HK1188129B - Pharmaceutical composition and dosage form comprising dronedarone, and preparation method thereof - Google Patents

Description

The present invention relates, in general, to an oral pharmaceutical composition containing an active substance with antiarrhythmic activity, and, more specifically, to a semi-solid or liquid pharmaceutical composition for use as a capsule-type galenic advantage, which includes at least one benzofuran derivative as an active substance with antiarrhythmic activity and at least one lipid excipient.

The present invention also relates to a process for preparing such a galenic form from the said pharmaceutical composition and is also related to the therapeutic application of such a composition or galenic form.

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

These include 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzo-furane or dronedaron and its pharmaceutically acceptable salts as described in patent EP1315709 and 2-n-butyl-3-(3,5-diiodo-4-diethylaminoethhoxy-benzoyl) benzofurane or amiodarone and its pharmaceutically acceptable salts as described in patent US 3248401. WO2005/048979 describes a modified pharmaceutical composition comprising micro-images containing an active substance such as dronedaron and coated with a control layer containing an excipient lipid of amphiphilic acid (H.L. 20-20 or amphiol, glycerol, monosodiol, glycerol, glycerol, monosodiol, glycerol, monosodiol, monosodiol).

WO0245693 describes a matrix comprising an active substance and different amphiphilic lipid excipients of HLB 2-20. Advantageously, the benzofuran derivative with antiarrhythmic activity is chosen from either dronedarone or 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamide-benzofuran of formula (D) in free base form represented below and its derivatives, such as pharmaceutically acceptable salts described below.

Err1:Expecting ',' delimiter: line 1 column 47 (char 46)

The antiarrhythmic compounds used in the framework of the invention, in particular dronedaron and amiodarone, in their basic form, or their salts, in particular their hydrochloride salts, are characterised by low solubility in aqueous media, which is a major disadvantage for oral administration of the active substance.

For example, the solubility curve of dronarone hydrochloride at room temperature and pH shows a maximum solubility of about 1 to 2 mg/ml at pH 3-5 but very low at pH 6-7 since it is only 10 μg/ml at pH 7 and amyodarone hydrochloride has a solubility of 0.3 to 0.9 mg/ml at room temperature in the pH range 3-4 and a few μg/ml at pH 7 Thus 400 mg of dronarone hydrochloride can be dissolved in 200 ml of buffered aqueous medium pH 4 (a solution of 0.0 to 0.0 mg/ml).However, in this medium diluted to 1/10 by an aqueous buffered solution at pH = 7 (aqueous solution 0,1M in Na2HPO4), the dronedaron hydrochloride precipitates (pH of the final medium = 6,7). These solubility conditions being similar to those recorded in the gastrointestinal tract, it can be assumed that the dronedaron hydrochloride will be subjected in the stomach to acid conditions favourable to its solubilization but upon entering the intestine, it will instead encounter a pH medium between 6 and 7, i.e. a non-soluble medium, in which it is likely to precipitate.

However, the absorption of the active substance is mainly intestinal and it is now well known that oral administration requires optimal maintenance of the active substance in solution in order to hope to obtain sufficient permeation through the gastrointestinal tract and therefore an acceptable exposure for a significant therapeutic effect.

In view of the solubility and bioavailability problem, a galenic form has been developed and is currently on the market, in the form of a 426 mg dronehydrochloride tablet, sold under the trade name Multaq®, and the recommended dosage for adults is one tablet twice daily, with a meal as a prerequisite for optimal action of the active substance.

However, due to a pre-systemic first-pass metabolism, the absolute bioavailability of this drug (taken with food) is only 15%. Concomitant food intake multiplies the bioavailability of the drug by a factor of 2-4 compared to taking the drug without food at the same time. After oral administration during a meal, maximum plasma concentrations in drone darone and its main circulating active metabolite (N-debutylmebolite) are reached in about 3 to 6 hours. The pharmaceutical dose of drone darone and its moderate metabolite causes a doubling of the dose and a rise in CUC of 2.50 to 3.0.

It is of course preferable for a patient to be able to benefit from therapeutic treatment without the need to take it with or without meals, especially in the treatment of heart rhythm disorders, especially arrhythmias.

The development of a pharmaceutical composition for the oral administration of an active substance with antiarrhythmic activity, capable of achieving acceptable bioavailability, irrespective of whether or not food is taken at the same time, i.e. a composition which requires a limited effect to be effective, remains of essential interest.

A new pharmaceutical composition has now been found, quite surprisingly and unexpectedly, which allows the oral administration of at least one antiarrhythmic active ingredient, advantageously 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamide-benzofuran or a derivative thereof such as one of its salts, without the disadvantages mentioned above. This composition, including at least one active ingredient included in a matrix made up of the other ingredients of the composition, in particular the other excipients, is sufficiently stable and has an appropriate solubility to pass through the gastrointestinal tract to the absorption site.

The present invention according to claim 1 thus concerns a pharmaceutical composition for oral administration of an active substance with antiarrhythmic activity, such as 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamide-benzofuran (i) in the basic form, (ii) in the pharmaceutically acceptable salt form, characterised by the fact that in addition to the active substance, it contains at least one amphiphiphilic lipid excipient of HLB value between 5 and 18 in that the lipid excipient is chosen from the polyoxylglycids in semi-solids. Depending on the composition of the invention, the excipient may be in the form of a capsule or a gel-like liquid.

For the purposes of this invention:Capsule, a hard-shell or mole galenic form;Gel, a hard-shell capsule, having two parts: one part called body and one part called head;Bioavailability, a term used to describe a pharmacokinetic property of drugs, i.e. the fraction of a dose that reaches the bloodstream. It measures the amount of absorbed drug that reaches the bloodstream and the rate of absorption of the drug;Acipe, any substance having a therapeutic effect, such as antiarrhythmic activity.Drone, in particular droneadarone in the basic form, as pharmaceutically acceptable salts of addition to organic or inorganic acids. These salts can be prepared with pharmaceutically acceptable acids, but salts of other useful acids, for example, for purification or isolation of compounds of formula (I) are also part of the invention.Excipient, any substance inactive or inert with respect to a living organism, unlike the active substance, which facilitates the preparation and administration of a drug;Lipid excipient, any excipient of the human body known as lipid solvent, advantageously amphetic, having a higher HbA value (Lipid 1), which is defined as follows in the invention and is inferior to the active substance;all ingredients other than the active substance (s) of the invention, in particular the excipients;HLB value, the hydrophilic-lipophilic balance value, according to the classification developed by Griffin, well known to the trade;Strengthening agent, an excipient which, by its amphiphilic properties, facilitates the wetting of powders, improves solubility/solubility and/or slows down the precipitation;Co-solvent, any solvent which improves the feasibility of the manufacturing process of the invention on the basis of the key parameters of viscosity and melting point of the said substance and the solubility of the said substance or matrix in the active substance;Diluent,an excipient used to obtain a volume of composition sufficient to produce a galenic form, e.g. a capsule, of the desired size and having the physical characteristics appropriate to the manufacturing technique chosen for the capsule;a disintegrating excipient, an excipient which allows the galenic form to be broken down satisfactorily and thus the active substance to disintegrate in the stomach by increasing the friability and reducing the hardness of the galenic form;an anti-adhesive, an excipient intended to prevent particles from sticking to each other and to the manufacturing material when the galenic form is manufactured, e.g. when filling the cells.Lubricant, an excipient designed to facilitate the manufacturing steps of galenic forms by their slippery role, i.e. by increasing the fluidity of particles in the tubes of machines; Plasticizer, an excipient designed to allow a constant release of the active substance of the galenic form by interscaling between polymer chains and allowing them to slip relative to each other.

The compositions of the invention include a first group of pharmaceutical compositions comprising: 1-60% by weight of at least one active substance in accordance with the invention, preferably 1 to 50%, even more preferably 10 to 45%, preferably 20 to 40%; 40-99% by weight of at least one lipid excipient in accordance with the invention, preferably 45 to 80%, even more preferably 50 to 60%,0-30% by weight of at least one compound selected from surfactants, co-solvents, diluents, disintegrators, lubricants, organic or inorganic bases and plasticizers, preferably 1 to 20%, preferably 1 to 10%, The percentage expressed in weight of the total weight of the composition.

The compositions of the invention include a second group of pharmaceutical compositions comprising: 1-60% by weight of at least one active substance in accordance with the invention, preferably between 1 and 50%, even more preferably between 10 and 45%, preferably between 20% and 40%; 37-99% by weight of at least one lipid excipient in accordance with the invention, preferably between 45 and 80%, even more preferably between 45% and 55%,0-30% by weight of at least one compound selected from surfactants, co-solvents, diluents, disintegrators, lubricants, organic or inorganic bases and plasticizers, preferably between 1 and 20%, preferably between 1 and 10%, The percentage expressed in weight of the total weight of the composition.

The compositions of the invention include a third group of pharmaceutical compositions comprising: 1-60% by weight of at least one active substance in accordance with the invention, preferably between 1 and 50%, even more preferably between 10 and 45%, even better between 20% and 40%; 40-99% by weight of at least one lipid excipient in accordance with the invention, preferably between 45 and 80%, even more preferably between 50% and 60%,0-30% by weight of at least one surfactant, preferably between 1% and 20%, even more preferably between 5% and 15%, and 0-29% by weight of at least one co-solvent, preferably between 1 and 20%, even more preferably between 2 and 15% The total of the compositions shall be 100% by weight.

The compositions of the invention include a fourth group of pharmaceutical compositions comprising: 1-60% by weight of at least one active substance in accordance with the invention, preferably between 1 and 50%, even more preferably between 10 and 45%, even better between 20% and 40%; 37-99% by weight of at least one lipid excipient in accordance with the invention, preferably between 45 and 80%, even more preferably between 50% and 60%, 0-30% by weight of at least one surfactant, preferably between 1% and 20%, even more preferably between 5% and 10%, and 0-29% by weight of at least one co-solvent, preferably between 1 and 20%, even more preferably between 2 and 15% The total of the compositions shall be 100% by weight.

The compositions of the invention include a fifth group of pharmaceutical compositions comprising: 60-200% by weight of at least one lipid excipient in accordance with the invention, preferably between 120 and 180%, even more preferably 180%0-30% by weight of at least one surfactant, preferably between 5% and 30%, even more preferably between 10% and 30%, preferably between 1 and 20%; The percentage expressed as weight in relation to the total active substance.

The pharmaceutical formulations of the invention include at least one active substance with antiarrhythmic activity and at least one lipid excipient.

Active substances with antiarrhythmic activity conforming to the invention include 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane in the basic form or dronedaron and its pharmaceutically acceptable salts described in patent EP1315709.

For example, 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane hydrochloride, 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane fumarate and 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane oxalate are included as pharmaceutically acceptable salts.

The composition of the invention includes 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane or 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane hydrochloride as the active substance.

Alternatively, the solubilization of the active substance in its basic form can be achieved by starting from pharmaceutically acceptable salts of droneodarone, as mentioned above, and reforming the active substance in its basic form in situ by pH change with an organic or inorganic base.

The compositions of the invention comprising at least one pharmaceutically acceptable salt of droneodarone, and including in addition at least one organic or inorganic base, with a stoichiometric molar advantage over the active substance in the base form, are part of the present invention.

For example, the nature of the base that can be used in the composition may be organic, such as ethanolamine, or mineral, such as soda or potash.

The active substance (s) of the invention is (are) present in the composition according to the invention in a proportion of 1-60% by weight, preferably between 1 and 50%, even more preferably between 10 and 45%, even better between 20% and 40% by weight in relation to the total weight of the composition.

The lipid excipient is an amphiphilic lipid excipient with an HLB value between 1 and 20 and a melting point below 50°C.

The lipid excipient is an amphiphilic lipid excipient with an HLB value between 2 and 20 and a melting point below 50°C.

A distinction is made between semi-solid amphiphilic excipients at room temperature and liquid amphilic excipients at room temperature.

The lipid excipient according to the invention may be selected from: Semi-solid substituted glycerides,Liquid substituted glycerides,Semi-solid substituted polyoxylglycerides,Liquid substituted polyoxylglycerides and mixtures thereof.

For example, one group may be mentioned in which the lipid excipient is selected from: as semi-solid substitute glycerides complying with the invention, e.g. gelucirides marketed under the brand name Gelucire® 33/01, Gelucire® 39/01 Gelucire® 43/01 and Geleol®, PeceolTM, as liquid substitute glycerides complying with the invention, e.g. as Labrafac Lipophile® WL1349, as semi-solid substitute polyoxylglycerides complying with the invention, e.g. marlure® 44/14, Gelucire® 50/13, as polyoxylglycerides complying with the invention, e.g. Labrafil® GCSM1921 and Labrafil® GCSM19250, as Labrafil® GCSM21 and Labrafil® GCSM2130

For example, another group in which the lipid excipient is selected from semi-solid substituted polyoxylglycerides conforming to the invention is Gelucyres marketed, in particular lauroyl macroglyceride marketed under the trade mark Gelucyres®44/14.

Where the active substance is present as a salt, the composition may be in the form of a solid dispersion of that active substance in a solid matrix at room temperature where a sufficient amount of lipid or semi-solid excipient is used or in the form of a solid dispersion in an oil at room temperature where a sufficient amount of liquid lipid excipient is used, the solubility of that active substance in the composition being further dependent on the pH of the medium in which the composition is found.

The lipid excipient, amphiphilic semi-solid at room temperature, of the composition of the invention has the advantage of allowing solid dispersion or hot solubilization of the active substance in the matrix of the composition and of facilitating the solution of the active substance when the matrix is dissolved in the aqueous gastric and/or intestinal environment.

The amphiphilic lipid excipient, liquid at room temperature, of the composition according to the invention, has the advantage of facilitating the solution of the active substance in the aqueous medium of the stomach and/or intestines.

The composition according to the invention preferably includes at least one lipid excipient, an amphiphiphilic one, with an HLB value between 5 and 18.

Lipid excipients, amphiphilic, with an HLB value between 5 and 18, conforming to the invention, may be selected from the group comprising: medium-chain mono- and di-glycerides, such as Capmul MCM® (HLB value between 5,5 and 6), marketed by Abitec,propylene glycol monolaurate, such as Lauroglycol® 90 (HLB value equal to 5) and Cap PG12®, respectively marketed by Gattefossé and Abitec,caprylocaproyl macrogol-8 glycerides, such as Labrasol® (HLB value equal to 14), marketed by Gattefossé,caproyl macrolglycerides, such as leucine® 44/14 (HLB value equal to 14) and Gelucine® Gelucine® (HLB value equal to 13), marketed by Abitec, such as caprylocaproyl macrogol-8 glycerides, such as GLB glyceride, which is the same as HLB glyceride, such as PG-8 (HLB value equal to 6), and those marketed by GLB.

In particular, the lipid excipient, amphiphilic, with an HLB value between 5 and 18, is selected from the group comprising Capmul MCM®, Lauroglycol® 90, Capmul PG12®, Labrasol®, Gelucire® 44/14, Gelucire® 50/13, Capmul® PG-8 and mixtures thereof.

According to one embodiment, lipid excipients conforming to the invention are selected from lipid excipients, amphiphilic, with an HLB value between 12 and 18.

The lipid excipient (s) conforming to the invention is (are) present in the composition according to the invention in a proportion of 40-99% by weight, preferably between 45 and 80%, and even more preferably between 50% and 60% by weight in relation to the total weight of the composition.

The lipid excipient (s) conforming to the invention is (are) present in the composition according to the invention in a proportion of 37-99% by weight, preferably between 45 and 80%, and even more preferably between 50% and 60% by weight in relation to the total weight of the composition.

The lipid excipient (s) conforming to the invention is (are) present in the composition according to the invention in a proportion of 100-200% by weight, preferably between 110 and 180%, and even more preferably between 50% and 60% by weight of the total active substance.

The pharmaceutical compositions of the invention may also contain at least one surfactant and/or at least one co-solvent.

The surfactant is advantageously hydrophilic and/or non-ionic. ethylene oxide/propylene oxide copolymers hereinafter referred to as poloxamers, such as poloxamer 124 marketed under the trade name SYNPERONIC PE/L44; poloxamer 188 marketed under the trade name PLURONIC F68 or SYNPERONIC PE/F68; poloxamer 237 marketed under the trade name PLURONIC F87 or SYNPERONIC PE/F87; poloxamer 338 marketed under the trade name SYNPERONIC PE/F108 or poloxamer 407 marketed under the trade name PLURONIC F127, SYNPERONIC PE/F127 or LUTRENWEXEN F127; polyoxylated polyethylene glycol polyesters, such as those marketed under the trade name CREMOPHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYHYH

In particular, the surfactant may be selected from: ethylene oxide/propylene oxide copolymers hereinafter referred to as poloxamers, such as poloxamer 124 marketed under the trade name SYNPERONIC PE/L44; poloxamer 188 marketed under the trade name PLURONIC F68 or SYNPERONIC PE/F68; or poloxamer 407 marketed under the trade name PLURONIC F127, SYNPERONIC PE/F127 or LUTROL F127; polyethylene castor oils, such as those marketed under the trade name CREMOPHOR RH40; polysorbate esters, such as polysorbate 60 marketed under the trade name TENWE 60; and polystyrene hydroxide, such as polystyrene hydroxide of HSOL 660 SOLUTARETE 615

The surfactant (s) according to the invention is or are preferably chosen from the ethylene oxide/propylene oxide copolymers called poloxamers, and even more preferably the poloxamer 407.

The surfactant may be present in the composition of the invention at a rate of 0% to 30% by weight of the total weight of the composition, preferably between 1% and 20% by weight, and even more preferably 5% to 15% by weight of surfactant.

The surfactant may be present in the composition of the invention at a rate of 0-30% by weight of at least one surfactant, preferably between 5% and 20%, and even more preferably between 10% and 20% by weight of the total active substance.

The co-solvent according to the invention may be chosen from organic solvents of alcohol or glycol derivatives.

The co-solvent is: Alcohols such as ethanol and isopropanol; Propylene glycol and its derivatives, possibly substituted, such as those marketed under the labelling labels Labrafac® PG, LauroglycolTM 90, LauroglycolTMFCC, CapryolTM90, CapryoTMPGMC.

The co-solvent may be present in the pharmaceutical composition of the invention at a rate of 0% to 29% by weight of the total weight of the composition, preferably between 1% and 20% by weight, and even more preferably between 2% and 15% by weight of co-solvent.

The co-solvent may be present in the pharmaceutical composition of the invention at a rate of 0-30% by weight of at least one co-solvent, preferably between 1 and 20% by weight of the total active substance.

Depending on one manufacturing method, the co-solvent is a derivative of substituted glycol and/or less than 29% by weight of the total weight of the composition, preferably the co-solvent is Propylene Glycol and/or approximately 20% by weight.

Depending on one embodiment, the co-solvent is a derivative of substituted glycol and/or less than 30% by weight of the total active substance, preferably the co-solvent is Propylene Glycol and/or approximately 20% by weight of the total active substance.

According to one embodiment, the composition according to the invention includes: 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane hydrochloride or 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy) benzoyl]-5-methylsulfonamidobenzofurane in the basic form, as the active substance, and/or at least one semi-solid lipid excipient of HLB between 1-20, preferably between 5-18, even more preferably between 12-18, preferably chosen from semi-solid substituted glycerides and semi-solid substituted polyoxylglycerides, preferably Gelucyr®44/14, and/or at least one surfactant, preferably chosen from the ethylene oxide/propylene oxide copolymers called poloxamer, more preferably poloxamer 407, and possibly at least one co-solvent as defined above.

This pharmaceutical composition is in liquid or semi-solid form, i.e. paste-like, depending on the consistency and nature of the excipient (s) used, including the lipid excipient, at room temperature. A lipid or semi-solid excipient at room temperature will result in the formation of a semi-solid matrix and thus a composition according to the invention of paste-like consistency whereas a liquid lipid excipient at room temperature will result in the formation of a liquid matrix and therefore a composition according to the invention of liquid consistency.

Thus, if the lipid excipient conforming to the invention is chosen from the lipid or semi-solid excipients, the composition conforming to the invention may be prepared by the implementation of known processes of solubilisation or solid dispersion at cold or hot in the lipid excipient forming a lipid matrix. The manufacture of the composition consists, for example, of a solubilisation or dispersion of the active substance conforming to the invention and possibly other excipients conforming to the invention, in said lipid excipient at a temperature of about 30°C to 60°C, such as for example a temperature of about 44°C, the said temperature being used as a function of the temperature of the lipid excipient melting.

According to a particularly advantageous embodiment, the manufacturing process of the invention consists in solubilizing the active substance, preferably 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofurane in the basic form, at approximately 44°C in the lipid excipient, preferably lauryl macroglycerides, such as Gelucire®44/14.

If the lipid excipient of the invention is chosen from liquid lipid excipients, the composition of the invention may be prepared by the application of known processes of solubilization or dispersion of the active substance in the lipid excipient forming a liquid lipid matrix at room temperature.

The methods of preparation of the pharmaceutical compositions according to the invention are carried out by the conventional techniques known to the professional.

The liquid or semi-solid pharmaceutical composition, as according to the invention, thus obtained, may then be incorporated into a capsule, as it is.

The composition may be made into powders, granules or may be incorporated into capsules or used as such.

The invention thus also concerns a galenic form comprising a pharmaceutical composition according to the invention.

This galenic form can be presented as a capsule containing the composition of the invention or possibly as a powder, granules which can be delivered in multi-dose containers or as unit doses such as packages, sachets.

Capsules are solid preparations consisting of a hard or soft shell of varying shape and capacity, usually containing a unit dose of active ingredient. The shell is made of gelatin or other natural or synthetic substances whose consistency can be adjusted by adding e.g. glycerol or sorbitol. Other excipients such as surfactants, opacifiers, antimicrobial preservatives, sweeteners, colours and/or flavourings can also be added to the composition of the capsule shells.

The capsules include capsules, soft-shell capsules, gastroresistant capsules and modified-release capsules.

The advantage is that the galenic form of the invention is a capsule.

The process of manufacturing capsules with a body and a head consists of (i) preparing the composition according to the invention by mixing the ingredients as defined above and then (ii) filling the head and/or capsule body parts by volumetric distribution by a process suitable for powders (compressor-dosing, an eraser process, an alternating eraser and settling or stuffing process, a endless screw process or a alveolar dosing process) or semi-solid (flow of the molten or liquid product), and finally closing the capsules by sealing the parts forming the head and body of the said capsule.

In the case of Soft Capsules the liquid preparation is poured at the same time as the capsule is formed in the matrices according to the conventional manufacturing process.

As an indication but not limited to, the amount of active substance may vary from 50 to 500 mg per unit of administration such as (i) a capsule, preferably a capsule, or (ii) a pouch of powder, or granules, and the amount of lipid excipient between 0.5 and 100 mg. Preferably, a galenic form of the invention, e.g. a capsule, may contain 200 to 400 mg of active substance.

The pharmaceutical composition of the invention and the galenic form containing such a composition are intended to limit the effect of a meal after oral administration in humans. The lipid excipient allows the active substance of the invention to be soluble and to be preserved from negative effects of pH in the intestinal tract, thereby significantly relieving the effect of a meal. The presence of a surfactant, such as poloxamer, in the said composition limits the recapturing and agglomeration of the active substance in the gastrointestinal tract. Figure 1 shows the curves of dissolution of capsules according to the invention (G1 to G6 capsules).Figure 2 shows the dissolution curves of the capsules according to the invention (Cells G4 to Cells G8), all these formulations containing the active substance according to the invention.Figure 3 shows the dissolution curves of the capsules according to the invention (Cells G1, G3, G9), all these formulations containing the active substance according to the invention.Figure 4 shows the dissolution curves of the capsules according to the invention (Cells G5, G10, G13), all these formulations containing the active substance according to the invention.Figure 5 shows the dissolution curves of the capsules according to the invention (Cells G1, G1, G3).G9, G11, G12), all of these formulations containing the active substance of the invention.Figure 6 shows the capsule dissolution curves according to the invention (Cells G1, G22, G24, G26, G28), all of these formulations containing the active substance of the invention.Figure 7 shows the capsule dissolution curves according to the invention (Cells G5, G23, G25, G27, G29), all of these formulations containing the active substance of the invention.

These curves express the % by weight of active substance released as a function of time, expressed in minutes. The vertical line in fat at 60 min represents the moment when an alkaline NaOH solution is added to the simulated gastric medium to simulate an intestinal medium.

Examples

Table A below shows the solubility of dronedarone hydrochloride and dronedarone base form in lipid excipients according to the invention. - What?

Compositions according to the invention have been manufactured, the composition of which is detailed in Tables 1, 3 and 4 below.

Comparative compositions, not conforming to the invention, have been manufactured, the composition of which is detailed in Table 2 below. - means absent from the composition. QS means in sufficient quantity. HCl salt means droneadarone chlorhydrate Base means droneadarone base form. Pol. means poloxamer . Geluc. means Glucide . Cream. RH40 means Cremofor RH40)

Dronedarone sous forme de chlorhydrate	213,0	213,0	213,0	-	-	-
Dronedarone sous forme de base	-	-	-	200,0	200,0	200,0
Lauroyl macrogolglycerides (gélucire 44/14)	357,0	343,7	237,0	343,7	357 ,0	237,0
Poloxamer 407	60,0	60,0	-	60,0	60,0	-
Hydroxyde de sodium*	-	14,4	-	-	-	-
Eau distillée*	-	38,9	-	38,9	-	-
Propylène glycol	40,0		-	-	40,0	-
Poids total (mg)	670,0	670,0	450,0	642,6	657,0	437,0

* correspond à une solution aqueuse à 27% d'hydroxyde de sodium

The percentages of these formulations G1 to G6 and other formulations of the invention are given in Tables 3 and 4 below. - What? Tableau 3

Composition centésimale par rapport à la formule totale
Gélule	% principe actif (éq base)	% de gélucire	% de tensioactif (TA)	% de propylène glycol (co-solvant)
G1	30 (sel HCl)	53 (Géluc.44/14)	9 (Pol. 407)	6
G2	30 (sel HCl)	51 (Géluc.44/14)	9 (Pol.407)	0
G3	44 (sel HCl)	53 (Géluc.44/14)	0	0
G4	31 (Base)	53 (Géluc.44/14)	9 (Pol.407)	0
G5	30 (Base)	54 (Géluc.44/14)	9 (Pol.407)	6
G6	46 (Base)	54 (Géluc.44/14)	0	0
G7	63 (400mg base)	37 (Géluc.44/14)	0	0
G8	36 (200mg base)	64 (Géluc.44/14)	0	0
G9 (= G1 sans TA)	33 (sel HCl)	59 (Géluc.44/14)	0	7
G10 (= G5 sans TA)	34 (Base)	60 (Géluc.44/14)	0	7
G11 (= G1 avec 5% TA)	32 (sel HCl)	58 (Géluc.44/14)	2 (Pol.407)	6
G12 (= G1 avec 10% TA)	32 (sel HCl)	57 (Géluc.44/14)	3 (Pol.407)	6
G13 (= G5 avec 10% TA)	32 (Base)	58 (Géluc.44/14)	3 (Pol.407)	6
G14	30 (sel HCl)	53 (Géluc.33/01)	9	6
G15	30 (base)	54 (Géluc.33/01)	9	6
G16	33	59	0	7
(sel HCl)	(Géluc.33/01)
G17	34 (base)	60 (Géluc.33/01)	0	7
G18	30 (sel HCl)	53 (Géluc.43/01)	9	6
G19	30 (base)	54 (Géluc.43/01)	9	6
G20	33 (sel HCl)	59 (Géluc.43/01)	0	7
G21	34 (base)	60 (Géluc.43/01)	0	7
G22	30 (sel HCl)	53 (Géluc.44/14)	9 (Pol.188)	6
G23	30 (base)	54 (Géluc.44/14)	9 (Pol.188)	6
G24	30 (sel HCl)	53 (Géluc.44/14)	9 (Crém. RH40)	6
G25	30 (base)	54 (Géluc.44/14)	9 (Crém. RH40)	6
G26	30 (sel HCl)	53 (Géluc.44/14)	9 (pluronic L44)	6
G27	30 (base)	54 (Géluc.44/14)	9 (pluronic L44)	6
G28	30 (sel HCl)	54 (Géluc.44/14)	9 (tween 60)	6
G29	30 (base)	54 (Géluc.44/14)	9 (tween 60)	6

Tableau 4

Composition centésimale par rapport au principe actif
Gélule	% de gélucire	% de tensioactif	% de propylène glycol (co-solvant)
G1	179 (Géluc.44/14)	30 (Pol.407)	20
G2	172 (Géluc.44/14)	30 (Pol.407)	0
G3	119 (Géluc.44/14)	0	0
G4	172 (Géluc.44/14)	30 (Pol.407)	0
G5	179 (Géluc.44/14)	30 (Pol.407)	20
G6	119 (Géluc.44/14)	0	0
G7	59 (Géluc.44/14)	0	0
G8	179 (Géluc.44/14)	0	0
G9 (= G1 sans TA)	179 (Géluc.44/14)	0	20
G10 (= G5 sans TA)	179 (Géluc.44/14)	0	20
G11 (= G1 avec 5% TA)	179 (Géluc.44/14)	5 (Pol.407)	20
G12 (= G1 avec 10% TA)	179 (Géluc.44/14)	10 (Pol.407)	20
G13 (= G5 avec 10% TA)	179 (Géluc.44/14)	10 (Pol.407)	20
G14	179 (Géluc. 33/01)	30 (Pol.407)	20
G15	179 (Géluc. 33/01)	30 (Pol.407)	20
G16	179 (Géluc. 33/01)	0	20
G17	179 (Géluc. 33/01)	0	20
G18	179 (Géluc. 43/01)	30 (Pol.407)	20
G19	179	30	20
(Géluc. 43/01)	(Pol.407)
G20	179 (Géluc. 43/01)	0	20
G21	179 (Géluc. 43/01)	0	20
G22	179 (Géluc.44/14)	30 (Pol. 188)	20
G23	179 (Géluc.44/14)	30 (Pol. 188)	20
G24	179 (Géluc.44/14)	30 (Crémophor RH40)	20
G25	179 (Géluc.44/14)	30 (Crémophor RH40)	20
G26	179 (Géluc.44/14)	30 (Pluronic L44)	20
G27	179 (Géluc.44/14)	30 (Pluronic L44)	20
G28	179 (Géluc.44/14)	30 (tween 60)	20
G29	179 (Géluc.44/14)	30 (Tween 60)	20

White opaque capsules of size 0 were then produced using the formulations of the examples below and using the formulations of comparator 2 for G1-G29 capsules of the invention and a non-conforming capsule, i.e. reference capsule.

Dronedarone sous forme de chlorhydrate	426	213
amidon prégélatinisé	60.0	86,2
lactose EFC	QS	129,2
talc	-	48,0
dioxide de silicone colloidal	2.4	1,2
stearate de magnésium	6.0	2,4
Hypromellose 6mPa.s	12.0	-
crospovidone	30.0	-
Poloxamer40	40	-
Poids total (mg)	640	480

The material required for the manufacture of the formulations and capsules, the modes of operation of which are described below, is as follows: Magnetic agitator, Becher, Precision Scale adapted to the weighted quantity, Thames 0.315 mm, Bathtub, Gilson 1000 μL piston pipette, Geller.

In addition, the 44/14 gelucyride used to make the compositions is heated to 55°C the night before the manufacture and is homogenised by hand by turning the pot.

Manufacture of the G1 capsule: Method of operation:

Weighing the 44/14 Glucyrin® pre-melted in the manufacturing vessel,Dronedarone in hydrochloride form is sifted over 0.315 mm mesh opening before weighing,Melt and mix the 44/14 Glucyrin® bath and Poloxamer 407 in slow agitation at 200 rpm for about 10 min at 55°C-60°C bath temperature,Add Propylene Glycol at 200 rpm and 55°C-60°C bath temperature,Progressive Addition and dispersion of 0.315 mm mesh opening before weighing,Dronedarone in hydrochloride bath is melted and mixed in slow agitation at 200-650 rpm. After mixing, the cells are automatically filled with 500 g of white water at a temperature of 55-60°C and then re-filled with a glass of glass at a temperature of 500-60°C. After mixing, the cells are automatically filled with a glass of white water at a temperature of 500-650°C.

Manufacture of the G2 capsule: Method of operation:

Weighing of the 44/14 gelucir® pre-melted in the manufacturing vessel,Dronedarone in hydrochloride form is sifted over 0.315 mm mesh opening before weighing,Melt and mix the 44/14 gelucir® and Poloxamer 407 under slow agitation at 200 rpm for about 10 min at 55°C-60°C tide bath temperature,Prolonged addition and rapid agitation dispersion of the 300-650 rpm pre-sifted dronedarone hydrochloride.After addition,mix for 10 min at 500 rpm at 55-60°C tide bath temperature,addition of the 27 per cent sodium gelucir® during the bath temperature, and automatic addition of 500-60°C temperature, the 500 gels are automatically filled with a solution of 500 g of white water and re-filled with a glass of water at a temperature of 500-60°C.

Manufacture of the G3 capsule: Operating mode:

Weigh the 44/14 gelucyr® pre-melted in the manufacturing flask.Droneadarone in hydrochloride form is sifted over 0.315 mm mesh opening before weighing.Progressive addition and rapid agitation dispersion of the pre-sifted droneadarone hydrochloride at a rate of 300-650 rpm during addition.After addition, mix for 30 min at a mixture rate of 350 rpm and at a bath temperature of 55°C-60°C.Fill with an automatic pipette of white opaque cells size 0.After the cells are filled with a solvent, the cells are filled with a solvent.The agitation rate during the distribution is 500 rpm and the bath temperature is 55-60°C. After the addition, the cells are placed in the gelatinous position for refrigeration at room temperature.

Manufacture of the G4 capsule: Method of operation:

Weighing of the gelucir® 44/14 pre-melted in the manufacturing vessel,Dronedarone is sifted over 0.315 mm mesh opening before weighing,Melting and mixing of the gelucir® 44/14 and Poloxamer 407 under slow agitation at an agitator speed of 200 rpm for about 10 min at a tide bath temperature of 55°C-60°C,Progressive addition and solubilisation under high agitation of the dronedarone in its pre-sifted base form at a speed of 300-650 rpm. After addition, mix for 30 min at a 500 rpm bath and at a bath temperature of 55-60°C, Addition of the water during the marsh agitator is done at a temperature of 500-60°C, during the bath, the cells are automatically filled with a white water vapor at a temperature of 55-60°C, and the water is automatically re-filled with a water vapor at a temperature of 500-60°C.

Manufacture of the G5 capsule: Operating mode:

Weighing of the 44/14 gelucir® pre-melted in the manufacturing vessel,Dronedarone is sifted over 0.315 mm mesh opening before weighing,Melt and mix the 44/14 gelucir® and Poloxamer 407 under slow stirring at an agitator speed of 200 rpm for about 10 min at a water bath temperature of 55°C-60°C,Addition of Propylene glycol at a water bath temperature of 55°C-60°C and a water bath temperature of 200 rpm,Progressive addition and solubilisation of the 0.315 mm mesh opening before weighing,Melt and mix the 44/14 gelucir® and Poloxamer 407 under slow stirring at an agitator speed of 300-650 rpm for about 10 min. After stirring, fill the 500 g white cells at a temperature of 55-60°C and automatically re-mix them with a water bath at a temperature of 500-600°C. After stirring, the mixture is re-filled at a temperature of 500 mL and re-mixed at a temperature of 55-60°C.

Manufacture of the G6 capsule: Operating mode:

Weighing of the 44/14 gelucir® pre-melted in the manufacturing vessel,Dronedarone is sifted over 0.315 mm mesh opening before weighing,Melt and mix the 44/14 gelucir® in slow agitation at 200 rpm agitator speed for about 10 min at 55°C-60°C immersion bath temperature,Progressive addition and rapid agitation solubilization of the dronedarone in its pre-sifted base at 300-650 rpm. After addition,mix for 30 min at 500 rpm mixing speed and 55°C-60°C immersion bath temperature,Release with an automatic 0.0 mm white marble pipe.The opaque capsules are filled with water at a temperature of 55-60°C and are automatically filled with water during the immersion. After closure, the capsules are placed vertically on the gel holder for solidification at room temperature.

The reference capsule is manufactured according to the same protocol as the G6 capsule with the proportions and ingredients as shown in Tables 1 and 2 above.

The manufacture of G7 to G29 capsules shall be carried out according to the same protocol as for G6 capsule with the proportions and ingredients as shown in Tables 3 and 4 above.

Assessment of the solubilization of the active substance in the aqueous environment in the gastrointestinal tract

In order to reproduce the effect of pH on the active substance and in particular on its dissolution during its passage through the gastrointestinal tract, a gastrointestinal medium was mimicked by reproducing the pH of the stomach and then the pH of the intestine via a pH jump. A study of the kinetics of dissolution was conducted using a simple in vitro pH jump dissolution test.

Prince:

The principle is to determine the solubilization of the formulated active substance by studying its dissolution kinetics at 37°C, first in a gastric pH 4 simulated medium, then in a intestinal pH 6.5 simulated medium, and this at a time interval compatible with the gastrointestinal tract.

• 000Materials and method

000Materials: precision scale (Mettler AE200 or AT261), pH meter (Knick or Schott Geräte or Inolab), thermostated solvent test 6 or 7 bowls (Sotax AT6 or AT7), 5 μm filter (PALL versus vapor 25 mm) with syringe (Térumo), UV spectrophotometer (Gilford Response II or Perkin Elmer) or HPLC (Merck or Agilent).

Dissolution media: The simulated physiological media representative of the gastrointestinal tract are obtained from the simulated gastric and intestinal fluids recommended by the USP, but used without pepsin or pancreatin.

• simulated gastric fluid - USP (without pepsin):

2 g sodium chloride per 900 ml of distilled water,pH adjusted to 1.2 with concentrated hydrochloric acid (37%),QSP 1000 ml with distilled water.

• simulated intestinal fluid - USP (without pancreatin):

6,8 g potassium dihydrogen phosphate per 900 ml of distilled water,pH adjusted to 7,5 with concentrated sodium hydroxide (10 M),QSP 1000 ml with distilled water.

The simulated gastric pH 4 medium is thus obtained by mixing in different proportions of the two simulated fluids and under control of a pH electrode.

The intestinal-type solution medium is adjusted to pH 6.5 with a few drops of concentrated soda (10M) to simulate the passage of the active substance into the intestinal opening without causing dilution.

Method of use:

Calibration: standard solutions of the active substance are prepared in a solvent medium, preferably in the mobile phase or ethanol, methanol, and then dosed at the wavelength characteristic of the active substance. A calibration line representative of the concentrations according to the optical densities (UV spectrophotometry dosing) or the peak areas (HPLC dosing) is then determined. The equation of the obtained line allows the concentration of the solubilised active substance to be determined from the measurement of the optical density or the peak area.000The kinetics of solubilization are first studied in a gastric pH 4 simulated medium in a 37°C thermostat-dissolved bowl, stirred with 75 rpm palettes for 1 hour with samples at 5, 15, 30, 45 and 60 minutes, then in the intestinal medium with a pH rise to 6.5 by adding a small volume of concentrated soda (example: 0.400 ml for 500 ml of pH 4 medium), under pH electrode control. The kinetics are then continued for up to 3 hours with samples at 75, 90, 120 and 180 minutes and each sample is filtered at 5 μm.Dosages: Two dosing methods may be used depending on the sensitivity required and the galenic form studied: UV spectrophotometry (for active substance alone) or HPLC (for active substance alone or formulated).

The concentration at time t is determined by means of the pre-established calibration. In a UV dosing by spectrophotometry, the full absorption spectrum is checked at least at the end of kinetics.

000 Results:

The solubilisation kinetics of the active substance (expressed as a percentage of the released product) with respect to time are plotted first at pH 4 (simulation of the gastric environment) and then at pH 6.5 (simulation of the intestinal environment) continuously on the same curve as shown in Figure 1.

The tablet shows a significant but noticeable improvement in the % of active substance released compared to the reference capsule but only under simulated intestinal pH conditions.

The G3 capsule containing droneedarone hydrochloride in a lipid excipient matrix in the absence of surfactant has a significantly improved % of active substance released compared to the reference capsule or tablet with an improved release under simulated gastric pH conditions.

The G1 capsule containing dronedarone hydrochloride in a lipid excipient matrix in the presence of surfactant has a very significant improvement in % of active substance released compared to the G3 capsule and compared to the reference capsule and tablet.

The G2 capsule containing basic dronedarone formed in situ in the lipid excipient matrix from the dronedarone hydrochloride showed a very significant improvement in the % of active substance released compared to the reference capsule, tablet and G3 capsule.

G4 and G5 capsules containing dronodarone as a free base in a lipid excipient matrix also show a very significant improvement in the % of active substance released compared to the reference capsule, tablet and G3 capsule with further dissolution behaviour equivalent to that of the G2 capsule.

The beneficial effect of the presence of the lipid excipient in formulations containing dronodarone in the base or hydrochloride form is shown in the curves shown in Figure 1 compared to the reference capsule and tablet which are free of it.

On the other hand, there is a very marked improvement in the % of active substance released for capsules which also contain surfactant in their composition compared to capsules which do not (G1 vs G3 and G5 vs G6).

In addition, in the case of formulations containing dronedaron in its base form in the matrix, the % profile of the active substance released is rapid from the first moments under simulated gastric pH conditions, unlike the formulation containing dronedaron hydrochloride, which is released at best at intestinal pH.

Effect of the level of Gelucir 44/14 on the basic form of dronedarone

The positive effect of the increase in the level of glue is shown by the curves shown in Figure 2.

Effect of the level of Glucyr 44/14 on the hydrochloride salt of dronedarone

The positive effect of the increase in the level of glue is shown by the curves shown in Figure 3.

Effect of surfactant level on the basic form of dronedarone

It can be seen from the curves shown in Figure 4 that the surfactant content in a composition according to the invention has no impact on the release of the active substance.

Effect of surfactant level on dronedarone hydrochloride salt

It can be seen from the curves shown in Figure 5 that the surfactant content in a composition according to the invention has a beneficial effect on the release of the active substance with an optimum rate between 10 and 30%.

Influence of surfactant nature on the basic form of dronedarone and dronedarone hydrochloride

Surfactant	HLB	% de HCl de dronedaron e à 180 min	% dronedarone forme base à 180 min
Pluronic L44	12	49,1	76,38
Chrem RH40	14	59,01	85,3
Tween 60	15	58,32	81,12
Polox 407	22	90,49	72,89
Polox 188	29	69,82	71,32

The curves shown in Figure 6 show that the release kinetics of the base form are equivalent regardless of the non-ionic surfactant used.

The curves shown in Figure 7 show that the kinetics of release of dronedarone hydrochloride are best for HLB between 15 and 25 and particularly around 22.

The following information shall be provided in the form of a summary of the results of the assessment:

Bioavailability is relative to the quantification of drug absorption. It is related to the fraction of the administered drug dose that reaches the general circulation and the rate at which it reaches it. Bioavailability for oral administration depends on digestive absorption and pre-systemic metabolism in the gut and liver among others.

Protocol: 12 healthy young subjects are given either on an empty stomach or during a high fat meal a single dose of 400 mg BID of droneedarone by absorption of G1, G2 or G3 capsules of the compositions defined above. Blood samples are collected regularly over 48 hours and the collected plasma is tested with LC-UV methods to determine the concentration of droneedarone in plasma over time.

Cmax, Tmax and AUC are measured on the resulting curves and the results are summarised in Tables 4 and 5.

Cmax is the peak plasma concentration of dronedaron.

tmax is the time to obtain Cmax.

AUC is the area under the curve or plasma concentration integral as a function of time t. - What?

4.57	8.22	2.57
AUC **	8.41	16.5	3.92

1.51	1.57	1.20
AUC****	1.45	1.47	1.22

6.60	2.18	1.26	3.08
Effet repas¤¤	16.5	2.83	1.46	5.12

Results:

The results indicate that, under fasted conditions, the bioavailability of the G1, G2, G3 capsules of the invention is significantly increased compared to the reference capsule, with the G2 capsule being the most effective.

It is also noted that the meal effect is significantly reduced for the capsules of the invention compared to the reference capsule, with the G2 capsule having the lowest meal effect of about 1,46.

The following information shall be provided in the form of a summary of the results of the assessment: The Protocol Treatment and administration

The dose used is 60 mg/ animal regardless of the period/ condition corresponding to 6 mg/ kg, (assuming a weight of 10 kg for a dog) and the 400 mg dose given to humans (i.e. approximately 6 mg/ kg for a human weight of 70 kg).

The conditions for administration are as follows: Fasting period: animals are not fed the night before dosing. Water and routine food (SSNIFFhdH) are given one hour and 4 hours after dosing respectively. Feeding period: animals are given 50g of a high fat diet (SSNIFF EF Dog FDA Model high fat), 10 minutes before dosing (this diet has an energy value of 100 kcal and is composed of 15% protein, 25% carbohydrates and 50-60% fat). Water and routine dog food (SSNIFFhdH) are then given one hour and 4 hours after dosing respectively.

A pre-treatment with pentagastrin is carried out 0.5 hours before dosing. pentagastrin (6 μg/kg, 0.25 mL/kg) is administered intramuscularly and maintains the animal's gastric pH between 2-3, mimicking human conditions.

The capsule dosing is followed by 30 mL of water by infusion, which is approximately 240 mL given to a human subject in a clinical trial.

Treatment is:Treatment 1: 60 mg of dronedarone hydrochlorate capsule on an empty stomach, orally (reference capsule) (ref 2)Treatment 2: 60 mg of dronedarone hydrochlorate capsule with glucyr and poloxamer 407, on an empty stomach, orally (=G1).Treatment 3: 60 mg of dronedarone in the form of a base reconstituted in situ from dronedarone hydrochloride capsule with glucyr and poloxamer 407, on an empty stomach, orally (=G2).Treatment 4: 60 mg of dronedarone capsule with glucyr and poloxamer 407, on an empty stomach, orally (=G5).Treatment: 60 mg of dronedarone capsule with glucyr and poloxamer 407, orally (=G. No.

Sampling and analysis

Blood samples are taken in plastic tubes containing lithium heparin as an anticoagulant at the following sampling times: before treatment and 0.5, 1, 2, 3, 4, 6, 8 and 24 hours after each treatment.

Plasma concentrations of dronedarone are determined using an exploratory liquid chromatography-coupled mass spectrometer (LC-MS/MS) dosing method, with a low limit of detection of 0.5 ng/mL for the test compounds.

Expression of results

Pharmacokinetic parameters are calculated from individual concentrations by non-compartmental analysis using WinNonLin 5.2.1 (Pharsight, USA) software and using theoretical sampling times (provided that the actual sampling times do not differ by more than 15% of theoretical times).

The following pharmacokinetic parameters were measured for each treatment: Cmax (ng/mL): corresponds to the maximum observed plasma concentration,tmax (h): corresponds to the observed time to reach the maximum concentration,AUClast: corresponds to the area under the plasma concentration curve or integral as a function of time t calculated by the t0 trapezoid method to the time corresponding to the last quantifiable concentration.AUC: corresponds to the area under the plasma concentration curve or integral as a function of time extrapolated to infinity.T1/2z; terminal elimination half-life

The following parameters were also assessed: The relative bioavailability of the drug at the time of administration to patients with severe renal impairment.

Results

Tableau 7 -Paramètres pharmacocinétiques de dronedarone (Mean±SD (CV%)) dans le groupe 1 (n=4 par formulation)

5.73±4.57 (80%)	2.50 (0.50-3.00)	18.9±14.2 (75%)	21.2±14.4 (68%)	1.88±0.624 (33%)
13.5±4.87 (36%)	1.50 (0.50-2.00)	45.0±17.8 (40%)	51.3±21.2 (41%)	2.53±0.377 (15%)
19.5±13.0 (67%)	1.00 (0.50-1.00)	53.3±33.4 (63%)	60.5±35.7 (59%)	2.70±0.762 (28%)

Tableau 7 -Paramètres pharmacocinétiques de dronedarone (Mean±SD (CV%)) dans le groupe 1 (n=4 par formulation)

*median (min-max)

Tableau 8 - Paramètres pharmacocinétiques de dronedarone (Mean±SD (CV%)) dans le groupe 2 (n=4 par formulation)

7.36±4.83 (66%)	1.00 (0.50-2.00)	21.5±13.9 (65%)	28.1±18.0 (64%)*	3.07±0.153 (5%)*
capsule avec Gelucire, dronedarone forme base et poloxamer à jeun	24.6±14.8 (60%)	1.00 (1.00-2.00)	62.3±34.0 (55%)	69.0±37.7 (55%)	2.40±0.535 (22%)
capsule avec Gelucire, dronedarone forme base et poloxamer nourri	16.9±7.41 (44%)	1.00 (1.00-2.00)	44.0±19.9 (45%)	48.0±21.5 (45%)	2.10±0.183 (9%)

Tableau 8 - Paramètres pharmacocinétiques de dronedarone (Mean±SD (CV%)) dans le groupe 2 (n=4 par formulation)

n=3; * median (min-max)

Tableau 9

4.52±3.04 (67%)	1.50 (0.50-6.00)	15.3±8.62 (56%)	15.6±7.73 (50%)	2.90±0.794 (27%)
15.6±4.99 (32%)	1.00 (1.00-2.00)	57.5±11.3 (20%)	66.8±10.1 (15%)	2.68±0.377 (14%)
capsule avec Gelucire,	30.7±12.7 (41%)	1.00 (0.50-2.00)	82.8±29.1 (35%)	91.8±31.5 (34%)	2.53±0.171 (7%)

Tableau 9

* médian (min-max)

All dogs receiving the reference formulation have similar exposure in the fasted state regardless of the group. - What? Tableau 10- Biodisponibilité relative de dronedarone (%) avec 90% CI en conditions à jeun (utilisant la capsule comme référence)

274 (120-625)	283 (112-716)	271 (119-613)
357 (157-812)	311 (123-785)	301 (133-682)
339 (159-724)	325 (177-595)	248 (134-459)*
401 (230-700)	432 (240-778)	500 (273-915)

Tableau 10- Biodisponibilité relative de dronedarone (%) avec 90% CI en conditions à jeun (utilisant la capsule comme référence)

n=3 for 2B1

All the tested formulations have a higher bioavailability than the reference capsule with a relative bioavailability of 271% to 500% on an empty stomach.

The formulas with glutamate with dronedarone hydrochloride and reconstituting the base in situ (Frel=301%) showed greater bioavailability than the reference capsule as in the clinical trial described above.

The gelucyr formulation using the native base exhibits a similar relative bioavailability to the gelucyr formulation using dronedarone hydrochloride and reconstituting the base in situ when compared to the fasting reference as indicated by confidence interval coverage.

The gelucir formulations with or without poloxamer show similar relative bioavailability with a 3- to 5-fold higher bioavailability compared to the reference capsule. Tableau 11- Rapport d'effet repas pour la capsule avec gelucire, dronedarone forme base avec poloxamère

nourri/à jeun	0.73 (0.35-1.53)	0.71 (0.41-1.23)	0.70 (0.41-1.21)

There is a tendency for a slight decrease in Cmax of 1.4-fold when the poloxamere gel capsule is administered with high-fat food. - What? Tableau 12- Rapport d'effet repas pour la capsule avec gelucire, dronedarone forme base sans poloxamer

nourri/à jeun	1.93 (1.16-3.21)	1.39 (0.82-2.35)	1.32 (0.81-2.16)

There is a trend towards a positive meal effect when the poloxamere-free gelucir capsule is administered with a high-fat meal, as Cmax is increased by 1.9 times, AUClast by 1.4 times and AUC by 1.3 times. However, this increase is not significant for AUC as 90% CI includes the unit.

Claims (19)

1. Pharmaceutical composition comprising at least one active principle selected from (i) 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of base, (ii) 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of a pharmaceutically acceptable salt, characterized in that it further comprises at least one amphiphilic lipid excipient with HLB value between 5 and 18 and in that said lipid excipient is selected from the semi-solid subsituted polyoxylglycerides.
2. Composition according to the preceding claim, characterized in that the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of a pharmaceutically acceptable salt is selected from 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran hydrochloride, 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran fumarate and 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran oxalate.
3. Composition according to either one of the preceding claims, characterized in that the active principle is selected from 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of base and 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran hydrochloride.
4. Composition according to any one of the preceding claims, characterized in that said composition further comprises at least one surfactant and/or at least one co-solvent.
5. Composition according to any one of the preceding claims, characterized in that said amphiphilic lipid excipient with HLB value between 5 and 18 has a melting point below 50°C.
6. Composition according to any one of the preceding claims, characterized in that it comprises 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran hydrochloride, as active principle.
7. Composition according to any one of the preceding claims, characterized in that said amphiphilic lipid excipient with HLB value between 5 and 18 is selected from the lauroyl macroglyceride marketed under the brand name Gelucire® 44/14 and Gelucire® 50/13.
8. Composition according to any one of the preceding claims, characterized in that said amphiphilic lipid excipient with HLB value between 5 and 18 is the lauroyl macroglyceride marketed under the brand name Gelucire® 44/14.
9. Composition according to one of the preceding claims, characterized in that it comprises:

   • 1-60 wt% of at least one active principle;

   • 40-99 wt% of at least one lipid excipient;

   • 0-30% of at least one compound selected from surfactants, co-solvents, diluents, disintegrants, lubricants, organic or inorganic bases and plasticizers,

   the percentages being expressed by weight relative to the total weight of said composition.
10. Composition according to one of the preceding claims, characterized in that it comprises:

    • 1-60 wt% of at least one active principle;

    • 40-99 wt% of at least one lipid excipient,

    • 0-30 wt% of at least one surfactant, and

    • 0-29 wt% of at least one co-solvent;

    the percentages being expressed by weight relative to the total weight of said composition.
11. Composition according to one of Claims 9 or 10, characterized in that it comprises:

    • 1-50 wt% of at least one active principle, advantageously between 10 and 45%, even better between 20% and 40%; and/or

    • 45-80 wt% of at least one lipid excipient, advantageously between 50% and 60%; and/or

    • 1-20 wt% of at least one surfactant, advantageously between 5% and 15%; and/or

    • 1-20 wt% of at least one co-solvent, advantageously between 2 and 15%.
12. Composition according to one of Claims 9 to 11, characterized in that the surfactant is hydrophilic and nonionic.
13. Composition according to one of Claims 9 to 12, characterized in that the surfactant is selected from:

    • ethylene oxide/propylene oxide copolymers;

    • polyethoxylated castor oils;

    • ethoxylated polysorbates, and

    • polyethylene hydroxystearates.
14. Composition according to any one of Claims 9 to 13, characterized in that the surfactant is poloxamer 407.
15. Composition according to any one of Claims 9 to 14, characterized in that the co-solvent is selected from the alcoholic organic solvents or the glycol derivatives.
16. Dosage form comprising a composition according to any one of Claims 1 to 15.
17. Dosage form according to Claim 16, characterized in that it is a capsule selected from hard capsules, soft shell capsules, enteric capsules and modified-release capsules.
18. Dosage form according to either one of Claims 16 to 17, characterized in that it is a hard capsule.
19. Dosage form according to any one of Claims 16 to 18, characterized in that it contains between 50 and 500 mg of active principle, advantageously between 200 and 400 mg of active principle.