AN AQUEOUS TOPICAL SOLUTION

FIELD OF THE INVENTION

The present invention relates to aqueous solutions of olopatadine or its pharmaceutically acceptable salt for topical administration and process for preparation thereof.

BACKGROUND OF THE INVENTION

Olopatadine hydrochloride is a carboxylic acid derivative of doxepin, chemically described as (Z)- I l -[3-dimethylamino propyl idene]-6, l 1-dihydrodibenz [b,e]oxepin-2-acetic acid, hydrochloride [C ₂ , H _r , NO, .HCI], as disclosed in U.S. Pat Nos.4,871 ,865 and 4,923,892 both assigned to Burroughs Wellcome. Olopatadine has antihistamine and antiasthmatic activity.

Olopatadine hydrochloride is commercially available in the U. S as 0.1 % and 0.2% sterile ophthalmic solutions under the brand names PATANOL ^® and PATADA Y ^® respectively, both marketed by Alcon. PATANOL ^® is indicated for the treatment of signs and symptoms of allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01% benzalkonium chloride as preservative, dibasic sodium phosphate, sodium chloride, hydrochloric acid and / or sodium hydroxide (to adjust the pH) and purified water. It has a pH of about 7, and osmolality of about 300mOsm/kg. PATADAY"' is indicated for the treatment of ocular itching associated with allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.2% olopatadine. 0 01 % benzalkonium chloride as preservative, povidone, dibasic sodium phosphate, sodium chloride, edetate disodium, hydrochloric acid and / or sodium hydroxide (to adjust the pH) and purified water It has a pH of about 7, and osmolality of about 300mOsm/kg.

One obstacle for preparing olopatadine hydrochloride aqueous solutions for topical delivery is the stability of the aqueous solutions of olopatadine hydrochloride over the shelf storage period. Olopatadine aqueous solutions of concentrations of 0.17% or higher were found to have physical stability problem when stored over the shelf life of the product. The olopatadine hydrochloride precipitates or crystallizes out of the formulated solution at the concentrations higher than 0.17%. Hence there is a need for preparing a stable, aqueous solutions of olopatadine hydrochloride containing olopatadine in concentrations of about 0.17% or greater, which are stable when stored over the shelf life of the product.

United States Patent No.6,995, 186 (Alcon Inc., 2006, the ' 186 patent) discloses topically administrate solution composition for treating allergic or inflammatory disorders of the eye and nose comprising olopatadine and a polymeric ingredient, where the polymeric ingredient is a polymeric physical stability enhancing ingredient consisting essentially of polyvinylpyrrolidone or polystyrene sulfonic acid in an amount sufficient to enhance the physical stability of the solution, and wherein the composition does not contain polyvinyl alcohol, polyvinyl acrylic acid. hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, xanthan gum. Polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodium carboxy methyl cellulose and xanthan gum have been disclosed in the ' 186 patent to cause physical instability of olopatadine solutions.

lnorder to overcome the physical stability problems associated with olopatadine aqueous solutions, we have tried various ingredients selected from hydroxypiOpyl-β-cyclodextrin (HPβCD). polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose 2910 (HPMC E4M premium), polyvinylpyrrolidone K-30, xanthan gum, sodium carboxymethylcellulose (Sodium CMC), carbopol 934P, polyvinyl alcohol, tyloxapol, vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids and mixtures thereof. Our copending application No: 748/MUM/2006, filed on 15 ^th May 2006 discloses, stable olopatadine hydrochloride solutions containing hydroxypropyl-β-cyclodextrin as the stability enhancing ingredient so as enhance the physical stability of the solution.

We have now surprisingly found that stable aqueous topical solutions of olopatadine hydrochloride can be prepared by using solublizers selected from tyloxapol or vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids and mixtures thereof.

SUMMARY OF THE INVENTION

In one aspect of the invention there is provided an aqueous topical solution comprising a therapeutically active ingredient consisting essentially of olopatadine or its pharmaceutically acceptable salt and a solubilizer selected from a group consisting of tyloxapol, vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids and mixtures thereof, wherein the aqueous topical solution is stable.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an aqueous topical solution comprising a therapeutically active ingredient consisting essentially of olopatadine or its pharmaceutically acceptable salt and a solubilizer selected from a group consisting of tyloxapol, vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids and mixtures thereof, wherein the aqueous topical solution is stable. The present invention also provides topical olopatadine hydrochloride aqueous solutions that are effective for treating allergic or inflammatory disorders of the nose or eye.

According to one embodiment of the present invention, the aqueous topical solution comprises olopatadine or its pharmaceutically acceptable salt, in concentrations ranging from about 0.1 7% to about 0.65%w/v of the solution. The solublizers are selected from tyloxapol or vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids. Tyloxapol may be used in concentrations ranging from about 0.01% to about 1.0% w/v of the solution and vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids may be used in concentrations ranging from about 0.01 % to about 1.0% w/v of the solution.

Unless indicated otherwise, all component concentrations are presented on a %(w/v) basis and all references to olopatadine are to olopatadine free base.

According to one embodiment of the present invention, the aqueous topical solution contains olopatadine or its pharmaceutically acceptable salts. Examples of the pharmaceutically acceptable salts of olopatadine includes 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 lriethylamine addition salt (also known as tromethamine). morpholine addition salt and piperidine addition salt. In a preferred embodiment of the present invention, the olopatadine for use in the aqueous topical solution is a hydrochloride salt. In a most preferred embodiment of the present invention, the olopatadine hydrochloride salt may be used in concentrations such that it is equivalent to the olopatadine free base ranging from about 0.17% to about 0.65%. Preferably, the solution formulations intended for use in the eye contain about 0.17% to about 0.25%

olopatadine and the solution formulations intended for use in the nose contain about 0.35% to about 0.65% olopatadine.

According to one embodiment of the present invention, the aqueous topical solution comprises vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids or tyloxapol. Vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids and tyloxapol are commercially available from variety of sources in different grades.

The term "'vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids" as used herein refers to diesters of a dicarboxylic acid wherein the two ester linkages occur to a phenolic hydroxy! group of the tocopherol and a hydroxy! group of polyethylene glycol. Polyethylene glycol is HO(CH ? CH ₂ O) _n H, otherwise known as polyoxyethylene glycol. The term ^■■ tocopherol" as used herein refers to a naturally occurring form of vitamin E, and may refer to a single compound or a mixture. Examples of tocopherols include α-tocopherol, dl-α-tocopherol, β- tocopherol, γ-tocopherol and δ-tocopherol. Polyethylene. glycol is the well known polymer of ethylene glycol. In vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids the polyethylene glycol moiety of the ester has a molecular weight in the range from about 600 to about 6000. preferably in the range from about 600 to about 1500. Such esters and methods for their preparation are disclosed in U.S. Pat. No. 2,680,749 (Cawley et al.). The most preferred ester is the α-tocopheryl polyoxyethylene glycol 1000 succinate (vitamin E TPGS), a polyoxyelhylene glycol ester of α-tocopheryl succinate wherein the polyoxyethylene glycol moiety of the molecule has an average molecular weight of about 1000. In a preferred embodiment of the present invention, the vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids in the aqueous topical solution may be used in concentrations ranging from about 0.01 % to about 1% and more preferably used in concentrations ranging from about 0.01% to about 0.5%. Generally, for solutions meant for ophthalmic administration preferable concentration of vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids is in the range from about 0.01 % to about 0.1 %; and for solutions meant for nasal administration, the concentration of vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids is in the range from about 0.1 % to about 0.5%.

Tyloxapol is a non-ionic surfactant of the alkyl aryl polyether alcohol type, also known as superinone or triton. Chemically it is known as 4-(l , l ,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane, and is commercially available from Rohm and Haas as Triton ^~ X-200 and from Sigma Aldrich Chemicals. In a preferred embodiment of the present invention, the

tyloxapol in llic aqueous topical solution will be used in concentrations ranging from about 0.01 % to about 1 % and more preferably used in concentrations ranging from about 0.01 % to about 0.5%. Generally, for solutions meant for ophthalmic administration preferable concentration of tyloxapol is in the range from about 0.01% to about 0.1 %; and for solutions meant for nasal administration, the concentration of tyloxapol is in the range from about 0.1% to about 0.3%.

The aqueous topical solution of the present invention may further include pharmaceutically acceptable excipients so as to provide a suitable carrier for the aqueous solution. The pharmaceutically acceptable carrier in the pharmaceutical aqueous topical solution of the present invention may be selected from water (water for injection) or an aqueous system (that is an aqueous vehicle) comprising at least a major proportion of water. The carrier may include other liquid vehicles that are conventionally used in topical eye and nose preparations.

The aqueous topical solution of the present invention may include an effective amount of an antimicrobial preservative. Examples of pharmaceutically acceptable preservatives that may be used in the present invention include, but are not limited to, benzethonium chloride, butylparaben, methyl paraben. ethyl paraben, propyl paraben, benzalkonium chloride, cetyl pyridinium chloride, thimerosal. chlorobiitanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate. sorbic acid and the like and mixtures thereof. The preferred preservative for the aqueous topical solution of the present invention is benzalkonium chloride. It may be used in concentrations ranging from about 0.005% to about 1%.

The aqueous topical solution of the present invention may include an effective amount of a chelating agent. Chelating agents remove trace amounts .of metal ions such as iron, copper and lead and acts as antioxidant synergist as otherwise these heavy metals catalyze oxidation reactions. Presently preferred chelating agents include different salts of edetic acid. These non- exclusively include edetate disodium, edetate calcium disodium, edetate tetrasodium. edetate trisodium. malic acid and the like and mixtures thereof. The preferred chelating agent for the aqueous topical solution of the present invention is disodium edetate. It may be used in concentrations ranging from about 0.005% to about 0.1 %.

The aqueous topical solution of the present invention may further include an effective amount of a tonicity agent. Examples of tonicity agents that may be used in the aqueous topical solution of the present invention include all pharmaceutically acceptable and pharmacologically inert water-

soluble compounds referred to in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Easton, Pennsylvania ( 1995). Preferred tonicity agent is sodium chloride, which may be added in an amount which renders the solution isoosmotic. The aqueous topical solution is intended to be administered as nasal solution or eye drops. The osmolality may be adjusted between 150 to 450 mOsm and more preferably between 250 to 350 mOsm.

The aqueous topical solution of the present invention may include an effective amount of buffering agent. The buffering agents are included to minimize any change in pH during shelf life of the aqueous topical solution. Examples of buffering agents include, but are not limited to, lactic acid, citric acid, tartaric acid, phosphoric acid, acetic acid, hydrochloric acid, nitric acid, tromethamine, sodium or potassium metaphosphate, sodium or potassium phosphate, dibasic sodium phosphate dodecahydrate, sodium or potassium acetate, ammonia, sodium carbonate, sodium or potassium hydroxide, dibasic sodium phosphate, sodium borate, and the like and mixtures thereof. Strong mineral acids like hydrochloric acid or strong bases such as sodium hydroxide may be used for adjusting pH. The pH of the aqueous topical solution intended for ophthalmic use have a pH 4 to 8, preferably a pH of 6.5 to7.5, and most preferably a pH of6.8 to 7.2. The aqueous topical solution intended to be administered to the nose have a pH adjusted between 3.0 to 6.0 and most preferably between 3.5 to 5.0.

The aqueous topical solution of the present invention may optionally include an effective amount of an antioxidant. The antioxidant may be one or more antioxidants, reducing agents and antioxidant synergist. The antioxidants may be one or more of acetyl cysteine, alpha tocopherol acetate, d-alpha tocopherol, dl-alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole (BHA). butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride and propyl gallate. The reducing agents may be one or more of ascorbic acid, calcium ascorbate, calcium bisulphate, calcium sulphite, ascorbic acid, isoascorbic acid, potassium metabi sulfite, sodium ascorbate, sodium bisulphate. sodium metabisulphite, sodium • sulphite, sodium thiosulphate and thioglycerol. The antioxidant synergist may be one or more of citric acid , edetic acid(EDTA) and its salts, hvdroxyquinoline sulphate, phosphoric acid, sodium citrate and tartaric acid. The antioxidants are used in amounts conventional to the pharmaceutical art.

The aqueous topical solution of the present invention may optionally include an effective amount of viscosity enhancer. An increase in viscosity of topical solutions will result in a longer

residence time in eye or nose, providing a longer time for drug absorption and effect. The list of viscosity enhancers that are conventionally used for topical solutions are given in the pharmacopoeias such as United States Pharmacopoeia, as well as in Remington: The Science and Practice of Pharmacy; edition 19; Mack Publishing Company, Eastoπ. Pennsylvania ( 1995). The viscosity enhancers are used in concentrations conventional to the pharmaceutical art.

The aqueous topical solution of the present invention is physically and chemically stable. The term '"chemically stable" as used herein means that the aqueous topical solution when stored on the shelf for up to two years has less than 2% total degradation products as determined by the area normalization method. The chemical stability may be assessed by accelerated stability testing. The aqueous topical solution of the present invention may be stored in a closed container at 30 ⁰ C / 65% relative humidity or 40 ⁰ C / 75% relative humidity or 2-8 ⁰ C (refrigeration condition) and analyzed at one month duration for up to three months or six months. It is generally accepted that a product is stable on the shelf over a period of two years, if the product is stable for three months at an accelerated stability test condition of 40 ⁰ C / 75% relative humidity.

The term "physically stable" as used herein means that when aqueous topical solution of the present invention is stored in a closed container crystals of olopatadine do not appear.

The chemical stability is assessed by evaluating the percent total degradation products in , olopatadine aqueous topical solutions that are subjected to an accelerated stability test conditions or ambient conditions using high performance liquid chromatography (HPLC). The chromatographic conditions for analyzing the degradation of olopatadine and the procedure for calculating the percent total degradation products in olopatadine aqueous topical solution is given below:

Column : Hypersil BDS C ₈ (250 X 4.6)

Flow rate : 1.0 ml/min

Temperature Ambient Detection 210 n m

Concentration 50/65 ppm Injection volume 20μl Run time 40 min Mobile Phase Buffer : Acetonitrile (720 : 280)

Buffer : 6.8 gin KHjPO ₄ is dissolved in 1000ml of water and the solution is adjusted to a pH of 4.5 with orthophosphoric acid. Retention time : 10.5 nϊin

Diluent : Mobile phase Standard preparation : 50/65 mg olopatadine HCl is dissolved in 100 ml with mobile phase.

A sample of 5 ml is diluted to 50 ml with mobile phase Test preparation : 2 ml of the olopatadine HCl solution is diluted with 200 ml of mobile phase

The percent total degradation products in the olopatadine aqueous topical solution is calculated by area normalization method (excluding peaks from placebo and diluent, if any) from the chromatogram obtained by injecting 20μl of test preparation as described above in chromatographic conditions for analyzing degradation of olopatadine. The formula for calculating the percent total degradation products in olopatadine aqueous topical solution is given below:

Peak area of individual degradation product

% Individual degradation product = X 100

Total area of all the peaks

% Total degradation products = Sum of all % individual degradation products

For llnished dosage forms (for example - tablets, solutions, etc) the value of percent individual degradation product should not be more than 1% and the percent total degradation products should not be more than 2%. A value of percent total degradation products lesser than 2% in the aqueous topical solution of the present invention is considered to be acceptable.

According to one embodiment of the present invention, the aqueous topical solution may be prepared by the following process: a. Dissolving vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids or tyloxapol in water for injection at 60 ⁰ C to 70 ⁰ C temperature and stirring to get a clear solution, b Dissolving olopatadine hydrochloride in water for injection and adding to the solution prepared in step (a).

c. Dissolving tonicity agent, buffering agent, chelating agent and antimicrobial preservative in die bulk solution prepared in step (a) and stirring to get clear solution. d. Adjusting of pH of the solution between 3.5-5.0 for nasal solution and between 6.8-7.2 for ophthalmic solution with hydrochloric acid and sodium hydroxide. e. Final adjustment of volume with water for injection apd measuring pH. f. Filtering of the solution through 2μm prefilter and then through 0.2μm nylon 66 membrane filter and transferring the solutions to sterile containers.

The aqueous topical solution of the present invention may be formulated to be dispensed in suitable containers as drops, sprays, metered sprays, aerosols and metered aerosols. The aqueous topical solution to be delivered as sprays may be filled in containers fitted with a spray pump with or without a metering valve. The aqueous topical solution to be delivered as aerosols may be filled into canisters suitable for delivering pharmaceutical aerosols. Canisters generally comprise a container capable of withstanding the vapour pressure of the propellant used such as a plastic or plastic-coated glass bottle or preferably a metal can, for example an aluminium can which may optionally be anodized, lacquer-coated and / or plastic-coated, which container is closed with a metering valve. The metering valves are designed to deliver a metered amount of the aqueous solution per actuation and incorporate gasket to prevent leakage of propellant through the valve.

In a preferred embodiment of the present invention, the aqueous topical solution is packed in. opaque plastic or glass containers. In a more preferred embodiment of the present invention, the container for an ophthalmic solution is an opaque, white low-density polyethylene container that has been sterilized using ethylene oxide like lupolen bottle. In another preferred embodiment of the present invention, the container for a nasal solution is a U. S. P type I amber color glass containers equipped with a nasal spray pump.

It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present invention. Therefore, it should be clearly understood that the following examples are illustrative only and are not intended to limit the scope of the present invention.

EXAMPLE 1

A topically administrable nasal solution of the present invention comprising olopatadine hydrochloride and vitamin E TPGS was prepared as described in table I below.

Table 1

*0.527% Olopatadine hydrochloride is equivalent to 0.5% Olopatadine free base Manufacturing Process

1 Vitamin E TPGS (Tocopheryl Polyethylene Glycol 1000 Succinate) is dissolved in water for injection at 60 ⁰ C to 70 ⁰ C temperature and stirred to get a clear solution.

2 Olopatadine hydrochloride is dissolved in water for injection, and added to the above solution under stirring.

3 Sodium chloride, dibasic sodium phosphate anhydrous and benzalkonium chloride (50%) solution are added to above bulk and stirred to get a clear solution.

4 The pH of the solution is adjusted such that it is between 3.5-5.0 using 5.0%v/v hydrochloric acid and 2.0%w/v with sodium hydroxide.

5 Final volume is made up with water for injection.

6 The solution is filtered through 2.0μm prefilter and 0.2μm nylon 66 membrane filter and transferred to U. S. P. type 1 amber glass containers.

EXAMPLE 2

Olopatadine hydrochloride aqueous, nasal solution containing vitamin E TPGS at concentrations of 0 1 %w/v and 0.5%w/v which were prepared in example 1 and as shown in table 1 , were packed in vials and stored at 30 ⁰ C / 65% relative humidity, 40 ⁰ C / 75% relative humidity and 2- 8 ⁰ C (refrigeration condition) for a period up to three months. The samples were analyzed using high performance liquid chromatography (HPLC) having hypersil BDS C _s column (250 X 4.6).

The percent total degradation products in olopatadine aqueous topical solution were calculated by area normalization method and the results obtained are summarized in table 2 below.

Table 2

EXAMPLE 3

Olopatadine hydrochloride aqueous, nasal solution containing vitamin E TPGS at concentrations of 0.1 and 0.5%\v/v which were prepared in example 1 and as shown in table I , were packed in vials and were stored at 30 ⁰ C / 65% relative humidity, 40 ⁰ C / 75% relative humidity and 2-8 ⁰ C (refrigeration temperature) for a period up to three months. The samples were observed visually at an interval of one month for a period up to three months and the solution was found to be clear without any crystallization or precipitation of olopatadine. The results are summarized in table 3 below.

Table 3

EXAMPLE 4

A topically administrable nasal solution of the present invention comprising olopatadine hydrochloride and tyloxapol was prepared as described in table 4 below.

Table 4

*0.665% Olopatadine hydrochloride is equivalent to 0.6% Olopatadine free base Manufacturing Process

1 Tyloxapol is dissolved in water for injection at 60 ⁰ C to 70 ⁰ C temperature and stirred to get a clear solution.

2 Olopatadine hydrochloride is dissolved in water for injection and added to the above solution under stirring.

3 Sodium chloride, dibasic sodium phosphate anhydrous and benzalkonium chloride (50%) solution are added to above bulk and stirred to get a clear solution.

4 The pH of the' solution is adjusted such that it is between 3.5-5.0 using 5.0%v/v hydrochloric acid and 2.0%w/v with sodium hydroxide.

5 Final volume is made up with water for injection.

6 The solution is filtered through 2.0μm prefilter and then through 0.2μm nylon 66 membrane filter and transferred to U. S. P. type I amber glass containers.

EXAMPLE 5

Olopatadine hydrochloride aqueous, nasal solution containing tyloxapol at concentrations of 0.1 , 0.2 and 0.3%\v/v, which were prepared in example 4 and shown in table 4, were packed in vials and stored at 30 ⁰ C / 65% relative humidity, 40 ⁰ C / 75% relative humidity and 2-8 ⁰ C (refrigeration temperature) for a period up to six months. The samples were analyzed using high performance liquid chromatography (HPLC) having hypersil BDS C ₈ column (250 X 4.6). The percent total degradation products in olopatadine aqueous topical solution is calculated by area normalization method and the results obtained are summarized in table 5 below.

Table 5

EXAMPLE 6

Olopatadine hydrochloride aqueous, nasal solutions containing tyloxapol at concentrations of 0 l %w/v. 0.2%\v/v and 0.3%w/v, which were prepared in example 4 and shown in table 4, were packed in vials and stored at 30 ⁰ C / 65% relative humidity, 40 ⁰ C / 75% relative humidity and 2- 8 ⁰ C (refrigeration condition) for a period up to six months. The samples were observed visually at an interval of one month for a period up to six months and the solutions were found to be clear without any crystallization or precipitation of olopatadine. The results are summarized in table 6 below

Table 6

EXAMPLE 7

A topically admin istrab Ie ophthalmic solution of the invention comprising olopatadinc hydrochloride and vitamin E TPGS was prepared as described in table 7 below.

Table 7

Quantity (%w/v)

Ingredients

Composition G

Olopatadine hydrochloride 0.22*

Vitamin E TPGS 0.05

Benzalkonium chloride solution (50%) 0.02

Sodium chloride 0.80

Dibasic sodium phosphate anhydrous 0.28

Di sod iu in edetate 0.01

NaOH / HCI q.s. pH 6.8-7.2

Water for Injection q.s. to 100

*0 22% Olopatadine hydrochloride is equivalent to 0.2% Olopatadine free base

Manufacturing Process

1 Vitamin E TPGS (Tocopheryl Polyethylene Glycol 1000 Succinate) is dissolved in water tor injection at 60 ⁰ C to 70 ⁰ C temperature and stirred to get a clear solution.

2 Olopatadine Hydrochloride is dissolved in water for injection, and added to the above solution under stirring.

3 Sodium chloride, di sodium edetate, dibasic sodium phosphate anhydrous and benzalkonium chloride (50%) solution are added to above bulk and stirred to get a clear solution.

4 The pH of the solution is adjusted such that it is between 6.8-7.2 using 5.0%v/v hydrochloric acid and 2.0%w/v with sodium hydroxide.

5 Final volume is made up with water for injection and pH of the solution is measured.

6 The solution is filtered through 2.0μm prefilter and then through 0.2μm nylon 66 membrane filter and transferred to 5 ml sterile lupolen bottle.

EXAMPLE 8

A topically aclministrable ophthalmic solution of the present invention comprising olopatadine hydrochloride and tyloxapol was prepared as described in table 8 below.

Table 8

Quantity (%w/v)

Ingredients

Composition H

Olopatadine hydrochloride 0.22*

Tyloxapol 0.05

Benzalkonium chloride solution (50%) 0.02

Sodium chloride 0.80

Dibasic sodium phosphate anhydrous 0.28

Di sod in m edetate 0.01

NaOH / HCI q.s. pH 6.8-7.2

Water for Injection q.s. 100

*0.22% Olopatadine hydrochloride is equivalent to 0.2% Olopatadine free base

Manufacturing Process

1 Tyloxapol is dissolved in water for injection at 60 ⁰ C to 70 ⁰ C temperature and stirred to get a clear solution.

2 Olopatadine hydrochloride is dissolved in water for injection, and added to the above solution under stirring.

3 Sodium chloride, disodium edetate, dibasic ■ sodium phosphate anhydrous and benzalkonium chloride (50%) solution are added to above bulk and stirred to get a clear solution.

4 The pH of the solution is measured and adjusted such that it is between 6.8-7.2 using 5.0%v/v hydrochloric acid and 2.0%w/v with sodium hydroxide.

5 Final volume is made up with water for injection and pH of the solution is measured.

6 The solution is filtered through 2.0μm prefilter and then through 0.2μm nylon 66 membrane filter and transferred to 5 ml sterile lupolen bottle.

EXAMPLE 9

Olopatadine hydrochloride aqueous solution containing vitamin E TPGS or tyloxapol at concentrations of 0.05%w/v which were prepared in example 4, example 7 and example 8, were packed in vials and stored at 30 ⁰ C / 65% relative humidity and at 40 ⁰ C / 75% relative humidity and 2-8 ⁰ C (refrigeration condition), for a period of six months. The samples were analyzed using high performance liquid chromatography (HPLC) having hypersil BDS C ₈ column (250 X 4.6). The percent total degradation products in olopatadine aqueous topical solution were calculated by area normalization method and the results obtained are summarized in table 9 below. No crystallization or precipitation was observed at the end of one month.

Table 9

EXAMPLE 10

Olopatadine hydrochloride aqueous solutions containing vitamin E TPGS or tyloxapol at concentrations of 0.05%w/v which were prepared in example 4, example 7 and example 8, were packed in vials and stored at 30 ⁰ C / 65% relative humidity and at 40 ⁰ C / 75% relative humidity and 2-8 C (refrigeration condition), for a period of six months. The samples were observed visually at an interval of one month for a period of six months and the solutions were found to be clear without any crystallization or precipitation of olopatadine. The results are summarized in table 10 below.

Table 10

COMPARATIVE EXAMPLES A-M

The compositions shown in table 1 1 and table 12 below were prepared and subjected to stability studies for evaluating the physical stability. The vials were studied for stability at two temperature conditions: one at room temperature (25° ± 2 ⁰ C) and the other at refrigeration temperature (2-8 ⁰ C) condition for a period of 14 days.

Table 11

Table 12

20

The compositions of comparative examples A-M shown in table 1 1 and table 12 were visually inspected at the end of 14 days for evaluating physical stability. The solutions were found to have crystals or the solutions were not clear at the end of 14 days. The results obtained are summarized in table 13 below.

Table 13

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.