FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
" PHARMACEUTICAL COMPOSITION FOR TOPICAL ADMINISTRATION
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA
The following specification describes the nature of this invention.

PHARMACEUTICAL COMPOSITION FOR TOPICAL ADMINISTRATION
FIELD OF THE INVENTION
The present invention relates to aqueous formulations 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)-ll-[3-(Dimethylamino) propyl-idene]-6,ll-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride [C21H23 N03 .HC1]. As taught in U.S. Pat Nos.4,871,865 and 4,923,892 both assigned to Burroughs Wellcome Co. Olopatadine has antihistamine and antiasthmatic activity.
Olopatadine hydrochloride is commercially available in the U.S as PATANOL®, 0.1% sterile ophthalmic solution marketed by Alcon. It is indicated for the treatment of signs and symptoms of allergic conjunctivitis. 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 approximately 7, and osmolality of approximately 300mOsm/kg.
United States Patent No.6,995,186 (Alcon Inc., 2006, the '186 patent) teaches topically administrable 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 has a viscosity of 1-2 cps, and 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 taught in the '186 patent to cause physical instability of olopatadine solutions. We have now found that stable aqueous solutions of olopatadine hydrochloride can be prepared by forming an inclusion complex with hydroxypropyl-/3-cyclodextrin (HPbCD). Optionally hydroxypropyl methylcellulose(HPMC) may be used which
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acts to stabilize the inclusion complex. The present invention provides topical olopatadine hydrochloride formulations that are effective for treating allergic or inflammatory disorders of the nose. The formulations of the present invention are aqueous solutions that comprise approximately about 0.17% to about 0.62% by weight of olopatadine or its pharmaceutically acceptable salt, hydroxypropyl- b-cyclodextrin and optionally hydroxypropyl methylcellulose, both in an amount sufficient to enhance the physical stability of the solution.
SUMMARY OF THE INVENTION
The present invention can be summarized as follows:
A). An inclusion complex of olopatadine or its pharmaceutically acceptable salt and
hydroxypropyl b-cylcodextrin.
B). An inclusion complex of olopatadine or its pharmaceutically acceptable salt as in A above, wherein, the ratio of olopatadine or its pharmaceutically acceptable salt to hydroxypropyl b-cylcodextrin is 1:1.65 to 1:50 by weight.
C). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt which comprises, an inclusion complex of olopatadine or its pharmaceutically acceptable salt with hydroxypropyl b-cylcodextrin as in A above, wherein, the amount of hydroxypropyl b-cylcodextrin present in the complex is sufficient to enhance the physical stability of the solution.
D). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt, comprising:
a) a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt; and
b) hydroxypropyl b-cylcodextrin and hydroxypropyl methylcellulose in an amount sufficient to enhance the physical stability of the solution.
E). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in C or D, wherein the said olopatadine or its pharmaceutically acceptable salt is present in an amount ranging from about 0.17% to about 0.62%w/v of the solution.
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F). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in C or D, wherein hydroxypropyl b-cylcodextrin is present in an amount ranging from about 1.0% to about 10% w/v of the solution.
G). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in D, wherein hydroxypropyl methylcellulose is present in amount ranging from about 0.01% to about l%w/v of the solution.
H). An aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in C or D, wherein the olopatadine or its pharmaceutically acceptable salt does not precipitate or crystallize out when stored over a prolonged period of time.
I). A Process for producing an aqueous topical solution of olopatadine or its pharmaceutically acceptable salt, comprising:
a) Dissolving hydroxypropyl b-cylcodextrin in sufficient quantity of water and adding a therapeutically effective amount of olopatadine or its pharmaceutically acceptable salt, with stirring to obtain a first solution;
b) Dissolving hydroxypropyl methylcellulose in sufficient quantity of water to obtain a second solution;
c) Mixing the above two solutions to get a clear solution; and
d) Adjusting the pH with aqueous hydrochloric acid and / or aqueous sodium hydroxide to obtain a pH of 3.5 to 5.0.
J). A process for producing an aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in I, wherein the olopatadine or its pharmaceutically acceptable salt is present in an amount ranging from about 0.17% to about 0.62%w/v of the solution.
K). A process for producing an aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in I, wherein hydroxypropyl b-cylcodextrin is present in an amount ranging from about 1.0% to about 10% w/v of the solution.
L) A process for producing an aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in I, wherein hydroxypropyl methylcellulose is present in amount ranging from about 0.01% to about l%w/v of the solution.
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M). A process for producing an aqueous topical solution of olopatadine or its pharmaceutically acceptable salt as defined in I, wherein the olopatadine or its pharmaceutically acceptable salt does not precipitate or crystallize out when stored over a prolonged period of time.
The term "physical stability" as used herein means that the olopatadine or its pharmaceutically acceptable salt is not precipitated or crystallized out of the solution when stored over a prolonged period of time, such as the shelf life of the aqueous solution.
The composition of the present invention uses 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 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. It may be used in an amount ranging from about 0.17%w/v to about 0.62%w/v.
The composition of the present invention includes cyclodextrin to enhance the physical stability of the solution. Cyclodextrins are a group of structurally related saccharides which are formed by enzymatic cyclization of starch by a group of amylases termed glycosyltransferases. Cyclodextrins are cyclic oligosaccharides, consisting of (alpha-l,4)-linked alpha-D-glucopyranose units, with a lipophilic central cavity and a hydrophilic outer surface. In aqueous solutions, cyclodextrins form inclusion complexes with many drugs through a process in which the water molecules located in the central cavity are replaced by either the whole drug molecule, or more frequently, by some lipophilic portion of the drug structure. Once included in the cyclodextrin cavity, the drug molecules may be dissociated through complex dilution, by replacement of the included drug by some other suitable molecule or, the drug may be transferred to the matrix for which it has the highest affinity. Importantly, since no covalent bonds are formed or broken during the drug-cyclodextrin complex formation, the complexes are in dynamic equilibrium with free drug and cyclodextrin molecules. In solution, the complexes are usually prepared by addition of an excess amount of the drug to an aqueous cyclodextrin solution. The
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most common naturally occurring cyclodextrins are alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin consisting of 6, 7 and 8 glucopyranose units, respectively. Of these three derivatives, beta-cyclodextrin appears to be the most useful pharmaceutical complexing agent due to its cavity size, availability, low cost and other properties. Cyclodextrin derivatives of current pharmaceutical interest include the hydroxypropyl derivatives of alpha-, beta- and gamma-cyclodextrin, sulfoalkylether cyclodextrins such as sulfobutylether beta-cyclodextrin, alkylated cyclodextrins such as the randomly methylated beta-cyclodextrin, and various branched cyclodextrins such as glucosyl- and maltosyl beta-cyclodextrin.
Useful cyclodextrins for use in the present invention includes alkyl cyclodextrins, hydroxy alkyl cyclodextrin, such as hydroxy propyl beta-cyclodextrin, carboxy alkyl cyclodextrins and sulfoalkyl ether cyclodextrin, such as sulfo butyl ether beta-cyclodextrin. Examples of suitable cyclodextrins for use in the present invention non-exclusively include alpha-cyclodextrin; beta-cyclodextrin; gamma-cyclodextrin; methyl alpha-cyclodextrin; methyl beta-cyclodextrin; methyl gamma-cyclodextrin; ethyl beta-cyclodextrin; butyl alpha-cyclodextrin; butyl beta-cyclodextrin; butyl gamma-cyclodextrin; pentyl gamma-cyclodextrin; hydroxyethyl beta-cyclodextrin; hydroxyethyl gamma-cyclodextrin; 2-hydroxypropyl alpha-cyclodextrin; 2-hydroxypropyl beta-cyclodextrin; 2-hydroxypropyl gamma-cyclodextrin; 2-hydroxybutyl beta-cyclodextrin; acetyl alpha-cyclodextrin; acetyl beta-cyclodextrin; acetyl gamma-cyclodextrin; propionyl beta-cyclodextrin; butyl beta-cyclodextrin; succinyl alpha-cyclodextrin; succinyl beta-cyclodextrin; succinyl gamma-cyclodextrin; benzoyl beta-cyclodextrin; palmityl beta-cyclodextrin; toluenesulfonyl beta-cyclodextrin; acetyl methyl beta-cyclodextrin; acetyl butyl beta-cyclodextrin; glucosyl alpha-cyclodextrin; glucosyl beta-cyclodextrin; glucosyl gamma-cyclodextrin; maltosyl alpha-cyclodextrin; maltosyl beta-cyclodextrin; maltosyl gamma-cyclodextrin; alpha-cyclodextrin carboxymethylether; beta-cyclodextrin carboxymethylether; gamma-cyclodextrin carboxymethylether; carboxymethylethyl beta-cyclodextrin; phosphate ester alpha-cyclodextrin; phosphate ester beta-cyclodextrin; phosphate ester gamma-cyclodextrin; 3-trimethylammonium-2-hydroxypropyl beta-cyclodextrin; sulfobutyl ether beta-cyclodextrin; carboxymethyl alpha-cyclodextrin; carboxymethyl beta-cyclodextrin; carboxymethyl gamma-cyclodextrin, and combinations thereof. The most preferred cyclodextrin for the present invention is hydroxy propyl beta-cyclodextrin. Hydroxypropyl beta-cyclodextrin may be used in an amount ranging from about 0.1% to about 20%w/v, most preferably in an amount ranging from about 1.0% to about 10% w/v.
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Olopatadine or its pharmaceutically acceptable salt forms an inclusion complex with hydroxypropyl beta-cyclodextrin. The ratio of olopatadine or its pharmaceutically acceptable salt to hydroxypropyl b-cylcodextrin in the inclusion complex is 1:1.65 to 1:50 by weight. The amount of hydroxypropyl b-cylcodextrin present in the inclusion complex is sufficient to enhance the physical stability of the olopatadine solution.
In an embodiment of the present invention, the composition may further include hydroxypropyl methylcellulose (HPMC), which acts as a stabilizer for the inclusion complex of hydroxypropyl beta-cyclodextrin and olopatadine or its pharmaceutically acceptable salt. Various grades of hydroxypropyl methylcellulose (available from Dow Chemical, U.S.A under the METHOCEL trademark) may be used in the present invention. The grades commercially available are categorized depending upon the chemical substitution and hydration rates, and may be used in the compositions of the present invention. Hydroxypropyl methylcellulose having a methoxy content of 19-24 % and hydroxypropyl content of 7-12 % with a fastest relative rate of hydration is available commercially under the brand name of Methocel Grade K. Hydroxypropyl methylcellulose with 28-30 % methoxy content and 7-12 % of hydroxypropyl content with a faster relative hydration rate as compared to the above grade is available commercially under the brand name of Methocel Grade E. Hydroxypropyl methylcellulose with 27-30 % methoxy content and 4-7.5 % of hydroxypropyl content with a slow relative hydration rate is available as Methocel F grade and that with 27.5-31.5 % methoxy content and 0 % hydroxypropyl content and with slowest rate of hydration is available as Methocel Grade A. In preferred embodiments of the aqueous composition of the present invention, hydroxypropyl methylcellulose, a 2%w/v aqueous solution of which has a viscosity of 4000 cps at 20°C, and which is commercially available as METHOCEL E4M is used. It may be used in an amount ranging from about 0.001%w/v to about 5%w/v, and most preferably in an amount ranging from about 0.01%w/v to about 1 %w/v.
The composition may further include pharmaceutically acceptable excipients so as to provide a suitable carrier for the aqueous solution. The pharmaceutically acceptable carrier in the pharmaceutical composition 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 solvents that are conventionally used in topical eye and nose preparations.
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The composition 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, ceryl pyridinium chloride, thimerosal, chlorobutanol, phenylethyl alcohol, benzyl alcohol, potassium sorbate, sodium benzoate, sorbic acid and the like and mixtures thereof. The preferred preservative for the aqueous compositions of the present invention is benzalkonium chloride. It may be used in an amount ranging from about 0.005% to about 1%.
The composition 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 compositions of the invention is disodium edetate. The chelating agent may be present in the aqueous solution composition in an amount ranging from about 0.005% to about 0.1% w/v.
The composition 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 composition 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). Pharmaceutically acceptable water-soluble salts of inorganic or organic acids, or non-ionic organic compounds with high water solubility, e.g. carbohydrates such as sugar, or amino acids, are generally preferred. The examples of agents used for rendering the solution isoosmotic include inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; sodium carbonate or sodium bicarbonate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, dextrose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose, inositol, xylitol, maltitol; water-soluble amino acids such as glycine, leucine,
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alanine, or methionine; urea and the like, and mixtures thereof. Preferred tonicity agent is sodium chloride, which may be added in an amount which renders the solution isoosmotic.
The composition 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 composition. 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 composition of present invention may be adjusted between 3.0 to 6.0 and most preferably between 3.5 to 5.0.
The composition 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 metabisulfite, 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, hydroxyquinoline sulphate, phosphoric acid, sodium citrate and tartaric acid. The antioxidants are used in amounts conventional to the pharmaceutical art.
The clear solution formulations of the present invention are preferably packed in U.S.P type I amber color glass containers equipped with a nasal spray pump.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
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EXAMPLE 1
A topically administrable nasal solution comprising olopatadine hydrochloride was prepared as described in Table 1 below.
Table 1

Ingredients Quantity
mg/ml %w/v
Olopatadine Hydrochloride 5.27 0.527
Hydroxy Propyl Beta Cyclodextrin (HP/3CD) 50.00 5.00
Hydroxy Propyl Methly Cellulose E4M 1.00 0.10
Benzalkonium chloride solution 0.20 0.02
Sodium Chloride 3.00 0.30
Dibasic Sodium Phosphate dodecahydrate 1.50 0.15
Edetate disodium 0.10 0.01
NaOH / HC1 q.s. pH 3.5-5.0 q.s. pH 3.5-5.0
Water For Injection q.s. to 1 ml q.s. to 100
Stage A
1. Hypromellose is dissolved in water for injection (WFI) till clear solution is formed.
Stage B
1. Hydroxypropyl beta-cyclodextrin (HPbCD) is dissolved in WFI in a container.
2. Disodium edetate, sodium chloride and dibasic sodium phosphate dodecahydrate are added to above container and stirred to get a clear solution.
3. Olopatadine hydrochloride is dissolved in water for injection (WFI) and added to the above solution in the container, under stirring.
Stage C
1. Solution obtained from Stage B is added to solution of stage A.
2. The pH of the solution is adjusted such that it is between 3.5-5.0 using 5.0% v/v Hydrochloric acid or 2% w/v Sodium Hydroxide.
3. Final volume is made up with water for injection.
4. The solution is filtered through 2.0um glass filter and 0.2um Nylon 66 membrane filter and transferred into U.S.P. Type I amber glass containers.
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EXAMPLE 2
Olopatadine hydrochloride aqueous solutions packed in vials were stored at 30°C / 65%Relative Humidity and at 40°C / 75%Relative Humidity for a period of one month. The samples were analyzed for the degradation of olopatadine. The results obtained are summarized in Table 2 below. No crystallization or precipitation was observed at the end of one month
Table 2

Storage Condition Time Period Degradation (%)
0 Month 0.02
30°C / 65%Relative Humidity 1 Month 0.07
40°C / 75%Relative Humidity 1 Month 0.19
EXAMPLE 3
Olopatadine hydrochloride aqueous solutions were packed in vials fitted with a conventional pump and actuator. These vials were subjected to freeze-thaw stability studies upto fourteen cycles, where each cycle involved storage for one day at low temperature (i.e. -10°C to -20°C), followed by storage for one day at high temperature (i.e. 40°C and 75%Relative Humidity). The samples were then analyzed for the degradation of olopatadine. The results obtained are summarized in Table 3 below.
Table 3

Time Period Degradation (%)
At day 0 0.02
At day 28 0.05
EXAMPLE 4
The compositions shown in Table 4 below were prepared and subjected to stability studies. The vials were studied for stability at two temperature conditions: one at room temperature (25° +4°C) and the other at refrigeration temperature (2-8°C) condition. Vials were observed for formation of crystals in the solution at the end of 14 days. The results are summarized in Table 5 below.
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Table 4

Ingredients (%w/v) Formulation#
A B C
Olopatadine hydrochloride yf yf yf
Hydroxy Propyl Methly Cellulose E4M (1.0) V - yf
Hydroxy Propyl Beta Cyclodextrin (3.0) - yf yf
Sodium chloride yf yf yf
Benzalkonium Chloride yf 4 V
Dibasic sodium phosphate Dodecahydrate V yf yf
NaOH / HC1 q.s. pH 3.5 -5.0 q.s. pH 3.5 -5.0 q.s. pH 3.5 -5.0
Purified Water q.s. to 100 q.s. to 100 q.s. to 100
#The concentrations of all ingredients in the three formulations (i.e. A, B, C) are kept same, except for HPMC and HP/3CD.
Table 5

Storage condition Formulation A Formulation B Formulation C
Room Temperature(25° ±4°C) Crystals observed Clear solution Clear solution
Refrigeration temperature(2-8°C) Crystals observed Clear solution Clear solution
Dated this 12th day of May 2006.
DILIP SHANGHVI,
CHAIRMAN AND MANAGING DIRECTOR,
SUN PHARMACEUTICAL INDUSTRIES LIMITED.
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