Tofacitinib citrate sustained-release tablets, preparation method and application thereof

Abstract

The application discloses a tofacitinib citrate sustained-release tablet and a preparation method and application thereof. The tofacitinib citrate sustained-release tablet comprises a tablet core and a coating film, and the tablet core comprises the following components in parts by weight: tofacitinib citrate 18 parts, a skeleton material 10-60 parts, a binder 1-10 parts, a filling agent 10-90 parts and a lubricant 1-3 parts. The coating film comprises the following components in parts by weight: hydroxypropyl methyl cellulose 20-30 parts, a plasticizer 1-5 parts, a solid binding peptide 1-5 parts and L-lactide 1-5 parts. The tofacitinib citrate sustained-release tablet of the application can not only achieve the purpose of delayed release in the body, but also greatly improve the bioavailability of the drug. Due to the improvement of the bioavailability of the drug, the dosage can be reduced, the same therapeutic effect can be achieved, and the incidence of adverse reactions can be reduced in clinical application.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical technology, in particular to tofacitinib citrate sustained-release tablets and a preparation method and application thereof. BACKGROUND

[0002] Janus Kinase (JAK) family is a kind of non-receptor tyrosine kinase in cells, including four members of JAK1, JAK2, JAK3 and TYK2, which plays a key regulatory role in a variety of cytokine receptor signal transduction pathways. JAK kinase catalyzes the transfer of the phosphate group of ATP to signal transduction proteins (such as STAT) through its ATP binding site, thereby mediating physiological processes such as inflammation, hematopoiesis and immune regulation. Inhibition of JAK kinase activity can effectively intervene in the above pathological signals, so JAK inhibitors are widely studied for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases.

[0003] Tofacitinib is an oral small molecule JAK inhibitor. As an ATP competitive antagonist, its structure is highly similar to ATP but does not contain a phosphate group, which can specifically bind to the ATP binding pocket of JAK kinase, block the kinase activity, and then inhibit cytokine signal transduction. Tofacitinib has been chemically optimized to have strong selective inhibitory ability for JAK1, JAK2 and JAK3, while having weak inhibitory effect on other non-targeted kinases, showing good targeting and safety.

[0004] At present, tofacitinib has been approved for the treatment of moderate to severe active rheumatoid arthritis patients who have poor response to methotrexate treatment or cannot tolerate it. Its efficacy not only lies in relieving symptoms, but also can slow down the progression of joint structure destruction, and the curative effect is comparable to that of biological agents such as adalimumab. Unlike biological agents that need to be injected, tofacitinib as a small molecule drug can be administered orally, greatly improving the convenience and compliance of patients taking the drug.

[0005] Tofacitinib exists in the form of citrate salt, and the salt type crystal formed has good stability and water solubility, which is suitable for the development of oral sustained-release preparations. The currently marketed tofacitinib citrate sustained-release tablets adopt an osmotic pump controlled-release tablet dosage form, which controls the water permeation of the inner core and the release of the drug through a semi-permeable membrane, achieving constant rate release in the gastrointestinal tract. This dosage form can be administered once a day, which helps to improve the patient's compliance. However, the existing osmotic pump system has a complex structure and high manufacturing cost, and some patients still have drug absorption fluctuations under the condition of gastrointestinal individual differences. In addition, tofacitinib is a hydrophilic small molecule, and there is an absorption window limit. If it cannot fully contact the absorption site during the release process, it may affect its bioavailability.

[0006] Therefore, how to further improve the oral bioavailability of tofacitinib while simplifying the process is still one of the key problems in the optimization of sustained-release preparations. SUMMARY

[0007] In view of the defects in the prior art, the present application provides a tofacitinib citrate sustained-release tablet and a preparation method and application thereof. Through the innovative design of the sustained-release coating film layer, the present application achieves the technical effect of improving the oral bioavailability of the drug on the basis of realizing time-delayed controlled release, and has outstanding technical progress and practical application value.

[0008] The present application provides a tofacitinib citrate sustained-release tablet, comprising a matrix tablet core and a coating film, wherein the matrix tablet core comprises the following components in parts by weight:

[0009] Tofacitinib citrate 18 parts;

[0010] Matrix material 10-60 parts;

[0011] Binder 1-10 parts;

[0012] Filling agent 10-90 parts;

[0013] Lubricant 1-3 parts;

[0014] The coating film comprises the following components in parts by weight:

[0015] Hydroxypropyl methyl cellulose 20-30 parts;

[0016] Plasticizer 1-5 parts;

[0017] Solid binding peptide 1-5 parts;

[0018] L-lactide 1-5 parts;

[0019] The amino acid sequence of the solid binding peptide is shown in any one of SEQ ID NO. 1-3.

[0020] In some embodiments, the mass ratio of the solid binding peptide and the L-lactide is (1-3): 1; by controlling the compounding ratio of the solid binding peptide and the L-lactide within the preferred range, the present application can maximize the drug absorption efficiency on the basis of ensuring the stability of the controlled release behavior, balance the matching of the release rate and the absorption window, and achieve the ideal drug release effect of time-delayed effect, high-efficiency absorption and high bioavailability.

[0021] In some embodiments, the mass ratio of the hydroxypropyl methyl cellulose, the solid binding peptide and the L-lactide is (20-40):(1-3):1.

[0022] In some embodiments, the matrix material is selected from any one of copolyvidone, carbomer, glyceryl behenate, sodium alginate, ethyl cellulose, carnauba wax, hydroxypropyl cellulose HPC-GXF, hydroxypropyl cellulose HPC-EXF, hydroxypropyl cellulose HPC-JXF, hydroxypropyl cellulose HPC-MXF, hydroxypropyl cellulose HPC-M, hydroxypropyl cellulose L, hydroxypropyl cellulose H, hydroxypropyl methyl cellulose HPMC K100 LV, hydroxypropyl methyl cellulose HPMC K100 M and hydroxypropyl methyl cellulose HPMC K4M.

[0023] In some embodiments, the binder is selected from one or more of hydroxypropyl methyl cellulose, povidone K30, povidone K90, copolyvidone, hydroxypropyl cellulose and ethyl cellulose.

[0024] In some embodiments, the filler is selected from one or more of lactose, corn starch, pregelatinized starch, microcrystalline cellulose, dibasic calcium phosphate, mannitol and sorbitol.

[0025] In some embodiments, the plasticizer is selected from any one or more of triethyl citrate, polyethylene glycol 3350, polyethylene glycol 4000, dioctyl phthalate, dibutyl phthalate, dioctyl adipate, dibutyl sebacate, dioctyl sebacate, di-n-butyl adipate, tricresyl phosphate and epoxidized soybean oil.

[0026] The present application also provides a preparation method of the tofacitinib citrate sustained-release tablet, comprising the following steps:

[0027] S1: each component in the matrix tablet core except the binder and the lubricant is weighed and sieved, then mixed in a granulating kettle, and the binder is added for granulation;

[0028] S2: after granulation, the granules are dried using a fluidized bed, and then the dried granules are sized, and the lubricant is added and mixed to press the matrix tablet;

[0029] S3: each component of the coating film is weighed and prepared into a coating liquid, and the matrix tablet is coated, and after coating, the coating is aged in an oven.

[0030] In some embodiments, in step S3, the step of preparing the coating liquid is as follows: hydroxypropyl methyl cellulose is added to a solvent, the plasticizer is continuously stirred and added, and the solid binding peptide and the L-lactide are continuously stirred and added to obtain the coating liquid.

[0031] In some embodiments, the solvent is one or more of water, ethanol, isopropyl alcohol and acetone; and the mass percentage of the solvent is 80-90%.

[0032] The application significantly improves the bioavailability and controlled release performance of tofacitinib by introducing solid binding peptide and L-lactide into the coating film of the sustained-release tablet. The amino acid sequence of the solid binding peptide is optimized and screened in the application, which has high affinity to the intestinal mucosa, can be actively adsorbed on the surface of the intestinal epithelial cells during drug release, thereby prolonging the residence time of the preparation in the absorption site, increasing the contact frequency of the drug and the epithelial cells, and promoting the transmembrane transport and passive absorption of the drug.

[0033] L-lactide is a biodegradable hydrophilic polymer, which can form a microporous structure by hydrolytic degradation when used as a controlled release carrier, so that tofacitinib is released at a relatively stable speed, the effective exposure per unit dose is improved, and the incidence of side effects after administration is reduced.

[0034] In summary, compared with the prior art, the application achieves the following technical effects:

[0035] 1. The application realizes the initial non-release or low-speed release of tofacitinib after oral administration by setting the matrix tablet core and the time-release coating film with a specific formula, effectively simulates the release curve of the original research osmotic pump preparation, improves the blood drug concentration fluctuation, introduces solid binding peptide and L-lactide into the coating film, significantly promotes the absorption of the drug in the intestinal tract, thereby greatly improving the relative bioavailability of tofacitinib citrate, and the AUC value is significantly better than that of the original research preparation; due to the improvement of the bioavailability of the drug, the dosage can be reduced, and the same therapeutic effect can be achieved, and the incidence of clinical adverse reactions can be reduced in clinic.

[0036] 2. The application does not depend on a complex osmotic pump system, but can realize controlled release and efficiency by reasonable coating design, is suitable for industrial production, reduces the production cost, and improves the consistency and controllability of the preparation.

[0037] 3. The early release behavior of the preparation of the application is more stable, the blood drug concentration fluctuation is small, the risk of peak concentration related adverse reactions is reduced, the minimum effective concentration required to maintain the therapeutic effect is maintained, and the therapeutic window is optimized. BRIEF DESCRIPTION OF DRAWINGS

[0038] In order to more clearly illustrate the technical scheme of the embodiments of the application, the following will briefly introduce the drawings needed to be used in the embodiments, and it should be understood that the following drawings only show some embodiments of the application, and should not be regarded as a limitation to the scope, and other related drawings can be obtained by those skilled in the art without creative labor on the premise of not paying creative labor.

[0039] Figure 1 The dissolution test result curve of the application. DETAILED DESCRIPTION

[0040] In order to make the person skilled in the art better understand the present application, the technical solutions in the embodiments of the present application are described clearly and completely. Obviously, the described embodiments are only a part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor should belong to the scope of protection of the present application.

[0041] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the materials, reagents, etc. used can be obtained from commercial channels.

[0042] L-serine ester is an amino acid derivative containing an ester group, which has strong hydrophilicity and polarity.

[0043] The present application uses molecular simulation and docking analysis tools to design peptide sequences combined with L-serine ester. The peptides are designed through amino acid property analysis (positively charged lysine, arginine, or hydrophobic amino acids such as phenylalanine, tryptophan, etc.), molecular docking, prediction of the binding mode and affinity between the peptide and L-serine ester, and the solid binding peptide with the amino acid sequence shown in SEQ ID NO. 1~3 is obtained. The above-mentioned polypeptide sequence is artificially synthesized.

[0044] The sources of raw materials for examples and comparative examples are as follows:

[0045] Tofacitinib citrate: brand TFBB-707-221107, Nanqunyou Pharmaceutical Technology Co., Ltd.;

[0046] Skeleton material A: ethyl cellulose, brand 10cp, manufacturer DOW;

[0047] Skeleton material B: carbomer, brand 971P NF, manufacturer Lubrizol;

[0048] Binder A: hydroxypropyl cellulose, brand LF, manufacturer Ashland;

[0049] Binder B: povidone, brand K29 / 32, manufacturer Ashland;

[0050] Filling agent: microcrystalline cellulose, brand 101, manufacturer JRS;

[0051] Lubricant: stearic acid, the same substance is used in parallel experiments;

[0052] Hydroxypropyl methyl cellulose: brand E50LV, manufacturer DOW;

[0053] Plasticizer: polyethylene glycol, manufacturer DOW;

[0054] L-serine ester: manufacturer Xingyan;

[0055] Solid binding peptide A: sequence as shown in SEQ ID NO. 1;

[0056] Solid binding peptide B: sequence as shown in SEQ ID NO. 2;

[0057] Solid binding peptide C: sequence as shown in SEQ ID NO. 3.

[0058] The preparation method of the tofacitinib citrate sustained-release tablets of the examples and comparative examples is as follows:

[0059] Tofacitinib citrate, a filler and a matrix material were sieved through a 30-mesh sieve once, mixed in a granulating pot, and then granulated by adding a binder solution. After granulation, the granules were dried in a fluidized bed at an inlet air temperature of 60°C until the loss on drying of the granules was less than 3%. The dried granules were then sized, with a sieve mesh size of 1.5 mm, and then a glidant and a lubricant were added and mixed for 5 min, and then the tablets were compressed.

[0060] Tabletting: A high-speed rotary tablet press was used, and a φ9mm circular shallow concave punch die was installed, and the final total mixture was tabletted, with a main pressure range of 2-10KN and a filling depth of 5-10mm, to obtain a tablet core containing the drug.

[0061] A coating liquid was prepared by adding a coating film material to a 70% ethanol aqueous solution, and the pot was set to a negative pressure of -30Pa, a pot rotation speed of 10rpm, and an inlet air volume of 150 m 3 / min. Hot air was continuously supplied to the pot body to maintain the tablet bed temperature at 40°C during coating, and the coating time was 4-6h, the solid content of the coating liquid was 8.42%, and the tablets were coated. The nozzle was kept at a distance of 20cm from the surface of the tablets, the liquid spraying speed was 50g / min, the spray gun atomization pressure was 0.25MPa, and the spray gun fan pressure was 0.25MPa. After sustained-release coating, the coating pot was used for continuous high-temperature aging, and the aging temperature was 65°C and the aging time was 8h.

[0062] Table 1 Technical solutions of examples (in weight parts)

[0063]

[0064] Table 2 Technical solutions of comparative examples (in weight parts)

[0065]

[0066] Performance test:

[0067] 1. Bioequivalence comparison experiment

[0068] The in vivo bioequivalence comparison experiment was carried out by using the tofacitinib sustained-release tablet samples prepared by Examples 1 and 2, the pure matrix samples and the osmotic pump tablets produced by the original drug (batch numbers FK3384 and 8155781). The steps are as follows:

[0069] SPF Wistar rats, half male and half female, weighing 180-220 g, were randomly divided into 17 groups, 3-4 rats in each group, and the two groups were given a dose of 5 mg / kg by gavage. About 0.4 mL of blood sample was collected by the orbital blood collection method at 0 (immediately), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 hours after administration, and was added with EDTA anticoagulant. The plasma was separated and stored at -80℃ after centrifugation at 3000 rpm for 10 minutes under the condition of 4℃. The concentration of tofacitinib in the plasma was determined by LC-MS / MS method, and the pharmacokinetic parameters of each group were calculated by non-compartment model method.

[0070] The results are shown in Table 3: wherein, T max is the peak time, C max is the maximum blood drug concentration, AUC last is the area under the drug-time curve from administration to the last measurement point, AUCinf is the area under the drug-time curve from administration to infinite time, and AUCEX is the relative bioavailability.

[0071] Table 3: In vivo bioequivalence comparison experiment

[0072]

[0073] As can be seen from the results in Table 1, the sustained-release tablets of the present application reasonably added with solid binding peptide and L-lactide show the advantages of delayed release effect, smooth rise of blood drug concentration, and significantly improved bioavailability. The maximum blood drug concentration (Cmax) is increased by nearly 1 times, and the maximum area under the blood drug-time curve (AUC) is also increased by nearly 30%. Compared with the pure matrix tablets, the highest blood drug concentration (Cmax) of the drug absorption of the matrix + coating tablets is reduced, and the area under the blood drug-time curve (AUC) is lower. It shows that the addition of the coating film of the present application can promote the absorption of tofacitinib drug. In Comparative Example 1, no solid binding peptide is added, in Comparative Example 2, no L-lactide is added, in Comparative Example 3, too much solid binding peptide is added, in Comparative Example 4, too much L-lactide is added, and in Comparative Example 5, no solid binding peptide and L-lactide is added, the drug sustained-release effect is poor, and the C max and AUC in the body are significantly lower than those of the examples.

[0074] 2. For the in vitro dissolution of tofacitinib sustained-release tablets, the following detection experiments were carried out:

[0075] According to the dissolution determination method (Chinese Pharmacopoeia 2020 edition four general rules), paddle method (with a sink basket), temperature 37℃, rotation speed 50 revolutions / minute, 900ml pH6.8 phosphate buffer as medium, test the drug release behavior, and compare with the drug release behavior of the marketed reference preparation (8155781), as shown in Table 4:

[0076] Table 4 Dissolution test results (unit: %)

[0077]

[0078] From the results of Table 4, the cumulative release rate of the self-made tofacitinib citrate sustained-release tablets at each time point is consistent with the reference preparation, the similarity factor f2 of the release curve is all above 50, which meets the in vitro similarity evaluation standard. The release is more stable in the later release stage, indicating that it has excellent sustained-release performance and has equivalent in vitro controlled release characteristics with the reference preparation, supporting its development as a high-quality generic drug or improved new drug. In contrast, the comparative example has a relatively slow release rate within 1-2h, which limits the early drug release and reduces the overall drug release efficiency.

[0079] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A tofacitinib citrate sustained-release tablet, characterized in that, The tablet core comprises a matrix core and a coating film, wherein the matrix core comprises, by weight, the following components: 18 parts of tofacitinib citrate; 10-60 parts of skeleton material; 1-10 parts adhesive; 10-90 parts of filler; 1-3 parts lubricant; The coating film comprises, by weight, the following components: 20-30 parts of hydroxypropyl methylcellulose; Plasticizer 1-5 parts; 1-5 parts of solid-bound peptides; L-lactide 1-5 parts; The amino acid sequence of the solid-bound peptide is shown in any one of SEQ ID NO.1~3; The skeleton material is selected from any one of copovidone, carbomer, glyceryl behenate, sodium alginate, ethyl cellulose, carnauba wax, hydroxypropyl cellulose HPC-GXF, hydroxypropyl cellulose HPC-EXF, hydroxypropyl cellulose HPC-JXF, hydroxypropyl cellulose HPC-MXF, hydroxypropyl cellulose HPC-M, hydroxypropyl cellulose L, hydroxypropyl cellulose H, hydroxypropyl methylcellulose HPMC K100 LV, hydroxypropyl methylcellulose HPMC K100 M, and hydroxypropyl methylcellulose HPMC K4M; The adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone K30, povidone K90, copovidone, hydroxypropyl cellulose, and ethyl cellulose; The filler is selected from one or more of lactose, corn starch, pregelatinized starch, microcrystalline cellulose, dicalcium phosphate, mannitol, and sorbitol; The plasticizer is selected from any one or more of triethyl citrate, polyethylene glycol 3350, polyethylene glycol 4000, dioctyl phthalate, dibutyl phthalate, dioctyl adipate, dibutyl sebacate, di-n-butyl adipate, tricresyl phosphate, and epoxidized soybean oil.

2. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that, The mass ratio of the solid-bound peptide to L-lactide is (1~3):

1.

3. The method for preparing tofacitinib citrate sustained-release tablets according to claim 1, characterized in that, Includes the following steps: S1: Weigh all components of the skeleton core except for the binder and lubricant, sieve them, mix them in the granulation pot, and then add the binder to granulate. S2: After granulation, the granules are dried in a fluidized bed, sized, and then mixed with a lubricant and pressed into tablets. S3: Weigh each component of the coating film by weight, prepare the coating solution, coat the uncoated film, and then age it in an oven.

4. The preparation method according to claim 3, characterized in that, In step S3, the steps for preparing the coating solution are as follows: hydroxypropyl methylcellulose is added to the solvent, plasticizer is added while stirring continuously, and solid-bound peptide and L-lactide are added while stirring continuously to obtain the coating solution.

5. The preparation method according to claim 4, characterized in that, The solvent is one or more of water, ethanol, isopropanol, and acetone; the mass percentage of the solvent is 80-90%.

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