CN108201534A

CN108201534A - A kind of Rui Kapabu takes orally sustained and controlled release medicament composition and application thereof

Info

Publication number: CN108201534A
Application number: CN201611170029.XA
Authority: CN
Inventors: 不公告发明人
Original assignee: Suzhou Suzhou Biological Medicine Co Ltd
Current assignee: Suzhou Suzhou Biological Medicine Co Ltd
Priority date: 2016-12-16
Filing date: 2016-12-16
Publication date: 2018-06-26
Also published as: CN110062628B; CN110062628A; WO2018108157A1

Abstract

The present invention relates to a kind of Rui Kapabu to take orally sustained and controlled release medicament composition, and it includes the dissolution Rui Kapabu of improvement form and rate of release adjusting matrix polymers.The body absorption behavior of described pharmaceutical composition, blood concentration and PARP enzyme suppression levels are controllable, with Rui Kapabu drugs carrying capacity and/or oral absorption and/or bioavilability and/or the advantage of blood concentration control and/or the control of enzyme suppression level is improved, can be used as unique preparation or with other therapy use in conjunction treating cancers.

Description

A kind of Rui Kapabu takes orally sustained and controlled release medicament composition and application thereof

Technical field

The present invention relates to Rui Kapabu field of pharmaceutical preparations, and in particular to a kind of Rui Kapabu takes orally sustained and controlled release medicament combination Object and application thereof.

Background technology

Fluoro- 1,3,4,5- tetrahydrochysene -2- of Rui Kapabu (Rucaparib), chemical name 8- [4- [(methylamino) methyl] benzene Base] -6H- pyrrolo-es [4,3,2-EF] [2] benzazepine -6- ketone, molecular formula C₁₉H₁₈FN₃O, molecular weight 323.46, tool There are following chemical constitutions：

Pfizer stops the new drug development to Rui Kapabu, and authorizes Clovis tumour company (Clovis within 2011 Oncology) new drug of the compound and market are developed；2012, the compound was as Orphan drug in US and European It is used for the research of oophoroma；2015, three line clinical applications of the drug as monotherapy were used for BRCA mutation ovaries The clinical treatment research of cancer, obtains good result, and therefore obtains the breakthrough sex therapy certification of U.S. FDA；The FDA of in August, 2016 It announces, New Drug Application of the Rucaparib as three lines treatment oophoroma of Clovis tumour company will be accepted, Rui Kapabu will As second of poly ADP transferases (PARP) inhibitor for being used for oncotherapy of FDA approval listings.

Poly ADP transferases (PARP) are the key factors in DNA excision repair pathways, and auspicious Kappa cloth can then inhibit PRAP enzymatic activitys, make DNA break it is single-stranded can not repair, genomic instability increases, and then can lead to the apoptosis of cell, especially It has stronger killing effect to there are the tumour cells of homologous recombination repair defect, and this binding mode of Rui Kapabu makes To multiple types tumour have treatment potentiality；In addition, since Rui Kapabu inhibits the specificity of damage dna repair pathways, The drug can also avoid the tumor drug resistance after chemotherapy, enhance DNA damage, strengthen the antitumor curative effect of previous chemotherapeutics.

Traditional chemotherapy of tumors pattern, due to lacking specific therapy target, antitumor drug is killing tumour cell Meanwhile human normal cell is also seriously compromised, larger toxic side effect is brought to body.And the PARP inhibitor such as Rui Kapabu It specific can then inhibit to grow along with DNA damage or the tumor cell line of homologous recombination repair defect, increase thin to tumour The toxicity and antitumor activity of born of the same parents, and lethal effect is had no to the normal histocyte of DNA repair functions, it is so far, to make Typical medicaments for neoplasm targeted therapy.Since its specificity is high, few side effects, cause in recent years more and more scientific researches and The great interest of medical personnel.

At present, Clovis tumour company is just carrying out the phosphatic intravenous formulations of Rui Kapabu and d-camphorsulfonic acid Multiple clinical researches such as the oral quick release tablet of salt, wherein phosphatic intravenous formulations entered II phase black in 2005 The Therapy study of plain knurl, the Therapy study for entering breast cancer and oophoroma in 2007, although the research starting of ejection preparation is more early, But various aspects are made slow progress, and Clovis seems to promote the new drug listing of oral preparation, the mouth of d-camphorsulfonic acid salt in emphasis Quick-release tablet is taken to the New Drug Application of the treatment of advanced ovarian cancer being mutated with BRCA, FDA approvals has been obtained and has accepted, and obtain Preferentially channel is evaluated, new drug application is also in May, 2016 submitted application.

It is found according to the result of study of Clovis tumour company, PARP inhibitor Rui Kapabu oral administration biaavailabilities are about 36%, T_maxIn 1-6 hourly variations, half-life period is about 17 hours, and after 240mg tablets are administered twice daily, blood concentration can 100% reaches expected rough concentration (2uM), plasma exposure amount presented with the increase of dosage it is linearly increasing, main 3/4 grade Toxicity includes anaemia, hemoglobin reduces and transaminase increases etc., and the dosage of II/III phases clinic is 600mgBID.

However, it is had some limitations at present in the normal oral quick-release tablet of research：1) in tablet 95% auspicious card Pabuk is discharged in 15 minutes, i.e., most drugs cause blood concentration to be dashed forward height in quickly being absorbed in the gastrointestinal tract short time, compared with Big blood concentration fluctuation causes more toxic side effect to generate；2) higher steady state blood concentration crest value also limits efficiently The further promotion of blood concentration, limits giving full play to for Rui Kapabu drug effects needed for enzyme inhibition；3) large dosage of multiple dosing Mode, the effective rate of utilization of drug is not high, and drug bioavailability is only 36%, most of drug loss, it is necessary into One step improves drug absorption；4) larger pharmaceutical oral dosage (600mg BID, 2-4 pieces are each), leads to patient's poor compliance, It is higher to also result in the cost that Key works Drug packing, storage and transport generate.

Further to improve the clinical cancer therapy curative effect of Rui Kapabu, the toxic side effect of drug is reduced, it is necessary to provide One kind can improve drug effective rate of utilization, at the same can accuracy controlling Rui Kapabu blood levels and fluctuation range excellent system Agent, the purpose of the present invention are exactly to develop a kind of Rui Kapabu pharmaceutical compositions, improve drug absorption efficiency, meanwhile, pass through control Its release behavior, the auspicious Kappa of accuracy controlling is distributed in absorption rate and soak time in gastrointestinal tract, and then blood medicine is dense in control volume Degree is horizontal and its fluctuation range, the blood concentration that can be improved and maintain internal PARP enzymes inhibition required further improve auspicious Kappa While the antitumor curative effect of cloth, the adverse reaction after medication is reduced.Another object of the present invention, which is then to provide, a kind of will control It treats what tablet or capsule size and/or quantity needed for effective dose minimize, takes the alap elegant formulations of the frequency, Improve patient's compliance.

Through patent retrieval, the formulation patent related with Rui Kapabu includes：The common mouth of Rui Kapabu d-camphorsulfonic acid salt Take quick-release tablet (US 2016051561, WO 2016028689) and Rui Kapabu phosphate and other cell drugs combination preparation (WO2006033006, EP 1793830, JP 2008513435) etc., it is specific as follows：

1) WO 2016028689A and United States Patent (USP) US 2016051561 disclose a kind of Rui Kapabu fast-release tablets for oral use Agent, active medicine Rui Kapabu gum camphor hydrochlorates in the invention, low with respect to other salt form hygroscopicity, compressibility is good, is suitable for The preparation and production of the solid tablet of dry granulation, more conducively high dose, drug dose is up to more than 45%；The auspicious card of the tablet Pabuk can in discharging more than 95% in 15 minutes, at present Clovis tumour company to the research of the ovarian cancer resistance of the tablet Into the New Drug Application stage.

2) WO 2006033006, EP 1793830 and JP 2008513435 then disclose a kind of Rui Kapabu phosphate group Solvate form and its composition is combined with other cytotoxic drugs, this group of patent disclose the phosphatic veins of Rui Kapabu Ejection preparation such as freeze-dried powder preparation, and illustrate corresponding dosage and combining form etc., at present the phosphate ejection preparation The II phases for having been enter into the oncotherapies such as breast cancer are clinical.

In terms of the patent of more than Rui Kapabu, the correlative study that sustained-release preparation is taken orally about Rui Kapabu there is no at present, To further improve the clinical efficacy of Rui Kapabu, accurate blood concentration and enzyme suppression level are provided, reduce used by tumor patients Adverse reaction after medicine improves the compliance of patient's medication, reduces storage and production cost, and the invention discloses one kind to release in vivo It lets pass as controllable Rui Kapabu pharmaceutical compositions.

Invention content

Large dosage of form of medication multiple daily often leads to the drug after taking orally, generates higher steady state blood medicine wave crest wave Dynamic and larger blood concentration fluctuation range (400mg, BID, C_min,ss<1ug/ml；C_max,ss>6ug/mL), crest value is excessively high removes Lead to the generation of the numerous side effects of Rui Kapabu quick releasing formulations, but will limit drug effect play needed for blood levels into One step is promoted.

The primary purpose of the present invention is according to the biological property of Rui Kapabu and the drug effect of clinical treatment and safety need It asks, by controlling its release behavior, the auspicious Kappa of accuracy controlling is distributed in absorption rate and soak time in gastrointestinal tract, and then controls Internal blood levels and its fluctuation range maintain internal blood concentration in the long-term steady-state of effective PARP enzymes suppression level, The antitumor curative effect of Rui Kapabu is improved, reduces the adverse reaction after medication.

It is a further object to provide a kind of tablet by needed for treatment effective dose or capsule size and/or numbers What amount minimize, the alap elegant formulations of the frequency are taken, improve patient's compliance.

The defects of present invention is for present in the current preparation of Rui Kapabu, provides a kind of Rui Kapabu oral controlled-releases medicine Compositions, the body absorption behavior of described pharmaceutical composition, blood concentration and PARP enzyme suppression levels are controllable, have and improve Rui Kapabu drugs carrying capacity and/or the control of oral absorption and/or bioavilability and/or blood concentration and/or enzyme suppression level The advantage of control, can be used as unique preparation or with other therapy combination therapies.

Rui Kapabu provided by the invention takes orally sustained and controlled release medicament composition and includes：Rui Kapabu dissolves out improvement form Rui Kapabu；With rate of release adjusting with matrix polymer (also referred to as release regulator).In addition, according to prepared dosage form, Can also include semi permeability clothing film material, barrier gown material, disintegrant, coating powder, plasticizer, pore-foaming agent, expanding material, Filler, osmotic pressure regulator (also referred to as penetration-assisting agent), lubricant, adhesive (also referred to as binder), coloring agent (are also referred to as Toner), antiplastering aid (also referred to as antitackiness agent), opacifier, the pharmacy such as diluent and/or other pharmaceutically acceptable additives it is auxiliary Material.

Active medicine Rui Kapabu in Rui Kapabu pharmaceutical compositions provided by the invention, belongs to insoluble drug, can Solubilization processing is carried out first, prepares salifie form, such as phosphate, hydrochloride, maleate, phenyl ring hydrochlorate, sulfate, camphoric acid Salt (preferably, gum camphor hydrochlorate) etc. is prepared as solubilizing composition, to improve the dissolution of drug.It is not limited to any reason By it has been recognised by the inventors that the solubilization processing is mixed by the matrix polymer for improving Rui Kapabu with that can realize drug solubility It is combined, changes the dispersion specific surface area in active agent formulation composition powder, hence improve the stripping property of drug Energy.The solubilization processing can include being co-mulled and made into, is high-pressure homogeneous, co-precipitation, solvent volatilization or melt extrusion etc..

In the present invention, Rui Kapabu includes Rui Kapabu free alkalis and its officinal salt, and pharmaceutical salt may be selected from salt Hydrochlorate, phosphate, sulfate, gum camphor hydrochlorate and benzene sulfonate etc..In the description of the present invention, it is special if without special description Different to describe such as Rui Kapabu hydrochlorides, Rui Kapabu maleates, then " Rui Kapabu " refers to that Rui Kapabu dissociates Alkali.

The Rui Kapabu of dissolution improvement form of the present invention includes：Rui Kapabu salt forms, Rui Kapabu are co-mulled and made into Mixture, Rui Kapabu be nanocrystalline and Rui Kapabu solid dispersions, preferably Rui Kapabu salt (such as Rui Kapabu phosphate and auspicious Kappa cloth gum camphor hydrochlorate etc.) and solid dispersions.The auspicious Kappa cloth of the salt form can conspicuousness improve its water solubility, The Rui Kapabu bulk pharmaceutical chemicals of salt form can be directly used for the preparation of sustained-release preparation；It is the Rui Kapabu co-milled mixtures, auspicious The nanocrystalline dissolving dissolving out capability that can improve controlled release form China and Sweden Kappa cloth with Rui Kapabu solid dispersions of Kappa cloth, carries simultaneously The absorption of high drug and bioavilability.

Rui Kapabu co-milled mixtures in the present invention by active medicine Rui Kapabu, solubilising matrix polymer and its His additive composition, by the way that the ingredient is co-mulled and made into prepare, drug powder grain size be generally fully ground to 100 microns with Under.Any theory is not limited to, it is described to be co-mulled and made into the dispersion specific surface area that increase drug in solid pharmaceutical preparation powder, thus change It has been apt to the dissolving out capability of drug.

The co-milled mixtures, the gross weight based on co-milled mixtures, the weight percent of Rui Kapabu is 5%- 60wt%, preferably 20%-40wt%, the weight percent of solubilized matrix polymer is 40%-95wt%, preferably 40%- 80wt%, the weight percent of other additives is 0%-15wt%, preferably 0.2%-10wt%.The total amount of above-mentioned each component is 100wt%.

Herein for the same component in same composition, when there are different numberical ranges, it is considered as disclosure All numerical value and all optional numberical ranges within the maximum magnitude, have preferably comprised all integers, have been accurate to The numerical value of the decimal of 1 and the numberical range being made from it after decimal point.For example, hereinbefore, the weight percent of Rui Kapabu The lower limit of ratio can be 5wt%, 6wt%, 7wt% ... or the upper limit of the weight percent of 59.9wt%, Rui Kapabu can Think 60wt%, 59wt%, 58wt% ... or 5.1wt%, that is, the weight percent of Rui Kapabu contains in these lower Limit the arbitrary combination between the upper limit, such as contain 5wt% to 6wt%, 59wt% to 60wt%, for another example, above other The weight percent of additive contains 0.1wt% to 12.5wt%, etc..It hereinafter, for brevity, will no longer Detailed repeat is done to the possibility value of the bound of each numberical range.

Rui Kapabu in the present invention it is nanocrystalline by active medicine Rui Kapabu, solubilising matrix polymer and/or other Additive forms, by by the ingredient is high-pressure homogeneous or coprecipitation is prepared into the particle of nano-scale and obtains.The height Pressure homogeneous method operates as follows：It will be prepared after high speed shear with matrix polymer aqueous solution by active medicine Rui Kapabu and solubilising Coarse-grain suspension, be added in high pressure homogenizer, recycle it is high-pressure homogeneous repeatedly, until the crystal grain prepared reaches 1000nm Hereinafter, freeze-drying sample, prepares homodisperse Rui Kapabu nanometer crystal powders.The coprecipitation operates as follows：Active drug After object Rui Kapabu elder generations are with a small amount of organic solvent such as acetone solution, it is added rapidly to largely dissolved with the aqueous solution of matrix polymer In, and Probe Ultrasonic Searching high frequency ultrasound (power reaches more than 100w) is utilized, to ensure the formation of active medicine nucleus and uniformly disperse, Nanocrystal solution until forming stable dispersion, is lyophilized sample, prepares homodisperse Rui Kapabu nanometer crystal powders.It is logical Crossing preparation becomes nanocrystalline, can reduce dispersion particle diameters of the active medicine Rui Kapabu in solid powder, significantly improve activity The specific surface area of drug hence improves the dissolving out capability of drug.Be not limited to any theory, it is described it is nanocrystalline can increase it is auspicious Dispersion specific surface area of the Kappa cloth in solid pharmaceutical preparation composition powder hence improves the dissolving out capability of drug.

During the Rui Kapabu is nanocrystalline, based on the nanocrystalline gross weights of Rui Kapabu, the weight percent of Rui Kapabu is 10%-99wt%, preferably 20%-50wt%；The weight percent of solubilising matrix polymer is 1-75%, preferably 1-65%, The weight percent of other additives is 0-10wt%, preferably 0-5%wt%.The total amount of above-mentioned each component is 100wt%.It is described The grain size of nanometer crystal composite is 50-1000nm.

Solid dispersions in the present invention are by active medicine Rui Kapabu, solubilising matrix polymer and other additive groups Into.In solid dispersions, the gross weight based on solid dispersions, the weight percent of Rui Kapabu is 5%-50wt%, preferably 20%-40wt%, the weight percent of solubilized matrix polymer is 45%-95wt%, preferably 50-80wt%, other additions The weight percent of object is 0-12wt%, preferably 0-10wt%.The total amount of above-mentioned each component is 100wt%.The solid dispersion Body can be manufactured by solvent evaporation method or melt extrusion method.The solvent evaporation method carries out as follows：By drug Rui Kapabu, solubilising It is dissolved to volatilizable organic solvent simultaneously with matrix polymer and/or other additives or organic in the mixed solvent, decompression are waved Organic solvent is sent out, the transparent intermediate product of gained is transferred to vacuum drying chamber drying, you can the dispersion of Rui Kapabu solids is made Body.The melt extrusion method carries out as follows：Will uniformly after drug Rui Kapabu, solubilising matrix polymer and/or other add Add object powder, be directly slowly added into melt extrusion device, collect melt extrusion object.Any theory is not limited to, it is described solid Body dispersion can make the solid dispersity of active medicine Rui Kapabu presentation upper state, to be molecularly dispersed in preparation group In the solid powder for closing object, the specific surface area of drug is improved to the maximum extent, hence improves the dissolving out capability of drug.

Rui Kapabu co-milled mixtures in the present invention, Rui Kapabu is nanocrystalline and Rui Kapabu solid dispersions in, Solubilising refers to can be used in stablizing with matrix polymer and/or the polymer of solubilising Rui Kapabu particles or molecule, Ke Yiwei Selected from povidone, copolyvidone, polyoxyethylene, Soluplus, hypromellose phthalate (HPMCP), acetic acid hydroxyl Propyl cellulose succinate, polyethylene glycol, poloxamer, polymethylacrylic acid, polyethyl acrylate, 1:12- hydroxy propyl-Betas- Cyclodextrin, hydroxypropyl methylcellulose (HPMC), polymethacrylates, hydroxypropyl cellulose, cellulose acetate phthalate (CAP) and the combination of one or more of the available solubilized polymer of other pharmacy.

Rui Kapabu co-milled mixtures in the present invention, Rui Kapabu is nanocrystalline and Rui Kapabu solid dispersions in, Other described additives can be selected from pharmaceutically common medicinal solubilizing surfactant (such as polyethylene glycol stearate, ten Sodium dialkyl sulfate etc.), the combination of lubricant, superfine silica gel powder, one or more of plasticizer etc..

Rate of release adjusting matrix polymer in the present invention can be sustained release bone well-known to those skilled in the art Frame host material may be, for example, selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, ethyl One or more kinds of combinations of cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, carbomer, preferably To be selected from one or more kinds of combinations of hydroxypropyl cellulose, sodium alginate, hydroxypropyl methylcellulose and carbomer.

Rui Kapabu provided by the invention takes orally the Rui Kapabu that sustained and controlled release medicament composition includes 50-800 parts by weight and is total to The rate of release adjusting matrix polymer of milled mixtures and 10-200 parts by weight；Or the auspicious Kappa of 50-800 parts by weight Cloth is nanocrystalline and the rate of release adjusting matrix polymer of 0.1-250 parts by weight；Or the Rui Kapabu of 50-900 parts by weight The rate of release adjusting matrix polymer of solid dispersions and 20-300 parts by weight.

It is 100-1400mg that patient needs the expection accumulated dose of Rui Kapabu taken daily.Single finished product tablet or capsule In the amount of contained active constituents of medicine Rui Kapabu be not particularly limited, can select as needed, such as can be 50mg ~300mg.It is preferred that only 1 the composition need to be taken daily, you can absorption rate and time in control Rui Kapabu bodies maintain Internal blood levels inhibit required effective range in PARP enzymes.The pharmaceutical composition of the present invention can improve Rui Kapabu PARP enzymes inhibition and oncotherapy effect, while reduce the toxic side effect of drug.

Rui Kapabu pharmaceutical compositions provided by the invention can be the sustained-release preparation of single sustained release phase or both contain speed It releases the speed mutually again containing sustained release phase and delays economic benefits and social benefits delivery formulations.

The sustained release is mutually the controlled release composition containing active constituents of medicine.The controlled release is mutually preferably selected from, but It is not limited to, controlled release tablet, controlled release piller, the controlled release composition in tablet, tablet or controlled release composition in capsule core are attached to bilayer Controlled release layer composition and its any form of combination in piece.

The quick-release is mutually the immediate release composition containing active constituents of medicine.The quick-release is mutually preferably selected from, but It is not limited to, it is fast-release tablet, quick-release ball, the immediate release composition in tablet, the quick-release coatings being wrapped in outside Dospan or capsule core, double Quick-release layer composition and its any form of combination in layer controlled release tablet.

The speed delays economic benefits and social benefits controlled release preparation while comprising sustained release phase and quick-release phase.In the slow economic benefits and social benefits controlled release preparation of the speed In, the active constituents of medicine in quick-release phase accounts for the 10-50wt% of active constituents of medicine total amount, preferably 20-40wt%；It is sustained phase In active constituents of medicine account for the 50-90wt%, preferably 60-80wt% of active constituents of medicine total amount.

Rui Kapabu pharmaceutical compositions provided by the present invention can be tablet or capsule, be preferably selected from osmotic pump controlled-releasing Piece, infiltration pump speed delay it is double release piece, matrix sustained release tablet, matrix type speed delays economic benefits and social benefits double-layer tablets, and matrix type speed delays economic benefits and social benefits coating tablet, base In the sustained release tablets of sustained release pellet, the speed based on sustained release pellet and fast release micropill delays double-effect tablet, the glue containing matrix type sustained release pellet Capsule, the capsule containing sustained release pellets, the capsule of the sustained release pellet containing quick-release coating delay containing fast release micropill and matrix type The speed for releasing pellet delays double-release capsule, the speed containing fast release micropill and sustained release pellets delays double-release capsule, is sustained containing matrix type The capsule of microplate, the matrix type containing quick-release coating are sustained the capsule of microplate and contain quick-release microplate and matrix type sustained release microplate Capsule.

Rui Kapabu pharmaceutical compositions provided by the invention can be used for the various types tumour with DNA repair function defects Clinical treatment, particularly for BRCA gene mutations relevant two or more combination cancers such as oophoroma, gastric cancer, mammary gland The treatment of cancer etc. and for the treatment with the relevant tumour of BRCA1 and BRCA2 gene mutations.

Rui Kapabu pharmaceutical compositions provided by the invention have controllable drug release behavior, in predetermined time period, Meet in the dissolution medium of sink conditions, release behavior and burst size are controllable.When using Chinese Pharmacopoeia dissolution method the Two subtraction units, when carrying out release behavior measure in the buffer solution that pH value is 1.2-7.8 under the conditions of 37 DEG C, auspicious Kappa in 1 hour The burst size of cloth is less than the 40% of Rui Kapabu total amounts, preferably 10%-30%；The Rui Kapabu amounts of release in 6-8 hours are auspicious card The 40-85% of Pabuk total amount, preferably 50%-70%；The amount of 12-16 hours release Rui Kapabu is more than Rui Kapabu total amounts 80%, preferably>90%；

Rui Kapabu pharmaceutical compositions according to the present invention, release testing result in vitro have following feature:

Table 1

Time (h)	% releases
		1	<40
2	10-50
		4	22-60
6	45-75
		8	55-85
12	>70
		16	>90%

Rui Kapabu pharmaceutical compositions provided by the invention, it is controllable auspicious by the control to release behavior and burst size Kappa is distributed in absorption rate and soak time in gastrointestinal tract, and it is small that the auspicious Kappa of the 10-50% in the pharmaceutical composition is distributed in 1-6 When interior absorption, 90% auspicious Kappa is distributed in 12-16 hours and absorbs in composition components.

Compared with quick-release tablet, the Rui Kapabu institutes under Rui Kapabu pharmaceutical compositions same dose provided by the present invention Maximum plasma concentration value (the C of acquisition_max) reduce at least 10%-70%, peak reaching time of blood concentration (T_max) extend at least 150% (preferably 200%-600%).By the control to blood concentration, peak time and area under the drug-time curve, realize to auspicious card Pabuk steady state plasma concentration is horizontal, free drug level fluctuation range, and PARP enzymes inhibit, the tune of internal safety and dosage rate Control.

Rui Kapabu pharmaceutical compositions provided by the present invention can accuracy controlling drug for internal steady state plasma concentration, Steady state plasma concentration valley value 1uM<C_min,ss<10uM, preferably 2ug/mL<C_min,ss<9ug/mL；Steady state plasma concentration crest value is 5uM<C_max,ss<25uM, preferably 6uM<C_max,ss<20uM.The sustained and controlled release medicament composition of the present invention can accuracy controlling Rui Kapabu Blood levels and fluctuation range are conducive to the enzyme needed for effective antitumor and inhibit blood levels (such as 50% or 90% The blood levels of enzyme inhibition rate) long-term maintenance, while reduce blood concentration fluctuation range, and then improving tumour cell PARP enzyme inhibition rates and antitumor curative effect while, reduce tumor patient medication after adverse reaction, increase patient medication Compliance.

Compared with common quick release preparation, Rui Kapabu pharmaceutical compositions provided by the present invention have the following advantages that：

1) controlled release and the absorption of drug can be achieved, the efficient of accurate blood concentration in vivo and long-time stable is provided PARP enzyme suppression levels persistently play inhibiting cancer drug effect；

2) drug absorption rate is controllable, and blood concentration range is controllable, and the fluctuation of blood concentration is small, reduces patient medication Adverse reaction；

3) can single-dose, need to only take daily primary, reduce the complicated processes of ordinary preparation medication, it is more convenient to face Bed medication；

4) due to controllable blood concentration and its fluctuation range, security window is larger, in treatment clinical course, dosage and gives Prescription case can flexible modulation, can more further provide for dosage, improve drug effect；

5) tablet needed for dose therapeutically effective or capsule size and/or quantity minimize, and improve patient's compliance Meanwhile facilitate production, storage and transport, improve commercial value；

Preferably to illustrate Rui Kapabu pharmaceutical compositions property provided by the invention, description below is for the present invention Detailed description, the scope of the present invention is not limited in any way.

1st, tablet

The Rui Kapabu slow-release tablet agent of the present invention, can be matrix type controlled release tablet, osmotic pump type controlled release tablets or based on slow Release the slow-release tablet of pellet.Wherein, matrix type controlled release tablet includes matrix sustained release tablet, matrix type speed delays economic benefits and social benefits double-layer tablets and skeleton Type speed delays economic benefits and social benefits coating tablet etc., osmotic pump type controlled release tablets include osmotic pump controlled release tablet and infiltration pump speed delay it is double release piece, based on sustained release The slow-release tablet of pellet includes the sustained release tablets based on sustained release pellet and the speed based on sustained release pellet and fast release micropill delays double-effect tablet.With The upper slow-release tablet specifically can realize drug release behavior of the present invention in the following manner.

1.1st, matrix type controlled release tablet

Delay the matrix tablet of economic benefits and social benefits release behavior the present invention provides Rui Kapabu controlled release matrix tablets and/or with speed.

Controlled release matrix tablet provided by the invention is mainly by sustained release phase and optional quick-release phase composition.

It is the slow economic benefits and social benefits release matrix tablet of speed by containing sustained release mutually with the double-layer tablets of quick-release phase composition, and only by sustained release phase group Into single-layer sheet, be common sustained-release matrix tablets.Fig. 1 and Fig. 2 respectively illustrates skeleton according to one embodiment of the present invention Type speed delays the structure diagram of economic benefits and social benefits release double-layer tablets and matrix type speed delays the structure diagram of economic benefits and social benefits release coating tablet.

The sustained release is mutually comprising 100-900 parts by weight, preferred 150-700 parts by weight, more preferable 200-600 total amounts part it is upper The Rui Kapabu of dissolution improvement form is stated, the rate of release adjusting of 10-300 parts by weight, preferably 30-150 parts by weight is gathered with matrix Other tablet typical additives of object, 0-50 parts by weight diluent and 0.2-30 parts by weight, preferably 1-30 parts by weight are closed, it will be each After component is sufficiently mixed, prepared by conventional method tabletting well-known to those skilled in the art.

As recorded above, herein for the same component in same composition, there are different numbers When being worth range, it is considered as all numerical value and all optional numberical ranges disclosed within the maximum magnitude, preferably comprises All integers are accurate to the numerical value of the decimal of 1 and the numberical range being made from it after decimal point.The discussion is for parts by weight It is also suitable.For example, hereinbefore, the lower limit that dissolves out the parts by weight of the Rui Kapabu of improvement form can be 100,110, 120th ... or 899 parts by weight, the upper limit for dissolving out the parts by weight of the Rui Kapabu of improvement form can be 900,890, 880th ... or 100.1 parts by weight, that is, the parts by weight of Rui Kapabu contain arbitrary group between these lower and upper limits It closes, such as contains 100 to 100.1 parts by weight, 110 to 890 parts by weight, etc..Hereinafter, for brevity, will not The possibility value of the bound of each numberical range is repeated again.

The rate of release adjusting matrix polymer can be selected from polyoxyethylene, hydroxypropyl cellulose, hypromellose Element, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, card The combination of one or more of wave nurse；It is preferably selected from hydroxypropyl cellulose, sodium alginate, hydroxypropyl methylcellulose and card The combination of one or more of wave nurse.

The diluent is selected from microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbierite, sucrose, starch, carboxylic The combination of one or more of methyl starch sodium.

Other described tablet typical additives, including the common lubrication of solid pharmaceutical preparation well-known to those skilled in the art One or more kinds of combinations of agent, colorant etc..The lubricant is selected from magnesium stearate, stearic acid, stearic rich horse The combination of one or more of sour sodium, talcum powder and superfine silica gel powder, the colorant are selected from iron oxide red, iron oxide The combination of one or more of Huang, iron oxide purple, iron oxide black, titanium dioxide.

The quick-release, which can mutually include above-mentioned dissolution, improves Rui Kapabu, disintegrant, diluent and other pieces of form Agent typical additives or comprising Rui Kapabu, solubilized matrix polymer and tablet often with other additives.

After each ingredient can be mutually sufficiently mixed by the quick-release, pass through conventional method pressure well-known to those skilled in the art Piece is prepared into release layer or by each ingredient while after dissolving, and outside coating to sustained release phase, drying forms quick-release clothing film.

In the quick-release phase of the Rui Kapabu comprising dissolution improvement form, the Rui Kapabu dosages for dissolving out improvement form can be with For 20-600 parts by weight, preferably 30-400 parts by weight, more preferable 50-250 parts by weight.The disintegrant is selected from the poly- dimension of crosslinking Ketone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross linked polyvinyl pyrrolidone, croscarmellose sodium and its The combination of his pharmaceutically one or more of common disintegrant, dosage can be 5-90 parts by weight, preferably 10-50 weights Measure part.The diluent is selected from microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbierite, sucrose, starch, carboxylic first The combination of one or more of base sodium starch, dosage can be 5-200 parts by weight, preferably 10-150 parts by weight.It is described Tablet is often with other additives, including in the common lubricant of solid pharmaceutical preparation well-known to those skilled in the art, colorant One or more kinds of combinations, dosage can be 0.2-30 parts by weight, preferably 1-30 parts by weight.The lubricant is choosing From the combination of one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica gel powder, dosage Can be 0.1-20 parts by weight, the colorant is selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide The combination of one or more of titanium, dosage can be 0-13 parts by weight.

In the quick-release phase comprising Rui Kapabu, solubilized matrix polymer and other tablet typical additives, Rui Kapabu Dosage can be 5-100 parts by weight, preferably 10-80 parts by weight, more preferable 20-60 parts by weight.It is described solubilising matrix polymer be Selected from povidone, copolyvidone, Soluplus, hypromellose phthalate (HPCP), polyethylene glycol, Bo Luosha The combination of one or more of nurse, hydroxypropyl methylcellulose (HPMC) and other materials, dosage can be 5-300 weight Part, preferably 20-200 parts by weight, more preferable 30-120 parts by weight.Other described tablet typical additives include crospovidone, Microcrystalline cellulose and pharmaceutical surfactant (such as lauryl sodium sulfate), mannitol, lubricant (such as magnesium stearate) Fast-release tablet typical additives well known to the skilled artisan in the art, dosage can be 0.1-150 parts by weight, preferably 0.5-100 Parts by weight.

In matrix type speed delays economic benefits and social benefits releasing piece, slow pair of the about entire speed of Rui Kapabu in quick-release phase is released in matrix tablet The 10-40wt% of Rui Kapabu gross weights, and it is about the slow double auspicious Kappas released in matrix tablet of entire speed to be sustained the Rui Kapabu in phase The 60-90wt% of cloth gross weight.

It is of the present invention that there are the slow double Rui Kapabu controlled release preparations for releasing behavior of speed, which is characterized in that the quick-release Active constituents of medicine in phase, according to the requirement of 2015 editions drug release determination methods of Chinese Pharmacopoeia, in the release for meeting sink conditions In medium, the active constituents of medicine being assigned in quick-release phase of preferably greater than 90wt% discharged in 2 hours, had in more preferable 1h The active constituents of medicine being assigned in quick-release phase release more than 90wt%；The sustained release phase pharmaceutical active ingredient release The time of more than 90wt% is preferably 10-16 hours；Sustained release phase pharmaceutical active ingredient release behavior meet zero level, level-one, Higuchi or Ritger-Peppas drug release models, preferably zero-order release.

1.2 osmotic pump type controlled release tablets

Osmotic pump controlled release tablet provided by the invention can be double-layer osmotic pump controlled-release tablet or double-layer osmotic pump speed delays and double releases piece. Fig. 3 and Fig. 4 respectively illustrates osmotic pump controlled release tablet according to one embodiment of the present invention and osmotic pump type speed delays economic benefits and social benefits release The structure diagram of piece.

Osmotic pump controlled release tablet provided by the invention mainly includes：

1) controlled release medicated layer：It is formed by controlled release drug containing layer composition, in rigid putamina, adjoins release hole；

2) push layer (alternatively referred to as boosting layer)：It is formed by promotion layer composition, in rigid putamina, far from drug release Hole side；

3) optional barrier layer, be clipped in rigid putamina inner surface and the label that is made of medicated layer and push layer it Between, it is formed by barrier gown composition through drying；

4) there is the rigid putamina of moisture permeable, formed by controlled release clothing coating solution through drying, which includes One or more release hole；

5) optionally, unrestricted aesthstic coat；

6) optionally, unrestricted quick-release medicated layer is formed by quick-release drug containing layer composition, positioned at rigid putamina/ Or outside optional aesthstic coat.Wherein, the gross weight based on osmotic pump controlled release tablet, Rui Kapabu account for osmotic pump controlled release tablet total weight 3-50wt%.

Wherein, the gross weight based on osmotic pump controlled release tablet, Rui Kapabu account for the 3-50wt% of osmotic pump controlled release tablet total weight.

The controlled release drug containing layer composition includes：50-600 parts by weight, preferably 80-500 parts by weight, more preferable 120-400 The Rui Kapabu of the dissolution improvement form of parts by weight；10-150 parts by weight, preferably 20-120 parts by weight, more preferable 30-100 weight The release regulator and 0-40 parts by weight, other pharmacy of preferably 0-30 parts by weight of part often use auxiliary material.

The Rui Kapabu of the dissolution improvement form can be selected from above-mentioned Rui Kapabu salts, and Rui Kapabu is co-mulled and made into Mixture, nanocrystalline or solid dispersions, preferably Rui Kapabu salts or Rui Kapabu solid dispersions.

The release regulator can be selected from povidone, copolyvidone, polyethylene oxide, carbomer, hypromellose In element, croscarmellose sodium, hydroxypropyl cellulose, one or more kinds of combinations of lauryl sodium sulfate.

Other pharmacy of the controlled release drug containing layer composition are often common without limitation in pharmaceutical tablets with auxiliary material Penetration-assisting agent, lubricant and colorant etc., dosage are the conventional selection in this field.The penetration-assisting agent be selected from sodium chloride, One or more kinds of combinations of lactose, mannitol, glucose, sucrose, fructose, preferably sodium chloride, can be 0-20 Parts by weight.The lubricant is to be hung selected from sodium stearyl fumarate, magnesium stearate, superfine silica gel powder, talcum powder, polyethylene glycols and the moon The combination of one or more of alcohol magnesium sulfate can be 0-20 parts by weight.The coloring agent be selected from iron oxide red, The combination of one or more of iron oxide yellow, iron oxide purple, iron oxide black etc. can be 0-10 parts by weight.

Generally comprised in the promotion layer composition rate of release adjusting promote osmopolymer, osmotic pressure accelerating agent and its His auxiliary material.

The rate of release adjusting rush osmopolymer belongs to high molecular polymer, in an aqueous medium, can inhale It receives moisture to be swollen, pushes the release of medicated layer drug.It can be ability that the rate of release adjusting, which promotees osmopolymer, Material known to field technique personnel, including being selected from polyoxyethylene, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, crosslinking carboxylic Sodium carboxymethylcellulose pyce, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl Base cellulose, croscarmellose sodium, crospovidone, copolyvidone, carbomer, alginic acid and/or its derivative One or more kinds of combinations, dosage can be 10-300 parts by weight, preferably 20-250 parts by weight, and more preferable 50-180 is heavy Measure part.

The osmotic pressure accelerating agent be selected from sodium chloride, lactose, mannitol, glucose, sucrose, fructose one or two Above combination, preferably sodium chloride, dosage can be 20-150 parts by weight, preferably 25-100 parts by weight.

Other auxiliary materials in the promotion layer composition include lubricant and colorant etc. without limitation, and dosage can be with For 0.5-30 parts by weight, preferably 2-20 parts by weight.The lubricant is one kind in sodium stearyl fumarate and odium stearate Or two or more combinations, dosage can be 0.2-15 parts by weight.The colorant be selected from iron oxide black, iron oxide red and One or more kinds of combinations of iron oxide yellow, dosage can be 0.5-15 parts by weight.

The controlled release medicated layer and push layer collectively form the label of osmotic pump controlled release tablet.Gross weight based on label, controlled release Medicated layer accounts for 40-80wt%, and push layer accounts for 20-60wt%.

The barrier layer can be sprayed on label by barrier gown coating solution and be formed through drying.The barrier gown Coating solution generally comprises barrier gown material and solvent.The barrier gown material is selected from hydroxypropyl methyl cellulose, povidone, is total to The combination of povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol, stearic one or more, but it is unlimited In these.The solvent includes one or more kinds of combinations of ethyl alcohol, water, acetone, isopropanol, but is not limited to these.Every Thickness from clothing can influence the release of pharmaceutical preparation, can be controlled by spraying dosage, it is however generally that, isolation clothing film relative to Label weightening 0-10wt%.

The rigidity putamina is alternatively referred to as controlled release clothing layer, is to be sprayed to by controlled release clothing coating solution by medicated layer and push layer shape Into label on through drying form, the rigid putamina generally relative to label increase weight 3-20wt%, preferably 5-15wt%.

The controlled release clothing coating solution includes the semi permeability clothing film material of 4-40 parts by weight, preferably 10-30 parts by weight, The plasticizer of 0-20 parts by weight, the pore-foaming agent of 0-20 parts by weight and 50-1000 parts by weight, preferably 200-800 parts by weight is molten Agent.

The semi permeability clothing film material be selected from cellulose acetate, ethyl cellulose, acrylic resin one kind or Two or more combinations.

The plasticizer is selected from Methyl Benzene-o-dicarboxylate, ethyl phthalate, dibutyl sebacate, lemon triethylenetetraminehexaacetic acid One or more kinds of combinations of ester, tributyl citrate, citroflex A-4, glycerol acetate, castor oil.

The pore-foaming agent be selected from glycerine, povidone, copolyvidone, propylene glycol, polyethylene glycol, water-soluble inorganic salt one Kind or two or more combinations.

The solvent is selected from one or more kinds of combinations of acetone, water, ethyl alcohol, isopropanol, dichloromethane, methanol.

The putamina contains one or more release holes, can be prepared and released by way of machine drilling or laser boring Medicine hole.Release hole can have any geometry character, such as round, ellipse, square, triangle, average pore size scope 0.3 ~1.2mm.

The aesthetics coat is sprayed on label by aesthstic coat coating solution and is formed through drying, can add packet without limitation One layer of aesthstic coat, the aesthetics coat usually without limitation plus are wrapped to general dual layer osmotic pump tablet.For with quick-release phase The speed of coating delays economic benefits and social benefits osmotic pump tablet and is then seldom applied to aesthstic coat.The aesthstic coat can improve the appearance of preparation, To increase the compliance of patient's medication, while provide colour code.The aesthetics coat coating solution is the conventional choosing in this field Select, including Opadry well known to the skilled artisan in the art and other can form the coating powder of the aesthstic coat. In addition, aesthstic coat coating solution may also include it is a kind of or several in colorant, plasticizer, opacifier, antitackiness agent, solvent Kind.The aesthstic coat is usually relative to label weightening 0-10wt%.

When there are during quick-release medicated layer, osmotic pump controlled release tablet is that slow pair of speed releases osmotic pump tablet.The quick-release medicated layer can It is sprayed on label by quick-release drug containing layer composition and is formed through drying.The quick-release drug containing layer composition includes：10-80 weight The solubilized matrix polymers compositions of active constituent Rui Kapabu, the 10-100 parts by weight of part, other pharmacy of 0-30 parts by weight are normal With auxiliary material and the solvent of 100-2000 parts by weight.The solubilising matrix polymers compositions be selected from povidone, copolyvidone, Soluplus, hypromellose phthalate (HPMCP), polyethylene glycol, poloxamer, polymethylacrylic acid, poly- third The group of one or more of olefin(e) acid ethyl ester, hydroxypropyl methylcellulose (HPMC), polymethacrylates, hydroxypropyl cellulose It closes.Other described pharmacy often include crospovidone, microcrystalline cellulose, pharmaceutical surfactant (such as 12 with auxiliary material Sodium alkyl sulfate) etc. fast-release tablet typical additives well known to the skilled artisan in the art；The solvent includes ethyl alcohol, acetone With the combination of one or more of water.

For speed slow economic benefits and social benefits release osmotic pump tablet, the about entire speed of Rui Kapabu in quick-release medicated layer is slow double to release osmotic pumps The 10-40wt% of Rui Kapabu gross weights in piece, the about entire speed of Rui Kapabu in controlled release medicated layer is slow double to release osmotic pump tablet In Rui Kapabu gross weights 60-90wt%.

The preparation method of Rui Kapabu osmotic pump controlled release tablets includes the following steps：1. dissolve out the Rui Kapabu of improvement form It prepares；2. the preparation of medicated layer；3. the preparation of promoting layer；4. the preparation of double-layer tablets；5. the system of optional double-layer tablets isolation clothing film It is standby；6. the preparation of clothing film；7. osmotic pump tablet clothing film punches；8. the optional aesthstic coat layer of packet；9. optional quick-release Medicated layer.It is above-mentioned 2.-conventional compacting well known to the skilled artisan in the art 9. may be used and coating method carries out.

The tablet of rigid putamina expoeridium quick-release medicated layer for infiltration pump speed delay it is double release piece, and be not coated with speed outside rigid putamina The tablet for releasing medicated layer is common permeable pump controlled-releasing tablet.

The slow double designs for releasing piece of speed can preferably play the drug effect of Rui Kapabu, because the design of quick-release phase ensures primary drugs Discharge rapidly, meet drug be rapidly reached effective PARP enzymes inhibit needed for blood levels, quick acting, and be sustained phase Design can ensure the steady release of later stage active constituent, it is ensured that effective enzyme inhibit needed for blood concentration long-time dimension It holds, and then keeps inhibition of enzyme activity, improve curative effect, while reduce the toxicity that blood concentration larger fluctuation is brought.

1.3. the controlled release tablet based on sustained release pellet

Another aspect of the present invention provides the slow-release tablet based on slow control pellet of Rui Kapabu.The Rui Kapabu based on The slow-release tablet of slow control pellet, can be the sustained release tablets based on sustained release pellet and the speed based on quick-release matrix/sustained release pellet delay it is double Imitate releasing piece.

In the slow economic benefits and social benefits releasing piece of the speed, quick-release matrix constitutes quick-release phase, and sustained release ball constitutes sustained release phase.Entire In the slow economic benefits and social benefits releasing piece of speed, the Rui Kapabu in the quick-release phase accounts for the 5-40wt% of Rui Kapabu total amounts；In the sustained release ball Rui Kapabu account for the 60-95wt% of Rui Kapabu total amounts.

The quick-release matrix may include above-mentioned dissolution improve the active constituents of medicine of form, disintegrant, diluent and its His tablet typical additives.

In the quick-release matrix of the active constituents of medicine including dissolving out improvement form, the Rui Kapabu of dissolution improvement form is used Amount can be 20-200 parts by weight, preferably 50-150 parts by weight.The disintegrant is selected from crospovidone, carboxymethyl starch Sodium, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, croscarmellose sodium and other are pharmaceutically common The combination of one or more of disintegrant, dosage can be 5-200 parts by weight, and preferably 10-100, more preferable 20-80 are heavy Measure part.The diluent is selected from microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbierite, sucrose, starch, carboxylic first The combination of one or more of base sodium starch, dosage can be 5-200 parts by weight, preferably 10-150 parts by weight.It is described Other tablet typical additives, including in the common lubricant of solid pharmaceutical preparation well-known to those skilled in the art, colorant One or more kinds of combinations, dosage can be 0.2-30 parts by weight, preferably 1-30 parts by weight.The lubricant is choosing From the combination of one or more of magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica gel powder, dosage Can be 0.1-20 parts by weight, the colorant is selected from iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black, titanium dioxide The combination of one or more of titanium, dosage can be 0-13 parts by weight.

The sustained release pellet may include coated slow release ball and matrix type sustained release pellet, can be unrestricted by blank capsule core (0-300 parts by weight), Rui Kapabu salts (such as phosphate, hydrochloride, benzene sulfonate, sulfate, camphor hydrochlorate etc.) are released Rate adaptation matrix or clothing film material and other auxiliary materials etc. are put, passes through wet method system well-known to those skilled in the art It is prepared by the conventional methods such as grain, extrusion spheronization, coating pan coating and/or fluidized bed granulation coating.For example, sustained release pellet passes through coating One pan coating of pot carries the preparation of the mode of medicine, wherein, Rui Kapabu is disperseed or is contained in blank capsule core, is formed and carries pill Then core is carrying one layer of clothing film material such as Sulisi of pill core outsourcing etc. to form sustained release clothing film, is forming the coating It is sustained ball.The blank capsule core is selected from sucrose capsule core, starch capsule core, microcrystalline cellulose capsule core, silica capsule core, hydroxypropyl The combination of one or more of cellulose capsule core.For another example, sustained release pellet is prepared by fluid bed process, wherein, it will be auspicious It after Kappa cloth is dissolved simultaneously with rate of release adjusting with matrix, is placed in spray-drying apparatus, blasts air-flow, spray drying collects sample Product, add in adhesive, and granulation, drying form the matrix type sustained release pellet.

In sustained release pellet, the rate of release adjusting matrix or clothing film material can be selected from shellac, adjacent benzene two Formic acid cellulose acetate (CAP), acrylic resin (Eudragit), ethyl cellulose (EC), polypropylene polysiloxanes, acetic acid are fine Tie up element, cellulose propionate, cellulose-acetate propionate, polyvinyl alcohol, polyvinylpyrrolidone (PVP), methylcellulose, hydroxypropyl One or more of cellulose, hydroxypropyl methyl cellulose (HPMC) etc..Other described auxiliary materials mainly include, but are not limited to Adhesive, plasticizer and pore-foaming agent etc..Wherein, described adhesive is sweet selected from polyethylene glycol (PEG), stearic acid, monostearate One or more of grease etc., the plasticizer be selected from propylene glycol, glycerine, polyethylene glycol (PEG), triacetin, One or more of acetyl list monoglyceride, phthalic acid ester, castor oil etc., the pore-foaming agent are selected from hydrophily liquid Carrier (glycerine, PEG200), carbohydrate (lactose, fructose, sucrose, mannose), surfactant (polyoxyethylene sorbitan monoleate, dodecyl Sodium sulphate etc.), one or more of macromolecule (povidone, hydroxypropyl methylcellulose etc.).

In one embodiment, the sustained release pellet includes the sky of 100-250 parts by weight, preferably 200-400 parts by weight White capsule core, preferably 10-150 parts by weight, 10-100 parts by weight, the Rui Kapabu salts of more preferable 30-100 parts by weight, 10- The release velocity modulation of 300 parts by weight saves matrix or clothing film material, the adhesive of 0-100 parts by weight, the cause of 0-12 parts by weight Hole agent and the plasticizer of 0-15 parts by weight.

Finally, sustained release ball direct tablet compressing is then prepared as the sustained release tablets based on sustained release pellet.If ease up by quick-release matrix The specification ratio for releasing pellet is uniformly mixed, then the tablet press machine by carrying special agitating function, tabletted, then can be prepared into The slow double release formulations of speed.

2nd, capsule

The present invention also provides sustained and controlled release capsule preparations, can be selected from the sustained and controlled release capsule based on pellet and based on tablet Sustained and controlled release capsule.Fig. 5 show according to one embodiment of the present invention containing quick-release ball and matrix type sustained-release micro-pill capsules Structure diagram, Fig. 6 shows the knot of the sustained-release micro-pill capsules being coated containing quick-release according to one embodiment of the present invention Structure schematic diagram, Fig. 7 show the capsule structure schematic diagram containing quick-release and sustained release tablets.

2.1st, the sustained and controlled release capsule based on pellet

The controlled release capsule being made of based on the sustained and controlled release capsule of pellet sustained release pellet of the present invention or by sustained release pellet and The speed of fast release micropill composition delays double-release capsule, can include the capsule containing matrix type sustained release pellet, contain sustained release pellets Capsule, the capsule of sustained release pellet containing quick-release coating, the speed containing fast release micropill and matrix type sustained release pellet, which are delayed, double releases glue Capsule and speed containing fast release micropill and sustained release pellets delay double-release capsule.

The sustained and controlled release capsule based on pellet of the present invention, can be spansule based on sustained release pellet and based on quick-release and The speed of sustained release pellet delays economic benefits and social benefits capsule.Capsule is released for the slow economic benefits and social benefits of the speed, fast release micropill constitutes quick-release phase, sustained release pellet group Into sustained release phase.Based on the fast gross weight delayed economic benefits and social benefits and release capsule China and Sweden Kappa cloth, the Rui Kapabu in quick-release phase accounts for 5-40wt%；It is slow The Rui Kapabu released in pellet accounts for 60-95wt%.

The sustained release pellets and composition, preparation method, material selection and the content of matrix type sustained release pellet etc. Description is identical with the sustained release pellet of 1.3 parts above, is not repeating herein.

Sustained release pellet containing quick-release coating can be directly coated with quick-release matrix to above-mentioned matrix type sustained release pellet or packet Clothing sustained release pellet surface and prepare.

The fast release micropill can pass through conventional coating method well-known to those skilled in the art by after quick-release stromatolysis It contains to blank capsule core and prepares or quick-release matrix is directly prepared into pellet and is made.

The description of composition, material selection and the content of the quick-release matrix etc. is same with the quick-release discrete phase of 1.2 parts above, It is not repeating herein.

Sustained release ball is carried out that capsule is filling is prepared into controlled release capsule, and weighs above-mentioned quick-release ball according to a certain percentage and eases up It ball is released, is uniformly mixed, then carries out that capsule is filling, then can prepare the slow double-release capsule preparation of speed or will be coated containing quick-release Sustained release pellet progress capsule is filling, can also prepare the slow double-release capsule preparation of speed.

2.2nd, the sustained and controlled release capsule based on microplate

The controlled release capsule that is made of the present invention is based on the sustained and controlled release capsule of microplate sustained release tablets or by sustained release microplate and speed The speed for releasing microplate composition delays double-release capsule, can include the capsule containing matrix type sustained release microplate, the skeleton containing quick-release coating The capsule of type sustained release microplate and the capsule containing quick-release microplate and matrix type sustained release microplate.In general, to be packed into hard shell capsules, Made Tablet diameter is all smaller, generally<5mm..

Capsule is released for the slow economic benefits and social benefits of speed, quick-release microplate constitutes quick-release phase, and sustained release microplate then constitutes sustained release phase.Based on glue The gross weight of capsule China and Sweden Kappa cloth, the Rui Kapabu in quick-release phase account for 5-40wt%；Rui Kapabu in sustained release phase accounts for 60- 95wt%.

The description of composition, preparation method, material selection and the content of the matrix sustained release tablet etc. and 1.2 part bone above The sustained release of frame type controlled release tablet is mutually identical, is not repeating herein.

Matrix sustained release tablet containing quick-release coating can be directly coated with quick-release matrix to above-mentioned matrix sustained release tablet table Face and prepare.

The fast-release tablet can quick-release matrix direct tablet compressing and prepare.

Matrix sustained release tablet carries out to capsule is filling is prepared into slow release capsule preparation, and according to a certain percentage by fast-release tablet With after sustained release tablets mixing carry out capsule it is filling or by the matrix sustained release tablet being coated containing quick-release carry out capsule it is filling, be prepared into The slow double-release capsule of speed.

Description of the drawings

Fig. 1 is the structure diagram that matrix type speed delays economic benefits and social benefits release double-layer tablets.

Fig. 2 is the structure diagram that matrix type speed delays economic benefits and social benefits release coating tablet.

Fig. 3 is the structure diagram of osmotic pump type controlled release tablets.

Fig. 4 is the structure diagram that osmotic pump type speed delays economic benefits and social benefits releasing piece.

Fig. 5 is the structure diagram containing quick-release ball and matrix type sustained-release micro-pill capsules.

Fig. 6 is the structure diagram for the sustained-release micro-pill capsules being coated containing quick-release.

Fig. 7 is that the structure of the capsule containing quick-release and sustained release tablets is intended to.

Fig. 8 is that the speed of embodiment 1 delays economic benefits and social benefits release matrix tablet release profiles.

Fig. 9 is the stripping curve of the quick-release tablet in comparative example 1.

When Figure 10 is the internal medicine that the quick-release tablet of comparative example 1 and the speed of embodiment 1 delay economic benefits and social benefits release matrix tablet Curve graph.

Figure 11 is release of the double-layer osmotic pump controlled-release tablet in the dissolution medium of pH 1.2,4.5 and 6.8 in embodiment 3 Curve.

Figure 12 is release profiles of the matrix sustained release tablet in the dissolution medium of pH6.8 in embodiment 4.

Specific embodiment

Following embodiment describes the preparation method and/or characterization result of exemplary composition of the present invention in general manner, owns Percentage be weight percentage, unless otherwise specified.Following embodiment is that the present invention is illustrated, without that should recognize To limit the scope of the present invention.In the examples below, the various processes and method not being described in detail are public in this field The conventional method known.

Experimental animal：Beasle dog 6, half male and half female, 8~10kg of weight.Source is that Beijing agate this biotechnology is limited Company.Animal subject carries out adaptability in 14 days a few days ago in experiment in the test site of Shanghai institute of materia medica Experimental Animal Center Raising.

Using single-punch tablet press (TDP-1, Guangzhou Xu Lang mechanical equipments Co., Ltd) tabletting.

Three-dimensional mixer is the T2F models purchased from TURBULA.

Melt extruder is the Pharma11 models purchased from Sai Mofei.

The slow economic benefits and social benefits release matrix tablet of 1 speed of embodiment

Release layer：The Rui Kapabu, superfine silica gel powder and Soluplus of recipe quantity are crossed into 60 mesh sieve and mixed with three-dimensional mixer It is even mixed 25 minutes under 30rpm after, be slowly added into the melt extruder being preheated, collect extrudate and simultaneously crushed 60 mesh Sieve, obtains Rui Kapabu solid dispersions.By gained Rui Kapabu solid dispersions and the other materials (disintegrant of recipe quantity PVPP XL) and other auxiliary materials (mannitol and magnesium stearate) are after mixing, treat that tabletting is used.

Slow release layer：After Rui Kapabu, PVP VA64 and the superfine silica gel powder of recipe quantity are crossed 60 mesh sieve and mixing, it is slowly added to To the melt extruder being preheated, collect extrudate and crushed 60 mesh and sieve to obtain Rui Kapabu solid dispersions.By gained The rate of release of Rui Kapabu solid dispersions and recipe quantity is adjusted with polymer HPMC K15M (BASF, Germany) and lubrication Agent magnesium stearate mixing treats that tabletting is used.

Tabletting：The speed that it is suitable that hardness is made in direct pressure closing, which is delayed, double releases matrix tablet.

Controlled release preparation is measured using dissolution method (two annex X C of Chinese Pharmacopoeia version in 2010) second subtraction unit Release, under the conditions of 37 DEG C, using the buffer solution of pH 6.8 as dissolution medium, rotating speed is 75 turns per minute, is operated in accordance with the law, is passed through 0.25,0.5,0.75,1,2,4,6,8,10,12,13 and 16h takes solution 6mL, centrifugation, and supernatant is taken to be surveyed as test solution Determine release.

According to UV-VIS spectrophotometry (two IV A of annex of Chinese Pharmacopoeia version in 2010), at the wavelength of 238nm Absorbance is measured respectively, measures the release of prescription tablet.

Releasing result is shown in Fig. 8.The slow economic benefits and social benefits skeleton double-layer tablets of speed realize in 30 minutes 20% or so drug quick release, 8h There is nearly 60% or so drug release in left and right, and residual drug can discharge complete in 16h or so.The release behavior can control auspicious Kappa The concentration range being distributed in blood can be rapidly achieved drug concentration needed for the inhibition of PARP enzymes, and maintain the concentration water after oral administration The flat long period.

1 quick-release tablet of comparative example

Quick-release tablet prescription is as follows：

Granular active ingredients Rui Kapabu d-camphorsulfonic acids salt and microcrystalline cellulose excipients PH101, mannitol sodium starch, Colloidal silicon dioxide and magnesium stearate are uniformly mixed in prescription ratio, sieving, are uniformly mixed in 3 D multi-directional mixer, with 98% Ethyl alcohol is bonding solvent, and be sieved particle, adds between the particle of recipe quantity after auxiliary materials and mixing, tabletting obtains quick-release tablet prescription.

Its dissolution determination is filled using dissolution method (two annex X C of Chinese Pharmacopoeia version in 2010) first method It puts, under the conditions of 37 DEG C, with the dissolution medium of 900mL pH 2.0, rotating speed is 75 turns per minute, is operated in accordance with the law, through 15,30,45, 60,75,90,105,120min take solution 6mL, centrifugation, and supernatant is taken to measure release as test solution.

Releasing result is shown in Fig. 9.The auspicious Kappa of active constituent is distributed in release 95% in 15 minutes or so in the comparison quick-release tablet More than.

EXPERIMENTAL EXAMPLE 1

The Rui Kapabu quick-release tablets of comparative example 1 and the speed of embodiment 1 are delayed economic benefits and social benefits release matrix tablet and are administered respectively In full abdomen beasle dog (n=3), taken respectively with 25mL water, blood taken in predetermined point of time after administration, blood sample under the conditions of 4 DEG C, with 4000rpm centrifuges 10min, takes upper plasma, is detected for the blood concentration of LC-MS, the result is shown in Figure 10.

Relative to the C of quick-release tablet_max(2750.3ng/mL) and AUC_0-h(19470h*ng/mL), the slow economic benefits and social benefits release bone of speed The C of frame tablet_max1589.4ng/mL is reduced to, reduces about 42%；AUC_0-hFor 20110h*ng/mL, variation<10%；By medicine When curve graph 10 result still as it can be seen that relative to quick-release tablet, the C of the slow economic benefits and social benefits release matrix tablet of speed_maxIt reduces, but can maintain The higher blood concentration lower long period, reduce blood concentration dash forward it is high bring toxic side effect while, can also extend PARP enzymes The time of blood levels needed for inhibition, preferably to play antitumous effect, while for drug dose climbing and most preferably The performance of drug effect provides the dosage space of bigger.

Embodiment 2：It is sustained pill capsule and/or the speed containing quick-release ball and sustained release ball delays economic benefits and social benefits capsule

1. it is sustained ball

I pill core) is carried

II) packet barrier gown

III) packet extended release coatings

2. quick-release ball

Preparation method is as follows：

Quick-release ball：By the auspicious Kappa cloth Rui Kapabu phosphate of recipe quantity and copolyvidone (VA64), it is dissolved or dispersed in It in 95% ethanol solution, is configured to quick-release ball and carries drug solns, by the way of fluidized bed coating, the crystallite for spraying into recipe quantity is fine In the plain blank capsule core of dimension, as quick-release ball.

It is sustained ball：It is appropriate to weigh rate of release adjusting matrix hydroxypropyl cellulose SSL, is scattered in 95% ethanol solution In, the coating solution that solid content is 10% is configured to, on magnetic stirring apparatus, is stirred；Rui Kapabu phosphoric acid is weighed again Salt recipe quantity is evenly dispersed in above-mentioned coating solution, and as carrying, medicine coating solution is spare.

Microcrystalline cellulose blank capsule core is added in into fluid bed, the operating parameters such as air quantity, temperature is adjusted, sprays into prepared load Medicine coating solution carries out load medicine, prepares the capsule core for carrying medicine.

Barrier gown clothing film ingredient is dissolved or dispersed in 95% ethanol solution, using fluidized bed coating mode, is injected to On the load pill core of recipe quantity；Obtain the load pill core of coating barrier gown.

Sustained release coating liquid aqueous dispersion is added in into suitable aqueous solution dilution, mixing as sustained release clothing film coating liquid, uses The mode of fluidized bed coating is injected on the load pill core of packet barrier gown, and sustained release ball is made.

Capsule is filling：Above-mentioned preparation completion sustained release ball is encapsulated, it is prepared into spansule.

After the quick-release ball and sustained release ball that above-mentioned preparation is completed are according to recipe quantity, abundant mixing, progress capsule is filling, prepares Cheng Suhuan double-release capsules.

3 double-layer osmotic pump controlled-release tablet of embodiment

Rui Kapabu and copolyvidone VA64 prepares solid dispersions with solvent evaporation method, i.e., ties up Rui Kapabu and copolymerization Ketone VA64 is dissolved in ethanol/acetone simultaneously, and (25/75, v/v), decompression can send out organic solvent, after dry in vacuum drying chamber, 60 mesh sieve was ground, treats that tabletting is used.

60 mesh were mixed with other auxiliary material 30 POVIDONE K 30 BP/USPs 90 and magnesium stearate of recipe quantity again to sieve and pass through three-dimensional mixer, 25min is mixed under 30rpm, obtains controlled release drug containing layer composition, treats that tabletting is used.

Precision weighs boosting layer auxiliary material, crosses 60 mesh and sieves and by being obtained after three-dimensional mixer mixing (25rpm, 30 minutes) uniformly To boosting layer composition.Using vertical compression mode, with above-mentioned medicated layer composition and the compacting of boosting layer composition comprising medicated layer and The osmotic pumps double-deck core of boosting layer.The label of compacting, with 4% cellulose acetate solution packet controlled release clothing layer, clothing film weightening 10%, obtain double-layer osmotic pump controlled-release tablet.

Double layer osmotic pump is measured using dissolution method (two annex X C of Chinese Pharmacopoeia version in 2010) second subtraction unit The release of controlled release tablet, under the conditions of 37 DEG C, respectively using the buffer solution of pH 1.2,4.5,6.8 as dissolution medium (7.65mL hydrochloric acid It is diluted with water to 1000mL and can be prepared by 1.2 dissolution mediums of pH；250mL 0.2mol/L potassium dihydrogen phosphates are separately added into 0mL and 112mL, you can the dissolution medium of pH4.5 and 6.8 is made respectively), rotating speed is 75 turns per minute, is operated in accordance with the law, through 0.5, 1,2,4,6,8,10,12,13,16h takes solution 6mL, centrifugation, and supernatant is taken to measure release as test solution.

Releasing result in different pH dissolution mediums is shown in Figure 11.The results show that double-layer osmotic pump controlled-release tablet is not substantially by pH It influencing, active constituent Rui Kapabu can maintain constant release substantially, and release in 1 hour is less than 10%, discharges 50% or so within 6 hours, More than 80% 12h releases, the overall duration that discharges is up to 14h.

Embodiment 4：Sustained-release matrix tablets

Rui Kapabu d-camphorsulfonic acids salt and PVP K30 (BASF, Germany) are crossed 60 mesh and sieved 3 times, then pass through three-dimensional Mixer mixes 25 minutes under the conditions of 30rpm, and mixture is slowly added into the melt extruder being preheated, and collects transparent squeeze Go out object and crushed 60 mesh sieve, obtain Rui Kapabu d-camphorsulfonic acid salt solid dispersions.Solid dispersions with recipe quantity and Rate of release, which is adjusted, uses matrix polymer hydroxypropyl cellulose (K4M, BASF, Germany), and with recipe quantity mixing, it is hard to add in lubricant Fatty acid magnesium, after remixing uniformly, the suitable sustained-release matrix tablets of hardness are made in tabletting.

Release the result is shown in Figure 12, sustained-release matrix tablets are less than 20% in release Rui Kapabu amounts in 1 hour, are released in 8 hours 55% or so is put, the drug release duration was up to 16 hours.

Claims

1. a kind of Rui Kapabu takes orally sustained and controlled release medicament composition, it includes：Dissolve out the Rui Kapabu of improvement form；With release speed Rate adjusting matrix polymer,

The Rui Kapabu of the dissolution improvement form includes：Rui Kapabu salts, Rui Kapabu co-milled mixtures, auspicious Kappa Cloth is nanocrystalline and Rui Kapabu solid dispersions, preferably Rui Kapabu solid dispersions,

Preferably, the rate of release adjusting matrix polymer is selected from hydroxypropyl cellulose, polyoxyethylene, hypromellose Element, methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copolyvidone, acrylic resin, card One or more kinds of combinations of wave nurse, are preferably selected from hydroxypropyl cellulose, sodium alginate, hydroxypropyl methylcellulose and Ka Bo One or more kinds of combinations of nurse.

2. Rui Kapabu according to claim 1 takes orally sustained and controlled release medicament composition, wherein, the Rui Kapabu medicine groups Closing object has following drug release behavior,

PH value is in the buffer solution of 1.2-7.8 under the conditions of use the second subtraction unit of Chinese Pharmacopoeia dissolution method, 37 DEG C When carrying out release behavior measure, release is less than the 40wt%, preferably 10-30% of Rui Kapabu total amounts in 1 hour；It releases within 6-8 hours Put the 45-85% of Rui Kapabu total amounts, preferably 50-70%；Release Rui Kapabu is more than the 80% of total amount within 12-16 hours, preferably> 90%；Alternatively,

The steady state plasma concentration valley value C of the Rui Kapabu pharmaceutical compositions_min,ssFor 0.2-4ug/mL, preferably 0.5-3ug/ mL；Steady state plasma concentration crest value C_max,ssFor 0.8-15ug/mL, preferably 1-12ug/mL, and the ratio of steady state plasma concentration peak bottom Value preferably smaller than 6.

3. Rui Kapabu according to claim 1 or 2 takes orally sustained and controlled release medicament composition, wherein

The Rui Kapabu co-milled mixtures are by active medicine Rui Kapabu, solubilising matrix polymer and other additive groups Into by the way that the ingredient is co-mulled and made into prepare；In the co-milled mixtures, based on the gross weight for being co-mulled and made into composition, auspicious card The weight percent of Pabuk is 5%-60wt%, preferably 20%-40wt%, and the weight percent of solubilized matrix polymer is 40%-95wt%, preferably 40%-80wt%, the weight percent of other additives is 0%-15wt%, preferably 0.2%- 10wt%；

The Rui Kapabu is nanocrystalline to be made of active medicine Rui Kapabu, solubilized matrix polymer and/or other additives, By by the ingredient is high-pressure homogeneous or coprecipitation is prepared into the particle of nano-scale and obtains；The Rui Kapabu is nanocrystalline In, based on the nanocrystalline gross weights of Rui Kapabu, the weight percent of Rui Kapabu is 10%-99wt%, preferably 20%- 50wt%；The weight percent of solubilising matrix polymer is 1-75wt%, preferably 1-65wt%, the weight hundred of other additives Divide than being 0-10wt%, preferably 0-5%wt%；The nanocrystalline grain size is preferably 50-1000nm；

The solid dispersions are made of active medicine Rui Kapabu, solubilized matrix polymer and other additives, by molten Agent volatility process or melt extrusion method manufacture, in solid dispersions, the gross weight based on solid dispersions, the weight hundred of Rui Kapabu Divide than being 5%-50wt%, preferably 20%-40wt%, the weight percent of solubilized matrix polymer is 45%-95wt%, excellent 50-80wt% is selected, the weight percent of other additives is 0-12wt%, preferably 0-10wt%.

4. Rui Kapabu according to claim 3 takes orally sustained and controlled release medicament composition, wherein,

The solubilising matrix polymer is selected from povidone, copolyvidone, polyoxyethylene, Soluplus, hypromellose Plain phthalic acid ester (HPMCP), hydroxypropylmethylcellulose acetate cellulose hemisuccinate ester, polyethylene glycol, poloxamer, polymethyl Acid, polyethyl acrylate, 1:12- hydroxypropyl-β-cyclodextrins, hydroxypropyl methylcellulose (HPMC), polymethacrylates, hydroxypropyl One or more of cellulose, cellulose acetate phthalate (CAP) and other pharmaceutical solubilized polymer Combination；

Other described additives be selected from pharmaceutically common medicinal solubilizing surfactant (such as polyethylene glycol stearate, Lauryl sodium sulfate etc.), the combination of lubricant, superfine silica gel powder, one or more of plasticizer etc..

5. Rui Kapabu according to any one of claim 1 to 4 takes orally sustained and controlled release medicament composition, it includes 50-900 Parts by weight, preferably 80-700 parts by weight, the dissolution of more preferable 120-600 parts by weight improve form Rui Kapabu；With 10-300 weights Measure part, preferably 20-250 parts by weight, the rate of release adjusting matrix polymer of more preferable 50-180 parts by weight.

6. Rui Kapabu according to any one of claim 1 to 5 takes orally sustained and controlled release medicament composition, it includes

The Rui Kapabu co-milled mixtures of 50-800 parts by weight and the rate of release adjusting matrix polymerisations of 10-200 parts by weight Object；Or

The Rui Kapabu of 50-800 parts by weight is nanocrystalline and the rate of release adjusting matrix polymer of 0.1-250 parts by weight；Or Person

The Rui Kapabu solid dispersions of 50-900 parts by weight and the rate of release adjusting matrix polymerisations of 20-300 parts by weight Object.

It is single sustained release 7. Rui Kapabu according to any one of claim 1 to 6 takes orally sustained and controlled release medicament composition The sustained-release preparation of phase not only mutually but also containing the speed for being sustained phase delayed economic benefits and social benefits delivery formulations containing quick-release；

Preferably,

The sustained release is mutually the controlled release composition containing active constituents of medicine, in controlled release tablet, controlled release piller, tablet Controlled release composition in controlled release composition, tablet or capsule core, the controlled release layer composition and its arbitrary form being attached in double-layer tablets Combination；

The quick-release is mutually the immediate release composition containing active constituents of medicine, for the speed in fast-release tablet, quick-release ball, tablet Release composition, be wrapped in Dospan or the quick-release coatings outside capsule core, the quick-release layer composition in two-layer release-controlled tablet and its appoint The combination of meaning form.

8. Rui Kapabu according to claim 7 takes orally sustained and controlled release medicament composition, wherein, in the slow economic benefits and social benefits controlled release of the speed In preparation, the active constituents of medicine in quick-release phase accounts for the 10-50wt% of active constituents of medicine total amount, preferably 20-40wt%；It is slow Release the 50-90wt% that the active constituents of medicine in phase accounts for active constituents of medicine total amount, preferably 60-80wt%.

It is tablet or glue 9. Rui Kapabu according to any one of claim 1 to 8 takes orally sustained and controlled release medicament composition Wafer, is preferably selected from osmotic pump controlled release tablet, infiltration pump speed delay it is double release piece, matrix sustained release tablet, matrix type speed delays economic benefits and social benefits double-layer tablets, Matrix type speed delays economic benefits and social benefits coating tablet, and the sustained release tablets based on sustained release pellet, the speed based on sustained release pellet and fast release micropill delays double-effect tablet, Capsule containing matrix type sustained release pellet, the capsule containing sustained release pellets, the capsule of the sustained release pellet containing quick-release coating, Speed containing fast release micropill and matrix type sustained release pellet delays double-release capsule, the speed containing fast release micropill and sustained release pellets delay it is double It releases capsule, the capsule containing matrix type sustained release microplate, be sustained the capsule of microplate and containing speed containing the matrix type that quick-release is coated Release the capsule of microplate and matrix type sustained release microplate.

10. the Rui Kapabu according to any one of claim 1-9 takes orally sustained and controlled release medicament composition and is used to prepare prevention Or tumour of the treatment with DNA repair function defects, especially with the relevant two or more combination cancer of BRCA gene mutations such as Oophoroma, gastric cancer, breast cancer and the purposes for the drug with the relevant tumour of BRCA1 and BRCA2 gene mutations.