WO2018108160A1 - 一种尼拉帕尼缓控释药物组合物及其用途 - Google Patents

一种尼拉帕尼缓控释药物组合物及其用途 Download PDF

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Publication number
WO2018108160A1
WO2018108160A1 PCT/CN2017/116561 CN2017116561W WO2018108160A1 WO 2018108160 A1 WO2018108160 A1 WO 2018108160A1 CN 2017116561 W CN2017116561 W CN 2017116561W WO 2018108160 A1 WO2018108160 A1 WO 2018108160A1
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release
weight
sustained
nilapani
parts
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PCT/CN2017/116561
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English (en)
French (fr)
Inventor
甘勇
孟冰雪
刘彦
朱春柳
郭仕艳
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苏州苏融生物医药有限公司
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Priority to CN201780075179.9A priority Critical patent/CN110035744A/zh
Publication of WO2018108160A1 publication Critical patent/WO2018108160A1/zh
Priority to US16/442,049 priority patent/US20190290629A1/en

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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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the present invention relates to the field of biopharmaceuticals, and in particular to a nilapani sustained-release pharmaceutical composition and a medicament thereof for preparing a medicament for preventing or treating a tumor, the composition according to the invention having a controlled release behavior, blood in vivo Drug concentration and PARP enzyme inhibitory activity.
  • Niraparib chemical name: (S)-2-(4-(piperidin-3-yl)phenyl)-2H-carbazole-7-carboxamide, the molecular formula is C 19 H 20 N 4 O, molecular weight 320.39, with the following chemical structure:
  • Nilapani (trade name Zejula) is a PARP enzyme inhibitor developed by the US biopharmaceutical company Tesaro. It was approved by the US Food and Drug Administration (FDA) in December 2014 and submitted to China CFDA in August 2017. A clinical application was submitted for indications of maintenance therapy in patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who responded completely or partially to platinum-based chemotherapy.
  • PARP polyadenosine diphosphate-ribose polymerase
  • BRCA1 and BRCA2 genes proteins encoded by BRCA1 and BRCA2 genes are involved in the repair of DNA double-strand damage through the homologous recombination (HR) pathway.
  • HR homologous recombination
  • PARP Poly ADP transferase
  • Tesaro's new drug application form is an immediate release capsule preparation of nilapanitrione tosylate monohydrate, the specification is 100mg (in Nilapani), and several clinical studies show that (FDA reviews, NDA) 4074987), Nilapani absorbs faster, oral bioavailability can reach 73%, blood concentration peak time is 3 hours, plasma half-life is more than 30 hours, and its plasma exposure is not affected by food, its exposure The maximum blood drug concentration is multiplied with the dose increase.
  • the clinical phase II/III dose is 300 mg/time/day, and the steady-state blood concentration is reached on days 12-14, and the peak and trough values are about 4.4 ⁇ M and 2.0 ⁇ M, respectively.
  • the conventional oral immediate release capsules currently under study still have certain limitations, mainly manifested by dose-limiting toxicity, and the steady-state blood drug concentration peak is several times or even ten times higher than the PARP enzyme IC90 value, resulting in more serious
  • the toxic side effects limit the efficacy of the drug.
  • the dose-limiting toxicity of nilapani is thrombocytopenia and anemia.
  • 69% of patients have reduced dose or dose discontinuation due to toxic side effects
  • 15% of patients discontinue treatment due to toxic side effects and 25% of patients have 3 -4 grade anemia
  • the object of the invention is to develop a nilapani pharmaceutical composition, which can accurately regulate the absorption rate and absorption time of nilapani in the gastrointestinal tract by controlling the release behavior, prevent the blood concentration from rising, and regulate nilapani.
  • the level of blood concentration in the body and its fluctuation range increase and maintain the blood concentration required for PARP enzyme inhibition in the body, further improve the anti-tumor effect of nilapani, and reduce the adverse reactions after administration.
  • Another object of the present invention is to provide an excellent formulation that minimizes the size and/or amount of tablets or capsules required for a therapeutically effective dose, with as low a frequency as possible, to improve patient compliance.
  • the present invention discloses a nilapani pharmaceutical composition with controlled release in vivo.
  • Nilapani instant release capsules often leads to high steady-state blood drug peak concentration after oral administration.
  • the excessive peak value leads to many side effects, affecting the quality of life of patients, and dose-limiting toxicity. Affect the efficacy of drugs.
  • the present invention provides an in vivo absorption behavior, blood drug concentration and PARP enzyme inhibition level according to the biological properties of nilapani and the efficacy and safety requirements of clinical treatment for the defects of the current preparation.
  • the tunable Nirapani pharmaceutical composition further enhances the clinical efficacy of nilapani, reduces adverse reactions after administration of the tumor patient, and increases patient compliance.
  • the present invention relates to a combination of novel drugs with improved nilapani drug loading and/or oral absorption and/or bioavailability and/or blood drug concentration control and/or enzyme inhibition level control and their use as sole formulations or with others The combination of therapy for the treatment of cancer.
  • the Nilapani sustained-release pharmaceutical composition provided by the invention has a controlled release behavior, and the release behavior and the release amount are controllable in a release medium that meets the sump condition within a predetermined period of time.
  • the second method of the Chinese Pharmacopoeia dissolution method when the release behavior is measured in a buffer solution with a pH of 1.2-7.8 at 37 ° C, the release of nirapani is less than 50% of the total amount of nilapani in 1 hour. %, preferably 30%, more preferably 10-25%; the amount of nilapani released in 16 hours is greater than 80% of the total amount of nilapani, more preferably >90%.
  • Nilapani sustained-release pharmaceutical composition provided by the invention can control the absorption rate and absorption time of nilapani in the gastrointestinal tract by controlling the release behavior and the release amount, and the controlled absorption behavior is controlled by the body.
  • Nirapani blood concentration levels and their range of fluctuations maintain long-term homeostasis in the body of small blood concentration fluctuations.
  • the Nilapani pharmaceutical composition provided by the invention has an effective steady-state blood concentration trough value of 0.5 ⁇ M ⁇ C min, ss ⁇ 4 ⁇ M, or even 1 ⁇ M ⁇ C min, ss ⁇ 3 ⁇ M in the canine; steady-state blood concentration peak It is 0.8 ⁇ M ⁇ C max, ss ⁇ 6 ⁇ M, even 2 ⁇ M ⁇ C max, ss ⁇ 5 ⁇ M, and the steady-state plasma concentration peak/bottom value is preferably less than 2, more preferably less than 1.5.
  • the maximum blood concentration value (C max ) obtained by the nipalani at the same dose of the pharmaceutical composition provided by the invention is reduced by at least 10%-50%, and the blood concentration is up to
  • the peak time (T max ) is extended by at least 50% (even 200% - 600%).
  • the Nilapani sustained-release composition comprises a dissolution-improved form of nilapani and a matrix polymer for drug release rate adjustment, and depending on the dosage form, the composition may further comprise other additives, such as disintegration.
  • Agent plasticizer, Porogens, swelling materials, fillers, osmotic pressure regulators (also known as penetration enhancers), lubricants, binders (also known as binders), dyes (also known as colorants), anti-adherents
  • One of the pharmaceutical excipients also known as anti-adherents
  • opacifiers diluents
  • coated powders coated powders, semi-permeable controlled release coating materials, barrier materials, and/or other pharmaceutically acceptable additives
  • other pharmaceutically acceptable additives Kind or a combination of two or more.
  • the active drug nilapani in the nilapani sustained-release pharmaceutical composition provided by the invention belongs to the poorly soluble drug, and in order to achieve good absorption and oral bioavailability, the dissolution treatment can be firstly performed to obtain the dissolution. Improved form of nilapani to improve drug dissolution.
  • the solubilization treatment can be prepared as a nilapani salt, such as a hydrochloride, a phosphate, a besylate, a camphorate, a maleate, a sulfate, or the like; Or by mixing nirapani with a matrix polymer which can improve the solubility of the drug, the dispersion specific surface area in the powder of the active pharmaceutical preparation composition is changed, thereby improving the dissolution property of the drug, and the solubilization treatment can be Including co-milling, high pressure homogenization, coprecipitation, solvent evaporation or melt extrusion.
  • a special description such as nilapani hydrochloride, nilapani maleate, etc., said "nilapani” means nilapani free Alkali.
  • the improved dissolution form of nilapani comprises: a compound of the corresponding salt form of nilapani free base, a co-milled mixture prepared from nilapani with other matrix adjuvants, and nilapani nanocrystals Or a solid dispersion of nilapani or the like; wherein the compound in the form of a salt is a pharmaceutically acceptable salt thereof, which may be selected from the group consisting of hydrochloride, phosphate, besylate, maleate, sulfate, and dextromethon
  • the salt form of nilapani can significantly improve its water solubility, the salt form of the nilapani bulk drug can be directly used for the preparation of the controlled release preparation; and the nilapani co-milling mixture, the nanocrystal Or a solid dispersion consisting essentially of the active drug nirapani and a pharmaceutically acceptable solubility improving matrix polymer and optionally other additives such as plasticizers and the like.
  • the nilapani co-milling mixture of the present invention consists of the active drug nirapani, a matrix polymer for solubility improvement, and optionally other pharmaceutically acceptable additives, prepared by mixing and co-milling the ingredients. .
  • the particle size of the drug powder can generally be sufficiently ground to less than 100 microns.
  • the co-milling can increase the dispersion specific surface area of the drug in the solid preparation powder, thereby improving the dissolution properties of the drug.
  • the weight percentage of nilapani is 5 to 60% by weight, preferably 20 to 40% by weight, and the weight percentage of the matrix polymer for solubilization is 40 to 95% by weight.
  • %, preferably 40-80% by weight, other additives are 0-15% by weight, preferably 0.2-10% by weight. The total amount of each of the above components was 100% by weight.
  • the weight percentage of nilapani is 5 to 60% by weight, preferably 20 to 40% by weight, and it is understood that the lower limit includes any of 5 to 20%.
  • weight percentage of the matrix polymer for solubilization similarly to the above understanding, the weight percentage thereof is 40 to 95% by weight, preferably 40 to 80% by weight, which is understood to be in any range of 40-(80% to 95%). This is not repeated.
  • the nilapani nanocrystals of the present invention consist of the active drug nirapani, a matrix polymer, and optionally other additives, prepared by high pressure homogenization or coprecipitation of the components.
  • the high-pressure homogenization method is as follows: the crude crystal suspension prepared by the high-speed shearing of the active drug nilapani and the matrix polymer aqueous solution is added to a high-pressure homogenizer, and the high-pressure homogenization is repeated several times until The prepared crystal particles are up to 1000 nm or less, and the sample is lyophilized to prepare a uniformly dispersed Nilapani nanocrystal powder.
  • the coprecipitation method is as follows: the active drug nilapani is first dissolved in a small amount of an organic solvent such as acetone, rapidly added to a large amount of an aqueous solution in which the matrix polymer is dissolved, and ultrasonically high frequency ultrasound is used to ensure the active drug.
  • the dispersed particle diameter of the active drug nirapani in the solid powder can be reduced, and the specific surface area of the active drug is remarkably improved, thereby improving the dissolution property of the drug.
  • the weight percentage of nilapani is 10-100% by weight, preferably 20-50% by weight; the weight percentage of the matrix polymer for solubilization is 0-75%, preferably 0-65%, and other additives are 0-10% by weight, preferably 0-5% by weight.
  • the total amount of each of the above components was 100% by weight.
  • the nanocrystalline composition has a particle size of 50 to 1000 nm. In the respective ranges of the above composition, similarly to the understanding in the above-described co-milling mixture, any value between any one of the lower limit values and the upper limit value is within the scope of the present invention, and is different herein. A narrative.
  • the solid dispersion in the present invention consists of the active drug nirapani, a matrix polymer for solubilization, and other additives.
  • the weight percentage of nilapani is 5-50% by weight, preferably 10-40% by weight, more preferably 20-40% by weight, based on the total weight of the solid dispersion
  • the weight percentage of the matrix polymer for solubilization is 45-95 wt%, preferably 50-80 wt%
  • other additives such as micronized silica gel, polyethylene glycol stearate, etc.
  • the total amount of each of the above components was 100% by weight.
  • the solid dispersion composition can be produced by a solvent evaporation method or a melt extrusion method.
  • the solvent volatilization method is carried out by dissolving the drug nirapani, the matrix polymer and/or other additives in a volatile organic solvent or an organic mixed solvent, volatilizing the organic solvent under reduced pressure, and volatilizing the organic solvent.
  • the intermediate product is transferred to a vacuum oven for drying to produce a solid dispersion of nirapani.
  • the melt extrusion process is carried out as follows: mixing The homogeneous drug nirapani, the matrix polymer and optionally other additive powders are added directly to the melt extruder and the melt extrudate is collected.
  • the solid dispersion enables the active drug nirapani to exhibit a high-state solid dispersion state, which is dispersed in a molecular form in a solid powder of the formulation composition, thereby maximizing the specific surface area of the drug. This improves the dissolution properties of the drug.
  • the active drug nilapani comprises nilapani free base and a pharmaceutically acceptable salt thereof, which Pharmaceutically acceptable salts can be selected from the group consisting of hydrochlorides, phosphates, besylates, camphorates, maleates, sulfates, and the like.
  • the cerium-soluble matrix polymer is capable of stabilizing and/or solubilizing nilapani a polymer of particles or molecules, which may be selected from the group consisting of povidone, copovidone, polyoxyethylene, Soluplus, hypromellose phthalate (HPMCP), hydroxypropylcellulose succinate acetate, poly Ethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 2-hydroxypropyl- ⁇ -cyclodextrin, hypromellose (HPMC), polymethacrylate, hydroxypropyl fiber
  • CAP cellulose acetate phthalate
  • other additives may be selected from pharmaceutically common plasticizers Agents and / or lubricants, etc.
  • the release rate adjusting matrix polymer (hereinafter sometimes referred to as a release regulator) in the present invention may be a sustained release matrix matrix material well known to those skilled in the art, and may be selected from cellulose derivatives, starch or derivatives thereof, and algae.
  • Acid, acrylic or methacrylic acid derivatives, polyethylene oxide, gums and carbohydrate-based polymers may be selected from the group consisting of polyoxyethylene, hydroxypropyl cellulose, hypromellose, methyl cellulose , one or a combination of two or more of hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably selected from polyoxyethylene, hydroxypropyl One or a combination of two or more of cellulose, sodium alginate, hypromellose, and carbomer.
  • the Nilapani sustained-release pharmaceutical composition provided by the present invention comprises 50-900 parts by weight, preferably 80-700 parts by weight, more preferably 120-600 parts by weight, of the dissolution-reducing form of nilapani; and 10-300 parts by weight Preferably, 20 to 250 parts by weight, more preferably 50 to 180 parts by weight, of the release rate adjusting matrix polymer.
  • the nerapanib oral sustained-release pharmaceutical composition comprises, 50-700 parts by weight of a compound of the form of the Nyrapani salt, and 10- 300 parts by weight of a matrix polymer for release rate adjustment; or 50 to 700 parts by weight of a nilapani co-milled mixture, and 10 to 200 parts by weight of a matrix polymer for release rate adjustment; or 50-800 weight Parts of nilapani nanocrystals, and 0.1-250 parts by weight of the release rate adjusting matrix polymer; or 50-900 parts by weight of the nilapani solid dispersion, and 20-300 parts by weight of the release rate adjustment Use a matrix polymer.
  • the nirapani pharmaceutical composition provided by the present invention may be a sustained release preparation of a single sustained release phase or a quick release double release preparation containing both an immediate release phase and a sustained release phase.
  • the sustained release phase is a controlled release composition comprising a pharmaceutically active ingredient.
  • the controlled release phase is preferably selected from, but not limited to, a controlled release tablet, a controlled release pellet, a controlled release composition in a tablet, a controlled release composition in a tablet or a pellet, incorporated into a bilayer tablet. Controlled release layer composition and combinations thereof in any form.
  • the immediate release phase is an immediate release composition containing a pharmaceutically active ingredient.
  • the immediate release phase is preferably selected from the group consisting of, but not limited to, an immediate release tablet, an immediate release tablet, an immediate release composition in a tablet, an immediate release coating layer wrapped around a controlled release tablet or a pellet core, and a double The immediate release layer composition in the layer controlled release tablet and any combination thereof.
  • the quick-acting double-effect controlled release preparation comprises both a sustained release phase and an immediate release phase.
  • the pharmaceutically active ingredient in the immediate release phase accounts for 10-50% by weight, preferably 20-40% by weight of the total active ingredient of the pharmaceutical; the active ingredient in the sustained-release phase accounts for the drug activity.
  • the total amount of the components is from 50 to 90% by weight, preferably from 60 to 80% by weight.
  • the nilapani pharmaceutical composition provided by the invention can be implemented in the following dosage forms, including a single sustained-release preparation and/or a quick-release double-effect release preparation, and is selected from the group consisting of sustained-release microspheres, quick-release double-release microspheres, and single Layer osmotic pump controlled release tablets, double osmotic pump controlled release tablets, quick double effect release osmotic pump tablets, slow release matrix tablets, quick double effect release matrix tablets, sustained release capsules and quick release double effect release capsules.
  • the dosage form of the dosage form per unit preparation may contain the pharmaceutically active ingredient 20 mg to 400 mg, preferably 50 mg to 400 mg, and the total expected dose to be taken daily in the human body is 100-800 mg, preferably 200 mg-500 mg/day per day.
  • the effective concentration range of the blood concentration level in the body can be maintained in the PARP enzyme inhibition, and the composition can improve the PARP enzyme inhibition effect and the tumor treatment effect of nilapani, and reduce the toxic side effects of the drug.
  • the present invention provides the preparation of the nilapani pharmaceutical composition for preventing or treating a tumor, in particular selected from the group consisting of: ovarian cancer, breast cancer, gastric cancer, lung cancer, blood cancer, pancreatic cancer, glioblastoma, epithelial ovary
  • a tumor in particular selected from the group consisting of: ovarian cancer, breast cancer, gastric cancer, lung cancer, blood cancer, pancreatic cancer, glioblastoma, epithelial ovary
  • drugs for cancer, tumors such as brain cancer.
  • nilapani pharmaceutical composition provided by the present invention can be used for clinical treatment of various types of tumors, but does not exclude the use of other anti-tumor drugs.
  • the drug absorption rate can be controlled, the blood drug concentration range can be adjusted, the fluctuation of blood drug concentration is small, and the adverse reactions of the patient medication are reduced;
  • Figure 1 is a schematic view showing the structure of an osmotic pump type controlled release sheet
  • FIG. 2 is a schematic structural view of an osmotic pump type quick release double-effect release sheet
  • FIG. 3 is a schematic structural view of a skeleton type quick-release double-effect release double-layer sheet
  • FIG. 4 is a schematic structural view of a skeleton type quick release double-effect release coated tablet
  • Figure 5 is a schematic view showing the structure of a capsule containing an immediate release and sustained release tablet
  • Figure 6 is a schematic view showing the structure of an immediate release pellet and a skeleton type sustained release pellet capsule according to an embodiment of the present invention
  • FIG. 7 is a schematic structural view of a sustained-release pellet capsule containing an immediate release coating according to an embodiment of the present invention.
  • Figure 8 is a quick double-effect matrix release curve in Example 1.
  • Figure 9 is a graph showing the release profile of the two-layer osmotic pump controlled release tablet in the release medium of pH 1.2, 4.5 and 6.8 in Example 3;
  • Example 10 is a release profile of the controlled release preparation in Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, and Example 10;
  • Figure 11 is a dissolution profile of the immediate release capsule of Comparative Example 1.
  • Figure 12 is a dissolution profile of the immediate release capsule of Comparative Example 2.
  • Figure 13 is a diagram showing the in vivo results of the instant release capsule of Comparative Example 1 and the quick-acting double-effect matrix tablet of Example 1.
  • Figure 14 is a graph showing the in vivo drug time of the immediate release capsule of Comparative Example 1 and the double-layer osmotic pump controlled release tablet of Example 3;
  • Figure 15 is a graph showing the in vivo drug time of the comparative example 2 immediate release capsule and the quick release double release double osmotic pump controlled release tablet of Example 4;
  • Figure 16 is a graph showing the time of enzyme inhibition time in PBMC of Comparative Example 2 immediate release capsule and the slow release double release double osmotic pump controlled release tablet of Example 4.
  • the sustained-release tablet of one of the types of Nilapani compositions provided by the present invention may be selected from the group consisting of an osmotic pump type controlled release tablet, a skeleton type controlled release tablet and a sustained release tablet based on sustained release pellets;
  • the pump-type controlled release tablets include osmotic pump controlled release tablets and osmotic pump speed double release tablets, and the skeleton type controlled release tablets include skeleton type sustained release tablets, skeleton type quick double effect double layer tablets and skeleton type quick double effect coating.
  • sustained release tablets based on the sustained release pellets include sustained release tablets based on sustained release pellets and quick-acting double-effect tablets for administering sustained-release pellets, and the above-mentioned controlled release tablets can be specifically obtained by the following methods.
  • the drug release behavior described in the present invention is achieved.
  • the osmotic pump controlled release sheet provided by the invention may be a single layer osmotic pump sheet, a single layer osmotic pump speed double release sheet, a double layer osmotic pump controlled release sheet or a double layer osmotic pump quick release double release sheet.
  • the double-layer osmotic pump controlled release sheet provided by the invention mainly comprises:
  • a controlled release drug-containing layer formed by a controlled release drug-containing layer composition, located in a rigid membrane shell adjacent to the drug release orifice;
  • a push layer also referred to as a boost layer formed by the push layer composition, located in the rigid membrane shell, away from the side of the drug release orifice;
  • a rigid membrane shell having moisture permeability which is obtained by drying a controlled release coating coating liquid, and the membrane shell comprises one or more drug releasing holes at one end;
  • nilapani accounts for 3 to 50% by weight of the total weight of the osmotic pump type controlled release tablets.
  • the controlled release drug-containing layer composition comprises: 50-600 parts by weight, preferably 80-500 parts by weight, more preferably 120-400 parts by weight of the dissolution-modified form of nilapani; 10-150 parts by weight, preferably 20- 120 parts by weight, more preferably 30 to 100 parts by weight of the release modifier, and 0 to 40 parts by weight, preferably 0 to 30 parts by weight, of other pharmaceutically acceptable excipients.
  • the dissolution-improved form of nilapani may be selected from the above-described nilapani salt, nilapani co-milled mixture, nanocrystalline or solid dispersion.
  • the release regulator may be selected from the group consisting of povidone, copovidone, polyethylene oxide, carbomer, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, ten One or a combination of two or more of sodium dialkyl sulfates.
  • the controlled release drug-containing layer composition is, without limitation, selected from the group consisting of penetration aids, lubricants, and colorants commonly used in pharmaceutical tablets, and the amounts thereof are conventionally selected in the art.
  • the penetration enhancer is selected from the group consisting of sodium chloride, lactose, mannitol, glucose, sucrose, fructose or a combination of two or more thereof, preferably sodium chloride, which may be 0-20 parts by weight.
  • the lubricant is one or a combination of two or more selected from the group consisting of sodium stearyl fumarate, magnesium stearate, silica gel, talc, polyethylene glycol, and magnesium sulfate. 0-20 parts by weight.
  • the coloring agent is one or a combination of two or more selected from the group consisting of iron oxide red, iron oxide yellow, iron oxide violet, iron oxide black, and the like, and may be 0 to 10 parts by weight.
  • the push layer composition typically comprises a release rate modulating permeation polymer, an osmotic pressure promoter, and other excipients.
  • the permeation-promoting polymer is a high molecular polymer which, in an aqueous medium, swells by absorbing water and promotes release of the drug in the drug-containing layer.
  • the release rate adjusting permeation-promoting polymer may be a material well known to those skilled in the art, and is selected from the group consisting of polyoxyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, and croscarmellose sodium.
  • crospovidone sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, croscarmellose sodium, crospovidone,
  • copolyvidone, carbomer, alginic acid and/or a derivative thereof may be used in an amount of 10 to 300 parts by weight, preferably 20 to 250 parts by weight, more preferably 50 to 180 parts by weight. .
  • the osmotic pressure promoter is one or a combination of two or more selected from the group consisting of sodium chloride, lactose, mannitol, glucose, sucrose, and fructose, preferably sodium chloride, and may be used in an amount of 20 to 150 parts by weight, preferably 25-100 parts by weight.
  • excipients in the push layer composition include, without limitation, a lubricant, a colorant, and the like, and may be used in an amount of 0.5 to 30 parts by weight, preferably 2 to 20 parts by weight.
  • the lubricant is one or a combination of two or more selected from the group consisting of sodium stearyl fumarate and sodium stearate, and may be used in an amount of from 0.2 to 15 parts by weight.
  • the colorant is one or a combination of two or more selected from the group consisting of iron oxide black, iron oxide red, and iron oxide yellow, and may be used in an amount of 0.5 to 15 parts by weight.
  • the controlled release drug-containing layer accounts for 40-80% by weight and the push layer accounts for 20-60% by weight based on the total weight of the core.
  • the insulating coating layer can be sprayed onto the core by the coating liquid and dried.
  • the barrier coating coating liquid generally comprises a barrier material and a solvent.
  • the barrier material is one or two selected from the group consisting of hydroxypropylmethylcellulose, povidone, copovidone, hydroxyethylcellulose, hydroxypropylcellulose, polyethylene glycol, and stearic acid. The combination above, but not limited to these.
  • the solvent includes one or a combination of two or more of ethanol, water, acetone, isopropyl alcohol, but is not limited thereto.
  • the thickness of the barrier can affect the release of the pharmaceutical formulation and can be controlled by the amount of spray applied.
  • the barrier film is 0-10% by weight relative to the core.
  • the rigid membrane shell may also be referred to as a controlled release coating layer, which is formed by spraying a controlled release coating coating liquid onto a core formed by a drug-containing layer and a pushing layer, and the rigid film shell is generally opposite to the sheet.
  • the core weight gain is from 3 to 20% by weight, preferably from 5 to 15% by weight.
  • the controlled release coating liquid comprises 4-40 parts by weight, preferably 10-30 parts by weight, of a semipermeable controlled release coating material, 0-20 parts by weight of a plasticizer, and 0-20 parts by weight of a porogen. And 50-1000 parts by weight, preferably 200-800 parts by weight of a solvent.
  • the semipermeable controlled release coating material is one or a combination of two or more selected from the group consisting of cellulose acetate, ethyl cellulose, and acrylic resin.
  • the plasticizer is selected from the group consisting of methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, glycerin One or a combination of two or more of acetate and castor oil.
  • the porogen is one or a combination of two or more selected from the group consisting of glycerin, povidone, copolyvidone, propylene glycol, polyethylene glycol, and a water-soluble inorganic salt.
  • the solvent is selected from one or a combination of two or more of acetone, water, ethanol, isopropanol, dichloromethane, and methanol.
  • the membrane shell contains one or more drug release holes, and the drug release holes can be prepared by mechanical drilling or laser drilling.
  • the drug delivery holes can have any geometric shape, such as a circle, an ellipse, a square, a triangle, etc., with an average pore size ranging from 0.3 to 1.2 mm.
  • the aesthetic outer garment is sprayed onto the core by an aesthetic outer coating liquid and dried, and may be unrestrictedly coated with a layer of aesthetic outerwear, which is generally unrestrictedly packaged into a conventional double osmosis pump sheet.
  • an aesthetic outer coating liquid is a conventional choice in the art, including Opadry and other coating powders that can form the aesthetic outerwear known to those skilled in the art.
  • the aesthetic outer coating liquid may further include one or more selected from the group consisting of a coloring agent, a plasticizer, an opacifier, an anti-adhesive agent, and a solvent.
  • the aesthetic outerwear typically gains from 0 to 10% by weight relative to the core of the tablet.
  • the single-layer osmotic pump controlled release tablet of the invention mainly comprises a single-layer core and a controlled-release coating film with a release orifice, which can improve the form of nilapani, release modifier, and penetration by a prescribed amount of dissolution.
  • Pressure promoter and other pharmaceutically-used excipients uniformly mixed and granulated, pressed single-layer tablet core; using a suspension coating method well known to those skilled in the art, outsourcing controlled release film material at the core; using laser drilling machine Punching is performed to form the single layer osmotic pump controlled release sheet.
  • the dissolution-improved form of nilapani, the release modifier, and the osmotic pressure promoter are as described under the double-layer osmotic pump sheet.
  • the single-layer core comprises 50-700 parts by weight, preferably 80-600 parts by weight, more preferably 120-400 parts by weight, based on the total weight of the single-layer core.
  • Improved form of nilapani 10 to 150 parts by weight, preferably 20 to 120 parts by weight, more preferably 30 to 100 parts by weight of the release modifier, and 1 to 400 parts by weight, preferably 1 to 300 parts by weight, of other pharmacies Excipients.
  • the porogen is in the sustained release coating film
  • the ratio is 0 to 30% by weight.
  • the weight gain of the controlled release coating film is 3 to 30 wt% of the single-layer osmotic pump controlled release sheet.
  • the osmotic pump controlled release tablet is a quick release double release osmotic pump sheet.
  • the immediate release drug-containing layer can be sprayed onto the core by an immediate release drug-containing layer composition and dried.
  • the immediate release drug-containing layer composition comprises: 10 to 80 parts by weight, preferably 20 to 50 parts by weight, of the active ingredient nirapani, 0-100 parts by weight, preferably 0-100 parts by weight, of the solubilizing matrix polymer group Parts, 0-30 parts by weight of other pharmaceutically acceptable excipients and 100-2000 parts by weight of solvent.
  • the solubilizing matrix polymer component is selected from the group consisting of povidone, copovidone, Soluplus, hypromellose phthalate (HPMCP), polyethylene glycol, poloxamer, polymethyl One or a combination of two or more of acrylic acid, polyethyl acrylate, hypromellose (HPMC), polymethacrylate, and hydroxypropyl cellulose.
  • HPMC hypromellose phthalate
  • HPMC hypromellose
  • HPMC hypromellose
  • HPMC hypromellose
  • the other commonly used auxiliary materials for pharmacy include crospovidone, microcrystalline cellulose, pharmaceutically acceptable surfactants (for example, sodium lauryl sulfate), and the like, which are commonly used in immediate release tablets, which are well known to those skilled in the art;
  • the solvent described includes one or a combination of two or more of ethanol, acetone, and water.
  • the nirapani in the immediate release drug-containing layer is about 10-40 wt% of the total weight of nilapani in the entire double-release osmotic pump sheet, and the controlled release drug-containing layer Nirapani is about 60-90% by weight of the total weight of nilapani in the entire slow-release double release osmotic pump sheet.
  • the preparation method of the Nilapani osmotic pump controlled release tablet comprises the following steps: 1 preparation of the improved form of nilapani; 2 preparation of the drug-containing layer; 3 preparation of the optional push layer; preparation of 4 cores; 5 optional isolation coating film preparation; preparation of 6 controlled release coating film; 7 osmotic pump sheet controlled release coating film perforation; 8 optional esthetic outer coating layer; 9 optional preparation of immediate release drug-containing layer.
  • the above 2-9 can be carried out by a conventional pressing and coating method well known to those skilled in the art.
  • the tablet with the rigid membrane shell outsourcing the immediate release drug-containing layer is an osmotic pump double-release tablet
  • the tablet with the outer layer of the rigid membrane shell not coated with the immediate release drug-containing layer is a common osmotic pump controlled release tablet.
  • 1 is a schematic structural view of an osmotic pump type controlled release sheet according to an embodiment of the present invention
  • FIG. 2 is a schematic structural view of an osmotic pump quick release double release sheet according to an embodiment of the present invention.
  • the design of the quick-release double-release tablets can better exert the efficacy of nilapani, and the design of the immediate release phase ensures the rapid release of the initial drug, and meets the blood drug concentration level required for the rapid PARP enzyme inhibition. It works, and the design of the sustained-release phase can ensure the smooth release of the active ingredients in the later period, ensuring the long-term maintenance of the blood concentration required for effective enzyme inhibition, thereby maintaining the inhibition of enzyme activity, improving the therapeutic effect, and reducing the blood concentration.
  • the present invention provides a nilapani sustained-release matrix tablet and/or a matrix tablet having a double-effect release behavior, depending on the specifications of the drug and the needs of the treatment.
  • the skeleton type controlled release tablet provided by the present invention is mainly composed of a sustained release phase (sustained release layer) containing a matrix polymer for release rate adjustment; and 2 an optional immediate release phase (immediate release layer).
  • FIG. 3 is a schematic structural view of a skeleton type quick-release double-effect release double-layer sheet; and FIG. 4 is a schematic structural view of a skeleton type quick-release double-effect release coated sheet.
  • a single layer sheet composed only of a sustained-release phase containing a matrix polymer for release rate adjustment is a general sustained-release matrix sheet, and a skeleton composed of a sustained-release phase and a immediate-release phase containing a matrix polymer for release rate adjustment.
  • the film is a quick double effect release matrix sheet, and the quick release layer and the sustained release layer can be stacked in the quick double effect release matrix sheet, or the immediate release layer can also be wrapped outside the sustained release layer.
  • the design of the immediate release phase of the quick-release double-effect release matrix sheet can well ensure the rapid release of the initial drug, meet the rapid onset of the drug, and quickly reach the therapeutic concentration, while the sustained-release phase can ensure the active ingredient in the later stage. Smooth release ensures that the blood drug concentration maintains an effective level for a long time, thereby maintaining the inhibition of enzyme activity, improving the therapeutic effect, and reducing the side effects caused by large fluctuations in blood drug concentration.
  • the sustained-release phase containing the matrix polymer for release rate adjustment can be sufficiently mixed with the pharmaceutically active component of the dissolution-improving form, the matrix polymer for release rate adjustment, a diluent, and other excipients, and the like.
  • the improved dissolution form of nilapani according to the invention a compound selected from the corresponding salt form of nilapani free base, nilapani and other matrix adjuvants A co-milled mixture, a nilapani nanocrystal or a nilapani solid dispersion, preferably a solid dispersion of nilapani and a compound in the form of a salt, more preferably a solid dispersion of nilapani.
  • the sustained release phase comprises 100 to 900 parts by weight, preferably 150 to 700 parts by weight, more preferably 200 to 600 parts by total of the above-mentioned dissolution-reduced form of nirapani, 10 to 300 parts by weight, preferably 30 to 150 parts by weight.
  • the release rate adjusting matrix polymer of the present invention is a slow release matrix matrix material well known to those skilled in the art, and may be selected from the group consisting of polyoxyethylene, hydroxypropyl cellulose, hypromellose, methyl cellulose, One or a combination of two or more of hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably hydroxypropyl cellulose, alginic acid Sodium, hypromellose and carbomer; the diluent of the present invention is selected from the following materials well known to those skilled in the art, microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose , one or a combination of two or more of starch, sodium carboxymethyl starch; other common additives for tablets according to the present invention, including a lubricant, a coloring agent commonly used in solid preparations well known to those skilled in the art Or
  • the optional immediate release phase may comprise the above-described dissolution-improved form of nilapani, a disintegrant, an optional diluent, and other additives commonly used in tablets, or may comprise nilapani, a solubilizing matrix polymer, and Other additives commonly used in tablets. They can be prepared by the following two preparation methods:
  • the first method is to sufficiently prepare a dissolution-improved form of a pharmaceutically active ingredient, a disintegrant, a diluent, and other excipients, and then prepare a tablet (immediate release phase) by a conventional method well known to those skilled in the art, wherein dissolution is improved.
  • the pharmaceutically active ingredient selected from the group consisting of a milled mixture of nilapani, a nanocrystalline or solid dispersion, preferably a solid dispersion of nilapani, in an amount of from 20 to 600 parts by weight, preferably from 30 to 400 parts by weight, more preferably 50-250 parts by weight;
  • the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone, cross-linked carboxymethyl cellulose
  • One or a combination of two or more kinds of disintegrators commonly used in sodium and other medicines may be used in an amount of 5 to 90 parts by weight, preferably 10 to 50 parts by weight;
  • the diluent of the present invention is selected from the group consisting of The following materials well known to those skilled in the art, one or a combination of two or more of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol,
  • the lubricant is 1 to 15 parts by weight, and the lubricant is one or a combination of two or more selected from the group consisting of magnesium stearate, stearic acid, sodium stearyl fumarate, talc, and micronized silica.
  • the colorant is one or a combination of two or more selected from the group consisting of iron oxide red, iron oxide yellow, iron oxide violet, iron oxide black, and titanium oxide.
  • the second preparation method of the optional immediate release phase comprises dissolving the free base of the pharmaceutically active ingredient or a compound thereof in the form of a salt, a solubilizing matrix polymer and other excipient components, and then coating it to the sustained release phase. , drying to form an immediate release coating film.
  • the pharmaceutically active ingredient is nilapani, which may be used in an amount of 5 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 60 parts by weight;
  • the solubilizing matrix polymer component is selected from the group consisting of
  • the matrix polymer is selected from the group consisting of povidone, copovidone, Soluplus, hypromellose phthalate (HPMCP), polyethylene glycol, poloxamer, hypromellose (HPMC)
  • HPMCP hypromellose phthalate
  • HPMC hypromellose
  • the other excipient ingredients include cross-linked polydimensional Ketone, microcrystalline cellulose, sodium lauryl sulfate and pharmaceutically acceptable surfactants, etc., are commonly used in quick release tablets, which are well known to those skilled in the art, and may be used in an amount of 0.1 to 150 parts by weight, preferably 0.5 to 100. Parts by weight.
  • the sustained-release phase carrier and/or the immediate release phase carrier are included; the pharmaceutically active component released in the sustained-release phase is contained in the sustained-release phase carrier, and the immediate release phase is contained.
  • the released drug is contained in an immediate release phase carrier; the quick release double acting release agent is characterized by an immediate release phase based on the total amount of the pharmaceutically active ingredient of the preparation of the present invention.
  • the pharmaceutically active ingredient accounts for 10 to 50% by weight of the total amount of the drug, preferably 20 to 40% by weight; and the sustained release phase contains 50 to 90% by weight of the pharmaceutically active ingredient, preferably 50 to 80% by weight.
  • the controlled release preparation of nilapani having the quick release behavior according to the present invention is characterized in that the pharmaceutically active ingredient in the immediate release phase is in accordance with the requirements of the Chinese Pharmacopoeia 2015 release test method.
  • the pharmaceutically active ingredient in the immediate release phase is in accordance with the requirements of the Chinese Pharmacopoeia 2015 release test method.
  • the release medium of the sump condition preferably more than 90% by weight of the pharmaceutically active ingredient dispensed into the immediate release phase is released within 2 hours, more preferably more than 90% by weight of the pharmaceutically active ingredient released into the immediate release phase is released within 1 hour.
  • the release time of the pharmaceutically active ingredient in the sustained-release phase is preferably 90% by weight or more, preferably 10-16 hours, more preferably 90% or more, and the release behavior of the pharmaceutically active ingredient in the sustained-release phase is in accordance with the zero-order, first-grade, Higuchi Or the Ritger-Peppas release model, preferably a zero-order release.
  • the present invention provides a controlled release formulation comprising a sustained release pellet and an optional immediate release matrix which can be subjected to the release behavior of the present invention by a tablet consisting of a sustained release pellet and an optional immediate release matrix.
  • the sustained release tablet based on the slow-release pellets of the Nilapani according to the present invention may be a sustained-release tablet based on sustained-release pellets and a quick-acting double-effect tablet based on the immediate release/sustained release pellets;
  • the quick-release double-effect release tablet and the immediate release matrix constitute an immediate release phase of the quick-acting double-effect release tablet, and the sustained-release pellet constitutes a sustained-release phase of the quick-acting double-effect release tablet; based on the total weight of the active ingredient of the drug,
  • the active ingredient nilapani in the immediate release phase accounts for 10-40% by weight of the total active drug content in the entire quick-acting double-effect release tablet;
  • the active ingredient nilapani in the sustained-release pellet accounts for the entire double-effect double-effect
  • the release tablet has 60 to 90% of the total active drug content.
  • the tablet consisting of the sustained release pill and the immediate release matrix comprises an immediate release matrix and a sustained release pellet in a structural composition;
  • the immediate release matrix can dissolve the improved form of the pharmaceutically active ingredient, a disintegrating agent,
  • the non-limiting diluent and other excipients are thoroughly mixed, they are prepared by tableting (immediate release phase) by conventional methods well known to those skilled in the art.
  • the dissolution-improving form of the pharmaceutically active ingredient is selected from the group consisting of a co-milled mixture of a compound of the nilapani salt form or a free base, a nanocrystal or a solid dispersion, preferably a compound of the form of a nilapani salt and a solid dispersion, more preferably a Nila a solid dispersion of Parney, in an immediate release matrix comprising a dissolution-improving form of the pharmaceutically active ingredient, the improved form of the nerapanib may be used in an amount of from 20 to 200 parts by weight, preferably from 50 to 150 parts by weight; said disintegration
  • the agent is selected from the group consisting of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone, croscarmellose sodium and other commonly used disintegrants.
  • One or a combination of two or more may be used in an amount of 5 to 200 parts by weight, preferably 10 to 100, more preferably 20 to 80 parts by weight; the diluent of the present invention is selected from the following materials well known to those skilled in the art.
  • the colorant is one or a combination of two or more selected from the group consisting of iron oxide red, iron oxide yellow, iron oxide violet, iron oxide black, and titanium oxide.
  • the sustained-release pellets may be granulated by a conventional method well known to those skilled in the art such as wet granulation by using a pharmaceutically active ingredient or a dissolution-improving form of the pharmaceutically active ingredient, a release rate adjusting substrate, and optionally other excipients, and the like.
  • the sustained release pellets are prepared by extrusion spheronization, coating pan coating and/or fluidized bed granulation coating; for example, the pharmaceutically active ingredient and the solubilizing matrix are polymerized by means of a one-pot coating drug in a coating pan.
  • the blank pellet core is selected from the group consisting of a sucrose pellet core, a starch pellet core, a microcrystalline cellulose pellet core, a silica pellet core, and a hydroxypropyl cellulose pellet core; for example, an active drug, a solubilizing matrix polymer
  • the release rate adjusting slow release matrix material or the like is placed in the fluidized bed, the airflow is blown, the medicine and the auxiliary material are uniformly mixed, and then sprayed into the binder to make it into granules, which are completed in one step by granulation, drying and coating.
  • the pharmaceutically active ingredient in the sustained release pellets of the present invention is nilapani;
  • the solubilizing matrix polymer component is selected from the group consisting of povidone, copovidone, Soluplus, hypromellose orthophthalic acid One of formate (HPMCP), polyethylene glycol, poloxamer, hypromellose (HPMC), polymethacrylate, hydroxypropyl cellulose, and its solubilizable polymer excipients or a combination of two or more;
  • the release-release matrix material for the release rate in the sustained-release pellets is selected from the group consisting of: shellac, cellulose acetate phthalate (CAP), acrylic resin (Eudragit), ethyl cellulose (EC), carbomer, polypropylene polysiloxane, cellulose acetate, cellulose propionate, cellulose acetate propionate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), methyl cellulose, hydroxypropyl fiber
  • the porogen is selected from the group consisting of a hydrophilic liquid carrier (glycerin, PEG 200), a saccharide (lactose, fructose, sucrose, mannose), a surfactant (polysorbate 80, sodium lauryl sulfate, etc.), Polymer (povidone, hypromellose, etc.).
  • a hydrophilic liquid carrier glycolin, PEG 200
  • saccharide lactose, fructose, sucrose, mannose
  • a surfactant polysorbate 80, sodium lauryl sulfate, etc.
  • Polymer povidone, hypromellose, etc.
  • the sustained release pellets comprise 100 to 500 parts by weight, preferably 200 to 400 parts by weight of a blank pellet core, 10 to 150 parts by weight, preferably 30 to 100 parts by weight of nilapani hydrochloride. 10 to 300 parts by weight of a release rate adjusting substrate or a controlled release coating material, 0 to 100 parts by weight of a binder, 0 to 12 parts by weight of a porogen, and 0 to 15 parts by weight of a plasticizer.
  • sustained release pellets are directly compressed into tablets to prepare a sustained release preparation. If the actual release requirements are required, the active ingredients of the immediate release matrix and the sustained release pellets are uniformly mixed according to a certain specification, and then passed through a special stirring function. Tablet press, compressed into tablets, can be prepared into a quick release double release preparation.
  • the sustained-release capsule preparation of one of the types of Nilapani compositions provided by the present invention may be selected from the group consisting of a pellet-based controlled release capsule and a microchip-based controlled release capsule; wherein the sustained release of the pellet is based on
  • the capsule comprises a capsule containing a skeleton type sustained-release pellet, a capsule containing a coated sustained-release pellet, a quick-acting double-effect capsule containing an immediate release pellet and a skeleton-type sustained-release pellet, and a sustained-release pellet and a coated sustained-release microparticle.
  • Pill's quick-acting double-effect capsule osmotic pump controlled release tablets, microchip-based controlled release capsules include capsules containing skeletal sustained-release microchips, and quick-acting double-effect capsules containing immediate-release microchips and skeleton-type slow-release microchips
  • the sustained release capsule described above can achieve the drug release behavior described in the present invention by:
  • FIG. 5 is a schematic structural view of a capsule containing an immediate release and sustained release tablet
  • FIG. 6 is a schematic structural view of a capsule containing an immediate release pellet and a skeleton sustained release pellet according to an embodiment of the present invention
  • FIG. 7 is an embodiment of the present invention.
  • the sustained release capsule based on the microchip of the invention is a controlled release capsule composed of a sustained release tablet or a quick release double release capsule composed of a sustained release microchip and an immediate release microchip, and may include a capsule containing a skeleton type sustained release microchip.
  • the tablets produced are small in diameter, typically ⁇ 5 mm.
  • the immediate-release microchips constitute the immediate release phase
  • the sustained-release microchips constitute the sustained-release phase.
  • Nirapani in the immediate release phase accounts for 10-40% by weight based on the total weight of Nyrapani in the capsule
  • Nirapani in the sustained release phase accounts for 60-90% by weight.
  • composition, preparation method, material selection and content of the skeleton-type sustained-release tablet is the same as that of the above-mentioned two-part skeleton-type controlled release tablet, and is not repeated here.
  • a skeleton type sustained release tablet containing an immediate release coating can be prepared by directly coating an immediate release matrix onto the surface of the above skeleton type sustained release sheet.
  • the immediate release tablet can be prepared by directly compressing the immediate release matrix.
  • composition, material selection and content of the immediate release matrix is the same as that of the immediate release matrix of the above three parts, and is not repeated here.
  • the sustained release capsule preparation can be prepared by capsule filling, and the immediate release tablet and the sustained release tablet are mixed according to a certain ratio, and then capsule filling is performed, or the skeleton type containing the immediate release coating is sustained release.
  • the tablets are prepared by capsule filling into a double-release capsule.
  • the present invention provides a controlled release preparation comprising a sustained release pellet and optionally an immediate release pellet, which can be delivered by a capsule preparation consisting of a sustained release pellet and an optional immediate release pellet. behavior.
  • the pellet-based controlled release capsule of the present invention may be a sustained release capsule based on sustained release pellets and a quick double effect capsule based on immediate release and sustained release pellets.
  • the immediate release pellets constitute an immediate release phase
  • the sustained-release pellets constitute a sustained-release phase.
  • nirapani in the immediate release phase accounts for 10-40% by weight
  • nilapani in the sustained-release pellets accounts for 60-90% by weight.
  • composition, preparation method, material selection and content of the coated sustained-release pellets and the skeleton-type sustained-release pellets are the same as those of the above-mentioned three-part sustained-release pellets, and are not repeated here.
  • the sustained release pellets containing the immediate release coating can be prepared by directly coating the surface of the above-mentioned skeleton type sustained release pellets or coated sustained release pellets with an immediate release matrix.
  • the immediate release pellets can be prepared by dissolving the immediate release matrix, encapsulating it into a blank pellet core by a conventional coating method well known to those skilled in the art, or directly preparing the immediate release matrix into pellets.
  • composition, material selection and content of the immediate release matrix is the same as that of the immediate release matrix of the above three parts, and is not repeated here.
  • the sustained release pill can be prepared into a controlled release capsule by capsule filling, and the above instant release pill and sustained release pill can be weighed according to a certain ratio, and evenly mixed, and then capsule filling can be used to prepare a quick release double release capsule preparation, or Sustained-release pellets containing an immediate release coating can be used for capsule filling, and a quick-release double-release capsule preparation can also be prepared.
  • Experimental animals Beagle dogs are male and female, weighing 8-10 kg.
  • the source is Beijing Mars Biotechnology Co., Ltd.
  • the test animals were subjected to adaptive feeding at the test site of the Experimental Animal Center of Shanghai Pharmaceutical Research Institute 14 days before the test day.
  • the three-dimensional mixer is a T2F model available from TURBULA.
  • the melt extruder was a Pharma 11 model available from Thermo Fisher.
  • Immediate release layer The prescribed amount of nilapani is uniformly mixed with the solubilized matrix adjuvant Soluplus and the micro-silica gel, and then prepared into a solid dispersion by melt extrusion, pulverized and sieved through 60 mesh, and the dosage and disintegration are prescribed.
  • the crospovidone PVPP XL and the lubricant magnesium stearate are uniformly mixed and used for tableting;
  • Sustained release layer the prescribed amount of nirapani and solubilized matrix excipient copolyvidone (PVP VA64) and micronized silica gel were prepared by the above melt extrusion method to prepare a solid dispersion, and then the release rate of the prescribed amount was adjusted.
  • Tableting Direct compression method to prepare a quick-acting double-effect release matrix sheet with appropriate hardness.
  • the release method of the controlled release preparation was determined by the second method of dissolution measurement (Chinese Pharmacopoeia 2010 edition two appendix X C). At 37 ° C, the buffer with different pH was used as the release medium, and the rotation speed was 75 rpm. According to the operation, 6 mL of the solution was taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12 and 13 h, centrifuged, and the supernatant was taken as the test solution to determine the release degree.
  • the absorbance was measured at a wavelength of 240 nm, and the release degree of the prescription tablet was measured.
  • the release results are shown in Figure 8.
  • the quick-acting double-effect matrix tablet achieves rapid release of nearly 20% of the drug within 30 minutes, and about 80% of the drug is released around 8 hours, and the remaining drug can be completely released around 12-13h.
  • the release behavior can control the rapid absorption of a portion of the drug after the oral administration of nirapani. After the desired blood concentration is reached, the drug is slowly absorbed by slowly releasing the drug to prevent the blood drug concentration from being too high and remains effective.
  • the PARP enzyme inhibits the required blood concentration.
  • Example 2 Sustained double-effect capsule containing instant release pill and sustained release pill (quick double release capsule)
  • the preparation method is as follows:
  • Immediate release pellet Dissolve or disperse nilapani hydrochloride and copolyvidone (VA64) in a 95% ethanol solution to prepare a drug-loading solution, and spray it into a prescription by fluidized bed coating.
  • the blank microcrystalline cellulose pellet core is used as an immediate release pellet.
  • Sustained-release pellets I) Preparation of drug-loaded pellet core: Weigh the prescribed amount of hydroxypropylcellulose (SSL) dispersed in 95% ethanol solution to prepare a coating liquid with a solid content of 10%, in a magnetic stirrer On the top, fully stir evenly; weigh the prescription of nilapani, and evenly disperse in the above coating liquid, and use it as a drug-loading coating solution.
  • SSL hydroxypropylcellulose
  • microcrystalline cellulose pellet core is added to the fluidized bed, and the operating parameters such as air volume (100 m 3 /h) and inlet air temperature (30-54 ° C) are adjusted, and the prepared drug-loading coating liquid is sprayed to carry the drug.
  • sustained release coating the aqueous dispersion of the sustained-release coating liquid, Su Lisi, is diluted with an appropriate amount of aqueous solution to a solid content of 10-15% by weight of the Sulis coating solution, and mixed, as a slow-release coating film coating liquid, using fluidization
  • the method of bed coating is sprayed onto the drug-loaded pellet core obtained in the step II) to prepare a sustained-release pellet.
  • Capsule filling The prepared sustained-release pellets are prepared into sustained-release capsules; the prepared immediate-release pills and sustained-release pellets are mixed according to different ratios, and the capsules are filled to obtain different immediate release/sustained release ratio activities.
  • the active ingredient of the instant release pill is less than 40% of the total amount of the active pharmaceutical ingredient of the capsule.
  • Nilapani and copolyvidone VA64 are prepared by solvent evaporation method, that is, nilapani and copolyvidone VA64 are simultaneously dissolved in an organic solvent of ethanol/acetone (40:60), and the organic solvent is evaporated under reduced pressure. Dry and smash, then The prescribed amount is mixed with povidone K90 and magnesium stearate, sieved, and uniformly mixed by a three-dimensional mixer to obtain a controlled release drug-containing layer composition to be used for tableting.
  • the booster layer auxiliary material was accurately weighed, sieved and mixed by a three-dimensional mixer (25 rpm, 30 minutes) to obtain a boost layer composition, and the double-layer core of the osmotic pump was pressed by a direct pressure method.
  • the pressed core was coated with 4% cellulose acetate acetone solution, and the film was weighted by 10% to prepare a conventional controlled release osmotic pump sheet.
  • the release of the controlled release osmotic pump tablets was determined by the method of determining the release of the controlled release formulation of Example 1.
  • the release results in different pH release media are shown in Figure 9.
  • the results showed that the double-layer osmotic pump controlled release tablets were basically not affected by pH.
  • the active ingredient nilapani could maintain a constant rate release, with less than 10% release in 1 hour, 50% release in 6 hours, and more than 80% release in 12 hours.
  • the total release time can be up to 14 hours.
  • Example 4 Sustained double release double osmotic pump controlled release tablet preparation
  • Nirapani and copovidone were sieved through a 60 mesh sieve for 3 times, and then mixed by a three-dimensional mixer at 30 rpm for 25 minutes. The mixture was slowly added to the preheated melt extruder to collect the transparent extrudate. The 60 mesh sieve was pulverized to obtain a solid dispersion of nirapani. Then, the prescription and other excipients except magnesium stearate were passed through a 60 mesh sieve and mixed by a three-dimensional mixer at 30 rpm for 25 min, and magnesium stearate was added and mixing was continued for 5 min to obtain a drug-containing layer composition, which was used for tableting. .
  • the booster layer excipient was accurately weighed, passed through a 60 mesh sieve and mixed by a three-dimensional mixer at 30 rpm for 30 min to obtain a boost layer composition.
  • the osmotic pump bilayer core comprising the drug-containing layer and the boost layer is pressed by the above-described drug-containing layer composition and the boost layer composition by a direct pressing method.
  • the pressed core was coated with a 3% cellulose acetate-0.2% PEG4000 solution to control the release layer, and the film was increased in weight by 10% to obtain a double-layer osmotic pump controlled release tablet.
  • the solid dispersion of nilapani is dissolved in the acetone solution, and the ratio of the immediate release layer to the sustained release layer is 25:75 to the obtained double-layer osmotic pump sheet, and the active ingredient of the immediate release layer is 25%. Wt, sustained-release layer active ingredient accounted for 75% by weight of double-release double-release osmotic pump tablets.
  • the release method of the double-release double-osmotic pump controlled release tablets was measured by the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix X C). At 37 ° C, it was buffered with 900 ml of 80 mM sodium acetate at pH 4.0. The liquid is the release medium, the rotation speed is 50 rpm, according to the law, 6mL of the solution is taken at 0.5, 1, 2, 4, 8, 12, 16, 20, 24h, centrifuged, and the supernatant is taken as the test solution, and the determination is carried out. Release.
  • the absorbance was measured at a wavelength of 240 nm, and the release degree of the prescription tablet was measured.
  • the release results are shown in Figure 10.
  • the results showed that the sustained-release double release osmotic pump controlled release tablets could release the immediate release layer drug within 2 hours, and the sustained release layer drug could maintain sustained release of more than 80% at a constant rate for 16 hours, and the release duration could reach 20 hours.
  • Example 5 Sustained-release skeletal coated tablets containing an immediate release coating layer
  • the preparation method is as follows:
  • sustained-release core of sustained-release skeletal coated tablets The prescribed amount of nilapani and poloxamer 188 were passed through a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then slowly added to the preheated A good melt extruder was used to collect the extrudate and pulverize through a 60 mesh screen to obtain a solid dispersion of nirapani.
  • the nilapani solid dispersion prepared above is mixed with the matrix polymer sodium alginate for dissolution rate adjustment, and then added with a lubricant magnesium stearate to be mixed, and compressed by a direct pressure method to obtain a suitable hardness. Sustained release tablet core.
  • Quick release coating According to the quick release coating prescription, the instant release coating liquid is prepared, and the sustained release tablet core is placed in a high-efficiency coating pan for quick release coating; finally, it is dried at 45 ° C for 12 hours to remove excess The organic solvent and water, that is, the sustained release skeleton coated tablets.
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release results are shown in FIG.
  • Example 6 Sustained release tablets based on sustained release pellets
  • the preparation method is as follows:
  • Drug-loaded pellet core Nilapani and VA64 are dissolved or dispersed in a 95% ethanol solution to prepare a drug-loading solution, which is sprayed into a prescription amount of sucrose blank pellet core by means of fluidized bed coating. Load the pellet core.
  • the component of the detaching coating film is dissolved or dispersed in a 95% ethanol solution, and sprayed into a prescribed amount of the drug-loaded pellet core by a fluidized bed coating method to obtain a drug-loaded pellet core containing the coating.
  • the aqueous dispersion of the sustained-release coating liquid is diluted with an appropriate amount of the aqueous solution, mixed, and used as a sustained-release coating film coating liquid, which is sprayed into the drug-loading pill core of the coating body by a fluidized bed coating method. Sustained release pills.
  • Slow and controlled release tablets the microcrystalline cellulose is added into ethanol to form granules, which are evenly mixed with the sustained release pills, and then added with silica or magnesium stearate, and uniformly mixed and then tableted.
  • Quick-release double-release tablets the above-prepared instant release pellets (loaded pellet core) and sustained-release pellets are thoroughly mixed according to the prescription amount, and then silica or magnesium stearate is added, and evenly mixed, the tablet is obtained. .
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release results are shown in FIG.
  • Example 7 Sustained release tablets based on sustained release pellets
  • nilapani p-toluenesulfonate hydrate 140g of microcrystalline cellulose, 100g of lactose, mix it through 80 mesh sieve, transfer it to the wet granulator, adjust the parameters, add hypromethane E15 mass percentage 1 % aqueous solution is used as a soft material for the adhesive, and the nilapani medicated pellets are prepared by extrusion spheronization, wherein the extrusion screen has a pore size of 0.5 mm, an extrusion speed of 20 r/min, a spheronization speed of 1000 r/min, and a fluidized bed 40.
  • Coating liquid ratio acrylic resin 14.5%, plasticizer triethyl citrate 5%, anti-adhesive talcum powder 10.5%, water balance.
  • nilapani sustained-release pellets 5g containing drug pellets, 12g of microcrystalline cellulose, 16g of lactose, 12g of 5% by weight of pvpK30, granules of 18 mesh, drying in oven at 40°C, sieved in 18 mesh Granules, 0.6 g of stearic acid, mixed and compressed.
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release results are shown in FIG.
  • Nirapani and copolyvidone VA64 were sieved through a 60 mesh sieve for 3 times, and ground in a ball mill to an average particle diameter of less than 30 ⁇ m to obtain a nilapani co-milling mixture.
  • the co-milled mixture was adjusted in a prescribed amount and release rate with a matrix polymer polyoxyethylene, ethyl cellulose through a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added with magnesium stearate for 5 minutes, pressure A microchip having a diameter of 4 mm.
  • Nirapani and copolyvidone VA64 were sieved through a 60 mesh sieve for 3 times, and ground into a ball mill to a particle size of less than 30 ⁇ m to obtain a nilapani co-milling mixture.
  • the co-milled mixture was passed through a 60 mesh sieve in a prescribed amount and crospovidone and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added with magnesium stearate for 5 minutes, and pressed into a microchip having a diameter of 4 mm.
  • Capsule filling The sustained-release microchips prepared above were filled and filled into capsules to prepare sustained-release capsules.
  • the prepared immediate release microchip and the sustained-release microchip were thoroughly mixed according to the prescription amount, and then filled into capsules to prepare a quick-release double-release capsule.
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release results are shown in FIG.
  • Sustained-release microchip Nirepani and 2-hydroxypropyl- ⁇ -cyclodextrin were sieved through a 60 mesh sieve for 3 times, and after adding 100 ml of water, high-speed shearing was carried out to obtain a crude suspension, followed by a high-pressure homogenizer. The cycle is homogenized to an average particle diameter of less than 1000 nm, and the nanocrystal solution is lyophilized in a lyophilizer to remove moisture.
  • the nanocrystalline powder was passed through a 60 mesh sieve, and the matrix polymer carbomer 934 passed through a 60 mesh sieve was adjusted at a prescribed amount and release rate and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, followed by the addition of sodium stearyl fumarate. 5 min, pressed into microchips with a diameter of 3 mm.
  • Immediate release microchip Nirapani and 2-hydroxypropyl- ⁇ -cyclodextrin were sieved through a 60 mesh sieve for 3 times. After adding 100 ml of water, high-speed shearing was performed to obtain a crude suspension, followed by a high-pressure homogenizer. The cycle is homogenized to an average particle diameter of less than 1000 nm, and the nanocrystal solution is lyophilized in a lyophilizer to remove moisture.
  • the nanocrystalline powder was passed through a 60 mesh sieve, and the formulation and lactose, croscarmellose sodium were passed through a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then sodium stearyl fumarate was added for 5 minutes. , pressed into a microchip with a diameter of 3 mm.
  • Capsule filling The sustained-release microchips prepared above were filled and filled into capsules to prepare sustained-release capsules.
  • the prepared immediate release microchip and the sustained-release microchip were thoroughly mixed according to the prescription amount, and then filled into capsules to prepare a quick-release double-release capsule.
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release results are shown in FIG.
  • nirapani and hypromellose E5 were passed through a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then slowly added to the preheated melt extruder to collect the extrudate. And pulverized through a 60 mesh sieve to obtain a verapani solid dispersion.
  • the Nirapani solid dispersion prepared above was sieved through a 60 mesh sieve with other excipients other than magnesium stearate and uniformly mixed by a three-dimensional mixer, and then mixed with magnesium stearate for 5 minutes to obtain a drug-containing layer combination.
  • the single layer osmotic pump tablet core is pressed by the above-described drug-containing layer composition by a direct pressing method.
  • the pressed core was coated with a 4% cellulose acetate-0.2% PEG4000 solution to control the release layer, and the film was increased in weight by 5% to obtain a single-layer osmotic pump controlled release tablet.
  • the release rate was determined in the same manner as in Example 4, using 80 mM sodium acetate buffer at pH 4.0 as the release medium, and the release profile is shown in FIG.
  • Immediate release capsule 1 (home made) is prepared by mixing 20% by weight of nilapani hydrochloride, 43% by weight of microcrystalline cellulose, 32% by weight of lactose, 2% by weight of micronized silica gel, 1% by weight of magnesium stearate and 2% by weight of sodium lauryl sulfate.
  • the absorbance was measured at a wavelength of 240 nm, and the dissolution rate of the capsule was measured.
  • the instant release capsule 2 (self-made) is prepared by uniformly mixing 50 wt% of nilapani p-toluenesulfonate hydrate, 49 wt% of lactose monohydrate, and 1 wt% of magnesium stearate, and directly into 0# gelatin hard capsule.
  • the dissolution was determined by the dissolution method (Chinese Pharmacopoeia 2015 edition two appendix X C) first method device, at 37 ° C, with 900mL pH 4.0 80mM sodium acetate buffer as the release medium, the rotation speed is 50 per minute Turn, operate according to the law, take 6mL of solution according to the predetermined time point, centrifuge, take the supernatant as the test solution, determine the release degree.
  • the absorbance was measured at a wavelength of 240 nm, and the dissolution rate of the capsule was measured.
  • the quick-acting double-effect matrix tablet can reach a certain blood drug concentration in a short time by the initial immediate release means, and then realize the drug blood drug concentration by means of sustained release means. Slowly rises, but avoids a sudden increase in blood concentration, and maintains the blood concentration of the effective PARP enzyme inhibition for a longer period of time, in order to better play the enzyme inhibition and anti-tumor effect, while climbing the drug dose and The best medicines provide more space.
  • the blood sample was centrifuged at 4000 rpm for 10 min at 4 ° C, and the upper plasma was taken for the blood concentration detection of LC-MS.
  • the results are shown in Fig. 14.
  • the double-layer osmotic pump tablet realizes the slow absorption of the drug, realizes the slow increase of the drug blood concentration, and the peak time and half-life of the drug blood drug concentration are prolonged, thereby avoiding the blood drug concentration. High, it is expected to better play the role of enzyme inhibition and anti-tumor, while providing more room for drug dose climbing and optimal drug efficacy.
  • the double-layer osmotic pump tablet realizes the slow absorption of the drug, realizes the slow increase of the drug blood concentration, and the peak time and half-life of the drug blood drug concentration are prolonged, avoiding the high blood concentration and the enzyme inhibition rate. Long-term maintenance, it is expected to better play the role of enzyme inhibition and anti-tumor, while providing more room for drug dose climbing and optimal drug efficacy.

Abstract

一种尼拉帕尼的缓控释药物组合物及其用途。所述缓控释药物组合物包含溶出改善形式的尼拉帕尼和释放速率调节用基质聚合物，该药物组合物的稳态血药浓度波谷值Cmin,ss为0.5-4μM；稳态血药浓度波峰值Cmax,ss为0.8-6μM。

Description

一种尼拉帕尼缓控释药物组合物及其用途 技术领域
本发明涉及生物制药领域，具体涉及一种尼拉帕尼缓控释药物组合物及其用于制备预防或***的药物的用途，根据本发明的组合物具有可控的释放行为、体内血药浓度和PARP酶抑制活性。
背景技术
尼拉帕尼(Niraparib)，化学名称为：(S)-2-(4-(哌啶-3-基)苯基)-2H-吲唑-7-羧酰胺，分子式为C19H20N4O，分子量为320.39，具有下述化学结构：
Figure PCTCN2017116561-appb-000001
尼拉帕尼(商品名Zejula)是一种由美国生物制药公司Tesaro研发的PARP酶抑制剂，由美国食品药品管理局(FDA)于2014年12月批准上市，于2017年8月向中国CFDA递交临床申请，适应症为复发性上皮性卵巢，输卵管或原发性腹膜癌患者的维持治疗，这些患者对铂类化疗完全或部分反应。
每个细胞每天会发生成千上万的DNA损伤，DNA损伤有两种，单链断裂和双链断裂。PARP(聚腺苷二磷酸-核糖聚合酶)主要修复单链断裂，BRCA1和BRCA2基因编码的蛋白通过同源重组(HR)通路参与DNA双链损伤的修复。而在肿瘤细胞中，PARP抑制剂使得PARP活性受到抑制，细胞中单链DNA断裂损伤不被修复并积聚，持续的单链DNA损伤在DNA复制过程中将转化为双链DNA损伤，由于BRCA1/2基因功能缺陷的肿瘤细胞不能通过HR修复双链DNA损伤，这将导致DNA复制叉的停止，产生细胞毒性，导致合成致死，最终靶向杀死肿瘤细胞。
多聚ADP转移酶(PARP)是DNA切除修复通路中的关键因子，而尼拉帕尼则能够抑制PRAP酶活性，使DNA断裂的单链无法修复、基因组不稳定性增加，进而可导致细胞的凋亡，尤其对存在同源重组修复缺陷的肿瘤细胞具有较强的杀灭作用，尼拉帕尼的这 种作用模式使之对两种以上的组合类型肿瘤具有治疗潜力；另外，由于尼拉帕尼对损伤DNA修复通路的特异性抑制，该药物也会避免化疗后的肿瘤耐药，增强DNA损伤，加强以往化疗药物的抗肿瘤疗效。
据Tesaro公布的来自晚期卵巢癌的研究数据和FDA公布的综述资料(FDA reviews，NDA 4074987)显示，针对有BRCA基因突变的卵巢癌，第一次化疗后，如果保持每日口服尼拉帕尼一次，中位“无进展生存时间”是21个月，而安慰剂对照组是5.5个月；针对无BRCA基因突变的患者，中位“无进展生存时间”是9.3个月，而安慰剂对照组是3.9个月，均具有显著差异。
目前，Tesaro公司进行新药申请的剂型为对甲苯磺酸尼拉帕尼一水合物的速释胶囊制剂，规格为100mg(以尼拉帕尼计)，多个临床研究结果显示(FDA reviews，NDA 4074987)，尼拉帕尼吸收较快，口服生物利用度可达73％，血药浓度达峰时间为3小时，血浆半衰期长达30多小时，其血浆暴露量不受食物影响，其暴露量与最大血药浓度随剂量增加而成倍增加。目前临床II/III期给药剂量为300mg/每次/天，第12-14天可达稳态血药浓度，其波峰和波谷值分别为4.4μM和2.0μM左右。
然而，目前在研的普通口服速释胶囊仍存在一定的局限性，主要表现为剂量限制毒性明显，稳态血药浓度峰值高于PARP酶IC90值几倍甚至十几倍，产生的较多严重的毒副作用，限制药物疗效的发挥。尼拉帕尼的剂量限制毒性为血小板减少和贫血，在临床研究中有69％的病人因为毒副作用选择剂量降低或剂量中断，15％的病人因毒副作用而终止治疗，25％的病人出现3-4级贫血，29％病人出现3-4级血小板减小，30％病人出现中性粒细胞减小，毒副作用严重。
为进一步提高尼拉帕尼的临床肿瘤治疗疗效，降低药物的毒副作用，有必要提供一种可防止血药浓度峰值过高，并精确调控尼拉帕尼血药浓度波动范围的优良制剂，本发明的目的就是开发一种尼拉帕尼药物组合物，通过控制其释放行为，精确调控尼拉帕尼于胃肠道内的吸收速率和吸收时间，防止血药浓度突高，调控尼拉帕尼的体内血药浓度水平及其波动范围，提高并维持体内PARP酶抑制所需的血药浓度，进一步提高尼拉帕尼的抗肿瘤疗效的同时，减少用药后的不良反应。本发明的另一个目的是提供一种将治疗有效剂量所需的片剂或胶囊大小和/或数量减至最少的，服用频次尽可能低的优良制剂，提高患者顺应性。
经专利检索，目前尚无与尼拉帕尼有关的制剂专利，更无关于尼拉帕尼口服缓控释制剂的相关研究，为进一步提高尼拉帕尼的临床疗效，精确控制其体内血药浓度和酶抑制水 平，减少肿瘤患者用药后的不良反应，改善患者服药的顺应性，本发明公开了一种体内释放行为可控的尼拉帕尼药物组合物。
发明内容
尼拉帕尼速释胶囊的大剂量给药形式，往往导致口服后药物产生较高的稳态血药波峰浓度，波峰值过高导致众多副作用的产生，影响患者的生活质量，同时剂量限制毒性影响药物疗效的发挥。
本发明则是根据尼拉帕尼的生物学性质和临床治疗的药效及安全性需求，针对其目前的制剂所存在的缺陷，提供了一种体内吸收行为、血药浓度和PARP酶抑制水平可调控的尼拉帕尼药物组合物，以进一步提高尼拉帕尼的临床疗效，减少肿瘤患者用药后的不良反应，并增加患者服药的顺应性。本发明涉及具有改进尼拉帕尼药物载量和/或口服吸收和/或生物利用度和/或血药浓度控制和/或酶抑制水平控制的新型药物的组合和他们作为唯一制剂或与其他疗法联合治疗癌症的用途。
本发明提供的尼拉帕尼缓控释药物组合物具有可控的释药行为，在预定的时间段内，在符合漏槽条件的释放介质中，其释放行为和释放量可控，当采用中国药典溶出度测定法第二法装置，37℃条件下pH值为1.2-7.8的缓冲溶液中进行释放行为测定时，1小时内尼拉帕尼的释放量小于尼拉帕尼总量的50％，优选30％，更优选10-25％；16小时释放尼拉帕尼的量大于尼拉帕尼总量的80％，更优选>90％。
本发明提供的尼拉帕尼缓控释药物组合物，通过对释放行为和释放量的控制，可调控尼拉帕尼于胃肠道内的吸收速率和吸收时间，可控的吸收行为进而控制体内尼拉帕尼血药浓度水平及其波动范围，维持体内较小血药浓度波动的长期稳态。本发明提供的尼拉帕尼药物组合物，在犬体内有效稳态血药浓度波谷值0.5μM<Cmin,ss<4μM，甚至1μM<Cmin,ss<3μM；稳态血药浓度波峰值为0.8μM<Cmax,ss<6μM，甚至2μM<Cmax,ss<5μM，且稳态血药浓度峰/谷值优选小于2，更优选小于1.5。
与在研的速释胶囊相比，本发明所提供的药物组合物相同剂量下的尼拉帕尼所获取的最大血药浓度值(Cmax)降低至少10％-50％，血药浓度达峰时间(Tmax)延长至少50％(甚至200％-600％)。通过对血药浓度、达峰时间以及药时曲线下面积的控制，实现对尼拉帕尼稳态血药浓度水平，游离血药浓度波动范围，PARP酶抑制，体内安全性和给药频次的调控。
本发明提供的尼拉帕尼缓控释组合物包含溶出改善形式的尼拉帕尼与药物释放速率调节用基质聚合物，根据剂型，所述组合物还可包含其他添加物，如选崩解剂、增塑剂、 致孔剂、膨胀材料、填充剂、渗透压调节剂(也称为助渗剂)、润滑剂、粘合剂(也称为黏合剂)、染色剂(也称为着色剂)、抗粘剂(也称为抗黏剂)、遮光剂、稀释剂、包衣粉、自半透性控释衣膜材料、隔离衣材料、和/或其他药学上可接受的添加物等药学辅料中的一种或两种以上的组合。
本发明提供的尼拉帕尼缓控释药物组合物中的活性药物尼拉帕尼，属于难溶性药物，为实现良好的吸收和口服生物利用度，可首先经过增溶手段的处理，得到溶出改善形式的尼拉帕尼，以改善药物的溶出。不局限于任何理论，发明人认为，所述增溶处理可制备成为尼拉帕尼盐，如盐酸盐、磷酸盐、苯磺酸盐、樟脑酸盐、马来酸盐、硫酸盐等；或通过将尼拉帕尼与可实现药物溶解度改善的基质聚合物混合在一起，改变了活性药物制剂组合物粉末中的分散比表面积，由此改善了药物的溶出性能，所述增溶处理可以包括共研磨、高压均质、共沉淀、溶剂挥发或熔体挤出等。在本发明的描述中，若无特殊描述，特殊描述如尼拉帕尼盐酸盐、尼拉帕尼马来酸盐等，则所述的“尼拉帕尼”是指尼拉帕尼游离碱。
本发明所述的溶出改善形式的尼拉帕尼包括：尼拉帕尼游离碱的相应盐形式的化合物、尼拉帕尼与其他基质辅料制备而成的共研磨混合物、尼拉帕尼纳米晶或尼拉帕尼固体分散体等；其中，盐形式化合物为其药学上可接受的盐，可选自盐酸盐、磷酸盐、苯磺酸盐、马来酸盐、硫酸盐和右旋樟脑酸盐等，盐形式的尼拉帕尼可显著性提高其水溶性，盐形式的尼拉帕尼原料药可直接用于缓控释制剂的制备；而尼拉帕尼共研磨混合物，纳米晶或固体分散体，则主要由活性药物尼拉帕尼和药学上可接受的溶解度改善用基质聚合物和任选的其他添加物如增塑剂等组成。
本发明中的尼拉帕尼共研磨混合物由活性药物尼拉帕尼、溶解度改善用基质聚合物和任选的药学上可接受的其他添加物组成，通过将所述成分混合并共研磨而制备。药物粉末粒径一般可充分研磨至100微米以下。不局限于任何理论，所述共研磨能增加药物在固体制剂粉末中的分散比表面积，由此改善了药物的溶出性能。
根据本发明，在共研磨混合物中，基于共研磨混合物的总重，尼拉帕尼的重量百分比为5-60wt％，优选20-40wt％，增溶用基质聚合物的重量百分比为40-95wt％，优选40-80wt％，其他添加物的重量百分比为0-15wt％，优选0.2-10wt％。上述各组分的总量为100wt％。
在本发明所涉及的组成范围中，如在以上共研磨混合物中各组成的范围中，可以理解的是，下限值之间的任一数值以及上限值之间的任一数值均在本发明的范围内，例如尼拉帕尼的重量百分比为5-60wt％，优选20-40wt％，可以理解为下限包括5-20％中的任一数 值，比如6％、7％、8％、9％、10％、11％、12％、13％、14％、15％、16％、17％、18％、19％；而上限包括40-60％中的任一数值，比如41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％。对于增溶用基质聚合物的重量百分比，与上述理解类似地，其重量百分比为40-95wt％，优选40-80wt％可以理解为在40-(80％-95％)的任一范围，在此不一一赘述。
本发明中的尼拉帕尼纳米晶由活性药物尼拉帕尼、基质聚合物和任选的其他添加物组成，通过将所述成分高压均质或共沉淀法制备。所述高压均质法如下操作：将由活性药物尼拉帕尼和基质聚合物水溶液经高速剪切后制备的粗晶混悬液，加入到高压均质机中，循环高压均质多次，直到制备出的晶体颗粒达1000nm以下，冻干样品，制备均匀分散的尼拉帕尼纳米晶体粉末。所述共沉淀法如下操作：活性药物尼拉帕尼先以少量的有机溶剂如丙酮溶解后，快速加入到大量溶有基质聚合物的水溶液中，并利用探头超声高频超声，以确保活性药物晶核的形成和均匀分散，直到形成稳定分散的纳米晶体溶液，冻干样品，制备均匀分散的尼拉帕尼纳米晶体粉末。通过制备成为纳米晶，能够降低活性药物尼拉帕尼在固体粉末中的分散粒径，显著提高活性药物的比表面积，由此改善了药物的溶出性能。
所述尼拉帕尼纳米晶中，基于尼拉帕尼纳米晶的总重，尼拉帕尼的重量百分比为10-100wt％，优选20-50wt％；增溶用基质聚合物的重量百分比为0-75％，优选0-65％，其他添加物的重量百分比为0-10wt％，优选0-5％wt％。上述各组分的总量为100wt％。所述纳米晶组合物的粒径为50-1000nm。在以上组成的各范围中，与上述共研磨混合物中的理解类似地，下限值之间的任一数值以及上限值之间的任一数值均在本发明的范围内，在此不一一赘述。
本发明中的固体分散体由活性药物尼拉帕尼、增溶用基质聚合物和其他添加物组成。在固体分散体中，基于固体分散体的总重，尼拉帕尼的重量百分比为5-50wt％，优选10-40wt％，更优选20-40wt％，增溶用基质聚合物的重量百分比为45-95wt％，优选50-80wt％，其他添加物(如微粉硅胶、聚乙二醇硬脂酸酯等)的重量百分比为0-12wt％，优选0-10wt％。上述各组分的总量为100wt％。在以上组成的各范围中，与上述共研磨混合物中的理解类似地，下限值之间的任一数值以及上限值之间的任一数值均在本发明的范围内，在此不一一赘述。该固体分散体组合物可通过溶剂挥发法或熔体挤出法制造。所述溶剂挥发法如下进行：将药物尼拉帕尼、基质聚合物和/或其他添加物同时溶解至可挥发的有机溶剂或有机混合溶剂中，减压挥发有机溶剂，将挥发有机溶剂后所得中间体产品转移至真空干燥箱干燥，即可制得尼拉帕尼固体分散体。所述熔体挤出法如下进行：将混合 均匀后的药物尼拉帕尼、基质聚合物和任选的其他添加物粉末，直接缓慢加入到熔体挤出器，收集熔体挤出物即可。不局限于任何理论，所述固体分散体能够使活性药物尼拉帕尼呈现高能态的固体分散状态，以分子形式分散在制剂组合物的固体粉末中，最大限度地提高了药物的比表面积，由此改善了药物的溶出性能。
在本发明的尼拉帕尼共研磨混合物、尼拉帕尼纳米晶和尼拉帕尼固体分散体中，活性药物尼拉帕尼包括尼拉帕尼游离碱和其可药用盐，其可药用的盐可选自盐酸盐、磷酸盐、苯磺酸盐、樟脑酸盐、马来酸盐、硫酸盐等。
在本发明的尼拉帕尼共研磨混合物、尼拉帕尼纳米晶和尼拉帕尼固体分散体中，増溶用基质聚合物指的是能够用于稳定和/或增溶尼拉帕尼颗粒或分子的聚合物，可以选自聚维酮、共聚维酮、聚氧乙烯、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、醋酸羟丙基纤维素琥珀酸酯、聚乙二醇、泊洛沙姆、聚甲基丙烯酸、聚丙烯酸乙酯、2-羟丙基-β-环糊精、羟丙甲纤维素(HPMC)、聚甲基丙烯酸酯、羟丙基纤维素、醋酸邻苯二甲酸纤维素(CAP)以及其他药学可用的常见增溶用聚合物辅料中的一种或两种以上的组合；所述的其他添加物可选自药学上常见的增塑剂和/或润滑剂等，所述的增塑剂可能选自PEG4000、邻苯二甲酸酯、小分子表面活性剂如Cremphor RH40和聚氧乙烯(40)硬脂酸酯以及其他药学常见的增塑剂中的一种或两种以上的组合，所述的润滑剂可选自微粉硅胶、硬脂酸镁等常见润滑剂中的一种或两种以上组合。
本发明中的释放速率调节用基质聚合物(以下有时称为释放调节剂)可以是本领域技术人员所熟知的缓释骨架基质材料，可选自纤维素衍生物、淀粉或其衍生物、藻酸盐、丙烯酸或甲基丙烯酸衍生物、聚环氧乙烷、树胶和基于碳水化合物的聚合物，例如可选自聚氧乙烯、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、乙基纤维素、海藻酸钠、聚维酮、共聚维酮、丙烯酸树脂、卡波姆的一种或两种以上的组合，优选为选自聚氧乙烯、羟丙基纤维素、海藻酸钠、羟丙甲纤维素和卡波姆的一种或两种以上的组合。
本发明提供的尼拉帕尼缓控释药物组合物包含50-900重量份，优选80-700重量份，更优选120-600重量份的溶出改善形式尼拉帕尼；和10-300重量份，优选20-250重量份，更优选50-180重量份的释放速率调节用基质聚合物。更具体地，对溶出改善形式的尼拉帕尼而言，本发明提供的尼拉帕尼口服缓控释药物组合物包含，50-700重量份的尼拉帕尼盐形式化合物，和10-300重量份的释放速率调节用基质聚合物；或者50-700重量份的尼拉帕尼共研磨混合物，和10-200重量份的释放速率调节用基质聚合物；或者50-800重 量份的尼拉帕尼纳米晶，和0.1-250重量份的释放速率调节用基质聚合物；或者50-900重量份的尼拉帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物。
本发明提供的尼拉帕尼药物组合物可以为单一缓释相的缓控释制剂或既含有速释相又含有缓释相的速缓双效释放制剂。
所述的缓释相是含有药物活性成分的控释组合物。所述的控释相优选为选自，但不限于，控释片、控释小丸、片剂中的控释组合物、片剂或丸芯中的控释组合物、结合到双层片中的控释层组合物及其任意形式的组合。
所述的速释相是含有药物活性成分的速释组合物。所述的速释相优选为选自，但不限于，速释片、速释丸、片剂中的速释组合物、包裹于控释片剂或丸芯外的速释包衣层、双层控释片中的速释层组合物及其任意形式的组合。
所述的速缓双效控释制剂同时包含缓释相和速释相。在所述速缓双效控释制剂中，速释相中的药物活性成分占药物活性成分总量的10-50wt％，优选为20-40wt％；缓释相中的药物活性成分占药物活性成分总量的50-90wt％，优选60-80wt％。
本发明提供的尼拉帕尼药物组合物可以以下剂型实施，包括单一的缓控释制剂和/或速缓双效释放制剂等剂型，选自缓释微球，速缓双释微球，单层渗透泵控释片，双层渗透泵控释片，速缓双效释放渗透泵片，缓释骨架片，速缓双效释放骨架片，缓释胶囊和速缓双效释放胶囊等剂型。所述剂型的每单位制剂(如单个药品或胶囊)可含有药物活性成分20mg～400mg，优选50mg～400mg，人体上每天需要服用的预期总剂量为100-800mg，优选每天服用200mg-500mg/天，即可维持体内血药浓度水平在PARP酶抑制所需的有效范围，该组合物可提高尼拉帕尼的PARP酶抑制效果和肿瘤治疗效果，同时降低药物的毒副作用。
本发明提供了所述尼拉帕尼药物组合物在制备用于预防或***，特别是选自：卵巢癌、乳腺癌、胃癌、肺癌、血癌、胰腺癌、胶质细胞瘤，上皮性卵巢癌，转移脑癌等的肿瘤的药物的用途。
本发明提供的尼拉帕尼药物组合物可用于各种类型肿瘤的临床治疗，但不排除与其他抗肿瘤药物联合用药。
与普通速释制剂相比，具有如下优点：
1)可控的血药浓度及其波动范围，安全窗口较大，临床治疗过程中，剂量和给药方案可灵活调节，可进一步提高给药剂量，提供长期更有效的PARP酶活性抑制，提高药效。
2)药物吸收速率可控，血药浓度范围可调控，血药浓度的波动小，减少了患者用药的不良反应；
3)有效治疗剂量所需的片剂或胶囊大小和/或数量减至最少，提高患者顺应性的同时，方便的生产、贮存和运输，提高商业价值。
附图说明
图1是渗透泵型控释片的结构示意图；
图2是渗透泵型速缓双效释放片的结构示意图；
图3是骨架型速缓双效释放双层片的结构示意图；
图4是骨架型速缓双效释放包衣片的结构示意图；
图5是含有速释和缓释片的胶囊结构示意图；
图6是根据本发明一个实施方式的含有速释丸和骨架型缓释微丸胶囊的结构示意图；
图7是根据本发明一个实施方式的含有速释包衣的缓释微丸胶囊的结构示意图；
图8是实施例1中的速缓双效骨架片释放曲线；
图9是实施例3中双层渗透泵控释片在pH 1.2、4.5和6.8的释放介质中的释放曲线；
图10是实施例4、实施例5、实施例6、实施例7、实施例8、实施例9、实施例10中缓控释制剂的释放曲线；
图11是对比实施例1中速释胶囊的溶出曲线；
图12是对比实施例2中速释胶囊的溶出曲线；
图13是对比实施例1速释胶囊与实施例1中速缓双效骨架片的体内结果图；
图14是对比实施例1速释胶囊和实施例3中双层渗透泵控释片的体内药时曲线图；
图15是对比实施例2速释胶囊和实施例4中速缓双释双层渗透泵控释片的体内药时曲线图；
图16是对比实施例2速释胶囊和实施例4中速缓双释双层渗透泵控释片的PBMC中酶抑制率时间曲线图。
具体实施方式
为更好的阐述本发明提供的尼拉帕尼药物组合物性质，下文的叙述是对于本发明的详细说明，对本发明的范围不构成任何限制：
本发明所提供的尼拉帕尼组合物类型之一的缓控释片剂，可以选自渗透泵型控释片，骨架型控释片和基于缓释微丸的缓控释片；其中渗透泵型控释片包括渗透泵控释片和渗透泵速缓双释片，骨架型控释片包括骨架型缓释片、骨架型速缓双效双层片和骨架型速缓双效包衣片等，基于缓释微丸的缓控释片包括基于缓释微丸的缓释片和给予缓释微丸的速缓双效片，以上所述的缓控释片具体可通过以下方式，实现本发明所述的释药行为。
1.渗透泵型控释片
本发明提供的渗透泵控释片可以是单层渗透泵片、单层渗透泵速缓双释片、双层渗透泵控释片或双层渗透泵速缓双释片。
本发明提供的双层渗透泵控释片主要包含：
1)控释含药层，其由控释的含药层组合物形成，位于刚性膜壳内，毗邻释药孔；
2)推动层(也可称为助推层)，其由推动层组合物形成，位于刚性膜壳内，远离释药孔一侧；
3)可选的隔离衣层，其夹在刚性膜壳内表面与由含药层和推动层组成的片芯之间，由隔离衣组合物经干燥而成；
4)具有水分渗透性的刚性膜壳，其由控释衣包衣液经干燥而成，该膜壳一端包含一个或者多个释药孔；
5)可选的，非限制性的美学外衣；
6)可选的，非限制性的速释含药层，其由速释含药层组合物形成，位于刚性膜壳/或可选的美学外衣外。
其中，尼拉帕尼占渗透泵型控释片总重量的3～50wt％。
所述控释含药层组合物包括：50-600重量份，优选80-500重量份，更优选120-400重量份的溶出改善形式的尼拉帕尼；10-150重量份，优选20-120重量份，更优选30-100重量份的释放调节剂，和0-40重量份，优选0-30重量份的其他药学常用辅料。
所述溶出改善形式的尼拉帕尼可以选自上述的尼拉帕尼盐、尼拉帕尼共研磨混合物、纳米晶或固体分散体。所述释放调节剂可以为选自聚维酮、共聚维酮、聚环氧乙烷、卡波姆、羟丙甲纤维素、交联羧甲基纤维素钠、羟丙基纤维素中、十二烷基硫酸钠的一种或两种以上的组合。
所述控释含药层组合物的其他药学常用辅料非限制性地选自药学片剂中常用的助渗剂、润滑剂和着色剂等，其用量为本领域中的常规选择。所述的助渗剂为选自氯化钠、乳糖、甘露醇、葡萄糖、蔗糖、果糖的一种或两种以上的组合，优选为氯化钠，其可以为 0-20重量份。所述润滑剂为选自硬脂富马酸钠、硬脂酸镁、微粉硅胶、滑石粉、聚乙二醇类和月挂醇硫酸镁中的一种或两种以上的组合，其可以为0-20重量份。所述染色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑等中的一种或两种以上的组合，其可以为0-10重量份。
所述推动层组合物中通常包含释放速率调节用促渗透聚合物、渗透压促进剂和其他辅料。
所述促渗透聚合物属于高分子聚合物，其在水性介质中，可以吸收水分发生溶胀，推动含药层药物的释放。所述释放速率调节用促渗透聚合物可以为本领域技术人员所熟知的材料，包括选自聚氧乙烯、羟丙基甲基纤维素、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、羟丙基甲基纤维素、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、共聚维酮、卡波姆、海藻酸和/或其衍生物的一种或两种以上的组合，其用量可以为10-300重量份，优选20-250重量份，更优选50-180重量份。
所述渗透压促进剂为选自氯化钠、乳糖、甘露醇、葡萄糖、蔗糖、果糖的一种或两种以上的组合，优选为氯化钠，其用量可以为20-150重量份，优选25-100重量份。
所述推动层组合物中的其他辅料非限制性地包括润滑剂和着色剂等，其用量可以为0.5-30重量份，优选2-20重量份。所述润滑剂为选自硬脂富马酸钠和硬脂酸钠中的一种或两种以上的组合，其用量可以为0.2-15重量份。所述着色剂为选自氧化铁黑、氧化铁红和氧化铁黄的一种或两种以上的组合，用量可以为0.5-15重量份。
所述控释含药层和推动层共同构成渗透泵控释片的片芯。基于片芯的总重，控释含药层占40-80wt％，推动层占20-60wt％。
所述的隔离衣层，可通过隔离衣包衣液喷涂到片芯上经干燥而成。所述的隔离衣包衣液通常包含隔离衣材料和溶剂。所述隔离衣材料为选自羟丙基甲基纤维素、聚维酮、共聚维酮、羟乙基纤维素、羟丙基纤维素、聚乙二醇、硬脂酸的一种或两种以上的组合，但不限于这些。所述溶剂包括乙醇、水、丙酮、异丙醇的一种或两种以上的组合，但不限于这些。隔离衣的厚度可影响药物制剂的释放，可通过喷涂用量加以控制，一般而言，隔离衣膜相对于片芯增重0-10wt％。
所述刚性膜壳也可称为控释衣层，是由控释衣包衣液喷涂到由含药层和推动层形成的片芯上经干燥而成，所述的刚性膜壳一般相对于片芯增重3-20wt％，优选5-15wt％。
所述的控释衣包衣液包括4-40重量份，优选10-30重量份的半透性控释衣膜材料，0-20重量份的增塑剂，0-20重量份的致孔剂，和50-1000重量份，优选200-800重量份的溶剂。
所述半透性控释衣膜材料为选自醋酸纤维素、乙基纤维素、丙烯酸树脂的一种或两种以上的组合。
所述增塑剂为选自邻苯二甲酸甲酯、邻苯二甲酸乙酯、癸二酸二丁酯、柠檬酸三乙酯、柠檬酸三丁酯、乙酰基柠檬酸三丁酯、甘油醋酸酯、蓖麻油的一种或两种以上的组合。
所述致孔剂为选自甘油、聚维酮、共聚维酮、丙二醇、聚乙二醇、水溶性无机盐的一种或两种以上的组合。
所述溶剂选自丙酮、水、乙醇、异丙醇、二氯甲烷、甲醇的一种或两种以上的组合。
所述膜壳含有一个或多个释药孔，可以通过机械钻孔或者激光打孔的方式制备释药孔。释药孔可以具有任何几何性状，如圆形、椭圆形、正方形、三角形等，平均孔径范围0.3～1.2mm。
所述美学外衣由美学外衣包衣液喷涂到片芯上经干燥而成，可以非限制性地加包一层美学外衣，该美学外衣一般是非限制性地加包至普通双层渗透泵片。对于具有速释相包衣的速缓双效渗透泵片则很少应用到美学外衣。所述的美学外衣可以改善制剂的外观，以增加患者服药的顺应性，同时提供颜色标识。所述美学外衣包衣液为本领域中的常规选择，包括本领域的技术人员所熟知的欧巴代以及其他可以形成所述的美学外衣的包衣粉。此外，美学外衣包衣液还可包括选自着色剂、增塑剂、遮光剂、抗黏剂、溶剂中的一种或者几种。所述的美学外衣通常相对于片芯增重0-10wt％。
本发明所述的单层渗透泵控释片，主要包含单层片芯和具有释药孔的控释衣膜，可以通过将处方量的溶出改善形式的尼拉帕尼、释放调节剂、渗透压促进剂以及其他药学常用辅料，混合均匀后制粒，压制单层片芯；采用本领域技术人员所熟知的悬浮包衣法，在片芯外包被控释衣膜材料；采用激光打孔机进行打孔，形成所述的单层渗透泵控释片。所述的溶出改善形式的尼拉帕尼、释放调节剂、渗透压促进剂同双层渗透泵片项下所述。所述的其他药用辅料包括促渗透聚合物、控释衣膜、润滑剂、着色剂等，同双层渗透泵片项下所述。所述的单层渗透泵控释片中，基于单层片芯的总重，所述单层片芯包含50-700重量份，优选80-600重量份，更优选120-400重量份的溶出改善形式的尼拉帕尼；10-150重量份，优选20-120重量份，更优选30-100重量份的释放调节剂，和1-400重量份，优选1-300重量份的其他药学常用辅料。基于缓释衣膜的总重，致孔剂在所述的缓释衣膜中 比例为0～30wt％。基于单层渗透泵控释片的总重，所述控释衣膜增重为单层渗透泵控释片的3～30wt％。
当存在速释含药层时，渗透泵控释片即为速缓双释渗透泵片。所述速释含药层可通过速释含药层组合物喷涂到片芯上经干燥而成。所述速释含药层组合物包括：10-80重量份，优选20-50重量份的活性成分尼拉帕尼，0-100重量份，优选0-100重量份的增溶基质聚合物组分、0-30重量份的其他药学常用辅料和100-2000重量份的溶剂。所述增溶基质聚合物组分为选自聚维酮、共聚维酮、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、聚乙二醇、泊洛沙姆、聚甲基丙烯酸、聚丙烯酸乙酯、羟丙甲纤维素(HPMC)、聚甲基丙烯酸酯、羟丙基纤维素中的一种或两种以上的组合。所述其他药学常用辅料包括交联聚维酮，微晶纤维素、可药用的表面活性剂(例如十二烷基硫酸钠)等本领域的技术人员所熟知的速释片常用添加剂；所述的溶剂包含乙醇、丙酮和水中的一种或两种以上组合。
对于速缓双效释放渗透泵片，速释含药层中的尼拉帕尼约为整个速缓双释渗透泵片中的尼拉帕尼总重的10-40wt％，控释含药层中的尼拉帕尼约为整个速缓双释渗透泵片中的尼拉帕尼总重的60-90wt％。
尼拉帕尼渗透泵控释片的制备方法包括如下步骤：①溶出改善形式的尼拉帕尼的制备；②含药层的制备；③可选的推进层的制备；④片芯的制备；⑤可选的隔离衣膜的制备；⑥控释衣膜的制备；⑦渗透泵片控释衣膜打孔；⑧可选的包美学外衣层；⑨可选的速释含药层的制备。上述的②-⑨可以采用本领域的技术人员所熟知的常规压制和包衣方法进行。
刚性膜壳外包被速释含药层的片剂为渗透泵速缓双释片，而刚性膜壳外未包被速释含药层的片剂为普通渗透泵控释片。图1为根据本发明的一个实施方式的渗透泵型控释片的结构示意图，图2为根据本发明的一个实施方式的渗透泵速缓双释片的结构示意图。
速缓双释片的设计可更好的发挥尼拉帕尼的药效，因速释相的设计保证初期药物的迅速释放，满足药物迅速达到有效PARP酶抑制所需的血药浓度水平，快速起效，而缓释相的设计可以保证后期活性成分的平稳释放，确保了有效酶抑制所需血药浓度的长时间维持，进而保持酶活性抑制，提高疗效，同时减小血药浓度较大波动带来的毒副反应。
2.骨架型缓控释片
根据药物的规格和治疗的需求，本发明提供一种尼拉帕尼缓释骨架片和/或具有双效释放行为的骨架片。本发明提供的骨架型控释片主要由①含有释放速率调节用基质聚合物的缓释相(缓释层)；和②可选的速释相(速释层)组成。
图3为骨架型速缓双效释放双层片的结构示意图；图4为骨架型速缓双效释放包衣片的结构示意图。其中仅由含有释放速率调节用基质聚合物的缓释相组成的单层片，是普通的缓释骨架片，而由含有释放速率调节用基质聚合物的缓释相和速释相组成的骨架片，是速缓双效释放骨架片，速缓双效释放骨架片中速释层和缓释层可以叠放，或者速释层也可以包在缓释层外。速缓双效释放骨架片的速释相的设计，可以很好地保证初期药物的迅速释放，满足药物迅速起效的需求，快速达到治疗浓度，而其缓释相则可以保证后期活性成分的平稳释放，确保在血药浓度长时间保持有效水平，进而保持酶活性抑制，提高疗效，同时减小血药浓度较大波动带来的毒副反应。
所述的含有释放速率调节用基质聚合物的缓释相，可将溶出改善形式的药物活性成分、释放速率调节用基质聚合物、稀释剂以及其他辅料等充分混合后，通过本领域技术人员所熟知的常规方法压片制备(缓释相)；本发明所述的溶出改善形式的尼拉帕尼，选自尼拉帕尼游离碱的相应盐形式的化合物、尼拉帕尼与其他基质辅料制备而成的共研磨混合物、尼拉帕尼纳米晶或尼拉帕尼固体分散体，优选尼拉帕尼固体分散体和盐形式的化合物，更优选尼拉帕尼固体分散体。
所述缓释相包含100-900重量份，优选150-700重量份，更优选200-600总量份的上述溶出改善形式的尼拉帕尼，10-300重量份，优选30-150重量份的释放速率调节用基质聚合物，0-50重量份稀释剂以及0.2-30重量份，优选1-30重量份的其他片剂常用添加剂，将各组分充分混合后，通过本领域技术人员所熟知的常规方法压片制备。
本发明所述释放速率调节用基质聚合物，是本领域技术人员所熟知的缓释骨架基质材料，可选自聚氧乙烯、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、乙基纤维素、海藻酸钠、聚维酮、共聚维酮、丙烯酸树脂、卡波姆中的一种或两种以上的组合，优选为羟丙基纤维素、海藻酸钠、羟丙甲纤维素和卡波姆；本发明所述的稀释剂选自下列本领域技术人员所熟知的材料，微晶纤维素、预胶化淀粉、蔗糖、甘露醇、山梨醇、蔗糖、淀粉、羧甲基淀粉钠中的一种或两种以上的组合；本发明所述的其他片剂常用添加剂，包括本领域技术人员所熟知的固体制剂常用的润滑剂、着色剂的一种或者两种以上的组合，所述的润滑剂为选自硬脂酸镁、硬脂酸、硬脂富马酸钠、滑石粉和微粉硅胶中的一种或两种以上的组合，所述着色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑、二氧化钛中的一种或两种以上的组合。
所述的可选的速释相可以包含上述溶出改善形式的尼拉帕尼、崩解剂、任选的稀释剂以及片剂常用其他添加剂，或者包含尼拉帕尼、增溶基质聚合物和其他片剂常用添加剂。其可分别通过以下两种制备方法制备：
第一种方法是将溶出改善形式的药物活性成分、崩解剂、稀释剂以及其他辅料等充分混合后，通过本领域技术人员所熟知的常规方法压片制备(速释相)，其中溶出改善形式的药物活性成分选自尼拉帕尼的研磨混合物，纳米晶或固体分散体，优选尼拉帕尼固体分散体，其用量可以为20-600重量份，优选30-400重量份，更优选50-250重量份；所述的崩解剂选自交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯比咯烷酮、交联羧甲基纤维素钠及其他药上常用的崩解剂中的一种或两种以上的组合，其用量可为用量可以为5-90重量份，优选10-50重量份；本发明所述的稀释剂选自下列本领域技术人员所熟知的材料，微晶纤维素、预胶化淀粉、蔗糖、甘露醇、山梨醇、蔗糖、淀粉、羧甲基淀粉钠中的一种或两种以上的组合，其用量可为0-90重量份，优选0-50重量份；本发明所述的片剂常用其他添加剂，包括本领域技术人员所熟知的固体制剂常用的润滑剂、着色剂中的一种或者两种以上的组合，其用量可以为0.1-30重量份，优选1-15重量份，所述的润滑剂为选自硬脂酸镁、硬脂酸、硬脂富马酸钠、滑石粉和微粉硅胶中的一种或两种以上的组合，所述着色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑、二氧化钛中的一种或两种以上的组合。
所述的可选速释相的第二种制备方法，是将药物活性成分的游离碱或其盐形式化合物、增溶基质聚合物和其他辅料成分，同时溶解后，包被至缓释相外，干燥形成速释衣膜。所述的药物活性成分是尼拉帕尼，其用量可以为5-100重量份，优选10-80重量份，更优选20-60重量份；所述的增溶基质聚合物组分选自所述的基质聚合物选自聚维酮、共聚维酮、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、聚乙二醇、泊洛沙姆、羟丙甲纤维素(HPMC)以及其他材料中的一种或两种以上的组合，其用量可以为5-300重量份，优选10-200重量份，更优选30-120重量份；所述的其他辅料成分包括交联聚维酮，微晶纤维素、十二烷基硫酸钠及可药用的表面活性剂等本领域的技术人员所熟知的速释片常用添加剂，其用量可以为0.1-150重量份，优选0.5-100重量份。
对于本发明所述的速缓双效骨架控释剂，包含缓释相载体和/或速释相载体；缓释相中释放的药物活性成分包含在缓释相载体内，而速释相中释放的药物包含在速释相载体中；基于本发明制剂的药物活性成分总量，该速缓双效释放行为的制剂的特征在于，速释相中 药物活性成分占药物总量的10～50wt％，优选为20～40wt％；缓释相含有50～90wt％的药物活性成分，优选为50～80wt％。
本发明所述的具有速缓双释行为的尼拉帕尼控释制剂，其特征在于，所述的速释相中的药物活性成分，按照中国药典2015版释放度测定法的要求，在符合漏槽条件的释放介质中，优选超过90wt％的分配到速释相中的药物活性成分在2小时内释放，更优选1小时内有超过90wt％的分配到速释相中的药物活性成分释放；所述缓释相中药物活性成分释放90wt％以上的时间优选为10-16小时，更优选16小时释放90％以上；缓释相中药物活性成分的释放行为符合零级、一级、Higuchi或Ritger-Peppas释药模型，优选为零级释药。
3.基于缓释微丸的缓控释片
本发明提供一种由缓释微丸和任选的速释基质组成的控释制剂，可以通过由缓释丸和任选的速释基质组成的片剂，实现本发明所述的释药行为。
本发明所述的尼拉帕尼基于缓控微丸的缓控释片，可以是基于缓释微丸的缓释片和基于速释/缓释微丸的速缓双效片；所述的速缓双效释放片，速释基质组成了速缓双效释放片的速释相，所述的缓释丸组成了速缓双效释放片的缓释相；基于药物活性成分的总重，所述速释相中活性成分尼拉帕尼占整个速缓双效释放片中总活性药物含量的10～40wt％；所述的缓释丸中活性成分尼拉帕尼占整个速缓双效释放片中总活性药物含量的60～90％。
本发明所述的由缓释丸和速释基质组成的片剂，在结构组成上包括速释基质和缓释丸；所述的速释基质可将溶出改善形式的药物活性成分、崩解剂、非限制性的稀释剂以及其他辅料充分混合后，通过本领域技术人员所熟知的常规方法压片制备(速释相)。其中，溶出改善形式的药物活性成分选自尼拉帕尼盐形式化合物或游离碱的共研磨混合物，纳米晶或固体分散体，优选尼拉帕尼盐形式化合物和固体分散体，更优选尼拉帕尼固体分散体，在包括溶出改善形式的药物活性成分的速释基质中，溶出改善形式的尼拉帕尼用量可以为20-200重量份，优选50-150重量份；所述的崩解剂选自交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯比咯烷酮、交联羧甲基纤维素钠及其他药上常用的崩解剂中的一种或两种以上的组合，用量可以为5-200重量份，优选10-100，更优选20-80重量份；本发明所述的稀释剂选自下列本领域技术人员所熟知的材料，如选自微晶纤维素、预胶化淀粉、蔗糖、甘露醇、山梨醇、蔗糖、淀粉、羧甲基淀粉钠中的一种或两种以上的组合，其用量可以为0-200重量份，优选10-150重量份；本发明所述的其他辅料，包括本领域技术人员所熟知的固体制剂常用的润滑剂、着色剂中的一种或者两种以上的组合，其 用量可以为0.2-30重量份，优选1-30重量份，所述的润滑剂为选自硬脂酸镁、硬脂酸、硬脂富马酸钠、滑石粉和微粉硅胶中的一种或两种以上的组合，所述着色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑、二氧化钛中的一种或两种以上的组合。
所述的缓释微丸可以通过将药物活性成分或溶出改善形式的药物活性成分、释放速率调节用基质、以及任选的其他辅料等通过本领域技术人员所熟知的常规方法如湿法制粒、挤出滚圆、包衣锅包衣和/或流化床制粒包衣制备缓释小丸；具体举例，如通过包衣锅一锅包衣载药的方式，将药物活性成分和增溶基质聚合物分散或包载于空白丸芯上，形成载药丸芯，然后在载药丸芯外包一层释放速率调节用基质缓释衣膜材料，形成所述的包衣缓释丸，本发明所述的空白丸芯选自蔗糖丸芯、淀粉丸芯、微晶纤维素丸芯、二氧化硅丸芯、羟丙基纤维素丸芯中的一种；再如，将活性药物、增溶基质聚合物和释放速率调节用缓释基质材料等置于流化床中，鼓入气流，使药物与辅料混合均匀，再喷入粘合剂，使之成为颗粒，制粒、干燥、包衣一步完成。
本发明所述的缓释微丸中的药物活性成分是尼拉帕尼；所述的增溶基质聚合物组分选自聚维酮、共聚维酮、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、聚乙二醇、泊洛沙姆、羟丙甲纤维素(HPMC)、聚甲基丙烯酸酯、羟丙基纤维素以及其可增溶性聚合物辅料中的一种或两种以上的组合；所述的缓释微丸中的释放速调节用缓释基质材料选自：虫胶、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸树脂(Eudragit)、乙基纤维素(EC)、卡波姆、聚丙烯聚硅氧烷、乙酸纤维素、丙酸纤维素、乙酸丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮(PVP)、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素(HPMC)、尤特奇等常见的市售缓释衣膜材料中的一种或几种的混合物；所述的缓释微丸中的其他辅料主要包括非限制性的粘合剂、增塑剂和致孔剂等；其中所述的粘合剂选自聚乙二醇(PEG)、硬脂酸、单硬脂酸甘油酯等，所述的增塑剂选自丙二醇、甘油、聚乙二醇(PEG)、甘油三醋酸酯、乙酰单甘油酸酯、邻苯二甲酸酯、蓖麻油等，所述的致孔剂选自亲水性液状载体(甘油、PEG200)、糖类(乳糖，果糖，蔗糖，甘露糖)、表面活性剂(聚山梨酯80、十二烷基硫酸钠等)、高分子(聚维酮、羟丙甲纤维素等)。
在一个实施方式中，所述缓释微丸包含100-500重量份，优选200-400重量份的空白丸芯，10-150重量份，优选30-100重量份的尼拉帕尼盐酸盐，10-300重量份的释放速调节用基质或控释衣膜材料，0-100重量份的粘合剂，0-12重量份的致孔剂，以及0-15重量份的增塑剂。
最后，将所述的缓释丸直接压片则制备成为缓释制剂，若根据实际释放需求，速释基质和缓释丸剂活性成分按一定的规格比例混合均匀，再通过带有特殊搅拌功能的压片机，压制成片剂，则可制备成速缓双释制剂。
本发明所提供的尼拉帕尼组合物类型之一的缓控释胶囊制剂，可以选自基于微丸的缓控释胶囊和基于微片的缓控释胶囊；其中基于微丸的缓控释胶囊包括含有骨架型缓释微丸的胶囊，含有包衣缓释微丸的胶囊，含有速释微丸和骨架型缓释微丸的速缓双效胶囊以及含有速释微丸和包衣缓释微丸的速缓双效胶囊渗透泵控释片，基于微片的缓控释胶囊包括含有骨架型缓释微片的胶囊以及含有速释微片和骨架型缓释微片的速缓双效胶囊；以上所述的缓控释胶囊可以通过以下方式，实现本发明所述的释药行为：
其中，图5为含有速释和缓释片的胶囊结构示意图，图6为根据本发明一个实施方式的含有速释丸和骨架型缓释微丸胶囊的结构示意图，图7为根据本发明一个实施方式的含有速释包衣的缓释微丸胶囊的结构示意图。
4.基于微片的缓控释胶囊
本发明基于微片的缓控释胶囊是由缓释片组成的控释胶囊或者由缓释微片和速释微片组成的速缓双释胶囊，可以包括含有骨架型缓释微片的胶囊、含有速释包衣的骨架型缓释微片的胶囊以及含有速释微片和骨架型缓释微片的胶囊。一般而言，为装入硬胶囊，所制成的药片直径都较小，一般<5mm。
对于速缓双效释胶囊，速释微片组成了速释相，缓释微片则组成了缓释相。基于胶囊中尼拉帕尼的总重，速释相中的尼拉帕尼占10-40wt％；缓释相中的尼拉帕尼占60-90wt％。
所述骨架型缓释片的组成、制备方法、材料选择和含量等的描述与上面2部分骨架型控释片的缓释相相同，在此不在重复。
含有速释包衣的骨架型缓释片可以用速释基质直接包衣至上述骨架型缓释片表面而制备。
所述速释片可速释基质直接压片而制备。
所述速释基质的组成、材料选择和含量等的描述与上面3部分的速释基质相同，在此不在重复。
将骨架型缓释片进行胶囊灌装可制备成缓释胶囊制剂，而按照一定比例将速释片和缓释片混匀后进行胶囊灌装，或将含有速释包衣的骨架型缓释片进行胶囊灌装则制备成速缓双释胶囊。
5.基于微丸的缓控释胶囊
本发明提供了一种由缓释微丸和任选的速释微丸组成的缓控释制剂，可以通过由缓释丸和任选的速释丸组成的胶囊制剂，实现本发明所述的释药行为。
本发明的基于微丸的缓控释胶囊，可以是基于缓释微丸的缓释胶囊和基于速释和缓释微丸的速缓双效胶囊。对于所述速缓双效释胶囊，速释微丸组成了速释相，缓释微丸组成了缓释相。基于速缓双效释胶囊中尼拉帕尼的总重，速释相中的尼拉帕尼占10-40wt％；缓释微丸中的尼拉帕尼占60-90wt％。
所述的包衣缓释微丸和骨架型缓释微丸的组成、制备方法、材料选择和含量等的描述与上面3部分的缓释微丸相同，在此不在重复。
含有速释包衣的缓释微丸可以用速释基质直接包衣至上述骨架型缓释微丸或包衣缓释微丸表面而制备。
所述速释微丸可将速释基质溶解后，通过本领域技术人员所熟知的常规包衣方法包载至空白丸芯而制备，或将速释基质直接制备成微丸而制得。
所述速释基质的组成、材料选择和含量等的描述与上面3部分的速释基质相同，在此不在重复。
将缓释丸进行胶囊灌装可制备成控释胶囊，而按照一定比例称取上述速释丸和缓释丸，混合均匀，然后进行胶囊灌装，则可制备速缓双释胶囊制剂，或者将含有速释包衣的缓释微丸进行胶囊灌装，也可制备速缓双释胶囊制剂。
具体实施例
以下实施例一般性地记载了本发明典型组合物的制备方法和/或表征结果，所有的百分比均为重量百分比，除非另有指明。以下实施例是对本发明的具体说明，而不应该认为是对本发明范围的限制。在以下实施例中，未详细描述的各种过程和方法是本领域中公知的常规方法。
实验动物：比格犬雌雄各半，体重8～10kg。来源均为北京玛斯生物技术有限公司。受试动物在试验日前14天均在上海药物研究所实验动物中心的试验场所进行适应性饲养。
采用单冲压片机(TDP-1，广州市旭朗机械设备有限公司)压片。
三维混合器为购自TURBULA的T2F型号。
熔体挤出机为购自赛默菲的Pharma11型号。
实施例1 速缓双效释放骨架片剂
Figure PCTCN2017116561-appb-000002
速释层：处方量的尼拉帕尼与增溶基质辅料Soluplus和微粉硅胶混合均匀后，经熔体挤出法制备成固体分散体，粉碎、过60目筛后，以处方量与崩解剂交联聚维酮PVPP XL以及润滑剂硬脂酸镁混合均匀后，待压片用；
缓释层：处方量的尼拉帕尼与增溶基质辅料共聚维酮(PVP VA64)和微粉硅胶以上述熔体挤出法，制备成为固体分散体，再与处方量的释放速率调节用缓释骨架基质材料HPMC K15M(BASF，德国)以及润滑剂硬脂酸镁，混匀，待压片用。
压片：直压法制成硬度适宜的速缓双效释放骨架片。
采用溶出度测定法(中国药典2010年版二部附录X C)第二法装置测定控释制剂的释放度，37℃条件下，以不同pH的缓冲液为释放介质，转速为每分钟75转，依法操作，经0.25，0.5，0.75，1，2，4，6，8，10，12和13h取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在240nm的波长处分别测定吸光度，测定处方片剂的释放度。
释放结果见图8。速缓双效骨架片实现30分钟内近20％左右的药物快速释放，8h左右有近80％左右的药物释放，剩余药物可于12-13h左右释放完全。该释放行为可控制尼拉帕尼口服后，一部分药物先快速吸收，达到预期的血药浓度后，通过缓慢的释放药物，实现药物的缓慢吸收，以防止血药浓度峰值过高，并维持有效PARP酶抑制所需的血药浓度。
实施例2 含有速释丸及缓释丸的速缓双效胶囊(速缓双释胶囊剂)
①缓释丸
I)载药丸芯
Figure PCTCN2017116561-appb-000003
Ⅱ)包隔离衣
Figure PCTCN2017116561-appb-000004
III)包缓释衣
Figure PCTCN2017116561-appb-000005
②速释丸
Figure PCTCN2017116561-appb-000006
制备方法如下：
速释丸：将尼拉帕尼盐酸盐与共聚维酮(VA64)，溶解或分散于95％的乙醇溶液中，配制成载药溶液，采用流化床包衣的方式，喷入处方量的空白微晶纤维素丸芯上，作为速释丸。
缓释丸：I）载药丸芯的制备：称取处方量的羟丙基纤维素（SSL）分散于95%的乙醇溶液中，配制成固含量为10%的包衣液，于磁力搅拌器上，充分搅拌均匀；再称取尼拉帕尼处方量，均匀地分散在上述包衣液中，作为载药包衣液备用。
将微晶纤维素丸芯加入流化床，调节风量（100m3/h）、进风温度（30-54°C）等操作参数，喷入配制好的载药包衣液，进行载药。
II）包隔离衣：将隔离衣衣膜成分聚维酮（K30）溶解或分散于95%乙醇溶液中，采用流化床包衣方式，喷入到处方量的步骤I）的载药丸芯上；
III）包缓释衣：将缓释包衣液水分散体苏丽丝加入适量的水溶液稀释为苏丽丝包衣液10-15wt%的固含量，混匀，作为缓释衣膜包衣液，采用流化床包衣的方式，喷入到步骤II）得到的载药丸芯上，制成缓释丸。
胶囊灌装：将上述制备完成缓释丸装胶囊，制备成缓释胶囊；将上述制备完成的速释丸和缓释丸按照不同比例混合，填装胶囊，可获得不同速释/缓释比例活性药物尼拉帕尼的胶囊制剂，一般速释丸中药物活性成分小于整个胶囊活性药物成分中总量的40%。
实施例3 渗透泵控释片制剂
Figure PCTCN2017116561-appb-000007
尼拉帕尼与共聚维酮VA64以溶剂挥发法制备固体分散体，即将尼拉帕尼和共聚维酮VA64同时溶于乙醇/丙酮(40:60)的有机溶剂，减压挥发掉有机溶剂，干燥粉碎，再以 处方量与聚维酮K90和硬脂酸镁混合，过筛，并通过三维混合器混合均匀，得到控释含药层组合物，待压片用。
精密称取助推层辅料，过筛并通过三维混合器混合(25rpm，30分钟)均匀后得到助推层组合物，采用直压方式，压制渗透泵双层片芯。
压制的片芯，以4％的醋酸纤维素丙酮溶液包衣，衣膜增重10％，制备普通控释渗透泵片。
采用实施例1测定控释制剂的释放度的方法测定控释渗透泵片的释放度。
不同pH释放介质中的释放结果见图9。结果显示，双层渗透泵控释片基本不受pH影响，活性成分尼拉帕尼基本可维持恒速释放，1小时释放小于10％，6小时释放50％左右，12小时释放80％以上，总体释放时长可达14小时。
实施例4 速缓双释双层渗透泵控释片制剂
Figure PCTCN2017116561-appb-000008
将尼拉帕尼与共聚维酮过60目筛3遍，再通过三维混合器在30rpm条件下混合25分钟，混合物缓慢加入到已预热好的熔体挤出机，收集透明挤出物并粉碎过60目筛，得到尼拉帕尼固体分散体。再以处方量与除硬脂酸镁外的其他辅料过60目筛并通过三维混合器在30rpm下混合25min，加入硬脂酸镁后继续混合5min，得到含药层组合物，待压片用。
精密称取助推层辅料，过60目筛并通过三维混合器在30rpm下混合30min后得到助推层组合物。
采用直压方式，用上述含药层组合物和助推层组合物压制包含含药层和助推层的渗透泵双层片芯。
压制的片芯，以3％醋酸纤维素-0.2％PEG4000溶液包控释衣层，衣膜增重10％，得到双层渗透泵控释片。
取尼拉帕尼固体分散体溶于丙酮溶液中，按速释层与缓释层含药量比为25:75包衣至所得双层渗透泵片，即得速释层活性成分占25％wt、缓释层活性成分占75％wt的速缓双释双层渗透泵片。
采用溶出度测定法(中国药典2010年版二部附录X C)第二法装置测定速缓双释双层渗透泵控释片的释放度，37℃条件下，以900ml pH 4.0的80mM乙酸钠缓冲液为释放介质，转速为每分钟50转，依法操作，经0.5，1，2，4，8，12，16，20，24h取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在240nm的波长处分别测定吸光度，测定处方片剂的释放度。
释放结果见图10。结果显示，速缓双释双层渗透泵控释片可在2h内释放速释层药物，缓释层药物基本可维持恒速释放16h释放80％以上，释药持续时间可达20小时。
实施例5 含有速释包衣层的缓释骨架包衣片
①缓释片芯的制备
Figure PCTCN2017116561-appb-000009
②速释包衣
Figure PCTCN2017116561-appb-000010
Figure PCTCN2017116561-appb-000011
制备方法如下：
缓释骨架包衣片的缓释片芯的制备：将处方量的尼拉帕尼和泊洛沙姆188过60目筛并以三维混合器在30rpm下混合25分钟后，缓慢加入到已预热好的熔体挤出机，收集挤出物并粉碎过60目筛得到尼拉帕尼固体分散体。将上述制得的尼拉帕尼固体分散体，与溶出速率调节用基质聚合物海藻酸钠混匀，再加入润滑剂硬脂酸镁混匀，用直压法压片，制成硬度适宜的缓释片芯。
包速释衣：按照速释包衣处方配制速释包衣液，将上述缓释片芯置高效包衣锅中进行速释衣包衣；最后在45℃条件下，干燥12小时，除去多余的有机溶剂和水分，即得缓释骨架包衣片。
释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放结果见图10。
实施例6 基于缓释微丸的缓控释片
①缓释丸
I)载药丸芯
Figure PCTCN2017116561-appb-000012
Ⅱ)包隔离衣
Figure PCTCN2017116561-appb-000013
III)包缓释衣
Figure PCTCN2017116561-appb-000014
Figure PCTCN2017116561-appb-000015
制备方法如下：
载药丸芯：将尼拉帕尼与VA64，溶解或分散于95％的乙醇溶液中，配制成载药溶液，采用流化床包衣的方式，喷入处方量的蔗糖空白丸芯上，作为载药丸芯。
缓释丸：
将隔离衣衣膜成分溶解或分散于95％乙醇溶液中，采用流化床包衣方式，喷入到处方量的载药丸芯上，得到包隔离衣的载药丸芯。
将缓释包衣液水分散体加入适量的水溶液稀释，混匀，作为缓释衣膜包衣液，采用流化床包衣的方式，喷入到包隔离衣的载药丸芯上，制成缓释丸。
缓控释片：将微晶纤维素加乙醇制成颗粒，与缓释丸混合均匀，再加入二氧化硅或硬脂酸镁，混合均匀后压片即得。
速缓双释片：将上述制备完成的速释丸(载药丸芯)和缓释丸按照处方量、充分混匀后，再加入二氧化硅或硬脂酸镁，混合均匀后压片即得。释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放结果见图10。
实施例7 基于缓释微丸的缓控释片
称取尼拉帕尼对甲苯磺酸酯水合物154g，微晶纤维素140g，乳糖100g，通过80目筛混合后，转移至湿法制粒机内，调整参数，加入羟丙甲E15质量百分比1％的水溶液作为粘合剂制软材，挤出滚圆制备尼拉帕尼含药微丸，其中挤出筛网孔径0.5mm，挤出速度20r/min，滚圆速度1000r/min，流化床40℃干燥，筛取30-40目含药微丸备用。将筛选好的尼拉帕尼微丸置于流化床中，配制包衣液，包衣制得尼拉帕尼缓释微丸。包衣液配比：丙烯酸树脂14.5％，增塑剂柠檬酸三乙酯5％，抗黏剂滑石粉10.5％，水余量。称取尼拉帕尼缓释微丸25g，含药微丸5g，微晶纤维素12g，乳糖16g，pvpK30质量百分比5％溶液12g，18目筛制粒，40℃烘箱干燥，18目筛整粒，硬脂酸0.6g，混合后压片。
释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放结果见图10。
实施例8 基于微片的缓控释胶囊
缓释微片
Figure PCTCN2017116561-appb-000016
速释微片
Figure PCTCN2017116561-appb-000017
缓释微片：将尼拉帕尼与共聚维酮VA64过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得尼拉帕尼共研磨混合物。将共研磨混合物以处方量和释放速率调节用基质聚合物聚氧乙烯、乙基纤维素过60目筛并于三维混合器中在30rpm下混合25分钟，再加入硬脂酸镁混合5min，压成直径为4mm的微片。
速释微片：将尼拉帕尼与共聚维酮VA64过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得尼拉帕尼共研磨混合物。将共研磨混合物以处方量和交联聚维酮过60目筛并于三维混合器中在30rpm下混合25分钟，再加入硬脂酸镁混合5min，压成直径为4mm的微片。
胶囊灌装：将上述制备得到的缓释微片灌装胶囊，制备成缓释胶囊。
将上述制备完成的速释微片和缓释微片按照处方量、充分混匀后，进行胶囊灌装，制备成速缓双释胶囊。
释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放结果见图10。
实施例9 基于微片的缓控释胶囊
缓释微片
Figure PCTCN2017116561-appb-000018
速释微片
Figure PCTCN2017116561-appb-000019
缓释微片：将尼拉帕尼与2-羟丙基-β-环糊精过60目筛3遍，加入100ml水后经高速剪切制得粗混悬液，再以高压均质机循环均质至平均粒径为低于1000nm，以冻干机将纳米晶溶液冻干以除去水分。将纳米晶粉末过60目筛，以处方量和释放速率调节用基质聚合物卡波姆934过60目筛并于三维混合器中在30rpm下混合25分钟，再加入硬脂富马酸钠混合5min，压成直径为3mm的微片。
速释微片：将尼拉帕尼与2-羟丙基-β-环糊精过60目筛3遍，加入100ml水后经高速剪切制得粗混悬液，再以高压均质机循环均质至平均粒径为低于1000nm，以冻干机将纳米晶溶液冻干以除去水分。将纳米晶粉末过60目筛，以处方量和乳糖、交联羧甲基纤维素钠过60目筛并于三维混合器中在30rpm下混合25分钟，再加入硬脂富马酸钠混合5min，压成直径为3mm的微片。
胶囊灌装：将上述制备得到的缓释微片灌装胶囊，制备成缓释胶囊。
将上述制备完成的速释微片和缓释微片按照处方量、充分混匀后，进行胶囊灌装，制备成速缓双释胶囊。释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放结果见图10。
实施例10 单层渗透泵控释片
Figure PCTCN2017116561-appb-000020
Figure PCTCN2017116561-appb-000021
将处方量的尼拉帕尼和羟丙甲纤维素E5过60目筛并以三维混合器在30rpm下混合25分钟后，缓慢加入到已预热好的熔体挤出机，收集挤出物并粉碎过60目筛得到维拉帕尼固体分散体。将上述制得的尼拉帕尼固体分散体与除硬脂酸镁外的其他辅料过60目筛并通过三维混合器混合均匀，然后加入硬脂酸镁后继续混合5min，得到含药层组合物，待压片用。
采用直压方式，用上述含药层组合物压制单层渗透泵片片芯。压制的片芯，以4％醋酸纤维素-0.2％PEG4000溶液包控释衣层，衣膜增重5％，得到单层渗透泵控释片。释放度测定方法同实施例4，以pH 4.0的80mM乙酸钠缓冲液为释放介质，释放曲线见图10。
对比实施例1
速释胶囊1(自制)由20wt％盐酸尼拉帕尼、43wt％微晶纤维素、32wt％乳糖、2wt％微粉硅胶、1wt％硬脂酸镁和2wt％十二烷基硫酸钠混合均匀后，直接装入0#明胶硬胶囊制成，其溶出度测定是采用溶出度测定法(中国药典2010年版二部附录X C)第一法装置，37℃条件下，以900mL pH 1.2的盐酸水溶液为释放介质，转速为每分钟75转，依法操作，按预定时间点取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2015年版二部附录ⅣA)，在240nm的波长处分别测定吸光度，测定胶囊的溶出度。
释放结果见图11。速释胶囊中活性成分尼拉帕尼于30分钟左右释放85％以上，1小时内基本释放完全。
对比实施例2
速释胶囊2(自制)由50wt％尼拉帕尼对甲苯磺酸酯水合物、49wt％乳糖一水合物、1wt％硬脂酸镁混合均匀后，直接装入0#明胶硬胶囊制成，其溶出度测定是采用溶出度测定法(中国药典2015年版二部附录X C)第一法装置，37℃条件下，以900mL pH 4.0的80mM乙酸钠缓冲液为释放介质，转速为每分钟50转，依法操作，按预定时间点取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在240nm的波长处分别测定吸光度，测定胶囊的溶出度。
释放结果见图12。速释胶囊中活性成分尼拉帕尼于45分钟释放80％以上，1小时内基本释放完全。
实验实施例1
尼拉帕尼速释胶囊(对比实施例1)和速缓双效控释片(实施例1)，分别给药于饱腹比格犬(n＝3)，用25mL水分别送服，给药后在预定时间点取血，血样在4℃条件下，以4000rpm，离心10min，取上层血浆，用于LC-MS的血药浓度检测，结果见图13。相对于胶囊制剂的Cmax(1503.4ng/mL)，速缓双效控释片的Cmax降低至1050.1ng/mL，降低了约30％；AUC0-24h变化<10％；由药时曲线图13结果仍可见，相对于速释胶囊，速缓双效骨架片可通过初始的速释手段，在短时间内达到某一血药浓度，而后通过缓释手段，实现了药物血药浓度的缓慢上升，但避免了血药浓度突高，并维持在有效PARP酶抑制所学的血药浓度下较长时间，以更好的发挥酶抑制作用和抗肿瘤效果，同时为药物剂量爬坡和最佳药效的发挥提供了更大的空间。
实验实施例2
尼拉帕尼速释胶囊(对比实施例1)和双层渗透泵控释片(实施例3)分别给药于饱腹比格犬(n＝3)，用25mL水分别送服，给药后在预定时间点取血，血样在4℃条件下，以4000rpm，离心10min，取上层血浆，用于LC-MS的血药浓度检测，结果见图14。相对于胶囊制剂的Cmax(1754.0ng/mL)，双层渗透泵片的Cmax降低至903.2ng/mL，降低了约49％；AUC0-24h变化<30％；由药时曲线图14结果仍可见，相对于速释胶囊，双层渗透泵片实现了药物的缓慢吸收，实现了药物血药浓度的缓慢上升，药物血药浓度达峰时间和半衰期得到延长，避免了血药浓度突高，有望更好的发挥酶抑制作用和抗肿瘤效果，同时为药物剂量爬坡和最佳药效的发挥提供了更大的空间。
实验实施例3
尼拉帕尼速释胶囊(对比实施例2)和速缓双释双层渗透泵控释片(实施例4)分别给药于饱腹比格犬(n＝3)，用25mL水分别送服，给药后在预定时间点取血，血样在4℃条件下，以4000rpm，离心10min，取上层血浆，用于LC-MS的血药浓度检测，结果见图15。另取0h、0.5h、6h、10h、15h、24h全血提取PBMC，以Trevigen公司HT PARP in vivo Pharmacodynamic Assay II试剂盒检测PARP酶抑制情况，结果见图16。
相对于胶囊制剂的Cmax(1138.7ng/mL)，双层渗透泵片的Cmax降低至678.0ng/mL，降低了约40％；AUC0-24h变化<30％；速释胶囊在10h酶抑制率低于50％，速缓双释双层渗透泵片在10h酶抑制率大于90％，酶抑制水平大于IC90时间达10h，由药时曲线图15和酶抑制率图16结果可见，相对于速释胶囊，双层渗透泵片实现了药物的缓慢吸收，实现了药物血药浓度的缓慢上升，药物血药浓度达峰时间和半衰期得到延长，避免了血药浓度突高，酶抑制率得到长期维持，有望更好的发挥酶抑制作用和抗肿瘤效果，同时为药物剂量爬坡和最佳药效的发挥提供了更大的空间。

Claims (10)

  1. 一种尼拉帕尼缓控释药物组合物，其包含溶出改善形式的尼拉帕尼和释放速率调节用基质聚合物；
    所述尼拉帕尼缓控释药物组合物的稳态血药浓度波谷值Cmin,ss为0.5-4μM；稳态血药浓度波峰值Cmax,ss为0.8-6μM。
  2. 根据权利要求1所述的尼拉帕尼缓控释药物组合物，其中，所述尼拉帕尼药物组合物的稳态血药浓度波谷值Cmin,ss为1-3μM；稳态血药浓度波峰值为Cmax,ss为2-5μM，且稳态血药浓度峰/谷值优选小于2，更优选小于1.5。
  3. 根据权利要求1或2所述的尼拉帕尼缓控释药物组合物，其中，所述尼拉帕尼药物组合物具有可控的释药行为，在预定的时间段内，在符合漏槽条件的释放介质中，其释放行为和释放量可控，当采用中国药典溶出度测定法第二法装置，37℃条件下pH值为1.2-7.8的缓冲溶液中进行释放行为测定时，1小时内尼拉帕尼的释放量小于尼拉帕尼总量的50％，优选30％，更优选10-25％；16小时释放尼拉帕尼的量大于尼拉帕尼总量的80％，更优选>90％。
  4. 根据权利要求1至3中任一项所述的尼拉帕尼缓控释药物组合物，其中
    所述溶出改善形式的尼拉帕尼包括：尼拉帕尼游离碱的相应盐形式的化合物、尼拉帕尼共研磨混合物、尼拉帕尼纳米晶和尼拉帕尼固体分散体，
    优选地，所述释放速率调节用基质聚合物为选自纤维素衍生物、淀粉或其衍生物、藻酸盐、丙烯酸或甲基丙烯酸衍生物、聚环氧乙烷、树胶和基于碳水化合物的聚合物，更优选选自聚氧乙烯、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、羟乙基纤维素、乙基纤维素、醋酸纤维素、海藻酸钠、聚维酮、共聚维酮、丙烯酸树脂、卡波姆的一种或两种以上的组合，优选为选自聚氧乙烯、羟丙基纤维素、海藻酸钠、羟丙甲纤维素和卡波姆的一种或两种以上的组合；
    优选地，所述尼拉帕尼盐形式化合物选自盐酸盐、磷酸盐、苯磺酸盐、马来酸盐、硫酸盐和右旋樟脑酸盐；
    优选地，所述尼拉帕尼共研磨混合物由活性药物尼拉帕尼、增溶用基质聚合物和其他添加物组成，通过将所述成分共研磨而制备；所述共研磨混合物中，基于共研磨组合物的总重，尼拉帕尼的重量百分比为5-60wt％，优选20-40wt％，增溶用基质聚合物的重量百分比为40-95wt％，优选40-80wt％，其他添加物的重量百分比为0-15wt％，优选0.2-10wt％；
    优选地，所述尼拉帕尼纳米晶由活性药物尼拉帕尼、增溶用基质聚合物和/或任选的其他添加物组成，通过将所述成分高压均质或共沉淀法制备成纳米尺寸的颗粒而得到；所述尼拉帕尼纳米晶中，基于尼拉帕尼纳米晶的总重，尼拉帕尼的重量百分比为10-100wt％，优选20-50wt％；增溶用基质聚合物的重量百分比为0-75wt％，优选0-65wt％，其他添加物的重量百分比为0-10wt％，优选0-5％wt％；所述纳米晶的粒径优选为50-1000nm；
    优选地，所述固体分散体由活性药物尼拉帕尼、增溶用基质聚合物和任选的其他添加物组成，通过溶剂挥发法或熔体挤出法制造，在固体分散体中，基于固体分散体的总重，尼拉帕尼的重量百分比为5-50wt％，优选10-40wt％，更优选20-40wt％，增溶用基质聚合物的重量百分比为45-95wt％，优选50-80wt％，其他添加物的重量百分比为0-12wt％，优选0-10wt％；
    优选地，所述的增溶用基质聚合物包括选自聚维酮、共聚维酮、聚氧乙烯、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、醋酸羟丙基纤维素琥珀酸酯、聚乙二醇、泊洛沙姆、聚甲基丙烯酸、聚丙烯酸乙酯、2-羟丙基-β-环糊精、羟丙甲纤维素(HPMC)、聚甲基丙烯酸酯、羟丙基纤维素、醋酸邻苯二甲酸纤维素(CAP)以及其他药学可用的常见增溶用聚合物辅料中的一种或两种以上的组合；
    优选地，所述的其他添加物选自药学上常见的增塑剂和/或润滑剂等，优选地，所述的增塑剂可选自PEG 4000、邻苯二甲酸酯、小分子表活性剂如Cremphor RH40和聚氧乙烯(40)硬脂酸酯以及其他药学常见的增塑剂中的一种或两种以上的组合，所述的润滑剂可选自微粉硅胶、硬脂酸镁等常见润滑剂中的一种或两种以上组合。
  5. 根据权利要求1至4中任一项所述的尼拉帕尼缓控释药物组合物，其包含50-900重量份，优选80-700重量份，更优选120-600重量份的溶出改善形式尼拉帕尼；和10-300重量份，优选20-250重量份，更优选50-180重量份的释放速率调节用基质聚合物；
    优选地，所述尼拉帕尼口服缓控释药物组合物包含：
    50-700重量份的尼拉帕尼盐形式化合物，和10-300重量份的释放速率调节用基质聚合物；或者
    50-700重量份的尼拉帕尼共研磨混合物，和10-200重量份的释放速率调节用基质聚合物；或者
    50-800重量份的尼拉帕尼纳米晶，和0-250重量份的释放速率调节用基质聚合物；或者
    50-900重量份的尼拉帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物。
  6. 根据权利要求1至5任一项所述的尼拉帕尼缓控释药物组合物，其为单一缓释相的缓控释制剂或既含有速释相又含有缓释相的速缓双效释放制剂，其中，
    优选地，
    所述的缓释相是含有药物活性成分的控释组合物，为选自控释片、控释小丸、片剂中的控释组合物、片剂或丸芯中的控释组合物、结合到双层片中的控释层组合物及其任意形式的组合；
    所述的速释相是含有药物活性成分的速释组合物，为选自速释片、速释丸、片剂中的速释组合物、包裹于控释片剂或丸芯外的速释包衣层、双层控释片中的速释层组合物及其任意形式的组合。
  7. 根据权利要求6所述的尼拉帕尼缓控释药物组合物，其中，在所述速缓双效控释制剂中，速释相中的药物活性成分占药物活性成分总量的10-50wt％，优选为20-40wt％；缓释相中的药物活性成分占药物活性成分总量的50-90wt％，优选60-80wt％。
  8. 根据权利要求1至7中任一项所述的尼拉帕尼缓控释药物组合物，其为片剂或胶囊剂，优选选自渗透泵控释片，渗透泵速缓双释片，骨架型缓释片，骨架型速缓双效双层片，骨架型速缓双效包衣片，基于缓释微丸的缓释片，基于缓释微丸和速释微丸的速缓双效片，含有骨架型缓释微丸的胶囊，含有包衣缓释微丸的胶囊，含有速释包衣的缓释微丸的胶囊、含有速释微丸和骨架型缓释微丸的速缓双释胶囊、含有速释微丸和包衣缓释微丸的速缓双释胶囊、含有骨架型缓释微片的胶囊、含有速释包衣的骨架型缓释微片的胶囊以及含有速释微片和骨架型缓释微片的胶囊。
  9. 根据权利要求1至8任一项所述的尼拉帕尼缓控释药物组合物用于制备预防或***，特别是选自：卵巢癌、乳腺癌、胃癌、肺癌、血癌、胰腺癌、胶质细胞瘤，上皮性卵巢癌，转移脑癌等肿瘤的药物的用途。
  10. 根据权利要求9所述的用途，其中，尼拉帕尼缓控释药物组合物每天需要服用的预期总剂量为100-800mg，优选每天服用200mg-500mg/天，单位制剂(如单个药品或胶囊)中所含的药物活性成分尼拉帕尼的量没有具体限制，可以根据需要选择，例如可以为可含有药物活性成分20～400mg，优选50mg～400mg。
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019067634A1 (en) * 2017-09-26 2019-04-04 Tesaro, Inc. NIRAPARIB FORMULATIONS
US20200017462A1 (en) 2017-03-27 2020-01-16 Tesaro, Inc. Niraparib compositions
WO2020072797A1 (en) * 2018-10-03 2020-04-09 Tesaro, Inc. Niraparib salts

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110038011A (zh) * 2019-03-13 2019-07-23 安庆瑄宇医药科技有限公司 一种尼拉帕尼组合药物及其制备方法
CN109875977A (zh) * 2019-03-13 2019-06-14 安庆瑄宇医药科技有限公司 一种尼拉帕尼抗癌药物及其制备方法
CN110075061A (zh) * 2019-03-13 2019-08-02 安庆瑄宇医药科技有限公司 一种尼拉帕尼口服液及其制备方法
US11395831B2 (en) * 2020-05-22 2022-07-26 Somerset Therapeutics, Llc. Combination products of tobramycin compounds and dexameihasone compounds
WO2023086779A1 (en) * 2021-11-10 2023-05-19 Crititech, Inc. Niraparib particles and uses thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084261A1 (en) * 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0700432D0 (en) * 2007-01-10 2007-02-21 Angeletti P Ist Richerche Bio Therapeutic compounds
CN101711752B (zh) * 2009-11-26 2011-09-21 中国科学院上海药物研究所 一种苯并异噁唑类衍生物的控释制剂及其制备方法
CN103417505B (zh) * 2012-05-24 2016-05-11 中国科学院上海药物研究所 具有双相释药行为的石杉碱甲控释制剂及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008084261A1 (en) * 2007-01-10 2008-07-17 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Amide substituted indazoles as poly(adp-ribose)polymerase (parp) inhibitors

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
JONES, PHILIP: "Discovery of 2-{4-[(3 S )-Piperidin-3-yl]phenyl}-2 H -indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 52, no. 22, 29 October 2009 (2009-10-29), pages 7170 - 7185, XP055263725, ISSN: 1520-4804 *
SANDHU, SHAHNEEN: "The poly(ADP-ribose) polymerase inhibitor niraparib ( MK 4827) in BRCA mutation carriers and patients with sporadic cancer: a pha- se 1 dose-escalation trial", THE LANCET ONCOLOGY, vol. 14, no. 9, 28 June 2013 (2013-06-28), pages 882 - 892, XP055407449, ISSN: 1470-2045, DOI: doi:10.1016/S1470-2045(13)70240-7 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20200017462A1 (en) 2017-03-27 2020-01-16 Tesaro, Inc. Niraparib compositions
US11091459B2 (en) 2017-03-27 2021-08-17 Tesaro, Inc. Niraparib compositions
US11673877B2 (en) 2017-03-27 2023-06-13 Tesaro, Inc. Niraparib compositions
WO2019067634A1 (en) * 2017-09-26 2019-04-04 Tesaro, Inc. NIRAPARIB FORMULATIONS
CN111278433A (zh) * 2017-09-26 2020-06-12 特沙诺有限公司 尼拉帕尼制剂
US11730725B2 (en) 2017-09-26 2023-08-22 Tesaro, Inc. Niraparib formulations
WO2020072797A1 (en) * 2018-10-03 2020-04-09 Tesaro, Inc. Niraparib salts
CN113166071A (zh) * 2018-10-03 2021-07-23 特沙诺有限公司 尼拉帕利盐
US20210347760A1 (en) * 2018-10-03 2021-11-11 Tesaro, Inc. Niraparib Salts
JP7472115B2 (ja) 2018-10-03 2024-04-22 テサロ， インコーポレイテッド ニラパリブ塩

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