DESC:
FIELD OF THE INVENTION:
The present invention relates to taste masked compositions comprising prochlorperazine. The present invention more particularly relates to taste masked granules and formulations of prochlorperazine and process of preparing the same, wherein the said process is simple, cost effective and requires less processing time.

BACKGROUND OF THE INVENTION:
Prochlorperazine (2-chloro-10- [3-(4-methyl-1-piperazinyl) propyl] - 10H-phenothiazine) is a dopamine (D2) receptor antagonist that belongs to the phenothiazine class of antipsychotic agents that are used for the antiemetic treatment of nausea and vertigo. It is also a highly potent typical antipsychotic. It is also used to treat migraine headaches. Intravenous administration can be used to treat status migrainosus. Prochlorperazine blocks the D2 somatodendritic autoreceptor, resulting in the blockade of postsynaptic dopamine receptors in the mesolimbic system and an increased dopamine turnover. Psychotic disorders such as schizophrenia are a group of serious illnesses that affect the mind. These illnesses alter a person's ability to think clearly, make good judgments, respond emotionally, communicate effectively, understand reality, and behave appropriately. Prochlorperazine also has anti-emetic effects, which can be attributed to dopamine blockade in the chemoreceptor trigger zone.

Prochlorperazine is very bitter in taste. The bitter taste of prochlorperazine creates challenge in manufacturing oral formulations. In general, taste masking is carried out by encapsulating the active ingredient inside a capsule or by means of micro-encapsulation techniques, wherein polymeric coating is applied to the active ingredients. Another approach to mask bitter taste of drug is the complexation of drug with the ion exchange resin. However, the technique of encapsulating the drug or formation of drug-resin complex is tedious and time consuming.

Hence, there is an unmet need in the art to provide process for preparing stable, cost effective taste masked formulation comprising prochlorperazine or pharmaceutically acceptable salt thereof, wherein the said process is simple and less time consuming. The present inventors have come out with a new composition and process for preparing taste masked compositions of prochlorperazine wherein the said process is simple, cost effective and requires less processing time.

SUMMARY OF THE INVENTION:
It is the primary object of the present invention to provide taste masked compositions of prochlorperazine and a simple, cost effective and less time consuming process to prepare such taste masked compositions of prochlorperazine.

In one aspect, the present invention relates to taste masked granules comprising prochlorperazine.

In another aspect, the present invention relates to a process for preparing taste masked granules comprising prochlorperazine.

In yet another aspect, the present invention relates to a process for preparing taste masked granules comprising prochlorperazine maleate.

In yet another aspect, the present invention relates to a process for preparing taste masked granules comprising prochlorperazine, wherein the said process is simple, cost effective and requires less processing time.

In yet another aspect, the present invention relates to formulation of taste masked granules comprising prochlorperazine, and one or more excipients.

In yet another aspect, the present invention relates to method of treating severe nausea and vomiting, schizophrenia, non psychotic anxiety or psychotic disorders using taste masked granules of prochlorperazine.

In one aspect, the present invention provides a taste masked composition of prochlorperazine, comprising prochlorperazine, carbomer, a pH dependent polymer, and one or more excipients.

In another aspect, the present invention provides a taste masked formulation of prochlorperazine comprising the taste masked composition of the present invention and one or more excipients selected from the group consisting of binders, fillers or diluents, lubricants, glidants, disintegrants, sweetener, flavouring agent and flavour enhancer.

In yet another aspect, the present invention provides a process for preparing taste masked composition of prochlorperazine, comprising steps of: mixing carbomer and purified water to form clear carbomer gel; mixing prochlorperazine and carbomer gel with continuous stirring; adding a pH dependent polymer to above mixture; optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of a composition; and optionally drying the composition.

DETAILED DESCRIPTION OF THE INVENTION:
The term “Prochlorperazine” as used in the present invention is meant to cover “Prochlorperazine” in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.

The term “composition” refers to a composition comprising prochlorperazine, at least one carbomer and at least one pH dependent polymer. Said composition may optionally contain one or more excipients. Said composition may be used for preparing a formulation.

The term “formulation” refers to dosage form in which the compositions of the present invention are intended to be prepared, and can be prepared. The formulations can be in the form such as oral tablets, orally disintegrating tablets, mouth dissolving tablets, capsules, pellets, sachet, suspensions, etc.

The present invention further provides a process of preparing composition comprising prochlorperazine and at least one carbomer and at least one pH dependent polymer.

Carbomer used in the present invention is branched, high molecular weight, homo and copolymers of acrylic acid, crosslinked with a polyalkenyl polyether. The molecular weight of crosslinked carbomer can be about 3 – 4.5 million depending on interlinkage of many polymer chains. In its presolvated state, the carbomer is a tightly coiled molecule and its thickening properties are limited. However, due to its relatively high molecular weight and extensive resin cross linking, the carbomer can generate a high viscosity gel. The example of suitable carbomer is carbopol 974 P. Carbopol 974 P can generate a high viscosity gel due to its relatively high molecular weight of approximately 3 million and extensive resin cross linking. Initially, gelation of this polymer is believed to occur as a result of partial swelling by water molecules. However, neutralization of the acidic groups of this polymer with an organic or inorganic base leads to further enhancement of viscosity and gelation. The acidic group of polymer is neutralised by basic groups of prochlorperazine which results in the formation of weak bond between drug and polymer. The weak bond results in the surface adsorption of polymer over drug molecule which eventually leads to taste masking of highly bitter prochlorperazine.

The bitterness of prochlorperazine was further masked by using pH dependent polymer. The preferred pH dependent polymer selected in the present invention is a basic polymer, which is soluble in acidic pH of stomach but is insoluble in slightly basic pH of saliva. The pH dependent polymer was added to white coloured paste of drug and carbomer. The pH dependent polymer prevents granules from dissolving in saliva and dissolves immediately after reaching stomach. Further, the pH dependent polymer masks the bitterness of prochlorperazine by ionic interaction with the drug. The preferred pH dependent polymer was polymethacrylate polymer such as Eudragit EPO. Eudragit EPO is a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. The Eudragit E polymers have Low viscosity, high pigment binding capacity and good adhesion. The Eudragit E polymers are swellable and permeable above pH 5 and soluble below pH 5.

In one embodiment, the present invention provides a taste masked composition of prochlorperazine wherein the prochlorperazine and carbomer are present in a weight ratio between about 1:0.75 and about 1:2. More preferably, the weight ratio between prochlorperazine and carbomer is 1:1.

In yet another embodiment, the present invention provides a taste masked composition of prochlorperazine wherein the prochlorperazine and pH dependent polymer are present in a weight ratio between about 1:1 and about 1:3. More preferably the weight ratio between prochlorperazine and pH dependent polymer is 1:1.5.

In yet another embodiment, the present invention provides a taste masked composition of prochlorperazine wherein carbomer and pH dependent polymer are present in a weight ratio between about 1: 0.5 to about 1: 3. More preferably the weight ratio between carbomer and pH dependent polymer is 1:1.5

In yet another embodiment, the present invention provides a taste masked composition of prochlorperazine wherein prochlorperazine is present from about 5 wt% to about 20 wt %. In preferred embodiment, the composition comprises from about 7 wt % to about 15 wt % of prochlorperazine.

In yet another embodiment, the present invention provides a taste masked composition of prochlorperazine wherein the carbomer is present from about 5 wt% to about 15 wt%. In preferred embodiment, the composition comprises from about 8 wt% to about 12 wt% of carbomer.

In yet another embodiment, the present invention provides a taste masked composition of prochlorperazine wherein the pH dependent polymer is present from about 5 wt% to about 20 wt%. In preferred embodiment, the composition comprises from about 8 wt% to about 16 wt% of pH dependent polymer.

In yet another embodiment, the present invention provides a process for preparing taste masked compositions of prochlorperazine wherein the said process requires less processing time as compared ion-exchange or coating based taste masking process.

In yet another embodiment, the present invention provides a process for preparing taste masked compositions of prochlorperazine wherein the prochlorperazine and carbomer are present in a weight ratio between about 1:0.75 and about 1:2. More preferably, the weight ratio between prochlorperazine and carbomer is 1:1.

In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine wherein the prochlorperazine and pH dependent polymer are present in a weight ratio between about 1:1 and about 1:3. More preferably the weight ratio between prochlorperazine and pH dependent polymer is 1:1.5.

In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine wherein carbomer and pH dependent polymer are present in a weight ratio between about 1: 0.5 to about 1: 3. More preferably the weight ratio between carbomer and pH dependent polymer is 1:1.5

In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine wherein prochlorperazine is present from about 5 wt% to about 20 wt %. In preferred embodiment, the composition comprises from about 7 wt % to about 15 wt % of prochlorperazine.

In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine wherein the carbomer is present from about 5 wt% to about 15 wt%. In preferred embodiment, the composition comprises from about 8 wt% to about 12 wt% of carbomer.

In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine wherein the pH dependent polymer is present from about 5 wt% to about 20 wt%. In preferred embodiment, the composition comprises from about 8 wt% to about 16 wt% of pH dependent polymer.

In yet another embodiment, the present invention provides a method of treating severe nausea and vomiting, schizophrenia, non psychotic anxiety or psychotic disorders using taste masked composition or formulations of prochlorperazine.

In a preferred embodiment of the present invention, the taste masked composition of the present invention is prepared in the form of granules. The process of preparing granules involves the steps of mixing carbomer and water in planetary mixer to form a clear carbomer gel. Further, prochlorperazine is added in carbomer gel with continuous and thorough mixing in planetary mixer for about 90 minutes to form white coloured paste. The continuous and thorough mixing of prochlorperazine and carbomer gel results in surface adsorption of carbomer on prochlorperazine, which results in taste masking of prochlorperazine. Further taste masking of prochlorperazine is achieved by adding pH dependent polymer with continuous mixing to the white coloured paste to form wet granules. The pH dependent polymer is a basic polymer which is insoluble in slightly alkaline pH of saliva, but dissolves in acidic pH of stomach. The pH dependent polymer masks the remaining bitterness of prochlorperazine by ionic interaction with the drug. The wet granules are further dried and sifted through # 30 sieve. The combined taste masking effect of carbomer and pH dependent polymer results in the complete taste masking of prochlorperazine granules which can be further formulated in oral dosage forms such as oral tablet, orally disintegrating tablets, mouth dissolving tablets, capsule, pellets or sachet.

The present process of preparing prochlorperazine granules was found to be more cost effective than the other methods for taste masking such as complexation of drug with ion exchange resin. The process of taste masking of drug by formation of drug-resin complex is more tedious and normally takes about 30-36 hours for completion. Whereas according to the present invention, the process of preparation of granules involves less processing steps and takes about 2-4 hours which eventually results in reducing processing cost. Further, the bitterness of the prochlorperazine was completely masked which results in more patient compliance.

In another embodiment, the present invention provides the taste masked composition of prochlorperazine comprising:
a) prochlorperazine,
b) carbomer,
c) a pH dependent polymer, and
d) one or more excipients.

In yet another embodiment, the present invention provides the taste masked granules of prochlorperazine comprising:
a) prochlorperazine,
b) carbomer,
c) one or more pH dependent polymer, and
d) one or more excipients.

In yet another embodiment, the present invention provides the taste masked granules of prochlorperazine comprising:
a) from about 5 wt % to about 20 wt% of prochlorperazine,
b) from about 5 wt% to about 15 wt% of carbomer,
c) from about 5 wt% to about 20 wt% of one or more pH dependent polymer, and
d) one or more excipients.

In yet another embodiment, the carbomer used in the present invention has viscosity from about 4000 cP to about 77000 cP at concentration of 0.5% in pH 7.5.

In yet another embodiment, the carbomer is selected from, but not limiting to, Carbopol 934, Carbopol 934P, Carbopol 940, Carbopol 941, Carbopol 1342, Carbopol 71G, Carbopol 971P, Carbopol 974P, Carbopol 980, Carbopol 981, Carbopol ETD 2020 and Carbopol Ultrez 10. The preferred carbomer in the present invention is carbopol 974P.

In yet another embodiment, the pH dependent polymer is basic in nature which is soluble in acidic pH below 4 and is insoluble in pH above 5.

In yet another embodiment, the pH dependent polymer is selected from Chitosan and Eudragit EPO. The preferred pH dependent polymer is Eudragit EPO.

In yet another embodiment, the present invention provides the taste masked granules of prochlorperazine comprising:
a) from about 5 wt % to about 20 wt% of prochlorperazine,
b) from about 5 wt% to about 15 wt% of Carbopol 974 P,
c) from about 5 wt% to about 20 wt% of Eudragit EPO, and
d) one or more excipients.

In one embodiment, the one or more excipients are selected from binders, fillers or diluents, lubricants, glidants, disintegrants.
The vehicle used in present invention is selected from Isopropyl Alcohol or purified water. The preferred vehicle is purified water.

In another preferred embodiment, the present invention provides a process for preparing taste masked composition comprising prochlorperazine and one or more excipients.
In yet another embodiment, the present invention provides a process for preparing taste masked composition of prochlorperazine, comprising steps of:
a) mixing carbomer and purified water to form clear carbomer gel,
b) mixing prochlorperazine and said carbomer gel with continuous stirring;
c) adding a pH dependent polymer to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of composition; and
e) optionally drying the compositions.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine, comprising steps of:
a) mixing carbomer and purified water to form clear carbomer gel,
b) mixing prochlorperazine and said carbomer gel with continuous stirring;
c) adding a pH dependent polymer to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of granules; and
e) drying the granules.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine, comprising steps of:
a) mixing carbopol 974 P and purified water to form clear carbopol gel;
b) mixing prochlorperazine and said carbopol gel with continuous stirring;
c) adding a Eudragit polymer to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of granules; and
e) drying the granules.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine, comprising steps of:
a) mixing from about 5 wt% to about 15 wt% of carbopol 974 P with purified water to form clear carbopol gel,
b) mixing from about 5 wt% to about 20 wt% of prochlorperazine to said carbopol gel with continuous stirring;
c) adding from about 5 wt% to about 20 wt% of Eudragit EPO to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of granules; and
e) drying the granules.

In yet another embodiment, the mixing is preferably performed in planetary mixer.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the granules can further be formulated in various dosage forms such as oral tablet, orally disintegrating tablets, mouth dissolving tablets, capsule and sachet.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the said granules can further be formulated in form of orally disintegrating tablets. .

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the said process requires less processing time as compared to ion-exchange or coating based taste masking process.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the prochlorperazine and carbomer are present in a weight ratio between about 1:0.75 and about 1:2. More preferably, the weight ratio between prochlorperazine and carbomer is 1:1.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the prochlorperazine and pH dependent polymer are present in a weight ratio between about 1:1 and about 1:3. More preferably the weight ratio between prochlorperazine and pH dependent polymer is 1:1.5.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein carbomer and pH dependent polymer are present in a weight ratio between about 1: 0.5 to about 1: 3. More preferably the weight ratio between carbomer and pH dependent polymer is 1:1.5.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein prochlorperazine is present from about 5 wt% to about 20 wt %. In preferred embodiment, the granules comprise from about 7 wt % to about 15 wt % of prochlorperazine.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the carbomer is present from about 5 wt% to about 15 wt%. In preferred embodiment, the granules comprise from about 8 wt% to about 12 wt% of carbomer.

In yet another embodiment, the present invention provides a process for preparing taste masked granules of prochlorperazine wherein the pH dependent polymer is present from about 5 wt% to about 20 wt%. In preferred embodiment, the granules comprise from about 8 wt% to about 16 wt% of pH dependent polymer.

In yet another embodiment, the present invention provides a method of treating severe nausea and vomiting, schizophrenia, non psychotic anxiety or psychotic disorders using taste masked granules or formulations of prochlorperazine.

The formulation according to present invention will, in general comprise of one or more excipients, apart from the taste masked composition of the present invention. Examples of pharmaceutical excipients include, but are not limited to pH dependent polymer, binders, fillers or diluents, lubricants, glidants, disintegrants, sweetener, flavouring agent and flavour enhancer. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.

The pH dependent polymers include but are not limited to cellulose based polymers such as hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose acetate trimellitate cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethylcellulose, ethyl hydroxyethylcellulose phthalate and the like. Acrylic copolymer such as styrene, acrylic acid copolymer, methyl acrylate, acrylic acid copolymer, methyl acrylate, methacrylic acid copolymer, butyl acrylate, styrene, acrylic acid copolymer, methacrylic acid, methyl methacrylate copolymer, Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), Poly(methacrylic acid-co-ethyl acrylate), Poly(methacrylic acid-co-methyl methacrylate), the commercially available under brand name Eudragit FS 30D, Eudragit L 100-55, Eudragit L 30D-55, Eudragit EPO, EUDRAGIT(R) L 100, EUDRAGIT(R) L 12,5, EUDRAGIT(R) S 100, EUDRAGIT(R) S 12,5 from Evonik. Maleic copolymer such as vinylacetate, maleic acid anhydride copolymer, styrene maleic acid anhydride copolymer, styrene maleic acid monoester copolymer, vinylmethylether maleic acid anhydride copolymer, ethylene maleic acid anhydride copolymer, vinylbutylether maleic acid anhydride copolymer, acrylonitrile methyl acrylate maleic acid anhydride copolymer, butyl acrylate styrene maleic acid anhydride copolymer and other materials known to one of ordinary skill in the art and combinations thereof. The preferred pH dependent polymer is selected from pH dependent Basic polymer such as Eudragit EPO.

Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and combinations thereof.

Fillers or diluents, which include, but are not limited to white sugar, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol (Pearlitol flash®), sucrose, starch, lactose, xylitol, sorbitol, kaolin, talc, microcrystalline cellulose, calcium carbonate, colloidal silicone dioxide, calcium phosphate dibasic or tribasic, calcium sulphate, and other materials known to one of ordinary skill in the art and combinations thereof.

Lubricants may be selected from, but are not limited to, those conventionally known in the art such as vegetable stearin, Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, sucrose esters of fatty acids, silica, colloidal anhydrous silica, microcrystalline wax, yellow beeswax, white beeswax, talc and other materials known to one of ordinary skill in the art and combinations thereof.

Glidants include, but are not limited to, magnesium stearate, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel pregelatinized starch, powdered cellulose and other materials known to one of ordinary skill in the art and combinations thereof.

The formulation according to present invention may also comprise a disintegrant which may be included in all or part of the oral dosage form to ensure rapid disintegration of the dosage form or part of the dosage form (for example, one of the layers in a bilayer tablet) after administration.

Disintegrants include, but are not limited to, alginic acid and alginates, carboxymethylcellulose calcium, carboxy methyl cellulose sodium, low-substituted hydroxypropyl cellulose, croscarmellose, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and pregelatinised starch, starches and other materials known to one of ordinary skill in the art and combinations thereof.

Sweetener include, but are not limited to, acesulfame potassium, aspartame, dextrates, dextrose, erythritol, fructose, galactose, maltitol, maltose, mannitol, saccharin, saccharin calcium, saccharin sodium, sorbitol, sucralose, sucrose, compressible sugar, confectioner’s sugar, syrup, tagatose and other materials known to one of ordinary skill in the art and combinations thereof.

Flavouring agents include but not limited to fennel oil, peppermint, anise oil, raspberry, caraway oil, rose oil, rosemary oil, cherry syrup, sarsaparilla syrup, lavender oil, spearmint oil, citric acid syrup, lemon oil, thyme oil, clove oil, mannitol, vanilla, orange oil, wild cherry syrup, ethyl vanillin, orange flower water.

Flavour enhancer include but not limited to Glutamic acid, Monosodium L-glutamate, Monoammonium L-glutamate, Magnesium di-L-glutamate, Disodium guanylate, Dipotassium guanylate, Calcium guanylate, Dipotassium inosinate, Prosweet MM 52, Calcium inosinate, Maltol, Ethyl maltol and other materials known to one of ordinary skill in the art and combinations thereof.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Example no. 1: Formulation of taste masked granules of Prochlorperazine maleate with carbopol® 974P & Eudragit® EPO in ratio 1:1 by wet granulation technique.

S. No. Ingredient Quantity (gm)
01 Prochlorperazine Maleate 05
02 Carbopol® 974P 05
03 Eudragit® EPO 05
04 Microcrystalline Cellulose
(Avicel® PH 102) 36
05 Purified water 90
Label claim: each 51 mg of dried granules contains Prochlorperazine Maleate 5 mg

Procedure:
1. Disperse carbopol® 974 P in purified water by continuous stirring in planetary mixture to form a gel.
2. Add prochlorperazine maleate in above carbopol® gel and mix well for 90 minutes.
3. Add Eudragit® EPO into step 2 and mix well for 20 minutes.
4. Finally add microcrystalline cellulose (Avicel PH102) into above step and carryout wet granulation in planetary mixture.
5. Granules were dried in hot air oven at 50-55ºC.
6. Dried granules were sifted through sieve # 30 (ASTM).

Example no. 2: Formulation of taste masked granules of Prochlorperazine Maleate with carbopol® 974P & Eudragit® EPO in ratio 1:1.5 by wet granulation technique.

S. No. Ingredient Quantity (gm)
01 Prochlorperazine Maleate 25.0
02 Carbopol® 974P 25.0
03 Eudragit® EPO 37.5
04 Microcrystalline Cellulose
(Avicel® PH 102) 182.5
05 Purified water 375.0
Label claim: each 54 mg of dried granules contains Prochlorperazine Maleate 5 mg

Procedure:
1. Disperse carbopol® 974 P in purified water by continuous stirring for 15 minutes in planetary mixture to form a gel.
2. Add prochlorperazine maleate in above carbopol® gel and mix well for 90 minutes.
3. Add Eudragit® EPO in to step 2 and mix well for 20 minutes.
4. Finally add microcrystalline cellulose (Avicel® PH102) into above step and carryout wet granulation in planetary mixture.
5. Granules were dried in hot air oven at 50-55ºC.
6. Dried granules were sifted through sieve # 30 (ASTM).

Example no. 3: Formulation of Prochlorperazine Mouth Dissolving (MD) tablets by using taste masked granules of example no. 2 (Batch size: 500 tablets).

S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Mannitol 155.0
03 Crospovidone 6.0
04 Saccharin sodium 1.2
05 Flavor raspberry 2.0
06 Magnesium stearate 1.8
Total weight 220.0

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, mannitol, crospovidone, saccharin sodium and flavor raspberry.
2. Lubricated above blend with magnesium stearate.
3. Tablets were compressed of above lubricated blend using 8.00 mm round shaped FFBE punch, plain on both sides.

Example no. 4: Formulation of Prochlorperazine MD tablets by using taste masked granules of example no. 2.

S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Pearlitol flash® 133.3
03 Croscarmellose sodium 8.0
04 Aspartame 0.2
05 Flavor raspberry 1.5
06 Colloidal silicon dioxide 1.5
07 Magnesium stearate 1.5
Total weight 200mg

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, mannitol, crospovidone, saccharin sodium and flavor raspberry.
2. Lubricated above blend with magnesium state.
3. Tablets were compressed of above lubricated blend using 8.00 mm round shaped FFBE punch, plain on both sides.

Example no. 5: Formulation of Prochlorperazine MD tablets by using taste masked granules of Example no. 2

S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Pearlitol flash® 131.0
03 Croscarmellose sodium 8.0
04 Aspartame 2.0
05 Flavor raspberry 2.0
06 Colloidal silicon dioxide 1.5
07 Magnesium stearate 1.5
Total weight 200 mg

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, Pearlitol flash®, crospovidone, aspartame, colloidal silicon dioxide and flavor raspberry.
2. Lubricated above blend with magnesium stearate.
3. Tablets were compressed of above lubricated blend using 8.00 mm round shaped FFBE punch, plain on both sides.

Example no. 6: Formulation of Prochlorperazine MD tablets by using taste masked granules of Example no. 2

S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Pearlitol flash® 177.2
03 Croscarmellose sodium 10.0
04 Aspartame 2.5
05 Flavor raspberry 2.5
06 Colloidal silicon dioxide 1.9
07 Magnesium stearate 1.9
Total weight 250 mg

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, Pearlitol flash®, crospovidone, aspartame, colloidal silicon dioxide and flavor raspberry.
2. Lubricated above blend with magnesium stearate.
3. Tablets were compressed of above lubricated blend using 8.00 mm round shaped FFBE punch, plain on both sides.

Example no. 7: Formulation of Prochlorperazine MD tablets by using taste masked granules of Example no: 2

S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Pearlitol flash® 219.0
03 Croscarmellose sodium 12.0
04 Aspartame 6.0
05 Flavor raspberry 4.4
06 Colloidal silicon dioxide 2.3
07 Magnesium stearate 2.3
Total weight 300 mg

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, Pearlitol flash®, crospovidone, aspartame, colloidal silicon dioxide and flavor raspberry.
2. Lubricated above blend with mganesium stearate.
3. Tablets were compressed of above lubricated blend using 10.00 mm round shaped FFBE punch, plain on both sides.

Example no. 8: Formulation of Prochlorperazine MD tablets by using taste masked granules of Example no: 2
S. No. Ingredient Qty per tablet (mg)
01 Prochlorperazine Maleate taste masked granules 54.0
02 Pearlitol flash 132.6
03 Croscarmellose sodium 6.0
04 Aspartame 2.0
05 Flavor raspberry 2.0
06 Prosweet MM 52 0.4
07 Colloidal silicon dioxide 1.0
08 Magnesium stearate 2.0
Total weight 200 mg

Procedure:
1. Mixed prochlorperazine maleate taste masked granules, Pearlitol flash, crospovidone, aspartame, colloidal silicon dioxide, Prosweet MM 52 and flavor raspberry.
2. Lubricated above blend with magnesium state.
3. Tablets were compressed of above lubricated blend using 8.00 mm round shaped FFBE punch, plain on both side.

The stability studies of tablets were conducted under different stability conditions such as 400C/75% RH, 250C/60% RH and 300C/65% RH from 1 month to 12 months. From the stability studies, it was observed that the tablets were stable under different stability conditions. Stability dissolution profile of formulation prepared as per example no. 4 using various stability conditions are shown in Table no. 1.

Table no. 1: Stability dissolution profile of formulation prepared as per example no. 4 using various stability conditions at predetermined time period:

Parameters Stability conditions (Pack: Alu-Alu Blister)
Initial 400C/75%RH 250C/60%RH 300C/65%RH
1M 2M 3M 6M 3M 6M 9M 12M 3M 6M 9M 12M
Assay (%) 103.5 103.5 103.2 102.6 100.0 101.4 101.7 101.9 101.0 102.6 100.2 103.0 102.1
DT (sec) 29 30 31 32 31 33 35 43 45 28 32 35 45
LOD (% w/w) 3.4 3.7 4.3 4.5 4.2 3.85 3.9 4.1 4.1 4.12 4.1 4.1 4.5
Dissolution Dissolution condition: USP apparatus II (paddle), 0.1N HCl, 500mL,75rpm
05 min. 99.2 97.8 99.1 97.5 95.3 94.9 98.8 96.2 98.2 97.0 95.3 99.8 92.5

While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof has been shown by way of examples and described above. It should be understood, however that embodiments described above are not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternatives falling within the spirit and the scope of the invention as defined by the appended claims.
,CLAIMS:We Claim:-
1. A taste masked composition of prochlorperazine, comprising:
a) prochlorperazine,
b) carbomer,
c) a pH dependent polymer, and
d) one or more excipients.

2. The composition as claimed in claim 1, wherein prochlorperazine and carbomer are present in a weight ratio between 1:0.75 and 1:2.

3. The composition as claimed in claim 1, wherein prochlorperazine and pH dependent polymer are present in a weight ratio between 1:1 and 1:3.

4. The composition as claimed in claim 1, wherein carbomer and pH dependent polymer are present in a weight ratio between 1:0.5 and 1:3.

5. The composition as claimed in claim 1, wherein the said carbomer is selected from Carbopol 934, Carbopol 934P, Carbopol 940, Carbopol 941, Carbopol 1342, Carbopol 71G, Carbopol 971P, Carbopol 974P, Carbopol 980, Carbopol 981, Carbopol ETD 2020 and Carbopol Ultrez 10.

6. The composition as claimed in claim 1, wherein the said pH dependent polymer is selected from pH dependent basic polymers.

7. The composition as claimed in claim 6, wherein the said pH dependent basic polymer is selected from chitosan and Eudragit EPO.

8. The composition as claimed in claim 1, wherein the one or more excipients are selected from binders, fillers or diluents, lubricants, glidants or disintegrants.

9. Taste masked granules of prochlorperazine, comprising:
(a) from 5 wt% to 20 wt% of prochlorperazine,
(b) from 5 wt% to 15 wt% of carbopol 974 P,
(c) from 5 wt% to 20 wt% of Eudragit EPO, and
(d) a diluent.

10. A taste masked formulation of prochlorperazine comprising:
(a) the taste masked composition as claimed in any of the preceding claims 1 to 9, and
(b) one or more excipients selected from the group consisting of binders, fillers or diluents, lubricants, glidants, disintegrants, sweetener, flavouring agent and flavour enhancer.

11. The formulation as claimed in claim 10, wherein the formulation is in the form of oral tablets, orally disintegrating tablets, mouth dissolving tablets, capsules, sachet, or suspensions.

12. A process for preparing taste masked composition of prochlorperazine, comprising steps of:
a) mixing carbomer and purified water to form clear carbomer gel;
b) mixing prochlorperazine and carbomer gel with continuous stirring;
c) adding a pH dependent polymer to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of a composition;
e) optionally drying the composition.

13. A process for preparing taste masked granules of prochlorperazine, comprising steps of:
a) mixing from about 5 wt% to about 15 wt% of carbopol 974 P with purified water to form clear carbopol gel,
b) mixing from about 5 wt% to about 20 wt% of prochlorperazine to said carbopol gel with continuous stirring;
c) adding from about 5 wt% to about 20 wt% of Eudragit EPO to above mixture;
d) optionally adding one or more excipients to above mixture and blending the mixture for a time sufficient to allow formation of granules; and
e) drying the granules.

14. The process as claimed in claim 12 or 13, wherein the mixing is performed in planetary mixer.

15. The taste masked composition, granules or formulation as claimed in any of the preceding claims, for use in the treatment of severe nausea and vomiting, schizophrenia, non psychotic anxiety or psychotic disorders.