Aprepitant micropellets, preparation method thereof, and preparations containing the same

Abstract

The present invention relates to the field of medicine, and in particular to aprepitant micropills, a preparation method thereof, and a preparation containing the same. The aprepitant micropills include a blank pellet core and an intermediate layer from the inside to the outside; the intermediate layer contains a drug and a first excipient; the drug is aprepitant and / or a pharmaceutically acceptable salt of aprepitant; the average particle size of the drug is 230-370nm. The present invention controls the particle size of the raw material in more detail, adds a surfactant of a higher fatty alcohol sulfate, and ensures the bioavailability of the product; at the same time, it can ensure that the dissolution curve does not change during the stability test, and ensures the good stability of the product.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and in particular to aprepitant micropill, a preparation method thereof and a preparation containing the micropill. Background Art

[0002] Aprepitant, chemical name is 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, molecular formula is C 23 H 21 F7N4O3, structural formula:

[0003]

[0004] Aprepitant is the first neurokinin-1 (NK-1) receptor blocker approved by the U.S. FDA in 2003. It blocks the action of substance P by binding to NK-1 receptors (mainly present in the central nervous system and its periphery). Aprepitant can pass through the blood-brain barrier and occupy the NK-1 receptors in the brain. It has selectivity and high affinity, while its affinity for NK-2 and NK-3 receptors is very low. At the same time, it also has low affinity for the targets of other drugs used to treat chemotherapy-induced nausea and vomiting symptoms (such as dopamine receptors and 5-HT receptors), and its effect in reducing nausea and vomiting is better than other drugs.

[0005] Aprepitant is a white or off-white powder that is almost insoluble in water. Since aprepitant is almost insoluble in water and has low bioavailability, an oral capsule in the form of nanocrystalline microspheres has been developed.

[0006] The dissolution and bioavailability of aprepitant still need to be improved. Summary of the invention

[0007] Aprepitant and grinding media are usually wet-grinded to grind aprepitant to nanometer particle size to improve solubility in water and bioavailability. However, the inventors have found that excessive grinding to reduce particle size will also increase the aggregation of the raw material drug, and cannot effectively improve the dissolution of the preparation, but may also reduce the dissolution of the preparation. Based on a large number of experiments, the inventors found that the reasonable range of the particle size of the aprepitant raw material drug can ensure the dissolution curve of the product. In addition, the preparation capsule will have a trend of slowing down the dissolution curve during the stability period, and the sample pellets during the stability period will have agglomeration during the dissolution process, slowing down the dissolution. Adding conventional magnesium stearate or talcum powder lubricants will slightly improve the agglomeration phenomenon, but due to the hydrophobicity of conventional lubricants, it will also affect the dissolution curve of the product. Therefore, aprepitant preparations (such as capsules or tablets) also need to maintain the dissolution curve during product stability.

[0008] The present invention aims to solve one of the technical problems in the prior art at least to some extent, or at least provide a commercial choice.

[0009] The present invention first provides an aprepitant micropill, which has good dissolution and bioavailability.

[0010] A kind of aprepitant micro-pill, the micro-pill comprises a blank pellet core and an intermediate layer from the inside to the outside; the intermediate layer contains a drug and a first excipient; the drug is aprepitant and / or a pharmaceutically acceptable salt of aprepitant; the average particle size of the drug is 230-370nm.

[0011] Aprepitant API is almost insoluble in water. Although wet grinding is used to reduce the average particle size of the API, which is beneficial to improving bioavailability, excessive grinding to a smaller average particle size of the API will also slow down the dissolution curve and affect the bioavailability of the preparation product. The present invention controls the average particle size of the API in more detail, ensures a good dissolution curve of the product, and can better control the product quality.

[0012] According to an embodiment of the present invention, the average particle size of the drug is 235-369 nm.

[0013] According to an embodiment of the present invention, the average particle size of the drug is 260-300 nm.

[0014] In some embodiments of the present invention, the average particle size of the drug is 230nm, 235nm, 260nm, 287nm, 300nm, 369nm or 370nm; preferably 287nm.

[0015] According to an embodiment of the present invention, the blank pellet core is selected from a sucrose pellet core or a microcrystalline cellulose pellet core, and the particle size is 0.5-0.7 mm.

[0016] According to an embodiment of the present invention, the first auxiliary material includes one or more of a suspending agent, an emulsifier, and a thickener. In some specific examples, the first auxiliary material consists of a suspending agent, an emulsifier, and a thickener.

[0017] According to an embodiment of the present invention, the suspending agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone.

[0018] According to an embodiment of the present invention, the emulsifier is sodium lauryl sulfate.

[0019] According to an embodiment of the present invention, the thickener is selected from one or more of sucrose, sorbitol, and dextrin.

[0020] According to an embodiment of the present invention, in the aprepitant microcapsules, the weight ratio of the blank pellet core to the intermediate layer is (15-25):(67-90), or can be optionally (15-25):(52-85); in some specific examples, it is 20:80.

[0021] According to an embodiment of the present invention, in the aprepitant microcapsules, the weight ratio of the suspending agent, the emulsifier and the thickener in the intermediate layer is (7-10):(0.1-0.2):(30-40), and can be optionally 9.6:0.2:35.

[0022] According to an embodiment of the present invention, the aprepitant microcapsules further include an outer layer, that is, the outer layer is outside the middle layer; the outer layer is a surfactant of higher fatty alcohol sulfate, which can be specifically selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, and sodium octadecyl sulfate, preferably sodium octadecyl sulfate.

[0023] The study found that the dissolution curve of aprepitant tended to slow down during the stability period. Ordinary magnesium stearate and talcum powder lubricants have certain hydrophobicity and cannot improve the dissolution curve of the product after adding them. The dissolution curve can be improved by adding surfactants of higher fatty alcohol sulfates, among which sodium octadecyl sulfate is the best, which can ensure that the dissolution curve of the product will not change during the stability period and ensure the good stability of the product. That is, using surfactants of higher fatty alcohol sulfates as the outer layer can ensure the dissolution rate of the product during the stability period and further improve the bioavailability.

[0024] According to an embodiment of the present invention, the higher fatty alcohol sulfate surfactant is micronized, for example, D90<75 μm.

[0025] According to an embodiment of the present invention, based on the total weight of the aprepitant micropellets, the content of the higher fatty alcohol sulfate surfactant is 0.1-0.3 wt %, and can be optionally 0.2 wt %.

[0026] According to an embodiment of the present invention, the aprepitant micropellets contain: 15wt%-25wt% blank pellet cores, 30wt%-40wt% aprepitant, 7wt%-10wt% suspending agent, 0.1wt%-0.2wt% emulsifier, 30wt%-40wt% thickener, and 0.1wt%-0.3wt% higher fatty alcohol sulfate surfactant.

[0027] According to an embodiment of the present invention, the components and proportions of the aprepitant pellets are as follows, in parts by weight:

[0028] Aprepitant micropellets:

[0029] 15-25 portions of blank pellet cores;

[0030] The middle layer includes:

[0031] 30-40 parts of aprepitant and / or a pharmaceutically acceptable salt of aprepitant;

[0032] 7-10 parts of suspending agent;

[0033] Emulsifier 0.1-0.2 parts;

[0034] Thickener 30-40 parts;

[0035] Some embodiments also include:

[0036] The outer layer contains 0.1-0.3 parts of surfactant of higher fatty alcohol sulfate.

[0037] The present invention also provides a method for preparing the aprepitant pellets, comprising:

[0038] 1) Wet-grinding a drug, a suspending agent and an emulsifier in the presence of water until the average particle size of the drug is 230-370 nm; the drug is aprepitant and / or a pharmaceutically acceptable salt of aprepitant;

[0039] 2) adding a thickener to the grinding liquid to prepare an aqueous dispersion;

[0040] 3) coating the aqueous dispersion onto blank pellet cores to prepare drug-loaded pellets.

[0041] In some embodiments, the solid content of the aqueous dispersion is 15-25%, and can be 20%.

[0042] In some embodiments, aprepitant micropellets are prepared by fluidized bed bottom spray coating process.

[0043] In some embodiments, the method for preparing the aprepitant pellets further comprises the following steps:

[0044] 4) Adding the surfactant of the higher fatty alcohol sulfate ester to the drug-loaded pellets, mixing evenly, and forming an outer layer to obtain the aprepitant pellets. That is, the surfactant of the higher fatty alcohol sulfate ester is added during the total mixing of the pellets.

[0045] The present invention also provides an aprepitant preparation, comprising the aprepitant pellets. The aprepitant preparation includes tablets, capsules, dry suspensions or pills, which can be prepared by conventional methods in the art. As a preferred embodiment, the aprepitant preparation is a capsule.

[0046] The present invention controls the particle size of the raw material medicine in more detail, ensures the dissolution curve and bioavailability of the product, and can also ensure that the dissolution curve does not change during the stability period. DETAILED DESCRIPTION

[0047] The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the art or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels.

[0048] The formula of Aprepitant micropellets in Example 1-5 is as follows (g):

[0049]

[0050]

[0051] The preparation method of aprepitant pellets in Example 1-5 is as follows:

[0052] (1) Weigh an appropriate amount of purified water, add hydroxypropyl cellulose and sodium lauryl sulfate, stir to dissolve completely, add aprepitant, stir to disperse evenly, and prepare a solution;

[0053] (2) wet grinding the solution; adding sucrose to the grinding solution to prepare an aqueous dispersion with a solid content of 20%;

[0054] (3) The aqueous dispersion is coated onto microcrystalline cellulose pellets using a fluidized bed bottom spray coating process to prepare drug-loaded pellets (which can be used as aprepitant pellets).

[0055] The difference between the aprepitant pellets in Examples 1-5 is that the average particle size of the raw material drug is different in step (2) of the preparation method, as follows:

[0056] Example 1 Example 2 Example 3 Example 4 Example 5 Average particle size nm 653 369 287 235 152

[0057] The drug-loaded pellets of Examples 1-5 were respectively filled into gelatin capsule shells to prepare aprepitant capsules.

[0058] Experiment 1

[0059] The aprepitant capsules of Examples 1-5 and the original preparation of batch R027651 (manufacturer: Merck Sharp & Dohme Ltd.) were tested for dissolution curves in 2.2% SDS medium (tested with reference to the dissolution test method in the JX2050137 standard). The results are shown in Table 1.

[0060] Table 1 Dissolution curve results of Examples 1-5

[0061]

[0062] Conclusion: The average particle size of the API in Example 1 is controlled to be relatively large, while the control range of the API in Example 5 is relatively small, and the dissolution of the preparations with smaller or larger APIs is relatively slow. The average particle size of the API in Examples 2-4 is controlled within an appropriate range, and the dissolution curve of the prepared preparations is similar to that of the original preparation.

[0063] Note: f2 refers to the similarity factor (f2) method in the non-model-dependent method. When the similarity factor (f2) value of two dissolution curves is not less than 50, the dissolution curves can be considered similar, and if it is less than 50, they are not similar.

[0064] The aprepitant pellets of Examples 6-10 are composed of the aprepitant-loaded pellets prepared in Example 3 and an outer layer, and the preparation method is to take the aprepitant-loaded pellets of Example 3, add the outer layer material, and mix them evenly.

[0065] The prescription of aprepitant pellets in Example 6-10 is as follows:

[0066] Aprepitant drug-loaded pellets (Example 3) 998g Outer Layer 2g

[0067] The difference between the aprepitant pellets in Examples 6-10 is only the material of the outer layer, as follows:

[0068] Example 6 Example 7 Example 8 Example 9 Example 10 Outer material Magnesium Stearate talcum powder Sodium Lauryl Sulfate Sodium cetyl sulfate Sodium octadecyl sulfate

[0069] Among them, sodium dodecyl sulfate, sodium hexadecyl sulfate and sodium octadecyl sulfate are micronized, and D90 is controlled to be less than 75 μm.

[0070] The aprepitant micropellets of Examples 6-10 were respectively filled into gelatin capsule shells to prepare aprepitant capsules.

[0071] Experiment 2

[0072] The aprepitant capsules prepared in Example 3, Example 6, Example 7, Example 8, Example 9, and Example 10 were placed at 40°C ± 2°C, 75% RH ± 5%, and the dissolution curves were tested after 0 month, 3 months, and 6 months. The results are shown in Table 2.

[0073] Table 2 Stability dissolution curve results of Example 3, Example 6-10

[0074]

[0075]

[0076] The micropellets of the capsules of Example 3 do not contain an outer layer. The micropellets of the capsules of Examples 6-8 are added with magnesium stearate, talc and micronized sodium dodecyl sulfate, respectively. During the stability process at 40°C±2°C and 75%RH±5%, the dissolution curve tends to slow down, but the trend is small. The samples with added sodium hexadecyl sulfate and sodium octadecyl sulfate have better dissolution, among which the sample with added sodium octadecyl sulfate has the best dissolution, and the dissolution curve does not change during the stability period.

[0077] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed by the present invention.

Claims

1. An aprepitant pellet, characterized in that: The micropellets include a blank core and an intermediate layer from the inside to the outside; the intermediate layer contains a drug and a first excipient, and the first excipient includes a suspending agent, an emulsifier, and a thickener; in the aprepitant micropellets, the weight ratio of the suspending agent, the emulsifier, and the thickener in the intermediate layer is 9.6:0.2:35; the drug is aprepitant and / or a pharmaceutically acceptable salt of aprepitant; the average particle size of the drug is 287nm; the aprepitant micropellets also include an outer layer; the outer layer is a surfactant of higher fatty alcohol sulfate; the surfactant of the higher fatty alcohol sulfate is selected from one or more of sodium hexadecyl sulfate and sodium octadecyl sulfate, and the surfactant of the higher fatty alcohol sulfate is micronized, and D90 is controlled to be less than 75μm; based on the total weight of the aprepitant micropellets, the content of the surfactant of the higher fatty alcohol sulfate is 2wt%.

2. The aprepitant pellets according to claim 1, characterized in that The suspending agent is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose and povidone; The emulsifier is sodium lauryl sulfate; The thickener is selected from one or more of sucrose, sorbitol and dextrin.

3. The aprepitant micropellets according to claim 1 or 2, characterized in that: In the aprepitant micropellets, the weight ratio of the blank pellet core to the middle layer is (15-25):(67-90).

4. The aprepitant pellets according to claim 1 or 2, characterized in that: In the aprepitant micropellets, the weight ratio of the blank pellet core to the middle layer is (15-25):(52-85).

5. The method for preparing aprepitant pellets according to any one of claims 1 to 4, characterized in that: include: 1) Wet-grind the drug, suspending agent and emulsifier in the presence of water until the average particle size of the drug is 287 nm; The drug is aprepitant and / or a pharmaceutically acceptable salt of aprepitant; 2) Adding a thickener to the grinding liquid to prepare a water dispersion; 3) coating the aqueous dispersion onto blank pellets to prepare drug-loaded pellets; 4) adding the higher fatty alcohol sulfate surfactant to the drug-loaded pellets, mixing evenly, and forming an outer layer; the higher fatty alcohol sulfate surfactant is selected from one or more of sodium hexadecyl sulfate and sodium octadecyl sulfate, and the higher fatty alcohol sulfate surfactant is micronized, and D90 is controlled to be less than 75 μm; based on the total weight of the aprepitant pellets, the content of the higher fatty alcohol sulfate surfactant is 2 wt%.

6. An aprepitant preparation, characterized in that: The invention comprises the aprepitant micropellets according to any one of claims 1 to 4.

7. The aprepitant preparation according to claim 6, characterized in that The aprepitant preparation includes tablets, capsules, dry suspensions or pills.

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