CN109432015B - Everolimus particles and preparation method thereof - Google Patents
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to everolimus particles and a preparation method thereof. The everolimus particles provided by the invention comprise the following components in parts by weight: 0.25-10 parts of everolimus, 0.0005-0.005 part of 2, 6-di-tert-butyl-4-methylphenol, 600 parts of starch 500-. The preparation method of the everolimus particles provided by the invention is simple, and the prepared everolimus particles are stable in quality, uniform in content, good in taste and excellent in dispersion performance, and can effectively meet the requirements of different groups on the dosage of medicines.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to everolimus particles and a preparation method thereof.
Background
Everolimus is a derivative of rapamycin, also known as 40-O- (2-hydroxyethyl) -rapamycin, and has the following structural formula:
everolimus is a research and development of pharmaceutical preparation of Nuohua, and everolimus tablets of Nuohua in 2003 are first marketed in Sweden and used for treating organ transplant rejection. FDA, EMA approved for antitumor in 2009, under the trade name femitor (AFINITOR), specifications 2.5mg, 5mg, 7.5mg, 10 mg. An immunosuppressant approved by FDA in 2010 for organ transplantation, trade name ZORTRESS, specification 0.25mg, 0.5mg, 0.75 mg.
Currently marketed everolimus dosage forms are tablets and dispersible tablets, and for patients with dysphagia, the dispersible tablets need to be stirred and dispersed with water for taking, but the mouthfeel of the dispersible tablets is not improved. For children and the like needing to adjust the dosage, the existing specification is difficult to meet the clinical requirement. In response to this problem, there is a need to develop a granular dosage form to meet the demand.
The prepared everolimus particles need to consider the unstable physical and chemical properties, and for small-sized granules such as 0.25 mg/bag, the proportion of the main drug in the materials is only 0.05-0.025%, the content of the main drug is easily uneven, and the requirements on the preparation process are very strict.
Chinese patent application CN102138903A discloses an everolimus solid oral pharmaceutical composition, which comprises a composition consisting of everolimus or derivatives thereof and an excipient, wherein the pH value of an aqueous solution of the composition is 4-7, and the everolimus or derivatives thereof accounts for 0.05-5% of the weight of the composition. The composition is prepared by adjusting the pH value of everolimus or derivatives thereof and an excipient, reasonably proportioning the formula and uniformly dispersing a main drug by using a fluidized bed wrapping technology, so that a preparation which is high in bioavailability and non-micronized and overcomes the defects of solubility and stability is obtained. The formula of the invention does not contain an antioxidant, and uses an acid-base regulator. According to the physicochemical properties of everolimus, everolimus is unstable to oxidants, acids and bases, and the composition cannot reach an ideal stable state.
At present, the problems of poor quality stability, uneven content, poor taste and poor dispersion performance are faced in the existing preparation of everolimus.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide everolimus particles and a preparation method thereof. The everolimus particles provided by the invention have the advantages of stable quality, uniform content, good taste and excellent dispersion performance, and can effectively meet the drug dosage requirements of different crowds.
The technical scheme of the invention is as follows:
everolimus particles comprise the following components in parts by weight: 0.25-10 parts of everolimus, 0.0005-0.005 part of 2, 6-di-tert-butyl-4-methylphenol, 600 parts of starch 500-.
Further, the everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
Further, the dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to the mass ratio of 3-5: 7-9: 6-8.
Furthermore, the dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7.
Further, the stabilizer is prepared from vitamin E, citric acid and sodium citrate according to the mass ratio of 3-8: 1-3: 2-5.
Further, the stabilizer is prepared from vitamin E, citric acid and sodium citrate according to a mass ratio of 5: 2: 3, and (3).
In addition, the invention also provides a preparation method of the everolimus particles, which comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 80-120 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 80-120 mesh sieve to obtain stabilizer;
s3, drying the starch for 1-2 hours at 60 ℃, and sieving the starch with a 80-100-mesh sieve for later use;
s4 pulverizing sucrose, and sieving with 80-100 mesh sieve;
s5, respectively sieving the dextrin, the polyvinylpolypyrrolidone and the micro-powder silica gel with a sieve of 80-100 meshes for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and dissolving the mixed powder in 30-50% ethanol solution to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 4-5 hours at 40 ℃, sieving by a 60-80-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
Further, the mass of the ethanol solution in the step S6 is 6% to 10% of the mass of the mixed powder.
Compared with the prior art, the invention has the following advantages:
(1) the dispersing agent consisting of xanthan gum, D-mannitol and Jerusalem artichoke powder is added, wherein the xanthan gum has an emulsifying effect, the D-mannitol can increase sweet taste and prevent powder adhesion, the Jerusalem artichoke powder can enable mixed substances to be better dispersed and improve mouthfeel, and after the three are jointly used, the everolimus can be well conditioned, so that the prepared everolimus particles have the effects of the three, the medicine content in the particles can be uniform, the mouthfeel is better, the medicine dispersibility is obviously improved, and the medicine content is more uniformly dispersed.
(2) The vitamin E stabilizer, the citric acid and the sodium citrate are added to form the stabilizer, wherein the vitamin E has certain antioxidant performance, the citric acid and the sodium citrate can adjust the pH value, and the combination of the vitamin E stabilizer, the citric acid and the sodium citrate can obviously improve the performance of each component, so that the prepared everolimus particles can effectively resist the change of the external environment and have more stable property.
(3) The preparation method is simple, and the prepared granular medicine is uniformly dispersed.
Detailed Description
The present invention is further described in the following description of the specific embodiments, which is not intended to limit the invention, but various modifications and improvements can be made by those skilled in the art according to the basic idea of the invention, within the scope of the invention, as long as they do not depart from the basic idea of the invention. Jerusalem artichoke powder is available from Xian jin Heng chemical industry Co.
Example 1 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.25 part of everolimus, 0.0005 part of 2, 6-di-tert-butyl-4-methylphenol, 500 parts of starch, 150 parts of dextrin, 30 parts of crospovidone, 1 part of micropowder silica gel, 2 parts of orange essence, 150 parts of sucrose, 50 parts of a dispersing agent and 10 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to the mass ratio of 3: 7: 8.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 3: 1: 2.
The preparation method of the everolimus particles comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 80 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 80 mesh sieve to obtain stabilizer;
s3, drying the starch for 1 hour at 60 ℃, and sieving the starch with a 80-mesh sieve for later use;
s4, crushing the sucrose, and sieving the crushed sucrose with a 80-mesh sieve for later use;
s5, respectively sieving dextrin, polyvinylpolypyrrolidone and the micro-powder silica gel with a 80-mesh sieve for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and then dissolving the mixed powder into 30% ethanol solution, wherein the mass of the ethanol solution is 6% of that of the mixed powder to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 4 hours at 40 ℃, sieving by a 60-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
Example 2 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 10 parts of everolimus, 0.005 part of 2, 6-di-tert-butyl-4-methylphenol, 600 parts of starch, 200 parts of dextrin, 50 parts of crospovidone, 5 parts of superfine silica gel powder, 5 parts of orange essence, 200 parts of cane sugar, 80 parts of dispersing agent and 20 parts of stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 5: 9: 8.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate according to a mass ratio of 8: 3: 5.
The preparation method of the everolimus particles comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 120 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 120 mesh sieve to obtain stabilizer;
s3, baking the starch for 2 hours at 60 ℃, and sieving the starch by a 100-mesh sieve for later use;
s4 crushing the cane sugar, and sieving the crushed cane sugar by a 100-mesh sieve for later use;
s5, respectively sieving the dextrin, the crospovidone and the micropowder silica gel with a 100-mesh sieve for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and then dissolving the mixed powder into 50% ethanol solution, wherein the mass of the ethanol solution is 10% of that of the mixed powder to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 5 hours at 40 ℃, sieving by a 80-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
Example 3 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 5: 2: 3, and (3).
The preparation method of the everolimus particles comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 100 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 100 mesh sieve to obtain stabilizer;
s3, drying the starch for 1 hour at 60 ℃, and sieving the starch by a 90-mesh sieve for later use;
s4 crushing the cane sugar, and sieving the crushed cane sugar by a 90-mesh sieve for later use;
s5, respectively sieving the dextrin, the polyvinylpolypyrrolidone and the micro-powder silica gel with a 90-mesh sieve for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and then dissolving the mixed powder into 40% ethanol solution, wherein the mass of the ethanol solution is 8% of that of the mixed powder to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 4 hours at 40 ℃, sieving by a 70-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
Example 4 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.5 part of everolimus, 0.001 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 180 parts of dextrin, 40 parts of crospovidone, 3 parts of micro-powder silica gel, 3 parts of orange essence, 170 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 7: 7.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 7: 3: 5.
The preparation method of the everolimus particles comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 90 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 90 mesh sieve to obtain stabilizer;
s3, drying the starch for 2 hours at 60 ℃, and sieving the starch by a 90-mesh sieve for later use;
s4 crushing the cane sugar, and sieving the crushed cane sugar by a 90-mesh sieve for later use;
s5, respectively sieving the dextrin, the polyvinylpolypyrrolidone and the micro-powder silica gel with a 90-mesh sieve for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and then dissolving the mixed powder into 40% ethanol solution, wherein the mass of the ethanol solution is 9% of that of the mixed powder to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 5 hours at 40 ℃, sieving by a 80-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
Comparative example 1 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum and D-mannitol in a mass ratio of 4: 8.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 5: 2: 3, and (3).
The preparation method of everolimus particles is similar to that of example 3, and is different from example 3 in that the dispersing agent consists of xanthan gum and D-mannitol and does not contain jerusalem artichoke powder.
Comparative example 2 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum and jerusalem artichoke powder according to a mass ratio of 4: 7.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 5: 2: 3, and (3).
The preparation method of everolimus particles is similar to that of example 3, and is different from example 3 in that the dispersing agent is composed of xanthan gum and jerusalem artichoke powder and does not contain D-mannitol.
Comparative example 3 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from D-mannitol and jerusalem artichoke powder according to a mass ratio of 8: 7.
The stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 5: 2: 3, and (3).
The preparation method of everolimus particles is similar to that of example 3, and is different from example 3 in that the dispersing agent consists of D-mannitol and jerusalem artichoke powder and does not contain xanthan gum.
Comparative example 4 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7.
The stabilizer is citric acid.
The preparation method of the everolimus particles is similar to that in example 3, and is different from that in example 3 in that the stabilizing agent is citric acid and does not contain vitamin E and sodium citrate.
Comparative example 5 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7.
The stabilizer is sodium citrate.
The preparation method of the everolimus particles is similar to that of the example 3, and is different from the example 3 in that the stabilizer is sodium citrate and does not contain vitamin E and citric acid.
Comparative example 6 Everolimus particles
Everolimus particles comprise the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent.
The dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7.
The stabilizer is vitamin E.
The preparation method of the everolimus particles is similar to that of the example 3, and is different from the example 3 in that the stabilizer is vitamin E and does not contain citric acid or sodium citrate.
Test example 1 Everolimus particle content uniformity test
1. Test materials: everolimus particles prepared in example 1, example 2, example 3, example 4, comparative example 1, comparative example 2 and comparative example 3.
2. The test method comprises the following steps: according to the content uniformity inspection method of 0941 in the general rules of the Chinese pharmacopoeia 2015 edition, 10 samples are taken, and the relative content x of each single dose with the marked amount of 100 is respectively measured according to the method specified under each variety itemiCalculating the mean value thereof
And standard deviation of
And the absolute value of the difference between the index amount and the mean value
If A +2.2S is less than or equal to L, the content uniformity of the test sample meets the specification:
if A + S > L, the specification is not met;
if A +2.2S is more than L and A + S is less than L, 20 retests of the test sample are taken; wherein L15 is constant.
3. As a result: the test results are shown in table 1.
TABLE 1 Everolimus particle content uniformity results
From the results in table 1, it can be seen that the uniformity of examples 1 to 4 and comparative examples 1 to 3 is satisfactory, but the uniformity of comparative examples 1 to 3 is relatively poor compared with each implementation, and from the above results, it can be seen that the addition of xanthan gum, D-mannitol and Jerusalem artichoke powder with single components can not improve the uniformity of everolimus particles well, but the mixed use of xanthan gum, D-mannitol and Jerusalem artichoke powder can improve the uniformity of everolimus particles significantly, and the uniformity of example 3 is the best example of the present invention.
Accelerated stability testing:
1. test materials: everolimus particles prepared in example 1, example 2, example 3, example 4, comparative example 5 and comparative example 6.
2. The test method comprises the following steps:
volume sedimentation ratio: the sedimentation volume ratio is measured according to the item of 0123 oral suspension of general rules of Chinese pharmacopoeia 2015 edition.
Content, related substances: measured according to the high performance liquid chromatography of the general regulation 0512 of the Chinese pharmacopoeia 2015 edition. Chromatographic conditions are as follows: AgiletzorbaxSB-C18 (150X4.6mm, 5 μm), detection wavelength 275nm, flow rate 1.0 mL/min; column temperature 45 ℃, sample size 20 μ L, mobile phase a: water, mobile phase B: methanol, mobile phase C: acetonitrile, gradient elution according to table 2:
TABLE 2 gradient elution Table
System applicability solution: appropriate amounts of 2, 6-di-tert-butyl-4-methylphenol reference, everolimus reference and sirolimus reference were weighed out precisely and diluted with acetonitrile to prepare 1mL of a solution containing 5. mu.L each of 2, 6-di-tert-butyl-4-methylphenol, everolimus and sirolimus.
Control solution: an appropriate amount of everolimus control was weighed out precisely and diluted with acetonitrile to prepare 1mL of a solution containing 5. mu.L of everolimus.
Test solution: taking a proper amount of particles, dispersing the particles into 1mL of solution containing 5 mu L of everolimus by using acetonitrile, shaking up and filtering.
Limitation: the total impurities can not exceed 2 percent, and the content of the total impurities is 93.0-107.0 percent of the marked amount.
Dissolution rate: measured by a dissolution measuring method according to the general rule 0931 in the 'Chinese pharmacopoeia' 2015 edition.
Taking 500mL of 0.4% sodium dodecyl sulfate aqueous solution as a dissolution medium, rotating at 50 rpm, taking a proper amount of solution after 30 minutes according to the method, and filtering to obtain a subsequent filtrate as a test solution. In addition, a proper amount of everolimus reference substance is precisely weighed, and a 0.4% sodium dodecyl sulfate solution is added to dissolve and dilute the everolimus reference substance to prepare a solution containing 20 mu g of everolimus in each 1mL of the reference substance solution. Precisely measuring 100 μ L of each of the reference solution and the sample solution, injecting into a liquid chromatograph, recording chromatogram, and calculating the elution amount of each tablet. The limit is 85% of the indicated amount and should be met.
3. And (3) test results: the test results are shown in tables 3 to 9
Table 3 example 1 experimental results
Table 4 example 2 experimental results
Table 5 example 3 experimental results
Table 6 example 4 experimental results
Table 7 experimental results of comparative example 4
Table 8 comparative example 5 experimental results
TABLE 9 comparative example 6 test results
From the test results shown in tables 3 to 9, the stability of the groups of examples 1 to 4 is good, no obvious change is caused, and each index meets the requirement, but compared with the groups of examples, the stability of each proportion group is poor, and the results show that the stability of everolimus particles cannot be obviously improved by vitamin E, citric acid and sodium citrate which are single components, but the stability of the everolimus particles can be obviously improved when the three components are combined. And example 3, which is the best example of the present invention, has the best stability.
The results of the above tests show that the everolimus particles prepared by the scheme of the invention have uniform dispersity and good stability, and the best performance in example 3 is the best example of the invention.
Claims (1)
1. Everolimus particles are characterized by comprising the following components in parts by weight: 0.35 part of everolimus, 0.00125 part of 2, 6-di-tert-butyl-4-methylphenol, 550 parts of starch, 150 parts of dextrin, 50 parts of crospovidone, 5 parts of micro-powder silica gel, 4 parts of orange essence, 180 parts of cane sugar, 60 parts of a dispersing agent and 15 parts of a stabilizing agent; the dispersing agent is prepared from xanthan gum, D-mannitol and jerusalem artichoke powder according to a mass ratio of 4: 8: 7, preparing a mixture; the stabilizer is prepared from vitamin E, citric acid and sodium citrate in a mass ratio of 5: 2: 3, preparing a composition;
the preparation method of the everolimus particles comprises the following steps:
s1 mixing Jerusalem artichoke powder, xanthan gum and D-mannitol, sieving with 80-120 mesh sieve to obtain powder;
s2 mixing vitamin E, citric acid and sodium citrate, and sieving with 80-120 mesh sieve to obtain stabilizer;
s3, drying the starch for 1-2 hours at 60 ℃, and sieving the starch with a 80-100-mesh sieve for later use;
s4 pulverizing sucrose, and sieving with 80-100 mesh sieve;
s5, respectively sieving the dextrin, the polyvinylpolypyrrolidone and the micro-powder silica gel with a sieve of 80-100 meshes for later use;
s6, mixing everolimus, 2, 6-di-tert-butyl-4-methylphenol, 60% of formula amount of orange essence and the stabilizer obtained in the step S2 to obtain mixed powder, and dissolving the mixed powder in 30-50% ethanol solution to obtain a wetting agent;
s7, uniformly mixing starch, dextrin, sucrose, crospovidone and the dispersing agent obtained in the step S1, spraying the wetting agent obtained in the step S6, mixing, shearing and granulating, drying for 4-5 hours at 40 ℃, sieving by a 60-80-mesh sieve, and grading to obtain rough granules;
s8, mixing the coarse particles and the silica gel micropowder obtained in the step S7 with the rest orange essence uniformly to obtain the orange essence.
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Effective date of registration: 20210902 Address after: 510670 room B03, building 301, No. 1, Nanxiang Second Road, Huangpu District, Guangzhou, Guangdong Patentee after: Guangzhou maikaian Biomedical Research Institute Co.,Ltd. Address before: 510670 room B03, building 301, No. 1, Nanxiang Second Road, high tech Industrial Development Zone, Guangzhou, Guangdong Patentee before: GUANGZHOU MEDCAN PHARMATECH Ltd. |