Ruxolitinib compositions and methods for preparing same

Abstract

The present invention discloses a ruxolitinib composition comprising: ruxolitinib or a pharma- ceutically acceptable salt thereof, an emulsifier, a co-emulsifier, a solvent, and an aqueous phase. The emulsifier comprises one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate. The co-emulsifier comprises propylene glycol monocaprylate. The solvent comprises one or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol. The ruxolitinib composition of the present invention has an ideal particle size and PDI. Furthermore, the present invention provides a ruxolitinib gel. Compared with ruxolitinib cream, the film permeation efficiency is improved, and the stability of administration to the outer skin under conditions of pH 5-7 is met; compared with ruxolitinib cream, and commercially available calcipotriol and benvitimod, the present invention achieves better efficacy in the aspect of psoriasis treatment.

Description

[Technical field]

[0001] The present invention relates to the field of pharmaceutical formulations, in particular to compositions comprising ruxolitinib or a pharma- ceutically acceptable salt thereof, and methods for preparing the compositions. [Background technology]

[0002] Ruxolitinib (chemical name: (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile) is an inhibitor of the tyrosine kinases JAK1 and JAK2 and is used to treat splenomegaly or other symptoms associated with adult patients with intermediate- or high-risk primary myelofibrosis (PMF) (also known as chronic idiopathic myelofibrosis), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia myelofibrosis (PET-MF).

[0003] [ka]

[0004] Chinese patent application publication number CN103002875B discloses a cream formed by oil-in-water emulsion for topical application to the skin. The cream has (R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propionitrile (i.e., ruxolitinib) or a pharma- ceutically acceptable salt thereof as a therapeutic agent, an oil phase selected from one or more of petrolatum, fatty alcohol, mineral oil, triglyceride, and dimethylsiloxane, an emulsifier component including one or more independently selected from glycerin fatty ester and sorbitan fatty acid ester, a solvent component including one or more independently selected from alkylene glycol and polyalkylene glycol, and a stabilizer component including one or more independently selected from polysaccharides. Topical preparations are generally required to have a pH value of 4.5 to 7, but the pH value of the patented preparation samples is approximately 3.1 to 3.6, which causes a certain degree of skin irritation when applied to patients and is not suitable for areas of skin with certain damage.

[0005] The US patent invention with publication number US20200405627A1 discloses a method for treating vitiligo by using an oil-in-water emulsion of 1.5% w / w ruxolitinib having an oil component selected from petrolatum, fatty alcohol, mineral oil, triglyceride, and polydimethylsiloxane, an emulsifier component selected from glycerol fatty acid ester and sorbitan fatty acid ester, a solvent component selected from alkylene glycol and polyalkylene glycol, and a stabilizer component selected from polysaccharides such as xanthan gum.

[0006] In vitro release testing is now recognized as an effective method for evaluating semi-solid formulations (e.g. creams, ointments, gels), which shows the efficacy of the formulation in vivo in vitro. In vitro release has the characteristics of strong operability, good reproducibility, and high sensitivity. Therefore, a suitable in vitro release testing method will promote the development of transdermal formulations. A Chinese patent invention with publication number CN111337640A discloses a method for quickly evaluating the in vitro release of topical formulations. At present, the in vitro release and permeation of topical formulations are mainly evaluated by Franz-type diffusion cells. In vitro release is carried out using artificial membranes, and permeation is carried out using isolated rat abdominal skin or Bama miniature pig skin or artificial bionic membrane (Strat-M® membrane) to investigate the skin permeation rate of the drug. Summary of the Invention

[0007] In one aspect, the invention provides a ruxolitinib composition comprising a therapeutic agent and an emulsifying agent.

[0008] In some embodiments according to the present invention, the therapeutic agent is ruxolitinib and / or a pharma- ceutically acceptable salt thereof, and the content of the free base is 0.5%-2.0% by weight of the composition.

[0009] In some embodiments according to the invention, the emulsifier is one or more of polyoxyethylene alkylaryl ether, polyoxyethylene monolaurate, polyoxyethylene monolaurate, polyoxyethylene lauryl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, and vitamin E succinate, preferably one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, and vitamin E succinate, more preferably one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate.

[0010] In some embodiments according to the present invention, the emulsifier is one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate, wherein the polyoxyethylene hydrogenated castor oil is one or more selected from RH20, RH30, RH40, RH50, and RH60, preferably one of RH40 and RH60, more preferably RH40; the polyoxyethylene castor oil is one or more selected from EL20, EL25, EL30, EL35, EL40, and EL60, preferably one or more of EL30, EL35, and EL40, more preferably EL35; and the vitamin E succinate is one or more selected from VE-TPGS400, VE-TPGS1000, and VE-TPGS1500, preferably VE-TPGS1000. The content of the emulsifier is 2% to 30%, more preferably 3% to 12% by weight of the composition.

[0011] In some embodiments according to the present invention, the ruxolitinib composition comprises a therapeutic agent, an emulsifier, and a co-emulsifier.

[0012] In some embodiments according to the present invention, the co-emulsifier comprises propylene glycol monocaprylate (capryol-90) in an amount of 0-10%, preferably 0-7%, by weight of the composition.

[0013] In some embodiments according to the present invention, the ruxolitinib composition comprises a therapeutic agent, an emulsifier, a co-emulsifier, and a solvent.

[0014] In some embodiments according to the present invention, the solvent is one or more of propylene glycol, diethylene glycol monoethyl ether (HP), and ethanol, and the content thereof is 0-60%, preferably 0-50%, by weight of the composition.

[0015] In some embodiments according to the present invention, the ruxolitinib composition comprises a therapeutic agent, an emulsifier, a co-emulsifier, a solvent, and an aqueous phase.

[0016] In some embodiments according to the present invention, the aqueous phase comprises water and optionally excipients. In order to meet the clinical requirements of different administration routes, pH adjusting agents, osmolality adjusting agents, preservatives, antioxidants, opacifying agents, etc. can be added to the water to further improve the formulation of the ruxolitinib composition, and the content of the aqueous phase, together with the content of the therapeutic agent, emulsifier, co-emulsifier and solvent, is such that the total weight of the composition reaches 100%.

[0017] In some embodiments of the invention, the ruxolitinib composition comprises: Therapeutic agent: ruxolitinib or a pharma- ceutically acceptable salt thereof Emulsifier: One or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate Co-emulsifier: Propylene glycol monocaprylate; Solvent: one or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol; and Water Appropriate amount ~100% by weight.

[0018] In some embodiments of the invention, the ruxolitinib composition comprises: Therapeutic Agent: 0.5% to 2.0% ruxolitinib or a pharma- ceutically acceptable salt thereof (based on the free base); Emulsifier: 2% to 30%, more preferably 3% to 12%, of one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate; Co-emulsifier: 0-10%, preferably 0-7% propylene glycol monocaprylate; Solvent: 0-60%, preferably 0-50%, of one or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol; and Water appropriate amount ~100% by weight, (Each weight is based on the total weight of the gel).

[0019] In one embodiment according to the invention, a method for preparing a ruxolitinib composition is as follows: 1) heating the therapeutic agent, the emulsifier and the co-emulsifier to 30-70°C, preferably 35-60°C, stirring, and then adding an aqueous phase to obtain a ruxolitinib composition; or 2) The therapeutic agent and the co-emulsifier are mixed and heated to 30-70°C, preferably 35-60°C, with stirring until dissolved, the emulsifier is added, stirred, and then the aqueous phase is added to obtain the ruxolitinib composition.

[0020] In one embodiment according to the invention, a method for preparing a ruxolitinib composition is as follows: 1) heating the therapeutic agent, emulsifier, solvent and co-emulsifier to 30-70°C, preferably 35-60°C, stirring, and then adding an aqueous phase to obtain a ruxolitinib composition; or 2) The therapeutic agent, co-emulsifier and solvent are heated to 30-70°C, preferably 35-60°C, with stirring until dissolved, the emulsifier is added, stirred, and then the aqueous phase is added to obtain the ruxolitinib composition.

[0021] In another aspect of the present invention, the present invention provides the use of the above-mentioned ruxolitinib composition, which can be used to prepare pharmaceutical formulations, including but not limited to tablets, granules, microtablets, ointments, creams and gels.

[0022] In yet another aspect of the present invention, the present invention provides the use of the above-mentioned ruxolitinib composition, particularly ruxolitinib gel. In addition to the above-mentioned ruxolitinib composition, the gel contains a gelling agent. The gelling agent is one or more selected from carbomer, methylcellulose, sodium carboxymethylcellulose, chitosan, gellan gum, guar gum, sodium carboxymethylcellulose, and hydroxypropylcellulose, preferably carbomer, and its content is 0.10% to 2.0%, more preferably 0.25% to 1.0%, by weight percentage.

[0023] In some embodiments, the ruxolitinib gel comprises: Therapeutic Agent: Ruxolitinib, or a pharma- ceutically acceptable salt thereof; Emulsifier: One or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate Co-emulsifier: Propylene glycol monocaprylate; Solvent: one or more selected from propylene glycol, diethylene glycol monoethyl ether, and ethanol Gelling agents: one or more selected from carbomer, methylcellulose, sodium carboxymethylcellulose, chitosan, gellan gum, guar gum, sodium carboxymethylcellulose, and hydroxypropylcellulose; and Water Appropriate amount ~100% by weight.

[0024] In some embodiments, the ruxolitinib gel comprises: Therapeutic Agent: 0.5% to 2.0% ruxolitinib, or a pharma- ceutically acceptable salt thereof (based on the free base); Emulsifier: 2% to 30%, preferably 3% to 12%, of one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate; Co-emulsifier: 0-10%, preferably 0-7% propylene glycol monocaprylate; Solvent: 0-60%, preferably 0-50%, more preferably 2%-50% of one or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol; Gel agent: 0.10% to 2.0%, preferably 0.25% to 1.0%, of one or more selected from carbomer, methylcellulose, sodium carboxymethylcellulose, chitosan, gellan gum, guar gum, sodium carboxymethylcellulose, and hydroxypropylcellulose; and Water appropriate amount ~100% by weight; (Each weight is based on the total weight of the gel).

[0025] In some embodiments, the ruxolitinib gel comprises: Therapeutic Agent: 0.5% to 2.0% ruxolitinib, or a pharma- ceutically acceptable salt thereof (based on the free base); Emulsifiers: 1%-10% polyoxyethylene hydrogenated castor oil, 1%-20% polyoxyethylene castor oil, and 0-20% vitamin E succinate; Co-emulsifier: 0-20% propylene glycol monocaprylate; Solvents: 1%-50% propylene glycol, 1%-10% diethylene glycol monoethyl ether, and 0-50% ethanol; Gel: 0.10% to 10.0% carbomer; and Water appropriate amount ~100% by weight; (Each weight is based on the total weight of the gel).

[0026] In some embodiments, the ruxolitinib gel comprises: Therapeutic Agent: 0.5% to 2.0% ruxolitinib, or a pharma- ceutically acceptable salt thereof (based on the free base); Emulsifiers: 1.0%-5.0% polyoxyethylene hydrogenated castor oil, 1-10% polyoxyethylene castor oil, and 0-10% vitamin E succinate; Co-emulsifier: 0-10% propylene glycol monocaprylate; Solvents: 1%-45% propylene glycol, 1%-5.0% diethylene glycol monoethyl ether, and 0-40% ethanol; Gel: 0.10% to 5.0% carbomer; and Water appropriate amount ~100% by weight; (Each weight is based on the total weight of the gel).

[0027] In some embodiments, the ruxolitinib gel comprises: Therapeutic Agent: 0.5% to 2.0% ruxolitinib, or a pharma- ceutically acceptable salt thereof (based on the free base); Emulsifiers: 1%-2% polyoxyethylene hydrogenated castor oil, 4%-10% polyoxyethylene castor oil, and 0%-5% vitamin E succinate; Co-emulsifier: 0-7% propylene glycol monocaprylate; Solvents: 5%-45% propylene glycol, 2%-5% diethylene glycol monoethyl ether, and 0-15% ethanol; Gel: 0.25% to 1.0% carbomer; and Water appropriate amount ~100% by weight; (Each weight is based on the total weight of the gel).

[0028] According to an embodiment of the present invention, a method for preparing a gel of ruxolitinib composition includes the following steps: mixing the ruxolitinib composition except for the aqueous phase, heating to 30-70°C, preferably 35-60°C, stirring to completely dissolve the excipients and dissolve the therapeutic agent, then stirring the swollen carbomer uniformly, and then adding the aqueous phase to obtain the ruxolitinib gel.

[0029] In yet another aspect, the present invention provides uses of the above-mentioned ruxolitinib compositions and ruxolitinib gels for treating one or more of the following diseases: dermatitis, psoriasis, vitiligo, hydronephritis, urticaria, and alopecia areata.

[0030] The present invention has the following beneficial effects: the ruxolitinib composition provided in the present invention has an average particle size in the range of 10-200 nm and a PDI value of 0.05-0.40, and can even reach an average particle size in the range of 10-100 nm and a PDI value of 0.05-0.20; and has the characteristics of good stability and being less likely to cause aggregation and flocculation. Furthermore, the gel prepared from the composition of the present invention has improved membrane permeation efficiency and stability when topically administered to the skin at a pH value of 5-7 compared to ruxolitinib cream. Furthermore, the gel prepared from the composition of the present invention has better efficacy in treating psoriasis compared to ruxolitinib cream and commercially available calcipotriol and benvitimod.

[0031] The problem solving of the present invention will be described below with examples. Those skilled in the art will understand that the following examples are merely for illustrating the present invention and should not be taken as limiting the scope of the present invention. If no specific techniques or conditions are described in the examples, they shall be in accordance with the techniques or conditions described in the technical literature or product instructions. All drugs or devices without manufacturer names are conventional products available on the market. [Brief description of the drawings]

[0032] [Figure 1] FIG. 1 shows the PASI scores 7 days after administration in Example 6. [Diagram 2] FIG. 2 is a plot of PASI appearance scores in Example 6. Detailed Description of the Invention

[0033] All reagents and materials used in the examples described below are commercially available.

[0034] "Diethylene glycol monoalkyl ether" should be understood as one or more diethylene glycols substituted with C1-C6 alkyl ethers. The diethylene glycol monoalkyl ethers are one or both of diethylene glycol monoethyl ether (DGME) and diethylene glycol monomethyl ether (DGMM).

[0035] In the examples of the present invention, HP refers to diethylene glycol monoalkyl ether, and further refers to diethylene glycol monoethyl ether.

[0036] In the present invention, "PDI" is an abbreviation for polydispersity index, and its physical meaning is the uniformity of particle size distribution. The smaller the value (distribution range), the more uniform the particle size distribution.

[0037] The mean particle size and PDI values ​​of the ruxolitinib compositions were detected by Malvern Nano S90. EXAMPLES

[0038] Example 1: Ruxolitinib composition and method for its preparation I. Formulation and composition The ruxolitinib composition of the invention comprises the following components: Therapeutic agent: ruxolitinib (the content was calculated based on the free base), Emulsifier: One or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate Co-emulsifier: Propylene glycol monocaprylate (Capryol-90), Solvent: One or more of propylene glycol, diethylene glycol monoethyl ether (HP), and ethanol Aqueous Phase: Contains water and pharma- ceutically acceptable excipients, including, but not limited to, pH adjusting agents, osmolality adjusting agents, preservatives, antioxidants, and opacifying agents.

[0039] II. Preparation of Ruxolitinib Compositions Formulations 1-7 were prepared by Method 1. Method 1: The therapeutic agent, emulsifier, co-emulsifier and solvent are mixed, heated to 50° C., stirred to completely dissolve the excipients and dissolve the therapeutic agent, and then an aqueous phase is added to obtain the ruxolitinib composition.

[0040] Formulations 8-14 were prepared by method 2. Method 2: The therapeutic agent, co-emulsifier and solvent are mixed, heated to 50°C and stirred to completely dissolve the excipients, and after dissolving the therapeutic agent, the emulsifier is added and stirred, and then the aqueous phase is added to obtain the ruxolitinib composition.

[0041] [Table 1]

[0042] [Table 2]

[0043] As shown in Tables 1 and 2, when the content of the therapeutic agent was 0.5-2.0%, the emulsifier was one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate, and the content thereof could be 3%-12% w / w; the content of the co-emulsifier was 0-7% w / w; the content of the solvent was 2%-50% w / w; and the total content of the aqueous phase, therapeutic agent, emulsifier, co-emulsifier, and solvent was 100%. The average particle size of the obtained ruxolitinib composition was 100 nm or less, and the PDI value was 0.2 or less.

[0044] Example 2: Examination of various emulsifiers The preparation method of Example 2 is the same as that of Example 1, except for the type and amount of emulsifier used, and is specifically shown in the following table: [Table 3]

[0045] As shown in Table 3, when the emulsifier was selected from Kolliphor hs15, glycerol fatty acid ester, poloxamer 407, Tween 80, polyoxyethylene cetyl ether, and polyoxyethylene sorbitan monolaurate, it was not possible to form a ruxolitinib composition having a desirable particle size or PDI value.

[0046] Example 3: Stability study of formulations of ruxolitinib compositions The ruxolitinib composition formulations of Example 1 were selected as formulations 2, 8, 9 and 12. The stability of the ruxolitinib composition formulations of the present invention was examined based on the changes in the average particle size and PDI value of the ruxolitinib composition formulations of the present invention after 1 month and 2 months at 25°C and 40°C. The detailed results are shown in Table 4.

[0047] [Table 4]

[0048] The above results demonstrate that the ruxolitinib composition provided by the present invention has good stability with no significant change in average particle size or PDI at room temperature or 40°C.

[0049] In addition, formulation 12 of the ruxolitinib composition in Example 1 was selected to study the pH stability of the ruxolitinib composition formulation of the present invention. Formulation 12 was adjusted to various pH values ​​using triethanolamine, and subjected to experiments at room temperature or under accelerated conditions to investigate the content of ruxolitinib in the formulation. Detailed results are shown in Table 5.

[0050] [Table 5]

[0051] There was no obvious change in the content of ruxolitinib at different pH values ​​from 3 to 7, and the ruxolitinib composition formulation of the present invention had good stability.

[0052] Example 4: Ruxolitinib gel and its stability Formulations 9, 10, and 12 from Example 2 were selected to prepare gel formulations 1, 2, and 3, respectively. The total weight of the gels was 100 g.

[0053] The preparation method is as follows: the ruxolitinib composition except for the aqueous phase is mixed, heated to 45°C, and stirred to completely dissolve the excipients, and after dissolving the therapeutic agent, the swollen carbomer is added and stirred uniformly, and then the aqueous phase is added to obtain a gel of the ruxolitinib composition.

[0054] The stability of the gel formulations provided in the present invention was investigated based on the content of ruxolitinib in gel formulations 1, 2 and 3. The detailed results are shown in Table 6.

[0055] [Table 6]

[0056] As a result, the pH values ​​of gel formulations 1, 2, and 3 were 5 to 7, and the content did not change significantly at either 25°C or 40°C, indicating good temperature stability.

[0057] Example 5: In Vitro Permeation and Release Studies of Ruxolitinib Gel Test method: A Franz diffusion cell (Tianjin Bowei Technology Co., Ltd., TP-6 ​​type) was used. An artificial membrane (Strat-M (registered trademark) Membrane) was fixed between the diffusion cell and the receiving cell, the diameter of the diffusion cell was 1.5 cm, and the volume of the receiving cell was 15 mL. Approximately 300 mg of ruxolitinib gel sample was filled into the diffusion cell, and the receiving liquid (0.05 M phosphate buffer with a pH value of 7.2 to 7.4) was injected into the receiving cell. The temperature of the water bath was 32 ± 1 °C, and the magnetic stirring speed at a constant temperature was 300 rpm / min. Every 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours, 1.5 mL of the receiving liquid was taken out from the receiving liquid cell, and the receiving liquid at the same temperature was replenished into the receiving cell at different times. The collected receiving fluid was centrifuged at high speed (18,000 rpm / min, 10 min), and the supernatant was collected and analyzed by HPLC to determine the receiving fluid concentration (C n ) was measured.

[0058] The cumulative amount of drug permeated per unit area is calculated by the following formula:

number

[0059] A comparative example was prepared with reference to the formulation shown in Table 4 of Example 3 of the specification of China Invention Patent No. CN103002875B granted to Incyte Holding Corporation (the concentration of ruxolitinib free base is 1.0%).

[0060] [Table 7]

[0061] From Table 8, it can be seen that gel formulations 1, 2 and 3 showed faster release and significantly higher in vitro release compared to the comparative cream.

[0062] Example 6: Study on the efficacy of ruxolitinib gel for psoriasis The drug of the present invention can effectively improve the symptoms of psoriasis. The therapeutic effect of the drug of the present invention on psoriasis can be further confirmed by the following test.

[0063] Animal studies: Establishment of a mouse model of psoriasis vulgaris (PSO) and drug treatment 1. Drugs and Reagents Test materials: 48 healthy SPF-level C57BL / 6J mice (half male and half female, 8-9 weeks old, weighing 20-25 g); model drug (5% imiquimod cream, Sichuan Mingxin Pharmaceutical); positive control drug (commercially available calcipotriol ointment, and commercially available bembitimod cream); blank gel formulation; commercially available ruxolitinib phosphate cream (refer to original patent cream, 1.5% ruxolitinib free base); Gel 1; and Gel 2. The formulations of Gel 1 and Gel 2 are shown in Table 8.

[0064] [Table 8]

[0065] 2. Test Method 2.1 Grouping Group division: 8 test groups, 6 animals in each group, total 48 animals. 1) Blank control group (no treatment other than hair removal) (N=6). 2) PSO model group (no treatment except for application of imiquimod for the model) (N=6). 3) PSO model + blank gel formulation group (twice a day, 15 mg / cm 2 (Applied topically for 7 consecutive days) (N=6). 4) PSO model + positive drug group A (0.005% calcipotriol ointment, 15 mg / cm twice a day) 2 topical application, administered for 7 consecutive days) (N=6). 5) PSO model + positive drug group B (1% benvitimod cream, 15 mg / cm twice daily) 2 , applied topically for 7 consecutive days) (N=6). 6) PSO model + gel 1 sample (twice a day, 15 mg / cm 2 topical application, administered for 7 consecutive days) (N=6). 7) PSO model + commercially available ruxolitinib cream (15 mg / cm twice daily) 2 topical application, administered for 7 consecutive days) (N=6). 8) PSO model + gel 2 samples (twice a day, 15 mg / cm 2 topical application, administered for 7 consecutive days) (N=6).

[0066] Testing process: Model preparation: Mice were acclimated for 7 days to prepare a mouse model of psoriasis vulgaris (PSO).

[0067] The model was created as follows: a skin area (approximately 2 cm × 3 cm) on the back of the mouse was exposed, and 50 mg of 5% imiquimod cream was applied topically every morning for 3 consecutive days to create the model, and the application of the drug for model creation was continued thereafter.

[0068] Model validation: This model has matured to SOP standards and no further mice will be used for model validation.

[0069] Treatment: (3 days after model creation), treatment with the corresponding drug was performed on day 4. During drug treatment, administration of 5% IMQ was continued to maintain the model, and administration of the drug for model creation was continued according to the administration days of the corresponding drug. Group 1): The blank control group (untreated) received no treatment. Group 2): To maintain the model, 5% imiquimod cream was applied to the model group at 62.5 mg per mouse, and no therapeutic treatment was given. Group 3): For model maintenance, the model group was treated with 5% imiquimod cream (62.5 mg per mouse) plus blank gel twice daily for 7 consecutive days. Group 4): For model maintenance, the model group was treated with 5% imiquimod cream (62.5 mg per mouse) and positive drug A (calcipotriol ointment) twice daily for 7 consecutive days. Group 5): For model maintenance, the model group was treated with 5% imiquimod cream (62.5 mg per mouse) and positive drug B (bembitimod cream) twice daily for 7 consecutive days. Group 6): To maintain the model, 5% imiquimod cream was applied to the model group at 62.5 mg per mouse, and the test drug (Gel 1 of this example) was applied twice a day for 7 consecutive days. Group 7): For model maintenance, 5% imiquimod cream was applied to each mouse at 62.5 mg, and the test drug (commercially available ruxolitinib phosphate cream) was applied twice daily to the model group for 7 consecutive days. The administration order was as follows: the treatment drug was administered once in the morning, the model preparation drug was administered once in the afternoon, and the treatment drug was administered once in the evening. Group 8): For model maintenance, 5% imiquimod cream was applied to the model group at 62.5 mg per mouse, and the test drug (Gel 2 of this example) was applied twice daily for 7 consecutive days.

[0070] Notes: To prevent the animals from licking the drug, after applying the gel to their backs, they were placed in separate cages without pads for a certain period of time (scheduled to be within 1 hour), and after allowing the gel to dry naturally, they were placed in feeding cages and fed normally. Individual feeding was prohibited because the animals were prone to depression; wrapping the applied area with gauze was prohibited because the drug could be absorbed.

[0071] 2.2 Test results: Pathological examination of drug-treated PSO model animals Testing process: The psoriasis-like lesion area and severity index (PASI) score of mice in each group was evaluated as follows: The changes in body weight and skin lesions of mice in each group were observed daily (body weight measurement: body weight was measured once a day for each mouse from the adaptation feeding to the end of administration, a total of 17 times; skin lesion score: score was evaluated once a day for each mouse from the model preparation period to the administration period, a total of 10 times) and recorded daily by digital photography. According to the PASI score criteria, the degree of erythema, scaling, and infiltration and thickening of the mouse skin lesions was scored from 0 to 4 points; the three scores were added together to obtain the total skin lesion severity score. After calculating the average score of the mice in each group, a trend line of the skin lesion score was drawn and the changes in the skin lesions of the mice in each group were observed.

[0072] 2.3 Statistical methods Results are expressed as mean ± standard error (Mean ± SEM) and analyzed using the statistical software SPSS 17.0. Differences between groups were compared using one-way analysis of variance (homogeneity of variance not assumed, Dunnett's T3). P < 0.05 indicates a statistically significant difference.

[0073] 3.Results Effects of gel, positive drug and commercial ruxolitinib phosphate cream on skin lesion appearance (PASI) in imiquimod-induced psoriasis model mice.

[0074] The PASI score was evaluated based on the degree of erythema, scale, infiltration and thickening of the skin lesions of the mice. From the score transition over 7 days, the PASI score of the drug group was significantly lower than that of the model group after 4 days of administration. On the 4th day of administration, the PASI scores of both the benvitimod group and the gel group of the present invention were significantly lower than that of the model group, and also significantly lower than that of the blank gel group (p<0.05, or p<0.01). On the 5th day of administration, the PASI score of the gel group of the present invention was significantly lower than that of the model group; the PASI score of the gel group of the present invention was significantly lower than that of the blank gel. On the 6th and 7th days of administration, the score of the gel group of the present invention was significantly lower than that of the model group and the blank gel group (p<0.01). Details are shown in Figures 1 and 2.

[0075] 4. Conclusion In this study, imiquimod-induced psoriasis mouse model was used to evaluate the protective effect of the present invention formulation, positive drug and commercial comparative ruxolitinib cream.The results show that the present invention gel, positive drug and commercial ruxolitinib cream can all significantly reduce the PASI score of mice.Compared with positive drug and commercial ruxolitinib cream, the present invention gel has better effect, and the present invention gel, positive drug and commercial ruxolitinib cream all have therapeutic effect on psoriasis, and the effect of the present invention gel in treating psoriasis locally is better than the same concentration of positive drug and commercial ruxolitinib cream.

[0076] In this specification, references to words such as "one embodiment," "some embodiments," "examples," "specific examples," or "some examples" mean that the particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In the present specification, the exemplary expressions of the above words do not necessarily refer to the same embodiment or example. Furthermore, particular features, structures, materials, or characteristics can be combined in any suitable manner in one or more embodiments or examples. Furthermore, the features of the various embodiments or examples described herein can be combined or combined without mutual inconsistency by one of ordinary skill in the art.

[0077] Although the embodiments of the present invention have been described above, it should be understood that the above embodiments are illustrative and cannot be construed as limiting the present invention. Changes, modifications, substitutions and variations may be made to the above embodiments by those skilled in the art within the scope of the present invention.

Claims

**Claim 1** A ruxolitinib composition, characterized in that the ruxolitinib composition contains a therapeutic agent and an emulsifier, wherein the therapeutic agent is ruxolitinib or a pharmaceutically acceptable salt thereof with a content based on the free base being 0.5% to 2.0% of the weight of the composition; the emulsifier is one or more of polyoxyethylene alkyl aryl ether, polyoxyethylene monolaurate, polyoxyethylene monolaurate, polyoxyethylene lauryl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene vegetable oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, and vitamin E succinate, preferably one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, polyoxyethylene monooleate, polyoxyethylene monolaurate, and vitamin E succinate, more preferably one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate. **Claim 2** The composition according to claim 1, characterized in that the emulsifier is one or more selected from polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate, wherein the polyoxyethylene hydrogenated castor oil is one or more selected from RH20, RH30, RH40, RH50, and RH60, preferably one of RH40 and RH60, more preferably RH40; the polyoxyethylene castor oil is one or more selected from EL20, EL25, EL30, EL35, EL40, and EL60, preferably one or more selected from EL30, EL35, and EL40, more preferably EL35; the vitamin E succinate is one or more selected from VE-TPGS400, VE-TPGS1000, and VE-TPGS1500, preferably VE-TPGS1000; and the content of the emulsifier is 2% to 30% of the weight of the composition, more preferably 3% to 12%. **Claim 3** The ruxolitinib composition according to claim 2, comprising a co-emulsifier, wherein the co-emulsifier is monocaprylate, and the content of the co-emulsifier is 0% to 10% of the weight of the composition, preferably 0% to 7%. **Claim 4** A ruxolitinib composition according to claim 3, comprising a solvent, wherein the solvent is selected from propylene glycol, diethylene glycol monoethyl ether, and ethanol, and the content of the solvent is 0% to 60% by weight of the composition, preferably 0% to 50% by weight.

5. A ruxolitinib composition according to claim 4, comprising an aqueous phase, wherein the aqueous phase comprises water and optionally an excipient, and the excipient is selected from one or more of a pH adjuster, an osmotic pressure adjuster, a preservative, and an opacifying agent; and the total content of the aqueous phase, the therapeutic agent, the emulsifier, the co-emulsifier, and the solvent is 100% by weight of the composition.

6. A method for preparing a ruxolitinib composition according to claim 5, characterized by comprising the following steps: Heating the therapeutic agent, the emulsifier, the co-emulsifier, and / or the solvent to 30 to 70 °C, preferably 35 to 60 °C, stirring, and then adding the aqueous phase to obtain the ruxolitinib composition.

7. A method for preparing a ruxolitinib composition according to claim 5, characterized by comprising the following steps: Mixing the therapeutic agent, the emulsifier, the co-emulsifier, and / or the solvent, heating to 30 to 70 °C, preferably 35 to 60 °C, with stirring until dissolved, adding the emulsifier and stirring, and then adding the aqueous phase to obtain the ruxolitinib composition.

8. Use of a ruxolitinib composition according to any one of claims 1 to 5 in the preparation of a pharmaceutical formulation, wherein the pharmaceutical formulation is selected from capsules, tablets, granules, microtablets, ointments, creams, and gels.

9. A ruxolitinib gel, characterized in that the gel comprises a ruxolitinib composition according to any one of claims 1 to 5 and a gelling agent.

10. The gelling agent is one or more selected from carbomer, gellan gum, guar gum, sodium carboxymethyl cellulose, and hydroxypropyl cellulose, preferably carbomer, and the content of the gelling agent is 0.10% to 2.0% by weight of the gel, preferably 0.25% to 1.0% by weight. The ruxolitinib gel according to claim 9.

11. A ruxolitinib gel, wherein the ruxolitinib gel is: Therapeutic agent: ruxolitinib or a pharmaceutically acceptable salt thereof; Emulsifier: one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate; Co-emulsifier: propylene glycol monocaprylate; Solvent: one or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol; Gelling agent: one or more selected from carbomer, methylcellulose, sodium carboxymethylcellulose, chitosan, gellan gum, guar gum, sodium carboxymethylcellulose, and hydroxypropylcellulose; and Water appropriate amount to 100% by weight A gel, characterized by comprising the above.

12. The ruxolitinib gel is: Therapeutic agent: 0.5% to 2.0% ruxolitinib, or a pharmaceutically acceptable salt thereof (based on the free base); Emulsifier: 2% to 30% of one or more of polyoxyethylene hydrogenated castor oil, polyoxyethylene castor oil, and vitamin E succinate; Co-emulsifier: 0 to 20% propylene glycol monocaprylate; Solvent: 0 to 60%, preferably 0 to 50%, more preferably 2% to 50% of one or two or more of propylene glycol, diethylene glycol monoethyl ether, and ethanol; Gelling agent: 0.10% to 2.0% of one or more selected from carbomer, methylcellulose, sodium carboxymethylcellulose, chitosan, gellan gum, guar gum, sodium carboxymethylcellulose, and hydroxypropylcellulose; and Water appropriate amount to 100% by weight; Each weight is based on the total weight of the gel; Comprising Preferably, the ruxolitinib gel is: Therapeutic agent: 0.5% to 2.0% ruxolitinib, or a pharmaceutically acceptable salt thereof (based on the free base); Emulsifier: 1% to 10% polyoxyethylene hydrogenated castor oil, 1% to 20% polyoxyethylene castor oil, and 0 to 20% vitamin E succinate; Co-emulsifier: 0 to 20% propylene glycol monocaprylate; Solvent: 1% to 50% propylene glycol, 1% to 10% diethylene glycol monoethyl ether, and 0 to 50% ethanol; Gelling agent: 0.10% to 2.0% carbomer; and Water appropriate amount to 100% by weight; Each weight is based on the total weight of the gel; Comprising More preferably, the ruxolitinib gel is: Therapeutic agent: 0.5% to 2.0% of ruxolitinib, or a pharmaceutically acceptable salt thereof (based on the free base); Emulsifier: 1.0% to 5.0% of polyoxyethylene hydrogenated castor oil, 1% to 10% of polyoxyethylene castor oil, and 0 to 10% of vitamin E succinate; Co-emulsifier: 0 to 10% of propylene glycol monocaprylate; Solvent: 1% to 45% of propylene glycol, 1% to 5.0% of diethylene glycol monoethyl ether, and 0 to 40% of ethanol; Gelling agent: 0.10% to 2.0% of carbomer; and Water q.s. to 100% by weight; Each weight is based on the total weight of the gel; comprising More preferably, the ruxolitinib gel is: Therapeutic agent: 0.5% to 2.0% of ruxolitinib, or a pharmaceutically acceptable salt thereof (based on the free base); Emulsifier: 1% to 2% of polyoxyethylene hydrogenated castor oil, 4% to 10% of polyoxyethylene castor oil, and 0 to 5% of vitamin E succinate; Co-emulsifier: 0 to 7% of propylene glycol monocaprylate; Solvent: 5% to 45% of propylene glycol, 2% to 5% of diethylene glycol monoethyl ether, and 0 to 15% of ethanol; Gelling agent: 0.25% to 1.0% of carbomer; and Water q.s. to 100% by weight; Each weight is based on the total weight of the gel; comprising The ruxolitinib gel according to claim 11, characterized in that.

13. A method for preparing the ruxolitinib gel according to claim 12, the method comprising the following steps: Mixing the ruxolitinib composition excluding the aqueous phase, heating to 30 to 70 °C, preferably 35 to 60 °C, stirring to completely dissolve the excipient, dissolve the therapeutic agent, then adding the swollen carbomer and stirring uniformly, and then adding the aqueous phase to obtain the ruxolitinib gel.

14. A medicament for use in the treatment of a disease, comprising the ruxolitinib composition according to any one of claims 1 to 5, wherein the disease is one or more of dermatitis, psoriasis, vitiligo, nephritis, urticaria, and alopecia areata.

15. A medicament for use in the treatment of a disease, comprising the ruxolitinib gel according to claim 9, wherein the disease is one or more of dermatitis, psoriasis, vitiligo, nephritis, urticaria, and alopecia areata. **Claim 16**: The pharmaceutical for use according to claim 15, wherein the gelling agent is at least one selected from carbomer, gellan gum, guar gum, sodium carboxymethyl cellulose and hydroxypropyl cellulose, preferably carbomer, and the content of the gelling agent is 0.10% to 2.0% by weight of the gel, preferably 0.25% to 1.0%. **Claim 17**: A pharmaceutical for use in the treatment of a disease, comprising the ruxolitinib gel according to claim 11 or 12, wherein the disease is at least one of dermatitis, psoriasis, vitiligo, nephritis, urticaria, and alopecia areata.

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