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WO2021037128A1 - Composition pharmaceutique contenant du chidamide et utilisation de cette dernière - Google Patents

Composition pharmaceutique contenant du chidamide et utilisation de cette dernière Download PDF

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Publication number
WO2021037128A1
WO2021037128A1 PCT/CN2020/111669 CN2020111669W WO2021037128A1 WO 2021037128 A1 WO2021037128 A1 WO 2021037128A1 CN 2020111669 W CN2020111669 W CN 2020111669W WO 2021037128 A1 WO2021037128 A1 WO 2021037128A1
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Prior art keywords
chidamide
pharmaceutical composition
inhibitor
glycoprotein
composition according
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Chinese (zh)
Inventor
鲁先平
山松
辛利军
张钰
王世刚
邓舟
潘德思
余金迪
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Shenzhen Chipscreen Biosciences Co Ltd
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Shenzhen Chipscreen Biosciences Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/15—Depsipeptides; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of medicines, in particular to a chidamide pharmaceutical composition and its application.
  • Chidamide (English name: Chidamide) is a new type of anti-cancer drug with a new chemical structure and global intellectual property rights independently designed and synthesized by Shenzhen Chips Biotechnology Co., Ltd. Chidamide has histone deacetylase inhibitory activity and belongs to the class of epigenetic regulators, which can be used for the treatment of various diseases, such as cancer, viral diseases, autoimmune diseases, metabolic diseases, etc.
  • the results of clinical studies that have been completed show that Chidamide has definite curative effects on various lymphomas including peripheral T-cell lymphomas, and also on some other solid tumors such as breast cancer, lung cancer, kidney cancer, colorectal cancer, and uterine cancer. Endometrial cancer has clinically beneficial effects, and its comprehensive indicators (safety, preliminary efficacy, pharmacokinetic characteristics) are better than the results of the same period of international studies of drugs with similar mechanisms of action.
  • Chidamide has extremely low solubility in water and low bioavailability, which leads to clinically poor drug absorption, high doses, and high gastrointestinal toxicity. Therefore, improving the bioavailability of chidamide is of great significance in reducing drug consumption, reducing drug production costs, and reducing gastrointestinal toxicity.
  • the purpose of the present invention is to provide a chidamide pharmaceutical composition, which can significantly improve the bioavailability of chidamide, and can be applied to the fields of medicine preparation and disease treatment related to chidamide .
  • a chidamide pharmaceutical composition includes chidamide and a P-glycoprotein inhibitor, and further, it also includes an immune checkpoint inhibitor.
  • the chidamide of the present invention has the structure shown in formula (1), and its chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3- Pyridine)acryloyl]aminomethyl]benzamide, in its structural formula, the configuration of 3-pyridineacryloyl is E type.
  • the research of the present invention found that the reason for the low oral bioavailability of Chidamide is not only its poor water solubility, but Chidamide as a substrate of intestinal P-gp is another important reason for reducing its oral bioavailability.
  • the effect of the P-gp efflux pump in the digestive tract reduces the absorption of chidamide into the blood.
  • the P-gp efflux pump also exists on the surface of tumor cells, which can lead to a decrease in drug efficacy and tumor cells' resistance to drugs. Therefore, the present invention starts from the discovery of the root cause of the problem and provides the combined application of Chidamide and P-gp inhibitor, which can significantly increase the bioavailability of Chidamide and improve the efficacy of Chidamide.
  • the pharmaceutical composition includes chidamide and a P-glycoprotein inhibitor.
  • the P-glycoprotein inhibitor of the present invention is selected from artificially synthesized P-glycoprotein inhibitors, natural P-glycoprotein inhibitors and pharmaceutical excipients P-glycoprotein inhibitors.
  • the P-glycoprotein inhibitor includes, but is not limited to, verapamil, dexverapamil, cyclosporine, dexnicodipine, transflupentixol, tamoxifen, Vaspoda (PSC833), Tariquidar, TPGS, ⁇ -cyclodextrin, PEG, piperine, VX-710, tetrandrine, FG020326, S-9788, GF-120918, LY-335979, DMDCK and MMDCK, It is selected from any one or two or more of them; in a specific embodiment of the present invention, the P-glycoprotein inhibitor is preferably verapamil or Tariquidar.
  • the mass ratio of chidamide and P-glycoprotein inhibitor is 10:1 to 1:10; in specific embodiments of the present invention, the mass ratio is 10:1, 9:1 , 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1 :6, 1:7, 1:8, 1:9 or 1:10.
  • the mass ratio of chidamide and P-glycoprotein inhibitor is 5:1 to 1:5, for example, 5:1, 4.5:1, 4:1, 3.5:1, 3 :1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1 , 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1 :3.5, 1:4, 1:4.5 or 1:5.
  • the pharmaceutical composition includes chidamide, and verapamil or Tariquidar, wherein the mass ratio of chidamide to verapamil or Tariquidar is 5:1 to 1:5, For example 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4 :1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 , 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.
  • the pharmaceutical composition includes chidamide, a P-glycoprotein inhibitor, and an immune checkpoint inhibitor.
  • the immune checkpoint inhibitor of the present invention is selected from one or more of anti-CTLA-4 antibody, anti-PD-1/PD-L1 antibody, anti-LAG-3 antibody, anti-TIM-3 antibody and anti-TIGIT antibody .
  • anti-CTLA-4 antibodies include but are not limited to Ipilimumab and Tremelimumab.
  • Anti-PD-1/PD-L1 antibodies include but are not limited to RMP 1-14, pembrolizumab, nivolumab, ztezolizumab, avelumab, durvalumab, tislelizumab, carrelizumab, tereprizumab, Sindizumab, Jie Nosumab, KN035, GLS-010 and CS1001 can be selected from any one or two or more of them.
  • Anti-LAG-3 antibodies include but are not limited to MGD013, FS118, Relatlimab, GSK2831781, LAG525, REGN3767 and TSR033.
  • Anti-TIM-3 antibodies include but are not limited to MBG453, TSR022, LY3321367, RO7121661, Sym023, INCAGN2390 and SHR1702.
  • Anti-TIGIT antibodies include but are not limited to tiragolumab, BGB-A1217, MK-7684, BMS-986207, AB154, ASP8374, IBI-939 and OMP-313M32.
  • the mass ratio of chidamide, P-glycoprotein inhibitor and immune checkpoint inhibitor is (1-10): (1-10): (1-10); wherein The chidamide, P-glycoprotein inhibitor and immune checkpoint inhibitor can be independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 in the mass ratio range of 1-10. Or 10.
  • the present invention provides a set of chidamide, P-glycoprotein inhibitors and immune checkpoint inhibitors with a mass ratio of 5:2:2 to illustrate the present invention. The anti-tumor effect of the pharmaceutical composition.
  • the AUC (area under the drug-time curve) of the pharmaceutical composition of the present invention is significantly improved compared with that of chidamide, the combined multiple is more than 1 times, and the maximum can reach At the same time, the maximum concentration of the drug is also significantly increased, the combined multiple is more than 1.5 times, and the highest can be more than 6 times; these results verify that chidamide, as a substrate of intestinal P-gp, can reduce its oral organism Another important reason for utilization.
  • the present invention proposes the use of the pharmaceutical composition in preparing chidamide preparations and/or drugs for treating diseases related to histone deacetylase mechanism of action.
  • the diseases related to the action mechanism of histone deacetylase include but are not limited to cancer, viral diseases, autoimmune diseases and blood system diseases.
  • the disease related to the action mechanism of histone deacetylase is cancer, such as lymphoma, breast cancer, lung cancer, kidney cancer, colorectal cancer, or endometrial cancer.
  • the disease related to the action mechanism of histone deacetylase is peripheral T-cell lymphoma.
  • the present invention also provides a chidamide preparation comprising the chidamide pharmaceutical composition of the present invention, more specifically, the chidamide pharmaceutical composition and pharmaceutically acceptable excipients .
  • the dosage forms of the preparations include, but are not limited to, tablets, capsules, pills, oral liquid preparations (such as syrups), granules, powders, ointments and dripping pills. All preparations can be prepared as sustained-release or controlled-release medicaments. Pharmaceuticals and other forms of pharmaceuticals in release.
  • the pharmaceutically acceptable excipients can be adjusted and selected according to the dosage form to be prepared.
  • the auxiliary materials can be selected from one or more of fillers, disintegrants, binders, and lubricants.
  • the present invention further provides a drug combination, which includes chidamide and a P-glycoprotein inhibitor.
  • the P-glycoprotein inhibitor is selected from the group consisting of artificially synthesized P-glycoprotein inhibitors, natural P-glycoprotein inhibitors, and pharmaceutical excipients P-glycoprotein inhibitors.
  • the P-glycoprotein inhibitor includes, but is not limited to, verapamil, dexverapamil, cyclosporine, dexnicodipine, transflupentixol, tamoxifen, Valspoda (PSC833), Tariquidar, TPGS, ⁇ -cyclodextrin, PEG, piperine, VX-710, tetrandrine, FG020326, S-9788, GF-120918, LY-335979, DMDCK and MMDCK Any one or two or more.
  • the P-glycoprotein inhibitor is preferably verapamil or Tariquidar.
  • the mass ratio of chidamide and P-glycoprotein inhibitor is 10:1 to 1:10; in specific embodiments of the present invention, the mass ratio is 10:1, 9:1 , 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1 :6, 1:7, 1:8, 1:9 or 1:10.
  • the mass ratio of chidamide and P-glycoprotein inhibitor is 5:1 to 1:5, for example, 5:1, 4.5:1, 4:1, 3.5:1, 3 :1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1 , 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1 :3.5, 1:4, 1:4.5 or 1:5.
  • the drug combination includes chidamide, and verapamil or Tariquidar, wherein the mass ratio of chidamide to verapamil or Tariquidar is 5:1 to 1:5, for example 5:1, 4.5:1, 4:1, 3.5:1, 3:1, 2.5:1, 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4: 1, 1.3:1, 1.2:1, 1.1:1, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5.
  • the drug combination includes chidamide, P-glycoprotein inhibitor, and immune checkpoint inhibitor.
  • the immune checkpoint inhibitor is selected from one of anti-CTLA-4 antibodies, anti-PD-1/PD-L1 antibodies, anti-LAG-3 antibodies, anti-TIM-3 antibodies, and anti-TIGIT antibodies Or two or more.
  • the anti-CTLA-4 antibodies include but are not limited to Ipilimumab and Tremelimumab.
  • the anti-PD-1/PD-L1 antibodies include, but are not limited to, RMP 1-14, pembrolizumab, nivolumab, ztezolizumab, avelumab, durvalumab, tislelizumab, carrelizumab, terepril Antibody, Sindizumab, Genozumab, KN035, GLS-010 and CS1001 can be selected from any one or two or more of them.
  • the anti-LAG-3 antibodies include but are not limited to MGD013, FS118, Relatlimab, GSK2831781, LAG525, REGN3767, and TSR033.
  • Anti-TIM-3 antibodies include but are not limited to MBG453, TSR022, LY3321367, RO7121661, Sym023, INCAGN2390 and SHR1702.
  • the anti-TIGIT antibodies include, but are not limited to, tiragolumab, BGB-A1217, MK-7684, BMS-986207, AB154, ASP8374, IBI-939, and OMP-313M32.
  • the mass ratio of chidamide, P-glycoprotein inhibitor and immune checkpoint inhibitor is (1-10): (1-10): (1-10); wherein The chidamide, P-glycoprotein inhibitor and immune checkpoint inhibitor can be independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 in the mass ratio range of 1-10. Or 10.
  • the chidamide, P-glycoprotein inhibitor and immune checkpoint inhibitor are located in the same or separate preparation units.
  • the present invention provides a method for inhibiting HDAC, which comprises administering to a subject in need thereof an effective amount of the chidamide pharmaceutical composition, chidamide preparation or pharmaceutical combination described herein A step of.
  • the drugs in the pharmaceutical composition may be administered simultaneously, separately, or sequentially.
  • the present invention provides a method for treating diseases related to the mechanism of action of histone deacetylase, which comprises administering an effective amount of the chidamide pharmaceutical composition described herein to a subject in need thereof, Steps of chidamide preparation or drug combination.
  • the disease related to the action mechanism of histone deacetylase is selected from cancer, viral disease, autoimmune disease and blood system disease.
  • the disease related to the action mechanism of histone deacetylase is cancer, such as lymphoma, breast cancer, lung cancer, kidney cancer, colorectal cancer, or endometrial cancer.
  • the disease related to the action mechanism of histone deacetylase is peripheral T-cell lymphoma.
  • the drugs in the pharmaceutical composition may be administered simultaneously, separately, or sequentially.
  • the present invention provides chidamide and P-sugar.
  • the reasonable application of the pharmaceutical composition of the protein inhibitor can significantly improve the bioavailability of the chidamide and improve the efficacy of the chidamide.
  • the present invention also found through research that Chidamide combined with P-glycoprotein inhibitor showed good anti-tumor efficacy, and the most significant anti-tumor efficacy is Chidamide combined with P-glycoprotein inhibitor and immune checkpoint suppression It shows that the combined application of chidamide, P-gp inhibitor and immune checkpoint inhibitor can further effectively improve the anti-tumor efficacy of chidamide.
  • Figure 1 shows the results of rat pharmacokinetic experiment of chidamide combined with verapamil
  • Figure 2 shows the results of the pharmacokinetic experiment of Chidamide combined with Tariquidar in rats
  • Figure 3 shows the results of the pharmacokinetic experiment of Chidamide combined with TPGS in rats
  • Figure 4 shows the results of rat pharmacokinetic experiment of chidamide combined with hydroxypropyl ⁇ cyclodextrin
  • Figure 5 shows the mouse tumor efficacy test of Chidamide combined with P-gp inhibitor
  • Figure 6 shows the mouse tumor efficacy test of chidamide combined with P-gp inhibitor and immune checkpoint inhibitor
  • Figure 7 shows that Chidamide combined with P-gp inhibitors and immune checkpoint inhibitors enhance the gene expression of cytokines TNF- ⁇ and IL-6.
  • the invention discloses a chidamide pharmaceutical composition and a preparation method and application thereof. Those skilled in the art can learn from the content of this article and appropriately improve the process parameters to achieve it. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all deemed to be included in the present invention.
  • the pharmaceutical composition and its application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously modify or appropriately modify the pharmaceutical composition and its application as described herein without departing from the content, spirit and scope of the present invention. In combination with, to realize and apply the technology of the present invention.
  • CS055 is chidamide
  • the efflux ratio (Efflux ratio) is calculated by Papp(B to A)/Papp(A to B).
  • the ratio is greater than 2, it means that the efflux ratio is mediated by P-gp.
  • the platoon mechanism works.
  • the efflux rate of chidamide reached 3.38, indicating that chidamide is a substrate of P-gp.
  • the ratio of other drugs except Digoxin is less than 2, indicating that not all drugs are substrates of P-glycoprotein.
  • Each rat in group 1 was given a suspension of chidamide (20mg/kg) alone at 20mg/kg, and each rat in group 2 was given a mixture of chidamide (20mg/kg) and verapamil (25mg/kg) at the same time. Suspension.
  • Each rat in group 1 was given a suspension of chidamide (20 mg/kg) alone, and each rat in group 2 was given a suspension of chidamide (20 mg/kg) and Tariquidar (12 mg/kg) at the same time.
  • Example 4 Rat pharmacokinetic test of chidamide combined with vitamin E polyethylene glycol succinate (TPGS)
  • Each rat in group 1 was given a suspension of chidamide at 20 mg/kg alone, and each rat in group 2 was given a mixture of chidamide (20 mg/kg) containing 40% hydroxypropyl ⁇ -cyclodextrin. Suspension.
  • Example 6 Tumor efficacy test of chidamide combined with P-gp inhibitor in mice
  • mice Forty female BALB/c mice aged 6-7 weeks were selected and randomly divided into 4 groups with 10 mice in each group. At the beginning of the experiment, each mouse axillary was inoculated subcutaneously with mouse intestinal cancer cell CT26, 5 *10 5 cells per mouse. The administration was started when the tumor grew to 50 mm 3 on 7 days after the inoculation, and the single-agent chidamide (25mg/kg), chidamide combined with Tariquida, chidamide combined with verapamil, and chidamide were given respectively. Amine combined with TPGS was continuously administered until 21 days after vaccination, during which the tumor growth of each group was measured every two days. The dosage and test results of each group are shown in Figure 5.
  • Example 7 Mice tumor efficacy test of chidamide combined with P-gp inhibitor and immune checkpoint inhibitor
  • mice Sixty female BALB/c mice aged 6-7 weeks were selected and randomly divided into 6 groups with 10 mice in each group. At the beginning of the experiment, each mouse axillary was inoculated subcutaneously with mouse intestinal cancer cell CT26, 5 *10 5 cells per mouse. The administration was started when the tumor grew to 50mm 3 7 days after inoculation. Solvent control was given. Chidamide (25mg/kg, gavage, once a day), Tariquidar (10mg/kg, gavage, once a day).
  • Example 8 Chidamide combined with P-gp inhibitors and immune checkpoint inhibitors enhance the gene expression of cytokines TNF- ⁇ and IL-6
  • mice in each experimental group were taken.
  • a single spleen cell suspension is obtained through steps such as separation and removal of red blood cells. Take 5*10 6 spleen cells from each group, and extract total RNA with TRIzol reagent (Invitrogen).
  • the cDNA was obtained by reverse transcription using Transcriptor First Strand cDNA Synthesis Kit (Roche), and then real-time quantitative PCR was performed on the ABI Prism 7000 PCR instrument using Roche's SYBR Green Master Dye and other reagents.
  • mice cytokine IL-6 and TNF- ⁇ genes are respectively, IL-6 Forward: 5'-GGAGCCCACCAAGAACGATAG-3', IL-6 Reverse: 5'-GTGAAGTAGGGAAGGCCGTG-3'; TNF- ⁇ Forward: 5 '-TGATCGGTCCCCAAAGGGAT-3', TNF- ⁇ Reverse: 5'-GCTACGACGTGGGCTACAGG-3'.
  • the primer sequence of the mouse internal reference ⁇ -actin is ⁇ -actin Forward: 5'-GTCGAGTCGCGTCCACC-3', ⁇ -actin Reverse: 5'-ACGATGGAGGGGAATACAGC-3'.
  • the relative expression results of splenic cytokines IL-6 and TNF- ⁇ genes in each group are shown in Figure 7.

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Abstract

L'invention concerne une composition pharmaceutique contenant du chidamide et une utilisation de cette dernière. La composition pharmaceutique contient du chidamide et un inhibiteur de glycoprotéine P, et l'utilisation raisonnable des deux peut améliorer la biodisponibilité du chidamide et l'efficacité du chidamide. L'utilisation combinée de chidamide et de l'inhibiteur de glycoprotéine P avec un inhibiteur de point de contrôle immunitaire peut en outre améliorer efficacement l'efficacité antitumorale du chidamide.
PCT/CN2020/111669 2019-08-28 2020-08-27 Composition pharmaceutique contenant du chidamide et utilisation de cette dernière Ceased WO2021037128A1 (fr)

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