Tofacitinib citrate sustained release tablet as well as preparation method and application thereof

Abstract

The invention discloses a tofacitinib citrate sustained release tablet as well as a preparation method and application thereof. Comprising a skeleton tablet core and a coating film, and the skeleton tablet core comprises the following components in parts by weight: 18 parts of tofacitinib citrate; 10-60 parts of a framework material; 1-10 parts of an adhesive; 10 to 90 parts of a filling agent; 1-3 parts of a lubricant; the coating film is prepared from the following components in parts by weight: 20 to 30 parts of hydroxypropyl methylcellulose; 1-5 parts of a plasticizer; 1-5 parts of solid binding peptide; 1 to 5 parts of L-lactide; the tofacitinib citrate sustained release tablet disclosed by the invention not only can achieve the purpose of delayed release in vivo, but also greatly improves the bioavailability of the medicine. As the bioavailability of the medicine is improved, not only can the administration dosage be reduced, but also the same treatment effect can be achieved, so that the occurrence rate of untoward effects in clinical application is reduced.

Description

Technical Field

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

[0002] The Janus kinase (JAK) family is a class of intracellular non-receptor tyrosine kinases, comprising four members: JAK1, JAK2, JAK3, and TYK2. They play a key role in regulating various cytokine receptor signaling pathways. Through their ATP-binding sites, JAK kinases catalyze the transfer of ATP phosphate groups to signaling proteins (such as STATs), thereby mediating physiological processes such as inflammation, hematopoiesis, and immune regulation. Inhibiting JAK kinase activity can effectively intervene in these pathological signaling pathways, leading to the widespread investigation of JAK inhibitors for the treatment of autoimmune diseases such as rheumatoid arthritis (RA).

[0003] Tofacitinib is an oral small molecule JAK inhibitor. As an ATP-competitive antagonist, its structure is highly similar to ATP but lacks a phosphate group. It specifically binds to the ATP-binding pocket of JAK kinases, blocking kinase activity and thereby inhibiting cytokine signaling. Through chemical structure optimization, tofacitinib has demonstrated strong selective inhibition of JAK1, JAK2, and JAK3, while exhibiting weak inhibition of other non-targeted kinases, demonstrating excellent targeting and safety.

[0004] Currently, tofacitinib is approved for the treatment of patients with moderate to severe active rheumatoid arthritis who have responded poorly to or are intolerant to methotrexate. Its efficacy is not only reflected in symptom relief but also in slowing the progression of joint structural damage, comparable to biologics such as adalimumab. Unlike biologics, which require injection, tofacitinib, as a small molecule, can be administered orally, significantly improving patient convenience and compliance.

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

[0006] Therefore, how to further improve the oral bioavailability of tofacitinib while simplifying the process remains one of the key issues in the current optimization of sustained-release formulations. Summary of the Invention

[0007] In response to the shortcomings of the prior art, the present invention proposes tofacitinib citrate sustained-release tablets, their preparation method, and applications. Through the innovative design of the sustained-release coating layer, the present invention not only achieves delayed controlled release, but also further improves the oral bioavailability of the drug, demonstrating outstanding technological advancement and practical application value.

[0008] The present invention provides a tofacitinib citrate sustained-release tablet, comprising a skeleton core and a coating film, wherein the skeleton core comprises the following components in parts by weight: 18 portions of tofacitinib citrate; 10~60 parts of skeleton material; 1-10 parts of adhesive; 10~90 parts of filler; 1~3 parts of lubricant; The coating film comprises the following components in parts by weight: 20-30 parts of hypromellose; 1~5 parts of plasticizer; 1-5 parts of solid-bound peptide; 1-5 parts of L-lactide; Wherein, the amino acid sequence of the solid binding peptide is shown in any one of SEQ ID NOs. 1 to 3.

[0009] In some embodiments, the mass ratio of the solid-binding peptide and L-lactide is (1-3):1; by controlling the compounding ratio of the solid-binding peptide and L-lactide within a preferred range, the present invention can maximize the drug absorption efficiency and balance the matching of the release rate and the absorption window on the basis of ensuring the stability of the controlled-release behavior, thereby achieving an ideal drug release effect of delayed onset, efficient absorption and high bioavailability.

[0010] In some embodiments, the mass ratio of the hydropropyl methylcellulose, the solid binding peptide and the L-lactide is (20-40): (1-3): 1.

[0011] In some embodiments, the matrix 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.

[0012] In some embodiments, the binder is selected from one or more of hydroxypropyl methylcellulose, povidone K30, povidone K90, copovidone, hydroxypropyl cellulose and ethyl cellulose.

[0013] In some embodiments, the filler is selected from one or more of lactose, corn starch, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, and sorbitol.

[0014] 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.

[0015] The present invention also provides a method for preparing the tofacitinib citrate sustained-release tablets, comprising the following steps: S1: Weigh all components of the matrix tablet except the binder and lubricant by weight, sieve them, mix them in a granulation pot, and then add the binder to granulate; S2: After granulation, the granules are dried in a fluidized bed, the dried granules are sized, and then a lubricant is added to mix and the tablets are pressed; S3: Weigh the components of the coating film by weight, prepare the coating solution, coat the plain tablets, and age them in an oven after coating.

[0016] In some embodiments, in step S3, the coating solution is prepared as follows: adding hydroxypropyl methylcellulose to a solvent, adding a plasticizer while continuously stirring, and adding a solid binding peptide and L-lactide while continuing to stir to obtain a coating solution.

[0017] In some embodiments, the solvent is one or more of water, ethanol, isopropanol and acetone; and the mass percentage of the solvent is 80-90%.

[0018] The present invention significantly improves the bioavailability and controlled-release performance of tofacitinib by introducing a synergistic design of a solid-binding peptide and L-lactide into the sustained-release tablet coating. The present invention optimizes and screens the amino acid sequence of the solid-binding peptide, which has a high affinity for the intestinal mucosa and can actively adsorb to the surface of intestinal epithelial cells during drug release, thereby prolonging the retention time of the preparation at the absorption site, increasing the frequency of contact between the drug and epithelial cells, and promoting transmembrane transport and passive absorption of the drug.

[0019] L-lactide is a biodegradable hydrophilic polymer. When used as a controlled-release carrier, it can form a microporous structure through hydrolysis, allowing tofacitinib to be released at a relatively steady rate, thereby increasing the effective exposure per unit dose and reducing the incidence of side effects after administration.

[0020] In summary, compared with the prior art, the present invention achieves the following technical effects: 1. The present invention achieves no initial release or slow release of tofacitinib after oral administration by providing a skeleton tablet core and a delayed-release coating film with a specific formula, effectively simulating the release curve of the original osmotic pump preparation and improving the fluctuation of blood drug concentration; the introduction of solid binding peptide and L-lactide into the coating film significantly promotes the absorption of the drug in the intestine, thereby greatly improving the relative bioavailability of tofacitinib citrate, and the AUC value is significantly better than that of the original preparation; due to the improvement of drug bioavailability, the dosage can be reduced while achieving the same therapeutic effect, which can reduce the incidence of clinical adverse reactions in clinical practice.

[0021] 2. The present invention does not rely on a complex osmotic pump system and can achieve controlled release and synergy enhancement only through reasonable coating design. It is suitable for industrial production, reduces production costs, and improves the consistency and controllability of the preparation.

[0022] 3. The early release behavior of the preparation of the present invention is smoother, the fluctuation of blood drug concentration is small, and the risk of peak concentration-related adverse reactions is reduced. At the same time, the minimum effective concentration required for therapeutic effect is maintained, and the therapeutic window is optimized. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following briefly introduces the drawings required for use in the embodiments. It should be understood that the following drawings only illustrate certain embodiments of the present invention and therefore should not be regarded as limiting the scope. For ordinary technicians in this field, other relevant drawings can be obtained based on these drawings without paying any creative work.

[0024] Figure 1 It is a dissolution test result curve of the present invention. DETAILED DESCRIPTION

[0025] To help those skilled in the art better understand the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work should fall within the scope of protection of the present invention.

[0026] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. The materials and reagents used are all commercially available unless otherwise specified.

[0027] L-lactide (L-serine ester) is an amino acid derivative containing an ester group, which has strong hydrophilicity and polarity.

[0028] The present invention uses molecular modeling and docking analysis tools to design peptide sequences that bind to L-lactide. The peptides are designed by analyzing the properties of amino acids (positively charged lysine, arginine, or hydrophobic amino acids such as phenylalanine and tryptophan). Molecular docking is then performed to predict the binding pattern and affinity between the peptide and L-lactide. Solid-state binding peptides with amino acid sequences such as those shown in SEQ ID NOs. 1 to 3 are then artificially synthesized.

[0029] The raw materials of the embodiments and comparative examples are as follows: Tofacitinib citrate: brand TFBB-707-221107, Nanchang Changyou Pharmaceutical Technology Co., Ltd. Frame material A: ethyl cellulose, brand 10 cp, manufacturer DOW; Framework material B: Carbomer, brand 971P NF, manufacturer Lubrizol; Binder A: Hydroxypropyl cellulose, brand LF, manufactured by Ashland; Adhesive B: povidone, brand K29 / 32, manufactured by Ashland; Filler: microcrystalline cellulose, brand 101, manufacturer JRS; Lubricant: stearic acid, the same substance was used in parallel experiments; Hydroxypropyl methylcellulose: brand E50LV, manufacturer DOW; Plasticizer: polyethylene glycol, manufacturer DOW; L-lactide: manufacturer Xingyan; Solid-bound peptide A: the sequence is shown in SEQ ID NO.1; Solid-bound peptide B: the sequence is shown in SEQ ID NO. 2; Solid-bound peptide C: the sequence is shown in SEQ ID NO.3.

[0030] The preparation methods of the tofacitinib citrate sustained-release tablets of this embodiment and the comparative example are as follows: Tofacitinib citrate, filler, and matrix material were sieved through a 30-mesh sieve, mixed in a granulator, and then granulated with the binder solution. After granulation, the granules were dried in a fluidized bed at 60°C inlet air temperature until the loss on drying was less than 3%. The dried granules were sized using a 1.5 mm sieve. A glidant and lubricant were then added and mixed for 5 minutes before pressing into plain tablets.

[0031] Tablet pressing: Use a high-speed rotary tablet press equipped with a φ9mm round shallow concave punch die to compress the final mixed material into tablets with a main pressing pressure range of 2-10KN and a filling depth of 5~10mm to obtain a tablet core containing the drug.

[0032] The coating film material was added to 70% ethanol aqueous solution to prepare the coating solution. The negative pressure in the pot was set to -30Pa, the pot speed was set to 10rpm, and the air inlet volume was set to 150m 3 / min, continuously ventilating hot air to the pan to maintain a tablet bed temperature of 40°C during coating. The coating time was 4-6 hours, with a coating solution solids content of 8.42%. Plain tablets were coated. The nozzle was maintained at a distance of 20 cm from the tablet surface, with a spray rate of 50 g / min, a spray gun atomization pressure of 0.25 MPa, and a spray gun fan pressure of 0.25 MPa. After sustained-release coating, the pan was subjected to continuous high-temperature aging at 65°C for 8 hours.

[0033] Table 1 Technical solutions of the embodiments (unit: parts by weight)

[0034] Table 2 Technical solutions of comparative examples (unit: parts by weight)

[0035] Performance testing: 1. Bioequivalence comparison experiment An in vivo bioequivalence comparison experiment was conducted using samples of tofacitinib sustained-release tablets prepared in Examples 1 and 2, pure matrix samples, and osmotic pump tablets produced using the original drug (batch numbers FK3384 and 8155781). The steps are as follows: SPF Wistar rats, half male and half female, weighing 180-220 g, were randomly divided into 17 groups, with 3-4 rats per group. Both groups received a 5 mg / kg dose via single oral gavage. Approximately 0.4 mL of blood was collected by retroorbital bleeding at 0 (immediately), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, and 36 hours after dosing. Blood samples were anticoagulated with EDTA and centrifuged at 3000 rpm for 10 minutes at 4°C. Plasma was separated and stored at -80°C until further use. Plasma tofacitinib concentrations were determined by LC-MS / MS, and pharmacokinetic parameters were calculated using a non-compartmental model.

[0036] The results are shown in Table 3: max is the peak time, C max is the maximum plasma drug concentration, AUC last is the area under the drug-time curve from drug administration to the last measurement point, AUC inf is the area under the drug-time curve from drug administration to infinite time, and AUC EX is the relative bioavailability.

[0037] Table 3 In vivo bioequivalence comparison experiment

[0038] As can be seen from the results in Table 1, the sustained-release tablets of the present invention with reasonable addition of solid-binding peptide and L-lactide show the advantages of delayed release onset, steady increase in blood drug concentration, and significantly improved bioavailability in vivo. The maximum blood drug concentration (Cmax) increased by nearly 1 times, and the area under the curve (AUC) of blood drug also increased by nearly 30%. Compared with the skeleton + coating tablets, the self-developed pure skeleton tablets have a lower maximum blood drug concentration (Cmax) of drug absorption, and the area under the curve (AUC) of blood drug is even lower. This shows that the addition of the coating film of the present invention can promote the absorption of the tofacitinib drug. In Comparative Example 1, no solid-binding peptide was added, in Comparative Example 2, no L-lactide was added, in Comparative Example 3, too much solid-binding peptide was added, in Comparative Example 4, too much L-lactide was added, and in Comparative Example 5, no solid-binding peptide and L-lactide were added. The drug sustained-release effect was poor, and the Cmax in the body was less than 20%. max and AUC were significantly lower than those in the examples.

[0039] 2. The following tests were conducted to determine the in vitro dissolution of tofacitinib citrate sustained-release tablets: According to the dissolution test method (General Rules of Part Four of the 2020 edition of the Chinese Pharmacopoeia), the paddle method (with a sinker) was used at a temperature of 37°C and a speed of 50 rpm, using 900 ml of pH 6.8 phosphate buffer as the medium. The drug release behavior was tested and compared with that of the commercially available reference preparation (8155781), as shown in Table 4: Table 4 Dissolution test results (unit: %)

[0040] As shown in the results of Table 4, the cumulative release rate of the self-made tofacitinib citrate sustained-release tablets of the present application at each time point maintains good consistency with the reference preparation, and the release curve similarity factor f2 is all more than 50, which meets the in vitro similarity evaluation standard. Release is more stable in the later release stage, showing that its sustained-release performance is excellent, and has the in vitro controlled-release characteristics comparable to the reference preparation, supporting its development basis as high-quality generic drugs or improved new drugs. In contrast, the drug release rate of the comparative example in 1~2h is relatively slow, resulting in limited early drug release, and overall drug release efficiency is relatively low.

[0041] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A tofacitinib citrate sustained-release tablet, characterized in that: The tablet comprises a skeleton core and a coating film, wherein the skeleton core comprises the following components in parts by weight: 18 portions of tofacitinib citrate; 10~60 parts of skeleton material; 1-10 parts of adhesive; 10~90 parts of filler; 1~3 parts of lubricant; The coating film comprises the following components in parts by weight: 20-30 parts of hypromellose; 1~5 parts of plasticizer; 1-5 parts of solid-bound peptide; 1-5 parts of L-lactide; Wherein, the amino acid sequence of the solid binding peptide is shown in any one of SEQ ID NOs. 1 to 3.

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

1.

3. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that The mass ratio of the hydroxypropyl methylcellulose, the solid binding peptide and the L-lactide is (20-40): (1-3):

1.

4. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that 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.

5. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that The binder is selected from one or more of hydroxypropyl methylcellulose, povidone K30, povidone K90, copovidone, hydroxypropyl cellulose and ethyl cellulose.

6. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that The filler is selected from one or more of lactose, corn starch, pregelatinized starch, microcrystalline cellulose, calcium hydrogen phosphate, mannitol and sorbitol.

7. The tofacitinib citrate sustained-release tablet according to claim 1, characterized in that 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.

8. The method for preparing the tofacitinib citrate sustained-release tablets according to claim 1, wherein: The steps include: S1: Weigh all components of the matrix tablet except the binder and lubricant by weight, sieve them, mix them in a granulation pot, and then add the binder to granulate; S2: After granulation, the granules are dried in a fluidized bed, the dried granules are sized, and then a lubricant is added to mix and the tablets are pressed; S3: Weigh the components of the coating film by weight, prepare the coating solution, coat the plain tablets, and age them in an oven after coating.

9. The preparation method according to claim 8, characterized in that In step S3, the steps of preparing the coating solution are as follows: adding hydroxypropyl methylcellulose to the solvent, adding the plasticizer while continuing to stir, and adding the solid binding peptide and L-lactide while continuing to stir to obtain the coating solution.

10. The preparation method according to claim 9, 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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