CN112957276A

CN112957276A - Multi-effect hydroxy pinacolone retinoic acid ester nano composition and preparation method and application thereof

Info

Publication number: CN112957276A
Application number: CN202110175444.9A
Authority: CN
Inventors: 刘卫; 吴航航; 罗佳; 沈慧慧; 陈家玲; 王曦; 吕赛龙
Original assignee: Wuhan Best Carrier Biotechnology Co ltd
Current assignee: Wuhan Best Carrier Biotechnology Co ltd
Priority date: 2021-02-06
Filing date: 2021-02-06
Publication date: 2021-06-15
Anticipated expiration: 2041-02-06
Also published as: CN112957276B

Abstract

The invention relates to the field of cosmetics, and in particular relates to a multi-effect hydroxy pinacolone retinoic acid ester nano composition which comprises hydroxy pinacolone retinoic acid ester, nicotinamide, glycyrrhetinic acid, an emulsifier, a co-emulsifier and polyhydric alcohol. The hydroxy pinacolone retinoic acid ester accounts for 0.1-10% of the total mass of the nano composition; the nicotinamide accounts for 0.1-10% of the total mass of the nano composition; the glycyrrhetinic acid accounts for 0.1-10% of the total mass of the nano composition. The nano composition disclosed by the invention wraps the hydroxy pinacolone retinoic acid ester, the nicotinamide and the glycyrrhetinic acid, so that the stability of the functional components is effectively improved. The three functional components of the nano composition are reasonably matched and synergically, enter deep tissues of skin through skin barriers, improve the bioavailability, increase the effects of resisting aging, removing acnes and whitening skin, are mild and non-irritant to the skin, and can be widely applied to cosmetics.

Description

Multi-effect hydroxy pinacolone retinoic acid ester nano composition and preparation method and application thereof

Technical Field

The invention relates to the technical field of cosmetics, in particular to a multi-effect hydroxy pinacolone retinoic acid ester nano composition and a preparation method and application thereof.

Background

Retinoids generally refer to compounds having the main basic structure of vitamin a and oxidative metabolites thereof, and have significant effects on aging resistance, acne removal, whitening, and the like. In most cases, the conversion of retinoids to retinoic acid has an effect on the skin. Wherein, the all-trans retinoic acid is a common active form of retinoic acid, can increase the expression of aquaporin 3(AQP3) in normal human skin, increase the permeability of cell membrane water, and participate in the secretion and absorption of water and the regulation of the balance between inside and outside of cells. However, overexpression of AQP3 increased transdermal water loss, causing dry and sensitive skin.

It has been shown that hydroxy pinacolone retinoic acid ester is a novel retinoid component, a derivative of retinoic acid, which is not converted into retinoic acid in vivo, and directly binds to cell Retinoic Acid Receptors (RARs) to exert its effect; niacinamide can suppress the over-expression of AQP3 induced by all-trans retinoic acid, and reduce the skin sensitivity; glycyrrhetinic acid is a high-activity anti-inflammatory component, and can reduce skin inflammation and sensitivity, and has auxiliary effects of resisting aging, removing acne, and whitening skin. However, the hydroxy pinacolone retinoic acid ester is sensitive to light and heat, is easy to oxidize and degrade after being directly added into a skin care product for a period of time, has poor stability, not only causes the efficacy of the skin care product to be reduced, but also causes skin irritation; the amide structure of nicotinamide is easily oxidized to generate nicotinic acid, which causes irritation to skin; the solubility of glycyrrhetinic acid is very small, the addition amount is low, and crystallization is easy to separate out. Moreover, the skin has a barrier function, and functional active substances hardly penetrate through the stratum corneum to reach the deep structure of the skin to play a role, so that the bioavailability is low, and the efficacy of the functional active substances cannot be fully played.

Disclosure of Invention

In view of the above, the invention provides a multi-effect hydroxy pinacolone retinoic acid ester nano-composition and a preparation method and application thereof. The multi-effect hydroxy pinacolone retinoic acid ester nano composition provided by the invention effectively improves the solubility, stability and skin permeability of hydroxy pinacolone retinoic acid ester, nicotinamide and glycyrrhetinic acid, reduces irritation, and has the effects of synergism and attenuation.

In order to solve the above problems, the present invention provides the following technical solutions:

the invention provides a multi-effect hydroxy pinacolone retinoic acid ester nano composition, which comprises hydroxy pinacolone retinoic acid ester, nicotinamide, glycyrrhetinic acid, an emulsifier, an auxiliary emulsifier and polyhydric alcohol;

the hydroxy pinacolone retinoic acid ester accounts for 0.1-10% of the total mass of the nano composition;

the nicotinamide accounts for 0.1-10% of the total mass of the nano composition;

the glycyrrhetinic acid accounts for 0.1-10% of the total mass of the nano composition.

Preferably, the total mass of the nano composition is 1-20% of the emulsifier, 1-20% of the co-emulsifier and 1-20% of the polyol.

Preferably, the emulsifier comprises one or more of polyglyceryl-10 stearate, polyglyceryl-10 diisostearate, polyoxyethylene hydrogenated castor oil, ceteareth, coco glucoside, macrogol laurate, lecithin, and polyglyceryl-10 myristate;

the coemulsifier comprises one or more of diethylene glycol monoethyl ether, PPG-26-butanol polyether-26, ethoxy diethylene glycol oleate, tridecyl alcohol polyether-9, coconut oil alcohol polyether-7, PPG-1-PEG-9 lauryl glycol ether and octyl dodecanol;

the polyalcohol comprises one or more of sorbitol, glycerol, 1, 3-propylene glycol, 1, 2-butanediol, 1, 2-pentanediol, 1, 2-hexanediol, dipropylene glycol, and polyethylene glycol-400.

Preferably, the multi-effect hydroxyppinacolone retinoic acid ester nano-composition further comprises a solvent for dissolving the efficacy active ingredient, wherein the solvent comprises liquid lipid and water;

based on the total mass of the nano composition, the liquid lipid accounts for 1-20%, and the water accounts for 0.1-95.7%.

Preferably, the liquid lipid comprises one or more of vegetable oil and fat and synthetic oil and fat.

The invention also provides a preparation method of the multi-effect hydroxy pinacolone retinoic acid ester nano composition in the technical scheme, which comprises the following steps:

mixing hydroxy pinacolone retinoic acid ester, glycyrrhetinic acid, liquid lipid, emulsifier, co-emulsifier and polyol to obtain an oil phase;

mixing nicotinamide and water to obtain a water phase;

mixing and emulsifying the water phase and the oil phase, and then carrying out micron treatment to obtain a micron-sized dispersion;

and carrying out nanocrystallization treatment on the micron-sized dispersion to obtain the multi-effect hydroxy pinacolone retinoic acid ester nano composition.

Preferably, the mixed emulsification mode comprises the following steps: the aqueous phase was added dropwise to the oil phase with stirring.

Preferably, the micron treatment is shear emulsification, and the nano treatment is high-pressure homogenization treatment or high-speed micro-jet treatment.

The invention also provides application of the multi-effect hydroxy pinacolone retinoic acid ester nano composition in cosmetics.

The invention provides a multi-effect hydroxy pinacolone retinoic acid ester nano composition, which comprises hydroxy pinacolone retinoic acid ester, nicotinamide, glycyrrhetinic acid, an emulsifier, an auxiliary emulsifier and polyhydric alcohol; wherein the hydroxy pinacolone retinoic acid ester accounts for 0.1-10% of the total mass of the nano composition; the nicotinamide accounts for 0.1-10% of the total mass of the nano composition; the glycyrrhetinic acid accounts for 0.1-10% of the total mass of the nano composition.

According to the nano composition provided by the invention, the active ingredient is wrapped in the auxiliary material, so that the solubility of the active ingredient can be increased, the stability of the active ingredient is improved, and the active ingredient can easily penetrate through a skin barrier to enter deep tissues of the skin to play a role on the premise of reducing the stimulation effect on the skin, the bioavailability is obviously improved, and the skin care effect is more excellent; wherein, the efficacy mechanism of the hydroxy pinacolone retinoic acid ester is as follows: (1) anti-aging, which can stimulate fibroblasts to synthesize collagen, increase skin elasticity, inhibit the activity of matrix metalloproteinase excessively stimulated by ultraviolet rays, and promote the synthesis of metalloproteinase tissue inhibitors, thereby inhibiting the fracture of collagen and fibroblasts and preventing photoaging; (2) removing acne, inhibiting TLR expression, preventing interleukin and interferon production, and inhibiting CD4⁺And CD8⁺The infiltration of lymphocytes and macrophages eliminates the obstruction of sebaceous glands and reduces the number of propionibacterium acnes flora; (3) whitening skin, inhibiting expression of tyrosinase and tyrosinase related protein, inhibiting melanin synthesis, and homogenizing skin color. Niacinamide, one of the vitamin B family members, has the mechanism of efficacy: (1) whitening, namely more remarkable effects of effectively reducing pigmentation and increasing skin glossiness through inhibiting the transport of melanosomes from melanocytes to surrounding keratinocytes; (2) acne removal, improving acne by inhibiting sebum secretion; (3) anti-aging, simultaneously used as precursor substances of NADH and NADPH, regulating the balance of NADH and NADPH in vivo, playing the roles of anti-aging and anti-oxidation, preventing spontaneous glycosylation reaction of protein and sugar, repairing DNA damage induced by ultraviolet, effectively protecting cells, especially cell membranes, from oxygen free radical damage, and preventing photoaging. One of the active ingredients of the nano composition is glycyrrhetinic acid which is a high-activity anti-inflammatory ingredient and can reduce skin inflammation and sensitivity, assist anti-aging, acne removal and whitening effects.

In addition, the hydroxy pinacolone retinoic acid ester, nicotinamide and glycyrrhetinic acid are contained in the same nano composition together in a reasonable amount, and active ingredients of different mechanisms are reasonably matched and synergized.

Furthermore, the nano composition provided by the invention has the characteristics of small particle size of 10-200 nm, large specific surface area, stronger adhesion and biocompatibility with cells, and can promote active ingredients to effectively permeate into active epidermis and dermis tissues and stay in the tissues for a long time, and can be slowly released and controlled to obviously improve the skin permeation amount and the skin retention amount of the active ingredients, so that the bioavailability of the active ingredients is improved, the transdermal targeted delivery of the three active ingredients is realized, and the anti-aging, anti-acne, whitening and skin-care effects of the three active ingredients are obviously enhanced.

Furthermore, the nano composition provided by the invention is easy to dissolve in water, can improve the solubility of active substances in water, and can be directly added into different types of anti-aging, anti-acne and whitening products, so that the cosmetics have the advantages of small anti-aging and anti-acne property, good stability, convenience in use and the like.

Drawings

FIG. 1 is a graph showing a comparison of the state of samples of the nano-composition of example 5 before and after 12 months of storage at room temperature;

FIG. 2 is a comparison graph of the state of the sample before and after being left at room temperature for 3 months in comparative example 1;

FIG. 3 is a comparison graph of the state of the sample before and after the sample is left at room temperature for 6 months in comparative example 2;

FIG. 4 is a comparison graph of the state of the sample before and after 9 months of storage at room temperature in comparative example 3;

FIG. 5 is a cumulative body skin penetration after 12 hours for the nanocomposite cream prepared in application example 1 and the general cream prepared in comparative example 5;

FIG. 6 is an in vitro skin retention of the nanocomposite cream prepared in application example 1 and the general cream prepared in comparative example 5;

FIG. 7 is a graph of comparative analysis of particle size versus skin penetration and retention for examples 13-17 and comparative example 8;

FIG. 8 is a graph of the average surface wrinkle reduction for samples Nos. 1-5; in comparison with the sample No. 3,^aP<0.05; in comparison with the sample No. 4,^bP<0.05; in comparison with the sample No. 5,^cP<0.05；

FIG. 9 shows the relative change rate of MI value of melanin of samples No. 1-5; in comparison with the sample No. 3,^aP<0.05; in comparison with the sample No. 4,^bP<0.05; in comparison with the sample No. 5,^cP<0.05。

Detailed Description

The present invention does not require any particular source of the components unless otherwise specified, and may be carried out using commercially available products well known to those skilled in the art.

The multi-effect hydroxy pinacolone retinoic acid ester nano composition provided by the invention preferably comprises 0.1-10% of hydroxy pinacolone retinoic acid ester by mass percentage, more preferably 0.5-8%, more preferably 1-6%, and most preferably 2-4%. In the invention, the multi-effect hydroxy pinacolone retinoic acid ester can stimulate fibroblasts to synthesize collagen, so that the skin elasticity is increased; can also inhibit activity of matrix metalloproteinase after being over-stimulated by ultraviolet rays, and promote synthesis of tissue inhibitor of metalloproteinase, thereby inhibiting collagen and fibrous tissue from breaking and preventing photoaging; and can inhibit TLR expression, prevent interleukin and interferon production, and inhibit CD4⁺And CD8⁺The infiltration of lymphocytes and macrophages eliminates the obstruction of sebaceous glands and reduces the number of propionibacterium acnes flora; can also inhibit the expression of tyrosinase and tyrosinase related protein, thereby inhibiting melanin synthesis and homogenizing skin color.

The multi-effect hydroxy pinacolone retinoic acid ester nano composition provided by the invention preferably comprises 0.1% -10% of nicotinamide by mass percentage; more preferably 0.5 to 8%, more preferably 1 to 6%, and most preferably 2 to 4%; in the invention, nicotinamide is one of vitamin B family members, and has more remarkable effects of effectively reducing pigmentation and increasing skin glossiness by inhibiting the transport of melanosomes from melanocytes to surrounding keratinocytes under the multiple functions of hydroxy pinacolone retinoic acid ester; niacinamide can also improve acne by inhibiting sebum secretion; simultaneously, the compound is used as a precursor substance of NADH and NADPH, regulates the balance of the NADH and the NADPH in vivo, plays the roles of anti-aging and anti-oxidation, prevents the spontaneous glycosylation reaction of protein and sugar, can also repair DNA damage induced by ultraviolet rays, effectively protects cells, particularly cell membranes from being damaged by oxygen free radicals, and prevents photoaging.

The multi-effect hydroxy pinacolone retinoic acid ester nano composition provided by the invention preferably comprises 0.1-10% of glycyrrhetinic acid in percentage by mass; more preferably 0.5 to 8%, more preferably 1 to 6%, and most preferably 2 to 4%; in the invention, the glycyrrhetinic acid is a high-activity anti-inflammatory component, and can reduce skin inflammation and sensitivity, and assist in anti-aging, acne removal and whitening.

In the invention, the multi-effect hydroxy pinacolone retinoic acid ester is compounded with nicotinamide and glycyrrhetinic acid, so that a synergistic effect exists. The anti-aging, anti-acne and whitening effects are better than those of single-component high-concentration use after the compound preparation is reasonably controlled, namely the anti-aging, anti-acne and whitening effects are improved by compounding the multi-effect hydroxy pinacolone retinoic acid ester with the nicotinamide and the glycyrrhetinic acid.

In the present invention, the multi-effect hydroxyppinacolone retinoic acid ester nano-composition preferably further comprises a solvent for dissolving the efficacy active ingredient, wherein the solvent comprises liquid lipid and water.

In the present invention, the liquid lipid includes, but is not limited to, one or more of vegetable oil and fat and synthetic oil and fat. The vegetable oil and fat is preferably one or more of cocoa seed fat, squalene and soybean oil, and is further preferably cocoa seed fat and/or soybean oil; the synthetic grease is preferably one or more of caprylic/capric triglyceride, isononyl isononanoate, isopropyl myristate, isopropyl palmitate, isoamyl laurate, simethicone, propylene glycol monocaprylate and glyceryl triacetate, and is further preferably one or more of caprylic/capric triglyceride, isononyl isononanoate, isopropyl myristate, isopropyl palmitate and glyceryl triacetate; more preferably, the lipid is one or more of caprylic/capric triglyceride, isopropyl myristate and isopropyl palmitate, and the liquid lipid consists of 2-3 of the above substances; more preferably, the liquid lipid is a mixture of dimethyl silicone oil, propylene glycol monocaprylate and cocoa seed butter, and the mass ratio of the dimethyl silicone oil, the propylene glycol monocaprylate and the cocoa seed butter is preferably 1-10: 1-5: 1-5, more preferably 5: 2: 3. in the invention, the liquid lipid and water form an oil-water interfacial film to wrap active ingredients under the action of the surfactant, the oil is very important for the existence of a single-phase region of the nano-emulsion and the solubilization of the medicament, and the single oil sometimes cannot meet the requirements of the nano-emulsion preparation on the oil phase and needs to be mixed with different oils.

In the present invention, the mass of the liquid lipid is 1 to 20%, preferably 5 to 15%, more preferably 6 to 12%, and still more preferably 8 to 10% of the total mass of the nano composition.

In the invention, the emulsifier is preferably one or more of polyglycerol-10 stearate, polyglycerol-10 diisostearate, coco glucoside, polyethylene glycol laurate, lecithin and polyglycerol-10 myristate, and is further preferably one or more of polyglycerol-10 stearate, polyglycerol-10 diisostearate, coco glucoside and lecithin, and the emulsifier is composed of 1-2 of the substances; more preferably, the emulsifier is a mixture of polyglycerol-10 stearate and polyglycerol-10 diisostearate, and the mass ratio of the polyglycerol-10 distearate to the polyglycerol-10 diisostearate is preferably 0.5-2: 1, more preferably 1: 1. in the invention, the emulsifier is selected from specific nonionic emulsifiers, has good skin compatibility, is mild and non-irritant, has high stability, and has the main function of forming a firm emulsion film so as to reduce the tension of an oil-water interface and also has a solubilizing effect on active ingredients. The dosage proportion of the emulsifier is proper, when the dosage is too small, the emulsifying capacity is low, the property is unstable, and when the dosage is too large, micelles are easy to form, and the release of the medicine is directly influenced. When different emulsifiers are used in a matching way, a compact and high-strength composite film is formed due to the interaction between the molecules of the emulsifiers, so that the nano composition is more stable.

In the invention, the mass of the emulsifier is 1-20% of the total mass of the nano composition, preferably 5-15%, more preferably 6-13%, and even more preferably 7-10%.

In the invention, the coemulsifier is preferably one or more of diethylene glycol monoethyl ether, PPG-26-butanol polyether-26, coconut oil alcohol polyether-7, PPG-1-PEG-9 lauryl glycol ether and octyl dodecanol, and is further preferably one or more of diethylene glycol monoethyl ether, PPG-26-butanol polyether-26 and octyl dodecanol, and the coemulsifier consists of 1 or 2 of the substances; more preferably, the coemulsifier is a mixture of diethylene glycol monoethyl ether and PPG-26-butanol polyether-26, and the mass ratio of the diethylene glycol monoethyl ether to the PPG-26-butanol polyether-26 is preferably 0.5-2: 1, more preferably 1: 1. in the invention, the co-emulsifier can improve the flexibility and firmness of an oil-water interface film, can also increase the solubility of the emulsifier, assists the emulsifier to adjust the lipophilic and hydrophilic balance value, and reduces the interface tension and the viscosity of the whole system.

In the invention, the mass of the co-emulsifier is 1-20%, preferably 5-15%, more preferably 6-13%, and even more preferably 7-10% of the total mass of the nano composition.

In the invention, the polyhydric alcohol is preferably one or more of sorbitol, glycerol, 1, 3-propylene glycol, butanediol, 1, 2-pentanediol, 1, 2-hexanediol and dipropylene glycol, and is more preferably one or more of glycerol, 1, 3-propylene glycol, butanediol, 1, 2-pentanediol and 1, 2-hexanediol, and the polyhydric alcohol is composed of 1-2 of the substances; more preferably, the polyhydric alcohol is a mixture of 1, 2-pentanediol and 1, 2-hexanediol, and the mass ratio of the two is preferably 0.5-2: 1, more preferably 1: 1. in the invention, the polyalcohol not only can play a role in emulsification assistance, change the rigidity of a nanoemulsion framework, improve the emulsification stability of liquid oil and fat, reduce the interfacial tension so as to form the nanoemulsion spontaneously and enlarge the formation area of the nanoemulsion, but also has a transdermal promotion function, can promote an active substance to penetrate through a skin cuticle and can improve the solubility and water dispersibility of an insoluble active substance.

In the present invention, the mass of the polyol is 1 to 20%, preferably 5 to 15%, more preferably 7 to 12%, and still more preferably 8 to 10% of the total mass of the nano composition.

The invention adopts water as solvent to dissolve nicotinamide; the water is preferably distilled water or purified water; removing other substances contained in the multi-effect hydroxy pinacolone retinoic acid ester nano composition, and the balance of water; specifically, the content of water is preferably 0.1-95.7%.

mixing nicotinamide and water to obtain a water phase;

The preparation method provided by the invention has the advantages that the oil phase and the water phase are respectively prepared, and the solubility of the active ingredients is improved. The micron-sized and nano-sized treatment is carried out in sequence, so that the functional components are promoted to enter deep tissues of the skin and target cells of the skin through skin barriers, the bioavailability of the functional components is remarkably improved, and the effects of resisting aging, removing acnes and whitening are enhanced. In addition, the nano composition has good stability and is mild and non-irritant to skin.

The invention mixes hydroxy pinacolone retinoic acid ester, glycyrrhetinic acid, liquid lipid, emulsifier, auxiliary emulsifier and polyol to obtain oil phase. In the invention, the mixing temperature is preferably 20-60 ℃, 30-50 ℃ and more preferably 35-45 ℃.

The invention mixes nicotinamide and water to obtain an aqueous phase, and preferably nicotinamide is added to water to obtain an aqueous phase. In the invention, the mixing temperature is preferably 20-60 ℃, more preferably 30-50 ℃, and even more preferably 35-45 ℃. The invention preferably carries out dissolution under the condition of water bath, so that the components are uniformly dispersed.

After obtaining the water phase and the oil phase, the invention mixes and emulsifies the oil phase and the water phase, and then carries out micron treatment to obtain the micron-sized dispersoid. In the present invention, the mixing and emulsifying method preferably includes: the aqueous phase was added dropwise to the oil phase. The dripping speed is preferably 1-8 drops/second, and more preferably 3-6 drops/second; more preferably, the dropwise adding of the water phase is carried out under the condition of stirring, and the stirring speed is preferably 400 r/min-800 r/min, and more preferably 500 r/min-700 r/min; the mixing and emulsifying temperature is preferably 20-60 ℃, more preferably 30-50 ℃, and even more preferably 35-45 ℃.

In the invention, the mode of the micron treatment is preferably high-speed shearing emulsification, and the shearing rotating speed of the shearing emulsification is preferably 3000-10000 rpm, more preferably 4000-8000 rpm, and more preferably 5000-7000 rpm; the shearing time is preferably 1-10 min, more preferably 3-8 min, and even more preferably 4-6 min; in the present invention, the particle diameter of the micronized dispersion obtained by the micronization treatment is preferably 1 μm to 100 μm, and more preferably 1 μm to 50 μm.

After the micron-sized dispersion is obtained, the micron-sized dispersion is subjected to nanocrystallization treatment to obtain the hydroxy pinacolone retinoic acid ester nano composition.

In the present invention, the nanocrystallization is preferably performed by high-pressure homogenization or high-pressure microfluidization. When the high-pressure homogenization treatment of the micron-sized dispersion to the nanometer-sized dispersion is selected, the pressure of the high-pressure homogenization treatment is preferably 300 to 1600bar, more preferably 500 to 1200bar, and even more preferably 700 to 1000 bar. The circulation frequency of the high-pressure homogenization is preferably 1-10 times, more preferably 2-8 times, and even more preferably 3-5 times; the high-pressure homogenizing temperature is preferably 20-60 ℃, more preferably 30-50 ℃, and even more preferably 35-45 ℃.

When the high-speed microjet technology is adopted to treat the micron-sized dispersion to the nanometer level, the pressure of the high-speed microjet treatment is preferably 6000-16000 psi, further preferably 8000-14000 psi, and more preferably 10000-12000 psi; the circulation frequency of the high-speed microjet treatment is preferably 1-10 times, more preferably 2-8 times, and even more preferably 3-5 times; the high-speed micro-jet treatment temperature is preferably 20-60 ℃, more preferably 30-50 ℃, and even more preferably 35-45 ℃.

In the invention, the particle size of the hydroxy pinacolone retinoic acid ester nano composition obtained through nanocrystallization treatment is preferably 10-200 nm, more preferably 10-150 nm, and even more preferably 10-100 nm.

The invention also provides application of the hydroxy pinacolone retinoic acid ester nano composition in preparation of cosmetics. Specifically, the nano composition provided by the invention is used for preparing cosmetics with the effects of resisting aging, removing acnes, whitening skin and the like. The form of the cosmetic includes, but is not limited to, lotions, essences, creams, lotions, masks, and gels. When the nanometer composition of the hydroxy pinacolone retinoic acid ester is used for preparing cosmetics, the nanometer composition can be directly added into various anti-aging, anti-acne and whitening product matrixes, and the use is convenient. The three active ingredients are loaded in the same nano carrier through a nano drug targeting carrier preparation technology, so that the prepared nano composition can effectively improve the light and heat stability of the hydroxy pinacolone retinoic acid ester and the solubility of glycyrrhetinic acid, reduce the irritation of nicotinamide and further increase the addition amount of active substances in a skin care product; the nano composition preferably accounts for 0.1-30% of the cosmetic quality, and more preferably accounts for 1-10%.

In order to further illustrate the present invention, the following examples are provided to describe the multi-effect hydroxyppinacolone retinoic acid ester nano-composition, its preparation method and application in detail, but they should not be construed as limiting the scope of the present invention.

In the following examples, unless otherwise specified, the percentages mentioned are the mass ratios of the corresponding components in the hydroxyppinacolone retinoic acid ester nano-composition.

Example 1

Mixing 0.1% of hydroxy pinacolone retinoic acid ester, 10% of glycyrrhetinic acid, 7% of caprylic/capric triglyceride, 7% of cocoa butter, 10% of polyglycerol-10 stearate, 7% of polyglycerol-10 diisostearate, 16% of diethylene glycol monoethyl ether and 6% of sorbitol, and heating in a water bath at 35 ℃ for dissolving to obtain an oil phase;

adding 0.5% nicotinamide into 36.4% purified water, heating in water bath at 35 deg.C for dissolving to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 5 drops/second, continuously stirring at a rotation rate of 400r/min, and after mixing, carrying out high-speed shearing emulsification for 8min at a rotation speed of 5000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 35 ℃ and the pressure of 500bar, circulating for 5 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 137.6 nm.

Example 2

Mixing 10% of hydroxy pinacolone retinoic acid ester, 0.1% of glycyrrhetinic acid, 10% of isononyl isononanoate, 5% of isopropyl myristate, 10% of polyoxyethylene hydrogenated castor oil, 8% of ceteareth, 6% of PPG-26-butanol polyether-26, 6% of ethoxy diglycol oleate and 7% of glycerol, and heating and dissolving in water bath at 40 ℃ to obtain an oil phase;

adding 1% nicotinamide into 36.9% purified water, and heating and dissolving in water bath at 40 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 4 drops/second, continuously stirring at a rotation rate of 700r/min, and after mixing, carrying out high-speed shearing emulsification for 6min at a rotation speed of 7000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 40 ℃ and the pressure of 800bar, circulating for 3 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 147.2 nm.

Example 3

Mixing 0.2% of hydroxy pinacolone retinoic acid ester, 0.2% of glycyrrhetinic acid, 0.5% of isopropyl palmitate, 0.5% of caprylic/capric triglyceride, 1% of coco glucoside, 1% of tridecyl polyether-9 and 10% of 1, 2-butanediol, and heating and dissolving in water bath at 25 ℃ to obtain an oil phase;

adding 10% nicotinamide into 76.6% purified water, and heating and dissolving in water bath at 25 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 3 drops/second, continuously stirring at a rotation rate of 800r/min, and after mixing, carrying out high-speed shearing emulsification for 10min at a rotation speed of 3000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 25 ℃ and the pressure of 700bar, circulating for 8 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 12.8 nm.

Example 4

Mixing 0.5% of hydroxy pinacolone retinoic acid ester, 0.5% of glycyrrhetinic acid, 2% of isoamyl laurate, 1% of isopropyl myristate, 5% of polyethylene glycol laurate, 5% of coco-fatty polyether-7, 10% of 1, 3-propylene glycol and 8% of dipropylene glycol, and heating and dissolving in water bath at 30 ℃ to obtain an oil phase;

adding 8% nicotinamide into 60% purified water, and heating and dissolving in water bath at 30 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 6 drops/second, continuously stirring at a rotation rate of 700r/min, and after mixing, carrying out high-speed shearing emulsification for 4min at a rotation speed of 4000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 30 ℃ and the pressure of 400bar, circulating for 5 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 25.7 nm.

Example 5

Mixing 8% of hydroxy pinacolone retinoic acid ester, 1% of glycyrrhetinic acid, 5% of dimethyl silicone oil, 2% of propylene glycol monocaprylate, 3% of cocoa seed fat, 7% of lecithin, 7% of polyglycerol-10 myristate, 8% of PPG-1-PEG-9 lauryl glycol ether and 12% of polyethylene glycol-400, and heating and dissolving in a water bath at 50 ℃ to obtain an oil phase;

adding 5% nicotinamide into 42% purified water, and heating and dissolving in water bath at 50 deg.C to obtain water phase;

dripping the water phase into the oil phase at a speed of 7 drops/second, continuously stirring at a rotation rate of 600r/min, and after mixing, carrying out high-speed shearing emulsification for 3min at a rotation speed of 8000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 50 ℃ and the pressure of 1200bar, circulating for 2 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 91.3 nm.

Example 6

Mixing 1% of hydroxy pinacolone retinoic acid ester, 5% of glycyrrhetinic acid, 4% of glyceryl triacetate, 4% of cocoa seed fat, 6% of polyglycerol-10 stearate, 6% of polyglycerol-10 diisostearate, 6% of octyldodecanol, 8% of 1, 2-pentanediol and 8% of 1, 2-hexanediol, and heating and dissolving in a water bath at 45 ℃ to obtain an oil phase;

adding 3% nicotinamide into 49% purified water, and heating and dissolving in 45 deg.C water bath to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 2 drops/second, continuously stirring at a rotation rate of 500r/min, and after mixing, carrying out high-speed shearing emulsification for 5min at a rotation speed of 6000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 45 ℃ and the pressure of 300bar, circulating for 10 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 86.7 nm.

Example 7

Mixing 5% of hydroxy pinacolone retinoic acid ester, 8% of glycyrrhetinic acid, 10% of squalene, 7% of soybean oil, 10% of coco glucoside, 9% of polyethylene glycol laurate, 10% of diethylene glycol monoethyl ether, 10% of PPG-26-butanol polyether-26 and 1% of sorbitol, and heating and dissolving in a water bath at 55 ℃ to obtain an oil phase;

adding 0.1% nicotinamide into 29.9% purified water, heating in water bath at 55 deg.C for dissolving to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 5 drops/second, continuously stirring at a rotation rate of 600r/min, and after mixing, carrying out high-speed shearing emulsification for 2min at a rotation speed of 9000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 55 ℃ and the pressure of 1000bar, circulating for 3 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 198.4 nm.

Example 8

Mixing 1% of hydroxy pinacolone retinoic acid ester, 1% of glycyrrhetinic acid, 3% of caprylic/capric triglyceride, 4% of isopropyl palmitate, 8% of polyglycerol-10 myristate, 3% of coco-fatty polyether-7, 10% of 1, 2-pentanediol and 10% of 1, 2-hexanediol, and heating and dissolving in a water bath at 20 ℃ to obtain an oil phase;

adding 5% nicotinamide into 55% purified water, and heating and dissolving in water bath at 20 deg.C to obtain water phase;

dripping the water phase into the oil phase at a speed of 3 drops/second, continuously stirring at a rotation rate of 600r/min, and after mixing, performing high-speed shearing emulsification for 4min at a rotation speed of 8000rpm to obtain a micron-sized dispersion;

subjecting the micrometer-sized dispersion to high-speed micro-jet treatment at 20 deg.C and 12000psi, circulating for 5 times, and cooling to room temperature to obtain nanometer composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 32.6 nm.

Example 9

Mixing 4% of hydroxy pinacolone retinoic acid ester, 3% of glycyrrhetinic acid, 2% of caprylic/capric triglyceride, 3% of cocoa butter, 3% of soybean oil, 10% of polyglycerol-10 myristate, 9% of PPG-1-PEG-9 lauryl glycol ether, 7% of 1, 3-propylene glycol and 7% of 1, 2-pentanediol, and heating and dissolving in water bath at 30 ℃ to obtain an oil phase;

adding 6% nicotinamide into 46% purified water, and heating and dissolving in water bath at 30 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 4 drops/second, continuously stirring at a rotation rate of 500r/min, and after mixing, carrying out high-speed shearing emulsification for 9min at a rotation speed of 4000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 30 ℃ and the pressure of 900bar, circulating for 4 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 78.5 nm.

Example 10

Mixing 6% of hydroxy pinacolone retinoic acid ester, 4% of glycyrrhetinic acid, 2% of glyceryl triacetate, 3% of isononyl isononanoate, 4% of isopropyl myristate, 10% of polyglycerol-10 stearate, 5% of lecithin, 5% of octyldodecanol, 10% of diethylene glycol monoethyl ether, 5% of 1, 2-hexanediol and 4% of 1, 2-butanediol, and heating and dissolving in a water bath at 35 ℃ to obtain an oil phase;

adding 7% nicotinamide into 35% purified water, and heating and dissolving in water bath at 35 deg.C to obtain water phase;

dripping the water phase into the oil phase at a speed of 8 drops/second, continuously stirring at a rotation rate of 800r/min, and after mixing, carrying out high-speed shearing emulsification for 7min at a rotation speed of 5000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-speed micro-jet treatment on the micron-sized dispersion at the temperature of 35 ℃ and the pressure of 8000psi, circulating for 2 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to be 116.1 nm.

Example 11

Mixing 7% of hydroxy pinacolone retinoic acid ester, 6% of glycyrrhetinic acid, 10% of isopropyl palmitate, 5% of squalene, 5% of soybean oil, 10% of polyglycerol-10 diisostearate, 10% of coco glucoside, 10% of PPG-26-butanol polyether-26, 4% of octyl dodecanol and 3% of propylene glycol, and heating and dissolving in water bath at 40 ℃ to obtain an oil phase;

adding 2% nicotinamide into 28% purified water, and heating and dissolving in water bath at 40 deg.C to obtain water phase;

dripping the water phase into the oil phase at a speed of 6 drops/second, continuously stirring at a rotation rate of 400r/min, and after mixing, carrying out high-speed shearing emulsification for 6min at a rotation speed of 6000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at 40 ℃ and 1600bar, circulating for 1 time, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected, and the particle size of the nano composition is 174.8 nm.

Example 12

Mixing 3% of hydroxy pinacolone retinoic acid ester, 7% of glycyrrhetinic acid, 6% of glyceryl triacetate, 3% of soybean oil, 3% of isopropyl myristate, 8% of lecithin, 8% of polyethylene glycol laurate, 9% of diethylene glycol monoethyl ether, 9% of PPG-26-butanol polyether-26 and 5% of 1, 2-pentanediol, and heating and dissolving in a water bath at 45 ℃ to obtain an oil phase;

adding 6% nicotinamide into 33% purified water, and heating and dissolving in a water bath at 45 ℃ to obtain a water phase;

dropwise adding the water phase into the oil phase at a speed of 5 drops/second, continuously stirring at a conversion rate of 500r/min, and after mixing, carrying out high-speed shearing emulsification for 5min at a rotation speed of 7000rpm to obtain a micron-sized dispersion;

performing high-speed micro-jet treatment on the micron-sized dispersion at 45 ℃ and under the pressure of 10000psi, circulating for 3 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 98.3 nm.

Example 13

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 2% of caprylic/capric triglyceride, 3% of squalene, 7% of lecithin, 7% of coco fatty polyether-7, 5% of glycerol and 10% of butanediol, and heating and dissolving in water bath at 60 ℃ to obtain an oil phase;

adding 4% nicotinamide into 58% purified water, and heating and dissolving in water bath at 60 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 1 drop/second, continuously stirring at a rotation rate of 400r/min, and after mixing, carrying out high-speed shearing emulsification for 1min at a rotation speed of 10000rpm to obtain a micron-sized dispersion;

subjecting the micrometer-sized dispersion to high-speed microfluidization at 60 deg.C and 9000psi, circulating for 4 times, and cooling to room temperature to obtain nanometer composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 61.3 nm.

Example 14

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 1% of cocoa butter, 3% of isopropyl palmitate, 8% of polyglycerol-10 stearate, 5% of diethylene glycol monoethyl ether, 5% of 1, 3-propylene glycol and 5% of 1, 2-pentanediol, and heating and dissolving in a water bath at 50 ℃ to obtain an oil phase;

adding 4% nicotinamide into 65% purified water, and heating and dissolving in water bath at 50 deg.C to obtain water phase;

dripping the water phase into the oil phase at a speed of 2 drops/second, continuously stirring at a rate of 500r/min, and after mixing, carrying out high-speed shearing emulsification for 2min at a rotation speed of 8000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at 50 ℃ and under the pressure of 500bar, circulating for 3 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 31.6 nm.

Example 15

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 2% of dimethyl silicone oil, 1% of propylene glycol monocaprylate, 1% of cocoa butter, 7% of coco glucoside, 3% of lecithin, 4% of diethylene glycol monoethyl ether, 2% of PPG-26-butanol polyether-26, 3% of 1, 3-propylene glycol and 3% of butanediol, and heating and dissolving in a water bath at 55 ℃ to obtain an oil phase;

adding 4% nicotinamide into 66% purified water, heating in water bath at 55 deg.C for dissolving to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 3 drops/second, continuously stirring at a rotation rate of 600r/min, and after mixing, carrying out high-speed shearing emulsification for 3min at a rotation speed of 7000rpm to obtain a micron-sized dispersion;

carrying out high-speed micro-jet treatment on the micron-sized dispersion at 55 ℃ and 11000psi, circulating for 2 times, and cooling to room temperature to obtain the nano-composite.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 11.7 nm.

Example 16

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 2% of soybean oil, 2% of cocoa butter, 6% of polyglycerol-10 diisostearic acid, 6% of lecithin, 3% of octyldodecanol, 2% of PPG-26-butanol polyether-26, 3% of 1, 2-pentanediol and 3% of 1, 2-hexanediol, and heating and dissolving in a water bath at 45 ℃ to obtain an oil phase;

adding 4% nicotinamide into 65% purified water, and heating and dissolving in 45 deg.C water bath to obtain water phase;

dripping the water phase into the oil phase at a speed of 5 drops/second, continuously stirring at a rotation rate of 600r/min, and after mixing, performing high-speed shearing emulsification for 4min at a rotation speed of 8000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 45 ℃ and the pressure of 900bar, circulating for 4 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 108.3 nm.

Example 17

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 2% of isononyl isononanoate, 5% of isopropyl myristate, 6% of polyglycerol-10 stearate, 3% of polyglycerol-10 diisostearate, 5% of octyldodecanol, 3% of coco-alcohol polyether-7, 3% of glycerol and 5% of 1, 3-propylene glycol, and heating and dissolving in a water bath at 35 ℃ to obtain an oil phase;

adding 4% nicotinamide into 60% purified water, and heating and dissolving in 35 deg.C water bath to obtain water phase;

dripping the water phase into the oil phase at a speed of 6 drops/second, continuously stirring at a rotation rate of 700r/min, and after mixing, carrying out high-speed shearing emulsification for 5min at a rotation speed of 7000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 35 ℃ and the pressure of 1000bar, circulating for 3 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 132.7 nm.

Comparative example 1 (comparison with example 5, containing only one liquid lipid dimethicone)

Mixing 8% of hydroxy pinacolone retinoic acid ester, 1% of glycyrrhetinic acid, 10% of dimethyl silicone oil, 7% of lecithin, 7% of polyglycerol-10 myristate, 8% of PPG-1-PEG-9 lauryl glycol ether and 12% of polyethylene glycol-400, and heating in a water bath at 50 ℃ for dissolving to obtain an oil phase;

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 82.6 nm.

Comparative example 2 (comparison with example 5, containing only one liquid lipid propylene glycol monocaprylate)

Mixing 8% of hydroxy pinacolone retinoic acid ester, 1% of glycyrrhetinic acid, 10% of propylene glycol monocaprylate, 7% of lecithin, 7% of polyglycerol-10 myristate, 8% of PPG-1-PEG-9 lauryl glycol ether and 12% of polyethylene glycol-400, and heating in a water bath at 50 ℃ for dissolving to obtain an oil phase;

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 101.3 nm.

Comparative example 3 (comparison with example 5, containing only one liquid lipid cocoa seed butter)

Mixing 8% of hydroxy pinacolone retinoic acid ester, 1% of glycyrrhetinic acid, 10% of cocoa seed fat, 7% of lecithin, 7% of polyglycerol-10 myristate, 8% of PPG-1-PEG-9 lauryl glycol ether and 12% of polyethylene glycol-400, and heating in water bath at 50 ℃ for dissolving to obtain an oil phase;

The particle size of the nano composition is detected to obtain the particle size of the nano composition of 76.8 nm.

Test example 1

Stability test

After the nano-composition prepared in the examples 1-17 and the comparative examples 1-3 is placed in a closed container at room temperature for 3, 6, 9 and 12 months, the particle size of the sample is detected, the properties of the sample are observed, the content of HPR in each sample is detected by High Performance Liquid Chromatography (HPLC), the percentage of the residual content of HPR after 12 months is calculated, and the stability of the nano-composition is comprehensively evaluated. Specific detection results are shown in table 1, and the appearance of the sample is shown in fig. 1-4.

TABLE 1 stability test results of a multi-effect hydroxyppinacolone retinoic acid ester nano-composition

As can be seen from Table 1, the particle size of the multi-effect hydroxy pinacolone retinoic acid ester nano composition prepared by high-pressure homogenization treatment and high-speed microjet treatment is 10-200 nm, the requirement of practical application is met, the particle size of a sample is not significantly changed after the sample is placed for 12 months, and the content of the sample is not significantly changed after the sample is placed for 12 months at the room temperature of HPR, so that the requirement of practical application is still met.

As can be seen from the graphs in FIGS. 1 to 4, the sample in example 5 is not agglomerated, discolored and layered after being placed for 12 months, and is still stable particularly under the condition of high concentration of active ingredients, and no crystallization phenomenon is found; the samples in comparative examples 1-3 are respectively precipitated in the 3 rd month, the 6 th month and the 9 th month, which shows that the nano composition prepared by compounding a plurality of oils has higher stability, and single oil cannot meet the requirements of the nano emulsion preparation on oil phase and is easy to crystallize and precipitate. Therefore, the pleiotropic hydroxy pinacolone retinoic acid ester nano composition provided by the invention has good stability.

Comparative example 4

Preparing a blank cream: heating 5% caprylic/capric triglyceride, 5% white oil, 2% cetostearyl alcohol, 2% steareth-2, and 2% steareth-21 in 75 deg.C water bath for melting to obtain oil phase; dissolving 5% propylene glycol, 0.15% carbomer and the balance of purified water in a water bath at 75 ℃ to obtain a water phase; dripping the oil phase into the water phase, stirring, mixing, shearing at 10000rpm for 3min, adding 0.15% triethanolamine, shearing for 2min, cooling, adding 0.5% phenoxyethanol, and stirring to obtain blank cream.

Test example 2

Irritation test

And (3) respectively mixing the nano composition samples prepared in the embodiments 8-13 with the blank cream in the comparative example 4 according to a mass ratio of 3: 7, compounding to prepare the composite cream for skin irritation test.

Taking 42 healthy rabbits with the weight of 2.0 +/-0.2 kg, randomly dividing the rabbits into 7 groups, removing hairs on two sides of the skin on the back of the rabbits 24 hours before the experiment, checking whether the removed hairs are injured 24 hours after the hairs are removed, and not suitable for skin irritation test of the injured skin. The composite cream prepared using the nano composition prepared in examples 8 to 13 was applied 3 times a day for 7 consecutive days while the blank cream was applied for comparison, and the test results were observed and listed in table 2.

Table 2 observations of skin irritation in composite creams and blanks prepared from examples 8-13

Note: "+" rabbit skin congestion, red swelling; "+ +" indicates that the congestion and red swelling still exist, but there is an increasing trend; "-" indicates no hyperemia or redness and swelling.

According to the test results in the table 2, the composite cream and the blank cream prepared by the nano-composition in the embodiment 8-13 have no hyperemia and red swelling after being smeared on the skin of rabbits, which indicates that the nano-composition provided by the invention has no irritation to the skin and high safety.

Application example 1

Preparing the nano composite cream: the nano composition prepared in the example 9 and the blank cream in the comparative example 4 are mixed according to the mass percentage of 1: 9, compounding, and shearing and emulsifying at 8000rpm for 2min to obtain the nanometer composite cream.

The nano composite cream comprises the following functional components in percentage by weight: 0.4% HPR, 0.6% nicotinamide, 0.3% glycyrrhetinic acid.

Comparative example 5 (efficacy ingredients of 0.4% HPR, 0.6% Nicotinamide and 0.3% Glycyrrhetinic acid)

Preparing common cream with the same functional components and content as the nano composite cream: heating and melting 0.4% HPR, 0.3% glycyrrhetinic acid, 5% caprylic/capric triglyceride, 5% white oil, 2% cetostearyl alcohol, 2% steareth-2 and 2% steareth-21 in 75 deg.C water bath to obtain oil phase; dissolving 0.6% nicotinamide, 5% propylene glycol, 0.15% carbomer and the balance purified water in a water bath at 75 ℃ to obtain a water phase; dripping the oil phase into the water phase, stirring, mixing, shearing at 10000rpm for 3min, adding 0.15% triethanolamine, shearing for 2min, cooling, adding 0.5% phenoxyethanol, and stirring to obtain common cream with the same effective components and content as the nanometer composite cream.

Comparative example 6 (efficacy components of 1% HPR and 0.3% Glycyrrhetinic acid)

Preparing common cream: heating and melting 1% HPR, 0.3% glycyrrhetinic acid, 5% caprylic/capric triglyceride, 5% white oil, 2% cetostearyl alcohol, 2% steareth-2, and 2% steareth-21 in 75 deg.C water bath to obtain oil phase; dissolving 5% propylene glycol, 0.15% carbomer and the balance of purified water in a water bath at 75 ℃ to obtain a water phase; dripping the oil phase into the water phase, stirring, mixing, shearing at 10000rpm for 3min, adding 0.15% triethanolamine, shearing for 2min, cooling, adding 0.5% phenoxyethanol, and stirring to obtain common cream.

Comparative example 7 (effective components of 1% nicotinamide and 0.3% Glycyrrhetinic acid)

Preparing common cream: heating 0.3% glycyrrhetinic acid, 5% caprylic/capric triglyceride, 5% white oil, 2% cetostearyl alcohol, 2% steareth-2, and 2% steareth-21 in 75 deg.C water bath for melting to obtain oil phase; dissolving 1% nicotinamide, 5% propylene glycol, 0.15% carbomer and the balance purified water in a water bath at 75 ℃ to obtain a water phase; dripping the oil phase into the water phase, stirring, mixing, shearing at 10000rpm for 3min, adding 0.15% triethanolamine, shearing for 2min, cooling, adding 0.5% phenoxyethanol, and stirring to obtain common cream.

Test example 3

In vitro transdermal test

The vertical Franz diffusion cell method is adopted to carry out the transdermal experiment of the in vitro rat skin. SD male rat abdominal skin is fixed between a receiving chamber and a supply chamber, 1g of each of the nanocomposite cream prepared in application example 1 and the common cream prepared in comparative example 5 is taken in the supply chamber, and ethanol with the mass fraction of 20% and normal saline with the mass fraction of 80% are taken as receiving liquid, and the receiving liquid is stirred and diffused at 37 ℃. 0.5mL of receiving solution was taken at 1,2, 4, 6, 8, 10, 12h and an equal amount of fresh receiving solution was immediately replenished. And (4) performing HPLC analysis, and calculating the cumulative permeation amount of the specific medicament per unit area at different times. After 12h, the skin is taken down, cleaned, cut into pieces, ground into homogenate, added with a proper amount of receiving liquid for centrifugation, and the supernatant is taken for HPLC analysis to calculate the skin retention amount of a specific medicament per unit area. The drug determined in this experiment was HPR. The experimental data are shown in fig. 5, fig. 6 and table 3.

Table 3 application example 1 and comparative example 6 results on cumulative skin penetration and cumulative skin retention after 12h

Group of	Application example 1	Comparative example 5
			Cumulative skin penetration (μ g/cm)²)	121.7	71.3
Cumulative skin retention (μ g/cm)²)	11.8	4.7

FIG. 5 is a cumulative body skin penetration after 12 hours for the nanocomposite cream prepared in application example 1 and the general cream prepared in comparative example 5; fig. 6 is an in vitro skin retention of the nanocomposite cream prepared in application example 1 and the general cream prepared in comparative example 5.

As can be seen from FIG. 5 and Table 3, comparative example 5 was preparedThe accumulated skin penetration amount of the common cream after 12 hours is only 71.3 mu g/cm²And the cumulative skin penetration after 12 hours of applying the nano-composite cream prepared in example 1 was 121.7 mug/cm²It is shown that the cumulative penetration of the active in the skin is significantly increased after encapsulation by the nanocomposition. The free active substance hardly penetrates through the skin stratum corneum to reach the skin deep layer structure due to the skin barrier effect to play a role, and after nano-encapsulation, the nano-carrier has small particle size, large specific surface area and stronger adhesiveness and biocompatibility with cells, so that the active substance can more effectively penetrate through the skin surface layer, enter the cells of the dermis layer and act on the cells of the dermis layer, the bioavailability is improved, and better anti-aging, anti-acne and whitening skin care effects are played.

As can be seen from FIG. 6 and Table 3, the general cream prepared in comparative example 5 had a skin retention of only 4.7. mu.g/cm after 12 hours²And the skin retention of the nano composite cream prepared in application example 1 after 12 hours is 11.8 mu g/cm²It is shown that the retention of the active in the skin is significantly increased after encapsulation by the nano-composition. After being nano-encapsulated, the active substance can be enriched at high concentration and retained for a long time, and is slowly released and controlled to be released, so that the bioavailability of the active substance is obviously improved, and the effects of resisting ageing, removing acnes, whitening and protecting skin are enhanced.

Comparative example 8

Mixing 2% of hydroxy pinacolone retinoic acid ester, 2% of glycyrrhetinic acid, 0.5% of soybean oil, 0.2% of cocoa seed fat, 0.8% of polyglycerol-10 diisostearate, 0.8% of octyldodecanol and 0.5% of 1, 3-propylene glycol, and heating in water bath at 25 ℃ for dissolving to obtain an oil phase;

adding 4% nicotinamide into 89.2% purified water, and heating and dissolving in water bath at 25 deg.C to obtain water phase;

dropwise adding the water phase into the oil phase at a speed of 2 drops/second, continuously stirring at a rotation rate of 400r/min, and after mixing, carrying out high-speed shearing emulsification for 8min at a rotation speed of 4000rpm to obtain a micron-sized dispersion;

and (3) carrying out high-pressure homogenization treatment on the micron-sized dispersion at the temperature of 25 ℃ and the pressure of 800bar, circulating for 6 times, and cooling to room temperature to obtain the nano composition.

The particle size of the nano composition is detected to obtain the particle size of the nano composition to be 7.8 nm.

Test example 4

Comparative analysis of particle size of the Nanocomposition with skin penetration and retention

The vertical Franz diffusion cell method is adopted to carry out the transdermal experiment of the in vitro rat skin. SD male rat abdominal skin is fixed between a receiving chamber and a supply chamber, 1g of each of examples 13-17 and comparative example 8 is taken in the supply chamber, and 20% ethanol and 80% physiological saline in mass fraction are taken as receiving liquid, and stirring and diffusion are carried out at 37 ℃. 0.5mL of receiving solution was taken at 1,2, 4, 6, 8, 10, 12h and an equal amount of fresh receiving solution was immediately replenished. And (4) performing HPLC analysis, and calculating the cumulative permeation amount of the specific medicament per unit area at different times. After 12h, the skin is taken down, cleaned, cut into pieces, ground into homogenate, added with a proper amount of receiving liquid for centrifugation, and the supernatant is taken for HPLC analysis to calculate the skin retention amount of a specific medicament per unit area. The drug determined in this experiment was HPR. The experimental data are shown in fig. 7 and table 4.

Table 4 particle size of the nano-composition and cumulative skin penetration and cumulative retention results

As can be seen from FIG. 7 and Table 4, the cumulative HPR penetration per unit area increased from 1121.9 μ g/cm as the particle size of the nanocomposite increased from 7.8nm to 132.7nm²Gradually reduced to 531.4. mu.g/cm²The smaller the particle size, the larger the cumulative permeation per unit area; when the particle size of the nano composition is 7.8nm, the skin retention per unit area of HPR is only 20.3 μ g/cm²It is shown that the cumulative active penetration is large but the skin retention is small when the particle size of the nano composition is less than 10 nm; when the particle diameter is 11.7 nm-108.3 nm, the skin retention per unit area is 65.6 mu g/cm²～86.5μg/cm²Skin accumulation compared to particle size less than 10nmThe retention is obviously increased; when the particle size of the nano composition is 132.7nm, the unit area skin retention of HPR is reduced to 46.7 mu g/cm²It is demonstrated that the cumulative active penetration and skin retention are small when the particle size of the nano-composition is greater than 100 nm. The relationship between the particle size and the cumulative skin penetration and cumulative skin retention is comprehensively considered, the particle size range is preferably 10-100 nm, the skin penetration and the skin retention can be better considered, and the effects of resisting aging, removing acnes and whitening skin are better achieved. In addition, as can be seen from table 4, the particle size ranges of examples 13 to 16 obtained by the high-speed micro-jet treatment and the high-pressure homogenization treatment are in the preferred range, and the cumulative skin permeation amount and the cumulative skin retention amount are both good, which indicates that the nano-composition with the good particle size, the cumulative skin permeation amount and the cumulative skin retention amount can be prepared by the high-speed micro-jet treatment and the high-pressure homogenization treatment.

Test example 5

Anti-aging efficacy test

A skin texture test of the nano composition is carried out by selecting a skin analysis tester VISIA, and the anti-aging effect of the nano composition is evaluated.

Test samples: the nano composition prepared in example 10 and the blank cream in comparative example 4 are mixed according to the mass percentage of 1: 9, compounding to obtain the nano composite cream which is a No. 1 sample; the nano composite cream prepared in application example 1 was designated as sample No. 2, and the common cream prepared in comparative examples 5 to 7 was designated as sample No. 3 to 5.

And selecting 30 volunteers with healthy skin, no cosmetic allergy history and age of 40-45 years from each group of 5 groups as subjects to carry out skin texture test. The trial parts are cheeks of the face, the skin surface texture of the trial part is tested by the same person before the test and after the samples are continuously used for 1 week, 2 weeks, 4 weeks and 8 weeks, the average surface wrinkle reduction amount of the test subject in different time periods is calculated, and the test results are shown in fig. 8 and table 5.

Average surface wrinkle reduction results for samples Nos. 51-5 in Table

As can be seen from fig. 8 and table 5, the nanocomposite cream of sample No. 1 and sample No. 2 can significantly reduce wrinkles on the surface of the skin, which indicates that the nanocomposite prepared by the high-pressure homogenization treatment and the high-speed microjet treatment of the present application can effectively inhibit the growth of wrinkles, has a good effect of improving wrinkles, and has a significant anti-aging effect; the sample No. 3 is common cream with the same active ingredients and content as the sample No. 2, and compared with the sample No. 3, the nano composite cream of the sample No. 2 has obvious difference on the average reduction amount of surface wrinkles, which shows that the anti-aging effect of the active substance is obviously enhanced after the active substance is encapsulated by the nano composition; the total active content of the samples No. 2-5 is the same, and compared with the samples No. 4 and No. 5, the average surface wrinkle reduction amount of the samples No. 2 and No. 3 is remarkably different, which shows that the HPR and nicotinamide can be used in a matched manner to realize synergistic effect, and the anti-aging effect is better than that of the HPR or nicotinamide used alone.

Test example 6

Acne treatment efficacy test

A skin and face analyzer VISIA CR and a face Image analysis software Image-Pro Plus are selected to take pictures of the subjects before and after use, and the acne and acne mark removing efficacy of the nano composition is evaluated.

Test samples: the same as in test example 5.

Selecting 30 volunteers with obvious acne growing skin, no cosmetic allergy history and 20-40 years old from 5 groups as subjects, wherein the trial parts are faces, particularly parts with acne and acne marks, photographing and analyzing the subjects before use and after 1 week, 2 weeks, 4 weeks and 8 weeks of use of samples by using a skin face analyzer VISIAC and facial Image analysis software Image-Pro Plus, and observing and analyzing the number of the acne marks after acne inflammation diminishing or fading degree and the number of the acne marks after the parts originally with the acne marks are used in the products or fading degree.

If 80% or more of the pox is not provided with the pox marks after the inflammation is removed, or 80% or more of the pox marks on the part originally provided with the pox marks are removed, the acne is excellent;

if 60 to 80 percent of the pox is not provided with the pox marks after the inflammation or only provided with the light pox marks, or 60 to 80 percent of the pox marks on the part originally provided with the pox marks are eliminated or only provided with the light pox marks, the effect is good;

if 40 to 60 percent of the pox is not provided with the pox marks after diminishing inflammation or only provided with the light pox marks, or if 40 to 60 percent of the pox marks on the part originally provided with the pox marks are eliminated or only provided with the light pox marks, the better effect is achieved;

if less than 40% of the pox spots are not printed or are printed with more obvious colors after being antiphlogistic, or if less than 40% of the pox spots originally provided with the pox spots are printed or are printed with more obvious colors, the acne is worse.

During the use of the samples, the subjects subjectively evaluated the irritation of the samples according to the individual trial, the results of which are shown in table 6.

Table 6 acne treatment efficacy test results

Group of	Sample No. 1	Sample No. 2	Sample No. 3	Sample No. 4	Sample No. 5
						Acne removing effect	Is excellent in	Is excellent in	Good effect	Is preferably used	Is preferably used
Acne mark removing effect	Is excellent in	Is excellent in	Is preferably used	Is poor	Is poor
						Irritation property	Mild	Mild	Slight stimulation	Slight stimulation	Apparent stimulation

As can be seen from Table 6, the nano composite cream of sample No. 1 and sample No. 2 can significantly reduce the number of facial acne and obviously lighten acne marks, which indicates that the nano composition prepared by the high-pressure homogenization treatment and the high-speed microjet treatment has significant acne and acne mark removing effects. The sample No. 3 is common cream with the same active ingredients and content as the sample No. 2, compared with the sample No. 3, the nano composite cream of the sample No. 2 has better acne and acne mark removing effects, and shows that the acne and acne mark removing effects of the active matter are obviously enhanced after being encapsulated by the nano composition; the total active content of the samples 2-5 is the same, and as can be seen from table 6, compared with the samples 4 and 5, the acne and acne mark removing effects of the samples 2 and 3 are better, which indicates that the synergistic effect of the HPR and nicotinamide can be achieved, and the acne removing effect is better than that of the HPR or nicotinamide used alone. The irritation results show that the irritation of the active substance is obviously reduced after the active substance is loaded by the nano-particles, and the nano-composition prepared by the application is mild and has no irritation.

Test example 7

Whitening efficacy test

A skin whitening test of the nano composition is carried out by selecting a skin melanin and heme tester Mexameter MX18, and the whitening effect of the nano composition is evaluated.

Test samples: the same as in test example 5.

30 adults with healthy skin, dark skin color and no cosmetic allergy history in each group of 5 groups were selected as subjects for skin whitening tests. The trial part is the inner area of the forearm, the skin melanin index MI value of the trial part is tested by the same person before the test and after the samples are continuously used for 1 week, 2 weeks, 4 weeks and 8 weeks, the higher the measured value is, the higher the melanin content in the skin is, the relative change rate (namely the relative initial value change rate) of the melanin MI value of the subject in different time periods is calculated, and the test results are shown in fig. 9 and table 7.

Results of relative change rate of melanin MI values of samples No. 71-5 in Table

As can be seen from fig. 9 and table 7, the nanocomposite cream of sample No. 1 and sample No. 2 can significantly reduce the melanin content of the skin, which indicates that the nano-composition prepared by the high-pressure homogenization treatment and the high-speed microjet treatment of the present application has significant whitening effect; the sample No. 3 is common cream with the active ingredients and the content the same as that of the sample No. 2, and compared with the sample No. 3, the nano composite cream of the sample No. 2 has obvious difference on the reduction of melanin content, which shows that the whitening effect of the active substances is obviously enhanced after the active substances are encapsulated by the nano composition; the total active content of the samples 2 to 5 is the same, and as can be seen from fig. 9 and table 7, compared with the samples 4 and 5, the samples 2 and 3 have significant difference in the reduction of melanin content, which indicates that the HPR and niacinamide used in combination can be synergistic and have better whitening effect than the HPR or niacinamide used alone.

In conclusion, the nano composition prepared by the invention can effectively improve the stability of the active substance, reduce the irritation of the active substance, promote the targeted transdermal delivery of the hydroxy pinatone retinoic acid ester, the nicotinamide and the glycyrrhetinic acid to the active epidermis and the dermis tissues, can be retained at high concentration for a long time, obviously improve the bioavailability of the active ingredient, realize the transdermal targeted delivery of the three active ingredients, and realize synergistic synergy when the three active ingredients are matched.

Although the present invention has been described with reference to the preferred embodiments, it should be understood that various changes and modifications can be made therein by those skilled in the art without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. A multi-effect hydroxy pinacolone retinoic acid ester nanometer composition comprises hydroxy pinacolone retinoic acid ester, nicotinamide, glycyrrhetinic acid, emulsifier, auxiliary emulsifier and polyalcohol;

2. The nano-composition according to claim 1, wherein the amount of the emulsifier is 1 to 20%, the amount of the co-emulsifier is 1 to 20%, and the amount of the polyol is 1 to 20% based on the total weight of the nano-composition.

3. The nano-composition according to claim 1 or 2, wherein the emulsifier comprises one or more of polyglyceryl-10 stearate, polyglyceryl-10 diisostearate, polyoxyl hydrogenated castor oil, ceteareth, coco glucoside, macrogol laurate, lecithin and polyglyceryl-10 myristate;

4. The nanocomposite of claim 1, wherein the multi-effect hydroxyppinacolone retinoic acid ester nanocomposite further comprises a solvent for dissolving an efficacy active ingredient, wherein the solvent comprises a liquid lipid and water;

5. The nanocomposite of claim 1 or 4, wherein the liquid lipid comprises one or more of a vegetable oil and a synthetic oil.

6. A process for preparing a nano-composition as claimed in any one of claims 1 to 5, comprising the steps of:

mixing nicotinamide and water to obtain a water phase;

7. The method for preparing the emulsion of claim 6, wherein the mixing and emulsifying manner comprises the following steps: the aqueous phase was added dropwise to the oil phase with stirring.

8. The method according to claim 6, wherein the micronizing treatment is shear emulsification and the nanocrystallizing treatment is high-pressure homogenization or high-speed microfluidization.

9. Use of the pleiotropic hydroxyppinacolone retinoic acid ester nano-composition according to any one of claims 1 to 5 or the nano-composition prepared by the preparation method according to any one of claims 6 to 8 in cosmetics.