STABLE COMPOSITIONS OF ETIFOXINE AND ITS SALTS FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical composition of anxiolytic agents. Particularly, the present invention relates to stable pharmaceutical composition of Etifoxine and its pharmaceutically acceptable salts thereof. More particularly, the present invention relates to stable pharmaceutical composition of Etifoxine hydrochloride comprising stabilizer and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Etifoxine hydrochloride is orally acting anxiolytic belonging to the class of benzoxazines. It is used in the short term treatment of anxiety. Etifoxine hydrochloride has been marketed for more than 33 years in France by Biocodex under the trademark of Stresam® 50mg capsules. Etifoxine Hydrochloride, a derivative of benzoxazines, it binds to |32 and (53 subunits of GABAA receptor complex to produce anxiolytic effects. It can be used along with benzodiazepines to potentiate the effect. Its half life has been reported to be about 1.5 hours.

Chemically Etifoxine Hydrochloride is 6-chloro-N-ethyl-4-methyl-4-phenyl- 4H-benzo[d][l,3]oxazin-2-amine and it molecular formula is Ci7Hi7ClN20. Structurally Etifoxine Hydrochloride is Stresam® capsules contain lactose monohydrate, microcrystalline cellulose, purified talc, anhydrous colloidal silica and magnesium stearate as inactive ingredients. FR 1571287 patent discloses Etifoxine and its process for preparing it. There is limited literature is available on Etifoxine Hydrochloride. The inventors tried to develop a generic formulation using same composition that of Stresam® 50mg capsules. The developed generic formulation was kept for stability as per guideline of International Conference on Harmonisation (ICH) Q1A(R2) step 4 version for 3 months at 40°C/75 RH (relative humidity) conditions and compared 3 months data with the initial data for parameters like Assay, dissolution, Related Substances. It was observed that the parameters like dissolution & assay results were comparable with the initial results but Related Substances values are higher compared to initial, particularly olefine impurity.

Stresam® 50mg capsules were also stored at 40°C/75 RH for 3 months and compared 3 months data with initial data for parameters like Assay, dissolution & Related Substances. It was observed that the parameters like dissolution & assay results are comparable with the initial results except Related Substances. The related substances values are higher compared to initial, particularly olefine impurity. The impurity contents measured in the generic formulation and in Stresam® 50mg before (initial) and after storage at 40°C/75 RH for 3 months are reported in the table below: The olefine impurity measured after the 3 months storage period in both test (Generic formulation) and reference product Stresam® is significantly above the acceptable limits mentioned in ICH guidelines Impurities in New Drug products ICH Q3B(R2) step 4version.

As there is limited literature available for Etifoxine, the reason for the formation of olefine impurity was not known. The present inventors have conducted forced degradation studies of Etifoxine hydrochloride for studying degradation pathway of Etifoxine hydrochloride. The inventors observed that Etifoxine hydrochloride is stable at stress conditions like base conditions, Humidity conditions, where as it is degraded at acidic condition, water stressed and thermal. It is observed that degradation is more in thermal condition. From the forced degradation studies the present inventors have concluded that the increased content of olefine impurity in Stresam® capsules and in the generic formulation may be due to thermal degradation of Etifoxine Hydrochloride. The present inventors during their continuous efforts to develop stable Etifoxine hydrochloride compositions have developed a composition comprising Etifoxine hydrochloride, stabilizing agent and one or more pharmaceutically acceptable excipients thereof, which are stable, mainly from thermal degradation.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a stable pharmaceutical composition comprising etifoxine and its pharmaceutically acceptable salts, stabilizer and one or more pharmaceutically acceptable excipients. Another main objective of the present invention is to provide a process for preparation of stable pharmaceutical composition comprising etifoxine and its pharmaceutically acceptable salts, stabilizer and one or more pharmaceutically acceptable excipients.

SUMMARY OF THE INVENTION

Accordingly, the present invention provides a stable pharmaceutical composition comprising etifoxine and its pharmaceutically acceptable salts, stabilizer and one or more pharmaceutically acceptable excipients. The present invention also provides a process for preparation of stable pharmaceutical composition comprising etifoxine and its pharmaceutically acceptable salts, stabilizer and one or more pharmaceutically acceptable excipients.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to stable pharmaceutical composition comprising etifoxine and its pharmaceutically acceptable salts, stabilizer and one or more pharmaceutically acceptable excipients. In another embodiment of the invention Etifoxine and its pharmaceutically acceptable salts are selected from hydrochloride, hydrobromide, potassium chloride, hydrogensulfate, methanesulfonate, succinate, tartarate. In yet another embodiment of the present invention more preferably salt is hydrochloride salt. In the description of this invention, the term "stable" means that the quantitative composition does not significantly changes over the time, during the entire shelf-life of the composition, namely for at least 6 months, advantageously for at least 12 months, more advantageously for at least 24 months, even more advantageously for at least 36 months. In particular, the amount in impurities does not increase during the entire shelf-life of the composition. More specifically, the content of olefine impurity does not increase during the entire shelf-life of the composition.

In addition, "Stable composition" or "stable Etifoxine and its salts composition" means the composition/product is stable and specifications are within the acceptable regulatory/ICH requirements during the entire shelf-life of the product in respect of Assay, Related Substances/impurities, and Dissolution etc. In still another embodiment of the present invention, the stable Etifoxine and its salts composition comprises less than 0.2% by weight, on the basis of the total weight of the composition, of the olefine impurity. In still another embodiment of the present invention this content is stable during the entire shelf-life of the composition, meaning that the content of olefine impurity is less than 0.2% by weight, on the basis of the total weight of the composition, at the manufacturing time but also after a period of at least 6 months, advantageously after a period of at least 12 months, more advantageously after a period of at least 24 months, even more advantageously after a period of at least 36 months.

Structurally define impurity is depicted below:

"Stabilizer" is an inactive excipient which prevents/reduces the formation of olefine impurity in etifoxine and its salts composition. Suitable stabilizers that may be used according to the present invention may be selected from fumaric acid, adipic acid, maleic acid and combinations thereof. The preferred stabilizer is fumaric acid. In still another embodiment of the invention One or more pharmaceutically acceptable excipients that may be used according to the present invention are selected from the group consisting of diluents, binders, disintegrants, lubricants, glidant and combinations thereof. In yet another embodiment suitable diluents that may be used according to the present invention are selected from the group consisting of microcrystalline cellulose, mannitol, lactose, starch, maize starch, wheat starch, potato starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

In still another embodiment the preferred diluent is lactose. In yet another embodiment of this invention suitable binders that may be used according to the present invention are selected from the group consisting of povidone, starch, potato starch, wheat starch, corn starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof. In yet embodiment of this invention suitable disintegrants that may be used according to the present invention are selected from the group consisting of sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose potassium, and combinations thereof. In yet embodiment of this invention suitable lubricants that may be used according to the present invention are selected from the group consisting of stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof. In still another embodiment of the invention the preferred lubricant is stearic acid. In yet another embodiment of this invention suitable Glidants that may be used according to the present invention are selected from the group consisting of calcium phosphate tribasic, powdered cellulose, colloidal silicon dioxide, magnesium oxide, magnesium silicate, magnesium trisilicate, starch, talc and combinations thereof.

In still another embodiment of this invention Stable Etifoxine and its salts composition according to the present invention may be in the form of immediate or modified release tablets, immediate or modified release capsules, suspension or injection. In yet another embodiment of this invention the stable Etifoxine and its salts composition of the invention is advantageously under the form of capsules. In still another embodiment of the invention stable Etifoxine and its salts composition according to the present invention may be prepared by any suitable process, such as direct compression, wet granulation and dry granulation. In yet another embodiment of this invention preferably stable composition of Etifoxine and its salts according to the present invention is prepared by direct compression process. The present invention further invention relates to the process of preparing the said composition. In an embodiment of the invention direct compression according to the present invention advantageously comprises the following steps:

a) Optionally sifting of all materials

b) blending of all sifted materials

c) optionally lubrication

d) Compression/filled into capsules.

The present invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the invention are given by way of illustration only. From the above discussion and these examples, one skilled in the art can ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and condition. The invention will be better understood from the following examples .However, those of ordinary of ordinary skill in the art will readily understand that these Examples are merely Illustrative of the invention that is defined in the claims that follow thereafter The present invention is further elaborated by the following examples However; these examples should not be construed to limit the scope of the invention.

The invention is illustrated by the following non limiting examples:
Examplel:

Composition of Etifoxine hydrochloride without stabilizer Brief description of the manufacturing process; Composition of Etifoxine hydrochloride without stabilizer

• Etifoxine hydrochloride sifted separately through #60mesh.

• Lactose monohydrate is sifted thoroughly through #40mesh.

• Sifted Etifoxine hydrochloride and lactose monohydrate are co-sifted and blended for 10 minutes.

• The above blend is lubricated with stearic acid for 5 minutes.

• The lubricated blend is filled into empty hard gelatin capsule shells.

Example 2:

Composition of Etifoxine hydrochloride with stabilizing agents Brief description of the manufacturing process: Composition of Etifoxine hydrochloride with stabilizing agents

• Etifoxine hydrochloride sifted separately through #60mesh.

• Fumaric acid is sifted thoroughly through #40mesh.

• Sifted Etifoxine hydrochloride and Fumaric acid are co-sifted through #40mesh.

• The above co-sifted mixture is co-sifted with lactose monohydrate and blended for 10 minutes.

• The above blend is lubricated with stearic acid for 5 minutes.

• The lubricated blend is filled into empty hard gelatin capsule shells.

Example 3: Composition of Etifoxine hydrochloride with stabilizing agents Composition of Etifoxine hydrochloride with stabilizing agents Stability studies: The above filled capsules of Example 1& 2 were packed in Al/PVC/PVdC blisters. These blisters and Stresam® (Reference product) were charged for stability at 40°C/75 RH and observed for 3 months. After 3 months, the capsules were analyzed for impurities (Related Substances) content using HPLC method as follows:

HPLC method
Column and packing : Symmetry C18,4.6 mm x 250 mm; 5um
1 mL of 88% Orthophosphoric acid dissolved in 1000
Buffer : mL of Milli-Q-Water and adjusted the pH to 6.5 with
Triethyl amine
Mobile Phase : Buffer: Acetonitrile (50:50 ratio)
Diluent : Buffer: Acetonitrile (26:74 ratio)
Column temperature : 25°C
Flow rate : 1.0 mL / minute
Injection volume : 20 uL
Detector Wavelength : 258 nm
Runtime : 60minutes

Sample solution Preparation

Weigh accurately 10 capsules and transfer into a 250 mL volumetric flask, dissolve and dilute to volume with diluent. Centrifuge the test solution at 3500 rpm for 10 min with cap. Dilute 3.0 mL of centrifuged solution to 10 mL with diluent.

Method

Inject 20 fiL portion of diluent as blank, and 2 preparations of Test solution into the HPLC, record the chromatograms and measure the peaks response. The comparative related substances data From the above data it was clearly shows that Example 2 according to the present invention olefine impurity is below 0.2% by weight, on the basis of the total weight of the composition, and thus complies ICH guidelines Impurities in New Drug products.

Claims:

1. A stable pharmaceutical composition comprising; anxiolytic agents, diluents, lubricants, glidant, stabilizing agent and combinations thereof and process of making such composition.

2. A stable pharmaceutical composition according to claim 1, wherein anxiolytic agent is Etifoxine and its salts.

3.A stable pharmaceutical composition according to claim 2, wherein salts are selected from hydrochloride, hydrobromide, potassium chloride, hydrogensulfate, methanesulfonate, succinate, tartarate.

4. A stable pharmaceutical composition according to claim 3, wherein preferfly salt is hydrochloride.

5. A stable pharmaceutical composition according to claim 1, wherein composition comprises Etifoxine hydrochloride as an active agent.

6.A stable pharmaceutical composition according to claim 1,wherein diluents is selected from microcrystalline cellulose, mannitol, lactose, starch, maize starch, wheat starch, potato starch, calcium hydrogen phosphate, sorbitol, sucrose, dicalcium phosphate and combinations thereof.

7. A stable pharmaceutical composition according to claim 6, wherein diluents is lactose.

8. A stable pharmaceutical composition according to claim 1, wherein lubricants/glidant are selected from the group consisting of stearic acid, magnesium stearate, sodium stearyl fumarate, fumaric acid, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, and combinations thereof.

9. A stable pharmaceutical composition according to claim 8, wherein lubricants is stearic acid.

10. A stable pharmaceutical composition according to claim 1, wherein stabilizer are selected from fumeric and citric acid.

11. A stable pharmaceutical composition according to claim 10, wherein stabilizer is fumaric acid.

12. A stable pharmaceutical composition according to claim 1, Wherein Etifoxine and its salts composition may be in the form of immediate or modified release tablets, immediate or modified release capsules, suspension or injection.

13. A stable pharmaceutical composition according to claiml2, wherein Etifoxine and its salts composition are preferly in the form of capsules.

14. A stable pharmaceutical composition according to claiml3, wherein the capsule is immediate release form.

15. A stable pharmaceutical composition according to claim 1, wherein process of preparing said composition by any suitable process, such as direct compression, wet granulation and dry granulation.

16. A stable pharmaceutical composition according to claim 15, wherein process of preparing composition is direct compression process.

17. A processes of preparing stable pharmaceutical composition comprises following steps:
a) Optionally sifting of all materials
b) blending of all sifted materials
c) optionally lubrication
d) Compression/filled into capsules.

18. A stable pharmaceutical composition of the preceding claims comprises olefin as impurity.

19. A stable pharmaceutical composition according to preceding claims, wherein olefine impurity is in the range from 0.1 to 0.6% at stress storage condition (40 C/75 % RH for three months.

20. A stable pharmaceutical composition according to preceding claims, wherein olefine impurity is preferably 0.2 % at stress storage condition (40 C/75 % RH for three months.

21. A stable pharmaceutical composition according to proceeding claims, wherein Etifoxine hydrochloride formulation is stable entire shelf-life of the composition.

22. A stable pharmaceutical composition according to claim 21, wherein olefine impurity is less than 0.2% by weight, after a period of at least 6 months.

23. A stable pharmaceutical composition according to claim 22,wherein olefine impurity is less than 0.2% by weight after a period of at least 24 months.

24. A stable pharmaceutical composition according to claim 22,wherein olefine impurity is less than 0.2% by weight after a period of at least 36 months.