MOUTH DISSOLVING TABLETS CONTAINING OLOPATADINE
Technical Field of Invention
The present invention relates to mouth dissolving tablets comprising olopatadine and the process of preparation of the same.
Background of the Invention
The conventional oral solid dosage forms, particularly tablets, for the administration of pharmaceutically active drugs are well known in the art. However, they have some inherent disadvantages like the need of sufficient amount of water to allow passing through the buccal cavity, delayed onset of action which depends upon the type of the tablet and its disintegration time and low patient compliance particularly with infants, minors and aged patients. To overcome these limitations, a new dosage form known as mouth dissolving dosage form is gaining acceptance as new means of oral drug delivery. The concept of mouth dissolving drug delivery emerged from the desire to provide patient with conventional way of taking their medications and simultaneously overcoming the major disadvantages of the conventional oral solid dosage forms. The major disadvantage of mouth dissolving drug delivery system is that, unpalatable and bitter drugs should be taste masked properly before administration Other terms used in the art to describe the mouth dissolving dosage forms include fast dissolving, quick dissolving, rapid dissolving, fast melting, melt-in mouth and orodispersible dosage forms
Mouth dissolving pharmaceutical compositions disintegrate rapidly or instantly in the oral cavity and allows administration of a solid dosage form of a pharmacologically active drug to a patient without the need to swallow the dosage form. These dosage forms are meant to disintegrate and/or dissolve in the oral cavity in matter of seconds or so without the aid of water to form a suspension or solution of the drug after mixing with the saliva. The saliva containing the dissolved or dispersed medicament is then swallowed and the drug is absorbed in the normal way Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down into the stomach and may produce rapid onset of action Thus the mouth dissolving formulations combines the advantages of both liquid and conventional tablet formulations, while also offering advantages over both traditional dosage forms. It provides the convenience of a tablet formulation, while also allowing the ease of
swallowing provided by a liquid formulation. Hence it would be advantageous to formulate mouth dissolving pharmaceutical composition containing a drug, for example, olopatadine or a pharmaceutically acceptable salt thereof.
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). 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. 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.
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 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
The present invention relates to mouth dissolving tablets comprising olopatadine or a pharmaceutically acceptable salt thereof and the process of preparation of the same.
Summary of the Invention
In one general aspect, it relates to mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s).

In another general aspect, it relates to mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s) wherein the other pharmaceutically acceptable excipient(s) comprises diluent(s), binder(s), disintegrant(s), flavoring agent(s), glidant(s) and/or lubricant(s).
In another general aspect, it relates to mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s) wherein the mouth dissolving tablets exhibit a hardness of about 3 kilopound (kp) or less.
In another general aspect, it relates to mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s) wherein the mouth dissolving tablets exhibit a percentage friability of less than about 1% and disintegration time of less than about 60 seconds.
In another general aspect, it relates to process of preparing mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s), wherein the process comprises of the following steps: I. one or more of binder(s) is dissolved or dispersed in a suitable solvent to form a binder
solution II olopatadine or a pharmaceutically acceptable salt thereof is dissolved or dispersed in the
binder solution of step (I) to form a suspension. III. one or more of sugars or sugar alcohols, one or more of superdisintegrants and one or
more of diluent(s) and/or d!sintegrant(s) are mixed together to form a blend and the
resulting blend is transferred to a suitable granulator.
IV the blend of step (III) is granulated with the suspension of step (II) and the granules formed thereby are dried and sized,
V the dried granules of step (IV) are mixed with one or more of sweetening agents; one or more of superdisintegrants; and one or more of diluent(s), disintegrant(s) and/or flavoring agent(s) to form the final blend
VI. the final blend of step (V) is lubricated with suitable lubricant(s) and compressed into tablets using appropriate tooling.
Detailed Description of the Invention
As used herein, the term "mouth dissolving tablets" refers to a tablet composition which disintegrates, as per the Indian Pharmacopoeia (2007), 5th Edition, Vol. I, Appendix 2.5.1., in less than 60 seconds; particularly in less than 30 seconds; more particularly in less than 10 seconds
The term "therapeutically effective amount" as used herein refers to the amount of olopatadine or pharmaceuticalty acceptable salt thereof contained in the mouth dissolving tablets 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 term "sweetening agent" as used herein refers to the pharmaceutical agents which are added to impart a sweet taste to the tablet formulation with an objective of masking the bitter taste of the active ingredient during oral administration. Sweetening agents used may be selected from, but are not limited to simple sugars like sucrose, lactose, galactose, fructose and the like; artificial sweetening agents like aspartame, acesulfame potassium, saccharin sodium, cyclamates, glycyrrhizin and the like. The sweetening agent may be present in an amount from about 0.1% to about 10%, particularly in an amount from about 1% to about 8%, more particularly in an amount from about 2% to about 6% by weight of the tablet.
The term "superdisintegrant" as used herein refers to the pharmaceutical agents which facilitate tablet disintegration when placed in the aqueous environment such as the mouth. The superdisintegrants according to the present invention facilitates the disintegration of the mouth dissolving tablets in time less than 60 seconds, particularly less than 30 seconds, more particularly less than 10 seconds when placed in mouth. Examples of the
superdisintegrants include but are not limited to modified starches like sodium starch glycolate, modified cellulose like carboxymethyl cellulose and its derivative e.g. croscarmellose sodium, cross-linked polyvinyl Ipyrrolidone, soy polysaccharide, cross-linked alginic acid and ion exchange resins like indion or polacrilin potassium. The superdisintegrant may be present intra-granularly in an amount from about 0% to about 10% by weight of the tablet and extra-granularly in an amount from about 0% to about 20% by weight of the tablet. In total, superdisintegrant may be present in an amount from about 1% to about 20%, particularly in an amount from about 2% to about 10% by weight of the tablet.
The sugars or sugar alcohols used may be selected from, but are not limited to mannitol, spray dried mannitol, lactose, sucrose, maltose, dextrose, sorbitol, xylitol, maltitol, lactitol, and maltodextrins In one of the embodiments the sugar or sugar alcohol may be mannitol. The sugar or sugar alcohol may be present in an amount from about 1% to about 80%, particularly in an amount from about 10% to about 60%, more particularly in an amount from about 20% to about 60% by weight of the tablet.
The diluent(s) used may be selected from, but are not limited to microcrystalline cellulose, lactose, 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 diluent(s) may be present in an amount from about 1% to about 90%, particularly in an amount from about 10% to 80%, more particularly in an amount from about 20% to about 60% by weight of the tablet.
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 binder(s) may be present in an amount from about 1% to about 20%, particularly in an amount from about 2% to 15% by weight of the tablet.
The disintegrant(s) used may be selected from, but are not limited to microcrystalline cellulose, polyvinyl pyrrolidone, low-substituted hydroxypropylcellulose, alginic acid, calcium salts and potassium salts of carboxymethyl cellulose, colloidal silicon dioxide, guar gum, magnesium aluminum silicate, methylcellulose, powdered cellulose, starch, and sodium alginate. The disintegrant(s) may be present in an amount from about 1% to about 80%, particularly in an amount from about 10% to about 60%, more particularly in an amount from about 20% to about 50% by weight of the tablet.
The flavoring agent(s) used may be selected from, but are not limited to the essential oils or water soluble extracts of menthol, wintergreen, peppermint, sweet mint, spearmint, vanillin, cherry, chocolate, cinnamon, clove, lemon, orange, raspberry, rose, spice, violet, herbal, fruit, strawberry, grape, pineapple, peach, kiwi, papaya, mango, coconut, apple, coffee, plum, watermelon, nuts, durean, green tea, grapefruit, banana, mixed fruit and combination thereof The flavoring agent(s) may be present in an amount from about 0.1% to about 10%, particularly in an amount from about 1% to about 6%, more particularly in an amount from about 1% to about 4% by weight of the tablet.
The glidant(s) may include, but are not limited to, colloidal silica, magnesium trisilicate, powdered cellulose, talc, tribasic calcium phosphate and the like. The glidant(s) may be present in an amount from about 0 1% to about 10%, particularly in an amount from about 1% to about 8%, more particularly in an amount from about 2% to about 4% by weight of the tablet
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. The lubricant(s) may be present in an amount from about 0 01% to about 5%, particularly in an amount from about 0.1% to about 3% by weight of the tablet.
One or more of the suitable solvents selected for granulation may include aqueous or nonaqueous solvent or mixtures thereof selected from one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water, and combination thereof.
The mouth dissolving tablets may be prepared by employing conventional techniques known in the art, comprising of dry granulation, wet granulation, direct compression and
combinations thereof
Hardness for the mouth dissolving tablets may be measured utilizing a Schleuniger digital hardness tester. Disintegration time for the tablets may be determined by following the procedure as per the indian Pharmacopoeia (2007), 5th Edition, Vol. !, Appendix 2.5.1. Percentage friability for the tablets may be determined utilizing a conventional friability test apparatus and following the procedure as per the Indian Pharmacopoeia (2007), 5m Edition, Vol I. Appendix 2.5 5
In one embodiment, the process of preparing mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s) comprises of the following steps:
i. binder(s) is dissolved or dispersed in a suitable solvent to form a binder solution. ii. olopatadine or a pharmaceutically acceptable salt thereof is dissolved or dispersed in the
binder solution of step (i) to form a suspension. iii. sugar or sugar alcohol, superdisintegrant and diluent(s) and/or disintegrant(s) are mixed
together to form a blend and the resulting blend is transferred to a suitable granulator. iv the btend of step (iii) is granulated with the suspension of step (ii) and the granules
formed thereby are dried and sized v. the dried granules of step (iv) are mixed with sweetening agent; superdisintegrant; and
diluent(s), disintegrant(s) and/or flavoring agent(s) to form the final blend, vi. the final blend of step (v) is lubricated with suitable lubricant(s) and compressed into tablets using appropriate tooling.
In another embodiment, the process of preparing mouth dissolving tablets comprising of a therapeutically effective amount of olopatadine or a pharmaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharmaceutically acceptable excipient(s) comprises of the following steps
i. povidone is dissolved or dispersed in purified water to form a binder solution. ii. olopatadine hydrochloride is dissolved or dispersed in the binder solution of step (i) to
form a suspension, iii mannitol croscarmellose sodium and microcrystailine cellulose are mixed together to
form a blend and the resulting blend is transferred to a suitable granulator. iv. the blend of step (iii) is granulated with the suspension of step (ii) and the granules
formed thereby are dried and sized. v. the dried granules of step (iv) are mixed with aspartame, crospovidone, microcrystalline
cellulose mixed fruit flavour and mint flavour to form the final blend. vi. the final blend of step (v) is lubricated with magnesium stearate and compressed into tablets using appropriate tooling.
The process for the preparation of a mouth dissolving pharmaceutical composition comprising an effective amount of olopatadine 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
Povidone was dissolved in purified water. Olopatadine was dispersed in the povidone solution to form a suspension. Mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together geometrically and shifted through sieve no. 44. The shifted blend was transferred to rapid mixer granulator. This blend was granulated with the suspension. The wet granules thus obtained were dried and subsequently passed through a suitable sieve. The dried granules were blended with shifted microcrystalline cellulose, crospovidone, aspartame, mixed fruit flavor and mint flavor in a suitable blender to form the final blend. The final blend thus obtained was lubricated with shifted magnesium stearate. The lubricated blend was compressed into tablets using suitable tooling. The tablet had hardness of between 2.3 to 2.6 kp and friability of 0.09%. The disintegration time in USP disintegration apparatus A was between 4-5 seconds.
Example 2

(Table Removed)
Povidone was dissolved in purified water. Olopatadine was dispersed in the povidone solution to form a suspension. Mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together geometrically and shifted through sieve no. 44. The shifted blend was transferred to rapid mixer granulator. This blend was granulated with the suspension The wet granules thus obtained were dried and subsequently passed through a suitable sieve. The dried granules were blended with shifted microcrystalline cellulose, crospovidone, aspartame mixed fruit flavor and mint flavor in a suitable blender to form the final blend The final blend thus obtained was lubricated with shifted magnesium stearate. The lubricated blend was compressed into tablets using suitable tooling. The tablet had hardness of between 2.3 to 2.5 kp and disintegration time in USP disintegration apparatus A was between 4-5 seconds
Example 3

(Table Removed)
Povidone was dissolved in purified water. Olopatadine was dispersed in the povidone solution to form a suspension. Mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together geometrically and shifted through sieve no. 44. The shifted blend was transferred to rapid mixer granulator. This blend was granulated with the suspension. The wet granules thus obtained were dried and subsequently passed through a suitable sieve. The dried granules were blended with shifted microcrystalline cellulose, crospovidone, aspartame, mixed fruit flavor and mint flavor in a suitable blender to form the final blend. The final blend thus obtained was lubricated with shifted magnesium stearate. The lubricated blend was compressed into tablets using suitable tooling. The tablet had hardness of between 2.4 to 2.7 kp and friability of 0.25%. The disintegration time in USP disintegration apparatus A was between 7-8 seconds.
Example 4

(Table Removed)
Povidone was dissolved in purified water. Olopatadine was dispersed in the povidone solution to form a suspension. Mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together geometrically and shifted through sieve no. 44. The shifted blend was transferred to rapid mixer granulator. This blend was granulated with the suspension. The wet granules thus obtained were dried and subsequently passed through a suitable sieve. The dried granules were blended with shifted microcrystalline cellulose crospovidone, aspartame, mixed fruit flavor and mint flavor in a suitable blender to form the final blend The final blend thus obtained was lubricated with shifted magnesium stearate. The lubricated blend was compressed into tablets using suitable tooling. The tablet had hardness of between 2.4 to 2,7 kp and friability of 0.18%. The disintegration time in USP disintegration apparatus A was between 5-6 seconds.

WE CLAIM:
1. A mouth dissolving tablet comprising of a therapeutically effective amount of olopatadine or a pharrnaceutically acceptable salt thereof, one or more sugars or sugar alcohols, one or more superdisintegrants, one or more sweetening agents and other pharrnaceutically acceptable excipients
2. The mouth dissolving tablet according to claim 1, wherein the other pharmaceutical^ acceptable excipients comprises of diluents, binders, disintegrants, flavoring agents, glidants and/or lubricants as herein described.
3. The mouth dissolving tablet according to claim 1, having hardness of about 3 kilopond or less.
4. The mouth dissolving tablet according to claim 1, having percentage friability of less than about 1%
5. The mouth dissolving tablet according to claim 1, having disintegration time of less than about 60 seconds,
6. The mouth dissolving tablet according to any of the preceding claims, prepared by a process wherein the process comprises the steps of:
i. dissolving or dispersing one or more of binder(s) in a suitable solvent to form the
binder solution. ii. dissolving or dispersing olopatadine or a pharrnaceutically acceptable salt thereof in
the binder solution of step (i) to form a suspension. iii. mixing one or more of sugars or sugar alcohols, one or more of superdisintegrants
and one or more of diluents and/or disintegrants to form a blend and transferring the
resulting blend to a suitable granulator. iv granulating the blend of step (iii) with the suspension of step (ii) and drying and sizing
the granules thus formed v. mixing the dried granules of step (iv) with one or more of sweetening agents; one or
more of superdisintegrants; and one or more of diluents, disintegrants and/or
flavoring agents to form the final blend. vi. lubricating the final blend of step (v) with a suitable lubricant and compressing the
lubricated blend into tablets using suitable tooling.
7, The mouth dissolving tablet according to claim 1, wherein the tablet comprises
olopatadine hydrochloride, povidone, croscarmellose sodium, mannitol, crospovidorie
and aspartame.
8. A mouth dissolving tablet comprising olopatadine or a pharmaceutically acceptable salt
thereof substantially as described and exemplified herein.