CN105326793A - Solid dispersion containing c-Met kinase inhibitor and preparation method and application of solid dispersion - Google Patents
Solid dispersion containing c-Met kinase inhibitor and preparation method and application of solid dispersion Download PDFInfo
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Abstract
The invention provides a solid dispersion containing c-Met kinase inhibitor and a preparation method and application of the solid dispersion. The solid dispersion contains one or more active ingredients chosen from compounds A01, A02, A03, A04, A05 and A06, and a pharmaceutically acceptable carrier. The solid dispersion can be higher in dissolution rate, improving bioavailability, granules obtained can also be moderate in hardness and good in fluidity and can be further prepared conveniently into pharmaceutical preparations for direct administration.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of solid dispersion comprising c-Met kinase inhibitor and its production and use.
Background technology
C-Met is the receptor tyrosine kinase regulating the formation of cell proliferation, form and motility.C-Met high expressed abnormal activation in tumor in the cancer and part of the overwhelming majority, all play pivotal role at links such as tumor development, Invasion and Metastasis, chemoresistant.Be different from other kinases, c-Met as the key node albumen in tumor signal network path, because of can with other kinases of surface, acceptor interaction and receiving much concern.Particularly, MET gene amplification and 20% EGFR-TKIs acquired drug-resistance closely related, the c-Met inhibitor therefore finding novel and high-efficiency has become the forward position focus of the world of medicine's research.
Chinese patent ZL201210322359.1 discloses a kind of receptor tyrosine kinase c-Met inhibitor being used as the high selectivity of antitumor drug, wherein recorded amount of activated good compound dissolubility in water is minimum, cause its oral artifact utilization rate lower, show comparatively significant individual variation, be unfavorable for the performance of its curative effect.
For improving the bioavailability of above-claimed cpd in animal and human body, reference preparation new technique related data, the method that insoluble drug improves dissolubility and then raising bioavailability is generally: medicine is carried out micronization processes by (1); (2) in prescription, cosolvent is added, as surfactant-based; (3) medicine is dispersed in the surface of the better adjuvant of water solublity; (4) crude drug is highly dispersed in a kind of disperse system (solid dispersion) existed in solid form formed in solid carrier; (5) medicine is adopted cyclodextrin inclusion technique, increase its dissolubility; (6) the new delivery system such as microsphere, microcapsule, liposome is prepared into; (7) chemical modification is as prodrug or salify.
Solid dispersion technology, due to simple, economical and effectiveness, is often proved to be the most common technique of the dissolution rate improving slightly solubility active pharmaceutical ingredient.
The mechanism that solid dispersion improves insoluble drug stripping mainly comprises: be dispersed in hydrophilic carrier and increase wettability; Reduce the surface area that therefore diameter of aspirin particle increases both sexes solid dispersion; Change medicine physical state, such as, medicine is become amorphous or molecularity from crystallization and disperse in the carrier.Improving dissolution rate may be one or more machine-processed coefficient results above-mentioned.
Summary of the invention
The present invention have been surprisingly found that, by active component and suitable carrier material, according to a certain percentage, by compositions prepared by solid dispersions technique, the object improving stripping and then improve bioavailability can be reached, can also make that the pellet hardness that obtains is moderate, good fluidity, the pharmaceutical preparation that can directly take can be prepared into easily further.
The present invention is directed to ordinary active ingredient dissolubility low, and then the problem causing bioavailability low, provide a kind of solid dispersion and preparation method thereof, and this solid dispersion is made tablet, capsule, granule further, thus medicine was both conveniently taken, can improve again the bioavailability of medicine further, more effectively play therapeutical effect, preparation technology is easy.
The present invention realizes concrete object by the ratio of the kind of screening vector material, screening vector and active component, preparation technology parameter.
Object of the present invention adopts following technical scheme to realize.
On the one hand, the invention provides a kind of solid dispersion, this solid dispersion comprises:
A. active component: be selected from following A01, A02, A03, A04, A05, A06 compound one or more:
and
B. pharmaceutically acceptable carrier.
Preferably, in above-mentioned solid dispersion, described pharmaceutically acceptable carrier be selected from acrylic resin, Polyethylene Glycol (PEG), polyvidone, hydroxypropyl emthylcellulose, Solutol HS15 (SolutolHS15) and poloxamer one or more; Preferably, described pharmaceutically acceptable carrier is selected from one or more in acrylic resin, Polyethylene Glycol, polyvidone, Solutol HS15 (SolutolHS15) and poloxamer; More preferably, described pharmaceutically acceptable carrier is selected from one or more especially in strange L100 (EudragitL100), PVP K30 and Macrogol 4000 (PEG4000) of acrylic resin.Solid dispersion of the present invention can adopt single carrier or adopt several carrier, jointly prepares with active component.
Preferably, in above-mentioned solid dispersion, the mass ratio of described active component and described pharmaceutically acceptable carrier is 1:(0.5-10); Preferably, the mass ratio of described active component and acrylic resin, Polyethylene Glycol, polyvidone, hypromellose is 1:(2-10); More preferably, the mass ratio of described active component and Solutol HS15 (SolutolHS15) is 1:(0.1-1); Most preferably, described active component and poloxamer fly mass ratio is 1:(0.1-1).
Preferably, described solid dispersion exists with amorphous form.
On the other hand, the invention provides a kind of method preparing above-mentioned solid dispersion, this preparation method comprises the steps:
(1) by active component: be selected from following A01, A02, A03, A04, A05, A06 compound one or more:
With pharmaceutically acceptable carrier solubilizes in organic solvent, obtain solution; And
(2) organic solvent in the solution that obtains of removing step (1), obtains solid dispersion composition.
Preferably, in above-mentioned preparation method, in step (1), described organic solvent can use solubilized above-mentioned substance or than be easier to disperse solvent, described organic solvent be selected from methanol, dehydrated alcohol, acetonitrile, isopropyl alcohol, dichloromethane, acetone, chloroform, butanone, n-butyl alcohol, sec-butyl alcohol one or more; Preferably, described organic solvent is acetonitrile, isopropyl alcohol, dehydrated alcohol-acetone, dehydrated alcohol-acetonitrile, dehydrated alcohol-dichloromethane, isopropyl alcohol-acetone, isopropyl alcohol-dichloromethane, methanol-acetone, methanol-acetonitrile or methanol dichloromethane, dehydrated alcohol-butanone, n-butyl alcohol-butanone, the tert-butyl alcohol-butanone.
Preferably, in above-mentioned preparation method, in step (2), the method for removing organic solvent can operate according to the conventional practices of this area, such as evaporation, spray drying method or fluid-bed drying; Preferably, for the present invention, the method removing organic solvent is evaporation; More preferably, for the present invention, the method removing organic solvent is Rotary Evaporators evaporation.
Preferably, in above-mentioned preparation method, the evaporating temperature of described evaporation is 20-80 DEG C, is preferably 40-70 DEG C.
Another aspect, the invention provides a kind of pharmaceutical preparation comprising above-mentioned solid dispersion and adjuvant.Wherein, described adjuvant is conventional pharmaceutically acceptable adjuvant, comprises filler, disintegrating agent, binding agent, lubricant or fluidizer.Concrete example can be microcrystalline Cellulose, lactose, hydroxypropyl cellulose, magnesium stearate etc., and the preparation method of this pharmaceutical preparation is the conventional practices of this area.
Preferably, described pharmaceutical preparation is tablet, capsule or granule.
Again on the one hand, the invention provides solid dispersion that a kind of above-mentioned solid dispersion or above-mentioned preparation method obtain for the preparation of the purposes in anti-tumor drug.
Compared with prior art, the present invention at least possesses following useful technique effect:
The active component that the present invention relates to dissolubility in water is all very low, it is insoluble causes oral artifact availability lower, affects medicine and plays curative effect, by adding suitable pharmaceutically acceptable carrier in these active component, the solid dispersion dissolution obtained is high, and bioavailability is good.
In a word, after have employed solid dispersion provided by the invention and preparation thereof, improve the bioavailability of medicine, more effectively play drug action, reduce drug cost.Meanwhile, solid dispersion hardness provided by the present invention is moderate, good fluidity, and can be prepared into the dosage form facilitating human body to take further, preparation is simple, is produced on a large scale, and is applicable to promoting the use of.
Accompanying drawing explanation
Below, describe embodiment of the present invention in detail by reference to the accompanying drawings, wherein:
Fig. 1 is the X-powder diffraction spectrum of the pharmaceutical composition of comparative example 1, embodiment 15 and embodiment 105;
Fig. 2 is the plasma concentration curve of embodiment 7, embodiment 105 and embodiment 195.
Detailed description of the invention
Contribute to understanding the present invention by following embodiment, but do not limit content of the present invention.
Wherein, if no special instructions, the assay method of dissolution is as follows:
Take appropriate amount of drug (being equivalent to crude drug 30mg) respectively, add in digestion instrument, pH6.8 phosphate buffer 1000ml is solvent, paddle method, and rotating speed 50 revs/min, carries out dissolution test.Respectively at sampling in 30 minutes as need testing solution; Take active component reference substance 15mg, to be dissolved in after methanol in 100ml volumetric flask, to pipette 5ml, with methanol dilution to 25ml, product solution in contrast; Measure the absorbance (correct with corresponding solution respectively and return to zero) of reference substance solution and need testing solution at wavelength 250nm place, calculate dissolution.
comparative example 1-6
Take 200mg active component (concrete active component is as shown in table 1), 400mg lactose, 200mg low-substituted hydroxypropyl cellulose (purchased from Huzhou Zhanwang Pharmaceutical Co., Ltd.), 400mg microcrystalline Cellulose, mix homogeneously, add 1% PVP K30 aqueous solution, be prepared into granule, dry in 40 ~ 50 DEG C of baking ovens, cross 18 mesh sieves after dry, make granule.
Measure the dissolution of the pharmaceutical composition of above-mentioned comparative example 1-6, result is as shown in table 1.
The composition of the pharmaceutical composition of table 1 comparative example 1-6 and content and dissolution results
embodiment 1-6
Active component 200mg (micronization processes, concrete active component is as shown in table 2), lactose 600mg, microcrystalline Cellulose 500mg, hydroxypropyl cellulose 200mg, get the active raw materials medicine of recipe quantity, lactose, hydroxypropyl cellulose (L-HPC), cross 80 mesh sieve mix homogeneously, appropriate with the PVP K30 aqueous solution of 0.5%, soft material processed, cross 24 mesh sieves to granulate, dry, add magnesium stearate mix homogeneously.
Measure the dissolution of the pharmaceutical composition of above-described embodiment 1-6, result is as shown in table 2.
The composition of the pharmaceutical composition of table 2 embodiment 1-6 and content and dissolution results
Found that, micronization processes can reach the effect improving dissolution, but increase rate is little.
embodiment 7-12
Active component 200mg (micronization processes, concrete active component is as shown in table 3), lactose 700mg, microcrystalline Cellulose 300mg, hydroxypropyl cellulose 250mg, sodium lauryl sulphate 5mg, get active raw materials medicine and the lactose of recipe quantity, put in mortar and grind 20min, add microcrystalline Cellulose, hydroxypropyl cellulose (L-HPC), cross 80 mesh sieve mix homogeneously, sodium lauryl sulphate is dissolved in 0.5% PVP K30 aqueous solution, appropriate with the PVP K30 aqueous solution of 0.5%, soft material processed, cross 24 mesh sieves to granulate, dry, add magnesium stearate mix homogeneously.
Measure the dissolution of the pharmaceutical composition of above-described embodiment 7-12, result is as shown in table 3.
The composition of the pharmaceutical composition of table 3 embodiment 7-12 and content and dissolution results
Found that, ground altogether by adjuvant and add the technology of solubilizing agent, on micronized basis, can the dissolution of increase active component slightly.
embodiment 13-42:
With acrylic resin especially strange L100 (EudragitL100) for matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 4) and especially strange L100 (EudragitL100), add dehydrated alcohol/acetone mixed solvent, stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 4.
The composition of the solid dispersion of table 4 embodiment 13-42 and content and dissolution, character, mobility result
As shown in Table 4, active component and especially strange L100 (EudragitL100) mass ratio are 1:(0.5-10) good solid dispersion can be obtained, wherein, preferred active component and especially strange L100 (EudragitL100) mass ratio are 1:(2-10), under this ratio, good solid dispersion can be obtained, this solid dispersion dissolution is high, moderate white particle, good fluidity in hardness, be beneficial to fill or tabletting.
embodiment 43-72:
Take mannitol as matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 5) and mannitol, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 5.
The composition of the solid dispersion of table 5 embodiment 43-72 and content and dissolution, character, mobility result
As shown in Table 5, active component and mannitol cannot form good solid dispersion, and dissolution does not improve significantly.
embodiment 73-102:
Take sorbitol as matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 6) and sorbitol, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 6.
The composition of the solid dispersion of table 6 embodiment 73-102 and content and dissolution, character, mobility result
As shown in Table 6, active component and sorbitol cannot form good solid dispersion, and dissolution does not improve significantly.
embodiment 103-132:
Take PVP K30 as matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 7) and PVP K30, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 7.
The composition of the solid dispersion of table 7 embodiment 103-132 and content and dissolution, character, mobility result
As shown in Table 7, active component and PVP K30 mass ratio are 1:(0.5-10) good solid dispersion can be obtained, wherein, preferred active component and PVP K30 mass ratio are 1:(2-10), under this ratio, good solid dispersion can be obtained, this solid dispersion dissolution obviously raises, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
embodiment 133-162:
Take PEG4000 as matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 8) and PEG4000, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 8.
The composition of the solid dispersion of table 8 embodiment 133-162 and content and dissolution, character, mobility result
As shown in Table 8, active component and PEG4000 mass ratio are 1:(0.5-10) good solid dispersion can be obtained, wherein, preferred active component and PEG4000 mass ratio are 1:(2-10), under this ratio, can in good solid dispersion, dissolution obviously raises, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
embodiment 163-192:
Take hydroxypropyl methylcellulose as matrix composition solid dispersion.Concrete steps are: take active component (concrete active component is as shown in table 9) and hydroxypropyl methylcellulose, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 9.
The composition of the solid dispersion of table 9 embodiment 163-192 and content and dissolution, character, mobility result
As shown in Table 9, active component and hydroxypropyl methylcellulose mass ratio are 1:(0.5-10) good solid dispersion can be obtained, wherein, preferred active component and hydroxypropyl methylcellulose mass ratio are 1:(2-10), under this ratio, can in good solid dispersion, dissolution obviously raises, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
embodiment 193-196:
Take A01 as active component, with crylic acid resin, especially strange L100 (EudragitL100), SolutolHS15 are matrix composition solid dispersion.Concrete steps are: take A01, especially strange L100 (EudragitL100) and SolutolHS15, add dehydrated alcohol/acetone mixed solvent, stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated, 40 DEG C.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 10.
The composition of the solid dispersion of table 10 embodiment 193-196 and content and dissolution, character, mobility result
As shown in Table 10, A01, especially strange L100 (EudragitL100) and SolutolHS15 mass ratio are 1:2:(0.1-5) good solid dispersion can be obtained, wherein, preferred A01, SolutolHS15 mass ratio is 1:(0.1-1), under this ratio, can in good solid dispersion, dissolution is high, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
embodiment 197-200:
Take A01 as active component, with crylic acid resin, especially strange L100 (EudragitL100), poloxamer are matrix composition solid dispersion.Concrete steps are: take A01, especially strange L100 (EudragitL100) and poloxamer, add dehydrated alcohol/acetone mixed solvent, stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated, 40 DEG C.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 11.
The composition of the solid dispersion of table 11 embodiment 197-200 and content and dissolution, character, mobility result
As shown in Table 11, A01, especially strange L100 (EudragitL100) and poloxamer mass ratio are 1:2:(0.1-5) good solid dispersion can be obtained, wherein, preferred A01, poloxamer mass ratio are 1:(0.1-1), under this ratio, can in good solid dispersion, dissolution is high, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
embodiment 201-204:
Take A01 as active component, with PVP K30, SolutolHS15 for matrix composition solid dispersion.Concrete steps are: take A01, PVP K30 and SolutolHS15, add dehydrated alcohol/acetone mixed solvent, and stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated, 40 DEG C.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.The dissolution of obtained solid dispersion, character, mobility result are as shown in table 12.
The composition of the solid dispersion of table 12 embodiment 201-204 and content and dissolution, character, mobility result
As shown in Table 12, A01, PVP K30 and SolutolHS15 mass ratio are 1:2:(0.1-5) good solid dispersion can be obtained, wherein, preferred A01, SolutolHS15 mass ratio is 1:(0.1-1), under this ratio, can in good solid dispersion, dissolution is high, the moderate white particle in hardness, good fluidity, is beneficial to fill or tabletting.
the mensuration of embodiment 205:X-x ray diffraction collection of illustrative plates
Sample treatment: the solid dispersion sample of comparative example 1, embodiment 15 and embodiment 105 is respectively through grinding and crossing 100 mesh sieves, and precision weighing 50mg is as powder x-ray diffraction test sample.
Experimental condition: CuK α radiation, graphite monochromator, pipe pressure 40Kv, pipe flow 150mA, 2 θ sweep limits 3-80 °, scanning speed 8 °/point, step-length 0.02 °.
Slit condition: divergent slit is 1 °, limit for height slit is 10mm, and antiscatter slits is 1 °, and reception slit is 0.15mm.
Sample measures powder x-ray diffraction by above-mentioned condition after treatment.Result as shown in Figure 1, can be found out, solid dispersion of the present invention does not have diffraction maximum, and namely solid dispersion of the present invention exists with unbodied form.
embodiment 206: the mensuration of bioavailability
Test specimen: the granule of embodiment 7, embodiment 105, embodiment 195 is respectively charged into capsule.
Laboratory animal: beasle dog, about body weight 12kg, is divided into 3 groups at random, often organizes 3.
Dosage: 45mg/kg.
Administering mode: fasting before the administration of oral administration group, freely drinks water, 4h feeding after administration.
Oral administration blood specimen collection: respectively at after (0h) before administration and administration 0.25,0.5,1,2,4,6,8,12,24h is from dog forelimb cephalic vein blood sampling 1mL, anticoagulant heparin, centrifugal separation plasma (4 DEG C of centrifugal 5min of 4000rpm) ,-80 DEG C of refrigerators are frozen and completed sample analysis in 1 month.
Biological sample treatment and analyses: 50 μ L plasma containing drugs, adds mark diphenhydramine (20ng/mL) methanol solution in 200 μ L, and 800 μ L methanol solutions, vortex 1min, 4 DEG C of centrifugal 10min of 12000rpm; Get supernatant 100 μ L and add 400 μ L diluents (methanol: water=80:20), vortex 1min, after getting dilution, sample is placed in interpolation pipe, 4 DEG C of centrifugal 5min of 12000rpm, sample introduction 5 μ L carries out LC-MS/MS quantitative analysis, obtains the concentration data of each plasma sample mesarcs medicine
Result as shown in Figure 2, can be found out, solid dispersion prepared by the present invention can significantly improve the bioavailability of medicine.
embodiment 207-236: the screening study of organic solvent
Be active fraction preparation solid dispersion with A01, concrete steps are: be that the ratio of 1:5 takes A01, Polyethylene Glycol PEG4000 with mass ratio, add different solvents, stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.Dissolving situation and the evaporation rate of solvent of use different organic solvents are as shown in table 13.
Table 13 uses dissolving situation and the evaporation rate of solvent of different organic solvents
Known according to upper table 13, select acetonitrile, isopropyl alcohol, dehydrated alcohol-acetone, dehydrated alcohol-acetonitrile, dehydrated alcohol-dichloromethane, isopropyl alcohol-acetone, isopropyl alcohol-dichloromethane, methanol-acetone, methanol-acetonitrile or methanol dichloromethane, dehydrated alcohol-butanone, n-butyl alcohol-butanone, the tert-butyl alcohol-butanone all can dissolve, solvent evaporation rate is very fast or moderate, and then infers and can form solid dispersion composition.
embodiment 237-264: the selection of evaporating temperature
Be active fraction preparation solid dispersion with A01, concrete steps are: be that the ratio of 1:2 takes A01, PVP K30 with mass ratio, add different solvents, stir, ultrasonic making it is dissolved completely, uses Rotary Evaporators solvent evaporated at different temperature.Put vacuum drying oven continuous drying 18h, scrape, cross 40 mesh sieves, obtain solid dispersion.Use the solvent evaporating state of different evaporating temperature as shown in table 14.
Table 14 uses the solvent evaporating state of different evaporating temperature
| Solvent | Evaporating temperature | Solvent evaporating state | |
| Embodiment 237 | Dehydrated alcohol/acetone | 20℃ | Solvent slow evaporation |
| Embodiment 238 | Dehydrated alcohol/acetone | 30℃ | Solvent slow evaporation |
| Embodiment 239 | Dehydrated alcohol/acetone | 40℃ | Evaporation rate of solvent is very fast |
| Embodiment 240 | Dehydrated alcohol/acetone | 50℃ | Evaporation rate of solvent is very fast |
| Embodiment 241 | Dehydrated alcohol/acetone | 60℃ | Evaporation rate of solvent is very fast |
| Embodiment 242 | Dehydrated alcohol/acetone | 70℃ | Evaporation rate of solvent is very fast |
| Embodiment 243 | Dehydrated alcohol/acetone | 80℃ | Easy generation bumping |
| Embodiment 244 | Methanol/acetone | 20℃ | Solvent normally evaporates |
| Embodiment 245 | Methanol/acetone | 30℃ | Evaporation rate of solvent is very fast |
| Embodiment 246 | Methanol/acetone | 40℃ | Evaporation rate of solvent is very fast |
| Embodiment 247 | Methanol/acetone | 50℃ | Evaporation rate of solvent is very fast |
| Embodiment 248 | Methanol/acetone | 60℃ | Evaporation rate of solvent is very fast |
| Embodiment 249 | Methanol/acetone | 70℃ | Easy generation bumping |
| Embodiment 250 | Methanol/acetone | 80℃ | Easy generation bumping |
| Embodiment 251 | Dehydrated alcohol/butanone | 20℃ | Solvent slow evaporation |
| Embodiment 252 | Dehydrated alcohol/butanone | 30℃ | Solvent slow evaporation |
| Embodiment 253 | Dehydrated alcohol/butanone | 40℃ | Evaporation rate of solvent is very fast |
| Embodiment 254 | Dehydrated alcohol/butanone | 50℃ | Evaporation rate of solvent is very fast |
| Embodiment 255 | Dehydrated alcohol/butanone | 60℃ | Evaporation rate of solvent is very fast |
| Embodiment 256 | Dehydrated alcohol/butanone | 70℃ | Evaporation rate of solvent is very fast |
| Embodiment 257 | Dehydrated alcohol/butanone | 80℃ | Easy generation bumping |
| Embodiment 258 | Isopropyl alcohol/acetone | 20℃ | Solvent slow evaporation |
| Embodiment 259 | Isopropyl alcohol/acetone | 30℃ | Solvent slow evaporation |
| Embodiment 260 | Isopropyl alcohol/acetone | 40℃ | Solvent slow evaporation |
| Embodiment 261 | Isopropyl alcohol/acetone | 50℃ | Evaporation rate of solvent is very fast |
| Embodiment 262 | Isopropyl alcohol/acetone | 60℃ | Evaporation rate of solvent is very fast |
| Embodiment 263 | Isopropyl alcohol/acetone | 70℃ | Evaporation rate of solvent is very fast |
| Embodiment 264 | Isopropyl alcohol/acetone | 80℃ | Evaporation rate of solvent is very fast |
From upper table 14, when 20-80 DEG C, all can carry out the preparation of solid dispersion, by preferably, evaporating temperature is when 40-70 DEG C, and most of solvent can volatilize fast, can form good solid dispersion composition.
embodiment 265: spray drying method prepares solid dispersion
Be active fraction preparation solid dispersion with A01, concrete steps are: be that the ratio of 1:2 takes A01, PVP K30 with mass ratio, add dehydrated alcohol/acetone, stir, ultrasonic making it is dissolved completely, and spraying dry, obtains solid dispersion.Dissolution determination is 92.1%.
Spray drying method also can be used for the preparation of the solid dispersion of this invention.
embodiment 266: fluid-bed drying prepares solid dispersion
Be active fraction preparation solid dispersion with A01, concrete steps are: be that the ratio of 1:2 takes A01, PVP K30 with mass ratio, add dehydrated alcohol/acetone, stir, ultrasonic making it is dissolved completely, and fluid bed drying, obtains solid dispersion.Dissolution determination is 89.6%.
Fluid-bed drying also can be used for the preparation of the solid dispersion of this invention.
embodiment 267: pharmaceutical preparation of the present invention (tablet)
Prescription:
Preparation method:
After the solid dispersion of embodiment 15 being crossed 40 mesh sieves, adjuvant (i.e. microcrystalline Cellulose, lactose, hydroxypropyl cellulose, magnesium stearate) mistake 80 mesh sieves, mix homogeneously, direct compression, both.
embodiment 268: pharmaceutical preparation of the present invention (capsule)
Prescription:
Preparation method:
After the solid dispersion of embodiment 105 being crossed 40 mesh sieves, adjuvant (i.e. microcrystalline Cellulose, lactose, hydroxypropyl cellulose, magnesium stearate) mistake 80 mesh sieves, mix homogeneously, direct fill capsule, both.
embodiment 269: pharmaceutical preparation of the present invention (tablet)
Prescription:
Preparation method:
After the solid dispersion of embodiment 166 being crossed 40 mesh sieves, adjuvant (i.e. microcrystalline Cellulose, lactose, hydroxypropyl cellulose, magnesium stearate) mistake 80 mesh sieves, solid dispersion, lactose, microcrystalline Cellulose mix homogeneously, granulate in right amount with 5% hypromellose aqueous solution, in 50 DEG C of aeration-dryings, cross 24 mesh sieves after dry and arrange.Additional hydroxypropyl cellulose, magnesium stearate, mix homogeneously, tabletting, to obtain final product.
Claims (10)
1. a solid dispersion, this solid dispersion comprises:
A. active component: be selected from following A01, A02, A03, A04, A05, A06 compound one or more:
B. pharmaceutically acceptable carrier.
2. solid dispersion according to claim 1, it is characterized in that, described pharmaceutically acceptable carrier be selected from acrylic resin, Polyethylene Glycol, polyvidone, hydroxypropyl emthylcellulose, Solutol HS15 (SolutolHS15) and poloxamer one or more; Preferably, described pharmaceutically acceptable carrier is selected from one or more in acrylic resin, Polyethylene Glycol, polyvidone, Solutol HS15 (SolutolHS15) and poloxamer; More preferably, described pharmaceutically acceptable carrier is selected from one or more in especially strange L100 (EudragitL100), PVP K30 and Macrogol 4000.
3. solid dispersion according to claim 1 and 2, is characterized in that, the mass ratio of described active component and described pharmaceutically acceptable carrier is 1:(0.5-10); Preferably, the mass ratio of described active component and acrylic resin, Polyethylene Glycol, polyvidone, hypromellose is 1:(2-10); More preferably, the mass ratio of described active component and Solutol HS15 (SolutolHS15) is 1:(0.1-1); Most preferably, described active component and poloxamer fly mass ratio is 1:(0.1-1).
4. solid dispersion according to any one of claim 1 to 3, is characterized in that, described solid dispersion exists with unbodied form.
5. a preparation method for the solid dispersion according to any one of Claims 1-4, this preparation method comprises the steps:
(1) by active component: be selected from following A01, A02, A03, A04, A05, A06 compound one or more:
With pharmaceutically acceptable carrier solubilizes in organic solvent, obtain solution; And
(2) organic solvent in the solution that obtains of removing step (1), obtains solid dispersion composition.
6. preparation method according to claim 5, it is characterized in that, in step (1), described organic solvent be selected from methanol, dehydrated alcohol, acetonitrile, isopropyl alcohol, dichloromethane, acetone, chloroform, butanone, n-butyl alcohol, sec-butyl alcohol one or more; Preferably, described organic solvent is acetonitrile, isopropyl alcohol, dehydrated alcohol-acetone, dehydrated alcohol-acetonitrile, dehydrated alcohol-dichloromethane, isopropyl alcohol-acetone, isopropyl alcohol-dichloromethane, methanol-acetone, methanol-acetonitrile or methanol dichloromethane, dehydrated alcohol-butanone, n-butyl alcohol-butanone, the tert-butyl alcohol-butanone.
7. the preparation method according to claim 5 or 6, is characterized in that, in step (2), the method for removing organic solvent is evaporation, spray drying method or fluid-bed drying; Preferably, the method removing organic solvent is evaporation; More preferably, the method removing organic solvent is Rotary Evaporators evaporation.
8. preparation method according to claim 7, is characterized in that, the evaporating temperature of described evaporation is 20-80 DEG C, is preferably 40-70 DEG C.
9. comprise a pharmaceutical preparation for solid dispersion according to any one of Claims 1-4 and adjuvant, preferably, described pharmaceutical preparation is tablet, capsule or granule.
10. the solid dispersion according to any one of Claims 1-4 is for the preparation of the purposes in anti-tumor drug.
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| CN201410385099.1A CN105326793A (en) | 2014-08-06 | 2014-08-06 | Solid dispersion containing c-Met kinase inhibitor and preparation method and application of solid dispersion |
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| CN108553441A (en) * | 2018-06-08 | 2018-09-21 | 北京阳光诺和药物研究有限公司 | A kind of Apixaban tablet and preparation method thereof |
| CN109833301A (en) * | 2017-11-29 | 2019-06-04 | 天津市保灵动物保健品有限公司 | A kind of dog cat terbinafine HCl flavor piece and its preparation process |
| CN116854694A (en) * | 2023-07-04 | 2023-10-10 | 北京浦润奥生物科技有限责任公司 | Crystal forms of [1,2,4] triazole [4,3-b ] pyridazine compound, and preparation method and application thereof |
| EP4142715A4 (en) * | 2020-04-26 | 2024-05-15 | Apollomics Inc | Novel pharmaceutical formulation for c-met inhibitor |
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| US20090264406A1 (en) * | 2008-02-28 | 2009-10-22 | Novartis Ag | 3-methyl-imidazo[1,2-b]pyridazine derivatives |
| CN103122000A (en) * | 2012-09-03 | 2013-05-29 | 中美冠科生物技术（太仓）有限公司 | High-selectivity c-Met kinase inhibitor used as antitumor drug |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109833301A (en) * | 2017-11-29 | 2019-06-04 | 天津市保灵动物保健品有限公司 | A kind of dog cat terbinafine HCl flavor piece and its preparation process |
| CN108553441A (en) * | 2018-06-08 | 2018-09-21 | 北京阳光诺和药物研究有限公司 | A kind of Apixaban tablet and preparation method thereof |
| CN108553441B (en) * | 2018-06-08 | 2019-11-08 | 北京阳光诺和药物研究有限公司 | A kind of Apixaban tablet and preparation method thereof |
| EP4142715A4 (en) * | 2020-04-26 | 2024-05-15 | Apollomics Inc | Novel pharmaceutical formulation for c-met inhibitor |
| CN116854694A (en) * | 2023-07-04 | 2023-10-10 | 北京浦润奥生物科技有限责任公司 | Crystal forms of [1,2,4] triazole [4,3-b ] pyridazine compound, and preparation method and application thereof |
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