CN103432077A - Chidamide solid dispersion preparation - Google Patents
Chidamide solid dispersion preparation Download PDFInfo
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Abstract
The invention relates to a solid dispersion preparation which contains a chidamide or 4-fluorochidamide solid dispersion, and auxiliary materials such as diluents, disintegrants, binders and lubricants. The solid dispersion contains the active component and polyvinylpyrrolidone. Polyvinylpyrrolidone and the active component are dissolved in an organic solvent and thoroughly mixed, the organic solvent is removed, and the resulting product is pulverized and sieved to obtain a solid dispersion; and then the auxiliary materials are added to further make solid dispersion preparations of different forms. After oral administration, the solid dispersion preparation has the advantages of rapid onset of action, high bioavailability, stable quality and good reproducibility.
Description
Technical field
The present invention relates to a kind of people and use pharmaceutical preparation, particularly relate to a kind of west and reach the aniline solid dispersed formulation.
Background technology
Histon deacetylase (HDAC) (histone deacetylase, HDAC) is an albuminoid enzyme, and chromosomal structural modification and gene expression regulation are played an important role.Generally, the acetylation of histone is conducive to dissociating of DNA and histone octamer, and nucleosomal structure is lax, thus make various transcription factor and collaborative transcription factor can with DNA binding site specific binding, the transcribing of activated gene.In nucleus, acetylation of histone and DNA methylase inhibitor process be in dynamic equilibrium, and jointly regulated and controled by acetylation of histone transferring enzyme (histone acetyltransferase, HAT) and histon deacetylase (HDAC).HAT transfers to the acetyl group of S-acetyl-coenzyme-A on the specific lysine residue of histone amino terminal, and HDAC makes DNA methylase inhibitor, with electronegative DNA, combines closely, and the chromatin densification is curling, and transcribing of gene is suppressed.In cancerous cell, the overexpression of HDAC causes the enhancing of deacetylation effect, by recovering the histone positive charge; thereby increase the gravitation between DNA and histone; make lax nucleosome become very tight, be unfavorable for the expression of specific gene, comprise some tumor suppressor genes.Antibiotic FR 901228 (histone deacetylase inhibitors; HDACi) can be by improving chromatin specific region acetylation of histone; thereby expression and the stability of regulating cell apoptosis and differentiation associated protein; cell death inducing and differentiation, become the antitumor drug that a class is new.HDACi not only has good therapeutical effect to multiple hematological system tumor and solid tumor, and has advantages of tumor cell relatively high selectivity and low toxicity.
The clinical experimental study result confirms, hdac inhibitor has clinical efficacy preferably to blood/lymphsystem tumor, comprises CTCL, PTCL, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), multiple myeloma (MM) etc.So far, two kinds of hdac inhibitor medicines are used for the treatment of CTCL by the U.S. FDA approval, are respectively SAHA and FK228.In May, the 2011 FK228 treatment for PTCL by the FDA approval again.
1999, Suzuki proposes o-benzoyl amido amino benzenes compounds as novel hdac inhibitor, entinostat (Entinostat wherein, MS-275) to the inhibition activity of HDAC, be 4.8 μ mol/L, to kinds of tumor cells, as breast carcinoma, colon cancer, leukemia, pulmonary carcinoma, ovarian cancer and cancer of pancreas etc., there is antiproliferative activity, solid tumor and lymphoma are had to significant oral active anticancer simultaneously.U.S. Pat 7244751B2 embodiment 2 discloses Compound C S02100055, chemical name N-(2-amino-4-fluorophenyl)-4-[N-3-(3-pyridine) acryloyl group] amino methyl] Benzoylamide, molecular formula C
22h
19fN
4o
2, structural formula is as follows:
US7244751B2 embodiment 5 and embodiment 6 reports, CS02100055 is a kind of effective hdac inhibitor, and has measured its IC to HDAC and kinds of tumor cells system
50value.
The people such as Yin Zihui have reported similar compound N-(amino-5 fluorophenyls of 2-)-4-[N-3-(3-pyridine) acryloyl group] amino methyl] (west reaches aniline to Benzoylamide; also make chidamide; in this patent the general designation west reach aniline) synthetic method; take pyridine carboxaldehyde as initiation material, react by Knoevenagel, make pyridyloxy acrylic acid; then with N; N '-phosphinylidyne diimidazole (CDI) is catalyst, by 2 step acylation reactions, and synthetic target product.Mild condition, easy and simple to handle, be applicable to suitability for industrialized production, hectogram level synthetic method, productive rate 29%." new antitumoral Antibiotic FR 901228 west reaches the synthetic of aniline ", Chinese Journal of New Drugs, the 6th phase 536-538 page in 2004.
Beam wide China in institute for drug control, Guangzhou waits the people to report that west reaches the aniline content assaying method, adopts HPLC and UV to measure west and reaches aniline content, and method is simple, quick, accurate, economical.(Guangdong pharmacy, the 15th volume the 4th phase 9-10 page in 2005)
The people such as He Xiangming report, west reaches aniline can bring into play Tuberculosis in vitro intestinal cancer LoVo cel l proliferation by inducing cell Cycle Arrest and apoptosis.(" west reaches the in vitro study that aniline suppresses Proliferation of Colon Cancer LoVo Cell Line ", oncology's magazine, 04 phase in 2009)
The people such as Cheng Hong report, west reaches aniline carcinoma of prostate DU145, PC3 Growth of Cells is had to obvious inhibitory action.(" west reaches aniline to human prostata cancer DU145 and the apoptotic impact of PC3 ", biotechnology communication, 02 phase in 2012)
The people such as Zhou Shan report, west reaches aniline can suppress stomach cancer cell SGC-7901 propagation in vitro.(" west reaches the impact research of aniline on SGC-7901 cell propagation, apoptosis and Notch1, Sirt1 gene expression ", Southeast China University's journal (medicine), 03 phase in 2012)
The people such as Li Yanying report, west reaches the propagation that aniline can suppress B lymphoma cell strain Raji, Maver and Z-138.(" west reaches the Function and its mechanisms research of aniline to the Human B lymphoma cell strain ", Chinese experimental hematology's magazine, 04 phase in 2012)
It is reported, reach aniline at Western China and entered for skin T lymphoma (CTCL) clinical research and for II/III phase clinical research stage of non-Hodgkin′s lymphomas.In addition, granted for the II/III clinical trial phase of solid tumor, be about to carry out the clinical trial of nonsmall-cell lung cancer, cancer of pancreas, carcinoma of prostate." clinical rational drug use magazine " (04 phase in 2010) report, west reaches aniline and has obtained U.S. food Drug Administration (FDA) clinical trial approval, in the U.S., launches clinical research.
Summary of the invention
The purpose of this invention is to provide a kind of west and reach the aniline solid dispersed formulation, be used for the treatment of clinically hematological system tumor (T lymphoma, non-Hodgkin′s lymphomas etc.) and various entity tumor (nonsmall-cell lung cancer, cancer of pancreas, breast carcinoma, carcinoma of prostate etc.).
The curative effect of active constituents of medicine itself is no doubt main, and dosage form also plays vital effect to the performance of curative effect.In design during pharmaceutical dosage form, must be simultaneously the aspects such as the stability of the character of active component (principal agent), preparation, bioavailability, quality control be all considered comprehensively.West reaches aniline and exists with crystal form, is dissolved in organic solvent for example dimethyl sulfoxide (DMSO) and dimethyl formamide (DMF), and dissolubility is approximately 20mg/ml.But it is very low that west reaches the dissolubility of aniline in aqueous solution, had a strong impact on bioavailability.Therefore, be necessary to research and develop a kind of west and reach the aniline preparation, accelerate its dissolution rate, thereby increase dissolution, improve bioavailability.
The present invention realizes the foregoing invention purpose by following technical solution: a kind of solid dispersion; contain active component and polyvinylpyrrolidone (PVP); the mass ratio of the two is active component: polyvinylpyrrolidone=1:0.5～10; preferred proportion is 1:1～7, and described active component is that west reaches aniline or N-(2-amino-4-fluorophenyl)-4-[N-3-(3-pyridine) acryloyl group] amino methyl] Benzoylamide (call 4-fluorine west in the following text and reach aniline).Polyvinylpyrrolidone and active component for example are dissolved in, in organic solvent (ethanol), stir evenly, remove organic solvent, pulverize and sieve and obtain solid dispersion.Remove organic solvent and can adopt the mode of lyophilization, drying under reduced pressure, spray drying or atomizing freeze drying.
The structural formula that reaches aniline from west can be found out, has inferior ethylene group, in four groups that are connected with carbon-carbon double bond, has two to be hydrogen atom, and two other is respectively 3-pyridine radicals and formamido group methyl, therefore has in theory isomers.4-fluorine west reaches in the molecular structure of aniline and also has same situation.Inventor's discovery, the E configuration is more stable, is more suitable for making medicine.Therefore, the E configuration is as preferred version of the present invention.
The inventor has tested the variety carrier material, such as PEG class, PVP, poloxamer (Polyxamer) and poloxamer and PEG mixture (mass ratio 1:10～3:1) etc., the aspect factors such as comprehensive drug loading, dissolution test, aging speed, find that PVP is more suitable as the carrier material of active component, general effect is more outstanding.Model to PVP is not particularly limited, and for example can be selected from model is one or more in K12, K15, K17, K25, K30, K60, K90.Infer theoretically, carrier material is higher with respect to the content of active component, more easily makes active component become amorphous substance by crystalline solid, and corresponding bioavailability is also higher.In practical application, should consider drug loading and bioavailability, determine the two mass ratio of active component and PVP, 1:0.5 for example, 1:1,1:3,1:5,1:7,1:9,1:10 etc.The weight of considering unit formulation is taken more convenient in 150～300mg left and right, and the content of active component generally all in 100mg, most of situation in 50mg, drug content is less, adjuvant is more, can suitably increase PVP with respect to the active component consumption, such as active component and PVP mass ratio 1:4 or be greater than 1:5, such as 1:6,1:8 etc., make the dispersibility of active component in carrier material better, and dissolution rate and dissolution are better.
The further technical scheme of the present invention is: a kind of solid dispersed formulation, contain above-mentioned solid dispersion, and one or more adjuvants in diluent, disintegrating agent, binding agent, lubricant.Active component accounts for the 0.1-30% of solid dispersed formulation gross weight, and preferred version is to account for 0.3-20%, is particularly preferably to account for 0.5-10% (in this patent as without specializing, % refers to mass percent).After in above-mentioned solid dispersion, adding adjuvant diluent, disintegrating agent, binding agent, lubricant, according to common process, can further be prepared into various forms of solid dispersed formulations, such as tablet, pill, granule and capsule etc., preferably make tablet.For example, use the pure water moistening after adding diluent, disintegrating agent, granulation, granulate, add the lubricant tabletting, can make tablet (plain sheet).As required, gained element sheet further coating etc. also.
In described adjuvant, disintegrating agent can be selected from a kind of in cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, polyvinylpolypyrrolidone, methylcellulose, pregelatinized Starch etc., the 0.1%-20% that the disintegrating agent consumption is the solid preparation total weight, preferably 0.2%-10%.
Wherein binding agent can be selected from a kind of in hypromellose, hydroxypropyl cellulose, microcrystalline Cellulose etc., the 0.2%-30% that binder dosage is the solid preparation total weight, preferably 0.5%-20%.Solid dispersion has viscosity with PVP after water-wet itself, and therefore can add less binding agent does not add binding agent even fully yet.
Wherein lubricant can be selected from a kind of in micropowder silica gel, magnesium stearate, Pulvis Talci, sodium lauryl sulphate etc., preferably talc powder or micropowder silica gel, the 0.1%-10% that lubricant quantity is the solid preparation total weight, preferably 0.1%-5%.
Except solid dispersion and disintegrating agent, binding agent, lubricant, other compositions are diluent, be selected from lactose (anhydrous or lactose monohydrate) but, one or more the mixture in microcrystalline Cellulose, Powderd cellulose vertical compression starch etc., the arbitrary proportion mixture of preferred lactose and microcrystalline Cellulose, for example lactose: microcrystalline Cellulose=4:1～1:3 (mass ratio).If make tablet, can optimize according to the compressibility of material the ratio of the two.Diluent accounts for solid preparation total weight % excursion can be larger.
In one embodiment, solid dispersion tablet contains above-mentioned solid dispersion, and disintegrating agent 0.5%-8% and lubricant 0.5%-5%, and all the other compositions are filleies, and active component accounts for the 0.5-10% of tablet total weight amount.Described active component is that west reaches aniline or 4-fluorine west reaches aniline, and preferably 4-fluorine west reaches aniline.
In another embodiment, solid dispersion tablet contains above-mentioned solid dispersion, and carboxymethyl starch sodium 0.5%-8% and Pulvis Talci 0.5%-5%, and all the other compositions are lactose and microcrystalline Cellulose, and active component accounts for the 0.5-10% of tablet total weight amount.Described active component is that west reaches aniline or 4-fluorine west reaches aniline, and preferably 4-fluorine west reaches aniline.
The content of active component in the unit solid preparation is 0.5mg～100mg, for example 5mg, 10mg or 30mg.In clinical practice, should, according to the type of disease and patient's concrete condition, rationally determine dosage.It is reported, it is 50mg that west reaches the aniline maximum tolerated dose, 3 times weekly; To the patients with advanced malignant tumor recommended dose, be≤50mg, 2 times weekly, or≤32.5mg, 3 times weekly, medication 4 weeks, stop 2 weeks.
Adopt the oral way administration, medication is convenient.Take medicine rear rapid-action, have that bioavailability is high, a steady quality, high repeatability and other advantages.
The specific embodiment
Below in conjunction with embodiment, the present invention is further illustrated.Embodiment is only indicative content, never means that it limits the scope of the invention by any way.
Embodiment 1 solvent method prepares west and reaches the aniline solid dispersion
Preparation method: take supplementary material by formula, add appropriate dehydrated alcohol that it is dissolved fully, stir evenly, rotary evaporation is except drying under reduced pressure in the rearmounted vacuum drying oven of desolventizing, pulverizes, to cross 60～100 mesh sieves standby.
Embodiment 2 spray drying methods prepare west and reach the aniline solid dispersion
Preparation method: take supplementary material by formula, add appropriate dehydrated alcohol that it is dissolved fully, stir evenly, spray drying is except desolventizing, pulverizes, to cross 60～100 mesh sieves standby.
Embodiment 3 freeze-dryings prepare 4-fluorine west and reach the aniline solid dispersion
Preparation method: take supplementary material by formula, add appropriate dehydrated alcohol that it is dissolved fully, stir evenly, lyophilization is except desolventizing, pulverizes, to cross 60～100 mesh sieves standby.
The standby 4-fluorine of embodiment 4 atomizing freeze drying legal systems west reaches the aniline solid dispersion
Prescription is with embodiment 3.
Preparation method: take supplementary material by formula, add appropriate dehydrated alcohol that it is dissolved fully, stir evenly, be sprayed to after freezing in low temperature nitrogen dry, pulverize again, to cross 60～100 mesh sieves standby.
Embodiment 5 west reach the preparation of aniline capsule
Preparation method: the solid dispersion powder is crossed to 80 mesh sieves, with lactose, microcrystalline Cellulose and the cross-linking sodium carboxymethyl cellulose equivalent dilution method that progressively increases, mix homogeneously, pure water is done the wetting agent wet granulation, after the wet grain drying granulate with encapsulated after Pulvis Talci is mixed homogeneously and get final product.
The preparation of embodiment 6 solid dispersion tablets
Preparation method: the solid dispersion powder is crossed to 80 mesh sieves, with lactose, microcrystalline Cellulose and the carboxymethyl starch sodium equivalent dilution method that progressively increases, mix homogeneously, pure water is done the wetting agent wet granulation, after the wet grain drying granulate with tabletting (pressure 2.5Kg/cm after the lubricant micropowder silica gel is mixed homogeneously
2) and get final product.
The system of embodiment 7 solid dispersion tablets respectively
Preparation method: with embodiment 6.
The preparation of embodiment 8 solid dispersion tablets
Preparation method: with embodiment 6.
The X-ray powder diffraction test
Instrument: x-ray powder diffraction instrument
Test specimen: solid dispersion (embodiment 2 prescription 6, embodiment 3 prescriptions 9～12), active component and PVP physical mixture (writing out a prescription the same), west reaches aniline and 4-fluorine west reaches the aniline crude drug
Working condition: the monochromatization of CuKd graphite monochromator diffraction, high pressure 30kv, pipe flow 50mA, scanning speed 2 θ/min
Sample thief is appropriate respectively, records the x-ray diffractogram of powder spectrum.
Result of the test: the collection of illustrative plates of physical mixture is basically identical with corresponding crude drug collection of illustrative plates characteristic peak.Solid dispersion (embodiment 2 prescriptions 6 and embodiment 3 prescriptions 9～12) collection of illustrative plates and PVP trace analysis approach, have no obvious characteristic peak, illustrate and wherein substantially there is no the active component crystal, analysis may be that PVP has suppressed crystallization behavior, causes it to be dispersed in carrier material PVP with unformed shape.
The In Vitro Dissolution test
Test specimen: tablet 1～tablet 12
Control sample: formula is with tablet 1～tablet 12, and active component and adjuvant physics mix rear wet granulation, tabletting
Dissolution investigation method: " two appendix XD of Chinese pharmacopoeia version in 2010 the second method oar method
Rotating speed: 50 rev/mins
Temperature: 37 ℃
Sample time: 10,30,45 minutes
Content assaying method: ultraviolet spectrophotometry
Measure wavelength: 258nm
The In Vitro Dissolution result of the test is indicated, (1) the average accumulated burst size of tablet 1～tablet 12 in 45 minutes all surpasses 71%, the average accumulated burst size of tablet 3,4,7,8,11,12 in 45 minutes all surpasses 74%, dissolution and dissolution velocity all apparently higher than with control sample, and have significant difference; (2) dissolution of active component and dissolution rate all constantly increase with the increase of carrier PVP ratio, but when carrier: during active component >=5:1, amplification is more and more less.
Accelerated stability test
Sampling respectively from tablet 1～12, with wrapping in aluminum-plastic blister, the outsourcing aluminium foil bag, put into climatic chamber (40 ℃ ± 1 ℃ of constant temperature, constant humidity RH75% ± 2.5%), place 6 months continuously, the 1st, 2,3,6 months the end of month, sampling was observed, and measured dissolution, related substance and active constituent content.
Through accelerated test 6 months, (1) tablet appearance was without significant change; (2) dissolution of 5 other samples of tablet (≤6%) in a slight decrease, other have no significant change, show that solid dispersion does not have obvious catabiosis; (3) active constituent content does not change.
Claims (10)
1. a solid dispersion; contain active component and polyvinylpyrrolidone; the mass ratio of the two is 1:0.5～10, and described active component is N-(2-amino-4-fluorophenyl)-4-[N-3-(3-pyridine) acryloyl group] amino methyl] Benzoylamide or west reach aniline.
2. solid dispersion according to claim 1, wherein the two mass ratio of active component and polyvinylpyrrolidone is 1:1～7.
3. solid dispersion according to claim 1, described active component is N-(2-amino-4-fluorophenyl)-4-[N-(E)-3-(3-pyridine) acryloyl group] amino methyl] Benzoylamide.
4. a solid dispersed formulation, contain solid dispersion claimed in claim 1, and one or more adjuvants in diluent, disintegrating agent, binding agent, lubricant.
5. solid dispersed formulation according to claim 4, described preparation is tablet or capsule.
6. solid dispersed formulation according to claim 4, wherein active component accounts for the 0.1-30% of solid dispersed formulation gross weight, the 0.1%-20% that the disintegrating agent consumption is the solid preparation total weight, the 0.2%-30% that binder dosage is the solid preparation total weight, the 0.1%-10% that lubricant quantity is the solid preparation total weight, other compositions are diluent.
7. solid dispersed formulation according to claim 6, wherein active component accounts for the 0.5-10% of solid dispersed formulation gross weight, the 0.2%-10% that the disintegrating agent consumption is the solid preparation total weight, the 0.5%-20% that binder dosage is the solid preparation total weight, the 0.1%-5% that lubricant quantity is the solid preparation total weight, other compositions are diluent.
8. a solid dispersion tablet, contain solid dispersion claimed in claim 1, and disintegrating agent 0.5%-8% and lubricant 0.5%-5%, and all the other compositions are filleies, and active component accounts for the 0.5-10% of tablet total weight amount.
9. a solid dispersion tablet, contain solid dispersion claimed in claim 1, and carboxymethyl starch sodium 0.5%-8% and Pulvis Talci 0.5%-5%, and all the other compositions are lactose and microcrystalline Cellulose, and active component accounts for the 0.5-10% of tablet total weight amount.
10. solid dispersion tablet according to claim 8 or claim 9, described active component is N-(2-amino-4-fluorophenyl)-4-[N-(E)-3-(3-pyridine) acryloyl group] amino methyl] Benzoylamide.
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| CN104771363A (en) * | 2014-01-14 | 2015-07-15 | 深圳微芯生物科技有限责任公司 | Chidamide solid dispersion and preparing method and application thereof |
| CN106916100B (en) * | 2014-04-04 | 2020-09-15 | 深圳微芯生物科技股份有限公司 | E-configuration benzamide compound and medicinal preparation thereof |
| WO2015149435A1 (en) * | 2014-04-04 | 2015-10-08 | 深圳微芯生物科技有限责任公司 | E-configuration benzamide compound and pharmaceutical formulation and application thereof |
| TWI577662B (en) * | 2014-04-04 | 2017-04-11 | Shenzhen Chipscreen Biosciences Ltd | E - Structureally Benzamide Compounds and Their Pharmaceutical Preparations and Applications |
| CN106916100A (en) * | 2014-04-04 | 2017-07-04 | 深圳微芯生物科技有限责任公司 | A kind of E benzamide compound and its pharmaceutical formulation |
| CN103880736A (en) * | 2014-04-04 | 2014-06-25 | 深圳微芯生物科技有限责任公司 | E-configuration benzamide compounds, and pharmaceutical preparation application thereof |
| US10287353B2 (en) | 2016-05-11 | 2019-05-14 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385130B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| US10385131B2 (en) | 2016-05-11 | 2019-08-20 | Huya Bioscience International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| US11535670B2 (en) | 2016-05-11 | 2022-12-27 | Huyabio International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| WO2020034916A1 (en) * | 2018-08-17 | 2020-02-20 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical use thereof |
| RU2770754C1 (en) * | 2018-08-17 | 2022-04-21 | Шэньчжэнь Чипскрин Байосайенсиз Ко., Лтд. | Combination of a histone deacetylase inhibitor and a protein kinase inhibitor and pharmaceutical application thereof |
| CN114681455A (en) * | 2018-08-17 | 2022-07-01 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
| CN110833544B (en) * | 2018-08-17 | 2022-08-09 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
| CN110833544A (en) * | 2018-08-17 | 2020-02-25 | 深圳微芯生物科技股份有限公司 | Combination of histone deacetylase inhibitor and protein kinase inhibitor and pharmaceutical application thereof |
| WO2021037091A1 (en) * | 2019-08-28 | 2021-03-04 | 深圳微芯生物科技股份有限公司 | Chidamide pharmaceutical composition, preparation method therefor and application thereof |
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