CN107320460B - Oral nilotinib nano preparation and preparation method thereof - Google Patents
Oral nilotinib nano preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an oral nano preparation of nilotinib, which comprises an active ingredient of nilotinib, main auxiliary materials, additional auxiliary materials and a stabilizer; wherein the mass content of nilotinib is 30-55%, the mass content of main auxiliary materials is 20-40%, the mass content of additional auxiliary materials is 2-10%, the mass content of stabilizing agents is 2-20%, and the particle size of the nilotinib nano preparation is less than 1 μm. The invention also discloses a preparation method of the oral nilotinib nano preparation. The oral nano preparation of nilotinib solves the problems of low solubility of the oral nano preparation in water, low bioavailability in human bodies and the like, is beneficial to improving the solubility and permeability of nilotinib, and finally improves the bioavailability of nilotinib, so that the dissolution performance of the oral nano preparation of nilotinib is greatly improved, and the dissolution rate of the oral nano preparation of nilotinib reaches 93-97% in 15 min.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to an oral nilotinib nano preparation and a preparation method thereof.
Background
Nilotinib (Nilotinib), chemically known as 4-methyl-3- ((4- (3-pyridyl) -2-pyrimidinyl) amino) -N- (5- (4-methyl-1H-imidazol-1-yl) -3- (trifluoromethyl) phenyl) benzamide, is a highly selective oral tyrosine kinase inhibitor developed by nova pharmaceutical, switzerland, its monohydrochloride monohydrate was approved by the U.S. FDA for marketing at 10 months 2007 under the trade name Tasigna, and was used clinically for the treatment of chronic myeloid leukemia where imatinib mesylate is not effective. The relative molecular mass is 529.5, and the structural formula is as follows:
nilotinib has been used clinically, is a high-affinity multi-targeted drug, has a greatly improved therapeutic effect compared with the first generation tyrosine kinase inhibitors, is more rapid in action, and has an obvious therapeutic effect on imatinib-resistant CML patients. Nilotinib has the advantages of high selectivity, few side effects and the like, so nilotinib is approved to be marketed for clinical treatment, shows superiority in treatment compared with the traditional antitumor drugs, overcomes the defects of poor selectivity, strong adverse reaction and the like in the treatment process of the traditional drugs, and has obvious clinical treatment effect.
Nilotinib belongs to BCS IV class, and is a low-solubility and low-permeability drug. The rate of absorption of the drug is largely dependent on the dissolution rate and therefore its low solubility limits the release of the drug from the dosage form into solution; meanwhile, the low permeability of nilotinib enables the slow absorption rate of the drug through the gastrointestinal tract after dissolution, which finally results in low bioavailability of the drug preparation. Therefore, improving the solubility and permeability of nilotinib is a key to improving its bioavailability. The dissolution of the medicine can be promoted by reducing the particle size of the medicine particles and increasing the specific surface area of the medicine particles; and the uptake efficiency of the particles by cells has a great relationship with the size of the particles, and if the particle size of the drug particles is reduced to the nanometer level, the obstacle of the drug to be transported across cell membranes and pass through epithelial cells and vascular endothelium is easier. Therefore, the nilotinib is subjected to nanocrystallization, and the solubility and the permeability of the nilotinib are improved, so that the nilotinib has great significance in improving the bioavailability of the drug.
Nilotinib developed by norwa pharmaceutical company of switzerland has been on the market in 2007, and the sales of nilotinib is increasing; in 2014, the global sales of the medicine is 15 billion dollars, and compared with 21% increase in 2013, the sales of the medicine is increased rapidly, and the medicine has a good prospect. However, at present, few research reports on improvement of the dissolution rate and the bioavailability of nilotinib are reported in China. Chinese patent application publication No. CN104306350A discloses a pharmaceutical composition containing nilotinib or a salt thereof, which is prepared by wet granulation. The defects are as follows: the binding force generated by the bridge of the granulating liquid in the wet granulation process can influence the growth, the particle size distribution and the like of the medicine, so that the binding force generated by the solid bridge directly influences the strength, the solubility and other properties of the granules, thereby influencing the dissolution of the medicine. The invention discloses a nilotinib oral preparation, which is disclosed in Chinese patent application with publication number CN104274837A, and the dissolution rate of nilotinib in the preparation is effectively improved by cyclodextrin inclusion technology. The defects are as follows: the cyclodextrin has certain physiological toxicity, and the method has the problems of complex preparation process and higher production cost.
Therefore, in order to overcome the existing defects, a new nilotinib preparation and a preparation method thereof need to be provided.
Disclosure of Invention
The first technical problem to be solved by the invention is to provide a nilotinib oral nano preparation; the oral nano preparation of nilotinib solves the problems of low solubility of the oral nano preparation in water, low bioavailability in human bodies and the like, is beneficial to improving the solubility and permeability of nilotinib, and finally improves the bioavailability of nilotinib, so that the dissolution performance of the oral nano preparation of nilotinib is greatly improved, and the dissolution rate of the oral nano preparation of nilotinib reaches 93-97% in 15 min.
The second technical problem to be solved by the invention is to provide a preparation method of the nilotinib oral nano preparation.
In order to solve the first technical problem, the invention adopts the following technical scheme:
an oral nano preparation of nilotinib comprises an active ingredient of nilotinib, main auxiliary materials, additional auxiliary materials and a stabilizer; wherein the mass content of the nilotinib is 30-55%, the mass content of the main auxiliary material is 20-40%, the mass content of the additional auxiliary material is 2-10%, and the mass content of the stabilizer is 2-20%, wherein the particle size of the nilotinib is less than 1 μm.
As a further improvement of the technical scheme, the main auxiliary materials comprise one or more of chitosan, lactose, trehalose, sucrose, glucose, mannitol, xylitol, corn starch, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, hydroxypropyl cellulose and crospovidone.
As a further improvement of the technical scheme, the additional auxiliary materials comprise one or more of silicon dioxide, magnesium stearate, colloidal silicon dioxide and talcum powder.
As a further improvement of the technical solution, the stabilizer comprises a surfactant and a polymer; wherein the surfactant comprises one or more of alkyl benzene sulfonate, alkyl sulfate, alkyl sulfonate and poloxamer; the polymer comprises one or more of polyvinylpyrrolidone, polyethylene glycol and TPGS (natural water-soluble VE).
In order to solve the second technical problem, the preparation method of the nilotinib oral nano-preparation provided by the invention comprises the following specific steps:
s1, preparing a nilotinib solution: dissolving nilotinib in an organic solvent to prepare a nilotinib solution;
s2, preparation of an anti-solvent for nilotinib: dissolving a stabilizer in an anti-solvent to obtain an anti-solvent containing the stabilizer;
s3, preparing a solvent-anti-solvent drug slurry: adding the nilotinib solution obtained in the step S1 into the anti-solvent containing the stabilizer obtained in the step S2, and quickly mixing to obtain nilotinib drug slurry;
s4, preparing nilotinib nano powder: drying the nilotinib drug slurry obtained in the step S3 to obtain nilotinib nano-powder;
s5, preparing the nilotinib oral nano preparation: and (4) uniformly mixing the powder obtained in the step (S4) with main auxiliary materials and additional auxiliary materials to prepare the oral nilotinib nano preparation.
As a further improvement of the technical scheme, in the step S1, the concentration of the nilotinib solution is 5-40 mg/mL. The concentration of the drug solution is too low, the mass production of the nano-drugs is difficult, and when the concentration is too high, the collision of nano-drug particles in the obtained drug slurry is aggravated, and the drug particles are seriously agglomerated. More preferably, the concentration of the nilotinib solution is 10-30 mg/mL.
Preferably, in step S1, the solvent in the nilotinib solution is selected from one or more of methanol, ethanol, acetonitrile, dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, acetone, and cyclohexanone. The solvent should be selected to dissolve the nilotinib in a large amount and have a low boiling point, which facilitates the subsequent drying process. More preferably, the solvent is selected from one or more of acetone, methanol, N-dimethylformamide and N, N-dimethylacetamide.
As a further improvement of the technical solution, in step S2, the stabilizer includes a surfactant and a polymer, the surfactant accounts for 0.5-5 wt% of the nilotinib content, and the polymer accounts for 5-50 wt% of the nilotinib content; while the total amount of stabilizer needs to meet the amount of 2-20 wt% in the final product.
As a further improvement of the technical solution, in step S2, the anti-solvent includes one or more of water, methanol, ethanol, and acetone;
preferably, in step S2, a main adjuvant that is soluble in the anti-solvent may be added to the anti-solvent. That is, the main auxiliary materials may be added in step S2 or step S5 depending on their solubility.
Preferably, in step S3, the volume ratio of the nilotinib solution to the antisolvent is 1/10-1/40. More preferably, the nilotinib solution is mixed with the anti-solvent at a volume ratio of 1/10-1/25, because the nilotinib drug solution has a low concentration and the drying time is reduced in order to increase the solid content of the drug slurry.
Preferably, in step S3, the rapid mixing includes magnetic stirring, mechanical stirring, or microchannel mixing; if magnetic stirring or mechanical stirring is used, mixing and stirring time is 2-40 min; because the rapid nucleation process is carried out after mixing, in order to prevent the drug particles from continuing to grow or crosslink and agglomerate after nucleation, the mixing time can be shortened, and preferably, the mixing and stirring time is 2-30 min; if microchannel mixing is used, the nilotinib solution feed rate is 0.5-5 mL/min.
Preferably, the temperature at which the nilotinib solution and the antisolvent are mixed in step S3 is 0 to 45 ℃.
In a further improvement of the technical scheme, in the step 4, the drying is freeze drying or spray drying.
The nilotinib nano-drug is prepared by matching conditions in the anti-solvent recrystallization process, such as the volume ratio of the solvent to the anti-solvent, the crystallization temperature, the drug concentration and the type and amount of the stabilizer, so that the aim of improving the solubility and permeability of the drug is fulfilled, and the dissolution performance of the drug is greatly improved.
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 nilotinib nano-drug is prepared by controlling the conditions in the anti-solvent recrystallization process, such as the solvent-anti-solvent volume ratio, the crystallization temperature, the drug concentration and the type and amount of the stabilizer, so that the purposes of improving the solubility and the permeability of the drug are achieved, the dissolution performance of the drug is greatly improved, the 15-min drug dissolution rate reaches 93-97%, the solvent can be effectively removed in the drying process, the product quality is high, the continuous operation can be realized, and the requirement of industrial large-scale production can be met.
Drawings
The following detailed description of embodiments of the invention is provided in connection with the accompanying drawings
Figure 1 shows a scanning electron micrograph of nilotinib drug substance of example 1.
Fig. 2 shows a scanning electron micrograph of nilotinib drug slurry of example 1.
Fig. 3 shows scanning electron micrographs of nilotinib drug slurry of example 1 after lyophilization and water redispersion.
Fig. 4 shows the dissolution profile of the oral nano-preparation of nilotinib prepared in example 1 and the physical mixture of the nilotinib drug substance and the adjuvant.
Fig. 5 shows a scanning electron micrograph of the nilotinib drug slurry of comparative example 1.
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.
Example 1
The preparation method of the oral nilotinib nano preparation comprises the following steps:
preparing a nilotinib raw material drug (shown in a scanning electron microscope image in figure 1) and N, N-dimethylformamide into a nilotinib N, N-dimethylformamide solution with the concentration of 15mg/mL, wherein the concentration of the nilotinib N, N-dimethylformamide solution is 40 mL; preparing natural water-soluble VE and deionized water into 600mL of 0.2mg/mL natural water-soluble VE aqueous solution, simultaneously adding 20mg of sodium dodecyl benzene sulfonate into the natural water-soluble VE aqueous solution to obtain an anti-solvent containing a stabilizer, adding a nilotinib solution, stirring for 10min by using a mechanical stirrer, and controlling the temperature of a reaction system to be 15 ℃ to obtain nilotinib drug slurry; and freeze-drying the obtained nilotinib drug slurry to obtain freeze-dried powder, and mixing the obtained freeze-dried powder with 400mg of lactose, 20mg of croscarmellose sodium, 15mg of talcum powder and 15mg of silicon dioxide to obtain the nilotinib oral nano-preparation.
Fig. 2 is a scanning electron micrograph of nilotinib drug slurry.
FIG. 3 is a scanning electron microscope image of freeze-dried powder of nilotinib drug slurry after freeze-drying redispersed with water, and SEM representation shows that the morphology of the nano-drug before and after freeze-drying has not changed much, and the particle size is less than 1 μm.
Dissolution rate test of nilotinib oral nano-formulations:
the in vitro dissolution test method is as follows: according to FDA regulation, sampling 900mL of hydrochloric acid solution with the pH of 1.0 as a dissolution medium according to a dissolution determination method I, sampling 5mL of hydrochloric acid solution at a preset time point respectively at the rotation speed of 100rpm, filtering, taking filtrate as a test solution, and equivalently supplementing fresh dissolution medium at the same temperature; the above solutions were taken and spectrophotometred (four 0401 ultraviolet-visible spectrophotometry in Chinese pharmacopoeia 2015), absorbance was measured at 265nm wavelength, and dissolution was calculated.
Fig. 4 shows a dissolution curve of the nilotinib oral nano-preparation prepared by the preparation method and the physical mixture of the raw material drug and the auxiliary materials. From the figure, the medicine dissolution rate of the prepared oral nilotinib nano preparation reaches 97% in 15min, and the physical mixing of the raw material medicine and the auxiliary materials in the same time is only 83%, so that the dissolution rate of the oral nilotinib nano preparation is greatly improved.
Example 2
Preparing 20mL of nilotinib N, N-dimethylformamide solution with the concentration of 10mg/mL by using nilotinib raw material medicine and N, N-dimethylformamide; preparing polyvinylpyrrolidone and deionized water into 300mL of 0.1mg/mL polyvinylpyrrolidone aqueous solution, and simultaneously adding 5mg poloxamer into the polyvinylpyrrolidone aqueous solution to obtain an antisolvent containing a stabilizer; injecting the prepared bulk drug solution and an anti-solvent into a microchannel reactor at the same time, adjusting the flow rates to be 2mL/min and 30mL/min respectively, collecting the product at the outlet of the microchannel reactor, and controlling the temperature of a reaction system to be 25 ℃ to obtain nilotinib nano-drug slurry; freeze-drying the obtained nilotinib nano-drug slurry to obtain freeze-dried powder; mixing the obtained lyophilized powder with 150mg lactose, 10mg crospovidone, 5mg magnesium stearate, 5mg colloidal silicon dioxide and 5mg talcum powder, and making into oral nilotinib nano preparation.
And redispersing the obtained freeze-dried powder with water, and obtaining the nano powder particles with the average particle size of less than 1 mu m through the freeze-drying according to the SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 96% in 15min, but the physical mixing of the raw material drug and the auxiliary materials in the same time is only 85%, so that the dissolution rate of the drug is effectively improved.
Example 3
Preparing the nilotinib raw material drug and N, N-dimethylformamide into 40mL of nilotinib N, N-dimethylformamide solution with the concentration of 15 mg/mL; preparing 800mL of 0.1mg/mL polyethylene glycol solution from polyethylene glycol, deionized water and ethanol, wherein the volume ratio of the ethanol to the water is 1:5, and simultaneously adding 20mg of sodium dodecyl benzene sulfonate and 50mg of lactose into the PEG solution to obtain an anti-solvent containing the polyethylene glycol, the sodium dodecyl benzene sulfonate and the lactose; adding the nilotinib solution into an anti-solvent, stirring for 5min by using a magnetic stirrer, and controlling the temperature of a reaction system to be 20 ℃ to obtain nilotinib nano-drug slurry; spray drying the obtained nilotinib nano-drug slurry to obtain spray-dried powder; mixing the obtained spray-dried powder with 350mg of lactose, 60mg of crospovidone, 15mg of magnesium stearate and 15mg of silicon dioxide to prepare the nilotinib oral nano preparation.
And (3) redispersing the spray-dried powder obtained after spray drying with water, wherein the average particle size of the particles is less than 1 mu m. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 95% in 15min, but the physical mixing of the raw material drug and the auxiliary materials at the same time is only 85%, so that the dissolution rate of the drug is effectively improved.
Example 4
Preparing 20mL of nilotinib N, N-dimethylformamide solution with the concentration of 10mg/mL by using nilotinib raw material medicine and N, N-dimethylformamide; preparing 300mL of 0.25mg/mL aqueous solution from polyvinylpyrrolidone and deionized water, and simultaneously adding 10mg of sodium dodecyl benzene sulfonate into the polyvinylpyrrolidone aqueous solution to obtain an anti-solvent containing a stabilizer; injecting the prepared bulk drug solution and an anti-solvent into a microchannel reactor, adjusting the flow rate to be 2mL/min and 30mL/min, collecting a product at an outlet of the microchannel reactor, and controlling the temperature of a reaction system to be 25 ℃ to obtain nilotinib nano-drug slurry; and freeze-drying the obtained nilotinib nano-drug slurry to obtain freeze-dried powder, and mixing the obtained freeze-dried powder with 150mg of mannitol, 20mg of crospovidone, 5mg of magnesium stearate and 5mg of silicon dioxide to obtain the nilotinib oral nano-preparation.
And (3) redispersing the freeze-dried powder obtained after freeze drying by using water, and obtaining the nano preparation particles with the average particle size of less than 1 mu m through the SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 95% in 15min, but the physical mixing of the raw material drug and the auxiliary materials at the same time is only 82%, so that the dissolution rate of the drug is effectively improved.
Example 5
Preparing nilotinib raw material medicine, dimethyl sulfoxide and ethanol into nilotinib solution with the concentration of 5mg/mL, wherein the volume ratio of the dimethyl sulfoxide to the ethanol is 3:1, wherein the concentration of the nilotinib is 40 mL; preparing polyethylene glycol and deionized water into 600mL of 0.1mg/mL polyethylene glycol aqueous solution, and simultaneously adding 6mg sodium dodecyl benzene sulfonate into the polyethylene glycol aqueous solution to obtain an anti-solvent containing a stabilizer; adding the nilotinib solution into an anti-solvent, stirring for 5min by using a mechanical stirrer, and controlling the temperature of a reaction system to be 30 ℃ to obtain nilotinib nano-drug slurry; and freeze-drying the obtained nilotinib nano-drug slurry to obtain freeze-dried powder, and mixing the obtained freeze-dried powder with 150mg of trehalose, 10mg of crospovidone, 10mg of croscarmellose sodium, 5mg of magnesium stearate and 5mg of silicon dioxide to obtain the nilotinib oral nano-preparation.
And (3) redispersing the freeze-dried powder by using water, and obtaining the nano powder particles with the average particle size of less than 1 mu m by means of SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 97% in 15min, but the physical mixing of the raw material drug and the auxiliary materials in the same time is only 84%, so that the dissolution rate of the drug is effectively improved.
Example 6
Preparing the nilotinib raw material drug and N, N-dimethylformamide into 40mL of nilotinib N, N-dimethylformamide solution with the concentration of 15 mg/mL; preparing 600mL of 0.1mg/mL polyethylene glycol aqueous solution by using PEG2000 and deionized water, and simultaneously adding 15mg of lauryl sodium sulfate and 200mg of mannitol into the polyethylene glycol aqueous solution to obtain an anti-solvent containing polyethylene glycol, lauryl sodium sulfate and mannitol; adding the nilotinib solution into a solvent, stirring for 5min by using a magnetic stirrer, and controlling the temperature of a reaction system to be 25 ℃ to obtain nilotinib nano-drug slurry; and freeze-drying the obtained nilotinib nano-drug slurry to obtain freeze-dried powder, and mixing the obtained freeze-dried powder with 200mg of mannitol, 30mg of hydroxypropyl methylcellulose, 20mg of crospovidone, 15mg of magnesium stearate and 15mg of colloidal silicon dioxide to obtain the nilotinib oral nano-preparation.
And (3) redispersing the freeze-dried powder by using water, and obtaining the nano powder particles with the average particle size of less than 1 mu m by means of SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 95% in 15min, and the physical mixing of the raw material drug and the auxiliary materials at the same time is only 80%, so that the dissolution rate of the drug is effectively improved.
Example 7
Preparing 20mL of nilotinib N, N-dimethylformamide solution with the concentration of 10mg/mL by using nilotinib raw material medicine and N, N-dimethylformamide; preparing polyvinylpyrrolidone and deionized water into 300mL of 0.15mg/mL polyvinylpyrrolidone aqueous solution, and simultaneously adding 10mg of sodium dodecyl benzene sulfonate into the polyvinylpyrrolidone aqueous solution to obtain an anti-solvent containing a stabilizer; injecting the prepared bulk drug solution and an anti-solvent into a microchannel reactor, adjusting the flow rates to be 2mL/min and 30mL/min respectively, and collecting a product at an outlet of the microchannel reactor to obtain nilotinib nano-drug slurry; and (3) carrying out spray drying on the obtained nano-drug slurry, and mixing the obtained spray-dried powder with 150mg of mannitol, 20mg of crospovidone, 5mg of magnesium stearate and 5mg of silicon dioxide to prepare the nilotinib oral nano-preparation.
And (3) redispersing the spray-dried powder by using water, and obtaining the nano powder particles with the average particle size of less than 1 mu m by SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 94% in 15min, but the physical mixing of the raw material drug and the auxiliary materials in the same time is only 83%, so that the dissolution rate of the drug is effectively improved.
Example 8
Preparing the nilotinib raw material drug and N, N-dimethylformamide into 20mL of nilotinib N, N-dimethylformamide solution with the concentration of 15 mg/mL; preparing 400mL of 0.1mg/mL polyethylene glycol aqueous solution from polyethylene glycol and deionized water, and simultaneously adding 10mg sodium dodecyl sulfate into the polyethylene glycol aqueous solution to obtain an anti-solvent containing a stabilizer; adding the nilotinib solution into an anti-solvent, stirring for 5min by using a magnetic stirrer, and controlling the temperature of a reaction system to be 20 ℃ to obtain nilotinib nano-drug slurry; and (3) carrying out spray drying on the obtained nilotinib nano-drug slurry, and mixing the obtained spray-dried powder with 250mg of lactose, 20mg of crospovidone, 10mg of magnesium stearate and 10mg of silicon dioxide to obtain the oral nilotinib nano-preparation.
And (3) redispersing the spray-dried powder by using water, and obtaining the nano powder particles with the average particle size of less than 1 mu m by SEM representation. As shown in the dissolution rate test result of example 1, the dissolution rate of the prepared oral nilotinib nanoparticle preparation reaches 95% in 15min, but the physical mixing of the raw material drug and the auxiliary materials at the same time is only 81%, so that the dissolution rate of the drug is effectively improved.
Comparative example 1
Example 1 was repeated with the only difference that: the anti-solvent is not added with natural water-soluble VE. The particle size of the nilotinib drug particles in the obtained slurry is larger than 5 μm. Fig. 5 shows a scanning electron micrograph of the nilotinib drug slurry of comparative example 1. The dissolution result shows that the medicine dissolution rate of the prepared nilotinib oral preparation for 15min is only 85%.
Comparative example 2
Example 1 was repeated with the only difference that: the temperature of the reaction system is controlled to be 50 ℃, the nilotinib medicament in the obtained slurry has poor stability and serious agglomeration, the particle size of the nilotinib medicament is more than 5 mu m, and the dissolution result shows that the medicament dissolution rate of the prepared nilotinib oral preparation for 15min is only 86%.
Comparative example 3
Example 1 was repeated with the only difference that: the anti-solvent is not added with sodium dodecyl benzene sulfonate. The nilotinib drug in the obtained slurry has poor stability and serious agglomeration, the particle size of the nilotinib drug is larger than 5 mu m, and the dissolution result shows that the drug dissolution rate of the prepared nilotinib oral preparation for 15min is only 82%.
Comparative example 4
Example 2 was repeated with the only difference that: the polyvinylpyrrolidone and deionized water are prepared into 300mL of 0.5mg/mL polyvinylpyrrolidone aqueous solution, which is more than 50 wt% of the nilotinib content. The nilotinib drug in the obtained slurry has poor stability and serious agglomeration, the particle size of the nilotinib drug is larger than 5 mu m, and the dissolution result shows that the drug dissolution rate of the prepared oral nilotinib nano preparation for 15min is only 80%.
Comparative example 5
Example 8 was repeated with the only difference that: the preparation does not contain magnesium stearate and silicon dioxide as auxiliary materials. The dissolution result shows that the medicine dissolution rate of the prepared nilotinib oral nano preparation for 15min is only 87%.
Comparative example 6
Example 8 was repeated with the only difference that: and drying the obtained nilotinib nano-drug slurry. The dissolution result shows that the medicine dissolution rate of the prepared nilotinib oral nano preparation for 15min is only 79%.
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 (2)
1. An oral nano preparation of nilotinib, which is characterized in that: comprises an active ingredient nilotinib, main auxiliary materials, additional auxiliary materials and a stabilizing agent; wherein the mass content of nilotinib is 30-55%, the mass content of main auxiliary materials is 20-40%, the mass content of additional auxiliary materials is 2-10%, the mass content of stabilizing agents is 2-20%, and the particle size of nilotinib nanoparticles in the nilotinib nano preparation is less than 1 μm;
the preparation method of the oral nilotinib nano preparation comprises the following specific steps:
s1, dissolving nilotinib in an organic solvent to prepare a nilotinib solution;
s2, dissolving the stabilizer in the anti-solvent to obtain the anti-solvent containing the stabilizer;
s3, adding the nilotinib solution obtained in the step S1 into the stabilizer-containing antisolvent obtained in the step S2, and quickly mixing to obtain nilotinib drug slurry;
s4, drying the nilotinib drug slurry obtained in the step S3 to obtain nilotinib nano powder;
s5, uniformly mixing the nilotinib nano powder obtained in the step S4 with main auxiliary materials and additional auxiliary materials to prepare the oral nilotinib nano preparation;
the stabilizer consists of a surfactant and a polymer; wherein the surfactant is selected from one or more of sodium dodecyl benzene sulfonate, sodium dodecyl sulfate and poloxamer; the polymer is selected from one or more of polyvinylpyrrolidone, polyethylene glycol and TPGS;
in step S1, the concentration of the nilotinib solution is 5-15 mg/mL;
in step S1, the solvent in the nilotinib solution is selected from one or more of ethanol, dimethyl sulfoxide, and N, N-dimethylformamide;
in step S2, the anti-solvent is water;
in step S3, the mixing temperature of the nilotinib solution and the anti-solvent is 15-30 ℃;
in step S3, the usage amount of the surfactant accounts for 2.5-5wt% of the content of nilotinib, and the usage amount of the polymer accounts for 10-37.5wt% of the content of nilotinib;
in step S3, the volume ratio of the nilotinib solution to the antisolvent is 1/15-1/20;
in step S4, the drying is freeze drying or spray drying;
the main auxiliary materials are selected from one or more of chitosan, lactose, trehalose, sucrose, glucose, mannitol, xylitol, corn starch, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose, hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone;
the additional auxiliary materials are selected from one or more of silicon dioxide, magnesium stearate, colloidal silicon dioxide and talcum powder.
2. The oral nanoformulation of nilotinib according to claim 1, wherein: in step S3, the rapid mixing includes magnetic stirring, mechanical stirring, or microchannel mixing; if magnetic stirring or mechanical stirring is used, mixing and stirring time is 2-40 min; if microchannel mixing is used, the nilotinib solution feed rate is 0.5-5 mL/min.
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| CN111904933B (en) * | 2019-05-08 | 2023-06-13 | 北京化工大学 | Transparent water-dispersed dasatinib nanoemulsion and preparation method thereof |
| EP3804703A1 (en) * | 2019-10-10 | 2021-04-14 | Bayer AG | Method for producing a nanoparticulate active agent |
| CN110960504A (en) * | 2019-10-31 | 2020-04-07 | 上海新黄河制药有限公司 | Hollow particle preparation method and dry powder inhalation preparation |
| CN111450097A (en) * | 2020-02-27 | 2020-07-28 | 中国人民解放军军事科学院军事医学研究院 | Application of Abl tyrosine kinase inhibitor in preparation of medicine for treating diseases caused by coronavirus |
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