CN105030685B - A kind of miscellaneous Shandong amine solid dispersions oral formulations of grace - Google Patents
A kind of miscellaneous Shandong amine solid dispersions oral formulations of grace Download PDFInfo
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- CN105030685B CN105030685B CN201510429742.0A CN201510429742A CN105030685B CN 105030685 B CN105030685 B CN 105030685B CN 201510429742 A CN201510429742 A CN 201510429742A CN 105030685 B CN105030685 B CN 105030685B
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- shandong amine
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Abstract
The invention discloses a kind of oral formulations of the miscellaneous Shandong amine solid dispersions of grace, the miscellaneous Shandong amine of the grace containing effective dose, also contain and be used to disperseing the water-soluble polymer carrier of the miscellaneous Shandong amine of grace, the mass ratio of the miscellaneous Shandong amine of grace and water-soluble polymer carrier is 1: 0.5~3.The present invention is effectively improved the solubility and dissolution rate of the miscellaneous Shandong amine of grace in preparation, so as to improve the bioavilability of the miscellaneous Shandong amine of grace, while also improves the quality stability and security of the miscellaneous Shandong amine of grace.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of solid for treating the miscellaneous Shandong amine of prostate cancer medicine grace disperses
Body oral formulations.
Background technology
The miscellaneous Shandong amine of grace is androgen receptor inhibitor, and action target spot is different from Cabazitaxel and abiraterone, can competed
Suppress the combination of androgen and acceptor to property, and can suppress androgen receptor nuclear translocation and this receptor and DNA it is mutual
Effect, the miscellaneous Shandong amine of experiment in vitro studies have shown that grace can suppress the propagation of prostate gland cancer cell and induce it dead, before mouse
The miscellaneous Shandong amine of grace can reduce the major metabolite of the miscellaneous Shandong amine of gross tumor volume grace and be gone for N- in the model experiment of row gland cancer heterograft
The miscellaneous Shandong amine of methyl grace, it is daily that it shows the adult human dose of the inhibitory activity medicine recommendation similar to the miscellaneous Shandong amine of grace in vitro
160mg, absorbed rapidly after medication, plasma concentration reaches highest level in 0.5~3h, and mean terminal half-life period is 5.8d, main
It is CYP2C8 and CYP3A4 to want metabolic enzyme.The medicine should avoid joining with strong CYP2C8 inhibitor (such as Gemfibrozil, gemfibrozil)
Close and use, if desired for co-administered, the miscellaneous Shandong amine dosage of grace should be reduced to 80mg, 1 time a day.
The miscellaneous Shandong amine of grace is developed by Astellas (Astellas) company, in 2012 through FDA (Food and Drug Adminstration)
(FDA) ratify for treating the late period male's castration for having spread or having recurred tolerance prostate cancer (castration-resistant
Prostate cancer), trade name Xtandi, the medicine is oral soft capsule preparation.Its relative molecular mass is 464.4,
CAS registration numbers are 915087-33-1, and structure is shown below.
The miscellaneous Shandong amine of grace is a kind of medicine of low dissolving hyposmosis, belongs to the classes of BCS IV, the miscellaneous Shandong of grace of Astellas company exploitation
Amine soft capsule is dissolved in a kind of high polymer material caprylic capric polyethylene glycol glycerol to ensure bioavilability using by the miscellaneous Shandong amine of grace
In ester.But the preparation dissolution rate according to said method produced is not high, its bioavilability is also low, into human body after easily separate out knot
It is brilliant.And the stability of the miscellaneous Shandong amine of grace and Labraso is poor, former triturate employ add BHT and
BHA composite antioxidant is to improve its stability, but clinically security is poor for both antioxidant, and soft capsule prepares work
Skill is complicated, and cost is higher.
The content of the invention
The purpose of the present invention is for defect present in prior art, there is provided a kind of solid dispersions mouth of the miscellaneous Shandong amine of grace
Oral solid preparation, the miscellaneous Shandong amine of grace in the oral formulations not only have very high dissolution rate and bioavilability, and with very
Good stability.
The technical scheme is that：
A kind of miscellaneous Shandong amine solid dispersions oral formulations of grace, the miscellaneous Shandong amine of the grace containing effective dose, also contain and be used to disperse
The mass ratio of the water-soluble polymer carrier of the miscellaneous Shandong amine of grace, the miscellaneous Shandong amine of grace and water-soluble polymer carrier is 1: 0.5~3.
Preferably, the water-soluble polymer carrier is non-ionic celluloses ether, PVP, polyethylene glycol, Bo Luosha
One or more in nurse.Wherein, the non-ionic celluloses ether refers to ethyl cellulose, methylcellulose, hydroxypropyl
Cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose etc..
It is further preferred that the water-soluble polymer carrier is PVP, the quality of the miscellaneous Shandong amine of the grace and PVP
Than for 1: 1.2~1.6.
Preferably, the solid dispersions oral formulations also contain pharmaceutically acceptable excipients, such as filler, bonding
Agent, disintegrant, lubricant etc..
Preferably, the oral formulations are tablet or capsule.
A kind of preparation method of the miscellaneous Shandong amine solid dispersions oral formulations of grace, it comprises the following steps：
1) water-soluble polymer carrier is dissolved in water or ethanol water, obtains the water that mass concentration is 15~30%
Insoluble polymer support solution；
2) the miscellaneous Shandong amine of grace is scattered in water-soluble polymer carrier solution, makes the miscellaneous Shandong amine of grace and water-soluble polymer carrier
Mass ratio be 1: 0.5~3, stirring, be spray-dried after homogeneous, obtain the miscellaneous Shandong amine solid dispersions of grace；
3) pharmaceutically acceptable excipients are added into the miscellaneous Shandong amine solid dispersions of grace, tablet or capsule is made.
Preferably, the water-soluble polymer carrier is PVP, and the mass ratio of the miscellaneous Shandong amine of the grace and PVP is 1:
1.2~1.6.
Preferably, the process conditions of the spray drying are：EAT is 130-160 DEG C, leaving air temp 50-70
DEG C, charging rate 10-20mL/min, spray pressure 0.1-0.5MPa.
The beneficial effects of the invention are as follows：
1) solubility and dissolution rate of the miscellaneous Shandong amine of grace in preparation are effectively improved, so as to improve the biology of the miscellaneous Shandong amine of grace
Availability, the better efficacy compared with existing preparation.
2) solid pharmaceutical preparation provided by the invention, the miscellaneous Shandong amine of grace is not easy to be oxidized, degraded, steady so as to improve the quality of preparation
Qualitative and security.
3) preparation technology of the present invention is simple, low production cost.
Embodiment
The present invention is described in detail with reference to embodiment, but should not be understood as entering the scope of the present invention
Capable limitation.
Embodiment 1
1) take ethyl cellulose, hydroxypropyl methyl cellulose, PVP K30, Macrogol 6000, poloxamer each respectively
60g, it is dissolved in the ethanol water that mass concentration is 60%, obtains the water-soluble polymer carrier solution that concentration is 20%；
2) the miscellaneous Shandong amine of 40g grace is scattered in above-mentioned five kinds of water-soluble polymer carrier solutions respectively, stirring, homogeneous are laggard
Row spray drying, it is 150 DEG C to control EAT, and leaving air temp is 60 DEG C, charging rate 10mL/min, and spray pressure is
0.3MPa, obtain the miscellaneous Shandong amine solid dispersions of grace；
3) lactose (filler) 80g, Ac-Di-Sol are respectively added into the miscellaneous Shandong amine solid dispersions of five kinds of grace
(disintegrant) 10g, magnesium stearate (lubricant) 2g, tabletting after being well mixed.
1. dissolution determination
The tablet and original for taking the preparation of above-described embodiment 1 grind each 6 of the miscellaneous Shandong amine soft capsule of grace, by Chinese Pharmacopoeia version two in 2010
Portion's annex dissolution method, using paddle method, 50 revs/min, by the use of pH1.0 cushioning liquid as dissolution medium, operate in accordance with the law,
Solution 5ml filterings are extracted when 10min, 20mim, 30min, 45min, 60min, take the μ l of subsequent filtrate 20 injection liquid chromatograph detections
Dissolution rate.
The dissolution determination result of the miscellaneous Shandong amine of the grace of table 1
| Preparation | 10min | 20min | 30min | 45min | 60min |
| Ethyl cellulose | 23.5 | 38.4 | 55.2 | 66.5 | 74.2 |
| Hydroxypropyl methyl cellulose | 26.8 | 42.1 | 57.6 | 70.1 | 77.5 |
| PVP K30 | 35.4 | 55.8 | 73.6 | 89.3 | 93.5 |
| Macrogol 6000 | 33.8 | 51.2 | 70.6 | 85.5 | 90.2 |
| Poloxamer | 31.2 | 48.7 | 68.3 | 79.4 | 85.5 |
| The miscellaneous Shandong amine soft capsule of grace | 8.2% | 35.6% | 55.4% | 56.8% | 59.4% |
As can be seen from the above results, miscellaneous its dissolution rate of Shandong amine solid dispersions oral formulations of grace that prepared by embodiment 1
It is significantly faster than that original grinds the miscellaneous Shandong amine soft capsule of grace.
2. Internal pharmacokinetics are tested
Rabbit 18 is taken, is divided into three groups, every group 6, gavages the tablet and the miscellaneous Shandong amine soft capsule of grace of embodiment 1 respectively, divide
Blood 2ml is not taken in 30,60,90,120,180,240,300min auricular veins, methanol ultrasonic extraction 10min. centrifugations, takes supernatant
The μ l sample introduction HPLC detection levels of liquid 20.By the miscellaneous Shandong amine plasma drug concentration data 3p87 software processings of the grace measured, TG-AUC
Calculated with trapezoidal method, calculate bioavilability.It the results are shown in Table 2.
The Bioavailability Determination result of the miscellaneous Shandong amine of the grace of table 2
| Preparation | AUC(ng·ml-1·min) | Cmax(ng·ml-1) | Tmax | F/% |
| Ethyl cellulose | 475.8 | 83.6 | 0.5~3h | 90.3 |
| Hydroxypropyl methyl cellulose | 488.1 | 89.5 | 0.5~3h | 92.3 |
| PVP K30 | 518.7 | 108.5 | 0.5~3h | 100.5 |
| Macrogol 6000 | 505.6 | 96.4 | 0.5~3h | 96.1 |
| Poloxamer | 495.8 | 95.7 | 0.5~3h | 94.4 |
| The miscellaneous Shandong amine soft capsule of grace | 114.2 | 16.7 | 0.5~3h | 18.6 |
As a result show, the miscellaneous Shandong amine solid dispersions oral formulations of grace prepared by embodiment 1, its vivo biodistribution availability is much
Higher than the miscellaneous Shandong amine soft capsule of grace.
3. stability test
Embodiment 1 and the miscellaneous Shandong amine soft capsule of grace, which are respectively placed in 60 DEG C of baking ovens, to be placed 10 days, is detected using HPLC methods, chromatogram
Post：Kromasil C18 (250mm × 4.6mm, 5 μm)；Mobile phase：0.1% trifluoroacetic acid-acetonitrile (35: 65), flow velocity：
1.0ml/min；Detection wavelength：250nm；Each sample is taken, adds mobile phase to be configured to 0.1mg/ml solution, is filtered, takes 20 μ l to note
Enter liquid chromatograph, calculate relevant material by area normalization method, investigate the situation of change about material, as a result see the table below.
Stable content testing result (%) of the table 3 about material
| Preparation | 0 day | 10 days |
| Ethyl cellulose | 0.09 | 0.15 |
| Hydroxypropyl methyl cellulose | 0.11 | 0.17 |
| PVP K30 | 0.10 | 0.14 |
| Macrogol 6000 | 0.09 | 0.15 |
| Poloxamer | 0.12 | 0.19 |
| The miscellaneous Shandong amine soft capsule of grace | 0.16 | 0.75 |
As a result show, the miscellaneous Shandong amine solid dispersions oral formulations of grace prepared by embodiment 1, it places 10 under 60 DEG C of high temperature
Caused relevant material is significantly lower than the soft capsule of the miscellaneous Shandong amine of grace after it, it was demonstrated that its stability is more preferable.
Embodiment 2
The miscellaneous Shandong amine piece of grace, is made up of following raw material：
Preparation method is：
1) PVP K30 is dissolved in 50% ethanol water, obtains the water-soluble polymer that mass concentration is 15%
Carrier solution；
2) the miscellaneous Shandong amine of grace is scattered in water-soluble polymer carrier solution, be spray-dried after stirring, homogeneous, controlled
EAT is 130 DEG C, and leaving air temp is 50 DEG C, charging rate 10mL/min, spray pressure 0.1MPa, obtains the miscellaneous Shandong of grace
Amine solid dispersions；
3) microcrystalline cellulose, Ac-Di-Sol, magnesium stearate are added into the miscellaneous Shandong amine solid dispersions of grace, is mixed
Tabletting after closing uniformly.
Every miscellaneous Shandong amine 40mg containing grace of this product, taking dose is that 1 tablet once, one time a day.
Embodiment 3
The miscellaneous Shandong amine capsule of grace, is made up of following raw material：
Preparation method is：
1) PVP is dissolved in 70% ethanol water, obtains the water-soluble polymer carrier that mass concentration is 30%
Solution；
2) the miscellaneous Shandong amine of grace is scattered in water-soluble polymer carrier solution, be spray-dried after stirring, homogeneous, controlled
EAT is 160 DEG C, and leaving air temp is 70 DEG C, charging rate 20mL/min, spray pressure 0.5MPa, obtains the miscellaneous Shandong of grace
Amine solid dispersions；
3) starch and magnesium stearate are added into the miscellaneous Shandong amine solid dispersions of grace, is filled after mixing with capsule, capsule is made
Agent.
Every miscellaneous Shandong amine 40mg containing grace of this product, taking dose is that 1 tablet once, one time a day.
Claims (1)
1. a kind of preparation method of the miscellaneous Shandong amine solid dispersions oral formulations of grace, it is characterised in that comprise the following steps：
1) take PVP K30 60g, be dissolved in mass concentration be 60% ethanol water in, obtain concentration be 20% it is water-soluble
Property polymer carrier solution；
2) the miscellaneous Shandong amine of 40g grace is scattered in above-mentioned water-soluble polymer carrier solution, is spray-dried after stirring, homogeneous,
It is 150 DEG C to control EAT, and leaving air temp is 60 DEG C, charging rate 10mL/min, spray pressure 0.3MPa, obtains grace
Miscellaneous Shandong amine solid dispersions；
3) lactose 80g, Ac-Di-Sol 10g, magnesium stearate 2g, mixing are added into the miscellaneous Shandong amine solid dispersions of grace
Tabletting after uniformly.
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| CN201510429742.0A CN105030685B (en) | 2015-07-21 | 2015-07-21 | A kind of miscellaneous Shandong amine solid dispersions oral formulations of grace |
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Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA3014088A1 (en) * | 2016-02-19 | 2017-08-24 | 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 |
| 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
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