CN113476315A - Long-acting moisturizing slow-release microsphere applied to sun screen and preparation method thereof - Google Patents
Long-acting moisturizing slow-release microsphere applied to sun screen and preparation method thereof Download PDFInfo
- Publication number
- CN113476315A CN113476315A CN202110747192.2A CN202110747192A CN113476315A CN 113476315 A CN113476315 A CN 113476315A CN 202110747192 A CN202110747192 A CN 202110747192A CN 113476315 A CN113476315 A CN 113476315A
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- microspheres
- slow
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- reaction
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims abstract description 9
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Abstract
The invention relates to the technical field of cosmetics, and discloses a long-acting moisturizing slow-release microsphere applied to a sun screen and a preparation method thereof, aiming at the problems that the existing sun screen has poor moisturizing and skin-care persistence and harsh slow-release conditions of slow-release microspheres in the sun screen. The essence comprises the following components in parts by weight: 2-5 parts of shea butter, 4-6 parts of squalane, 10-15 parts of hyaluronic acid, 1-3 parts of vitamin E and 8-10 parts of n-butanol. According to the invention, the essence liquid is filled in the porous hydrogel and can swell under the condition of filling light in the slow-release microspheres, and the polymer cracked under the light is adopted to carry out hole sealing on the slow-release microspheres, so that the long-acting slow release of the essence liquid in the slow-release microspheres is finally realized, and a better water replenishing and skin caring effect is achieved.
Description
Technical Field
The invention relates to the technical field of cosmetics, in particular to a long-acting moisturizing slow-release microsphere applied to a sun screen and a preparation method thereof.
Background
The makeup base mainly aims at protecting the skin and relieving the stimulation of adverse factors to the skin; in addition, the sun screen also has the function of isolating ultraviolet rays because the sun screen contains a sun screen agent, the sun screen agent is a layer of protective barrier closest to the skin, people usually need to make up for a long time in daytime, the fitting degree of the color makeup is reduced if the skin is dry, on one hand, the cosmetic effect of the appearance is easy to be poor, on the other hand, the skin quality is poor due to long-time water shortage, the existing sun screen agent becomes a simple dry coating layer after the solvent is volatilized, the skin comfort level is poor, and therefore, the development of the color makeup sun screen agent which can supplement water for a long time and can effectively isolate has important significance. The addition of the slow release microspheres with good release stability in the sun screen is the primary choice, but the existing slow release microspheres added have strict release conditions and are often required to be mixed with multiple components to promote slow release.
The invention discloses a preparation method of rabeprazole sodium enteric-coated sustained-release microspheres and an oral solid preparation containing the same, and relates to sustained-release microspheres containing exendin-4, wherein the sustained-release microspheres are obtained by an emulsification and crosslinking technology and have a W/O/W structure, an inner water phase contains a main drug exendin-4, an intermediate oil phase contains polylactic-glycolic acid copolymer (PLGA), and an outer water phase contains polyvinyl alcohol (PVA). The obtained microspheres have smooth surfaces and particle sizes of 40-100 mu m; the drug loading of the microspheres is between 0.4 and 0.8 percent. The invention also relates to an injection prepared from the sustained-release microspheres. The invention also relates to a preparation method of the sustained-release microsphere. The sustained-release microsphere has the advantages of high drug loading, high encapsulation rate, stable release rate, long sustained release time (more than 4 weeks), biodegradability and the like, so that the administration times can be obviously reduced, the surgical implantation and the surgical taking out before and after administration are avoided, the clinical application is facilitated, the compliance of patients is greatly improved, and the long-acting antidiabetic treatment effect is achieved.
The slow release microspheres have the defects that the slow release microspheres need intestinal solution to be dissolved, triggered and released, and the slow release microspheres cannot be applied to the effect of continuously preserving moisture and replenishing water in sunscreen cream.
Disclosure of Invention
The invention provides a long-acting moisturizing slow-release microsphere applied to a sun screen and a preparation method thereof, aiming at overcoming the problems that the existing sun screen has poor persistence of moisturizing and skin care and the slow-release conditions of the slow-release microsphere in the sun screen are harsh.
In order to achieve the purpose, the invention adopts the following technical scheme:
the long-acting moisturizing slow-release microspheres applied to the sun screen are filled with porous hydrogel and essence, the surfaces of the slow-release microspheres are sealed by a photo-cracking polymer, and the essence in the slow-release microspheres is slowly released under the expansion and extrusion effects of the porous hydrogel under the illumination effect.
The sun screen is closest to the skin, and in order to ensure the long-acting moisturizing effect and the skin-adhering effect of the sun screen, the addition component needs to be introduced to realize the function of moisturizing and repairing the skin by releasing essence for a long time. The invention introduces the slow release microspheres with the long-acting moisturizing and skin care functions, the slow release microspheres fill porous hydrogel into hollow porous titanium dioxide hollow microspheres, essence is filled in pores of the porous hydrogel, and light-degradable flexible polymers are introduced into pores on the surfaces of the porous titanium dioxide hollow microspheres for sealing the pores, so that the premature outflow of the essence in the slow release microspheres is prevented. The porous hydrogel in the sustained-release microspheres has a good storage effect on the essence on one hand; on the other hand, the volume of the porous hydrogel begins to expand when light is irradiated, and the porous hydrogel with the expanded volume is gradually extruded into the pores under the limitation of the volume of the porous titanium dioxide hollow microspheres, so that essence in the pores of the porous hydrogel is promoted to flow outwards and be absorbed by the pores, and the effects of moisturizing, long-acting moisturizing and skin care are achieved.
Preferably, the essence comprises the following components in parts by weight: 2-5 parts of shea butter, 4-6 parts of squalane, 10-15 parts of hyaluronic acid, 1-3 parts of vitamin E and 8-10 parts of n-butanol.
Preferably, the preparation process of the sustained-release microspheres comprises the following steps:
(1) dissolving galactose accounting for 60-70% of the total mass of the galactose in water, heating to 165-170 ℃ for reaction for 5-6h, decompressing and filtering after the reaction is finished, collecting a product, and freeze-drying for 12-14h to obtain a template microsphere; adding the template microspheres into distilled water, performing ultrasonic dispersion for 15-20min, sequentially adding concentrated sulfuric acid, titanium sulfate and the residual mass of galactose, uniformly mixing, heating to 160-170 ℃ for reaction for 6-8h, centrifugally collecting, cleaning with distilled water, drying at 60-70 ℃ for 10-12h, and finally calcining at 500-550 ℃ to remove the template microspheres to obtain porous titanium dioxide hollow microspheres;
(2) dissolving activated spiropyran in ethanol to form an activated spiropyran solution with the mass concentration of 25-30%, N-isopropylacrylamide, pore-forming agent povidone, diethylenetriamine and dicumyl peroxide, uniformly mixing, continuously adding porous titanium dioxide hollow microspheres into the mixture, soaking for 30-40min, carrying out blue light irradiation pre-reaction for 10-15min, separating out the porous titanium dioxide hollow microspheres, and continuously carrying out blue light irradiation reaction for 0.8-1h to obtain the porous hydrogel microspheres;
(3) dissolving carboxyl-terminated polytetramethylene glycol in acetone, adding the porous hydrogel microspheres obtained in the step (2) and azobisisobutyronitrile, heating to 65-75 ℃ for reacting for 40-45min, continuously adding end-isonitrile polytetramethylene glycol, heating to 85-90 ℃, preserving heat for 1.2-1.7h, cooling to room temperature, washing, separating, and drying by air blasting to obtain grafted porous hydrogel microspheres;
(4) dipping the grafted porous hydrogel microspheres into essence under the condition of keeping out of the sun, and carrying out ultrasonic treatment for 45-60min to obtain the grafted porous hydrogel microspheres loaded with the essence;
(5) under the condition of keeping out of the sun, dissolving 4-pyridylaldehyde and cyclohexanone peroxide in ethanol, adding the grafted porous hydrogel microspheres loaded with essence, heating to 75-80 ℃, stirring for 1.5-1.8h, cooling to room temperature, alternately cleaning with deionized water and absolute ethyl alcohol, and air-drying at room temperature to obtain slow-release microspheres;
the preparation process of the sustained-release microsphere has the specific reaction mechanism: firstly, carrying out a reaction on galactose at a high temperature to form a C template microsphere, continuously adding titanium sulfate and the rest galactose to obtain a porous microsphere under the action of concentrated sulfuric acid, and then calcining at a high temperature to obtain a porous titanium dioxide hollow microsphere; performing polymerization reaction on a carbon-carbon double bond on monomer N-isopropyl acrylamide and a double bond of hydroxyethyl methacrylate on activated spiropyran, adding a cross-linking agent diethylenetriamine and an initiator dicumyl peroxide to perform the combined action, and simultaneously forming porous hydrogel in the porous titanium dioxide hollow microspheres under the action of a pore-forming agent povidone, wherein the process for forming the porous hydrogel comprises the steps of performing hydrosol in the porous titanium dioxide hollow microspheres firstly, and continuously forming the porous hydrogel after separation; grafting carboxyl-terminated polytetramethylene glycol and end isocyano polytetramethylene glycol on the surface of the porous hydrogel microsphere to form a flexible pore sealing chain; the step (4) is carried out in a dark environment, so that the volume of the porous hydrogel can be shrunk, the holes can be enlarged, and more essence can be filled in the ultrasonic process; and (5) performing an encapsulation reaction, wherein a carboxyl group on the carboxyl-terminated polytetramethylene glycol, an isonitrile group on the end isonitrile polytetramethylene glycol and an aldehyde group on the 4-pyridylaldehyde perform a hydrogen bond stacking reaction under the action of an initiator cyclohexanone peroxide to form an isonitrile group to capture a hydroxyl group on the aldehyde group to perform an addition reaction to form an amido bond, the amido bond and the 4-pyridylaldehyde form a carbon-carbon bond, and carbon of the 4-pyridylaldehyde which loses the hydroxyl group receives hydrogen on the carboxyl group to form an ester bond, so that a complete flexible polymer is formed, a hole sealing effect is achieved, the phenomenon that the essence leaks out of the microspheres slowly released before use can be prevented, and the waste of the essence is avoided. Under the action of illumination, C-O bond degradation of ester formed by electron induction can occur, ester bonds are separated from carbon on the 4-pyridylaldehyde, and at the moment, carbon-oxygen bonds between carboxyl and the 4-pyridylaldehyde are broken, namely, the polymer is cracked under the action of light induction.
The porous titanium dioxide hollow microspheres are selected mainly because titanium dioxide has high refractivity and high photoactivity, so that sunlight and skin can be well isolated, and the sun protection performance of the sun screen is improved.
Preferably, in the step (1), the mass ratio of galactose, concentrated sulfuric acid and titanium sulfate is 6: 0.5-0.8: 2-2.5.
Preferably, in the step (2), the mass ratio of the activated spiropyran solution, the N-isopropylacrylamide, the pore-forming agent povidone, the diethylenetriamine, the dicumyl peroxide and the porous titanium dioxide hollow microspheres is 5-8: 1-1.2: 0.8-1: 0.5-1: 0.4-0.8: 10-12.
Preferably, the activated spiropyran has a molecular structure containing hydroxyethyl methacrylate groups and sulfonate groups, and is prepared by the following steps: dissolving N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran in acetone, adding hydroxyethyl methacrylate and concentrated sulfuric acid solution with mass concentration of 60-70%, heating to 80-90 ℃ to carry out etherification reaction for 1.8-2.5h, continuously adding concentrated sulfuric acid solution with mass concentration of 95-98%, heating to 108-112 ℃ to carry out sulfonation reaction for 1.5-2h, carrying out rotary evaporation and concentration on the reaction solution after the reaction is finished, and carrying out column chromatography purification to obtain the final product of activated spiropyran, wherein the mass ratio of the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran, hydroxyethyl methacrylate, the concentrated sulfuric acid solution with mass concentration of 60-70% to the concentrated sulfuric acid solution with mass concentration of 95-98% is 4: 1-1.5: 0.8-0.9: 1-1.05.
The activation process for activating the spiropyran molecules is as follows: the hydroxyl on the molecule of the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran and the hydroxyl on the hydroxyethyl methacrylate are subjected to etherification reaction, then under the action of concentrated sulfuric acid, meta-position hydrogen on two benzene rings on the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran is replaced by sulfonic acid groups in a sulfuric acid molecule, sulfonation reaction is carried out, and two sulfonic acid groups are introduced into the molecular structure. Under the condition of no light, C-O bonds on activated spiropyran molecules are broken to form hydrophilic hydroxyl groups and N ═ C double bonds on nitrogen heterocycles, and the volume is shrunk; under the action of illumination, after nitrogen on the nitrogen heterocyclic ring of the activated spiropyran molecule obtains electrons, C-O bonds are connected, the molecules can be mutually exclusive, the volume of the whole activated spiropyran molecule is expanded, and the switching of dark and illumination conditions is accompanied with reversible expansion and contraction of the volume; after the activated spiropyran molecules are expanded due to illumination, the internal charge density is reduced, and the reduction of the charge density is beneficial to the diffusion of the essence from the activated spiropyran hydrogel, so that the essence in the porous hydrogel has multiple release promoting effects.
Preferably, in the step (3), the mass ratio of the carboxyl-terminated polytetramethylene glycol, the porous hydrogel microspheres, the azobisisobutyronitrile and the end isonitrile-terminated polytetramethylene glycol is 2: 8-10: 1.2-1.4: 2.8-3.2.
Preferably, the carboxyl-terminated polytetramethylene glycol preparation process comprises the following steps: adding polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine into a reaction device with an air condensation pipe, a stirrer, a thermometer and nitrogen protection, mixing, heating to 170-175 ℃ for reaction for 5-5.8h, cooling to room temperature, separating a product, and extracting impurities from the product with diethyl ether to obtain the polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine, wherein the mass ratio of the polybutylene glycol to the phthalic anhydride to the catalyst 3-amino-2-methylpyridine is 1: 1-1.4: 0.2-0.3.
The polytetramethylene glycol can be carboxylated at the end under the action of an activator phthalic anhydride and a catalyst 3-amino-2-methylpyridine, and the carboxyl-terminated polytetramethylene glycol required by hole sealing of the invention is obtained.
Preferably, the preparation process of the terminal isocyano polytetramethylene glycol comprises the following steps: dissolving polybutylene glycol in ethanol, adding p-toluenesulfonyl chloride and tetrahydrofuran, stirring and heating to 90-95 ℃, reacting for 1.2-1.5h, adding allyl alcohol, and continuing to react for 1-1.2h under heat preservation to obtain terminal propenyl polybutylene glycol; uniformly mixing terminal propenyl polybutylene glycol, 2-methyl isocyanoacrylate and diacyl peroxide, heating to 80-90 ℃, reacting for 2-2.4h, separating, and carrying out chromatography to obtain the compound, wherein the mass ratio of polybutylene glycol to p-toluenesulfonyl chloride to tetrahydrofuran to allyl alcohol is 1: 1.2-1.4: 0.2-0.5: 0.8-1.2; the mass ratio of the terminal propenyl polybutylene glycol to the 2-isocyano methyl acrylate to the diacyl peroxide is 2: 0.8-1: 0.2-0.4.
The preparation principle of the end-isocyano polytetramethylene glycol is as follows: under the action of a catalyst tetrahydrofuran, introducing p-toluenesulfonyl groups at two ends of the polytetramethylene glycol, then adding allyl alcohol to react to generate terminal propenyl polytetramethylene glycol, carrying out polymerization reaction on the terminal propenyl and double bonds in 2-methyl isocyanoacrylate under the action of an initiator oxidized diacyl, introducing isocyano, and finally forming the terminal isocyano polytetramethylene glycol.
Adopt the polytetramethylene glycol as flexible hole sealing chain body because the polytetramethylene glycol itself has the effect of moisturizing nutrition to the skin, the nature of polytetramethylene glycol is very mild, and the texture is fresh and cool not sticky, does not have the injury to the skin after the use, and is nontoxic nonirritant, can also adsorb moisture, avoids volatilizing of moisture, can also alleviate the dry condition of skin, desalts skin fine lines, still has the effect of inhibiting the bacterium simultaneously. The joint action of the carboxyl-terminated polytetramethylene glycol and the end isocyano polytetramethylene glycol is adopted, so that the joint action of the sustained-release microspheres and the skin can be promoted.
Preferably, in the step (5), the mass ratio of the 4-pyridylaldehyde to the cyclohexanone peroxide to the essence-loaded grafted porous hydrogel microspheres is 1: 2-2.4: 4-5.
Therefore, the invention has the following beneficial effects:
(1) according to the invention, the interior of the slow-release microspheres is filled with essence which swells under the condition of illumination, the porous hydrogel is filled with essence, the slow-release microspheres are sealed by adopting polymers cracked under illumination, the polymer molecular chains are cracked to release the essence under illumination, the porous hydrogel is expanded to promote the release of the essence, and the long-acting slow release of the essence in the slow-release microspheres is finally realized under the condition;
(2) under the action of illumination, activated spiropyran molecules obtain electrons, C-O bonds are connected, the molecules repel each other, the volume of the whole activated spiropyran molecules is expanded, the charge density in the activated spiropyran molecules is reduced after the activated spiropyran molecules are expanded, the reduction of the charge density is beneficial to flowing of essence from the activated spiropyran hydrogel, and the multiple release promotion effect of the essence in the porous hydrogel is realized;
(3) carboxyl on the carboxyl-terminated polytetramethylene glycol, isonitrile groups on the end isonitrile polytetramethylene glycol and aldehyde groups on the 4-pyridylaldehyde form a complete flexible polymer, so that the phenomenon that hydrogen ions on the original carboxyl are separated from carbon on the 4-pyridylaldehyde under the action of illumination and the carbon-oxygen bond between the carboxyl and the 4-pyridylaldehyde is broken to lose the packaging effect due to the fact that essence exudes before use can be prevented;
(4) the invention realizes the effect of slowly releasing essence only by self condition induction by means of illumination, has the effects of long-acting moisture preservation and skin protection, and overcomes the problems of skin dryness after long-time makeup and skin removal and fitting.
Detailed Description
Example 1
The slow-release microspheres are filled with porous hydrogel and moisturizing and skin-care essence, the surfaces of the slow-release microspheres are sealed by a photo-cracking polymer, and the moisturizing and skin-care essence in the slow-release microspheres is slowly released under the expansion and extrusion effects of the porous hydrogel under the illumination effect.
The water-replenishing skin-care essence comprises the following components in parts by weight: 3.5 parts of shea butter, 5 parts of squalane, 13 parts of hyaluronic acid, 2 parts of vitamin E and 9 parts of n-butyl alcohol.
The preparation process of the sustained-release microsphere comprises the following steps:
(1) dissolving galactose accounting for 65% of the total mass of the galactose in water, heating to 168 ℃ for reaction for 5.5h, decompressing and filtering after the reaction is finished, collecting a product, and freeze-drying for 13h to obtain a template microsphere; adding the template microspheres into distilled water, performing ultrasonic dispersion for 18min, sequentially adding concentrated sulfuric acid, titanium sulfate and the residual mass of galactose, uniformly mixing, heating to 165 ℃ for reaction for 7h, centrifugally collecting, cleaning with distilled water, drying at 65 ℃ for 11h, and finally calcining at 525 ℃ to remove the template microspheres to obtain porous titanium dioxide hollow microspheres; the mass ratio of the galactose to the concentrated sulfuric acid to the titanium sulfate is 6: 0.6: 2.3;
(2) dissolving activated spiropyran in ethanol to form an activated spiropyran solution with the mass concentration of 28%, N-isopropylacrylamide, pore-forming agent povidone, diethylenetriamine and dicumyl peroxide, uniformly mixing, continuously adding porous titanium dioxide hollow microspheres into the mixture, soaking for 35min, carrying out blue light irradiation pre-reaction for 12min, separating out the porous titanium dioxide hollow microspheres, and continuously carrying out blue light irradiation reaction for 0.9h to obtain porous hydrogel microspheres; the mass ratio of the activated spiropyran solution to the N-isopropylacrylamide to the pore-forming agent povidone, diethylenetriamine to the dicumyl peroxide to the porous titanium dioxide hollow microspheres is 6.5: 1.1: 0.9: 0.8: 0.6: 11;
the activated spiropyran molecular structure contains hydroxyethyl methacrylate groups and sulfonate groups, and the preparation process comprises the following steps: dissolving N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran in acetone, adding hydroxyethyl methacrylate and a concentrated sulfuric acid solution with the mass concentration of 65%, heating to 85 ℃ for etherification reaction for 2.1h, continuously adding a concentrated sulfuric acid solution with the mass concentration of 96.5%, heating to 110 ℃ for sulfonation reaction for 1.8h, performing rotary evaporation and concentration on the reaction solution after the reaction is finished, and performing column chromatography purification to obtain a final product, namely the activated spiropyran, wherein the mass ratio of the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran, hydroxyethyl methacrylate, the concentrated sulfuric acid solution with the mass concentration of 65% to the concentrated sulfuric acid solution with the mass concentration of 96.5% is 4: 1.2: 0.85: 1.02;
(3) dissolving carboxyl-terminated polytetramethylene glycol in acetone, adding the porous hydrogel microspheres obtained in the step (2) and azobisisobutyronitrile, heating to 70 ℃ for reaction for 42min, continuously adding end-isonitrile polytetramethylene glycol, heating to 88 ℃, keeping the temperature for 1.5h, cooling to room temperature, washing, separating, and drying by blowing to obtain grafted porous hydrogel microspheres; the mass ratio of carboxyl-terminated polytetramethylene glycol to porous hydrogel microspheres to azodiisobutyronitrile to end isonitrile polytetramethylene glycol is 2: 9: 1.3: 3;
the preparation process of the carboxyl-terminated polytetramethylene glycol comprises the following steps: adding polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine into a reaction device with an air condensation pipe, a stirrer, a thermometer and nitrogen protection, mixing, heating to 172 ℃, reacting for 5.4h, cooling to room temperature, separating a product, extracting impurities from the product with diethyl ether to obtain the polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine, wherein the mass ratio of the polybutylene glycol to the phthalic anhydride to the catalyst 3-amino-2-methylpyridine is 1: 1.2: 0.25;
the preparation process of the end-isocyano polytetramethylene glycol comprises the following steps: dissolving polybutylene glycol in ethanol, adding p-toluenesulfonyl chloride and tetrahydrofuran, stirring and heating to 92 ℃ for reaction for 1.35h, adding allyl alcohol, and continuing to perform heat preservation reaction for 1.1h to obtain terminal propenyl polybutylene glycol; uniformly mixing terminal propenyl polybutylene glycol, 2-methyl isocyanoacrylate and diacyl peroxide, heating to 85 ℃ for reaction for 2.2h, separating, and carrying out chromatography to obtain the compound, wherein the mass ratio of polybutylene glycol to p-toluenesulfonyl chloride to tetrahydrofuran to allyl alcohol is 1: 1.3: 0.35: 1; the mass ratio of the terminal propenyl polybutylene glycol to the 2-isocyano methyl acrylate to the diacyl peroxide is 2: 0.9: 0.3;
(4) dipping the grafted porous hydrogel microspheres into essence under the condition of keeping out of the sun, and carrying out ultrasonic treatment for 55min to obtain the grafted porous hydrogel microspheres loaded with the essence;
(5) under the condition of keeping out of the sun, dissolving 4-pyridylaldehyde and cyclohexanone peroxide in ethanol, adding the grafted porous hydrogel microspheres loaded with essence, heating to 78 ℃, stirring for 1.6h, cooling to room temperature, alternately cleaning with deionized water and absolute ethyl alcohol, and air-drying at normal temperature to obtain slow-release microspheres; the mass ratio of the 4-pyridylaldehyde to the cyclohexanone peroxide to the essence-loaded grafted porous hydrogel microspheres is 1: 2.2: 4.5.
example 2
The slow-release microspheres are filled with porous hydrogel and moisturizing and skin-care essence, the surfaces of the slow-release microspheres are sealed by a photo-cracking polymer, and the moisturizing and skin-care essence in the slow-release microspheres is slowly released under the expansion and extrusion effects of the porous hydrogel under the illumination effect.
The water-replenishing skin-care essence comprises the following components in parts by weight: 2 parts of shea butter, 4 parts of squalane, 10 parts of hyaluronic acid, 1 part of vitamin E and 8 parts of n-butyl alcohol.
The preparation process of the sustained-release microsphere comprises the following steps:
(1) dissolving galactose accounting for 60% of the total mass of the galactose in water, heating to 165 ℃ for reaction for 5 hours, decompressing and filtering after the reaction is finished, collecting a product, and freeze-drying for 12 hours to obtain a template microsphere; adding the template microspheres into distilled water, performing ultrasonic dispersion for 15min, sequentially adding concentrated sulfuric acid, titanium sulfate and the residual mass of galactose, uniformly mixing, heating to 160 ℃, reacting for 6h, centrifugally collecting, cleaning with distilled water, drying at 60 ℃ for 10h, and finally calcining at 500 ℃ to remove the template microspheres to obtain porous titanium dioxide hollow microspheres; the mass ratio of the galactose to the concentrated sulfuric acid to the titanium sulfate is 6: 0.5: 2;
(2) dissolving activated spiropyran in ethanol to form an activated spiropyran solution with the mass concentration of 25%, N-isopropylacrylamide, pore-forming agent povidone, diethylenetriamine and dicumyl peroxide, uniformly mixing, continuously adding porous titanium dioxide hollow microspheres into the mixture, soaking for 30min, carrying out blue light irradiation pre-reaction for 10min, separating out the porous titanium dioxide hollow microspheres, and continuously carrying out blue light irradiation reaction for 0.8h to obtain porous hydrogel microspheres; the mass ratio of the activated spiropyran solution to the N-isopropylacrylamide to the pore-forming agent povidone, diethylenetriamine to the dicumyl peroxide to the porous titanium dioxide hollow microspheres is 5: 1: 0.8: 0.5: 0.4: 10;
the activated spiropyran molecular structure contains hydroxyethyl methacrylate groups and sulfonate groups, and the preparation process comprises the following steps: dissolving N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran in acetone, adding hydroxyethyl methacrylate and a concentrated sulfuric acid solution with the mass concentration of 60%, heating to 80 ℃ for etherification reaction for 1.8h, continuously adding a concentrated sulfuric acid solution with the mass concentration of 95%, heating to 108 ℃ for sulfonation reaction for 1.5h, performing rotary evaporation and concentration on the reaction solution after the reaction is finished, and performing column chromatography purification to obtain a final product, namely, activated spiropyran, wherein the mass ratio of the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran, hydroxyethyl methacrylate, the concentrated sulfuric acid solution with the mass concentration of 60% to the concentrated sulfuric acid solution with the mass concentration of 95% is 4: 1: 0.8: 1;
(3) dissolving carboxyl-terminated polytetramethylene glycol in acetone, adding the porous hydrogel microspheres obtained in the step (2) and azobisisobutyronitrile, heating to 65 ℃ for reacting for 40min, continuously adding end-isonitrile polytetramethylene glycol, heating to 85 ℃, keeping the temperature for 1.2h, cooling to room temperature, washing, separating, and drying by air blasting to obtain grafted porous hydrogel microspheres; the mass ratio of carboxyl-terminated polytetramethylene glycol to porous hydrogel microspheres to azodiisobutyronitrile to end isonitrile polytetramethylene glycol is 2: 8: 1.2: 2.8 of;
the preparation process of the carboxyl-terminated polytetramethylene glycol comprises the following steps: adding polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine into a reaction device with an air condensation pipe, a stirrer, a thermometer and nitrogen protection, mixing, heating to 170 ℃, reacting for 5 hours, cooling to room temperature, separating a product, extracting impurities from the product with diethyl ether to obtain the polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine, wherein the mass ratio of the polybutylene glycol to the phthalic anhydride to the catalyst 3-amino-2-methylpyridine is 1: 1: 0.2;
the preparation process of the end-isocyano polytetramethylene glycol comprises the following steps: dissolving polybutylene glycol in ethanol, adding p-toluenesulfonyl chloride and tetrahydrofuran, stirring and heating to 90 ℃ for reaction for 1.2h, adding allyl alcohol, and continuing to perform heat preservation reaction for 1h to obtain terminal propenyl polybutylene glycol; uniformly mixing terminal propenyl polybutylene glycol, 2-methyl isocyanoacrylate and diacyl peroxide, heating to 80 ℃ for reaction for 2 hours, separating and carrying out chromatography to obtain the compound, wherein the mass ratio of polybutylene glycol to p-toluenesulfonyl chloride to tetrahydrofuran to allyl alcohol is 1: 1.2: 0.2: 0.8; the mass ratio of the terminal propenyl polybutylene glycol to the 2-isocyano methyl acrylate to the diacyl peroxide is 2: 0.8: 0.2;
(4) dipping the grafted porous hydrogel microspheres into essence under the condition of keeping out of the sun, and carrying out ultrasonic treatment for 45min to obtain the grafted porous hydrogel microspheres loaded with the essence;
(5) under the condition of keeping out of the sun, dissolving 4-pyridylaldehyde and cyclohexanone peroxide in ethanol, adding the grafted porous hydrogel microspheres loaded with essence, heating to 75 ℃, stirring for 1.5h, cooling to room temperature, alternately cleaning with deionized water and absolute ethyl alcohol, and air-drying at normal temperature to obtain slow-release microspheres; the mass ratio of the 4-pyridylaldehyde to the cyclohexanone peroxide to the essence-loaded grafted porous hydrogel microspheres is 1: 2: 4.
example 3
The slow-release microspheres are filled with porous hydrogel and moisturizing and skin-care essence, the surfaces of the slow-release microspheres are sealed by a photo-cracking polymer, and the moisturizing and skin-care essence in the slow-release microspheres is slowly released under the expansion and extrusion effects of the porous hydrogel under the illumination effect.
The water-replenishing skin-care essence comprises the following components in parts by weight: 5 parts of shea butter, 6 parts of squalane, 15 parts of hyaluronic acid, 3 parts of vitamin E and 10 parts of n-butyl alcohol.
The preparation process of the sustained-release microsphere comprises the following steps:
(1) dissolving galactose accounting for 70% of the total mass of the galactose in water, heating to 170 ℃ for reaction for 6 hours, decompressing and filtering after the reaction is finished, collecting a product, and freeze-drying for 14 hours to obtain a template microsphere; adding the template microspheres into distilled water, performing ultrasonic dispersion for 20min, sequentially adding concentrated sulfuric acid, titanium sulfate and the residual mass of galactose, uniformly mixing, heating to 170 ℃, reacting for 8h, centrifugally collecting, cleaning with distilled water, drying at 70 ℃ for 12h, and finally calcining at 550 ℃ to remove the template microspheres to obtain porous titanium dioxide hollow microspheres; the mass ratio of the galactose to the concentrated sulfuric acid to the titanium sulfate is 6: 0.8: 2.5;
(2) dissolving activated spiropyran in ethanol to form an activated spiropyran solution with the mass concentration of 30%, N-isopropylacrylamide, pore-forming agent povidone, diethylenetriamine and dicumyl peroxide, uniformly mixing, continuously adding porous titanium dioxide hollow microspheres into the mixture, soaking for 40min, carrying out blue light irradiation pre-reaction for 15min, separating out the porous titanium dioxide hollow microspheres, and continuously carrying out blue light irradiation reaction for 1h to obtain porous hydrogel microspheres; the mass ratio of the activated spiropyran solution, the N-isopropyl acrylamide, the pore-foaming agent povidone, the diethylenetriamine, the dicumyl peroxide and the porous titanium dioxide hollow microspheres is 8: 1.2: 1: 1: 0.8: 12;
the activated spiropyran molecular structure contains hydroxyethyl methacrylate groups and sulfonate groups, and the preparation process comprises the following steps: dissolving N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran in acetone, adding hydroxyethyl methacrylate and concentrated sulfuric acid solution with the mass concentration of 70%, heating to 90 ℃ for etherification reaction for 2.5h, continuously adding concentrated sulfuric acid solution with the mass concentration of 98%, heating to 112 ℃ for sulfonation reaction for 2h, performing rotary evaporation and concentration on reaction liquid after the reaction is finished, and performing column chromatography purification to obtain a final product, namely activated spiropyran, wherein the mass ratio of the N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran, hydroxyethyl methacrylate, concentrated sulfuric acid solution with the mass concentration of 70% to the concentrated sulfuric acid solution with the mass concentration of 98% is 4: 1.5: 0.9: 1.05;
(3) dissolving carboxyl-terminated polytetramethylene glycol in acetone, adding the porous hydrogel microspheres obtained in the step (2) and azobisisobutyronitrile, heating to 75 ℃ for reacting for 45min, continuously adding end-isonitrile polytetramethylene glycol, heating to 90 ℃, preserving heat for 1.7h, cooling to room temperature, washing, separating, and drying by air blasting to obtain grafted porous hydrogel microspheres; the mass ratio of carboxyl-terminated polytetramethylene glycol to porous hydrogel microspheres to azodiisobutyronitrile to end isonitrile polytetramethylene glycol is 2: 10: 1.4: 3.2;
the preparation process of the carboxyl-terminated polytetramethylene glycol comprises the following steps: adding polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine into a reaction device with an air condensation pipe, a stirrer, a thermometer and nitrogen protection, mixing, heating to 175 ℃, reacting for 5.8h, cooling to room temperature, separating a product, extracting impurities from the product with diethyl ether to obtain the polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine, wherein the mass ratio of the polybutylene glycol to the phthalic anhydride to the catalyst 3-amino-2-methylpyridine is 1: 1.4: 0.3;
the preparation process of the end-isocyano polytetramethylene glycol comprises the following steps: dissolving polybutylene glycol in ethanol, adding p-toluenesulfonyl chloride and tetrahydrofuran, stirring and heating to 95 ℃ for reaction for 1.5h, adding allyl alcohol, and continuing to perform heat preservation reaction for 1.2h to obtain terminal propenyl polybutylene glycol; uniformly mixing terminal propenyl polybutylene glycol, 2-methyl isocyanoacrylate and diacyl peroxide, heating to 90 ℃, reacting for 2.4h, separating, and carrying out chromatography to obtain the compound, wherein the mass ratio of polybutylene glycol to p-toluenesulfonyl chloride to tetrahydrofuran to allyl alcohol is 1: 1.4: 0.5: 1.2; the mass ratio of the terminal propenyl polybutylene glycol to the 2-isocyano methyl acrylate to the diacyl peroxide is 2: 1: 0.4;
(4) dipping the grafted porous hydrogel microspheres into essence under the condition of keeping out of the sun, and carrying out ultrasonic treatment for 60min to obtain the grafted porous hydrogel microspheres loaded with the essence;
(5) under the condition of keeping out of the sun, dissolving 4-pyridylaldehyde and cyclohexanone peroxide in ethanol, adding the grafted porous hydrogel microspheres loaded with essence, heating to 80 ℃, stirring for 1.8h, cooling to room temperature, alternately cleaning with deionized water and absolute ethyl alcohol, and air-drying at normal temperature to obtain slow-release microspheres; the mass ratio of the 4-pyridylaldehyde to the cyclohexanone peroxide to the essence-loaded grafted porous hydrogel microspheres is 1: 2.4: 5.
comparative example 1
The difference from the example 1 is that the porous hydrogel is not added in the sustained-release microspheres, and the rest steps are the same as the step in the uniform example 1.
Comparative example 2
The difference from example 1 was that the porous hydrogel was replaced with the hyaluronic acid hydrogel, and the rest of the procedure was the same as in example 1.
Comparative example 3
The difference from the example 1 is that the slow release microspheres are not sealed, and the rest steps are the same as those in the example 1.
Performance test:
for the above examples and comparative examples, the release rate of the sustained release microspheres in the application environment of the simulated make-up cream coating was used to evaluate the sustained release effect of the sustained release microspheres on the essence.
And calculating the content of the essence in the simulated environment according to the standard curve, and calculating the release rate of the essence.
The release rate (%) is the total amount of essence released in the environment/(the mass of essence supported by the sustained-release microspheres) × 100
The time set in the experiment is simulated according to the time of the sun screen staying on the skin, and the sun screen is stored for 12 hours before illumination.
TABLE 1 result of essence retention rate of sustained-release microspheres under illumination
And (4) conclusion: the examples 1-3 show that the sustained-release microspheres prepared by the additive components and the preparation process have good sustained-release effect and long sustained-release time, and the essence can be fully released and has good moisturizing effect on skin.
The difference between the comparative example 1 and the example 1 is that the porous hydrogel is not added in the sustained-release microspheres; after the flexible polymer sealed by the slow-release microspheres is subjected to photo-cracking after illumination, the moisturizing essence in the slow-release microspheres is released too early and quickly, so that the release duration of the moisturizing essence is short, and the purpose of long-acting continuous moisturizing cannot be achieved. The difference between the comparative example 2 and the example 1 is that the porous hydrogel is replaced by hyaluronic acid hydrogel, the essence is contained in the hyaluronic acid hydrogel, the hydrogel has a good capacity storage effect on the essence, the internal essence cannot be effectively released after the flexible polymer sealed by the slow-release microspheres is subjected to light pyrolysis, and the release rate of the essence is low within a long time (10 h). The difference between the comparative example 3 and the example 1 is that the slow release microspheres are not sealed; the essence can be greatly lost during early storage, and the essence can be prematurely released after being coated on the face, so that the effect of sustained release is not achieved.
As can be seen from the data of examples 1-3 and comparative examples 1-3, only the scheme within the scope of the claims of the present invention can satisfy the above requirements in all aspects, and a scheme for preparing sustained-release microspheres for a sun screen with excellent comprehensive properties can be obtained. The change of the mixture ratio, the replacement/addition/subtraction of raw materials or the change of the feeding sequence can bring corresponding negative effects.
The raw materials and equipment used in the invention are common raw materials and equipment in the field if not specified; the methods used in the present invention are conventional in the art unless otherwise specified.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, alterations and equivalents of the above embodiments according to the technical spirit of the present invention are still within the protection scope of the technical solution of the present invention.
Claims (10)
1. The long-acting moisturizing slow-release microspheres applied to the sun screen are characterized in that porous hydrogel and moisturizing skin care essence are filled in the slow-release microspheres, and the surfaces of the slow-release microspheres are sealed by a photolysis polymer.
2. The long-acting moisturizing slow-release microsphere applied to a sun screen according to claim 1, wherein the moisturizing and skin-care essence comprises the following components in parts by weight: 2-5 parts of shea butter, 4-6 parts of squalane, 10-15 parts of hyaluronic acid, 1-3 parts of vitamin E and 8-10 parts of n-butanol.
3. The preparation method of the long-acting moisturizing slow-release microspheres applied to the sun screen according to claim 1 is characterized by comprising the following steps:
(1) dissolving galactose accounting for 60-70% of the total mass of the galactose in water, heating to 165-170 ℃ for reaction for 5-6h, decompressing and filtering after the reaction is finished, collecting a product, and freeze-drying for 12-14h to obtain a template microsphere; adding the template microspheres into distilled water, performing ultrasonic dispersion for 15-20min, sequentially adding concentrated sulfuric acid, titanium sulfate and the residual mass of galactose, uniformly mixing, heating to 160-170 ℃ for reaction for 6-8h, centrifugally collecting, cleaning with distilled water, drying at 60-70 ℃ for 10-12h, and finally calcining at 500-550 ℃ to remove the template microspheres to obtain porous titanium dioxide hollow microspheres;
(2) dissolving activated spiropyran in ethanol to form an activated spiropyran solution with the mass concentration of 25-30%, N-isopropylacrylamide, pore-forming agent povidone, diethylenetriamine and dicumyl peroxide, uniformly mixing, continuously adding porous titanium dioxide hollow microspheres into the mixture, soaking for 30-40min, carrying out blue light irradiation pre-reaction for 10-15min, separating out the porous titanium dioxide hollow microspheres, and continuously carrying out blue light irradiation reaction for 0.8-1h to obtain the porous hydrogel microspheres;
(3) dissolving carboxyl-terminated polytetramethylene glycol in acetone, adding the porous hydrogel microspheres obtained in the step (2) and azobisisobutyronitrile, heating to 65-75 ℃ for reacting for 40-45min, continuously adding end-isonitrile polytetramethylene glycol, heating to 85-90 ℃, preserving heat for 1.2-1.7h, cooling to room temperature, washing, separating, and drying by air blasting to obtain grafted porous hydrogel microspheres;
(4) dipping the grafted porous hydrogel microspheres into essence under the condition of keeping out of the sun, and carrying out ultrasonic treatment for 45-60min to obtain the grafted porous hydrogel microspheres loaded with the essence;
(5) under the condition of keeping out of the sun, dissolving 4-pyridylaldehyde and cyclohexanone peroxide in ethanol, adding the grafted porous hydrogel microspheres loaded with essence, heating to 75-80 ℃, stirring for 1.5-1.8h, cooling to room temperature, alternately cleaning with deionized water and absolute ethyl alcohol, and air-drying at room temperature to obtain the slow-release microspheres.
4. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3, wherein in the step (1), the mass ratio of galactose to concentrated sulfuric acid to titanium sulfate is 6: 0.5-0.8: 2-2.5.
5. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3, wherein in the step (2), the mass ratio of the activated spiropyran solution, the N-isopropylacrylamide, the pore-foaming agent povidone, the diethylenetriamine, the dicumyl peroxide and the porous titanium dioxide hollow microspheres is 5-8: 1-1.2: 0.8-1: 0.5-1: 0.4-0.8: 10-12.
6. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3 or 5, wherein the activated spiropyran molecular structure contains hydroxyethyl methacrylate groups and sulfonate groups, and the preparation process comprises: dissolving N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran in acetone, adding hydroxyethyl methacrylate and concentrated sulfuric acid solution with the mass concentration of 60-70%, heating to 80-90 ℃ to perform etherification reaction for 1.8-2.5h, continuously adding concentrated sulfuric acid solution with the mass concentration of 95-98%, heating to 108-112 ℃ to perform sulfonation reaction for 1.5-2h, performing rotary evaporation and concentration on the reaction solution after the reaction is finished, and performing column chromatography purification to obtain the final product activated spiropyran; the mass ratio of N-hydroxyethyl-3, 3-dimethyl-6-nitroindoline spiropyran, hydroxyethyl methacrylate, 60-70% of concentrated sulfuric acid solution with mass concentration to 95-98% of concentrated sulfuric acid solution with mass concentration is 4: 1-1.5: 0.8-0.9: 1-1.05.
7. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3, wherein in the step (3), the mass ratio of the carboxyl-terminated polytetramethylene glycol to the porous hydrogel microspheres to the azobisisobutyronitrile to the end isocyano polytetramethylene glycol is 2: 8-10: 1.2-1.4: 2.8-3.2.
8. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3 or 7, wherein the preparation process of the carboxyl-terminated polytetramethylene glycol is as follows: adding polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine into a reaction device with an air condensation pipe, a stirrer, a thermometer and nitrogen protection, mixing, heating to 170-175 ℃ for reaction for 5-5.8h, cooling to room temperature, separating a product, and extracting impurities from the product with diethyl ether to obtain the polybutylene glycol, phthalic anhydride and catalyst 3-amino-2-methylpyridine, wherein the mass ratio of the polybutylene glycol to the phthalic anhydride to the catalyst 3-amino-2-methylpyridine is 1: 1-1.4: 0.2-0.3.
9. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3 or 7, wherein the preparation process of the end isocyano polybutylene glycol is as follows: dissolving polybutylene glycol in ethanol, adding p-toluenesulfonyl chloride and tetrahydrofuran, stirring and heating to 90-95 ℃, reacting for 1.2-1.5h, adding allyl alcohol, and continuing to react for 1-1.2h under heat preservation to obtain terminal propenyl polybutylene glycol; uniformly mixing terminal propenyl polybutylene glycol, 2-methyl isocyanoacrylate and diacyl peroxide, heating to 80-90 ℃, reacting for 2-2.4h, separating, and carrying out chromatography to obtain the compound, wherein the mass ratio of polybutylene glycol to p-toluenesulfonyl chloride to tetrahydrofuran to allyl alcohol is 1: 1.2-1.4: 0.2-0.5: 0.8-1.2; the mass ratio of the terminal propenyl polybutylene glycol to the 2-isocyano methyl acrylate to the diacyl peroxide is 2: 0.8-1: 0.2-0.4.
10. The preparation method of the long-acting moisturizing slow-release microspheres for the sun screen according to claim 3, wherein in the step (5), the mass ratio of the 4-pyridylaldehyde to the cyclohexanone peroxide to the grafted porous hydrogel microspheres loaded with the essence is 1: 2-2.4: 4-5.
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| CN115317675A (en) * | 2022-08-23 | 2022-11-11 | 苏州中天医疗器械科技有限公司 | Drug eluting stent and preparation method and application thereof |
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