Field of the Invention
The present invention relates to taste masked orally disintegrating ondansetron formulations, process of making thereof and method of using such formulations.
Background of the Invention
Ondansetron, 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl]-4H-carbazol-4-one is a selective serotonin 5HT3 receptor blocking agent. It is widely used in the prevention of nausea and vomiting associated with cancer chemotherapy, radiotherapy and that occurring post-operatively.
Oral administration is the most preferred and popular route due to ease of ingestion, pain avoidance, versatility, provision of self-medication and most importantly, patient compliance. Among the oral formulations the tablets, capsules and pills are the most widely used. Despite of their advantages, oral solid dosage formulations suffer from several drawbacks. Difficulty in swallowing (dysphagia) is common among all age groups and is more prominent in elderly or pediatric patients and, this is also seen in swallowing conventional tablets and capsules. In case of patients with psychosis and other mental disorders the administration of conventional solid dosage form is not always suitable due to patient noncompliance. The problem of swallowing is also more evident in traveling patients who may not have ready access to water. Orally disintegrating formulations overcome these problems by allowing the convenient oral administration in case of pediatric/geriatric patients, stroke victims, bedridden patients who cannot swallow the conventional solid oral formulations. These kinds of formulations would also be useful in patients who refuse to swallow the conventional tablets or capsules. Apart from the enhanced patient compliance, orally disintegrating formulations may also improve the bioavailability of certain drug candidates by enhancing dissolution and absorption.
U.S. Patents 5,955,488 and 6,063,802 disclose freeze-dried dosage form of ondansetron for oral administration capable of being rapidly disintegrating in the mouth. However, this product has poor physical integrity of its physical structure and also suffers from high production cost. Also these dosage forms are fragile thus requiring
special packaging, storage and handling conditions and, patient counseling in using these formulations.
WO 00/57857 teaches a rapidly disintegrating tablet for oral administration comprising a therapeutically effective amount of an active ingredient, spray dried mannitol, crospovidone, citric acid and one or more pharmaceutically acceptable excipients.
WO 04/096214 describes a taste masked orally disintegrating composition of ondansetron or a pharmaceutically acceptable salt thereof. The composition comprises a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
WO 05/077341 discloses an orally disintegrating pharmaceutical composition comprising ondansetron, a filler and at least one disintegrant. This composition is effective in providing taste masking without using any additional taste masking agent.
The prior art teach the use of conventional taste masking agents to obtain pleasant feel orally disintegrating formulations. An ideal orally disintegrating formulation must disintegrate in saliva while maintaining the pleasant taste and mouth feel to allow maximum patient acceptability. Thus, taste masking is of critical importance in the formulation of acceptable orally disintegrating formulations. Current methods of taste masking include sweeteners and flavors; however, these are not a sufficient means for taste-masking many bitter or foul tasting drugs like ondansetron. The other methods of taste masking include adsorption onto or complexation with carriers and spray coating of drug particles. In case of coated or lyophilized particles, the particle coating used for taste masking might be compromised by fracture during compression at higher pressures and, formulations with low applied compression pressure might give a weaker and fragile composition.
In the recent years, ion exchange resins have gained popularity, as both taste masking agents as well as disintegrating agents in the development of orally disintegrating formulations. These ion exchange resins provide an effective and superior taste masking compared to conventional taste masking agents. Drug resinates, i.e., drug and resin complexes, are insoluble and hence, even resinate of
bitter drugs have virtually no taste. With proper selection of the ion exchange resin, the drug is not released in the mouth so that the patient does not taste the drug when it is swallowed. When the drug resinate comes into contact with the gastrointestinal fluids, such as the acid of the stomach, the drug is released from the resinate, directly into solution and then absorbed in the usual way. Also, these resins impart increased strength to the tablets with increase in the compression pressure without prolonging the disintegration time, which, otherwise, is a common trend in case of conventional taste masking agents or disintegrants.
Of late, some orally disintegrating formulations have been reported that use ion exchange resins for taste masking and/or for enhancing dispersibility/disintegration.
U.S. patent 5,071,646 teaches a method of producing an ion exchange resin composition that readily disperses in water. The resin compositions are obtained by granulating the ion exchange resin having an active ingredient bound thereto with a sugar or sugar alcohol, and a sufficient amount of water, alcohol or aqueous alcohol to facilitate granulation. WO 97/09036 discloses an improved process of preparing a granular pharmaceutical ion exchange resin composition compared to US5071646. The granulation process is characterized by the use of an aqueous solution of sugar or sugar alcohol as a granulating medium.
US20050036977 discloses a taste-masked resinate that contains a bitter tasting water-insoluble active substance complexed to an ion-exchange resin in a taste-masking effective amount. The taste-masked resinate may be employed in the manufacture of pharmaceutical compositions, including dosage forms such as rapid-disintegrating tablets, rapid-disintegrating films, effervescent tablets, chewable tablets, chewing gum, suspensions, sprinkle granules and powder for reconstitution in suspension.
US20030186938 discloses a water-dispersible formulation of paroxetine for immediate oral administration comprising a dry blend of paroxetine, a water-soluble dispersing agent, and a taste-masking agent, as a dispersible powder or moulded into a tablet. This patent application teaches the use of potassium salt of polyacrylic acid ion exchange resins, such as Polacrilin K, in obtaining an effective taste masked composition of paroxetine.
However, none of the prior art discussed above disclose or suggest the use of ion exchange resins in the formulation of taste masked orally disintegrating composition of ondansetron. Thus the present invention relates to the development of taste masked orally disintegrating ondansetron formulations with superior taste masking and better disintegration characteristics. Further, these formulations are cost effective and are easy to manufacture on commercial scale without requiring complex processing steps.
Summary of the Invention
According to one embodiment there is provided a taste masked orally disintegrating ondansetron formulation comprising ondansetron resinate, a disintegrant and optionally one or more pharmaceutically acceptable excipients. The ondansetron resinate comprises ondansetron, an ion exchange resin and optionally a pH modifying agent. The formulation provides effective taste masking of ondansetron along with quick oral disintegration thereby enhancing patient acceptability.
According to another embodiment there is provided a process for the preparation of a taste masked orally disintegrating ondansetron formulation, the process comprising the steps of: a) adding ondansetron, an ion exchange resin and optionally a pH modifying agent to an aqueous medium, optionally stirring, followed by filtration and drying to obtain ondansetron resinate particles; b) mixing the ondansetron resinate particles of step a) with a disintegrant and optionally one or more pharmaceutically acceptable excipients to obtain a blend; and c) filling the blend into a pack or compressing the blend into tablets.
According to further embodiment there is provided a method of treating one or more of emesis, nausea, and vomiting associated with cancer chemotherapy, radiotherapy, and/or that occurring post-operatively in a patient in need thereof, the method comprising administering a taste masked orally disintegrating ondansetron formulation comprising ondansetron resinate, a disintegrant and optionally one or more pharmaceutically acceptable excipients.
Detailed Description of the Invention
The term 'orally disintegrating' as used herein refers to the composition, which disperses in water or saliva within about 60 seconds or less, preferably within about 30 seconds or less.
The "ondansetron resinate" comprises ondansetron, an ion exchange resin and optionally a pH modifying agent.
Ondansetron includes ondansetron, single enantiomers, pharmaceutically acceptable salts, solvates and mixtures thereof.
The "ion exchange resins" preferably include cation exchange resins. The cation exchange resins may be derived from copolymers of acrylic acid and divinylbenzene having macroreticular matrix and containing carboxylic acid groups. A particularly suitable cation exchange resins useful in the present invention may be polacrilin potassium, polacrilex resin and the like. Amberlite resin grade IRP-88 (Amberlite IRP-88) (commercial name of polacrilin potassium) uses potassium ion as the exchange ion. Amberlite resin grade IRP-64 (Amberlite IRP-64) (commercial name of polacrilex resin) uses hydrogen ion as the exchange ion. Preferably, the cation exchange resin is polacrilin potassium (Amberlite IRP-88). The ratio of ion exchange resin to ondansetron ranges from 4:1 to 12:1. Preferably, the ratio of ion exchange resin to ondansetron is from 4:1 to 10:1. More preferably, the ratio of ion exchange resin to ondansetron is 5:1.
The term "pH modifying agent" may include one or more of citric acid, ascorbic acid, tartaric acid, ethanoic acid and mixtures thereof. These agents aid in the formation of ondansetron resinates preferably by providing the media pH that induce the ionization of the ondansetron or formation of charged ondansetron molecules in the aqueous media. This ionization favors the formation of ondansetron resin complex (resinate) in the aqueous medium. Preferably, the pH modifying agent is citric acid.
Suitable disintegrants include one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose and mixtures thereof. Among these, croscarmellose sodium is preferred one. The disintegrant may be present from about 1% to about 15% w/w of the formulation.
Preferably, the disintegrant is present in an amount from about 2% to about 10% w/w of the formulation.
The "pharmaceutically acceptable excipients" may be selected from one or more of fillers, binders, lubricants, sweetening agents, coloring agents, flavoring agents and mixtures thereof. The fillers may include saccharides selected from one or more of lactose, sucrose and glucose; and sugar alcohols selected from one or more of mannitol, sorbitol, xylitol, maltitol and mixtures thereof. Preferably, the filler is mannitol, more preferably spray dried mannitol (Pearlitol SD 200). The fillers may be present from about 10% to about 90% w/w of the formulation. Preferably, the fillers are present in an amount from about 30% to about 80% w/w of the formulation.
The binder may be selected from one or more of vinylpyrrolidone, cellulose, carbopol and gum. The lubricants may be selected from one or more of talc, colloidal silicon dioxide, magnesium stearate and zinc stearate. The amount of lubricants may be from about 0.1% to about 8% w/w. Preferably, the amount of lubricant is from about 0.5% to about 5% w/w. Suitable sweetening agents include one or more of aspartame, saccharin sodium, sucralose and acesulfam K.
The formulations of the present invention can be provided in the form of granules, tablets or in any other suitable oral dosage forms packed into sachet, bottles, unit dose pack or any other suitable packs.
The process for the preparation of a taste masked orally disintegrating ondansetron formulation includes formation of a ondansetron resinate by adding ondansetron, an ion exchange resin and optionally pH modifying agents in an aqueous medium. The aqueous suspension is stirred continuously for sufficient period of time while maintaining the required pH to allow the formation of ondansetron resinate complex. The aqueous suspension containing resinate is then filtered, dried and screened through suitable screen to obtain properly sized ondansetron resinate particles. These ondansetron resinate particles are mixed with the disintegrant and optionally one or more pharmaceutically acceptable excipients to obtain a blend. The blend is filled into sachets or compressed into tablets.
The "mixing" as used herein means blending, dry granulation or wet granulation. For example, in case of directly compressed tablets, the mixing means blending of ondansetron resinate particles with disintegrant and other optional excipients and proceeding for compression directly. Alternatively, the mixture of ondansetron resinate particles, disintegrant and other optional excipients can be either taken for dry granulation (compaction) or wet granulation. These granules can then be filled in to sachets or can be compressed into tablets.
The "pack" as used herein may include sachets, bottles, unit dose packs, multi dose packs, or any other suitable packs used to provide an effective packing/containment for oral dosage forms.
The following non-limiting examples further illustrate the taste masked orally disintegrating ondansetron formulations and process of making such formulations.
Example 1
(Formula Removed)
Process of preparation:
1. Ondansetron, polacrilin potassium and citric acid were sifted through a suitable screen to obtain a blend.
2. The blend of step 1 was suspended in water with stirring, while maintaining the aqueous media pH 5.5-5.7, to form ondansetron-resin complex (resinate).
3. The suspension of step 2 was filtered to separate the ondansetron-resin complex.
4. The ondansetron-resin complex of step 3 was dried and screened through suitable screen to obtain resinate particles.
5. Spray dried mannitol, croscarmellose sodium, aspartame, sucralose, talc, colloidal silicon dioxide, magnesium stearate, prosweet flav, strawberry/grape flavor and flavor mint were sifted along with resinate particles of step 4 through a suitable screen to obtain final blend.
6. The blend of step 5 was compressed using suitable tooling.

(Formula Removed)
Process of preparation:
1. Ondansetron, polacrilin potassium and citric acid were sifted through a suitable screen to obtain a blend.
2. The blend of step 1 was suspended in water with stirring/while maintaining the aqueous media pH 5.5-5.7, to form ondansetron-resin complex (resinate).
3. The suspension of step 2 was filtered to separate the ondansetron-resin complex.
4. The ondansetron-resin complex of step 3 was dried and screened through suitable screen to obtain resinate particles.
5. Spray dried mannitol, croscarmellose sodium and magnesium stearate, were sifted along with resinate particles of step 4 through a suitable screen to obtain a blend.
6. The blend of step 5 was compacted, milled and passed through suitable screen
to obtain granules.
7. Spray dried mannitol, croscarmellose sodium, aspartame, sucralose, talc, colloidal silicon dioxide, magnesium stearate, prosweet flav, strawberry/grape flavor and flavor mint were sifted through a suitable screen to obtain a blend.
8. The granules of step 6 were mixed with the blend of step 7 to obtain a final blend.
9. The blend of step 8 was compressed using suitable tooling.
Evaluation of disintegration time and taste masking parameters
(Formula Removed)
Determined as per USP standard procedure using purified water as a medium.

WE CLAIM:
1. A taste masked orally disintegrating ondansetron formulation comprising ondansetron resinate, a disintegrant and optionally one or more pharmaceutically acceptable excipients.
2. The formulation according to claim 1 wherein the ondansetron resinate comprises ondansetron, an ion exchange resin and optionally a pH modifying agent.
3. The formulation according to claim 2 wherein the ion exchange resin is cation exchange resin.
4. The formulation according to claim 3 wherein the cation exchange resin comprises one or more of polacrilin potassium, polacrilex resin and mixtures thereof.
5. The formulation according to claim 2 wherein the pH modifying agent is selected from one or more of citric acid, ascorbic acid, tartaric acid, ethanoic acid and mixtures thereof.
6. The formulation according to claim 1 wherein the disintegrant comprises one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, sodium carboxymethylcellulose, hydroxypropyl cellulose and mixtures thereof.
7. The formulation according to claim 1 wherein the pharmaceutical^ acceptable excipients are selected from one or more of fillers, binders, lubricants, sweetening agents, coloring agents, flavoring agents and mixtures thereof.
8. The formulation according to claim 7 wherein the fillers comprise saccharides selected from one or more of lactose, sucrose and glucose; and sugar alcohols selected from one or more of mannitol, sorbitol, xylitol, maltitol and mixtures thereof.
9. The formulation according to claim 7 wherein the lubricants are selected from one or more of talc, magnesium stearate, colloidal silicon dioxide, zinc stearate and mixtures thereof.
10. A process for the preparation of a taste masked orally disintegrating ondansetron formulation, the process comprising the steps of: a) adding ondansetron, an ion exchange resin and optionally a pH modifying agent to an aqueous medium, optionally stirring, followed by filtration and drying to obtain ondansetron resinate particles; b) mixing the ondansetron resinate particles of step a) with a disintegrant and optionally one or more pharmaceutical^ acceptable excipients to obtain a blend; and c) filling the blend into a pack or compressing the blend into tablets.
11. The process according to claim 10 wherein the mixing comprises blending, dry granulation or wet granulation.
12. The process according to claim 10 wherein the ion exchange resin is cation exchange resin.
13. The process according to claim 12 wherein the cation exchange resin comprises one or more of polacrilin potassium, polacrilex resin and mixtures thereof.
14. A method of treating one or more of emesis, nausea, and vomiting associated with cancer chemotherapy, radiotherapy, and/or that occurring post-operatively in a patient in need thereof, the method comprising administering a taste masked orally disintegrating ondansetron formulation comprising ondansetron resinate, a disintegrant and optionally one or more pharmaceutically acceptable excipients.