A multi-layered osmotic controlled-release acid formulation and a method for preparing the same

Abstract

The application provides a multi-layer penetration controlled-release acid preparation and a preparation method thereof, and belongs to the field of cosmetics. The preparation is composed of Aspergillus oryzae fermentation substrate freeze-dried powder, composite alpha-hydroxy acid, salicylic acid, poloxamer 407, polyhydric alcohol and non-ionic surfactant. The freeze-dried powder is obtained by co-fermenting olea europaea leaves and curcuma and refining through ultrafiltration. A temperature-sensitive phase change system is constructed by using poloxamer, so that the product is changed from a liquid state to a gel state at body temperature, and the synergistic controlled release of acid components and bioactive substances is realized. The preparation process adopts low-temperature swelling and vacuum freeze-drying technology, so that the stability of the system and the efficiency of the active substances are ensured. The application significantly reduces the irritation of high-concentration acid, improves the black suppression and repair effect, and is suitable for precise improvement of hyperpigmentation problems such as chloasma.

Description

Technical Field

[0001] This invention belongs to the field of cosmetics, and particularly relates to a multilayer permeation-controlled sustained-release acid preparation and its preparation method. Background Technology

[0002] The application of acidic active ingredients in dermatology and cosmetic care has a long history and plays a vital role. Various organic acids are widely used to improve skin texture, regulate keratinocyte metabolism, promote epidermal renewal, and alleviate certain skin problems. For example, members of the alpha-hydroxy acid (AHA) family, due to their excellent hydrating abilities and ability to promote keratinocyte exfoliation, are often added to anti-aging and skin-brightening products.

[0003] Although the efficacy of acidic ingredients has been widely proven, numerous technical challenges remain in their practical application. When acidic substances act directly on the skin, especially at higher concentrations, they can easily cause immediate irritation, such as stinging, redness, and itching. This irritation not only reduces comfort during use but may also lead to temporary damage to the skin barrier function, making it particularly unsuitable for people with sensitive skin. How to minimize irritation while ensuring efficacy is one of the core issues in ongoing research in this field.

[0004] The stability of acidic ingredients in formulations is also a major challenge. Many organic acids are easily degraded or inactivated in aqueous systems due to factors such as pH, temperature, light, and metal ions. The residence time and penetration behavior of active ingredients on the skin surface directly affect their final effect. In traditional formulations (such as aqueous solutions and regular creams), acidic ingredients are often released rapidly and in large quantities and penetrate into the skin after application. This "burst release" effect may exacerbate the aforementioned skin irritation and also shorten the time that the active ingredients remain on the skin surface, failing to achieve the goal of long-lasting and gentle skincare.

[0005] In recent years, the use of natural plant raw materials for fermentation to obtain functional ingredients rich in active metabolites has become a research hotspot in the cosmetics field. The fermentation process utilizes the enzyme system of microorganisms to biotransform macromolecules in plant raw materials into smaller, more easily absorbed active ingredients, while also producing new beneficial secondary metabolites such as organic acids, polyphenols, polysaccharides, and various enzymes. These fermentation products often possess multiple functions, including nutrition, conditioning, and preservative effects. However, how to scientifically combine complex fermentation products with acids of known efficacy, enabling them to work synergistically in a stable system while maintaining gentleness and sustained-release effects, still requires sophisticated formulation design and process exploration.

[0006] In summary, there is an urgent need to develop a novel acidic formulation. This formulation should effectively integrate acidic active ingredients from multiple sources, significantly reduce skin irritation while ensuring efficacy, through scientific formulation design and manufacturing technology, achieve stable and sustained release of active ingredients, and possess good physical and chemical stability, thereby meeting the market's urgent demand for highly effective, gentle, and long-lasting acidic skin care products. Summary of the Invention

[0007] The first objective of this invention is to provide a controlled-release acid formulation, comprising, by weight, the following components: Aspergillus oryzae fermentation substrate freeze-dried powder 3.0-6.0 Complex α-hydroxy acid 3.0-5.0 Salicylic acid 1.5-2.0 Polosham 407 15-25 Polyols 10-20 Nonionic surfactant 1.5-3.0 The substrate of the freeze-dried Aspergillus oryzae fermentation substrate powder is composed of olive leaves and turmeric in a mass ratio of 2:1 to 6:1.

[0008] Preferably, the composite α-hydroxy acid is composed of glycolic acid, lactic acid, and citric acid in a mass ratio of (2-3):(2-3):1.

[0009] Preferably, it also includes basic amino acids to adjust the pH of the controlled-release acid preparation to 3.8-4.5.

[0010] Preferably, it also includes at least 0.05 parts of a soothing component, said soothing component being bisabolol and / or asiaticoside.

[0011] Preferably, the method for preparing the Aspergillus oryzae fermentation substrate freeze-dried powder includes the following steps: S1: Mix dried olive leaves and turmeric in a mass ratio of 2:1 to 6:1, crush them, add 1.5-2.0 times the weight of the substrate with water to soak them; and adjust the initial pH value to 5.5-6.5 to obtain the fermentation substrate, and sterilize it; S2: Inoculate with Aspergillus oryzae at a rate of at least 5% v / w, and carry out aerobic fermentation for at least 72 hours at a temperature of 28-30℃ and a humidity of 80%-90%. Fermentation is considered complete when the pH value of the fermentation system decreases by more than 1.2 units, and the fermented cooked material is obtained. S3: After inactivating the fermented cooked material, extract it with ethanol solution, collect the extract, filter it with an ultrafiltration membrane, and collect the permeate; S4: Add excipients to the permeate and freeze-dry under vacuum to obtain the freeze-dried powder of the fermentation substrate.

[0012] In step S1, the fermentation substrate, calculated based on the total mass of olive leaves and turmeric, also contains the following components: Carbon source, at least 0.5%. Nitrogen source, at least 0.3%. Potassium dihydrogen phosphate, at least 0.1%. Magnesium sulfate, at least 0.05%.

[0013] In step S3, the method for ethanol solution extraction is as follows: using an ethanol solution with a volume fraction of 30%-50% as a solvent, ultrasonically extracting twice at 45-55℃, each time for at least 30 minutes; after centrifuging to remove residue, the extract is filtered through a microfiltration membrane and then filtered through an ultrafiltration membrane.

[0014] In step S4, the vacuum freeze-drying includes: Pre-freezing: Cool to a maximum of -40°C and maintain for at least 4 hours; Sublimation drying: Vacuum degree 10-20 Pa, heat to the maximum -5℃, and maintain for at least 18 hours; Drying: Heat to a maximum of 35°C and maintain for at least 6 hours.

[0015] A second objective of this invention is to provide a method for preparing the aforementioned controlled-release acid formulation, comprising the following steps: S1: Mix polyol with water, add composite α-hydroxy acid and salicylic acid in sequence, stir at 40-50℃ until completely dissolved to obtain acid matrix solution; S2: Cool the acid matrix solution to ≤10℃, add poloxamer 407 and nonionic surfactant, and let it stand at 4-8℃ to swell until a liquid matrix is ​​formed; S3: Maintain the system temperature ≤15℃, add the remaining components except for the basic amino acids to the liquid matrix and stir until reconstituted; then adjust the pH value to 3.8-4.5 to obtain the controlled-release acid preparation.

[0016] Preferably, the controlled-release acid formulation has temperature-sensitive phase change characteristics, being a flowing liquid at 20-25°C and a non-flowing gel at 32-35°C.

[0017] The controlled-release acid formulation described in this invention is based on the synergistic effect of physical phase change controlled release and biotransformation enhancement. In-situ thermosensitive film-forming mechanism: Utilizing a thermally reversible gel network formed by a high concentration of poloxamer 407 as a carrier. At room temperature, the polymer chains within the system are in a loose state, exhibiting a low-viscosity liquid, facilitating coating and penetration. When the product comes into contact with the skin (approximately 32-35°C), the hydrophobic ends of the polymer molecules rapidly associate to form a physical cross-linked network, causing the formulation to quickly transform from a liquid state to a non-flowing gel state. This gel network can lock acidic components and active substances onto the skin surface, establishing a miniature "active reservoir."

[0018] Gradient molecular penetration and sustained-release logic: The gel matrix, by increasing diffusion resistance, alters the conventional instantaneous release and penetration pattern of acidic preparations. The complex α-hydroxy acid and salicylic acid are released at a gradient rate, first softening the stratum corneum and opening biochemical channels. Subsequently, with the assistance of nonionic surfactants, small-molecule fermentation active ingredients can continuously and deeply penetrate skin tissue, avoiding the severe pain and barrier damage caused by the instantaneous contact of high-concentration acids with the skin.

[0019] The principle of Aspergillus oryzae-directed biotransformation: Through the co-fermentation of olive leaves and turmeric substrates by Aspergillus oryzae, the reductases and hydrolases secreted by the microorganisms convert the original curcumin-like components in the substrates into tetrahydrocurcumin, which has higher bioavailability, and convert oleuropein into the potent antioxidant hydroxytyrosol. This biotransformation not only enhances the whitening and anti-inflammatory efficacy of the raw materials, but also removes large molecular impurities through ultrafiltration purification, ensuring the long-term chemical stability of the bioactive ingredients in acidic and electrolyte environments.

[0020] The controlled-release acid formulation provided by this invention has the following significant advantages compared to existing technologies: Significantly reduces irritation and enhances safety: The controlled-release action of the thermosensitive gel alters the instantaneous release characteristics of acidic components, effectively alleviating stinging, redness, and stress reactions during chemical peels. Even with a high total acid content, it maintains excellent gentleness, making it especially suitable for people with melasma and fragile skin barriers.

[0021] Synergistic effect for precise solution to pigmentation problems: This formulation no longer relies solely on physical exfoliation, but achieves a deep combination of "acid exfoliation" and "biological melanin inhibition". The highly active components in the fermentation products complement the acid components, inhibiting melanin synthesis signals at the source while metabolizing keratin, which can more effectively improve dull skin tone and pigmentation, and prevent pigmentation backflow after acid peels.

[0022] Excellent biostability and purity: Utilizing specific ultrafiltration purification technology and vacuum freeze-drying process, not only are allergenic proteins and unstable impurities from the fermentation process eliminated, but the physical stability of active ingredients in complex acidic systems is also ensured. The freeze-dried powder can be rapidly reconstituted during preparation without precipitation, guaranteeing color stability and efficacy consistency throughout the product's shelf life.

[0023] Easy to use and with strong adhesion: The unique liquid-to-gel conversion property solves the pain points of ordinary water-based peeling products, such as easy dripping and inconvenient operation. After being applied to the target area, the product can quickly fix itself, enhancing the residence time of the active ingredient in specific areas, improving bioavailability, and eliminating the need for complicated neutralization steps, greatly optimizing the user experience. Detailed Implementation

[0024] To better understand the present invention, the present invention will be further described below with reference to specific serial numbers. The terminology used in the serial numbers is for describing specific embodiments and does not constitute a limitation on the scope of protection of the present invention.

[0025] In the specific implementation methods, unless otherwise specified, the experimental methods used are all conventional methods, and the materials and reagents used are all commercially available unless otherwise specified.

[0026] Unless otherwise specified, percentages, % and so on in the specific implementation method are assumed to be mass percentages.

[0027] The Aspergillus oryzae strain used in this invention is a commercially available strain.

[0028] The olive leaves used in this invention are those of the olive tree Olea europaea L.

[0029] The turmeric used in this invention is the mature rhizome of Curcuma longa L.

[0030] Example 1: Preparation of low-ratio Aspergillus oryzae fermentation freeze-dried powder Includes the following steps: S1 Substrate Pretreatment: Mix dried olive leaves and dried turmeric in a 2:1 mass ratio and grind to 200 mesh using a ball mill. Add a nutrient solution (1.5 times the substrate mass) to the substrate, containing 0.5% glucose, 0.3% yeast extract, 0.1% potassium dihydrogen phosphate, and 0.05% magnesium sulfate. Adjust the initial pH to 5.5 using arginine and sterilize at 121°C for 20 minutes.

[0031] S2 inoculation fermentation: After cooling, inoculate with Aspergillus oryzae at a rate of 5% v / w and carry out aerobic fermentation for 72 hours at a temperature of 29±1℃ and a humidity of 80-90%.

[0032] After 72 hours, the pH value was tested every 6 hours. Fermentation was considered complete when the pH value was ≤ 4.3.

[0033] S3 Extraction and Refining: Inactivate the fermented cooked material at 80℃ for 30 minutes.

[0034] A 30% ethanol solution (solvent-liquid ratio 1:8) was used as the solvent, and the mixture was ultrasonically extracted twice at 45℃ for 60 min each time.

[0035] The extract was centrifuged to remove residue, filtered through a 0.45 μm microfiltration membrane, and then purified through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da. The permeate was collected.

[0036] S4 Vacuum freeze drying: Add 1.0% trehalose to the permeate as an excipient.

[0037] Turn on the vacuum freeze dryer: Pre-freeze: cool to -40℃ and hold for 4 hours; Sublimation drying: vacuum degree 20Pa, heat to -10℃ and hold for 18 hours; Desorption drying: heat to 25℃ and hold for 6 hours to obtain freeze-dried powder.

[0038] Example 2: Preparation of high-ratio Aspergillus oryzae fermentation freeze-dried powder Includes the following steps: S1 Substrate Pretreatment: A mixture of dried olive leaves and dried turmeric (6:1 mass ratio) was ground to 200 mesh using a ball mill. A nutrient solution (2.0 times the substrate mass) containing 1.5% glucose, 1.0% yeast extract, 0.15% potassium dihydrogen phosphate, and 0.08% magnesium sulfate was added to the substrate. The initial pH was adjusted to 6.5 using arginine, and the mixture was sterilized at 121°C for 20 minutes.

[0039] S2 inoculation fermentation: After cooling, inoculate with Aspergillus oryzae at a rate of 5% v / w and carry out aerobic fermentation for 72 hours at a temperature of 29±1℃ and 80-90% humidity.

[0040] After 72 hours, the pH value was tested every 6 hours. Fermentation was considered complete when the pH value was ≤ 4.7.

[0041] S3 Extraction and Refining: Inactivate the fermented cooked material at 80℃ for 30 minutes.

[0042] A 50% ethanol solution (solvent-liquid ratio 1:10) was used as the solvent, and the mixture was ultrasonically extracted twice at 55℃ for 30 min each time.

[0043] The extract was centrifuged to remove residue, filtered through a 0.45 μm microfiltration membrane, and then purified through an ultrafiltration membrane with a molecular weight cutoff of 3000 Da. The permeate was collected.

[0044] S4 Vacuum freeze drying: 3.0% trehalose and 0.5% hydroxypropyl-β-cyclodextrin were added to the permeate as excipients.

[0045] Turn on the vacuum freeze dryer: Pre-freeze: cool to -50℃ and hold for 4 hours; Sublimation drying: vacuum degree 10Pa, heat to -10℃ and hold for 18 hours; Desorption drying: heat to 35℃ and hold for 8 hours to obtain freeze-dried powder.

[0046] Example 3: The preparation of freeze-dried powder fermented with Aspergillus oryzae of olive differs from that of Example 1 in that the substrate in step S1 is only olive leaves.

[0047] Example 4: Preparation of freeze-dried powder fermented with Aspergillus turmeric The difference from Example 1 is that the substrate in step S1 is only turmeric.

[0048] Example 5 Preparation of lyophilized powder fermented with alcohol-based Aspergillus oryzae The difference from Example 1 is that after centrifuging and removing the residue in step S3, the ethanol extract is directly proceeded to step S4; without purification.

[0049] Example 6 Preparation of freeze-dried olive leaf-turmeric powder Includes the following steps: S1 extract pretreatment: Take dried olive leaves and dried turmeric in a mass ratio of 2:1 and mix them. Then grind them to 200 mesh using a ball mill.

[0050] S2 Extraction and Purification: Using a 30% ethanol solution as the solvent (solid-to-solid ratio 1:10), ultrasonic extraction was performed twice at 45℃, each time for 60 min.

[0051] The extract was centrifuged to remove residue, filtered through a 0.45 μm microfiltration membrane, and then purified through an ultrafiltration membrane with a molecular weight cutoff of 1000 Da. The permeate was collected.

[0052] S4 Vacuum freeze drying: Add 1.0% trehalose to the permeate as an excipient.

[0053] Turn on the vacuum freeze dryer: Pre-freeze: cool to -40℃ and hold for 4 hours; Sublimation drying: vacuum degree 20Pa, heat to -10℃ and hold for 18 hours; Desorption drying: heat to 25℃ and hold for 6 hours to obtain freeze-dried powder.

[0054] Example 7 Preparation of controlled-release acid formulation Includes the following steps: S1: Weigh out the required raw materials according to the serial numbers and addition amounts in Table 1.

[0055] Table 1

[0056] Note: Table 1 does not include arginine, as arginine is only used to adjust pH, so its content is not included in the calculation.

[0057] S2: Mix the polyol with water, add the composite α-hydroxy acid and salicylic acid in sequence, and stir at 40-50℃ until completely dissolved to obtain an acid matrix solution; S3: Cool the acid matrix solution to ≤10℃, add poloxamer 407 and nonionic surfactant, and let it stand at 4-8℃ to swell until a liquid matrix is ​​formed; S4: Maintain the system temperature ≤15℃, add the remaining components except arginine to the liquid matrix and stir until reconstituted; then adjust the pH value to 3.8-4.5 using arginine to obtain the controlled-release acid preparation.

[0058] Performance testing The samples prepared in the foregoing embodiments were subjected to performance tests; the details are as follows: (1) Tyrosinase inhibition rate test (in vitro biochemical method) Objective: To demonstrate the inhibitory effect of fermented freeze-dried powder on the core enzyme of melanin synthesis.

[0059] Reagent preparation: L-DOPA solution (substrate), tyrosinase solution (from mushrooms), PBS buffer (pH 6.8).

[0060] Experimental Groups: Blank control group (A0): PBS buffer + tyrosinase solution + L-DOPA.

[0061] Raw material sample group (A1): 6% aqueous solution of each lyophilized powder prepared in Examples 1-6 (pH adjusted to 6.8) + enzyme solution + substrate.

[0062] Sample background group (A2): 6% aqueous solution of each lyophilized powder prepared in Examples 1-6 + buffer solution (to counteract sample color interference).

[0063] Operating steps: Add PBS buffer and the sample solution to be tested to a 96-well plate.

[0064] Add tyrosinase solution and preheat at 37°C for 10 minutes.

[0065] Quickly add L-DOPA solution to initiate the reaction.

[0066] Incubate at 37°C for 30 minutes. Measure the absorbance at 475 nm using a microplate reader.

[0067] Calculation formula: Inhibition rate % = [1 - (A1 - A2) / A0] × 100% The results are shown in Table 2.

[0068] (2) Inflammatory factor inhibition test (cell model method) Objective: To demonstrate that the formulation can relieve inflammation caused by acid irritation, exhibiting a soothing effect.

[0069] Cell line: Human immortalized keratinocytes (HaCaT).

[0070] Inducing agent: 0.2% compound acid stimulating solution (composed of glycolic acid, lactic acid and salicylic acid in a mass ratio of 1.2:1.2:1.5).

[0071] Test substances: the lyophilized powders prepared in Examples 1-6. Experimental Groups: Blank control group: Cells were cultured using only serum-free culture medium.

[0072] Acid-induced group (positive control): Cells were treated with 0.2% compound acid stimulation solution.

[0073] Fermentation powder protection group (test group): First, add culture medium containing 1% concentration of lyophilized fermentation substrate powder for pre-incubation for 4 hours, and then add 0.2% compound acid stimulation solution for treatment.

[0074] Operating steps: Cell seeding: HaCaT cells were seeded into 24-well plates, approximately 1 × 10⁶ cells per well. 5 Cells were cultured until 80% confluence.

[0075] Pretreatment: Remove the old culture medium, add the corresponding pretreatment culture medium to the test group and the control group respectively, and incubate at 37°C for 4 hours.

[0076] Inflammation induction: Except for the blank control group, 0.2% compound acid stimulation solution was added to each well to simulate the chemical stress caused by acid brushing.

[0077] Sample collection: After culturing for another 24 hours, collect the supernatant from each well and centrifuge at 3000 rpm for 10 minutes at 4°C.

[0078] ELISA assay: The concentration of inflammatory factors in the supernatant was determined using a double-antibody sandwich method with a Human TNF-α and IL-6 ELISA kit.

[0079] The results are shown in Table 3.

[0080] (3) T 50 T 80 Parametric method Objective: To characterize sustained-release performance by the time required to reach 50% or 80% of the cumulative maximum permeation.

[0081] 1. Pre-experiment preparation: Experimental equipment: Franz diffusion cell (vertical type), constant temperature water bath circulation system, HPLC (high performance liquid chromatography).

[0082] Test group (Examples): Each preparation of Example 7.

[0083] 2. Experimental operation steps First step: Establish a standard curve. Use HPLC to measure the standard concentration curve of hydroxytyrosol to ensure accurate conversion of the solute mass in the receiving solution.

[0084] Second step: Assemble the Franz diffusion cell. Fix the processed ex vivo skin in the diffusion cell, and the effective diffusion area is 1.5 cm².

[0085] Inject the degassed receiving solution (PBS buffer containing 20% ethanol) into the receiving cell and start magnetic stirring.

[0086] Set the water bath temperature to 32 °C and equilibrate for 30 minutes.

[0087] Third step: Sample addition and timed sampling. Add a precise weight (0.5 g) of the preparation to the supply cell.

[0088] Set the sampling time points: 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h.

[0089] Immediately replenish the same volume and same temperature of fresh receiving solution after each sampling.

[0090] Fourth step: Calculate the cumulative permeation amount (Q n ) Measure the concentration C of the receiving solution at each time point by HPLC n , and calculate the cumulative permeation amount per unit area: ; where V is the volume of the receiving cell, and V i is the sampling volume.

[0091] 3. Extraction and calculation of the values of T 50 and T 80 Determine the end point: Take the cumulative permeation amount at 24 hours as 100%. Find the interval: Find two adjacent time points before and after the cumulative permeation percentage is between 50% and 80% in the data table.

[0092] Calculate by linear interpolation method: If the permeation percentage at time point t1 is P1, the permeation percentage at time t2 is P2, and P1 < 50% < P2, then: ; ; The calculation method of T80 is the same.

[0094] The results are shown in Table 4.

[0095] Table 2

[0096] Table 3

[0097] Table 4

[0098] The indicator component in Table 4 is hydroxytyrosol.

[0099] The results in Tables 2, 3, and 4 show: Comparison of freeze-dried powders with different processes and substrate compositions reveals that the fermentation process and dual-substrate combination described in this invention exhibit significant advantages in bioactivity. The tyrosinase inhibition rates of Examples 1 and 2 are not only far higher than those of Example 6 (without fermentation), but also significantly better than those of Examples 3 and 4 (fermented with a single substrate). This demonstrates that *Aspergillus oryzae*, during the co-fermentation of olive leaves and turmeric substrates, produces secondary metabolites with higher melanin-inhibiting activity (such as hydroxytyrosol and tetrahydrocurcumin) through directed biotransformation, and that there is a clear synergistic effect between the two substrates. Furthermore, Example 1 outperforms Example 5 (without ultrafiltration), further confirming the crucial contribution of ultrafiltration in removing macromolecular impurities and concentrating core active ingredients to enhancing the final whitening efficacy of the product.

[0100] In the acid-irritated HaCaT cell model, the experimental results clearly outlined the technical logic of this invention in ensuring the safety of high-concentration acid preparations. Examples 1 and 2, as test groups, showed significantly stronger inhibitory effects on TNF-α and IL-6 than the unfermented raw material group (Example 6) and the single substrate group (Examples 3 and 4), indicating that the co-fermentation product has stronger anti-inflammatory and cytoprotective effects at the biological level, and can antagonize the chemical stress caused by complex acids from the source. Furthermore, Example 1 showed a better downregulation rate of pro-inflammatory factors than the unrefined Example 5, indicating that the ultrafiltration process effectively removed potentially irritating metabolic byproducts from the fermented raw materials, significantly reducing the potential irritation of the preparation to skin cells, and achieving a deep balance between exfoliating efficacy and gentle performance.

[0101] The results of transdermal diffusion experiments kinetically confirmed the controlled-release value of the thermosensitive phase change system of this invention. Groups containing poloxamer 407 (numbers 1, 2, and 3) showed [results] at T [temperature]. 50 With T 80All parameters showed an overwhelming advantage over the poloxamer-free group (number 4), with a significantly prolonged penetration time, successfully achieving the transition from "instantaneous release" to "controlled sustained release." This proves that the temperature-sensitive matrix described in the claims does indeed construct a robust physical gel network at 32°C, providing effective diffusion resistance for the active ingredient. Comparison with numbers 1 and 2 also reveals that the sustained-release effect increases with increasing matrix concentration, demonstrating the controllability of the penetration rate in this invention. The rapid penetration in number 4 due to the lack of a gel shield explains why common acid preparations are more prone to inducing barrier damage.

[0102] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A controlled-release acid formulation, characterized by comprising: Calculated by parts by weight, it includes the following components: Aspergillus oryzae fermentation substrate freeze-dried powder 3.0-6.0 Complex α-hydroxy acid 3.0-5.0 Salicylic acid 1.5-2.0 Polosham 407 15-25 Polyols 10-20 Nonionic surfactant 1.5-3.0 The substrate of the freeze-dried Aspergillus oryzae fermentation substrate powder is composed of olive leaves and turmeric in a mass ratio of 2:1 to 6:

1.

2. The controlled release acid formulation according to claim 1, wherein The composite α-hydroxy acid is composed of glycolic acid, lactic acid, and citric acid in a mass ratio of (2-3):(2-3):

1.

3. The controlled release acid formulation according to claim 1, wherein It also includes basic amino acids, used to adjust the pH of the controlled-release acid preparation to 3.8-4.

5.

4. The controlled release acid formulation according to claim 1, wherein The product, by weight, also includes at least 0.05 parts of a soothing component, which is bisabolol and / or asiaticoside.

5. The controlled release acid formulation according to claim 1, wherein The preparation method of the freeze-dried Aspergillus oryzae fermentation substrate powder includes the following steps: S1: Mix dried olive leaves and turmeric in a mass ratio of 2:1 to 6:1, crush them, add 1.5-2.0 times the weight of the substrate with water to soak them; and adjust the initial pH value to 5.5-6.5 to obtain the fermentation substrate, and sterilize it; S2: Inoculate with Aspergillus oryzae at a rate of at least 5% v / w, and carry out aerobic fermentation for at least 72 hours at a temperature of 28-30℃ and a humidity of 80%-90%. Fermentation is considered complete when the pH value of the fermentation system decreases by more than 1.2 units, and the fermented cooked material is obtained. S3: After inactivating the fermented cooked material, extract it with ethanol solution, collect the extract, filter it with an ultrafiltration membrane, and collect the permeate; S4: Add excipients to the permeate and freeze-dry under vacuum to obtain the freeze-dried powder of the fermentation substrate.

6. The modified-release acid formulation according to claim 5, wherein In step S1, the fermentation substrate, calculated based on the total mass of olive leaves and turmeric, also contains the following components: Carbon source, at least 0.5%. Nitrogen source, at least 0.3%. Potassium dihydrogen phosphate, at least 0.1%. Magnesium sulfate, at least 0.05%.

7. The modified-release acid formulation according to claim 5, wherein In step S3, the method for ethanol solution extraction is as follows: using an ethanol solution with a volume fraction of 30%-50% as a solvent, ultrasonically extracting twice at 45-55℃, each time for at least 30 minutes; after centrifuging to remove residue, the extract is filtered through a microfiltration membrane and then filtered through an ultrafiltration membrane.

8. The controlled release acid formulation according to claim 5, wherein In step S4, the vacuum freeze-drying includes: Pre-freezing: Cool to a maximum of -40°C and maintain for at least 4 hours; Sublimation drying: Vacuum degree 10-20 Pa, heat to the maximum -5℃, and maintain for at least 18 hours; Drying: Heat to a maximum of 35°C and maintain for at least 6 hours.

9. Process for the preparation of a modified-release acid formulation according to any one of claims 1 to 8, characterized in that, Includes the following steps: S1: Mix polyol with water, add composite α-hydroxy acid and salicylic acid in sequence, stir at 40-50℃ until completely dissolved to obtain acid matrix solution; S2: Cool the acid matrix solution to ≤10℃, add poloxamer 407 and nonionic surfactant, and let it stand at 4-8℃ to swell until a liquid matrix is ​​formed; S3: Maintain the system temperature ≤15℃, add the remaining components except for the basic amino acids to the liquid matrix and stir until reconstituted; then adjust the pH value to 3.8-4.5 to obtain the controlled-release acid preparation.

10. A modified-release acid formulation according to any one of claims 1 to 8, characterised in that, The controlled-release acid formulation has temperature-sensitive phase change characteristics, and it is a flowing liquid at 20-25℃ and a non-flowing gel at 32-35℃.

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