CN111544327A

CN111544327A - Inclusion compound of alcohol-soluble active substance and cyclodextrin, preparation method and application thereof

Info

Publication number: CN111544327A
Application number: CN202010543285.9A
Authority: CN
Inventors: 郑中博; 吕舒宁; 丛远华; 冯春波; 乔小玲
Original assignee: Shanghai Jahwa United Co Ltd
Current assignee: Shanghai Jahwa United Co Ltd
Priority date: 2020-06-15
Filing date: 2020-06-15
Publication date: 2020-08-18

Abstract

The invention discloses an inclusion compound of an alcohol-soluble active substance and cyclodextrin, which is prepared by the following steps: (a) dissolving an alcohol-soluble active substance with a polyhydric alcohol to obtain an active substance phase; (b) dissolving cyclodextrin in an aqueous solvent as a cyclodextrin phase; (c) adding the active phase to the cyclodextrin phase; and (d) adding a water-soluble antioxidant, wherein the clathrate comprises 0.01-1.6 wt% alcohol-soluble active; wherein the clathrate comprises 1-15 wt% of a polyol; wherein the inclusion complex comprises 0.5 to 12 wt% of cyclodextrin; wherein the inclusion compound comprises 0.01-0.5 wt% of a water-soluble antioxidant; wherein the weight ratio of the alcohol-soluble active substance to the cyclodextrin is 1:6 to 1: 80. The invention also relates to the application of the clathrate compound in cosmetics.

Description

Inclusion compound of alcohol-soluble active substance and cyclodextrin, preparation method and application thereof

Technical Field

The invention belongs to the technical field of cosmetics, and particularly relates to an inclusion compound of an alcohol-soluble active substance and cyclodextrin, a preparation method and application thereof.

Background

Aging is an irresistible natural process of life and is influenced by various factors such as heredity, environment, psychology and the like. Wrinkles are one of the manifestations of human physiological aging, and usually occur in people over 30 years old, and are more pronounced in middle-aged and elderly women. With the development of science and technology, anti-aging cosmetics are more and more concerned by people. In recent years, the research and development of natural plant extract components for resisting aging have become a research hotspot in the field of cosmetics at home and abroad.

The alcohol soluble active substance is active substance capable of dissolving in ethanol or other alcohol solvents, such as resveratrol, ferulic acid, tetrahydrocurcumin, etc.

Resveratrol (Res for short), also called as stilbestrol, is a stilbene compound, is an antitoxin produced by plants under fungal infection, ultraviolet irradiation or pathological conditions, is also used as an antioxidant and an antimutagen, is widely present in giant knotweed rhizome, peanut, grape, mulberry, sweetberry, chinaroot greenbrier and other plants, and is at least found in 72 plants of 31 genera of 21 families at present.

The proven biochemical and pharmacological properties of resveratrol have the effects of resisting atherosclerosis, coronary heart disease, ischemic heart disease and hyperlipidemia, and also have the functions of resisting oxidation and removing free radicals. Research in 1997 of the university of illinois medical school of chicago in the united states shows that resveratrol can effectively inhibit nuclear transcription factor of kappa B (NF-kappa B) protein in tumor cells, so that cancer cells die, malignant tumor diffusion is prevented, and cancer prevention or cancer cell attack is achieved through different biochemical pathways and molecular regulation. Therefore, resveratrol is known as a green anticancer active agent after paclitaxel, and in recent years, resveratrol is widely researched and applied to the industries of medicine and health, health care, beauty treatment and the like. In China, resveratrol is also listed in the catalog of Chinese names of International cosmetic raw material standards (2010 edition) issued by the State food and drug administration.

Resveratrol is an active substance with very strong anti-aging effect, is listed as one of 100 most effective anti-aging substances in 'anti-aging san Ding', also has the effect of ultraviolet radiation prevention, and has very wide application prospect in the field of cosmetics based on the effect.

Resveratrol generally has two configurations (the structure is shown as formula 1), namely cis-Resveratrol (cis-Resveratrol) with the maximum absorption wavelength of 286nm, trans-Resveratrol (trans-Resveratrol) with the maximum absorption wavelength of 306nm, and trans-isomer with relatively strong physiological activity, so that research on Resveratrol mainly takes trans-structure as a main part.

However, resveratrol has poor stability, and decomposition or conversion of resveratrol is caused by temperature, ultraviolet irradiation, continuous heating, acid-base conditions, oxidizing agents, free radicals and the like. Trans-resveratrol has strong physiological activity, but has poor solubility, is only soluble in organic solvents such as ether, chloroform, methanol, ethanol, acetone, ethyl acetate and the like, is difficult to dissolve in water (for example, the solubility in water is only 30mg/L), has weak capability of penetrating through the stratum corneum, and has poor thermal stability and light stability, so that the effective concentration for really playing a role is low, and the bioavailability is not high.

The literature, namely research on the thermal stability and the photoisomerization reaction of trans-resveratrol in trans-and cis-resveratrol photostability research, shows that the concentration of resveratrol at high temperature is greatly changed, and the effective content loss is high; under the action of ultraviolet light, trans-resveratrol can quickly generate isomerization reaction to generate cis-resveratrol, two benzene rings of a cis-structure cannot be coplanar due to space obstruction, and the conjugation degree is not as good as that of the trans-structure, so that the cis-resveratrol can be in an advantageous conformation when photochemical equilibrium is achieved. In addition to cis-trans isomerization, trans-resveratrol itself also undergoes side reactions, such as removal of hydrogen from phenolic hydroxyl groups, addition of intermediate double bonds to stilbene backbone, etc. Therefore, under the action of ultraviolet light, although the concentration of cis-resveratrol gradually increases in a period of time, the total concentration of the two resveratrol is still reduced because side reactions consume the resveratrol at the same time.

Ferulic acid is a phenolic acid widely existing in the plant world, and is a research hotspot in multiple fields of medicines, foods, beauty and skin care products and the like due to the super-strong oxidation resistance and the function of removing free radicals, particularly has the functions of whitening, removing freckles, preventing sun and the like, and has wide development prospect in the beauty and skin care product industry.

Ferulic acid can enter human body in a transdermal absorption mode, and the permeability coefficient and the concentration have positive correlation, so that the ferulic acid can be completely used as an active ingredient to be applied to beauty cosmetics to play a role. Ferulic acid has the following three characteristics: 1) the antioxidant has strong antioxidant effect, can effectively remove various free radicals such as hydrogen peroxide, superoxide radical, hydroxyl radical and the like, is a natural free radical scavenger, and can also remove excessive active oxygen in a body and inhibit oxygen stress by inhibiting the generation of lipid peroxide MDA; 2) the ferulic acid can be used as a natural sunscreen agent, has the maximum ultraviolet absorption peaks of 236nm and 322nm, and can prevent or reduce the damage of ultraviolet rays in the wavelength range to the skin; 3) skin whitening effect, the formation of skin melanin (melanin) is the most fundamental cause of skin darkening, with tyrosinase being a key enzyme in melanin formation. Research proves that ferulic acid can obviously inhibit the activity of tyrosinase and the proliferation and synthesis of melanocytes, and can reduce the generation of melanin so as to achieve the effects of whitening skin and removing freckles.

However, ferulic acid is a rather unstable substance and is susceptible to degradation by external factors (such as light, pH, temperature, etc.). This is described in both the patent (CN 101862272) and the literature (stability study of ferulic acid, the eleventh research on organic analysis and Bioanalytical society, Kuo Hao, Xushi Hai, Hu Xiao just et al, 2001). Prior art systems containing ferulic acid (e.g., oil-in-water or water-in-oil formulations) undergo oxidative degradation and severe discoloration during long-term storage, thus greatly inhibiting the use of this material in the cosmetic field. Therefore, there is a great demand for a stable system containing ferulic acid in the market.

In order to improve the stability of ferulic acid, patent CN101862272 proposes a method for chemically modifying ferulic acid to obtain ferulic acid derivatives. Although stability and solubility of the ferulic acid derivative are obviously improved, the structure belongs to a new substance, and is not in the catalogue of names of used cosmetic raw materials (2015 edition), so that application, registration and approval time of the new substance has a long way, and the risk of non-approval exists.

Ferulic acid is a cosmetic raw material with whitening, antioxidant and other effects, but has poor and unstable water solubility.

Tetrahydrocurcumin (THC) is a natural functional whitening raw material as the most active and main metabolite generated in the in-vivo metabolism process of curcumin, is prepared by hydrogenating curcumin separated from turmeric, and is widely used in various skin care products for whitening, removing freckles and resisting oxidation. The tyrosinase inhibiting activity is 80 times that of arbutin which is a mainstream whitening product. Tetrahydrocurcumin has the effects of removing freckles, whitening and resisting aging, but the application of tetrahydrocurcumin is limited due to the property of almost not dissolving in water.

The cyclodextrin is a cyclic oligosaccharide compound which is obtained by enzymatic cyclization of starch and is formed by connecting 6-12 glucose molecules. The modified beta-cyclodextrin is divided into three types of alpha, beta and gamma according to the structure, and also comprises modified methyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin and the like.

The resveratrol is wrapped by the cyclodextrin, namely the cyclodextrin and the resveratrol form an inclusion compound structure, so that the solubility of the resveratrol can be obviously improved, the stability of the resveratrol is enhanced, the bioavailability of the resveratrol is improved, and the like.

For example, patent CN1500479 discloses an inclusion compound of resveratrol and hydroxypropyl- β -cyclodextrin and a preparation method thereof, wherein the resveratrol is dissolved by an organic solvent, and then subjected to inclusion, filtration, freeze drying and other processes to obtain loose powder.

For another example, patent CN103948933 discloses an inclusion compound of resveratrol and cyclodextrin, which is also prepared by dissolving resveratrol with organic solvent, then performing inclusion, and preparing the inclusion compound into tablets, capsules, oral liquid and other forms.

For another example, patent CN105903033 discloses an inclusion compound of resveratrol and sulfobutyl ether-beta-cyclodextrin and a preparation method thereof, wherein the inclusion compound is obtained by adding resveratrol into a sulfobutyl-beta-cyclodextrin solution for inclusion at 50 ℃, filtering and then performing freeze drying at-80 ℃.

However, for the existing process technology of coating resveratrol by cyclodextrin, organic solvents (methanol, ethanol, chloroform, acetone and the like) are used, and distillation removal is needed in the subsequent process, so that the problem of organic solvent residue is difficult to avoid; meanwhile, distillation equipment, freeze drying equipment, spray drying equipment or the like is required, the equipment is high in cost and complicated in operation process, and the existing process technology needs to consume a large amount of energy and manpower.

In order to solve the problems, the invention replaces organic solvent with Polyol commonly used in cosmetics for the first time, and creatively uses the operation process of a Polyol Dilution Method (PD Method for short) to stably and efficiently wrap alcohol-soluble active substances (such as resveratrol and the like) in cyclodextrin.

Disclosure of Invention

In one aspect, the invention provides an inclusion complex of an alcohol soluble active and a cyclodextrin, the inclusion complex prepared by:

(a) dissolving an alcohol-soluble active substance with a polyhydric alcohol to obtain an active substance phase;

(b) dissolving cyclodextrin in an aqueous solvent as a cyclodextrin phase;

(c) adding the active phase to the cyclodextrin phase; and

(d) adding a water-soluble antioxidant into the mixture,

wherein the clathrate comprises 0.01-1.6 wt% alcohol soluble active;

wherein the clathrate comprises 1-15 wt% of a polyol;

wherein the inclusion complex comprises 0.5 to 12 wt% of cyclodextrin;

wherein the inclusion compound comprises 0.01-0.5 wt% of a water-soluble antioxidant;

wherein the weight ratio of the alcohol-soluble active substance to the cyclodextrin is 1:6 to 1: 80.

In a preferred embodiment, in the inclusion complex of an alcohol-soluble active and a cyclodextrin according to the invention, the alcohol-soluble active is selected from: resveratrol, ferulic acid, and tetrahydrocurcumin.

In a preferred embodiment, in the inclusion complex of an alcohol soluble active and a cyclodextrin of the present invention, the cyclodextrin is selected from the group consisting of: one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.

In a preferred embodiment, in the inclusion complex of an alcohol-soluble active and a cyclodextrin of the present invention, the polyol is selected from the group consisting of: one or more of propylene glycol, 1, 3-propylene glycol, butanediol, dipropylene glycol, polyethylene glycol-8, glyceryl polyether-26, and methyl gluceth-20.

In a preferred embodiment, in the inclusion complex of an alcohol-soluble active and a cyclodextrin of the present invention, the water-soluble antioxidant is selected from the group consisting of: one or more of sodium ascorbyl phosphate, citric acid, arbutin, glutathione, ergothioneine, glucosyl hesperidin, and thioctic acid.

In a preferred embodiment, in the inclusion complex of an alcohol soluble active and a cyclodextrin of the present invention, the weight ratio of the alcohol soluble active to the cyclodextrin is about 1: 8.

In a preferred embodiment, the inclusion complex of an alcohol soluble active and a cyclodextrin of the present invention comprises 0.1 to 1 wt% of the alcohol soluble active.

In a preferred embodiment, in the inclusion complex of an alcohol-soluble active and a cyclodextrin of the present invention, the inclusion complex comprises 1.5 to 5 wt% of a polyol.

In a preferred embodiment, in the inclusion complex of an alcohol-soluble active and a cyclodextrin of the present invention, the inclusion complex comprises 1 to 5 wt% of cyclodextrin.

In a preferred embodiment, the inclusion complex of an alcohol soluble active and a cyclodextrin of the present invention comprises 0.1 to 0.25 wt.% of a water soluble antioxidant.

In another aspect, the invention also relates to the use of an inclusion complex of an alcohol-soluble active and a cyclodextrin in a cosmetic.

Drawings

Fig. 1 shows TEM results of resveratrol and hydroxypropyl- β -cyclodextrin inclusion compound prepared by polyol dilution.

Figure 2 shows the infrared spectrum of resveratrol.

Figure 3 shows the ir spectrum of hydroxypropyl- β -cyclodextrin.

Figure 4 shows the ir spectrum of a physical mixture of resveratrol and hydroxypropyl- β -cyclodextrin.

Fig. 5 shows the infrared spectrum of the resveratrol and cyclodextrin inclusion compound obtained in example 1.

Detailed Description

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described herein. For the purposes of the present invention, the following terms are defined below.

The term "about" as used herein refers to an amount, level, value, dimension, size, or amount that differs by up to 30%, 20%, or 10% as compared to the amount, level, value, dimension, size, or amount of a reference. The percentages used herein are by weight unless otherwise indicated.

Throughout the specification and claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The invention adopts the polyhydric alcohol commonly used in the cosmetics for the first time to replace the organic solvent, and particularly adopts the operation process of a polyhydric alcohol Dilution Method (PD Method for short) to stably and efficiently wrap alcohol-soluble active matters (such as resveratrol) in cyclodextrin to form an inclusion compound of the alcohol-soluble active matters (such as resveratrol) and the cyclodextrin. Then, water-soluble antioxidant is added to play a role in synergistic protection, so that the obtained inclusion compound is more stable in the storage process.

Alcohol soluble actives

RESVERATROL (3, 4', 5-trihydroxystilbene), also known as RESVERATROL, has the INCI name RESVERATROL, is a natural plant extract, exists in 72 plants of at least 21 families and 31 genera, such as red grapes, peanuts, mulberries, polygonum cuspidatum, asteraceae plants (knotted), raspberry, blueberry, and the like, and is a polyphenol compound. In recent years, more and more scientific research has shown the multifunctional benefits of resveratrol. Resveratrol is found to be an extremely potent antioxidant, regulator of genetic expression via signaling, inhibitor of inflammatory mediators, and anti-aging substance, and is capable of reducing melanin synthesis. Resveratrol can therefore be used in cosmetic compositions as a unique active ingredient in personal care products.

Although resveratrol has the above-mentioned biological activity and excellent skin whitening effect, it is difficult to formulate it into a cosmetic composition. The compound is difficult to dissolve in water (the solubility of the compound in water is about 0.03g/Kg (namely 0.003 percent) at 25 ℃), is easy to react with other chemical substances, is unstable to light, and can only be stabilized for several days even under the condition of keeping out of the sun in a high-purity resveratrol ethanol solution in a Microherb stability test. Therefore, when it is used in cosmetics, it is difficult to stably maintain it in the shelf life.

In addition, resveratrol is also unstable in cosmetic compositions in the form of O/W or W/O compositions, it causes phase separation in the composition and changes the apparent color from white to yellowish brown. Thus, it has not been possible to make resveratrol be present in cosmetics at high levels so far. Furthermore, resveratrol has a tendency to precipitate (crystallize) in aqueous cosmetic compositions.

However, ferulic acid is a rather unstable substance and is susceptible to degradation by external factors (such as light, pH, temperature, etc.). Prior art systems containing ferulic acid (e.g., oil-in-water or water-in-oil formulations) undergo oxidative degradation and severe discoloration during long-term storage, thus greatly inhibiting the use of this material in the cosmetic field. Therefore, there is a great demand for a stable system containing ferulic acid in the market.

The inclusion compound of the alcohol-soluble active substance (such as resveratrol) and cyclodextrin is prepared by innovatively adopting a polyol dilution method, and the inclusion compound is tested by a centrifugal test, a high-temperature and illumination test, an infrared characterization test, a Transmission Electron Microscope (TEM) test and the like, so that the alcohol-soluble active substance (such as resveratrol) can be stably and efficiently wrapped in cyclodextrin molecules.

In some preferred embodiments, the inclusion complex comprises an alcohol soluble active (e.g., resveratrol, etc.) in an amount of about 0.01 to about 1.6% by weight, preferably about 0.1 to about 1% by weight. In some more preferred embodiments, the alcohol soluble active (e.g., resveratrol, etc.) is present in the clathrate at about 0.25-0.5 wt%.

Cyclodextrin

There are many ways to increase the dissolution of the active agent, thereby achieving rapid dissolution of the active agent and potentially making the active agent more readily absorbed and available after administration by the oral route. These methods include: adding cosolvent, adding surfactant, adding cyclodextrin, salifying, making into amorphous state, making into cocrystallization, and making into nanoparticles.

Many methods and processes suffer from one or the other of these problems. The research shows that: inclusion by cyclodextrin is a fairly effective option. Based on the structure of the active agent (e.g., resveratrol, etc.), the active agent can form an inclusion complex with the cyclodextrin. Literature reports indicate that inclusion complex formation can be achieved by a variety of methods, including solution saturation methods, spray drying methods, freeze drying methods, and the like.

Cyclodextrins are non-reducing cyclic glucose oligosaccharides produced from starch. There are three common cyclodextrins with 6, 7 or 8 glucose units (alpha-, beta-and gamma-cyclodextrins, respectively) linked by alpha-1, 4 glycosidic bonds. Cyclodextrins act as molecular reservoirs by trapping guest molecules (guest molecules) in their internal cavities, thereby forming inclusion complexes. Alpha-cyclodextrin has a smaller cavity and beta-and gamma-cyclodextrin have a larger cavity.

Cyclodextrins suitable for use in the present invention include alpha-, beta-and gamma-cyclodextrins, but beta-and gamma-cyclodextrins are preferred due to the larger internal cavity. Cyclodextrins have been chemically modified, particularly β -cyclodextrins, to improve the solubility of the parent cyclodextrin. Hydroxyethyl β -cyclodextrin, hydroxypropyl β -cyclodextrin (e.g., 2-hydroxypropyl- β -cyclodextrin), methylated β -cyclodextrin, glucosyl β -cyclodextrin, and sulfobutylether β -cyclodextrin are examples of cyclodextrins that have been chemically modified to improve their solubility. In some aspects of the invention, a beta-cyclodextrin will be used that includes a chemically modified beta-cyclodextrin. In some aspects, the chemically modified β -cyclodextrin will be hydroxypropyl β -cyclodextrin or sulfobutylether β -cyclodextrin. In some aspects, the cyclodextrin will be a gamma cyclodextrin, including a chemically modified gamma cyclodextrin. In some aspects, the cyclodextrin is a hydroxypropyl cyclodextrin (e.g., HP4.3- β -cyclodextrin, HP5.5- β -cyclodextrin, HP7.6- β -cyclodextrin, and HP4.5- γ -cyclodextrin). In other aspects, the cyclodextrin will be a sulfobutylether beta-cyclodextrin (e.g., SBE 6.6-beta-cyclodextrin, SBE 6.7-beta-cyclodextrin, SBE 6.8-beta-cyclodextrin, SBE 4.1-beta-cyclodextrin, and SBE4.6et 3.5-beta-cyclodextrin). In other aspects, the cyclodextrin will be a sulfobutylether gamma-cyclodextrin (e.g., SBE 4.3-gamma-cyclodextrin, SBE 4.6-gamma-cyclodextrin, SBE 5.2-gamma-cyclodextrin, and SBE5.6et 6.3-gamma-cyclodextrin). As used herein, a "chemically modified beta cyclodextrin" is a beta cyclodextrin that has been chemically modified to have at least improved solubility compared to its parent cyclodextrin (i.e., unmodified cyclodextrin).

Once the active agent (e.g., resveratrol, etc.) is fully included with the β -cyclodextrin, its dissolution is significantly improved and bioavailability is improved compared to the active agent itself.

In a preferred embodiment of the invention, the cyclodextrin employed is selected from: one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin (methyl cyclodextrin) and hydroxypropyl-beta-cyclodextrin (hydroxypropyl cyclodextrin).

In some preferred embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to cyclodextrin is about 1:6 to 1: 80. In some more preferred embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to cyclodextrin is about 1:8 to 1: 80. In some embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to cyclodextrin is about 1:6 to 1:60, 1:6 to 1:50, 1:6 to 1:20, 1:6 to 1: 10. In some embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to cyclodextrin is about 1:8 to 1:60, 1:8 to 1:50, 1:8 to 1:20, 1:8 to 1: 10.

In some preferred embodiments, the cyclodextrin content of the inclusion compound is 0.5 to 12% by weight, preferably 1 to 5% by weight.

Polyhydric alcohols

The polyhydric alcohol is widely applied in cosmetics, not only has the efficacy of a humectant, but also has the function of promoting active substances to permeate into skin. Therefore, the polyhydric alcohol does not need to be removed by distillation equipment or freeze drying in the later stage of the process of coating the alcohol-soluble active substance (such as resveratrol and the like) by the cyclodextrin, and the problem of organic solvent residue is well avoided. Meanwhile, for cosmetic production enterprises, the semi-finished product produced by the process can be directly applied to the production of cosmetic products.

Compared with the existing cyclodextrin coating technology, the technology for preparing the cyclodextrin-coated alcohol-soluble active substance (such as resveratrol) by using the polyol dilution method disclosed by the invention well avoids the problem of organic solvent residue, and has obvious advantages because the subsequent process does not need to be processed by distillation equipment, freeze drying equipment or spray drying equipment and the like.

Meanwhile, the new technology and the prior art are consistent in the aspects of cyclodextrin encapsulation efficiency, stability, solubility improvement and the like. Therefore, for cosmetic production enterprises, the semi-finished product produced by the process technology can be directly applied to the production of cosmetic products.

In some embodiments of the invention, the polyol is selected from: one or more of propylene glycol, 1, 3-propanediol, butylene glycol, dipropylene glycol, polyethylene glycol-8 (PEG400, INCI name is PEG-8), glyceryl polyether-26, and methyl gluceth-20.

In some preferred embodiments, the weight ratio of alcohol-soluble active (e.g., resveratrol, etc.) to polyol in the clathrate is from about 1:8 to about 1: 100. In some more preferred embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to polyol is about 1:8 to 1: 80. In some embodiments, the weight ratio of alcohol soluble active (e.g., resveratrol, etc.) to polyol is about 1:8 to 1:50, 1:8 to 1:30, 1:8 to 1:20, 1:8 to 1: 10.

In some preferred embodiments, the polyol content of the clathrate is from about 1 to about 15 weight percent, preferably from about 1.5 to about 5 weight percent.

Water-soluble antioxidant

The water-soluble antioxidant is added into the cyclodextrin inclusion compound to play a role in cooperative protection, so that the prepared inclusion compound is more stable in the storage process.

In some embodiments of the invention, the water-soluble antioxidant is selected from: one or more of sodium ascorbyl phosphate, citric acid, arbutin, glutathione, ergothioneine, glucosyl hesperidin, and thioctic acid.

In some preferred embodiments, the water-soluble antioxidant is present in the clathrate in an amount of about 0.01 to about 0.5 weight percent, preferably about 0.1 to about 0.25 weight percent.

Preparation method

The inclusion complex of an alcohol soluble active (e.g., resveratrol, etc.) and a cyclodextrin described in the present invention, a general method for its preparation, comprises the steps of:

according to the dosage of the formula, firstly dissolving alcohol-soluble active substances (such as resveratrol and the like) by using polyhydric alcohol at room temperature (25-50 ℃) to be in a transparent and clear state to be used as active substances; then uniformly mixing the cyclodextrin and the aqueous solvent to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, adding the water-soluble antioxidant, and stirring to dissolve completely.

The invention adopts a polyol dilution method, takes alcohol-soluble active substances (such as resveratrol and the like) as representative active substances to study, dissolves the alcohol-soluble active substances (such as resveratrol and the like) in the polyol in advance, adds the alcohol-soluble active substances into an aqueous solution containing cyclodextrin, can prepare an inclusion compound solution of the alcohol-soluble active substances (such as resveratrol and the like) and the cyclodextrin by only one simple operation, and finally adds a water-soluble antioxidant to play a role in synergistic protection. The process can be realized only by conventional stirring equipment without complex equipment such as heating equipment, distillation equipment, freeze drying or spray drying and the like, completely avoids the use of organic solvents, and is a very suitable industrial large-scale production process.

In some embodiments, the aqueous solvent in which the cyclodextrin is dissolved is preferably water, such as deionized water.

An inclusion compound solution of an alcohol-soluble active substance (such as resveratrol) and cyclodextrin, which is prepared by using a polyol dilution method, is subjected to centrifugal test, high-temperature and illumination test, infrared characterization, Transmission Electron Microscope (TEM) and the like, so that the alcohol-soluble active substance (such as resveratrol) can be stably and efficiently wrapped in cyclodextrin molecules. Compared with the existing cyclodextrin coating technology, the technology for preparing the cyclodextrin-coated alcohol-soluble active substance (such as resveratrol) by using the polyol dilution method disclosed by the invention well avoids the problem of organic solvent residue, and has obvious advantages because the subsequent process does not need to be processed by distillation equipment, freeze drying equipment or spray drying equipment and the like. Meanwhile, the new technology and the prior art are consistent in the aspects of cyclodextrin encapsulation efficiency, stability, solubility improvement and the like. For ferulic acid and tetrahydrocurcumin, the operation process of the polyol dilution method can also form a stable encapsulated state. Therefore, for cosmetic production enterprises, the semi-finished product produced by the process technology can be directly applied to the production of cosmetic products.

Application method

The active agent-cyclodextrin inclusion compounds of the present invention can be topically applied to mammalian skin. In one embodiment, the skin is subject to acne problems. In another embodiment, the skin requires an exfoliating treatment. The active agent-cyclodextrin inclusion complex can be applied to skin in need of treatment according to a suitable treatment regimen, e.g., from up to 2 times per day to as little as 1 time per week (e.g., once per day, once every two days, once per week), etc.

In certain embodiments, the active agent-cyclodextrin inclusion compounds of the present invention can be used to treat other desired conditions associated with the skin. For example, the active agent-cyclodextrin inclusion compounds of the present invention are useful for treating post-inflammatory hyperpigmentation, for reducing pore size, for reducing sebum production, and for reducing scarring.

The technical aspects of the present invention will be described in detail below with reference to preferred embodiments, but the scope of the present invention is not limited to these embodiments, and the technical aspects of the present invention are intended to be described and not limited. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the manufacturer. All percentages and parts are by weight unless otherwise indicated.

(I) test materials

(II) Experimental instrument

1. Fixed agitator IKA RW20

2. HWS 28 model of constant temperature water bath Shanghai-Hengchun scientific instruments Co., Ltd

3. Weighing balance METTLER TOLEDO PL602-S

Example 1: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 95.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1 percent of sodium ascorbyl phosphate is added and stirred to be dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Comparative example 1: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; uniformly mixing 0.25% of hydroxypropyl-beta-cyclodextrin and 97.4% of deionized water until the mixture is in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Finally, 0.1 percent of sodium ascorbyl phosphate is added and stirred to be dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Comparative example 2: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; uniformly mixing 1% of hydroxypropyl-beta-cyclodextrin and 96.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Finally, 0.1 percent of sodium ascorbyl phosphate is added and stirred to be dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Comparative example 3: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; uniformly mixing 1.5% of hydroxypropyl-beta-cyclodextrin and 96.15% of deionized water until the mixture is in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Finally, 0.1 percent of sodium ascorbyl phosphate is added and stirred to be dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Test example 1: investigation of stability of inclusion compound by using different cyclodextrin amounts

The stability evaluation method was as follows: the resveratrol and cyclodextrin inclusion compounds prepared in example 1, comparative example 2 and comparative example 3 were placed in a constant temperature chamber stable at room temperature (25 ℃), and the results were examined after 1 day and 7 days, respectively. And observing whether the sample has the condition that the particulate solid is separated out. If the sample is normally unchanged around a certain time within 7 days, it is denoted "ok"; the appearance of a small amount of solid precipitation indicates "slight precipitation"; the appearance of a significant solid precipitation phenomenon indicates "precipitation". The results are shown in the following table.

Table 1: investigation of stability of inclusion compound by using different cyclodextrin amounts

Sample source	After 1 day	After 7 days
			Example 1	ok	ok
Comparative example 1	Precipitation out of	Precipitation out of
			Comparative example 2	Slight precipitation	Slight precipitation
Comparative example 3	ok	Slight precipitation

As shown in table 1, it was found from the results of comparative example 1 and comparative example 1 that, for encapsulating the same content (0.25%) of resveratrol, a stable inclusion compound was also obtained with 2% hydroxypropyl- β -cyclodextrin (example 1). In contrast, the inclusion compound was unstable by using 0.25% hydroxypropyl-. beta. -cyclodextrin, and a white solid was precipitated after 1 day (comparative example 1); from the results of comparative examples 2 and 3, it was found that increasing the amount of hydroxypropyl- β -cyclodextrin used also increased the stability of the inclusion compound. The results show that the dosage of the cyclodextrin plays an important role in the stability of the inclusion compound in the process of preparing the resveratrol and cyclodextrin inclusion compound.

Example 2: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 95.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of arbutin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 3: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 95.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of glucosyl hesperidin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Comparative example 4: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 2% PEG400 at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 95.75% of deionized water until the mixture is in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. A transparent, uniform and clear solution state is formed, and the inclusion process is finished. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Test example 2: investigation of stability of clathrate by water-soluble antioxidant

The stability evaluation method was as follows: the resveratrol and cyclodextrin inclusion compound prepared in example 1, example 2, example 3 and comparative example 4 were placed in a refrigerator at 4 ℃, a high-temperature (48 ℃) incubator and a light box, respectively, and the results after 30 days were examined. Wherein, the specific setting parameters of illumination are as follows: PERCIVAL CU-41L5 illumination box, cold white fluorescent lamp (visible range 400-800 nm), temperature 25 ℃, illumination set as 75 μmol/m 2/s. The samples were observed for color change. If the sample is normally unchanged around a certain time within 30 days, it is denoted "ok"; the appearance of slight yellowing indicates "slight yellowing"; the appearance of yellowing indicates "yellowing". The results are shown in the following table.

Table 2: investigation of stability of clathrate by water-soluble antioxidant

Sample source	Refrigerator at 4 DEG C	Thermostat at 48 DEG C	Illumination box
				Example 1	ok	ok	Slight yellowing
Example 2	ok	ok	Slight yellowing
				Example 3	ok	ok	Slight yellowing
Comparative example 4	ok	Slight yellowing	Yellowing of hair

As shown in table 2, the four experiments of comparative example 1, example 2, example 3 and comparative example 4 were performed under 4 ℃ refrigerator conditions, and it was found that the stability of the clathrate compound was ok and no yellowing occurred; compared with the results of a thermostat at 48 ℃, the stability of the clathrate compound is improved by adding the water-soluble antioxidant, and the clathrate compound can be placed at 48 ℃ for 30 days by sodium ascorbyl phosphate (example 1), arbutin (example 2) and glucosyl hesperidin (example 3) without yellowing phenomenon, and slight yellowing phenomenon can occur in the absence of the water-soluble antioxidant (comparative example 4); as a result of examination in a light box, it was found that the yellowing phenomenon was remarkably reduced when no water-soluble antioxidant was added (comparative example 4), and when a water-soluble antioxidant was added (examples 1, 2, and 3). The addition of the water-soluble antioxidant plays an important role in the stability of the inclusion compound in the process of preparing the resveratrol and cyclodextrin inclusion compound.

Test example 3: determination of Infrared Spectroscopy (IR)

Respectively carrying out infrared spectrum characterization on resveratrol, hydroxypropyl- β -cyclodextrin, the physical mixture of resveratrol and hydroxypropyl- β -cyclodextrin and the resveratrol and cyclodextrin inclusion compound obtained in example 1, measuring by using a Fourier infrared spectrometer (equipment model: Thermo Nicolet iS10), carrying out IR test after tabletting, and scanning the range of 400-4000 cm^-1(ii) a The resulting spectra are shown in FIGS. 2-5.

The infrared spectrogram (figure 2) of resveratrol shows that the resveratrol is 1583cm^-1No benzene ring in the molecular structure of cyclodextrin, so that no benzene ring vibration signal appears (figure 3). in the physical mixture of resveratrol and hydroxypropyl- β -cyclodextrin, 1585cm of resveratrol is still displayed on the spectrogram^-1There appears a distinct vibration signal of the benzene ring skeleton, indicating that the two do not interact (fig. 4). From the infrared spectrum results of the resveratrol and cyclodextrin inclusion compound obtained in example 1, it was found that the benzene ring skeleton vibration signal of resveratrol was shifted to 1593cm-1, which indicates that veratryl alcohol entered the inner cavity of cyclodextrin to form the inclusion compound.

Example 4: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 0.5% PEG400 and 2% propylene glycol at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 95.15% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1 percent of sodium ascorbyl phosphate is added and stirred to be dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 5: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 4% 1, 3-propylene glycol at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; then 2% hydroxypropyl-beta-cyclodextrin and 93.65% deionized water are uniformly mixed to be in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of citric acid is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 6: preparation of resveratrol and cyclodextrin inclusion compound

Dissolving 0.25% resveratrol with 3% butanediol at room temperature (25-50 deg.C) to obtain transparent and clear state as active phase; uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 94.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of arbutin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 7: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.5 percent of resveratrol by using 4.5 percent of dipropylene glycol (25-50 ℃) to be in a transparent and clear state to be used as an active phase; uniformly mixing 4% of hydroxypropyl-beta-cyclodextrin and 90.9% of deionized water until the mixture is in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% glutathione is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 8: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.25% of resveratrol by using 5% of glyceryl polyether 26 (25-50 ℃) to be in a transparent and clear state to be used as an active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 92.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% ergothioneine is added and stirred to dissolve completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 9: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.25% of resveratrol by using 5% of methyl glucitol polyether-20 (25-50 ℃) until the resveratrol is in a transparent and clear state and is used as an active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 92.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of glucosyl hesperidin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 10: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.1% resveratrol by using 1% PEG400 (25-50 ℃) to be in a transparent and clear state to be used as an active phase; then uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 96.8% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1 percent of lipoic acid is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 11: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.01 percent of resveratrol by using 1 percent of PEG400 (25-50 ℃) to be in a transparent and clear state to be used as an active phase; then 0.5 percent of alpha-cyclodextrin and 98.39 percent of deionized water are uniformly mixed to be in a transparent and clear state to be used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1 percent of lipoic acid is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 12: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, firstly dissolving 0.01 percent of resveratrol by using 1 percent of PEG400 (25-50 ℃) to be in a transparent and clear state to be used as an active phase; then 0.8 percent of beta-cyclodextrin and 98.18 percent of deionized water are uniformly mixed until the mixture is in a transparent and clear state and is used as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.01% of arbutin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 13: preparation of resveratrol and cyclodextrin inclusion compound

Under the condition of room temperature, 1.6 percent of resveratrol is dissolved by 10 percent of PEG400 and 5 percent of dipropylene glycol (25-50 ℃) to be in a transparent and clear state to be used as an active phase; uniformly mixing 12% of hydroxypropyl-beta-cyclodextrin, 0.2% of gamma-cyclodextrin, 0.1% of methyl-beta-cyclodextrin and 70.6% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.3% of arbutin, 0.1% of ergothioneine and 0.1% of glucosyl hesperidin are added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the resveratrol and the cyclodextrin. Placing in shade for storage.

Example 14: preparation of inclusion compound of ferulic acid and cyclodextrin

Dissolving 0.25% ferulic acid with 3% butanediol at room temperature (25-75 deg.C) to obtain transparent and clear solution as active phase; uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 94.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of arbutin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the inclusion compound of the ferulic acid and the cyclodextrin. Placing in shade for storage.

Example 15: preparation of tetrahydrocurcumin and cyclodextrin inclusion compound

At room temperature, dissolving 0.25% tetrahydrocurcumin with 3% butanediol (25-75 deg.C) to obtain transparent and clear solution as active phase; uniformly mixing 2% of hydroxypropyl-beta-cyclodextrin and 94.65% of deionized water to obtain a transparent and clear state as a cyclodextrin phase; and then, slowly dripping the cyclodextrin phase into the active phase, keeping the stirring state (the rotating speed is 30rpm), and stirring for 10-15 minutes after finishing dripping. Forming a transparent, uniform and clear solution state, and finishing the inclusion process; finally, 0.1% of arbutin is added, and the mixture is stirred and dissolved completely. Discharging, and finishing the preparation of the clathrate compound of tetrahydrocurcumin and cyclodextrin. Placing in shade for storage.

Test example 4: stability of resveratrol and Cyclodextrin Inclusion Compounds (subject to the Inclusion Compound obtained in example 7) at different temperatures

The resveratrol and cyclodextrin inclusion compound prepared in example 7 were used as the study subjects and placed in a refrigerator at room temperature, 4 ℃, a refrigerator at-18 ℃, a high temperature (40 ℃) incubator, a high temperature (48 ℃) incubator, and a light box, respectively, and the time of 60 days was examined. And after the investigation is finished, analyzing and testing the resveratrol content, and calibrating the resveratrol content analysis and measurement by adopting liquid chromatography (HPLC). The initial resveratrol content was 0.5%, while observing the appearance and color change of the sample. For the index of appearance and color change of the sample, if there is no change normally around a certain time within 60 days, it means "ok"; the appearance of slight yellowing indicates "slight yellowing"; the appearance of a small amount of solid precipitation indicates "slight precipitation"; the results after the stability study are shown in the following table:

table 3: investigation of resveratrol content after standing at different temperatures

As shown in table 3, the content of resveratrol was still maintained at 95% or more by examining for 60 days under three conditions of room temperature, 4 ℃ refrigerator and-18 ℃; the content of the resveratrol can be kept above 90 percent after being inspected for 60 days in a high-temperature (40 ℃ and 48 ℃) thermostat, which shows that the resveratrol and cyclodextrin inclusion compound prepared by adopting a polyol dilution method has good high-temperature stability and ideal active content; under the condition of an illumination box, the effective content of the resveratrol still can be kept above 85 percent, which shows that the technology provided by the invention can well improve the illumination stability of the resveratrol.

Test example 5: transmission Electron Microscope (TEM) characterization of resveratrol and cyclodextrin inclusion compounds

The characterization method comprises the following steps: microscopic morphology characterization (test image is the effect of amplifying actual sample by 20 ten thousand times) of the resveratrol and cyclodextrin inclusion compound prepared in example 7 as a research object was performed by using an apparatus of a transmission electron microscope (TEM, model: Tecnai G2S-TWIN), the sample mass fraction is 1%, and the analysis test result is shown in the following FIG. 1.

According to TEM scanning results, the inclusion compound of resveratrol and cyclodextrin does not exist in insoluble powder crystals in the solution, and the size of the inclusion compound in the solution is relatively uniform and the inclusion compound exists in the form of aggregates with the size of about 20-30 nm. The cyclodextrin has obvious solubilizing effect on resveratrol, and can stably and efficiently wrap resveratrol in the inner cavity of the resveratrol.

Test example 6: stability Studies of active and Cyclodextrin Inclusion

The active material and the cyclodextrin inclusion compound prepared in examples 4 to 15 were used as the subjects, and the subjects were placed in a high-temperature (40 ℃) incubator, a high-temperature (48 ℃) incubator, and an illumination oven, respectively, to examine the time period of 60 days. After the investigation is finished, if the appearance and color change indexes of the sample are not changed normally before and after a certain time within 60 days, the index is denoted as 'ok'; the appearance of slight yellowing indicates "slight yellowing"; the results after the stability study are shown in the following table:

table 4: stability Studies of active and Cyclodextrin Inclusion

As shown in table 4, the results of six experimental stability tests of examples 4, 5, 6, 7, 8, and 9 revealed that the stability of the inclusion compound was ok, and that the selection of the polyol and the type of the water-soluble antioxidant were widely varied; the results of three experiments of example 10, example 11 and example 12 in a light box show that the content of resveratrol plays an important role in determining whether the sample turns yellow; from the results of three experiments, i.e., example 10, example 11 and example 12, it is understood that stable cyclodextrin inclusion compounds can be obtained by the polyol dilution method of the present invention for resveratrol, ferulic acid or tetrahydrocurcumin. The method has obvious effects on improving the solubility, the stability and the biocompatibility of the active substances.

Application example 1: preparation of anti-aging moisturizing essence lotion

According to the information in the following table, deionized water, glycerol, anhydrous betaine and tetrahydro-methyl pyrimidine carboxylic acid are added into a preparation pot under the condition of room temperature (25-35 ℃), and the mixture is stirred and fully mixed (the rotating speed is 30 rpm). After the mixture is transparent and clear, adding hyaluronic acid, hydroxyethyl cellulose and xanthan gum, and fully stirring until no particles exist. Adding phenoxyethanol and p-hydroxyacetophenone, and stirring until the mixture is completely dissolved. Adding the ginseng extract, the osmanthus flower extract, the resveratrol obtained in the example 7 and the cyclodextrin inclusion compound, and stirring and mixing uniformly. Sampling and detecting the central control index. After the test was completed, the material was discharged through a 400-mesh filter bag. And (5) obtaining transparent clear liquid, finishing the preparation of the anti-aging moisturizing essence water, and storing in a sealed and light-proof way.

Application example 2: preparation of whitening and moisturizing sleeping mask

According to the formula (A, B, C) information in the following table, deionized water, glycerin, nicotinamide, and tetrahydro-methyl pyrimidine carboxylic acid are added into a preparation pot under the room temperature condition (25-35 ℃), and the mixture is stirred and fully mixed (the rotating speed is 30 rpm). After the mixture is transparent and clear, hyaluronic acid and xanthan gum are added and fully stirred until no particles exist. Adding phenoxyethanol and p-hydroxyacetophenone, and stirring until the mixture is completely dissolved. Adding Poria extract, radix Paeoniae extract, resveratrol obtained in example 7 and cyclodextrin clathrate, stirring and mixing. Add Acryloyldimethyl ammonium taurate/VP copolymer and mix well (homogenizing at 2000rpm), finally add squalane and mix well. Sampling and detecting the central control index. After the test was completed, the material was discharged through a 400-mesh filter bag. The milky white semitransparent jelly is obtained and is stored in a sealed and light-proof way.

Claims

1. An inclusion complex of an alcohol soluble active and a cyclodextrin, the inclusion complex prepared by:

(b) dissolving cyclodextrin in an aqueous solvent as a cyclodextrin phase;

(c) adding the active phase to the cyclodextrin phase; and

(d) adding a water-soluble antioxidant into the mixture,

wherein the clathrate comprises 0.01-1.6 wt% alcohol soluble active;

wherein the clathrate comprises 1-15 wt% of a polyol;

wherein the inclusion complex comprises 0.5 to 12 wt% of cyclodextrin;

2. The clathrate of claim 1, wherein the alcohol soluble active is selected from the group consisting of: resveratrol, ferulic acid, and tetrahydrocurcumin.

3. The clathrate of claim 1, wherein the cyclodextrin is selected from the group consisting of: one or more of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.

4. The clathrate of claim 1, wherein the polyol is selected from the group consisting of: one or more of propylene glycol, 1, 3-propylene glycol, butanediol, dipropylene glycol, polyethylene glycol-8, glyceryl polyether-26, and methyl gluceth-20.

5. The clathrate of claim 1, wherein the water-soluble antioxidant is selected from the group consisting of: one or more of sodium ascorbyl phosphate, citric acid, arbutin, glutathione, ergothioneine, glucosyl hesperidin, and thioctic acid.

6. The inclusion complex of claim 1, wherein the weight ratio of the alcohol-soluble active to the cyclodextrin is about 1: 8.

7. A clathrate as claimed in claim 1 wherein the clathrate comprises 0.1-1 wt% alcohol soluble active.

8. A clathrate as claimed in claim 1 wherein the clathrate comprises 1.5-5 wt% polyol.

9. The clathrate of claim 1, wherein the clathrate comprises 1-5 wt.% cyclodextrin.

10. A clathrate as claimed in claim 1 wherein the clathrate comprises 0.1-0.25 wt% water soluble antioxidant.

11. Use of the clathrate of claim 1 in cosmetics.