Field of the invention

The present invention relates to anti-allergic topical ophthalmic solution of dibenzoxepin derivative. Particularly the present invention relates to an anti¬allergic topical ophthalmic solution of olopatadine and its pharmaceutically acceptable salt.

Background of the invention

Olopatadine is a carboxylic acid derivative of doxepin and is first disclosed in US 4,871,865, US 5,641,805, is a relatively selective H,-receptor antagonist and is used in the treatment of allergic eye diseases. Chemically, it is designated as 1 l-[(Z)-3-(dimethylamino)propylidene]-6-l l-dihydrodibenz[b,e] oxepin-2-acetic acid.

Commercially it is available as ophthalmic solution marketed under the trade name Patanol® or Pataday® and as nasal spray under the trade name Patanase®. Patanol® contains 0.1% of olopatadine hydrochloride as active ingredient and the inactive ingredients include benzalkonium chloride 0.01 %, dibasic sodium phosphate, sodium chloride, hydrochloric acid/ sodium hydroxide (to adjust the pH) and purified water. Pataday® contains 0.2% of olopatadine hydrochloride as active ingredient and the inactive ingredients include benzalkonium chloride, povidone, dibasic sodium phosphate, sodium chloride, edetate disodium, hydrochloric acid / sodium hydroxide (to adjust the pH) and purified water.

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%. To overcome this, US 6,995,186 and US 7,402,609 discloses topical solution comprising 0.17-0.62% (w/v) of olopatadine and a polymeric 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 has a viscosity of 1-2 cps, and does not contain polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodiumcarboxy methylcellulose or xanthan gum.

US '186 further discloses that polyvinylpyrrolidone or polystyrene sulfonic acid enhances the physical stability of solutions containing 0.17-0.62% (w/v) of olopatadine and further discloses that the solutions at the viscosity of 1-2 cps does not cause blurring, and is easily processed during manufacturing, transfer and filling operations.

US '186 further discloses that topical solutions containing 0.2 % of olopatadine and 0.1% of polyvinyl alcohol produces fibre like particles when subjected to stability studies.

US 6,375,973 discloses benzalkonium chloride free compositions of olopatadine that comprise polyquaternium-1 as a preservative and are suitable for patients wearing contact lenses.

US 6,743,439 discloses a preserved, aqueous pharmaceutical solution composition comprising olopatadine, a cationic preservative, and a sulfonated styrene/maleic anhydride copolymer.

US 2005/0209312 discloses composition comprising olopatadine and stabilized chlorine dioxide or saccharide as preservative.

US 2010/0227917 discloses an eye drop comprising olopatadine and a polyvalent weak acid, an acidic amino acid or a basic amino acid.

WO 2008/015695 A2 discloses an inclusion complex of olopatadine or its pharmaceutically acceptable salt and hydroxyalkyl-P-cylcodextrin.
WO 2008/093358 A2 discloses topical solution comprising olopatadine and a solubilizer selected from tyloxapol, vitamin E tocopheryl polyethylene glycol diesters of dicarboxylic acids.

EP 2114367 Al discloses a composition consisting 0.54 - 0.62 % of olopatadine hydrochloride, phosphate salt, sodium chloride, benzalkonium chloride, sodium edetate and water and is free of polyvinyl pyrrolidone, polystyrene sulfonic acid, polyvinyl alcohol, polyvinyl acrylic acid, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose or xanthan gum.

IN 2476/MUM/2008 discloses a composition comprising olopatadine and gamma irradiated polyvinyl pyrrolidone.

Few of the above prior art references discloses the compositions of olopatadine using different preservatives such as polyquaternium-1, stabilized chlorine dioxide or saccharide, hydroxyalkyl-|3-cylcodextrin, tyloxapol, vitamin E tocopherol polyethylene glycol diesters of dicarboxylic acids and other references discloses the use of polyvinylpyrrolidone or polystyrene sulfonic acid enhances the physical stability of solutions containing 0.17-0.62% (w/v) of olopatadine. During the development of topical ophthalmic solutions of olopatadine, the inventors of the present invention found that polyvinyl alcohol at a concentration of 1.0 to 1.4% stabilizes the ophthalmic solutions containing 0.2% of olopatadine.

Objective of the invention

Accordingly, the objective of present invention is to provide a stable ophthalmic composition comprising olopatadine or its pharmaceutically acceptable salt that is therapeutically equivalent to reference product.

Summary of the invention

Accordingly, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, less than about 1.8% (w/v) of polyvinyl alcohol, and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to about 1.4% (w/v) of polyvinyl alcohol, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of more than about 2 cps.

In another embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of more than about 2-4 cps.

In yet another embodiment, the present invention also provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to about 1.4% (w/v) of polyvinyl alcohol and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of about 2-4 cps.

Detailed description of the invention

The present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, less than about 1.8% (w/v) of polyvinyl alcohol, and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to about 1.4% (w/v) of polyvinyl alcohol, and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of more than about 2 cps.

In another embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of more than about 2-4 cps.

In yet another embodiment, the present invention also provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to about 1.4% (w/v) of polyvinyl alcohol and one or more pharmaceutically acceptable excipients, wherein the said solution has a viscosity of about 2-4 cps.

In an embodiment of the present invention, the pharmaceutically acceptable excipients are selected from but not limited to a group comprising tonicity adjusting agent, buffer, preservative, chelating agent and pH adjusting agent.
Solutions that are isotonic with the lachrymal secretions cause minimal discomfort to the corneal tissue. Hence, the tonicity of the solution has to be adjusted to maintain the formulation at an osmolality of at least about 300 mOsmol/kg. Suitable tonicity adjusting agent is selected from sodium chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol, sorbitol, glucose and the like, and mixtures thereof.

To stabilize or to maintain the ophthalmic formulation at the desired pH, an effective minor amount of at least one buffer component has to be incorporated into the ophthalmic formulation. Suitable buffer is selected from but not limited to a group comprising phosphate buffer, acetate buffer, borate buffer, citrate buffer, and the like, and mixtures thereof.

Ophthalmic formulations are typically packed in multidose form. In order to inhibit the growth of microbial contaminants and suppress biodegradation, preservatives are added. Suitable preservative is selected from but not limited to a group comprising benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, p-hydroxybenzoate, and the like, and mixtures thereof.

The amount of preservatives may range from about 0.001% to 1.0% (w/v).
Suitable chelating agent is selected from but not limited to edetic acid, edetic acid salts like disodium edetate, sodium edetate, edetate calcium disodium, trisodium edetate and the like, and mixtures thereof.

The compositions of present invention have a pH of about 4 to 8 preferably about 5-8. Suitable pH adjusting agent is selected from but not limited to a group comprising hydrochloric acid, sodium hydroxide, acetic acid, phosphoric acid, and mixtures thereof.

In embodiments, the compositions of the present invention have a viscosity of about 2 to 4 cps, preferably about 2.2 to 3.0 cps.

In a preferred embodiment, the present invention provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt; about 1.0 to 1.4% (w/v) of polyvinyl alcohol; and one or more pharmaceutically acceptable excipients selected from tonicity adjusting agent, buffer, preservative, chelating agent, and pH adjusting agent in a suitable vehicle, wherein the said solution has a viscosity of about 2-4 cps.

The vehicle used according to present invention is water for injection or purified water.

The compositions of the present invention optionally contain chelating agent.
In another embodiment, the present invention also provides a stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt; about 1.0 to 1.4% (w/v) of polyvinyl alcohol; benzalkonium chloride; phosphate buffer; sodium chloride and disodium edentate, wherein said solution has a viscosity of about 2-4 cps.

The pharmaceutical compositions of present invention are packaged in plastic containers, preferred container being a low density polyethylene container that is sterilized using gamma radiation or ethylene oxide.

The present invention also provides a method of treating ocular itching associated with allergic conjunctivitis and signs and symptoms of allergic conjunctivitis by administering a stable ophthalmic composition of the present invention.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1

The processing steps involved in manufacturing Olopatadine ophthalmic solution as given in examples 1 -3 are as follows:

i) water for injection was taken in SS vessel,
ii) polyvinyl alcohol was added to 40% of water for injection of step (i) under
stirring to get a clear solution,
iii) edetate disodium, sodium chloride and dibasic sodium phosphate one by one
was dissolved in 30% of water for injection of step (i), under stirring to get a
clear solution,
iv) the solution of step (ii) was mixed with the solution of step (iii),
v) to the solution of step (iv), benzalkonium chloride was added under stirring
to get a clear solution,
vi) olopatadine hydrochloride was added to the solution of step (v) under
stirring to get a clear solution,
vii) the pH of the solution was checked and adjusted to 7.0 using hydrochloric
acid / sodium hydroxide,
viii) the volume was made up with water for injection,
ix) the solution of step (viii) was filtered using 0.22um filter and filled in LDPE bottle.

The processing steps involved in manufacturing Olopatadine ophthalmic solution as given in example 4 are as follows:

i) water for injection was taken in SS vessel,
ii) polyvinyl alcohol was added to 40% of water for injection of step (i) under stirring to get a clear solution,
iii) sodium chloride and dibasic sodium phosphate one by one was dissolved in
30% of water for injection of step (i), under stirring to get a clear solution,
iv) the solution of step (ii) was mixed with the solution of step (iii),
v) to the solution of step (iv), benzalkonium chloride was added under stirring to get a clear solution,
vi) olopatadine hydrochloride was added to the solution of step (v) under
stirring to get a clear solution,
vii) the pH of the solution was checked and adjusted to 7.0 using hydrochloric acid / sodium hydroxide,
viii) the volume was made up with water for injection,
ix) the solution of step (viii) was filtered using 0.22um filter and filled in LDPE bottle.

The pH and osmolality of the solution prepared according to example-1 & 2
and Pataday ® was measured and the results are given in table 1.

The compositions of example 1 and example 2 were subjected to freeze thaw stability studies at -20° C/40° C and 2-8° C / 40° C, two different set of samples were kept for two days in -20°C and 2-8°C for 2 days and same samples were kept at 40°C for two days. The cycle was repeated for 6 times and samples were observed for physical stabilization, up to 6 cycles. The compositions were visually inspected and no re-crystallization or precipitation was observed at the end of 6 cycles.

Claims:

1. A stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, less than about 1.8% (w/v) of polyvinyl alcohol and one or more pharmaceutically acceptable excipients.

2. A stable ophthalmic composition according to claim 1, comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to 1.4% (w/v) of polyvinyl alcohol and one or more pharmaceutically acceptable excipients.

3. A stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients, wherein said solution has a viscosity of about 2-4 cps.

4. A stable ophthalmic composition according to claim 1 and 3, comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt, about 1.0 to 1.4% (w/v) of polyvinyl alcohol and one or more pharmaceutically acceptable excipients, where in said solution has a viscosity of about 2-4 cps.

5. The composition of claim 1 and 3, wherein one or more pharmaceutically acceptable excipients are selected from a group comprising tonicity adjusting agent, buffer, preservative, chelating agent, pH adjusting agent, and mixtures thereof.

6. The composition of claim 5, wherein tonicity adjusting agent is selected from a group comprising sodium chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol, sorbitol, glucose, and mixtures thereof.

7. The composition of claim 5, wherein buffer is selected from a group comprising phosphate buffer, acetate buffer, borate buffer, citrate buffer, and mixtures thereof.

8. A stable ophthalmic composition according to claim 1 and 3, comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt; about 1.0 to 1.4% (w/v) of polyvinyl alcohol; benzalkonium chloride; phosphate buffer; sodium chloride; and disodium edentate, wherein said solution has a viscosity of about 2-4 cps.

9. The composition of claim 1 and 3, wherein the composition is packaged in low density polyethylene container.

10. A stable ophthalmic composition comprising about 0.2% (w/v) of olopatadine or its pharmaceutically acceptable salt; about 1.0 to 1.4% (w/v) of polyvinyl alcohol; and one or more pharmaceutically acceptable excipients selected from a group comprising tonicity adjusting agent, buffer, preservative, chelating agent and pH adjusting agent in a suitable vehicle, wherein said solution has a viscosity of about 2-4 cps.