Tacrolimus foaming agent as well as preparation method and application thereof

Abstract

The invention discloses a tacrolimus foaming agent as well as a preparation method and application thereof, and relates to the field of medicines. The tacrolimus foaming agent provided by the invention comprises a liquid medicine and a propellant, the liquid medicine is prepared from the following components: 0.01 to 3 weight percent of tacrolimus, 52.5 to 62.5 weight percent of ethanol, 1.2 to 3.6 weight percent of foam carrier, 0.2 to 1.5 weight percent of surfactant, 0.1 to 5.1 weight percent of stabilizer and the balance of water; the content of the propellant is 6.0-8.5% of the weight of the liquid medicine; the propellant is prepared from the following components in percentage by weight: 50 to 60 percent of propane, 10 to 20 percent of isobutane and 20 to 32 percent of butane. According to the invention, long-term storage and application of the tacrolimus foaming agent are realized, the tacrolimus foaming agent is superior to the rucotinib phosphate emulsifiable paste for treating vitiligo, and a new choice can be provided for vitiligo treatment.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, and more particularly to a tacrolimus foaming agent, its preparation method, and its application. Background Technology

[0002] Vitiligo is an acquired polygenic autoimmune disease characterized by the loss of epidermal melanocytes, resulting in depigmented white patches on the skin and mucous membranes. The pathogenesis of vitiligo is complex, involving multiple factors including genetics, immunity, neurology, and endocrine function. Currently, it is believed that the pathogenesis of vitiligo is mainly related to the destruction of melanocytes, autoimmune responses, oxidative stress, and neuroinflammation. Commonly used clinical treatments include topical corticosteroids, immunomodulators, and phototherapy; however, these methods have limitations in efficacy, significant side effects, and poor patient compliance.

[0003] Tacrolimus is a typical calcineurin inhibitor. Its core function is to inhibit the activation and proliferation of immune cells such as T lymphocytes, thereby suppressing abnormal immune responses. Currently, it is available in tablets, extended-release tablets, extended-release capsules, granules, injections, eye drops, and ointments. In organ transplantation, tacrolimus is approved for the prevention of acute rejection after heart, kidney, and liver transplants, and can also treat acute rejection in transplant patients who are unresponsive to or intolerant of other immunosuppressants. In dermatology, tacrolimus is a first-line topical immunomodulator for the treatment of atopic dermatitis, particularly suitable for patients who do not respond well to or cannot tolerate glucocorticoid therapy. Currently, tacrolimus ointment formulations have potential applications in the treatment of vitiligo, but their direct use also has significant drawbacks: the affected skin area is large, and the inherent thick and sticky nature of the ointment base makes it difficult to apply evenly, easily staining clothing and significantly reducing patient compliance; in addition, vitiligo lesions may be distributed in areas with dense hair, and the ointment tends to adhere to the hair, making it difficult to fully contact the lesions, and since tacrolimus is dispersed in the ointment base, the locally dissolved drug concentration is low, making it difficult to release in a short time, and the drug is easily removed from the skin over time, affecting drug absorption, thus making it unsuitable for the treatment of vitiligo.

[0004] Given the clinical challenges of vitiligo treatment, such as the variable lesion areas, difficulty in reaching the affected areas with systemic medication, and poor absorption of drugs through the skin, developing a topical, fast-release tacrolimus formulation for vitiligo treatment is the optimal choice. A hydroalcoholic foam formulation is the preferred dosage form for clinical application. The inherent high concentration of ethanol in the foam matrix can quickly and briefly open the stratum corneum, promoting rapid drug penetration. It is easy to apply, particularly to skin folds and areas with dense hair, allowing for precise drug delivery to meet the needs of vitiligo treatment. However, it is important to note that foam formulations still face challenges related to temperature sensitivity and physical stability in practical applications. Existing formulations can only be stored and used at room temperature (15-25℃). High temperatures in summer can cause rapid defoaming, making it difficult to complete the drug delivery process, while low temperatures in winter can lead to product precipitation and insufficient product uniformity, making it difficult to cope with complex and variable application environments. Furthermore, the core challenge in developing tacrolimus into a fast-release foam formulation lies in stability control. Tacrolimus in solid form exhibits better stability; therefore, most marketed formulations of tacrolimus exist in crystalline form, with only injectable formulations in a dissolved state. Injectable tacrolimus is a formulation of anhydrous ethanol and polyoxyethylene 60 hydrogenated castor oil, requiring dilution with physiological saline or glucose and administration within 24 hours to prevent bacterial contamination and degradation of the active ingredient. Furthermore, other studies have found that tacrolimus undergoes irreversible degradation in aqueous solutions, and water is an indispensable component of hydroalcoholic foaming agents. Therefore, optimizing the formulation to improve the environmental adaptability and long-term storage stability of tacrolimus foaming agents has become a crucial step in formulation development.

[0005] In conclusion, developing a tacrolimus foam formulation that can be stored stably for a long period of time and improves the skin permeability of the drug can effectively treat vitiligo and improve the patient's user experience, which has important clinical significance. Summary of the Invention

[0006] The purpose of this invention is to provide a tacrolimus foam formulation that can be stored and used for extended periods from low temperatures to room temperature, and to apply it to the treatment of vitiligo. By optimizing the dosage form, improving skin penetration and patient compliance, a more effective treatment option is provided for vitiligo patients.

[0007] The objective of this invention is achieved through the following technical solutions.

[0008] A tacrolimus foaming agent is provided, comprising a pharmaceutical solution and a propellant; the pharmaceutical solution comprises the following components: 0.01–3 wt% tacrolimus, 52.5–62.5 wt% ethanol, 1.2–3.6 wt% foam carrier, 0.2–1.5 wt% surfactant, 0.1–5.1 wt% stabilizer, and the balance being water; the propellant is a mixed alkane composed of propane, isobutane, and butane; the content of the propellant is 6.0–8.5% of the weight of the pharmaceutical solution.

[0009] Preferably, the propellant comprises the following components: 50–60 wt% propane, 10–20 wt% isobutane, and 20–32 wt% butane. By adjusting the proportions of the propellant, the above-mentioned liquid is completely dissolved from low temperature (5±3℃) to room temperature (20±5℃), and the propellant is able to spray out foam with good properties under suitable pressure.

[0010] Preferably, the foam carrier is selected from C16-C18 fatty alcohols.

[0011] More preferably, the foam carrier is selected from one or both of hexadecyl alcohol and octadecyl alcohol.

[0012] Preferably, the surfactant is selected from one or more of polysorbate 60, polysorbate 80, and polyethylene glycol 15-hydroxystearate.

[0013] Preferably, the stabilizer is selected from one or more of butylated hydroxytoluene, hydroxypropyl betacyclodextrin, polyethylene glycol ester succinate, and polyethylene glycol 400.

[0014] Furthermore, the liquid also includes a thickener of 0–5 wt%; the thickener is selected from one or more of glycerol, propylene glycol, and carbomer.

[0015] Furthermore, the solution also includes a pH adjuster of 0.01–0.2 wt%; the pH adjuster is selected from one or more of potassium citrate, sodium citrate, citric acid, lactic acid, and sodium hydroxide.

[0016] The preparation method of the above-mentioned tacrolimus foam agent includes the following steps: mixing ethanol, foam carrier, surfactant, stabilizer and water at 65-75°C, cooling to 30-40°C and adding tacrolimus to dissolve to obtain a drug solution; placing the drug solution in a sealed container and filling it with a propellant to obtain the tacrolimus foam agent.

[0017] The present invention also provides the pharmaceutical use of the above-mentioned tacrolimus foam, which can be used to prepare drugs or preparations for treating vitiligo.

[0018] To obtain the above-mentioned technical solution of this application, the present invention conducted the following experimental research.

[0019] The technical challenge this invention aims to address is that the storage temperature range of commercially available or investigational hydroalcoholic foam systems is narrow, making it difficult to achieve stable storage of tacrolimus foam formulations. Furthermore, these systems are difficult to use normally in summer and winter. If the temperature is above room temperature, the foam defoams rapidly, making it difficult to complete the drug administration process. If the temperature is below room temperature, the foam may solidify into a semi-solid or precipitate crystals into a suspension, making it difficult to administer the drug evenly. Therefore, it is necessary to study the components and dosages in tacrolimus foam formulations in order to broaden the applicable temperature range of this dosage form, enabling long-term storage and use while ensuring the stability of the drug.

[0020] The test items (physical stability and chemical stability), test methods, and quality standards for the tacrolimus foam preparations prepared in the following test examples are shown in Table 1 below: Table 1. Test items, test methods and quality standards for the stability of tacrolimus foam.

[0021] Note: The active ingredient refers to tacrolimus. Considering weighing error, feeding error and detection error, the content of the active ingredient ranges from 95.00% to 105.00%, which is in line with the Chinese Pharmacopoeia standard.

[0022] (1) Study on the proportion of ethanol Table 2. Composition of prescriptions for Experimental Examples 1-7

[0023] Note: In Table 2, propane / isobutane / butane (50 / 20 / 30) represents a propellant composed of 50 wt% propane, 20 wt% isobutane, and 30 wt% butane; the content of the propellant (propane / isobutane / butane) in each test example is its weight percentage relative to the propellant solution. The same expressions in the following tables have the same meaning.

[0024] According to the formulations shown in Table 2, tacrolimus foam formulations for test examples 1-7 were prepared respectively. The production process is as follows: cetyl alcohol, octadecyl alcohol, polysorbate 60, ethanol, glycerol, dibutylhydroxytoluene, potassium citrate, citric acid, and purified water (excluding tacrolimus and propellant (propane / isobutane / butane)) were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure vessel and filled with propellant to obtain the tacrolimus foam formulations for the corresponding test examples.

[0025] The stability of the tacrolimus foams prepared in Examples 1–7 was tested. The test results are shown in Table 3 below: Table 3. Detection results of tacrolimus foaming agents in Test Examples 1–7

[0026] Note: M represents month, D represents day.

[0027] Table 3 shows that the physical and chemical stability of the tacrolimus foam in Experiments 1, 3, 4, 5, and 6 met the requirements, indicating that the addition of ethanol to the tacrolimus foam solution at 52.5-62.5 wt% met the application requirements.

[0028] The physical stability test results of Example 1 are as follows: Figure 1As shown; the physical stability test results of Experiment Example 3 are as follows. Figure 2 As shown; the physical stability test results of Experiment Example 5 are as follows. Figure 3 As shown; the physical stability test results of Experiment Example 7 are as follows. Figure 4 As shown.

[0029] (2) Research on foam carriers Table 4. Composition of the prescriptions for Experimental Examples 8-12

[0030] According to the formulations shown in Table 4, tacrolimus foam formulations for test examples 8-12 were prepared. The production process was as follows: Except for tacrolimus and the propellant (propane / isobutane / butane), cetyl alcohol, octadecyl alcohol, polysorbate 60, ethanol, glycerol, butylated hydroxytoluene, potassium citrate, citric acid, and purified water were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure vessel, and the propellant was added to obtain the corresponding tacrolimus foam formulation for the test examples.

[0031] The stability of the tacrolimus foams prepared in Examples 8-12 was tested. The test results are shown in Table 5 below: Table 5. Detection results of tacrolimus foaming agents in Test Examples 8-12

[0032] The test results in Table 5 show that the physical and chemical stability of the tacrolimus foam in test examples 9, 10, and 11 meet the requirements, indicating that the addition amount of foam carrier in the tacrolimus foam solution is 1.2–3.6 wt% to meet the application requirements.

[0033] The physical stability test results of Example 8 are as follows: Figure 5 As shown; the physical stability test results of Experiment Example 10 are as follows. Figure 6 As shown; the physical stability test results of Experiment 12 are as follows. Figure 7 As shown.

[0034] (3) Surfactant research Table 6. Composition of prescriptions for Experimental Examples 13-18

[0035] According to the formulations shown in Table 6, tacrolimus foam formulations for test examples 13-18 were prepared. The production process is as follows: Except for tacrolimus and the propellant (propane / isobutane / butane), cetyl alcohol, octadecyl alcohol, polysorbate 60 or polysorbate 80 or polyethylene glycol 15-hydroxystearate, ethanol, glycerin, butylated hydroxytoluene, potassium citrate, citric acid, and purified water were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure vessel, and the propellant was added to obtain the corresponding tacrolimus foam formulation for the test examples.

[0036] The stability of the tacrolimus foams prepared in Examples 13–18 was tested. The results are shown in Table 7 below: Table 7. Detection results of tacrolimus foaming agents in Test Examples 13–18

[0037] Table 7 shows that the physical and chemical stability of the tacrolimus foam in test examples 13, 14, 16, and 17 met the requirements, indicating that the amount of surfactant added to the tacrolimus foam solution at 0.2–1.5 wt% met the application requirements.

[0038] The physical stability test results of Example 13 are as follows: Figure 8 As shown; the physical stability test results of Test Example 15 are as follows. Figure 9 As shown; the physical stability test results of Test Example 17 are as follows. Figure 10 As shown.

[0039] (4) Stabilizer research Table 8. Composition of the prescriptions for Experimental Examples 19-22

[0040] According to the formulations shown in Table 8, tacrolimus foam formulations for test examples 19–22 were prepared. The production process was as follows: Except for tacrolimus and the propellant (propane / isobutane / butane), cetyl alcohol, octadecyl alcohol, polysorbate 60, ethanol, glycerol, butylated hydroxytoluene / hydroxypropyl betacyclodextrin / polyethylene glycol e-succinate / polyethylene glycol 400, potassium citrate, citric acid, and purified water were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure vessel, and the propellant was added to obtain the corresponding tacrolimus foam formulation for the test examples.

[0041] The stability of the tacrolimus foams prepared in Examples 19–22 was tested. The test results are shown in Table 9 below: Table 9. Detection results of tacrolimus foaming agents in Test Examples 19–22

[0042] Table 9 shows that the physical and chemical stability of the tacrolimus foam in test examples 20, 21, and 22 meets the requirements, indicating that the amount of stabilizer added to the tacrolimus foam solution is 0.1–5.1 wt% to meet the application requirements. The chemical stability of the tacrolimus foam in test example 19 is not as good as that in test examples 20, 21, and 22, especially its stability at 40°C.

[0043] The physical stability test results of Example 19 are as follows: Figure 11 As shown; the physical stability test results of test example 21 are as follows. Figure 12 As shown.

[0044] (5) Propellant Research Table 10. Composition of prescriptions for test cases 23–33

[0045] According to the formulations shown in Table 10, tacrolimus foam formulations for test examples 23–33 were prepared. The production process was as follows: Except for tacrolimus and the propellant (propane / isobutane / butane), cetyl alcohol, octadecyl alcohol, polysorbate 60, ethanol, glycerol, dibutylhydroxytoluene, potassium citrate, citric acid, and purified water were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure vessel and filled with the propellant shown in Table 9 to obtain the tacrolimus foam formulations for the corresponding test examples.

[0046] The stability of the tacrolimus foams prepared in Examples 23–33 was tested. The test results are shown in Table 11 below: Table 11. Detection results of tacrolimus foaming agents in Test Examples 23–33

[0047] Continued from Table 11

[0048] Table 11 shows that the tacrolimus foam formulations in Examples 24, 25, 30, and 32 exhibit excellent drug stability at low temperatures and good stability at room temperature. The liquid and foam properties meet the standards, allowing for long-term storage. This indicates that a propellant concentration of 6.0–8.5 wt% of the liquid, composed of 50–60 wt% propane, 10–20 wt% isobutane, and 20–32 wt% butane, meets application requirements. Furthermore, analysis of the physical stability test results in Table 11 suggests that the crystals or semi-solids precipitated in Examples 23, 27, 29, 31, and 33 are cetyl alcohol and / or octadecyl alcohol, which act as foam carriers. Comparative analysis shows that reducing the proportion of the polar component isobutane in the propellant reduces the overall polarity of the system, promotes the dissolution of the foam carrier, and ensures uniform drug delivery within the low-temperature to room-temperature range. Additionally, adjusting the proportions of the non-polar components propane and butane ensures appropriate pressure within the low-temperature to room-temperature range, enabling normal drug delivery.

[0049] The physical stability test results of Example 23 are as follows: Figure 13 As shown; the physical stability test results of test example 25 are as follows. Figure 14 As shown; the physical stability test results of test example 27 are as follows. Figure 15 As shown; the physical stability test results of test example 29 are as follows. Figure 16 As shown; the physical stability test results of test example 31 are as follows. Figure 17 As shown; the physical stability test results of test example 33 are as follows. Figure 18 As shown.

[0050] As can be seen from the test results of the above test examples 1–33, foaming agents containing tacrolimus, with 52.5–62.5 wt% ethanol, 1.2–3.6 wt% foam carrier, 0.2–1.5 wt% surfactant, and 0.1–5.1 wt% stabilizer in the drug solution, and with the propellant composed of 50–60 wt% propane, 10–20 wt% isobutane, and 20–32 wt% butane, and the amount of propellant added accounting for 6.0–8.5 wt% of the drug solution, exhibit good foaming agent stability and can achieve long-term storage from low temperature to room temperature.

[0051] This prescription is applicable not only to tacrolimus, but also to other drugs soluble in ethanol-water systems, and can be stored and used in the range of low temperature to room temperature.

[0052] This invention optimizes the formulation through extensive testing, achieving long-term storage and application of tacrolimus foam while ensuring clinical compliance and rapid drug penetration and local accumulation in the skin. This foam is superior to ruxolitinib phosphate cream for treating vitiligo, providing a new option for vitiligo treatment. Attached Figure Description

[0053] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the following description of the embodiments will be briefly introduced. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0054] Figure 1 The results of the physical stability test for Example 1; Figure 2 The results of the physical stability test for Example 3; Figure 3 The results of the physical stability test for Example 5; Figure 4 The results of the physical stability test for Example 7; Figure 5 The results of the physical stability test for Example 8; Figure 6 The results of the physical stability test for Example 10; Figure 7 The results of the physical stability test for Example 12; Figure 8 The results of the physical stability test for Example 13; Figure 9 The results of the physical stability test for Example 15; Figure 10 The results of the physical stability test for Example 17; Figure 11 The results of the physical stability test for Example 19; Figure 12 The results of the physical stability test for Example 21; Figure 13 The results of the physical stability test for Example 23; Figure 14 The results of the physical stability test for Example 25; Figure 15 The results of the physical stability test for Example 27; Figure 16 The results of the physical stability test for Example 29; Figure 17 The results of the physical stability test for Example 31; Figure 18 The results of the physical stability test for Example 33; Figure 19 The results of the physical stability test for Example 1; Figure 20 The results of the physical stability test for Example 5; Figure 21 Results for skin retention per unit area; Figure 22 Criteria for successful establishment of vitiligo mouse model; Figure 23 This is a graph showing the changes in the white spot score in mice. Figure 24 The image shows the changes in white patches in mice of each group. Detailed Implementation

[0055] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0056] It should also be further understood that the term "and / or" as used in this specification and the appended claims refers to any combination of one or more of the associated listed items and all possible combinations, and includes such combinations.

[0057] Table 12 Tacrolimus Foaming Agent Raw Material Components in Examples 1–7

[0058] According to the raw material components shown in Table 12, tacrolimus foams of Examples 1-7 were prepared respectively. The production process is as follows: Cetyl alcohol, octadecyl alcohol, polysorbate 60, ethanol, glycerol, dibutylhydroxytoluene, potassium citrate, citric acid, and purified water (excluding tacrolimus and propellant (propane / isobutane / butane)) were mixed and stirred at 70±5℃ until dissolved. After cooling to 35±5℃, tacrolimus was added and stirred until dissolved to obtain a drug solution. The drug solution was filled into an aluminum pressure tank and filled with propellant to obtain the tacrolimus foam of the corresponding example.

[0059] The stability of the tacrolimus foams prepared in Examples 1-7 was tested, and the results are shown in Table 13 below.

[0060] Table 13 Detection results of tacrolimus foaming agents in Examples 1-7

[0061] Table 13 shows that the tacrolimus foaming agents in Examples 1-7 have good stability and can be stored for a long time.

[0062] The physical stability test results of Example 1 are as follows: Figure 19 As shown; the physical stability test results of Example 5 are as follows. Figure 20 As shown.

[0063] 2. In vitro transdermal studies Example 5 was used to conduct an in vitro transdermal study, employing tacrolimus ointment (Protopic). ® (0.1%) was used as a control.

[0064] (1) In vitro transdermal conditions The conditions for in vitro transdermal testing are shown in Table 14.

[0065] Table 14 Summary of in vitro transdermal test conditions

[0066] (2) Skin integrity test The transdermal water loss (TEWL) method was used, with TEWL ≤ 15 g / m². 2 / hr is used as the standard to verify the integrity of pigskin.

[0067] (3) Experimental scheme Skin was placed between the receiving and supply chambers of the Franz diffusion cell, and tacrolimus foam (defoamed solution) and tacrolimus ointment (Protopic) from Example 5 were applied. ® Tacrolimus (0.1%) was evenly applied to the skin, and samples were taken at different time points to detect the tacrolimus content and calculate the cumulative permeation (ng / cm³). 2 Additionally, after the final sampling point, residual samples on the skin were removed, and the skin was minced and homogenized in an automated sample grinder. 15 mL of acetonitrile was added to extract tacrolimus, and the sample was analyzed to calculate the retention rate per unit area (ng / cm²). 2 ).

[0068] (4) Results of in vitro transdermal treatment The results of the in vitro transdermal test skin retention are shown in Table 15.

[0069] Table 15 Results of skin retention in in vitro transdermal test

[0070] Note: ** indicates a significant difference compared to 0.1% tacrolimus ointment (P < 0.01, t-test).

[0071] Results of skin retention per unit area as follows Figure 21 As shown.

[0072] The results show that the tacrolimus foam formulation of Example 5 rapidly accumulates in the skin within 2-4 hours, and the skin retention amount after 24 hours is significantly higher than that of tacrolimus ointment (P < 0.01). This indicates that the foam formulation reversibly opens the stratum corneum, promoting rapid drug penetration into the skin and facilitating the rapid therapeutic effect of tacrolimus through local skin retention. Furthermore, the 24-hour cumulative penetration amount of the tacrolimus foam formulation of Example 5 is lower than that of tacrolimus ointment, effectively avoiding systemic toxic side effects and demonstrating better safety.

[0073] 3. Animal testing Based on the aforementioned results, Example 5, tacrolimus foam, was selected for animal experiments. A mouse model of vitiligo was established using 40% monobenzone cream, and tacrolimus ointment (Protopic) was used. ® (0.1%) and ruxolitinib phosphate cream (Opzelura) ® (1.5%) served as a positive control to verify the therapeutic effect of tacrolimus foam on vitiligo.

[0074] Animal modeling C57BL / 6 black mice were used for modeling. A 2×3cm area was shaved off the center of the back to serve as the drug administration area. The area was first cleaned with sterile water. 80mg of 40% monobenzone cream was weighed and applied to the area with a finger. Each mouse was massaged for 1-2 minutes to ensure full absorption and no residue. The modeling period was approximately 50 days. Successful modeling was defined as follows: Figure 22 As shown.

[0075] Dosing regimen Treatment medications were applied daily in the morning in the following groups: low-dose tacrolimus foam (50 mg), high-dose tacrolimus foam (100 mg), blank foam (50 mg), tacrolimus ointment (50 mg), and ruxolitinib phosphate cream (50 mg). In the afternoon, 40% monobenzone cream (80 mg) was applied. This treatment lasted for 6 weeks. Patients were weighed and photographed every Monday. ImageJ software was used to calculate the proportion of vitiligo area to the total treated area, and the scores were adjusted according to the severity of the vitiligo. The scores were as follows: 0: 0%, 1: 1–10%, 2: 11–25%, 3: 26–50%, 4: 51–75%, 5: 76–100%.

[0076] Experimental results After the experiment, the white spot scores of mice in each group were statistically analyzed, as shown in Table 16. Figure 23 and Figure 24 As shown in the figure, in vitiligo model mice, the repigmentation rate of the low-dose and high-dose tacrolimus foam groups was significantly higher than that of the tacrolimus ointment group and the ruxolitinib phosphate cream group, and the repigmentation speed was also faster.

[0077] Table 16 Changes in White Spot Score in Mice

[0078] Note: Compared with the blank foaming agent group, ****: P<0.0001; After the experiment, the weight of mice in each group was counted, as shown in Table 17 below. The weight changes of mice during the drug administration and observation phases were within the normal range, with no abnormalities.

[0079] Table 17. Average body weight (g) of mice in each group.

[0080] The above experimental results demonstrate that tacrolimus foam can effectively treat vitiligo, compared to the original tacrolimus ointment (Protopic). ® (0.1%) and ruxolitinib phosphate cream (Opzelura), which has been approved by the FDA for the treatment of vitiligo. ® It has a faster and higher degree of repigmentation, and no obvious toxic side effects during the treatment period.

[0081] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any person skilled in the art can easily conceive of various equivalent modifications or substitutions within the technical scope disclosed in the present invention, and these modifications or substitutions should all be covered within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A tacrolimus foaming agent, characterized in that, Includes liquid medicine and propellant; The solution comprises the following components: tacrolimus 0.01–3 wt%, ethanol 52.5–62.5 wt%, foam carrier 1.2–3.6 wt%, surfactant 0.2–1.5 wt%, stabilizer 0.1–5.1 wt%, and the balance being water; The content of the propellant is 6.0–8.5% of the weight of the liquid drug; the composition of the propellant is as follows: propane 50–60 wt%, isobutane 10–20 wt%, butane 20–32 wt%.

2. The tacrolimus foaming agent according to claim 1, characterized in that, The foam carrier is selected from C16-C18 fatty alcohols.

3. The tacrolimus foaming agent according to claim 1, characterized in that, The foam carrier is selected from one or both of hexadecyl alcohol and octadecyl alcohol.

4. The tacrolimus foaming agent according to claim 1, characterized in that, The surfactant is selected from one or more of polysorbate 60, polysorbate 80, and polyethylene glycol 15-hydroxystearate.

5. The tacrolimus foaming agent according to claim 1, characterized in that, The stabilizer is selected from one or more of butylated hydroxytoluene, hydroxypropyl beta-cyclodextrin, polyethylene glycol succinate, and polyethylene glycol 400.

6. The tacrolimus foaming agent according to any one of claims 1–5, characterized in that, The solution also includes a thickener of 0–5 wt%; the thickener is selected from one or more of glycerol, propylene glycol, and carbomer.

7. The tacrolimus foaming agent according to claim 6, characterized in that, The solution also includes a pH adjuster of 0.01–0.2 wt%.

8. The tacrolimus foaming agent according to claim 7, characterized in that, The pH adjuster is selected from one or more of potassium citrate, sodium citrate, citric acid, lactic acid, and sodium hydroxide.

9. The method for preparing the tacrolimus foaming agent according to any one of claims 1-8, characterized in that, Includes the following steps: Ethanol, foam carrier, surfactant, stabilizer and water are mixed at 65-75°C and cooled to 30-40°C. Tacrolimus is then added to dissolve the mixture to obtain a drug solution. The drug solution is placed in a sealed container and filled with a propellant to obtain the tacrolimus foam.

10. The use of the tacrolimus foam formulation as described in any one of claims 1-8 in the preparation of a drug or formulation for treating vitiligo.

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