Hyaluronic acid multiple emulsion with improved stability, preparation method and application thereof

Abstract

The present invention discloses a multiple emulsion containing hyaluronic acid, a preparation method thereof and an application thereof. The multiple emulsion comprises an oil phase, a W / O emulsifier, an O / W emulsifier and a hyaluronic acid composition. In the present invention, the hyaluronic acid composition is added to the multiple emulsion and used as the outer aqueous phase of the W / O / W emulsion. The addition of the hyaluronic acid composition can improve the stability of the multiple emulsion and promote the absorption of active ingredients in the multiple emulsion. Active ingredients with irritation can be encapsulated in the inner phase of the multiple emulsion, and the addition of the hyaluronic acid composition can effectively solve the problem of irritation of cosmetics.

Description

Technical Field

[0001] The present invention relates to the technical field of hyaluronic acid, and particularly to a hyaluronic acid multiple emulsion with improved stability, a preparation method thereof and an application thereof. Background Art

[0002] Traditional emulsions only have two types: O / W type and W / O type. The W / O type emulsion has a bright appearance, good moisturizing and emollient effects, but it is sticky when applied, has a poor skin feel, and is not easy to clean; while the O / W type emulsion has good spreadability and a refreshing skin feel, but its moisturizing effect and emollient effect are both inferior to those of the W / O type emulsion.

[0003] Multiple emulsion is a multi-layer emulsion formed by dispersing one emulsion in another continuous phase. Generally, it is a highly dispersed and multi-phase system with different particle sizes. There are various types, and the two types of W / O / W and O / W / O are the most common. Structurally, the multiple emulsion has a unique multi-compartment structure of "two membranes and three phases". For example, the W / O / W type multiple emulsion contains an outer aqueous phase, an oil phase and an inner aqueous phase. The oil phase wraps the inner aqueous phase and is then suspended in the outer aqueous phase to form an emulsion. This special structure can dissolve some substances with different properties in different phases to achieve effects such as isolation, antioxidant and controlled release. Therefore, it has been favored by many formulators in the cosmetics field.

[0004] However, due to this special "two membranes and three phases" structure of the multiple emulsion, the multi-phase interface of the multiple emulsion has a very high interfacial energy, which causes the emulsion to easily break and coalesce, and stratification will occur after storing for several weeks. Therefore, its application is also restricted to a certain extent. At the same time, whether the active ingredients in skin care products can play their roles depends on whether the substance can reach specific skin sites. Therefore, how to promote the absorption of active substances by the skin while maintaining the stability of the multiple emulsion is very important. Summary of the Invention

[0005] In view of the above problems, the present invention provides a multiple emulsion containing hyaluronic acid. The multiple emulsion is of the W / O / W type. Adding a hyaluronic acid composition as the outer aqueous phase in the multiple emulsion can improve the stability of the multiple emulsion and promote the transdermal absorption rate of the multiple emulsion.

[0006] The specific technical solution of the present invention is as follows:

[0007] 1. A multiple emulsion containing hyaluronic acid, the multiple emulsion comprising an oil phase, a W / O type emulsifier, an O / W type emulsifier and a hyaluronic acid composition.

[0008] 2. The multiple emulsion according to item 1, wherein the hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt.

[0009] 3. The multiple emulsion according to item 2, wherein the hyaluronic acid or its salt is 20-60% by mass percentage in the hyaluronic acid composition, preferably 25-40%;

[0010] The acetylated hyaluronic acid or its salt is 10-50% by mass percentage, preferably 20-35%;

[0011] The hydrolyzed hyaluronic acid or its salt is 30-70% by mass percentage, preferably 40-55%.

[0012] 4. The hyaluronic acid composition according to any one of items 1-3, wherein

[0013] The molecular weight of the hyaluronic acid or its salt is 100k-500kDa, preferably 150k-300kDa, more preferably 210k-300kDa;

[0014] The molecular weight of the acetylated hyaluronic acid or its salt is 10k-100kDa, preferably 10k-50kDa, more preferably 20k-30kDa; and

[0015] The molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k-20kDa, preferably 3k-15kDa, more preferably 3k-10kDa.

[0016] 5. The multiple emulsion according to any one of items 1-4, wherein the hyaluronic acid composition is 0.01-10% by mass percentage in the multiple emulsion, preferably 0.05-2%;

[0017] The oil phase is 20-50%, preferably 20-35%.

[0018] 6. The multiple emulsion according to any one of items 1-5, wherein the oil phase is selected from one or more of squalane, rice bran oil, GTCC, coconut oil and ISIS (isooctyl isononanoate).

[0019] 7. The multiple emulsion according to any one of items 1-6, wherein the O / W emulsifier is selected from one or more of alkyl glycosides, polyglyceryl-10 stearate, polyglyceryl-10 oleate and hydrogenated lecithin.

[0020] 8. The multiple emulsion according to any one of items 1-7, wherein the W / O emulsifier is selected from one or more of polyglyceryl-2 dimer hydroxystearate, polyglyceryl-2 oleate, polyglyceryl-3 diisostearate, cetyl PEG / PPG-10 / 1 polydimethylsiloxane, sorbitan sesquioleate and PEG-20 glyceryl tristearate.

[0021] 9. The multiple emulsion according to any one of items 1-8, wherein the multiple emulsion further contains an active ingredient. Preferably, the molecular weight of the active ingredient is <1000 Da. More preferably, based on the mass percentage in the multiple emulsion, the active ingredient is 0.1-0.5%.

[0022] 10. The multiple emulsion according to item 9, wherein the active ingredient is selected from one or more of glabridin, resveratrol, coenzyme Q10, astaxanthin, ceramide, and retinol.

[0023] 11. A method for preparing the multiple emulsion according to any one of items 1-10, which comprises the following steps:

[0024] Using deionized water as phase A;

[0025] Mixing an oil phase, a W / O emulsifier, and optionally an active ingredient to obtain phase B, and then adding phase A to phase B to obtain a W / O primary emulsion;

[0026] Mixing a hyaluronic acid composition and an O / W emulsifier in water to obtain phase C, and then adding the W / O primary emulsion to phase C to obtain a multiple emulsion.

[0027] 12. The method according to item 11, wherein the multiple emulsion is a W / O / W type multiple emulsion.

[0028] 13. Use of a hyaluronic acid composition in the cosmetic field, preferably in a multiple emulsion, more preferably in a multiple emulsion that requires improved stability. The hyaluronic acid composition contains hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt.

[0029] 14. The use according to item 13, wherein, based on the mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20-60%, preferably 25-40%;

[0030] The acetylated hyaluronic acid or its salt is 10-50%, preferably 20-35%;

[0031] The hydrolyzed hyaluronic acid or its salt is 30-70%, preferably 40-55%.

[0032] 15. The use according to item 13 or 14, wherein the molecular weight of the hyaluronic acid or its salt is 100k-500kDa, preferably 150k-300kDa, more preferably 210k-300kDa;

[0033] The molecular weight of the acetylated hyaluronic acid or its salt is 10k - 100kDa, preferably 10k - 50kDa, and more preferably 20k - 30kDa; and

[0034] The molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k - 20kDa, preferably 3k - 15kDa, and more preferably 3k - 10kDa.

[0035] Effects of the Invention

[0036] In the present invention, by adding a hyaluronic acid composition to a multiple emulsion as the outer aqueous phase of a W / O / W type emulsion, the addition of the hyaluronic acid composition can improve the stability of the multiple emulsion and promote the absorption of active ingredients in the multiple emulsion; irritating active ingredients can be encapsulated in the inner phase of the multiple emulsion, and the addition of the hyaluronic acid composition can effectively solve the problem of irritation in cosmetics. Description of the Drawings

[0037] Figure 1 It is a microscope photograph of the multiple emulsion obtained in Example 1

[0038] Figure 2 It is a schematic diagram of skin retention amount during the penetration promotion test using the multiple emulsion described in Example 1 and the multiple emulsion described in Comparative Example 1 in Experimental Example 3. Detailed Embodiments

[0039] The following provides a detailed description of the present invention in conjunction with the embodiments described with reference to the drawings, where the same numbers in all the drawings represent the same features. Although specific embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments described herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art.

[0040] It should be noted that in the specification and claims, certain terms are used to refer to specific components. Those skilled in the art should understand that technicians may use different terms to refer to the same component. The specification and claims do not use the difference in terms as a way to distinguish components, but use the difference in functions of components as the criterion for distinction. For example, the terms "comprising" or "including" mentioned throughout the specification and claims are open-ended terms and should be interpreted as "including but not limited to". The subsequent description in the specification is for the purpose of describing the preferred embodiments of implementing the present invention, but the description is for the general purpose of the specification and is not intended to limit the scope of the present invention. The scope of protection of the present invention shall be determined by the scope defined by the appended claims.

[0041] The present invention provides a multiple emulsion containing hyaluronic acid, and the multiple emulsion comprises an oil phase, a W / O emulsifier, an O / W emulsifier and a hyaluronic acid composition.

[0042] The W / O emulsifier is a water-in-oil emulsifier, and the O / W emulsifier is an oil-in-water emulsifier.

[0043] In one embodiment, the hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt.

[0044] The acetylated hyaluronic acid or its salt is obtained by acetylating hyaluronic acid or its salt, and the introduction of acetyl groups endows the acetylated hyaluronic acid or its salt with lipophilicity.

[0045] The hydrolyzed hyaluronic acid or its salt is an oligomeric hyaluronic acid or its salt produced by enzyme degradation technology, with a smaller molecular weight and being more easily absorbed through the skin into the epidermis and dermis.

[0046] In one embodiment, calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%, preferably 25 - 40%;

[0047] the acetylated hyaluronic acid or its salt is 10 - 50%, preferably 20 - 35%;

[0048] the hydrolyzed hyaluronic acid or its salt is 30 - 70%, preferably 40 - 55%.

[0049] For example, calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt can be 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60% or any range therebetween;

[0050] the acetylated hyaluronic acid or its salt can be 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range therebetween;

[0051] the hydrolyzed hyaluronic acid or its salt can be 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or any range therebetween.

[0052] In one embodiment, the molecular weight of the hyaluronic acid or its salt is 100k - 500kDa, preferably 150k - 300kDa, and more preferably 210k - 300kDa; the molecular weight of the acetylated hyaluronic acid or its salt is 10k - 100kDa, preferably 10k - 50kDa, and more preferably 20k - 30kDa; and the molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k - 20kDa, preferably 3k - 15kDa, and more preferably 3k - 10kDa.

[0053] For example, the molecular weight of the hyaluronic acid or its salt can be 100kDa, 110kDa, 120kDa, 130kDa, 140kDa, 150kDa, 160kDa, 170kDa, 180kDa, 190kDa, 200kDa, 210kDa, 220kDa, 230kDa, 240kDa, 250kDa, 260kDa, 270kDa, 280kDa, 290kDa, 300kDa, 350kDa, 400kDa, 450kDa, 500kDa or any range therebetween;

[0054] the molecular weight of the acetylated hyaluronic acid or its salt can be 10kDa, 20kDa, 30kDa, 40kDa, 50kDa, 60kDa, 70kDa, 80kDa, 90kDa, 100kDa or any range therebetween;

[0055] the molecular weight of the hydrolyzed hyaluronic acid or its salt can be 0.8kDa, 0.9kDa, 1kDa, 2kDa, 3kDa, 4kDa, 5kDa, 6kDa, 7kDa, 8kDa, 9kDa, 10kDa, 11kDa, 12kDa, 13kDa, 14kDa, 15kDa, 16kDa, 17kDa, 18kDa, 19kDa, 20kDa or any range therebetween.

[0056] The hyaluronate or acetylated hyaluronate or hydrolyzed hyaluronate refers to metal ion salts, such as sodium salt, potassium salt, calcium salt, zinc salt, etc., and the commonly used one is sodium salt.

[0057] In one embodiment, based on the mass percentage in the multiple emulsion, the hyaluronic acid composition is 0.01 - 10%, preferably 0.05 - 2%;

[0058] the oil phase is 20 - 50%, preferably 20 - 35%.

[0059] For example, in terms of the mass percentage in the multiple emulsion, the hyaluronic acid composition can be 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or any range therebetween;

[0060] The oil phase can be 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20% or any range therebetween.

[0061] Regarding the contents of the O / W type emulsifier and the W / O type emulsifier, the present invention does not impose any restrictions, and they can be selected according to needs as long as the functions of the present invention can be achieved.

[0062] In one embodiment, the oil phase is selected from one or more of squalane, rice bran oil, GTCC, coconut oil, and ISIS, and for example, it can be selected from two, three, or more than four of them.

[0063] GTCC is caprylic / capric triglyceride, which is an excellent moisturizing oil with good spreading property, making the skin feel smooth but not greasy and being easily absorbed by the skin. It plays a very good role in making the cosmetics uniform and delicate, making the skin smooth and shiny.

[0064] In one embodiment, the O / W type emulsifier is selected from one or more of alkyl polyglycoside (APG1214), polyglyceryl-10 stearate, polyglyceryl-10 oleate, and hydrogenated lecithin, and for example, it can be selected from two, three, or more than four of them.

[0065] Alkyl polyglycoside refers to alkyl polyglucoside (Alkyl Polyglucoside, abbreviated as APG) synthesized from glucose and fatty alcohol, which refers to glycosides with the number of sugar units greater than or equal to 2 in complex glycoside compounds, collectively referred to as alkyl polysaccharides (or alkyl polyglycosides). Generally, the degree of polymerization n of alkyl polyglycosides is in the range of 1.1 - 3, and R is an alkyl group of C8 - C16. APG is a white solid powder or light yellow oily liquid at room temperature, highly soluble in water and relatively insoluble in common organic solvents.

[0066] In one embodiment, the W / O emulsifier is selected from one or more of polyglyceryl-2 dimer hydroxystearate, polyglyceryl-2 oleate, polyglyceryl-3 diisostearate, cetyl PEG / PPG-10 / 1 polydimethylsiloxane, sorbitan sesquioleate, and PEG-20 glyceryl tristearate. For example, it can be selected from two, three, or more than four of them.

[0067] In one embodiment, the multiple emulsion further contains an active ingredient. Preferably, the molecular weight of the active ingredient is < 1000 Da.

[0068] The active ingredient can be any active ingredient known to those skilled in the art that can be used in skin care products or gel-type medical devices. For example, it can be selected from one or more of glabridin, resveratrol, coenzyme Q10, astaxanthin, ceramide, retinol, ectoin, ergothioneine, aminobutyric acid, tranexamic acid, and glutathione. For example, it can be selected from two, three, or more than four of them.

[0069] In one embodiment, the multiple emulsion contains an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition. The hyaluronic acid composition contains hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt.

[0070] In one embodiment, the multiple emulsion contains an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition. The hyaluronic acid composition contains hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt. Calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%, preferably 25 - 40%;

[0071] The acetylated hyaluronic acid or its salt is 10 - 50%, preferably 20 - 35%;

[0072] The hydrolyzed hyaluronic acid or its salt is 30 - 70%, preferably 40 - 55%.

[0073] In one embodiment, the multiple emulsion contains an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition. The hyaluronic acid composition contains hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt. Calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%, preferably 25 - 40%;

[0074] The acetylated hyaluronic acid or its salt is 10 - 50%, preferably 20 - 35%;

[0075] The hydrolyzed hyaluronic acid or its salt is 30 - 70%, preferably 40 - 55%, and the molecular weight of the hyaluronic acid or its salt is 100k - 500kDa, preferably 150k - 300kDa, more preferably 210k - 300kDa;

[0076] The molecular weight of the acetylated hyaluronic acid or its salt is 10k - 100kDa, preferably 10k - 50kDa, more preferably 20k - 30kDa; and

[0077] The molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k - 20kDa, preferably 3k - 15kDa, more preferably 3k - 10kDa.

[0078] In one embodiment, the multiple emulsion comprises an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition. The hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt. Based on the mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%, preferably 25 - 40%;

[0079] The acetylated hyaluronic acid or its salt is 10 - 50%, preferably 20 - 35%;

[0080] The hydrolyzed hyaluronic acid or its salt is 30 - 70%, preferably 40 - 55%, and the molecular weight of the hyaluronic acid or its salt is 100k - 500kDa, preferably 150k - 300kDa, more preferably 210k - 300kDa;

[0081] The molecular weight of the acetylated hyaluronic acid or its salt is 10k - 100kDa, preferably 10k - 50kDa, more preferably 20k - 30kDa; and

[0082] The molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k - 20kDa, preferably 3k - 15kDa, more preferably 3k - 10kDa;

[0083] Based on the mass percentage in the multiple emulsion, the hyaluronic acid composition is 0.01 - 10%, preferably 0.05 - 2%;

[0084] The oil phase is 20 - 50%, preferably 20 - 35%;

[0085] Preferably, the oil phase is selected from one or more of squalane, rice bran oil, GTCC, coconut oil, and ISIS (isoisononyl isononanoate);

[0086] Preferably, the O / W emulsifier is selected from one or more of alkyl glycoside, polyglyceryl-10 stearate, polyglyceryl-10 oleate, and hydrogenated lecithin;

[0087] Preferably, the W / O emulsifier is selected from one or more of polyglyceryl-2 dimer hydroxystearate, polyglyceryl-2 oleate, polyglyceryl-3 diisostearate, cetyl PEG / PPG-10 / 1 polydimethylsiloxane, sorbitan sesquioleate, and PEG-20 glyceryl tristearate;

[0088] Preferably, the multiple emulsion further comprises an active ingredient. Preferably, the molecular weight of the active ingredient is < 1000 Da. More preferably, based on the mass percentage in the multiple emulsion, the active ingredient is 0.1 - 0.5%;

[0089] Preferably, the active ingredient is selected from one or more of glabridin, resveratrol, coenzyme Q10, astaxanthin, ceramide, and retinol;

[0090] For the multiple emulsion of the present invention, using the hyaluronic acid composition as the external aqueous phase of the multiple emulsion can provide the stability of the multiple emulsion and can promote the transdermal absorption of the multiple emulsion.

[0091] The present invention provides a method for preparing the above-mentioned multiple emulsion, which comprises the following steps:

[0092] Take water as phase A;

[0093] Mix the oil phase, W / O emulsifier and optional active ingredient to obtain phase B, and then add phase A to phase B to obtain the W / O primary emulsion;

[0094] Mix the hyaluronic acid composition and O / W emulsifier into water to obtain phase C, and then add the W / O primary emulsion to phase C to obtain the multiple emulsion.

[0095] In one embodiment, the multiple emulsion is a W / O / W type multiple emulsion.

[0096] The present invention provides the use of the hyaluronic acid composition in the cosmetic field, preferably in the multiple emulsion, more preferably in the multiple emulsion that needs to improve stability. The hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt.

[0097] In one embodiment, based on the mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%, preferably 25 - 40%;

[0098] The acetylated hyaluronic acid or its salt is 10 - 50%, preferably 20 - 35%;

[0099] The hydrolyzed hyaluronic acid or its salt is 30-70%, preferably 40-55%.

[0100] In one embodiment, the molecular weight of the hyaluronic acid or its salt is 100k-500kDa, preferably 150k-300kDa, and more preferably 210k-300kDa;

[0101] The molecular weight of the acetylated hyaluronic acid or its salt is 10k-100kDa, preferably 10k-50kDa, and more preferably 20k-30kDa; and

[0102] The molecular weight of the hydrolyzed hyaluronic acid or its salt is 0.8k-20kDa, preferably 3k-15kDa, and more preferably 3k-10kDa.

[0103] During the experiment, the inventor creatively invented a method for improving the stability of multiple emulsions. By adding a hyaluronic acid composition to the multiple emulsion, the stability of the multiple emulsion can be improved, and the transdermal absorption of the multiple emulsion can also be promoted.

[0104] Examples

[0105] The present invention generally and / or specifically describes the materials and test methods used in the experiments. In the following examples, unless otherwise specifically stated, % represents wt%, that is, weight percentage. For reagents or instruments whose manufacturers are not indicated, they are all conventional reagent products that can be obtained through commercial purchase. Among them, the hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt are all purchased from Bloomage Biotechnology Co., Ltd.

[0106] Example 1

[0107] (1) Start the constant temperature water bath and maintain the temperature at 40-50°C. Take an appropriate amount of deionized water in beaker A and preheat it in the constant temperature water bath to obtain phase A.

[0108] (2) Weigh squalane, polyglyceryl-2 oleate, and retinol into beaker B, then stir evenly and preheat it in the constant temperature water bath to obtain phase B.

[0109] (3) Add phase A to phase B to prepare a W / O primary emulsion.

[0110] (4) Weigh deionized water, the hyaluronic acid composition, and polyglyceryl-10 stearate into beaker C and mix to obtain the C phase. Then add the W / O primary emulsion to the C phase and stir evenly to prepare the W / O / W multiple emulsion. Among them, the contents of each component are shown in Table 1. Calculated as the mass percentage in hyaluronic acid, sodium hyaluronate with a molecular weight of 150 kDa accounts for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounts for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounts for 35%. The microscopic schematic diagram of the obtained multiple emulsion is as shown in Figure 1 shown.

[0111] Examples 2 - 13

[0112] For Examples 2 - 13, the multiple emulsion was prepared according to the method of Example 1. Among them, the contents of each component are shown in Table 1. Calculated as the mass percentage in hyaluronic acid, sodium hyaluronate with a molecular weight of 150 kDa accounts for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounts for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounts for 35%.

[0113] Example 14

[0114] For Example 14, the multiple emulsion was prepared according to the method of Example 1. The components are the same as those in Example 1, but the difference lies in the different contents of various sodium hyaluronates in the hyaluronic acid composition. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 150 kDa accounts for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounts for 20%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounts for 55%.

[0115] Example 15

[0116] For Example 15, the multiple emulsion was prepared according to the method of Example 1. The components are the same as those in Example 1, but the difference lies in the different contents of various sodium hyaluronates in the hyaluronic acid composition. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 150 kDa accounts for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounts for 20%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounts for 55%.

[0117] Example 16

[0118] For Example 16, the multiple emulsion was prepared according to the method of Example 1. The components are the same as those in Example 1, but the difference lies in the different contents of various sodium hyaluronates in the hyaluronic acid composition. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 150 kDa accounts for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounts for 25%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounts for 50%.

[0119] Example 17

[0120] Example 17 was prepared to obtain a multiple emulsion according to the method of Example 1. Each component was the same as that in Example 1, except that the contents of various sodium hyaluronates in the hyaluronic acid composition were different. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 210 kDa accounted for 25%, acetylated sodium hyaluronate with a molecular weight of 20 kDa accounted for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 10 kDa accounted for 35%.

[0121] Example 18

[0122] Example 18 was prepared to obtain a multiple emulsion according to the method of Example 1. Each component was the same as that in Example 1, except that the contents of various sodium hyaluronates in the hyaluronic acid composition were different. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 300 kDa accounted for 25%, acetylated sodium hyaluronate with a molecular weight of 30 kDa accounted for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 3 kDa accounted for 35%.

[0123] Example 19

[0124] Example 19 was prepared to obtain a multiple emulsion according to the method of Example 1. Each component was the same as that in Example 1, except that the contents of various sodium hyaluronates in the hyaluronic acid composition were different. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 300 kDa accounted for 25%, acetylated sodium hyaluronate with a molecular weight of 50 kDa accounted for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 15 kDa accounted for 35%.

[0125] Example 20

[0126] Example 20 was prepared to obtain a multiple emulsion according to the method of Example 1. Each component was the same as that in Example 1, except that the contents of various sodium hyaluronates in the hyaluronic acid composition were different. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 100 kDa accounted for 25%, acetylated sodium hyaluronate with a molecular weight of 10 kDa accounted for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 20 kDa accounted for 35%.

[0127] Example 21

[0128] Example 21 The multiple emulsion was prepared according to the method of Example 1. The components were the same as those in Example 1, except that the contents of various sodium hyaluronates in the hyaluronic acid composition were different. Calculated as the mass percentage in the hyaluronic acid composition, sodium hyaluronate with a molecular weight of 500 kDa accounted for 25%, acetylated sodium hyaluronate with a molecular weight of 100 kDa accounted for 40%, and hydrolyzed sodium hyaluronate with a molecular weight of 0.8 kDa accounted for 35%.

[0129] Comparative Examples 1 - 3

[0130] The multiple emulsions obtained by the preparation method described in Example 1 for Comparative Examples 1 to 3, in which the contents of each component are shown in Table 1.

[0131] Among them, the difference between Comparative Example 3 and Example 1 is that Comparative Example 3 only uses acetylated hyaluronic acid, while Example 1 is a multiple emulsion obtained by using a hyaluronic acid composition.

[0132] Table 1 Contents of each component in Examples and Comparative Examples

[0133]

[0134]

[0135] Experimental Example 1 Stability Test

[0136] High - temperature test: Place the sample to be tested in a suitable clean container and place it at 55 °C for 10 days. Sampling is carried out on the 5th and 10th days to observe the layering of the sample.

[0137] Low - temperature test: Place the sample to be tested in a suitable clean container and place it at - 20 °C for 5 days. Sampling is carried out on the 5th day to observe the layering of the sample.

[0138] Centrifugal stability: Pour about 2 / 3 of the height of the sample to be tested into a centrifuge tube and plug it with a stopper. Then place it in an electro - thermal constant - temperature incubator pre - adjusted to 38 °C and keep it for 1 h. Immediately transfer it to a centrifuge and adjust the centrifuge to a centrifugal speed of 2000 r / min and rotate for 30 min, then take it out and observe.

[0139] The test results are shown in Table 2 below. From the data in Table 2, it can be seen that the addition of the hyaluronic acid composition has an important impact on the stability of the multiple emulsion. The multiple emulsion without the addition of the hyaluronic acid composition has poor heat - resistance, cold - resistance and centrifugal stability when placed at room temperature. After adding the hyaluronic acid composition, the stability of the multiple emulsion is significantly improved.

[0140] Table 2 Test results of heat - resistance, cold - resistance and centrifugal stability

[0141]

[0142]

[0143] Experimental Example 2 Patch Test

[0144] Tear open the package of the patch tester, measure 0.025 mL or 0.025 g of the prepared sample and add it to the chamber. Apply the patch tester to the flexor side of the forearm of the subject, and gently press it with the palm to make it evenly adhere to the skin for 24 h.

[0145] Observe and record the reaction results at 30 min, 24 h, and 48 h after removing the patch tester according to Table 4. The results are shown in Table 5.

[0146] Table 3 Skin Reaction Grading Criteria for Skin-Closed Patch Test

[0147]

[0148] Table 4 Patch Test Results

[0149]

[0150]

[0151] It can be seen from the results in Table 4 that the multiple emulsion obtained by the present invention has less irritation, and basically or rarely shows irritation reactions.

[0152] Experimental Example 3 Permeation Enhancement Test

[0153] Perform Franz diffusion cell permeation experiments on Example 1 (test substance) and Comparative Example 1 (control product) to explore the permeation enhancement effect of the hyaluronic acid composition on the active substance (retinol). Fix the excised porcine skin between the supply chamber and the receiving chamber of the Phoenix DB-6 transdermal test system, and add about 16 mL of the receiving solution to the sampling tube according to the liquid height in the sampling tube, exhaust the air, and make the dermal layer of the skin in close contact with the receiving solution. Then add 49 μL of the 15% (m / v) test sample to the skin surface, and use a stainless steel stir bar to evenly spread the sample radially from the center of the skin to the edge. There are 3 replicate parallel samples for each sample. Keep a constant water bath at (32 ± 1) °C and stir evenly at a speed of 300 rpm / min. After diffusion for 20 h, collect the samples on the skin surface, inside the skin, and in the receiving solution of the porcine skin, and detect them by high performance liquid chromatography to investigate the in vitro transdermal effects of different samples. The results are as Figure 2 and Table 5.

[0154] Calculation Method

[0155] Retention ratio in skin = Detected amount of the test substance in the skin / Detected amount of the control product in the skin

[0156] Table 5 Test Results of Retention Ratio in Skin

[0157]

[0158] As can be seen from Table 5 and Figure 2 it can be seen that at the 20h node, compared with the group without the addition of the hyaluronic acid composition, the retention amount of the active substance in the skin increased by 28% after the addition of the hyaluronic acid composition. This shows that the hyaluronic acid composition can promote the retention of the active substance, thereby further promoting the transdermal absorption of the active substance by the skin.

[0159] In summary, adding the hyaluronic acid composition to the multiple emulsion in the present invention can improve the stability of the multiple emulsion, which is relatively stable at low and high temperatures, without obvious delamination, and can promote the absorption of the active ingredients in the multiple emulsion.

[0160] The above are only the preferred embodiments of the present invention, and are not intended to limit the present invention in other forms. Any person skilled in the art may use the technical content disclosed above to make changes or modifications into equivalent embodiments with equivalent changes. However, any simple modifications, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention without departing from the technical solution content of the present invention still fall within the protection scope of the technical solution of the present invention.

Claims

1. A multiple emulsion containing hyaluronic acid, the multiple emulsion comprising an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition; The hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt; Calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%; The acetylated hyaluronic acid or its salt is 10 - 50%; The hydrolyzed hyaluronic acid or its salt is 30 - 70%; The molecular weight of the hyaluronic acid or its salt is 150k - 300kDa; The molecular weight of the acetylated hyaluronic acid or its salt is 10k - 50kDa; The molecular weight of the hydrolyzed hyaluronic acid or its salt is 3k - 15kDa; Calculated by mass percentage in the multiple emulsion, the hyaluronic acid composition is 0.05 - 2%; The oil phase is 20 - 35%; The multiple emulsion is a W / O / W type multiple emulsion; The oil phase is selected from one or more of squalane, rice bran oil, caprylic / capric triglyceride, coconut oil, and isononyl isononanoate; The O / W emulsifier is selected from one or both of polyglyceryl-10 stearate and polyglyceryl-10 oleate; The W / O emulsifier is selected from one or more of polyglyceryl-2 dimer hydroxystearate, polyglyceryl-2 oleate, and polyglyceryl-3 diisostearate.

2. The multiple emulsion according to claim 1, wherein, Calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 25 - 40%; The acetylated hyaluronic acid or its salt is 20 - 35%; The hydrolyzed hyaluronic acid or its salt is 40 - 55%.

3. The multiple emulsion according to claim 1, wherein the molecular weight of the hyaluronic acid or its salt is 210k - 300kDa; The molecular weight of the acetylated hyaluronic acid or its salt is 20k - 30kDa; and The molecular weight of the hydrolyzed hyaluronic acid or its salt is 3k - 10kDa.

4. The multiple emulsion according to any one of claims 1 - 3, wherein, The multiple emulsion further comprises an active ingredient.

5. The multiple emulsion according to claim 4, wherein, The molecular weight of the active ingredient < 1000Da.

6. The multiple emulsion according to claim 4, wherein, Calculated by mass percentage in the multiple emulsion, the active ingredient is 0.1 - 0.5%.

7. The multiple emulsion according to claim 4, wherein, The active ingredient is selected from one or more of glabridin, resveratrol, coenzyme Q10, astaxanthin, ceramide, and retinol.

8. A method for preparing the multiple emulsion according to any one of claims 1 - 7, which comprises the following steps: Using deionized water as phase A; Mixing the oil phase, the W / O emulsifier, and optionally the active ingredient to obtain phase B, and then adding phase A to phase B to obtain a W / O primary emulsion; Mixing the hyaluronic acid composition and the O / W emulsifier in water to obtain phase C, and then adding the W / O primary emulsion to phase C to obtain the multiple emulsion.

9. Use of a hyaluronic acid composition in cosmetics, which is for non-therapeutic purposes and is for use in enhancing the stability of a multiple emulsion, wherein the hyaluronic acid composition comprises hyaluronic acid or its salt, acetylated hyaluronic acid or its salt, and hydrolyzed hyaluronic acid or its salt; calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 20 - 60%; the acetylated hyaluronic acid or its salt is 10 - 50%; the hydrolyzed hyaluronic acid or its salt is 30 - 70%; the molecular weight of the hyaluronic acid or its salt is 150k - 300kDa; the molecular weight of the acetylated hyaluronic acid or its salt is 10k - 50kDa; and the molecular weight of the hydrolyzed hyaluronic acid or its salt is 3k - 15kDa; the multiple emulsion comprises an oil phase, a W / O emulsifier, an O / W emulsifier, and a hyaluronic acid composition; the content of the hyaluronic acid composition in the multiple emulsion is 0.05 - 2%; the content of the oil phase in the multiple emulsion is 20 - 35%; the oil phase is selected from one or more of squalane, rice bran oil, caprylic / capric triglyceride, coconut oil, and isononyl isononanoate; the O / W emulsifier is selected from one or both of polyglyceryl-10 stearate and polyglyceryl-10 oleate; the W / O emulsifier is selected from one or more of polyglyceryl-2 dimer hydroxystearate, polyglyceryl-2 oleate, and polyglyceryl-3 diisostearate.

10. The use according to claim 9, wherein, calculated by mass percentage in the hyaluronic acid composition, the hyaluronic acid or its salt is 25 - 40%; the acetylated hyaluronic acid or its salt is 20 - 35%; the hydrolyzed hyaluronic acid or its salt is 40 - 55%.

11. The use according to any one of claims 9 - 10, wherein, the molecular weight of the hyaluronic acid or its salt is 210k - 300kDa; the molecular weight of the acetylated hyaluronic acid or its salt is 20k - 30kDa; and the molecular weight of the hydrolyzed hyaluronic acid or its salt is 3k - 10kDa.

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