Topical formulation of baricitinib and use thereof

Abstract

The present application solves the problems in the prior art, and provides a topical formulation composition of baricitinib or a pharmaceutically acceptable salt thereof. By means of optimizing the composition of a formula, the stability, transdermal efficiency, and clinical applicability of the formulation are significantly improved.

Description

A topical formulation of baricitinib and its uses

[0001] This application claims priority to Chinese Patent Application No. 202510369772.0, filed on March 27, 2025, entitled "A Baricitinib Topical Preparation and Its Use", the entire contents of which are incorporated herein by reference. Technical Field

[0002] This application belongs to the field of pharmaceutical formulation technology, specifically relating to a baricitinib topical formulation and its uses. Background Technology

[0003] Autoimmune diseases are a group of systemic diseases that can affect multiple tissues and organs, with skin lesions being a common clinical manifestation. Janus tyrosine kinase (JAK) signaling is involved in the formation of skin lesions in various autoimmune diseases. JAK is a member of the cytoplasmic tyrosine kinase family and plays an important role in the signaling cascade of various type I and type II cytokine receptors. JAK can be divided into four subtypes: JAK1, JAK2, JAK3, and TYK2. JAK1 / 2 and TYK2 are expressed in almost all cells (excluding mature erythrocytes), while JAK3 is expressed only in hematopoietic cells, bone marrow cells, and lymphocytes. JAK-mediated signaling pathways include the JAK-STAT pathway, the MAPK pathway, and the PI3K-AKT pathway. The JAK-STAT pathway is involved in regulating erythrocyte and platelet proliferation, as well as cellular responses to cytokines, interferons, and growth factors. In the autoimmune microenvironment, numerous inflammatory cytokines can bind to corresponding JAK receptor subunits, further activating and promoting the expression of STAT regulatory proteins and their downstream genes. Simultaneously, the JAK-STAT pathway can interact with other inflammatory signaling pathways such as MAPK and PKB / mTOR. After cytokines bind to cell surface receptors, JAK-related receptors form dimers and are phosphorylated and activated, subsequently recruiting cytoplasmic STAT proteins, which are then phosphorylated and translocated to the nucleus, regulating the transcription and expression of downstream genes. JAK inhibitors can significantly block the JAK-STAT pathway and, in conjunction with other inflammatory pathways, significantly downregulate inflammatory cytokine levels, inhibit lymphocyte proliferation and differentiation, reduce the production of abnormal antibodies, and improve clinical symptoms such as atopic dermatitis, synovitis, arthralgia, and alopecia areata.

[0004] Baricitinib, as a reversible selective JAK1 / 2 inhibitor, can significantly downregulate the levels of inflammatory cytokines IL-6, IL-17, IL-22, and IL-23 and the chemokine MCP-1 by inhibiting the JAK-STAT pathway, inhibiting the phosphorylation levels of STAT1 / 3 and STAT1, significantly reducing the level of B cell autoantibodies and B cell activating factors, decreasing double-negative T cells, and simultaneously increasing regulatory T cells and follicular regulatory T cells, preventing immune complex deposition and immune cell infiltration, thus exerting a powerful anti-inflammatory effect.

[0005] However, for atopic dermatitis, long-term oral administration of baricitinib tablets may be necessary. The potential for serious adverse reactions (such as malignant tumors) has been flagged by the U.S. Food and Drug Administration (FDA), which warns of safety risks associated with long-term oral administration. Compared to systemic therapy, topical formulations may reduce the safety risks associated with long-term oral administration.

[0006] In the prior art, CN112168774A discloses a baricitinib cream with polyethylene glycol-7 stearate as the base. A low-speed stirring process improves the cream's smoothness and high-temperature stability. However, its active ingredient content is low (0.1wt%-0.5wt%), and it is not optimized for transdermal efficiency, potentially limiting its application in deep skin diseases (such as alopecia areata). Furthermore, the cream's excipient system is relatively simple, and there is still a slight risk of oil-water separation during long-term storage. Its efficacy against specific skin diseases has not been clearly verified.

[0007] On the other hand, CN115068407A proposes a baricitinib gel, which enhances drug permeability by adding transdermal penetration enhancers (such as propylene glycol and ethanol) and chelating agents (such as disodium EDTA), and is optimized for the treatment of alopecia areata. However, the preparation process of this gel is costly, and some formulations contain high concentrations of ethanol or isopropanol, which may irritate sensitive skin and affect patient compliance. In addition, there is limited stability data for existing gels under high temperature or long-term storage conditions, and excipient compatibility still needs further verification.

[0008] Given the problems existing in the current technology, there is an urgent need to develop a topical formulation of baricitinib that combines high transdermal permeability, excellent stability, and low irritation to meet clinical needs. Summary of the Invention

[0009] This application addresses the problems in the prior art by providing a topical formulation composition of baricitinib or its pharmaceutically acceptable salts and excipients, which significantly improves the stability, transdermal efficiency, and clinical suitability of the formulation by optimizing the formulation composition.

[0010] This application provides a baricitinib topical formulation and its use, comprising the active ingredient baricitinib or a pharmaceutically acceptable salt thereof and excipients.

[0011] The active ingredient baricitinib accounts for 0.1% to 3.0% of the total weight of the baricitinib topical preparation; preferably, the weight of baricitinib accounts for 0.2% to 3.0% of the total weight of the baricitinib topical preparation; preferably, the weight of baricitinib accounts for 0.2% to 2.0% of the total weight of the baricitinib topical preparation; preferably, the weight of baricitinib accounts for 0.5% to 2.0% of the total weight of the baricitinib topical preparation; preferably, the weight of baricitinib accounts for 1.0% to 2.0% of the total weight of the baricitinib topical preparation; preferably, the weight of baricitinib accounts for 1.0% to 1.5% of the total weight of the baricitinib topical preparation.

[0012] As a preferred technical solution, the excipient is selected from one or more of solvents, solubilizers, emulsifiers, and pH adjusters.

[0013] As a preferred technical solution, the solvent is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, polyethylene glycol 400, anhydrous ethanol, isosorbide dimethyl ether, d-α-tocopherol polyethylene glycol 1000 succinate, isopropanol, and propylene glycol monooctanoate.

[0014] Preferably, the solvent is one or both of diethylene glycol monoethyl ether and polyethylene glycol 400.

[0015] As a preferred technical solution, the solvent accounts for 20% to 50% of the total weight of the baricitinib topical preparation, and more preferably, the solvent accounts for 30% to 40% of the total weight of the baricitinib topical preparation.

[0016] As a preferred technical solution, the solvent is a mixture of diethylene glycol monoethyl ether and polyethylene glycol 400, wherein the ratio of diethylene glycol monoethyl ether to polyethylene glycol 400 is 15-55:45-85 (%, w / w), preferably 15-20:80-85 (%, w / w), and more preferably 20:80 (%, w / w).

[0017] As a preferred technical solution, the solvent is a mixture of diethylene glycol monoethyl ether and polyethylene glycol 400; the weight of the diethylene glycol monoethyl ether accounts for 5% to 10% of the total weight of the baricitinib topical preparation, preferably 6% to 8% of the total weight of the baricitinib topical preparation; the weight of the polyethylene glycol 400 accounts for 20% to 40% of the total weight of the baricitinib topical preparation, preferably 24% to 32% of the total weight of the baricitinib topical preparation.

[0018] As a preferred technical solution, the solubilizer is selected from one or more of propylene glycol monooctanoate, polyethylene glycol glycerol octanoate-capric acid, glycerol mono- and dioctanoate-capric acid, and N-methylpyrrolidone.

[0019] Preferably, the solubilizer is N-methylpyrrolidone.

[0020] As a preferred technical solution, the weight of the solubilizer accounts for 1% to 3% of the total weight of the baricitinib topical preparation, and more preferably, the weight of the solubilizer accounts for 2% to 3% of the total weight of the baricitinib topical preparation.

[0021] As a preferred technical solution, the emulsifier is selected from one or more of polyethylene glycol-7 stearate, oleoyl polyoxyethylene glycerol ester, mono- and di-stearyl glycerol esters, Tween 20, and Tween 80.

[0022] Preferably, the emulsifier is polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester.

[0023] As a preferred technical solution, the emulsifier accounts for 5% to 30% of the total weight of the baricitinib topical preparation, and more preferably, the emulsifier accounts for 10% to 20% of the total weight of the baricitinib topical preparation.

[0024] As a preferred technical solution, the emulsifier is a mixture of polyethylene glycol-7 stearate and oleoyl polyoxyethylene glyceride; wherein the weight of polyethylene glycol-7 stearate accounts for 10% to 20% of the total weight of the baricitinib topical preparation, preferably, the weight of polyethylene glycol-7 stearate accounts for 8% to 14% of the total weight of the baricitinib topical preparation; and the weight of oleoyl polyoxyethylene glyceride accounts for 1% to 10% of the total weight of the baricitinib topical preparation, preferably, the weight of oleoyl polyoxyethylene glyceride accounts for 2% to 8% of the total weight of the baricitinib topical preparation.

[0025] As a preferred technical solution, the pH adjuster is selected from one or more of phosphoric acid, hydrochloric acid, citric acid, fumaric acid, tartaric acid, and sodium citrate.

[0026] Preferably, the pH adjuster is phosphoric acid.

[0027] As a preferred technical solution, the pH adjuster accounts for 0.1% to 1% of the total weight of the baricitinib topical preparation, and preferably, the pH adjuster accounts for 0.2% of the total weight of the baricitinib topical preparation.

[0028] As a preferred technical solution, the pH of the baricitinib topical formulation is 3.5-5, preferably 4-4.5.

[0029] As a preferred technical solution, the baricitinib topical formulation includes creams, ointments, latexes, gels, etc., with creams being the preferred formulation.

[0030] Another aspect of this application provides a method for preparing a baricitinib topical formulation, wherein the baricitinib topical formulation is a cream, comprising the following steps:

[0031] (1) Preparation of raw material phase: Weigh the prescribed amount of baricitinib, solvent, solubilizer and pH adjuster into a beaker, heat and stir to dissolve baricitinib.

[0032] (2) Preparation of cream phase: The emulsifier is heated and melted, and the purified water is heated to 70-80°C. The purified water is added to the emulsifier mixture at 70-80°C, and the cream phase is obtained by shearing.

[0033] (3) Add the raw material phase to the cream phase while stirring, and stir to obtain baricitinib cream.

[0034] This application further provides the use of baricitinib topical formulation in the preparation of drugs for treating autoimmune diseases, preferably, the autoimmune diseases include atopic dermatitis, adult severe alopecia areata, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, systemic lupus erythematosus, etc.

[0035] The beneficial technical effects of this application are as follows:

[0036] (1) Baricitinib is poorly soluble in water. This application provides a system with high solubility for baricitinib. The baricitinib topical formulation prepared based on this system has good transdermal effect.

[0037] (2) This application provides a topical formulation of baricitinib with good skin feel, uniform and fine droplet size, and good thermal stability.

[0038] (3) This application provides a stable pH range for the baricitinib topical formulation, within which the baricitinib topical formulation has good stability.

[0039] (4) The topical formulation of baricitinib of this application has a good therapeutic effect on mouse atopic dermatitis induced by fluorescein isothiocyanate, and is low in irritation, safe and effective. Attached Figure Description

[0040] The accompanying drawings, which are provided to further illustrate this application and form part of this application, illustrate exemplary embodiments of this application and are used to explain this application, but do not constitute an undue limitation of this application.

[0041] Figure 1 shows the results of the ear thickness test in the in vivo efficacy test of Example 9;

[0042] Figure 2 shows the results of the ear weight test in the in vivo efficacy test of Example 9. Detailed Implementation

[0043] The specific embodiments of this application are described in detail below. It should be noted that the embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application.

[0044] The active pharmaceutical ingredient (API) baricitinib is supplied by Tiandi Hengyi Pharmaceutical Co., Ltd. The production process of baricitinib complies with the requirements of the 2010 edition of the Good Manufacturing Practice for Pharmaceuticals, and the quality standards of the API are in accordance with the API registration standards of the API supplier.

[0045] Example 1 Solvent System Screening

[0046] ① Solvent screening

[0047] Using the solubility of the active pharmaceutical ingredient (API) as an indicator, the dissolution effect of each solvent on baricitinib was investigated. The solvent with high API solubility was selected as the preferred solvent. The test results are shown in Table 1.

[0048] Solubility determination: Take 10g of solvent into a 50ml centrifuge tube, add 1g of baricitinib raw material, seal, place in a 55℃ constant temperature shaker, shake for 1h, and then determine the amount of baricitinib dissolved by high performance liquid chromatography.

[0049] High performance liquid chromatography (HPLC) conditions: octadecylsilane-bonded silica gel was used as the packing material; 0.1% phosphoric acid solution (pH adjusted to 2.5 with triethylamine)-methanol (60:40) was used as the mobile phase; the detection wavelength was 290 nm; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; and the injection volume was 10 μL.

[0050] Table 1 Solvent Screening

[0051] The results showed that diethylene glycol monoethyl ether and polyethylene glycol 400 had good solubility for baricitinib.

[0052] ② Solvent combination screening

[0053] The above-mentioned preferred solvent combinations may help improve the solubility of baricitinib. The screening results are shown in Table 2 below.

[0054] Table 2 Solvent Combination Screening

[0055] The results showed that the mixed solvents with a diethylene glycol monoethyl ether:polyethylene glycol ratio of 15%:85% and a diethylene glycol monoethyl ether:polyethylene glycol 400 ratio of 20%:80% exhibited the highest solubility for baricitinib.

[0056] Considering that diethylene glycol monoethyl ether can be used as both a solvent and a penetration enhancer, and that the solubility of baricitinib is highest when the ratio of diethylene glycol monoethyl ether to polyethylene glycol 400 is 20% to 80%, diethylene glycol monoethyl ether and polyethylene glycol 400 were selected as solvents with a ratio of 20% to 80% for further screening.

[0057] ③ Solubilizer Screening

[0058] Based on the above solvent types and proportions, the solubilizing effects of propylene glycol monocaprylate, polyethylene glycol glycerol monocaprylate, polyethylene glycol monocaprylate, glycerol monocaprylate, glycerol dicaprylate, and N-methylpyrrolidone as solubilizers were investigated using the solubility of the active pharmaceutical ingredient as an indicator. Solubilizers with high solubility of the active pharmaceutical ingredient were selected as preferred solubilizers. The test results are shown in Table 3.

[0059] Solubility determination: Take 10g of solvent (containing 1% solubilizer) into a 50ml centrifuge tube, add 1g of baricitinib raw material, seal, place in a 55℃ constant temperature shaker, shake for 1h, and then determine the amount of baricitinib dissolved by high performance liquid chromatography.

[0060] High performance liquid chromatography (HPLC) conditions: octadecylsilane-bonded silica gel was used as the packing material; 0.1% phosphoric acid solution (pH adjusted to 2.5 with triethylamine)-methanol (60:40) was used as the mobile phase; the detection wavelength was 290 nm; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; and the injection volume was 10 μL.

[0061] Table 3 Solubilizer Screening

[0062] The results showed that N-methylpyrrolidone had the highest solubilizing effect on baricitinib (43.93 mg / g) when used as a solubilizer. Therefore, N-methylpyrrolidone is preferred as a solubilizer.

[0063] Example 2 Prescription Screening 1

[0064] The following are prescriptions 1-6, see Table 4 below for details (" / " indicates that the excipient was not added).

[0065] Table 4 Prescriptions 1-6

[0066] The baricitinib compositions in Formulations 1-6 of Examples 2 are cream formulations of baricitinib, and the preparation methods are all the same, as follows:

[0067] Preparation of active pharmaceutical ingredient: Weigh the prescribed amount of baricitinib, solvent and N-methylpyrrolidone into a beaker, heat and stir to dissolve baricitinib.

[0068] Cream phase preparation: Polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester were heated and melted, and purified water was heated to 70-80℃. The purified water was added to the mixture of polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester at 70-80℃, and the cream phase was obtained by shearing.

[0069] The active pharmaceutical ingredient phase is added to the cream phase under stirring, and the mixture is stirred to obtain baricitinib cream.

[0070] Example 3 Performance Test

[0071] In vitro transdermal experiments were conducted on the baricitinib cream formulations of Examples 2, Formulations 1-6 and the comparative examples. The test results are shown in Table 5 below (" / " indicates that this performance test was not performed).

[0072] In vitro transdermal test: In vitro transdermal tests were performed using samples from formulations 1–6 and the control group. 0.03 g of the test sample was taken and diffused using the vertical diffusion cell method (United States Pharmacopeia 43rd Edition, 1724). 12 ml of 20% PEG400 phosphate buffer (pH 7.4) was used as the diffusion medium, with a diffusion speed of 600 rpm and a receiving area of ​​1.77 cm². 2 The sample loading amount was 0.03 g, the test temperature was 32℃, and the skin barrier was controlled by Bama pigs. The procedure was performed according to the prescribed method, and samples were taken at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 10 h, 16 h, 20 h, 24 h, 30 h, 36 h, and 48 h. All samples were sampled, and the replenishment volume was 16 ml. The cumulative release and dissolution flux of the samples were determined by HPLC.

[0073] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1% phosphoric acid solution (pH adjusted to 2.5 with triethylamine)-methanol (60:40) was used as the mobile phase; the detection wavelength was 290 nm; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; and the injection volume was 100 μL.

[0074] The results showed that the comparative formulations without diethylene glycol monoethyl ether and polyethylene glycol had almost no transdermal effect; the transdermal effect was poor when the solvent content in formulation 1 was low; for formulations 2-6, the transdermal effect was better when the solvent content was 30-40% and the solubilizer content was 2-3%; furthermore, samples from formulations 2-4 were permeated through the skin within 0.25 hours, indicating that the transdermal effect was better when the diethylene glycol monoethyl ether: polyethylene glycol ratio was 6-8:24-32; formulations 5 and 6 also showed samples permeating through the skin within 0.5 hours, indicating that diethylene glycol monoethyl ether and polyethylene glycol, used alone as solvents, also had good transdermal effects. In the overall trend of transdermal effect, the combined use of diethylene glycol monoethyl ether and polyethylene glycol resulted in higher average cumulative penetration and average flux over 48 hours compared to using either alone, indicating that the combined use was more effective than using either alone.

[0075] Example 4 Prescription Screening 2

[0076] The following are prescriptions 7-10, see Table 6 below for details (" / " indicates that the excipient was not added).

[0077] Table 6 Prescriptions 7-10

[0078] The baricitinib compositions in formulations 7-10 of Examples 4 are cream formulations of baricitinib, and the preparation methods are all the same, as follows:

[0079] Preparation of active pharmaceutical ingredient: Weigh the prescribed amounts of baricitinib, diethylene glycol monoethyl ether, polyethylene glycol 400 and N-methylpyrrolidone into a beaker, and heat and stir to dissolve baricitinib.

[0080] Cream phase preparation: Polyethylene glycol-7 stearate, oleoyl polyoxyethylene glycerol ester, and mono- and di-stearic acid glycerol esters were heated and melted, and purified water was heated to 70-80°C. The purified water was added to the mixture of polyethylene glycol-7 stearate, oleoyl polyoxyethylene glycerol ester, and mono- and di-stearic acid esters at 70-80°C, and the cream phase was obtained by shearing.

[0081] The active pharmaceutical ingredient phase is added to the cream phase under stirring, and the mixture is stirred to obtain baricitinib cream.

[0082] Example 5 Performance Test

[0083] The type and amount of emulsifier / co-emulsifier affect the droplet size and skin feel of the formulation. Using droplet size and skin feel as indicators, the type and amount of emulsifier / co-emulsifier are screened.

[0084] Droplet size determination: The cream sample was applied to a glass slide and observed and the droplet size was determined under a microscope.

[0085] Skin feel evaluation: **Content:** Apply 50 μl of sample to the tip of the index finger, gently press and rub with the thumb and index finger, repeating 5 times to assess the thickness and consistency. **Spreadability, Softness, and Greasiness:** Apply 70 μl of sample to the back of the hand, repeatedly rubbing in circular motions 8 times. Evaluate the spreadability, softness, and greasiness of the sample during application. **Post-application Gloss, Film Residue, Post-application Stickiness, and Post-application Greasiness:** Apply 70 μl of sample to the back of the hand, repeatedly rubbing in circular motions 20 times. After 1 minute, visually inspect the gloss of the applied sample. Check for sample film residue by kneading the skin surface with two fingers, check for sample stickiness by patting the skin with the outer edge of the palm, and check for post-application greasiness by scraping and rubbing the remaining sample from the skin surface with fingers. Score according to Skin Feel Rating Table 7.

[0086] Table 7 Skin Feel Rating Table

[0087] The droplet size and skin feel of baricitinib cream formulations of prescriptions 3 and 7-10 were tested, and the test results are shown in Table 8 below (" / " indicates that this performance test was not performed).

[0088] Table 8 Performance Test Results

[0089] The results showed that the droplet sizes of formulations 3, 7, 8, and 10 were all relatively small, ranging from 1.102 μm to 1.840 μm. Furthermore, the samples exhibited moderate consistency, good softness and spreadability, low greasiness, moderate gloss after application, no film residue, low adhesion and greasiness, and high overall evaluation scores. Therefore, polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester were selected as the preferred emulsifier and co-emulsifier, respectively, with dosages of 8.0–14.0% and 2.0–8.0%.

[0090] Example 6 Prescription Screening 3

[0091] The following are prescriptions 11-13, see Table 9 below for details (" / " indicates that the excipient was not added).

[0092] Table 9 Prescriptions 11-13

[0093] The baricitinib compositions in formulations 11-13 of Examples 6 are cream formulations of baricitinib, and the preparation methods are all the same, as follows:

[0094] Preparation of active pharmaceutical ingredient: Weigh the prescribed amounts of baricitinib, diethylene glycol monoethyl ether, polyethylene glycol 400, N-methylpyrrolidone and phosphoric acid into a beaker, and heat and stir to dissolve baricitinib.

[0095] Cream phase preparation: Polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester were heated and melted, and purified water was heated to 70-80℃. The purified water was added to the mixture of polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester at 70-80℃, and the cream phase was obtained by shearing.

[0096] The active pharmaceutical ingredient phase is added to the cream phase under stirring, and the mixture is stirred to obtain baricitinib cream.

[0097] Example 7 Stability Test

[0098] Stability test method: Formulas 11 to 13 were filled into aluminum pharmaceutical ointment tubes and placed at high temperature (40℃) for 10 days and 30 days respectively. The relevant substances of the samples were tested and the screening results are shown in Table 10.

[0099] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material (Thermo Scientific BDS Hypersil C18, 150 mm × 4.6 mm, 5 μm or equivalent column); 0.1% phosphoric acid solution (adjusted to pH 3.0 with triethylamine) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to the table below (a ghost peak trapping column was added between the gradient mixer and the injector); the detection wavelength was 290 nm; the column temperature was 30 °C; the flow rate was 1.0 mL per minute; and the injection volume was 50 μL.

[0100] Elution gradient table

[0101] Table 10 Stability Test Results

[0102] The results showed that formulation 13 increased both the maximum single impurity and total impurities under high temperature (40℃) conditions for 30 days, but the increases were small and within the limits. Formulations 11 and 12 also showed increases in maximum single impurities under high temperature (40℃) conditions for 30 days, with relatively large increases, but still within the limits. Therefore, the pH range was tentatively set at 3.5-5.0. Furthermore, Table 10 shows that the higher the pH value, the smaller the increase in maximum single impurities, indicating that the increase in maximum single impurities is pH-related. Considering that baricitinib has high solubility at low pH, pH 4.5-5.0 conditions may affect the solubility of the raw materials; therefore, formulation 12, with a pH range of 4.0-4.5, is the preferred formulation.

[0103] Example 8 Prescription Screening 4

[0104] The following are prescriptions 14-18, see Table 11 below for details (" / " indicates that the excipient was not added).

[0105] Table 11 Prescriptions 14-18

[0106] The baricitinib compositions in formulations 14-18 of Examples 8 are cream formulations of baricitinib, and the preparation methods are all the same, as follows:

[0107] Preparation of active pharmaceutical ingredient: Weigh the prescribed amounts of baricitinib, diethylene glycol monoethyl ether, polyethylene glycol 400, N-methylpyrrolidone and phosphoric acid into a beaker, and heat and stir to dissolve baricitinib.

[0108] Cream phase preparation: Polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester were heated and melted, and purified water was heated to 70-80℃. The purified water was added to the mixture of polyethylene glycol-7 stearate and oleoyl polyoxyethylene glycerol ester at 70-80℃, and the cream phase was obtained by shearing.

[0109] The active pharmaceutical ingredient phase is added to the cream phase under stirring, and the mixture is stirred to obtain baricitinib cream.

[0110] Example 9: In vivo efficacy experiment

[0111] Animal experiments:

[0112] A mouse model of atopic dermatitis induced by fluorescein isothiocyanate was established to explore the pharmacodynamic activities of different formulations on mice with atopic dermatitis. Hair was removed from the abdomen at Day 0 (approximately 3×3 cm). 2 Mice were randomly divided into a normal control group (n=6) and a fluorescein isothiocyanate induction group (n=48) based on their body weight. In the fluorescein isothiocyanate induction group, 300 μL of 0.5% fluorescein isothiocyanate solution was applied to the abdomen on Day 0 and Day 1. On Day 5, ear thickness and body weight were measured, and mice were randomly assigned to the following groups: G2: model group / n=6, G3: prescription 12 / n=6, G4: prescription 14 / n=6, G5: prescription 15 / n=6, G6: prescription 16 / n=6, G7: prescription 17 / n=6, G8: prescription 18 / 6, and G9: criborone cream / n=6. On Day 5 and Day 12, 20 μL of 0.5% fluorescein isothiocyanate solution was applied to both the inner and outer sides of the right ear to stimulate activity. The medication was administered twice daily on Day 5, Day 6, Day 12, and Day 13. Ear thickness was measured 24 hours after fluorescein isothiocyanate excitation, specifically on Day 5 (before excitation), Day 6, Day 12, and Day 13. Ear weight was measured at the end of the experiment.

[0113] Experimental results:

[0114] 1) Ear thickness: After excitation with fluorescein isothiocyanate, the ear thickness of the model group was significantly different from that of the normal group (P < 0.01), with thicknesses of 0.263 mm (G2) and 0.183 mm (G1) at the endpoint of the experiment. Prescriptions 12 (G3), 14 (G4), 15 (G5), 16 (G6), 17 (G7), 18 (G8), and criborone cream (G9) were all effective, with ear thicknesses (G3-G9) of 0.248 mm, 0.252 mm, 0.238 mm, 0.236 mm, 0.242 mm, 0.242 mm, and 0.252 mm at the endpoint of the experiment. The statistical results are shown in Figure 1.

[0115] 2) Ear weight: Compared with the normal group, the ear weight of the model group was significantly increased. Furthermore, compared with the model group, the ear weight of each drug-treated group was significantly decreased (P < 0.01). The ear weights of each group (G1-G9) were: 0.0337g, 0.0554g, 0.0481g, 0.0499g, 0.0404g, 0.0400g, 0.0478g, 0.0478g, and 0.0501g. The statistical results are shown in Figure 2.

[0116] The results showed that prescriptions 12, 14, 15, 16, 17, and 18 were effective in reducing ear thickness. Regarding ear weight reduction, all treatment groups showed a significant decrease in ear weight compared to the model group (P < 0.01). The degree of reduction in ear thickness and weight indicates that baricitinib cream is significantly effective in the atopic dermatitis model. Furthermore, no skin redness or swelling was observed during the preclinical study. In conclusion, baricitinib cream is safe and effective.

[0117] The above description is only a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the scope of protection of this application.

Claims

1. A topical formulation of baricitinib, characterized in that, It includes the active ingredient baricitinib or a pharmaceutically acceptable salt thereof and excipients, wherein the active ingredient baricitinib accounts for 0.1% to 3.0% of the total weight of the baricitinib topical preparation.

2. The baricitinib topical formulation according to claim 1, characterized in that, The excipient is selected from one or more of solvents, solubilizers, emulsifiers, and pH adjusters.

3. The baricitinib topical formulation according to claim 2, characterized in that, The solvent is selected from one or more of propylene glycol, diethylene glycol monoethyl ether, polyethylene glycol 400, anhydrous ethanol, isosorbide dimethyl ether, d-α-tocopherol polyethylene glycol 1000 succinate, isopropanol, and propylene glycol monooctanoate.

4. The baricitinib topical formulation according to claim 2, characterized in that, The solvent accounts for 20% to 50% of the total weight of the baricitinib topical formulation.

5. The baricitinib topical formulation according to claim 3, characterized in that, The solvent is one or both of diethylene glycol monoethyl ether and polyethylene glycol 400.

6. The baricitinib topical formulation according to claim 5, characterized in that, The solvent is diethylene glycol monoethyl ether and polyethylene glycol 400, and the ratio of diethylene glycol monoethyl ether to polyethylene glycol 400 is 15-55:45-85 (%, w / w).

7. The baricitinib topical formulation according to claim 6, characterized in that, The weight of the diethylene glycol monoethyl ether accounts for 5% to 10% of the total weight of the baricitinib topical formulation; the weight of the polyethylene glycol 400 accounts for 20% to 40% of the total weight of the baricitinib topical formulation.

8. The baricitinib topical formulation according to claim 2, characterized in that, The solubilizer is selected from one or more of propylene glycol monocaprylate, polyethylene glycol glycerol octanoate-capric acid ...

9. The baricitinib topical formulation according to claim 8, characterized in that, The solubilizer accounts for 1% to 3% of the total weight of the baricitinib topical formulation.

10. The baricitinib topical formulation according to claim 2, characterized in that, The emulsifier is selected from one or more of polyethylene glycol-7 stearate, oleoyl polyoxyethylene glycerol ester, mono- and di-stearyl glycerol esters, Tween 20, and Tween 80.

11. The baricitinib topical formulation according to claim 10, characterized in that, The emulsifier accounts for 5% to 30% of the total weight of the baricitinib topical formulation.

12. The baricitinib topical formulation according to claim 1, characterized in that, The pH of the topical baricitinib formulation is 3.5–5.

0.

13. The baricitinib topical formulation according to any one of claims 1-12, characterized in that, The types of baricitinib topical formulations include creams, ointments, latexes, and gels.

14. Use of the baricitinib topical formulation according to any one of claims 1-12 in the preparation of a medicament for treating autoimmune diseases; preferably, the autoimmune diseases include atopic dermatitis, adult severe alopecia areata, rheumatoid arthritis, psoriatic arthritis, systemic juvenile idiopathic arthritis, and systemic lupus erythematosus.

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