WO2022121566A1 - 包含柠檬酸三乙酯和甘氨酸的稳定组合物 - Google Patents
包含柠檬酸三乙酯和甘氨酸的稳定组合物 Download PDFInfo
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- WO2022121566A1 WO2022121566A1 PCT/CN2021/128552 CN2021128552W WO2022121566A1 WO 2022121566 A1 WO2022121566 A1 WO 2022121566A1 CN 2021128552 W CN2021128552 W CN 2021128552W WO 2022121566 A1 WO2022121566 A1 WO 2022121566A1
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- WIPO (PCT)
- Prior art keywords
- urea
- glycine
- triethyl citrate
- composition
- active agent
- Prior art date
Links
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 title claims abstract description 176
- 239000000203 mixture Substances 0.000 title claims abstract description 108
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 239000001069 triethyl citrate Substances 0.000 title claims abstract description 91
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 title claims abstract description 91
- 235000013769 triethyl citrate Nutrition 0.000 title claims abstract description 91
- 239000004471 Glycine Substances 0.000 title claims abstract description 88
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 69
- 239000007864 aqueous solution Substances 0.000 claims abstract description 58
- 239000013543 active substance Substances 0.000 claims abstract description 57
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 34
- 230000000087 stabilizing effect Effects 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 10
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 230
- 239000004202 carbamide Substances 0.000 claims description 116
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 238000002360 preparation method Methods 0.000 claims description 24
- CLAHOZSYMRNIPY-UHFFFAOYSA-N 2-hydroxyethylurea Chemical compound NC(=O)NCCO CLAHOZSYMRNIPY-UHFFFAOYSA-N 0.000 claims description 22
- 229940031575 hydroxyethyl urea Drugs 0.000 claims description 22
- 239000006071 cream Substances 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 15
- 239000006210 lotion Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 239000003792 electrolyte Substances 0.000 claims description 7
- 230000001815 facial effect Effects 0.000 claims description 7
- 229910001428 transition metal ion Inorganic materials 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 19
- 230000007062 hydrolysis Effects 0.000 abstract description 18
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- 239000000523 sample Substances 0.000 description 51
- 210000003491 skin Anatomy 0.000 description 47
- 239000002537 cosmetic Substances 0.000 description 46
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 36
- 238000013112 stability test Methods 0.000 description 35
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- 238000011105 stabilization Methods 0.000 description 13
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- 238000013329 compounding Methods 0.000 description 12
- 239000011159 matrix material Substances 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- 150000001875 compounds Chemical class 0.000 description 4
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- 229910052725 zinc Inorganic materials 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
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- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 description 2
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- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
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- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 2
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- YBHYYFYQHRADCQ-UHFFFAOYSA-N 2-aminoacetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound NCC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O YBHYYFYQHRADCQ-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 101710125298 Beta-defensin 2 Proteins 0.000 description 1
- 102100038326 Beta-defensin 4A Human genes 0.000 description 1
- 101710176951 Beta-defensin 4A Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
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- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004909 Moisturizer Substances 0.000 description 1
- 235000019482 Palm oil Nutrition 0.000 description 1
- OQILCOQZDHPEAZ-UHFFFAOYSA-N Palmitinsaeure-octylester Natural products CCCCCCCCCCCCCCCC(=O)OCCCCCCCC OQILCOQZDHPEAZ-UHFFFAOYSA-N 0.000 description 1
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- REZZEXDLIUJMMS-UHFFFAOYSA-M dimethyldioctadecylammonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC REZZEXDLIUJMMS-UHFFFAOYSA-M 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000004664 distearyldimethylammonium chloride (DHTDMAC) Substances 0.000 description 1
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- 125000004494 ethyl ester group Chemical group 0.000 description 1
- GJQLBGWSDGMZKM-UHFFFAOYSA-N ethylhexyl palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(CC)CCCCC GJQLBGWSDGMZKM-UHFFFAOYSA-N 0.000 description 1
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- PRJKNHOMHKJCEJ-UHFFFAOYSA-N imidazol-4-ylacetic acid Chemical compound OC(=O)CC1=CN=CN1 PRJKNHOMHKJCEJ-UHFFFAOYSA-N 0.000 description 1
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- OTVAEFIXJLOWRX-NXEZZACHSA-N thiamphenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CO)NC(=O)C(Cl)Cl)C=C1 OTVAEFIXJLOWRX-NXEZZACHSA-N 0.000 description 1
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Classifications
-
- 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
- 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
- A61K8/37—Esters of carboxylic acids
-
- 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
- A61K8/42—Amides
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/52—Stabilizers
Definitions
- the present invention relates to the field of cosmetics, in particular to a stable composition comprising triethyl citrate and glycine for achieving stabilization in an aqueous solution that is hydrolyzed to produce ammonia, and a stabilization technique.
- Urea is a very useful moisturizing ingredient. It exists in the stratum corneum of the skin and is the main component of the skin's natural moisturizing factor NMF. For the skin, urea has the effect of moisturizing and softening the dead skin cells. Urea is one of the natural moisturizing factors in the skin, and its effects of moisturizing, softening the skin, and promoting transdermal penetration have been widely reported in the literature.
- urea can also improve the skin barrier and antibacterial by regulating gene expression.
- the paper “Urea uptake enhances human barrier function and antibacterial defense by regulating epidermal gene expression” Journal of Dermatology Research Susanne G.-B., (2012) 132, 1561–1572
- urea increases the genes associated with skin barrier
- the expression of AMP, LL-37 and ⁇ -defensin-2, and the mechanism of action of urea were studied in detail. According to the results of the study, the authors believe that it is not just a metabolite of the body, but as a small molecule regulator, it has the effect of modifying the expression of skin barrier-related genes.
- urea can also be used as a medicine for the treatment of skin diseases such as psoriasis, allergic dermatitis, eczema, and seborrheic dermatitis.
- the urea aqueous solution is not stable, and a hydrolysis reaction occurs to generate ammonia, which leads to an increase in the pH value of the aqueous solution. Moreover, as the temperature increases, the rate of urea hydrolysis increases accordingly.
- the present invention unexpectedly found that in the aqueous solution containing active agents such as urea, the combined use of triethyl citrate and glycine can significantly inhibit the hydrolysis of active agents such as urea, and improve the stability of the aqueous solution containing active agents such as urea, especially pH stability. Therefore, the present invention uses triethyl citrate and glycine in combination for the first time to provide a new and more stable composition containing active agents with moisturizing effects such as urea, which can also be added to external skin preparations to achieve Moisturizing effect.
- the present invention provides a stable composition comprising triethyl citrate and glycine, the composition being an aqueous solution, the aqueous solution further comprising an active agent hydrolyzed to produce ammonia, wherein the active agent is combined with citric acid
- the weight ratio of triethyl ester is 1:1 to 100:1, and the weight ratio of active agent to glycine is 1:1 to 10:1.
- the active agent in the composition of the present invention is selected from the group consisting of urea, hydroxyethylurea, or combinations thereof.
- the weight ratio of the active agent to triethyl citrate in the composition of the present invention is 1:1 to 10:1.
- the weight ratio of active agent to glycine in the composition of the present invention is 1:1.
- the water content of the composition of the present invention is at least 15% by weight.
- compositions of the present invention further comprise electrolytes, transition metal ions, solid powders, or combinations thereof.
- the pH of the composition of the present invention is maintained below 8.5.
- the present invention also provides a method of stabilizing an aqueous solution comprising an active agent hydrolyzed to produce ammonia, the method comprising the combined use of triethyl citrate and glycine, wherein the active agent is combined with triethyl citrate
- the weight ratio of the active agent to glycine is 1:1 to 100:1, and the weight ratio of the active agent to glycine is 1:1 to 10:1.
- the present invention also relates to the use of the composition in an external preparation for skin.
- the external preparation for skin is selected from the group consisting of: facial cleanser, lotion, lotion, cream, and facial mask.
- the present invention discovers for the first time that the combined use of triethyl citrate and glycine can provide a more stable composition containing active agents such as urea.
- active agents such as urea.
- the hydrolysis of active agents such as urea in the composition of the present invention is significantly inhibited, which is beneficial to maintain the stability of the composition, especially the pH stability.
- the present invention unexpectedly finds that the use of triethyl citrate and glycine after compounding can not only reduce the amount of triethyl citrate, but also improve the pH value stability and reduce the amount of triethyl citrate and high concentration of citric acid. Risk of adverse reactions associated with the use of ethyl esters. Accordingly, the present invention also relates to a stabilization method comprising the combined use of a stabilization system of triethyl citrate and glycine for stabilizing compositions susceptible to hydrolysis in aqueous solution to produce ammonia.
- the present invention also provides a new stabilization system with better effect, which is especially suitable for a composition that is prone to hydrolysis to produce ammonia in an aqueous solution.
- Compositions obtained using the stabilizing system of the present invention are capable of retaining the function of the active agent, such as the moisturizing function.
- the active agent such as the moisturizing function.
- urea as the active agent
- higher moisturizing performance can be achieved using the stabilizing system of the present invention, while urea or glycine alone did not show positive moisturizing results.
- Active agents such as active agents having moisturizing properties, are included in the compositions of the present invention.
- the active agents in the compositions of the present invention are susceptible to hydrolysis under storage conditions.
- the active agents in the compositions of the present invention are susceptible to hydrolysis to ammonia under storage conditions.
- the active agent used in the compositions of the present invention is urea or a derivative thereof.
- Urea is a very useful moisturizing ingredient. It exists in the stratum corneum of the skin and is the main component of the skin's natural moisturizing factor NMF. For the skin, urea has the effect of moisturizing and softening the cuticle, so it can also prevent the cuticle from blocking the pores, thereby improving the problem of acne. Urea is often used as a moisturizing ingredient in masks, skin lotions, creams, hand creams and other products.
- Hydroxyethyl urea as the hydroxyethyl derivative of urea, is a brand-new humectant with outstanding advantages. Compared with traditional moisturizing agents, hydroxyethyl urea has a more significant moisturizing effect, smooth application feeling, non-sticky, non-greasy, moisturizing and comfortable feeling in skin care products, and its own non-ionic properties. Very broad applicability.
- hydroxyethyl urea can achieve the same effect at a lower formulation cost; even in basic formulas based on glycerin and propylene glycol, hydroxyethyl urea can reduce other effects by reducing The dosage of the components of the cream appearance (such as silicone oil), to achieve better moisturizing effect, smoother coating feeling, the same or even lower formula cost. Even under extreme conditions, 6% relative humidity, hydroxyethyl urea can form a liquid crystal phase with the skin stratum corneum and prevent the stratum corneum from transforming into a solid crystalline phase to achieve the purpose of softening the skin.
- the components of the cream appearance such as silicone oil
- urea and its derivatives eg, hydroxyethyl urea
- urea and its derivatives have excellent moisturizing effect and skin feel, and are safe for skin and eyes, it can be widely used in: skin care products, various creams and lotions ; Essence and various transparent products; Bath products; Sun protection products;
- aqueous solutions of such active agents are often unstable and prone to hydrolysis to produce ammonia, resulting in an increase in the pH of the aqueous solution.
- active agents eg, urea or its derivatives
- hydrolysis rate of the active agent increases accordingly.
- the present invention combines triethyl citrate and glycine for the first time, which can significantly inhibit the hydrolysis of the active agent (for example, urea or its derivatives) and improve the stability of the product.
- the active agent for example, urea or its derivatives
- this compounded composition can remain stable and retain the moisturizing effect of the active agent.
- the composition comprises 1-20% by weight of an active agent (eg, urea or a derivative thereof). In some embodiments of the invention, the composition comprises 1-10% by weight of an active agent (eg, urea or a derivative thereof). In some embodiments of the invention, the composition comprises 5-10% by weight of an active agent (eg, urea or a derivative thereof).
- Triethyl citrate the chemical name is triethyl 2-hydroxy-1,2,3-propanetricarboxylate.
- Triethyl citrate is a colorless liquid with fruity aroma and has a certain solubility in aqueous solution.
- Triethyl citrate has antioxidant properties and can be used as a stabilizer for oils in cosmetics.
- it is widely used in cosmetics as a fixative (for example, see, Screening and Research of Fixatives in Food Flavor, Ai Bin, CNKI: CDMD: 2.1017.800868).
- Triethyl citrate can be slowly hydrolyzed in aqueous solution to generate citric acid, which gradually reduces the pH value of the aqueous solution. Therefore, it can be expected that compounding it with an active agent such as urea that hydrolyzes to release ammonia can inhibit the increase of the pH value of the active agent aqueous solution.
- the present inventors have unexpectedly discovered that a synergistic stabilization effect can be achieved by combining triethyl citrate and glycine. Compared with pure triethyl citrate, the system obtained by compounding the two can better stabilize the solution that is prone to hydrolysis to produce ammonia, such as the aqueous solution containing urea or its derivatives.
- the compositions of the present invention comprise 0.1-10% by weight of triethyl citrate. In some embodiments of the invention, the composition comprises 0.1-5% by weight of triethyl citrate. In some embodiments of the invention, the composition comprises 0.1-1% by weight of triethyl citrate. In a specific embodiment of the present invention, the composition comprises 0.5% by weight of triethyl citrate.
- the weight ratio of active agent (eg, urea or a derivative thereof) to triethyl citrate in the composition of the present invention is from 1:1 to 100:1. In some embodiments of the present invention, the weight ratio of active agent (eg, urea or a derivative thereof) to triethyl citrate in the composition of the present invention is from 1:1 to 50:1. In some embodiments of the present invention, the weight ratio of active agent (eg, urea or a derivative thereof) to triethyl citrate in the composition of the present invention is from 1:1 to 20:1.
- the weight ratio of active agent (eg, urea or a derivative thereof) to triethyl citrate in the composition of the present invention is from 1:1 to 10:1. In some embodiments of the present invention, the weight ratio of active agent (eg, urea or a derivative thereof) to triethyl citrate in the composition of the present invention is from 10:1 to 20:1.
- Glycine one of the twenty common amino acids, appears as odorless white crystals at room temperature and has good solubility in aqueous solutions.
- glycine can be converted from glucose and is one of the twenty basic amino acids that make up proteins (see, eg, "Personal Care Composition Containing Taurine, Arginine, Glycine", CN108430587A).
- Glycine has a wide range of applications in food, medicine and agriculture, and is also used as a variety of chemical raw materials or pharmaceutical raw materials and intermediates, such as the raw materials of cephalosporins, thiamphenicol intermediates, synthetic imidazole acetic acid intermediates, etc. (such as See, "Study and Molecular Simulation of Glycine Crystallization Process under Additive Conditions," Wang Lu).
- glycine can be used as a skin conditioning agent, which can improve the skin conditioning ability (for example, see, "Cosmetic Raw Materials Handbook", Li Dongguang), and has a good application prospect in the cosmetic industry.
- the pH value of the urea aqueous solution is maintained by utilizing the acid-base regulating ability of glycine.
- the present inventors have unexpectedly discovered that a synergistic stabilization effect can be achieved by combining triethyl citrate and glycine.
- the present invention unexpectedly finds that the pH value stability of the urea aqueous solution is greatly improved by compounding triethyl citrate and glycine, and the improvement effect is better than using triethyl citrate or glycine alone.
- the introduction of glycine can reduce the dosage of triethyl citrate, improve pH value stability, reduce the risk of adverse reactions and reduce product cost.
- the present invention provides a new combination of additives with better effects for skin care products and skin medicines, and provides technical support for the safe application of urea in skin care products.
- compositions of the present invention comprise 1-20% by weight of glycine. In some embodiments of the invention, the composition comprises 1-10% by weight of glycine. In some embodiments of the invention, the composition comprises 1-5 wt% glycine.
- the weight ratio of active agent (eg, urea or a derivative thereof) to glycine in the composition of the present invention is from 1:1 to 10:1. In some embodiments of the present invention, the weight ratio of active agent (eg, urea or a derivative thereof) to glycine in the composition of the present invention is from 1:1 to 5:1. In a specific embodiment of the present invention, the weight ratio of the active agent (eg, urea or its derivatives) to glycine in the composition of the present invention is 1:1.
- compositions of the present invention may also contain other ingredients.
- the compositions of the present invention may also contain electrolytes, transition metal ions, solid powders, and the like, which may have catalytic properties.
- the compositions of the present invention further comprise glycine, sodium chloride, PCA-Cu, zinc sulfate, zinc oxide, silica, or combinations thereof.
- the combination of triethyl citrate and glycine as a stable system for a composition containing an active agent such as urea has good performance, For example, the pH of the aqueous solution is stable and satisfactory.
- compositions of the present invention are primarily concerned with stabilization against aqueous solutions. Accordingly, the compositions of the present invention may also contain water or other aqueous carriers.
- the weight ratio of water in the composition of the present invention is at least 15%. In some embodiments of the present invention, the water content of the composition is 15-90% by weight. In some embodiments of the present invention, the water content of the composition is 15-80% by weight. In some embodiments of the present invention, the water content of the composition is 15-70% by weight. In other preferred embodiments, the weight ratio of water in the compositions of the present invention is at least 20%. In some embodiments of the present invention, the water content of the composition is 20-90% by weight. In some embodiments of the present invention, the water content of the composition is 20-80% by weight. In other preferred embodiments, the weight ratio of water in the composition of the present invention is at least 25%.
- the water content of the composition is 25-90% by weight. In some embodiments of the invention, the composition has a water content of 25-80% by weight. In other preferred embodiments, the weight ratio of water in the composition of the present invention is at least 50%.
- the pH of the composition of the present invention conforms to the provisions of national laws and regulations.
- the pH of the composition of the present invention is 4.0-8.5.
- the pH of the composition of the present invention is equal to or less than 8.5.
- the pH of the composition of the present invention is equal to or less than 7.5.
- the pH of the composition of the present invention is equal to or less than 7.
- the pH of the composition of the present invention is equal to or less than 6.5.
- composition of the present invention can be used as an additive with moisturizing effect in an external preparation for skin.
- composition of the present invention can be used in cosmetics as an additive with moisturizing effect.
- the cosmetic is selected from the group consisting of: facial cleanser, lotion, lotion, cream, gel, and facial mask. Different dosages are added according to different types of preparations.
- an external preparation for skin with moisturizing effect comprising the composition of the present invention prepared according to the method of the present invention and an excipient acceptable in the cosmetic field.
- the external preparation for skin is a general concept of all ingredients generally used on the outside of the skin, and may be, for example, a cosmetic composition.
- the cosmetic composition can be basic cosmetic, facial cosmetic, body cosmetic, hair care cosmetic, etc.
- the dosage form thereof is not particularly limited, and can be reasonably selected according to different purposes.
- the cosmetic composition also contains different medium or base excipients that are permitted in cosmetic aspects according to different dosage forms and purposes.
- the composition of the present invention may be used in an amount of 0.001-20% by weight in the external preparation for skin.
- the preferred weight percent is 0.01-20 wt%.
- a more preferred weight percent is 0.01-10 wt%.
- a more preferred weight percent is 0.1-5 wt%.
- the dosage of the composition of the present invention in the external preparation for skin may be 0.001-10% by weight, 0.002-10% by weight, 0.003-10% by weight, 0.01-10% by weight, 0.02- 10% by weight, 0.03-10% by weight, 0.1-10% by weight, 0.2-10% by weight, 0.3-10% by weight.
- the dosage of the composition of the present invention in the external preparation for skin may be 0.001-1% by weight, such as 0.002-1% by weight, 0.003-1% by weight, 0.01-1% by weight, 0.02% by weight - 1% by weight, 0.03-1% by weight, 0.1-1% by weight, 0.2-1% by weight, 0.3-1% by weight.
- the product can be applied to the skin of the user in any desired manner.
- the product can be applied directly by hand, or the product can be applied using a device such as a cotton pad or other implement.
- the composition is advantageously applied to the skin in order to facilitate sample absorption.
- the composition can be left on the applied area for a desired level of time, such as about 5 seconds to about 5 minutes. Alternatively, the composition can be left on the applied area and applied continuously until absorbed.
- Triethyl citrate purchased from Shanghai Gaowei Industrial Co., Ltd.;
- Glycine purchased from Xilong Science Co., Ltd.;
- Glutamate purchased from Sinopharm Group Shanghai Reagent Co., Ltd.;
- Potassium dihydrogen phosphate purchased from Sinopharm Group Shanghai Reagent Co., Ltd.;
- Citric acid purchased from Hunan Dongting Citric Acid Chemical Co., Ltd.;
- PCA-Cu Sodium copper pyrrolidone carboxylate
- Zinc sulfate purchased from Merck Chemical Technology (Shanghai) Co., Ltd.;
- Zinc oxide purchased from Merck Chemical Technology (Shanghai) Co., Ltd.;
- Hydroxyethylurea (50% aqueous solution), purchased from Shanghai Gaowei Industrial Co., Ltd.;
- 26# white oil purchased from Zhejiang Xinzhengyuan Technology Co., Ltd.;
- Methylparaben purchased from UENO Chemical Industry Co., Ltd.;
- Glycerol purchased from Tyco Brown (Zhangjiagang) Co., Ltd.;
- Distearyl dimethyl ammonium chloride purchased from Witco Co., Ltd.;
- Ethylhexyl Palmitate purchased from Palm Oil (Klang) Sdn Bhd.
- pH meter Model SevenMulti from Mettler Toledo
- Moisture content tester Cornemeter CM825
- the dosage unit of each component in the above embodiment is g.
- Example 1-Example 4 urea background, using triethyl citrate or glycine alone, and comparing the use effect of triethyl citrate and glycine after compounding.
- Example 4-Example 7 Comparison of glycine and other amino acids, and the use effect of common buffer potassium dihydrogen phosphate.
- Example 8-Example 17 Effects of different ratios of triethyl citrate and glycine on the pH value of aqueous urea solution.
- Example 18-Example 22 The contents of triethyl citrate and glycine were fixed, and the effects of electrolytes, excessive metal ions, and solid powders on the pH value of the urea aqueous solution were investigated.
- Example 19 which was dark blue due to the addition of copper salt, and Examples 21 and 22 which were suspensions due to the addition of a water-insoluble powder.
- the pH of the vast majority of samples is between 4.0 and 7 after preparation, and no pH adjustment is required after preparation.
- the pH value was higher than 6.5 due to the addition of an alkaline component, and the pH value was adjusted by adding citric acid.
- the pH value of the solution was 11.21, and after adding citric acid, the pH value was 5.67; after the preparation of Example 21, the pH value was 7.23, and a small amount of citric acid was added to adjust the pH value to 5.80.
- Table 4 shows the pH value of the samples of each embodiment at 48° C. for different times and the changes in the properties of the samples.
- Table 4 lists the pH values of each example after being placed at 48°C for different times. It is necessary to point out that the hydrolysis of urea will bring two problems to the use of cosmetics: First, the risk of laws and regulations, the allowable range of the pH value of cosmetics such as water preparations, lotions and creams by national regulations is 4.0-8.5. between. Second, the consumer's use experience, it is conceivable that if the sample overflows with ammonia smell, it will seriously affect the consumer's use experience. According to the results of this experiment, if the pH value of the sample is above 7.5, the smell of ammonia can generally be smelled.
- Example 1 After the 5% urea aqueous solution (Example 1) was placed at 48° C. for 15 days, the pH reached 9.08, and there was a serious overflow of ammonia odor. After that, with the increase of heating time, the pH of the sample still increased slightly, and the pH of the sample reached 9.44 after the stability test in March. After the addition of 0.5% triethyl citrate (Example 2) or 5% glycine (Example 3) to the aqueous urea solution, the tendency to increase the pH of the aqueous urea solution was significantly suppressed.
- 0.5% triethyl citrate Example 2
- 5% glycine Example 3
- the pH values of the above two samples were respectively 8.80 and 7.70 after being heated at 48°C for 3 months, and the pH values of the samples at each time point were lower than the pH value of the urea aqueous solution. It can be seen that the use of triethyl citrate and glycine compound can play a better role in stabilizing the pH value of the urea aqueous solution. However, after the above two samples were placed at 48°C for March, the pH value of the aqueous solution still increased significantly. After the stability test was completed, the smell of ammonia could be smelled, which still could not fully meet the needs of cosmetic use.
- Examples 4-7 compare the pH stabilizing ability of glycine, glutamic acid, arginine and KH 2 PO 4 on aqueous urea solutions. After being placed at 48°C for 3 months, the pH values of the four samples were 6.18, 8.04, 7.69 and 8.12 in turn. Except for the pH stability effect of Example 5 to Example 7, the pH stability effect was not as good as that of Example 4. After that, the smell of ammonia can be smelled. According to the above comparative test, the stability of glycine to urea aqueous solution is better than that of glutamic acid, arginine and KH 2 PO 4 .
- Example 8-Example 10 investigated the stabilizing ability of the amount of triethyl citrate on the aqueous urea solution.
- the pH values were 8.80, 7.95, 6.81 and 6.29 after being placed at 48°C for 3 months. It can be seen that with the increase of the mass ratio of triethyl citrate to urea, the pH stability of the sample is better. However, high concentrations of triethyl citrate can cause color changes after prolonged heating.
- Example 8 (triethyl citrate content of 1%) was heated at 48°C for 3 months, and the solution was slightly brown to the naked eye.
- Example 11 On the basis of Example 3, the amount of triethyl citrate was increased from 0.5% to 1% , after 3 months of heat placement, the pH values of the two samples were 5.95 and 6.18, respectively.
- Example 4 (0.5% triethyl citrate + 5% glycine) and Example 10 (5% triethyl citrate) have similar pH stability to the urea aqueous solution.
- Example 4 circumvents the risk of possible thermal instability of a high concentration aqueous solution of triethyl citrate.
- the cost of glycine is much lower than that of triethyl citrate, the cost of Example 4 is only about 40% of that of Example 10.
- Example 4 shows a good ability to stabilize the pH aqueous solution, and there is still a large redundancy for the application in cosmetics. If the content of triethyl citrate and glycine can be reduced on the basis of meeting cosmetic application standards, not only can the cost be reduced, but also the impact on the bearing capacity of the emulsion system can be reduced. Examples 12-17 examine the stability of samples with lower triethyl citrate and glycine content to the pH of aqueous urea.
- Example 14 When the fixed triethyl citrate content is 0.5%, the glycine content is 5% (Example 4), 2.5% (Example 12), 1% (Example 13) and 0.5% (Example 14) The samples were placed at 48°C The pH values after 3 months were 6.18, 6.73, 7.40 and 8.25. Except for Example 14, the other three-point samples did not smell ammonia overflow after the three-month stability test.
- Example 18-Example 22 investigated the effects of electrolytes, transition metal ions and solid powders that may have catalytic properties on the urea stabilization system. After being placed at 48°C for 3 months, on the basis of Example 4, 2% sodium chloride (Example 18), PCA-Cu (Example 19), zinc sulfate (Example 20), and zinc oxide powder (Example 19) were added 21) and the silica powder (Example 22) samples had pH values of 5.90, 6.05, 6.01, 6.42 and 6.09, respectively.
- Table 5 shows the water content of the stratum corneum (mean ⁇ SD, A.U.) for each sample at different times.
- Table 6 shows the difference in water content of the stratum corneum (test time point data-basic value) for each sample at different times of quality inspection (mean ⁇ SD, A.U.).
- the blank area has only a slight change from the base value at each time test point.
- the urea aqueous solution Example 1
- the skin water content at each time point decreased to a certain extent compared with the basic value, but it was not statistically significant.
- the glycine aqueous solution was applied, the water content of the skin surface decreased significantly compared with the basic value at each test point, and it was statistically significant.
- urea and glycine are generally considered to have moisturizing properties, our experimental results show that the ideal moisturizing effect cannot be achieved simply by applying their aqueous solutions. The reason for this phenomenon may be the precipitation of urea and glycine crystals. After the sample is coated and the water evaporates, fine crystals can be observed on the skin surface. The precipitation of crystals affects its penetration and absorption by the skin. interferes with the test value.
- Example 3 After compounding urea and triethyl citrate (Example 3), the moisturizing efficiency of the sample was significantly improved compared with the urea aqueous solution. At the test points of 1h, 4h and 6h, the skin surface water content increased by 6.00, 4.10 and 4.86 respectively compared to the base value, and the first point had a statistical difference compared with the blank sample.
- Example 4 in which urea, triethyl citrate, and glycine were compounded in a mass ratio of 10:1:10 only slightly increased the epidermal water content at several test time points, which was not statistically significant.
- phase A raw materials into a 1000mL glass beaker according to the amount shown in Table 7, seal it with plastic wrap, and preheat in a 90°C water bath for 30min.
- phase B raw materials into a 500mL glass beaker according to the amount shown in Table 7, seal with plastic wrap, and preheat in a 90°C water bath for 30min.
- phase A After the preheating of phase A is completed, take it out from the water bath, and homogenize it at a speed of 5000rpm for 2min, until the material is uniform. After that, in the homogeneous stirring at 5000 rpm, slowly add the B phase to the A phase (the addition is completed in 1 min), and continue to keep the 5000 rpm homogenization for 2 minutes after the addition is completed until the material is uniform. After homogenization, the beaker was sealed with plastic wrap for use.
- Example 23 After the preform used in Example 23 was cooled to about 50° C., 134.25 g of the preform was weighed in a 250 ml glass beaker, and the corresponding raw materials were added according to Table 8. After that, the sample was homogenized at a speed of 5000 rpm for 2 min to make the material evenly mixed. The prepared sample was transferred to 150 ml of PET with a transparent lid, and the pH value was measured overnight and its properties were observed.
- the quality of the creams prepared in Examples 24-28 are all 150g, and Example 24 is a base material as a comparison without adding additives such as urea.
- Example 25-28 the content of urea in the prepared cream is 5%.
- triethyl citrate with a mass fraction of 0.5% was added, while in Examples 27 and 28, 0.5% triethyl citrate was added. 5% glycine by mass.
- Table 9 shows the properties and pH values of Examples 24-28 at various time points in the high temperature stability test.
- Example 24 appeared as a white soft cream (viscosity from 8000mPa ⁇ s to 20000mPa ⁇ s), and remained stable in the three-month high-temperature stability test, regardless of its properties or pH value.
- the sample (Example 25) added with 5% urea on the basis of the matrix formulation has no significant difference in performance of the new sample with the matrix formulation.
- the pH value of the feed rose to 9.00 in only 15 days, and then increased further with time, rising to 9.26 after the stability test in March.
- the feed began to emit ammonia odor, and it continued to intensify over time.
- the sample (Example 26) added with 5% urea and 0.5% triethyl citrate on the basis of the matrix formula has no significant difference between the new sample and the basic formula, but in the time-dependent stability test, its pH showed obvious There is an upward trend. After the stability test in March, the pH value of the material body rose to 8.92, and there was a clear ammonia smell. The sample showed demulsification and delamination after the high temperature and time stability test in March, which did not meet the relevant requirements of the national cosmetics regulations. In addition, in the high temperature elapsed time test, the thickening of the material body is serious, and it is a white cream in the stability observation in January, and a thick white cream (viscosity) in the stability observation in two and three months.
- the new sample has no significant difference with the basic formula, but in the stability test over time, its pH performance It first decreased and then increased (the pH decrease in the first 15 days may be due to the reconstitution of cationic micelles), and the final pH value was 6.21, which was far from the national cosmetics regulations, and could not detect the smell of ammonia, which satisfied consumers.
- Demand for cosmetic use Although the viscosity of its material body has increased slightly, changing from white ointment to white cream, the rising trend of viscosity is not likely to lead to product quality problems, and the range of change is limited, and cream products are not easily perceived by consumers.
- Table 11 lists the pH values of each example after being placed at 48°C for different times. Because the pH value of the hydroxyethyl urea raw material is relatively high, the pH values after the configuration of Examples 29 and 30 are 8.49 and 7.09, respectively. Therefore, citric acid is added to adjust the pH value, and the initial pH value of the above two embodiments after adjustment is 6.05 respectively. and 5.29 (a small addition of citric acid greatly changes the pH of the sample). However, the initial pH values of Examples 31 and 32 were below 7, so the pH values were not adjusted before being placed at high temperature.
- the pH of the 5% hydroxyethyl urea aqueous solution (Example 29) increased significantly in the high temperature and time stability test, rising to 8.61 in 15 days, and reaching 9.19 after the stability test in March, exceeding the standard permitted by the national cosmetic regulations , and can smell ammonia from 60 days.
- Adding 0.5% triethyl citrate (Example 30) or 5% glycine (Example 31) alone the pH was 7.76 and 8.02 after the three-menstrual stability test, respectively. Although the regulatory standards were met, the pH changed significantly. Affect the properties of the material or the stability of additives.
- phase A raw materials into a 1000mL glass beaker according to the amount shown in Table 12, seal it with plastic wrap, and preheat in a 90°C water bath for 30min.
- phase B raw materials into a 500mL glass beaker according to the amount shown in Table 5, seal it with plastic wrap, and preheat in a 90°C water bath for 30min.
- phase A After the preheating of phase A is completed, take it out from the water bath, and homogenize it at a speed of 5000rpm for 2min, until the material is uniform. After that, in the homogeneous stirring at 5000 rpm, slowly add the B phase to the A phase (the addition is completed in 1 min), and continue to keep the 5000 rpm homogenization for 2 minutes after the addition is completed until the material is uniform. After homogenization, the beaker was sealed with plastic wrap for use.
- Example 33 After the preform used in Example 33 was cooled to about 50° C., 126.75 g of the preform used in Example 33 was weighed in a 250 ml glass beaker, and the corresponding raw materials were added according to Table 13. After that, the sample was homogenized at a speed of 5000 rpm for 2 min to make the material evenly mixed. The prepared sample was transferred to 150 ml of PET with a transparent lid, and the pH value was measured overnight and its properties were observed. The quality of the creams prepared in Examples 34-37 are all 150 g, and the theoretical content of hydroxyethyl urea is 5%. In addition, 0.5% by mass of triethyl citrate was added in Examples 35 and 37, while 5% by mass of glycine was added in Examples 36 and 37.
- Example 34 35 36 37 Hydroxyethylurea (50%) 15 15 15 15 15 Triethyl citrate 0 0.75 0 0.75 Glycine 0 0 7.5 7.5 Deionized water 8.25 7.5 0.75 0
- Table 14 shows the properties and pH values of Examples 34-37 at various time points in the high temperature stability test (adding the test data of Example 24 as a comparison).
- Example 34 The stability test results of Examples 34-37 and blank Example 24 are shown in Table 12.
- the matrix formulation (Example 24) performed well in the high temperature and time stability test, and its pH value and properties did not change significantly.
- the 5% hydroxyethyl urea sample (Example 34) was added to the matrix formulation, and its initial pH was increased (from 4.55 to 6.33) compared to the matrix formulation.
- the pH value has increased significantly.
- the pH value reached 8.78, and the smell of ammonia can be smelled, which cannot meet the requirements of regulations and consumers for cosmetics.
- the sample of adding 5% hydroxyethyl urea and 0.5% triethyl citrate (Example 35)
- the pH value of the freshly prepared sample increased to 6.22
- the pH value of the material body increased after the three-month stability test to 7.21.
- the viscosity of this sample increased significantly in the stability test. After the stability test in March, the viscosity of the material increased by about 230% (33250 mPa ⁇ s), and it changed from a white ointment to a white cream since February.
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Abstract
本发明提供了一种包含柠檬酸三乙酯和甘氨酸的稳定组合物，所述组合物为水性溶液，所述水性溶液还包含水解产生氨的活性剂，其中，所述活性剂与柠檬酸三乙酯的重量比为1:1至100:1，所述活性剂与甘氨酸的重量比为1:1至10:1。本发明还涉及稳定化包含水解产生氨的活性剂的水性溶液的方法以及稳定组合物在皮肤外用剂中的应用。
Description
本发明涉及化妆品领域，具体涉及在水解产生氨的水性溶液中实现稳定化作用的包含柠檬酸三乙酯和甘氨酸的稳定组合物以及稳定技术。
尿素是一种很好用的保湿成分，它就存在于肌肤的角质层当中，属于肌肤天然保湿因子NMF的主要成分。对肌肤来说，尿素具有保湿以及柔软角质的功效。尿素是皮肤中的天然保湿因子之一，其保湿，软化肌肤，促进经皮渗透等功效已被文献广泛报道。
文献“仪器和皮肤科医生评估甘油和尿素对特应性皮炎患者干性皮肤的影响”(《皮肤研究和技术》，Lodén M.,等)报道了使用含有4％尿素的保湿霜30天后，35位受试者的皮肤电容值平均值从35A.U.上升到了42A.U.(皮肤表层含水量越高，电容值越高)、表皮水分流失量平均值从约11g/(m
2·h)下降到约8,5g/(m
2·h)，干燥度总分平均值自3.2下降至0.8，以上实验结果均显著优于未添加尿素的对照组且具有统计学差异，证明了尿素保湿、柔肤、强韧肌肤屏障的功效。
文献“尿素对人表皮、皮肤的影响”(Hellgren等)报道了将干燥后的表皮浸没于10％尿素溶液中，90h基本达到平衡后表皮吸水量接近初始质量的300％，吸水量约等于浸没于蒸馏水中样品的3倍。干燥皮肤吸水量的增加，来自于尿素水溶液提高了表皮的渗透性。
文献“透皮促渗剂对两种锌盐经皮渗透新的影响”(Science Technology and Engineering，2016；16:1671-1815陈传秀，金青，谭然然课题组)研究了尿素对共轭亚油酸锌及葡萄糖酸锌的影响，结果发现，在料体中加入2％尿素，共轭亚油酸锌的单位时间累积渗透量由188.23μg/cm
2上升到了388.04μg/cm
2，葡萄糖酸锌的单位时间累积渗透量由682.26μg/cm
2上升到了 1020.49μg/cm
2，且随着尿素含量的提升渗透速率仍有进一步的提高。
近年来的研究表明，尿素还可通过调控基因表达，达到提高皮肤屏障和抗菌的作用。例如，文献“尿素摄取通过调节表皮基因表达增强人体屏障功能和抗菌防御”(皮肤病研究杂志Susanne G.-B.,(2012)132,1561–1572)报道了尿素可提高与皮肤屏障相关基因AMP、LL-37及β-防卫素-2的表达，并对尿素的作用机理进行了详细的研究。根据研究结果，作者认为并非只是机体代谢产物，而作为一种小分子调节剂，具有修饰皮肤屏障相关基因表达的效果。此外，《尿素和皮肤：一个著名的分子重访》公开了尿素还可以作为药品，应用于牛皮鲜、过敏性皮炎、湿疹、溢脂性皮炎等皮肤疾病的治疗。
但是，尿素水溶液并不稳定，会发生水解反应生成氨，导致其水溶液pH值的上升。而且，随着温度的提高，尿素水解的速度亦相应增加。对于这种现象学术界有大量的理论研究(例如参见，陈侠，白凤霞，庞腾等，ADC废水中尿素的水解动力学研究[J]，天津科技大学学报，2019(1)，doi:10.13364/j.issn.1672-6510.20170111)，并且应用于制氨及相应的生产应用中(例如参见，花立存，吴春华，马文杰等，两种尿素水解制氨技术理论分析及应用对比[J]，热力发电，2019，48(11)，doi:
10.19666/j.rlfd.201903056)。但是，在化妆品应用中，尿素的水解会导致料体pH升高并且释放氨味，造成化妆品无法满足国家法规标准(pH＜8.5)，并且造成消费者使用的不适。例如，在本发明测试例1中的实验中，5％尿素水溶液48℃放置7天，其pH值从6.69上升至9.08，并且可闻到明显的氨味。因此，尿素的不稳定性严重限制了其在化妆品中的应用。
本发明意外的发现，在含有尿素等活性剂的水溶液中，联合使用柠檬酸三乙酯和甘氨酸能够明显抑制尿素等活性剂的水解，提高含尿素等活性剂的水溶液的稳定性，尤其是pH稳定性。因此，本发明首次将柠檬酸三乙酯和甘氨酸组合使用，提供了一种新的、稳定性更好的含有尿素等具有保湿作用的活性剂的组合物，其也可以加入皮肤外用剂中实现保湿效果。
发明内容
一方面，本发明提供了包含柠檬酸三乙酯和甘氨酸的稳定组合物，所述组合物为水性溶液，所述水性溶液还包含水解产生氨的活性剂，其中，所述活性剂与柠檬酸三乙酯的重量比为1:1至100:1，所述活性剂与甘氨酸的重量比为1:1至10:1。
在优选的实施方式中，本发明组合物中的活性剂选自：尿素、羟乙基脲或它们的组合。
在优选的实施方式中，本发明组合物中所述活性剂与柠檬酸三乙酯的重量比为1:1至10:1。
在优选的实施方式中，本发明组合物中活性剂与甘氨酸的重量比为1:1。
在优选的实施方式中，本发明组合物的含水量至少为15重量％。
在优选的实施方式中，本发明组合物还包含电解质、过渡金属离子、固体粉末或它们的组合。
在优选的实施方式中，本发明组合物的pH保持低于8.5。
另一方面，本发明还提供了稳定化包含水解产生氨的活性剂的水性溶液的方法，所述方法包括组合使用柠檬酸三乙酯和甘氨酸，其中，所述活性剂与柠檬酸三乙酯的重量比为1:1至100:1，所述活性剂与甘氨酸的重量比为1:1至10:1。
又一方面，本发明还涉及所述组合物在皮肤外用剂中的应用。
在优选的实施方式中，皮肤外用剂选自：洁面乳、化妆水、乳液、膏霜、面膜。
发明详述
本发明首次发现将柠檬酸三乙酯和甘氨酸组合使用，能够提供一种稳定性更好的含有尿素等活性剂的组合物。本发明的组合物中尿素等活性剂的水解得到显著的抑制，有利于保持组合物的稳定性，尤其是pH稳定性。
本发明意外地发现，将柠檬酸三乙酯和甘氨酸复配后使用，不仅可以降低柠檬酸三乙酯的用量，而且在改善pH值稳定性之余，还可降低与高浓度的柠檬酸三乙酯的使用相关的不良反应的风险。因此，本发明也涉及一 种稳定化方法，该方法包括联合使用柠檬酸三乙酯和甘氨酸的稳定体系，用于稳定在水溶液中易于发生水解产生氨的组合物。
此外，本发明还提供了一种新的、具有更佳效果的稳定体系，尤其适用于在水溶液中易于发生水解产生氨的组合物。采用本发明的稳定系统得到组合物能够保留活性剂的功能，例如保湿功能。例如，在采用尿素作为活性剂的实施方式中，采用本发明的稳定体系能够实现较高的保湿性能，而单独使用尿素或甘氨酸并未表现出阳性的保湿结果。
为了提供更简明的描述，本文给出的一些数量表述没有用术语“约”修饰。应当理解，无论是否明确地使用了术语“约”，本文所给出的每个量都意在指代实际的给定值，并且还意在指代由本领域的普通技术人员可合理推测出的这些给定值的近似值，包括这些给定值的由实验和/或测量条件所引起的近似值。
为了提供更简洁的描述，本文中一些数量表述被叙述为约X量至约Y量的范围。应当理解，当叙述范围时，该范围并不限制于所叙述的上下界限，而应包括约X量至约Y量的整个范围或它们之间的任何量。
活性剂
本发明的组合物中包含活性剂，例如具有保湿功效的活性剂。在一些优选的实施方式中，本发明的组合物中的活性剂在储存条件下容易发生水解。在一些更优选的实施方式中，本发明的组合物中的活性剂在储存条件下容易发生水解生成氨。例如，在一个具体的实施方式中，本发明的组合物中使用的活性剂是尿素或其衍生物。
尿素是一种很好用的保湿成分，它就存在于肌肤的角质层当中，属于肌肤天然保湿因子NMF的主要成分。对肌肤来说，尿素具有保湿以及柔软角质的功效，所以也能够防止角质层阻塞毛细孔，藉此改善粉刺的问题。尿素常用于面膜、护肤水、膏霜、护手霜等产品中用作保湿成份。
羟乙基尿素作为尿素的羟乙基衍生物，是一种全新的，具有突出优势的保湿剂。与传统的保湿剂相比，羟乙基尿素具有更显著的保湿效果，滑爽的涂敷感觉，在护肤产品中不发粘、不油腻、滋润的舒适感觉，以及自 身非离子性带来的极广泛的适用性。而且与昂贵的保湿剂相比，羟乙基尿素能够以更低的配方成本，来达到相同的效果；即使在以甘油、丙二醇为主的基础配方中，羟乙基尿素也可以通过减少其他影响膏霜外观的组份的用量(如硅油)，来达到更佳的保湿效果，更滑爽的涂布感觉，相同甚至更低的配方成本。即使在极端条件，6％相对湿度的情况下，羟乙基尿素也能通过和皮肤角质层形成液晶相，阻止角质层向固体晶相转化，来达到使皮肤柔软的目的。
由于尿素及其衍生物(例如，羟乙基尿素)具有出色的保湿效果和肤感，而且对皮肤和眼睛是安全的，所以它可以被广泛的应用于：护肤品，各种膏霜和乳液；精华液及各种透明产品；沐浴产品；防晒产品；彩妆；脱毛、除臭产品；发用品，例如香波、护发素、头发定型产品、染发产品、者哩水等。
然而，这种活性剂(例如，尿素或其衍生物)的水溶液常常不稳定，容易发生水解而产生氨，导致其水溶液pH值的上升。而且，随着温度的提高，活性剂的水解速度亦相应增加。
本发明首次将柠檬酸三乙酯和甘氨酸进行组合，可以显著抑制活性剂(例如，尿素或其衍生物)的水解，提高产品的稳定性。相对于单纯的活性剂(例如，尿素或其衍生物)的水溶液而言，这种复配的组合物能够保持稳定，保留活性剂的保湿功效。
在本发明的一些实施方式中，组合物包含1-20重量％的活性剂(例如，尿素或其衍生物)。在本发明的一些实施方式中，组合物包含1-10重量％的活性剂(例如，尿素或其衍生物)。在本发明的一些实施方式中，组合物包含5-10重量％的活性剂(例如，尿素或其衍生物)。
柠檬酸三乙酯
柠檬酸三乙酯，化学名称是2-羟基-1,2,3-丙三羧酸三乙酯。柠檬酸三乙酯是一种具有果香的无色液体，在水溶液中具有一定的溶解度。柠檬酸三乙酯具有抗氧化性能，在化妆品中可以用作油脂的稳定剂。此外，因其挥发持久且较缓慢，作为定香剂在化妆品中有广泛应用(例如参见，食用 香精中定香剂的筛选与研究，艾斌，CNKI:CDMD:2.1017.800868)。
柠檬酸三乙酯在水溶液中可缓慢水解生成柠檬酸使其水溶液pH值逐渐降低，因此可以预期，将其与尿素等水解释放氨的活性剂复配，可以抑制活性剂水溶液pH值的上升。
使用柠檬酸三乙酯作为尿素的pH稳定剂已见诸报道。例如，李银汉等(一种长效保湿组合物及其应用，CN109602638A)报道了将尿素同柠檬酸三乙酯、聚丙烯酸增稠剂以及卡波姆复配，部分样品在40℃放置1月后表现出较好的稳定性。然而该尿素复配体系在化妆品应用中仍有诸多局限性。首先，其稳定性测试周期为40℃放置1个月，低于国家化妆品检验法规40℃放置3个月的标准。其次，复配体系的pH稳定性能有限，实施例中大多数样品在低于国家标准的测试条件下依然出现明显的稳定性问题。再次，随着尿素分解导致料体的pH和电导率变化，添加的增稠剂的粘度也会出现明显变化导致料体的性质发生改变。究其原因，在于单独使用柠檬酸三乙酯与尿素复配，其对尿素水溶液pH值缓冲能力有限。如需使尿素水溶液pH值满足化妆品使用的标准，需较大使用量，届时会进一步产生成本高昂、料体变色(详见测试例1)，以及化妆品安全性风险。因此，本领域仍然需要开发更高效、更稳定、成本更低廉的稳定体系，该稳定体系尤其适用于在储存条件下容易发生水解生成氨的活性剂，例如尿素及其衍生物。
本发明意外地发现，将柠檬酸三乙酯和甘氨酸进行组合，可以实现协同的稳定作用。相对于单纯的柠檬酸三乙酯，两者复配得到的体系能够更好地稳定容易发生水解产生氨的溶液，例如包含尿素或其衍生物的水溶液。
在本发明的一些实施方式中，本发明组合物包含0.1-10重量％的柠檬酸三乙酯。在本发明的一些实施方式中，组合物包含0.1-5重量％的柠檬酸三乙酯。在本发明的一些实施方式中，组合物包含0.1-1重量％的柠檬酸三乙酯。在本发明的一个具体的实施方式中，组合物包含0.5重量％的柠檬酸三乙酯。
在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与柠檬酸三乙酯的重量比为1:1至100:1。在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与柠檬酸三乙酯的重量比为 1:1至50:1。在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与柠檬酸三乙酯的重量比为1:1至20:1。在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与柠檬酸三乙酯的重量比为1:1至10:1。在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与柠檬酸三乙酯的重量比为10:1至20:1。
甘氨酸
甘氨酸是二十种常见氨基酸之一，室温下呈现为无味的白色晶体，在水溶液中有着良好的溶解性。在人体中，甘氨酸可以有葡萄糖转化而来，是组成蛋白质的二十种基础氨基酸之一(例如参见，“包含牛磺酸、精氨酸、甘氨酸的个人护理组合物”，CN108430587A)。
甘氨酸在食品、医药、农业中具有广泛的应用，同时也作为多种化工原料或医药的原料和中间体，如头孢菌素的原料，甲砜霉素中间体，合成咪唑乙酸中间体等(例如参见，“添加剂条件下的甘氨酸结晶过程研究及分子模拟”，王禄)。对皮肤护理而言，甘氨酸可以作为皮肤调理剂，可改善皮肤调理能力(例如参见，《化妆品原料手册》，李东光)，在化妆品工业中具有良好的应用前景。本发明中利用甘氨酸的酸碱调节能力，维持尿素水溶液的pH值。
本发明意外地发现，将柠檬酸三乙酯和甘氨酸进行组合，可以实现协同的稳定作用。例如，本发明意外地发现，将柠檬酸三乙酯和甘氨酸复配后使用，尿素水溶液的pH值稳定性有了极大地提高，且改善的效果优于单独使用柠檬酸三乙酯或甘氨酸。甘氨酸的引入可降低柠檬酸三乙酯的用量，改善pH值稳定性之余，亦可降低产生不良反应的风险以及降低产品成本。
此外，尿素-柠檬酸三乙酯-甘氨酸复配体系表现出较好的保湿性能，而单独使用尿素或甘氨酸并未表现出阳性的保湿结果，可见原料间产生了良性的相互作用。因此，本发明为护肤品和皮肤医药品提供了新的、具有更佳效果的添加剂的组合，为尿素在护肤品中的安全应用提供了技术支持。
在本发明的一些实施方式中，本发明组合物包含1-20重量％的甘氨酸。在本发明的一些实施方式中，组合物包含1-10重量％的甘氨酸。在本发明 的一些实施方式中，组合物包含1-5重量％的甘氨酸。
在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与甘氨酸的重量比为1:1至10:1。在本发明的一些实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与甘氨酸的重量比为1:1至5:1。在本发明一个具体的实施方式中，本发明组合物中活性剂(例如尿素或其衍生物)与甘氨酸的重量比为1:1。
其他成分
本发明的组合物还可包含其他成分。例如，本发明的组合物还可以包含可能具有催化性能的电解质、过渡金属离子及固体粉末等。在一些实施方式中，本发明的组合物还包含甘氨酸、氯化钠、PCA-Cu、硫酸锌、氧化锌、二氧化硅或它们的组合。
例如，在本发明的测试例中，在存在电解质、过渡金属粒子或固体界面的条件下，组合使用柠檬酸三乙酯和甘氨酸作为含有尿素等活性剂的组合物的稳定体系具有良好的表现，例如水溶液pH稳定且符合要求。这些测试例也进一步说明了本发明的稳定体系具有广泛的适用性。因此，本发明的组合物中可以包含化妆品领域可接受的各种成分。
水性溶液
本发明主要涉及针对水性溶液的稳定化作用。因此，本发明组合物还可包含水或其它含水载体。
在优选的实施方式中，本发明组合物中水的重量比至少为15％。在本发明的一些实施方式中，组合物的含水量为15-90重量％。在本发明的一些实施方式中，组合物的含水量为15-80重量％。在本发明的一些实施方式中，组合物的含水量为15-70重量％。在其它优选的实施方式中，本发明组合物中水的重量比至少为20％。在本发明的一些实施方式中，组合物的含水量为20-90重量％。在本发明的一些实施方式中，组合物的含水量为20-80重量％。在其它优选的实施方式中，本发明组合物中水的重量比至少为25％。在本发明的一些实施方式中，组合物的含水量为25-90重量％。在本发明的一些实施方式中，组 合物的含水量为25-80重量％。在其它优选的实施方式中，本发明组合物中水的重量比至少为50％。
本发明的组合物的pH符合国家法律法规的规定。在一些实施方式中，本发明的组合物的pH为4.0-8.5。在优选的实施方式中，本发明的组合物的pH等于或小于8.5。在优选的实施方式中，本发明的组合物的pH等于或小于7.5。在更优选的实施方式中，本发明的组合物的pH等于或小于7。在更优选的实施方式中，本发明的组合物的pH等于或小于6.5。
皮肤外用剂
本发明的组合物可以作为具有保湿功效的添加剂应用于皮肤外用剂中。在一个具体的实施方式中，本发明的组合物可以作为具有保湿功效的添加剂应用于化妆品中。在一个具体的实施方式中，所述化妆品选自：洁面乳、化妆水、乳液、膏霜、啫喱、面膜。根据制剂的不同类型添加不同的用量。
在本发明的另一方面，提供了一种具有保湿功效的皮肤外用剂，所述皮肤外用剂包含按照本发明方法制备得到的本发明组合物及化妆品领域可接受的赋形剂。
所述皮肤外用剂是通常用于皮肤外部的所有成分的统称概念，例如可以是化妆品组合物。所述化妆品组合物中可以是基础化妆品、面部妆容化妆品、身体用化妆品、头发护理用化妆品等，对其剂型无特殊限制，根据不同目的可合理选择。
所述化妆品组合物中根据剂型和目的的不同还含有不同的化妆品学层面允许的介质或基质赋形剂。
在一些优选的实施方式中，所述皮肤外用剂中本发明组合物的用量可以是0.001-20重量％。优选的重量百分比为0.01-20重量％。更优选的重量百分比为0.01-10重量％。更优选的重量百分比为0.1-5重量％。在本发明一些优选的实施方式中，所述皮肤外用剂中本发明组合物的用量可以是0.001-10重量％，0.002-10重量％，0.003-10重量％，0.01-10重量％，0.02-10重量％，0.03-10重量％，0.1-10重量％，0.2-10重量％，0.3-10重量％。在本发明一些优选的实 施方式中，所述皮肤外用剂中本发明组合物的用量可以是0.001-1重量％，例如0.002-1重量％，0.003-1重量％，0.01-1重量％，0.02-1重量％，0.03-1重量％，0.1-1重量％，0.2-1重量％，0.3-1重量％。
使用方法
可以任何期望的方式将产品施用到使用者的皮肤。在一些方面，产品可用手直接涂抹，或者可使用装置诸如化妆棉或其它工具来施用产品。将组合物有利地施用到皮肤，以便有助于样品吸收。可将组合物留在施用的区域上持续期望的时间水平，诸如约5秒至约5分钟。或者，可将组合物留在施用的区域上并持续涂抹直至吸收。
下面结合具体实施例，以进一步阐述本发明。有必要在此指出的是，实施例只用于对本发明进行进一步的说明，不能理解为对本发明保护范围的限制，该领域的技术熟练人员可以根据上述本发明的内容做出一些非本质的改进和调整。下列实施例中未注明具体条件的试验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另有说明，所有的百分比和份数按重量计。
实验材料
尿素，购自国药集团上海试剂有限公司；
柠檬酸三乙酯，购自上海高维实业有限公司；
甘氨酸，购自西陇科学股份有限公司；
谷氨酸，购自国药集团上海试剂有限公司；
精氨酸，购自上海汇朗化学有限公司；
磷酸二氢钾，购自国药集团上海试剂有限公司；
柠檬酸，购自湖南洞庭柠檬酸化学有限公司；
氯化钠，购自中盐东兴盐化股份有限公司；
吡咯烷酮羧酸钠铜(PCA-Cu)，购自法国仙婷创新实验室；
硫酸锌，购自购自默克化工技术(上海)有限公司；
氧化锌，购自默克化工技术(上海)有限公司；
二氧化硅(H53)，购自科丝发(上海)贸易有限公司；
羟乙基脲(50％水溶液)，购自上海高维实业有限公司；
26#白油，购自浙江新正源科技有限公司；
羟苯甲酯，购自UENO化学工业有限公司；
甘油，购自泰柯棕化(张家港)有限公司；
二硬脂基二甲基氯化铵，购自美国威科(Witco)有限公司；
棕榈酸乙基己酯，购自棕榈油(巴生)私人有限公司。
实验仪器
称量天平：METTLER TOLEDO公司PB4002-N型
48℃烘箱：MMM公司MMM707型
pH计：Mettler Toledo公司SevenMulti型
含水量测试仪：Cornemeter CM825
水浴锅：上海一恒科技有限公司HWS28型电热恒温水浴锅
均质机：Polytron公司PT 3100D型
实施例1-22：含尿素的组合物的制备
按表1-3所示的重量称取适量原料，加入50ml规格的PET密封塑瓶中，称取适量去离子水，加入PET密封塑瓶，将PET密封塑瓶封口后，振摇直至固体完全溶解。待固体完全溶解混合均匀后，测定样品pH值，如初始pH值高于7，则加入柠檬酸溶液使样品pH值达到6左右。
表1
表2
表3
以上实施例中各组分的用量单位均为g。
上述实施例可分为四组：
(1)实施例1-实施例4：尿素本底，单独使用柠檬酸三乙酯或甘氨酸， 及柠檬酸三乙酯与甘氨酸复配后的使用效果比较。
(2)实施例4-实施例7：甘氨酸与其它氨基酸，以及常用缓冲剂磷酸二氢钾使用效果比较。
(3)实施例8-实施例17：不同柠檬酸三乙酯以及甘氨酸配比对尿素水溶液pH值的影响。
(4)实施例18-实施例22：固定柠檬酸三乙酯和甘氨酸的含量，考察电解质，过度金属离子，固体粉末对尿素水溶液pH值的影响。
由于尿素、柠檬酸三乙酯、甘氨酸良好的溶解性，绝大多数样品仅需振摇几次即可完全溶解，形成透明澄清溶液。例外的包括，实施例19由于添加了铜盐而呈现深蓝色，实施例21和22因加入了非水溶性的粉末而呈现为悬浊液。
绝大多数样品配置后的pH在4.0至7之间，配置后无须调整pH值。然而实施例6和实施例21因加入了碱性成分使pH值高于6.5，而加入柠檬酸调节pH值。实施例6制备后溶液pH值为11.21，加入柠檬酸后pH值为5.67；实施例21制备后pH值为7.23，加入少量柠檬酸调节pH值为5.80。
测试例1：高温稳定性考察
称取实施例1-22样品50g，加入PET密封塑瓶中，置入48℃烘箱放置3月。定期将PET密封瓶从冰箱中取出，冷却后观察样品性状并测定其pH值。
表4显示了各实施例的样品于48℃放置不同时间的pH值及样品性状的变化。
表4
表4列出了各实施例在48℃放置不同时间后的pH值。有必要指出，尿素的水解会为化妆品的使用带来两方面的问题：其一，法律法规风险，国家法规对国家法规对水剂、乳液及膏霜等化妆品pH值的允许范围在4.0-8.5之间。其二，消费者使用感受，可以想象，倘若样品溢出氨味，会严重影响消费者的使用感受。根据本次实验结果，若样品pH值达到7.5以上，则普遍能闻出氨味。
5％尿素水溶液(实施例1)在48℃放置15天后，pH即达到9.08，并且有严重的氨味溢出。此后，随着加热时间的增长，样品pH仍然有小幅度的上升，在3月稳定性测试后样品pH达到9.44。向尿素水溶液加入0.5％柠檬酸三乙酯(实施例2)或5％甘氨酸(实施例3)之后，尿素水溶液pH上升的趋势得到了显著的抑制。以上两样品，在48℃加热3月后pH值分别为8.80与7.70，且各时间点样品pH都低于尿素水溶液的pH值。可见，使用柠檬酸三乙酯与甘氨酸复配，可以对尿素水溶液pH值起到较好的稳定作用。然而，以上两样品经过3月48℃放置后，水溶液pH值仍有比较明显的上涨，在稳定性测试完毕后，可嗅出氨味，依然无法完全满足化妆品的使用的需要。将0.5％的柠檬酸三乙酯与5％的甘氨酸复配后(实施例4)，尿素水溶液pH稳定性有了进一步提升，48℃放置3月后，样品的pH仅上 升至6.18，且完全没有氨味溢出，满足化妆品应用的需要。以上实验可知，柠檬酸三乙酯和甘氨酸都有稳定尿素水溶液pH值的作用，而将两者复配后其稳定效应更强。
实施例4-实施例7比较了甘氨酸、谷氨酸、精氨酸与KH
2PO
4对尿素水溶液的pH稳定能力。经过3个月的48℃放置，四份样品的pH值依次为6.18、8.04、7.69与8.12，实施例5-实施例7除pH稳定性效果不及实施例4之外，在放置2到3月后，均可嗅出氨味。根据以上对比试验可知，甘氨酸对尿素水溶液的稳定性，优于谷氨酸、精氨酸以及KH
2PO
4。
实施例8-实施例10考察了柠檬酸三乙酯的用量对尿素水溶液的稳定能力。对5％尿素水溶液，添加0.5％、1％、2％及5％尿素后，48℃放置3月后pH值依次为8.80、7.95、6.81和6.29。可见，随柠檬酸三乙酯与尿素质量比的增加，样品的pH稳定性越好。但是，高浓度的柠檬酸三乙酯在长时间加热后，会产生颜色的变化。实施例8(柠檬酸三乙酯含量1％)在48℃加热3月后，肉眼可以分辨溶液呈现出略微的棕色，当柠檬酸三乙酯含量继续提高至2％(实施例9)与5％时(实施例10)，48℃加热后可以分辨出明显的棕色。高浓度柠檬酸三乙酯水溶液在长时间加热后的不稳定性，会影响化妆品的观感，不利于其在生产中的实际应用。
柠檬酸三乙酯含量对尿素水溶液pH影响的趋势在和甘氨酸复配样品中亦有体现，实施例11在实施例3的基础上，将柠檬酸三乙酯的用量自0.5％提升至1％，经过3月热放置，两份样品的pH值分别为5.95与6.18。值得一提的是，实施例4(0.5％柠檬酸三乙酯+5％甘氨酸)与实施例10(5％柠檬酸三乙酯)对尿素水溶液pH稳定能力相仿。与此同时，实施例4规避了高浓度柠檬酸三乙酯水溶液可能的热不稳定的风险。此外需要一提的是，因甘氨酸的成本远低于柠檬酸三乙酯，实施例4的成本仅为实施例10的40％左右。
实施例4表现出了良好的稳定pH水溶液能力，且对于化妆品中的应用尚有较大冗余。如能在满足化妆品应用标准的基础上降低柠檬酸三乙酯和甘氨酸的含量，除可降低成本之外，亦能减少对乳化体系承载能力的冲击。实施例12-实施例17考察了较低柠檬酸三乙酯和甘氨酸含量的样品对尿素 水溶液pH的稳定性能。固定柠檬酸三乙酯含量为0.5％时，甘氨酸含量为5％(实施例4)、2.5％(实施例12)、1％(实施例13)和0.5％(实施例14)样品48℃放置3月后的pH值分别为6.18、6.73、7.40和8.25。除了实施例14，其它三分样品在三月稳定性测试后均未闻到氨味溢出。固定甘氨酸含量为2.5％时，柠檬酸三乙酯用量为0.5％(实施例12)、0.2％(实施例15)、0.1％(实施例16)和0.05％(实施例17)的样品48℃放置3月后pH值分别为6.73、7.12、7.46和7.66，且各样品均未闻到氨味溢出。以上实验结果表明，柠檬酸三乙酯和甘氨酸含量的增加能够增强尿素水溶液的pH稳定性。且在实施例4的基础上，在满足化妆品使用要求的前提下，柠檬酸三乙酯和甘氨酸的添加量具有一定下调空间。
实施例18-实施例22考察了可能具有催化性能的电解质、过渡金属离子及固体粉末对尿素稳定体系的影响。经过3个月48℃放置后，在实施例4基础上添加2％氯化钠(实施例18)、PCA-Cu(实施例19)、硫酸锌(实施例20)、氧化锌粉末(实施例21)和二氧化硅粉末(实施例22)样品的pH值分别为5.90、6.05、6.01、6.42和6.09。以上实验结果表明，在存在电解质、过渡金属粒子或固体界面的条件下，柠檬酸三乙酯和甘氨酸复配的尿素水溶液pH稳定体系依然具有良好的表现，表明该体系具有广泛的实用性。然而，需要指出的是，实施例21经过3月48℃放置后，添加的氧化锌固体完全溶解，转变为透明澄清溶液。其原因在于，尿素分解释放的NH
3或NH
4
+与Zn发生络合，使后者转变为可溶性的锌氨络离子，从而使固体溶解。如将本文报道的尿素水溶液稳定体系与具有形成水溶性氨络合物的金属固体粉末复配需加以特别的关注。
测试例2：保湿性能考察
(1)志愿者选取：选取10名手前臂部位无明显疤痕、无明显干燥脱屑及色素沉着的18-60岁健康成年人作为受试者。
(2)描点及分组：对手前臂部位进行描点和分组，每个志愿者描点面积为2×4cm
2，实验共分6组：空白组、实施例1组、5％甘氨酸组、实施例3组、实施例4组、实施例12组。
(4)测定皮肤生理参数基础值：用清水清洁受试者手前臂，使受试者在恒温恒湿室(21±1℃，50％±5％湿度)内静坐30分钟后，分别用以下仪器对受试者手前臂进行测试，测试受试者前臂内侧基础值，包含参数指标有皮肤水分，涂抹样品，使用量为2mg/cm
2，涂抹至样品吸收，测试涂抹样品后1h，4h及6h的水分值。
表5显示了各个样品不同时间质检角质层含水量(均值±SD，A.U.)。
表5
| 测试样品 | 基础值 | 1h | 4h | 6h |
| 空白 | 23.16±5.50 | 23.33±5.19 | 22.93±5.56 | 23.96±5.39 |
| 实施例1 | 27.25±4.25 | 24.98±5.01 | 25.38±4.98 | 25.18±5.35 |
| 5％甘氨酸 | 21.85±4.81 | 27.85±6.61* | 25.95±5.68* | 26.53±5.54* |
| 实施例3 | 22.16±5.33 | 14.04±3.64* | 15.36±4.25* | 16.70±6.24* |
| 实施例4 | 23.78±5.33 | 25.17±6.12 | 23.57±5.04 | 24.36±6.52 |
| 实施例12 | 23.33±6.79 | 28.76±6.21* | 25.91±5.17* | 25.96±5.32* |
*表示与基础值相比具有显著性差异(p<0.05)
表6显示了各个样品不同时间质检角质层含水量差值(测试时间点数据-基础值)(均值±SD，A.U.)。
表6
| 测试样品 | 1h | 4h | 6h |
| 空白 | -0.18±1.77 | -0.23±1.98 | 0.81±1.88 |
| 实施例1 | -2.26±3.15 | -1.87±3.03 | -2.07±4.37 |
| 5％甘氨酸 | -8.12±2.94* | -6.80±2.35* | -5.46±2.51* |
| 实施例3 | 6.00±4.19* | 4.10±2.90 | 4.86±3.01 |
| 实施例4 | 1.39±3.95 | -0.21±4.27 | 0.58±4.48 |
| 实施例12 | 5.43±4.18* | 2.58±4.21 | 2.63±4.47 |
*表示与基础值相比具有显著性差异(p<0.05)
由表5和表6可知，在测试的6小时内，空白区域在各个时间测试点与基础值相比仅有略微变化。尿素水溶液(实施例1)涂布后，各时间点的皮肤含水量相比基础值有一定下降，但尚不具备统计学意义。甘氨酸水溶液涂布后，皮肤表面含水量在各个测试点相比基础值都有大幅度下降，且具备统计学意义。尽管尿素和甘氨酸普遍被认为具有保湿功效，但我们的 实验结果表明并非简单涂布其水溶液就能够起到理想的保湿效果。造成该现象的原因可能在于尿素与甘氨酸晶体的析出，在样品涂布待水分蒸发后，肉眼可观察到皮肤表面有细微晶体附着，晶体析出影响了其渗透以及被皮肤吸收利用，并且可能对仪器的测试值产生干扰。
将尿素与柠檬酸三乙酯复配后(实施例3)，样品的保湿效能相比尿素水溶液出现明显改观。在1h、4h、6h的测试点，相比于基础值皮肤表面含水量分别上升了6.00，4.10与4.86，其中第一个点相比空白样具有统计学差异。尿素、柠檬酸三乙酯、甘氨酸以10：1：10质量比复配的实施例4，在几个测试时间点的表皮含水量都只有略微提高，并不具有统计学意义。然而，调整三者的质量比为10：1：5时，在三个测试时间点内，皮肤表面含水量相比于基础值分别上升了5.43、2.58与2.63，其中第一个数据相比空白样具有统计学差异。以上实验结果表明，将尿素、柠檬酸三乙酯、甘氨酸以合适的比例复配后，可以表现出显著优于尿素和甘氨酸水溶液的保湿效果，且三者的配比对于其保湿效果的发挥有具有明显的影响。
实施例23：化妆品配方的预制物的制备
按表7所示的用量将A相原料加入1000mL玻璃烧杯中，用保鲜膜封口后，90℃水浴锅预热30min。按表7所示的用量将B相原料加入500mL玻璃烧杯中，用保鲜膜封口后，90℃水浴锅预热30min。
A相预热完成后从水浴锅中取出，以5000rpm的速度均质2min，待料体均匀。此后，在5000rpm均质搅拌中，缓缓将B相加入A相(1min加完)，加料完成后继续保持5000rpm均质2分钟至料体均匀。均质完毕后，烧杯以保鲜膜封口待用。
表7
实施例24-28：含尿素缓冲体系的化妆品配方的制备
待实施例23所用预制物冷却至约50℃后，于250ml玻璃烧杯中称取预制物134.25g，并按表8加入对应原料。此后将样品以5000rpm的速度均质2min使料体混合均匀，所配制样品转移至150ml透明带盖PET中，隔夜测定pH值并观察其性状。
实施例24-28所制备的膏霜质量均为150g，其中实施例24为作为对比的基料未添加尿素等添加剂。实施例25-28中尿素在所制备膏霜中的含量均为5％，实施例26和28中添加了质量分数为0.5％的柠檬酸三乙酯，而实施例27和实施例28中添加了质量分数为5％的甘氨酸。
表8
测试例3：高温稳定性测试
将150g实施例24-28样品加入PET密封塑瓶中，置入48℃烘箱放置3月。定期将PET密封瓶从冰箱中取出，静置冷却过夜后观察样品性状并测定其pH值。
表9显示了实施例24-28在高温稳定性测试各时间点的性状及pH值。
表9
实施例24-28的稳定性测试结果如表9所示。基质配方(实施例24)外观呈现为白色软霜(粘度自8000mPa·s至20000mPa·s)，并且在三月高温经时稳定性测试中保持稳定，不论其性状抑或pH值均基本保持稳定。在基质配方基础上加入5％尿素的样品(实施例25)，其新制样品性能与基质配方并无明显差异。但在高温稳定性测试中，仅仅15天料体pH值即上升至9.00，此后随时间进一步上升，在3月稳定性测试后上升至9.26。此外，从一月稳定性测试开始，料体即开始散发氨味，并且随时间推演不断加剧，三月经时稳定性样品的氨味已相当刺鼻。以上实验结果标明，向基质配方中直接添加尿素，无法满足化妆品法规及消费者使用的基本要求。此外，料体在稳定性测试中出现了增稠的现象，自15天经时稳定性测试开始，样品即从白色软霜转变为白色膏霜(粘度自2000mPa·s至50000mPa·s)，其原因可能来自于碱性条件下阳离子表面活性剂胶束结构的重构。在基质配方基础上加入5％尿素及0.5％柠檬酸三乙酯的样品(实施例26)，其新制样品与基础配方亦无明显差异，但在经时稳定性测试中，其pH表现出明 显上升趋势，三月稳定性测试后料体pH值上升至8.92，并且散发出明显氨味。该样品在三月高温经时稳定性测试后，出现了破乳，分层的现象，不满足国家化妆品法规的相关要求。此外，该样品在高温经时测试中，料体的增稠情况严重，在一月稳定性观察中表现为白色膏霜，而在二三月稳定性观察中表现为白色厚质膏霜(粘度大于50000mPa·s)，料体性状的极明显变化亦对化妆品在使用期间的一致性造成负面影响。在基质配方基础上加入5％尿素及5％甘氨酸样品(实施例27)，其新制样品与基础配方无明显差异，但在经时稳定性测试中，其pH表现出单调上升趋势，三月稳定性测试后料体pH值上升至7.49，满足化妆品法规的需求，但是该样品在三月稳定性测试后可嗅出氨味，可能影响消费者对于产品的使用感受。总而言之，该样品能够大致满足法规及消费者的要求，然而接近临界配比，可能因为配方批次差异出现质量问题。
在基质配方基础上加入5％尿素、0.5％柠檬酸三乙酯及5％甘氨酸样品(实施例28)，其新制样品与基础配方无明显差异，但在经时稳定性测试中，其pH表现先下降再上升(最初15天pH下降可能来源于阳离子胶束的重构)，最终pH值为6.21，距离国家化妆品的法规尚有较大冗余，且未能察觉到氨味，满足消费者对化妆品使用的需求。尽管其料体粘度出现了小幅度上升，从白色软膏转变为白色膏霜，但粘度有所上升的趋势不易导致产品的质量问题，且变化幅度有限，对膏霜类产品不易被消费者感知。根据以上实验结果可以推论，将尿素与柠檬酸三乙酯及甘氨酸复配后，应用于化妆品实际配方中亦显著高于单独添加尿素，或者仅与甘氨酸或柠檬酸三乙酯复配的样品。
实施例29-32：羟乙基脲缓冲体系样品的制备
按表10所示的重量称取适量原料，加入50ml规格的PET密封塑瓶中，称取适量去离子水，加入PET密封塑瓶，将PET密封塑瓶封口后，振摇直至固体完全溶解。待固体完全溶解混合均匀后，测定样品pH值，如初始pH值高于7，则加入柠檬酸溶液使样品pH值达到6左右。
表10
测试例4：高温稳定性考察
称取实施例29-32样品50g，加入PET密封塑瓶中，置入48℃烘箱放置3月。定期将PET密封瓶从冰箱中取出，冷却后观察样品性状并测定其pH值。表11显示了各样品于48℃放置不同时间的pH值，及样品性状的变化。
表11
表11列出了各实施例在48℃放置不同时间后的pH值。因羟乙基脲原料的pH值较高，实施例29和30配置后pH值分别为8.49和7.09，故加入柠檬酸对pH值进行调节，调节后以上两实施例的初始pH值分别为6.05和5.29(少量柠檬酸加入即极大改变样品pH值)。而实施例31与32的初始pH值在7以下，故在高温放置前未对其pH值加以调节。5％羟乙基脲水溶液(实施例29)在高温经时稳定性测试中pH有明显上升，15天上升至8.61，3月稳定性测试结束后达到了9.19，超过了国家化妆品法规许可的标准，并且从60天起能够闻到氨味。单独加入0.5％柠檬酸三乙酯(实施例30)或5％甘氨酸(实施例31)样品，在三月经时稳定性测试后pH分别为7.76及8.02，尽管满足法规标准，但pH明显改变可能影响料体的性状或添加剂的稳定性。相比之下，同时加入柠檬酸三乙酯与甘氨酸后(实施例32)，样品的高温稳定性得到进一步提升，90天稳定性测试后，料体pH值仅从 5.49小幅上升至5.85。可见，将柠檬酸三乙酯和甘氨酸同时与羟乙基脲复配后，羟乙基脲水溶液的稳定性能够得到显著提升。
实施例33：化妆品配方的预制物的制备
按表12所示的用量将A相原料加入1000mL玻璃烧杯中，用保鲜膜封口后，90℃水浴锅预热30min。按表5所示的用量将B相原料加入500mL玻璃烧杯中，用保鲜膜封口后，90℃水浴锅预热30min。
A相预热完成后从水浴锅中取出，以5000rpm的速度均质2min，待料体均匀。此后，在5000rpm均质搅拌中，缓缓将B相加入A相(1min加完)，加料完成后继续保持5000rpm均质2分钟至料体均匀。均质完毕后，烧杯以保鲜膜封口待用。
表12
实施例34-37：含羟乙基脲缓冲体系的化妆品配方的制备
待实施例33所用预制物冷却至约50℃后，于250ml玻璃烧杯中称取实施例33所用预制物126.75g，并按表13加入对应原料。此后将样品以5000rpm的速度均质2min使料体混合均匀，所配制样品转移至150ml透明带盖PET中，隔夜测定pH值并观察其性状。实施例34-37所制备的膏霜质量均为150g，羟乙基脲的理论含量为5％。此外，实施例35和37中添加了质量分数为0.5％的柠檬酸三乙酯，而实施例36和实施例37中添加了质量分数为5％的甘氨酸。
表13
| 实施例 | 34 | 35 | 36 | 37 |
| 羟乙基脲(50％) | 15 | 15 | 15 | 15 |
| 柠檬酸三乙酯 | 0 | 0.75 | 0 | 0.75 |
| 甘氨酸 | 0 | 0 | 7.5 | 7.5 |
| 去离子水 | 8.25 | 7.5 | 0.75 | 0 |
测试例5：高温稳定性测试
将150g实施例34-37样品加入PET密封塑瓶中，置入48℃烘箱放置3月。定期将PET密封瓶从冰箱中取出，静置冷却过夜后观察样品性状并测定其pH值。
表14显示了实施例34-37在高温稳定性测试各时间点的性状及pH值(加入实施例24测试数据作为对比)。
表14
实施例34-37及空白样实施例24的的稳定性测试结果如表12所示。基质配方(实施例24)在高温经时稳定性测试中表现良好，其pH值和性状均无明显改变。在基质配方基础上加入5％羟乙基脲样品(实施例34)，其初始pH值相比基质配方有所提高(自4.55上升至6.33)。在高温稳定性测试中，其pH值有明显上升，在三月稳定性测试后pH值达到8.78，并且可嗅出氨味，无法满足法规及消费者对化妆品的要求。在基质配方基础上加入5％羟乙基脲及0.5％柠檬酸三乙酯的样品(实施例35)，其新制样 品的pH上升至6.22，且在三月稳定性测试后料体pH值上升至7.21。此外，该样品在稳定性测试中粘度提升较明显，三月稳定性测试后料体粘度上升约230％(33250mPa·s)，自二月起从白色软膏转变为白色膏霜。在基质配方基础上加入5％羟乙基脲及5％甘氨酸样品(实施例36)，其新制样品pH值为6.21，三月高温稳定性测试后料体pH值上升至7.49，满足化妆品法规的需求。在基质配方基础上加入5％羟乙基脲、0.5％柠檬酸三乙酯及5％甘氨酸样品(实施例37)，其新制样品pH值为6.07，三月稳定性测试后样品pH下降为5.65(15天粘度下降可能源于胶束的重构)。以上实验结果表明，羟乙基脲对于配方稳定性的挑战小于尿素，且将檬酸三乙酯及甘氨酸复配使用后，依然可以表现出更优的料体pH稳定性。
Claims (10)
- 一种包含柠檬酸三乙酯和甘氨酸的稳定组合物，所述组合物为水性溶液，所述水性溶液还包含水解产生氨的活性剂，其中，所述活性剂与柠檬酸三乙酯的重量比为1:1至100:1，所述活性剂与甘氨酸的重量比为1:1至10:1。
- 如权利要求1所述的稳定组合物，其特征在于，所述活性剂选自：尿素、羟乙基脲或它们的组合。
- 如权利要求1或2所述的稳定组合物，其特征在于，所述活性剂与柠檬酸三乙酯的重量比为1:1至10:1。
- 如权利要求1或2所述的稳定组合物，其特征在于，所述活性剂与甘氨酸的重量比为1:1。
- 如权利要求1或2所述的稳定组合物，其特征在于，所述组合物的含水量至少为15重量％。
- 如权利要求1或2所述的稳定组合物，其特征在于，所述组合物还包含电解质、过渡金属离子、固体粉末或它们的组合。
- 如权利要求1或2所述的稳定组合物，其特征在于，所述组合物的pH保持低于8.5。
- 一种稳定化包含水解产生氨的活性剂的水性溶液的方法，所述方法包括组合使用柠檬酸三乙酯和甘氨酸，其中，所述活性剂与柠檬酸三乙酯的重量比为1:1至100:1，所述活性剂与甘氨酸的重量比为1:1至10:1。
- 如权利要求1或2所述的稳定组合物在皮肤外用剂中的应用。
- 如权利要求9所述的应用，其特征在于，所述皮肤外用剂选自：洁面乳、化妆水、乳液、膏霜、面膜。
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