GB2491380A - Pharmaceutical composition comprising dronedarone hydrochloride that exhibits a reduced food effect - Google Patents

Abstract

A pharmaceutical dosage form comprising dronedarone hydrochloride and a pharmaceutically acceptable carrier that comprises a phospholipid and/or an ionic surfactant. The said dosage form enhances bioavailability by improving the amount of dronedarone absorbed by the body under fasting conditions â i.e., is less affected by food intake. The composition is of use in the treatment of atrial fibrillation and atrial flutter.

Description

I

Improvements in or relating to organic compounds The invention relates to pharmaceutical compositions comprising dronedarone hydrochloride, in particular, compositions that do not exhibit a food effect when administered orally to a mammalian subject. Still more particularly, the invention relates to such compositions, which when administered orally to a mammalian subject are bioequivalcnt to a dronedarone formulation containing 400mg of dronedarone free base, such as the drug marketed under the trade name Multaq®.

A major problem in delivering many biologically active compounds to humans or animals concerns their poor absorption, which may be due their low solubility in aqueous media, poor mucous membrane permeability or both. These factors, alone or in combination, will adversely affect bioavailability, variability and efficacy of such compounds. Lipophilic compounds can have particular problems in this regard, as can compounds having a high molecular weight. Formulating such compounds presents a difficult challenge to the pharmaceutical industry from both technical and commercial perspectives. As a consequence, many compounds that possess promising pharmacological activity are abandoned in the late stages of development because of poor andlor erratic bioavailability.

A particular challenge is the development of carriers or vehicles that improves the bioavailability of lipophilic or high molecular weight compounds, which at the same time is efficient and non-toxic for oral administration and can be manufactured in a simple fashion as conventional dosage forms.

Pharmaceutically acceptable carriers are required to improve delivery and maximise performance of active compounds. A carrier must be compatible with biological systems and able to deliver an active compound in a desired manner. Above all, the components used in such carriers must be non-toxic and conform to specifications that give reproducible performance. An efficient drug carrier system may provide the key to unlocking the clinical potential of problematic compounds in drug discovery programmes.

Dronedarone is a benzofuran derivative, its chemical name is N-{2-butyl-3-[4-(3 -dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide. The compound, its pharmaceutically acceptable salts, and methods of making same are described in US5223510.

It is sold in its hydrochloride form under the brand name MULTAQ®. it is indicated to reduce the risk of cardiovascular hospitalisation in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), particularly those with a recent episode of AF/AFL and associated cardiovascular risk factors.

The recommended dosage of MULTAQ® is 400 mg (free base) administered twice daily to adults. MULTAQ® should be taken as one tablet with the morning meal and one tablet with the evening meal. Each tablet contains 426 rug of dronedarone HC1, which corresponds to 400 mg free base.

Dronedarone, in the form of its hydrochloride salt, is eharaeterised by low solubility in aqueous media and poor bioavailability. Furthermore, its bioavailability is affected by the intake of food. More specifically, the bioavailability of dronedarone hydrochloride without food is extremely low, i.e. about 4% and only increases to approximately 15% when it is administered with a high fat meal.

it is known that the absorption and bioavailability of a drug can be affected by a variety of is factors when administered orally. Such factors include the presence of food in the gastrointestinal tract. In general, the gastric residence time of a drug is significantly longer in fed subj ects than in fasted subjects. If the bioavailability of a drug is affected beyond a certain point due to the presence of food in the gastrointestinal tract, the drug substance is said to exhibit a food effect. The difference in the bioavailability between the fed and fasted state means that dronedarone HC1, and in particular the product Maltaq® can be said to exhibit a significant food effect.

Food effects raise serious concerns because of the potential for fluctuations in the extent of absorption of a drug into the bloodstream of a subject that depends on the time that is elapsed between administration of the drug and the subject's last meal.

US patent 7,323,493 describes an oral dosage form of dronedarone, which is claimed to exhibit a lower food effect than a so-called standard capsule formulation. This is achieved by employing, as part of the dosage form, a non-ionic bydrophilic surfactant, optionally in combination with one or more pharmaceutical exeipients. However, this document does not address the issue of a food effect and the applicant is unaware of any dosage forms currently sold or under development, which can be administered to a patient independently of the consideration of food.

The provision of a pharmaceutical composition comprising dronedarone hydrochloride, which is capable of providing an acceptable bioavailability independently of the fed or fasted state of a patient remains an unmet need.

The invention addresses shortcomings of the existing dronedarone formulations and provides pharmaceutical compositions comprising dronedarone hydrochloride having an acceptable pharmacokinetic profile when administered to a mammalian subject irrespective of whether the subject is in a fed or fasted state.

The invention provides a pharmaceutical composition, which when administered orally to a mammalian subject is at least bioequivalent to the composition that is commercially marketed under the trade name Multaq® in 400mg dose (based on dronedarone free base), when administered to a mammalian subject in both the fed and fasted states.

As used herein, the term "bioavailability" denotes the degree to which a drug becomes available to target tissue after administration orally to a mammalian subject.

Parameters often used in the measurement of bioavailability are Tmax, Cmax and AUC 04, which are well known in the art and which are more fully explained in guidelines given by the US Food and Drug Administration (US FDA) and European Medicines Agency (EMEA).

"Tmax" denotes the time to reach the maximal plasma concentration (Cmax) after administration; whereas AUC 1)4 denotes the area under the plasma concentration versus time curve from time 0 to time t, especially, AUC 024 is the area under the plasma concentration versus time curve from time 0 to time 24 hours, at steady state conditions.

In the present context, the term "improved bioavailability" is intended to mean that administration of a composition according to the invention will result in a bioavailability that is at least the same or greater compared to the bioavailability obtained after administration of a commercially available product containing dronedarone hydrochloride in the same amounts.

In a first aspect of the invention there is provided a pharmaceutical composition comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid and/or an ionic surfactant, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedaronc free base exhibits a pharmacokinetic profile characterised by an AUC24 that is substantially the same as Multaq® in the fed state, more particularly an AUC24 of about 500, still more particularly 350 to 650 ng.hr/ml.

in another aspect of the invention there is provided a pharmaceutical composition comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid or an ionic surfactant, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone free base exhibits a pharmacokinetic profile characterised by a Cmax that is substantially the same as Multaq® in the fed state, more particularly a Cmax of about 90, more particularly 70 to 120 ng/ml.

in another aspect of the invention there is provided a pharmaceutical composition comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid or an ionic surfactant, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedaronc free base exhibits a pharmacokinetic profile characterised by a Tmax that is substantially the same as Multaq® in the fed state, more particularly a Tmax of about 5, more particularly 3 to 7 hours.

in another aspect of the present invention there is provided a pharmaceutical composition comprising dronedaronc hydrochloride and a pharmaceutically acceptable carrier comprising a phospholipid andlor an ionic surfactant, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedaronc free base exhibits an AUC024 of about 500 ng.hr/ml, a Cmax of about 90 ng/ml and a Tmax of about S hours.

in another aspect of the invention the pharmaceutical composition herein above defined, when administered orally to a patient is biocquivalcnt to a commercially available dosage form of dronedaronc hydrochloride equivalent to 400mg base marketed under the brand name Multaq®.

As used herein, the terms "bioequivalent", "biocquivalence" or "bioequivalency denote a scientific basis on which generic and brand name drugs are compared with one another. it is an important concept relating to the regulatory acceptance of generic drug products, in the sense that for generic approval, a generic drug should be bioequivalent to a reference drug product.

Drugs are bioequivalent if they enter circulation at the same rate when given in similar doses under similar conditions. Parameters often used in bioequivalence studies are Tmax, Cmax and AUC04 as defined above.

Bioequivalency of two compositions (i.e. a generic product and a reference product) is established by a 90% Confidence Interval (CI) of between 0.80 and 1.25 for both Cmax and AUC under United States FDA regulatory guidelines, or a 90% CI for AUC of between 0.80 to 1.25 and a 90% CI for Cmax of between 0.70 to 1.43 under the European regulatory guidelines (EMEA). The difference between a bioequivalence parameter described above measured after oral administration to a mammal should be less than about 125% and more than about 80% with respect to AUC and less than about 143% and more than about 70% for Cmax.

At least one of these parameters may be applied in order to determine whether or not is bioequivalenee is established. More particularly, AUC and Cmax are examined in order to determine whether or not bioequivalence is established.

The term "confidence interval" refers to a statistical range with a specified probability that a given parameter lies within the range.

Confidence intervals represent a reasoned statement about the true mean of a population based on a random sample. When taking a mean value from a random sample, most likely the mean of that sample will not be the true mean of the population, but only an estimate.

The confidence interval represents a range of values around the sample mean that will include the true mean.

Confidence intervals are expressed as a percentage (usually 90 or 95%). This simply means that if a researcher was to take 100 random samples, he could be certain that 90 or 95 times that the range of values expressed by the confidence interval procedure would include the true mean of a population from which the samples were drawn.

In the context of the present invention, with regard to the establishment of bioequivalency of the dronedarone hydrochloride composition, it may be compared with a reference composition that is the commercially available Multaq® composition containing 400mg dronedarone free base.

Further, pharmaceutical compositions of the invention may also reduce or negate the need for co-administration simultaneously with, or following shortly after, intake of food, thereby allowing patients more freedom to choose when to administer their medication.

The absence or reduction of a food effect for dronedarone hydrochloride can be concluded when the 90% confidence intervals for the ratio of the geometric means based on log transformed data in clinical studies of fed and fasted treatments fall within 80% to 125% for AUC and 70% to 143% for Cmax. The difference between a bioequivalence parameter measured after oral administration to a mammal with and without food, respectively, is more than about 80% and less than 125% for AUC and more than about 70% and less than 143% for Cmax.

in another aspect of the present invention there is provided a pharmaceutical composition compiising dronedarone hydrochloride dispersed in a carrier containing a phospholipid, optionally as hereinabove described, wherein the difference between a bioequivalenee parameter measured after oral administration to a mammal with and without food, respectively, is more than about 80% and less than 125% with respect to AUC and more than about 70% and less than 143% for Cmax.

As stated above, the comparison for determining the presence or absence of a food effect is made between a sample of fed and fasted patients. As used herein, a patient in a fed state is defined as having been fed a high fat meal containing fat, especially when fed at least 1000 calories, 50 % of which are from fat as more fully described in United States FDA or EMEA Guidelines. Alternatively, the fed patient may have taken a medium or light fat meal comprising 30% fat as set forth in AMA ( American Heart Association) guidelines.

Furthermore, a fed patient may be defined as somebody who has fasted, e.g. for at least 10 hours overnight and then has consumed an entire test meal within 30 minutes of first ingestion. in a representative method, the pharmaceutical composition is administered with nil of water within 5 minutes after completion of the meal. No food is then allowed for at least 4 hours post-dose. Water can be allowed ad libitum after 2 hours. A representative high fat, high calorie test meal comprises 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast \vith butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk to provide protein calories, 250 carbohydrate calories, and 500 to 600 fat calories.

A patient in a fasted state may be defined as a subject who has not eaten any food, e.g. the patient has fasted for at least 10 hours before the administration of a pharmaceutical composition and who does not eat any food and continues to fast for at least 4 hours after the administration. The pharmaceutical composition is preferably administered with 180 ml of water during the fasting period, and water can be allowed ad libitum after 2 hours.

In another aspect of the invention there is provided a method of reducing or eliminating the difference between one or more bioequivalence parameters (defined above) measured after oral administration of a pharmaceutical composition defined herein to a mammalian subject in a fasted state compared with a mammalian subject in a fed state, the method comprising the step of employing in said composition a pharmaceutically acceptable carrier comprising a phospholipid and/or an ionic surfactant. More particularly, in said method, said pharmaceutical composition is bioequivalent to a commercially available formulation containing 400mg of dronedarone free base sold under the name Multaq®, as defined by bioequivalence guidelines given by the U.S. Food and Drug Administration or the corresponding European regulatory agency (EMEA).

in a particular embodiment of the method sct forth above, one or more of the pharmacokinetic parameters AUC, Tmax or Cmax of said pharmaceutical composition administered orally to a fasted patient is increased relative to the parameter when said composition is administered orally to a patient in a fed state.

As already stated herein, dronedaronc hydrochloride is a poorly soluble drug. Its oral bioavailability will be affected by its dissolution in the intestinal lumen of a subject.

Indeed, in US 7,323,493 the authors attribute entirely the problem of poor bioavailability to the drug's poor solubility in intestinal media and propose to remedy the situation by employing non-ionic bydrophilic surfactants in a carrier material for the drug. However, applicant believes that as well as addressing poor solubility, one should also address the permeability of the drug through the intestinal mucosa.

The present invention proposes the use of a phospholipid-or ionic surfactant-containing carrier material in which to formulate the drug. The use of a phospholipid or ionic surfactant not only acts as an aid to drug solubilisation, it may also generate an environment around the drug substance that mimics the environment created by the release of endogenous or natural surfactants such as phospholipids as part of the process of digestion after the intake of food. it is believed that phospholipids or ionic surfactants may interact with the drug to form micelles that in turn interact with the unstirred water layer s (UWL) -a bicarbonate-rich layer of mucus that maintains pH levels at around 7 at the villi surface -and the intestinal mucosa, to enhance absorption therethrough.

An in-vitro dissolution test employing a bio relevant dissolution medium, which mimics the gastrointestinal conditions in the fed state, for example by containing phospholipid and bilary salts, may be useful in predicting the in-vivo performance of dronedarone hydrochloride formulations of the present invention in both the fed and fasted state. in vivo phospholipids are degraded by hydrolytic action of digestive enzymes (e.g. phospholipase A2), which generate a fatty acid and a lysophosphatidylcholine molecule. These lysophosphatidylcholines are not only good solubilisers, but also promote the formation of mixed micelles around drug particles thereby promoting their interaction with the aforementioned mucusa. Biorelevant dissolution media are useful for forecasting of formulations and food effects on dissolution and performance of orally administered drugs.

Most used biorelevant dissolution media are known in the art as FaSS1F and FeSS1F, respectively Fasted State Simulated Intestinal Fluid and Fed state Simulated intestinal Fluid.

The present invention provides in another of its aspects a dosage form as herein described, which releases dronedarone hydrochloride according to the profile of an immediate release formulation. Dronedarone is a BCS class IV active ingredient exhibiting a pH dependent solubility, it is most soluble at pH between 3 and 5 and therefore the optimal pH to achieve sink conditions should be within that range. In a particular aspect of the invention, dronedarone HCL formulations defined herein when tested in a phosphate buffer pH 4.5 in USP apparatus II at the paddles speed of 50 rpm release at least 80% of their content within minutes.

in another aspect of the invention there is provided a method of treating any of the conditions for which the product Maltaq is indicated including paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial flutter, the method comprising the step of administering to a patient in need thereof a dosage form as herein defined.

Dronaderone is indicated 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 eardioverted.

Atrial Fibrillation (AF) is the most sustained cardiac rhythm abnormally seen in clinical practice. Atrial Fibrillation (AF) is a condition in which the upper chambers of the heart beat in an uncoordinated and disorganized fashion, resulting in an irregular and fast heart rhythm (i.e. an irregular rate and irregular rhythm). Atrial flutter is an abnormally fast heart rhythm that occurs in the atria of the heart, but the rate is slower than atrial fibrillation.

Atrial flutter frequently degenerates to atrial fibrillation. However, it may persist for months or even years. AF is the most common sustained cardiac rhythm disturbance, increasing in prevalence with age. Anti-arrbythmic drugs to maintain sinus rhythm in patients with AF are based on the following three objectives: rate control; prevention of thromboembolism and correction of rhythm disturbance.

After restoration of sinus rhythm, antiarrhytmic agents ace often initiated for long-term maintenance. The usc of agents to maintain sinus rhythm is necessary because approximately 71-84% of patients convert back to AF within one year. The current recommendations available for maintenance of sinus rhythm are class 1C agents (propafenone and flecainide) and class Ill agents (amiodarone, dofetilide and dotalol). Class 1 C are currently rarely used because their risk of proarrhythmia and mortality in patients with structural heart disease Amiodarone is one of the most frequently used antiarrhythmic agents for maintenance of sinus rhythm and one of the most effective compared to other antiarrhythmics. It carries with it a lower risk of proarrhytbmia and neutral mortality risk in patients with structural heart disease. However amiodarone poses a high risk toxicity profile hypo!hyperthyroidism, interstitial lung disease, corneal micro deposits, abnormal liver function and skin discoloration). Dronedaronc is a multi-channel blocker that affects the calcium, potassium and sodium channels and has non-competitive anti-adrenergic properties. Unlike amiodarone, this drug does not contain an iodine radical and hence does not result in adverse effects on thyroid and lung functions. Safety rather than efficacy considerations primarily guide the choice of therapy.

The only recommended dosage of MULTAQ® is 400 mg (dronedarone free base) twice daily in adults. YRJLTAQ® should be taken as one tablet with the morning meal and one tablet with the evening meal.

Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidinc, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) should be stopped before starting MTJLTAQ®.

MJJLTAQ® 400 mg tablets are provided as white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and "4142" code on the other side.

in yet another aspect of the present invention there is provided a process for preparing a dosage form as defined herein, the process complising the step of dispersing dronedarone hydrochloride in a suitable pharmaceutical carrier comprising a phospholipid and/or an ionic surfactant and optionally one or more pharmaceutically acceptable excipients.

Details of one or more embodiments of the invention are set forth in the description belo\v.

Other features, objects and advantages of the invention will be apparent from the following

description and claims.

The pharmaceutically acceptable carrier useful in the present invention comprises a phospholipid and/or an ionic surfactant as well as any other optional pharmaceutical excipients.

The phospholipid may be a single phospholipid or a mixture of two or more phospholipids, for example a mixture of two or a mixture of three or a mixture of four or a mixture of five or a mixture of from six to about ten phospholipids. Phospholipids could be either from egg or soybean origin. Grades of phospholipids are mainly characterized by their content of phosphatidyleholine, lysophosphatidyleholine and phosphatidylethanolamine. For the present invention the preferred grade contains more than 70% of phosphatidyleholine.

Suitable phospholipids include saturated phospholipids; unsaturated phospholipids, naturally derived phospholipids, synthetic phospholipids and semi synthetic phospholipids, animal and plant phospholipids, egg phospholipids, soya bean phospholipids, corn phospholipids, wheat germ, flax, cotton, and sunflower seed phospholipids, milk fat phospholipids, purified phospholipids from these and other natural sources, glycerophospholipids, phosphatides, phospholipids containing fatty acid esters including palmitate, stearate, oleate, linoleate, and arachidonate, which esters can be mixtures and mixtures of isomers in the phospholipids, phospholipids composed of fatty acids containing one or more double bonds such as dioleoyl phosphatidyleholine and egg phosphatidyleholine that are not stable as powders but are hygroseopic and can absorb S moisture and become gummy, phospholipids composed of saturated fatty acids that are stable as powders and are relatively less amenable to absorption of moisture, phosphatidyiserines, phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols, phosphatidylglyeerols such as L-alpha-dimyristoyl phosphatidylglycerol also known as I, 2-dimyristoyl-sn-glycero-3-phospho (rae-i-lJlyeerol) and also known as DMPG phosphatidic acid, hydrogenated natural phospholipids, and commercially available saturated and unsaturated phospholipids such as those available from Avanti Polar Lipids Inc. of Alabaster, Alabama, USA.

The phospholipid may be salted or desalted, hydrogenated, or partially hydrogenated. The phospholipid can be a mixture of these phospholipids.

Preferred phospholipids include Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100H, a hydrogenated soybean phosphatidyleholine, Phospholipon 90H, Lipoid SPC-3, egg phospholipid, purified egg phospholipid, and mixtures thereof. A preferred phospholipid is Lipoid E80.

The concentration of phospholipid added to the formulations prepared according to this invention can be present in the range of 0.1 to 50%, preferably 0.2 to 20%, and more preferably 0.4 to 15%. A preferred level of phospholipids, e.g. Lipoid E80 is from about 0.4 % to 15%, more preferably from about 0.5°/a to about 10%, and most preferably from 2 to 5% of the drug amount. The amount of phospholipid mentioned is calculated on the basis of free base.

The ionic surfactant may comprise one or more anionic, cationic and zwitterionic surfaetant materials.

A non-exhaustive list of anionic surfactants includes ammonium lauryl sulphate, dioctyl sodium sulfosuccinate, perfluorobutanesulfonic acid, perfluorononanoie acid, perfluorooetanesulfonic acid, perfluorooctanoic acid, sodium laureth sulphate, sodium lauryl sulphate, sodium octyl sulphate, sodium dodeeyibenzenesulfonate, sodium lauroyl sarcosinate, sodium palmate, sodium stearate and triethanolamine lauryl sulphate.

A non-exhaustive list of cationic surfactants includes benzalkonium chloride, benzethonium chloride, eetrimonium bromide, cetrimonium chloride, dimethyldioctadecylammonium chloride, lauryl methyl gluceth-1 0 hydroxypropyl dimonium chloride, stearalkonium chloride, and tetramethylammonium hydroxide.

A non-exhaustive list of zwitterionic surfactants includes those based on primary, secondary, tertiary or quaternary ammonium surfactants.

Of course, the skilled person will appreciate that other ionic surfactants suitable for pharmaceutical use may be employed in the present invention.

The pharmaceutical carrier may contain other excipients, the nature of which will depend upon the intended physical form of the pharmaceutical composition, i.e. whether the composition will be in the form of a compressed tablet, a capsule, a powder or the like.

Generally however, excipients will be employed that are useful in assisting in the redispersion of dronedarone hydrochloride embedded in the carrier into an aqueous suspension once the composition or dosage form containing said composition is ingested.

Such excipients may be chosen based on their hydrophilic character, their wettability or their hygroscopicity, or their characteristics as disintegrants. The excipients may also include fillers or bulking agents that may assist in the further compounding of formulating of the pharmaceutical formulation into a suitable dosage form.

Suitable excipients include hydroxyl-containing, hydrophilic, relatively low molecular weight (e.g. less than 50,000) compounds such as sugars, including monosaccharides, disaccharides, trisaccharides, sucrose, raffinose, lactose, mannitol, sorbitol, trehalosc, glycerol, dextrose, fructose, pentoses, hexoses, xylitol and mixtures thereof.

Excipients may be useful as protectants in drying processes, such as ciyoprotectants in a lyophilization process or as additives in a spray drying process or an evaporation process, preventing or substantially reducing particle fusion, combination and suspension degradation during drying, and assisting in the resuspension of particles from a dried state to form a suspension of the particles. Dry small particles containing the drug can be produced for example as a lyophilizate which is a solid produced from a cooled dispersion of particles by the process of freezing the aqueous carrier to a solid comprising a dispersion in ice and then removing the water by subliming the ice under reduced pressure. The excipients can also reduce or depress the freezing point of aqueous compositions in which they are dissolved or partially dissolved.

The excipients can be added in amounts from 0.1% to about 60% w/w or more depending on the intended use.

in a particular embodiment, the pharmaceutical carrier comprises a phospholipid and/or an ionic surfactant material; and carbohydrates and/or sugar or sugar alcohol such as monosaccharides, disaccharides, trisaccharides, sucrose, raffinosc, lactose, mannitol, sorbitol, trehalose, glycerol, dextrose, fructose, a pentosc, a hexose, xylitol, and mixtures thereof.

The optional ingredients, when present, may be employed in amounts of about 5% to about 40%, preferably about I 0/ to about 30%.

The pharmaceutical composition described above comprising droncdarone hydrochloride, dispersed in the carrier may be dried to form a solid particulate form and employed as such as a finished dosage form suitable for administration to a mammalian subject. However, in is many cases it will be more convenient to present the pharmaceutical composition in a dosage form together with additional pharmaceutical adjuvants. Accordingly, the pharmaceutical composition can be further compounded or formulated with other pharmaceutically acceptable adjuvants to produce a dosage form. For example, the composition may be dried, and granulated with said adjuvants before being filled into capsules or sachets, suspended in a syrup, or compacted to form a tablet. The selection of pharmaceutical adjuvants can be made having regard to the nature of the intended dosage form.

The dosage form may be presented in the form of solid dosage forms including tablets, beads, capsules, grains, pills, granulates, granules, powder, pellets, sachets, lozenges, troches and the like. in a powdered form dispersible in a beverage, or suspended or dissolved in a liquid oil form.

Suitable pharmaceutical adjuvants include one or more materials selected from the group of fillers, binders, lubricants, disintegrants, sweeteners, colours, glidants, surfactants, and the like.

Suitable fillers may include one or more of microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, calcium phosphate, calcium sulphate, kaolin, dry starch, powdered sugar, and the like, lactose (e.g. spray-dried lactose, a-lactose, b-lactose, Tablettose®, various grades of Pharmatose®, Microtose® or Fast-Floe®), microcrystalline cellulose (various grades of Avicel®, Elcema®, Vivacel®, Ming Tai® or Solka-Floc®), hydroxypropy.lcellulose, L-hydroxypropylcellulose (low substituted), hydroxypropyl methylcellulose (HPMC) (e.g., Methocel E, F and K, Metolose SH of Shin-Etsu, Ltd. such as, e.g. the 4,000 cps grades of Methocel E and Mctolosc 60 SH, the 4,000 cps grades of Methocel F and Metolose 65 SH, the 4,000, 15,000 and 100,000 cps grades of Methocel K; and the 4,000, 15,000, 39,000 and 100,000 grades of Metolose 90 SH), methylcellulose polymers (such as, e.g., Methocel A, Methocel A4C, Methocel A15C, Methocel A4M), bydroxyethylcellulosc, sodium carboxymctbylcellulose, carboxymetbylene, carboxymethylhydroxyethylcellulose and other cellulose derivatives, sucrose, agarose, sorbitol, mannitol, dextrins, maltodextrins, starches or modified starches (including potato starch, maize starch and rice starch), calcium phosphate (e.g. basic calcium phosphate, calcium hydrogen phosphate, dicalcium phosphate hydrate), calcium sulphate, calcium carbonate, sodium alginate, collagen and the like.

Suitable binders may include one or more of povidone, starch, stearic acid, gums, hydroxypropylmethyl cellulose, acacia, alginic acid, agar, calcium carrageenan, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum. hydroxypropyl mcthylcellulose. methylcellulose, pectin, PEG, povidonc, pregelatinizcd starch etc. Other adjuvants in a dosage form according to the invention may be antioxidants like e.g. ascorbic acid, ascorbyl palmitatc, butylatcd hydroxyanisole (BHA), butylated hydroxytolucne (BHT), hypophosphorous acid, monothioglycerol, potassium metabisulfitc, propyl gallate, sodium formaldehylde sulfoxylatc, sodium metabisulfitc, sodium thiosulfatc, tocopherol, tocopherol acetate, tocopherol hemisuccinate, TPGS or other tocopherol derivatives. The carrier composition may also contain e.g., stabilising agents. The concentration of an antioxidant and/or a stabilizing agent in the carrier composition is normally from about 0.1 % w/w to about 5% w/w.

Suitable lubricants may include one or more of magnesium stcarate, zinc stearate, calcium stcarate, stearic acid. sodium stearyl flimarate, hydrogenated vegetable oil, glyceryl behenate, talc, magnesium stearate, calcium stearate, stearic acid, colloidal silicon dioxide, magnesium carbonate, magnesium oxide, calcium silicate, microcrystalline cellulose, starches, mineral oil, waxes, glyceryl behenate, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, sodium laurylsulfate, sodium stearyl fumaratc, and hydrogenated vegetable oils. Preferably, the lubricant is magnesium stearate or talc, more particularly magnesium stcarate and talc in combination.

Suitablc disintcgrants may include one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, alginic acid or alginates, microcrystalline cellulose, hydroxypropyl cellulose and other cellulose derivatives, croscarmellose sodium, crospovidone, polacrillin potassium, sodium starch glycolate, starch, pregelatinizcd starch, carboxymethyl starch (e.g. Primogel(R) and Explotab(R)), starches, clays, celluloses, alginatcs, gums, cross-linked polymers (such as cross-linked polyvinylpyrrolidone and cross-linked sodium earboxymetbyleellulose), sodium starch glycolate, low-substituted hydroxypropyl cellulose, and soy polysaecharides. Preferably, the disintegrant is a modified cellulose gum such as e.g. cross-linked sodium earboxymethylcellulose.

Suitable glidants may include one or more of colloidal silicon dioxide, tale and the like.

iS Colouring agents may be selected from any FDA approved colours for oral use.

In another aspect of the invention there is provided a process of forming a pharmaceutical composition comprising fine particles of dronedarone hydrochloride dispersed in a carrier as hereinabove described, said process comprising the step of dispersing dronedarone hydrochloride in a carrier containing phospholipid and/or an ionic surfactant and optionally one or more pharmaceutically acceptable excipients..

Such a process comprises contacting a dronedarone hydrochloride, the phospholipid and/or an ionic surfaetant and any of the other optional exeipients for a time and under conditions sufficient to provide very fine particles of dronedarone hydrochloride dispersed in a matrix containing phospholipids and/or an ionic surfaetant. The additional exeipients can be added to this matrix either before, during, or after dispersion of the dronedarone hydrochloride in the phospholipid and/or ionic surfactant.

In a particular embodiment of the process according to the present invention, the pharmaceutical composition may be formed by a method comprising the steps of: (a) Preparation of a dispersion of drug and phospholipids, ionic surfactants or both under high shear mixing (e.g. Ultra Turrax). in particular, the phospholipids and/or surfactant can be added to water or a buffer before addition of dronedarone HCI under high shear mixing to produce a homogenous dispersion.

(b) Preparing a fine suspension by subjecting the dispersion formed from step a) to high pressure homogenisation. In particular, high pressure homogenisation for about 10 to 30 minutes at an initial homogenizing pressure of about 500 bars (+/-100 bars) in a static or dynamic interaction chamber, before increasing the homogenizing pressure to around 1500 bars (1-!-100 bars). The time taken to homogenisc the dispersion will depend on the particular particle size distribution that is required, which can be measured using conventional techniques such as laser diffraction.

(c) Drying the resulting fine suspension. Drying may be carried out on a top spray fluid bed dryer. The fine suspension may be mixed with a binder, e.g. 10% polyvinylpyrrolidone (PYP) and any other excipients mentioned hereinabove.

Thereafter, the mixture may be sprayed onto a hydrophilic carrier such as lactose monohydrate.

is The dried material, when reconstituted in a fluid, is adapted to redisperse in order to form particles of dronedarone having a particle size distribution substantially similar to the particle size distribution of the fine dispersion after homogenisation.

The particle size distribution of the re-constituted dried fine suspension can be measured by LD (Laser Diffraction) and PCS (Photon Correlation Spectroscopy), both of which techniques arc well known to persons skilled in the art and need no further elaboration here.

The liquid carrier used in step a) described above may include water, sterile water, water for injection, and buffered water such as phosphate buffered water.

To limit partial solubilisation of the drug during homogenization process the p1-I of the buffer is preferably held outside the 3 to S pH range. The pH of the carrier is preferably established at room temperature before mixing with the phospholipid andlor ionic surfactant and the dronedarone hydrochloride. The pH may be adjusted by addition of an acid or base such as HC1 or NaOH to a solution of a phosphate salt. Preferably the aqueous carrier contains no dissolved oxygen.

The dronedaronc hydrochloride used in a process according to the invention may be in the form of a powder or small crystals or small pieces that are less than about 5 mm in diameter to facilitate mixing. if the drug consists of larger particles, it can be milled to about 5 mm or smaller before forming the admixture used in this invention to facilitate mixing.

Dronedarone hydrochloride can be homogenised to form fine particles by a process of high pressure homogenization as stated hereinabove. The homogenization process is a process that can be done in the presence of the phospliolipid such as Lipoid E80, an ionic surfactant, or both, and optionally in the presence of pharmaceutically acceptable exeipients such as those described above. The suspension niay be maintained at low temperature (S to 30°C) during high pressure treatment to avoid any degradation of the drug and / or exeipients which are present in the suspension during the homogenisation process? Water may be subsequently removed from the pharmaceutical composition by lyophilization, spray drying or fluid bed drying to form a substantially dry powder comprising a solid matrix containing fine particles of dronedarone hydroehloiide. The water can also be removed by other suitable means such as by evaporation or the like.

it is generally accepted that water insoluble or poorly water-soluble drugs can be made is more soluble when presented in the form of small particles. in many cases, however, it is known that small particles must be stabilized against particle size growth and agglomeration by the addition of one or niore surface active agents at some point in the preparation of the particles, especially in an homogenisation process, which entails particle size reduction employing the input of mechanical energy. Because they are bioeompatible and well tolerated in vivo, preferred surface active agents or particle stabilizers are phospholipids, and preferred small particles of dronedarone hydrochloride are stabilized by phospholipid, ionic surfactant, or both. However, the invention contemplates the addition of other surface active agents into the drug mixture before, during or after particle size reduction.

Accordingly, by means of the present invention it is possible to produce a pharmaceutical composition substantially as herein described comprising a stable suspension of fine dronedarone hydrochloride particles in a carrier containing phospholipid and/or ionic surfaetant. The dronedarone hydrochloride particles may have a volume weighted mean particle size smaller than 10 micrometers, more preferably smaller than 5 micrometers, even more preferably smaller than 4 micrometers, even more preferably smaller than 3 micrometers, yet even more preferably smaller than 2 micrometers, yet even more preferably smaller than 0.5 micrometers.

In a particular embodiment of the invention a homogenate comprising dronedarone hydrochloride and a phospholipid and/or ionic surfactant can be formed by adding the phospholipids and! or ionic surfactant and dronedarone hydrochloride to an aqueous carrier and then mixed at high shear, for example for up to 30 minutes at a shear rate of up to 10,000rpm.

The aqueous carrier and the admixture can be contained in a pressurized closed system such as a stainless steel vessel in which high speed shear can be applied. The vessel is preferably connected through suitable piping and valves to a homogenization apparatus which further comprises a reservoir and optionally a return pipe that can carry homogenate from the homogenizer back to the vessel if used in a continuous or batch-wise mode.

After the dronedarone hydrochloride and a phospholipid and/or ionic surfactant are added to the aqueous carrier, the admixture can then be homogenized. In general, it is preferred that the temperature is at or up to about 20°C -E/-10°C during the homogenization process During preparation of the admixture, high shear mixing is applied. Suitable shear is derived is for example from propeller-containing mixers, homogenizers, blenders, sonieators or other devices capable of producing a suspension. Suitable shear rates can range between 500 to 10,000 rpm, preferably 2,000 to 5, 000 rpm. High shear mixing can be continued for up to minutes or even longer if needed to form a suspension containing the drug.

As used herein, homogenization refers to the creation of a homogenate or uniform distribution of small particles containing drug in an aqueous carrier as a result of an energetic process being applied to the suspension comprising drug phospholipid and/or ionic surfactant in an aqueous carrier wherein the homogenate and the small particles produced are at least transiently stable toward phase separation into larger particles or droplets or non-uniform solid or liquid domains. Homogenization can be achieved by input of mechanical energy such as by high shear mixing, ultra high shear mixing, high speed blending, microfluidization, and milling such as by dispersion milling, ball milling, attrition milling, vibrator milling, and media milling, or by application of sonic energy in the form of sonieation. Preferably in the ease of a mill being used in this process wherein the mill contains media or grinding media, such media is removed in a filtration or other suitable separation process to provide homogenized compositions of this invention.

Homogenization is preferably achieved by passing a mixture, e.g. a crude suspension of drug and phospholipid and/or ionic surfactant in an aqueous fluid under high pressure, for example under more than 1000 psi. through a tiny orifice which can result in a decrease in the average diameter and an increase in the number and surface area of particles or droplets in the antecedent composition and produce small particles.

The concentration of thc phospholipid iii the aqueous carrier can vary between 0.1% w/w and 90% WIW, preferably between 0.1% wlw and 50% w/w, and more preferably between 0.2% and 20%, and most preferably between 0.5% to 10% w/w of the drug amount (based on free base). The concentration of dronedarone hydrochloride in the aqueous carrier can vary between 0.1 % w/w and 90% w/w, preferably between 0.5% w/w and 50% w/w, and more preferably between 1% and 20% w/w. The phospholipid can be added to the aqueous can-icr at any temperature below its decomposition point. When used as a mixture with an ionic surfactant, the individual components can be added separately to the aqueous can-icr or combined as mixtures before addition.

is The ionic surfactant may be employed in amounts of 0.1 to 10% by weight.

Homogenization of the suspension containing the drug can be carried out in equipment suitable for that process. Useful equipment includes but is not limited to commercially available high pressure homogenization equipment such as APV Gaulin MiS, Avestin Emulsiflcx CS or C50, MFIC Microftuidizer Ml 1OEH, and other microfluidizers and homogenizers. Homogenization can also be carried out using high shear and ultra high shear mechanical mixers and mills and propeller-containing mixers than can impart sufficient turbulence or energy transfer to the particles to form stable small particles of this invention, Homogenization may be carried out at a first pressure range in the homogenization chamber of a homogenization apparatus. The first pressure range can be from 2,000 psi to 30, 000 psi, preferably about 5,000 psi to 20,000 psi, and more preferably from about 3,000 psi to about 10,000 psi, in one aspect of the invention, between each homogenization pass the processed suspension may be returned batch-wise from the receiving vessel back into the reservoir such as by means of a pump or by pouring, and the homogenization step is repeated. Between each homogenization step, the suspension may be cooled down by a heat exchanger. In another aspect, the processed suspension may be fed directly back into the reservoir in a continuous process. If the initial volume of the suspension beforc homogenization is defined as a "volume pass", then the number of volume passes made through the homogenizer in this manner can range from one to about 20 to produce a homogenate of the drug.

Any of the optional pharmaceutical cxc ipients referred to hereinabove can be added at any stage of the homogenisation process, i.e. to the admixture of drug and phospholipid and br ionic surfactant; to the suspension or to the homogenate. They can be added as solids, as liquids, as solutions in the aqueous carrier when soluble therein, or in combinations thereof.

The total amount of additional exeipients that can be added ranges from about 0.1% to about 50%, preferably from 1% to about 30%, and more preferably from about 2% to about 30%.

The resultant pharmaceutical composition emerging from the homogenisation process can be dried using conventional drying techniques.

When drying is done by spray drying, the cooled homogenate may be fed into the spray dryer as a liquid, preferably at a temperature range below the melting point of dronedarone hydrochloride.

When drying is done by fluid bed drying the homogenate, optionally together with other excipients mentioned herein, will be sprayed onto carrier particles such as beads, non-pareils or the like.

When drying is done by lyophilization, the aqueous carrier of the cooled dispersion is frozen and the composition is lyophilized under reduced pressure and application of heat to the frozen suspension to provide a lyophilizate comprising a matrix of small particles containing dronedarone hydrochloride.

Freezing and lyophilization are preferably done in a conventional freeze dryer, for example, in a Usifroid freeze dryer using conventional techniques. Freezing can be done using the freezing apparatus in the freeze dryer or by other means such as by freezing using liquefied gas such as liquid nitrogen or by freezing methods employing solid carbon dioxide as a cooling agent.

Lyophilization can be done on frozen dispersions in bulk such as on dispersions added to trays and then frozen or on dispersions that have been added to vials, for example in 2 mL or 10 mL vials, and then frozen. At this stage, additional adjuvants can be added to facilitate reconstitution of the lyophilizate.

The dried pharmaceutical compositions of the present invention can be used as finished dosage forms for administration to a patient, or they can be further blended, compounded or formulated with pharmaceutical adjuvants as hereinabove described, in the preparation of a dosage form.

Finished dosage forms as tablets may be prepared utilizing conventional tabletting techniques. A general method of manufacture involves blending the dried pharmaceutical composition obtained from the drying step described hereinabove with a water-soluble or amphiphilic dilucnt, hydrophilic binder and optionally a portion of a disintcgrant. Any other ingredients. such as lubricants, (e.g. magnesium stearate) and additional disintegrants may be added to the granules and mixed. This mixture is then compressed into a suitable size and shape using conventional tabletting machines such as a rotary tablet press.

if capsules are to be prepared, they may also be formed by utilizing conventional methods.

iS A general method of manufacture involves blending the dried pharmaceutical composition obtained from the drying step described hereinabove with a water-soluble or amphiphilic diluent, hydrophilic binder and optionally a portion of a disintegrant. Any other ingredients, such as lubricants, (e.g. magnesium stearate) and additional disintegrants, may be added to the granules and mixed. The resulting mixture may then be filled into a suitable size hard-shell gelatin capsule using conventional capsule-filling machines.

Preferably the finished dosage form is in the form of a tablet.

There now follows a series of examples that serve to illustrate the invention.

Example 1

10% wiw dronedaronc HC1, 0.5% w/w Octowet 78PG, 0.5% w/w Lipold S75 and water qsp 100% w/w are mixed together with stirring to form a suspension. 100 nil of the suspension is passed through the Avestin C50 High Pressure Homogenizer (HPH) while its temperature is maintained below 15°C. First the suspension is processed at a homogenizing pressure of 500 bars for ten minutes and then at 1500 bars. After 30 minutes of high pressure homogenization, the particle size of the nanosuspension is measured by LD: D50= 630 nm, D90= 850 nm and D99= 940 nm. The mean particle size measured by PCS (Photon Correlation Speetroscopy) is around 450 "rn with a polydispersity index (PT) of 0.3. After 60 minutes of HPH, the particle size of the nanosuspension is measured again by LD: D50=' 490 nm, D90" 610 nm and D99'= 740 nm. The mean particle size measured by PCS (Photon Correlation Speetroscopy) is around 360 nm with a polydispersity index (PT) of 0.2.

Drying of the resulting fine suspension is conducted in a top spray fluid bed dryer. First, the fine suspension is mixed with 10% polyvinyl pyrrolidone (PVP) as a binder overnight.

Then the mixture is sprayed onto spray dried lactose monohydrate. The particle size distribution of the resuspended dried nanosuspension is then measured by LD (Laser Diffraction) and PCS (Photon Correlation Spectroscopy). The Particle Size Distribution (PSD) obtained by LU is as follow: D50= 510 urn, D90 630 nm and D99 780 nm. The mean particle size measured by PCS is 380 nm with a PT of 0.3.

ExamjAe2 20% w/w dronedarone HC1, 0.5% w/w DOSS (dioctyl sulphosuecinate), 2 % Lipoid S75 and water qsp 100% w/w are mixed to form a suspension. 100 ml of the suspension is passed through the Avestin C50 High Pressure Homogenizer (HPH) at a temperature of 15°C. First the suspension is processed at an homogenizing pressure of 500 bars for ten minutes and then at 1500 bars. After 30 minutes of high pressure homogenization, the particle size of the nanosuspension is measured by LD: D50= 580 nm, D90= 750 nm and D99=' 910 nm. The mean particle size measured by PCS (Photon Correlation Spectroscopy) is around 480 nm with a polydispersity index (P1) of 0.2. After 60 minutes of HPH, the particle size of the nanosuspension is measured again by LU: D50= 490 nm, D90= 650 nm and D99= 770 nm. The mean particle size measured by PCS is around 380 nm with a polydispersity index (PT) of 0.2.

Drying of the resulting nanosuspension is conducted in a top spray fluid bed dryer. First, the nanosuspension is mixed with 10% polyvinyl pyrrolidone (PYP) as a binder and 10% mannitol as ballast overnight. Then the mixture is sprayed onto spray dried lactose monohydrate. The particle size distribution of the resuspended dried nanosuspension is then measured by LU and PCS. The Particle Size Distribution (PSD) obtained by LU is as follow: D50 500 urn, D90= 680 urn and D99== 810 urn. The mean particle size measured by PCS is 420 urn with a P1 of 0.2.

Example 3

30% w/w dronedarone HC1, I % w/w Octowet 75 P0, 2% Lipoid S100 and water qsp 100% w/w are mixed to form a suspension. 100 ml of the suspension is passed through the Avestin C50 High Pressure Homogenizer (HPH) at a temperature of 15°C. First the suspension is processed at an homogenizing pressure of 500 bars for ten minutes and then at 1500 bars. After 30 minutes of high pressure homogenization, the particle size of the nanosuspension is measured by LD: D50= 620 nm, D90= 780 nm and D99= 940 nm. The mean particle size measured by PCS is around 520 urn with a polydispersity index (P1) of 0.2. After 60 minutes of HIPH, the particle size of the nanosuspension is measured again by LD: D50= 590 nrn, D90= 710 nrn and D99= 870 urn. The mean particle size measured by PCS will be around 490 nm with a polydispersity index (Pr) of 0.3.

Drying of the resulting nanosuspension is conducted in a top spray fluid bed dryer. First, is the nanosuspension is mixed with 10% polyvinyl pyrrolidone (PVP) as a binder and 10% maltodextrin as ballast overnight. Then the mixture is sprayed on spray dried lactose monohydrate. The particle size distribution of the resuspended dried nanosuspension is then measured by LD and PCS. The Particle Size Distribution (PSD) obtained by LD is as follow: D50= 580 nm, D90= 720 nm and D99== 860 nm. The mean particle size measured by PCS is 500 nm with a PT of 0.2.

Example 4

30% w/w dronedarone HC1, 4 % Lipoid S 75 and water qsp 100% w/w are mixed to form a suspension. 100 ml of the suspension is passed through the Avestin C50 High Pressure Homogenizer (HPH) at a temperature of 15°C. First the suspension is processed at an homogenizing pressure of 500 bars for ten minutes and then at 1500 bars. After 30 minutes of high pressure homogenization, the particle size of the nanosuspension is measured by LD: D50= 800 nm, D90= 950 nm and D99= 990 nm. The mean particle size measured by PCS is around 700 nm with a polydispersity index (PT) of 0.2. After 60 minutes of HPH, the particle size of the nanosuspension is measured again by LD: D50= 750 nm, D90== 800 nm and D99= 870 nm. The mean particle size measured by PCS will be around 610 nm with a polydispersity index (PT) of 0.1.

Drying of the resulting nanosuspension is conducted in a top spray fluid bed dryer. First, mix the nanosuspension with 5% mannitol, 5 % maltodextrin, 25% Na CMC and 1% SLS.

Then the mixture is sprayed on spray dried lactose monohydrate. The particle size distribution of the resuspended dried nanosuspension is then measured by LD and PCS. The Particle Size Distribution (PSD) obtained by LD is as follow: D50 810 nm, D90= 920 nm and D99 1200 nm. The mean particle size measured by PCS is 790 nm with a P1 of 0.3.

Example S

15% w/w dronedarone HC1, 4 % SLS (sodium lauiyl sufiphate) and water qsp 100% w/w arc mixed to form a suspension. 100 ml of the suspension is passed through the Avestin C50 High Pressure Homogenizer (HPH) at a temperature of 15°C. First the suspension is processed at an homogenizing pressure of 500 bars for ten minutes and then at 1500 bars.

After 30 minutes of high pressure homogenization, the particle size of the nanosuspension is measured by LD: D50= 660 nm, D90= 765 nm and D99= 930 nm. The mean particle size is measured by PCS is around 725 nm with a polydispersity index (PT) of 0.2. After 60 minutes of HPH, the particle size of the nanosuspension is measured again by LD: D50= 645 nm, D90= 755 nm and D99 905 nm. The mean particle size measured by PCS will be around 690 nm with a polydispersity index (PT) of 0.1.

Drying of the resulting nanosuspension is conducted in a top spray fluid bed dryer. First, mix the nanosuspension with 5% sucrose, S % maltodextrin, 2.5% Na CMC and 1% SLS.

Then the mixture is sprayed on spray dried lactose monohydrate. The particle size distribution of the resuspended dried nanosuspension is then measured by LD and PCS. The Particle Size Distribution (PSD) obtained by LD is as follow: D50= 760 nm, D90= 900 nm and D99= 1200 nm. The mean particle size measured by PCS is 890 nm with a P1 of 0.3.

ExamDle 6: g of dried granules from Example 3 (corresponding to 42g of dronedarone HCI) are mixed with 5 g Kollidon CL (erospovidone), 3.5 g AeDiSol (croscamiellose sodium), lOg Pearlitol DC (mannitol) 0.5 g Colloidal silicon dioxide and 1 g magnesium stearate. The final blend is then tableted on a reciprocating tablet press (Korseh EKO, Berlin Germany) to a unit weight of 1.0 14 g. Each tablet contains 426 mg of dronedarone HC1 corresponding to 400 mg dronedarone base.

Claims (11)

1. Claims: 1. A dosage form comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid, an ionic surfactant or a mixture thereof, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone base exhibits a pharmacokinetic profile characterised by an AUC024 of about 500, more particularly 350 to 650 ng.hr/ml.
2. 2. A pharmaceutical composition comprising dronedarone hydrochloride dispersed in a pharmaceutically acceptable carrier comprising a phospholipid, an ionic surfactant or a mixture thereof, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone base exhibits a pharmaeokinetie profile eharacterised by a Cmax of about 90, more particularly 70 to 120 ng/ml.
3. 3. A pharmaceutical composition comprising dronedarone hydrochloride dispersed in a iS pharmaceutically acceptable carrier comprising a phospholipid, an ionic surfactant or a mixture thereof, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone base exhibits a pharmacokinetic profile characterised by a Tmax of about 5 hours, more particularly 3 to 7 hours.
4. 4. A pharmaceutical composition comprising dronedarone hydrochloride and a pharmaceutically acceptable carrier comprising a phospholipid, an ionic surfactant, which composition when administered to a mammalian subject orally in fasting conditions at a single dose of 400 mg of dronedarone base exhibits an AUC024 of about 500, more particularly 350 to 650 ng.hr/ml, a Cmax of about 90, more particularly 70 to 120 ng/ml and a Tmax of about 5 hours, more particularly 3 to 7 hours.
5. 5. A pharmaceutical composition according to any of the preceding claims, which, when administered orally to a mammalian subject is bioequivalcnt to a dosage form of dronedarone hydrochloride containing 400mg dronedaronc free base.
6. 6. A pharmaceutical composition, which when tested in a phosphate buffer pH 4.5 in USP apparatus II at a paddle speed of 50 rpm, releases at least 80% of its content within 60 minutes.
7. 7. A pharmaceutical formulation according to any of the preceding claims containing a phospholipid selected from the group consisting of Lipoid E80, Lipoid EPC, Lipoid SPC, DMPG, Phospholipon 100Ff, a hydrogenated soybean phosphatidyleholine, Phospholipon 90Ff, Lipoid SPC-3, egg phospholipid, purified egg phospholipid, and mixtures thereof
8. 8. A pharmaceutical formulation according to any of the preceding claims wherein the phospholipid contains more than 70% of phosphatidylcholine.
9. 9. A pharmaceutical composition according to any of the preceding claims wherein phospholipid is present in the range of 0. Ito 50%, preferably 0.2 to 20%, and more preferably 0.4 to 15% by weight based on the amount of dronedaronc free base contained in said composition.
10. 10. A pharmaceutical composition according to any of the preceding claims wherein the particle size of the drug particles dispersed in the composition, as measured by laser diffraction, is D50= 580 nm to 750 urn, D90== 750 nm to 910 nm, and D99= 910 nni to 1 lOOnm, and the mean particle size measured by photon correlation spectroscopy is about iS 480 nm to 800 nm with a polydispersity index of about 0.2 to about 0.4.
11. 11. The use of a composition as defined in any of the preceding claims in the treatment of paroxysmal atrial fibrillation, persistent atrial fibrillation, or atrial flutter.