CN112972279A - Idebenone, mesoporous bioglass composite carrier, preparation method thereof and cosmetics - Google Patents
Idebenone, mesoporous bioglass composite carrier, preparation method thereof and cosmetics Download PDFInfo
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- 239000005312 bioglass Substances 0.000 title claims abstract description 111
- JGPMMRGNQUBGND-UHFFFAOYSA-N idebenone Chemical compound COC1=C(OC)C(=O)C(CCCCCCCCCCO)=C(C)C1=O JGPMMRGNQUBGND-UHFFFAOYSA-N 0.000 title claims abstract description 83
- 229960004135 idebenone Drugs 0.000 title claims abstract description 82
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 239000002131 composite material Substances 0.000 title claims abstract description 26
- 239000002537 cosmetic Substances 0.000 title claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 239000000243 solution Substances 0.000 claims abstract description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000011575 calcium Substances 0.000 claims abstract description 28
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 27
- 238000005406 washing Methods 0.000 claims abstract description 27
- 239000010703 silicon Substances 0.000 claims abstract description 26
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 23
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000001035 drying Methods 0.000 claims abstract description 22
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 22
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000011574 phosphorus Substances 0.000 claims abstract description 21
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000007864 aqueous solution Substances 0.000 claims abstract description 20
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- BOTDANWDWHJENH-UHFFFAOYSA-N Tetraethyl orthosilicate Chemical group CCO[Si](OCC)(OCC)OCC BOTDANWDWHJENH-UHFFFAOYSA-N 0.000 claims description 9
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- ZCCIPPOKBCJFDN-UHFFFAOYSA-N calcium nitrate Chemical group [Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ZCCIPPOKBCJFDN-UHFFFAOYSA-N 0.000 claims description 6
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- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
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- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical class COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
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- ICSSIKVYVJQJND-UHFFFAOYSA-N calcium nitrate tetrahydrate Chemical compound O.O.O.O.[Ca+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O ICSSIKVYVJQJND-UHFFFAOYSA-N 0.000 description 1
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- MGJZITXUQXWAKY-UHFFFAOYSA-N diphenyl-(2,4,6-trinitrophenyl)iminoazanium Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1N=[N+](C=1C=CC=CC=1)C1=CC=CC=C1 MGJZITXUQXWAKY-UHFFFAOYSA-N 0.000 description 1
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
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Images
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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/35—Ketones, e.g. benzophenone
- A61K8/355—Quinones
-
- 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
- A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
- A61K8/25—Silicon; Compounds thereof
-
- 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
- A61Q19/08—Anti-ageing preparations
-
- 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
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
-
- 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
- A61K2800/522—Antioxidants; Radical scavengers
-
- 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
- A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
-
- 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
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/82—Preparation or application process involves sonication or ultrasonication
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Gerontology & Geriatric Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Emergency Medicine (AREA)
- Silicates, Zeolites, And Molecular Sieves (AREA)
Abstract
The invention relates to the technical field of cosmetics, in particular to idebenone, a mesoporous bioglass composite carrier, a preparation method thereof and cosmetics. The method comprises the following steps: dissolving a template agent in a hydrochloric acid aqueous solution to obtain a template agent solution; dissolving a calcium source and a phosphorus source in a template solution; then, adding a silicon source dropwise into the system, and stirring at constant temperature for reaction; carrying out suction filtration, water washing, alcohol washing, drying, calcining and ball milling on the obtained suspension to obtain mesoporous bioglass powder; dissolving idebenone in ethanol water solution, mixing with mesoporous bioglass powder, stirring for adsorption, centrifuging, washing and drying. The carrier and the loading substance of the loading system have uniform and sustained release characteristics. The carrier can realize the sustainable release of calcium, phosphorus and silicon ions, and promote the regeneration of skin tissues; the load substance idebenone also has the characteristic of sustained and slow release, thereby effectively reducing the potential irritation. Meanwhile, the particle has simple preparation process and good biocompatibility, and is suitable for expanded production.
Description
Technical Field
The invention relates to the technical field of cosmetics, in particular to idebenone, a mesoporous bioglass composite carrier, a preparation method thereof and cosmetics.
Background
Idebenone (Idebenone), chemical name is 6- (10-hydroxydecyl) -2, 3-dimethoxy-5-methyl-1, 4-benzoquinone. Idebenone has strong antioxidant and free radical scavenging activity, and is used in treating mitochondrial diseases, such as Parkinson's disease, Alzheimer's disease, etc. Idebenone is a structural analogue of coenzyme Q10, and the 10-6 carbon atom replaces 50 carbon atoms of the 6-position side chain of coenzyme Q10, thereby exhibiting better antioxidant effect than coenzyme Q10. In recent years, idebenone has been widely used in the cosmetic field. Idebenone can increase skin moisture content, reduce skin roughness and dryness, and reduce fine lines on skin. Idebenone at a concentration of 0.5% is capable of reducing IL-1 β, IL-6 and MMP-1, and is a potential cosmetic efficacy ingredient.
However, idebenone has a small molecular weight and a high permeation rate during use, and thus is irritating to the skin and eyes, and may cause discomfort during use. Meanwhile, idebenone is unstable in chemical property and easy to degrade and inactivate under a heating condition; in addition, idebenone is limited in its use in aqueous cosmetic formulations because it is difficult to dissolve in aqueous solutions. Therefore, in order to effectively utilize idebenone, the above-mentioned problems need to be solved.
Bioactive glass is inorganic glass with specific biological and physiological functions and its main component is Na2O-CaO-SiO2-P2O5The system has good biocompatibility and bioactivity. By adopting a sol-gel method, CaO-SiO can be synthesized2-P2O5The ternary bioglass system has a high specific surface area. The obtained bioglass material changes the traditional compact structure, can form a porous structure, and widens the chemical composition range of bioglass materials. The material can quickly form a hydrated silicon-rich gel layer through ion exchange, and has certain angiogenesis stimulating and antibacterial effects.
Mesoporous materials have been increasingly used in the field of biological medicine due to their nanoporous structures suitable for immobilizing related drugs, high specific surface area and pore volume favorable for biological activity. Compared with bioglass with the same chemical composition, the introduction of the mesopores brings more excellent bioactivity kinetics, and the improved structural property and the high specific surface area of the mesopores can accelerate the surface reaction speed and the release of ion dissolved products. At present, no product combining the mesoporous bioglass carrier and idebenone is available.
Disclosure of Invention
In view of the above, the invention provides idebenone, a mesoporous bioglass composite carrier, a preparation method thereof and cosmetics. According to the invention, the mesoporous bioglass carrier is combined with the efficient antioxidant idebenone in the cosmetic science, so that on one hand, the solubility of the idebenone can be improved, and a better bioavailability is realized by controlling the release; on one hand, the favorable biological performance of the mesoporous bioglass is utilized, and the metabolism and regeneration of the skin are promoted through the dissolution of calcium, silicon, phosphorus and other particles, so that the stability of idebenone is improved and the controllable release is provided.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of idebenone and mesoporous bioglass composite carrier, which comprises the following steps:
dissolving a template agent P123 in a hydrochloric acid aqueous solution to obtain a template agent solution;
dissolving a calcium source and a phosphorus source in a template solution;
thirdly, dropwise adding a silicon source into the system, and stirring at constant temperature for reaction to obtain a suspension;
step four, carrying out suction filtration, washing, alcohol washing, drying, calcining and ball milling on the suspension to obtain mesoporous bioglass powder;
and step five, dissolving idebenone in ethanol, mixing with the mesoporous bioglass powder, stirring, adsorbing, centrifuging, washing and drying to obtain the idebenone and mesoporous bioglass composite carrier.
In the present invention, the preparation method of the composite carrier comprises the following steps: the mesoporous bioglass is synthesized by adopting a solvent volatilization induction self-assembly method. Taking P123 as a template agent, dissolving in an acidic aqueous solution, and respectively adding calcium nitrate and triethyl phosphate as a calcium source and a phosphorus source. After the materials are fully dissolved, tetraethoxysilane is used as a silicon source, and the materials are stirred at constant temperature for reaction. And carrying out suction filtration, washing, drying, calcining and ball milling on the prepared suspension to finally obtain mesoporous bioglass powder with different apertures. And (3) taking bioglass as a carrier, adsorbing and compounding the bioglass with idebenone through a pore effect, and then centrifugally drying to obtain the idebenone/mesoporous bioglass composite carrier.
The invention also provides a preparation method of the idebenone and mesoporous bioglass composite carrier, which comprises the following steps:
dissolving a template agent P123 in a hydrochloric acid aqueous solution to obtain a template agent solution;
dissolving a calcium source, a phosphorus source and a pore-expanding agent in a template agent solution;
thirdly, dropwise adding a silicon source into the system, stirring at constant temperature for reaction, and carrying out high-pressure hydrothermal reaction to obtain a suspension;
step four, carrying out suction filtration, washing, alcohol washing, drying, calcining and ball milling on the suspension to obtain mesoporous bioglass powder;
and step five, dissolving idebenone in ethanol, mixing with the mesoporous bioglass powder, stirring, adsorbing, centrifuging, washing and drying to obtain the idebenone and mesoporous bioglass composite carrier.
Preferably, in the first step, the concentration of the hydrochloric acid aqueous solution is 1-3 mol/L; the dosage ratio of the template agent to the hydrochloric acid aqueous solution is (8-10): 200-300) in g/mL.
Preferably, the concentration of the hydrochloric acid aqueous solution is 2 mol/L; the dosage ratio of the template agent to the hydrochloric acid aqueous solution is (8-10): 240 in g/mL.
Preferably, the template is dissolved by vigorous stirring in a water bath at 45 ℃.
Preferably, the calcium source is calcium nitrate or calcium nitrate tetrahydrate.
Preferably, the source of phosphorus is triethyl phosphate.
Preferably, the pore-expanding agent is 1,3, 5-trimethylbenzene.
Preferably, the silicon source is tetraethoxysilane.
Preferably, the dosage ratio of the calcium source, the phosphorus source, the silicon source and the template agent solution is (1-3): (0.5-0.8): (14-18): (200-300).
Preferably, the dosage ratio of the calcium source, the phosphorus source, the silicon source, the pore-expanding agent and the template agent solution is (1-3): (0.5-0.8): (14-18): (10-12): (200-300).
Preferably, in the third step, the temperature of the constant-temperature stirring reaction is 40-50 ℃ and the time is 20-30 hours.
Preferably, the reaction is stirred at a constant temperature of 45 ℃ for 24 hours.
Preferably, in the third step, the temperature of the high-pressure hydrothermal reaction is 95-100 ℃ and the time is 20-30 hours. In the present invention, the high pressure is a pressure slightly higher than the normal pressure.
Preferably, in the fourth step, the drying temperature is 55-65 ℃, and the calcining temperature is 540-560 ℃.
Preferably, in the fourth step, the drying temperature is 60 ℃ and the calcining temperature is 550 ℃.
Preferably, in the fifth step, the concentration of idebenone in the ethanol aqueous solution is 0.1-10 mg/mL, and the stirring and adsorbing time is 12-72 hours.
Preferably, in the fifth step, the concentration of idebenone in the ethanol water solution is 0.1-2 mg/mL, and the stirring and adsorbing time is 12 hours.
The invention also provides the idebenone and mesoporous bioglass composite carrier prepared by the preparation method, and the pore diameter of the mesoporous bioglass is 4-40 nm.
Preferably, the pore diameter of the mesoporous bioglass is 4 nm.
The invention also provides a cosmetic, which comprises the idebenone and mesoporous bioglass composite carrier, wherein the concentration of the idebenone and mesoporous bioglass composite carrier in the cosmetic is less than or equal to 1000 mug/mL.
The invention provides idebenone, a mesoporous bioglass composite carrier, a preparation method thereof and cosmetics. The preparation method comprises the following steps: dissolving a template agent P123 in a hydrochloric acid aqueous solution to obtain a template agent solution; dissolving a calcium source and a phosphorus source in a template solution; then, adding a silicon source dropwise into the system, and stirring at constant temperature for reaction to obtain a suspension; carrying out suction filtration, water washing, alcohol washing, drying, calcining and ball milling on the suspension to obtain mesoporous bioglass powder; dissolving idebenone in ethanol, mixing with the mesoporous bioglass powder, stirring for adsorption, centrifuging, washing and drying. The invention has the following advantages:
the carrier and the loading substance of the loading system have uniform and sustained release characteristics. The carrier can realize the sustainable release of calcium, phosphorus and silicon ions, and promote the regeneration of skin tissues; the load substance idebenone also has the characteristic of sustained and slow release, thereby effectively reducing the potential irritation. Meanwhile, the particle has simple preparation process and good biocompatibility, and is suitable for expanded production. The particles can be well used in skin external products, and can use water-insoluble idebenone in water phase such as aqua and gel system.
Compared with the related technology, the preparation method of the idebenone and mesoporous bioglass composite carrier provided by the invention has the following advantages:
(1) the bioglass material with the ordered mesoporous structure is prepared relatively simply through a sol-gel system at low temperature. The mesoporous bioglass mainly comprises CaO-SiO2-P2O5The ternary system has good biocompatibility. The structural characteristics ensure an ordered pore structure, highly uniform size and accurate control of the drug immobilization and release kinetics; the high specific surface area ensures the adsorption capacity of the drug; silanol containing surfaces, can also be easily further functionalized to better control drug loading and release.
(2) Through physicochemical characterization and investigation of mesoporous bioglass with different apertures and appearances, the mesoporous bioglass with the mesoporous size of 4nm is determined to have the optimal physical adsorption characteristic through the surface appearance and the specific surface area; meanwhile, by a biological investigation method, the leaching liquor of the mesoporous bioglass carrier can promote the proliferation of fibroblasts by a calcium and silicon ion dissolution mode;
(3) the optimal idebenone concentration and the carrier loading time are determined through static and dynamic adsorption experiments, and the subsequent active matter loading is guided and optimized through the optimization of the adsorption experiments;
(4) the active substance and the carrier substance in the invention are nontoxic and green, have excellent biological safety and no use risk;
(5) the idebenone and mesoporous bioglass carrier provided by the invention can be used for effectively loading idebenone and realizing the sustained and slow release of the idebenone, so that the potential irritation is effectively reduced, and meanwhile, the particle is simple in preparation process and good in biocompatibility, can be well used in skin external products and is suitable for expanded production.
Drawings
FIG. 1 is a schematic diagram showing the molecular structures of coenzyme Q10 and idebenone;
FIG. 2 is a transmission electron micrograph of bioglass with a pore size of 4 nm;
FIG. 3 is a transmission electron micrograph of bioglass with a pore size of 40 nm;
FIG. 4 is a transmission electron microscope image of the non-mesoporous bioglass;
FIG. 5 is a transmission electron micrograph of macroporous bioglass;
FIG. 6 shows the static adsorption efficiency of bioglass carriers with different pore sizes;
FIG. 7 shows the dynamic adsorption efficiency of 4nm mesoporous bioglass;
FIG. 8 is an optical photograph of the supernatant before and after loading with the drug powder;
FIG. 9 is the change in OD value of the supernatant before and after loading;
FIG. 10 is a graph of active release curves for different pore size carriers;
FIG. 11 is an ion elution profile of calcium ions and silicon ions at different times;
FIG. 12 is a graph of the proliferative effect of MBG on fibroblasts;
FIG. 13 shows DPPH radical scavenging ability tests of different concentrations of composite particles.
Detailed Description
The invention discloses idebenone, a mesoporous bioglass composite carrier, a preparation method thereof and cosmetics, and can be realized by appropriately improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The idebenone and mesoporous bioglass composite carrier, the preparation method thereof and the reagents or instruments used in the cosmetics can be purchased from the market.
The invention is further illustrated by the following examples:
example 1 preparation of Small mesoporous bioglass
Adopts a solvent volatilization induction self-assembly method, takes Tetraethoxysilane (TEOS) as a silicon source and tetrahydrate calcium nitrate (Ca (NO)3)2·4H2O) and triethyl phosphate (TEP) are respectively used as a calcium source and a phosphorus source to synthesize the high-activity bioglass with Si, Ca, P, 85, 10 and 5. The method comprises the following specific steps:
8g P123 was added as a template to 240mL of 2mol/L aqueous HCl and stirred vigorously in a water bath at 45 ℃ until completely dissolved. 2.44g Ca (NO) were added in sequence3)2·4H2O and 0.745g TEP as a calcium source and a phosphorus source. After the mixture was sufficiently dissolved, 17.13g of TEOS was added dropwise to the system as a silicon source, and the mixture was stirred at a constant temperature of 45 ℃ for 24 hours. And carrying out suction filtration, water washing for 3 times, alcohol washing for 3 times, drying at 60 ℃, calcining in a muffle furnace at 550 ℃ and ball milling on the prepared suspension to finally obtain mesoporous bioglass powder with regular pore passages of hexagonal mesoporous structures with smaller pore diameters.
From the transmission electron microscope characterization result in fig. 2, the prepared mesoporous bioglass has a very obvious ordered mesoporous structure. The mesoporous template P123 can form a regular pore passage through self-assembly of the micelle in an aqueous solution, so that ordered mesopores on a final material are mediated.
Example 2 preparation of Large mesoporous bioglass
9.6g P123 as a template was added to 240mL of 2mol/L aqueous HCl, stirred vigorously in a water bath at 45 ℃ until completely dissolved, and 12g of TMB (1,3, 5-trimethylbenzene) was added as a pore-expanding agent. 2.12g Ca (NO) was added in sequence3)2·4H2O and 0.663g TEP as a calcium source and a phosphorus source. After the mixture is fully dissolved, 14.92g of TEOS is dripped into the system to be used as a silicon source, the mixture is stirred at the constant temperature of 45 ℃ and reacts for 24 hours, and then the hydrothermal reaction is carried out for 24 hours at the high pressure of 100 ℃. And carrying out suction filtration, water washing for 3 times, alcohol washing for 3 times, drying at 60 ℃, calcining in a muffle furnace at 550 ℃ and ball milling on the prepared suspension to finally obtain mesoporous bioglass powder MBG-40 with larger pore diameter and irregular pore channels.
From the transmission electron microscope characterization result in fig. 3, the prepared mesoporous bioglass has a larger mesoporous channel structure, and the mesoporous structure of the mesoporous bioglass shows a disordered characteristic. The mesoporous template agent P123 can form a regular pore channel through micelle self-assembly in an aqueous solution, and the pore channel structure is further amplified by introducing the pore-expanding agent TMB, so that a disordered mesoporous structure with a larger pore diameter is finally presented.
Comparative example 1 preparation of a bioglass
2.12g Ca (NO) was added to 240mL of 2mol/L HCl aqueous solution sequentially with stirring in a 45 ℃ water bath3)2·4H2O and 0.663g TEP as a calcium source and a phosphorus source. After the mixture is fully dissolved, 14.92g of TEOS is dripped into the system to be used as a silicon source, the mixture is stirred at the constant temperature of 45 ℃ and reacts for 24 hours, and then the prepared suspension is subjected to suction filtration, water washing for 3 times, alcohol washing for 3 times, drying at 60 ℃, calcining at 550 ℃ in a muffle furnace and ball milling to finally obtain the biological glass powder BG without mesopores.
As can be seen from the surface topography analysis in fig. 4, the bioglass without the addition of the template agent and the pore-expanding agent shows a compact structure without mesopores, and there is a significant difference in apparent topography from the mesoporous bioglass.
Comparative example 2 preparation of macroporous bioglass
9.6g P123 as a template was added to 250mL of 2mol/L HCl aqueous solution, stirred vigorously in a water bath at 45 ℃ until completely dissolved, and 13.4g of TMB was added as a pore-expanding agent. 2.12g Ca (NO) was added in sequence3)2·4H2O and 0.663g TEP as a calcium source and a phosphorus source. After the mixture is fully dissolved, 14.92g of TEOS is dripped into the system to be used as a silicon source, the mixture is stirred at the constant temperature of 45 ℃ and reacts for 24 hours, and then the hydrothermal reaction is carried out for 24 hours at the high pressure of 100 ℃. And carrying out suction filtration, water washing for 3 times, alcohol washing for 3 times, drying at 60 ℃, calcining in a muffle furnace at 550 ℃ and ball milling on the prepared suspension to finally obtain mesoporous bioglass powder MBG-50 with large pore diameter and irregular pore channels.
From the transmission electron microscope characterization result in fig. 5, after the TMB ratio is increased, the prepared mesoporous bioglass has a larger pore structure and exceeds the mesoporous range (2-50 nm); the structure of the material also shows disorder characteristics. The mesoporous template agent P123 can form a regular pore channel through micelle self-assembly in an aqueous solution, and the pore channel structure is further amplified by introducing the pore-expanding agent TMB, so that a disordered mesoporous structure with a larger pore diameter is finally presented.
Example 3 analysis of specific surface area and mesoporous Structure
Based on the materials prepared in examples 1 and 2 and comparative examples 1 and 2, the specific surface area and the mesoporous structure thereof were characterized by BET adsorption test and small-angle XRD.
In the BET analysis, after moisture is removed by heat treatment, mesoporous parameters are measured by N2 adsorption-desorption test. In the small-angle XRD analysis, the sample powder was pressed into a tablet and then measured in a range of 0.5 ° to 8 ° by an X-ray diffractometer.
TABLE 1 analysis of specific surface area and mesoporous structure of different materials
| Material | Specific surface area (m)2.g-1) | Pore diameter (nm) |
| Example 1 Small mesopores | 546.19 | 4.29 |
| Example 2 Large mesopores | 412.76 | 34.46 |
| Comparative example 1 non-mesoporous | 18.38 | - |
| Comparative example 2 macropore | 398.48 | 53.4 |
From the results in Table 1, it is understood that the specific surface area of the small mesoporous bioglass is 546.19m2.g-1The diameter of the pore channel is 4.29 nm. The specific surface area of the large mesoporous bioglass is about 412.76m2.g-1The diameter of the pore channel is 34.46 nm. For non-mesoporous materials, the specific surface area is reduced significantly, only about 20m2.g-1. The small mesoporous and large mesoporous bioglass has better specific surface area and adsorption characteristic. After the content of the pore-expanding agent is further increased, the diameter of the obtained pore channel reaches 53.4nm, which exceeds the mesoporous range by definition, and the specific surface area is also reduced. The large mesopores have a good size effect on protein active substances and can promote protein adsorption. In consideration of the application of the invention to the idebenone micromolecular active substance, the small mesoporous bioglass with stronger adsorption to micromolecules is adopted as the optimal carrier.
Example 4 measurement of static adsorption Capacity of mesoporous bioglass
Respectively selecting 20mg of small mesoporous bioglass (MBG-M), large mesoporous bioglass (MBG-LM), macroporous bioglass (MBG-L) and non-Mesoporous Bioglass (MBG) as carriers, and dispersing the carriers in 5mL of ethanol. And idebenone was introduced at different final concentrations (0.1, 0.5, 1.0, 2.0, 5.0, 10.0mg/mL), sonicated for 10min and loaded with magnetic stirring at 400rpm for 24 hours at room temperature. After equilibrium of adsorption was reached, centrifugation was carried out at 6000rpm for 10min, and the resulting supernatant was measured for absorbance at λ -280 nm and the concentration of released drug was determined by comparison with a standard curve. And centrifugally drying to obtain the idebenone/mesoporous bioglass composite carrier. Wherein the adsorption efficiency is (total mass of idebenone-mass of idebenone in supernatant)/total mass of idebenone.
As can be seen from the results of fig. 6, the adsorption capacity of each of the four materials decreased as the concentration of idebenone increased; the bioglass with small mesopores and large mesopore structures has better adsorption efficiency; second order macroporous bioglass; while the non-porous material was significantly less efficient at adsorption than the sample set with the nanoporous structure. For the bioglass group in the mesoporous range, the adsorption efficiency is about 80% in the concentration range of 0.1-2 mg/mL. Under the same idebenone concentration (2mg/mL), the adsorption efficiency of the macroporous bioglass group and the nonporous bioglass group is 72 percent and 62 percent, and is lower than that of the mesoporous bioglass group. Idebenone has a molecular weight of 338, which is approximately between a few nanometers in molecular size. The size of the mesopores is matched with the size of idebenone, and the size effect of the pore channels exists besides physical adsorption, so that the adsorption capacity is improved. Therefore, the bioglass component with a mesoporous structure has the strongest advantage in the loading of the small molecule idebenone.
Example 5 measurement of dynamic adsorption Capacity of mesoporous bioglass and idebenone
20mg of the obtained mesoporous bioglass particles are dispersed in 5mL of ethanol, and idebenone active substance is introduced to ensure that the final concentration is 2.0 mg/mL. Sonicate for 10min and magnetically stir at 400rpm for 2, 4, 8, 12, 24, 48 hours at room temperature. After equilibrium of adsorption was reached, centrifugation was carried out at 6000rpm for 10min, and the resulting supernatant was measured for absorbance at λ -280 nm and the concentration of released drug was determined by comparison with a standard curve.
Wherein the adsorption amount is (total mass of idebenone-mass of idebenone in supernatant)/total mass of idebenone.
From the results of fig. 7, it is understood that the adsorption amount of the active material gradually increases as the load time increases. Under the loading time of 12 hours, the adsorption efficiency of the active matter reaches the maximum adsorption efficiency of 80 percent; with further increase in time, the adsorption efficiency did not increase significantly. The mesoporous bioglass is used as a load, and the active matter is saturated in 12 hours. Therefore, an adsorption equilibrium time of 12 hours was finally selected as the optimum adsorption time for the subsequent adsorption experiments.
Meanwhile, collecting supernatant before and after loading through a mesoporous bioglass loaded idebenone system, and taking an optical photo of the supernatant. As can be seen from fig. 8, the particle powder obtained after loading was orange-yellow. Meanwhile, the idebenone solution before and after loading has obvious color difference. The idebenone concentration before loading is higher, and the idebenone is darker orange; and the concentration of idebenone in the loaded supernatant is obviously reduced, and the OD value is 1.37. The intuitive result also shows that the mesoporous bioglass has good adsorption property. Figure 9 further measures the idebenone content in solution before and after loading by full wavelength scanning. There was a very strong absorption peak at 280nm before loading, while the OD value at this point decreased significantly after loading. Similarly, the second strong absorption peak at another 400nm also shows that after mesoporous bioglass is introduced for loading, idebenone can be enriched on bioglass through physical combination and pore channel effect.
Example 6 measurement of Release ability of mesoporous bioglass and idebenone
10mg of drug-loaded particles are weighed, dispersed in 10mL of ethanol, and placed in a constant temperature shaking box at 37 ℃ with the shaking speed of 80rpm and the amplitude of 20 mm. At different time nodes (1, 2, 4, 8, 12, 24 hours), the suspension was removed and centrifuged at 6000rpm for 10 min. The resulting supernatant was measured for absorbance at λ 280nm and the concentration of idebenone released was determined by comparison with a standard curve. At the same time, 10ml of fresh ethanol was supplemented, keeping the volume constant. And calculating the accumulated drug release amount to obtain the in-vitro drug release curve of the drug-loaded particles.
As can be seen from the release profile of fig. 10, the cumulative amount of idebenone released gradually increased with the increase of the release time. Among the four groups of samples, the bioglass group (MBG-M) with a mesoporous structure shows obvious controlled release characteristics. The macroporous group shows a certain slow release capacity, but the burst release phenomenon is improved compared with the mesoporous group. The MBG group without mesopores has obvious burst release phenomenon, and the saturated release amount is reached at 4 hr; while the MBG-M group released a certain amount of drug within 24 hr. Therefore, the mesoporous bioglass is used as a carrier of the active substance, and provides a better release curve. Furthermore, the sustained release effect after loading contributes to a reduction in irritation compared to free idebenone.
Example 7 ion elution Property of mesoporous bioglass
And (3) soaking the prepared mesoporous bioglass in SBF simulated body fluid for 48h, and measuring the concentrations of calcium ions and silicon ions in the solution at different time points by utilizing ICP-MS.
As can be seen from the experimental results of fig. 11, there is a rapid release characteristic of calcium ions and silicon ions in the initial stage. With further increase in time, the ions remain at a steady release rate. The result shows that the mesoporous bioglass has better degradability, can provide stable ion release and has potential advantages for skin repair.
Example 8 cell proliferation promoting Properties
And detecting the proliferation promoting capacity of the mesoporous bioglass leaching solution by adopting an MTT method.
(a) Mixing mesoporous bioglass with a culture medium, adding 30mg bioglass particles into 100mL of the culture medium, incubating and leaching at 37 ℃ for 24h, collecting leaching liquor, and placing at 4 ℃ for later use.
(b) Using fibroblast as model, inoculating the cells into 96-well culture plate, wherein the number of cells in each well is 3000-2Culturing in an incubator overnight;
(c) to be completely attached with cellsAfter the wall is completed, the culture solution in each well is used to replace the leaching solution and the common culture medium, and the temperature is kept constant at 37 ℃ and 5% CO2For 24, 48 and 72 hours;
(d) after the culture is finished, adding 30 mu L of MTT reagent into each hole, and continuously incubating for 4 hours at 37 ℃;
(e) the upper layer of liquid was removed, 200. mu.L of DMSO (dimethyl sulfoxide) was added to each well, followed by shaking at 37 ℃ for 10min to dissolve the purple crystalline formazan sufficiently, 150. mu.L of this was taken out of each well and put into a new 96-well microplate to measure the absorbance value of each well at a wavelength of 570nm, so as to remove the influence of cells and particles deposited at the bottom on the absorbance value.
As can be seen from the MTT results in fig. 12, the mesoporous bioglass leach solution has an effect of promoting the proliferation of fibroblasts. After 24, 48 and 72 hours of culture, the measured cell activity (OD value) is obviously improved relative to a control group, which indicates that the leaching liquor after the ions are dissolved out of the mesoporous bioglass has the function of promoting proliferation of fibroblasts and has potential repairing and anti-aging functions for skin.
Example 9 antioxidant capacity of composite particles
The antioxidant property of the composite particles is verified by adopting a DPPH free radical scavenging experiment.
(1) 0.002g of DPPH was dissolved in 50mL of ethanol to prepare a 0.1mM DPPH solution, which was stored in the dark.
(2) Composite particles of 0.3125, 0.625, 1.25, 2.5, 5, 10mg/mL were prepared, respectively.
(3) Respectively adding a sample group, a control group and a blank group with different concentrations into a 96-well plate,
(sample group): sample solution 100. mu.L + DPPH solution 100. mu.L (3 wells per concentration)
(blank group): sample solution 100. mu.L + Anhydrous ethanol 100. mu.L (3 wells per concentration)
(control group): DPPH alcoholic solution 100. mu.L + Water 100. mu.L
(4) After each group was prepared, incubated for 30 minutes at room temperature in the dark.
(5) The absorbance at 517nm was measured, the average value was taken, and the DPPH clearance of the sample at each concentration was calculated by the following formula:
clearance rate ═ 1- (A)sample-Ablank)/Acontrol)*100％
As can be seen from the test results of fig. 13, the active-loaded particles were able to exert the effect of removing radicals, exhibiting concentration-dependent antioxidant properties. The loading condition is mild, chemical reaction is not involved, and loading and controlled release are carried out only through physical adsorption at normal temperature and the channel effect of mesopores, so that the active substance can keep better activity in the loading process.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (12)
1. The preparation method of the idebenone and mesoporous bioglass composite carrier is characterized by comprising the following steps:
dissolving a template agent P123 in a hydrochloric acid aqueous solution to obtain a template agent solution;
dissolving a calcium source and a phosphorus source in a template solution;
thirdly, dropwise adding a silicon source into the system, and stirring at constant temperature for reaction to obtain a suspension;
step four, carrying out suction filtration, washing, alcohol washing, drying, calcining and ball milling on the suspension to obtain mesoporous bioglass powder;
and step five, dissolving idebenone in ethanol, mixing with the mesoporous bioglass powder, stirring, adsorbing, centrifuging, washing and drying to obtain the idebenone and mesoporous bioglass composite carrier.
2. The preparation method of the idebenone and mesoporous bioglass composite carrier is characterized by comprising the following steps:
dissolving a template agent P123 in a hydrochloric acid aqueous solution to obtain a template agent solution;
dissolving a calcium source, a phosphorus source and a pore-expanding agent in a template agent solution;
thirdly, dropwise adding a silicon source into the system, stirring at constant temperature for reaction, and carrying out high-pressure hydrothermal reaction to obtain a suspension;
step four, carrying out suction filtration, washing, alcohol washing, drying, calcining and ball milling on the suspension to obtain mesoporous bioglass powder;
and step five, dissolving idebenone in ethanol, mixing with the mesoporous bioglass powder, stirring, adsorbing, centrifuging, washing and drying to obtain the idebenone and mesoporous bioglass composite carrier.
3. The preparation method according to claim 1 or 2, wherein in the first step, the concentration of the hydrochloric acid aqueous solution is 1 to 3 mol/L; the dosage ratio of the template agent to the hydrochloric acid aqueous solution is (8-10): 200-300) in g/mL.
4. A production method according to claim 1 or 2, characterized in that the calcium source is calcium nitrate or calcium nitrate tetrahydrate, the phosphorus source is triethyl phosphate, the pore-expanding agent is 1,3, 5-trimethylbenzene, and the silicon source is ethyl orthosilicate.
5. The preparation method according to claim 1, wherein the calcium source, the phosphorus source, the silicon source and the template solution are used in a ratio of (1-3): (0.5-0.8): (14-16): (200-300).
6. The preparation method according to claim 2, wherein the calcium source, the phosphorus source, the silicon source, the pore-expanding agent and the template agent solution are used in a ratio of (1-3): (0.5-0.8): (14-16): (10-12): (200-300).
7. The preparation method according to claim 1 or 2, wherein in the third step, the constant-temperature stirring reaction is carried out at a temperature of 40-50 ℃ for 20-30 hours.
8. The preparation method according to claim 2, wherein in the third step, the temperature of the high-pressure hydrothermal reaction is 95-100 ℃ and the time is 20-30 hours.
9. The method according to claim 1 or 2, wherein in the fourth step, the drying temperature is 55-65 ℃ and the calcining temperature is 540-560 ℃.
10. The method according to claim 1 or 2, wherein in the fifth step, the concentration of idebenone in the aqueous ethanol solution is 0.1 to 10mg/mL, and the time for stirring and adsorbing is 12 to 72 hours.
11. The idebenone and mesoporous bioglass composite carrier prepared by the preparation method of any one of claims 1 to 10, wherein the pore diameter of the mesoporous bioglass is 4-40 nm.
12. A cosmetic comprising the idebenone or mesoporous bioglass composite carrier according to claim 11, wherein the concentration of the idebenone or mesoporous bioglass composite carrier in the cosmetic is less than or equal to 1000 μ g/mL.
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