Claims:We claim:
1. A stable tiopronin oral solution comprising of a therapeutically effective amount of tiopronin or a pharmaceutically acceptable salt thereof, at least one vehicle, at least one preservative, at least one antioxidant, at least one buffering agent and at least one flavoring agent; wherein the pH of the oral solution is about 4-8 and the concentration of tiopronin in the oral solution is about 25 to 100 mg/ml.

2. The Tiopronin oral solution as claimed in claim 1, wherein the vehicle is selected from the group comprising of butylene glycol, polyethylene glycol, propylene glycol, glycerin monostearate, sorbitol, ethanol and propylene glycol or a combination thereof.

3. The Tiopronin oral solution as claimed in claim 1, wherein the preservative is selected from the group comprising of benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben, monothioglycerol, benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben and monothioglycerol or a combination thereof.

4. The Tiopronin oral solution as claimed in claim 1, wherein the antioxidant is selected from the group comprising of Propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, carbon dioxide, chelating agents, citric acid monohydrate, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, monothioglycerol, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, Sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sulfur dioxide or a combination thereof.

5. The Tiopronin oral solution as claimed in claim 1, wherein the buffering agent is selected from the group comprising of adipic acid, tartaric acid, boric acid, citric acid monohydrate, HCl, maleic acid, adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, dibasic sodium phosphate, diethanolamine, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate and triethanolamine or a combination thereof.

6. The Tiopronin oral solution as claimed in claim 1, wherein the flavoring agent is selected from the group comprising of anchovy, apple, banana, bubble Gum, butterscotch, marshmallow, vanilla, cherry, grape, peanut butter, peppermint, pina colada, raspberry, strawberry, tutti fruitti, vanilla butternut and venison or a combination thereof.

7. A method for preventing or treating cystinuria comprising administering to a patient in need thereof the tiopronin oral solution of claim 1.

8. A method for preventing or treating Wilson’s disease comprising administering to a patient in need thereof the tiopronin oral solution of claim 1.
, Description:TECHNICAL FIELD OF THE INVENTION
The invention in general relates to pharmaceutical dosage forms comprising a thiol compound. Particularly, the invention relates to oral pharmaceutical composition comprising tiopronin and method of administration of the said oral pharmaceutical composition for prevention of cystine stone formation in patients with homozygous cystinuria.

BACKGROUND ART
Tiopronin (THIOLA) is a reducing and complexing thiol compound approved for the treatment of cystinuria. Currently approved Tiopronin (THIOLA) is available in tablet dosage form which has a poor bioavailability i.e. about 60%. Further, the dose of tiopronin should not be arbitrary but should be based on that amount required to reduce urinary cystine concentration to below its solubility limit. Therefore, the current dosing of tiopronin exhibits poor oral dosing characteristics.

SUMMARY OF THE INVENTION
Herein disclosed is a stable multi-dose tiopronin oral solution comprising of a therapeutically effective amount of tiopronin or a pharmaceutically acceptable salt thereof, at least one vehicle, at least one preservative, at least one antioxidant, at least one buffering agent and at least one flavoring agent; wherein the pH of the oral solution is 4-8 and the concentration of tiopronin in the oral solution is about 25 to 100 mg/ml.
The stable multi-dose tiopronin oral solution according to the invention comprises of at least one vehicle selected from the group comprising of butylene glycol, polyethylene glycol, propylene glycol, glycerin monostearate, sorbitol, ethanol and propylene glycol or a combination thereof. The tiopronin oral solution as disclosed herein may comprise a single vehicle or a combination of any of the above listed vehicles.
The tiopronin oral solution according to the invention comprises of at least one selected from the group comprising of benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben, monothioglycerol, benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben and monothioglycerol or a combination thereof. The tiopronin oral solution as disclosed herein may comprise more than one preservative. The preservative may single or a combination of two or more of the above listed preservatives.
The tiopronin oral solution according to the invention comprises of at least one antioxidant selected from the group comprising of propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, carbon dioxide, chelating agents, citric acid monohydrate, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, monothioglycerol, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, Sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sulfur dioxide or a combination thereof. The tiopronin oral solution as disclosed herein may comprise more than one antioxidant or a combination of two or more antioxidants.
The tiopronin oral solution according to the invention comprises of at least one buffering agent selected from the group comprising of adipic acid, tartaric acid, boric acid, citric acid monohydrate, HCl, maleic acid, adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, dibasic sodium phosphate, diethanolamine, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate and triethanolamine or a combination thereof. The tiopronin oral solution as disclosed herein may comprise more than one buffering agent and may be a combination of two or more of the above said buffering agents.
The tiopronin oral solution according to the invention comprises of at least one flavoring agent selected from the group comprising of anchovy, apple, banana, bubble Gum, butterscotch, marshmallow, vanilla, cherry, grape, peanut butter, peppermint, pina colada, raspberry, strawberry, tutti fruitti, vanilla butternut and venison or a combination thereof. The tiopronin oral solution as disclosed herein may comprise more than one flavoring agent. The flavoring agent may be a combination of two or more of the above said flavoring agents.
Further, the invention discloses a method of prevention or treatment of cystinuria comprising administering to a patient in need thereof tiopronin oral solution. The invention also discloses a method of prevention or treatment of Wilson’s disease comprising administering to a patient in need thereof tiopronin oral solution.

DETAILED DESCRIPTION OF THE INVENTION
Disclosed herein is a stable multi-dose tiopronin oral solution formulation for the treatment of cystinuria and also to treat Wilsons’s disease. The tiopronin oral solution formulation according to this invention provides enhanced bioavailability and improved systemic availability.
The multi-dose tiopronin oral solution comprises of a therapeutically effective amount of tiopronin or a pharmaceutically acceptable salt thereof, at least one vehicle, at least one preservative, at least one antioxidant, at least one buffering agent and at least one flavoring agent. The pH of the tiopronin oral solution as disclosed herein is about 4-8 and the concentration of the tiopronin in the oral solution is about 25 to 100 mg/ml. The tiopronin oral solution is provided in multi-dose bottle for easy administration to treat cystinuria and also for the treatment of Wilsons disease. The multi dose tiopronin oral solution comprises of about 25 mg to 100 mg of tiopronin or its pharmaceutically acceptable salts, preferably about 50 mg of tiopronin.
The multi-dose tiopronin oral solution according to the invention comprises of at least one vehicle selected from the group comprising of butylene glycol, polyethylene glycol, propylene glycol, glycerin monostearate, sorbitol, ethanol and propylene glycol or a combination thereof. The multi-dose tiopronin oral solution according to the invention comprises of about 40% to 90% w/w of vehicle. According to one embodiment the tiopronin oral solution comprises of 25% to 50% w/v of vehicle. According to another embodiment the tiopronin oral solution comprises of 25% to 40% w/v of vehicle. According to one embodiment the multi-dose tiopronin oral solution as disclosed herein comprises of a single vehicle or a combination of two or more vehicles.
The multi-dose tiopronin oral solution according to the invention comprises of at least one preservative selected from the group comprising of benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben, monothioglycerol, benzalkonium chloride, benzoic acid, benzyl alcohol, boric acid, bronopol, butylated hydroxyanisole, butylene glycol, butylparaben, calcium acetate, cationic, and bentonite, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, dimethyl ether, ethylparaben, hexetidine, imidurea, inactivation by magnesium trisilicate, isopropyl alcohol, lactic acid, methylparaben and monothioglycerol or a combination thereof. The multi-dose tiopronin oral solution according to the invention comprises of about 0.001% to 3% w/v of preservative. According to one embodiment the tiopronin oral solution comprises of 0.5% to 1.0% w/v of preservative. The multi-dose tiopronin oral solution as disclosed herein comprises of a single preservative or a combination of two or more preservatives.
The multi-dose tiopronin oral solution according to the invention comprises of at least one antioxidant selected from the group comprising of Propyl & octyl esters of gallic acid, tocopherols or vitamin E, sodium sulfite, ascorbic acid (vit. C), alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, carbon dioxide, chelating agents, citric acid monohydrate, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, monothioglycerol, phosphoric acid, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, Sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate and sulfur dioxide or a combination thereof. The multi-dose tiopronin oral solution according to the invention comprises of about 0.05% to 5% w/v of antioxidant. According to one embodiment the tiopronin oral solution comprises of about 0.1% to 2% w/v of antioxidant. The multi-dose tiopronin oral solution as disclosed herein comprises of an antioxidant or a combination of two or more antioxidants.
The multi-dose tiopronin oral solution according to the invention comprises of at least one buffering agent selected from the group comprising of adipic acid, tartaric acid, boric acid, citric acid monohydrate, HCl, maleic acid, adipic acid, ammonia solution, boric acid, calcium carbonate, calcium hydroxide, calcium lactate, calcium phosphate, tribasic, dibasic sodium phosphate, diethanolamine, methionine, monobasic sodium phosphate, monoethanolamine, monosodium glutamate, phosphoric acid, potassium citrate, sodium acetate, sodium bicarbonate, sodium borate, sodium carbonate, sodium citrate dihydrate, sodium hydroxide, sodium lactate and triethanolamine or a combination thereof. The multi-dose tiopronin oral solution according to the invention comprises of about 0.005% to 1% w/w of buffering agent. The multi-dose tiopronin oral solution as disclosed herein comprises of one buffering agent or a combination of two or more buffering agents.
The multi-dose tiopronin oral solution according to the invention comprises of at least one flavoring agent selected from the group comprising of anchovy, apple, banana, bubble Gum, butterscotch, marshmallow, vanilla, cherry, grape, peanut butter, peppermint, pina colada, raspberry, strawberry, tutti fruitti, vanilla butternut and venison or a combination thereof. The multi-dose tiopronin oral solution as disclosed herein may comprise more than one flavoring agent. The flavoring agent may be a combination of two or more of the above said flavoring agents.
According to one embodiment the multidose tiopronin oral solution is prepared by adding vehicle to the required quantity of water and stirring well to prepare the glycerin phase. To the glycerin phase a preservative is added under stirring and continuing the stirring till a clear solution is obtained. After dissolving the preservative, buffering agent is added under stirring and continuing the stirring for 10 – 15 minutes or till a clear solution is obtained (Phase – I). Dissolving the API in vehicle under stirring and continuing stirring till a clear solution is obtained. After dissolving the API, antioxidant is added and stirring is continued till a clear solution is obtained (Phase – II). Then Phase – I is added to Phase – II and stirred well. Finally, flavor is added and volume is made up to the required quantity with purified water. In certain embodiments of the tiopronin oral solution the vehicle is a combination of two vehicles.

Tiopronin Oral solution compositions
Table 1
S No API/Excipient(s) mg/ml % w/v
1 Tiopronin 50.00 5.00
2 Glycerin 250.00 25.00
3 PEG 400 400.00 40.00
4 Sodium benzoate 0.50 0.05
5 Citric acid 0.37 0.037
6 Volume make up with water Upto 1ml
7 pH 3 - 4

Table 2
S No API/Excipient(s) mg/ml % w/v
1 Tiopronin 50.00 5.00
2 Glycerin 250.00 25.00
3 PEG 400 400.00 40.00
4 Sodium benzoate 0.50 0.05
5 Citric acid 0.37 0.037
6 Honey flavor 1.00 0.10
7 Volume make up with water Upto 1 ml
8 pH 3 - 4

Table 3
S No API/Excipient(s) mg/ml % w/v
1 Tiopronin 50.00 5.00
2 Glycerin 250.00 25.00
3 PEG 400 400.00 40.00
4 Sodium benzoate 0.50 0.05
5 BHA 0.15 0.015
6 Citric acid 0.05 0.005
7 Honey flavor 1.00 0.10
8 Volume make up with glycerin Upto 1 ml
9 pH 6 - 7

Table 4
S No API/Excipient(s) mg/ml % w/v
1 Tiopronin 50.00 5.00
2 Glycerin 500.00 50.00
3 Ethanol 20.00 2.00
4 Sodium benzoate 0.50 0.05
5 Citric acid 0.05 0.005
7 Grape flavor 1.00 0.10
8 Volume make up with glycerin Upto I ml
9 pH 6 - 7
With nitrogen purging
Manufacturing procedures for Tiopronin oral solution
Example 1
Add vehicle to the required quantity of water and stir well, and to this add preservative under stirring and continue the stirring till a clear solution is obtained. After dissolving the preservative, add buffering agent under stirring and continue stirring for 10 – 15 minutes to get a clear solution (Phase – I). Dissolve API in vehicle under stirring and continue stirring for 5 – 15 minutes to obtain a clear solution. After dissolving the API, add antioxidant to it and continue the stirring till a clear solution is obtained (Phase – II). Add Phase – I to Phase – II and stir well. Finally add the flavor and make up the volume to the required volume with purified water.

Example 2
Glycerin is added to the required quantity of water and stirred well to prepare the glycerin phase. To the glycerin phase, sodium benzoate is added under stirring and the stirring is continued till a clear solution is obtained. After dissolving the sodium benzoate in the glycerin phase, citric acid is added under stirring and the stirring is continued for 10 – 15 minutes to get a clear solution (Phase – I). Separately tiopronin is dissolved in PEG 400 under stirring and continued the stirring for 5 – 15 minutes to obtain a clear solution (Phase – II). Then Phase – I is added to Phase – II and stirred well. Finally, the volume is made up to the required volume with purified water.

Example 3
First Glycerin phase is prepared by adding glycerin to the required quantity of water and stirred well. To the glycerin phase, sodium benzoate is added under stirring and the stirring is continued till a clear solution is obtained. After dissolving the sodium benzoate in the glycerin phase, citric acid is added under stirring and the stirring is continued for 10 – 15 minutes to get a clear solution (Phase – I). Separately tiopronin is dissolved in PEG400 under stirring and continued the stirring for 5 – 15 minutes to obtain a clear solution (Phase – II). Then Phase – I is added to Phase – II and stirred well. Finally, flavor is added and volume is made up to the required volume with purified water.

Example 4
Glycerin is added to the required quantity of water and stirred well to prepare the glycerin phase. To the glycerin phase, sodium benzoate is added under stirring and the stirring is continued till a clear solution is obtained. After dissolving the sodium benzoate in the glycerin phase, citric acid is added under stirring and the stirring is continued till a clear solution is obtained (Phase – I). Separately tiopronin is dissolved in PEG 400 under stirring and continued the stirring till a clear solution is obtained. After dissolving the API, BHA is added to the said solution and stirred well to obtain a clear solution (Phase – II). Then Phase – I is added to Phase – II and stirred well. Finally, flavor is added and volume is made up to the required volume with glycerin. The pH of the said tiopronin oral solution is 6 – 7.

Example 5
Sodium benzoate is dissolved in required quantity of glycerin under stirring with nitrogen purging, continuing the stirring till a clear solution is obtained. To this solution is added citric acid and stirred for about 10 – 15 minutes or till a clear solution is obtained. Nitrogen purging is maintained during the dissolving of citric acid. Tiopronin is dissolved in ethanol under stirring and continued the stirring for 5 to 15 minutes or till a clear solution is obtained. After dissolving the API in ethanol, BHA is added to the said solution and stirred well to obtain a clear solution (Phase – II). Then Phase – I is added to Phase – II and stirred well under nitrogen purging. Finally, flavor is added and volume is made up to the required quantity with glycerin and the solution is kept under nitrogen purging for about 30 to 60 minutes before filling the solution into container.

Example 6
Sodium benzoate is dissolved in required quantity of glycerin under stirring with nitrogen purging, continuing the stirring till a clear solution is obtained. To this solution is added citric acid and/or disodium hydrogen phosphate hydrate and stirred for about 10 – 15 minutes or till a clear solution is obtained. Nitrogen purging is maintained during the dissolving of citric acid. tiopronin is dissolved in PEG400 under stirring and continued the stirring for 5 to 15 minutes or till a clear solution is obtained (Phase – II). Then Phase – I is added to Phase – II and stirred well under nitrogen purging. Finally, flavor is added and volume is made up to the required quantity with PEG400 and the solution is kept under nitrogen purging for about 30 minutes before filling the solution into container.

In one embodiment the invention provides a method for preventing or treating cystinuria comprising of administering to a patient in need thereof the tiopronin oral solution comprising of a therapeutically effective amount of tiopronin or a pharmaceutically acceptable salt thereof, at least one vehicle, at least one preservative, at least one antioxidant, at least one buffering agent and at least one flavoring agent. In another embodiment the invention provides a method for preventing or treating Wilson’s disease comprising of administering to a patient in need thereof the tiopronin oral solution comprising of a therapeutically effective amount of tiopronin or a pharmaceutically acceptable salt thereof, at least one vehicle, at least one preservative, at least one antioxidant, at least one buffering agent and at least one flavoring agent.