WO2023138667A1 - Préparation de composé de senaparib et de témozolomide et son procédé de préparation - Google Patents

Préparation de composé de senaparib et de témozolomide et son procédé de préparation Download PDF

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Publication number
WO2023138667A1
WO2023138667A1 PCT/CN2023/073208 CN2023073208W WO2023138667A1 WO 2023138667 A1 WO2023138667 A1 WO 2023138667A1 CN 2023073208 W CN2023073208 W CN 2023073208W WO 2023138667 A1 WO2023138667 A1 WO 2023138667A1
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Prior art keywords
senaparib
mixture
compound preparation
cancer
temozolomide
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PCT/CN2023/073208
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English (en)
Chinese (zh)
Inventor
蔡遂雄
马宁
赵立平
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上海瑛派药业有限公司
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Publication of WO2023138667A1 publication Critical patent/WO2023138667A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to a compound preparation of senaparib and temozolomide and a preparation method thereof.
  • PARP Poly(ADP-ribose) polymerase
  • PARP inhibitors to treat cancer is primarily based on two mechanisms.
  • PARP inhibitors can be independently used as anticancer drugs for cancer cells with DNA repair defects to directly kill these cells (synthetic lethality), such as triple negative breast cancer cells with BRCA1 or BRCA2 deletion.
  • DNA repair defects to directly kill these cells (synthetic lethality)
  • BRCA1 or BRCA2 deletion the DNA repair defects to directly kill these cells.
  • PARP inhibitors When PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapy and anticancer drugs, they can inhibit DNA repair and produce synergistic effects, thereby greatly enhancing the efficacy of DNA-damaging anticancer drugs.
  • Temozolomide (Temozolamide, TMZ) chemical name is 3,4-dihydro-3-methyl-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, is a new oral alkylating agent antineoplastic drug, has broad-spectrum antitumor activity, can pass through the blood-brain barrier, oral bioavailability is close to 100%, can effectively treat newly diagnosed and recurrent glioblastoma and anaplastic astrocytoma, and prolong the survival period of patients , and was safe and well tolerated.
  • temozolomide does not directly play a role after oral administration. At physiological pH, it is rapidly converted into the active compound MTIC (5-(3-methyltriazene-1-)imidazole-4-amide) through a non-enzymatic pathway.
  • the combination of PARP inhibitors and TMZ has the clinical therapeutic advantage of synergizing efficacy and reducing toxicity.
  • each drug is administered separately in the combination drug, and the patient takes a large amount of drugs, the burden is heavy, and the compliance is poor; and the doctor needs to adjust according to the patient
  • the required dose is prescribed; if there are individual drugs from multiple manufacturers, the controllability of drug use is poor. Therefore, the development of fixed combination preparations is very necessary, which can improve the safety and compliance of medication; the development of multi-specification compound preparations is also beneficial for doctors to prescribe; compound preparations are also conducive to storage and transportation management.
  • Senaparib solid dispersion preparations can obtain high solubility and oral bioavailability, due to its hygroscopicity may cause solid dispersion bonding and agglomeration, there are great challenges in the mixing uniformity and content uniformity of the ingredients when preparing compound preparations.
  • temozolomide another main component in the compound preparation, has a small content in the compound preparation prescription and is easily hydrolyzed under neutral and alkaline conditions, which may have problems with mixing uniformity, content uniformity and stability. Therefore, there is still a need in the art for formulation formulations and production processes that can solve the above problems and meet the needs of formulation production, and the prepared formulations have an appropriate dissolution rate and excellent storage stability, and the production cost is reasonable.
  • the first aspect of the present invention provides a compound preparation, which contains an active ingredient and a pharmaceutically acceptable auxiliary material, 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%.
  • the second aspect of the present invention provides a method for preparing the compound preparation according to any embodiment of the present invention, the method comprising: providing a first mixture containing temozolomide and some adjuvants, mixing senaparib and the remaining adjuvants with the first mixture, and finally mixing the resulting mixture with all the lubricants; or first mixing senaparib and all the remaining adjuvants to prepare a second mixture, and then mixing the first mixture and the second mixture to prepare the final mixture.
  • the third aspect of the present invention provides a kit containing the compound preparation according to any embodiment of the present invention.
  • the fourth aspect of the present invention provides the application of the compound preparation according to any embodiment of the present invention in the preparation of a drug for treating cancer.
  • the fifth aspect of the present invention provides a method for treating cancer, the method comprising administering a therapeutically effective amount of the compound preparation according to any embodiment of the present invention to a subject in need; wherein, the therapeutically effective amount is a daily dose of senaparib of 20-100 mg, preferably a daily dose of 20-80 mg; and a daily dose of temozolomide of 5-30 mg, preferably a daily dose of 10-20 mg.
  • compositions, methods, etc. include the listed elements and do not exclude others.
  • compositions described herein comprise the active ingredient in admixture with other chemical ingredients.
  • PARP inhibitors are used in combination with commonly used DNA-damaging chemotherapeutic anticancer drugs, since PARP inhibitors are used as sensitizers of chemotherapeutic anticancer drugs, high doses of chemotherapeutic anticancer drugs are generally combined with low doses of PARP inhibitors. In clinical trials, high doses of chemotherapy and anticancer drugs are generally combined with low doses of PARP inhibitors.
  • the determined clinical phase II dose is Olaparib 150 mg and TMZ 75 mg/m 2 (the dose after conversion based on the body surface area of a 60 kg adult is 1.62 m 2 is 121.5 mg) once a day (Catherine Hanna et al. 2020, Neuro Oncol. 1-11).
  • the daily dose of temozolomide is 75mg/m 2 (equivalent to 121.5mg) when it is combined with radiotherapy in the treatment of newly diagnosed glioblastoma multiforme, which is similar to the daily dose of 150mg/m 2 (equivalent to 243mg) when it is used as adjuvant single drug therapy.
  • the present invention finds that the use of a non-toxic low dose of an alkylating agent anticancer drug (such as TMZ) to cause DNA damage, combined with an effective dose of a PARP inhibitor with a capture function (such as 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, senaparib), can cause synthetic lethality, and obtain low toxicity and high anticancer efficacy.
  • an alkylating agent anticancer drug such as TMZ
  • a PARP inhibitor with a capture function such as 5-fluoro-1-(4-fluoro-3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)quinazoline-2,4(1H,3H)-dione, senaparib
  • the present invention provides an anti-tumor compound preparation, which contains active ingredients and pharmaceutically acceptable adjuvants, and the active ingredients are 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%.
  • the complex Based on the total weight of the prescription, the content of senaparib is 2.0%-10.0%. In some embodiments, based on the total weight of the compound preparation, the content of senaparib is 4.0%-10.0%. In some embodiments, based on the total weight of the compound preparation, the content of temozolomide is 2.0%-8.0%.
  • the ratio of senaparib content to temozolomide content is 1-8. In some embodiments, in the compound preparation of the present invention, the ratio of the content of senaparib to the content of temozolomide is 2-4. In some embodiments, the amount of temozolomide contained in the compound preparation is such that when one or more doses of the compound preparation are administered to meet the daily dosage, the amount of temozolomide ingested by the individual is about 1/12 to about 1/5 of the known daily dose of temozolomide when used alone or in combination with other drugs.
  • the daily dose of temozolomide ingested by the individual is about 5 mg to about 40 mg; in some embodiments, the daily dose of temozolomide ingested by the individual is about 5 mg to about 30 mg; in some embodiments, the daily dose of temozolomide ingested by the individual is about 10 mg to about 20 mg. In some embodiments, one dose of the compound preparation contains senaparib and temozolomide to meet the daily dosage requirement.
  • each dose of the compound preparation contains 10 mg to 80 mg of senaparib. In some embodiments, in the compound preparation, each dose of the compound preparation contains 20 mg to 40 mg of senaparib.
  • the content of senaparib is 4.0% to 10.0%
  • the content of temozolomide is 2.0% to 8.0%
  • each dose of the compound preparation contains 5 mg to 30 mg of temozolomide.
  • each dose of the compound preparation contains 10 mg to 80 mg of senaparib.
  • each dose of the compound preparation contains 10 mg to 40 mg of senaparib.
  • less than 5wt%, more preferably less than 1wt%, of senaparib contained in the compound preparation of the present invention is in crystalline form.
  • the pharmaceutically acceptable auxiliary materials described herein include one or more of carriers, fillers, disintegrants, glidants, lubricants, binders, solubilizers, surfactants and pH regulators.
  • the carrier is a commonly used carrier for preparing solid dispersions of active pharmaceutical ingredients, including succinic hypromellose acetate, hydroxypropylmethylcellulose phthalate, and optional surfactants, etc., preferably hydroxypropylmethylcellulose phthalate.
  • the carrier is a carrier that complies with the regulations of various pharmacopoeias. Calculated on a dry basis, in the exemplary hydroxypropyl methylcellulose phthalate, the content of methoxyl group is 12.0% to 28.0%, the content of 2-hydroxypropoxyl group is 4.0% to 23.0%, and the content of acetyl group is 2.0% to 16.0%. %, the content of succinyl group is 4.0% ⁇ 28.0%.
  • An exemplary hydroxypropyl methylcellulose phthalate is HP-55.
  • the weight ratio of senaparib to the carrier may be 1:2 to 1:3.
  • the content of hydroxypropyl methylcellulose phthalate is 7%-30%, more preferably 13%-20%.
  • the combination formulations described herein contain a surfactant.
  • exemplary surfactants include poloxamers.
  • the content of the surfactant is 0.5% to 2.2% of the total weight of the compound preparation, preferably 0.9% to 1.5%.
  • the combination formulations described herein comprise a solid dispersion of senaparib comprising senaparib, hydroxypropylmethylcellulose phthalate as described herein, and optionally a surfactant.
  • the weight ratio of senaparib to hydroxypropylmethylcellulose phthalate is 1:2 to 1:3.
  • the solid dispersion described herein is the solid dispersion disclosed in PCT/CN2016/078262, the entire contents of which are incorporated herein by reference.
  • hydroxypropyl methylcellulose phthalate accounts for 65%-77% of the total weight of the solid dispersion, more preferably 73%-77%; senaparib accounts for 23%-35% of the total weight of the solid dispersion.
  • the solid dispersion consists of senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 to 1:3.
  • the solid dispersion consists of senaparib and hydroxypropylmethylcellulose phthalate in a weight ratio of 1:2 or 1:3.
  • the solid dispersion further contains the surfactant.
  • the content of the surfactant is 2-5%.
  • the solid dispersion consists of senaparib, hydroxypropylmethylcellulose phthalate and poloxamer in a weight ratio of 1:2.8:0.2.
  • less than 10 wt%, preferably less than 5 wt%, more preferably less than 1 wt% of senaparib in the solid dispersion used in the present application is in crystalline form, most preferably no senaparib in crystalline form.
  • the content of the solid dispersion is 8% to 60%. In some embodiments, based on the total weight of the compound preparation, the content of the solid dispersion is 8%-40%. In some embodiments, based on the total weight of the compound preparation, the content of the solid dispersion is 15%-40%.
  • the filler may be selected from one or more of starch, pregelatinized starch, mannitol, lactose, sucrose, cyclodextrin and microcrystalline cellulose.
  • the filler used in the compound preparation described herein is one or more of microcrystalline cellulose, mannitol and lactose.
  • the content of the filler may be 20%-85%.
  • the filler contains The amount is 56% to 85%.
  • the filler content is 70%-82%.
  • the filler content is 75%-82%.
  • the filler comprises microcrystalline cellulose.
  • the D90 of the microcrystalline cellulose is 170-480 ⁇ m. In some embodiments, the D90 of the microcrystalline cellulose is 170-283 ⁇ m. In other embodiments, the D90 of the microcrystalline cellulose is 275-480 ⁇ m. Described D90 adopts Malvern Mastersizer 2000 laser particle size analyzer, according to particle size and particle size distribution measurement method, is measured with the refractive index of test sample 1.45.
  • the content of microcrystalline cellulose is 8% to 50%. In some embodiments, based on the total weight of the pharmaceutical composition, the content of microcrystalline cellulose is 10%-28%, preferably 15%-20%.
  • the filler also includes mannitol.
  • the particle size distribution of particle size > 75 ⁇ m is not less than 70%, preferably not less than 80%.
  • the particle size distribution of said mannitol with a particle size >75 ⁇ m is not less than 90%.
  • the particle size distribution is measured by a dry method using a laser particle size analyzer; wherein, the vibration injection speed is 15% to 30%, the Auger Speed is 30% to 45%, and the shading range is 4% to 12%.
  • the content of mannitol is 20%-70%. In some embodiments, based on the total weight of the pharmaceutical composition, the content of mannitol is 50%-65%, preferably 55%-65%.
  • the fillers are microcrystalline cellulose and mannitol, wherein the D90 of the microcrystalline cellulose is 170-480 ⁇ m, preferably 275-480 ⁇ m, and in the mannitol, the particle size distribution of the particle size > 75 ⁇ m is not less than 70%, preferably not less than 80%, more preferably not less than 90%.
  • the content of microcrystalline cellulose is 8% to 50%, preferably 10% to 28%, more preferably 15% to 20%; the content of mannitol is 20% to 70%, preferably 50% to 65%, more preferably 55% to 65%.
  • the amount of mannitol used is 0.5 to 8 times, such as 0.5 to 1, or 2 to 8 times the amount of microcrystalline cellulose (by weight).
  • the disintegrating agent may be selected from sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, carboxymethyl cellulose calcium, pregelatinized starch, sodium alginate and any combination thereof.
  • the disintegrant is crospovidone, sodium starch glycolate, or a mixture thereof.
  • the content of the disintegrant may be 0.1%-10%, preferably 0.5%-4%.
  • the disintegrant is crospovidone and/or sodium starch glycolate, and the total content of crospovidone and/or sodium starch glycolate is 0.5%-4% based on the total weight of the compound preparation.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • the glidant may be selected from powdered cellulose, magnesium trisilicate, colloidal silicon dioxide, talc and any combination thereof.
  • a preferred glidant is colloidal silicon dioxide.
  • the content of the glidant may be 0.1%-10%, preferably 0.5%-3%, more preferably 1%-3%.
  • the lubricant may be selected from zinc stearate, glyceryl monostearate, glyceryl palmitate stearate, magnesium stearate, sodium stearate fumarate and any combination thereof.
  • a preferred lubricant is magnesium stearate.
  • the content of the lubricant may be 0.1%-3%, preferably 0.3%-1%, such as 0.5 ⁇ 0.1%.
  • the pH regulator is an acidic pH regulator, which can 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 regulator is tartaric acid. Based on the total weight of the compound preparation, the content of the acidic pH regulator is 0.1%-5%, preferably 0.1%-3%.
  • the compound preparation herein may also contain binders.
  • the binder can be selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, povidone and any combination thereof.
  • a preferred binder is hydroxypropyl cellulose.
  • the content of the binder is 0.1%-5%, preferably 0.1%-3%.
  • the compound preparation herein may also contain surfactants and/or coating materials.
  • the surfactant may be selected from one or more of sodium lauryl sulfate, poloxamer, taurine, lauroyl polyoxyethylene (6, 8, 12, 32) glyceride and polysorbates.
  • the coating material can be selected from Opadry full formula film coating system.
  • compositions such as carriers, surfactants, fillers, disintegrants, glidants, lubricants, binders, pH regulators and coating materials, etc. are all pharmaceutically acceptable carriers routinely used in this field and meet the requirements of various pharmacopoeias.
  • the compound preparation of the present invention 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%; carrier, 7% to 30%, preferably 13% to 20%; filler, 56% to 85%, preferably 70% % ⁇ 82%, more preferably 75% ⁇ 82%; disintegrant, 0.1% ⁇ 10%, preferably 0.5% ⁇ 4%; glidant, 0.1% ⁇ 10%, preferably 0.5% ⁇ 3%, more preferably 1% ⁇ 3%; lubricant, 0.1% ⁇ 3%, preferably 0.3% ⁇ 1%; pH regulator, 0.1% ⁇ 5%, preferably 0.1% ⁇ 3%; 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 the senaparib to the carrier is 1:2 to 1:3,
  • the compound preparation of the present invention contains: solid dispersion of senaparib, 8%-60%; temozolomide, 1.0%-10.0%, preferably 2.0%-8.0%; filler, 56%-85%, preferably 70%-82%, more preferably 75%-82%; disintegrant, 0.1%-10%, preferably 0.5%-4%; .1% to 10%, preferably 0.5% to 3%, more preferably 1% to 3%; lubricant, 0.1% to 3%, preferably 0.3% to 1%; pH regulator, 0.1% to 5%, preferably 0.1% to 3%; and optional binder, 0.1% to 5%, preferably 0.1% to 3%; It is composed of acid ester, and less than 5wt%, more preferably less than 1wt% of senaparib is in crystalline form; preferably, the filler is microcrystalline cellulose and mannitol, wherein the D90 of microcrystalline cellulose is 170-480 ⁇ m, preferably 275-
  • the compound preparation is an oral solid preparation, preferably a tablet, capsule or granule.
  • the compound preparation is a capsule, preferably, the capsule shell of the capsule is selected from a vegetable capsule shell and a gelatin capsule shell, preferably a gelatin capsule shell.
  • the present invention provides a method for preparing the compound preparation of the present invention, the method comprising providing a mixture containing temozolomide and some adjuvants, then mixing senaparib and the remaining adjuvants with the mixture to prepare a final mixture, and preparing the compound preparation, such as capsules or tablets, from the final mixture.
  • the lubricant can be added last (part of the total lubricant contained in the compound preparation can be contained in the mixture containing temozolomide and part of the excipients, or part of it can be mixed with the mixture containing temozolomide and part of the excipients together with senaparib combined, so the lubricant added last is the remaining lubricant) and mixed again with the previously prepared mixture containing senaparib and temozolomide to obtain the final mixture.
  • the method comprises: mixing senaparib and the remaining auxiliary materials except the lubricant with the first mixture to obtain a second mixture, and then mixing the second mixture with the remaining lubricant to prepare the final mixture; or mixing senaparib with part of the lubricant, part of the glidant, and all the remaining other auxiliary materials with the first mixture to obtain the second mixture, and then mixing the second mixture with the remaining lubricant and glidant to prepare the final mixture.
  • the first mixture may contain temozolomide, fillers, disintegrants and pH regulators, and optionally one or more of glidants, lubricants and binders.
  • the various excipients contained in the first mixture may be only a part or all of the corresponding excipients contained in the compound preparation.
  • the filler in the first mixture can be one or both of the two or more fillers used in the compound preparation; for example, when using mannitol and microcrystalline cellulose as described herein as fillers, the filler contained in the first mixture can be all the microcrystalline cellulose contained in the compound preparation.
  • the filler in the first mixture is a part of each filler used in the compound preparation; as when using mannitol and microcrystalline cellulose as described herein as fillers, the first mixture may contain 5 to 15 wt% or 8 to 12 wt% of mannitol and 15 to 28 wt% or 20 to 24 wt% of microcrystalline cellulose, and the percentage by weight is based on the respective total weight of the mannitol and microcrystalline cellulose used in the compound preparation.
  • the glidant when the first mixture contains a glidant, can be all the glidant contained in the compound preparation, or a part such as 1-5wt% of the glidant; when the first mixture contains a lubricant, the lubricant can be all the lubricant contained in the compound preparation, or a part such as 2-10wt% of the lubricant; Disintegrant.
  • the first mixture is mixture a, which contains temozolomide, a pH regulator (such as tartaric acid), mannitol accounting for 5-15wt% or 8-12wt% of the total weight of mannitol in the compound preparation, a glidant (such as silicon dioxide) accounting for 1-5wt% of the total weight of silica in the compound preparation, a lubricant (such as stearic acid) accounting for 2-10wt% of the lubricant contained in the compound preparation, and 15-28wt in the total weight of microcrystalline cellulose in the compound preparation.
  • the first mixture is mixture b, which contains temozolomide, microcrystalline cellulose, a pH regulator and a disintegrant.
  • the first mixture is mixture c, which contains temozolomide, microcrystalline cellulose, pH regulator, disintegrant and binder.
  • the preparation of the first mixture includes: adding each component of the first mixture into a mixer, and mixing at a rotational speed of 40-55 rpm. It should be understood that the mixing time can be determined according to the amount of materials and the performance of the mixer. Exemplary mixing times are 1 to 5 minutes.
  • the mixture after mixing the first 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 of dry granulation can be set as roller pressure 2-4kN, roller speed 1-5rpm, feed speed 25-35rpm, and pass through a 24-mesh sieve.
  • the second mixture comprises the first mixture, senaparib, and the remaining materials except lubricant.
  • all other materials (including senaparib) except the lubricant are mixed with the first mixture, and mixed at a rotation speed of 40-55 rpm for 1-5 minutes to obtain the second mixture.
  • the second mixture is passed through a 30-mesh sieve, and then mixed with the lubricant to obtain the final mixture, which can be made into capsules or tablets.
  • the second mixture contains the first mixture, senaparib, a glidant accounting for 40-60 wt% of the glidant contained in the compound preparation, a lubricant accounting for 55-75 wt% of the lubricant contained in the compound preparation, and the remaining other materials.
  • the glidant accounting for 40-60 wt% of the glidant contained in the compound preparation the lubricant accounting for 55-75 wt% of the lubricant contained in the compound preparation, and the remaining other materials are mixed with the first mixture, and mixed at a speed of 40-55 rpm for 1-5 minutes to obtain the second mixture.
  • the second mixture is passed through a 30-mesh sieve, and then mixed with the remaining glidant and lubricant to obtain the final mixture.
  • the final mixture is made into tablets.
  • the preparation method of the compound preparation of the present invention also includes the preparation method of the solid dispersion.
  • the preparation method of an exemplary dispersion includes: dissolving senaparib and hypromellose phthalate in a mixed solution of tetrahydrofuran and methanol (7:3, v/v), spray-drying the resulting solution, and collecting the spray-dried particles obtained by vacuum drying to obtain the dispersion.
  • the senaparib-containing mixture generally contains a certain amount of fillers and glidants, and optionally contains one or more of disintegrants, binders and lubricants.
  • the mixture containing temozolomide may generally contain a certain amount of fillers, pH regulators and disintegrants, and may optionally contain one or more of binders, glidants and lubricants.
  • the preparation method of the present invention is characterized in that auxiliary materials are gradually added and premixing times are increased, thereby improving the mixing uniformity of temozolomide.
  • the present invention provides a kit, which contains the compound preparation described in any embodiment herein.
  • the quantity of the compound preparation contained in the kit satisfies the patient's administration for at least one day; wherein, the dosage for one day is: 20-100 mg of senaparib, and 5-30 mg of temozolomide; more preferably, the dosage for one day is: 20-80 mg of senaparib, and 10-20 mg of temozolomide.
  • the present invention also provides the application of the compound preparation described in any embodiment herein in the preparation of a drug for treating cancer; preferably, the cancer is selected from: liver cancer, melanoma, Hodgkin's disease, non-Hodgkin's lymphoma, acute lymphoblastic leukemia, chronic lymphocytic 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 insulinoma, malignant carcinoid cancer, choriocarcinoma, mycosis granuloma, head and neck cancer, osteogenic sarcoma, pancreatic cancer, acute myeloid leukemia, hairy cell leukemia, rhabdomyosarcoma, Ka
  • the two active ingredients in the pharmaceutical composition of the present invention can produce a synergistic effect, can reduce the dosage of PARP inhibitor and temozolomide at the same time, and improve the safety and tolerance of medication.
  • the present invention develops formulation prescriptions and processes in a targeted manner, adopts suitable pharmaceutically acceptable excipients and processes, successfully realizes the combination of senaparib and temozolomide in the same formulation unit, obtains oral solid compound preparations with good oral bioavailability, uniform content and good stability, and realizes large-scale production while improving drug compliance of patients.
  • Moisture detection method take the sample to be tested and weigh it, then heat it with an infrared radiator, continuously record the lost mass, stop drying when the specified requirements are met, and automatically calculate the moisture content through the differential weight.
  • Example 1 Effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell NCI-H209
  • the CCK-8 detection method was used to determine the inhibitory effect of senaparib combined with TMZ on the growth of human small cell lung cancer cell NCI-H209.
  • the resuscitated human small cell lung cancer cells NCI-H209 were inoculated into a culture dish, added with experimental medium (RPMI1640+20% FBS), and placed in a 37°C, 5% CO 2 incubator for static culture.
  • Single drug add 5 ⁇ L diluted culture medium containing the corresponding concentration of compound and 5 ⁇ L medium respectively; combined drug: add 5 ⁇ L diluted medium containing the corresponding concentration of compound and 5 ⁇ L medium containing the final concentration of 50 ⁇ M TMZ respectively.
  • the final concentration of DMSO was 2 ⁇ .
  • the plate was then placed in a 37°C, 5% CO 2 incubator for 5 days. Add 20 ⁇ L of CCK-8 detection reagent to each well, continue to incubate for 2 hours, shake for 10 minutes and place in a multi-function reader to read the absorbance value (OD value) at 450/650 nm wavelength.
  • % cell viability OD compound /OD DMsO x 100.
  • the combined drug index was calculated using Calc ⁇ Syn software.
  • Table 1 summarizes the inhibitory effect data (IC 50 ) of each compound and its combination on the growth of human small cell lung cancer cell NCI-H209.
  • Table 2 lists the combination index (CI) of senaparib and TMZ.
  • CI ⁇ 0.1 means that the drug combination has a strong synergistic effect
  • 0.1 ⁇ CI ⁇ 1 means that the drug combination has a synergistic effect
  • CI>1 means that there is no synergistic effect.
  • Table 1 Inhibitory effect data of compounds on human small cell lung cancer cell NCI-H209 growth (IC 50 )
  • the results show that the combination of senaparib and TMZ has a strong synergistic effect on inhibiting the proliferation of human small cell lung cancer NCI-H209 cells.
  • Example 2 In vivo pharmacodynamic study of senaparib combined with TMZ in NCI-H209 human small cell lung cancer xenograft model in nude mice
  • N is the number of animals, 10 tumor-bearing nude mice in each group; p.o. is oral administration; QD is once a day; continuous administration for 21 days.
  • the solvent, the composition is 10% DMSOin10% HP- ⁇ -CD PBS.
  • the vehicle control group was intragastrically administered 20 ⁇ L/g vehicle according to body weight; the TMZ and senaparib single administration group was intragastrically administered 10 ⁇ L/g vehicle first, and then intragastrically administered 10 ⁇ L/g drug; the combined administration group was intragastrically administered 10 ⁇ L/g TMZ first, and then 30 minutes later intragastrically administered 10 ⁇ L/g senaparib of the corresponding concentration.
  • body weight change (%) (W t -W 1 )/W 1 ⁇ 100%, where W 1 was the body weight measured during the group administration (i.e. D1), and W t was the body weight on the recording day.
  • Body weight change (%) was a measure of treatment-related toxicity (mean weight loss greater than 15%, treatment stopped or regimen adjusted until recovery; mean body weight loss greater than 20%, experiment terminated).
  • the evaluation index of anti-tumor activity is expressed as relative tumor proliferation rate T/C (%) and tumor growth inhibition rate TGI (%).
  • mice were randomly selected in each group, and 300 ⁇ L of whole blood was collected from the orbits into BD K2 EDTA anticoagulant tubes (REF367841) for blood routine testing.
  • Graph-Pad Prism 6.0 software two-way ANOVA was used to carry out mean and relative tumor volumes among the groups. Comparison of mean tumor volumes. Compared with the control group (vehicle), * p ⁇ 0.05 (with statistical difference), ** p ⁇ 0.01 (with significant statistical difference), *** p ⁇ 0.001 (with extremely significant statistical difference); compared with TMZ group, # p ⁇ 0.05 (with statistical difference), ## p ⁇ 0.01 (with significant statistical difference), ### p ⁇ 0.001 (with extremely significant statistical difference); compared with senaparib group, + p ⁇ 0.05 (statistical difference), ++ p ⁇ 0.01 (significant statistical difference), +++ p ⁇ 0.001 (very significant statistical difference).
  • Average body weight change (%) the average weight change (%) of nude mice in each group compared with the initial body weight at the beginning of treatment.
  • the TMZ 3mg/kg and senaparib 10mg/kg single administration groups had no significant inhibitory effect on tumor proliferation, while the combined administration had a very significant inhibitory effect on tumor proliferation (p ⁇ 0.0001); compared with the single administration group, the two combined administration groups showed a significant synergistic effect of the combination of TMZ and senaparib (p ⁇ 0.0001).
  • Tumor volume decreased in the co-administered group of senaparib 10mg/kg and TMZ 3mg/kg compared with day 0. The specific results are shown in Table 5 below.
  • 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.
  • mice in each group were taken for blood routine testing.
  • the erythrocytes in all the drug groups did not decrease significantly, and were within the normal range; the platelets did not change much, but increased slightly in the combination drug group.
  • All administration groups showed a decrease in leukocytes. The reduction in the combination drug group was more obvious, but it was still within a reasonable range, and the toxic effects on animals were limited.
  • senaparib combined with TMZ administered once a day for 21 consecutive days showed a very significant anti-tumor effect on the NCI-H209 human small cell lung cancer nude mouse xenograft tumor model, and had obvious synergistic effects.
  • the body weight of the high-dose combined administration group only slightly decreased, and no obvious toxic and side effects were observed.
  • Embodiment three the preparation of senaparib solid dispersion
  • An exemplary preparation method includes: dissolving senaparib and hypromellose 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 a solid dispersion of senaparib. After testing, in the solid dispersion powder, the crystalline form of senaparib is less than 1wt%.
  • Embodiment four auxiliary material screening
  • Capsules were prepared according to the formula shown in Table 8 below (the dosage of each component is in mg), and the excipients were screened.
  • microcrystalline cellulose D90: 170-283 ⁇ m.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • Capsule preparation method Add the respective components of the capsule into a universal mixer, and mix at 40 rpm for 5 minutes. Then use a 40-mesh sieve to sieve; the sieved material was mixed at 40 rpm for 8 minutes. Magnesium stearate was passed through a 30-mesh sieve and added to the universal mixer, and then mixed at 40 rpm for 3 minutes. The obtained mixed powder is filled into gelatin hollow capsule shells to obtain oral capsules.
  • the mixed powder of capsules 1-4 has significantly increased bulk density, significantly decreased Carr index, and significantly improved material fluidity.
  • the particle size control range of the filler (microcrystalline cellulose) in capsules 1-4 is D90: 170-283 ⁇ m, and the particle size control range of mannitol is greater than 75 ⁇ m (200 mesh) and the particle size distribution is not less than 70%, which effectively improves the fluidity of the material and meets the filling requirements.
  • Oral capsules 5-7 containing senaparib solid dispersion were prepared according to the formula shown in Table 10 below (the dosage of each component is in mg).
  • the prescription for a single 10mg capsule is:
  • microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) must not be smaller than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • Preparation method Add the ingredients of each capsule into a hopper mixer and mix for 3 minutes at 15 rpm. Then use a 30-mesh sieve to sieve; the sieved material was mixed at 15 rpm for 10 minutes. Magnesium stearate was passed through a 30-mesh sieve and added to the mixer, and then mixed at 15 rpm for 3 minutes. The obtained mixed powder is filled into gelatin hollow capsule shells to obtain oral capsules.
  • the mixed powder of capsules 5-7 has significantly increased bulk density, significantly decreased Carr index, and significantly enhanced material fluidity.
  • Table 15 Test data of content uniformity of capsules 5-7
  • the particle size of the filler (microcrystalline cellulose) in capsules 5-7 is D90: 275-480 ⁇ m.
  • the particle size control range of mannitol is greater than 75 ⁇ m (200 mesh) and the particle size distribution is not less than 90%.
  • the particle size of the filler is nearly double that of capsules 1-4, which further improves the fluidity of materials and the adaptability of capsule filling on automatic equipment.
  • it is surprisingly found that the increase of the particle size of the auxiliary material will not lead to the phenomenon of stratification and uneven content of the material during the mixing and filling process.
  • the mixing uniformity of the formula materials is better, and the content uniformity of the finished capsule is better, indicating that the formula can well improve the physical and chemical properties of the solid dispersion powder, and meet the requirements of the direct mixing filling capsule process. At the same time, it has the required dissolution characteristics.
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3. It has been detected that the crystalline form of senaparib in the solid dispersion is ⁇ 1wt%.
  • the particle size control range of microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) shall not be less than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • comparative compound capsule 1 Temozolomide and other auxiliary materials were sieved and mixed for 10 minutes to obtain a temozolomide premix, which was packed into a gelatin hollow capsule shell by a capsule filling machine to obtain comparative compound capsule 1.
  • the first mixture is passed through a 20-mesh sieve, and the sieved material is re-added to the universal mixer of step (1), and after mixing for 10 minutes at a rotating speed of 46 rpm, dry granulation is carried out with a dry granulator using the following parameters: roller pressure 3kN, roller speed 2rpm, feed speed 30rpm, large sieve sieve mesh is 24 mesh;
  • step (3) Add the senaparib solid dispersion, the remaining mannitol, the remaining silicon dioxide, the remaining microcrystalline cellulose and the remaining crospovidone into the universal mixer of step (1), and mix with the granules prepared in step (2) at a speed of 46 rpm for 3 minutes to obtain the second mixture;
  • step (3) Pack the final mixture obtained in step (3) into gelatin hollow capsule shells with a capsule filling machine to obtain the compound capsule 2.
  • step (1) adding the solid dispersion of senaparib, mannitol and silicon dioxide into the mixing equipment of step (1) to mix with the first mixture to obtain the second mixture;
  • step (3) Compress the final mixture obtained in step (3) into a plain tablet, and then coat the compressed tablet to obtain the oral tablet 3 .
  • step (3) Compress the final mixture obtained in step (3) into a plain tablet, and then coat the plain tablet to obtain the oral tablet.
  • Embodiment 6 Preparation and dissolution rate of senaparib and temozolomide oral compound capsule
  • Compound capsules 3-6 were prepared according to the formula shown in Table 19.
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3, and the crystalline form of senaparib in the solid dispersion powder is less than 1%.
  • the particle size control range of microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) shall not be less than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • the preparation method of compound capsule 3-6 comprises the following steps:
  • Dissolution testing method refer to the second method (paddle method) of "Chinese Pharmacopoeia” 2015 edition general rule ⁇ 0931> (dissolution and release testing method), set the water bath temperature of the automatic sampling dissolution apparatus to 37 ⁇ 0.5°C, select 0.1N hydrochloric acid buffer solution containing 1% CTAB as the dissolution medium, and the volume is 900mL.
  • the dissolution medium used in compound capsule 7 is 0.1N hydrochloric acid buffer solution containing 3% CTAB, and other dissolution conditions are the same as compound capsule 3-5.
  • Embodiment seven the preparation and the dissolution rate of the compound capsule of senaparib and temozolomide containing different fillers and disintegrants
  • Compound Capsules 7-9 were prepared according to the formula shown in Table 21. Detect 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. The dissolution detection method is the same as in Example 6, and the results are shown in Table 22.
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3, and the crystalline form of senaparib in the solid dispersion powder is ⁇ 1 wt%.
  • Embodiment 8 Preparation and dissolution rate of oral compound capsules containing senaparib and temozolomide in different proportions of fillers and different lubricants
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3, and the crystalline form of senaparib in the solid dispersion powder is ⁇ 1 wt%.
  • the particle size control range of microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) shall not be less than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • Embodiment 9 Preparation and dissolution rate of compound capsules of senaparib and temozolomide with different disintegrant dosages
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3. It has been detected that the crystalline form of senaparib in the solid dispersion is ⁇ 1wt%.
  • the particle size control range of microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) shall not be less than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • Embodiment 10 Oral compound of senaparib and temozolomide containing different proportions of acidic pH additives Capsule preparation and dissolution
  • Compound Capsules 14-16 were prepared according to the formula shown in Table 27, and the method described above was used to detect the mixing uniformity of temozolomide in the final mixture of each compound capsule and the dissolution rate of senaparib in the final product capsule.
  • the dissolution detection method was the same as in Example 6, and the results were shown in Table 28.
  • the solid dispersion is composed of senaparib and hypromellose phthalate HP-55 in a weight ratio of 1:3. It has been detected that the crystalline form of senaparib in the solid dispersion is ⁇ 1wt%.
  • the particle size control range of microcrystalline cellulose is D90: 275-480 ⁇ m.
  • Mannitol particle size control the particle size distribution greater than 75 ⁇ m (200 mesh) shall not be less than 90%.
  • the particle size control range of crospovidone is D90: 270-385 ⁇ m.
  • Embodiment 11 Stability comparison of Compound Capsule 14 and TMZ single reference preparation (marketed product)
  • the stability of the compound capsule 14 prepared in Example 10 and the TMZ single reference preparation was tested under accelerated conditions (40° C./75% RH).
  • the staking time points are 0/1/3 month and 0/3 month respectively.
  • the inspection items such as TMZ content and related substances were detected at each time point, and the results are shown in Table 29.
  • the compound capsule 15 was placed under accelerated conditions for 3 months, the content did not change significantly, and the total impurity content increased slightly, but the increase was smaller than that of the TMZ single prescription reference preparation, which could meet the stability requirements.
  • Comparative Example 1 Toxicity and tumor inhibitory effects of low-dose senaparib+high-dose TMZ in MX-1 human breast cancer mouse model
  • the filtered cell suspension into a sterile centrifuge tube at 1000rpm for 5min. Discard the supernatant, resuspend the pellet with sterile PBS, and wash once at 1000 rpm for 5 min. Discard the supernatant, add an appropriate amount of PBS to resuspend, count, and adjust the number of cells to 5 ⁇ 10 6 /mL.
  • the cell suspension was mixed well, and 5 ⁇ 10 5 cells (0.1 mL) per mouse were injected subcutaneously at the axilla of the right forelimb of the mouse. When the average volume of the tumor reaches about 50mm 3 , randomize the group according to the tumor volume and start dosing, grouping and dosing See Table 30 for the scheme.
  • the vehicle, the composition is 10% DMSO in 10% HP- ⁇ -CD PBS.
  • the vehicle control group was intragastrically administered 20 ⁇ L/g vehicle according to body weight; the TMZ and senaparib single administration group was intragastrically administered 20 ⁇ L/g of the drug; the combined administration group was first intragastrically administered 10 ⁇ L/g of AZD2281 or senaparib at the corresponding concentration, and then 10 ⁇ L/g TMZ was intragastrically administered after 45 minutes.
  • tumor diameter dynamically observe the anti-tumor drug effect of the test substance. Tumor volume and animal body weight were measured daily.
  • both the TMZ administration group and the combined administration group had different degrees of weight loss.
  • the body weight of the senaparib 1mg/kg combined with TMZ administration group decreased by 15%, and the AZD2281 20mg/kg combined with TMZ administration group lost about 12%.
  • the average body weight of each group is shown in Table 31.
  • the relative tumor proliferation rate [T/C (%)] of each group after administration for 5 days during the experiment is shown in Table 32 below.
  • senaparib combined with TMZ administered once a day for 5 consecutive days showed a significant anti-tumor effect on the nude mouse xenograft tumor model of MX-1 human small cell lung cancer, and had a synergistic effect.
  • the body weight of the mice decreased significantly (up to 15%).
  • the tumor volume began to increase continuously on the 10th day.

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Abstract

La présente invention concerne une préparation de composé de senaparib et de témozolomide et son procédé de préparation. La préparation de composé contient des principes actifs et des adjuvants pharmaceutiquement acceptables, les principes actifs étant le senaparib et le témozolomide, sur la base du poids total de la préparation de composé, la teneur en senaparib est de 2,0 à 15,0 %, et la teneur en témozolomide est de 1,0 à 10,0 %. Dans la préparation de composé préparée par le procédé de la présente invention, les deux médicaments présentent un bon taux de dissolution et une bonne uniformité et une bonne stabilité de contenu.
PCT/CN2023/073208 2022-01-21 2023-01-19 Préparation de composé de senaparib et de témozolomide et son procédé de préparation WO2023138667A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103097361A (zh) * 2011-04-01 2013-05-08 南京英派药业有限公司 1-(芳基甲基)喹唑啉-2,4(1h,3h)-二酮作为parp抑制剂及其应用
US20180071290A1 (en) * 2015-04-03 2018-03-15 Impact Therapeutics, Inc. Solid Pharmaceutical Formulation of PARP Inhibitors and Use Thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103097361A (zh) * 2011-04-01 2013-05-08 南京英派药业有限公司 1-(芳基甲基)喹唑啉-2,4(1h,3h)-二酮作为parp抑制剂及其应用
US20180071290A1 (en) * 2015-04-03 2018-03-15 Impact Therapeutics, Inc. Solid Pharmaceutical Formulation of PARP Inhibitors and Use Thereof

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