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    • 专利摘要:
    The present invention relates to a composition comprising as active ingredient a pharmaceutically acceptable salt of elafibranor characterized in that the pharmaceutically acceptable salt of elafibranor is chosen from at least one salt of choline, or of ethanolamine, or of diethanolamine, or of L-lysine, or piperazine, or calcium or tromethamine. The invention more particularly relates to the use of elafibranor salts for improving stability and solubility compared to elafibranor in its base form. These salts make it possible to establish pharmaceutical formulations in various advantageous forms such as intravenous injections or enteral formulations having a faster absorption, less variable and therefore a better bioavailability.
    公开号:FR3056909A1
    申请号:FR1659438
    申请日:2016-09-30
    公开日:2018-04-06
    发明作者:Claude Laruelle；Ludovic Bonnafous
    申请人:Nashpharm；
    IPC主号:
    专利说明:

    TECHNICAL AREA
    The present invention relates to drugs derived from elafibranor.
    The invention relates in particular to a composition soluble in aqueous media having improved intestinal absorption. It relates to the use of pharmaceutically acceptable salts of elafibranor (GFT505), which can be used in pharmaceutical compositions.
    The invention relates more particularly to the use of elafibranor salts with a view to improving stability and solubility compared to elafibranor in its base form. These salts make it possible to establish pharmaceutical formulations in various advantageous forms such as intravenous injections or enteral formulations with faster absorption, less variable and therefore better bioavailability.
    STATE OF THE ART
    Elafibranor, also cited under its code name GFT505, is an experimental molecule from the company Genfit originally developed for the treatment of metabolic diseases including diabetes, insulin resistance, dyslipidemia. Its current therapeutic target is the treatment of liver diseases, in particular non-alcoholic steatohepatitis (NASH).
    Its chemical name is acid 2- [2,6 dimethyl-4- [3- [4- (methylthio) phenyl] -3-oxo1 (E) -propenyl] phenoxyl] -2-methylpropanoic acid, with the chemical formula C22H24O4S and a weight molecular weight of 384.489 g / mol. Its chemical structure of formula I is given in Figure 1
    According to patent EP 1525177 B1 of Genfit which describes the use, the preparation of molecules of the family of 1,3-diphenylprop-2-in-1-one, elafibranor, called compound 29 in this document, is identified by an NMR spectrum (1H DMSO) with the following characteristics (δ ppm): 1.39 (s, 6H), 2.22 (s, 6H), 2.57 (s, 3H), 7.40 (d, J = 8.55Hz, 2H), 7.57 (s, 2H), 7.62 (d, J = 15.5Hz, 1H), 7.83 (d, J = 15.5Hz, 1H), 8.10 (d, J = 8.55Hz, 2H), 12.97 (s, 1H) SM ( ES- MS): 383.3 (M- 1).
    There are no other publicly available elements providing further details on the physicochemical identification of this molecule which has the same phenoxylated propanoic acid group as the molecules of the fibrate family (Figure 2).
    Molecules belonging to the fibrate family are known for their low aqueous solubility, whether in the form of an ester or a carboxylic acid such as elafibranor (GFT505). In addition, there are notable variabilities in the pharmacokinetics of these molecules, such as for example fenofibrate whose pharmaceutical formulations have been the subject of regular contributions of pharmaceutical innovation work to remedy these drawbacks and thus improve bioavailability.
    The other information available on elafibranor essentially concerns the preclinical, clinical and toxicological properties of this molecule. Elafibranor is indeed identified as a co-activator of the PPARa / nucléaires nuclear receptors. All clinical trials have shown a very good tolerance profile for this molecule, supported in particular by high-dose toxicological studies in animals, including carcinogenicity studies.
    Elafibranor (GFT05) also has beneficial effects on nonalcoholic steatohepatitis NASH with the improvement of biochemical markers of hepatic dysfunction, in particular hepatic enzymes: ALAT, ASAT, yGT, andALP7.
    Currently, there is no in-depth description of the physicochemical data for elafibranor, whether it is the chemical molecule alone or as an active molecule in a pharmaceutical composition. No physiologically acceptable salt has been described in patents or scientific publications.
    Elafibranor (GFT505) has been described since 2003 in several patents from the company Genfit which cover any therapeutic application and, since 2009, on a new specific therapeutic application, in particular for the treatment of nonalcoholic steatohepatitis NASH.
    Patent EP1525177 and US7943661 relate to a new family of chalcone derivatives. They describe the process for the preparation and the use of substituted 1,3-diphenylprop-2-en-1-one derivatives of formula II below (FIG. 3), which includes the elafibranor molecule (compound 29 described in the description, claim 25), for any therapeutic application, without limitation to a specific disease.
    The second family of patents EP2504005, US8772342 and US9221751 relates to compounds for use in a method of treatment of a hepatic disorder selected from the group consisting of hepatic fibrosis or hepatic steatosis.
    In particular, claim 7 relates to the elafibranor molecule for use in the treatment of hepatic fibrosis or fatty liver. Claims 9 and 10 relate to a pharmaceutical composition comprising a compound of formula III below (Figure 4) in a method of treatment of a hepatic disorder selected from the group consisting of hepatic fibrosis or fatty liver.
    The patent EP2504005B1 was the subject of a divisional application EP2641596A1 concerning the compounds claimed in the patent EP2504005B1, but used this time only in the specific context of the diseases: liver cirrhosis, alcohol-related diseases, hepatic diseases immune mediated.
    Other patents dealing with elafibranor should be noted. Patent US7566737B relates to a pharmaceutical composition comprising an association between a substituted 1,3-diphenylprop-2-en-l-one derivative of formula II, including the elafibranor molecule, and another ingredient having therapeutic activity.
    Patent US8895619B deals with a method of treatment of hepatic fibrosis by the administration of the molecule Elafibranor (claims 1-7, 10-11) and in particular for treating cirrhosis (claims 8-9).
    Application US2016 / 0051501 relates to a method of treatment of a viral or alcohol-related or immune-related liver disease with a compound of formula III.
    Elafibranor is not cited in other patents. Only study results appear in several articles, the first of which were published in 2007 (Fruchart, Am J Cardiol 2007; 100 [suppl]: 41N-46N; in 2013: Fruchart Cardiovascular Diabetology 2013, 12:82).
    The poster "The hepatic and extra-hepatic profile of resolution of steatohepatitis induced by GFT-505 (elafibranor) by Sanyal AJ et al., Deals with the results of a phase 2b study (Golden505) putting forward a daily dose of 80 or 120 mg elafibranor administered to 270 NASH patients (3 groups including diabetics and non-diabetics). There is no information on the pharmaceutical composition of the 40 mg capsules used for this study or on the physico-chemical characteristics of elafibranor or the rationale for administration before breakfast.
    Pharmacokinetic parameters whose metabolism is not publicly available for elafibranor despite the phase 1 studies that have been performed. In 2012, in the dose research study "Comparative Bioavailability - Gender Effect - Single and Multiple Ascending Dose Safety and Pharmacokinetic Study of GFT505, modifications were made by the company Genfit in the formulations of elafibranor. A study of the relative bioavailability between new and old formulations has been carried out, over a dose range up to 300 mg. There is no publication of results or information which justifies and supports the reasons for this formulation work.
    Elafibranor as described in the Genfit patents is used in particular dosage forms. In particular, elafibranor is not in the form of intravenous injections or in effective formulations by the enteral route.
    Surprisingly, it has been found that the use of pharmaceutically acceptable salts specific for Elafibranor improves the stability and the solubility of the latter, thus allowing new galenic form and better bioavailability.
    BRIEF DESCRIPTION OF THE FIGURES
    The aims, objects, as well as the characteristics and advantages of the invention will emerge more clearly from the detailed description of an embodiment of the latter which is illustrated by the following accompanying figures in which:
    Figure 1: Chemical formula of Elafibranor.
    Figure 2: Chemical formula of fibrates and the common chemical grouping of fibrates and elafibranor.
    Figure 3: Chemical formula derived from substituted 1,3-diphenylprop-2-en-1-one including Elafibranor.
    Figure 4: General formula of a compound of patent application EP2504005 comprising Elafibranor.
    Figure 5: Synthesis diagram of elafibranor (GFT505)
    Figure 6A: RNM 1H spectrum elafibranor (GFT505)
    Figure 6B: UPLCMS elafibranor (GFT505)
    Figure 6C: UV spectrum elafibranor (GFT505)
    Figure 7A: 1 H NMR spectrum of elafibranor choline salt (GFT505)
    Figure 7B: UV / IPLCMS spectra of elafibranor choline salt (GFT505)
    STATEMENT OF THE INVENTION
    Before starting a detailed review of embodiments of the invention, there are set out below optional features which may optionally be used in combination or alternatively.
    The invention relates to a composition comprising as active ingredient a pharmaceutically acceptable salt of elafibranor, characterized in that the pharmaceutically acceptable salt of elafibranor is chosen from at least one salt of choline, or of ethanol amine, or of diethanolamine, or of L-lysine, or piperazine, or calcium or tromethamine.
    Advantageously, the pharmaceutically acceptable salt is the choline salt.
    Advantageously, the composition is in a form suitable for administration by the enteral route.
    Advantageously, the composition is in a form suitable for administration by the parenteral route.
    The parenteral modes of administration allow rapid absorption and optimal bioavailability.
    Advantageously, the composition is in a form suitable for administration by the intravenous route.
    Advantageously, the elafibranor salt is micronized or of amorphous structure.
    Advantageously, the elafibranor salt is in the form of a powder for soluble injection preparation.
    Advantageously, the composition is in a form suitable for administration by subcutaneous route.
    Advantageously, the composition comprises at least one excipient, chosen from binders, disintegrating agents, diluents, lubricants, surfactants, buffering agents, flow agents, colorants, flavors, sweeteners, solvents or preservatives.
    Advantageously, the composition comprises more than 50% of the particles of size less than or equal to 10 μm and all of the particles of size less than 20 μm.
    Advantageously, the pharmaceutically acceptable salt of elafibranor is configured to have a solubility at least equal to 10 mg / ml in 0.9% NaCl physiological medium.
    Advantageously, the elafibranor salt is configured to have a dissolution profile in simulated FaSSIF and FeSSIF media greater than 90% after 30 minutes.
    Advantageously, the pharmaceutically acceptable salt of elafibranor (GFT505) is configured to be photostable.
    Photostable means the ability to be less sensitive to light.
    Advantageously, the composition is intended to be used in the treatment of hepatic diseases.
    Advantageously, liver disease consists of non-alcoholic fatty liver disease (NAFLD).
    Advantageously, the composition is intended for use in the treatment of hepatic diseases characterized in that the hepatic disease consists of non-alcoholic steatohepatitis (NASH).
    Advantageously, liver disease consists of hepatic fibrosis.
    Advantageously, liver disease consists of cirrhosis.
    Advantageously, liver disease consists of autoimmune liver diseases.
    Advantageously, the mode of administration consists of an oral administration.
    Advantageously, the mode of administration consists of administration by subcutaneous route.
    Advantageously, the drug form consists of a powder for oral suspension.
    The pharmaceutically acceptable salt of elafibranor has the advantage of having better solubility in water compared to the base form.
    Advantageously, the drug form consists of the form of an injectable solution, a tablet, a dispersible tablet, an orodispersible tablet, a capsule, a soluble tablet, a lyophilisate, an effervescent tablet, a chewable tablet, an extended-release tablet, a sachet.
    Advantageously, the dissolution profile in simulated FaSSIF and FeSSIF media of the pharmaceutically acceptable salt of elafibranor has a percentage of dissolution greater than 90% after 30 minutes.
    Advantageously, the drug form comprises particles of elafibranor, with at least 50% of the particles being of sizes less than 10 μm.
    Advantageously, the composition comprises at least one physiologically acceptable excipient, in particular at least one among binders, disintegrating agents, diluents, lubricants, surfactants, buffering agents, flow agents, dyes, flavors, sweeteners, solvents or preservatives.
    The invention relates to a use of a composition comprising as active principle at least one pharmaceutically acceptable salt of elafibranor (GFT505) for obtaining a medicament intended for use in the treatment or prevention of diseases, in particular in hepatopathy including, but not limited to, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, autoimmune liver disease.
    In another aspect, the invention relates to the preparation of pharmaceutically acceptable salts of elafibranor (GFT505) demonstrating physicochemical properties more advantageous than the base form of elafibranor, in particular with regard to solubility and / or stability.
    DETAILED DESCRIPTION
    The present invention relates to the use of a pharmaceutically acceptable salt of elafibranor as well as any one of its derivatives, in one of its crystalline forms possibly polymorphic, or else according to an amorphous crystal structure, in the preparation of a drug for the treatment or prevention of diseases, in particular liver diseases such as non-alcoholic fatty liver disease (NASH and NAFLD), fibrosis, cirrhosis or cancer, autoimmune diseases.
    The invention also relates to the use of a pharmaceutically acceptable salt of 2- [2,6 dimethyl-4- [3- [4- (methylthio) phenyl] -3-oxo-1 (E) propenyl] acid] phenoxyl] -2-methylpropanoic acid, with the chemical formula C22H24O4S (Figure 1), which can be used in a pharmaceutical composition to prevent or treat diseases, in particular liver diseases.
    By pharmaceutically acceptable salt is meant, by way of example and in a non-exhaustive manner, the physiological salts of: choline, ethanol amine, diethanolamine, L-lysine, piperazine, calcium and tromethamine.
    The pharmaceutically acceptable salt is, for example, in one of its optionally polymorphic crystalline forms, or else in an amorphous crystalline structure.
    The pharmaceutical composition of the invention can be administered enterally, parenterally, topically or subcutaneously. According to a mode of administration, the composition is administered enterally, such as, for example, a tablet, a capsule, a soft capsule, a lyophylisate, a dispersible, orodispersible, effervescent or soluble tablet, an oral solution, a powder for oral suspension.
    According to a preferred mode of administration, the composition is administered intravenously, subcutaneously, in the form for example of an injectable solution, of a powder for injectable solution.
    The formulations intended to be administered by the intravenous or oral route advantageously contain a salt of micronized elafibranor or of amorphous structure in order to optimize the aqueous solubility and the enteric dissolution if necessary. The size distribution of the elafibranor salt particles which have a crystal structure is characterized in that more than 50% of the particles are less than or equal to 10 µm, and all the particles are less than 20 µm in size.
    The particles are measured using a Malvern type laser granulometer or equivalent, and a validated wet method (wetting with a surfactant) is preferred.
    One of the preferred pharmaceutical compositions of the invention is a powder for injection that is soluble and stable under normal temperature and humidity conditions, ie 25 ° C / 60% RH (ICH conditions).
    The following examples are given to illustrate the invention and do not in any way constitute a limitation thereof.
    EXAMPLES
    EXAMPLE 1: Synthesis and characterization of elafibranor (GFT505)
    The Applicant has decided to prepare samples of elafibranor to assess the feasibility of the stages of the synthesis of this molecule and to characterize the physicochemical properties of the product obtained. The procedure is inspired by the information described in patent EP 1525177 B1 for the synthesis of compound 29. The steps are reproduced identically.
    Experimental protocol
    The compound is synthesized from 1- [4-methylthiophenyl] -3- [3,5-dimethyltertiobutyloxycarbonyldimethylmethyloxyphenyl] prop-2-en-1-one.
    Step 1: 1- [4-methylthiophenyl] - (E) -3- [3,5-dimethyl-4-hydroxyphenyl] prop-2-en-1-one (intermediate 1)
    4-methylacetophenone (20 g, 0.12 mol, 1 eq) and 3,5-dimethyl-4hydroxybenzaldehyde (18 g, 0.12 mol, 1 eq) are dissolved in 300 ml of 4N HCl in dioxane. The reaction medium is stirred for 30 h and then the solvents are evaporated. Purification by hot recrystallization from 70 mL of isopropanol and 12 mL of water: 33 g (yellow solid, yield: 92%).
    Gross formula: Ci 8 H 18 O 2 S
    ESI-MS m / z = 299.18 [M + H] +
    1 H NMR DMSO-d6 δ ppm: 2.18 (s, 6H), 2.53 (s, 3H), 7.36 (d, J = 8.5Hz, 2H), 7.47 (s, 2H), 7.57 (d, J = 15 , 5Hz, 1H), 7.69 (d, J = 15.5Hz, 1H), 8.05 (d, J = 8.5Hz, 2H), 8.93 (s, 1H)
    Step 2: 1- [4-methylthiophenyl] - (E) -3- [3,5-dimethyl-4tertiobutylcarbonyldimethylmethyloxyhenyl] prop-2-en-1-one (intermediate 2)
    Cesium carbonate (87 g, 0.134 mol, 4 eq) and tetrabutylammonium iodide (12 g, 0.033 mol, 0.5 eq) are added to a solution of intermediate 1 (20 g, 0.067 mol, 1 eq) in 50mL of a DMSO / water mixture (3/2). The reaction medium is stirred for 30 min at 80 ° C. and the tert-butyl bromoisobutyrate (30 g, 0.134 mol, 2 eq) is added. Then 2 additions of 2 eq of tert-butyl bromoisobutyrate diluted to 50% in DMSO are each made 1 hour apart. The reaction medium is stirred for 2 days at 80 ° C. The reaction medium is left to cool to room temperature then 1.5L of water is added and the product is extracted with dichloromethane (4 times). The organic phase is dried on a phase separator cartridge and evaporated to dryness. Purification on silica gel (cyclohexane / ethyl acetate: 95/5 to 80/20): 18g (orange solid, yield: 61%)
    Gross formula: C26H32O4S
    ESI-MS m / z = 441.33 [M + H] +
    1 H NMR DMSO-d6 δ ppm: 1.36 (s, 6H), 2.19 (s, 6H), 2.48 (broad peak, H2O + 9H), 2.54 (s, 3H), 7.38 (d, J = 8.4Hz, 2H), 7.55 (s, 2H), 7.59 (d, J = 15.6Hz, 1H), 7.80 (d, J = 15.6Hz, 1H), 8.07 (d, J = 8.4Hz, 2H) ίο
    Step 3: 1- [4-methylthiophenyl] - (E) -3- [3,5-dimethyl-4carboxydimethylmethyloxyhenyl] prop-2-en-1-one
    Intermediate 2 (25 g, 0.057 mol, 1 eq) is dissolved in 50 ml of dichloromethane and 22 ml of trifluoroacetic acid (5 eq, 0.284 mol) is added gently. The reaction medium is stirred for 3 h 30 min at room temperature then the solvents are evaporated to dryness. Purification on silica gel (dichloromethane / Methanol: 100/0 -> 95/5): 13 g (yellow solid, yield 60%).
    Gross formula: C22H24O4S
    ESI-MS m / z = 385.25 [M + H] +
    1 H NMR DMSO-d6 δ ppm: 1.36 (s, 6H), 2.19 (s, 6H), 2.54 (s, 3H), 7.37 (d, J = 8.6Hz, 2H), 7.55 (s, 2H), 7.59 (d, J = 15.6Hz, 1H), 7.80 (d, J = 15.6Hz, 1H), 8.07 (d, J = 8.6Hz, 2H), 12.94 (s, 1H)
    The reaction scheme is given in FIG. 5.
    Results
    The analysis data for the 10.1 g of the batch obtained (EM0274L2) are summarized below:
    Molecular mass: 384.5 (exact mass: 384.1);
    1 H NMR spectrum: Conforms to the structure, see spectrum in FIG. 6A below.
    - LCMS: TR = 1.42mn, m / z: 385.00 = [M + H] +;
    - Purity:> 98% (1H NMR and LCMS);
    Melting point: 144-145 ° C.
    The appearance of the product is a solid amorphous yellow powder. The product has significant absorption in the near visible range with an Apex at approximately 347 nm.
    The information is detailed in Figures 6.
    The product obtained conforms in terms of chemical purity and demonstrates absorption in the near visible range which requires that the chemical stability to light and the phototoxicity must therefore be verified.
    EXAMPLE 2 Measurement of Solubility of Elafibranor (GFT505)
    In an experiment carried out for the invention, it was shown that elafibranor (GFT505) displayed a chemical structure related to the family of fibrates (Figure 2). As elafibranor is a carboxylic acid, the Applicant has chosen to check the aqueous solubility of this molecule in order to decide on the feasibility of developing pharmaceutical compositions in accordance with the expectations of the patients, which are more effective and better tolerated by the patients.
    io Experimental protocol
    The thermodynamic solubility of elafibranor base is studied over a period of 24 hours and 72 hours in various aqueous buffers in the presence or absence of surfactants. Lot n ° EM0274L2 is used for this work. The product is dissolved in the solvents indicated in table 1. After 24 hours and 72 hours of incubation at room temperature (22 - 24 ° C), the solutions are removed and then filtered on 0.2 pm polycarbonate filters in flasks for LCMS analyzes, and diluted once in DMSO before stirring for 2 minutes (Vortex or sonication).
    Results
    The results of thermodynamic solubility are given in table 1 below:
    Solvents Solubility after 24 h Solubility after 72 h pM mg / mL pM mg / mL PH 4.6 buffer 114 0.044 110 0.042 PH 7.4 buffer 504 0.194 609 0.234 PH 8.5 buffer 4419 1.701 4270 1.644 Propylene glycol 33520 12.905 35081 13.506 PolyethyleneGlycol 400 39022 15,023 40971 15,774
    Table 1: elafibranor thermodynamic solubility in aqueous media.
    The solubility of elafibranor is poor in an aqueous medium. It increases as a function of pH, going from 114 to 4419 pM of pH 4.6 to 8.5. The addition of co-solvent such as propylene glycol or PEG 400 significantly improves the solubility of the molecule.
    EXAMPLE 3 Preparation of Elafibranor Salts (GFT505)
    One of the preferred modes of administration is the parenteral route. In order to achieve this, the Applicant has prepared elafibranor salts with the aim of improving the solubility of elafibranor in order to be able to produce injectable solutions or powders for injectable preparation.
    Experimental protocol
    The salts are made from a batch of elafibranor previously synthesized.
    Se / de choline:
    g of GFT505 (2.6 mmol) and 104 mg of NaOH (1 eq, 2.6 mmol) are suspended in 10 ml of isopropanol and 14 ml of methanol and heated to 65 ° C. A solution of 365 mg of Choline.Cl (1eq, 2.6 mmol) in 1.5 ml of isopropanol is added and the yellow reaction medium is stirred for 30 minutes at 65 ° C. After returning to room temperature, the fine suspension is filtered, washed with 2x1 ml of isopropanol and then concentrated to dryness. The precipitation / crystallization tests for the yellow solid residue have not yet worked.
    After 5 days of drying at 45 ° C under high vacuum (<10-2 mbar), 820 mg of bright yellow solid is obtained (Lot CP0686). Traces of solvent (15% isopropanol) are detected by NMR.
    The products are kept cool (2-8 ° C) and under inert gas to avoid any degradation. A complete analysis of elafibranor salts is carried out, including identification and chemical purity.
    Results:
    The results are presented in Figures 7 in a non-exhaustive manner:
    EXAMPLE 4 Solubility test of different elafibranor salts (GFT505)
    This example presents the solubility characteristics of different forms and salts of elafibranor, for administration by the parenteral route or in the context of an enteral rapid-release composition.
    The kinetics of solubilization is determined in aqueous media (water and pharmacopoeia buffers such as pH 7.4; 6.0 and 4.5 in particular), at room temperature. The results are shown in Tables 2 and 3.
    Products Molecular weight Fusion pointin ° C Solubility(according to Ph. Eur.) amorphous elafibranor 384 144/145 Very slightly soluble Ethanolamine salt 428 - Quite soluble Meglumine salt 562 - Soluble L-lysine salt 513 - Very soluble Tromethamine salt 488 - Soluble Choline salt 487 197/199 Very soluble
    Table 2: solubility of different elafibranor salts.
    Solvents Elafibranor (GFT505)choline salt Elafibranor (GFT505)Amorphous free base μΜ mg / mL μΜ mg / mL PH 4.6 buffer ND ND 114 0.044 PH 7.4 buffer 82000 40 504 0.194 PH 8.5 buffer ND ND 4419 1.701 Propylene glycol - - 33520 12.905 Polyethylene Glycol400 - - 39022 15,023
    Table 3: solubility free base elafibranor and choline salt in aqueous media.
    Choline salt, for example, has a solubility at least 150 times greater than elafibranor in its free base form.
    EXAMPLE 5 Kinetics of dissolution of oral formulations of elafibranor salts.
    The Applicant has studied the dissolution profile of several batches of capsules containing respectively choline salts and free elafibranor base of amorphous structure, in unit dose equivalent to 120 mg in the form of elafibranor base.
    The dissolution tests were carried out on most of the formulations in media buffered to pH 6.0 USP and in gastric media simulating the nourished and fasting conditions, with the addition of enzymes (media called FeSSIF and FaSSIF respectively). The USP type II pallet system was used for the tests with 1000 ml volume, 37 ° C and the samples, taken at 0, 2, 5, 10, 15, 20, 30, 45 and 60 minutes were analyzed by HPLC without renewal of the media.
    Results
    The results show that elafibranor in the form of choline salt is very quickly dissolved in the two media FaSSIF and FeSSIF. At the end of the test (60 minutes), 100% of the active substance is dissolved for the formulations and there are no differences depending on the dissolution medium studied for the choline salt of elafibranor, which does not this is not the case for formulations containing elafibranor in free base form.
    The kinetics of dissolution are notably faster for formulations based on choline salt.
    In conclusion, the impact of elafibranor salt on the dissolution properties is surprising. The tests on salt-based formulations have a similar profile regardless of the medium simulating the taking or not of meals.
    On the basis of these predictive in vitro data, it is therefore probable that the formulations based on choline salts have an improved absorption linked to a higher solubility and a faster dissolution, making it possible to be free from any impact / any linked variation. when taking food.
    EXAMPLE 6 Stability of elafibranor and its salts.
    The Applicant has decided to verify the stability of elafibranor in the form of the free base and of salts after exposure to light and at room temperature.
    Experimental protocol
    Samples were prepared in the form of powder alone and aqueous solutions for the following samples: elafibranor, elafibranor choline.
    The stability is measured over a period of 7 to 14 days by UPLCMS, with calculation of the recovery rate of the peak of elafibranor relative to the initial value and measurement of its purity index. The products are exposed to daylight and to room temperature.
    The reference samples are stored cool (2-8 ° C), protected from light by aluminum foil and under inert gas for the solid product.
    Results io Table 4 below shows, as an example, the qualitative photostability results of choline salt (recovery in%) according to its physical state (solution or powder) after storage for two weeks.
    Products T0 data Stability 14days(solution) Stability 14 days(powder) Choline salt 100 > 90% ~ 90%
    Table 4: elafibranor salt photostability (recovery / theory)
    They demonstrate that elafibranor in the form of salt, in particular choline, has a medium change in color to light (photosensitivity), yellow to medium yellow, whether in powder form or in solution, with less intensity than the GT505 in its free basic form. Recovery after 14 days of storage is included in the standard 100 ± 10%.
    Temperature has no impact on stability. Light degradation products have not been identified.
    权利要求:
    Claims (19)
    [1" id="c-fr-0001]
    1. Composition comprising as active ingredient a pharmaceutically acceptable salt of elafibranor, characterized in that the pharmaceutically acceptable salt of elafibranor is chosen from at least one salt of choline, or of ethanol amine, or of diethanolamine, or of L-lysine , or piperazine, or calcium or tromethamine.
    [2" id="c-fr-0002]
    2. Composition according to the preceding claim, characterized in that the pharmaceutically acceptable salt is the choline salt.
    [3" id="c-fr-0003]
    3. Composition according to any one of the preceding claims, characterized in that it is in a form suitable for administration by the enteral route.
    [4" id="c-fr-0004]
    4. Composition according to any one of claims 1 and 2 characterized in that it is in a form suitable for administration by the parenteral route.
    [5" id="c-fr-0005]
    5. Composition according to the preceding claim, characterized in that it is in a form suitable for administration by the intravenous route.
    [6" id="c-fr-0006]
    6. Composition according to any one of the two preceding claims, in which the elafibranor salt is micronized or of amorphous structure.
    [7" id="c-fr-0007]
    7. Composition according to any one of the three preceding claims, in which the elafibranor salt is in the form of a powder for soluble injection preparation.
    [8" id="c-fr-0008]
    8. Composition according to any one of claims 1 and 2 characterized in that it is in a form suitable for administration by the subcutaneous route.
    [9" id="c-fr-0009]
    9. Composition according to any one of the preceding claims, characterized in that it comprises at least one excipient, chosen from binders, disintegrating agents, diluents, lubricants, surfactants, buffering agents, flow, colors, flavors, sweeteners, solvents or preservatives.
    [10" id="c-fr-0010]
    10. Composition according to any one of the preceding claims, characterized in that it comprises more than 50% of the particles of size less than or equal to 10 μm and all of the particles of size less than 20 μm.
    [11" id="c-fr-0011]
    11. Composition according to any one of the preceding claims, characterized in that the pharmaceutically acceptable salt of elafibranor is configured to have a solubility at least equal to 10 mg / ml in physiological medium NaCI 0.9%.
    [12" id="c-fr-0012]
    12. Composition according to any one of the preceding claims, characterized in that the elafibranor salt is configured to have a dissolution profile in simulated FaSSIF and FeSSIF media greater than 90% after 30 minutes.
    [13" id="c-fr-0013]
    13. Composition according to any one of the preceding claims, in which the pharmaceutically acceptable salt of elafibranor (GFT505) is configured to be photostable.
    [14" id="c-fr-0014]
    14. Composition according to any one of the preceding claims, intended for use in the treatment of hepatic diseases.
    [15" id="c-fr-0015]
    15. Composition according to the preceding claim, in which the liver disease consists of non-alcoholic fatty liver disease (NAFLD).
    [16" id="c-fr-0016]
    16. Composition according to claim 14 intended for use in the treatment of hepatic diseases characterized in that the hepatic disease consists of non-alcoholic steatohepatitis (NASH).
    [17" id="c-fr-0017]
    17. Composition according to claim 14, in which the hepatic disease consists of hepatic fibrosis.
    [18" id="c-fr-0018]
    18. Composition according to claim 14, in which the hepatic disease consists of cirrhosis.
    [19" id="c-fr-0019]
    19. The composition of claim 14 wherein the liver disease consists of autoimmune liver diseases.
    1/9
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    同族专利:
    公开号 | 公开日
    EP3518916A1|2019-08-07|
    US11185520B2|2021-11-30|
    WO2018060372A1|2018-04-05|
    BR112019006435A2|2019-06-25|
    EP3518916B1|2021-07-07|
    FR3056909B1|2019-04-19|
    CA3038726A1|2018-04-05|
    CN110234320A|2019-09-13|
    US20190274982A1|2019-09-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP1525177A1|2002-07-08|2005-04-27|Genfit|Substituted 1,3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof|
    US20050148594A1|2002-12-17|2005-07-07|Cink Russell D.|Salts of fenofibric acid and pharmaceutical formulations thereof|
    EP2641596A1|2009-11-26|2013-09-25|Genfit|Use of 1,3-diphenylprop-2-en-1-one derivatives for treating liver disorders|
    WO2016154258A1|2015-03-26|2016-09-29|T3D Therapeutics, Inc.|Methods of treating liver disease using indane acetic acid derivatives|
    CN101780049A|2009-01-20|2010-07-21|北京利乐生制药科技有限公司|Enteric solid preparation using feinuobeite acid and feinuobeite salt as major ingredients and preparation method thereof|
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    WO2012106382A1|2011-01-31|2012-08-09|Genoa Pharmaceuticals, Inc.|Aerosol pirfenidone and pyridone analog compounds and uses thereof|WO2019099761A1|2017-11-16|2019-05-23|Teva Pharmaceuticals International Gmbh|Solid state forms of elafibranor|
    US20210309608A1|2018-08-03|2021-10-07|Genfit|Elafibranor salts|
    WO2021233874A1|2020-05-18|2021-11-25|Genfit|Elafibranor for the treatment of primary sclerosing cholangitis|
    法律状态:
    2017-09-28| PLFP| Fee payment|Year of fee payment: 2 |
    2018-04-06| PLSC| Publication of the preliminary search report|Effective date: 20180406 |
    2018-09-27| PLFP| Fee payment|Year of fee payment: 3 |
    2019-09-26| PLFP| Fee payment|Year of fee payment: 4 |
    2020-09-28| PLFP| Fee payment|Year of fee payment: 5 |
    2021-09-29| PLFP| Fee payment|Year of fee payment: 6 |
    优先权:
    申请号 | 申请日 | 专利标题
    FR1659438|2016-09-30|
    FR1659438A|FR3056909B1|2016-09-30|2016-09-30|COMPOSITION COMPRISING AT LEAST ONE PHARMACEUTICALLY ACCEPTABLE SALT OF SOLUBLE ELAFIBRANOR IN AQUEOUS MEDIA HAVING IMPROVED INTESTINAL ABSORPTION|FR1659438A| FR3056909B1|2016-09-30|2016-09-30|COMPOSITION COMPRISING AT LEAST ONE PHARMACEUTICALLY ACCEPTABLE SALT OF SOLUBLE ELAFIBRANOR IN AQUEOUS MEDIA HAVING IMPROVED INTESTINAL ABSORPTION|
    EP17777046.8A| EP3518916B1|2016-09-30|2017-09-28|Composition comprising at least one water-soluble pharmaceutically acceptable salt of elafibranor having improved intestinal absorption|
    BR112019006435A| BR112019006435A2|2016-09-30|2017-09-28|composition comprising at least one pharmaceutically acceptable salt of soluble elafibranor and composition for the treatment of liver disease|
    US16/338,219| US11185520B2|2016-09-30|2017-09-28|Composition comprising at least one water-soluble pharmaceutically acceptable salt of elafibranor having improved intestinal absorption|
    CA3038726A| CA3038726A1|2016-09-30|2017-09-28|Composition comprising at least one water-soluble pharmaceutically acceptable salt of elafibranor having improved intestinal absorption|
    CN201780073672.7A| CN110234320A|2016-09-30|2017-09-28|Include at least one pharmaceutically acceptable composition according to Rabat salt for being dissolved in aqueous medium and there is improvement intestinal absorption|
    PCT/EP2017/074701| WO2018060372A1|2016-09-30|2017-09-28|Composition comprising at least one water-soluble pharmaceutically acceptable salt of elafibranor having improved intestinal absorption|
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