WO2013024411A1 - Co-milled formulation of dronedarone - Google Patents

Co-milled formulation of dronedarone Download PDF

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Publication number
WO2013024411A1
WO2013024411A1 PCT/IB2012/054085 IB2012054085W WO2013024411A1 WO 2013024411 A1 WO2013024411 A1 WO 2013024411A1 IB 2012054085 W IB2012054085 W IB 2012054085W WO 2013024411 A1 WO2013024411 A1 WO 2013024411A1
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WO
WIPO (PCT)
Prior art keywords
dronedarone
formulation
pharmaceutically acceptable
cellulose
milled
Prior art date
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PCT/IB2012/054085
Other languages
French (fr)
Inventor
Munish Talwar
Rucha KULKARNI
Shamsunder DODIYA
Original Assignee
Lupin Limited
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Publication of WO2013024411A1 publication Critical patent/WO2013024411A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

Definitions

  • Cardiac arrhythmias are disturbances to the natural rhythm of the heart caused due to abnormal electric activity in the heart.
  • the heart has a 'pacemaker', called the sinus node, in the atrium of the right hand side of the heart that generates electrical impulses. These are transmitted through specialized conductive tissues to the muscles of the right and left ventricles, where they cause the muscular contractions that pump blood around the body.
  • Arrhythmias can be life-threatening medical emergencies which can result in cardiac arrest and sudden death.
  • the normal beating of the heart ranges between 60 and 100 beats per minute under resting conditions.
  • Arrhythmias take the form of slowing down (bradycardia) or speeding up (tachycardia) of the rate outside these limits, or of the insertion or deletion of beats from the normal pattern.
  • Atrial fibrillation is the most common type of chronic arrhythmia. In itself, it is not a major cause of death, but it is linked to an increased risk of heart failure and stroke. AF develops when a disturbance in the electrical signals causes the atrial chambers of the heart to quiver rather than pump correctly. This quivering at times causes the formation of blood pools inside the atrium which may form clots. These blood clots can cause a stroke if they break off, travel through the body, and block flow to the brain. AF is associated with coronary heart disease, hypertension, rheumatic heart disease or hyperthyroidism, and requires treatment alongside these conditions. The method of cardiac rhythm management depends firstly on whether or not the affected person is stable or unstable.
  • Medications are generally used to prevent and/or manage arrhythmia.
  • Class IA Class IA -Quinidine, Procainamide, Disopyramide; Class IB- Lidocaine, Tocainide, Mexiletine; Class IC- Encainide, Flecainide; Beta-Adrenergic Blockers (Class ll)-Propranolol, Acebutolol, Esmolol Sotalol; Drugs that Prolong Repolarization (Class III)- Dronedarone, Amiodarone; Calcium Channel Blockers (Class IV)- Verapamil, Diltiazem, Mebefradil; Miscellaneous- Adenosine, Digoxin.
  • Dronedarone hydrochloride (Multaq®; Sanofi-Aventis) was approved to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age > 70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter > 50 mm or left ventricular ejection fraction [LVEF] ⁇ 40%), who are in sinus rhythm or who will be cardioverted).
  • AF paroxysmal or persistent atrial fibrillation
  • AFL atrial flutter
  • LVEF left atrial flutter
  • US5223510 assigned to Sanofi Aventis discloses the product dronedarone.
  • therapeutic composition containing the compounds of the invention can be made using substances like lactose, starches, polyvinylpyrrolidone etc.
  • the patent discloses only one example of a capsule containing the compound of the invention and starches.
  • US7323493 assigned to Sanofi Aventis relates to a solid pharmaceutical composition for oral administration characterized in that it comprises a benzofuran derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable salts thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients.
  • solubility of dronedarone hydrochloride at room temperature is pH dependent, with dronedarone showing maximum solubility around pH values of 3 to 5 (about 1 to 2 mg/ml), but very low solubility at pH values of about 6 to 7 (10 mcg/ml).
  • the aqueous solution of dronedarone hydrochloride at pH 4 if diluted with a buffer to pH 7, dronedarone hydrochloride precipitates at the pH of about 6.7.
  • US 2008/01 39645 filed by Sanofi Aventis relates to a solid pharmaceutical composition for oral administration characterized in that it comprises a benzofuran derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable salts thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients.
  • US 2007/0243257 filed by Sanofi Aventis relates to a solid pharmaceutical composition
  • said pharmaceutically acceptable polymer matrix comprises a blend of (i) polydextrose, in the form of a continuous polydextrose phase, in order to promote the disintegration of the composition in an aqueous medium, and (ii) at least one polymer other than polydextrose, in the form of a continuous phase of this polymer, whereby the polydextrose is in a concentration of at least 20 wt % and the at least one polymer other than polydextrose is in a concentration of at least 20 wt % in relation to the total weight of said pharmaceutically acceptable polymer matrix.
  • US5985915 assigned to Sanofi discloses pharmaceutical formulation containing benzofuran derivatives and pharmaceutically acceptable ingredients.
  • the only example disclosed in the patent is a gelatine capsule containing a very low dose of dronedarone.
  • WO2010015939 filed by Sanofi Aventis discloses a method for prevention of stroke or ischemia using dronedarone.
  • the patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant.
  • WO 201 1 /1 35581 filed by Cadila Healthcare 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 or making such compositions.
  • WO 201 1 /1 35582 filed by Cadila Healthcare relates to a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants.
  • One embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient.
  • the formulation is a tablet formulation.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein dronedarone is co-milled with one or more pharmaceutically acceptable excipients
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein at least 90% of dronedarone with one or more pharmaceutically acceptable excipients has a particle size of less than about 15 microns.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients comprise solubility enhancer.
  • solubility enhancer is ionic surfactant.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone, ionic surfactant as solubility enhancer and one or more pharmaceutically acceptable excipient.
  • the formulation is a tablet formulation.
  • Another embodiment discloses a process for the preparation of a co-milled formulation of dronedarone comprising the steps of co-milling dronedarone and one or more pharmaceutically acceptable excipients.
  • Fig. 1 shows the release profiles of dronedarone for examples 1 , 2, 3 and Multaq® according to measurements under the USP basket method of 100 rpm in 1000 ml phosphate buffer at pH 4.5 at 37°C.
  • the invention relates to a co-milled formulation of dronedarone comprising dronedarone or pharmaceutically acceptable salts, esters, metabolites, prodrugs or enantiomers thereof and one or more pharmaceutically acceptable excipient.
  • formulation or “composition” as used herein refers to the drug with pharmaceutically acceptable excipients.
  • dronedarone would include all forms of dronedarone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof.
  • the most preferred form is dronedarone hydrochloride.
  • the co-milled formulation of the present invention may be in the form of tablets (single layered tablets, multilayered tablets, mini tablets, caplets, matrix tablets, and tablet within a tablet), pellets, beads, granules, spheroids, particles, compact, powders, tablets in capsules, microspheres, matrix formulations, and capsules.
  • the formulation is a tablet.
  • the co-milled formulation of the present invention may be immediate release formulation, orally disintegrating formulation, controlled release formulation, prolonged release formulation, timed release formulation, modified release formulation, site specific formulation, sustained release formulation, extended release formulation, slow release formulation, orally disintegrating extended release formulation, pulsatile release formulation, delayed release formulation, osmotic dosage form, bioadhesive formulation, gastroretentive formulation and other such dosage forms.
  • the formulation is immediate release formulation.
  • co-milling means milling a combination, e.g. a mixture of more than one solid compound. Co-milling reduces the particulate size of the active ingredient and of the excipient.
  • Co-milled dronedarone refers to pre-blending or co-milling of dronedarone with one or more pharmaceutically acceptable excipients. Preferably the pre-blending or co-milling is carried out with mannitol and polyvinylpyrrolidone.
  • the invention provides a process for preparing co-milled dronedarone wherein at least 90% of dronedarone co-milled with pharmaceutically acceptable excipients has a particle size of less than about 15 microns. Processing dronedarone to bring the particle size within a particular narrow range can also enhance manufacturing capability, allowing the preparation of pharmaceutical compositions that exhibit an improved bioavailability of dronedarone.
  • "Co-milled blend” refers to dronedarone co-milled with pharmaceutically acceptable excipients in powder or granular form comprised of a plurality of discrete particles, or individual units of mass.
  • the individual particles of the co-milled blend of the present invention can be regular-shaped, or they can have an irregular shape. When the particles have an irregular shape, nominal size of a particle refers to the dimension of the so-called equivalent sphere, a concept known in the field of particle size analysis.
  • the individual particles of a sample or aliquot of the co-milled blend of the present invention are not of uniform size. Rather, a sample or aliquot of the co-milled blend of the present invention is comprised of particles of different sizes that can be size- classified or distributed in an array of discrete, adjacent intervals of particle size. If the size of the intervals is small enough, the array of particle sized approaches a continuum of particle sizes. This collection of discrete particle size intervals together with their population is referred to as the particle size distribution (PSD).
  • PSD particle size distribution
  • Measurement and characterization of particle size distributions is known in the art. It is possible to compare samples of co-milled blend on the basis of individual points on a cumulative particle size distribution curve.
  • the number "X” represents the percentage (number, volume, or weight) of particles in the population having a nominal size up to and including "Y”.
  • the d (O.X) measurement depicts a volume average.
  • pharmaceutically-acceptable excipients includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of dronedarone.
  • a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient.
  • the formulation is a tablet formulation.
  • a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein dronedarone is co-milled with one or more pharmaceutically acceptable excipients
  • the co-milled formulation comprising dronedarone may further contain one or more pharmaceutically acceptable excipient such as binder; diluent; lubricant; disintegrating agent; glidant; stabilizer; solubility enhancers; and osmotic agent.
  • pharmaceutically acceptable excipient such as binder; diluent; lubricant; disintegrating agent; glidant; stabilizer; solubility enhancers; and osmotic agent.
  • binder examples include, potato starch; pregelatinized starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose and sodium carboxy methyl cellulose; hydroxypropyl Starch, polymethacrylates; carbomers; natural gums such as acacia, alginic acid and guar gum; lactose
  • diluent includes microcrystalline cellulose; lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose; dibasic or tribasic calcium phosphate; saccharides; confectioner's sugar; compressible sugar; sugar spheres; dextrates; dextrin; dextrose; fructose; maltose; lactitol; maltodextrin; mannitol; sucrose; glyceryl palmitostearate; semithicone; Magnesium aluminum silicate; starch; pregelatinized starch; maltitol; xylitol; erythritol; isomalt; sorbitol; polymethacrylates; talc; trehalose; ammonium alginate; calcium carbonate; ethyl cellulose; magnesium carbonate; magnesium oxide and calcium sulphate.
  • the disintegrating agent includes povidone, low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium starch glucolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate ; colloidal silicon dioxide.
  • the lubricant includes Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; Glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; Octyldodecanol; Sodium stearyl fumarate and colloidal silica.
  • Suitable stabilizer includes naturally occurring as well as synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; organic acids like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodium cholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate and sodium taurocholate; saturated and unsaturated fatty acids or fatty alcohols; ethoxylated fatty acids or fatty alcohols and their esters and ethers; alkylaryl-polyether alcohols such as esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglycerides; synthetic biodegradable polymers like block co-polymers of polyoxyethylene and polyoxypropyleneoxide; ethoxylated sorbitanesters or sorbitanethers; amino acids, polypeptides
  • the glidant includes magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogel.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients comprise solubility enhancer.
  • solubility enhancer is ionic surfactant.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone, ionic surfactant as solubility enhancer and one or more pharmaceutically acceptable excipient.
  • the formulation is a tablet formulation.
  • the solubility enhancer includes buffers like citrate, phosphate buffers etc.; cosolvents like ethanol, Polethylene glycol, poly vinyl pyrrolidone, co-povidone etc; surfactants; bile salts and complexants like cyclodextrins & its derivatives etc, Phospholipids, lecithin, casein, tragacanth etc. If surfactant is used as solubility enhancer in the formulation of dronedarone then it does not comprise of non-ionic surfactant.
  • Surfactant which may be used includes ionic surfactant which is classified as anionic or cationic.
  • Anionic surfactants may be selected from AlkyI sulfates: ammonium lauryl sulfate, sodium lauryl sulfate (SDS, sodium dodecyl sulfate, another name for the compound);Alkyl ether sulfates: sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), sodium myreth sulfate; Sulfonates; Docusates: dioctyl sodium sulfosuccinate; Sulfonate fluorosurfactants: perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate; AlkyI benzene sulfonates; Phosphates: AlkyI aryl ether phosphate AlkyI ether phosphate; Carboxylates; AlkyI carboxylates: Fatty acid salts (soaps): sodium stearate; Sodium la
  • Cationic surfactants may be selected from: based on pH-dependent primary, secondary or tertiary amines: primary amines become positively charged at pH ⁇ 1 0, secondary amines become charged at pH ⁇ 4; Octenidine dihydrochloride; Permanently charged quaternary ammonium cation; Alkyltrimethylammonium salts: cetyl trimethylammonium bromide (CTAB) a.k.a.
  • CTAC cetyl trimethylammonium chloride
  • CPC Cetylpyridinium chloride
  • POEA Polyethoxylated tallow amine
  • BAC Benzalkonium chloride
  • BZT Benzethonium chloride
  • DODAB Dioctadecyldimethylammonium bromide
  • the preferred ionic surfactant includes docusate sodium or sodium lauryl sulfate
  • the co-milled formulation may further comprise of coating.
  • the coating may be functional or nonfunctional coating.
  • the term "functional coating” as used herein means the coating that modifies the release of the formulation.
  • the pore forming agent may be polymeric or non polymeric in nature. Any water soluble material present in the coating which dissolves and forms pores in the coating layer may act as pore forming agents. Pore forming agents may be selected form of potassium salts such as potassium chloride, sodium salts as sodium chloride, calcium salts, magnesium salts, amino acids, weak acids, carbohydrates such as sucrose; mannitol; sorbitol, lactose (anhydrous, monohydrate, spraydried), polymers with amino and/or acid functions or polyvinyl pyrrolidine. Examples are aspargine, glutamine, leucin, neroleucine, meglumine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide.
  • Plasticizer include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoct
  • the formulation may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous / nonaqueous solvents), melt granulation, solid dispersion, direct compression, double compression, extrusion spheronization, layering, high shear mixture granulation, fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like.
  • Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction.
  • the milling of the granules may be carried out according to conventional milling methods, which includes jet milling, rolling milling, hammer milling, centrifugal-impact milling and sieving pebble milling, cutter milling or use of a mortar and pestle.
  • Another embodiment discloses a process for the preparation of a co-milled formulation of dronedarone comprising the steps of co-milling dronedarone and one or more pharmaceutically acceptable excipients.
  • Co-milling of dronedarone is carried out by co-milling dronedarone with pharmaceutically acceptable excipients.
  • the co-milling process of the present invention may be extended such that some or all of one or more aforementioned pharmaceutically acceptable excipients are blended with dronedarone, prior to co- milling to enhance the formulation properties of dronedarone, for instance processability and improved dissolution compared to non-co-milled formulation.
  • the pharmaceutically acceptable excipients are selected from binder, disintegrating agent, diluent, lubricant, glidant, solubility enhancer, stabilizer and osmotic agent.
  • Dronedarone, mannitol and polyvinyl pyrrolidone may optionally contain an ionic surfactant as solubility enhancer.
  • the solubility enhancer may optionally be added to the co-milled dronedarone.
  • Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein at least 90% of dronedarone with one or more pharmaceutically acceptable excipients has a particle size of less than about 15 microns.
  • the solvent which may be used for manufacturing the formulation may be aqueous, non-aqueous or combination thereof.
  • the coating operation may be conducted in standard equipment such as a fluid bed coater, a wurster coater or a rotary bed coater.
  • the coating may be aqueous, nonaqueous or combination of the two.
  • step I The weighed quantity of Dronedarone HCI, mannitol and polyvinyl pyrrolidone K-30 sifted through 40 # SS Sieve and passed through air jet mill.
  • II. The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes.
  • step I II Polyvinylpyrrolidone K-30 and docusate sodium are dissolved in purified water and used to granulate the blend of step I I. IV.
  • the wet granules of step I II dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
  • step IV The dried granules of step IV are passed through 20 # SS Sieve.
  • VI The extra granular quantity of sodium starch glycolate, aerosil and talc is passed through 40 # SS sieve and mixed well with granules of step V for 10 minutes.
  • step VI The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for 2 minutes.
  • step VI I The blend of step VI I is compressed in to a tablet using 1 9 * 8.5 mm capsule- shaped punch using suitable physical parameters and coated with film coating solution.
  • step I The weighed quantity of Dronedarone HCI, mannitol, sodium lauryl sulfate and polyvinyl pyrrolidone were sifted through 40 # SS Sieve and passed through air jet mill.
  • step I The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes.
  • step III HPMC E5 is dissolved in in purified water and used to granulate the blend of step II.
  • step III The wet granules of step III are dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
  • step IV The dried granules of step IV are passed through 20 # SS Sieve.
  • step VI The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for 2 minutes.
  • step I The weighed quantity of dronedarone HCI, mannitol and polyvinyl pyrrolidone K-30 were sifted through 40 # SS Sieve.
  • step I The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes.
  • step III Polyvinylpyrrolidone K-30 and docusate sodium are dissolved in purified water and used to granulate the blend of step III.
  • IV. The wet granules of step IV are dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
  • step VI The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for mix for 2 minutes.
  • step VII The blend of step VII is compressed in to a tablet using 19 * 8.5 mm capsule-shaped punch using suitable physical parameters and coated with film coating solution.
  • Example 1 and 2 are co-milled formulations of dronedarone while example 3 in non-co-milled dronedarone formulation.
  • Table 1 Drug Release Profile
  • Results of the particle size data are as indicated in Table 2 and 3 below: Table 2: Results of particle size data of dronedarone with excipients

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Abstract

The present invention relates to a co-milled formulation comprising dronedarone and one or more pharmaceutically acceptable excipients. The invention also relates to process for making such compositions.

Description

CO-MILLED FORMULATION OF DRONEDARONE
FIELD OF THE INVENTION:
The present invention relates to a co-milled formulation comprising dronedarone or pharmaceutically acceptable salts, esters, metabolites, prodrugs or enantiomers thereof and pharmaceutically acceptable ingredients. BACKGROUND OF THE INVENTION:
Cardiac arrhythmias are disturbances to the natural rhythm of the heart caused due to abnormal electric activity in the heart. The heart has a 'pacemaker', called the sinus node, in the atrium of the right hand side of the heart that generates electrical impulses. These are transmitted through specialized conductive tissues to the muscles of the right and left ventricles, where they cause the muscular contractions that pump blood around the body. Arrhythmias can be life-threatening medical emergencies which can result in cardiac arrest and sudden death.
The normal beating of the heart ranges between 60 and 100 beats per minute under resting conditions. Arrhythmias take the form of slowing down (bradycardia) or speeding up (tachycardia) of the rate outside these limits, or of the insertion or deletion of beats from the normal pattern.
Atrial fibrillation (AF) is the most common type of chronic arrhythmia. In itself, it is not a major cause of death, but it is linked to an increased risk of heart failure and stroke. AF develops when a disturbance in the electrical signals causes the atrial chambers of the heart to quiver rather than pump correctly. This quivering at times causes the formation of blood pools inside the atrium which may form clots. These blood clots can cause a stroke if they break off, travel through the body, and block flow to the brain. AF is associated with coronary heart disease, hypertension, rheumatic heart disease or hyperthyroidism, and requires treatment alongside these conditions. The method of cardiac rhythm management depends firstly on whether or not the affected person is stable or unstable. When an arrhythmia is serious, urgent treatment may be required to restore a normal rhythm. This may include: electrical "shock" therapy (defibrillation or cardioversion), or implanting a temporary pacemaker. Medications are generally used to prevent and/or manage arrhythmia. There are many classes of antiarrhythmic medications, with different mechanisms of action which include Sodium Channel Blockers (Class I) e.g. Class IA -Quinidine, Procainamide, Disopyramide; Class IB- Lidocaine, Tocainide, Mexiletine; Class IC- Encainide, Flecainide; Beta-Adrenergic Blockers (Class ll)-Propranolol, Acebutolol, Esmolol Sotalol; Drugs that Prolong Repolarization (Class III)- Dronedarone, Amiodarone; Calcium Channel Blockers (Class IV)- Verapamil, Diltiazem, Mebefradil; Miscellaneous- Adenosine, Digoxin.
Dronedarone hydrochloride is N-{2-butyl-3-[4-(3-dibutylaminopropoxy) benzoyl] benzofuran-5-yl} methane sulfonamide, hydrochloride. Dronedarone hydrochloride is freely soluble in methylene chloride and methanol, and insoluble in water.
Figure imgf000003_0001
The effects of dronedarone most likely result from its electrophysiological properties belonging to all four Vaughan-Williams classes. Dronedarone is a multichannel blocker inhibiting the potassium currents (including IK (Ach), IKur, IKr, IKs) and thus prolonging cardiac action potential and refractory periods (Class II I). It also inhibits the sodium currents (Class lb) and the calcium currents (Class IV). It non- competitively antagonizes adrenergic activities (Class I I). Dronedarone works by altering currents passing through potassium, sodium, and calcium channels, thereby prolonging conduction in the heart. This helps maintain a regular heart rhythm or sinus rhythm and slows the heart rate.
The available dosage for dronedarone is 400 mg oral tablet to be administered twice a day with meals. Dronedarone hydrochloride (Multaq®; Sanofi-Aventis) was approved to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age > 70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter > 50 mm or left ventricular ejection fraction [LVEF] < 40%), who are in sinus rhythm or who will be cardioverted). Dronedarone is also found to be useful in prevention of stroke or transient ischemic attack, prevention of permanent atrial fibrillation, prevention of cardioversion, regulating potassium levels in blood, for prevention of cardiac arrhythmia and increased creatinine level, and reducing death rate after infarction. The primary advantage of dronedarone is its comparatively lower side- effect profile vis-a-vis amiodarone.
There are number of prior arts which disclose formulations comprising dronedarone.
US5223510 assigned to Sanofi Aventis discloses the product dronedarone. The patent mentions that therapeutic composition containing the compounds of the invention can be made using substances like lactose, starches, polyvinylpyrrolidone etc. The patent discloses only one example of a capsule containing the compound of the invention and starches. US7323493 assigned to Sanofi Aventis relates to a solid pharmaceutical composition for oral administration characterized in that it comprises a benzofuran derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable salts thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients. Further, it discloses that solubility of dronedarone hydrochloride at room temperature is pH dependent, with dronedarone showing maximum solubility around pH values of 3 to 5 (about 1 to 2 mg/ml), but very low solubility at pH values of about 6 to 7 (10 mcg/ml). The aqueous solution of dronedarone hydrochloride at pH 4 if diluted with a buffer to pH 7, dronedarone hydrochloride precipitates at the pH of about 6.7. Since these solubility conditions are similar to those recorded in the gastrointestinal tract, it can be assumed that dronedarone hydrochloride risks being subjected, in the stomach, to acidic conditions which are favorable to its solubilization, but, on the other hand, risks encountering a medium of pH 6 to 7 once it enters the intestine, in which it will precipitate. This behavior in intestinal medium explains the low bio-availability of dronedarone hydrochloride in vivo and the differences observed after administration with or without food, since it has been observed that the bio-availability of dronedarone hydrochloride in dogs and in man is increased after the intake of food, in particular fats, which can greatly modify the precipitation kinetics of this active principle and also help to place it in emulsion form.
US 2008/01 39645 filed by Sanofi Aventis relates to a solid pharmaceutical composition for oral administration characterized in that it comprises a benzofuran derivative with antiarrhythmic activity, or one of the pharmaceutically acceptable salts thereof, as an active principle, and a pharmaceutically acceptable nonionic hydrophilic surfactant optionally in combination with one or more pharmaceutical excipients. US 2007/0243257 filed by Sanofi Aventis relates to a solid pharmaceutical composition comprising a solid dispersion containing at least one active principle (Benzofuran derivative) and a pharmaceutically acceptable polymer matrix, characterized in that said pharmaceutically acceptable polymer matrix comprises a blend of (i) polydextrose, in the form of a continuous polydextrose phase, in order to promote the disintegration of the composition in an aqueous medium, and (ii) at least one polymer other than polydextrose, in the form of a continuous phase of this polymer, whereby the polydextrose is in a concentration of at least 20 wt % and the at least one polymer other than polydextrose is in a concentration of at least 20 wt % in relation to the total weight of said pharmaceutically acceptable polymer matrix.
US5985915 assigned to Sanofi discloses pharmaceutical formulation containing benzofuran derivatives and pharmaceutically acceptable ingredients. The only example disclosed in the patent is a gelatine capsule containing a very low dose of dronedarone.
WO2010015939 filed by Sanofi Aventis discloses a method for prevention of stroke or ischemia using dronedarone. The patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant.
WO2009150535 filed by Sanofi Aventis discloses a method for prevention of atrial fibrillation using dronedarone. The patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant. WO2009150534 filed by Sanofi Aventis discloses a method for prevention of cardioversion using dronedarone. The patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant. WO2009144551 filed by Sanofi Aventis discloses a method of using dronedarone for regulating potassium levels in blood. The patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant. US 2010/0048694 filed by Sanofi Aventis discloses a method of using dronedarone for the prevention of cardiovascular hospitalization or mortality. The patent discloses unitary dosage form of dronedarone along with poloxamer as surfactant.
WO 201 1 /1 35581 filed by Cadila Healthcare 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 or making such compositions.
WO 201 1 /1 35582 filed by Cadila Healthcare relates to a pharmaceutical composition comprising dronedarone or pharmaceutically acceptable salts thereof and one or more surfactant/s other than nonionic hydrophilic surfactants.
Although number of approaches have been disclosed in the prior art for preparing a formulation comprising dronedarone none describe a surfactant free formulation of dronedarone. The prior art suggests that solubility of dronedarone hydrochloride is pH dependent, with dronedarone showing maximum solubility around pH values of 3 to 5, but very low solubility at pH about 6 to 7 where it tends to precipitate. Similarly in the gastrointestinal tract, it can be assumed that dronedarone hydrochloride solubilizes in the acidic conditions of stomach but risks precipitation at intestinal pH, this property of dronedarone hydrochloride is responsible for its low bioavailability in vivo. Prior art further suggests the use of nonionic surfactants to overcome the solubility problem of dronedarone and improve its oral bioavailability. In contrast, we have surprisingly found that the co-milled formulation of dronedarone as disclosed herein showed dissolution properties comparable to the marketed formulations containing nonionic surfactant (Multaq®, Sanofi Aventis). SUMMARY OF THE INVENTION:
One embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient. Preferably the formulation is a tablet formulation. Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein dronedarone is co-milled with one or more pharmaceutically acceptable excipients
Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein at least 90% of dronedarone with one or more pharmaceutically acceptable excipients has a particle size of less than about 15 microns.
Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients comprise solubility enhancer. Preferably solubility enhancer is ionic surfactant.
Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone, ionic surfactant as solubility enhancer and one or more pharmaceutically acceptable excipient. Preferably the formulation is a tablet formulation. Another embodiment discloses a process for the preparation of a co-milled formulation of dronedarone comprising the steps of co-milling dronedarone and one or more pharmaceutically acceptable excipients. BRIEF DESCRIPTION OF THE DRAWINGS:
Fig. 1 shows the release profiles of dronedarone for examples 1 , 2, 3 and Multaq® according to measurements under the USP basket method of 100 rpm in 1000 ml phosphate buffer at pH 4.5 at 37°C. DETAILED DESCRIPTION OF THE INVENTION:
The invention relates to a co-milled formulation of dronedarone comprising dronedarone or pharmaceutically acceptable salts, esters, metabolites, prodrugs or enantiomers thereof and one or more pharmaceutically acceptable excipient. The term "formulation" or "composition" as used herein refers to the drug with pharmaceutically acceptable excipients.
As used herein the term dronedarone would include all forms of dronedarone or pharmaceutically acceptable salts, esters, solvates, hydrates, metabolites, prodrugs or isomers thereof. The most preferred form is dronedarone hydrochloride.
The co-milled formulation of the present invention may be in the form of tablets (single layered tablets, multilayered tablets, mini tablets, caplets, matrix tablets, and tablet within a tablet), pellets, beads, granules, spheroids, particles, compact, powders, tablets in capsules, microspheres, matrix formulations, and capsules. Preferably the formulation is a tablet.
The co-milled formulation of the present invention may be immediate release formulation, orally disintegrating formulation, controlled release formulation, prolonged release formulation, timed release formulation, modified release formulation, site specific formulation, sustained release formulation, extended release formulation, slow release formulation, orally disintegrating extended release formulation, pulsatile release formulation, delayed release formulation, osmotic dosage form, bioadhesive formulation, gastroretentive formulation and other such dosage forms. Preferably the formulation is immediate release formulation.
The term "co-milling" means milling a combination, e.g. a mixture of more than one solid compound. Co-milling reduces the particulate size of the active ingredient and of the excipient. Co-milled dronedarone refers to pre-blending or co-milling of dronedarone with one or more pharmaceutically acceptable excipients. Preferably the pre-blending or co-milling is carried out with mannitol and polyvinylpyrrolidone.
The invention provides a process for preparing co-milled dronedarone wherein at least 90% of dronedarone co-milled with pharmaceutically acceptable excipients has a particle size of less than about 15 microns. Processing dronedarone to bring the particle size within a particular narrow range can also enhance manufacturing capability, allowing the preparation of pharmaceutical compositions that exhibit an improved bioavailability of dronedarone. "Co-milled blend" refers to dronedarone co-milled with pharmaceutically acceptable excipients in powder or granular form comprised of a plurality of discrete particles, or individual units of mass. The individual particles of the co-milled blend of the present invention can be regular-shaped, or they can have an irregular shape. When the particles have an irregular shape, nominal size of a particle refers to the dimension of the so-called equivalent sphere, a concept known in the field of particle size analysis.
The individual particles of a sample or aliquot of the co-milled blend of the present invention are not of uniform size. Rather, a sample or aliquot of the co-milled blend of the present invention is comprised of particles of different sizes that can be size- classified or distributed in an array of discrete, adjacent intervals of particle size. If the size of the intervals is small enough, the array of particle sized approaches a continuum of particle sizes. This collection of discrete particle size intervals together with their population is referred to as the particle size distribution (PSD).
Measurement and characterization of particle size distributions is known in the art. It is possible to compare samples of co-milled blend on the basis of individual points on a cumulative particle size distribution curve. The measurements are represented as d (O.X) =Y (where X and Y are Arabic numerals), each "d" describing an individual point on a cumulative PSD curve. The number "X" represents the percentage (number, volume, or weight) of particles in the population having a nominal size up to and including "Y". Thus, d (0.9) =15 μηη is characteristic of a PSD in which 90% (number, volume, or weight) of the particles in a population have a nominal size of about 15 μηη or less (at least some particles having a nominal dimension of 15 μηη) and so forth. When PSD is determined by the well-known laser- diffraction method described herein, the d (O.X) measurement depicts a volume average.
The skilled artisan knows that the results of PSD determination by one technique can be correlated with that from another technique on an empirical basis by routine experimentation.
The term "pharmaceutically-acceptable excipients" as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of dronedarone. One embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient. Preferably the formulation is a tablet formulation. Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein dronedarone is co-milled with one or more pharmaceutically acceptable excipients
The co-milled formulation comprising dronedarone may further contain one or more pharmaceutically acceptable excipient such as binder; diluent; lubricant; disintegrating agent; glidant; stabilizer; solubility enhancers; and osmotic agent.
Examples of binder includes, potato starch; pregelatinized starch; modified starch; gelatin; wheat starch; corn starch; celluloses such as methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose and sodium carboxy methyl cellulose; hydroxypropyl Starch, polymethacrylates; carbomers; natural gums such as acacia, alginic acid and guar gum; lactose
(anhydrous, monohydrate, spraydried); liquid glucose; dextrin; sodium alginate; kaolin; povidone; syrup; polyethylene oxide; polyvinyl pyrrolidone; poly vinyl alcohol; poly-N-vinyl amide; polyethylene glycol; sucrose; polydextrose; gelatin; poly propylene glycol; tragacanth; glyceryl behenate; hydrogenated vegetable oil; zein; castor oil; paraffin; higher aliphatic alcohols; higher aliphatic acids; long chain fatty acids; fatty acid esters; agar; chitosan; maltodextrin; magnesium aluminum silicate; inulin and wax-like materials such as fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic acid; copovidone; dextrates, sunflower oil and stearyl alcohol.
Examples of diluent includes microcrystalline cellulose; lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose; dibasic or tribasic calcium phosphate; saccharides; confectioner's sugar; compressible sugar; sugar spheres; dextrates; dextrin; dextrose; fructose; maltose; lactitol; maltodextrin; mannitol; sucrose; glyceryl palmitostearate; semithicone; Magnesium aluminum silicate; starch; pregelatinized starch; maltitol; xylitol; erythritol; isomalt; sorbitol; polymethacrylates; talc; trehalose; ammonium alginate; calcium carbonate; ethyl cellulose; magnesium carbonate; magnesium oxide and calcium sulphate.
The disintegrating agent includes povidone, low-substituted hydroxypropyl cellulose; cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethylcellulose; hydroxypropyl starch; sodium starch glycolate; sodium starch glucolate; sodium carboxymethylcellulose; carboxymethyl cellulose calcium; sodium carboxymethyl starch; ion-exchange resins such as polacrillin potassium; microcrystalline cellulose; starches and pregelatinized starch; formalin-casein; clays such as bentonite or veegum; guar gum; celluloses or cellulose derivatives; sodium alginate; calcium alginate; alginic acid; chitosan; magnesium aluminum silicate ; colloidal silicon dioxide.
The lubricant includes Mg, Al or Ca or Zn stearate; polyethylene glycol; polyvinyl alcohol; glyceryl behenate; glyceryl monostearate; Glyceryl palmitostearate; potassium benzoate; sodium benzoate; mineral oil; sodium stearyl fumarate; palmitic acid, myristic acid; stearic acid; hydrogenated vegetable oil; hydrogenated castor oil; talc; hydrogenated soybean oil; stearyl alcohol; leucine; sodium lauryl sulfate; ethylene oxide polymers; poloxamer; Octyldodecanol; Sodium stearyl fumarate and colloidal silica.
Suitable stabilizer includes naturally occurring as well as synthetic phospholipids, their hydrogenated derivatives and mixtures thereof; organic acids like acetic acid, tartaric acid, citric acid, fumaric acid, lactic acid, and mixtures thereof sphingolipids and glycosphingolipids; physiological bile salts such as sodium cholate, sodium dehydrocholate, sodium deoxycholate, sodium glycocholate and sodium taurocholate; saturated and unsaturated fatty acids or fatty alcohols; ethoxylated fatty acids or fatty alcohols and their esters and ethers; alkylaryl-polyether alcohols such as esters and ethers of sugars or sugar alcohols with fatty acids or fatty alcohols; acetylated or ethoxylated mono- and diglycerides; synthetic biodegradable polymers like block co-polymers of polyoxyethylene and polyoxypropyleneoxide; ethoxylated sorbitanesters or sorbitanethers; amino acids, polypeptides and proteins such as gelatine and albumin; or combination thereof.
The glidant includes magnesium trisilicate; powdered cellulose; starch; talc; tribasic calcium phosphate; calcium silicate; magnesium silicate; magnesium trisilicate; colloidal silicon dioxide; and silicon hydrogel. Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients wherein the pharmaceutically acceptable excipients comprise solubility enhancer. Preferably solubility enhancer is ionic surfactant.
Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone, ionic surfactant as solubility enhancer and one or more pharmaceutically acceptable excipient. Preferably the formulation is a tablet formulation.
The solubility enhancer includes buffers like citrate, phosphate buffers etc.; cosolvents like ethanol, Polethylene glycol, poly vinyl pyrrolidone, co-povidone etc; surfactants; bile salts and complexants like cyclodextrins & its derivatives etc, Phospholipids, lecithin, casein, tragacanth etc. If surfactant is used as solubility enhancer in the formulation of dronedarone then it does not comprise of non-ionic surfactant.
Surfactant which may be used includes ionic surfactant which is classified as anionic or cationic.
Anionic surfactants may be selected from AlkyI sulfates: ammonium lauryl sulfate, sodium lauryl sulfate (SDS, sodium dodecyl sulfate, another name for the compound);Alkyl ether sulfates: sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), sodium myreth sulfate; Sulfonates; Docusates: dioctyl sodium sulfosuccinate; Sulfonate fluorosurfactants: perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate; AlkyI benzene sulfonates; Phosphates: AlkyI aryl ether phosphate AlkyI ether phosphate; Carboxylates; AlkyI carboxylates: Fatty acid salts (soaps): sodium stearate; Sodium lauroyl sarcosinate; Carboxylate fluorosurfactants: perfluorononanoate, perfluorooctanoate (PFOA or PFO); and combinations thereof.
Cationic surfactants may be selected from: based on pH-dependent primary, secondary or tertiary amines: primary amines become positively charged at pH < 1 0, secondary amines become charged at pH < 4; Octenidine dihydrochloride; Permanently charged quaternary ammonium cation; Alkyltrimethylammonium salts: cetyl trimethylammonium bromide (CTAB) a.k.a. hexadecyl trimethyl ammonium bromide, cetyl trimethylammonium chloride (CTAC); Cetylpyridinium chloride (CPC); Polyethoxylated tallow amine (POEA); Benzalkonium chloride (BAC); Benzethonium chloride (BZT); 5-Bromo-5-nitro-1 ,3-dioxane; Dimethyldioctadecylammonium chloride; Dioctadecyldimethylammonium bromide (DODAB); Zwitterionic (amphoteric): based on primary, secondary or tertiary amines or quaternary ammonium cation with Sulfonates: CHAPS (3-[(3-
Cholamidopropyl)dimethylammonio]-1 -propanesulfonate); Sultaines: cocamidopropyl hydroxysultaine; Carboxylates; Amino acids;Betaines: cocamidopropyl betaine; Phosphates: lecithin; and combinations thereof.
The preferred ionic surfactant includes docusate sodium or sodium lauryl sulfate The co-milled formulation may further comprise of coating. The coating may be functional or nonfunctional coating. The term "functional coating" as used herein means the coating that modifies the release of the formulation.
The pharmaceutically acceptable excipient which may be added to the coating may include pore forming agents, lubricants, plasticizers and colorants.
The pore forming agent may be polymeric or non polymeric in nature. Any water soluble material present in the coating which dissolves and forms pores in the coating layer may act as pore forming agents. Pore forming agents may be selected form of potassium salts such as potassium chloride, sodium salts as sodium chloride, calcium salts, magnesium salts, amino acids, weak acids, carbohydrates such as sucrose; mannitol; sorbitol, lactose (anhydrous, monohydrate, spraydried), polymers with amino and/or acid functions or polyvinyl pyrrolidine. Examples are aspargine, glutamine, leucin, neroleucine, meglumine, isoleucine, magnesium citrate, magnesium phosphate, magnesium carbonate, magnesium hydroxide, magnesium oxide.
Plasticizer include for example acetylated monoglycerides; butyl phthalyl butyl glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl phthalyl ethyl glycolate; glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl phthalate; acetyl monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethyl hexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2- ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate.
The formulation may be manufactured by various methods known in the art such as by dry granulation, slugging, roller compaction, wet granulation (using aqueous / nonaqueous solvents), melt granulation, solid dispersion, direct compression, double compression, extrusion spheronization, layering, high shear mixture granulation, fluid bed granulation, spray drying, steam granulation, moisture activated dry granulation, moist granulation, thermal adhesion granulation, foam granulation and the like. Compaction of the blend into coprimate may be carried out using a slugging technique or roller compaction. The milling of the granules may be carried out according to conventional milling methods, which includes jet milling, rolling milling, hammer milling, centrifugal-impact milling and sieving pebble milling, cutter milling or use of a mortar and pestle.
Another embodiment discloses a process for the preparation of a co-milled formulation of dronedarone comprising the steps of co-milling dronedarone and one or more pharmaceutically acceptable excipients.
Co-milling of dronedarone is carried out by co-milling dronedarone with pharmaceutically acceptable excipients. The co-milling process of the present invention may be extended such that some or all of one or more aforementioned pharmaceutically acceptable excipients are blended with dronedarone, prior to co- milling to enhance the formulation properties of dronedarone, for instance processability and improved dissolution compared to non-co-milled formulation. Preferably the pharmaceutically acceptable excipients are selected from binder, disintegrating agent, diluent, lubricant, glidant, solubility enhancer, stabilizer and osmotic agent. More preferably co-milling of dronedarone is carried out by blending mannitol and polyvinyl pyrrolidone with dronedarone to achieve the desired particle size and improved dissolution profile. Dronedarone, mannitol and polyvinyl pyrrolidone may optionally contain an ionic surfactant as solubility enhancer. The solubility enhancer may optionally be added to the co-milled dronedarone.
Another embodiment discloses a co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipient wherein at least 90% of dronedarone with one or more pharmaceutically acceptable excipients has a particle size of less than about 15 microns.
The solvent which may be used for manufacturing the formulation may be aqueous, non-aqueous or combination thereof. The coating operation may be conducted in standard equipment such as a fluid bed coater, a wurster coater or a rotary bed coater. The coating may be aqueous, nonaqueous or combination of the two.
The invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims. The following Example illustrates the invention:
Example 1 :
Figure imgf000019_0001
Procedure:
I. The weighed quantity of Dronedarone HCI, mannitol and polyvinyl pyrrolidone K-30 sifted through 40 # SS Sieve and passed through air jet mill. II. The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes.
I II. Polyvinylpyrrolidone K-30 and docusate sodium are dissolved in purified water and used to granulate the blend of step I I. IV. The wet granules of step I II dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
V. The dried granules of step IV are passed through 20 # SS Sieve. VI. The extra granular quantity of sodium starch glycolate, aerosil and talc is passed through 40 # SS sieve and mixed well with granules of step V for 10 minutes.
VII. The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for 2 minutes. I II. The blend of step VI I is compressed in to a tablet using 1 9*8.5 mm capsule- shaped punch using suitable physical parameters and coated with film coating solution.
Example 2:
Figure imgf000021_0001
Procedure:
I. The weighed quantity of Dronedarone HCI, mannitol, sodium lauryl sulfate and polyvinyl pyrrolidone were sifted through 40 # SS Sieve and passed through air jet mill. I. The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes. III. HPMC E5 is dissolved in in purified water and used to granulate the blend of step II.
IV. The wet granules of step III are dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
V. The dried granules of step IV are passed through 20 # SS Sieve.
VI. The extra granular quantity of sodium starch glycolate and aerosil is passed through 40 # SS sieve and mixed well with granules of step V for 10 minutes.
VII. The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for 2 minutes.
VIII. The blend of step VII is compressed in to a tablet using 19*8.5 mm capsule-shaped punch using suitable physical parameters and coated with film coating solution.
Example 3:
Figure imgf000023_0001
Procedure:
I. The weighed quantity of dronedarone HCI, mannitol and polyvinyl pyrrolidone K-30 were sifted through 40 # SS Sieve. I. The blend of step I is loaded in rapid mixer granulator and dry mixed for 5 minutes. III. Polyvinylpyrrolidone K-30 and docusate sodium are dissolved in purified water and used to granulate the blend of step III. IV.The wet granules of step IV are dried in fluidized bed dryer at 60 °C inlet temperature till its LOD reaches between 1 .5-2.5% w/w at 60 °C up to constant weight.
V.The dried granules of step V are passed through 20 # SS Sieve. Vl.The extra granular quantity of sodium starch glycolate, aerosil and talc is passed through 40 # SS sieve and mixed well with granules of step V for 10 minutes.
VII. The blend of step VI is lubricated using magnesium stearate (passed through 60# SS Sieve) for mix for 2 minutes.
VIII. The blend of step VII is compressed in to a tablet using 19*8.5 mm capsule-shaped punch using suitable physical parameters and coated with film coating solution.
DISSOLUTION DATA:
A comparison of the dissolution profiles of the formulation prepared according to example 1 , 2, 3 and Multaq® was carried out in USP Paddle method of 75 RPM in 1000 ml phosphate buffer at pH 4.5 at 37°C. Example 1 and 2 are co-milled formulations of dronedarone while example 3 in non-co-milled dronedarone formulation. Table 1 : Drug Release Profile
Figure imgf000025_0001
SUMMARY OF PARTICLE SIZE DATA:
A comparison of the particle size data of the co-milled formulation of dronedarone was carried out in Malvern Master Sizer 2000.
Results of the particle size data are as indicated in Table 2 and 3 below: Table 2: Results of particle size data of dronedarone with excipients
Figure imgf000025_0002
Table 3: Results of particle size data of dronedarone with excipients
Figure imgf000026_0001

Claims

1 . A co-milled formulation of dronedarone comprising dronedarone and one or more pharmaceutically acceptable excipients.
2. The formulation of Claim 1 , wherein dronedarone is co-milled with one or more pharmaceutically acceptable excipients.
3. The formulation of Claim 2, wherein at least 90% of dronedarone co-milled with one or more pharmaceutically acceptable excipients has a particle size of less than about 15 microns.
4. The formulation of Claim 1 , wherein the pharmaceutically acceptable excipients comprises solubility enhancer.
5. The formulation of Claim 4, wherein the solubility enhancer is selected from buffer, ethanol, polyethylene glycol, poly vinyl pyrrolidone, co-povidone, cyclodextrin or its derivatives, surfactant, bile salt, phospholipid, pharmaceutically acceptable oil or triglyceride, lecithin, casein or tragacanth.
6. The formulation of Claim 5, wherein the solubility enhancer is ionic surfactant selected from alkyl sulfates, alkyl ether sulfates, sulfonates, alkyl benzene sulfonates, alkyl ether phosphate or alkyl carboxylates.
7. The formulation of Claim 6, wherein the ionic surfactant comprises docusate sodium or sodium lauryl sulfate.
8. A process for the preparation of a co-milled formulation of dronedarone comprising the step of co-milling dronedarone and one or more pharmaceutically acceptable excipients.
9. The process as claimed in Claim 8 wherein the one or more pharmaceutically acceptable excipient is selected from the group consisting of binder, disintegrating agent, diluent, lubricant, glidant, solubility enhancer, stabilizer and osmotic agent.
10. The process as claimed in Claim 9, wherein the solubility enhancer is selected from buffer, ethanol, polyethylene glycol, poly vinyl pyrrolidone, co-povidone, cyclodextrin or its derivatives, surfactant, bile salt, phospholipid, pharmaceutically acceptable oil or triglyceride, lecithin, casein or tragacanth.
1 1 . The process as claimed in Claim 9, wherein the binder is selected from potato starch, pregelatinized starch, modified starch, gelatin, wheat starch, corn starch, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, ethyl cellulose, sodium carboxy methyl cellulose, hydroxypropyl starch , polymethacrylates, carbomers, acacia, alginic acid, guar gum, lactose, liquid glucose, dextrin, sodium alginate, kaolin, povidone, polyethylene oxide, polyvinyl pyrrolidone, poly vinyl alcohol, poly-N-vinyl amide, polyethylene glycol, sucrose, polydextrose, gelatin, poly propylene glycol, tragacanth, glyceryl behenate, hydrogenated vegetable oil, zein, castor oil, paraffin, higher aliphatic alcohols, higher aliphatic acids, long chain fatty acids, fatty acid esters, agar, chitosan, maltodextrin, magnesium aluminum silicate, inulin, , fatty alcohols, fatty acid esters, fatty acid glycerides, hydrogenated fats, hydrocarbons, stearic acid, copovidone, dextrates, sunflower oil or stearyl alcohol.
12. The process as claimed in Claim 9, wherein the diluent is selected from microcrystalline cellulose, lactose, cellulose powdered, cellulose silicified, cellulose acetate, methyl cellulose, microcrystalline lactose, dibasic or tribasic calcium phosphate, saccharides, confectioner's sugar, compressible sugar, sugar spheres, dextrates, dextrin, dextrose, fructose, maltose, lactitol, maltodextrin, mannitol, sucrose, glyceryl palmitostearate, semithicone, magnesium aluminum silicate, starch, pregelatinized starch, maltitol, xylitol, erythritol, isomalt, sorbitol, polymethacrylates, talc, trehalose, ammonium alginate, calcium carbonate, ethyl cellulose, magnesium carbonate, magnesium oxide or calcium sulphate.
PCT/IB2012/054085 2011-08-12 2012-08-10 Co-milled formulation of dronedarone WO2013024411A1 (en)

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