WO2018108152A1 - 一种奥拉帕尼口服缓控释药物组合物及其用途 - Google Patents

一种奥拉帕尼口服缓控释药物组合物及其用途 Download PDF

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WO2018108152A1
WO2018108152A1 PCT/CN2017/116475 CN2017116475W WO2018108152A1 WO 2018108152 A1 WO2018108152 A1 WO 2018108152A1 CN 2017116475 W CN2017116475 W CN 2017116475W WO 2018108152 A1 WO2018108152 A1 WO 2018108152A1
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release
weight
olaparib
sustained
parts
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PCT/CN2017/116475
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English (en)
French (fr)
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甘勇
朱全垒
郭仕艳
朱春柳
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中国科学院上海药物研究所
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Priority to CN201780011153.8A priority Critical patent/CN110035757B/zh
Priority to ES17880064T priority patent/ES2873389T3/es
Priority to JP2019532698A priority patent/JP6888226B2/ja
Priority to US16/469,458 priority patent/US20200108008A1/en
Priority to EP17880064.5A priority patent/EP3556369B1/en
Publication of WO2018108152A1 publication Critical patent/WO2018108152A1/zh

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • 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
    • A61K9/20—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
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • 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

Definitions

  • the invention relates to the field of olapani pharmaceutical preparations, in particular to an oral sustained-release pharmaceutical composition of olaparib and a use thereof.
  • Olaparib chemical name 1-(cyclopropanyl)-4-[5-[(3,4-dihydro-4-oxo-1-pyridazinyl)methyl]-2 -Fluorobenzoyl]piperazine, having a molecular formula of C 24 H 23 FN 4 O 3 , having a molecular weight of 434.46, having the following chemical structure:
  • Olapani (trade name LYNPARZAR) is a new drug developed by AstraZeneca for tumor-targeted therapy. Its capsules were approved by the US Food and Drug Administration (FDA) in December 2014, and the tablets were approved by the FDA. Approved in August 2017, it is the first FDA-approved poly ADP transferase (PARP) inhibitor for cancer treatment.
  • PARP poly ADP transferase
  • PARP poly ADP transferase
  • olaparib is able to inhibit PRAP enzyme activity, making the single strand of DNA cleavage unrepairable, increasing genomic instability, which in turn leads to cellular Apoptosis, especially for tumor cells with defects in homologous recombination repair, has a strong killing effect.
  • olaparib This mode of action of olaparib has therapeutic potential for a variety of tumors; in addition, due to olpa
  • the specific inhibition of the damage repair ability, the drug will also avoid tumor resistance after chemotherapy, enhance DNA damage after chemotherapy, in order to enhance the killing effect on the tumor.
  • AstraZeneca is conducting a number of phase III clinical studies to investigate the treatment of olapani for cancers associated with BRCA gene mutations such as ovarian cancer, stomach cancer, and breast cancer.
  • Olapani can specifically inhibit the growth of tumor cell lines, increase the toxicity and anti-tumor activity on tumor cells, and has no killing effect on normal tissue cells of DNA repair function. It is a typical drug for tumor targeted therapy so far.
  • the emergence of Olapani is Patients with advanced tumors carrying BRCA1 and BRCA2 mutations provide an opportunity to treat weapons and survive, as well as an example of a deeper understanding and individualized treatment of the underlying pathogenesis of the disease.
  • the immediate release capsule preparation of olapani is usually rapidly peaked within 0.5 to 3 hours after oral administration and is rapidly eliminated. Therefore, in order to achieve a higher blood concentration (>IC 90 value) and exert a strong enzyme inhibition effect, the 50 mg specification immediate release capsule preparation developed by AstraZeneca needs to be higher than 200 mg/2 times/day. It can be maintained for longer than IC 90 for a long time to achieve the desired PARP enzyme inhibitory activity, while the steady-state plasma concentrations of 100mg/2 times/day and 400mg/1 times/day are difficult to maintain at IC 90 for a long time. the above.
  • the results of the phase II clinical efficacy study also found that the dose of 400mg/2 times / day compared to the dose of 200mg / 2 times / day, the patient showed a certain number of advantages in the progression-free survival, The former has a progression-free survival of 8.8 months, while the latter has 6.5 months; in addition, the overall effective rate of the former is 33%, while the latter is 25%, although the two modes of administration do not show statistical results in terms of therapeutic effect.
  • Significant differences in learning, but from the quantitative advantages shown by the experimental results, AstraZeneca finally chose a dose of 400mg/2 times / day for the new drug application and the listing of capsule products. In addition, AstraZeneca's new dose of Olapani tablets in 2017 was 300mg/2 times/day.
  • Olapani nanoparticle preparation (WO2015031536A1)
  • olaparib solid dispersion and its common tablets and capsules (CN104434809A)
  • olaparib solid dispersion Body and its tablets (WO2010041051, CN102238945A), etc., as follows:
  • WO2015031536A1 discloses an olaparib nanoparticle preparation, the olaparib cationic liposome of the invention having a particle size of 80-200 nm, loaded with a drug (or even modified with PEG), and placed in a degradable polymer In the matrix, the drug is delivered in the form of an injection. Compared with oral olaparib, it prolongs the half-life of blood concentration, and at the same time, enters the blood vessels of tumor tissue in the form of nanoparticles, and slowly releases the drug, thereby achieving sustained release function.
  • CN104434809A discloses an olaparib solid dispersion, the olaparib solid dispersion of the invention, using povidone K 30 as a main material, solvent evaporation method, spray drying method or hot melt extrusion method
  • the prepared olaparib solid dispersion is mixed and compressed with other fillers, lubricants, etc., or prepared into a capsule preparation.
  • WO2010041051 A1 discloses an olaparib solid dispersion preparation which effectively improves the bioavailability of olaparib by the preparation of a solid dispersion preparation.
  • Olapani immediate release preparations are not ideally absorbed, requiring multiple doses of high doses, resulting in higher steady-state plasma peaks and larger blood drug concentration fluctuations (400 mg, BID, C min, ss ⁇ 1 ⁇ g /ml; C max, ss > 6 ⁇ g / mL; 300mg tablets, BID, C min, ss ⁇ 1 ⁇ g / ml, C max, ss > 7 ⁇ g / mL), resulting in uncontrolled clinical efficacy of olrapani immediate release preparation There are a number of security issues.
  • the primary object of the present invention is to precisely control the absorption rate and absorption time of olapani in the gastrointestinal tract by controlling the release behavior of olrapani according to its biological properties and the efficacy and safety requirements of clinical treatment.
  • the blood drug concentration level and its fluctuation range in the body maintain the long-term homeostasis of the blood drug concentration in the body to the effective PARP enzyme inhibition level, improve the anti-tumor effect of olrapani, 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 provides an oral sustained-release pharmaceutical composition of olaparib, which has controllable in vivo absorption behavior, blood drug concentration and PARP enzyme inhibition level, and has improved olaparibide drug
  • the advantages of loading and/or oral absorption and/or bioavailability and/or blood concentration control and/or enzyme inhibition level control can be used as the sole formulation or in combination with other therapies to treat cancer.
  • the olaparib oral sustained-release pharmaceutical composition provided by the present invention comprises: a dissolution-improved form of olaparib; and a matrix polymer for release rate adjustment (also referred to as a release regulator).
  • a semipermeable controlled release coating material a covering material, a disintegrating agent, a coating powder, a plasticizer, a porogen, an expanding material, a filler, and the like may also be included.
  • Osmotic pressure regulator also known as penetration enhancer
  • lubricant also known as binder
  • dye also known as colorant
  • anti-adhesive also known as anti-adhesive
  • shading Pharmaceutical excipients such as agents, diluents and/or other pharmaceutically acceptable additives.
  • the active drug olaparibide in the olaparibil pharmaceutical composition provided by the present invention belongs to a poorly soluble drug, and is first subjected to solubilization treatment to prepare a solubilizing composition to improve dissolution of the drug.
  • solubilization treatment can be prepared by chemical means into a salt form compound of olaparib; or by mixing olaparib with a matrix polymer which can improve drug solubility.
  • the dispersion specific surface area in the powder of the active pharmaceutical preparation composition is changed, thereby improving the dissolution properties of the drug, which may include co-milling, high pressure homogenization, coprecipitation, solvent evaporation or melt extrusion, and the like.
  • the dissolution-improved form of olaparib mainly includes: olaparibide (which may be selected from the group consisting of hydrochloride, besylate, sulfate, maleate, camphorate, etc.), olrapani co-milling Mixture, olaparib nanocrystals and olaparib solid dispersion.
  • olaparibide which may be selected from the group consisting of hydrochloride, besylate, sulfate, maleate, camphorate, etc.
  • olrapani co-milling Mixture olaparib nanocrystals and olaparib solid dispersion.
  • the olrapani co-milling mixture, olaparib nanocrystals and olaparib solid dispersion can improve the dissolution and dissolution properties of olaparib in the controlled release dosage form while improving the absorption and bioavailability of the drug.
  • the olaparib co-milling mixture consists of the active drug olaparib, a solubilizing matrix polymer and other additives, prepared by co-milling the ingredients.
  • the particle size of the drug powder is generally 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 olaparib is from 5 to 60% by weight, preferably from 20 to 40% by weight, based on the total weight of the co-milled mixture, and the weight percentage of the matrix polymer for solubilization is from 40 to 95% by weight, preferably 40. - 80% by weight, the weight percentage of other additives is 0-15% by weight, preferably 0.2-10% by weight. The total amount of each of the above components was 100% by weight.
  • the olaparib nanocrystals of the present invention are composed of the active drug olaparib, a matrix polymer for solubilization, and/or other additives, and are prepared into nanosized particles by high pressure homogenization or coprecipitation of the components. And get it.
  • the high pressure homogenization method is as follows: a crude crystal suspension prepared by high-speed shearing of an aqueous solution of the active drug olapaib and the solubilizing matrix polymer is added to a high pressure homogenizer, and the high pressure homogenization is performed. Multiple times, until the prepared crystal particles reached 1000 nm or less, the sample was lyophilized to prepare a uniformly dispersed olaparib nanocrystal powder.
  • the coprecipitation method is as follows: the active drug olaparib 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 for solubilization is dissolved, and ultrasonic high frequency ultrasound (power) is utilized by the probe. Up to 100w or more) to ensure the formation and uniform dispersion of the active drug nucleus until a stable dispersion of the nanocrystal solution is formed, and the sample is lyophilized to prepare a uniformly dispersed olaparib nanocrystal powder.
  • an organic solvent such as acetone
  • the dispersed particle diameter of the active drug olaparib 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 nanocrystals can increase the dispersion specific surface area of olaparib in the powder of the solid preparation composition, thereby improving the dissolution properties of the drug.
  • the weight percentage of olaparib 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.
  • the solid dispersion in the present invention consists of the active drug olaparib, a matrix polymer for solubilization, and other additives.
  • the weight percentage of olaparib is 5 to 50% by weight, preferably 10 to 40% by weight, more preferably 20 to 40% by weight, based on the total weight of the solid dispersion, and the weight percentage of the matrix polymer for solubilization is 45-95 wt%, preferably 50-80 wt%, other additives are 0-12 wt%, preferably 0-10 wt%.
  • the total amount of each of the above components was 100% by weight.
  • the solid dispersion can be produced by a solvent evaporation method or a melt extrusion method.
  • the solvent evaporation method is carried out by dissolving the drug olaparib, the matrix polymer for solubilization and/or other additives into a volatile organic solvent or an organic mixed solvent, and volatilizing the organic solvent under reduced pressure, and vacuum drying the oven. Drying can produce a solid dispersion of olaparib.
  • the melt extrusion method is carried out as follows: the uniformly mixed drug olaparib, the solubilizing matrix polymer and/or other additive powder are directly added to the melt extruder directly, and the melt extrusion is collected. Things can be.
  • the solid dispersion enables the active drug olaparib to exhibit a high-state solid dispersion state, which is dispersed in a molecular form in the solid powder of the formulation composition, thereby maximizing the specific surface area of the drug. This improves the dissolution properties of the drug.
  • the matrix polymer for solubilization refers to the ability to stabilize and/or solubilize olaparib 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, Polyethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 2-hydroxypropyl- ⁇ -cyclodextrin, hypromellose (HPMC), polymethacrylate, hydroxypropyl One or a combination of two or more of cellulose, cellulose acetate phthalate (CAP), and other pharmaceutically acceptable solubilizing polymers.
  • the other additives may be selected from pharmaceutically acceptable pharmaceutically soluble solubilizing surfactants (eg, One or a combination of two or more of polyethylene glycol stearate, sodium lauryl sulfate, etc., a lubricant, a fine powder silica gel, a plasticizer, and the like.
  • pharmaceutically acceptable pharmaceutically soluble solubilizing surfactants eg, One or a combination of two or more of polyethylene glycol stearate, sodium lauryl sulfate, etc., a lubricant, a fine powder silica gel, a plasticizer, and the like.
  • the release rate adjusting matrix polymer (hereinafter sometimes referred to as a release regulator) in the present invention may be a high molecular polymer having a release rate adjusting effect, which is a sustained release skeleton matrix material well known to those skilled in the art and may be selected from a cellulose derivative, a starch or a derivative thereof, an alginate, an acrylic or methacrylic acid derivative, a polyethylene oxide, a gum, and a carbohydrate-based polymer, for example, may be selected from the group consisting of hydroxypropylcellulose and hydroxy One or more of propimethylcellulose, methylcellulose, hydroxyethylcellulose, ethylcellulose, cellulose acetate, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer
  • the combination is preferably one or a combination of two or more selected from the group consisting of hydroxypropylcellulose, sodium alginate, hypromellose, and carbomer.
  • the drug olaparib includes olaparib free base and a pharmaceutically acceptable salt thereof, and the pharmaceutically acceptable salt thereof may be selected from the group consisting of hydrochloride, phosphate, sulfate, maleate, dextrorotanoate and benzene. Sulfonate and the like.
  • the olaparib oral 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 a dissolution-improved form of olaparib; and 0.1-300
  • the release rate adjusting matrix polymer is preferably 20-250 parts by weight, more preferably 50-180 parts by weight, based on parts by weight.
  • it comprises, (a) 50-600 parts by weight of olaparib salt, and 10-250 parts by weight of a matrix polymer for release rate adjustment; or (b) 50-700 parts by weight of ola Panier co-milling the mixture, and 10-200 parts by weight of the matrix polymer for release rate adjustment; or (c) 50-800 parts by weight of olaparib nanocrystals, and 0.1-250 parts by weight of the release rate adjusting matrix a polymer; or (d) 50-900 parts by weight of an olaparib solid dispersion, and 20 to 300 parts by weight of a matrix polymer for release rate adjustment.
  • the olaparib oral sustained-release pharmaceutical composition provided by the present invention may further comprise from 1 to 400 parts by weight, preferably from 2 to 300 parts by weight, more preferably from 5 to 250 parts by weight, of other additives.
  • it may further comprise 1-300 parts by weight of other additives, and in the above (b), may further contain 1-150 parts by weight of other additives, and in the above (c), It contains 1 to 200 parts by weight of other additives, and in the above (d), it may further contain 1 to 200 parts by weight of other additives.
  • the other additives may be selected from, but not limited to, release rate adjusting permeation-promoting polymers, semi-permeable controlled release coating materials, barrier materials, solubilizers, disintegrants, coating powders, plasticizers, Pore, expansion material, filler, osmotic pressure regulator (also known as penetration enhancer, osmotic pressure accelerator), lubricant, binder (also known as binder), dye (also known as colorant) Pharmaceutical excipients such as anti-adherents (also known as anti-adherents), opacifiers, diluents, and/or other pharmaceutically acceptable additives.
  • release rate adjusting permeation-promoting polymers such as release rate adjusting permeation-promoting polymers, semi-permeable controlled release coating materials, barrier materials, solubilizers, disintegrants, coating powders, plasticizers, Pore, expansion material, filler, osmotic pressure regulator (also known as penetration enhancer, osmotic pressure accelerator), lubricant
  • the expected total dose of olaparib that the human body needs to take daily is 100-1400 mg.
  • the amount of the pharmaceutically active ingredient olaparib contained in a single finished tablet or capsule is not particularly limited and may be selected as needed, and may be, for example, 20 to 400 mg or 50 mg to 300 mg.
  • the composition is administered once a day, and the rate and time of absorption in the olaparib can be controlled to maintain the effective range of blood concentration in the body for inhibition of PARP enzyme.
  • the pharmaceutical composition of the present invention can enhance the PARP enzyme inhibitory effect and tumor therapeutic effect of olaparib, while reducing the toxic side effects of the drug.
  • the olaparibil 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 (also referred to as a controlled release phase) is a controlled release composition containing 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 olaparibil pharmaceutical composition provided by the invention may be a tablet or a capsule, preferably selected from the group consisting of an osmotic pump controlled release tablet, an osmotic pump speed double release tablet, a skeleton type sustained release tablet, and a skeleton type slow double effect double Layer, skeletal type double-effect coated tablet, sustained release tablet based on sustained release pellets, quick-acting double-effect tablet based on sustained-release pellets and immediate-release pellets, capsule containing skeleton type sustained-release pellets, containing Capsule for coated sustained-release pellets, capsule containing sustained-release pellets of immediate release coating, quick-release double-release capsule containing immediate release pellets and skeleton sustained-release pellets, containing immediate-release pellets and coated sustained-release micro
  • the olaparibil pharmaceutical composition provided by the invention can be used for preparing a medicament for preventing or treating tumors, preferably, the tumor is selected from various types of tumors with defects in DNA repair function, in particular for preparing prevention or treatment with BRCA gene.
  • a drug for two or more combination cancers related to mutation such as ovarian cancer, gastric cancer, breast cancer, and the like, and a medicament for preparing a tumor for preventing or treating a tumor associated with BRCA1 and BRCA2 gene mutation.
  • the olaparibil pharmaceutical composition provided by the present invention has a controlled release behavior, and the release behavior and release amount are controllable in a release medium that meets the sump condition within a predetermined period of time.
  • the release behavior is measured in a buffer solution with a pH of 1.2-7.8 at 37 ° C, and the release is less than 50% of the total amount of olaparibine within 1 hour, preferably 1
  • the release in less than 40% of the total amount of olaparib, more preferably 10-30%; the release of olrapani over 16 hours is greater than 80% of the total, preferably >90%.
  • the olapani pharmaceutical composition provided by the present invention controls the absorption rate and absorption time of olaparib in the gastrointestinal tract by controlling the release behavior and the release amount.
  • the maximum blood concentration value (C max ) obtained by the olapani at the same dose of the pharmaceutical composition provided by the present invention is reduced by at least 10-70%, and the plasma concentration peak time ( T 1/2 ) is extended by at least 30%.
  • the olaparibide pharmaceutical composition provided by the invention can precisely regulate the steady-state blood drug concentration of the drug in the body, and the steady-state blood drug concentration trough value C min, ss is 0.2-4 ⁇ g/mL, preferably 0.5-3 ⁇ g/mL;
  • the steady-state blood concentration peak value C max,ss is 0.8-15 ⁇ g/mL, preferably 1-12 ⁇ g/mL, which can reach the IC 90 value of the blood drug concentration required for cancer cell inhibition, and the steady-state blood concentration peak/
  • the ratio of the valleys is preferably less than 6, more preferably less than 4.
  • a single or double dose of 100 mg to 1400 mg per day can maintain a steady state plasma concentration level for an effective PARP enzyme inhibition level for a long period of time.
  • the pharmaceutical composition provided by the invention can maintain the effective concentration level of opalapani for the long-term inhibition of PARP enzyme activity in vivo by regulating the concentration range of olapanic blood concentration (50% and 90% PARP enzyme activity inhibition center)
  • the drug blood concentration is required to be the IC50 and IC90 values of PARP enzyme activity), accurately regulate the activity of PARP enzyme in vivo, and achieve high-efficiency and low-toxic treatment of drugs.
  • the plasma concentration of olaparib is maintained at least 13 above the IC50 and IC90 values respectively. Hours and 6 hours.
  • the controlled release pharmaceutical composition of the invention can precisely regulate the plasma concentration level and fluctuation range of olapaini, is beneficial to the long-term maintenance of the blood concentration level required for enzyme inhibition, and reduces the fluctuation range of blood drug concentration, thereby improving the tumor
  • the PARP enzyme inhibition rate and anti-tumor efficacy of the cells reduce the adverse reactions of the tumor patients after administration, and increase the compliance of the patients.
  • 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;
  • the olaparib sustained-release tablet of the present invention may be an osmotic pump type controlled release tablet, a skeleton type controlled release tablet or a sustained release tablet based on sustained release pellets.
  • the osmotic pump type controlled release tablets include osmotic pump controlled release tablets and osmotic pump quick release double release tablets
  • the skeleton type controlled release tablets include skeleton type sustained release tablets, skeleton type slow double effect double layer tablets and skeleton type quick release doubles.
  • the sustained-release pellets based on the sustained-release pellets include sustained-release tablets based on sustained-release pellets and quick-acting double-effect tablets based on sustained-release pellets and immediate-release pellets.
  • the sustained release tablet described above can specifically achieve the drug release behavior of the present invention in the following manner.
  • 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): it is formed by a push layer composition, located in a 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;
  • Olapani accounts for 3-50% by weight of the total weight of the osmotic pump 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 olaparib; 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 olaparib may be selected from the above-described olaparib salt, olaparib co-milled mixture, nanocrystals 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 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, 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 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 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, etc., 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 having a release orifice, which can improve the form of olrapani, release regulator, 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 olaparib, 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 olaparib 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 proportion of the porogen in the sustained release coating film is from 0 to 30% by weight based on the total weight of the sustained release coating film. Based on the total weight of the single-layer osmotic pump controlled release sheet, 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: 10-80 parts by weight of active ingredient olaparib, 0-100 parts by weight, preferably 10-100 parts by weight of solubilizing matrix polymer component, 0-30 parts by weight Other pharmacy commonly used adjuvants 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.
  • olaparib in the immediate release drug-containing layer is about 10-40% by weight of the total weight of olaparib in the entire double-release osmotic pump sheet, and the controlled release drug-containing layer
  • the olaparib is about 60-90% by weight of the total weight of olaparib in the entire double-release osmotic pump sheet.
  • the preparation method of the olapaini osmotic pump controlled release tablet comprises the following steps: 1 preparation of the improved form of olaparib; preparation of the medicated layer; preparation of the optional propelling 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 immediate release medicated 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 view showing the structure of an osmotic pump type controlled release sheet according to an embodiment of the present invention
  • FIG. 2 is a view showing the structure of an osmotic pump type 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 olapani.
  • 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 invention also provides an olaparib controlled release matrix tablet and/or a matrix tablet having a quick double effect release behavior
  • the controlled release matrix sheet provided by the invention mainly consists of a sustained release phase and an optional immediate release phase.
  • the double-layer sheet composed of the sustained-release phase and the immediate-release phase is a quick-acting double-effect release matrix sheet
  • the single-layer sheet composed only of the sustained-release phase is an ordinary sustained-release matrix sheet.
  • 3 is a schematic view showing the structure of a skeleton type quick-acting double-effect release double-layer sheet according to an embodiment of the present invention
  • FIG. 4 is a schematic view showing the structure of a skeleton type quick-release double-effect release coated sheet according to an embodiment of the present invention.
  • 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 dissolution-reduced form of olaparib, 10 to 300 parts by weight, preferably 30 to 150 parts by weight.
  • the release rate adjusting matrix polymer may be selected from the group consisting of polyoxyethylene, hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, One or a combination of two or more of povidone, copolyvidone, acrylic resin, carbomer; preferably selected from the group consisting of hydroxypropylcellulose, sodium alginate, hypromellose, and carbomer One or a combination of two or more.
  • the diluent is one or a combination of two or more selected from the group consisting of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch, sodium carboxymethyl starch.
  • the other tablet commonly used additives include one or a combination of two or more kinds of lubricants, colorants, and the like which are commonly used in solid preparations well known to those skilled in the art.
  • 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 coloring agent being selected from the group consisting of iron oxide red, One or a combination of two or more of iron oxide yellow, iron oxide violet, iron oxide black, and titanium oxide.
  • the immediate release phase may comprise the above-described dissolution-improved form of olaparib, a disintegrant, a diluent, and other additives commonly used in tablets, or other additives commonly used in olaparib, solubilizing matrix polymers, and tablets.
  • the immediate release phase may be prepared by thoroughly mixing the components, and then preparing into an immediate release layer by a conventional method well known to those skilled in the art, or simultaneously dissolving the components, coating the sustained release phase, and drying to form a rapid rate. Release film.
  • the dissolution-modified form of olaipani may be used in an amount of 20 to 600 parts by weight, preferably 30 to 400 parts by weight, more preferably 50 to 250 parts by weight.
  • the disintegrant is selected from the group consisting of cross-linked poly One or more of a ketone, sodium carboxymethyl starch, a low-substituted hydroxypropyl cellulose, a cross-linked polyethylene pyrrolidone, a croscarmellose sodium, and other pharmaceutically-acceptable disintegrants
  • the combination may be used in an amount of 5 to 90 parts by weight, preferably 10 to 50 parts by weight.
  • the diluent is one or a combination of two or more selected from the group consisting of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch, sodium carboxymethyl starch, and the amount may be 5- 200 parts by weight, preferably 10 to 150 parts by weight.
  • the tablet is usually used with other additives, including one or a combination of two or more of the lubricants and colorants commonly used in solid preparations well known to those skilled in the art, and may be used in an amount of 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight. Share.
  • 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, and the amount may be 0.1-20 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 titanium oxide, and may be used in an amount of 0 to 13 parts by weight.
  • the amount of olaipani may be from 5 to 100 parts by weight, preferably from 10 to 80 parts by weight, more preferably from 20 to 60 parts by weight.
  • the solubilizing matrix polymer is selected from the group consisting of povidone, copovidone, Soluplus, hypromellose phthalate (HPCP), polyethylene glycol, poloxamer, hypromellose One or a combination of two or more of (HPMC) and other materials may be used in an amount of 5 to 300 parts by weight, preferably 20 to 200 parts by weight, more preferably 30 to 120 parts by weight.
  • additives for other tablets include crospovidone, microcrystalline cellulose, and pharmaceutically acceptable surfactants (such as sodium lauryl sulfate), mannitol, lubricants (such as magnesium stearate), and the like.
  • Additives for immediate release tablets well known to those skilled in the art may be used in an amount of from 0.1 to 150 parts by weight, preferably from 0.5 to 100 parts by weight.
  • olaparib in the immediate release phase is about 10-40 wt% of the total weight of olaparib in the entire slow release double release matrix tablet
  • the sustained release phase is Rapani is about 60-90% by weight of the total weight of olaparib in the entire slow release double release matrix tablet.
  • the olaparib controlled release preparation 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 time of the pharmaceutically active ingredient in the sustained-release phase is preferably 90% by weight or more, preferably 10-16 hours, preferably 16 hours 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 Ritger - Peppas release model, preferably zero-order release.
  • sustained release tablet of olaparib based on controlled release pellets.
  • the sustained-release tablet based on the sustained-release pellets of the olrapani may be a sustained-release tablet based on sustained-release pellets, and a quick-release double-effect release tablet based on an immediate-release matrix/sustained-release pellet.
  • the immediate release matrix constitutes an immediate release phase
  • the sustained-release pellet constitutes a sustained-release phase.
  • olaparib in the immediate release phase accounts for 10-40% by weight of the total amount of olaparib
  • the olrapani in the sustained-release pellet accounts for the total amount of olrapani 60-90% by weight.
  • the immediate release matrix may include the above-described dissolution-improving form of the pharmaceutically active ingredient, a disintegrant, a diluent, and other conventional additives for tablets.
  • the dissolution-modified form of olaipani may be used in an amount of from 20 to 200 parts by weight, preferably from 50 to 150 parts by weight.
  • the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone, croscarmellose sodium, and other pharmaceutically useful
  • One or a combination of two or more of the disintegrants 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 is one or a combination of two or more selected from the group consisting of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch, sodium carboxymethyl starch, and the amount may be 5- 200 parts by weight, preferably 10 to 150 parts by weight.
  • the other tablet commonly used additives including one or a combination of two or more of the lubricants and colorants commonly used in solid preparations well known to those skilled in the art, may be used in an amount of 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight. Share.
  • 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, and the amount may be 0.1-20 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 titanium oxide, and may be used in an amount of 0 to 13 parts by weight.
  • the sustained-release pellets may comprise a coated sustained-release pellet and a skeleton-type sustained-release pellet, which may be, without limitation, a blank pellet core (0-300 parts by weight), an olaparib salt (for example, a hydrochloride salt, Benzene sulfonate, sulfate, camphorate, etc.), release rate adjusting matrix or controlled release coating material, and other excipients, etc., by wet granulation, extrusion spheronization, coating pans well known to those skilled in the art It is prepared by conventional methods such as coating and/or fluidized bed granulation coating.
  • an olaparib salt for example, a hydrochloride salt, Benzene sulfonate, sulfate, camphorate, etc.
  • release rate adjusting matrix or controlled release coating material and other excipients, etc.
  • the sustained-release pellets are prepared by a one-pot coating drug-loading method in a coating pan, wherein olaparib is dispersed or encased on a blank pellet core to form a drug-loading pellet core, and then a drug-loading core is outsourced.
  • a layered release coating material such as Su Lisi or the like to form a sustained release coating film to form the coated sustained release pellet.
  • the blank pellet core is one or a combination of two or more 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.
  • the sustained-release pellets are prepared by a fluidized bed method, wherein the olrapani and the release rate adjusting matrix are simultaneously dissolved, placed in a spray drying apparatus, blasted into a gas stream, sprayed dry, collected, and added to the paste. The mixture is granulated and dried to form the skeleton-type sustained-release pellet.
  • the release rate adjusting substrate or the controlled release coating material may be selected from the group consisting of shellac, cellulose acetate phthalate (CAP), acrylic resin (Eudragit), and ethyl cellulose (EC). ), polyacrylic polysiloxane, cellulose acetate, cellulose propionate, cellulose acetate propionate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), methyl cellulose, hydroxypropyl cellulose, hydroxypropyl group One or more of cellulose (HPMC) and the like.
  • the other excipients mainly include, but are not limited to, a binder, a plasticizer, a porogen, and the like.
  • the binder is one or more selected from the group consisting of polyethylene glycol (PEG), stearic acid, glyceryl monostearate, etc.
  • the plasticizer is selected from the group consisting of propylene glycol, glycerin, and poly One or more of ethylene glycol (PEG), triacetin, acetyl monoglyceride, phthalate, castor oil, etc.
  • the porogen It is selected from hydrophilic liquid carrier (glycerin, PEG200), sugar (lactose, fructose, sucrose, mannose), surfactant (polysorbate 80, sodium lauryl sulfate, etc.), polymer (polydimensional) One or more of a ketone, hypromellose, and the like.
  • the sustained release pellets comprise from 100 to 500 parts by weight, preferably from 200 to 400 parts by weight, of a blank pellet core, from 10 to 150 parts by weight, preferably from 30 to 100 parts by weight, of olaparibide. 10-300 parts by weight of the release rate adjusting substrate or controlled release coating material, 0-100 parts by weight of the binder, 0-12 parts by weight of the porogen, and 0-15 parts by weight of the plasticizer.
  • sustained-release pellets were directly compressed and prepared into sustained-release tablets based on sustained-release pellets. If the ratio of the immediate release matrix and the sustained-release pellets is uniformly mixed, and then compressed into tablets by a tableting machine with a special stirring function, a quick-release double-release preparation can be prepared.
  • the present invention also provides a controlled release capsule preparation which may be selected from the group consisting of a pellet-based controlled release capsule and a tablet-based controlled release capsule.
  • the micropellet-based controlled release capsule of the present invention is a controlled release capsule composed of sustained release pellets or a quick release double release capsule composed of sustained release pellets and immediate release pellets, and may include sustained release pellets containing skeleton type.
  • Fig. 5 is a view showing the structure of a quick-release double-release capsule containing an immediate release pellet and a skeleton-type sustained-release pellet
  • Fig. 6 is a schematic view showing the structure of a capsule containing a sustained-release pellet of an immediate release coating.
  • 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.
  • the olaparib in the immediate release phase accounts for 10-40% by weight
  • the olrapani 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 sustained-release pellets of the above section 1.3, 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 Section 1.2 above, and is not repeated here.
  • the sustained release pill can be prepared into a controlled release capsule by capsule filling, and the above-mentioned immediate release pill and sustained release pill are weighed according to a certain ratio. After mixing evenly, and then performing capsule filling, a quick-release double-release capsule preparation or a sustained-release pellet containing an immediate release coating can be prepared for capsule filling, and a quick-release double-release capsule preparation can also be prepared.
  • 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.
  • Figure 7 shows the structural intent of a capsule containing an immediate release and sustained release tablet.
  • the immediate-release microchips constitute the immediate release phase
  • the sustained-release microchips constitute the sustained-release phase.
  • olaparib in the immediate release phase is 10-40% by weight
  • olaparib in the sustained release phase is 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 1.2-part skeleton-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 Section 1.2 above, 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.
  • 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 an immediate release pellet and a skeleton type sustained release pellet capsule
  • Figure 6 is a schematic view showing the structure of a sustained-release pellet capsule containing an immediate release coating
  • Figure 7 is a structural view of a capsule containing an immediate release and sustained release tablet
  • Figure 8 is a graph showing the release profile of the two-layer osmotic pump controlled release tablet of Example 1 in a release medium of pH 1.2, 4.5 and 6.8;
  • Figure 9 is a graph showing the release profiles of the preparations of Example 2, Example 5, Example 6, Example 7, Example 9, and Example 11 in a release medium at pH 6.8;
  • Figure 10 is a graph showing the release profile of the sustained-release tablet of Example 3 in a release medium at pH 6.8;
  • Figure 11 is a release curve of the quick double effect matrix tablet of Example 4.
  • Figure 12 is a dissolution profile of the immediate release capsule preparation of Comparative Example 1.
  • Figure 13 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 1;
  • Figure 14 is a graph showing the in vivo drug time of the immediate release capsule of Comparative Example 1 and the quick-acting double-effect tablet of Example 4;
  • Figure 15 is a graph showing the in vivo drug time of the immediate release capsule of Comparative Example 1 and the quick-acting double-effect tablet of Example 2;
  • Figure 16 is a graph showing PARP enzyme inhibition rate time in canine PBMC of the immediate release capsule of Comparative Example 1 and the quick-acting double-effect tablet of Example 2.
  • 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.
  • Olapani and copolyvidone VA64 prepared a solid dispersion by solvent evaporation method, that is, olrapani and copolyvidone VA64 were simultaneously dissolved in ethanol/acetone (25/75, v/v), and the organic solvent was evaporated under reduced pressure. After drying in a vacuum drying oven, it is ground and pulverized through a 60 mesh sieve and used for tableting. The obtained solid dispersion was dissolved in water of a leaking condition at 37 ° C, 100 rpm, and the pharmaceutically active ingredient was dissolved in 90% or more in 30 minutes. Under the same conditions, the olrapani compound powder was less than 60% dissolved for 2h.
  • the formulation was mixed with other excipients through a 60 mesh sieve and mixed by a three-dimensional mixer at 30 rpm for 25 minutes to obtain a drug-containing layer composition to be 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 4% cellulose acetate 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 release method of the double-layer osmotic pump controlled release tablets was determined by the second method of dissolution measurement (Chinese Pharmacopoeia 2010 edition two appendix X C), and the buffers of pH 1.2, 4.5, and 6.8 were released at 37 ° C, respectively.
  • the medium (7.65mL hydrochloric acid diluted with water to 1000mL can be used to prepare pH1.2 release medium; 250mL 0.2mol/L potassium dihydrogen phosphate solution is added to 0mL and 112mL of 0.2mol/L sodium hydroxide solution respectively, then the pH4 can be prepared separately.
  • the rotation speed is 75 rpm, according to the law, take 6mL of solution 0.5,1,2,4,6,8,10,12,13,16h, centrifuge, take the supernatant as Test the solution and determine the release rate.
  • the absorbance was measured at a wavelength of 278 nm, and the release degree of the prescription tablet was measured.
  • the release results in different pH release media are shown in Figure 8.
  • the results showed that the double-layer osmotic pump controlled release tablets were basically not affected by pH.
  • the active ingredient olaparib could maintain a constant rate release, with less than 10% release in 1 hour, 50% release in 6 hours, and more than 90% release in 12 hours. Release time can be 12-13h.
  • Example 2 Sustained double release double osmotic pump controlled release tablets
  • the olrapani and copolyvidone 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, and the extrudate was collected and pulverized. After 60 mesh sieve, get Orapa Ni-solid dispersion. 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 olaparib is dissolved in the acetone solution, and the ratio of the immediate release layer to the sustained release layer is 2:8 to the obtained double-layer osmotic pump sheet, so that the active ingredient of the immediate release layer accounts for 20%.
  • the wt, sustained-release layer active ingredient accounts for 80% by weight of the double-release double-permeation pump sheet.
  • the release method of the double-release double-osmotic pump controlled release tablets was measured by the second method of dissolution test (Chinese Pharmacopoeia 2010 edition two appendix X C).
  • the buffer of pH 6.8 was used as the release medium.
  • the rotation speed is 75 revolutions per minute, according to the law, after 0.5,1,2 4,6,8,10,12,13,16h was taken as 6 mL of the solution, centrifuged, and the supernatant was taken as a test solution, and the degree of release was measured.
  • the absorbance was measured at a wavelength of 278 nm, and the release degree of the prescription tablet was measured.
  • the release results in the pH 6.8 release medium are shown in Figure 9.
  • 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 the sustained release at a constant rate, releasing more than 80% at 16h and releasing the drug for 16 hours.
  • Olapani and povidone K30 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. And pulverized through a 60 mesh sieve to obtain a solid dispersion of olaparib. The solid dispersion was adjusted in a prescribed amount and release rate with a matrix polymer hydroxypropylcellulose (K4M), sodium lauryl sulfate over a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then added to the prescription. The magnesium stearate was mixed for 5 minutes and compressed to prepare a sustained-release matrix tablet of suitable hardness.
  • K4M matrix polymer hydroxypropylcellulose
  • the method for measuring the release rate of olaparib sustained-release matrix tablets was the same as in Example 1, using a buffer of pH 6.8 as a release medium.
  • the sustained-release matrix tablets release less than 20% of olrapani in one hour, about 80% in 8 hours, more than 90% in 16 hours, and a drug release duration of up to 10 hours.
  • Immediate release layer The prescribed amount of olaparib, micronized silica gel and Soluplus were sieved 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 and squeeze. The product was pulverized and pulverized through a 60 mesh sieve to obtain an olaparib solid dispersion.
  • the resulting olaparib solid dispersion is mixed with other materials such as disintegrant PVPP XL and other adjuvants such as mannitol and magnesium stearate to be tableted.
  • Sustained release layer After the prescribed amount of olaparib, micronized silica gel and povidone K30 are sieved through 60 mesh and mixed, slowly added to the preheated melt extruder, and the extrudate is collected and pulverized. A 60 mesh screen gave a solid dispersion of olaparib.
  • the resulting olaparib solid dispersion was mixed with a prescribed amount of the release rate adjusting polymer HPMC K15M and the lubricant magnesium stearate for tableting.
  • the direct compression method is used to make a double-layered double-release sheet with a suitable 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 of pH 6.8 was used as the release medium, and the rotation speed was 75 rpm. According to the law, 6mL of the solution was taken at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 13 and 16h, centrifuged, and the supernatant was taken as the test solution to determine the release degree.
  • the absorbance was measured at a wavelength of 278 nm, and the release degree of the obtained tablet was measured.
  • the release results are shown in Figure 11.
  • the quick-acting double-effect skeleton double-layer tablet can release about 20% of the drug in 30 minutes, and about 60% of the drug is released in about 8 hours, and the drug is completely released in about 16 hours.
  • the release behavior can control the concentration range of olapani in the blood, and can quickly reach the concentration of the drug required for PARP inhibition after oral administration, and maintain the concentration level. Long time.
  • Example 5 Sustained-release skeletal coated tablet 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 olaparib and poloxamer 188 was 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, the extrudate was collected and pulverized through a 60 mesh screen to give an olaparib solid dispersion.
  • the olaparib 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 1, using a buffer of pH 6.8 as the release medium.
  • the release curve is shown in Figure 9.
  • Example 6 Sustained-release pill capsule or quick-acting double-effect capsule containing immediate release pill and sustained-release pill
  • the preparation method is as follows:
  • Immediate release pellet Dissolve or disperse olapanic hydrochloride and VA64 in 95% ethanol solution, prepare a drug-loading solution, and spray a prescribed amount of microcrystalline cellulose by fluidized bed coating. On the blank pellet core, as an immediate release pellet.
  • the prescribed amount of olrapani hydrochloride was weighed and uniformly dispersed in the above coating liquid, and used as a drug-loading coating solution.
  • microcrystalline cellulose blank pellet core is added to the fluidized bed, and the operating parameters such as air volume and temperature are adjusted, and the prepared drug-loading coating liquid is sprayed to carry the drug to obtain the drug-loading 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.
  • sustained-release pellets prepared above were encapsulated to prepare sustained-release capsules.
  • the prepared immediate release pellets and sustained-release pellets 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 1, using a buffer of pH 6.8 as the release medium.
  • the release curves of sustained-release capsules and quick-release double-release capsules are shown in Figure 9, respectively.
  • Example 7 based on sustained release pellets of sustained release pellets
  • the preparation method is as follows:
  • Drug-loaded pellet core Olapani and VA64, dissolved or dispersed in 95% ethanol solution, formulated into a drug-loading solution, sprayed into the prescription amount of sucrose blank pellet core by means of fluidized bed coating, as 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 added to the talc powder and an appropriate amount of the aqueous solution, and mixed as a slow-release coating film coating liquid, which is sprayed into the drug-loading pill core of the coating body by a fluidized bed coating method. Made into 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 1, using a buffer of pH 6.8 as the release medium. The release curve is shown in Figure 9.
  • Example 8 based on sustained release pellets of sustained release pellets
  • olaparib besylate 140g of microcrystalline cellulose, 100g of lactose, mix it through 80 mesh sieve, transfer it to the wet granulator, adjust the parameters, add hypromellose E15 mass percentage 1%
  • the aqueous solution is used as a binder to make a soft material, and the olapapine-containing 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 of 40 ° C. Dry and sieve 30-40 mesh drug-containing pellets for use.
  • Coating liquid ratio acrylic resin 14.5% plasticizer triethyl citrate 5% anti-adhesive talcum powder 10.5% water balance.
  • olaparib sustained-release pellets 5g of drug-containing pellets, 12g of microcrystalline cellulose, 16g of lactose, 12g of 5% by weight of pvpK30, 18g of granules, 40°C oven drying, 18 mesh sieve Granules, 0.6 g of stearic acid, mixed and compressed.
  • Sustained-release microchip Olapani and copolyvidone VA64 were sieved through a 60 mesh sieve for 3 times, and added to a ball mill to grind to an average particle diameter of less than 30 ⁇ m to obtain an olrapani co-milled 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.
  • Immediate release microchip Olapani and copolyvidone VA64 were sieved through a 60 mesh sieve for 3 times, and added to a ball mill to grind to an average particle diameter of less than 30 ⁇ m to obtain an olrapani co-milled 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 1, using a buffer of pH 6.8 as the release medium.
  • the release curve is shown in Figure 9.
  • Example 10 micro-slice based controlled release capsule
  • Sustained-release microchip Orapani 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 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 Orapani and 2-hydroxypropyl- ⁇ -cyclodextrin were sieved through a 60 mesh sieve for 3 times, added with 100 ml of water, and then subjected to high-speed shearing 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.
  • a prescribed amount of olaparib and hypromellose E5 was 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.
  • the granulated solid dispersion of olaparib was obtained by pulverizing through a 60 mesh sieve.
  • the above-prepared solid mixture of olaparib and other excipients other than magnesium stearate were passed through a 60 mesh sieve and passed through The three-dimensional mixer was uniformly mixed, and then magnesium stearate was added and mixing was continued for 5 minutes to obtain a drug-containing layer composition to be used for tableting.
  • 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 1, using a buffer of pH 6.8 as the release medium.
  • the release curve is shown in Figure 9.
  • Preparation method at a temperature of 65 ° C, 10% by weight of olapaini was dispersed in Glucire 44/14, and after stirring for 12 hours, about 60 ° C, hydroxypropylated fiber capsules (0#) were filled.
  • the dissolution test is based on the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix X C) first method device, at 37 ° C, with 500mL pH 6.8 Tris buffer as the release medium, the rotation speed is 100 rpm, according to law After operation, 6 mL of the solution was taken at 15, 30, 45, 60, 75, 90, 105, 120 min, centrifuged, and the supernatant was taken as a test solution to determine the degree of release.
  • the absorbance was measured at a wavelength of 278 nm, and the release degree of the capsule was measured.
  • the release results are shown in Figure 12.
  • the active ingredient olaparib in the immediate release capsule is released more than 90% in about 45 minutes, and the basic release is complete within 2 hours.
  • Capsule preparation was taken 1 mL from the extremities before administration (0h) and 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12 and 24h after administration
  • double-layer osmotic pump controlled release tablets 1 mL of blood was taken from the extremities before administration (0 h) and 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24 h after administration.
  • the blood samples were centrifuged at 4000 rpm for 10 min at 4 ° C to obtain the upper plasma. Blood concentration measurement for LC-MS, the results are shown in Figure 13.
  • the enzyme inhibition rate of immediate release capsules was less than 50% at 10h, the enzyme inhibition rate of the double-release double-permeability pump tablets was greater than 90% at 10h, and the enzyme inhibition level was greater than IC90 for 10h, from the drug time curve 15 and Figure 16 results.
  • the high-speed plasma concentration of the double-release double-permeation pump sheet can maintain a stable blood concentration for a long time, so as to better exert the enzyme inhibition effect and the anti-tumor effect. Provides a larger dose space for drug dose ramping and optimal drug performance.

Abstract

一种奥拉帕尼口服缓控释药物组合物，其包含溶出改善形式的奥拉帕尼和释放速率调节用基质聚合物。所述药物组合物的体内吸收行为、血药浓度和PARP酶抑制水平可控，改进了奥拉帕尼药物载量和/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，可作为唯一制剂或与其他疗法联合应用治疗癌症。

Description

一种奥拉帕尼口服缓控释药物组合物及其用途 技术领域
本发明涉及奥拉帕尼药物制剂领域，具体涉及一种奥拉帕尼口服缓控释药物组合物及其用途。
背景技术
奥拉帕尼(Olaparib)，化学名称为1-(环丙甲酰基)-4-[5-[(3,4-二氢-4-氧代-1-酞嗪基)甲基]-2-氟苯甲酰]哌嗪，分子式为C24H23FN4O3，分子量为434.46，具有下述化学结构：
Figure PCTCN2017116475-appb-000001
奥拉帕尼(商品名LYNPARZAR)是阿斯利康公司研发的用于肿瘤靶向治疗的新药，其胶囊剂由美国食品药品管理局(FDA)于2014年12月批准上市，片剂由FDA于2017年8月批准上市，它是FDA首个批准上市用于肿瘤治疗的一种多聚ADP转移酶(PARP)抑制剂。多聚ADP转移酶(PARP)是DNA切除修复通路中的关键因子，而奥拉帕尼则能够抑制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，奥拉帕尼的这种作用模式使之对多种肿瘤具有治疗潜力；另外，由于奥拉帕尼对DNA损伤修复能力的特异性抑制，该药物也会避免化疗后的肿瘤耐药，增强化疗后的DNA损伤，以加强对肿瘤的杀灭效果。目前，阿斯利康正开展多个III期临床研究，考察奥拉帕尼用于与BRCA基因突变相关的癌症如卵巢癌、胃癌、乳腺癌等的治疗。
众所周知，传统的肿瘤化疗模式，由于缺乏特定的治疗靶点，抗肿瘤药物在杀死肿瘤细胞的同时，也严重损害了人体正常细胞，给机体带来较大的毒副作用。靶向治疗又称为“生物导弹”，由于其特异性高、副作用少、疗效好，近年来引起了广大科研和医务工作者的浓厚兴趣。大部分肿瘤在增值过程中伴随着DNA损伤或同源重组修复缺陷。奥拉帕尼能够特异性抑制肿瘤细胞系生长，增加对肿瘤细胞的毒性和抗肿瘤活性，而对DNA修复功能正常组织细胞并无杀伤作用，是目前为止，作为肿瘤靶向治疗的典型药物。奥拉帕尼的出现为 携带BRCA1和BRCA2基因突变的晚期肿瘤患者提供了治疗武器和生存的机会，也是对疾病潜在致病机制有更深入了解和个体化治疗的一个实例。
据阿斯利康研究并报道的临床前和临床药动药效数据结果可发现，奥拉帕尼于体内的稳态血药浓度与其所产生酶抑制活性以及毒副作用都直接相关。乳腺癌肿瘤小鼠模型的研究结果发现，仅当血液暴露量持续大于50％PARP酶抑制水平(IC50值)13h以上或大于IC90值6h以上时，方可发挥降低肿瘤体积的效果(FDA reviews，NDA 3663410)。阿斯利康的机理模型法结果显示稳态游离血药浓度达IC90以上时单链断裂和临床活性显著增加。然而，奥拉帕尼的速释胶囊制剂口服后，通常在0.5～3小时内迅速达峰，并快速消除。因此，为达较高的血药浓度(>IC90值)，并发挥较强的酶抑制效果，阿斯利康研制的50mg规格速释胶囊制剂，需在高于200mg/2次/天的剂量下给药，方可长时间维持在IC90以上，达到理想的PARP酶抑制活性，而100mg/2次/天和400mg/1次/天的稳态血药浓度则难以长时间维持在IC90以上。其II期临床药效的研究结果也发现，400mg/2次/天的剂量相对于200mg/2次/天的给药剂量，患者在无进展生存期方面，显示出一定的数量上的优势，前者无进展生存期为8.8个月，而后者为6.5个月；另外，前者的总体有效率为33％，而后者为25％，虽然此两种给药方式在治疗效果上并未显示出统计学上的显著性差异，但从实验结果显示的数量优势，阿斯利康最终选择了400mg/2次/天的剂量用以新药申请和胶囊产品的上市。此外，阿斯利康2017年新上市的奥拉帕尼片剂用量为300mg/2次/天。
然而，奥拉帕尼速释制剂在研发，生产以及临床运用的过程中，仍显示出较多的局限性：
1)血药浓度峰谷波动严重，剂量限制性毒性明显。速释制剂虽可快速达PARP酶抑制所需的血药浓度水平，但体内消除较快，为长期维持在有效酶抑制所需的血药浓度水平，需较高的口服剂量(胶囊400mg，BID或片剂300mg，BID)，这导致奥拉帕尼的稳态血药浓度波动范围较大(400mg胶囊，BID，Cmin,ss<1μg/ml；Cmax,ss>6μg/mL；300mg片剂，BID，Cmin,ss～1μg/ml，Cmax,ss>7μg/mL)，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，常见毒副作用有恶心、疲劳、呕吐、腹泻、味觉障碍等，严重副作用包括骨髓增生异常综合征、急性骨髓性白血病及肺炎；
2)生物利用度低，需大剂量服药。市售胶囊生物利用度约10-20％，日剂量为800mg，片剂虽生物利用度有所提高，但日剂量仍为600mg。由于药物的疗效与酶抑制率的维持时间相关，为了维持PARP酶抑制所需的浓度游离血药浓度，需大剂量服药，药物利用率低；
3)临床用药不便，成本高。较大的药物口服剂量(400mg剂量，8颗0#胶囊，BID)，也导致药品的生产、包装、贮存和运输代价高，患者顺应性差。
为进一步提高奥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 可精确调控奥拉帕尼血药浓度水平和波动范围的优良制剂。
经专利检索，与奥拉帕尼有关的制剂专利包括：奥拉帕尼纳米颗粒制剂(WO2015031536A1)，奥拉帕尼固体分散体及其普通片剂和胶囊(CN104434809A)，奥拉帕尼固体分散体及其片剂(WO2010041051、CN102238945A)等，具体如下：
1)WO2015031536A1公开了一种奥拉帕尼纳米颗粒制剂，此发明的奥拉帕尼阳离子脂质体，粒径为80-200nm，装载药物(甚或修饰以PEG)后，置于可降解聚合物基质中，以注射形式递药。与口服奥拉帕尼相比，延长了血药浓度半衰期，同时，以纳米颗粒形式进入肿瘤组织血管中，缓慢释放药物，进而达到缓释功能。
2)CN104434809A公开了一种奥拉帕尼固体分散体，此发明的奥拉帕尼固体分散体，以聚维酮K 30为主要材料，以溶剂挥发法、喷雾干燥法或热熔挤出法等制备的奥拉帕尼固体分散体，与其他填充剂、润滑剂等混合压片，或制备成胶囊制剂。
3)WO2010041051A1中公开了一种奥拉帕尼固体分散体制剂，通过固体分散体制剂的制备，有效提高了奥拉帕尼的生物利用度。
上述专利检索结果可见，目前尚无关于奥拉帕尼口服缓控释制剂的相关研究。
发明内容
奥拉帕尼速释制剂吸收不理想，需多次大剂量的给药，由此产生较高的稳态血药峰值和较大的血药浓度波动(400mg，BID，Cmin,ss<1μg/ml；Cmax,ss>6μg/mL；300mg片剂，BID，Cmin,ss～1μg/ml，Cmax,ss>7μg/mL)，导致奥拉帕尼速释制剂临床疗效不可控和存在一系列安全性问题。
本发明首要目的是针对奥拉帕尼的生物学性质和临床治疗的药效及安全性需求，通过控制其释放行为，精确调控奥拉帕尼于胃肠道内的吸收速率和吸收时间，进而控制体内血药浓度水平及其波动范围，维持体内血药浓度于有效PARP酶抑制水平的长期稳态，提高奥拉帕尼的抗肿瘤疗效，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。
为了实现上述目的，本发明提供一种奥拉帕尼口服缓控释药物组合物，所述药物组合物的体内吸收行为、血药浓度和PARP酶抑制水平可控，具有改进奥拉帕尼药物载量和/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优势，可作为唯一制剂或与其他疗法联合应用治疗癌症。
本发明提供的奥拉帕尼口服缓控释药物组合物包含：溶出改善形式的奥拉帕尼；和释放速率调节用基质聚合物(也称为释放调节剂)。此外，根据所制备的剂型，还可以包括半透性控释衣膜材料、隔离衣材料、崩解剂、包衣粉、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、稀释剂和/或其他药学上可接受的添加物等药学辅料。
本发明提供的奥拉帕尼药物组合物中的活性药物奥拉帕尼，属于难溶性药物，首先经过进行增溶处理，制备成增溶组合物，以改善药物的溶出。不局限于任何理论，发明人认为，所述增溶处理可通过化学手段，制备成为奥拉帕尼的盐形式化合物；也可通过将奥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。
溶出改善形式的奥拉帕尼主要包括：奥拉帕尼盐化物(可选自盐酸盐、苯磺酸盐、硫酸盐、马来酸盐、樟脑酸盐等)、奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体。所述奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体能改善控释剂型中奥拉帕尼的溶解溶出性能，同时提高药物的吸收和生物利用度。
所述奥拉帕尼共研磨混合物由活性药物奥拉帕尼、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。药物粉末粒径一般充分研磨至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。
在共研磨混合物中，基于共研磨混合物的总重，奥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％。
本发明中的奥拉帕尼纳米晶由活性药物奥拉帕尼、增溶用基质聚合物和/或其他添加物组成，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。所述高压均质法如下操作：将由活性药物奥拉帕尼和增溶用基质聚合物的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，制备均匀分散的奥拉帕尼纳米晶体粉末。所述共沉淀法如下操作：活性药物奥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增溶用基质聚合物的水溶液中，并利用探头超声高频超声(功率达100w以上)，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，制备均匀分散的奥拉帕尼纳米晶体粉末。通过制备成为纳米晶，能够降低活性药物奥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。不局限于任何理论，所述纳米晶能够增加奥拉帕尼在固体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。
所述奥拉帕尼纳米晶中，基于奥拉帕尼纳米晶的总重，奥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。
本发明中的固体分散体由活性药物奥拉帕尼、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，奥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％。上述各组分的总量为100wt％。所述固体分散体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：将药物奥拉帕尼、增溶用基质聚合物和/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，真空干燥箱干燥，即可制得奥拉帕尼固体分散体。所述熔体挤出法如下进行：将混合均匀后的药物奥拉帕尼、增溶用基质聚合物和/或其他添加物粉末，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奥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。
在本发明的奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体中，增溶用基质聚合物指的是能够用于稳定和/或增溶奥拉帕尼颗粒或分子的聚合物，可以为选自聚维酮、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)以及其他可药用的增溶聚合物中的一种或两种以上的组合。
在本发明的奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体中，所述其他添加物可为选自药学上常用的药用增溶表面活性剂(例如聚乙二醇硬脂酸酯、十二烷基硫酸钠等)、润滑剂、微粉硅胶、增塑剂等中的一种或两种以上的组合。
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)可以是具有释放速率调节作用的高分子聚合物，为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，例如可为选自羟丙基纤维素、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。
在本发明的奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体中，活性 药物奥拉帕尼包括奥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、硫酸盐、马来酸盐、右旋樟脑酸盐和苯磺酸盐等。
本发明提供的奥拉帕尼口服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的奥拉帕尼；和0.1-300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。更特别地，其包含，(a)50-600重量份的奥拉帕尼盐化物，和10-250重量份的释放速率调节用基质聚合物；或者(b)50-700重量份的奥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(c)50-800重量份的奥拉帕尼纳米晶，和0.1-250重量份的释放速率调节用基质聚合物；或者(d)50-900重量份的奥拉帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物。
本发明提供的奥拉帕尼口服缓控释药物组合物中还可以包含1-400重量份，优选2-300重量份，更优选5-250重量份的其它添加剂。特别地，在上述(a)中，还可以包含1-300重量份的其它添加剂，在上述(b)中，还可以包含1-150重量份的其它添加剂，在上述(c)中，还可以包含1-200重量份的其它添加剂，在上述(d)中，还可以包含1-200重量份的其它添加剂。
所述其它添加剂可以选自，但不限于，释放速率调节用促渗透聚合物、半透性控释衣膜材料、隔离衣材料、增溶剂、崩解剂、包衣粉、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，渗透压促进剂)、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、稀释剂和/或其他药学上可接受的添加物等药学辅料。
人体每天需要服用的奥拉帕尼的预期总剂量为100-1400mg。单个成品药片或胶囊中所含的药物活性成分奥拉帕尼的量没有具体限定，可以根据需要选择，例如可以为20～400mg或50mg～300mg。优选每天只需服用1次该组合物，即可控制奥拉帕尼体内的吸收速率和时间，维持体内血药浓度水平在PARP酶抑制所需的有效范围。本发明的药物组合物能够提高奥拉帕尼的PARP酶抑制效果和肿瘤治疗效果，同时降低药物的毒副作用。
本发明提供的奥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(也称为控释相)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％。
本发明所提供的奥拉帕尼药物组合物可以为片剂或胶囊剂，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。
本发明提供的奥拉帕尼药物组合物可用于制备预防或***的药物，优选地，所述肿瘤选自DNA修复功能缺陷的各种类型肿瘤，特别是用于制备预防或治疗与BRCA基因突变相关的两种以上的组合癌症如卵巢癌、胃癌、乳腺癌等的药物，以及用于制备预防或治疗与BRCA1和BRCA2基因突变相关的肿瘤的药物。
本发明提供的奥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小时内释放小于奥拉帕尼总量的50％，优选1小时内释放小于奥拉帕尼总量的40％，更优选10-30％；16小时释放奥拉帕尼大于总量的80％，优选>90％。
本发明提供的奥拉帕尼药物组合物，通过对释放行为和释放量的控制，控制奥拉帕尼于胃肠道内的吸收速率和吸收时间。与速释胶囊制剂相比，本发明所提供的药物组合物相同剂量下的奥拉帕尼所获取的最大血药浓度值(Cmax)降低至少10-70％，血药浓度达峰时间(T1/2)延长至少30％。通过对血药浓度、达峰时间以及药时曲线下面积的控制，实现对奥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。
本发明提供的奥拉帕尼药物组合物可精确调控药物于体内的稳态血药浓度，其稳态血药浓度波谷值Cmin,ss为0.2-4μg/mL，优选0.5-3μg/mL；其稳态血药浓度波峰值Cmax,ss为0.8-15μg/mL，优选1-12μg/mL，可达癌细胞酶抑制所需血药浓度的IC90值，且稳态血药浓度峰/谷的比值优选小于6，更优选小于4。每天单次或两次给药100mg-1400mg的剂量，可长时间维持稳态血药浓度水平于有效的PARP酶抑制水平。本发明提供的药物组合物，可通过调控奥拉帕尼血药浓度范围，使奥拉帕尼长期维持在体内PARP酶活性抑制所需的有效浓度水平(50％和90％PARP酶活性抑制所需药物血药浓度，分别为PARP酶活性的IC50 和IC90值)，精确地调控体内PARP酶活性，实现药物高效低毒治疗，奥拉帕尼血药浓度在IC50和IC90值以上分别维持至少13小时和6小时。
本发明的缓控释药物组合物可精确调控奥拉帕尼血药浓度水平和波动范围，有利于酶抑制所需血药浓度水平的长期维持，同时降低血药浓度波动范围，进而在提高肿瘤细胞的PARP酶抑制率和抗肿瘤疗效的同时，减少了肿瘤患者用药后的不良反应，增加患者服药的顺应性。
与普通速释制剂相比，本发明提供的奥拉帕尼药物组合物具有如下优点：
1)可实现药物的可控释放和吸收，提供精确的体内血药浓度和长时间稳定的高效肿瘤酶抑制水平，药效持久；
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)可单次给药，每天只需服用一次，减少了普通制剂用药的繁琐过程，更加方便临床用药；
4)由于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。
5)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。
为更好的阐述本发明提供的奥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，但本发明的范围不限于下述内容。
1、片剂
本发明的奥拉帕尼缓控释片剂，可以为渗透泵型控释片，骨架型控释片或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基于缓释微丸和速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。
1.1、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，基于渗透泵控释片的总重，奥拉帕尼占渗透泵控释片总重量的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奥拉帕尼；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奥拉帕尼可以选自上述的奥拉帕尼盐化物、奥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。所述着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奥拉帕尼、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奥拉帕尼、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奥拉帕尼；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重量份的活性成分奥拉帕尼，0-100重量份，优选10-100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，速释含药层中的奥拉帕尼约为整个速缓双释渗透泵片中的奥拉帕尼总重的10-40wt％，控释含药层中的奥拉帕尼约为整个速缓双释渗透泵片中的奥拉帕尼总重的60-90wt％。
奥拉帕尼渗透泵控释片的制备方法包括如下步骤：①溶出改善形式的奥拉帕尼的制备；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。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显示了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显示了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奥拉帕尼的药效，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。
1.2、骨架型控释片
本发明还提供奥拉帕尼控释骨架片和/或具有速缓双效释放行为的骨架片，
本发明提供的控释骨架片主要由缓释相和可选的速释相组成。
由含有缓释相和速释相组成的双层片，是速缓双效释放骨架片，而仅由缓释相组成的单层片，是普通的缓释骨架片。图3显示了根据本发明一个实施方式的骨架型速缓双效释放双层片的结构示意图，图4显示了根据本发明一个实施方式的骨架型速缓双效释放包衣片的结构示意图。
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奥拉帕尼，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。
所述释放速率调节用基质聚合物，可为选自聚氧乙烯、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；优选为选自羟丙基纤维素、海藻酸钠、羟丙甲纤维素和卡波姆中的一种或两种以上的组合。
所述稀释剂为选自微晶纤维素、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。所述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、着色剂等的一种或者两种以上的组合。所述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。
所述速释相可以包含上述溶出改善形式的奥拉帕尼、崩解剂、稀释剂以及其他片剂常用添加剂，或者包含奥拉帕尼、增溶基质聚合物和片剂常用其他添加剂。
所述速释相可以将各成分充分混合后，通过本领域技术人员所熟知的常规方法压片制备成速释层，或者将各成分同时溶解后，包被至缓释相外，干燥形成速释衣膜。
在包含溶出改善形式的奥拉帕尼的速释相中，溶出改善形式的奥拉帕尼用量可以为20-600重量份，优选30-400重量份，更优选50-250重量份。所述崩解剂为选自交联聚维 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学上常用的崩解剂中的一种或两种以上的组合，用量可以为5-90重量份，优选10-50重量份。所述稀释剂为选自微晶纤维素、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，用量可以为5-200重量份，优选10-150重量份。所述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，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，用量可以为0.1-20重量份，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，用量可以为0-13重量份。
在包含奥拉帕尼、增溶基质聚合物和其他片剂常用添加剂的速释相中，奥拉帕尼用量可以为5-100重量份，优选10-80重量份，更优选20-60重量份。所述增溶基质聚合物为选自聚维酮、共聚维酮、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPCP)、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，用量可以为5-300重量份，优选20-200重量份，更优选30-120重量份。所述其他片剂常用添加剂包括交联聚维酮，微晶纤维素、及可药用的表面活性剂(如十二烷基硫酸钠)、甘露醇、润滑剂(如硬脂酸镁)等本领域的技术人员所熟知的速释片常用添加剂，用量可以为0.1-150重量份，优选0.5-100重量份。
在骨架型速缓双效释放片中，速释相中的奥拉帕尼约为整个速缓双释骨架片中的奥拉帕尼总重的10-40wt％，而缓释相中的奥拉帕尼约为整个速缓双释骨架片中的奥拉帕尼总重的60-90wt％。
本发明所述的具有速缓双释行为的奥拉帕尼控释制剂，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1h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，优选16小时释放90wt％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。
1.3、基于缓释微丸的缓控释片
本发明另一方面提供奥拉帕尼的基于缓控微丸的缓控释片。所述奥拉帕尼的基于缓控微丸的缓控释片，可以是基于缓释微丸的缓释片，和基于速释基质/缓释微丸的速缓双效释放片。
在所述速缓双效释放片中，速释基质组成了速释相，缓释丸组成了缓释相。在整个速 缓双效释放片中，所述速释相中的奥拉帕尼占奥拉帕尼总量的10-40wt％；所述缓释丸中的奥拉帕尼占奥拉帕尼总量的60-90wt％。
所述速释基质可包括上述溶出改善形式的药物活性成分、崩解剂、稀释剂以及其他片剂常用添加剂。
在包括溶出改善形式的药物活性成分的速释基质中，溶出改善形式的奥拉帕尼用量可以为20-200重量份，优选50-150重量份。所述崩解剂为选自交联聚维酮、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学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。所述稀释剂为选自微晶纤维素、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，用量可以为5-200重量份，优选10-150重量份。所述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、着色剂中的一种或者两种以上的组合，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，用量可以为0.1-20重量份，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，用量可以为0-13重量份。
所述的缓释微丸可包含包衣缓释丸和骨架型缓释微丸，可非限制性的由空白丸芯(0-300重量份)、奥拉帕尼盐化物(例如盐酸盐，苯磺酸盐，硫酸盐，樟脑酸盐等)、释放速率调节用基质或控释衣膜材料以及其他辅料等，通过本领域技术人员所熟知的湿法制粒、挤出滚圆、包衣锅包衣和/或流化床制粒包衣等常规方法制备。例如，缓释微丸通过包衣锅一锅包衣载药的方式的制备，其中，将奥拉帕尼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控释衣膜材料如苏丽丝等以构成缓释衣膜，形成所述的包衣缓释丸。所述空白丸芯为选自蔗糖丸芯、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或两种以上的组合。再如，缓释微丸通过流化床方式制备，其中，将奥拉帕尼与释放速率调节用基质同时溶解后，置于喷雾干燥仪器中，鼓入气流，喷干，收集样品，加入粘合剂，制粒、干燥，形成所述的骨架型缓释微丸。
在缓释微丸中，所述释放速率调节用基质或控释衣膜材料可为选自虫胶、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸树脂(Eudragit)、乙基纤维素(EC)、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)等中的一种或几种。所述其他辅料主要包括，但不限于，粘合剂、增塑剂和致孔剂等。其中，所述粘合剂为选自聚乙二醇(PEG)、硬脂酸、单硬脂酸甘油酯等中的一种或几种，所述增塑剂为选自丙二醇、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、蓖麻油等中的一种或几种，所述致孔剂 为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)中的一种或几种。
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重量份的奥拉帕尼盐化物，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，将缓释丸直接压片则制备成为基于缓释微丸的缓释片。若按速释基质和缓释微丸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。
2、胶囊剂
本发明还提供了缓控释胶囊制剂，其可以选自基于微丸的缓控释胶囊和基于片剂的缓控释胶囊。
2.1、基于微丸的缓控释胶囊
本发明的基于微丸的缓控释胶囊是由缓释微丸组成的控释胶囊或由缓释微丸和速释微丸组成的速缓双释胶囊，可以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以及含有速释微丸和包衣缓释微丸的速缓双释胶囊。图5显示了含有速释微丸和骨架型缓释微丸的速缓双释胶囊的结构示意图，图6显示了含有速释包衣的缓释微丸的胶囊的结构示意图。
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奥拉帕尼的总重，速释相中的奥拉帕尼占10-40wt％；缓释微丸中的奥拉帕尼占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1.3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1.2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。
2.2、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。图7显示了含速释和缓释片的胶囊的结构意图。
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。基于胶囊中奥拉帕尼的总重，速释相中的奥拉帕尼占10-40wt％；缓释相中的奥拉帕尼占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1.2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1.2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。
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是含有速释丸和骨架型缓释微丸胶囊的结构示意图；
图6是含有速释包衣的缓释微丸胶囊的结构示意图；
图7是含速释和缓释片的胶囊的结构意图；
图8是实施例1的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9是实施例2、实施例5、实施例6、实施例7、实施例9、实施例11的制剂在pH6.8的释放介质中的释放曲线；
图10是实施例3的骨架缓释片在pH6.8的释放介质中的释放曲线；
图11是实施例4的速缓双效骨架片的释放曲线；
图12是对比实施例1的速释胶囊制剂的溶出曲线；
图13是对比实施例1的速释胶囊和实施例1的双层渗透泵控释片的体内药时曲线图；
图14是对比实施例1的速释胶囊与实施例4的速缓双效片的体内药时曲线图；
图15是对比实施例1的速释胶囊与实施例2的速缓双效片的体内药时曲线图；
图16是对比实施例1的速释胶囊与实施例2的速缓双效片的犬PBMC中PARP酶抑制率时间曲线图。
具体实施方式
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双层渗透泵控释片
Figure PCTCN2017116475-appb-000002
奥拉帕尼与共聚维酮VA64以溶剂挥发法制备固体分散体，即将奥拉帕尼和共聚维酮VA64同时溶于乙醇/丙酮(25/75，v/v)，减压挥发掉有机溶剂，于真空干燥箱中干燥后，研磨粉碎过60目筛，待压片用。所得固体分散体在漏槽条件的水中,37℃,100rpm下,药物活性成分可于30分钟内溶出90％以上。而在相同条件下，奥拉帕尼化合物粉末2h溶出小于60％.
再以处方量与其他辅料过60目筛并通过三维混合器在30rpm下混合25min，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4％的醋酸纤维素溶液包控释衣层，衣膜增重10％，得到双层渗透泵控释片。
采用溶出度测定法(中国药典2010年版二部附录X C)第二法装置测定双层渗透泵控释片的释放度，37℃条件下，分别以pH 1.2、4.5、6.8的缓冲液为释放介质(7.65mL盐酸加水稀释至1000mL即可制得pH1.2释放介质；250mL 0.2mol/L磷酸二氢钾溶液分别加入0mL和112mL的0.2mol/L氢氧化钠溶液，即可分别制得pH4.5和6.8的释放介质)，转速为每分钟75转，依法操作，经0.5，1，2，4，6，8，10，12，13，16h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278nm的波长处分别测定吸光度，测定处方片剂的释放度。
不同pH释放介质中的释放结果见图8。结果显示，双层渗透泵控释片基本不受pH影响，活性成分奥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，12h释放90％以上，总体释放时长可达12-13h。
实施例2速缓双释双层渗透泵控释片
Figure PCTCN2017116475-appb-000003
将奥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，收集挤出物并粉碎过60目筛，得到奥拉帕 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。
取奥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2:8包衣至所得双层渗透泵片，即得速释层活性成分占20％wt、缓释层活性成分占80％wt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pH 6.8的缓冲液为释放介质(250mL 0.2mol/L磷酸二氢钾溶液加入112mL的0.2mol/L氢氧化钠溶液，即可分别制得6.8的释放介质)，转速为每分钟75转，依法操作，经0.5，1，2，4，6，8，10，12，13，16h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278nm的波长处分别测定吸光度，测定处方片剂的释放度。
pH6.8释放介质中的释放结果见图9。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16小时。
实施例3缓释骨架片
Figure PCTCN2017116475-appb-000004
将奥拉帕尼与聚维酮K30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，得到奥拉帕尼固体分散体。固体分散体以处方量和释放速率调节用基质聚合物羟丙基纤维素(K4M)、十二烷基硫酸钠过60目筛并于三维混合器中在30rpm下混合25分钟，再加入处方量的硬脂酸镁混合5分钟，压片，制成硬度适宜的缓释骨架片。
奥拉帕尼缓释骨架片释放度测定方法同实施例1，以pH6.8的缓冲液为释放介质。
结果见图10，缓释骨架片于1小时内释放奥拉帕尼量小于20％，8小时内释放80％左右，16小时内释放大于90％，释药持续时间可达10小时。
实施例4速缓双释骨架双层片
Figure PCTCN2017116475-appb-000005
速释层：将处方量的奥拉帕尼、微粉硅胶和Soluplus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目筛得到奥拉帕尼固体分散体。
将所得奥拉帕尼固体分散体与处方量的其他材料如崩解剂PVPP XL和其他辅料如甘露醇和硬脂酸镁混合均匀后，待压片用。
缓释层：将处方量的奥拉帕尼、微粉硅胶和聚维酮K30过60目筛并混匀后，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目筛得到奥拉帕尼固体分散体。
将所得奥拉帕尼固体分散体与处方量的释放速率调节用聚合物HPMC K15M和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释骨架双层片。
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pH6.8的缓冲液为释放介质，转速为每分钟75转，依法操作，经0.25，0.5，0.75，1，2，4，6，8，10，12，13和16h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278nm的波长处分别测定吸光度，测定所得片剂的释放度。
释放结果见图11。速缓双效骨架双层片实现30分钟内20％左右的药物快速释放，8h左右有近60％左右的药物释放，16h左右药物释放完全。该释放行为可控制奥拉帕尼于血液中的浓度范围，能在口服后快速达到PARP酶抑制所需药物浓度，并维持该浓度水平较 长时间。
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(100片)
Figure PCTCN2017116475-appb-000006
②速释包衣
Figure PCTCN2017116475-appb-000007
制备方法如下：
缓释骨架包衣片的缓释片芯的制备：将处方量的奥拉帕尼和泊洛沙姆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目筛得到奥拉帕尼固体分散体。将上述制得的奥拉帕尼固体分散体，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1，以pH6.8的缓冲液为释放介质。释放曲线见图9。
实施例6缓释丸胶囊或含有速释丸及缓释丸的速缓双效胶囊
①缓释丸
I)载药丸芯
Figure PCTCN2017116475-appb-000008
Ⅱ)包隔离衣
Figure PCTCN2017116475-appb-000009
Figure PCTCN2017116475-appb-000010
III)包缓释衣
Figure PCTCN2017116475-appb-000011
②速释丸
Figure PCTCN2017116475-appb-000012
制备方法如下：
速释丸：将奥拉帕尼盐酸盐与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，喷入处方量的微晶纤维素空白丸芯上，作为速释丸。
缓释丸：
称取释放速率调节用基质羟丙基纤维素SSL适量，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；
再称取奥拉帕尼盐酸盐处方量，均匀地分散在上述包衣液中，作为载药包衣液备用。
将微晶纤维素空白丸芯加入流化床，调节风量、温度等操作参数，喷入配制好的载药包衣液，进行载药，得到载药丸芯。
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。
胶囊灌装：将上述制备得到的缓释丸装胶囊，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1，以pH6.8的缓冲液为释放介质。缓释胶囊和速缓双释胶囊的释放曲线分别见图9。
实施例7基于缓释微丸的缓控释片
①缓释丸
I)载药丸芯
Figure PCTCN2017116475-appb-000013
Figure PCTCN2017116475-appb-000014
Ⅱ)包隔离衣
Figure PCTCN2017116475-appb-000015
III)包缓释衣
Figure PCTCN2017116475-appb-000016
制备方法如下：
载药丸芯：将奥拉帕尼与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滑石粉和适量的水溶液，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1，以pH6.8的缓冲液为释放介质。释放曲线见图9。
实施例8基于缓释微丸的缓控释片
称取奥拉帕尼苯磺酸盐60g，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，加入羟丙甲纤维素E15质量百分比1％的水溶液作为粘合剂制软材，挤出滚圆制备奥拉帕尼含药微丸，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。
将筛选好的奥拉帕尼微丸置于流化床中，配制包衣液，包衣制得奥拉帕尼缓释微丸。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。
称取奥拉帕尼缓释微丸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。
实施例9基于微片的缓控释胶囊
缓释微片
Figure PCTCN2017116475-appb-000017
速释微片
Figure PCTCN2017116475-appb-000018
缓释微片：将奥拉帕尼与共聚维酮VA64过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得奥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：将奥拉帕尼与共聚维酮VA64过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得奥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1，以pH6.8的缓冲液为释放介质。释放曲线见图9。
实施例10基于微片的缓控释胶囊
缓释微片
Figure PCTCN2017116475-appb-000019
Figure PCTCN2017116475-appb-000020
速释微片
Figure PCTCN2017116475-appb-000021
缓释微片：将奥拉帕尼与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：将奥拉帕尼与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。
实施例11单层渗透泵控释片
Figure PCTCN2017116475-appb-000022
将处方量的奥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目筛得到奥拉帕尼固体分散体。将上述制得的奥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1，以pH6.8的缓冲液为释放介质。释放曲线见图9。
对比实施例1速释胶囊制剂
制备方法：在65℃条件下，将重量比为10％的奥拉帕尼分散于Glucire44/14中，持续搅拌12h后，60℃左右，灌装羟丙甲纤维胶囊(0#)。
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500mL pH 6.8的Tris缓冲液为释放介质，转速为每分钟100转，依法操作，经15，30，45，60，75，90，105，120min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278nm的波长处分别测定吸光度，测定胶囊的释放度。
释放结果见图12。速释胶囊中活性成分奥拉帕尼于45分钟左右释放90％以上，2小时内基本释放完全。
实验实施例1
将对比实施例1的奥拉帕尼胶囊(参比胶囊)和实施例1的双层渗透泵控释片(受试片剂)分别给药于饱腹比格犬(n＝3)，用50mL水分别送服。胶囊制剂于给药前(0h)和给药后0.25、0.5、1.0、1.5、2.0、3.0、4.0、6.0、8.0、10、12和24h经四肢静脉取血1mL，双层渗透泵控释片于给药前(0h)和给药后1.0、2.0、4.0、6.0、8.0、10、12和24h经四肢静脉取血1mL，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T1/2(2.6h)，Cmax(1590.1ng/mL)和AUC0-h(7155.7h*ng/mL)，双层渗透泵控释片的T1/2延长至6.1h，延长了约135％；Cmax降低至922.9ng/mL，降低了约42％；AUC0-h为7881.3h*ng/mL，变化<10％。
实验实施例2
100mg当量的对比实施例1的奥拉帕尼胶囊(参比胶囊)和实施例4的速缓双释骨架双层片(速缓双效片)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(4374.9ng/mL)，T1/2(3.84h)和AUC0-h(22570h*ng/mL)，速缓 双释骨架双层片的Cmax降低至2397.2ng/mL，降低了约45％；T1/2延长至9.92h，增加了158％；AUC0-h为29110h*ng/mL，变化<30％。由药时曲线图14结果仍可见，相对于速释胶囊，速缓双效骨架双层片的在较高的血药浓度可维持较长时间平稳血药浓度，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剂量空间。
实验实施例3
将对比实施例1的奥拉帕尼胶囊(参比胶囊)和实施例2的速缓双释双层渗透泵片(速缓双释制剂)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(4576.3ng/mL)，T1/2(3.42h)和AUC0-h(25163h*ng/mL)，速缓双释双层渗透泵片的Cmax降低至2154.2ng/mL，降低了约53％；T1/2延长至12.96h，增加了279％；AUC0-h为32259h*ng/mL。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和图16结果仍可见，相对于速释胶囊，速缓双释双层渗透泵片的在较高的血药浓度可维持较长时间平稳血药浓度，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剂量空间。

Claims (10)

  1. 一种奥拉帕尼口服缓控释药物组合物，其包含：溶出改善形式的奥拉帕尼；和释放速率调节用基质聚合物，
    所述奥拉帕尼口服缓控释药物组合物的稳态血药浓度波谷值Cmin,ss为0.2-4μg/mL；稳态血药浓度波峰值Cmax,ss为0.8-15μg/mL。
  2. 根据权利要求1所述的奥拉帕尼口服缓控释药物组合物，其中所述奥拉帕尼药物组合物的稳态血药浓度波谷值Cmin,ss为0.5-3μg/mL；稳态血药浓度波峰值Cmax,ss为1-12μg/mL，且稳态血药浓度峰/谷的比值优选小于6，更优选小于4。
  3. 根据权利要求1或2所述的奥拉帕尼口服缓控释药物组合物，其中，所述奥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小时内释放小于奥拉帕尼总量的50％，优选40％，更优选10-30％，16小时释放奥拉帕尼大于总量的80％，优选>90％。
  4. 根据权利要求1至3中任一项所述的奥拉帕尼口服缓控释药物组合物，其中
    所述溶出改善形式的奥拉帕尼包括：奥拉帕尼盐化物、奥拉帕尼共研磨混合物、奥拉帕尼纳米晶和奥拉帕尼固体分散体，
    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，更优选选自羟丙基纤维素、聚氧乙烯、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，所述奥拉帕尼盐化物选自盐酸盐、苯磺酸盐、硫酸盐、马来酸盐、樟脑酸盐；
    优选地，所述奥拉帕尼共研磨混合物由活性药物奥拉帕尼、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，奥拉帕尼的重量百分比为5-60wt％，优选20-40wt％，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，所述奥拉帕尼纳米晶由活性药物奥拉帕尼、增溶用基质聚合物和/或其他添加物组成，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；所述奥拉帕尼纳米晶中，基于奥拉帕尼纳米晶的总重，奥拉帕尼的重量百分比为10-99wt％，优选 20-50wt％；增溶用基质聚合物的重量百分比为1-75wt％，优选1-65wt％，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奥拉帕尼、增溶用基质聚合物和其他添加物组成，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，奥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，所述增溶用基质聚合物为选自聚维酮、共聚维酮、聚氧乙烯、Soluplus、羟丙甲纤维素邻苯二甲酸酯、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、聚甲基丙烯酸酯、羟丙基纤维素、醋酸邻苯二甲酸纤维素以及其他可药用的增溶聚合物中的一种或两种以上的组合；
    优选地，所述其他添加物为选自药用增溶表面活性剂(例如聚乙二醇硬脂酸酯、十二烷基硫酸钠)、润滑剂、微粉硅胶、增塑剂等中的一种或两种以上的组合。
  5. 根据权利要求1至4中任一项所述的奥拉帕尼口服缓控释药物组合物，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的奥拉帕尼；和0.1-300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，所述奥拉帕尼口服缓控释药物组合物还包含1-400重量份，优选2-300重量份，更优选5-250重量份的其它添加剂；
    优选地，所述奥拉帕尼口服缓控释药物组合物包含：
    50-600重量份的奥拉帕尼盐化物，和10-250重量份的释放速率调节用基质聚合物，优选还包含1-300重量份的其它添加剂；或者
    50-700重量份的奥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，优选还包含1-150重量份的其它添加剂；或者
    50-800重量份的奥拉帕尼纳米晶，和0.1-250重量份的释放速率调节用基质聚合物，优选还包含1-200重量份的其它添加剂；或者
    50-900重量份的奥拉帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物，优选还包含1-200重量份的其它添加剂，
    其中，所述其它添加剂为药学辅料，优选选自释放调节剂、半透性控释衣膜材料、隔离衣材料、增溶剂、崩解剂、包衣粉、增塑剂、致孔剂、膨胀材料、填充剂、渗透压调节剂、润滑剂、粘合剂、着色剂、抗粘剂、遮光剂、稀释剂和其他药学上可接受的添加物。
  6. 根据权利要求1至5中任一项所述的奥拉帕尼口服缓控释药物组合物，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；
    优选地，所述的速释相为选自速释片、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所述的奥拉帕尼口服缓控释药物组合物，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6所述的奥拉帕尼口服缓控释药物组合物，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中任一项所述的奥拉帕尼口服缓控释药物组合物用于制备预防或***的药物的用途，优选地，所述肿瘤选自具有DNA修复功能缺陷的肿瘤，特别地，选自与BRCA基因突变相关的两种以上的组合癌症如卵巢癌、胃癌、乳腺癌，以及用于与BRCA1和BRCA2基因突变相关的肿瘤。
  10. 根据权利要求9所述的用途，其中奥拉帕尼口服缓控释药物组合物每天需要服用的预期总量按奥拉帕尼计为100-1400mg，单个成品药片或胶囊中所含的药物活性成分奥拉帕尼的量为20mg～400mg，优选50mg～300mg。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021164755A1 (zh) * 2020-02-21 2021-08-26 上海宣泰医药科技股份有限公司 奥拉帕尼药物组合物及其制剂、制备方法和用途
WO2021220120A1 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
CN115175668A (zh) * 2019-12-20 2022-10-11 三养控股公司 具有改善的奥拉帕尼的溶解度和生物利用率的组合物
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109293576A (zh) * 2018-11-08 2019-02-01 威海贯标信息科技有限公司 一种小粒度奥拉帕尼的制备方法
US20220233550A1 (en) * 2019-05-31 2022-07-28 Beigene, Ltd. Parp inhibitor pellet preparation and preparation process therefor
WO2021141538A1 (en) * 2020-01-08 2021-07-15 Agency For Science, Technology And Research Combination therapy
CN113350349B (zh) * 2020-03-04 2022-11-11 中国科学院上海药物研究所 奥拉帕尼溶出增强组合物
CN112438954B (zh) * 2020-11-29 2022-09-27 北京康立生医药技术开发有限公司 一种奥拉帕利释放相关的药物组合物
WO2024012572A1 (zh) * 2022-07-14 2024-01-18 西藏海思科制药有限公司 一种杂芳基衍生物的药物组合物及其在医药上的应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010041051A1 (en) 2008-10-07 2010-04-15 Astrazeneca Uk Limited Pharmaceutical formulation 514
CN103417505A (zh) * 2012-05-24 2013-12-04 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
WO2015031536A1 (en) 2013-08-27 2015-03-05 Northeastern University Nanoparticle drug delivery system and method of treating cancer and neurotrauma
CN104434809A (zh) 2014-12-10 2015-03-25 北京科莱博医药开发有限责任公司 一种奥拉帕尼固体分散体制剂及其制备方法
CN104873457A (zh) * 2009-06-02 2015-09-02 陶氏环球技术有限责任公司 缓释剂型

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010139111A1 (en) * 2009-06-02 2010-12-09 Dow Global Technologies Inc. Sustained release dosage form

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010041051A1 (en) 2008-10-07 2010-04-15 Astrazeneca Uk Limited Pharmaceutical formulation 514
CN102238945A (zh) 2008-10-07 2011-11-09 阿斯利康(英国)有限公司 药物制剂514
CN104873457A (zh) * 2009-06-02 2015-09-02 陶氏环球技术有限责任公司 缓释剂型
CN103417505A (zh) * 2012-05-24 2013-12-04 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
WO2015031536A1 (en) 2013-08-27 2015-03-05 Northeastern University Nanoparticle drug delivery system and method of treating cancer and neurotrauma
CN104434809A (zh) 2014-12-10 2015-03-25 北京科莱博医药开发有限责任公司 一种奥拉帕尼固体分散体制剂及其制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Chinese Pharmacopoeia", 2010
See also references of EP3556369A4

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115175668A (zh) * 2019-12-20 2022-10-11 三养控股公司 具有改善的奥拉帕尼的溶解度和生物利用率的组合物
WO2021164755A1 (zh) * 2020-02-21 2021-08-26 上海宣泰医药科技股份有限公司 奥拉帕尼药物组合物及其制剂、制备方法和用途
WO2021220120A1 (en) 2020-04-28 2021-11-04 Rhizen Pharmaceuticals Ag Novel compounds useful as poly(adp-ribose) polymerase (parp) inhibitors
WO2022090938A1 (en) 2020-10-31 2022-05-05 Rhizen Pharmaceuticals Ag Phthalazinone derivatives useful as parp inhibitors
WO2022215034A1 (en) 2021-04-08 2022-10-13 Rhizen Pharmaceuticals Ag Inhibitors of poly(adp-ribose) polymerase

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CN108201536A (zh) 2018-06-26
EP3556369A4 (en) 2020-01-01
EP3556369B1 (en) 2021-04-14
JP6888226B2 (ja) 2021-06-16
EP3556369A1 (en) 2019-10-23
US20200108008A1 (en) 2020-04-09
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