FIELD OF INVENTION:

The present invention relates to composition comprising the immediate release dosage form of Tianeptine and its pharmaceutically acceptable salt. In particular, the present invention is directed to the formulation of the immediate release tablets containing
Tianeptine Sodium.

BACKGROUND TO THE INVENTION:

Tianeptine is a tricyclic compound with the chemical name 7-[(3-chloro-6,l,l-dihydro-6-methyldibenzo[c, f][l,2]thiazepin-l l-yl)amino]heptanoic acid S,S-dioxide represented by the structural formula 1.

Tianeptine is an antidepressant. The free form of Tianeptine is amphoteric and an amorphous sodium salt is known in the art. The sulfate salt of Tianeptine can be used to provide pharmaceutical compositions for the treatment of conditions known in the art, such as one or more depressive disorders, irritable bowel syndrome (IBS), attention deficit hyperactivity disorder (ADHD), one or more neurodegenerative diseases, and asthma.

Tianeptine and its sodium salt was first disclosed in U.S. Patent No. 3,758,528. This patent also discloses the preparation of the Tianeptine and its pharmaceutically acceptable salts.

EP 0 803 253 Al relates to a matrix tablet for the prolonged release of the sodium salt of Tianeptine, wherein this prolonged release is controlled by the use of a polymer derived from cellulose and of a calcium salt. The manufacturing process includes a wet granulation method employed with the active ingredient, the inorganic salt and lactose without using any binder.

FR 2881350 relates to an oral galenic form comprising Tianeptine or its salts administered in the form of film coated tablet comprises a tablet core and a film-coating.

IN 244675, assigned to Torrent Pharmaceuticals Limited, relates to a novel modified release dosage form and a process for the preparation thereof, comprising of a high solubility active ingredient, which utilizes dual retard technique to effectively reduce the quantity of release controlling agents. It may optionally comprise another additional active ingredient as an immediate release form or modified release form.

Tianeptine sodium 12.5 mg sugar coated tablets (i.e., STABLON, Coaxil, or Tatinol) are currently approved in some countries in Europe. Latin America, Asia, and part of the Middle East for the treatment of one or more depressi\ e disorders. The preparation of sugar coated tablets is a very tedious process and it involves lot of steps and some of the common problems observed are cracking and splitting of the sugar coat which is caused by excess residual moisture. These sugar coated tablets are very sensitive towards storage conditions.
Therefore, there is a need to develop a stable, uncoated immediate release dosage form of Tianeptine Sodium employing an economic and quick process.

OBJECT OF THE INVENTION;

The main object of the present invention, is to provide an immediate release dosage form of Tianeptine and its pharmaceutically acceptable salt and a process for the preparation
thereof.

SUMMARY OF THE INVENTION;

The main aspect of the present invention is to provide an immediate release dosage form comprising Tianeptine and its pharmaceutically acceptable salts.

The other aspect of the present invention is to provide the uncoated immediate release tablets comprising Tianeptine and its pharmaceutically acceptable salts.

Further aspect of the present invention provides a process for manufacturing an uncoated immediate release oral pharmaceutical dosage form of Tianeptine or its pharmaceutically acceptable salts thereof, comprising the following steps:

(1) screening the active ingredient and one or more pharmaceutically acceptable
excipients;

(2) dry mixing the content of step (1);

(3) preparing a binder solution;

(4) adding the binder solution of step (3) to the dry blend of step (2);

(5) screening the wet mass obtained from step (4);

(6) performing a granulation;

(7) drying the granules obtained from step (6);

(8) optionally compressing the content of step (7) to obtain a tablet or filling the granules into a capsule.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an immediate release uncoated oral pharmaceutical dosage form of Tianeptine and its pharmaceutically acceptable salts thereof. Wherein the in vitro dissolution rate of the dosage form provides at least 99% of the active ingredient dissolved within 90 minutes as measured by USP Paddle Method at 100 rpm at 900 ml of dissolution buffer at 37° C.

The present invention relates to the formulation of an uncoated immediate release oral pharmaceutical dosage form of Tianeptine and its pharmaceutically acceptable salts, which shows improved drug release profiles than the existing marketed forms. The purpose for manufacturing the immediate release oral pharmaceutical dosage form of the present invention utilizes rapid mixer granulator to prepare good homogenous granules with excellent flow properties and desired dissolution profiles.

The present invention is able to obtain an immediate release dosage form of Tianeptine sodium using a wet granulation process to obtain good granules and flow properties. Povidone plays a very important role as binder used in solution in order to get good granules when used in the range of about 0.5 to about 15% w/w of the composition.
In a preferred embodiment of the present invention, the immediate release oral pharmaceutical dosage form comprises Tianeptine sodium as the active ingredient and the other pharmaceutically acceptable excipients added to the composition for a variety of purposes. One or more pharmaceutically acceptable excipients may be present in the composition of the present invention, such as for examples, diluents, binders, lubricants, glidants, and alkalinizing agent. As understood by a person skilled in the art, these excipients are conventional excipients which are well known in the pharmaceutical art.

According to one embodiment of the present invention binders include, but are not limited to, acacia, alginic acid, carbomers, carboxymethyl cellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, chitosan, confectioner's sugar, cottonseed oil, dextrates, dextrin, dextrose, ethylcellulosc, gelatin, glucose, glyceryl behenate, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxy ethyl methyl cellulose, hydroxylpropyl cellulose, hypromellose, magnesium aluminum silicate, maltodextrin, maltodextrin, maltose, methylcellulose, microciystalline cellulose, poloxamer, polydextrose, polyethylene oxide, polymethyl acrylates, povidone, sodium alginate, starch, pregelantized starch, stearic acid, sucrose, svinflower oil, zein and mixtures thereof.

In another embodiment of the present invention lubricants include, but are not limited to, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, light mineral oil, magnesium lauryl sulfate, magnesium stearate, medium chain triglycerides, mineral oil, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulfate, soditmi stearyl fumarate, stearic acid, talc, zinc stearate and mixtures thereof.

According to another embodiment of the present invention disintegrants include, but are not limited to alginic acid, crosslinked polyvinyl pyrrolidone, com starch, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g., Ac-Di-Sol® Primellose®.), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KoUidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, maize starch and
modified starches, methyl cellulose, microcrystalline cellulose, polyacrilin potassium, potato starch, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g., Explotab), pregelatinized starch, starch and mixtures thereof.

According to another embodiment of the present invention diluents include, but are not limited to, calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, ethyl cellulose, fhictose, fumaric acid, glyceryl palmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, medium chaim glyceride, microcrystalline cellulose, polydextrose, polymethylacrylates, potassium chloride, powdered cellulose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelantized starch, sterilizable maize, sucrose, sugar spheres, talc, tragacanth, trehalose, tribasic calcium phosphate, xylitol and mixtures thereof

According to one more embodiment of the present invention surfactants comprises non-ionic surfactants like alkyl poly(ethylene oxide),a poly(ethyleneoxide), Copolymers of poly(ethylene oxide) and poly(prop}lene oxide) (commercially called Poloxamers or Poloxamines), alkyl polyglucosidcs like octly glucoside, decyl maltoside, fatty alcohols like Cetyl alcohol, oleyl alcohol, Cocamide MEA, Cocamide DEA, Polysorbates like Tween 20, Tween 80; anionic surfactants such as Perfluorooctanoate, perfluorooctanesulfonate, sodium dodecyl sulfate, ammonium lauryl sulfate, sodium lauiyl sulfate, alkyl benzene sulfonate, soaps or fatty acid salts and cationic surfactants such as Cetyl trimethylammonium bromide, cetylpyridinium chloride, polyethoxylated tallow amine, benzalkonivim chloride, benzethonium chloride, and cetrimide (alkyltrimethylammonium bromide, predominantly CM alkyl).

According to further embodiment of the present invention solvent comprises: Isopropyl alcohol, ethanol, n-butanol, acetone, purified water or combination thereof

The present invention also relates to the process for manufacturing an oral pharmaceutical dosage form containing active ingredient Tiemeptine sodium, in an immediate release form comprises the following steps:

(1) screening the active ingredient and pharmaceutically acceptable excipients;

(2) dry mixing the content of step (1);

(3) preparing a binder solution;

(4) adding the binder solution of step (3) to the dry blend of step (2);

(5) performing a granulation;

(6) screening the wet mass obtained from step (5);

(7) drying the granules obtained from step (6); and

(8) optionally compressing the content of step (7) mixed with lubricants.

In a preferred embodiment of the present invention, the active ingredient, and pharmaceutically acceptable excipients for use in step (1) are the following: Tianeptine or a pharmaceutically acceptable salt and a diluent, a rate confroUing polymer, a binder and a glidant.

A composition for tablet or capsule filling may be prepared by wet granulation. In wet granulation, the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically granulation fluid, which causes the powders to clump into granules. The granules are screened and/or milled, dried and then screened and/or milled to a desired paiticie size. The granules may then be compressed into tablets, or other excipients may be added prior to tabletting, such as a glidant and/or a lubricant.

The granules can be manufactured in accordance with conventional techniques in which the active ingredient and other pharmaceutically acceptable excipients are mixed and granulated by adding solution of binder in a low or high shear mixer. The granules are then dried preferably, in a fluidized bed dryer. The dried granules are sieved and mixed with lubricants and disintegrants. Alternatively, the manufacture of granules can also be made by direct mixing of the directly compressible excipients or by roller compaction.

As used herein "Tianeptine" is any Tianeptine moiety containing substance that exhibits pharmaceutical activity and specifically includes Tianeptine free base or its pharmaceutically acceptable salts thereof and mixtures or combinations of two or more of any such Tianeptine substances. Examples of usefiil Tianeptine pharmaceutically acceptable salts include Tianeptine sodium, Tianeptine potassium, Tianeptine calcium, Tianeptine sfrontium, Tianeptine bromide, Tianeptine hydrochloride.

The term "immediate release" as used herein in relation to the compositions according to the present invention, or used in any other context herein, means release which is not a modified release and releases 99%, or more, of the active ingredient within 90 minutes.

The term "immediate release dosage form" as used herein can be described as a dosage form which allows the drug to dissolve in the gastrointestinal contents, with no intention of delaying or prolonging the dissolution or absorption of the drug (as per US FDA guideline for "SUPAC-MR : Modified Release Solid Oral Dosage Forms").

The term "dosage form" is intended to denote any form of the formulation that contains an amount sufficient to achieve a therapeutic effect with a single administration.

In the one preferred embodiment the pharmaceutical composition comprising Tianeptine suited for oral administration like tablets, capsules, mups and sachets.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

The present invention can be illustrated in one of its embodiment by the following non-limiting examples.

Example 1

The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus II (USP Paddle Method), using the following parameters:

Speed: 100 rpm
Dissolution Media: 900ml 6.8 tri-basic sodium phosphate buffer
Temperature: 37° C

The dissolution results are set out in Table 2 below:

Table 2 - Dissolution Rate of Tianeptine Sodium Tablets of Example 1
Time (min) Reference Product (% dissolved) Tablets from Example 1 (% dissolved)

Example 2; Preparation of 13.5 mg tablets of Tianeptine Sodium tablets:

Name of Ingredients

The tablets obtained from Example 1 were subsequently tested for in vitro dissolution rate, measured by Apparatus II (USP Paddle Method), using the following parameters:
Speed: 100 rpm
Dissolution Media: 900ml 6.8 tri-basic sodium phosphate buffer
Temperature: 37° C

The dissolution results are set out in Table 2 below:

Table 4 - Dissolution Rate of Tianeptine Sodium Tablets of Example 2

WE CLAIM:

1) A pharmaceutical composition comprising an uncoated immediate release dosage form comprising Tianeptine and its pharmaceutically acceptable salts.

2) The pharmaceutical composition according to claim 1, comprising an uncoated immediate release dosage form comprising Tianeptine and its pharmaceutically acceptable salts, which provides a dissolution rate of atleast 99% in 90 minutes as measured by USP paddle method at 100 rpm at 900 ml of dissolution buffer at 37°C.

3) The pharmaceutical composition according to claim 1, comprises uncoated immediate release tablet of Tianeptine and its pharmaceutically acceptable salts thereof.

4) A process for the preparation of immediate release dosage form of Tianeptine and its pharmaceutically acceptable salts comprising the following steps:

(1) screening the active ingredient and one or more pharmaceutically acceptable
excipients;

(2) dry mixing the content of step (1);

(3) preparing a binder solution;

(4) adding the binder solution of step (3) to the dry blend of step (2);

(5) screening the wet mass obtained from step (4);

(6) performing a granulation;

(7) drying the granules obtained from step (6);

(8) optionally compressing the content of step (7) to obtain a tablet or filling the granules into a capsule.

5) The pharmaceutical composition according to claim 1 and 3, comprises pharmaceutically acceptable excipients, selected from the group of glidants, lubricants, fillers, binders, disintegrants, diluents, surfactants, and solutions.

6) The pharmaceutical composition according to claim 1, wherein the related dosage forms are selected from the group of capsules, tablets, mups and sachets.