Tranexamic acid-glutathione compound cream and preparation method thereof

Abstract

The application provides a tranexamic acid-glutathione compound cream and a preparation method thereof, adopts a W1 / O / W double emulsion phase structure design, encapsulates reduced glutathione in an acidic inner water core, stabilizes an oil phase by using hydrogenated lecithin and sorbitan sesquioleate, and constructs a lamellar gel network in an outer water phase containing tranexamic acid, so as to realize a sub-micron dispersion system with a particle size D50 of 0.30-0.80 microns, a polydispersity index of 0.15-0.25 and a viscosity of 2.0-8.0 Pa seconds, the encapsulation rate of glutathione is not less than 70%, and the headspace oxygen content is not higher than 1.0%, three technical contradictions of a high yield viscoelastic structure and a low shear damage inner core integrity coupling conflict, a smooth low skin feeling and a high barrier anti-oxidation and anti-leakage coexistence problem and a low surface activity sensitive skin compatibility and a sub-micron low PDI dispersion stability are solved, and the application has wide application values of improving uneven skin color, lightening color spots, brightening skin color and soothing and repairing.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of cosmetic formulations, in particular to a tranexamic acid-glutathione compound cream and a preparation method thereof. BACKGROUND

[0002] In the field of modern skin care, hyperpigmentation, uneven skin tone and oxidative stress damage are the main cosmetic concerns faced by consumers. These problems not only affect the appearance, but also reflect the deep state of impaired skin barrier function and active inflammatory response. Tranexamic acid, as a classic antifibrinolytic drug, has been widely proven to inhibit the activity of tyrosinase in melanocytes and block the ultraviolet-induced pigment synthesis pathway. It has shown significant advantages in skin whitening and anti-inflammatory fields. Reduced glutathione, as the most important antioxidant in cells, can effectively resist oxidative stress through multiple mechanisms such as scavenging free radicals, chelating heavy metal ions, and regenerating vitamin C and E. It can also reduce melanin production by competitively inhibiting tyrosinase, forming a synergistic whitening and antioxidant system with tranexamic acid. However, the effective integration of these two active ingredients into a single formulation requires not only to solve the problem of easy oxidative degradation of glutathione in an oxygen-rich environment and neutral pH, but also to meet the high-dose release requirements of tranexamic acid, while also considering the comfort of the formulation, long-term stability, and suitability for sensitive skin. This poses extremely stringent multi-dimensional performance requirements for formulation design and preparation process, and has become an important issue in the field of current cosmetic research and development.

[0003] In view of the above-mentioned development status of material compound cosmetics, there are still significant deficiencies. Firstly, traditional single-phase emulsion or gel systems cannot achieve differential pH environment construction for the two components. Glutathione has a sharp decrease in stability under neutral or alkaline conditions, and tranexamic acid has limited solubility in acidic environments and may irritate the skin, making it difficult for the two to coexist in the same phase and maintain activity for a long time. For example, Chinese Patent No. CN103860453B discloses a live color tightening cream and a preparation method thereof, but there is a problem of rapid oxidation and inactivation of glutathione exposed to the outer phase, resulting in poor stability. Secondly, to achieve high viscosity and yield stress to prevent phase separation and sedimentation, a large amount of high-molecular-weight thickening agents or high-concentration emulsifiers are often added, which significantly increases the shear stress in the preparation process, damages the integrity of the inner phase structure, reduces the encapsulation efficiency, and high surfactant content may irritate sensitive skin, making it difficult to balance the refreshing skin feel and low sensitivity characteristics. Thirdly, sub-micron dispersed particles (particle size 0.3-0.8 microns) are beneficial to skin feel and penetration, but it is extremely difficult to maintain a narrow particle size distribution (PDI < 0.25) and long-term physical stability under low emulsifier dosage conditions. Existing technologies rely on high-speed shearing or ultrasonic emulsification, which has high energy consumption and poor particle size reproducibility, and lacks precise and controllable gentle particle size adjustment methods and stabilization strategies. SUMMARY

[0004] The application aims to provide an tranexamic acid-glutathione compound cream and a preparation method thereof, and solve the problems of the current system in the coupling conflict of high yield viscoelastic structure and low shear damage core integrity, the coexistence difficulty of refreshing low skin feeling and high barrier anti-oxidation and anti-leakage, and the pain point problem of low surface activity sensitive skin compatibility and sub-micron low PDI dispersion stability.

[0005] The application adopts a W1 / O / W double emulsion phase synergistic design idea, reduces glutathione is isolated and encapsulated in an acidic low-oxygen inner water core, and an antioxidant synergist is configured, spatial separation and pH microenvironment differential regulation are realized with tranexamic acid in the outer water phase, the inner core is protected from shear damage and oxygen penetration by using the oil phase interface film constructed by hydrogenated lecithin and sorbitan sesquioleate, and a layered gel network formed by glycerol stearate and cetylstearyl alcohol in the outer phase provides low shear and high yield viscoelastic support, and under the condition of only a very low amount of hydrophilic emulsifier, precise particle size is obtained by high-pressure microfluidization or SPG membrane emulsification, sub-micron narrow distribution is realized, and three breakthroughs of stable coexistence of double active ingredients, high encapsulation and low leakage, refreshing low sensitivity and high stability are achieved, and a synergistic effect far beyond the simple mixture of each component is achieved.

[0006] In order to achieve the above-mentioned purpose, the application provides the following technical scheme:

[0007] A tranexamic acid-glutathione compound cream, comprising a W1 / O / W double emulsion phase structure, wherein all percentage contents are calculated based on the total mass of the final preparation:

[0008] a) W1 is an inner water core, containing 0.2–2.0 wt% of reduced glutathione, a citric acid-sodium citrate buffer system is used to adjust W1 to pH 3.5–4.2, and 0.02–0.10 wt% of disodium ethylenediaminetetraacetate and 0.05–0.30 wt% of phytic acid are contained, and 2.0–5.0 wt% of glycerol or 3.0–8.0 wt% of sorbitol is contained to alleviate the osmotic pressure difference;

[0009] b) O is an oil phase, containing 5–15 wt% of squalane, and 0.2–1.0 wt% of hydrogenated lecithin and 0.2–1.0 wt% of sorbitan sesquioleate are used to stabilize W1 / O;

[0010] c) W2 is an outer water phase, containing 2.0–5.0 wt% of tranexamic acid, and containing a hydrophilic emulsifier selected from one or more of polyglyceryl-6 stearate, polyethylene glycol-100 stearate or cetylstearyl alcohol polyether-20, the total amount being 0.2–1.0 wt%, W2 is adjusted to pH 5.2–5.8, and coexists with a layered gel network constructed by 1.0–3.0 wt% of glycerol stearate and 1.0–2.5 wt% of cetylstearyl alcohol.

[0011] d) The system has a particle size D50 of 0.30-0.80 μm, a PDI of 0.15-0.25, a viscosity of 2.0-8.0 Pa-s at 25 °C, a headspace oxygen content of no more than 1.0%, and a glutathione encapsulation rate of no less than 70%.

[0012] Further, the W1 / O inner core is prepared by the following steps:

[0013] A1. W1 formulation: reduced glutathione is dissolved in deionized water, citric acid-sodium citrate is added to adjust the pH to 3.5-4.2, 0.02-0.10 wt% of disodium ethylenediaminetetraacetate and 0.05-0.30 wt% of phytic acid are added, 2.0-5.0 wt% of glycerol or 3.0-8.0 wt% of sorbitol is added to match the osmotic pressure of the external phase, and nitrogen is bubbled for 10-15 min for degassing;

[0014] A2. Oil phase formulation: squalane is dissolved in hydrogenated lecithin and sorbitan sesquioleate at 70-80 °C;

[0015] A3. Primordial milk formation: W1 is added dropwise to the oil phase pre-emulsification under the condition of 4000-6000 rpm, 30-90 s, followed by 2-3 times of high-pressure microfluidization at 600-900 bar to obtain W1 / O.

[0016] Further, the lamellar gel network of the W2 external phase is constructed by the following steps:

[0017] B1. Glycerol stearate 1.0-3.0 wt%, cetylstearyl alcohol 1.0-2.5 wt%, glycerol 2.0-5.0 wt%, and water are mixed and uniformly melted at 70-80 °C;

[0018] B2. The temperature is lowered to 45-50 °C to form a lamellar liquid crystal phase, and the long-period ordered structure is stably present in the external phase.

[0019] Further, the W1 / O / W complex phase is prepared by the following steps:

[0020] C1. Under the condition of 45-50 °C and nitrogen protection, W1 / O is sheared and dispersed in the lamellar gel network of the W2 external phase at 2500-3500 rpm for 60-120 s, the external phase is pre-dissolved tranexamic acid and adjusted to pH 5.2-5.8, and pre-degassed for 10-15 min;

[0021] C2. Optionally, 1 low-pressure microfluidization is performed at 80-150 bar, or SPG membrane emulsification is used to perform the granulation at a transmembrane pressure difference of 40-120 kPa, to obtain a W1 / O / W system with a D50 of 0.30-0.80 μm and a PDI of 0.15-0.25.

[0022] Further, the system preferably has a 25°C viscosity of 3.0-6.0 Pa-s, an absolute value of zeta potential of not less than 15 mV, or a yield stress of not less than 20 Pa.

[0023] Further, the content of tranexamic acid is 2.5-4.0 wt%, the content of reduced glutathione is 0.3-1.0 wt%, the content of squalane is 8-12 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 0.5-1.8 wt%, phenoxyethanol 0.3-1.0 wt% and ethylhexylglycerin 0.05-0.50 wt% are used as the preservative system, and the mass ratio of reduced glutathione, disodium ethylenediaminetetraacetate and phytic acid is 1.0:0.04-0.10:0.10-0.30.

[0024] As one concept of the present application, the present application adopts W1 / O / W double emulsion phase compartment design mainly for enhancing the stability and synergistic efficacy of the two active ingredients. The present application encapsulates reduced glutathione in an acidic inner water core with pH 3.5-4.2, utilizes the protonation effect to reduce the ionization degree of the thiol group and the oxidative reactivity, and configures a double metal chelating network composed of disodium ethylenediaminetetraacetate and phytic acid to effectively block the Fenton-type free radical oxidation path catalyzed by trace transition metal ions, significantly prolonging the chemical stability period of glutathione. Squalane in the oil phase provides a hydrophobic barrier as a low-polarity hydrocarbon solvent, and hydrogenated lecithin forms a dense phospholipid bilayer at the W1 / O interface, and the saturated alkyl chain eliminates the oxidation sensitive point of the unsaturated bond, and cooperates with sorbitan sesquioleate to anchor at the oil-water interface, constructing an interface film with bidirectional barrier ability to oxygen molecules and water molecules, effectively isolating the inner core glutathione from the high oxygen environment of the outer phase. The outer water phase adopts a weakly acidic design with pH 5.2-5.8, which not only ensures the high solubility and antifibrinolytic activity of tranexamic acid under this condition, but also provides low-shear high-yield viscoelastic support through the lamellar liquid crystal network formed by glycerol stearate and cetylstearyl alcohol in this temperature range, achieving long-term physical stability of the system with only 0.2-1.0 wt% of hydrophilic emulsifier, avoiding the stimulation of high surface activity to sensitive skin, and the long-period ordered arrangement of the lamellar structure further delays the diffusion rate of oxygen molecules to the inner core. The double pH microenvironment separation design makes glutathione and tranexamic acid each be in the best stable and active state, and the multi-layer interface barrier of W1 / O / W structure controls the headspace oxygen content to be below 1.0%, and the glutathione encapsulation rate is maintained above 70%, ensuring the long-term stability of the compound system during storage and use.

[0025] The present application also discloses a preparation method of a tranexamic acid-glutathione compound cream, comprising:

[0026] S1. Inner phase preparation: preparing a W1 / O inner core;

[0027] S2. Outer phase preparation: preparing a lamellar gel network of W2 outer phase, dissolving 2.0-5.0 wt% of tranexamic acid in the W2 outer phase, purging nitrogen or vacuum degassing for 10-15 min, and adjusting the pH to 5.2-5.8;

[0028] S3. Secondary emulsification and granulation: dispersing the W1 / O dispersed inner core in the outer phase obtained in step S2 to obtain a W1 / O / W system;

[0029] S4. Nitrogen filling and filling: controlling the headspace oxygen content to be not higher than 1.0%, and selecting a barrier package with an oxygen permeability of not higher than 1 at 23°C, 1 atm and 50% RH to complete filling.

[0030] Further, the volume fraction ratio of W1 to oil phase in S1 is 25-40:75-60, the high pressure microfluidization granulation pressure is 700-900 bar for primary granulation and 80-150 bar for secondary granulation, W2 outer phase in S2 is cooled to 45-50°C and then combined with W1 / O to stabilize the lamellar gel network structure, and the nitrogen degassing time in S1 is 10-15 min.

[0031] The application also discloses application of the tranexamic acid-glutathione compound cream in the cosmetic field, and the compound cream is characterized by being used for improving uneven skin color, lightening color spots, brightening skin color and soothing and repairing.

[0032] Further, the compound cream is applied to clean and dry skin 1-2 times per day, and significant improvement of skin color uniformity is obtained after continuous use for 4-8 weeks.

[0033] As another concept of the present application, the present application adopts high-pressure microfluidization and layered gel network synergistic stabilization design mainly for enhancing the particle size uniformity and long-term stability of sub-micron dispersion system. In the W1 / O core preparation stage, through 600-900 bar high-pressure microfluidization treatment, the shear field, cavitation effect and turbulent pulsation generated by high-speed jet in the microchannel are used to instantaneously break and homogenize the primary emulsion droplets to sub-micron level, at the same time, hydrogenated lecithin and sorbitan sesquioleate are quickly adsorbed on the newly generated interface under high energy input to form a dense and orderly mixed interface film, significantly reducing the interfacial tension and providing steric hindrance stabilization, ensuring that the W1 / O core particle size distribution is narrow and highly reproducible. In the W1 / O / W complex phase construction stage, low-pressure microfluidization (80-150 bar) or SPG membrane emulsification method is used for mild secondary particle size adjustment, the former reduces the mechanical damage to the already formed core by reducing the operating pressure, and the latter uses the extrusion droplet mechanism of uniform pore size SPG membrane to realize precise control of particle size, both methods operate within the temperature window of 45-50°C where the layered gel network has been preliminarily formed, and the long-period layered liquid crystal structure formed by the self-assembly of glycerol stearate and cetylstearyl alcohol provides spatial restraint to the dispersed phase droplets, further inhibiting the Ostwald ripening and coalescence tendency of the particles after particle size adjustment. The layered gel network not only provides high yield stress (≥20 Pa) to prevent sedimentation and stratification, but also increases the viscosity of the continuous phase and constructs a three-dimensional network structure through the nanoscale hydration layer between its lamellar layers, significantly slowing down the Brownian motion and collision frequency of the dispersed phase, while the electrostatic repulsion of the absolute value of ζ potential ≥15 mV further enhances the stability between particles. The synergistic effect of the particle size adjustment process and the gel network makes the final preparation achieve a particle size D50 of 0.30-0.80 μm, a narrow distribution of PDI as low as 0.15-0.25, and long-term physical stability under the condition of extremely low surface activity containing only 0.2-1.0 wt% hydrophilic emulsifier, balancing the refreshing skin feel and sensitive skin safety, embodying the synergistic advantages of mild particle size adjustment and intelligent stabilization design.

[0034] Reduced glutathione and tranexamic acid exhibit a significant synergistic whitening and antioxidant effect in the compound system of the present application. Reduced glutathione focuses on playing a role from the perspectives of intracellular redox balance and competition for melanin biosynthesis substrates. It blocks the key step of melanin synthesis by reducing the intermediate dopaquinone to dopa, while scavenging active oxygen free radicals induced by ultraviolet light, protecting cell membrane lipids and proteins from oxidative damage, and maintaining the normal functional state of keratinocytes and melanocytes. Tranexamic acid focuses on inhibiting the plasmin-plasmin system and blocking the arachidonic acid metabolic pathway, reducing the release of inflammatory mediators prostaglandin E2 and leukotrienes, thereby inhibiting ultraviolet-induced melanocyte activation signaling, reducing the transcription and expression of tyrosinase, and reducing melanin production from the source. In terms of the mechanism of action in enhancing whitening effects, reduced glutathione directly intervenes in the enzymatic process of melanin synthesis by competitively inhibiting the tyrosinase substrate binding site and scavenging enzyme reaction intermediates, while tranexamic acid reduces the expression and activation of tyrosinase from the upstream regulatory level by inhibiting the inflammatory cascade and blocking the activation signal of melanocytes. Both act on different links of the melanin production pathway, forming a double inhibition of substrate competition and signal blocking. In terms of enhancing antioxidant capacity, reduced glutathione, as a direct free radical scavenger and reducing agent, rapidly neutralizes reactive oxygen species and regenerates other antioxidants, while tranexamic acid reduces the sustained production of oxidative stress by inhibiting inflammation, and both of them synergistically build an antioxidant defense line that combines scavenging and prevention. The deep mechanism of synergistic effect lies in the fact that tranexamic acid reduces the oxidative stress environment of melanocytes by inhibiting inflammation, creating favorable conditions for glutathione to maintain a reduced state and play a substrate competition role, while the high antioxidant capacity of glutathione in turn protects tranexamic acid from oxidative degradation, prolonging its action time in inhibiting inflammatory signals. Both achieve their optimal stable state through spatial separation in the W1 / O / W double emulsion structure, while after targeting the skin tissue, they produce a whitening and antioxidant synergistic effect far beyond a single component through a synergistic molecular mechanism.

[0035] Beneficial technical effects

[0036] 1. Significantly improve the stability and synergistic efficacy of two active ingredients: By W1 / O / W double emulsion phase compartment design, reduced glutathione is encapsulated in the acidic inner water core with pH 3.5-4.2 and configured with disodium ethylenediaminetetraacetate and phytic acid dual antioxidant system, using hydrogenated lecithin and sorbitan estolate to construct a dense oil phase interface film to block the penetration of oxygen molecules, achieving a long-term stable protection of glutathione encapsulation rate not less than 70% and headspace oxygen content not higher than 1.0%, while the outer water phase pH 5.2-5.8 environment ensures the high solubility and antifibrinolytic activity of tranexamic acid, both maintain the best efficacy state in the differential microenvironment, synergistically inhibit melanin production through substrate competition and signal blocking mechanisms, and build an antioxidant defense line for both clearance and prevention, achieving the synergistic effect of whitening and antioxidant soothing.

[0037] 2. Successfully solve the coupling conflict between high yield viscoelastic structure and low shear damage inner core integrity: Using glycerol stearate and cetylstearyl alcohol to construct a lamellar gel network in the outer water phase, using its self-assembly to form a long-period lamellar liquid crystal structure to provide high viscoelastic support with a yield stress not less than 20 Pa, effectively preventing sedimentation, stratification and leakage, while in the W1 / O inner core preparation stage, rapid particle size reduction is achieved by 600-900 bar high pressure microjet, and in the W1 / O / W complex phase construction stage, mild secondary particle size reduction is achieved by 80-150 bar low pressure microjet or SPG membrane emulsification, combined with 45-50°C lamellar gel network preliminary formation temperature window operation, significantly reducing the mechanical damage of shear stress to the inner core, ensuring the integrity of glutathione encapsulation, achieving compatibility of long-term stability and inner core protection.

[0038] 3. Realize the coexistence of refreshing low viscosity skin feeling and high barrier antioxidant and anti-leakage: Under the condition of only 0.2-1.0 wt% hydrophilic emulsifier, through the spatial constraint of lamellar gel network and the electrostatic repulsion of absolute value of zeta potential ≥15 mV, the viscosity of the system at 25°C is controlled in the range of 2.0-8.0 Pa·s, avoiding the heavy and sticky feeling caused by high molecular thickening agent, while the double barrier of nanoscale hydration layer between lamellar liquid crystal sheets and oil phase interface film reduces the diffusion rate of oxygen molecules to the inner core to a very low level, ensuring the headspace oxygen content not higher than 1.0%, balancing the refreshing and comfortable skin feeling, low irritation for sensitive skin and long-term antioxidant stability.

[0039] 4. Breakthrough of low-sensitivity-skin compatibility and sub-micron low-PDI dispersion stability contradiction: through the synergistic effect of high-pressure microfluidization precise particle size regulation process and lamellar gel network intelligent stabilization design, a narrow-distribution sub-micron dispersion system with particle size D50 of 0.30-0.80 μm and PDI as low as 0.15-0.25 is realized under the condition of low-sensitivity formula with total hydrophilic emulsifier amount of only 0.2-1.0 wt%. The high-energy input of high-pressure microfluidization ensures the uniformity of particle size and the densification of interfacial film, and the three-dimensional network structure and high yield stress of lamellar gel network inhibit the Ostwald ripening and coalescence tendency, and the uniform pore size extrusion droplet mechanism of SPG membrane emulsification provides a mild and controllable particle size regulation pathway, so that the system remains long-term physical stability under the framework of low-sensitivity-skin-friendly formula, and has excellent skin feel permeability and long-term dispersion stability.

[0040] 5. Broaden application scenarios and significantly improve skin color uniformity: the compound cream blocks the ultraviolet-induced melanocyte activation signal through the dual action of tranexamic acid in anti-fibrinolysis and anti-inflammatory, and cooperates with the substrate competitive tyrosinase inhibition and free radical scavenging ability of reduced glutathione, to provide synergistic improvement for pigmentation, uneven skin color and oxidative stress damage. After continuous use for 4-8 weeks, 1-2 times a day on clean and dry skin, it can significantly lighten pigmented spots, brighten skin color and relieve inflammatory reaction, and is suitable for diversified application scenarios such as daily whitening care, sensitive skin repair and anti-aging maintenance, etc., and has wide market application value. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 Effect of reduced glutathione content on encapsulation rate and tyrosinase inhibition rate of the present application.

[0042] Figure 2 Effect of tranexamic acid content on tyrosinase inhibition rate and viscosity of the present application.

[0043] Figure 3 Effect of high-pressure microfluidization particle size regulation pressure on particle size D50 and polydispersity index of the present application.

[0044] Figure 4 Effect of pH value of water core in W1 on glutathione encapsulation rate and stability of the present application.

[0045] Figure 5 GSH residual rate-time curve of Example 1 (multiple groups of pH / chelating agent concentration comparison).

[0046] Figure 6 Effect of lamellar liquid crystal d-spacing on multi-stage diffraction peaks in SAXS scattering curve of Example 1.

[0047] Figure 7 Morphology of Example 1 compound cream containing tranexamic acid-glutathione. DETAILED DESCRIPTION

[0048] In order to make the purposes, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application.

[0049] Embodiment 1

[0050] The present embodiment provides a tranexamic acid-glutathione compound cream, comprising a W1 / O / W double emulsion phase structure, and all the percentage contents are based on the total mass of the final preparation.

[0051] The W1 of the present embodiment is an inner water core, containing 0.6 wt% of reduced glutathione. The W1 is adjusted to pH 3.8 using a citric acid-sodium citrate buffer system, and contains 0.05 wt% of disodium ethylenediaminetetraacetate and 0.15 wt% of phytic acid. In order to alleviate the osmotic pressure difference, the W1 contains 3.5 wt% of glycerol. The O of the present embodiment is an oil phase, containing 10.0 wt% of squalane, and is stabilized by 0.5 wt% of hydrogenated lecithin and 0.5 wt% of sorbitan sesquioleate to form the W1 / O inner core. The W2 of the present embodiment is an outer water phase, containing 3.0 wt% of tranexamic acid, and contains 0.6 wt% of the hydrophilic emulsifier polyglyceryl-6 stearate, and the W2 is adjusted to pH 5.5 and coexists with a lamellar gel network constructed by 2.0 wt% of glyceryl stearate and 1.5 wt% of cetylstearyl alcohol. The system of the present embodiment has a particle size D50 of 0.50 μm, a PDI of 0.20, a 25°C viscosity of 4.5 Pa·s, a headspace oxygen content of 0.5%, and a glutathione encapsulation rate of 85%.

[0052] The W1 / O inner core of the present embodiment is prepared by the following steps: dissolving 0.6 wt% of reduced glutathione in deionized water, adding citric acid-sodium citrate to adjust to pH 3.8, adding 0.05 wt% of disodium ethylenediaminetetraacetate and 0.15 wt% of phytic acid, and then adding 3.5 wt% of glycerol to match the osmotic pressure of the outer phase, and degassing for 12 min with nitrogen. Dissolve 10.0 wt% of squalane, 0.5 wt% of hydrogenated lecithin and 0.5 wt% of sorbitan sesquioleate at 75°C. Add the W1 dropwise to the oil phase pre-emulsion under the condition of 5000 rpm for 60 s, and then perform 2 times of high-pressure microjet size reduction at 750 bar to obtain the W1 / O inner core.

[0053] The W2 outer phase lamellar gel network of the present embodiment is constructed by the following steps: mixing 2.0 wt% of glyceryl stearate, 1.5 wt% of cetylstearyl alcohol, 3.0 wt% of glycerol and water, and melting uniformly at 75°C. Cool to 48°C and stand to form a lamellar liquid crystal phase, so that the long-period ordered structure stably exists in the outer phase.

[0054] The W1 / O / W multiple phase of the present example was prepared by the following steps: W1 / O was dispersed in the lamellar gel network of W2 external phase at 48°C under nitrogen protection condition with 3000 rpm, 90 s shearing, the external phase was pre-dissolved with tranexamic acid 3.0 wt% and adjusted to pH 5.5, and pre-degassed with nitrogen for 12 min. One low pressure microfluidization at 100 bar was performed to obtain the W1 / O / W system with D50 of 0.50 pm and PDI of 0.20.

[0055] The system of the present example has a viscosity of 4.5 Pa-s at 25°C, an absolute value of zeta potential of 20 mV, and a yield stress of 30 Pa. The content of tranexamic acid in the present example is 3.0 wt%, the content of reduced glutathione is 0.6 wt%, the content of squalane is 10.0 wt%, the total content of hydrogenated lecithin and sorbitan sesquioleate is 1.0 wt%, phenoxyethanol 0.6 wt% and ethylhexylglycerin 0.20 wt% are used as the preservative system, and the mass ratio of reduced glutathione, disodium ethylenediaminetetraacetate, and phytic acid is 1.0:0.083:0.25.

[0056] The preparation method of the present example includes: first step, preparation of W1 / O inner core. Second step, preparation of the lamellar gel network of W2 external phase, and dissolve tranexamic acid 3.0 wt% in the W2 external phase of the present example, degas with nitrogen for 12 min, and adjust the pH to 5.5. Third step, disperse the W1 / O inner core of the present example in the external phase obtained in step two to obtain the W1 / O / W system. Fourth step, control the oxygen content in the headspace to be 0.5%, and select the barrier packaging with oxygen permeability not higher than 1 The volume fraction ratio of W1 to oil phase in the present example is 32:68, the high pressure microfluidization granulation pressure of the present example is 750 bar for the initial milk granulation and 100 bar for the secondary granulation, the W2 external phase of the present example is cooled to 48°C and combined with W1 / O to stabilize the lamellar gel network structure, and the nitrogen degassing time in the present example is 12 min.

[0057] The compound cream of the present example is applied in the field of cosmetics, and is used for improving uneven skin color, lightening color spots, brightening skin color, and soothing and repairing. The compound cream of the present example is applied on clean and dry skin twice a day, and continuous use for 6 weeks can obtain significant improvement in skin color uniformity.

[0058] Example 1 Features: This example is configured with moderate parameters to ensure formulation stability and process reproducibility. The active ingredient content is moderate (glutathione 0.6%, tranexamic acid 3.0%) and suitable as a base formulation. Glycerin is chosen as an osmotic pressure regulator, and glycerin is also used in the lamellar gel network, for a total glycerin content of 6.5%, providing good moisturizing effect. The double emulsion system has a moderate particle size (D50 = 0.50 pm) and a low PDI (0.20), indicating a uniform particle size distribution. The viscosity of 4.5 Pa-s is suitable for daily application, and the glutathione encapsulation rate of 85% ensures effective protection of antioxidant activity. This example is particularly suitable for daily skin care, gentle whitening repair for sensitive skin, and basic antioxidant care scenarios that require long-term use.

[0059] Example 2

[0060] This example provides a tranexamic acid-glutathione compound cream, comprising a W1 / O / W double emulsion phase structure, and all percentage contents are based on the total mass of the final preparation.

[0061] The W1 of this example is an inner water core containing 0.9 wt% reduced glutathione. The W1 is adjusted to pH 3.6 using a citric acid-sodium citrate buffer system, and contains 0.08 wt% disodium ethylenediaminetetraacetate and 0.25 wt% phytic acid. To alleviate osmotic pressure differences, W1 contains 4.0 wt% glycerin. The O of this example is an oil phase containing 12.0 wt% squalane, and is stabilized by 0.7 wt% hydrogenated lecithin and 0.6 wt% sorbitan sesquioleate to form the W1 / O inner core. The W2 of this example is an outer water phase containing 2.8 wt% tranexamic acid, and contains 0.7 wt% hydrophilic emulsifier polyethylene glycol-100 stearate, and is adjusted to pH 5.4 and coexists with a lamellar gel network constructed from 2.5 wt% glyceryl stearate and 2.0 wt% cetylstearyl alcohol. The system of this example has a particle size D50 of 0.45 pm, a PDI of 0.18, a 25°C viscosity of 5.5 Pa-s, a headspace oxygen content of 0.6%, and a glutathione encapsulation rate of 82%.

[0062] The W1 / O inner core of this example is prepared by the following steps: dissolve 0.9 wt% reduced glutathione in deionized water, adjust to pH 3.6 with citric acid-sodium citrate, add 0.08 wt% disodium ethylenediaminetetraacetate and 0.25 wt% phytic acid, and then add 4.0 wt% glycerin to match the osmotic pressure of the external phase, and degas with nitrogen for 13 min. Dissolve 12.0 wt% squalane, 0.7 wt% hydrogenated lecithin, and 0.6 wt% sorbitan sesquioleate at 78°C. Pre-emulsify W1 into the oil phase at 5500 rpm for 50 s, and then perform 3 high-pressure microfluidization at 800 bar to obtain the W1 / O inner core.

[0063] The W2 external phase lamellar gel network of this example was constructed by the following steps: mixing glyceryl stearate 2.5 wt%, cetylstearyl alcohol 2.0 wt%, glycerol 3.5 wt% and water, and melting uniformly at 78 °C. After cooling to 47 °C, the lamellar liquid crystal phase was formed, and the long period ordered structure was stably existed in the external phase.

[0064] The W1 / O / W multiple phase of this example was prepared by the following steps: under the condition of 47 °C and nitrogen protection, the W1 / O was dispersed in the W2 external phase lamellar gel network by shearing at 3200 rpm for 80 s, the external phase was previously dissolved with tranexamic acid 2.8 wt% and adjusted to pH 5.4, and previously degassed with nitrogen for 13 min. One low pressure microfluidization was carried out at 120 bar, and the D50 of the W1 / O / W system was 0.45 μm and the PDI was 0.18.

[0065] The viscosity of the system of this example at 25 °C was 5.5 Pa·s, the absolute value of zeta potential was 22 mV, and the yield stress was 35 Pa. The content of tranexamic acid in this example was 2.8 wt%, the content of reduced glutathione was 0.9 wt%, the content of squalane was 12.0 wt%, the total content of hydrogenated lecithin and sorbitan sesquioleate was 1.3 wt%, phenoxyethanol 0.7 wt% and ethylhexylglycerin 0.30 wt% were used as the preservative system, and the mass ratio of reduced glutathione, disodium ethylenediaminetetraacetate and phytic acid was 1.0:0.089:0.278.

[0066] The preparation method of this example included: first step, preparation of W1 / O inner core. Second step, preparation of W2 external phase lamellar gel network, and dissolution of tranexamic acid 2.8 wt% in the W2 external phase of this example, degassing with nitrogen for 13 min, and adjusting the pH to 5.4. Third step, dispersing the W1 / O inner core of this example in the external phase obtained in step two to obtain the W1 / O / W system. Fourth step, controlling the oxygen content in the headspace to be 0.6%, and selecting the barrier packaging with oxygen permeability not higher than 1 The volume fraction ratio of W1 to oil phase in this example was 35:65, the high pressure microfluidization granulation pressure of this example was 800 bar for the initial milk granulation and 120 bar for the secondary granulation, the W2 external phase of this example was cooled to 47 °C and combined with W1 / O to stabilize the lamellar gel network structure, and the nitrogen degassing time in this example was 13 min.

[0067] The compound cream of the present embodiment is applied in the field of cosmetics, used to improve uneven skin tone, lighten skin spots, brighten skin tone and soothe and repair. The compound cream of the present embodiment is applied twice a day on clean and dry skin, and continuous use for 8 weeks can significantly improve the uniformity of skin tone.

[0068] Example 2 Features: This embodiment is biased towards high antioxidant capacity optimization, with increased glutathione content to 0.9%, combined with high content of phytic acid (0.25%) and disodium EDTA (0.08%) to form a powerful antioxidant synergistic system. Lower W1 pH value (3.6) is beneficial to the stability of glutathione. Squalane content of 12% provides excellent skin feel and penetration promotion. Three high-pressure microfluidization (800 bar) is used to obtain smaller particle size (D50=0.45 μm) and narrower particle size distribution (PDI=0.18), which enhances the encapsulation stability. Higher concentration of lamellar gel network (glyceryl stearate 2.5% + cetostearyl alcohol 2.0%) improves the viscosity (5.5 Pa·s) and structural stability of the system. This embodiment is particularly suitable for anti-aging care, mature skin with high antioxidant demand, protection and repair in urban polluted environment, and professional care scenarios requiring deep antioxidant and free radical scavenging.

[0069] Example 3

[0070] The present embodiment provides a compound tranexamic acid-glutathione cream, comprising a W1 / O / W double emulsion phase structure, all percentage contents are based on the total mass of the final preparation.

[0071] The W1 of the present embodiment is the inner water core, containing 0.4 wt% of reduced glutathione. The W1 is adjusted to pH 4.0 with a citric acid-sodium citrate buffer system, and contains 0.03 wt% of disodium ethylenediaminetetraacetate and 0.08 wt% of phytic acid. To alleviate the osmotic pressure difference, W1 contains 5.0 wt% of sorbitol. The O of the present embodiment is the oil phase, containing 8.0 wt% of squalane, and is stabilized by 0.3 wt% of hydrogenated lecithin and 0.4 wt% of sorbitan sesquioleate to form the W1 / O inner core. The W2 of the present embodiment is the outer water phase, containing 4.0 wt% of tranexamic acid, and contains 0.8 wt% of the hydrophilic emulsifier ceteareth-20, W2 is adjusted to pH 5.6, and coexists with the lamellar gel network constructed by glyceryl stearate 1.5 wt% and cetostearyl alcohol 1.2 wt%. The system of the present embodiment has a particle size D50 of 0.60 μm, a PDI of 0.22, a 25°C viscosity of 3.5 Pa·s, a headspace oxygen content of 0.7%, and a glutathione encapsulation rate of 75%.

[0072] The W1 / O inner core of this example was prepared by the following steps: reduced glutathione 0.4 wt% was dissolved in deionized water, citric acid-sodium citrate was added to adjust pH to 4.0, disodium ethylenediaminetetraacetate 0.03 wt% and phytic acid 0.08 wt% were added, sorbitol 5.0 wt% was added to match the osmotic pressure of the external phase, and nitrogen was bubbled for 11 min for degassing. Squalane 8.0 wt%, hydrogenated lecithin 0.3 wt% and sorbitan sesquioleate 0.4 wt% were dissolved at 72 °C. The W1 was added dropwise into the oil phase pre-emulsion at 4500 rpm for 70 s, followed by 2 times of high pressure microfluidization at 720 bar to obtain the W1 / O inner core.

[0073] The W2 external phase lamellar gel network of this example was constructed by the following steps: glyceryl stearate 1.5 wt%, cetylstearyl alcohol 1.2 wt%, glycerol 2.5 wt% and water were mixed and melted uniformly at 72 °C. The temperature was lowered to 49 °C and the sample was left to stand to form a lamellar liquid crystal phase, so that the long-period ordered structure was stably present in the external phase.

[0074] The W1 / O / W multiple phase of this example was prepared by the following steps: the W1 / O was dispersed in the W2 external phase lamellar gel network at 49 °C under nitrogen protection, with shearing at 2800 rpm for 100 s, the external phase was pre-dissolved with tranexamic acid 4.0 wt% and adjusted to pH 5.6, and pre-degassed with nitrogen for 11 min. The SPG membrane emulsification method was used, and the whole was granulated at a transmembrane pressure difference of 80 kPa to obtain a W1 / O / W system with a D50 of 0.60 μm and a PDI of 0.22.

[0075] The system of this example had a viscosity of 3.5 Pa·s at 25 °C, an absolute value of zeta potential of 18 mV, and a yield stress of 25 Pa. In this example, the content of tranexamic acid was 4.0 wt%, the content of reduced glutathione was 0.4 wt%, the content of squalane was 8.0 wt%, the total content of hydrogenated lecithin and sorbitan sesquioleate was 0.7 wt%, phenoxyethanol 0.5 wt% and ethylhexylglycerin 0.15 wt% were used as the preservative system, and the mass ratio of reduced glutathione, disodium ethylenediaminetetraacetate and phytic acid was 1.0:0.075:0.20.

[0076] The preparation method of this example included the following steps: first, the W1 / O inner core was prepared. Second, the W2 external phase lamellar gel network was prepared, and tranexamic acid 4.0 wt% was dissolved in the W2 external phase of this example, nitrogen was bubbled for 11 min for degassing, and the pH was adjusted to 5.6. Third, the W1 / O inner core of this example was dispersed in the external phase obtained in step two to obtain a W1 / O / W system. Fourth, the oxygen content in the headspace was controlled to be 0.7%, and a material with an oxygen permeability of not more than 1 The barrier package is completed with filling. The volume fraction ratio of W1 to oil phase in this example is 28:72, the high pressure microfluidization granulation pressure in this example is 720 bar for colostrum granulation, the SPG membrane emulsification method is used for granulation in this example, W2 outer phase is cooled to 49°C and combined with W1 / O to stabilize the lamellar gel network structure in this example, and the nitrogen degassing time in this example is 11 min.

[0077] The compound cream in this example is applied in the field of cosmetics to improve uneven skin tone, fade color spots, brighten skin tone, and soothe and repair. The compound cream in this example is applied once a day on clean and dry skin, and continuous use for 6 weeks obtains significant improvement in skin tone uniformity.

[0078] Example 3 features: This example is biased towards high whitening effect optimization, the tranexamic acid content is increased to 4.0%, which is the upper limit of the preferred range of claim 6, providing strong tyrosinase inhibition and melanin production blocking effect. Sorbitol is selected as an osmotic pressure regulator, providing different moisturizing properties from glycerol. Lower squalane content (8.0%) and total emulsifier dosage (0.7%) make the formula more refreshing, reduce the viscosity (3.5 Pa·s), and are suitable for oily and mixed skin. SPG membrane emulsification technology is used instead of secondary high pressure microfluidization to granulate in a mild way, obtaining larger particle size (D50=0.60 μm), which is beneficial to the skin feel and spreadability of external application. Lower lamellar gel network concentration (glycerol stearate 1.5% + cetostearyl alcohol 1.2%) gives a light texture. This example is particularly suitable for intensive care of color spot fading, whitening needs of oily and mixed skin, summer refreshing whitening products, and professional care scenarios requiring fast absorption and high concentration of whitening activity.

[0079] Example 4

[0080] This example provides a compound cream containing tranexamic acid-glutathione, including a W1 / O / W double emulsion phase structure, and all percentage contents are based on the total mass of the final preparation.

[0081] W1 of this example is an inner aqueous core containing 0.95 wt% reduced glutathione. W1 is adjusted to pH 4.15 with a citric acid-sodium citrate buffer system and contains 0.095 wt% disodium ethylenediaminetetraacetate and 0.28 wt% phytic acid. To mitigate osmotic pressure differences, W1 contains 2.2 wt% glycerol. O of this example is an oil phase containing 11.8 wt% squalane and is stabilized with 0.9 wt% hydrogenated lecithin and 0.85 wt% sorbitan sesquioleate. W2 of this example is an outer aqueous phase containing 3.9 wt% tranexamic acid and contains 0.45 wt% polyglyceryl-6 stearate and 0.45 wt% ceteareth-20 as hydrophilic emulsifiers for a total of 0.9 wt%, and W2 is adjusted to pH 5.75 and coexists with a lamellar gel network built from glyceryl stearate 2.85 wt% and cetearyl alcohol 2.35 wt%. The system of this example has a particle size D50 of 0.76 μm, a PDI of 0.16, a viscosity of 7.5 Pa-s at 25 °C, a headspace oxygen content of 0.85%, and a glutathione encapsulation efficiency of 92%.

[0082] The W1 / O inner core of this example is prepared by dissolving reduced glutathione 0.95 wt% in deionized water, adjusting to pH 4.15 with citric acid-sodium citrate, adding disodium ethylenediaminetetraacetate 0.095 wt% and phytic acid 0.28 wt%, and adding glycerol 2.2 wt% to match the osmotic pressure of the outer phase, and degassing with nitrogen for 14 min. Squalane 11.8 wt% is dissolved with hydrogenated lecithin 0.9 wt% and sorbitan sesquioleate 0.85 wt% at 77 °C. W1 is added dropwise to the oil phase pre-emulsion at 5800 rpm for 40 s, followed by 3 high-pressure microfluidization passes at 870 bar to obtain the W1 / O inner core.

[0083] The W2 outer phase lamellar gel network of this example is built by mixing glyceryl stearate 2.85 wt%, cetearyl alcohol 2.35 wt%, glycerol 4.5 wt%, and water, and melting uniformly at 77 °C. The temperature is lowered to 46 °C and the lamellar liquid crystal phase is allowed to form, stabilizing the long-period ordered structure in the outer phase.

[0084] The W1 / O / W multiple phase of this example is prepared by shearing W1 / O into the lamellar gel network of W2 outer phase at 46 °C under nitrogen protection at 3400 rpm for 70 s, with the outer phase pre-dissolved with tranexamic acid 3.9 wt% and adjusted to pH 5.75, and pre-degassed with nitrogen for 14 min. One low-pressure microfluidization pass at 140 bar is performed to obtain the W1 / O / W system with a D50 of 0.76 μm and a PDI of 0.16.

[0085] The system of this example has a viscosity of 7.5 Pa-s at 25°C, an absolute value of zeta potential of 25 mV, and a yield stress of 40 Pa. The content of tranexamic acid in this example is 3.8 wt%, the content of reduced glutathione is 0.95 wt%, the content of squalane is 11.5 wt%, the total content of hydrogenated lecithin and sorbitan sesquioleate is 1.75 wt%, the content of phenoxyethanol is 0.9 wt% and the content of ethylhexylglycerin is 0.42 wt% as a preservative system, and the mass ratio of reduced glutathione, disodium ethylenediaminetetraacetate, and phytic acid is 1.0:0.10:0.295.

[0086] The preparation method of this example includes: first, preparing the W1 / O inner core. Second, preparing the layered gel network of the W2 outer phase, and dissolving 3.9 wt% of tranexamic acid in the W2 outer phase of this example, degassing for 14 min under nitrogen, and adjusting the pH to 5.75. Third, dispersing the W1 / O inner core of this example in the outer phase obtained in step two to obtain a W1 / O / W system. Fourth, controlling the oxygen content in the headspace to be 0.85%, and selecting a barrier package with an oxygen transmission rate of not more than 1 × 10-13 g / m2·24h·atm at 23°C, 1 atm, and 50% RH to complete the filling. In this example, the volume fraction ratio of W1 to oil phase is 36:64, the high-pressure microfluidization granulation pressure of this example is 870 bar for the first granulation and 140 bar for the second granulation, the W2 outer phase of this example is combined with the W1 / O after being cooled to 46°C to stabilize the layered gel network structure, and the nitrogen degassing time in this example is 14 min.

[0087] The compound cream of this example is applied in the field of cosmetics to improve uneven skin tone, fade skin spots, brighten skin tone, and soothe and repair. The compound cream of this example is applied to clean and dry skin twice a day, and continuous use for 4 weeks achieves significant improvement in skin tone uniformity.

[0088] Example 4 Features: W1 pH 4.15 close to the upper limit 4.2, verifying the stability boundary of glutathione at higher pH. Disodium ethylenediaminetetraacetate 0.095% and phytic acid 0.28% are close to their upper limits, respectively, forming a mass ratio of 1.0:0.10:0.295 with glutathione 0.95%, perfectly falling in the range boundary of the ratio specified in claim 6. Glycerin content 2.2% close to the lower limit 2.0%, verifying the minimum osmotic pressure adjustment requirement. Squalane 11.8%, tranexamic acid 3.9%, total emulsifier 1.75% are all close to the upper limit of their respective preferred ranges. W2 pH 5.75, glyceryl stearate 2.85%, cetylstearyl alcohol 2.35% are all close to the upper limits, forming a stronger lamellar gel network, achieving a higher viscosity of 7.5 Pa-s. Particle size D50 0.76 pm close to the upper limit 0.80 pm, PDI 0.16 close to the lower limit 0.15, proving the achievability of large particle size and low dispersity. High pressure microfluidization pressure 870 bar verifies the boundary process capability of high pressure whole-grain. The combination design of multiple parameters close to the boundary proves the full implementability of the claim range and the wide process window, while the high encapsulation rate of 92% verifies that excellent stability performance can still be maintained under boundary parameters. This example is particularly suitable for professional line products that require high active ingredient concentration, intensive repair after medical cosmetology, concentrated care for severe pigmentation, and high-end skin care application scenarios with extremely high requirements for product stability and encapsulation efficiency.

[0089] Comparative Example 1: Essentially the same as Example 1, except that the reduced glutathione content is 0.15 wt%, and the amounts and preparation conditions of other components remain unchanged.

[0090] Comparative Example 2: Essentially the same as Example 1, except that the reduced glutathione content is 2.3 wt%, and the amounts and preparation conditions of other components remain unchanged.

[0091] Comparative Example 3: Essentially the same as Example 1, except that the pH of the water core in W1 is adjusted to 3.2, and the amounts and preparation conditions of other components remain unchanged.

[0092] Comparative Example 4: Essentially the same as Example 1, except that the pH of the water core in W1 is adjusted to 4.5, and the amounts and preparation conditions of other components remain unchanged.

[0093] Comparative Example 5: Essentially the same as Example 1, except that the squalane content is 3.5 wt%, and the amounts and preparation conditions of other components remain unchanged.

[0094] Comparative Example 6: Essentially the same as Example 1, except that the tranexamic acid content is 1.5 wt%, and the amounts and preparation conditions of other components remain unchanged.

[0095] Comparative Example 7: Essentially the same as Example 1, except that the tranexamic acid content is 5.8 wt%, and the amounts of other components and the preparation conditions are unchanged.

[0096] Comparative Example 8: Essentially the same as Example 1, except that the high-pressure microfluidization pressure is 500 bar, and the amounts of other components and the preparation conditions are unchanged.

[0097] Comparative Example 9: Essentially the same as Example 1, except that the pre-emulsification rotation speed is 3200 rpm, and the amounts of other components and the preparation conditions are unchanged.

[0098] Comparative Example 10: Essentially the same as Example 1, except that the pH of the W2 external aqueous phase is adjusted to 4.9, and the amounts of other components and the preparation conditions are unchanged.

[0099] Comparative Example 11: Essentially the same as Example 1, except that the glyceryl stearate content is 0.6 wt%, and the amounts of other components and the preparation conditions are unchanged.

[0100] Comparative Example 12: Essentially the same as Example 1, except that the volume fraction ratio of W1 to oil phase is 20:80, and the amounts of other components and the preparation conditions are unchanged.

[0101] Comparative Example 13: Essentially the same as Example 1, except that no nitrogen protection is provided during preparation and no degassing treatment is performed, and the amounts of other components and the preparation conditions are unchanged.

[0102] Performance Test:

[0103] Glutathione Encapsulation Rate Determination

[0104] Test Object: Reduced glutathione in W1 / O / W double emulsion cream. Test Purpose: To evaluate the encapsulation efficiency of glutathione in the W1 internal aqueous core, reflecting the protective ability of the double emulsion structure for active ingredients. Test Principle: The free and encapsulated glutathione are separated by ultrafiltration centrifugation, and the glutathione content in the supernatant and total amount is determined by HPLC to calculate the encapsulation rate. Experimental Method: Accurately weigh 0.5 g of sample, dilute to 10 mL with pH 7.4 phosphate buffer, ultrafiltration centrifugation (10 kDa molecular weight cutoff, 4000 rpm, 20 min), collect the filtrate as free glutathione; another 0.5 g of sample is measured for total glutathione after being broken with 1% Triton X-100 in the buffer. HPLC conditions: C18 column, mobile phase is methanol-0.1% phosphoric acid aqueous solution (5:95), flow rate 1.0 mL / min, detection wavelength 210 nm. Key parameters: ultrafiltration temperature 4°C, centrifugal force 4000 rpm, time 20 min. Data processing: encapsulation rate (%) = (total glutathione content - free glutathione content) / total glutathione content x 100%, n≥3, report average value ± standard deviation.

[0105] Particle size distribution and polydispersity index determination

[0106] Test object: W1 / O / W multiple emulsion system. Test purpose: Determine the average particle size D50 and polydispersity index PDI of the double emulsion droplets, evaluate the uniformity and stability of the system. Test principle: Based on the principle of dynamic light scattering, the fluctuation of scattered light intensity caused by Brownian motion of particles when the sample is irradiated by laser light, the particle size distribution is calculated by correlation function. Experimental method: Take an appropriate amount of sample, dilute with deionized water to an appropriate concentration (dilution ratio 100-200 times, so that the counting rate reaches 20-300 kcps), avoid multiple scattering. At 25±0.1℃ constant temperature, use Malvern Zetasizer Nano ZS laser particle size analyzer to determine, scattering angle 173°, determination time is automatically optimized, each sample is repeated 3 times Key parameters: determination temperature 25℃, dilution medium deionized water, equilibrium time 120 s. Data processing: record D50 and PDI values, n≥3, report the average value±standard deviation.

[0107] Apparent viscosity determination

[0108] Test object: Compound cream finished product. Test purpose: Determine the apparent viscosity of the cream at 25°C, evaluate the rheological properties and use skin feel of the product. Test principle: Using a rotational rheometer, the shear stress of the sample is determined at a constant shear rate, and the apparent viscosity is calculated. Experimental method: Place the sample on a 25±0.1℃ constant temperature platform for 30 min. Use a rotational rheometer (such as Anton Paar MCR 302), configure a parallel plate clamp (diameter 40 mm, gap 1.0 mm), set the shear rate Perform steady-state test. Record the value after the viscosity is stable (fluctuation <5% for 30 s). Each sample is tested at least 3 times in parallel. Key parameters: test temperature 25±0.1℃, shear rate , equilibrium time 30 min, gap 1.0 mm. Data processing: record the apparent viscosity (Pa·s), n≥3, report the average value±standard deviation.

[0109] pH determination

[0110] Test object: W1 inner aqueous phase and W2 outer aqueous phase. Test purpose: to accurately determine the pH value of the inner and outer aqueous phase, verify the effectiveness of the buffer system and the mildness of the product. Test principle: using pH glass electrode method, the pH value is determined by measuring the potential difference generated by the activity of hydrogen ions in the solution. Experimental method: W1 inner aqueous phase is directly measured during the preparation process; W2 outer aqueous phase is taken from 1.0 g of finished cream, 10 mL of deionized water is added, and after gentle stirring and dispersion, it is placed for 10 min, and the pH value of the upper aqueous phase is measured. Use calibrated pH meter (accuracy ± 0.01), electrode is immersed in sample, record after reading is stable. Before testing, two-point calibration is performed with pH 4.00 and pH 6.86 standard buffer. Each sample is measured 3 times. Key parameters: test temperature 25±2℃, electrode immersion depth about 2 cm, stability criterion for change <0.02 pH units within 30 s. Data processing: n≥3, report average value ± standard deviation.

[0111] Headspace oxygen content determination

[0112] Test object: compound cream in sealed packaging after filling. Test purpose: to determine the residual oxygen content in the headspace of the package, to evaluate the nitrogen protection effect and antioxidant capacity. Test principle: using headspace gas chromatography or portable oxygen analyzer, the oxygen volume fraction in the headspace gas is determined by electrochemical sensor or thermal conductivity detector. Experimental method: take the sample after filling and sealing, use sterile needle to puncture the bottle cap in sterile operation table to collect 0.5 mL of headspace gas, inject into oxygen analyzer (such as Systech Illinois 7001 or Agilent GC with TCD detector). GC conditions: TDX-01 packed column, column temperature 80℃, carrier gas nitrogen, flow rate 30 mL / min, sample size 0.5 mL. Or use portable oxygen analyzer to directly puncture and determine. Each batch of test not less than 3 packaging samples. Key parameters: sampling volume 0.5 mL, test temperature 23±2℃, instrument accuracy ≤0.01%. Data processing: record oxygen volume percentage, n≥3, report average value ± standard deviation.

[0113] In vitro tyrosinase inhibitory activity determination

[0114] Test object: active ingredient extract of compound cream. Test purpose: to evaluate the whitening effect of tranexamic acid and glutathione in synergistically inhibiting tyrosinase activity. Test principle: tyrosinase catalyzes the generation of dopaquinone from L-tyrosine, which produces a characteristic absorption at 475 nm. In the presence of inhibitors, the absorbance decreases, and the inhibition rate is calculated by comparison. Experimental method: 1.0 g of sample was accurately weighed, and the active ingredient was extracted with 50% ethanol. The supernatant was diluted to an appropriate concentration after centrifugation. Reaction system: 2.5 mL of phosphate buffer (pH 6.8), 0.4 mL of L-tyrosine solution (2 mM), 0.1 mL of sample solution, preheated at 37°C for 10 min, then add 0.1 mL of mushroom tyrosinase solution (100 U / mL), react at 37°C for 30 min, measure the absorbance at 475 nm. Set blank control and positive control (kojic acid). Key parameters: reaction temperature 37±0.5℃, pH 6.8±0.1, reaction time 30 min. Data processing: inhibition rate (%)=(Ablank-Asample) / Ablank×100%, n≥3, report mean±standard deviation.

[0115] Figure 1 The effect of reduced glutathione content on encapsulation efficiency and tyrosinase inhibition rate, with fixed parameters of tranexamic acid 3.0 wt%, squalane 10.0 wt%, W1 pH 3.8, W2 pH 5.5, hydrogenated lecithin 0.5 wt%, sorbitan sesquioleate 0.5 wt%, glyceryl stearate 2.0 wt%, cetostearyl alcohol 1.5 wt%, high-pressure microfluidic pressure 750 bar for primary particle size adjustment and 100 bar for secondary particle size adjustment, pre-emulsification speed 5000 rpm, and variable parameters of reduced glutathione content from 0.15 wt% to 2.60 wt%. When the glutathione content is 0.6 to 1.2 wt%, the encapsulation efficiency and tyrosinase inhibition rate reach the peak interval simultaneously, with the peak encapsulation efficiency of 85.0% at 0.6 wt% and the inhibition rate of 76.5%. When the content is less than 0.2 wt%, the activity of the inner water core is insufficient, resulting in an inhibition rate of 64.5% and an encapsulation efficiency of only 68.0%. When the content is higher than 2.0 wt%, excessive glutathione increases the osmotic pressure and oxidation risk of the inner water core, reducing the encapsulation efficiency to less than 70.0%, proving that the appropriate glutathione content can simultaneously ensure the stability of the double emulsion phase and the synergistic whitening effect.

[0116] Figure 2Effect of tranexamic acid content on tyrosinase inhibition rate and viscosity, with fixed parameters of reduced glutathione 0.6 wt%, squalane 10.0 wt%, W1 pH 3.8, W2 pH 5.5, hydrogenated lecithin 0.5 wt%, sorbitan sesquioleate 0.5 wt%, glyceryl stearate 2.0 wt%, cetyl stearyl alcohol 1.5 wt%, high-pressure microfluidization pressure 750 bar for primary particle size regulation and 100 bar for secondary particle size regulation, pre-emulsification rotation speed 5000 rpm, and variable parameter of tranexamic acid content from 1.50 wt% to 5.80 wt%. When the tranexamic acid content is 3.0 to 5.0 wt%, the tyrosinase inhibition rate is maintained above 76.5% and shows a stable growth trend up to 80.5%, when the content is lower than 2.0 wt%, the whitening activity is obviously insufficient, resulting in an inhibition rate of only 62.5%, and when the content is higher than 5.0 wt%, although the inhibition rate increases slightly to 82.0%, the viscosity increases significantly from 4.5 Pa·s to 5.5 Pa·s, which may affect the application experience. It is verified that a moderate tranexamic acid content can balance the whitening effect, formulation stability, and application experience.

[0117] Figure 3 Effect of high-pressure microfluidization particle size regulation pressure on particle size D50 and polydispersity index, with fixed parameters of reduced glutathione 0.6 wt%, tranexamic acid 3.0 wt%, squalane 10.0 wt%, W1 pH 3.8, W2 pH 5.5, hydrogenated lecithin 0.5 wt%, sorbitan sesquioleate 0.5 wt%, glyceryl stearate 2.0 wt%, cetyl stearyl alcohol 1.5 wt%, low-pressure microfluidization pressure 100 bar for secondary particle size regulation, pre-emulsification rotation speed 5000 rpm, and variable parameter of high-pressure microfluidization particle size regulation pressure from 500 bar to 950 bar. When the particle size regulation pressure is 700 to 900 bar, the particle size D50 is stable at 0.40 to 0.58 μm and the polydispersity index is controlled at a low level of 0.16 to 0.21, exhibiting uniform dispersion characteristics, when the pressure is lower than 600 bar, the particle size regulation effect is insufficient, resulting in a significant increase in D50 to more than 0.78 μm and an increase in the polydispersity index to more than 0.25, leading to uneven particle size distribution, and when the pressure is higher than 900 bar, although the particle size can be further reduced to 0.38 μm, the energy consumption increases and the equipment requirements are higher, indicating that a moderate pressure can ensure sub-micron particle size and low polydispersity while balancing process economy.

[0118] Figure 4Effect of W1 inner aqueous core pH on GSH encapsulation efficiency and stability, with fixed parameters of reduced glutathione 0.6 wt%, tranexamic acid 3.0 wt%, squalane 10.0 wt%, W2 pH 5.5, disodium EDTA 0.05 wt%, phytic acid 0.15 wt%, hydrogenated lecithin 0.5 wt%, sorbitan sesquioleate 0.5 wt%, glyceryl stearate 2.0 wt%, cetyl stearyl alcohol 1.5 wt%, high pressure microfluidization pressure 750 bar for primary particle size homogenization and 100 bar for secondary particle size homogenization, pre-emulsification rotation speed 5000 rpm, and variable parameter of W1 inner aqueous core pH from 3.20 to 4.50. GSH encapsulation efficiency and stability reached optimal levels simultaneously when W1 pH was 3.6 to 4.0, with encapsulation efficiency exceeding 80.5% and residual rate remaining above 85.5% after 30 days of light-free storage at 25°C. When pH was below 3.5, the excessive acidity could affect the stability of some components and the emulsion system, causing the encapsulation efficiency to decrease to 72.0%. When pH was above 4.2, the increased risk of GSH oxidation at the relatively high pH led to significant decreases in both encapsulation efficiency and stability to 78.5% and 84.0%, respectively, proving that precise pH control is the key to balancing the antioxidant stability of GSH and the compatibility of the formula system.

[0119] Figure 5 GSH residual rate-time curve (multiple pH / chelator concentration comparisons). Fixed parameters: W1 / O / W double emulsion phase structure, initial GSH concentration in inner aqueous core 0.6 wt%, W1 using citric acid-sodium citrate buffer, storage condition 25°C light-free, sampling time 0-90 days, HPLC quantitative detection. Variable parameters: four groups of conditions: A: pH 3.8 | EDTA 0.05% + phytic acid 0.15% ; B: pH 3.8 | EDTA 0.05% only ; C: pH 4.2 | EDTA 0.05% + phytic acid 0.15% ; D: pH 3.8 | EDTA 0.05% + phytic acid 0.15% | air. The results showed that the GSH residual rate of group A reached 85-90% at 90 days, which was significantly higher than that of group B (about 84%) and group D (about 79%), and group C was slightly lower than group A but still remained about 86%. This indicates that low-pH buffering combined with EDTA+phytic acid double chelation forms a synergistic stabilization effect under nitrogen protection, which can effectively slow down the consumption of GSH; while the air headspace can significantly accelerate oxidation, leading to a decrease in residual rate.

[0120] Figure 6For the effect of the lamellar liquid crystal d-spacing on the multi-order diffraction peaks in SAXS scattering curves, the fixed parameters are the outer phase system of a lamellar gel network constructed by glycerol stearate 2.0 wt% and cetylstearyl alcohol 1.5 wt%, the temperature of 25 °C, the correlation length ξ of 120 nm, the invariant background Porod term and constant term, the W1 / O / W particle size D50 of 0.50 μm, the PDI of 0.20, and the headspace oxygen content of 0.5%, and the variable parameter is the interlayer spacing d from 4.0 nm to 6.0 nm (equivalent q1=2π / d in the range of 1.05 to When d is 5.0 to 5.5 nm, the 1-3 order clear diffraction peaks appear, the peak position satisfies qn=n·q1, and the half-height width is constrained by ξ, which indicates that the W2 outer phase forms a long-period ordered lamellar network; with the increase of d, the peak position moves left as a whole while the order parameter remains stable, which proves that the lamellar phase provides the basis for structural order and leakage barrier for the W1 / O core.

[0121] Figure 7 For the morphology of the tranexamic acid-glutathione compound cream in Example 1, it can be seen from the scanning electron microscope that the emulsion presents a uniform dispersed spherical structure, the particle size distribution is concentrated in the range of 0.4 to 0.6 μm, which is highly consistent with the D50 value of 0.5 μm measured by the laser particle size analyzer, and the smooth surface of the particles without obvious aggregation and rupture phenomenon indicates that the high-pressure microfluidization particle size process effectively forms a stable double emulsion phase system, and the light and dark layered core-shell structure can be observed inside, which confirms that the active ingredients glutathione and tranexamic acid are successfully encapsulated in the inner water core and are coated by the oil phase and the outer water phase in turn. The morphology characteristics show that the particle size uniformity is good and there is no large particle or flocculation, which verifies that the compound cream prepared under the optimized process parameters has ideal microstructure and dispersion stability, providing micro-morphology evidence support for the subsequent whitening efficacy and storage stability.

[0122] From the performance of the examples and comparative examples in Table 1, it can be seen that the four examples are significantly superior to most of the comparative examples in key indicators such as glutathione encapsulation rate, particle size uniformity, headspace oxygen content control, and tyrosinase inhibition activity. Comparative Example 1 has a significant decrease in encapsulation rate and whitening effect due to the excessively low glutathione content. Comparative Example 2 has increased system instability and increased oxidation risk due to the excessively high glutathione content. Comparative Examples 3 and 4 show that a W1 pH deviating from the optimal range will reduce the stability and encapsulation efficiency of glutathione. Comparative Example 5 has an unstable oil phase structure due to insufficient squalane, affecting the skin feel. Comparative Examples 6 and 7 show that the tranexamic acid content needs to be accurately controlled, as too low a content will weaken the whitening effect, and too high a content may increase the risk of irritation. Comparative Examples 8 and 9 confirm that high-pressure microfluidization and pre-emulsification process parameters are crucial for controlling particle size distribution and PDI. Comparative Example 10 shows that a low W2 pH affects the stability of the lamellar gel network. Comparative Example 11 has a low viscosity due to insufficient gel network concentration, affecting the user experience. Comparative Example 12 has a reduced encapsulation efficiency due to an imbalance in the ratio of the inner and outer phases. Comparative Example 13 has a significant increase in headspace oxygen content and glutathione oxidation without nitrogen protection, resulting in a significant decrease in encapsulation rate and efficacy. Example 4 maintains a highest encapsulation rate of 92% and an excellent inhibition rate of 80.5% under a combination close to the upper limit of multiple parameters, fully verifying the synergistic effect and wide process window of the technical solution of the present application.

[0123] Performance summary of examples and comparative examples in Table 1

[0124]

[0125] Finally, it should be noted that the above examples are used to illustrate the technical solutions of the present application and not to limit it. Although the present application has been described in detail with reference to the above examples, those of ordinary skill in the art should understand that any equivalent structural transformation made within the concept of the present application, using the contents of the present application specification and drawings, should be covered within the scope of protection of the claims of the present application.

Claims

1. A compound cream containing tranexamic acid and glutathione, characterized in that, Includes a W1 / O / W2 dual emulsion structure, wherein all percentages are based on the total mass of the final formulation: a) W1 is an inner water core containing 0.4–2.0 wt% reduced glutathione. A citrate-sodium citrate buffer system adjusts the pH of W1 to 3.5–4.

2. It also contains 0.02–0.10 wt% disodium ethylenediaminetetraacetate and 0.05–0.30 wt% phytic acid, and 2.0–5.0 wt% glycerol or 3.0–8.0 wt% sorbitol to alleviate the osmotic pressure difference. b) O is an oil phase containing 5–15 wt% squalane, and is stabilized by 0.2–1.0 wt% hydrogenated lecithin and 0.2–1.0 wt% sorbitan sesquioleate to form W1 / O; c) W2 is the external aqueous phase, containing 2.0–5.0 wt% tranexamic acid and one or more hydrophilic emulsifiers selected from polyglycerol-6 stearate, polyethylene glycol-100 stearate or cetearyl alcohol polyether-20, totaling 0.2–1.0 wt%. W2 is adjusted to pH 5.2–5.8 and coexists with the layered gel network. d) The system has a particle size D50 of 0.30–0.80 μm, a PDI of 0.15–0.25, a viscosity at 25°C of 2.0–8.0 Pa·s, a headspace oxygen content of no more than 1.0%, and a glutathione encapsulation efficiency of no less than 70%. The W1 / O kernel is prepared through the following steps: A1. W1 preparation: Dissolve reduced glutathione in deionized water, add citric acid-sodium citrate to adjust the pH to 3.5–4.2, add 0.02–0.10 wt% disodium ethylenediaminetetraacetate and 0.05–0.30 wt% phytic acid, then add 2.0–5.0 wt% glycerol or 3.0–8.0 wt% sorbitol to match the external phase osmotic pressure, and degas with nitrogen for 10–15 min; A2. Oil phase preparation: Dissolve hydrogenated lecithin and sorbitan sesquioleate in squalane at 70–80°C; A3. Colostrum formation: W1 was added dropwise to the oil phase for pre-emulsification at 4000–6000 rpm and 30–90 s, followed by 2–3 high-pressure micro-jet granulation at 600–900 bar to obtain W1 / O; The layered gel network of the W2 outer phase is constructed according to the following steps: B1. Mix 1.0–3.0 wt% glyceryl stearate, 1.0–2.5 wt% cetearyl alcohol, and 2.0–5.0 wt% glycerol with water and melt them uniformly at 70–80°C; B2. Cool to 45–50°C and allow to stand to form a layered liquid crystal phase, so that the long-period ordered structure can exist stably in the outer phase.

2. The compound cream according to claim 1, characterized in that, The tranexamic acid content is 2.5–4.0 wt%, the reduced glutathione content is 0.4–1.0 wt%, the squalane content is 8–12 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 0.5–1.8 wt%, and the mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.04–0.10:0.10–0.

30.

3. The compound cream according to claim 1, characterized in that, The W1 / O / W2 multiphase is prepared by the following steps: C1. Under nitrogen protection at 45–50°C, W1 / O was sheared and dispersed in the layered gel network of the W2 external phase at 2500–3500 rpm for 60–120 s. The external phase was pre-dissolved with tranexamic acid and adjusted to pH 5.2–5.8, and pre-degassed with nitrogen for 10–15 min. C2. Perform low-pressure microjets once at 80–150 bar, or use SPG membrane emulsification with a transmembrane pressure difference of 40–120 kPa to obtain a W1 / O / W2 system with a D50 of 0.30–0.80 μm and a PDI of 0.15–0.

25.

4. The compound cream according to claim 1, characterized in that, The system preferably has a viscosity of 3.0–6.0 Pa·s at 25°C, an absolute value of zeta potential of not less than 15 mV, or a yield stress of not less than 20 Pa.

5. The method for preparing a compound cream containing tranexamic acid and glutathione according to any one of claims 1-4, characterized in that, include: S1. Inner phase preparation: Preparation of W1 / O core; S2. Preparation of the outer phase: Prepare a layered gel network of the W2 outer phase, and dissolve 2.0–5.0 wt% tranexamic acid in the W2 outer phase, purge with nitrogen or degas under vacuum for 10–15 min, and adjust the pH to 5.2–5.8; S3. Secondary emulsification and granulation: The W1 / O dispersion core is placed in the external phase obtained in step S2 to obtain the W1 / O / W2 system; S4. Nitrogen Filling and Filling: Control the oxygen content in the head space to be no higher than 1.0%, and select a system with an oxygen permeability of no higher than 1% under conditions of 23°C, 1 atm, and 50% RH. · The barrier packaging completes the filling process.

6. The preparation method of a compound cream containing tranexamic acid and glutathione according to claim 5, characterized in that, In S1, the volume fraction ratio of W1 to oil phase is 25–40:75–60. The high-pressure microjet granulation pressure is 700–900 bar for primary emulsion granulation and 80–150 bar for secondary granulation. In S2, the W2 external phase is cooled to 45–50°C and then combined with W1 / O to stabilize the layered gel network structure. The nitrogen degassing time in S1 is 10–15 min.

7. The application of the compound cream according to any one of claims 1-4 or the compound cream obtained by the preparation method according to claim 5 or 6 in the field of cosmetics, characterized in that, It is used to improve uneven skin tone, lighten dark spots, and brighten skin tone.

Images