CN110062628B

CN110062628B - Ruicapalb oral sustained and controlled release pharmaceutical composition and application thereof

Info

Publication number: CN110062628B
Application number: CN201780075213.2A
Authority: CN
Inventors: 甘勇; 孟冰雪; 郭仕艳; 朱春柳
Original assignee: Science Rainbow Biopharma Co ltd
Current assignee: Science Rainbow Biopharma Co ltd
Priority date: 2016-12-16
Filing date: 2017-12-15
Publication date: 2023-02-17
Anticipated expiration: 2037-12-15
Also published as: CN110062628A; CN108201534A; WO2018108157A1

Abstract

An oral sustained-release pharmaceutical composition of Ruipab, comprising a dissolution-improved form of Ruipab and a release rate modifying matrix polymer. The pharmaceutical composition has controllable in vivo absorption behavior, blood drug concentration and PARP enzyme inhibition level, improves the drug loading of the Ruipab and/or oral absorption and/or bioavailability and/or blood drug concentration control and/or enzyme inhibition level control, and can be used as a unique preparation or combined with other therapies for treating cancers.

Description

Oral sustained and controlled release pharmaceutical composition of Ruipafebu and application thereof

Technical Field

The invention relates to the field of Ruipafebu pharmaceutical preparations, in particular to a Ruipafebu oral sustained-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 C ₁₉ H ₁₈ FN ₃ O, molecular weight 323.46, having the following chemical structure:

ricapab was developed by the Gilles de la Tourette tumor Inc. (Clovis Oncology) for new drugs and marketing; in 2012, this compound was used as an orphan drug in the us and europe for the study of ovarian cancer; in 2015, the drug, as a three-line clinical drug of monotherapy, was used for clinical treatment research of BRCA mutant ovarian cancer, achieving good effect, and thus obtaining breakthrough therapy certification of the U.S. Food and Drug Administration (FDA); FDA approval was obtained at 12 months 2016 for patients with advanced ovarian cancer associated with two or more lines of chemotherapy and mutations in the BRCA gene, and rebamipide became 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 studied in phase II melanoma in 2005, and in breast cancer and ovarian cancer in 2007, although the study of injection has been earlier, the progress in various aspects is slow, clovis seems to focus on promoting the marketing of new drugs for oral preparations, and oral immediate-release tablet of D-camphorsulfonate has been approved by FDA.

According to the research results of Clovis tumor company, the PARP inhibitor Ruocapab oral bioavailability is about 36%, T _max The half-life is about 17 hours in 1-6 hours, after 240mg tablets are taken twice a day, the blood concentration can reach 100% to the expected trough concentration (2 mu M), the plasma exposure amount shows linear increase along with the increase of the dose, the main grade 3/4 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) Dose-limiting toxicity was evident: because the curative effect of the medicament is related to the maintaining time of the enzyme inhibition rate, the blood concentration fluctuation range of the quick-release preparation is larger, in order to maintain the concentration free blood concentration required by PARP enzyme inhibition, a large dose of medicament taking is needed, the peak value of the blood concentration is overhigh, and more serious toxic and side effects are generated; 2) Bioavailability needs to be improved: the bioavailability of the tablet is about 36% and the daily dose is 1200mg (600 mg BID). Because the curative effect of the medicine is related to the maintaining time of the enzyme inhibition rate, in order to maintain the concentration free blood concentration required by PARP enzyme inhibition, large dose of medicine is needed, the medicine utilization rate is low, most of the medicine is lost, and the medicine absorption needs to be further improved; 3) Larger oral doses of drug (600mg BID,2-4 tablets per time) result in poor patient compliance and are costly to package, store and ship.

In order to further improve the clinical tumor treatment efficacy of the Rukappab and reduce the toxic and side effects of the drug, the invention aims to develop a good preparation which can improve the effective utilization rate of the drug and accurately regulate and control the blood concentration level and fluctuation range of the Rukappab, improve the absorption efficiency of the drug, and simultaneously accurately regulate and control the absorption rate and absorption time of the Rukappab in the gastrointestinal tract by controlling the release behavior of the Rukappab, so as to control the blood concentration level and fluctuation range of the blood, maintain the blood concentration required by the PARP enzyme inhibition in vivo, further improve the anti-tumor efficacy of the Rukappab 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.

Upon patent search, formulation patents related to Ruipab include: the conventional oral quick-release tablet of the dicamba dexcamphorsulfonate (US 2016051561, WO 2016028689) and the combined preparation of the dicamba phosphate and other cell medicines (WO 2006033006, EP 1793830, JP 2008513435) and the like are as follows:

1) WO 2016028689A and US 2016051561 disclose a rapid-release tablet for oral administration of procapab, in which the active drug procapab D-camphorate has low hygroscopicity and good compressibility compared with other salt forms, is suitable for dry granulation, is more beneficial to the preparation and production of high-dose solid tablets, and the drug dose can reach more than 45%; the Ruipab of the tablet can release more than 95% in 15 minutes, and the Ruipab tablet of Clowers tumor company is approved by FDA at present.

2) WO 2006033006, EP 1793830 and JP 2008513435 disclose a form of a composition of racepab phosphate and a combination composition thereof with other cytotoxic drugs, and this group of patents disclose intravenous injection preparations of racepab phosphate such as lyophilized powder preparations, and describe corresponding administration dosage and combination forms and the like, and the phosphate injection preparations have been introduced into phase II clinical practice of tumor treatment such as breast cancer and the like at present.

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-dose administration form for multiple times every day often leads to the drug after oral administration, generates higher steady-state blood drug peak value and larger blood drug concentration fluctuation range, and the too high wave peak value leads to the generation of a plurality of side effects of the rapid release preparation of the Ruocapab, and further limits the further improvement of the blood drug 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.

Aiming at the defects of the existing preparation of the Rukappab, the invention provides the Rukappab oral controlled-release pharmaceutical composition, the in-vivo absorption behavior, the blood concentration and the PARP enzyme inhibition level of the pharmaceutical composition can be regulated, 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 the Rukappab can be realized, and the Rukappab oral controlled-release pharmaceutical composition can be used as a unique preparation or combined treatment with other therapies.

The oral sustained and controlled release pharmaceutical composition of the Ruicapab provided by the invention comprises: a dissolution-improved form of licarpa; 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.

Active medicine Ruipafebu in the Ruipafebu pharmaceutical composition provided by the invention belongs to insoluble medicines, and in order to realize good absorption and oral bioavailability, solubilization treatment can be firstly carried out to obtain nilapanib with improved dissolution so as to improve the dissolution of the medicines. Without being bound by any theory, the inventors believe that the solubilization treatment can be made into a salt form, such as phosphate, hydrochloride, maleate, benzoate, sulfate, camphorate (preferably, d-camphorate), etc., or into a solubilizing composition to improve the dissolution of the drug. Without being bound by any theory, the inventors believe that the solubilization process changes the specific surface area of dispersion in the powder of the active pharmaceutical formulation composition by mixing the licarpb with a matrix polymer that effects an improvement in the solubility of the drug, 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 licarbapre includes licarbapre free base and pharmaceutically acceptable salts thereof, which may be selected from hydrochloride, phosphate, sulfate, maleate, camsylate, besylate, and the like. 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 Ruipab of the present invention comprises: a licarbap hydrochloride, a licarbap co-ground mixture, a licarbap nanocrystal, and a licarbap 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 5-60wt%, preferably 20-40wt% of the licarpan, 40-95wt%, preferably 40-80wt% of the solubilizing matrix polymer, and 0-15wt%, preferably 0.2-10wt% of other additives, based on the total weight of the co-mulled mixture. The total amount of the components is 100wt%.

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 cloth may be 5wt%, 6wt%, 7wt%, 8230 \8230;, or 59.9wt%, and the upper limit of the weight percentage of the licarpan cloth may be 60wt%, 59wt%, 58wt%, 8230 \8230;, or 5.1wt%, i.e., the weight percentage of the licarpan cloth includes any combination between these lower and upper limits, such as including 5wt% to 6wt%,59wt% to 60wt%, and further such as the weight percentage of the other additives in the above including 0.1wt% to 12.5wt%, 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 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 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 is operated as follows: dissolving an active drug Ruipab in a small amount of organic solvent such as acetone, quickly adding into a large amount of aqueous solution dissolved with a matrix polymer, performing ultrasonic high-frequency ultrasound 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 Ruipafebu is prepared into the nano-crystalline, so that the dispersion particle size of the active drug Ruipafebu in solid powder can be reduced, the specific surface area of the active drug can be obviously increased, and the dissolution performance of the drug can be 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.

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

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 licarpa is 5 to 50wt%, preferably 10 to 40wt%, more preferably 20 to 40wt%, the weight percentage of the matrix polymer for solubilization is 45 to 95wt%, preferably 50 to 80wt%, and the weight percentage of the other additives is 0 to 12wt%, preferably 0 to 10wt%, based on the total weight of the solid dispersion. The total amount of the components is 100wt%. The solid dispersion can be produced by a solvent evaporation method or a melt extrusion method. The solvent evaporation method is carried out as follows: dissolving the drug Ruipafebu, the matrix polymer for solubilization and/or other additives into a volatile organic solvent or organic mixed solvent, decompressing and volatilizing the organic solvent, and drying in a vacuum drying oven to obtain the Ruipafebu solid dispersion. The melt extrusion process was carried out as follows: and (3) directly and slowly adding the uniformly mixed 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 enables the active drug Ruipab to be in a high-energy state solid dispersion state, and the active drug Ruipab is molecularly dispersed in the solid powder of the preparation composition, 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 more than two selected from povidone, copovidone, polyoxyethylene, soluplus, hypromellose phthalate (HPMCP), hydroxypropyl cellulose acetate succinate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethyl acrylate, 2-hydroxypropyl-beta-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 release rate modifying matrix polymer (hereinafter sometimes referred to as a release modifier) in the present invention may be a high molecular polymer having a release rate modifying effect, and is a sustained-release matrix material well known to those skilled in the art, and may be selected from cellulose derivatives, starch or derivatives thereof, alginates, acrylic acid or methacrylic acid derivatives, polyethylene oxide, gums, and carbohydrate-based polymers, for example, one or a combination of two or more selected from hydroxypropyl cellulose, hypromellose, methyl cellulose, hydroxyethyl cellulose, ethyl cellulose, cellulose acetate, sodium alginate, povidone, copovidone, acrylic resins, carbomers, and preferably one or a combination of two or more selected from hydroxypropyl cellulose, sodium alginate, hypromellose, and carbomer.

In the inventive licarbap cloth co-milled mixtures, licarbap cloth nanocrystals and licarbap cloth solid dispersions, the active drug licarbap cloth comprises a licarbap cloth free base and pharmaceutically acceptable salts thereof, which can be selected from hydrochloride, phosphate, sulfate, maleate, camsylate, besylate and the like.

The oral sustained and controlled release pharmaceutical composition of the invention comprises 50 to 900 weight parts, preferably 80 to 700 weight parts, more preferably 120 to 600 weight parts of dissolution-improved form of the licarpa; 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; more specifically, it comprises 50 to 800 parts by weight of a Ricapabu salt, and 10 to 250 parts by weight of a release rate-regulating matrix polymer; or 50 to 800 parts by weight of a Ruipab co-ground mixture, and 10 to 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 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 the Ruipab required to be taken by the patient per day is 100-1400mg. 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, 20 to 400mg or 50 to 300mg. 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 slow-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 10-50wt%, preferably 20-40wt% of the total amount of the active pharmaceutical ingredients; the pharmaceutical active ingredient in the sustained-release phase accounts for 50-90wt%, preferably 60-80wt% of the total amount of the pharmaceutical active ingredient.

The Ruicapab 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 dual-release tablet, a framework type slow-release dual-effect double-layer tablet, a framework type slow-release dual-effect coated tablet, a slow-release tablet based on a slow-release pellet, a slow-release dual-effect tablet based on a slow-release pellet and a quick-release pellet, a capsule containing a framework type slow-release pellet, a capsule containing a quick-release coated slow-release pellet, a slow-release dual-release capsule containing a quick-release pellet and a framework type slow-release pellet, a slow-release dual-release capsule containing a quick-release pellet and a coated slow-release pellet, a capsule containing a framework type slow-release micro-tablet, a capsule containing a quick-release coated framework type slow-release micro-tablet and a capsule containing a quick-release micro-tablet and a framework type slow-release micro-tablet.

The Ruipab pharmaceutical composition provided by the invention can be used for preparing and preventing or treating tumors, preferably, the tumors are selected from various tumors with DNA repair function defects, and particularly, the Ruipab pharmaceutical composition is used for preparing and preventing or treating more than two combined cancers related to BRCA gene mutation, such as ovarian cancer, gastric cancer, breast cancer and the like, and 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 the second method device for Chinese pharmacopoeia dissolution test method is adopted to carry out release behavior test in a buffer solution with the pH value of 1.2-7.8 at 37 ℃, the release amount of the Ruipab within 1 hour is less than 50 percent, preferably 40 percent, more preferably 10-30 percent of the total amount of the Ruipab, and the release amount of the Ruipab within 16 hours is more than 80 percent, preferably more than 90 percent of the total amount of the Ruipab.

The Ruipafe medicinal composition provided by the invention can regulate and control the absorption rate and the absorption time of the Ruipafe in the gastrointestinal tract by controlling the release behavior and the release amount. 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 50% (preferably 200% -600%). The Ruicapa is controlled by controlling the blood concentration, the time of peak arrival and the area under the curve of the time of drugThe regulation and control of the blood concentration level of the homeostasis, the fluctuation range of the free blood concentration, the PARP enzyme inhibition, the in vivo safety and the administration frequency.

The Ruipafeb 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 C of the steady-state blood concentration _min，ss Is 0.2-4. Mu.g/mL, preferably 0.5-3. Mu.g/mL; peak value C of steady state blood concentration _max.ss Is 0.8-15. Mu.g/mL, preferably 1-12. Mu.g/mL, and the peak/trough ratio of the steady-state blood concentration is preferably less than 6, more preferably less than 4.. 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) 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;

4) 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 100 to 900 parts by weight, preferably 150 to 700 parts by weight, more preferably 200 to 600 parts by weight of the above dissolution-improved form of Ricapab, 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 respective 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 Ruicapa cloth may be 100, 110, 120, \8230;, or 899 weight part, and the upper limit of the weight part of the dissolution-improved form of the Ruicapa cloth may be 900, 890, 880, \8230;, or 100.1 weight part, i.e., the weight part of the Ruicapa cloth includes any combination of 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-used additives include one or a combination of two or more of lubricants, colorants, and the like, which are commonly 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 contain the dissolution improved form of licarbamide described above, a disintegrant, a diluent, and other additives commonly used in tablets, or include licarbamide, a solubilizing matrix polymer, and other additives commonly used in tablets.

The immediate release phase may be prepared by mixing the components thoroughly and tabletting to form an immediate release layer by conventional methods known to those skilled in the art, or by dissolving the components simultaneously, coating the delayed release phase, and drying to form an immediate 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 contain other additives commonly used in the art, 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 licarbap, the solubilized matrix polymer and other additives commonly used in tablets, the amount of licarbap may be from 5 to 100 parts by weight, preferably from 10 to 80 parts by weight, more preferably from 20 to 60 parts by weight. The solubilizing matrix polymer is one or a combination of more than two of povidone, copovidone, soluplus, hydroxypropyl methylcellulose phthalate (HPMCP), polyethylene glycol, poloxamer, hydroxypropyl methylcellulose (HPMC) and other materials, and the dosage of the solubilizing matrix polymer is 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 sustained-release dual-effect tablet, the total weight of the Ruipab in the quick-release phase is about 10-40wt% of that in the entire sustained-release matrix, and the total weight of the Ruipab in the sustained-release phase is about 60-90wt% of that in the entire sustained-release matrix.

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 90wt% of the medicinal active ingredient distributed in the rapid release phase is preferably released within 2 hours, and more than 90wt% of the medicinal active ingredient distributed in the rapid release phase is preferably released within 1 hour; the time for releasing more than 90wt% of the active ingredients in the slow release phase within 16 hours is preferably 10-16 hours, and more preferably more than 90% within 16 hours; (ii) a The release behavior of the active ingredients in the sustained-release phase conforms to the zero-order, first-order, higuchi or Ritger-Peppas drug release model, and the release is preferably zero-order drug release.

1.2 osmotic pump type controlled release tablet

The osmotic pump controlled release tablet provided by the invention can be a single-layer osmotic pump tablet, a single-layer osmotic pump speed slow double release tablet, 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 double-layer 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) An optional isolation coating layer is sandwiched between the inner surface of the rigid membrane shell and a tablet core consisting of a drug-containing layer and a push layer, and is formed by drying an 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 3-50wt% 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 3-50wt% 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 dissolution improving form of licarpa; 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 ricarapabrb may be selected from the group consisting of the aforesaid ricarapabrb salts, ricarapabrb co-milled mixtures, nanocrystals or solid dispersions.

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 40-80wt%, and the push layer accounts for 20-60wt%.

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 coat 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 influence the release of the pharmaceutical formulation and can be controlled by the amount of spray applied, typically, the weight of the barrier coat film is increased by 0-10wt% 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 3-20wt%, preferably 5-15wt% relative to the tablet core.

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

The semipermeable controlled-release coating film 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 round, oval, square, triangle and the like, and the average pore diameter ranges from 0.3 mm to 1.2mm.

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 coat may improve the appearance of the formulation to increase patient compliance for dosing while providing color indication. 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 0-10wt% relative to the core.

The single-layer osmotic pump controlled release tablet mainly comprises a single-layer tablet core and a controlled release coating film with drug release holes, and the tablet can be prepared by uniformly mixing the prescription amount of dissolution-improved Ruipab, release regulator, osmotic pressure promoter and other common pharmaceutical auxiliary materials, granulating and pressing the single-layer tablet core; coating the core with a controlled release coating material using a suspension coating method well known to those skilled in the art; and (3) punching by adopting a laser punching machine to form the single-layer osmotic pump controlled release tablet. The dissolution-improved Ruicapab, the release regulator and the osmotic pressure promoter are the same as those of the double-layer osmotic pump tablet. The other pharmaceutic adjuvants comprise an osmosis-promoting polymer, a controlled-release coating film, a lubricant, a colorant and the like, and are as described in the section of the double-layer osmotic pump tablet. In the single-layer osmotic pump controlled release tablet, based on the total weight of the single-layer tablet core, the single-layer tablet core comprises 50 to 700 parts by weight, preferably 80 to 600 parts by weight, and more preferably 120 to 400 parts by weight of dissolution improved form Ruipab; 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 1 to 400 parts by weight, preferably 1 to 300 parts by weight of other pharmaceutically common adjuvants. Based on the total weight of the slow release coating film, the pore-forming agent accounts for 0 to 30 weight percent of the slow release coating film. Based on the total weight of the single-layer osmotic pump controlled release tablet, the weight of the controlled release coating is 3 to 30 weight percent of the single-layer osmotic pump controlled release tablet.

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 prepared by spraying the composition containing the quick-release drug-containing layer on the tablet core and drying. The immediate release drug-containing layer composition comprises: 10-80 parts of active ingredient Ruipafebu, 0-100 parts of solubilizing matrix polymer component, preferably 10-100 parts of solubilizing matrix polymer component, 0-30 parts of other pharmaceutical common auxiliary materials and 100-2000 parts of solvent. The solubilization 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. Such other pharmaceutically common adjuvants include crospovidone, microcrystalline cellulose, pharmaceutically acceptable surfactants (e.g., sodium lauryl sulfate), and like common additives for immediate release tablets, which are well known to those skilled in the art; 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 10-40wt% 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 60-90wt% of the total weight of the Ruipab in the whole rapid-release double-effect release osmotic pump tablet.

The preparation method of the Ruicapab osmotic pump controlled release tablet comprises the following steps: (1) preparation of dissolution improved forms of licarpa; (2) preparing a medicine-containing layer; (3) preparing an optional propelling layer; (4) preparing a tablet core; (5) preparing an optional isolation coating film; (6) preparing a controlled release coating film; (7) perforating the osmotic pump tablet controlled release coating film; (8) optionally coating an aesthetic outer coating layer; (9) an optional immediate release drug-containing layer. The above-mentioned (2) to (9) can be carried out by a conventional compression 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 dual-release tablet can better exert the drug effect of the Ruipafebu, and the design of the fast-release phase ensures the rapid release of the initial drug, so that the drug can rapidly reach the blood concentration level required by effective PARP enzyme inhibition, the fast effect is realized, and the design of the slow-release phase can ensure the stable release of the later active ingredients, thereby ensuring the long-time maintenance of the blood concentration required by the effective enzyme inhibition, further keeping the enzyme activity inhibition, improving the curative effect, and simultaneously reducing the toxic and side effects caused by the great fluctuation of the blood concentration.

1.3. Sustained-release tablets based on sustained-release pellets

Another aspect of the present invention provides a sustained-release tablet of licarbapu 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 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 10-40wt% of the total weight of the Ruipab; the total weight of the Ruipab in the sustained-release pill is 60-90wt%.

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 common additives for tablets include one or a combination of two or more of lubricants and colorants commonly used for 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.

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-forming agent and the like. The pore-forming agent is one or more selected from hydrophilic liquid carriers (glycerin, PEG 200), 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 100 to 250 parts by weight, preferably 200 to 400 parts by weight of a 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 a racepab salt, 10 to 300 parts by weight of a matrix for release rate adjustment or a controlled-release coating material, 0 to 100 parts by weight of a binder, 0 to 12 parts by weight of a pore-forming agent, and 0 to 15 parts by weight of a 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 is a schematic structure diagram of a capsule containing immediate-release pellets and skeleton-type sustained-release pellets according to an embodiment of the present invention, fig. 6 is a schematic structure diagram of a sustained-release pellet capsule containing an immediate-release coating according to an embodiment of the present invention, and fig. 7 is a schematic structure diagram 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 micro-pills is a controlled-release capsule consisting of sustained-release micro-pills or a sustained-release dual-release capsule consisting of sustained-release micro-pills and quick-release micro-pills, and can comprise a capsule containing skeleton type sustained-release micro-pills, a capsule containing coated sustained-release micro-pills, a capsule containing quick-release coated sustained-release micro-pills, a sustained-release dual-release capsule containing quick-release micro-pills and skeleton type sustained-release micro-pills and a sustained-release capsule containing quick-release micro-pills and coated sustained-release micro-pills.

The sustained-release capsule based on the micro-pills can be a sustained-release capsule based on the sustained-release micro-pills and a slow-release double-effect capsule based on quick-release micro-pills and sustained-release micro-pills. 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 10 to 40 percent; the proportion of the Ruipab in the sustained-release pellet is 60-90wt%.

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 pellets containing the quick-release coating can be prepared by directly coating the quick-release matrix on the surfaces of the skeleton type sustained-release pellets or the coated sustained-release pellets.

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 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-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 < 5mm. .

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. The weight of the Ruipab in the quick-release phase is 10-40wt% based on the total weight of the Ruipab in the capsule; the Ruipab in the slow-release phase accounts for 60-90wt%.

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 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 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 framework 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 structural schematic diagram of a capsule containing an immediate release pill 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 and dual release matrix tablet of example 1.

FIG. 9 is the release profile of the bi-layer osmotic pump controlled release tablet of example 3 in release media at pH 1.2, 4.5 and 6.8.

FIG. 10 is a release profile of the sustained-release matrix tablet of example 4 in a release medium at pH 6.8.

FIG. 11 is the release profile of the formulations of example 5, example 6, example 7, example 8, and example 9 in a release medium at pH2.0 HCl.

FIG. 12 is a dissolution profile of the immediate release tablet of comparative example 1.

Figure 13 is a graph comparing the in vivo dosing profiles of the immediate release tablet of example 1 and the sustained dual release matrix tablet of example 1.

FIG. 14 is a graph comparing the in vivo dosing profiles of the immediate release tablet of example 1 and the bi-layer osmotic pump controlled release tablet of example 3.

FIG. 15 is a graph comparing the in vivo drug profiles of the immediate release tablet of example 1 and the controlled release tablet of the sustained release dual release bilayer osmotic pump of example 5.

FIG. 16 is a time plot of PARP enzyme inhibition in canine PBMCs comparing the immediate release tablet of example 1 with the sustained release dual release bilayer osmotic pump controlled release tablet of example 5.

Detailed Description

The following examples generally set forth the preparation and/or characterization of typical compositions of the present 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: the beagle dogs are half male and female and have the weight of 8-10 kg. 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 pressed using a single punch tablet machine (TDP-1, asahan mechanical Equipment Co., ltd., guangzhou).

The three-dimensional mixer is a model T2F available from TURBULA.

The melt extruder was a Pharma11 model from semaphenanthrene.

EXAMPLE 1 Slow Dual Release matrix tablet

A quick release layer: sieving the Ruipafebu, the superfine silica gel powder and the Soluplus with a 60-mesh sieve, mixing for 25 minutes at 30rpm by using a three-dimensional mixer, slowly adding the mixture into a preheated melt extruder after uniformly mixing, collecting an extrudate, crushing the extrudate, and sieving with the 60-mesh sieve to obtain the Ruipafebu 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: sieving the prescription dose of the Ruipafebu, PVP VA64 and superfine silica gel powder with a 60-mesh sieve, uniformly mixing, slowly adding into a preheated melt extruder, collecting the extrudate, crushing, and sieving with the 60-mesh sieve to obtain the Ruipafebu solid dispersion. The obtained nicalpab solid dispersion was mixed with the prescribed release rate adjusting polymer HPMC K15M (BASF, germany) and the lubricant magnesium stearate and tabletted for tabletting.

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 adopting a dissolution rate measuring method (appendix X C of the second part of the 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 2010 edition of the Chinese pharmacopoeia), and the release of the prescribed tablet was measured.

The release results are shown in FIG. 8. The slow-release double-effect framework double-layer tablet realizes about 20 percent of quick release of the medicine within 30 minutes, about 60 percent of the medicine is released within about 6 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.

Example 2 sustained-release pill capsules and/or fast-release and slow-release double-effect capsules containing quick-release pills and sustained-release pills

(1) Sustained-release pill

I) Medicine-carrying pill core

II) coating of barrier coating

III) coating 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 (VA 64) 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 cores in a fluidized bed coating manner to obtain the quick-release pills.

Sustained-release pills: weighing a proper amount of matrix hydroxypropyl cellulose (SSL) for adjusting the release rate, dispersing the matrix hydroxypropyl cellulose (SSL) into 95% ethanol solution to prepare coating liquid with the solid content of 10%, and fully and uniformly stirring the coating liquid 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 core in the prescribed amount by fluidized bed coating method; obtaining the drug-loaded pill core of the coating isolation coating.

Adding appropriate amount of water solution into the water dispersion of 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 Ruipafeb and the copovidone VA64, namely dissolving the Ruipafeb and the copovidone VA64 in ethanol/acetone (25/75, v/v), volatilizing the organic solvent under reduced pressure, drying in a vacuum drying oven, grinding, crushing, sieving with a 60-mesh sieve, and tabletting.

Mixing with other adjuvants such as polyvidone K90 and magnesium stearate, sieving with 60 mesh sieve, mixing with a 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 double-layer tablet core containing the medicine-containing layer and the boosting layer is pressed by the medicine-containing layer composition and the boosting layer composition in a direct-pressing mode. And (3) coating the controlled-release coating with a 4% cellulose acetate solution, and increasing the weight of the coating 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 the 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 (7.65 mL of hydrochloric acid is diluted by adding water to 1000mL to prepare the release media with pH value of 1.2 at the temperature of 37 ℃, 250mL of 0.2mol/L of 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 supernatant is taken as a test solution, and the release degree is measured.

The release results in different pH release media are shown in FIG. 9. 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 tablets

Sieving the licarbap cloth dexcamphorsulfonate and the povidone K30 for 3 times through a 60-mesh sieve, then mixing for 25 minutes under the condition of 30rpm through a three-dimensional mixer, slowly adding the mixture into a preheated melt extruder, collecting transparent extrudate, crushing and sieving through the 60-mesh sieve to obtain the licarbap cloth dexcamphorsulfonate solid dispersion. The solid dispersion is prepared into a sustained-release matrix tablet with proper hardness by uniformly mixing a matrix polymer, namely hydroxypropyl cellulose (K4M) according to the prescription amount and the release rate, adding a lubricant, namely magnesium stearate, uniformly mixing and tabletting.

The release rate measuring method is the same as that of the example 2, the pH2.0 HCl solution is used as a release medium, the release rate result is shown in figure 10, 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.

Example 5 Slow Dual Release bilayer osmotic Pump controlled Release tablets

Sieving Ruicapab dexcamphorsulfonate and other adjuvants except magnesium stearate with 60 mesh sieve, mixing well in three-dimensional mixer, adding into fluidized bed, spraying 6% copovidone (VA 64) ethanol-water solution, granulating, drying until water content is less than 5%, sieving with 20 mesh sieve, grading, adding magnesium stearate, mixing for 5min to obtain medicinal layer composition, and tabletting.

Precisely weighing the auxiliary materials of the boosting layer, sieving by a 60-mesh sieve, and mixing for 30min at 30rpm by a three-dimensional mixer to obtain the composition of the boosting layer.

The osmotic pump double-layer tablet core containing the medicine-containing layer and the boosting layer is pressed by the medicine-containing layer composition and the boosting layer composition in a direct-pressing mode.

Pressing tablet core, coating controlled release coating layer with 3% cellulose acetate-0.2% PEG4000 solution, and coating film weight increasing 10% to obtain double-layer osmotic pump controlled release tablet.

Dissolving the Ruipafenib D-camphorsulfonate in an acetone solution, and coating the solution according to the drug content ratio of the quick release layer to the slow release layer of 2: 8 until the obtained double-layer osmotic pump tablet is obtained, namely the fast-release double-layer osmotic pump tablet with the active ingredients of the quick release layer accounting for 20wt% and the slow release layer accounting for 80wt%.

The release degree of the fast-slow double-release double-layer osmotic pump controlled release tablet is measured by adopting a dissolution rate measuring method (appendix X C of the second part of the 2010 edition of Chinese pharmacopoeia) second method device, pH2.0 HCl solution is used as a release medium at the temperature of 37 ℃, the rotating speed is 75 revolutions per minute, 6mL of solution is taken according to the method after 0.5,1,2,4,6,8, 10, 12, 16 and 20 hours, the solution is centrifuged, the supernatant is taken as a test solution, and the release degree is measured.

The release results are shown in FIG. 11. The result shows that the fast-release and slow-release double-layer osmotic pump controlled release tablet can release the medicine of the fast-release layer within 2 hours, the medicine of the slow-release layer can basically maintain the constant-speed release, more than 80 percent of the medicine is released within 16 hours, and the medicine release duration can reach 16 hours.

EXAMPLE 6 Single layer osmotic Pump controlled Release tablets

Sieving Ruicapab D-camphorsulfonate and other adjuvants except magnesium stearate with 60 mesh sieve, mixing well in three-dimensional mixer, adding into fluidized bed, spraying ethanol-water solution of polyvidone (K30) 7%, granulating, drying until water content is less than 5%, sieving with 20 mesh sieve, grading, adding magnesium stearate, mixing for 5min to obtain medicinal layer composition, and tabletting.

The tablet core of the single-layer osmotic pump tablet is pressed by the composition containing the drug layer in a direct-pressing mode. Coating the tablet core with PEG4000 solution (4% cellulose acetate-0.2%) to obtain a controlled release coating, and increasing the weight of the coating by 5% to obtain a single-layer osmotic pump controlled release tablet. The release rate was determined in the same manner as in example 5, using HCl solution of pH2.0 as the release medium, and the release results are shown in FIG. 11.

Example 7 sustained-release tablets based on sustained-release pellets

(1) Sustained-release pill

I) Medicine-carrying pill core

II) coating of barrier coating

III) coating the sustained Release coating

The preparation method comprises the following steps:

medicine carrying pill core: dissolving or dispersing Ruipafebu p-toluenesulfonate in 95% ethanol solution to prepare a drug-loaded solution, and spraying the drug-loaded solution onto a blank pellet core of sucrose according to the prescription amount in a fluidized bed coating manner to obtain the drug-loaded pellet core.

Sustained-release pills:

and dissolving or dispersing the film component of the isolation coating in a 95% ethanol solution, and spraying the solution onto the pellet cores in the prescription amount by adopting a fluidized bed coating mode to obtain the pellet cores coated with the isolation coating.

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

Sustained and controlled release tablets: adding ethanol into microcrystalline cellulose, granulating, mixing with delayed release pill, adding silicon dioxide or magnesium stearate, mixing, and tabletting.

Fast and slow double release tablet: mixing the above prepared quick-release pill (drug-loaded pill core) and sustained-release pill, adding silicon dioxide or magnesium stearate, mixing, and tabletting.

The release rate was determined in the same manner as in example 5, using HCl solution of pH2.0 as the release medium, and the release results are shown in FIG. 11.

Example 8 sustained-release tablets based on sustained-release pellets

516g of Ruipahu dexcamphorsulfonate, 120g of microcrystalline cellulose and 90g of lactose are weighed, mixed through a 80-mesh sieve, transferred to a wet granulation machine, parameters are adjusted, a water solution with the mass percent of 1% of hydroxypropyl methylcellulose E is added to be used as an adhesive to prepare a soft material, and the soft material is extruded and rounded to prepare Ruipahu nity drug-containing pellets, wherein the aperture of an extrusion sieve is 0.5mm, the extrusion speed is 20r/min, the rounding speed is 1000r/min, drying is carried out at 40 ℃ of a fluidized bed, and 30-40-mesh drug-containing pellets are sieved for later use. And (3) placing the screened Ruipafebu pellets in a fluidized bed, preparing a coating solution, and coating to obtain the Ruipafebu sustained-release pellets. The coating liquid proportion is as follows: 14.5 percent of acrylic resin, 5 percent of plasticizer triethyl citrate, 10.5 percent of anti-sticking agent talcum powder and the balance of water. Weighing 30g of slow-release Ruicapab pellets, 6g of drug-containing pellets, 10g of microcrystalline cellulose, 12g of lactose, 14g of a solution with the mass percentage of pvpK30 being 5%, granulating by using a 18-mesh sieve, drying by using a 40-DEG C oven, finishing granules by using the 18-mesh sieve, and 0.6g of stearic acid, mixing and tabletting. The release rate was determined in the same manner as in example 5, using HCl solution of pH2.0 as the release medium, and the release results are shown in FIG. 11.

Example 9 sustained/controlled Release Capsule based on Microtablet

Sustained-release micro-tablets

Quick-release micro-tablet

Sustained-release micro-tablets: and (3) sieving the Ruicapalb and the copovidone VA64 for 3 times by using a 60-mesh sieve, and adding the Ruicapalb and the copovidone VA64 into a ball mill to grind until the average grain diameter is less than 30um to obtain a Ruicapalb co-grinding mixture. The co-milled mixture was screened through a 60 mesh screen with the formulated amount and release rate modifying matrix polymers polyoxyethylene, ethylcellulose and mixed in a three-dimensional mixer at 30rpm for 25 minutes, then magnesium stearate was added and mixed for 5 minutes and pressed into microtablets with a diameter of 4 mm.

Quick-release micro-tablets: and sieving the Ruicapa cloth and the copovidone VA64 for 3 times through a 60-mesh sieve, and adding the Ruicapa cloth and the copovidone VA64 into a ball mill to be ground until the average grain diameter is less than 30um to obtain the Ruicapa cloth co-ground mixture. The co-milled mixture was sieved through a 60 mesh sieve with the prescribed amount and crospovidone and mixed in a three-dimensional mixer at 30rpm for 25 minutes, then magnesium stearate was added and mixed for 5 minutes and pressed into micro-tablets with a diameter of 4 mm.

And (3) capsule filling: and filling the sustained-release micro-tablets into capsules to prepare the sustained-release capsules.

And (3) fully and uniformly mixing the prepared quick-release micro-tablets and sustained-release micro-tablets according to the prescription amount, and then filling capsules to prepare the quick-release and sustained-release capsules. The release rate was determined in the same manner as in example 5, using HCl solution of pH2.0 as the release medium, and the release results are shown in FIG. 11.

Example 10 sustained/controlled Release Capsule based on Microtablet

Sustained-release micro-tablets

Quick-release micro-tablet

Sustained-release micro-tablets: sieving Ruicapa and 2-hydroxypropyl-beta-cyclodextrin with 60 mesh sieve for 3 times, adding 100ml water, high-speed shearing to obtain coarse suspension, circularly homogenizing with high-pressure homogenizer until the average particle diameter is less than 1000nm, and lyophilizing to remove water. The nanocrystalline powder was sieved through a 60 mesh sieve, sieved through a 60 mesh sieve with the matrix polymer carbomer 934 for prescription amount and release rate adjustment and mixed in a three-dimensional mixer at 30rpm for 25 minutes, then added with sodium stearyl fumarate and mixed for 5 minutes, and pressed into micro-tablets with a diameter of 3 mm.

Quick-release micro-tablets: sieving Ruicapa and 2-hydroxypropyl-beta-cyclodextrin with 60 mesh sieve for 3 times, adding 100ml water, high-speed shearing to obtain coarse suspension, circularly homogenizing with high-pressure homogenizer until the average particle diameter is less than 1000nm, and lyophilizing to remove water. Sieving the nanocrystalline powder with a 60-mesh sieve, sieving the nanocrystalline powder with lactose and croscarmellose sodium in a prescribed amount with a 60-mesh sieve, mixing in a three-dimensional mixer at 30rpm for 25 minutes, adding sodium stearyl fumarate, mixing for 5min, and pressing into micro-tablets with a diameter of 3 mm.

And (3) capsule filling: and filling the sustained-release micro-tablets into capsules to prepare sustained-release capsules.

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

COMPARATIVE EXAMPLE 1 immediate Release tablet

The prescription of the quick-release tablet is as follows:

weighing Ruipafenib dextro camphorsulfonate and auxiliary materials of microcrystalline cellulose PH101, mannitol sodium starch, colloidal silicon dioxide and magnesium stearate, uniformly mixing according to a prescription proportion, sieving, uniformly mixing in a three-dimensional multi-directional mixer, taking 98% ethanol as a bonding solvent, granulating, drying, adding the auxiliary materials among particles according to the prescription amount, uniformly mixing, and tabletting to obtain the prescription of the quick-release tablet.

The dissolution rate is determined by adopting a dissolution rate determination method (appendix X C of the second part of the 2010 edition of Chinese pharmacopoeia) first method device, using 900mL of release medium with pH2.0 at 37 ℃, rotating at 75 revolutions per minute, operating according to the method, taking 6mL of solution after 15, 30, 45, 60, 75, 90, 105 and 120min, centrifuging, taking supernatant as a test solution, and determining the release rate.

The release results are shown in FIG. 12. The active ingredient of the rapid-release tablet for comparison releases over 95 percent of the rapid-release tablet in about 15 minutes.

Experimental example 1

The immediate release tablet of the racepabu of comparative example 1 and the sustained and dual release matrix tablet of example 1 were administered to a saturated beagle dog (n = 3) with 25mL of water, and blood was collected at a predetermined time point after administration, centrifuged at 4000rpm for 10min at 4 ℃, and the upper plasma was collected for plasma concentration detection by LC-MS, and the results are shown in fig. 13.

C relative to immediate release tablets _max (2750.3 ng/mL) and AUC _0-h (19470h ng/mL), fast and slow dual release matrix tablet C _max Reduced to 1589.4ng/mL, a reduction of about 42%; AUC _0-h 20110h ng/mL, variation < 10%; it can still be seen from the results of the time course graph 13 that the C of the matrix tablet is released slowly and slowly compared with the immediate release tablet _max The 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 medicament dosage ramp and optimal medicinal effect.

Experimental example 2

The immediate release tablet of the racecopab of comparative example 1 and the bi-layer osmotic pump controlled release tablet of example 3 were administered to a saturated beagle dog (n = 3), respectively, with 50mL of water. The quick-release tablet is taken for 1mL through veins of limbs at 0.25,0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12 and 24h before administration (0 h) and after administration, the double-layer osmotic pump controlled release tablet is taken for 1mL through veins of limbs at 1.0, 2.0, 4.0, 6.0, 8.0, 10, 12 and 24h before administration (0 h) and after administration, a blood sample is centrifuged for 10min at 4000rpm under the condition of 4 ℃, and upper plasma is taken for detecting the blood concentration of LC-MS, and the result is shown in figure 14.

C relative to immediate release tablets _max (2467.1 ng/mL) and AUC _0-h (21804.8 h ng/mL), C of the double-layer osmotic pump controlled release tablet _max Reduced to 1487.6ng/mL, a reduction of about 40%; AUC _0-h 22482.6h ng/mL, variation < 10%.

Experimental example 3

The rapid-release tablet of the Ruicapab in comparative example 1 and the controlled-release tablet of the sustained-release bi-layer osmotic pump in example 5 were administered to a saturated beagle dog (n = 3) separately with 25mL of water, blood was taken at a predetermined time point after administration, blood samples were centrifuged at 4000rpm for 10min at 4 ℃, and upper plasma was taken for plasma concentration detection by LC-MS, and the results are shown in FIG. 15. PBMC was extracted from 0h, 1h, 6h, 10h, 15h and 24h whole blood, and PARP enzyme inhibition was detected by the kit HT PARP in vivo Pharmacodynamic Assay II from Trevigen, see FIG. 16.

C relative to immediate release tablets _max (2246.0 ng/mL) and AUC _0-h (20829.5 h ng/mL), and C of fast-slow double-release double-layer osmotic pump controlled release tablet _max Reduced to 1265.0ng/mL, a reduction of about 44%; AUC _0-h 22944.9h. Compared with the quick-release tablet, the quick-release tablet has the advantages that the enzyme inhibition rate is lower than 90% in 10h, the enzyme inhibition rate is higher than 90% in 15h, and the results of the time curve diagram 15 and the enzyme inhibition rate diagram 16 still show that the quick-release tablet can maintain the stable blood concentration for a longer time at higher blood concentration, so that the enzyme inhibition effect and the anti-tumor effect are better exerted, and a larger dosage space is provided for the dosage ramp and the optimal drug effect.

Claims

1. An oral sustained and controlled release pharmaceutical composition of Ruicapab, the composition has controllable release behavior, in the predetermined time quantum, in the release medium according with condition of the leak trough, its release behavior and release amount are controllable, when adopting Chinese pharmacopoeia dissolution rate determination second method apparatus, carry on the release behavior determination in the buffer solution with pH value of 1.2-7.8 under the condition of 37 duC, release less than 50% of Ruicapab total amount within 1 hour, release Ruicapab more than 80% of the total amount within 16 hours,

wherein, the first and the second end of the pipe are connected with each other,

the composition is a sustained-release matrix tablet which is a single-layer tablet consisting of a sustained-release phase, wherein the sustained-release phase comprises 100-900 parts by weight of dissolution-improved Ruipab, 10-300 parts by weight of a matrix polymer for release rate adjustment, 0-50 parts by weight of a diluent and 0.2-30 parts by weight of other common additives for tablets, wherein the matrix polymer for release rate adjustment is one or a combination of more than two selected from hydroxypropyl cellulose, ethyl cellulose, povidone, copovidone and carbomer;

or

The composition is a slow-release double-effect release matrix tablet, which is a double-layer tablet consisting of a slow-release phase and a quick-release phase,

the sustained-release phase comprises 100-900 parts by weight of dissolution-improved Ruipab, 10-300 parts by weight of matrix polymer for release rate adjustment, 0-50 parts by weight of diluent and 0.2-30 parts by weight of other common additives for tablets, wherein the matrix polymer for release rate adjustment is one or the combination of two selected from copovidone and hypromellose;

the quick release phase comprises 20-600 parts by weight of dissolution-improved Ruipab, 5-90 parts by weight of disintegrant, 5-200 parts by weight of diluent and 0.2-30 parts by weight of other common tablet additives; or the quick release phase comprises the Ruipape, the solubilization matrix polymer and other common tablet additives, wherein the quantity of the Ruipape is 5-100 parts by weight, the quantity of the solubilization matrix polymer is 5-300 parts by weight, and the quantity of the other common tablet additives is 0.1-150 parts by weight; the solubilization matrix polymer is one or more of polyvidone, copovidone, soluplus, hypromellose phthalate, polyethylene glycol, poloxamer and hypromellose;

in the rapid-slow double-effect release matrix tablet, the total weight of the Ruipab in the rapid-release phase is 10-40wt% of that in the whole rapid-slow double-effect release matrix tablet, and the total weight of the Ruipab in the slow-release phase is 60-90wt% of that in the whole rapid-slow double-effect release matrix tablet;

or alternatively

The composition is a bi-layer osmotic pump controlled release tablet, comprising:

controlled release drug-containing layer: it is formed from a controlled release drug-containing layer composition;

push layer or booster layer: formed from a push layer composition;

wherein the Ruicapab accounts for 3-50wt% 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: 50-600 parts by weight of dissolution-improved form of licarpa; 10-150 parts of release regulator and 0-40 parts of other common pharmaceutical excipients, wherein the release regulator is one or the combination of two of povidone and copovidone;

the push layer composition comprises a release rate adjusting penetration-promoting polymer, an osmotic pressure promoter and other auxiliary materials, wherein the release rate adjusting penetration-promoting polymer is one or a combination of more than two of hydroxypropyl methylcellulose, copovidone and carbomer, the dosage of the release rate adjusting penetration-promoting polymer is 10-300 parts by weight, the osmotic pressure promoter is one or a combination of more than two of sodium chloride, lactose, mannitol, glucose, sucrose and fructose, the dosage of the osmotic pressure promoter is 20-150 parts by weight, the dosage of the other auxiliary materials in the push layer composition is 0.5-30 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, and based on the total weight of the tablet core, the controlled-release drug-containing layer accounts for 40-80wt%, and the push layer accounts for 20-60wt%;

or

The composition is a single layer osmotic pump controlled release tablet comprising a single layer tablet core comprising 50-700 parts by weight of dissolution improving form of nicalpab, based on the total weight of the single layer tablet core; 10-150 parts of release regulator and 1-400 parts of other common pharmaceutical excipients, wherein the release regulator is povidone;

or

The composition is a slow-release double-release osmotic pump tablet and comprises a controlled-release tablet core and a quick-release medicine-containing layer, wherein the controlled-release tablet core comprises the controlled-release medicine-containing layer and a boosting layer, a release regulator in the controlled-release medicine-containing layer is one or the combination of two of povidone and copovidone, and a penetration-promoting polymer for regulating the release rate in the boosting layer is one or the combination of more than two of hydroxypropyl methyl cellulose, copovidone and carbomer; the quick-release drug-containing layer is formed by spraying a quick-release drug-containing layer composition onto a tablet core and drying, wherein the quick-release drug-containing layer composition comprises: 10-80 parts of active ingredient Ruipab, 0-100 parts of solubilizing matrix polymer component, 0-30 parts of other common pharmaceutical excipients and 100-2000 parts of solvent, wherein the solubilizing matrix polymer is one or the combination of more than two of povidone, copovidone, soluplus, hydroxypropyl methylcellulose phthalate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethylacrylate, hydroxypropyl methylcellulose, polymethacrylate and hydroxypropyl cellulose; the total weight of the Ruipab in the quick-release drug-containing layer is 10-40wt% of that of the whole slow-release osmotic pump tablet, and the total weight of the Ruipab in the controlled-release drug-containing layer is 60-90wt% of that of the whole slow-release osmotic pump tablet;

or

The composition is a sustained-release tablet based on sustained-release pellets, which is a sustained-release tablet based on sustained-release pellets or a rapid-release matrix/sustained-release pellet-based slow-release dual-effect release tablet,

in the slow-release double-effect release tablet, a quick-release matrix forms a quick-release phase, a slow-release pill forms a slow-release phase, and in the whole slow-release double-effect release tablet, the Ruipape in the quick-release phase accounts for 10-40wt% of the total weight of the Ruipape; the total weight of the Ruipab in the sustained-release pill is 60-90wt%,

the quick release matrix comprises a medicinal active ingredient in a dissolution improvement form, a disintegrating agent, a diluting agent and other common additives for tablets, wherein the dosage of the dissolution improvement form of the Ruipab is 20-200 parts by weight, the dosage of the disintegrating agent is 5-200 parts by weight, the dosage of the diluting agent is 5-200 parts by weight, the dosage of the other common additives for tablets is 0.2-30 parts by weight,

the sustained-release pellet comprises a coated sustained-release pellet and a skeleton-type sustained-release pellet, and is prepared from a blank pellet core, a Ruipab hydrochloride, a matrix for release rate adjustment or a controlled-release coating material and other auxiliary materials, wherein the blank pellet core is one or a 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, in the sustained-release pellet, the matrix for release rate adjustment or the controlled-release coating material is one or more selected from acrylic resin and ethyl cellulose, the other auxiliary materials comprise an adhesive, a plasticizer and a pore-forming agent, and the sustained-release pellet comprises 100-250 parts by weight of the blank pellet core, 10-150 parts by weight of the Ruipab hydrochloride, 10-300 parts by weight of the matrix for release rate adjustment or the controlled-release coating material, 0-100 parts by weight of the adhesive, 0-12 parts by weight of the pore-forming agent and 0-15 parts by weight of the plasticizer;

or

The composition is a sustained-release capsule based on pellets, and is a controlled-release capsule consisting of sustained-release pellets or a fast-release dual-release capsule consisting of sustained-release pellets and quick-release pellets, for the fast-release dual-release capsule, the quick-release pellets form a quick-release phase, the sustained-release pellets form a slow-release phase, and based on the total weight of the Ruipab in the fast-release dual-release capsule, the Ruipab in the quick-release phase accounts for 10-40wt%; the proportion of the Ruipab in the sustained-release pellet is 60-90wt%,

the quick release pellet is prepared by coating a blank pellet core with a quick release matrix after the quick release matrix is dissolved, or directly preparing the quick release matrix into the pellet,

the sustained-release pellets and the immediate-release matrix are as described above;

or

The composition is a sustained and controlled release capsule based on micro-tablets, which is a controlled release capsule consisting of sustained release tablets or a fast and slow dual-release capsule consisting of sustained release tablets and fast release tablets,

for the fast-slow double-release capsule, the fast-release tablet forms a fast-release phase, the slow-release tablet forms a slow-release phase, and the Ruipapab in the fast-release phase accounts for 10-40wt% based on the total weight of the Ruipapab in the capsule; the Ruipab in the slow-release phase accounts for 60-90wt%;

the sustained-release tablet is the sustained-release matrix tablet, and the quick-release tablet is the quick-release phase;

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

the Ruicapab salt is selected from hydrochloride, benzene sulfonate, sulfate, maleate, phosphate and camphorate;

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 Rukappab is 5-60wt%, the weight percent of the solubilizing matrix polymer is 40-95wt%, and the weight percent of the other additives is 0-15wt%, 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 10-99wt% based on the total weight of the Ruipab nanocrystal; the weight percentage of the matrix polymer for solubilization is 1-75wt%, and the weight percentage of other additives is 0-10wt%; the grain size of the nano crystal is 50-1000nm;

the solid dispersion consists of an active drug, namely Ruipab, a matrix polymer for solubilization and other additives, and is manufactured through a solvent volatilization method or a melt extrusion method, wherein in the solid dispersion, the weight percentage of the Ruipab is 5-50wt%, the weight percentage of the matrix polymer for solubilization is 45-95wt%, and the weight percentage of the other additives is 0-12wt% based on the total weight of the solid dispersion;

the matrix polymer for solubilization is one or the combination of more than two of povidone, copovidone, polyoxyethylene, soluplus, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose acetate succinate, polyethylene glycol, poloxamer, polymethacrylic acid, polyethylacrylate, 2-hydroxypropyl-beta-cyclodextrin, hydroxypropyl methylcellulose, polymethacrylate, hydroxypropyl cellulose and cellulose acetate phthalate;

the other additives are one or a combination of more than two of solubilizing surface active agents, lubricants, superfine silica gel powder and plasticizers in pharmacy;

the steady-state blood concentration wave trough value C of the Ruicapab medicine composition _min,ss 0.5-3 mug/mL; peak value of steady state blood concentrationC _max,ss 1-12 mug/mL, and the ratio of peak/trough of steady state blood concentration is less than 6.

2. The oral sustained and controlled release pharmaceutical composition of Ruicapab according to claim 1, wherein,

the peak/trough ratio of the steady-state blood concentration of the Ruipab pharmaceutical composition is less than 4.

3. A Ruicapab oral sustained and controlled release pharmaceutical composition according to claim 1, wherein the Ruicapab pharmaceutical composition has a controllable release profile, which is controllable and releases less than 40% of the total amount of Ruicapab within 1 hour, and releases more than 90% of the total amount of Ruicapab within 16 hours, when measured in a release medium meeting sink conditions, in a release medium at 37 ℃ using the apparatus of the second Chinese pharmacopoeia dissolution test method, wherein the release profile and the release amount are controllable.

4. The oral sustained or controlled release pharmaceutical composition of claim 1,

the Ruipab co-ground mixture consists of the active drug Ruipab, a solubilizing matrix polymer and other additives, prepared by co-grinding the ingredients; in the co-mulled mixture, the weight percent of the Rukappab is 20-40wt%, the weight percent of the solubilizing matrix polymer is 40-80wt%, and the weight percent of the other additives is 0.2-10wt%, 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 the Ruipab is 20-50wt% based on the total weight of the Ruipab nanocrystal; 1-65wt% of solubilizing matrix polymer, 0-5 wt% of other additives; the grain size of the nano-crystal is 50-1000nm;

the solid dispersion consists of an 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 10-40wt%, the weight percentage of the solubilizing matrix polymer is 50-80wt%, and the weight percentage of the other additives is 0-10wt% based on the total weight of the solid dispersion.

5. The oral sustained and controlled release pharmaceutical composition of claim 1, which is a sustained-release double-effect release matrix tablet, comprising an immediate release layer and a sustained release layer, wherein the immediate release layer comprises the following components: 20g of Ruicapab, 60g of Soluplus, 1g of superfine silica gel powder, 8g of polyvinylpolypyrrolidone, 5g of mannitol and 3g of magnesium stearate; the slow release layer comprises the following components: 80g of Ruicapab, 250g of copovidone, 2.5g of superfine silica gel powder, 75g of hydroxypropyl methylcellulose and 3g of magnesium stearate.

6. The oral sustained and controlled release pharmaceutical composition of Ruipab according to claim 1, which is a sustained release pill capsule or a dual-effect sustained and controlled release capsule containing an immediate release pill and a sustained release pill, wherein the sustained release pill comprises a core carrying a drug, a barrier coat and a sustained release coat, and the core carrying the drug comprises the following components: 100g of Ruipab phosphate, 400g of microcrystalline cellulose blank pill core, 100g of hydroxypropyl cellulose and 400ml of 95% ethanol; the components of the isolation coat corresponding to 600g of the medicine-carrying pill core are as follows: 50g of povidone and 200ml of 95% ethanol; the corresponding slow release coating of the drug-loaded pill core of 650g of the isolation coating comprises the following components: 200ml of ethyl cellulose aqueous dispersion and 200ml of water; the quick-release pill comprises the following components: 25g of Ruicapalb phosphate, 50g of copovidone, 100g of microcrystalline cellulose blank pill core and 300ml of 95% ethanol.

7. The oral sustained and controlled release pharmaceutical composition of Ruicapab according to claim 1, which is a bilayer osmotic pump controlled release tablet comprising a drug-containing layer core and a boosting layer core, wherein the drug-containing layer core comprises the following components: 5g of Ruicapab, 12g of copovidone, 2g of povidone and 0.3g of magnesium stearate; the boosting layer tablet core comprises the following components: 8.4g of sodium carboxymethyl starch, 1.7g of hydroxypropyl methylcellulose, 0.6g of carbomer, 5.8g of sodium chloride, 3.6g of copovidone, 0.2g of red ferric oxide and 0.2g of magnesium stearate.

8. The oral sustained and controlled release pharmaceutical composition of claim 1, wherein the sustained release matrix tablet is a sustained release matrix tablet comprising the following components: 8g of Ruicapab dexcamphorsulfonate, 24g of povidone, 6g of hydroxypropyl cellulose and 0.2g of magnesium stearate.

9. The Ruicapab oral sustained-release pharmaceutical composition according to claim 1, which is a sustained-release double-layer osmotic pump controlled-release tablet, and comprises a drug-containing layer tablet core and a boosting layer tablet core, wherein the drug-containing layer tablet core comprises the following components: 17.2g of Ruipafebu dextrocamphorsulfonate, 2g of polyvidone, 1g of copovidone, 0.5g of sodium dodecyl sulfate and 0.3g of magnesium stearate; the boosting layer tablet core comprises the following components: 6.5g of sodium carboxymethyl starch, 1.5g of hydroxypropyl methylcellulose, 0.4g of carbomer, 4.8g of sodium chloride, 3g of copovidone, 0.1g of black iron oxide and 0.1g of magnesium stearate.

10. The oral sustained and controlled release pharmaceutical composition of Ruicapab according to claim 1, wherein the composition is a monolayer osmotic pump controlled release tablet, and the monolayer osmotic pump controlled release tablet comprises the following components: 34.4g of Ruicapab dexecamsulfonate, K906.2g of povidone, 30.0 g of povidone K, 12g of sodium chloride, 0.5g of sodium dodecyl sulfate and 0.4g of magnesium stearate.

11. The oral sustained and controlled release pharmaceutical composition of claim 1, which is a sustained and controlled release tablet based on sustained release pellets, comprising a core of the pellet, a barrier coat and a sustained and controlled release coat, wherein the core of the pellet comprises the following components: 200g of Ruipab p-toluenesulfonate, 400g of a sucrose blank pellet core and 400ml of 95% ethanol; the components of the isolation coat corresponding to the 700g drug-loaded pill core are as follows: 50g of hydroxypropyl methylcellulose and 200ml of 95% ethanol; the components of the slow release coating corresponding to 750g of the drug-loaded pill core coated with the isolation coating are as follows: eudragit NE30D 150g, talcum powder 5g, PEG4000 15g, water 750ml.

12. The oral sustained and controlled release pharmaceutical composition of claim 1, which is a sustained and controlled release tablet based on sustained release pellets, comprising the following components: 30g of Ruicapalb sustained-release pellets, 6g of drug-containing pellets, 10g of microcrystalline cellulose, 12g of lactose and 14g of a 5% solution of pvpK30 in mass percentage; the Ruicapalb sustained-release pellet comprises a drug-containing pellet and a coating; the drug-containing pellet comprises the following components: 516g of licarbapamide camsylate, 120g of microcrystalline cellulose and 90g of lactose; the coating liquid used for coating is prepared by the following steps: 14.5 percent of acrylic resin, 5 percent of plasticizer triethyl citrate, 10.5 percent of anti-sticking agent talcum powder and the balance of water.

13. The oral sustained and controlled release pharmaceutical composition of Ruipab according to claim 1, which is a sustained and controlled release capsule based on micro-tablets, comprising sustained release micro-tablets and immediate release micro-tablets, wherein the sustained release micro-tablets comprise the following components: 10g of Ruicapab, 20g of copovidone, 5g of polyoxyethylene, 2g of ethyl cellulose and 0.3g of magnesium stearate; the quick-release micro-tablet comprises the following components: 10g of Ruicapab, 20g of copovidone, 3g of crospovidone and 0.3g of magnesium stearate.

14. The oral sustained and controlled release pharmaceutical composition of claim 1, which is a sustained and controlled release capsule based on micro-tablets, comprising sustained and immediate release micro-tablets, wherein the sustained and controlled release micro-tablets comprise the following components: 15g of Ruipab, 30g of 2-hydroxypropyl-beta-cyclodextrin, 10g of carbomer and 0.3g of sodium stearyl fumarate; the quick-release micro-tablet comprises the following components: 15g of Ruicapab, 30g of 2-hydroxypropyl-beta-cyclodextrin, 8g of lactose, 2g of croscarmellose sodium and 0.3g of sodium stearyl fumarate.