FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See Sections 10 and rule 13]
Title: "Novel melt in mouth oral dosage form of Palonosetron"
Applicant: (a) Astron Research Limited
(b) Nationality: Indian
(c) 10th Floor, Premier House Bodakdev, Opp. Gurudwara Sarkhej - Gandhinagar Highway Ahmedabad 380054
Gujarat, India.
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention
The present invention relates to novel and stabilized oral formulation of
Palonosetron. The oral formulation comprises of melt in mouth tablets of
Palonosetron or pharmaceutically acceptable salts thereof and the process of
preparing the said oral formulation.
Background
Palonosetron is a selective 5-HT3 receptor antagonist. Palonosetron is marketed in the form of its hydrochloride salt.
The chemical name of this compound is (3aR)-2-[(3s)-l-azabicyclo [2.2.2] oct-3-yl]-2, 3, 3a, 4, 5, 6-hexahydrol-oxo-1H-benz[de]isoquinoline hydrochloride or 2-(quinuclidin-3(S)-yl-2, 3, 3a(S), 4,5,6-hexahydro-lH-benz[de] isoquinolin-1-one hydrochloride.
Palonosetron and its synthesis were first disclosed in U.S. patent no. 5,202,333. Palonosetron hydrochloride is marketed in the US under the trade name Aloxi® by Helsinn Healthcare. Aloxi is available as single 0.25mg or 0.075mg injections for intravenous use. Aloxi® is also available as 0.5mg soft gelatin capsules for oral use. These formulations are indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy, and for the prevention of nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy. Aloxi® intravenous is also indicated for the prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

WO2004/067005 apparently discloses stable liquid formulations of Palonosetron useful for the preparation of injectable and liquid oral medicaments. The authors of WO2004/067005 disclose that intravenous formulations of Palonosetron suffer from shelf life stability issues. Allegedly, in order to address the stability problems associated with injectable Palonosetron formulations, the authors provide solution formulations having a pH range of from about 4.0 to about 6.0, and optionally excipients including mannitol and a chelating agent.
US2008/0152704 (WO2008/049552) appears to disclose soft gelatin capsule formulations consist of a soft gelatin based outer capsule shell having low oxygen permeability, and a capsule filling which is a continuous lipophilic phase containing Palonosetron dissolved in aqueous component, which is miscibilized or homogenized in the lipophilic phase by a surfactant. The authors of this publication report that the disclosed soft-gel capsules are stable and provide the desired bioavailability upon oral ingestion. According to the authors, the continuous liquid phase provides ease of processing and composition uniformity. Further, the authors disclose that the soft outer shell having a particular oxygen permeability is preferred due to the ability of the shell to hold liquid and to resist oxygen transmission.
US2008/0152704 discloses representative gel-cap formulations that incorporate an antioxidant such as butylated hydroxyanisole, in order to provide the required stability.
US2009/0004254 discloses Palonosetron containing film formulation. However, film formulation poses stability issues and not easy to manufacture at large scale as compared to tablet formulation.

WO2010/077669 discloses Palonosetron orally disintegrating formulation consisting of sweeteners and flavoring agents for the taste masking. However, taste masking using ion-exchange resins as disclosed in the present invention is much better than other taste masking agents.
Sunil H. Makwana et al, Journal of Pharmaceutical Sciences and Research (2010), 2(4), (232-239) discloses orodispersible tablet formulation comprising ion exchange resin. However, it is related with ondansetron hydrochloride.
Palonosetron is required to be a fast-acting drug and thus must have a high bioavailability. In prior art formulations and publications the high bioavailability, allegedly has been achieved by providing the drug as a liquid preparation, for example as an intravenous injection or other liquid preparation such as an encapsulated liquid. In view of the known stability problems associated with liquid formulations containing Palonosetron and its salts, there is a need to provide stable dosage forms, preferably without the use of one or more excipient or chemical agent to prevent oxygen mediated degradation of Palonosetron in the dosage form. Preferably, it would be desirable to provide a dosage form comprising Palonosetron or a pharmaceutically acceptable salt thereof in the solid phase.
One of the main obstacles to the production of solid Palonosetron compositions is that Palonosetron is a low dose drug (0.25mg, 0.5mg or 0.75mg per unit dosage form). This presents a problem because the incorporation of such small quantities of drug into a final dosage form can result in poor content uniformity. Another challenge is that the active agent needs to be fast acting, and thus must have a good bioavailability profile. Again available capsule dosage form is difficult to swallow for some patients, especially pediatric and geriatric patients.

It would therefore be highly desirable to provide a dosage form containing Palonosetron or a pharmaceutically acceptable salt thereof wherein the drug is in solid phase, and in which the bioavailability of the drug is comparable to that of liquid formulation and it is easy to swallow. It would further be desirable to provide a formulation of Palonosetron or a pharmaceutically acceptable salt thereof that is stable and is easy to manufacture. It would further be desirable to provide a solid Palonosetron composition having a good dissolution profile, good blend and/or content uniformity and good stability.
Objects of Invention
The main object of the invention is to provide a melt-in-mouth dosage form comprising Palonosetron hydrochloride, which disintegrate in the oral cavity in less than 60 second, upon contact with saliva by formation of an easy-to-swallow suspension.
Another object of the present invention is to provide a solid oral dosage form of Palonosetron having a good dissolution profile, good blend and/or content uniformity and good stability.
Still another aspect of the present invention is to provide a solid oral dosage form of Palonosetron which is having good and acceptable taste upon oral administration.
Still another aspect of the present invention is to provide a stable solid oral dosage form of Palonosetron which disintegrates in the oral cavity having a disintegration time of less than 60 second, more preferably less than 30 second and most preferably less than 25 second when measured at 37°C.

Still another aspect of the present invention is to provide process for the preparation of stable orally disintegrating tablet formulation of palonosetron hydrochloride.
Summary of the Invention
In an embodiment, the present invention provides a dosage form for oral administration comprising a solid admixture of Palonosetron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The dosage form is a solid dosage form. The formulation is preferably in the form of a powder, granules, a tablet including orally disintegrating tablet, or melt in mouth tablet.
In another embodiment, the present invention provides a process for the preparation of the dosage forms by dry or wet granulation, preferably by wet granulation, of Palonosetron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
Detailed Description of the Invention
The term "melt-in-mouth" used herein is defined as a pharmaceutical formulation which disintegrates in the oral cavity in less than 60 second, upon contact with saliva by formation of an easy-to-swallow suspension.
As used herein, and unless otherwise indicated, the term Palonosetron is taken to include pharmaceutically acceptable salts thereof. Preferably the Palonosetron in the formulations and processes of the present invention is in the form of Palonosetron hydrochloride.

As used herein, and unless otherwise indicated, percentages.of excipients are given as weight % relative to the weight of the dosage form.
The present invention provides a dosage form for oral administration comprising solid admixture of Palonosetron or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The dosage form for oral administration of the present invention can be a solid dosage form. The dosage form may be in the form of a powder (e.g. as a sprinkle formulation) or granules or formed into a tablet (e.g. by compression).
Since the active agent is present in a solid admixture with excipients, the dosage forms of the present invention offer a further advantage in their ease of handling and manufacture compared to liquid soft capsule formulations and i.v. solutions.
The dosage forms of any embodiments of the present invention preferably include at least one pharmaceutically acceptable excipient selected from the group comprising of a binder/complexing agent, disintegrant, diluent, glidant and lubricant. A dosage form according to the invention can include a pharmaceutically acceptable excipient, wherein the pharmaceutically acceptable excipient is a combination of at least one binder/complexing agent, at least one disintegrant, at least one diluent, and at least one lubricant, and optionally at least one glidant. A glidant is preferably used when the dosage form is a tablet such as orally disintegrating tablet or melt in mouth tablet. The glidant is preferably colloidal silicon dioxide.
Preferred complexing agents include ion-exchange resins, cyclodextrins which are specially designed for taste masking of bitter drugs in oral formulations. Such ion-exchange resins may be selected from the Cross linked acrylic-copolymers such as Indion 204, Indion 414, Indion 234, Amberlite IRP-69, Tulsion-335 etc.

A complex is made from the drug and Indion 204 (ion-exchange resin). The nature of the complex is such that the average cation concentration of about 40 meq/ml and pH of 6.7 in saliva is not able to break the complex. The complex is weak enough to be broken down by the hydrochloric acid present in the stomach. Thus the complex is absolutely tasteless and stable with no after taste, but at the same time, its bioavailability is not affected.
Indion 204 is a high molecular weight cross linked polymer. It is therefore not absorbed by body tissue and is totally safe for human consumption. Tests for toxicological tolerance show that it does not have any pronounced physiological action at recommended dosage levels and is definitely non-toxic. Experiments on mice have shown LD 50 value of Indion 204 to be approximately 4,500 mg/kg body weight.
Preferred disintegrants include alginic acid, carboxymethylcellulose sodium or calcium, cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, sodium bi carbonate, sodium starch glycolate, pregelatanized starch, tartaric acid, citric acid and mixtures thereof, and preferably the disintegrant is selected from the group comprising of pregelatanized starch, croscarmellose sodium and sodium starch glycolate. Especially preferred are superdisintegrants such as croscarmellose sodium (e.g. Ac-Di-Sol®, an internally crosslinked sodium carboxymethyl cellulose).
Suitable diluents for any of the dosage forms of the present invention can be selected from the group comprising of calcium carbonate, calcium hydrogen phosphate (also known as dicalcium phosphate, calcium monohydrogen phosphate or dibasic

calcium phosphate), cellulose, microcrystalline cellulose, ethyl cellulose, magnesium carbonate, magnesium oxide, mannitol, dextrin, dextrose, sorbitol, lactose, starch, sucrose, xylitol and mixtures thereof. Preferred diluents are lactose, microcrystalline cellulose, and mannitol and starch. Combination of mannitol and calcium hydrogen phosphate, or mannitol and lactose, or mannitol and microcrystalline may also be used in the dosage forms of any embodiment of the present invention.
The dosage forms of any embodiment of the present invention preferably include a lubricant. Suitable lubricants include those selected from comprising of calcium stearate, glycerin monostearate, magnesium lauryl sulfate, magnesium stearate, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate or mixtures thereof. Magnesium stearate is the preferred lubricant for the oral disintegrating or melt in mouth tablets.
The dosage form of the present invention, particularly in the tablet (such as orally disintegrating tablet or melt in mouth tablet) formulations, may further comprise a glidant. The glidant is preferably colloidal silicon dioxide.
Further for the dosage forms of the present invention such as orally disintegrating tablet or melt in mouth tablets, they may further comprise of flavors, sweeteners and taste masking agents, or a combination thereof. Such dosage forms may be prepared by a dry or wet granulation process, preferably by a wet granulation process.
In another embodiment of the present invention the orally disintegrating or melt in mouth tablets of the present invention comprising of (wt% based on total weight of the tablet) Palonosetron hydrochloride in an amount of about 0.05 to about 2.0 wt %, preferably about 0.1 to about 1.0 wt %, and more preferably about 0.3 to about 0.8

wt %; diluent in an amount of about 60 to about 90 wt %, preferably about 75 to about 85 wt % and most preferably about 77 to about 82 wt %, preferably wherein the diluent is a mixture of mannitol and microcrystalline cellulose; complexing agent in an amount of about 0.5 to about 6.0 wt %, preferably about 1.0 to 2.0 wt %, and preferably wherein the complexing agent is Indion 204; disintegrant in an amount of about 1.0 to 15.0 wt %, preferably about 5.0 to 12.0 wt %, and most preferably 6.0 to 10.0 wt %, and preferably wherein the disintegrant contains croscarmellose sodium; lubricant in an amount of about 0.1 to about 3.0 wt %, preferably about 0.5 to about 1.2 wt % and most preferably about 0.7 to about 1.0 wt %, preferably wherein the lubricant is magnesium stearate; glidant in an amount of about 0.05 to about 2.0 wt %, preferably about 0.15 to about 0.8 wt % and most preferably about 0.2 to about 0.6 wt %, preferably wherein the glidant is colloidal anhydrous silica.
In the present invention, the ratio of active ingredient to ion exchange resin is in the range of 1:0.5 to 1:8, preferably 1:3.
The invention is intended to be illustrated by the following non-limiting example and process of preparing the dosage form of the present invention.
Example:
The table-1 provides the composition and followed by procedure used to prepare Palonosetron hydrochloride melt in mouth tablet

Table-1
Sr.
No Ingredients Class % in formulation
w/w
Mixing
1. Mannitol (Pearlitol SD 200) Diluent 43.00
2. Microcrystalline Cellulose (Avicel PH 112) Filler 36.81
3. Croscarmellose sodium Disintegrant 3.00
Binder (Complexation)
4. Indion 204 Cation exchange resin 1.68
5. Palonosetron hydrochloride Active drug 0.56
6, Purified water Vehicle
Blend ing & Lubrication
7. Aspartame Sweetener 4.75
8. Croscarmellose Sodium Disintegrant 4.00
9. Vanilla Flavour 4.75
10. Colloidal Anhydrous silica Glidant 0.40
11. Peppermint flavor Flavour 0.25
12. Magnesium stearate Lubricant 0.80
Total 100.00
Brief manufacturing procedure:
1. Pearlitol SD 200, Avicel PH 112 and Croscarmellose sodium were sifted and granulated with complexation binder solution of Indian 204, Palonosetron HC1 and purified water. Granules were dried and sized.
2. Sized granules were lubricated with sifted Aspartame, Croscarmellose sodium, Vanilla flavor, Aerosil, peppermint flavor and Magnesium stearate.
3. Tablets were compressed using specified tooling.

The prepared formulation was further evaluated for the stability and other formulation parameters and the result obtained are represented in table-2.

5 Table-2
Sr. No Test Formulation (Initial) Formulation
(1 Month, 40°C & 75% RH) Formulation
(3 Month, 40°C & 75 % RH) Formulation (6 Month, 40°C & 75 %RH)
1. Average weight (mg) 101.5 101.8 101.4 101.2
2. Assay 98.3 % w/w 97.4 % w/w 95.3 % w/w 94.7 % w/w
3. Dissolution (%) 99(97-102) 98 (96-98) 95(83-100) 88 (84-93)
5. Related Substance
Single
Total 0.097 % 0.13% 0.21 % 1.00% 0.32 % 1.01 % 0.48 % 1.03 %
6. Water content (%) 3.85 3.48 2.96 2.9
7. Hardness in Kp 2 2.4 2.7 2.6
8. Disintegration test (at 37 °C) 20 second 22 second 30 second 30 second
9. Content uniformity 98 (94-102) - - -

We claim:
1. A stable rapidly disintegrating pharmaceutical composition comprising
Palonosetron or a pharmaceutically acceptable salt thereof and at least one
pharmaceutically acceptable excipient.
2. The pharmaceutical composition of claim-1, wherein the composition is in the
form of powder, compressed tablet, effervescent tablet, capsule or sprinkle
formulation.
3. The pharmaceutical composition of claim-1, wherein the composition
disintegrates in less than 60 second when comes in contact with aqueous fluid or
saliva.
4. The pharmaceutical composition of claim-1, wherein the orally disintegrating formulation of Palonosetron has a content uniformity of about 90% to about 110% with an associated relative standard deviation of about 5% or less, as measured by the concentration of Palonosetron or pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition of claim-1, wherein the pharmaceutically acceptable excipients are selected from binder, complexing agent, disintegrant, diluent, glidant, lubricant and flavoring agent.
6. The pharmaceutical composition of claim-5, wherein the pharmaceutically acceptable excipient is disintegrating agent selected from alginic acid,

carboxymethylcellulose sodium or calcium, cellulose, colloidal silicon dioxide, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium aluminum silicate, microcrystalline cellulose, sodium bi carbonate, sodium starch glycholate, pregelatanized starch, tartaric acid, citric acid and mixtures thereof.
6. The pharmaceutical composition of claim-5, wherein the complexing agent is selected from the ion-exchange resins and cyclodextrins.
7. The pharmaceutical composition of claim-6, wherein the ion-exchange resins selected from the group of Indion 204, Indion 414, Indion 234, Amberlite IRP-69, Tulsion-335 or their mixture thereof and the ratio of active ingredient to ion exchange resin is in the range of 1:0.5 to 1:8..
8. The pharmaceutical composition of claim-5, wherein the Palonosetron
hydrochloride is in an amount of about 0.05 to about 2.0 wt %, diluent in an amount
of about 60 to about 90 wt %, complexing agent in an amount of about 0.5 to about
6.0 wt %, disintegrant in an amount of about 1.0 to 15.0 wt %, lubricant in an
amount of about 0.1 to about 3.0 wt % and glidant in an amount of about 0.05 to
about 2.0 wt %.
10. A process for preparing stable orally disintegrating Palonosetron composition comprising:
a) Dissolve the drug, ion exchange resin in aqueous solution.
b) Sift the other excipients and prepare granules using aqueous mixture of step-a.
c) Size the granules of step-b and lubricate it.

d) Optionally the granules of step-c, compressed into tablet or filled in to capsule shell.