Field of the Invention:

The present invention relates to a novel solid pharmaceutical composition of dronedarone, its salts and also relates to the method of preparation of the pharmaceutical composition.

Background of the invention

Dronedarone is chemically known as N-(2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl]benzofuran-5-yI}methane sulfonamide, represented by formula-1.

Dronedarone blocks potassium, sodium and calcium charmels and also has anti-adrenergic properties. Dronedarone is an anti-arrhythmic that is effective in maintaining sinus rhythm in patients presenting atrial fibrillation or atrial flutter. Specifically potasssium ion is the principal osmotically active intracellular ion and plays an important role in the regulation of intracellular volume. A constant and stable potassium concentration is essential for the function of enzyme systems and also for good growth and cell division. Potassium contributes to establishing the resting potential of the cell membrane and, consequently, changes in potassium concentration, in particular in the extracellular compartment, have effects on cell excitability in the nervous, muscle and cardiac system. A decrease in potassium concentration is known to increase cardiac hyperexcitability at the ventricular level, which can result in serious, potentially deadly, rhythm disorders. The deleterious role of a decrease in potassium concentration has been documented in disparate clinical situations. Eating habits with a reduced potassium intake may lead to sudden death in predisposed individuals, even without any structural cardiac pathology.

Finally, it has been shown that the decrease in potassium concentration induces atrial fibrillations (Manoach M., J. Mol. Cell. Cardiol., 1998, 30(6): A4[8]). Dronedarone
or a pharmaceutically acceptable salt thereof, are used for the preparation of a
medicament for regulating the potassium level in the blood. Among the
pharmaceutically acceptable salts of dronedarone, mention may be made of the hydrochloride.

The dose of dronedarone administered per day, orally, may reach 800 mg, taken in one or more intakes. More specifically, the dose of dronedarone administered may be taken with food. More specifically, the dose of dronedarone administered per day, orally, may reach 800 mg, taken in two intakes with a meal.

The antiarrhythmic compounds used in the context of the invention, in particular dronedarone in the form of their hydrochloride, is characterized by low solubility in aqueous medium. For example, the solubility curve of dronedarone hydrochloride at room temperature and as a function of the pH reveals a maximum solubility around pH values of 3 to 5, of about 1 to 2 mg/ml, but very low solubility at pH values of about 6 to 7, since it is only 10 [mu]g/ml at pH=7.

Thus it is possible to dissolve 400 mg of dronedarone hydrochloride in 200 ml of aqueous medium buffered to pH=4.

Dronedarone tablets are marketed by the irmovator as Multaq. Multaq contains dronedarone hydrochloride, hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate and coating with hypromellose, polyethylene glycol 6000, titaniiun dioxide, camauba wax.

US 7323493 discloses a solid pharmaceutical composition of benzofuran derivatives along with non-ioninic surfactants like poloxomer. Poloxmer is claimed to increase the solubility of the API.

The present invention uses anionic surfactant docusate sodium with a combination of betacyclodextrin, which improves the solubility of active pharmaceutical ingredient in the solid pharmaceutical composition.

Summary of the invention:

Accordingly the first aspect of the present invention provides a solid pharmaceutical composition which comprises; a therapeutic amount of dronedarone or its pharmaceutically acceptable salts along with an anionic surfactant in combination with betacyclodextrin and pharmaceutical acceptable carriers.

The second aspect of the present invention provides a solid pharmaceutical composition which comprises, a therapeutic amount of dronedarone or its pharmaceutically acceptable salts,in combination with an anionic surfactant along with atleast one solubility enhancer, atleast one filler, atleast one binder, atleast one disintegrant, optionally one glidant and optionally coated the pharmaceutical composition with coating agent.

The third aspect of the present invention provides the method for the preparation of dronedarone solid pharmaceutical composition.

Detailed Description of the invention:

As used herein dronedarone refers its free base or pharmaceutically acceptable salts, or mixtures thereof. The pharmaceutically acceptable salts of dronedarone include, for example, acid addition salts, such as salts of hydrochloric acid.

The pharmaceutical composition according to the invention preferably comprises from 50 to 80%, particularly preferably from 55 to 65%, of dronedarone or its pharmaceutically acceptable salts thereof (all the percentages are % by weight based on the weight of the pharmaceutical preparation).Based on the individual dose, the pharmaceutical preparation comprises generally from 50 to 800 mg of dronedarone, particularly preferably from 200 to 400 mg.

The first aspect of the present invention provides a solid pharmaceutical composition which comprises; a therapeutic amount of dronedarone or its pharmaceutically acceptable salts along with an anionic surfactant in combination with betacyclodextrin and one or more of pharmaceutical acceptable carriers.

The anionic surfactant used in the present aspect is preferably docusate sodium which is used in combination with betacyclodextrin which enhances the solubility of the active ingredient i.e dronedarone hydrochloride.

The second aspect of the present invention provides a solid pharmaceutical composition which comprises of a therapeutic amount of dronedarone or its pharmaceutically acceptable salts, in combination with an anionic surfactant along with atleast one solubility enhancer, atleast one filler, atleast one binder, atleast one disintegrant, optionally one glidant and optionally coated the pharmaceutical composition with coating agent. Preferably the anionic surfactant used is docusate sodium which is used in combination solubility enhancer betacyclodextrin.

The pharmaceutical preparation advantageously comprises from 7 to 30%, preferably from 8% to 28%, particularly preferably from 14 to 26% by weight of the solubility enhancer relative to the said pharmaceutical composition.

According to the present invention anionic surfactant selected from the group consisting of sulfates such as alkylsulfates like ammonium lauryl sulfate, sodiumlauryl sulfate; alkylether sulfates like sodium laureth sulfate, sodium myreth sulfate; sulfonates such as docusates like dioctyl sodium sufosuccinate, docusate sodium; Sulfonate fluorosurfactants like perfluorooctane sulfonate, perfluorobutane sulfonate; slkyl benzene sulfonates; phosphates such as alkyl aryl ether phosphate, alkyl ether phosphate and like; Carboxylates such as alkyl carboxylates like fatty acid salts; sodium lauryl sarcosinate; carboxylate fluorosurfactants like perfluorononanoate, perfluorooctanoate and like.
Particularly preferance according to the invention is given to using docusate sodium. The pharmaceutical preparation advantageously comprises from 0.1 to 1%, preferably from 0.2% to 0.6% by weight of the surfactant relative to the said pharmaceutical composition.

According to the present invention the binder is selected from the group consisting of com starch, polyvinyl pyrrolidone (povidone), vinylpyrrolidone-vinylacetate copolymer (copovidone) and cellulose derivatives like hydroxy methylcellulose, hydroxy ethylcellulose, hydroxy propylcellulose and hydroxyl propylmethylcellulose. Particular preference according to the invention is given to using hydroxypropyl cellulose and hydroxypropylmethyl cellulose. The pharmaceutical preparation advantageously comprises from 1 to 3%, preferably from 1.1% to 2%, particularly preferably from 1.5 to 2.1% by weight of the binder relative to the said pharmaceutical composition.

According to the present invention the filler is selected from polyols such as mannitol, xylitol, sorbitol; polysaccharides such as dextrates, maltodextrin and cyclodextrins; dibasic calcium phosphate, kaolin, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate mixtures thereof. Particular preference according to the invention is given to using mannitol. The pharmaceutical preparation advantageously comprises from 5 to 30%, preferably from 8 to 25%, particularly preferably from 10 to 20% by weight of filler.

According to the present invention the disintegrant is selected from the group consisting of starch, pregelatinized starch, starch glycolates, crosslinked polyvinylpyrrolidone and sodium carboxymethylcellulose (croscarmellose sodium). Particular preference according to the invention is given to using croscarmellose sodium. The pharmaceutical preparation advantageously comprises from 1.5 to 6%, preferably from 2 to 5%, particularly preferably from 2.5 to 3.5% by weight of the disintegrant.

According to the present invention the lubricant is selected from the group consisting of from the group consisting of fatty acids and their salts. Particular preference according to the invention is given using magnesium stearate. The pharmaceutical preparation advantageously comprises from 0.1 to 1%, particularly preferably from 0.2 to 0.6% by weight of the lubricant.

According to the present invention the glidant is selected from the group consisting of from the group consisting of colloidal silicon dioxide, calcium silicate, magnesium silicate, silicon hydrogel, talc. Particular preference according to the invention is given using colloidal silicon dioxide. The pharmaceutical preparation advantageously comprises from 0.2 to 2%, preferably from 0.5 to 1.5%, particularly preferably from 0.8 to 1.2% by weight of the glidant.

The third aspect of the present invention provides the method for the preparation of dronedarone solid pharmaceutical composition which comprises;

a) Shifting all ingredients by using appropriate mesh,

b) complexing dronedarone hydrochloride with solubility enhancer, fïUer and then with a binder solution,

c) drying the obtained granules,

d) oversizing the obtained granules,

e) mixing the granules with disintegrant, glidant and anionic surfactant in a blender,

f) lubricating the obtained granules in above step,

g) compressing the granules obtained in preceding step into tablets, h) coating of tablets obtained in preceding step.

In a preferred embodiment of the present invention, the process for preparation of solid pharmaceutical composition of dronedarone or its salts, comprises of the following steps;

a) Shifting all ingredients by using appropriate mesh,

b) complexing dronedarone hydrochloride with betacyclodextrin, lactose monohydrate and then with a binder solution such as hydroxypropyl cellulose solution,

c) drying the obtained granules,

d) oversizing the obtained granules,

e) mixing the granules with docusate sodium, crosscarmellose sodium and colloidal silicon dioxide in a blender,

f) lubricating the obtained granules in above step with magnesium stearate,

g) compressing the granules obtained in preceding step into tablets, h) coating of tablets obtained in preceding step.

The term complexing herein used, mixing dronedarone with solubility enhancer by dry method or wet method (i.e by dissolving in a solvent).

The colors may be selected from any FDA approved colors for internal use. The formulation may optionally be coated.

The dosage form may be in tablet or capsule form or pellets, however, the tablet form is particularly suitable. The tablets may further be coated. For coating, any formulation, which is customary in pharmaceutical technology, such as, for example, opadry white or the combination of hydroxypropyl methyl cellulose and/or polyethylene glycol and titanium dioxide.

The composition of the present invention can be prepared by carrying out known process involving, in particular, techniques of granulation via a wet or dry route, via fusion or via direct tableting for the formation of tablets. More preferably, tablets can be prepared by wet granulation technique and via direct tableting.

The invention is further illustrated by the following examples but they should not be construed as limiting the scope of the invention any way.
Process:

Example1:

Table-1

Process:

All the ingredients were sifted using appropriate mesh. Compound-I is complexed with betacyclodextrin solution and then lactose monohydrate was mixed in Rapid mixer to form a uniform blend. The binder solution was prepared with hydroxy propylcellulose and water. This binder solution was added to the above blend until coagulate mass obtained. The obtained granules were dried. The dried granules were screened and then the resulting granules were mixed in blender with croscarmellose sodium, colloidal silicondioxide and docusate sodium. Then the granules were lubricated with magnesium stearate and mixed for 10 minutes. The lubricated blend was then subjected to compression on a machine to make tablets. The cores were coated in a coating pan with opadry white.

Process for the preparation of examples equal to the example-l.

Example 3

Table-3

Process:

All the ingredients were sifted using appropriate mesh. Compound-I is complexed with betacyclodextrin solution and then maltodextrin was mixed in Rapid mixer to form a uniform blend. The binder solution was prepared with hydroxy propylcellulose and water. This binder solution was added to the above blend until coagulate mass obtained. The obtained granules were dried. The dried granules were screened and then the resulting granules were mixed in blender with croscarmellose sodium, colloidal silicondioxide and docusate sodium. Then the granules were lubricated with magnesium stearate and mixed for 10 minutes. The lubricated blend was then subjected to compression on a machine to make tablets. The cores were coated in a coating pan with opadry white.

We claim:

1. A solid pharmaceutical composition for oral administration comprising a benzofuran derivative selected from the group consisting of dronedarone or a pharmaceutically acceptable salt, an anionic surfactant in combination with a solubility enhancer preferably betacyclodextrin and optionally in combination with one or more pharmaceutically acceptable excipients.

2. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutically acceptable salt of dronedarone is dronedarone hydrochloride.

3. A solid pharmaceutical composition according to claim 1 wherein the solubility enhancer being present in a proportion of from 8 to 30%, preferably from 10% to 28%, particularly preferably from 14 to 26% by weight of the solubility enhancer relative to the said pharmaceutical composition.

4. A solid pharmaceutical composition which comprises of dronedarone or its pharmaceutically acceptable salts along with an anionic surfactant in combination with atleast one solubility enhancer, one filler, atleast one disintegrant, atleast one binder, atleast one lubricant and/ or a glidant.

5. A solid pharmaceutical composition according to preceding claims wherein solubility enhancer is betacyclodextrin, filler is lactose monohydrate, disintegrant is crascarmellose sodium, anionic surfactant is docusate sodium, lubricant is magnesium stearate, and glidant is coUoidal silicon dioxide.

6. A solid pharmaceutical composition which is comprising of dronedarone hydrochloride along with docusate sodium, betacyclodextrin, lactose monohydrate, crascarmellose sodium, magnesium stearate, and colloidal silicon dioxide and optionally a coating agent.

7. A solid pharmaceutical composition for oral administration according claims 1 to 6, wherein the composition is in the form of a tablet, a capsule, pellets or granules.

8. A process for the preparation of solid pharmaceutical composition according to claims 1 to 7, characterized in the following steps:

a) Shifting all ingredients by using appropriate mesh,

b) complexing dronedarone hydrochloride with a solubility enhancer, fiUer and then with a binder solution,

c) drying the obtained granules,

d) oversizing the obtained granules,

e) mixing the granules with disintegrant, glidant and anionic surfactant in a blender,

f) lubricating the obtained granules in above step,

g) compressing the granules obtained in preceding step into tablets,

h) coating of tablets obtained in preceding step.

9. A process for the preparation of solid pharmaceutical composition according to
claim 8, characterized in the following steps:

a) Shifting all ingredients by using appropriate mesh,

b) complexing dronedarone hydrochloride with betacyclodextrin, lactose

c) monohydrate and then with a binder solution such as hydroxypropyl cellulose solution,

d) drying the obtained granules,

e) oversizing the obtained granules,

f) mixing the granules with docusate sodium, crosscarmellose sodium and colloidal silicon dioxide in a blender,

g) lubricating the obtained granules in above step with magnesium stearate, h) compressing the granules obtained in preceding step into tablets,

i) coating of tablets obtained in preceding step.

10. The pharmaceutical composition for oral administration according to claiml-9, characterized in that the preparation comprises from 200 to 400 mg of dronedarone or its pharmaceutically acceptable salts based on an individual dosage.