EXTENDED RELEASE DOSAGE FORM CONTAINING OLOPATADINE FOR
ORAL ADMINISTRATION
Technical Field of Invention
The present invention relates to extended release dosage form for oral administration comprising oiopatadine and the process of preparation of the same.
Background of the Invention
Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption are well known in the art as modified release dosage forms. Many terms are used to describe modified-release dosage forms including extended release, prolonged release, controlled-release, slow-release and sustained-release which by definition have a reduced rate of release of active substance and hence these terms are, in general, interchangeable.
The various approaches for extended release oral drug delivery systems include 1) matrix based system or 2) release-modifying film coated system or 3) multiparticulate system. The matrix system is based on hydrophilic polymers in which the drug and the hydrophilic polymers are mixed together and then formed as a tablet by conventional compression process. The release of the drug from the matrix initializes with the diffusion of water into the matrix of the tablet which causes polymer in the matrix to swell. Thus the drug gets dissolved and diffuses out to be absorbed. In release-modifying film coated system the drug is formulated into a core (tablets or pellets) and is surrounded by a polymeric film. The film acts as a release rate controlling barrier and controls the release of the drug from the core. The Multiparticulate system is based on small beads, where each small bead is further composed of many layers. Some layers contain drug substance, others are rate controlling polymers.
Extended release pharmaceutical preparations regulates the release of the incorporated active ingredient(s) over time thereby accomplishing therapeutic effectiveness and/or convenience objectives not offered by conventional dosage forms. It is widely known in the art that modified release of active ingredient(s) improves patient's compliance by reducing the dosing frequency and attenuates adverse events related to fluctuations in drug plasma concentration due to immediate release dosage forms. Hence it would be advantageous to formulate an extended release dosage form for oral administration containing a drug, for example, oiopatadine or a pharmaceutically acceptable salt thereof.
Oiopatadine is a selective histamine HI receptor antagonist which has a inhibitory action on production/release of chemical mediators (leukotrienes, thromboxane and platelet aggregation

factor). Olopatadine and its acid addition salt, metal salt, ammonium salt, organic amine addition salt and amino acid addition salt thereof are disclosed in US Patent No. 5,116,863. 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. Olopatadine is commercially available as the hydrochloride salt under the trade names ALLELOCK® conventional tablets from Kyowa Hakko Kogyo Co., Ltd., Japan, as PATADAY™ ophthalmic solution for topical administration to the eyes from Alcon Laboratories Inc., USA, 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.
ALLELOCK® conventional tablets are currently administered twice daily, in morning and before going to bed. Hence, it would be advantageous to formulate once daily dosage regimen for olopatadine HCI as it would exhibit better patient compliance in outpatient therapy, thereby eliminating the complications and residual morbidity resulting from non-adherence with the prescribed medication. In general once daily formulation offers the advantage of patient compliance to an extent of 84%, while the twice and thrice daily regimens shows compliance only to an extent of 75% and 59% respectively. The elimination half life of olopatadine is 8-12 hrs in plasma which is entirely compatible, from the pharmacokinetic point of view, with the design of a once daily extended-release formulation. Olopatadine being a amphoteric compound with low lipophilicity, shows low incidence of CNS side effects. There are also references in the art which describes that an increased plasma concentration of olopatadine by 1.7 times, over that achieved by 5 mg twice daily formulation, do not cause serious safety concern.
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 covers 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 pharmaceutically 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 comprising olopatadine and a polymeric ingredient, the improvement wherein the amount of olopatadine in the solution is 0.17-0.62% (w/v), 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.

In the present invention, the inventors describe the extended release dosage form for oral administration comprising an effective amount of olopatadine or a pharmaceutically acceptable salt thereof.
Summary of the Invention
In one general aspect, it relates to an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients.
In another general aspect, it relates to an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein other pharmaceutically acceptable excipient(s) is selected from one or more of diluent(s), binder(s), lubricant(s) and glidant(s).
In another general aspect, it relates to an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein the extended release dosage form comprises a tablet core containing olopatadine or a pharmaceutically acceptable salt thereof and a coating containing the rate-controlling polymer over said tablet core.
In another general aspect, it relates to an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein the extended release dosage form comprises pellets wherein each pellet comprises an inert core onto which is applied a coating containing olopatadine or a pharmaceutically acceptable salt thereof and a binder and said coated core is further coated with coating containing the rate-controlling polymer.
In another general aspect, it relates to a process of preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein the process comprises of dispersing olopatadine or pharmaceutically acceptable salt thereof in the rate-controlling polymer and one or more pharmaceutically acceptable excipient(s) selected from diluent(s), binder(s), lubricant(s) and glidant(s) and processing into a dosage form.

In another general aspect, it relates to a process of preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein the process comprises of applying a coating containing rate-controlling polymer over a tablet core containing olopatadine or a pharmaceutically acceptable salt thereof.
In another general aspect, it relates to a process of preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein the process comprises of applying over each pellet a coating containing olopatadine or a pharmaceutically acceptable salt thereof and a binder and onto which coated core is further applied a coating containing the rate-controlling polymer.
In another general aspect, it relates to an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients wherein olopatadine remains available in therapeutically affective amount for a period of upto 24 hrs to a human subject in need thereof.
Detailed Description of the Invention
As used herein, the term "extended release dosage form" refers to a dosage form which maintains the therapeutic blood concentration of the drug over a prolonged period of time thereby reducing the dosing frequency of the drug. The extended release dosage form can be further illustrated as a dosage form wherein the drug is dispersed in a rate-controlling polymer, or which has a core containing the drug and is further coated with a rate controlling polymer, or which has pellets wherein each pellet has an inert core containing the drug and is coated with a rate controlling polymer.
The term "therapeutically effective amount" as used herein refers to the amount of olopatadine or pharmaceutically acceptable salt thereof contained in the orally administered composition is of sufficient quantity to reduce, eliminate, treat, prevent or control the symptoms of a disease or condition affecting a human. Generally, the dosage may be between 1 and 100 mg; particularly, it may be between 1 and 50 mg; more particularly it may be between 1 and 20 mg.
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 of the embodiments the salt form of olopatadine may be olopatadine hydrochloride.
The rate controlling polymer may be both hydrophilic and hydrophobic polymers selected from one or more of methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, xanthum gum, polyethylene oxide, ethylcellulose, cellulose acetate, polyvinyl pyrollidone, and enteric polymers selected from one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropylmethyl phthalate, hydroxypropyl methylcellulose acetate succinate; enteric grades of methacrylic acid and ammoniomethacrylic acid polymers, such as Eudragit L30D-55, Eudragit FS30D and combinations thereof.
Other pharmaceutically acceptable excipients may be selected from diluent(s), binder(s), glidant(s), and lubricant(s).
The diluent(s) used may be selected from, but are not limited to, lactose, microcrystalline cellulose, starch, pregelatinized starch, calcium sulphate, calcium carbonate, kaolin, powered cellulose, polyols such as mannitol, sorbitol, xylitol, lactitol, dicalcium phosphate, tricalcium phosphate or combinations thereof.
The binder(s) used may be selected from, but are not limited to, carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, starch and its derivative like corn starch and pregelatinized starch, polyvinylpyrrolidone, polyethylene glycols, polyvinyl acetate, polyvinyl alcohol or combinations thereof.
The glidant(s) used may be selected from, but are not limited to, colloidal silica, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate and the like. Colloidal silica may be colloidal silica anhydrous.
The lubricant(s) used may be selected from, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate and the like.
Suitable solvents for granulation or coating processes may include aqueous or non-aqueous solvent or mixtures thereof selected from one or more of methylene chloride, isopropyl alcohol, polyvinyl alcohol, acetone, methanol, ethanol, water, and combination thereof.

The extended release dosage form may be prepared by employing conventional techniques known in the art, comprising of dry granulation, wet granulation, direct compression and combinations thereof. The extended release dosage form may be prepared by mixing a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt and rate controlling polymer and other pharmaceutically acceptable excipients; further granulating the blend or directly compressing into a dosage form. The extended release dosage form may also be obtained by coating the core or pellets containing olopatadine or pharmaceutically acceptable salt thereof with a rate-controlling coating containing the rate-controlling polymer wherein the coating excipient may further comprise of one or more of other film forming polymer(s) and plasticizer(s).
The film forming polymer(s) may be selected from one or more of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl hydroxyethyl cellulose, ethylcellulose and sodium carboxymethyl cellulose.
The plasticizer(s) may be selected from acetyltributyl citrate, acetyltriethyl citrate, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, triacetin, tributyl citrate, or triethyl citrate.
The pellets used for extended release may be selected from one or more of non pareils seeds comprising sugar and corn starch, MCC pellet, starch pellet, glass pellets and the like. In one of the embodiments the pellets may be sugar spheres.
In one embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceutically acceptable salt thereof and one or more of the pharmaceutically acceptable excipient(s) selected from diluent(s), binder(s) and glidant(s) are mixed in a suitable blender; ii. the blended material of step (i) is roll compacted and sized in a suitable mesh to form
granules; iii. the granules of step (ii) are mixed with one or more of rate-controlling polymers; and
one or more of other pharmaceutical excipient(s); iv. the blend of step (iii) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically

acceptable salt thereof, a rate-controlling polymer, and other pharmaceuticaliy acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceuticaliy acceptable salt thereof, one or more of rate-controlling polymer; and one or more of the pharmaceuticaliy acceptable excipient(s) selected from diluent(s), binder(s) and glidant(s) are mixed in a suitable blender; ii. the blended material of step (i) is roll compacted and sized in a suitable mesh to form
granules; iii. the granules of step (ii) are optionally mixed with one or more of other pharmaceutical
excipient(s); iv. the blend of step (iii) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceuticaliy acceptable salt thereof, a rate-controlling polymer, and other pharmaceuticaliy acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceuticaliy acceptable salt thereof and one or more of the pharmaceuticaliy acceptable excipient(s) selected from diluent(s) and binder(s) are mixed in a suitable blender; ii. the blended material of step (i) is granulated with a suitable solvent; iii. the granules of step (ii) are dried and sized; iv. the dried granules of step (iii) are mixed with one or more of rate-controlling polymer;
and one or more of other pharmaceutical excipient(s); v. the granules of step (iv) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceuticaliy acceptable salt thereof, a rate-controlling polymer, and other pharmaceuticaliy acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceuticaliy acceptable salt thereof, one or more of rate-controlling polymer; and one or more of the pharmaceuticaliy acceptable excipient(s) selected from diluent(s) and binder(s) are mixed in a suitable blender; ii. the blended material of step (i) is granulated with a suitable solvent; iii. the granules of step (ii) are dried and sized;
iv. the dried granules of step (iii) are optionally mixed with one or more of other pharmaceutical excipient(s);

v. the granules of step (iv) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceutically acceptable salt thereof and one or more of the pharmaceutically acceptable excipient(s) selected from diluent(s), and binder(s) are mixed in a suitable blender; ii. the blend of step (i) is mixed with one or more of rate-controlling polymer; and one or
more of other pharmaceutical excipient(s); iii. the blend of step (ii) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceutically acceptable salt thereof, one or more of rate-controlling polymer and one or more of the pharmaceutically acceptable excipient(s) selected from diluent(s) and binder(s) are mixed in a suitable blender; ii. the blend of step (i) is optionally mixed with one or more of other pharmaceutical
excipient(s); iii. the blend of step (ii) is lubricated with a suitable lubricant and compressed into a tablet using appropriate tooling.
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients comprises of the following steps;
i. olopatadine or a pharmaceutically acceptable salt thereof and one or more of the pharmaceutically acceptable excipient(s) selected from diluent(s), binder(s), and glidant(s) are mixed in a suitable blender; ii. the blend of step (i) is lubricated with a suitable lubricant(s) and compressed into tablet with appropriate tooling;

iii. the compressed tablets of step (ii) is applied with a coating solution comprising one or more of rate controlling polymer and other pharmaceutically acceptable excipient(s) in suitable solvent(s).
In another embodiment, the process for preparing an extended release dosage form for oral administration comprising of a therapeutically effective amount of oiopatadine or a pharmaceutically acceptable salt thereof, a rate-controlling polymer, and other pharmaceutically acceptable excipients comprises of the following steps; a.
i. oiopatadine or its pharmaceutically acceptable salt thereof and one or more of polymeric binder(s) are dissolved or suspended in a suitable solvent and coated on sugar pellets to give first type of pellets; ii. the drug layered pellets of step (i) are optionally seal coated with a film forming polymer; b.
i. oiopatadine or its pharmaceutically acceptable salt thereof and one or more of polymeric binder(s) are dissolved or suspended in a suitable solvent and coated on sugar pellets; ii. the coated pellets of step (i) are further coated with enteric polymer dissolved in a suitable solvent to give second type of pellets. These two types of pellets can be mixed in different weight ratios to provide a desired dissolution profile or in-vivo profile.
The process for the preparation of an extended release dosage form for oral administration comprising an effective amount of oiopatadine or pharmaceutically acceptable salt thereof is further illustrated by the following examples but should not be construed as limiting the invention.
Example 1
(Table Removed)
Procedure
Olopatadine hydrochloride and the other intra granular materials were dispensed in quantities as per the formula and then sifted through a suitable sieve. The shifted intra granular materials were mixed in a polybag for few minutes. The mixed material thus obtained was compacted in a roller compactor and suitably sized by passing through a suitable mesh to form granules. The shifted extra granular materials (except magnesium stearate) were mixed with the granules. Magnesium stearate was then added to the above mixed material and mixed for few minutes. The lubricated blend thus obtained was compressed into tablets using a suitable tooling.
Example 2
(Table Removed)

Procedure
Olopatadine hydrochloride and the other intra granular materials were dispensed in quantities as per the formula and then sifted through a suitable sieve. Polyvinyl alcohol was dissolved in purified water under constant stirring to obtain polyvinyl alcohol solution. The shifted intra granular material obtained was granulated with polyvinyl alcohol solution and the wet mass was dried. The dried material was suitably sized by passing through a suitable mesh to form granules. The granules thus obtained were mixed with magnesium stearate. The lubricated blend thus obtained was compressed into tablets using a suitable tooling.
The extended release compositions may also be prepared as coated tablet such as given below: Example 3
(Table Removed)

Procedure
Olopatadine hydrochloride, lactose monohydrate, microcrystalline cellulose and pregelatinized starch are dispensed and shifted through a sieve of 40 mesh size. The shifted materials are mixed in a polybag. The blend is lubricated with shifted magnesium stearate. The lubricated blend is compressed into tablets using suitable tooling. The compressed tablets are applied with a coat with coating materials as per the formula given above.
Further, the extended release compositions may also be prepared as pellets filled in a suitable capsule such as given below:

Example 4
(Table Removed)

Procedure
Step I: Olopatadine hydrochloride, crospovidone and hypromellose solution or suspension in purified water is prepared and coated on sugar spheres. The drug layered pellets are seal coated with a coating containing hypromellose in purified water.
Step II: Olopatadine hydrochloride, crospovidone and hypromellose solution or suspension in purified water are prepared and coated on sugar spheres. The drug layered pellets are seal coated with a coating containing hypromellose in purified water. Enteric coating containing hypromellose phthalate and diethyl phthalate dissolved in acetone, is applied over the seal coated pellets.
Step III: Olopatadine hydrochloride, crospovidone and hypromellose solution or suspension in purified water is prepared and coated on sugar spheres. The drug layered pellets are seal coated with a coating containing hypromellose in purified water. Enteric coating containing Eudragit FS 30D dissolved in purified water is applied over the hyperomellose seal coat.
Step IV: The pellets obtained from step I, II and III are mixed and filled in suitable capsules.

WE CLAIM:
1) A extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate controlling polymer, and other pharmaceutically acceptable excipients.
2) The extended release dosage form according to claim 1, wherein the rate-controlling polymer is selected from one or more of methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, xanthum gum, polyethylene oxide, ethylcellulose, cellulose acetate, polyvinyl pyrollidone, cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl phthalate, hydroxypropylmethyl phthalate, hydroxypropyl methylcellulose acetate succinate, enteric grades of methacrylic acid and ammoniomethacrylic acid polymers, such as Eudragit L30D-55, Eudragit FS30D and combinations thereof.
3) The extended release dosage form according to claim 1, wherein other pharmaceutically acceptable excipient(s) is selected from one or more of diluent(s), binder(s), lubricant(s) and glidant(s).
4) The extended release dosage form according to claim 1, wherein the extended release dosage form comprises of:

a) a tablet core which comprises olopatadine or a pharmaceutically acceptable salt thereof;
b) a coating containing the rate controlling polymer over said core.

5) The extended release dosage form according to claim 1, wherein the extended release dosage form comprises pellets wherein each pellet comprises an inert core onto which is applied a coating containing olopatadine or a pharmaceutically acceptable salt thereof and a binder and the said coated core is further coated with a coating containing the rate controlling polymer.
6) A process of preparing an extended release dosage according to claim 1, wherein the process comprises of dispersing olopatadine or pharmaceutically acceptable salt thereof in the rate-controlling polymer and one or more pharmaceutically acceptable excipient(s) selected from diluent(s), binder(s), lubricant(s) and glidant(s) and processing into a tablet.
7) A process of preparing an extended release dosage according to claim 4, wherein the process comprises of applying a coating containing rate-controlling polymer over the tablet core comprising olopatadine or a pharmaceutically acceptable salt thereof.

8) A process of preparing an extended release dosage according to claim 5, wherein the process comprises of applying over each pellet a coating containing olopatadine or a pharmaceutically acceptable salt thereof and a binder and onto which coated core is further applied a coating containing the rate-controlling polymer.
9) The extended release dosage form according to claim 1, wherein olopatadine remains available in therapeutically affective amount for a period of upto 24 hrs to a human subject in need thereof.
10) A extended release dosage form for oral administration comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, a rate controlling polymer, and other pharmaceutically acceptable excipients substantially as described and exemplified herein.