A tofacitinib citrate sustained release tablet

Abstract

The present application provides a kind of tofacitinib citrate sustained-release preparation, which is composed of tablet core, sustained-release layer coating and color layer coating, and the sustained-release layer coating has drug release small holes. By adjusting the composition of osmotic pressure forming agent and its dosage ratio with sustained-release agent, further optimizing the composition and coating weight of sustained-release layer coating, not only the defect of slow dissolution rate after long-term storage when using sorbitol as osmotic pressure forming agent alone is avoided, but also the initial release rate of tofacitinib citrate sustained-release tablet is improved, and slow and sustained release can be maintained for 6 hours, the drug release is more complete, the blood drug concentration is kept at a uniform and stable level for a long time, the fluctuation of blood drug concentration during the interval of administration is reduced, the bioavailability is further improved, the adverse reactions are reduced, and the clinical efficacy and safety are protected.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a tofacitinib citrate sustained-release tablet and its preparation method. Background Technology

[0002] Tofacitinib citrate is a prescription oral Janus kinase (JAK) inhibitor originally developed by Pfizer. It selectively inhibits JAK kinase, blocking the JAK / STAT pathway, thereby inhibiting cell signal transduction and related gene expression and activation. It is used to treat various immune diseases such as rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Currently marketed products are Pfizer's Xeljanz and Xeljanz XR. Xeljanz is an immediate-release tablet of tofacitinib citrate, requiring twice-daily dosing, which lacks convenience and has poor compliance. Xeljanz XR is the first once-daily oral JAK inhibitor used to treat rheumatoid arthritis. Using this sustained-release formulation reduces the dosing frequency to once daily (11 mg, QD) while maintaining the same efficacy as Xeljanz (5 mg BID), effectively improving patient convenience and compliance. However, the inventors of this patent application discovered that the marketed Xeljanz XR formulation has a dissolution rate of only 2% within 1 hour (in a dissolution medium at pH 6.8 and a rotation speed of 50 rpm), exhibiting a significant time lag in initial release. This results in a slow onset of action in first-time users and affects the additive effect of blood drug concentrations from multiple doses, hindering the maintenance of a uniform and stable blood drug concentration. Therefore, it is necessary to further improve the initial release rate of the tofacitinib citrate extended-release formulation to reduce the time lag effect.

[0003] WO2014147526A1 (Chinese counterpart CN105101952A) is a patent filed by the original research company for a sustained-release formulation, providing a tofacitinib citrate osmotic pump-type sustained-release tablet. This osmotic pump-type sustained-release tablet, in a dissolution medium at pH 6.8 and a rotation speed of 50 rpm, dissolves no more than 30% within 1 hour, no less than 35% and no more than 75% within 2.5 hours, and no less than 75% within 5 hours. However, the inventors of this patent discovered during the research and development process that the patent's definition of the in vitro dissolution behavior of the formulation is too broad, making it difficult to precisely control its bioavailability in vivo.

[0004] WO2014147526A1 (Chinese counterpart CN105101952A) also suggests that for sustained-release formulations, the bioavailability of tofacitinib citrate decreases with increasing release duration, making shorter sustained-release formulations preferred. Studies show that the Tmax of a single dose of tofacitinib citrate sustained-release formulation in humans is approximately 3-4 hours. 1 / 2The duration is approximately 6-7 hours. The inventors of this application have discovered that a slow, sustained release after 4 hours, and especially after 6 hours, is crucial for maintaining blood drug levels during dosing intervals. Shorter sustained release times can lead to greater fluctuations in blood drug concentrations with multiple doses.

[0005] Furthermore, both the marketed formulation and WO2014147526A1 use sorbitol (also known as sorbitol) as an osmogen (i.e., an osmotic pressure forming agent) to prepare tofacitinib citrate osmotic pump sustained-release tablets. Sorbitol has a low melting point and high hygroscopicity, requiring special humidity control during preparation, posing a challenge to the industrial production process. Due to its high hygroscopicity, sorbitol easily agglomerates with other materials during the premixing step, reducing material flowability and decreasing the uniformity of content and dissolution in the formulation. Moreover, the resulting sustained-release formulation is susceptible to external environmental influences during storage, leading to changes in the content of related substances, active ingredients, and dissolution rate. Therefore, there is an urgent need to develop a sustained-release formulation of tofacitinib citrate with better dissolution uniformity and stability, making it more suitable for industrial production. Summary of the Invention

[0006] Based on the aforementioned deficiencies in the prior art, the present invention aims to provide a sustained-release formulation of tofacitinib citrate, which improves the initial release rate, reduces time lag, and improves the stability of blood drug concentration and bioavailability while maintaining the overall release time essentially unchanged; and further improves dissolution uniformity and formulation stability, ensuring product quality.

[0007] This invention provides a tofacitinib citrate sustained-release formulation, comprising a tablet core, a sustained-release coating, and a color coating, wherein the sustained-release coating has drug-release pores; characterized in that the tablet core is made of the following components by weight percentage:

[0008] Tofacitinib citrate 7％-11％ Osmotic pressure forming agent 62％-70％ Sustained-release materials 14％-22％ Copolyvinylpyrrolidone 3％-9％ magnesium stearate 0.5％-1.8％

[0009] Preferably, the chip core is made of the following components by weight percentage:

[0010] Tofacitinib citrate 8％-10％ Osmotic pressure forming agent 64％-68％ Sustained-release materials 16％-20％ Copolyvinylpyrrolidone 4％-8％ magnesium stearate 1％-1.5％

[0011] More preferably, the core is made of the following components by weight percentage:

[0012] Tofacitinib citrate 8.885％ Osmotic pressure forming agent 66.115％ Sustained-release materials 18％ Copolyvinylpyrrolidone 6％ magnesium stearate 1％

[0013] In some embodiments, the osmotic pressure forming agent is a composition of sorbitol and sodium chloride, wherein the weight ratio of the two is sorbitol:sodium chloride = (1-10):1, preferably (3-7):1, more preferably (3-5):1 or (3-4):1, more preferably (3-3.5):1.

[0014] In some embodiments, the sustained-release material is hydroxyethyl cellulose, preferably one or a combination of hydroxyethyl cellulose 250L and hydroxyethyl cellulose 250G. When the sustained-release material is a combination of hydroxyethyl cellulose 250L and hydroxyethyl cellulose 250G, the weight ratio of the two is hydroxyethyl cellulose 250L: hydroxyethyl cellulose 250G = (1-7):1, preferably (1-5):1, more preferably (1.5-5):1, and most preferably (2-3):1.

[0015] In some embodiments, the chip core is made of the following components by weight percentage:

[0016] Tofacitinib citrate 7％-11％ Sorbitol 48.0％-60.0％ Sodium chloride 6％-19％ Hydroxyethylcellulose 9％-27％ Copolyvinylpyrrolidone 3％-9％ magnesium stearate 0.5％-1.8％

[0017] Preferably, the chip core is made of the following components by weight percentage:

[0018] Tofacitinib citrate 8-10％ Sorbitol 50％-58％ Sodium chloride 8％-17％ Hydroxyethylcellulose 250L 9-18％ 250g of hydroxyethyl cellulose 0-9％ Copolyvinylpyrrolidone 4％-8％ magnesium stearate 0.5％-1.5％

[0019] Preferably, the chip core is made of the following components by weight percentage:

[0020] Tofacitinib citrate 8-10％ Sorbitol 50％-58％ Sodium chloride 8％-17％ Hydroxyethylcellulose 250L 11％-15％ Hydroxyethylcellulose 250g 3％-7％ Copolyvinylpyrrolidone 4％-8％ magnesium stearate 1％-1.5％

[0021] More preferably, the core is made of the following components by weight percentage:

[0022] Tofacitinib citrate 8.885％ Sorbitol 50％ Sodium chloride 16.115％ Hydroxyethylcellulose 250L 13％ Hydroxyethylcellulose 250g 5％ Copolyvinylpyrrolidone 6％ magnesium stearate 1％

[0023] In some embodiments, the sorbitol is preferably sorbitol SI150; the copovidone is preferably copovidone VA64.

[0024] The sustained-release coating is made of cellulose acetate and hydroxypropyl cellulose. In some embodiments, the weight ratio of the two is cellulose acetate:hydroxypropyl cellulose = 5:5, and the weight gain of the sustained-release coating accounts for 9%-12% of the tablet core weight, preferably 10%-11%. In other embodiments, the weight ratio of the two is cellulose acetate:hydroxypropyl cellulose = 6:4, and the weight gain of the sustained-release coating accounts for 8%-9% of the tablet core weight. In some embodiments, the hydroxypropyl cellulose is preferably hydroxypropyl cellulose EF; the cellulose acetate is preferably cellulose acetate 398-10.

[0025] The color coating described in this invention is solely for cosmetic purposes and has minimal impact on drug dissolution and release. Color coating materials suitable for this invention include hydroxypropyl methylcellulose, hydroxypropyl cellulose, acrylic resin No. 4, styrene-vinylpyridine copolymer, polyvinylpyrrolidone, etc. Preferably, Opadry coating powder containing hydroxypropyl methylcellulose is used. For example, film coating premix 03K640007-CN. In some embodiments, the color coating accounts for 2.5% to 3.5% of the weight of the perforated tablet. Preferably, the weight gain of the color coating accounts for 3.0% to 3.5% of the weight of the perforated tablet.

[0026] The tofacitinib citrate sustained-release formulation of this invention has drug-release pores on its sustained-release coating. These pores can be formed after the sustained-release coating using mechanical or thermal tools, or by a light beam (e.g., laser), ion beam, or other high-energy source; laser drilling is preferred. Each formulation unit may contain one or more drug-release pores, preferably one. The pore size is 0.45 mm to 0.85 mm, preferably 0.55 mm to 0.80 mm, or 0.60 mm to 0.75 mm, more preferably 0.65 mm.

[0027] The present invention also provides a sustained-release formulation of tofacitinib citrate, wherein the sustained-release formulation, in a dissolution medium at pH 6.8 and a rotation speed of 50 rpm, dissolves 5%-10% in 1 hour, 10%-30% (preferably 15%-25%) in 1.5 hours, 45%-55% (preferably 45%-50%) in 2.5 hours, 70-80% in 4 hours, greater than 85%-95% (preferably 85%-90%) in 6 hours, and more than 90% (preferably more than 95%) in 8-10 hours.

[0028] The present invention also provides a method for preparing the above-mentioned tofacitinib citrate sustained-release formulation, characterized in that it includes the following steps: pretreatment of raw materials and excipients, granulation, tableting, sustained-release coating, perforation, and color coating.

[0029] In some embodiments, the preparation method includes the following steps:

[0030] (1) Pretreatment of raw and auxiliary materials: Weigh the following according to the prescription: ① tablet core components: tofacitinib citrate, sorbitol, sodium chloride, 250L hydroxyethyl cellulose, 250G hydroxyethyl cellulose, copovidone, magnesium stearate, ② sustained-release coating materials: cellulose acetate and hydroxypropyl cellulose, ③ color coating materials; pulverize and sieve them separately for later use.

[0031] (2) Granulation

[0032] ① Premix: Add sorbitol, tofacitinib citrate, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone, and sodium chloride to the granulator and mix evenly.

[0033] ② Granulation: Add anhydrous ethanol to the granulator, stir, granulate, wet granulate, and dry.

[0034] ③ Granulation and mixing: Add magnesium stearate and dry granulate using a granulator; mix the granulated material evenly.

[0035] (3) Tableting: Use a tablet press to press tablets to obtain tablet cores.

[0036] (4) Sustained-release coating

[0037] ①Preparation of sustained-release coating solution: Pour an appropriate amount of purified water and acetone into a mixing tank, add the prescribed amount of hydroxypropyl cellulose, stir well, then add the prescribed amount of cellulose acetate, stir well and set aside.

[0038] ② Preheating and edge grinding: Preheat the coating pan body, add the sheet cores, and grind the edges;

[0039] ③ Sustained-release coating: Spray the sustained-release coating solution prepared in step ①, coat, and dry to obtain sustained-release coated tablets.

[0040] (5) Drilling: Take the sustained-release coated tablet and use a laser to drill holes in the sustained-release coating to obtain a perforated tablet.

[0041] (6) Color layer coating

[0042] ①Preparation of color coating solution: Add the prescribed amount of color coating material to an appropriate amount of purified water, stir well, and set aside.

[0043] ② Base coat: Before coating, spray a small amount of color coating liquid onto the coating pan and let it dry.

[0044] ③ Color coating: Place the perforated sheet in the coating pan, preheat the pan, spray in the remaining color coating liquid, and dry.

[0045] In some embodiments, the sieving in step (1) refers to sieving through a 20-40 mesh sieve, preferably a 30 mesh sieve.

[0046] In some embodiments, the premixing step in step (2) is as follows: a portion of the prescribed amount of sorbitol and the prescribed amounts of tofacitinib citrate, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone, and sodium chloride are added to a granulator and mixed evenly; then the remaining sorbitol is added to the granulator and mixed evenly.

[0047] In some embodiments, the portion of sorbitol described in step (2) accounts for 30% to 70% of the total sorbitol dosage, preferably 40% to 60%, and more preferably 50%.

[0048] In some embodiments, the amount of anhydrous ethanol used in step (2) is 8%-12% of the total weight of the core components, preferably 9%-11%, and more preferably 10%.

[0049] In some embodiments, the sieve used in step (2) wet granulation has a mesh size of 10×10mm.

[0050] In some embodiments, the sieve aperture used in step (2) dry granulation is 0.8-1.2 mm, preferably 1.0 mm.

[0051] In some embodiments, the weight of the core in step (3) is 150-250 mg, preferably 200 mg; the thickness is 3.5-4.2 mm, preferably 3.6-4.0 mm; and the hardness is 60-130 N, preferably 65-120 N.

[0052] In some embodiments, the sustained-release coating solution prepared in step (4) has a solid content of 3%-8% (w / w), preferably 4%-6% (w / w), and more preferably 5% (w / w).

[0053] In some embodiments, when preparing the sustained-release coating solution in step (4), the weight ratio of purified water to acetone is 1:(7-11), preferably 1:(8-10), and more preferably 1:9.

[0054] In some embodiments, step (5) involves punching one or more drug release holes on each sustained-release coated tablet, preferably one hole. The diameter of the drug release hole is 0.45mm-0.85mm, preferably 0.55mm-0.80mm, or 0.60mm-0.75mm, more preferably 0.65mm.

[0055] In some embodiments, the solid content of the color coating liquid in step (6) is 8-16% (w / w), preferably 10%-14%, more preferably 12%.

[0056] In some embodiments, in step (6) color coating, the small amount of color coating liquid sprayed in step ② base coat accounts for 5% to 10% of the total amount of color coating liquid, preferably 7% to 9%, and more preferably 8%.

[0057] During the development of tofacitinib citrate extended-release tablets, the inventors discovered that the initial release lag of the marketed formulation was relatively long, with only 2% dissolution within 1 hour. This resulted in a prolonged onset of action after the first dose and was not conducive to maintaining a stable and uniform blood drug concentration during multiple dosings. The original formulation patent CN105101952A provided a scheme with a faster initial release rate (dissolution less than 30% within 1 hour) and argued that choosing a formulation with a shorter sustained-release time is beneficial for improving bioavailability and reducing immune damage caused by excessive inhibition of the JAK3 and JAK1 signaling pathways. However, excessively rapid early release of the extended-release formulation leads to a rapid increase in blood drug concentration and an excessively high Cmax, and can cause weaker release in the later stages, with a significant decrease in Cmin, resulting in increased fluctuations in blood drug levels. Therefore, further research on a sustained-release formulation of tofacitinib citrate is necessary. To address the aforementioned issues, the inventors of this patent explored different osmotic pressure forming agents and their combinations, screened the ratio of osmotic pressure forming agents to sustained-release agents, and further optimized the composition and weight gain of the sustained-release coating. This not only improved the initial release rate of tofacitinib citrate sustained-release tablets but also maintained a slow, delayed release after 6 hours, resulting in more complete drug release. This ensured that the blood drug concentration remained at a uniform and stable level over a long period, reduced fluctuations in blood drug concentration during dosing intervals, further improved bioavailability, reduced adverse reactions, and contributed to ensuring clinical efficacy and safety.

[0058] This invention uses sodium chloride to replace part of sorbitol as an osmotic pressure forming agent, which further improves the dissolution uniformity of the formulation and avoids the defects of slow dissolution rate and increase of related substances after long-term storage when using sorbitol alone as an osmotic pressure forming agent.

[0059] During the research and development process, the inventors discovered that directly applying a color coating to perforated tablets resulted in black spots on the tablet surface, affecting its appearance. Applying a partial color coating solution as a base coat, drying it, and then adding the tablets for color coating effectively avoids black spots on the product surface and improves the yield rate. Attached Figure Description

[0060] Figure 1 Dissolution profiles of the product of this invention and the reference formulation.

[0061] Figure 2 Mean plasma concentration-time curves of tofacitinib citrate after subjects took the test formulation and reference formulation orally on an empty stomach. Wherein, T represents the test formulation (the product of this invention), and R represents the reference formulation.

[0062] Figure 3 Dissolution curves of the product of this invention and the product of Comparative Example 1. Detailed Implementation

[0063] The technical solution of the present invention will be described in detail below through some embodiments, but the present invention is not limited to the following embodiments. Any methods and materials similar to or equivalent to those described can be applied to the method of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0064] Unless otherwise specified in the examples, standard conditions or manufacturer-recommended conditions shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art.

[0065] 1. Dissolution test

[0066] Unless otherwise specified, the dissolution curves described in this invention are determined according to the following method:

[0067] (1) Preparation of dissolution medium

[0068] Weigh 54.48g of potassium dihydrogen phosphate and 7.20g of sodium hydroxide into 8000ml of degassed water, dissolve and mix well, and adjust the pH to 6.8 with phosphoric acid or sodium hydroxide solution.

[0069] (2) Dissolution method

[0070] Dissolution apparatus: Second method (paddle method) + settling basket

[0071] Speed: 50 rpm

[0072] Temperature: 37.0℃±0.5℃

[0073] Dissolution medium: 900ml

[0074] Sample volume collected: 5ml

[0075] Sampling time: 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours.

[0076] (3) Determination by high performance liquid chromatography

[0077] ①The chromatographic conditions for high performance liquid chromatography are as follows:

[0078] Column: Agilent ZORBAX SB-C18, 4.6 mm × 150 mm, 5 μm

[0079] Column temperature: 30℃

[0080] Flow rate: 1.0 ml / min

[0081] Detection wavelength: 289nm

[0082] Injection volume: 20 μl

[0083] ② Preparation of the mobile phase

[0084] Buffer solution: Weigh 2.72g of potassium dihydrogen phosphate and 1.01g of sodium heptanesulfonate and dissolve them in 1000ml of water. Adjust the pH to 3.0 with phosphoric acid and mix well.

[0085] Mobile phase: Acetonitrile-buffered buffer (24:76), mixed thoroughly, filtered through a 0.45 μm filter membrane, and degassed.

[0086] ③ Reference solution

[0087] Accurately weigh approximately 20 mg of tofacitinib citrate reference standard into a 100 mL volumetric flask, dissolve and dilute to the mark with dissolution medium, and mix well. Accurately measure 5 mL into a 50 mL volumetric flask, dilute to the mark with dissolution medium, and mix well. The concentration of the tofacitinib citrate reference standard solution is 0.02 mg / mL.

[0088] ④ Test sample

[0089] Following the dissolution method described in (2) above, place 6 tofacitinib citrate sustained-release tablets in a settling basket and then into 6 dissolution cups. Start timing immediately from the moment the test sample comes into contact with the dissolution medium. The automatic dissolution apparatus has a sampling needle filter tip with a pore size of 10 μm and a sampling volume of 5 ml, which serves as the test solution.

[0090] ⑤ Measurement

[0091] Inject the same volume (20 μl) of blank solvent (dissolution medium), reference solution and test solution respectively, record the chromatograms, and calculate the dissolution amount of each tablet.

[0092] The calculation formula is as follows:

[0093] Correction factor

[0094]

[0095] In the formula: The average peak area of ​​tofacitinib citrate measured in the reference solution;

[0096] W 对 : Sample weight of the reference standard, in grams;

[0097] Reference standard %: The percentage content of the reference standard;

[0098] 312.4: Molecular weight of tofacitinib;

[0099] 504.5: Molecular weight of tofacitinib citrate.

[0100] Dissolution amount

[0101] Dissolution amount at the first sampling point t＝1 % = A 样1 ×V×K×100%

[0102] Dissolution at the second sampling point t＝2 % = {A 样2 ×[VV w [×(2-1)]+A 样1 ×V w}×K×100%

[0103] Dissolution at the 3rd sampling point t＝3 % = {A 样3 ×[VV w ×(3-1)]+(A 样2 +A 样1 )×V W}×K×100%

[0104] Dissolution at the nth sampling point t＝n % = {A 样n ×[VV w ×(n-1)]+(A 样n-1 +A 样n-2 +……+A 样2 +A 样1 )×V W}×K×100%

[0105] In the formula: A 样 The peak area of ​​tofacitinib citrate was measured in the sample solution;

[0106] V: Volume of dissolution medium, 900 ml;

[0107] V w Sampling volume: 5 ml.

[0108] n: Number of samples.

[0109] 2. Related Substance Detection Methods

[0110] The determination was performed using high performance liquid chromatography.

[0111] (1) Chromatographic conditions for high performance liquid chromatography

[0112] Column: Agilent ZORBAX Eclipse XDB C18, 4.6*150mm, 3.5μm

[0113] Column temperature: 30℃

[0114] Flow rate: 1.0 ml / min

[0115] Detection wavelength: 280nm

[0116] Injection volume: 10 μl

[0117] Sample chamber temperature: 10℃

[0118] (2) Mobile phase

[0119] Mobile phase A: Weigh 3.0g of ammonium formate and dissolve it in 1000ml of purified water. Adjust the pH to 4.3 with formic acid, filter through a 0.45μm filter membrane, and degas.

[0120] Mobile phase B: Acetonitrile, filtered through a 0.45 μm filter membrane and degassed.

[0121] The gradient elution conditions are as follows:

[0122] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 5 95 5 40 40 60 40.1 10 90 47 10 90 47.1 95 5 55 95 5

[0123] 3. Content detection methods

[0124] The determination was performed using high performance liquid chromatography (HPLC), and the specific HPLC detection conditions were the same as those for the dissolution test.

[0125] 4. Accelerated stability test

[0126] The packaged drug was stored at 40℃±2℃ and 75%±5%RH for 6 months to evaluate its stability.

[0127] The medication uses double-layer packaging. First, it is inner-packaged with pharmaceutical-grade aluminum foil and solid PVC pharmaceutical-grade rigid sheet, then outer-packaged with a polyester / aluminum / polyethylene pharmaceutical packaging composite film in a pillow-like shape. A solid pharmaceutical paper bag containing silica gel desiccant is placed inside the outer packaging bag.

[0128] 5. Detection method for residual solvent acetone

[0129] The determination was performed using gas chromatography.

[0130] (1) The chromatographic conditions for gas chromatography are as follows:

[0131] GC column: Agilent DB-624 (30m × 0.53mm, film thickness 3.0μm)

[0132] Carrier gas: high-purity nitrogen; Flow rate: 2.0 ml / min

[0133] Inlet temperature: 150℃; Split ratio: 5:1

[0134] Temperature program: Initial temperature 45℃, hold for 10 minutes, then increase to 220℃ at a rate of 45℃ / minute, and hold at 220℃ for 5 minutes.

[0135] Detector: FID; Detector temperature: 240℃

[0136] Hydrogen flow rate: 30 ml / min; Air flow rate: 300 ml / min

[0137] (2) Headspace conditions:

[0138] Operating mode: Constant; Injection mode: Time-based

[0139] Equilibrium temperature: 90℃; Injection needle temperature: 120℃; Pipette temperature: 150℃

[0140] Equilibrium time: 30 minutes; Cycling time: 30 minutes; Headspace pressure: 18 psi

[0141] Injection time: 0.05 minutes; needle withdrawal time: 0.1 minutes; pressurization time: 1 minute.

[0142] Example 1: Investigation of the dosage of osmotic pressure forming agent (sorbitol SI150, sodium chloride)

[0143] The dosage of osmotic pressure forming agents (sorbitol SI150 and sodium chloride) was screened, and the specific formulation is as follows:

[0144]

[0145] Note: *17.77g tofacitinib citrate is equivalent to 11g tofacitinib.

[0146] **Perforated tablets are obtained by laser perforation of sustained-release coated tablets. The perforation diameter is 0.65mm, which has a minimal impact on the tablet weight. The weight of perforated tablets is approximately equal to that of sustained-release coated tablets.

[0147] The preparation method is as follows:

[0148] 1. Pretreatment of raw and auxiliary materials

[0149] Weigh out the following components in the order specified in the prescription: ① tablet core components: tofacitinib citrate, sorbitol SI150, sodium chloride, hydroxyethyl cellulose 250L, hydroxyethyl cellulose 250G, copovidone VA64, magnesium stearate; ② sustained-release coating materials: cellulose acetate 398-10, hydroxypropyl cellulose EF; ③ film coating premix 03K640007-CN; pulverize and pass through a 30-mesh sieve for later use.

[0150] 2. Granulation

[0151] (1) Premixing: Add 50% of the prescribed amount of sorbitol SI150, as well as the prescribed amount of tofacitinib citrate, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone VA64, and sodium chloride to the granulator and mix evenly; then add the remaining sorbitol SI150 to the granulator and mix evenly.

[0152] (2) Granulation: Spray anhydrous ethanol, granulate, wet granulate, screen with a mesh size of 10×10mm, and dry. Control the material temperature ≤45.0℃ during the drying process. The amount of anhydrous ethanol used is 10% (w / w) of the total amount of the tablet core components.

[0153] (3) Granulation and mixing: Dry granulation is performed using a granulator with a screen aperture of 1.0 mm. Magnesium stearate is added and passed through the granulator along with the material. The granulated material is then mixed evenly.

[0154] 3. Tableting: The tablets are compressed using a tablet press to obtain tablet cores. The theoretical tablet weight of the core is 200mg, the tablet thickness is 3.60~4.00mm, and the hardness is 68~118N.

[0155] 4. Sustained-release coating

[0156] (1) Preparation of sustained-release coating solution: Pour purified water and acetone into a mixing tank (the weight ratio of purified water to acetone is 1:9), slowly add hydroxypropyl cellulose EF, stir well, and then slowly add cellulose acetate 398-10 and stir well for later use. The solid content of the sustained-release coating solution is 5% (w / w).

[0157] (2) Edge grinding: Place the film core in the coating pan and control the grinding time to 3-10 minutes, depending on the condition of the film surface.

[0158] (3) Sustained-release coating: Spray the sustained-release coating solution prepared in step (1) into the solution, coat, and dry to obtain sustained-release coated tablets.

[0159] 5. Perforation: Take a sustained-release coated tablet and use a laser to perforate the sustained-release coating. The perforation diameter is 0.65mm, resulting in a perforated tablet.

[0160] 6. Color-coated layers

[0161] (1) Preparation of color coating solution: Pour purified water into a mixing tank, add film coating premix 03K640007-CN, and stir well. The solid content of the resulting color coating solution is 12% (w / w).

[0162] (2) Base coat: Spray the coating pan with liquid before coating. Spray in 8% of the total amount of color coating liquid and let it dry.

[0163] (3) Color coating: Place the perforated sheet in a coating pan, spray in the remaining color coating liquid, coat, and dry to obtain the final product.

[0164] The specific dosages of sorbitol and sodium chloride, and the dissolution curves of the resulting tablets are shown in Table 1-1.

[0165] Table 1-1 Effect of Osmotic Pressure Forming Agent on Dissolution Curve

[0166]

[0167] The results showed that when the proportion of sorbitol SI150 (the osmotic pressure forming agent) was 50.0%-58.0%, and the proportion of sodium chloride was 8.115%-16.115% (i.e., formulations 1-1, 1-2, and 1-3), the dissolution curves showed no significant differences (see Table 1-1). Furthermore, after 6 months of accelerated storage, the dissolution curves of formulations 1-1 to 1-3 did not change significantly (see Table 1-2).

[0168] Formulas 1-4, using sorbitol alone as an osmoregulator, exhibited a significantly faster initial release rate than the sorbitol + sodium chloride regimen, with a dissolution rate as high as 25% at 1.5 hours, approximately 1.67 times the dissolution rate of the other three groups at the same time point. However, from 6 to 10 hours, only 4% of the drug was released, significantly lower than formulas 1-1 to 1-3 (approximately 10%), and the total dissolution rate at 10 hours was also lower than that of formulas 1-1 to 1-3. This will lead to a rapid rise in blood drug concentration in the early stages after medication administration; however, due to the weak release in the later stages, it is difficult to maintain a stable and uniform blood drug concentration. Furthermore, after accelerated storage for 6 months, the initial dissolution rate of formulas 1-4 significantly slowed down, with the dissolution rate at 1 hour decreasing from 9% to 3%, only one-third of the original data; the dissolution rate at 1.5 hours also decreased from 25% to 16%, less than two-thirds of the original data. This suggests that using sorbitol alone as an osmoregulator results in a slower initial dissolution rate and poor dissolution stability after long-term storage.

[0169] Table 1-2 Effect of accelerated storage for 6 months on the dissolution curve of the formulation.

[0170]

[0171] Note: NA was not detected. The dissolution curves of formulations 1-2 and 1-3 showed no significant change after 6 months of accelerated storage; therefore, specific data are not presented to save space.

[0172] Example 2: Investigation of the dosage ratio of sustained-release materials (250L of hydroxyethyl cellulose and 250G of hydroxyethyl cellulose)

[0173] Referring to Formulation 1-1 of Example 1 and its preparation method, only the ratio of sustained-release materials 250L and 250G of hydroxyethyl cellulose was adjusted. The specific dosage values ​​and the results of the dissolution curve are shown in Table 2.

[0174] The results showed that as the amount of hydroxyethyl cellulose 250L increased and the amount of hydroxyethyl cellulose 250G decreased, the dissolution rate tended to accelerate.

[0175] Table 2. Effect of the composition of the sustained-release material on the dissolution curve.

[0176]

[0177] Example 3: Investigation of the ratio of osmotic pressure forming agent to sustained-release material

[0178] Referring to Formulation 1-1 and the preparation method in Example 1, the ratio of osmotic pressure forming agent (sorbitol, sodium chloride) to sustained-release material (hydroxyethyl cellulose 250L, hydroxyethyl cellulose 250G) was adjusted. The specific dosage values ​​and the measured dissolution curve results are shown in Table 3.

[0179] The results showed that, compared with formulation 3-1, formulation 3-2 increased the amount of osmotic pressure forming agent and reduced the amount of sustained-release material. The resulting formulation dissolved faster and was almost completely released within 6 hours (94% dissolution). However, it was weak in the later stages of release, with only 4% released between 6 and 10 hours, which was not conducive to maintaining a uniform and stable blood drug concentration.

[0180] Compared to formulation 3-1, formulation 3-3 reduces the amount of osmotic pressure forming agent and increases the amount of sustained-release material, resulting in a slower initial release rate, with only 4% dissolution in 1 hour and a significant initial release lag.

[0181] Table 3. Effect of the ratio of osmotic pressure forming agent to sustained-release material on the dissolution curve.

[0182]

[0183] Note: The relative ratio of sorbitol, the osmotic pressure forming agent, to sodium chloride is the same as in Formulation 1-1 of Example 1, and the relative ratio of 250L of hydroxyethyl cellulose and 250G of hydroxyethyl cellulose, the sustained-release material, is the same as in Formulation 1-1 of Example 1.

[0184] Example 4: Investigation of Adhesive (Copovidone VA64) Dosage

[0185] Referring to Formulation 1-1 of Example 1 and its preparation method, the amount of binder (copovidone VA64) was investigated, and the weight of the tablet core was adjusted accordingly. Specific dosage values ​​and the measured dissolution curve results are shown in Table 4.

[0186] The results showed that when the proportion of the binder copolyvinyl ether VA64 was in the range of 4.0%-8.0%, the measured dissolution curves showed no significant difference.

[0187] Table 4 Effect of binder dosage on dissolution curve

[0188]

[0189] Note: *Calculated based on a theoretical core weight of 200mg. Only the dosage of copovidone VA64 was adjusted; the weight (mg) of the remaining components in each sustained-release tablet remained the same as the theoretical core weight of 200mg.

[0190] Example 5: Investigation of Lubricant (Magnesium Stearate) Dosage

[0191] Referring to Formulation 1-1 of Example 1 and its preparation method, the amount of lubricant (magnesium stearate) was investigated, and the tablet core weight was adjusted accordingly. The specific dosage values ​​and the results of the dissolution curve measurements are shown in Table 5.

[0192] It is generally believed that the dissolution rate of osmotic pump-type sustained-release tablets mainly depends on the osmotic pressure forming agent, the sustained-release material, the sustained-release coating, and the pore size of the drug release pores. However, the results in Table 5 show that the dissolution rate is faster when the amount of magnesium stearate is 0.5%, compared with magnesium stearate content of 1% and 1.5%.

[0193] Table 5 Effect of Lubricant Dosage on Dissolution Curve

[0194]

[0195]

[0196] Note: *Calculated based on a theoretical core weight of 200mg. Only the amount of magnesium stearate was adjusted; the weight (mg) of the remaining components in each sustained-release tablet remained the same as the theoretical core weight of 200mg.

[0197] Example 6: Investigation of sustained-release coating (cellulose acetate, hydroxypropyl cellulose)

[0198] Referring to Formulation 1-1 of Example 1 and its preparation method, only the amount of cellulose acetate and hydroxypropyl cellulose in the sustained-release coating was adjusted. The specific amounts and the results of the dissolution curves are shown in the table below.

[0199] Table 6-1 Composition of sustained-release coating and its effect on dissolution curve (1)

[0200]

[0201] Table 6-2 Composition of sustained-release coating and its effect on dissolution curve (2)

[0202]

[0203] Table 6-3 Composition of sustained-release coating and its effect on dissolution curve (3)

[0204]

[0205]

[0206] During the research and development process, the inventors discovered that when the sustained-release formulation is dissolved in a pH 6.8 dissolution medium at a rotation speed of 50 rpm, the initial release rate can be improved and the time lag reduced. Furthermore, the long sustained-release duration is beneficial for maintaining a stable and uniform blood drug concentration and reducing fluctuations in blood drug concentration.

[0207] The results in Tables 6-1, 6-2, and 6-3 show that the lower the amount of cellulose acetate, the higher the amount of hydroxypropyl cellulose, and the less the weight gain of the sustained-release coating, the faster the dissolution rate of the resulting sustained-release tablets.

[0208] (1) When the ratio of cellulose acetate to hydroxypropyl cellulose is 5:5, the weight gain of the sustained-release coating is 7.7% or 8.2%, more than 10% dissolves in 1 hour, more than 80% dissolves in 4 hours, and more than 95% dissolves in 6 hours. The release rate is too fast, which is not conducive to maintaining a stable and uniform blood drug concentration.

[0209] When the ratio of cellulose acetate to hydroxypropyl cellulose is 4:6, the weight gain of the sustained-release coating is 8.9%-12.1%, and the release effect is too fast and not ideal.

[0210] (2) When the ratio of cellulose acetate to hydroxypropyl cellulose is 6:4, the weight gain of the sustained-release coating is 9.8%-12%, the dissolution rate is less than 5% in 1 hour, the initial dissolution rate is too slow, and the initial time lag is obvious.

[0211] (3) When the ratio of cellulose acetate to hydroxypropyl cellulose is 6:4 and the weight gain of the sustained-release coating is 8.3%, or when the ratio of cellulose acetate to hydroxypropyl cellulose is 5:5 and the weight gain of the sustained-release coating is 9%-12%, the dissolution behavior of the resulting formulation meets the requirements.

[0212] In addition to the ratio of cellulose acetate to hydroxypropyl cellulose and the weight gain of the sustained-release coating, the inventors also investigated the effect of the solid content of the coating solution on the efficacy of the formulation (see Table 6-4). They found that under the same formulation conditions, (1) when the solid content of the sustained-release coating solution is low (e.g., 3%), the drying time after coating is long, and the formulation is exposed to heating conditions for a long time, resulting in a significant increase in related substances and a higher residual amount of acetone solvent in the resulting formulation. (2) If the solid content of the coating solution is too high (e.g., 8%), it will cause uneven coating, an uneven surface of the sustained-release coated tablets, and cracks and breaks in the coating film. Therefore, the solid content of the sustained-release coating solution is preferably 4%-6%, and more preferably 5%.

[0213] Table 6-4 Effects of liquid-solid content in sustained-release coating on related substances and residual solvents

[0214]

[0215] Note: The sustained-release coating consists of cellulose acetate and hydroxypropyl cellulose in a ratio of 5:5, and the weight gain of the sustained-release coating is 5%.

[0216] Example 7: Study on Drilling Hole Diameter

[0217] During the process research phase, the inventors investigated the pore size of the drug release orifice. With the same formulation, the pore sizes were 0.45 mm, 0.65 mm, and 0.85 mm, respectively. The dissolution curves under pH 6.8 and 50 rpm conditions are shown in Table 7.

[0218] Table 7 shows that the dissolution curves of the resulting formulations did not differ significantly when the pore size was in the range of 0.45–0.85 mm.

[0219] Table 7. Effect of perforation diameter on dissolution curve

[0220]

[0221]

[0222] Example 8: Stability of the product of the present invention

[0223] Tofacitinib citrate sustained-release tablets were prepared according to Formulation 1-1 and the method in Example 1, and influencing factor tests and accelerated stability tests were conducted. The results are shown in the table below.

[0224] Table 8-1 Test of Influencing Factors of the Product of the Invention

[0225]

[0226] Table 8-2 Accelerated stability test of the product of the present invention

[0227]

[0228] Example 9: Comparison of dissolution characteristics between the product of the present invention and commercially available products

[0229] The product of the present invention was obtained using Formulation 1-1 and the preparation method of Example 1. The dissolution behavior of the product of the present invention was compared with that of a commercially available reference formulation (pH 6.8 medium, 50 rpm).

[0230] The reference formulation is tofacitinib citrate extended-release tablets (trade name: ) manufactured by Pfizer Labs Division of Pfizer Inc, NY. XR), batch number: CH3273.

[0231] Table 9 Comparison of dissolution curves of the product of this invention and the reference formulation

[0232]

[0233] Table 9 Figure 1 The results showed that only 2% of the reference formulation dissolved within 1 hour, with a significant initial release lag, which was not conducive to rapid onset of action after the first dose and also affected the cumulative effect of blood drug concentrations after multiple doses. Furthermore, the dissolution uniformity among different formulation units of the reference formulation was poor, with a dissolution RSD as high as 89.4% at 1 hour and as high as 32.8% at 1.5 hours.

[0234] Compared with the reference formulation, the formulation of the present invention dissolves faster initially, with a dissolution rate of up to 7% at 1 hour, and the dissolution rates at 1.5 hours, 2 hours, and 2.5 hours are also significantly higher than those of the reference formulation. Furthermore, the formulation of the present invention exhibits better dissolution uniformity, with RSDs at all detection time points being less than 20%.

[0235] Furthermore, after 10 hours, the reference formulation was 94% dissolved, while the formulation of the present invention was 97% dissolved, indicating more complete dissolution.

[0236] Example 10: Comparison of pharmacokinetic characteristics of the product of the present invention and the reference formulation

[0237] The inventors further compared the absorption and metabolism of the formulation product of this invention (Formulation 1-1 of Example 1) with the reference formulation in the human body, using tofacitinib citrate extended-release tablets as described in this invention as the test formulation (T), and using tofacitinib citrate extended-release tablets (trade name: ) manufactured by Pfizer Labs Division of Pfizer Inc, NY. XR (batch number: CH3273) is the reference preparation (R). In accordance with the relevant regulations for bioequivalence studies, the pharmacokinetic characteristics of the test preparation and the reference preparation are compared in healthy subjects under fasting conditions.

[0238] This trial was a single-center, randomized, open-label, two-formulation, single-dose, two-cycle, crossover design, fasting component study. Subjects were randomly assigned 1:1 to either the TR or RT group. Each subject underwent two cycles, receiving one oral dose of the test formulation and one oral dose of the reference formulation, with a 7-day washout period between cycles.

[0239] This trial enrolled 28 participants, one of whom withdrew voluntarily during the second cycle (taking the reference formulation). Participants fasted overnight for at least 10 hours before each cycle, and then, according to a randomization table, took one tablet of the test formulation or one tablet of the reference formulation orally on an empty stomach with 240 mL of water. Water intake was prohibited for 1 hour before and 1 hour after administration (except for water used for medication administration); free water intake was permitted at other times. Fasting was prohibited for 4 hours after administration. Venous blood samples were collected at 22 time points: 0 h before administration (within 1 hour of administration) and at 0.5, 1.0, 1.5, 2.0, 2.33, 2.67, 3.0, 3.33, 3.67, 4.0, 4.33, 4.67, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, and 30.0 hours after administration. Blood drug concentrations were determined by LC-MS / MS, and pharmacokinetic evaluation parameters such as Cmax, AUC0-t, AUC0-∞, Tmax, t1 / 2, and λz were calculated.

[0240] The results show (see Table 10 and...) Figure 2 With a single dose, the formulation of this invention has a faster early release rate than the reference formulation, a smaller initial release lag effect, a faster early blood drug concentration ramp-up rate, shorter Tmax and t1 / 2, and higher Cmax and bioavailability (AUC) than the reference formulation.

[0241] During the entire trial, after administration of the reference formulation, a total of 4 subjects (14.8%) experienced 5 adverse events; after administration of the test formulation, a total of 2 subjects (7.1%) experienced 3 adverse events, all of which were mild (Grade 1). No serious adverse events occurred with either the reference formulation or the test formulation.

[0242] Table 10 Comparison of pharmacokinetic parameters between the product of this invention and the reference formulation

[0243]

[0244] Note: a Tmax is expressed as median (minimum, maximum). One subject withdrew from the trial voluntarily in the second cycle (while taking the reference formulation).

[0245] Comparative Example 1

[0246] 11 mg tofacitinib (i.e., tofacitinib citrate) sustained-release tablets were prepared according to the method and formulation described in Example 18 Study D of Patent CN105101952A as the formulation product of Comparative Example 1.

[0247] The dissolution curves were measured in pH 6.8 medium with stirring at 50 rpm, and the results are shown in Table 11-1 below. It can be seen that the initial release rate of the product of this invention is faster than that of Comparative Example 1. Furthermore, the formulation of this invention continues to release slowly and continuously between 6 h and 10 h, while the product of Comparative Example 1 only dissolves 4% between 6 h and 8 h, and the dissolution amount remains unchanged between 8 h and 10 h. Ultimately, the cumulative dissolution amount is less than that of the product of this invention (see Table 11-1). Figure 3 ).

[0248] The same test conditions as in Example 9 were used to conduct the influencing factor test. The results showed that after 10 days of storage, the related substances in the product of Comparative Example 1 increased significantly, and the stability was significantly lower than that of the product of the present invention.

[0249] Table 11-1 Comparison of dissolution curves of the product of the present invention and the product of Comparative Example 1

[0250]

[0251]

Claims

1. A sustained-release formulation of tofacitinib citrate, comprising a tablet core, a sustained-release coating, and a color coating, wherein the sustained-release coating has drug release pores; characterized in that, The chip core is made of the following components by weight percentage: The sustained-release coating is made of cellulose acetate and hydroxypropyl cellulose; the weight ratio of the two is cellulose acetate:hydroxypropyl cellulose = 5:5, and the weight gain of the sustained-release coating accounts for 9%-12% of the core weight; or, the weight ratio of the two is cellulose acetate:hydroxypropyl cellulose = 6:4, and the weight gain of the sustained-release coating accounts for 8%-9% of the core weight. The color coating layer accounts for 2.5% to 3.5% of the weight of the perforated sheet; Each formulation unit contains one drug release orifice; the orifice diameter is 0.45mm-0.85mm.

2. The tofacitinib citrate sustained-release formulation as described in claim 1, characterized in that, The sustained-release coating has a cellulose acetate to hydroxypropyl cellulose ratio of 5:5, and the weight gain of the sustained-release coating accounts for 10% to 11% of the tablet core weight.

3. The tofacitinib citrate sustained-release formulation according to any one of claims 1-2, characterized in that, The color coating layer accounts for 3.0% to 3.5% of the weight of the perforated sheet.

4. The tofacitinib citrate sustained-release formulation according to any one of claims 1-2, characterized in that, The diameter of the drug release orifice is 0.55mm-0.80mm.

5. The tofacitinib citrate sustained-release formulation as described in claim 4, characterized in that, The diameter of the drug release orifice is 0.60mm-0.75mm.

6. The tofacitinib citrate sustained-release formulation as described in claim 5, characterized in that, The diameter of the drug release orifice is 0.65 mm.

7. The method for preparing the tofacitinib citrate sustained-release formulation according to any one of claims 1-6, characterized in that: It includes the following steps: pretreatment of raw materials and excipients, granulation, tableting, sustained-release coating, perforation, and color coating.

8. The preparation method according to claim 7, characterized in that: It includes the following steps: (1) Pretreatment of raw and auxiliary materials: Weigh the following according to the prescription: ① tablet core components: tofacitinib citrate, sorbitol, sodium chloride, 250L hydroxyethyl cellulose, 250G hydroxyethyl cellulose, copovidone, magnesium stearate, ② sustained-release coating materials: cellulose acetate and hydroxypropyl cellulose, ③ color coating materials; pulverize and sieve them separately for later use. (2) Granulation ① Premix: Add sorbitol, tofacitinib citrate, 250L of hydroxyethyl cellulose, 250G of hydroxyethyl cellulose, copovidone, and sodium chloride to the granulator and mix evenly; ② Granulation: Add anhydrous ethanol to the granulator, stir, granulate, wet granulate, and dry; ③ Granulation and mixing: Add magnesium stearate and dry granulate using a granulator; mix the granulated material evenly. (3) Tableting: Use a tablet press to compress tablets to obtain tablet cores; (4) Sustained-release coating ①Preparation of sustained-release coating solution: Pour an appropriate amount of purified water and acetone into a mixing tank, add the prescribed amount of hydroxypropyl cellulose, stir well, then add the prescribed amount of cellulose acetate, stir well and set aside. ② Preheating and edge grinding: Preheat the coating pan body, add the sheet cores, and grind the edges; ③ Sustained-release coating: Spray the sustained-release coating solution prepared in step ①, coat, and dry to obtain sustained-release coated tablets; (5) Perforation: Take the sustained-release coated tablet and use a laser to perforate the sustained-release coating to obtain perforated tablets; (6) Color layer coating ①Preparation of color coating solution: Add the prescribed amount of color coating material to an appropriate amount of purified water, stir well, and set aside; ② Base coat: Before coating, spray the coating pan with liquid base coat; spray in a small amount of color coating liquid and let it dry; ③ Color coating: Place the perforated sheet in the coating pan, preheat the pan, spray in the remaining color coating liquid, and dry.

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