FORM 2
THE PATENT ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"STABLE PHARMACEUTICAL COMPOSITION OF OLOPATADINE"
2. APPLICANT:
(a) NAME: INDOCO REMEDIES LIMITED.
(b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956

(c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION:
The present invention relates to a stable pharmaceutical composition of olopatadine and a process for the preparation thereof. In particular, the invention relates to the stable formulation comprising olopatadine and polyvinyl pvrrolidone with a low content of impurities like peroxide, which originate from the use of polyvinyl pyrrolidone. The invention also concerns to a method of reducing the peroxide content which is associated with the use of polyvinyl pyrrolidone in the olopatadine formulation.
BACKGROUND OF THE INVENTION:
Olopatadine is an inhibitor of the release of histamine from mast cell and relatively selective histamine HI-antagonist that inhibits the in vivo and in vitro type 1 immediate hypersensitivity reaction including inhibition of histamine induced effects on human conjunctival epithelial cells.
It has been approved in USA, Europe, Canada and in most countries including India for the relief of signs and symptoms of allergic conjunctivitis and allergic rhinitis and currently in the USA; the marketed compositions of Olopatadine hydrochloride are accessible as ophthalmic drops (0.1 % and 0.2% solution) and nasal spray (0.665 %).
Castillo et al in US Pat. No. 6,995,186 discloses the 0.2 % ophthalmic solution of olopatadine hydrochloride which comprises dibasic sodium phosphate, sodium chloride, edentate disodium, benzalkonium chloride and purified water. Further, the ophthalmic solution contains the polymers like polyvinyl pyrrolidone or polystyrene sulfonic acid which is believed to enhance the physical stability of the solution.
Both polyvinyl pyrrolidone or polystyrene sulfonic acid are known polymers and are commercially available in a number of molecular weights; however, Castillo et al in US Pat. No. 6,995,186 supports the use of polyvinyl pyrrolidone which have average molecular weights between 50,000 to 60,000 and polystyrene sulfonic acid which have average molecular weights between 75,000- 1,000,000.
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Castillo et al claim that the addition of these polymers particularly polyvinyl pyrrolidone enhance the physical stability of the solution; however; the major disadvantage associated with its use is the formation of peroxide impurities. Although peroxide impurities are inherently present when PVP is manufactured, however its quantity further increases due to exposure to air and heat. It acts as a natural oxidizing agent and is a serious consideration when the polyvinyl pyrrolidone is employed for certain pharmaceutically active compounds or mixtures of compounds.
Numerous studies have been done to confirm the impact of the presence of peroxide impurities on the drugs. For example: Peroxide residues in povidone were shown to be responsible for the enhanced formation of N-oxide degradation product of the oestrous receptor modulator, raloxifene. Also, the presence of peroxide impurities in povidone has been proved to contribute significantly to color change in danofloxacin formulation. It has also been demonstrated that peroxide impurities have an adverse effect on various other drugs like doxycycline. metformin and molsidomine. Thus, numerous attempts have been made by the inventors to minimize the peroxide content in the polyvinyl pyrrolidone. To name a few, US Pat. No.6,562,900 by Buhler et al describes a method wherein the peroxide cleaving enzymes like peroxidase and catalase and heavy metals like copper, cobalt, zinc and manganese are added to the solution of polyvinyl pyrrolidone for its stabilization. Jn Pat. Publication no. WO200608376I by Rohioff et al, the polymer is treated with alumina to remove peroxides and boiled for 30 min and filtered. Before use, PVP is further treated with a solution of methionine to reduce the peroxide content. US Pat. No. 6,995,186 by Castillo et al advocates the use of freshly-produced and thermally treated batches of polyvinyl pyrrolidone for eliminating the peroxide levels in the solution.
However, it has been found by the present inventors that the most of the teachings of the prior art were inept to sufficiently control the level of peroxide in the polyvinyl pyrrolidone. It might also be mentioned that Health Authorities all over the world are very concerned about the level of impurities and degradation products present either in the drug substance or the final dosage form. As a consequence, regulatory approval norms today are very stringent about the level of impurities present in the drug substance or a drug product. Since, polyvinyl pyrrolidone is an important excipient in a large no. of
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pharmaceutical formulations including olopatadine, the presence of impurities like peroxide in polyvinyl pyrrohdone is a crucial issue which needs to be seriously dealt with. Thus, the present invention is a step forward in this direction and overcomes the limitation of the prior art methods. It provides a novel and simple method for stabilization of polyvinyl pyrrolidone in which the peroxide impurity is reduced to a negligible amount. Such a stable polyvinyl pyrrolidone solution can be effectively used for the preparation of number of pharmaceutical formulation like olopatadine.
OBJECTS OF THE INVENTION:
An object of the present invention is to provide a stable pharmaceutical composition of
olopatadine.
Another object of the present invention is to provide a stable pharmaceutical composition of olopatadine which further comprises of polyvinyl pyrrolidone and other pharmaceuticaly acceptable excipients.
Yet another object of the present invention is to provide a stable pharmaceutical composition of olopatadine and polyvinyl pyrrolidone wherein the polyvinyl pyrrolidone enhances the stability of the solution.
Further object of the present invention is to provide a stable pharmaceutical composition of olopatadine wherein the polyvinyl pyrrolidone used is free of impurities or contains substantially negligible amount of impurities.
Still further object of the present invention is to provide a stable pharmaceutical composition of olopatadine wherein the level of impurities in polyvinyl pyrrolidone is reduced to a negligible amount by the irradiation of polyvinyl pyrrolidone with gamma rays.
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DETAILED DESCRIPTION OF THE INVENTION:
In their endeavor to find a suitable method for the reducing the impurities like peroxide in polyvinyl pyrrolidone, the present inventors have found that irradiating the polyvinyl pyrrolidone with the gamma rays reduces the level of impurities to a negligible amount. This polyvinyl pyrrolidone irradiated with gamma rays can be effectively used as an excipient in a number of pharmaceutical compositions including olopatadine.
Pharmaceutical composition of olopatadine comprising the gamma sterilized polyvinyl pyrrolidone possess not only a remarkably long storage life, but also, exhibit negligible drop in potency as well as significantly superior quality in terms of minimal and acceptable levels of degradation products and impurities formed during storage of the solution.
Thus, in the first embodiment, the invention provides a novel, stable oral pharmaceutical
composition of olopatadine.
Thus, in the second embodiment, the invention provides a novel, stable oral pharmaceutical composition of olopatadine which further comprises polyvinyl pyrrolidone and other pharmaceutical excipients.
In the third embodiment, the invention provides a stable pharmaceutical oral composition of olopatadine and polyvinyl pyrrolidone wherein polyvinyl pyrrolidone has been irradiated with the gamma rays.
In the fourth embodiment, the invention provides a stable pharmaceutical oral composition of olopatadine and polyvinyl pyrrolidone wherein irradiating the polyvinyl pyrrolidone with the gamma rays reduces the quantity of peroxide impurities to a negligible amount.
In the fifth embodiment, the invention provides a process for the preparation of stable pharmaceutical oral composition of olopatadine and polyvinyl pyrrolidone.
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The invention further provides a stable pharmaceutical composition of oiopatadine and polyvinyl pyrrolidone which can be used for the treatment of allergic conjunctivitis. This pharmaceutical composition of oiopatadine, polyvinyl pyrrolidone and other pharmaceutical excipients are preferably prepared as ophthalmic solutions. The composition may contain 0.05 % to 0.5 % of oiopatadine hydrochloride.
Polyvinylpyrrolidone is a water-soluble polymer made from the monomer N-Vinylpyrrolidone. It is widely used as an excipient in number of dosage forms like tablet, capsule, ophthalmics etc. When polyvinylpyrrolidone is irradiated with approximately 25 Kgy of gamma rays, the peroxide content is reduced to a negligible amount; which can be used as an excipient in various pharmaceutical compositions including oiopatadine.
As used herein, negligible amount of peroxide can be understood to mean the quantity of peroxide less than 200 ppm in the polyvinyl pyrrolidone.
Typically, the ophthalmic formulations of the invention will contain apart from polyvinyl pyrrolidone, some or all of the pharmaceutical!}' acceptable ophthalmic excipients, preservative or additives, appropriate for preparation of the formulations for the invention. These excipients and additives are present in concentrations known and used in the art for ophthalmic formulations in concentrations acceptable in pharmaceutical sciences.
These may also contain isotonization agents, like sodium chloride in quantities of 0-5% by weight, preferably 0.3-2% by weight, by preference 0.5-1.25% by weight, or sorbitol in quantities of 0-10% by weight, preferably 2-6% by weight, by preference 3-5% by weight and chelating agents, like EDTA or its sodium salt in quantities of 0-0.002% by weight, preferably 0.0008-0.0012%) by weight.
The aqueous ophthalmic compositions of the present invention may further contain water which has no physiologically or ophthalmically harmful constituents. Typically purified or deionized water is used.
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The pH can be adjusted by adding any physiologically and ophthalmically acceptable pH adjusting acids, bases or buffers to within the range of about 5.0 to 8.5. Examples of acids include acetic, boric, citric, lactic, phosphoric, hydrochloric, and the like, and examples of bases include sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, tromethamine, THAM (trishydroxymethylamino-methane), and the like. Salts and buffers include citrate/dextrose, sodium bicarbonate, ammonium chloride and mixtures of the aforementioned acids and bases.
The osmotic pressure of the aqueous ophthalmic composition is generally from about 10 miiliosmolar (mOsM) to about 400 mOsM, more preferably from 260 to 340 mOsM. If necessary, the osmotic pressure can be adjusted by using appropriate amounts of physiologically and ophthalmically acceptable salts or excipients. Sodium chloride is preferred to approximate physiologic fluid, and amounts of sodium chloride ranging from about 0.01% to about 1% by weight, and preferably from about 0.05% to about 0.45% by weight, based on the total weight of the composition, are typically used. Equivalent amounts of one or more salts made up of cations such as potassium, ammonium and the like and anions such as chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate, bisulfate, sodium bisulfate, ammonium, sulfate, and the like can also be used in addition to or instead of sodium chloride to achieve osmolalities within the above-stated range. Similarly, a sugar such as mannitol, dextrose, sorbitol, glucose and the like can also be used to adjust osmolality.
Examples of useful preservatives that can be employed in the present invention are benzalkonium chloride (preferably in a concentration of about 0.0001% to about 0.1 %), chlorobutanol (preferably in a concentration of about 0.1% to about 10%), EDTA, methylparaben and propylparaben (parahydrobenzoic acid derivative), phenylethyl alcohol (substituted alcohol), chlorhexidine, chlorobutanof polyaminopropyl biguanide, polysorbate 20, or other preservatives as understood by those skilled in the art. Other than for benzalkonium chloride and chlorobutanol, the preservative is preferably in a concentration of about 0.0001% to about 10%, more preferably in a concentration of about 0.001% to about 1%, and most preferably in a concentration of about 0.01% to about 1%.
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Further, excipients may also include stabilizers and/or antioxidants to prevent drug degradation. Stabilizers may include sodium bisulfate or metabisulfate. preferably in a concentration ranging from about 0.01% to about 0.03%.
The topical formulation of the present invention can be packaged as single doses, is
administered into the eye in the form of drops, and is useful for the treatment of allergic
conjunctivitis.
It should be understood that the list of ingredients above is merely a representative
sampling of those that can be used with the present invention.
The following examples are intended to illustrate the present invention and its advantages. They must in no case be considered as limiting the scope of the present invention.
Example 1: Comparison of the Peroxide Content in the Polyvinyl Pyrrolidone
Sr. No. Type Peroxide Content
(ppm)
1. PVP Untreated 400
2. PVP heated at 105 °C for 3 hrs. 371.4
PVP treated at a pH 11-13 for 30-120 min (as given
3. 271.99
in US 6,995,186)
4. PVP irradiated with 25 KGy of Gamma rays 195.43
Example 1 clearly demonstrates that exposure of PVP to approximately 25 KGy of gamma rays significantly reduces the content of peroxide impurities. Using the gamma sterilized Polyvinyl Pyrrolidone. different Olopatadine hydrochloride Ophthalmic Solutions were prepared; these are covered in Table 2- 5.
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Example 2: Olopatadine hydrochloride Ophthalmic Solution

Ingredients Quantity
Olopatadine Hydrochloride 0.222%
Polyvinyl Pyrrolidone 1.5%
Potassium chloride 0.15%
Phenyl mercuric nitrate 0.004%
Citric acid 0.1%
Boric acid 0.2%
Borax 0.14%
Sodium Hydroxide/ Hydrochloric acid q.s to pH 7
Purified water q.sto 100
Procedure:
a. Polyvinyl pyrrolidone (which has been irradiated with 25 KGy of Gamma rays) is
dissolved in around 50 ml of purified water.
b. In other vessel suitable quantities of potassium chloride, phenyl mercuric nitrate,
citric acid, boric acid and borax were dissolved in another 50 ml of purified water
with continuous stirring.
c. The Polyvinyl pyrrolidone solution of step a was added to the solution of step b.
d. Sodium hydroxide or hydrochloric acid was added dropwise to the solution of step
d to adjust the pH to 7.
e. The resulting solution is then filtered through a sterilizing filter.
f. The sterile solution is then transferred under sterile conditions into the suitable
containers.
Example 3: Olopatadine hydrochloride Ophthalmic Solution

S.No Ingredients Quantity
1. Olopatadine Hydrochloride 0.222%
2. Polyvinyl Pyrrolidone 1.65%
Calcium chloride 0.2%
4. Methyl paraben 0. 4%
5. Propyl Paraben 0.2%
6. Citric acid 0.3%
7. Boric acid 0.2 %
8. Borax 0.14%
9. Sodium Hydroxide/ Hydrochloric acid q.s to pH 7
10. Purified water q.sto 100
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Procedure:
a. Polyvinyl pyrrolidone (which has been irradiated with 25 KGy of Gamma rays) is
dissolved in around 50 ml of purified water.
b. In other vessel suitable quantities of calcium chloride, methyl paraben, propyl
paraben. citric- acid, boric acid and borax were dissolved in another 50 ml of
purified water with continuous stirring.
c. The Polyvinyl pyrrolidone solution of step a was added to the solution of step b.
d. Sodium Hydroxide or Hydrochloric acid was added dropwise to the solution of
step d to adjust the pH to 7.
e. The resulting solution is then filtered through a sterilizing filter.
f. The sterile solution is then transferred under sterile conditions into the suitable
containers.
Example 4: Olopatadine hydrochloride Ophthalmic Solution
S.No Ingredients Quantity
Olopatadine Hydrochloride 0.222%
Polyvinyl Pyrrolidone 1.8 %
Potassium chloride 0.2 %
Sorbicacid 0.4%
Citric acid 0.1 %
Tromethamine 0.2 %
Sodium Hydroxide/ Hydrochloric acid q.s to pH 7
Purified water q.s to 100
Procedure:
a. Polyvinyl pyrrolidone (which has been irradiated with 25 KGy of Gamma rays) is
dissolved in around 50 ml of purified water.
b. In other vessel suitable quantities of potassium chloride, sorbic acid, citric acid,
tromethamine were dissolved in another 50 ml of purified water with continuous
stirring.
c. The polyvinyl pyrrolidone solution of step a was added to the solution of step b.
d. Sodium Hydroxide or hydrochloric acid was added dropwise to the solution of
step d to adjust the pH to 7.
e. The resulting solution is then filtered through a sterilizing filter.
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f. The sterile solution is then transferred under sterile conditions into the suitable containers.
Example 5: Olopatadine hydrochloride Ophthalmic Solution

S.No Ingredients Quantity
1. Olopatadine Hydrochloride 0.222%
2. Polyvinyl Pyrrolidone 1.8%
3. Potassium chloride 0.2 %
4. Sorbic acid 0. 4 %
5. Citric acid 0.1 %
6. Boric acid 0.2 %
7. Borax 0.14%
8. Sodium Hydroxide/ Hydrochloric acid q.s to pH 7
9. Purified water q.sto 100
Procedure:
a. Polyvinyl pyrrolidone (which has been irradiated with 25 KGy of Gamma rays) is
dissolved in around 50 mi of purified water.
b. In other vessel suitable quantities of potassium chloride, sorbic acid, citric acid,
boric acid and borax were dissolved in another 50 ml of purified water with
continuous stirring.
c. The polyvinyl pyrrolidone solution of step a was added to the solution of step b.
d. Sodium Hydroxide or hydrochloric acid was added dropwise to the solution of
step d to adjust the pH to 7.
e. The resulting solution is then filtered through a sterilizing filter.
f. The sterile solution is then transferred under sterile conditions into the suitable
containers.
Pharmaceutical compositions of olopatadine hydrochloride were kept at room temperature and refrigerated conditions. These were analyzed after on month. The results are shown in table 1.
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Table 1: Physical Stability of Samples of Olopatadine Hydrochloride stored at Room temperature and Refrigerated temperature.

Formulation
as given in
Example no. Olopatadine Hydrochloride Samples observed after

0 Days 15 Days 30 Days

R.T Refrigerated temperature R.T Refrigerated temperature R.T Refrigerated temperature
2 Clear Clear Clear Clear Clear Clear
3 Clear Clear Clear Clear Clear Clear
4 Clear Clear Clear Clear Clear Clear
5 Clear Clear Clear Clear Clear Clear
All the samples were found to be clear even after 1 month. No particles or crystals were observed in any of the sample. However, the samples were further examined by Coulter counter method and light obstruction method to assess the presence of various particles. It was found that all the samples meet the required USP/EP specification.
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We Claim,
1. A stable pharmaceutical composition of olopatadine comprising gamma irradiated polyvinyl pyrrolidone and other pharmaceutical^ acceptable excipients.
2. A stable pharmaceutical composition of claim 1; wherein polyvinyl pyrrolidone is irradiated with gamma rays to reduce the content of impurities.
3. A stable pharmaceutical composition of claim 1; wherein the polyvinyl pyrrolidone used after irradiation with gamma rays contains negligible quantity of peroxide impurities.
4. A stable pharmaceutical composition of claim 1; wherein the composition comprises 0.05 % to 0.5 % of olopatadine hydrochloride.
5. A stable pharmaceutical composition of claim 1; wherein the composition is prepared as ophthalmic solution.
6. A stable pharmaceutical composition of claim 1 and 5; wherein the composition is prepared as ophthalmic drops.
7. A stable pharmaceutical composition of claim 1; wherein the pharmaceutica] excipients are selected from isotonization agents, tonicity agents, pH adjusting agents and preservatives.
Dated this 24th day of November, 2008
r r Dr. Gopakumar G. Nair
Agent for the Applicant
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