Pharmaceutical preparations

Abstract

The present invention relates to pharmaceutical formulations and methods for preparing pharmaceutical formulations. In particular, the present invention relates to pharmaceutical formulations and methods for preparing pharmaceutical formulations comprising Compound I and a diluent.

Description

【Technical Field】 【0001】 The present invention relates to pharmaceutical preparations and methods for manufacturing pharmaceutical preparations. In particular, the present invention relates to pharmaceutical preparations containing Compound I and diluents and methods for manufacturing pharmaceutical preparations. 【0002】 The pharmaceutical preparations of the present invention can be used to treat diseases mediated by the Wnt signaling pathway, such as cancer, for example, biliary tract cancer, or to enhance the effect of anti-cancer treatment. 【0003】 The described invention provides a pharmaceutical preparation proposed for inhibiting Wnt-mediated signal transduction. This includes paracrine signal transduction in the tissues surrounding the tumor and autocrine and paracrine signal transduction in cancer cells. 【Background Art】 【0004】 The Wnt gene encodes a large and highly conserved family of secreted growth factors. During normal development, the transcription of Wnt family genes is strictly controlled both temporally and spatially. To date, 19 Wnt proteins have been discovered in humans. All Wnt proteins are cysteine-rich glycoproteins of 38 - 43 kDa. Wnt plays various roles in controlling cell fate, migration, proliferation, and death during development. In adults, the role of Wnt is thought to be related to maintaining tissue homeostasis by abnormal signal transduction associated with various cancers. 【0005】 Wnt proteins undergo posttranslational modifications, which have been shown in several mutational experiments to be essential for effective protein transport and secretion (Tang, et al. (2012) Dev. Biol 364, 32-41, Takada, R. et al (2006) Dev. Cell 11, 791-801). Palmitoylation of Wnt proteins occurs at several conserved amino acids (C77, S209) and is carried out by porcupine, an O-acetyltransferase of the endoplasmic reticulum. Mutations in porcupine have been shown to cause developmental disorders, including focal dermal hypoplasia, through impaired Wnt pathway signaling (Grzeschik, et al. (2007) Nat. Genet, 39 pp.833-835). The porcupine dependence of Wnt ligand signaling, and a series of pieces of evidence linking Wnt pathway signaling to cancer, have identified porcupine as a potential anti-cancer target. 【0006】 WO2016 / 055786 relates to a novel small molecule porcupine inhibitor (PORCN) that prevents the secretion and downstream activation of the wingless-type MMTV Integration Site (Wnt) ligand pathway. The disclosed compound has been shown to be active both in vitro and in vivo in relevant ring finger protein 43 (RNF43) mutant cancer models, demonstrating an in vivo therapeutic margin. RNF43 mutations are known to occur in both gastric and pancreatic cancers. Furthermore, preclinical evidence suggests that biliary tract cancer patients are sensitive to PORCN inhibition due to a high Wnt ligand-driven response. 【0007】 The present invention relates to a formulation of a specific compound (referred to herein as Compound I) of WO2016 / 055786. [Overview of the project] [Problems that the invention aims to solve] 【0008】 Previously, pharmaceutical formulations of Compound I were prepared as solid blend formulations containing the active pharmaceutical ingredient (API) at active ingredient concentrations of 5.0 mg, 10.0 mg, 20.0 mg, and 40.0 mg, with the API mixed with conventional excipients for such formulations. However, it has since become clear that lower active ingredient concentrations are required, particularly at doses of 0.5 mg and 1.0 mg per capsule. Using conventional manufacturing approaches, achieving the required capsule uniformity and content uniformity at lower active ingredient concentrations in solid blend formulations is challenging. 【0009】 An object of certain embodiments of the present invention is to provide a pharmaceutical formulation containing compound I in an effective dose. An object of certain embodiments of the present invention is to provide a pharmaceutical formulation containing compound I in a low dose, for example, an active ingredient content lower than that described in a particular clinical study. 【0010】 A particular embodiment of the present invention aims to provide a method for producing a pharmaceutical formulation containing compound I. 【0011】 A particular embodiment of the present invention is to provide a method for producing a pharmaceutical formulation containing compound I in a low dose and uniformly. A particular embodiment of the present invention is to provide a method for producing a pharmaceutical formulation containing compound I that is uniform in a low dose and uniformly in a batch, in accordance with the requirements for uniformity of dosage units (uniformity of content) described in the relevant pharmacopoeia, such as Section 2.9.40 of the European Pharmacopoeia. A particular embodiment of the present invention is to provide a method for producing a pharmaceutical formulation containing compound I that has a consistent active ingredient content across capsules compared to compound I in a low dose, both on average and in individual dose units, demonstrating an active ingredient content in the range of 90–110% of the label claim as measured by HPLC analysis. 【0012】 An object of a particular embodiment of the present invention is to provide a method for producing a stable pharmaceutical formulation containing compound I, which is homogeneous in low doses. 【0013】 Certain embodiments of the present invention satisfy some or all of the above objectives. [Means for solving the problem] 【0014】 Brief summary of the disclosure According to a first aspect of the present invention, the following compound I is dispersed in a semi-solid diluent: [ka] Compound I A semi-solid pharmaceutical formulation containing the above is provided. 【0015】 By combining compound I with a semi-solid diluent, the inventors discovered that the desired homogeneity of the API (active pharmaceutical ingredient) in the formulation could be achieved. The resulting formulation can be encapsulated in capsules. For example, gelatin capsules may be used. The capsules can then be administered to patients in need. 【0016】 Semi-solid diluents can be amphiphilic substances in which polyalkylene glycols, such as polyethylene glycol, bond to lipophilic or hydrophobic molecular entities. A polyethylene glycol chain may contain 3 to 70 alkylene glycol (e.g., ethylene glycol) units. Semi-solid formulations formed using these diluents are particularly beneficial for achieving stable formulations. 【0017】 The melting point of the semi-solid diluent can be in the range of 40°C to 55°C, for example, 42°C to 51°C. The theoretical HLB (hydrophilic-lipophilic balance, i.e., the degree to which a component is hydrophilic or lipophilic) of the semi-solid diluent can be in the range of 10 to 20, for example, 12 to 17. 【0018】 In some embodiments, the semi-solid formulation contains a Gelucire® component. The name Gelucire® is followed by a set of two numbers: the first value (e.g., 44) indicates the melting point in Celsius, and the second value (e.g., 14) indicates the theoretical HLB (hydrophilic-lipophilic balance), i.e., the degree to which the component is hydrophilic or lipophilic. The melting point of the Gelucire® component may be in the range of 40°C to 55°C, for example, 42°C to 51°C, for example, 44°C, 48°C, or 50°C. The theoretical HLB may be in the range of 1 to 20, for example, 12 to 17, for example, 01, 13, 14, or 16. 【0019】 In some embodiments, the semi-solid diluent is selected from the group comprising polyethylene glycol, e.g., PEG (e.g., PEG1000 or variants with a higher Mw), water-soluble surfactants, e.g., Gelucire® 48 / 16, water-dispersible surfactants, e.g., Gelucire® 44 / 14 or Gelucire® 50 / 13, or hard fats, e.g., Gelucire® 43 / 01, vitamin E polyethylene glycol succinate (TPGS), polyoxyl 35 castor oil, e.g., Kolliphor EL, polyoxyl 40 castor oil, e.g., Kolliphor RH40, Solutol HS15 (polyoxyethylene ester of 12-monohydroxystearic acid), glyceryl stearate (Imwitor 900), and capric / caprylic glyceryl esters such as Capmul MCM. In some embodiments, the semi-solid diluent is selected from the group comprising water-soluble surfactants, water-dispersible surfactants, hard fats, vitamin E polyethylene glycol succinate, medium-chain triglycerides, and polyoxyl 35 castor oil. 【0020】 In some embodiments, the semi-solid diluent is selected from the group comprising vitamin E polyethylene glycol succinate and lauroyl macrogol-32 glyceride. Therefore, in some embodiments, the semi-solid diluent is vitamin E polyethylene glycol succinate. Therefore, in some embodiments, the semi-solid diluent is a PEGylated lipid, for example, Gelucire® 44 / 14 (lauroyl macrogol-32 glyceride). In some embodiments, the semi-solid diluent is Gelucire® 48 / 16 (macrogol-32 stearate), Gelucire® 50 / 13 (stearoyl macrogol-32 glyceride), or Gelucire® 43 / 01 (hard fat). Gelucire® 48 / 16 is polyethylene glycol monostearate (type I) NF, consisting of PEG-32 (MW1500) esters of palmitic acid (C16) and stearic acid (C18). It is solid at ambient temperature. Gelucire® 44 / 14 is a lauroyl polyoxyl / macrogol 32 glyceride NF / EP, consisting of small amounts of mono, di, and triglycerides, and mainly PEG-32 (MW 1500) monoesters and diesters of lauric acid (C12). Gelucire® 50 / 13 is a stearoyl polyoxyl / macrogol 32 glyceride NF / EP, consisting of mono, di, and triglycerides, and PEG-32 (MW 1500) monoesters and diesters of palmitic acid (C16) and stearic acid (C18). Gelucire® 43 / 01 is composed of mono, di, and triglyceride esters of fatty acids (C8-C18), with the triester portion being the main component. 【0021】 Compound I is particularly compatible with vitamin E polyethylene glycol succinate and Gelucire® 44 / 14, which is polyethylene glycol glyceride. 【0022】 In some embodiments, the semi-solid pharmaceutical formulation further comprises an antioxidant. In some embodiments, the antioxidant can be selected from butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). 【0023】 In some embodiments, the semi-solid pharmaceutical formulation further comprises a pharmaceutically acceptable excipient selected from the group consisting of sodium lauryl sulfate, poloxamer, and other surfactants. In some embodiments, the semi-solid pharmaceutical formulation further comprises a polymeric agent, for example, a polymeric agent that can inhibit the precipitation of Compound I. In some embodiments, the polymeric agent is selected from the group consisting of polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), methylcellulose, and copovidone. 【0024】 In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of 0.1% w / w to about 10% w / w. In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of 0.5% w / w to about 5% w / w. In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w or about 5% w / w. In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of 0.5% w / w to about 3% w / w. In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of 1.5% w / w to about 2.5% w / w. In some embodiments, the semi-solid pharmaceutical formulation comprises Compound I in an amount of 1% w / w to about 2% w / w. 【0025】 In some embodiments, the semi-solid pharmaceutical formulation contains Compound I at a total dosage of about 0.05 mg to about 5 mg. In some embodiments, the semi-solid pharmaceutical formulation contains Compound I at a total dosage of about 0.25 mg to about 2.5 mg. In some embodiments, the semi-solid pharmaceutical formulation contains Compound I at a total dosage of about 0.25 mg to about 1.5 mg. In some embodiments, the semi-solid pharmaceutical formulation contains Compound I at a total dosage of about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg or about 2.5 mg. In some embodiments, the semi-solid pharmaceutical formulation contains Compound I at a total dosage of about 0.5 mg to about 1 mg. 【0026】 In one embodiment, the semi-solid pharmaceutical formulation comprises: Compound I present in an amount of 0.5% w / w to 3% w / w; vitamin E polyethylene glycol succinate in an amount of 97% w / w to 99.5% w / w. In one embodiment, the semi-solid pharmaceutical formulation comprises: Compound I present in an amount of 1% w / w to 2% w / w; vitamin E polyethylene glycol succinate in an amount of 98% w / w to 99% w / w. 【0027】 In some embodiments, the semi-solid pharmaceutical formulation is encapsulated in a capsule. In some embodiments, the capsule is a gelatin capsule. In some embodiments, the capsule is a plant-derived capsule such as HPMC. In some embodiments, the semi-solid pharmaceutical formulation is encapsulated in a gelatin capsule such as an opalescent gelatin capsule (gelatin and titanium dioxide). 【0028】 In one embodiment, the semi-solid pharmaceutical formulation contains about 0.5 mg to 2 mg of Compound I and about 48.0 mg to about 49.5 mg of vitamin E polyethylene glycol succinate in total dosage. In one embodiment, the semi-solid pharmaceutical formulation is encapsulated in a gelatin capsule and contains about 0.5 mg to 2 mg of Compound I and about 48 mg to about 49.5 mg of vitamin E polyethylene glycol succinate in total dosage. 【0029】 In one embodiment, the semi-solid pharmaceutical formulation contains approximately 0.75 mg to 1.25 mg of compound I and approximately 48.75 mg to 49.25 mg of vitamin E polyethylene glycol succinate in total dose. In one embodiment, the semi-solid pharmaceutical formulation contains approximately 0.75 mg to 1.25 mg of compound I and approximately 48.75 mg to 49.25 mg of vitamin E polyethylene glycol succinate encapsulated in a gelatin capsule in total dose. 【0030】 In one embodiment, the semi-solid pharmaceutical formulation contains about 0.25 mg to about 0.75 mg of compound I and about 49.25 mg to about 49.75 mg of vitamin E polyethylene glycol succinate in total dose. In one embodiment, the semi-solid pharmaceutical formulation contains about 0.25 mg to about 0.75 mg of compound I and about 49.25 mg to about 49.75 mg of vitamin E polyethylene glycol succinate in total dose, encapsulated in a gelatin capsule. 【0031】 In one embodiment, the semi-solid pharmaceutical formulation contains about 1 mg of compound I and about 49 mg of vitamin E polyethylene glycol succinate in total dose. In one embodiment, the semi-solid pharmaceutical formulation contains about 1 mg of compound I and about 49 mg of vitamin E polyethylene glycol succinate in total dose, encapsulated in a gelatin capsule. 【0032】 In one embodiment, the semi-solid pharmaceutical formulation contains about 0.5 mg of compound I and about 49.5 mg of vitamin E polyethylene glycol succinate in total dose. In one embodiment, the semi-solid pharmaceutical formulation contains about 0.5 mg of compound I and about 49.5 mg of vitamin E polyethylene glycol succinate in total dose, encapsulated in a gelatin capsule. 【0033】 The semi-solid pharmaceutical formulation of the present invention can be used for medical purposes. 【0034】 The semi-solid pharmaceutical formulation of the present invention can be used for the treatment of cancer. 【0035】 The present invention also provides a method for treating cancer, the method comprising administering a therapeutically acceptable amount of a semi-solid formulation of the first embodiment to a subject in need of treatment. 【0036】 Cancers may be selected from sarcomas, melanomas, skin cancers, hematological malignancies, lymphomas, carcinomas, adenomas, and leukemias. Certain cancers, sarcomas, melanomas, skin cancers, hematological malignancies, lymphomas, carcinomas, and leukemias that can be treated with the compounds of the present invention may be selected from esophageal squamous cell carcinoma, gastric cancer, glioblastoma, astrocytoma; retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumor, basal cell carcinoma, non-small cell lung cancer, brain tumors, hormone-resistant prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, biliary tract cancers such as bile duct cancer, thymic cancer, cervical cancer, head and neck squamous cell carcinoma, and head and neck cancers. 【0037】 Cancer can be a solid tumor. Cancer can be selected from among gastric cancer, pancreatic cancer, colorectal cancer, thymic cancer, and biliary tract cancer such as bile duct cancer. Cancer can be selected from among among among among colorectal cancer, thymic cancer, and bile duct cancer. Cancer can be selected from among among among among among among colorectal cancer, pancreatic cancer, and bile duct cancer. Cancer can be a biliary tract cancer such as bile duct cancer. Cancer can be a thymic cancer. Cancer can be a colorectal cancer. Cancer can be a pancreatic cancer. 【0038】 The semi-solid pharmaceutical formulation of the present invention may be used for the treatment of diseases regulated by Porcn. 【0039】 The present invention also provides a method for treating a disease regulated by Porcn, the method comprising administering a therapeutically acceptable amount of a semi-solid formulation of the first embodiment to a subject in need of treatment. 【0040】 Diseases regulated by Porcn include cancer. 【0041】 The diseases that can be regulated by Porcn may be selected from dermatofibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, hepatic fibrosis, proteinuria, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy, and retinopathy of prematurity. 【0042】 The semi-solid pharmaceutical formulation of the present invention may be used to treat diseases selected from dermatofibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, hepatic fibrosis, proteinuria, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy, and retinopathy of prematurity. 【0043】 The present invention also provides a method for treating a disease selected from dermatofibrosis, idiopathic pulmonary fibrosis, renal interstitial fibrosis, hepatic fibrosis, proteinuria, kidney graft rejection, osteoarthritis, Parkinson's disease, cystoid macular edema, cystoid macular edema associated with uveitis, retinopathy, diabetic retinopathy, and retinopathy of prematurity, the method comprising administering a therapeutically acceptable amount of a semi-solid formulation of the first embodiment to a subject in need thereof. 【0044】 According to a second aspect of the present invention, a method for producing a semi-solid pharmaceutical preparation is provided, the method comprising the following steps: (i) A step of dissolving a semi-solid diluent; (ii) Disperse compound I in a molten semi-solid diluent to form a molten blend; (iii) A step of filling the capsule shell with the molten blend. 【0045】 In some embodiments, the method of the second embodiment may be used to provide the semi-solid pharmaceutical formulations of the first embodiment and related embodiments. 【0046】 In some embodiments, step (ii) includes dissolving compound I in a semi-solid diluent. In some embodiments, step (ii) further includes mixing compound I with the molten semi-solid diluent from step (i). 【0047】 In some embodiments, the method may further include a step of sieving compound I to remove clumps before the step of dissolving compound I in the diluent. 【0048】 In some embodiments, compound I and the molten diluent are continuously mixed using a suitable mixer to produce a homogeneous solution. 【0049】 Capsule filling can be performed using conventional capsule filling methods and apparatus suitable for molten semi-solid formulations. Capsules can be filled using various methods for distributing a fixed amount of formulation into an empty capsule shell. This may include manual filling methods using volumetric pipettes or methods using automated capsule filling machines. In an exemplary filling process, the capsule body and cap are separated, and the body is secured using a capsule holder. In manual filling, a pipette is used to measure a known volume and weight of formulation and dispense it into the capsule body. After filling is complete, the cap is returned and manually secured to the capsule body. For filling using automated systems, commercially available machines that achieve the same functionality as manual filling are used. 【0050】 In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 30°C to about 90°C. In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 40°C to about 80°C. In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, or about 80°C. In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 45°C to about 80°C. In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 50°C to about 60°C. In some embodiments, the melting of the semi-solid diluent is carried out at a temperature of about 55°C. 【0051】 Detailed description Throughout this description and claims, the terms “includes” and “contains” and their variations mean “includes, but not limited to,” and are not intended to exclude (and do not exclude) other parts, additives, ingredients, integers, or steps. Throughout this description and claims, unless the context requires otherwise, singular nouns include plural nouns. In particular, where indefinite articles are used, unless the context requires otherwise, the specification should be understood to consider both singular and plural nouns. 【0052】 Features, integers, properties, compounds, chemical parts, or groups described in connection with specific aspects, embodiments, or examples of the present invention should be understood to be applicable to any other aspects, embodiments, or examples described herein, insofar as they do not conflict with such other aspects, embodiments, or examples. All features disclosed herein (including the appended claims, abstract, and drawings) and / or all steps of the methods or processes disclosed herein may be combined in any combination, except for combinations in which at least some of such features and / or steps are mutually exclusive. The present invention is not limited to the details of the embodiments described herein. The present invention extends to any novel features, any novel combinations of features disclosed herein (including the appended claims, abstract, and drawings), or any novel steps of any methods or processes disclosed herein. 【0053】 The term "semi-solid" refers to a substance that possesses properties of both a liquid and a solid at room temperature, i.e., a substance with viscosity and rigidity intermediate between a solid and a liquid. At lower temperatures, the substance may exhibit solid properties. At higher temperatures, the substance may exhibit liquid properties. The term "semi-solid" can also refer to a waxy solid that is waxy at room temperature but softens and / or melts at high temperatures. 【0054】 The term "stable" refers to both chemical and physical stability. The term "stable" can indicate the chemical and / or physical stability of a compound or composition over a period of time (e.g., 6 months) at approximately 20°C to 40°C and approximately 50% RH to 80% RH. For example, a compound or composition may be chemically and / or physically stable over a period of 24 hours. A compound or composition may be chemically and / or physically stable over a period of up to 6 months. A compound or composition may be chemically and / or physically stable over a period of 12 months. A compound or composition may be chemically and / or physically stable over a period of up to 12 months. A compound or composition may be chemically and / or physically stable over a period of up to 24 months or up to 36 months. This composition may be physically and chemically stable for 6 months at 40°C / 75% RH. This composition may be physically and chemically stable for 24 months at 25°C / 60% RH. 【0055】 The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application and made available to the public together with this specification, the contents of all such papers and documents are incorporated herein by reference. [Examples] 【0056】 Example 1 Compound I can be prepared according to the procedure outlined in the general scheme of WO2016 / 055786. Alternatively, Compound I can be prepared according to the procedure outlined in Example 9 of WO2016 / 055786. 【0057】 Experimental stability / excipient compatibility tests were conducted, demonstrating the compatibility of compound I with vitamin E polyethylene glycol succinate and gelatin capsule shells in the prototype formulation over a period of more than one month at 25°C / 60% RH and 40°C / 75% RH. Since no significant degradation of compound I was observed, the combination of compound I, vitamin E polyethylene glycol succinate, and gelatin capsule shells was selected for use in capsules containing compound I. Stability evaluation of the selected formulation to support the establishment of shelf life is reported in Example 2. Small-scale manufacturability tests also demonstrated that the formulation could be consistently filled into gelatin capsules to the required fill weight, providing acceptable assay and dose unit uniformity (content uniformity). A homogeneous solution of compound I is formed more readily by vitamin E polyethylene glycol succinate (TPGS), enabling good content uniformity to be achieved at low active ingredient content. 【0058】 Example 2 Compound I 0.5 mg and 1 mg capsules are manufactured from blends of the active pharmaceutical ingredient at concentrations of 1% w / w and 2% w / w, respectively, and mixed with excipients. Table 1 shows the batch formulations of the Compound I capsule blend in 500 g batch sizes for the two different capsule active ingredient contents. The batch size of the Compound I capsule blend can be adjusted as needed to support the needs of a daily adjusted clinical program of the ingredient. 【0059】 Table 1: Batch formulations of Compound I capsule blend [Table 1] * The amount of compound I in the formulation can be corrected by purity, water, and solvent. The concentration of vitamin E polyethylene glycol succinate is also adjusted to maintain the same total blend weight. 【0060】 Method explanation Capsules of Compound I are manufactured from a mixture of the active pharmaceutical ingredient and excipients according to the batch formulations listed in Table 1, using conventional mixing and capsule filling processes in accordance with Good Manufacturing Practice (OKP) standards. Vitamin E polyethylene glycol succinate is melted at a product temperature of 45°C to 80°C. Compound I is passed through a sieve of the appropriate size as needed (pre-screening) to remove any lumps, and then added to the molten vitamin E polyethylene glycol succinate. Both components are continuously mixed using a suitable mixer to produce a visually verifiable homogeneous solution. The appropriate amount of molten blend is precisely transferred to a gelatin capsule shell to achieve the target capsule filling weight (see Table 2). In this example, filling is performed manually, with the capsule body and cap being manually separated and the body secured using a capsule holder. A known volume and weight of the molten formulation is injected into the capsule using a pipette, and then the cap and body are manually joined. The molten blend is continuously mixed during the capsule filling process at a temperature suitable for maintaining the formulation in a molten state as described above. 【0061】 Table 2: Components of Compound I pharmaceuticals [Table 2] 【0062】 Manufacturing process and control of compound I The TIFF0007876538000004.tif74158 sample is tested according to the following method: The following is an outline of the analytical procedure used to test compound I in 0.5 mg and 1.0 mg capsules. a) Appearance (AM003): Visual inspection of Compound I capsules reveals size #3 milky white capsules free of physical defects. b) Identity, Content Uniformity, Assay, and Related Substances by UPLC (AM402): UHPLC reverse-phase method is used for assay / related substance, content uniformity, and identification tests of Compound I capsules, and is suitable for testing 0.5 mg and 1.0 mg capsules. Details of the chromatography conditions are shown in Table 3. 【0063】 Table 3: UHPLC retention time of the compound [Table 3] 【0064】 Two working standards (system compatibility standards) are prepared for the assay at 0.1 mg / mL in diluent, and one at 0.02 mg / mL in diluent for content uniformity. Sensitivity standards are prepared by diluting the standard solution to 0.1% and 0.05%. Preparation of content uniformity samples: Prepare working sample solutions at all doses of active ingredient at 0.02 mg / mL. Preparation of assay / related substance samples: Prepare two working sample solutions at all doses of active ingredient at 0.1 mg / mL each. 【0065】 Table 4 shows the batch analysis data for 0.5 mg and 1.0 mg capsules of compound I. 【0066】 Table 4: Batch analysis data for 0.5 mg and 1.0 mg capsules of Compound I [Table 4] The pharmaceuticals listed in Table 2 have been shown to be physically and chemically stable for 6 months at 40°C / 75% RH and for 24 months at 25°C / 60% RH. 【0067】 The drugs listed in Table 2 were administered to patients in Phase I clinical studies targeting adults with advanced solid tumors (e.g., colorectal cancer, biliary tract cancer, and thymic cancer). Pharmacokinetic studies demonstrated that the drugs listed in Table 2 facilitated good absorption and appropriate drug exposure. Furthermore, preliminary clinical efficacy was observed in some patients with potential Wnt ligand-dependent biliary tract tumors, colorectal tumors, and thymic tumors. 【0068】 Example 3 Four batches of Compound I, two each of 0.5 mg and 1.0 mg capsules, are used in accelerated, intermediate, and long-term storage evaluations to support the determination of shelf life, enabling further extensions of the shelf life. 【0069】 Table 5: Determination of quality shelf life [Table 5] The samples were tested according to the method of Example 2. The samples were tested according to the assay and related substances according to the details in Table 6. 【0070】 Table 6: Shelf life of capsules for compound I [Table 6] 【0071】 Table 7: Stability data for 0.5 mg Compound I capsules (accelerated at 40°C / 75%RH) [Table 7] 【0072】 Table 8: Stability data for 0.5 mg Compound I capsules (intermediate conditions: 30°C / 65%RH) [Table 8] 【0073】 Table 9: Stability data for 0.5 mg Compound I capsules (long-term, 25°C / 60%RH) [Table 9] 【0074】 Table 10: Stability data for 1.0 mg Compound I capsule (accelerated 40°C / 75%RH) [Table 10] 【0075】 Table 11: Stability data for 1.0 mg Compound I capsule (intermediate conditions: 30°C / 65%RH) Table 11 【0076】 Table 12: Stability data for 1.0 mg Compound I capsule (long-term, 25°C / 60%RH) Table 12 【0077】 Table 13: Stability data for 0.5 mg compound IGMP clinical capsules (accelerated 40°C / 75%RH) Table 13 【0078】 Table 14: Stability data for 0.5 mg compound IGMP clinical capsules (intermediate conditions: 30°C / 65%RH) Table 14 【0079】 Table 15: Stability data for 0.5 mg compound IGMP clinical capsules (long term, 25°C / 60%RH) Table 15 【0080】 Table 16: Stability data for 1.0 mg compound IGMP clinical capsules (accelerated 40°C / 75%RH) Table 16 【0081】 Table 17: Stability data for 1.0 mg compound IGMP clinical capsules (intermediate conditions: 30°C / 65%RH) Table 17 【0082】 Table 18: Stability data for 1.0 mg compound IGMP clinical capsules (long-term, 25°C / 60%RH) Table 18 【0083】 Example 4 Table 19 below shows the chemical instability (increase in related substances over time) of PEG1500 + / - antioxidant (AO) and Gelucire 44 / 14 compared to the good stability of TPGS + AO. Table 19: Chemical instability [Table 19]

Claims

[Claim 1] The following compound I, dispersed in a semi-solid diluent: 【Chemistry 1】 Compound I A semi-solid pharmaceutical preparation containing, A semi-solid pharmaceutical preparation in which the semi-solid diluent is vitamin E polyethylene glycol succinate. [Claim 2] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.1% w / w to about 10% w / w. [Claim 3] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.5% w / w to about 5% w / w. [Claim 4] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.5% w / w to about 3% w / w. [Claim 5] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.05 mg to about 5 mg. [Claim 6] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.25 mg to about 2.5 mg. [Claim 7] The semi-solid pharmaceutical preparation according to claim 1, wherein compound I is present in an amount of about 0.5 mg to about 1 mg. [Claim 8] Pharmaceutical preparations, Compound I present in amounts of 0.5% w / w to 3% w / w; and A semi-solid pharmaceutical preparation according to claim 1, comprising vitamin E polyethylene glycol succinate in an amount of 97% w / w to 99.5% w / w. [Claim 9] The semi-solid pharmaceutical preparation according to claim 1, wherein the semi-solid pharmaceutical preparation is enclosed in a gelatin capsule. [Claim 10] A method for manufacturing a semi-solid pharmaceutical preparation, comprising the following steps: (i) A step of dissolving a semi-solid diluent, which is vitamin E polyethylene glycol succinate; (ii) Compound I: 【Chemistry 2】 Compound I A step of dispersing in a molten semi-solid diluent to form a molten blend; (iii) Step of filling the capsule shell with the molten blend; A method that includes this. [Claim 11] The method according to claim 10, wherein the dispersion includes dissolving compound I in a molten semi-solid diluent. [Claim 12] The method according to claim 10, wherein the capsule is a gelatin capsule. [Claim 13] The method according to claim 10, wherein step (i) is performed at a temperature of approximately 45°C to approximately 80°C. [Claim 14] The method according to claim 10, wherein compound I is present in an amount of 0.1% w / w to 10% w / w. [Claim 15] The method according to claim 14, wherein compound I is present in an amount of 0.5% w / w to 3% w / w. [Claim 16] The method according to claim 14, wherein compound I is present in an amount of 1% w / w to 2% w / w. [Claim 17] The method according to claim 10, wherein compound I is present in an amount of about 0.05 mg to about 5 mg. [Claim 18] The method according to claim 17, wherein compound I is present in an amount of about 0.25 mg to about 2.5 mg. [Claim 19] The method according to claim 10, wherein step (i) is carried out at a temperature of about 45°C to about 80°C, the semi-solid diluent is vitamin E polyethylene glycol succinate, and compound I is dissolved in an amount of 0.5% w / w to 3% w / w. [Claim 20] A pharmaceutical preparation according to claim 1, for use as a drug. [Claim 21] A pharmaceutical preparation according to claim 1, for use in the treatment of cancer. [Claim 22] The pharmaceutical preparation according to claim 21, wherein the cancer is a solid tumor. [Claim 23] A pharmaceutical formulation for use according to claim 21, wherein the cancer is selected from gastric cancer, thymic cancer, pancreatic cancer, and biliary tract cancer.