Dacrotamide sustained release preparation

Abstract

The invention provides a dalotamide sustained release preparation, and relates to the technical field of drug sustained release. The dalotamide sustained-release preparation sequentially comprises a medicine core layer, a sustained-release layer and an auxiliary material layer from inside to outside, the slow-release layer comprises a slow-release material composed of polyacrylic resin and polyethylene oxide according to the weight ratio of 1: 1-10: 1. Preferably, the polyacrylic resin is selected from Eudragit RS 100, and the weight-average molecular weight of the polyethylene oxide is not less than 200,000. The dalotamide sustained-release preparation disclosed by the invention is good in sustained-release performance, the sustained-release time can be as long as 20-24 hours, and the blood concentration can be stabilized.

Description

Technical Field

[0001] The invention belongs to the technical field of drug sustained-release and relates to a darolutamide sustained-release preparation. Background Art

[0002] Daroltamide, with the chemical name N-[(S)-1-(5-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propyl-2-yl]-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, is a non-steroidal androgen receptor (AR) antagonist that competitively binds to AR and blocks the activation of AR, thereby inhibiting the growth of prostate cancer cells. Daroltamide has a unique molecular structure, which gives it a higher AR affinity and a lower blood-brain barrier penetration rate, so it has better efficacy and higher safety. Daroltamide tablets are currently available in the United States, Japan, the European Union, China and other countries and regions for the treatment of adult patients with non-metastatic castration-resistant prostate cancer at high risk of metastasis. It can also be combined with docetaxel to treat adult patients with metastatic hormone-sensitive prostate cancer.

[0003] The raw material of darolutamide is poorly soluble in water, and the low water solubility directly affects the dissolution performance and bioavailability of its oral preparation. The existing darolutamide tablets need to be taken orally twice a day, and repeated administration for 2-5 days can reach a steady state, which is not patient-friendly. The above problems need to be solved urgently. Summary of the invention

[0004] Developing a darolutamide preparation with sustained release, good dissolution performance, high bioavailability and stable blood drug concentration is of great significance for improving the efficacy of darolutamide and improving its friendliness to patients. Based on this, the present invention provides a darolutamide sustained release preparation.

[0005] The technical solution of the present invention is as follows:

[0006] A darolutamide sustained-release preparation, comprising, from inside to outside, a drug core layer, a sustained-release layer and an excipient layer;

[0007] The sustained-release layer comprises a sustained-release material composed of polyacrylic acid resin and polyethylene oxide in a weight ratio of 1:1-10:1.

[0008] Preferably, the weight proportion of the sustained-release layer in the darolutamide sustained-release preparation is not less than 10%.

[0009] Preferably, the polyacrylic acid resin is selected from Eudragit RS100.

[0010] Preferably, the weight average molecular weight of the polyethylene oxide is not less than 200,000.

[0011] More preferably, the weight average molecular weight of the polyethylene oxide is not less than 500,000.

[0012] Preferably, the drug core layer contains darolutamide, and the weight proportion of darolutamide in the drug core layer is not less than 50%.

[0013] More preferably, the D90 particle size of darolutamide is no more than 30 μm.

[0014] More preferably, the drug core layer also contains a filler.

[0015] Preferably, the auxiliary material layer is selected from one or a combination of disintegrants and lubricants.

[0016] Preferably, the weight proportion of the auxiliary material layer in the darolutamide sustained-release preparation is not less than 0.1%.

[0017] The beneficial effects of the present invention are:

[0018] (1) The present invention uses a combination of polyacrylic acid resin and polyethylene oxide as a sustained-release material, which can significantly improve the sustained-release performance of darolamide, provide continuous and stable dissolution performance, and improve bioavailability.

[0019] (2) Further use of polyethylene oxide with a larger molecular weight can not only improve the mechanical strength of the sustained-release layer, which is beneficial to improving the stability of the preparation during tableting and avoiding or reducing the damage of the preparation during tableting, but also achieve better sustained-release performance, making the drug release more stable and lasting. The release time can reach 20-24 hours, which can reduce the number of medications. DETAILED DESCRIPTION

[0020] The technical solution of the present invention is further illustrated and described below through specific implementation methods.

[0021] The present invention provides a darolutamide sustained-release preparation, which comprises a drug core layer, a sustained-release layer and an excipient layer in sequence from the inside to the outside;

[0022] The sustained-release layer comprises a sustained-release material composed of polyacrylic acid resin and polyethylene oxide in a weight ratio of 1:1-10:1.

[0023] In order to provide a darolutamide preparation with good sustained-release performance, the darolutamide sustained-release preparation provided by the present invention is coated with a sustained-release layer on the outside of the drug core layer, and the sustained-release layer comprises a sustained-release material composed of polyacrylic acid resin and polyethylene oxide. Polyacrylic acid resin is a sustained-release coating material. When it is coated on the surface of the drug core layer, a sustained-release layer can be formed. The sustained-release layer can control the release rate of the drug, thereby prolonging the efficacy, reducing the number of medications, and improving the convenience of medication for patients. Polyacrylic acid resin is insoluble in water, but can swell and form a large number of micropores. The diameter of these micropores is usually between 0.1μm-0.6μm, allowing the drug in the drug core layer to pass through these micropores and be released into the external environment, such as human body fluids. Polyethylene oxide has good water solubility. When the sustained-release material comes into contact with moisture, the sustained-release layer can absorb water faster and form more and / or larger micropores faster, thereby improving the initial release rate of the drug in the drug core layer, and providing a stable and continuous drug release rate, which is conducive to balancing blood drug concentration.

[0024] In the present invention, the weight ratio of polyacrylic acid resin to polyethylene oxide is not particularly limited, and for example, it can be any value of 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, etc. Preferably, the weight ratio of polyacrylic acid resin to polyethylene oxide can be 3:1-8:1.

[0025] In a preferred embodiment of the present invention, the weight proportion of the sustained-release layer in the darolutamide sustained-release preparation is not less than 10%. If the weight proportion of the sustained-release layer is low, the thickness of the sustained-release layer will be thin, resulting in a faster release, poor sustained-release performance, and insufficient support for the mechanical strength of the preparation, and the preparation is prone to breakage during tableting. For example, the weight proportion of the sustained-release layer in the darolutamide sustained-release preparation can be 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, etc., any value, without special restrictions.

[0026] In a preferred embodiment of the present invention, the polyacrylic acid resin is selected from Eudragit RS100. Eudragit RS 100 is a copolymer composed of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate chloride in a molar ratio of 1:2:0.1, with a number average molecular weight of about 150,000. It is insoluble in water but can swell and form a large number of microchannels. Moreover, Eudragit RS100 has high mechanical strength, can provide good mechanical strength for the sustained-release layer, and has a good supporting effect on the preparation structure during tableting and storage.

[0027] In a preferred embodiment of the present invention, the weight average molecular weight Mw of polyethylene oxide is not less than 200,000. It is further found in the present invention that the use of polyethylene oxide with a higher molecular weight is beneficial to the sustained release performance and mechanical strength of the darolutamide sustained release preparation. (1) The hydrophilicity of polyethylene oxide with a lower molecular weight is stronger and it is easy to dissolve when it comes into contact with water, so it has a better pore-forming effect on the sustained release layer, and the sustained release layer is more likely to form more and / or larger micropores, and the drug in the drug core layer is released faster from the micropores, and the initial drug release rate is significantly increased. Polyethylene oxide with a higher molecular weight has the function of forming a hydrophilic gel skeleton, and can form a gel layer by absorbing water, so as to better control the release rate of the drug in the drug core layer. Compared with the use of polyethylene oxide with a lower molecular weight, the use of polyethylene oxide with a higher molecular weight has a significantly lower initial drug release rate of the darolutamide sustained release preparation, and can achieve a longer sustained release, and the sustained release time can be as long as 20-24h. (2) Polyethylene oxide with a lower molecular weight has a better plasticizing effect on polyacrylic acid resin, which will reduce the mechanical strength of the sustained-release layer, which is not conducive to maintaining the stability of the sustained-release preparation structure during tableting, and the tablets are more likely to break during tableting. Polyethylene oxide with a higher molecular weight has high mechanical strength and poor plasticizing effect, and can maintain or further improve the mechanical strength of the sustained-release layer. For example, the weight average molecular weight of polyethylene oxide can be 200,000, 300,000, 500,000, 600,000, 800,000, 1 million, 1.2 million, 1.5 million, 1.7 million, 1.8 million, 2 million, 2.2 million, 2.5 million, 2.7 million, 3 million, 3.5 million, 4 million, etc. More preferably, the weight average molecular weight of polyethylene oxide is not less than 500,000, or further preferably, the weight average molecular weight of polyethylene oxide is not less than 1 million.

[0028] In a preferred embodiment of the present invention, the drug core layer contains darolamide, and the weight proportion of darolamide in the drug core layer is not less than 50%. For example, the weight proportion of darolamide in the drug core layer can be any value of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, etc., without special restrictions. The weight of darolamide in the drug core layer of the present invention is not particularly limited, and can be 200mg, 250mg, 300mg, 350mg, 400mg, 450mg, 500mg and other different specifications.

[0029] In a more preferred embodiment of the present invention, the D90 particle size of darolutamide does not exceed 30 μm. In order to improve the dissolution performance and bioavailability of darolutamide, darolutamide can be pre-micronized, such as obtained by air flow crushing. For example, the D90 particle size of darolutamide can be 30 μm, 28 μm, 27 μm, 25 μm, 22 μm, 20 μm, 18 μm, 15 μm, 12 μm, 10 μm, etc.

[0030] In a more preferred embodiment of the present invention, the drug core layer also contains a filler. The filler is not particularly limited and can be microcrystalline cellulose, hydroxypropyl cellulose, mannitol, xylitol, sorbitol and sucrose, etc. For example, the drug core layer can be composed of darolamide and a filler, such as 60wt% darolamide and 40wt% of a filler, 70wt% darolamide and 30wt% of a filler, 80wt% darolamide and 20wt% of a filler, etc.

[0031] In a preferred embodiment of the present invention, the auxiliary material layer is selected from one or a combination of disintegrants and lubricants. For example, the disintegrant can be selected from one or a combination of two or more of cross-linked carboxymethyl cellulose sodium, hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose, preferably cross-linked carboxymethyl cellulose sodium. For example, the lubricant can be selected from one or a combination of two or more of micro-powdered silica gel, magnesium stearate, and talc, preferably micro-powdered silica gel.

[0032] In a preferred embodiment of the present invention, the weight proportion of the auxiliary material layer in the darolutamide sustained-release preparation is not less than 0.1%. For example, when the auxiliary material layer is a disintegrant, the weight proportion of the disintegrant in the darolutamide sustained-release preparation can be 1-4%; when the auxiliary material layer is a lubricant, the weight proportion of the lubricant in the darolutamide sustained-release preparation can be 0.1-0.5%. The auxiliary material layer can also be a combination of a disintegrant and a lubricant.

[0033] The preparation method of the darolamide sustained-release preparation of the present invention is not particularly limited. An exemplary preparation method may comprise the following steps (1)-(4):

[0034] (1) Preparation of drug core layer: Add darolamide drug powder (or filler) and appropriate amount of water into a wet granulator and mix evenly to form a soft material with certain viscosity; use an extrusion spheronization machine to prepare soft granules from the soft material, soften it in a fluidized bed for drying, and sieve it after drying to select drug-containing granules with a mesh size of 30-40;

[0035] (2) Preparation of sustained-release layer: polyacrylic acid resin and polyethylene oxide are mixed, and an appropriate amount of 90 wt% ethanol is added to dissolve to obtain a coating liquid; the coating liquid is evenly sprayed onto the above-mentioned drug-containing particles using a fluidized bed for coating, and dried to form drug-containing sustained-release particles.

[0036] (3) Preparation of auxiliary material layer: The above-mentioned drug-containing sustained-release particles are added to the auxiliary materials using a three-dimensional mixer to mix and obtain a mixture.

[0037] (4) Tablet pressing: The above mixture is directly pressed into tablets using a tablet press to obtain a darolutamide sustained-release preparation. The compression pressure of the tablet press can be 50-80N, such as 65N.

[0038] The technical solution of the present invention is further described and illustrated according to various embodiments below.

[0039] Example 1

[0040] The darolutamide sustained-release preparation consists of a drug core layer, a sustained-release layer and an excipient layer. The drug core layer material is a combination of 300 mg darolutamide (D90 particle size 25 μm) and 100 mg microcrystalline cellulose, the sustained-release layer is a combination of 45 mg Eudragit RS100 and 15 mg polyethylene oxide (Mw is 2000), and the excipient layer material is a combination of 10 mg cross-linked sodium carboxymethyl cellulose and 1 mg micropowder silica gel. The preparation method is as follows:

[0041] Preparation of drug core layer: Add darolamide drug powder (or filler) and appropriate amount of water into a wet granulator and mix evenly to form a soft material with certain viscosity; use an extrusion spheronization machine to prepare soft granules from the soft material, soften it in a fluidized bed for drying, sieve it after drying, and select 35 mesh drug-containing granules;

[0042] Preparation of sustained-release layer: polyacrylic acid resin and polyethylene oxide are mixed, and an appropriate amount of 90wt% ethanol is added to dissolve to obtain a coating liquid; the coating liquid is evenly sprayed onto the above-mentioned drug-containing particles using a fluidized bed for coating, and dried to form drug-containing sustained-release particles.

[0043] Preparation of auxiliary material layer: Use a three-dimensional mixer to add the above-mentioned drug-containing sustained-release particles into the cross-linked sodium carboxymethyl cellulose for premixing, and then add micro-powdered silica gel for total mixing to obtain a mixture.

[0044] Tablet pressing: The above mixture is directly pressed into tablets using a tablet press to obtain a darolutamide sustained-release preparation. The compression pressure of the tablet press is 65N.

[0045] Example 2

[0046] The difference between this embodiment and embodiment 1 is that in embodiment 1, the Mw of polyethylene oxide is adjusted from 2000 to 20,000. The other steps remain unchanged.

[0047] Example 3

[0048] The difference between this embodiment and embodiment 1 is that in embodiment 1, the Mw of polyethylene oxide is adjusted from 2000 to 200,000. The other steps remain unchanged.

[0049] Example 4

[0050] The difference between this embodiment and embodiment 1 is that in embodiment 1, the Mw of polyethylene oxide is adjusted from 2000 to 500,000. The other steps remain unchanged.

[0051] Example 5

[0052] The difference between this embodiment and embodiment 1 is that in embodiment 1, the Mw of polyethylene oxide is adjusted from 2000 to 2 million. The other steps remain unchanged.

[0053] Example 6

[0054] The difference between this embodiment and embodiment 5 is that in embodiment 5, Eudragit RS100 is adjusted from 45 mg to 30 mg, and polyethylene oxide is adjusted from 15 mg to 10 mg. The other steps remain unchanged.

[0055] Comparative Example 1

[0056] The difference between this comparative example and Example 1 is that in Example 1, the sustained-release layer is omitted, that is, the darolamide preparation does not have sustained-release properties. The remaining steps remain unchanged.

[0057] Comparative Example 2

[0058] The difference between this comparative example and Example 1 is that in Example 1, polyethylene oxide is replaced by an equal weight of Eudragit RS100. The remaining steps remain unchanged.

[0059] Comparative Example 3

[0060] The difference between this comparative example and Example 1 is that in Example 1, Eudragit RS100 is replaced by polyethylene oxide (Mw is 2000) of equal weight. The other steps remain unchanged.

[0061] Comparative Example 4

[0062] The difference between this comparative example and Example 1 is that in Example 1, Eudragit RS100 is replaced by polyethylene oxide (Mw is 200,000) of equal weight. The other steps remain unchanged.

[0063] Comparative Example 5

[0064] The difference between this comparative example and Example 1 is that in Example 1, the sustained-release layer is replaced with a combination of 45 mg of hypromellose and 15 mg of ethyl cellulose, and the remaining steps remain unchanged.

[0065] Example 7

[0066] The darolutamide sustained-release preparation consists of a drug core layer, a sustained-release layer and an excipient layer. The drug core layer material is a combination of 300 mg darolutamide (D90 particle size 20 μm) and 30 mg microcrystalline cellulose, the sustained-release layer is a combination of 30 mg Eudragit RS100 and 30 mg polyethylene oxide (Mw is 500,000), and the excipient layer material is a combination of 10 mg cross-linked sodium carboxymethyl cellulose and 1 mg micro-powdered silica gel.

[0067] The preparation method of this embodiment is the same as that of embodiment 1.

[0068] Example 8

[0069] The difference between this embodiment and embodiment 7 is that in embodiment 7, Eudragit RS100 is adjusted from 30 mg to 45 mg, and polyethylene oxide is adjusted from 30 mg to 15 mg. The other steps remain unchanged.

[0070] Example 9

[0071] The difference between this embodiment and embodiment 7 is that in embodiment 7, Eudragit RS100 is adjusted from 30 mg to 53 mg, and polyethylene oxide is adjusted from 30 mg to 7 mg. The other steps remain unchanged.

[0072] Comparative Example 6

[0073] The difference between this comparative example and Example 7 is that in Example 7, Eudragit RS100 is adjusted from 30 mg to 20 mg, and polyethylene oxide is adjusted from 30 mg to 40 mg. The other steps remain unchanged.

[0074] Performance tests of the darolamide formulations of Examples 1-9 and Comparative Examples 1-6.

[0075] 1. Dissolution performance test

[0076] 1. Preparation of dissolution medium:

[0077] pH = 1.2 hydrochloric acid solution: Take 7.65 mL of concentrated hydrochloric acid, add it into purified water while stirring, and make up to 1000 mL to obtain a pH = 1.2 hydrochloric acid solution.

[0078] 2. Determination:

[0079] (1) Preparation of test samples: darolamide preparations of Examples 1-9 and Comparative Examples 1-6.

[0080] (2) Collection of dissolution liquid: Measure 900 mL of dissolution medium and place it in the dissolution cup. When the temperature of the dissolution medium is constant at 37°C ± 0.5°C, place the test sample in the dissolution cup, set the speed to 75 rpm, and start the timer. Take samples at the specified time, draw an appropriate amount of dissolution liquid, filter it through a 0.45 μm microporous membrane, and collect the filtrate.

[0081] (3) Content determination: After diluting the filtrate with a solvent, the absorbance at a wavelength of 272 nm was measured using a high performance liquid chromatography ultraviolet detector to calculate the release rate (%) of darolutamide. The results are shown in Table 1 below.

[0082] Table 1 Release rate / %

[0083] 1h 4h 8h 12h 16h 20h 24h Example 1 23.7 55.4 74.1 82.3 85.6 90.7 91.5 Example 2 20.8 50.5 72.6 80.5 82.6 88.3 91.7 Example 3 18.5 46.3 68.2 75.7 80.5 86.0 91.1 Example 4 15.7 42.6 63.5 71.5 78.7 84.5 90.9 Example 5 13.4 36.7 53.8 63.3 74.1 78.4 86.5 Example 6 15.1 40.4 55.9 65.5 76.2 80.0 89.3 Comparative Example 1 40.7 68.6 87.8 92.1 92.5 93.3 93.9 Comparative Example 2 6.9 15.6 26.2 48.2 56.3 72.4 79.9 Comparative Example 3 35.8 65.2 80.2 89.1 92.6 92.3 93.5 Comparative Example 4 30.8 63.6 79.9 88.3 90.1 90.9 90.1 Comparative Example 5 28.5 61.6 85.8 92.1 92.1 92.6 92.6 Example 7 17.6 42.6 66.9 74.1 82.5 89.3 91.2 Example 8 15.3 40.7 63.7 70.9 78.2 84.0 90.1 Example 9 10.6 23.3 40.6 53.0 64.2 75.8 83.4 Comparative Example 6 22.4 47.4 72.9 84.3 87.5 89.9 91.5

[0084] It can be seen from the data results in Table 1 that the darolutamide sustained-release preparation of the present invention has good sustained-release performance. When a larger molecular weight polyethylene oxide is used, the initial release rate of the drug is more appropriate, and the release rate is more stable and sustained.

[0085] 2. Determination of drug-time curve

[0086] (1) Preparation of test samples: C 14 Daroltamide was labeled, and two tablets of Daroltamide ordinary tablets were prepared according to the method of Comparative Example 1, one tablet of Daroltamide sustained-release preparation was prepared according to the method of Comparative Example 2, and one tablet of Daroltamide sustained-release preparation was prepared according to the methods of Examples 3 and 5.

[0087] (2) Experimental animals and groups: Beagle dogs, male, weighing 8-10 kg, were randomly divided into groups, 3 in each group.

[0088] (3) Administration: The beagle dogs in the darolutamide regular tablet group were given one tablet of darolutamide regular tablet every 12 hours after meals; the beagle dogs in the darolutamide extended-release preparation group were given one tablet of darolutamide extended-release preparation after meals.

[0089] (4) Collection and processing of plasma samples: 4 mL of blood was collected from the forelimb vein before administration and 0.25 h, 0.5 h, 1 h, 2 h, 3 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 20 h, and 24 h after administration. The blood was anticoagulated with 1% heparin, centrifuged at 800 × g for 10 min, and the plasma was separated and stored at -80°C for testing.

[0090] (5) Content determination: Plasma samples at different time points were taken into centrifuge tubes, 200 μL of acetonitrile solution was added, vortexed for 60 seconds, centrifuged at 1500×g for 10 minutes at 4°C, and 20 μL of the supernatant was injected. The concentration of darolamide was determined by ultraviolet high performance liquid chromatography-tandem mass spectrometry detection. The results are shown in Tables 2 and 3 below.

[0091] Table 2 Blood drug concentration (unit: μg / ml)

[0092]

[0093]

[0094] It can be seen from the data in Table 2 that the darolutamide sustained-release preparation of the present invention can have a long duration of action in vivo, which can be as long as more than 20 hours. The pharmacodynamic effect time of one tablet of darolutamide sustained-release preparation is equivalent to the pharmacodynamic effect of two tablets of darolutamide ordinary tablets.

[0095] Table 3 Pharmacokinetic parameters

[0096] Comparative Example 1 Comparative Example 2 Example 3 Example 5 <![CDATA[AUC (0-12h) (μg·h / mL)]]> 588.53 495.36 496.23 577.41 <![CDATA[C max (μg / mL)]]> 58.43 28.29 42.28 41.48 <![CDATA[T max (h)]]> 14 10 4 6 <![CDATA[T 1 / 2 (h)]]> 18.11 22.8 11.51 15.10

[0097] As can be seen from the data in Table 3 above, the darolamide sustained-release preparation of the present invention has a higher bioavailability than ordinary tablets, and the effect of one sustained-release preparation is equivalent to that of two ordinary preparations. Example 5 uses a higher molecular weight polyethylene oxide and polyacrylic acid resin composition as a sustained-release material, which has a more stable blood drug concentration in animals and meets the formulation design requirements of once-daily administration. From the data in Comparative Example 2, it can be seen that the sustained-release layer uses polyacrylic acid resin alone, and the release is too slow, resulting in low blood drug concentration and a long half-life.

[0098] 3. Tablet breakage rate test

[0099] According to the tableting method of Example 1 (pressing pressure 80N), 1000 tablets of the darolamide preparations of Examples 1-9 and Comparative Examples 1-6 were respectively pressed continuously, and the preparation breakage rates were counted. The results are shown in Table 4 below.

[0100] Table 4 Damage rate / %

[0101]

[0102]

[0103] It can be seen from the data results in Table 4 above that the tablet breakage rate of the darolutamide sustained-release preparation of the present invention is low, especially when the weight-average molecular weight of polyethylene oxide reaches 200,000 or more, the breakage rate is significantly reduced.

[0104] As described above, the basic principles, main features and advantages of the present invention are shown and described. Those skilled in the art should understand that the present invention is not limited by the above embodiments, which are only preferred embodiments of the present invention and cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the scope of the present invention and the content of the specification should still be within the scope of the present invention. The scope of protection required by the present invention is defined by the attached claims and their equivalents.

Claims

1. A darolamide sustained-release preparation, characterized in that: From inside to outside, it includes a drug core layer, a sustained-release layer and an excipient layer; The sustained-release layer comprises a sustained-release material composed of polyacrylic acid resin and polyethylene oxide in a weight ratio of 1:1-10:

1.

2. The sustained-release preparation of darolamide according to claim 1, characterized in that: The weight proportion of the sustained-release layer in the darolutamide sustained-release preparation is not less than 10%.

3. The sustained-release preparation of darolamide according to claim 1, characterized in that: The polyacrylic acid resin is selected from Eudragit RS100.

4. The sustained-release preparation of darolamide according to claim 1, characterized in that: The weight average molecular weight of the polyethylene oxide is not less than 200,000.

5. The darolamide sustained-release preparation according to claim 4, characterized in that: The weight average molecular weight of the polyethylene oxide is not less than 500,000.

6. The sustained-release preparation of darolamide according to claim 1, characterized in that: The drug core layer contains darolutamide, and the weight proportion of darolutamide in the drug core layer is not less than 50%.

7. The sustained-release preparation of darolamide according to claim 6, characterized in that: The D90 particle size of the darolamide is no more than 30 μm.

8. The sustained-release preparation of darolamide according to claim 6, characterized in that: The drug core layer also contains a filler.

9. The sustained-release preparation of darolutamide according to claim 1, characterized in that: The auxiliary material layer is selected from one or a combination of disintegrants and lubricants.

10. The sustained-release preparation of darolamide according to claim 1, characterized in that: The weight proportion of the auxiliary material layer in the darolutamide sustained-release preparation is not less than 0.1%.

Images