WO2011135581A2

WO2011135581A2 - Pharmaceutical compositions of dronedarone

Info

Publication number: WO2011135581A2
Application number: PCT/IN2011/000270
Authority: WO
Inventors: Sunilendu Bhushan Roy; Sushrut Krishnaji Kulkarni; Pranav Dhirajbhai Jogani
Original assignee: Cadila Healthcare Limited
Priority date: 2010-04-28
Filing date: 2011-04-26
Publication date: 2011-11-03
Also published as: WO2011135581A8; WO2011135581A3

Abstract

A pharmaceutical composition is disclosed, said composition comprising dronedarone or pharmaceutically acceptable salts thereof, wherein said composition is devoid of surfactant.

Description

PHARMACEUTICAL COMPOSITIONS OF DRONEDARONE

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition of dronedarone or salts thereof, characterized in that said composition does not contain surfactant(s), preferably nonionic hydrophilic surfactant(s). The invention also relates to process of making such compositions.

BACKGROUND OF THE INVENTION

Dronedarone is a benzofuran derivative having antiarrythmic properties. The oral tablets of dronedarone hydrochloride are marketed in USA under the brand name Multaq^® by Sanofi-Aventis in the strength equivalent to 400 mg dronedarone free base.

Chemically, dronedarone hydrochloride is N-{2-butyl-3-[4-(3- dibutylaminopropoxy)benzoyl]benzofuran-5 -yl } methanesulfonamide, hydrochloride, having a structure of Formula 1,

[Formula 1]

U.S. patent No. 5,223,510 describes dronedarone and its pharmaceutical acceptable salts.

U.S. Patent No. 7,323,493 and U.S. application No. 2008/139645 discloses solid pharmaceutical composition for oral administration comprising dronedarone or a pharmaceutically acceptable salt thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant.

U.S. application No. 2007/243257 discloses a solid pharmaceutical composition comprising a solid dispersion containing dronedarone and a pharmaceutically acceptable polymer matrix, which is a blend of polydextrose and at least one other polymer.

PCT application No. 2009/144550 discloses use of dronedarone or a pharmaceutically acceptable salt thereof, for the preparation of a medicament, wherein said medicament is taken with food, for use in the prevention of mortality and/or of cardiovascular hospitalizations.

The solubility of dronedarone hydrochloride is very low 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 μg/ml at pH=7.

Prior art attempts as mentioned above exemplify the use of nonionic hydrophilic surfactant for improving the bioavailability of dronedarone hydrochloride in the compositions. It has been mentioned that nonionic hydrophilic surfactants especially poloxamers are necessary to make solid pharmaceutical compositions of dronedarone hydrochloride with improved bioavailability.

To that end, it has now been found, surprisingly, that pharmaceutical compositions prepared according to the invention overcome all the above mentioned problems even without use of one or more surfactants.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a pharmaceutical composition comprising dronedarone or salts thereof, wherein the composition does not contain surfactant.

In other general aspect, there is provided a pharmaceutical composition comprising dronedarone or salts thereof, wherein the composition does not contain nonionic hydrophilic surfactant.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutical composition may further include one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipients may include one or more binders, fillers, lubricants, disintegrants, glidants and the like.

In another general aspect, there is provided a pharmaceutical composition comprising micronized dronedarone or salts thereof, wherein the composition does not contain surfactant.

In another general aspect, there is provided a pharmaceutical composition comprising micronized dronedarone or salts thereof, wherein the composition does not contain nonionic hydrophilic surfactant. In another general aspect there is provided a pharmaceutical composition of dronedarone or salts thereof, wherein said composition does not contain surfactant, characterized in that said composition exhibits no significant difference in rate and/or extent of absorption of dronedarone or salts thereof as compared to marketed formulation of dronedarone hydrochloride available under the trade name Multaq^®.

In another general aspect, there is provided a method for treatment of arrythmia, wherein said method comprises administering a pharmaceutical composition of dronedarone or salts thereof, characterized in that said composition does not contain surfactant.

In another general aspect, there is provided a method for treatment of arrythmia, wherein method comprises administering a pharmaceutical composition of dronedarone or salts thereof, characterized in that said composition does not contain nonionic hydrophilic surfactant.

In still another general aspect, there is provided a process for preparing a pharmaceutical composition of dronedarone or salts thereof, wherein the composition does not contain surfactant, which process comprises of mixing dronedarone or salts thereof with one or more pharmaceutically acceptable excipients and converting the mixture thus obtained into suitable pharmaceutical dosage form.

In still another general aspect, there is provided a process for preparing a pharmaceutical composition of dronedarone or salts thereof, wherein the composition does not contain nonionic hydrophilic surfactant, which process comprises of mixing dronedarone or salts thereof with one or more pharmaceutically acceptable excipients and converting the mixture thus obtained into suitable pharmaceutical dosage form.

Embodiments of the process may include one or more of the following features. For example, the process may further include mixing, granulating or coating etc with one or more pharmaceutically acceptable excipients and converting the into suitable dosage form. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

DETAILED DESCRIPTION OF THE INVENTION

The inventors of the invention have discovered that when dronedarone compositions are prepared without using any surfactant, these compositions still exhibit better or at least same bioavailability as compared to the tablets marketed under the trade name Multaq^® which contains nonionic hydrophilic surfactant. The inventors have noticed that by judicial selection of excipients in its optimum concentrations, and particularly without using any additional surfactants, the dronedarone formulations can be made with improved release profile and bioavailability, thus there is no need to increase bulk of composition.

The compositions of invention can be immediate release, extended release, sustained release, controlled release, modified release and delayed release. Such compositions can be prepared using rate controlling polymers.

The term "dronedarone" used throughout the specification refers to not only dronedarone per se, but also its pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof. Preferred salt of dronedarone is its hydrochloride.

The amount of dronedarone or pharmaceutically acceptable salt thereof in the pharmaceutical composition may range from about 30% to about 80 w/w of the composition. Preferably, the amount of dronedarone or pharmaceutically acceptable salt thereof in the pharmaceutical composition range from about 50 mg to about 500 mg.

The pharmaceutical composition described herein was found to retain at least 80% of potency of dronedarone or salt thereof when stored for at least three months at 40°C and 75% relative humidity or at 50°C and 80% relative humidity.

The pharmaceutical composition of the present invention exhibits a dissolution profile such that at least 30% of dronedarone is released within 30 minutes when measured in USP Type II dissolution apparatus, at 75rpm using 100ml medium of pH 4.5 Phosphate buffer. Moreover, it was also found that the composition exhibits no significant difference in rate and/or extent of absorption of dronedarone when compared with marketed formulation of equivalent strength (Multaq®).

The pharmaceutical compositions as described herein may be prepared by processes known to the person having ordinary skill in the art of pharmaceutical technology such as direct compression, wet or dry granulation, slugging, hot melt granulation, hot melt extrusion, fluidized bed granulation, extrusion-spheronization, spray drying and solvent evaporation.

In one embodiment, the compositions may be prepared by mixing, compressing, coating, granulating dronedarone or salts thereof with one or more pharmaceutically acceptable excipients, lubricated and formulated into suitable dosage form.

In still another embodiment, the compositions may be prepared by mixing and granulating dronedarone or salts thereof with one or more pharmaceutically acceptable excipients to form granules. The granules can be mixed with other pharmaceutically acceptable excipients, lubricated and formulated into suitable dosage form. Further, the dosage form can be coated with film-forming polymers.

Suitable dosage form compri ses one or more of tablet, capsule, granule, powder, pellet, caplet, minitablet, lozenges, capsule filled with minitablets and/or pellets, multilayer tablet, granules for suspension, granules or powder filled in sachet.

The composition of the present invention can be coated to give film-coated tablets.

The pharmaceutically acceptable excipients may include one or more binders, diluents, lubricants, disintegrants, glidants and the like.

Suitable diluents may include one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide; sugars such as lactose or sucrose; sugar alcohols such as mannitol, sorbitol, erythritol and the like. The amount of diluent in the pharmaceutical composition may present in the amount ranging from about 10% to about 80% w/w of the composition.

Suitable disintegrants may include one or more of croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, cross- linked polyvinylpyrrolidone and the like. The amount of disintegrant in the pharmaceutical composition may present in the amount ranging from about 8% to about Suitable binders may include one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, starch, pregelatinized starch, corn starch, maize starch, sodium alginate, gums, synthetic resins and the like. The amount of binder in the pharmaceutical composition may present in the amount ranging from about 5% to about 15% w/w of the composition. Binder may be present in extragranular and/or intragranular portion of the composition.

Suitable lubricants and glidants may include one or more of talc, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate, kaolin and the like.

The present invention further provides a method of treating angina pectoris, hypertension, arrythmias, or cerebral circulatory insufficiency comprising administering to human in need thereof a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof.

The invention is further illustrated by the following examples which are provided to be exemplary of the invention and do not limit the scope of the invention. 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.

Example 1

Table 1

8 Opadry white 6-24

9 Water Q. S.

Procedure: Dronedarone hydrochloride, lactose and maize starch were mixed and granulated with aqueous solution of hydroxypropyl methylcellulose. The granules were dried and mixed with crospovidone and colloidal silicon dioxide. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets were then film-coated.

Example 2

Table 2

Procedure: Dronedarone hydrochloride, lactose monohydrate and corn starch were mixed and granulated with aqueous solution of hydroxypropyl methylcellulose. The granules were dried and mixed with colloidal silicon dioxide, magnesium stearate and remaining quantity of hydroxypropyl methylcellulose. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling.

Example 3

Table 3

4 Hydroxypropyl methylcellulose 30.0

5 Water Q. S.

6 Hydroxypropyl methylcellulose 15.0

7 Crospovidone 4.0

8 Colloidal silicon dioxide 2.0

9 Magnesium stearate 9.0

Procedure: Dronedarone hydrochloride, lactose monohydrate and corn starch were mixed and granulated with aqueous solution of hydroxypropyl methylcellulose. The granules were dried and mixed with crospovidone, colloidal silicon dioxide, magnesium stearate and remaining quantity of hydroxypropyl methylcellulose. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling.

Example 4

Table 4

Procedure: Dronedarone hydrochloride, lactose monohydrate and corn starch were mixed and granulated with aqueous solution of hydroxypropyl methylcellulose and polyethylene glycol. The granules were dried and mixed with crospovidone, colloidal silicon dioxide, magnesium stearate and remaining quantity of hydroxypropyl methylcellulose. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. Example 5

Dissolution study:

Dissolution study of reference product (Multaq®) and formulation of Example 3 and 4 of the invention was carried with USP Dissolution apparatus (Paddle) at 75rpm using 100ml medium of pH 4.5 Phosphate buffer.

Table 5

Dissolution study of Formulation of Example 3 of the invention was subjected to storage at 40°C and 75% relative humidity and % drug release was determined with USP Dissolution apparatus (Paddle) at 75rpm using 100ml medium of pH 4.5 Acetate buffer after.

Table 6 ·

Example 6

Stability study: The stability of the formulation of Example 2 & 3 was carried out using 60cc heavy weight HDPE bottle at 40°C and 75% relative humidity and at 50°C and 80% relative humidity.

Table 7

Claims

We claim:

1. A pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, characterized in that said composition is devoid of surfactant.

2. The pharmaceutical composition as claimed in claim 1, wherein the surfactant is nonionic hydrophilic surfactant.

3. The pharmaceutical composition as claimed in claim 1 , wherein the pharmaceutically acceptable salt is the hydrochloride.

4. The pharmaceutical composition as claimed in claim 1, wherein the composition contains about 30% to about 80% w/w of dronedarone or pharmaceutically acceptable salts thereof.

5. The pharmaceutical composition as claimed in claim 1, wherein the composition further comprises one or more of diluents, disintegrants, binders, lubricants and/or glidants.

6. The pharmaceutical composition as claimed in claim 5, wherein the diluent comprises one or more of microcrystalline cellulose, starch, dibasic calcium phosphate, tribasic calcium phosphate, calcium carbonate, dextrose, kaolin, magnesium carbonate, magnesium oxide, sugars and sugar alcohols.

7. The pharmaceutical composition as claimed in claim 5, wherein the disintegrant comprises one or more of croscarmellose sodium, sodium starch glycolate, starch, pregelatinized starch, corn starch, maize starch, sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.

8. The pharmaceutical composition as claimed in claim 5, wherein the binder comprises one or more of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carbomers, dextrin, ethyl cellulose, methylcellulose, shellac, zein, gelatin, polymethacrylates, polyvinyl pyrrolidone, pregelatinized starch, sodium alginate, gums and synthetic resins.

9. The pharmaceutical composition as claimed in claim 5, wherein the lubricant and/or glidant comprises one or more of magnesium stearate, calcium stearate, zinc stearate; colloidal silicon dioxide, finely divided silicon dioxide, stearic acid, hydrogenated vegetable oil, glyceryl palmitostearate, glyceryl monostearate, glyceryl behenate, polyethylene glycols, powdered cellulose, starch, sodium stearyl fumarate, sodium benzoate, mineral oil, magnesium trisilicate and kaolin.

10. The pharmaceutical composition as claimed in claim 5, wherein the amount of diluent is about 10% to about 80% w/w of the composition.

1 1. The pharmaceutical composition as claimed in claim 6, wherein the diluent is_ lactose.

12. The pharmaceutical composition as claimed in claim 5, wherein the amount of disintegrant is about 8% to about 15% w/w of the composition.

13. The pharmaceutical composition as claimed in claim 7, wherein the disintegrant comprises one or more of starch, pregelatinized starch, corn starch and maize starch.

14. The pharmaceutical composition as claimed in claim 5, wherein the amount of binder is about 5 to about 15% w/w of the composition.

15. The pharmaceutical composition as claimed in claim 8, wherein the binder is hydroxypropyl methylcellulose.

16. The pharmaceutical composition as claimed in claim 15, wherein the hydroxypropyl methylcellulose is present both in intragranular and extragranular portion.

17. The pharmaceutical composition as claimed in claim 1, wherein said composition comprises one or more of tablet, capsule, granule, powder, pellet, caplet, minitablet, lozenges, capsule filled with minitablets and/or pellets, multi-layer tablet, granules for suspension, granules and powder filled in sachet.

18. A pharmaceutical composition comprising micronized dronedarone or pharmaceutically acceptable salts thereof, characterized in that said composition is devoid of surfactant.

19. The pharmaceutical composition as claimed in claim 18, wherein said surfactant is nonionic hydrophilic surfactant.

20. The pharmaceutical composition as claimed in claim 1, wherein said composition exhibits dissolution profile such that at least 30% of dronedarone is released within 30 minutes when measured in USP Type II dissolution apparatus, at 75rpm using 100ml medium of pH 4.5 Phosphate buffer.

21. The pharmaceutical composition as claimed in claim 1, wherein said composition exhibits no significant difference in rate and/or extent of absorption of dronedarone or pharmaceutically acceptable salts thereof as compared to commercially marketed formulation of sirolimus marketed under the trade name Multaq^®.

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22. A pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, characterized in that the composition is devoid of surfactant and retains at least 80% of the potency of dronedarone when stored for three months at 40°C and 75% relative humidity.

23. A pharmaceutical composition comprising:

(a) about 50 to about 500 mg of dronedarone or pharmaceutically acceptable salt thereof,

(a) about 20 to about 150 mg of lactose,

(c) about 20 to about 80 mg of starch,

(d) about 5 to about 40 mg of hydroxypropyl methylcellulose,

(e) about 0.5 to about 15 mg of colloidal silicon dioxide,

(f) about 1 to about 16 mg of magnesium stearate,

wherein said composition is devoid of surfactant.

24. The pharmaceutical composition as claimed in claim 23, wherein said composition further comprises about 2 to about 20mg of polyethylene glycol.

25. The pharmaceutical composition as claimed in claim 23, wherein said composition further comprises about 1 to about 80mg of crospovidone.

26. A process of preparing a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, which process comprises of mixing, compressing, coating or granulating dronedarone or pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients, characterized in that said composition is devoid of surfactant.

27. The process as claimed in claim 26, wherein said surfactant is nonionic hydrophilic surfactant.

28. A process of preparing the pharmaceutical composition as claimed in claim 23, wherein said process comprises steps of:

(a) mixing lactose and starch with dronedarone or pharmaceutically acceptable salt thereof; ^'

(b) preparing a granulating vehicle using water and part quantity of hydroxypropyl methylcellulose;

(c) granulating the mixture of step (a) using the granulating vehicle prepared in step (b);

(d) blending the resulting granules with colloidal silicon dioxide, magnesium stearate and remaining quantity of hydroxypropyl methylcellulose;

(e) converting granules prepared in step (d) in to suitable dosage form;

(f) optionally, film coating the dosage form.

29. A method of treating angina pectoris, hypertension, arrythmias, or cerebral circulatory insufficiency comprising administering to human in need thereof, a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof, characterized in that said composition is devoid of surfactant.

30. The method as claimed in claim 29, wherein said surfactant is nonionic hydrophilic surfactant.