CN111166724A - Regorafenib nano dispersion, tablet and preparation method thereof - Google Patents
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Abstract
The invention discloses a regorafenib nano dispersion, a tablet and a preparation method thereof; the dispersion comprises regorafenib and a carrier material, wherein the weight ratio of regorafenib to the carrier material is as follows: 1:0.5-1: 15; the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate; the regorafenib tablet comprises the regorafenib nano-dispersion and a pharmaceutical excipient. The dissolution rate of the regorafenib nano tablet can reach more than or equal to 90 percent within 30 minutes, so that higher blood concentration can be quickly reached, the bioavailability of regorafenib is effectively improved, and the drug effect can be better exerted; the preparation method is simple and is easy for continuous production.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a regorafenib nano dispersion and a preparation method thereof, and a pharmaceutical nano tablet containing the nano dispersion and a preparation method thereof.
Background
Regorafenib (Regorafenib), a novel oral multi-kinase inhibitor, is approved by the FDA in 2012 and 2013, respectively, for the treatment of metastatic colorectal cancer and gastrointestinal stromal tumors, with the chemical name 4- {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -ureide]-3-fluorophenoxy } -pyridine-2-carboxylic acid methylamine having the molecular formula C21H15ClF4N4O3The molecular weight is 482, the melting point is 206-210 ℃, and the molecular structure is as follows:
regorafenib belongs to the class II of Biopharmaceutical Classification Systems (BCS), i.e., the bioavailability and clinical efficacy of regorafenib are limited by the low dissolution rate caused by poor solubility in water.
In order to improve the solubility, a lot of work is done by the predecessors, and through researches on four crystal forms (i, ii, iii and monohydrate crystal forms) of regorafenib, namely WO2008/058644a1, WO2008/055629a1 and CN101547903A, regorafenib monohydrate has higher solubility than other crystal forms. The marketed formulation regorafenib (under the trade name Stivarga) takes its monohydrate form, but regorafenib monohydrate remains practically insoluble in water.
Chinese patent application CN103923001 adopts a salt formation technology to make regorafenib into a ciclesonide salt and an ethanesulfonate, but the two regorafenib salt forms have the same solubility as regorafenib monohydrate, so the problem of low solubility of regorafenib is not solved essentially.
Chinese patent application CN105879049A discloses that regorafenib solubility is improved by adopting cyclodextrin inclusion technique, thereby improving dissolution rate and in vivo anti-tumor activity.
Chinese patent application CN107213127A discloses that the solubility of regorafenib is improved by making it into a solid dispersion of sorbitol-regorafenib-povidone "sandwich" structure. However, the preparation process of the method is complex and is not easy to realize continuous production.
None of the above prior art solutions well solve the solubility problem of regorafenib.
Disclosure of Invention
The first technical problem to be solved by the present invention is to provide a regorafenib nanodispersion.
The second technical problem to be solved by the invention is to provide a regorafenib tablet; the dissolution rate of the regorafenib nano tablet can reach more than or equal to 90 percent within 30 minutes, so that higher blood concentration can be quickly reached, the bioavailability of regorafenib is effectively improved, and the drug effect can be better exerted.
The third technical problem to be solved by the invention is to provide a preparation method of the regorafenib nano-dispersion.
The fourth technical problem to be solved by the invention is to provide a preparation method of regorafenib tablets.
In order to solve the first technical problem, the invention adopts the following technical scheme:
a regorafenib nanodispersion comprising regorafenib and a carrier material, wherein the weight ratio of regorafenib to carrier material is: 1:0.5-1: 15; the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
In order to solve the second technical problem, the invention adopts the following technical scheme:
a regorafenib tablet comprising a regorafenib nanodispersion and a pharmaceutical excipient.
In order to solve the third technical problem, the preparation method of the regorafenib nano-dispersion of the present invention comprises the following specific steps:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) and (3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion.
As a further improvement of the technical scheme, in the step 1), the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
Preferably, in step 1), the weight ratio of the regorafenib to the carrier material is: 1:0.5-1:15.
Preferably, in step 1), the solvent is selected from one or more of methanol, absolute ethanol, dimethyl sulfoxide, acetone, dimethylformamide and tetrahydrofuran.
Preferably, in the step 1), the concentration of the regorafenib solution is 1-20 mg/mL.
Preferably, in step 1), the concentration of the aqueous carrier solution is 0.025 to 300 mg/mL.
As a further improvement of the technical scheme, in the step 2), the feeding rate of the regorafenib is 20-50 mL/min; the feeding rate of the carrier water solution is 20-1000 mL/min.
Preferably, in the step 2), the rotating speed of the super-gravity rotating packed bed is 500-2840rpm, and the recrystallization temperature is 0-50 ℃.
In order to solve the fourth technical problem, the preparation method of the regorafenib tablet provided by the invention comprises the following steps:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion;
4) weighing regorafenib nano dispersion according to the prescription amount, sieving with a 80-mesh sieve, adding a pharmaceutical excipient sieved with a 100-mesh sieve, and uniformly mixing; and directly tabletting the powder by using a single-punch tabletting machine to obtain the regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
As a further improvement of the technical scheme, in the step 4), the pharmaceutical excipient comprises one or more of pregelatinized starch, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium carboxymethyl starch, silica gel micropowder, croscarmellose sodium and polyvinylpyrrolidone.
Any range recited herein is intended to include the endpoints and any number between the endpoints and any subrange subsumed therein or defined therein.
The starting materials of the present invention are commercially available, unless otherwise specified, and the equipment used in the present invention may be any equipment conventionally used in the art or may be any equipment known in the art.
Compared with the prior art, the invention has the following beneficial effects:
the dissolution rate of the regorafenib nano tablet can reach more than or equal to 90 percent within 30 minutes, so that higher blood concentration can be quickly reached, the bioavailability of regorafenib is effectively improved, and the drug effect can be better exerted; the preparation method is simple and is easy for continuous production.
Drawings
The following detailed description of embodiments of the invention is provided in connection with the accompanying drawings
Fig. 1 is a scanning electron microscope image of regorafenib drug substance;
fig. 2 is a scanning electron micrograph of a regorafenib nanosuspension in example 1 of the present invention;
fig. 3 is a scanning electron microscope image of water redispersion of a spray-dried regorafenib nanodispersion in example 1 according to the present invention;
fig. 4 is an X-ray diffraction (XRD) pattern of regorafenib nanodispersion and regorafenib drug substance in example 1 of the present invention.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
As one aspect of the present invention, the present invention provides a regorafenib nanodispersion, including regorafenib and a carrier material, wherein the weight ratio of regorafenib to carrier material is: 1:0.5-1: 15; the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
As another aspect of the present invention, the present invention is a regorafenib tablet comprising a regorafenib nanodispersion and a pharmaceutical excipient.
As another aspect of the present invention, the present invention provides a preparation method of regorafenib nano-dispersion, comprising the following specific steps:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) and (3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion.
In certain embodiments of the present invention, in step 1), the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
In certain embodiments of the present invention, in step 1), the weight ratio of regorafenib to carrier material is: 1:0.5-1: 15; preferably 1:3 to 1: 10; more preferably 1:5 to 1: 7.
In certain embodiments of the present invention, in step 1), the solvent is selected from one or more of methanol, absolute ethanol, dimethyl sulfoxide, acetone, dimethylformamide and tetrahydrofuran.
In certain embodiments of the invention, in step 1), the regorafenib solution has a concentration of 1-20mg/mL, or 1-18mg/mL, or 1-16mg/mL, or 1-14mg/mL, or 1-12mg/mL, or 1-10mg/mL, or 1-8mg/mL, or 1-6mg/mL, or 1-4mg/mL, or 1-2mg/mL, or 5-20mg/mL, or 5-18mg/mL, or 5-16mg/mL, or 5-14mg/mL, or 5-12mg/mL, or 5-10mg/mL, or 5-8mg/mL, or 10-20mg/mL, or 10-18mg/mL, or 10-16mg/mL, or, Or 10-14mg/mL, or 10-12mg/mL, or 15-20mg/mL, or 15-18 mg/mL.
In certain embodiments of the invention, in step 1), the aqueous carrier solution has a concentration of 0.025 to 300mg/mL, or 0.05 to 300mg/mL, or 0.1 to 300mg/mL, or 1 to 250mg/mL, or 1 to 200mg/mL, or 1 to 150mg/mL, or 1 to 100mg/mL, or 1 to 50mg/mL, or 10 to 300mg/mL, or 10 to 250mg/mL, or 10 to 200mg/mL, or 10 to 150mg/mL, or 10 to 100mg/mL, or 10 to 50mg/mL, or 50 to 300mg/mL, or 50 to 250mg/mL, or 50 to 200mg/mL, or 50 to 150mg/mL, or 50 to 100mg/mL, Or 100-300mg/mL, or 100-250mg/mL, or 100-200mg/mL, or 100-150mg/mL, or 150-300mg/mL, or 150-250mg/mL, or 150-200mg/mL, or 200-300mg/mL, or 200-250 mg/mL.
In certain embodiments of the invention, in step 2), the regorafenib feed rate is from 20 to 50 mL/min; the feeding rate of the carrier water solution is 20-1000mL/min, or 50-900mL/min, or 50-800mL/min, or 50-700mL/min, or 50-600mL/min, or 50-500mL/min, or 50-400mL/min, or 50-300mL/min, or 50-200mL/min, or 50-100mL/min, or 100-1000mL/min, or 100-900mL/min, or 100-800mL/min, or 100-700mL/min, or 100-600mL/min, or 100-500mL/min, or 100-400mL/min, or 100-300mL/min, or 100-200mL/min, or 300-1000mL/min, Or 300-9000mL/min, or 300-800mL/min, or 300-700mL/min, or 300-600mL/min, or 300-500mL/min, or 300-400mL/min, or 500-1000mL/min, or 500-900mL/min, or 500-800mL/min, or 500-700mL/min, or 500-600mL/min, or 700-1000mL/min, or 700-900mL/min, or 700-800 mL/min.
In certain embodiments of the invention, in step 2), the super-gravity rotating packed bed rotates at 500-2840rpm, or 500-2500rpm, or 500-2000rpm, or 500-1500rpm, or 500-1000rpm, or 1000-2840rpm, or 1000-2500rpm, or 1000-2000rpm, or 1000-1500rpm, or 1500-2840rpm, or 1500-2500rpm, or 1500-2000 rpm; the recrystallization temperature is 0-50 deg.C, or 0-40 deg.C, or 0-30 deg.C, or 0-20 deg.C, or 0-10 deg.C, or 10-50 deg.C, or 10-40 deg.C, or 10-30 deg.C, or 10-20 deg.C, or 20-50 deg.C, or 20-40 deg.C, or 20-30 deg.C, or 30-50 deg.C, or 30-40 deg.C, or 40-50 deg.C.
As another aspect of the present invention, a method for preparing a regorafenib tablet according to the present invention comprises the steps of:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion;
4) weighing regorafenib nano dispersion according to the prescription amount, sieving with a 80-mesh sieve, adding a pharmaceutical excipient sieved with a 100-mesh sieve, and uniformly mixing; and directly tabletting the powder by using a single-punch tabletting machine to obtain the regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
In certain embodiments of the present invention, in step 4), the pharmaceutical excipient comprises one or more of pregelatinized starch, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium carboxymethyl starch, aerosil, croscarmellose sodium and polyvinylpyrrolidone.
The regorafenib nano tablet is finally obtained by mutually matching the technical characteristics of a solvent, a carrier, the weight ratio of regorafenib to a carrier material, the regorafenib feeding rate, the rotating speed of a super-gravity rotating packed bed, crystallization, spray drying and the like, and the dissolution rate of the regorafenib nano tablet can reach more than or equal to 90% within 30 minutes, so that higher blood concentration can be quickly reached, the bioavailability of regorafenib is effectively improved, and the drug effect can be better exerted.
Example 1
A preparation method of regorafenib tablets comprises the following steps:
1) preparing 50mL regorafenib acetone solution with the concentration of 15mg/mL by regorafenib and acetone; preparing 1000mL of carrier aqueous solution of 5.25mg/mL by polyvinylpyrrolidone and deionized water;
2) turning on the super-gravity rotating packed bed, and adjusting the rotating speed to 2272 rpm; starting a feeding pump, respectively pumping the regorafenib acetone solution and the carrier solution into a rotary packed bed for recrystallization reaction, controlling the feeding rate of the regorafenib acetone solution to be 45mL/min, the feeding rate of the carrier aqueous solution to be 900mL/min, and controlling the temperature of a reaction system to be 20 ℃ to obtain a regorafenib nano suspension;
3) spray drying the obtained regorafenib nano suspension to obtain a regorafenib nano dispersion;
4) sieving regorafenib nano dispersion by a sieve of 80 meshes, and then sieving 32 parts of regorafenib nano dispersion and a sieve of 100 meshes to obtain a pre-dispersion109 parts of gelatinized starch and 7.5 parts of low-substituted hydroxypropyl cellulose (for example, low-substituted hydroxypropyl cellulose available from Tianjin Xiansi Biochemical technology Co., Ltd. in the manufacturer)
) And 1.5 parts of magnesium stearate are uniformly mixed, and the powder is directly tabletted by a single-punch tablet machine to obtain regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
Example 2
A preparation method of regorafenib tablets comprises the following steps:
1) preparing 50mL of regorafenib acetone solution with the concentration of 5mg/mL by regorafenib and acetone; preparing 750mL of carrier aqueous solution of 1mg/mL by polyvinylpyrrolidone and deionized water;
2) turning on the super-gravity rotating packed bed, and adjusting the rotating speed to 2272 rpm; starting a feeding pump, respectively pumping the regorafenib acetone solution and the carrier solution into a rotary packed bed for recrystallization reaction, controlling the feeding rate of the regorafenib acetone solution to be 45mL/min, the feeding rate of the carrier water solution to be 675mL/min, and controlling the temperature of a reaction system to be 0 ℃ to obtain regorafenib nano suspension;
3) spray drying the obtained regorafenib nano suspension to obtain a regorafenib nano dispersion;
4) sieving the regorafenib nano dispersion by a sieve of 80 meshes, then uniformly mixing 8 parts of the regorafenib nano dispersion with 68 parts of pregelatinized starch, 7.5 parts of low-substituted hydroxypropyl cellulose and 1.5 parts of magnesium stearate which are sieved by a sieve of 100 meshes, and directly tabletting the powder by a single-punch tablet machine to obtain regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
Example 3
A preparation method of regorafenib tablets comprises the following steps:
1) preparing 50mL regorafenib methanol solution with the concentration of 15mg/mL by regorafenib and methanol; preparing 1000mL of carrier aqueous solution of 5.25mg/mL by using polyvinylpyrrolidone and sodium dodecyl sulfate in a mass ratio of 1:0.2 and deionized water;
2) starting the super-gravity rotating packed bed, and adjusting the rotating speed to 800 rpm; starting a feeding pump, respectively pumping the regorafenib acetone solution and the carrier solution into a rotary packed bed for recrystallization reaction, controlling the feeding rate of the regorafenib methanol solution to be 45mL/min, the feeding rate of the carrier aqueous solution to be 900mL/min, and controlling the temperature of a reaction system to be 20 ℃ to obtain a regorafenib nano suspension;
3) spray drying the obtained regorafenib nano suspension to obtain a regorafenib nano dispersion;
4) sieving the regorafenib nano dispersion by a sieve of 80 meshes, then uniformly mixing 32 parts of the regorafenib nano dispersion with 109 parts of pregelatinized starch, 7.5 parts of low-substituted hydroxypropyl cellulose and 1.5 parts of magnesium stearate which are sieved by a sieve of 100 meshes, and directly tabletting the powder by a single-punch tablet machine to obtain regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
Comparative example 1
Example 1 was repeated with the following differences: and 3) desolventizing and drying the obtained regorafenib nano suspension by using a conventional method without spray drying.
Comparative example 2
Example 2 was repeated with the following differences: in the step 2), the feeding rate of the regorafenib is 10 mL/min; the rotating speed of the supergravity rotating packed bed is 400 rpm; the recrystallization temperature in the rotary packed bed is 60 ℃;
comparative example 3
Example 3 was repeated with the following differences: in the step 2), the reactor adopts a common reaction kettle to replace a supergravity rotating packed bed.
Comparative example 4
A preparation method of regorafenib tablets comprises the following steps: sieving regorafenib raw material medicines by a sieve of 80 meshes, then uniformly mixing 4 parts of regorafenib raw material medicines with 28 parts of polyvinylpyrrolidone, 109 parts of pregelatinized starch, 7.5 parts of low-substituted hydroxypropyl cellulose and 1.5 parts of magnesium stearate which are sieved by a sieve of 100 meshes, and directly tabletting the powder by adopting a single-punch tablet machine to obtain regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
Experimental Effect 1
The dissolution rates of the above-mentioned control sample and sample were examined using the regorafenib tablets prepared in examples 1-3 and comparative examples 1-4 as samples, respectively.
The in-vitro dissolution rate of the regorafenib tablet is measured by a D-800LS intelligent dissolution instrument under the following measurement conditions: the stirring rate was 100 rpm; the temperature was 37 ℃ and the dissolution medium was 1% SDS acetate buffer (pH 4.5) in a dissolution volume of 900 mL.
A measurement step: putting a tablet containing 40mg of regorafenib active ingredient into a dissolution cup; taking 4mL of the solution within 30min, and adding 4mL of blank dissolution medium to keep the volume of the dissolution medium at 900 mL; filtering the sample solution by using a 0.45-micrometer needle type filter, diluting the sample solution to a certain concentration by using a blank dissolution medium, measuring an absorption characteristic peak at 262nm by using an ultraviolet spectrophotometer, and calculating the corresponding dissolution rate according to a regorafenib standard curve.
The results of the experiment are shown in table 1 below:
TABLE 1 dissolution test
| Sample (I) | Dissolution rate | Sample (I) | Dissolution rate |
| Tablet of example 1 | 97.48％ | Tablet of comparative example 1 | 60.23％ |
| Tablet of example 2 | 92.64％ | Tablet of comparative example 2 | 30.67％ |
| Tablet preparation in example 3 | 90.66％ | Tablet of comparative example 3 | 23.28％ |
| Tablet of comparative example 4 | 6.12％ |
As can be seen from the experimental results of table 1 above, the in vitro dissolution rate of the tablet comprising the regorafenib nanodispersion of the present invention (examples 1-3) can reach more than 90% at 30 minutes; whereas comparative examples 1-3 lacking the conditions of the present invention have in vitro dissolution rates significantly lower than the effects of the present invention; if the raw material medicines are directly used for preparing the tablets, the in-vitro dissolution rate is extremely low.
The regorafenib nano-tablets prepared in example 1 were placed in an open weighing bottle, and subjected to high temperature tests at 40 ℃ and 60 ℃ respectively in a stability test box under the conditions of no illumination and 30% relative humidity, and sampled for appearance and dissolution examination at 0, 5 and 10 days.
Table 2 results of regorafenib nanoplates at high temperatures
The regorafenib nanosheets prepared in example 1 were placed in an open weighing bottle, subjected to high humidity tests at 75% and 95% relative humidity respectively in a stability test box at 20 ℃ without light, sampled for 0, 5 and 10 days, and examined for appearance and dissolution, and the results are shown in table 3.
Table 3 results of regorafenib nanoplates at high humidity
The regorafenib nanosheet prepared in example 1 was placed in an open weighing bottle, a high light test of light intensity (4500 ± 500) lux was performed in a stability test box under conditions of a relative humidity of about 30% and a temperature of about 20 ℃, samples were taken at 0, 5 and 10 days for dissolution examination, and the results are shown in table 4.
Table 4 results of regorafenib nanoplates in high light
The results show that: the appearance and dissolution of the regorafenib nano tablet are not influenced at high temperature; the humidity has a large influence on dissolution of the regorafenib nano-tablets, and the nano-tablets are placed in a dry place for storage; dissolution rate and appearance of the regorafenib nano tablet are not obviously changed under the condition of strong light, so that the regorafenib nano tablet is not influenced by the strong light in a short time.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. Not all embodiments are exhaustive. All obvious changes and modifications which are obvious to the technical scheme of the invention are covered by the protection scope of the invention.
Claims (8)
1. A regorafenib nanodispersion comprising regorafenib and a carrier material, wherein the weight ratio of regorafenib to carrier material is as follows: 1:0.5-1: 15; the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
2. A regorafenib tablet characterized by: comprising the regorafenib nanodispersion of claim 1 and a pharmaceutical excipient.
3. A process for the preparation of a regorafenib nanodispersion as claimed in claim 1, comprising the steps of:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) and (3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion.
4. A process for the preparation of a regorafenib nanodispersion as claimed in claim 3, wherein: in the step 1), the carrier material is selected from one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, hydroxypropyl cellulose, mannitol, lactose, sodium dodecyl sulfate, sodium dodecyl benzene sulfonate and sodium alginate.
5. A process for the preparation of a regorafenib nanodispersion as claimed in claim 3, wherein: preferably, in step 1), the weight ratio of the regorafenib to the carrier material is: 1:0.5-1: 15;
preferably, in step 1), the solvent is selected from one or more of methanol, absolute ethanol, dimethyl sulfoxide, acetone, dimethylformamide and tetrahydrofuran;
preferably, in the step 1), the concentration of the regorafenib solution is 1-20 mg/mL;
preferably, in step 1), the concentration of the aqueous carrier solution is 0.025 to 300 mg/mL.
6. A process for the preparation of a regorafenib nanodispersion as claimed in claim 3, wherein: in the step 2), the feeding rate of the regorafenib is 20-50 mL/min; the feeding speed of the carrier aqueous solution is 20-1000 mL/min; preferably, in the step 2), the rotating speed of the super-gravity rotating packed bed is 500-2840rpm, and the recrystallization temperature is 0-50 ℃.
7. A process for the preparation of regorafenib tablets as claimed in claim 2, comprising the steps of:
1) dissolving regorafenib in a solvent to prepare a regorafenib drug solution; dissolving a carrier in water to prepare a carrier aqueous solution;
2) pumping the regorafenib drug solution and the carrier aqueous solution prepared in the step 1) into a supergravity rotating packed bed at a certain feeding rate respectively, and carrying out liquid-phase precipitation crystallization reaction to obtain a regorafenib nano suspension;
3) carrying out spray drying on the regorafenib nano suspension obtained in the step 2) to obtain a regorafenib nano dispersion;
4) weighing regorafenib nano dispersion according to the prescription amount, sieving with a 80-mesh sieve, adding a pharmaceutical excipient sieved with a 100-mesh sieve, and uniformly mixing; and directly tabletting the powder by using a single-punch tabletting machine to obtain the regorafenib tablets, wherein each tablet contains 20mg of regorafenib active ingredients.
8. A method of preparing regorafenib tablets as claimed in claim 7, wherein: in the step 4), the pharmaceutical excipient comprises one or more of pregelatinized starch, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium carboxymethyl starch, superfine silica gel powder, cross-linked sodium carboxymethyl cellulose and polyvinylpyrrolidone.
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| CN112842998A (en) * | 2021-01-19 | 2021-05-28 | 深圳市简一生物科技有限公司 | Regorafenib dispersant and preparation method thereof |
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Application publication date: 20200519 |