Capsule formulation containing thienopyrimidine derivative, preparation method therefor, and use thereof

Abstract

Provided is a capsule formulation containing a thienopyrimidine derivative, comprising: 8-9 parts by weight of the thienopyrimidine derivative, 58-60 parts by weight of a filler, 25-30 parts by weight of an acidifier, and 5-6 parts by weight of a binder. The capsule formulation is used for treating diseases caused by abnormal cell proliferation caused by EGFR overexpression.

Description

A capsule formulation containing a thiophene pyrimidine derivative, its preparation method and application Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a capsule formulation containing thiophene pyrimidine derivatives, its preparation method, and its application. Background Technology

[0002] Epidermal growth factor receptor (EGFR, Erbb1) is involved in the proliferation of both normal and malignant tumor cells. EGFR overexpression has been found to be associated with cancers such as lung cancer, breast cancer, head and neck cancer, and bladder cancer.

[0003] The EGFR family comprises four receptor tyrosine kinases: EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2, ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Tyrosine kinases play a role in signal transduction. They bind ligands to the receptor's ligand-binding domain extracellularly, forming active homodimers or heterodimers, leading to autophosphorylation of EGFR and activation of stopping proteins (Greulich H. Chen, PLoS Med, 2005, 2, e313; Olayioye MA, EMBO J, 2000, 19, 3159-3167). These signals promote cellular processes such as proliferation, protein synthesis, angiogenesis, cell growth, and survival.

[0004] EGFR overexpression is present in approximately 70% of cancer patients (Seymour, LK, Curr Drug Targets, 2001, 2, 117-133). EGFR tyrosine kinase has become a therapeutic target, and several drugs have been developed to inhibit kinase activity and block its signal transduction pathway as ATP competitors, such as the FDA-approved Tarceva, Irressa, and Gilotrif (all 4-amino-quinazoline inhibitors). These drugs have been widely used in patients with EGFR-overexpressing non-small cell lung cancer (NSCLC), including wild-type and active mutation patients (W. Pao, Nat. Rev. Cancer, 2010, 10, 760-774; R. Rosell, Lancet Oncol, 2012, 13, 239-246; NULin, Breast Cancer Res, 2004, 6, 204-210).

[0005] Two common active mutations were found in patients: L858R and E746-A750 deletion. Mechanistic studies suggest that the clinical activity of Tarceva and Iressa in patients with active mutations may be a result of the combined effects of the enhanced binding affinity of the inhibitor to the mutant kinase and the addiction of mutant cells to proto-oncogenes (JA. Engelman, Science, 2007, 316, 1039-1043).

[0006] However, these first- and second-generation inhibitors with a 4-amino-quinazoline core structure are not effective in approximately 50% of patients with relapsed and acquired resistance diseases such as NSCLC. Acquired resistance is caused by mutations in the T790M gate residue (LV. Sequist, Sci Transl Med, 2011, 3, 75ra26; S. Kobayashi, N Engl J Med, 2005, 352, 786-792; W. Pao, PLoS Med, 2005, 2, 373; JA. Engelman, Semin Respir Crit Care Med, 2005, 26, 314-322). This mutation (the second mutation) increases the binding affinity of ATP for EGFR tyrosine kinase and affects the thermodynamic and kinetic binding properties of these formulations (CH. Yun, Proc Natl Acad Sci USA, 2008, 105, 2070-2075; Cancer Cell, 2007, 11, 217-227; M. Azam, Nat Struct Mol Biol, 2008, 15, 1109-1118; TA. Carter, Proc Natl Acad Sci USA, 2005, 102, 11011-11016). The larger methionine side chain in the choke region prevents those drug molecules from interacting with the ATP binding pocket at clinically effective concentrations.

[0007] Second-generation covalent EGFR inhibitors, such as the FDA-approved afatinib and the clinical-tested compound HKI-272, are effective in patients with the T790M mutation. However, the use of afatinib in patients with active mutations is limited due to dose-limiting toxicity that causes inhibition of wild-type EGFR.

[0008] Pyrimidine derivatives, represented by osimertinib, are third-generation EGFR-TKIs that are effective and selective inhibitors of mutant epidermal growth factor receptor (EGFR) tyrosine kinases without affecting wild-type EGFR, thus reducing side effects.

[0009] The thiophene pyrimidine derivative described in this invention, as a third-generation EGFR-TKI, also exhibits strong inhibitory activity against EGFR-19del and L858R, two EGFR-sensitive gene mutations. It also shows strong inhibitory activity against EGFR19del / T790M and EGFRL858R / T790M, two drug-resistant dual-gene mutations resulting from resistance to first- and second-generation EGFR inhibitors. Furthermore, this thiophene pyrimidine derivative demonstrates good selectivity for the aforementioned tumor mutation genes and EGFR wild-type. Therefore, this thiophene pyrimidine derivative exhibits good inhibitory activity against tumors with the aforementioned sensitive / resistant gene mutations, demonstrating a good tumor-suppressive effect; secondly, its low activity against EGFR wild-type reduces the side effects of the compound, alleviating patient suffering and improving patient compliance. Animal pharmacokinetic studies have shown that this thiophene pyrimidine derivative is orally absorbed, exhibiting varying bioavailability across different animal species and sexes, ranging from 40% to 60%. The thiophene pyrimidine derivative is distributed in tissues greater than in plasma, with the highest distribution observed in lung tissue.

[0010] Therefore, this thiophene pyrimidine derivative exhibits good tumor-suppressive activity, low side effects, and ideal pharmacokinetic performance. Based on these factors, there is an urgent need to develop stable, orally effective formulations of thiophene pyrimidine derivatives suitable for preclinical animal studies and human administration during clinical trials. Summary of the Invention

[0011] As a novel thiophene pyrimidine derivative, the purpose of this invention is to provide a capsule formulation containing a thiophene pyrimidine derivative, its preparation method, and its application. In drug development, there is a need to develop stable, orally effective formulations of thiophene pyrimidine derivatives suitable for preclinical animal studies and human administration during clinical trials for oral medications. Through research and development of thiophene pyrimidine derivatives protected by patents (US10829495B2 / CN108289895B), this invention has, for the first time, successfully screened and prepared a capsule formulation of the aforementioned thiophene pyrimidine derivative, which has been successfully used in preclinical and clinical studies.

[0012] This invention relates to crystalline compounds of thiophene pyrimidine derivatives, which is being proposed for the first time.

[0013] The present invention provides a capsule formulation containing a thiophene pyrimidine derivative, wherein the composition and content of the capsule formulation include: 8-9 parts by weight of the thiophene pyrimidine derivative, 58-60 parts by weight of the filler, 25-30 parts by weight of the acidifier, 5-6 parts by weight of the binder, etc.

[0014] Specifically, the filler is selected from one or more of lactose monohydrate 316 (spray-dried lactose 316), mannitol, microcrystalline cellulose, pregelatinized starch, etc.; preferably, it is mannitol.

[0015] Specifically, the acidifying agent is selected from one or more of L-tartaric acid, L-lactic acid, etc., preferably L-tartaric acid.

[0016] Specifically, the adhesive is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose E5, povidone K30, etc.; preferably, it is low-substituted hydroxypropyl cellulose.

[0017] Preferably, the composition and content of the capsule formulation include: 8.77 parts by weight of thiophene pyrimidine derivative, 59.65 parts by weight of mannitol as filler, 26.32 parts by weight of L-tartaric acid as acidifier, and 5.26 parts by weight of low-substituted hydroxypropyl cellulose as binder, etc.

[0018] The “capsule formulation containing thiophene pyrimidine derivatives” proposed in this invention is the first time this invention has been used.

[0019] The present invention also provides a method for preparing the thiophene pyrimidine derivative-containing capsule formulation as described above, the preparation method comprising the following steps:

[0020] (1) Weigh the amount of thiophene pyrimidine derivative (API) and excipients such as fillers, acidifiers, and adhesives as described above;

[0021] (2) The API weighed in step (1) is crushed and passed through a 60-80 mesh sieve; preferably, the API weighed in step (1) is crushed and passed through an 80 mesh sieve.

[0022] (3) Pass the acidifier and half of the filler as described above through a 60-80 mesh sieve together as material B; the API as material A; and the binder and the remaining half of the filler as described above through a 60-80 mesh sieve together as material C; preferably, the acidifier and half of the filler as described above are passed through a 60 mesh sieve together, and the binder and the remaining half of the filler as described above are passed through a 60 mesh sieve together.

[0023] (4) Add the materials into the mixing container in the order of material B, material A and material C, and mix at 10-20 rpm for 30-50 min to prepare the mixed powder; preferably, mix at 10 rpm for 30 min.

[0024] The step (4) further includes using a sampler to measure the uniformity of the mixed powder obtained in step (4); preferably, the sampling includes a total of 7 sampling points, as shown in Figure 11, of which 6 points are hexagonal on the upper layer of the powder and 1 point is at the center of the powder.

[0025] (5) After the materials in step (4) are mixed, pour out the mixed powder obtained in step (4) from the mixing container and put it into the material container to be filled into capsules; preferably, the material container to be filled is a PE plastic bag;

[0026] (6) After the uniformity of the mixed powder content in step (4) is determined, the mixed powder in step (5) that is placed in the container of the material to be filled is encapsulated to obtain a capsule sample.

[0027] (7) The capsule sample obtained in step (6) is added with a desiccant, bottled, and sealed to prepare a thiophene pyrimidine derivative capsule formulation;

[0028] In step (4), the humidity range of the mixture is 50%-80%, preferably 65.5%-73.2%.

[0029] In step (6), the humidity range of the capsule filling is 50%-80%, preferably 62.7%-71.8%.

[0030] In step (6), the capsules used for capsule filling include #0, #4 capsules, etc.

[0031] When using #4 capsules for filling, the compression depth is 3+3 mm; when using #0 capsules for filling, the compression depth is 2 mm.

[0032] In step (7), each bottle contains 2-4g of desiccant, preferably 4g.

[0033] In step (7), the bottling specifications include 10mg, 30mg, etc.; wherein, 30mg specification: 15 tablets / bottle; 10mg specification: 30 tablets / bottle.

[0034] In step (7), the humidity range of the seal is 45%-60%; preferably, it is 51.3%-57.0%.

[0035] The present invention also provides a pharmaceutical / pharmaceutical composition comprising the capsule formulation described above.

[0036] Furthermore, the drug / drug composition can be used alone and / or in combination with one or more drugs that regulate protein kinases involved in multiple disease states, antitumor drugs that inhibit one or more biological targets, chemotherapy drugs, radiotherapy, immunotherapy drugs, etc.

[0037] The term "combined use" includes the co-administration of the drug / pharmaceutical composition of the present invention with other biologically active ingredients (e.g., but not limited to, a second different antitumor drug) and non-pharmacological therapies (e.g., but not limited to, surgery or radiation therapy). For example, the drug / pharmaceutical composition of the present invention can be used with other pharmaceutically active compounds, preferably compounds capable of enhancing the effect of the drug / pharmaceutical composition of the present invention. The drug / pharmaceutical composition of the present invention can be administered simultaneously (as a single formulation or separate formulation) or sequentially with other drug therapies. Generally, combination therapy involves the administration of two or more drugs in a single cycle or course of therapy.

[0038] Specifically, the pharmaceutical / pharmaceutical composition described in this invention can be administered co-administered with one or more other pharmaceuticals that regulate protein kinases involved in various disease states. Examples of these kinases may include, but are not limited to, serine / threonine-specific kinases, receptor tyrosine-specific kinases, and non-receptor tyrosine-specific kinases. Serine / threonine kinases include mitosis-activated protein kinase (MAPK), meiosis-specific kinase (Aurora), RAF, and Aurora kinase. Examples of receptor kinase families include epidermal growth factor receptor (EGFR) (e.g., HER2 / neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, Xmrk, DER, Let23); fibroblast growth factor (FGF) receptors (e.g., FGF-R1, GFF-R2 / BEK / CEK3, FGF-R3 / CEK2, FGF-R4 / TKF, KGF-R); hepatocyte growth / diffusion factor receptor (HGFR) (e.g., MET, RON, SEA, SEX); and insulin receptors. (e.g., IGFI-R); Eph (e.g., CEK5, CEK8, EBK, ECK, EEK, EHK-1, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDK5, SEK); Axl (e.g., Mer / Nyk, Rse); RET; and platelet-derived growth factor receptor (PDGFR) (e.g., PDGFα-R, PDGβ-R, CSF1-R / FMS, SCF-R / C-KIT, VEGF-R / FLT, NEK / FLK1, FLT3 / FLK2 / STK-1). Non-receptor tyrosine kinase families include, but are not limited to, BCR-ABL (e.g., p43abl, ARG); BTK (e.g., ITK / EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK, and SYK.

[0039] Specifically, the drug / drug composition described in this invention can be combined with antitumor drugs (e.g., small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets, such as vorinostat (Zolinza), tykerb, Gleevec, Sutent, Sprycel, Nexavar, Sorafinib, CNF2024, RG108, BMS387032, Affinitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PD184322, Obatadax, ABT737, and AEE788. Such combinations can enhance efficacy compared to the effects achieved by any single drug and can prevent or delay the emergence of drug-resistant mutants.

[0040] Specifically, the drug / pharmaceutical composition described in this invention is administered in combination with a chemotherapy drug. The chemotherapy drug is administered at various stages of the disease to shrink tumors, destroy cancer cells that remain after surgery, and cause, maintain, and / or alleviate symptoms associated with cancer or its treatment. Examples of these drugs include, but are not limited to, alkylated drugs such as mustard gas derivatives (nitrogen mustard, cyclophosphamide, chlorambucil, melphalan, ifosfamide), ethylenimine (thiotepa, hexamethylmelamine), alkyl sulfonates / esters (busulfan), hydrazine and triazine (hexamethylmelamine, procarbazine, temozolomide, and temozolomide), nitrosoureas (carmustine, lomustine, and streptozotocin), ifosfamides and metal salts (carboplatin, cisplatin, and oxaliplatin); plant alkaloids such as podophyllotoxin (etoposide and tenisopide), taxanes (paclitaxel and docetaxel), vinca alkaloids (vincristine, vinblastine, vinorelbine, and vinorelbine), and camptothecin analogs (irinotecan and topotecan); and antitumor antibiotics such as chromomycin (actinomycin D and procamycin). Anthracyclines (doxorubicin, daunorubicin, epirubicin, mitoxantrone, penoxuridine, and demethoxydaunorubicin), and other antibiotics such as mitomycin, actinomycin D, and bleomycin; antimetabolites such as folic acid antagonists (methotrexate, pemetrexed, raltitrexed, aminopterin), pyrimidine antagonists (5-fluorouracil, fluorouracil deoxyribonucleoside, cytarabine, capecitabine, and gemcitabine), and purine antagonists (6-mercaptopurine). Inhibitors of adenosine deaminase (cladribine, fludarabine, mercaptopurine, clofarabine, thioguanine, nerabine, and pentostatin); topoisomerase inhibitors such as topoisomerase I inhibitors (irinotecan, topotecan) and topoisomerase II inhibitors (acridine, etoposide, etoposide phosphate, teniposide); monoclonal antibodies (alemumab, gemtuzumab ozogamicin, rituximab, trastuzumab, tiimomab, cetuximab, panitumumab, tosimomab, bevacizumab); and other antitumor drugs such as ribonucleotide reductase inhibitors (hydroxyurea); corticosteroid inhibitors (mitotan); enzymes (asparaginase and pegaspargase); antimicrotubule drugs (estradiol mustard); and retinoids (bexarotin, isotretinoin, retinoic acid (ATRA)).

[0041] Specifically, the drug / drug composition described in this invention is administered together with a chemotherapy drug. The chemotherapy drug serves to protect the body or minimize the side effects of chemotherapy. Examples of such drugs include, but are not limited to, Amfostine, mesna, and dexrazoxane.

[0042] In one aspect of the invention, the drug / drug composition described herein is administered in conjunction with radiotherapy. The radioactive material is typically delivered inward (to implant radioactive material near the cancer site) or outward from a machine employing proton (X-ray or gamma-ray) or particle radiation. When the combination therapy also includes radiotherapy, the radiotherapy can be administered at any suitable time, as long as the combined effect of the therapeutic drug and the radiotherapy is achieved. For example, in suitable cases, the beneficial effect can still be achieved when radiotherapy is temporarily suspended for several days or even weeks while the therapeutic drug is being administered.

[0043] Specifically, the pharmaceutical / pharmaceutical composition described in this invention can be used in combination with immunotherapeutic drugs. One form of immunotherapy is to induce an active, systemic, tumor-specific immune response in the host by administering a vaccine composition at a site distant from the tumor. Various types of vaccines have been proposed, including isolated tumor antigen vaccines and vaccines against individual genes. Another approach is to use tumor cells from the subject to be treated, or derivatives of such cells (reviewed by Schirrmacher et al. (1995) J. Cancer Res. Clin. Oncol. 121:487). In U.S. Patent 5,484,596, Hanna Jr. et al. claimed protection for a method of treating resectable cancer to prevent recurrence or metastasis, comprising surgically removing the tumor, dispersing the cells with collagenase, irradiating the cells, and immunizing the patient with at least three consecutive doses of approximately 10⁷ cells.

[0044] In one embodiment, the pharmaceutical / pharmaceutical composition of the present invention can be used to induce or inhibit apoptosis, a physiological cell death process crucial for normal development and homeostasis. Alterations in the apoptosis pathway contribute to the pathogenesis of a variety of human diseases. The compounds of the present invention, as regulators of apoptosis, can be used to treat a variety of human diseases associated with apoptosis abnormalities, including cancers (particularly, but not limited to, follicular lymphoma, cancers associated with p53 mutations, hormone-related tumors of the breast, prostate, and ovaries, and precancerous lesions such as familial adenomatous polyposis), viral infections (including, but not limited to, herpesviruses, poxviruses, Epstein-Barr virus, Sindbis virus, and adenoviruses), autoimmune diseases (including, but not limited to, lupus erythematosus, systemic lupus erythematosus, immune-mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel disease, and autoimmune diabetes), blood disorders (chronic anemia and aplastic anemia), and cancer pain.

[0045] The drug / drug composition described in this invention may be included in a container, package, or dispenser along with instructions for administration.

[0046] The present invention also provides the use of the thiophene pyrimidine derivative-containing capsule formulation as described above, or the preparation method as described above, or the drug / drug composition as described above in the preparation of a drug for treating diseases caused by abnormal cell proliferation due to overexpression of EGFR.

[0047] As described above in the capsule formulation, preparation method, drug / drug composition, and application, the structural formula of the thiophene pyrimidine derivative is shown in formula (I).

[0048] And / or, the thiophene pyrimidine derivative is a crystalline compound having one or more characteristics selected from the group consisting of:

[0049] 1) The crystalline compound has a basic X-ray powder diffraction pattern as shown in Figure 2;

[0050] 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 3;

[0051] 3) The crystalline compound has a DSC spectrum as shown in Figure 4;

[0052] 4) The crystalline compound has a TGA spectrum as shown in Figure 4; and / or,

[0053] The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; it exhibits relatively good physicochemical stability at 25℃ / 60%RH and 40℃ / 75%RH; it has good thermal stability at 80℃; and it has low hygroscopicity at a constant temperature of 25℃ as humidity increases from 0%RH to 80%RH; and / or,

[0054] The method for preparing the crystalline compound includes the following steps: using an amorphous thiophene pyrimidine derivative as the starting material, preparing a suspension in a solvent, stirring at 20-55°C for 1-5 days, and then separating the solid to obtain the crystalline compound; wherein, the solvent is selected from one or more of propanol, dichloromethane, ethyl acetate, etc., and the ratio of the thiophene pyrimidine derivative to the solvent is (15-100) mg: (0.5-2) mL.

[0055] The beneficial effects of this invention include: through the research and development of patented thiophene pyrimidine derivatives, this invention has for the first time successfully screened and prepared thiophene pyrimidine derivative capsule formulations, which have been successfully used in preclinical and clinical studies. Attached Figure Description

[0056] To more clearly illustrate the technical solutions in the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the accompanying drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0057] Figure 1 is an XRPD diagram of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention;

[0058] Figure 2 is an XRPD diagram (with numbers) of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention;

[0059] Figure 3 is the XRPD peak finding report of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention;

[0060] Figure 4 is a TGA / DSC diagram of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention;

[0061] Figure 5 is a summary of the physicochemical stability results of the thiophene pyrimidine derivative crystal compounds in Example 1 of the present invention;

[0062] Figure 6 is a table comparing the impurities in terms of the physicochemical stability of the thiophene pyrimidine derivative crystal compounds in Example 1 of the present invention;

[0063] Figure 7 is a comparison of HPLC chromatograms of the physicochemical stability of the thiophene pyrimidine derivative crystal compounds in Example 1 of the present invention;

[0064] Figure 8 is an XRPD overlay of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention before and after stable placement;

[0065] Figure 9 is a DVS diagram of the crystalline compound of the thiophene pyrimidine derivative in Example 1 of the present invention;

[0066] Figure 10 is a comparison of the crystal forms of the thiophene pyrimidine derivative before and after DVS testing in Example 1 of the present invention;

[0067] Figure 11 is a sampling point diagram of the mixing uniformity in Embodiment 2 of the present invention. Detailed Implementation

[0068] The present invention will be further described in detail below with reference to specific embodiments. Except for the contents specifically mentioned below, the processes, conditions, and experimental methods for implementing the present invention are all common knowledge and general knowledge in the art, and the present invention does not have any particular limitations.

[0069] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0070] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limitations. Therefore, other examples of exemplary embodiments may have different values.

[0071] This invention discloses a capsule formulation containing a thiophene pyrimidine derivative, its preparation method, and its application. The composition and content of the thiophene pyrimidine derivative capsule formulation include: 8-9 parts by weight of the thiophene pyrimidine derivative, 58-60 parts by weight of a filler, 25-30 parts by weight of an acidifying agent, and 5-6 parts by weight of a binder. This invention also discloses the application of the tablet and its preparation method in the preparation of a drug for treating diseases caused by abnormal cell proliferation due to EGFR overexpression. This invention has broad application prospects.

[0072] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0073] Example 1: Preparation of crystalline compounds of thiophene pyrimidine derivatives

[0074] ~100 mg of amorphous thiophene pyrimidine derivatives were added to 2 mL of solvent (IPA, EtOAc) to prepare a suspension. After stirring magnetically at room temperature for ~2 days, the solid was separated and XRPD was tested. Crystalline compounds were successfully obtained in both cases.

[0075] The crystalline compounds of the thiophene pyrimidine derivatives prepared in this invention were analyzed using the following methods:

[0076] 1. Powder X-ray diffraction analysis (XRPD)

[0077] The light source was Cu K, the X-ray intensity was 40 kV / 40 mA, the scanning mode was Theta-theta, the scanning angle range was 4° to 40°, the step size was 0.05°, and the scanning speed was 0.5 seconds / step.

[0078] 2. Differential Scanning Calorimetry (DSC)

[0079] Weigh an appropriate amount of sample and place it in a non-sealed aluminum dish. In a nitrogen flow environment (50 mL / min), equilibrate the sample at 25°C, and then heat it from 25°C to 300°C at a heating rate of 10°C / min.

[0080] 3. Thermogravimetric analysis (TGA)

[0081] Weigh an appropriate amount of sample and place it in a platinum sample pan. In an environment with nitrogen flow of sample (60 mL / min) and nitrogen flow of balance (40 mL / min), heat from room temperature to 300°C at a heating rate of 10°C / min.

[0082] Experimental results show that the XRPD of the crystalline compound is shown in Figures 1-3, and the TGA / DSC is shown in Figure 4. It loses 0.9% weight when heated to 150℃; a sharp endothermic peak is observed at 167.5℃ (initial temperature). Based on the small TGA weight loss and the absence of thermal changes observed before melting, the crystalline compound is presumed to be an amorphous type.

[0083] 4. Physicochemical stability assessment of the crystalline compounds: Solid samples of the crystalline compounds were placed openly at 25℃ / 60%RH for 1 week and at 40℃ / 75%RH for 1 week, respectively, and then sealed at 80℃ for 36 hours. The chemical purity and changes in the solid crystal form were assessed using HPLC area purity and XRPD characterization results. The experimental results are summarized in Figure 5. The HPLC area percentage purity / initial purity of the thiophene pyrimidine derivative crystalline compounds after one week under the three conditions was 99.0%–100.1%, and the solid crystal form remained unchanged. The crystalline compounds exhibited good physicochemical stability at 25℃ and 40℃, but slight degradation was observed at 80℃. A summary of impurities detected by HPLC is shown in Figure 6, the HPLC chromatogram is shown in Figure 7, and the XRPD overlay of the solid crystalline compounds is shown in Figure 8.

[0084] 5. Hygroscopicity Assessment of the Crystalline Compound: The hygroscopicity of the crystalline compound was assessed by dynamic moisture adsorption (DVS) testing. At a constant temperature of 25°C, the DVS test results (Figure 9) showed that when the humidity increased from 0% to 80% RH, the sample of the crystalline compound gained 1.0 wt% in moisture absorption, indicating that the crystalline compound has slight hygroscopicity. XRPD results (Figure 10) showed that the solid crystalline compound remained essentially the same before and after DVS.

[0085] Physicochemical stability tests showed that the crystalline compound exhibited relatively good physicochemical stability at 25℃ / 60%RH and 40℃ / 75%RH, with purity fluctuating between 99.9% and 100.1% after one week of storage. After 36 hours of storage at 80℃, the purity was 99.0% of its initial value, indicating slight degradation. Dynamic moisture adsorption (DVS) tests showed that at a constant temperature of 25℃, the crystalline compound gained 1.0% weight due to moisture absorption when the humidity increased from 0%RH to 80%RH, indicating that the crystalline compound has slight hygroscopic properties.

[0086] Example 2: Preparation of capsule formulation containing thiophene pyrimidine derivatives

[0087] Based on the preliminary stability study results of the early formulation process, this invention selects direct powder mixing, manual capsule blister packs and semi-automatic capsule filling machine to fill capsules, and examines the density of the final mixture, angle of repose, capsule weight difference (different filling parameters), and content to confirm the feasibility of process scale-up.

[0088] 1. Scale-up formulation process for capsules containing thiophene pyrimidine derivatives

[0089] The API was pulverized and passed through an 80-mesh sieve. The acidifier and half of the filler were passed through a 60-mesh sieve and mixed at 100 revolutions. Then, the API, the binder passed through a 60-mesh sieve, and the other half of the filler were added and mixed at 100, 200, and 300 revolutions. 1000 capsules were prepared using a semi-automatic capsule blister pack. Specific formulation and preparation process information are shown in Table 1.

[0090] Table 1. Scale-up formulation process for capsules containing thiophene pyrimidine derivatives (1000 capsules)

[0091] The capsule formulation containing thiophene pyrimidine derivatives obtained from the scale-up production of this formulation process has passed the test. The IND (Investigational New Drug Application) batch preparation of the thiophene pyrimidine derivative capsule formulation will now begin.

[0092] 2. Batch preparation of IND (Investigational New Drug Application) for capsule formulations containing thiophene pyrimidine derivatives.

[0093] 2.1 Further scale-up production was carried out based on the formulation and process of the thiophene pyrimidine derivative capsule formulation of batch 1, and two sizes of capsules (10mg and 30mg) were filled using a semi-automatic capsule filling machine.

[0094] 2.2 Specific preparation process:

[0095] 2.2.1 API was pulverized through an 80-mesh sieve; acidifier was pulverized through a 60-mesh sieve.

[0096] 2.2.2 Pass half the amount of filler and the whole amount of acidifier together through a 60-mesh sieve as material B; weigh out the amount of API as material A; pass the other half of the amount of filler and binder together through a 60-mesh sieve as material C;

[0097] 2.2.3 Add the materials B, A, and C into a 5L conical mixing tank in that order, and mix at 10 rpm. After 30 minutes, use a sampler to measure the uniformity of the powder mixture (7 sampling points: 6 points on the upper hexagonal layer of powder and 1 point at the center of the powder, as shown in Figure 11) (humidity range: 65.5%-73.2%).

[0098] 2.2.4 After mixing, pour the powder out of the mixing bucket and put it into a PE plastic bag for capsule filling;

[0099] 2.2.5 After the uniformity of the mixed powder content is determined, capsules (4#, compression depth: 3+3; 0#, compression depth: 2mm) are filled (humidity range: 62.7%-71.8%).

[0100] 2.2.6 Add desiccant (4g desiccant per bottle), bottle (30mg specification: 15 tablets / bottle; 10mg specification: 30 tablets / bottle), and seal (humidity range: 51.3%-57.0%).

[0101] 2.3 Quality studies of two batches of production samples for each of the two specifications showed that: the content was between 90.0% and 110.0%, which met the requirements; related substances, single impurity: ≤0.2%, total impurities: ≤2.0%, which met the requirements; dissolution, in pH 4.0 medium, the dissolution rate should not be less than 70% of the labeled amount after 30 minutes, which met the requirements; moisture ≤2.0%, which met the requirements.

[0102] 2.4 The accelerated stability (40℃ / 75%RH, 6 months) and long-term stability (25℃ / 60%RH, 24 months) studies of two batches of production samples for each of the two specifications showed that: the content was between 90.0% and 110.0%, which met the requirements; related substances, single impurity: ≤0.2%, total impurities: ≤2.0%, which met the requirements; dissolution, the dissolution rate at 30 min should not be less than 70% of the labeled amount, which met the requirements; moisture ≤2.0%, which met the requirements.

[0103] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0104] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0105] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0106] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1 to 5” is disclosed, the described range should be interpreted as including ranges “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range. Moreover, the technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0107] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

Claims

1. A capsule formulation containing a thiophene pyrimidine derivative, characterized in that, The composition and content of the capsule formulation containing thiophene pyrimidine derivatives include: 8-9 parts by weight of thiophene pyrimidine derivatives, 58-60 parts by weight of filler, 25-30 parts by weight of acidifier, and 5-6 parts by weight of binder.

2. The capsule formulation containing thiophene pyrimidine derivatives as described in claim 1, characterized in that, The filler is selected from one or more of lactose monohydrate 316, mannitol, microcrystalline cellulose, and pregelatinized starch.

3. The capsule formulation containing thiophene pyrimidine derivatives as described in claim 1, characterized in that, The acidifying agent is selected from one or more of L-tartaric acid and L-lactic acid.

4. The capsule formulation containing thiophene pyrimidine derivatives as described in claim 1, characterized in that, The adhesive is selected from one or more of low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose E5, and povidone K30.

5. The capsule formulation containing thiophene pyrimidine derivatives as described in claim 1, characterized in that, The composition and content of the capsule formulation containing thiophene pyrimidine derivatives include: 8.77 parts by weight of thiophene pyrimidine derivatives, 59.65 parts by weight of mannitol, 26.32 parts by weight of L-tartaric acid, and 5.26 parts by weight of low-substituted hydroxypropyl cellulose.

6. A method for preparing a capsule formulation containing a thiophene pyrimidine derivative as described in claim 1, characterized in that, The preparation method includes the following steps: (1) Weigh the thiophene pyrimidine derivatives and excipients, fillers, acidifiers and binders as described above; (2) The thiophene pyrimidine derivative weighed in step (1) is pulverized and passed through a 60-80 mesh sieve; (3) Pass the acidifier and half of the filler as described above through a 60-80 mesh sieve together as material B; pass the API as material A; pass the binder and the remaining half of the filler as described above through a 60-80 mesh sieve together as material C; (4) Add the materials into the mixing container in the order of material B, material A and material C, and mix at 10-20 rpm for 30-50 min to prepare the mixed powder. (5) After the materials in step (4) are mixed, pour out the mixed powder obtained in step (4) from the mixing container and put it into the container to be filled into capsules. (6) After the uniformity of the mixed powder content in step (4) is determined, the mixed powder in step (5) that is placed in the container of the material to be filled is encapsulated to obtain a capsule sample. (7) The capsule sample obtained in step (6) is added with a desiccant, bottled, and sealed to prepare a thiophene pyrimidine derivative capsule formulation.

7. The preparation method according to claim 6, characterized in that, Step (4) further includes using a sampler to measure the uniformity of the mixed powder obtained in step (4).

8. The preparation method according to claim 6, characterized in that, In step (4), the humidity range of the mixture is 50%-80%; and / or, in step (6), the humidity range of the capsule filling is 50%-80%; and / or, in step (6), the capsules used for capsule filling include #0 and #4 capsules; and / or, in step (7), the desiccant is 2-4g per bottle; and / or, in step (7), the bottling specifications include 10mg and 30mg; and / or, in step (7), the humidity range of the sealing is 45%-60%.

9. The preparation method according to claim 8, characterized in that, In step (6), when using #4 capsules for filling, the compression depth is 3+3; when using #0 capsules for filling, the compression depth is 2mm.

10. A drug / drug composition, characterized in that, It includes capsule formulations containing thiophene pyrimidine derivatives as described in any one of claims 1-5.

11. The pharmaceutical / pharmaceutical composition according to claim 10, characterized in that, The drug / drug composition may be used alone and / or in combination with one or more drugs that regulate protein kinases involved in multiple disease states, antitumor drugs that inhibit one or more biological targets, chemotherapy drugs, radiotherapy, or immunotherapy drugs.

12. The use of the thiophene pyrimidine derivative capsule formulation as described in any one of claims 1-5, or the preparation method as described in any one of claims 6-9, or the drug / drug composition as described in claim 10 or 11 in the preparation of a medicament for treating a disease caused by abnormal cell proliferation due to overexpression of EGFR.

13. The capsule formulation containing a thiophene pyrimidine derivative, the preparation method, the pharmaceutical / pharmaceutical composition, and the application as described in any one of claims 1-12, characterized in that, The structural formula of the thiophene pyrimidine derivative is shown in formula (I). And / or, the thiophene pyrimidine derivative is a crystalline compound having one or more characteristics selected from the group consisting of: 1) The crystalline compound has a basic X-ray powder diffraction pattern as shown in Figure 2; 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 3; 3) The crystalline compound has a DSC spectrum as shown in Figure 4; 4) The crystalline compound has a TGA spectrum as shown in Figure 4; and / or, The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; it exhibits relatively good physicochemical stability at 25℃ / 60%RH and 40℃ / 75%RH; it has good thermal stability at 80℃; and it has low hygroscopicity at a constant temperature of 25℃ as humidity increases from 0%RH to 80%RH; and / or, The method for preparing the crystalline compound includes the following steps: using an amorphous thiophene pyrimidine derivative as the starting material, preparing a suspension in a solvent, stirring at 20-55°C for 1-5 days, and then separating the solid to obtain the crystalline compound; wherein, the solvent is selected from one or more of propanol, dichloromethane, and ethyl acetate, and the ratio of the thiophene pyrimidine derivative to the solvent is (15-100) mg: (0.5-2) mL.

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