CN104586770A - Hot-melt extrusion preparation of pazopanib hydrochloride and preparation method of hot-melt extrusion preparation - Google Patents
Hot-melt extrusion preparation of pazopanib hydrochloride and preparation method of hot-melt extrusion preparation Download PDFInfo
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- CN104586770A CN104586770A CN201410842083.9A CN201410842083A CN104586770A CN 104586770 A CN104586770 A CN 104586770A CN 201410842083 A CN201410842083 A CN 201410842083A CN 104586770 A CN104586770 A CN 104586770A
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Abstract
The invention discloses a hot-melt extrusion preparation of pazopanib hydrochloride and a preparation method of the hot-melt extrusion preparation. The hot-melt extrusion preparation is characterized by comprising the following components in parts by weight: 1 part of pazopanib hydrochloride, 10 parts of a hydrophilic polymer material and 3 parts of polyethylene glycol.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of hot-melt extruded preparation and hot-melt extruded method thereof, concrete, hot-melt extruded preparation relating to a kind of pazopanib hydrochloride and preparation method thereof.
Background technology
Pazopanib hydrochloride (Pazopanib Hydrochloride, GW 786034) be the tyrosine kinase inhibitor of a kind of vascular endothelial growth factor receptor (VEGFR), researched and developed by GlaxoSmithKline PLC company (GlaxoSmithKline).In October, 2009 by GlaxoSmithKline PLC company as far back as the granted listing of the U.S..In June, 2010, Ge Lan element group company (Glaxo Group Ltd.) is again in the granted this product listing of European Union, and in JIUYUE, 2012 is gone on the market in Japan, and trade name is: VOTRIENT.In October, 2009, pazopanib was advanced renal cell carcinoma as far back as the indication that the U.S. is granted, and in April, 2012 is at the granted new indication of the U.S.: soft tissue sarcoma.
Pazopanib hydrochloride chemical name is 5-[[4-[(2,3-dimethyl-2H-indazole-6-base) methylamino] pyrimidine-2-base] is amino]-2-Methyl benzenesulfonyl amine hydrochlorate.Its chemical structural formula is as follows:
Molecular formula: C
21h
23n
7o
2sHCl
Molecular weight: 473.99
No. CAS: 635702-64-6
Pazopanib hydrochloride is generally white to micro-yellow crystalline powder, moist without drawing, and the atomic water being dissolved in pH1.1 is almost insoluble in the aqueous medium of pH4 or more.Biopharmaceutics (BCS) classification of pazopanib hydrochloride belongs to 2 classes (low solubility, high osmosis).
The conventional method improving insoluble drug bioavailability has micronization technology and solid dispersion technology.But after drug micronization, surface free energy is comparatively large, has spontaneous coalescent trend, reduces micronization effect.Traditional solid dispersion preparation method has: fusion method, solvent method, polishing, spray drying method, although drug-eluting speed can be improved, but because these preparation methoies exist the problems such as complex process, repeatability are low, organic solvent residual, industrialization promotion difficulty is larger.
Such as, show in the documents and materials such as EMEA, raw material granularity distribution D90≤20 μm need be controlled, but in actual micronization process, dust is large, is unfavorable for producing and labor protection.
In addition, in the pazopanib hydrochloride tablet medicament description that FDA announces, Core formulation consists of: pazopanib hydrochloride, microcrystalline Cellulose, carboxymethyl starch sodium, polyvidone (K30) and magnesium stearate.Adopt traditional solid dispersion technology to prepare preparation, complex process, industrialization difficulty is large.
In recent years, hot-melt extruded method enjoys the concern of domestic and international Pharmaceutical study person as a kind of novel method preparing solid dispersion.The method, by the singe screw heated piecemeal or double screw extruder, realizes the transmission conveying of material, shear-mixed and melt extruded.Relative to traditional preparation method, it is high that hot-melt extruded method has production efficiency, without the need to organic solvent, is suitable for the features such as suitability for industrialized production.But the fusing point of pazopanib hydrochloride is more than 285 ~ 289 DEG C, and for this medicine with higher melt, hot-melt extruded method easily causes the thermal decomposition of medicine and carrier, thus limits the extensive use of the method.
Summary of the invention
In view of the deficiencies in the prior art, inventor intends providing a kind of novel solid dispersion preparation technology, for this has been great many of experiments work, in test, inventor expects utilizing hot-melt extruded legal system for solid dispersion, crude drug, polymer adjuvant are added in extruder simultaneously, material is made to experience Solid Conveying and Melting, melting, melt Conveying three stage, under the strong shear effect of kneading device and screw element, obtain the shaped article of highly mixing dispersion, particularly valuable is that preparation technology is easy to realize industrial amplification production.
Present invention employs copolyvidone (PVP-VA64, polyvidone-S630) or Soluplus as dispersible carrier material, but, because pazopanib hydrochloride fusing point is high, more than 285 DEG C, if directly utilize hot-melt extruded, need temperature high, otherwise pazopanib hydrochloride is non-fusible, be difficult to be uniformly dispersed in the carrier.Therefore reduce hot-melt extruded temperature, seem particularly important.In test, the creationary proposition of inventor, Polyethylene Glycol selected by plasticizer, also has the effect of solubilizing agent simultaneously.Polyethylene Glycol fusing point is low, temperature can be reduced and easily change expressing technique process, the screw rod shearing effect of sufficient intensity can be obtained again, thus effectively improve medicine dispersity in the carrier, effectively can reduce glass transition temperature, and also have larger dissolubility to medicine.
In the present invention, inventor is creationary use Polyethylene Glycol in pazopanib hydrochloride hot-melt extruded, as solubilizing agent and plasticizer, achieve beyond thought effect, hot melting temperature can be reduced to 130 ~ 180 DEG C, not only reduce energy consumption, and ensure that the stability of medicine.
The invention provides a kind of hot-melt extruded preparation method of pazopanib hydrochloride solid dispersion, principal character is with hydrophilic high molecular material copolyvidone (PVP-VA64, polyvidone S630), Soluplus is as main dispersible carrier material, add plasticizer Polyethylene Glycol, easyization expressing technique process, effectively improve the dispersity of medicine in solid dispersion, make the raising that the dissolution in vitro of medicine in dissolution medium obtains by a relatively large margin.
For achieving the above object, the invention provides a kind of hot-melt extruded solid dispersion of pazopanib hydrochloride.Concrete, this dispersion comprises pazopanib hydrochloride, hydrophilic high molecular material and Polyethylene Glycol (polyoxyl stearate class).Wherein, described hydrophilic high molecular material is one or both in copolyvidone, Soluplus, preferably Soluplus; The molecular weight of preferred Polyethylene Glycol is 2000-6000.
Further, the invention provides by the pazopanib hydrochloride preparation of the hot-melt extruded solid dispersion preparation of above-mentioned pazopanib hydrochloride.Hot-melt extruded solid dispersion by above-mentioned pazopanib hydrochloride is prepared into capsule further, tablet, lamination method are wrapped on micropill or at preparation outer surface coating, makes corresponding solid preparation.
Particularly, a kind of hot-melt extruded solid dispersion of pazopanib hydrochloride solid dispersion or preparation, comprise the composition of following weight ratio:
Pazopanib hydrochloride 1 part
Hydrophilic high molecular material 7-12 part
Polyethylene Glycol 2-4 part
More preferably comprise the preparation of the composition of following weight ratio
Pazopanib hydrochloride 1 part
Hydrophilic high molecular material 10 parts
Polyethylene Glycol 3 parts
Wherein, the molecular weight of Polyethylene Glycol is 2000-6000, and the molecular weight being preferably Polyethylene Glycol is 4000.
Another object of the present invention is to the preparation method that a kind of above-mentioned solid dispersion is provided.The hot-melt extrusion process of the hot-melt extruded solid dispersion of described pazopanib hydrochloride solid dispersion, comprises the following steps:
1) cross 60 ~ 100 mesh sieves after crude drug pazopanib hydrochloride and pharmaceutic adjuvant being pulverized respectively, mix in proportion, make physical mixture; Pharmaceutic adjuvant is above-mentioned hydrophilic high molecular material and plasticizer;
2) setting the extrusion temperature of double screw extruder is 130 ~ 240 DEG C, and temperature starts screw rod after being raised to setting value, by step 1) in physical mixture be added in extruder, through melting, extruding, finally extrude with ribbon;
3), after the cooling of ribbon extrudate, pulverization process crosses 20-80 mesh sieve, obtains medicine solid dispersion granule or powder.
4) step 3) gained granule or powder as granule or powder direct packaging, or are processed into capsule, tablet, lamination method are wrapped on micropill or at preparation outer surface coating, make corresponding solid preparation.
The present invention adopts the hot-melt extruded solid dispersion of differential scanning calorimetry to pazopanib hydrochloride to investigate, and in differential scanning calorimetric analysis result display extrudate, pazopanib hydrochloride melting absworption peak disappears (see accompanying drawing 2)
Compared with traditional handicraft, the present invention has following beneficial effect:
(1) the hot-melt extruded solid dispersion of pazopanib hydrochloride provided by the invention or preparation of Chinese medicine pazopanib hydrochloride disperse in carrier material evenly; When not using Surfactant SDS, in dissolution medium, all can reach the effect of Fast Stripping, dissolution rate be still obviously better than former triturate.Improve the bioavailability of insoluble drug, reduce dosage, reduce adverse effect.
(2) preparation technology in the present invention is simple, and energy consumption is little, no solvent residue, and whole process can not introduce other impurity, is easy to realize continuous mass production.
Accompanying drawing explanation
Fig. 1: pazopanib hydrochloride crude drug, physical mixture, import sheet (Votrient 200mg, lot number: R659074) and the drug-eluting curve chart of pazopanib hydrochloride solid dispersion (embodiment 1 ~ 4, comparative example 1 ~ 4);
Fig. 2: differential scanning calorimetric analysis (DSC) collection of illustrative plates of the pazopanib hydrochloride solid dispersion (extrudate) of preparation in embodiment 4;
Fig. 3: differential scanning calorimetric analysis (DSC) collection of illustrative plates of the pazopanib hydrochloride solid dispersion (physical mixture) of preparation in comparative example 4;
Fig. 4: differential scanning calorimetric analysis (DSC) collection of illustrative plates of pazopanib hydrochloride crude drug.
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, the invention will be further described.It is to be understood that following explanation is only to explain the present invention, its content is not limited.If no special instructions, the content of following each composition used is weight percentage.
All adopting in following examples and carry out differential scanning calorimetric analysis with the following method: the sample taking 10 milligrams is placed in aluminum dish, is reference substance with alumina crucible, and in nitrogen current, temperature elevating range is 20 DEG C ~ 300 DEG C, scans with the ramp of 10 DEG C/min.
Embodiment 1
Pazopanib hydrochloride 1 part
PVP-S630 12 parts
Macrogol 4000 2 parts
Preparation technology: mix homogeneously is prepared into physical mixture, arranges extruder temperature at 180 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, melting, extrude and obtain bands, cooling, pulverized 40 mesh sieves, obtained pazopanib hydrochloride solid dispersion particles.
Embodiment 2
Pazopanib hydrochloride 1 part
PVP-VA64 7 parts
Macrogol 4000 2 parts
Preparation technology: mix homogeneously is prepared into physical mixture, arranges extruder temperature at 150 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, melting, extrude and obtain bands, cooling, pulverized 40 mesh sieves, obtained pazopanib hydrochloride solid dispersion particles.
Embodiment 3
Pazopanib hydrochloride 1 part
PVP-VA64 10 parts
Macrogol 4000 4 parts
Preparation technology: mix homogeneously is prepared into physical mixture, arranges extruder temperature at 165 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, melting, extrude and obtain bands, cooling, pulverized 40 mesh sieves, obtained pazopanib hydrochloride solid dispersion particles.
Embodiment 4
Pazopanib hydrochloride 1 part
Soluplus 10 parts
Macrogol 4000 3 parts
Preparation technology: mix homogeneously is prepared into physical mixture, arranges extruder temperature at 130 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, melting, obtain ribbon extrudate, cooling, pulverized 40 mesh sieves, obtained pazopanib hydrochloride solid dispersion particles.
Comparative example 1
Pazopanib hydrochloride 1 part
Soluplus 10 parts
Preparation technology: mix homogeneously is prepared into physical mixture, extruder temperature is set at 130 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, be heated to 235 DEG C of whole meltings, extrude and obtain bands, cooling, pulverize 40 mesh sieves, obtain pazopanib hydrochloride solid dispersion particles.
Comparative example 2
Pazopanib hydrochloride 1 part
Macrogol 4000 7 parts
Preparation technology: mix homogeneously is prepared into physical mixture, extruder temperature is set at 130 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, be heated to 230 DEG C of meltings, extrude to obtain bands, cooling, pulverize 40 mesh sieves, obtain pazopanib hydrochloride solid dispersion particles.
Comparative example 3
Pazopanib hydrochloride 1 part
PVP-VA64 10 parts
Poloxamer 4 parts
Preparation technology: mix homogeneously is prepared into physical mixture, extruder temperature is set at 130 DEG C, after temperature is raised to setting value and is stable, at the uniform velocity add physical mixture, be heated to 232 DEG C of meltings, extrude to obtain bands, cooling, pulverize 40 mesh sieves, obtain pazopanib hydrochloride solid dispersion particles.
Comparative example 4
Pazopanib hydrochloride 1 part
Soluplus 10 parts
Macrogol 4000 3 parts
Preparation technology: mix homogeneously is prepared into physical mixture.
Checking embodiment
Dissolution determination: accurate weighting raw materials, physical mixture, extrudate powder appropriate (be equivalent to medicine and be about 10mg) respectively, according to Chinese Pharmacopoeia 2010 editions two annex XC second methods, with 900mLpH4.5 acetate buffer for dissolution medium, rotating speed is 75r/min, in 5, and 10,15,20,30,45, get solution 5ml during 60min, and supplement identical temperature, the dissolution medium of same volume simultaneously, filter, as need testing solution through the microporous filter membrane of 0.45 μm; It is appropriate that another precision takes pazopanib hydrochloride reference substance, make 10 μ g/mL product solution in contrast, according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2010 two annex VD), be filler with octadecyl silane, 40% acetonitrile-water is mobile phase, determined wavelength is 270nm, and precision measures 20 μ l injection liquid chromatographies, record chromatogram.Stripping quantity is added up with calculated by peak area medicine by external standard method.
The drug-eluting curve data of pazopanib hydrochloride crude drug, physical mixture, import sheet (Votrient 200mg, lot number: R659074) and pazopanib hydrochloride solid dispersion (embodiment 1 ~ 4, comparative example 1 ~ 4).
It can be seen from the table: embodiment of the present invention 1-4 stripping is rapid; Comparative example 1, do not add Polyethylene Glycol, and melt temperature is high, form dispersion, because lacking plasticizer and porogen, therefore stripping is slow; Comparative example 2, do not use Soluplus as solid dispersion carrier, therefore stripping are slow; Comparative example 3, and use poloxamer instead and substitute Polyethylene Glycol, effect is bad; Comparative example 4, and be only a physical mixed objects system, do not form solid dispersion, stripping is poor; Pazopanib hydrochloride raw material is because of poor solubility, therefore during simple determination of raw material stripping, stripping is the poorest; The stripping of import sheet is not because preparing solid dispersion system, and the stripping comparatively embodiment of the present invention is poor.Dissolution determination result demonstrates superiority of the present invention further.(see accompanying drawing 1)
The present invention also adopts the hot-melt extruded solid dispersion of differential scanning calorimetry to pazopanib hydrochloride to investigate, in differential scanning calorimetric analysis result display extrudate, pazopanib hydrochloride melting endothermic peak disappears, and in physical mixture, still have pazopanib hydrochloride melting endothermic peak, illustrate that extrudate is solid dispersion, wherein pazopanib hydrochloride is with unformed existence, and in physical mixture, pazopanib hydrochloride still exists with crystal formation.(see accompanying drawing 2,3,4).
Claims (5)
1. a hot-melt extruded preparation for pazopanib hydrochloride solid dispersion, it is characterized in that comprising pazopanib hydrochloride, Polyethylene Glycol and hydrophilic high molecular material, and its weight ratio is as follows:
Pazopanib hydrochloride 1 part
Hydrophilic high molecular material 7-12 part
Polyethylene Glycol 2-4 part
Hydrophilic high molecular material described in above formula is one or both in copolyvidone, Soluplus, preferably Soluplus.
2. pazopanib hydrochloride according to claim 1, Polyethylene Glycol and hydrophilic high molecular material are preferably as follows weight ratio:
Pazopanib hydrochloride 1 part
Hydrophilic high molecular material 10 parts
Polyethylene Glycol 3 parts.
3. Polyethylene Glycol preferred molecular weight according to claim 1 is 2000-6000.
4. the hot-melt extrusion process of pazopanib hydrochloride solid dispersion according to claim 1, is characterized in that comprising following step:
1) cross 60 ~ 100 mesh sieves after crude drug pazopanib hydrochloride and pharmaceutic adjuvant being pulverized respectively, mix homogeneously, makes physical mixture; Pharmaceutic adjuvant is above-mentioned hydrophilic high molecular material and plasticizer;
2) setting the extrusion temperature of double screw extruder is 130 DEG C ~ 290 DEG C, and temperature starts screw rod after being raised to setting value, by step 1) in mixture be added in extruder, through melting, extruding, finally extrude with ribbon;
3), after the cooling of ribbon extrudate, pulverization process crosses 20 ~ 80 mesh sieves, obtains medicine solid dispersion granule or powder.
5. according to claim 4 gained granule or powder as granule or powder direct packaging, or be processed into capsule or tablet.
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Cited By (5)
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| CN109212042A (en) * | 2017-06-30 | 2019-01-15 | 齐鲁制药有限公司 | A kind of analysis method using liquid chromatography and mass spectrometry hydrochloric acid training azoles Pa Nijiyin toxic impurities |
| CN110664771A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Pharmaceutical composition containing pexaparib hydrochloride and preparation method thereof |
| CN111773230A (en) * | 2020-08-17 | 2020-10-16 | 深圳市道科思医药有限公司 | Hot-melt extruded tenofovir disoproxil pharmaceutical composition |
| WO2022040446A1 (en) * | 2020-08-19 | 2022-02-24 | Nanocopoeia, Llc | Amorphous pazopanib particles and pharmaceutical compositions thereof |
| CN115671110A (en) * | 2021-07-30 | 2023-02-03 | 上海博志研新药物技术有限公司 | Pazopanib oral pharmaceutical composition, preparation method and application thereof |
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| US20070071813A1 (en) * | 2005-09-23 | 2007-03-29 | Ahmed Hashim A | Novel dosage formulation |
| CN103282025A (en) * | 2010-10-29 | 2013-09-04 | Abbvie公司 | Melt-extruded solid dispersions containing an apoptosis-nducing agent |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109212042A (en) * | 2017-06-30 | 2019-01-15 | 齐鲁制药有限公司 | A kind of analysis method using liquid chromatography and mass spectrometry hydrochloric acid training azoles Pa Nijiyin toxic impurities |
| CN110664771A (en) * | 2018-07-03 | 2020-01-10 | 江苏海悦康医药科技有限公司 | Pharmaceutical composition containing pexaparib hydrochloride and preparation method thereof |
| CN111773230A (en) * | 2020-08-17 | 2020-10-16 | 深圳市道科思医药有限公司 | Hot-melt extruded tenofovir disoproxil pharmaceutical composition |
| WO2022040446A1 (en) * | 2020-08-19 | 2022-02-24 | Nanocopoeia, Llc | Amorphous pazopanib particles and pharmaceutical compositions thereof |
| CN115671110A (en) * | 2021-07-30 | 2023-02-03 | 上海博志研新药物技术有限公司 | Pazopanib oral pharmaceutical composition, preparation method and application thereof |
| CN115671110B (en) * | 2021-07-30 | 2024-05-10 | 上海云晟研新生物科技有限公司 | Pazopanib oral pharmaceutical composition, preparation method and application thereof |
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