Field of the invention
The present invention relates to stable oral concentrate composition comprising antidepressant. More particularly, the present invention relates to oral concentrate composition comprising sertraline hydrochloride thereof and one or more pharmaceutically acceptable excipients, wherein the composition contains more than 40%w/w of water.
The present invention also relates to preparation of stable oral concentrate composition comprising sertraline hydrochloride thereof and one or more pharmaceutically acceptable excipients, wherein the composition contains 40 -60% w/w of water.
Background of the invention
Sertraline is chemically known as (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenamine. Sertraline and its pharmaceutically acceptable acid addition salts are disclosed for the first time in US patent No. 4,536,518. Sertraline hydrochloride is a selective serotonin reuptake inhibitor (SSRI) for oral administration and is useful as an antidepressant.
Tablet, capsule and oral concentrate formulations of sertraline hydrochloride are commercially available in different countries and are currently marketed under the tradename Zoloft™ in the US.
Many of the commercially available oral concentrate drug products are conventionally aqueous. For example, SINEQUAN Concentrate contains the active ingredient, doxepin hydrochloride, and the inert ingredients of glycerin, methylparaben, peppermint oil, propylparaben and water. TRILAFON Concentrate contains the active ingredient, perphenazine, and the inert ingredients of ethanol, citric acid, flavors, menthol, sodium phosphate, sorbitol, sugar and water.

US patent No. 6,727,283 describes an essentially non aqueous, filterable, liquid concentrate solution of sertraline hydrochloride for oral administration comprising about 18 mg/ml to about 78 mg/ml of sertraline hydrochloride and ethanol and glycerin in an amount of about 8 to about 50% ethanol by weight in glycerin. This patent further describes that essentially non-aqueous when used herein refers to the amount of water that is present in the final drug product, which amount is consistent with the amount of water potentially contributed by the active ingredient and/or by the excipients. However, no water is directly added to the final drug product.
WO 2005/034910 describes oral liquid pharmaceutical compositions comprising sertraline or a pharmaceutical^ acceptable salts thereof and water, wherein the water comprises greater than about 10% w/w to about 40%w/w of the composition.
The marketed oral concentrate of sertraline hydrochloride available in the US contains not less than 90% of organic solvents and the composition described in WO 2005/034910 contains not less than 60 % of organic solvents of total weight of the composition.
Sertraline hydrochloride is a life style drug and continuous intake of the drug is required. Hence, minimizing the total contents of organic solvents will result in better patient safety profile without compromising the product efficacy and stability.
With the aim of developing stable formulations of oral concentrate of sertraline hydrochloride with less contents of organic solvent, the inventors of the present invention found that the solubility and stability of sertraline hydrochloride can be maintained by maintaining the total water content in more than 40%w/w concentration, thereby reducing the quantity of non-aqueous solvents and thus minimizing the organic solvents intake/consumption per day.

Objective of the invention
The main objective of the present invention is to provide stable oral concentrate of sertraline with less organic solvent content.
Yet another objective of the present invention is to provide new, cost effective stable oral concentrate of sertraline.
Yet another objective of the present invention is to provide stable oral concentrate of sertraline, which has acceptable and pleasant taste.
Summary of the invention
Accordingly, the present invention provides stable oral concentrate composition comprising sertraline, water, ethanol and a solubilizer, wherein total water content is more than 40% w/w of the composition.
In yet another embodiment of the present invention, the stable oral concentrate composition further comprises one or more pharmaceutically acceptable excipients.
Detailed description of the invention
The term oral concentrate used herein refers to a strong solution provided for dilution before use.
In another embodiment of the present invention, the amount of water present in the oral concentrate is more than 40%w/w of the composition, which includes added water and water, which is part of the active ingredient and excipients.
In yet another embodiment of the present invention, the total content of nonaqueous solvents is not more than 60% w/w of the composition.
In yet another embodiment of the present invention, stable oral concentrate composition of sertraline may optionally contain one or more pharmaceutically acceptable excipients such as non-aqueous vehicle, preservatives, solubilizers, and flavoring agents.

The term solubilizer according to the present invention includes glycols like propylene glycols, polyethylene glycol, acidifier selected from the group consisting of weak organic acids such as citric acid, tartaric acid, acetic acid, benzoic acid, ascorbic acid, fumaric acid, maleic acid, lactic acid, phosphoric acid, sorbic acid, amino acids and the like; inorganic acids such as hydrochloric acid, sulfuric acid and the like; surface active agents selected from anionic, cationic and non ionic such as polysorbate 80, sodium lauryl sulfate and the like; solubility enhancers such as dextrins.
The amount of solubilizer used may range from about 0.1 to about 600 mg/ml of the composition.
The term preservative used herein refers to an additive or excipient that preserves the quality of the formulation from a chemical or microbiological standpoint. Suitable preservatives, which may be used according to the present invention are selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), benzoic acid, sodium benzoate, propyl gallate, ascorbic acid, ascorbyl palmitate, sodium metabisulite, sodium bisulfite, sodium thiosulfate, sodium hydroxide, cysteine, ethylenediamine tetraacetic acid (EDTA) or its salts, citric acid, triethanolamine, ethanol, thioglycerol, methylparaben and propylparaben and combinations thereof.
The amount of preservative that may range from about 0.01 to about 8.0 mg/ml of the composition, preferably, from 0.01 to 5.0 mg/ml of the composition.
The flavoring agents used according to the present invention are selected from the group consisting of menthol, spearmint, peppermint, tutti frutti flavor, peppermint flavor and the like.
The pharmaceutically acceptable non-aqueous vehicles of the present invention are selected from glycerin, propylene glycol, polyethylene glycols, ethanol and the like or mixtures thereof.

The amount of sertraline hydrochloride present in the oral concentrate of the present invention range from about 1 mg/ml up to about 80 mg/ml of the composition. Preferably, it is present in an amount of about 10 to about 30 mg/ml of the composition.
The present invention also provides the use of oral concentrate of sertraline, which comprises, diluting the oral concentrate in suitable diluent or beverage prior to oral administration.
The diluents which may be used according to the present invention are selected from water, vegetable juice, grapefruit juice, tomato juice, orange juice, ginger ale, lemon-lime soda, lemonade, cranberry juice, pineapple juice, prune juice, orange drink.
In yet another embodiment of the present invention, there is provided a manufacturing process for the preparation of oral concentrate of sertraline comprising dissolving sertraline hydrochloride and / or preservatives, flavoring agents in a non aqueous vehicle, adding water and /or flavoring agents, make up the volume with water, filtering the resulting oral concentrate and filling the filtered oral concentrate in to suitable containers.
In yet another embodiment of the present invention, there is provided a method for treating or preventing diseases or conditions, such as depression, anorexia, chemical dependencies, anxiety-related disorders (such as panic disorder, obsessive-compulsive disorder, generalized anxiety disorder, phobias, post traumatic stress disorder and avoidant personality disorder), premature ejaculation, cancer and post myocardial infarction which comprises: a) diluting the oral concentrate in a suitable diluent or beverage; and b) orally administering the resulting solution to a patient in need thereof.
The following example further exemplifies the inventions and is not intended to limit the scope of the inventions. It is obvious to those skilled in the art to find

out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

We claim :
1. A stable oral concentrate composition comprising sertraline, water, ethanol and a solubilizer, wherein total water content is more than 40% w/w of the composition.
2. The stable oral concentrate composition as claimed in claim 1, wherein the total content of non-aqueous solvents is not more than 60% w/w of the composition.
3. The stable oral concentrate composition as claimed in claim 1, further comprises one or more pharmaceutically acceptable excipients such as non-aqueous vehicle, preservative, solubilizer, and flavoring agents.
4. The stable oral concentrate composition as claimed in claim 1, wherein the solubilizer is selected from the group consisting of propylene glycol, polyethylene glycol, citric acid, tartaric acid, acetic acid, benzoic acid, ascorbic acid, fumaric acid, maleic acid, lactic acid, phosphoric acid, sorbic acid, amino acids, hydrochloric acid, sulfuric acid, polysorbate 80, sodium lauryl sulfate or dextrins.
5. The oral concentrate composition as claimed in claim 3, wherein the preservative is selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole, benzoic acid, sodium benzoate, propyl gallate, ascorbic acid, ascorbyl palmitate, sodium metabisulite, sodium bisulfite, sodium thiosulfate, sodium hydroxide, cysteine, ethylenediamine tetraacetic acid or its salts, citric acid, triethanolamine, ethanol, thioglycerol, methylparaben and propylparaben and combinations thereof.
6. The oral concentrate composition as claimed in claim 3, wherein the nonaqueous vehicle is selected from glycerin, ethanol, propylene glycol, polyethylene glycols or mixtures thereof.
7. The oral concentrate composition as claimed in claim 3, wherein the flavoring agent is selected from the group consisting of menthol, spearmint, peppermint, tutti frutti flavor, peppermint flavor or mixtures thereof.

8. A method of treating diseases or conditions selected from the group consisting of depression, anorexia, chemical dependencies, anxiety-related disorders, which comprises: a) diluting oral concentrate composition of sertraline hydrochloride claimed in claim 1, in a diluent or beverage and b) orally administering the resulting aqueous solution to a patient in need thereof.
9. The method of claim 8, wherein the diluent is selected from the group consisting of water, vegetable juice, grapefruit juice, tomato juice, orange juice, ginger ale, lemon-lime soda, lemonade, cranberry juice, pineapple juice, prune juice or orange drink.