TW202038917A - Extended release formulation containing tofacitinib or pharmaceutically acceptable salts thereof and preparation method for the same - Google Patents

Abstract

Disclosed is an extended release formulation including tofacitinib or pharmaceutically acceptable salts thereof, an extended release agent, and a hydrophilic binder, which extended release formulation makes effects equivalent to those of an immediate release formulation despite having a lower drug content, that is, 10 mg, than the existing commercial extended release products, and involves a simple production process to secure high productivity and high economic feasibility.

Description

Extended release formulation containing tofacitinib or its pharmaceutically acceptable salts and preparation method thereof

The present invention relates to an extended-release formulation containing tofacitinib or its pharmaceutically acceptable salts and its manufacturing method, and more particularly to an extended-release formulation containing tofacitinib or its pharmaceutically acceptable salts and as an extension The extended release formulation of the hydrophilic substance of the release agent, which ensures the stable and sustained release of the drug in the body, and allows once a day to be administered to obtain the desired therapeutic effect. More specifically, although the dosage is lower (10 mg) than the existing commercially available extended-release products, the extended-release formulation has the same effect as the immediate-release formulation, and is more than existing in terms of simple manufacturing process, high productivity and high economic feasibility. Commercially available extended release products have advantages.

The active substance tofacitinib of the present invention has 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino group ]Piperidin-1-yl}-3-oxopropionitrile (3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl) -amino]piperidin-1-yl}-3-oxopropanenitrile) and the chemical structure represented by the following chemical formula 1:

[Chemical formula 1]

As disclosed in WO2001/042246, tofacitinib of Chemical Formula 1 has inhibitory activity against protein kinases such as Janus Kinase 3 (JAK3), and is used in organ transplantation, xeno transplantation, lupus ), multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, type 1 diabetes and complications from diabetes, cancer, asthma, Atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia, and other adaptations that require immunosuppression It provides many benefits as an immunosuppressive agent when it is affected.

In addition, the preparation method of Chemical Formula 1 and its pharmaceutically acceptable salts is disclosed in WO2002/096909, and the tofacitinib citrate described in WO2003/048162 is used as the main ingredient of Xeljanz ^® tablets sold in Korea. ingredient. Xeljanz ^® lozenge is a drug used for the treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. It is an immediate-release formula containing 5 mg of tofacitinib citrate (as a twice daily Administered at the same dose).

Compared with immediate-release formulations, extended-release formulations continue to release the drug for a period of time to achieve a consistent blood concentration of the drug within the treatment range for a long time, and reduce the fluctuation of the blood concentration of the drug that may be caused by frequent administration of the immediate-release formulation. The reduced number of daily doses provided by extended-release formulations can reduce the occurrence of side effects and improve patient compliance. In the manufacture of tablets from drugs with low recommended doses such as tofacitinib, more excipients than active ingredients are used, so it is difficult to ensure the uniformity of the content of active ingredients in each tablet. As an extended-release formulation, it can contain a higher drug load, and it is necessary to deliver low-dose drugs in the form of an extended-release formulation, which has an advantage in ensuring the uniformity of drug content.

WO2012/100949 related to prolonged release formulations with tofacitinib as the active ingredient indicates that tofacitinib can be prepared as a modified release formulation. WO2014/147526 also discloses that the extended-release formulations using tofacitinib as the active ingredient can be prepared by the usual techniques for the production of extended-release formulations, such as matrix systems (tablets or multiparticulates), isotonic systems Or storage system (reservoir system), etc. In this regard, a typical example is an extrudable core system formulation using an osmotic system. However, the bioavailability of tofacitinib decreases with the release time. Therefore, the pharmacokinetics of the extended-release formulation of tofacitinib with a daily dose of 10 mg stated in WO201/100949 is not equivalent to the immediate-release formulation of tofacitinib at the same dose. As a solution to this problem, an extended release formulation of tofacitinib with a higher dose (11 mg) appeared in WO2014/147526. With the help of osmotic extrudable core system, the bioavailability of extended-release formulations is exactly the same as that of immediate-release formulations within the confidence interval (CI) of 90%. In the hydrophilic matrix system, even higher doses are used to extend the release The bioavailability of the formula is not equal to that of the immediate release formula. In fact, the tofacitinib product marketed in the United States under the Xeljanz XR ^® brand is an osmotic controlled-release oral delivery system (OROS) formulation with a daily dose of 11 mg, which is higher than the daily dose of 10 mg for immediate-release formulations . However, OROS formulations have weaknesses in their complex production process, resulting in low productivity and economic feasibility.

Cross references to related applications [Patent Document] [Patent Document 1] WO2012/100949 [Patent Document 2] WO2014/147526

technical problem

In an attempt to solve the problems of the conventional technology, the inventors of the present invention have researched and found that in addition to using extended release agents, hydrophilic binders can also be used to produce extended release formulations that can ensure stable and sustained release of drugs. Therefore, the completion of the present invention can achieve the same bioavailability as the immediate-release formulation even without using the immediate-release formulation exceeding the same daily dose.

Therefore, the object of the present invention is to provide an extended-release formulation for the prevention or treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, wherein the extended-release formulation contains tofacitinib as an active Ingredients, and in addition to the use of extended release adhesives, hydrophilic adhesives are also used to ensure that the active ingredients are dispersed in the hydrophilic matrix for stable and sustained release.

Another object of the present invention is to provide a prolonged release formulation with a hydrophilic matrix dosage form. Compared with the existing commercially available prolonged release products, although the content of tofacitinib or its pharmaceutically acceptable salts is lower, its use At least two hydrophilic matrices produce the same effect as the immediate release formulation, and involve simple production procedures to ensure high productivity and high economic feasibility.

way of solving the problem

In order to achieve the purpose of the present invention, an extended release formulation comprising tofacitinib or a pharmaceutically acceptable salt thereof, an extended release agent and a hydrophilic binder is provided.

In the extended release formulation, tofacitinib or a pharmaceutically acceptable salt thereof can be selected from tofacitinib citrate, tofacitinib aspartate, Tofacitinib succinate (tofacitinib succinate), tofacitinib orotate (tofacitinib orotate), tofacitinib palmate (tofacitinib palmate), tofacitinib stearate (tofacitinib stearate), Tofacitinib benzoate, tofacitinib ascorbate, tofacitinib oleate, tofacitinib sulfonate, tofacitinib ascorbate Tofacitinib sulfate, tofacitinib dodecyl sulfate, tofacitinib cyclamate, tofacitinib edisulfonate ( tofacitinib edisylate), tofacitinib nitrate, tofacitinib maleate or tofacitinib phosphate.

In the extended release formulation, the extended release agent may be any pharmaceutically acceptable extended release agent; preferably, it is selected from polyvinylpyrrolidone ( PVP), hydroxypropyl methylcellulose (HPMC) ), hydroxypropyl methylcellulose phthalate (hydroxypropyl methylcellulose phthalate), methylcellulose (methylcellulose, MC), sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl fiber Hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), pectin, cyclodextrin, galactomannan, polyethylene glycol ( PEG) , At least one of the group consisting of ethylcellulose (EC) and gelatin (gelatin); more preferably HPMC.

The hydrophilic binder can be any pharmaceutically acceptable hydrophilic binder; preferably selected from microcrystalline cellulose, sucrose, titanium dioxide, and hydroxypropyl cellulose (HPC) One or two of the group consisting of polyvinylpyrrolidone (PVP), corn starch and lactose hydrate; more preferably HPC, PVP or a combination of HPC and PVP.

When the hydrophilic adhesive is a combination of two selected hydrophilic adhesives, the mixing ratio of the two adhesives can be 1:4 to 4:1.

In the extended release formulation, the content of tofacitinib may be 10 mg.

In the extended release formulation, relative to the total weight of the formulation, the content of the hydrophilic binder may be 5.0 to 20.0 wt%.

In the extended release formulation, tofacitinib can be dispersed in a hydrophilic matrix.

In another aspect of the present invention, an extended release formulation is provided, which comprises: tofacitinib or a pharmaceutically acceptable salt thereof; hydroxypropyl methylcellulose (HPMC) as an extended release agent; Hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone as a hydrophilic binder; lactose monohydrate as a diluent; and magnesium stearate as a lubricant.

In yet another aspect of the present invention, there is provided a method for preparing an extended-release formula, which comprises: mixing tofacitinib or a pharmaceutically acceptable salt thereof as a main ingredient with an excipient to prepare a mixture ; The mixture is made into granules by extrusion and shaping; the granules are compressed into tablets; and the tablets are coated.

Technical effect

The extended release formula of the present invention is effectively used for the prevention and treatment of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. More specifically, in addition to the extended release agent, a hydrophilic binder is added to ensure the stable and sustained release of the active ingredient from the extended release formulation, so the extended release formulation with a daily dose not higher than the immediate release formulation can have The same bioavailability of the immediate-release formula. In particular, it is possible to provide an extended release formulation involving a simple process to ensure high productivity and high economic feasibility.

The present invention is designed based on the following facts, although the existing tofacitinib extended-release formulations contain a higher content of tofacitinib than the daily dose of immediate-release formulations, and use OROS technology involving complex manufacturing processes, except for the use of extended-release agents to control In addition to the viscosity of the hydrophilic matrix, the extended-release formulation of tofacitinib using a hydrophilic adhesive has the same beneficial effects as the immediate-release formulation, although it does not exceed the same daily dose as the immediate-release formulation, it can also be simply The process of production.

The present invention is specifically based on the fact that the extended release formulation uses a combination of at least two hydrophilic binders. For example, hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone ( PVP) can be used in a stable and continuous manner The active ingredient tofacitinib is released in the hydrophilic matrix; while the extended-release formulation using a single hydrophilic binder has drug release retardation or extremely accelerated initial drug release.

The extended-release formulation for preventing or treating rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis as provided according to the present invention comprises tofacitinib or a pharmaceutically acceptable salt thereof, an extended-release agent, and Hydrophilic adhesive.

In the present invention, the USP Apparatus II (paddle) slurry method (50 rpm) is applied to 900 ml of potassium phosphate buffer (pH = 6.8) as a dissolving solvent to dissolve the extended release formulation of the present invention at 37°C. At an appropriate time point, an aliquot of the dissolving medium was taken out and filtered; the filtrate was subjected to high performance liquid chromatography (HPLC) to determine the content of the dissolved drug. The dissolution curve shows that the extended release formulation of the present invention releases 45% or less of the drug at the 2 hour time point, and releases 50 to 80% of the drug at the 3 hour time point.

The tofacitinib used in the present invention may include tofacitinib free salt or a pharmaceutically acceptable acid addition salt thereof (unless otherwise specified, tofacitinib or a pharmaceutically acceptable salt thereof is referred to as "Tofacitinib"). Examples of tofacitinib used herein are tofacitinib citrate, tofacitinib aspartate, tofacitinib succinate, tofacitinib orotate, tofacitin Nipalmitate, tofacitinib stearate, tofacitinib benzoate, tofacitinib ascorbate, tofacitinib oleate, tofacitinib sulfonate, tofacitinib Sulfate, tofacitinib lauryl sulfate, tofacitinib cyclohexylamine sulfonate, tofacitinib ethanedisulfonate, tofacitinib nitrate, tofacitinib maleate Salt or tofacitinib phosphate. Optimally, tofacitinib is tofacitinib citrate.

The prolonged release agent used in the prolonged release formulation of the present invention may include a pharmaceutically acceptable prolonged release agent; preferably selected from polyvinylpyrrolidone (PVP), cellulose polymers (e.g., hydroxypropyl methylcellulose) (HPMC), hydroxypropyl methyl cellulose phthalate, methyl cellulose (MC), sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl cellulose or hydroxypropyl cellulose (HPC )), at least one of the group consisting of pectin, cyclodextrin, galactomannan, polyethylene glycol (PEG), ethyl cellulose (EC) and gelatin; more preferably HPMC.

The hydrophilic binder used in the extended release formulation of the present invention may include a pharmaceutically acceptable hydrophilic binder; preferably selected from the group consisting of microcrystalline cellulose, sucrose, titanium dioxide, hydroxypropyl cellulose, and polyvinylpyrrolidone ( One or two of the group consisting of PVP), corn starch and lactose hydrate; more preferably HPC, PVP and the like; most preferably a combination of HPC and PVP. In particular, the use of low-viscosity HPC has a more ideal effect, which can release drugs slowly over time. Preferably, the viscosity measured with a Brookfield viscometer in a 2% aqueous solution at 20°C is 6.0-10.0 mPa•s.

The extended release formulation of the present invention has a form in which tofacitinib is dispersed in a hydrophilic matrix. In the stomach, the hydrophilic matrix reacts with the aqueous vehicle to form a gel layer around the lozenge, so tofacitinib can be slowly released through the gel layer over a period of time. In addition to the extended release agent, the extended release formulation of the present invention also uses a hydrophilic binder to ensure the stable and continuous release of the active ingredient tofacitinib at a consistent rate.

The hydrophilic binder may be included in a content of 5.0 to 20.0 wt%, preferably 10.0 to 17.5 wt%, relative to the total weight of the formulation. The content of the hydrophilic binder below 5.0 wt% is too low to control the viscosity of the hydrophilic matrix for stable drug release; and the content of the hydrophilic binder above 20.0 wt% is not economical and problematic Yes, an excessive amount of hydrophilic binder may cause problems in the granulation process and cause inconvenience to the administration of drugs due to the increase in the total weight of the unit preparation. When the hydrophilic adhesive is composed of two selected hydrophilic adhesives, the mixing ratio of the two hydrophilic adhesives is preferably 1:4 to 4:1, most preferably 2:3.

The extended release formulation of the present invention may further include pharmaceutically acceptable excipients, such as diluents, colorants, sweeteners, surfactants, lubricants, stabilizers and the like.

The diluent used herein may include lactose, microcrystalline cellulose, starch and the like. More specifically, the lactose used herein can be, but is not limited to, lactose monohydrate, lactose anhydride, spray-dried lactose monohydrate, etc.; the microcrystalline cellulose used herein can be but It is not limited to microcrystalline cellulose, silicate microcrystalline cellulose, etc.; and the starch used herein may be, but is not limited to, corn starch, pregelatinized starch, etc.

The coloring agent used herein may include at least one selected from titanium dioxide, iron sulfate, or any coloring agent recommended by FD&C.

The sweetener used herein may comprise at least one selected from sucralose, sucrose, dextrose, fructose, glucose, glucose syrup, or maltose.

The lubricant used herein may include at least one selected from talc, stearyl fumarate, magnesium stearate, hydrogenated castor oil, and the like.

The extended release formulation of the present invention may include a pharmaceutically acceptable film coating. The film coating used herein may be selected from at least one of the excipients commonly used for coating oral preparations, such as hyperomellose, titanium dioxide, PEG, iron oxide, talc and the like.

The extended release formulation of the present invention can be made into a variety of dosage forms. Examples of dosage forms may include lozenges (for example, plain tablets, coated tablets, multilayer tablets or tablet-within-tablets), powders, granules or capsule. Preferably, the dosage form may be a lozenge.

The extended-release formulation of the present invention may contain tofacitinib in an amount of about 5 to 15 mg, preferably 10 mg. The route of administration of the extended-release formulation of the present invention can be determined as the most suitable one, preferably oral.

The invention also provides methods for preparing extended release formulations. In one embodiment, the method for preparing an extended release formulation according to the present invention includes the following steps: (1) mixing tofacitinib or a pharmaceutically acceptable salt thereof as a main ingredient with excipients to prepare a mixture; (2) The mixture is made into granules by squeezing and sieving; (3) the granules are compressed into tablets; and (4) coated tablets.

Hereinafter, the present invention will be described in detail with reference to the following examples, which are given only to illustrate the present invention, not to limit the scope of the present invention.

[Examples 1 to 4]

The combination given in Table 1 below, with tofacitinib aspartate as the main component, lactose monohydrate as the diluent, HPMC (Methocel K100LV CR) as the extended release agent, and two hydrophilic binders (HPC-L and PVP K30) are mixed together, and magnesium stearate is added as a lubricant. The mixture thus obtained was extruded in a dry granulator and sieved into dry granules, and compressed into unit tablets in a rotary tablet press.

[Table 1] Example 1 Example 2 Example 3 Example 4 Tofacitinib aspartate 14.26 mg 14.26 mg 14.26 mg 14.26 mg Lactose monohydrate 63.85% 63.85% 63.85% 63.85% Methocel K100LV CR 15% 15% 15% 15% HPC-L 10% 7.5% 5% 2.5% PVP K30 2.5% 5% 7.5% 10% Magnesium stearate 2 % 2 % 2 % 2 % sum 100% 100% 100% 100%

[Comparative Examples 1 and 2]

The combination given in Table 2 below uses tofacitinib aspartate as the main ingredient, lactose monohydrate as the diluent, HPMC (Methocel K100LV CR) as the extended release agent, and a single hydrophilic binder (HPC -L or PVP K30) are mixed together and magnesium stearate is added as a lubricant. The mixture thus obtained was extruded in a dry granulator and sieved into dry granules, and compressed into unit tablets in a rotary tablet press.

[Table 2] Comparative example 1 Comparative example 2 Tofacitinib aspartate 14.26 mg 14.26 mg Lactose monohydrate 63.85% 63.85% Methocel K100LV CR 15% 15% HPC-L 12.5% - PVP K30 - 12.5% Magnesium stearate 2 % 2 % sum 100% 100%

[Experimental example 1] Dissolution curve test

According to USP dissolution test 2 with a rotary paddle apparatus, Examples 1 to 4 and Comparative Examples 1 and 2 and the commercial extended release product Xeljanz XR ^® tablets (control group drug, 11 mg tofacitinib) were performed Dissolution test. More specifically, the test procedure was performed with a 50 rpm slurry at 37°C with 900 ml potassium phosphate buffer (pH = 6.8) as the dissolution medium. During the test, an aliquot of the dissolution medium was taken out at an appropriate time point and filtered; and the filtrate was used to determine the content of the dissociated tofacitinib by high performance liquid chromatography (HPLC) and establish a dissolution curve. The results are presented in Table 3 and Figure 1.

[table 3] Time (minutes) Control group Comparative example Instance 1 2 1 2 3 4 30 0.25 8.53 10.72 9.89 10.54 8.69 10.04 60 5.20 16.97 23.10 18.15 17.32 18.97 21.41 120 34.85 33.80 50.62 36.88 41.30 41.18 44.78 150 49.41 41.59 60.91 45.74 51.44 53.41 54.41 180 63.97 49.37 71.19 54.60 61.57 63.19 64.04 210 71.08 56.32 76.84 62.12 67.13 69.27 71.38 240 78.19 63.27 82.48 69.63 73.69 75.89 78.71 360 92.80 84.67 89.27 87.95 88.47 90.20 88.91

For a BCS class 3 drug tofacitinib, it has high solubility and low biofilm penetration. The absorption of the drug in the body depends on the penetration of the drug itself. Without using excipients that may affect the biofilm penetration of the extended release formulation of the present invention as the extended release formulation, the in vivo penetration characteristics are consistent with the physical and chemical properties of tofacitinib. Therefore, in this case, it is possible to predict the degree of in vivo drug release from the results of in vitro dissolution. For Xeljanz XR ^® tablets, a commercially available extended release product with a T _max of 3 to 4 hours, in order to dissolve the same degree of drug in the body, the drug dissolution at a time point of 2-4 hours is very important for the in vitro dissolution test. The drug dissolution rate is 20 to 42% in 2 hours, 33 to 56% in 2.5 hours, 46 to 65% in 3 hours, 55 to 70 in 3.5 hours and 72 to 76% in 4 hours.

As can be seen from the results of the dissolution test in Table 3 and Figure 1, the extended release formulations of the present invention, Examples 1 to 4, have a dissolution rate (within ±10%) at the time point of 2-4 hours Similar to the control group (Xeljanz XR ^® lozenge). On the other hand, compared with the control group, Comparative Example 1 using HPC as a single aqueous binder showed a stable drug release rate and delayed overall dissolution; and Comparative Example 2 using PVP1 as a single hydrophilic binder had an accelerated rate The initial drug release, and the drug release rate decreased over time, and overall it showed faster drug dissolution than the control group. It is confirmed from the results that the novel extended-release formulation of the present invention can be used as a hydrophilic binder in a suitable mixing ratio by using a combination of HPC and PVP to ensure a desired dissolution profile.

[Experimental example 2] PK curve test (5 mg Xeljanz ^® IR tablet BID and the novel extended release formula QD of the present invention)

This is an open-label, randomized, unit dose, 2 cycles, 2 treatment, and 4 crossover study in healthy male subjects. During each treatment period, the subjects received an oral dose of the extended-release formulation (example) or the immediate-release formulation (Xeljanz ^® IR lozenge) of the present invention in a washout period with an interval of 7 days. The extended-release formula received by each subject was one tablet with a unit dose of 10 mg, and the immediate-release formula was two tablets with a unit dose of 5 mg. The PK curves are compared, and the results are presented in Figure 2. As can be seen from the graph in Figure 2, the C between the groups administered with the extended-release formulation of the present invention containing 10 mg tofacitinib daily and the group taking 5 mg Xeljanz ^® IR tablets twice daily There is no significant difference in _max and AUC.

[Experimental example 3] Pre-meal/post-meal PK curve test (the novel extended release formula QD of the present invention, before and after meal)

Evaluate the effect of food on the novel extended release formulation of the present invention. The results are presented in Table 4 and Figure 3.

[Table 4] C _max AUC 90% Cl T/R ratio 90% Cl T/R ratio Before meal 94 ~ 118 105 92 ~ 110 100 After meal 116 ~ 147 76 97 ~ 108 98

As can be seen from the graphs in Table 4 and Figure 3, there was no significant difference in AUC between the groups taking the novel extended-release formula before and after the meal. Therefore, food does not affect the effect of the novel extended-release formula of the present invention, which proves that the novel extended-release formula meets the standards of the extended-release formula.

Industrial availability

The extended release formula of the present invention effectively prevents or treats rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, and can be used as a medical product in the pharmaceutical industry and medical care institutions.

no.

Figure 1 is a graph showing the drug dissolution of the extended-release formulation of the present invention, the extended-release formulation containing a single hydrophilic binder, and the commercially available extended-release product. Figure 2 is a comparison diagram showing the PK curves of the extended release formulation of the present invention and the commercial extended release product. Figure 3 is a graph showing the comparison of the PK curves of the extended release formulation of the present invention before and after meals.

Claims (12)

An extended-release formulation comprising tofacitinib or its pharmaceutically acceptable salts, an extended-release agent, and a hydrophilic binder. An extended release formulation comprising tofacitinib or a pharmaceutically acceptable salt thereof, an extended release agent and a hydrophilic binder, the extended release formulation having a drug release of 45% or less at a time point of 2 hours , And have 50 to 80% drug release at 3 hours. The extended-release formulation according to claim 1 or 2, wherein the tofacitinib or a pharmaceutically acceptable salt thereof is selected from tofacitinib citrate, tofacitinib aspartic acid Salt (tofacitinib aspartate), tofacitinib succinate, tofacitinib orotate, tofacitinib palmate, tofacitinib stearic acid Salt (tofacitinib stearate), tofacitinib benzoate, tofacitinib ascorbate, tofacitinib oleate, tofacitinib sulfonate ( tofacitinib sulfonate), tofacitinib sulfate, tofacitinib dodecyl sulfate, tofacitinib cyclamate, tofacitinib Tofacitinib edisylate, tofacitinib nitrate, tofacitinib maleate and tofacitinib phosphate. The extended release formulation according to claim 1 or 2, wherein the extended release agent is selected from polyvinylpyrrolidone ( PVP), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl phthalate Methyl cellulose (hydroxypropyl methylcellulose phthalate), methyl cellulose (methylcellulose, MC), sodium carboxymethyl cellulose (CMC-Na), hydroxyethyl cellulose (hydroxyethyl cellulose), hydroxypropyl Cellulose (hydroxypropyl cellulose, HPC), pectin (pectin), cyclodextrin (cyclodextrin), galactomannan (galactomannan), polyethylene glycol ( PEG), ethyl cellulose (ethylcellulose, EC) ) And at least one of the group consisting of gelatin. The extended release formulation according to claim 1 or 2, wherein the hydrophilic binder is selected from the group consisting of microcrystalline cellulose, sucrose, titanium dioxide, and hydroxypropyl cellulose (HPC) , Polyvinylpyrrolidone (PVP), corn starch (corn starch) and lactose hydrate (lactose hydrate) consisting of one or two of the group. The extended release formulation according to claim 5, wherein the hydrophilic binder is selected from the group consisting of hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), or a combination of HPC and PVP. The extended release formulation according to claim 5, wherein, when the hydrophilic adhesive is a combination of two hydrophilic adhesives, the mixing ratio of the two selected adhesives is 1:4 to 4:1. The extended release formulation according to claim 1, wherein the content of tofacitinib is 10 mg. The extended release formulation according to claim 1, wherein the content of the hydrophilic binder is 5.0 to 20.0 wt% relative to the total weight of the formulation. The extended-release formulation according to claim 1, wherein the extended-release formulation further comprises at least one selected from diluents, colorants, sweeteners, surfactants, lubricants, and stabilizers. The extended release formulation according to claim 1, wherein tofacitinib is dispersed in a hydrophilic matrix. An extended release formulation, which contains: Tofacitinib or its pharmaceutically acceptable salts; Hydroxypropyl methylcellulose (HPMC) as an extended release agent; Hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP) as a hydrophilic binder; Lactose monohydrate as a diluent; and Magnesium stearate as a lubricant.

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