WO2011135582A2

WO2011135582A2 - Pharmaceutical compositions of dronedarone

Info

Publication number: WO2011135582A2
Application number: PCT/IN2011/000271
Authority: WO
Inventors: Sunilendu Bhushan Roy; Sushrut Krishnaji Kulkarni; Ajay Kumar Handa; Pravav 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: WO2011135582A3

Abstract

A pharmaceutical composition is disclosed, said composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants.

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 contains one or more surfactants other than nonionic hydrophilic surfactants. 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,

,HCI

[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 disclose 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 nonionic hydrophilic surfactant.

SUMMARY OF THE INVENTION

In one general aspect, there is provided a pharmaceutical composition comprising dronedarone or salts thereof, wherein the composition contains one or more surfactants other than nonionic hydrophilic surfactants.

In another general aspect, there is provided a pharmaceutical composition comprising dronedarone or salts thereof, wherein the composition comprises one or more ionic or lipophilic surfactants.

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, surfactants, glidants and the like.

In another general aspect, there is provided a pharmaceutical composition comprising micronized dronedarone or salts thereof, wherein the composition contains one or more surfactants other than nonionic hydrophilic surfactants.

In another general aspect there is provided a pharmaceutical composition of dronedarone or salts thereof, wherein said composition contains one or more surfactants other than nonionic hydrophilic surfactants, 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 method comprises administering a pharmaceutical composition of dronedarone or salts thereof, characterized in that said composition contains one or more surfactants other than nonionic hydrophilic surfactants.

In still another general aspect, there is provided a process for preparing a pharmaceutical composition of dronedarone or salts thereof, wherein the composition contains one or more surfactants other than nonionic hydrophilic surfactants, 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 with one or more surfactants other than nonionic hydrophilic surfactants, these compositions exhibit better or at least same bioavailability as compared to the tablets marketed under the trade name Multaq^®. The inventors have noticed that by using one or more surfactants other than nonionic hydrophilic surfactants, compositions can be made with improved release profile and hence desired bioavailability can be achieved. 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.

Suitable surfactants may include one or more of ionic surfactants and lipophilic surfactants. Ionic surfactants may include one or more of anionic, cationic or zwitterionic surfactants. The pharmaceutical compositions of this invention do not contain nonionic hydrophilic surfactants like poloxamers (pluronic^®), polysorbates (tween^®), polyethylene hydroxystearates (solutol^®), polyethoxylated castor oils (cremophor^®) etc.

Suitable cationic surfactants may include one or more of quaternary ammonium compounds, such as benzalkonium chloride, cetyl trimethyl ammonium bromide and dodecyl dimethyl ammonium bromide, hexadecyl (cetyl) trimethylammonium bromide, dodecyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides, dodecylamine hydrochloride, and the like.

Suitable anionic surfactants may include one or more of sodium lauryl sulphate, sodium dodecyl sulphate, ammonium lauryl sulphate, alkyl benzene sulfonate, perfluorooctanoate, perfluorooctanesulfonate etc.; cationic surfactants may be selected from benzalkonium chloride, benzethonium chloride, polyethoxylated tallow amine, cetylpyridinium chloride, cetyl trimethylammonium bromide, hexadecyl trimethyl ammonium bromide and other alkyltrimethyl ammonium salts etc.; or amphoteric surfactants may be selected from dodecyl betaine, cocamidopropyl betaine, cocoampho glycinate etc. The ionic surfactants may also include alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides, and the like.

The lipophilic surfactants may include fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group from glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; PEG sorbitan fatty acid esters, PEG glycerol fatty acid esters, polyglycerized fatty acid, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters; and the like.

Suitable zwitterionic surfactants may include one or more of alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates and acyl glutamates wherein the alkyl and acyl groups have from 8 to 18 carbon atoms such as cocamidopropyl betaine, sodium cocoamphoacetate, cocamidopropyl hydroxysultaine, and sodium cocamphopropionate, and the like.

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.

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.

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 comprises 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 pharmaceutically acceptable excipients may include one or more binders, diluents, lubricants, disintegrants, lubricants/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 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 disintegrant in the pharmaceutical composition may present in the amount ranging from about 8% to about 15% w/w of the composition.

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 binder in the pharmaceutical composition may present in the amount ranging from about 5% to about 15% w/w 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

Procedure: Dronedarone hydrochloride, lactose and microcrystalline cellulose were mixed and granulated with aqueous solution of sodium lauryl sulphate. Granules were dried and mixed with colloidal silicon dioxide. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets were film-coated. Example 2

Table 2

Procedure: Dronedarone hydrochloride, lactose and pregelatinized starch were mixed and granulated with aqueous solution of docusate sodium and povidone. Granules were dried and mixed with colloidal silicon dioxide. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets were film-coated.

Example 3

Table 3

Procedure: Dronedarone hydrochloride, lactose and lecithin were mixed and granμlated with aqueous solution of povidone. Granules were dried and mixed with colloidal silicon dioxide. The granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets were film-coated. Example 4

Table 4

Procedure: Dronedarone hydrochloride, microcrystalline cellulose, lactose and potassium oleate were mixed and granulated with aqueous solution of povidone. Granules were dried and mixed with pregelatinized starch and colloidal silicon dioxide. The "granules were lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets were film-coated.

Claims

We claim:

1. A pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants.

2. A pharmaceutical composition comprising micronized dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants.

3. The pharmaceutical composition as claimed in claim 1, wherein the surfactant comprises one or more of anionic, cationic and zwitterionic surfactants.

4. The pharmaceutical composition as claimed in claim 3, wherein the anionic surfactant comprises one or more of potassium laurate; sodium dodecyl sulphate; alkyl polyoxy ethylene sulfates; sodium alginates; sodium lauryl sulphate, sodium heptadecyl sulphate; alkyl benzene sulfonic acids or salts thereof, sodium or amino salts of dodecylbenzene sulphonic acid; lecithins, hydrogenated lecithins; lysolecithins, hydrogenated lysolecithins; sodium butylnaphthalene sulphonate, sodium dioctyl sulphosuccinate, N-acyl-N-alkyl fatty acid taurates; sulfated polyoxyethylated alcohols; sulfated oils; dioctyl sodium sulfosuccinate, phosphatidyl choline, phosphatidyl glycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid or salts, glyceryl esters, sodium carboxymethylcellulose, cholic acid and bile acids or salts thereof.

5. The pharmaceutical composition as claimed in claim 3, wherein the cationic surfactant comprises one or more of quaternary ammonium compounds, benzalkonium chloride, cetyl trimethyl ammonium bromide, dodecyl dimethyl ammonium bromide, hexadecyl (cetyl) trimethylammonium bromide, dodecyl pyridinium chloride, lauryl dimethyl benzyl ammonium chloride, acyl carnitine hydrochlorides, alkyl pyridinium halides and dodecylamine hydrochloride.

6. The pharmaceutical composition as claimed in claim 3, wherein the lipophilic surfactant comprises one or more of fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols, sterol derivatives; polyoxyethylated sterols or sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- or di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group from glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids or sterols; oil-soluble vitamins/vitamin derivatives; PEG sorbitan fatty acid esters, PEG glycerol fatty acid esters, polyglycerized fatty acid, polyoxyethylene-polyoxypropylene block copolymers and sorbitan fatty acid esters.

7. The pharmaceutical composition as claimed in claim 3, wherein the zwitterionic surfactant comprises one or more of alkyl betaines, alkyl amidopropyl betaines, alkyl sulphobetaines, alkyl glycinates, alkyl carboxyglycinates, alkyl amphopropionates, alkyl amidopropyl hydroxysultaines, acyl taurates or acyl glutamates, cocamidopropyl betaine, sodium cocoamphoacetate, cocamidopropyl hydroxysultaine and sodium cocamphopropionate.

8. The pharmaceutical composition as claimed in claim 3, wherein the amount of anionic, cationic or zwitterionic surfactants ranges from about 0.1% to about 70% w/w of the composition.

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

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

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

12. The pharmaceutical composition as claimed in claim 11, 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.

13. The pharmaceutical composition as claimed in claim 1 1, 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.

14. The pharmaceutical composition as claimed in claim 1 1, 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.

15. The pharmaceutical composition as claimed in claim 1 1, 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.

16. The pharmaceutical composition as claimed in claim 1 1, wherein the amount of diluent is about 10% to about 80% w/w of the composition.

17. The pharmaceutical composition as claimed in claim 12, wherein the diluent is lactose.

18. The pharmaceutical composition as claimed in claim 1 1, wherein the amount of disintegrant is about 8% to about 15% w/w of the composition.

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

20. The pharmaceutical composition as claimed in claim 1 1 , wherein the amount of binder is about 5 to about 15% w/w of the composition.

21. The pharmaceutical composition as claimed in claim 14, wherein the binder is polyvinyl pyrrolidone.

22. 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.

23. 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.

24. 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 dronedarone marketed under the trade name Multaq^®.

25. A pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic surfactants, wherein said composition retains at least 80% of the potency of dronedarone when stored for three months at 40°C and 75% relative humidity.

26. The pharmaceutical composition as claimed in claim 1, wherein said composition retains at least 80% of the potency of dronedarone when stored for three months at 50°C and 80% relative humidity.

27. A pharmaceutical composition comprising:

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

(b) about 5 to about 150 mg of lactose, (c) about I to about 50 mg of surfactant,

(d) about 1 to about 16 mg of colloidal silicon dioxide,

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

characterized in that said surfactant is not a nonionic surfactant.

28. The pharmaceutical composition as claimed in claim 27, wherein said composition further comprises about 5 to about 150 mg of microcrystalline cellulose.

29. The pharmaceutical composition as claimed in claim 27, wherein said composition further comprises about 2 to about 50 mg of polyvinyl pyrrolidone.

30. The pharmaceutical composition as claimed in claim 27, wherein said composition further comprises about 5 to about 100 mg of pregelatinized starch.

31. 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 surfactant/s other than nonionic surfactants.

32. The process for preparing the pharmaceutical composition as claimed in claim 27, wherein said process comprises steps of:

(a) mixing lactose with dronedarone or pharmaceutically acceptable salt thereof;

(b) preparing a granulating vehicle using water and surfactant;

(c) granulating the mixture of step (a) using the granulating vehicle prepared in step (b); (d) blending the resulting granules with colloidal silicon dioxide and magnesium stearate;

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

(f) optionally, film coating the dosage form.

33. 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 and one or more surfactant/s, other than nonionic surfactants.