Claims:We claim:

1. An orally disintegrating tablet comprising taste masked granules of Metopimazine and one or more pharmaceutically acceptable excipients.

2. The orally disintegrating tablet as claimed in claim 1, wherein the taste masked granules comprise Metopimazine and taste masking agents.

3. The taste masked granules as claimed in claim 2, wherein said taste masking agents include lipid excipients selected from one or more of glyceryl dibehenate (Compritol® 888 ATO), glyceryl palmitostearate (Precirol® ATO 5), polyethylene glycol monostearate (Gelucire® 48/16), carnauba wax, stearic acid, palmitic acid, beeswax, microcrystalline wax, hydrogenated castor powder (Kolliwax HCO), lecithin, hydrogenated cottonseed oil; polymers selected from one or more of copovidone (Kollidon VA 64), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus), povidone (Kollidon 12 PF, Kollidon 17 PF, Kollidon 30 and Kollidon 90 F), polyvinyl acetate–povidone (Kollidon SR), polyethylene glycol-polyvinyl alcohol grafted copolymer (Kollicoat IR), methacrylate polymers (Eudragit EPO), polyethylene oxide, polyvinyl acetate, cellulose derivatives selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose.

4. The taste masked granules as claimed in claim 3, wherein said taste masking agent is glyceryl dibehenate.

5. The taste masked granules as claimed in claim 2, wherein the ratio of Metopimazine and taste masking agents is from about 1:1 to about 1:5.

6. A process for the preparation of taste masked granules of Metopimazine using hot melt extrusion comprising:
a. mixing Metopimazine and taste masking agents,
b. passing the blend of Metopimazine and taste masking agents through hot melt extruder at a temperature of 800C to 1200C,
c. sizing hot melt extrudates to form taste masked granules.
7. An orally disintegrating tablet comprising taste masked granules of Metopimazine and one or more pharmaceutically acceptable excipients, wherein the tablet releases greater than about 70% of the total amount of Metopimazine in 15 minutes when tested for dissolution using United States Pharmacopoeia Apparatus 2 with paddle speed at 50 rpm in 900 mL of 0.1N HCl.

8. The orally disintegrating tablet as claimed in claim 7, wherein said excipients comprise one or more of diluents, disintegrants, flavors, sweeteners, glidants and lubricants.

9. The orally disintegrating tablet as claimed in claim 7, comprising taste masked granules of Metopimazine from about 10% to about 35% by weight, microcrystalline cellulose and mannitol from about 40% to about 70% by weight, crospovidone from about 3% to about 10% by weight, peppermint flavor from about 1% to about 3% by weight, aspartame from about 1% to about 3% by weight, colloidal silicon dioxide from about 0.5% to about 2% by weight and magnesium stearate from about 0.5% to about 2% by weight.

10. The orally disintegrating tablet as claimed in claim 7, wherein the tablet is prepared by direct compression.
, Description:FIELD OF THE INVENTION
The present invention relates to orally disintegrating tablets comprising Metopimazine and process for its preparation.
BACKGROUND OF THE INVENTION
Metopimazine is chemically known as 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl) piperidine-4-carboxamide and has a molecular weight of 445.6 with the following structural formula:

Metopimazine is a dopamine D2 receptor antagonist used for the prevention and treatment of nausea and vomiting.
Metopimazine and process for its preparation are disclosed in DE1092476.
Currently, Metopimazine orally disintegrating tablets are available as an oral lyophilisate formulation under the brand name of VOGALENE LYOC®. They are prepared using proprietary LYOC® technology which utilizes the concept of freeze drying. Such orally disintegrating tablets suffer from many disadvantages like:
• increased price due to high cost of production
• time consuming manufacturing process
• may degrade at higher humidity conditions which require special packing
• poor physical resistance (easy to break)

Also, due to rapid disintegration of orally disintegrating tablets, taste masking of bitter active substances like Metopimazine is an obstacle for the development of orally disintegrating tablets formulation. The efficiency of taste masking is often a key determinant for the success of specialized dosage forms like orally disintegrating tablets.

Taste masking techniques often relies on two major approaches. The first is to add excipients like sweeteners, flavors and effervescent agents to mask the unpleasant taste, the second is to avoid the contact of bitter and unpleasant drugs with taste buds.
Nevertheless, the first approach of adding the additives is not sufficient for complete taste masking. There are several methods for the second approach including enteric coating, microencapsulation, complexation, spray drying etc., wherein each method suffers from its own disadvantages. For example, in enteric coating, the coating of fine particle materials is usually unsuccessful and the coatings of granular particles are readily ruptured by chewing, compression and most coatings do not have an acceptable in vivo drug releasing mechanism.
FR 2845914B1 discloses an orally disintegrating tablets formulation comprising drug (Metopimazine is one among several drugs listed), at least a first and a second disintegrant, at least a powdery agent and at least one lubricant.
EP 2359812A1 discloses a method for preparing an orally disintegrating tablets formulation by lyophilization process.

However, nothing in the art teaches about taste masking of bitter active substances in an orally disintegrating tablets formulation which has been a challenge for formulation scientists.
In order to solve the above conventional problems, an object of the invention is to provide an orally disintegrating dosage form having taste masking effects, rapid disintegration rates and sufficient hardness.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine.

SUMMARY OF THE INVENTION
In one embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine.
In another embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine, wherein the granules are prepared using hot melt extrusion of Metopimazine and taste masking agents.

In a more preferred embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine, wherein the ratio of Metopimazine and taste masking agents is from about 1:1 to about 1:5, preferably 1:2.
In another embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine and other conventional excipients as an extra granular component.
In one embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine comprising;
from about 15% to about 50% by weight of Metopimazine and
from about 50% to about 85% by weight of taste masking agents,
Wherein said granules are prepared using hot melt extrusion.
In another embodiment, the present invention provides an orally disintegrating tablets formulation comprising:
from about 10% to about 40% by weight of taste masked granules of Metopimazine,
from about 60% to about 90% by weight of one or more conventional excipients,
Wherein said formulation is prepared by direct compression process.
In a more preferred embodiment, the present invention provides an orally disintegrating tablets formulation comprising:
Taste masked granules of Metopimazine comprising glyceryl dibehenate as a taste masking agent,
Crospovidone as a disintegrant,
Microcrystalline cellulose and mannitol as diluents,
Peppermint flavor as a flavoring agent,
Aspartame as a sweetener,
Colloidal silicon dioxide as a glidant and
Magnesium stearate as a lubricant.
In yet another embodiment, the present invention provides a process for the preparation of an orally disintegrating tablets formulation of Metopimazine comprising;
a. Mixing Metopimazine and taste masking agents,
b. Passing the blend of Metopimazine and taste masking agents through hot melt extruder at a temperature of 800C to 1200C,
c. Sizing hot melt extrudates to form taste masked granules, followed by pre-lubrication with diluents, disintegrants, flavors, sweeteners and glidants,
d. Lubricating the above blend and compressing into tablet.
In another preferred embodiment, the present invention provides an orally disintegrating tablet comprising taste masked granules of Metopimazine and one or more pharmaceutically acceptable excipients, wherein the composition releases greater than or equal to about 70% of the total amount of Metopimazine in 15 minutes.

DETAILED DESCRIPTION OF THE INVENTION
The present invention is related to an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine prepared by hot melt extrusion, which provides rapid disintegration rates, effective taste masking, smooth mouth feel (no aftertaste), sufficient hardness to resist destruction during the course of manufacture, storage and complete drug release.

US Food and Drug Administration (FDA) defines orally disintegrating tablets (ODT) as “a solid dosage form containing active pharmaceutical substances, which disintegrates rapidly, usually within seconds, when placed on the tongue”. Disintegration time for orally disintegrating tablets generally ranges from several seconds to about a minute.

Unless otherwise indicated, this disclosure uses the following definitions.

The term “orally disintegrating tablets” includes inter alia orodispersible tablets, fast melt tablets, fast disintegrating tablets etc.
The term “Hot melt extrusion” itself can be described as a process in which materials i.e drug and/ or excipients melt or soften under elevated temperature, pressure and is forced through an orifice by screws.
The term “% by weight” refers to % by weight of total pharmaceutical composition.
The present invention is related to an orally disintegrating tablets formulation comprising Metopimazine. More specifically the present invention is related to an orally disintegrating tablets formulation comprising the taste masked granules of Metopimazine, wherein the granules are prepared using hot melt extrusion of Metopimazine and taste masking agents.
Hot melt extrusion (HME) offers a relatively newer approach to taste-masking and provides advantages such as absence of organic solvents in the process, fewer processing steps, continuous operation and scale-up capabilities.
The pharmaceutical compositions according to the present invention, includes therapeutically effective amount of Metopimazine in the form of taste masked granules, further comprise one or more pharmaceutically acceptable excipients selected from group consisting of diluents, dry binders, disintegrants, flavors, sweeteners, glidants and lubricants or any other excipients known in the art.
Suitable examples of taste masking agents include lipid excipients and polymers.
Lipid excipients are selected from one or more of glyceryl dibehenate (Compritol® 888 ATO), Glyceryl palmitostearate (Precirol® ATO 5), Polyethylene glycol monostearate (Gelucire® 48/16), carnauba wax, stearic acid, palmitic acid, beeswax, microcrystalline wax, hydrogenated castor powder (Kolliwax HCO), lecithin, hydrogenated cottonseed oil etc., preferably glyceryl dibehenate.
Polymers are selected from one or more of copovidone (Kollidon VA 64), polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus), povidone (Kollidon 12 PF, Kollidon 17 PF, Kollidon 30 and Kollidon 90 F), polyvinyl acetate–povidone (Kollidon SR), polyethylene glycol-polyvinyl alcohol grafted copolymer (Kollicoat IR), methacrylate polymers (Eudragit EPO), polyethylene oxide, polyvinyl acetate, cellulose derivatives selected from hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose, hydroxypropyl cellulose.
Suitable examples of diluents include microcrystalline cellulose, silicified microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, sorbitol, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide or combinations thereof, preferably combination of microcrystalline cellulose and mannitol.
Suitable examples of dry binders include copovidone, microcrystalline cellulose, partially pregelatinized starch, hydroxylpropyl methyl cellulose, hydroxy propyl cellulose or combinations thereof.
Suitable examples of disintegrants include crospovidone, croscarmellose sodium, sodium starch glycolate, crosslinked alginic acid, soy polysaccharides, Ion exchange resins like polacrilin potassium and low substituted hydroxypropyl cellulose or combinations thereof, preferably crospovidone.
Suitable examples of flavors include tutti frutti, black cherry flavor, peppermint flavor, orange flavor, menthol, vanilla or combinations thereof, preferably peppermint flavor.
Suitable examples of sweeteners include aspartame, acesulfame potassium, sucrose, sucralose, sodium saccharin or combinations thereof, preferably aspartame.
Suitable examples of lubricants and/or glidants include colloidal silicon dioxide, sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talc or combinations thereof.
The tablets described herein may be prepared by conventional tableting techniques using commonly available equipment known to persons skilled in the art. The preparation process comprises involving direct compression.
In one embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine comprising;
from about 15% to about 50% by weight of Metopimazine and
from about 50% to about 85% by weight of taste masking agents.
In a preferred embodiment, the present invention provides an orally disintegrating tablets formulation comprising taste masked granules of Metopimazine comprising;
from about 15% to about 50% by weight of Metopimazine and
from about 50% to about 85% by weight of glyceryl dibehenate,
wherein said granules are prepared by hot melt extrusion of Metopimazine and glyceryl dibehenate at a temperature of 800C to 1200C, followed by sizing hot melt extrudates.
In another embodiment, the present invention provides an orally disintegrating tablets formulation comprising:
Taste masked granules of Metopimazine from about 5% to about 50% by weight,
Diluents from about 30% to about 80% by weight,
Dry binders from about 0% to about 5% by weight,
Disintegrants from about 2% to about 12% by weight,
Flavors from about 0.5% to about 5% by weight,
Sweeteners from about 0.5% to about 5% by weight,
Glidants from about 0.5% to about 2% by weight and
Lubricants from about 0.5% to about 2% by weight,
In a more preferred embodiment, the present invention provides an orally disintegrating tablets formulation comprising:
Taste masked granules of Metopimazine from about 10% to about 35% by weight,
Microcrystalline cellulose and mannitol from about 40% to about 70% by weight,
Crospovidone from about 3% to about 10% by weight,
Peppermint flavor from about 1% to about 3% by weight,
Aspartame from about 1% to about 3% by weight,
Colloidal silicon dioxide from about 0.5% to about 2% by weight, and
Magnesium stearate from about 0.5% to about 2% by weight,
Wherein said formulation is prepared by direct compression.
In another preferred embodiment, the present invention provides an orally disintegrating tablet comprising taste masked granules of Metopimazine and one or more pharmaceutically acceptable excipients, wherein the tablet releases greater than about 70% of the total amount of Metopimazine in 15 minutes when tested for dissolution using United States Pharmacopoeia Apparatus 2 with paddle speed at 50 rpm in 900 mL of 0.1N HCl.
The following examples are intended to be illustrative and non-limiting:
Example 1: Metopimazine orally disintegrating tablets:
Table 1
S.NO Ingredients Quantity (mg/tablet)
1 Metopimazine 7.50
2 Glyceryl dibehenate (Compritol 888 ATO) 15.00
3 Colloidal silicon dioxide (Aerosil 200) 0.55
4 Peppermint Flavor (DC117 PH) 1.50
4 Aspartame 2.00
5 Crospovidone (Polyplasdone XL) 5.00
6 Microcrystalline Cellulose 102 (Avicel PH 102) 76.05
7 Mannitol (Pearlitol SD 200) 10.00
8 Magnesium Stearate 2.40
Tablet weight 120.00

Manufacturing procedure:
1) Sifted Metopimazine & glyceryl dibehenate through 40# mesh sieve.
2) Loaded step (1) material into hot melt extruder at a temperature of 80 to 1200C and passed the hot melt extrudates through roller and collected dried granules.
3) Sized step (2) granules by passing through 40# mesh sieve.
4) Sifted colloidal silicon dioxide, crospovidone, peppermint flavor, microcrystalline cellulose, mannitol & aspartame through 40# mesh sieve and mixed with step (3) granules for 10min.
5) Magnesium stearate is added to blend of step (4) and mixed for 5 min.
6) Compressed the blend of step (5) into tablets.

Comparison of in-vitro dissolution profile:
The Metopimazine orally disintegrating tablets of example 1 and reference product (VOGALENE LYOC®) were subjected to dissolution studies in 900 ml of 0.1N HCl at 37°C ± 0.5°C using USP apparatus II with paddle speed at 50 rpm.
Table 2: The comparative dissolution data

Time (min.) Drug released (Percent w/w)
VOGALENE LYOC® Example 1
0 0 0
3 42 57.8
6 64.8 77.1
9 79.0 83.5
12 86.6 85.5
15 90.9 87.1
20 94.9 88.6
30 96.7 90.9
45 98.0 91.4
60 98.9 92.5

Based on the above results, the release profile of Metopimazine orally disintegrating tablets of example 1 is found to be similar to Reference product.

The stability of Metopimazine orally disintegrating tablets of example 1 stored at 400C/75% relative humidity (RH) was determined at periodic intervals over a 3 month period by determining the impurity levels and dissolution.

Impurity levels were determined by HPLC and the data is presented in table 3 as a percentage of specific impurity:

Table 3: Impurity data (stability)
Name of the Impurity Percentage of Impurity
Initial 1 Month 3 Month
MTO Impurity A Not detected Not detected Not detected
MTO Impurity B 0.03 0.03 0.06
MTO Impurity C Not detected Not detected Not detected
MTO Impurity D 0.05 0.05 0.03
MTO 1 Not detected Not detected Not detected
Total Impurities 0.27 0.31 0.20

Dissolution studies were conducted in 900 ml of 0.1N HCl at 37°C ± 0.5°C using USP apparatus II with paddle speed at 50 rpm. The dissolution data is presented in Table 4 as a percentage (%) release into the medium of the total Metopimazine in the tablet:

Table 4: Dissolution data (stability)

Time (min.) Drug released (Percent w/w)
Initial 1 Month 3 Month
3 57.8 43.2 37.5
6 77.1 69.6 70.2
9 83.5 76.1 78.3
12 85.5 80.0 81.4
15 87.1 81.9 83.7
20 88.6 84.2 85.4
30 90.9 86.1 86.4
45 91.4 87.5 88.7
60 92.5 87.5 89.0

Based on the above stability data, it can be concluded that Metopimazine orally disintegrating tablets as per the present invention are stable as there is no increase in impurities and no significant change of drug release from initial values up to 3 months’ storage at accelerated conditions.