STABLE FLUINDIONE COMPOSITIONS
FIELD OF THE INVENTION

The present invention relates to stable pharmaceutical composition of anticoagulant. Particularly, the present invention relates to stable pharmaceutical composition of Fluindione. More particularly, the present invention relates to stable pharmaceutical composition of Fluindione further comprising one or more antioxidants and one or more pharmaceutically acceptable excipients.

BACKGROUND OF THE INVENTION

Fluindione is an oral Indanedione anticoagulant with actions similar to those of Warfarin ((RS)-4-hydroxy-3-(3-oxo-l-phenylbutyl)-2H-chromen-2-one). It is mainly used in the management of thromboembolic disorders. Fluindione has been marketed for more than 20 years in France by Procter & Gamble Pharmaceuticals under the trademark of Previscan® 20 mg tablets.
Fluindione, a derivative of Indanedione, is a vitamin K antagonist with a long half-life. It inhibits the production of active forms of clotting factors II, VII, DC, and X. Its half-life has been reported to be about 31 hours.
Coagulation factors II, VII, IX and X and the anticoagulant proteins C and S are synthesized mainly in the liver and are biologically inactive unless 9 to 13 of amino--terminal glutamate residues are carboxylated to form the Ca2+-binding γ-carboxyglutamate (Gla) residues. This reaction of the descarboxy precursor proteins requires carbon dioxide, molecular oxygen and vitamins in their reduced form, and is catalyzed by y-glutamyl cardoxylase in the rough endoplasmic reticulum. Carboxylation is directly coupled to the oxidation of vitamin K to its corresponding epoxide.

Fluindione decreases blood coagulation by inhibiting vitamin K epoxide reductase, an enzyme that recycles oxidized vitamin K to its reduced form after it has participated in the carboxylation of several blood coagulation proteins, mainly factor II and factor VII. For this reason, Fluindione is also referred to as vitamin K antagonists.

Chemically Fluindione is 2- (4-fluorophenyl)-l,3-indanedione and its molecular formula is C15H9FO2. Structurally Fluindione is represented bellow.

Previscan® 20 mg tablets contain wheat starch, anhydrous lactose, alginic acid, potato starch, stearic acid and talc as inactive ingredients.

FR 1369396 patent discloses Fluindione and its process for preparing it.

The inventors tried to develop a generic formulation using same composition that of Previscan® 20mg tablets. 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. Relative Substances. It was observed that the parameters like dissolution & assay results were comparable with the initial results but that the Relative Substances values are higher compared to initial, particularly for the 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (PI) and 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) impurities.

Previscan® 20mg tablets were also stored at 40°C/75 RH for 3 months and compared 3 months data with initial data for parameters like Assay, dissolution & Relative Substances. It was observed that the parameters like dissolution & assay results are comparable with the initial results except Relative Substances. The related substances values are higher compared to initial, particularly the 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-1,3-dione (PI) and 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) impurities.

The impurity contents measured in the generic formulation and in Previscan® 20mg before (initial) and after storage at 40°C/75 RH for 3 months are reported in the table 1 below:

I I After storage at 40'>e/75RH
Initial for Smooths
Generic Generic
Impurity name Previscan® formulation Previscan® formulation
2-(4-fluoro-phenyI)-2-hydroperoxy-indan-l,3-dione
(PI) 1.11% 0.19% 1.77% 1.23%
2-(4-fluoro-plienyl)-2-hydroxy-
indan-l,3-dione (P2) 0.30% 0.09% 0.52% 0.63%
Table 1. Comparative Related substances data for Generic and Reference Product
(Previscan®)
The impurity contents, namely the contents in 2-(4-fluoro-phenyl)-2-hydroperoxy-
indan-l,3-dione (P1) and in 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2), measured after the 3 months storage period in both test (Generic formulation) and reference product (Previscan®) are 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 Fluindione, the reason for the presence of 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (P1) and 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) impurities was not known. The present inventors have conducted forced degradation studies of Fluindione for studying degradation pathway of Fluindione. The inventors observed that Fluindione is stable to stress conditions like light, temperature and in high acid conditions. However, the inventors discovered that Fluindione is sensitive to basic conditions and oxidation conditions.

During forced degradation studies of Fluindione the present inventors have observed that Fluindione is get oxidised into two main oxidation products: namely one is 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (P1) and the other one is 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2). These two oxidation products were isolated and their structures were characterized by IR, 1H NMR, 13C NMR, Mass spectrometry.

From the forced degradation studies the present inventors have concluded that the increased content in impurities (PI and P2) in Previscan® tablets and in the generic formulation may results from the oxidation of Fluindione.
The present inventors during their continuous efforts to develop stable Fluindione compositions, have developed a composition comprising Fluindione, one or more antioxidants and one or more pharmaceutically acceptable excipients thereof, which is stable in the entire shelf-life of 36 months, mainly from oxidative degradation, with the consequence that the impurities content is maintained low.

SUMMARY OF THE INVENTION

Specifically, the present invention provides a stable Fluindione composition comprising Fluindione, one or more antioxidants and one or more pharmaceutically acceptable excipients.
In the description of this invention, the term "stable" means that the quantitative composition does not significantly changes over the tune, during the entire shelf-life of the composition, namely for at least 3 months, advantageously for at least 6 months, more advantageously for at least 12 months, even more advantageously for at least 36 months, hi particular, the amount in impurities does not increase during the entire shelf-life of the composition. More specifically, the content of 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (PI) and/or of 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) does not increase during the entire shelf-life of the composition. In addition, "Stable composition" or "stable Fluindione 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, Dissolution etc.
In an advantageous embodiment of the present invention, the stable Fluindione composition comprises less than 0.5% by weight, on the basis of the total weight of the composition, of the 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (P1) impurity. This content is stable during the entire shelf-life of the composition, meaning that the content in 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (P1) is less than 0.5% by weight, on the basis of the total weight of the composition, at the manufacturing time but also after a period of at least 3 months, advantageously after a period of at least 6 months, more advantageously after a period of at least 12 months, even more advantageously after a period of at least 36 months.

Structurally 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione, referred to as PI, is depicted below:

In another advantageous embodiment of the present invention, the stable Fluindione composition comprises less than 0.5% by weight, on the basis of the total weight of the composition, of 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) impurity. This content is stable during the entire shelf-life of the composition, meaning that the content in 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione (P2) is less than 0.5% by weight, on the basis of the total weight of the composition, at the manufacturing time but also after a period of at least 3 months, advantageously after a period of at least 6 months, more advantageously after a period of at least 12 months, even more advantageously after a period of at least 36 months.

Structurally 2-(4-fluoro-phenyl)-2-hydroxy-indan-l,3-dione, referred to as P2, is depicted below:

In a preferred embodiment of the invention, the stable Fluindione composition comprises, on the basis of the total weight of the composition, less than 0.5% by weight of 2-(4-fluoro-phenyl)-2-hydroperoxy-indan-l,3-dione (PI) and less than 0.5% by weight of 2-(4-fluoro-phenyI)-2-hydroxy-indan-l,3-dione (P2), at the manufacturing time but also after a period of at least 3 months, advantageously after a period of at least 6 months, more advantageously after a period of at least 12 months, even more advantageously after a period of at least 36 months.

The stable Fluindione composition advantageously comprises, on the basis of the total weight of the composition, from 5% by weight to 20% by weight of Fluindione, more advantageously from 8% by weight to 15% by weight of Fluindione, still more advantageously from 9% by weight to 13% by weight of Fluindione even more advantageously from 10% by weight to 11 % by weight of Fluindione.

The stable Fluindione composition advantageously comprises, on the basis of the total weight of the composition, from 0.01% to 5% by weight of antioxidants, more advantageously from 0.05% to 3% by weight of antioxidants, still more advantageously from 0.1 % to 2% by weight of antioxidants, even more advantageously from 0.3% to 1 % by weight of antioxidants.

The stable Fluindione composition advantageously comprises, on the basis of the total weight of the composition, from 94.99% by weight to 75% by weight of; pharmaceutically acceptable excipients, more advantageously from 91.95% by weight to 82% by weight of pharmaceutically acceptable excipients, still more advantageously from 90.9% by weight to 85% by weight of pharmaceutically acceptable excipients even more advantageously from 89.7% by weight to 88% by weight of pharmaceutically acceptable excipients.
One or more Antioxidants that may be used according to the present invention are selected from the group consisting of ascorbic acid, sodium ascorbate citric acid, sodium citrate, anhydrous citric acid, sodium citrate anhydrous, butylated hydroxyl anisole, butylated hydroxyl toluene, sodium tatrate, sodium metabisulfate, alpha tocopherol and combinations thereof. The preferred antioxidants are anhydrous citric acid, sodium citrate anhydrous and sodium metabisulfate.

One or more pharmaceutically acceptable excipients that may be used according to the present invention are selected from the group consistinof diluents, binders, disintegrants, lubricants, glidant and combinations thereof.
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. The preferred diluent is mannitol.

Suitable binders that may be used according to the present invention are selected from the group consisting of povidone, alginic acid, starch, potato starch, wheat starch, com starch, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, gelatin and combinations thereof The preferred binder is alginic acid.

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, starch, and combinations thereof.
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 hehenate, and combinations thereof. The preferred lubricant is stearic acid.

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. The preferred glidant is talc.

Stable Fluindione 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.

The stable Fluindione composition of the invention is advantageously under the form of tablets. Advantageously, each tablet comprises 20 mg of Fluindione. In each tablet, the antioxidant content is advantageously from 0.3 to 2 mg.

Stable Fluindione composition according to the present invention may be prepared by any suitable process, such as direct compression, wet granulation and dry granulation.

Preferably stable composition of Fluindione according to the present invention is prepared by direct compression process.

Direct compression according to the present invention advantageouly 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 invention is illustrated by the following non limiting examples: Comparative Example 1: Composition without antioxidants
Ingredient Qty mg/tablet
Fluindione 20.00
Mannitol 160.0
Alginic acid 10.0
Talc 3.0
Stearic acid 2.0
Tablet weight 195.0

Table 2 Brief description of the manufacturing process:

Fluindione and alginic acid were sifted separately through #80 mesh (177 microns ) and #40mesh (420 microns) respectively and blended for 10 minutes in a blender. Purified talc and stearic acid are added to the blend. The resulting blend is then lubricated for 5 minutes and then compressed into tablets or filled into capsules.

Example 2: Composition with Antioxidants:

Ingredient Qty mg/tablet
Fluindione 20.00
Mannitol 158.86
Alginic acid 5.00
Citric acid anhydrous 0.57
Sodium citrate anhydrous 0.57
Purified Talc 3.00
Stearic acid 2.00
Tablet weight (mg) 190.00

Tables Brief description of the manufacturing process:

Fluindione, alginic acid, mannitol, citric acid anhydrous, and sodium citrate anhydrous were sifted through #40 mesh (420 microns) and blended for 10 minutes in a blender, purified talc and stearic acid are added to the blend and the resulting blend is lubricated for 5 minutes and then compressed into tablets or filled into capsules.

Example 3: Composition with Antioxidants

Ingredient Qty mg/tablet
Fluindione 20.00
Mannitol 159.43
Alginic acid 5.00
Sodium metabisulfate 0.57
Purified Talc 3.00
Stearic acid 2.00
Tablet weight (mg) 190.00
Table 4

Brief description of the manufacturing process:

Fluindione, alginic acid, mannitol, sodium metabisulfate were sifted through #40 mesh (420 microns) and blended for 10 minutes in a blender, purified talc and stearic acid are added to the blend and the resulting blend is lubricated for 5 minutes and then compressed into tablets or filled into capsules.

Example 4: stability studies

The above compressed tablets of Example 1, 2, 3 were packed in PVC/Al blisters. These blisters and Previscan® (Reference product) were charged for stability at 40°C/75 RH and observed for 6 months. After 6 months, the tablets were analyzed for impurities (Related Substances) using HPLC method as follows:

HPLC Column Phenomenex phenosphere CN 80A° 250 x 4.6 mm, 5µm
Detector Wavelength 235 nm
Flow rate 1.0 ml / minute
Injection Volume 5 µl
Column temperature 30°C
Run time about 45 minutes
Diluent Acetonitrile: Milli-Q-Water (80:20)

Table 5: HPLC conditions

The comparative related substances data was given below:

Initial (%by weight) I After storage at 40°C/75 RH for 6
Impurity name months (%by weight)
Previscan® Ex 1 Ex 2 Ex 3 Previscan® Ex 1 Ex2 Ex3
2-(4-fluoro-
phenyl)-2-
hydroperoxy- 1.11 0.07 0.13 0.06 2.85 0.69 0.18 0.08
indan-l^-dione
(PI)
2-(4-fluoro-
phenyl)-2-hydroxy-
0.30 0.06 0.05 0.09 0.87 1.47 0.3 0.1
indan-l,3-dione
(P2)

Table 6. Comparative Related substances data for Example 1.2,3 and Previscan
The other tests of Dissolution and Assays are within the acceptable limits and there is no noticeable change observed after storage.
From the above data it was clearly shows that in Examples 2 & 3 according to the present invention the contents in 2-(4-fluro-phenyl)-2-hydroperoxy-indan-l,3-dione (PI) and 2-(4-fluro-phenyl)-2-hydroxy-indan-l,3-dione (P2) impurities are well below 0.5% by weight, on the basis of the total weight of the composition, and thus complies as per the ICH guidelines Impurities in New Drug products.

Claims:

1. Stable Fluindione composition wherein the composition comprises Fluindione, one or more antioxidants, and one or more pharmaceutically acceptable excipients.

2. Stable Fluindione composition of claim 1, wherein the content of 2-(4-fluro-phenyl)-2-hydroperoxy-indan-l,3-dione impurity (P1) is less than 0.5% by weight, on the basis of the total weight of the composition.

3. Stable Fluindione composition of claims 1 or 2, wherein the content of 2-(4-fluro-phenyl)-2-hydroxy-indan-l,3-dione impurity (P2) is less than 0.5% by weight, on the basis of the total weight of the composition.

4. Stable Fluindione composition of claim 1, wherein one or more antioxidants are selected from the group consisting of ascorbic acid, sodium ascorbate citric acid, sodium citrate, anhydrous citric acid, sodium citrate anhydrous, butylated hydroxyl anisole, butylated hydroxyl toluene, sodium tatrate, sodium metabisulfate, alpha tocopherol and combinations thereof.

5. Stable Fluindione composition of claim 1, wherein one or more pharmaceutically
acceptable excipients are selected from the group consisting of diluents, binders,
disintegrants, lubricants, glidant and combinations thereof.

6. Stable Fluindione composition of claim 1, wherein the composition is prepared by direct
compression, wet granulation and dry granulation, most preferably by direct compression.