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

Abstract

Provided is a capsule formulation containing the mesylate of a thienopyrimidine derivative, comprising: 75-80 parts by weight of the mesylate of the thienopyrimidine derivative, 15-20 parts by weight of a filler, 3-5 parts by weight of a disintegrant, and 1-2 parts by weight of a glidant. The capsule formulation is used for treating diseases caused by abnormal cell proliferation caused by EGFR overexpression.

Description

A capsule formulation containing thiophene pyrimidine derivative methanesulfonate, 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 derivative methanesulfonate, 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, SeminRespir 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] To address the shortcomings of existing technologies, this invention, as a novel thiophene pyrimidine derivative, aims to provide a thiophene pyrimidine derivative mesylate capsule formulation, its preparation method, and its applications. 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. Through research and development of thiophene pyrimidine derivatives protected by patents (US10829495B2 / CN108289895B), this invention has successfully screened and prepared the aforementioned thiophene pyrimidine derivative mesylate capsule formulation for the first time, and it has been successfully used in preclinical and clinical studies.

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

[0013] This invention provides a capsule formulation containing thiophene pyrimidine derivative mesylate, wherein the composition and content of the capsule formulation include: 75-80 parts by weight of thiophene pyrimidine derivative mesylate, 15-20 parts by weight of filler, 3-5 parts by weight of disintegrant, 1-2 parts by weight of gliding agent, 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 lactose monohydrate 316.

[0015] Specifically, the disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, sodium carboxymethyl starch, etc.; preferably, it is croscarmellose sodium.

[0016] Specifically, the flow aid is selected from one or more of colloidal silica, talc, etc., preferably colloidal silica.

[0017] Preferably, the composition and content of the capsule formulation include: 78.2 parts by weight of thiophene pyrimidine derivative methanesulfonate, 31616.8 parts by weight of filler lactose monohydrate, 4 parts by weight of disintegrant croscarmellose sodium, 1 part by weight of glidant colloidal silica, 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 mesylate capsule formulation as described above, the preparation method comprising the following steps:

[0020] (1) Weighing: Weigh the thiophene pyrimidine derivative methanesulfonate (API) and excipients such as fillers, disintegrants, and flow aids;

[0021] (2) Premixing: Mix the weighed API, gliding agent and disintegrant from step (1) and pass through a 40-60 mesh sieve; rinse the PE bag containing the raw material with filler and then pass through a 40-60 mesh sieve;

[0022] Preferably, the API, gliding agent and disintegrant weighed in step (1) are mixed and then passed through a 40-mesh sieve; the PE bag containing the raw material is rinsed with filler and then passed through a 40-mesh sieve.

[0023] (3) General mixing: Add the above sieved material into the hopper, with an estimated filling volume of 50-75% (calculated based on a loose density of 0.36 g / ml), a mixing speed of 10-20 rpm, and a mixing time of 10-30 min;

[0024] Preferably, the sieved material is added to the hopper, with an estimated filling volume of 75% (calculated based on a bulk density of 0.36 g / ml), a mixing speed of 20 rpm, and a mixing time of 10 min to obtain a mixed powder.

[0025] The step (3) further includes using a sampler to measure the uniformity of the mixed powder obtained in step (3); preferably, the sampling includes a total of 7 sampling points, as shown in Figure 9, of which 6 points are hexagonal on the upper layer of the powder and 1 point is at the center of the powder.

[0026] (4) Capsule filling: Capsules are filled to obtain capsule samples; preferably, capsule filling is performed using a capsule filling machine.

[0027] (5) Packaging: The capsule sample obtained in step (4) is inner packaged; preferably, the prepared sample is inner packaged in a high-density polyethylene bottle for oral solid pharmaceuticals, a desiccant is added and the bottle is sealed.

[0028] The present invention also provides a pharmaceutical / pharmaceutical composition comprising the capsule formulation described above.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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)).

[0034] 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.

[0035] 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.

[0036] 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.

[0037] 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 pharmaceutical / pharmaceutical composition of the present invention, as a regulator of apoptosis, can be used to treat a variety of human diseases associated with apoptosis abnormalities, including cancer (particularly, but not limited to, follicular lymphoma, cancer associated with p53 mutations, hormone-related tumors of the breast, prostate, and ovary, 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.

[0038] The drug / drug composition described in this invention may be included in a container, package, or dispenser along with instructions for administration.

[0039] The present invention also provides the use of the thiophene pyrimidine derivative mesylate 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.

[0040] As described above in the capsule formulation, preparation method, drug / drug composition, and application, the structural formula of the thiophene pyrimidine derivative mesylate is shown in formula (I).

[0041] And / or, the thiophene pyrimidine derivative methanesulfonate is a crystalline compound having one or more characteristics selected from the group consisting of:

[0042] 1) The crystalline compound has a basic X-ray powder diffraction pattern as shown in Figure 3;

[0043] 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 4;

[0044] 3) The crystalline compound has a basic DSC spectrum as shown in Figure 5;

[0045] 4) The crystalline compound has a TGA spectrum as shown in Figure 5;

[0046] 5) The crystalline compound has the basic characteristics shown in Figure 6. 1 HNMR spectrum;

[0047] 6) The crystalline compound has a DSC curve as shown in Figure 7 after heating to 150°C;

[0048] 7) The crystalline compound has essentially the XRPD overlay images before and after heating shown in Figure 8; and / or,

[0049] The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; its initial melting point is around 226°C; it exhibits good physical and chemical stability within 2 weeks under high temperature (60°C) and accelerated conditions (40°C / 75% RH); and / or,

[0050] The preparation method of the crystalline compound includes the following steps: placing a thiophene pyrimidine derivative methanesulfonate sample in a glass bottle, adding an appropriate amount of solvent, sonicating to promote dissolution, filtering through a 0.45-0.5 μm filter membrane into a new sample bottle, placing the sample bottle open in a fume hood, allowing the solvent to evaporate naturally at room temperature, and obtaining the sample after a large amount of solid has precipitated is the crystalline compound; wherein, the solvent includes one or more of dichloromethane, methanol, etc., and the ratio of the thiophene pyrimidine derivative methanesulfonate to the solvent is (80-100 mg): (6-70 ml).

[0051] The beneficial effects of this invention include: through the research and development of derivatives of patented thiophene pyrimidine derivatives, this invention has for the first time successfully screened and prepared a thiophene pyrimidine derivative mesylate capsule formulation, which has been successfully used in preclinical and clinical studies. Attached Figure Description

[0052] 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.

[0053] Figure 1 is a polarized light microscope image (×100) of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0054] Figure 2 is an XRPD diagram of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0055] Figure 3 is an XRPD diagram (with numbers) of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0056] Figure 4 is the XRPD peak finding report of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0057] Figure 5 is the DSC & TGA diagram of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention;

[0058] Figure 6 shows the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of this invention. 1 HNMR spectrum;

[0059] Figure 7 is a DSC image of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention after heating to 150°C;

[0060] Figure 8 is an XRPD overlay of the crystalline compound of the thiophene pyrimidine derivative methanesulfonate in Example 1 of the present invention before and after heating;

[0061] Figure 9 is a sampling point diagram of the mixing uniformity in Embodiment 2 of the present invention. Detailed Implementation

[0062] 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.

[0063] 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.

[0064] 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.

[0065] This invention discloses a capsule formulation containing a thiophene pyrimidine derivative mesylate, its preparation method, and its application. The composition and content of the capsule formulation include: 75-80 parts by weight of the thiophene pyrimidine derivative mesylate, 15-20 parts by weight of a filler, 3-5 parts by weight of a disintegrant, and 1-2 parts by weight of a gliding agent. 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.

[0066] Unless otherwise specified, the experimental materials used in the examples are all conventional biochemical reagents.

[0067] Example 1: Preparation of crystalline compounds of thiophene pyrimidine derivative methanesulfonate

[0068] In this invention, three portions of thiophene pyrimidine derivative methanesulfonate sample (yellow powder), approximately 80 mg / portion, were weighed and placed in a glass bottle. An appropriate amount of the solvent corresponding to that in Table 1 was added, and the sample was sonicated to dissolve it. The solution was then filtered through a 0.45 μm filter membrane into a new sample bottle. The sample bottle was placed open in a fume hood, and the solvent was allowed to evaporate naturally at room temperature (19.6℃~23.0℃). After a large amount of solid precipitated, the sample was characterized by XRPD.

[0069] The crystalline compounds of the thiophene pyrimidine derivative methanesulfonate prepared in this invention were analyzed using the following methods:

[0070] 1. Polarizing microscopy observation (PLM)

[0071] Take a small amount of sample, place it on a graduated glass slide, add an appropriate amount of liquid paraffin to disperse it, cover it with a coverslip, and observe the particle shape, size and crystal properties under a 10x objective lens of a microscope. Use an orthogonal polarizer to display the birefringence properties and crystal habit of the sample, and take a picture with a digital camera.

[0072] 2. Powder X-ray diffraction analysis (XRPD)

[0073] 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.

[0074] 3. Differential Scanning Calorimetry (DSC)

[0075] 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.

[0076] 4. Thermogravimetric analysis (TGA)

[0077] 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.

[0078] 5. One-dimensional proton NMR spectrum (NMR) 1 H NMR)

[0079] Weigh approximately 5 mg of sample into an NMR tube, add 0.6 mL of deuterated dimethyl sulfoxide (DMSO d6) to dissolve the sample into a clear solution, and scan the sample solution using a Bruker Advance III 400 MHz NMR spectrometer according to the general method to acquire sample data.

[0080] The experimental results show that the sample obtained in the dichloromethane and methanol system is a crystalline compound of thiophene pyrimidine derivative methanesulfonate. The experimental results are summarized in Table 1. The PLM (polarizing light microscopy), DSC, TGA, XRPD and NMR characterization results of the crystalline compound are shown in Figures 1 to 6.

[0081] The aforementioned crystalline compound exhibits significant birefringence under polarized light microscopy, displaying granular crystallites with a particle size range of 0–30 μm. X-ray powder diffraction analysis shows that the sample possesses multiple distinct characteristic diffraction peaks, confirming its crystalline nature. DSC & TGA curves of the crystalline compound indicate an initial melting point of 226.05 °C. The DSC heat flow curve shows two endothermic peaks before 150 °C, corresponding to a 1.815% weight loss on the TGA curve. 1 Based on the H NMR results, it is speculated that the endothermic peak and weight loss are caused by the volatilization of a small amount of residual acetone solvent in the sample.

[0082] After heating the above crystalline compound to 150°C using TGA, the two endothermic peaks before 150°C disappeared, indicating that the residual acetone solvent had been removed (Figure 7). Furthermore, the crystal form of the compound remained unchanged after heating (Figure 8), indicating that acetone was only a small amount of solvent adsorbed on the surface and did not enter the crystal lattice. Based on the combined results of DSC, TGA, and heating experiments, the crystalline compound is an anhydrous and solvent-free crystalline form (anhydrate).

[0083] According to salt type screening studies, the crystalline compound of the thiophene pyrimidine derivative methanesulfonate is a single anhydrous crystal with characteristic XRPD diffraction peaks; the initial melting point is around 226℃; and it exhibits good physical and chemical stability within 2 weeks under high temperature (60℃) and accelerated conditions (40℃ / 75%RH).

[0084] Table 1 Summary of experimental results using the solution evaporation method

[0085] Example 2: Direct Mixing and Filling Capsule Formulation

[0086] This invention attempts to use a direct-mixing and capsule filling process to investigate the changes in impurities after direct-mixing powder is filled into capsule formulations.

[0087] 1. Prescription Information

[0088] See Table 2 for prescription information.

[0089] Table 2. Formulations for direct-mix filling capsules

[0090] 2. Preparation process

[0091] The formulations of the thiophene pyrimidine derivative mesylate capsules of the present invention, batch 1 and batch 2, have the same formulation ratio and share the same batch of intermediate powder. The thiophene pyrimidine derivative mesylate capsules are filled with 300mg and 420mg of thiophene pyrimidine derivative mesylate capsules respectively using 0# HPMC.

[0092] 2.1 Preparation of intermediate powder mixing

[0093] Weigh the API and excipients according to the prescription in Table 2, pass them through a 40-mesh sieve, and mix them at 100 revolutions per minute.

[0094] Intermediate powder mixing

[0095] Loose density: 0.3690 g / ml, tapped density: 0.4258 g / ml;

[0096] Angle of repose: 39.1°, Moisture content: 0.86%.

[0097] When API (DCG038-21002) of batch number submitted is mixed with 316 spray-dried lactose (lactose monohydrate) with excellent flowability at a formulation ratio of 78.2%, the mixed powder can achieve good flowability for API batch number DCG038-21002, which can meet the process requirements for material flowability.

[0098] 2.2 Capsule disintegration

[0099] The capsule breakage and disintegration times of the samples both met the requirements of the 2020 edition of the Chinese Pharmacopoeia, which stipulates that hard capsules should completely disintegrate within 30 minutes. Disintegration tests were conducted according to the methods provided in the 2020 edition of the Chinese Pharmacopoeia. After the capsule shell dissolved and broke, the contents diffused out of the shell with the medium. Both the capsule breakage time and disintegration time were within the normal range, and no clumping of the contents was observed.

[0100] 3. Related substances: Single impurity: ≤0.2%, total impurities: ≤2.0%, meets the requirements.

[0101] 4. Using a direct mixing and filling process, 100mg and 200mg capsules containing thiophene pyrimidine derivative mesylate were trial-produced.

[0102] 4.1 Prescription Optimization—Prescription Information:

[0103] The prescription information for prescription optimization is detailed in Table 3.

[0104] Table 3 Prescription information for prescription optimization

[0105] 4.2 Preparation process

[0106] Weigh the materials and pass them through a 40-mesh sieve. Mix them manually in a stainless steel bucket at 100 revolutions per minute. Mix the intermediate powders. Manually fill the capsules using 10*10 capsule blister packs (200mg: No. 0 capsule blister pack; 100mg: No. 3 capsule blister pack & or No. 2 capsule blister pack).

[0107] 4.3 Characteristics of intermediate mixed powder

[0108] The specific characteristics of the intermediate mixed powder are shown in Table 4.

[0109] Table 4. Characteristics of intermediate mixed powders

[0110] Conclusion: The intermediate powder mixtures all exhibited good flowability, with formulations F3, F4, and F5 showing worse flowability than F1 and F2. Based on the powder science data (flowability and angle of repose) obtained during the optimization process of formulations F1-F5, formulations F1 and F2 can be determined as optimal formulations. Given the stability test results previously conducted on formulation F1 (accelerated stability test for 1 month, total impurities and individual impurities all met requirements), F1 is determined to be the optimal formulation.

[0111] 4.4 Key points of the preparation process: The key points of the direct mixing and filling capsule process are detailed in Table 5.

[0112] Table 5 Key Points of Direct Mixing Capsule Filling Process

[0113] Table 4 shows the two single-filling parameters for the two specifications.

[0114] 5. Prepare two batches of capsules in 100mg and 200mg strengths, with each batch consisting of 2000 capsules / batch. The formulations and processes for the 100mg and 200mg capsules containing thiophene pyrimidine derivative mesylate are shown in Table 6.

[0115] Table 6. Formulations and manufacturing processes for 100mg and 200mg mesylate capsules containing thiophene pyrimidine derivatives.

[0116] 6. Disintegration Test: The shell breakage time and disintegration time of the samples both met the requirement of the 2020 edition of the Chinese Pharmacopoeia that hard capsules should completely disintegrate within 30 minutes. The disintegration test was conducted according to the method provided in the 2020 edition of the Chinese Pharmacopoeia. After the capsule shell dissolved and broke, the contents diffused out of the shell with the medium. The capsule breakage time and dissolution time were both within the normal range, and no clumping of the contents was observed.

[0117] 7. Intermediate test results: content 100.3%, RSD 0.3%, results are qualified.

[0118] 8. Finished product test results: The content is between 90.0% and 110.0%, which meets the requirements; related substances, single impurity: ≤0.2%, total impurities: ≤2.0%, which meets 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 meets the requirements; moisture ≤2.0%, which meets the requirements.

[0119] 9. Stability Results: Accelerated stability (40℃ / 75%RH, 6 months) and long-term stability (25℃ / 60%RH, 12 months) studies of the two specifications of production samples 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.

[0120] 10. Based on the preparation of the 100mg and 200mg mesylate capsule formulations containing thiophene pyrimidine derivatives in step 5 of Example 2 of the present invention, a 120mg mesylate capsule formulation containing thiophene pyrimidine derivatives was prepared using the same formulation and process, with a batch size of 5000 capsules / batch. The formulation and process of the 120mg mesylate capsule formulation containing thiophene pyrimidine derivatives are shown in Table 6.

[0121] Table 6. Formulation and manufacturing process of 120mg mesylate capsules containing thiophene pyrimidine derivatives.

[0122] 11. Disintegration Test: The shell breakage time and disintegration time of the samples both met the requirement of the 2020 edition of the Chinese Pharmacopoeia that hard capsules should completely disintegrate within 30 minutes. The disintegration test was conducted according to the method provided in the 2020 edition of the Chinese Pharmacopoeia. After the capsule shell dissolved and broke, the contents diffused out of the shell with the medium. The capsule breakage time and dissolution time were both within the normal range, and no clumping of the contents was observed.

[0123] 12. Finished product test results: The content is between 90.0% and 110.0%, which meets the requirements; related substances, single impurity: ≤0.2%, total impurities: ≤2.0%, which meets the requirements; dissolution, the dissolution rate at 30 min should not be less than 70% of the labeled amount, which meets the requirements; moisture ≤2.0%, which meets the requirements.

[0124] 13. Stability Results: The accelerated stability study (40℃ / 75%RH, 2 months) of the production samples 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.

[0125] 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.

[0126] 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.

[0127] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0128] 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.

[0129] 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 thiophene pyrimidine derivative mesylate, characterized in that, The composition and content of the thiophene pyrimidine derivative methanesulfonate capsule formulation include: 75-80 parts by weight of thiophene pyrimidine derivative methanesulfonate, 15-20 parts by weight of filler, 3-5 parts by weight of disintegrant, and 1-2 parts by weight of gliding agent.

2. The mesylate capsule formulation containing thiophene pyrimidine derivative 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; and / or the disintegrant is selected from one or more of croscarmellose sodium, croscarmellose, and carboxymethyl starch sodium.

3. The mesylate capsule formulation containing thiophene pyrimidine derivative as described in claim 1, characterized in that, The flow aid is selected from one or more of colloidal silica and talc.

4. The mesylate capsule formulation containing thiophene pyrimidine derivative as described in claim 1, characterized in that, The composition and content of the thiophene pyrimidine derivative methanesulfonate capsule formulation include: 78.2 parts by weight of thiophene pyrimidine derivative methanesulfonate, 31616.8 parts by weight of lactose monohydrate, 4 parts by weight of croscarmellose sodium, and 1 part by weight of colloidal silica.

5. A method for preparing a mesylate capsule formulation containing a thiophene pyrimidine derivative as described in claim 1, characterized in that, The preparation method includes the following steps: (1) Weighing: Weigh the thiophene pyrimidine derivative methanesulfonate and excipients such as fillers, disintegrants and flow aids; (2) Premixing: The thiophene pyrimidine derivative mesylate, flow aid and disintegrant weighed in step (1) are mixed and passed through a 40-60 mesh sieve; the PE bag containing the raw material is rinsed with filler and then passed through a 40-60 mesh sieve. (3) Total mixing: Add the above sieved material into the hopper, calculate the expected filling volume based on a bulk density of 0.36 g / ml to 50-75%, mix at a speed of 10-20 rpm and a mixing time of 10-30 min to obtain mixed powder; (4) Capsule filling: Capsules are filled to obtain capsule samples; (5) Packaging: The capsule sample obtained in step (4) is inner packaged.

6. The preparation method according to claim 5, characterized in that, The step (3) further includes using a sampler to measure the uniformity of the mixed powder obtained in step (3).

7. A drug / drug composition, characterized in that, It includes mesylate capsule formulations containing thiophene pyrimidine derivatives as described in any one of claims 1-4.

8. The pharmaceutical / pharmaceutical composition according to claim 7, 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.

9. The use of the thiophene pyrimidine derivative mesylate capsule formulation as described in any one of claims 1-4, or the preparation method as described in claim 5 or 6, or the drug / drug composition as described in claim 7 or 8 in the preparation of a medicament for treating a disease caused by abnormal cell proliferation due to overexpression of EGFR.

10. The thiophene pyrimidine derivative mesylate capsule formulation, preparation method, pharmaceutical / pharmaceutical composition, and application as described in any one of claims 1-9, characterized in that, The structural formula of the thiophene pyrimidine derivative methanesulfonate is shown in formula (I). And / or, the thiophene pyrimidine derivative methanesulfonate 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 3; 2) The crystalline compound has a basic XRPD peak finding report as shown in Figure 4; 3) The crystalline compound has a basic DSC spectrum as shown in Figure 5; 4) The crystalline compound has a TGA spectrum as shown in Figure 5; 5) The crystalline compound has the basic characteristics shown in Figure 6. 1 H NMR spectrum; 6) The crystalline compound has a DSC curve as shown in Figure 7 after heating to 150°C; 7) The crystalline compound has essentially the XRPD overlay images before and after heating shown in Figure 8; and / or, The crystalline compound is an anhydrous crystal with a single melting point and characteristic XRPD diffraction peaks; the initial melting point is around 226°C; and it exhibits good physical and chemical stability within 2 weeks under high temperature (60°C) and accelerated conditions (40°C / 75% RH). And / or, The preparation method of the crystalline compound includes the following steps: placing a thiophene pyrimidine derivative methanesulfonate sample in a glass bottle, adding an appropriate amount of solvent, sonicating to promote dissolution, filtering through a 0.45-0.5 μm filter membrane into a new sample bottle, placing the sample bottle open in a fume hood, allowing the solvent to evaporate naturally at room temperature, and obtaining the sample after a large amount of solid has precipitated is the crystalline compound; wherein, the solvent includes one or more of dichloromethane and methanol, and the ratio of the thiophene pyrimidine derivative methanesulfonate to the solvent is (80-100 mg): (6-70 ml).

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