WO2018108151A1 - 一种维利帕尼缓控释药物组合物及其用途 - Google Patents

一种维利帕尼缓控释药物组合物及其用途 Download PDF

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WO2018108151A1
WO2018108151A1 PCT/CN2017/116472 CN2017116472W WO2018108151A1 WO 2018108151 A1 WO2018108151 A1 WO 2018108151A1 CN 2017116472 W CN2017116472 W CN 2017116472W WO 2018108151 A1 WO2018108151 A1 WO 2018108151A1
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release
weight
sustained
velipani
parts
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PCT/CN2017/116472
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English (en)
French (fr)
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甘勇
孟冰雪
郭仕艳
朱春柳
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苏州苏融生物医药有限公司
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Priority to CN201780075192.4A priority Critical patent/CN110035751A/zh
Publication of WO2018108151A1 publication Critical patent/WO2018108151A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention relates to the field of virlipani pharmaceutical preparations, in particular to a velipani oral sustained-release pharmaceutical composition and use thereof.
  • Veliparib chemical name 2-[(2R)-2-methyl-2-pyrrolidinyl]-1H-benzimidazole-7-carboxamide, of the formula C 13 H 16 N 4 O With a molecular weight of 244.29, it has the following chemical structure:
  • Willipani is an orally effective PARP1/2 inhibitor developed by AbbVie. It entered the clinic as early as 2007. So far, 90 clinical studies have been carried out. The indications include: triple negative breast cancer, non-small cell lung cancer, ovarian cancer, melanoma, brain cancer and so on. Willipani combined with DNA-damaging chemotherapy drugs to treat pleomorphic glioblastoma, epithelial ovarian cancer, and metastatic brain cancer in 2008, 2009, and 2014, respectively, received the FDA orphan drug title. In 2010, EMA awarded Willipani the title of orphan drug for ovarian cancer.
  • triple-negative breast cancer patients continued to receive an anthracycline chemotherapy after treatment with velipani, carboplatin, and paclitaxel, and the results showed complete response to the ivlipani group.
  • the rate was 52%, compared with 26% in the control group.
  • velipani combined with chemotherapy drugs to treat tumors in patients without genotyping, while Wilipani, BMN-673, Rikapatu These are the first tumor patients who are resistant to BRCA mutations.
  • triple-negative breast cancer does not currently have good targeted treatments. If it is successful, Willipani will be well placed to meet this clinical gap.
  • Reversible PARP enzyme inhibitors as catalytically active regions of PARP enzymes, especially for drugs such as velipani which eliminate extremely fast in vivo, in order to achieve effective PARP enzyme inhibitory activity required for tumor growth inhibition in vivo, PARP enzyme inhibition required The long-term maintenance of the free blood drug concentration level is extremely important.
  • the current preparation for clinical phase II/III is the velipani instant release capsule.
  • the release of the drug is extremely fast, which makes the drug in the body difficult to maintain for a long time, and is quickly eliminated.
  • the clinical efficacy shows certain limitations: 1) immediate release capsule Although it can quickly achieve the blood concentration level of PARP enzyme, the elimination of the drug is faster in vivo, and it is required to maintain a high oral dose (>400 mg, BID.) for the long-term maintenance of the blood concentration level required for effective enzyme inhibition. This results in a large range of steady-state blood drug concentration fluctuations in velipani.
  • the peak value of steady-state blood drug concentration is several times or even ten times higher than the IC50 value required for PARP enzyme inhibition, resulting in more serious side effects.
  • the primary object of the present invention is to control the biological properties of vilipani and the efficacy and safety requirements of clinical treatment, and to control the absorption rate and absorption time of velipani in the gastrointestinal tract by controlling the release behavior, thereby controlling
  • the blood concentration level and its fluctuation range in the body maintain the long-term steady state of the blood concentration of the active PARP enzyme, improve the anti-tumor effect of velipani 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 a Willipani sustained-release pharmaceutical composition which is controllable in vivo absorption behavior, blood drug concentration and PARP enzyme inhibition level.
  • the invention also provides pharmaceutical compositions having improved velipani drug loading and/or oral absorption and/or bioavailability and/or blood concentration control and/or enzyme inhibition level control and their use as sole formulations or other The combination of therapy for the treatment of cancer.
  • the velipani controlled release pharmaceutical composition provided by the present invention comprises: a dissolution-improved form of velipani, and a release rate adjusting matrix polymer (also referred to as a release regulator).
  • a semi-permeable controlled release coating material, a covering material, a disintegrating agent, a coating powder, a plasticizer, a porogen, an expanding material, a filler, an osmotic pressure adjusting agent may also be included.
  • the active drug velipani in the velipani pharmaceutical composition provided by the invention belongs to a poorly soluble drug and can be subjected to solubilization treatment to improve the dissolution of the drug.
  • solubilization treatment can be prepared by chemical means into a salt form compound of velipani, or by mixing vilipani with a matrix polymer which can improve drug solubility. Together, the dispersion specific surface area in the powder of the active pharmaceutical preparation composition is changed, thereby improving the dissolution properties of the drug.
  • the solubilization treatment may include co-milling, high pressure homogenization, coprecipitation, solvent evaporation or melt extrusion, and the like.
  • Dissolution-improved forms of virippani include, velipani salt (optionally selected from the group consisting of hydrochloride, besylate, sulfate, maleate, camphorate, etc.), velipani co-milling mixture , Wilipani nanocrystals and velipani solid dispersion.
  • velipani salt optionally selected from the group consisting of hydrochloride, besylate, sulfate, maleate, camphorate, etc.
  • velipani co-milling mixture velipani co-milling mixture
  • Wilipani nanocrystals Wilipani nanocrystals
  • velipani solid dispersion improve controlled release dosage forms by significantly increasing the surface area of the drug and/or the high energy state dispersion of the drug molecule.
  • the dissolution and dissolution properties of veullipani improve the absorption and bioavailability of the drug.
  • the velipani co-milling mixture is composed of the active drug velipani, a matrix polymer for solubilization, and other additives, and is prepared by co-milling the components, and the particle diameter 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 velimpani is from 5 to 60% by weight, preferably from 20 to 40% by weight, based on the total weight of the co-milled composition, 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.
  • all numerical values and all optional numerical ranges within the maximum range are disclosed, preferably all integers are included.
  • the lower limit of the weight percentage of velipani may be 5 wt%, 6 wt%, 7 wt%, ..., or 59.9 wt%
  • the upper limit of the weight percentage of velipani may be 60 wt%, 59 wt%.
  • the weight percentage of vilipani comprises any combination between these lower and upper limits, such as comprising 5 wt% to 6 wt%, 59 wt% to 60 wt%,
  • the weight percentages of the other additives above include from 0.1 wt% to 12.5% wt%, and the like. In the following, for the sake of brevity, the possible values of the upper and lower limits of each numerical range will not be described again.
  • the ribipani nanocrystals in the present invention are composed of the active drug vilipani, a matrix polymer for solubilization, and other additives, and are prepared by preparing the nanosized particles by high pressure homogenization or coprecipitation of the components. .
  • the high pressure homogenization method is as follows: the crude crystal suspension prepared by the high speed shearing of the aqueous solution of the active drug velipani and the matrix polymer for solubilization is added to the high pressure homogenizer, and the high pressure homogenization is repeated. Then, until the prepared crystal particles reached 1000 nm or less, the sample was lyophilized to prepare a uniformly dispersed virippani nanocrystal powder.
  • the coprecipitation method is as follows: the active drug velipani 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 ultrasonically high-frequency ultrasonically irradiated with a probe. The formation and uniform dispersion of the active drug nucleus is ensured until a stable dispersion of the nanocrystal solution is formed, and the sample is lyophilized to prepare a uniformly dispersed virippani nanocrystal powder.
  • an organic solvent such as acetone
  • the dispersed particle size of the active drug velipani 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 virlipani in the powder of the solid preparation composition, thereby improving the dissolution properties of the drug.
  • the weight percentage of velimpani is 10-99% by weight, preferably 20-50% by weight based on the total weight of the vilipani nanocrystal; the weight percentage of the matrix polymer for solubilization It is from 1 to 75 wt%, preferably from 1 to 65 wt%, and the other additives are from 0 to 10% by weight, preferably from 0 to 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 vilipani, a matrix polymer for solubilization, and other additives.
  • the weight percentage of velipani is 5-50% by weight, preferably 10-40% by weight, more preferably 20-40% by weight, based on the total amount of the solid dispersion
  • 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 simultaneously dissolving the drug vilipani, 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 to obtain the intermediate
  • the vollippine solid dispersion can be prepared by transferring the body product to a vacuum oven for drying.
  • the melt extrusion method is carried out as follows: the uniformly mixed drug vilipani, 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 velipani to exhibit a high-state solid dispersion state, which is dispersed in a molecular form in a solid powder of the formulation composition, thereby maximizing the specific surface area of the drug. This improves the dissolution properties of the drug.
  • the matrix polymer for solubilization refers to the ability to stabilize and/or solubilize velipani a polymer of particles or molecules, which may be selected from the group consisting of povidone, copovidone, polyoxyethylene, Soluplus, hypromellose phthalate (HPMCP), hydroxypropylcellulose succinate acetate, poly Ethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 2-hydroxypropyl- ⁇ -cyclodextrin, hypromellose (HPMC), polymethacrylate, hydroxypropyl fiber
  • CAP cellulose cellulose acetate phthalate
  • the additional 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 microsilica gel, and a plasticizer.
  • 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 microsilica gel, and a plasticizer.
  • the release rate adjusting matrix polymer (hereinafter sometimes referred to as a release regulator) in the present invention is a sustained release matrix matrix material well known to those skilled in the art, and may be selected from cellulose derivatives, starch or derivatives thereof, and alginic acid.
  • Salt acrylic or methacrylic acid derivatives, polyethylene oxide, gums and carbohydrate-based polymers, for example, may be selected from the group consisting of hydroxypropyl cellulose, polyoxyethylene, hypromellose, methyl cellulose, One or a combination of two or more of hydroxyethyl cellulose, ethyl cellulose, cellulose acetate, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably selected from hydroxypropyl group One or a combination of two or more of cellulose, polyoxyethylene, sodium alginate, hypromellose, and carbomer.
  • the active drug viricani comprises velipani free base and a pharmaceutically acceptable salt thereof, which
  • the pharmaceutically acceptable salts may be selected from the group consisting of velipani hydrochloride, velipani phosphate, velipani sulfate, velipani maleate, velipani dextroglobate and welli Panibenzenesulfonate and the like.
  • the velimpani 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 the dissolution-reducing form of velipani; and 0.1-300 weight Parts, preferably 20-250 parts by weight, more preferably 50-180 parts by weight of the matrix polymer for release rate adjustment; more specifically, 50-700 parts by weight of velipani salt, and 10-250 parts by weight a matrix polymer for release rate adjustment; or 50-700 parts by weight of a velipani co-milled mixture, and 10-200 parts by weight of a matrix polymer for release rate adjustment; or 50-800 parts by weight of velipani Nanocrystalline, and 0.1-250 parts by weight of the matrix polymer for release rate adjustment; or 50-900 parts by weight of the velipani solid dispersion, and 20-300 parts by weight of the matrix polymer for release rate adjustment.
  • the expected total dose of velimpani that the patient needs to take per day is 100-1400 mg, and the amount of velipani containing the pharmaceutically active ingredient in the single-package dose of the velipani pharmaceutical composition provided by the present invention (for example, a single tablet or capsule) is not Specifically, it can be selected as needed, and for example, it can be 20 to 400 mg or 50 mg to 300 mg.
  • the composition is administered once a day, and the absorption rate and time in the velipani can be controlled, and the blood drug concentration level in the body can be maintained in an effective range required for PARP enzyme inhibition.
  • the pharmaceutical composition of the present invention can improve the dimension. Lipani's PARP enzyme inhibits the effect of tumor treatment and reduces the side effects of the drug.
  • the velipani pharmaceutical composition provided by the present invention may be a sustained release preparation of a single sustained release phase or a quick release double release preparation containing both an immediate release phase and a sustained release phase.
  • the sustained release phase is a controlled release composition comprising a pharmaceutically active ingredient.
  • the controlled release phase is preferably, but not limited to, a controlled release composition selected from the group consisting of a controlled release tablet, a controlled release pellet, a tablet, or a controlled release composition in a tablet or pellet, incorporated into a bilayer tablet. Controlled release layer compositions 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, but not limited to, an immediate release composition selected from the group consisting of an immediate release tablet, an immediate release pellet, 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 velippani 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, skeleton type slow-acting double-effect coated tablets, sustained-release tablets based on sustained-release pellets, quick-acting double-effect tablets based on sustained-release pellets and immediate-release pellets, capsules containing skeleton-type sustained-release pellets, and containing Capsules for coated sustained-release pellets, capsules containing immediate-release coated sustained-release pellets, quick-release double-release capsules containing immediate-release pellets and skeleton-type sustained-release pellets, containing immediate-release pellets and coated sustained-release micro
  • the velipani pharmaceutical composition provided by the invention can be used for preparing a medicament for preventing or treating tumors.
  • the tumor is selected from various types of tumors with defects in DNA repair function, especially for triple negative breast cancer, non-small.
  • the velipani pharmaceutical composition provided by the invention is combined with a DNA-damaging chemotherapeutic drug, and can be used for the treatment of glioblastoma multiforme, epithelial ovarian cancer and metastatic brain cancer.
  • the velipani 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
  • the release within 1 hour is less than 50% of the total amount of velipani, preferably 35% or less, preferably 10% to 30%; 16 hours of release of vilipani is greater than 70% of the total amount, preferably >90%.
  • the voriconib pharmaceutical composition provided by the present invention controls the absorption rate and absorption time of velipani in the gastrointestinal tract by controlling the release behavior and the release amount.
  • the maximum blood concentration value (C max ) obtained by the velipani 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 max) extended more than 30%, preferably 200-800%.
  • the pirepani 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 0.2-8 ⁇ g/mL, preferably 0.5-6 ⁇ g/mL;
  • the blood concentration peak value C max,ss is 0.8-20 ⁇ 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 peak/bottom value of the steady blood plasma concentration is preferred. Less than 6, more preferably less than 4.
  • a single dose of 100 mg to 1400 mg per day and/or twice can maintain the steady-state plasma concentration level required for inhibition of anti-tumor PARP enzyme activity for a long period of time.
  • the pharmaceutical composition provided by the invention can regulate the concentration range of velipani blood concentration, and maintain velipani for a long time to maintain the effective concentration level required for inhibition of PARP enzyme activity in vivo, accurately regulate PARP enzyme activity in vivo, and realize medicine. Efficient and low toxicity treatment.
  • the controlled release pharmaceutical composition of the invention can precisely regulate the concentration level and fluctuation range of velipani blood concentration, is beneficial to the long-term maintenance of the blood concentration level required for enzyme inhibition, and simultaneously 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 velipani controlled release tablet of the present invention may be a skeleton type controlled release tablet, an osmotic pump type controlled release tablet or a controlled release tablet based on sustained release pellets.
  • the skeleton type controlled release tablets include a skeleton type sustained release sheet, a skeleton type quick double effect double layer sheet and a skeleton type quick double effect coating sheet
  • the osmotic pump type controlled release sheet includes an osmotic pump controlled release sheet and an osmotic pump.
  • Sustained-release double-release tablets, controlled release tablets based on sustained-release pellets include sustained-release pellets based on sustained-release pellets and quick-acting double-effect tablets based on sustained-release pellets and immediate-release pellets, and the controlled release tablets described above are specifically
  • the drug release behavior described in the present invention can be achieved in the following manner.
  • the skeleton type controlled release tablet provided by the invention mainly comprises a sustained release phase; and an optional immediate release phase.
  • the skeleton sheet composed of the sustained-release phase and the immediate-release phase is a quick-acting double-effect release matrix sheet
  • the skeleton sheet composed only of the sustained-release phase is an ordinary sustained-release matrix sheet.
  • 1 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. 2 is a schematic structural view showing a skeleton type quick-release double-effect release coated sheet according to an embodiment of the present invention.
  • the sustained release phase comprises 50 to 600 parts by weight, preferably 80 to 500 parts by weight, more preferably 120 to 400 parts by weight, of the dissolution-reduced form of velipani; 10 to 150 parts by weight, preferably 20 to 120 parts by weight, more Preferably, 30 to 100 parts by weight of the matrix polymer for release rate adjustment, 0 to 40 parts by weight of the diluent, and 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight, of other tablet-based additives. After the components are thoroughly mixed, they are prepared by tableting by a conventional method well known to those skilled in the art.
  • the lower limit of the weight fraction of the dissolution-improved vilipani may be 50, 60, 70, ..., or 599 parts by weight
  • the upper limit of the weight of the velipani may be 600, 590, 580, ..., or 50.1 parts by weight, i.e., parts by weight of vilipani include any combination between these lower and upper limits, such as 50 to 50.1 parts by weight, 110 to 590 parts by weight, and the like.
  • parts by weight of vilipani include any combination between these lower and upper limits, such as 50 to 50.1 parts by weight, 110 to 590 parts by weight, and the like.
  • 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, poly One or a combination of two or more of ketene, copolyvidone, acrylic resin, carbomer; preferably one selected from the group consisting of hydroxypropylcellulose, sodium alginate, hypromellose, and carbomerkind 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 conventional additives for tablets 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 silica gel.
  • the colorant is one or a combination of two or more selected from the group consisting of iron oxide red, iron oxide yellow, iron oxide violet, iron oxide black, and titanium oxide.
  • the immediate release phase may comprise the above-described dissolution-improved form of velipani, a disintegrant, a diluent, and other additives commonly used in tablets, or may comprise vilipani, a solubilizing matrix polymer, and other conventional additives for 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 velimpani may be used in an amount of from 20 to 600 parts by weight, preferably from 30 to 400 parts by weight, more preferably from 50 to 250 parts by weight, in the immediate release phase of the velipani containing the dissolution-improved form;
  • 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 common collapses.
  • One or a combination of two or more of the decomposers is from 5 to 90 parts by weight, preferably from 10 to 50 parts by weight, in the immediate release phase.
  • 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 is in immediate release.
  • the phase is 5 to 200 parts by weight, preferably 10 to 150 parts by weight.
  • the other tablet commonly used additives include one or a combination of two or more kinds of lubricants and colorants commonly used in solid preparations well known to those skilled in the art, which is 0.2 to 30 parts by weight in the immediate release phase, preferably 1 to 30 parts by weight.
  • 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 is 0.1-20 in the immediate release phase.
  • 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 is 0-113 parts by weight in the immediate release phase. .
  • velipani in an immediate release phase comprising vilipani, a solubilizing matrix polymer and other commonly used additives for tablets, velipani can be used in an amount of 5 to 100 parts by weight, preferably 10 to 80 parts by weight, more preferably 20 to 60. Parts by weight.
  • the solubilizing matrix polymer is selected from the group consisting of povidone, copovidone, Soluplus, hypromellose phthalate (HPCP), polyethylene glycol, poloxamer, hypromethylene fiber
  • HPCP hypromellose phthalate
  • HPMC hypromethylene fiber
  • Common additives for other tablets include crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone, croscarmellose sodium, microcrystalline cellulose And a pharmaceutically acceptable surfactant (sodium dodecyl sulfate), mannitol, a lubricant (such as magnesium stearate), and the like, and an additive for an immediate release tablet, which is well known to those skilled in the art, may be used in an amount of 0.1. - 150 parts by weight, preferably 0.5 to 100 parts by weight.
  • the velimpani in the immediate release phase is about 10-40% by weight of the total weight of velipani in the entire quick-acting double-effect matrix tablet, and the Willy in the sustained-release phase.
  • Panier is about 60-90% by weight of the total weight of velipani in the entire quick-acting double-effect matrix tablet.
  • the velipani 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, more preferably 90% or more, and the release behavior of the pharmaceutically active ingredient in the sustained-release phase is in accordance with the zero-order, first-grade, Higuchi or
  • the Ritger-Peppas release model is preferably a zero-order release.
  • the osmotic pump controlled release sheet comprises a single layer osmotic pump sheet, a single layer osmotic pump speed double release sheet, a double layer osmotic pump controlled release sheet or a double layer osmotic pump quick release double release sheet.
  • the double-layer osmotic pump controlled release sheet provided by the invention mainly comprises:
  • a controlled release drug-containing layer formed by a controlled release drug-containing layer composition, located in a rigid membrane shell adjacent to the drug release orifice;
  • a push layer also referred to as a boost layer formed by the push layer composition, located in the rigid membrane shell, away from the side of the drug release orifice;
  • a rigid membrane shell having moisture permeability which is obtained by drying a controlled release coating coating liquid, and the membrane shell comprises one or more drug releasing holes at one end;
  • Wilipani accounts for 3 to 50% by weight of the total weight of the osmotic pump type controlled release tablets.
  • the controlled release drug-containing layer composition comprises: a dissolution-improved form of velipani; a release regulator and other pharmaceutically acceptable excipients, and the like.
  • 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 a dissolution-improved form of wilipani; 10-150 parts by weight Preferably, 20 to 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 are preferred.
  • the dissolution-improved form of virippani may be selected from the above-described vilipani salt, velipani co-milling mixture, nanocrystal or solid dispersion.
  • the release regulator may be selected from the group consisting of povidone, copovidone, polyethylene oxide, carbomer, hydroxypropyl cellulose, croscarmellose sodium, hydroxypropyl cellulose, twelve One or a combination of two or more of sodium alkyl sulfates.
  • compositions of the controlled release drug-containing layer composition are, without limitation, selected from the group consisting of penetration aids, lubricants, and colorants commonly used in pharmaceutical tablets, and the amounts thereof are conventionally selected in the art.
  • the penetration enhancer is selected from the group consisting of sodium chloride, lactose, mannitol, glucose, sucrose, fructose, or a combination of two or more thereof, preferably sodium chloride, which is in the controlled release drug-containing layer composition. 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.
  • the drug-containing layer composition is 0-20 parts by weight.
  • the dyeing 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, etc., and is 0 to 10 parts by weight in the controlled release drug-containing layer composition. .
  • the push layer composition typically comprises a release rate modulating permeation polymer, an osmotic pressure promoter, and other excipients.
  • the release rate adjusting permeation-promoting polymer is a high molecular polymer which, in an aqueous medium, can absorb water to swell and promote release of 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 hydroxypropylmethylcellulose, hydroxypropylcellulose, croscarmellose sodium, cross-linked poly Wortone, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, croscarmellose sodium, crospovidone, carbomer, alginic acid and/or derivatives thereof
  • One or a combination of two or more kinds may be used in the push layer composition 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 the amount is 20 in the push layer composition. - 150 parts by weight, preferably 25-100 parts by weight.
  • the other excipients in the push layer composition include, without limitation, a lubricant, a colorant, and the like, and are used in the push layer composition in an amount of from 0.5 to 30 parts by weight, preferably from 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 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 is used in an amount of 0.3 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 and optionally 0-20 parts by weight of a plasticizer, 0-20 parts by weight.
  • 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 the aesthetic outer garment is generally unrestricted and packaged into a common double-layer osmotic pump sheet for quick and double effect with instant release coating. Osmotic pump sheets are seldom applied to aesthetic outer garments; the aesthetic outerwear can improve the appearance of the formulation to increase patient compliance and provide color identification.
  • the 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. Further, 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 velipani, 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 velipani, release modifier, osmotic pressure promoter is as described under the double 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.
  • 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 the active ingredient vilipani, 0-100 parts by weight, preferably 10-100 parts by weight of the 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.
  • the other pharmaceutically acceptable excipients include crospovidone, microcrystalline cellulose, pharmaceutically acceptable surfactants (e.g., 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 includes one or a combination of two or more of ethanol, acetone, and water.
  • the velipani in the immediate release drug-containing layer is about 10-40% by weight of the total weight of velipani in the entire double-release osmotic pump sheet, and the controlled release drug-containing layer
  • the vilipani in the middle is about 60-90% by weight of the total weight of velipani in the entire double-release osmotic pump sheet.
  • the preparation method of the velipani osmotic pump controlled release tablet of the present invention comprises the following steps: 1 preparation of improved dissolution form of velipani; preparation of 2 drug-containing layer; 3 preparation of optional propulsion layer; Preparation of core; 5 preparation of optional barrier film; preparation of 6 controlled release film; 7 osmotic pump controlled release film punching; 8 optional preparation of esthetic coat layer; 9 optional speed Preparation of the drug-containing layer.
  • the above 2-9 can be carried out by a conventional pressing and coating method well known to those skilled in the art.
  • the tablet with the rigid membrane shell outsourcing the immediate release drug-containing layer is an osmotic pump double-release tablet
  • the tablet with the outer layer of the rigid membrane shell not coated with the immediate release drug-containing layer is a common osmotic pump controlled release tablet.
  • Fig. 3 is a schematic view showing the structure of an osmotic pump type controlled release sheet according to an embodiment of the present invention
  • Fig. 4 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 velipani, because 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 toxic side effects caused by fluctuations.
  • the present invention provides a sustained-release pellet based on controlled-release pellets of velipani, which can be sustained-release based on sustained-release pellets. Tablets and quick-acting double-effect release tablets based on sustained-release pellets/immediate release matrix.
  • the immediate release matrix constitutes an immediate release phase
  • the sustained-release pellet constitutes a sustained-release phase
  • the velipani in the immediate-release phase accounts for the entire quick-acting double-effect release tablet.
  • the total vilipani content is 10-40% by weight
  • the velipani in the sustained-release phase accounts for 60%-90% by weight of the total velimpani content in the entire quick-release double-effect release tablet.
  • 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 velimpani is 20-200 parts by weight, preferably 50-150 parts by weight in the immediate release phase;
  • the disintegrant is selected One of self-crosslinking povidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyethylene pyrrolidone, croscarmellose sodium, and other pharmaceutically-acceptable disintegrants
  • the combination of two or more kinds is 5 to 90 parts by weight, preferably 10 to 50 parts by weight, in the immediate release matrix.
  • the diluent is one or a combination of two or more of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch, sodium carboxymethyl starch, in the immediate release phase. 5-200 parts by weight, preferably 10-150 parts by weight.
  • the other commonly used additives for tablets include one or a combination of two or more kinds of lubricants and colorants commonly used in solid preparations well known to those skilled in the art, and 0.2 to 30 parts by weight, preferably 1 - in the immediate release phase. 30 parts by weight.
  • 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 microsilica, in an amount of from 0.1 to 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 titanium oxide, and is 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 a non-limiting blank pellet core, a velipani salt (for example, a hydrochloride, a besylate, a sulfate, The camphor salt, etc., the release rate adjusting matrix or the controlled release coating material, and other excipients, etc., by wet granulation, extrusion spheronization, coating pan coating, and/or fluidized bed granulation well known to those skilled in the art. It is prepared by a conventional method such as coating.
  • a velipani salt for example, a hydrochloride, a besylate, a sulfate, The camphor salt, etc., the release rate adjusting matrix or the controlled release coating material, and other excipients, etc.
  • the sustained-release pellets can be prepared by a one-pot coating drug-loading method in a coating pan, wherein the velipani is dispersed or packaged on a blank pellet core to form a drug-loaded pellet core, and then a drug-loading core is outsourced.
  • the layer release rate is adjusted by using a matrix controlled release coating material 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 velipani and the release rate adjusting matrix are simultaneously dissolved, placed in a spray drying apparatus, blown into a gas stream, dried, collected, and bonded.
  • the granule-type sustained-release pellets are formed by granulating and drying.
  • the release rate adjusting sustained release matrix or controlled release coating material may be selected from shellac, cellulose acetate phthalate (CAP), acrylic resin (Eudragit), ethyl cellulose. (EC), carbomer, polypropylene polysiloxane, cellulose acetate, cellulose propionate, cellulose acetate propionate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), methyl cellulose, hydroxypropyl fiber One or a combination of two or more of hydroxypropylmethylcellulose (HPMC), Eudragit, etc.; the other excipients mainly include, but are not limited to, a binder, a plasticizer, a porogen, and the like.
  • the binder is one or a combination of two or more selected from the group consisting of polyethylene glycol (PEG), stearic acid, glyceryl monostearate, and the like, and the plasticizer is selected from the group consisting of propylene glycol.
  • PEG polyethylene glycol
  • stearic acid stearic acid
  • glyceryl monostearate glyceryl monostearate
  • the porogen is selected Self-hydrophilic liquid carrier (glycerol, PEG200), sugar (lactose, fructose, sucrose, mannose), surfactant (polysorbate 80, sodium lauryl sulfate, etc.), polymer (povidone, One or a combination of two or more of hypromellose or the like.
  • Self-hydrophilic liquid carrier glycerol, PEG200
  • sugar lactose, fructose, sucrose, mannose
  • surfactant polysorbate 80, sodium lauryl sulfate, etc.
  • polymer povidone, One or a combination of two or more of hypromellose or the like.
  • the blank pellet core is 100-500 parts by weight, preferably 200-400 parts by weight
  • the vilipani salt is 10-100 parts by weight
  • the release rate adjusting substrate is 10 - 300 parts by weight
  • the binder is 0-100 parts by weight
  • the porogen is 0-12 parts by weight
  • the plasticizer is 0-15 parts by weight.
  • sustained-release pellets are directly compressed into a sustained-release tablet based on sustained-release pellets. If the ratio of the immediate-release matrix and the sustained-release pellets is uniformly mixed, the tableting machine with a special stirring function is used. When compressed into tablets, it can be prepared into a quick release double release preparation.
  • 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 sustained release capsule based on the microchip of the invention is a controlled release capsule composed of a sustained release microchip or a quick release double release capsule composed of a sustained release microchip and an immediate release microchip, and may include a skeleton type sustained release microchip.
  • the resulting microchips 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.
  • velipani in the immediate release phase is 10-40% by weight
  • velipani in the sustained release phase is 60-90% by weight.
  • composition, preparation method, material selection and content of the skeleton type sustained-release sheet is the same as that of the above-mentioned 1.1 part of the skeleton type controlled release sheet, 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 1.1 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.
  • 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 velipani accounts for the entire double-effect release. 10 to 40% by weight of the total velipani in the capsule
  • velipani in the sustained-release pellets accounts for 60 to 90% by weight of the total velipani in the entire double-release capsule.
  • 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 instant release pill and sustained release pill can be weighed according to a certain ratio, and evenly mixed, and then capsule filling can be used to prepare a quick release double release capsule preparation, or Sustained-release pellets containing an immediate release coating can be used for capsule filling, and a quick-release double-release capsule preparation can also be prepared.
  • Fig. 1 is a schematic view showing the structure of a skeleton type double-effect release double-layer sheet.
  • FIG. 2 is a schematic view showing the structure of a skeleton type quick release double-effect release coated tablet.
  • Figure 3 is a schematic view showing the structure of an osmotic pump type controlled release sheet.
  • Fig. 4 is a schematic view showing the structure of an osmotic pump type quick release double-effect release sheet.
  • Fig. 5 is a schematic view showing the structure of an immediate release pellet and a skeleton type sustained release pellet.
  • Fig. 6 is a schematic view showing the structure of a sustained-release pellet capsule containing an immediate release coating.
  • Fig. 7 is a structural view of a capsule containing an immediate release tablet and a sustained release tablet.
  • Figure 8 is a graph showing the release profile of the sustained release tablet of Example 1 in a release medium at pH 1.2, 4.5 and 6.8.
  • Figure 9 is a graph showing the release profile of the two-layer osmotic pump controlled release tablet of Example 2 in a release medium of pH 1.2, 4.5 and 6.8.
  • Figure 10 is a graph showing the release profile of the quick double effect matrix tablet of Example 3.
  • Figure 11 is a graph showing the release profiles of the slow release formulations of Example 6, Example 7, Example 8, Example 9, Example 10, and Example 11.
  • Figure 12 is a graph showing the release profile of the immediate release capsule 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 quick double effect matrix tablet of Example 3.
  • 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 6.
  • Figure 15 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 6.
  • 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.
  • the velipani and solubilized matrix polymer povidone K30 were prepared by solvent evaporation method, ie, velipani and povidone K30 (BASF, Germany) were dissolved in organic solvent (ethanol/acetone, In 40/60, v/v), the organic solvent is volatilized under reduced pressure, dried and pulverized, and then copolymerized with the sustained release matrix matrix polymer hydroxypropyl cellulose (K4M, Shanghai Kalakang) and other auxiliary materials.
  • organic solvent ethanol/acetone, In 40/60, v/v
  • the ketone VA64 (BASF, Germany), the micro-silica gel and the magnesium stearate were mixed, passed through a 60 mesh sieve and mixed by a three-dimensional mixer at 30 rpm for 30 minutes, and after being uniformly mixed, it was used for tableting.
  • a single-press tablet press is used to form a sustained-release matrix sheet.
  • 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).
  • the buffers of pH 1.2, 4.5, and 6.8 were used as the release medium (7.65 mL).
  • the pH 1.2 release medium can be prepared by diluting hydrochloric acid with water to 1000 mL; 250 mL 0.2 mol/L potassium dihydrogen phosphate solution can be separately added to 0 mL and 112 mL to obtain a release medium of pH 4.5 and 6.8, respectively.
  • 75 rpm, according to the law 6 mL of the solution was taken at 1, 2, 4, 6, 8, 9, 10, 12 h, centrifuged, and the supernatant was taken as the test solution to determine the release degree.
  • the absorbance was measured at a wavelength of 269 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 two-layer osmotic pump controlled release tablets were basically not affected by pH.
  • the active ingredient vilipani could maintain a constant rate of release, with less than 20% release in 1 hour, 60-70% release in 6 hours, and 90% release in 10 hours. the above.
  • Velipani and solubilized matrix polymer copolyvidone VA64 mixed uniformly in a three-dimensional multi-directional motion mixer, added to the melt extruder, collected and extruded and cooled solid product, crushed, passed 60 mesh The sieve was mixed with other additives, povidone K90 and magnesium stearate, by a three-dimensional mixer at 30 rpm for 30 minutes, and uniformly mixed for tableting.
  • a boost layer composition Precisely weigh a prescribed amount of propellant layer excipient (including a matrix polymer for release rate adjustment such as hypromellose, carbomer, etc.), and uniformly mix to obtain a boost layer composition.
  • propellant layer excipient including a matrix polymer for release rate adjustment such as hypromellose, carbomer, etc.
  • the above-mentioned drug-containing layer composition is lightly pressed by a single punching machine, and then the boosting layer composition is added, and pressed into a double-layer core of the osmotic pump containing the drug-containing layer and the boosting layer.
  • the pressed core was coated with 4% cellulose acetate solution, coated with LABCOATING experimental multi-functional high-efficiency intelligent coating machine, and the film was gained by 10% to obtain a double-layer osmotic pump controlled release tablet.
  • the release method of the osmotic pump control reagent was determined by the second method of dissolution measurement (Chinese Pharmacopoeia 2010 edition two appendix X C). At 37 ° C, 900 ml of pH 1.2, 4.5, 6.8 buffer was used as the release medium.
  • the rotation speed is 75 rpm, and according to the method, 6 mL of the solution is taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 13, 16 h, centrifuged, and the supernatant is taken. The liquid was used as a test solution to measure the degree of release.
  • the absorbance was measured at a wavelength of 269 nm, and the release degree of the prescription tablet was measured.
  • the release results in different pH release media are shown in Figure 9.
  • the results showed that the double-layer osmotic pump controlled release tablets were basically not affected by pH.
  • the active ingredient vilipani 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.
  • Immediate release layer Prescribe the amount of velipani, micronized silica gel and solubilized matrix polymer Soluplus through a 60 mesh sieve and mix in a three-dimensional mixer at 30 rpm for 30 minutes. After mixing, slowly add to the preheated The melt extruder, the extrudate was collected and pulverized through a 60 mesh screen to give a virlipani solid dispersion.
  • the resulting voriconil solid dispersion is mixed with other materials such as disintegrant PVPP XL and other adjuvants such as mannitol and magnesium stearate by a three-dimensional mixer at 30 rpm for 30 minutes, mixed uniformly, and then to be tableted. use.
  • Sustained release layer The prescribed amount of velippani, micronized silica gel and solubilized matrix polymer povidone K30 were passed through a 60 mesh sieve and mixed by a three-dimensional mixer at 30 rpm for 30 minutes, mixed, and slowly added to the The melt extruder was preheated, the extrudate was collected and pulverized through a 60 mesh screen to obtain a virlipani solid dispersion.
  • the resulting voriconil solid dispersion was mixed with a prescribed amount of the release rate adjusting polymer HPMC K15M and the lubricant magnesium stearate for tableting.
  • Tableting The tablet is gently pressed with a single punching machine, and then the sustained-release layer powder is added, and then pressed into a moderately slow-release double-release double-layer skeleton controlled release tablet having 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 hydrochloric acid aqueous solution of pH 1.2 and 6.8 was used as the release medium, and the rotation speed was 75 per minute. Turn, according to the law, take 6.5, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 13h to take 6mL of the solution, centrifuge, take the supernatant as the test solution, determine the release.
  • the absorbance was measured at a wavelength of 269 nm, and the release degree of the obtained tablet was measured.
  • the release results are shown in Figure 10.
  • the quick-acting double-effect skeleton double-layer tablet can release about 20% of the drug in one hour, and about 70%-75% of the drug is released in about 8 hours, and the remaining drug can be completely released in about 12 hours.
  • the immediate release release behavior can achieve velipani, quickly reach the blood concentration level required for effective anti-tumor PARP enzyme inhibition in vivo, and then the sustained release behavior can achieve the velipani blood concentration at this level. Long-term maintenance to improve anti-tumor effects.
  • Example 4 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 pills Dissolve or disperse vilipani hydrochloride and copolyvidone VA64 in 95% ethanol solution to prepare a drug-loading solution, spray the prescribed amount of microcrystalline fiber by fluidized bed coating. It is used as a quick release pill.
  • Sustained-release pellet Weigh the release rate to adjust the amount of matrix hydroxypropylcellulose (SSL), disperse in 95% ethanol solution, prepare a coating solution with a solid content of 10%, stir well on a magnetic stirrer. Uniform; weighed the prescription of velipani hydrochloride, uniformly dispersed in the above coating liquid, and used as a drug-loading coating solution.
  • SSL matrix hydroxypropylcellulose
  • microcrystalline cellulose blank pellet core is added to the fluidized bed, sprayed into the prepared drug-loading coating liquid, and the drug is loaded to obtain a drug-loaded pellet core.
  • the isolated coating film component povidone (K30) was 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 Sulis is diluted with an appropriate amount of the aqueous solution, mixed, and used as a sustained-release coating film coating liquid, and sprayed into the drug-loading pill core of the coating clothes by a fluidized bed coating method. Made into sustained release pills.
  • Capsule filling Capsules prepared as described above are prepared into sustained-release capsules, or
  • the instant release pill and the sustained release pill prepared as described above were thoroughly mixed according to the prescription amount, and then filled into a capsule to prepare a quick release double release capsule preparation.
  • Example 5 Sustained-release pellets containing an immediate release coating layer
  • the preparation method is as follows:
  • Drug loading First, velipani and povidone K30, dissolved or dispersed in 95% ethanol solution, formulated into a drug-loading solution, sprayed into the prescription amount of blank cane pills by fluidized bed coating On the core, as a drug-loading pellet core;
  • Packing clothing Dissolving or dispersing the component film copolyvidone VA64 in 95% ethanol solution, spraying into the prescription drug core by fluidized bed coating;
  • Slow-release coating the slow-release coating liquid Eudragit NE30D aqueous dispersion is added to the talc powder and an appropriate amount of aqueous solution, and mixed as a slow-release coating film coating liquid, which is sprayed into the fluidized bed coating method.
  • the drug-loaded pellet core coated with the gown is made into a sustained-release pellet.
  • Quick-release dressing Disperse velipani and hydroxypropyl methylcellulose (E5) in 95% ethanol solution, mix as an immediate release coating solution, and apply fluidized bed coating. The method is sprayed onto the sustained release pellet to prepare a sustained release granule containing an immediate release coating layer.
  • Capsule filling The prepared sustained-release granules containing the immediate release coating layer were filled in capsules according to the prescribed amount to prepare a quick-release double-release capsule preparation.
  • Example 6 Sustained double release double osmotic pump controlled release tablets
  • the velipani and copovidone were sieved through a 60 mesh sieve for 3 times, and then mixed by a three-dimensional mixer at 30 rpm for 25 minutes. The mixture was slowly added to the preheated melt extruder, and the extrudate was collected and pulverized. After 60 mesh sieves, a voriconi solid dispersion was obtained. 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-0.3% 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 velipani solid dispersion is dissolved in an ethanol-acetone solution, and the ratio of the immediate release layer to the sustained release layer is 3:7 to the obtained double-layer osmotic pump sheet, so that the active ingredient of the immediate release layer is obtained. 30%wt, sustained-release layer active ingredient accounted for 70%wt of double-release double-release osmotic pump tablets.
  • the release method of the double-release double-osmotic pump controlled release tablets was measured by the second method of dissolution test (Chinese Pharmacopoeia 2010 edition two appendix X C). At 37 °C, the hydrochloric acid aqueous solution of pH 1.2 was used as the release medium. The rotation speed is 75 rpm, according to the law, 6 mL of the solution is taken at 0.5, 1, 2, 4, 6, 8, 10, 12, 13, 16h, centrifuged, and the supernatant is taken as the test solution to determine the release degree. .
  • the absorbance was measured at a wavelength of 269 nm, and the release degree of the prescription tablet was measured.
  • Example 7 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 velippani 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 was used to collect the extrudate and pulverize through a 60 mesh screen to obtain a virlipani solid dispersion.
  • the dispaliani solid dispersion obtained 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 6, using a hydrochloric acid aqueous solution of pH 1.2 as the release medium, and the release curve is shown in FIG.
  • Example 8 based on sustained release pellets of sustained release pellets
  • the preparation method is as follows:
  • Drug-loaded pellet core Dissolve or disperse velipani and VA64 in 95% ethanol solution, prepare a drug-loading solution, and spray it into the prescription sucrose blank pellet core by fluidized bed coating. Load the pellet core.
  • the components of the detaching coating film were dissolved or dispersed in a 95% ethanol solution, and sprayed into a loaded drug-carrying 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 to be mixed, and is used as a slow-release coating film coating liquid, and is sprayed into the drug-loading pellet core of the coating body by a fluidized bed coating method. Into the sustained release pill.
  • 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 6, using a hydrochloric acid aqueous solution of pH 1.2 as the release medium, and the release curve is shown in FIG.
  • Sustained-release microchip Willipani and Soluplus 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, and the velipani 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 Willipani and Soluplus 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, and the velipani 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 6, using a hydrochloric acid aqueous solution of pH 1.2 as the release medium, and the release curve is shown in FIG.
  • Example 10 based on sustained release pellets of sustained release pellets
  • aqueous solution is used as a binder for soft material, and the velipani-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.
  • the screened Willipani pellets were placed in a fluidized bed to prepare a coating liquid, and the velipani sustained-release pellets were prepared by coating.
  • Coating liquid ratio acrylic resin 14.5% plasticizer triethyl citrate 5% anti-adhesive talcum powder 10.5% water balance.
  • the release rate was determined in the same manner as in Example 6, using a hydrochloric acid aqueous solution of pH 1.2 as the release medium, and the release curve is shown in FIG.
  • verapamil and hypromellose E5 were passed through a 60 mesh sieve and mixed in a three-dimensional mixer at 30 rpm for 25 minutes, and then slowly added to the preheated melt extruder to collect the extrudate. And pulverized through a 60 mesh sieve to obtain a verapani solid dispersion.
  • the prepared verapamil solid dispersion and the other excipients except magnesium stearate were sieved through a 60 mesh sieve and uniformly mixed by a three-dimensional mixer, and then mixed with magnesium stearate for 5 minutes to obtain a drug-containing layer combination.
  • Object 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 6, using a hydrochloric acid aqueous solution of pH 1.2 as the release medium, and the release curve is shown in FIG.
  • Gelatin instant release capsule contains 21wt% vilipani hydrochloride, 43wt% microcrystalline cellulose, 32wt% lactose, 2wt% micronized silica gel, 1wt% magnesium stearate and 2% sodium lauryl sulfate After mixing evenly, it is directly packed into 0# hard capsules; its dissolution is determined by the dissolution method (Chinese Pharmacopoeia 2010 edition two appendix X C) first method device, at 37 ° C, with 900mL pH 1.2 The aqueous solution of hydrochloric acid is the release medium, the rotation speed is 75 rpm, and the operation is carried out according to the law. After 15, 30, 45, 60, 75, 90, 105, 120 minutes, 6 mL of the solution is taken, centrifuged, and the supernatant is taken as the test solution, and the determination is carried out. Release.
  • the absorbance was measured at a wavelength of 278 nm, and the release degree of the capsule was measured.
  • the C max (2679.9 ng/mL) and AUC 0-h (9034h*ng/mL) slow-acting double-effect controlled release tablets have a Cmax reduced to 904.4 ng/mL relative to the capsule formulation, which is reduced by about 66%; AUC 0 -h is 10043.5h*ng/mL, the change is ⁇ 10%; from the results of the drug-time curve of Figure 13, it can be seen that the higher blood concentration can be maintained longer than the immediate release capsule. Time to stabilize the blood concentration to better play the role of enzyme inhibition and anti-tumor, while providing a larger dose space for the best efficacy.
  • the enzyme inhibition rate of immediate release capsules was less than 90% 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 of Figure 14 and Figure 15 It can still be seen that compared with the immediate release capsule, the high-speed plasma concentration of the double-release double-osmotic pump controlled-release tablets can maintain a stable blood concentration for a long time, so as to better exert the enzyme inhibition and anti-tumor effect. At the same time, it provides a larger dose space for drug dose climbing and optimal drug efficacy.

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Abstract

一种维利帕尼口服缓控释药物组合物，该组合物包含溶出改善形式的维利帕尼和释放速率调节用基质聚合物。本发明的药物组合物可通过调控维利帕尼的体外释药行为调控维利帕尼于体内的吸收速率和吸收时间，进而精确地调控维利帕尼于体内的血药浓度水平及血药浓度波动范围，以高效持久地发挥维利帕尼对体内PARP酶的抑制活性，进而提高药物治疗效果，并降低药物毒副作用。

Description

一种维利帕尼缓控释药物组合物及其用途 技术领域
本发明涉及维利帕尼药物制剂领域，具体涉及一种维利帕尼口服缓控释药物组合物及其用途。
背景技术
维利帕尼(Veliparib)，化学名称为2-[(2R)-2-甲基-2-吡咯烷基]-1H-苯并咪唑-7-甲酰胺，分子式为C 13H 16N 4O，分子量为244.29，具有下述化学结构：
Figure PCTCN2017116472-appb-000001
维利帕尼是AbbVie公司开发的口服有效的PARP1/2抑制剂。最早于2007年进入临床，目前为止共开展90项临床研究，适应症包括：三阴性乳腺癌、非小细胞肺癌、卵巢癌、黑素瘤、脑癌等。维利帕尼与DNA损伤性化疗药物联用，治疗多形性成胶质细胞瘤，上皮性卵巢癌，转移脑癌分别于2008年、2009年、2014年获得FDA孤儿药称号。EMA于2010年授予维利帕尼治疗卵巢癌的孤儿药称号。在一项维利帕尼辅助治疗的II期临床试验中，三阴性乳腺癌患者接受维利帕尼，卡铂和紫杉醇治疗后继续以蒽环类药物化疗，结果显示维利帕尼组完全应答率为52％，而对照组为26％。
维利帕尼与其他PARP抑制剂的最大不同在于，维利帕尼与化疗药物联用治疗肿瘤是在没有基因分型的患者中展开，而维利帕尼，BMN-673，瑞卡帕布等均是首先针对BRCA突变的肿瘤患者。除了化疗以外，三阴性乳腺癌目前并没有很好的靶向治疗措施，维利帕尼如果能成功，将很好的满足这个临床缺口。
据AbbVie公布的研究结果发现，维利帕尼吸收较快，口服速释胶囊制剂后，血药浓度达峰时间(Tmax)为1.2-2.5h；Cmax/AUC等随着剂量的提高成线性提高，但该药物体内血药浓度半衰期较短(t 1/2＝6h)，体内消除较快，导致有效的PARP酶活性抑制所需药物浓度难以长时间维持，因此，临床中需每天两次以上的大剂量给药(单独用药剂量dosa>400mg/次)。
作为PARP酶催化活性区域的可逆性PARP酶抑制剂，尤其对于体内消除极快的维利帕尼等药物而言，为达到体内肿瘤生长抑制所需的有效PARP酶抑制活性，PARP酶抑制所需的游离血药浓度水平的长时间维持极为重要。
然而，目前进入临床II/III期的制剂为维利帕尼速释胶囊，药物释放极快，导致体内药物难以长期维持，快速被消除，临床疗效显示出一定的局限性：1)速释胶囊虽可快速达PARP酶有效抑制所的血药浓度水平，但药物体内消除较快，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(>400mg，BID.)，这导致维利帕尼的稳态血药浓度波动范围较大，稳态血药浓度峰值高于PARP酶抑制所需IC50值的几倍甚至十几倍，产生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)400mgBID的口服方式，血药浓度峰值过高，产生的副作用限制了PARP酶抑制所需游离血药浓度长时间维持，影响药物疗效的充分发挥；3)较大的药物口服剂量(400mg-600mg BID剂量)，也导致药品的生产、包装、贮存和运输代价高，患者顺应性差。
为进一步提高维利帕尼的单独用药，或联合用药时的临床抗肿瘤疗效，降低药物的毒副作用，有必要提供一种可精确调控维利帕尼血药浓度水平和波动范围的优良制剂。
经专利检索，目前尚无公开的维利帕尼控释制剂专利。
发明内容
多次大剂量的给药，产生较高稳态血药峰值和较大的血药浓度波动(400mg，BID，C min,ss<1μg/ml；C max,ss>6μg/mL)，除了导致维利帕尼速释制剂众多副作用和安全性问题，更会限制药效发挥所需的血药浓度水平的进一步提升和药效的发挥。
本发明首要目的是针对维利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，精确调控维利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，提高维利帕尼的抗肿瘤疗效，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，本发明提供了一种体内吸收行为、血药浓度和PARP酶抑制水平可控的维利帕尼缓控释药物组合物。本发明还提供了具有改进维利帕尼药物载量和/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药物组合物和他们作为唯一制剂或其他疗法联合治疗癌症的用途。
本发明提供的维利帕尼控释药物组合物包含：溶出改善形式的维利帕尼，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)、染色剂(也称为着色剂)、润滑剂、粘合剂(也称为黏合剂)、抗粘剂(也称为抗黏剂)、遮光剂、稀释剂以及其他药学上可接受的添加物等药学辅料。
本发明提供的维利帕尼药物组合物中的活性药物维利帕尼，属于难溶性药物，可经过进行增溶处理，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，制备成为维利帕尼的盐形式化合物，也可通过将维利帕尼与可实现药物溶解度改善的基质聚合物混合在一起，改变了活性药物制剂组合物粉末中的分散比表面积，由此改善了药物的溶出性能。所述增溶处理可以包括共研磨、高压均质、共沉淀、溶剂挥发或熔体挤出等。
溶出改善形式的维利帕尼包括，维利帕尼盐化物(可选自盐酸盐、苯磺酸盐、硫酸盐、马来酸盐、樟脑酸盐等)、维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体。不限于任何理论，所述维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体通过显著性提高的药物表面积和/或药物分子高能态分散状态，改善控释剂型中维利帕尼的溶解溶出性能，同时提高药物的吸收和生物利用度。
所述维利帕尼共研磨混合物由活性药物维利帕尼、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，基于共研磨组合物的总重，维利帕尼的重量百分比为5-60wt％，优选20-40wt％，增溶用基质聚合物的重量百分比为40-95wt％，优选40-80wt％，其他添加物的重量百分比为0-15wt％，优选0.2-10wt％。上述各组分的总量为100wt％。
在本文中对于同一组合物中的同一组分而言，在出现不同数值范围时，视为公开了在所述最大范围之内的所有数值和所有可选的数值范围，优选包含了所有整数、精确到小数点后1位的小数的数值和由其组成的数值范围。例如，在上文中，维利帕尼的重量百分比的下限可以为5wt％、6wt％、7wt％、……、或59.9wt％，维利帕尼的重量百分比的上限可以为60wt％、59wt％、58wt％、……、或5.1wt％，即，维利帕尼的重量百分比包含了在这些下限和上限之间的任意组合，如包含了5wt％至6wt％，59wt％至60wt％，又如，上文中的其他添加物的重量百分比包含了0.1wt％至12.5wt％，等等。在下文中，为了简要的目的，将不再对每个数值范围的上下限的可能取值做赘述。
本发明中的维利帕尼纳米晶由活性药物维利帕尼、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：将由活性药物维利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，制备均匀分散的维利帕尼纳米晶体粉末。所述共沉淀法如下操作：活性药物维利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，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，制备均匀分散的维利帕尼纳米晶体粉末。通过制备成为纳米晶，能够降低活性药物维利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维利帕尼在固体制剂组合物粉末的分散比表面积，由此改善了药物的溶出性能。
在所述维利帕尼纳米晶中，基于维利帕尼纳米晶的总重，维利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0-5wt％。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维利帕尼、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量，维利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％。该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：将药物维利帕尼、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，将所得中间体产品转移至真空干燥箱干燥，即可制得维利帕尼固体分散体。所述熔体挤出法如下进行：将混合均匀后的药物维利帕尼、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维利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。
在本发明的维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体中，增溶用基质聚合物指的是能够用于稳定和/或增溶维利帕尼颗粒或分子的聚合物，可以选自聚维酮、共聚维酮、聚氧乙烯、Soluplus、羟丙甲纤维素邻苯二甲酸酯(HPMCP)、醋酸羟丙基纤维素琥珀酸酯、聚乙二醇、泊洛沙姆、聚甲基丙烯酸、聚丙烯酸乙酯、2-羟丙基-β-环糊精、羟丙甲纤维素(HPMC)、聚甲基丙烯酸酯、羟丙基纤维素、醋酸邻苯二甲酸纤维素(CAP)以及其他可药用的增溶材聚合物中的一种或两种以上的组合。
在本发明的维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体中，所述的其他添加物可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、和增塑剂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)是本领域技术人员所熟知的缓释骨架基质材料，可选自纤维素衍生物、淀粉或其衍生物、藻酸盐、丙烯酸或甲基丙烯酸衍生物、聚环氧乙烷、树胶和基于碳水化合物的聚合物，例如可选自羟丙基纤维素、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、聚氧乙烯、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。
在本发明的维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体中，活性药物维利帕尼包括维利帕尼游离碱和其可药用盐，其可药用的盐可选自维利帕尼盐酸盐、维利帕尼磷酸盐、维利帕尼硫酸盐、维利帕尼马来酸盐、维利帕尼右旋樟脑酸盐和维利帕尼苯磺酸盐等。
本发明提供的维利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维利帕尼；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；更具体而言，包含50-700重量份的维利帕尼盐化物，和10-250重量份的释放速率调节用基质聚合物；或者50-700重量份的维利帕尼共研磨混合物，和10-200重量份的释放速率调节用基质聚合物；或者50-800重量份的维利帕尼纳米晶，和0.1-250重量份的释放速率调节用基质聚合物；或者50-900重量份的维利帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物。
患者每天需要服用的维利帕尼的预期总剂量为100-1400mg，本发明提供的维利帕尼药物组合物单包装剂量(例如单个药片或胶囊)含药物活性成分维利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，即可控制维利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可提高维利帕尼的PARP酶抑制效果和肿瘤治疗效果，同时降低药物的毒副作用。
本发明提供的维利帕尼药物组合物可以为单一缓释相的缓控释制剂或既含有速释相又含有缓释相的速缓双效释放制剂。
所述的缓释相是含有药物活性成分的控释组合物。所述的控释相优先为，但不限于，选自控释片、控释小丸、片剂中的控释组合物、片剂或丸芯中的控释组合物、结合到双层片中的控释层组合物及其任意形式的组合。
所述的速释相是含有药物活性成分的速释组合物。所述的速释相优选为，但不限于，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。
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％。
本发明所提供的维利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。
本发明提供的维利帕尼药物组合物可用于制备预防或治疗肿瘤的药物，优选地，所述肿瘤选自DNA修复功能缺陷的各种类型肿瘤，特别是用于三阴性乳腺癌、非小细胞肺癌、卵巢癌、黑素瘤、脑癌等的药物，以及用于与BRCA1和BRCA2基因突变相关的肿瘤的药物。本发明提供的维利帕尼药物组合物与DNA损伤性化疗药物联用，可用于多形性成胶质细胞瘤，上皮性卵巢癌，转移脑癌的治疗。
本发明提供的维利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小时内释放小于维利帕尼总量的50％以下，优选35％以下，优选10％-30％；16小时释放维利帕尼大于总量的70％以上，优选>90％。
本发明提供的维利帕尼药物组合物，通过对释放行为和释放量的控制，控制维利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维利帕尼所获取的最大血药浓度值(C max)降低至少10-70％，血药浓度达峰时间(T max)延长30％以上，优选200-800％。通过对血药浓度、达峰时间以及药时曲线下面积的控制，实现对维利帕尼稳态血药浓度水平，游离血药浓度波动范围，PARP酶抑制性，体内安全性和给药频次的调控。
本发明提供的维利帕尼药物组合物可精确调控药物于体内的稳态血药浓度，稳态血药浓度波谷值C min,ss为0.2-8μg/mL，优选0.5-6μg/mL；稳态血药浓度波峰值C max,ss为0.8-20μg/mL，优选1-12μg/mL，可达癌细胞抑制所需血药浓度的IC 90值，且稳态血药浓度峰/谷值优选小于6，更优选小于4。每天单次和/或两次给药100mg-1400mg的剂量，可长时间维持抗肿瘤PARP酶活性抑制所需稳态血药浓度水平。本发明提供的药物组合物，可通过调控维利帕尼血药浓度范围，使维利帕尼长期维持在体内PARP酶活性抑制所需的有效浓度水平，精确地调控体内PARP酶活性，实现药物高效低毒治疗。
本发明的缓控释药物组合物可精确调控维利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，本发明提供的维利帕尼药物组合物具有如下优点：
1)可实现药物的可控释放，提供精确的体内血药浓度和长时间稳定的高效肿瘤抑制水平，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维利帕尼药物组合物性质，下文的叙述是对于本发明的详细说明，对本发明的范围不构成任何限制：
1、片剂
本发明的维利帕尼控释片剂，可以为骨架型控释片、渗透泵型控释片或基于缓释微丸的控释片。其中，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，渗透泵型控释片包括渗透泵控释片和渗透泵速缓双释片，基于缓释微丸的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.骨架型控释片
本发明提供的骨架型控释片主要由缓释相；和可选的速释相组成。
由缓释相和速释相组成的骨架片，是速缓双效释放骨架片，而仅由缓释相组成的骨架片，是普通的缓释骨架片。图1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2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50-600重量份，优选80-500重量份，更优选120-400重量分的溶出改善形式的维利帕尼；10-150重量份，优选20-120重量份，更优选30-100重量份的释放速率调节用基质聚合物，0-40重量份的稀释剂以及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。
如在前文中记载的，在本文中对于同一组合物中的同一组分而言，在出现不同数值范围时，视为公开了在所述最大范围之内的所有数值和所有可选的数值范围，优选包含了所有整数、精确到小数点后1位的小数的数值和由其组成的数值范围。该论述对于重量份也适用。例如，在上文中，溶出改善形式的维利帕尼的重量份的下限可以为50、60、70、……、或599重量份，维利帕尼的重量份的上限可以为600、590、580、……、或50.1重量份，即，维利帕尼的重量份包含了在这些下限和上限之间的任意组合，如包含了50至50.1重量份，110至590重量份，等等。在下文中，为了简要的目的，将不再对每个数值范围的上下限的可能取值做赘述。
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。
所述的其他片剂常用添加剂包括本领域技术人员所熟知的固体制剂常用的润滑剂、着色剂等的一种或者两种以上的组合。所述的润滑剂为选自硬脂酸镁、硬脂酸、硬脂富马酸钠、滑石粉和微粉硅胶中的一种或两种以上的组合。所述着色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑、二氧化钛中的一种或两种以上的组合。
所述的速释相可以包含上述溶出改善形式的维利帕尼、崩解剂、稀释剂以及其他片剂常用添加剂，或者包含维利帕尼、增溶基质聚合物和其他片剂常用添加剂。
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维利帕尼的速释相中，溶出改善形式的维利帕尼用量可以为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，其在速释相中为5-90重量份，优选10-50重量份。所述的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，其在速释相中为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，其在速释相中为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，并在速释相中为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，并在速释相中为0-13重量份。
在包含维利帕尼、增溶基质聚合物和其他片剂常用添加剂的速释相中，维利帕尼的用量可以为5-100重量份，优选10-80重量份，更优选20-60重量份。所述的增溶基质聚合物为选自聚维酮、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，其用量可以为5-300重量份，优选10-200重量份。所述其他片剂常用添加剂包括交联聚维酮、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、微晶纤维素、及可药用的表面活性剂(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，其用量可以为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，速释相中的维利帕尼约为整个速缓双效骨架片中维利帕尼总重的10-40wt％，而缓释相中的维利帕尼约为整个速缓双效骨架片中维利帕尼总重的60-90wt％。
本发明所述的具有速缓双释行为的维利帕尼控释制剂，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，更优选16小时释放90％以上；缓释相中药物活性成分的释放行为符合零级、一级、Higuchi或Ritger-Peppas释药模型，优选为零级释药。
1.2、渗透泵型控释片
本发明提供的渗透泵控释片包括单层渗透泵片、单层渗透泵速缓双释片、双层渗透泵控释片或双层渗透泵速缓双释片。
本发明提供的双层渗透泵控释片主要包含：
1)控释含药层，其由控释的含药层组合物形成，位于刚性膜壳内，毗邻释药孔；
2)推动层(也可称为助推层)，其由推动层组合物形成，位于刚性膜壳内，远离释药孔一侧；
3)可选的隔离衣层，其夹在刚性膜壳内表面与由含药层和推动层组成的片芯之间，由隔离衣组合物经干燥而成；
4)具有水分渗透性的刚性膜壳，其由控释衣包衣液经干燥而成，该膜壳一端包含一个或者多个释药孔；
5)可选的，非限制性的美学外衣；
6)可选的，非限制性的速释含药层，其由速释含药层组合物形成，位于刚性膜壳/或可选的美学外衣外。
其中，维利帕尼占渗透泵型控释片总重量的3～50wt％。
所述控释含药层组合物包括：溶出改善形式的维利帕尼；释放调节剂和其他药学常用辅料等。
具体而言，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重量分的溶出改善形式的维利帕尼；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。
所述的溶出改善形式的维利帕尼可以选自上述的维利帕尼盐化物、维利帕尼共研磨混合物、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、羟丙基纤维素、交联羧甲基纤维素钠、羟丙基纤维素、十二烷基硫酸钠中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，其在控释含药层组合物中为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，其在控释含药层组合物中为0-20重量份。所述染色剂为选自氧化铁红、氧化铁黄、氧化铁紫、氧化铁黑等中的一种或两种以上的组合，其在控释含药层组合物中为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。
所述释放速率调节用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、羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮、卡波姆、海藻酸和/或其衍生物的一种或两种以上的组合，在推动层组合物中，其用量在推动层组合物中占可以为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，在推动层组合物中，其用量为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，在推动层组合物中，其用量为0.5-30重量份，优选2-20重量份。其中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，其用量为0.3-15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和非必需的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，该美学外衣一般是非限制性的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维利帕尼、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维利帕尼、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维利帕尼；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。所述的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重量份的活性成分维利帕尼，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重量份的溶剂组成。所述的增溶基质 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，速释含药层中的维利帕尼约为整个速缓双释渗透泵片中的维利帕尼总重的10-40wt％，控释含药层中的维利帕尼约为整个速缓双释渗透泵片中的维利帕尼总重的60-90wt％。
本发明所述的维利帕尼渗透泵控释片的制备方法包括如下步骤：①溶出改善形式的维利帕尼的制备；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的制备；⑨可选的速释含药层的制备。上述的②-⑨可以采用本领域的技术人员所熟知的常规压制和包衣方法进行。
刚性膜壳外包被速释含药层的片剂为渗透泵速缓双释片，而刚性膜壳外未包被速释含药层的片剂为普通渗透泵控释片。图3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4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维利帕尼的药效，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。
1.3、基于缓释微丸的控释片
本发明另一方面提供维利帕尼的基于缓控微丸的缓控释片，所述维利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缓释微丸/速释基质所组成的速缓双效释放片。
在所述速缓双效释放片中，速释基质组成了速释相，所述缓释丸组成了缓释相；所述速释相中的维利帕尼占整个速缓双效释放片中总维利帕尼含量的10～40wt％；所述缓释相中的维利帕尼占整个速缓双效释放片中总维利帕尼含量的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，溶出改善形式的维利帕尼在速释相中为20-200重量份，优选50-150重量份；所述的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，在速释基质中为5-90重量份，优选10-50重量份。所述的稀释剂为微晶纤维素、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，在速释相中为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，在速释相中占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，可由非限制性的空白丸芯、维利帕尼盐化物(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，缓释微丸可通过包衣锅一锅包衣载药的方式制备，其中，将维利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释放速率调节用基质控释衣膜材料以构成缓释衣膜，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，将维利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缓释基质或控释衣膜材料可以为选自虫胶、邻苯二甲酸醋酸纤维素(CAP)、丙烯酸树脂(Eudragit)、乙基纤维素(EC)、卡波姆、聚丙烯聚硅氧烷、乙酸纤维素、丙酸纤维素、乙酸丙酸纤维素、聚乙烯醇、聚乙烯吡咯烷酮(PVP)、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素(HPMC)、尤特奇等中的一种或两种以上的组合；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两种以上的组合，所述的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两种以上的组合，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)中的一种或两种以上的组合。
在一个实施方式的所述缓释微丸中，空白丸芯为100-500重量份，优选200-400重量份，维利帕尼盐化物为10-100重量份，释放速调节用基质为10-300重量份，粘合剂为0-100重量份，致孔剂为0-12重量份，以及增塑剂为0-15重量份。
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、基于微片的缓控释胶囊
本发明基于微片的缓控释胶囊是由缓释微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，所制成的微片直径都较小，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。基于胶囊中维利帕尼的总重，速释相中的维利帕尼占10-40wt％；缓释相中的维利帕尼占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1.1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1.1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。
2.2、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。对于所述的速缓双释胶囊，速释微丸组成了速释相，缓释微丸则组成了缓释相；所述的速释相中的维利帕尼占整个速缓双效释放胶囊中总维利帕尼的10～40wt％；所述的缓释微丸中的维利帕尼占整个速缓双效释放胶囊中总维利帕尼的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。
附图说明
图1是骨架型速缓双效释放双层片的结构示意图。
图2是骨架型速缓双效释放包衣片的结构示意图。
图3是渗透泵型控释片的结构示意图。
图4是渗透泵型速缓双效释放片的结构示意图。
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是含有速释片和缓释片的胶囊的结构意图。
图8是实施例1骨架缓释片在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10是实施例3的速缓双效骨架片的释放曲线。
图11是实施例6、实施例7、实施例8、实施例9、实施例10、实施例11的缓控释制剂的释放曲线。
图12是对比实施例1的速释胶囊的释放曲线。
图13是对比实施例1的速释胶囊和实施例3的速缓双效骨架片的体内药时曲线图。
图14是对比实施例1的速释胶囊和实施例6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6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缓释骨架片
Figure PCTCN2017116472-appb-000002
将维利帕尼与增溶基质聚合物聚维酮K30以溶剂挥发法制备固体分散体，即将维利帕尼和聚维酮K30(BASF，德国)，同时溶于有机溶剂(乙醇/丙酮，40/60,v/v)中，减压挥发掉有机溶剂，干燥粉碎，再以处方量与缓释骨架基质聚合物羟丙基纤维素(K4M，上海卡乐康公司)以及其他辅料如共聚维酮VA64(BASF，德国)、微粉硅胶和硬脂酸镁等混合，过60目筛并通过三维混合器在30rpm下，混合30分钟，待混合均匀后，待压片用。
采用单冲压片机压片，制成缓释骨架片。
采用溶出度测定法(中国药典2010年版二部附录X C)第二法装置测定控释制剂的释放度，37℃条件下，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，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1，2，4，6，8，9，10，12h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Ⅳ A)，在269nm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，活性成分维利帕尼基本可维持恒速释放，1小时释放小于20％，6小时释放60-70％左右，10小时释放90％以上。
实施例2双层渗透泵控释片
Figure PCTCN2017116472-appb-000003
Figure PCTCN2017116472-appb-000004
维利帕尼与增溶基质聚合物共聚维酮VA64，以三维多向运动混合器混合均匀后，加入到熔体挤出机，收集挤出并放凉的固体产品后，粉碎，过60目筛，再以处方量与其他添加剂聚维酮K90和硬脂酸镁通过三维混合器在30rpm下，混合30分钟，混合均匀，待压片用。
精密称取处方量的推进层辅料(包含释放速率调节用基质聚合物如羟丙甲纤维素、卡波姆等)，混合均匀后得到助推层组合物。采用单冲压片机以直压方式，先将用上述含药层组合物轻压，再添加助推层组合物，压制成为包含有含药层和助推层的渗透泵双层片芯。压制的片芯以4％的醋酸纤维素溶液为包衣液，以LABCOATING实验型多功能高效智能包衣机包衣，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)第二法装置测定渗透泵控制试剂的释放度，37℃条件下，分别以900ml pH 1.2、4.5、6.8的缓冲液为释放介质(制备方法见实施例1)，转速为每分钟75转，依所述方法操作，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269nm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9。结果显示，双层渗透泵控释片基本不受pH影响，活性成分维利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3速缓双释骨架双层片
Figure PCTCN2017116472-appb-000005
Figure PCTCN2017116472-appb-000006
速释层：将处方量的维利帕尼、微粉硅胶和增溶基质聚合物Soluplus过60目筛并以三维混合器在30rpm下，混合30分钟，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目筛得到维利帕尼固体分散体。
将所得维利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通过三维混合器在30rpm下，混合30分钟，混合均匀后，待压片用。
缓释层：将处方量的维利帕尼、微粉硅胶和增溶基质聚合物聚维酮K30过60目筛并通过三维混合器在30rpm下，混合30分钟，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目筛得到维利帕尼固体分散体。
将所得维利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：用单冲压片机先轻轻压制含药层，再加入缓释层粉末后，压制成为硬度适宜的速缓双释双层骨架控释片。
采用溶出度测定法(中国药典2010年版二部附录X C)第二法装置测定控释制剂的释放度，37℃条件下，以pH 1.2和6.8的盐酸水溶液为释放介质，转速为每分钟75转，依法操作，经0.25，0.5，0.75，1，2，4，6，8，10，12，和13h取溶液6mL，离心，取上清液作为供试品溶液，测定释放度。
按照紫外-可见分光光度法(中国药典2010年版二部附录ⅣA)，在269nm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10。速缓双效骨架双层片实现1小时内20％左右的药物快速释放，8h左右有近70％-75％左右的药物释放，剩余药物可于12h左右释放完全。前期的速释释放行为可实现维利帕尼，于体内快速达到有效抗肿瘤PARP酶抑制所需的血药浓度水平，之后的缓释行为，则可实现维利帕尼血药浓度在该水平的长期维持，以提高抗肿瘤效果。
实施例4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 PCTCN2017116472-appb-000007
II)包隔离衣
Figure PCTCN2017116472-appb-000008
III)包缓释衣
Figure PCTCN2017116472-appb-000009
②速释丸
Figure PCTCN2017116472-appb-000010
制备方法如下：
速释丸：将盐酸维利帕尼与共聚维酮VA64，溶解或分散于95％的乙醇溶液中，配制成载药溶液，采用流化床包衣的方式，喷入处方量的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；再称取盐酸维利帕尼处方量，均匀地分散在上述包衣液中，作为载药包衣液备用。
将微晶纤维素空白丸芯加入流化床，喷入配制好的载药包衣液，进行载药，得到载药丸芯。
将隔离衣衣膜成分聚维酮(K30)溶解或分散于95％乙醇溶液中，采用流化床包衣方式，喷入到处方量的载药丸芯上，得到包隔离衣的载药丸芯。
将缓释包衣液苏丽丝的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，或者
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制剂。
实施例5含速释包衣层的缓释小丸胶囊
I)载药丸芯
Figure PCTCN2017116472-appb-000011
II)包隔离衣
Figure PCTCN2017116472-appb-000012
III)包缓释衣
Figure PCTCN2017116472-appb-000013
IV)包速释衣
Figure PCTCN2017116472-appb-000014
制备方法如下：
载药：首先，将维利帕尼与聚维酮K30，溶解或分散于95％乙醇溶液中，配制成载药溶液，采用流化床包衣的方式，喷入到处方量的空白蔗糖丸芯上，作为载药丸芯；
包隔离衣：将隔离衣膜成分共聚维酮VA64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；
包缓释衣：将缓释包衣液尤特奇NE30D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，喷入到已包覆了隔离衣的载药丸芯上，制成缓释丸。
包速释衣：将维利帕尼和粘合剂羟丙基甲基纤维素(E5)，分散于95％的乙醇溶液中，混匀，作为速释衣包衣液，采用流化床包衣的方式，喷入到缓释丸上，制成含有速释包衣层的缓释颗粒。
胶囊灌装：将上述制备完成的含有速释包衣层的缓释颗粒，按照处方量进行胶囊灌装，制备速缓双释胶囊制剂。
实施例6速缓双释双层渗透泵控释片
Figure PCTCN2017116472-appb-000015
将维利帕尼与共聚维酮过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，得到维利帕尼固体分散体。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-0.3％PEG4000溶液包控释衣层，衣膜增重10％，得到双层渗透泵控释片。
取维利帕尼固体分散体溶于乙醇-丙酮溶液中，按速释层与缓释层含药量比为3:7包衣至所得双层渗透泵片，即得速释层活性成分占30％wt、缓释层活性成分占70％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 1.2的盐酸水溶液为释放介质，转速为每分钟75转，依法操作，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269nm的波长处分别测定吸光度，测定处方片剂的释放度。
释放结果见图11。
实施例7含有速释包衣层的缓释骨架包衣片
①缓释片芯的制备
Figure PCTCN2017116472-appb-000016
②速释包衣
Figure PCTCN2017116472-appb-000017
制备方法如下：
缓释骨架包衣片的缓释片芯的制备：将处方量的维利帕尼和泊洛沙姆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目筛得到维利帕尼固体分散体。将上述制得的维利帕尼固体分散体，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6，以pH 1.2的盐酸水溶液为释放介质，释放曲线见图11。
实施例8基于缓释微丸的缓控释片
①缓释丸
I)载药丸芯
Figure PCTCN2017116472-appb-000018
Ⅱ)包隔离衣
Figure PCTCN2017116472-appb-000019
III)包缓释衣
Figure PCTCN2017116472-appb-000020
制备方法如下：
载药丸芯：将维利帕尼与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6，以pH 1.2的盐酸水溶液为释放介质，释放曲线见图11。
实施例9基于微片的缓控释胶囊
缓释微片
Figure PCTCN2017116472-appb-000021
速释微片
Figure PCTCN2017116472-appb-000022
缓释微片：将维利帕尼与Soluplus过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得维利帕尼共研磨混合物。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：将维利帕尼与Soluplus过60目筛3遍，加入球磨机研磨至平均粒径小于30μm，得维利帕尼共研磨混合物。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6，以pH 1.2的盐酸水溶液为释放介质，释放曲线见图11。
实施例10基于缓释微丸的缓控释片
称取维利帕尼苯磺酸盐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，挤出滚圆制备维利帕尼含药微丸，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。
将筛选好的维利帕尼微丸置于流化床中，配制包衣液，包衣制得维利帕尼缓释微丸。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。称取维利帕尼缓释微丸25g，含药微丸5g，微晶纤维素12g，乳糖16g，pvpK30质量百分比5％溶液12g，18目筛制粒，40℃烘箱干燥，18目筛整粒，硬脂酸0.6g，混合后压片。释放度测定方法同实施例6，以pH 1.2的盐酸水溶液为释放介质，释放曲线见图11。
实施例11单层渗透泵控释片
Figure PCTCN2017116472-appb-000023
将处方量的维拉帕尼和羟丙甲纤维素E5过60目筛并以三维混合器在30rpm下混合25分钟后，缓慢加入到已预热好的熔体挤出机，收集挤出物并粉碎过60目筛得到维拉帕尼固体分散体。将上述制得的维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6，以pH 1.2的盐酸水溶液为释放介质，释放曲线见图11。
对比实施例1明胶速释胶囊
明胶速释胶囊(参比胶囊)由含有21wt％盐酸维利帕尼、43wt％微晶纤维素、32wt％乳糖、2wt％微粉硅胶、1wt％硬脂酸镁和2％十二烷基硫酸钠等混合均匀后，直接装入0#硬胶囊所组成；其溶出度测定是采用溶出度测定法(中国药典2010年版二部附录X C)第一法装置，37℃条件下，以900mL pH 1.2的盐酸水溶液为释放介质，转速为每分钟75转，依法操作，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维利帕尼于30分钟左右释放90％以上，45分钟内基本释放完全。
实验实施例1
将对比实施例1中的维利帕尼速释胶囊和实施例3中所述的速缓双效控释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13。相对于胶囊制剂的C max(2679.9ng/mL)和AUC 0-h(9034h*ng/mL)速缓双效控释片的C max降低至904.4ng/mL，降低了约66％；AUC 0-h为10043.5h*ng/mL，变化<10％；由图13的药时曲线的结果可见，相对于速释胶囊，速缓双效骨架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，同时为最佳药效的发挥提供了更大的剂量空间。
实验实施例2
将对比实施例1的维利帕尼速释胶囊(参比胶囊)和实施例6的速缓双释双层渗透泵控释片(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。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15。
相对于胶囊制剂的C max(2509.0ng/mL)和AUC 0-h(9905.0h*ng/mL)，速缓双释双层渗透泵控释片的C max降低至955.0ng/mL，降低了约62％；AUC 0-h为11372.0h*ng/mL。速释胶囊在10h酶抑制率低于90％，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14和图15结果仍可见，相对于速释胶囊，速缓双释双层渗透泵控释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. 一种维利帕尼口服缓控释药物组合物，其包含：溶出改善形式的维利帕尼；和释放速率调节用基质聚合物，
    所述维利帕尼药物组合物的稳态血药浓度波谷值C min,ss为0.2-8μg/mL；稳态血药浓度波峰值C max,ss为0.8-20μg/mL。
  2. 根据权利要求1所述的维利帕尼口服缓控释药物组合物，其中，所述维利帕尼药物组合物的稳态血药浓度波谷值C min,ss为0.5-6μg/mL；稳态血药浓度波峰值C max,ss为1-12μg/mL，且稳态血药浓度峰/谷值优选小于6，更优选小于4。
  3. 据权利要求1或2所述的维利帕尼口服缓控释药物组合物，其中，所述维利帕尼药物组合物具有可控的释药行为，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小时内释放小于维利帕尼总量的50％，优选35％，更优选10-30％；16小时释放维利帕尼大于总量的70％，优选>90％。
  4. 根据权利要求1至3中任一项所述的维利帕尼口服缓控释药物组合物，其中
    所述溶出改善形式的维利帕尼包括：维利帕尼盐化物、维利帕尼共研磨混合物、维利帕尼纳米晶和维利帕尼固体分散体，
    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、聚氧乙烯、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，所述维利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，所述维利帕尼共研磨混合物由活性药物维利帕尼、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，维利帕尼的重量百分比为5-60wt％，优选20-40wt％，增溶用基质聚合物的重量百分比为40-95wt％，优选40-80wt％，其他添加物的重量百分比为0-15wt％，优选0.2-10wt％；
    优选地，所述维利帕尼纳米晶，由活性药物维利帕尼、增溶用基质聚合物和其他添加物组成，通过将所述成分高压均质或共沉淀法制备成纳米尺寸的颗粒而得到；所述维拉帕尼纳米晶中，基于维利帕尼纳米晶的总重，维利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0-5wt％。所述纳米晶组合物的粒径为50-1000nm；
    优选地，所述固体分散体由活性药物维利帕尼、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，维利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(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；
    优选地，所述其他添加物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。
  5. 根据权利要求1至4中任一项所述的维利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维利帕尼；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，所述维利帕尼口服缓控释药物组合物包含：
    50-700重量份的维利帕尼盐化物，和10-250重量份的释放速率调节用基质聚合物；或者
    50-700重量份的维利帕尼共研磨混合物，和10-200重量份的释放速率调节用基质聚合物；或者
    50-800重量份的维利帕尼纳米晶组合物，和0.1-250重量份的释放速率调节用基质聚合物；或者
    50-900重量份的维利帕尼固体分散体，和20-300重量份的释放速率调节用基质聚合物。
  6. 根据权利要求1至5中任一项所述的维利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；
    优选地，
    所述的缓释相是含有药物活性成分的控释组合物，为选自控释片、控释小丸、片剂中的控释组合物、片剂或丸芯中的控释组合物、结合到双层片中的控释层组合物及其任 意形式的组合；
    所述的速释相是含有药物活性成分的速释组合物，为选自速释片、速释丸、片剂中的速释组合物、包裹于控释片剂或丸芯外的速释包衣层、双层控释片中的速释层组合物及其任意形式的组合。
  7. 根据权利要求6所述的维利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1至7中任一项所述的维利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中任一项所述的维利帕尼口服缓控释药物组合物用于制备预防或治疗肿瘤的药物的用途，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BRCA基因突变的三阴性乳腺癌、非小细胞肺癌、卵巢癌、黑素瘤、脑癌，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，其中维利帕尼口服缓控释药物组合物每天需要服用的预期总量按维利帕尼计为100-1400mg，单个成品药片或胶囊中所含的药物活性成分维利帕尼的量为20mg～400mg，优选50mg～300mg。
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