OLOPATADINE HYDROCHLORIDE NASAL SPRAY Technical Field of Invention
The present invention relates to a pharmaceutical composition of olopatadine suitable for nasal administration and processes for the preparation of the same.
Background of the Invention
Nasal route of drug administration is an efficient local delivery route to treat various allergic or inflammatory disorders of the nose. This route of administration has significant advantages over the conventional enteral and parenteral routes of drug administration. As compared to parenteral route, nasal drug administration eliminates the pain and the fear associated with needle and therefore makes the route of administration a much easier one for drug administration and also enhances patient compliance. It also decreases the incidences of needle injury and do not require trained persons for the administration. Further, nasal drug delivery eliminates the gastric and hepatic drug degradation associated with the oral route of drug administration. Other advantages of nasal administration over oral administration include the fast onset of action and fewer side effects due to the potentially reduced dosage of the drug.
Olopatadine is a selective histamine H1 receptor antagonist which has an inhibitory action on production/release of chemical mediators (leukotrienes, thromboxane and platelet aggregation factor). Olopatadine is commercially available as the hydrochloride salt under the trade names ALLELOCK® conventional tablets from Kyowa Hakko Kogyo Co., Ltd., Japan, and as PATADAY™ ophthalmic solution for topical administration to the eyes from Alcon Laboratories Inc., USA, and as PATANOL® ophthalmic solution for topical administration to the eyes from Alcon Laboratories Inc., USA, and as PATANASE® nasal spray, a metered-spray solution, for intranasal administration from Alcon Laboratories Inc., USA.
US Patent No. 5,116,863 discloses olopatadine and its salts. It also discloses pharmaceutical composition of olopatadine comprising a pharmaceutical carrier. The EP Patent No. 0214779B1 describes olopatadine generically and process of preparation of the same. The PCT application WO/2006/057769 discloses a method of delivering a nasal spray comprising the steps of providing a sprayer having a formulation comprising olopatadine and delivering a spray of said formulation to a subject's nose. The US Patent No. 5,641,805 discloses a method of treating allergic eye diseases in humans by topically administering to the eye a composition comprising a therapeutically effective amount of olopatadine or a pharmaceutical^ acceptable salt. The US Patent No. 6,995,186 discloses a topically administrable solution composition for treating allergic or inflammatory disorders of the eye and nose. The PCT application WO/2008/097220 discloses a topical olopatadine formulation for treating allergic or inflammatory disorders of the nose which comprises of olopatadine, phosphate buffer, sodium chloride, a pH adjusting agent and water. Sodium chloride is added in the formulation as a tonicity adjusting agent. However, the presence of sodium chloride causes a significant reduction in the rate of dissolution of olopatadine.
The inventors of the present invention have found that a pharmaceutical composition suitable for nasal administration of olopatadine can be prepared without the use of sodium chloride.
Summary of the Invention
In one general aspect, it relates to pharmaceutical composition of olopatadine suitable for nasal administration comprising of.
a) 0.4 - 0.8 % (w/w) olopatadine or a pharmaceutical^ acceptable salt thereof;
b) 0.005-0.02 % (w/w) benzalkonium chloride;
c) 0.5-4.0 % (w/w) glycerin;
d) 0.005-0.02 % (w/w) edetate disodium;
e) 0.2-0.8 % (w/w) phosphate salt;
f) pH adjusting agent(s);
g) purified water.
In another general aspect, it relates to pharmaceutical composition of olopatadine suitable for nasal administration wherein the pharmaceutical composition is prepared by the process which comprises of the following steps: I.
a) phosphate salt is dissolved in sufficient quantity of purified water to form the solution;
b) edetate disodium and glycerin are dissolved in the solution of step (a) under constant stirring to form the clear solution;
c) benzalkonium chloride is dissolved in the clear solution of step (b) under constant stirring to form the bulk solution.
II.
d) olopatadine or pharmaceutically acceptable salt thereof is dissolved in sufficient
quantity of purified water to form the drug solution.
III.
e) drug solution of step II is transferred to the bulk solution of step I under constant stirring to form the final drug solution;
f) pH of the final drug solution of step (e) is adjusted in the pH range of 3.4-3.9, by adding sufficient amount of pH adjusting agent(s).
Detailed Description of the Invention
As used herein, the term "pharmaceutical composition suitable for nasal administration" refers to any form of the nasal spray composition that can be delivered so, for local and systemic effects. The nasal spray may comprise olopatadine hydrochloride for the treatment of allergic rhinitis. Generally, the dose of olopatadine hydrochloride may be between 0.4 - 0.8 % w/w; particularly, it may be between 0.5 - 0.7 % w/w.
The term "pharmaceutically acceptable salt" as used herein refers to inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate; organic acid salts such as acetate, maleate, fumarate, tartrate and citrate. In one embodiment, the salt form of olopatadine is olopatadine hydrochloride.
The term "phosphate salt" as used herein relates to salts of phosphoric acid which contributes to the buffer capacity of the composition by maintaining the pH of the composition with the pH range of 3.4-3.9. Suitable phosphate salts used may be selected from, but are not limited to monobasic sodium phosphate, dibasic sodium phosphate, tribasic sodium phosphate, monobasic potassium phosphate, dibasic potassium phosphate and tribasic potassium phosphate. The phosphate salt may be present in an amount ranging from 0.2-0.8% (w/w), particularly in an amount ranging from 0.3-0.6 % w/w. In one embodiment, the phosphate salt is dibasic sodium phosphate.
The term "pH adjusting agent(s)" as used herein relates to agent(s) which are used to adjust the pH of the composition within the targeted pH range of 3.4-3.9. Suitable pH adjusting agent(s) used may be selected from, but are not limited to hydrochloric acid and sodium hydroxide.
In one embodiment, the process of preparing pharmaceutical composition of
olopatadine suitable for nasal administration comprises of the following steps:
I.
a) 0.2-0.8 % w/w of phosphate salt is dissolved in sufficient quantity of purified water to form the solution;
b) 0.005-0.02 % w/w edetate disodium and 0.5-4.0 % w/w glycerin are dissolved in the solution of step (a) under constant stirring to form the clear solution;
c) 0.005-0.02 % w/w benzalkonium chloride is dissolved in the clear solution of step (b) under constant stirring to form the bulk solution.
II.
d) 0.4 - 0.8 % w/w olopatadine or pharmaceutical^ acceptable salt thereof is
dissolved in sufficient quantity of purified water to form the drug solution.
III.
e) drug solution of step II is transferred to the bulk solution of step I under constant stirring to form the final drug solution;
f) pH of the final drug solution of step (e) is adjusted in the pH range of 3.4-3.9, by adding sufficient amount of pH adjusting agent(s).
The process for the preparation of pharmaceutical composition of olopatadine suitable for nasal administration is further illustrated by the following examples but should not be construed as limiting the invention.
EXAMPLE 1 (Table Removed)
Procedure
I.
a) Diabasic sodium phosphate was dissolved in sufficient quantity of purified water under constant stirring to form the solution;
b) Disodium edetate and glycerin were dissolved in the solution of step (a) under constant stirring to form the clear solution;
c) Benzalkonium chloride was dissolved in the clear solution of step (b) under constant stirring to form the bulk solution.
II.
d) Olopatadine hydrochloride was dissolved in sufficient quantity of purified water
under constant stirring to form the drug solution.
III.
e) Drug solution of step II was transferred to the bulk solution of step I under constant stirring to form the final drug solution;
f) pH of the final drug solution of step (e) was adjusted in the pH range 3.4-3.9 with sufficient amount hydrochloric acid and/or sodium hydroxide.

WE CLAIM:
1) A pharmaceutical composition of olopatadine suitable for nasal administration
comprising of:
a) 0.4 - 0.8 % (w/w) olopatadine or a pharmaceutically acceptable salt thereof;
b) 0.005-0.02 % (w/w) benzalkonium chloride;
c) 0.5-4.0 % (w/w) glycerin;
d) 0.005-0.02 % (w/w) edetate disodium;
e) 0.2-0.8 % (w/w) phosphate salt;
f) pH adjusting agent(s);
g) purified water.
2) The pharmaceutical composition according to claim 1, wherein the phosphate
salt is selected from one or more of monobasic sodium phosphate, dibasic
sodium phosphate, tribasic sodium phosphate, monobasic potassium
phosphate, dibasic potassium phosphate, tribasic potassium phosphate and
combinations thereof.
3) The pharmaceutical composition according to claim 1, wherein the pH adjusting
agent(s) is selected from one or more of hydrochloric acid, sodium hydroxide and combinations thereof.
4) The pharmaceutical composition according to claim 1, prepared by the process
wherein the process comprises of the following steps;
I.
a) phosphate salt is dissolved in sufficient quantity of purified water to form the solution;
b) edetate disodium and glycerin are dissolved in the solution of step (a) under constant stirring to form the clear solution;
c) benzalkonium chloride is dissolved in the clear solution of step (b) under constant stirring to form the bulk solution.
II.
d) olopatadine or pharmaceutically acceptable salt thereof is dissolved in
sufficient quantity of purified water to form the drug solution.
III.
e) drug solution of step II is transferred to the bulk solution of step I under constant stirring to form the final drug solution;
f) pH of the final drug solution of step (e) is adjusted in the pH range of 3.4-3.9, by adding sufficient amount of pH adjusting agent(s).
5) A pharmaceutical composition of olopatadine suitable for nasal administration substantially as described and exemplified herein.