrous particles, some   Same   FT Cycle 3 - same           small white particles       Day 6   Same   Same   FT Cycle 4 - same       Day 7   Same   Same   FT Cycle 5 - same       Day 8   Same   Same   FT Cycle 6 - Clear, many fibrous and       Day 9   Same   Same   small white particles       Day 12   Same   Clear, many fibrous and some small               white particles, crystallization on               bottom/sides of vial       Day 13   Same   Same       Day 14   Clear, many fibrous and small white   Same           particles (more than previous)                 A portion of the pre-filtered solution was transferred into three 20 mL glass vials and placed at the respective storage conditions for visual observation.              a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.             
 
         [0052]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 7C 
               
             
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 7A Post-filtration 
               
             
          
           
               
                 Observations 
                 Bottle 1 (at RT) 
                 Bottle 2 (at 4° C.) 
                 Bottle 3 (at FTC a ) 
               
               
                   
               
               
                 Initial 
                 Clear, very few fibrous particles 
                 Clear, very few fibrous particles 
                 Clear, very few fibrous particles 
               
               
                 Day 1 
                 Clear, a few fibrous particles, 
                 Same 
                 FT Cycle 1 - Clear, few fibrous particles, 
               
               
                   
                 one small white particle 
                   
                 few small white particles 
               
               
                 Day 2 
                 Same 
                 Clear, a few fibrous particles, some small 
                 FT Cycle 2 - Clear, few fibrous particles, 
               
               
                   
                   
                 white particles 
                 very few small white particles 
               
               
                 Day 5 
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles, very few 
                 FT Cycle 3 - same 
               
               
                   
                   
                 small white particles 
               
               
                 Day 6 
                 Same 
                 Same 
                 FT Cycle 4 - same 
               
               
                 Day 7 
                 Same 
                 Same 
                 FT Cycle 5 - same 
               
               
                 Day 8 
                 Same 
                 Same 
                 FT Cycle 6 - same 
               
               
                 Day 9 
                 Same 
                 Same 
               
               
                 Day 12 
                 Same 
                 Same 
               
               
                 Day 13 
                 Same 
                 Same 
               
               
                 Day 14 
                 Same 
                 Clear, a few fibrous and small white 
               
               
                   
                   
                 particles 
               
               
                   
               
               
                   Note:    
               
               
                   A portion of the twice-filtered solution was transferred into three 50 mL media bottles and placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
             
          
         
       
     
         [0053]     After nine days of observation, the post-filtration portion of Formulation 7A was split and a stir bar was added to each sample as a seeding agent (the stir bar was not rotating). Visual observations were recorded and the results are shown in Table 7 D.  
                                                                     TABLE 7D                                       7A Post-filtration                Bottle 1 (at RT)   Bottle 3 (at 4° C.)   Bottle 5 (at FTC a )            Observations   With Stir Bar Added As a Seeding Agent                    Initial b     Clear, a few fibrous particles   Clear, a few fibrous particles   Clear, a few fibrous particles       Day 3   Same   Clear, a few fibrous particles, very few   FT Cycle 1 - Clear, a few fibrous               small white particles   particles, very few small white                   particles       Day 4   Same   Same   FT Cycle 2 - same       Day 5   Same   Same                   a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.              b Initial observations were performed prior to addition of stir bars.             
 
         [0054]     To other portions of composition 7A split after nine days of observation, excess olopatadine (a few small granules) was added to both the pre-filtration and post-filtration samples to determine if seeding would cause olopatadine to precipitate. Visual observations were recorded on the indicated days. The results are shown in Tables 7 E (unfiltered composition) and 7 F (filtered composition).  
                                     TABLE 7E                                       7A Pre-filtration (with excess olopatadine HCl)            Observations   Bottle 1 (at RT)   Bottle 2 (at FTC a )               Initial b     Clear, many fibrous   Clear, many fibrous particles,           particles, some small white   some small white particles           particles       Day 3   Clear, many fibrous/small   FT Cycle 1 - clear, many           white particles (powdery   fibrous/small white particles           settling)   (powdery settling)       Day 4   Same   FT Cycle 2 - same       Day 5   Same                   a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.              b Initial observations were performed prior to addition of excess olopatadine HCl.             
 
         [0055]    
       
         
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 7F 
               
             
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 7A Post-filtration 
               
             
          
           
               
                   
                 Bottle 2 (at RT) 
                 Bottle 4 (at 4° C.) 
                 Bottle 6 (at FTC a ) 
               
             
          
           
               
                 Observations 
                 With Excess Olopatadine HCl Added (1-2 small granules) 
               
               
                   
               
             
          
           
               
                 Initial b   
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
               
               
                 Day 3 
                 Clear, many fibrous and small white 
                 Clear, many fibrous and small white 
                 FT Cycle 1 - Clear, many 
               
               
                   
                 particles 
                 particles (powdery at bottom of vial, 
                 fibrous/small white particles (powdery 
               
               
                   
                   
                 settling) 
                 at bottom of vial, settling) 
               
               
                 Day 4 
                 Same 
                 Same 
                 FT Cycle 2 - same 
               
               
                 Day 5 
                 Same 
                 Same 
               
               
                   
               
               
                   A portion of the solutions that had been through nine days of observations at RT and 4° C. and four FT cycles were transferred into three 20 mL glass vials and spiked with olopatadine HCl. These units were then placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
               
                     b Initial observations were performed prior to addition of excess olopatadine HCl.    
               
             
          
         
       
     
         [0056]     The stability of the composition “7B” (containing BAC and EDTA) was evaluated in the same fashion. The results are shown in Tables 7G (Pre-filtration), 7H (Post-filtration), 7I (with stir bar added after 9 days), 7J (with excess olopatadine added after 9 days; pre-filtration), and 7K (with excess olopatadine added after 9 days; post-filtration).  
                                         TABLE 7G                                       7B Pre-filtration            Observations:   Bottle 1 (at RT)   Bottle 2 (at 4° C.)   Bottle 3 (at FTC a )               Initial   Clear, many fibrous particles, a few   Clear, many fibrous particles, a few   Clear, many fibrous particles, a few           small white particles   small white particles   small white particles       Day 1   Clear, some fibrous particles, small   Same   FT Cycle 1 - Same           white particles       Day 2   Same   Same   FT Cycle 2 - Same       Day 5   Clear, many fibrous particles, some   Same   FT Cycle 3 - Same           small white particles       Day 6   Same   Same   FT Cycle 4 - same       Day 7   Same   Same   FT Cycle 5 - same       Day 8   Same   Same   FT Cycle 6 - Clear, many fibrous and       Day 9   Same   Same   small white particles       Day 12   Same   Same       Day 13   Same   Same       Day 14   Clear, many fibrous and small white   Same           particles (more than previous)                 A portion of the pre-filtered solution was transferred into three 20 mL glass vials and placed at the respective storage conditions for visual observation.              a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.             
 
         [0057]    
       
         
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 7H 
               
             
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 7B Post-filtration 
               
             
          
           
               
                 Observations 
                 Bottle 1 (at RT) 
                 Bottle 2 (at 4° C.) 
                 Bottle 3 (at FTC a ) 
               
               
                   
               
               
                 Initial 
                 Clear, very few fibrous particles 
                 Clear, very few fibrous particles 
                 Clear, very few fibrous particles 
               
               
                 Day 1 
                 Clear, a few fibrous particles 
                 Same 
                 FT Cycle 1 - Clear, few fibrous particles, 
               
               
                   
                   
                   
                 few small white particles 
               
               
                 Day 2 
                 Same 
                 Clear, a few fibrous particles, some small 
                 FT Cycle 2 - Clear, few fibrous particles, 
               
               
                   
                   
                 white particles 
                 very few small white particles 
               
               
                 Day 5 
                 Same 
                 Clear, a few fibrous particles, very few 
                 FT Cycle 3 - same 
               
               
                   
                   
                 small white particles 
               
               
                 Day 6 
                 Same 
                 Same 
                 FT Cycle 4 - same 
               
               
                 Day 7 
                 Same 
                 Same 
                 FT Cycle 5 - same 
               
               
                 Day 8 
                 Same 
                 Same 
                 FT Cycle 6 - same 
               
               
                 Day 9 
                 Same 
                 Same 
               
               
                 Day 12 
                 Same 
                 Clear, a few fibrous and small white 
               
               
                   
                   
                 particles (more than previous) 
               
               
                 Day 13 
                 Same 
                 Clear, a few fibrous/small white particles, 
               
               
                   
                   
                 light layer of crystallization forming on 
               
               
                   
                   
                 bottom/sides of bottle 
               
               
                 Day 14 
                 Same 
                 Same 
               
               
                   
               
               
                   Note:    
               
               
                   A portion of the twice-filtered solution was transferred into three 50 mL media bottles and placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
             
          
         
       
     
         [0058]    
       
         
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 7I 
               
             
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 7B Post-filtration 
               
             
          
           
               
                   
                 Bottle 7 (at RT) 
                 Bottle 9 (at 4° C.) 
                 Bottle 11 (at FTC a ) 
               
             
          
           
               
                 Observations 
                 With Stir Bar Added 
               
               
                   
               
             
          
           
               
                 Initial b   
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
               
               
                 Day 3 
                 Clear, a few fibrous particles, very few 
                 Clear, a few fibrous and small white 
                 FT Cycle 1 - Clear, a few fibrous 
               
               
                   
                 small white particles 
                 particles 
                 particles, very few small white 
               
               
                   
                   
                   
                 particles 
               
               
                 Day 4 
                 Same 
                 Clear, a few fibrous/small white 
                 FT Cycle 2 - Clear, a few fibrous and 
               
               
                   
                   
                 particles, powdery at bottom of vial, 
                 small white particles 
               
               
                   
                   
                 settling 
               
               
                 Day 5 
                 Same 
                 Clear, settling on bottom, many very 
               
               
                   
                   
                 fine white particles 
               
               
                   
               
               
                   Note:    
               
               
                   A portion of the solutions that had been through nine days of observations at RT and 4° C. and four FT cycles were transferred into three 20 mL glass vials with stir bars added and placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
               
                     b Initial observations were performed prior to addition of stir bars.    
               
             
          
         
       
     
         [0059]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE 7J 
               
             
             
               
                   
               
               
                   
               
               
                 Obser- 
                 7B Pre-filtration (with excess olopatadine HCl) 
               
             
          
           
               
                 vations 
                 Bottle 3 (at RT) 
                 Bottle 4 (at FTC a ) 
               
               
                   
               
               
                 Initial b   
                 Clear, many fibrous particles, 
                 Clear, many fibrous particles, 
               
               
                   
                 some small white particles 
                 some small white particles 
               
               
                 Day 3 
                 Clear, many fibrous/small 
                 FT Cycle 1 - clear, many 
               
               
                   
                 white particles (light powdery 
                 fibrous/small white particles 
               
               
                   
                 settling) 
                 (powdery settling) 
               
               
                 Day 4 
                 Same 
                 FT Cycle 2 - same 
               
               
                 Day 5 
                 Same 
               
               
                   
               
               
                   A portion of the pre-filtered solutions that had been through nine days of observations at RT and 4° C. and four FT cycles were transferred into three 20 mL glass vials and spiked with olopatadine HCl. The units were then placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
               
                     b Initial observations were performed prior to addition of excess olopatadine HCl.    
               
             
          
         
       
     
         [0060]    
       
         
               
               
             
               
               
               
               
             
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 7K 
               
             
             
               
                   
                   
               
               
                   
                   
               
               
                   
                 7B Post-filtration 
               
             
          
           
               
                   
                 Bottle 8 (at RT) 
                 Bottle 10 (at 4° C.) 
                 Bottle 12 (at FTC a ) 
               
             
          
           
               
                 Observations 
                 With Excess Olopatadine Added (1-2 small granules) 
               
               
                   
               
             
          
           
               
                 Initial b   
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
                 Clear, a few fibrous particles 
               
               
                 Day 3 
                 Clear, many fibrous and small white 
                 Clear, many fibrous and small white 
                 FT Cycle 1 - Clear, many 
               
               
                   
                 particles 
                 particles (powdery at bottom of vial, 
                 fibrous/small white particles (powdery 
               
               
                   
                   
                 settling) 
                 at bottom of vial, settling) 
               
               
                 Day 4 
                 Same 
                 Clear, many fibrous/small white 
                 FT Cycle 2 - same 
               
               
                   
                   
                 particles, crystallization at bottom of 
               
               
                   
                   
                 vial 
               
               
                 Day 5 
                 Same 
                 Same 
               
               
                   
               
               
                   A portion of the solutions that had been through nine days of observations at RT and 4° C. and four FT cycles were transferred into three 20 mL glass vials and spiked with olopatadine HCl. These units were then placed at the respective storage conditions for visual observation.    
               
               
                     a Freeze-thaw cycle performed at 24 hour freeze/24 hour thaw except over weekends.    
               
               
                     b Initial observations were performed prior to addition of excess olopatadine HCl.    
               
             
          
         
       
     
       EXAMPLE 12  
     Effect of Phosphate Buffer  
       [0061]     The compositions shown below in Table 8 were prepared using a compounding procedure similar to that described in Example 1. In all four cases, the NaCl was added after olopatadine during the compounding. All four compositions contained the equivalent of 110% of a 0.6% targeted concentration. Two of the compositions were formulated at a pH of 3.95 and two at 4.10 to test an extreme condition. The results are shown in Table 8.  
                                                         TABLE 8                                   Formulation 12A   Formulation 12B   Formulation 12C   Formulation 12D           % (w/v)   % (w/v)   % (w/v)   % (w/v)                                    Olopatadine HCl   0.732   0.732   0.732   0.732       Benzalkonium Chloride   0.01   0.01   0.01   0.01       Disodium EDTA   0.01   0.01   0.01   0.01       Sodium Chloride   0.41   0.41   0.8   0.8       Dibasic Sodium Phosphate,   0.5   0.5   —   —       Anhydrous       Sodium Hydroxide   pH to 3.95   pH to 4.10   pH to 3.95   pH to 4.10       Hydrochloric Acid   pH to 3.95   pH to 4.10   pH to 3.95   pH to 4.10       Purified Water   qs 100%   qs 100%   qs 100%   qs 100%       Visual Observations:       Initial   Clear solution   Clear solution   Clear solution   Clear solution       Room Temperature (4 days)   Remained clear   Remained clear   Remained clear   Remained clear       4° C. (4 days)   Remained clear on   Remained clear on days 1, 2,   Remained clear on days 1, 2, 3,   Remained clear on days 1, 2,           days 1, 2, 3 and 4. No   and 3. On day 4, a very small   and 4. No precipitate was   and 3. On day 4, a significant           precipitate was found.   amount of clear crystals   found.   amount of clear crystals formed               formed at the bottom of       at the bottom of the glass vial.               the glass vial.                 Comparing the results of Formulations B and D demonstrates that compositions with phosphate buffer are more stable against crystal formation than compositions without phosphate buffer.             
 
       EXAMPLE 13  
     Storage Stability  
       [0062]     The solution stability of the composition of Example 1 was examined by preparing variations of the composition at the pH&#39;s shown in Table 9 and subjecting the samples to 13 freeze-thaw cycles (same cycles as described in Example 11 above). Following the last cycle, the samples were stored in the freezer for approximately three weeks and then analyzed. The amount of olopatadine (pre- and post-filtration, 0.2 μM filter) was determined by HPLC assay as a percent of the labeled amount (0.6%). The samples were evaluated using four tests of solution clarity: “Nephelos” values were obtained using a turbidimeter (HF Scientific, Inc., Model No. DRT100B); “Clarity” was determined by visual observation using a method similar to the Ph. Eur. (5 th  Edition) method for evaluating solution clarity and degree of opalescence; “Precipitate” was determined by visual inspection and the presence of absence of precipitates was recorded; “Particles by Visual Observation” was determined by visual inspection under a light box where not more than 3 particles per 5 mL sample is considered “essentially particle free.” Osmolality and pH were also determined for each composition. The results are shown in Table 9. In four of the five cases (Samples 1-4), the compositions were clear solutions following the freeze-thaw cycling study, demonstrating the composition of Example 1 is a stable aqueous solution despite the absence of a polymeric physical stability-enhancing agent. The sample that did not remain a clear solution is Sample 5 (pH=4.45).  
                                                                                                                         TABLE 9                                       Olopatadine Assay   Pre filtration Physical Test Results                (% of label)       Particles by                Pre-   Post-   Nephelos 1             Visual   Osmolality           Sample Lot   Filtration   Filtration   (In NTU)   Clarity   Precipitate   Observation   mOsm/Kg   pH                    1   99   100   0.3   Clear,   None   Essentially   280   3.83           99   99       NMT       particle-free                       EP1       2   99   100   0.2   Clear,   None   Essentially   288   3.94           97   99       NMT       particle-free                       EP1       3   100    101   0.2   Clear,   None   Essentially   285   4.01           98   99       NMT       particle-free                       EP1       4    98,   98   0.5   Clear,   None   Essentially   287   4.15            99,   99       NMT       particle-free                       EP1       5   98   98   (a) Crystal   Clear,   None   Essentially   294   4.45           98   98   Form In one   NMT       particle-free                   Test Tube   EP1                   (b) Other                   test tube                   clear                   (0.6, 0.5) 2                     1 Nephelos (Turbidity) of ≦3 NTU is considered clear solution as per Ph. Eur. (5 th  Ed.)              2 Pre and post olopatadine assay, nephalos, clarity, precipitate, particles by visual observation, osmolality and pH were performed using clear solution from second test tube.             
 
         [0063]     This 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 special 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.