CN105030685A - Oral preparation of enzalutamide solid dispersion - Google Patents
Oral preparation of enzalutamide solid dispersion Download PDFInfo
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- CN105030685A CN105030685A CN201510429742.0A CN201510429742A CN105030685A CN 105030685 A CN105030685 A CN 105030685A CN 201510429742 A CN201510429742 A CN 201510429742A CN 105030685 A CN105030685 A CN 105030685A
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Abstract
The invention discloses an oral preparation of enzalutamide solid dispersion. The oral preparation contains enzalutamide with effective dose, and also contains a water-soluble polymer carrier for dispersing enzalutamide, wherein the weight ratio of enzalutamide to the water-soluble polymer carrier is 1 to 0.5-3. With the oral preparation, the solubility and the dissolution rate of enzalutamide in the preparation is effectively improved, so that the bioavailability of enzalutamide is improved, and the quality stability and safety of enzalutamide are improved.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of carcinoma of prostate medicine grace for the treatment of and mix the solid dispersion oral formulations of Shandong amine.
Background technology
Grace Shandong amine of mixing is androgen receptor inhibitor, action target spot is different from Cabazitaxel and abiraterone, the combination of androgen and receptor can be suppressed competitively, and the nuclear translocation of androgen receptor and the interaction of this receptor and DNA can be suppressed, experiment in vitro research display, grace Shandong amine of mixing can suppress the propagation of prostate gland cancer cell and induce it dead, in the heteroplastic model experiment of Prostate Carcinoma of Mice, grace is mixed, and can to reduce the mix major metabolite of Shandong amine of gross tumor volume grace be that N-demethyl grace is mixed Shandong amine to Shandong amine, its adult human dose showing that similar this medicine of inhibit activities of Shandong amine of mixing to grace recommends in vitro is 160mg every day, absorb rapidly after taking medicine, plasma concentration reaches top level in 0.5 ~ 3h, the mean terminal half-life is 5.8d, main metabolic enzyme is CYP2C8 and CYP3A4.This medicine should be avoided and strong CYP2C8 inhibitor (as gemfibrozil, gemfibrozil) conbined usage, as needs co-administered, should reduce grace and mix Shandong amine dosage to 80mg, every day 1 time.
Grace Shandong amine of mixing is developed by Astellas (Astellas) company, male's castration tolerance carcinoma of prostate in the late period (castration-resistantprostatecancer) of spreading or recurring is used for the treatment of through FDA (Food and Drug Adminstration) (FDA) approval in 2012, commodity are called Xtandi, and this medicine is oral soft capsule preparation.Its relative molecular mass is 464.4, CAS registration number is 915087-33-1, and structure is shown below.
Grace Shandong amine of mixing is a kind of medicine of low dissolving hyposmosis, and belong to BCS IV class, the grace of Astellas company exploitation mixes Shandong amine soft capsule for ensureing bioavailability, adopts Shandong amine of grace being mixed to be dissolved in a kind of macromolecular material Labraso.But the preparation dissolution according to said method produced is not high, and its bioavailability is also low, all easy crystallization after entering human body.And grace is mixed, the stability of Shandong amine and Labraso is all poor, former triturate have employed add BHT and BHA composite antioxidant to improve its stability, but these two kinds of antioxidant safeties are clinically poor, and soft capsule complicated process of preparation, cost is higher.
Summary of the invention
The object of the invention is the defect for existing in prior art, providing the solid dispersion oral solid formulation that a kind of grace mixes Shandong amine, the Shandong amine of mixing of the grace in this oral formulations not only has very high dissolution and bioavailability, and has good stability.
Technical scheme of the present invention is:
A kind of grace is mixed Shandong amine solid dispersion oral formulations, and the grace containing effective dose is mixed Shandong amine, and also containing for disperseing grace to mix the water-soluble polymer carrier of Shandong amine, the mix mass ratio of Shandong amine and water-soluble polymer carrier of described grace is 1: 0.5 ~ 3.
Preferably, described water-soluble polymer carrier is one or more in non-ionic celluloses ether, polyvidone, Polyethylene Glycol, poloxamer.Wherein, described non-ionic celluloses ether refers to ethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, sodium carboxymethyl cellulose etc.
Further preferably, described water-soluble polymer carrier is polyvidone, and the mix mass ratio of Shandong amine and polyvidone of described grace is 1: 1.2 ~ 1.6.
Preferably, described solid dispersion oral formulations also contains pharmaceutically acceptable excipient, as filler, binding agent, disintegrating agent, lubricant etc.
Preferably, described oral formulations is tablet or capsule.
Grace is mixed the preparation method of Shandong amine solid dispersion oral formulations, and it comprises the following steps:
1) by water-soluble polymer carrier solubilizes in water or ethanol water, obtain the water-soluble polymer carrier solution that mass concentration is 15 ~ 30%;
2) Shandong amine of grace being mixed is scattered in water-soluble polymer carrier solution, makes the mix mass ratio of Shandong amine and water-soluble polymer carrier of grace be 1: 0.5 ~ 3, stirs, carries out spraying dry after homogenizing, obtains grace and to mix Shandong amine solid dispersion;
3) in grace mixes Shandong amine solid dispersion, add pharmaceutically acceptable excipient, make tablet or capsule.
Preferably, described water-soluble polymer carrier is polyvidone, and the mix mass ratio of Shandong amine and polyvidone of described grace is 1: 1.2 ~ 1.6.
Preferably, described spray-dired process conditions are: inlet temperature is 130-160 DEG C, and leaving air temp is 50-70 DEG C, and charging rate is 10-20mL/min, and spray pressure is 0.1-0.5MPa.
The invention has the beneficial effects as follows:
1) effectively improve grace in preparation to mix the dissolubility of Shandong amine and dissolution, thus improve grace and to mix the bioavailability of Shandong amine, better efficacy compared with existing preparation.
2) solid preparation provided by the invention, grace is mixed not easily oxidized, the degraded of Shandong amine, thus improves quality stability and the safety of preparation.
3) preparation technology of the present invention is simple, low production cost.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described in detail, but should not be understood as the restriction that scope is carried out.
Embodiment 1
1) get ethyl cellulose, hydroxypropyl emthylcellulose, PVP K30, polyethylene glycol 6000, each 60g of poloxamer respectively, being dissolved in mass concentration is in the ethanol water of 60%, obtains the water-soluble polymer carrier solution that concentration is 20%;
2) Shandong amine of 40g grace being mixed respectively is scattered in above-mentioned five kinds of water-soluble polymer carrier solutions, spraying dry is carried out after stirring, homogenizing, controlling inlet temperature is 150 DEG C, leaving air temp is 60 DEG C, charging rate is 10mL/min, spray pressure is 0.3MPa, obtains grace and to mix Shandong amine solid dispersion;
3) in five kinds of grace mix Shandong amine solid dispersion, lactose (filler) 80g, cross-linking sodium carboxymethyl cellulose (disintegrating agent) 10g, magnesium stearate (lubricant) 2g is respectively added, tabletting after mix homogeneously.
1. dissolution determination
Get tablet prepared by above-described embodiment 1 and former grace of grinding is mixed each 6 of Shandong amine soft capsule, by Chinese Pharmacopoeia version in 2010 two annex dissolution methods, adopt paddle method, 50 revs/min, with the buffer solution of pH1.0 as dissolution medium, operate in accordance with the law, extract solution 5ml when 10min, 20mim, 30min, 45min, 60min and filter, get subsequent filtrate 20 μ l injection liquid chromatography and detect dissolution.
Table 1 grace is mixed the dissolution determination result of Shandong amine
| Preparation | 10min | 20min | 30min | 45min | 60min |
| Ethyl cellulose | 23.5 | 38.4 | 55.2 | 66.5 | 74.2 |
| Hydroxypropyl emthylcellulose | 26.8 | 42.1 | 57.6 | 70.1 | 77.5 |
| PVP K30 | 35.4 | 55.8 | 73.6 | 89.3 | 93.5 |
| Polyethylene glycol 6000 | 33.8 | 51.2 | 70.6 | 85.5 | 90.2 |
| Poloxamer | 31.2 | 48.7 | 68.3 | 79.4 | 85.5 |
| Grace is mixed Shandong amine soft capsule | 8.2％ | 35.6％ | 55.4％ | 56.8％ | 59.4％ |
As can be seen from the above results, the grace that prepared by embodiment 1 Shandong its dissolution rate of amine solid dispersion oral formulations of mixing obviously to be mixed Shandong amine soft capsule faster than former grace of grinding.
2. Internal pharmacokinetics experiment
Get rabbit 18, be divided into three groups, often organize 6, gavage the tablet of embodiment 1 and grace respectively to mix Shandong amine soft capsule, respectively at 30,60,90,120,180,240,300min auricular vein gets blood 2ml, methanol supersound extraction 10min. is centrifugal, gets supernatant 20 μ l sample introduction HPLC detection level.The grace recorded mixed Shandong amine plasma drug concentration data 3p87 software processes, area under curve calculates with trapezoidal method, calculates bioavailability.The results are shown in Table 2.
Table 2 grace is mixed the Bioavailability Determination result of Shandong amine
| Preparation | AUC(ng·ml -1·min) | Cmax(ng·ml -1) | Tmax | F/％ |
| Ethyl cellulose | 475.8 | 83.6 | 0.5～3h | 90.3 |
| Hydroxypropyl emthylcellulose | 488.1 | 89.5 | 0.5～3h | 92.3 |
| PVP K30 | 518.7 | 108.5 | 0.5～3h | 100.5 |
| Polyethylene glycol 6000 | 505.6 | 96.4 | 0.5～3h | 96.1 |
| Poloxamer | 495.8 | 95.7 | 0.5～3h | 94.4 |
| Grace is mixed Shandong amine soft capsule | 114.2 | 16.7 | 0.5～3h | 18.6 |
Result shows, grace prepared by embodiment 1 is mixed Shandong amine solid dispersion oral formulations, and in its body, bioavailability to be mixed Shandong amine soft capsule higher than grace far away.
3. stability test
Embodiment 1 and grace Shandong amine soft capsule of mixing is placed in 60 DEG C of baking ovens respectively and places 10 days, adopts HPLC method to detect, chromatographic column: KromasilC18 (250mm × 4.6mm, 5 μm); Mobile phase: 0.1% trifluoroacetic acid-acetonitrile (35: 65), flow velocity: 1.0ml/min; Determined wavelength: 250nm; Get each sample, add the solution that mobile phase is mixed with 0.1mg/ml, filter, get 20 μ l injection liquid chromatographies, calculate related substance by area normalization method, investigate the situation of change of related substance, the results are shown in following table.
The stable content testing result (%) of table 3 related substance
| Preparation | 0 day | 10 days |
| Ethyl cellulose | 0.09 | 0.15 |
| Hydroxypropyl emthylcellulose | 0.11 | 0.17 |
| PVP K30 | 0.10 | 0.14 |
| Polyethylene glycol 6000 | 0.09 | 0.15 |
| Poloxamer | 0.12 | 0.19 |
| Grace is mixed Shandong amine soft capsule | 0.16 | 0.75 |
Result shows, grace prepared by embodiment 1 is mixed Shandong amine solid dispersion oral formulations, and it places the related substance produced afterwards for 10 days and is starkly lower than grace and mixes the soft capsule of Shandong amine under 60 DEG C of high temperature, proves that its stability is better.
Embodiment 2
Grace is mixed Shandong amine sheet, is made up of following raw material:
Preparation method is:
1) PVP K30 is dissolved in 50% ethanol water, obtains the water-soluble polymer carrier solution that mass concentration is 15%;
2) Shandong amine of grace being mixed is scattered in water-soluble polymer carrier solution, carries out spraying dry after stirring, homogenizing, and controlling inlet temperature is 130 DEG C, leaving air temp is 50 DEG C, charging rate is 10mL/min, and spray pressure is 0.1MPa, obtains grace and to mix Shandong amine solid dispersion;
3) in grace mixes Shandong amine solid dispersion, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, magnesium stearate is added, tabletting after mix homogeneously.
The every sheet of this product to be mixed Shandong amine 40mg containing grace, and taking dose is each 1, every day 1 time.
Embodiment 3
Grace is mixed Shandong amine capsule, is made up of following raw material:
Preparation method is:
1) polyvidone is dissolved in 70% ethanol water, obtains the water-soluble polymer carrier solution that mass concentration is 30%;
2) Shandong amine of grace being mixed is scattered in water-soluble polymer carrier solution, carries out spraying dry after stirring, homogenizing, and controlling inlet temperature is 160 DEG C, leaving air temp is 70 DEG C, charging rate is 20mL/min, and spray pressure is 0.5MPa, obtains grace and to mix Shandong amine solid dispersion;
3) in grace mixes Shandong amine solid dispersion, add starch and magnesium stearate, mix rear capsule-filling, make capsule.
This product every to be mixed Shandong amine 40mg containing grace, and taking dose is each 1, every day 1 time.
Claims (8)
1. a grace is mixed Shandong amine solid dispersion oral formulations, grace containing effective dose is mixed Shandong amine, it is characterized in that: also containing for disperseing grace to mix the water-soluble polymer carrier of Shandong amine, the mix mass ratio of Shandong amine and water-soluble polymer carrier of described grace is 1: 0.5 ~ 3.
2. grace as claimed in claim 1 is mixed Shandong amine solid dispersion oral formulations, it is characterized in that: described water-soluble polymer carrier is one or more in non-ionic celluloses ether, polyvidone, Polyethylene Glycol, poloxamer.
3. grace as claimed in claim 2 is mixed Shandong amine solid dispersion oral formulations, it is characterized in that: described water-soluble polymer carrier is polyvidone, and the mix mass ratio of Shandong amine and polyvidone of described grace is 1: 1.2 ~ 1.6.
4. grace as claimed in claim 1 is mixed Shandong amine solid dispersion oral formulations, it is characterized in that: also containing pharmaceutically acceptable excipient.
5. grace as claimed in claim 1 is mixed Shandong amine solid dispersion oral formulations, it is characterized in that: described oral formulations is tablet or capsule.
6. grace is mixed a preparation method for Shandong amine solid dispersion oral formulations, it is characterized in that comprising the following steps:
1) by water-soluble polymer carrier solubilizes in water or ethanol water, obtain the water-soluble polymer carrier solution that mass concentration is 15 ~ 30%;
2) Shandong amine of grace being mixed is scattered in water-soluble polymer carrier solution, makes the mix mass ratio of Shandong amine and water-soluble polymer carrier of grace be 1: 0.5 ~ 3, stirs, carries out spraying dry after homogenizing, obtains grace and to mix Shandong amine solid dispersion;
3) in grace mixes Shandong amine solid dispersion, add pharmaceutically acceptable excipient, make tablet or capsule.
7. grace as claimed in claim 6 is mixed the preparation method of Shandong amine solid dispersion oral formulations, it is characterized in that: described water-soluble polymer carrier is polyvidone, and the mix mass ratio of Shandong amine and polyvidone of described grace is 1: 1.2 ~ 1.6.
8. grace is mixed the preparation method of Shandong amine solid dispersion oral formulations as claimed in claim 6, it is characterized in that: described spray-dired process conditions are: inlet temperature is 130-160 DEG C, leaving air temp is 50-70 DEG C, and charging rate is 10-20mL/min, and spray pressure is 0.1-0.5MPa.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107530325A (en) * | 2016-02-19 | 2018-01-02 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing imidazolines derivative |
| WO2018037310A1 (en) | 2016-08-20 | 2018-03-01 | Ftf Pharma Private Limited | Pharmaceutical composition comprising an androgen receptor inhibitor |
| CN108815129A (en) * | 2018-07-12 | 2018-11-16 | 天津双硕医药科技有限公司 | A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace |
| CN111217757A (en) * | 2020-01-06 | 2020-06-02 | 武汉大学 | Enzalutamide compound and pharmaceutical composition preparation thereof |
| CN111617028A (en) * | 2020-07-14 | 2020-09-04 | 扬子江药业集团江苏紫龙药业有限公司 | Oral preparation containing ibrutinib and preparation method |
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| CN104768935A (en) * | 2012-09-11 | 2015-07-08 | 雷迪博士实验室有限公司 | Enzalutamide polymorphic forms and its preparation |
| CN105188699A (en) * | 2013-10-14 | 2015-12-23 | 杭州普晒医药科技有限公司 | Solid form of enzalutamide, preparation method and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014043208A1 (en) * | 2012-09-11 | 2014-03-20 | Medivation Prostate Therapeutics, Inc. | Formulations of enzalutamide |
| CN104768935A (en) * | 2012-09-11 | 2015-07-08 | 雷迪博士实验室有限公司 | Enzalutamide polymorphic forms and its preparation |
| CN105188699A (en) * | 2013-10-14 | 2015-12-23 | 杭州普晒医药科技有限公司 | Solid form of enzalutamide, preparation method and use thereof |
Cited By (11)
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| CN107530325A (en) * | 2016-02-19 | 2018-01-02 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition containing imidazolines derivative |
| JP2019505526A (en) * | 2016-02-19 | 2019-02-28 | ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． | Pharmaceutical composition containing an imidazoline derivative |
| EP3417857A4 (en) * | 2016-02-19 | 2019-10-23 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing imidazoline derivative |
| CN107530325B (en) * | 2016-02-19 | 2021-02-23 | 江苏恒瑞医药股份有限公司 | Pharmaceutical composition containing imidazoline derivatives |
| TWI732822B (en) * | 2016-02-19 | 2021-07-11 | 大陸商江蘇恆瑞醫藥股份有限公司 | A pharmaceutical composition comprising imidazoline derivatives |
| AU2017220970B2 (en) * | 2016-02-19 | 2021-12-16 | Jiangsu Hengrui Medicine Co., Ltd. | Pharmaceutical composition containing imidazoline derivative |
| WO2018037310A1 (en) | 2016-08-20 | 2018-03-01 | Ftf Pharma Private Limited | Pharmaceutical composition comprising an androgen receptor inhibitor |
| CN108815129A (en) * | 2018-07-12 | 2018-11-16 | 天津双硕医药科技有限公司 | A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace |
| CN111217757A (en) * | 2020-01-06 | 2020-06-02 | 武汉大学 | Enzalutamide compound and pharmaceutical composition preparation thereof |
| CN111217757B (en) * | 2020-01-06 | 2021-03-19 | 武汉大学 | Enzalutamide compound and pharmaceutical composition preparation thereof |
| CN111617028A (en) * | 2020-07-14 | 2020-09-04 | 扬子江药业集团江苏紫龙药业有限公司 | Oral preparation containing ibrutinib and preparation method |
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