FIELD OF INVENTION

This invention relates to pharmaceutical composition for oral administration comprising fluindione or its pharmaceutically acceptable salts.

More particularly, the invention relates to stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts, ascorbic acid and optionally one or more pharmaceutically acceptable excipient(s), and further also relates to processes for preparing the same.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Fluindione is a fluorinated derivative of phenindione which is an anticoagulant that functions as a vitamin K antagonist. It is chemically known, 2- (4-fluorophenyl)-l, 3-indanedione, having chemical structure as below:

Oral anticoagulants induce their anticoagulation effect by interfering with the cyclic inter conversion of vitamin K and vitamin K epoxide. Oral vitamin K antagonists are effective and widely used agents for the treatment of venous thrombosis and the prevention of systemic embolism in patients with prosthetic heart valves and atrial fibrillation.

Fluindione is commercially available has Previscan®, which is a 20 mg tablet, used for the prevention of thromboembolic complications.

Prior art literatures relating to fluindione pharmaceutical compositions are discussed below.

Great Britain Patent No. 915472A discloses fluindione and its process of preparation.

European Publication No. 2324820 discloses stable fluindione composition comprising one or more antioxidants. Further, the publication also discloses impurity levels obtained on long term storage in the composition. Also, it discloses that antioxidants can be used to reduce the level of impurities formed on storage, but there were no specific studies performed to show that ascorbic acid could be used as an antioxidant which can reduce the level of impurities formed on long term storage.

It is known from the above mentioned prior art that, pharmaceutical composition comprising fluindione on storage due to oxidation develop significant amount of impurities in the composition which are above the acceptable pharmacopoeial limits.

Although the above prior art represents an attempt to overcome the stability problems of fluindione composition, still there exists a need for a stable fluindione pharmaceutical composition using conventional and readily available antioxidants and stabilizers. The present inventors surprisingly found that, pharmaceutical composition comprising fluindione and ascorbic acid as an antioxidant significantly reduce the level of impurities and are stable on long term storage by preventing oxidative degradation.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s) for oral administration.

More particularly, the invention relates to a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant and optionally one or more pharmaceutically acceptable excipient(s) for oral administration.

One of the objectives of the invention relates to a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant and optionally one or more pharmaceutically acceptable excipient(s) for oral administration.

Another objective of the invention relates to the process of preparing a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant and optionally one or more pharmaceutically acceptable excipient(s).

Another objective of the invention relates to a stable pharmaceutical composition in the form of tablet comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant and optionally one or more pharmaceutically acceptable excipient(s).

Another objective of the invention relates to comparative study of the stability for the tablet comprising fluindione or its pharmaceutically acceptable salts with that of the marketed Previscan® at accelerated stability conditions at 40±2°C and 75±5% relative humidity, wherein the tablets essentially comprises ascorbic acid as an antioxidant.

Yet another objective of the invention relates to stable pharmaceutical tablet comprising fluindione or its pharmaceutically acceptable salts, and optionally one or more pharmaceutically acceptable excipient(s), having comparable in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Previscan®, wherein the tablets essentially comprises ascorbic acid as an antioxidant.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and one or more pharmaceutically acceptable excipient(s). More particularly, the invention relates to a stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant and optionally one or more pharmaceutically acceptable excipient(s) for oral administration.

As mentioned in the background of the invention, it is very difficult to prepare a stable pharmaceutical composition of fluindione or its pharmaceutically acceptable salts because of its oxidative degradation and thereby increasing the level of impurities in the dosage form.

It was surprisingly found that pharmaceutical composition comprising fluindione and ascorbic acid as an antioxidant significantly reduce the level of impurities and are stable on long term storage by preventing oxidative degradation.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for fluindione or its pharmaceutically acceptable salts or derivatives thereof.

In context of the invention, terms like "antioxidant(s)" or "stabilizer(s)" may be used interchangeably and synonymously for ascorbic acid.

According to an embodiment of the invention, it includes the process for preparing a stable pharmaceutical composition comprising fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of: granulating fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients; optionally sifting, milling and blending the material obtained; compressing the blend obtained into tablets or filled in to capsules.

More specifically, an embodiment of the invention relates to a process for preparing a stable pharmaceutical composition comprising fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of:

i) granulating fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients to get granules;

ii) optionally sifting, milling and blending the granules of step i) to get a blend;

iii) compressing the blend of step ii) into tablets.

According to an embodiment of the invention, it includes the process for preparing a stable pharmaceutical composition comprising fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of: combining fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients and granulating them and optionally sifting, milling and blending the granules; compressing the blend obtained into tablets or filled in to capsules.

According to an embodiment of the invention, it includes the process for preparing a stable pharmaceutical composition comprising fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of: i) mixing fluindione and optionally one or more pharmaceutically acceptable excipients ii) adding ascorbic acid, binder and granulating with material obtained in step i) and drying; iii) optionally sifting and milling the material obtained with one or more additional pharmaceutical excipients and blending v) compressing the blend obtained into tablets.

According to an embodiment of the invention, it includes wet granulation process for preparing stable pharmaceutical composition comprising fluindione or its pharmaceutically acceptable salts and ascorbic acid as an antioxidant with optionally one or more pharmaceutical excipient(s) using granulation techniques such as fluid bed granulator or rapid mixer granulator. More preferably, rapid mixer granulator (RMG) is used as granulation technique.

Wet granulation process for preparing stable pharmaceutical composition involves admixing of active ingredient, binder and optionally one or more pharmaceutical excipient(s), forming a wet granulation mixture using aqueous or non-aqueous solvent(s), drying the granules, sieving the dried granules, blending the granules with one or more excipient(s) and compressing the granules into tablet form.

The wording herein below is implied with in the concept of invention as follows:

"Fluindione" as used herein refers to fluindione as base and/ or their pharmaceutically acceptable salts, solvates, enantiomers, diastereomers and polymorphs thereof which may be present in crystalline or amorphous forms.

The term "pharmaceutical composition" as used herein, refers to composition comprising fluindione or their pharmaceutically acceptable salts and optionally with one or more pharmaceutically acceptable excipient(s) which may be in the form of granules, pellets, mini-tablets, tablets, modified release tablets and capsules filled with granules or pellets. More preferably, the pharmaceutical composition is a tablet.

The term "long term storage" as used herein, refers to pharmaceutical composition of fluindione or their pharmaceutically acceptable salts having storage or shelf-life for at least 24 weeks at different temperature and storage conditions.

The term "impurity" as used herein, refers to fluindione degradation products as formed in the pharmaceutical composition. The term "total impurities" as used herein, refers to the sum of all the degradation products like acid impurity, methoxy impurity, benzylidine impurity and any other unknown impurities as formed in the pharmaceutical composition, upon storage at various conditions.

The term "stable pharmaceutical composition" means that the amount of the corresponding total impurities within the pharmaceutical composition has not increased by more than 1% by weight from the initial amount of fluindione after storage at about 40±2°C and 75±5% relative humidity for 4 weeks to 24 weeks period. Preferably, the corresponding content of total impurities has not increased by more than 0.5% by weight of the initial amount of fluindione after storage at about 40±2°C and 75±5% relative humidity for 4 weeks to 24 weeks period. More preferably, the corresponding content of total impurities has not increased by more than 0.3% by weight of the initial amount of fluindione after storage at about 40±2°C and 75±5% relative humidity for 4 weeks to 24 weeks period.

Also, the pharmaceutical composition comprising fluindione after storage at about 40±2°C and 75±5% relative humidity shows assay in the range of 95% to 105% of label claim at the end of 24 weeks. Preferably, the assay in the range of 98% to 102% of label claim at the end of 24 weeks.

The pharmaceutical composition of the invention in addition to the active ingredient may comprise one or more pharmaceutically acceptable excipient(s) which include, but are not limited to diluent(s), binder(s), disintegrant(s), antioxidant(s), glidant(s), lubricant(s) and the like.

Suitable diluent(s) according to the invention include, but are not limited to lactose monohydrate, lactose anhydrous, sucrose, dextrose, maize starch, potato starch, rice starch, wheat starch, potato starch, pregelatinized starch, sorbitol, manntiol, microcrystalline cellulose (Avicel PH 101, Avicel PH 102, Avicel PH 112, Avicel PH 113), silicified microcrystalline cellulose, cellulose derivatives, dicalcium phosphate, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate or magnesium oxide and the combinations thereof.

Suitable binder(s) according to the invention include, but are not limited to cellulose derivatives such as maize starch, wheat starch, rice starch, potato starch etc, acacia, alginic acid, carbomer copolymer, copovidone, microcrystalline cellulose, dextrin, ethyl cellulose, gelatin, guar gum, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, polyvinylpyrrolidone or povidone (PVP-K25, PVP-K29, PVP-K30, PVP-K90), polyethylene oxide or sodium carboxymethylcellulose and the combinations thereof.

Suitable disintegrant(s) according to the invention include, but are not limited to cross-linked polyvinylpyrollidone, sodium starch glycolate, maize starch, pregelatinized starch, salts of carboxy methyl cellulose, microcrystalline cellulose, alginic acid, sodium alginate, guar gum, low-substituted hydroxypropyl cellulose and the combinations thereof.

Suitable antioxidant(s) or stabilizer(s) according to the invention include, but are not limited to ascorbic acid, sodium ascorbate, citric acid, sodium citrate, anhydrous citric acid, sodium citrate anhydrous, propyl gallate, butylated hydroxyl anisole, butylated hydroxyl toluene, sodium pyrosulfite, sodium nitrite, sodium tatrate, potassium metabisulphite, potassium bisulphite, potassium sulphite, alpha tocopherol and the combinations thereof. Preferably ascorbic acid is used. The amount of ascorbic acid used in the composition ranges from 0.001% to 1.5% by weight of the composition, preferably from 0.25% to 1.5% by weight of the composition, more preferably from 0.5% to 1% by weight of the composition.

Suitable glidant(s) and lubricant(s) according to the invention include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearic acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, glyceryl behenate and the combinations thereof.

Suitable aqueous and non-aqueous solvent(s) according to the invention include, but are not limited to purified water, isopropyl alcohol, ethanol, methylene chloride, acetone and the like and mixtures thereof. Preferably, aqueous solvent(s) are used.

The pharmaceutical composition according to an embodiment of the invention may optionally be coated with functional and/or non-functional coating using film-forming polymer(s).

The stable fluindione composition according to the invention may be prepared by any suitable process, such as direct compression, wet granulation or dry granulation. Preferably wet granulation is used.

According to an embodiment of the invention, the process for preparing stable pharmaceutical composition comprising fluindione, antioxidant and optionally one or more pharmaceutically acceptable excipient(s) involves the following steps:

(i) fluindione and other excipient(s) are blended, for example, in a planetary mixer or a rapid mixer granulator;

(ii) suitable antioxidant, binder is mixed with a granulating liquid like water, isopropyl alcohol or acetone or dichloromethane and other hydro-alcoholic solvent(s) such as isopropyl alcohol-water mixture; preferably water is used to make the binder solution;

(iii) the blend obtained in step (i) is granulated with binder solution obtained in step (ii) to obtain the granulate;

(iv) dry the granulate obtained in step (iii) using fluid bed dryer;

(v) dried material obtained in step (iv) is sifted using mechanical sifter and milled using Quadro Comil using appropriate screen;

(vi) add suitable disintegrant which is sifted in appropriate mesh;

(vii) blend the material obtained in step (v) & (vi) in to a suitable blender;

(viii) lubricants and suitable other excipient(s) are sifted and added to the material obtained in the step (vii) and are compressed in conventional manner using appropriate tooling.

According to another embodiment of the invention, the process for preparing stable pharmaceutical composition comprising fluindione, antioxidant and optionally one or more pharmaceutically acceptable excipient(s) involves the following steps:

(i) preparing intragranular mixture of fluindione, antioxidant, binder, disintegrant optionally with other pharmaceutical acceptable excipient(s) using aqueous or non-aqueous solvent;

(ii) preparing extragranular mixture with disintegrant, lubricant and suitable other excipient(s);

(iii) mixing the intragranular and extragranular portion together to make the final blend;

(iv) lubricating the above blend and compressing the lubricated blend into tablets using appropriate tooling and;

(v) optionally coating the tablets.

According to an embodiment of the invention, the comparative study is performed between the commercially available formulation Previscan® and the tablet according to the present invention, after subjecting both of them to accelerated stability conditions at 40±2°C and 75±5% relative humidity for 4 week to 24 week period to monitor and analyze the impurity level.

A further embodiment of the invention, relates to fluindione composition in the form of oral tablet, wherein the tablet possess comparable in-vitro dissolution profile and is bio-equivalent to the commercially available tablets of Previscan®, wherein the tablets essentially comprises ascorbic acid as a stabilizer.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1:

A. Unit Composition:

Table-1

B. Brief Manufacturing Process:

1. Sift fluindione, lactose monohydrate and alginic acid through mesh #30.
2. Load the step 1 material into rapid mixer granulator and mix.
3. Disperse maize starch in the purified water to make binder solution.
4. Granulate the material of step 2 using the binder solution of step 3.
5. Dry the material of Step 4 using fluid bed processor at inlet temperature of 60°C, till LOD is not more than 1.0%w/w.
6. Sift the material of step 5 through mesh #30.
7. Mill the oversize portion of step 6 using Quadro Comil fitted with screen 40G.
8. Sift potato starch through mesh #30.
9. Load the material of step 6, 7 and 8 into suitable blender and blend.
10. Sift talc and stearic acid through mesh #60.
11. Add the material of step 10 to step 9 and blend.
12. Compress the blend of Step 11 using rotary compression machine, fitted with appropriate tooling.

Examples 2-4:

The composition comprising fluindione were studied/ experimented with various antioxidants.
A. Unit Composition:

Table-2

B. Brief Manufacturing Process of Example 2:

1. Sift fluindione, lactose monohydrate and alginic acid through mechanical sifter/ Quadro Comil fitted with appropriate screen.
2. Load the step 1 material into rapid mixer granulator and mix.
3. Dissolve sodium sulfite in purified water and disperse maize starch under stirring.
4. Granulate the material of step 2 using the binder solution of step 3.
5. Dry the material of Step 4 using fluid bed processor at inlet temperature of 55°C±5°C, till LOD is not more than 1.5%w/w (IR Moisture Balance at 105°C).
6. Sift the material of step 5 through mechanical sifter fitted with an appropriate sieve.
7. Mill the oversize portion of step 6 using Quadro Comil fitted with appropriate screen.
8. Sift potato starch through mechanical sifter/ Quadro Comil fitted with appropriate screen.
9. Load the material of step 6, 7 and 8 into suitable blender and blend.
10. Sift talc and stearic acid through mechanical sifter/ Quadro Comil fitted with appropriate screen.
11. Add the material of step 10 to step 9 and blend.
12. Compress the blend of Step 11 using rotary compression machine, fitted with appropriate tooling.

Brief Manufacturing Process of Example 3-4:

The compositions given in Example 3 & 4 were prepared according to the procedure given for Example 2 by replacing with ascorbic acid and citric acid/ sodium citrate.

Based on the above studies and experiments (discussed below), ascorbic acid was selected as a suitable antioxidant for further studies.

Example 5-8:

The composition comprising fluindione were optimized with different levels of ascorbic acid.
A. Unit Composition:

Table-3

B. Brief Manufacturing Process:

1. Sift fluindione, lactose monohydrate and alginic acid through mesh #30.
2. Load the step 1 material into rapid mixer granulator and mix.
3. Dissolve ascorbic acid in purified water and disperse maize starch to make binder solution.
4. Granulate the material of step 2 using the binder solution of step 3.
5. Dry the material of Step 4 using dryer at inlet temperature of 60°C, till LOD is not more than 1.0%w/w.
6. Sift the material of step 5 through mesh #30.
7. Mill the oversize portion of step 6 using Quadro Comil fitted with screen 40G.
8. Sift potato starch through mesh #30.
9. Load the material of step 6, 7 and 8 into suitable blender and blend.
10. Sift talc and stearic acid through mesh #60.
11. Add the material of step 10 to step 9 and blend.
12. Compress the blend of Step 11 using rotary compression machine, fitted with appropriate tooling.

Previscan® 20 mg tablets and tablets from examples - 1 & 3 packed in blister were subjected to accelerated stability testing at 40±2°C and 75±5% relative humidity up to 24 weeks period. The tablets were analyzed using HPLC method to identify the impurities. The results are depicted in table - 4.

Also, the percentage purity of the tablets of example - 3 of the invention was studied; the results of individual impurities identified in the tablets using HPLC method are depicted in table - 5.

The results show that significant amount of impurities were formed in Previscan® 20 mg tablets and in tablets of example - 1 (without any antioxidant). Previscan® 20 mg tablets showed 2.176 %w/w of total impurities at the end of 24 weeks and the tablets of example -1 showed 2.633 %w/w of total impurities. But, the tablets of example - 3 having ascorbic acid showed only 0.379 %w/w at the end of 24 weeks.

The results indicates that when compared to Previscan® 20 mg and example - 1 of the invention, the tablets prepared with ascorbic acid in example -3 showed decreased level of impurities and found to be stable on long term storage.

Table-4

Table-5

Comparative dissolution data;

Fluindione tablets prepared according to example - 3 and commercially available tablets of Previscan® were subjected to in-vitro dissolution profile by using USP type II dissolution apparatus using 900ml of pH 6.8 phosphate buffer at 50 rpm and the resultant data is compiled in table - 6.

Table-6

The above result shows that tablet of example - 3 exhibit similar drug release with respect to the commercially available tablets of Previscan®.

Bio-equivalence Study:

The test (example - 3) and reference product (Previscan® 20 mg) were evaluated for in-vivo studies under fasting condition in healthy human volunteers (N=16). The plasma samples were analyzed for fluindione. The results of the study are depicted in table 7.

Table-7

Test Product (T): Fluindione tablets 20mg of the Example 3. Reference Product (R): Previscan0 Tablets 20 mg.

The above result shows that tablet of example - 3 meets the bio-equivalence requirement with respect to the commercially available tablets of Previscan®.

We Claim:

1. A stable pharmaceutical composition comprising:

i) fluindione or its pharmaceutically acceptable salts thereof;

ii) ascorbic acid and

iii) optionally one or more pharmaceutically acceptable excipients, wherein said composition has content of total impurities not more than about 1 %w/w.

2. The stable pharmaceutical composition according to claim 1, wherein the content of total impurities is not more than about 0.5 %w/w.

3. The stable pharmaceutical composition according to claim 1, wherein the content of total impurities is not more than about 0.4 %w/w.

4. The stable pharmaceutical composition according to claim 1, wherein said composition has assay in the range of 95% to 105% of label claim.

5. The stable pharmaceutical composition according to claim 1, wherein the composition is stored at about 40±2°C and 75±5% relative humidity for a period of up to about 24 weeks.

6. The stable pharmaceutical composition according to claim 1, wherein the amount of ascorbic acid is present up to 1.5% by weight of the composition.

7. The stable pharmaceutical composition according to claim 1, wherein one or more pharmaceutically acceptable excipients are selected from the group consisting of diluent(s), binder(s), disintegrant(s), glidant(s), lubricant(s) or combinations thereof.

8. A process for preparing a stable pharmaceutical composition comprising fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients, wherein the process involves the steps of:

i) granulating fluindione, ascorbic acid and optionally one or more pharmaceutically acceptable excipients to get granules;

ii) optionally sifting, milling and blending the granules of step i) to get a blend;

iii) compressing the blend of step ii) into tablets.

9. A tablet comprising fluindione, having the following unit composition: