Composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or derivative thereof and cosmetic

Abstract

The invention provides a hyaluronic acid or hyaluronic acid derivative targeted composite anti-inflammatory and anti-aging component liposome and cosmetics, and relates to the technical field of biomedical materials. The hyaluronic acid or hyaluronic acid derivative targeted composite anti-inflammatory and anti-aging component liposome is prepared from the following components in parts by weight: 0.1 to 5.0 parts of hyaluronic acid or hyaluronic acid derivative, 0.1 to 5.0 parts of pterostilbene, 0.1 to 5.0 parts of milk peptide compound, 0.05 to 2.0 parts of silymarin, 0.05 to 2.0 parts of ceramide NP, 20.0 to 60.0 parts of water, 10.0 to 40.0 parts of liquid grease, 10.0 to 40.0 parts of glycerol, 1.0 to 10.0 parts of lecithin, 0.5 to 5.0 parts of tocopheryl acetate, 1.0 to 5.0 parts of 1, 2-hexanediol and 0.1 to 2.0 parts of pH (Potential of Hydrogen) regulator. The liposome can be specifically combined with a hyaluronic acid surface receptor in skin, so that an active matter directly plays a role at an action target.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedical materials, and in particular to a hyaluronic acid or derivative thereof targeted composite anti-inflammatory and anti-aging component liposome and cosmetics. Background Art

[0002] In the field of skin care, as we age, the skin barrier will experience a characteristic decline in immunity, known as skin immunosenescence. Senescent cells secrete pro-inflammatory cytokines, promote chronic inflammation, destroy the skin microenvironment, impair the epidermal barrier function, and accelerate the aging of fibroblasts, which leads to wrinkles and loss of elasticity.

[0003] Milk peptide complexes, pterostilbene and silymarin all have excellent anti-inflammatory and antioxidant effects, but they face some limitations in practical applications. Pterostilbene has low water solubility and stability, is easy to crystallize and precipitate in oils with low polarity, and is easy to change color when in contact with air. Hyaluronic acid or sodium hyaluronate, and milk peptide complexes are all water-soluble ingredients, which are difficult to be used together with oil-soluble ingredients, and milk peptide complexes are easy to precipitate in the formula. Milk peptide complexes are all water-soluble ingredients with weak fat solubility. They are difficult to penetrate the lipid stratum corneum barrier composed of ceramides, cholesterol esters, and fatty acids. They have weak penetration ability and thus low bioavailability. However, pterostilbene and silymarin are easy to precipitate after dissolution in application scenarios due to their low water solubility and poor stability, and are easy to change color after contact with air. These characteristics make it difficult for them to be applied to actual formulas to achieve skin care effects.

[0004] The oil-soluble ingredient pterostilbene’s target for anti-inflammatory effects is usually in the active epidermis and dermis, and the percutaneous permeability of pure pterostilbene is low. If the active substance cannot act on the target site after percutaneous absorption, it cannot fully exert its effect. In addition, when encapsulating active ingredients, the existing liposome technology has problems such as poor stability caused by the increase in liposome particle size and obstructed transdermal absorption, and the ethanol introduced in the preparation process needs to be removed in the subsequent process, otherwise the residual solvent may irritate the skin and cause allergies.

[0005] In view of this, the present invention is proposed. Summary of the invention

[0006] One of the purposes of the present invention is to provide a hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging component liposome to solve at least one of the above technical problems in the prior art.

[0007] The second object of the present invention is to provide a method for preparing hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging component liposomes.

[0008] A third object of the present invention is to provide a cosmetic.

[0009] In order to achieve the above-mentioned purpose of the present invention, the following technical solutions are particularly adopted:

[0010] The first aspect of the present invention provides a hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging component liposome, which comprises, by weight:

[0011] 0.1-5.0 parts of hyaluronic acid or its derivatives, 0.1-5.0 parts of pterostilbene, 0.1-5.0 parts of milk peptide complex, 0.05-2.0 parts of silymarin, 0.05-2.0 parts of ceramide NP, 20.0-60.0 parts of water, 10.0-40.0 parts of liquid oil, 10.0-40.0 parts of glycerin, 1.0-10.0 parts of lecithin, 0.5-5.0 parts of tocopherol acetate, 1.0-5.0 parts of 1,2-hexanediol, and 0.1-2.0 parts of pH adjuster.

[0012] Furthermore, the particle size of the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives is 30 to 300 nm.

[0013] Furthermore, the hyaluronic acid or its derivative is at least one of hyaluronic acid, sodium hyaluronate and hydrolyzed sodium hyaluronate.

[0014] Furthermore, the lecithin includes at least one of soybean lecithin, hydrogenated lecithin and lysolecithin.

[0015] Preferably, the soybean lecithin has a phosphatidylcholine content of ≥80%.

[0016] Preferably, the content of hydrogenated phosphatidylcholine in the hydrogenated lecithin is ≥ 75%.

[0017] More preferably, the soybean lecithin has a phosphatidylcholine content of ≥90%.

[0018] More preferably, the content of hydrogenated phosphatidylcholine in the hydrogenated lecithin is ≥ 90%.

[0019] Furthermore, the liquid oil includes at least one of caprylic / capric triglyceride, isopropyl lauroyl sarcosinate and propylene carbonate.

[0020] Furthermore, the milk peptide complex contains lactose, whey protein and lactic acid.

[0021] The second aspect of the present invention provides a method for preparing the hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposomes, comprising the following steps:

[0022] A. Lecithin and liquid oil are first mixed uniformly to obtain a first mixture; then silymarin, ceramide NP, pterostilbene and tocopherol acetate are dissolved in the first mixture to obtain an oil phase.

[0023] B. The milk peptide complex and part of the water are mixed uniformly for a second time to obtain a second mixture, and then part of the pH regulator is added to the second mixture until it is completely dissolved, and then the remaining pH regulator is added until it is completely dissolved, and finally glycerol is added and mixed uniformly for a third time to obtain an inner water phase; hexylene glycol, hyaluronic acid or its derivatives and the remaining water are mixed uniformly for a fourth time to obtain an outer water phase.

[0024] C. Under stirring, the inner aqueous phase is added dropwise into the oil phase to hydrate the oil phase and wrap the inner aqueous phase to obtain liposome colostrum; the liposome colostrum is added dropwise into the outer aqueous phase to obtain liposome intermediate emulsion; finally, the liposome intermediate emulsion is homogenized to obtain composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives.

[0025] Furthermore, in step A, the first mixing is performed under vacuum.

[0026] Preferably, the temperature of the first mixing is 70-80° C., and the time is 20-40 min.

[0027] Preferably, the first mixing includes stirring mixing.

[0028] Preferably, the stirring and mixing speed is 300-500 rpm.

[0029] Preferably, in step A, the dissolution temperature of the silymarin and the ceramide NP is 70-80°C.

[0030] Preferably, in step A, the dissolution temperature of the pterostilbene and the tocopherol acetate is 50-60°C.

[0031] Furthermore, the mass ratio of the partial water to the remaining water in step B is 1:3.

[0032] Preferably, in step C, the inner water phase is heated to 50-60° C. and then added dropwise into the oil phase.

[0033] Preferably, the dropping speed of the inner aqueous phase is 50 to 200 mL / min.

[0034] Preferably, the dripping speed of the liposome colostrum is 10 to 60 mL / min.

[0035] Preferably, after the liposome colostrum is added dropwise, the mixture is stirred at 200 to 400 rpm for 10 to 20 minutes to obtain the liposome intermediate emulsion.

[0036] Furthermore, the homogenization pressure is 10000-20000 psi.

[0037] Preferably, the number of cycles of the homogenization is 2 to 6 times.

[0038] Preferably, the discharge temperature after homogenization is 10-30°C.

[0039] The third aspect of the present invention provides a cosmetic comprising the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives.

[0040] Compared with the prior art, the present invention has at least the following beneficial effects:

[0041] The composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives provided by the present invention are used to compositely encapsulate the active ingredients pterostilbene, milk peptide complex and silymarin by liposome technology, and the targeted delivery characteristics of hyaluronic acid or its derivatives are utilized to significantly improve the skin permeability and bioavailability of these active ingredients. Hyaluronic acid or its derivatives are physically combined with the surface of liposomes to achieve targeted delivery in the skin, so that the active ingredients can directly play a role at the target point, thereby effectively solving the problem of limited skin permeability and difficulty in transdermal absorption of active ingredients due to solubility and stability problems in the prior art, improving the transdermal retention rate of active substances, and can target the inflammation area, which can significantly improve the application effect of the active substances.

[0042] The preparation method provided by the present invention does not use organic solvents during the preparation process, thus eliminating the risk of solvent residues, improving the safety and stability of the product, enabling it to be conveniently added to various external preparations and arbitrarily matched with cosmetic formulas, thereby significantly improving the application effect of the active substance.

[0043] The cosmetics provided by the present invention, in view of the advantages of the above-mentioned hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging ingredient liposomes, enable the prepared cosmetics to enhance the anti-inflammatory and anti-aging effects, and also improve the safety, stability and transdermal absorption capacity of the product, thereby providing consumers with an anti-aging option that is efficient, safe and applicable to a wide range of people. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0045] Figure 1 A schematic diagram of the structure of the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives of the present invention;

[0046] Figure 2 This is the particle size distribution diagram of the targeted composite anti-inflammatory and anti-aging component liposomes of hydrolyzed sodium hyaluronate prepared in Example 1;

[0047] Figure 3 The appearance change diagram of the emulsion provided for Test Example 2;

[0048] Figure 4 This is a comparison chart of the skin retention data after penetration obtained in Test Example 3;

[0049] Figure 5 This is a comparison chart of the skin stratification retention after penetration obtained in Test Example 3. DETAILED DESCRIPTION

[0050] The embodiments of the present invention will be described in detail below in conjunction with the embodiments and examples, but those skilled in the art will understand that the following embodiments and examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. Based on the embodiments in the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0051] The first aspect of the present invention provides a hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging component liposome, which comprises, by weight:

[0052] 0.1-5.0 parts of hyaluronic acid or its derivatives, 0.1-5.0 parts of pterostilbene, 0.1-5.0 parts of milk peptide complex, 0.05-2.0 parts of silymarin, 0.05-2.0 parts of ceramide NP, 20.0-60.0 parts of water, 10.0-40.0 parts of liquid oil, 10.0-40.0 parts of glycerin, 1.0-10.0 parts of lecithin, 0.5-5.0 parts of tocopherol acetate, 1.0-5.0 parts of 1,2-hexanediol, and 0.1-2.0 parts of pH adjuster.

[0053] The composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives provided by the present invention are used to compositely encapsulate the active ingredients pterostilbene, milk peptide complex and silymarin by liposome technology, and the targeted delivery characteristics of hyaluronic acid or its derivatives are utilized to significantly improve the skin permeability and bioavailability of these active ingredients. Hyaluronic acid or its derivatives are physically combined with the surface of liposomes to achieve targeted delivery in the skin, so that the active ingredients can directly play a role at the target point, thereby effectively solving the problem of limited skin permeability and difficulty in transdermal absorption of active ingredients due to solubility and stability problems in the prior art, improving the transdermal retention rate of active substances, and can target the inflammation area, which can significantly improve the application effect of the active substances.

[0054] Specifically, in aging skin, the levels of inflammatory factors and chemokines in keratinocytes and fibroblasts increase, inhibiting the growth of fibroblasts and keratinocytes, causing collagen degradation, hyaluronic acid consumption, and elastin fiber denaturation. The milk peptide complex contains the natural signal molecule TGF-β, which can help mature skin regenerate and recover, promote the synthesis of type I collagen, hyaluronic acid and fibronectin, tighten the skin, enhance elasticity, and have anti-aging effects. ROS oxidative stress releases inflammatory factors, causing skin aging. Pterostilbene is a natural analogue of resveratrol that can quench harmful free radicals in the skin and has excellent antioxidant and anti-inflammatory effects. The main component of silymarin is silybin, which has multiple effects such as anti-inflammatory, anti-allergic, improving skin and delaying aging, and anti-oxidation. The present invention utilizes liposome technology to co-encapsulate the water-soluble active substance milk peptide complex and the oil-soluble active substances pterostilbene and silymarin, thereby achieving compatibility between the active substances, solving the problems of easy discoloration, crystal precipitation, and difficulty in transdermal absorption of the active substances, improving the penetration ability of the active substances in the skin, facilitating formulation application, and thus better achieving the anti-aging and anti-inflammatory effects in practical applications.

[0055] Hyaluronic acid is a naturally occurring linear polysaccharide and an important component of the extracellular matrix. It is distributed in the human epidermis, dermis and subcutaneous tissue. Sodium hyaluronate is the sodium salt form of hyaluronic acid. Hyaluronic acid derivatives also include hydrolyzed hyaluronic acid, acetylated sodium hyaluronate, silanized hyaluronic acid, etc. Hyaluronic acid and its derivatives have good non-immunogenicity, moisturizing, repairing, biodegradable and biocompatible properties. In liposomes, because the chemical structure of hyaluronic acid and its derivatives contains carboxyl, hydroxyl and acetyl groups, their hydrophobic structural regions can form complexes with phospholipids, which can be modified to the surface of nanocarriers to construct drug delivery systems, improve the biocompatibility of drugs, and give nanocarriers active targeting effects, thereby improving drug delivery efficiency. In addition, hyaluronic acid and its derivatives can bind to cell surface receptors such as CD44 / RHAMM / ICAM-1 that are associated with diseases such as inflammatory cells, tissue damage cells, and cancer cells, and can target liposomes loaded with active ingredients to sites of inflammation, tissue damage, and other sites to achieve repair, anti-inflammatory, and cell renewal metabolism effects.

[0056] Hyaluronic acid and its derivatives can specifically bind to the hyaluronic acid surface receptors of inflammatory cells, thereby achieving a targeted effect in the delivery of active substances. Based on the chemical structural characteristics of hyaluronic acid or sodium hyaluronate containing carboxyl, hydroxyl and acetyl groups, the present invention uses intermolecular forces, van der Waals forces and other mechanisms to modify anti-inflammatory and anti-aging liposomes to obtain hyaluronic acid or sodium hyaluronate targeted composite anti-inflammatory and anti-aging component liposomes, improve liposome stability, synergistically promote penetration with liposomes, and promote the active substances to play a role at inflammatory targets.

[0057] The milk peptide complex composed of lactose, whey protein and lactic acid contains the natural signal molecule TGF-β, which can help mature skin regenerate and recover, promote the synthesis of type I collagen, hyaluronic acid and fibronectin, make the skin firmer and enhance elasticity, thereby reducing obvious signs of aging.

[0058] Pterostilbene is a natural analogue of resveratrol with excellent antioxidant and anti-inflammatory effects. It can quench harmful free radicals in the skin and activate cell autophagy.

[0059] like Figure 1 As shown in the figure, pterostilbene, milk peptide complex and silymarin are encapsulated as anti-inflammatory and anti-aging active substances using liposome technology. The targets of inflammatory anti-aging are usually in the active epidermis and dermis. In order to achieve local anti-inflammatory and immune regulation of the skin, the active substance load is solved, so that the active substance can better penetrate into the epidermis and dermis to exert anti-inflammatory and anti-aging effects. Ceramide NP and phosphatidylcholine have similar structures. The molecular interaction between the two allows ceramide NP to be embedded in the phospholipid molecules, promoting the stability of the phospholipid bilayer structure of the liposome. This embedding process is like cleverly weaving ceramide NP into the delicate "net" of the phospholipid membrane, making it a part of the phospholipid membrane structure, thus laying a solid foundation for subsequent structural construction. Furthermore, hyaluronic acid and its derivatives, due to their unique chemical properties, can interact with phospholipid molecules and ceramides already embedded in the phospholipid membrane through hydrogen bonds. This hydrogen bond interaction is a non-covalent bond, which allows hyaluronic acid and its derivatives to be firmly anchored on the outside of the phospholipid membrane while retaining the original structure. In this way, hyaluronic acid and its derivatives are like being cleverly "stuck" to the surface of the phospholipid membrane, forming a stable outer layer structure. Through this clever structural design, a composite anti-inflammatory and anti-aging component liposome based on hyaluronic acid or its derivatives is finally obtained. This liposome not only has good stability, but also can directly bind to the hyaluronic acid receptors widely expressed on the skin cell membrane with the help of the targeting properties of hyaluronic acid or its derivatives, accurately delivering anti-inflammatory and anti-aging active substances to the target site, thereby exerting efficient anti-inflammatory and anti-aging effects, bringing a new solution to the field of skin care.

[0060] The present invention does not introduce any toxic or harmful organic solvents, does not introduce chemical penetration enhancers such as azone that are not welcome in cosmetics, and does not introduce any unwelcome solubilizers or surfactants, thereby achieving safe and effective application of anti-inflammatory and anti-aging active ingredients.

[0061] Typically but not limiting, the weight percentage of hyaluronic acid or its derivatives can be, for example, 0.1, 1.0, 2.0, 3.0, 4.0 or 5.0 parts, or any value in the range of 0.1 to 5.0; the weight percentage of pterostilbene can be, for example, 0.1, 1.0, 2.0, 3.0, 4.0 or 5.0 parts, or any value in the range of 0.1 to 5.0; the weight percentage of milk peptide complex can be, for example, 0.1, 1.0, 2.0, 3.0, 4.0 or 5.0 parts, or any value in the range of 0.1 to 5.0. 1 to 5.0; the weight portion of silymarin can be, for example, 0.05, 0.5, 1.0, 1.5 or 2.0 parts, or any value within the range of 0.05 to 2.0; the weight portion of ceramide NP can be, for example, 0.05, 0.5, 1.0, 1.5 or 2.0 parts, or any value within the range of 0.05 to 2.0; the weight portion of water can be, for example, 20.0, 30.0, 40.0, 50.0 or 60.0 parts, or any value within the range of 20.0 to 60.0 any value; the weight portion of liquid fat can be, for example, 10.0 parts, 20.0 parts, 30.0 parts or 40.0 parts, or any value within the range of 10.0 to 40.0; the weight portion of glycerol can be, for example, 10.0 parts, 20.0 parts, 30.0 parts or 40.0 parts, or any value within the range of 10.0 to 40.0; the weight portion of lecithin can be, for example, 1.0 parts, 2.0 parts, 3.0 parts, 4.0 parts, 5.0 parts, 6.0 parts, 7.0 parts, 8.0 parts, 9.0 parts or 10.0 parts, or 1.0 ~10.0; the weight portion of tocopherol acetate can be, for example, 0.5 parts, 1.0 parts, 2.0 parts, 3.0 parts, 4.0 parts or 5.0 parts, or any value in the range of 0.5 to 5.0; the weight portion of 1,2-hexanediol can be, for example, 1.0 parts, 2.0 parts, 3.0 parts, 4.0 parts or 5.0 parts, or any value in the range of 1.0 to 5.0; the weight portion of the pH adjuster can be, for example, 0.1 parts, 0.5 parts, 1.0 parts or 2.0 parts, or any value in the range of 0.1 to 2.0.

[0062] Furthermore, the particle size of the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives is 30 to 300 nm. The liposome has a large specific surface area, which significantly increases the contact area between the active substance and the skin and can increase its penetration effect.

[0063] Furthermore, the hyaluronic acid or its derivative is at least one of hyaluronic acid, sodium hyaluronate and hydrolyzed sodium hyaluronate.

[0064] Hydrolyzed sodium hyaluronate is a product that breaks down high-molecular-weight sodium hyaluronate through enzymes, making it more permeable to the skin.

[0065] Furthermore, the lecithin includes at least one of soybean lecithin, hydrogenated lecithin and lysolecithin.

[0066] Soy lecithin is an important component of human biological membranes. It plays a key role in maintaining the physiological activity of biological membranes and the normal metabolism of the body. It is also a common component for artificially preparing liposomes. Liposomes prepared by ingredients such as soybean lecithin can achieve dual embedding of water-soluble and oil-soluble substances through the phospholipid bilayer formed by self-assembly. Through liposome technology, the solubility of active substances can be improved, helping active substances to penetrate the skin barrier to reach the deep layer of the skin, increasing the retention of active substances in the skin, and better exerting the efficacy of active substances. Ceramide exists in the extracellular lipid matrix of the epidermal barrier and is composed of fatty acids and sphingosine bases. The phosphatidylcholine molecules contained in lecithin are similar to its structure. Ceramide interacts with phosphatidylcholine molecules, so that the tail chains can be hinged to each other to form a stable and tight micro-region structure, which is conducive to the formation of liposome structure during use.

[0067] Preferably, the soybean lecithin has a phosphatidylcholine content of ≥80%.

[0068] Preferably, the content of hydrogenated phosphatidylcholine in the hydrogenated lecithin is ≥ 75%.

[0069] More preferably, the soybean lecithin has a phosphatidylcholine content of ≥90%.

[0070] More preferably, the content of hydrogenated phosphatidylcholine in the hydrogenated lecithin is ≥ 90%.

[0071] Phosphatidylcholine is a natural emulsifier and moisturizer. The phosphatidylcholine content in soybean lecithin is generally 20-40%. Since the molecular structure of phosphatidylcholine is similar to that of ceramide NP, lecithin with a high content of phosphatidylcholine is more easily combined with ceramide NP, promoting the stability of the system and further facilitating the formation of liposome structure during use.

[0072] Soy lecithin with high phosphatidylcholine content (≥90%) and hydrogenated lecithin with high hydrogenated phosphatidylcholine content (≥75%) have good skin affinity. Ceramide and phosphatidylcholine can interact with each other molecularly to promote the stability of the phospholipid bilayer structure of liposomes. Ceramide NP effectively combines with phospholipids and can effectively act on skin tissue after acting on the skin, instantly repairing the skin barrier, while enhancing the water-locking ability of the skin's stratum corneum, improving the skin's dehydration state, and reducing skin peeling and desquamation symptoms.

[0073] Furthermore, the liquid oil includes at least one of caprylic / capric triglyceride, isopropyl lauroyl sarcosinate and propylene carbonate.

[0074] Furthermore, the milk peptide complex contains lactose, whey protein and lactic acid.

[0075] The second aspect of the present invention provides a method for preparing the hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposomes, comprising the following steps:

[0076] A. Lecithin and liquid oil are first mixed uniformly to obtain a first mixture; then silymarin, ceramide NP, pterostilbene and tocopherol acetate are dissolved in the first mixture to obtain an oil phase.

[0077] B. The milk peptide complex and part of the water are mixed uniformly for a second time to obtain a second mixture, and then part of the pH regulator is added to the second mixture until it is completely dissolved, and then the remaining pH regulator is added until it is completely dissolved, and finally glycerol is added and mixed uniformly for a third time to obtain an inner water phase; hexylene glycol, hyaluronic acid or its derivatives and the remaining water are mixed uniformly for a fourth time to obtain an outer water phase.

[0078] C. Under stirring, the inner aqueous phase is added dropwise into the oil phase to hydrate the oil phase and wrap the inner aqueous phase to obtain liposome colostrum; the liposome colostrum is added dropwise into the outer aqueous phase to obtain liposome intermediate emulsion; finally, the liposome intermediate emulsion is homogenized to obtain composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives.

[0079] The preparation method provided by the present invention does not use organic solvents during the preparation process, thus eliminating the risk of solvent residues, improving the safety and stability of the product, enabling it to be conveniently added to various external preparations and arbitrarily matched with cosmetic formulas, thereby significantly improving the application effect of the active substance.

[0080] The pH regulator mainly adjusts the pH value of the solution during the preparation process to ensure the successful preparation of the aqueous phase. In actual implementation, the pH regulator includes citric acid or sodium hydroxide.

[0081] Furthermore, in step A, the first mixing is performed under vacuum.

[0082] Preferably, the temperature of the first mixing is 70-80° C., and the time is 20-40 min.

[0083] Typically but not limitatively, the temperature of the first mixing can be, for example, 70°C, 72°C, 75°C, 78°C or 80°C, or any value within the range of 70°C to 80°C; the time of the first mixing can be, for example, 20 min, 25 min, 30 min, 35 min or 40 min, or any value within the range of 20 min to 40 min.

[0084] Preferably, the first mixing includes stirring mixing.

[0085] Preferably, the stirring and mixing speed is 300 to 500 rpm. Typically but not limiting, the stirring and mixing speed may be, for example, 300 rpm, 350 rpm, 400 rpm, 450 rpm or 500 rpm, or any value within the range of 300 rpm to 500 rpm.

[0086] Preferably, in step A, the dissolution temperature of silymarin and the ceramide NP is 70-80° C. Typically but not limitatively, in step A, the dissolution temperature of silymarin and the ceramide NP can be, for example, 70° C., 72° C., 75° C., 78° C. or 80° C., or any value within the range of 70° C. to 80° C.

[0087] Preferably, in step A, the dissolution temperature of the pterostilbene and the tocopherol acetate is 50-60° C. Typically but not limitatively, in step A, the dissolution temperature of the pterostilbene and the tocopherol acetate may be, for example, 50° C., 52° C., 55° C., 58° C. or 60° C., or any value within the range of 50° C. to 60° C.

[0088] Furthermore, the mass ratio of the partial water to the remaining water in step B is 1:3.

[0089] Preferably, in step C, the inner water phase is heated to 50-60° C. and then added dropwise into the oil phase.

[0090] Preferably, the dripping speed of the inner aqueous phase is 50-200 mL / min. At this dripping speed, the oil phase is given hydration time to allow phosphatidylcholine and ceramide NP to self-assemble into a phospholipid molecular layer to form liposome colostrum, which encapsulates silymarin, ceramide NP, pterostilbene and milk peptide complex.

[0091] Preferably, the dripping speed of the liposome colostrum is 10-60 mL / min. At this slow dripping speed, the integrity of the liposome structure in the liposome colostrum is ensured, so that hyaluronic acid or its derivatives adhere to the surface of the liposome through hydrogen bonding.

[0092] Preferably, after the liposome colostrum is added dropwise, the mixture is stirred at 200 to 400 rpm for 10 to 20 minutes to obtain the liposome intermediate emulsion.

[0093] Furthermore, the homogenization pressure is 10000-20000 psi. Typically but not limiting, the homogenization pressure may be, for example, 10000 psi, 12000 psi, 14000 psi, 16000 psi, 18000 psi or 20000 psi, or any value within the range of 10000-20000 psi.

[0094] Preferably, the number of homogenization cycles is 2 to 6. Typically but not limiting, the number of homogenization cycles may be, for example, 2, 3, 4, 5 or 6 times, or any integer value within the range of 2 to 6 times.

[0095] Preferably, the discharge temperature after homogenization is 10-30° C. Typically but not limiting, the discharge temperature after homogenization may be, for example, 10° C., 15° C., 20° C., 25° C. or 30° C., or any value within the range of 10° C. to 30° C.

[0096] The third aspect of the present invention provides a cosmetic comprising the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives.

[0097] The cosmetics provided by the present invention, in view of the advantages of the above-mentioned hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging ingredient liposomes, enable the prepared cosmetics to enhance the anti-inflammatory and anti-aging effects, and also improve the safety, stability and transdermal absorption capacity of the product, thereby providing consumers with an anti-aging option that is efficient, safe and applicable to a wide range of people.

[0098] The composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives can be conveniently added to water, lotions, creams, essences, and facial masks. The appropriate proportion of the composition of the scheme added to cosmetics is 1-50%.

[0099] The application of the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives in cosmetics of the present invention is preferably added at a temperature below 40° C. during the cold preparation stage of the formula.

[0100] The present invention is further described below by specific examples and comparative examples, but it should be understood that these examples are only used for more detailed description and should not be understood as limiting the present invention in any form. The raw materials used in the examples and comparative examples of the present invention, if no specific conditions are specified, are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially.

[0101] The milk peptide complex used in the following examples and comparative examples was purchased from Chemisches Laboratorium Dr. KurtRichter GmbH.

[0102] Example 1

[0103] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate, the raw materials are as follows:

[0104]

[0105] The preparation method is as follows:

[0106] 1. Place soybean lecithin (phosphatidylcholine ≥ 90%) and liquid oil in a clean container, preheat in a 75°C water bath, and stir continuously at 400 rpm under high temperature and vacuum conditions for 30 minutes to obtain a yellow clear liquid.

[0107] 2. Dissolve silymarin and ceramide NP in the solution obtained in step 1 at 80°C, stir until completely dissolved, and cool to 55°C to obtain a clear liquid.

[0108] 3. Dissolve pterostilbene and tocopherol acetate in the solution obtained in step 2, and stir rapidly at 55° C. until they are completely dissolved, to obtain a transparent liquid as the active phospholipid phase, i.e., the oil phase.

[0109] 4. Place the milk peptide complex in a clean container, add water, continue stirring at room temperature until dispersed, add citric acid, stir until dissolved, then add sodium hydroxide, stir until dissolved, then add glycerin, stir until uniform to obtain a colorless transparent liquid as the inner water phase.

[0110] 5. Place hexylene glycol and hydrolyzed sodium hyaluronate in a clean container and stir with water until completely dissolved to obtain the external aqueous phase.

[0111] 6. Preheat the inner water phase obtained in step 4 to 55°C and inject it dropwise into the oil phase obtained in step 3. During the injection process, the oil phase is stirred at a low speed to hydrate the phospholipid phase and wrap the inner water phase. After the injection is completed, keep stirring and cool to room temperature to obtain liposome colostrum.

[0112] 7. Inject the encapsulated intermediate obtained in step 6 dropwise into the external aqueous phase obtained in step 5. During the injection process, the external aqueous phase is stirred at a low speed. After the injection is completed, stir at 200 rpm for 20 minutes to obtain a sodium hyaluronate-modified liposome intermediate emulsion.

[0113] 8. The sodium hyaluronate-modified liposome intermediate emulsion obtained in step 7 is homogenized using high-pressure microfluidization technology, the homogenization pressure is controlled to be 20,000 psi, the number of cycles is 3, and the discharge temperature is 25°C to obtain a light yellow translucent liquid which is a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate.

[0114] Example 2

[0115] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 1 is that 3.0wt% of soybean lecithin (phosphatidylcholine ≥ 90%) and 3.0wt% of hydrogenated lecithin (hydrogenated phosphatidylcholine ≥ 90%) are used to replace the soybean lecithin (phosphatidylcholine ≥ 90%) in Example 1, and the remaining raw materials and steps are the same as those in Example 1 and are not repeated here.

[0116] Example 3

[0117] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 1 is that the same weight of hydrogenated lecithin (hydrogenated phosphatidylcholine ≥ 90%) is used to replace the soybean lecithin (phosphatidylcholine ≥ 90%) in Example 1, and the remaining raw materials and steps are the same as those in Example 1 and are not repeated here.

[0118] Example 4

[0119] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 1 is that the amount of pterostilbene is 3.0wt%. The remaining raw materials and steps are the same as those in Example 1 and will not be repeated here.

[0120] Example 5

[0121] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 1 is that the amount of pterostilbene is 5.0wt%, the amount of soybean lecithin (phosphatidylcholine ≥ 90%) is 10.0wt%, and the remaining raw materials and steps are the same as those in Example 1 and will not be repeated here.

[0122] Example 6

[0123] This embodiment provides a composite anti-inflammatory and anti-aging ingredient liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 5 is that a combination of 5wt% caprylic / capric triglyceride and 15wt% lauroyl sarcosine isopropyl ester is used to replace 20wt% caprylic / capric triglyceride, and the remaining raw materials and steps are the same as those in Example 5 and are not repeated here.

[0124] Example 7

[0125] This embodiment provides a sodium hyaluronate-targeted composite anti-inflammatory and anti-aging component liposome. The difference from Example 1 is that 0.5wt% hyaluronic acid is used to replace the hydrolyzed sodium hyaluronate in Example 1. The remaining raw materials and steps are the same as those in Example 1 and will not be repeated here.

[0126] Example 8

[0127] This embodiment provides a sodium hyaluronate-targeted composite anti-inflammatory and anti-aging component liposome. The difference from Example 1 is that 3.0 wt % sodium hyaluronate is used to replace the hydrolyzed sodium hyaluronate in Example 1. The remaining raw materials and steps are the same as those in Example 1 and will not be repeated here.

[0128] Example 9

[0129] This embodiment provides a composite anti-inflammatory and anti-aging component liposome targeted by hydrolyzed sodium hyaluronate. The difference from Example 1 is that the same weight of soybean lecithin (phosphatidylcholine ≥ 70%) is used to replace the soybean lecithin (phosphatidylcholine ≥ 90%) in Example 1, and the remaining raw materials and steps are the same as those in Example 1 and will not be repeated here.

[0130] Comparative Example 1

[0131] This comparative example provides a pterostilbene solution, wherein the pterostilbene accounts for 0.5wt% and the rest is Tween 80. The solution can be obtained by uniformly mixing the two.

[0132] Test Example 1

[0133] The product was dispersed with laboratory pure water to obtain a 1% pure water dispersion, and then the particle size and PDI were tested using the BeNano180zeta Pro particle size tester. The test conditions were: 25°C, equilibration time 120s, and test angle 173°. Specific data are shown in Table 1 and Figure 2 .

[0134] Table 1

[0135] Sample name Appearance Particle size / nm PDI Example 1 Light yellow slightly transparent liquid 55.19 0.171 Example 2 Light yellow slightly transparent liquid 61.75 0.208 Example 3 Light yellow opaque liquid 93.11 0.243 Example 4 Light yellow slightly transparent liquid 145.31 0.124 Example 5 Light yellow slightly transparent liquid 124.6 0.154 Example 6 Light yellow slightly transparent liquid 127.76 0.187 Example 7 Light yellow slightly transparent liquid 219.45 0.296 Example 8 Light yellow slightly transparent liquid 275.76 0.305 Example 9 Light yellow opaque liquid 252.89 0.438

[0136] As can be seen from Table 1, the particle size of the composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives provided by the present invention is generally less than 300 nm, which is conducive to penetration in the skin. The dispersion index PDI of Examples 1-6 is less than 0.3, indicating that the prepared liposomes not only have a small particle size, but also have a relatively uniform particle size dispersion.

[0137] Figure 2 The particle size distribution diagram of the hydrolyzed sodium hyaluronate targeted composite anti-inflammatory and anti-aging ingredient liposomes prepared in Example 1 is shown. The average particle size of Example 1 is 55.19 nm and the PDI is 0.171, indicating that the product particle size is small and uniform, which is conducive to ensuring the stability and permeability of the product.

[0138] Test Example 2

[0139] The hydrolyzed sodium hyaluronate targeted composite anti-inflammatory and anti-aging component liposome obtained in Example 1 was added into the emulsion formula. The specific formula is as follows:

[0140]

[0141]

[0142] The emulsion was placed at room temperature, -18°C, 45°C, and 4°C for 48 hours and 30 days, and the appearance and pH value of the product were visually observed at room temperature and without direct sunlight. Specific data are shown in Table 2 and Figure 3 .

[0143] Table 2

[0144]

[0145] From Table 2 and Figure 3 It can be seen that by adding 50% of the liposomes of Example 1, the appearance and pH can be kept stable under four temperature conditions of room temperature, 4°C, 45°C, and -18°C for 30 days, without discoloration, stratification, or precipitation. This indicates that the composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives provided by the present invention can be stably used in the formula.

[0146] Test Example 3

[0147] The liposomes or solutions obtained in the examples and comparative examples were compared in terms of their permeability, and the specific method was as follows:

[0148] The samples of Examples 1-9 and Comparative Example 1 were added to the essence matrix respectively, stirred evenly, and the samples to be tested were obtained, and the content of pterostilbene in each group of samples to be tested was ensured to be consistent, wherein the content of pterostilbene was 0.05%; the samples of Example 1 and Comparative Example 1 were prepared to test samples in the same manner, wherein the content of pterostilbene was 0.019%. All samples to be tested were prepared using a uniform essence gel matrix, which had a formula of: 3% propylene glycol, 3% glycerol, 0.8% thickener SIMULGEL FL (hydroxyethyl acrylate & sodium dimethyl taurate copolymer & isohexadecane & polysorbate 60), and the rest was water.

[0149] According to the in vitro transdermal test guidelines of the OECD / OCDE "European OECD Chemical Testing Guidelines", the transdermal verification is carried out. The specific operation method is as follows:

[0150] During the experiment, the Bama pig skin was first placed in a phosphate buffer solution (pH 7.4) for hydration for 30 minutes. After hydration, the surface moisture of the Bama pig skin was wiped dry and the Bama pig skin was placed between the receiving cell and the supply cell of the Franz diffusion cell, with the Bama pig skin epidermis facing the diffusion chamber and the dermis facing the receiving chamber. The receiving cell contained phosphate buffer solution (pH 7.4); 0.1g of sample was added to the supply cell; the assembled Franz diffusion cell was placed in the transdermal diffusion instrument, and the experimental conditions were set as follows: temperature was 37°C, stirring speed was 600rpm, and penetration time was 12h. After 12h of the penetration experiment, the residual sample on the skin surface was cleaned, the skin was ground, and the pterostilbene retained in the Bama pig skin was extracted with 80% methanol. The skin retention amount of pterostilbene was quantitatively analyzed by high performance liquid chromatography. The specific data are shown in Table 3. Figure 4 and Figure 5 .

[0151] Table 3

[0152]

[0153]

[0154] As can be seen from Table 3, the skin retention amount of the pterostilbene essence prepared by the composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives provided by the present invention is higher than that of the pterostilbene essence that has not been technically treated, indicating that the composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives of the present invention significantly enhance the transdermal retention rate of the active substance, and the transdermal absorption capacity of the active substance is improved by the process of the present invention, which helps the active substance to better achieve the anti-inflammatory and anti-aging effects in the skin.

[0155] Figure 4 The comparison of the skin retention data after penetration of the pterostilbene essence prepared in Example 1 and Comparative Example 1 with 10% of each is shown. The test results show that after 12 hours of penetration, the skin retention of the pterostilbene essence prepared in Example 1 using liposome technology is 3.28 μg / cm 2 , which is 3.2 times the retention rate of the untreated pterostilbene essence prepared in Example 1, indicating that the composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives of the present invention significantly enhance the transdermal retention rate of the active substance, and the process of the present invention improves the transdermal absorption capacity of the active substance, which helps the active substance to better achieve anti-inflammatory and anti-aging effects in the skin.

[0156] Figure 5 The comparison of the amount of pterostilbene essence prepared in Example 1 and Comparative Example 1 after penetration is shown. The test results show that after 12 hours of penetration, the total amount of pterostilbene essence prepared in Example 1 using liposome technology retained in the skin is 2.335 μg / cm 2, which is 3.57 times the total amount of pterostilbene essence prepared in Example 1 without treatment. Compared with the control group, at the same active ingredient concentration, the amount of pterostilbene essence prepared in Example 1 in all skin layers is significantly improved, especially in the dermis, where the amount in the dermis is 4.08 times that of the essence prepared in Example 1. The test results show that the composite anti-inflammatory and anti-aging ingredient liposomes targeted by hyaluronic acid or its derivatives of the present invention can achieve more penetration of active ingredients into the skin, especially near the dermis, which helps the active ingredients to better achieve anti-inflammatory and anti-aging effects in the skin.

[0157] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein by equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A hyaluronic acid or its derivatives targeted composite anti-inflammatory and anti-aging component liposome, characterized in that: In parts by weight, it includes: 0.1-5.0 parts of hyaluronic acid or its derivatives, 0.1-5.0 parts of pterostilbene, 0.1-5.0 parts of milk peptide complex, 0.05-2.0 parts of silymarin, 0.05-2.0 parts of ceramide NP, 20.0-60.0 parts of water, 10.0-40.0 parts of liquid oil, 10.0-40.0 parts of glycerin, 1.0-10.0 parts of lecithin, 0.5-5.0 parts of tocopherol acetate, 1.0-5.0 parts of 1,2-hexanediol, and 0.1-2.0 parts of pH adjuster.

2. The hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposome according to claim 1, characterized in that: The hyaluronic acid or its derivative is at least one of hyaluronic acid, sodium hyaluronate and hydrolyzed sodium hyaluronate.

3. The hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposome according to claim 1, characterized in that: The lecithin comprises at least one of soybean lecithin, hydrogenated lecithin and lysolecithin; Preferably, the soybean lecithin has a phosphatidylcholine content of ≥80%; Preferably, the hydrogenated phosphatidylcholine content in the hydrogenated lecithin is ≥ 75%; More preferably, the soybean lecithin has a phosphatidylcholine content of ≥90%; More preferably, the content of hydrogenated phosphatidylcholine in the hydrogenated lecithin is ≥ 90%.

4. The hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposome according to claim 1, characterized in that: The liquid oil comprises at least one of caprylic / capric triglyceride, isopropyl lauroyl sarcosinate and propylene carbonate.

5. The hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposome according to claim 1, characterized in that: The milk peptide complex contains lactose, whey protein and lactic acid.

6. A method for preparing the hyaluronic acid or its derivative targeted composite anti-inflammatory and anti-aging component liposome according to any one of claims 1 to 5, characterized in that: The following steps are involved: A, lecithin and liquid oil are first mixed uniformly to obtain a first mixture; then silymarin, ceramide NP, pterostilbene and tocopherol acetate are dissolved in the first mixture to obtain an oil phase; B. Mixing the milk peptide complex and part of the water for a second time to obtain a second mixture, then adding part of the pH regulator to the second mixture until it is completely dissolved, then adding the remaining pH regulator until it is completely dissolved, and finally adding glycerol for a third time to obtain an inner water phase; mixing hexylene glycol, hyaluronic acid or its derivatives and the remaining water for a fourth time to obtain an outer water phase; C. Under stirring, the inner aqueous phase is added dropwise into the oil phase to hydrate the oil phase and wrap the inner aqueous phase to obtain liposome colostrum; the liposome colostrum is added dropwise into the outer aqueous phase to obtain liposome intermediate emulsion; finally, the liposome intermediate emulsion is homogenized to obtain composite anti-inflammatory and anti-aging component liposomes targeted by hyaluronic acid or its derivatives.

7. The preparation method according to claim 6, characterized in that: In step A, the first mixing is performed under vacuum; Preferably, the temperature of the first mixing is 70-80°C and the time is 20-40 minutes; Preferably, the first mixing includes stirring mixing; Preferably, the stirring and mixing speed is 300 to 500 rpm; Preferably, in step A, the dissolution temperature of the silymarin and the ceramide NP is 70-80° C.; Preferably, in step A, the dissolution temperature of the pterostilbene and the tocopherol acetate is 50-60°C.

8. The preparation method according to claim 6, characterized in that: The mass ratio of the partial water to the remaining water in step B is 1:3; Preferably, in step C, the inner water phase is heated to 50-60° C. and then added dropwise into the oil phase; Preferably, the dripping speed of the inner aqueous phase is 50 to 200 mL / min; Preferably, the dripping speed of the liposome colostrum is 10 to 60 mL / min; Preferably, after the liposome colostrum is added dropwise, the mixture is stirred at 200 to 400 rpm for 10 to 20 minutes to obtain the liposome intermediate emulsion.

9. The preparation method according to claim 6, characterized in that: The homogenization pressure is 10000-20000psi; Preferably, the number of cycles of the homogenization is 2 to 6 times; Preferably, the discharge temperature after homogenization is 10-30°C.

10. A cosmetic, characterized in that: The invention comprises the composite anti-inflammatory and anti-aging component liposome targeted by hyaluronic acid or its derivatives as claimed in any one of claims 1 to 5.

Images