WO2023274401A1 - 一种甜菜碱水杨酸共晶及其制备方法和应用 - Google Patents

一种甜菜碱水杨酸共晶及其制备方法和应用 Download PDF

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WO2023274401A1
WO2023274401A1 PCT/CN2022/103316 CN2022103316W WO2023274401A1 WO 2023274401 A1 WO2023274401 A1 WO 2023274401A1 CN 2022103316 W CN2022103316 W CN 2022103316W WO 2023274401 A1 WO2023274401 A1 WO 2023274401A1
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betaine
salicylic acid
pressure
eutectic
crystal
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PCT/CN2022/103316
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English (en)
French (fr)
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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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深圳市萱嘉生物科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/12—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of acyclic carbon skeletons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/10—Washing or bathing preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the technical fields of medicine and cosmetics, in particular to a co-crystal of betaine salicylic acid and a preparation method and application thereof.
  • Beta-hydroxy acids (BHAs) in salicylic acid are similar to alpha-hydroxy acids (AHAs), and have the function of accelerating the exfoliation of scaly keratinocytes.
  • Salicylic acid belongs to aromatic beta-hydroxy acids, and its efficacy in skin care products It has already been fully recognized by people.
  • salicylic acid can be used to treat acne through topical administration; in the field of cosmetics, it can improve the fine lines and wrinkles caused by the aging of the body's internal functions, as well as the wrinkles, sagging, and spots caused by photoaging. question.
  • trimethylglycine in betaine in skin care has also been used in the cosmetics industry for a long time. It can enhance the moisture, elasticity and hydration of the skin.
  • the molecular structure of betaine is very special. There are both anions in the same molecule. Charges also have cationic charges, and human skin is all negatively charged under normal physiological conditions, so molecules with positive charges have a natural affinity for the skin, and are especially suitable for skin care products.
  • betaine salicylate combines the effects of salicylic acid on acne and firming skin and betaine on moisturizing and moisturizing. It can promote skin metabolism, exfoliate dead skin cells and improve skin elasticity.
  • betaine salicylate has certain irritation and can cause irritation to skin and eyes. Therefore, the application of betaine and salicylic acid in medicine and cosmetics needs to be improved.
  • the present invention provides a betaine salicylate co-crystal, its preparation method and application.
  • the molecular formula of the betaine salicylic acid co-crystal is C12H17NO5
  • the co-crystal comprises betaine molecules and salicylic acid molecules
  • the molar ratio between the betaine molecules and the salicylic acid molecules is 1:1.
  • the betaine salicylic acid co-crystal has a particle size of (240 ⁇ 15) nm to (520 ⁇ 30) nm.
  • a kind of preparation method of betaine salicylic acid co-crystal, its key is: comprise the following steps:
  • S2 pumps the suspension from a high-pressure pump to a high-pressure homogenizer, passes through a homogenizing valve, and the pressure of the homogenizing valve is 600bar-1200bar;
  • S3 depressurizes the receiving chamber of the high-pressure homogenizer to the second pressure at the second temperature to volatilize the solvent to obtain the betaine salicylic acid eutectic.
  • the pressure of the homogenizing valve is 800 bar.
  • the first temperature is the temperature at which the solvent is liquid under the first pressure.
  • the second temperature is a temperature at which the solvent is in a gaseous state at a second pressure.
  • the solvent is liquid CO2.
  • the first pressure is 10MPa-30MPa
  • the first temperature is 110-130°C
  • the second temperature is normal temperature
  • the second pressure is normal pressure
  • the present invention includes at least one of the following beneficial technical effects:
  • a betaine salicylic acid eutectic disclosed by the invention has very low irritation. Its irritation is significantly lower than that of salicylic acid monomer, and its pH value is milder than that of salicylic acid monomer, which reduces the occurrence of allergies. Betaine salicylate co-crystal also appears to be milder than betaine salicylate.
  • a kind of betaine salicylic acid eutectic disclosed by the present invention is prepared by betaine and salicylic acid, retains the effect of betaine and salicylic acid simultaneously, has the effect of betaine moisturizing, anti-allergy, reducing irritation and Salicylic acid has bactericidal, anti-inflammatory, anti-acne, exfoliating and other effects.
  • Adding betaine salicylic acid eutectic has a better effect in leave-on products such as lotion and cream and wash-off products such as facial cleanser, shampoo and shower gel.
  • the present invention has obtained betaine salicylic acid eutectic with high pressure homogeneous method.
  • betaine salicylate is obtained by methods such as rotary steaming and recrystallization, and it is difficult to form betaine salicylate eutectic.
  • the betaine salicylic acid eutectic obtained by the high-pressure homogenization method has high purity and adjustable particle size.
  • Fig. 1 is the molecular structure schematic diagram of the betaine salicylic acid cocrystal of the embodiment of the present invention 1;
  • Fig. 2 is the single crystal molecular packing schematic diagram of the betaine salicylic acid eutectic of embodiment 1 of the present invention
  • Fig. 3 is the proton nuclear magnetic spectrum of the betaine salicylic acid eutectic of the embodiment of the present invention 1;
  • Fig. 4 is the TGA figure of the betaine salicylic acid eutectic of the embodiment of the present invention 1;
  • Fig. 5 is the TGA figure of betaine salicylic acid physical mixture
  • Figure 6 is a visia-cr image of a volunteer's face
  • Figure 7 is the H NMR spectrum of the reaction product of Comparative Example 1 of the present invention.
  • Salicylic acid is a fat-soluble organic acid with a chemical formula of C 7 H 6 O 3 and a structural formula of Appearance is white crystalline powder, melting point is 158 ⁇ 161°C.
  • salicylic acid is mainly used as a raw material in the pharmaceutical industry, and can be used to prepare drugs such as aspirin, sodium salicylate, and salicylamide.
  • the commonly used salicylic acid solution with a concentration of 1-2wt.% is used to treat acne, which can help the skin to effectively remove the accumulated keratin around the pores and on the skin surface, anti-inflammatory and antibacterial, and more importantly, it can also Break down the clogging plugs (blackheads/whiteheads) formed by cell debris and oil in the hair follicles, unblock the pores, and destroy the growth environment of bacteria.
  • Betaine is a kind of alkaloid, its chemical name is N,N,N-trimethylglycine, its chemical structure is similar to that of amino acid , it is a quaternary ammonium base, its molecular formula is C 5 H 11 NO 2 , and its structural formula is Appearance is white crystalline powder, melting point is 301-305°C.
  • betaine can be used for anti-tumor, lowering blood pressure, anti-peptic ulcer and gastrointestinal dysfunction, and treating liver diseases.
  • betaine can moisturize the skin, penetrate through the stratum corneum of the skin to protect the balance of cells, and increase the water content of the surface skin.
  • betaine has the same moisturizing effect as glycerin, but unlike glycerin, which fixes water molecules, betaine allows water molecules to be completely absorbed and utilized by living cells. When a water molecule occupies the middle of the betaine zwitterion, it will easily release its own water molecule to the surrounding liquid.
  • the moisturizing mechanism of betaine is superior to other humectants, and it can keep moisturizing even at low concentrations.
  • co-crystal is that two or more different molecules interact with each other through hydrogen bonds, ⁇ - ⁇ interaction van der Waals force and other intermolecular interactions to form a crystalline material regularly arranged in the same crystal lattice.
  • Eutectic is an effective way to change the physical and chemical properties of some components such as solubility, melting point, hygroscopicity, compressibility, and density.
  • existing betaine salicylate the transfer of proton has taken place between betaine and salicylic acid, and betaine and salicylic acid combine together by ionic action, it is reported that salicylic acid betaine salt has certain skin and Eye irritation.
  • the betaine salicylic acid co-crystal synthesized by the present invention has no proton transfer, and the betaine molecule and the salicylic acid molecule are combined through supramolecular interaction, and the betaine salicylate co-crystal of the present invention has obvious irritation Smaller than betaine salicylate, it is widely used in cosmetics.
  • a kind of preparation method of betaine salicylic acid co-crystal provided by the invention comprises the following steps:
  • the solvent can be liquid CO 2 , petroleum ether, ethyl acetate, and the like. Among them, liquid CO 2 is preferred, and liquid CO 2 has the characteristics of non-toxicity, non-flammability and moderate price.
  • the molar ratio of betaine to salicylic acid is 1:1.
  • Autoclave refers to a kind of reactor operated under high pressure. The pressure of autoclave is set to 10-30MPa, preferably 20MPa; the temperature is set to 110-130 ° C, preferably 115 ° C; It is preferably 700r/min; the stirring time is 1-8h, preferably 4h; a suspension of betaine and salicylic acid is formed.
  • the pressure of the homogeneous valve is 600bar-1200bar, preferably 800bar.
  • the high-pressure homogenizer is a mechanism that uses a high-pressure reciprocating pump as the power to transmit and transport materials. It transports liquid materials or solid particles with liquid as a carrier to the homogenization valve (high-pressure homogenization chamber). The materials to be processed pass through the homogenization valve. During the process, the strong shearing, impact, cavitation and turbulent swirl action generated under high pressure make the liquid material or solid particles with liquid as the carrier ultrafine.
  • the homogenizing valve accepts the high-pressure liquid material delivered by the collecting pipe to complete the tasks of ultra-fine crushing, emulsification and homogenization.
  • the high-pressure homogenizer can make the material in the suspension state flow through the chamber with a special internal structure (high-pressure homogenization chamber/homogenization valve) at high speed under the action of ultra-high pressure (up to 4138bar), so that the material undergoes physical, A series of changes such as chemical and structural properties, and finally achieve a homogeneous effect.
  • step S1 After the suspension of betaine and salicylic acid is uniformly dispersed in step S1, it is transported to the homogenizing valve of the high-pressure homogenizer through a high-pressure pump.
  • the higher the pressure of the homogenizing valve the better the refining effect of the material.
  • the pressure of the homogenizing valve By adjusting the pressure of the homogenizing valve, the force on the suspension of betaine and salicylic acid can be adjusted. When the pressure of the homogenizing valve is higher, the force on the suspension of betaine and salicylic acid is greater, and the betaine And the refinement effect of salicylic acid is better.
  • betaine and salicylic acid react to obtain betaine-salicylic acid eutectic.
  • the pressure of the homogenizing valve the particle size of the betaine salicylic acid eutectic can be regulated, and the greater the pressure, the smaller the particle size of the final betaine salicylic acid eutectic.
  • S3 depressurizes the receiving chamber of the high-pressure homogenizer to the second pressure at the second temperature to volatilize the solvent to obtain the betaine salicylic acid eutectic.
  • liquid CO 2 is selected as the solution, and the second temperature and second pressure are normal temperature and pressure, so that the liquid CO 2 is a gas. After rapid decompression, the liquid CO2 volatilizes and is separated from the betaine salicylic acid eutectic without solvent residue and solvate formation, and high-purity betaine salicylic acid eutectic with uniform particle size is obtained.
  • the second temperature can be adjusted to the temperature at which the solvent is gaseous at the second pressure.
  • the preparation method of the betaine salicylic acid co-crystal of the present invention is prepared by a high-pressure homogenization method, the steps are simple, no purification is required, and the betaine salicylic acid co-crystal with stable crystal form and adjustable particle size can be obtained.
  • S2 pumps the suspension from a high-pressure pump to a high-pressure homogenizer, passes through a homogenizing valve, and sets the pressure of the homogenizing valve to 800 bar;
  • S3 depressurizes the receiving chamber of the homogenizer to normal pressure at normal temperature to volatilize the liquid CO 2 to obtain betaine salicylic acid eutectic.
  • the molecular structure diagram of the betaine salicylic acid co-crystal is shown in Figure 1.
  • the molecular formula is C 12 H 17 NO 5 , which is composed of betaine molecules and salicylic acid molecules. There is no proton between betaine molecules and salicylic acid molecules.
  • the salicylic acid molecule has a carboxyl group and a phenolic hydroxyl group, which can form hydrogen bonds with N and O on betaine, where N on betaine acts as a hydrogen bond acceptor, and OH in the carboxyl group of salicylic acid acts as a hydrogen bond
  • the donor of the betaine forms an OH ⁇ N hydrogen bond; the O on betaine acts as the acceptor of another hydrogen bond, and the OH of the phenolic hydroxyl group of salicylic acid acts as the donor of the hydrogen bond to form the second OH ⁇ ⁇ O hydrogen bonding.
  • Molecules spontaneously present a stable three-dimensional structure that is regularly arranged in parallel. In the state that no external force is required, molecules can spontaneously aggregate, recognize, and form more functional eutectic polymers with stable structures through internal hydrogen bonds between molecules, single crystal molecules of betaine salicylic acid eutectic
  • the stacking diagram is shown in Figure 2.
  • the betaine salicylic acid co-crystal and the physical mixture of betaine salicylic acid exhibit different decomposition temperatures, and the decomposition temperature of the physical mixture of betaine salicylic acid is 211.49 °C
  • the decomposition temperature of alkali salicylic acid co-crystal is significantly lower than that of betaine salicylic acid physical mixture, which is 190.77°C. It shows that the betaine salicylic acid co-crystal of the present invention is different from the betaine salicylic acid physical mixture in structure.
  • Optically active substances are called optically active substances or photoactive substances.
  • Test substance betaine salicylic acid eutectic 2% aqueous solution, betaine salicylate 2% aqueous solution, betaine 2% aqueous solution, salicylic acid 2% DMSO aqueous solution.
  • Negative control blank control.
  • Experimental animals experimental rabbits, 7 in each group.
  • Experimental method Using the self-comparison method of the left and right sides of the same body, apply the test substance directly on the skin preparation area, and use the closed patch test method to place 0.020-0.025ml of the test substance in the spot tester, and apply hypoallergenic tape for external use Apply it on the curved side of the forearm of the subject, remove the test substance after 24 hours, observe the skin reaction at 0.5, 24, and 48 hours after removal, and evaluate the stimulation intensity according to Table 8.
  • the negative control group has a total of 28 areas, and no stimulation reaction occurred in the negative control group, which proves that the experiment is effective and the results are credible.
  • the 2% aqueous solution of betaine has no irritation reaction at 0.5h, 24h, and 48h, which proves that betaine is mild and has low irritation.
  • Salicylic acid 2% DMSO aqueous solution has obvious irritation, two cases of irritation occurred in 0.5h, and different degrees of irritation occurred in 48h.
  • the irritation of betaine salicylate 2% aqueous solution was significantly lower than that of salicylic acid, only 1 case appeared in 24 hours, and 2 cases of irritation occurred in 48 hours.
  • the betaine salicylic acid eutectic 2% aqueous solution provided by the present invention performs well in the irritation test, and no irritation occurs at 0.5h, 24h, and 48h, and is milder than betaine salicylate.
  • UVB ultraviolet-keratinocytes
  • test cells are: keratinocytes.
  • keratinocytes were inoculated into 6-well plates, placed in an incubator with appropriate temperature, relative humidity and carbon dioxide concentration, and subjected to strict incubation for 24 hours. After the cell plating rate in the 6-well plate reached the standard, the drug was divided into groups, and each well was uniformly administered according to the same dose, and the culture was continued for 24 hours in an incubator with the same temperature, humidity and carbon dioxide concentration, and three groups were set up in parallel for each group. After the cultivation is completed, the corresponding groups are irradiated under the same conditions, and then all the well plates that need to be tested for superoxide dismutase (SOD) activity in the later stage are replaced with fresh culture medium, and placed in the same condition. Incubate again for 24 h. Finally, the cultured keratinocytes were detected by enzyme-linked immunosorbent assay (ELISA) for inflammatory factors (IL 1 ⁇ , TNF ⁇ , IL 8) and inflammatory mediators (PGE2).
  • ELISA enzyme-linked immunosorbent assay
  • Liquid preparation prepare the working liquid of the test substance according to Table 10.
  • BC group is the blank control group
  • NC group is the negative control group
  • PC group is the positive control group
  • the t-test method is used for statistical analysis. Compared with the BC group, the significance is represented by #, p value ⁇ 0.05 is represented by #, and p value ⁇ 0.01 is represented by ##; Compared with the group, significance is represented by *, p value ⁇ 0.05 is represented by *, and p value ⁇ 0.01 is represented by **.
  • the IL-1 ⁇ content in the NC group increased significantly (p ⁇ 0.01); compared with the NC group, the IL-1 ⁇ content in the PC group decreased significantly (p ⁇ 0.01), indicating that this experiment is effective.
  • the t-test method is used for statistical analysis. Compared with the BC group, the significance is represented by #, p value ⁇ 0.05 is represented by #, and p value ⁇ 0.01 is represented by ##; Compared with the NC group, significance is represented by *, p value ⁇ 0.05 is represented by *, and p value ⁇ 0.01 is represented by **.
  • the TNF- ⁇ content in the NC group increased significantly (P ⁇ 0.01); compared with the NC group, the TNF- ⁇ content in the PC group decreased significantly (P ⁇ 0.01), indicating that the experiment is effective.
  • the TNF- ⁇ content of the sample betaine salicylic acid co-crystal decreased significantly (P ⁇ 0.01), which proved that the betaine salicylic acid co-crystal had a significant inhibitory effect on the inflammatory factor TNF- ⁇ , betaine salicylic acid Acid co-crystals have anti-inflammatory properties.
  • the t-test method is used for statistical analysis. Compared with the BC group, the significance is represented by #, p value ⁇ 0.05 is represented by #, and p value ⁇ 0.01 is represented by ##; Compared with the NC group, significance is represented by *, p value ⁇ 0.05 is represented by *, and p value ⁇ 0.01 is represented by **.
  • the IL-8 content of the NC group was significantly increased (p ⁇ 0.01); compared with the NC group, the IL-8 content of the PC group was significantly decreased (p ⁇ 0.01), indicating that the experiment was effective.
  • the IL-8 content of the sample betaine salicylic acid co-crystal decreased significantly (p ⁇ 0.01), which proved that the betaine salicylic acid co-crystal had a significant inhibitory effect on the inflammatory factor IL-8, and betaine salicylic acid Acid co-crystals have anti-inflammatory properties.
  • the t-test method is used for statistical analysis. Compared with the BC group, the significance is represented by #, p value ⁇ 0.05 is represented by #, and p value ⁇ 0.01 is represented by ##; Compared with the NC group, significance is represented by *, p value ⁇ 0.05 is represented by *, and p value ⁇ 0.01 is represented by **.
  • the PGE2 content of the NC group increased significantly (p ⁇ 0.01); compared with the NC group, the PGE2 content of the PC group decreased significantly (p ⁇ 0.01), indicating that the experiment was effective.
  • the PGE2 content of the sample betaine salicylic acid cocrystal decreased significantly (p ⁇ 0.05), which proved that the betaine salicylic acid cocrystal had a significant inhibitory effect on the inflammatory mediator PGE2, and the betaine salicylic acid cocrystal had a significant inhibitory effect on the inflammatory mediator PGE2. Anti-inflammatory effect.
  • the sample betaine salicylic acid cocrystal has a significant inhibitory effect on IL-1 ⁇ produced by UVB stimulation at an exposure dose of 0.25 mg/mL (p ⁇ 0.05); - ⁇ , IL-8 have significant inhibitory effects (p ⁇ 0.01); have significant inhibitory effects on PGE2 (p ⁇ 0.05), suggesting that the betaine salicylic acid cocrystal sample has anti-inflammatory effect.
  • the antioxidant efficacy test based on "outdoor ultraviolet (UVB)-keratinocytes” is carried out on betaine monomer, salicylic acid monomer and betaine salicylic acid eutectic.
  • test cells are: keratinocytes.
  • keratinocytes were inoculated into 6-well plates, placed in an incubator with appropriate temperature, relative humidity and carbon dioxide concentration, and subjected to strict incubation for 24 hours. After the cell plating rate in the 6-well plate reached the standard, the drug was divided into groups, and each well was uniformly administered according to the same dose, and the culture was continued for 24 hours in an incubator with the same temperature, humidity and carbon dioxide concentration, and three groups were set up in parallel for each group. After the culture is completed, the corresponding groups are irradiated under the same conditions, and then all the well plates that need to be tested for superoxide dismutase (SOD) activity in the later stage are replaced with fresh culture medium, and placed in the same culture condition. The cultured keratinocytes were cultured again for 24 hours, and finally the antioxidant factors were tested for the cultured keratinocytes.
  • SOD superoxide dismutase
  • BC group is the blank control group
  • NC group is the negative control group
  • PC group is the positive control group
  • the ROS content of the NC group increased significantly (p ⁇ 0.01); compared with the NC group, the ROS content of the PC group decreased significantly (p ⁇ 0.01), indicating that the test is effective.
  • the SOD content of the NC group decreased significantly (p ⁇ 0.01); compared with the NC group, the SOD content of the PC group increased significantly (p ⁇ 0.01), indicating that the test was effective.
  • the sample betaine salicylic acid cocrystal has a significant inhibitory effect on ROS stimulated by UVB at an exposure dose of 0.25 mg/mL (p ⁇ 0.01), and has a significant inhibitory effect on intracellular SOD Vitality has a significant improvement effect (p ⁇ 0.05), showing antioxidant effect.
  • Test strains Staphylococcus aureus, Escherichia coli, Candida albicans, Stapylococcus epidemidi, Propionibacterium acnes;
  • the bacterial suspension used in the test should be cultured and counted for viable bacteria, and the concentration should be 5 ⁇ 10 5 cfu/mL ⁇ 5 ⁇ 10 6 cfu/mL.
  • the test group has no The antibacterial (inhibitor) concentration corresponding to the highest dilution of bacterial growth is the MIC of the sample against the tested bacteria.
  • the MICs of betaine salicylic acid cocrystals are all low, and have antibacterial effects on five kinds of bacteria, among which there is a good antibacterial effect on Propionibacterium acnes, at a concentration of 5 mg/mL It has a better antibacterial effect. It is mainly due to the activation of monocyte receptors by Propionibacterium acnes, which leads to the production of IL-12 and IL-8, which triggers inflammation.
  • Salicylic acid-betaine co-crystal and salicylic acid are on related target proteins (PDB number : 3v2y) have similar action sites. Compared with the action sites of monomeric compounds, salicylic acid-betaine co-crystals can generate new action sites with ARG-174 and ARG-498, enhance binding energy, and improve Molecular efficacy.
  • Table 19 Formula of an acne-removing essence whose active ingredient is betaine salicylic acid co-crystal
  • Viscosity 3#, 60rpm, 895mps.s
  • Tested material the anti-acne essence obtained in Example 1.
  • the red feature in the photo is the imaging color of porphyrin under visia-cr, and porphyrin can be used as a marker of Propionibacterium acnes. It can be seen from the images that after 28 days of using the acne essence, the number of porphyrins (Propionibacterium acnes) was significantly reduced, and the red features on the face of the volunteers were reduced by an average of 40.85%. It is proved that the anti-acne essence in Example 1 has obvious anti-inflammatory and anti-acne effects.
  • Example 1 The difference from Example 1 is that the pressure of the homogeneous valve in S2 is set to 600 bar.
  • the single crystal data and hydrogen spectrum data of the betaine salicylic acid cocrystal tested are the same as those in Example 1, and the purity exceeds 98%.
  • Example 1 The difference from Example 1 is that the pressure of the homogeneous valve in S3 is set to 1200 bar.
  • the single crystal data and hydrogen spectrum data of the betaine salicylic acid cocrystal tested are the same as those in Example 1, and the purity exceeds 98%.
  • the particle size detection of the betaine salicylic acid eutectic obtained in Example 1, Example 2, and Example 3 of the present invention was performed using a laser particle size analyzer.
  • the laser particle size analyzer measures the particle size distribution based on the physical phenomenon that the particles can scatter the laser light. Because the laser has good monochromaticity and strong directionality, a beam of parallel laser light will irradiate to infinite distance in an infinite space without hindrance, and there is little divergence during the propagation process. When the light beam is blocked by particles, part of the light will be scattered. The propagation direction of the scattered light will form an angle ⁇ with the propagation direction of the main beam. Scattering theory and experimental results prove that the size of the scattering angle ⁇ is related to the size of the particle.
  • the particle size of the betaine salicylic acid eutectic can be obtained on the order of hundreds of nanometers, but when the homogenizing valve pressure is 800bar, the particle uniformity is somewhat different from that of 600bar.
  • the pressure of the homogenizing valve is as high as 1200bar, the betaine salicylic acid eutectic particle size is smaller and the uniformity is better, but the high pressure is easy to cause blockage of the high-pressure homogenizer, reducing the pressure of the high-pressure homogenizer
  • the service life is therefore preferably a homogeneous valve pressure of 800 bar.
  • Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the pressure of the homogeneous valve in S2 is set to 400 bar. Attempt to culture the single crystal of the reaction product, and the obtained single crystal was detected to be salicylic acid, indicating that the co-crystal could not be obtained under the conditions of Comparative Example 1.
  • Figure 7 is the H NMR spectrum of the reaction product. As can be seen from Figure 7, the salicylic acid betaine co-crystal with a molecular ratio of 1:1 cannot be obtained under the conditions of Comparative Example 1, and it is speculated that it is an incomplete mixture, salicylic acid The molecular ratio of acid:betaine is between 1:1.2-2.

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Abstract

本发明提供一种甜菜碱水杨酸共晶及其制备方法和应用，涉及医药、化妆品技术领域。一种甜菜碱水杨酸共晶，所述甜菜碱水杨酸共晶为斜方晶系，空间群为Pbca，晶胞参数为，晶胞体积本发明提供的甜菜碱水杨酸共晶，能够改善甜菜碱水杨酸盐的刺激性问题。

Description

一种甜菜碱水杨酸共晶及其制备方法和应用
本申请要求申请号为CN202110752866.8、申请日为2021年07月02日，以及专利名称为“一种甜菜碱水杨酸共晶及其制备方法和应用”的专利申请文件的优先权。
技术领域
本发明涉及医药、化妆品技术领域，具体涉及一种甜菜碱水杨酸共晶及其制备方法和应用。
背景技术
水杨酸中的β-羟基酸(BHAs)与α-羟基酸(AHAs)相似，具有加速鳞片状角质细胞剥落的功能，水杨酸属于芳香族β-羟基酸，其在护肤品中的功效早已得到人们的充分认可。水杨酸在医药领域中，通过局部用药可以用来治疗暗疮；在化妆品领域中，能够改善由于身体内部机能老化导致的幼纹和皱纹，以及由光老化引起的皱纹、松弛下垂、斑点等皮肤问题。
甜菜碱中的三甲基甘氨酸在肌肤护理方面的功能也早就应用于化妆品行业，具有增强皮肤的滋润度、弹性及水合作用，甜菜碱的分子结构很特别，同一个分子中既有阴离子电荷也有阳离子电荷，而人类的皮肤在一般生理条件下全部带负电荷，因此含有正电荷的分子对皮肤具有天然的亲和力，特别适用于护肤品。
然而，水杨酸具有较强的刺激性，为了降低水杨酸的刺激性，甜菜碱水杨酸盐被广泛添加在医药、化妆品中。甜菜碱水杨酸盐结合了水杨酸祛痘紧肤和甜菜碱滋润保湿的功效，能促进皮肤新陈代谢、死皮脱落，改善皮肤弹性。但甜菜碱水杨酸盐具有一定的刺激性，对皮肤、眼睛会产生刺激，因此，甜菜碱和水杨酸在医药、化妆品中的应用还有待改善。
发明内容
为了改善甜菜碱水杨酸盐的刺激性问题，本发明提供一种甜菜碱水杨酸共晶及其制备方法和应用。
一种甜菜碱水杨酸共晶，其关键在于：所述甜菜碱水杨酸共晶为斜方晶系，空间群为Pbca，晶胞参数为
Figure PCTCN2022103316-appb-000001
α＝β＝γ＝90°，Z＝8，晶胞体积
Figure PCTCN2022103316-appb-000002
优选的，所述甜菜碱水杨酸共晶的分子式为C12H17NO5，所述共晶包括甜菜碱分子和水杨酸分子，所述甜菜碱分子和水杨酸分子的摩尔比为1:1。
优选的，所述甜菜碱水杨酸共晶的粒度为(240±15)nm～(520±30)nm。
一种甜菜碱水杨酸共晶的制备方法，其关键在于：包括以下步骤：
S1在高压釜中加入溶剂以及甜菜碱和水杨酸，在第一压力与第一温度下搅拌，形成甜菜碱和水杨酸的混悬液；
S2将所述混悬液由高压泵泵至高压均质机，通过均质阀，均质阀的压力为600bar-1200bar；
S3在第二温度下对高压均质机接收室进行减压至第二压力，使溶剂挥发，得到甜菜碱水杨酸共晶。
优选的，所述均质阀的压力为800bar。
优选的，所述第一温度为所述溶剂在第一压力下为液态的温度。
优选的，所述第二温度为所述溶剂在第二压力下为气态的温度。
优选的，所述溶剂为液态CO2。
优选的，所述第一压力为10MPa-30MPa，第一温度为110-130℃，第二温度为常温，第二 压力为常压。
一种如前述的甜菜碱水杨酸共晶在医药、化妆品领域中的应用。
综上所述，本发明包括以下至少一种有益技术效果：
1.本发明公开的一种甜菜碱水杨酸共晶刺激性很低。其刺激性明显低于水杨酸单体，pH值较水杨酸单体更温和，有降低了过敏情况的发生。相对于甜菜碱水杨酸盐，甜菜碱水杨酸共晶也表现得更温和。
2.本发明公开的一种甜菜碱水杨酸共晶由甜菜碱和水杨酸制备，同时保留了甜菜碱和水杨酸的功效，具有甜菜碱保湿、抗过敏、降低刺激性的作用与水杨酸杀菌、消炎、去粉刺、去角质等功效。甜菜碱水杨酸共晶添加在乳液、面霜等停留型和洗面奶、洗发水、沐浴露等洗去型产品中都有较佳的效果。
3.本发明以高压均质法得到了甜菜碱水杨酸共晶。旋蒸重结晶等方法得到的一般为甜菜碱水杨酸盐，很难生成甜菜碱水杨酸共晶。高压均质法得到的甜菜碱水杨酸共晶纯度高、粒度可调控。
附图说明
图1是本发明实施例1的甜菜碱水杨酸共晶的分子结构示意图；
图2是本发明实施例1的甜菜碱水杨酸共晶的单晶分子堆积示意图；
图3是本发明实施例1的甜菜碱水杨酸共晶的核磁氢谱；
图4是本发明实施例1的甜菜碱水杨酸共晶的TGA图；
图5是甜菜碱水杨酸物理混合物的TGA图；
图6是志愿者脸部visia-cr图像；
图7为本发明对比例1反应产物的核磁氢谱。
具体实施方式
为使本发明的目的、技术方案及优点更加清楚、明确，以下参照附图并举实施例对本发明进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
水杨酸是一种脂溶性的有机酸，化学式为C 7H 6O 3，结构式为
Figure PCTCN2022103316-appb-000003
外观为白色的结晶粉状物，熔点为158～161℃。在医药领域中，水杨酸主要作为医药工业的原料，可用于制备阿司匹林、水杨酸钠、水杨酰胺等药物的。在化妆品领域中，常用的浓度为1-2wt.％的水杨酸溶液治疗痘痘，可以帮助皮肤有效地脱去毛孔口周围和皮肤表面的堆积的角质，消炎抗菌，更主要的是还可以打碎毛囊里的细胞碎片和油脂形成的阻塞栓(黑头/白头)，通畅毛孔，破坏细菌的生长环境。
甜菜碱是一种生物碱，化学名称为N,N,N-三甲基甘氨酸，化学结构与 氨基酸相似，属季铵碱类物质，分子式为C 5H 11NO 2，结构式为
Figure PCTCN2022103316-appb-000004
外观为白色结晶性粉末，熔点为301～305℃。甜菜碱在医药领域，可用于抗肿瘤，降血压，抗消化性溃疡及胃肠功能障碍，治疗肝脏疾病等。甜菜碱在化妆品领域，可以对皮肤起到保湿作用，通过皮肤角质层渗透进来保护细胞的平衡，增加表层皮肤含水量的作用。虽然甜菜碱和甘油一样具有保湿作用，但是与甘油的固定水分子不同，甜菜碱是允许水分子完全被全活细胞吸收利用的。当一个水分子占据甜菜碱两性离子中间时就会很容易的将自身的水分子释放到周边液体上。而甜菜碱的保湿机理性能优于其他保湿剂，即使低浓度下也能持久保湿。
共晶的定义是两种或两种以上不同的分子通过氢键、π-π相互作用范德华力等分子间相互作用，形成在同一晶格中规则排布的结晶材料。共晶是改变一些成分溶解度、熔点、引湿性、压缩性、密度等理化性质的有效途径。现有的甜菜碱水杨酸盐，甜菜碱与水杨酸之间发生了质子的转移，甜菜碱与水杨酸通过离子作用结合在一起，据报道水杨酸甜菜碱盐具有一定的皮肤和眼刺激性。本发明合成出的甜菜碱水杨酸共晶，未发生质子转移，甜菜碱分子与水杨酸分子之间通过超分子相互作用结合在一起，本发明中水杨酸甜菜碱共晶刺激性明显小于水杨酸甜菜碱盐，在化妆品中应用广泛。
本发明提供的一种甜菜碱水杨酸共晶的制备方法，包括以下步骤：
S1在高压釜中加入溶剂、甜菜碱、水杨酸，在高压釜中加入溶剂以及甜菜碱和水杨酸，在第一压力与第一温度下搅拌，形成甜菜碱和水杨酸的混悬液。
具体的，溶剂可为液态CO 2、石油醚和乙酸乙酯等。其中优选为液态CO 2，液态CO 2具有无毒、不易燃以及价格适中的特点。甜菜碱与水杨酸的投料摩尔比为1:1。高压釜是指在高压下操作的一种反应器，高压釜压力设置为10-30MPa，优选为20MPa；温度设置为110-130℃，优选为115℃；搅拌速度2为600-750r/min，优选为700r/min；搅拌时间为1-8h，优选为4h；形成甜菜碱和水杨酸的混悬液。在压力为10-30MPa，温度为110-130℃时，CO 2为液态，甜菜碱与水杨酸在液态CO 2中溶解度较小，在搅拌条件下，通过机械作用使甜菜碱与水杨酸颗粒充分分散并混合均匀。溶剂选用液态CO 2可有效避免溶剂化物的生成，液态CO 2作为一种超临界流体，可在常温常压下迅速膨胀气化，有效避免溶剂残留。在选择其他溶剂时，第一压力与第一温度可以调整，使得溶剂在第一压力下为液态。
S2将所述混悬液由高压泵泵至高压均质机，通过均质阀。
具体的，均质阀的压力为600bar-1200bar，其中优选为800bar。混悬液在高压泵的泵送过程中，保持压力和温度基本不变。高压均质机是以高压往复泵为动力传递和输送物料的机构，将液态物料或以液体为载体的固体颗粒输送至均质阀(高压均质腔)部分，要处理物料在通过均质阀的过程中，在高压下产生的强烈的剪切、撞击、空穴和湍流蜗旋作用，从而使液态物料或以液体为载体的固体颗粒得到超微细化。均质阀接受集流管输送过来高压液料，完成超细粉碎、乳化、匀浆任务。高压均质机可以使悬浊液状态的物料在超高压(最高可达4138bar)作用下，高速流过具有特殊内部结构的容腔(高压均质腔/均质阀)，使物料发生物理、化学、结构性质等一系列变化，最终达到均质的效果。
甜菜碱和水杨酸的混悬液经过S1步骤分散均匀后，通过高压泵输送至高压均质机的均质阀，均质阀的压力越高对物料的细化效果越好。通过调节均质阀的压力，可调控甜菜碱和水杨酸混悬液受到的力，当均质阀的压力越大时，甜菜碱和水杨酸混悬液受到的力越大，甜菜碱和水杨酸的细化效果越好。同时，在高压高速混合的条件下，甜菜碱与水杨酸发生反应，得到甜菜碱水杨酸共晶。此外，通过调节均质阀的压力，能够调控甜菜碱水杨酸共晶粒度的大小，压力越大最终得到的甜菜碱水杨酸共晶粒度越小。
S3在第二温度下对高压均质机接收室进行减压至第二压力，使溶剂挥发，得到甜菜碱水杨酸共晶。
具体的，溶液选择液态CO 2，第二温度和第二压力为常温常压，使得液态CO 2为气体。经过快速减压，液态CO 2挥发，与甜菜碱水杨酸共晶分离，无溶剂的残留与溶剂化物的生成，得到粒度均一的高纯度甜菜碱水杨酸共晶。选择其他溶剂时，第二温度可以调整为该溶剂在第二压力下为气态的温度。
本发明的甜菜碱水杨酸共晶制备方法，通过高压均质法制备，步骤简单，不需纯化，能够得到晶型稳定，粒度可调控的甜菜碱水杨酸共晶。
以下结合实施例对本发明进行详细解释。
实施例1
一种甜菜碱水杨酸共晶的制备方法：
S1在高压釜中加入液态CO 2、甜菜碱、水杨酸，其中甜菜碱与水杨酸的投料摩尔比为1:1，高压釜压力设置为20MPa，温度设置为115℃，搅拌速度为700r/min，搅拌4h，形成甜菜碱和水杨酸的混悬液；
S2将所述混悬液由高压泵泵至高压均质机，通过均质阀，均质阀的压力设置为800bar；
S3在常温下对均质机接收室进行减压至常压，使液态CO 2挥发，得到甜菜碱水杨酸共晶。
甜菜碱水杨酸共晶的分子结构示意图如图1所示，分子式为C 12H 17NO 5，由甜菜碱分子和水杨酸分子组成，甜菜碱分子和水杨酸分子之间未发生质子转移，水杨酸分子有一个羧基和一个酚羟基，能够与甜菜碱上的N和O形成氢键，其中甜菜碱上的N作为氢键的受体，水杨酸羧基中的OH作为氢键的给体形成了一处O-H···N氢键；甜菜碱上的O作为另一氢键的受体，水杨酸酚羟基的OH作为氢键的给体形成了第二处O H···O氢键。分子自发呈现出并行排列为规律的稳定三维结构。在不需要外力作用的状态下，分子与分子之间能够通过内部氢键作用，自发的聚合、识别、组成结构稳定的更多功能共晶聚合体，甜菜碱水杨酸共晶的单晶分子堆积示意图如图2所示。
对实施例1得到的甜菜碱水杨酸共晶进行X-射线单晶衍射测试，具体测试参数为：SuperNova，Dual，Cu at zero，AtlasS2衍射仪，温度为100.00(10)K，结构分析采用Olex2与ShelXL。X-射线单晶衍射测试结果如表1所示：
表1：甜菜碱水杨酸共晶单晶数据表
Figure PCTCN2022103316-appb-000005
Figure PCTCN2022103316-appb-000006
本发明制得的甜菜碱水杨酸共晶的原子坐标(×10 4)和等同各向同性原子位移参数
Figure PCTCN2022103316-appb-000007
分析数据如表2所示，U(eq)定义为正交U ij张量的痕量的三分之一。
表2：甜菜碱水杨酸共晶的原子坐标和等同各向同性原子位移参数
Figure PCTCN2022103316-appb-000008
Figure PCTCN2022103316-appb-000009
本发明制得的甜菜碱水杨酸共晶的各向异性原子位移参数分析数据如表3所示，其中，各向异性原子位移因子幂呈式：2π 2[h 2a* 2U 11+2hka*b*U 12+…]。
表3：甜菜碱水杨酸共晶的各向异性原子位移参数
Figure PCTCN2022103316-appb-000010
本发明制得的甜菜碱水杨酸共晶的各化学键键长分析数据如表4所示。
表4：共晶的各化学键键长
Figure PCTCN2022103316-appb-000011
Figure PCTCN2022103316-appb-000012
本发明制得的甜菜碱水杨酸共晶的各化学键键角(°)分析数据如表5所示。
表5：甜菜碱水杨酸共晶的各化学键键角
Figure PCTCN2022103316-appb-000013
Figure PCTCN2022103316-appb-000014
本发明制得的甜菜碱水杨酸共晶的氢原子坐标
Figure PCTCN2022103316-appb-000015
及各项同性原子位移参数
Figure PCTCN2022103316-appb-000016
分析数据如表6所示。
表6：甜菜碱水杨酸共晶的氢原子坐标及各项同性原子位移参数
Figure PCTCN2022103316-appb-000017
对本实施例得到的甜菜碱水杨酸共晶进行核磁共振氢谱(1H-NMR)表征，实验选用MeOD作为测试溶剂，结果如图2所示，数据如下： 1H NMR(400MHz,MeOD)δ7.87(dd,J＝7.9,1.7Hz,1H),7.45(ddd,J＝8.4,7.3,1.8Hz,1H),6.97–6.83(m,2H),3.92(s,2H),3.30(s,9H)。从核磁氢谱图中可以清晰的找到水杨酸酚环的4个氢原子，甜菜碱亚甲基的2个氢原子，以及甜菜碱3个甲基的9个氢原子；其余为少量残留水峰和氘代试剂峰，未见明显杂质峰。甜菜碱水杨酸超分子共晶化合物中，甜菜碱与水杨酸以1:1的分子比例存在，纯度超过98％。
甜菜碱水杨酸共晶分解温度测试
1.实验方法
分别称取甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物(混合物中甜菜碱、水杨酸的摩尔比为1:1)，采用TGA热重分析仪，在50℃保温5min，50℃升温至350℃，升温速率10℃/min，记录重量随时间变化图像。
2.实验结果
如图3和图4的TGA图所示，甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物表现出了不同的分解温度，甜菜碱水杨酸物理混合物的分解温度为211.49℃，甜菜碱水杨酸共晶的分解温度显著低于甜菜碱水杨酸物理混合物的分解温度，为190.77℃。说明本发明的甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物结构不同。
甜菜碱水杨酸共晶比旋光度测试
1.实验原理
当平面偏振光通过某种介质时，有的介质对偏振光没有作用，即透过介质的偏振光的偏振面保持不变。而有的介质却能使偏振光的偏振面发生旋转。这种能旋转偏振光的偏振面的性质叫做旋光性。具有旋光性的物质叫做旋光物质或光活性物质。
2.实验方法
分别称取适量的甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物(混合物中甜菜碱水杨酸的摩尔比为1:1)，配制为浓度0.1％的水溶液，进行比旋光度测试。
3.实验结果
根据表7结果，甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物比旋光度差异明显，证明甜菜碱水杨酸共晶在溶液中还存在共晶结构而不会解体。
表7：甜菜碱水杨酸共晶与甜菜碱水杨酸物理混合物比旋光度
成分 比旋光度
甜菜碱水杨酸共晶 -49.047°
甜菜碱水杨酸物理混合物 -1.885°
甜菜碱水杨酸共晶的刺激性试验
1.实验材料及实验方法：
受试物：甜菜碱水杨酸共晶2％水溶液、甜菜碱水杨酸盐2％水溶液、甜菜碱2％水溶液、水杨酸2％DMSO水溶液。
阴性对照：空白对照。
实验动物：实验用兔，每组7只。
实验方法：采用同体左右侧自身对比法，将受试物直接涂于备皮处，以封闭式斑贴试验方法，将受试物0.020～0.025ml置于斑试器内，外用低致敏胶带贴敷于受试者前臂曲侧，24小时后去除受试物，分别于去除后0.5、24、48小时观察皮肤反应，按表8进行刺激强度评价。
表8：皮肤刺激反应评分标准
Figure PCTCN2022103316-appb-000018
Figure PCTCN2022103316-appb-000019
2.试验结果
对受试物进行48h皮肤刺激性试验，具体结果见下表：
表9：皮肤刺激性试验结果汇总
Figure PCTCN2022103316-appb-000020
根据表9中数据可以看出，由于采用同体左右侧自身对比法，阴性对照组共计为28个区域，阴性对照组中均未出现刺激反应，证明实验有效，结果可信。甜菜碱2％水溶液在0.5h、24h、48h均未出现刺激反应，证明甜菜碱温和、刺激性低。水杨酸2％DMSO水溶液具有明显的刺激性，在0.5h就出现了两例刺激性反应，48h时均出现不同程度的刺激性反应。甜菜碱水杨酸盐2％水溶液的刺激性较水杨酸明显降低，仅在24h出现1例，48h出现2例刺激性反应。本发明提供的 甜菜碱水杨酸共晶2％水溶液刺激性测试表现良好，在0.5h、24h、48h均未出现刺激反应，较甜菜碱水杨酸盐更为温和。
甜菜碱水杨酸共晶抗炎功效测试
本发明对甜菜碱单体、水杨酸单体、甜菜碱水杨酸共晶进行了基于“户外紫外线(UVB)-角质形成细胞”的抗炎功效测试。
1.测试细胞为：角质形成细胞。
2.辐照条件：300mJ/cm 2。
3.材料的准备与测试的方法：将角质形成细胞接种至6孔板中，置于温度、相对湿度和二氧化碳浓度合适的培养箱中，进行严格的孵育培养24h。待6孔板中的细胞铺板率达标后，分组给药，每孔按照相同的剂量统一进行给药，在同样温度、湿度和二氧化碳浓度的培养箱中继续培养24h，每组设置三组平行。培养完成后，对相应组别进行同条件的辐照，再将后期需要进行超氧化物歧化酶(SOD)活力检测的所有孔板进行换液操作，更换新鲜培养液，置于相同条件的培养箱中再次培养24h。最后使用酶联免疫吸附测定(ELISA)法对培养完成的角质形成细胞进行炎症因子(IL 1α、TNFα、IL 8)和炎症介质(PGE2)检测。
4.配液：按照表10配制受试物工作液。
表10：抗炎功效实验设计
Figure PCTCN2022103316-appb-000021
注：BC组为空白对照组，NC组为阴性对照组，PC组为阳性对照组。
5.实验结果如表11-14所示。
表11：IL-1α检测结果汇总
Figure PCTCN2022103316-appb-000022
Figure PCTCN2022103316-appb-000023
注：采用t-test方法进行统计分析，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为##；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*，p value<0.01表示为**。
与BC组相比，NC组IL-1α含量显著上升(p<0.01)；与NC组相比，PC组IL-1α含量显著下降(p<0.01)；表明本次实验有效。
与NC组相比，样品甜菜碱水杨酸共晶的IL-1α含量显著下降(p<0.05)，证明甜菜碱水杨酸共晶对炎症因子IL-1α具有显著抑制作用，甜菜碱水杨酸共晶具有抗炎功效。
表12：TNF-α检测结果汇总
Figure PCTCN2022103316-appb-000024
注：采用用t-test方法进行统计分析，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为##；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*，p value<0.01表示为**。
与BC组相比，NC组TNF-α含量显著上升(P<0.01)；与NC组相比，PC组TNF-α含量显著下降(P<0.01)；表明本次实验有效。
与NC组相比，样品甜菜碱水杨酸共晶的TNF-α含量显著下降(P<0.01)，证明甜菜碱水杨酸共晶对炎症因子TNF-α具有显著抑制作用，甜菜碱水杨酸共晶具有抗炎功效。
表13：IL-8检测结果汇总
Figure PCTCN2022103316-appb-000025
Figure PCTCN2022103316-appb-000026
注：采用用t-test方法进行统计分析，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为##；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*，p value<0.01表示为**。
与BC组相比，NC组IL-8含量显著上升(p<0.01)；与NC组相比，PC组IL-8含量显著下降(p<0.01)；表明本次实验有效。
与NC组相比，样品甜菜碱水杨酸共晶的IL-8含量显著下降(p<0.01)，证明甜菜碱水杨酸共晶对炎症因子IL-8具有显著抑制作用，甜菜碱水杨酸共晶具有抗炎功效。
表14：PGE2检测结果汇总
Figure PCTCN2022103316-appb-000027
注：采用用t-test方法进行统计分析，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为##；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*，p value<0.01表示为**。
与BC组相比，NC组PGE2含量显著上升(p<0.01)；与NC组相比，PC组PGE2含量显著下降(p<0.01)；表明本次实验有效。
与NC组相比，样品甜菜碱水杨酸共晶的PGE2含量显著下降(p<0.05)，证明甜菜碱水杨酸共晶对炎症介质PGE2具有显著抑制作用，甜菜碱水杨酸共晶具有抗炎功效。
综上，结合表11-14中数据，样品甜菜碱水杨酸共晶在0.25mg/mL的暴露剂量下，对UVB刺激产生的IL-1α有显著的抑制作用(p<0.05)；对TNF-α、IL-8有显著的抑制作用(p<0.01)；对PGE2有显著的抑制作用(p<0.05)，提示甜菜碱水杨酸共晶样品具有抗炎功效。
甜菜碱水杨酸共晶抗氧化功效测试
本发明对甜菜碱单体、水杨酸单体、甜菜碱水杨酸共晶进行了基于“户外紫外线(UVB)-角质形成细胞”的抗氧化功效测试。
1.测试细胞为：角质形成细胞。
2.辐照条件：300mJ/cm 2。
3.材料的准备与测试的方法：将角质形成细胞接种至6孔板中，置于温度、相对湿度和二氧化碳浓度合适的培养箱中，进行严格的孵育培养24h。待6孔板中的细胞铺板率达标后，分组给药，每孔按照相同的剂量统一进行给药，在同样温度、湿度和二氧化碳浓度的培养箱中继续培养24h，每组设置三组平行。培养完成后，对相应组别进行同条件的辐照，再将后期需要进行超氧化物歧化酶(SOD)活力检测的所有孔板进行换液操作，更换新鲜培养液，置于相同条件的培养箱中再次培养24h最后对培养完成的角质形成细胞进行抗氧化因子检测。
4.配液：按照下表15配制受试物工作液。
表15：抗氧化功效实验设计
Figure PCTCN2022103316-appb-000028
注：BC组为空白对照组，NC组为阴性对照组，PC组为阳性对照组。
5.实验结果如表16和表17所示。
表16：ROS含量检测结果汇总
Figure PCTCN2022103316-appb-000029
注：汇总各样品的MFI(平均荧光强度)值，用t-test方法进行统计分析时，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为#；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*；p value<0.01表示为*。
与BC组相比，NC组ROS含量显著上升(p<0.01)；与NC组相比，PC组ROS含量显著下降(p<0.01)；表明本次试验有效。
与NC组相比，样品甜菜碱水杨酸共晶的ROS含量显著下降(p<0.01)，证明甜菜碱水杨酸 共晶对ROS有抑制作用。
表17：SOD活力检测结果汇总
Figure PCTCN2022103316-appb-000030
注：汇总各样品的MFI(平均荧光强度)值，用t-test方法进行统计分析时，NC组与BC组相比，显著性以#表示，p value<0.05表示为#，p value<0.01表示为#；样品组、阳性对照组与NC组相比，显著性以*表示，p value<0.05表示为*；p value<0.01表示为*。
与BC组相比，NC组SOD含量显著下降(p<0.01)；与NC组相比，PC组SOD含量显著上升(p<0.01)；表明本次试验有效。
与NC组相比，样品甜菜碱水杨酸共晶的SOD含量显著上升(p<0.05)，证明甜菜碱水杨酸共晶对SOD活力有提升作用。
综上，结合表16、17中数据，样品甜菜碱水杨酸共晶在0.25mg/mL的暴露剂量下，对UVB刺激产生的ROS有显著的抑制作用(p<0.01)，对细胞内SOD活力有显著提升作用(p<0.05)，表现出抗氧化功效。
最小抑菌浓度测定试验(营养肉汤稀释法)
1.原理
实验标准：《消毒技术规范2002年版》
本试验将不同浓度的抑菌剂混合溶解于营养肉汤培养基中，然后接种细菌，通过细菌的生长与否，确定抗(抑)菌剂抑制受试菌生长的最低浓度，即最小抑菌浓度(Minima1-Inhibitory Concentration,MIC)。本方法适用于可溶性抑菌产品。
2.试验器材
(1)试验菌株：金黄葡萄球菌(Staphylococcus aureus)、大肠杆菌(Escherichia coli)、白假丝酵母菌(Candida albicans)、表皮葡萄球菌(Stapylococcus epidemidi)、痤疮丙酸杆菌(Propionibacterium acnes)；
(2)甜菜碱水杨酸共晶水溶液；
(3)营养肉汤培养基；
(4)稀释液；
(5)吸管、试管；
(6)37℃培养箱。
3.操作步骤
(1)制备金黄葡萄球菌(Staphylococcus aureus)、大肠杆菌(Escherichia coli)、白假丝酵母菌(Candida albicans)、表皮葡萄球菌(Stapylococcus epidemidi)、痤疮丙酸杆菌(Propionibacterium acnes)悬液；
(2)含抗菌剂培养基配制：将甜菜碱水杨酸共晶水溶液用蒸馏水做多倍系列稀释成不同 浓度的受试液，取各稀释度受试液2.5ml加入到含2.5ml双倍浓度营养肉汤的试管中；
(3)取0.1ml含菌量约为10 8cfu/ml菌悬液接种于含抗(抑)菌剂的营养肉汤的试管中，作为试验组样本；
(4)以同样方法接种不含抗(抑)菌剂的营养肉汤的试管中，作为阳性对照组样本；
(5)取2支含营养肉汤的试管中，作为阴性对照组样本；
(6)将试验组样本、阳性对照组样本及阴性对照组样本放置37℃培养箱中，培养48h，观察结果；
(7)试验中应将试验用菌悬液进行活菌培养计数，其作用浓度应为5×10 5cfu/mL～5×10 6cfu/mL。
4.试验结果
当阳性对照管有细菌生长(混浊)，阴性对照管无菌生长(透明)，试验用菌悬液的作用浓度为5×10 5cfu/mL～5×10 6cfu/mL时，试验组无菌生长的最高稀释度所对应的抗(抑)菌剂浓度，为该样品对受试菌的MIC。
根据表18，甜菜碱水杨酸共晶的MIC都较低，对五种菌都有抑菌作用，其中对痤疮丙酸杆菌(Propionibacterium acnes)有良好的抑菌效果，在5mg/mL的浓度下就有较好的抑菌作用。主要是由于痤疮丙酸杆菌激活单核细胞受体，进而导致IL-12、IL-8产生，引发了炎症，水杨酸-甜菜碱共晶和水杨酸在相关靶点蛋白上(PDB编号：3v2y)有近似的作用位点，相对于单体化合物的作用位点，水杨酸-甜菜碱共晶能够与ARG-174，ARG-498产生新的作用位点，增强结合能，提高超分子的功效。
表18：最小抑菌浓度测定试验
试验菌 MIC(mg/mL)
金黄葡萄球菌(Staphylococcus aureus) 15
大肠杆菌(Escherichia coli) 20
白假丝酵母菌(Candida albicans) 5
表皮葡萄球菌(Stapylococcus epidemidi) 7.5
痤疮丙酸杆菌(Propionibacterium acnes) 5
甜菜碱水杨酸共晶祛痘精华液应用
提供一种有效成分为甜菜碱水杨酸共晶的祛痘精华液，具体配方如表19：
表19：一种有效成分为甜菜碱水杨酸共晶的祛痘精华液配方
Figure PCTCN2022103316-appb-000031
Figure PCTCN2022103316-appb-000032
PH:5.5-6.0
工艺：
1.将卡波U20均匀撒入水中搅拌均匀，然后升温加热至80-85℃，黄原胶与G260预先混合加入以上水溶液，加入A相剩余部分，充分水合完全。
2.降温至45℃以下加入C相各组分混合均匀，
3.B相升温至80-85℃加热溶解，溶解好后加入A+C相中，搅拌均匀即可。
外观：无色半透流动液体
PH:5.55
粘度：3#，60rpm，895mps.s
人体功效测试
1.实验材料及实验方法：
受试材料：实施例1得到的祛痘精华液。
实验者：选取18-55岁志愿者10人，要求痘痘肌严重，脸部泛红炎症明显的人群，排除患有皮肤炎症未愈者；依赖性糖尿病患者；有慢性呼吸系统患者；哺乳期或妊娠妇女；脸上有鲜红斑痣、瘢痕；体质高敏者。
实验方法：连续28天早晚使用祛痘精华液，采用visia皮肤检测仪在使用第0、7、14、21、28天后检测，共检测5次。
2.试验结果
对受试者进行皮肤检测，对比使用祛痘精华液第0天与第28天后的脸部visia-cr图像，结果如图6所示。照片中红色特征为卟啉在visia-cr下成像颜色，卟啉可作为痤疮丙酸杆菌标志物。从图像中可以看出，使用祛痘精华液28天后，卟啉(痤疮丙酸杆菌)数量明显减少，受试志愿者脸部红色特征平均减少40.85％。证明实施例1中祛痘精华液具有明显的抗炎祛痘效果。
实施例2
与实施例1的区别在于，S2中均质阀的压力设置为600bar。测试甜菜碱水杨酸共晶的单晶数据以及氢谱数据与实施例1中相同，纯度超过98％。
实施例3
与实施例1的区别在于，S3中均质阀的压力设置为1200bar。测试甜菜碱水杨酸共晶的单晶数据以及氢谱数据与实施例1中相同，纯度超过98％。
对本发明实施例1、实施例2、实施例3得到的甜菜碱水杨酸共晶进行粒度检测，所用设备为激光粒度仪。激光粒度仪是根据颗粒能使激光产生散射这一物理现象测试粒度分布的。由于激光具有很好的单色性和极强的方向性，所以一束平行的激光在没有阻碍的无限空间中将会照射到无限远的地方，并且在传播过程中很少有发散的现象。当光束遇到颗粒阻挡时，一部分光将发生散射现象。散射光的传播方向将与主光束的传播方向形成一个夹角θ。散射理论和实验结果证明，散射角θ的大小与颗粒的大小有关，颗粒越大，产生的散射光的θ角就越小；颗粒越小，产生的散射光的θ角就越大。均质阀压力不同时，得到的甜菜碱水杨酸共晶粒度不同，具体数值如表20。
表20：不同条件下甜菜碱水杨酸共晶的粒度
Figure PCTCN2022103316-appb-000033
由表7数据可知，在均质阀压力为600bar与800bar时，甜菜碱水杨酸共晶的粒径可得到几百纳米级，但均质阀压力为800bar时，颗粒均匀度相对600bar有所降低，当均质阀压力更高达到1200bar时，甜菜碱水杨酸共晶的粒径更小，均匀度也更好，但压力大容易对高压均质机造成堵塞，降低高压均质机的使用寿命，因此优选为均质阀压力为800bar。
对比例1
对比例1与实施例1的区别之处在于，S2中均质阀的压力设置为400bar。尝试对反应产物进行单晶的培养，拿到的单晶经检测发现是水杨酸，说明对比例1条件下无法得到共晶。图7为反应产物的核磁氢谱，从图7中可以看出对比例1的条件下无法得到分子比为1:1的水杨酸甜菜碱共晶体，推测为反应不完全的混合物，水杨酸：甜菜碱的分子比在1:1.2-2之间。
以上均为本发明的较佳实施例，并非依此限制本发明的保护范围，故：凡依本发明的机构、形状、原理所做的等效变化，均应涵盖于本发明的保护范围之内。

Claims (10)

  1. 一种甜菜碱水杨酸共晶，其特征在于：所述甜菜碱水杨酸共晶为斜方晶系，空间群为Pbca，晶胞参数为
    Figure PCTCN2022103316-appb-100001
    α＝β＝γ＝90°，Z＝8，晶胞体积
    Figure PCTCN2022103316-appb-100002
  2. 根据权利要求1所述的甜菜碱水杨酸共晶，其特征在于：所述甜菜碱水杨酸共晶的分子式为C 12H 17NO 5，所述共晶包括甜菜碱分子和水杨酸分子，所述甜菜碱分子和水杨酸分子的摩尔比为1:1。
  3. 根据权利要求1所述的甜菜碱水杨酸共晶，其特征在于：所述甜菜碱水杨酸共晶的粒度为(240±15)nm～(520±30)nm。
  4. 一种如权利要求1-3中任一项所述的甜菜碱水杨酸共晶的制备方法，其特征在于：包括以下步骤：
    S1在高压釜中加入溶剂以及甜菜碱和水杨酸，在第一压力与第一温度下搅拌，形成甜菜碱和水杨酸的混悬液；
    S2将所述混悬液由高压泵泵至高压均质机，通过均质阀，均质阀的压力为600bar-1200bar；
    S3在第二温度下对高压均质机接收室进行减压至第二压力，使溶剂挥发，得到甜菜碱水杨酸共晶。
  5. 根据权利要求4所述的甜菜碱水杨酸共晶的制备方法，其特征在于：所述均质阀的压力为800bar。
  6. 根据权利要求4所述的甜菜碱水杨酸共晶的制备方法，其特征在于：所述第一温度为所述溶剂在第一压力下为液态的温度。
  7. 根据权利要求4所述的甜菜碱水杨酸共晶的制备方法，其特征在于：所述第二温度为所述溶剂在第二压力下为气态的温度。
  8. 根据权利要求4所述的甜菜碱水杨酸共晶的制备方法，其特征在于：所述溶剂为液态CO 2。
  9. 根据权利要求8所述的甜菜碱水杨酸共晶的制备方法，其特征在于：所述第一压力为10MPa-30MPa，第一温度为110-130℃，第二温度为常温，第二压力为常压。
  10. 一种如权利要求1-3中任一项所述的甜菜碱水杨酸共晶在医药、化妆品领域中的应用。
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