A sustained-release upatin tablet and a preparation method thereof

Abstract

This application relates to the field of pharmaceutical technology and specifically discloses an upadacitinib sustained-release tablet and a method for preparing the same. Based on the solubility characteristics of upadacitinib, the present invention develops an upadacitinib sustained-release tablet with a gastric retention effect. This sustained-release tablet overcomes the drawback that drug dissolution is affected by differences in gastrointestinal pH, achieving sustained release in a low pH environment. Furthermore, the production process is simple, making it suitable for industrial production and clinical use.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, more specifically, it relates to a kind of upatinib sustained-release tablets and preparation method thereof. BACKGROUND

[0002] Upatinib is an effective JAK1 inhibitor, and has shown good efficacy in the treatment of various autoimmune diseases and inflammatory diseases in clinical trials. It has been approved for 7 indications, namely atopic dermatitis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, axial spondyloarthritis (radiographic negative axial spondyloarthritis), moderate to severe active ulcerative colitis, and moderate to severe active Crohn's disease, with a wide range of suitable populations.

[0003] Upatinib is a white to light brown crystalline powder, easily soluble in water and ethanol. The original preparation of upatinib sustained-release tablets on the market in China is produced by AbbVie Deutschland GmbH&Co KG, and is divided into three specifications of 15mg, 30mg and 45mg. The solubility of upatinib in different buffer media is pH-dependent, and the solubility of upatinib decreases significantly as the pH increases. Therefore, the dissolution of upatinib is quite different in different pH environments. Based on the above reasons, upatinib may be precipitated or difficult to dissolve in the intestinal tract, resulting in lower bioavailability.

[0004] Upatinib has multiple crystal forms, among which the solubility of hemihydrate is much lower than that of amorphous. Amorphous upatinib has high hygroscopicity, which is not conducive to production and storage. Patent CN116270645A discloses using tartaric acid, fumaric acid, citric acid, succinic acid, maleic acid and their combinations as pH adjusters. The patent controls the temperature suitable for upatinib dissolution at 37℃, and has a dissolution environment lower than pH 3.8. Patent CN117357492A discloses a kind of upatinib sustained-release tablets, which also uses tartaric acid or citric acid as pH adjuster. The raw and auxiliary material composition (by mass percentage) is as follows: upatinib 1-10%, release retardant 5-50%, filler 20-70%, pore-forming agent 10-50% and lubricant 0.1-5%. The drug release rate of the upatinib sustained-release tablets obtained by the invention is smooth, which can reduce the frequency of drug administration for patients and improve the drug compliance of patients. Patent CN118370734A discloses a kind of upatinib sustained-release tablets and preparation method thereof. The upatinib sustained-release tablets comprise 1.3-11.49% upatinib, 15-50% pH adjuster and the balance of sustained-release tablet auxiliary materials by weight ratio. In a neutral dissolution environment represented by pH 6.8 phosphate buffer solution, the upatinib sustained-release tablets have a good dissolution rate, and the preferred pH adjuster is malic acid. Acidic pH adjuster is also used.

[0005] For the related art in the above, the inventors believe that for the above properties of upatinib, the current related preparations all use to increase the acidic regulator to improve the dissolution environment of the raw material drug. However, in the human body, the pH environment of the gastrointestinal tract changes more complexly, and the absorption effect produced by simply adding a quantitative acidic regulator is quite different between different populations, and it is often difficult to achieve good drug delivery effect. SUMMARY

[0006] In the related art, the absorption effect produced by adding a quantitative acidic regulator is quite different between different populations, and it is often difficult to achieve good drug delivery effect. In order to improve this defect, the present application provides a kind of upatinib sustained-release tablets and its preparation method.

[0007] In the first aspect, the present application provides a kind of upatinib sustained-release tablets, adopts the following technical scheme:

[0008] A kind of upatinib sustained-release tablets, including the following weight parts of components: upatinib 15-45 parts, drug carrier 15-90 parts, sustained-release skeleton material 600-800 parts, filling agent 40-60 parts, swelling agent 200-300 parts, lubricant 2-5 parts;The swelling agent includes non-water-soluble polymer, the non-water-soluble polymer has carboxymethyl sodium group or pyrrolidone ring in molecule, and the carrier is porous silicon carrier.

[0009] By adopting the above technical scheme, the present application selects the combination of porous silicon carrier and upatinib, and adds swelling agent and sustained-release skeleton material and other aids to prepare upatinib sustained-release tablets. After taking the sustained-release tablets of the present application, the carboxymethyl sodium group, pyrrolidone ring and other groups in the swelling agent can promote the volume expansion of the sustained-release tablets, and the sustained-release tablets can be expanded to a size greater than the diameter of the pylorus in a short time, thereby hindering the sustained-release tablets from entering the intestinal tract and making the sustained-release tablets stay in the stomach. The sustained-release tablets staying in the stomach can release upatinib drugs for a long time under suitable pH conditions, and the sustained-release skeleton material can maintain the integrity of the sustained-release tablets when swelling occurs, so that the sustained-release tablets are not easy to enter the intestinal tract due to disintegration. Through the synergistic effect of the sustained-release skeleton material, the porous silicon carrier and upatinib, the upatinib sustained-release tablets can stay in the stomach of the patient for a long time, realize long-acting release, and the release effect is less affected by pH, thereby achieving good drug delivery effect.

[0010] As a preferred, the phase state of the upatinib is hemihydrate crystal form C or amorphous, and the weight ratio of the upatinib to the drug carrier is 1:(1.5-2.5).

[0011] By adopting the technical scheme, when the weight ratio of ulipristal and the drug carrier is 1:(1.5-2.5), the powder obtained after dry granulation has high solubility and very low hygroscopicity. When the weight ratio of ulipristal and the drug carrier exceeds the range, the solubility of amorphous and hemihydrate ulipristal decreases to different degrees.

[0012] Preferably, the D90 particle size of ulipristal is 10-30 μm.

[0013] By adopting the technical scheme, the particle size range of ulipristal is preferred, and ulipristal can be well matched with the porous silicon carrier in the range, which helps to maintain ideal anti-hygroscopicity.

[0014] Preferably, the porous silicon carrier is Parteck SLC.

[0015] By adopting the technical scheme, the pore size of ulipristal and PARTECK SLC is similar, and when the weight ratio of the two is 1:(1.5-2.5), the solubility of the drug can be significantly improved after dry granulation to form a consolidated body. PARTECK SLC can make ulipristal fully adsorbed in the pores, thus having good anti-hygroscopicity.

[0016] Preferably, the sustained-release matrix material is composed of insoluble matrix material and erodible matrix material.

[0017] By adopting the technical scheme, the insoluble matrix material can maintain the stability of the overall structure when the sustained-release tablet swells, and the erodible matrix material can make the sustained-release tablet maintain good drug release effect while swelling.

[0018] Preferably, the insoluble matrix material includes at least one of Eudragit, ethyl cellulose, konjac glucomannan.

[0019] Preferably, the erodible matrix material includes at least one of hypromellose, polyoxyethylene, sodium alginate, polyvinyl alcohol, carbomer.

[0020] Preferably, the lubricant is stearic acid or a fatty acid salt.

[0021] Preferably, the swelling agent is one of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch.

[0022] By adopting the technical scheme, the swelling agent can make the sustained-release tablet maintain the integrity of the structure while swelling and maintain good drug release effect by cooperating with the sustained-release matrix material.

[0023] In a second aspect, the application provides a preparation method of the ulpristin sustained-release tablet.

[0024] A preparation method of the ulpristin sustained-release tablet, comprising the following steps:

[0025] (1) mixing ulpristin with a drug carrier and sieving for use;

[0026] (2) dry-pressing and crushing the mixture obtained in step (1) by a dry granulator and sieving for use;

[0027] (3) mixing a filler, a sustained-release matrix material and an expanding agent with the material obtained in step (2) and sieving for use;

[0028] (4) mixing a lubricant with the material obtained in step (3) to obtain intermediate granules;

[0029] (5) die-pressing the intermediate granules to obtain the ulpristin sustained-release tablet.

[0030] By adopting the above technical scheme, the production process of the application is simple in operation, suitable for industrialized production, and the medicine produced by this method is convenient for clinical use and storage.

[0031] In summary, the application has the following beneficial effects:

[0032] 1. According to the dissolution characteristics of ulpristin, the application develops an ulpristin sustained-release tablet with a gastric retention effect, which can be retained in the stomach for a long time, overcoming the defect that the dissolution of the medicine is affected by the pH difference in the gastrointestinal tract, achieving sustained release in a low-pH environment, and the production process is simple, suitable for industrialized production and clinical use and storage.

[0033] 2. Through the synergistic effect of the sustained-release matrix material, the porous silicon carrier and ulpristin, the ulpristin sustained-release tablet can be retained in the patient's stomach for a long time, achieving long-acting release, and the release effect is less affected by pH, achieving good drug delivery effect. DETAILED DESCRIPTION

[0034] The application will be further described in detail below in combination with examples and comparative examples, and the raw materials involved in the application can be obtained by market purchase.

[0035] Examples

[0036] Examples 1-5

[0037] The following will be described taking Example 1 as an example.

[0038] Example 1

[0039] In this embodiment, the phase state of the upatinib is hemihydrate crystal form C, the D90 particle size of the upatinib is 10 μm; the drug carrier is Parteck SLC; the sustained-release matrix material is a mixture of insoluble matrix material and erodible matrix material in a weight ratio of 47:13, the insoluble matrix material is Eudragit RL, and the erodible matrix material is hypromellose (type 2208); the filler is microcrystalline cellulose, the bulking agent is cross-linked polyvinylpyrrolidone (Kollidon CL), and the lubricant is stearic acid.

[0040] This embodiment provides a sustained-release upatinib tablet, which comprises the following components in parts by weight: upatinib 15 mg, drug carrier 15 mg, sustained-release matrix material 600 mg, filler 40 mg, bulking agent 200 mg, and lubricant 2 mg.

[0041] This embodiment provides a preparation method of a sustained-release upatinib tablet, which comprises the following steps:

[0042] (1) mixing upatinib and a drug carrier, and passing the mixture through a 100-mesh sieve for use;

[0043] (2) drying and compressing the mixture obtained in step (1) by a dry granulator, and crushing and passing the mixture through a 60-mesh sieve for use;

[0044] (3) mixing a filler, a sustained-release matrix material, a bulking agent, and the material obtained in step (2), and passing the mixture through a sieve for use;

[0045] (4) mixing a lubricant and the material obtained in step (3) to obtain intermediate granules.

[0046] (5) die pressing the intermediate granules to obtain a sustained-release upatinib tablet.

[0047] As shown in Table 1, the main difference between Examples 1-5 is that the amount of the drug carrier is different, and the phase state of upatinib in Examples 2-5 is amorphous.

[0048] Table 1 Amount of drug carrier

[0049] Sample Drug carrier / mg Example 1 15 Example 2 22.5 Example 3 30 Example 4 37.5 Example 5 45

[0050] Example 6

[0051] The difference between this embodiment and Example 3 is that the phase state of upatinib is hemihydrate crystal form C.

[0052] As shown in Table 2, the difference between Examples 7-10 and Example 3 is that the raw material ratio of the upatinib sustained-release tablet is different.

[0053] Table 2 Raw material ratio of upatinib sustained-release tablet

[0054]

[0055] Example 11

[0056] The difference between this example and Example 3 is that the D90 particle size of upatinib is 20 pm.

[0057] Example 12

[0058] The difference between this example and Example 3 is that the D90 particle size of upatinib is 30 pm.

[0059] Example 13

[0060] The difference between this example and Example 3 is that the D90 particle size of upatinib is 40 pm.

[0061] Example 14

[0062] The difference between this example and Example 3 is that the insoluble matrix material is selected as ethyl cellulose (Ethocel Standard 10 Premium).

[0063] Example 15

[0064] The difference between this example and Example 3 is that the insoluble matrix material is selected as konjac glucoside (KGM-100).

[0065] Example 16

[0066] The difference between this example and Example 3 is that the erodible matrix material is selected as polyoxyethylene (PEO N80).

[0067] Example 17

[0068] The difference between this example and Example 3 is that the erodible matrix material is selected as sodium alginate.

[0069] Example 18

[0070] The difference between this example and Example 3 is that the erodible matrix material is selected as polyvinyl alcohol (type 1735).

[0071] Example 19

[0072] The difference between this example and Example 3 is that the erodible matrix material is selected as carbomer.

[0073] Example 20

[0074] The difference between this example and Example 3 is that the lubricant is selected as magnesium stearate.

[0075] Example 21

[0076] This example differs from Example 3 in that the lubricant is calcium stearate.

[0077] Example 22

[0078] This example differs from Example 3 in that the lubricant is sodium stearyl fumarate.

[0079] Example 23

[0080] This example differs from Example 3 in that the bulking agent is crosscarmellose sodium (Ac-Di-Sol).

[0081] Example 24

[0082] This example differs from Example 3 in that the bulking agent is sodium carboxymethyl starch (Primogel).

[0083] Example 25

[0084] This example differs from Example 3 in that the filler is lactose.

[0085] Example 26

[0086] This example differs from Example 3 in that the filler is starch.

[0087] Example 27

[0088] This example differs from Example 3 in that the filler is gelatinized starch.

[0089] Example 28

[0090] This example differs from Example 3 in that the filler is mannitol.

[0091] Comparative Example

[0092] Comparative Example 1

[0093] This comparative example differs from Example 3 in that step (2) is not performed in the process of preparing the upatinib sustained release tablet.

[0094] Comparative Example 2

[0095] This comparative example differs from Example 6 in that the Eudragit is replaced with the same weight of hypromellose.

[0096] Comparative Example 3

[0097] This comparative example differs from Example 6 in that the components of the upatinib sustained release tablet do not include a bulking agent.

[0098] Performance Test Test Method

[0099] I. Solubility and hygroscopicity test

[0100] Test object: Examples 1-6, Comparative Example 1.

[0101] Test method: The material obtained after sieving in step (2) of the preparation process of Examples 1-6 and the material obtained after sieving in step (1) of Comparative Example 1 were tested for solubility and hygroscopicity in a medium with pH 1.2, and the results are shown in Table 3.

[0102] Table 3 Solubility and hygroscopicity

[0103] Sample Solubility / (mg / mL) Hygroscopicity / % Example 1 33.2 0.03 Example 2 62.4 0.06 Example 3 83.3 0.05 Example 4 71.4 0.87 Example 5 60.1 25.3 Example 6 82.5 0.02 Comparative Example 1 50.8 23.1

[0104] II. Dissolution test of sustained-release tablets

[0105] Test object: Examples 3, 6-28 and Comparative Examples 2-3.

[0106] Test condition: The dissolution device was a basket device at 100 rpm, the dissolution medium was a pH 1.2 hydrochloric acid solution, the volume of the dissolution medium was 900 ml, the dissolution temperature was 37±0.5°C, and the dissolution was sampled at 1 h, 2 h, 4 h, 6 h, 8 h and 12 h for determination of the dissolution, and the results are shown in Table 4.

[0107] Table 4 Dissolution

[0108]

[0109]

[0110] III. Swelling test of sustained-release tablets

[0111] Test object: Examples 3, 6-28 and Comparative Examples 2-3.

[0112] Test condition: According to the ratio of the sustained-release tablets, the tablets were pressed using an oval punch of 18 mm x 12 mm (thickness of 8 mm), the dissolution device was a basket device at 100 rpm, the dissolution medium was a pH 1.2 hydrochloric acid solution, the volume of the dissolution medium was 900 ml, the dissolution temperature was 37±0.5°C, and the dissolution was sampled at 1 h, 2 h, 4 h, 6 h, 8 h and 12 h for determination, and if the length, width and height of the sample all exceeded 9 mm, it was recorded as qualified, otherwise it was unqualified, and the results are shown in Table 5.

[0113] Table 5 Swelling

[0114]

[0115]

[0116] It can be seen from Examples 1-6 and Comparative Example 1 in combination with Table 3 that when the ratio of Uptanas to PARTECK SLC is 1:(1.5-2.5) and after processing by step (2), Uptanas has high solubility and almost no hygroscopicity. When the ratio of Uptanas to PARTECK SLC is outside the range of 1:(1.5-2.5), the solubility of hemihydrate crystal form C of Uptanas is relatively low, and the sample prepared from amorphous Uptanas has high hygroscopicity. The results of Comparative Example 1 show that the mixture of amorphous Uptanas and PARTECK SLC in step (1) is also highly hygroscopic, which is not conducive to subsequent production and storage. The above results show that the compounding of Uptanas and PARTECK SLC in the manner of the present application can significantly improve the solubility of the drug and reduce the hygroscopicity of the drug.

[0117] It can be seen from Examples 3, 6 and Comparative Example 2 in combination with Tables 4-5 that although Comparative Example 2 achieves good dissolution results, since it only adds an erodible matrix material, the sample cannot guarantee that the length, width and height are all greater than 9 mm (the diameter of the pylorus) at 6 h, and is easily discharged to the intestine subsequently, resulting in poor drug delivery effect. Comparative Example 3 not only has poor dissolution results, but also has not fully expanded to a suitable size at 2 h, considering that the gastric emptying time of the human body is 2-3 h, the sample of Comparative Example 3 cannot effectively achieve sustained drug delivery.

[0118] The above examples are merely an explanation of the present application and are not a limitation of the present application, and those skilled in the art can make modifications to the examples of the present application without creative contribution after reading the present specification, but as long as they are within the scope of the claims of the present application, they are protected by the Patent Law.

Claims

1. An upadacitinib sustained-release tablet, characterized in that: The invention comprises the following components in parts by weight: 15-45 parts of upadacitinib, 15-90 parts of a drug carrier, 600-800 parts of a sustained-release matrix material, 40-60 parts of a filler, 200-300 parts of a bulking agent, and 2-5 parts of a lubricant; the bulking agent comprises a water-insoluble polymer having a sodium carboxymethyl group or a pyrrolidone ring in its molecule; the carrier is a porous silicon carrier; the physical state of upadacitinib is hemihydrate crystal form C or amorphous form; the weight ratio of upadacitinib to drug carrier is 1:(1.5-2.5); the porous silicon carrier is Parteck SLC; the sustained-release matrix material comprises an insoluble matrix material and an erodible matrix material; the insoluble matrix material is Eudragit; the erodible matrix material is hypromellose; the lubricant is stearic acid or a fatty acid salt; and the bulking agent is one of crospovidone, croscarboxymethyl cellulose sodium, and sodium carboxymethyl starch.

2. The upadacitinib sustained-release tablet according to claim 1, characterized in that The D90 particle size of upadacitinib is 10-30 μm.

3. The method for preparing upadacitinib sustained-release tablets according to any one of claims 1-2, characterized in that: The following steps are involved: (1) Mix upadacitinib and the drug carrier and sieve them for later use; (2) The mixture obtained in step (1) is dry-pressed and crushed by a dry granulator, and sieved for later use; (3) Mixing the filler, sustained-release skeleton material, and expander with the material obtained in step (2), and sieving the mixture for later use; (4) mixing the lubricant with the material obtained in step (3) to obtain intermediate particles; (5) Punching and tableting the intermediate granules to obtain upadacitinib sustained-release tablets.

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