CN114533568A - Whitening co-carried ionic liquid type liposome and preparation method thereof - Google Patents
Whitening co-carried ionic liquid type liposome and preparation method thereof Download PDFInfo
- Publication number
- CN114533568A CN114533568A CN202210018187.2A CN202210018187A CN114533568A CN 114533568 A CN114533568 A CN 114533568A CN 202210018187 A CN202210018187 A CN 202210018187A CN 114533568 A CN114533568 A CN 114533568A
- Authority
- CN
- China
- Prior art keywords
- ionic liquid
- whitening
- liposome
- shearing
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 239000002608 ionic liquid Substances 0.000 title claims abstract description 132
- 230000002087 whitening effect Effects 0.000 title claims abstract description 123
- 239000002502 liposome Substances 0.000 title claims abstract description 103
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- ZSBXGIUJOOQZMP-JLNYLFASSA-N Matrine Chemical compound C1CC[C@H]2CN3C(=O)CCC[C@@H]3[C@@H]3[C@H]2N1CCC3 ZSBXGIUJOOQZMP-JLNYLFASSA-N 0.000 claims abstract description 36
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- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 15
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- BJRNKVDFDLYUGJ-UHFFFAOYSA-N p-hydroxyphenyl beta-D-alloside Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(O)C=C1 BJRNKVDFDLYUGJ-UHFFFAOYSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
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- 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
- A61K8/34—Alcohols
- A61K8/347—Phenols
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- 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
- A61K8/35—Ketones, e.g. benzophenone
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- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
- A61K8/4926—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having six membered rings
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- 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
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- 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
- A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
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- 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
- A61K2800/59—Mixtures
- A61K2800/592—Mixtures of compounds complementing their respective functions
- A61K2800/5922—At least two compounds being classified in the same subclass of A61K8/18
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Abstract
The invention particularly discloses a whitening co-carried ionic liquid type liposome and a preparation method thereof, wherein the liposome comprises the following components in percentage by mass: whitening active ingredients: 2.0-10.0%, ionic liquid: 10.0-50.0%, phospholipid: 2.0-10.0%, cholesterol: 0.2-1.0%, emulsifier: 5.0-15.0%, stabilizer: 0.2-1.0 percent, and the balance of pure water, accounting for 100 percent. The liposome has the advantages of high stability, high entrapment rate, high drug loading, good transdermal absorption in skin, long retention time, slow release, synergistic effect of whitening active substances and the like; the preparation method adopts the antiviral matrine ionic liquid as the solvent, on one hand, the use of organic solvent is avoided, and the preparation method is environment-friendly and pollution-free; meanwhile, the preparation method is simple and can be used for industrial and large-scale production. On the other hand, the prepared liposome can also play a role in resisting virus.
Description
Technical Field
The invention belongs to the technical field of cosmetics, and particularly relates to a whitening co-carried ionic liquid type liposome and a preparation method thereof.
Background
The demand of Asian consumers for skin whitening far exceeds that of other areas, and the demand for whitening and spot-lightening effects is urgent. In the market, raw materials for whitening and spot-lightening are diversified, and the quantity of the traditional raw materials (vitamin C derivatives, tartaric acid, kojic acid and dipalmitate thereof, beta-arbutin) to the subsequent tranexamic acid, alpha-arbutin, various extracts and the like is hundreds. However, the raw materials generally take two to three months to take effect initially, and consumers are easy to lose patience. In recent years, many para-derivatives of resorcinol have been applied to cosmetic formulations as a whitening raw material, and 4-butyl resorcinol is considered to be a very effective novel whitening raw material. When researchers compare and study the whitening performance, the 4-butyl resorcinol is proved to have 24 times stronger whitening effect than kojic acid and 310 times stronger whitening effect than arbutin, can strongly inhibit melanin synthesis, and is known as the second strong whitening component on the earth surface. Tetrahydrocurcumin is obtained by hydrogenating curcumin extracted from root of Curcuma longa of Zingiberaceae, and has antiinflammatory, antioxidant, oxygen free radical scavenging, liver protecting, fibrosis resisting, tumor activity preventing and Alzheimer disease preventing effects. Because of the wide biological efficacy of tetrahydrocurcumin, the research in the field of cosmetics is more and more extensive in recent years, and the research finds that the tetrahydrocurcumin has obvious efficacy in the aspects of whitening, anti-inflammation, antioxidation and the like, and is applied to the field of cosmetics as a natural-source functional whitening raw material. However, 4-butylresorcinol and tetrahydrocurcumin have the defects of being difficult to dissolve in water, large in irritation, easy to oxidize and discolor and the like, so that the application of the 4-butylresorcinol and the tetrahydrocurcumin in cosmetics is greatly limited.
Liposomes, also known as lipid globules, are closed vesicles formed by embedding a bioactive substance within a phospholipid bilayer structure formed by amphiphilic lipid molecules, similar to the structure of a cell membrane, and mainly composed of phospholipids and cholesterol, also known as artificial biofilms. The liposome can effectively solve the problems of solubility, stability, irritation, odor, difficult formulation, bioavailability and the like of bioactive substances. Since the first liposome cosmetic "capture" developed by color of Lanchome, France in 1986, liposomes have received increasing attention in the cosmetic field and have been widely used in this field. The traditional liposome preparation method generally comprises a reverse evaporation method, a film dispersion method, an ethanol injection method, a multiple emulsion method, a freeze drying method, a melting method, a freeze thawing method, a spray drying method and the like. However, the preparation methods of these liposomes have various disadvantages such as complicated operation steps, more organic solvents, and difficulty in mass production on a large scale, and thus, the conventional liposome preparation methods have limited applications in the cosmetic field.
The ionic liquid is a liquid mixture formed by anion and cation according to a certain stoichiometric ratio under certain conditions. The ionic liquid has the advantages of simple preparation process, low volatility, high stability, high conductivity, nonflammability and the like, and is widely applied to various fields. The matrine ionic liquid is prepared by taking matrine extracted from sophora flavescens as a cation precursor and taking one or more of coconut oil aminobutyric acid, capric acid, lauric acid, myristic acid, palmitic acid and Omega-9 fatty acid as an anion precursor through ionization modification, and has the antiviral effect of the matrine and the moisturizing effect of the coconut oil acid.
Disclosure of Invention
The first purpose of the invention is to provide a whitening co-carried ionic liquid type liposome, which uses matrine type ionic liquid as a solvent to entrap whitening active substances 4-butylresorcinol and tetrahydrocurcumin, can effectively improve the drug loading, water solubility and stability of the whitening active substances, increase the transdermal absorption capacity of the whitening active substances, improve the retention amount of the whitening active substances in skin, and simultaneously play a synergistic whitening role.
The second objective of the present invention is to provide a preparation method of the whitening co-carried ionic liquid type liposome, wherein the preparation method avoids the use of organic solvents, and the preparation method is simple and can be industrially and massively produced.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a whitening co-carried ionic liquid liposome comprises the following components: whitening active ingredients, ionic liquid, phospholipid, cholesterol, an emulsifier, a stabilizer and pure water.
Further, the components by mass percent: whitening active ingredients: 2.0-10.0%, ionic liquid: 10.0-50.0%, phospholipid: 2.0-10.0%, cholesterol: 0.2-1.0%, emulsifier: 5.0-15.0%, stabilizer: 0.2-1.0 percent, and the balance of pure water, accounting for 100 percent.
Further, the whitening active ingredients are 4-butyl resorcinol and tetrahydrocurcumin.
Further, the ionic liquid is at least one of matrine caproic acid ionic liquid, matrine caprylic acid ionic liquid, matrine capric acid ionic liquid, matrine lauric acid ionic liquid, matrine myristic acid ionic liquid and matrine palmitic acid ionic liquid.
Further, the phospholipid is at least one of soybean lecithin, hydrogenated lecithin, lysolecithin and egg yolk lecithin.
Further, the emulsifier is at least one of PEG-40 hydrogenated castor oil, polysorbate-20, polysorbate-60, polysorbate-80, polyglycerol-10-laurate, polyglycerol-10-oleate, and polyglycerol-10-myristate.
Further, the stabilizer is at least one of EDTA-2Na, sodium metabisulfite, tocopherol (vitamin E) and tocopherol ethyl acetate.
A preparation method of the whitening co-carried ionic liquid liposome comprises the following steps:
(1) preparing an oil phase: dissolving whitening active ingredients, ionic liquid, phospholipid and cholesterol in water bath at 50-70 deg.C, and magnetically stirring;
(2) preparing an aqueous phase: dissolving emulsifier, stabilizer and pure water in water bath at 50-70 deg.C, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under the shearing condition, wherein the shearing rotating speed is 5000-10000 rpm; the shearing temperature is 50-70 ℃; shearing for 3-8min to obtain colostrum;
(4) high-pressure homogenization: homogenizing the primary emulsion at high pressure of 500-1000 bar; homogenizing at 50-70 deg.C; and (4) circulating for 5-10 times, and cooling to room temperature to obtain the whitening co-carried ionic liquid type liposome.
Further, in the step (3), the shearing rotation speed is 6000-; the shearing temperature is 55-65 ℃; the shearing time is 4-6 min.
Further, in the step (4), the homogenizing pressure is 600-800 bar; homogenizing at 55-65 deg.C; the cycle times were 6-8.
The invention has the beneficial effects that:
the whitening co-carried ionic liquid type liposome has the advantages of high stability, high entrapment rate, high drug loading rate, good transdermal absorption in skin, long retention time, slow release, synergistic effect of whitening active substances and the like.
The preparation method adopts the antiviral matrine ionic liquid as the solvent, so that on one hand, the use of an organic solvent is avoided, and the preparation method is environment-friendly and pollution-free; meanwhile, the preparation method is simple and can be used for industrial and large-scale production. On the other hand, the prepared whitening co-carried ionic liquid type liposome can also play a role in resisting viruses.
Drawings
Fig. 1 is an appearance view of a whitening co-carried ionic liquid type liposome.
Fig. 2 is a particle size diagram of the whitening co-carried ionic liquid type liposome.
Fig. 3 is a graph of the particle size stability test result of the whitening co-carried ionic liquid type liposome.
FIG. 4 is a graph showing the results of 4-butylresorcinol content test; wherein 577 is 4-butylresorcinol.
FIG. 5 is a graph showing the results of the tetrahydrocurcumin content test, wherein THC is tetrahydrocurcumin.
FIG. 6 is a graph of the cumulative permeation test results of the whitening co-carried ionic liquid type liposome; wherein 577 is 4-butylresorcinol; THC is tetrahydrocurcumin.
FIG. 7 is a graph of the cumulative retention of the whitening co-loading ionic liquid type liposomes; wherein 577 is 4-butylresorcinol; THC is tetrahydrocurcumin.
FIG. 8 is a graph of the cumulative release rate test results of the whitening co-loading ionic liquid type liposome; wherein 577 is 4-butylresorcinol; THC is tetrahydrocurcumin.
FIG. 9 is a graph showing the results of tyrosinase activity assay.
Detailed Description
The following is further detailed by way of specific embodiments:
the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention relates to a whitening co-ion-carrying liquid liposome, which comprises the following components in percentage by mass: whitening active ingredients: 2.0-10.0%, ionic liquid: 10.0-50.0%, phospholipid: 2.0-10.0%, cholesterol: 0.2-1.0%, emulsifier: 5.0-15.0%, stabilizer: 0.2-1.0 percent, and the balance of pure water, accounting for 100 percent. Wherein the whitening active ingredients are 4-butyl resorcinol and tetrahydrocurcumin. The ionic liquid is at least one of matrine caproic acid ionic liquid, matrine caprylic acid ionic liquid, matrine capric acid ionic liquid, matrine lauric acid ionic liquid, matrine myristic acid ionic liquid and matrine palmitic acid ionic liquid. The phospholipid is at least one of soybean lecithin, hydrogenated lecithin, lysolecithin, and yolk lecithin. The emulsifier is at least one of PEG-40 hydrogenated castor oil, polysorbate-20, polysorbate-60, polysorbate-80, polyglycerol-10-laurate, polyglycerol-10-oleate, and polyglycerol-10-myristate. The stabilizer is at least one of EDTA-2Na, sodium pyrosulfite, tocopherol (vitamin E) and tocopherol ethyl acetate.
The preparation method of the whitening co-carried ion liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving whitening active ingredients, ionic liquid, phospholipid and cholesterol in water bath at 50-70 deg.C, and magnetically stirring;
(2) preparing an aqueous phase: dissolving emulsifier, stabilizer and pure water in water bath at 50-70 deg.C, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under the shearing condition, wherein the shearing rotating speed is 5000-10000 rpm; the shearing temperature is 50-70 ℃; shearing for 3-8min to obtain colostrum;
(4) high-pressure homogenization: homogenizing the primary emulsion at high pressure of 500-1000 bar; homogenizing at 50-70 deg.C; and (4) circulating for 5-10 times, and cooling to room temperature to obtain the whitening co-carried ionic liquid type liposome.
Preferably, in the step (3), the shearing rotation speed is 6000-9000 rpm; the shearing temperature is 55-65 ℃; the shearing time is 4-6 min. In the step (4), the homogenizing pressure is 600-800 bar; homogenizing at 55-65 deg.C; the cycle times were 6-8.
The preparation method avoids using organic solvent, is simple, and can be industrially applied to cosmetics in large scale.
The technical solution of the present invention will be further described with reference to the following examples.
Example 1
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 1.0% of 4-butylresorcinol, 1.0% of tetrahydrocurcumin, 10.0% of matrine lauric acid ionic liquid, 2.0% of hydrogenated lecithin, 0.2% of cholesterol, 2.0% of PEG-40 hydrogenated castor oil, 3.0% of polysorbate-80, 0.1% of EDTA-2Na, 0.1% of sodium metabisulfite and the balance of pure water, which are 100% in total.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 1.0% of 4-butylresorcinol, 1.0% of tetrahydrocurcumin, 10.0% of matrine lauric acid ionic liquid, 2.0% of hydrogenated lecithin and 0.2% of cholesterol in a water bath at the temperature of 50 ℃, and uniformly stirring by magnetic force for later use;
(2) preparing a water phase: dissolving 2.0% PEG-40 hydrogenated castor oil, 3.0% polysorbate-80, 0.1% EDTA-2Na, 0.1% sodium metabisulfite and 80.6% pure water in water bath at 50 deg.C, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition, wherein the shearing speed is 5000rpm, the shearing temperature is 50 ℃, and the shearing time is 3min, so as to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 500bar, homogenizing at 50 deg.C for 5 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 2
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 2.0% of 4-butylresorcinol, 2.0% of tetrahydrocurcumin, 50.0% of matrine caproic acid ionic liquid, 2.0% of soybean lecithin, 1.0% of egg yolk lecithin, 0.3% of cholesterol, 5.0% of PEG-40 hydrogenated castor oil, 2.0% of polyglycerol-10-myristate, 0.1% of EDTA-2Na, 0.1% of sodium metabisulfite and the balance of pure water, which are 100% in total.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 2.0% of 4-butylresorcinol, 2.0% of tetrahydrocurcumin, 50.0% of matrine caproic acid ionic liquid, 2.0% of soybean lecithin, 1.0% of egg yolk lecithin and 0.3% of cholesterol in a water bath at the temperature of 55 ℃, and uniformly stirring by magnetic force for later use;
(2) preparing an aqueous phase: dissolving 5.0% PEG-40 hydrogenated castor oil, 2.0% polyglycerol-10-myristate, 0.1% EDTA-2Na, 0.1% sodium metabisulfite and 35.5% pure water in 55 deg.C water bath, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition at 6000rpm, 55 deg.C for 4min to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 600bar and 55 deg.C for 6 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 3
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 3.0% of 4-butylresorcinol, 2.0% of tetrahydrocurcumin, 40.0% of matrine caprylic acid ionic liquid, 5.0% of soybean lecithin, 0.5% of cholesterol, 8.0% of polyglycerol-10-oleate, 5.0% of polysorbate-20, 0.2% of EDTA-2Na, 0.2% of tocopherol ethyl acetate and the balance of pure water, wherein the total amount is 100%.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 3.0% of 4-butylresorcinol, 2.0% of tetrahydrocurcumin, 40.0% of matrine octanoic acid ionic liquid, 5.0% of soybean lecithin and 0.5% of cholesterol in a water bath at the temperature of 60 ℃, and uniformly mixing by magnetic stirring for later use;
(2) preparing an aqueous phase: dissolving 8.0% polyglycerol-10-oleate, 5.0% polysorbate-20, 0.2% EDTA-2Na, 0.2% tocopherol ethyl acetate and 36.1% pure water in water bath at 60 deg.C, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition, with shearing rotation speed of 7000rpm, shearing temperature of 60 deg.C, and shearing time of 5min to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 700bar at 60 deg.C for 7 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 4
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 3.0% 4-butylresorcinol, 3.0% tetrahydrocurcumin, 30.0% matrine decanoic acid ionic liquid, 2.0% soybean lecithin, 4.0% lysolecithin, 1.0% cholesterol, 5.0% polyglycerol-10-laurate, 5.0% polyglycerol-10-myristate, 0.2% EDTA-2Na, 0.2% sodium metabisulfite, 0.6% tocopherol (vitamin E), and the balance pure water, to total 100%.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 3.0% of 4-butylresorcinol, 3.0% of tetrahydrocurcumin, 30.0% of matrine decanoic acid ionic liquid, 2.0% of soybean lecithin, 4.0% of lysolecithin and 1.0% of cholesterol in a water bath at the temperature of 65 ℃, and uniformly stirring by magnetic force for later use;
(2) preparing an aqueous phase: dissolving 5.0% of polyglycerol-10-laurate, 5.0% of polyglycerol-10-myristate, 0.2% of EDTA-2Na, 0.2% of sodium metabisulfite, 0.6% of tocopherol (vitamin E) and 46.0% of pure water in a water bath at the temperature of 65 ℃, and uniformly mixing by magnetic stirring for later use;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition, with the shearing speed of 8000rpm, the shearing temperature of 65 deg.C, and the shearing time of 6min to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 800bar at 65 deg.C for 8 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 5
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 4.0% 4-butylresorcinol, 4.0% tetrahydrocurcumin 40.0% matrine decanoic acid ionic liquid, 5.0% soybean lecithin, 5.0% lysolecithin, 1.0% cholesterol, 5.0% polyglycerol-10-laurate, 5.0% polyglycerol-10-myristate, 0.2% EDTA-2Na, 0.2% sodium metabisulfite, 0.6% tocopherol (vitamin E), and the balance pure water, totaling 100%.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 4.0% 4-butylresorcinol, 4.0% tetrahydrocurcumin, 40.0% matrine decanoic acid ionic liquid, 5.0% soybean lecithin, 5.0% lysolecithin and 1.0% cholesterol in a water bath at 70 ℃, and uniformly mixing by magnetic stirring for later use;
(2) preparing an aqueous phase: dissolving 5.0% of polyglycerol-10-laurate, 5.0% of polyglycerol-10-myristate, 0.2% of EDTA-2Na, 0.2% of sodium metabisulfite, 0.6% of tocopherol (vitamin E) and 30.0% of pure water in a water bath at the temperature of 70 ℃, and uniformly mixing by magnetic stirring for later use;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition with a shearing speed of 9000rpm, a shearing temperature of 70 deg.C, and a shearing time of 7min to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 900bar at 70 deg.C for 9 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 6
A whitening co-carried ionic liquid liposome comprises the following components in percentage by mass: 5.0% 4-butylresorcinol, 5.0% tetrahydrocurcumin 40.0% matrine palmitate ionic liquid, 5.0% soy lecithin, 1.0% cholesterol, 5.0% polysorbate-60, 10.0% polysorbate-80, 0.2% EDTA-2Na, 0.2% sodium metabisulfite, 0.6% tocopherol (vitamin E) and the balance pure water, totaling 100%.
The preparation method of the whitening co-carried ionic liquid type liposome comprises the following steps:
(1) preparing an oil phase: dissolving 5.0% of 4-butylresorcinol, 5.0% of tetrahydrocurcumin, 40.0% of matrine palmitate ionic liquid, 5.0% of soybean lecithin and 1.0% of cholesterol in a water bath at the temperature of 70 ℃, and uniformly stirring by magnetic force for later use;
(2) preparing an aqueous phase: dissolving 5.0% polysorbate-60, 10.0% polysorbate-80, 0.2% EDTA-2Na, 0.2% sodium metabisulfite, 0.6% tocopherol (vitamin E) and 28.0% pure water in 70 deg.C water bath, and mixing under magnetic stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under shearing condition with the shearing rotation speed of 10000rpm, the shearing temperature of 70 ℃ and the shearing time of 8min to obtain primary emulsion;
(4) high-pressure homogenization: homogenizing under high pressure at 1000bar at 70 deg.C for 10 times, and cooling to room temperature to obtain whitening co-carried ionic liquid liposome.
Example 7
The preparation method of the whitening co-carried ionic liquid type liposome cream comprises the following steps:
(1) according to the conventional cream preparation method, 2.0% of PEG-10 polydimethylsiloxane, 1.0% of sucrose stearate, 1.0% of stearyl alcohol, 4.5% of glyceryl monostearate and 3.0% of jojoba oil are used as oil phases and melted in a water bath at 75 ℃; dissolving 5.0% glycerol, 5.0% propylene glycol, 0.3% triethanolamine, 0.2% carbomer 2020 and 78.0% pure water in 75 deg.C water bath as water phase; mixing the oil phase and the water phase, stirring, and emulsifying to obtain blank cream.
(2) The blank cream and the whitening co-carried ionic liquid type liposome obtained in the embodiment 6 are compounded according to the mass ratio of 4:1 to obtain the whitening co-carried ionic liquid type liposome cream containing 1.0% of 4-butylresorcinol and 1.0% of tetrahydrocurcumin, which is called liposome cream for short.
Comparative example 1
1.0% 4-butylresorcinol and 1.0% tetrahydrocurcumin were dissolved in ethanol, respectively.
Comparative example 2
Adding 1.0% of 4-butyl resorcinol and 1.0% of tetrahydrocurcumin into the blank cream obtained in the example 7 to obtain whitening raw cream, which is called raw cream for short.
The raw material cream and the liposome cream contain 4-butylresorcinol and tetrahydrocurcumin with the same content, and are characterized in that the raw material cream is added with free active ingredients, and the liposome cream is added with active ingredients after liposome is entrapped.
Experimental example 1
The appearance of the whitening co-ionic liquid type liposome obtained in example 1 of the present invention was observed.
The results are shown in fig. 1, wherein a is the stock solution of the whitening co-ionic liquid type liposome obtained in example 1, B is diluted 10 times the stock solution, and C is diluted 100 times the stock solution. The result shows that the whitening co-carried ionic liquid type liposome prepared by the preparation method has good appearance and high transmittance.
Experimental example 2
The results of examining the particle size, PDI, potential, and encapsulation efficiency of the whitening co-carried ionic liquid liposome obtained in examples 1 to 6 of the present invention are shown in table 1, wherein the particle size of the whitening co-carried ionic liquid liposome obtained in example 1 is shown in fig. 2.
Table 1: results of examining particle size, PDI, potential, and encapsulation efficiency of the whitening co-carried ionic liquid type liposomes obtained in examples 1 to 6
| Group of | Particle size (nm) | PDI | Electric potential (mV) | Encapsulation efficiency (%) |
| Example 1 | 49.68 | 0.192 | -32.12 | 99.89 |
| Example 2 | 54.71 | 0.158 | -30.84 | 99.68 |
| Example 3 | 78.24 | 0.189 | -34.77 | 98.61 |
| Example 4 | 83.76 | 0.150 | -36.18 | 99.01 |
| Example 5 | 90.52 | 0.212 | -34.65 | 98.12 |
| Example 6 | 86.45 | 0.209 | -38.45 | 98.33 |
As can be seen from Table 1, the whitening co-carried ionic liquid type liposome obtained by the invention wraps two whitening active substances simultaneously, has an entrapment rate of 98% and a particle size of less than 100nm, and can better promote the active substances to enter the skin to exert a whitening effect. PDI less than 0.3 indicates a uniform particle size distribution. The Zeta potential can be used to predict the physical stability of liposome dispersions, with higher absolute values of the potential indicating more stable systems. The absolute value of the potential of the whitening co-carried ionic liquid type liposome prepared by the method is more than 30mV, which shows that the whitening co-carried ionic liquid type liposome prepared by the method has high stability.
Experimental example 3
The particle size stability test was performed on the whitening co-carried ionic liquid type liposome obtained in example 1 of the present invention.
The experimental method is as follows: the whitening co-carried ionic liquid type liposome is respectively placed under the conditions of normal temperature and dark (RT), normal temperature illumination (illumination), 4 ℃ illumination (4 ℃) and 45 ℃ illumination (45 ℃), and the particle size of the whitening co-carried ionic liquid type liposome is measured respectively on the day of preparation (indicated by 0), after 1 month, after 2 months and after 3 months.
The test results are shown in fig. 3, and it can be seen from the results that the particle size of the whitening co-loading ionic liquid type liposome has no significant change under various conditions, which indicates that the whitening co-loading ionic liquid type liposome of the present invention has good thermodynamic stability.
Experimental example 4
The content stability tests of 4-butylresorcinol and tetrahydrocurcumin are carried out on the whitening co-carried ionic liquid type liposome obtained in the example 1 of the invention and the ethanol solution in the comparative example 1.
The experimental method is as follows:
(1) preparation of 4-butyl resorcinol standard solution
Accurately weighing 100mg of 4-butyl resorcinol powder in a brown volumetric flask, adding 50mL of methanol, ultrasonically dissolving for 5min, and fixing the volume of the methanol to 100mL to prepare a 1000 mu g/mL 4-butyl resorcinol solution. Respectively and precisely measuring 50, 100, 200, 400, 600, 800 and 1000 mu L of solution in a 10mL brown volumetric flask, and metering the volume of methanol to a scale mark to obtain 4-butylresorcinol standard solution with the concentration of 5, 10, 20, 40, 60, 80 and 100 mu g/mL respectively.
(2) 4-butyl resorcinol chromatographic conditions
Agilent TC-C18 chromatography column (4.6 mm. times.250 mm, 5 μm); the mobile phase is methanol: acetonitrile: water 43:42: 15; the flow rate is 1 mL/min; the detection wavelength is 230 nm; the column temperature is 30 ℃; the amount of sample was 10. mu.L.
(3) Preparation of tetrahydrocurcumin standard solution
Accurately weighing 100mg of tetrahydrocurcumin powder in a brown volumetric flask, adding 50mL of methanol, ultrasonically dissolving for 5min, and diluting the methanol to 100mL to prepare 1000 mu g/mL of tetrahydrocurcumin solution. Precisely measuring 50, 100, 200, 400, 600, 800 and 1000 mu L of the solution in a 10mL brown volumetric flask, and metering the volume of methanol to a scale mark to obtain the tetrahydrocurcumin standard solution with the concentration of 5, 10, 20, 40, 60, 80 and 100 mu g/mL respectively.
(4) Chromatographic condition of tetrahydrocurcumin
Agilent TC-C18 chromatography column (4.6 mm. times.250 mm, 5 μm); the mobile phase is acetonitrile: 0.1% aqueous formic acid 50: 50; the flow rate is 1 mL/min; the detection wavelength is 280 nm; the column temperature was 35 ℃; the amount of sample was 20. mu.L.
(5) The ethanol solution in the comparative example 1 and the whitening co-carried ionic liquid type liposome obtained in the example 1 are placed under the illumination condition of 45 ℃, and the content of 4-butylresorcinol and tetrahydrocurcumin is detected respectively on the day of preparation (indicated by 0), after 1 month, after 2 months and after 3 months. And (3) placing the same mass of the ethanol solution in the comparative example 1 and the whitening co-carried ionic liquid type liposome obtained in the example 1 into a brown volumetric flask, performing constant volume with methanol, performing ultrasonic treatment at room temperature for 30min to demulsify the whitening co-carried ionic liquid type liposome, completely dissolving 4-butyl resorcinol and tetrahydrocurcumin in the methanol, shaking up, filtering with a 0.22 mu m filter membrane, and respectively detecting the contents of the 4-butyl resorcinol and the tetrahydrocurcumin according to the high performance liquid chromatography detection method.
The test results are shown in fig. 4 and 5, and it can be seen from the results that compared with the whitening co-carried ionic liquid type liposome obtained in example 1, the ethanol solution in comparative example 1 has a protective effect on both 4-butylresorcinol and tetrahydrocurcumin, so that the retention rate is obviously improved, and the stability is increased.
Experimental example 5
The liposome cream obtained in example 7 of the present invention and the raw material cream obtained in comparative example 2 were subjected to in vitro transdermal tests.
The experimental method is as follows:
(1) before the experiment, a skin model with the thickness of 300 +/-50 mu m is prepared by a skin grafting knife, and then the skin model is cut into small round blocks with the size of a receiving pool and is put into normal saline for later use. Phosphate buffer (pH 7.4) containing 5% tween 80 was used as the receiving medium in this experiment. During the experiment, the skin model is fixed between the release tank and the receiving tank, so that one side of the horny layer faces the release tank, one side of the corium layer faces the receiving tank, the skin is tightly attached to the receiving liquid, and no air bubble is generated between the skin model and the receiving tank. The liposome cream obtained in example 7 was then applied evenly to the skin surface, the temperature of the receiving cell was maintained at 37. + -. 0.5 ℃ and magnetons were placed in the receiving cell and kept at 300rpm during the experiment. The experimental control group is the raw material cream obtained in the comparative example 2, and the control group and the experimental group are provided with three repetitions.
(2) Sampling 1mL in 0.5, 1, 2, 4, 6, 8, 10 and 24 hours respectively, simultaneously adding 1mL of fresh receiving medium with the same temperature, filtering the sampled product by using a 0.22 mu m filter membrane, and carrying out sample injection analysis according to the high performance liquid chromatography detection method to obtain the skin permeation quantity of the whitening co-carried ionic liquid type liposome.
(3) After 24 hours of in-vitro transdermal behavior investigation, taking down the skin, wiping the residual cream on the surface, taking the skin at the transdermal position, shearing, adding 1.5mL of ethanol for homogenization, carrying out ultrasonic treatment for 1 hour to leach 4-butylresorcinol and tetrahydrocurcumin in the skin, transferring the homogenate into a centrifuge tube, carrying out vortex mixing, carrying out centrifugation at 12000rpm/min for 10min, carrying out re-extraction on the residue once by using 1mL of ethanol, combining two supernatants, mixing uniformly, taking the supernatant, filtering by using a 0.22 mu m filter membrane, and carrying out sample injection analysis according to the high performance liquid chromatography detection method to obtain the transdermal retention of the whitening co-carried ionic liquid type liposome.
The test results are shown in fig. 6 and 7, and it can be seen from the results that the penetration amount of 4-butylresorcinol and tetrahydrocurcumin in the skin of the whitening co-carried ionic liquid type liposome cream is obviously higher than that of the unencapsulated raw material cream. Therefore, compared with the unencapsulated raw material cream, the whitening co-carried ionic liquid type liposome cream has the advantages that 4-butylresorcinol and tetrahydrocurcumin have good transdermal absorption within the testing time; meanwhile, the retention amount of 4-butylresorcinol in the whitening co-carried ionic liquid type liposome cream is 2.6 times of that of the raw material cream, and the retention amount of tetrahydrocurcumin in the skin is 3.6 times of that of the raw material cream, so that the whitening active substance in the whitening co-carried ionic liquid type liposome cream has higher retention amount in the skin after being wrapped.
Experimental example 6
And carrying out in-vitro release test on the whitening co-carried ionic liquid type liposome.
The experimental method is as follows:
this experiment was performed using dialysis for in vitro release testing. Pretreatment of a dialysis bag: the dialysis bag was cut into 10cm pieces, boiled in a large volume of 2% (m/v) sodium bicarbonate and 1mmol/L EDTA (pH 8) for 10min, rinsed thoroughly with purified water, and boiled in 1mmol/L EDTA (pH 8) for 10 min. And cleaning the dialysis bag with pure water after cooling, and refrigerating and storing the dialysis bag with 30% ethanol to ensure that the dialysis bag is always immersed in liquid. From this time, the dialysis bag must be worn with gloves, and before use, the dialysis bag is filled with water and then drained, and then cleaned. The temperature of the air bath shaking table is set to be 37 +/-0.5 ℃, and the oscillation frequency is set to be a constant speed of 100 r/min. Each group was set with 3 replicates, 2mL of the whitening co-loaded ionic liquid liposome obtained in example 1 was placed in a dialysis bag, the air bubbles were removed, both ends were tied up with a band, placed in 30mL of 1% Tween 80 in PBS (pH 7.0), sampled 1mL for 0.5, 1, 2, 4, 6, 8, 10, 24h, respectively, and supplemented with 1mL of fresh release medium at the same temperature. The sample was filtered through a 0.22 μm filter. In the same way, 4-butyl resorcinol ethanol solution and tetrahydrocurcumin ethanol solution with the same mass concentration are used as controls to carry out in-vitro release test. And (4) carrying out sample injection analysis according to the detection method, calculating the cumulative release rate, and drawing a drug release curve.
The test results are shown in fig. 8, and it can be seen from the results that the 4-butyl resorcinol ethanol solution is completely released at 10h, the tetrahydrocurcumin ethanol solution is also completely released at 24h, while the cumulative release rate of 4-butyl resorcinol in the whitening co-supported ionic liquid type liposome at 24h is 69.78 ± 3.44%, and the cumulative release rate of tetrahydrocurcumin at 24h is 61.34 ± 2.36%. Therefore, the whitening co-carried ionic liquid type liposome has a certain slow release effect on 4-butyl resorcinol and tetrahydrocurcumin.
Experimental example 7
And (3) testing the tyrosinase activity inhibition rate of the whitening co-carried ionic liquid type liposome. Tyrosinase is a key enzyme for catalyzing melanin synthesis, inhibits the activity of tyrosinase, and can block the synthesis of melanin, thereby achieving the effect of skin whitening.
The experimental method is as follows:
(1) after seeding B16 melanoma cells to a 96-well plate at a cell density of 3X 104 cells/0.2 mL, the plate was placed in an incubator at 37 ℃ and cultured in DMEM medium supplemented with 10% fetal bovine serum and 1% antifungal antibiotic for 24 hours, then the cells were washed with 100. mu.L of PBS buffer, 100. mu.L of 1% Triton X-100 PBS buffer was added to each well, and after 30min of lysis with a mixer at 37 ℃, 50. mu.L of the supernatant was taken to another 96-well plate, and 50. mu.L of each sample solubilized with PBS was added.
(2) And uniformly mixing PBS and the whitening co-carried ionic liquid type liposome obtained in the example 1 according to the mass ratio of 9:1 to obtain a PBS whitening co-carried ionic liquid type liposome solution containing 0.1% of 4-butylresorcinol and 0.1% of tetrahydrocurcumin.
(3) A PBS solution containing only 0.1% 4-butylresorcinol was prepared as a control group 1.
(4) PBS solution containing only 0.1% tetrahydrocurcumin was prepared as a control group 2.
(5) PBS without any whitening component was used as blank control.
(6) To the above sample, 50. mu.L of 0.1% L-DOPA solution (prepared with a 0.1M PBS buffer pH 6.8, the reaction mixture should be used within 2 hours after preparation) was added, and the absorbance values at the reaction time of 0min and 10min were measured at 475nm at a reaction temperature of 37 ℃. From the absorbance values, the inhibition ratios of control 1, control 2 and example 1 were calculated, assuming that the blank control was 100%.
The test results are shown in fig. 9, and it can be seen from the results that the whitening co-carried ionic liquid type liposome obtained in example 1 of the present invention has good tyrosinase activity inhibition effect, and the effect is significantly stronger than that of a single whitening active substance, which indicates that after being compounded, the whitening co-carried ionic liquid type liposome has a synergistic tyrosinase activity inhibition effect.
It should be noted that, in this document, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
The foregoing is merely an example of the present invention, and common general knowledge in the field of known specific structures and characteristics is not described herein in any greater extent than that known in the art at the filing date or prior to the priority date of the application, so that those skilled in the art can now appreciate that all of the above-described techniques in this field and have the ability to apply routine experimentation before this date can be combined with one or more of the present teachings to complete and implement the present invention, and that certain typical known structures or known methods do not pose any impediments to the implementation of the present invention by those skilled in the art. It should be noted that, for those skilled in the art, without departing from the structure of the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (10)
1. A whitening co-carried ionic liquid liposome is characterized in that: comprises the following components: whitening active ingredients, ionic liquid, phospholipid, cholesterol, an emulsifier, a stabilizer and pure water.
2. The whitening co-ionic liquid liposome of claim 1, wherein: the weight percentages of the components are as follows: whitening active ingredients: 2.0-10.0%, ionic liquid: 10.0-50.0%, phospholipid: 2.0-10.0%, cholesterol: 0.2-1.0%, emulsifier: 5.0-15.0%, stabilizer: 0.2-1.0 percent, and the balance of pure water, which accounts for 100 percent.
3. The whitening co-ionic liquid liposome of claim 2, wherein: the whitening active ingredients are 4-butyl resorcinol and tetrahydrocurcumin.
4. The whitening co-ionic liquid liposome of claim 2, wherein: the ionic liquid is at least one of matrine caproic acid ionic liquid, matrine caprylic acid ionic liquid, matrine capric acid ionic liquid, matrine lauric acid ionic liquid, matrine myristic acid ionic liquid and matrine palmitic acid ionic liquid.
5. The whitening co-ionic liquid liposome of claim 2, wherein: the phospholipid is at least one of soybean lecithin, hydrogenated lecithin, lysolecithin and egg yolk lecithin.
6. The whitening co-ionic liquid liposome of claim 2, wherein: the emulsifier is at least one of PEG-40 hydrogenated castor oil, polysorbate-20, polysorbate-60, polysorbate-80, polyglycerol-10-laurate, polyglycerol-10-oleate, and polyglycerol-10-myristate.
7. The whitening co-ionic liquid liposome of claim 2, wherein: the stabilizer is at least one of EDTA-2Na, sodium metabisulfite, tocopherol and tocopherol ethyl acetate.
8. The preparation method of the whitening co-carried ionic liquid liposome according to any one of claims 1 to 7, characterized in that: the method comprises the following steps:
(1) preparing an oil phase: dissolving whitening active ingredients, ionic liquid, phospholipid and cholesterol in water bath at 50-70 deg.C, and magnetically stirring;
(2) preparing an aqueous phase: dissolving emulsifier, stabilizer and pure water in water bath at 50-70 deg.C, and magnetically stirring;
(3) high-speed shearing: slowly adding the oil phase into the water phase under the shearing condition, wherein the shearing rotating speed is 5000-10000 rpm; the shearing temperature is 50-70 ℃; shearing for 3-8min to obtain colostrum;
(4) high-pressure homogenization: homogenizing the primary emulsion at high pressure of 500-1000 bar; homogenizing at 50-70 deg.C; and (4) circulating for 5-10 times, and cooling to room temperature to obtain the whitening co-carried ionic liquid type liposome.
9. The preparation method of the whitening co-carried ionic liquid liposome according to claim 8, characterized in that: in the step (3), the shearing rotation speed is 6000-9000 rpm; the shearing temperature is 55-65 ℃; the shearing time is 4-6 min.
10. The preparation method of the whitening co-carried ionic liquid liposome according to claim 8, characterized in that: in the step (4), the homogenizing pressure is 600-800 bar; homogenizing at 55-65 deg.C; the cycle times were 6-8.
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| CN114931517A (en) * | 2022-06-07 | 2022-08-23 | 欧诗漫生物股份有限公司 | Whitening body and preparation method and application thereof |
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