Indian Patents. 199668:"A PROCESS FOR THE PREPARATION OF STABLE AQUEOUS SOLUTION OF RISPERIDONE COMPRISING POLYHYDRIC ALC OHOL AS SWEETNER"

Title of Invention	"A PROCESS FOR THE PREPARATION OF STABLE AQUEOUS SOLUTION OF RISPERIDONE COMPRISING POLYHYDRIC ALC OHOL AS SWEETNER"
Abstract	The present invention relates to the process of preparation of stable aqueous solution of risperidone. The risperidone solution comprises risperidone, antioxidant, polyhydric alcohol as sweetener, and buffering agent to maintain the pH within the range of 2 to 4.

Full Text	The present invention relates to a method for the preparation of stable aqueous solution of risperidone for oral administration. US Patent No. 4,804, 663 discloses an oral solution containing a 1,2-benzisoxazol-3-yl derivative, preservatives, tartaric acid, sodium-saccharin, flavors, and the polyhydric alcohols such as sorbitol and glycerol. However, comparable solutions wherein the benzisoxazole derivative was risperidone, were found to exhibit an unsatisfactory physicochemical stability. And, sorbitol was found to cause decomposition of risperidone upon storage of the solution at elevated temperatures. A similar observation was made with the maltitol, suggesting that risperidone is incompatible with polyhydric alcohols. Due to this incompatibility of risperidone with sorbitol, US Pat. Nos. 5,453,425 and 5,616,587 disclose an aqueous solution of risperidone essentially free of polyhydric alcohols such as mannitol, fructose, sucrose, maltose and the like. Use of polyhydric alcohols, including sorbitol as a sweetener has many advantages, as these provide bulk and sweetness with a clean, cool pleasant taste. Sorbitol provides one-third fewer calories than sugar. It is an excellent humectant, texturizing and anti-crystallizing agent. Moreover Polyhydric alcohols are resistant to metabolism by oral bacteria, which break down sugars, and starches to release acids that may lead to cavities or erode tooth enamel. They are, therefore, non-cariogenic. Sorbitol is slowly absorbed, therefore, when sorbitol is used, the rise in blood glucose and the insulin response associated with the ingestion of glucose is significantly reduced. Therefore Sorbitol can be used as an alternative to sugar for people with diabetes. Moreover, Sorbitol has been affirmed as GRAS (Generally Recognized As Safe) by the U.S. Food and Drug Administration and is approved for use by the European Union and numerous countries around the world, including Australia, Canada and Japan. Sorbitol is very stable, chemically inert and can withstand high temperatures. Moreover, the commercially available risperidone aqueous solution "Risperdal" needs to be diluted with 100ml of beverage before consuming. However polyhydric alcohol such as sorbitol, mannitol, fructose, sucrose, and maltose when used as bulk sweeteners give palatable aqueous solution, which can be administered as such.without any dilution. Hence, in view of the above advantages of polyhydric alcohols, it would be desirable to develop a method for stabilization of aqueous solution of risperidone containing polyhydric alcohols as sweeteners. In the present invention, we have discovered that a stable aqueous solution of risperidone can be prepared even with polyhydric alcohols. By experimentation in our lab, we have discovered that a stable aqueous solution of risperidone containing polyhydric alcohols can be prepared by reducing the solid content and increasing the available water concentration of the aqueous solution. US Patent No. 4,804, 663 describes the aqueous solution of risperidone with less than 30% average available water content and solid content up to about 70%. However we found that by reducing the solid content up to 10% and increasing the water content up to 90%, a stable aqueous solution of risperidone can be obtained. This solution was stable when kept for 4 weeks at a temperature of 80°C. Accordingly, the present invention relates to a process for the preparation of stable aqueous solution of risperidone for oral administration comprising: a. risperidone such as herein described, b. stabilizing amount of antioxidant such as herein described, c. polyhydric alcohol as sweetener such as herein described, and d. buffering agent such as herein described, to maintain the pH of the said solution within the range of about 2 to about 4. e.other conversional ingredients when on herein described It also provides a method for the preparation of stable aqueous solution of risperidone comprising polyhydric alcohols as sweeteners, wherein the solution further comprises stabilizing amount of antioxidants. The solution prepared by the method of the present invention showed excellent stability and palatability and could be used without any further dilution. The term "stable" as herein defined refers to a solution wherein, after storage for a period uprtb 4 weeks at a temperature of 80° C or below, the residual amount of risperidone is 80% or more of the initial risperidone concentration. The term risperidone (3-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ) as used herein comprises the free base form and the pharmaceutically acceptable acid addition salts thereof. The amount of risperidone in the present compositions ranges from 0.01 % to 1 %. The term polyhydric alcohols include monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose; other sugars such as ribose, glycerine, sorbitol, xylitol, maltitol, erythritol, inositol, lactitol monohydrate, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, mannitol, polyethylene glycol, glycerol or mixtures thereof. The preferred sweeteners are sucrose and sorbitol that can be used in an amount of about 5 % to about 50% by weight of the total weight of solution. The antioxidants for the present invention may be selected from any of the three classes of antioxidant i.e. true antioxidants, reducing agents and antioxidant synergist. The true antioxidants may be selected from the group consisting of acetylcysteine, alpha tocopherol acetate, d- alpha tocopherol, dl- alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate and the like. The reducing agents may be selected from the group consisting of ascorbic acid, calicum ascorbate, calcium bisulphite, calcium sulphite, isoascorbic acid, potassium metabisulphite, sodium ascorbate, sodium bisulphite, sodium metabisulphite, sodium sulphite, sodium thiosulphate, thioglycerol and the like. The antioxidant synergists may be selected from the group consisting of citric acid, edetic acid (EDTA) and its salts such as disodium EDTA, hydroxyquinoline sulphate, phosphoric acid, sodium citrate, tartaric acid and the like. Antioxidants, which are safe for ingestion and have sufficient solubility in the solution to make a stable single-phase composition, stable over a wide range of temperatures and pH values, Compatible with other components of the solution are preferred. Mixtures of two or more of the foregoing may also be used. The concentration of antioxidant may vary from about 0.01% to about 5.0% by weight of the total weight of solution. The term "stabilizing amount" as used herein refers to an amount of antioxidants, which is sufficient to stabilize the risperidone solution. Besides the above the oral solution of the present invention may also comprise of some other pharmaceutical additives such as antimicrobial preservatives, buffering agents, solubilizers, viscosity enhancing agents, colors, flavors and the like. The preservatives of the present invention may be selected from benzoic acid, sorbic acid, methyl paraben or salts thereof, propyl paraben or salts thereof, benzyl alcohol and benzylalkonium chloride. The concentration of the preservatives may range from 0.05% to 2%. Suitable solubilizer of the present invention may be a co-solvent, complexing agent, surfactant, wetting agent or the like. Viscosity enhancing agents of the present invention may be selected from hydroxypropyl methylcellulose (some forms of which are available from Dow Chemical, Midland, Mich. USA under the METHOCEL trademark), hydroxpropyl cellulose and the like to provide a viscous mouth-feel similar to that of a traditional syrup. Colors and flavors of the present invention may be selected from any FDA approved color or flavor suitable for oral use. Suitable flavoring substances are vanilla, cherry, raspberry, black currant, strawberry, Caramel Chocolate, Mint Cool, Fantasy flavors and the like. The total concentration of the flavoring substances may range from 0.01% to 2.0%. The oral solutions according to the present invention have a pH from 2 to 6. The pH of the composition may be maintained by addition of buffers. Buffers may be selected from acid-base combinations such as succinic, tartaric, lactic, or citric acid with sodium hydroxide or disodium hydrogen phosphate. The aqueous solution of the present invention may be prepared by: (a) dissolving preservatives, stabilizers and acid component of the buffering system in hot purified water, (b) followed by cooling; (c) dissolving risperidone under continuous stirring in the solution of previous step (d) followed by addition of sweetener (e) adding colors and flavors; and (f) adjusting pH with the basic component of the buffering system and making up the volume. The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto. Example 1 (Table Removed)Process: 1. Benzoic acid was dissolved in purified water at 60°C. 2. Tartaric acid was dissolved in solution of step 1, followed by cooling to a temperature of less than 30°C. 3. Risperidone was then dissolved into the above solution under continuous stirring. 4. Sorbitol solution (70%) was mixed with the bulk of step 3, proceeded by the addition of Artificial Creme De Vanilla Flavor and Artificial Raspberry Flavor. 5. The pH of the above, solution'of step 4 was then adjusted between 3-4 with sodium hydroxide solution, followed by volume makeup using purified water. 6. The bulk of step 5 was finally filtered through Sum polypropylene filter and filled into suitable containers. Example 2 (Table Removed)Process: 1. Benzoic acid and EDTA disodium were dissolved in purified water at 60°C. 2. Tartaric acid was dissolved in solution of step 1, followed by cooling to a temperature of less than 30°C. 3. Risperidone was then dissolved into the above solution under continuous stirring. 4. Sorbitol solution (70%) was mixed with the bulk of step 3, proceeded by the addition of Artificial Creme De Vanilla Flavor and Artificial Raspberry Flavor. 5. The pH of the above solution of step 4 was then adjusted between 3-4 with sodium hydroxide solution, followed by volume makeup using purified water. 6. The bulk of step 5 was finally filtered through 5µm polypropylene filter and filled into suitable containers. The above solutions when subjected to accelerated stability i.e. at a temperature of 80° C for a period up to 4 weeks, showed excellent stability. This is clearly evident from the data given in Table-1. Table 1. Accelerated stability data generated at 80°C for a period of four weeks(Table Removed) WE CLAIM: 1. A method for the preparation of stable aqueous solution of risperidone for oral administration, comprising polyhydric alcohols as sweeteners. 2. The method according to claim 1 wherein the aqueous solution of risperidone further comprises a stabilizing amount of antioxidant. 3. The method according to claim 2 wherein the antioxidant may be selected from true antioxidants, reducing agents and antioxidant synergist. 4. The method according to claim 3 wherein the true antioxidants is selected from the group consisting of acetylcysteine, alpha tocopherol acetate, d- alpha tocopherol, dl- alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate and the like. 5. The method according to claim 4 wherein the true antioxidant is cysteine. 6. The method according to claim 4 wherein the true antioxidant is cysteine hydrochloride. 7. The method according to claim 4 wherein the true antioxidant is butylated hydroxytoluene. 8. The method according to claim 4 wherein the true antioxidant is butylated hydroxyanisole. 9. The method according to claim 3 wherein the reducing agents is selected from the group consisting of ascorbic acid, calicum ascorbate, calcium bisulphite, calcium sulphite, ascorbic acid, isoascorbic acid, potassium metabisulphite, sodium ascorbate, sodium bisulphite, sodium metabisulphite, sodium sulphite, sodium thiosulphate, thioglycerol and the like. 10.The method according to claim 9 wherein the reducing agent is sodium metabisulphite. 11. The method according to claim 9 wherein the reducing agent is ascorbic acid. 12.The method according to claim 9 wherein the reducing agent is sodium ascorbate. 13. The method according to claim 3 wherein the antioxidant synergist is selected from the group consisting of citric acid, edetic acid (EDTA) and its salts, hydroxyquinoline sulphate, phosphoric acid, sodium citrate, tartaric acid and the like. 14.The method according to claim 13 wherein the antioxidant synergist is citric acid. 15. The method according to claim 13 wherein the antioxidant synergist is selected from edetic acid and its salts. 16. The method according to claim 15 wherein the edetic acid salt is disodium EDTA. 17.The method according to claim 13 wherein the antioxidant synergist is sodium citrate. 18.The method according to claim 13 wherein the antioxidant synergist is tartaric acid. 19.The method according to claim 2 wherein the antioxidant is present in the concentration of from about 0.01 % to about 5.0% by weight of the total weight of solution. 20. The method according to claim 1 wherein the polyhydric alcohol is selected from the group consisting of monosaccharides, disaccharides and other sugars. 21.The method according to claim 20 wherein monosaccharide is glucose (dextrose) or fructose (levulose). 22.The method according to claim 20 wherein disaccharide is sucrose, lactose, maltose or cellobiose. 23. The method according to claim 22 wherein disaccharide is sucrose. 24.The method according to claim 20 wherein other sugars are ribose, glycerine, sorbitol, xylitol, maltitol, erythritol, inositol, lactitol monohydrate, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, mannitol, polyethylene glycol and glycerol. 25. The method according to claim 24 wherein the other sugar is sorbitol. 26.The method according to claim'1 or 2 wherein the stable aqueous solution of risperidone further comprises of other pharmaceutical additives. 27. The method according to claim 26 wherein the other pharmaceutically acceptable additives are selected from the group consisting of preservatives, buffering agents, solubilizers, viscosity enhancing agents, colors, flavors and the like. 28.The method according to claim 27 wherein the preservative is selected from the group consisting of benzoic acid, sorbic acid, methyl paraben or salts thereof, propyl paraben or salts thereof, benzyl alcohol and benzylalkonium chloride. 29.The method according to claim 28 wherein the preservative is benzoic acid. 30. The method according to claim 27 wherein the buffering agents are acid-base combinations. 31.The method according to claim 30 wherein acid is succinic, tartaric, lactic, or citric acid and base is sodium hydroxide or disodium hydrogen phosphate. 32.The method according to claim 31 wherein the acid is tartaric acid and base is sodium hydroxide. 33.The method according to claim 27 wherein the flavors are selected from vanilla, cherry, raspberry, black currant, strawberry, Caramel Chocolate, Mint Cool and Fantasy flavors and combinations thereof. 34.The method according to claim 33 wherein the flavor is a combination of Vanilla and Raspberry. 35. A process for the preparation of stable aqueous solution of risperidone for oral administration, comprising polyhydric alcohol as sweetener, optionally with stabilizing amount of antioxidant and other pharmaceutically acceptable additives substantially as described and illustrated by the examples herein.

Full Text

The present invention relates to a method for the preparation of stable aqueous solution of risperidone for oral administration.
US Patent No. 4,804, 663 discloses an oral solution containing a 1,2-benzisoxazol-3-yl derivative, preservatives, tartaric acid, sodium-saccharin, flavors, and the polyhydric alcohols such as sorbitol and glycerol.
However, comparable solutions wherein the benzisoxazole derivative was risperidone, were found to exhibit an unsatisfactory physicochemical stability. And, sorbitol was found to cause decomposition of risperidone upon storage of the solution at elevated temperatures. A similar observation was made with the maltitol, suggesting that risperidone is incompatible with polyhydric alcohols.
Due to this incompatibility of risperidone with sorbitol, US Pat. Nos. 5,453,425 and 5,616,587 disclose an aqueous solution of risperidone essentially free of polyhydric alcohols such as mannitol, fructose, sucrose, maltose and the like.
Use of polyhydric alcohols, including sorbitol as a sweetener has many advantages, as these provide bulk and sweetness with a clean, cool pleasant taste. Sorbitol provides one-third fewer calories than sugar. It is an excellent humectant, texturizing and anti-crystallizing agent. Moreover Polyhydric alcohols are resistant to metabolism by oral bacteria, which break down sugars, and starches to release acids that may lead to cavities or erode tooth enamel. They are, therefore, non-cariogenic.

Sorbitol is slowly absorbed, therefore, when sorbitol is used, the rise in blood glucose and the insulin response associated with the ingestion of glucose is significantly reduced. Therefore Sorbitol can be used as an alternative to sugar for people with diabetes.
Moreover, Sorbitol has been affirmed as GRAS (Generally Recognized As Safe) by the U.S. Food and Drug Administration and is approved for use by the European Union and numerous countries around the world, including Australia, Canada and Japan.
Sorbitol is very stable, chemically inert and can withstand high temperatures. Moreover, the commercially available risperidone aqueous solution "Risperdal" needs to be diluted with 100ml of beverage before consuming. However polyhydric alcohol such as sorbitol, mannitol, fructose, sucrose, and maltose when used as bulk sweeteners give palatable aqueous solution, which can be administered as such.without any dilution.
Hence, in view of the above advantages of polyhydric alcohols, it would be desirable to develop a method for stabilization of aqueous solution of risperidone containing polyhydric alcohols as sweeteners.
In the present invention, we have discovered that a stable aqueous solution of risperidone can be prepared even with polyhydric alcohols. By experimentation in our lab, we have discovered that a stable aqueous solution of risperidone containing polyhydric alcohols can be prepared by reducing the solid content and increasing the available water concentration of the aqueous solution. US Patent No. 4,804, 663 describes the aqueous solution of risperidone with less than 30% average available water content and solid content up to about 70%. However we found

that by reducing the solid content up to 10% and increasing the water content up to 90%, a stable aqueous solution of risperidone can be obtained. This solution was stable when kept for 4 weeks at a temperature of 80°C. Accordingly, the present invention relates to a process for the preparation of stable aqueous solution of risperidone for oral administration comprising:
a. risperidone such as herein described,
b. stabilizing amount of antioxidant such as herein described,
c. polyhydric alcohol as sweetener such as herein described, and
d. buffering agent such as herein described, to maintain the pH of the said solution
within the range of about 2 to about 4.
e.other conversional ingredients when on herein described
It also provides a method for the preparation of stable aqueous solution of risperidone comprising polyhydric alcohols as sweeteners, wherein the solution further comprises stabilizing amount of antioxidants.
The solution prepared by the method of the present invention showed excellent stability and palatability and could be used without any further dilution.
The term "stable" as herein defined refers to a solution wherein, after storage for a period uprtb 4 weeks at a temperature of 80° C or below, the residual amount of risperidone is 80% or more of the initial risperidone concentration.
The term risperidone (3-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr ahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one ) as used herein comprises the free base form
and the pharmaceutically acceptable acid addition salts thereof. The amount of risperidone in the present compositions ranges from 0.01 % to 1 %.
The term polyhydric alcohols include monosaccharides such as glucose (dextrose), fructose (levulose); disaccharides such as sucrose, lactose, maltose, cellobiose; other sugars such as ribose, glycerine, sorbitol, xylitol, maltitol, erythritol, inositol, lactitol monohydrate, propylene glycol, galactose, mannose, xylose, rhamnose, glutaraldehyde, invert sugars, mannitol, polyethylene glycol, glycerol or mixtures thereof. The preferred sweeteners are sucrose and sorbitol that can be used in an amount of about 5 % to about 50% by weight of the total weight of solution.
The antioxidants for the present invention may be selected from any of the three classes of antioxidant i.e. true antioxidants, reducing agents and antioxidant synergist. The true antioxidants may be selected from the group consisting of acetylcysteine, alpha tocopherol acetate, d- alpha tocopherol, dl- alpha tocopherol, ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene (BHT), cysteine, cysteine hydrochloride, propyl gallate and the like. The reducing agents may be selected from the group consisting of ascorbic acid, calicum ascorbate, calcium bisulphite, calcium sulphite, isoascorbic acid, potassium metabisulphite, sodium ascorbate, sodium bisulphite, sodium metabisulphite, sodium sulphite, sodium thiosulphate, thioglycerol and the like. The antioxidant synergists may be selected from the group consisting of citric acid, edetic acid (EDTA) and its salts such as disodium EDTA, hydroxyquinoline sulphate, phosphoric acid, sodium citrate, tartaric acid and the like.
Antioxidants, which are safe for ingestion and have sufficient solubility in the solution to make a stable single-phase composition, stable over a wide range of temperatures and pH values,
Compatible with other components of the solution are preferred. Mixtures of two or more of the foregoing may also be used. The concentration of antioxidant may vary from about 0.01% to about 5.0% by weight of the total weight of solution.
The term "stabilizing amount" as used herein refers to an amount of antioxidants, which is sufficient to stabilize the risperidone solution.
Besides the above the oral solution of the present invention may also comprise of some other pharmaceutical additives such as antimicrobial preservatives, buffering agents, solubilizers, viscosity enhancing agents, colors, flavors and the like. The preservatives of the present invention may be selected from benzoic acid, sorbic acid, methyl paraben or salts thereof, propyl paraben or salts thereof, benzyl alcohol and benzylalkonium chloride. The concentration of the preservatives may range from 0.05% to 2%.
Suitable solubilizer of the present invention may be a co-solvent, complexing agent, surfactant, wetting agent or the like.
Viscosity enhancing agents of the present invention may be selected from hydroxypropyl methylcellulose (some forms of which are available from Dow Chemical, Midland, Mich. USA under the METHOCEL trademark), hydroxpropyl cellulose and the like to provide a viscous mouth-feel similar to that of a traditional syrup.
Colors and flavors of the present invention may be selected from any FDA approved color or flavor suitable for oral use. Suitable flavoring substances are vanilla, cherry, raspberry, black currant, strawberry, Caramel Chocolate, Mint Cool, Fantasy flavors and the like. The total concentration of the flavoring substances may range from 0.01% to 2.0%.
The oral solutions according to the present invention have a pH from 2 to 6. The pH of the composition may be maintained by addition of buffers. Buffers may be selected from acid-base combinations such as succinic, tartaric, lactic, or citric acid with sodium hydroxide or disodium hydrogen phosphate.
The aqueous solution of the present invention may be prepared by:
(a) dissolving preservatives, stabilizers and acid component of the buffering system in hot
purified water,
(b) followed by cooling;
(c) dissolving risperidone under continuous stirring in the solution of previous step
(d) followed by addition of sweetener
(e) adding colors and flavors; and
(f) adjusting pH with the basic component of the buffering system and making up the volume.
The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
Example 1
(Table Removed)Process:
1. Benzoic acid was dissolved in purified water at 60°C.
2. Tartaric acid was dissolved in solution of step 1, followed by cooling to a temperature of
less than 30°C.
3. Risperidone was then dissolved into the above solution under continuous stirring.
4. Sorbitol solution (70%) was mixed with the bulk of step 3, proceeded by the addition of
Artificial Creme De Vanilla Flavor and Artificial Raspberry Flavor.
5. The pH of the above, solution'of step 4 was then adjusted between 3-4 with sodium
hydroxide solution, followed by volume makeup using purified water.
6. The bulk of step 5 was finally filtered through Sum polypropylene filter and filled into
suitable containers.
Example 2
(Table Removed)Process:
1. Benzoic acid and EDTA disodium were dissolved in purified water at 60°C.
2. Tartaric acid was dissolved in solution of step 1, followed by cooling to a temperature
of less than 30°C.
3. Risperidone was then dissolved into the above solution under continuous stirring.
4. Sorbitol solution (70%) was mixed with the bulk of step 3, proceeded by the addition
of Artificial Creme De Vanilla Flavor and Artificial Raspberry Flavor.
5. The pH of the above solution of step 4 was then adjusted between 3-4 with sodium
hydroxide solution, followed by volume makeup using purified water.
6. The bulk of step 5 was finally filtered through 5µm polypropylene filter and filled into
suitable containers.
The above solutions when subjected to accelerated stability i.e. at a temperature of 80° C for a period up to 4 weeks, showed excellent stability. This is clearly evident from the data given in Table-1.
Table 1. Accelerated stability data generated at 80°C for a period of four weeks(Table Removed)

WE CLAIM:
1. A method for the preparation of stable aqueous solution of risperidone for oral
administration, comprising polyhydric alcohols as sweeteners.
2. The method according to claim 1 wherein the aqueous solution of risperidone further
comprises a stabilizing amount of antioxidant.
3. The method according to claim 2 wherein the antioxidant may be selected from true
antioxidants, reducing agents and antioxidant synergist.
4. The method according to claim 3 wherein the true antioxidants is selected from the group
consisting of acetylcysteine, alpha tocopherol acetate, d- alpha tocopherol, dl- alpha
tocopherol, ascorbyl palmitate, butylated hydroxyanisole(BHA), butylated hydroxytoluene
(BHT), cysteine, cysteine hydrochloride, propyl gallate and the like.
5. The method according to claim 4 wherein the true antioxidant is cysteine.
6. The method according to claim 4 wherein the true antioxidant is cysteine hydrochloride.
7. The method according to claim 4 wherein the true antioxidant is butylated
hydroxytoluene.
8. The method according to claim 4 wherein the true antioxidant is butylated
hydroxyanisole.
9. The method according to claim 3 wherein the reducing agents is selected from the group
consisting of ascorbic acid, calicum ascorbate, calcium bisulphite, calcium sulphite,
ascorbic acid, isoascorbic acid, potassium metabisulphite, sodium ascorbate, sodium
bisulphite, sodium metabisulphite, sodium sulphite, sodium thiosulphate, thioglycerol and
the like.
10.The method according to claim 9 wherein the reducing agent is sodium metabisulphite.

11. The method according to claim 9 wherein the reducing agent is ascorbic acid. 12.The method according to claim 9 wherein the reducing agent is sodium ascorbate.
13. The method according to claim 3 wherein the antioxidant synergist is selected from the group consisting of citric acid, edetic acid (EDTA) and its salts, hydroxyquinoline sulphate, phosphoric acid, sodium citrate, tartaric acid and the like.
14.The method according to claim 13 wherein the antioxidant synergist is citric acid.
15. The method according to claim 13 wherein the antioxidant synergist is selected from
edetic acid and its salts.
16. The method according to claim 15 wherein the edetic acid salt is disodium EDTA.
17.The method according to claim 13 wherein the antioxidant synergist is sodium citrate.
18.The method according to claim 13 wherein the antioxidant synergist is tartaric acid.
19.The method according to claim 2 wherein the antioxidant is present in the concentration of from about 0.01 % to about 5.0% by weight of the total weight of solution.
20. The method according to claim 1 wherein the polyhydric alcohol is selected from the group consisting of monosaccharides, disaccharides and other sugars.
21.The method according to claim 20 wherein monosaccharide is glucose (dextrose) or fructose (levulose).
22.The method according to claim 20 wherein disaccharide is sucrose, lactose, maltose or cellobiose.
23. The method according to claim 22 wherein disaccharide is sucrose.
24.The method according to claim 20 wherein other sugars are ribose, glycerine, sorbitol, xylitol, maltitol, erythritol, inositol, lactitol monohydrate, propylene glycol, galactose,
mannose, xylose, rhamnose, glutaraldehyde, invert sugars, mannitol, polyethylene glycol and glycerol.
25. The method according to claim 24 wherein the other sugar is sorbitol.
26.The method according to claim'1 or 2 wherein the stable aqueous solution of risperidone further comprises of other pharmaceutical additives.
27. The method according to claim 26 wherein the other pharmaceutically acceptable additives are selected from the group consisting of preservatives, buffering agents, solubilizers, viscosity enhancing agents, colors, flavors and the like.
28.The method according to claim 27 wherein the preservative is selected from the group consisting of benzoic acid, sorbic acid, methyl paraben or salts thereof, propyl paraben or salts thereof, benzyl alcohol and benzylalkonium chloride.
29.The method according to claim 28 wherein the preservative is benzoic acid.
30. The method according to claim 27 wherein the buffering agents are acid-base combinations.
31.The method according to claim 30 wherein acid is succinic, tartaric, lactic, or citric acid and base is sodium hydroxide or disodium hydrogen phosphate.
32.The method according to claim 31 wherein the acid is tartaric acid and base is sodium hydroxide.
33.The method according to claim 27 wherein the flavors are selected from vanilla, cherry, raspberry, black currant, strawberry, Caramel Chocolate, Mint Cool and Fantasy flavors and combinations thereof.
34.The method according to claim 33 wherein the flavor is a combination of Vanilla and Raspberry.
35. A process for the preparation of stable aqueous solution of risperidone for oral administration, comprising polyhydric alcohol as sweetener, optionally with stabilizing amount of antioxidant and other pharmaceutically acceptable additives substantially as described and illustrated by the examples herein.

Documents:

859-del-2002-abstract.pdf

859-del-2002-claims.pdf

859-del-2002-correspondence-others.pdf

859-del-2002-correspondence-po.pdf

859-del-2002-description (complete).pdf

859-del-2002-form-1.pdf

859-del-2002-form-2.pdf

859-del-2002-form-3.pdf

859-del-2002-petition-138.pdf

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Patent Number

199668

Indian Patent Application Number

859/DEL/2002

PG Journal Number

41/2007

Publication Date

12-Oct-2007

Grant Date

08-Oct-2007

Date of Filing

23-Aug-2002

Name of Patentee

RANBAXY LABORATORIES LIMITED

Applicant Address

19, NEHRU PLACE, NEW DELHI-110 019, INDIA.

Inventors:

#	Inventor's Name	Inventor's Address
1	RAJIV MALIK	RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR - 18, UDYOG VIHAR, INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
2	ASHISH GOGIA	RANBAXY LABORATORIES LIMITED, PLOT NO. 20, SECTOR - 18, UDYOG VIHAR, INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.
3	SUNILENDU BHUSHAN ROY	RANBAXY LABORATORIES LIMKITED, PLOT NO. 20, SECTOR-18, UDYOG VIHA, INDUSTRIAL AREA, GURGAON-122001 (HARYANA), INDIA.

PCT International Classification Number

A61K 009/08

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA