Compound cream containing tranexamic acid-glutathione and preparation method thereof

Abstract

The invention provides tranexamic acid-glutathione-containing compound emulsifiable paste and a preparation method thereof.W1 / O / W double emulsion phase structural design is adopted, reduced glutathione is encapsulated in an acidic inner water core, an oil phase is stabilized through hydrogenated lecithin and sorbitan sesquioleate, an outer water phase contains tranexamic acid, a layered gel network is constructed, and the tranexamic acid-glutathione-containing compound emulsifiable paste is prepared. A submicron dispersion system with the particle size D50 of 0.30-0.80 microns, the polydispersity index of 0.15-0.25 and the viscosity of 2.0-8.0 Pa seconds is realized, the encapsulation efficiency of glutathione is not lower than 70%, the oxygen content of a head space is not higher than 1.0%, and the encapsulation efficiency of glutathione is not lower than 70%. The three technical contradictions of coupling conflict between a high-yield viscoelastic structure and low-shear damage kernel integrity, coexistence of fresh and cool low-viscosity skin feeling and high-barrier anti-oxidation and anti-leakage and opposite low-surface-activity sensitive skin compatibility and submicron low-PDI dispersion stability are solved; the traditional Chinese medicine composition has wide application values of improving skin color unevenness, fading color spots, brightening skin color, soothing and repairing.

Description

Technical Field

[0001] This invention relates to the field of cosmetic formulation technology, specifically to a compound cream containing tranexamic acid and glutathione and its preparation method. Background Technology

[0002] In the field of modern skin care, pigmentation, uneven skin tone, and oxidative stress damage are major beauty concerns for consumers. These problems not only affect appearance but may also reflect underlying conditions such as impaired skin barrier function and active inflammatory responses. Tranexamic acid, a classic antifibrinolytic drug, has had its mechanism of action—inhibiting melanocyte tyrosinase activity and blocking UV-induced pigment synthesis pathways—widely confirmed, demonstrating significant advantages in skin whitening and anti-inflammation. Reduced glutathione, as one of the most important intracellular antioxidants, effectively combats oxidative stress through multiple mechanisms, including scavenging free radicals, chelating heavy metal ions, and regenerating vitamins C and E. Simultaneously, it competitively inhibits tyrosinase to reduce melanin production, forming a synergistic whitening and antioxidant system with tranexamic acid. However, effectively integrating these two active ingredients into a single formulation requires addressing the issue of glutathione's easy oxidation and degradation in an oxygen-rich environment and at neutral pH, while also meeting the high-dose release requirements of tranexamic acid. Simultaneously, it must consider the skin comfort, long-term stability, and suitability for sensitive skin. This places extremely stringent multi-dimensional performance requirements on formulation design and preparation processes, making it an important topic in the current field of cosmetic research and development.

[0003] The current state of development of compound cosmetics based on the aforementioned materials has significant shortcomings. Firstly, traditional single-phase emulsion or gel systems cannot achieve differentiated pH environments for the two components. Glutathione's stability decreases sharply under neutral or alkaline conditions, and tranexamic acid has limited solubility in acidic environments and may irritate the skin, making it difficult for both to coexist and maintain activity in the same phase for extended periods. For example, Chinese patent CN103860453B discloses a revitalizing and firming moisturizing cream and its preparation method, but it suffers from the drawback of rapid oxidative inactivation and poor stability due to glutathione exposure to the external phase. Secondly, conventional emulsion systems often require the addition of large amounts of polymeric thickeners or high-concentration emulsifiers to achieve high viscosity and yield stress to prevent phase separation and sedimentation. However, this significantly increases shear stress during preparation, damages the integrity of the internal phase structure, reduces encapsulation efficiency, and the high surfactant content poses a risk of irritation to sensitive skin, making it difficult to balance a refreshing feel with hypoallergenic properties. Third, while submicron-sized dispersed particles (0.3-0.8 micrometers in diameter) are beneficial for skin feel and penetration, maintaining a narrow particle size distribution (PDI<0.25) and long-term physical stability under low emulsifier dosage conditions is extremely difficult. Existing technologies mostly rely on high-speed shearing or ultrasonic emulsification, which consumes a lot of energy and has poor particle size reproducibility. There is a lack of precise and controllable mild granulation methods and stabilization strategies. Summary of the Invention

[0004] The purpose of this invention is to provide a compound cream containing tranexamic acid and glutathione and its preparation method, which solves the current problems of coupling conflict between high yield viscoelastic structure and low shear damage core integrity, coexistence of refreshing and low stickiness skin feel and high barrier antioxidant and anti-leakage, and the contradiction between low surfactant and sensitive skin compatibility and submicron low PDI dispersion stability.

[0005] This invention employs a W1 / O / W dual emulsion phase synergistic design concept. By isolating and encapsulating reduced glutathione in an acidic, hypoxic inner water core and configuring an antioxidant synergist, it achieves spatial separation and differential pH microenvironment regulation with tranexamic acid in the outer water phase. The oil phase interface film constructed by hydrogenated lecithin and sorbitan sesquioleate protects the core from shear damage and oxygen permeation. At the same time, the layered gel network formed by glyceryl stearate and cetearyl alcohol in the outer phase provides viscoelastic support with low shear and high yield. With only a very low amount of hydrophilic emulsifier required, it achieves precise particle size reduction to a submicron narrow distribution through high-pressure microfluidic jet or SPG membrane emulsification. This results in a triple breakthrough of stable coexistence of dual active ingredients, high encapsulation and low leakage, and refreshing, low-allergenic and highly stable performance. The synergistic effect of a single system far exceeds that of simple mixing of individual components.

[0006] To achieve the above objectives, the present invention provides the following technical solution: A compound cream containing tranexamic acid and glutathione, comprising a W1 / O / W dual emulsion phase structure, wherein all percentage contents are based on the total mass of the final formulation: a) W1 is an inner water core containing 0.2–2.0 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 EDTA and 0.05–0.30 wt% phytic acid, and to alleviate the osmotic pressure difference, it contains 2.0–5.0 wt% glycerol or 3.0–8.0 wt% sorbitol. 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, in total of 0.2–1.0 wt%. W2 is adjusted to pH 5.2–5.8 and coexists with a layered gel network constructed from 1.0–3.0 wt% glycerol stearate and 1.0–2.5 wt% cetearyl alcohol. 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 head space oxygen content of no more than 1.0%, and a glutathione encapsulation efficiency of no less than 70%.

[0007] Furthermore, 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.

[0008] Furthermore, 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.

[0009] Furthermore, the W1 / O / W multiphase is prepared through 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. Optionally, a low-pressure microjets can be used for granulation once at 80–150 bar, or granulation can be performed using the SPG membrane emulsification method with 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.

[0010] Furthermore, the viscosity of the system at 25°C is preferably 3.0–6.0 Pa·s, the absolute value of the zeta potential is not less than 15 mV, or its yield stress is not less than 20 Pa.

[0011] Furthermore, the tranexamic acid content is 2.5–4.0 wt%, the reduced glutathione content is 0.3–1.0 wt%, the squalane content is 8–12 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 0.5–1.8 wt%, and phenoxyethanol 0.3–1.0 wt% and ethylhexylglycerin 0.05–0.50 wt% are used as the preservative system. The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.04–0.10:0.10–0.30.

[0012] As a concept of this invention, the W1 / O / W dual emulsion compartmentalization design is mainly used to enhance the stability and synergistic efficacy of the two active ingredients. This invention encapsulates reduced glutathione in an acidic inner water core at pH 3.5-4.2, utilizing the protonation effect to reduce the ionization degree and oxidative reactivity of its thiol groups. Simultaneously, a dual metal chelate network composed of disodium ethylenediaminetetraacetate and phytic acid is configured to effectively block the Fenton-type free radical oxidation pathway catalyzed by trace transition metal ions, significantly extending the chemical stability period of glutathione. In the oil phase, squalane, as a low-polarity hydrocarbon solvent, provides a hydrophobic barrier. Hydrogenated lecithin forms a dense phospholipid bilayer at the W1 / O interface, and its saturated alkyl chains eliminate oxidation-sensitive sites of unsaturated bonds. Combined with the anchoring effect of sorbitan sesquioleate at the oil-water interface, an interfacial membrane with bidirectional barrier capabilities against oxygen and water molecules is constructed, effectively isolating the core glutathione from the high-oxygen environment of the outer phase. The external aqueous phase is designed with a weakly acidic pH of 5.2-5.8, ensuring both the high solubility and antifibrinolytic activity of tranexamic acid under these conditions. Furthermore, the layered liquid crystal network formed by the self-assembly of glyceryl stearate and cetearyl alcohol within this temperature range provides viscoelastic support with low shear and high yield strength. This achieves long-term physical stability of the system with only 0.2-1.0 wt% hydrophilic emulsifier, avoiding the irritation of sensitive skin caused by high surfactant activity. Simultaneously, the long-term ordered arrangement of the layered structure further slows the diffusion rate of oxygen molecules to the core. The dual pH microenvironment separation design keeps glutathione and tranexamic acid in their optimal stable and active states. The multi-layered interface barrier of the W1 / O / W structure controls the oxygen content in the headspace below 1.0%, maintaining the glutathione encapsulation rate above 70%, ensuring the long-lasting stability of the compound system's efficacy during long-term storage and use.

[0013] This invention also discloses a method for preparing a compound cream containing tranexamic acid and glutathione, comprising: 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 / W 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.

[0014] Furthermore, in S1, the volume fraction ratio of W1 to the 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, and the nitrogen degassing time in S1 is 10–15 min.

[0015] This invention also discloses the application of tranexamic acid-glutathione compound cream in the cosmetics field, characterized in that it is used to improve uneven skin tone, lighten pigmentation, brighten skin tone, and soothe and repair.

[0016] Furthermore, the compound cream is applied to clean, dry skin 1–2 times daily, and after 4–8 weeks of continuous use, significant improvement in skin tone evenness is achieved.

[0017] As another aspect of this invention, the synergistic stabilization design of high-pressure microjets and layered gel networks is primarily used to enhance the particle size uniformity and long-term stability of the submicron dispersion system. In the W1 / O core preparation stage, a 600-900 bar high-pressure microjets process utilizes the shear force field, cavitation effect, and turbulent pulsation generated by the high-speed jet in the microchannel to instantly break up and homogenize the primary emulsion droplets to the submicron level. Simultaneously, hydrogenated lecithin and sorbitan sesquioleate are rapidly adsorbed onto the newly formed interface under high energy input, forming a dense and ordered mixed interface film. This significantly reduces interfacial tension and provides steric hindrance stability, ensuring a narrow W1 / O core particle size distribution and high reproducibility. In the W1 / O / W multiphase construction stage, gentle secondary granulation was performed using either low-pressure microfluidics (80-150 bar) or SPG membrane emulsification. The former reduces mechanical damage to the already formed core by lowering the operating pressure, while the latter utilizes the extrusion droplet mechanism of the uniform-pore-size SPG membrane to achieve precise particle size control. Both methods were operated within a temperature window of 45-50°C after the layered gel network had initially formed. The spatial confinement effect of the long-period layered liquid crystal structure formed by the self-assembly of glyceryl stearate and cetearyl alcohol on the dispersed phase droplets further suppressed the Ostwald ripening and aggregation tendency of the particles after granulation. The layered gel network not only provides high yield stress (≥20 Pa) to prevent sedimentation and stratification, but its nanoscale hydration layers between the layers also significantly delay the Brownian motion and collision frequency of the dispersed phase by increasing the viscosity of the continuous phase and constructing a three-dimensional network structure. At the same time, the electrostatic repulsion with an absolute value of ζ potential ≥15 mV further enhances the stability between particles. The synergistic effect of granulation and gel network enables the final formulation to achieve a narrow distribution with a particle size D50 of 0.30-0.80 μm and a PDI as low as 0.15-0.25. It maintains long-term physical stability under extremely low surfactant conditions containing only 0.2-1.0 wt% hydrophilic emulsifier, taking into account both a refreshing skin feel and safety for sensitive skin, demonstrating the synergistic advantages of gentle granulation and intelligent stabilization design.

[0018] Reduced glutathione and tranexamic acid exhibit a significant synergistic whitening and antioxidant effect in the compound system of this invention. Reduced glutathione focuses on acting from the perspective of intracellular redox balance and competition for melanin biosynthesis substrates. It blocks a key step in melanin synthesis by reducing the intermediate dopaquinone to dopa, while simultaneously scavenging UV-induced reactive oxygen species, 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 plasminogen-plasmin system and blocking the arachidonic acid metabolic pathway, reducing the release of inflammatory mediators prostaglandin E2 and leukotrienes, thereby inhibiting UV-induced melanocyte activation signaling, reducing the transcriptional expression and enzyme activity of tyrosinase, and reducing melanin production at its source. In terms of their mechanisms of action in enhancing skin whitening effects, reduced glutathione directly intervenes in the enzymatic process of melanin synthesis by competitively inhibiting the substrate binding site of tyrosinase and scavenging free radicals, intermediates of the enzymatic reaction. Tranexamic acid, on the other hand, reduces the expression and activation level of tyrosinase from an upstream regulatory level by inhibiting the inflammatory cascade and blocking melanocyte activation signals. Both act on different stages of the melanin production pathway, forming a dual inhibition of substrate competition and signal blocking. Regarding 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 continuous generation of oxidative stress by inhibiting the inflammatory response. Together, they construct an antioxidant defense line that combines scavenging and prevention. The underlying mechanism of the 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 its reduced state and exert its substrate competitive role. In turn, glutathione's highly efficient antioxidant capacity protects tranexamic acid from oxidative degradation and prolongs its inhibitory effect on inflammatory signals. In the W1 / O / W dual emulsion structure, the two achieve their optimal stability through spatial separation. After targeting skin tissue, they produce a whitening and antioxidant synergistic effect far exceeding that of a single ingredient through a synergistic molecular mechanism.

[0019] Beneficial technical effects 1. Significantly enhances the stability and synergistic efficacy of dual active ingredients: Through a W1 / O / W dual emulsion compartmentalization design, reduced glutathione is encapsulated in an acidic inner water core with a pH of 3.5-4.2 and configured with a dual antioxidant system of disodium EDTA and phytic acid. A dense oil phase interface membrane constructed with hydrogenated lecithin and sorbitan sesquioleate blocks oxygen molecule penetration, achieving long-term stable protection with an encapsulation rate of no less than 70% for glutathione and an oxygen content in the head space of no more than 1.0%. At the same time, the pH 5.2-5.8 environment of the outer water phase ensures the high solubility and antifibrinolytic activity of tranexamic acid. Both ingredients maintain their optimal efficacy in the differentiated microenvironment. Through a dual mechanism of substrate competition and signal blocking, they synergistically inhibit melanin production and construct an antioxidant defense line that combines removal and prevention, achieving a synergistic effect of whitening and spot fading, as well as antioxidant and soothing effects.

[0020] 2. Successfully resolved the coupling conflict between high-yield viscoelastic structure and low-shear damage core integrity: A layered gel network constructed from glyceryl stearate and cetearyl alcohol in the outer aqueous phase was used. The self-assembled long-period layered liquid crystal structure provided high viscoelastic support with a yield stress of not less than 20 Pa, effectively preventing sedimentation, delamination, and leakage. At the same time, during the W1 / O core preparation stage, high-pressure microfluidic jetting at 600-900 bar was used for rapid granulation, and during the W1 / O / W phase construction stage, low-pressure microfluidic jetting at 80-150 bar or SPG membrane emulsification and gentle secondary granulation were used. Combined with the initial temperature window operation of the layered gel network at 45-50°C, the mechanical damage of shear stress to the core was significantly reduced, ensuring the integrity of glutathione encapsulation and achieving compatibility between long-term stability and core protection.

[0021] 3. Achieving a refreshing, low-stickiness feel while maintaining high barrier properties for anti-oxidation and anti-leakage: With only 0.2-1.0 wt% hydrophilic emulsifier and extremely low surfactant, the system maintains a viscosity of 2.0-8.0 Pa·s at 25°C through the spatial confinement of the layered gel network and the electrostatic repulsion synergistic stabilization mechanism with an absolute value of ζ potential ≥15 mV. This avoids the heavy, sticky feeling caused by polymer thickeners. At the same time, the dual barrier of the nano-level hydration layer between the layered liquid crystal sheets and the oil phase interface film reduces the diffusion rate of oxygen molecules to the core to an extremely low level, ensuring that the oxygen content in the head space is no higher than 1.0%. This balances a refreshing and comfortable feel, low irritation to sensitive skin, and long-term antioxidant stability.

[0022] 4. Overcoming the contradiction between low surfactant compatibility with sensitive skin and submicron low PDI dispersion stability: Through the synergistic effect of high-pressure microfluidic precision granulation technology and intelligent stabilization design of layered gel network, a narrow-distribution submicron dispersion system with a particle size D50 of 0.30-0.80 μm and a PDI as low as 0.15-0.25 is achieved under low-sensitivity formulation conditions with a total hydrophilic emulsifier content of only 0.2-1.0 wt%. The high energy input of high-pressure microfluidic ensures particle size uniformity and interfacial membrane densification. The three-dimensional network structure and high yield stress of the layered gel network inhibit Ostwald ripening and aggregation tendencies. The uniform pore size extrusion droplet mechanism of SPG membrane emulsification provides a gentle and controllable granulation method, enabling the system to maintain long-term physical stability within the framework of low surfactant sensitive skin-friendly formulation, while possessing both excellent skin feel and long-term dispersion stability.

[0023] 5. Expanding application scenarios and significantly improving skin tone evenness: The compound cream blocks UV-induced melanocyte activation signals through the dual antifibrinolytic and anti-inflammatory effects of tranexamic acid. Combined with the substrate-competitive tyrosinase inhibition and free radical scavenging ability of reduced glutathione, it provides synergistic improvement for pigmentation, uneven skin tone, and oxidative stress damage. Apply to clean, dry skin 1-2 times daily for 4-8 weeks to significantly lighten dark spots, brighten skin tone, and soothe inflammatory responses. It is suitable for diverse applications such as daily whitening care, sensitive skin repair, and anti-aging maintenance, and has broad market application value. Attached Figure Description

[0024] Figure 1 The effect of reduced glutathione content on encapsulation efficiency and tyrosinase inhibition rate is investigated in this invention.

[0025] Figure 2 This invention investigates the effect of tranexamic acid content on tyrosinase inhibition rate and viscosity.

[0026] Figure 3 This invention relates to the effect of high-pressure microjet granulation pressure on particle size D50 and polydispersity index.

[0027] Figure 4 This invention investigates the effect of pH value of the water core in W1 on the encapsulation efficiency and stability of glutathione.

[0028] Figure 5 Example 1: GSH residue rate-time curve (comparison of multiple groups of pH / chelating agent concentrations).

[0029] Figure 6 The effect of the d-spacing of the layered liquid crystal on the multi-level diffraction peaks in the SAXS scattering curve of Example 1.

[0030] Figure 7 This is a morphological image of the compound cream containing tranexamic acid and glutathione in Example 1. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings.

[0032] Example 1 This embodiment provides a compound cream containing tranexamic acid-glutathione, comprising a W1 / O / W dual emulsion structure, and all percentage contents are based on the total mass of the final formulation.

[0033] In this embodiment, W1 is the inner aqueous core, containing 0.6 wt% reduced glutathione. W1 is adjusted to pH 3.8 using a citrate-sodium citrate buffer system and contains 0.05 wt% disodium ethylenediaminetetraacetate and 0.15 wt% phytic acid. To alleviate osmotic pressure differences, W1 contains 3.5 wt% glycerol. In this embodiment, O is the oil phase, containing 10.0 wt% squalane, and is stabilized with 0.5 wt% hydrogenated lecithin and 0.5 wt% sorbitan sesquioleate to form the W1 / O core. In this embodiment, W2 is the outer aqueous phase, containing 3.0 wt% tranexamic acid and 0.6 wt% polyglycerol-6 stearate as a hydrophilic emulsifier. W2 is adjusted to pH 5.5 and coexists with a layered gel network constructed from 2.0 wt% glycerol stearate and 1.5 wt% cetearyl alcohol. The system in this embodiment has a particle size D50 of 0.50 μm, a PDI of 0.20, a viscosity of 4.5 Pa·s at 25°C, a headspace oxygen content of 0.5%, and a glutathione encapsulation efficiency of 85%.

[0034] The W1 / O core of this embodiment was prepared through the following steps: 0.6 wt% of reduced glutathione was dissolved in deionized water, and the pH was adjusted to 3.8 with the addition of citric acid-sodium citrate. 0.05 wt% of disodium ethylenediaminetetraacetate and 0.15 wt% of phytic acid were added, followed by 3.5 wt% of glycerol to match the external phase osmotic pressure. Nitrogen gas was then introduced for degassing for 12 min. 0.5 wt% of hydrogenated lecithin and 0.5 wt% of sorbitan sesquioleate were dissolved in 10.0 wt% of squalane at 75°C. W1 was added dropwise to the oil phase for pre-emulsification at 5000 rpm for 60 s, followed by two high-pressure microfluidic granulation processes at 750 bar to obtain the W1 / O core.

[0035] The W2 external phase layered gel network of this embodiment was constructed according to the following steps: 2.0 wt% glyceryl stearate, 1.5 wt% cetearyl alcohol, and 3.0 wt% glycerol were mixed with water and melted uniformly at 75°C. The mixture was then cooled to 48°C and allowed to stand to form a layered liquid crystal phase, allowing the long-period ordered structure to exist stably in the external phase.

[0036] The W1 / O / W multiphase in this embodiment was prepared through the following steps: W1 / O was sheared and dispersed in a layered gel network of the W2 outer phase at 3000 rpm for 90 s under nitrogen protection at 48°C. The outer phase was pre-dissolved with 3.0 wt% tranexamic acid and adjusted to pH 5.5, and pre-degassed with nitrogen for 12 min. Low-pressure microfluidic granulation was performed once at 100 bar to obtain a W1 / O / W system with a D50 of 0.50 μm and a PDI of 0.20.

[0037] The system in this embodiment 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. In this embodiment, the tranexamic acid content is 3.0 wt%, the reduced glutathione content is 0.6 wt%, the squalane content is 10.0 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 1.0 wt%, and phenoxyethanol (0.6 wt%) and ethylhexylglycerin (0.20 wt%) are used as the preservative system. The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.083:0.25.

[0038] The preparation method of this embodiment includes: First, preparing the W1 / O core. Second, preparing a layered gel network of the W2 outer phase, and dissolving 3.0 wt% tranexamic acid in the W2 outer phase of this embodiment, degassing with nitrogen for 12 min, and adjusting the pH to 5.5. Third, dispersing the W1 / O core of this embodiment in the outer phase obtained in step two to obtain the W1 / O / W system. Fourth, controlling the oxygen content in the headspace to 0.5%, and selecting an oxygen permeability of no more than 1% under conditions of 23°C, 1 atm, and 50% RH. The barrier packaging completes the filling. In this embodiment, the volume fraction ratio of W1 to the oil phase is 32:68. The high-pressure microjet granulation pressure in this embodiment is 750 bar for primary emulsion granulation and 100 bar for secondary granulation. In this embodiment, the W2 external phase is cooled to 48°C and then combined with W1 / O to stabilize the layered gel network structure. In this embodiment, the nitrogen degassing time is 12 min.

[0039] The compound cream of this embodiment is used in the cosmetics field to improve uneven skin tone, lighten dark spots, brighten skin tone, and soothe and repair. This compound cream is applied twice daily to clean, dry skin, and continuous use for 6 weeks results in a significant improvement in skin tone evenness.

[0040] Example 1 Features: This example uses moderate parameter configurations to ensure formulation stability and process reproducibility. The active ingredient content is moderate (glutathione 0.6%, tranexamic acid 3.0%), suitable as a base formulation. Glycerin is chosen as an osmotic pressure regulator, and is also used in the layered gel network, with a total glycerin content of 6.5%, providing good moisturizing effects. The dual emulsification system has a moderate particle size (D50 = 0.50 μm) and a low PDI (0.20), indicating uniform particle size distribution. The viscosity of 4.5 Pa·s is suitable for daily application, and the 85% glutathione encapsulation rate ensures effective protection of antioxidant activity. This example is particularly suitable for daily skincare, gentle whitening and repair of sensitive skin, and basic antioxidant care scenarios requiring long-term use.

[0041] Example 2 This embodiment provides a compound cream containing tranexamic acid-glutathione, comprising a W1 / O / W dual emulsion structure, and all percentage contents are based on the total mass of the final formulation.

[0042] In this embodiment, W1 is the inner aqueous core, containing 0.9 wt% reduced glutathione. W1 is adjusted to pH 3.6 using a citrate-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% glycerol. In this embodiment, O is the oil phase, containing 12.0 wt% squalane, and is stabilized with 0.7 wt% hydrogenated lecithin and 0.6 wt% sorbitan sesquioleate to form the W1 / O core. In this embodiment, W2 is the outer aqueous phase, containing 2.8 wt% tranexamic acid and 0.7 wt% polyethylene glycol-100 stearate as a hydrophilic emulsifier. W2 is adjusted to pH 5.4 and coexists with a layered gel network constructed from 2.5 wt% glycerol stearate and 2.0 wt% cetearyl alcohol. The system in this embodiment has a particle size D50 of 0.45 μm, a PDI of 0.18, a viscosity of 5.5 Pa·s at 25°C, a headspace oxygen content of 0.6%, and a glutathione encapsulation efficiency of 82%.

[0043] The W1 / O core of this embodiment was prepared through the following steps: 0.9 wt% of reduced glutathione was dissolved in deionized water, and the pH was adjusted to 3.6 with the addition of citric acid-sodium citrate. 0.08 wt% of disodium ethylenediaminetetraacetate and 0.25 wt% of phytic acid were added, followed by the addition of 4.0 wt% glycerol to match the external phase osmotic pressure. Nitrogen gas was then introduced for degassing for 13 min. 0.7 wt% of hydrogenated lecithin and 0.6 wt% of sorbitan sesquioleate were dissolved in 12.0 wt% squalane at 78°C. W1 was added dropwise to the oil phase for pre-emulsification at 5500 rpm for 50 s, followed by three high-pressure microfluidic granulation processes at 800 bar to obtain the W1 / O core.

[0044] The W2 external phase layered gel network of this embodiment was constructed according to the following steps: 2.5 wt% glyceryl stearate, 2.0 wt% cetearyl alcohol, and 3.5 wt% glycerol were mixed with water and melted uniformly at 78°C. The mixture was then cooled to 47°C and allowed to stand to form a layered liquid crystal phase, allowing the long-period ordered structure to exist stably in the external phase.

[0045] The W1 / O / W multiphase in this embodiment was prepared through the following steps: W1 / O was sheared and dispersed in the layered gel network of the W2 outer phase at 3200 rpm for 80 s under nitrogen protection at 47°C. The outer phase was pre-dissolved with 2.8 wt% tranexamic acid and adjusted to pH 5.4, and pre-degassed with nitrogen for 13 min. Low-pressure microfluidic granulation was performed once at 120 bar to obtain a W1 / O / W system with a D50 of 0.45 μm and a PDI of 0.18.

[0046] The system in this embodiment has a viscosity of 5.5 Pa·s at 25°C, an absolute value of zeta potential of 22 mV, and a yield stress of 35 Pa. In this embodiment, the tranexamic acid content is 2.8 wt%, the reduced glutathione content is 0.9 wt%, the squalane content is 12.0 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 1.3 wt%, and phenoxyethanol (0.7 wt%) and ethylhexylglycerin (0.30 wt%) are used as the preservative system. The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.089:0.278.

[0047] The preparation method of this embodiment includes: First, preparing the W1 / O core. Second, preparing a layered gel network of the W2 outer phase, and dissolving 2.8 wt% tranexamic acid in the W2 outer phase of this embodiment, degassing with nitrogen for 13 min, and adjusting the pH to 5.4. Third, dispersing the W1 / O core of this embodiment in the outer phase obtained in step two to obtain the W1 / O / W system. Fourth, controlling the oxygen content in the headspace to 0.6%, and selecting an oxygen permeability of no more than 1% under conditions of 23°C, 1 atm, and 50% RH. The barrier packaging completes the filling. In this embodiment, the volume fraction ratio of W1 to the oil phase is 35:65. The high-pressure microjet granulation pressure in this embodiment is 800 bar for primary emulsion granulation and 120 bar for secondary granulation. In this embodiment, the W2 external phase is cooled to 47°C and then combined with W1 / O to stabilize the layered gel network structure. In this embodiment, the nitrogen degassing time is 13 min.

[0048] The compound cream of this embodiment is used in the cosmetics field to improve uneven skin tone, lighten dark spots, brighten skin tone, and soothe and repair. This compound cream is applied twice daily to clean, dry skin, and continuous use for 8 weeks results in a significant improvement in skin tone evenness.

[0049] Example 2 Features: This example focuses on optimizing for high antioxidant capacity, increasing the glutathione content to 0.9%, combined with high levels of phytic acid (0.25%) and disodium EDTA (0.08%) to form a powerful synergistic antioxidant system. A lower W1 pH (3.6) is beneficial for glutathione stability. A squalane content of 12% provides excellent skin feel and penetration enhancement. Three high-pressure microfluidic granulation processes (800 bar) are used to obtain finer particle sizes (D50 = 0.45 μm) and narrower particle size distribution (PDI = 0.18), enhancing encapsulation stability. A higher concentration of layered gel network (glyceryl stearate 2.5% + cetearyl alcohol 2.0%) increases the system viscosity (5.5 Pa·s) and structural stability. This example is particularly suitable for anti-aging care, mature skin requiring enhanced antioxidant capabilities, protection and repair in urban polluted environments, and professional skincare scenarios requiring deep antioxidant and free radical scavenging.

[0050] Example 3 This embodiment provides a compound cream containing tranexamic acid-glutathione, comprising a W1 / O / W dual emulsion structure, and all percentage contents are based on the total mass of the final formulation.

[0051] In this embodiment, W1 is the inner aqueous core, containing 0.4 wt% reduced glutathione. W1 is adjusted to pH 4.0 using a citrate-sodium citrate buffer system and contains 0.03 wt% disodium EDTA and 0.08 wt% phytic acid. To alleviate osmotic pressure differences, W1 contains 5.0 wt% sorbitol. In this embodiment, O is the oil phase, containing 8.0 wt% squalane, and is stabilized with 0.3 wt% hydrogenated lecithin and 0.4 wt% sorbitan sesquioleate to form the W1 / O core. In this embodiment, W2 is the outer aqueous phase, containing 4.0 wt% tranexamic acid and 0.8 wt% cetearyl alcohol polyether-20, a hydrophilic emulsifier. W2 is adjusted to pH 5.6 and coexists with a layered gel network constructed from 1.5 wt% glyceryl stearate and 1.2 wt% cetearyl alcohol. The system in this embodiment has a particle size D50 of 0.60 μm, a PDI of 0.22, a viscosity of 3.5 Pa·s at 25°C, a headspace oxygen content of 0.7%, and a glutathione encapsulation efficiency of 75%.

[0052] The W1 / O core of this embodiment was prepared through the following steps: 0.4 wt% of reduced glutathione was dissolved in deionized water, and the pH was adjusted to 4.0 with the addition of citric acid-sodium citrate. 0.03 wt% of disodium ethylenediaminetetraacetate and 0.08 wt% of phytic acid were added, followed by 5.0 wt% of sorbitol to match the external phase osmotic pressure. Nitrogen gas was introduced for degassing for 11 min. 0.3 wt% of hydrogenated lecithin and 0.4 wt% of sorbitan sesquioleate were dissolved in 8.0 wt% of squalane at 72°C. W1 was added dropwise to the oil phase for pre-emulsification at 4500 rpm for 70 s, followed by two high-pressure microfluidic granulation processes at 720 bar to obtain the W1 / O core.

[0053] The W2 external phase layered gel network of this embodiment was constructed according to the following steps: 1.5 wt% glyceryl stearate, 1.2 wt% cetearyl alcohol, and 2.5 wt% glycerol were mixed with water and melted uniformly at 72°C. The mixture was then cooled to 49°C and allowed to stand to form a layered liquid crystal phase, allowing the long-period ordered structure to exist stably in the external phase.

[0054] The W1 / O / W multiphase in this embodiment was prepared through the following steps: W1 / O was sheared and dispersed in a layered gel network of the W2 outer phase at 2800 rpm for 100 s under nitrogen protection at 49°C. The outer phase was pre-dissolved with 4.0 wt% tranexamic acid and adjusted to pH 5.6, and pre-degassed with nitrogen for 11 min. Granulation was performed using the SPG membrane emulsification method with 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.

[0055] The system in this embodiment has 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 embodiment, the tranexamic acid content is 4.0 wt%, the reduced glutathione content is 0.4 wt%, the squalane content is 8.0 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 0.7 wt%, and phenoxyethanol (0.5 wt%) and ethylhexylglycerin (0.15 wt%) are used as the preservative system. The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.075:0.20.

[0056] The preparation method of this embodiment includes: First, preparing the W1 / O core. Second, preparing a layered gel network of the W2 outer phase, and dissolving 4.0 wt% tranexamic acid in the W2 outer phase of this embodiment, degassing with nitrogen for 11 min, and adjusting the pH to 5.6. Third, dispersing the W1 / O core of this embodiment in the outer phase obtained in step two to obtain the W1 / O / W system. Fourth, controlling the oxygen content in the headspace to 0.7%, selecting an oxygen permeability of no more than 1% under conditions of 23°C, 1 atm, and 50% RH. The barrier packaging completes the filling. In this embodiment, the volume fraction ratio of W1 to the oil phase is 28:72. The high-pressure microjet granulation pressure in this embodiment is 720 bar for primary emulsion granulation. This embodiment uses SPG membrane emulsification for granulation. In this embodiment, the W2 external phase is cooled to 49°C and then combined with W1 / O to stabilize the layered gel network structure. In this embodiment, the nitrogen degassing time is 11 min.

[0057] The compound cream of this embodiment is used in the cosmetics field to improve uneven skin tone, lighten dark spots, brighten skin tone, and soothe and repair. This compound cream is applied once daily to clean, dry skin, and continuous use for 6 weeks results in a significant improvement in skin tone evenness.

[0058] Example 3 Features: This example focuses on optimizing for high whitening effects, increasing the tranexamic acid content to 4.0%, which is the upper limit of the preferred range of claim 6, providing potent tyrosinase inhibition and melanin production blocking effects. Sorbitol is selected as an osmotic pressure regulator, providing moisturizing properties different from glycerin. The lower squalane content (8.0%) and total emulsifier amount (0.7%) make the formula more refreshing and reduce viscosity (3.5 Pa·s), suitable for oily and combination skin. SPG membrane emulsification technology is used instead of secondary high-pressure microjets to gently granulate and obtain a larger particle size (D50=0.60 μm), which is beneficial for the skin feel and spreadability of topical application. The lower concentration of the lamellar gel network (glyceryl stearate 1.5% + cetearyl alcohol 1.2%) gives it a lightweight texture. This example is particularly suitable for intensive care for fading pigmentation, whitening needs of oily and combination skin, refreshing whitening products for summer, and professional care scenarios requiring rapid absorption and high concentration of whitening activity.

[0059] Example 4 This embodiment provides a compound cream containing tranexamic acid-glutathione, comprising a W1 / O / W dual emulsion structure, and all percentage contents are based on the total mass of the final formulation.

[0060] In this embodiment, W1 is the inner water core, containing 0.95 wt% reduced glutathione. W1 is adjusted to pH 4.15 using a citrate-sodium citrate buffer system and contains 0.095 wt% disodium ethylenediaminetetraacetate and 0.28 wt% phytic acid. To alleviate osmotic pressure differences, W1 contains 2.2 wt% glycerol. In this embodiment, O is the oil phase, containing 11.8 wt% squalane, and is stabilized with 0.9 wt% hydrogenated lecithin and 0.85 wt% sorbitan sesquioleate to form the W1 / O core. In this embodiment, W2 is the external aqueous phase, containing 3.9 wt% tranexamic acid and 0.45 wt% polyglycerol-6 stearate and 0.45 wt% cetearyl alcohol polyether-20 as hydrophilic emulsifiers, totaling 0.9 wt%. W2 is adjusted to pH 5.75 and coexists with a layered gel network constructed from 2.85 wt% glycerol stearate and 2.35 wt% cetearyl alcohol. The system in this embodiment 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%.

[0061] The W1 / O core of this embodiment was prepared through the following steps: 0.95 wt% of reduced glutathione was dissolved in deionized water, and the pH was adjusted to 4.15 with the addition of citric acid-sodium citrate. 0.095 wt% of disodium ethylenediaminetetraacetate and 0.28 wt% of phytic acid were added, followed by the addition of 2.2 wt% of glycerol to match the external phase osmotic pressure. Nitrogen gas was then introduced for degassing for 14 min. 0.9 wt% of hydrogenated lecithin and 0.85 wt% of sorbitan sesquioleate were dissolved in 11.8 wt% of squalane at 77°C. W1 was added dropwise to the oil phase for pre-emulsification at 5800 rpm for 40 s, followed by three high-pressure microfluidic granulation processes at 870 bar to obtain the W1 / O core.

[0062] The W2 external phase layered gel network of this embodiment was constructed according to the following steps: 2.85 wt% glyceryl stearate, 2.35 wt% cetearyl alcohol, and 4.5 wt% glycerol were mixed with water and melted uniformly at 77°C. The mixture was then cooled to 46°C and allowed to stand to form a layered liquid crystal phase, allowing the long-period ordered structure to exist stably in the external phase.

[0063] The W1 / O / W multiphase in this embodiment was prepared through the following steps: W1 / O was sheared and dispersed in a layered gel network of the W2 outer phase at 3400 rpm for 70 s under nitrogen protection at 46°C. The outer phase was pre-dissolved with 3.9 wt% tranexamic acid and adjusted to pH 5.75, and pre-degassed with nitrogen for 14 min. Low-pressure microfluidic granulation was performed once at 140 bar to obtain a W1 / O / W system with a D50 of 0.76 μm and a PDI of 0.16.

[0064] The system in this embodiment 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. In this embodiment, the tranexamic acid content is 3.8 wt%, the reduced glutathione content is 0.95 wt%, the squalane content is 11.5 wt%, the total amount of hydrogenated lecithin and sorbitan sesquioleate is 1.75 wt%, and phenoxyethanol (0.9 wt%) and ethylhexylglycerin (0.42 wt%) are used as the preservative system. The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.10:0.295.

[0065] The preparation method of this embodiment includes: First, preparing the W1 / O core. Second, preparing a layered gel network of the W2 outer phase, and dissolving 3.9 wt% tranexamic acid in the W2 outer phase of this embodiment, degassing with nitrogen for 14 min, and adjusting the pH to 5.75. Third, dispersing the W1 / O core of this embodiment in the outer phase obtained in step two to obtain the W1 / O / W system. Fourth, controlling the oxygen content in the headspace to 0.85%, and selecting an oxygen permeability of no more than 1% under the conditions of 23°C, 1 atm, and 50% RH. The barrier packaging completes the filling. In this embodiment, the volume fraction ratio of W1 to the oil phase is 36:64. The high-pressure microjet granulation pressure in this embodiment is 870 bar for primary emulsion granulation and 140 bar for secondary granulation. In this embodiment, the W2 external phase is cooled to 46°C and then combined with W1 / O to stabilize the layered gel network structure. In this embodiment, the nitrogen degassing time is 14 min.

[0066] The compound cream of this embodiment is used in the cosmetics field to improve uneven skin tone, lighten dark spots, brighten skin tone, and soothe and repair. This compound cream is applied twice daily to clean, dry skin, and continuous use for 4 weeks results in a significant improvement in skin tone evenness.

[0067] Features of Example 4: W1, with a pH of 4.15, is close to the upper limit of 4.2, validating the stability boundary of glutathione at higher pH levels. Disodium EDTA (0.095%) and phytic acid (0.28%) are both close to their upper limits, forming a mass ratio of 1.0:0.10:0.295 with 0.95% glutathione, perfectly falling within the range specified in claim 6. The glycerol content of 2.2% is close to the lower limit of 2.0%, validating the minimum osmotic pressure adjustment requirement. Squalane (11.8%), tranexamic acid (3.9%), and total emulsifier (1.75%) are all close to their respective preferred upper limits. W2, with a pH of 5.75, glyceryl stearate (2.85%), and cetearyl alcohol (2.35%), is close to its upper limit, forming a stronger layered gel network and achieving a higher viscosity of 7.5 Pa·s. The particle size D50 of 0.76 μm is close to the upper limit of 0.80 μm, and the PDI of 0.16 is close to the lower limit of 0.15, demonstrating the feasibility of large particle size and low dispersion. A high-pressure microjets at 870 bar validates the boundary processing capability of high-pressure granulation. The combined design of multiple parameters close to the boundary demonstrates the full feasibility of the claim scope and the breadth of the process window, while the high encapsulation efficiency of 92% verifies that excellent stability can still be maintained under the boundary parameters. This embodiment is particularly suitable for professional-grade products requiring high concentrations of active ingredients, intensive repair after medical aesthetic procedures, concentrated care for severe pigmentation, and high-end skincare applications with extremely high requirements for product stability and encapsulation efficiency.

[0068] Comparative Example 1: Basically the same as Example 1, except that the content of reduced glutathione is 0.15 wt%, and the amount of other components and preparation conditions remain unchanged.

[0069] Comparative Example 2: It is basically the same as Example 1, except that the content of reduced glutathione is 2.3 wt%, while the amount of other components and preparation conditions remain unchanged.

[0070] Comparative Example 3: It is basically the same as Example 1, except that the pH of the water core in W1 is adjusted to 3.2, while the amount of other components and preparation conditions remain unchanged.

[0071] Comparative Example 4: It is basically the same as Example 1, except that the pH of the water core in W1 is adjusted to 4.5, while the amount of other components and preparation conditions remain unchanged.

[0072] Comparative Example 5: It is basically the same as Example 1, except that the squalane content is 3.5 wt%, while the amounts of other components and preparation conditions remain unchanged.

[0073] Comparative Example 6: It is basically the same as Example 1, except that the tranexamic acid content is 1.5 wt%, while the amounts of other components and preparation conditions remain unchanged.

[0074] Comparative Example 7: Basically the same as Example 1, except that the tranexamic acid content is 5.8 wt%, while the amounts of other components and preparation conditions remain unchanged.

[0075] Comparative Example 8: It is basically the same as Example 1, except that the high-pressure microjet granulation pressure is 500 bar, while the amount of other components and preparation conditions remain unchanged.

[0076] Comparative Example 9: Basically the same as Example 1, except that the pre-emulsification speed was 3200 rpm, while the amount of other components and preparation conditions remained unchanged.

[0077] Comparative Example 10: Basically the same as Example 1, except that the pH of the external aqueous phase W2 was adjusted to 4.9, while the amounts of other components and preparation conditions remained unchanged.

[0078] Comparative Example 11: Basically the same as Example 1, except that the content of glyceryl stearate is 0.6 wt%, while the amount of other components and preparation conditions remain unchanged.

[0079] Comparative Example 12: Basically 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 preparation conditions remain unchanged.

[0080] Comparative Example 13: It is basically the same as Example 1, except that nitrogen gas is not introduced for protection and degassing is not performed during the preparation process, while the amount of other components and preparation conditions remain unchanged.

[0081] Performance testing: Glutathione encapsulation efficiency determination Test Subject: Reduced glutathione in W1 / O / W dual-phase emulsion cream. Test Objective: To evaluate the encapsulation efficiency of glutathione in the water core of W1, reflecting the protective ability of the dual-phase structure for the active ingredient. Test Principle: Free and encapsulated glutathione were separated by ultrafiltration centrifugation. The glutathione content in the supernatant and total amount was determined by HPLC, and the encapsulation efficiency was calculated. Experimental Method: 0.5 g of sample was accurately weighed and diluted to 10 mL with pH 7.4 phosphate buffer. The sample was then subjected to ultrafiltration centrifugation (10 kDa molecular weight cutoff, 4000 rpm, 20 min), and the filtrate was collected as free glutathione. Another 0.5 g of sample was demulsified with buffer containing 1% Triton X-100, and the total glutathione was determined. HPLC Conditions: C18 column, mobile phase: methanol-0.1% phosphate aqueous solution (5:95), flow rate: 1.0 mL / min, detection wavelength: 210 nm. Key parameters: Ultrafiltration temperature 4℃, centrifugation force 4000rpm, time 20 min. Data processing: Encapsulation efficiency (%) = (Total glutathione content - Free glutathione content) / Total glutathione content × 100%, n≥3, report mean ± standard deviation.

[0082] Particle size distribution and polydispersity index determination Test Object: W1 / O / W dual-phase system. Test Objective: To determine the average particle size (D50) and polydispersity index (PDI) of the dual-phase droplets, and to evaluate the homogeneity and stability of the system. Test Principle: Based on the principle of dynamic light scattering, the Brownian motion of particles during laser irradiation causes fluctuations in scattered light intensity. The particle size distribution is calculated using a correlation function. Experimental Method: Take an appropriate amount of sample and dilute it with deionized water to a suitable concentration (dilution factor 100-200 times, achieving a count rate of 20-300 kcps), avoiding multiple scattering. Maintain a constant temperature of 25±0.1℃ and measure using a laser particle size analyzer such as a Malvern Zetasizer Nano ZS with a scattering angle of 173°. The measurement time is automatically optimized. Each sample is measured three times. Key parameters: measurement temperature 25℃, dilution medium deionized water, equilibration time 120 s. Data Processing: Record the D50 and PDI values, n≥3, and report the mean ± standard deviation.

[0083] Apparent viscosity measurement Test Subject: Compound Cream (finished product). Test Objective: To determine the apparent viscosity of the cream at 25°C, and to evaluate the product's rheological properties and skin feel. Test Principle: A rotational rheometer is used to measure the shear stress of the sample at a constant shear rate, and the apparent viscosity is calculated. Experimental Method: The sample is placed on a constant temperature platform at 25±0.1°C for equilibration for 30 min. A rotational rheometer (e.g., Anton Paar MCR 302) is used, with a parallel plate clamp (40 mm diameter, 1.0 mm gap), and the shear rate is set. Perform steady-state testing. Record the values ​​after the viscosity stabilizes (fluctuation <5% for 30 s). At least three parallel samples should be tested for each sample. Key parameters: test temperature 25±0.1℃, shear rate... Equilibrium time 30 min, gap 1.0 mm. Data processing: Record apparent viscosity (Pa·s), n≥3, report mean ± standard deviation.

[0084] pH value measurement Test Subjects: W1 inner water core and W2 outer aqueous phase. Test Objective: To accurately determine the pH value of the inner and outer aqueous phases, verifying the effectiveness of the buffer system and the mildness of the product. Test Principle: The pH value is determined by measuring the potential difference generated by the hydrogen ion activity in the solution using the pH glass electrode method. Experimental Method: For the W1 inner water core, the pH value is directly measured from the inner aqueous phase during the preparation process; for the W2 outer aqueous phase, 1.0 g of the finished cream is added to 10 mL of deionized water, gently stirred to disperse, and allowed to stand for 10 min. The pH value of the upper aqueous phase is then measured. A calibrated pH meter (accuracy ±0.01) is used. The electrode is immersed in the sample, and the reading is recorded after stabilization. Two-point calibration is performed using pH 4.00 and pH 6.86 standard buffer solutions before testing. Each sample is measured three times. Key Parameters: Test temperature 25±2℃, electrode immersion depth approximately 2 cm, stability criterion <0.02 pH units change within 30 s. Data Processing: n≥3, report mean ± standard deviation.

[0085] Headspace oxygen content measurement Test Subject: Compound cream in sealed packaging after filling. Test Objective: To determine the residual oxygen content in the headspace of the packaging and evaluate the nitrogen-filled protective effect and antioxidant capacity. Test Principle: Headspace gas chromatography or a portable oxygen analyzer is used to determine the oxygen volume fraction in the headspace gas via an electrochemical sensor or thermal conductivity detector. Experimental Method: Take a sealed sample and, in a sterile operating table, puncture the cap with a sterile needle to collect 0.5 mL of gas from the headspace. Inject this gas into an oxygen analyzer (e.g., Systech Illinois 7001 or Agilent GC with a TCD detector). GC Conditions: TDX-01 packed column, column temperature 80℃, carrier gas nitrogen, flow rate 30 mL / min, injection volume 0.5 mL. Alternatively, a portable oxygen analyzer can be used for direct puncture measurement. At least three packaging samples should be tested per batch. Key Parameters: Sampling volume 0.5 mL, test temperature 23±2℃, instrument accuracy ≤0.01%. Data Processing: Record the oxygen volume percentage, n≥3, and report the mean ± standard deviation.

[0086] In vitro tyrosinase inhibitory activity assay Test Subject: Extract of active ingredients from compound cream. Test Objective: To evaluate the whitening effect of tranexamic acid and glutathione synergistically inhibiting tyrosinase activity. Test Principle: Tyrosinase catalyzes the formation of dopaquinone from L-tyrosine, producing characteristic absorption at 475 nm. Absorbance decreases in the presence of inhibitors; the inhibition rate is calculated by comparison. Experimental Method: Accurately weigh 1.0 g of sample, extract the active ingredient with 50% ethanol, centrifuge, and dilute the supernatant to a suitable concentration. Reaction System: 2.5 mL phosphate buffer (pH 6.8), 0.4 mL L-tyrosine solution (2 mM), 0.1 mL sample solution. After preheating at 37℃ for 10 min, add 0.1 mL mushroom tyrosinase solution (100 U / mL), react at 37℃ for 30 min, and measure absorbance at 475 nm. A blank control and a positive control (kojic acid) were included. Key Parameters: Reaction temperature 37±0.5℃, pH 6.8±0.1, reaction time 30 min. Data processing: Inhibition rate (%) = (A blank - A sample) / A blank × 100%, n≥3, report mean ± standard deviation.

[0087] Figure 1 The effects of reduced glutathione content on encapsulation efficiency and tyrosinase inhibition rate were investigated. The parameters were fixed as follows: 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%, cetearyl alcohol 1.5 wt%. High-pressure microjet flow was used at 750 bar for colostrum granulation and 100 bar for secondary granulation, with a pre-emulsification speed of 5000 rpm. The variable parameter was the reduced glutathione content, ranging from 0.15 wt% to 2.60 wt%. When the glutathione content is between 0.6 and 1.2 wt%, the encapsulation efficiency and tyrosinase inhibition rate reach their peak values ​​simultaneously. The peak encapsulation efficiency is around 0.6 wt%, reaching 85.0%, and the inhibition rate reaches 76.5%. When the content is below 0.2 wt%, insufficient active substances in the inner water core lead to a decrease in the inhibition rate to 64.5% and an encapsulation efficiency of only 68.0%. When the content is above 2.0 wt%, excessive glutathione increases the osmotic pressure of the inner water core and the risk of oxidation, causing the encapsulation efficiency to drop below 70.0%. This demonstrates that an appropriate glutathione content can simultaneously ensure the stability of the dual emulsion phase and synergistic whitening effect.

[0088] Figure 2The effects of tranexamic acid content on tyrosinase inhibition rate and viscosity were investigated using the following parameters: 0.6 wt% reduced glutathione, 10.0 wt% squalane, pH 3.8 for W1, pH 5.5 for W2, 0.5 wt% hydrogenated lecithin, 0.5 wt% sorbitan sesquioleate, 2.0 wt% glyceryl stearate, 1.5 wt% cetearyl alcohol, a high-pressure microjet flow of 750 bar for primary emulsion granulation and 100 bar for secondary granulation, and a pre-emulsification speed of 5000 rpm. The parameters varied by 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 remains above 76.5% and maintains a stable upward trend to reach 80.5%. When the content is below 2.0 wt%, the whitening activity is significantly insufficient, resulting in an inhibition rate of only 62.5%. When the content is above 5.0 wt%, although the inhibition rate is slightly improved to 82.0%, the viscosity increases significantly from 4.5 Pa·s to 5.5 Pa·s, which may affect the skin feel after application. This verifies that a moderate tranexamic acid content can balance whitening efficacy with formula stability and user experience.

[0089] Figure 3 The effects of high-pressure microfluidic granulation pressure on particle size D50 and polydispersity index were investigated. The parameters were fixed as follows: 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%, cetearyl alcohol 1.5 wt%. The low-pressure microfluidic pressure was 100 bar for secondary granulation, and the pre-emulsification speed was 5000 rpm. The high-pressure microfluidic granulation pressure was varied from 500 bar to 950 bar. When the granulation 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, showing uniform dispersion characteristics. When the pressure is below 600 bar, the granulation effect is insufficient, which causes D50 to increase significantly to above 0.78 μm and the polydispersity index to rise to above 0.25, resulting in uneven particle size distribution. When the pressure is above 900 bar, although the particle size can be further reduced to 0.38 μm, the energy consumption increases and the equipment requirements are higher. This shows that medium pressure can ensure submicron particle size and low polydispersity while taking into account the economic efficiency of the process.

[0090] Figure 4The effect of the pH value of the W1 inner water core on the encapsulation efficiency and stability of glutathione was investigated. The fixed parameters were: 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%, cetearyl alcohol 1.5 wt%, high-pressure microjet pressure of 750 bar for primary emulsion granulation and 100 bar for secondary granulation, and pre-emulsification speed of 5000 rpm. The variable parameter was the pH value of the W1 inner water core from 3.20 to 4.50. When the pH is between 3.6 and 4.0, the encapsulation efficiency and stability of glutathione reach the optimal level simultaneously. The encapsulation efficiency exceeds 80.5%, and the residual rate remains above 85.5% after 30 days of storage at 25°C in the dark. When the pH is below 3.5, the acidity is too strong, which may affect the stability of some components and the emulsion system, causing the encapsulation efficiency to drop to 72.0%. When the pH is above 4.2, the oxidation risk of glutathione increases at relatively high pH, ​​resulting in a significant decrease in both encapsulation efficiency and stability to 78.5% and 84.0%, respectively. This proves that precise pH control is the key to balancing the antioxidant stability of glutathione with the compatibility of the formulation system.

[0091] Figure 5 This is a GSH residue-time curve (comparison of multiple pH / chelating agent concentrations). The fixed parameters were a W1 / O / W dual-phase emulsion structure, with an initial GSH concentration of 0.6 wt% in the inner water core. W1 used a citrate-sodium citrate buffer. Storage conditions were 25°C in the dark. Sampling time ranged from 0 to 90 days, and HPLC quantitative detection was performed. The varying parameters were four conditions: A: pH 3.8 | EDTA 0.05% + phytic acid 0.15% | B: pH 3.8 | EDTA only 0.05% | 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 group A achieved a GSH residue rate of 85–90% after 90 days, significantly higher than group B (approximately 84%) and group D (approximately 79%). Group C was slightly lower than group A but still maintained approximately 86%. This indicates that the low pH buffer and the dual chelation of EDTA and phytic acid under nitrogen protection create a synergistic stabilizing effect, effectively slowing down GSH consumption; while the air headspace significantly accelerates oxidation, leading to a decrease in residue rate.

[0092] Figure 6To investigate the effect of interlayer spacing (d) on multi-level diffraction peaks in SAXS scattering curves, the following parameters were fixed: an external phase system consisting of a layered gel network constructed from 2.0 wt% glycerol stearate and 1.5 wt% cetearyl alcohol; a temperature of 25°C; a correlation length (ξ) of 120 nm; unchanged background Porod and constant terms; a W1 / O / W particle size (D50) of 0.50 μm; a PDI of 0.20; and a headspace oxygen content of 0.5%. The interlayer spacing (d) was varied from 4.0 nm to 6.0 nm (equivalent q1 = 2π / d ranging from 1.05 to...). (Range). Clear diffraction peaks of orders 1-3 appear in the range of 5.0 to 5.5 nm, with peak positions satisfying qn=n·q1 and the full width at half maximum (FWHM) constrained by ξ, indicating that the W2 outer phase forms a long-period ordered layered network; as d increases, the peak positions shift to the left as a whole while the order parameter remains stable, proving that the layered phase provides the basis for the structurally ordered physical fixation and leakage barrier of the W1 / O core.

[0093] Figure 7 The image shows the morphology of the compound cream containing tranexamic acid and glutathione in Example 1. Scanning electron microscopy reveals a uniformly dispersed spherical structure with a particle size distribution concentrated in the range of 0.4 to 0.6 μm, highly consistent with the D50 value of 0.5 μm measured by a laser particle size analyzer. The smooth particle surfaces without obvious aggregation or breakage indicate that the high-pressure microfluidic granulation process effectively formed a stable dual-phase emulsion system. The internal light and dark layered core-shell structure confirms that the active ingredients glutathione and tranexamic acid were successfully encapsulated in the inner water core and sequentially coated by the oil and outer water phases. Morphological characteristics show good particle size uniformity and the absence of large particles or flocculents, verifying that the compound cream prepared under optimized process parameters possesses ideal microstructure and dispersion stability, providing microscopic morphological evidence to support its subsequent whitening efficacy and storage stability.

[0094] As can be seen from the performance of the examples and comparative examples in Table 1, the four examples significantly outperformed most of the comparative examples in key indicators such as glutathione encapsulation efficiency, particle size uniformity, head space oxygen content control, and tyrosinase inhibitory activity. Comparative Example 1 showed a significant decrease in encapsulation efficiency and whitening effect due to excessively low glutathione content, while Comparative Example 2 experienced increased system instability and oxidation risk due to excessively high glutathione content. Comparative Examples 3 and 4 showed that deviations from the optimal pH range in W1 reduced glutathione stability and encapsulation efficiency. Comparative Example 5 suffered from unstable oil phase structure due to insufficient squalane, affecting skin feel. Comparative Examples 6 and 7 indicated that tranexamic acid content needs precise control; too low a content weakens the whitening effect, while too high a content may increase the risk of irritation. Comparative Examples 8 and 9 confirmed that high-pressure microfluidics and pre-emulsification process parameters are crucial for particle size distribution and PDI control. Comparative Example 10 showed that low pH in W2 affected the stability of the layered gel network. Comparative Example 11 suffered from excessively low viscosity due to insufficient gel network concentration, affecting the user experience. The imbalance in the internal and external phase ratio in Comparative Example 12 reduced encapsulation efficiency. In Comparative Example 13, the lack of nitrogen protection led to a surge in oxygen content in the headspace and glutathione oxidation, resulting in a significant decrease in encapsulation efficiency and efficacy. Example 4, even with a combination of parameters nearing their upper limits, maintained a maximum encapsulation efficiency of 92% and an excellent inhibition rate of 80.5%, fully validating the synergistic effect and broad process window of the present invention.

[0095] Table 1 Summary of performance of examples and comparative examples

[0096] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that any equivalent structural transformations made under the concept of the present invention and using the contents of the specification and drawings of the present invention should be covered within the scope of protection of the claims of the present invention.

Claims

1. A compound cream containing tranexamic acid and glutathione, characterized in that, This includes a W1 / O / W dual emulsion structure, where all percentages are based on the total mass of the final formulation: a) W1 is an inner water core containing 0.2–2.0 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, in total of 0.2–1.0 wt%. W2 is adjusted to pH 5.2–5.8 and coexists with a layered gel network constructed from 1.0–3.0 wt% glycerol stearate and 1.0–2.5 wt% cetearyl alcohol. 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 efficiency of no less than 70%.

2. The compound cream according to claim 1, characterized in that, 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.

3. The compound cream according to claim 1, characterized in that, The layered gel network 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.

4. The compound cream according to claim 1, characterized in that, The W1 / O / W 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. Optionally, a low-pressure microjets can be used for granulation once at 80–150 bar, or granulation can be performed using the SPG membrane emulsification method with 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.

5. 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.

6. The compound cream according to claim 1, characterized in that: The preservative system consists of tranexamic acid (2.5–4.0 wt%), reduced glutathione (0.3–1.0 wt%), squalane (8–12 wt%), hydrogenated lecithin and sorbitan sesquioleate (0.5–1.8 wt%), phenoxyethanol (0.3–1.0 wt%) and ethylhexylglycerin (0.05–0.50 wt%). The mass ratio of reduced glutathione, disodium EDTA, and phytic acid is 1.0:0.04–0.10:0.10–0.

30.

7. A method for preparing a compound cream containing tranexamic acid and glutathione according to any one of claims 1-6, 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 / W 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.

8. The preparation method of a compound cream containing tranexamic acid and glutathione according to claim 7, 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.

9. The application of the compound cream according to any one of claims 1-6 or the compound cream obtained by the preparation method according to claim 7 or 8 in the field of cosmetics, characterized in that, It is used to improve uneven skin tone, lighten dark spots, brighten skin tone, and soothe and repair.

10. The application according to claim 9, characterized in that, The compound cream is applied to clean, dry skin 1–2 times daily, and after 4–8 weeks of continuous use, significant improvement in skin tone evenness can be achieved.

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