CN113620827B - Betaine salicylic acid eutectic crystal and preparation method and application thereof - Google Patents

Betaine salicylic acid eutectic crystal and preparation method and application thereof Download PDF

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CN113620827B
CN113620827B CN202110752866.8A CN202110752866A CN113620827B CN 113620827 B CN113620827 B CN 113620827B CN 202110752866 A CN202110752866 A CN 202110752866A CN 113620827 B CN113620827 B CN 113620827B
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betaine
salicylic acid
eutectic
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CN113620827A (en
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张嘉恒
王振元
韩知璇
干瑞靖
李雪云
王天晓
吴称玉
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Shenzhen Shanhai Innovation Technology Co ltd
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Shenzhen Xuanjia Biological Technology Co ltd
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Abstract

The invention provides a betaine salicylic acid eutectic crystal and a preparation method and application thereof, and relates to the technical field of medicines and cosmetics. The betaine salicylic acid eutectic is an orthorhombic crystal system, a space group is Pbca, and unit cell parameters are
Figure DDA0003145660030000011
α ═ β ═ γ ═ 90 °, Z ═ 8, unit cell volume
Figure DDA0003145660030000012
The present invention providesThe betaine salicylic acid eutectic can improve the irritation problem of betaine salicylate.

Description

Betaine salicylic acid eutectic crystal and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicines and cosmetics, in particular to a betaine salicylic acid eutectic crystal and a preparation method and application thereof.
Background
The beta-hydroxy acids (BHAs) in salicylic acid have the function of accelerating the exfoliation of squamous keratinocytes similar to alpha-hydroxy acids (AHAs), and the salicylic acid belongs to aromatic beta-hydroxy acids, and the efficacy of the salicylic acid in skin care products is well accepted for a long time. Salicylic acid is used in the pharmaceutical field to treat acne by topical application; in the field of cosmetics, it is possible to improve skin problems such as young lines and wrinkles due to aging of internal functions of the body, and wrinkles, sagging, spots, etc. due to photoaging.
The function of trimethylglycine in betaine in the aspect of skin care is also applied to the cosmetic industry for a long time, the betaine has very special molecular structure, the same molecule has both anionic charge and cationic charge, and human skin has all negative charges under common physiological conditions, so the molecule containing positive charges has natural affinity to the skin and is particularly suitable for skin care products.
However, salicylic acid has a strong irritant property, and betaine salicylate is widely added to medicines and cosmetics in order to reduce the irritant property of salicylic acid. The betaine salicylate combines the effects of removing acne and firming skin of salicylic acid and moistening and moisturizing betaine, and can promote skin metabolism, exfoliation of dead skin and improve skin elasticity. However, betaine salicylate has certain irritation and can cause irritation to skin and eyes, so that the application of betaine and salicylic acid in medicines and cosmetics is still to be improved.
Disclosure of Invention
In order to solve the problem of irritation of betaine salicylate, the invention provides a betaine salicylic acid eutectic and a preparation method and application thereof.
The key of the betaine salicylic acid eutectic crystal is as follows: the betaine salicylic acid eutectic is in an orthorhombic system, a space group is Pbca, and unit cell parameters are
Figure BDA0003145660010000011
α ═ β ═ γ ═ 90 °, Z ═ 8, unit cell volume
Figure BDA0003145660010000012
Preferably, the molecular formula of the betaine salicylic acid eutectic is C12H17NO5The eutectic comprises betaine molecules and salicylic acid molecules, and the molar ratio of the betaine molecules to the salicylic acid molecules is 1:1.
Preferably, the granularity of the betaine salicylic acid eutectic is (240 +/-15) nm to (520 +/-30) nm.
The key point of the preparation method of the betaine salicylic acid eutectic is that: the method comprises the following steps:
s1 adding solvent, betaine and salicylic acid into an autoclave, and stirring at a first pressure and a first temperature to form a suspension of the betaine and the salicylic acid;
s2, pumping the suspension from a high-pressure pump to a high-pressure homogenizer, and passing the suspension through a homogenizing valve, wherein the pressure of the homogenizing valve is 600-1200 bar;
and S3, decompressing the receiving chamber of the high-pressure homogenizer to a second pressure at a second temperature, and volatilizing the solvent to obtain the betaine salicylic acid eutectic.
Preferably, the pressure of the homogenizing valve is 800 bar.
Preferably, the first temperature is a temperature at which the solvent is liquid at a first pressure; the second temperature is a temperature at which the solvent is gaseous at a second pressure.
Preferably, the molar ratio of the fed betaine to the fed salicylic acid is 1:1, and the solid-to-liquid ratio of the total of the betaine and the salicylic acid to the solvent is 1:4-1:6 (kg: L).
Preferably, the solvent is liquid CO2。
Preferably, the first pressure is 10MPa-30MPa, the first temperature is 110-.
The betaine salicylic acid eutectic can be applied to the fields of medicines and cosmetics.
In summary, the present invention includes at least one of the following beneficial effects:
1. the betaine salicylic acid eutectic disclosed by the invention has low irritation. The irritation of the compound is obviously lower than that of a salicylic acid monomer, the pH value of the compound is milder than that of the salicylic acid monomer, and the occurrence of allergy is reduced. Betaine salicylic acid co-crystals also appear milder relative to betaine salicylate.
2. The betaine salicylic acid eutectic disclosed by the invention is prepared from betaine and salicylic acid, retains the effects of betaine and salicylic acid, and has the effects of moisturizing betaine, resisting allergy and reducing irritation, and the effects of sterilizing, diminishing inflammation, removing acne, removing cutin and the like of salicylic acid. The betaine salicylic acid eutectic crystal has better effect when added into staying type products such as emulsion and face cream and washing type products such as facial cleanser, shampoo and bath lotion.
3. The betaine salicylic acid eutectic is obtained by a high-pressure homogenization method. The betaine salicylate obtained by methods such as rotary evaporation recrystallization and the like is generally betaine salicylate, and betaine salicylic acid eutectic is difficult to generate. The betaine salicylic acid eutectic obtained by the high-pressure homogenization method has high purity and adjustable particle size.
Drawings
FIG. 1 is a schematic diagram of the molecular structure of betaine salicylic acid cocrystals according to example 1 of the present invention;
FIG. 2 is a schematic diagram of the stacking of single crystal molecules of the betaine salicylic acid eutectic of example 1 of the present invention;
FIG. 3 is the nuclear magnetic hydrogen spectrum of the betaine salicylic acid co-crystal of example 1 of the present invention;
FIG. 4 is a TGA profile of a betaine salicylic acid co-crystal of example 1 of the present invention;
FIG. 5 is a TGA profile of a physical mixture of betaine salicylic acid;
FIG. 6 is a visia-cr image of a volunteer's face;
FIG. 7 is a nuclear magnetic hydrogen spectrum of the reaction product of comparative example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention clearer and clearer, the present invention is further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Salicylic acid is a fat-soluble organic acid with the chemical formula C7H6O3Structural formula is
Figure BDA0003145660010000031
White crystalline powder with a melting point of 158-161 ℃. In the field of medicine, salicylic acid is mainly used as a raw material in the pharmaceutical industry and can be used for preparing medicines such as aspirin, sodium salicylate, salicylamide and the like. In the field of cosmetics, salicylic acid solution with a concentration of 1-2 wt.% is commonly used for treating acnes, can help skin effectively remove accumulated cutin around hair orifices and on the skin surface, diminish inflammation and resist bacteria, and more importantly can also break down blocking plugs (black heads/white heads) formed by cell debris and grease in hair follicles, clear pores and destroy the growth environment of bacteria.
Betaine is an alkaloid with chemical name of N, N, N-trimethylglycine, chemical structure similar to amino acid, and belongs to quaternary ammonium base material with molecular formula of C5H11NO2Structural formula is
Figure BDA0003145660010000032
White crystalline powder in appearance and melting pointIs 301-305 ℃. Betaine is used in medicine field, and can be used for resisting tumor, lowering blood pressure, resisting peptic ulcer and gastrointestinal dysfunction, treating liver diseases, etc. Betaine has effects of moisturizing skin, protecting cell balance by penetrating into skin stratum corneum, and increasing water content of skin. Although betaine has a moisturizing effect like glycerol, betaine, unlike glycerol's fixed water molecules, allows water molecules to be completely absorbed and utilized by whole living cells. When one water molecule occupies the middle of the betaine zwitterion, the self water molecule can be easily released to the surrounding liquid. The moisturizing mechanism performance of the betaine is superior to that of other moisturizing agents, and the betaine can be used for lasting moisturizing even at low concentration.
Eutectic is defined as a crystalline material in which two or more different molecules form a regular arrangement in the same crystal lattice through intermolecular interactions such as hydrogen bonds, pi-pi interaction van der waals forces, and the like. The eutectic crystal is an effective way for changing the physical and chemical properties of some components, such as solubility, melting point, hygroscopicity, compressibility, density and the like. In the existing betaine salicylate, proton transfer occurs between betaine and salicylic acid, the betaine and the salicylic acid are combined together through the ionic action, and the salicylic acid betaine salt has certain skin and eye irritation. The betaine salicylic acid eutectic synthesized by the invention does not generate proton transfer, betaine molecules and salicylic acid molecules are combined together through supermolecular interaction, the irritation of the betaine salicylic acid eutectic is obviously less than that of betaine salicylate, and the betaine salicylic acid eutectic is widely applied to cosmetics.
The invention provides a preparation method of betaine salicylic acid eutectic, which comprises the following steps:
s1 adding solvent, betaine and salicylic acid into an autoclave, adding the solvent, the betaine and the salicylic acid into the autoclave, and stirring at a first pressure and a first temperature to form a suspension of the betaine and the salicylic acid.
In particular, the solvent may be liquid CO2Petroleum ether and ethyl acetate, and the like. Among them, liquid CO is preferred2Liquid CO2Has the advantages of no toxicity, no flammability and priceModerate characteristic. The feeding molar ratio of the betaine to the salicylic acid is 1:1, and the solid-liquid ratio of the total of the betaine and the salicylic acid to the solvent is 1:4-1:6 (kg: L). Autoclave means a reactor operating at high pressure, the autoclave pressure being set at 10-30MPa, preferably 20 MPa; the temperature is set to 110-130 ℃, and is preferably 115 ℃; the stirring speed is 600-750r/min, preferably 700 r/min; the stirring time is 1-8h, preferably 4 h; a suspension of betaine and salicylic acid is formed. CO at the pressure of 10-30MPa and the temperature of 110-130 DEG C2In liquid form, betaine and salicylic acid are in liquid CO2The medium solubility is low, and under the stirring condition, the betaine and the salicylic acid particles are fully dispersed and uniformly mixed through the mechanical action. The solvent is liquid CO2Can effectively avoid the generation of solvate and liquid CO2As a supercritical fluid, the composite material can be rapidly expanded and gasified at normal temperature and normal pressure, and solvent residue is effectively avoided. When other solvents are selected, the first pressure and the first temperature may be adjusted such that the solvent is liquid at the first pressure.
S2 the suspension is pumped from the high pressure pump to the high pressure homogenizer and through the homogenizing valve.
In particular, the pressure of the homogenizing valve is 600bar to 1200bar, wherein 800bar is preferred. The suspension is maintained at substantially constant pressure and temperature during pumping by the high pressure pump. The high-pressure homogenizer is a mechanism which takes a high-pressure reciprocating pump as power to transmit and convey materials, liquid materials or solid particles taking liquid as a carrier are conveyed to a homogenizing valve (high-pressure homogenizing cavity), and the materials to be treated have strong shearing, impacting, cavitation and turbulent vortex effects generated under high pressure in the process of passing through the homogenizing valve, so that the liquid materials or the solid particles taking liquid as a carrier are subjected to ultramicro refining. The homogenizing valve receives the high-pressure liquid material conveyed by the collecting pipe to complete the tasks of ultrafine grinding, emulsification and homogenate. The high-pressure homogenizer can make the material in suspension state flow through the containing cavity (high-pressure homogenizing cavity/homogenizing valve) with special internal structure at high speed under the action of ultrahigh pressure (up to 4138bar), so that the material is subjected to a series of changes of physical, chemical and structural properties, and the like, and finally the homogenizing effect is achieved.
And (3) after the suspension of the betaine and the salicylic acid is uniformly dispersed in the step S1, conveying the suspension to a homogenizing valve of a high-pressure homogenizer through a high-pressure pump, wherein the higher the pressure of the homogenizing valve is, the better the refining effect on the material is. The pressure of the homogenizing valve is adjusted, the force borne by the suspension of the betaine and the salicylic acid can be adjusted, and when the pressure of the homogenizing valve is higher, the force borne by the suspension of the betaine and the salicylic acid is higher, and the refining effect of the betaine and the salicylic acid is better. Meanwhile, under the condition of high-pressure and high-speed mixing, the betaine and the salicylic acid react to obtain the betaine salicylic acid eutectic. In addition, the size of the eutectic crystal of the betaine salicylic acid can be regulated and controlled by adjusting the pressure of the homogenizing valve, and the larger the pressure is, the smaller the granularity of the eutectic crystal of the betaine salicylic acid finally obtained is.
And S3, decompressing the receiving chamber of the high-pressure homogenizer to a second pressure at a second temperature, and volatilizing the solvent to obtain the betaine salicylic acid eutectic.
Specifically, the solution is liquid CO2The second temperature and the second pressure are normal temperature and normal pressure, so that the liquid CO is2Is a gas. After rapid pressure reduction, liquid CO2Volatilizing, separating with the betaine salicylic acid eutectic, and obtaining the high-purity betaine salicylic acid eutectic with uniform granularity without solvent residue and solvate generation. When other solvents are selected, the second temperature may be adjusted to a temperature at which the solvent is gaseous at the second pressure.
The preparation method of the betaine salicylic acid eutectic is prepared by a high-pressure homogenization method, has simple steps, does not need purification, and can obtain the betaine salicylic acid eutectic with stable crystal form and adjustable particle size.
The present invention is explained in detail below with reference to examples.
Example 1
A preparation method of betaine salicylic acid eutectic comprises the following steps:
s1 liquid CO was added to the autoclave2Betaine and salicylic acid, wherein the feeding molar ratio of the betaine to the salicylic acid is 1:1, and the solid-liquid ratio of the total of the betaine and the salicylic acid to the solvent is 1:5 (kg: L). The pressure of the autoclave is set to be 20MPa, the temperature is set to be 115 ℃, the stirring speed is 700r/min, and the stirring is carried out for 4 hours to form betaine and salicylic acidSuspension;
s2, pumping the suspension to a high-pressure homogenizer by a high-pressure pump, and passing the suspension through a homogenizing valve, wherein the pressure of the homogenizing valve is set to be 800 bar;
s3 reducing pressure of the receiving chamber of the homogenizer to normal pressure at normal temperature to make liquid CO2And volatilizing to obtain the betaine salicylic acid eutectic.
The molecular structure of betaine salicylic acid eutectic is shown in figure 1, and the molecular formula is C12H17NO5The betaine salicylic acid compound comprises betaine molecules and salicylic acid molecules, proton transfer does not occur between the betaine molecules and the salicylic acid molecules, the salicylic acid molecules have a carboxyl group and a phenolic hydroxyl group and can form a hydrogen bond with N and O on the betaine, wherein the N on the betaine is used as a receptor of the hydrogen bond, and OH in the salicylic acid carboxyl is used as a donor of the hydrogen bond to form an O-H-N hydrogen bond; the O on the betaine is used as an acceptor of another hydrogen bond, and the-OH of the phenolic hydroxyl group of the salicylic acid is used as a donor of the hydrogen bond to form a second O-H.O hydrogen bond. The molecules spontaneously exhibit a stable three-dimensional structure with a regular arrangement. Under the condition of no external force action, molecules can spontaneously polymerize, recognize and form a more functional eutectic polymer with stable structure through hydrogen bond action, and the schematic diagram of the single crystal molecule stacking of the betaine salicylic acid eutectic is shown in figure 2.
The betaine salicylic acid eutectic obtained in example 1 was subjected to an X-ray single crystal diffraction test with specific test parameters: SuperNova, Dual, Cu at zero, atlas 2 diffractometer at 100.00(10) K and structural analysis using Olex2 and ShelXL. The results of the X-ray single crystal diffraction test are shown in Table 1:
table 1: betaine salicylic acid eutectic single crystal data table
Figure BDA0003145660010000061
The atomic coordinate (multiplied by 10) of the betaine salicylic acid eutectic crystal prepared by the invention4) And equivalent isotropic atomic displacement parameter
Figure BDA0003145660010000062
Analytical data are shown in Table 2, U (eq) is defined as orthogonal UijOne third of the trace amount of the tensor.
Table 2: atomic coordinates and equivalent isotropic atomic shift parameters of betaine salicylic acid co-crystals
Figure BDA0003145660010000071
The analytical data of the anisotropic atomic displacement parameters of the betaine salicylic acid eutectic prepared by the invention are shown in table 3, wherein the power of the anisotropic atomic displacement factor is shown as the following formula: -2 pi2[h2a*2U11+2hka*b*U12+…]。
Table 3: anisotropy atom shift parameter of betaine salicylic acid eutectic
Figure BDA0003145660010000072
Figure BDA0003145660010000081
The bond length analysis data of each chemical bond of the betaine salicylic acid eutectic prepared by the invention is shown in table 4.
Table 4: length of each chemical bond of eutectic
Figure BDA0003145660010000082
The analytical data of each bond angle (°) of the betaine salicylic acid co-crystal prepared by the present invention are shown in table 5.
Table 5: bond angles of various chemical bonds of betaine salicylic acid eutectic
Figure BDA0003145660010000083
Figure BDA0003145660010000091
The hydrogen atom coordinate of the betaine salicylic acid eutectic crystal prepared by the invention
Figure BDA0003145660010000092
And isotropic atomic displacement parameter
Figure BDA0003145660010000093
Analytical data are shown in table 6.
Table 6: hydrogen atom coordinate and isotropic atom displacement parameter of betaine salicylic acid eutectic
Figure BDA0003145660010000094
Figure BDA0003145660010000101
The betaine salicylic acid eutectic obtained in this example was characterized by nuclear magnetic resonance hydrogen spectroscopy (1H-NMR), and MeOD was used as the test solvent in the experiment, and the results are shown in fig. 3, and the data are as follows:1h NMR (400MHz, MeOD) δ 7.87(dd, J ═ 7.9,1.7Hz,1H),7.45(ddd, J ═ 8.4,7.3,1.8Hz,1H),6.97 to 6.83(m,2H),3.92(s,2H),3.30(s, 9H). 4 hydrogen atoms of the salicylic acid phenolic ring, 2 hydrogen atoms of the betaine methylene group and 9 hydrogen atoms of the betaine 3 methyl group can be clearly found from the nuclear magnetic hydrogen spectrum diagram; the rest are a small amount of residual water peak and deuterated reagent peak, and no obvious impurity peak is found. In the betaine salicylic acid supermolecule eutectic compound, betaine and salicylic acid exist in a molecular ratio of 1:1, and the purity is over 98%.
Betaine salicylic acid eutectic decomposition temperature test
1. Experimental method
Respectively weighing a physical mixture of betaine salicylic acid eutectic and betaine salicylic acid (the molar ratio of betaine to salicylic acid in the mixture is 1:1), keeping the temperature at 50 ℃ for 5min by adopting a TGA thermogravimetric analyzer, heating the temperature to 350 ℃ at 50 ℃, heating the temperature at a speed of 10 ℃/min, and recording an image of the weight changing along with time.
2. Results of the experiment
As shown by the TGA plots of fig. 4 and 5, the physical mixture of betaine salicylic acid co-crystal and betaine salicylic acid showed different decomposition temperatures, the decomposition temperature of the physical mixture of betaine salicylic acid was 211.49 ℃, and the decomposition temperature of the betaine salicylic acid co-crystal was significantly lower than that of the physical mixture of betaine salicylic acid, 190.77 ℃. The betaine salicylic acid eutectic of the invention is different from the betaine salicylic acid physical mixture in structure.
Betaine salicylic acid eutectic specific optical rotation test
1. Principle of experiment
When plane-polarized light passes through a medium, some media have no effect on the polarized light, i.e., the plane of polarization of the polarized light transmitted through the medium remains unchanged. While some media rotate the plane of polarization of polarized light. This property of rotating the plane of polarization of polarized light is called optical rotation. A substance having optical activity is called an optically active substance or an optically active substance.
2. Experimental methods
Weighing proper amount of physical mixture of betaine salicylic acid eutectic and betaine salicylic acid (the molar ratio of the betaine salicylic acid in the mixture is 1:1), preparing into 0.1% aqueous solution, and testing specific optical rotation.
3. Results of the experiment
According to the results in table 7, the specific optical rotation difference between the betaine salicylic acid eutectic and the betaine salicylic acid physical mixture is obvious, and the betaine salicylic acid eutectic is proved to have a eutectic structure in the solution without disintegration.
Table 7: specific optical rotation of physical mixture of betaine salicylic acid eutectic and betaine salicylic acid
Composition (I) Specific rotation
Betaine salicylic acid cocrystal -49.047°
Betaine salicylic acid physical mixture -1.885°
Irritation test of betaine salicylic acid cocrystal
1. Experimental materials and experimental methods:
the test substance: betaine salicylic acid eutectic 2% water solution, betaine salicylate 2% water solution, betaine 2% water solution, and salicylic acid 2% DMSO water solution.
Negative control: blank control.
Experimental animals: experimental rabbits were used, 7 per group.
The experimental method comprises the following steps: directly coating a test object on a skin preparation position by adopting a homeomorphic left-right self-contrast method, placing 0.020-0.025 ml of the test object in a spot tester by a closed spot test method, externally applying hypoallergenic adhesive tape on the curved side of the forearm of a subject, removing the test object after 24 hours, observing skin reactions at 0.5 hour, 24 hour and 48 hour after removal respectively, and evaluating the stimulation intensity according to a table 8.
Table 8: skin irritation response scoring criteria
Figure BDA0003145660010000111
2. Test results
The test substance was subjected to a 48h skin irritation test, and the specific results are shown in the following table:
table 9: summary of skin irritation test results
Figure BDA0003145660010000121
As can be seen from the data in Table 9, the negative control groups have 28 areas in total and have no irritation reaction due to the adoption of the homeomorphic left-right self-contrast method, so that the experiment is proved to be effective and the result is credible. No stimulation reaction occurs in the betaine 2% aqueous solution in 0.5h, 24h and 48h, and the mild and low stimulation of the betaine is proved. Salicylic acid 2% DMSO aqueous solution has obvious irritation, two irritation reactions appear at 0.5h, and irritation reactions of different degrees appear at 48 h. The irritation of 2% water solution of betaine salicylate is obviously reduced compared with salicylic acid, and only 1 case appears in 24h, and 2 cases appear in 48 h. The betaine salicylic acid eutectic 2% aqueous solution provided by the invention has good irritation test performance, does not have irritation reaction within 0.5h, 24h and 48h, and is milder than betaine salicylic acid salt.
Betaine salicylic acid cocrystal anti-inflammatory efficacy test
According to the invention, a betaine monomer, a salicylic acid monomer and a betaine salicylic acid eutectic are subjected to an anti-inflammatory efficacy test based on 'outdoor Ultraviolet (UVB) -keratinocyte'.
1. The test cells were: keratinocytes are formed.
2. Irradiation conditions: 300mJ/cm2。
3. Method of material preparation and testing: keratinocytes were seeded in 6-well plates and placed in incubators with appropriate temperature, relative humidity and carbon dioxide concentration for a stringent incubation culture for 24 h. And (3) after the cell plating rate in the 6-hole plate reaches the standard, the medicines are administered in groups, each hole is uniformly administered according to the same dose, the medicines are continuously cultured for 24 hours in an incubator with the same temperature, humidity and carbon dioxide concentration, and three groups of medicines are arranged in parallel in each group. After the culture is finished, irradiating the corresponding groups under the same condition, then performing liquid replacement operation on all pore plates needing to be subjected to superoxide dismutase (SOD) activity detection in the later period, replacing fresh culture solution, and placing in an incubator under the same condition for culturing for 24h again. Finally, the cultured keratinocytes were tested for inflammatory factors (IL-1. alpha., TNF. alpha., IL-8) and inflammatory mediators (PGE2) using enzyme-linked immunosorbent assay (ELISA).
4. Preparing liquid: test article working solutions were prepared according to table 10.
Table 10: experimental design of anti-inflammatory efficacy
Figure BDA0003145660010000131
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
5. The results of the experiments are shown in tables 11-14.
Table 11: summary of IL-1. alpha. assay results
Figure BDA0003145660010000132
Figure BDA0003145660010000141
Note: the statistical analysis is carried out by adopting a t-test method, compared with the BC group, the significance of the NC group is represented by #, the p value <0.05 is represented by #, and the p value <0.01 is represented by # #; the significance of the sample group and the positive control group was represented by p value <0.05 and p value <0.01, compared to the NC group.
Compared with the BC group, the content of IL-1 alpha in the NC group is obviously increased (p is less than 0.01); compared with the NC group, the content of the IL-1 alpha in the PC group is obviously reduced (p is less than 0.01); the experiment is effective.
Compared with an NC group, the IL-1 alpha content of the sample betaine salicylic acid eutectic is remarkably reduced (p is less than 0.05), and the betaine salicylic acid eutectic is proved to have a remarkable inhibiting effect on an inflammatory factor IL-1 alpha and has an anti-inflammatory effect.
Table 12: summary of TNF-alpha assay results
Figure BDA0003145660010000142
Note: the statistical analysis is carried out by adopting a t-test method, compared with a BC group, the significance of an NC group is represented by # and p value <0.05 is represented by #, and p value <0.01 is represented by # #; the significance of the sample group and the positive control group was represented by p value <0.05 and p value <0.01, compared to the NC group.
Compared with the BC group, the content of the TNF-alpha in the NC group is obviously increased (p is less than 0.01); compared with the NC group, the content of TNF-alpha in the PC group is obviously reduced (p is less than 0.01); the experiment is effective.
Compared with an NC group, the content of TNF-alpha of the sample betaine salicylic acid eutectic is remarkably reduced (p is less than 0.01), and the betaine salicylic acid eutectic is proved to have a remarkable inhibiting effect on inflammatory factor TNF-alpha and has an anti-inflammatory effect.
Table 13: summary of IL-8 assay results
Figure BDA0003145660010000151
Note: the statistical analysis is carried out by adopting a t-test method, compared with a BC group, the significance of an NC group is represented by # and p value <0.05 is represented by #, and p value <0.01 is represented by # #; the significance of the sample group and the positive control group was represented by p value <0.05 and p value <0.01, compared to the NC group.
Compared with the BC group, the IL-8 content in the NC group is obviously increased (p is less than 0.01); compared with the NC group, the content of the IL-8 in the PC group is obviously reduced (p is less than 0.01); the experiment is effective.
Compared with an NC group, the IL-8 content of the sample betaine salicylic acid eutectic is remarkably reduced (p is less than 0.01), and the betaine salicylic acid eutectic is proved to have a remarkable inhibiting effect on an inflammatory factor IL-8 and an anti-inflammatory effect.
Table 14: summary of PGE2 test results
Figure BDA0003145660010000152
Note: the statistical analysis is carried out by adopting a t-test method, compared with a BC group, the significance of an NC group is represented by # and p value <0.05 is represented by #, and p value <0.01 is represented by # #; the significance of the sample group and the positive control group was represented by p value <0.05 and p value <0.01, compared to the NC group.
Compared with the BC group, the content of PGE2 in the NC group is obviously increased (p is less than 0.01); the content of PGE2 in the PC group is obviously reduced compared with that in the NC group (p is less than 0.01); the experiment is effective.
Compared with an NC group, the content of PGE2 in the sample betaine salicylic acid eutectic is remarkably reduced (p is less than 0.05), and the betaine salicylic acid eutectic is proved to have a remarkable inhibiting effect on an inflammation medium PGE2 and has an anti-inflammatory effect.
In summary, in combination with the data in tables 11-14, the betaine salicylic acid cocrystal of the sample has a significant inhibitory effect on IL-1 alpha produced by UVB stimulation at an exposure dose of 0.25mg/mL (p < 0.05); has obvious inhibition effect on TNF-alpha and IL-8 (p is less than 0.01); the compound has a remarkable inhibition effect on PGE2 (p is less than 0.05), and the betaine salicylic acid eutectic sample is suggested to have an anti-inflammatory effect.
Betaine salicylic acid eutectic antioxidant efficacy test
The invention carries out the antioxidant efficacy test based on 'outdoor Ultraviolet (UVB) -keratinocyte' on betaine monomers, salicylic acid monomers and betaine salicylic acid eutectic crystals.
1. The test cells were: keratinocytes are formed.
2. Irradiation conditions: 300mJ/cm2。
3. Method of material preparation and testing: keratinocytes were seeded in 6-well plates and placed in incubators with appropriate temperature, relative humidity and carbon dioxide concentration for a stringent incubation culture for 24 h. And (3) after the cell plating rate in the 6-hole plate reaches the standard, the medicines are administered in groups, each hole is uniformly administered according to the same dose, the medicines are continuously cultured for 24 hours in an incubator with the same temperature, humidity and carbon dioxide concentration, and three groups of medicines are arranged in parallel in each group. After the culture is finished, irradiating the corresponding groups under the same condition, then performing liquid replacement operation on all pore plates needing to be subjected to superoxide dismutase (SOD) activity detection in the later period, replacing fresh culture solution, placing the culture solution in an incubator under the same condition for culturing for 24h again, and finally detecting the antioxidant factors of the cultured keratinocytes.
4. Preparing liquid: test article working solutions were prepared as in table 15 below.
Table 15: experimental design of antioxidant effect
Figure BDA0003145660010000161
Note: the BC group is a blank control group, the NC group is a negative control group, and the PC group is a positive control group.
5. The results of the experiment are shown in tables 16 and 17.
Table 16: summary of ROS content measurements
Figure BDA0003145660010000171
Note: the MFI (mean fluorescence intensity) values of the samples are summarized, and when the statistical analysis is carried out by a t-test method, the significance of the NC group is represented by # compared with the BC group, p value <0.05 is represented by #, and p value <0.01 is represented by #; the significance of the sample group and the positive control group compared with the NC group is shown in the form of p value < 0.05; p value <0.01 is denoted as x.
ROS content was significantly increased in NC compared to BC (p < 0.01); the ROS content in the PC group was significantly reduced compared to the NC group (p < 0.01); the test is effective.
Compared with the NC group, the ROS content of the sample betaine salicylic acid eutectic is obviously reduced (p is less than 0.01), and the fact that the betaine salicylic acid eutectic has an inhibition effect on ROS is proved.
Table 17: summary of SOD Activity detection results
Figure BDA0003145660010000172
Note: the MFI (mean fluorescence intensity) values of the samples are summarized, and when the statistical analysis is carried out by a t-test method, the significance of the NC group is represented by # compared with the BC group, p value <0.05 is represented by #, and p value <0.01 is represented by #; the significance of the sample group and the positive control group compared with the NC group is shown in the form of p value < 0.05; p value <0.01 is denoted as x.
Compared with the BC group, the SOD content of the NC group is obviously reduced (p < 0.01); compared with the NC group, the SOD content of the PC group is obviously increased (p is less than 0.01); the test is effective.
Compared with the NC group, the SOD content of the betaine salicylic acid eutectic is obviously increased (p is less than 0.05), and the betaine salicylic acid eutectic is proved to have the effect of improving the SOD activity.
In conclusion, combining the data in tables 16 and 17, the betaine salicylic acid eutectic has a significant inhibition effect (p <0.01) on ROS generated by UVB stimulation and a significant improvement effect (p <0.05) on the activity of SOD in cells under the exposure dose of 0.25mg/mL, and shows antioxidant efficacy.
Minimum inhibitory concentration test (nutrient broth dilution method)
1. Principle of
The experimental standard is as follows: disinfection technical Specification 2002 edition
In the test, bacteriostats with different concentrations are mixed and dissolved in a nutrient broth culture medium, then bacteria are inoculated, and the minimum Concentration of the bacteriostat for inhibiting the growth of the tested bacteria, namely the minimum bacteriostasis Concentration (MIC), is determined according to the growth or non-growth of the bacteria. The method is suitable for soluble bacteriostatic products.
2. Test equipment
(1) Test strains: staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Escherichia coli), Candida albicans (Candida albicans), Staphylococcus epidermidis (Staphylococcus epidermidis), Propionibacterium acnes (Propionibacterium acnes);
(2) betaine salicylic acid eutectic aqueous solution;
(3) nutrient broth medium;
(4) diluting the solution;
(5) a straw and a test tube;
(6)37 ℃ incubator.
3. Procedure for the preparation of the
(1) Preparing a suspension of Staphylococcus aureus (Staphylococcus aureus), Escherichia coli (Escherichia coli), Candida albicans (Candida albicans), Staphylococcus epidermidis (Staphylococcus epidermidis), Propionibacterium acnes (Propionibacterium acnes);
(2) preparing a culture medium containing an antibacterial agent: diluting betaine salicylic acid eutectic water solution with distilled water in multiple times series to obtain test solutions with different concentrations, and adding 2.5ml of each diluted test solution into a test tube containing 2.5ml of double-concentration nutrient broth;
(3) taking 0.1ml of the mixture with a bacterial content of about 108cfu/ml of the bacterial suspension was inoculated into a test tube containing a nutrient broth containing an anti- (bacteriostatic) agent as a test group sample;
(4) inoculating a test tube of nutrient broth without the anti-bacteria agent in the same way to be used as a positive control group sample;
(5) taking 2 test tubes containing the nutrient broth as negative control group samples;
(6) placing the test group sample, the positive control group sample and the negative control group sample in an incubator at 37 ℃, culturing for 48h, and observing the result;
(7) the test bacterial suspension should be subjected to viable bacteria culture counting, and the action concentration should be 5 × 105cfu/mL～5×106cfu/mL。
4. Test results
When the positive control tube has bacteria growth (turbidity) and the negative control tube has bacteria growth (transparency), the active concentration of the test bacterial suspension is 5X 105cfu/mL～5×106The concentration of the anti-bacteria agent corresponding to the highest dilution for aseptic growth of the test group is the MIC of the sample to the tested bacteria when cfu/mL.
According to the table 18, the betaine salicylic acid eutectic has low MIC and has bacteriostatic effects on five bacteria, wherein the betaine salicylic acid eutectic has good bacteriostatic effect on Propionibacterium acnes (Propionibacterium acnes), and has good bacteriostatic effect at a concentration of 5 mg/mL. Mainly because propionibacterium acnes activates monocyte receptors, IL-12 and IL-8 are generated, inflammation is triggered, salicylic acid-betaine eutectic and salicylic acid have approximate action sites on related target protein (PDB number: 3v2y), and compared with the action sites of monomeric compounds, the salicylic acid-betaine eutectic can generate new action sites with ARG-174 and ARG-498, so that the binding energy is enhanced, and the effect of supramolecules is improved.
Table 18: minimum inhibitory concentration determination test
Test bacterium MIC(mg/mL)
Staphylococcus aureus (Staphylococcus aureus) 15
Escherichia coli (Escherichia coli) 20
Candida albicans (Candida albicans) 5
Staphylococcus epidermidis (Stapylococcus epidomidii) 7.5
Propionibacterium acnes (Propionibacterium acnes) 5
Application of betaine salicylic acid eutectic acne-removing essence
The acne-removing essence containing the betaine salicylic acid eutectic as the active ingredient is provided, and the specific formula is shown in table 19:
table 19: formula of acne-removing essence containing betaine salicylic acid eutectic as active ingredient
Figure BDA0003145660010000191
Figure BDA0003145660010000201
PH:5.5-6.0
The process comprises the following steps:
1. uniformly scattering carbomer 20 in water, stirring, heating to 80-85 deg.C, mixing xanthan gum with G260, adding the above water solution, adding the rest of phase A, and hydrating completely.
2. Cooling to below 45 deg.C, adding phase C components, mixing,
and 3, heating the phase B to 80-85 ℃, dissolving, adding the dissolved phase A and the phase C, and stirring uniformly.
Appearance: colorless semi-permeable flowing liquid
PH:5.55
Viscosity: 3#, 60rpm, 895mps
Human body efficacy testing
1. Experimental materials and experimental methods:
test materials: the acne removing essence obtained in example 1.
The experimenter: selecting 10 persons of 18-55-year-old volunteers, and excluding those with severe acne muscle and obvious facial reddening inflammation; patients with dependent diabetes mellitus; patients with chronic respiratory system; lactating or pregnant women; the face has nevus flammeus and scar; those with high-sensitivity constitution.
The experimental method comprises the following steps: the acne removing essence is continuously used for 28 days in the morning and evening, and is detected by a visia skin detector for 5 times after 0, 7, 14, 21 and 28 days.
2. Test results
The skin test of the subjects was performed, and the results of comparing the visia-cr images of the face after the 0 th day and the 28 th day using the acne-removing essence are shown in fig. 6. The red color in the picture is characterized by the imaging color of porphyrin under visia-cr, and the porphyrin can be used as a propionibacterium acnes marker. As can be seen from the images, the number of porphyrins (Propionibacterium acnes) is obviously reduced after the acne-removing essence is used for 28 days, and the red face features of the tested volunteers are reduced by 40.85% on average. The acne removing essence in the embodiment 1 is proved to have obvious anti-inflammatory and acne removing effects.
Example 2
The difference from embodiment 1 is that the pressure of the homogenizing valve in S2 is set to 600 bar. The single crystal data and hydrogen spectrum data of the tested betaine salicylic acid eutectic are the same as those in example 1, and the purity is over 98%.
Example 3
The difference from embodiment 1 is that the pressure of the homogenizing valve in S3 was set to 1200 bar. The single crystal data and hydrogen spectrum data of the tested betaine salicylic acid eutectic are the same as those in example 1, and the purity exceeds 98%.
The betaine salicylic acid eutectic obtained in the embodiments 1, 2 and 3 of the invention is subjected to particle size detection by using a laser particle size analyzer. Laser particle sizers measure the particle size distribution based on the physical phenomenon that particles scatter laser light. Because the laser has good monochromaticity and strong directivity, a parallel laser beam can irradiate an infinite space without obstruction and has little divergence in the process of propagation. When the light beam encounters a particle blockage, a scattering phenomenon occurs in a portion of the light. The direction of propagation of the scattered light will form an angle theta with the direction of propagation of the main beam. The scattering theory and experimental results prove that the size of the scattering angle theta is related to the size of the particles, and the larger the particles are, the smaller the theta angle of the generated scattered light is; the smaller the particle, the larger the angle theta of the scattered light produced. When the homogenizing valve pressure is different, the obtained betaine salicylic acid eutectic crystal has different particle sizes, and the specific numerical values are shown in table 20.
Table 20: granularity of betaine salicylic acid eutectic under different conditions
Figure BDA0003145660010000211
As can be seen from the data in table 7, when the homogenizing valve pressure is 600bar and 800bar, the grain size of the betaine salicylic acid eutectic can be several hundred nanometers, but when the homogenizing valve pressure is 800bar, the grain uniformity is reduced relative to 600bar, when the homogenizing valve pressure is higher to 1200bar, the grain size of the betaine salicylic acid eutectic is smaller and the uniformity is better, but the high pressure easily blocks the high-pressure homogenizer, and the service life of the high-pressure homogenizer is reduced, so the homogenizing valve pressure is preferably 800 bar.
Comparative example 1
Comparative example 1 differs from example 1 in that the pressure of the homogenizing valve in S2 was set to 400 bar. The reaction product was cultured in the form of a single crystal, and the obtained single crystal was examined to find salicylic acid, indicating that no cocrystal could be obtained under the conditions of comparative example 1. Fig. 7 is a nuclear magnetic hydrogen spectrum of the reaction product, and it can be seen from fig. 7 that the salicylic acid betaine co-crystal with a molecular ratio of 1:1 cannot be obtained under the conditions of comparative example 1, salicylic acid: the molecular ratio of betaine is between 1:1.2-2, presumably an incompletely reacted mixture.
The above are all preferred embodiments of the present invention, and the protection scope of the present invention is not limited thereby, so: all equivalent changes made according to the mechanism, shape and principle of the invention are covered by the protection scope of the invention.

Claims (6)

1. The betaine salicylic acid eutectic crystal is characterized in that: the betaine salicylic acid eutectic is in an orthorhombic system, a space group is Pbca, and unit cell parameters are
Figure FDA0003593232700000011
Figure FDA0003593232700000012
α ═ β ═ γ ═ 90 °, Z ═ 8, unit cell volume
Figure FDA0003593232700000013
2. Betaine salicylic acid co-crystal according to claim 1, characterized in thatCharacterized in that: the molecular formula of the betaine salicylic acid eutectic is C12H17NO5The eutectic comprises betaine molecules and salicylic acid molecules, and the molar ratio of the betaine molecules to the salicylic acid molecules is 1:1.
3. Betaine salicylic acid co-crystal according to claim 1, characterized in that: the granularity of the betaine salicylic acid eutectic is (240 +/-15) nm to (520 +/-30) nm.
4. A process for the preparation of a betaine salicylic acid co-crystal according to any one of claims 1-3, characterized in that: the method comprises the following steps:
s1 adding solvent, betaine and salicylic acid into an autoclave, and stirring at a first pressure and a first temperature to form a suspension of the betaine and the salicylic acid;
s2, pumping the suspension to a high-pressure homogenizer by a high-pressure pump, and passing through a homogenizing valve with the pressure of 600-1200 bar;
s3, decompressing the receiving chamber of the high-pressure homogenizer to a second pressure at a second temperature, and volatilizing the solvent to obtain the betaine salicylic acid eutectic;
the solvent is liquid CO2The first pressure is 10MPa-30MPa, the first temperature is 110-.
5. The method for preparing the betaine salicylic acid co-crystal according to claim 4, wherein the method comprises the following steps: the pressure of the homogenizing valve is 800 bar.
6. The method for preparing the betaine salicylic acid co-crystal according to claim 4, wherein the method comprises the following steps: the molar ratio of the fed betaine to the fed salicylic acid is 1:1, the solid-liquid ratio of the total of the betaine and the salicylic acid to the solvent is 1:4-1:6, and the contrast unit kg: and L.
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