CN115581678A - Riparitinib tablet composition and preparation method thereof - Google Patents
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Abstract
The invention relates to a repatinib tablet composition and a preparation method thereof, and belongs to the technical field of medicines. The repatinib tablet composition comprises 5-15% of repatinib, 2-10% of solid dispersing agent, 40-80% of filler, 4-10% of disintegrating agent and 0.5-2% of lubricant. The invention discloses a replanib tablet composition taking replanib as an active ingredient, which is prepared by preparing replanib into a solid dispersion by a hot-melt extrusion process and then preparing the replanib tablet composition by a direct tabletting method. The ripentinib composition can be dissolved out for 30min in vitro by more than 85%, and has the advantages of high dissolution rate, good dissolution effect, high bioavailability, contribution to in vivo absorption and good stability.
Description
Technical Field
The invention relates to a repatinib tablet composition and a preparation method thereof, and belongs to the technical field of medicines.
Background
Ripeptinib is a tyrosine kinase inhibitor and is useful in treating cancer patients with abnormal mutations in KIT and PDGFRA kinases. The chemical name of rapatinib is: 1- (4-bromo-5- [ 1-ethyl-7- (methylamino) -2-oxo-1, 2-dihydro-1, 6-naphthyridin-3-yl)]-2-fluorophenyl) -3-phenylurea having the formula C 24 H 21 BrFN 5 O 2 The molecular weight is 510.36, the CAS is 1442472-39-0, and the chemical structure is shown as follows:
the repatinib is a lipophilic weakly-alkaline slightly-soluble drug, is almost insoluble in an aqueous medium, and is not beneficial to absorption of the drug in a body. Researches find that the dissolution rate of the Ruipainib original research reagent (the trade name is called Qinlock/QINLOCK, and the national standard character HJ 20210022) is slow and can reach more than 85% in 60 min; in addition, the stability is poor, and after 3 months of accelerated test, the increase amplitude of related substances is more than 34% compared with 0 day.
Therefore, in order to better meet the requirements of clinical and market, a rapitinib tablet composition with higher dissolution rate and better stability is developed, and has important economic and social benefits.
Disclosure of Invention
The invention aims to provide a replanib tablet composition and a preparation method thereof, replanib is used as an active ingredient of the replanib tablet composition, the replanib is prepared into a solid dispersion by adopting a hot-melt extrusion process, and then the replanib tablet composition is prepared by adopting a direct tabletting method, and the specific technical scheme is as follows:
in one aspect, the invention provides a repatinib tablet composition, which comprises the following components in percentage by weight:
the sum of the weight percentages of the components is 100 percent.
Further, the solid dispersing agent is one or more of povidone, hypromellose acetate succinate, copovidone and cholesterol stearate.
Furthermore, the solid dispersing agent consists of hydroxypropyl methyl cellulose acetate succinate and cholesterol stearate, and the mass ratio of the hydroxypropyl methyl cellulose acetate succinate to the cholesterol stearate is 1 (1-2).
In the solid dispersing agent, the cholesterol stearate is used, so that the dissolution effect is improved; in addition, the combination of the rapamitinib and hydroxypropyl methylcellulose acetate succinate is found to improve the drug-loading rate of the rapamitinib to over 60 percent, and simultaneously, the stability of the drug can be obviously improved.
As is known in the art: in general, the larger the amount of solid dispersant used, the larger the dispersion of API (active ingredient) in the solid dispersant, the less the risk of aggregation of amorphous molecules with each other, and the more stable the amorphous solid dispersion, especially for APIs where amorphization of API is difficult. Thus, the drug loading of solid dispersions is typically between 10 and 30%, primarily to balance the stability of the solid dispersion with the feasibility of subsequent formulation development. The solid dispersant is used too little, and the solid dispersion is unstable; the solid dispersion is used too much, the animal test preparation before clinic can not be prepared, and in the later preparation development, the weight of the preparation is larger, and the compliance of patients is reduced.
For example: by comparing the dissolution behaviors of the ritonavir/copovidone solid dispersion and the carrier (solid dispersing agent) at different drug loading rates in the research, the research finds that: when the drug loading is improved to 50%, the dissolution rates of the drug and the carrier are very low; when the drug loading is 10%, both the drug and the carrier can maintain a high dissolution level. In addition, the dissolution rate of the drug can be influenced by selecting different carrier materials, different carriers have different crystallization inhibition capabilities, and the selection of a proper carrier based on the API properties is important.
Further, the filler is one or more of spray-dried lactose, mannitol, microcrystalline cellulose and corn starch.
Furthermore, the filler consists of spray-dried lactose and microcrystalline cellulose, and the mass ratio of the spray-dried lactose to the microcrystalline cellulose is 1 (5-8).
Microcrystalline cellulose has filling, bonding and disintegrating properties, and has good compressibility, bonding and fluidity, and when a direct compression method is adopted, microcrystalline cellulose is preferably used as a filler. In the present invention, it is also necessary to use a part of spray-dried lactose as a filler, which can promote the dissolution of the drug. The content (mass%) of spray-dried lactose should not be too high, which would otherwise tend to deteriorate compressibility and result in a significant decrease in the yield of the final repatinib tablet composition. Therefore, the mass ratio between spray-dried lactose and microcrystalline cellulose needs to be controlled, which is preferably 1 (5-8).
Further, the disintegrant is one or more of sodium carboxymethyl starch, crospovidone, and low-substituted hydroxypropyl cellulose. In the invention, the disintegrant is preferably crospovidone, and the disintegrating effect is good.
Further, the lubricant is one or more of magnesium stearate, calcium stearate, superfine silica gel powder and hard sodium fumarate.
Preferably, the lubricant consists of magnesium stearate and aerosil according to the mass ratio of (1-2) to 1.
The solid dispersion prepared from the repatinib and the solid dispersing agent by adopting a hot-melt extrusion process has certain viscosity, and multiple tests show that the anti-sticking effect can be optimal only when the magnesium stearate and the micro-powder silica gel are combined, so that sticking during tabletting is avoided.
Further, the rapamitinib raw material is crushed to obtain rapamitinib with D90 less than 20 mu m, which is required to meet the requirement of in vivo absorption, has too large granularity, poor in vitro dissolution effect and is not beneficial to absorption.
In another aspect, the invention provides a preparation method of a repatinib tablet composition, comprising the following steps:
s1, crushing a repatinib raw material, and separating to obtain the repatinib with the D90 of less than 20 microns for later use;
s2, adding Ripimtinib with the D90 being less than 20 mu m and a solid dispersing agent into hot-melt extrusion equipment for hot-melt extrusion operation to obtain an extruded material, and crushing the extruded material to obtain a solid dispersion;
s3, uniformly mixing the solid dispersion, the filler, the disintegrating agent and the lubricant to obtain a mixture;
and S4, tabletting the mixture to obtain the repatinib tablet composition.
Further, in the step S1, a jet mill is used for crushing the reprotinib raw material, the feeding speed is 0.5-1.5 kg/h, the crushing pressure is 0.7-0.9 MPa, and a cyclone separator is adopted for separation, so that the reprotinib with the D90 of less than 20 microns is obtained;
in the step S2, when the hot-melt extrusion equipment carries out hot-melt extrusion operation, the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h; crushing the extruded material, and sieving the crushed material with a 50-70-mesh sieve to obtain a solid dispersion;
in step S3, when the lubricant consists of magnesium stearate and aerosil, the solid dispersion, the filler, the disintegrant and the aerosil are added into a three-dimensional mixing device to be mixed for 30-60 min, and then the magnesium stearate is added and mixed for 5-10 min to obtain a mixture;
in step S4, the mixture is tabletted by a rotary tablet machine, and the hardness of the tabletted tablet is 6 kgf-9 kgf.
If the hot-melt extrusion temperature is too high, part of the solid dispersing agent can be decomposed and degraded; if the amount is too low, the dispersion in the molten state is poor, resulting in uneven dispersion, which ultimately affects the stability of the drug. The hot-melt extrusion temperature may be 130 deg.C, 140 deg.C, 150 deg.C, 160 deg.C, 170 deg.C, 180 deg.C, etc.
In the hot-melt extrusion operation, the screw rotation speed, the feeding speed, the particle size of the solid dispersion and the like all affect the properties of the solid dispersion, thereby affecting the dissolution and stability of the solid dispersion in the medicine.
The invention has the beneficial effects that:
1) The invention discloses a repatinib tablet composition with repatinib as an active ingredient, which is prepared by preparing the repatinib into a solid dispersion by adopting a hot-melt extrusion process and then adopting a direct tabletting method. The repatinib tablet composition can be used for treating cancer patients with KIT and PDGFRA kinase abnormal mutation.
2) The ripeptinib tablet composition can be dissolved out for 30min in vitro by more than 85%, and has the advantages of high dissolution rate, good dissolution effect and high bioavailability, and is more favorable for in vivo absorption.
3) Compared with 0 day, the original preparation has the dissolution rate reduced by 8.7% and the related substances increased by 34.2% after 3 months of accelerated test. Compared with the original preparation, the rapamitinib tablet composition has lower growth rate of related substances and better stability than the original preparation.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
Formulation 1 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 16 +/-1 mu m for later use.
And 2, adding reprotinib with the D90 of 16 +/-1 mu m, hydroxypropyl methylcellulose acetate succinate and cholesterol stearate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h, so as to obtain an extruded material, and sieving the extruded material through a 60-mesh sieve after crushing, so as to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 62.5%.
And 3, adding the solid dispersion, the spray-dried lactose, the microcrystalline cellulose, the crospovidone and the aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding the magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletting is 6 kgf-9 kgf, and thus obtaining the repatinib tablet composition.
Example 2
Formulation 2 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 10 +/-1 mu m for later use.
And 2, adding the reprotinib with the D90 of 10 +/-1 mu m, hydroxypropyl methylcellulose acetate succinate and cholesterol stearate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h, so as to obtain an extruded material, and sieving the extruded material through a 60-mesh sieve after crushing, so as to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 63.2%.
And 3, adding the solid dispersion, spray-dried lactose, microcrystalline cellulose, crospovidone and aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletting is 6 kgf-9 kgf, and thus obtaining the repatinib tablet composition.
Example 3
Formulation 3 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 6 +/-1 mu m for later use.
And 2, adding the reprotinib with the D90 of 6 +/-1 mu m, hydroxypropyl methylcellulose acetate succinate and cholesterol stearate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h, so as to obtain an extruded material, and sieving the extruded material through a 60-mesh sieve after crushing, so as to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 61.5%.
And 3, adding the solid dispersion, the spray-dried lactose, the microcrystalline cellulose, the crospovidone and the aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding the magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletting is 6 kgf-9 kgf, and thus obtaining the repatinib tablet composition.
Example 4
Formulation 4 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 16 +/-1 mu m for later use.
And 2, adding the reprotinib with the D90 of 16 +/-1 mu m and the hydroxypropyl methylcellulose acetate succinate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h, so as to obtain an extruded material, and sieving the extruded material with a 60-mesh sieve after crushing, so as to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 62.5%.
And 3, adding the solid dispersion, spray-dried lactose, microcrystalline cellulose, crospovidone and aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletted tablet is 6-9 kgf, so as to obtain the rapamitinib tablet composition.
Example 5
Formulation 5 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 10 +/-1 mu m for later use.
Step 2, adding the repropatinib with the D90 of 10 +/-1 mu m and the cholesterol stearate into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h, so as to obtain an extruded material, and sieving the extruded material through a 60-mesh sieve after crushing, so as to obtain the solid dispersion. Wherein the drug loading of the solid dispersion is 63.2%.
And 3, adding the solid dispersion, the spray-dried lactose, the microcrystalline cellulose, the crospovidone and the aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding the magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletted tablet is 6-9 kgf, so as to obtain the rapamitinib tablet composition.
Example 6
Formulation 6 (Components in wt%)
The preparation method of the repatinib tablet composition comprises the following steps:
step 1, crushing the reprotinib raw material by using a jet mill at a feeding speed of 0.5-1.5 kg/h and a crushing pressure of 0.7-0.9 MPa, and separating by using a cyclone separator to obtain the reprotinib with the D90 of 6 +/-1 mu m for later use.
And 2, adding the reprotinib and the povidone of which the D90 is 6 +/-1 mu m into hot-melt extrusion equipment for hot-melt extrusion operation, wherein the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h to obtain an extruded material, and crushing the extruded material and then sieving the crushed material by using a 60-mesh sieve to obtain the solid dispersion. Wherein the drug loading of the solid dispersion was 61.5%.
And 3, adding the solid dispersion, the spray-dried lactose, the microcrystalline cellulose, the crospovidone and the aerosil into a three-dimensional mixing device for mixing for 30-60 min, then adding the magnesium stearate and mixing for 5-10 min to obtain a mixture.
And 4, tabletting the mixture by adopting a rotary tablet machine, wherein the hardness of the tabletting is 6 kgf-9 kgf, and thus obtaining the repatinib tablet composition.
Example 7
Dissolution test
Dissolution test tests were performed on the formulations and original preparations (HJ 20210022, national Standard) corresponding to examples 1 to 6.
Dissolution is determined by reference to dissolution and release determination methods (second method of 0931, the four general rules of the 2020 edition of Chinese pharmacopoeia).
The instrument comprises: high performance liquid chromatograph and dissolution rate tester.
Dissolution medium: pH =4.5 acetate buffer solution containing 0.25% sodium lauryl sulfate.
Volume of dissolution medium: 900mL.
Rotating speed: 75 revolutions per minute.
Sampling time: 10min, 15min, 20min, 30min, 45min, 60min.
Taking the corresponding preparation and original preparation of examples 1-6, according to the dissolution and release determination method (0931 second method of the four ministry of general rules of 2020 edition of Chinese pharmacopoeia), taking 900mL of acetate buffer solution with pH =4.5 containing 0.25% sodium dodecyl sulfate as dissolution medium, paddle method 75 rpm, operating according to the method, taking solution according to sampling time to determine, the dissolution curve determination data is shown in Table 1:
TABLE 1
| 10min | 15min | 20min | 30min | 45min | 60min | ||
| Example 1 | From product (%) | 31.1 | 51.5 | 71.6 | 88.3 | 94.0 | 96.2 |
| Example 2 | From product (%) | 36.1 | 57.3 | 72.4 | 89.6 | 95.4 | 97.5 |
| Example 3 | From product (%) | 42.2 | 65.1 | 78.1 | 92.4 | 97.3 | 98.3 |
| Example 4 | From product (%) | 36.1 | 50.2 | 64.2 | 81.2 | 88.6 | 90.2 |
| Example 5 | From preparation (%) | 29.1 | 49.2 | 67.8 | 79.9 | 85.5 | 91.1 |
| Example 6 | From preparation (%) | 24.2 | 42.5 | 59.1 | 75.3 | 82.4 | 90.1 |
| Original preparation | Commercially available (%) | 28.6 | 48.3 | 64.1 | 77.2 | 84.1 | 90.4 |
And (4) conclusion: the corresponding formulations in examples 1-3 exhibited dissolution rates of 85% or more in 30min in vitro and better than the original formulation (the original formulation reached 85% or more (90.4%) only in 60 min). The corresponding preparations in examples 1 to 3 have high dissolution rate, good dissolution effect and higher bioavailability, and are more favorable for in vivo absorption.
Stability test
Taking the corresponding preparation and original preparation in examples 1-6, placing the raw material drug and preparation stability test guiding principle (9001 in the four parts of the Chinese pharmacopoeia 2020 edition) for 3 months under the condition of 40 ℃/RH75% according to the required conditions of the raw material drug and preparation stability test guiding principle (pharmaceutical preparation), carrying out accelerated test investigation, wherein the detection results of dissolution rate and related substances are shown in Table 2:
TABLE 2
And (4) conclusion: the formulations of examples 1 to 3 showed good stability, lower growth rate of the related substances and better stability than the original drug substance, as compared with 0 day, when the dissolution rate and the related substances were not much changed after the accelerated test was carried out for 3 months. Compared with 0 day, the dissolution rate of the original preparation is reduced by 8.7 percent and the growth rate of related substances is increased by 34.2 percent after 3 months of accelerated test.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.
Claims (10)
1. The repatinib tablet composition is characterized by comprising the following components in percentage by weight:
the sum of the weight percentages of the components is 100 percent.
2. A repatinib tablet composition according to claim 1, wherein: the solid dispersing agent is one or more of povidone, hydroxypropyl methylcellulose acetate succinate, copovidone and cholesterol stearate.
3. A rapamitinib tablet composition according to claim 2, wherein: the solid dispersing agent consists of hydroxypropyl methyl cellulose acetate succinate and cholesterol stearate, and the mass ratio of the hydroxypropyl methyl cellulose acetate succinate to the cholesterol stearate is 1 (1-2).
4. A repatinib tablet composition according to claim 1, wherein: the filler is one or more of spray-dried lactose, mannitol, microcrystalline cellulose and corn starch.
5. A repatinib tablet composition according to claim 4, wherein: the filler consists of spray-dried lactose and microcrystalline cellulose, and the mass ratio of the spray-dried lactose to the microcrystalline cellulose is 1 (5-8).
6. A repatinib tablet composition according to claim 1, wherein: the disintegrant is one or more of sodium carboxymethyl starch, crospovidone and low-substituted hydroxypropyl cellulose.
7. A repatinib tablet composition according to claim 1, wherein: the lubricant is one or more of magnesium stearate, calcium stearate, superfine silica gel powder and hard sodium fumarate.
8. A repatinib tablet composition according to claim 1, wherein: the replanib is obtained by crushing a replanib raw material, wherein D90 is less than 20 mu m.
9. A process for the preparation of a repatinib tablet composition according to any of claims 1 to 8, characterized in that it comprises the following steps:
s1, crushing a reprotinib raw material, and separating to obtain reprotinib with the D90 of less than 20 microns for later use;
s2, adding the repatinib with the D90 of less than 20 microns and the solid dispersing agent into hot-melt extrusion equipment for hot-melt extrusion operation to obtain an extruded material, and crushing the extruded material to obtain a solid dispersion;
s3, uniformly mixing the solid dispersion, the filling agent, the disintegrating agent and the lubricating agent to obtain a mixture;
and S4, tabletting the mixture to obtain the repatinib tablet composition.
10. A method of preparing a repatinib tablet composition according to claim 9, wherein:
in the step S1, a pneumatic pulverizer is used for pulverizing the reprotinib raw material, the feeding speed is 0.5-1.5 kg/h, the pulverizing pressure is 0.7-0.9 MPa, and a cyclone separator is used for separating to obtain the reprotinib with the D90 being less than 20 microns;
and/or the presence of a gas in the gas,
in the step S2, when the hot-melt extrusion equipment carries out hot-melt extrusion operation, the rotating speed of a screw is 120-200 rpm, the hot-melt extrusion temperature is 130-180 ℃, and the feeding speed is 0.8-1.2 kg/h; crushing the extruded material, and sieving the crushed material with a 50-70-mesh sieve to obtain a solid dispersion;
and/or the presence of a gas in the gas,
in step S3, when the lubricant consists of magnesium stearate and aerosil, the solid dispersion, the filler, the disintegrant and the aerosil are added into a three-dimensional mixing device to be mixed for 30-60 min, and then the magnesium stearate is added and mixed for 5-10 min to obtain a mixture;
and/or the presence of a gas in the atmosphere,
in step S4, the mixture is tabletted by a rotary tablet machine, and the hardness of the tabletted tablet is 6 kgf-9 kgf.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105283203A (en) * | 2013-06-03 | 2016-01-27 | 信越化学工业株式会社 | Composition for heat melt extrusion and method for producing heat melt extruded product using same |
| CN106265526A (en) * | 2016-09-22 | 2017-01-04 | 山东大学 | The solid dispersion of a kind of antifungal drug posaconazole and preparation method and application |
| US20200261449A1 (en) * | 2019-02-18 | 2020-08-20 | Slayback Pharma Llc | Pharmaceutical compositions of nilotinib |
| US20220071993A1 (en) * | 2018-12-13 | 2022-03-10 | Sunshine Lake Pharma Co., Ltd. | A vilazodone solid dispersion and preparation method thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105283203A (en) * | 2013-06-03 | 2016-01-27 | 信越化学工业株式会社 | Composition for heat melt extrusion and method for producing heat melt extruded product using same |
| CN106265526A (en) * | 2016-09-22 | 2017-01-04 | 山东大学 | The solid dispersion of a kind of antifungal drug posaconazole and preparation method and application |
| US20220071993A1 (en) * | 2018-12-13 | 2022-03-10 | Sunshine Lake Pharma Co., Ltd. | A vilazodone solid dispersion and preparation method thereof |
| US20200261449A1 (en) * | 2019-02-18 | 2020-08-20 | Slayback Pharma Llc | Pharmaceutical compositions of nilotinib |
Non-Patent Citations (1)
| Title |
|---|
| 李慧等: "固体分散技术在速释、缓释滴丸剂中的应用", 中国中医药信息杂志, vol. 12, no. 4, pages 105 - 107 * |
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