WO2017135259A1 - 共結晶 - Google Patents
共結晶 Download PDFInfo
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- WO2017135259A1 WO2017135259A1 PCT/JP2017/003453 JP2017003453W WO2017135259A1 WO 2017135259 A1 WO2017135259 A1 WO 2017135259A1 JP 2017003453 W JP2017003453 W JP 2017003453W WO 2017135259 A1 WO2017135259 A1 WO 2017135259A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to a pharmaceutical composition containing a co-crystal.
- Non-patent Document 1 Absorption of a drug from the intestinal tract is determined by a dissolution process or a membrane permeation process.
- the dissolution process often becomes the rate-limiting step, and it can be expected that the bioavailability of the drug is increased by improving the solubility.
- solvates including hydrates or crystal polymorphs differ in crystal physicochemical properties including solubility. Controlling to a single crystal form is important for keeping the quality of pharmaceutical products constant (Non-patent Document 2).
- co-crystal generally means a multi-component crystal including an intermolecular interaction in which components constituting the co-crystal are linked by other than ionic bonds
- Non-patent Document 3 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- Trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide is known to have Smo inhibitory action and useful as a preventive or therapeutic agent for cancer (Patent Document 1).
- Non-Patent Document 4 Since it is suggested that the drug has good membrane permeability (Non-Patent Document 4), it is necessary to improve the solubility of the drug in order to increase bioavailability. In addition, since this drug forms a solvate with many organic solvents, and various crystal polymorphs are derived from the solvate (Non-patent Document 5), production with controlled crystal form is difficult.
- the present invention relates to 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2) useful as a preventive or therapeutic agent for cancer.
- -Phenylethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide was It is easier to control the crystal form that is important for the quality of pharmaceuticals in manufacturing by suppressing the formation of solvates while having higher solubility than stable crystals composed of a single drug component. It is aimed.
- a co-crystal of ethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide can be provided.
- the present invention relates to (1) 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- Co-crystal of (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide and (2) L-malic acid or L-tartaric acid (Hereinafter referred to as “co-crystal of the present invention”).
- co-crystal refers to an intermolecular interaction other than ionic bonds (for example, hydrogen bonds, van der Waals forces, ⁇ - ⁇ bonds, etc.). ) Means crystals connected by Whether a certain compound is a co-crystal or a salt in which constituent components are linked by ionic bonds can be confirmed by single crystal X-ray diffraction or infrared spectroscopy (Schultheiss N. et al. "Pharmaceutical” Cocrystals "and” Their “Physicochemical” Properties ",” Crystal “Growth” & “Design,” 9, “2009.” 2950-2967).
- 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2- Trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide can be produced by a known method as described in Patent Document 1, for example.
- the malic acid that forms a co-crystal with trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide includes L-malic acid, D-malic acid, DL- Malic acid can be mentioned, and L-malic acid is particularly preferable.
- the above co-crystal is characterized by powder X-ray diffraction lattice spacing (d) of 11.7 ⁇ 0.2, 10.7 ⁇ 0.2, 10.0 ⁇ 0.2, 8.6 ⁇ 0.2, 8.4 ⁇ 0.2, 5.8 ⁇ 0.2 and 4.9 ⁇ 0.2 angstroms
- d powder X-ray diffraction lattice spacing
- the tartaric acid that forms a co-crystal with trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide includes L-tartaric acid, D-tartaric acid, DL-tartaric acid, meso -Tartaric acid can be mentioned, and L-tartaric acid is particularly preferable.
- the above co-crystal is characterized by powder X-ray diffraction lattice spacing (d) of 12.0 ⁇ 0.2, 11.0 ⁇ 0.2, 10.1 ⁇ 0.2, 8.4 ⁇ 0.2, 8.7 ⁇ 0.2, 5.9 ⁇ 0.2 and 4.9 ⁇ 0.2 angstroms
- d powder X-ray diffraction lattice spacing
- Co-crystals with powder X-ray diffraction patterns with typical peaks 12.0 ⁇ 0.2, 11.0 ⁇ 0.2, 10.1 ⁇ 0.2, 8.4 ⁇ 0.2, 8.7 ⁇ 0.2, 7.6 ⁇ 0.2, 7.3 ⁇ 0.2, 5.9 ⁇ 0.2 and 4.9 ⁇ 0.2
- the co-crystal is prepared by a known method (for example, a slow cooling method from a solution, an antisolvent, such as described in Qiao, N et al., Pharmac “Pharmaceutical cocrystals: An overview”, International Journal of Pharmaceutics, 419, 2011. 1-11). (Addition method, solvent evaporation method, slurry ripening method, co-grinding method, melting method, etc.) or a combination of these principles can be used to produce an organic compound and a co-crystal former.
- the co-crystal of the present invention interacts with, for example, a human Smo protein and changes its three-dimensional structure, thereby inhibiting complex formation with a protein involved in signal transduction in the cytoplasm and inhibiting the Hedgehog signaling system. Inhibit.
- the co-crystal of the present invention interacts with the human Smo protein and inhibits the Hedgehog signaling system by directly inhibiting the complex formation of the human Smo protein and the protein involved in the Hedgehog signaling system in the cytoplasm.
- the co-crystal of the present invention interacts with a modification site received from a protein involved in the Hedgehog signal transduction system of the Smo protein, for example, phosphorylation site, etc., thereby inhibiting modification such as phosphorylation of Smo and inhibiting the Hedgehog signal transduction system. Inhibit.
- the co-crystal of the present invention is useful as a Smo inhibitor for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.).
- the co-crystals of the present invention can be used to treat diseases that may be affected by Smo, such as cancer [eg, colon cancer (eg, colon cancer, rectal cancer, anal cancer, familial colon cancer, hereditary nonpolyposis colon cancer, Gastrointestinal stromal tumors), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, pancreatic endocrine tumor, etc.), pharyngeal cancer, laryngeal cancer , Esophageal cancer, gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquam
- the co-crystal of the present invention is effective for glioma, medulloblastoma, basal cell tumor, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, stomach cancer, colon cancer, rhabdomyosarcoma and breast cancer. is there.
- the co-crystal of the present invention can be administered orally or parenterally as it is or with a pharmacologically acceptable carrier.
- dosage forms for oral administration of the co-crystal of the present invention include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), Syrups, emulsions, suspensions and the like can be mentioned, and dosage forms for parenteral administration include, for example, injections, infusions, drops, suppositories and the like.
- an appropriate base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc. It is also effective to make a combined sustained-release preparation.
- the co-crystal of the present invention when the co-crystal of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and when produced into pills and granules. Can be produced by containing an excipient, a binder, a disintegrant and the like.
- excipients when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions or suspensions, suspending agents, surfactants It can be produced by adding an emulsifier and the like.
- excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
- binder examples include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
- disintegrants include starch and calcium carbonate.
- the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
- sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
- surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
- suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
- emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
- coloring agents, preservatives, fragrances, flavoring agents, stabilizers, thickeners and the like that are usually used in the pharmaceutical field are appropriately used. An appropriate amount can be added.
- intravenous injections In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions and the like are included as injections, and iontophoretic transdermal agents and the like are included as sustained-release preparations.
- Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the co-crystal of the present invention in a sterile aqueous or oily liquid.
- Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants, and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc.
- the oily liquid include sesame oil and soybean oil.
- benzyl benzoate As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended.
- the prepared injection solution is usually filled in an ampoule.
- the content of the cocrystal of the present invention in the preparation of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 2 to 85% by weight, based on the whole preparation, More preferably, it is about 5 to 70% by weight.
- the content of the additive in the preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
- the co-crystal of the present invention can be used safely with stability and low toxicity.
- the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc.
- the daily dose for an adult Is an active ingredient (6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2 , 2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide), about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 To 200 mg, which can be administered once or in 2 to 3 divided doses.
- the co-crystal of the present invention When the co-crystal of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection).
- a liquid for example, an injection.
- the single dose varies depending on the administration subject, target organ, symptom, administration method, and the like.
- the active ingredient (6-ethyl-N- [1- ( Hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro -1H-pyrrolo [3,2-c] pyridine-2-carboxamide) of about 0.01 to about 100 mg, preferably about 0.01 to about 50 mg, more preferably about 0.01 to about 20 mg by intravenous injection. It is convenient to administer.
- room temperature means about 15-30 ° C.
- the powder X-ray diffraction measurement was performed using a Cu—K ⁇ ray by a sample horizontal multipurpose X-ray diffraction apparatus Ultimate IV manufactured by Rigaku Corporation.
- Single crystal X-ray diffraction was measured with a curved imaging plate single crystal automatic X-ray structure analyzer R-AXIS RAPID II manufactured by Rigaku Corporation using Cu-K ⁇ rays.
- the initial phase was determined by the direct method, and the structure was refined by SHELXL-97.
- the solubility was 6-ethyl-N- [in distilled water in which each crystal was shaken at 37 ° C. for 24 hours, Japanese Pharmacopoeia dissolution test first solution, fasting artificial intestinal fluid (FaSSIF) or satiety artificial intestinal fluid (FeSSIF).
- the dissolution test was evaluated by the rotating paddle method (paddle rotation speed: 50 rpm) in fasting artificial intestinal fluid (FaSSIF) at 37 ° C. using powder in which lactose of the same weight as the crystal powder was physically mixed.
- JP1 Japanese Pharmacopoeia Dissolution Test First Solution
- FaSSIF Fasting Artificial Intestinal Fluid
- FeSSIF Saturated Artificial Intestinal Fluid API: 6-Ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4- Oxo-5- (2-oxo-2-phenylethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide
- Example 1 Co-crystal of API and L-malic acid
- About 1 g of API anhydrous crystals were dissolved in 10 mL of acetone and about 130 mg of L-malic acid in about 1 mL of ethanol at 50 ° C. and mixed.
- the resulting solution was filtered while hot at 50 ° C., and about 17 mL of n-heptane was slowly added.
- the precipitate obtained by allowing the resulting solution to cool at room temperature was collected by filtration and dried under reduced pressure at 80 ° C. to obtain crystals.
- the obtained crystals show the pattern shown in FIG. 1 as measured by powder X-ray diffraction, and have a d value of 11.7 angstroms, 10.0 angstroms, 8.6 angstroms, 5.8 angstroms, and 4.9 angstroms.
- a peak was observed.
- differential scanning calorimetry a peak accompanying melting or decomposition with the peak at around 153 ° C. shown in FIG. 2 was observed.
- thermogravimetry as shown in FIG. 3, no significant weight reduction was observed up to the temperature at which the peak observed in the differential scanning calorimetry was observed, so the crystal did not contain a solvent. It was supported to be anhydrous crystals. Further, the resulting crystals show the infrared absorption spectra of Fig.
- the interatomic distance between the carbon atom and the oxygen atom in the carboxylic acid of L-malic acid in the obtained X-ray crystal structure was 1.16 (1) angstrom and 1.306 (7) angstrom, or 1.211 (9 ) Angstrom and 1.313 (6) Angstrom, and L-malic acid in the crystal is in a non-ionized state and is a co-crystal due to the asymmetry of carbon and oxygen atoms in the same carboxylic acid functional group. It was supported.
- Example 2 Co-crystal of API and L-tartaric acid
- About 1 g of API anhydride crystals were dissolved in about 10 mL of methyl ethyl ketone and about 146 mg of L-tartaric acid in about 1 mL of ethanol at 75 ° C. and mixed.
- the resulting solution was filtered while hot at 75 ° C., and approximately 9.5 mL of n-heptane was slowly added.
- the precipitate obtained by allowing the resulting solution to cool at room temperature was collected by filtration and dried under reduced pressure at 80 ° C. to obtain crystals.
- the obtained crystal shows the pattern of FIG. 6 by powder X-ray diffraction measurement, and is characterized by a d value of 12.0 angstrom, 10.1 angstrom, 8.7 angstrom, 5.9 angstrom, and 4.9 angstrom. Showed a strong peak.
- differential scanning calorimetry a peak accompanying melting or decomposition with the peak at around 170 ° C. shown in FIG. 7 was observed.
- thermogravimetry as shown in FIG. 8, no significant weight reduction was observed near the temperature at which the peak observed in the above differential scanning calorimetry was observed, so the crystal does not contain a solvent. It was supported to be anhydrous crystals. Further, the obtained crystal showed the infrared absorption spectrum of FIG.
- the distance between the carbon atom and oxygen atom of the carboxylic acid of L-tartaric acid in the obtained X-ray crystal structure is 1.230 (6) angstrom and 1.313 (4) angstrom, or 1.219 (5), respectively. Angstrom and 1.323 (4) angstrom, and L-tartaric acid in the crystal is in a non-ionized state due to the asymmetry of carbon atom and oxygen atom in the same carboxylic acid functional group. Supported.
- Table 3 shows the results of examining the crystal form of the residue obtained by subjecting a co-crystal of API and L-malic acid, or a co-crystal of API and L-tartaric acid, and an anhydrous crystal of API to each other in a slurry experiment in each solvent.
- Table 4 shows the results of examining the crystal form of the precipitate obtained by recrystallization from each organic solvent. None of the co-crystals was found to have a solvate of the co-crystal, suggesting that it is less likely to form a solvate as compared to the anhydrous API free crystal.
- Formulation Example 1 A pharmaceutical containing the co-crystal of the present invention as an active ingredient can be produced, for example, by the following formulation. 1. Capsule (1) 40 mg of co-crystal obtained in Example 1 (2) Lactose 70mg (3) Microcrystalline cellulose 9mg (4) Magnesium stearate 1mg 1 capsule 120mg After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
- Tablet (1) 40 mg of co-crystal obtained in Example 1 (2) Lactose 58mg (3) Corn starch 18mg (4) Microcrystalline cellulose 3.5mg (5) Magnesium stearate 0.5mg 1 tablet 120mg After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
- 6-ethyl-N- [1- (hydroxyacetyl) piperidin-4-yl] -1-methyl-4-oxo-5- (2-oxo) is useful as a preventive or therapeutic agent for cancer.
- -2-phenylethyl) -3- (2,2,2-trifluoroethoxy) -4,5-dihydro-1H-pyrrolo [3,2-c] pyridine-2-carboxamide A co-crystal having improved solubility and / or difficulty in forming a solvate can be obtained.
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Abstract
Description
薬物の腸管からの吸収は、溶解過程あるいは膜透過過程が律速段階となる(非特許文献1)。難溶性薬物の場合、溶解過程が律速段階になることが多く、溶解性を向上させることにより薬物の生物学的利用能を増加させることが期待できる。
水和物を含む溶媒和物あるいは結晶多形はそれぞれ、溶解性をはじめとした結晶の物理化学的特性が異なることが知られている。単一の結晶形に制御することは、医薬品の品質を一定に保つ上で重要である(非特許文献2)。
「共結晶」とは、一般に、該共結晶を構成する成分が、イオン結合以外で結びつく分子間相互作用を含む多成分結晶を意味する(非特許文献3)。
6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドは、Smo阻害作用を有し、癌の予防または治療剤として有用であることが知られている(特許文献1)。
本薬物の膜透過性は良好であることが示唆されていることから(非特許文献4)、生物学的利用能を増加させるためには、薬物の溶解性を向上させる必要がある。また、本薬物は多くの有機溶媒と溶媒和物を形成し、さらにその溶媒和物から多種の結晶多形が誘導されるため(非特許文献5)、結晶形を制御した製造は難しい。
〔2〕(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶である〔1〕記載の共結晶;
〔3〕粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する〔2〕記載の共結晶;
〔4〕(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶である〔1〕記載の共結晶;
〔5〕粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する〔4〕記載の共結晶;
〔6〕〔1〕記載の共結晶を含有してなる医薬;
〔7〕Smo阻害剤である〔6〕記載の医薬;
〔8〕癌の予防および/または治療剤である〔6〕記載の医薬;
〔9〕哺乳動物に対し、〔1〕記載の共結晶の有効量を投与することを特徴とする、該哺乳動物におけるSmoの阻害方法;
〔10〕哺乳動物に対し、〔1〕記載の共結晶の有効量を投与することを特徴とする、該哺乳動物における癌の予防および/または治療方法;
〔11〕癌の予防および/または治療に使用するための、〔1〕記載の共結晶;および
〔12〕癌の予防および/または治療剤を製造するための、〔1〕記載の共結晶の使用。
本発明は、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸またはL-酒石酸との共結晶(以下、「本発明の共結晶」とする)を提供する。
(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
また、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2、8.6±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
さらに、上記共結晶としては、粉末X線回折の格子面間隔(d)が11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、7.5±0.2、7.2±0.2、5.8±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、または11.7±0.2、10.7±0.2、10.0±0.2、8.6±0.2、8.4±0.2、7.5±0.2、7.2±0.2、5.8±0.2、4.9±0.2、4.5±0.2および4.2±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
また、(1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2、8.7±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
さらに、上記共結晶としては、粉末X線回折の格子面間隔(d)が12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、7.6±0.2、7.3±0.2、5.9±0.2および4.9±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶、または12.0±0.2、11.0±0.2、10.1±0.2、8.4±0.2、8.7±0.2、7.6±0.2、7.3±0.2、5.9±0.2、4.9±0.2、4.7±0.2および4.5±0.2オングストロームに特徴的なピークが現れる粉末X線回折パターンを有する共結晶が好ましい。
本発明の共結晶を経口投与する場合の剤形としては、例えば、錠剤(糖衣錠、フィルムコーティング錠を含む)、丸剤、顆粒剤、散剤、カプセル剤(ソフトカプセル剤、マイクロカプセル剤を含む)、シロップ剤、乳剤、懸濁剤等が挙げられ、また、非経口投与する場合の剤形としては、例えば、注射剤、注入剤、点滴剤、坐剤等が挙げられる。また、適当な基剤(例、酪酸の重合体、グリコール酸の重合体、酪酸-グリコール酸の共重合体、酪酸の重合体とグリコール酸の重合体との混合物、ポリグリセロール脂肪酸エステル等)と組み合わせ徐放性製剤とすることも有効である。
結合剤の例としては、5ないし10重量%デンプンのり液、10ないし20重量%アラビアゴム液またはゼラチン液、1ないし5重量%トラガント液、カルボキシメチルセルロース液、アルギン酸ナトリウム液、グリセリン等が挙げられる。
崩壊剤の例としては、でんぷん、炭酸カルシウム等が挙げられる。
滑沢剤の例としては、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、精製タルク等が挙げられる。
甘味剤の例としては、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン、単シロップ等が挙げられる。
界面活性剤の例としては、ラウリル硫酸ナトリウム、ポリソルベート80、ソルビタンモノ脂肪酸エステル、ステアリン酸ポリオキシル40等が挙げられる。
懸濁化剤の例としては、アラビアゴム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、メチルセルロース、ベントナイト等が挙げられる。
乳化剤の例としては、アラビアゴム、トラガント、ゼラチン、ポリソルベート80等が挙げられる。
実施例において、室温は、約15~30℃を意味する。
粉末X線回折測定は、Cu-Kα線を用い、株式会社リガク社製試料水平型多目的X線回折装置Ultima IVにより測定した。示差走査熱量測定あるいは熱重量測定は、メトラー・トレド社製DSC1/700/903-2あるいはメトラー・トレド社製TGA/DSC1/LF/629-2を用いて、昇温速度5℃/分で測定した。赤外分光スペクトルは、島津製作所社製フーリエ変換赤外分光光度計Shimadzu IR Prestige-21にSmiths Detection社製Dura Sample IR IIを装着して、全反射法吸収測定法にて分解能4cm-1で測定した。ラマン分光測定は、Kaiser Optical Systems社製RXN2に励起波長1064nmのレーザー光源を用いて測定した。単結晶X線回折は、Cu-Kα線を用い、株式会社リガク社製湾曲イメージングプレート単結晶自動X線構造解析装置R-AXIS RAPID IIにより測定した。直接法で初期位相を決定し、SHELXL-97で構造を精密化した。溶解度は、各結晶を37℃で24時間振とうした蒸留水、日本薬局方溶出試験第1液、空腹時人工腸液(FaSSIF)あるいは飽食時人工腸液(FeSSIF)中の6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドの濃度とした。固有溶解速度測定は、結晶粉末のみを圧縮成型したディスクを用いて、0.2%(w/v)のラウリル硫酸ナトリウムを含む20mmoL/Lのリン酸ナトリウム緩衝液(pH6.8)中で回転ディスク法(回転数:100rpm)により評価した。溶出試験は、結晶粉末と同重量の乳糖を物理的に混合した粉末を用いて、37℃の空腹時人工腸液中(FaSSIF)において回転パドル法(パドル回転数:50rpm)で評価した。溶液中の薬物濃度はWaters社製Alliance HPLCシステムe2695と検出器2789を用いた液体クロマトグラフ法(分離カラムは:YMCPackPro C18 4.6mmφ×150mm、温度:40℃、移動相:20mmol/Lリン酸ナトリウム緩衝液(pH6.8)/アセトニトリル=60/40(v/v)、流速:1mL/分、紫外吸収検出波長:240nm)で決定した。スラリー実験は、結晶粉末に試験溶媒を添加して約25℃で24時間懸濁攪拌して得られた残渣をろ取して、結晶形を粉末X線回折測定あるいはラマン分光法で確認した。再結晶実験では、結晶をエタノール、アセトン、2-プロパノール、テトラヒドロフラン、メチルエチルケトン、酢酸エチル、酢酸イソプロピル、アニソールあるいは酢酸イソブチルに55℃で溶解させてフィルターろ過したのち、5℃まで徐冷あるいは、溶液にn-ヘプタンを添加して同じく5℃まで徐冷して得られた析出物の結晶形を粉末X線回折測定あるいはラマン分光法で確認した。
その他の本明細書中の記号は以下の意味を示す。
JP1:日本薬局方溶出試験第1液
FaSSIF:空腹時人工腸液
FeSSIF:飽食時人工腸液
API:6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミド
APIとL-リンゴ酸との共結晶
約1gのAPIの無水物結晶を10mLのアセトンに、約130mgのL-リンゴ酸を約1mLのエタノールにそれぞれ50℃で溶解して、混和させた。得られた溶液を50℃に保ちながら熱時ろ過して約17mLのn-ヘプタンをゆっくり加えた。得られた溶液を室温で放冷することにより得られた析出物をろ取して、80℃で減圧乾燥して結晶を得た。
APIとL-酒石酸との共結晶
約1gのAPIの無水物結晶を約10mLのメチルエチルケトンに、約146mgのL-酒石酸を約1mLのエタノールにそれぞれ75℃で溶解して、混和させた。得られた溶液を75℃に保ちながら熱時ろ過して、約9.5mLのn-ヘプタンをゆっくり加えた。得られた溶液を室温で放冷することにより得られた析出物をろ取して、80℃で減圧乾燥して結晶を得た。
本発明の共結晶を有効成分として含有する医薬は、例えば、次のような処方によって製造することができる。
1.カプセル剤
(1)実施例1で得られた共結晶 40mg
(2)ラクトース 70mg
(3)微結晶セルロース 9mg
(4)ステアリン酸マグネシウム 1mg
1カプセル 120mg
(1)、(2)、(3)および(4)の1/2を混和した後、顆粒化する。これに残りの(4)を加えて全体をゼラチンカプセルに封入する。
(1)実施例1で得られた共結晶 40mg
(2)ラクトース 58mg
(3)コーンスターチ 18mg
(4)微結晶セルロース 3.5mg
(5)ステアリン酸マグネシウム 0.5mg
1錠 120mg
(1)、(2)、(3)、(4)の2/3および(5)の1/2を混和した後、顆粒化する。残りの(4)および(5)をこの顆粒に加えて錠剤に加圧成型する。
日局注射用蒸留水50mlに実施例1で得られた共結晶50mgを溶解した後、日局注射用蒸留水を加えて100mlとする。この溶液を滅菌条件下でろ過し、次にこの溶液1mlずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。
Claims (12)
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸またはL-酒石酸との共結晶。
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-リンゴ酸との共結晶である請求項1記載の共結晶。
- 粉末X線回折の格子面間隔(d)が11.7±0.2、10.0±0.2および8.6±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する請求項2記載の共結晶。
- (1) 6-エチル-N-[1-(ヒドロキシアセチル)ピペリジン-4-イル]-1-メチル-4-オキソ-5-(2-オキソ-2-フェニルエチル)-3-(2,2,2-トリフルオロエトキシ)-4,5-ジヒドロ-1H-ピロロ[3,2-c]ピリジン-2-カルボキサミドと、(2) L-酒石酸との共結晶である請求項1記載の共結晶。
- 粉末X線回折の格子面間隔(d)が12.0±0.2、10.1±0.2および8.7±0.2オングストロームに特徴的ピークが現れる粉末X線回折パターンを有する請求項4記載の共結晶。
- 請求項1記載の共結晶を含有してなる医薬。
- Smo阻害剤である請求項6記載の医薬。
- 癌の予防および/または治療剤である請求項6記載の医薬。
- 哺乳動物に対し、請求項1記載の共結晶の有効量を投与することを特徴とする、該哺乳動物におけるSmoの阻害方法。
- 哺乳動物に対し、請求項1記載の共結晶の有効量を投与することを特徴とする、該哺乳動物における癌の予防および/または治療方法。
- 癌の予防および/または治療に使用するための、請求項1記載の共結晶。
- 癌の予防および/または治療剤を製造するための、請求項1記載の共結晶の使用。
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JP2021522312A (ja) * | 2018-06-21 | 2021-08-30 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 3−((1R,3R)−1−(2,6−ジフルオロ−4−((1−(3−フルオロプロピル)アゼチジン−3−イル)アミノ)フェニル)−3−メチル−1,3,4,9−テトラヒドロ−2H−ピリド[3,4−b]インドール−2−イル)−2,2−ジフルオロプロパン−1−オールの固体形態及び置換されたフェニル又はピリジニル部分を含む縮合三環式化合物を調製するための方法とそれらの使用方法 |
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---|---|---|---|---|
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JP2016017099A (ja) | 2014-07-04 | 2016-02-01 | 富士フイルム株式会社 | 新規化合物、染色又は捺染用着色組成物、インクジェット捺染用インク、布帛を捺染する方法、及び染色又は捺染された布帛 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011513199A (ja) * | 2008-02-26 | 2011-04-28 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
JP4719317B2 (ja) | 2008-02-26 | 2011-07-06 | 武田薬品工業株式会社 | 縮合複素環誘導体およびその用途 |
JP2016017099A (ja) | 2014-07-04 | 2016-02-01 | 富士フイルム株式会社 | 新規化合物、染色又は捺染用着色組成物、インクジェット捺染用インク、布帛を捺染する方法、及び染色又は捺染された布帛 |
Non-Patent Citations (15)
Title |
---|
ABRAMOV, YURIY A. ET AL.: "Rational Coformer or Solvent Selection for Pharmaceutical Cocrystallization or Desolvation", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 101, no. 10, 2012, pages 3687 - 3697, XP055397627, ISSN: 1520-6017 * |
GORDON L. AMIDON ET AL.: "A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability", PHARMACEUTICAL RESEARCH, vol. 12, 1995, pages 413 - 420 |
GOUD, N.R. ET AL.: "The role of cocrystals in pharmaceutical science", DRUG DISCOVERY TODAY, vol. 13, 2008, pages 440 - 446 |
IWATA, K. ET AL.: "Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism", CRYSTAL GROWTH & DESIGN, vol. 14, 2012, pages 3335 - 3342 |
IWATA, KENTARO ET AL.: "Cocrystallization Enhanced TAK-441 Aqueous Solubility and Suppressed High Solvatomorphism", CRYSTAL GROWTH & DESIGN, vol. 16, no. 8, 22 June 2016 (2016-06-22), pages 4599 - 4606, XP055533179, ISSN: 1528-7483 * |
IWATA, KENTARO ET AL.: "Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate- Trapping Polymorphism", CRYSTAL GROWTH & DESIGN, vol. 14, no. 7, 2014, pages 3335 - 3342, XP055533172, ISSN: 1528-7483 * |
OHASHI, T. ET AL.: "Discovery of the investigational drug TAK-441, a pyrrolo[3,2-c]pyridine derivative, as a highly potent and orally active hedgehog signaling inhibitor: Modification of the core skeleton for improved solubility", BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, 2012, pages 5507 - 5517, XP028938236, DOI: doi:10.1016/j.bmc.2012.07.034 |
QIAO, N ET AL.: "Pharmaceutical cocrystals: An overview", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 419, 2011, pages 1 - 11, XP028306606, DOI: doi:10.1016/j.ijpharm.2011.07.037 |
QIAO, NING ET AL.: "Pharmaceutical cocrystals: An overview", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 419, no. 1-2, 2011, pages 1 - 11, XP028306606, ISSN: 0378-5173 * |
ROLF HILFIKER: "Polymorphism: In the Pharmaceutical Industry", 2006, WILEY-VCH VERLAG GMBH & CO. KGAA |
SCHULTHEISS N. ET AL.: "Pharmaceutical Cocrystals and Their Physicochemical Properties", CRYSTAL GROWTH & DESIGN, vol. 9, 2009, pages 2950 - 2967, XP055011939, DOI: doi:10.1021/cg900129f |
SCHULTHEISS, NATE ET AL.: "Pharmaceutical Cocrystals and Their Physicochemical Properties", CRYSTAL GROWTH & DESIGN, vol. 9, no. 6, 2009, pages 2950 - 2967, XP055011939, ISSN: 1528-7483 * |
See also references of EP3412667A4 |
SHAN, NING ET AL.: "The role of cocrystals in pharmaceutical science", DRUG DISCOVERY TODAY, vol. 13, no. 9 / 10, 2008, pages 440 - 446, XP055127319, ISSN: 1359-6446 * |
TAKASHI KOJIMA ET AL.: "Application of in situ Raman Microscopy to Cocrystal Screening", JOURNAL OF PHARMACEUTICAL MACHINERY AND ENGINEERING, vol. 21, no. 2, 2012, pages 23 - 28, XP009512548, ISSN: 2186-3237 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2021522312A (ja) * | 2018-06-21 | 2021-08-30 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 3−((1R,3R)−1−(2,6−ジフルオロ−4−((1−(3−フルオロプロピル)アゼチジン−3−イル)アミノ)フェニル)−3−メチル−1,3,4,9−テトラヒドロ−2H−ピリド[3,4−b]インドール−2−イル)−2,2−ジフルオロプロパン−1−オールの固体形態及び置換されたフェニル又はピリジニル部分を含む縮合三環式化合物を調製するための方法とそれらの使用方法 |
JP2021191750A (ja) * | 2018-06-21 | 2021-12-16 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | 3−((1R,3R)−1−(2,6−ジフルオロ−4−((1−(3−フルオロプロピル)アゼチジン−3−イル)アミノ)フェニル)−3−メチル−1,3,4,9−テトラヒドロ−2H−ピリド[3,4−b]インドール−2−イル)−2,2−ジフルオロプロパン−1−オールの固体形態及び置換されたフェニル又はピリジニル部分を含む縮合三環式化合物を調製するための方法とそれらの使用方法 |
Also Published As
Publication number | Publication date |
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EP3412667B1 (en) | 2021-11-03 |
US20210115039A1 (en) | 2021-04-22 |
HUE057240T2 (hu) | 2022-04-28 |
JPWO2017135259A1 (ja) | 2018-11-22 |
CN108884094B (zh) | 2021-09-21 |
US20200048245A1 (en) | 2020-02-13 |
CA3013183A1 (en) | 2017-08-10 |
EP3954372A1 (en) | 2022-02-16 |
EA035376B1 (ru) | 2020-06-03 |
CN113788826A (zh) | 2021-12-14 |
JP6827429B2 (ja) | 2021-02-10 |
CN108884094A (zh) | 2018-11-23 |
DK3412667T3 (da) | 2022-01-10 |
PT3412667T (pt) | 2022-01-20 |
US10906898B2 (en) | 2021-02-02 |
ES2902513T3 (es) | 2022-03-28 |
EP3412667A1 (en) | 2018-12-12 |
EA201891736A1 (ru) | 2019-02-28 |
EP3412667A4 (en) | 2019-09-18 |
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