A compound preparation of Senaparib and temozolomide and its preparation method

Abstract

This invention provides a compound preparation of senaparib and temozolomide and a method for preparing the same. The compound preparation of this invention contains an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is senaparib and temozolomide, and the content of senaparib is 2.0%–15.0% and the content of temozolomide is 1.0%–10.0% by weight of the total compound preparation. The compound preparation prepared using the method of this invention exhibits good dissolution, content uniformity, and stability for both drugs.

Description

Technical Field

[0001] This invention relates to a compound preparation of senaparib and temozolomide and its preparation method. Background Technology

[0002] Poly(ADP-ribose) polymerase (PARP) catalyzes the addition of poly(ADP-ribose) to target protein molecules from NAD+, a crucial component of DNA repair. This process is essential for maintaining the integrity and stability of DNA and chromosomes, and is vital for the survival of mammalian cells. The vast majority of intracellular ADP-ribose polymerization activity is catalyzed by PARP-1. Several PARP inhibitors, including olaparib, have been approved for the treatment of BRCA-mutated ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer.

[0003] The use of PARP inhibitors to treat cancer is primarily based on two mechanisms. First, PARP inhibitors can act independently as anticancer drugs against cancer cells with DNA repair defects, directly killing these cells (synthetic lethality), such as triple-negative breast cancer cells lacking BRCA1 or BRCA2. Second, due to the rapid growth of cancer cells, their DNA replication is far greater than that of normal cells; therefore, DNA-damaging drugs can selectively cause the death of cancer cells. However, due to the presence of DNA repair enzymes such as PARP, the efficacy of these drugs cannot be fully realized.

[0004] When PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapy drugs, they can produce a synergistic effect by inhibiting DNA repair, thereby greatly enhancing the efficacy of DNA-damaging chemotherapy drugs.

[0005] Temozolomide (TMZ), chemically named 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetraazine-8-carboxamide, is a novel oral alkylating agent antitumor drug with broad-spectrum antitumor activity. It can cross the blood-brain barrier, has near 100% oral bioavailability, and is effective in treating newly diagnosed and recurrent glioblastomas and anaplastic astrocytomas, prolonging patient survival. It also exhibits good safety and tolerability. As a prodrug, temozolomide does not exert its effect directly after oral administration. At physiological pH, it is rapidly converted to the active compound MTIC (5-(3-methyltriazene-1-)imidazol-4-amide) via a non-enzymatic pathway.

[0006] The combination of PARP inhibitors and TMZ offers clinical advantages in synergistic efficacy and reduced toxicity. Traditionally, combination therapy involves administering each drug individually, resulting in multiple doses for patients, a heavy burden, and poor compliance. Furthermore, physicians need to prescribe medications based on the patient's required dosage. If multiple manufacturers offer individual drugs, the controllability of medication use is poor. Therefore, the development of fixed-formulation combination drugs is essential to improve medication safety and compliance. The development of multi-strength combination formulations also facilitates physician prescribing and improves storage and transportation management.

[0007] While Senaparib solid dispersions offer high solubility and oral bioavailability, their hygroscopicity can lead to aggregation and clumping, posing significant challenges to ensuring uniform mixing and content of this component in compound formulations. Furthermore, temozolomide, another key component in compound formulations, is present in small amounts and is prone to hydrolysis under neutral and alkaline conditions, potentially causing issues with mixing uniformity, content uniformity, and stability. Therefore, there remains a need in the art for formulations and manufacturing processes that address these challenges, meet the requirements of pharmaceutical production, and produce formulations with appropriate dissolution rates, excellent storage stability, and reasonable production costs. Summary of the Invention

[0008] The first aspect of the present invention provides a compound preparation containing an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is senaparib and temozolomide, wherein, based on the total weight of the compound preparation, the content of senaparib is 2.0% to 15.0% and the content of temozolomide is 1.0% to 10.0%.

[0009] A second aspect of the present invention provides a method for preparing a compound preparation according to any embodiment of the present invention, the method comprising: providing a first mixture containing temozolomide and a portion of excipients; mixing senaparib and the remaining excipients with the first mixture; and finally mixing the resulting mixture with all the lubricant; or first mixing senaparib and all the remaining excipients to prepare a second mixture, and then mixing the first mixture and the second mixture to prepare a final mixture.

[0010] A third aspect of the present invention provides a medicine box containing the compound preparation described in any embodiment of the present invention.

[0011] The fourth aspect of the present invention provides the use of the compound preparation described in any embodiment of the present invention in the preparation of a medicament for treating cancer.

[0012] The fifth aspect of the present invention provides a method for treating cancer, the method comprising administering to a desired subject a therapeutically effective amount of the compound preparation described in any embodiment of the present invention; wherein the therapeutically effective amount is a daily dose of 20-100 mg of senaparib, preferably a daily dose of 20-80 mg; and a daily dose of 5-30 mg of temozolomide, preferably a daily dose of 10-20 mg.

[0013] The detailed description of various aspects of the present invention is as follows. Detailed Implementation

[0014] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as embodiments) can be combined with each other to form preferred technical solutions.

[0015] Unless otherwise defined, the technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0016] The terms “comprising,” “including,” or grammatical variations thereof, as used in this invention, mean that the compositions and methods, etc., include the listed elements and do not exclude others.

[0017] Unless explicitly indicated to the contrary, all ranges referenced herein are inclusive; that is, the range includes the upper and lower limits of the range as well as all values ​​in between. For example, temperature ranges, percentages, equivalent ranges, etc., described herein include the upper and lower limits of the range as well as any values ​​in a continuous interval between them. Furthermore, it should be understood that the sum of the weight percentages of all components in the pharmaceutical compositions of the present invention shall equal 100%.

[0018] The compositions described in this invention comprise a mixture of active ingredients and other chemical components.

[0019] In this invention, "optionally" and "optionally" mean that they can be selected or not selected, such as optional filler means containing filler or not containing filler.

[0020] When PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapeutic drugs, because PARP inhibitors act as sensitizers for these drugs, a high-dose combination of the chemotherapeutic drug and a low-dose PARP inhibitor is generally used. In clinical trials, this combination of high-dose chemotherapeutic drugs and low-dose PARP inhibitors is also common. For example, in a phase I clinical trial of olaparib combined with TMZ for the treatment of brain tumors, the determined phase II clinical dose (RP2D) was olaparib 150 mg and TMZ 75 mg / m². 2 (Based on the body surface area of ​​a 60kg adult being 1.62m²) 2The converted dose is 121.5 mg once daily (Catherine Hanna et al. 2020, Neuro Oncol. 1-11). The existing temozolomide drug, when used in combination with radiotherapy for the treatment of newly diagnosed glioblastoma multiforme, is at a daily dose of 75 mg / m². 2 (equivalent to 121.5 mg), and when used as adjunctive monotherapy, the daily dose is 150 mg / m². 2 (Equivalent to 243mg) similar.

[0021] This invention discovers that the application of non-toxic, low-dose alkylating anticancer drugs (such as TMZ) to induce DNA damage, combined with an effective dose of a PARP inhibitor with a trapping function (such as 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazin-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, senaparib), can induce synthetic lethality, resulting in a low-toxicity, high-efficiency anticancer drug.

[0022] Therefore, the present invention provides an antitumor compound preparation containing an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient is senaparib and temozolomide; wherein, based on the total weight of the compound preparation, the content of senaparib is 2.0% to 15.0%, and the content of temozolomide is 1.0% to 10.0%. In some embodiments, the content of senaparib is 2.0% to 10.0% based on the total weight of the compound preparation. In some embodiments, the content of senaparib is 4.0% to 10.0% based on the total weight of the compound preparation. In some embodiments, the content of temozolomide is 2.0% to 8.0% based on the total weight of the compound preparation.

[0023] In some embodiments, the ratio of senaparib content to temozolomide content in the compound preparation of the present invention is 1 to 8. In some embodiments, the ratio of senaparib content to temozolomide content in the compound preparation of the present invention is 2 to 4. In some embodiments, the amount of temozolomide contained in the compound preparation satisfies the following condition: when one or more doses of the compound preparation are administered to meet the daily dosage, the amount of temozolomide ingested by an individual is about 1 / 12 to about 1 / 5 of the known daily dose of temozolomide used alone or in combination with other drugs. Further, when one or more doses of the compound preparation are administered, the daily dose of temozolomide ingested by an individual is about 5 mg to about 40 mg; in some embodiments, the daily dose of temozolomide ingested by an individual is about 5 mg to about 30 mg; in some embodiments, the daily dose of temozolomide ingested by an individual is about 10 mg to about 20 mg. In some implementations, a single dose of the compound preparation containing senaparib and temozolomide may be sufficient to meet the daily dosage requirements.

[0024] In some embodiments, each dose of the compound formulation contains 10 mg to 80 mg of senaparib. In some embodiments, each dose of the compound formulation contains 20 mg to 40 mg of senaparib.

[0025] In some embodiments, the compound preparation of the present invention contains 4.0% to 10.0% senaparib and 2.0% to 8.0% temozolomide by total weight, and each dose of the compound preparation contains 5 mg to 30 mg of temozolomide. In some embodiments, each dose of the compound preparation contains 10 mg to 80 mg of senaparib. In some embodiments, each dose of the compound preparation contains 10 mg to 40 mg of senaparib.

[0026] In some embodiments, less than 5 wt%, more preferably less than 1 wt%, of the senaparib contained in the compound preparation of the present invention is in crystalline form.

[0027] Pharmaceutically acceptable excipients as described herein include one or more of the following: carriers, fillers, disintegrants, glidants, lubricants, binders, solubilizers, surfactants, and pH adjusters.

[0028] In this document, the carrier is a commonly used carrier for preparing solid dispersions of active pharmaceutical ingredients, including succinic hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose phthalate, and optional surfactants, preferably hydroxypropyl methylcellulose phthalate. In this document, the carrier conforms to the pharmacopoeias of various countries. On a dried basis, the exemplary hydroxypropyl methylcellulose phthalate contains 12.0%–28.0% methoxy groups, 4.0%–23.0% 2-hydroxypropoxy groups, 2.0%–16.0% acetyl groups, and 4.0%–28.0% succinyl groups. The exemplary hydroxypropyl methylcellulose phthalate is HP-55.

[0029] In the compound formulations described herein, the weight ratio of senaparib to the carrier can be from 1:2 to 1:3. In some embodiments, the content of hydroxypropyl methylcellulose phthalate is 7% to 30%, more preferably 13% to 20%, based on the total weight of the compound formulation.

[0030] In some embodiments, the compound formulations described herein contain a surfactant. Exemplary surfactants include poloxamer. When contained, the surfactant content is 0.5% to 2.2% of the total weight of the compound formulation, preferably 0.9% to 1.5%.

[0031] In some embodiments, the compound formulation described herein contains a solid dispersion of senaparib, which contains senaparib, the hydroxypropyl methylcellulose phthalate described herein, and optionally a surfactant. Preferably, the weight ratio of senaparib to hydroxypropyl methylcellulose phthalate is 1:2 to 1:3. In some embodiments, the solid dispersion described herein is the solid dispersion disclosed in PCT / CN2016 / 078262, the entire contents of which are incorporated herein by reference. Preferably, in the solid dispersion, hydroxypropyl methylcellulose phthalate accounts for 65% to 77% of the total weight of the solid dispersion, more preferably 73% to 77%; and senaparib accounts for 23% to 35% of the total weight of the solid dispersion. In a preferred embodiment, the solid dispersion consists of senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 to 1:3. In some embodiments, the solid dispersion comprises senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 or 1:3. In other embodiments, the solid dispersion further contains the surfactant. Preferably, the surfactant content is 2-5% by weight of the total solid dispersion. In some embodiments, the solid dispersion comprises senaparib, hydroxypropyl methylcellulose phthalate, and poloxamer in a weight ratio of 1:2.8:0.2. Preferably, less than 10 wt%, more preferably less than 5 wt%, more preferably less than 1 wt% of the senaparib in the solid dispersion used in this application is in crystalline form, and most preferably, non-crystalline senaparib.

[0032] In some embodiments, the content of solid dispersion in the compound preparation is 8% to 60% based on the total weight of the compound preparation. In some embodiments, the content of solid dispersion is 8% to 40% based on the total weight of the compound preparation. In some embodiments, the content of solid dispersion is 15% to 40% based on the total weight of the compound preparation.

[0033] In this document, the filler may be selected from one or more of starch, pregelatinized starch, mannitol, lactose, sucrose, cyclodextrin, and microcrystalline cellulose. In some embodiments, the filler used in the compound formulation described herein is one or more of microcrystalline cellulose, mannitol, and lactose. In this document, the filler content may be 20% to 85% based on the total weight of the compound formulation. In some embodiments, the filler content is 56% to 85% based on the total weight of the compound formulation. In some embodiments, the filler content is 70% to 82% based on the total weight of the compound formulation. In some embodiments, the filler content is 75% to 82% based on the total weight of the compound formulation.

[0034] Preferably, the filler comprises microcrystalline cellulose. Preferably, the D90 of the microcrystalline cellulose is 170–480 μm. In some embodiments, the D90 of the microcrystalline cellulose is 170–283 μm. In other embodiments, the D90 of the microcrystalline cellulose is 275–480 μm. The D90 is determined using a Malvern Mastersizer 2000 laser particle size analyzer, according to the particle size and particle size distribution determination method, with a refractive index of 1.45 for the test sample.

[0035] Preferably, the content of microcrystalline cellulose is 8% to 50% based on the total weight of the compound preparation. In some embodiments, the content of microcrystalline cellulose is 10% to 28% based on the total weight of the pharmaceutical composition, preferably 15% to 20%.

[0036] Preferably, the filler further includes mannitol. Preferably, the mannitol has a particle size distribution of at least 70% particles > 75 μm, more preferably at least 80%. In a particularly preferred embodiment, the mannitol has a particle size distribution of at least 90% particles > 75 μm. The particle size distribution is determined using a laser particle size analyzer for dry analysis; wherein the vibration feed rate is 15%–30%, the Auger speed is 30%–45%, and the shading range is 4%–12%.

[0037] Preferably, the mannitol content is 20% to 70% based on the total weight of the compound preparation. In some embodiments, the mannitol content is 50% to 65% based on the total weight of the pharmaceutical composition, preferably 55% to 65%.

[0038] In a preferred embodiment, the filler in the compound formulation of the present invention is microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and the mannitol has a particle size distribution of not less than 70%, preferably not less than 80%, and more preferably not less than 90% for particles >75 μm. Preferably, based on the total weight of the compound formulation, the content of microcrystalline cellulose is 8%-50%, preferably 10%-28%, and more preferably 15%-20%; the content of mannitol is 20%-70%, preferably 50%-65%, and more preferably 55%-65%.

[0039] Preferably, in the compound preparation of the present invention, the amount of mannitol is 0.5 to 8 times, such as 0.5 to 1 times, or 2 to 8 times, the amount of microcrystalline cellulose (by weight).

[0040] In this document, the disintegrant may be selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, pregelatinized starch, sodium alginate, and any combination thereof. In some embodiments, the disintegrant is crospovidone, sodium carboxymethyl starch, or a mixture thereof. Typically, the content of the disintegrant is 0.1% to 10% by weight of the compound preparation, preferably 0.5% to 4%. In a preferred embodiment, the disintegrant is crospovidone and / or sodium carboxymethyl starch, and the total content of crospovidone and / or sodium carboxymethyl starch by weight of the compound preparation is 0.5% to 4%. In some embodiments, the particle size control range of crospovidone is D90: 270 to 385 μm.

[0041] In this document, the flow aid may be selected from powdered cellulose, magnesium trisilicate, colloidal silica, talc, and any combination thereof. Colloidal silica is a preferred flow aid. The content of the flow aid, based on the total weight of the compound preparation, may be 0.1% to 10%, preferably 0.5% to 3%, and more preferably 1% to 3%.

[0042] In this document, the lubricant may be selected from zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, sodium fumarate stearate, and any combination thereof. Magnesium stearate is a preferred lubricant. The lubricant content, based on the total weight of the compound preparation, may be 0.1% to 3%, preferably 0.3% to 1%, such as 0.5 ± 0.1%.

[0043] In this document, the pH adjuster is an acidic pH adjuster, which may be selected from one or more of citric acid, tartaric acid, sorbic acid, malic acid, lactic acid, fumaric acid, and adipic acid; the preferred pH adjuster is tartaric acid. The content of the acidic pH adjuster is 0.1% to 5% based on the total weight of the compound preparation, preferably 0.1% to 3%.

[0044] In some embodiments, the compound formulation described herein may also contain a binder. The binder may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, povidone, and any combination thereof. Hydroxypropyl cellulose is a preferred binder. In some embodiments, the binder content is 0.1% to 5%, preferably 0.1% to 3%.

[0045] In some embodiments, the compound formulations described herein may also contain surfactants and / or coating materials. The surfactants may be selected from one or more of sodium dodecyl sulfate, poloxamer, taurine, lauroyl polyoxyethylene (6, 8, 12, 32) glycerides, and polysorbates. The coating materials may be selected from the Opadry full-formulation film coating system.

[0046] It should be understood that the various excipients contained in the pharmaceutical composition, such as carriers, surfactants, fillers, disintegrants, flow aids, lubricants, binders, pH adjusters and coating materials, are all pharmaceutically acceptable carriers commonly used in the field and comply with the requirements of pharmacopoeias of various countries.

[0047] In some embodiments, the compound formulation of the present invention, based on the total weight of the compound preparation, contains: senaparib, 2.0% to 15.0%, preferably 2.0% to 10.0%, more preferably 4.0% to 10.0%; temozolomide, 1.0% to 10.0%, preferably 2.0% to 8.0%; a carrier, 7% to 30%, preferably 13% to 20%; a filler, 56% to 85%, preferably 70% to 82%, more preferably 75% to 82%; and a disintegrant, 0.1% to 10%. % (preferably 0.5% to 4%); flow aid, 0.1% to 10%, preferably 0.5% to 3%, more preferably 1% to 3%; lubricant, 0.1% to 3%, preferably 0.3% to 1%; pH adjuster, 0.1% to 5%, preferably 0.1% to 3%; optional binder, 0.1% to 5%, preferably 0.1% to 3%; and optional surfactant, 0.5% to 2.2%; preferably, the carrier is hydroxypropyl methylcellulose phthalate, more preferably HP- 55; Preferably, the weight ratio of senaparib to the carrier is 1:2 to 1:3, such as 1:2 or 1:3; the filler is microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and the mannitol has a particle size distribution of >75 μm of not less than 70%, preferably not less than 80%, more preferably not less than 90%; preferably, the content of microcrystalline cellulose is 8%-50% based on the total weight of the compound preparation. Preferably, the content of mannitol is 10%–28%, more preferably 15%–20%; the content of mannitol is 20%–70%, preferably 50%–65%, more preferably 55%–65%; preferably, the disintegrant is crospovidone and / or sodium carboxymethyl starch, preferably, the particle size control range of crospovidone is D90: 270–385 μm; preferably, the flow aid is colloidal silica; preferably, the lubricant is magnesium stearate and / or stearic acid; preferably, the binder is hydroxypropyl cellulose.

[0048] In some embodiments, the compound formulation of the present invention, based on the total weight of the compound preparation, contains: a solid dispersion of senaparib, 8% to 60%; temozolomide, 1.0% to 10.0%, preferably 2.0% to 8.0%; a filler, 56% to 85%, preferably 70% to 82%, more preferably 75% to 82%; a disintegrant, 0.1% to 10%, preferably 0.5% to 4%; and a gliding agent, 0.1% to 10%, preferably 0.5% to 4%. 3%, more preferably 1% to 3%; lubricant, 0.1% to 3%, preferably 0.3% to 1%; pH adjuster, 0.1% to 5%, preferably 0.1% to 3%; and optionally binder, 0.1% to 5%, preferably 0.1% to 3%; preferably, the solid dispersion powder consists of senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 to 1:3, and less than 5 wt% of senaparib, more preferably... Preferably, less than 1 wt% is in crystalline form; preferably, the filler is microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170-480 μm, preferably 275-480 μm, and the mannitol has a particle size distribution of not less than 70%, preferably not less than 80%, and more preferably not less than 90% with a particle size >75 μm; preferably, based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8%-50%, preferably 10%-28%, and more preferably 15%-20%; the content of mannitol is 20%-70%, preferably 50%-65%, and more preferably 55%-65%; preferably, the disintegrant is crospovidone and / or sodium carboxymethyl starch, preferably, the particle size control range of crospovidone is D90: 270-385 μm; preferably, the flow aid is colloidal silica; preferably, the lubricant is magnesium stearate and / or stearic acid; preferably, the binder is hydroxypropyl cellulose.

[0049] In some embodiments, the compound preparation is an oral solid dosage form, preferably a tablet, capsule, or granule. In some embodiments, the compound preparation is a capsule, preferably, the capsule shell is selected from plant-based capsule shells and gelatin capsule shells, preferably gelatin capsule shells.

[0050] In some embodiments, the present invention provides a method for preparing a compound formulation of the present invention, the method comprising providing a mixture containing temozolomide and a portion of excipients, then mixing senaparib and the remaining excipients with the mixture to prepare a final mixture, and preparing the compound formulation, such as capsules or tablets, from the final mixture. In the case of mixing senaparib and the remaining excipients with the temozolomide-containing mixture, a lubricant may be added last (a portion of all the lubricant contained in the compound formulation may be included in the mixture containing temozolomide and a portion of the lubricant, or a portion of it may be mixed together with senaparib with the mixture containing temozolomide and a portion of the excipients, so that the last added lubricant is the remaining lubricant), and mixed again with the previously prepared mixture containing senaparib and temozolomide to obtain the final mixture.

[0051] Specifically, the method includes: mixing senaparib and the remaining excipients other than the lubricant with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant to prepare a final mixture; or mixing senaparib with a portion of the lubricant and a portion of the flow aid, as well as all the remaining excipients, with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant and flow aid to prepare a final mixture.

[0052] The first mixture may contain temozolomide, fillers, disintegrants, and pH adjusters, as well as optional flow aids, lubricants, and binders. It should be understood that the various excipients contained in the first mixture may be only a portion of, or all of, the corresponding excipients contained in the compound formulation. For example, the fillers in the first mixture may be one or two of the two or more fillers used in the compound formulation; for example, when mannitol and microcrystalline cellulose as described herein are used as fillers, the fillers contained in the first mixture may be all the microcrystalline cellulose contained in the compound formulation. Alternatively, the fillers in the first mixture may be a portion of each filler used in the compound formulation; for example, when mannitol and microcrystalline cellulose as described herein are used as fillers, the first mixture may contain 5–15 wt% or 8–12 wt% mannitol and 15–28 wt% or 20–24 wt% microcrystalline cellulose, where each weight percentage is based on the total weight of mannitol and microcrystalline cellulose used in the compound formulation. Similarly, when the first mixture contains a gliding agent, the gliding agent may be all of the gliding agents contained in the compound preparation, or a portion such as 1 to 5 wt% of the gliding agent; when the first mixture contains a lubricant, the lubricant may be all of the lubricant contained in the compound preparation, or a portion such as 2 to 10 wt% of the lubricant; when the first mixture contains a disintegrant, the disintegrant may be all of the disintegrant contained in the compound preparation, or a portion such as 15 to 25 wt% of the disintegrant.

[0053] In some embodiments, the first mixture is mixture a, which contains temozolomide, a pH adjuster (such as tartaric acid), 5-15 wt% or 8-12 wt% mannitol of the total weight of the compound preparation, 1-5 wt% flow aid (such as silica) of the total weight of the compound preparation, 2-10 wt% lubricant (such as stearic acid) of the lubricant contained in the compound preparation, 15-28 wt% or 20-24 wt% microcrystalline cellulose of the total weight of the compound preparation, a binder, and 15-25 wt% disintegrant (such as crospovidone) of the total weight of the disintegrant in the compound preparation.

[0054] In some embodiments, the first mixture is mixture b, which contains temozolomide, microcrystalline cellulose, a pH adjuster, and a disintegrant.

[0055] In some embodiments, the first mixture is mixture c, which contains temozolomide, microcrystalline cellulose, pH adjuster, disintegrant, and binder.

[0056] In some embodiments, the preparation of the first mixture includes adding the components of the first mixture to a mixer and mixing at a speed of 40 to 55 rpm. It should be understood that the mixing time can be determined based on the amount of material and the performance of the mixer, etc. An exemplary mixing time is 1 to 5 minutes.

[0057] In some embodiments, for mixture a, after mixing the first mixture, the mixture can be passed through a 20-mesh sieve, and then mixed at a speed of 40-55 rpm for a period of time, such as 5-15 minutes, and then dry granulated. The parameters for dry granulation can be set as follows: roller pressure 2-4 kN, roller speed 1-5 rpm, feed speed 25-35 rpm, and passing through a 24-mesh sieve.

[0058] In some embodiments, the second mixture contains the first mixture, senaparib, and the remaining materials other than the lubricant. In these embodiments, after the first mixture is prepared, all materials other than the lubricant (including senaparib) are mixed with the first mixture at a speed of 40-55 rpm for 1-5 minutes to obtain the second mixture. The second mixture is then passed through a 30-mesh sieve and mixed with the lubricant to obtain the final mixture, which can be formulated into capsules or tablets.

[0059] In some embodiments, the second mixture contains the first mixture, senaparib, 40-60 wt% of a flow aid as a percentage of the flow aid in the compound formulation, 55-75 wt% of a lubricant as a percentage of the lubricant in the compound formulation, and the remaining other materials. In these embodiments, after preparing the first mixture, senaparib, 40-60 wt% of a flow aid as a percentage of the flow aid in the compound formulation, 55-75 wt% of a lubricant as a percentage of the lubricant in the compound formulation, and the remaining other materials are mixed with the first mixture at a speed of 40-55 rpm for 1-5 minutes to obtain the second mixture. The second mixture is then passed through a 30-mesh sieve and mixed with the remaining flow aid and lubricant to obtain the final mixture, which can be formulated into tablets.

[0060] In this document, senaparib can be provided as a solid dispersion as described herein. Therefore, in some embodiments, the preparation method of the compound formulation of the present invention further includes a method for preparing the solid dispersion. An exemplary method for preparing the dispersion includes: dissolving senaparib and hydroxypropyl methylcellulose phthalate in a mixed solution of tetrahydrofuran and methanol (7:3, v / v), spray-drying the resulting solution, and collecting the spray-dried particles under vacuum to obtain the dispersion.

[0061] In some embodiments, mixtures containing senaparib typically contain a certain amount of filler and flow aid, optionally containing one or more of a disintegrant, binder, and lubricant. Mixtures containing temozolomide typically contain a certain amount of filler, pH adjuster, and disintegrant, optionally containing one or more of a binder, flow aid, and lubricant. There are no particular limitations on the content of each excipient in each mixture, as long as the active ingredient can be mixed evenly. The preparation method of the present invention is characterized by the gradual addition of excipients and an increase in the number of premixing times, thereby improving the mixing uniformity of temozolomide.

[0062] In some embodiments, the present invention provides a pillbox containing the compound preparation described in any of the embodiments herein. Preferably, the amount of the compound preparation contained in the pillbox is sufficient for a patient to take the medication for at least one day; wherein the daily dosage is: senaparib 20-100 mg, temozolomide 5-30 mg; more preferably, the daily dosage is: senaparib 20-80 mg, temozolomide 10-20 mg.

[0063] This invention also provides the use of the compound preparation described in any embodiment of this document in the preparation of a medicament for treating cancer; preferably, the cancer is selected from: liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, neuroblastoma, breast cancer, ovarian cancer, Wilms' tumor, cervical cancer, testicular cancer, soft tissue sarcoma, primary macroglobulinemia, bladder cancer, chronic myeloid leukemia, primary brain cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, colon cancer, malignant pancreatic islet tumor, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides. Head and neck cancer, osteosarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Kaposi's sarcoma, genitourinary tumors, thyroid cancer, esophageal cancer, malignant hypercalcemia, cervical hyperplasia, renal cell carcinoma, endometrial cancer, polycythemia vera, idiopathic thrombocythemia, adrenocortical carcinoma, skin cancer, and prostate cancer. A method for treating cancer is also provided, the method comprising administering a therapeutically effective amount of the compound preparation described in any embodiment of the present invention to the desired subject; wherein the therapeutically effective amount is a daily dose of senaparirib 20-100 mg and a daily dose of temozolomide 5-30 mg; preferably, the therapeutically effective amount is a daily dose of senaparirib 20-80 mg and a daily dose of temozolomide 10-20 mg.

[0064] The pharmaceutical preparations prepared according to this invention have the following advantages:

[0065] (1) The two active ingredients in the pharmaceutical composition of the present invention can produce a synergistic effect, which can simultaneously reduce the dosage of PARP inhibitor and temozolomide and improve the safety and tolerability of the drug.

[0066] (2) The present invention specifically develops formulations and processes, and adopts appropriate pharmaceutically acceptable excipients and processes to successfully combine senaparib and temozolomide in the same formulation unit to obtain oral solid compound preparations with good oral bioavailability, uniform content and good stability, thereby improving patient compliance and achieving large-scale production.

[0067] The present invention will be further explained below with reference to embodiments. It should be understood that the following embodiments are only used to explain the present invention and are not intended to limit the scope of the present invention in any way.

[0068] The following methods are used in the following embodiments:

[0069] Loose density / tapered density testing method: Take the sample to be tested, accurately weigh its mass M, slowly pour it into a glass graduated cylinder, carefully scrape the top level, avoiding compaction of powder, and record the apparent volume V0 at the nearest graduation line. Fix the cylinder to the density tester and tap it 10 times, 500 times, and 1250 times, recording the corresponding volume V. 10 V 500 V 1250 And accurate to the smallest scale. If V 500 With V 1250 If the difference is less than 2 mL, take V. 1250 As the vibratory volume; if V 500 With V 1250 If the difference is greater than 2 mL, increase the number of tapping cycles until the volume difference between two consecutive records is less than 2 mL. Loose density = m / V0; Tapped density = m / V n In the formula, V n The tapped volume is given by the Cartesian index, which is calculated as (tap density - loose density) / tap density * 100%.

[0070] Angle of repose detection method: The injection method is used, that is, the sample to be tested is poured into the funnel, and the sample falls freely from the funnel, forming a cone of height h on a disk of radius r, where tanA = h / r, and A is the angle of repose.

[0071] Moisture detection method: Weigh the sample to be tested, then heat it with an infrared radiator, continuously record the mass loss, and end the drying process when the specified requirements are met. The moisture content is automatically calculated by differential weight.

[0072] Other materials, reagents, and methods mentioned in the embodiments are conventional materials, reagents, and methods used in the art, unless otherwise stated.

[0073] Example 1: Effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell line NCI-H209

[0074] In this example, the CCK-8 assay was used to determine the inhibitory effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell line NCI-H209. The revived human small cell lung cancer cell line NCI-H209 was inoculated into a culture dish, and experimental medium (RPMI1640 + 20% FBS) was added. The cells were then placed in an incubator at 37°C and 5% CO2 for static culture. Cells with good growth status and appropriate confluence were used for the experiment. The cells were centrifuged at 800 rpm for 5 min, the supernatant was discarded, and the cells were resuspended with fresh medium. The cells were inoculated into a 96-well cell culture plate at an appropriate cell density, with 190 μL of cell suspension added to each well. The stock solutions of the test compounds (including senaparib, TMZ, and the reference compound AZD2281) were serially diluted in DMSO at ratios of 1:3 and 1:10 to 10 concentrations (the last concentration was the DMSO negative control). For each concentration, 5 μL was added to 120 μL of medium (25-fold dilution), and the mixture was shaken well. For single drug treatment: 5 μL of the diluted medium containing the corresponding concentration of the compound and 5 μL of medium were added separately; for combined drug treatment: 5 μL of the diluted medium containing the corresponding concentration of the compound and 5 μL of medium containing TMZ at a final concentration of 50 μM were added separately. The final concentration of DMSO was 2‰. Subsequently, the culture plate was placed in an incubator at 37°C and 5% CO2 for 5 days. 20 μL of CCK-8 detection reagent was added to each well, and after continued incubation for 2 hours, the plate was shaken for 10 minutes and then placed in a multi-functional reader to measure the absorbance value (OD value) at a wavelength of 450 / 650 nm. The data was analyzed using the software GraphPad Prism 6.0. The inhibitory activity of the compound on cell proliferation was plotted with cell survival rate and compound concentration as coordinates. Cell survival rate % = OD 化合物 / OD DMSO × 100. The IC 50 value was fitted with a sigmoidal dose-response curve equation: Y = 100 / (1 + 10^(LogC - LogIC 50 )), where C is the compound concentration. The combination index was calculated using the CalcuSyn software.

[0075] Table 1 summarizes the data on the inhibitory effect of each compound and its combination on the growth of human small cell lung cancer cell line NCI-H209 (IC 50 ). Table 2 lists the combination index (CI) of senaparib and TMZ. CI < 0.1 indicates a very strong synergistic effect of the drug combination; 0.1 < CI < 1 indicates a synergistic effect of the drug combination, and CI > 1 indicates no synergistic effect.

[0076] Table 1: Data on the inhibitory effect of compounds on the growth of human small cell lung cancer cells NCI-H209 (IC50, 100%) 50 )

[0077] compound <![CDATA[IC 50 (nM)]]> TMZ ＞100000 senaparib 113.2 50μM TMZ+senaparib 6.847 AZD2281 2176 50μM TMZ+AZD2281 199.1

[0078] Table 2: Combination Therapy Index (CI) of Senaparib and TMZ

[0079] <![CDATA[C senaparib (nM)]]> <![CDATA[C TMZ (nM)]]> Cell survival rate % CI 0.1 50000 0.841 5.045 0.33 50000 0.8599 6.996 1 50000 0.8661 7.916 10 50000 0.2685 0.062 33 50000 0.139 0.065 100 50000 0.1382 0.191 333 50000 0.1238 0.548

[0080] Therefore, the results, as determined by the CCK-8 assay, showed that the combination of senaparib and TMZ had a strong synergistic effect on inhibiting the proliferation of human small cell lung cancer NCI-H209 cells.

[0081] Example 2: In vivo pharmacodynamic study of senaparib in combination with TMZ in a nude mouse xenograft model of NCI-H209 human small cell lung cancer

[0082] To evaluate the antitumor activity of the compound senaparib in combination with TMZ in a nude mouse xenograft model of NCI-H209 human small cell lung cancer. For this purpose, NCI-H209 human small cell lung cancer cells were seeded subcutaneously into the mammary gland region of the right axilla of nude mice. The cell seeding density was 2 × 10⁶ cells / year. 6 Log-phase cells were inoculated and used after xenograft formation. Vigorously growing tumor tissue was cut into 1×1×1mm pieces. 3 Small pieces were inoculated subcutaneously into the mammary gland area of ​​the right axilla of each BALB / c nude mouse. The tumors were inoculated when the average tumor volume reached approximately 124.08 (57.16-280.79) mm. 3 At that time, patients were randomly grouped according to tumor volume and started receiving medication. The grouping and administration regimens are shown in Table 3.

[0083] Table 3: Animal grouping and dosing regimens for in vivo efficacy studies of senaparib combined with TMZ

[0084] Group N compound therapy Dosage (mg / kg) Dosage volume (μL / g) route of administration Dosing regimen 1 10 solvent -- 20 po QD x21D 2 10 TMZ 3mg / kg 20 po QD x21D 3 10 senaparib 10mg / kg 20 po QD x21D 4 10 senaparib+TMZ 5+3mg / kg 20 po QD x21D 5 10 senaparib+TMZ 10+3mg / kg 20 po QD x21D

[0085] Note 1: Dosage was administered at a dose of 20 μL / g based on the body weight of nude mice.

[0086] Note 2: N is the number of animals, 10 tumor-bearing nude mice per group; po means oral administration; QD means once a day; continue administration for 21 days.

[0087] Note 3: The solvent is 10% DMSO in 10% HP-β-CD PBS.

[0088] Note 4: The solvent control group was given 20 μL / g of solvent by gavage according to body weight; the TMZ and senaparib monotherapy groups were given 10 μL / g of solvent by gavage first, followed by 10 μL / g of the drug by gavage; the combined therapy group was given 10 μL / g of TMZ by gavage first, followed by 10 μL / g of the corresponding concentration of senaparib by gavage 30 min later.

[0089] After administration of the drug to the groups, the nude mice were weighed twice a week and their weight was recorded. Weight change (%) = (W) t -W1) / W1×100%, where W1 is the body weight measured at the time of group administration (i.e., D1), W t To record daily weight. Weight change (%) is a measure of treatment-related toxicity (treatment is stopped or adjusted until recovery if average weight loss exceeds 15%; the trial is terminated if average weight loss exceeds 20%). Tumor diameter (length and width) is measured twice weekly using calipers, and tumor volume (length × width) is calculated. 2 / 2), and relative tumor volume RTV = V t / V1, where V1 is the tumor volume measured at the time of grouped drug administration (i.e., D1), V t The tumor volume at each measurement. The evaluation indicators of antitumor activity are expressed as relative tumor proliferation rate (T / C%) and tumor growth inhibition rate (TGI%). T / C (%) = T RTV / C RTV ×100%, where T RTV For the treatment group RTV, compounds with a T / C (%) of less than 50 were defined as active (effective); C RTV The solvent control group has a fixed RTV; TGI (%) = [(CV)] t -CV1)-(TV t -TV1)] / (CV t -CV1)×100%, where CV t The tumor volume of the solvent control group was recorded on the same day. CV1 represents the tumor volume of the solvent control group at the time of drug administration. TV t The tumor volume of the treatment group was recorded on the same day, and TV1 was the tumor volume of the treatment group at the time of administration.

[0090] After the experiment, three nude mice were randomly selected from each group, and 300 μL of whole blood was collected from their orbital fossa into BD K2 EDTA anticoagulant tubes (REF367841) for routine blood tests.

[0091] Two-way ANOVA using Graph-Pad Prism 6.0 software was used to compare the mean tumor volume and relative mean tumor volume among the groups. Compared with the control group (solvent), * p < 0.05 (statistically significant)** p < 0.01 (statistically significant difference) *** p < 0.001 (highly statistically significant difference); compared with the TMZ group, # p < 0.05 (statistically significant) ## p < 0.01 (statistically significant difference) ### p < 0.001 (highly statistically significant difference); compared with the senaparib group, + p < 0.05 (statistically significant) ++ p < 0.01 (statistically significant difference) +++ p < 0.001 (There is a highly statistically significant difference).

[0092] Experimental results

[0093] 1. Weight

[0094] During the administration period, compared with the solvent control group, there was no difference in body weight change in the TMZ monotherapy group; the body weight gain in the senaparib monotherapy group was slightly slower in the later stage of administration; the body weight of the combined administration group (senaparib 5mg / kg + TMZ 3mg / kg) did not increase during the administration period; the average body weight of the combined administration group (senaparib 10mg / kg + TMZ 3mg / kg) decreased slightly during the administration period, but did not exceed 5%, as shown in Table 4 below.

[0095] Table 4: Average Body Weight and Weight Changes

[0096]

[0097] Note 1: Mean weight change (%): The mean weight change (%) of nude mice in each group compared with their initial weight at the start of treatment.

[0098] 2. Tumor volume

[0099] Compared with the solvent control group, TMZ 3 mg / kg and senaparib 10 mg / kg alone did not significantly inhibit tumor proliferation, while the combined administration showed a highly significant inhibitory effect on tumor proliferation (p<0.0001). Compared with the single administration groups, both combined administration groups showed a significant synergistic effect of TMZ and senaparib (p<0.0001). The tumor volume in the senaparib 10 mg / kg and TMZ 3 mg / kg combined administration group decreased compared with day 0. Specific results are shown in Table 5 below.

[0100] Table 5: Changes in mean tumor size in nude mice of each group (Mean±SD, n=10, tumor volume: mm) 3)

[0101]

[0102]

[0103] Note: Compared with the control group (solvent), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001;

[0104] Compared with the TMZ group, #p<0.05, ##p<0.01, ###p<0.001, ####p<0.0001;

[0105] Compared with the senaparib group, +p<0.05, ++p<0.01, +++p<0.001, and ++++p<0.0001.

[0106] 3. Evaluation indicators of antitumor activity

[0107] The relative tumor proliferation rate [T / C (%)] and tumor growth inhibition rate [TGI (%)] of each group during the experiment are shown in Table 6 below.

[0108] Table 6: Evaluation Indicators of Antitumor Activity

[0109] Group compound therapy TGI (%) T / C (%) 1 solvent - - 2 TMZ (3mpk, QD) <![CDATA[31.66 **** ]]> <![CDATA[64.03 **** ]]> 3 senaparib(10mpk, QD) <![CDATA[18.80 ** ]]> <![CDATA[79.12 ** ]]> 4 senaparib+TMZ(5+3mpk, QD) <![CDATA[98.03 ****####++++ ]]> <![CDATA[16.43 ****####++++ ]]> 5 senaparib+TMZ(10+3mpk, QD) <![CDATA[109.93 ****####++++ ]]> <![CDATA[3.25 ****####++++ ]]>

[0110] Note 1: Compared with the control group (vehicle), * p < 0.05 ** p < 0.01, *** p < 0.001, **** p < 0.0001;

[0111] Compared to the TMZ group, # p < 0.05 ## p < 0.01, ### p < 0.001 ＃＃## p < 0.0001;

[0112] Compared to the senaparib group, + p < 0.05 ++ p < 0.01, +++ p < 0.001 ++++ p < 0.0001.

[0113] 4. Blood routine test results

[0114] At the end of the experiment, three mice from each group underwent routine blood tests. Red blood cell counts did not decrease significantly in any of the drug groups and remained within the normal range; platelet counts showed little change, with a slight increase in the combined drug group. White blood cell counts decreased in all drug-treated groups. The decrease was more pronounced in the combined drug group, but still within a reasonable range, indicating limited toxicity to the animals.

[0115] In summary, senaparib combined with TMZ, administered once daily for 21 consecutive days, demonstrated a highly significant antitumor effect on the NCI-H209 human small cell lung cancer xenograft model in nude mice, with a clear synergistic effect. Meanwhile, the high-dose combination group experienced only a slight decrease in body weight, and no obvious toxic side effects were observed.

[0116] Example 3: Preparation of senaparib solid dispersion

[0117] The formulations of the solid dispersions are shown in Table 7.

[0118] Table 7

[0119] Element weight percentage senaparib 25.0％ Hydroxypropyl methylcellulose phthalate HP-55 75.0％

[0120] The senaparib solid dispersions used in the various embodiments were prepared using the method disclosed in PCT / CN2016 / 078262. An exemplary preparation method includes: dissolving senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a mixed solution of tetrahydrofuran and methanol (7:3, v / v), then spray-drying the solution, and drying the collected spray-dried particles in a vacuum dryer to obtain the senaparib solid dispersion. Upon testing, the crystalline form of senaparib in the solid dispersion powder was <1 wt%.

[0121] Example 4: Screening of excipients

[0122] Capsules were prepared according to the formula shown in Table 8 below (the dosage of each component is in mg), and excipients were screened.

[0123] Table 8

[0124] Element Capsule 1 Capsule 2 Capsule 3 Capsule 4 senaparib solid dispersion 40.00 40.00 40.00 40.00 Microcrystalline cellulose pH102* 60.95 62.10 61.80 61.80 Mannitol 100SD** 121.00 122.15 123.60 123.60 Cross-linked polyvinylpyrrolidone XL*** / / / 1.15 Cross-linked carboxymethyl cellulose sodium 4.60 2.30 1.15 / colloidal silica 2.30 2.30 2.30 2.30 magnesium stearate 1.15 1.15 1.15 1.15 Gelatin empty capsule No. 0 1 pill 1 pill 1 pill 1 pill Total 230.00 230.00 230.00 230.00

[0125] *: The particle size control range of microcrystalline cellulose is D90: 170~283μm.

[0126] **Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) is not less than 70%.

[0127] ***: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0128] Capsule preparation method: Add each component of the capsule to a universal mixer and mix at 40 rpm for 5 minutes. Then sieve through a 40-mesh sieve; mix the sieved material at 40 rpm for 8 minutes. Sift magnesium stearate through a 30-mesh sieve and add it to the universal mixer, then mix at 40 rpm for 3 minutes. Fill the resulting mixture into gelatin hollow capsule shells to obtain oral capsules.

[0129] The angle of repose, moisture content, bulk density, tap density, and Karl ellipse index of the mixed powders of each capsule and the senaparib solid dispersion were measured. The results are shown in Table 9 below.

[0130] Table 9

[0131]

[0132] As shown in Table 9, compared with the solid dispersion powder, the bulk density of the mixed powder of capsules 1-4 is significantly increased, the Karl Fischer index is significantly decreased, and the material flowability is significantly improved. The particle size control range of the filler (microcrystalline cellulose) in capsules 1-4 is D90: 170–283 μm, and the particle size control range of mannitol is a particle size distribution of not less than 70% with a particle size greater than 75 μm (200 mesh), effectively improving the material flowability and meeting the filling requirements.

[0133] Prepare oral capsules containing senaparib solid dispersion according to the formulations shown in Table 10 below (each component is in mg). The formulation for a single 10 mg capsule is as follows:

[0134] Table 10

[0135]

[0136]

[0137] *: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0138] **Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0139] ***: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0140] Preparation method: Add the ingredients of each capsule to a hopper mixer and mix at 15 rpm for 3 minutes. Then sieve through a 30-mesh sieve; mix the sieved material at 15 rpm for 10 minutes. Sift magnesium stearate through a 30-mesh sieve and add it to the mixer, then mix at 15 rpm for 3 minutes. Fill the resulting powder into gelatin hollow capsule shells to obtain oral capsules.

[0141] The angle of repose, moisture content, bulk density, tap density, and Karl ellipse index of the mixed powders of each capsule and the senaparib solid dispersion were measured. The results are shown in Table 11 below.

[0142] Table 11

[0143]

[0144] As can be seen from the results in Table 11, compared with the solid dispersion powder, the bulk density of the mixed powder of capsules 5-7 is significantly increased, the Karl Fischer index is significantly decreased, and the material flowability is significantly enhanced.

[0145] Capsule filling test

[0146] The mixed powder prepared by capsule formulation 5-7 was filled into capsules using the In-CAP fully automatic capsule filling machine. After the machine was adjusted to reach the target filling weight, the capsules were filled and the weight was measured. The results are shown in Tables 12-14.

[0147] Table 12: Capsule weighing results during the filling process of the mixed powder prepared from Capsule 5

[0148]

[0149]

[0150] Table 13: Capsule weighing results during the filling process of the mixed powder prepared from Capsule 6

[0151]

[0152]

[0153] Table 14: Capsule weighing results during the filling process of the mixed powder prepared from Capsule 7

[0154]

[0155] During the preparation of capsule formulation 5-7, a control check was performed every 10 minutes. The results in Table 12-14 show that during the 70-minute filling process, the weight of all capsules remained within the limits, and the relative standard deviation was small. These results demonstrate that the excipients in capsule formulation 5-7 effectively improved the flowability of the material, meeting the equipment's capsule filling requirements.

[0156] Content uniformity test

[0157] The content uniformity of capsules 5-7 was tested, and the results are shown in Table 15.

[0158] Table 15: Content uniformity test data for capsules 5-7

[0159]

[0160]

[0161] The results in Table 15 show that the content uniformity of capsules 5-7 all meet the requirements.

[0162] The filler (microcrystalline cellulose) in capsules 5-7 has a particle size D90 of 275-480 μm, and the mannitol has a particle size distribution of no less than 90% greater than 75 μm (200 mesh). The filler particle size is nearly double that of capsules 1-4, further improving the material's flowability and adaptability to capsule filling on fully automated equipment. Surprisingly, the increased particle size of the excipients did not lead to stratification or uneven content during mixing and filling. Scale-up trials showed good mixing uniformity of the formulated materials and good content uniformity in the finished capsules, indicating that the formulation effectively improves the deficiencies in the physicochemical properties of solid dispersion powders, meeting the requirements of direct-mixing and filling capsule processes while possessing the necessary dissolution characteristics.

[0163] Example 5: Effect of different preparation processes on the mixing uniformity of temozolomide in compound preparations

[0164] The compound preparation formulation and preparation process of this embodiment are shown in Table 16 below.

[0165] Table 16: Different Compound Capsules and Their Preparation Processes

[0166]

[0167]

[0168] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a weight ratio of 1:3. The crystalline form of senaparib in the solid dispersion is less than 1 wt%.

[0169] **: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0170] ***: Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0171] ****: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0172] Preparation of Comparative Compound Capsules 1: Temozolomide and other excipients were sieved and mixed for 10 min to obtain temozolomide premix, which was then filled into gelatin empty capsule shells using a capsule filling machine to obtain Comparative Compound Capsules 1.

[0173] Preparation of Compound Capsule 1: Dry granulation and capsule filling

[0174] (1) Temozolomide, tartaric acid, a portion of mannitol (11% of the total weight of mannitol), a portion of silica (3% of the total weight of silica), a portion of stearic acid (6% of the total weight of stearic acid), a portion of microcrystalline cellulose (22% of the total weight of microcrystalline cellulose), hydroxymethyl cellulose and a portion of crospovidone (18% of the total weight of crospovidone) were added to a universal mixer and mixed at 46 rpm for 3 minutes to obtain the first mixture;

[0175] (2) Pass the first mixture through a 20-mesh sieve, and add the sieved material back into the universal mixer of step (1). Mix at 46 rpm for 10 minutes, and then use a dry pellet mill with the following parameters for dry pelleting: roller pressure 3kN, roller speed 2rpm, feed speed 30rpm, and large sieve screen 24 mesh.

[0176] (3) Add senaparib solid dispersion, remaining mannitol, remaining silica, remaining microcrystalline cellulose and remaining crosslinked polyvinyl ketone to the universal mixer of step (1) and mix with the particles obtained in step (2) at 46 rpm for 3 minutes to obtain the second mixture.

[0177] (4) After taking out the second mixture and passing it through a 20-mesh sieve, put it back into the universal mixer of step (1) and mix it at 46 rpm for 10 minutes. Then add the remaining stearic acid that has passed through a 20-mesh sieve and mix it at 10 rpm for 3 minutes to obtain the final mixture.

[0178] (5) The final mixture is filled into gelatin empty capsule shells using a capsule filling machine to obtain the compound capsule preparation 1.

[0179] Preparation of Compound Capsules 2: Direct Mixing and Filling Capsules

[0180] (1) Temozolomide, microcrystalline cellulose, tartaric acid and crospovidone were added to a universal mixer and mixed at 46 rpm for 3 minutes to obtain the first mixture;

[0181] (2) Add the solid dispersion of senaparib, mannitol and colloidal silica to the universal mixer of step (1) and mix with the first mixture at 46 rpm for 3 minutes to obtain the second mixture;

[0182] (3) Pass the second mixture through a 30-mesh sieve, add the sieved material back into the universal mixer of step 1, add magnesium stearate that has passed through a 30-mesh sieve, mix, and obtain the final mixture.

[0183] (4) The final mixture obtained in step (3) is filled into gelatin hollow capsule shells using a capsule filling machine to obtain the compound capsule preparation 2.

[0184] Preparation of Compound Tablet 3: Direct Mixing and Tableting

[0185] (1) Temozolomide, microcrystalline cellulose, tartaric acid and crospovidone were premixed using a mixing device of suitable volume to obtain the first mixture;

[0186] (2) Add the solid dispersion of senaparib, mannitol and silica to the mixing equipment of step (1) and mix with the first mixture to obtain the second mixture;

[0187] (3) The second mixture is sieved, and the sieved material is added back to the mixing equipment of step 1. The sieved lubricant is then added and mixed to obtain the final mixture.

[0188] (4) The final mixture obtained in step (3) is pressed into tablets, and then the pressed tablets are coated to obtain the oral tablet 3.

[0189] Preparation of Compound Tablet 4: Dry Granulation and Tableting

[0190] (1) Temozolomide, microcrystalline cellulose, tartaric acid, crospovidone and hydroxypropyl cellulose were mixed to obtain the first mixture;

[0191] (2) Mix the solid dispersion of senaparib, lactose, a portion of the gliding agent (50% of the total weight of the gliding agent) and a portion of the lubricant (67% of the total weight of the lubricant) with the first mixture to obtain the second mixture;

[0192] (3) Take out the second mixture and granulate it using a dry granulation equipment. Mix the granulated material with the remaining flow aid and the remaining lubricant to obtain the final mixture.

[0193] (4) The final mixture obtained in step (3) is pressed into a tablet, and then coated to obtain the oral tablet.

[0194] High-performance liquid chromatography (HPLC) was used to test and compare the mixing uniformity of temozolomide during the preparation of compound capsules 1, compound capsules 1 and 2, and compound tablets 3 and 4. The results are shown in Table 17 below.

[0195] Table 17

[0196]

[0197] The intermediate control data for compound capsules 1 and 2 and compound tablets 3 are shown in Table 18 below.

[0198] Table 18

[0199]

[0200]

[0201] The results of the mixing uniformity test for compound capsules (Table 17) show that under small-batch conditions, simple mixing of temozolomide and other excipients resulted in poor mixing uniformity (RSD = 4.2%). Scale-up production using this process carries a high risk of uneven mixing. Mixing compound capsules 1 and 2, as well as compound tablets 3 and 4, using an equal-volume incremental mixing method significantly improved the mixing uniformity of temozolomide (RSD less than 1%), thus significantly reducing the risk of uneven mixing during scale-up production. Meanwhile, the control results in Table 18 show that the weight difference between capsules (tablets) and compound tablets 3 was small during capsule filling or tableting processes, indicating stable processes and demonstrating that the formulation's flow properties meet the requirements of filling or tableting processes.

[0202] Example 6: Preparation and dissolution of oral compound capsules containing senaparib and temozolomide

[0203] Prepare compound capsules 3-6 according to the formula shown in Table 19.

[0204] Table 19

[0205]

[0206] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-SS in a weight ratio of 1:3. The content of senaparib in the powder of this solid dispersion is less than 1%.

[0207] **: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0208] ***: Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0209] ****: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0210] The preparation method of compound capsules 3-6 includes the following steps:

[0211] (1) Temozolomide, microcrystalline cellulose, tartaric acid and crospovidone were added to a universal mixer and mixed at 46 rpm for 3 minutes to obtain the first mixture;

[0212] (2) Add the solid dispersion of senaparib, mannitol and colloidal silica to the universal mixer of step (1) and mix with the first mixture at 46 rpm for 3 minutes to obtain the second mixture;

[0213] (3) Pass the second mixture through a 30-mesh sieve, add the sieved material back into the universal mixer of step 1, add magnesium stearate that has passed through a 30-mesh sieve, mix, and obtain the final mixture.

[0214] (4) The final mixture obtained in step (3) is filled into a gelatin empty capsule shell to obtain a compound capsule.

[0215] The mixing uniformity of temozolomide in the final mixture of compound capsules 3-6, and the dissolution rate of senaparib in the final product capsules were tested. Dissolution test method: Refer to the General Rules of the 2015 Edition of the Chinese Pharmacopoeia. <0931> (Dissolution and Release Determination Method) Second Method (Paddle Method): The water bath temperature of the automatic sampling dissolution apparatus was set to 37±0.5℃, and a 0.1N hydrochloric acid buffer solution containing 1% CTAB was used as the dissolution medium, with a volume of 900mL. Samples were taken at 10, 15, 20, 30, 45, and 60 minutes, followed by a 30-minute rotation at the maximum speed (250 rpm). All samples were filtered through a nylon needle filter membrane and analyzed according to the sample dissolution determination method. The results are shown in Table 20.

[0216] Table 20

[0217]

[0218]

[0219] *: The dissolution medium used in the dissolution method of Compound Capsules 7 is 0.1N hydrochloric acid buffer containing 3% CTAB. Other dissolution conditions are the same as those for Compound Capsules 3-5.

[0220] As can be seen from the results in Table 20, the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules both meet the formulation quality control requirements.

[0221] Example 7: Preparation and dissolution of compound capsules containing senaparib and temozolomide with different fillers and disintegrants

[0222] Compound capsules 7-9 were prepared according to the formulation shown in Table 21, using the method described in Compound Capsule 2 of Example 5. The mixing uniformity of temozolomide in the final mixture of Compound Capsules 7-9 and the dissolution rate of senaparib in the final product capsules were tested. The dissolution rate test method was the same as in Example 6, and the results are shown in Table 22.

[0223] Table 21

[0224]

[0225] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a weight ratio of 1:3. The crystalline form of senaparib in the solid dispersion powder is less than 1 wt%.

[0226] Table 22

[0227]

[0228] As can be seen from the results in Table 22, the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules both meet the formulation quality control requirements.

[0229] Example 8: Preparation and dissolution of oral compound capsules containing senaparib and temozolomide with different proportions of fillers and lubricants.

[0230] Using the method described in Compound Capsule 2 of Example 5, oral compound capsules containing different proportions of fillers and additional lubricants, as shown in Table 23, were prepared into compound capsules 10-12 containing senaparib and temozolomide. The mixing uniformity of temozolomide in the final mixture of compound capsules 10-12 and the dissolution rate of senaparib in the final product capsules were tested. The dissolution rate test method was the same as in Example 6, and the results are shown in Table 24 below.

[0231] Table 23

[0232]

[0233]

[0234] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a weight ratio of 1:3. The crystalline form of senaparib in the solid dispersion powder is less than 1 wt%.

[0235] **: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0236] ***: Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0237] ****: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0238] Table 24

[0239]

[0240] As can be seen from the results in Table 24, the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules both meet the requirements of formulation quality control.

[0241] Example 9: Preparation and dissolution of compound capsules containing senaparib and temozolomide with different amounts of disintegrants

[0242] Compound capsule 13 was prepared according to the method described in Compound Capsule 2 of Example 5, as shown in Table 25. The mixing uniformity of senaparib and temozolomide in the final mixture of Compound Capsule 13, as well as the dissolution rate of the two active ingredients in the final product capsule, were tested. The dissolution rate testing method was the same as in Example 6, and the results are shown in Table 26.

[0243] Table 25: Formula of Compound Capsules 13

[0244]

[0245]

[0246] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a weight ratio of 1:3. The crystalline form of senaparib in the solid dispersion is less than 1 wt%.

[0247] **: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0248] ***: Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0249] ****: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0250] Table 26

[0251]

[0252] The results in Table 26 show that the mixing uniformity of the two active ingredients and the dissolution of the final product capsules meet the requirements for formulation control and quality control.

[0253] Example 10: Preparation and dissolution of oral compound capsules containing Senaparib and temozolomide in different proportions of acidic pH additives.

[0254] Using the preparation method described in Compound Capsule 2 of Example 5, Compound Capsules 14-16 were prepared according to the formula shown in Table 27. The mixing uniformity of temozolomide in the final mixture of each compound capsule and the dissolution rate of senaparib in the final product capsule were tested using the method described above. The dissolution rate test method was the same as in Example 6. The results are shown in Table 28.

[0255] Table 27

[0256]

[0257] *: The solid dispersion is composed of senaparib and hydroxypropyl methylcellulose phthalate HP-55 in a weight ratio of 1:3. The crystalline form of senaparib in the solid dispersion is less than 1 wt%.

[0258] **: The particle size control range of microcrystalline cellulose is D90: 275~480μm.

[0259] ***: Mannitol particle size control: The particle size distribution of particles larger than 75μm (200 mesh) shall not be less than 90%.

[0260] ****: The particle size control range of cross-linked polyvinyl chloride is D90: 270~385μm.

[0261] Table 28

[0262]

[0263]

[0264] As can be seen from the results in Table 28, the mixing uniformity of temozolomide and the dissolution rate of senaparib in the final product capsules both meet the formulation quality control requirements.

[0265] Example 11: Stability Comparison of Compound Capsules 14 and TMZ Single-Agent Reference Formulation (Marketed Product)

[0266] The stability of the compound capsule 14 prepared in Example 10 and the TMZ single-component reference preparation was tested under accelerated conditions (40℃ / 75%RH). The sampling time points were 0 / 1 / 3 months and 0 / 3 months. The TMZ content, related substances, and other parameters were tested at each time point, and the results are shown in Table 29.

[0267] The results show that after three months of accelerated storage, the content of Compound Capsules 15 did not change significantly, and the total impurity content increased slightly, but the increase was smaller than that of the TMZ single-component reference preparation, which meets the stability requirements.

[0268] Table 29

[0269]

[0270] Note: *TMZ single-component reference formulation is a marketed product manufactured by SUN Pharmaceutical Industries Ltd.

[0271] Comparative Example 1: Toxicity and Tumor Suppression of Low-Dose Senaparib + High-Dose TMZ in the MX-1 Human Breast Cancer Mouse Model

[0272] To evaluate the antitumor activity of low-dose senaparib combined with high-dose TMZ in a nude mouse xenograft model of human breast cancer using the MX-1 cell line. For this purpose, MX-1 human breast cancer cells were subcutaneously seeded into the axillary region of nude mice. The cell seeding density was 1.0 × 10⁻⁶ cells / year. 6 Log-phase cells were seeded to form xenografts and passaged three times in nude mice before use. Tumors in good growth condition without necrosis were selected, washed thoroughly with sterile PBS, and quickly minced. The cells were then homogenized in a tissue homogenizer, grinding thoroughly clockwise, and passed through a 200-mesh filter. The filtered cell suspension was centrifuged at 1000 rpm for 5 minutes in a sterile centrifuge tube. The supernatant was discarded, and the pellet was resuspended in sterile PBS, washed once at 1000 rpm for 5 minutes. The supernatant was discarded again, and the cells were resuspended in an appropriate amount of PBS, counted, and adjusted to 5 × 10⁶ cells / year. 6 / mL. Thoroughly mix the cell suspension, at a concentration of 5 × 10⁹ / mL per mouse. 5 One cell (0.1 mL) was injected subcutaneously into the axilla of the right forelimb of a mouse. When the average tumor volume reached approximately 50 mm²... 3 At that time, patients were randomly grouped according to tumor volume and started receiving medication. The grouping and administration regimens are shown in Table 30.

[0273] Table 30: Animal grouping and dosing regimens for in vivo pharmacodynamic experiments with senaparib in combination with TMZ

[0274] Group N compound therapy Dosage (mg / kg) Dosage volume (μL / g) route of administration Dosing regimen 1 9 solvent -- 20 po QD 5D 2 9 TMZ 62.5 mg / kg 20 Po QD 5D 3 9 AZD2281 20 + 62.5 mg / kg 20 po QD 5D 4 9 senaparib 1mg / kg 20 po QD 5D 5 9 senaparib+TMZ 1+62.5mg / kg 20 po QD 5D

[0275] Note 1: Dosage was administered at a dose of 20 μL / g based on the body weight of nude mice.

[0276] Note 2: Each group consisted of 9 tumor-bearing nude mice; po was oral administration; QD 5D was once daily for 5 consecutive days, followed by observation for 1-2 weeks after drug withdrawal. The average tumor volume in each group reached 5000 mmHg. 3 Animals were euthanized promptly. In groups 1 and 4, animals were euthanized on day 8 after the start of administration; in group 2, animals were euthanized on day 14 after the start of administration; in group 3, animals were euthanized on day 17 after the start of administration; and in group 5, animals were euthanized on day 21 after the start of administration.

[0277] Note 3: The solvent is 10% DMSO in 10% HP-β-CD PBS.

[0278] Note 4: The solvent control group was given 20 μL / g of solvent by gavage according to body weight; the TMZ and senaparib single administration groups were given 20 μL / g of the drug by gavage; the combined administration group was given 10 μL / g of the corresponding concentration of AZD2281 or senaparib by gavage first, and then 10 μL / g of TMZ by gavage 45 min later.

[0279] The antitumor drug effect of the test substance was dynamically observed by measuring tumor diameter. Tumor volume and animal weight were measured daily.

[0280] Experimental results

[0281] 1. Weight

[0282] Regarding weight changes, both the TMZ monotherapy group and the combination therapy group experienced varying degrees of weight loss. After 5 consecutive days of administration, the senaparib 1 mg / kg combined with TMZ group experienced a weight loss of 15%, while the AZD2281 20 mg / kg combined with TMZ group experienced a weight loss of approximately 12%. The average weight of each group is shown in Table 31.

[0283] Table 31: Average Weight

[0284] Group compound therapy Average body weight on day 0 (g) Average weight (g) on ​​day 5 1 solvent 18.87±1.14 20.08±1.00 2 TMZ (62.5 mg / kg) 19.73±2.02 18.31±2.06 3 AZD2281+TMZ (20+62.5mg / kg) 20.34±1.46 17.88±0.90 4 senaparib (1 mg / kg) 19.00±2.19 19.86±2.14 5 senaparib + TMZ (1 + 62.5 mg / kg) 19.33±2.05 16.42±2.29

[0285] 2. Evaluation indicators of antitumor activity

[0286] The relative tumor proliferation rate [T / C (%)] of each group 5 days after administration during the experiment is shown in Table 32 below.

[0287] Table 32: Evaluation Indicators of Antitumor Activity

[0288] Group compound therapy T / C (%) 1 solvent - 2 TMZ (62.5 mg / kg) 37.04 3 AZD2281+TMZ (20+62.5mg / kg) 15.75 4 senaparib (1 mg / kg) 98.89 5 senaparib + TMZ (1 + 62.5 mg / kg) 6.62

[0289] The changes in tumor size in each group of nude mice are shown in Table 33 below.

[0290] Table 33: Tumor size changes in nude mice in each group (Mean±SD, n=9, tumor volume: mm) 3 )

[0291]

[0292] In summary, senaparib combined with TMZ, administered once daily for 5 consecutive days, showed significant antitumor effects in the MX-1 human small cell lung cancer xenograft model in nude mice, and exhibited a synergistic effect. However, in the 1 mg / kg senaparib combined administration group, the mice experienced a significant decrease in body weight (up to 15%) after 5 consecutive days of administration, and the tumor volume began to increase continuously from day 10 after drug withdrawal.

[0293] While the invention has been fully described, those skilled in the art will understand that the same practices can be carried out under broad and equivalent conditions, formulations, and other parameters without affecting the scope of the invention or any embodiments thereof. All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety.

Claims

1. A compound preparation for treating cancer, comprising an active ingredient and pharmaceutically acceptable excipients, said active ingredient being senaparib and temozolomide, wherein, The content of senaparib is 2.0% to 15.0% and the content of temozolomide is 1.0% to 10.0% based on the total weight of the compound preparation; the cancers mentioned are selected from small cell lung cancer and breast cancer.

2. The compound preparation according to claim 1, characterized in that, Pharmaceutically acceptable excipients include one or more of the following: carriers, fillers, disintegrants, flow aids, lubricants, binders, surfactants, and pH adjusters.

3. The compound preparation according to claim 1, characterized in that, The pharmaceutically acceptable excipients include carriers, fillers, disintegrants, glidants, lubricants, and pH adjusters, and optionally also contain one or two of binders and surfactants.

4. The compound preparation according to claim 3, characterized in that, The carrier is succinic hydroxypropyl methylcellulose acetate, hydroxypropyl methylcellulose phthalate, or a mixture thereof; and / or The filler is selected from one or more of starch, pregelatinized starch, mannitol, lactose, sucrose, cyclodextrin, and microcrystalline cellulose; and / or The disintegrant is selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, pregelatinized starch, sodium alginate, and any combination thereof; and / or The flow aid is selected from powdered cellulose, magnesium trisilicate, colloidal silica, talc, and any combination thereof; and / or The lubricant is selected from zinc stearate, glyceryl monostearate, glyceryl stearate palmitate, magnesium stearate, sodium fumarate stearate, and any combination thereof; and / or The adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, and povidone; and / or The surfactant is selected from one or more of sodium dodecyl sulfate, poloxamer, taurine, lauroyl polyoxyethylene glycerol, and polysorbate; and / or The pH adjuster is an acidic pH adjuster, selected from one or more of citric acid, tartaric acid, sorbic acid, malic acid, lactic acid, fumaric acid, and adipic acid.

5. The compound preparation according to claim 3, characterized in that, The filler is selected from one or more of microcrystalline cellulose, mannitol, and lactose.

6. The compound preparation according to claim 3, characterized in that, The disintegrant is crospovidone or sodium carboxymethyl starch.

7. The compound preparation according to claim 3, characterized in that, The flow aid is colloidal silica.

8. The compound preparation according to claim 3, characterized in that, The lubricant is magnesium stearate.

9. The compound preparation according to claim 3, characterized in that, The pH adjuster is tartaric acid.

10. The compound preparation according to claim 3, characterized in that, Based on the total weight of the compound preparation, The carrier content is 7% to 30%; and / or The filler content is 56%~85%; and / or The content of the disintegrant is 0.1% to 10%; and / or The content of the gliding agent is 0.1%~10%; and / or The lubricant content is 0.1%~3%; and / or The adhesive content is 0.1% to 5%; and / or The surfactant content is 0.5% to 2.2%; and / or The pH adjuster has a content of 0.1% to 5%.

11. The compound preparation according to claim 3, characterized in that, The carrier content is 13% to 20% based on the total weight of the compound preparation.

12. The compound preparation according to claim 3, characterized in that, The weight ratio of senaparib to the carrier is 1:2 to 1:3 based on the total weight of the compound preparation.

13. The compound preparation according to claim 3, characterized in that, The content of the filler is 70% to 82% based on the total weight of the compound preparation.

14. The compound preparation according to claim 3, characterized in that, The content of the filler is 75% to 82% based on the total weight of the compound preparation.

15. The compound preparation according to claim 3, characterized in that, The content of the disintegrant is 0.5% to 4% based on the total weight of the compound preparation.

16. The compound preparation according to claim 3, characterized in that, The content of the gliding agent is 1% to 3% based on the total weight of the compound preparation.

17. The compound preparation according to claim 3, characterized in that, The content of the lubricant is 0.3% to 1% based on the total weight of the compound preparation.

18. The compound preparation according to claim 3, characterized in that, The content of the lubricant is 0.5 ± 0.1% based on the total weight of the compound preparation.

19. The compound preparation according to claim 3, characterized in that, The content of the adhesive is 0.1% to 3% based on the total weight of the compound preparation.

20. The compound preparation according to claim 3, characterized in that, The content of the surfactant is 0.9% to 1.5% based on the total weight of the compound preparation.

21. The compound preparation according to claim 3, characterized in that, The content of the pH adjuster is 0.1% to 3% based on the total weight of the compound preparation.

22. The compound preparation according to claim 1, characterized in that, The compound preparation contains hydroxypropyl methylcellulose phthalate, wherein the weight ratio of senaparib to hydroxypropyl methylcellulose phthalate is 1:2 to 1:3; or the compound preparation contains hydroxypropyl methylcellulose phthalate and a surfactant, wherein the weight ratio of senaparib, hydroxypropyl methylcellulose phthalate and the surfactant is 1:2.8:0.

2.

23. The compound preparation according to claim 1, characterized in that, The compound formulation contains a solid dispersion of senaparib; wherein the solid dispersion contains senaparib, hydroxypropyl methylcellulose phthalate, and optionally a surfactant.

24. The compound preparation according to claim 23, characterized in that, The solid dispersion contains, by total weight, 65% to 77% hydroxypropyl methylcellulose phthalate, 23% to 35% senaparib, and 2% to 5% surfactant.

25. The compound preparation according to claim 24, characterized in that, The solid dispersion contains 73% to 77% hydroxypropyl methylcellulose phthalate by weight of the solid dispersion.

26. The compound preparation according to claim 23, characterized in that, The solid dispersion is composed of active ingredients senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 or 1:3, or composed of senaparib, hydroxypropyl methylcellulose phthalate and poloxamer in a weight ratio of 1:2.8:0.

2.

27. The compound preparation according to claim 4, characterized in that, Calculated on a dry basis, the hydroxypropyl methylcellulose phthalate contains 12.0% to 28.0% methoxy groups, 4.0% to 23.0% 2-hydroxypropoxy groups, 2.0% to 16.0% acetyl groups, and 4.0% to 28.0% succinyl groups.

28. The compound preparation according to claim 4, characterized in that, The microcrystalline cellulose has a D90 of 170~480μm; the mannitol has a particle size distribution of not less than 70% with a particle size >75μm.

29. The compound preparation according to claim 28, characterized in that, The microcrystalline cellulose has a D90 of 170~283μm or 275~480μm.

30. The compound preparation according to claim 28, characterized in that, The mannitol has a particle size distribution of not less than 80% with a particle size >75μm.

31. The compound preparation according to claim 28, characterized in that, The mannitol has a particle size distribution of not less than 90% with a particle size >75μm.

32. The compound preparation according to claim 1, characterized in that, In the compound preparation, the content of senaparib is 1 to 8 times that of temozolomide.

33. The compound preparation according to claim 1, characterized in that, In the compound preparation, the content of senaparib is 2 to 4 times that of temozolomide.

34. The compound preparation according to claim 1, characterized in that, Each dose of the compound preparation contains 10-100 mg of senaparib and 5-40 mg of temozolomide.

35. The compound preparation according to claim 34, characterized in that, Each dose of the compound preparation described herein contains 10-80 mg of senaparib.

36. The compound preparation according to claim 34, characterized in that, Each dose of the compound preparation described herein contains 10-20 mg of temozolomide.

37. The compound preparation according to claim 1, characterized in that, Based on its total weight, this compound preparation contains: senaparib, 2.0%~15.0%; Temozolomide, 1.0%~10.0%; Carrier, 7%~30%; Filler, 56%~85%; Disintegrant, 0.1%~10%; Gliding agent, 0.1%~10%; Lubricant, 0.1%~3%; pH adjuster, 0.1%~5%; Optional adhesive, 0.1%~5%; and Optional surfactant, 0.5% to 2.2%.

38. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 2.0% to 10.0% senaparib.

39. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 4.0% to 10.0% senaparib.

40. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains temozolomide, ranging from 2.0% to 8.0%.

41. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains a carrier, ranging from 13% to 20%.

42. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 70% to 82% filler.

43. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 75% to 82% filler.

44. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 0.5% to 4% disintegrants.

45. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 0.5% to 3% of a gliding agent.

46. ​​The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 1% to 3% of a gliding agent.

47. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 0.3% to 1% lubricant.

48. The compound preparation according to claim 37, characterized in that, Based on its total weight, this compound preparation contains 0.1% to 3% pH adjuster.

49. The compound preparation according to claim 37, characterized in that, Based on its total weight, the compound preparation contains optional binders, 0.1% to 3%.

50. The compound preparation according to claim 37, characterized in that, The carrier is hydroxypropyl methylcellulose phthalate.

51. The compound preparation according to claim 37, characterized in that, The carrier is HP-55.

52. The compound preparation according to claim 37, characterized in that, The weight ratio of senaparib to the carrier is 1:2 to 1:

3.

53. The compound preparation according to claim 37, characterized in that, The filler is microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170~480μm, and the particle size distribution of the mannitol with a particle size >75μm is not less than 70%.

54. The compound preparation according to claim 53, characterized in that, The D90 of microcrystalline cellulose is 275~480μm.

55. The compound preparation according to claim 53, characterized in that, In the mannitol, the particle size distribution with a particle size >75μm is not less than 80%.

56. The compound preparation according to claim 53, characterized in that, In the mannitol, the particle size distribution with a particle size >75μm is not less than 90%.

57. The compound preparation according to claim 53, characterized in that, Based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8% to 50%; the content of mannitol is 20% to 70%.

58. The compound preparation according to claim 57, characterized in that, The content of microcrystalline cellulose is 10% to 28% based on the total weight of the compound preparation.

59. The compound preparation according to claim 57, characterized in that, The content of microcrystalline cellulose is 15% to 20% based on the total weight of the compound preparation.

60. The compound preparation according to claim 57, characterized in that, The mannitol content is 50% to 65% based on the total weight of the compound preparation.

61. The compound preparation according to claim 57, characterized in that, The mannitol content is 55% to 65% based on the total weight of the compound preparation.

62. The compound preparation according to claim 37, characterized in that, The disintegrant is crospovidone and / or sodium carboxymethyl starch.

63. The compound preparation according to claim 62, characterized in that, The particle size control range of cross-linked polyvinylpyrrolidone is D90: 270~385μm.

64. The compound preparation according to claim 37, characterized in that, The flow aid is colloidal silica.

65. The compound preparation according to claim 37, characterized in that, The lubricant is magnesium stearate and / or stearic acid.

66. The compound preparation according to claim 37, characterized in that, The adhesive is hydroxypropyl cellulose.

67. The compound preparation according to claim 37, characterized in that, The pH adjuster is tartaric acid.

68. The compound preparation according to claim 1, characterized in that, Based on its total weight, the compound preparation contains: solid dispersions of senaparib, 8% to 60%; Temozolomide, 1.0%~10.0%; Filler, 56%~85%; Disintegrant, 0.1%~10%; Gliding agent, 0.1%~10%; Lubricant, 0.1%~3%; pH adjuster, 0.1%~5%; and Optional adhesive, 0.1% to 5%.

69. The compound preparation according to claim 68, characterized in that, The compound preparation contains temozolomide at a concentration of 2.0% to 8.0% based on its total weight.

70. The compound preparation according to claim 68, characterized in that, The compound preparation contains 70% to 82% filler by its total weight.

71. The compound preparation according to claim 68, characterized in that, The compound preparation contains 75% to 82% filler by its total weight.

72. The compound preparation according to claim 68, characterized in that, Based on its total weight, the compound preparation contains 0.5% to 4% disintegrant.

73. The compound preparation according to claim 68, characterized in that, Based on its total weight, the compound preparation contains 0.5% to 3% of a gliding agent.

74. The compound preparation according to claim 68, characterized in that, Based on its total weight, the compound preparation contains 1% to 3% of a gliding agent.

75. The compound preparation according to claim 68, characterized in that, The compound preparation contains 0.3% to 1% lubricant by its total weight.

76. The compound preparation according to claim 68, characterized in that, The compound preparation contains 0.1% to 3% pH adjuster based on its total weight.

77. The compound preparation according to claim 68, characterized in that, The compound preparation contains, by its total weight, an optional binder, of 0.1% to 3%.

78. The compound preparation according to claim 68, characterized in that, The solid dispersion powder is composed of senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 to 1:3, and less than 5% by weight of senaparib is in crystalline form.

79. The compound preparation according to claim 68, characterized in that, The solid dispersion powder is composed of senaparib and hydroxypropyl methylcellulose phthalate in a weight ratio of 1:2 to 1:3, and less than 1% by weight of senaparib is in crystalline form.

80. The compound preparation according to claim 68, characterized in that, The filler is microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170~480μm, and the particle size distribution of the mannitol with a particle size >75μm is not less than 70%.

81. The compound preparation according to claim 80, characterized in that, The D90 of microcrystalline cellulose is 275~480μm.

82. The compound preparation according to claim 80, characterized in that, In the mannitol, the particle size distribution with a particle size >75μm is not less than 80%.

83. The compound preparation according to claim 80, characterized in that, In the mannitol, the particle size distribution with a particle size >75μm is not less than 90%.

84. The compound preparation according to claim 80, characterized in that, Based on the total weight of the compound preparation, the content of microcrystalline cellulose is 8% to 50%; the content of mannitol is 20% to 70%.

85. The compound preparation according to claim 84, characterized in that, The content of microcrystalline cellulose is 10% to 28% based on the total weight of the compound preparation.

86. The compound preparation according to claim 84, characterized in that, The content of microcrystalline cellulose is 15% to 20% based on the total weight of the compound preparation.

87. The compound preparation according to claim 84, characterized in that, The mannitol content is 50% to 65% based on the total weight of the compound preparation.

88. The compound preparation according to claim 84, characterized in that, The mannitol content is 55% to 65% based on the total weight of the compound preparation.

89. The compound preparation according to claim 68, characterized in that, The disintegrant is crospovidone and / or sodium carboxymethyl starch.

90. The compound preparation as described in claim 89, characterized in that, The particle size control range of cross-linked polyvinylpyrrolidone is D90: 270~385μm.

91. The compound preparation according to claim 68, characterized in that, The flow aid is colloidal silica.

92. The compound preparation according to claim 68, characterized in that, The lubricant is magnesium stearate and / or stearic acid.

93. The compound preparation as described in claim 68, characterized in that, The adhesive is hydroxypropyl cellulose.

94. The compound preparation as described in claim 68, characterized in that, The pH adjuster is tartaric acid.

95. The compound preparation according to claim 1, characterized in that, The compound preparation is an oral solid dosage form.

96. The compound preparation according to claim 1, characterized in that, The compound preparation is in the form of capsules, tablets, or granules.

97. The compound preparation according to claim 96, characterized in that, The capsule shell is selected from plant capsule shells and gelatin capsule shells.

98. The compound preparation as described in claim 96, characterized in that, The capsule shell is a gelatin capsule shell.

99. The method for preparing the compound preparation according to any one of claims 1-98, characterized in that, The method includes: providing a first mixture containing temozolomide and a portion of excipients; mixing senaparib and the remaining excipients other than the lubricant with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant to prepare a final mixture; or mixing senaparib with a portion of the lubricant and a portion of the gliding agent, as well as all the remaining excipients, with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant and gliding agent to prepare a final mixture.

100. The method as described in claim 99, characterized in that, The method includes the following steps: (1) Mix temozolomide, a filler, a pH acidity adjuster and a disintegrant to obtain mixture 1; (2) The solid dispersion of senaparib, another filler and a flow aid are mixed with the first mixture to obtain the second mixture; (3) Sieve the second mixture, and mix the sieved material with the lubricant to obtain the final mixture; (4) The final mixture obtained in step (3) is filled into capsule shells to obtain oral capsules; Alternatively, the method may include the following steps: (1) Mix temozolomide, a portion of filler, pH acidity adjuster, binder, a portion of disintegrant, a portion of flow aid and a portion of lubricant to obtain mixture 1; (2) After sieving the first mixture, mix it again, and then granulate the resulting mixture using a dry granulation device; (3) Mix the solid dispersion of senaparib, the remaining filler, the remaining glidant and the remaining disintegrant with the material obtained after dry granulation in step (2) to obtain the second mixture; (4) After taking out the second mixture obtained in step (3) and sieving it, mix it with the remaining lubricant to obtain the final mixture; (5) The final mixture obtained in step (4) is filled into a capsule shell to obtain an oral capsule.

101. The method as described in claim 99, characterized in that, The method includes the following steps: (1) Mix temozolomide, a filler, a pH acidity adjuster and a disintegrant to obtain mixture 1; (2) Mix the solid dispersion of senaparib, another filler and flow aid with the first mixture to obtain the second mixture; (3) Sieve the second mixture, and mix the sieved material with the lubricant to obtain the final mixture; (4) The final mixture obtained in step (3) is compressed into tablets, and then the tablets are coated to obtain the oral tablets; Alternatively, the method may include the following steps: (1) Temozolomide, a filler, a pH acidity adjuster, a disintegrant and a binder are mixed to obtain the first mixture; (2) Mix the solid dispersion of senaparib, another filler, a portion of the flow aid and a portion of the lubricant with the first mixture to obtain the second mixture; (3) Take out the second mixture and granulate it using a dry granulation equipment. Mix the granulated material with the remaining flow aid and the remaining lubricant to obtain the final mixture; (4) The final mixture obtained in step (3) is pressed into a tablet, and then coated to obtain the oral tablet.

102. A medicine box containing any one of the compound preparations according to claims 1-98.

103. The medicine box as described in claim 102, characterized in that, The amount of compound preparation contained in the medicine box is sufficient for a patient to take the medicine for at least one day; wherein the daily dosage is: senaparib 20~100mg; temozolomide 5~30mg.

104. The medicine box as described in claim 103, characterized in that, The daily dosage of senaparib is 20-80 mg.

105. The medicine box as described in claim 103, characterized in that, The daily dosage of temozolomide is 10-20 mg.

106. The use of the compound preparation according to any one of claims 1-98 in the preparation of a medicament for treating cancer, wherein the cancer is selected from breast cancer and small cell lung cancer.

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