HK1188129A - Pharmaceutical composition and dosage form comprising dronedarone, and preparation method thereof - Google Patents

Description

The present invention generally relates to an oral pharmaceutical composition containing an active ingredient with antiarrhythmic activity. More specifically, the invention concerns a semisolid or liquid pharmaceutical composition intended to be advantageously used in the form of a capsule dosage form, said composition comprising at least one benzofuran derivative, as the active ingredient with antiarrhythmic activity, and at least one lipidic excipient.

The present invention also relates to a process for preparing such a pharmaceutical form based on the said pharmaceutical composition, and is also related to the application of such a composition or such a pharmaceutical form in therapy.

By "benzofuran derivative with antiarrhythmic activity," it is meant in the context of the present invention, a benzofuran compound selected from those described in the patents US 3248401, US 5223510 and EP 338746 as well as in the patent applications WO 88/07996, WO 89/02892, WO 90/02743 and WO 94/29289.

Among these compounds, one can mention 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzo-furan or dronedarone and its pharmaceutically acceptable salts described in patent EP1315709, as well as 2-n-butyl-3-(3,5-diiodo-4-diethylaminoethoxy-benzoyl) benzofuran or amiodarone and its pharmaceutically acceptable salts described in patent US 3248401. WO2005/048979 describes a modified release pharmaceutical composition comprising microtablets containing an active ingredient such as dronedarone coated with a controlling layer containing an amphiphilic lipid excipient with an HLB value of 1-20 (e.g., fatty acid esters, glyceryl monostearate; glycerol monooleate, or Geleol).

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

By "pharmaceutically acceptable salt," it is meant a salt that is not toxic to the individual to whom it is administered when given in standard doses. Thus, for example, the following may be named as pharmaceutically acceptable salts of dronedarone: the hydrochloride of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofurane, the fumarate of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofurane, and the oxalate of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofurane.

The antiarrhythmic compounds used within the scope of the invention, notably dronedarone and amiodarone, in the form of the free base or their salts, particularly their hydrochloride salts, are characterized by low water solubility, which constitutes a major drawback for the oral administration of the active ingredient. Thus, the solubility of these antiarrhythmic compounds is low in simulated gastric medium (3 mg/ml at pH = 1.5) and very low in simulated intestinal medium (1 µg/ml at pH = 6.5).

For example, the solubility curve of dronedarone hydrochloride at room temperature as a function of pH reveals a maximum solubility of approximately 1 to 2 mg/ml in the pH range of 3 to 5, but very low at pH values around 6 to 7, since it is only 10 µg/ml at pH = 7. As for amiodarone hydrochloride, its solubility at room temperature is 0.3 to 0.9 mg/ml in the pH range of 3 to 4 and a few µg/ml at pH = 7. Thus, it is possible to dissolve 400 mg of dronedarone hydrochloride in 200 ml of aqueous buffer solution adjusted to pH = 4 (aqueous solution of 0, ...1 M in NaH2PO4). On the other hand, in this diluted medium (1/10 dilution with a buffer solution at pH = 7, aqueous solution 0.1 M in Na2HPO4), dronedarone hydrochloride precipitates (final medium pH = 6.7). These solubility conditions are similar to those found in the gastrointestinal tract; therefore, it can be assumed that dronedarone hydrochloride will be subjected in the stomach to acidic conditions favorable for its dissolution. However, as soon as it enters the intestine, it will encounter a medium with a pH between 6 and 7, i.e., a non-solubilizing environment, where it may precipitate.

Alternatively, the absorption of the active ingredient mainly occurs at the intestinal level, and it is now well established that oral administration requires an optimal dissolution of the active ingredient in order to hope for sufficient permeation throughout the gastrointestinal tract, and thus an acceptable exposure, leading to a significant therapeutic effect.

Considering the issues of solubility and bioavailability, a pharmaceutical formulation has been developed and is currently on the market. It is available as a 426mg film-coated tablet containing 400 mg of dronedarone hydrochloride, sold under the commercial name Multaq®. The recommended dosage for adults is one tablet taken twice daily, and it must be taken with meals to ensure optimal activity of the active ingredient.

Indeed, from a pharmacokinetic perspective, after oral administration with a meal, dronedarone is well absorbed (at least 70%). However, due to first-pass presystemic metabolism, the absolute bioavailability of this drug (taken with food) is only 15%. Concurrent consumption of food increases the bioavailability of the product by a factor of 2 to 4 compared to taking the drug without simultaneous food intake. After oral administration with a meal, peak plasma concentrations of dronedarone and its main active circulating metabolite (N-debutylated metabolite) are reached within 3 to 6 hours. The pharmacokinetics of dronedarone and its N-debutylated metabolite show a moderate deviation from dose proportionality: doubling the dose results in an increase in Cmax and AUC by a factor of approximately 2.5 to 3.0.

Alternatively, it is clearly preferable for a patient to be able to benefit from a therapeutic treatment without the constraint of taking it with or without meals, particularly in the field of treating heart rhythm disorders, especially arrhythmias.

The development of a pharmaceutical composition for oral administration of an active ingredient with antiarrhythmic activity, capable of providing acceptable bioavailability regardless of whether food is concurrently ingested, that is, a composition involving a limited meal effect to be effective, remains therefore of essential interest.

It has now been surprisingly and unexpectedly found a new pharmaceutical composition allowing oral administration of at least one antiarrhythmic active ingredient, advantageously 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofuran or a derivative thereof, such as, for example, one of its salts, without the above-mentioned disadvantages. This composition comprising at least one active ingredient included in a matrix formed by the other ingredients of said composition, in particular other excipients, proves to be sufficiently stable and exhibits appropriate solubility to remain in the gastrointestinal tract until the absorption site. This composition can also be taken on an empty stomach or with a light snack or a low-fat meal, in one or more doses.

The present invention according to claim 1 relates to a pharmaceutical composition for oral administration of an active ingredient with antiarrhythmic activity, such as, for example, 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamido-benzofuran (i) in the form of a base, (ii) in the form of a pharmaceutically acceptable salt, characterized in that it comprises, in addition to said active ingredient, at least one amphiphilic lipid excipient having an HLB value between 5 and 18, wherein said lipid excipient is selected from semi-solid substituted polyoxylglycerides. The composition according to the invention may be in the form of a semi-solid or liquid galenic dosage form. Indeed, it can advantageously be packaged in the form of a capsule, even more advantageously in the form of a hard capsule.

In the context of the present invention, the following terms are understood as: - Capsule: a dosage form with a hard or soft shell; - Gelatin capsule: a hard-shell capsule, consisting of two parts: one part called the body and the other part called the cap; - Bioavailability: a term used to describe a pharmacokinetic property of drugs, namely, the fraction of a dose that reaches the bloodstream. It evaluates the amount of drug absorbed that reaches the bloodstream and the rate of absorption of said drug; - Active ingredient: any substance having a therapeutic effect, such as, for example, an antiarrhythmic effect. In the context of the invention, it particularly refers to any benzofuran derivative having antiarrhythmic activity.defined below, in particular the dronedarone in the form of a base, in the form of pharmaceutically acceptable salts with organic or inorganic acids. These salts can be prepared with pharmaceutically acceptable acids, but also the salts of other useful acids, for example, for the purification or isolation of compounds of formula (I), are also part of the invention. Excipient: any inactive or inert substance with respect to a living organism, in contrast to the active ingredient and which facilitates the preparation and administration of a drug; Lipidic excipient: any excipient known to those skilled in the art as a lipid solvent, advantageously amphiphilic, having an HLB value (term defined below), which according to the invention is lower than 20 and higher than 1; Matrix:The entire set of ingredients other than the active principle or principles of the composition according to the invention, in particular the excipients; HLB value, the hydrophilic-lipophilic balance value, according to the classification developed by Griffin, well known to those skilled in the art; Surfactant, an excipient which, due to its amphiphilic properties, facilitates the wetting of powders, improves solubility/solubilization and/or retards reprecipitation; Co-solvent, any solvent that enhances the feasibility of the manufacturing process of the composition according to the invention based on key parameters such as the viscosity and melting point of the matrix of said composition as well as the solubilization or dispersion of the active ingredient within said matrix; Diluent,A bulking agent used to obtain a sufficient composition volume for manufacturing a galenic form, for example, a capsule of the desired size and possessing physical characteristics suitable for the chosen manufacturing technique for the capsule; Disintegrant, an excipient that allows satisfactory disintegration of the galenic form, thus enabling the disintegration of the active ingredient in the stomach by increasing the friability and decreasing the hardness of the galenic form; Anti-adherent, an excipient intended to prevent particles from sticking together and to the manufacturing equipment during the production of the galenic form, for example during the filling of capsules.Lubricant, an excipient intended to facilitate the manufacturing steps of pharmaceutical forms by their slippery role, that is, by increasing the flowability of particles within the machine's tubing; Plasticizer, an excipient intended to enable the constant release of the active ingredient from the pharmaceutical form by inserting itself between polymer chains and allowing them to slide over each other. It is selected according to its solubility.

Among the compositions according to the invention, one can mention a first group of pharmaceutical compositions comprising: from 1 to 60% by weight of at least one active ingredient according to the invention, advantageously from 1 to 50%, even more advantageously from 10 to 45%, better still from 20% to 40%; from 40 to 99% by weight of at least one lipidic excipient according to the invention, advantageously from 45 to 80%, even more advantageously from 50% to 60%; from 0 to 30% by weight of at least one compound selected from surfactants, cosolvents, diluents, disintegrants, lubricants, organic or inorganic bases, and plasticizers, advantageously from 1 to 20%, better still from 1 to 10%; the percentages being expressed by weight relative to the total weight of said composition.

Among the compositions according to the invention, a second group of pharmaceutical compositions can be mentioned, comprising: from 1 to 60% by weight of at least one active ingredient according to the invention, advantageously from 1 to 50%, even more advantageously from 10 to 45%, preferably from 20% to 40%; from 37 to 99% by weight of at least one lipidic excipient according to the invention, advantageously from 45 to 80%, even more advantageously from 45% to 55%; from 0 to 30% by weight of at least one compound selected from surfactants, cosolvents, diluents, disintegrants, lubricants, organic or inorganic bases, and plasticizers, advantageously from 1 to 20%, even more advantageously from 1 to 10%; the percentages being expressed as weight per weight of the total weight of said composition.

Among the compositions according to the invention, a third group of pharmaceutical compositions can be mentioned, comprising: from 1 to 60% by weight of at least one active ingredient according to the invention, advantageously from 1 to 50%, even more advantageously from 10 to 45%, preferably from 20 to 40%; from 40 to 99% by weight of at least one lipidic excipient according to the invention, advantageously from 45 to 80%, even more advantageously from 50 to 60%; from 0 to 30% by weight of at least one surfactant, advantageously from 1 to 20%, even more advantageously from 5 to 15%; and from 0 to 29% by weight of at least one cosolvent, advantageously from 1 to 20%, even more advantageously from 2 to 15%; the percentages being expressed by weight relative to the total weight of the said composition. The total of the composition amounts to 100% by weight.

Among the compositions according to the invention, a fourth group of pharmaceutical compositions can be mentioned, comprising: from 1-60% by weight of at least one active ingredient according to the invention, advantageously between 1 and 50%, even more advantageously between 10 and 45%, still more advantageously between 20% and 40%; from 37-99% by weight of at least one lipidic excipient according to the invention, advantageously between 45 and 80%, even more advantageously between 50% and 60%; from 0-30% by weight of at least one surfactant, advantageously between 1% and 20%, even more advantageously between 5% and 10%; and from 0-29% by weight of at least one cosolvent, advantageously between 1 and 20%, even more advantageously between 2 and 15%; the percentages being expressed by weight relative to the total weight of said composition. The total of the compositions amounts to 100% by weight.

Among the compositions according to the invention, a fifth group of pharmaceutical compositions can be mentioned, comprising: from 60 to 200% by weight of at least one lipidic excipient according to the invention, advantageously between 120 and 180%, even more advantageously 180%; from 0 to 30% by weight of at least one surfactant, advantageously between 5% and 30%, even more advantageously between 10% and 30%; from 0 to 30% by weight of at least one cosolvent, advantageously between 1 and 20%; the percentages being expressed as weight relative to the total active ingredient weight.

Pharmaceutical compositions according to the invention include at least one active ingredient with antiarrhythmic activity and at least one lipid excipient.

Among the active ingredients having antiarrhythmic activity according to the invention, one can mention 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of a base or dronedarone, and its pharmaceutically acceptable salts described in patent EP1315709.

As pharmaceutically acceptable salts, for example, the chloride of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, the fumarate of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, and the oxalate of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran can be mentioned.

Advantageously, the composition according to the invention comprises 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran or the hydrochloride of 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran as the active ingredient.

According to one variant, the solubilization of the active ingredient in its base form can be achieved by starting from pharmaceutically acceptable salts of dronedarone, as mentioned above, and reforming the active ingredient in its base form in situ by changing the pH with an organic or inorganic base.

The compositions according to the invention comprising at least one pharmaceutically acceptable salt of dronedarone, and further comprising at least one organic or inorganic base, advantageously in a stoichiometric molar amount relative to the active ingredient in the form of a base, are part of the present invention.

As an indication, the nature of the base that can be used in the composition may be organic, such as for example ethanolamine, or mineral, such as for example soda ash or caustic potash. Advantageously, it is soda ash.

The active principle or principles conforming to the invention are present in the composition according to the invention in an amount ranging from 1-60% by weight, advantageously from 1 to 50%, even more advantageously from 10 to 45%, and preferably from 20% to 40% by weight relative to the total weight of the composition.

The lipidic excipient is an amphiphilic lipidic excipient with a HLB value ranging from 1 to 20 and a melting temperature lower than 50°C.

The lipidic excipient is an amphiphilic lipidic excipient with a HLB value ranging from 2 to 20 and a melting temperature lower than 50°C.

Amphiphilic semi-solid excipients at room temperature and amphiphilic liquid excipients at room temperature are distinguished.

The lipidic excipient according to the invention can be selected from: Semi-solid substituted glycerides, Liquid substituted glycerides, Semi-solid substituted polyoxylglycerides, Liquid substituted polyoxylglycerides, and their mixtures.

For example, one can mention a group in which the lipidic excipient is chosen from: semi-solid substituted glycerides according to the invention, such as the commercially available Gellucers, for example under the brand name Gelucire® 33/01, Gelucire® 39/01, Gelucire® 43/01 and Geleol®, Peceol™; liquid substituted glycerides according to the invention, such as those commercially available, for example under the name Labrafac Lipophile® WL1349; semi-solid substituted polyoxylglycerides according to the invention, such as the Gellucers commercially available, for example under the brand name Gélucire® 44/14, Gélucire® 50/13; liquid substituted polyoxylglycerides according to the invention, such as those commercially available, for example under the brand names Labrafil® M1944CS, Labrafil® M2125CS, Labrafil® M2130CS and Labrasol®.

For example, one can mention another group in which the lipid excipient is chosen from semi-solid substituted polyoxylglycerides that comply with the invention, such as the Gélucire products, particularly the lauryl macroglyceride marketed under the brand name Gélucire® 44/14.

When the active ingredient is in the form of a salt, the composition may be in the form of a dispersion of said solid active ingredient in a solid matrix at ambient temperature, in the case where a lipid or semisolid excipient is used in sufficient quantity, or in the form of a dispersion of solid in an oil at ambient temperature, in the case where a liquid lipid excipient is used in sufficient quantity. Furthermore, the solubility of said active ingredient in the composition also depends on the pH of the medium in which the composition is located.

The lipidic excipient, a semi-solid amphiphilic substance at room temperature, of the composition according to the invention has the advantage of enabling the dispersion of a solid or hot solubilization of the active ingredient within the matrix of said composition, and facilitating the dissolution of the active ingredient when the matrix dissolves in the aqueous gastric and/or intestinal environment.

The lipidic excipient, which is amphiphilic and liquid at room temperature, of the composition according to the invention has the advantage of facilitating the dissolution of the active ingredient in the gastric and/or intestinal aqueous medium.

Advantageously, the composition according to the invention comprises at least one lipidic, amphiphilic excipient having an HLB value between 5 and 18.

Lipidic excipients with an HLB value ranging from 5 to 18, as specified in the invention, can be selected from the group consisting of: medium-chain mono- and diglycerides, such as for example Capmul MCM® (HLB value between 5.5 and 6), marketed by Abitec company; propylene glycol monolaurate, such as for example Lauroglycol® 90 (HLB value equal to 5) and Capmul PG12®, respectively marketed by Gattefossé and Abitec companies; caprylic/caproyl polyethylene glycol-8 glycerides, such as for example Labrasol® (HLB value equal to 14), marketed by Gattefossé company; lauroyl polyglyceryl glycerides, such as for example Gelucire® 44/14 (HLB value equal to 14) and Gelucire® 50/13 (HLB value equal to 13), marketed by Gattefossé company; propylene glycol monocaprylate, such as for example Capmul® PG-8 (HLB value equal to 6), marketed by Abitec company; and mixtures thereof.

In particular, the lipidic, amphiphilic excipient having a HLB value ranging from 5 to 18 is selected from the group consisting of Capmul MCM®, Lauroglycol® 90, Capmul PG12®, Labrasol®, Gelucire® 44/14, Gelucire® 50/13, Capmul® PG-8, and mixtures thereof.

According to one embodiment, the lipidic excipients according to the invention are selected from lipidic, amphiphilic excipients having an HLB value between 12 and 18.

The lipidic excipient(s) complying with the invention is or are present in the composition according to the invention in an amount ranging from 40-99% by weight, advantageously between 45 and 80%, even more advantageously between 50% and 60% by weight relative to the total weight of the composition.

The lipidic excipient(s) conforming to the invention is/are present in the composition according to the invention in an amount ranging from 37-99% by weight, advantageously between 45 and 80%, even more advantageously between 50% and 60% by weight relative to the total weight of the composition.

The lipid excipient(s) compliant with the invention is/are present in the composition according to the invention in an amount ranging from 100-200% by weight, advantageously between 110 and 180%, even more advantageously between 50% and 60% by weight relative to the total active ingredient weight.

The pharmaceutical compositions according to the invention can further include at least one surfactant and/or at least one cosolvent.

The surfactant is advantageously hydrophilic and/or non-ionic. It can be selected from: ethylene oxide/propylene oxide copolymers hereinafter referred to as poloxamers, such as poloxamer 124 marketed under the brand SYNPERONIC PE/L44; poloxamer 188 marketed under the brand PLURONIC F68 or SYNPERONIC PE/F68; poloxamer 237 marketed under the brand PLURONIC F87 or SYNPERONIC PE/F87; poloxamer 338 marketed under the brand SYNPERONIC PE/F108 or poloxamer 407 marketed under the brand PLURONIC F127, SYNPERONIC PE/F127 or LUTROL F127; polyethoxylated castor oils, such as those marketed under the brand CREMOPHOR RH40; ethoxylated polysorbates, such as polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80, marketed respectively under the brands TWEEN 20, TWEEN 40, TWEEN 60, and TWEEN 80; and polyethylene hydroxystearates, such as polyethylene hydroxystearate 660 marketed under the brand SOLUTOL HS15.

In particular, the surfactant can be selected from: ethylene oxide/propylene oxide copolymers hereinafter referred to as poloxamers, such as poloxamer 124 marketed under the brand SYNPERONIC PE/L44; poloxamer 188 marketed under the brand PLURONIC F68 or SYNPERONIC PE/F68; or poloxamer 407 marketed under the brands PLURONIC F127, SYNPERONIC PE/F127 or LUTROL F127; polyethylene glycol castor oils, such as those marketed under the brand CREMOPHOR RH40; ethoxylated polysorbates, such as polysorbate 60 marketed under the brand TWEEN 60; and polyethylene hydroxystearates, such as polyethylene hydroxystearate 660 marketed under the brand SOLUTOL HS15.

Advantageously, the surfactant or surfactants conforming to the invention are selected from ethylene oxide/propylene oxide copolymers called poloxamers, and even more advantageously, it is poloxamer 407.

The said surfactant may be present in the composition according to the invention in an amount ranging from 0% to 30% by weight relative to the total weight of the composition, advantageously from 1% to 20% by weight, even more advantageously from 5% to 15% by weight of surfactant.

The said surfactant may be present in the composition according to the invention in an amount of 0-30% by weight of at least one surfactant, advantageously between 5% and 20%, even more advantageously between 10% and 20%, by weight relative to the total weight of active ingredient.

The co-solvent agent according to the invention can be selected from alcoholic organic solvents or glycol derivatives.

As cosolvents, one can mention: Alcohols such as ethanol and isopropanol; Propylene glycol and its derivatives, optionally substituted, such as those marketed under the brand names Labrafac® PG, Lauroglycol™ 90, Lauroglycol™ FCC, Capryol™ 90, Capryol™ PGMC.

The said cosolvent can be present in the pharmaceutical composition according to the invention in an amount ranging from 0% to 29% by weight relative to the total weight of the composition, advantageously between 1% and 20% by weight, even more advantageously from 2% to 15% by weight of cosolvent.

The said cosolvent may be present in the pharmaceutical composition according to the invention in an amount of 0-30% by weight of at least one cosolvent, advantageously between 1 and 20% by weight relative to the total active ingredient weight.

According to one embodiment, the co-solvent is a substituted glycol derivative and/or has a weight content lower than 29% relative to the total weight of said composition; advantageously, the co-solvent is propylene glycol and/or has a weight content of approximately 20%.

According to one embodiment, the co-solvent is a substituted glycol derivative and/or present in an amount less than 30% by weight relative to the total weight of the active ingredient, advantageously the co-solvent is Propylene Glycol and/or present in an amount of about 20% by weight relative to the total weight of the active ingredient.

According to one embodiment, the composition according to the invention comprises: the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran hydrochloride or the 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran in the form of a base, as the active ingredient, and/or at least one semi-solid lipid excipient with an HLB value between 1-20, advantageously between 5-18, even more advantageously between 12-18, advantageously selected from substituted semi-solid glycerides and substituted semi-solid polyoxylglycerides, preferably Gélucire® 44/14, and/or at least one surfactant, advantageously selected from ethylene oxide/propylene oxide copolymers known as poloxamers, more advantageously poloxamer 407, and optionally at least one cosolvent as defined above.

This pharmaceutical composition is in a liquid or semi-solid form, that is, of a paste-like consistency, depending on the consistency and nature of the excipient(s) used, among others, the lipidic excipient, at ambient temperature. A lipidic or semi-solid excipient at ambient temperature will lead to the formation of a semi-solid matrix and therefore to a paste-like composition according to the invention, whereas a liquid lipidic excipient at ambient temperature will result in the formation of a liquid matrix and therefore to a liquid composition according to the invention.

Thus, in the case where the lipidic excipient according to the invention is selected from lipidic or semisolid excipients, the composition according to the invention can be prepared by implementing known solubilization or solid dispersion techniques, either at a cold or hot temperature within the lipidic excipient forming a lipidic matrix. The manufacturing of the composition consists, for example, in solubilizing or dispersing the active ingredient according to the invention and optionally other excipients according to the invention in said lipidic excipient at a temperature ranging from approximately 30°C to 60°C, such as, for example, a temperature of approximately 44°C, said temperature being chosen depending on the melting point of the lipidic excipient used.

According to a particularly advantageous embodiment, the manufacturing process of the composition according to the invention consists in dissolving the active ingredient, advantageously 2-n-butyl-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-5-methylsulfonamidobenzofuran, in the form of a base, at approximately 44°C in the lipidic excipient, advantageously lauryl macroglycerides, such as, for example, Gelucire® 44/14.

In the case where the lipidic excipient, in accordance with the invention, is selected from liquid lipidic excipients, the composition according to the invention can be prepared by using known methods for solubilizing or dispersing the active ingredient in the lipidic excipient, forming a liquid lipidic matrix at ambient temperature.

The preparation processes of the pharmaceutical compositions according to the invention are carried out by the classical techniques known to those skilled in the art.

The pharmaceutical composition, which is a liquid or semi-solid, as obtained according to the invention, can then be directly incorporated into a capsule. Encapsulation is carried out using conventional encapsulation methods, taking into account the physico-chemical constraints of said composition and said process.

This composition can optionally be converted into powders, granules, or may optionally be incorporated into capsules or used as is.

Thus, the invention also aims at a pharmaceutical formulation comprising a pharmaceutical composition according to the invention.

This dosage form can be presented as a capsule containing the composition according to the invention, or optionally as powders, granules that can be dispensed in multi-dose containers or in unit doses such as packages, sachets.

Capsules are solid preparations consisting of a hard or soft shell, varying in shape and capacity, generally containing a single dose of active ingredient. The shell is made from gelatin or other natural or synthetic substances whose consistency can be adjusted by adding, for example, glycerin or sorbitol. Other excipients such as surfactants, opacifiers, antimicrobial preservatives, sweeteners, colorants, and/or flavoring agents may also be added to the capsule shell formulation.

Examples of capsules include: capsules, soft gelatin capsules, enteric-coated capsules, and modified-release capsules.

Fortunately, the dosage form according to the invention is a capsule.

The manufacturing process of capsules comprising a body and a cap consists of (i) preparing the composition according to the invention by mixing the ingredients as defined above, and then (ii) filling the capsule cap and/or body parts by volumetric distribution according to an appropriate method for powders (compressor-doser, a scraping method, a combined scraping and compacting or ramming method, a screw feeder method, or a cell dosing method) or for semi-solids (pouring of molten or liquid product), and finally closing the capsules by fitting together the parts forming the cap and body of said capsule.

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

By way of example but not limitation, the amount of active ingredient can vary from 50 to 500 mg per dosage unit, such as for example (i) a capsule, advantageously a gelatin capsule, or (ii) a powder sachet, or granules, and the amount of lipid excipient ranges from 0.5 to 100 mg. Preferably, a pharmaceutical formulation according to the invention, for example a capsule, can include between 200 and 400 mg of active ingredient.

The pharmaceutical composition according to the invention and the galenic form comprising such a composition aims to limit the meal effect after oral administration in humans. The lipidic excipient allows, on one hand, to dissolve the active ingredient according to the invention and, on the other hand, to protect it from the negative effects of pH in the intestinal tract, thus significantly reducing the meal effect. The presence of a surfactant, such as, for example, poloxamer, in said composition allows to limit the reprecipitation and agglomeration of the active ingredient during the gastrointestinal tract. Figure 1 shows the dissolution curves of capsules according to the invention (Capsules G1 to G6).of a reference capsule and a 10% poloxamer comparative tablet, all these formulations containing the active ingredient according to the invention. Figure 2 shows the dissolution curves of capsules according to the invention (Capsules G4 to G8), all these formulations containing the active ingredient according to the invention. Figure 3 shows the dissolution curves of capsules according to the invention (Capsules G1, G3, G9), all these formulations containing the active ingredient according to the invention. Figure 4 shows the dissolution curves of capsules according to the invention (Capsules G5, G10, G13), all these formulations containing the active ingredient according to the invention. Figure 5 shows the dissolution curves of capsules according to the invention (Capsules G1,G9, G11, G12), all these formulations containing the active ingredient according to the invention. Figure 6 shows the dissolution curves of capsules according to the invention (Capsules G1, G22, G24, G26, G28), all these formulations containing the active ingredient according to the invention. Figure 7 shows the dissolution curves of capsules according to the invention (Capsules G5, G23, G25, G27, G29), all these formulations containing the active ingredient according to the invention.

These curves show the percentage by weight of active ingredient released as a function of time, expressed in minutes. The thick vertical line at 60 minutes represents the moment when an alkaline NaOH solution is added to the simulated gastric medium to simulate an intestinal environment.

EXAMPLES

The table A below shows the solubility of dronedarone hydrochloride and the dronedarone base form in lipidic excipients according to the invention.

Compositions according to the invention have been made, whose composition is detailed in the tables 1, 3 and 4 below.

Comparative compositions, not in accordance with the invention, were prepared, whose composition is detailed in Table 2 below. The amounts of compounds used to prepare said compositions are expressed in mg in said Tables 1 and 2. "–" means absent from the composition. "QS" means in a sufficient quantity. "HCl salt" means dronedarone hydrochloride. "Base" means dronedarone base form. "Pol." means "poloxamer". "Geluc." means "Gelucire". "Crém. RH40" means "Crémophor 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 centesimal composition of these formulations G1 to G6 and other formulations according to the invention is expressed in the tables 3 and 4 below. 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

Then, opaque white size 0 capsules were manufactured using the compositions from the examples below and using the composition of Comparative Example 2, to obtain capsules G1-G29 according to the invention and one non-conforming capsule, i.e., the reference capsule. The composition of Comparative Example 1, which is not in accordance with the invention, was used to manufacture a non-conforming tablet.

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 equipment necessary for the manufacture of the compositions and capsules, whose operating procedures are described below, is as follows: Magnetic stirrer, Beaker, Precision balance suitable for the weighed amount, Sieve 0.315 mm, Water bath, Gilson pipette 1000 µL with piston, Capsule filler.

Moreover, the gelucire 44/14 used to manufacture the formulations is heated in an oven at 55°C the evening before production. Homogenization is performed manually by inverting the pot.

Production of the G1 capsule: Operating procedure:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for preparation. The dronedarone in the form of hydrochloride is sieved through a sieve with an aperture of 0.315 mm before weighing. Melt and mix GELUCIRE® 44/14 and Poloxamer 407 under slow stirring at a stirrer speed of 200 rpm for approximately 10 minutes at a water bath temperature of 55°C-60°C. Add propylene glycol at a stirrer speed of 200 rpm and a water bath temperature of 55°C-60°C. Gradually add and disperse the previously sieved dronedarone hydrochloride under high stirring at a speed of 300-650 rpm. After addition, stir for 30 minutes at a mixing speed of 500 rpm and a water bath temperature of 55°C-60°C. Fill with an automatic pipette into opaque white size 0 capsules. The capsules are filled by individual weighing. The stirring speed during filling is 500 rpm and the water bath temperature is 55°C-60°C. After closing, the capsules are placed vertically on the capsule filler for solidification at room temperature.

Production of the G2 capsule: Operating procedure:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for manufacturing. Dronedarone hydrochloride is sieved through a 0.315 mm mesh before weighing. Melt and mix GELUCIRE® 44/14 and Poloxamer 407 under slow stirring at an agitator speed of 200 rpm for approximately 10 minutes at a water bath temperature of 55°C-60°C. Gradually add and disperse the previously sieved dronedarone hydrochloride under vigorous stirring at a speed of 300-650 rpm. After addition, stir for 10 minutes at a mixing speed of 500 rpm at a water bath temperature of 55°C-60°C. Add the 27% sodium hydroxide solution at an agitation speed of 500 rpm. After addition, continue mixing for 30 minutes at a water bath temperature of 55°C-60°C. Fill size 0 opaque white capsules using an automatic pipette. The capsules are filled by individual weighing. The agitation speed during filling is 500 rpm and the water bath temperature is 55°C-60°C. After closing, the capsules are placed vertically on the capsule filler for solidification at room temperature.

Production of the G3 capsule: Operating Procedure:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for preparation. The dronedarone in the form of hydrochloride is sieved through a sieve with an opening of 0.315 mm before weighing. Gradually add and disperse the previously sieved dronedarone hydrochloride under vigorous stirring at a speed of 300-650 rpm during the addition. After addition, mix for 30 minutes at a mixing speed of 350 rpm and a water bath temperature of 55°C-60°C. Fill with an automatic pipette into opaque white size 0 capsules. The capsules are filled by individual weighing. The stirring speed during filling is 500 rpm and the water bath temperature is 55°C-60°C. After closing, the capsules are placed in a vertical position on the capsule filler for solidification at room temperature.

Production of the G4 capsule: Operating procedure:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for preparation. Dronedarone is sieved through a sieve with an aperture of 0.315 mm before weighing. Melt and mix GELUCIRE® 44/14 and Poloxamer 407 under slow stirring at a stirrer speed of 200 rpm for approximately 10 minutes at a water bath temperature of 55°C-60°C. Gradually add and dissolve the previously sieved dronedarone base under vigorous stirring at a speed of 300-650 rpm during addition. After addition, stir for 30 minutes at a mixing speed of 500 rpm and a water bath temperature of 55°C-60°C. Gradually add water under stirring at a stirrer speed of 500 rpm for about 10 minutes and at a water bath temperature of 55°C-60°C. Fill with an automatic pipette into size 0 opaque white capsules. The capsules are filled by individual weighing. The stirring speed during distribution is 500 rpm and the water bath temperature is 55°C-60°C. After closing, the capsules are placed in a vertical position on the capsule filler for solidification at room temperature.

Production of the G5 capsule: Operating Procedure:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for preparation. Dronedarone is sieved through a 0.315 mm mesh before weighing. Melt and mix GELUCIRE® 44/14 and Poloxamer 407 under slow stirring at an impeller speed of 200 rpm for approximately 10 minutes at a water bath temperature of 55°C–60°C. Add propylene glycol at an impeller speed of 200 rpm and a water bath temperature of 55°C–60°C. Gradually add and dissolve the previously sieved base form of dronedarone under high-speed stirring at a speed of 300–650 rpm during addition. After addition, stir for 30 minutes at a mixing speed of 500 rpm and a water bath temperature of 55°C–60°C. Fill with an automatic pipette into size 0 opaque white capsules. The capsules are filled by individual weighing. The stirring speed during filling is 500 rpm and the water bath temperature is 55°C–60°C. After closing, the capsules are placed vertically in the capsule filler for solidification at room temperature.

Production of the G6 capsule: Operating Mode:

Weigh the melted GELUCIRE® 44/14 previously melted in the beaker used for manufacturing. Dronedarone is sieved through a 0.315 mm mesh before weighing. Melt and mix the GELUCIRE® 44/14 under slow stirring at 200 rpm for approximately 10 minutes at a water bath temperature of 55°C-60°C. Gradually add and dissolve the previously sieved dronedarone base under intense stirring at a speed of 300-650 rpm. After addition, stir for 30 minutes at a mixing speed of 500 rpm and a water bath temperature of 55°C-60°C. Fill with an automatic pipette into size 0 opaque white capsules. The capsules are filled by individual weighing. The stirring speed during filling is 500 rpm and the water bath temperature is 55°C-60°C. After closing, the capsules are placed vertically in the capsule filler for solidification at room temperature.

The production of the reference capsule is carried out according to the same protocol as that of the G6 capsule, using the proportions and ingredients indicated in the tables 1 and 2 above. The tablet composed of the comparative composition 1 as indicated in table 2 is manufactured using conventional techniques for producing such pharmaceutical forms.

The manufacturing of capsules G7 to G29 is carried out according to the same protocol as that of capsule G6, with the proportions and ingredients as indicated in tables 3 and 4 above.

EVALUATION OF THE SOLUBILIZATION OF THE ACTIVE INGREDIENT OF THE PHARMACEUTICAL COMPOSITION IN AQUEOUS MEDIA DURING THE GASTROINTESTINAL TRACT

In order to reproduce the effect of pH on the active ingredient, and in particular on its dissolution during its passage through the gastrointestinal tract, a gastrointestinal medium was simulated by reproducing the pH of the stomach followed by the pH of the intestine through a pH shift. A dissolution kinetic study was conducted using a simple in vitro dissolution test with a pH shift.

000Principle:

The principle consists of determining the solubilization of the active ingredient by studying its dissolution kinetics at 37°C, first in a simulated gastric medium with pH 4, then in a simulated intestinal medium with pH 6.5, within a time frame compatible with the gastrointestinal tract.

• 000 Materials and Methods

Equipment: precision balance (Mettler AE200 or AT261), pH meter (Knick or Schott Geräte or Inolab), dissolution apparatus with thermostat 6 or 7 vessels (Sotax AT6 or AT7), 5 µm filter (PALL versapore 25 mm) with syringe (Térumo), UV spectrophotometer (Gilford Response II or Perkin Elmer) or HPLC (Merck or Agilent).

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

• Simulated gastric fluid - USP (without pepsin):

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

• Simulated intestinal fluid - USP (without pancreatin):

6.8 g of disodium hydrogen phosphate in 900 ml of distilled water, pH adjusted to 7.5 with concentrated sodium hydroxide (10 M), and then brought up to 1000 ml with distilled water.

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

The intestinal dissolution medium is adjusted to pH 6.5 with a few drops of concentrated sodium hydroxide (10M) to simulate the passage of the active ingredient into the beginning of the intestine, without causing dilution.

Method:

Calibration: Standard solutions of the active ingredient are prepared in a solvent medium, preferably in the mobile phase or ethanol, methanol, and then measured at the characteristic wavelength of the active ingredient. A calibration curve representing concentrations as a function of optical densities (spectrophotometry UV) or peak areas (HPLC analysis) is then determined. The equation of the obtained line allows determining the concentration of the dissolved active ingredient from the measurement of optical density or peak area. Solubilization Kinetics: The concentration used corresponds to the dose in 250 ml (i.e., 4 capsules in a 500 ml bowl).The solubilization kinetics are first studied in a simulated gastric medium at pH 4, where the samples are dissolved in thermostated beakers at 37°C, under stirring with paddles at 75 rpm for 1 hour, with sampling at 5, 15, 30, 45, and 60 minutes. Then, the study is continued in an intestinal medium, with a pH increase to 6.5 by adding a small volume of concentrated sodium hydroxide (for example: 0.400 ml for 500 ml of pH 4 medium), under control of a pH electrode. The kinetics are carried out for up to 3 hours, with sampling at 75, 90, 120, and 180 minutes, and each sample is filtered through a 5 µm filter before analysis.Dosages: Two methods of analysis can be used depending on the required sensitivity and the galenic form being studied: UV spectrophotometry (for the active substance alone) or HPLC (for the active substance alone or in formulation).

The concentration at time t is determined using the previously established calibration. During a UV analysis by spectrophotometry, the complete absorption spectrum is checked at least at the end of the kinetics. Similarly, the pH of the medium is checked at the end of the kinetics.

000Results:

The dissolution kinetics of the active ingredient (expressed as the percentage of product released) as a function of time is first plotted at pH 4 (simulating the gastric medium), then at pH 6.5 (simulating the intestinal medium), continuously on the same curve shown in Figure 1. The dissolution kinetics was measured under the same conditions for capsules G1-G7 and for the reference capsule whose composition was defined above.

The tablet shows a significant but sensitive improvement in the percentage of active ingredient released compared to the reference capsule, but only under simulated intestinal pH conditions.

The G3 capsule containing dronedarone hydrochloride in a lipid excipient matrix without surfactant shows a significant improvement in the percentage of active ingredient released compared to the reference capsule or the tablet, in addition to better release under simulated gastric pH conditions.

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

The G2 capsule containing dronedarone base formed in situ within the lipid excipient matrix from dronedarone hydrochloride shows a very significant improvement in the percentage of active ingredient released compared to the reference capsule, the tablet, and the G3 capsule.

The G4 and G5 capsules containing dronedarone as the free base in a lipid excipient matrix also show a very significant improvement in the percentage of active ingredient released compared to the reference capsule, the tablet, and the G3 capsule, in addition to exhibiting a dissolution behavior equivalent to that of the G2 capsule.

As can be seen from the curves shown in Figure 1, the beneficial effect of the lipid excipient in formulations containing dronedarone as the base or hydrochloride, compared to the reference capsule and the tablet that do not contain it.

On the other hand, a very clear improvement in the percentage of active ingredient released is observed for the capsules containing an additional surfactant in their composition compared to the capsules that do not contain it (G1 curve versus G3 curve and G5 curve versus G6 curve).

Moreover, in the case of formulations containing dronedarone in its base form within the matrix, the release profile of the active ingredient is rapid from the very first moments under simulated gastric pH conditions, in contrast to the formulation containing dronedarone hydrochloride, whose release is observed only under intestinal pH conditions at best.

Impact of the Gelucire 44/14 concentration on the base form of dronedarone

From the curves presented in Figure 2, it can be observed that increasing the gelucire rate has a positive effect.

Impact of the Gelucire 44/14 concentration on dronedarone hydrochloride salt

As seen from the curves presented in Figure 3, there is a positive effect from increasing the gelucire concentration.

Impact of the surfactant concentration on the base form of dronedarone

It can be observed from the curves presented in Figure 4 that the surfactant content in a composition according to the invention has no effect on the release of the active ingredient.

Effect of the surfactant concentration on dronedarone hydrochloride salt

As can be seen from the curves presented in Figure 5, the surfactant content in a composition according to the invention has a beneficial effect on the release of the active ingredient, with an optimal range between 10 and 30%.

Influence of the nature of the surfactant on the base form of dronedarone and on 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

It can be observed from the curves presented in Figure 6 that the release kinetics of the base form are equivalent regardless of the non-ionic surfactant used.

It can be observed from the curves presented in Figure 7 that the release kinetics of dronedarone hydrochloride show better profiles for an HLB between 15 and 25, and particularly around 22.

BIOAVAILABILITY EVALUATION

Bioavailability refers to the quantification of drug absorption. It is related to the fraction of the administered drug dose that reaches the general circulation and to the rate at which it does so. Bioavailability for oral administration depends on gastrointestinal absorption and first-pass metabolism in the intestine and liver, among other factors.

Protocol: 12 healthy young subjects receive a single dose of 400 mg of dronedarone twice daily (BID), either in a fasted state or during a high-fat meal, by taking the defined G1, G2, or G3 capsules described above. Blood samples are collected regularly over 48 hours, and the obtained plasma is analyzed using LC-UV methods to determine the concentration of dronedarone in plasma over time.

Cmax, Tmax, and AUC are measured on the resulting curves. The obtained results are summarized in the following tables 4 and 5.

Cmax corresponds to the peak plasma concentration of dronedarone.

Tmax corresponds to the time required to achieve Cmax.

AUC corresponds to the area under the curve or the integral of plasma concentration as a function of time t.

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 fasting conditions, the bioavailability of the capsules G1, G2, G3 according to the invention significantly increases compared to the reference capsule. The G2 capsule was the most effective.

It is also observed that the satiety effect significantly decreases for the capsules according to the invention compared to the reference capsule, with the G2 capsule showing the lowest satiety effect, on the order of 1.46.

BIOAVAILABILITY EVALUATION Protocol Processing and Administration

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

The administration conditions are as follows: Fasting period: animals are not fed the night before dosing. Water and regular food (SSNIFFhdH) are provided respectively one hour and four hours after administration. Fed period: animals receive 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 consists of 15% protein, 25% carbohydrates, and 50-60% fat). Water and regular dog food (SSNIFFhdH) are then given respectively one hour and four hours after administration.

A pretreatment with pentagastrin is performed 0.5 hour before testing. Pentagastrin (6 µg/kg, 0.25 mL/kg) is administered intramuscularly and allows maintaining the gastric pH of the animal between 2-3, thus mimicking human conditions.

The dose with the capsule is followed by 30 mL of water by gavage, which corresponds approximately to a volume of 240 mL given to a human subject during a clinical trial.

The treatments are: Treatment 1: 60 mg of dronedarone hydrochloride in a capsule under fasting conditions, oral route (reference capsule) (ref 2). Treatment 2: 60 mg of dronedarone hydrochloride in a capsule with gélucire and poloxamer 407, under fasting conditions, oral route (=G1). Treatment 3: 60 mg of dronedarone base reconstituted in situ from dronedarone hydrochloride in a capsule with gélucire and poloxamer 407, under fasting conditions, oral route (=G2). Treatment 4: 60 mg of dronedarone base in a capsule with gélucire and poloxamer 407, under fasting conditions, oral route (=G5). Treatment 5: 60 mg of dronedarone base in a capsule with gélucire and poloxamer 407, under fed conditions, oral route (=G5). Treatment 6: 60 mg of dronedarone base in a capsule with gélucire and without poloxamer 407, under fasting conditions, oral route (=G8). Treatment 7: 60 mg of dronedarone base in a capsule with gélucire and without poloxamer 407, under fed conditions, oral route (=G8).

Sampling and Analysis

Blood samples are collected 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 administration of each treatment.

Plasma concentration of dronedarone is determined using an exploratory assay method based on liquid chromatography coupled with a mass spectrometer (LC-MS/MS). The lower limit of detection with this method for the tested compounds is 0.5 ng/mL.

Reporting of Results

Pharmacokinetic parameters are calculated from individual concentrations using non-compartmental analysis with the WinNonLin 5.2.1 software (Pharsight, USA), and using theoretical sampling times (provided that the actual sampling times do not differ by more than 15% from the 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 time observed at which the maximum concentration is achieved, AUClast: corresponds to the area under the curve or integral of plasma concentration versus time t calculated by the trapezoidal method from t0 to the time corresponding to the last quantifiable concentration. AUC: corresponds to the area under the curve or integral of plasma concentration versus time extrapolated to infinity. T1/2z: terminal elimination half-life.

The following parameters were also evaluated: relative bioavailability in terms of Cmax and AUC, and the food effect ratio on Cmax and AUC.

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 show a similar exposure under fasting conditions, regardless of the group. 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 showed higher bioavailability than the reference capsule, with a relative bioavailability ranging from 271% to 500% under fasting conditions.

Formulations containing Gelucire with dronedarone hydrochloride and in situ base reconstitution (Frel=301%) showed higher bioavailability than the reference capsule, as in the clinical trial described above.

Gelucire-based formulations using the native base exhibit a similar relative bioavailability to Gelucire-based formulations using dronedarone hydrochloride and reconstituting the base in situ when compared to the reference under fasting conditions, as indicated by the confidence interval recovery.

Gelucire-based formulations, with or without poloxamer, show a 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 toward a slight decrease in Cmax by 1.4-fold when the gelucire capsule with poloxamer is administered with a high-fat meal. This decrease is not statistically significant because the 90% CI includes unity. 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 tendency toward a positive food effect when the gelucire-free capsule is administered with a high-fat meal. Indeed, Cmax is increased by 1.9 times, AUClast by 1.4 times, and AUC by 1.3 times. However, this increase is not statistically significant regarding AUC, as the 90% CI includes unity.

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.