Eutectic

Abstract

Improve the solubility of organic compounds. (1) Co-crystals of 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 and (2) L-malic acid or L-tartaric acid.

Description

[0001] This application is a divisional application of a Chinese patent application with application number 201780018561.6 (invention title: cocrystal, application date: January 31, 2017). Technical Field

[0002] The present invention relates to a pharmaceutical composition containing a cocrystal. Background Art

[0003] For a drug to be absorbed from the intestine, the dissolution process or the membrane permeation process is the rate-determining step (Non-Patent Document 1). In the case of a poorly soluble drug, the dissolution process is usually the rate-determining step, and an increase in the bioavailability of the drug is expected by improving the solubility.

[0004] It is known that solvates including hydrates and crystal polymorphs each have different physicochemical properties of crystals, including solubility. Controlling the single crystal form is very important for maintaining the stability of the drug quality (Non-Patent Document 2).

[0005] A "cocrystal" generally refers to a multicomponent crystal containing intermolecular interactions, wherein the components constituting the cocrystal are connected by interactions other than ionic bonds (Non-Patent Document 3).

[0006] It is known that 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 has Smo inhibitory activity and is used as a prophylactic or therapeutic agent for cancer (Patent Document 1).

[0007] It has been proposed that this drug has good membrane permeability (Non-Patent Document 4). Therefore, in order to improve the bioavailability, it is necessary to improve the solubility of the drug. This drug forms solvates with many organic solvents and various polymorphs are induced by the solvates (Non-Patent Document 5), which makes it difficult to control the crystal form in the preparation.

[0008] [Literature List]

[0009] [Patent Document]

[0010] Patent Document 1: JP-B-4719317

[0011] [Non-Patent Document]

[0012] Non-Patent Document 1: 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 12 (1995) 413-420

[0013] Non-Patent Document 2: Rolf Hilfiker "Polymorphism: In the Pharmaceutical Industry", WILEY-VCH Verlag GmbH & Co. KGaA (2006)

[0014] Non-Patent Document 3: Goud, N.R. et al., "The role of cocrystals in pharmaceutical science", Drug Discovery Today, Vol. 13 (2008) 440-446

[0015] Non-Patent Document 4: 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, 20, 2012. 5507-5517

[0016] Non-Patent Document 5: Iwata, K. et al., "Solid Form Selection of Highly Solvating TAK-441 Exhibiting Solvate-Trapping Polymorphism", Crystal Growth & Design, 14, 2012. 3335-3342 Summary of the Invention

[0017] [Problems to be Solved by the Invention]

[0018] The object of the present invention is to obtain, during preparation, by co-crystallizing 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 (used as a prophylactic or therapeutic agent for cancer), a solubility higher than that of the conventional stable crystals composed of a single drug component, and further to inhibit the formation of solvates, facilitating the control of crystal forms important for the quality of pharmaceuticals.

[0019] [Means for Solving the Problem]

[0020] In an attempt to achieve the above object, the present inventors conducted in-depth research and obtained a co-crystal that increases the solubility of 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 and does not easily form solvates. Based on this finding, the present invention is as described below.

[0021] [1] (1) A co-crystal of 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 and (2) L-malic acid or L-tartaric acid;

[0022] [2] The co-crystal of [1], which is a co-crystal of (1) 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 and (2) L-malic acid;

[0023] [3] The co-crystal of [2], which shows, by powder X-ray diffraction, characteristic peaks in the powder X-ray diffraction pattern at lattice spacings (d) of 11.7 ± 0.2, 10.0 ± 0.2, and 8.6 ± 0.2 Å;

[0024] [4] The co-crystal of [1], which is a co-crystal of (1) 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 and (2) L-tartaric acid;

[0025] [5][4] cocrystals, which exhibited a powder X-ray diffraction pattern with characteristic peaks at lattice spacings (d) of 12.0 ± 0.2, 10.1 ± 0.2, and 8.7 ± 0.2 angstroms;

[0026] [6] A drug comprising a cocrystal of [1];

[0027] [7][6] drugs that are Smo inhibitors;

[0028] [8][6], which is a preventive and / or therapeutic agent for cancer;

[0029] [9] A method for inhibiting Smo in a mammal, the method comprising: administering to the mammal an effective amount of a co-crystal of [1];

[0030]

[10] A method for preventing and / or treating cancer in a mammal, the method comprising: administering to the mammal an effective amount of a co-crystal of [1];

[0031]

[11] [1] co-crystal for use in preventing and / or treating cancer; and

[0032]

[12] Use of the co-crystal of [1] in the preparation of a preventive and / or therapeutic agent for cancer.

[0033] [Effects of the Invention]

[0034] The present invention can provide a co-crystal of 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, which has excellent solubility and is suppressed from easily forming a solvate. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Shown is a powder X-ray diffraction pattern of a co-crystal of 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 and L-malic acid.

[0036] Figure 2 Shown is the differential scanning calorimetry curve of the co-crystal of 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 and L-malic acid.

[0037] Figure 3 Thermogravimetric curve of the cocrystal of 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 and L-malic acid.

[0038] Figure 4 Infrared absorption spectrum of the cocrystal of 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 and L-malic acid.

[0039] Figure 5 Raman spectrum of the cocrystal of 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-zy-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide and L-malic acid.

[0040] Figure 6 Powder X-ray diffraction pattern of the cocrystal of 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 and L-tartaric acid.

[0041] Figure 7 Differential scanning calorimetry curve of the cocrystal of 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 and L-tartaric acid.

[0042] Figure 8 Thermogravimetric curve of the cocrystal of 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 and L-tartaric acid.

[0043] Figure 9The infrared absorption spectrum of the co-crystal of 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 and L-tartaric acid.

[0044] Figure 10 The Raman spectrum of the co-crystal of 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 and L-tartaric acid.

[0045] Figure 11 The intrinsic dissolution rate (A) and elution characteristics (B) of the following crystals are shown: the anhydrous crystal of the free form of 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 (circles), the co-crystal of 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 and L-malic acid (triangles), and the co-crystal of 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 and L-tartaric acid (squares). Detailed Description of the Invention

[0046] The present invention provides (1) 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 and (2) a co-crystal of L-malic acid or L-tartaric acid (hereinafter referred to as "the co-crystal of the present invention").

[0047] In the present invention, a "cocrystal" refers to a crystal in which the organic compound and the cocrystal former constituting the cocrystal are bound by intermolecular interactions other than ionic bonds (e.g., hydrogen bonds, van der Waals forces, π-π bonds, etc.). Whether a certain compound is a cocrystal or a salt in which the constituent components are bound by ionic bonds can be demonstrated by single crystal X-ray diffraction method, infrared spectroscopic analysis, etc. (Schultheiss N. et al., "Pharmaceutical Cocrystals and Their Physicochemical Properties", Crystal Growth & Design, 9, 2009. 2950-2967).

[0048] For example, 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 prepared by known methods such as the method described in Patent Document 1.

[0049] Examples of malic acid that forms a cocrystal with 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,2-trifluoroethoxy)-in 4,5-dihydro-1H-pyrrolo[3,2-c]pyridine-2-carboxamide include L-malic acid, D-malic acid, and DL-malic acid. Among these, L-malic acid is preferred.

[0050] As the cocrystal of (1) 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 and (2) L-malic acid, a cocrystal is preferred as follows: It shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 11.7 ± 0.2, 10.0 ± 0.2, and 8.6 ± 0.2 Å.

[0051] As a cocrystal of (1) 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 and (2) L-malic acid, preferably a cocrystal as follows: which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 11.7 ± 0.2, 10.0 ± 0.2, 8.6 ± 0.2, 5.8 ± 0.2 and 4.9 ± 0.2 Å.

[0052] In addition, as the above cocrystal, preferably a cocrystal as follows: a cocrystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (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 Å, a cocrystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 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 and 4.9 ± 0.2 Å, or a cocrystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 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 and 4.2 ± 0.2 Å.

[0053] Examples of tartaric acid that form a cocrystal with 6-ethyl-N-[1-(hydroxyacetyl)piperidin-4-yl]-1-methyl-4-oxo-5-(2-oxo-2-phenylethyl)-3-(2,2,....

[0054] As a cocrystal of (1) 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 and (2) L-tartaric acid, preferably a cocrystal as follows: which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 12.0 ± 0.2, 10.1 ± 0.2 and 8.7 ± 0.2 Å.

[0055] As a co-crystal of (1) 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 and (2) L-tartaric acid, preferably a co-crystal as follows: which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 12.0 ± 0.2, 10.1 ± 0.2, 8.7 ± 0.2, 5.9 ± 0.2 and 4.9 ± 0.2 Å.

[0056] In addition, as the above co-crystal, preferably a co-crystal as follows: a co-crystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (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 Å, a co-crystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 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 Å, or a co-crystal which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 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 and 4.5 ± 0.2 Å.

[0057] For example, co-crystals can be prepared using organic compounds and co-crystal formers, for example, by using known methods, such as those described in Qiao, N et al., "Pharmaceutical cocrystals: An overview", International Journal of Pharmaceutics, 419, 2011.1 - 11 (for example, the method of slow cooling from solution, the method of adding a poor solvent, the method of solvent evaporation, the method of slurry aging, the method of co-grinding, the method of melting, etc.), or a combination of their principles.

[0058] For example, the cocrystal of the present invention interacts with human Smo protein and changes its spatial structure, thereby inhibiting the formation of a complex with proteins involved in cytoplasmic signal transduction and inhibiting the Hedgehog signal transduction system. Alternatively, the cocrystal of the present invention interacts with human Smo protein to directly inhibit the formation of a complex between human Smo protein and proteins involved in the Hedgehog signal transduction system in the cytoplasm, thereby inhibiting the Hedgehog signal transduction system. Alternatively, the cocrystal of the present invention interacts with a site of Smo protein (e.g., phosphorylation site, etc., which is modified by proteins involved in the Hedgehog signal transduction system), thereby inhibiting such modification (e.g., phosphorylation of Smo, etc.) and inhibiting the Hedgehog signal transduction system.

[0059] Accordingly, the co-crystals of the present invention are used as Smo inhibitors in mammals (e.g., mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). The co-crystals of the present invention are used as medicaments, e.g., medicaments for preventing or treating diseases that may be affected by Smo, such as cancer [e.g., colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor, etc.), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (e.g., pancreatic ductal carcinoma, pancreatic endocrine gland tumor, etc.), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (e.g., papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma, etc.), duodenal cancer, small intestine cancer, breast cancer (e.g., invasive ductal carcinoma of breast, ductal carcinoma in situ, inflammatory breast cancer, etc.), ovarian cancer (e.g., ovarian epithelial cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor, etc.), testicular tumor, prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone-dependent prostate cancer, etc.), liver cancer (e.g., hepatocellular carcinoma, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (e.g., medullary thyroid cancer, etc.), kidney cancer (e.g., renal cell carcinoma, transitional cell carcinoma of renal pelvis and ureter, etc.), uterine cancer (e.g., cervical cancer, corpus cancer, uterine sarcoma, etc.), brain tumor (e.g., medulloblastoma, glioma, pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, pituitary adenoma, etc.), retinoblastoma, skin cancer (e.g., basal cell carcinoma, malignant melanoma, etc.), sarcoma (e.g., rhabdomyosarcoma, leiomyosarcoma, soft tissue sarcoma, etc.), malignant bone tumor, bladder cancer, blood cancer (e.g., multiple myeloma, leukemia, malignant lymphoma, Hodgkin's disease, chronic myeloproliferative diseases, etc.), unknown primary tumor, etc.], cancer growth inhibitor, cancer metastasis inhibitor, apoptosis promoter, etc. Among these, the co-crystals of the present invention are effective for, e.g., brain tumor, skin cancer, lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, gastric cancer, colorectal cancer, sarcoma, and breast cancer. In particular, the co-crystals of the present invention are effective for glioma, medulloblastoma, basal cell carcinoma, small cell lung cancer, pancreatic cancer, bile duct cancer, prostate cancer, esophageal cancer, gastric cancer, colorectal cancer, rhabdomyosarcoma, and breast cancer.

[0060] The co-crystals of the present invention can be administered orally or parenterally as such or in the form of a mixture with a pharmaceutical carrier.

[0061] The oral dosage forms of the eutectic of the present invention are, for example, tablets (including sugar-coated tablets, film-coated tablets), pills, granules, powders, capsules (including soft capsules, microcapsules), syrups, emulsions, suspensions, etc. The dosage forms for parenteral administration are, for example, injections, injections, drops, suppositories, etc. In addition, by combining the eutectic with a suitable base material (such as polymers of butyric acid, polymers of glycolic acid, copolymers of butyric acid - glycolic acid, mixtures of polymers of butyric acid and polymers of glycolic acid, polyglyceryl fatty acid esters, etc.), sustained-release preparations can be effectively prepared.

[0062] For the methods of preparing the above-mentioned dosage forms of the eutectic of the present invention, known preparation methods commonly used in the relevant fields can be used. When preparing the above-mentioned dosage forms, appropriate amounts of additives commonly used in the pharmaceutical field, such as excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, etc., can be added as needed for the preparation.

[0063] When preparing the eutectic of the present invention into tablets, for example, it can be prepared by adding excipients, binders, disintegrants, lubricants, etc. When preparing pills or granules, it can be prepared by adding excipients, binders, disintegrants, etc. When preparing powders or capsules, it can be prepared by adding excipients, etc. When preparing syrups, it can be prepared by adding sweeteners, etc. When preparing emulsions or suspensions, it can be prepared by adding suspending agents, surfactants, emulsifiers, etc.

[0064] Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.

[0065] Examples of binders include 5 - 10wt% starch liquid paste, 10 - 20wt% gum arabic solution or gelatin solution, 1 - 5wt% tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerol, etc.

[0066] Examples of disintegrants include starch, calcium carbonate, etc.

[0067] Examples of lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc powder, etc.

[0068] Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerol, simple syrup, etc.

[0069] Examples of surfactants include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyethylene 40 stearate, etc.

[0070] Examples of suspending agents include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite, and the like.

[0071] Examples of emulsifying agents include gum arabic, tragacanth, gelatin, polysorbate 80, and the like.

[0072] In addition, when preparing the above dosage forms of the cocrystal of the present invention, appropriate amounts of colorants, preservatives, fragrances, corrective agents, stabilizers, thickeners, and the like typically used in the pharmaceutical field can be added as required.

[0073] As injections, intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drops, and the like can be mentioned. As sustained-release preparations, iontophoretic skin preparations, and the like can be mentioned.

[0074] Such injections are prepared by using a method known per se, or by dissolving, suspending, or emulsifying the cocrystal of the present invention in a sterilized aqueous liquid or oily liquid. As the aqueous liquid for injections, physiological saline, isotonic solutions containing glucose or other auxiliary drugs (for example, D-sorbitol, D-mannitol, sodium chloride, and the like) can be mentioned, and they can be used in combination with a suitable solubilizer, such as an alcohol (for example, ethanol), a polyol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), and the like. As the oily liquid, sesame oil, soybean oil, and the like can be mentioned, and they can be used in combination with a solubilizer, such as benzyl benzoate, benzyl alcohol, and the like. In addition, a buffer (for example, phosphate buffer, sodium acetate buffer), a soothing agent (for example, benzalkonium chloride, procaine hydrochloride, and the like), a stabilizer (for example, human serum albumin, polyethylene glycol, and the like), a preservative (for example, benzyl alcohol, phenol, and the like), and the like can be incorporated. The prepared injections are generally filled in ampoules.

[0075] Although the content of the cocrystal of the present invention in the medicament of the present invention varies depending on the form of the pharmaceutical preparation, it is generally about 0.01 to 10^0 wt%, preferably about 2 to 85 wt%, more preferably about 5 to 70 wt% relative to the entire preparation.

[0076] Although the content of the additive in the medicament of the present invention varies depending on the form of the pharmaceutical preparation, it is generally about 1 to 99.9 wt%, preferably about 10 to 90 wt% relative to the entire preparation.

[0077] The eutectic of the present invention is stable and of low toxicity, and can be used safely. Although the daily dose varies depending on the patient's symptoms and body weight, the type of compound, the route of administration, etc., for example, in the case of oral administration to a cancer patient, the daily dose for an adult (body weight approximately 60 kg) for 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) is approximately 1 to 1000 mg, preferably approximately 3 to 300 mg, more preferably approximately 10 to 200 mg, and can be administered once a day, or divided into 2 or 3 portions per day.

[0078] When the eutectic of the present invention is administered parenterally, it is generally administered in the form of a liquid preparation (e.g., an injection). Although the dose varies depending on the subject of administration, the target organ, the symptoms, the administration method, etc., for example, per 1 kg of body weight, the dose for 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) in the form of an injection is usually approximately 0.01 mg to approximately 100 mg, preferably approximately 0.01 to approximately 50 mg, more preferably approximately 0.01 to approximately 20 mg, and is preferably administered by intravenous injection.

[0079] Examples

[0080] The present invention will be described in more detail below with reference to the examples and formulation examples. However, the present invention is not limited by the following examples and formulation examples, and appropriate changes can be made for implementation as long as they are suitable for the above and following points. All such changes are included within the technical scope of the present invention.

[0081] In the examples, room temperature means approximately 15 - 30 °C.

[0082] Powder X-ray diffraction measurement was carried out using Cu-Kα radiation, and a horizontal multi-purpose X-ray diffraction system Ultima IV manufactured by Rigaku Corporation was used for the measurement. Differential scanning calorimetry or thermogravimetric measurement was carried out using DSC1 / 700 / 903-2 manufactured by Mettler Toledo, or TGA / DSC1 / LF / 629-2 manufactured by Mettler Toledo, and the measurement was carried out at a heating rate of 5 °C / min. Fourier transform infrared spectrophotometer Shimadzu IRPrestige-21 manufactured by Shimadzu Corporation was used, and Dura Sample IR II manufactured by Smiths Detection was installed. The total reflection method absorption measurement method was used at a resolution of 4 cm -1The infrared spectrum was measured. The Raman spectrum was measured using RXN2 manufactured by Kaiser Optical Systems and a laser light source with an excitation wavelength of 1064 nm. The single crystal X-ray diffraction was measured using Cu-Kα radiation and the R-AXIS RAPID II, a bending imaging plate single crystal automatic X-ray structure analyzer manufactured by Rigaku Corporation. The initial phase was determined by the direct method, and the structure was refined by SHELXL-97. As the solubility, the concentration of 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 in distilled water, Japanese Pharmacopoeia dissolution test first fluid, fasted state simulated intestinal fluid (FaSSIF), or fed state simulated intestinal fluid (FeSSIF) after shaking the respective crystals at 37 °C for 24 hours was used. Using a compression molded disk of a single crystal powder, the intrinsic dissolution rate was evaluated by the rotating disk method (rotation speed: 100 rpm) in 20 mmol / L sodium phosphate buffer (pH 6.8) containing 0.2% (w / v) sodium lauryl sulfate. The dissolution test was performed using a powder obtained by physically mixing the crystal powder and lactose of the same weight as the crystal powder, and was evaluated by the rotating paddle method (paddle rotation speed: 50 rpm) in fasted state simulated intestinal fluid (FaSSIF) at 37 °C. The drug concentration in the solution was measured by liquid chromatography (separation column: YMCPack Pro C18 4.6 mm × 150 mm, temperature: 40 °C, mobile phase: 20 mmol / L sodium phosphate buffer (pH 6.8) / acetonitrile = 60 / 40 (v / v), flow rate: 1 mL / min, ultraviolet absorption detection wavelength: 240 nm) using an Alliance HPLC system e2695 manufactured by Waters and a detector 2789. As a slurry experiment, the test solvent was added to the crystal powder, the mixture was stirred in a suspended state at about 25 °C for 24 hours, the obtained residue was collected by filtration, and the crystal form was determined by powder X-ray diffraction measurement or Raman spectroscopy. In the recrystallization experiment, at 55 °C, the crystal was dissolved in ethanol, acetone, 2-propanol, tetrahydrofuran, methyl ethyl ketone, ethyl acetate, isopropyl acetate, anisole, or isobutyl acetate, filtered through a filter, cooled to 5 °C, or after adding n-heptane to the solution, cooled to 5 °C, and the crystal form of the obtained precipitate was determined by powder X-ray diffraction measurement or Raman spectroscopy.

[0083] The other symbols in this specification refer to the following meanings.

[0084] JP1: Japanese Pharmacopoeia dissolution test first fluid

[0085] FaSSIF: Fasted State Simulated Intestinal Fluid

[0086] FeSSIF: Fed State Simulated Intestinal Fluid

[0087] 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

[0088] Example 1

[0089] Co-crystal of API and L-malic acid

[0090] At 50 °C each, dissolve approximately 1 g of anhydrous crystals of API in 10 mL of acetone, dissolve approximately 130 mg of L-malic acid in approximately 1 mL of ethanol, and blend them together. Filter the resulting solution hot while maintaining at 50 °C, and slowly add approximately 17 mL of n-heptane. Allow the resulting solution to cool to room temperature, filter to collect the resulting precipitate, and dry under reduced pressure at 80 °C to obtain crystals.

[0091] Measured by powder X-ray diffraction, the obtained crystals showed Figure 1 a pattern and had characteristic peaks at d values of 11.7 Å, 10.0 Å, 8.6 Å, 5.8 Å, and 4.9 Å. In differential scanning calorimetry, a peak related to melting or decomposition was observed near the apex shown in Figure 2 at approximately 153 °C. In thermogravimetry, as Figure 3 shown, no significant weight loss was observed up to approximately the temperature at which the peak was observed in the above differential scanning calorimetry, thus demonstrating that the crystals are solvent-free anhydrous crystals. The obtained crystals showed Figure 4 an infrared absorption spectrum, and the carbonyl stretching vibration of the carboxylic acid of L-malic acid was near 1730 cm -1 −1, thus demonstrating that the L-malic acid in the crystals is in a non-ionic state and is a co-crystal. Additionally, in the Raman spectrum shown in Figure 5 the obtained crystals showed at 1625 cm -1There are characteristic peaks nearby. The X-ray crystal structure parameters and structure refinement parameters are shown in Table 1-1. The obtained X-ray crystal structure indicates that the obtained crystal is an anhydrous crystal composed of 1 molecule of L-malic acid relative to 2 molecules of API. In the obtained X-ray crystal structure, the interatomic distances between the carbon atom and the oxygen atom in the carboxylic acid of L-malic acid are 1.16(1) Å and 1.306(7) Å, or 1.211(9) Å and 1.313(6) Å, respectively. From the asymmetry of the carbon atom and the oxygen atom in the same carboxylic acid functional group, it is also proved that L-malic acid in the crystal is in a non-ionic state and is a co-crystal.

[0092] Example 2

[0093] Co-crystal of API and L-tartaric acid

[0094] Respectively at 75 °C, approximately 1 g of anhydrous API crystals were dissolved in approximately 10 mL of methyl ethyl ketone, approximately 146 mg of L-tartaric acid was dissolved in approximately 1 mL of ethanol, and they were blended together. The obtained solution was hot filtered while maintaining at 75 °C, and approximately 9.5 mL of n-heptane was slowly added. The obtained solution was cooled to room temperature, the obtained precipitate was collected by filtration, and dried under reduced pressure at 80 °C to obtain crystals.

[0095] Measured by powder X-ray diffraction, the obtained crystals showed Figure 6 a pattern, and had characteristic peaks at d values of 12.0 Å, 10.1 Å, 8.7 Å, 5.9 Å, and 4.9 Å. In differential scanning calorimetry, a peak related to melting or decomposition near the apex shown in Figure 7 around 170 °C was observed. In thermogravimetric determination, as shown in Figure 8 , no significant weight loss was observed up to approximately the temperature at which the peak was observed in the above differential scanning calorimetry. Therefore, it was proved that the crystals were solvent-free anhydrous crystals. The obtained crystals showed Figure 9 an infrared absorption spectrum, and the carbonyl stretching vibration of the carboxylic acid derived from L-tartaric acid was near 1734 cm -1 Therefore, it was proved that L-tartaric acid in the crystal was in a non-ionic state and was a co-crystal. In addition, in the Raman spectrum shown in Figure 10 , the obtained crystals showed at 1625 cm -1There are characteristic peaks nearby. The X-ray crystal structure parameters and structure refinement parameters are shown in Table 1-1. The obtained X-ray crystal structure indicates that the obtained crystal is an anhydrous crystal composed of 1 molecule of L-tartaric acid relative to 2 molecules of API. In the obtained X-ray crystal structure, the interatomic distances between the carbon atom and the oxygen atom in the carboxylic acid of L-tartaric acid are 1.230(6) Å and 1.313(4) Å, or 1.219(5) Å and 1.323(4) Å respectively. From the asymmetry of the carbon atom and the oxygen atom in the same carboxylic acid functional group, it is also proved that L-tartaric acid in the crystal is in a non-ionic state and is a co-crystal.

[0096] [Table 1-1]

[0097] X-ray crystal structure parameters and structure refinement parameters of the co-crystals of API and L-malic acid or L-tartaric acid

[0098]

[0099] In addition, other crystals from the same batch as the crystals used to obtain the data in Table 1-1 above were measured and analyzed under the same conditions. When refining the structure in a model that reflects two filling modes of L-malic acid in the crystal by arranging the hydrogen atom model of the methyl group with difference Fourier synthesis, the obtained X-ray crystal structure parameters and structure refinement parameters are shown in Table 1-2.

[0100] [Table 1-2]

[0101] X-ray crystal structure parameters and structure refinement parameters of the co-crystals of API and L-malic acid or L-tartaric acid

[0102]

[0103] The solubilities of the co-crystals of API and L-malic acid or API and L-tartaric acid and the anhydrous crystal of free API are shown in Table 2, and the results of the intrinsic dissolution rate and dissolution test are shown in Figure 11 . Compared with the anhydrous crystal of free API, all co-crystals show high solubility.

[0104] [Table 2]

[0105] Solubilities of the anhydrous crystal of free API, the co-crystal of API and L-malic acid, and the co-crystal of API and L-tartaric acid in various aqueous solutions

[0106]

[0107] Slurry experiments were conducted on the co-crystals of API and L-malic acid or the co-crystals of API and L-tartaric acid, as well as the anhydrous crystals of free API in various solvents, and the results of the crystal forms of the residues are shown in Table 3. Additionally, the crystal forms of the precipitates obtained by recrystallization from various organic solvents were examined, and the results are shown in Table 4. None of the co-crystals showed solvates of the co-crystals, and it was shown that compared with the anhydrous crystals of free API, the co-crystals were not easily formed into solvates.

[0108] [Table 3]

[0109] Crystal forms of residues after slurry experiments in various solvents

[0110]

[0111] [Table 4]

[0112] Crystal forms of precipitates obtained from various solvents by recrystallization experiments

[0113]

[0114]

[0115] *All obtained co-crystals were the same as the crystal forms used.

[0116] Formulation Example 1

[0117] A drug containing the co-crystal of the present invention as an active ingredient can be prepared, for example, according to the following formulation.

[0118] 1. Capsules

[0119] (1) Co-crystal obtained in Example 1: 40 mg

[0120] (2) Lactose: 70 mg

[0121] (3) Microcrystalline cellulose: 9 mg

[0122] (4) Magnesium stearate: 1 mg

[0123] 1 capsule: 120 mg

[0124] Mix (1), (2), (3) and 1 / 2 of (4), and granulate. Add the remaining part of (4), and encapsulate all in capsules.

[0125] 2. Tablets

[0126] (1) Co-crystal obtained in Example 1: 40 mg

[0127] (2) Lactose: 58 mg

[0128] (3) Corn starch: 18 mg

[0129] (4) Microcrystalline cellulose: 3.5 mg

[0130] (5) Magnesium stearate: 0.5 mg

[0131] 1 tablet: 120 mg

[0132] Mix (1), (2), (3), 2 / 3 of (4) and 1 / 2 of (5), and granulate. Add the remaining parts of (4) and (5) to the granules, and press into tablets.

[0133] Formulation Example 2

[0134] Dissolve the cocrystal (50 mg) obtained in Example 1 in distilled water for injection of the Japanese Pharmacopoeia (50 ml). Then, add distilled water for injection of the Japanese Pharmacopoeia to make up to 100 ml. Filter this solution under sterile conditions, obtain the solution (1 ml), fill it into an injection vial under aseptic conditions, freeze-dry, and seal.

[0135] Industrial Applicability

[0136] According to the present invention, a cocrystal with improved solubility and / or inhibited tendency to form solvates can be obtained, thereby enhancing the effect of 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-pyrrole[3,2-c]pyridine-2-carboxamide used as a prophylactic or therapeutic agent for cancer.

[0137] This application is based on Patent Application 2016-017099 (filed in Japan), the entire content of which is incorporated herein.

Claims

1. A co-crystal of (1) 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 and (2) L-malic acid, which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 11.7 ± 0.2, 10.0 ± 0.2, 8.6 ± 0.2, 5.8 ± 0.2 and 4.9 ± 0.2 Å.

2. A co-crystal of (1) 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 and (2) L-tartaric acid, which shows by powder X-ray diffraction that the powder X-ray diffraction pattern has characteristic peaks at lattice spacings (d) of 12.0 ± 0.2, 10.1 ± 0.2, 8.7 ± 0.2, 5.9 ± 0.2 and 4.9 ± 0.2 Å.

3. A medicament comprising the co-crystal according to claim 1 or 2.

4. Use of the co-crystal according to claim 1 or 2 in the preparation of a Smo inhibitor.

5. The use according to claim 4, wherein the Smo inhibitor is used for preventing and / or treating cancer.

Images