Technical Field of the Invention
The present invention is directed to a taste masked resinate of desloratadine, its method of preparation, orally disintegrating dosage forms containing the same and uses thereof.
Background of the invention
Desloratadine is a well-known anti-histaminic compound. Chemically it is, 8-chloro-6,11- dihydro - 11 - (4-piperdinylidene) - 5H- benzo [5,6] cyclohepta [1,2-6]pyridine. It is indicated in allergic rhinitis, pruritis and idiopathic urticaria. Desloratadine is associated with a peculiar bitter taste, which stymies its formulation as an orally disintegrating dosage form. However, knowing that orally disintegrating dosage forms are endowed with the utmost pro i.e. they dissolve or disintegrate in the oral cavity in a relatively short time and do not need to be swallowed with water thus making the administration of medication easier. This is especially convenient for children and the elderly, who have traditionally had difficulties swallowing conventional dosage forms. In view of patient convenience it would be beneficial to formulate desloratadine as an orally disintegrating dosage form.
There are many different approaches to taste-mask pharmaceutically or physiologically active ingredients having an objectionable taste profile. These include simple wet granulation or roller compaction with excipients like flavours and sweeteners. Co-spray drying the active ingredient with a polymer can also be employed to veil the drug. If further taste masking is considered necessary, the resultant particles can be sealed with a suitable coating polymers, which include, for example, hydroxypropyl methylcellulose, ethylcellulose, methacrylates, Kollicoat®, and polyvinylpyrrolidone. Other approaches for taste masking embrace utilizing cyclodextrins and ion-exchange resins. The issue of taste masking is the most noteworthy with orally disintegrating dosage forms as skillful taste masking is the foremost requirement to hide the bitterness of the active ingredient.
Orally disintegrating dosage forms are well known from the literature. U.S. Patent No. 6,740,339 discloses quickly disintegrating solid preparations containing sugar alcohol, a disintegrating agent and celluloses. The sugar alcohol used therein has particle size between 30 to 300um. Another approach that has been disclosed
includes the use of sugar alcohol with two different particle sizes, one having finer particle size of 5 to 90pm and another having particle size of 90pm to 500pm. The advantage of using particular size of sugar alcohols is mentioned as having improved fluidity of tabletting blend during production of tablets.
U.S. Patent application 2003/0175355 discloses a drug formulation for gastrointestinal deposition comprising a free flowing plurality of particles comprising an active ingredient and a water soluble excipient wherein the particles have mean diameter of more than 10pm to about 1 mm and wherein the formulation is capable of dissolving or dispersing in a patient's mouth within 1 minute after administration without the co-administration of a fluid. The disclosed formulations have been prepared by melt granulation. The water soluble excipient has negative heat of solution of less than or equal to -7 Kcal/kg and is preferably a sugar alcohol or a combination of sugar alcohol.
The approach of utilizing an ion-exchange resin to taste-mask a disagreeable tasting active ingredient for oral administration has also been explored for some time, for example, U.S. Patent No. 5,071,646 discloses a granulated resin composition prepared by wet granulation comprising ion-exchange resin, a pharmacologically active ingredient bound thereto with the resin and a sugar or sugar alcohol. The patent further discloses that granular product containing drug-resin complex is readily dispersible than the powder product formed of a wetted mass and the granulated product gave homogeneous product in which the drug substance is dispersed uniformly throughout the composition while the dry mixed powder was non-homogeneous, the drug substance being non-uniformly distributed throughout the composition.
U.S. Patent No. 6,077,532 also discloses a process for preparing a granular pharmaceutical ion-exchange resin composition that is readily dispersible in water by granulating an ion exchange resin, having a pharmacologically active ingredient bound thereto using an aqueous solution of a sugar or sugar alcohol as a granulating medium instead of water. The disclosed process claims to provide better content uniformity.
U.S. Patent application 2005/0036977 relates to a taste-masked resinate that contains a water-insoluble active ingredient complexed to an ion-exchange resin in a taste-masking effective amount. It further discloses a process for preparing rapid disintegrating, taste-masked tablet, which comprises the step of filling a plurality of divided dosage units with a suspension containing resinate, one or more of carrier materials, structure imparting water soluble excipients, thickening agents, neutralizing agents, sweetening agents etc.; and removing the water from the finished dosage units by drying, for example, by lyophilization, centrifugation, spray drying, evaporation with or without heat source, filtration with or without a vacuum or combinations thereof.
Currently, taste-masking of desloratadine by complexation with ion-exchange resin is not known. The present invention relates specifically to a taste masked resinate of desloratadine, its method of preparation, orally disintegrating dosage forms containing the same and use thereof.
Summary of the Invention
In one general aspect, the present invention relates to a resinate comprising desloratadine complexed with a cation-exchange resin.
In another aspect, it relates to an orally disintegrating dosage form comprising a resinate comprising desloratadine complexed with a cation exchange resin, saccharide, disintegrant and other pharmaceutical^ acceptable excipients.
In another aspect, it relates to an orally disintegrating dosage from comprising a resinate comprising desloratadine complexed with a cation exchange resin, saccharide in an amount of 15% to 80% w/w, disintegrant in an amount of 0% to 15% w/w and other pharmaceutical^ acceptable excipients in an amount of 1% to 10% w/w of the dosage form.
In another aspect, it relates to a process for preparation of the orally disintegrating dosage form, wherein the process comprises blending resinate comprising desloratadine complexed with a cation exchange resin, saccharide, disintegrant and

other pharmaceutical^ acceptable excipients and processing the blend into a dosage form using suitable tooling.
In another aspect, it relates to a method of treatment of medical conditions responsive to desloratadine therapy comprising administering an orally disintegrating dosage form comprising a resinate comprising desloratadine complexed with a cation-exchange resin.
Detailed Description of the Invention
The preparation of a drug-resin complex or resinate is well known for e.g. from U.S. Patent No. 2,990,332 and British patents GB 824,337 and GB 1,218,102. In general, the drug is mixed with an aqueous suspension of the resin suspended in a liquid medium to allow for the complexation of drug with the resin. The resinate so formed may be separated via removal of the medium by evaporation or spray drying. In the present case, desloratadine and a cation exchange resin are suspended in a medium e.g. purified water to form a resinate dispersion. The medium may be removed by drying by means of rotary evaporation/thin film drying technique or by filtration. A solid taste masked resinate is obtained. Optionally, a pH adjusting agent, for example, citric acid or hydrochloric acid may be added to the suspension of desloratadine and cation exchange resin to adjust the pH such that maximum complexation is achieved.
One of the essential requirements for orally disintegrating dosage forms is that they need to disintegrate in a short period of time when placed in the oral cavity. The time for an orally disintegrating dosage form to disintegrate in the oral cavity also varies by product and the method of manufacturing. A compressed dosage form will typically take slightly longer time to disintegrate than freeze-dried dosage forms due to a different bonding mechanism and differences in porosity between the two dosage forms. However, by careful choice of excipients, the compressed dosage forms disintegration characteristics may be adjusted and similar to those of freeze dried dosage forms can be easily made.
An orally disintegrating dosage form as described herein means that the dosage form when placed in mouth would disintegrate in less than one minute, particularly in less than 40 seconds and more particularly in less than 20 seconds.
The orally disintegrating dosage forms of desloratadine with taste-masked properties may be prepared by first preparing a desloratadine-cation exchange resinate and then secondly, formulating the resinate into an orally disintegrating dosage form by mixing with saccharides(s) disintegrant(s) and other excipients like ,diluent(s) sweetening agent(s), flavoring agent(s) and lubricating agent(s).
Desloratadine for complexation with a resin may be used as a base. The ion exchange resin is a cation exchange resin, for example, Amberlite IRP-88 sold by Rohm and Haas Company. The ratio of desloratadine to resin may be from about 1:1 to about 1:10, particularly, from about 1:2 to about 1:6 by weight. The resinate may be incorporated in the dosage form in an amount sufficient to provide a unit therapeutic dose of desloratadine. Typically, the resinate may be incorporated in amount such that a dose of desloratadine from 0.1 mg to about 10 mg may be contained in the dosage form.
The saccharide may be selected from sugars like lactose, sucrose, maltose, glucose, and dextrose; and from sugar alcohols like mannitol, xylitol, sorbitol or mixtures thereof. Particularly suitable is mannitol.
The disintegrant may be selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinised starch, starch and starch derivatives, low hydroxypropyl cellulose, Polacrillin potassium and combinations thereof.
The diluents may be selected from microcrystalline cellulose, lactose, sucrose, mannitol, starches or modified starches and mixtures thereof.
Lubricating agent(s) may be selected from colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate and mixtures thereof.
Sweetening agent(s) may be selected from any natural or artificial sweeteners such as glucose, dextrose, fructose, saccharin, cyclamate, aspartame, sugar alcohols such as sorbitol, mannitol, xylitol and mixtures thereof.
Flavoring agent(s) may be selected from natural or synthetic flavoring agents such as volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins and extracts derived from plants, leaves, flowers, fruits, and stems and combinations thereof.
The orally disintegrating dosage form may be a tablet or granules filled in a sachet. Preferably the dosage form is a tablet.
In one embodiment, the process for the preparation of the orally disintegrating tablet comprises the steps of: (a) preparation of a taste-masked resinate of desloratadine and a cation exchange resin in an aqueous medium, if necessary balancing the medium pH by means of a suitable pH adjusting agent and drying the resinate suspension so formed by rotary evaporation/thin film drying technique to obtain a solid taste masked resinate; (b) blending the resinate with saccharide, disintegrant and other pharmaceutical^ acceptable excipients and compressing the blend into a tablet form using suitable tooling.
The following examples are illustrative of the invention, and is not intended to be construed as limiting the invention.
Example 1:-Preparation of desloratadine resinate
S. No. Ingredients Qty
(mg/tab)
Drug resinate complex
1. Desloratadine 5.0
2. Amberlite IRP 88 15.0
3. Citric acid anhydrous 3
4. Purified water q.s.
Process: Desloratadine and amberlite IRP 88 are suspended in purified water followed by addition of citric acid with continuous stirring. Subsequently, the resinate
dispersion is dried by means of rotary evaporation to obtain a solid taste masked resinate.
Alternatively, the resinate may be prepared by using hydrochloric acid instead of citric acid such as in example 2 below.
Example 2:-Preparation of desloratadine resinate
S. No. Ingredients Qty
(mg/tab)
Drug resinate complex
1. Desloratadine 5.0
2. Amberlite IRP 88 15.0
3. HCI q.s to adjust pH to
6.5
4. Purified water q.s.
Process: Desloratadine and amberlite IRP 88 are suspended in purified water followed by addition of hydrochloric acid with continuous stirring. Subsequently, the resinate dispersion is dried by means of rotary evaporation to obtain a solid taste masked resinate.
Example 3 Preparation of orally disintegrating tablets containing desloratadine resinate.
(TABLE REMOVED)

Process: Ingredients 1 to 6 are sifted through a suitable mesh and blended in a blender for 20 minutes. The above blend is mixed with colloidal silicon dioxide and magnesium stearate and compressed into a tablet using appropriate tooling.

WE CLAIM:-
1. A resinate comprising desloratadine complexed with a cation-exchange resin.
2. An orally disintegrating dosage form comprising resinate comprising desloratadine complexed with a cation exchange resin, saccharide, disintegrant and other pharmaceutically acceptable excipients.
3. The orally disintegrating dosage form according to claim 2 wherein the saccharide is selected from sugar and sugar alcohol.
4. The orally disintegrating dosage form according to claim 3, wherein the sugar is selected from lactose, sucrose, maltose, glucose, dextrose and mixtures thereof.
5. The orally disintegrating dosage form according to claim 3 wherein the sugar alcohol is selected from mannitol, xylitol, sorbitol and mixtures thereof.
6. The orally disintegrating dosage form according to claim 2, wherein the disintegrant is selected from sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, alginic acid and alginates, pregelatinized starch, starch and starch derivatives, low hydroxypropyl cellulose, polacrillin potassium and combinations thereof.
7. The orally disintegrating dosage form according to claim 2 wherein the other pharmaceutically acceptable excipients are selected from diluent(s) sweetening agent(s), flavoring agent(s) and lubricating agent(s).
8. The orally disintegrating dosage form according to claim 7 wherein the diluent is selected from microcrystalline cellulose, lactose, sucrose, mannitol, starches or modified starches and mixtures thereof.
9. The orally disintegrating dosage form according to claim 7, wherein the sweetening agent is selected from the group consisting of glucose, dextrose, fructose, saccharin, cyclamate, aspartame, sorbitol, mannitol, xylitol and mixtures thereof.
10. The orally disintegrating dosage form according to claim 7, wherein the flavoring agent is selected from the group consisting of natural or synthetic flavoring agents.
11. The orally disintegrating dosage form according to claim 7, wherein the lubricating agent is selected from colloidal silicon dioxide, talc, stearic acid, magnesium stearate, calcium stearate and mixtures thereof.
12. The orally disintegrating dosage form according to claims 1 or 2 wherein the dosage from is a tablet.
13. An orally disintegrating dosage from comprising a resinate comprising desloratadine complexed with a cation exchange resin, saccharide in an amount of 15% to 80% w/w, disintegrant in an amount of 0% to 15% w/w and other pharmaceutical;y acceptable excipients in an amount of 1% to 10% w/w of the dosage form.
14. A process for preparation of the orally disintegrating dosage form, wherein the process comprises blending resinate comprising desloratadine complexed with a cation exchange resin with saccharide, disintegrant and other pharmaceutically acceptable excipients and processing the blend into a dosage form.
15. The process according to claim 14, wherein the solid dosage form is a tablet.
16. The process according to claim 15, wherein the tablet is prepared by direct compression.
17. A method of treatment of medical conditions responsive to desloratadine therapy comprising administering an orally disintegrating dosage form comprising a resinate comprising desloratadine complexed with a cation-exchange resin.
18. The method according to claim 16, wherein the medical condition is selected from allergic rhinitis, pruritis and idiopathic urticaria.