Field of the Invention
The present invention relates to orally disintegrating ondansetron formulations and process of making thereof.
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. One of the drawbacks of conventional tablets and capsules is difficulty in swallowing (dysphagia), common among all age groups and more prominent in elderly or pediatric patients. 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. Apart from the enhanced patient compliance, orally disintegrating formulations may also improve the bioavailability of certain drug candidates by enhancing dissolution and absorption.
Orally disintegrating tablets (ODTs) are distinguished from conventional sublingual tablets, lozenges, and buccal tablets that require more than a minute to dissolve in the mouth. ODTs are also called orodisperse, mouth-dissolving, quick-dissolve, fast-melt, and rapid disintegrating tablets.
Orally disintegrating formulations of ondansetron are previously known in the art.
WO 99/47126 discloses a rapidly dispersing tablet prepared by using a water-soluble non-saccharide polymer as a binder together with an active ingredient followed by humidifying the tablet.

US Patent 6,656,492 discloses a quick disintegrating tablet that includes plurality of drug-containing particles. Each particle comprises a bitter tasting drug, a pharmaceutical preparation carrier and a saccharide.
WO 95/33446 discloses a non-rupturable, fast-dissolving taste masking composition providing immediate release of pharmaceutically acceptable active ingredients. The composition comprises a non-rupturable drug matrix comprising a taste masking agent and a pharmaceutically acceptable active ingredient.
WO 00/57857 describes 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. The citric acid used therein stimulates the salivary gland to facilitate saliva secretion, thereby accelerating the disintegration of tablets.
WO 04/096214 describes a composition for oral administration that disintegrates in the oral cavity within about 60 seconds and masks a bitter taste of ondansetron or a pharmaceutically acceptable salt thereof. The composition includes a therapeutically effective amount of ondansetron or a pharmaceutically acceptable salt thereof and an alkalizing agent.
US Patent Application 20040198794 teaches that use of 'microcrystalline ondansetron' is more preferred for use in pharmaceutical final dosage forms. This patent application teaches that ondansetron base has a particle size wherein at least 99% of the particles are within the range of 0.1 to 200, more preferably 0.1 to 100, still more preferably 0.1 to 63 microns.
Particle size is perhaps the most important solid state parameter that affects a number of physical and chemical properties of the drug substances. Drug particle size has a critical effect on the content uniformity of solid dosage forms, where poor content uniformity would result if a drug powder were not dispersed evenly throughout a mixture with excipients. A leading cause of poor content uniformity is a mismatch of drug and excipient particle size and density leading to segregation during manufacture, especially for low drug to excipient ratio blends. The concept of ideal mixing was presented to demonstrate that poor content uniformity resulted, even with ideal mixing,

if the drug particle size distribution is not proper. Sometimes, the process requirements dictate the need for particle size modification. Large particle size is a major cause of segregation problems during mixing operation and too small a particle size can exacerbate the problems of drug agglomeration during mixing operation and problem of sticking and picking during tablet compression. This provides a scientific rationale for setting a drug particle size specification that is conducive to content uniformity and processing requirements before expensive and time-consuming formulation development begins.
It was observed that ondansetron having a specific particle size distribution i.e. mixture containing suitable proportions of coarse and fine particles, is more suitable for the preparation of orally disintegrating tablets. The advantages include ease of manufacturing and minimized compression problems during scale up.
Accordingly, it is an object of the present invention to provide orally disintegrating ondansetron formulations with acceptable disintegration characteristics and taste masking. Further, these formulations are cost effective and are easy to manufacture on commercial scale.
Summary of the Invention
According to one embodiment there is provided an orally disintegrating ondansetron formulation comprising:
a) ondansetron particles having a D90of not more than 30 microns;
b) ondansetron particles having a Dgo ranging from 90-200 microns;
c) one or more disintegrants, and
d) optionally, one or more pharmaceutically acceptable excipients; wherein the
proportion of (a) to (b) ranges from 80:20 to 95:5.
According to another embodiment there is provided an orally disintegrating ondansetron formulation comprising:
a) ondansetron particles having a D90of not more than 30 microns;
b) ondansetron particles having a D90 ranging from 90-200 microns;
c) one or more disintegrants, and

d) optionally, one or more pharmaceutically acceptable excipients; wherein the proportion of (a) to (b) is 90:10.
According to another embodiment there is provided a process for the preparation of an orally disintegrating ondansetron formulation, the process comprising the steps of:
a) mixing ondansetron particles having a Dgo of not more than 30 microns with
ondansetron particles having a Dgo ranging from 90-200 microns in a proportion ranging
from 80:20 to 95:5 to obtain ondansetron premix;
b) adding one or more disintegrants, and optionally one or more pharmaceutically
acceptable excipients to the ondansetron premix, followed by granulation to obtain
granules;
c) mixing the granules with optionally one or more disintegrants and one or more
pharmaceutically acceptable excipients to obtain a blend; and
d) compressing the blend into tablets.
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 term 'Ondansetron' includes ondansetron free base, single enantiomers, pharmaceutically acceptable salts, solvates and mixtures thereof.
The orally disintegrating formulation comprises a mixture of fine and coarse ondansetron particles. The 'fine' ondansetron particles have a D90 of not more than 30 microns; and the 'coarse' ondansetron particles have a Dgo ranging from 90-200 microns. The fine and coarse ondansetron particles are mixed in a proportion ranging from 80:20 to 95:5. Preferably, the proportion of fine and coarse ondansetron particles is 90:10.
D90 represents the 90th percentile of the particle size distribution as measured by volume i.e. Dgo is a value on the distribution such that 90% of the particles have a volume of this value or less.

Particle size analyzer by Malvern was used to measure the particle size distribution. It is highly robust, reliable and high speed instrument. It has the flexibility to allow wet and dry measurements to be made in rapid succession, as well as enabling the user to change rapidly from aqueous to solvent based dispersions.
Suitable disintegrants include one or more of croscarmellose sodium, sodium starch glycolate, crospovidone, sodium carboxymethyl cellulose, hydroxypropyl cellulose and mixtures thereof. Preferably, the disintegrant is croscarmellose sodium. The disintegrant may be present from 1% to 15% w/w of the formulation. Preferably, the disintegrant is present in an amount from 2% to 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 10% to 90% w/w of the formulation. Preferably, the fillers are present in an amount from 30% to 80% w/w of the formulation.
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 0.1% to 8% w/w. Preferably, the amount of lubricant ranges from 0.5% to 5% w/w.
Suitable sweetening agents include one or more of cyclamate or salts thereof; saccharin or salts thereof; sucralose, acesulfam K or aspartame.
The orally disintegrating formulation is preferably in the form of tablets, which may be prepared by either direct compression or wet/dry granulation.
The process for the preparation of the orally disintegrating tablet includes mixing of fine ondansetron and coarse ondansetron particles to obtain ondansetron premix. This ondansetron premix is further mixed with the disintegrant and optionally one or

more pharmaceutically acceptable excipients to obtain a blend. The blend is granulated (dry or wet granulation) and the granules are further mixed with disintegrant and optionally one or more pharmaceutically acceptable excipients to obtain a final blend. The final blend is compressed into tablets.
The following non-limiting examples further illustrate the orally disintegrating ondansetron formulations and process of making such formulations:
Example 1

(Table Remove) Brief manufacturing Process:
1. All the ingredients were accurately weighed.
2. Ondansetron Fine and Ondansetron Coarse were mixed in non-shear blender for
15minutes to obtain ondansetron premix.
3. The ondansetron premix of step 2, Aspartame, Croscarmellose sodium and Mannitol
were sieved on a mechanical vibratory sifter through sieve # 35.
4. The material of step 3 was transferred to a rapid mixer granulator and was mixed for
10 minutes.
5. The material of step 4 was granulated using purified water.
6. The wet granules of step 5 were dried in fluid bed drier at 50-60°C till the loss on
drying is less than 2.0% w/w.
7. The dried granules of step 6 were sifted through sieve # 45 and the oversize
granules were passed through multimill using 1mm screen at low speed.
8. The extra granular Croscarmellose sodium, Mannitol, Aspartame, Strawberry
guarana, Colloidal silicon dioxide were sifted through sieve # 45 on a mechanical
vibratory sifter.
9. The materials of step 7 and 8 were blended in a non-shear blender for 20 minutes.
10. Talc and Magnesium stearate were sifted through sieve # 45 on a mechanical
vibratory sifter.
11. The material of step 9 was blended with the material of the step 10 in a non-shear
blender for 5 minutes.
12. The blend of step 11 was compressed into tablets.

WE CLAIM:
1. An orally disintegrating ondansetron formulation comprising:
a) ondansetron particles having a Dgo of not more than 30 microns;
b) ondansetron particles having a Dgo ranging from 90-200 microns;
c) one or more disintegrants, and
d) optionally, one or more pharmaceutically acceptable excipients; wherein the
proportion of (a) to (b) ranges from 80:20 to 95:5.

2. 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.
3. The formulation according to claim 1, wherein the pharmaceutically acceptable
excipients are selected from one or more of fillers, lubricants, sweetening
agents, coloring agents, flavoring agents and mixtures thereof.
4. The formulation according to claim 3, 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.
5. The formulation according to claim 3, wherein the lubricants are selected from
one or more of talc, magnesium stearate, colloidal silicon dioxide, zinc stearate
and mixtures thereof.
6. The formulation according to claim 3, wherein the sweeteners are selected from
the group consisting of cyclamate or salts thereof; saccharin or salts thereof;
sucralose, acesulfam K or aspartame.
7. The formulation according to claim 1, wherein the proportion of (a) to (b) is
90:10.

8. A process for the preparation of orally disintegrating formulation, the process
comprising the steps of:
a) mixing ondansetron particles having a D90 of not more than 30 microns with
ondansetron particles having a Dgo ranging from 90-200 microns in a proportion
ranging from 80:20 to 95:5 to obtain ondansetron premix;
b) adding one or more disintegrants, and optionally one or more
pharmaceutically acceptable excipients to the ondansetron premix, followed by
granulation to obtain granules;
c) mixing the granules with optionally one or more disintegrants and one or more
pharmaceutically acceptable excipients to obtain a blend; and
d) compressing the blend into tablets.
9. An orally disintegrating ondansetron formulation substantially described and
exemplified herein.