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; WO2018108157A1; CN110062628A

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

Ruicapalb oral sustained and controlled release pharmaceutical composition and application thereof

Technical Field

The invention relates to the field of Ruicapa preparation, in particular to a Ruicapa oral sustained and controlled release pharmaceutical composition and application thereof.

Background

Rucapeb (Rucaparib), chemical name 8-fluoro-1, 3,4, 5-tetrahydro-2- [4- [ (methylamino) methyl group]Phenyl radical]-6H-pyrrolo [4,3,2-EF][2]Benzazepin-6-ones of formula C₁₉H₁₈FN₃O, molecular weight 323.46, having the following chemical structure:

in 2011, whether the pfeizu stopped the development of new drugs for the rebamipide, clovis tumor (clovis oncology) was authorized to develop new drugs and markets for the compound; in 2012, the compound was used as an orphan in the us and europe for the study of ovarian cancer; in 2015, the drug is used for clinical treatment research of BRCA mutant ovarian cancer as a three-line clinical drug of monotherapy, has good effect, and thus obtains the breakthrough therapy certification of the FDA in the United states; the FDA announced 8 months in 2016 that Rucaparib, a member of the clarvis oncology, will be accepted as a new drug for the three-line treatment of ovarian cancer, and that ricapab will become the second poly ADP transferase (PARP) inhibitor approved by the FDA for tumor therapy.

Poly ADP transferase (PARP) is a key factor in a DNA excision repair pathway, and Rukappab can inhibit PRAP enzyme activity, so that a broken single strand of DNA cannot be repaired, the instability of a genome is increased, and further apoptosis of cells can be caused, and particularly, the Rakappab has a strong killing effect on tumor cells with homologous recombination repair defects, and the action mode of the Rukappab has treatment potential on various tumors; in addition, due to the specific inhibition of the Ruipab on the damaged DNA repair pathway, the medicine can also avoid the tumor resistance after chemotherapy, enhance the DNA damage and enhance the anti-tumor curative effect of the traditional chemotherapy medicines.

In the traditional tumor chemotherapy mode, due to the lack of specific treatment targets, the antitumor drugs can kill tumor cells and also seriously damage normal cells of a human body, thereby bringing great toxic and side effects to the body. The PARP inhibitors such as Ruipab can specifically inhibit the growth of tumor cell lines accompanied with DNA damage or homologous recombination repair defects, increase the toxicity and the anti-tumor activity on tumor cells, have no killing effect on tissue cells with normal DNA repair functions, and are typical medicaments for tumor targeted therapy at present. Due to high specificity and few side effects, the method has attracted more and more intense interests of scientific research and medical workers in recent years.

Currently, many clinical studies such as intravenous injection of Richapabub phosphate and oral immediate-release tablet of D-camphorsulfonate are being conducted by Clovis tumor Inc., wherein intravenous injection of phosphate has been conducted in 2005 for the treatment of melanoma, and in 2007 for the treatment of breast cancer and ovarian cancer, although the research of injection has been started earlier, the progress in each aspect is slow, Clovis seems to be focused on promoting the marketing of new drugs for oral preparations, and the application of oral immediate-release tablet of D-camphorsulfonate for new drugs for the treatment of advanced ovarian cancer with BRCA mutation has been accepted by FDA approval and has gained a priority channel, and the application of new drugs for marketing has also been filed in 2016, month 5.

According to the research result of cloviss tumor company, the PARP inhibitor Ruipab oral bioavailability is about 36 percent, T_maxAfter 240mg tablets are taken twice a day, the blood concentration can reach 100% to the expected trough concentration (2uM) after 1-6 hours, the half-life is about 17 hours, the plasma exposure amount is linearly increased along with the increase of the dose, the main 3/4 grade toxicity comprises anemia, hemoglobin reduction, transaminase increase and the like, and the clinical administration dose of the II/III phase is 600mg BID.

However, the common oral immediate release tablets currently under investigation have certain limitations: 1) 95% of the Ruipab in the tablet is released within 15 minutes, namely most of the medicine is quickly absorbed in the gastrointestinal tract within a short time, so that the blood concentration is high, the fluctuation of the blood concentration is large, and more toxic and side effects are generated; 2) the higher steady-state blood concentration peak value also limits the further improvement of the blood concentration required by high-efficiency enzyme inhibition and limits the full play of the drug effect of the Ruipape; 3) the effective utilization rate of the medicine is not high in a mode of large-dose multi-time administration, the bioavailability of the medicine is only 36%, most of the medicine is lost, and the medicine absorption needs to be further improved; 4) larger oral doses of drug (600mg BID,2-4 tablets per time) result in poor patient compliance and also result in costly packaging, storage and shipping of the drug product.

In order to further improve the clinical tumor treatment efficacy of the Ruipab and reduce the toxic and side effects of the drug, the invention aims to develop a Ruipab drug composition which can improve the effective utilization rate of the drug and accurately regulate and control the blood concentration level and fluctuation range of the Ruipab. It is another object of the present invention to provide a superior formulation that minimizes the size and/or number of tablets or capsules required for a therapeutically effective dose, with as low a frequency of administration as possible, and with improved patient compliance.

Upon patent search, formulation patents related to Ruipab include: the preparation method comprises the following steps of (1) preparing a normal oral quick-release tablet of the racepab dextrocamphorsulfonate (US 2016051561, WO 2016028689), a combined preparation of the racepab phosphate and other cell medicines (WO2006033006, EP 1793830, JP 2008513435) and the like:

1) WO 2016028689a and US 2016051561 disclose a rapid release tablet of oral racepab, in which the active drug racepab dexampholate has low hygroscopicity and good compressibility compared to other salt forms, is suitable for dry granulation, is more beneficial for the preparation and production of high-dose solid tablets, and the drug dose can reach more than 45%; the Ruocapab of the tablet can release more than 95 percent within 15 minutes, and the research of Clovis tumor company on the ovarian cancer resistance of the tablet enters the new drug application stage at present.

2) WO2006033006, EP 1793830 and JP 2008513435 disclose a form of a composition of racepabub phosphate, and a combination composition thereof with other cytotoxic drugs, and this group of patents discloses intravenous injection preparations of racepab phosphate such as lyophilized powder preparations, and states corresponding administration doses and combination forms, etc., which have been currently used in phase II clinical trials for tumor therapy such as breast cancer.

From the above mentioned patent of the Ruipab, no research related to the oral sustained and controlled release preparation of Ruipab is available at present, and the invention discloses a Ruipab pharmaceutical composition with controllable in vivo release behavior, in order to further improve the clinical efficacy of Ruipab, provide accurate blood drug concentration and enzyme inhibition level, reduce the adverse reaction after the administration of tumor patients, improve the compliance of the patients in administration, and reduce the storage and production cost.

Disclosure of Invention

The large dosage form for multiple times a day is often used for producing the drug after oral administration, and the drug generates higher steady state blood drug peak fluctuation and larger blood drug concentration fluctuation range (400mg, BID, C)_min,ss<1ug/ml；C_max,ss>6ug/mL), too high a peak value can cause a plurality of side effects of the immediate release preparation of the Ruipab, and can limit further improvement of the blood concentration level required by the drug effect.

The invention aims to accurately regulate and control the absorption rate and absorption time of the Ruipab in gastrointestinal tracts by controlling the release behavior of the Ruipab according to the biological property of the Ruipab and the drug effect and safety requirements of clinical treatment, further control the blood concentration level and the fluctuation range thereof in vivo, maintain the long-term steady state of the blood concentration in vivo at the effective PARP enzyme inhibition level, improve the anti-tumor curative effect of the Ruipab and reduce the adverse reaction after the drug is taken.

It is another object of the present invention to provide a superior formulation that minimizes the size and/or number of tablets or capsules required for a therapeutically effective dose, with as low a frequency of administration as possible, and that improves patient compliance.

The invention provides a controlled-release pharmaceutical composition for oral administration of Ruocapab, aiming at the defects of the current preparation of Ruocapab, wherein the absorption behavior, blood concentration and PARP enzyme inhibition level in vivo of the pharmaceutical composition can be regulated, and the pharmaceutical composition has the advantages of improving the drug loading and/or oral absorption and/or bioavailability and/or blood concentration control and/or enzyme inhibition level control of Ruocapab, and can be used as a unique preparation or combined with other therapies for treatment.

The oral sustained and controlled release pharmaceutical composition of the Ruicapab provided by the invention comprises: (ii) licarpb or a dissolution-improved form of licarpb; and a matrix polymer for release rate adjustment (also referred to as a release modifier). In addition, according to the prepared dosage form, pharmaceutical excipients such as semipermeable controlled-release coating film materials, barrier coating materials, disintegrants, coating powders, plasticizers, pore-forming agents, swelling materials, fillers, osmotic pressure regulators (also referred to as permeation aids), lubricants, binders (also referred to as binders), coloring agents (also referred to as coloring agents), anti-sticking agents (also referred to as anti-sticking agents), opacifiers, diluents and/or other pharmaceutically acceptable additives may be further included.

The active drug Ruipab in the Ruipab pharmaceutical composition provided by the invention belongs to a slightly soluble drug, and can be firstly solubilized to prepare a salt form, such as phosphate, hydrochloride, maleate, benzene hydrochloride, sulfate, camphorate (preferably, D-camphorate) and the like, or prepared into a solubilizing composition to improve the dissolution of the drug. Without being bound by any theory, the inventors believe that the solubilization process alters the specific surface area of dispersion in the powder of the active pharmaceutical formulation composition by mixing the Ruipab with a matrix polymer that achieves improved drug solubility, thereby improving the dissolution properties of the drug. The solubilization process may include co-milling, high pressure homogenization, co-precipitation, solvent evaporation or melt extrusion, etc.

In the present invention, the Ruipab includes Ruipab free base and its pharmaceutically acceptable salts, which may be selected from hydrochloride, phosphate, sulfate, D-camphorate, benzenesulfonate, etc. In the description of the present invention, unless otherwise specified, specific descriptions such as licarpb hydrochloride, licarpb maleate and the like, the term "licarpb" refers to the licarpb free base.

The dissolution-improved form of the present invention provides a Ruipab comprising: the formulations of the inventive formulations are preferably selected from the group consisting of a form of a Ruipab salt, a Ruipab co-ground mixture, a Ruipab nanocrystal, and a Ruipab solid dispersion, preferably a Ruipab salt (e.g., Ruipab phosphate, Ruipab dexcamphorate, etc.) and a solid dispersion. The salt form of the Ruipaprb can remarkably improve the water solubility of the Ruipaprb, and the salt form of the Ruipaprb raw material medicine can be directly used for preparing a sustained-release preparation; the Ruipab co-ground mixture, the Ruipab nanocrystal and the Ruipab solid dispersion can improve the dissolution and dissolution performance of the Ruipab in a controlled release dosage form, and simultaneously improve the absorption and bioavailability of a medicament.

The inventive Ruipab co-ground mixture consists of the active drug Ruipab, a solubilizing matrix polymer and other additives, and is prepared by co-grinding the ingredients, and the particle size of the drug powder is generally well ground to below 100 microns. Without being bound by any theory, the co-milling can increase the dispersion specific surface area of the drug in the solid formulation powder, thereby improving the dissolution properties of the drug.

The co-mulled mixture comprises, based on the total weight of the co-mulled mixture, 5% to 60% by weight, preferably 20% to 40% by weight, of the Ricapab, 40% to 95% by weight, preferably 40% to 80% by weight, of the solubilizing matrix polymer, and 0% to 15% by weight, preferably 0.2% to 10% by weight, of other additives. The total amount of the components is 100 wt%.

When different numerical ranges appear for the same component of the same composition herein, all numbers within the stated maximum range and all alternative numerical ranges are deemed to be disclosed, and all integers, fractional numbers to the 1 st decimal point and numerical ranges consisting of them are preferably included. For example, in the above, the lower limit of the weight percentage of the licarpan may be 5 wt%, 6 wt%, 7 wt%, … …, or 59.9 wt%, and the upper limit of the weight percentage of the licarpan may be 60 wt%, 59 wt%, 58 wt%, … …, or 5.1 wt%, i.e., the weight percentage of the licarpan includes any combination between these lower and upper limits, such as 5 wt% to 6 wt%, 59 wt% to 60 wt%, and as another example, the weight percentage of the other additives in the above includes 0.1 wt% to 12.5 wt%, and so on. In the following, for the sake of brevity, possible values of the upper and lower limits of each numerical range will not be described in detail.

The Ruipab nanocrystal consists of an active drug Ruipab, a solubilizing matrix polymer and/or other additives, and is obtained by preparing the components into nanometer-sized particles by a high-pressure homogenization or coprecipitation method. The high-pressure homogenization method is operated as follows: adding a coarse-crystal suspension prepared by shearing an active drug namely the Ruipab and a matrix polymer aqueous solution for solubilization at a high speed into a high-pressure homogenizer, circularly homogenizing for multiple times at a high pressure until the prepared crystal particles are less than 1000nm, freeze-drying a sample, and preparing uniformly dispersed Ruipab nano-crystal powder. The coprecipitation method operates as follows: dissolving an active drug Ruipab in a small amount of organic solvent such as acetone, quickly adding the dissolved active drug Ruipab into a large amount of aqueous solution dissolved with a matrix polymer, performing ultrasonic high-frequency ultrasound (the power reaches more than 100 w) by using a probe to ensure the formation and uniform dispersion of active drug crystal nuclei until a stably dispersed nano crystal solution is formed, freeze-drying a sample, and preparing uniformly dispersed Ruipab nano crystal powder. The active drug Ruipab is prepared into the nano-crystal, so that the dispersion particle size of the active drug Ruipab in solid powder can be reduced, the specific surface area of the active drug is obviously improved, and the dissolution performance of the drug is improved. Without being bound to any theory, the nanocrystals can increase the dispersion specific surface area of the Ruipab in the solid preparation composition powder, thereby improving the dissolution performance of the drug.

In the Ruipab nanocrystal, the weight percentage of Ruipab is 10-99 wt%, preferably 20-50 wt%, based on the total weight of the Ruipab nanocrystal; the weight percentage of the solubilizing matrix polymer is 1 to 75%, preferably 1 to 65%, and the weight percentage of the other additives is 0 to 10%, preferably 0 to 5%. The total amount of the components is 100 wt%. The grain size of the nanocrystalline composition is 50-1000 nm.

The solid dispersion of the present invention consists of the active drug, licarpa, a solubilizing matrix polymer and other additives. In the solid dispersion, the weight percentage of the licarpan is 5 to 50 wt%, preferably 20 to 40 wt%, the weight percentage of the solubilizing base polymer is 45 to 95 wt%, preferably 50 to 80 wt%, and the weight percentage of the other additives is 0 to 12 wt%, preferably 0 to 10 wt%, based on the total weight of the solid dispersion. The total amount of the components is 100 wt%. The solid dispersion may be manufactured by a solvent evaporation method or a melt extrusion method. The solvent evaporation method is carried out as follows: dissolving the drug Ruicapa, the solubilizing matrix polymer and/or other additives into a volatilizable organic solvent or an organic mixed solvent at the same time, decompressing and volatilizing the organic solvent, and transferring the obtained transparent intermediate product to a vacuum drying oven for drying to obtain the Ruicapa solid dispersion. The melt extrusion process was carried out as follows: directly and slowly adding the homogenized medicine Ruipab, the solubilizing matrix polymer and/or other additive powder into a melt extruder, and collecting the melt extrudate. Without being bound by any theory, the solid dispersion can enable the active drug Ruipab to be in a high-energy state solid dispersion state and be dispersed in a solid powder of a preparation composition in a molecular form, so that the specific surface area of the drug is maximally increased, and the dissolution performance of the drug is improved.

In the ricarapabric mixture, the ricarapabric nanocrystal and the ricarapabric solid dispersion, the solubilizing matrix polymer refers to a polymer capable of stabilizing and/or solubilizing the ricarapabric particles or molecules, and may be one or a combination of two or more selected from povidone, copovidone, polyoxyethylene, Soluplus, hypromellose phthalate (HPMCP), hydroxypropyl cellulose acetate succinate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 1: 12-hydroxypropyl- β -cyclodextrin, Hypromellose (HPMC), polymethacrylate, hydroxypropyl cellulose, Cellulose Acetate Phthalate (CAP) and other pharmaceutically acceptable solubilizing polymers.

In the licarpan co-ground mixture, the licarpan nanocrystal and the licarpan solid dispersion of the present invention, the other additive may be one or a combination of two or more selected from pharmaceutically commonly used solubilizing surfactants (e.g., polyethylene glycol stearate, sodium lauryl sulfate, etc.), lubricants, aerosil, plasticizers, and the like.

The matrix polymer for adjusting the release rate in the present invention may be a sustained-release matrix material well known to those skilled in the art, and may be, for example, one or a combination of two or more selected from hydroxypropyl cellulose, hypromellose, methylcellulose, hydroxyethyl cellulose, ethylcellulose, sodium alginate, povidone, copovidone, acrylic resin, and carbomer, and preferably one or a combination of two or more selected from hydroxypropyl cellulose, sodium alginate, hypromellose, and carbomer.

The oral sustained and controlled release pharmaceutical composition of the Ruicapa B comprises 50 to 800 parts by weight of a Ruicapa B co-ground mixture and 10 to 200 parts by weight of a release rate adjusting matrix polymer; or 50 to 800 parts by weight of Ruipab nanocrystals, and 0.1 to 250 parts by weight of a matrix polymer for release rate adjustment; or 50 to 900 parts by weight of a Ruipab solid dispersion, and 20 to 300 parts by weight of a release rate regulating matrix polymer.

The expected total dose of Ruipab required to be taken by the patient per day is 100-1400 mg. The amount of the pharmaceutically active ingredient, namely, the licarpan contained in a single finished tablet or capsule is not particularly limited, and may be selected as required, and may be, for example, 50mg to 300 mg. Preferably, the composition is administered only 1 time per day to control the rate and duration of absorption of the Ricaparobe and maintain plasma levels within the effective range required for PARP enzyme inhibition. The pharmaceutical composition provided by the invention can improve the PARP enzyme inhibition effect and the tumor treatment effect of Ruipab, and simultaneously reduce the toxic and side effects of the medicine.

The Ruicapalb pharmaceutical composition provided by the invention can be a single sustained-release phase sustained-release preparation or a rapid-release double-effect release preparation containing both a quick-release phase and a sustained-release phase.

The sustained release phase is a controlled release composition containing a pharmaceutically active ingredient. The controlled release phase is preferably selected from, but not limited to, a controlled release tablet, a controlled release pellet, a controlled release composition in a tablet or pellet core, a controlled release layer composition incorporated into a bi-layer tablet, and any combination thereof.

The quick-release phase is a quick-release composition containing a medicinal active component. The immediate release phase is preferably selected from, but not limited to, an immediate release tablet, an immediate release pellet, an immediate release composition in a tablet, an immediate release coating layer surrounding a controlled release tablet or pellet core, an immediate release layer composition in a bilayer controlled release tablet, and any combination thereof.

The quick-release double-effect controlled release preparation simultaneously comprises a slow release phase and a quick release phase. In the slow and slow dual-effect controlled release preparation, the active pharmaceutical ingredients in the quick release phase account for 10-50 wt%, preferably 20-40 wt% of the total amount of the active pharmaceutical ingredients; the pharmaceutical active ingredient in the sustained-release phase accounts for 50-90 wt%, preferably 60-80 wt% of the total amount of the pharmaceutical active ingredient.

The Ruipafeb pharmaceutical composition provided by the invention can be a tablet or a capsule, and is preferably selected from an osmotic pump controlled-release tablet, an osmotic pump slow-release double-release tablet, a skeleton type slow-release double-effect coating tablet, a slow-release tablet based on a slow-release pellet, a slow-release double-effect tablet based on a slow-release pellet and a quick-release pellet, a capsule containing a skeleton type slow-release pellet, a capsule containing a coated slow-release pellet, a capsule containing a quick-release coated slow-release pellet, a fast-release double-release capsule containing a quick-release pellet and a skeleton type slow-release pellet, a fast-release double-release capsule containing a quick-release pellet and a coated slow-release pellet, a capsule containing a skeleton type slow-release micro-tablet, a capsule containing a quick-release coated skeleton type slow-release micro tablet and a capsule containing a.

The Ruipab pharmaceutical composition provided by the invention can be used for clinical treatment of various tumors with DNA repair function defects, particularly for treatment of more than two combined cancers related to BRCA gene mutation, such as ovarian cancer, gastric cancer, breast cancer and the like, and for treatment of tumors related to BRCA1 and BRCA2 gene mutation.

The Ruicapab pharmaceutical composition provided by the invention has controllable drug release behavior, and the release behavior and the release amount are controllable in a release medium meeting the conditions of a leak groove within a preset time period. When a second method device for determining the dissolution rate in Chinese pharmacopoeia is adopted to determine the release behavior in a buffer solution with the pH value of 1.2-7.8 at 37 ℃, the release amount of the Ruipab in 1 hour is less than 40 percent of the total amount of the Ruipab, and the preferred range is 10-30 percent; the release amount of the Ruipab in 6-8 hours is 40-85% of the total Ruipab, preferably 50-70%; the amount of release of the licarpan in 12-16 hours is more than 80%, preferably > 90% of the total amount of the licarpan;

the Ruipafeb pharmaceutical composition has the following characteristics in vitro release degree detection result:

TABLE 1

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

The Ruipape pharmaceutical composition provided by the invention can regulate and control the absorption rate and absorption time of Ruipape in the gastrointestinal tract by controlling the release behavior and the release amount, wherein 10-50% of Ruipape in the pharmaceutical composition is absorbed within 1-6 hours, and 90% of Ruipape in the composition is absorbed within 12-16 hours.

Compared with the quick release tablet, the maximum blood concentration value (C) of the Ruocapab obtained by the Ruocapab pharmaceutical composition provided by the invention under the same dosage_max) The reduction is at least 10-70%, and the peak time (T) of the blood concentration is reduced_max) Elongation of at least 150% (preferably 200% -600%). The regulation and control of the steady-state blood concentration level, the fluctuation range of the free blood concentration, the PARP enzyme inhibition, the in-vivo safety and the administration frequency of the Ruocapab are realized by controlling the blood concentration, the peak reaching time and the area under the curve of the administration time.

The Ruicapab medicine composition provided by the invention can accurately regulate and control the steady-state blood concentration of the medicine in vivo, and the wave trough value of the steady-state blood concentration is 1uM<C_min,ss<10uM, preferably 2ug/mL<C_min,ss<9 ug/mL; the peak value of steady blood concentration is 5uM<C_max,ss<25uM, preferably 6uM<C_max,ss<20 uM. The sustained-release pharmaceutical composition can accurately regulate and control the blood concentration level and fluctuation range of the Ruipafebu, is beneficial to the long-term maintenance of the enzyme inhibition blood concentration level (such as the blood concentration level with 50 percent or 90 percent enzyme inhibition rate) required by effective anti-tumor, and simultaneously reduces the fluctuation range of the blood concentration, thereby improving the PARP enzyme inhibition rate and anti-tumor curative effect of tumor cells, reducing the adverse reaction of a tumor patient after medication and increasing the medication compliance of the patient.

Compared with the common quick-release preparation, the Ruicapab pharmaceutical composition provided by the invention has the following advantages:

1) can realize the controllable release and absorption of the medicine, provide accurate in vivo blood concentration and long-term stable high-efficiency PARP enzyme inhibition level, and play the tumor inhibition efficacy for a long time;

2) the drug absorption rate is controllable, the blood concentration range is adjustable, the fluctuation of the blood concentration is small, and the adverse reaction of the patient in drug administration is reduced;

3) the preparation can be taken once every day, so that the complicated process of the common preparation is reduced, and the clinical medication is more convenient;

4) because of controllable blood concentration and fluctuation range thereof, the safety window is larger, the dosage and the administration scheme can be flexibly adjusted in the clinical treatment process, and the dosage can be further provided for the medicament, so that the medicament effect is improved;

5) minimizing the size and/or number of tablets or capsules required for effective therapeutic dosages, while improving patient compliance, facilitating manufacture, storage and transportation, and increasing commercial value;

to better illustrate the properties of the pharmaceutical composition of Ruipab provided by the present invention, the following description is a detailed description of the present invention and should not be taken as limiting the scope of the present invention.

1. Tablet formulation

The Ruicapalb sustained-release tablet can be a framework type controlled-release tablet, an osmotic pump type controlled-release tablet or a sustained-release tablet based on sustained-release pellets. The matrix type controlled release tablet comprises a matrix type sustained release tablet, a matrix type slow double-effect double-layer tablet, a matrix type slow double-effect coating tablet and the like, the osmotic pump type controlled release tablet comprises an osmotic pump controlled release tablet and an osmotic pump slow double-effect tablet, and the slow controlled release tablet based on the sustained release pellet comprises a sustained release tablet based on the sustained release pellet and a slow double-effect tablet based on the sustained release pellet and the quick release pellet. The sustained-release tablets described above can specifically realize the drug release behavior of the present invention in the following manner.

1.1 matrix type controlled release tablets

The invention provides a Ruicapalb controlled-release matrix tablet and/or a matrix tablet with a slow-release double-effect release behavior.

The controlled release matrix tablet provided by the invention mainly comprises a slow release phase and an optional quick release phase.

The double-layer tablet consisting of a sustained-release phase and a quick-release phase is a quick-release double-effect release matrix tablet, while the single-layer tablet consisting of the sustained-release phase is a common sustained-release matrix tablet. Fig. 1 and 2 show a structural schematic diagram of a skeleton-type slow and dual-effect release double-layer tablet and a structural schematic diagram of a skeleton-type slow and dual-effect release coating tablet respectively according to one embodiment of the invention.

The sustained-release phase comprises 900 parts by weight, preferably 150 parts by weight, more preferably 200 parts by weight, of the above dissolution-improving form of Ricapa cloth in total, 10 to 300 parts by weight, preferably 30 to 150 parts by weight, of the release rate-regulating matrix polymer, 0 to 50 parts by weight of a diluent and 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight, of other usual additives for tablets, and is prepared by tabletting by a conventional method well known to those skilled in the art after the components are sufficiently mixed.

As noted above, where different numerical ranges appear for the same component of the same composition, all numbers within the stated maximum range and all alternative numerical ranges are deemed to be disclosed herein, and all integers, decimal values to the 1 st decimal place exactly after the decimal point and numerical ranges consisting of them are preferably included. The discussion also applies to parts by weight. For example, in the above, the lower limit of the weight part of the dissolution-improved form of the licarpan may be 100, 110, 120, … …, or 899 weight parts, and the upper limit of the weight part of the dissolution-improved form of the licarpan may be 900, 890, 880, … …, or 100.1 weight parts, that is, the weight part of the licarpan includes any combination between these lower and upper limits, such as 100 to 100.1 weight parts, 110 to 890 weight parts, and so forth. In the following, for the sake of brevity, possible values of the upper and lower limits of each numerical range will not be described in detail.

The matrix polymer for adjusting the release rate can be one or the combination of more than two of polyoxyethylene, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethyl cellulose, sodium alginate, povidone, copovidone, acrylic resin and carbomer; preferably one or more of hydroxypropyl cellulose, sodium alginate, hypromellose and carbomer.

The diluent is one or the combination of more than two of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch and sodium carboxymethyl starch.

The other tablet-forming additives include one or a combination of two or more of lubricants, colorants, and the like, which are generally used for solid formulations, and are well known to those skilled in the art. The lubricant is one or a combination of more than two of magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica powder, and the colorant is one or a combination of more than two of iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black and titanium dioxide.

The immediate release phase may comprise the dissolution-improved form of licarbamide described above, disintegrants, diluents and other additives commonly used in tablets, or comprise licarbamide, a solubilizing matrix polymer and other additives commonly used in tablets.

The quick-release phase can be prepared by mixing the components thoroughly and tabletting by conventional methods well known to those skilled in the art to form a quick-release layer, or dissolving the components simultaneously, coating the slow-release phase, and drying to form a quick-release coating film.

In the immediate release phase comprising the dissolution-improved form of the licarbau, the dissolution-improved form of the licarbau may be used in an amount of 20 to 600 parts by weight, preferably 30 to 400 parts by weight, more preferably 50 to 250 parts by weight. The disintegrant is one or more selected from crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, croscarmellose sodium and other pharmaceutical commonly used disintegrants, and the amount of the disintegrant is 5 to 90 parts by weight, preferably 10 to 50 parts by weight. The diluent is one or a combination of more than two of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch and sodium carboxymethyl starch, and the dosage of the diluent is 5 to 200 parts by weight, preferably 10 to 150 parts by weight. The tablet may be used with other additives, including one or a combination of two or more of lubricants and colorants commonly used in solid formulations, which are well known to those skilled in the art, and may be used in an amount of 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight. The lubricant is one or a combination of more than two of magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica powder, the using amount can be 0.1-20 parts by weight, the colorant is one or a combination of more than two of iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black and titanium dioxide, and the using amount can be 0-13 parts by weight.

In the immediate release phase comprising the licarpa, the solubilizing matrix polymer and other additives commonly used in tablets, the amount of licarpa may be 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 one or a combination of more than two of povidone, copovidone, Soluplus, hydroxypropyl methylcellulose phthalate (HPCP), polyethylene glycol, poloxamer, hydroxypropyl methylcellulose (HPMC) and other materials, and the dosage of the solubilizing matrix polymer can be 5-300 parts by weight, preferably 20-200 parts by weight, and more preferably 30-120 parts by weight. The other common additives for tablets include crospovidone, microcrystalline cellulose, and pharmaceutically acceptable surfactants (such as sodium lauryl sulfate), mannitol, lubricants (such as magnesium stearate), etc., which are well known to those skilled in the art, and can be used in an amount of 0.1 to 150 parts by weight, preferably 0.5 to 100 parts by weight.

In the matrix type fast-slow double-effect release tablet, the total weight of the Ruipab in the fast-release phase is 10-40 wt% of the total weight of the Ruipab in the whole fast-slow double-release matrix tablet, and the total weight of the Ruipab in the slow-release phase is 60-90 wt% of the total weight of the Ruipab in the whole fast-slow double-release matrix tablet.

The Ruicapab controlled release preparation with the rapid-release and slow-release behaviors is characterized in that in a release medium meeting the sink condition, according to the requirements of a release degree measurement method in Chinese pharmacopoeia 2015 edition, more than 90 wt% of the medicinal active ingredient distributed in the rapid release phase is preferably released within 2 hours, and more than 90 wt% of the medicinal active ingredient distributed in the rapid release phase is preferably released within 1 hour; the time for releasing more than 90 wt% of the active pharmaceutical ingredient in the sustained-release phase is preferably 10-16 hours; the release behavior of the active ingredients in the sustained-release phase conforms to the zero-order, first-order, Higuchi or Ritger-Peppas release model, and the zero-order release is preferred.

1.2 osmotic pump type controlled release tablet

The osmotic pump controlled release tablet provided by the invention can be a double-layer osmotic pump controlled release tablet or a double-layer osmotic pump speed-slow double release tablet. Fig. 3 and 4 show the schematic structure of an osmotic pump controlled release tablet and an osmotic pump type slow-release dual-effect release tablet, respectively, according to an embodiment of the present invention.

The osmotic pump controlled release tablet provided by the invention mainly comprises:

1) controlled release drug-containing layer: formed of a controlled release drug-containing layer composition within a rigid membrane shell adjacent to a drug release aperture;

2) push layer (also referred to as boost layer): the push layer composition is formed and is positioned in the rigid membrane shell and away from one side of the drug release hole;

3) the optional isolation coating layer is clamped between the inner surface of the rigid membrane shell and the tablet core consisting of the drug-containing layer and the push layer and is formed by drying the isolation coating composition;

4) a rigid membrane shell with moisture permeability, which is formed by drying a controlled release coating liquid, wherein one end of the membrane shell comprises one or more drug release holes;

5) an optional, non-limiting aesthetic coat;

6) optionally, a non-limiting immediate release drug-containing layer formed from an immediate release drug-containing layer composition, located outside the rigid membrane shell and/or optional aesthetic outer garment. Wherein the Ruicapa is 3-50 wt% of the total weight of the osmotic pump controlled release tablet based on the total weight of the osmotic pump controlled release tablet.

Wherein the Ruicapa is 3-50 wt% of the total weight of the osmotic pump controlled release tablet based on the total weight of the osmotic pump controlled release tablet.

The controlled release drug-containing layer composition comprises: 50 to 600 parts by weight, preferably 80 to 500 parts by weight, more preferably 120 to 400 parts by weight of a dissolution-improved form of revapram; 10 to 150 parts by weight, preferably 20 to 120 parts by weight, more preferably 30 to 100 parts by weight of a release modifier, and 0 to 40 parts by weight, preferably 0 to 30 parts by weight of other pharmaceutically customary auxiliaries.

The dissolution-improved form of ricepab may be selected from the group consisting of the above mentioned ricepab hydrochloride, a ricepab co-milled mixture, a nanocrystal or a solid dispersion, preferably a ricepab hydrochloride or a ricepab solid dispersion.

The release regulator can be one or more of polyvidone, copovidone, polyethylene oxide, carbomer, hypromellose, croscarmellose sodium, hydroxypropyl cellulose, and sodium lauryl sulfate.

The other pharmaceutically common excipients for the controlled release of the drug-containing layer composition are selected from, but not limited to, penetration aids, lubricants, colorants, and the like, which are commonly used in pharmaceutical tablets, and the amount thereof is conventionally selected in the art. The penetration enhancer is one or more of sodium chloride, lactose, mannitol, glucose, sucrose and fructose, preferably sodium chloride, and can be 0-20 weight parts. The lubricant is one or more of sodium stearyl fumarate, magnesium stearate, silica gel micropowder, pulvis Talci, polyethylene glycol and lauryl sulfate, and is 0-20 weight parts. The coloring agent is one or more of red iron oxide, yellow iron oxide, purple iron oxide, black iron oxide, etc., and is 0-10 weight parts.

The push layer composition typically includes a release rate modifying penetration-promoting polymer, an osmotic pressure-promoting agent, and other adjuvants.

The penetration-promoting polymer for regulating the release rate belongs to a high-molecular polymer, and can absorb water to swell in an aqueous medium so as to promote the release of the drug-containing layer. The release rate modifying penetration enhancing polymer may be a material well known to those skilled in the art, and includes one or a combination of two or more selected from the group consisting of polyoxyethylene, hydroxypropylmethylcellulose, hydroxypropylcellulose, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, croscarmellose sodium, crospovidone, copovidone, carbomer, alginic acid and/or derivatives thereof, and may be used in an amount of 10 to 300 parts by weight, preferably 20 to 250 parts by weight, and more preferably 50 to 180 parts by weight.

The osmotic pressure promoter is one or the combination of more than two of sodium chloride, lactose, mannitol, glucose, sucrose and fructose, preferably sodium chloride, and the dosage of the osmotic pressure promoter can be 20-150 parts by weight, preferably 25-100 parts by weight.

Other adjuvants in the push layer composition include, but are not limited to, lubricants, colorants, and the like, and may be used in amounts of 0.5 to 30 parts by weight, preferably 2 to 20 parts by weight. The lubricant is one or more of sodium stearyl fumarate and sodium stearate, and can be used in an amount of 0.2-15 parts by weight. The colorant is one or the combination of more than two of iron oxide black, iron oxide red and iron oxide yellow, and the using amount can be 0.5 to 15 parts by weight.

The controlled-release drug-containing layer and the push layer jointly form a tablet core of the osmotic pump controlled-release tablet. Based on the total weight of the tablet core, the controlled release drug-containing layer accounts for 40-80 wt%, and the push layer accounts for 20-60 wt%.

The isolating coating layer can be formed by spraying the isolating coating liquid on the tablet core and drying. The barrier coat coating solution generally comprises a barrier coat material and a solvent. The isolation coating material is one or a combination of more than two selected from hydroxypropyl methyl cellulose, povidone, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, polyethylene glycol and stearic acid, but is not limited to the above. The solvent includes one or a combination of two or more of ethanol, water, acetone, and isopropyl alcohol, but is not limited thereto. The thickness of the barrier coat can affect the release of the pharmaceutical formulation and can be controlled by the amount of spray applied, typically, the barrier coat film is increased by 0-10 wt% relative to the core.

The rigid membrane shell can also be called a controlled release coating layer and is formed by spraying controlled release coating liquid on a tablet core formed by a medicine-containing layer and a push layer and drying, and the weight of the rigid membrane shell is increased by 3-20 wt%, preferably 5-15 wt% relative to the tablet core.

The controlled release coating liquid comprises 4 to 40 weight parts, preferably 10 to 30 weight parts of semipermeable controlled release coating film material, 0 to 20 weight parts of plasticizer, 0 to 20 weight parts of pore-forming agent and 50 to 1000 weight parts, preferably 200 to 800 weight parts of solvent.

The semipermeable controlled-release coating material is one or the combination of more than two of cellulose acetate, ethyl cellulose and acrylic resin.

The plasticizer is one or a combination of more than two of methyl phthalate, ethyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, acetyl tributyl citrate, triacetin and castor oil.

The pore-forming agent is one or the combination of more than two of glycerol, povidone, copovidone, propylene glycol, polyethylene glycol and water-soluble inorganic salt.

The solvent is selected from one or the combination of more than two of acetone, water, ethanol, isopropanol, dichloromethane and methanol.

The membrane shell comprises one or more drug releasing holes, and the drug releasing holes can be prepared by mechanical drilling or laser drilling. The drug release holes can have any geometric shape, such as a circle, an ellipse, a square, a triangle and the like, and the average pore diameter ranges from 0.3 mm to 1.2 mm.

The aesthetic coat is formed by spraying the aesthetic coat coating liquid on the tablet core and drying, and can be coated with a layer of aesthetic coat in a non-limiting way, and the aesthetic coat is generally coated with a common double-layer osmotic pump tablet in a non-limiting way. Slow release dual action osmotic pump tablets having a fast release phase coating are rarely applied to aesthetic coatings. The aesthetic coating can improve the appearance of the formulation to increase patient compliance for dosing while providing color identification. The aesthetic outer coating solution is a conventional choice in the art and includes opadry as well known to those skilled in the art and other coating powders that can be formed into the aesthetic outer coating. In addition, the aesthetic outer coating liquid can also comprise one or more selected from coloring agents, plasticizers, opacifiers, anti-sticking agents and solvents. The aesthetic coat is typically increased by 0-10 wt% relative to the core.

When the quick-release medicine-containing layer exists, the osmotic pump controlled-release tablet is a quick-slow double-release osmotic pump tablet. The quick-release drug-containing layer can be formed by spraying the composition containing the quick-release drug-containing layer on a tablet core and drying. The immediate release drug-containing layer composition comprises: 10-80 parts of active ingredient Ruipab, 10-100 parts of solubilizing matrix polymer component, 0-30 parts of other pharmaceutically common auxiliary materials and 100-2000 parts of solvent. The solubilizing matrix polymer component is one or more of polyvidone, copovidone, Soluplus, hypromellose phthalate (HPMCP), polyethylene glycol, poloxamer, polymethacrylic acid, polyethylacrylate, Hypromellose (HPMC), polymethacrylate, and hydroxypropyl cellulose. The other common pharmaceutical auxiliary materials comprise crospovidone, microcrystalline cellulose, medicinal surfactant (such as sodium dodecyl sulfate) and other common additives of the quick-release tablet, which are well known by the technical personnel in the field; the solvent comprises one or more of ethanol, acetone and water.

For the rapid-release double-effect release osmotic pump tablet, the total weight of the Ruipab in the rapid-release drug-containing layer is 10-40 wt% of the total weight of the Ruipab in the whole rapid-release double-effect release osmotic pump tablet, and the total weight of the Ruipab in the controlled-release drug-containing layer is 60-90 wt% of the total weight of the Ruipab in the whole rapid-release double-effect release osmotic pump tablet.

The preparation method of the Ricapamide osmotic pump controlled release tablet comprises the following steps of preparing the Ricapamide in ① dissolution improved form, preparing a ② drug-containing layer, preparing a ③ propelling layer, preparing a ④ double-layer tablet, preparing a ⑤ optional double-layer tablet isolation coating film, preparing a ⑥ controlled release coating film, perforating a ⑦ osmotic pump tablet controlled release coating film, preparing a ⑧ optional aesthetic coating layer, preparing a ② 0 optional quick release drug-containing layer, and preparing the ② - ⑨ by adopting a conventional pressing and coating method well known to those skilled in the art.

The tablet coated with the quick-release medicine-containing layer outside the rigid membrane shell is an osmotic pump slow-release double-release tablet, and the tablet not coated with the quick-release medicine-containing layer outside the rigid membrane shell is a common osmotic pump controlled-release tablet.

The design of the fast-slow double-release tablet can better exert the drug effect of the Ruipab, the design of the fast-release phase ensures the rapid release of the initial drug, the requirement that the drug rapidly reaches the blood concentration level required by effective PARP enzyme inhibition is met, the fast effect is achieved, the design of the slow-release phase can ensure the stable release of the later active ingredients, the long-time maintenance of the blood concentration required by the effective enzyme inhibition is ensured, the enzyme activity inhibition is further kept, the curative effect is improved, and meanwhile, the toxic and side effects caused by the large fluctuation of the blood concentration are reduced.

1.3. Controlled release tablet based on sustained release pellets

In another aspect, the invention provides sustained-release tablets of nicalpab based on sustained-release pellets. The slow-release tablet based on the slow-release pellet of the Ruicapab can be a slow-release tablet based on the slow-release pellet and a fast-release matrix/slow-release pellet-based slow-release double-effect release tablet.

In the quick-release and slow-release double-effect release tablet, a quick-release matrix forms a quick-release phase, and a slow-release pill forms a slow-release phase. In the whole quick-release and slow-release double-effect release tablet, the Ruipab in the quick-release phase accounts for 5-40 wt% of the total weight of the Ruipab; the total weight of the Ruipab in the sustained-release pill is 60-95 wt%.

The immediate release matrix may include the above-described dissolution modifying forms of the pharmaceutically active ingredient, disintegrants, diluents and other common additives to tablets.

In the immediate release matrix comprising the pharmaceutically active ingredient in a dissolution-improved form, the amount of the dissolution-improved form of the licarpb may be 20 to 200 parts by weight, preferably 50 to 150 parts by weight. The disintegrant is one or a combination of more than two selected from crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, croscarmellose sodium and other pharmaceutical commonly used disintegrants, and the dosage of the disintegrant is 5 to 200 parts by weight, preferably 10 to 100 parts by weight, and more preferably 20 to 80 parts by weight. The diluent is one or a combination of more than two of microcrystalline cellulose, pregelatinized starch, sucrose, mannitol, sorbitol, sucrose, starch and sodium carboxymethyl starch, and the dosage of the diluent is 5 to 200 parts by weight, preferably 10 to 150 parts by weight. The other additives commonly used for tablets include one or a combination of two or more of lubricants and colorants commonly used for solid formulations well known to those skilled in the art, and may be used in an amount of 0.2 to 30 parts by weight, preferably 1 to 30 parts by weight. The lubricant is one or a combination of more than two of magnesium stearate, stearic acid, sodium stearyl fumarate, talcum powder and superfine silica powder, the using amount can be 0.1-20 parts by weight, the colorant is one or a combination of more than two of iron oxide red, iron oxide yellow, iron oxide purple, iron oxide black and titanium dioxide, and the using amount can be 0-13 parts by weight.

The sustained-release pellets can comprise coated sustained-release pellets and skeleton-type sustained-release pellets, and can be prepared by a conventional method such as wet granulation, extrusion spheronization, coating pan coating and/or fluidized bed granulation coating, which is well known to those skilled in the art, by non-limiting methods such as blank pellet cores (0-300 parts by weight), Ruipabab hydrochloride (such as phosphate, hydrochloride, benzene sulfonate, sulfate, camphorate and the like), matrix for release rate adjustment or controlled-release coating film materials and other auxiliary materials. For example, the sustained-release pellet is prepared by coating the drug-loaded pellet in a coating pan in one pan, wherein the Ruipab is dispersed or coated on a blank pellet core to form a drug-loaded pellet core, and then a layer of controlled-release coating material such as Sulisi is coated on the drug-loaded pellet core to form a sustained-release coating, thereby forming the coated sustained-release pellet. The blank pellet core is one or the combination of more than two of sucrose pellet core, starch pellet core, microcrystalline cellulose pellet core, silicon dioxide pellet core and hydroxypropyl cellulose pellet core. For another example, the sustained-release pellet is prepared by a fluidized bed method, wherein the matrix for regulating the release rate and the licarpa are simultaneously dissolved, then the mixture is placed in a spray drying instrument, air flow is blown, spray drying is carried out, samples are collected, the adhesive is added, and the granulation and drying are carried out to form the skeleton type sustained-release pellet.

In the sustained-release pellet, the release rate regulating matrix or the controlled-release coating material may be one or more selected from shellac, Cellulose Acetate Phthalate (CAP), acrylic resin (Eudragit), Ethyl Cellulose (EC), polypropylene polysiloxane, cellulose acetate, cellulose propionate, cellulose acetate propionate, polyvinyl alcohol, polyvinyl pyrrolidone (PVP), methyl cellulose, hydroxypropyl methyl cellulose (HPMC), and the like. The other auxiliary materials mainly comprise, but are not limited to, an adhesive, a plasticizer, a pore-foaming agent and the like. The pore-forming agent is one or more selected from hydrophilic liquid carriers (glycerin, PEG200), saccharides (lactose, fructose, sucrose, mannose), surfactants (polysorbate 80, sodium dodecyl sulfate and the like), and macromolecules (povidone, hypromellose and the like).

In one embodiment, the sustained-release pellet comprises 250 parts by weight, preferably 200 parts by weight, of the blank pellet core, 10 to 150 parts by weight, preferably 10 to 100 parts by weight, more preferably 30 to 100 parts by weight, of the Ricapabu hydrochloride, 10 to 300 parts by weight of the matrix or the controlled-release coating material for regulating the release rate, 0 to 100 parts by weight of the binder, 0 to 12 parts by weight of the pore-forming agent, and 0 to 15 parts by weight of the plasticizer.

Finally, the sustained-release pill is directly tabletted to prepare the sustained-release tablet based on the sustained-release pellet. If the quick-release matrix and the sustained-release pellet are uniformly mixed according to the specification proportion, and then the mixture is pressed into tablets by a tablet press with a special stirring function, the fast-release and sustained-release preparation can be prepared.

2. Capsule preparation

The present invention also provides a sustained-release capsule formulation, which may be selected from a pellet-based sustained-release capsule and a tablet-based sustained-release capsule. Fig. 5 shows a schematic structure of a capsule containing immediate release pellets and matrix-type sustained-release pellets according to an embodiment of the present invention, fig. 6 shows a schematic structure of a sustained-release pellet capsule containing an immediate release coating according to an embodiment of the present invention, and fig. 7 shows a schematic structure of a capsule containing immediate release and sustained-release tablets.

2.1 sustained-release Capsule based on micropellets

The sustained-release capsule based on the pellets is a controlled-release capsule consisting of sustained-release pellets or a sustained-release capsule consisting of sustained-release pellets and quick-release pellets, and can comprise a capsule containing skeleton type sustained-release pellets, a capsule containing coated sustained-release pellets, a capsule containing quick-release coated sustained-release pellets, a sustained-release capsule containing quick-release pellets and skeleton type sustained-release pellets and a sustained-release capsule containing quick-release pellets and coated sustained-release pellets.

The sustained-release capsule based on the micro-pill can be a sustained-release capsule based on the sustained-release micro-pill and a slow-release double-effect capsule based on quick-release micro-pill and sustained-release micro-pill. For the rapid-release and slow-release dual-effect capsule, the rapid-release pellets form a rapid-release phase, and the slow-release pellets form a slow-release phase. Based on the total weight of the Ruipab in the quick-release and slow-release double-effect capsule, the weight of the Ruipab in the quick-release phase is 5 to 40 percent; the proportion of the Ruipab in the sustained-release pellet is 60-95 wt%.

The composition, preparation method, material selection, content and the like of the coated sustained-release pellets and the matrix sustained-release pellets are the same as those of the sustained-release pellets in the section 1.3 above, and are not repeated here.

The sustained-release pellet containing the quick-release coating can be prepared by directly coating the quick-release matrix on the surface of the framework type sustained-release pellet or the coated sustained-release pellet.

The immediate release pellets can be prepared by dissolving the immediate release matrix and then coating it onto a blank pellet core by conventional coating methods well known to those skilled in the art, or by preparing the immediate release matrix directly into pellets.

The description of the composition, material selection, content, etc. of the immediate release matrix is the same as that of the immediate release matrix of section 1.2 above and will not be repeated here.

The sustained-release pill can be prepared into a controlled-release capsule by encapsulating, and the quick-release pill and the sustained-release pill are weighed according to a certain proportion, uniformly mixed and encapsulated, so that the fast-and-sustained-release capsule preparation can be prepared, or the sustained-release pellet containing the quick-release coating can be encapsulated and encapsulated, or the fast-and-sustained-release capsule preparation can be prepared.

2.2 sustained/controlled release Capsule based on Microtablets

The sustained-release capsule based on the micro-tablets is a controlled-release capsule consisting of sustained-release tablets or a fast-release dual-release capsule consisting of sustained-release micro-tablets and fast-release micro-tablets, and can comprise a capsule containing framework type sustained-release micro-tablets, a capsule containing fast-release coating framework type sustained-release micro-tablets and a capsule containing fast-release micro-tablets and framework type sustained-release micro-tablets. Generally, tablets made for hard gelatin capsules are small in diameter, typically <5 mm. .

For the fast-release and slow-release dual-effect capsule, the fast-release micro-tablets form a fast-release phase, and the slow-release micro-tablets form a slow-release phase. (ii) the rapid release phase comprises from 5 to 40 wt% of the licarbab based on the total weight of the licarbab in the capsule; the Ruipab in the slow-release phase accounts for 60-95 wt%.

The description of the composition, preparation method, material selection and content, etc. of the matrix-type sustained release tablet is the same as that of the above 1.2 part of the matrix-type controlled release tablet, and will not be repeated here.

The matrix-type sustained-release tablet containing a quick-release coating can be prepared by directly coating the surface of the matrix-type sustained-release tablet with a quick-release matrix.

The immediate release tablet can be prepared by direct compression of an immediate release matrix.

The matrix type sustained release tablets are encapsulated to prepare a sustained release capsule preparation, and the quick release tablets and the sustained release tablets are uniformly mixed according to a certain proportion and then encapsulated, or the matrix type sustained release tablets containing quick release coatings are encapsulated to prepare the fast-release and sustained-release capsule.

Drawings

FIG. 1 is a structural schematic diagram of a skeleton type slow release double-effect release double-layer tablet.

Fig. 2 is a structural schematic diagram of a skeleton type slow and slow double-effect release coating tablet.

Fig. 3 is a schematic structural view of an osmotic pump type controlled release tablet.

Fig. 4 is a structural schematic diagram of an osmotic pump type slow and slow release double-effect release tablet.

FIG. 5 is a schematic structural diagram of a capsule containing an immediate release pellet and a matrix-type sustained release pellet.

FIG. 6 is a schematic diagram of a sustained release pellet capsule with an immediate release coating.

Figure 7 is a schematic of the structure of a capsule containing immediate release and extended release tablets.

Figure 8 is the release profile of the sustained dual release matrix tablet of example 1.

FIG. 9 is a dissolution profile of the immediate release tablet of comparative example 1.

Figure 10 is a graph comparing the in vivo dosing time for the immediate release tablet of example 1 and the sustained dual release matrix tablet of example 1.

FIG. 11 is the release profile of the bilayer osmotic pump controlled release tablet of example 3 in release media at pH 1.2, 4.5 and 6.8.

FIG. 12 is the release profile of the matrix sustained release tablet of example 4 in a release medium at pH 6.8.

Detailed Description

The following examples generally describe the preparation and/or characterization of exemplary compositions of the invention, all percentages being by weight unless otherwise indicated. The following examples are intended to be illustrative of the present invention and should not be construed as limiting the scope thereof. In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.

Experimental animals: 6 beagle dogs, half male and half female dogs and 8-10 kg body weight. The sources are all Beijing Ma Si Biotech limited. The test animals were kept in an adaptive manner at the test site of the laboratory animal center of Shanghai pharmaceutical research institute 14 days before the test day.

The tablets were prepared using a single-punch tablet press (TDP-1, Asahan mechanical Equipment Co., Ltd., Guangzhou).

The three-dimensional mixer is model T2F from turboula.

The melt extruder was a model of Pharma11 available from seraphenan.

EXAMPLE 1 Slow Dual Release matrix tablet

A quick release layer: sieving the prescription dose of the Ruipab, the micropowder silica gel and the Soluplus through a 60-mesh sieve, uniformly mixing by a three-dimensional mixer, mixing for 25 minutes at 30rpm, slowly adding into a preheated melt extruder, collecting an extrudate, crushing and sieving through the 60-mesh sieve to obtain the Ruipab solid dispersion. The obtained Ruipab solid dispersion is uniformly mixed with other materials (a disintegrating agent PVPP XL) and other auxiliary materials (mannitol and magnesium stearate) according to the prescription amount, and then the mixture is tabletted.

A slow release layer: screening the prescription dose of the Ruipab, PVP VA64 and aerosil through a 60-mesh sieve, uniformly mixing, slowly adding into a preheated melt extruder, collecting the extrudate, crushing and screening through the 60-mesh sieve to obtain the Ruipab solid dispersion. The obtained nicalpab solid dispersion was mixed with the prescribed amount of the release rate modifying polymer HPMC K15M (BASF, germany) and the lubricant magnesium stearate and was ready for tableting.

Tabletting: the fast-slow double-release matrix tablet with proper hardness is prepared by a direct compression method.

The release degree of the controlled release preparation is measured by a dissolution method (appendix X C of the second part of 2010 edition of Chinese pharmacopoeia) second method device, under the condition of 37 ℃, using buffer solution with pH6.8 as a release medium, rotating at 75 revolutions per minute, operating according to the method, taking 6mL of solution through 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, 13 and 16h, centrifuging, taking supernatant as a test solution, and measuring the release degree.

The absorbance was measured at a wavelength of 238nm according to ultraviolet-visible spectrophotometry (appendix IV A of the second part of the pharmacopoeia 2010 edition) to determine the release of the tablets.

The release results are shown in FIG. 8. The quick-release double-effect framework double-layer tablet realizes about 20% of medicine quick release within 30 minutes, about 60% of medicine release within about 8 hours, and the rest medicine can be completely released within about 16 hours. This release profile controls the concentration range of the Ruipab in blood, rapidly achieves the drug concentration required for PARP enzyme inhibition after oral administration, and maintains this level for a prolonged period of time.

COMPARATIVE EXAMPLE 1 immediate Release tablet

The immediate release tablet formulation is as follows:

the active component of the granules, namely the Ruipab dexcamphorsulfonate, and auxiliary materials, namely microcrystalline cellulose PH101, mannitol sodium starch, colloidal silicon dioxide and magnesium stearate, are uniformly mixed according to the prescription proportion, sieved and uniformly mixed in a three-dimensional multi-directional mixer, 98 percent ethanol is used as a bonding solvent, the granules are sieved, the auxiliary materials among granules in the prescription amount are added and uniformly mixed, and then the quick-release tablet prescription is obtained by tabletting.

The dissolution rate is determined by adopting a dissolution rate determination method (appendix X C of the second part of 2010 edition of Chinese pharmacopoeia) first method device, taking 6mL of solution after 15, 30, 45, 60, 75, 90, 105 and 120min by using 900mL of release medium with pH 2.0 at 37 ℃ and rotating at 75 revolutions per minute, centrifuging, taking supernatant as test solution, and determining the release rate.

The release results are shown in FIG. 9. The active ingredient of the rapid-release comparative tablet is more than 95% released in about 15 minutes.

Experimental example 1

The immediate release tablet of the racepabu of comparative example 1 and the fast-slow dual release matrix tablet of example 1 were administered to a saturated beagle dog (n ═ 3) with 25mL of water, and blood was taken at a predetermined time point after administration, and blood samples were centrifuged at 4000rpm for 10min at 4 ℃.

C relative to immediate release tablets_max(2750.3ng/mL) and AUC_0-h(19470h ng/mL), fast and slow dual release matrix tablet C_maxReduced to 1589.4ng/mL, a reduction of about 42%; AUC_0-h20110h ng/mL, change<10 percent; it can still be seen from the results of the time course graph 10 that the C of the matrix tablet is released slowly and slowly compared with the immediate release tablet_maxThe compound can be maintained at a higher blood concentration for a longer time, reduce the toxic and side effects caused by the sudden high blood concentration, prolong the time of the blood concentration level required by PARP enzyme inhibition, better exert the anti-tumor effect and provide a larger dosage space for the dosage ramp of the medicine and the exertion of the optimal medicine effect.

Example 2: sustained-release pill capsule and/or quick-release double-effect capsule containing quick-release pill and sustained-release pill

① sustained-release pill

I) Medicine-carrying pill core

II) coating isolation coating

III) coating of the sustained Release coating

② quick-release pill

The preparation method comprises the following steps:

quick-release pill: dissolving or dispersing prescription dose of Ruipafebribub phosphate and copovidone (VA64) in 95% ethanol solution to prepare quick-release pill drug-carrying solution, and spraying the quick-release pill drug-carrying solution onto prescription dose of microcrystalline cellulose blank pill core in a fluidized bed coating manner to obtain the quick-release pill.

Sustained-release pill: weighing a proper amount of a matrix hydroxypropyl cellulose (SSL) for adjusting the release rate, dispersing the matrix hydroxypropyl cellulose (SSL) into a 95% ethanol solution to prepare a coating solution with the solid content of 10%, and fully and uniformly stirring the coating solution on a magnetic stirrer; and weighing the prescription amount of the Ruipafebu phosphate, and uniformly dispersing the Ruipafebu phosphate in the coating liquid to serve as a medicine-carrying coating liquid for later use.

Adding microcrystalline cellulose blank pill core into fluidized bed, regulating operation parameters such as air quantity and temperature, spraying prepared drug-loaded coating liquid, carrying out drug loading, and preparing drug-loaded pill core.

Dissolving or dispersing the film component of the isolation coating in 95% ethanol solution, and spraying onto the medicine-carrying pill cores in the prescribed amount by adopting a fluidized bed coating mode; obtaining the drug-loaded pill core of the coating isolation coating.

Adding appropriate amount of water solution into the water dispersion of the sustained-release coating solution, diluting, mixing to obtain sustained-release coating solution, and spraying onto the core of the drug-loaded pill coated with the isolation coating by fluidized bed coating to obtain sustained-release pill.

And (3) capsule filling: and (3) encapsulating the prepared sustained-release pills to prepare sustained-release capsules.

And (3) fully and uniformly mixing the prepared quick-release pills and sustained-release pills according to the prescription amount, and filling capsules to prepare the quick-release and sustained-release capsules.

EXAMPLE 3 double layer osmotic Pump controlled Release tablets

The preparation method comprises the steps of preparing a solid dispersion by a solvent volatilization method of the Ruicapa cloth and the copovidone VA64, namely dissolving the Ruicapa cloth and the copovidone VA64 in ethanol/acetone (25/75, v/v), removing the organic solvent by decompression, drying in a vacuum drying oven, grinding, crushing, sieving with a 60-mesh sieve, and tabletting.

Mixing with povidone K90 and magnesium stearate as other adjuvants, sieving with 60 mesh sieve, mixing with three-dimensional mixer at 30rpm for 25min to obtain controlled release medicinal layer composition, and tabletting.

And precisely weighing auxiliary materials of the boosting layer, sieving the auxiliary materials by a 60-mesh sieve, and uniformly mixing the auxiliary materials by a three-dimensional mixer (25rpm for 30 minutes) to obtain the composition of the boosting layer. The osmotic pump bilayer tablet core containing the drug-containing layer and the boosting layer is pressed by the above drug-containing layer composition and boosting layer composition in a vertical compression mode. And (3) coating a controlled-release coating layer by using 4% of cellulose acetate solution, and increasing the weight of the coating film by 10% to obtain the double-layer osmotic pump controlled-release tablet.

The release degree of the double-layer osmotic pump controlled release tablet is measured by adopting a dissolution rate measuring method (appendix X C of the second part of 2010 edition of Chinese pharmacopoeia), a second method device is adopted to measure the release degree of the double-layer osmotic pump controlled release tablet, buffer solutions with pH values of 1.2, 4.5 and 6.8 are respectively used as release media (7.65mL of hydrochloric acid is diluted by adding water to 1000mL to prepare the release media with pH value of 1.2; 250mL of 0.2mol/L potassium dihydrogen phosphate solution is respectively added with 0mL and 112mL to prepare the release media with pH values of 4.5 and 6.8), the rotating speed is 75 r/min, the operation is carried out according to the method, 6mL of the solution is taken after 0.5, 1, 2, 4, 6, 8, 10, 12, 13 and 16h, the solution is centrifuged, and the supernatant is taken as a test.

The release results in different pH release media are shown in FIG. 11. The result shows that the double-layer osmotic pump controlled release tablet is not affected by pH basically, the active ingredient Ruipab can be released at a constant speed basically, the release rate is less than 10% in 1 hour, the release rate is about 50% in 6 hours, the release rate is more than 80% in 12 hours, and the total release time can reach 14 hours.

Example 4: sustained-release matrix tablet

The Ruipab dexcamphorsulfonate and povidone K30(BASF, Germany) were sieved through a 60 mesh sieve for 3 times, and then mixed through a three-dimensional mixer at 30rpm for 25 minutes, the mixture was slowly added to a preheated melt extruder, and the transparent extrudate was collected and pulverized and sieved through a 60 mesh sieve to obtain Ruipab dexcamphorsulfonate solid dispersion. The solid dispersion is prepared into a sustained-release matrix tablet with proper hardness by uniformly mixing a matrix polymer hydroxypropyl cellulose (K4M, BASF, Germany) with a prescription amount and a release rate adjusting amount, adding a lubricant magnesium stearate, uniformly mixing, and tabletting.

The release rate result is shown in figure 12, the quantity of the Ruipafe released by the sustained-release matrix tablet in 1 hour is less than 20%, the release rate in 8 hours is about 55%, and the release duration can reach 16 hours.

Claims

1. An oral sustained and controlled release pharmaceutical composition of nicalpab comprising: a dissolution-improved form of licarpa; and a matrix polymer for regulating the release rate,

the dissolution-improved form of nicalpab comprises: a licarbap hydrochloride, a licarbap co-ground mixture, a licarbap nanocrystal and a licarbap solid dispersion, preferably a licarbap solid dispersion,

preferably, the release rate adjusting matrix polymer is one or a combination of two or more selected from hydroxypropyl cellulose, polyoxyethylene, hypromellose, methylcellulose, hydroxyethyl cellulose, ethylcellulose, sodium alginate, povidone, copovidone, acrylic resin and carbomer, and is preferably one or a combination of two or more selected from hydroxypropyl cellulose, sodium alginate, hypromellose and carbomer.

2. The oral sustained and controlled release pharmaceutical composition of Ruicapa according to claim 1, wherein the Ruicapa pharmaceutical composition has a drug release behavior,

when a second method device of Chinese pharmacopoeia dissolution determination method is adopted to perform release behavior determination in a buffer solution with the pH value of 1.2-7.8 at 37 ℃, the release is less than 40 wt% of the total amount of Ruicapab within 1 hour, and the preferred release is 10-30%; 45-85%, preferably 50-70% of the total amount of the Ruipafeb released in 6-8 hours; release of greater than 80%, preferably > 90%, of the total in 12-16 hours; or,

the steady-state blood concentration wave trough value C of the Ruicapab medicine composition_min,ssIs 0.2-4ug/mL, preferably 0.5-3 ug/mL; peak value C of steady state blood concentration_max,ssIs 0.8-15ug/mL, preferably 1-12ug/mL, and the steady state blood concentration peak/trough ratio is preferably less than 6.

3. The oral sustained and controlled release pharmaceutical composition of claims 1 or 2, wherein

The Ruipab co-ground mixture consists of the active drug Ruipab, a solubilizing matrix polymer and other additives, and is prepared by co-grinding the ingredients; in the co-mulled mixture, the weight percent of the licarpa is 5% to 60%, preferably 20% to 40%, the weight percent of the solubilizing matrix polymer is 40% to 95%, preferably 40% to 80%, and the weight percent of the other additives is 0% to 15%, preferably 0.2% to 10%, based on the total weight of the co-mulled composition;

the Ruipab nanocrystal consists of an active drug Ruipab, a matrix polymer for solubilization and/or other additives, and is obtained by preparing the components into nano-sized particles by a high-pressure homogenization or coprecipitation method; in the Ruipab nanocrystal, the weight percentage of Ruipab is 10-99 wt%, preferably 20-50 wt%, based on the total weight of the Ruipab nanocrystal; the weight percentage of the solubilizing matrix polymer is 1 to 75 wt%, preferably 1 to 65 wt%, and the weight percentage of other additives is 0 to 10 wt%, preferably 0 to 5 wt%; the grain size of the nano crystal is preferably 50-1000 nm;

the solid dispersion consists of the active drug Ruipab, a solubilizing matrix polymer and other additives, and is manufactured by a solvent evaporation method or a melt extrusion method, wherein the weight percentage of the Ruipab in the solid dispersion is 5-50 wt%, preferably 20-40 wt%, the weight percentage of the solubilizing matrix polymer is 45-95 wt%, preferably 50-80 wt%, and the weight percentage of the other additives is 0-12 wt%, preferably 0-10 wt%, based on the total weight of the solid dispersion.

4. The oral sustained and controlled release pharmaceutical composition of claim 3,

the matrix polymer for solubilization is one or the combination of more than two of povidone, copovidone, polyoxyethylene, Soluplus, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl cellulose acetate succinate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethylacrylate, 1: 12-hydroxypropyl- β -cyclodextrin, hydroxypropyl methylcellulose (HPMC), polymethacrylate, hydroxypropyl cellulose, Cellulose Acetate Phthalate (CAP) and other medicinal solubilization polymers;

the other additives are one or more of pharmaceutically-acceptable solubilizing surfactants (such as polyethylene glycol stearate and sodium lauryl sulfate), lubricant, silica gel micropowder, and plasticizer.

5. The oral sustained or controlled release pharmaceutical composition of racelpaabric of any of claims 1 to 4, comprising 50 to 900 parts by weight, preferably 80 to 700 parts by weight, more preferably 120 to 600 parts by weight of dissolution-improved form of racelpaabric; and 10 to 300 parts by weight, preferably 20 to 250 parts by weight, more preferably 50 to 180 parts by weight of a release rate regulating matrix polymer.

6. The oral sustained and controlled release pharmaceutical composition of any of claims 1-5, comprising licarbapu

50-800 parts by weight of a Ruipab co-ground mixture, and 10-200 parts by weight of a release rate modifying matrix polymer; or

50 to 800 parts by weight of Ruipab nanocrystals, and 0.1 to 250 parts by weight of a release rate-regulating matrix polymer; or

50 to 900 parts by weight of a Ruipab solid dispersion, and 20 to 300 parts by weight of a release rate regulating matrix polymer.

7. The oral sustained and controlled release pharmaceutical composition of Ruicapab according to any one of claims 1 to 6, which is a sustained and controlled release formulation of a single sustained release phase or a dual-effect sustained release formulation containing both an immediate release phase and a sustained release phase;

preferably, the first and second electrodes are formed of a metal,

the sustained-release phase is a controlled-release composition containing a pharmaceutical active ingredient, and is selected from a controlled-release tablet, a controlled-release pellet, a controlled-release composition in a tablet or a pellet core, a controlled-release layer composition combined in a bilayer tablet and a combination of any form thereof;

the quick-release phase is a quick-release composition containing a medicinal active component, and is selected from quick-release tablets, quick-release pills, quick-release compositions in tablets, quick-release coating layers coated outside the controlled-release tablets or pill cores, quick-release layer compositions in double-layer controlled-release tablets and any form of combination thereof.

8. The oral sustained and controlled release pharmaceutical composition of claim 7, wherein in the sustained-release dual-effect controlled release formulation, the pharmaceutical active ingredient in the immediate release phase accounts for 10-50 wt%, preferably 20-40 wt% of the total amount of the pharmaceutical active ingredient; the pharmaceutical active ingredient in the sustained-release phase accounts for 50-90 wt%, preferably 60-80 wt% of the total amount of the pharmaceutical active ingredient.

9. The oral sustained-release pharmaceutical composition of Ruicapab according to any one of claims 1 to 8, which is a tablet or a capsule, preferably selected from the group consisting of osmotic pump controlled-release tablets, osmotic pump sustained-release tablets, matrix sustained-release double-effect double-layer tablets, matrix sustained-release tablets, sustained-release tablets based on sustained-release pellets, sustained-release double-effect tablets based on sustained-release pellets and immediate-release pellets, capsules containing matrix sustained-release pellets, capsules containing coated sustained-release pellets, capsules containing immediate-release coated sustained-release pellets, sustained-release double-release capsules containing immediate-release pellets and matrix sustained-release pellets, sustained-release double-release capsules containing immediate-release pellets and coated sustained-release pellets, capsules containing matrix sustained-release pellets, capsules containing immediate-release coated matrix sustained-release pellets, and capsules containing immediate-release pellets and matrix sustained-release pellets.

10. Use of the oral sustained and controlled release pharmaceutical composition of Ricapabu according to any one of claims 1-9 for the preparation of a medicament for the prevention or treatment of tumors with defects in DNA repair function, in particular combined cancers of two or more related to BRCA gene mutations, such as ovarian cancer, gastric cancer, breast cancer, and for tumors related to BRCA1 and BRCA2 gene mutations.