Compound preparation for treating alopecia areata and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a tablet composition for treating alopecia areata and a preparation method thereof.The tablet composition is a composition comprising two main drugs including finasteride and baricitinib and is prepared by mixing and pressing finasteride particles and baricitinib particles which are prepared through specific auxiliary materials and a process, the finasteride granules and the baricitinib granules have good Karl index and Hausner ratio after being mixed, the pressed tablet composition has good performance in a plurality of test items such as acceleration for 6 months, long-term 6 months and high-humidity test, and the auxiliary material formula and the process can simultaneously meet the quality requirements of finasteride and baricitinib. Meanwhile, the degradation condition of the main medicine is relieved, the increase of related impurities of finasteride and baricitinib is reduced, the quality stability of the medicine under different storage conditions is improved, and the safety and effectiveness of the medicine within the period of validity and the integrity of the appearance of the tablet are ensured.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and specifically discloses a compound preparation for treating alopecia areata and a preparation method thereof. Background Art

[0002] Conventional treatment drugs (such as glucocorticoids) are only effective for patients with mild to moderate alopecia areata and the treatment is not thorough. Among the approved drugs for the treatment of alopecia areata, minoxidil increases the blood supply to the hair follicles by dilating the scalp blood vessels. This provides more oxygen and nutrients to the hair follicles, which contributes to the health of the hair follicles and the growth of hair. However, it has little effect on severe alopecia areata and requires long-term medication to maintain the effect. In addition, minoxidil is mostly applied externally and may cause skin irritation.

[0003] In patients with androgenic alopecia, 5α-reductase and dihydrotestosterone (DHT) are more active in the hair loss areas (such as the top of the head), and the number of dihydrotestosterone (DHT) receptors in this area is also more. Dihydrotestosterone (DHT) will harm the hair matrix cells in the hair follicles. The hair matrix cells are deprived of food, the hair follicles shrink, and the hair changes from terminal hair to vellus hair, becoming thinner and thinner, and eventually falling off. Finasteride is a 5α-reductase inhibitor. By inhibiting 5α-reductase, it can reduce the dihydrotestosterone (DHT) content in serum and scalp by 60%~70%, thereby preventing DHT from damaging the hair papilla and fundamentally controlling and treating hair loss.

[0004]

[0005] Baricitinib is a Janus kinase (JAKs) inhibitor that can reduce inflammation and immune responses by inhibiting the effects of JAK1 and JAK2. JAK is mainly composed of three parts: receptor, JAK kinase and STAT. The latest research believes that alopecia areata is a T-cell-mediated autoimmune inflammatory response to the growth phase of hair follicles, and IFN-γ produced by CD8+NKG2D+T cells is a key factor in the onset of alopecia areata. Therefore, baricitinib, as a JAK inhibitor, can effectively treat alopecia areata.

[0006]

[0007] Single-ingredient treatment is only effective for mild alopecia areata, and has little effect on alopecia areata with complex pathology. The efficacy has certain limitations. Compound preparations are a treatment method that can be sustained and effective or can permanently reverse alopecia areata.

[0008] Compared with single-drug preparations, compound preparation excipients and processing methods must consider the impact on multiple active ingredients at the same time. When developing compound solid preparations of baricitinib and finasteride, the selection of processing methods and excipients is crucial. Since there are certain differences in the properties of baricitinib and finasteride, improper selection may lead to an increase in impurities and loss of the main drug content during storage, thereby affecting the quality and safety of the preparation. The selection of excipients and processing technology must take into account the properties of both drugs, baricitinib and finasteride. It is necessary to consider the possible decline of the main drug under different storage conditions, the generation of impurities, and the fluidity and compressibility of the tablet powder before compression, and ensure that the comprehensive performance of the baricitinib and finasteride compound main drug tablets in terms of disintegration and stability achieves good results. Summary of the invention

[0009] In view of the prior art, the first aspect of the present invention provides a composition for treating alopecia areata, comprising a main drug, D-mannitol, microcrystalline cellulose, a first lubricant, lactose, sodium carboxymethyl starch, pregelatinized starch, hydroxypropyl methylcellulose, a second lubricant, low-substituted carboxypropyl methylcellulose, The main drug includes one or more of baricitinib or a pharmaceutically acceptable salt thereof, finasteride or a pharmaceutically acceptable salt thereof.

[0010] In some specific embodiments of the composition for treating alopecia areata of the first aspect, the composition comprises 4 to 10 parts by mass of a main drug, 24 to 30 parts by mass of D-mannitol, 104 to 130 parts by mass of microcrystalline cellulose, 1.6 to 2.0 parts by mass of a first lubricant, 72 to 90 parts by mass of lactose, 8 to 10 parts by mass of sodium carboxymethyl starch, 16 to 20 parts by mass of pregelatinized starch, 0.48 to 0.60 parts by mass of hydroxypropyl methylcellulose, 1.2 to 1.5 parts by mass of a second lubricant, and 8 to 10 parts by mass of low-substituted carboxypropyl methylcellulose, wherein the main drug comprises one or more of baricitinib or a pharmaceutically acceptable salt thereof, and finasteride or a pharmaceutically acceptable salt thereof.

[0011] In some specific embodiments of the composition for treating alopecia areata of the first aspect, it includes 5 parts by mass of baricitinib, 5 parts by mass of finasteride, 30 parts by mass of D-mannitol, 130 parts by mass of microcrystalline cellulose, 2 parts by mass of a first lubricant, 90 parts by mass of lactose, 10 parts by mass of sodium carboxymethyl starch, 20 parts by mass of pregelatinized starch, 0.6 parts by mass of hydroxypropyl methylcellulose, 1.5 parts by mass of a second lubricant, and 10 parts by mass of low-substituted carboxypropyl methylcellulose.

[0012] In some specific embodiments of the composition for treating alopecia areata of the first aspect, it includes 8 parts by mass of the main drug, 24 parts by mass of D-mannitol, 104 parts by mass of microcrystalline cellulose C, 1.6 parts by mass of the first lubricant, 72 parts by mass of lactose, 8 parts by mass of sodium carboxymethyl starch, 16 parts by mass of pregelatinized starch, 1.2 parts by mass of the second lubricant, and 8 parts by mass of low-substituted carboxypropyl methylcellulose.

[0013] In some specific embodiments of the composition for treating alopecia areata of the first aspect, the main drug includes 4-5 parts by weight of baricitinib and 4-5 parts by weight of finasteride.

[0014] In some specific embodiments of the composition for treating alopecia areata of the first aspect, the first lubricant and the second lubricant are each independently selected from one or a combination of magnesium stearate, silicon dioxide, calcium stearate, polyethylene glycol, and talc. The second aspect of the present invention provides a method for preparing a tablet composition for treating alopecia areata, comprising the steps of: S1: baricitinib or a pharmaceutically acceptable salt thereof, D-mannitol and microcrystalline cellulose are mixed at a first vibration frequency, sieved, a first lubricant is added, mixed again at a second vibration frequency, sieved, and baricitinib particles are prepared; S2: Finasteride or a pharmaceutically acceptable salt thereof is premixed with lactose, sodium carboxymethyl starch and pregelatinized starch, and the mixture is mixed with a solution of hydroxypropyl methylcellulose to obtain a soft material, which is sieved and dried, and a second lubricant and low-substituted carboxypropyl methylcellulose are added to obtain finasteride particles; S3: The baricitinib granules are mixed with the finasteride granules, compressed into tablets, and coated to obtain a tablet composition.

[0015] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, the S1 step is to mix 4 to 5 parts by mass of baricitinib with 24 to 30 parts by mass of D-mannitol and 104 to 130 parts by mass of microcrystalline cellulose at a first vibration frequency, and add 1.6 to 2 parts by mass of a first lubricant.

[0016] In some specific embodiments of the method for preparing the tablet composition according to the second aspect, in the step S1, the first vibration frequency is 25-30 Hz, and in some specific embodiments of the method for preparing the tablet composition according to the second aspect, in the step S1, the first vibration frequency is 27 Hz.

[0017] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S1, the second vibration frequency is 25-30 Hz. In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S1, the second vibration frequency is 28 Hz.

[0018] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, the roller pressing pressure in the step S1 is 28 to 30 bar. In some specific embodiments of the method for preparing a tablet composition according to the second aspect, the roller pressing pressure in the step S1 is 29 bar.

[0019] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S1, the speed of the roller pressing is 8-9 rpm.

[0020] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, the speed of passing the screen in step S1 is 100-110 rpm. In some specific embodiments of the method for preparing a tablet composition according to the second aspect, the speed of passing the screen in step S1 is 105 rpm.

[0021] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S2, 4 to 5 parts by mass of finasteride are premixed with 72 to 90 parts by mass of lactose, 8 to 10 parts by mass of sodium carboxymethyl starch, and 16 to 20 parts by mass of pregelatinized starch to obtain a soft material.

[0022] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S2, the mass fraction of the second lubricant is 1.2 to 1.5. In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S2, the mass fraction of the second lubricant is 1.3.

[0023] In some specific embodiments of the method for preparing a tablet composition proposed in the second aspect, in the step S2, the mass fraction of the low-substituted carboxypropyl methyl cellulose is 8 to 10. In some specific embodiments of the method for preparing a tablet composition proposed in the second aspect, in the step S2, the mass fraction of the low-substituted carboxypropyl methyl cellulose is 9.

[0024] In some specific embodiments of the method for preparing the tablet composition according to the second aspect, in step S2, the solution of hydroxypropyl methylcellulose is a mixed solution of hydroxypropyl methylcellulose in ethanol and water.

[0025] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S2, the mass fraction of the hydroxypropyl methylcellulose solution is 15-25%. In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S2, the mass fraction of the hydroxypropyl methylcellulose solution is 20%.

[0026] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, the mass mixing ratio of the baricitinib particles to the finasteride particles in step S3 is (133-167):(109-137).

[0027] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the baricitinib particles and the finasteride particles are mixed at a rate of 10 to 30 Hz. In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the baricitinib particles and the finasteride particles are mixed at a rate of 20 Hz.

[0028] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S3, an 8 mm punch is used for tableting.

[0029] In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S3, the tableting hardness is 80N to 120N. In some specific embodiments of the method for preparing a tablet composition according to the second aspect, in the step S3, the tableting hardness is 100N.

[0030] In some specific embodiments of the method for preparing the tablet composition according to the second aspect, in the step S3, the coating is performed using Opadry coating solution.

[0031] In some specific embodiments of the method for preparing the tablet composition of the second aspect, in the step S3, the coating liquid has a mass fraction of 15% w / w of Opadry coating liquid with a solid content.

[0032] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the inlet air temperature of the coating is 50~70°C. In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the inlet air temperature of the coating is 60°C.

[0033] In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the temperature of the coated tablet bed is 35°C~45°C. In some specific embodiments of the method for preparing the tablet composition proposed in the second aspect, in the step S3, the temperature of the coated tablet bed is 40°C.

[0034] The third aspect of the present invention provides a composition for treating alopecia areata prepared by any method embodiment of the second aspect.

[0035] In the present invention, impurity A is a baricitinib impurity CAS: 2964606-42-4, ; Impurity B is finasteride impurity CAS: 98319-24-5, ; Impurity I is finasteride impurity CAS: 103335-41-7, ; In the baricitinib granulation step of the present invention: the specific model of microcrystalline cellulose is VIVAPUR®102; the specific model of lactose in the finasteride granulation step is SuperTab ® 11SD; the specific model of sodium carboxymethyl starch in the finasteride granulation step is VIVASTAR ® P, the specific model of low-substituted carboxypropyl methylcellulose is LH-21, and the hydroxypropyl methylcellulose is E5 hydroxypropyl methylcellulose; The coating powder model is Opadry 88A640033 (Colorcon), and its ingredients are polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, sodium lauryl sulfate, and caprylic and capric monoglycerides.

[0036] The combined use of finasteride and baricitinib has a significant effect in promoting hair growth. Specifically, baricitinib can eliminate the effects of T cell-mediated immune responses on hair follicle epithelial cells. The JAK-STAT channel of hair follicle epithelial cells affects the operation of the hair follicle cycle, blocks the downstream signal transduction of cytokines and receptors, and interferes with the differentiation of Th17, Th1 and Th2 cells, inducing hair follicles to enter and remain in the resting phase. JAK inhibitors can bind to JAK, preventing it from binding and activating STAT, allowing hair follicles in the hair loss area to get rid of the negative repressive effects of cytokines on the hair follicle cycle, enter the growth phase, and lead to hair regeneration.

[0037] In addition, JAK inhibitors can also act directly on hair follicles, promote the occurrence of the growth phase, prolong the growth phase of hair follicles, promote blood vessel proliferation and hair regeneration. Finasteride reduces the negative effects of DHT on hair follicles by preventing DHT from binding to receptors in hair follicle cells. This can prevent further atrophy of hair follicles, promote hair regrowth, and slow down or stop the process of hair loss. Both can act on hair follicles, inhibit the negative effects of adverse factors on hair follicles, and make hair grow again. The two have a synergistic effect and can exert higher efficacy.

[0038] Advantages of the invention: The present invention provides a tablet composition comprising finasteride and baricitinib, which is formed by mixing and compressing finasteride particles and baricitinib particles obtained by specific excipients and processes. The finasteride particles and baricitinib particles of the present invention have good Carr index and Hausner ratio after mixing, and the compressed tablet composition performs well in multiple test items such as accelerated 6-month, long-term 6-month and high-humidity tests. The excipient formula and process can simultaneously meet the quality requirements of finasteride and baricitinib, while reducing the increase of impurities related to finasteride and baricitinib, reducing the degradation of finasteride and baricitinib components during long-term storage, enhancing the quality stability of the drug under different storage conditions, and ensuring its safety and effectiveness within the validity period and the integrity of the tablet appearance. DETAILED DESCRIPTION

[0039] The present invention is further described below in conjunction with specific embodiments. It is worth noting that these embodiments are only used to illustrate the present invention and are not intended to limit the present invention in any way. Improvements and adjustments made by technicians according to the present invention in practical applications still fall within the scope of protection of the present invention.

[0040] Example 1 Baricitinib granulation steps: 5g of baricitinib, 30g of D-mannitol and 130g of microcrystalline cellulose are added, the vibration mixer is set to a primary vibration frequency of 30Hz and mixed for 15min, and sieved through 14 mesh. 2g of magnesium stearate is weighed and added, the vibration mixer is set to a secondary vibration frequency of 30Hz and mixed for 5min, and the mixed materials are dry granulated, the feed speed is set to 20.0rpm, the roller oil pressure is 30bar, the roller speed is 9.0rpm, the granulation speed is 100.0rpm, and the sieve is passed through a 1.2mm sieve to obtain baricitinib particles.

[0041] Finasteride granulation steps: 5g of finasteride, 90g of lactose, 10g of sodium carboxymethyl starch and 20g of pregelatinized starch were added to the wet granulator and premixed for 5 minutes. 0.6g of hydroxypropyl methylcellulose was dissolved in a 20% ethanol aqueous solution to prepare a 20% hydroxypropyl methylcellulose binder solution, and wet granulation was performed to obtain a soft material that was passed through a 14-mesh sieve and dried in an oven at 60°C. Then, 1.5g of magnesium stearate and 10g of low-substituted carboxypropyl methylcellulose were added and mixed for 10 minutes to obtain finasteride granules.

[0042] Total mixing and coating step: 167g of the prepared baricitinib granules and 137.1g of finasteride granules were placed in a three-dimensional mixer with a mixing speed of 10-30Hz. After mixing for 10min, tablets were pressed using an 8mm die to control the hardness to about 80N-120N. A 15% (w / w) solid content Opadry coating solution was prepared, the inlet air temperature was set at 50-70°C, and the tablet bed temperature was set at 35°C-45°C for film coating. The coating weight gain was controlled at 2%-6% to obtain 316.3mg / tablet compound tablets.

[0043] Example 2 Baricitinib granulation steps: 4g of baricitinib, 24g of D-mannitol and 104g of microcrystalline cellulose were added, the vibration mixer was set to a primary vibration frequency of 25Hz and mixed for 15min, and 16 mesh was sieved. 1.6g of magnesium stearate was weighed and added, and the vibration mixer was set to a secondary vibration frequency of 25Hz and mixed for 5min. The mixed materials were dry granulated, and the feed speed was set to 25.0rpm, the roller oil pressure was 28bar, the roller speed was 8.0rpm, the granulation speed was 110.0rpm, and the sieve was passed through a 1.2mm sieve to obtain baricitinib granules.

[0044] Finasteride granulation steps: 4 g of finasteride, 72 g of lactose, 8 g of sodium carboxymethyl starch and 16 g of pregelatinized starch were added to the wet granulator and premixed for 5 min. 0.48 g of hydroxypropyl methylcellulose was dissolved in 20% ethanol solution to prepare a 20% hydroxypropyl methylcellulose binder solution, and wet granulation was performed to obtain a soft material, which was passed through a 14-mesh sieve and dried in an oven at 60°C. Then, 1.2 g of magnesium stearate and 8 g of low-substituted carboxypropyl methylcellulose were added and mixed for 10 min to obtain finasteride granules.

[0045] Total mixing and coating step: 133.6g of the prepared baricitinib granules and 109.68g of finasteride granules were placed in a three-dimensional mixer with a mixing speed of 10-30Hz. After mixing for 9 minutes, tablets were pressed using an 8mm die to control the hardness to about 80N-120N. A 15% (w / w) solid content of Opadry coating solution was prepared, the inlet air temperature was set to 50-70°C, and the tablet bed temperature was set to 35°C-45°C for film coating. The coating weight gain was controlled at 2%-6% to obtain 126.5mg / tablet compound tablets.

[0046] Example 3 According to the ICH guidelines, the tablets were placed under accelerated and long-term conditions for 6 months, and the impurities in the tablets were tested to obtain Table 1.

[0047] Table 1 The accelerated 6-month test conditions are (40℃±2℃, RH75%±5%); the long-term 6-month test conditions are (25℃±2℃, RH60%±5%); The content of the main drug % is the standard peak area ratio relative to 5 mg of the main drug; In Table 3, impurity A is CAS: 2964606-42-4, impurity A% is calculated relative to the main peak area of ​​baricitinib, impurity B is CAS: 98319-24-5, impurity B% is calculated relative to the main peak area of ​​finasteride, impurity I is CAS: 103335-41-7, impurity I% is calculated relative to the main peak area of ​​finasteride, and the tablets prepared in Example 1 have a small decrease in the main drug content on the 0th day of the accelerated 6-month and long-term 6-month tests, and the peak areas of impurities A, impurity B and impurity I in liquid chromatography detection have no significant increase, indicating that the preparation method of the tablets of the present invention gives the sample good stability.

[0048] Example 4 According to the method of "Guidelines for Stability Testing of Raw Materials and Preparations" (General Rule 9001) of the "Chinese Pharmacopoeia", the tablets of Example 1 were subjected to a high humidity test to examine the change pattern of the preparation over time under the influence of humidity, and the shelf life of the drug was established through the test.

[0049] Example 1 The tablets were placed in a constant humidity sealed container at 25°C and a relative humidity of 90%±5% for 10 days. Samples were taken on the 5th and 10th days and tested according to the requirements of the key stability inspection items. At the same time, the weight of the test sample before and after the test was accurately weighed to examine the hygroscopic and deliquescent properties of the tablets, and Table 2 was obtained.

[0050] Table 2 High humidity test results Example 5 According to the "Disintegration Time Test Method" (General Rule 0921) of the Chinese Pharmacopoeia, the disintegration test was carried out on the tablets of Example 1, and the results are shown in Table 3: Table 3 Tablet disintegration test Example 6 According to the method of the Chinese Pharmacopoeia (General Rule 0993), the mixed granules in each group of Table 4 were mixed in the three-dimensional mixer for 10 minutes before tableting and the Carr index and Hausner ratio tests were performed. The content uniformity was tested according to the Chinese Pharmacopoeia (General Rule 0941), and the results are shown in Table 4: Table 4 Carr index, Hausner ratio and uniformity test The results show that the particles have good fluidity, good mixing uniformity and good content uniformity as shown by the Carr index and Hausner ratio.

[0051] Comparative Example 1 The baricitinib granulation step and the finasteride granulation step in Example 1 were fed with equal mass replacement to obtain Table 5: Table 5 Replacement table of components in Example 1 Wherein "△" represents the same type of feeding amount as in Example 1; Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the baricitinib granulation step is changed from the original dry granulation to wet granulation to obtain Group 9, specifically as follows: Baricitinib granulation steps: 5g of baricitinib, 30g of D-mannitol and 130g of VIVAPUR were added ® 102 microcrystalline cellulose was premixed in a wet granulator for 5 min and mixed for 10 min, and wet granulated with purified water to obtain a soft material with a 14-mesh sieve; after drying in a fluidized bed at 60 °C, granulation was performed with a 1.2 mm sieve; 2 g of magnesium stearate was added and the granules after granulation were mixed for 10 min.

[0052] Finasteride granulation steps: add 90 g of SuperTab to 5 g of finasteride ® 11SD Lactose, 10 g VIVASTAR ® P sodium carboxymethyl starch and 20 g pregelatinized starch were premixed in a wet granulator for 5 min. 0.6 g E5 hydroxypropyl methylcellulose was dissolved in 20% ethanol solution to prepare a 20% hydroxypropyl methylcellulose binder solution, and wet granulation was performed to obtain a soft material that was passed through a 14-mesh sieve and dried in an oven at 60°C. Then, 1.5 g magnesium stearate and 10 g LH-21 low-substituted carboxypropyl methylcellulose were added and mixed for 10 min.

[0053] Total mixing and coating step: 167g of the prepared baricitinib granules and 137.1g of finasteride granules were placed in a three-dimensional mixer with a mixing speed of 10-30Hz. After mixing for 10min, tablets were pressed using an 8mm die to control the hardness to about 80N-120N. A 15% (w / w) solid content Opadry coating solution was prepared, the inlet air temperature was set at 50-70°C, and the tablet bed temperature was set at 35°C-45°C for film coating. The coating weight gain was controlled at 2%-6% to obtain a compound tablet.

[0054] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the finasteride granulation step is changed from the original wet granulation to dry granulation, and Group 10 is obtained, specifically as follows: Baricitinib granulation steps: 5g of baricitinib, 30g of D-mannitol and 130g of VIVAPUR were added® 102 microcrystalline cellulose, set the vibration mixer to a primary vibration frequency of 30 Hz and mix for 15 minutes, and sieve through a 14-mesh screen. Weigh 2 g of magnesium stearate and add it, set the vibration mixer to a secondary vibration frequency of 30 Hz and mix for 5 minutes, then dry granulate the mixed material, set the feed speed to 20.0 rpm, the roller oil pressure to 30 bar, the roller speed to 9.0 rpm, the granulation speed to 100.0 rpm, and sieve through a 1.2 mm sieve.

[0055] Finasteride granulation steps: add 90 g of SuperTab to 5 g of finasteride ® 11SD Lactose, 10 g VIVASTAR ® P sodium carboxymethyl starch, 0.6g E5 hydroxypropyl methylcellulose and 20g pregelatinized starch were mixed in a mixer for 10 minutes. The mixed materials were dry granulated, with the feed speed set at 20.0rpm, roller oil pressure at 30bar, roller speed at 9.0rpm, granulation speed at 100.0rpm, and passed through a 1.2mm sieve; 1.5g magnesium stearate and 10g LH-21 low-substituted carboxypropyl methylcellulose were added and the granules after granulation were mixed in a mixer for 10min.

[0056] Total mixing and coating step: 167g of the prepared baricitinib granules and 137.1g of finasteride granules were placed in a three-dimensional mixer with a mixing speed of 10-30Hz. After mixing for 10min, tablets were pressed using an 8mm die to control the hardness to about 80N-120N. A 15% (w / w) solid content Opadry coating solution was prepared, the inlet air temperature was set at 50-70°C, and the tablet bed temperature was set at 35°C-45°C for film coating. The coating weight gain was controlled at 2%-6% to obtain a compound tablet.

[0057] Comparative Example 4 The difference between Comparative Example 4 and Example 1 is that the sieve mesh number and vibration frequency in the baricitinib granulation step, the sieve mesh number in the finasteride granulation step, the air inlet temperature and the tablet bed temperature in the total mixing step are different, and Table 6 is obtained: Table 6 Parameter substitution table for the preparation steps of the homemade preparation (dry method) in Example 1 “——” indicates that the parameters are the same as those in the corresponding steps of Example 1, and “×” indicates that there is no such step.

[0058] Example 7 Performance Test: According to the ICH guidelines, the tablets prepared from Groups 1 to 14 were placed under accelerated and long-term conditions for 6 months, and the impurity components in the tablets were tested to obtain Table 9.

[0059] Table 9 Accelerated 6-month content and impurity test results of group 1 to group 14 tablets: The accelerated 6-month test conditions are (40℃±2℃, RH75%±5%); In Tables 9 and 10, the main content of baricitinib on day 0 of groups 1 to 12 was in the range of 100±0.2, and the main content of finasteride was in the range of 100±0.3.

[0060] According to the ICH guidelines, the tablets prepared from Groups 1 to 12 were placed under long-term conditions for up to 6 months, and the impurity components in the tablets were tested to obtain Table 10.

[0061] Table 10 Long-term 6-month content and impurity test results of group 1 to group 14 tablets Long-term 6-month test conditions: (25°C ± 2°C, RH 60% ± 5%) The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A tablet composition for treating alopecia areata, characterized in that: Including, main drug, D-mannitol, microcrystalline cellulose, first lubricant, lactose, sodium carboxymethyl starch, pregelatinized starch, hydroxypropyl methylcellulose, second lubricant, low-substituted carboxypropyl methylcellulose, The main drug includes one or more of baricitinib or a pharmaceutically acceptable salt thereof, finasteride or a pharmaceutically acceptable salt thereof.

2. The tablet composition for treating alopecia areata according to claim 1, characterized in that: The invention comprises 4 to 10 parts by weight of a main drug, 24 to 30 parts by weight of D-mannitol, 104 to 130 parts by weight of microcrystalline cellulose, and 1.6 to 2.0 parts by weight of a first lubricant. 72-90 parts by weight of lactose, 8-10 parts by weight of sodium carboxymethyl starch, 16-20 parts by weight of pregelatinized starch, 0.48-0.60 parts by weight of hydroxypropyl methylcellulose, 1.2-1.5 parts by weight of a second lubricant, and 8-10 parts by weight of low-substituted carboxypropyl methylcellulose.

3. A tablet composition for treating alopecia areata according to any one of claims 1 or 2, characterized in that: The invention comprises 5 parts by mass of baricitinib, 5 parts by mass of finasteride, 30 parts by mass of D-mannitol, 130 parts by mass of microcrystalline cellulose, 2 parts by mass of a first lubricant, 90 parts by mass of lactose, 10 parts by mass of sodium carboxymethyl starch, 20 parts by mass of pregelatinized starch, 0.6 parts by mass of hydroxypropyl methylcellulose, 1.5 parts by mass of a second lubricant, and 10 parts by mass of low-substituted carboxypropyl methylcellulose.

4. A tablet composition for treating alopecia areata according to any one of claims 1 or 2, characterized in that: The invention comprises 8 parts by mass of a main drug, 24 parts by mass of D-mannitol, 104 parts by mass of microcrystalline cellulose C, 1.6 parts by mass of a first lubricant, 72 parts by mass of lactose, 8 parts by mass of sodium carboxymethyl starch, 16 parts by mass of pregelatinized starch, 1.2 parts by mass of a second lubricant, and 8 parts by mass of low-substituted carboxypropyl methylcellulose.

5. The tablet composition for treating alopecia areata according to claim 1, characterized in that: The main drug includes 4-5 parts by weight of baricitinib and 4-5 parts by weight of finasteride, and / or the first lubricant and the second lubricant are each independently selected from one or a combination of magnesium stearate, silicon dioxide, calcium stearate, polyethylene glycol, and talc.

6. A method for preparing a tablet composition for treating alopecia areata, comprising the steps of: S1: baricitinib or a pharmaceutically acceptable salt thereof, D-mannitol and microcrystalline cellulose are mixed at a first vibration frequency, sieved, a first lubricant is added, mixed again at a second vibration frequency, sieved, and baricitinib particles are prepared; S2: Finasteride or a pharmaceutically acceptable salt thereof is premixed with lactose, sodium carboxymethyl starch and pregelatinized starch, and the mixture is mixed with a solution of hydroxypropyl methylcellulose to obtain a soft material, which is sieved and dried, and a second lubricant and low-substituted carboxypropyl methylcellulose are added to obtain finasteride particles; S3: The baricitinib granules are mixed with the finasteride granules, compressed into tablets, and coated to obtain a tablet composition.

7. The method for preparing a tablet composition for treating alopecia areata according to claim 6, characterized in that: The step S1 is to mix 4-5 parts by mass of baricitinib, 24-30 parts by mass of D-mannitol, and 104-130 parts by mass of microcrystalline cellulose at a first vibration frequency, and add 1.6-2 parts by mass of a first lubricant.

8. The method for preparing a composition for treating alopecia areata according to any one of claims 6 or 7, characterized in that: In the step S1, the first vibration frequency is 25-30 Hz, and / or, in the step S1, the second vibration frequency is 25-30 Hz, and / or, in the step S1, the rolling pressure is 28-30 bar, and / or, in the step S1, the rolling speed is 8-9 rpm, and / or, in the step S1, the screening speed is 100-110 rpm.

9. The method for preparing a composition for treating alopecia areata according to any one of claims 6 to 8, characterized in that: In the step S2, 4 to 5 parts by mass of finasteride are premixed with 72 to 90 parts by mass of lactose, 8 to 10 parts by mass of sodium carboxymethyl starch, and 16 to 20 parts by mass of pregelatinized starch to obtain a soft material, and / or, in the step S2, the mass part of the second lubricant is 1.2 to 1.5, and / or, in the step S2, the mass part of low-substituted carboxypropyl methylcellulose is 8 to 10, and / or, in the step S2, the solution of hydroxypropyl methylcellulose is a mixed solution of hydroxypropyl methylcellulose, ethanol and water, and / or, in the step S2, the mass fraction of the solution of hydroxypropyl methylcellulose is 15 to 25%.

10. The method for preparing a composition for treating alopecia areata according to any one of claims 6 to 9, characterized in that: In the step S3, the mixing ratio of baricitinib granules to finasteride granules by mass is (133-167):(109-137), and / or, in the step S3, the baricitinib granules and the finasteride granules are mixed at a rate of 10-30 Hz, and / or, in the step S3, an 8 mm punch is used for tableting, and / or, in the step S3, the tableting hardness is 80N-120N, and / or, in the step S3, Opadry coating solution is used for coating, and / or, in the step S3, the coating solution has a mass fraction of 15% w / w solid content of Opadry coating solution, and / or, in the step S3, the air inlet temperature of the coating is 50-70°C, and / or, in the step S3, the tablet bed temperature of the coating is 35°C-45°C.

Images