CN112245366A - Permeation-promoting composition containing hyaluronic acid and application of permeation-promoting composition in cosmetics - Google Patents

Permeation-promoting composition containing hyaluronic acid and application of permeation-promoting composition in cosmetics Download PDF

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CN112245366A
CN112245366A CN202011334455.9A CN202011334455A CN112245366A CN 112245366 A CN112245366 A CN 112245366A CN 202011334455 A CN202011334455 A CN 202011334455A CN 112245366 A CN112245366 A CN 112245366A
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hyaluronic acid
promoting
permeation
penetration
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CN112245366B (en
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耿凤
郭文逸
李红红
郭学平
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Bloomage Biotech Co Ltd
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Shandong Huaxi Haiyu Biological Medicine Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73Polysaccharides
    • A61K8/735Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34Alcohols
    • A61K8/345Alcohols containing more than one hydroxy group
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37Esters of carboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/67Vitamins
    • A61K8/676Ascorbic acid, i.e. vitamin C
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783Angiosperms [Magnoliophyta]
    • A61K8/9789Magnoliopsida [dicotyledons]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/10Anti-acne agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00Preparations for care of the skin

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Abstract

The penetration-promoting composition containing the hyaluronic acid comprises, by weight, 2-5 parts of the hyaluronic acid, 1-3 parts of bis-diethoxydiol cyclohexane and 8-15 parts of polyhydric alcohol. The composition of the invention is added with hyaluronic acid with different molecular weights, bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and polyalcohol, has better permeation effect, and is combined with components with strong permeation and absorption functions to further promote the absorption of the hyaluronic acid and the bis-diethoxydol cyclohexane 1, 4-dicarboxylate. The permeation-promoting composition containing hyaluronic acid is combined with various acne-removing components to prepare a hyaluronic acid permeation-promoting acne-removing product, which can realize long-acting moisture preservation and has a better acne-removing effect.

Description

Permeation-promoting composition containing hyaluronic acid and application of permeation-promoting composition in cosmetics
Technical Field
The invention belongs to the field of cosmetics, and particularly relates to a penetration-promoting composition containing hyaluronic acid and application thereof in cosmetics.
Background
The transdermal absorption of cosmetics is very important and is a key point affecting whether cosmetics are effective or not. The more effective components absorbed by the skin, the more remarkable the effect. The transdermal absorption of the functional components on the skin mainly comprises the following ways: 1. hydration. When the skin absorbs a large amount of water and is sufficiently hydrated, the stratum corneum can expand into a porous state, and the barrier function is reduced, thereby facilitating the penetration of substances. Practice proves that the transdermal speed of the functional substance can be increased by 4 to 5 times, and the skin temperature can be increased from 32 ℃ to 37 ℃, so that the blood circulation is accelerated. 2. Osmotic pressure. The greater the osmotic pressure on the outside of the skin, the greater the osmotic capacity. 3. Diffusion effect. The effective components are absorbed by the skin through the skin artery channel, stratum corneum transport (including intracellular diffusion and intercellular diffusion) and epidermis deep layer and dermis transport, thereby entering the body tissue. 3. The substances at the skin acupoints are absorbed. Compared with other skins, the skin at the acupuncture points has low impedance, large capacitance and high potential, and is beneficial to the transdermal absorption of substances. 4. Absorption of substances at the mucosa. For example, sublingual mucosa, nasal mucosa, rectal mucosa and the like of the oral cavity are common parts for external application of the medicine, and the mucosa has no cuticle, so that the medicine can penetrate easily and quickly. 5. Surfactant or transdermal enhancer. 6. Promoting action of aromatic medicine.
The prior art has a variety of transdermal penetration enhancers such as polyols, lipids, moisturizers, and transdermal enhancing peptides. Wherein the polyhydric alcohol comprises glycerol, propylene glycol, 1, 3-butanediol, 1, 2-hexanediol and pentanediol; the lipids include ceramide, cholesterol, squalane, egg yolk lecithin, soybean lecithin and hydrogenated lecithin; the humectant comprises bis-diethoxydiethylene glycol cyclohexane 1, 4-dicarboxylate, caprylic/capric triglyceride, 147 dimethyl ether, hydrolyzed glycosaminoglycans, shea butter and PEG castor oil; transdermal enhancing peptides include transdermal peptide TD-1, skin and cell penetrating peptide SPACE, dermal localization peptide DLP, leader peptide-12 and T2 peptide.
Patent CN109172430A discloses a permeation-promoting composition containing small molecular group water, which comprises 0.1-3 parts of bis-diethoxydiethylene glycol cyclohexane 1, 4-dicarboxylate, 3-21 parts of seawater, 0.3-2 parts of sodium bis (lauramide glutamine) lysine and 0.1-1 part of hydrogenated lecithin. Wherein, the bis-diethoxydiol cyclohexane 1, 4-dicarboxylate interacts with small molecular group water to change the arrangement of skin stratum corneum cells so as to improve the permeability of skin.
Patent CN102579276B A penetration promoting composition for cosmetics comprises amino acid humectant (5-15 wt%), sodium hyaluronate (1-3 wt%), nicotinamide (5-15 wt%), allantoin (0.1-0.5 wt%), and deionized water (75-77 wt%). The composition of the present invention swells the stratum corneum into a porous state by hydration, thereby facilitating penetration of the substance.
Patent CN105749333B A hyaluronic acid medical dressing and a preparation method thereof, the hyaluronic acid medical dressing comprises, by mass, 0.1-5% of hyaluronic acid, 5-20% of vaseline, 0.1-1% of carbomer, 0.1-0.5% of propylene glycol, 0.01-1% of glycerol, 0.05-1% of allantoin, 0.05-1% of D-panthenol and 0.01-1% of hydroquinone. The dressing disclosed by the invention is compounded by hyaluronic acid with different molecular weights, and hydroquinone is added in the hyaluronic acid, so that the hyaluronic acid and the hydroquinone have a synergistic effect when used together, can deeply permeate into the skin, can promote wound healing, and has an anti-inflammatory effect.
Patent CN108635247A cosmetic composition containing sodium hyaluronate contains 3.0-15.0% of sodium hyaluronate, 71.0-91.0% of polyol, 5.0-12.0% of skin feeling regulating and penetration enhancer and 1.0-3.0% of solubilizer. Wherein the sodium hyaluronate consists of medium molecular sodium hyaluronate with the molecular weight of 80-100 ten thousand daltons, small molecular sodium hyaluronate with the molecular weight of 20-40 ten thousand daltons and hydrolyzed sodium hyaluronate with the molecular weight of 8000 daltons. The skin feeling regulating and penetration enhancer is one or the mixture of at least two of magnesium aspartate, zinc gluconate, copper gluconate and calcium pantothenate. This patent does not teach the use of hyaluronic acid as a penetration enhancer.
It can be seen from the above technique that the existing penetration enhancer has single function, and cannot increase the penetration enhancing effect of the product from multiple angles, and the cosmetics capable of improving the skin not only require the penetration enhancing effect, but also consider the absorption effect, because the penetration enhancing and the absorption are indispensable, the final effect of improving the skin is influenced.
The invention content is as follows:
the invention aims to overcome the defects in the prior art and provide a penetration-promoting composition containing hyaluronic acid and application thereof in cosmetics. The composition of the invention is added with hyaluronic acid with different molecular weights, bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and polyalcohol, has better permeation effect, and is combined with components with strong permeation and absorption functions to further promote the absorption of the hyaluronic acid and the bis-diethoxydol cyclohexane 1, 4-dicarboxylate. The permeation-promoting composition containing hyaluronic acid is combined with various acne-removing components, so that the prepared hyaluronic acid permeation-promoting acne-removing product can realize long-acting moisture preservation and has a better acne-removing effect.
The invention aims to provide a penetration-promoting composition containing hyaluronic acid, which comprises 2-5 parts of hyaluronic acid, 1-3 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 8-15 parts of polyalcohol by weight.
The hyaluronic acid is a mixture of macromolecular hyaluronic acid, small molecular hyaluronic acid, cross-linked hyaluronic acid and high-affinity hyaluronic acid, and the mass ratio of the macromolecular hyaluronic acid, the small molecular hyaluronic acid and the cross-linked hyaluronic acid to the high-affinity hyaluronic acid is 1 (1-3) to (2-4) to (1-4).
Wherein:
the molecular weight of the macromolecular hyaluronic acid is more than or equal to 1000kDa, and the macromolecular hyaluronic acid has good film forming property and can realize long-term water locking;
the molecular weight of the small molecular hyaluronic acid is 100-500 kDa, and the small molecular hyaluronic acid has good hydration effect;
the hyaluronic acid is crosslinked, so that double water locking is realized, and the moisture retention is more durable. Is prepared by the following steps: reacting sodium hyaluronate with a cross-linking agent to obtain cross-linked sodium hyaluronate gel A; respectively granulating the cross-linked sodium hyaluronate gel A to obtain gel B with the particle size of 100-800 mu m and gel C with the particle size of 70-100 mu m; mixing the gel B and the gel C, and crosslinking again to obtain crosslinked hyaluronic acid; wherein, the mass ratio of sodium hyaluronate: crosslinking agent 1: (100-2000), the cross-linking agent is one or more of polyethylene glycol, 1, 4-butanediol diglycidyl ether, divinyl sulfone, glutaraldehyde and diepoxide.
The high-affinity hyaluronic acid further enhances the water locking function and is prepared by the following method: taking cationic guar gum and hyaluronic acid and/or hyaluronate as raw materials, and carrying out complexation reaction in polyhydric alcohol to obtain the product, wherein the molecular weight of the hyaluronic acid and/or hyaluronate is 3kDa-2000kDa, and the molecular weight of the cationic guar gum is 100kDa-2000kDa, and the ratio of the hyaluronic acid and/or hyaluronate: the mass ratio of the cationic guar gum is 1: (0.01-100), wherein the polyol accounts for 10-20% of the high-affinity hyaluronic acid by mass.
The bis-diethoxydiol cyclohexane 1, 4-dicarboxylic acid ester is an oleophilic and hydrophilic amphoteric substance, acts on intercellular lipid pathways through epidermal penetration, and opens the stratum corneum for a short time, so that water-soluble ingredients can enter the inside of the skin, and the penetration effect of the water-soluble ingredients on the stratum corneum is improved. Moreover, experimental researches show that the skin care product can not cause damage to the skin.
The polyhydric alcohol is composed of one or more of glycerol, propylene glycol, polyethylene glycol, sorbitol, 1, 3-butanediol, 1, 2-hexanediol and pentanediol, and preferably glycerol.
The penetration-promoting composition containing hyaluronic acid also comprises 1-2 parts of azone.
The invention also aims to provide an application of the penetration-promoting composition containing hyaluronic acid, wherein the penetration-promoting composition containing hyaluronic acid is used for the hyaluronic acid penetration-promoting acne-removing moisturizing skin care lotion, the hyaluronic acid penetration-promoting acne-removing moisturizing skin care lotion comprises 5-10 parts of the penetration-promoting composition containing hyaluronic acid, 0.1-2 parts of oligomeric hyaluronic acid, 1-2 parts of a thickening agent, 1-4 parts of dipotassium glycyrrhizinate and 5-20 parts of deionized water, and the molecular weight of the oligomeric hyaluronic acid is less than 10 kDa.
The thickening agent is one or a combination of more of xanthan gum, high molecular fiber, nutrient wiredrawing protein sodium and coconut oil.
The dipotassium glycyrrhizinate has the effects of resisting inflammation, resisting allergy, preserving moisture and the like, and can realize the removal of acne marks.
The hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion can also comprise 1-3 parts of vitamin C derivatives and 2-5 parts of purslane extracts, wherein:
the vitamin C derivative is composed of one or more of sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl palmitate and ascorbyl glucoside, and is preferably ascorbyl glucoside.
The preparation method of the hyaluronic acid skin-care lotion capable of promoting permeation, removing acnes and moisturizing comprises the following steps:
s1: weighing the raw materials according to the component proportion of the permeation-promoting composition containing the hyaluronic acid, and uniformly mixing to obtain the permeation-promoting composition containing the hyaluronic acid;
s2: preparing materials according to the raw material proportion of the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent, a hyaluronic acid permeation-promoting composition and a vitamin C derivative, heating to 70-80 ℃, and uniformly stirring;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid, dipotassium glycyrrhizinate and purslane extract, and stirring until the oligomeric hyaluronic acid, the dipotassium glycyrrhizinate and the purslane extract are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
In step S1, the penetration enhancer composition containing hyaluronic acid is prepared by mixing polyhydric alcohol and bis-diethoxydiol cyclohexane 1, 4-dicarboxylate, heating to 37-45 deg.c, and stirring for 15-30min to obtain a mixture;
and sequentially adding the prepared macromolecular hyaluronic acid, the prepared small molecular hyaluronic acid, the prepared cross-linked hyaluronic acid and the prepared high-affinity hyaluronic acid into the mixture, stirring for 40-50min, adding azone, and uniformly stirring to obtain the permeation-promoting composition containing the hyaluronic acid.
In the step S2, the stirring time is 10-30 min.
In the step S2, when the vitamin C derivative is added, the vitamin C derivative is mixed with bis-diethoxydiol cyclohexane 1, 4-dicarboxylate in proportion, and then added into an emulsifying pot, followed by stirring and dissolving.
In the step S3, the stirring time is 15-30 min.
The invention has the beneficial effects that:
the permeation-promoting composition containing hyaluronic acid disclosed by the invention realizes long-term water locking without loss by adding macromolecular hyaluronic acid; hydration is realized through small molecular hyaluronic acid; through adding the cross-linked hyaluronic acid, double water locking is realized, and the moisture retention is more durable; through the addition of the high-affinity hyaluronic acid, the hyaluronic acid is better in affinity with the skin, the water locking function is further deepened, and the interaction of the four kinds of hyaluronic acid realizes different permeation promoting mechanisms, so that multiple water locking, moisturizing and permeation promoting functions are realized. In combination with the addition of bis-diethoxydiethylene glycol cyclohexane 1, 4-dicarboxylate and polyol, further enhances the penetration of the composition. The composition is combined with ingredients with strong penetration and absorption functions to further promote the absorption of the composition. The hyaluronic acid permeation-promoting acne-removing product prepared by combining the hyaluronic acid-containing permeation-promoting composition with various acne-removing components can realize long-acting moisture preservation and has a better acne-removing effect.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples.
In the following examples, the emulsifying pan used was a Fruk complete emulsifying apparatus, the type of which was FISCO-10L. All hyaluronic acid was obtained from Huaxi Biotech Ltd. The other ingredients are all commercially available.
In the following examples, cross-linked hyaluronic acid was prepared by the following method: reacting sodium hyaluronate with a cross-linking agent to obtain cross-linked sodium hyaluronate gel A; respectively granulating the cross-linked sodium hyaluronate gel A to obtain gel B with the particle size of 100-800 mu m and gel C with the particle size of 70-100 mu m; mixing the gel B and the gel C, and crosslinking again to obtain crosslinked hyaluronic acid; wherein, the mass ratio of sodium hyaluronate: crosslinking agent 1: (100-2000), the crosslinking agent is polyethylene glycol.
The high-affinity hyaluronic acid is prepared by the following method: taking cationic guar gum and hyaluronic acid and/or hyaluronate as raw materials, and carrying out complexation reaction in polyhydric alcohol to obtain the product, wherein the molecular weight of the hyaluronic acid and/or hyaluronate is 3kDa-2000kDa, the molecular weight of cationic guar gum is 100kDa-2000kDa, and the molecular weight of hyaluronic acid and/or hyaluronate is: the mass ratio of the cationic guar gum is 1: (0.01-100), wherein the polyol accounts for 10-20% of the high-affinity hyaluronic acid by mass.
The molecular weight of the oligomeric hyaluronic acid is less than 10 kDa.
Example 1
The penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.35 parts of macromolecular hyaluronic acid (1200kDa), 0.7 parts of small molecular hyaluronic acid (400kDa), 0.7 parts of cross-linked hyaluronic acid, 0.35 parts of high-affinity hyaluronic acid, 1.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 8 parts of glycerol;
a skin care lotion containing hyaluronic acid for promoting penetration, removing acne and moisturizing comprises the permeation promoting composition containing hyaluronic acid, and further comprises 0.1 part of oligomeric hyaluronic acid, 1 part of a thickening agent, 1 part of dipotassium glycyrrhizinate and 5 parts of deionized water, wherein in the embodiment, the thickening agent is xanthan gum.
A preparation method of a hyaluronic acid-containing skin moisturizer capable of promoting permeation, removing acnes and moisturizing skin comprises the following steps:
s1: weighing the raw materials according to the component proportion of the permeation-promoting composition containing the hyaluronic acid, and uniformly mixing to obtain the permeation-promoting composition containing the hyaluronic acid;
s2: preparing materials according to the raw material proportion of the hyaluronic acid-containing anti-acne moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent and a hyaluronic acid permeation promoting composition, heating to 70-80 ℃, and stirring for 15 min;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid and dipotassium glycyrrhizinate, and stirring until the oligomeric hyaluronic acid and the dipotassium glycyrrhizinate are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
Example 2
The penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.4 part of macromolecular hyaluronic acid (1200kDa), 0.4 part of small molecular hyaluronic acid (400kDa), 0.8 part of cross-linked hyaluronic acid, 0.8 part of high-affinity hyaluronic acid, 2.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 10 parts of glycerol;
the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the permeation-promoting composition containing hyaluronic acid, and further comprises 0.5 part of oligomeric hyaluronic acid, 1 part of a thickening agent, 1 part of dipotassium glycyrrhizinate and 5 parts of deionized water, wherein in the embodiment, the thickening agent is xanthan gum.
A preparation method of a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing is the same as that in example 1.
Example 3
The penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.5 part of macromolecular hyaluronic acid (1200kDa), 1.5 parts of small molecular hyaluronic acid (400kDa), 1.0 part of cross-linked hyaluronic acid, 2.0 parts of high-affinity hyaluronic acid, 3.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 15 parts of glycerol;
the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the permeation-promoting composition containing hyaluronic acid, and further comprises 1 part of oligomeric hyaluronic acid, 2 parts of a thickening agent, 3 parts of dipotassium glycyrrhizinate and 10 parts of deionized water, wherein in the embodiment, the thickening agent is xanthan gum.
A preparation method of a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing is the same as that in example 1.
Example 4
A penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.4 part of macromolecular hyaluronic acid (1200kDa), 0.8 part of small molecular hyaluronic acid (400kDa), 1.6 parts of cross-linked hyaluronic acid, 0.8 part of high-affinity hyaluronic acid, 3.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 15 parts of polyethylene glycol;
the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the permeation-promoting composition containing hyaluronic acid, and further comprises 2 parts of oligomeric hyaluronic acid, 2 parts of a thickening agent, 4 parts of dipotassium glycyrrhizinate and 20 parts of deionized water, wherein in the embodiment, the thickening agent is xanthan gum.
A preparation method of a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing is the same as that in example 1.
Example 5
A penetration-promoting composition containing hyaluronic acid comprises the components of, by weight, 0.4 part of macromolecular hyaluronic acid (1500kDa), 0.8 part of small molecular hyaluronic acid (300kDa), 1.6 parts of cross-linked hyaluronic acid, 0.8 part of high-affinity hyaluronic acid, 3.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 15 parts of glycerol; also comprises 1 part of azone.
The hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the permeation-promoting composition containing hyaluronic acid, and also comprises 2 parts of oligomeric hyaluronic acid, 2 parts of a thickening agent, 4 parts of dipotassium glycyrrhizinate and 20 parts of deionized water, wherein in the embodiment, the thickening agent is nutrient wiredrawing protein sodium.
A preparation method of a hyaluronic acid-containing skin moisturizer capable of promoting permeation, removing acnes and moisturizing skin comprises the following steps:
s1: weighing the raw materials according to the component proportion of the permeation-promoting composition containing the hyaluronic acid, mixing the polyhydric alcohol and the bis-diethoxydiol cyclohexane 1, 4-dicarboxylate, heating to 37-45 ℃, and stirring for 15-30min to obtain a mixture;
adding the prepared macromolecular hyaluronic acid, the prepared small molecular hyaluronic acid, the prepared cross-linked hyaluronic acid and the prepared high-affinity hyaluronic acid into the mixture in sequence, stirring for 40-50min, adding azone, and uniformly stirring to obtain the permeation-promoting composition containing hyaluronic acid.
S2: preparing materials according to the raw material proportion of the hyaluronic acid-containing anti-acne moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent and a hyaluronic acid permeation promoting composition, heating to 70-80 ℃, and stirring for 15 min;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid and dipotassium glycyrrhizinate, and stirring until the oligomeric hyaluronic acid and the dipotassium glycyrrhizinate are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
Example 6
The penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.4 part of macromolecular hyaluronic acid (1200kDa), 0.8 part of small molecular hyaluronic acid (400kDa), 1.6 parts of cross-linked hyaluronic acid, 0.8 part of high-affinity hyaluronic acid, 2.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 10 parts of glycerol; also comprises 1 part of azone.
The hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the hyaluronic acid-containing permeation-promoting composition, and further comprises 1 part of oligomeric hyaluronic acid, 1 part of a thickening agent, 3 parts of dipotassium glycyrrhizinate, 1.0 part of ascorbyl glucoside and 10 parts of deionized water, wherein in the embodiment, the thickening agent is xanthan gum.
A preparation method of a skin care lotion containing hyaluronic acid for promoting penetration, removing acne and moisturizing is the same as that in example 5.
The difference is that S2: preparing materials according to the raw material proportion of the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent, a hyaluronic acid permeation-promoting composition and a vitamin C derivative, heating to 70-80 ℃, and uniformly stirring;
example 7
A penetration-promoting composition containing hyaluronic acid comprises, by weight, 0.4 part of macromolecular hyaluronic acid (1200kDa), 0.8 part of small molecular hyaluronic acid (400kDa), 1.6 parts of cross-linked hyaluronic acid, 0.8 part of high-affinity hyaluronic acid, 3.0 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 15 parts of propylene glycol; also comprises 2 parts of azone.
The hyaluronic acid permeation-promoting acne-removing moisturizing skin lotion comprises the hyaluronic acid-containing permeation-promoting composition, and further comprises 2 parts of oligomeric hyaluronic acid, 2 parts of a thickening agent, 4 parts of dipotassium glycyrrhizinate, 20 parts of deionized water and 2 parts of a purslane extract, wherein in the embodiment, the thickening agent is coconut oil.
A preparation method of a skin care lotion containing hyaluronic acid for promoting penetration, removing acne and moisturizing is the same as that in example 5.
The difference is that S3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid, dipotassium glycyrrhizinate and purslane extract, and stirring until the oligomeric hyaluronic acid, the dipotassium glycyrrhizinate and the purslane extract are completely dissolved;
example 8
A penetration enhancing composition comprising hyaluronic acid is as in example 5.
The hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion comprises the hyaluronic acid-containing permeation-promoting composition, and further comprises 2 parts of oligomeric hyaluronic acid, 2 parts of a thickening agent, 4 parts of dipotassium glycyrrhizinate, 20 parts of deionized water, 5 parts of a purslane extract and 3 parts of ascorbyl palmitate.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acne and moisturizing is as in example 5.
The difference is that S2: preparing materials according to the raw material proportion of the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent, a hyaluronic acid permeation-promoting composition and a vitamin C derivative, heating to 70-80 ℃, and uniformly stirring;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid, dipotassium glycyrrhizinate and purslane extract, and stirring until the oligomeric hyaluronic acid, the dipotassium glycyrrhizinate and the purslane extract are completely dissolved;
example 9
A penetration enhancing composition comprising hyaluronic acid is the same as in example 8.
Hyaluronic acid skin moisturizer capable of promoting permeation, removing acnes and moisturizing skin is the same as in example 8.
A preparation method of a hyaluronic acid-containing skin moisturizer capable of promoting permeation, removing acnes and moisturizing skin comprises the following steps:
s1: weighing raw materials according to the component proportion of the permeation-promoting composition containing hyaluronic acid, uniformly mixing polyalcohol and bis-diethoxydiol cyclohexane 1, 4-dicarboxylate, heating to 37-45 ℃, and stirring for 15-30min to obtain a mixture;
adding the prepared macromolecular hyaluronic acid, the prepared small molecular hyaluronic acid, the prepared cross-linked hyaluronic acid and the prepared high-affinity hyaluronic acid into the mixture in sequence, stirring for 40-50min, adding azone, and uniformly stirring to obtain the permeation-promoting composition containing hyaluronic acid.
S2: preparing materials according to the raw material proportion of the hyaluronic acid-containing anti-acne moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent, a hyaluronic acid permeation promoting composition and ascorbic acid glucoside, heating to 70-80 ℃, and stirring for 30 min;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid and dipotassium glycyrrhizinate, and stirring until the oligomeric hyaluronic acid and the dipotassium glycyrrhizinate are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
Comparative example 1
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that 2.0 parts of glycerin;
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 2
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that 0.1 part of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate;
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 3
A penetration promoting composition comprising hyaluronic acid, as in example 5, except that 0.9 parts of macromolecular hyaluronic acid (1200kDa), 0.9 parts of small molecular hyaluronic acid (400kDa), 0.9 parts of cross-linked hyaluronic acid, 0.9 parts of high-affinity hyaluronic acid;
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 4
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that it does not comprise macromolecular hyaluronic acid (1200 kDa);
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 5
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that it does not comprise small molecule hyaluronic acid (400 kDa);
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 6
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that it does not comprise cross-linked hyaluronic acid;
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
Comparative example 7
A penetration enhancing composition comprising hyaluronic acid, as in example 5, except that it does not comprise high affinity hyaluronic acid;
a hyaluronic acid penetration-promoting acne-removing moisturizing lotion is prepared in the same manner as in example 5, except that the penetration-promoting composition containing hyaluronic acid is used.
A method for preparing a skin care lotion containing hyaluronic acid for promoting penetration, removing acnes and moisturizing, which is the same as example 9.
TABLE 1 penetration enhancing composition formulations containing hyaluronic acid
Figure BDA0002796773740000091
Figure BDA0002796773740000101
Application example 1
Dipotassium glycyrrhizinate skin permeability test
1. The experimental method comprises the following steps: fresh pig dorsal skin was debrided of hair and subcutaneous tissue and cut to size for use. Skin permeability studies were performed using Franz lateral diffusion cells. The back skin of the pig is fixed between two diffusion cells, the receiving solution is isotonic PBS (pH7.0-7.4), the test solutions are skin care solutions of examples 1-9 and comparative examples 1-7 respectively, and the transdermal test is carried out in triplicate in a circulating water bath at 37 ℃. Samples were taken at 4h, 8h and 24h after the start of the test, and the contents of the components in the receptor fluid, the stratum corneum, the top layer and the dermis of the skin were measured, respectively, to calculate the cumulative transmittance or retention (%).
2. Method for detecting cumulative transmittance or retention (%) of each component
2.1 treatment of the receiving fluid sample: after sampling, the sample was filtered through a 0.22 μm filter to prepare a test sample. Detecting and calculating the effective component accumulated transmittance.
2.2 treatment of stratum corneum samples: taking down the pigskin on the diffusion pool, sucking off excessive moisture on the skin surface by using filter paper, repeatedly sticking and tearing one side of the skin cuticle by using a transparent adhesive tape for 20 times, and completely sticking and tearing the cuticle on the transparent adhesive tape. Putting the transparent adhesive tape into a glass bottle, adding quantitative purified water, and ultrasonically extracting dipotassium glycyrrhizinate in the horny layer. The extract was filtered through a 0.22 μm filter to prepare a sample. And cutting the back skin of a blank pig which is not used for the transdermal test into the same size as the transdermal test, treating by the same method, and using the extract as a blank control of a stratum corneum sample to deduct the influence of the inherent components in the stratum corneum. The cumulative retention rate of the effective components in the stratum corneum is detected and calculated.
2.3 treatment of epidermal and dermal layer samples: cutting the back skin of the pig with the cuticle layer torn off, placing the cut back skin into a glass bottle, adding quantitative purified water, and ultrasonically extracting dipotassium glycyrrhizinate. The extract was filtered through a 0.22 μm filter to prepare a sample. And taking a blank pig back skin which is not used for the transdermal test, cutting the blank pig back skin into the same size as the transdermal test, performing the same treatment, and using the extract as a blank control of the epidermis and dermis samples to deduct the influence of inherent components in the epidermis and dermis. The cumulative retention rate of the effective components in the epidermis and the dermis layers is detected and calculated.
2.4 detection method of dipotassium glycyrrhizinate: detecting the content of dipotassium glycyrrhizinate by liquid chromatography of SN/T1500-2004.
3. The calculation formula of the accumulated transmittance or retention (%) of dipotassium glycyrrhizinate is as follows:
the cumulative transmittance (%) — total permeation amount in the receiving solution/total amount in the test solution diffusion cell 100%.
The cumulative retention (%) — total retention in the skin/total amount in the test solution diffusion cell 100%.
4. Test results
The cumulative transmittance and retention rate of dipotassium glycyrrhizinate in each sample are shown in table 2 below.
TABLE 2 cumulative permeation rate of dipotassium glycyrrhizinate in receiving solution
Figure BDA0002796773740000111
TABLE 3 cumulative residence rate of dipotassium glycyrrhizinate
Figure BDA0002796773740000112
Figure BDA0002796773740000121
As can be seen from the above table, the cumulative transmittance of comparative example 1, comparative example 2 and comparative example 5 is low, indicating that the polyhydric alcohol, bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and small molecular hyaluronic acid are the most important factors affecting the transdermal permeability, and the components have synergistic effect in the transdermal absorption rate. While the cumulative transmission in the receiving solution is higher for examples 5-9 than for examples 1-4, which illustrates the benefit of increased transdermal transport by addition of azone.
The retention rate of the hyaluronic acid in the horny layer, the epidermis and the dermis is lower in the comparative examples 6 and 7, which shows that the retention rate of the functional components can be increased by adding the cross-linked hyaluronic acid and the high-affinity hyaluronic acid, and the using effect of the product is improved.
Application example 2
51 volunteers with the average age of 25-45 years are selected, the skin is oily skin with mild and moderate acne, 21 male volunteers and 30 female volunteers are selected. The skin lotions prepared in examples 1 to 9 and comparative examples 1 to 7 were randomly divided into 17 groups of 3 skin lotions each, and used as experimental groups and control groups, and blank groups without the product. Applying moisturizing lotion on face of subject twice a day in the morning and evening with the guide dosage of 2mg/cm2And continuously used for 4 weeks. During the experiment, the subject was not able to apply any other cosmetic product at the experimental site.
1. Moisture retention efficacy test
The moisture content of the skin of each group was measured using a corneometer cm825 skin tester on the 0 th, 7 th, 14 th and 28 th days of application in an indoor environment at 20 ℃ and a relative humidity of 50%, and the results are shown in table 2.
TABLE 2 moisture content variation of skin
Day 0 Day 7 Day 14 Day 28
Example 1 50.57 61.59 65.95 70.13
Example 2 50.86 62.15 68.88 72.06
Example 3 51.49 64.27 67.48 69.57
Example 4 49.06 62.11 65.0 67.29
Example 5 52.90 66.45 71.76 73.45
Example 6 50.24 64.60 67.52 71.10
Example 7 53.15 68.09 72.82 74.60
Example 8 55.00 68.27 71.28 79.27
Example 9 58.67 70.11 73.90 81.56
Comparative example 1 45.25 51.82 53.05 54.28
Comparative example 2 41.58 53.08 53.74 53.97
Comparative example 3 45.80 58.06 60.80 61.92
Comparative example 4 41.63 43.08 53.58 54.71
Comparative example 5 43.82 46.11 55.41 56.05
Comparative example 6 42.75 45.40 56.18 57.52
Comparative example 7 41.66 43.13 53.55 54.95
Blank group 35.59 38.37 43.23 40.15
The contrast shows that the penetration promoting composition contains the hyaluronic acid composition, so that the transdermal absorption effect of the active ingredients can be improved, the moisturizing effect is good, the skin wettability can be fully improved, and no adverse reaction is caused.
2. Acne removing effect experiment
In an indoor environment with the temperature of 20 ℃ and the relative humidity of 50%, the acne mark removing effect of each group of people is recorded on the days 0, 7, 14 and 28 after smearing, the acne mark removing effect is scored by testers according to the feelings of the testers, the score is 10, the higher the score is, the better the effect is, and the result is shown in table 3.
TABLE 3 acne mark removing effect evaluation table
Figure BDA0002796773740000131
Figure BDA0002796773740000141
The acne removing cream has the advantages of high skin penetration rate for acne removing effect, increased permeability of acne removing components, high skin retention rate, strengthened absorption of effective components, and remarkable acne removing effect by adding the acne removing components of vitamin C and purslane.
Various other changes and modifications to the above embodiments and concepts will become apparent to those skilled in the art, and all such changes and modifications are intended to be included within the scope of the present invention as defined in the appended claims.

Claims (10)

1. The penetration-promoting composition containing hyaluronic acid is characterized by comprising, by weight, 2-5 parts of hyaluronic acid, 1-3 parts of bis-diethoxydiol cyclohexane 1, 4-dicarboxylate and 8-15 parts of polyhydric alcohol, wherein:
the hyaluronic acid is a mixture of macromolecular hyaluronic acid, small molecular hyaluronic acid, cross-linked hyaluronic acid and high-affinity hyaluronic acid, and the mass ratio of the macromolecular hyaluronic acid, the small molecular hyaluronic acid and the cross-linked hyaluronic acid to the high-affinity hyaluronic acid is 1 (1-3) to (2-4) to (1-4).
2. The pro-osmotic composition comprising hyaluronic acid according to claim 1, further comprising azone in an amount of 1-2 parts.
3. The pro-osmotic composition comprising hyaluronic acid according to claim 1 or 2, wherein the molecular weight of said macromolecular hyaluronic acid is greater than or equal to 1000 kDa; the molecular weight of the small molecular hyaluronic acid is 100kDa-500 kDa; the cross-linked hyaluronic acid is prepared by the following method: reacting sodium hyaluronate with a cross-linking agent to obtain cross-linked sodium hyaluronate gel A; respectively granulating the cross-linked sodium hyaluronate gel A to obtain gel B with the particle size of 100-800 mu m and gel C with the particle size of 70-100 mu m; mixing the gel B and the gel C, and crosslinking again to obtain crosslinked hyaluronic acid; wherein, the mass ratio of sodium hyaluronate: crosslinking agent 1: (100-2000), the cross-linking agent is one or more of polyethylene glycol, 1, 4-butanediol diglycidyl ether, divinyl sulfone, glutaraldehyde and diepoxide; the high-affinity hyaluronic acid is prepared by the following method: taking cationic guar gum and hyaluronic acid and/or hyaluronate as raw materials, and carrying out complexation reaction in polyhydric alcohol to obtain the product, wherein the molecular weight of the hyaluronic acid and/or hyaluronate is 3kDa-2000kDa, the molecular weight of cationic guar gum is 100kDa-2000kDa, and the molecular weight of hyaluronic acid and/or hyaluronate is: the mass ratio of the cationic guar gum is 1: (0.01-100), wherein the polyol accounts for 10-20% of the high-affinity hyaluronic acid by mass.
4. The penetration enhancing composition of hyaluronic acid according to claim 1 or 2, wherein the polyol consists of one or more of glycerol, propylene glycol, polyethylene glycol, sorbitol, 1, 3-butanediol, 1, 2-hexanediol and pentanediol.
5. The hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion is characterized by comprising 10-25 parts of the permeation-promoting composition containing hyaluronic acid of claim 1 or 2, 0.1-2 parts of oligomeric hyaluronic acid, 1-2 parts of a thickening agent, 1-4 parts of dipotassium glycyrrhizinate and 5-20 parts of deionized water;
the thickening agent is one or a combination of more of xanthan gum, high molecular fiber, nutrient wiredrawing protein sodium and coconut oil.
6. The hyaluronic acid penetration-promoting acne-removing moisturizing lotion as claimed in claim 5, further comprising 1-3 parts of vitamin C derivatives and/or 2-5 parts of purslane extract, wherein:
the vitamin C derivative is composed of one or more of sodium ascorbyl phosphate, magnesium ascorbyl phosphate, ascorbyl palmitate and ascorbyl glucoside.
7. The preparation method of the hyaluronic acid penetration-promoting acne-removing moisturizing lotion as claimed in claim 5, which is characterized by comprising the following steps:
s1: weighing the raw materials according to the component proportion of the permeation-promoting composition containing the hyaluronic acid, and uniformly mixing to obtain the permeation-promoting composition containing the hyaluronic acid;
s2: preparing materials according to the raw material proportion of the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent and a hyaluronic acid permeation-promoting composition, heating to 70-80 ℃, and uniformly stirring;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid and dipotassium glycyrrhizinate, and stirring until the oligomeric hyaluronic acid and the dipotassium glycyrrhizinate are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
8. The preparation method of the hyaluronic acid penetration-promoting acne-removing moisturizing lotion as claimed in claim 6, which is characterized by comprising the following steps:
s1: weighing the raw materials according to the component proportion of the permeation-promoting composition containing the hyaluronic acid, and uniformly mixing to obtain the permeation-promoting composition containing the hyaluronic acid;
s2: preparing materials according to the raw material proportion of the hyaluronic acid permeation-promoting acne-removing moisturizing skin care lotion, adding deionized water into an emulsifying pot, sequentially adding a weighed thickening agent, a hyaluronic acid permeation-promoting composition and a vitamin C derivative, heating to 70-80 ℃, and uniformly stirring;
s3: when the temperature of the emulsifying pot is reduced to 50-65 ℃, sequentially adding the weighed oligomeric hyaluronic acid, dipotassium glycyrrhizinate and purslane extract, and stirring until the oligomeric hyaluronic acid, the dipotassium glycyrrhizinate and the purslane extract are completely dissolved;
s4: when the temperature of the emulsifying pot is reduced to room temperature, the hyaluronic acid skin-care lotion for promoting the penetration, removing acnes and moisturizing is prepared.
9. The method for preparing the hyaluronic acid penetration-promoting acne-removing moisturizing lotion as claimed in claim 7 or 8, wherein in step S1, the penetration-promoting composition containing hyaluronic acid is prepared by mixing polyhydric alcohol and bis-diethoxydiol cyclohexane 1, 4-dicarboxylate, heating to 37-45 ℃, and stirring for 15-30min to obtain a mixture;
adding the prepared macromolecular hyaluronic acid, the prepared small molecular hyaluronic acid, the prepared cross-linked hyaluronic acid and the prepared high-affinity hyaluronic acid into the mixture in sequence, stirring for 40-50min, adding azone, and uniformly stirring to obtain the permeation-promoting composition containing hyaluronic acid.
10. The preparation method of the hyaluronic acid penetration-promoting, acne-removing and moisturizing lotion according to claim 7 or 8, wherein in the step S2, the stirring time is 10-30 min;
in the step S2, when the vitamin C derivative is added, the bis-diethoxydiol cyclohexane 1, 4-dicarboxylate in the penetration enhancer composition containing hyaluronic acid may be mixed with the vitamin C derivative according to a certain ratio, and then added into an emulsifying pot, and stirred to dissolve; in the step S3, the stirring and dissolving time is 15-30 min.
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