Relecotinib cream and preparation method thereof

Abstract

The invention discloses a rucotinib cream and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The cream comprises a therapeutic agent, an oil component, an emulsifier component, a solubilizer component and water, wherein the therapeutic agent is rucotinib or a pharmaceutically acceptable salt of rucotinib; polysorbate 20 is adopted as a solubilizer component, so that the solubility and the stability of the active components are effectively improved. The preparation method mainly comprises the following steps: dissolving the chelating agent, the polysorbate 20 and the antibacterial agent in water, heating for dissolving, and adding the rucotinib phosphate and the stabilizer to form a water phase; heating and melting the oil component and the emulsifier to form an oil phase; and finally, carrying out high-shear mixing emulsification on the two phases at a high temperature, adding phenoxyethanol, and cooling under a low-shear condition to obtain a finished product. Through optimized components and a specific preparation process, the physical stability and medication uniformity of the cream are remarkably improved, the product quality is controllable, and the cream is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a ruxolitinib cream and a preparation method thereof. BACKGROUND

[0002] Ruxolitinib is a Janus kinase (JAK) inhibitor, and its phosphate form is developed into a topical external preparation (such as a cream, an ointment) for treating atopic dermatitis, vitiligo and other autoimmune skin diseases. In the topical external preparation, ensuring that the active pharmaceutical ingredient is fully dissolved in the matrix and remains stable is a prerequisite for effective delivery and clinical efficacy.

[0003] At present, a composite solvent system of propylene glycol and polyethylene glycol is often used in the prior art to dissolve and load ruxolitinib phosphate. This combination utilizes the strong solubility of propylene glycol and the solubilization and stabilization effect of polyethylene glycol to form the basis of early preparations. However, this solvent system has many inherent defects and technical problems that need to be solved in practical application and long-term use. First, propylene glycol is a known potential skin irritant, especially for the target patient population whose skin barrier has already been damaged, and it often causes stinging, burning, itching and even contact dermatitis and other adverse reactions after use, which not only seriously affects the medication comfort and tolerance of patients, but also directly leads to a decrease in treatment compliance. Second, polyethylene glycol may also exacerbate this irritation to some extent, and together with the hygroscopicity of propylene glycol, it poses a potential threat to the chemical stability of the preparation, that is, it may absorb moisture and accelerate the degradation of the active ingredient. In addition, this solvent system often gives the cream a sticky skin feel, affecting the patient experience. Therefore, the existing solvent system based on propylene glycol and polyethylene glycol has inherent irritancy, potential stability problems and poor use experience, which has become an important bottleneck limiting the maximization of clinical benefits of ruxolitinib external preparations, and it is urgent to develop a milder, more stable and patient-friendly alternative solvent system to break through this technical difficulty.

[0004] In view of this, the present application is proposed. SUMMARY

[0005] In view of the above technical problems, the purpose of the present application is to provide a ruxolitinib cream and a preparation method thereof.

[0006] The present application is implemented as follows: The present application provides a ruxolitinib cream, which comprises, by weight percentage: a therapeutic agent 1%-2%, an oil component 20%-27%, an emulsifier component 1%-9%, a solubilizer component 1%-6% and water 50-70%; The therapeutic agent comprises ruxolitinib or a pharmaceutically acceptable salt thereof; The solubilizer component is polysorbate 20.

[0007] In some preferred embodiments, the therapeutic agent is ruxolitinib phosphate.

[0008] In some preferred embodiments, the oil component comprises at least one of an emollient, an occlusive agent, a stiffening agent, or a skin care agent.

[0009] In some preferred embodiments, the oil component comprises at least one of light liquid paraffin, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone 350, cyclopentasiloxane, and medium-chain triglyceride.

[0010] In some preferred embodiments, the emollient comprises at least one of light liquid paraffin, squalane, isopropyl myristate, and medium-chain triglyceride; the occlusive agent comprises white petrolatum; the stiffening agent comprises at least one of cetyl alcohol and stearyl alcohol; and the skin care agent comprises at least one of dimethicone 350 and cyclopentasiloxane.

[0011] In some preferred embodiments, the emulsifier comprises at least one of self-emulsifying glyceryl stearate, polyethylene glycol-7-stearate, and polysorbate 20.

[0012] In some preferred embodiments, the cream further comprises a stabilizer component and a bacteriostatic agent component.

[0013] In some preferred embodiments, the stabilizer comprises at least one of xanthan gum and polysorbate 20; and the bacteriostatic agent comprises at least one of methyl paraben, propyl paraben, and phenoxyethanol.

[0014] In some preferred embodiments, the cream further comprises a chelating agent component, and the chelating agent comprises disodium ethylenediaminetetraacetate.

[0015] The present application also provides a preparation method of a ruxolitinib cream, comprising the following steps: dissolving a chelating agent in water, adding polysorbate 20, stirring until uniform, and then adding methyl paraben and propyl paraben, and dissolving by water bath heating; adding ruxolitinib phosphate into the dissolved solution, stirring to dissolve, and then adding a stabilizer, stirring to swell to prepare an aqueous phase mixed solution, and placing in a 70-80℃ environment for standby; stirring and mixing the oil component and the emulsifier component uniformly, and then heating to 70-80℃ to melt to form a uniform oil phase mixture; mixing the aqueous phase mixed solution and the oil phase mixture under high shear to form an emulsion, adding phenoxyethanol to the emulsion, mixing and cooling, and mixing under low shear to cool to 15-30℃ to obtain the ruxolitinib cream.

[0016] The present application has the following beneficial effects: The present application uses 1-6% polysorbate 20 to replace propylene glycol and polyethylene glycol in the prior art as the solvent of luspaterin, which improves the safety of the drug, reduces the skin irritation of polysorbate 20, avoids the stinging and burning sensation of the patient, especially the skin barrier damaged patients, thereby significantly improving the drug tolerance and laying the foundation for improving the treatment compliance. Moreover, polysorbate 20 can effectively encapsulate drug molecules by forming micelles, which not only ensures the solubility, but also enhances the physical and chemical stability of the preparation, delays the degradation of the active ingredient, and prolongs the product shelf life. At the same time, its surface active properties can gently adjust the structure of the stratum corneum, which is expected to promote the penetration of the drug through the skin and increase the drug concentration at the target site, thereby creating conditions for enhancing the efficacy. In addition, the new formula significantly improves the patient's experience, eliminates the common sticky feeling of the original formula, and gives the cream a more refreshing skin feel. The successful replacement of this solvent system simultaneously improves the safety, stability and patient friendliness, providing an optimization direction for the development of a new generation of high-performance luspaterin external preparation. BRIEF DESCRIPTION OF DRAWINGS

[0017] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following will briefly introduce the drawings needed to be used in the embodiments. It should be understood that the following drawings only show some embodiments of the present application, and therefore should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can also be obtained without creative labor.

[0018] Figure 1 The microscope image of the luspaterin phosphate cream of the present application; Figure 2 The microscope image of Opzelura cream; Figure 3 The in vitro release curve of the luspaterin phosphate cream of the present application. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be described clearly and completely. The specific conditions are not specified in the embodiments, which are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The reagents or instruments used are not specified by the manufacturer, which are conventional products that can be purchased on the market.

[0020] The luspaterin cream and its preparation method provided in the present application will be described in detail below.

[0021] In a first aspect, the present application provides a roxadustat cream comprising, by weight percentage: a therapeutic agent 1-2%, an oil component 20-27%, an emulsifier component 1-9%, a solubilizer component 1-6%, and water 50-70%; The therapeutic agent comprises roxadustat or a pharmaceutically acceptable salt thereof, preferably roxadustat phosphate; The solubilizer component is polysorbate 20.

[0022] It should be noted that the weight percentage of the therapeutic agent in the roxadustat cream is calculated based on the free base, and the solubilizer component is added to the aqueous phase, and the concentration in the aqueous solution is 2-10%.

[0023] In the present application, polysorbate 20 with a concentration of 1-6% is selected as a solubilizer, replacing the propylene glycol and polyethylene glycol used as a solvent component in the prior art, which has the following advantages: first, polysorbate 20 is a very mild non-ionic surfactant, widely used in cosmetics and drugs. Its skin irritation is much lower than that of propylene glycol. For patients with atopic dermatitis who need long-term and large-area use, the use of polysorbate 20 can greatly improve the drug experience and compliance. Second, polysorbate 20 can encapsulate roxadustat molecules by forming micelles, effectively isolating water, oxygen and light, which can improve the chemical stability of the active ingredient, slow down the degradation, prolong the shelf life of the product, and have good chemical stability. As a surfactant, polysorbate 20 can help the active ingredient to be more evenly dispersed in the oil phase or aqueous phase of the cream, reducing the risk of precipitation and stratification, making the preparation more uniform and stable, and having good physical stability. Third, the propylene glycol and polyethylene glycol selected in the prior art may cause a sticky feeling, while polysorbate 20 usually has a clearer skin feel, is easy to spread, and feels more comfortable after use. And as a surfactant, polysorbate 20 can reversibly change the arrangement order of the stratum corneum lipids, reduce the resistance of the skin barrier, and thus may promote the transdermal absorption of roxadustat. Finally, the use of a single component (polysorbate 20) instead of two solvents (propylene glycol and PEG) can make the formula more concise, reduce the complexity of raw material quality control and production process, and at the same time reduce the production cost.

[0024] Based on this, the inventors propose to use polysorbate 20 as a solubilizer to dissolve the drug substance roxadustat in a polysorbate aqueous solution, and to study the solubility of roxadustat. An appropriate amount of roxadustat phosphate is added to about 5 ml of the solvent system in Table 1, and continuously shaken at room temperature for 24 h. If the sample is clear during shaking, additional roxadustat phosphate is added to saturate the solution. After shaking, the sample is filtered and appropriately diluted for HPLC analysis to detect its solubility.

[0025] The results are shown in Table 1. Ruxolitinib phosphate has very low solubility in polysorbate 20 (<10 mg / ml). However, the solubility of ruxolitinib phosphate in 2%-10% aqueous solutions of polysorbate 20 is not lower than that in solvent systems of propylene glycol and polyethylene glycol. This confirms that polysorbate 20, as a solubilizer, has sufficient solubility for ruxolitinib phosphate in its aqueous solution.

[0026] Table 1. Solubility of ruxolitinib phosphate in different solvent systems

[0027] In some preferred embodiments, the oil component includes at least one selected from light liquid paraffin, white petrolatum, cetyl alcohol, stearyl alcohol, dimethicone 350, cyclopentamethoxysiloxane, and medium-chain triglycerides.

[0028] In some preferred embodiments, the oil component includes at least one of a moisturizing agent, an occlusive agent, a hardening agent, or a skin care agent; The emollient includes at least one of light liquid paraffin, squalane, isopropyl myristate, and medium-chain triglycerides; The occlusive agent includes white petrolatum; The hardener includes at least one of cetyl alcohol and stearyl alcohol; The skin care agent includes at least one of dimethicone 350 and cyclopentamethoxysiloxane.

[0029] In some preferred embodiments, the emulsifier includes at least one of self-emulsifying glyceryl stearate, polyethylene glycol-7-stearate, and polysorbate 20.

[0030] In some preferred embodiments, the cream further includes a stabilizer component and an antibacterial component.

[0031] In some preferred embodiments, the stabilizer includes at least one of xanthan gum and polysorbate 20; The antibacterial agent includes at least one of methylparaben, propylparaben, and phenoxyethanol.

[0032] In some preferred embodiments, the chelating agent includes disodium ethylenediaminetetraacetate.

[0033] Secondly, the present invention also provides a method for preparing ruxolitinib cream, which includes the following steps: S1. Dissolve the chelating agent in water and add polysorbate 20 to obtain a polysorbate 20 aqueous solution with a concentration of 2%-10%.

[0034] In the embodiments of this application, 80%-90% of the weighed purified water, representing the total water volume, is poured into a container. After dissolving the chelating agent, the weighed polysorbate 20 is gradually added to the water under continuous, moderate-intensity mechanical stirring. This stirring process aims to disperse the viscous polysorbate 20 into fine droplets through the shear force of the liquid, preventing it from clumping or adhering to the container walls and the stirring paddle. After all the polysorbate 20 has been added, stirring should continue until the solution becomes clear, homogeneous, and free of any visible oil droplets or particles. Subsequently, the container and its inner walls that held the polysorbate 20 are carefully rinsed with the remaining purified water, and all the washings are incorporated into the solution. Finally, the total water volume specified in the formula is added, followed by a brief stirring to ensure overall homogeneity. The resulting aqueous solution of polysorbate 20 is a clear and transparent solution.

[0035] S2. Add methylparaben and propylparaben, and dissolve them by heating in a water bath.

[0036] In the embodiments of this application, the stirring speed is 200-400 rpm and the water bath temperature is 60-70℃.

[0037] S3. Add ruxolitinib phosphate to the dissolved solution, stir to dissolve, then add a stabilizer, stir to swell and prepare an aqueous mixed solution, and keep it at 70-80℃ for later use.

[0038] S4. Stir and mix the oil component and emulsifier component evenly, then heat to 70-80℃ to melt them and form a uniform oil phase mixture.

[0039] S5. Under high shear conditions, the aqueous phase mixture and the oil phase mixture are mixed to form an emulsion. Phenoxyethanol is added to the emulsion and mixed and cooled. Under low shear conditions, the mixture is cooled to 15-30℃ to obtain ruxolitinib cream.

[0040] In the embodiments of this application, the high-shear rotation speed is 10,000-20,000 rpm. High shear force can overcome the interfacial tension between the two phases, ensuring that the oil phase is uniformly dispersed in the aqueous phase, forming a fine-grained and evenly distributed emulsion structure. This is the core of ensuring a delicate, stable, and non-layered cream texture. The low-shear rotation speed is 5,000-10,000 rpm. After the emulsion has formed, excessively high shear will input too much energy and heat, potentially damaging the already formed emulsion structure or even causing demulsification. Secondly, low-speed stirring is sufficient to achieve uniform distribution of phenoxyethanol and effective heat dissipation of the system, while preventing the formation of large amounts of air that are difficult to eliminate due to vigorous stirring. Finally, slow cooling helps the cream matrix (such as those derived from hardeners cetyl alcohol and stearyl alcohol) to steadily recover and build its crystal form, thereby obtaining a better and more stable final texture.

[0041] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0042] Example 1 This embodiment provides a ruxolitinib phosphate cream, the formulation of which is as follows:

[0043] Its preparation method includes the following steps: S1. Dissolve disodium edetate in water, add polysorbate 20 and stir until homogeneous; S2. Add methylparaben and propylparaben, and dissolve them by heating in a water bath. S3. Add ruxolitinib phosphate to the dissolved solution, stir to dissolve, then add xanthan gum, stir to swell and prepare an aqueous mixed solution, and keep it at 75°C for later use. S4. Mix the light liquid paraffin, self-emulsifying glyceryl stearate, polysorbate 20, white petrolatum, cetyl alcohol, octadecanol, dimethicone 350 and medium chain triglyceride evenly, and then heat to 75°C to melt it and form a homogeneous oil phase mixture. S5. Under high shear conditions, the aqueous phase mixture and the oil phase mixture are mixed to form an emulsion. Phenoxyethanol is added to the emulsion and mixed and cooled. Under low shear conditions, the mixture is mixed and cooled to room temperature to obtain ruxolitinib cream.

[0044] Example 2 This embodiment provides a ruxolitinib phosphate cream and its preparation method, the steps of which are the same as those in Example 1, the only difference being the different types of oil components. The formulation of this embodiment is as follows:

[0045] Example 3 This embodiment provides a ruxolitinib phosphate cream and its preparation method, the steps of which are the same as those in Example 1, the only difference being the combination of different types of emulsifiers. The formulation of this embodiment is as follows:

[0046] Comparative Example 1 This comparative example provides a ruxolitinib phosphate cream and its preparation method, the steps of which are the same as those in Example 1, the only difference being: the use of 9% polysorbate 20 for solubilization. The formulation of this comparative example is as follows:

[0047] This comparative example generated a large amount of persistent foam during preparation, and oil-water separation occurred after being placed at 40°C for 30 days, indicating poor stability.

[0048] Test case The ruxolitinib phosphate cream prepared in Examples 1-3 and the commercially available Opzelura cream were used for testing. Opzelura cream is an original formulation approved by the European Union.

[0049] Stability test The microstructure of Example 1 and Opzelura cream was observed using a Leica DM2700P microscope, as follows: Figure 1 and Figure 2 As shown, compared with the commercially available original product Opzelura, no obvious large droplets were observed under a microscope in the cream of Example 1, and the structure was more uniform and delicate, suggesting that its emulsion system was more stable, which helps to maintain the homogeneity and appearance quality of the formulation.

[0050] The ruxolitinib phosphate creams prepared in Examples 1-3 were subjected to physicochemical tests after being placed at 40°C for 30 days: the cream's properties were visually inspected; viscosity was measured using an Anton Paar MCR102e rheometer; pH was measured using a Mettler FE28 pH meter; and the content was determined by HPLC. The test results are shown in Table 1.

[0051] Table 1. Physicochemical test results of ruxolitinib phosphate cream

[0052] As shown in Table 1, the ruxolitinib phosphate creams prepared in Examples 1 to 3 exhibited good performance in terms of physicochemical stability and in vitro release behavior. After being placed at 40°C for 30 days, the creams in the three examples did not show significant changes in appearance, pH value, or active ingredient content; only the viscosity decreased slightly, indicating that their physical and chemical stability was ideal and could meet the basic requirements for storage and use. Furthermore, Comparative Example 1, due to the use of a high concentration of polysorbate 20 as a solubilizer, generated a large amount of persistent foam during preparation and exhibited oil-water separation in the stability test, further confirming the advantages of the formulation design used in Examples 1–3 in terms of formulation stability.

[0053] The in vitro release test of ruxolitinib phosphate and Opzelura cream prepared in Example 1 of this application included the following steps: Diffusion cell system: A vertical diffusion cell system with a standard open-cap frosted glass-like surface, an injection hole diameter of 15 mm, and a diffusion cell volume of 15 ml (final volume after adding the rotor).

[0054] Artificial membrane: 0.45μm nylon membrane; Accepting solution medium: pH 6.8 phosphate buffer containing 30% anhydrous ethanol; Stirring speed: 600 rpm; Sample loading: Place 0.3g of sample evenly onto the synthetic membrane; Sampling time: 40 min, 60 min, 80 min, 100 min, 120 min, 140 min; Sampling method: Take 1 ml of receiving solution at each time point and add 1 ml of new receiving solution.

[0055] The test results are shown in Table 2 and Figure 3 As shown.

[0056] Table 2. Results of in vitro release assay

[0057] According to the test results, the average release rate of Example 1 is similar to that of commercially available Opzelura cream. Figure 1 Calculations showed that the confidence interval for the ratio of drug release rate between Example 1 and Opzelura cream was 79.48% to 90.95%, which is within the range of 75% to 133.33%, demonstrating that Example 1 and Opzelura cream have consistent in vitro release.

[0058] Skin irritation test The skin irritation of the pharmaceutical composition prepared in this invention was investigated by comparing the ruxolitinib phosphate prepared in Example 1 of this application with commercially available Opzelura cream.

[0059] Experimental protocol Eight New Zealand rabbits (2.0-3.5 kg each) were randomly divided into two groups of four, with half males and half females. Each group received a different test drug once daily for seven consecutive days. The different groups were as follows: Group I: Positive control group, commercially available Opzelura cream formulation; Group II: Ruxolitinib phosphate cream of Example 1; Experimental methods: Twenty-four hours prior to the experiment, the fur on the rabbit's back in the area to be treated was shaved. The shaved area was 3 cm × 3 cm, and the treatment area was 2.5 cm × 2.5 cm. The shaved area must have clear and neat boundaries, and the shaved area must be uniform. Twenty-four hours after shaving, 0.5 g of the corresponding preparation was applied to the shaved area once daily for seven consecutive days. Twenty-four hours after each application, the test drug was washed off with purified water. The skin was allowed to dry before the next application. Skin reactions were observed visually under natural light one hour after each drug removal and one hour and 24 hours after the last drug removal. Scoring was performed according to Table 3, and irritation intensity was assessed according to Table 4. The scoring method referred to the "Technical Guidelines for Studies of Irritation, Allergy, and Hemolysis of Chemical Drugs". The skin irritation intensity scoring results are shown in Table 5.

[0060] Table 3. Skin Irritation Response Scoring Criteria

[0061] Table 4. Evaluation Criteria for Skin Irritation Intensity

[0062] Experimental results Table 5. Skin Irritation Intensity Scoring Results

[0063] As can be seen from the irritation scores in the table above, Group I (Opzelura cream) showed no irritation on day 1, and mild irritation on days 2-7 (scores were 0.5, 1, 1.25, 1.25, 2, and 2.25 respectively). Group II (Example 1) showed no irritation except on days 5-7 (scores 0.5, 0.75, and 0.5). Commercially available Qpzeilux cream (Group I) caused varying degrees of erythema reactions after multiple administrations, with some animals even showing moderate to severe erythema, especially in the later stages (e.g., 1 hour after the 7th administration), where the erythema score reached as high as 3, indicating some skin irritation. In contrast, the ruxolitinib phosphate cream (Group II) prepared in Example 1 of this invention showed generally milder skin reactions throughout the experimental period, with erythema and edema scores remaining at low levels. No severe reactions occurred, and all irritation reactions completely subsided 24 hours after the last administration, demonstrating good skin tolerance.

[0064] In summary, the formulation of this invention is significantly superior to commercially available products in reducing skin erythema, demonstrating that using polysorbate 20 as a solubilizer instead of propylene glycol and polyethylene glycol in the solvent system has a significant advantage in reducing local irritation. This not only helps avoid stinging or burning sensations in patients, especially those with impaired skin barrier function, but also provides experimental evidence for the safety and tolerability of long-term use, thereby potentially significantly improving patient adherence.

[0065] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A roscovitine cream, characterized in that, It comprises by weight percentage: 1%-2% of therapeutic agent, 20%-27% of oil component, 1%-9% of emulsifier component, 1%-6% of solubilizer component and 50-70% of water; The therapeutic agent comprises luspaterin or pharmaceutically acceptable salt thereof; The solubilizer component is polysorbate 20.

2. The roscovitine cream according to claim 1, wherein The therapeutic agent is luspaterin phosphate.

3. The roscovitine cream according to claim 1, wherein The oil component comprises at least one of emollient, occlusive agent, stiffening agent or skin care agent.

4. The roscovitine cream according to claim 1, wherein The oil component comprises at least one of light liquid paraffin, white vaseline, cetyl alcohol, stearyl alcohol, dimethicone 350, cyclopentasiloxane and medium chain triglyceride.

5. The roscovitine cream according to claim 3, wherein The emollient comprises at least one of light liquid paraffin, squalane, isopropyl myristate and medium chain triglyceride; the occlusive agent comprises white vaseline; the stiffening agent comprises at least one of cetyl alcohol and stearyl alcohol; the skin care agent comprises at least one of dimethicone 350 and cyclopentasiloxane.

6. The roscovitine cream according to claim 1, wherein The emulsifier comprises at least one of self-emulsifying glyceryl stearate, macrogol-7-stearate and polysorbate 20.

7. The lucotinib cream according to claim 1, wherein The cream further comprises stabilizer component and bacteriostatic agent component.

8. The roscovitine cream according to claim 7, wherein The stabilizer comprises at least one of xanthan gum and polysorbate 20; the bacteriostatic agent comprises at least one of methyl paraben, propyl paraben and phenoxyethanol.

9. The lucotinib cream according to claim 1, wherein The cream further comprises chelating agent component, and the chelating agent comprises disodium ethylenediaminetetraacetate.

10. A process for the preparation of a Lucotinib cream as claimed in any one of claims 1 to 9, characterized in that, The method comprises the following steps: Dissolve the chelating agent in water, add polysorbate 20, stir until uniform, then add methyl paraben and propyl paraben, and dissolve by water bath heating; Add luspaterin phosphate to the dissolved solution, stir to dissolve, then add the stabilizer, stir to swell to prepare the water phase mixed solution, and place in 70-80℃ for standby; Stir the oil component and the emulsifier component until uniform, then heat to 70-80℃ to melt to form the uniform oil phase mixture; Mix the water phase mixed solution and the oil phase mixture under high shear to form the emulsion, add phenoxyethanol to the emulsion, mix and cool to 15-30℃ under low shear, thereby obtaining the luspaterin cream.

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