Everolimus micro-tablet as well as preparation method and application thereof

Abstract

The invention provides everolimus micro-tablets as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The everolimus micro-tablet provided by the invention is prepared from the following components in percentage by mass: 0.1%-10% of everolimus, 0.02%-0.2% of an antioxidant, 9%-25% of a carrier, 10%-30% of a disintegrating agent, 0.1%-3% of a lubricating agent and the balance of a filling agent, the specification of the everolimus micro-tablets is that each tablet contains 0.005 to 2mg of everolimus; wherein the disintegrating agent is at least one of cross-linked povidone, cross-linked sodium carboxymethyl cellulose, corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, sodium alginate, bentonite and colloidal magnesium aluminum silicate; the carrier is selected from at least one of hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose and polyethylene glycol. The everolimus micro-tablet is good in dissolution performance and content uniformity, and fills the blank of related products and preparation methods.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations and relates to an everolimus microtablet and a preparation method and application thereof. Background Art

[0002] Everolimus is a derivative of rapamycin, also known as everolimus, with a molecular formula of: C 53 H 83 NO 14 , molecular weight: 958.22, structural formula is as follows:

[0003]

[0004] Everolimus was developed by Novartis Pharmaceuticals. In 2003, Novartis's Everolimus tablets were first launched in Sweden for the treatment of organ transplant rejection. In 2009, FDA and EMA approved it for anti-tumor use under the trade name AFINITOR, with specifications of 2.5mg, 5mg, 7.5mg, and 10mg. In 2010, FDA approved it as an immunosuppressant for organ transplantation under the trade name ZORTRESS, with specifications of 0.25mg, 0.5mg, and 0.75mg.

[0005] At present, the oral preparations of everolimus on the market are mainly conventional tablets, and the dosage specifications are for adults, but in clinical application, everolimus usually needs to be adjusted in dosage according to the effect. When everolimus is used for children, the existing everolimus dosage form cannot meet the individualized medication, cannot be conveniently and accurately divided into doses, and cannot achieve precise drug administration. In addition, when the existing drug dosage forms are taken, due to the large volume, the compliance of children, the elderly and patients with dysphagia is poor. In view of this problem, it is necessary to invent a miniature tablet to meet the demand.

[0006] Mini-tablets (abbreviated as mini-tablets) usually refer to mini-tablets with a diameter of less than 3 mm that are pressed by a special tablet press. Mini-tablets are generally multi-unit preparations. After oral administration, the micro-tablets are evenly dispersed in the gastrointestinal tract, reducing the irritation to the gastrointestinal tract. The gastrointestinal transport and absorption of the drug are less affected by the gastric emptying rate and therefore have small individual differences. The drug release behavior of the micro-tablet is the sum of the drug release behaviors of multiple small units that make up a dose. After oral administration, defects in the preparation process of individual small units will not have a serious impact on the drug release behavior of the overall preparation. For people with large individual differences in drug metabolism, such as the elderly and young children, or for drugs whose dosage needs to be adjusted at any time, micro-tablets are a relatively ideal dosage form. Patients can count and take micro-tablets according to individualized medication plans, and the measurement is more accurate. Compared with other multi-unit dosage forms, micro-tablets have more regular shapes and more uniform sizes. Since the microtablets are pressed by a fixed mold, they have the characteristics of ordinary tablets. Their tablet weight and size are precisely controllable, and the production reproducibility is good. Each microtablet unit is equal in size, weight, and drug content.

[0007] Chinese patent application 202210369669.2 discloses an everolimus solid dispersion, an everolimus tablet and a preparation method thereof. The everolimus solid dispersion is mainly made of everolimus, butylated hydroxytoluene, hypromellose and lactose; the particle size D90 of the everolimus solid dispersion is ≤400μm. The solvent residue and moisture content in the everolimus solid dispersion of this technology are both low, and the prepared tablets have low impurity content, good stability and solubility, and a high degree of fit with the dissolution curve of the original preparation. However, this technology does not provide an everolimus microtablet and a preparation method thereof.

[0008] Chinese patent application 201810030124.2 discloses an everolimus pharmaceutical composition. The pharmaceutical composition comprises: an everolimus solid dispersion in the form of microparticles; a diluent, a lubricant, an optional disintegrant, and an optional binder, wherein the composition of the everolimus solid dispersion comprises: everolimus, an antioxidant, a carrier, and a dispersant. It also relates to everolimus solid dispersions, everolimus solid pharmaceutical compositions, and pharmaceutical uses of everolimus solid dispersions. The pharmaceutical compositions and solid dispersions of the technology present excellent technical effects, such as excellent dissolution performance, physical stability, and chemical stability. However, the technology does not provide an everolimus microtablet and a method for preparing the same.

[0009] Chinese patent application 201310721611.0 discloses a stable everolimus tablet. It contains everolimus, 2,6-di-tert-butyl-4-methylphenol, and one or more of a filler, a binder, a disintegrant, and a lubricant, wherein the everolimus is micronized before tableting, and the median particle size D50 value after micronization does not exceed 100 μm. The everolimus tablets prepared by this technology have the advantages of faster dissolution rate, good stability, low production cost, stable and controllable process parameters, etc. However, this technology does not provide an everolimus microtablet and a preparation method thereof.

[0010] In summary, the prior art cannot provide a method for preparing everolimus microtablets with higher uniformity. Summary of the invention

[0011] In view of this, in view of the problem that the prior art has not yet provided a method for preparing everolimus microtablets with higher uniformity, the object of the present invention is to provide an everolimus microtablet and a preparation method and application thereof.

[0012] In order to achieve the above-mentioned object of the invention, on the one hand, the present invention provides an everolimus microtablet, which is composed of the following components by mass percentage:

[0013] Everolimus 0.1%-10%, antioxidant 0.02%-0.2%, carrier 9%-25%, disintegrant 10%-30%, lubricant 0.1%-3%, and the balance is filler; the specification of the everolimus microtablet is that each tablet contains 0.005-2 mg of everolimus; wherein the disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, sodium alginate, bentonite, and colloidal magnesium aluminum silicate; the carrier is selected from at least one of hydroxypropyl methylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, and polyethylene glycol.

[0014] The diameter of the everolimus microtablet can be 1mm, 1.1mm, 1.2mm, 1.3mm, 1.4mm, 1.5mm, 1.6mm, 1.7mm, 1.8mm, 1.9mm, 2mm, 2.1mm, 2.2mm, 2.3mm, 2.4mm, 2.5mm, 2.6mm, 2.7mm, 2.8mm, 2.9mm, 3mm, 3.1mm, 3.2mm, 3.3mm, 3.4mm, 3.5mm, 3.6mm, 3.7mm, 3.8mm, 3.9mm, 4mm, 4.1mm, 4.2mm, 4.3mm, 4.4mm, 4.5mm, 4.6mm, 4.7mm, 4.8mm, 4.9mm, 5mm.

[0015] Preferably, the diameter of the everolimus microtablet is ≤3 mm.

[0016] Preferably, the antioxidant is at least one of butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, lecithin, propyl gallate and ethyl gallate.

[0017] More preferably, and as a specific embodiment of the present invention, the antioxidant is butylated hydroxytoluene.

[0018] Preferably, the lubricant is at least one of magnesium stearate, talc, micro-powder silica gel, sodium stearyl fumarate and stearic acid.

[0019] More preferably, and as a specific embodiment of the present invention, the lubricant is magnesium stearate.

[0020] Preferably, the filler is at least one of anhydrous lactose, lactose monohydrate, sucrose, mannitol and dextrin.

[0021] More preferably, and as a specific embodiment of the present invention, the filler is anhydrous lactose.

[0022] Preferably, the disintegrant is at least one of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, corn starch, cross-linked sodium carboxymethyl cellulose, and sodium alginate.

[0023] Preferably, the everolimus microtablets are composed of the following ingredients by mass percentage: 2%-5% everolimus, 0.04%-0.06% antioxidant, 18%-20% carrier, 14%-20% disintegrant, 0.5%-2% lubricant, and the balance is filler.

[0024] More preferably, and as an example of the present invention, the everolimus microtablets are composed of the following ingredients by mass percentage: 5% everolimus, 0.04% antioxidant, 20% carrier, 18% disintegrant, 2% lubricant, and the balance is filler.

[0025] On the other hand, the present invention provides a method for preparing everolimus microtablets, wherein the preparation method is selected from one of a coprecipitation method, a wet granulation method, a spray drying method, and a fluidized bed granulation method.

[0026] Preferably, the preparation method is a coprecipitation method, comprising the following steps:

[0027] S011, mixing a formula amount of everolimus, an antioxidant, a carrier, and 30%-70% (more preferably 50%) of a formula amount of a filler with an organic solvent to obtain a solid-liquid mixture;

[0028] S012, drying the solid-liquid mixture obtained in step S011, crushing and sieving to obtain a granular material;

[0029] S013, mixing the granular material obtained in step S012 with the formula amount of disintegrant, lubricant, and the remaining formula amount of filler, and tableting to obtain everolimus microtablets.

[0030] Preferably, the organic solvent is at least one of methanol, ethanol, acetone and dichloromethane.

[0031] More preferably, the organic solvent is a mixture of ethanol and acetone.

[0032] More preferably, and as an embodiment of the present invention, the organic solvent is a mixture of ethanol and acetone in a volume ratio of 10:1 to 1:10.

[0033] Preferably, the preparation method is a wet granulation method, comprising the following steps:

[0034] S021, mixing a formulated amount of everolimus, an antioxidant and an organic solvent to obtain a solution;

[0035] S022, adding the solution obtained in step S021 into a wet granulation pot containing a formulated amount of carrier, stirring and granulating to obtain wet granules;

[0036] S023, wet granulating, drying, crushing and screening the wet granules obtained in step S022 to obtain granular materials;

[0037] S024, mixing the granular material obtained in step S023 with a formula amount of filler, disintegrant, and lubricant, and tableting to obtain everolimus microtablets.

[0038] Preferably, the organic solvent is at least one of methanol, ethanol, acetone and dichloromethane.

[0039] More preferably, the organic solvent is a mixture of ethanol and acetone.

[0040] More preferably, and as an embodiment of the present invention, the organic solvent is a mixture of ethanol and acetone in a volume ratio of 10:1 to 1:10.

[0041] Preferably, the preparation method is a spray drying method, comprising the following steps:

[0042] S031, mixing a formulated amount of everolimus, an antioxidant, a carrier and an organic solvent to obtain a solution;

[0043] S032, spraying the solution obtained in step S031 into a spray drying device to obtain a dry dispersion;

[0044] S033, mixing the dry dispersion obtained in step S032 with a formula amount of filler, disintegrant, and lubricant, dry granulating, and tableting to obtain everolimus microtablets.

[0045] Preferably, the organic solvent is at least one of methanol, ethanol, acetone and dichloromethane.

[0046] More preferably, the organic solvent is a mixture of ethanol and acetone.

[0047] More preferably, and as an embodiment of the present invention, the organic solvent is a mixture of ethanol and acetone in a volume ratio of 10:1 to 1:10.

[0048] Preferably, the preparation method is a fluidized bed granulation method, comprising the following steps:

[0049] S041, mixing a formulated amount of everolimus, an antioxidant, a carrier and an organic solvent to obtain a solution;

[0050] S042, spraying the solution obtained in step S041 onto 30%-70% (more preferably 50%) of the formula amount of filler and the formula amount of disintegrant in the fluidized bed, granulating to obtain dry granules;

[0051] S043, the dry granules obtained in step S042 are sized, mixed with the remaining amount of disintegrant and lubricant in the formula, and tableted to obtain everolimus microtablets.

[0052] Preferably, the organic solvent is at least one of methanol, ethanol, acetone and dichloromethane.

[0053] More preferably, the organic solvent is a mixture of ethanol and acetone.

[0054] More preferably, and as an embodiment of the present invention, the organic solvent is a mixture of ethanol and acetone in a volume ratio of 10:1 to 1:10.

[0055] In yet another aspect, the present invention provides use of the everolimus microtablet or the preparation method of the everolimus microtablet in producing everolimus microtablet products.

[0056] Compared with the prior art, the present invention has the following beneficial effects:

[0057] The invention provides a tablet dosage form formula of everolimus microtablets, which achieves the effects of faster dissolution and better content uniformity by optimizing the types of carriers and disintegrants used and the content ratio of each component, and can be simultaneously applied to four processes (coprecipitation method, wet granulation method, spray drying method, fluidized bed granulation method) for preparation, has strong versatility, and has broad application prospects. DETAILED DESCRIPTION

[0058] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is merely an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, which should also fall within the scope of the present invention.

[0059] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0060] In the following examples, the sources of some reagents are shown in Table 1.

[0061] Table 1

[0062] name Manufacturer / Source Item No. / Specification Everolimus Zhejiang Kangrun Pharmaceutical Co., Ltd. / Hydroxypropyl methylcellulose JRS E3 Povidone BASF Corporation K30 Anhydrous lactose Kerry Inc. DTHV Crospovidone ISP CHEMICALS LLC XL Croscarmellose Sodium International N&H USA, Inc. SD-711 Sodium alginate International Flavors&Fragrances Inc. PH1033 Low substituted hydroxypropyl cellulose Anhui Shanhe Pharmaceutical Excipients Co., Ltd. SH-LH22 Magnesium Stearate Huzhou Zhanwang Pharmaceutical Co., Ltd. / Polyethylene glycol Nanjing Well Pharmaceutical Group Co., Ltd. / Hydroxypropylcellulose Anhui Shanhe Pharmaceutical Excipients Co., Ltd. SH-SL

[0063] Examples 1 to 6 provide the formulations of everolimus microtablets. The specific ingredients and weight percentages are shown in Table 2 ("-" represents the absence of this substance).

[0064] Table 2

[0065]

[0066]

[0067] Examples 7 to 10 provide formulations of everolimus microtablets. The specific ingredients and weight percentages are shown in Table 3 ("-" represents the absence of this substance).

[0068] Table 3

[0069]

[0070] Comparative Examples 1 to 4 provide formulations of everolimus microtablets. The specific ingredients and weight percentages are shown in Table 4 ("-" represents the absence of this substance).

[0071] Table 4

[0072]

[0073]

[0074] Preparation Example 1: Coprecipitation method

[0075] The everolimus microtablet formulations provided in Examples 1 to 10 and Comparative Examples 1 to 4 are prepared according to the following method to obtain everolimus microtablets. The specific steps are as follows:

[0076] Add 50% of the formula weight of everolimus, antioxidant, carrier and filler to an organic solvent (a mixture of anhydrous ethanol and anhydrous acetone in a volume ratio of 10:1), and stir mechanically for 2 hours to fully dissolve and swell the materials. Then spread the obtained solid-liquid mixture on a tray and place it in a vacuum oven for drying at a temperature of 50°C and a vacuum of 0.1MPa for 48 hours; grind the dried solid, control the grinding temperature below 30°C, and pass through a 0.3mm aperture sieve after grinding; mix the obtained material with the remaining filler, disintegrant and lubricant, and place it on a high-speed rotary tablet press for tableting, and control the main pressure within 16kN to obtain everolimus microtablets.

[0077] The everolimus microtablets prepared according to the method of Example 1 are respectively recorded as EMT-A01, EMT-A02, EMT-A03, EMT-A04, EMT-A05, EMT-A06, EMT-A07, EMT-A08, EMT-A09, EMT-A10, EMT-B01, EMT-B02, EMT-B03 and EMT-B04. The size of the microtablet is ≤3 mm in diameter, which can be 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm. In this example, the microchip is a disc with a diameter of 3 mm.

[0078] Preparation Example 2: Wet granulation method

[0079] The everolimus microtablet formulation provided in Example 4 is prepared according to the following method to obtain everolimus microtablets, which are recorded as EMT-A11.

[0080] Add the formula amount of everolimus and antioxidant to an organic solvent (a mixture of anhydrous ethanol and anhydrous acetone in a volume ratio of 1:1), stir to fully dissolve, and then spray into a wet granulation pot containing a formula amount of carrier, adjust the atomization pressure to 0.04-0.10MPa, the stirring speed to 90-200rpm, and the shear speed to 1000-1500rpm for granulation. After wet granulation, the particles are placed in a fluidized bed for drying at a drying temperature of 60°C for 3 hours; after drying, the particles are crushed, the crushing temperature is controlled below 30°C, and after crushing, the particles are passed through a 0.2mm aperture sieve; after the sieved material is evenly mixed with the formula amount of filler, disintegrant and lubricant, the material is placed in a high-speed rotary tablet press for tableting, and the main pressure is controlled within 16kN to obtain everolimus microtablets. The size of the microchip is a diameter ≤ 3 mm, which can be 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm. In this example, the microchip is a round chip with a diameter of 3 mm.

[0081] Preparation Example 3: Spray Drying

[0082] The everolimus microtablet formulation provided in Example 5 is prepared according to the following method to obtain everolimus microtablets, which are recorded as EMT-A12.

[0083] The formula amount of everolimus, antioxidant and carrier are added to an organic solvent (a mixture of anhydrous ethanol and anhydrous acetone in a volume ratio of 10:1) and fully dissolved. Use a spray gun with an aperture of 1.0 mm, control the air inlet temperature at 50°C, the air outlet temperature at 50°C, the atomization pressure at 0.04 MPa, and spray drying at a moderate feeding speed; mix the spray-dried material with the formula amount of filler, disintegrant and lubricant; perform dry granulation, and the granulation screen aperture is 0.5 mm; mix evenly after dry granulation, and place on a high-speed rotary tablet press for tableting, and control the main pressure within 16 kN to obtain everolimus microtablets. The size of the microchip is a diameter ≤ 3 mm, which can be 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm. In this example, the microchip is a round chip with a diameter of 3 mm.

[0084] Preparation Example 4: Fluidized Bed Granulation

[0085] The everolimus microtablet formulation provided in Example 6 is prepared according to the following method to obtain everolimus microtablets, which are recorded as EMT-A13.

[0086] Add the formulated amount of everolimus, antioxidants and carriers to an organic solvent (a mixture of anhydrous ethanol and anhydrous acetone in a volume ratio of 10:1) and stir to fully dissolve. Preheat the filler and 50% of the formulated amount of disintegrant in a fluidized bed, perform fluidized bed granulation under the conditions of an inlet air temperature of 60°C, an outlet air temperature of 60°C and a moderate liquid addition speed, and then dry to a moisture content of less than 1.0%, and perform granulation of the dry granules with a granulation pore size of 0.5 mm; then mix evenly with the remaining amount of disintegrant and the formulated amount of lubricant, place on a high-speed rotary tablet press for tableting, and control the main pressure within 16 kN to obtain everolimus microtablets. The size of the microchip is a diameter ≤ 3 mm, which can be 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3 mm. In this example, the microchip is a round chip with a diameter of 3 mm.

[0087] Effect evaluation

[0088] 1. Dissolution test.

[0089] The test method is as follows:

[0090] The entire operation should be carried out under light-proof conditions. Take this product and measure it according to the dissolution and release test method (Chinese Pharmacopoeia 2020 Edition Part 4 General Rules 0931 Method 2).

[0091] The specific steps are as follows: use 500mL of 0.4% sodium dodecyl sulfate solution as the dissolution medium, rotate at 50 revolutions per minute, operate according to the law, take the solution for filtration after 5 minutes and 10 minutes, and take the filtrate as the test solution. Accurately weigh an appropriate amount of everolimus reference substance, add 0.4% sodium dodecyl sulfate (SDS) solution to dissolve and dilute to make a solution containing about 10μg of everolimus per 1mL, as the reference substance solution. Accurately measure 100μL of the reference substance solution and the test solution, determine according to the method under the content determination item, and calculate the dissolution amount of each tablet. The limit is 85% of the labeled amount.

[0092] The dissolution rates of each everolimus microtablet sample in 0.4% SDS aqueous solution are shown in Table 5.

[0093] Table 5

[0094]

[0095]

[0096] As can be seen from the above table, the dissolution rates of the EMT-A01 to EMT-A13 everolimus microtablets provided in the embodiments of the present invention are all higher than the limit requirements, and can be quickly disintegrated and released completely after taking, which is conducive to better absorption in the body, thereby improving bioavailability. However, the dissolution rates of the EMT-B01 to EMT-B03 everolimus microtablets provided in the comparative examples are not as good as those of EMT-A01 to EMT-A13.

[0097] 2. Content uniformity and content test.

[0098] Evaluated according to the content uniformity test method of Part IV of the 2020 edition of the Chinese Pharmacopoeia.

[0099] Take 10 test samples and determine the relative content of each single dose with the labeled amount as 100 according to the method specified under each variety. Calculate the mean and standard deviation S as well as the absolute value A of the difference between the labeled amount and the mean.

[0100]

[0101] If A+2.2S≤L, the content uniformity of the test sample meets the requirements;

[0102] If A+S>L, it does not meet the requirements;

[0103] If A+2.2S>L and A+S≤L, another 20 samples should be taken for retesting.

[0104] In the above formula, L is a specified value. Unless otherwise specified, L = 15.0.

[0105] Content uniformity determination method: Take 1 tablet of this product in a 10mL volumetric flask, dissolve it in 30% acetonitrile aqueous solution, stir, centrifuge, filter, take the supernatant as the test solution, and determine the content according to the method under the content determination item.

[0106] Content determination method: Take 500 tablets of this product, accurately weigh, grind, accurately weigh an appropriate amount of fine powder (equivalent to 10 mg of everolimus) and place it in a 100mL volumetric flask, add 30% acetonitrile aqueous solution, stir to dissolve, filter, and use as the test solution; take an appropriate amount of everolimus reference substance, accurately weigh, add 30% acetonitrile aqueous solution to prepare a solution containing approximately 10 μg of everolimus per 1mL, and determine the content according to the method under the content determination item.

[0107] The test results of each everolimus microtablet sample are shown in Table 6.

[0108] Table 6

[0109]

[0110] As can be seen from the table above, the content uniformity and content results of the EMT-A01 to EMT-A13 everolimus microtablets provided in the embodiments of the present invention meet the requirements, while the content of the EMT-B01 to EMT-B03 everolimus microtablets provided in the comparative examples meets the requirements, but the content uniformity results do not meet the requirements.

[0111] 3. Friability test under the condition of relative humidity less than 40%.

[0112] Inspection method: For tablets weighing 0.65g or less, take a number of tablets to make the total weight about 6.5g; for tablets weighing more than 0.65g, take 10 tablets. Use a hair dryer to blow away the powder that falls off the tablets, weigh accurately, place in a cylinder, and rotate 100 times. Take out, remove the powder in the same way, weigh accurately, the weight loss shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected. This test is generally performed only once. If the weight loss exceeds 1%, it should be repeated twice, and the average weight loss of the three times shall not exceed 1%, and no broken, cracked or crushed tablets shall be detected.

[0113] The experimental results of each everolimus microtablet sample are shown in Table 7.

[0114] Table 7

[0115]

[0116]

[0117] It can be seen from the above table that the friability of the everolimus microtablets EMT-A01 to EMT-A13 and EMT-B01 to EMT-B04 provided in the embodiments of the present invention all meet the requirements, with a weight loss of less than 1.0%, and no broken, cracked or crushed tablets.

[0118] 4. Research results of crushed particle size.

[0119] The measurement method of each group of crushed particle size is as follows:

[0120] Put 0.5g sample into 30mL purified water, shake for about 7min, 25℃, 200rpm. Stir 30mL dispersion evenly, pipette appropriate amount into dispersion medium. Specific measurement parameters are shown in Table 8.

[0121] Table 8

[0122] parameter Settings Dispersion medium water Sample refractive index 1.548 Absorption rate 0.01 Speed 1000 Refractive index 5％-10％ Sample testing time 10s Built-in ultrasound closure

[0123] The everolimus microtablet formulation provided in Example 1 was prepared according to Preparation Example 1, and the crushed particle size was measured. The crushed particle size test results of the three microtablets are shown in Table 9.

[0124] Table 9

[0125]

[0126] It can be seen from the above table that when the crushed particle size D90 does not exceed 412μm, the impact on product quality is small.

[0127] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. An everolimus microtablet, characterized in that: The components by mass percentage are: Everolimus 0.1%-10%, antioxidant 0.02%-0.2%, carrier 9%-25%, disintegrant 10%-30%, lubricant 0.1%-3%, and the balance is filler; the specification of the everolimus microtablet is that each tablet contains everolimus 0.005-2mg; Wherein, the disintegrant is at least one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, corn starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, sodium alginate, bentonite, and colloidal magnesium aluminum silicate; The carrier is selected from at least one of hydroxypropyl methylcellulose, povidone, hydroxypropyl cellulose and polyethylene glycol.

2. The everolimus microtablet according to claim 1, characterized in that The diameter of the everolimus microtablet is ≤3 mm.

3. The everolimus microtablet according to claim 1, characterized in that The antioxidant is at least one of butylated hydroxytoluene, butylated hydroxyanisole, vitamin E, lecithin, propyl gallate, and ethyl gallate; the lubricant is at least one of magnesium stearate, talcum powder, micro-powder silica gel, sodium stearyl fumarate, and stearic acid; and the filler is at least one of anhydrous lactose, lactose monohydrate, sucrose, mannitol, and dextrin.

4. The everolimus microtablet according to claim 1, characterized in that: The disintegrant is at least one of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, corn starch, cross-linked sodium carboxymethyl cellulose, and sodium alginate.

5. The method for preparing the everolimus microtablet according to any one of claims 1 to 4, characterized in that: The preparation method is selected from one of co-precipitation, wet granulation, spray drying and fluidized bed granulation.

6. The preparation method according to claim 5, characterized in that: The preparation method is a coprecipitation method, comprising the following steps: S011, mixing a formula amount of everolimus, an antioxidant, a carrier, and 30% to 70% of the formula amount of a filler with an organic solvent to obtain a solid-liquid mixture; S012, drying the solid-liquid mixture obtained in step S011, crushing and sieving to obtain a granular material; S013, mixing the granular material obtained in step S012 with the formula amount of disintegrant, lubricant, and the remaining amount of filler, and tableting to obtain everolimus microtablets.

7. The preparation method according to claim 5, characterized in that: The preparation method is a wet granulation method, comprising the following steps: S021, mixing a formulated amount of everolimus, an antioxidant and an organic solvent to obtain a solution; S022, adding the solution obtained in step S021 into a wet granulation pot containing a formulated amount of carrier, stirring and granulating to obtain wet granules; S023, wet granulating, drying, crushing and screening the wet granules obtained in step S022 to obtain granular materials; S024, mixing the granular material obtained in step S023 with a formula amount of filler, disintegrant, and lubricant, and tableting to obtain everolimus microtablets.

8. The preparation method according to claim 5, characterized in that: The preparation method is a spray drying method, comprising the following steps: S031, mixing a formulated amount of everolimus, an antioxidant, a carrier and an organic solvent to obtain a solution; S032, spraying the solution obtained in step S031 into a spray drying device to obtain a dry dispersion; S033, mixing the dry dispersion obtained in step S032 with a formula amount of filler, disintegrant, and lubricant, dry granulating, and tableting to obtain everolimus microtablets.

9. The preparation method according to claim 5, characterized in that: The preparation method is a fluidized bed granulation method, comprising the following steps: S041, mixing a formulated amount of everolimus, an antioxidant, a carrier and an organic solvent to obtain a solution; S042, spraying the solution obtained in step S041 onto the formula filler and 30%-70% of the formula weight of the disintegrant in the fluidized bed, granulating to obtain dry granules; S043, the dry granules obtained in step S042 are sized, mixed with the remaining amount of disintegrant and lubricant in the formula, and tableted to obtain everolimus microtablets.

10. Use of the preparation method of the everolimus microtablet according to any one of claims 1 to 4 or the everolimus microtablet according to any one of claims 5 to 9 in the production of everolimus microtablet products.

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