CN110151590A - Retinol retinoic acid ester nanometer formulation and its preparation method and application - Google Patents
Retinol retinoic acid ester nanometer formulation and its preparation method and application Download PDFInfo
- Publication number
- CN110151590A CN110151590A CN201910529443.2A CN201910529443A CN110151590A CN 110151590 A CN110151590 A CN 110151590A CN 201910529443 A CN201910529443 A CN 201910529443A CN 110151590 A CN110151590 A CN 110151590A
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- CN
- China
- Prior art keywords
- acid ester
- retinoic acid
- retinol
- nanometer formulation
- retinol retinoic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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Classifications
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Abstract
The present invention provides retinol retinoic acid ester nanometer formulations and its preparation method and application, specifically, nanometer formulation prepared by the present invention contains flavol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol as active constituent, show significant synergy, it is horizontal that hyaluronic acid in skin can significantly be improved, it is non-stimulated to skin, and show apparent anti-aging effects.
Description
Technical field
The invention belongs to biomedicine field, in particular it relates to a kind of retinol retinoic acid ester nanometer formulation and
Preparation method and use.
Background technique
Vitamin A (vitamin A, VA) is that one group of category alltrans retinol (alltrans-retinol) is active
The derivative of β-ionone (β-ionone), including retinol, retinene, retinoic acid and esters.VA is needed by human micro
Nutrient plays an important role to visual development, immune function, reproductive system, growth and development etc..
Since VA derivative (retinol, retinoic acid etc.) is more sensitive to light, oxygen, temperature, metal ion, and compare
It is easy the stimulation such as to cause red swelling of the skin, itch, is tight, application of the VA derivative in skin care item is relatively more limited always.
Retinol retinoic acid ester is obtained by the hydroxyl of retinol and the esterification of retinoic acid.Retinol retinoic acid
Ester remains ring end group and side chain alkenyl, still has the bioactivity of retinol and retinoic acid, and internal test shows: promoting skin
Skin power of regeneration is better than retinol and retinoic acid.The IC 50 of retinol retinoic acid ester is higher than retinol by 60%, therefore retinol
The cytotoxicity of retinoic acid ester is lower, and use is safer.Retinol retinoic acid ester the optical stabilization for improving retinol it is fixed, change
While learning stability, reduce the irritation of retinol and yellow acid.
The bioavilability of retinol retinoic acid ester is poor, is directly appended to be difficult to play due effect in preparation.
Summary of the invention
The purpose of the present invention is to provide a kind of retinol retinoic acid ester nanometer formulations and its preparation method and application.
The first aspect of the present invention provides a kind of retinol retinoic acid ester nanometer formulation, the retinol retinoic acid ester
Nanometer formulation is liposome nanometer formulation, and includes:
Retinol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol.
In another preferred example, the average grain diameter of the retinol retinoic acid ester nanometer formulation is 10-50nm.
In another preferred example, the retinol retinoic acid ester nanometer formulation includes:
Retinol retinoic acid ester 2-10 parts by weight；
Ascorbyl palmitate 0.1-1 parts by weight；With
Alpha-tocopherol 0.1-1 parts by weight.
In another preferred example, the retinol retinoic acid ester nanometer formulation includes:
Retinol retinoic acid ester 4-6 parts by weight；
Ascorbyl palmitate 0.2-0.5 parts by weight；With
Alpha-tocopherol 0.2-0.5 parts by weight.
The second aspect of the present invention provides a kind of cosmetic composition, includes the present invention in the cosmetic composition
Retinol retinoic acid ester nanometer formulation described in first aspect.
In another preferred example, in the cosmetic composition, the content of the retinol retinoic acid ester nanometer formulation is
0.01%-10%.
In another preferred example, in the cosmetic composition, the content of the retinol retinoic acid ester nanometer formulation is
0.05%-5%.
In another preferred example, in the cosmetic composition, the content of the retinol retinoic acid ester nanometer formulation is
0.5%-3%.
In another preferred example, the dosage form of the cosmetics be solid dosage forms, semisolid dosage form or liquid dosage form, such as it is molten
Liquid, gel, cream, lotion, paste, creme, paste, cake, pulvis, patch etc..
The third aspect of the present invention provides a kind of preparation method of retinol retinoic acid ester nanometer formulation, the method
Comprising steps of
(1) it takes retinol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol to be dissolved in ethyl alcohol, obtains mixed liquor one；
(2) it takes membrane material to be dissolved in mixed liquor one, is heated to about 40 DEG C, the ethyl alcohol removed in solution under 1330Pa obtains mixed liquor
Two；
(3) mixed liquor two is added into PBS buffer solution, obtains mixed liquor three；
(4) mixed liquor three is transferred in high pressure homogenizer after homogeneous, by 0.22 μm of filtering with microporous membrane degerming, is made
Nano liposomes are the retinol retinoic acid ester nanometer formulation.
In another preferred example, the mixed liquor one of the step (1) includes:
Retinol retinoic acid ester 2-10 parts by weight；
Ascorbyl palmitate 0.1-1 parts by weight；With
Alpha-tocopherol 0.1-1 parts by weight.
In another preferred example, the mixed liquor one of the step (1) includes:
Retinol retinoic acid ester 4-6 parts by weight；
Ascorbyl palmitate 0.2-0.5 parts by weight；With
Alpha-tocopherol 0.2-0.5 parts by weight.
The fourth aspect of the present invention provides the use of retinol retinoic acid ester nanometer formulation described in first aspect present invention
On the way, cosmetics, health care product or drug are used to prepare.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 shows the electromicroscopic photograph of liposome nanometer formulation obtained.
Fig. 2 shows nanometer formulation particle diameter distribution.
Fig. 3 is that mouse tissue is sliced result.
Fig. 4 is subject's eye circumference skin photo.
Specific embodiment
The present inventor obtains a kind of retinol retinoic acid ester nanometer formulation and its preparation side by extensive and in-depth research
Method, nanometer formulation prepared by the present invention contain flavol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol as activity at
Point, significant synergy is shown, it is horizontal can significantly to improve hyaluronic acid in skin.
Before describing the present invention, it should be understood that the present invention is not limited to the specific method and experiment conditions, because this
Class method and condition can change.It should also be understood that its purpose of the term as used herein is only that description specific embodiment, and
And it is not intended to be restrictive, the scope of the present invention will be limited only by the claims which follow.
Unless otherwise defined, otherwise whole technologies used herein and scientific term all have such as fields of the present invention
The normally understood identical meanings of those of ordinary skill.As used herein, in use, term in mentioning the numerical value specifically enumerated
" about " mean that the value can change not more than 1% from the value enumerated.For example, as used herein, statement " about 100 " includes 99 Hes
101 and between whole values (for example, 99.1,99.2,99.3,99.4 etc.).
Stable contain flavol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol conduct the present invention provides a kind of
Active constituent obtains nano liposome preparations.
It is that membrane material includes that liposome (Liposomes), which is by phosphatide, cholesterol etc.,.It can shape when phosphatide is dispersed in water
At multilayer micro-capsule, and every layer is lipid bilayer, is separated between each layer by water phase, and this micro-capsule is exactly liposome.Lipid
Body can be divided into unilamelar liposome, multilamelar liposome.Since the basic structure of organism plasma membrane is also phospholipid bilayer tunic, lipid
Body has the structure similar with biological cell, therefore has good biocompatibility.
Phosphatide is the main chemical compositions for constituting liposome, wherein most representational is lecithin.Lecithin is main
From yolk and soybean, preparation cost is low, and property is stablized, and belongs to neutral phospholipid.Phosphatidyl choline forms many cell membranes
Main component, and prepare the primary raw material of liposome.
The membrane material that nano liposomes provided by the invention are selected can be phosphatide and cholesterol, and wherein phosphatide includes but unlimited
In soybean lecithin, egg yolk lecithin.
Cholesterol is also another important composition ingredient of liposome, it is the important component of many natural biological films, itself
Membrane structure is not formed, but is inserted into immobilized artificial membrane.Cholesterol, which is added, can change the phase transition temperature of adipose membrane, to influence
The permeability and mobility of film.Therefore cholesterol has the function of stablizing phospholipid bilayer film.
Main advantages of the present invention are:
1) nanometer formulation prepared by the present invention contains flavol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol conduct
Active constituent shows significant synergy, and it is horizontal can significantly to improve hyaluronic acid in skin.
2) nanometer formulation prepared by the present invention, it is non-stimulated to skin, and show apparent anti-aging effects.
Combined with specific embodiments below, the further old present invention in detail.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.The experimental method of detailed conditions is not specified in the following example, usually according to conventional strip
Part such as U.S. Sambrook.J etc. writes " Molecular Cloning: A Laboratory room guide " (Huang Peitang etc. is translated, Beijing: Science Press, 2002)
Described in condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number be by weight
It calculates.Experimental material used in following embodiment and reagent can obtain unless otherwise instructed from commercially available channel.
Embodiment 1 prepares nanometer formulation
Method in referenced patent document CN1411368A prepares nanometer formulation.By retinol retinoic acid ester 5g, Vitamin C
Sour palmitate 0.3g and alpha-tocopherol 0.3g are dissolved in ethyl alcohol, amount to 100mL mixed solution.Egg yolk lecithin 50g is dissolved in
In mixed solution, 40 DEG C are heated to, the alcohol solvent in solution is removed at 1330Pa.Remaining liq is added to 500ml PBS
In buffer, it is dispersed with stirring.
Using high-pressure emulsification machine by above-mentioned dispersion emulsifying soln, the dispersion liquid after emulsification passes through 0.22 μm of filtering with microporous membrane
Degerming.15g filtrate is filling in freeze-drying bottle, then freeze-drying bottle is put into freeze dryer, room temperature-operating carries out at 4000Pa
Gas degassing.Concentration is carried out at 40 DEG C after degassing, under the conditions of 1330Pa obtains concentrate.Concentrate is cooled to -40 DEG C, then
Solution temperature, which is increased to 40 DEG C, at high vacuum condition (1.33Pa) makes solution foaming.At 30 DEG C, vacuum under the conditions of 13.3Pa
The dry bubbling solution is sealed freeze-drying bottle with after nitrogen supercharging to atmospheric pressure after vacuum drying, the liposome nanometer system of acquisition
Agent is named as nanometer formulation A.
Fig. 1 shows the electromicroscopic photograph of liposome nanometer formulation obtained；
Fig. 2 shows nanometer formulation particle diameter distribution.
It prepares the only liposome nanometer formulation comprising retinol retinoic acid ester respectively by the above method and (is named as nanometer system
Agent B)；It only include the liposome nanometer formulation (being named as nanometer formulation C) of ascorbyl palmitate；Only comprising alpha-tocopherol
Liposome nanometer formulation (is named as nanometer formulation D)；Liposome comprising retinol retinoic acid ester and ascorbyl palmitate
Nanometer formulation (is named as nanometer formulation E)；And the liposome nanometer formulation comprising retinol retinoic acid ester and alpha-tocopherol
(being named as nanometer formulation F)；Wherein, the dosage of each active material is same as above.
Embodiment 2 promotes the expression of internal mucopolysaccharide (hyaluronic acid) to test
1. experimental animal
Healthy male SPF grades of mouse of 6~8 week old, weight are (23 ± 2) g.Temperature (25 ± 2) DEG C, humidity (40 ±
10) it is raised in the environment of %.
2. the foundation of animal model, grouping and administration
Mouse is divided into blank group, model group, matrix group, positive controls, experimental group I, experimental group II, experimental group at random
III, experimental group IV, experimental group V, every group of 6 mouse.
Mouse adaptive feeding carries out depilation processing after l weeks, with 6% vulcanized sodium, exposes the skin of 3cm × 3cm.Except sky
Outside white group, remaining each group reference literature [ZHONG W, LIU N, XIE Y, et a1.Antioxidant and antiageing
activities of mycelial polysaceharides from Lepista sordid[J].Int J Biol
Macromol, 2013,60 (6): 355-359] establishing skin aging model, and D- galactolipin 1.09/ is subcutaneously injected daily
(kg.d)。
Blank group is subcutaneously injected daily and the isometric physiological saline of D- galactolipin, and totally 10 days；
Matrix group smears conventional skin care emulsion matrix 10mg/cm after modeling2；
Experimental group I smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation A2；
Experimental group II smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation B2；
Experimental group III smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation C2；
Experimental group IV smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation D2；
Experimental group V smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation E2；
Experimental group VI smears the facial treatment milk matrix 10mg/cm for containing 1% nanometer formulation F2。
Model group and blank group are disregarded.It is continuous smear 28 days after fasting for 24 hours, after mouse skin is cleaned, using neck
Vertebra dislocation method puts to death mouse, and skin is cut simultaneously freezen protective rapidly.Separately setting skin irritatin group mouse 7 is served only for skin irritation
Experiment.
Facial treatment milk matrix components are as follows: citric acid monoglyceride 1.5%, isopropyl palmitate 3%, is spat jojoba oil 2%
Warm -60 3%, beeswax 3%, atoleine 3%, Carbopol 941 0.1%, glycerol 3%, hydroxyethyl cellulose 0.1%, EDTA
Disodium 0.01%, triethanolamine 0.01%, surplus are distilled water, and above-mentioned each component adds up to 100%.
Acute multiple skin irritation test
Mouse back side by skin irritatin group shaving and after cleaning is divided into two regions (2.5cm × 2.5cm), and left side applies
The skin care milk 0.5g of each group is smeared, right side is blank control, uses immobilization with adhesive tape after being covered with gauze again, for 24 hours rear cleaning skin, observation
1h, for 24 hours, after 48h smear position dermoreaction.
It is continuous to smear 14 days, observe and record the dermoreaction for smearing position.Referring to " safety evaluation of cosmetics program and
Method " stimulate the reaction evaluation and stimulus intensity evaluation are carried out to skin.
The results show that in addition to experimental group III, experimental group V, the skin of remaining each experimental group be not coated with skin care milk skin phase
Than not occurring the phenomenon that oedema and erythema, it was demonstrated that skin care milk of the present invention is to no skin irritation.Through a long time is repeatedly carried on the back to mouse
After portion's dermal application skin care milk of the present invention, compared with blank skin, the phenomenon that skin after smearing has no erythema and oedema, it was demonstrated that
It is nonirritant to skin that skin care milk of the present invention is smeared for a long time.The cutaneous manifestations of experimental group III have gone out apparent erythema, continuous to apply
There is serious oedema after smearing 14 days.The side effect of experimental group V is weaker, but is still able to observe that slight skin is red
Spot.Should the result shows that, ascorbyl palmitate nanometer formulation has more serious irritation to skin, and retinol retinoic acid ester
Presence, the side effect of ascorbyl palmitate can be significantly reduced, deposited simultaneously in retinol retinoic acid ester and alpha-tocopherol
In case, the side effect of ascorbyl palmitate can be completely eliminated.
The appearance features of mouse skin are observed
Observe the form of the appearances such as color, smooth degree, the wrinkle of each group back of mice baring skin.
The appearance of mouse skin is observed, finds blank group skin smooth, the colour of skin is moist, and no wrinkle generates.Model group mouse
Dry skin, relaxation, color is obscure and has wrinkle to be formed.For matrix group compared with model group, improvement is unobvious.Except experimental group
The side effect of III is significant, and outer in the experiment of stopping in the 14th day, the skin condition of remaining each experimental mice has compared with model group
Improve, wherein the state of the more other each groups of the skin condition of experimental group I is more preferable, dry to alleviate, and skin colour improves, and wrinkle is bright
It is aobvious to mitigate.
Mouse skin hyaluronic acid (HA) assay
The mice skin tissue for taking 0.5g, with the homogenate of PBS buffer solution preparation 10%, centrifugation takes supernatant, according to
Sour (HA) detection kit of mouse zona matter (being purchased from Shanghai Yan Sheng biochemical reagents Co., Ltd) specification is operated, and is measured small
The content of HA in mouse skin.The experimental results are shown inthe following table:
| Group | HA content (mg/g) | Group | HA content (mg/g) |
| Blank group | 2.64 | Experimental group II | 2.56 |
| Model group | 1.86 | Experimental group IV | 2.28 |
| Matrix group | 2.24 | Experimental group V | 2.63 |
| Experimental group I | 2.82 | Experimental group VI | 2.47 |
The result shows that experimental group I can remarkably promote the expression of hyaluronic acid in Mice Body, after continuous use, in skin
The content of hyaluronic acid is higher by 6.8% than blank group, shows retinol retinoic acid ester, ascorbyl palmitate and α-life
The nanometer formulation for educating the combination preparation of phenol three has significant synergy.
Epidermis and skin corium in microexamination mouse tissue slice, hyaluronic acid can have illicit sexual relations with albumen (HABP) combination
Colour response, partial results from figure as shown in figure 3, can significantly observe, hyaluronic acid contents are bright in the slice of experimental group I
The aobvious content higher than hyaluronic acid in blank group histotomy.And in model group, hyaluronic acid contents significantly reduce.
Recovery test of the embodiment 3 to aging caused by UV
It chooses 60 volunteers and participates in test, the age 25-45 years old, be randomly divided into 3 groups: A group, B group, C group.
Wherein A group uses the facial treatment milk matrix for containing 1% nanometer formulation A；
B group uses the facial treatment milk matrix for containing 1% nanometer formulation B；
C group uses the facial treatment milk matrix for containing 1% nanometer formulation E.
Once in the morning and once at night, subject is paid a return visit at the 4th, 8,12 week of test respectively.Use Visiometer
SV 600 (CK, Germany) records subject in different test phase periocualr skin situations.
Test result:
The skin of A group subject is obviously improved, and 100% A group subject indicates their eye circumference skin
Elasticity is improved, and the B group subject of 60% (12/20) indicates that eye circumference elasticity of skin is improved, the C of 70% (14/20)
Group subject indicates that eye circumference elasticity of skin is improved.
Typical result is as shown in Figure 4.
12nd week, it was 1.28% that the visible wrinkle of A group subject, which improves, higher than the 0.72% of the 0.61% and C group of B group.
To the reparation of light injury performance, A group, which improves 8.61%, B group and improves 4.43%, C group, improves 4.68%.
In addition to this, " edge effect is successively decreased " (product long, effect be can't see gradually) of A group is weaker, and A group is hard
It holds and uses product in one-year age it can be seen that the change of skin.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of retinol retinoic acid ester nanometer formulation, which is characterized in that the retinol retinoic acid ester nanometer formulation is lipid
Body nanometer formulation, and include:
Retinol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol.
2. retinol retinoic acid ester nanometer formulation as described in claim 1, which is characterized in that the retinol retinoic acid ester is received
The average grain diameter of metric system agent is 10-50nm.
3. retinol retinoic acid ester nanometer formulation as described in claim 1, which is characterized in that the retinol retinoic acid ester is received
Metric system agent includes:
Retinol retinoic acid ester 2-10 parts by weight；
Ascorbyl palmitate 0.1-1 parts by weight；With
Alpha-tocopherol 0.1-1 parts by weight.
4. retinol retinoic acid ester nanometer formulation as described in claim 1, which is characterized in that the retinol retinoic acid ester is received
Metric system agent includes:
Retinol retinoic acid ester 4-6 parts by weight；
Ascorbyl palmitate 0.2-0.5 parts by weight；With
Alpha-tocopherol 0.2-0.5 parts by weight.
5. a kind of cosmetic composition, which is characterized in that include retinol described in claim 1 in the cosmetic composition
Retinoic acid ester nanometer formulation.
6. cosmetic composition as claimed in claim 5, which is characterized in that in the cosmetic composition, the retinol
The content of retinoic acid ester nanometer formulation is 0.01%-10%.
7. cosmetic composition as claimed in claim 5, which is characterized in that the dosage form of the cosmetics is solid dosage forms, half
Solid dosage forms or liquid dosage form.
8. cosmetic composition as claimed in claim 5, which is characterized in that the dosage form of the cosmetics is solution, gel, cream
Frost, lotion, paste, creme, paste, cake, pulvis, patch etc..
9. the purposes of retinol retinoic acid ester nanometer formulation as described in claim 1, which is characterized in that be used to prepare makeup
Product, health care product or drug.
10. a kind of preparation method of retinol retinoic acid ester nanometer formulation, which is characterized in that the method includes the steps:
(1) it takes retinol retinoic acid ester, ascorbyl palmitate and alpha-tocopherol to be dissolved in ethyl alcohol, obtains mixed liquor one；
(2) it takes membrane material to be dissolved in mixed liquor one, is heated to about 40 DEG C, the ethyl alcohol removed in solution under 1330Pa obtains mixed liquor two；
(3) mixed liquor two is added into PBS buffer solution, obtains mixed liquor three；
(4) mixed liquor three is transferred in high pressure homogenizer after homogeneous, by 0.22 μm of filtering with microporous membrane degerming, nanometer is made
Liposome is the retinol retinoic acid ester nanometer formulation.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111920702A (en) * | 2020-08-21 | 2020-11-13 | 上海益好纳米科技有限公司 | Retinol nano liposome and preparation method thereof |
| CN112294683A (en) * | 2020-02-28 | 2021-02-02 | 上海寻梦说生物科技有限公司 | Cosmetic with epidermis moisturizing and skin anti-wrinkle effects and preparation and application thereof |
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| US20040062781A1 (en) * | 2001-01-16 | 2004-04-01 | Young-Soy Roh | Retinol derivatives and process for preparing same |
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| CN112294683A (en) * | 2020-02-28 | 2021-02-02 | 上海寻梦说生物科技有限公司 | Cosmetic with epidermis moisturizing and skin anti-wrinkle effects and preparation and application thereof |
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