Amorphous form of 5-bromopyridine-3-yl3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1h-1,2,3-triazole-1-yl]-1-thio-α-d-galactopyranoside

Abstract

To provide an amorphous solid dispersion composition comprising stabilized amorphous form of a compound that is a galectin 3 inhibitor useful for treating various disorders or diseases.SOLUTION: Provided is an amorphous solid dispersion composition comprising a mixture of an amorphous form of a compound of formula (I) and a polymer selected from polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), and the like.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to amorphous forms of the compound of formula I. The amorphous forms of the compound of formula I can be stabilized by polymers when sprayed onto inert particles and when prepared as amorphous solid dispersions. [Background technology]

[0002] The compounds of formula I are described as Galectin 3 inhibitors useful for treating various disorders or diseases as described in International Patent Application Publication No. WO2016120403. The compounds of formula I are highly crystalline but have relatively low solubility, which makes it difficult to prepare formulations suitable for toxicology and clinical trials. Summary of the Invention

[0003] The amorphous form approach described herein allows for the preparation of convenient dosage forms for the treatment of mammalian, e.g., human, diseases that would not have been possible without the present invention. Thus, any disease, disorder and / or condition described herein can be treated using the formulations of the present invention.

[0004] Material characterization of the compound of formula I shows it to be highly crystalline by XRPD. The high melting point of 233.7°C suggests that it forms a very stable crystalline structure. Thermogravimetric analysis (TGA) data shows no signs of hydration, and dynamic vapor sorption (DVS) indicates that the compound of formula I is not hygroscopic and shows no signs of hydrate formation.

[0005] Excipients were required to increase the solubility of the compound of Formula I, and multiple iterations of solution formulations were developed for toxicity testing because previous solution formulations had issues with limited exposure and poor tolerability.

[0006] Two different amorphous formulations, both containing the amorphous compound of formula I, were discovered and studied: 1) an amorphous spray-dried dispersion (ASD) and 2) a structured drug composition prepared by spray coating / drug layering of the amorphous compound of formula I onto inert microspheres.

[0007] The ASD formulation was found to be stable for 4 weeks at 25° C. / 60% RH and 40° C. / 75% RH. Drug-layered formulations of the compound of formula I coated onto inert microspheres were achieved and found to be stable for 12 months at 25° C. / 60% RH and 6 months at 40° C. / 75%.

[0008] In a broad aspect, the present invention relates to amorphous forms of the compound of formula I. [ka]

[0009] In another aspect, the present invention relates to a pharmaceutical composition comprising an amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient.

[0010] In a further aspect, the present invention relates to a liquid composition comprising a mixture of a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I and a solution of the compound of formula I, and optionally a solution of a pharma- ceutically acceptable excipient.

[0011] In yet another aspect, the present invention relates to an amorphous solid dispersion composition comprising a mixture of an amorphous compound of formula I and a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient. In one embodiment, the mixture has a weight ratio of the amorphous compound of formula I to the polymer ranging from 1:0.5 to 1:5, such as 1:1 to 1:3, such as 1:2. In a further embodiment, the amorphous compound of formula I is present in a concentration of 0.5% w / w to 90% w / w, and the polymer is present in a concentration of at least 0.1% w / w, optionally adding 100% w / w with a pharma- ceutically acceptable excipient.

[0012] In a further aspect, the present invention relates to a tablet or capsule composition for oral administration comprising the amorphous solid dispersion composition of the present invention.Typically, the present invention relates to a tablet composition.In a particular embodiment, the oral composition such as a tablet or capsule is administered once a day.In another embodiment, the oral composition such as a tablet or capsule is administered twice a day.

[0013] In yet another aspect, the present invention relates to a drug layered composition comprising: a) an inert solid core having an outer surface; and b) a mixture of an amorphous compound of formula I, a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient, the mixture being a layer on the outer surface of the inert solid core. Typically, the mixture is deposited on the surface of the inert solid core by spraying a solution of the mixture in a suitable solvent. In another embodiment, the mixture has a weight ratio of the amorphous compound of formula I to the polymer ranging from 1:0.5 to 1:5, such as 1:1 to 1:3, such as 1:2. In a further embodiment, the amorphous compound of formula I is present in a concentration of 0.5% w / w to 20% w / w, the polymer is present in a concentration of 1% w / w to 40% w / w, and the inert solid core is present in a concentration of 40% w / w to 98.5% w / w, optionally with the addition of a pharma- ceutically acceptable excipient to make up to 100% w / w.

[0014] In a further aspect, the present invention relates to a capsule composition for oral administration, such as once a day or twice a day, comprising the drug layered composition of the present invention. It has been found that the drug layered composition of the present invention is easily encapsulated into pharmaceutical hard shell capsules, either manually or by suitable manufacturing equipment, allowing for adjustment of the dose contained in the capsule.

[0015] In the above aspects and embodiments in which a polymer for stabilizing the amorphous form of the compound of formula I is part of the composition, such polymers can be polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose (HEC), methylcellulose (MC), polyvinylpyrrolidone vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), such as (PVP K30), crospovidone, hydroxypropylmethylcellulose (hypromellose), such as hypromellose 603 (HPMC 603), hypromellose 606 (HPMC 606), hypromellose 615 (HPMC 615), hypromellose phthalate-55 (HP-55), and hypromellose acetate succinate-LF (HPMCAS-LF), Eudragit L100-55, poloxamer, and Gelucire 44 / 14, and preferably hydroxypropyl methylcellulose, e.g. HPMC 603.

[0016] In a further embodiment, a pharma- ceutically acceptable additive is present.When the layer is applied to the drug layered composition of the present invention, the additive may include a pore-forming excipient.When a pore-forming excipient is present, it is typically present in the layer at a concentration of up to 20% w / w.The pore-forming excipient used herein is known to those skilled in the art, and in one embodiment, is selected from the group consisting of calcium dihydrogen phosphate, lactose, hydroxypropyl cellulose and microcrystalline cellulose (including their mixtures).

[0017] In the above aspects and embodiments in which an inert solid core is part of the composition, the inert solid core is made from a material selected from the group consisting of sugars, e.g., starch and sucrose, and microcrystalline cellulose (MCC), preferably MCC.

[0018] In a further embodiment, the inert solid core has a size in the range of 50 to 2000 μm, for example 100 to 1400 μm.

[0019] In a further aspect, the present invention relates to a method for preparing a liquid composition comprising a mixture of a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I and a solution of the compound of formula I, and optionally a solution of a pharma- ceutically acceptable excipient, comprising the steps of: a) preparing a solution or dispersion of a polymer, dissolving a compound of formula I in the solution or dispersion, and optionally dissolving a pharma- ceutically acceptable excipient in the solution or dispersion, thereby providing a liquid composition; or b) preparing a first solution or dispersion of a polymer and a second solution of a compound of formula I, mixing the first and second solutions, and optionally dissolving a pharma- ceutically acceptable excipient in the first or second solution or dispersion, or in the mixture, thereby providing a liquid composition.

[0020] In yet another aspect, the present invention provides a method for preparing an amorphous solid dispersion composition comprising a mixture of an amorphous compound of formula I and a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient, comprising the steps of: The present invention relates to a method comprising the steps of spray drying a liquid composition comprising a mixture of a solution of a compound of formula I and a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I, and optionally a solution of a pharma- ceutically acceptable excipient, and recovering the amorphous solid dispersion composition.

[0021] As used herein and throughout the specification and claims, "solid dispersion" means a dry composition, such as a dry powder.

[0022] In a further aspect, the present invention provides a method for preparing a drug layered composition comprising: a) an inert solid core having an outer surface; and b) a mixture of an amorphous compound of formula I, a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient, wherein the mixture is applied as a layer on the outer surface of the inert solid core; The present invention relates to a method comprising spraying a liquid composition comprising a mixture of a solution of a compound of formula I and a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I, and optionally a solution of a pharma- ceutically acceptable excipient, onto an inert solid core, and recovering the drug layer composition. In one embodiment, the spraying is spray coating or fluidized bed coating.

[0023] In a further aspect, the present invention provides a compound of formula I, [ka] The present invention relates to an oral composition, optionally including a pharma- ceutically acceptable excipient, in which the compound of formula I is present in an amount of 0.1-1000 mg, for example 1-1000 mg. Preferably, the composition is a solid oral composition, such as a tablet or capsule. Typically, one tablet or one capsule is a unit dose form containing that amount of the compound of formula I. However, in a treatment, one or more unit doses may be administered, such as 1-4 unit doses, for example a capsule containing 5 mg of the compound of formula I, or four capsules each containing 5 mg, totaling a dose of 20 mg.

[0024] In one embodiment, the oral composition is in a unit dosage form.

[0025] In a further embodiment, the compound of formula I is present in an amount of 5-900 mg, for example, 10-800 mg, 20-700 mg, 30-600 mg, 40-500 mg, 50-400 mg, 60-300 mg, 70-200 mg, 80-100 mg. In another embodiment, the compound of formula I is present in an amount of 0.1 mg to 1000 mg, for example, 0.1 to 1 mg, for example, 0.2 to 0.8 mg. One example is administration of 5 mg of the compound of formula I, another example is administration of 20 mg of the compound of formula I, a further example is administration of 50 mg of the compound of formula I, and yet another example is administration of 200 mg of the compound of formula I. Each unit dose may contain 1 mg to 200 mg, for example, administration of 20 mg may be performed by giving four capsules each containing 5 mg of the compound of formula I to a human subject.

[0026] In yet another embodiment, the pharma- ceutically acceptable excipient is present in a concentration of 0.1 to 99.5% w / w, for example 10% w / w to 99.5% w / w, and the compound of formula I is present in a concentration of 0.5% w / w to 90% w / w.

[0027] In a further embodiment, the pharma- ceutically acceptable excipient is one or more selected from the group consisting of polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose (HEC), methylcellulose (MC), polyvinylpyrrolidone vinyl acetate (PVP / VA), polyvinylpyrrolidone, hydroxypropylmethylcellulose (hypromellose), hypromellose phthalate, hypromellose acetate succinate, Eudragit, Gelucire 44 / 14, sugars such as starch and sucrose, microcrystalline cellulose (MCC) and pore-forming excipients such as calcium dihydrogen phosphate, lactose, hydroxypropylcellulose and microcrystalline cellulose, and mixtures thereof.

[0028] In a further aspect, the invention relates to a method for treating a mammal, e.g., a human, disease characterized by inflammation; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmological fibrosis, and fibrosis of the skin and heart; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, e.g., carcinoma, sarcoma, leukemia, and lymphoma, e.g., T-cell lymphoma; metastasizing cancer; autoimmune diseases, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; cardiac disease; heart failure; pathological angiogenesis, e.g., ocular angiogenesis, or a disease or condition associated with ocular angiogenesis, e.g., angiogenesis associated with cancer; and the like. and eye diseases, e.g., age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases, e.g., diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma, and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, e.g., nonalcoholic steatohepatitis or nonalcoholic fatty liver disease. In one embodiment, the disease or disorder is NASH. In another embodiment, the disease or disorder is cancer. In a further embodiment, the disease or disorder is renal fibrosis. In one embodiment, the oral composition is administered once daily, such as 1 to 4 unit doses once daily. In another embodiment, the oral composition is administered twice daily, such as 1 to 4 unit doses twice daily. In particular, the daily amount is 5 mg to 900 mg. In another embodiment, the daily amount is 0.1 to 5 mg, e.g., 0.1 to 1 mg. In particular, the amount twice daily is between 1 mg and 500 mg, for example between 5 mg and 200 mg.

[0029] In yet another aspect, the present invention provides a method for the treatment of a mammalian disease characterized by inflammation; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and dermal and cardiac fibrosis; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, e.g., carcinoma, sarcoma, leukemia, and lymphoma, e.g., T-cell lymphoma; metastasizing cancer; autoimmune diseases, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; cardiac disease; heart failure; pathological angiogenesis, e.g., ocular angiogenesis, or a disease or condition associated with ocular angiogenesis, e.g., angiogenesis associated with cancer. and ophthalmic diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases, such as diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease, comprising administering a therapeutically effective amount of a composition of the invention, such as an amorphous solid dispersion composition or a drug layered composition and any one of the embodiments defined above. In a further embodiment, the oral composition is administered once or twice daily, such as 1 to 4 unit doses once or twice daily. In particular, the once daily amount is 5 mg to 900 mg. In particular, the twice daily amount is 1 mg to 500 mg, such as 5 mg to 200 mg.

[0030] In one embodiment of the method of treatment, the composition comprises an amount of 5-900 mg, e.g., 10-800 mg, 20-700 mg, 30-600 mg, 40-500 mg, 50-400 mg, 60-300 mg, 70-200 mg of a compound of formula I. In a further embodiment, 1-4 unit doses of a compound of formula I are administered, e.g., 1-4 capsules or tablets each containing 5-200 mg of a compound of formula I, e.g., 10-100 mg of a compound of formula I.

[0031] Another aspect of the present invention relates to a combination therapy comprising administering a compound of formula (I) of the present invention together with a therapeutically active compound different from the compound of formula (I) (interchangeably referred to as a "different therapeutically active compound"). In one embodiment, the present invention relates to a combination of a compound of formula (I) and a different therapeutically active compound for use in the treatment of a disorder associated with the binding of galectin-3 to its ligand in a mammal. Such disorders are disclosed below.

[0032] In one embodiment of the present invention, a therapeutically effective amount of at least one compound of formula (I) of the present invention is administered to a mammal in need thereof in combination with a different therapeutically active compound.In a further embodiment, the above combination of the compound of formula (I) with a different therapeutically active compound is effective in treating inflammation; fibrosis, such as pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and fibrosis of the skin and heart; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, such as carcinoma, sarcoma, leukemia, and lymphoma, such as T-cell lymphoma; metastatic cancer; autoimmune diseases, such as psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; heart disease; heart failure; pathological angiogenesis. the mammal suffering from a disorder selected from the group consisting of: ocular angiogenesis, e.g., ocular angiogenesis, or a disease or condition associated with ocular angiogenesis, e.g., angiogenesis associated with cancer; and ocular diseases, e.g., age-related macular degeneration and corneal angiogenesis; atherosclerosis; metabolic diseases, e.g., diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases, including Hermansky-Pudlak syndrome, mesothelioma; and liver disorders, e.g., nonalcoholic steatohepatitis or nonalcoholic fatty liver disease.

[0033] Non-limiting groups of cancers that are given as examples of cancers that may be treated, managed and / or prevented by administration of a compound of formula (I) in combination with a different therapeutically active compound are colon cancer, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, and sarcoma. sarcoma, synovium, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioblastoma, neuronoma, craniopharyngioma, schwannoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia and lymphoma, acute lymphocytic leukemia and acute myeloid polycythemia vera. myelocytic polycythemia vera), multiple myeloma, Waldenström hypergammaglobulinemia, and heavy chain disease, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, rectal cancer, urinary tract cancer, uterine cancer, oral cancer, skin cancer, gastric cancer cancer), brain tumors, liver cancer, laryngeal cancer, esophageal cancer, breast tumors, childhood null acute lymphoblastic leukemia (ALL), thymic ALL, B-cell ALL, acute myeloid leukemia, myelomonocytic leukemia, acute megakaryocytic leukemia, Burkitt's lymphoma, acute myeloid leukemia, chronic myeloid leukemia, and T-cell leukemia, small cell lung cancer and large non-small cell lung cancer. cell lung carcinoma), acute granulocytic leukemia, germ cell tumor, endometrial cancer, gastric cancer, head and neck cancer, chronic lymphoid leukemialeukemia, hairy cell leukemia and thyroid cancer.

[0034] In some embodiments of the present invention, administration of at least one compound of formula (I) of the present invention and at least one additional therapeutic agent exhibits therapeutic synergy.In some embodiments of the method of the present invention, the measurement of response to treatment observed after administration of both at least one compound of formula (I) of the present invention and the additional therapeutic agent is improved compared to the same measurement of response to treatment observed after administration of either at least one compound of formula (I) of the present invention or the additional therapeutic agent alone.

[0035] A further aspect of the present invention relates to a combination therapy comprising administering to a mammal in need thereof a compound of formula (I) of the present invention together with an antifibrotic compound different from the compound of formula (I).In a further embodiment, such an antifibrotic compound can be selected from the following non-limiting group of antifibrotic compounds: pirfenidone, nintedanib, simtuzumab (GS-6624, AB0024), BG00011 (STX100), PRM-151, PRM-167, PEG-FGF21, BMS-986020, FG-3019, MN-001, IW001, SAR156597, GSK2126458mPAT-1251 and PBI-4050.

[0036] Yet another aspect of the present invention relates to combination therapy comprising administering a compound of formula (I) to a mammal in need thereof in combination with additional conventional cancer treatments, such as chemotherapy or radiation therapy, or treatments with immune stimulants, gene therapy, antibody therapy, and treatments using dendritic cells.

[0037] In one embodiment, the compound of formula (I) is administered with at least one additional therapeutic agent selected from antitumor chemotherapeutic agents. In further embodiments, the antitumor chemotherapeutic agent is selected from all-trans retinoic acid, Actimide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gemcitabine, hydroxyurea, idarubicin, irinotecan, lenalidomide, leucovorin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, revlimid, temozolomide, teniposide, thioguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine. In one embodiment, the chemotherapy agent for use in the combination of drugs can be a combination of different chemotherapy agents.Suitable combinations include FOLFOX and IFL.FOLFOX is a combination that includes 5-fluorouracil (5-FU), leucovorin and oxaliplatin.IFL treatment includes irinotecan, 5-FU and leucovorin.

[0038] In further embodiments of the invention, the additional conventional cancer treatment comprises radiation therapy. In some embodiments, the radiation therapy comprises localized radiation therapy delivered to the tumor. In some embodiments, the radiation therapy comprises total body irradiation.

[0039] In another embodiment of the present invention, the additional cancer treatment is selected from the group of immune stimulants, such as cytokines and antibodies. Such cytokines may be selected from the group consisting of, but not limited to, GM-CSF, type I IFN, interleukin 21, interleukin 2, interleukin 12 and interleukin 15. The antibody is preferably an immune stimulant antibody, such as anti-CD40 antibody or anti-CTLA-4 antibody. The immune stimulant may also be a substance that can deplete immune inhibitory cells (e.g., regulatory T cells) or factors, and said substance may be, for example, E3 ubiquitin ligase. E3 ubiquitin ligases (HECT, RING and U-box proteins) have emerged as key molecular regulators of immune cell function, and each may be involved in regulating immune response during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins are also involved in the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 negatively regulate T cell growth factor production and proliferation, respectively.

[0040] In some embodiments of the present invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from checkpoint inhibitors.In some embodiments of the present invention, the checkpoint inhibitor acts on one or more of the following non-limiting targets: CEACAM1, Galectin-9, TIM3, CD80, CTLA4, PD-1, PD-L1, HVEM, BTLA, CD160, VISTA, B7-H4, B7-2, CD155, CD226, TIGIT, CD96, LAG3, GITF, OX40, CD137, CD40, IDO and TDO.These are known targets, and some of these targets are described in Melero et al., Nature Reviews Cancer (2015). Examples of checkpoint inhibitors administered together with the compounds of formula (1) include anti-PD-1: nivolumab, pembrolizumab, cemiplimab; anti-PD-L1: atezolizumab, avelumab, durvalumab; and one anti-CTLA-4: ipilimumab. Each of these checkpoint inhibitors can be the subject of an embodiment in combination with any one of the compounds of formula (1).

[0041] In some embodiments of the invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from inhibitors of indoleamine-2,3-dioxygenase (IDO).

[0042] In some embodiments of the present invention, the compound of formula (I) is administered with at least one additional therapeutic agent selected from one or more inhibitors of the CTLA4 pathway. In some embodiments, the inhibitors of the CTLA4 pathway are selected from one or more antibodies against CTLA4.

[0043] In some embodiments of the invention, the compound of formula (I) is administered together with at least one additional therapeutic agent selected from one or more inhibitors of the PD-1 / PD-L pathway, hi some embodiments, the one or more inhibitors of the PD-1 / PD-L pathway are selected from one or more antibodies against PD-1, PD-L1 and / or PD-L2. [Brief description of the drawings]

[0044] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The compound of Formula I will be tested in a Phase 1, randomized, double-blind, placebo-controlled, first-in-human study evaluating the safety, tolerability, and pharmacokinetics of orally administered compound of Formula I in healthy adult subjects and adult subjects with suspected signs of nonalcoholic steatohepatitis (NASH) and liver fibrosis.

[0046] The study is intended to obtain safety, tolerability and pharmacokinetic data for single and multiple doses of the compound of formula I administered orally to healthy subjects, and includes an optional portion to obtain safety and tolerability data for multiple doses of the compound of formula I administered orally to subjects suspected of having nonalcoholic steatohepatitis (NASH) and liver fibrosis.

[0047] Based on the results obtained from first-in-human studies using single doses and multiple ascending doses, it was concluded that the compound of formula (I) is safe and well tolerated in humans and that the favorable PK parameters support once or twice daily dosing in a particular dose range, typically 5 mg to 200 mg once or twice daily, for example 10 mg to 100 mg twice daily.

[0048] The compound of formula (I) has the chemical name (IUPAC) 5-bromopyridin-3-yl 3-deoxy-3-[4-(3,4,5-trifluorophenyl)-1H-1,2,3-triazol-1-yl]-1-thio-α-D-galactopyranoside. [ka]

[0049] The compounds are referred to herein as "compounds of Formula I."

[0050] In the liquid composition comprising a mixture of a dissolved or dispersed polymer for stabilizing the amorphous form of the compound of formula I and a solution of the compound of formula I, the polymer is dissolved or dispersed in a suitable solvent that depends on the polymer used. Those skilled in the art can easily screen various solvents and solvent mixtures to find the most suitable solvent, such as when HPMC is used, dichloromethane, ethanol, water, or a mixture of water and acetone are suitable. Furthermore, the compound of formula I can be dissolved in various solvents such as acetone, tetrahydrofuran, DMSO, methanol, ethanol, dichloromethane, and the like, where those skilled in the art can screen suitable solvents or solvent mixtures to find the most suitable solvent. For example, for the compound of formula I, acetone and THF are preferred, and in particular a mixture of acetone in water. It should be noted that the polymer and the compound of formula I may be dissolved in the same solvent.

[0051] When preparing a liquid composition comprising a mixture of a solution of a dissolved or dispersed polymer for stabilizing the amorphous form of the compound of formula I and a solution of the compound of formula I, and optionally a solution of a pharma- ceutically acceptable additive, the polymer is dissolved or dispersed in a first solvent, and the compound of formula I is dissolved in a second solvent. The first and second solvents may be the same or different. For example, the polymer may be dissolved in a solvent such as a mixture of acetone and water, and then the compound of formula I is dissolved in the same solvent solution containing the polymer. The order of dissolving the polymer and the compound of formula I is not important, but in one embodiment, it is preferred to dissolve the polymer first, and then dissolve the compound of formula I in the solvent containing the polymer, and in a second embodiment, it is preferred to dissolve the polymer in one solvent, dissolve the compound of formula I in a different solvent, and mix the two solutions. Optionally, a pharma- ceutically acceptable additive is dissolved in any one of the solutions, for example in the first or second solution or dispersion, or in a mixture of the first and second solutions or dispersions, or in the solution or dispersion comprising the polymer and / or the compound of formula I. The pharma- ceutically acceptable additive is typically selected from suitable surfactants and / or pore-forming excipients.

[0052] The amorphous compound of formula I can be stabilized as an amorphous solid dispersion or a drug layer composition.

[0053] Thus, the present invention relates to an amorphous solid dispersion composition comprising a mixture of an amorphous compound of formula I and a polymer for stabilizing the amorphous form of the compound of formula I. Optionally, a pharma- ceutically acceptable excipient may be included in the composition.

[0054] The weight ratio of the amorphous compound of formula I to the polymer can vary depending on the polymer used to provide the most stable amorphous compound of formula I, with a preferred range being 1:0.5 to 1:5. A more preferred weight ratio is 1:1 to 1:3, with an optimal weight ratio of about 1:2, to prevent recrystallization of the amorphous form of the compound of formula I in the amorphous solid dispersion over time. Additionally or independently, the amorphous compound of formula I is present in a concentration of 0.5% w / w to 90% w / w, and the polymer is present in a concentration of at least 0.1% w / w, optionally with the addition of a pharma- ceutically acceptable excipient to make up to 100% w / w. For example, the amorphous compound of formula I is present in a concentration selected from the ranges consisting of 1% w / w to 80% w / w, 2 to 70% w / w, 5 to 60% w / w, 10 to 50% w / w, and 20 to 40% w / w. Preferably, the amorphous compound of formula I is present in a concentration in the range of 30-40% w / w. For example, the polymer is present in a concentration selected from the ranges consisting of 0.1% w / w-99% w / w, 1-80% w / w, 5-70% w / w, 10-60% w / w, 20-50% w / w and 30-40% w / w. Preferably, the polymer is present in a concentration in the range of 60-70% w / w.

[0055] The amorphous solid dispersion compositions of the present invention can be filled into capsules or compressed into tablets for oral administration.

[0056] Typically, the present invention relates to a tablet composition for oral administration comprising the amorphous solid dispersion composition of the present invention. The above-mentioned weight ratio of the amorphous compound of formula I to the polymer and the concentration of the amorphous compound of formula I and the polymer before adding excipients such as binders, disintegrants, lubricants, fillers, etc. also apply to the tablets of the present invention.

[0057] The present invention further relates to a drug layered composition comprising: a) an inert solid core having an outer surface; and b) a mixture of an amorphous compound of formula I and a polymer for stabilizing the amorphous form of the compound of formula I, the mixture being applied as a layer, for example, by spraying the mixture dissolved in a suitable solvent onto the outer surface of the inert solid core and evaporating the solvent. The weight ratio of the amorphous compound of formula I to the polymer can be varied to provide the most stable drug layered composition, with a preferred range being 1:0.5-1:5. To prevent recrystallization of the amorphous form of the compound of formula I in the drug layered composition over time, a more preferred weight ratio is 1:1-1:3, with the most preferred weight ratio being about 1:2. Additionally or independently, the amorphous compound of formula I is present in a concentration of 0.5% w / w to 20% w / w, the polymer is present in a concentration of 1% w / w to 40% w / w, the inert solid core is present in a concentration of 40% w / w to 98.5% w / w, and optionally a pharma- ceutically acceptable excipient is added to make up to 100% w / w. For example, the amorphous compound of formula I is present in a concentration selected from the ranges consisting of 1% w / w to 18% w / w, 5% w / w to 15% w / w, 7% w / w to 15% w / w, and 10% w / w to 14% w / w. For example, the polymer is present in a concentration selected from the ranges consisting of 1% w / w to 40% w / w, 5% w / w to 35% w / w, 10% w / w to 30% w / w, and 15% w / w to 25% w / w. For example, the inert solid core is present in a concentration selected from the range consisting of 45% w / w to 90% w / w, 50% w / w to 80% w / w, and 60% w / w to 70% w / w. Preferably, the drug layered composition comprises the amorphous compound of formula I in a concentration of 1 to 12% w / w, the polymer in a concentration of 2 to 24% w / w, and the inert solid core in a concentration of 64 to 97% w / w. One example is 1.2% w / w of the amorphous compound of formula I, 2.4% w / w of the polymer, and 96.4% w / w of the inert solid core, and another example is 12% w / w of the amorphous compound of formula I, 24% w / w of the polymer, and 64% w / w of the inert solid core. Another preferred embodiment relates to a drug layered composition comprising an amorphous compound of formula I in a concentration of 1-12% w / w, a polymer in a concentration of 2-24% w / w, an inert solid core in a concentration of 45-90% w / w, and a pore-forming excipient in a concentration of 5-20% w / w.An example is 12% w / w amorphous compound of formula I, 24% w / w polymer, 56.8% w / w inert solid core and 7.2% w / w pore-forming excipients.

[0058] The mixture of amorphous compound of formula I and polymer may be layered onto the entire surface or only a portion of the surface of the inert solid core, with the inert solid core simply functioning as a carrier.

[0059] The drug layer composition of the present invention is typically filled into a capsule suitable for oral administration. Such a capsule may be a gelatin capsule, such as a size 0 Licap hard shell gelatin capsule.

[0060] In the above aspects and embodiments in which a polymer for stabilizing the amorphous form of the compound of formula I is part of the composition, such polymer is selected from one or more of the group consisting of polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose (HEC), methylcellulose (MC), polyvinylpyrrolidone vinyl acetate (PVPVA), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (hypromellose or HPMC), hypromellose phthalate, and hypromellose acetate succinate (HPMC-AS), Eudragit, poloxamer, and Gelucire.

[0061] In a preferred embodiment, the polymer is selected from one or more of the group consisting of polyethylene glycol (PEG300 to PEG10000), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose (HEC), methylcellulose (MC), polyvinylpyrrolidone vinyl acetate (PVP / VA), polyvinylpyrrolidone, e.g. (PVP K30), hydroxypropylmethylcellulose (hypromellose), e.g. hypromellose 603 (HPMC 603), hypromellose 606 (HPMC 606), hypromellose 615 (HPMC 615), hypromellose phthalate-55 (HP-55), and hypromellose acetate succinate-LF (HPMCAS-LF), Eudragit L100-55, and Gelucire 44 / 14, preferably hydroxypropylmethylcellulose, e.g. HPMC 603.

[0062] In further embodiments, the amorphous compound of formula I is present in the composition, e.g., the drug layer composition or the amorphous solid dispersion composition, in an amount of 0.1 mg to 1000 mg, e.g., 5 mg to 900 mg. In further embodiments, the compound of formula I is present in an amount of 10 to 800 mg, 20 to 700 mg, 30 to 600 mg, 40 to 500 mg, 50 to 400 mg, 60 to 300 mg, 70 to 200 mg, 80 to 150 mg, or 90 to 100 mg. Preferably, one tablet contains the compound of formula I in an amount of 1 to 200 mg, e.g., 5 to 100 mg. Preferably, one capsule contains the compound of formula I in an amount of 1 to 200 mg, e.g., 5 to 100 mg. In a typical embodiment, this amount is administered once a day or twice a day.

[0063] In the above aspects and embodiments where an inert solid core is part of the composition, the inert solid core is made from a material selected from the group consisting of sugar and microcrystalline cellulose (MCC).

[0064] Typically the solid core is made from starch, sucrose and microcrystalline cellulose (MCC), preferably MCC.

[0065] In a further embodiment, the inert solid core has a size large enough to carry a therapeutically relevant amount of the amorphous compound of formula I, typically at least 40 μm, such as at least 50 μm. Since the drug layered composition should fit into a capsule for oral administration, the size should not exceed 3000 μm, as such large particles may also carry less active drugs and thus not be optimal for capsules. Preferred inert cores should be in the range of 50-2000 μm, such as 100-1400 μm, 100-200 μm, 200-355 μm, 355-500 μm, 500-710 μm, 710-1000 μm and 1000-1400 μm.

[0066] In a method of preparing an amorphous solid dispersion composition of the present invention, spray drying of a liquid composition comprising a mixture of a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I and a dissolved compound of formula I can be carried out using a ProCepT 4M8 Trix spray dryer with the following parameters: [Table 1]

[0067] In a method of preparing a drug layered composition of the present invention, spraying of a liquid composition comprising a mixture of a dissolved or dispersed polymer for stabilizing the amorphous form of the compound of formula I and a dissolved compound of formula I onto an inert solid core can be carried out using a fluidized bed equipped with a Wurster insert, such as an Aeromatic STREA-1 or a Glatt GPCG3, with the following coating solution and parameters ("API" is used interchangeably with "compound of formula I"): [Table 2]

[0068] The terms "treatment" and "treating" as used herein refer to the management and care of a patient with the aim of combating a condition, such as a disease or disorder. The terms are intended to include the full range of treatments for a given condition suffered by a patient, such as administering active compounds to alleviate symptoms or complications, to slow the progression of a disease, disorder or condition, to alleviate or relieve symptoms and complications, and / or to cure or eliminate a disease, disorder or condition, as well as to prevent a condition, where prevention should be understood as the management and care of a patient with the aim of combating a disease, condition or disorder, including administering active compounds to prevent the onset of symptoms or complications. Treatment may be chronic. The patient to be treated may be a human subject diagnosed with pulmonary fibrosis or other types of pulmonary fibrosis, renal fibrosis, or NASH.

[0069] As used herein, "pharmaceutical acceptable excipients" are intended to include, but are not limited to, carriers, excipients, diluents, adjuvants, colorants, fragrances, preservatives, and the like that one of ordinary skill in the art would consider for use in formulating the compounds of the present invention to produce pharmaceutical compositions.

[0070] The adjuvant, diluent, excipient and / or carrier that can be used in the composition of the present invention must be pharma- ceutically acceptable in the sense that it is compatible with the compound of formula (I) and other components of the pharmaceutical composition and is not harmful to its recipient.It is preferable that the composition does not contain any substance that may cause adverse reactions, such as allergic reactions.The adjuvant, diluent, excipient and carrier that can be used in the pharmaceutical composition of the present invention are well known to those skilled in the art.

[0071] As mentioned above, the compositions disclosed herein, particularly the pharmaceutical compositions, may further comprise at least one pharma- ceutically acceptable adjuvant, diluent, excipient and / or carrier in addition to the compounds disclosed herein. The total amount of the active ingredient and the pharma-ceutically acceptable adjuvant, diluent, excipient and / or carrier does not constitute more than 100% by weight (100% w / w) of the composition, particularly the pharmaceutical composition.

[0072] Further embodiments of the processes are described in the experimental section herein, with each individual process and each starting material constituting an embodiment that may form part of an embodiment.

[0073] The above embodiments should be understood to refer to any one of the aspects described herein (such as "method of treatment," "pharmaceutical composition," "compound for use as a medicament," or "compound for use in a method") and any one of the embodiments described herein, unless it is specified that the embodiment relates to a particular aspect or aspects of the invention.

[0074] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0075] All headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

[0076] Any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or clearly contradicted by context.

[0077] As used in the context of describing the invention, the terms "a" and "an" and "the" and similar referents are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0078] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated herein as if set forth individually herein. Unless otherwise indicated, all exact values ​​provided herein represent corresponding approximations (e.g., where appropriate, all exact exemplary values ​​provided with respect to a particular factor or measurement can also be considered to provide the corresponding approximate measurement modified by "about").

[0079] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context.

[0080] Any and all examples provided herein, or the use of exemplary language (e.g., "etc.") are intended merely to better clarify the invention and do not limit the scope of the invention unless otherwise indicated. No language in the specification should be construed as indicating any element essential to the practice of the invention unless expressly stated.

[0081] Citations and incorporation of patent documents herein are done for convenience only and do not reflect any opinion regarding the validity, patentability and / or enforceability of such patent documents.

[0082] A description herein of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" in reference to a single or multiple elements is intended to provide support for similar aspects or embodiments of the invention that "consists of," "consists essentially of," or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0083] This invention includes all modifications and equivalents of the subject matter recited in the embodiments or claims presented herein to the maximum extent permitted by applicable law.

[0084] The present invention is further illustrated by the following examples, which should not be interpreted as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, both separately and in any combination thereof, be material for realizing the invention in diverse forms thereof.

[0085] experiment Amorphous Solid Dispersions A small test batch of API-HPMC 603 (1:2) spray dried dispersion (SDD) was prepared using a 4M8 TriX spray dryer from ProCepT. One gram of HPMC 603 was dissolved in 22.2 mL of DCM / ethanol (1 / 1) solution (45 mg / mL) and 500 mg of API was dissolved in 10 ml of tetrahydrofuran (THF) (50 mg / mL). The two solutions were mixed at room temperature, filtered through a 45 μm filter, and subsequently spray dried using the parameters listed below.

[0086] Parameters used for spray drying: [Table 3]

[0087] The prepared SDD was characterized by X-ray powder diffraction (XRPD) and modulated differential scanning calorimetry (mDSC). The XRPD data showed that the SDD was amorphous, and the single Tg at 109° C. obtained from the mDSC scan indicated the formation of a miscible system between the API and HPMC 603 without phase separation. The spray drying yield was 78% with an HPLC assay of 97%.

[0088] FIG. 1 is an XRPD diffractogram of API / HPMC 603 (1:2) SDD.

[0089] FIG. 2 is an mDSC thermogram (inverted signal) of API / HPMC 603 (1:2) SDD showing a Tg at 109° C.

[0090] The dissolution results of API-HPMC 603 SDD compared to unformulated API are shown in Figure 3. Due to the low solubility of the API, less than 12% of the API (i.e., 0.011 mg / mL in FaSSIF) was released in the dissolution medium over 18 hours from capsules containing only the API. Compared to unformulated API, API-HPMC603 SDD filled capsules showed at least 8-fold higher solubility of the API and a significantly improved dissolution profile, with more than 97% of the API released within 18 hours (0.096 mg / mL in FaSSIF).

[0091] Because plug formation was observed with SDD, a third formulation was prepared consisting of a physical mixture of poloxamer 188 and SDD. The addition of poloxamer 188 prevented plug formation and increased the disintegration / dissolution rate of the API (i.e., 74% (0.073 mg / mL) with poloxamer 188 vs. 43% (0.042 mg / mL) without poloxamer 188 after 2 hours of dissolution).

[0092] Four-week stability studies were performed on SDD prepared with and without poloxamer. There were no changes in the assay or dissolution profile after storage for up to four weeks at 25°C / 60% RH and 40°C / 75% RH. SDD remained amorphous at both conditions, but the Tg appeared to shift to 60-70°C during storage.

[0093] The surfactant SLS, which aids in the dispersion of SDD, was also evaluated as an alternative to poloxamer 188. SDD containing both poloxamer and sodium lauryl sulfate (SLS) resulted in similar release profiles, but in the presence of SLS, the SDD powder was completely visibly dispersed in the dissolution medium within 10 minutes, which was faster than when poloxamer 188 was used (approximately 30 minutes).

[0094] Spray Coating / Drug Layering of Amorphous Compounds of Formula I Drug layering on a small scale (30 g of layered pellets) was carried out by using an Aeromatic coater (fluidized bed experimental unit, STREA-1 from GEA Niro Inc.) The composition of the coating solution and the parameters used during the drug layering process are given below.

[0095] Coating solutions and parameters used for drug layering process: [Table 4]

[0096] The coating solution for applying the drug:polymer mixture on the inert cores was prepared as follows. To prepare 200 mL of coating solution, 12 g of HPMC 603 was added to 40 mL of distilled water in a beaker, and the mixture was heated to 70-80 °C while stirring using a magnetic stirrer. After the HPMC 603 was completely dispersed, the solution was cooled to room temperature, resulting in a clear HPMC 603 solution. 140 mL of acetone was added to the solution, and the mixture was stirred using a magnetic stirrer until a homogenous solution was obtained. To this, 6 g of API was added, and the solution was stirred until all of the API was dissolved. During the process, the beaker was sealed using parafilm to prevent the evaporation of acetone. Finally, the coating solution was sieved through a 0.25 mm mesh before use.

[0097] 30 g of VIVAPUR® Microcrystalline Cellulose (MCC) Spheres 700 (710-1000 μm) from JRS were used for drug layering. The final composition of the drug-layered MCC spheres is shown below:

[0098] Composition of drug layered pellets: [Table 5]

[0099] The resulting drug layered pellets were analyzed by UV-HPLC to determine drug loading and by SEM, XRPD to determine dissolution in biorelevant media.

[0100] UV-HPLC results showed that the drug loading of the pellets was 12.19% and no degradation of the API was observed. XRPD showed that the API remained amorphous after drug layering.

[0101] The dissolution profile of the drug-layered pellets was compared to that of the API alone and the ASD formulation (a physical mixture of SDD (API:HPMC603=1:2) and poloxamer 188) (see Figure 4). The drug-layered pellets show a similar maximum release rate within 3 hours as the ASD formulation, but the initial release rate is slightly slower, with approximately 33% of the API released within 30 minutes (compared to approximately 50% released from the ASD formulation).

[0102] To further explore the slower dissolution, an HPC coating was applied to the surface of the drug-layered pellets (7% weight gain). The coating process was carried out using a Caleva mini-coater dryer, spraying the coating solution onto 5 g of drug-layered pellets for approximately 1 hour to achieve a 7% polymer weight gain. The coating solution used was a 5% w / w HPC solution in water, and the parameters used and the composition of the final HPC-coated drug-layered pellets are listed below.

[0103] Parameters used for HPC coating: [Table 6]

[0104] Composition of HPC coated drug layered pellets: [Table 7]

[0105] Dissolution testing of the HPC-coated pellets showed that the HPC-coated pellets were completely dispersed in biorelevant dissolution media within 30 min, but the dissolution profile was not improved (see Figure 5).

[0106] A 4-week stability study was performed on the drug layered pellets. Size 00 Licap hard shell gelatin capsules were manually filled with the drug layered pellets (410 mg pellets / capsule, equivalent to 50 mg API). Capsules were placed in closed glass vials and incubated at 25°C / 60% RH and 40°C / 75%. At each time point (T=0, 7 days and 4 weeks) samples were analyzed / characterized by XRPD, SEM and dissolution.

[0107] Stability test results show that the pellets remain unchanged after 4 weeks of storage at 25°C / 60% RH and 40°C / 75%. The dissolution profile of the drug-layered pellets did not change at either condition. XRPD also confirmed that the API remained amorphous and showed no evidence of recrystallization during the 4-week period when stored at both 25°C / 60% RH and 40°C / 75%. SEM results of the drug-layered pellets show that no obvious morphological changes to the surface of the pellets were observed during 4 weeks of storage at both 25°C / 60% RH and 40°C / 75%.

[0108] On a larger scale (1-4 kg coated pellets), drug layering was performed using a Glatt GPCG3 fluid bed with a 6 or 7 inch Wurster insert. The equipment parameters used during the drug layering process are listed below. Two different drug loaded MCC spheres were prepared.

[0109] Parameters used for drug layering process: [Table 8]

[0110] The coating solution was prepared as follows: Water was placed in a jacketed mixing bowl and heated to 35-37°C. HPMC was slowly added to the heated water while mixing, then the mixture was heated to 52-55°C and mixing was continued until a homogenous dispersion was formed. The mixture was cooled to room temperature and mixing was continued until a clear solution was obtained. The HPMC aqueous solution and acetone were mixed together in a glass vessel suitable for feeding solutions into a fluid bed coater. The API was dissolved in the HPMC aqueous solution / acetone mixture. The MCC microspheres were transferred to the bowl of the fluid bed coater and spray coated with the API / HPMC aqueous solution / acetone mixture until the desired amount of drug layering was achieved. The final composition of the drug-layered MCC spheres is shown below.

[0111] Composition of drug layered pellets: [Table 9]

[0112] Use of pore formers: Additional drug layering studies were performed with the inclusion of pore formers in the layering solution. Pore formers, such as calcium dihydrogen phosphate, lactose, hydroxypropyl cellulose, and microcrystalline cellulose, are excipients added to the layering solution along with HPMC 603 and the compound of formula I that form small pores or channels in the coating. The pores allow for more rapid wetting of the layered coating, thus increasing the drug release rate from the coated microspheres. These excipients can be added at concentrations up to 20% w / w. The excipients can be dissolved in the HPMC 603 polymer water solution or in the final acetone / water solution containing the compound of formula I prior to spray coating.

[0113] An example of a drug layered pellet containing pore-forming excipients has the following composition:

[0114] Composition of drug layered pellets with pore-forming excipients: [Table 10]

[0115] The above composition was used to prepare drug-layered pellets. SEM analysis showed the presence of pores on the surface of the coated pellets. Dissolution testing showed a faster release profile than the drug-layered pellets without calcium dihydrogen phosphate.

[0116] Pharmacokinetic data in humans The first part of this study is designed to obtain safety, tolerability and pharmacokinetic data for a single oral dose of the compound of Formula I in healthy subjects using the drug layered formulation described above.

[0117] Experimental data obtained from healthy subject cohort A1: Compound of formula I (API) 5 mg Six healthy subjects in a fasting state were orally administered a single dose of 5 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were dosed 24 hours before the remaining subjects. Blood samples were obtained by venipuncture for pharmacokinetic analysis of plasma API concentration at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0118] Experimental data obtained from healthy subject cohort A2: Compound of formula I 20 mg Six healthy subjects in a fasting state were orally administered a single dose of 20 mg capsules of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were dosed 24 hours before the remaining subjects. Blood samples for pharmacokinetic analysis of plasma API concentration were obtained by venipuncture at pre-dose and then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after dosing. See the table below.

[0119] Experimental data obtained from fasted healthy subjects cohort A3: Compound of formula I (API) 50 mg Six healthy subjects in a fasting state were orally administered a single dose of 50 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were dosed 24 hours before the remaining subjects. Blood samples were obtained by venipuncture for pharmacokinetic analysis of plasma API concentration at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0120] Experimental data obtained from Cohort A3, healthy subjects in the fed state: Compound of formula I (API) 50 mg Six healthy subjects in a fed state were orally administered a single dose of 50 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were administered 24 hours before the remaining subjects. Blood samples for pharmacokinetic analysis of plasma API concentration were obtained by venipuncture at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0121] Experimental data obtained from healthy subject cohort A4: Compound of formula I (API) 50 mg (as 10 x 5 mg capsules) Six healthy subjects in a fasting state were orally administered a single dose of 50 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were dosed 24 hours before the remaining subjects. Blood samples were obtained by venipuncture for pharmacokinetic analysis of plasma API concentration at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0122] Experimental data obtained from healthy subject cohort A5: Compound of formula I (API) 100 mg Six healthy subjects in a fasting state were orally administered a single dose of 100 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were dosed 24 hours before the remaining subjects. Blood samples were obtained by venipuncture for pharmacokinetic analysis of plasma API concentration at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0123] Experimental data obtained from healthy subject cohort A6: Compound of formula I (API) 200 mg Six healthy subjects in a fasting state were orally administered a single dose of 200 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were administered 24 hours before the remaining subjects. Blood samples for pharmacokinetic analysis of plasma API concentration were obtained by venipuncture at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0124] Experimental data obtained from healthy subject cohort A7: Compound of formula I (API) 400 mg Six healthy subjects in a fasting state were orally administered a single dose of 400 mg capsule of the compound of formula I, and two subjects were administered a placebo. The first two subjects (one active and one placebo) were administered 24 hours before the remaining subjects. Blood samples for pharmacokinetic analysis of plasma API concentration were obtained by venipuncture at pre-dose, then 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours after dosing. See the table below.

[0125] [Table 11]

[0126] The second part of the study is designed to obtain safety, tolerability and pharmacokinetic data for the compound of Formula I administered orally twice daily for 10 days to healthy subjects using the drug layered formulation described above.

[0127] Experimental data obtained from healthy subjects cohort B1: Compound of formula I (API) 50 mg Eight healthy subjects were orally administered a 50 mg capsule of the compound of formula I, and three subjects were orally administered a placebo, twice daily for 10 days. Blood samples for pharmacokinetic analysis of plasma API concentration were obtained by venipuncture before dosing on day 1, and then at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours after dosing. Blood sampling was repeated on day 10. See the table below.

[0128] Experimental data obtained from healthy subjects cohort B2: 100 mg of compound of formula I Eight healthy subjects were orally administered a 100 mg capsule of the compound of formula I, and three subjects were orally administered a placebo, twice daily for 10 days. Blood samples for pharmacokinetic analysis of plasma API concentrations were obtained by venipuncture at pre-dose on day 1, then at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post-dose. Blood sampling was repeated on day 10. See the table below.

[0129] [Table 12]

Claims

1. Amorphous Forms of the Compound of Formula I 【Chemistry 1】

2. 10. A pharmaceutical composition comprising the amorphous form of claim 1 and, optionally, a pharma- ceutically acceptable excipient.

3. a mixture of a dissolving or dispersing polymer for stabilizing the amorphous form of the compound of formula I and a solution of the compound of formula I; 【Chemistry 2】 and optionally a solution of a pharma- ceutically acceptable excipient.

4. An amorphous solid dispersion composition comprising a mixture of an amorphous compound of formula I and a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient.

5. 5. The composition of claim 4, wherein the mixture has a weight ratio of the amorphous compound of formula I to the polymer in the range of 1:0.5 to 1:

5.

6. 6. A composition according to claim 4 or 5, wherein the amorphous compound of formula I is present in a concentration of from 0.5% w / w to 90% w / w and said polymer is present in a concentration of at least 0.1% w / w, optionally adding pharma- ceutically acceptable excipients to make up 100% w / w.

7. A tablet composition for oral administration, comprising the amorphous solid dispersion composition according to any one of claims 4 to 6.

8. 1. A drug layered composition comprising: a) an inert solid core having an outer surface; and b) a mixture of an amorphous compound of formula I, a polymer for stabilizing the amorphous form of the compound of formula I, and optionally a pharma- ceutically acceptable excipient, wherein said mixture is a layer on the outer surface of said inert solid core.

9. 9. The drug layer composition of claim 8, wherein the mixture dissolved in a suitable solvent is sprayed onto the surface of the inert solid core.

10. 10. The drug layer composition of claim 8 or 9, wherein said mixture has a weight ratio of amorphous compound of formula I to said polymer in the range of 1:0.5 to 1:

5.

11. 11. The drug layer composition of any one of claims 8 to 10, wherein the amorphous compound of formula I is present in a concentration of 0.5% w / w to 20% w / w, said polymer is present in a concentration of 1% w / w to 40% w / w, and said inert solid core is present in a concentration of 40% w / w to 98.5% w / w, optionally including pharma- ceutically acceptable excipients to make up 100% w / w.

12. A capsule composition for oral administration comprising the drug layer composition according to any one of claims 8 to 11.

13. 13. The composition according to any one of claims 3 to 12, wherein the polymer for stabilising the amorphous form of the compound of formula I is one or more selected from the group consisting of polyethylene glycol (PEG), carboxymethylethylcellulose (CMEC), ethylcellulose, hydroxyethylcellulose (HEC), methylcellulose (MC), polyvinylpyrrolidone vinyl acetate (PVP / VA), polyvinylpyrrolidone, hydroxypropylmethylcellulose (hypromellose), hypromellose phthalate, hypromellose acetate succinate, Eudragit and Gelucire 44 / 14, preferably hydroxypropylmethylcellulose.

14. The composition of any one of claims 8 to 13, wherein the pharma- ceutically acceptable excipient is present and comprises a pore-forming excipient.

15. 15. The composition of claim 14, wherein the pore-forming excipient is present in the layer at a concentration of up to 20% w / w.

16. 16. The composition of claim 14 or 15, wherein the pore-forming excipient is selected from the group consisting of calcium dihydrogen phosphate, lactose, hydroxypropyl cellulose and microcrystalline cellulose.

17. The composition according to any one of claims 8 to 16, wherein the inert solid core is made of a material selected from the group consisting of sugars, such as starch and sucrose, and microcrystalline cellulose (MCC).

18. The composition according to any one of claims 8 to 17, wherein the inert solid core has a size in the range of 50 to 2000 μm.

19. 19. A composition according to any one of claims 2 to 18, comprising said amorphous compound of formula I in an amount of 0.1 mg to 1000 mg, for example 5 mg to 900 mg, 10 to 800 mg, 20 to 700 mg, 30 to 600 mg, 40 to 500 mg, 50 to 400 mg, 60 to 300 mg, 70 to 200 mg, 80 to 150 mg or 90 to 100 mg, typically in an amount of 5 to 200 mg, preferably in an amount of 10 to 100 mg.

20. A method for preparing the liquid composition of claim 3, comprising the steps of: a) preparing a solution or dispersion of said polymer, dissolving a compound of formula I in said solution or dispersion, and optionally dissolving a pharma- ceutically acceptable excipient in said solution or dispersion, thereby providing said liquid composition; or b) preparing a first solution or dispersion of said polymer and a second solution of a compound of formula I, mixing said first and second solutions, and optionally dissolving a pharma- ceutically acceptable excipient in said first or second solution or dispersion, or in said mixture, thereby providing said liquid composition.

21. 5. A method for preparing the amorphous solid dispersion composition of claim 4, comprising the steps of:

4. A method comprising spray drying the liquid composition of claim 3 and recovering the solid amorphous dispersion composition.

22. 9. A method for preparing the drug layer composition of claim 8, comprising:

4. A method comprising spraying the liquid composition of claim 3 onto an inert solid core and recovering the drug layer composition.

23. 23. The method of claim 22, wherein the spraying is spray coating or fluidized bed coating.

24. Inflammation in mammals, e.g., humans; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and fibrosis of the skin and heart; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, e.g., carcinoma, sarcoma, leukemia, and lymphoma, e.g., T-cell lymphoma; metastatic cancer; autoimmune diseases, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; cardiac disease; heart failure; pathological angiogenesis, e.g., ocular angiogenesis or diseases associated with ocular angiogenesis.

20. The composition of any one of claims 4 to 19 for use in a method for treating a disease or disorder selected from the group consisting of: angiogenesis associated with cancer; eye diseases, such as age-related macular degeneration and corneal neovascularization; atherosclerosis; metabolic diseases, such as diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, such as non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

25. 25. The method of claim 24, wherein the composition comprising a compound of formula I is administered once a day or twice a day.

26. The present invention relates to a method for treating inflammation in a mammal, comprising administering a therapeutically effective amount of a composition according to any one of claims 4 to 19; fibrosis, e.g., pulmonary fibrosis, hepatic fibrosis, renal fibrosis, ophthalmic fibrosis, and fibrosis of the skin and heart; scarring; keloid formation; abnormal scar formation; surgical adhesions; septic shock; cancer, e.g., carcinoma, sarcoma, leukemia, and lymphoma, e.g., T-cell lymphoma; metastatic cancer; autoimmune diseases, e.g., psoriasis, rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus; metabolic disorders; cardiac disease; heart failure; pathological conditions. A method for treating a disease or disorder selected from the group consisting of angiogenesis, e.g., ocular angiogenesis, or a disease or condition associated with ocular angiogenesis, e.g., angiogenesis associated with cancer; ocular diseases, e.g., age-related macular degeneration and corneal angiogenesis; atherosclerosis; metabolic diseases, e.g., diabetes; type 2 diabetes; insulin resistance; obesity; diastolic HF; asthma and other interstitial lung diseases including Hermansky-Pudlak syndrome, mesothelioma; liver disorders, e.g., non-alcoholic steatohepatitis or non-alcoholic fatty liver disease.

27. 27. The method of claim 26, wherein the composition comprising a compound of formula I is administered once daily or twice daily.

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