KR20190090729A - A Novel Tofacitinib Salt, Preparation Methods thereof and Pharmaceutical Compositions Comprising thereof - Google Patents

Abstract

The present invention relates to tofacitinib camphorsulfonate monohydrate, a manufacturing method thereof, and a pharmaceutical composition comprising the same. Since tofacitinib camphorsulfonate monohydrate according to the present invention has an excellent effect equal to or more than all of them in terms of acceleration, stability according to severe storage conditions, photostability, thermal stability, pH stability, solubility, and the like as compared with tofacitinib citrate, the pharmaceutical composition of the present invention can be usefully used for preventing or treating diseases selected from a group consisting of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

Description

A novel salt of tofacitinib, a preparation method thereof, and a pharmaceutical composition comprising the same {A Novel Tofacitinib Salt, Preparation Methods

The present invention relates to a novel salt of tofacitinib, a preparation method thereof, and a pharmaceutical composition comprising the same. More specifically, the present invention relates to a camphorsulfonate monohydrate of tofacitinib, a preparation method thereof, and a pharmaceutical composition comprising the same.

Tofacitinib {3-((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidin-1-yl) -3-oxopropanenitrile} is a compound represented by the following formula.

Tofacitinib is useful as an inhibitor of protein kinases, such as the enzyme Janus kinase 3 (hereinafter also referred to as 'JAK3'), and exhibits activity that inhibits the increase in inflammatory cytokines characteristic of rheumatoid arthritis and the like.

This tofacitinib is disclosed for the first time in International Patent Publication No. 2001/042246. However, specific salts of tofacitinib are not specifically disclosed.

Regarding the salts of tofacitinib, International Publication No. 2003/048162 discloses specifically for tofacitinib citrate, which is an active ingredient of a tablet product sold under the trade name Xeljanz.

Furthermore, amorphous acetate in International Publication No. 2012/135338, amorphous tartarate, amorphous maleate, amorphous oxalate in International Publication No. 2013/090490, US Publication No. 2015/225406 Hydrochloride, bromate, and the like.

On the other hand, the drug absorption process, that is, the drug in the gastrointestinal tract can be absorbed only when the solid drug is dissolved in the liquid phase, which acts as an essential factor of drug solubility. In addition, in the case of oral preparations, the solubility increase may be a significant improvement effect because it acts as a big factor in the change of the dosage form, such as immediate release, sustained release, or combination.

However, tofacitinib citrate, which is used in commercially available products, is poorly soluble and thus improves solubility, and at the same time, it is easy to formulate, having physicochemical stability and nonhygroscopicity, which is equal to or higher than the residual solvent standard recommended in the ICH guideline. One new salt has not yet been found. Therefore, it is necessary to develop a new salt that can replace the tofacitinib citrate by achieving the above effects.

International Publication No. 2001/042246 International Publication No. 2003/048162 International Publication No. 2012/135338 International Publication No. 2013/090490 United States Patent Application Publication No. 2015/225406

An object of the present invention is a novel salt of tofacitinib and a method for preparing the same, which can be applied to mass production and can be obtained in high quality with homogeneous quality while showing excellent photostability, thermal stability, pH stability and solubility, and the like. It is to provide a pharmaceutical composition containing as an active ingredient.

In order to solve the above problems, the present invention provides a tofacitinib camphorsulfonate monohydrate which is a novel salt of tofacitinib, a preparation method thereof, and a pharmaceutical composition comprising the same as an active ingredient.

Hereinafter, each will be described in detail.

Tofacitinib Camphor sulfonate Monohydrate

The present invention provides tofacitinib camphorsulfonate monohydrate. The tofacitinib camphorsulfonate monohydrate of the present invention is a compound represented by the following formula (1).

[Formula 1]

In addition, the tofacitinib camphor sulfonate monohydrate of the present invention is crystalline.

The tofacitinib camphor sulfonate monohydrate of the present invention has a 2θ value of 6.07 °, 7.82 °, 13.82 °, 16.52 °, 21.54 ° and 23.59 ° with a 2θ value of the powder X-ray diffraction spectroscopy pattern. It may include three or more diffraction peaks selected from the group consisting of. In addition, the tofacitinib camphorsulfonate monohydrate of the present invention has a 2θ value of 12.05 °, 13.02 °, 18.35 °, 19.36 °, 20.43 °, 25.70 °, 26.97 °, and 28.58 ° of the powder X-ray diffraction spectrum pattern. It may further comprise one or more diffraction peaks selected from the group consisting of 2θ (± 0.2 °) values of 29.54 °. In addition, the tofacitinib camphor sulfonate monohydrate of the present invention may exhibit a powder X-ray diffraction spectroscopy pattern of FIG. 1.

In addition, the tofacitinib camphor sulfonate monohydrate of the present invention exhibits an endothermic peak of about 148 ° C. (148.07 ° C.) when the temperature rising rate is 10 ° C./min, as shown in the DSC result of FIG. 2, and the starting melting point is 145 to 145 ° C. 150 ° C. In addition, the tofacitinib camphor sulfonate monohydrate of the present invention may exhibit a differential scanning calorimetry of FIG. 2.

In addition, the tofacitinib camphor sulfonate monohydrate of the present invention may exhibit a thermogravimetric analysis (TGA) pattern of FIG. 3.

In addition, the tofacitinib camphor sulfonate monohydrate of the present invention is 216.2, 161.7, 143.3, 143.0, 123.8, 116.1, 104.6, 101.8, 58.2, 47.1, 46.8, 44.2, 42.1, 41.1, 37.8, 35.2, 30.9, 29.8, ¹³ C NMR signals at 26.4, 24.2, 20.0, 19.5, and 13.6 ppm.

In addition, the tofacitinib camphorsulfonate monohydrate of the present invention may contain 2 to 4% water as measured by Karl-Fischer measurement.

The present invention invented a novel salt of tofacitinib that was not used at all in the prior art. Compared with tofacitinib citrate monohydrate according to the present invention, as compared with tofacitinib citrate, the stability, light stability, thermal stability, and pH stability according to acceleration and harsh storage conditions show an excellent or better effect. It can be kept stable in the long term without changing the content. Therefore, the tofacitinib camphor sulfonate monohydrate of the present invention can be obtained as a raw material of high purity, and the increase of the flexible material is remarkably low even during long-term storage, so that high purity can be maintained for a long time. In addition, the tofacitinib camphorsulfonate monohydrate of the present invention has low hygroscopicity and can maintain the monohydrate form for a long time without losing moisture.

The tofacitinib camphorsulfonate monohydrate of the present invention exhibits excellent solubility values and excellent pharmacological effects compared to tofacitinib citrate at various pH conditions, and thus can be used for various indications such as rheumatoid arthritis, psoriatic arthritis or ulcerative colitis. It can be usefully used as a new effective ingredient of the curable pharmaceutical composition, the tofacitinib camphorsulfonate monohydrate of the present invention shows a high bioavailability when oral administration, it can exhibit an excellent therapeutic effect even at a small dose The patient's convenience of medication can be significantly improved. In addition, the tofacitinib camphorsulfonate monohydrate of the present invention has a rapid onset of action, has a thermodynamically stable form, and the tofacitinib camphorsulfonate monohydrate according to the present invention exhibits low hygroscopicity in a relative humidity range. Therefore, it is very advantageous in the processing and storage of pharmaceutical products and is easy to formulate, and the preparation is prepared using tofacitinib camphorsulfonate monohydrate according to the present invention, or the preparation is maintained in the same state even after preparation of the preparation containing the same. The uniformity of the content can be kept stable for a long time and can be easily applied to mass production. In addition, the morphology of the morphology (habit) can not minimize the needle shape, or the shape of the needle shape can be minimized, and as a result, the drug loading rate can be increased as the bulk density, flowability, compressibility, etc. are improved. In addition, tofacitinib camphorsulfonate monohydrate according to the present invention may have advantageous packaging, thermodynamics, kinetics, surface properties, mechanical properties, filterability or high chemical purity.

Tofacitinib Camphor sulfonate Monohydrate  Manufacturing method

The present invention provides a method for preparing tofacitinib camphorsulfonate monohydrate represented by the following formula (1).

[Formula 1]

The preparation method of the present invention includes the steps of (a) reacting tofacitinib and camphorsulfonic acid in water and an organic solvent.

In addition, the manufacturing method of the present invention may further comprise the following steps:

(b) depositing a product in the reaction solution of step (a); And

(c) filtering and drying the product of step (b).

The camphorsulfonic acid of step (a) is preferably used in an amount of 0.5 to 2.0 equivalents, and more preferably 1.0 to 1.5 equivalents, based on 1.0 equivalent of tofacitinib.

The organic solvent of step (a) is preferably used 1 to 50 mL per 1 g of tofacitinib, more preferably 15 to 20 mL per 1 g of tofacitinib.

The organic solvent of step (a) may be a solvent selected from the group consisting of methanol, ethanol, 2-propanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate and a mixed solvent thereof, 2-propanol, ethyl acetate or It is preferred to use a mixed solvent thereof, more preferably 2-propanol.

In the step (a), the higher the ratio of water, the lower the yield or crystal precipitation may become impossible, so the mixing ratio of water and the organic solvent is preferably used in a volume ratio of 1: 5 to 1:50, and 1:15 to More preferably, it is used in a volume ratio of 1:20.

Drying of step (c) may be carried out at 35 to 50 ℃.

According to the preparation method of the present invention, the tofacitinib camphorsulfonate monohydrate of the present invention can be obtained in a high purity and high yield through a simple process, and mass production is possible. The tofacitinib camphor sulfonate monohydrate thus produced shows excellent effects in terms of stability, light stability, thermal stability, pH stability, and solubility according to storage conditions of acceleration and harshness.

Tofacitinib Camphor sulfonate Monohydrate  Pharmaceutical composition comprising

The present invention provides a pharmaceutical composition comprising tofacitinib camphorsulfonate monohydrate represented by the following Chemical Formula 1 as an active ingredient.

[Formula 1]

Compared with tofacitinib citrate monohydrate according to the present invention, as compared with tofacitinib citrate, the stability, light stability, thermal stability, and pH stability according to acceleration and harsh storage conditions show an excellent or better effect. In the long term, it can be stably maintained without a change in content, and exhibits excellent solubility values compared to tofacitinib citrate at various pH conditions. Thus, the pharmaceutical composition of the present invention can be used for rheumatoid arthritis, psoriatic arthritis and It can be usefully used for the prevention or treatment of diseases selected from the group consisting of ulcerative colitis.

The composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the tofacitinib camphorsulfonate monohydrate which is an active ingredient for administration. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol and one or more of these components. If necessary, an antioxidant, , And other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into injectable solutions, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like. Accordingly, the composition of the present invention may be a patch, a liquid, a pill, a capsule, a granule, a tablet, a suppository, or the like. These formulations may be prepared by conventional methods used in the art for formulation or by methods disclosed in Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA, and formulated into various formulations depending on the individual disease or component. Can be.

The composition of the present invention can be administered orally or parenterally (eg, applied intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is based on the weight, age, sex and health of the patient. The range varies depending on the diet, the time of administration, the method of administration, the rate of excretion and the severity of the disease. The daily dose of tofacitinib camphorsulfonate monohydrate of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and may be administered once to several times a day.

The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar medicaments in addition to tofacitinib camphorsulfonate monohydrate.

Rheumatism  arthritis, Dryness  A method for preventing or treating a disease selected from the group consisting of arthritis and ulcerative colitis

The invention is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis comprising administering to a mammal comprising a human in a therapeutically effective amount of a pharmaceutical composition comprising tofacitinib camphorsulfonate monohydrate Provided are methods for preventing or treating a disease.

Mammals including humans include mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, rats, mice and the like.

As used herein, the term "therapeutically effective amount" refers to a pharmaceutical composition comprising tofacitinib camphorsulfonate monohydrate effective for the prevention or treatment of a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. In the amount of tofacitinib camphorsulfonate monohydrate administered to a subject to be treated, to prevent the occurrence or recurrence of a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis, or Tofacitinib camphorsulfonate monohydrate that mitigates, inhibits direct or indirect pathological consequences, prevents metastasis, slows progression, alleviates or temporarily alleviates the condition, or improves prognosis. It may include all amounts of pharmaceutical compositions comprising. That is, the therapeutically effective amount encompasses all doses in which the symptoms of a condition selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis are improved or cured by the pharmaceutical composition comprising the tofacitinib camphorsulfonate monohydrate. Can be interpreted as

The method of preventing or treating a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis of the present invention, by administering tofacitinib camphorsulfonate monohydrate, not only treats the disease itself before the onset of symptoms, It also includes inhibiting or avoiding symptoms. In the management of a disease, the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition and the route by which the active ingredient is administered. The frequency of dose and dose will vary with the age, weight and response of the individual patient. Appropriate dosing regimens can be readily selected by those of ordinary skill in the art which will of course consider these factors. In addition, the pharmaceutical composition of the present invention is a method for preventing or treating a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis is a combination of tofacitinib camphorsulfonate monohydrate and an additional active agent to help treat the disease. It may further comprise a therapeutically effective amount of administration, wherein the additional active agent may have a synergistic or adjuvant effect with tofacitinib camphorsulfonate monohydrate.

Rheumatism  arthritis, Dryness  Use for the manufacture of a medicament for the treatment of a disease selected from the group consisting of arthritis and ulcerative colitis

The present invention also provides the use of tofacitinib camphorsulfonate monohydrate for the manufacture of a medicament for the treatment of a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. Tofacitinib camphorsulfonate monohydrate for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier, and the like, and may be prepared in a complex formulation with other active agents to have a synergistic action of the active ingredients.

The matters mentioned in the uses, compositions and methods of treatment of the invention apply equally unless they contradict each other.

The tofacitinib camphor sulfonate monohydrate of the present invention is excellent in photostability, thermal stability, pH stability and solubility, and prevents or treats a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis. It can be usefully used as a new active ingredient of the pharmaceutical composition for.

1 shows a powder X-ray diffraction spectroscopy (“PXRD”) pattern of tofacitinib camphorsulfonate monohydrate according to the present invention.
Figure 2 shows a differential scanning calorimetry ("DSC") curve of tofacitinib camphorsulfonate monohydrate according to the present invention.
Figure 3 shows a thermogravimetric analysis ("TGA") curve of tofacitinib camphorsulfonate monohydrate according to the present invention.
Figure 4 is a graph showing the solubility test of tofacitinib camphorsulfonate monohydrate according to the present invention, a comparison with tofacitinib citrate as a control.

Hereinafter, the present invention will be described in more detail with reference to the following examples and experimental examples. However, the following Examples and Experimental Examples are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

Used equipment  And measurement conditions

1) Since tofacitinib camphorsulfonate monohydrate was not registered in the US Pharmacopeia, self-initiation was established through high performance liquid chromatography (HPLC) analysis and impurities were analyzed. Purity of the prepared compound was determined by high performance liquid chromatography (HPLC). Stationary phase (Chromatopak 250 X 4.6 mm X 5 μm) and mobile phase A (2 M potassium dihydrogen phosphate and 4.6 M 1-octane sulfonate mixed buffer: acetonitrile = 90: 10) and mobile phase B (2 M dihydrogen phosphate) A mixture of potassium and 4.6M 1-octane sulfonate buffer (buffer: acetonitrile = 30: 70) was used and measured at a flow rate of 1.0 mL / min, column temperature of 25 ° C., and wavelength of 210 nm. The buffers used as mobile phases A and B were prepared by adjusting 2.72 g of potassium dihydrogen phosphate and 1.0 g of sodium 1-octane sulfonate to 1000 mL of distilled water to adjust the pH to 5.5.

2) The nuclear magnetic resonance spectrum (NMR) was measured using a 400 MHz FT-NMR spectrometer (Bruker, Germany), and the melting point was measured using a melting point measuring instrument (Auto Melting Point Apparatus, B ㆌ chi, B-540).

3) Thin Film Xray Diffraction Spectrum was measured using a D8 Advance X-ray Powder Diffraction Spectrometer (Bruker, Germany).

4) Differential Scanning Calorimeter (DSC) is the 2010 DSC V4.4E Exo up. Using a Universal V4.7A TA instrument was measured under the conditions of Method 10 to 200, Comment 10 ℃ / min, N2 = 100 mL / min.

5) TGA (Thermogravimetric Analysis) was measured under the conditions of Method Ramp, Comment 10 ℃ / min, 600C, N2 = 100 mL / min using SDT Q600 V20.9 Build 20.

6) The solubility was calculated by multiplying the area of the sample solution and the area of STD by dilution factor using the Agilent 1200 Infinity series.

STD preparation: Take 20 mg of tofacitinib into a 200 mL volumetric flask and fill the mark with each test solution (0.2 mg / mL concentration as tofacitinib).

Preparation of sample solution: Tofacitinib camphorsulfonate monohydrate and tofacitinib citrate were added to 5 mL of each test solution in excess for 30 hours at room temperature for 5 hours, and then filtered to 0.45 um filter. Dilute to sample solution.

7) Light stability was spread by spreading tofacitinib camphorsulfonate monohydrate and tofacitinib citrate monohydrate into the chalet at 4500 lux by using EYELA LSD-300D. Cumulative dose 1 parking 735,000 lux, 2 parking 1,470,000 lux, 3 Samples were taken at 2,205,000 lux for parking and 2,940,000 lux for 4 parking.

8) The non-hygroscopicity is obtained by spreading tofacitinib camphorsulfonate monohydrate and tofacitinib citrate to the chalet by using Karl-Fisher measurement method using Metrohm 890 Titrando, 803 Ti Stand. Analyzed.

9) Tofacitinib used in the reaction was prepared under the conditions of the examples of WO 2001/042246.

Example 1: 3 -(( 3R, 4R )-4- methyl -3- ( Methyl (7H-pyrrolo [2,3-d] Pyrimidin-4-yl) amino) Camphor sulfonate Monohydrate  ( Tofacitinib Camphor sulfonate Monohydrate ) Preparation of Crystal Form

31.2 g (0.10 mol) 3-((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1 -Yl) -3-oxopropanenitrile and 25.5 g (0.11 mol) of camphorsulfonic acid were added and dissolved in 62 mL distilled water. 624 mL of isopropyl alcohol was added and stirred at room temperature for 12 hours or more. The resulting crystals were filtered under reduced pressure after stirring for at least 2 hours while maintaining at 5 to 10 ° C. The filtrate was washed with 31 mL of isopropyl alcohol and dried in vacuo at 40 to 45 ° C. to obtain 50.1 g (92%) of tofacitinib camphorsulfonate monohydrate.

Purity: 99.99% by HPLC

¹ H NMR (DMSO- d ₆ , 400 MHz, ppm): δ 0.72 (s, 3H), 1.01 (s, 3H), 1.06-1.03 (m, 3H), 1.33-1.23 (m, 2H), 1.62-1.59 (m, 1H), 1.78 (d, 1H), 1.92 (t, 1H), 2.21 (d, 1H), 1.85-1.81 (m, 1H), 2.40-2.39 (m, 1H), 2.48 (m, 1H ), 2.64 (t, 1H), 2.43 (d, 1H), 2.91 (d, 1H), 3.35 (s, 3H), 3.41 (m, 2H), 3.90-3.73 (m, 2H), 3.99-4.16 ( m, 2H), 4.62 (m, 1H), 6.86 (s, 1H), 7.46 (s, 1H), 8.43 (m, 1H), 12.77 (m, 1H)

¹³ C NMR (DMSO- d ₆ , 400 MHz, ppm): δ 13.6, 19.5, 20.0, 24.2, 26.4, 29.8, 30.9, 35.2, 37.8, 41.1, 42.1, 44.2, 46.8, 47.1, 58.2, 101.8, 104.6, 116.1 , 123.8, 143.0, 143.3, 161.7, 216.2

PXRD: as shown in FIG. 1

DSC: About 148 ° C (148.07 ° C)

Moisture Content (Karl-Fisher Meter): 3.26%

Example 2: 3 -(( 3R, 4R )-4- methyl -3- ( Methyl (7H-pyrrolo [2,3-d] Pyrimidin-4-yl) amino) Camphor sulfonate Monohydrate  ( Tofacitinib Camphor sulfonate Monohydrate ) Preparation of Crystal Form

31.2 g (0.10 mol) 3-((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1 -Yl) -3-oxopropanenitrile and 25.5 g (0.11 mol) of camphorsulfonic acid were added and dissolved in 62 mL distilled water. 624 mL of ethyl acetate was added and stirred at room temperature for at least 12 hours. The resulting crystals were stirred for at least 2 hours while maintaining at 5 to 10 ° C and filtered under reduced pressure. The filtrate was washed with 31 mL of ethyl acetate and dried in vacuo at 40 to 45 ° C. to obtain 55.1 g (90%) of tofacitinib camphorsulfonate monohydrate.

Where ¹ H NMR spectrum, XRD and DSC data are the same as tofacitinib camphorsulfonate monohydrate of Example 1.

Moisture Content (Karl-Fisher Meter): 3.18%

Example  3: Preparation of Tablet

The compound of Example 1            9 mg

Microcrystalline cellulose 122 mg

Lactose Carb  61 mg

Carboxymethyl Cellulose Sodium   6 mg

Magnesium stearate   2 mg

Tablets were prepared by tableting according to the conventional method for preparing tablets.

Comparative Example  One: Tofacitinib  Preparation of Citrate (International Publication No. 2003/048162 Example  3 Note)

3-((3R, 4R) -4-methyl-3- (methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino) piperidine-1- dissolved in 3120 mL of acetone 31.2 g (0.10 mole) of the 1) -3-oxopropanenitrile (0.10 mol) was heated to 40 ° C. To this solution was added 21.1 mg (0.11 mol) of pulverized citric acid. The resulting mixture was stirred at 40 ° C. for 2 hours, then at 30 ° C. for 4 hours and at room temperature for an additional 18 hours. At this point, the solid was collected by filtration, washed with acetone and dried in vacuo to give 38.0 g (75%) of the title compound as a white crystalline solid.

Purity: 99.93% by HPLC

DSC: 214 ℃

Moisture Content (Karl-Fisher Meter): 0.07%

Comparative Example  2: preparation of tablets

Compound of Comparative Example 1            8 mg

Microcrystalline cellulose 121 mg

Lactose Carb  61 mg

Carboxymethyl Cellulose Sodium   6 mg

Magnesium stearate   2 mg

Tablets were prepared by tableting according to the conventional method for preparing tablets.

Test Example  1: solubility test

The solubility of tofacitinib camphorsulfonate monohydrate obtained in Example 1 and tofacitinib citrate obtained in Comparative Example 1 was measured in pH 1.2, 4.0, 6.8, and 7.5 buffer solutions reflecting various pH in vivo and the results are shown below. It is shown in Table 1 and FIG.

[Table 1]

As shown in Table 1 above, the solubility of the tofacitinib camphorsulfonate monohydrate of the present invention was 1.2 to 18.9 times better at various pH conditions than tofacitinib citrate. Such excellent solubility indicates the advantage of not adding special difficulties to the manufacturing process of the finished drug as a solid preparation for oral administration, and the advantage of bringing about an increase in bioavailability when the obtained finished drug is taken.

In addition, the tofacitinib camphorsulfonate monohydrate of the present invention exhibited even solubility to pH change compared to Comparative Example 1, which was compared with the oral administration of the finished drug product using the raw material according to the present invention. Compared with the case of adopting the raw material of Example 1 shows the advantage that the difference in bioavailability according to the pH change before and after meals can be less.

Test Example  2: accelerated stability test

The tofacitinib camphorsulfonate monohydrate of the present invention was subjected to an acceleration stability test to confirm what aspect it shows according to the acceleration test conditions.

Specifically, stability experiments were performed using tofacitinib citrate prepared in Comparative Example 1 as a control. The experiment was carried out with each compound accelerated test (40 ℃, relative humidity 75%) and analyzed by HPLC (purity,%) and the results are shown in Table 2 below.

[Table 2]

As can be seen in Table 2, the tofacitinib camphorsulfonate monohydrate of the present invention is very stable even under the acceleration conditions, it can be seen that the stability is equal to tofacitinib citrate. Accordingly, the tofacitinib camphorsulfonate monohydrate of the present invention is stable in manufacturing process, easy to handle and very useful for mass production.

Test Example  3: harsh stability test

The tofacitinib camphorsulfonate monohydrate of the present invention was subjected to a severe stability test to determine what the appearance was according to the harsh test conditions.

Specifically, stability experiments were performed using the tofacitinib citrate prepared in Comparative Example as a control. The experiment was conducted by harsh test (60 ℃, 75% relative humidity) with each compound and analyzed by HPLC (purity,%) and the results are shown in Table 3 below.

[Table 3]

As can be seen in Table 3, the tofacitinib camphorsulfonate monohydrate of the present invention is very stable even under the harsh conditions, and it can be seen that the stability is equal to tofacitinib citrate. Accordingly, the tofacitinib camphorsulfonate monohydrate of the present invention is excellent in stability and easy to handle and store, and is very useful for mass production in pharmacological terms.

Test Example  4 : Light stability  exam

Tofacitinib camphorsulfonate monohydrate of the present invention was subjected to a light stability test to determine what the appearance is according to light.

Specifically, tofacitinib citrate prepared in Comparative Example 1 as a control light irradiation 4500 lux cumulative dose 1 parking 735,000 lux, 2 parking 1,470,000 lux, 3 parking 2,205,000 lux, 4 parking 2,940,000 lux light stability test Was carried out, and the results are shown in Table 4 below.

 [Table 4]

As can be seen in Table 4, the tofacitinib camphorsulfonate monohydrate of the present invention is very stable even in the stability check irradiated to the light, it can be seen that the light stability and tofacitinib citrate is equivalent. Therefore, the tofacitinib camphorsulfonate monohydrate of the present invention is excellent in light stability and is very useful in packaging and storage conditions during formulation.

Test Example  5: Non-hygroscopic  exam

Water absorbed films in the solid state with a high pharmaceutical content can act as a factor for hydrolysis and chemical degradation, so it is desirable to make non-hygroscopic salts for stable formulations. Thus, the tofacitinib camphor sulfonate monohydrate of the present invention was subjected to a non-hygroscopic test in order to confirm what aspect of moisture absorption.

Specifically, the non-hygroscopic experiment was performed using the tofacitinib citrate prepared in Comparative Example 1 as a control. In the experiment, each salt was measured when each salt was exposed at 25 ° C. and 60% relative humidity for 1 month. The results are shown in Table 5 below.

[Table 5]

As can be seen in Table 5, the tofacitinib camphorsulfonate monohydrate according to the present invention exhibits a very low non-hygroscopicity in the relative humidity of the range in which the experiment was conducted can be stored stably even if the raw material is exposed to moisture in the air Able to know.

Therefore, tofacitinib camphor sulfonate according to the present invention is excellent in storage stability, can be stored for a long time, and can be easily manufactured.

Test Example  6: Formulation Stability Test

In order to determine whether or not tofacitinib camphorsulfonate monohydrate obtained according to the preparation method of the present invention can be used for medical purposes, the stability test of the formulation was carried out as follows.

Specifically, HDPE / LDPE bottles were packaged as coated tablets for the stability test of the formulations obtained in Example 3 and Comparative Example 2, and both accelerated conditions (40 ° C., 75%, sealed or open) and harsh conditions (60 ° C. sealed) were used. After storage for 1 month under the different conditions, a significant change rate was measured through a tablet content test and a flexible test. The results are shown in Table 6 and Table 7 below.

TABLE 6

[Table 7]

As can be seen in Table 6 and Table 7, the tofacitinib camphorsulfonate monohydrate according to the present invention was found to be excellent after the tableting under the formulation conditions obtained in Example 3, without significant change in content and formation of analogues. That is, even after implementing the solid drug product by adopting the raw material according to the present invention, by improving the physicochemical properties of the drug, it is advantageous in the absorption, processing, storage, etc. of the drug and ultimately it is very advantageous for the commercialization of the drug. .

Claims (19)

Tofacitinib camphorsulfonate monohydrate represented by the following formula (1).
[Chemical Formula 1]

The tofacitinib camphorsulfonate monohydrate according to claim 1, which is crystalline. 3. The powder X-ray diffraction pattern of claim 2 wherein the 2X value is selected from the group consisting of 2θ (± 0.2 °) values of 6.07 °, 7.82 °, 13.82 °, 16.52 °, 21.54 ° and 23.59 °. Tofacitinib camphorsulfonate monohydrate, comprising at least two diffraction peaks. The powder X-ray diffraction pattern has a 2θ value of 12.05 °, 13.02 °, 18.35 °, 19.36 °, 20.43 °, 25.70 °, 26.97 °, 28.58 ° and 29.54 ° Tofacitinib camphorsulfonate monohydrate, further comprising at least one diffraction peak selected from the group consisting of The tofacitinib camphorsulfonate monohydrate according to claim 2, which exhibits the powder X-ray diffraction spectrophotometry pattern of FIG. 1. The tofacitinib camphorsulfonate monohydrate according to claim 2, wherein the starting melting point is 145 to 150 ° C. 7. The tofacitinib camphorsulfonate monohydrate according to claim 6, having a differential scanning calorimetry (DSC) endothermic peak at 148.07 ° C when the rate of heating is 10 ° C / min. The tofacitinib camphor sulfonate monohydrate according to claim 7, which shows a differential scanning calorimetry of FIG. 2. The tofacitinib camphorsulfonate monohydrate according to claim 2, which shows the thermogravimetric analysis (TGA) pattern of FIG. 3. The method of claim 2, wherein 216.2, 161.7, 143.3, 143.0, 123.8, 116.1, 104.6, 101.8, 58.2, 47.1, 46.8, 44.2, 42.1, 41.1, 37.8, 35.2, 30.9, 29.8, 26.4, 24.2, 20.0, 19.5, And tofacitinib camphorsulfonate monohydrate showing a ¹³ C NMR signal at 13.6 ppm. (a) reacting tofacitinib and camphorsulfonic acid in water and an organic solvent,
A process for preparing tofacitinib camphorsulfonate monohydrate according to claim 1. 12. The method of claim 11 further comprising the steps of: (b) precipitating the product; And
(c) filtering and drying;
Manufacturing method further comprising. The method according to claim 11, wherein the camphorsulfonic acid of step (a) is added in a molar ratio of 1.0 to 1.5 equivalents based on 1.0 equivalent of tofacitinib. The method of claim 11, wherein the organic solvent of step (a) is a solvent selected from the group consisting of methanol, ethanol, 2-propanol, butanol, methyl acetate, ethyl acetate, isopropyl acetate, and a mixed solvent thereof. The method according to claim 14, wherein the organic solvent of step (a) is 2-propanol, ethyl acetate or a mixed solvent thereof. The method of claim 11, wherein the volume ratio of the water and the organic solvent of the step (a) is 1:15 to 1:20. The method of claim 12, wherein the drying of step (c) is carried out at 35 to 50 ℃. A pharmaceutical composition for the prophylaxis or treatment of a disease selected from the group consisting of rheumatoid arthritis, psoriatic arthritis and ulcerative colitis using the tofacitinib camphorsulfonate monohydrate of any one of claims 1 to 10 as an active ingredient. The pharmaceutical composition of claim 18, which is orally administered.

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