Sustained-release composition containing azelaic acid composite liposome and application of sustained-release composition in acne treatment and skin repair

Abstract

The invention relates to the technical field of skin care, and discloses a sustained-release composition containing azelaic acid composite lipidosome and application of the sustained-release composition in acne treatment and skin repair. Comprising a composite liposome, an encapsulated active component and a dispersion medium, the composite liposome is composed of a lipid bilayer, the lipid bilayer comprises phospholipid, cholesterol and pegylated phospholipid, and the phospholipid is a mixture of hydrogenated soybean phospholipid and dipalmitoyl phosphatidylcholine; the encapsulated active component comprises a fat-soluble component and a water-soluble component; the water-soluble components comprise a hamamelis virginiana leaf water extract and a herba portulacae extract; the dispersion medium is a phosphate buffer solution; by optimizing lipid composition, introducing surface modification and constructing a multi-layer release system, the invention aims to synergistically exert multiple effects of antibiosis, anti-inflammation, cutin regulation, red fading, repair and the like, and provides an efficient, mild and integrated solution for acne and sequelae skin problems thereof.

Description

Technical Field

[0001] This invention relates to the field of skincare technology, specifically to a sustained-release composition containing azelaic acid complex liposomes and its application in acne treatment and skin repair. Background Technology

[0002] Acne is a common chronic inflammatory disease of the pilosebaceous unit, characterized by comedones, papules, and pustules. After the remission period, persistent erythema or post-inflammatory hyperpigmentation often remains. Severe cases can even develop atrophic or hypertrophic scars, significantly impacting the patient's appearance and mental well-being.

[0003] Azelaic acid, a natural straight-chain saturated dicarboxylic acid, has been widely recognized in dermatology for its multiple therapeutic effects, including significantly inhibiting the proliferation of Propionibacterium acnes, regulating abnormal differentiation of keratinocytes, reducing perifollicular inflammation, and competitively inhibiting tyrosinase activity. These effects demonstrate clear therapeutic efficacy for both active acne and post-inflammatory hyperpigmentation. However, azelaic acid has extremely low solubility in aqueous media, limiting its bioavailability in water-based topical formulations. Furthermore, its topical application often causes adverse reactions such as stinging, itching, and scaling, leading to decreased patient tolerance and treatment adherence.

[0004] In the field of functional skincare, witch hazel leaf water, with its astringent and anti-inflammatory properties, purslane extract, with its soothing and repairing effects, and tea tree oil, with its broad-spectrum antibacterial activity, are all commonly used active ingredients in the adjunctive treatment of acne. However, these ingredients differ significantly in their physicochemical properties, covering different polarities from water-soluble to oil-soluble. Achieving efficient co-loading and stable delivery of multiple active ingredients, and on this basis, exerting a synergistic therapeutic effect, is currently a key technological bottleneck in formulation development.

[0005] Liposomes, as an advanced carrier system with a bilayer phospholipid structure, can simultaneously encapsulate both hydrophilic and lipophilic active substances, effectively improving the stability and transdermal permeability of ingredients, and reducing skin irritation through sustained-release action. However, to date, there are no publicly available research reports on the synergistic therapeutic and repair effects of azelaic acid, witch hazel leaf water, purslane extract, and tea tree oil integrated into a composite liposome carrier, and on their synergistic therapeutic and repair effects on acne and post-acne skin problems.

[0006] Based on this, the present invention provides a sustained-release composition containing azelaic acid complex liposomes. Summary of the Invention

[0007] To address the problems in the prior art, the present invention provides a sustained-release composition containing azelaic acid complex liposomes. This composition can efficiently co-load multiple active ingredients with complementary effects, solving the problems of poor transdermal permeability, high local irritation, and difficulty in synergistic delivery of multiple components of azelaic acid.

[0008] The technical solution adopted by this invention to solve its technical problem is: A sustained-release composition containing azelaic acid complex liposomes includes complex liposomes, encapsulated active ingredients, and a dispersion medium; The composite liposomes account for 20-30% of the total weight of the composition; The composite liposome is composed of a lipid bilayer comprising phospholipids, cholesterol, and polyethylene glycol-modified phospholipids. The phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of (2:1) to (4:1); the molar ratio of cholesterol to total phospholipids is (0.2:1) to (0.4:1); and the polyethylene glycol-modified phospholipids are DSPE-PEG2000, accounting for 2%-6% of the total phospholipids. The encapsulated active ingredients include fat-soluble and water-soluble components. The fat-soluble components include azelaic acid and tea tree oil, with azelaic acid accounting for 5%-15% of the dry weight of the composition and tea tree oil accounting for 0.5%-3% of the dry weight of the composition. The water-soluble components include American witch hazel leaf water extract and purslane extract. The American witch hazel leaf water extract accounts for 15%-35% of the total aqueous phase volume, and the purslane extract has a concentration of 0.3%-1.5% in the total aqueous phase. The dispersion medium is a phosphate buffer solution with a pH of 5.0-6.5, and the dispersion medium accounts for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

[0009] As a further technical solution, the "thin-film hydration-high-pressure homogenization combined method" is adopted, including the following steps: (1) Lipid film formation: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and antioxidants are dissolved in an organic solvent and a uniform lipid film is formed by rotary evaporation. The antioxidant is ascorbic acid, and the amount added is 0.1-0.3% of the total mass of the composition. The mass ratio of the dissolved substance to the organic solvent methanol is 1:1.5; (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water, and purslane extract were mixed, heated to 45-65℃, and pre-dispersed evenly; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) is hydrated using the preheated aqueous phase in step (2) at 45-65℃ under nitrogen protection to obtain a multilayer liposome crude suspension. (4) Particle size uniformity: The coarse suspension obtained in step (3) is circulated 3-5 times under a pressure of 400-800 bar by a high-pressure homogenizer, or extruded 3-5 times through a polycarbonate membrane with a pore size of 100 nm to obtain a composite liposome suspension with uniform particle size and stable structure. (5) Purification and formulation: Unencapsulated free drugs and impurities are removed by dialysis filtration through a 0.22μm sterile filter membrane, preservatives are added, pH is adjusted to 5.0-6.5, and the product is obtained after sterile filtration.

[0010] As a further technical solution, the organic solvent in step (1) is one or a mixture of chloroform, methanol or ethanol.

[0011] As a further technical solution, the hydration in step (3) is as follows: add an isothermal and equal volume of phosphate buffer hydration medium, and then rotate at low speed to completely peel off and swell the lipid membrane from the bottle wall; The low-speed rotation speed is 75 r / min.

[0012] As a further technical solution, the preservative in step (5) is phenoxyethanol, and the amount of preservative added is 0.3-0.5% of the total mass of the composition.

[0013] Application of azelaic acid-containing complex liposome sustained-release composition in the preparation of topical formulations for the treatment of acne and skin repair.

[0014] As a further technical solution, the topical preparation includes creams, serums, gels, or masks.

[0015] As a further technical solution, the cream is composed of an oil phase, an aqueous phase, and the azelaic acid-containing complex liposome sustained-release composition, wherein the components are in parts by weight as follows: Oil phase: 20 parts of C14-22 alcohol, 20 parts of C12-20 alkyl glucoside, 10 parts of isononyl isononanoate, 25 parts of shea butter, 25 parts of jojoba seed oil, 10 parts of sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts of hydrogenated polyisobutylene, and 30 parts of polydimethylsiloxane. Aqueous phase: 20 parts butylene glycol, 10 parts glycerin, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol, and 30-60 parts water. 20-50 parts of azelaic acid complex liposome sustained-release composition; 30-50 parts water.

[0016] As a further technical solution, the preparation method of the cream is as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane are heated and melted at a temperature of 85-88℃ for 10-12 minutes to obtain the oil phase; S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at a speed of 100-120 rpm and homogenized for 10 min. Then, it is kept warm and stirred for 30 min, and then cooled and stirred for 60 min until it condenses to obtain the cream.

[0017] The composite liposomes have an average particle size of 100-200 nm, a polydispersity index (PDI) of less than 0.25, an absolute value of zeta potential greater than 25 mV, a total encapsulation efficiency of azelaic acid greater than 80%, an encapsulation efficiency of water-soluble active ingredients greater than 70%, and in in vitro transdermal experiments, they can maintain a stable azelaic acid release rate for 48 hours, with a significantly higher cumulative skin penetration than ordinary azelaic acid cream.

[0018] The beneficial effects of this invention are: 1. Highly efficient co-loading and synergistic effect: Through the complex liposome structure, four major functional ingredients with different polarities, namely azelaic acid, witch hazel, purslane and tea tree oil, are successfully integrated into the same system, realizing multi-target synergistic treatment of "antibacterial-anti-inflammatory-keratin regulation-redness reduction-repair", which has a comprehensive improvement effect on acne and its sequelae.

[0019] 2. Significantly reduces irritation and improves tolerability: The encapsulation and sustained-release effect of liposomes on azelaic acid avoids instantaneous contact of high-concentration drugs with the skin, effectively reducing adverse reactions such as burning and stinging, and improving patient compliance. At the same time, the addition of anti-inflammatory and soothing ingredients further neutralizes potential irritation.

[0020] 3. Enhanced transdermal delivery and bioavailability: Nanoscale liposomes can promote the penetration of active ingredients into the stratum corneum of the skin, especially through the hair follicle pathway, to the pilosebaceous unit of acne lesions, thereby achieving a higher effective concentration locally and improving efficacy.

[0021] 4. Good stability and flexible application: The obtained composite liposome suspension has excellent chemical and physical stability. It can be used directly as a serum or added as a highly effective active ingredient to various skin care formulations such as gels, lotions, and masks. It has broad application prospects. Attached Figure Description

[0022] Figure 1 For high-precision 3D facial images; Figure 2 The image shows the appearance of the composite liposomes prepared in Example 2; Figure 3 The image shows a transmission electron microscope (TEM) image of the composite liposomes prepared in Example 2. Detailed Implementation

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0024] This invention provides a sustained-release composition containing azelaic acid complex liposomes, as well as a method for preparing the composition and its application in the preparation of topical formulations for treating acne and repairing skin. The composition can efficiently co-load multiple complementary active ingredients, solving the problems of poor transdermal permeability, high local irritation, and difficulty in synergistic delivery of multiple components of azelaic acid. The preparation method is stable and suitable for large-scale production, and can effectively control the particle size, encapsulation efficiency, and stability of liposomes.

[0025] The azelaic acid-containing complex liposome sustained-release composition of the present invention includes complex liposomes, encapsulated active ingredients, and a dispersion medium.

[0026] In this invention, the composite liposomes account for 20-30% of the total weight of the composition, preferably 25%. The composite liposomes are composed of a lipid bilayer comprising phospholipids, cholesterol, and polyethylene glycol-modified phospholipids. The phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of 2-4:1, preferably 3:1. The molar ratio of cholesterol to total phospholipids is 0.2-0.4:1, preferably 0.3:1. The polyethylene glycol-modified phospholipids are DSPE-PEG2000, accounting for 2%-6% of the total phospholipids, preferably 4%.

[0027] In this invention, the encapsulated active ingredients include fat-soluble and water-soluble components. The fat-soluble components include azelaic acid and tea tree oil, with azelaic acid accounting for 5%-15% of the dry weight of the composition, preferably 10%, and tea tree oil accounting for 0.5%-3% of the dry weight of the composition, preferably 1.5%. The water-soluble components include witch hazel leaf water extract and purslane extract, with the witch hazel leaf water extract accounting for 15%-35% of the total aqueous phase volume, preferably 25%, and the purslane extract having a concentration of 0.3%-1.5% in the total aqueous phase, preferably 0.9%.

[0028] In this invention, the dispersion medium is a phosphate buffer solution with a pH of 5.0-6.5, preferably a phosphate buffer solution with a pH of 5.8, and the dispersion medium accounts for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

[0029] This invention also provides a method for preparing the above-mentioned azelaic acid-containing composite liposome sustained-release composition, which employs a "film hydration-high pressure homogenization combined method" and includes the following steps: (1) Formation of lipid film: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and antioxidants are dissolved in an organic solvent and a uniform lipid film is formed by rotary evaporation. The antioxidant is ascorbic acid, and the amount added is 0.1-0.3% of the total mass of the composition, preferably 0.2% of the total mass of the composition. The mass ratio of the dissolved substance to the organic solvent methanol is 1:1.5. (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water and purslane extract are mixed, heated to 45-65℃ and pre-dispersed evenly, preferably heated to 55℃; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) is hydrated using the preheated aqueous phase in step (2) at 45-65℃ under nitrogen protection to obtain a multilayer liposome crude suspension. The preferred hydration temperature is 55℃. (4) Particle size uniformity: The coarse suspension obtained in step (3) is circulated 3-5 times under a pressure of 400-800 bar by a high-pressure homogenizer, or extruded 3-5 times through a polycarbonate membrane with a pore size of 100 nm to obtain a composite liposome suspension with uniform particle size and stable structure. Preferably, it is circulated 4 times under a pressure of 600 bar by a high-pressure homogenizer. (5) Purification and formulation: Unencapsulated free drugs and impurities are removed by dialysis filtration through a 0.22μm sterile filter membrane, preservatives are added, pH is adjusted to 5.0-6.5, and sterile filtration is performed to obtain the product. It is preferred to adjust the pH to 5.8.

[0030] In this invention, the organic solvent in step (1) is one or more of chloroform, methanol or ethanol, preferably methanol.

[0031] In this invention, hydration in step (3) is as follows: adding an isothermal and equal-volume phosphate buffer hydration medium, and then rotating at low speed to completely peel off and swell the lipid membrane from the bottle wall; the rotation speed is 75 r / min.

[0032] In this invention, the preservative in step (5) is phenoxyethanol, and the amount of preservative added is 0.3-0.5% of the total mass of the composition, preferably 0.4% of the total mass of the composition.

[0033] This invention also provides the application of the above-mentioned azelaic acid-containing complex liposome sustained-release composition in the preparation of topical formulations for treating acne and repairing skin. The topical formulations include creams, serums, gels, or masks, preferably creams.

[0034] In this invention, the cream is composed of an oil phase, an aqueous phase, and the azelaic acid-containing complex liposome sustained-release composition. The components, by weight, are as follows: the oil phase consists of 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / acryloyldimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, and 30 parts polydimethylsiloxane; the aqueous phase consists of 20 parts butylene glycol, 10 parts glycerin, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, and 10 parts bisabolol; the azelaic acid-containing complex liposome sustained-release composition consists of 20-50 parts; and water consists of 30-60 parts.

[0035] In this invention, the preparation method of the cream is as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane are heated and melted at a temperature of 85-88℃ for 10-12 min to obtain the oil phase. The preferred heating temperature is 86℃ and the heating time is 11 min. S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at a speed of 100-120 rpm, homogenized for 10 min, then kept warm and stirred for 30 min, and then cooled and stirred for 60 min until condensation, thus obtaining the cream. The preferred stirring speed is 110 rpm.

[0036] The azelaic acid-containing liposome sustained-release composition provided by this invention simultaneously encapsulates water-soluble and lipid-soluble active ingredients through liposomes, achieving multi-component synergistic delivery of azelaic acid, witch hazel leaf water, purslane extract, and tea tree oil. This composition can simultaneously treat active acne, reduce post-acne erythema and pigmentation, and promote the recovery of skin barrier function. The preparation method is stable and suitable for large-scale production, effectively controlling the particle size, encapsulation rate, and stability of the liposomes. When applied to topical formulations, the resulting products are mild, low in irritation, and have good improvement effects on acne and post-acne skin problems.

[0037] To further illustrate the present invention, the following detailed description is provided through the embodiments. The raw materials used in the present invention are all commercially available conventional raw materials, and there are no special restrictions.

[0038] Example 1: Step 1: Preparation of azelaic acid-containing complex liposome sustained-release composition: 1.1 Prepare the raw materials according to the following proportions: the complex liposomes account for 20% of the total weight of the composition; the phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of 2:1; the molar ratio of cholesterol to total phospholipids is 0.2:1; DSPE-PEG2000 accounts for 2% of the total phospholipids; azelaic acid accounts for 5% of the dry weight of the composition; tea tree oil accounts for 0.5% of the dry weight of the composition; witch hazel leaf water extract accounts for 15% of the total aqueous phase volume; purslane extract has a concentration of 0.3% in the total aqueous phase; the dispersion medium is phosphate buffer with a pH of 5.0, accounting for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

[0039] 1.2 The composition was prepared using a combined thin-film hydration-high-pressure homogenization method, specifically as follows: (1) Formation of lipid film: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and ascorbic acid are dissolved in methanol. The amount of ascorbic acid added is 0.1% of the total mass of the composition. The mass ratio of the dissolved substance to methanol is 1:1.5. A uniform lipid film is formed by rotary evaporation. (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water, and purslane extract were mixed, heated to 45°C, and pre-dispersed evenly; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) was hydrated using the preheated aqueous phase in step (2) at 45°C under nitrogen protection. An isothermal and equal volume of phosphate buffer hydration medium was added, and then the lipid film was completely peeled off and swollen from the bottle wall by rotating at a low speed of 75 r / min to obtain a multilayer liposome crude suspension. (4) Particle size uniformity: The coarse suspension obtained in step (3) is circulated three times under a pressure of 400 bar by a high-pressure homogenizer to obtain a composite liposome suspension with uniform particle size and stable structure. (5) Purification and formulation: Unencapsulated free drugs and impurities were removed by dialysis filtration through a 0.22μm sterile filter membrane. Phenoxyethanol was added at a rate of 0.3% of the total mass of the composition. The pH was adjusted to 5.0. After sterile filtration, a sustained-release composition containing azelaic acid complex liposomes was obtained.

[0040] Step 2: Prepare a cream for treating acne and repairing skin. 2.1 Prepare raw materials according to the following parts by weight: Oil phase: 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, 30 parts polydimethylsiloxane; Aqueous phase: 20 parts butanediol, 10 parts glycerol, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol; 20 parts azelaic acid-containing complex liposome sustained-release composition; 60 parts water.

[0041] 2.2 The cream was prepared using an emulsification molding method, specifically as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane were heated and melted at 85°C for 10 min to obtain the oil phase. S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at 100 rpm for 10 minutes, followed by stirring at a constant temperature for 30 minutes, and then stirring at a lower temperature for 60 minutes until condensation, thus obtaining a cream for treating acne and repairing skin.

[0042] Example 2: Step 1: Preparation of azelaic acid-containing complex liposome sustained-release composition: 1.1 Prepare the raw materials according to the following proportions: the complex liposomes account for 25% of the total weight of the composition; the phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of 3:1; the molar ratio of cholesterol to total phospholipids is 0.3:1; DSPE-PEG2000 accounts for 4% of the total phospholipids; azelaic acid accounts for 10% of the dry weight of the composition; tea tree oil accounts for 1.5% of the dry weight of the composition; North American witch hazel leaf water extract accounts for 25% of the total aqueous phase volume; purslane extract has a concentration of 0.9% in the total aqueous phase; the dispersion medium is phosphate buffer with a pH of 5.8, accounting for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

[0043] 1.2 The composition was prepared using a combined thin-film hydration-high-pressure homogenization method, specifically as follows: (1) Formation of lipid film: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and ascorbic acid are dissolved in methanol. The amount of ascorbic acid added is 0.2% of the total mass of the composition. The mass ratio of the dissolved substance to methanol is 1:1.5. A uniform lipid film is formed by rotary evaporation. (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water, and purslane extract were mixed, heated to 55°C, and pre-dispersed evenly; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) was hydrated using the preheated aqueous phase in step (2) at 55°C under nitrogen protection. An isothermal and equal volume of phosphate buffer hydration medium was added, and then the lipid film was completely peeled off and swollen from the bottle wall by rotating at a low speed of 75 r / min to obtain a multilayer liposome crude suspension. (4) Particle size uniformity: The coarse suspension obtained in step (3) is circulated 4 times under 600 bar pressure by a high pressure homogenizer to obtain a composite liposome suspension with uniform particle size and stable structure. (5) Purification and formulation: Unencapsulated free drugs and impurities were removed by dialysis filtration through a 0.22μm sterile filter membrane. Phenoxyethanol was added at a rate of 0.4% of the total mass of the composition. The pH was adjusted to 5.8. After sterile filtration, a sustained-release composition containing azelaic acid complex liposomes was obtained.

[0044] Step 2: Prepare a cream for treating acne and repairing skin. 2.1 Prepare raw materials according to the following parts by weight: Oil phase: 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, 30 parts polydimethylsiloxane; Aqueous phase: 20 parts butanediol, 10 parts glycerol, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol; 30 parts azelaic acid-containing complex liposome sustained-release composition; 50 parts water.

[0045] 2.2 The cream was prepared using an emulsification molding method, specifically as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane were heated and melted at 86℃ for 11 min to obtain the oil phase. S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at 110 rpm for 10 minutes, followed by stirring at a constant temperature for 30 minutes, and then stirring at a lower temperature for 60 minutes until condensation, thus obtaining a cream for treating acne and repairing skin.

[0046] Example 3: Step 1: Preparation of azelaic acid-containing complex liposome sustained-release composition: 1.1 Prepare the raw materials according to the following proportions: the complex liposomes account for 30% of the total weight of the composition; the phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of 4:1; the molar ratio of cholesterol to total phospholipids is 0.4:1; DSPE-PEG2000 accounts for 6% of the total phospholipids; azelaic acid accounts for 15% of the dry weight of the composition; tea tree oil accounts for 3% of the dry weight of the composition; witch hazel leaf water extract accounts for 35% of the total aqueous phase volume; purslane extract has a concentration of 1.5% in the total aqueous phase; the dispersion medium is phosphate buffer with a pH of 6.5, accounting for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

[0047] 1.2 The composition was prepared using a combined thin-film hydration-high-pressure homogenization method, specifically as follows: (1) Formation of lipid film: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and ascorbic acid are dissolved in methanol. The amount of ascorbic acid added is 0.3% of the total mass of the composition. The mass ratio of the dissolved substance to methanol is 1:1.5. A uniform lipid film is formed by rotary evaporation. (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water, and purslane extract were mixed, heated to 65°C, and pre-dispersed evenly; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) was hydrated using the preheated aqueous phase in step (2) at 65°C under nitrogen protection. An isothermal and equal volume of phosphate buffer hydration medium was added, and then the lipid film was completely peeled off and swollen from the bottle wall by rotating at a low speed of 75 r / min to obtain a multilayer liposome crude suspension. (4) Particle size uniformity: The crude suspension obtained in step (3) is circulated 5 times under 800 bar pressure by a high pressure homogenizer to obtain a composite liposome suspension with uniform particle size and stable structure. (5) Purification and formulation: Unencapsulated free drugs and impurities were removed by dialysis filtration through a 0.22μm sterile filter membrane. Phenoxyethanol was added at a rate of 0.5% of the total mass of the composition. The pH was adjusted to 6.5. After sterile filtration, a sustained-release composition containing azelaic acid complex liposomes was obtained.

[0048] Step 2: Prepare a cream for treating acne and repairing skin. 2.1 Prepare raw materials according to the following parts by weight: Oil phase: 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, 30 parts polydimethylsiloxane; Aqueous phase: 20 parts butanediol, 10 parts glycerol, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol; 50 parts azelaic acid-containing complex liposome sustained-release composition; 30 parts water.

[0049] 2.2 The cream was prepared using an emulsification molding method, specifically as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane were heated and melted at 88°C for 12 min to obtain the oil phase. S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at 120 rpm for 10 minutes, followed by stirring at a constant temperature for 30 minutes, and then stirring at a lower temperature for 60 minutes until condensation, thus obtaining a cream for treating acne and repairing skin.

[0050] Comparative Example 1: Step 1: Prepare the raw materials: Prepare the raw materials according to the following parts by weight: Oil phase: 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, 30 parts polydimethylsiloxane; Aqueous phase: 20 parts butylene glycol, 10 parts glycerin, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol; 20 parts azelaic acid, 10 parts tea tree oil; 50 parts water.

[0051] Step 2: Prepare acne cream: The cream was prepared using an emulsification molding method, specifically as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane were heated and melted at 86℃ for 11 min to obtain the oil phase. S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, azelaic acid, and tea tree oil were added to water and stirred until homogeneous to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at a speed of 110 rpm and homogenized for 10 min. Then, it is kept warm and stirred for 30 min, and then cooled and stirred for 60 min until it condenses to obtain the acne cream.

[0052] The efficacy of the azelaic acid complex liposome sustained-release composition and cream prepared in Example 2 of this invention was determined: Using the Antera 3D skin imaging system from the Netherlands, a 28-day clinical observation trial was conducted to systematically evaluate and compare the effects of the formulation in Example 2 and the formulation in Comparative Example 1 on the improvement of acne lesions. The trial included 15 acne volunteers who met the inclusion criteria, employing a randomized, double-blind, self-controlled or group-controlled design. Throughout the trial period, at four pre-set key time points—days 0, 9, 18, and 27—high-precision three-dimensional images of fixed target areas on the volunteers' faces were acquired using the Antera 3D imaging system under strictly controlled standardized environmental and lighting conditions. The device, through multispectral imaging technology, can quantitatively analyze multiple biological parameters, including the volume of inflammatory papules, the depth of pustules, the size of pores, and skin surface texture and erythema index, thereby achieving objective and quantitative tracking of acne severity and its evolution. This trial aims to scientifically analyze the differences and dynamic characteristics of the two formulations in inhibiting inflammation, promoting lesion regression, and improving overall skin appearance using these precise time-series data.

[0053] like Figure 1 The results showed that the formulation of Example 2 was significantly superior to that of Comparative Example 1 in improving post-acne erythema. Quantitative data from the Antera 3D imaging system showed that by day 27, the erythema index in the target area of ​​Example 2 decreased significantly from baseline compared to the initial state (43% in Example 2, 27% in Comparative Example 1), and the difference was statistically significant from day 9 onwards (p<0.05). Furthermore, it was confirmed that Example 2 could more effectively reduce subcutaneous inflammation-related heme accumulation, accelerate the fading of red marks, and leave no obvious papular marks.

[0054] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A sustained-release composition containing azelaic acid complex liposomes, characterized in that, It includes complex liposomes, encapsulated active ingredients, and dispersion media; The composite liposomes account for 20-30% of the total weight of the composition; The composite liposome is composed of a lipid bilayer, which includes phospholipids, cholesterol, and polyethylene glycol-modified phospholipids. The phospholipids are a mixture of hydrogenated soybean phospholipids and dipalmitoylphosphatidylcholine in a mass ratio of (2:1) to (4:1); the molar ratio of cholesterol to total phospholipids is (0.2:1) to (0.4:1); and the polyethylene glycol-modified phospholipids are DSPE-PEG2000, accounting for 2%-6% of the total phospholipids. The encapsulated active ingredients include fat-soluble and water-soluble components. The fat-soluble components include azelaic acid and tea tree oil, with azelaic acid accounting for 5%-15% of the dry weight of the composition and tea tree oil accounting for 0.5%-3% of the dry weight of the composition. The water-soluble components include American witch hazel leaf water extract and purslane extract, with the American witch hazel leaf water extract accounting for 15%-35% of the total aqueous phase volume and the purslane extract having a concentration of 0.3%-1.5% in the total aqueous phase; The dispersion medium is a phosphate buffer solution with a pH of 5.0-6.5, and the dispersion medium accounts for the remainder of the composition excluding the complex liposomes and the encapsulated active ingredients.

2. The method for preparing the azelaic acid-containing complex liposome sustained-release composition according to claim 1, characterized in that, The "thin-film hydration-high-pressure homogenization combined method" includes the following steps: (1) Lipid film formation: Phospholipids, cholesterol, DSPE-PEG2000, azelaic acid, tea tree oil and antioxidants are dissolved in an organic solvent and a uniform lipid film is formed by rotary evaporation. The antioxidant is ascorbic acid, and the amount added is 0.1-0.3% of the total mass of the composition. The mass ratio of the dissolved substance to the organic solvent methanol is 1:1.5; (2) Aqueous phase preparation: Phosphate buffer, glycerol, witch hazel leaf water, and purslane extract were mixed, heated to 45-65℃, and pre-dispersed evenly; (3) Hydration and preparation of primary liposomes: The lipid film formed in step (1) is hydrated using the preheated aqueous phase in step (2) at 45-65℃ under nitrogen protection to obtain a multilayer liposome crude suspension. (4) Particle size uniformity: The coarse suspension obtained in step (3) is circulated 3-5 times under a pressure of 400-800 bar by a high-pressure homogenizer, or extruded 3-5 times through a polycarbonate membrane with a pore size of 100 nm to obtain a composite liposome suspension with uniform particle size and stable structure. (5) Purification and formulation: Unencapsulated free drugs and impurities are removed by dialysis filtration through a 0.22μm sterile filter membrane, preservatives are added, pH is adjusted to 5.0-6.5, and the product is obtained after sterile filtration.

3. The method for preparing the azelaic acid-containing complex liposome sustained-release composition according to claim 2, wherein the organic solvent in step (1) is one or more of chloroform, methanol or ethanol.

4. The preparation method of the azelaic acid-containing composite liposome sustained-release composition according to claim 2, wherein the hydration in step (3) is: adding an isothermal and equal-volume phosphate buffer hydration medium, and then rotating at low speed to completely peel off and swell the lipid membrane from the bottle wall; The low-speed rotation speed is 75 r / min.

5. In the preparation method of the azelaic acid-containing composite liposome sustained-release composition according to claim 2, the preservative in step (5) is phenoxyethanol, and the amount of preservative added is 0.3-0.5% of the total mass of the composition.

6. The use of the azelaic acid-containing complex liposome sustained-release composition as described in claim 1 in the preparation of a topical formulation for treating acne and repairing skin.

7. The application according to claim 6, characterized in that, The topical preparations include creams, serums, gels, or masks.

8. The application according to claim 6, characterized in that, The cream comprises an oil phase, an aqueous phase, and the azelaic acid-containing complex liposome sustained-release composition, wherein the components are, by weight, as follows: Oil phase: 20 parts C14-22 alcohol, 20 parts C12-20 alkyl glucoside, 10 parts isononyl isononanoate, 25 parts shea butter, 25 parts jojoba seed oil, 10 parts sodium acrylate / sodium acryloyl dimethyl taurate copolymer, 25 parts hydrogenated polyisobutylene, and 30 parts polydimethylsiloxane. Aqueous phase: 20 parts butylene glycol, 10 parts glycerin, 25 parts 1,2-hexanediol, 5 parts xanthan gum, 5 parts allantoin, 20 parts trehalose, 5 parts disodium EDTA, 30 parts witch hazel leaf water, 20 parts purslane, 10 parts bisabolol, and 30-60 parts water. 20-50 parts of azelaic acid complex liposome sustained-release composition; 30-50 parts water.

9. The application according to claim 6, characterized in that, The preparation method of the cream is as follows: S1 oil phase preparation: C14-22 alcohol, C12-20 alkyl glucoside, isononyl isononanoate, shea butter, jojoba seed oil, sodium acrylate / sodium acryloyl dimethyl taurate copolymer, hydrogenated polyisobutylene, and polydimethylsiloxane are heated and melted at a temperature of 85-88℃ for 10-12 minutes to obtain the oil phase; S2 aqueous phase preparation: Butylene glycol, glycerol, 1,2-hexanediol, xanthan gum, allantoin, trehalose, disodium EDTA, witch hazel leaf water, purslane, bisabolol, and azelaic acid-containing complex liposome sustained-release composition were added to water and stirred evenly to obtain the aqueous phase; S3 Emulsification and Shaping: The oil phase is added to the aqueous phase under rapid stirring at a speed of 100-120 rpm and homogenized for 10 min. Then, it is kept warm and stirred for 30 min, and then cooled and stirred for 60 min until it condenses to obtain the cream.

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