Non-irritating cooling liquid and method of making same

Abstract

The present application relates to the technical field of external liquid medicine, and discloses a non-irritating cooling liquid medicine and a preparation method thereof, which comprises CO40, WS-23, vitamin E, IPBC, propylene glycol, benzethonium chloride, benzalkonium chloride, purified water, citric acid / sodium citrate buffer, panthenol, butanediol and 1,2-hexanediol. In the preparation, the CO40 is heated and WS-23 and vitamin E are added to obtain a cooling and soothing base liquid, then IPBC, propylene glycol and the buffer are mixed to obtain a bacteriostatic and preservative base liquid, then a moisturizing and penetrating base liquid is prepared, and finally the base liquids are sequentially injected and mixed by constant temperature stirring to obtain the non-irritating cooling liquid medicine. The present application adopts CO40 to wrap WS-23 and combines vitamin E to prevent the analysis and oxidation, cooperates with a composite preservative system and a step-by-step mixing process, reduces the irritation by matching the skin acid-base environment, avoids flocculation caused by component mixing, and improves the overall stability and physical uniformity of the liquid medicine.

Description

Technical Field

[0001] This invention relates to the field of external medicine technology, specifically to a non-irritating cooling medicine and its preparation method. Background Technology

[0002] Cooling solutions, a common topical skin preparation, are typically applied to the skin's surface to provide a cooling sensation through physical or chemical action, often used to soothe skin discomfort. With increasing demands for skincare, modern cooling solutions not only need to provide basic cooling and soothing functions but also require the addition of antibacterial and preservative ingredients to maintain product condition and inhibit bacterial growth. To enhance the user experience, the formulas often include moisturizing and penetrating ingredients to help active substances better contact and penetrate the skin's stratum corneum.

[0003] However, existing cooling liquids suffer from several technical defects in actual production and application. Regarding formulation stability, the cooling agents in the formula are prone to crystallization during storage, and some active ingredients are easily oxidized and destroyed in the air, resulting in poor overall chemical stability of the liquid. In terms of mildness, traditional antibacterial and preservative systems often irritate the skin and neglect the adjustment of the formula's pH environment, making it difficult to match the natural state of the human skin surface. Regarding preparation processes and efficacy, conventional production usually involves directly mixing multiple preservatives, humectants, and cooling ingredients. This mixing process easily leads to physical repulsion between components, resulting in flocculation or phase separation, leading to poor physical homogeneity of the liquid, and conventional liquids are relatively insufficient in promoting skin penetration and repair.

[0004] In summary, existing products struggle to simultaneously achieve chemical stability, mild and non-irritating antibacterial effects, and excellent physical homogeneity, thus limiting their overall performance during long-term storage and actual use. Therefore, providing a non-irritating cooling solution and its preparation process that can prevent the leaching and oxidation of active ingredients, reduce skin irritation, and ensure uniform mixing of the system is a problem that needs to be solved in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a non-irritating cooling liquid and its preparation method. It solves the problems of poor chemical stability caused by the easy crystallization and precipitation of cooling agents and the easy oxidation of active ingredients in existing cooling liquids. It also solves the problems of traditional antibacterial and preservative systems irritating human skin and having an acid-base environment that does not match the skin's condition. Furthermore, it solves the problems of poor physical uniformity and insufficient penetration-promoting and repairing effects caused by the direct mixing of multiple components leading to flocculation.

[0006] To address the above problems, the present invention provides the following technical solution:

[0007] This invention provides a non-irritating cooling liquid, employing the following technical solution:

[0008] A non-irritating cooling liquid, comprising the following ingredients in parts by weight:

[0009] CO40: 10 to 20 servings;

[0010] WS-23: 0.5 to 4 parts;

[0011] Vitamin E: 0.2 to 2 parts;

[0012] IPBC: 0.1 to 1 copy;

[0013] Propylene glycol: 10 to 20 parts;

[0014] Benzyl chloride: 0.1 to 1 part;

[0015] Benzalkonium chloride: 0.6 parts to 3.5 parts;

[0016] Purified water: 0.5 to 2.5 parts;

[0017] Citric acid / sodium citrate buffer: 0.1 to 0.5 parts;

[0018] Panthenol: 0.2 to 2 parts;

[0019] Butylene glycol: 7 to 15 parts;

[0020] 1,2-Hexanediol: 1 part to 5 parts.

[0021] By employing the above technical solution, CO40 is used as a solubilizing carrier to micellize and encapsulate WS-23, forming a stable and homogeneous solution and preventing WS-23 from crystallizing and precipitating. Combined with the antioxidant properties of Vitamin E, the system is protected from oxidative damage, enhancing the chemical stability of the solution. A composite antibacterial and preservative system is constructed using IPBC, benzyl chloride, benzalkonium chloride, and purified water. With the aid of propylene glycol, this system forms a broad-spectrum antibacterial effect covering Gram-positive bacteria, Gram-negative bacteria, and fungi. Panthenol, butylene glycol, and 1,2-hexanediol are introduced as moisturizing and penetrating components. The permeability-enhancing effect of alcohol molecules allows the active ingredients to penetrate the skin's stratum corneum barrier, reaching the target site. Simultaneously, panthenol exerts a soothing and repairing effect, reducing the potential irritation from polyols and quaternary ammonium salts. The above raw materials are synergistically combined, thus achieving a comprehensive effect that combines long-lasting cooling, gentle and non-irritating properties, highly effective antibacterial activity, and deep moisturizing penetration.

[0022] Preferably, the pH value of the citric acid and sodium citrate buffer solution is 5.5 to 6.5.

[0023] By adopting the above technical solution, the pH value of the drug solution is controlled in the weakly acidic range of 5.5 to 6.5, which is compatible with the acid-base environment of the sebum film on the surface of human skin, reducing the acid-base irritation of the drug solution to the skin; at the same time, the weakly acidic environment can maintain the antibacterial activity of the composite antibacterial and preservative system and prevent the vitamin E from being degraded and ineffective under alkaline conditions.

[0024] Preferably, the CO40, WS-23, and vitamin E constitute a cooling and soothing base solution; the IPBC, propylene glycol, benzyl chloride, benzalkonium chloride, purified water, and citric acid and sodium citrate buffer solution constitute an antibacterial and preservative base solution; the panthenol, butylene glycol, and 1,2-hexanediol constitute a moisturizing and penetrating base solution; and the non-irritating cooling solution is prepared by mixing the cooling and soothing base solution, the antibacterial and preservative base solution, and the moisturizing and penetrating base solution.

[0025] By employing the above technical solution, the raw materials are formed into independent cooling and soothing base liquid, antibacterial and preservative base liquid, and moisturizing and penetrating base liquid. WS-23 and CO40 are mixed independently to ensure complete solubilization; cationic quaternary ammonium salts and IPBC are concentrated in a weakly acidic buffer system to prevent physical competition with nonionic surfactants; moisturizing and penetration-enhancing components are dissolved independently to ensure uniform dispersion. Premixing the base liquids before final compounding avoids localized oversaturation, flocculation, or phase separation caused by one-time mixing of multiple components, significantly improving the physical stability of the system.

[0026] The second aspect of this invention provides a method for preparing a non-irritating cooling liquid, employing the following technical solution:

[0027] A method for preparing a non-irritating cooling liquid includes the following steps:

[0028] The CO40 is heated, then the WS-23 is added, and the mixture is stirred at a constant temperature until it is completely dissolved and becomes transparent. After cooling, the vitamin E is added and stirred evenly to obtain a cooling and soothing base liquid.

[0029] At room temperature, the IPBC is added to the propylene glycol and stirred until completely dissolved. Then, the benzyl chloride, benzalkonium chloride, purified water, and citric acid and sodium citrate buffer are added in sequence and stirred at a constant speed to obtain the antibacterial and preservative base solution.

[0030] The butanediol and 1,2-hexanediol were mixed, and then the panthenol was added and stirred until completely dissolved to obtain a moisturizing and penetrating base liquid.

[0031] Slowly inject the antibacterial and preservative base liquid into the cooling and soothing base liquid, and maintain the stirring speed to perform preliminary mixing to obtain a preliminary mixture.

[0032] Add the moisturizing and penetrating base liquid to the preliminary mixture, continue stirring at a constant temperature, and cool to room temperature to obtain a non-irritating and cooling medicinal solution.

[0033] By adopting the above technical solution, a step-by-step process for preparing the base liquid and mixing it sequentially is used, with temperature and stirring speed controlled according to the physicochemical properties of each component. First, heating increases the molecular thermal motion of CO40, prompting WS-23 to enter the micelles. Then, a cooling step is used to add vitamin E to prevent oxidation and inactivation due to high temperatures. Second, the antibacterial and preservative base liquid is prepared at room temperature to ensure the structural stability of the preservative components. Finally, the antibacterial and preservative base liquid and the moisturizing and penetrating base liquid are slowly injected sequentially into the cooling and soothing base liquid while maintaining a constant stirring speed. Mechanical stirring promotes uniform dispersion of the base liquids, preventing emulsification damage caused by sudden changes in interfacial tension, and ensuring a clear, uniform, stable, and non-irritating cooling solution is obtained.

[0034] Preferably, in the step of heating the CO40, the heating temperature is 50°C to 60°C.

[0035] By adopting the above technical solution, the kinematic viscosity of CO40 can be significantly reduced in the temperature range of 50℃ to 60℃, the encapsulation rate of CO40 on WS-23 can be accelerated, and the cloud point phenomenon of surfactant caused by excessive temperature can be avoided, ensuring that the micelle formation process is in a stable state.

[0036] Preferably, in the step of adding vitamin E after cooling, the temperature is cooled to 35°C to 40°C.

[0037] By adopting the above technical solution, the temperature range of 35℃ to 40℃ preserves the fluidity of the system, promotes the uniform dispersion of vitamin E, and is below the critical temperature at which vitamin E undergoes significant thermal oxidation, thus ensuring the stability of the bioactivity of the antioxidant components.

[0038] Preferably, in the step of slowly injecting the antibacterial and preservative base liquid into the cooling and soothing base liquid, the injection temperature is 35℃~40℃.

[0039] By adopting the above technical solution, the injection temperature is controlled at 35℃~40℃, avoiding an excessive temperature gradient between the antibacterial and preservative base liquid at room temperature and the cooling and soothing base liquid, preventing a sudden drop in local solubility and crystallization of components due to temperature changes, and ensuring a smooth phase transition during the mixing process.

[0040] Preferably, in the step of maintaining the stirring speed for preliminary mixing, the stirring speed is 150 r / min to 250 r / min.

[0041] By adopting the above technical solution, a rotation speed of 150r / min to 250r / min can provide sufficient fluid dynamic shear force to disperse the fluid and promote the effective fusion of different base liquids. At the same time, it avoids cavitation effect caused by excessive rotation speed or the formation of microbubbles by entraining air into the liquid, thus ensuring the physical uniformity and appearance transparency of the finished product.

[0042] Preferably, in the step of continuing constant temperature stirring, the stirring time is 20 min to 30 min.

[0043] By adopting the above technical solution, a stirring time of 20 to 30 minutes can ensure that all components are fully diffused and reach chemical potential equilibrium, avoid concentration gradients caused by excessively short stirring time, and improve the long-term storage stability of the drug solution.

[0044] This invention provides a non-irritating cooling liquid and its preparation method. It has the following beneficial effects:

[0045] 1. This invention uses CO40 as a solubilizing carrier to encapsulate WS-23 to form a stable and homogeneous solution structure. Combined with the antioxidant properties of vitamin E, it effectively prevents WS-23 from crystallizing and protects the active ingredients from oxidative damage, thereby improving the overall chemical stability of the non-irritating cooling liquid and ensuring the performance of the cooling and soothing base liquid.

[0046] 2. This invention constructs a composite antibacterial and preservative system by dissolving IPBC, benzyl chloride and benzalkonium chloride in propylene glycol and combining it with citric acid / sodium citrate buffer solution. This allows the acid-base environment of the antibacterial and preservative base solution to be well matched with the state of the human skin surface, providing comprehensive antibacterial and preservative effects while effectively reducing the irritation of the non-irritating cooling medicine solution to the skin.

[0047] 3. This invention introduces panthenol, butylene glycol and 1,2-hexanediol to formulate a moisturizing and penetrating base solution to promote penetration and repair. It also combines a preparation process in which a cooling and soothing base solution, an antibacterial and preservative base solution and a moisturizing and penetrating base solution are prepared in steps and then injected and mixed at a constant temperature. This avoids flocculation caused by direct mixing of different components and ensures the physical homogeneity of the non-irritating cooling solution. Attached Figure Description

[0048] Figure 1 The image shows the UV-Vis absorption spectrum of the supernatant after Escherichia coli treatment with the drug solution.

[0049] Figure 2 Fourier transform infrared spectrum of solid precipitate;

[0050] Figure 3 Dynamic ion current spectrum of transdermal release of cooling ingredients;

[0051] Figure 4The image shows the UV-Vis absorption spectrum of the supernatant from the red blood cell hemolysis test. Detailed Implementation

[0052] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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.

[0053] Examples 1-3:

[0054] Example 1:

[0055] This embodiment provides a method for preparing a non-irritating cooling liquid, including the following steps:

[0056] Heat 10 kg of CO40 to 50°C, then add 0.5 kg of WS-23 and stir at a constant temperature until completely dissolved and transparent; cool to 35°C, add 0.2 kg of vitamin E, stir evenly, and obtain a cooling and soothing base solution;

[0057] At room temperature, 0.1 kg of IPBC was added to 10 kg of propylene glycol and stirred until completely dissolved; then 0.1 kg of benzyl chloride, 0.6 kg of benzalkonium chloride, 0.5 kg of purified water and 0.1 kg of citric acid / sodium citrate buffer with a pH of 5.5 were added sequentially and stirred at a constant speed to obtain the antibacterial and preservative base solution.

[0058] Mix 7 kg of butanediol with 1 kg of 1,2-hexanediol, then add 0.2 kg of panthenol and stir until completely dissolved to obtain a moisturizing and penetrating base solution.

[0059] At a temperature of 35℃, the obtained antibacterial and preservative base liquid was slowly injected into the obtained cooling and soothing base liquid, and the stirring speed was kept at 150r / min for preliminary mixing to obtain a preliminary mixture.

[0060] Add the obtained moisturizing and penetrating base liquid to the initial mixture, continue stirring at a constant temperature for 20 minutes, and cool to room temperature to obtain a non-irritating and cooling solution.

[0061] Example 2:

[0062] This embodiment provides a method for preparing a non-irritating cooling liquid, including the following steps:

[0063] Heat 11.2 kg of CO40 to 55°C, then add 2.8 kg of WS-23 and stir at a constant temperature until completely dissolved and transparent; cool to 38°C, add 0.5 kg of vitamin E, stir evenly, and obtain a cooling and soothing base solution;

[0064] At room temperature, 0.1 kg of IPBC was added to 13.15 kg of propylene glycol and stirred until completely dissolved; then 0.15 kg of benzyl chloride, 1.1 kg of benzalkonium chloride, 1.0 kg of purified water and 0.3 kg of citric acid / sodium citrate buffer with a pH of 6.0 were added sequentially and stirred at a constant speed to obtain the antibacterial and preservative base solution.

[0065] Mix 7.5 kg of butanediol with 2 kg of 1,2-hexanediol, then add 0.5 kg of panthenol and stir until completely dissolved to obtain a moisturizing and penetrating base solution.

[0066] At a temperature of 38℃, the obtained antibacterial and preservative base liquid was slowly injected into the obtained cooling and soothing base liquid, and the stirring speed was kept at 200r / min for preliminary mixing to obtain a preliminary mixture.

[0067] Add the obtained moisturizing and penetrating base liquid to the initial mixture, continue stirring at a constant temperature for 25 minutes, and cool to room temperature to obtain a non-irritating and cooling solution.

[0068] Example 3:

[0069] This embodiment provides a method for preparing a non-irritating cooling liquid, including the following steps:

[0070] Heat 20 kg of CO40 to 60°C, then add 4 kg of WS-23 and stir at a constant temperature until completely dissolved and transparent; cool to 40°C, add 2 kg of vitamin E, stir well to obtain a cooling and soothing base solution;

[0071] At room temperature, 1 kg of IPBC was added to 20 kg of propylene glycol and stirred until completely dissolved; then 1 kg of benzyl chloride, 3.5 kg of benzalkonium chloride, 2.5 kg of purified water and 0.5 kg of citric acid / sodium citrate buffer with a pH of 6.5 were added in sequence and stirred at a constant speed to obtain the antibacterial and preservative base solution.

[0072] Mix 15 kg of butanediol with 5 kg of 1,2-hexanediol, then add 2 kg of panthenol and stir until completely dissolved to obtain a moisturizing and penetrating base solution.

[0073] At a temperature of 40℃, the obtained antibacterial and preservative base liquid was slowly injected into the obtained cooling and soothing base liquid, and the stirring speed was kept at 250r / min for preliminary mixing to obtain a preliminary mixture.

[0074] Add the obtained moisturizing and penetrating base liquid to the initial mixture, continue stirring at a constant temperature for 30 minutes, and cool to room temperature to obtain a non-irritating and cooling solution.

[0075] Comparative Examples 1-5:

[0076] Comparative Example 1:

[0077] Compared with Example 2, the difference lies in the preparation steps. Specifically, all the formulation components are added to the reactor at once, heated to 55°C, and the stirring speed is controlled at 200 r / min. The stirring is continued for 60 minutes until all solids are completely dissolved. Then, the mixture is cooled to room temperature and discharged. The step-by-step preparation is no longer performed. All other parameters and steps are the same.

[0078] Comparative Example 2:

[0079] Compared with Example 2, the difference lies in the preparation steps. Specifically, WS-23, IPBC, benzyl chloride, benzalkonium chloride, and purified water are all added to a heated mixture of propylene glycol, butanediol, and 1,2-hexanediol for dissolution; vitamin E and panthenol are added to CO40 for dissolution; finally, the two phases are mixed at 38°C, stirred at a constant temperature for 25 minutes, and cooled to room temperature. All other parameters and steps are the same.

[0080] Comparative Example 3:

[0081] Compared with Example 2, the difference is that vitamin E and panthenol in the formula were removed and replaced with 1.0 kg of purified water, while the other parameters and steps are the same.

[0082] Comparative Example 4:

[0083] Compared with Example 2, the difference is that 7.5 kg of butanediol and 2 kg of 1,2-hexanediol in the formula were removed and replaced with 9.5 kg of propylene glycol in equal amounts; at the same time, in the preparation steps, the separate preparation of the moisturizing penetrating base solution was eliminated, and panthenol was directly added to propylene glycol along with IPBC and other substances at room temperature for mixing, while the other parameters and steps were the same.

[0084] Comparative Example 5:

[0085] Compared with Example 2, the difference is that 0.3 kg of citric acid / sodium citrate buffer solution was removed from the formula and replaced with 0.3 kg of 0.1 mol / L NaOH solution, so that the system is weakly alkaline. All other parameters and steps are the same.

[0086] Test Examples 1-4:

[0087] Test Example 1: Broad-spectrum bactericidal and bacteriostatic efficacy test

[0088] Experimental description:

[0089] This experiment aimed to evaluate the bactericidal efficacy of different drug solutions against common pathogenic bacteria and fungi, and to analyze their bactericidal effects in conjunction with a cell contents leakage test. The bactericidal rate was statistically analyzed according to the Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 1121, Antibacterial Efficacy Test Method. Simultaneously, ultraviolet-visible spectrophotometry was used to detect the leakage of macromolecules such as nucleic acids from bacteria after treatment with the drug solutions to verify the antibacterial effect.

[0090] Experimental steps:

[0091] Typical test strains of Escherichia coli, Staphylococcus aureus, Candida albicans, and Aspergillus niger, respectively, in the logarithmic growth phase, were washed with sterile physiological saline and diluted to prepare concentrations of 10. 7 CFU / mL to 10 8 CFU / mL bacterial suspension;

[0092] Take the non-irritating and cooling medicinal solutions obtained in each example, inoculate them with the prepared bacterial suspensions, mix them evenly, and let them act at room temperature for 3 minutes.

[0093] After the reaction time is over, take a sample and add it to a broth culture medium containing the appropriate neutralizing agent to terminate the sterilization reaction;

[0094] Then, serial dilutions were performed, and an appropriate amount of the diluted solution was spread on an agar plate and incubated in an incubator at a suitable temperature for a specified time. The number of surviving colonies was counted and the sterilization rate was calculated.

[0095] The Escherichia coli group was selected, and the supernatant was collected by centrifugation after 3 minutes of incubation. The supernatant was then scanned in the full wavelength range of 230 nm to 330 nm using a UV-Vis spectrophotometer, and the changes in absorbance of the test liquid were recorded.

[0096] Experimental data:

[0097] Table 1. Sterilization rate and absorbance at 260nm after 3 minutes of drug action.

[0098] Test samples E. coli sterilization rate (%) Sterilization rate of Staphylococcus aureus (%) Candida albicans sterilization rate (%) Aspergillus niger sterilization rate (%) absorbance at 260nm Blank control group 0.000 0.000 0.000 0.000 0.043 Example 1 99.992 99.995 99.914 99.907 0.785 Example 2 99.997 99.998 99.983 99.981 1.106 Example 3 99.999 99.999 99.992 99.994 1.258

[0099] Experimental conclusion:

[0100] As shown in the statistical data in Table 1, the non-irritating cooling solution obtained in the examples achieved a kill rate of over 99.99% against both typical Gram-negative and Gram-positive bacteria, while also maintaining significant inhibitory activity against fungi and molds. The long carbon chain structure of quaternary ammonium salts can adsorb and penetrate the bacterial lipid bilayer, and the slightly acidic environment enhances the charge stability of the quaternary ammonium ions. Meanwhile, iodopropynyl butylcarbamate compensates for the relatively weak antifungal activity of quaternary ammonium salts.

[0101] See attached document Figure 1The solid line marked with a circle in the blank control group (untreated with the drug solution) shows a gentle trend, indicating that the cell membrane structure is intact and there is no leakage of macromolecules. The solid lines marked with triangles in Example 1 and those marked with squares in Example 3 both exhibit obvious absorption peaks at 260 nm. With increasing concentration of the active ingredient, the peak height of the solid line marked with squares is significantly higher than that of the solid line marked with triangles, which is consistent with the increasing trend of absorbance data in Table 1, confirming that the drug solution can disrupt the microbial cell membrane and block metabolic pathways.

[0102] Test Example 2: Characterization of Low-Temperature Anti-Crystallization Stability

[0103] Experimental description:

[0104] This experiment evaluated the physical stability of the drug solution at low temperatures and analyzed the effects of different preparation processes on the dissolution state of multiple solid solutes. Accelerated refrigeration tests were used to monitor changes in liquid turbidity, and Fourier transform infrared spectroscopy was used to identify the structures of the solid precipitates, verifying the role of the stepwise dissolution process in maintaining solution homogeneity.

[0105] Experimental steps:

[0106] Take 100 mL of each of the drug solutions obtained in Examples 1 to 3, Comparative Examples 1 and 2, and put them into transparent glass reagent bottles and tighten and seal them with polytetrafluoroethylene gaskets.

[0107] The sealed glass bottle was placed in a constant temperature refrigerator at 4°C, and the continuous observation period was set to 90 days.

[0108] During the testing period, samples were taken periodically, and after standing at room temperature, the turbidity value of the liquid was measured using a turbidity meter. At the same time, a high-intensity light source was used to observe and record whether any turbidity or crystallization occurred inside the liquid.

[0109] After the test, for samples with solid precipitates, vacuum filtration was performed using a microporous membrane with a pore size of 0.22 μm, and the solid residue on the membrane was collected.

[0110] The collected solid residue was placed in a vacuum drying oven and dried at room temperature for 24 hours. It was then mixed with potassium bromide powder, compressed into tablets, and analyzed using a Fourier transform infrared spectroscopy system at 500 cm⁻¹. -1 Up to 4000cm -1 Total internal reflection scanning was performed within the wavelength range to obtain the infrared spectral data of the precipitate.

[0111] Experimental data:

[0112] Table 2. Record of turbidity changes and solid precipitation of the drug solution at different refrigeration times.

[0113] Test samples Day 0 Turbidity / NTU Turbidity on day 7 / NTU Turbidity on day 15 / NTU Turbidity on day 30 / NTU Turbidity on day 90 / NTU Appearance of precipitates Example 1 0.12 0.15 0.14 0.18 0.23 No solid precipitation Example 2 0.15 0.18 0.22 0.25 0.31 No solid precipitation Example 3 0.21 0.26 0.33 0.38 0.45 No solid precipitation Comparative Example 1 0.26 14.85 38.62 75.31 108.44 White needle-like crystals Comparative Example 2 0.19 0.42 16.27 44.15 69.83 flocculent suspension sediment

[0114] Experimental conclusion:

[0115] Experimental conclusion:

[0116] Referring to the turbidity monitoring data in Table 2, it can be seen that the turbidity values ​​of the drug solutions obtained in each example remained within the range of 0.12 NTU to 0.45 NTU in a low-temperature environment for up to 90 days, maintaining a transparent and clear state without any solid precipitation. Comparative Example 1 showed a significant increase in turbidity on day 7, accompanied by the appearance of white needle-like crystals. Comparative Example 2 showed a significant increase in turbidity on day 15, with the formation of flocculent suspended precipitates. Conventional mixing operations are insufficient to guarantee the physical stability of complex systems at low temperatures.

[0117] See attached document Figure 2 The spectral characteristics shown are as follows: the solid line with a triangular marker corresponding to the precipitate in Comparative Example 1 at a wavenumber of 3300 cm⁻¹. -1 The area exhibits an absorption peak for nitrogen-hydrogen bond stretching vibrations, and this peak is observed at 1645 cm⁻¹. -1 A distinct absorption peak was observed at the carbonyl group of the amide bond, confirming that the crystals were unencapsulated cooling agent WS-23. The solid line with a circular marker corresponding to the precipitate in Comparative Example 2 reached 1710 cm⁻¹. -1 The presence of a carbonyl stretching vibration peak in the presence of the urethane structure confirms that the precipitate is the preservative iodopropynyl butylcarbamate. Single-stage feeding or incorrect feeding sequence can lead to dissolution competition; the stepwise dissolution process utilizes a polyol solvent to create spatial isolation, avoiding competitive crystallization among multiple components.

[0118] Test Example 3: Evaluation of the onset and duration of cooling sensation on human skin and dynamic monitoring of transdermal release

[0119] Experimental description:

[0120] This experiment aimed to evaluate the onset and duration of the cooling sensation of the drug solution on the human skin surface, and to verify the effects of different preparation processes and solvent systems on the release rate of the active ingredient by combining in vitro transdermal release kinetics testing. Clinical onset and duration data were obtained through human sensory evaluation. Simultaneously, changes in the intensity of the cooling component ion current in the diffusion cell receiving solution were continuously monitored using liquid chromatography-tandem mass spectrometry (LC-MS / MS), and the molecular release and transdermal penetration behavior were presented in spectral form.

[0121] Experimental steps:

[0122] Recruit healthy volunteers and apply 0.5 mL of the test sample to the inner side of the left and right forearms of the volunteers at a room temperature of 25°C.

[0123] A double-blind, randomly assigned test sample was used. The time when volunteers perceived a significant cooling sensation and the time when the cooling sensation subsided were recorded, and the average value was calculated.

[0124] Ex vivo skin tissue was used as a permeability barrier and fixed in a diffusion cell. The same amount of the test sample was added to the supply cell, and the receiving cell was filled with phosphate buffer containing bovine serum albumin.

[0125] Maintain the system temperature at a constant 32℃ and continue stirring, then start the liquid chromatography-tandem mass spectrometry system for online real-time monitoring;

[0126] The intensity of the multi-reaction monitoring ion current of cooling molecules in the receiving cell was collected and recorded from 0 to 120 seconds to generate a dynamic ion current spectrum for transdermal release.

[0127] Experimental data:

[0128] Table 3. Evaluation of the cooling sensation and onset time of the medicinal solution on the human body.

[0129] Test samples Average onset time / s Average duration / min Example 1 5.24 104.6 Example 2 4.18 126.3 Example 3 3.75 148.9 Comparative Example 1 15.62 93.5 Comparative Example 4 11.27 106.1

[0130] Experimental conclusion:

[0131] Referring to the human sensory evaluation data in Table 3, it can be seen that the solutions obtained in the examples all produced a noticeable cooling sensation on the skin within a short time and the effect lasted for a relatively long period. The onset time remained between 3.75s and 5.24s. The onset time of Comparative Example 1 was prolonged to 15.62s. The onset time of Comparative Example 4 was 11.27s, indicating a slower release rate. The differences in data reflect the direct impact of the preparation process and solvent system on the skin penetration behavior of the active ingredients.

[0132] See attached document Figure 3 In Comparative Example 1, the solid line marked with an asterisk rose slowly in the initial stage, confirming that the one-time mixing operation made it difficult for the active ingredient to quickly detach from the matrix. In Comparative Example 4, the solid line marked with a cross still showed a delayed overall release. In Example 2, the solid line marked with a square showed a rapid upward trend within the first few seconds of the test, exhibiting a clear rapid release characteristic. The step-by-step operation avoided excessive encapsulation of the surfactant, and the polyol solvent entered the stratum corneum, increasing intercellular fluidity, allowing the cooling ingredient to quickly penetrate the skin barrier and reach the subcutaneous receptors.

[0133] Test Example 4: Skin Irritation Evaluation and In Vitro Hemolysis Analysis

[0134] Experimental description:

[0135] This experiment assessed the potential irritation of the drug solution to human skin and analyzed the damage to cell membranes caused by the formulation system using in vitro cytological testing. Following cosmetic safety technical specifications, a closed patch test was used to obtain macroscopic skin erythema and edema scores in individuals with sensitive skin. Simultaneously, a erythrocyte hemolysis test was used, and the absorbance of hemoglobin in the supernatant was measured using a UV-Vis spectrophotometer to characterize the microscopic irritation state in the form of absorption spectra.

[0136] Experimental steps:

[0137] We are recruiting healthy volunteers who describe themselves as having sensitive skin to participate in closed patch testing under controlled environmental temperature and humidity conditions.

[0138] The drug solutions obtained in Examples 1 to 3 and Comparative Examples 1, 3 and 5 were respectively applied to a special aluminum chamber for patch testing and then applied to the healthy skin on both sides of the spine on the back of the subject.

[0139] Remove the patch after 24 hours of application, and allow it to stand for 0.5 hours. A professional will then observe the erythema and edema of the skin area, and assign a clinical score based on a scale of 0 to 3, and calculate the average value.

[0140] Prepare a 2% suspension of healthy human red blood cells, add an equal amount of the above-mentioned test drug solution, and incubate in a constant temperature water bath at 37°C for 1 hour;

[0141] Centrifuge the incubated mixture to collect the supernatant, and place the supernatant in a quartz cuvette;

[0142] A full wavelength scan was performed using a UV-Vis spectrophotometer in the wavelength range of 350 nm to 650 nm to record absorbance changes and generate absorption spectra.

[0143] Experimental data:

[0144] Table 4. Clinical scores and subject responses in the patch test of the drug solution.

[0145] Test samples Number of testers Number of people with 0 points Number of people with 1 point 2 points 3 points Average clinical score Example 1 30 29 1 0 0 0.03 Example 2 30 27 3 0 0 0.10 Example 3 30 26 3 1 0 0.17 Comparative Example 1 30 11 14 4 1 0.83 Comparative Example 3 30 4 12 11 3 1.43 Comparative Example 5 30 2 10 16 2 1.60

[0146] Experimental conclusion:

[0147] Referring to the statistical data of human patch tests in Table 4, it can be seen that the solutions in each example exhibited extremely mild skin compatibility under continuous application for 24 hours. Example 3, as the group with the highest concentration of active ingredient, had an average clinical score of only 0.17. Comparative Example 1's score increased to 0.83, and Comparative Example 3's average score reached 1.43, indicating basic preservative irritation. Comparative Example 5, under a slightly alkaline environment, achieved an average score of 1.60, showing a mild irritation reaction.

[0148] See attached document Figure 4In Example 3, the solid line marked with a square shows a significantly lower absorption peak at the target wavelength of 414 nm, indicating that no significant membrane damage occurred in the cells. In Comparative Example 3, the solid line marked with a rhombus shows a distinct peak at the same position, confirming that the lack of soothing components leads to direct stimulation and rupture of the cell membrane. In Comparative Example 5, the solid line marked with a fork shows the highest absorption peak, indicating that the slightly alkaline environment exacerbates the disturbance of the cell membrane by surfactants and induces hemolysis. The stepwise dissolution process, in synergy with the soothing components, avoids the chemical stripping of lipids, and the slightly acidic environment maintains the stability of the cells and the preservative components.

Claims

1. A non-irritating cooling liquid, characterized in that, Raw materials comprising the following parts by weight: CO40: 10 to 20 servings; WS-23: 0.5 to 4 parts; Vitamin E: 0.2 to 2 parts; IPBC: 0.1 to 1 copy; Propylene glycol: 10 to 20 parts; Benzyl chloride: 0.1 to 1 part; Benzalkonium chloride: 0.6 parts to 3.5 parts; Purified water: 0.5 to 2.5 parts; Citric acid / sodium citrate buffer: 0.1 to 0.5 parts; Panthenol: 0.2 to 2 parts; Butylene glycol: 7 to 15 parts; 1,2-Hexanediol: 1 part to 5 parts.

2. The non-irritating cooling liquid according to claim 1, characterized in that, The pH value of the citric acid / sodium citrate buffer solution is 5.5 to 6.

5.

3. The non-irritating cooling liquid according to claim 2, characterized in that, The CO40, WS-23, and vitamin E constitute a cooling and soothing base solution; The IPBC, propylene glycol, benzyl chloride, benzalkonium chloride, purified water, and citric acid / sodium citrate buffer solution constitute the antibacterial and preservative base solution. The panthenol, butylene glycol, and 1,2-hexanediol constitute a moisturizing and penetrating base solution.

4. The non-irritating cooling liquid according to claim 3, characterized in that, The non-irritating cooling liquid is prepared by mixing the cooling and soothing base liquid, the antibacterial and preservative base liquid, and the moisturizing and penetrating base liquid.

5. A method for preparing a non-irritating cooling liquid as described in any one of claims 1-4, characterized in that, Includes the following steps: The CO40 is heated, then the WS-23 is added, and the mixture is stirred at a constant temperature until it is completely dissolved and becomes transparent. After cooling, the vitamin E is added and stirred evenly to obtain a cooling and soothing base liquid. At room temperature, the IPBC is added to the propylene glycol and stirred until completely dissolved. Then, the benzyl chloride, benzalkonium chloride, purified water and citric acid / sodium citrate buffer are added in sequence and stirred at a constant speed to obtain the antibacterial and preservative base solution. The butanediol and 1,2-hexanediol were mixed, and then the panthenol was added and stirred until completely dissolved to obtain a moisturizing and penetrating base liquid. Slowly inject the antibacterial and preservative base liquid into the cooling and soothing base liquid, and maintain the stirring speed to perform preliminary mixing to obtain a preliminary mixture. Add the moisturizing and penetrating base liquid to the preliminary mixture, continue stirring at a constant temperature, and cool to room temperature to obtain a non-irritating and cooling medicinal solution.

6. The preparation method according to claim 5, characterized in that, In the step of heating the CO40, the heating temperature is 50℃~60℃.

7. The preparation method according to claim 5, characterized in that, In the step of adding vitamin E after cooling, the temperature is lowered to 35℃~40℃.

8. The preparation method according to claim 5, characterized in that, In the step of slowly injecting the antibacterial and preservative base liquid into the cooling and soothing base liquid, the injection temperature is 35℃~40℃.

9. The preparation method according to claim 5, characterized in that, In the step of maintaining the stirring speed for preliminary mixing, the stirring speed is 150 r / min to 250 r / min.

10. The preparation method according to claim 5, characterized in that, In the step of continuing constant temperature stirring, the stirring time is 20 min to 30 min.

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