Temperature response type cycloxaprid controlled release system and preparation method thereof

Abstract

The invention provides a temperature response type cycloxaprid controlled release system and a preparation method thereof, and belongs to the technical field of alkali insecticides. The temperature response type cycloxaprid controlled release system provided by the invention comprises a poly (N-isopropylacrylamide) temperature-sensitive hydrogel and a polyurethane-cycloxaprid oil-in-water microcapsule, wherein the poly (N-isopropylacrylamide) hydrogel and the polyurethane-cycloxaprid oil-in-water microcapsule form a semi-interpenetrating network structure. According to the invention, polyurethane and poly (N-isopropylacrylamide) temperature-sensitive (PNIPAAm) hydrogel are utilized to form a semi-interpenetrating network structure, so that the low critical transition temperature of a controlled release system is reduced, and the controlled release system has good thermal stability and temperature-sensitive characteristics. According to data of an embodiment, the temperature response type cycloxaprid controlled release system obtained by the invention has good drug release performance and good stability in an environment of 20-31 DEG C.

Description

Technical Field

[0001] The invention belongs to the technical field of alkali insecticides, and particularly relates to a temperature-responsive cycloheximide controlled-release system and a preparation method thereof. Background Art

[0002] Cyclomethoxadone is a cis-neonicotinoid insecticide independently developed in my country. It has excellent insecticidal activity against most pests of the order Homoptera, especially rice planthoppers, aphids and whiteflies. It is also effective against pests of the orders Lepidoptera, Coleoptera and Diptera. It can be used in agriculture and horticulture such as rice, vegetables, fruit trees, wheat, cotton and corn. It can be used for stem and leaf treatment as well as seed treatment. Cyclomethoxadone is a class of acetylcholine receptor antagonists that act on the central nervous system of insects. Its unique mechanism of action means that there is no cross-resistance between this type of product and conventional insecticides. It has low toxicity to mammals and good environmental compatibility. It also has a wide insecticidal spectrum, high activity, long-lasting effect, and is not easy to develop drug resistance. For example, cyclomethoxadone has little effect on mammals and non-target organisms such as Daphnia, fish, algae, soil microorganisms and other plants, and its safety for bees is more than 10 times that of imidacloprid.

[0003] It is reported that the insecticidal activity of cycloheximidine is greatly affected by temperature, and the activity increases greatly with the increase of temperature, that is, it shows a positive temperature effect. Therefore, when used in different seasons, due to the difference in temperature, the control effect of the same concentration on target pests will also show obvious differences. When used at lower temperatures, if the concentration is insufficient, the control effect will not meet the requirements and must be supplemented, which will accelerate the growth rate of the target's resistance to cycloheximidine; when used under high temperature conditions, cycloheximidine is easy to decompose, which reduces the efficacy, affects the insecticide timeliness, and has high control costs. In the prior art, by including technology, for example, preparing cycloheximidine into microcapsules to give cycloheximidine preparations sustained release, so as to improve its decomposition rate and stability, thereby ensuring its effectiveness in agricultural applications, but in different temperature environments, it is still impossible to effectively control the release of cycloheximidine. Summary of the invention

[0004] In view of this, the object of the present invention is to provide a temperature-responsive cycloheximide controlled-release system and a preparation method thereof. The temperature-responsive cycloheximide controlled-release system provided by the present invention has good thermal stability and temperature-sensitive properties.

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions:

[0006] The present invention provides a temperature-responsive cycloheximide controlled-release system, comprising poly-N-isopropylacrylamide temperature-sensitive hydrogel and polyurethane-cycloheximide oil-in-water microcapsules, wherein the poly-N-isopropylacrylamide hydrogel and polyurethane-cycloheximide oil-in-water microcapsules form a semi-interpenetrating network structure;

[0007] The mass ratio of the poly (N-isopropylacrylamide) thermosensitive hydrogel to the polyurethane-epoxycycloheximide oil-in-water microcapsules is 1:5 to 10:1;

[0008] The poly N-isopropylacrylamide thermosensitive hydrogel is obtained by polymerizing N-isopropylacrylamide in water under the action of a crosslinking agent and an initiator;

[0009] The polyurethane-epoxycycloheximide oil-in-water microcapsules include an aqueous phase and polyurethane-epoxycycloheximide microcapsules dispersed in the aqueous phase, the polyurethane-epoxycycloheximide microcapsules include a capsule wall and a capsule core, the capsule core includes epoxycycloheximide and an organic solvent, the capsule wall is polyurethane, and the polyurethane is cross-linked by isocyanate and a curing agent;

[0010] The curing agent is an alcohol monomer and / or an amine monomer.

[0011] Preferably, the mass ratio of cycloheximide to isocyanate is 1:1 to 10:1;

[0012] The isocyanate includes one or more of isophorone diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, tetramethylxylylene diisocyanate and lysine diisocyanate.

[0013] Preferably, the mass ratio of the N-isopropylacrylamide to the cross-linking agent is 5:500 to 30:100;

[0014] The crosslinking agent is one or more of N,N'-methylenebisacrylamide, dicumyl peroxide, triallyl isocyanurate and butanediol diglycidyl ether.

[0015] Preferably, the mass ratio of N-isopropylacrylamide to initiator is 5:2 to 30:2;

[0016] The initiator is any two of sodium persulfate, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, N,N,N',N'-tetramethyl-1,2-ethylenediamine, tetramethylethylenediamine and 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide.

[0017] Preferably, the alcohol monomer includes one or more of ethylene glycol, glycerol, polyether polyol and polyester polyol;

[0018] The amine monomers include one or more of ethylenediamine, hexamethylenediamine, polyetheramine, 1,2-propylenediamine, butanediamine, diethylenetriamine, triethylenetetramine and tetraethylenepentamine.

[0019] Preferably, the mass ratio of cycloheximide to the organic solvent is 1:5 to 1:40;

[0020] The organic solvent is one or more of cyclohexanone, butyl acetate, cyclohexanone, decanoic acid amide, methyl acetate, dimethyl carbonate, octanol and diethyl carbonate.

[0021] Preferably, the aqueous phase comprises an aqueous surfactant solution; the mass fraction of the surfactant in the aqueous surfactant solution is 0.5 to 10 wt %.

[0022] The present invention also provides a method for preparing the temperature-responsive cycloheximide controlled-release system described in the above technical solution, comprising the following steps:

[0023] Mix cycloheximide and an organic solvent, heat to a molten state, cool to 55-65° C., add isocyanate and mix to obtain an oil phase;

[0024] The oil phase is added dropwise to the water phase for emulsification to obtain an O / W emulsion;

[0025] Adding the curing agent aqueous solution dropwise into the O / W emulsion to carry out a cross-linking reaction to obtain polyurethane-epoxycyclan oil-in-water microcapsules;

[0026] N-isopropylacrylamide, a crosslinking agent, an initiator and water are mixed, and a polymerization reaction is carried out under the protection of an inert gas to obtain a poly-N-isopropylacrylamide thermosensitive hydrogel;

[0027] The polyurethane-epoxycycladim oil-in-water microcapsules and the poly (N-isopropylacrylamide) thermosensitive hydrogel are mixed to obtain the temperature-responsive epoxycycladim controlled-release system.

[0028] Preferably, the mass ratio of the oil phase to the water phase is 1:6 to 10:1.

[0029] Preferably, the mass ratio of the O / W emulsion to the curing agent is 10 to 100:1;

[0030] The mass fraction of the curing agent in the curing agent aqueous solution is 1 to 20%.

[0031] The invention provides a temperature-responsive epoxy cypermethrin controlled-release system, comprising poly (N-isopropylacrylamide) thermosensitive hydrogel and polyurethane-epoxy cypermethrin oil-in-water microcapsules, wherein the poly (N-isopropylacrylamide) thermosensitive hydrogel and the polyurethane-epoxy cypermethrin oil-in-water microcapsules form a semi-interpenetrating network structure; the mass ratio of the poly (N-isopropylacrylamide) thermosensitive hydrogel to the polyurethane-epoxy cypermethrin oil-in-water microcapsules is 1:5-10:1; the poly (N-isopropylacrylamide) thermosensitive hydrogel is obtained by polymerizing N-isopropylacrylamide in water under the action of a crosslinking agent and an initiator; the polyurethane-epoxy cypermethrin oil-in-water microcapsules comprise an aqueous phase and polyurethane-epoxy cypermethrin microcapsules dispersed in the aqueous phase, the polyurethane-epoxy cypermethrin microcapsules comprise a capsule wall and a capsule core, the capsule core comprises epoxy cypermethrin and an organic solvent, the capsule wall is polyurethane, and the polyurethane is cross-linked by isocyanate and a curing agent; the curing agent is an alcohol monomer and / or an amine monomer. The present invention uses an initiator and a crosslinking agent to initiate the polymerization of N-isopropylacrylamide monomer to form poly-N-isopropylacrylamide (PNIPAAm); PNIPAAm is hydrophilic at room temperature, but undergoes a reversible phase change within a certain temperature range (32-37°C), changing from hydrophilic to hydrophobic. This property enables the PNIPAAm-based porous hydrogel to regulate its water absorption and drug release properties according to the ambient temperature. At the same time, after PNIPAAm is used to modify polyurethane, the semi-interpenetrating network structure formed is IPN-PNIPAAm / PU hydrogel has thermosensitive properties, which can enhance its biocompatibility and reduce irritation to biological tissues. Its lower critical transition temperature (LCST) is 3°C lower than that of PNIPAAm, and it has good thermal stability and thermosensitive properties. The water-in-oil microcapsules synthesized with PU are hydrophilic. When the temperature is low, they combine with PNIPAAm to control the release of drugs slowly. When the temperature rises, PU and PNIPAAm separate from each other, and the drug can be released in large quantities, achieving thermosensitive controlled release, thereby achieving improved efficacy and reduced loss at high temperatures. It can be seen from the data in the examples that the temperature-responsive cycloheximide controlled-release system obtained by the present invention has good drug release performance and good stability in an environment of 20 to 31°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative labor.

[0033] Figure 1 This is a SEM image of the polyurethane microcapsules prepared in Example 1;

[0034] Figure 2 The release behavior curves of the temperature-responsive cycloheximide controlled-release system obtained in Example 1 at different temperatures. DETAILED DESCRIPTION

[0035] The present invention provides a temperature-responsive cycloheximide controlled-release system, comprising poly-N-isopropylacrylamide temperature-sensitive hydrogel and polyurethane-cycloheximide oil-in-water microcapsules, wherein the poly-N-isopropylacrylamide hydrogel and polyurethane-cycloheximide oil-in-water microcapsules form a semi-interpenetrating network structure;

[0036] The mass ratio of the poly (N-isopropylacrylamide) thermosensitive hydrogel to the polyurethane-epoxycycloheximide oil-in-water microcapsules is 1:5 to 10:1;

[0037] The poly N-isopropylacrylamide thermosensitive hydrogel is obtained by polymerizing N-isopropylacrylamide in water under the action of a crosslinking agent and an initiator;

[0038] The polyurethane-epoxycycloheximide oil-in-water microcapsules include an aqueous phase and polyurethane-epoxycycloheximide microcapsules dispersed in the aqueous phase, the polyurethane-epoxycycloheximide microcapsules include a capsule wall and a capsule core, the capsule core includes epoxycycloheximide and an organic solvent, the capsule wall is polyurethane, and the polyurethane is cross-linked by isocyanate and a curing agent;

[0039] The curing agent is an alcohol monomer and / or an amine monomer.

[0040] In the present invention, unless otherwise specified, the raw materials involved are commercially available products well known in the art.

[0041] In the present invention, the mass ratio of the poly N-isopropylacrylamide thermosensitive hydrogel and the polyurethane-epoxycycloheximide oil-in-water microcapsules is 1:5 to 10:1, preferably 1:3 to 6:1. In a specific embodiment of the present invention, the mass ratio of the poly N-isopropylacrylamide thermosensitive hydrogel and the polyurethane-epoxycycloheximide oil-in-water microcapsules is 5:1. The poly N-isopropylacrylamide thermosensitive hydrogel and the polyurethane-epoxycycloheximide oil-in-water microcapsules form a semi-interpenetrating network structure, so that the temperature-responsive cycloheximide controlled-release system has a low critical transition temperature, and good thermal stability and temperature-sensitive properties.

[0042] In the present invention, the poly N-isopropylacrylamide thermosensitive hydrogel is obtained by polymerization of N-isopropylacrylamide in water under the action of a crosslinking agent and an initiator. In the present invention, the crosslinking agent is preferably one or more of N,N'-methylenebisacrylamide, diisopropylbenzene peroxide, triallyl isocyanurate and butanediol diglycidyl ether, more preferably N,N'-methylenebisacrylamide, diisopropylbenzene peroxide or triallyl isocyanurate. In the present invention, the mass ratio of N-isopropylacrylamide and the crosslinking agent is preferably 5:500 to 30:100, more preferably 10:300 to 25:100, and further preferably 15:200 to 20:100. In a specific embodiment of the present invention, the mass ratio of N-isopropylacrylamide and the crosslinking agent is 20:300.

[0043] In the present invention, the initiator is preferably any two of sodium persulfate, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, N,N,N',N'-tetramethyl-1,2-ethylenediamine, tetramethylethylenediamine and 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide, and more preferably any two of sodium persulfate, dibenzoyl peroxide, azobisisobutyronitrile, N,N,N',N'-tetramethyl-1,2-ethylenediamine, tetramethylethylenediamine and 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide. In a specific embodiment of the present invention, the initiator is a combination of sodium persulfate and tetramethylethylenediamine, a combination of dibenzoyl peroxide and N,N,N',N'-tetramethyl-1,2-ethylenediamine, and a combination of azobisisobutyronitrile and 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide. In the present invention, the mass ratio of any two of the initiators is preferably 1:1.

[0044] In the present invention, the mass ratio of N-isopropylacrylamide to initiator is preferably 5:2 to 30:2, more preferably 10:2 to 25:2, and further preferably 15:2 to 20:2. In a specific embodiment of the present invention, the mass ratio of N-isopropylacrylamide to initiator is 20:2.

[0045] In the present invention, the polyurethane-epoxypridon oil-in-water microcapsules include a water phase and polyurethane-epoxypridon microcapsules dispersed in the water phase.

[0046] In the present invention, the polyurethane-epoxycyclohexanone microcapsules include a capsule wall and a capsule core, and the capsule core includes epoxycyclohexanone and an organic solvent. In the present invention, the organic solvent is preferably one or more of cyclohexanone, butyl acetate, cyclohexanone, condensed amide, methyl acetate, dimethyl carbonate, octanol and diethyl carbonate, more preferably cyclohexanone, butyl acetate or dimethyl carbonate, and the epoxycyclohexanone has good solubility in the organic solvent. In the present invention, the mass ratio of the epoxycyclohexanone to the organic solvent is preferably 1:5 to 1:40, more preferably 1:10 to 1:30, and further preferably 1:15 to 1:20. In a specific embodiment of the present invention, the mass ratio of epoxycyclohexanone to the organic solvent is 1:10.

[0047] In the present invention, the capsule wall is polyurethane, and the polyurethane is obtained by cross-linking isocyanate and curing agent. In the present invention, the isocyanate preferably includes one or more of isophorone diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, tetramethylxylene diisocyanate and lysine diisocyanate, more preferably isophorone diisocyanate, toluene diisocyanate or diphenylmethane diisocyanate. In the present invention, the mass ratio of cyclohexylcarbamide to isocyanate is preferably 1:1 to 10:1, more preferably 3:1 to 8:1, and further preferably 5:1 to 6:1. In a specific embodiment of the present invention, the mass ratio of cyclohexylcarbamide to isocyanate is 3:1.

[0048] In the present invention, the curing agent is an alcohol monomer or an amine monomer, the alcohol monomer preferably includes one or more of ethylene glycol, propylene glycol, polyether polyol and polyester polyol, more preferably ethylene glycol, and the amine monomer includes one or more of ethylenediamine, hexamethylenediamine, polyetheramine, 1,2-propylenediamine, butanediamine, diethylenetriamine, triethylenetetramine and tetraethylenepentamine, more preferably diethylenetriamine or hexamethylenediamine.

[0049] In the present invention, the aqueous phase preferably includes an aqueous surfactant solution. In the present invention, the mass fraction of the surfactant in the aqueous surfactant solution is preferably 0.5 to 10%, more preferably 1 to 8%, and further preferably 2 to 6%. In the present invention, the surfactant is preferably polyvinyl alcohol.

[0050] The temperature-responsive cycloheximide controlled-release system provided by the present invention utilizes polyurethane and poly N-isopropylacrylamide thermosensitive (PNIPAAm) hydrogel to form a semi-interpenetrating network structure, thereby reducing the lower critical transition temperature of the controlled-release system. PNIPAAm undergoes a reversible phase change at different temperatures, switching between hydrophilicity and hydrophobicity. This characteristic enables the PNIPAAm-based porous hydrogel to regulate its water absorption and drug release properties according to the ambient temperature. At the same time, PNIPAAm can enhance its biocompatibility and reduce irritation to biological tissues through appropriate surface modification. The water-in-oil microcapsules synthesized by PU are hydrophilic. When the temperature is low, they combine with PNIPAAm to control the drug release more slowly. When the temperature rises, PU and PNIPAAm separate from each other, and the drug can be released in large quantities, thereby realizing temperature-sensitive controlled release, thereby realizing improved drug efficacy and reduced drug loss at high temperatures.

[0051] The present invention also provides a method for preparing the temperature-responsive cycloheximide controlled-release system described in the above technical solution, comprising the following steps:

[0052] Mixing cycloheximide with an organic solvent, heating to a molten state, cooling to 55-65° C., adding isocyanate and mixing to obtain an oil phase;

[0053] The oil phase is added dropwise to the water phase for emulsification to obtain an O / W emulsion;

[0054] Adding the curing agent aqueous solution dropwise into the O / W emulsion to carry out a cross-linking reaction to obtain polyurethane-epoxycyclan oil-in-water microcapsules;

[0055] N-isopropylacrylamide, a crosslinking agent, an initiator and water are mixed, and a polymerization reaction occurs under the protection of an inert gas to obtain a poly-N-isopropylacrylamide thermosensitive hydrogel;

[0056] The polyurethane-epoxicab oil-in-water microcapsules and the poly (N-isopropylacrylamide) thermosensitive hydrogel are mixed to obtain a temperature-responsive epoxicab controlled-release system.

[0057] The invention mixes cycloheximide with an organic solvent, heats the mixture to a molten state, cools the mixture to 55-65° C., adds isocyanate and mixes the mixture to obtain an oil phase.

[0058] In the present invention, the heating temperature is preferably 75 to 95°C, more preferably 80 to 90°C.

[0059] The present invention has no special requirements for the mixing method, and the commonly used technical means of the present invention, such as stirring, can be used.

[0060] After obtaining the oil phase, the present invention drops the oil phase into the water phase for emulsification to obtain an O / W emulsion.

[0061] In the present invention, the aqueous phase preferably includes an aqueous surfactant solution, which has been discussed above and will not be repeated here. In the present invention, the mass ratio of the oil phase to the aqueous phase is preferably 1:6 to 10:1, more preferably 2:5 to 8:2, and further preferably 2:3 to 6:4.

[0062] In the present invention, the emulsification temperature is preferably 50-90°C, more preferably 55-70°C, and further preferably 60°C. The emulsification is preferably carried out under high-speed shearing conditions, and the high-speed shearing speed is preferably 7000-10000rpm, and more preferably 8000rpm. The emulsification time is preferably 10-25min, and more preferably 15-20min, and the emulsification time is calculated from the end of the oil phase dropwise addition.

[0063] In the present invention, the dripping is preferably: the oil phase is dripped into the surfactant aqueous solution at 60° C., and high-speed shearing is performed during the dripping process. The present invention has no special requirements for the dripping rate, and dripping can be performed drop by drop.

[0064] After obtaining the O / W emulsion, the present invention drips the curing agent aqueous solution into the O / W emulsion to carry out a cross-linking reaction to obtain the polyurethane-epoxycyclan oil-in-water microcapsules.

[0065] In the present invention, the mass fraction of the curing agent in the curing agent aqueous solution is preferably 1 to 20%, more preferably 5 to 15%, and further preferably 8 to 12%. In a specific embodiment of the present invention, the mass fraction of the curing agent in the curing agent aqueous solution is 5%. The present invention has no special requirements for the preparation method of the curing agent aqueous solution, and the preparation method well known to those skilled in the art can be used.

[0066] In the present invention, the mass ratio of the O / W emulsion to the aqueous curing agent solution is preferably 10 to 100:1, more preferably 20 to 80:1, and further preferably 40 to 70:1.

[0067] In the present invention, the aqueous curing agent solution is preferably added dropwise to the O / W emulsion at 60°C.

[0068] In the present invention, the temperature of the cross-linking reaction is preferably 50 to 100° C., more preferably 60 to 80° C., and the time is preferably 1 to 3 hours, more preferably 1.5 to 2 hours. The time of the cross-linking reaction is calculated from the end of the dropwise addition of the curing agent aqueous solution. During the cross-linking reaction, the isocyanate in the O / W emulsion reacts with the curing agent in the curing agent aqueous solution to generate polyurethane.

[0069] The invention mixes N-isopropylacrylamide, a crosslinking agent, an initiator and water, and performs polymerization reaction under the protection of an inert gas to obtain a poly-N-isopropylacrylamide thermosensitive hydrogel.

[0070] In the present invention, the polymerization reaction temperature is preferably 50-100° C., more preferably 60-80° C., and the time is preferably 2-5 hours, more preferably 3-5 hours. Under the action of the crosslinking agent and the initiator, the N-isopropylacrylamide monomer is polymerized to form a poly-N-isopropylacrylamide thermosensitive hydrogel.

[0071] The present invention has no special requirements for the mixing method, and the commonly used technical means of the present invention, such as stirring, can be used.

[0072] After obtaining the poly(N-isopropylacrylamide) thermosensitive hydrogel, the present invention mixes the polyurethane-epoxycycladim oil-in-water microcapsules and the poly(N-isopropylacrylamide) thermosensitive hydrogel to obtain a temperature-responsive epoxycycladim controlled-release system. During the mixing process, the PNIPAAm-based porous hydrogel polymerizes with the polyurethane in the polyurethane-epoxycycladim microcapsules to form a semi-interpenetrating network structure Semi IPN-PNIPAAm / PU hydrogel.

[0073] In the present invention,

[0074] In the present invention, the mixing is preferably carried out under stirring conditions, the stirring speed is preferably 100 to 500 rpm, more preferably 300 to 400 rpm, the time is preferably 0.5 to 2 hours, more preferably 1 to 1.5 hours. In the present invention, the mixing is preferably carried out under normal temperature conditions.

[0075] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution of the present invention will be clearly and completely described in conjunction with specific embodiments below. The described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Any modification, equivalent replacement, improvement, etc. made to the implementation methods of the present invention based on the technical essence and general principles of the present invention without creative work should be within the scope of protection of the present invention.

[0076] Example 1

[0077] 1 g of cyclohexanone was added to 10 g of cyclohexanone, and the mixture was heated at 80° C. to melt. The temperature was then lowered to 60° C., and 1 g of isophorone diisocyanate was added and stirred until the mixture became transparent, thereby forming an oil phase.

[0078] 2 g of PVA powder was mixed with 98 g of deionized water, and heated and stirred in an oil bath at 80° C. for 4 h to obtain a 2 wt % PVA aqueous solution.

[0079] At 60° C., 12 g of the oil phase was slowly dropped into 12 g of a 2 wt % PVA aqueous solution, with shearing performed at 8000 rpm during the dropping process. After the dropping was completed, the solution was sheared at 8000 rpm for 15 min to obtain an O / W emulsion.

[0080] At 60° C., 5 g of a 10 wt % triethylenetetramine aqueous solution was added dropwise to 24 g of the O / W emulsion. After the addition was completed, the mixture was reacted at 60° C. for 1.5 h and cooled to room temperature to obtain polyurethane-epoxycyclan oil-in-water microcapsules.

[0081] Weigh 1 g of N-isopropylacrylamide (NIPAAm), 50 mg of sodium persulfate (APS), 50 mg of tetramethylethylenediamine (TMEDA), 50 mg of N,N'-methylenebisacrylamide (MBA) and 10 g of deionized water and mix them. 2 Under protection, the reaction was stirred at 60°C for 3 h to obtain PNIPAAm thermosensitive hydrogel.

[0082] 29 g of polyurethane-epoxicillin oil-in-water microcapsules were mixed with 11.15 g of PNIPAAm thermosensitive hydrogel and stirred at 300 rpm for 1 h to obtain a temperature-responsive epoxicillin controlled-release system.

[0083] Example 2

[0084] 2 g of cycloheximide was added to 8 g of butyl acetate, heated at 80° C. to melt, the temperature was lowered to 60° C., 1 g of toluene diisocyanate was added, and stirred until transparent to form an oil phase.

[0085] The preparation of PVA aqueous solution is the same as in Example 1.

[0086] At 60° C., 10 g of the oil phase was slowly dropped into 10 g of a 2 wt % PVA aqueous solution, with shearing performed at 8000 rpm during the dropping process. After the dropping was completed, the solution was sheared at 8000 rpm for 15 min to obtain an O / W emulsion.

[0087] At 60° C., 4 g of a 5 wt % aqueous solution of diethylenetriamine was added dropwise to 20 g of the O / W emulsion. After the addition was completed, the mixture was reacted at 60° C. for 1.5 h and cooled to room temperature to obtain polyurethane-epoxycarbamimidone oil-in-water microcapsules.

[0088] Weigh 3 g NIPAAm, 60 mg dibenzoyl peroxide (BPO), 60 mg N,N-dichloro-N',N'-dimethyl-p-phenylenediamine (TEMDA), 60 mg diisopropylbenzene peroxide (DCP) and 9 g deionized water and mix. 2 Under protection, the reaction was stirred at 60°C for 3 h to obtain PNIPAAm thermosensitive hydrogel.

[0089] 24 g of polyurethane-epoxicillin oil-in-water microcapsules were mixed with 12.18 g of PNIPAAm thermosensitive hydrogel and stirred at 300 rpm for 1 h to obtain a temperature-responsive epoxicillin controlled-release system.

[0090] Example 3

[0091] 0.5 g of cycloheximide was added to 10 g of dimethyl carbonate, and heated to 80° C. to melt. The temperature was lowered to 60° C., and 1 g of diphenylmethane diisocyanate was added and stirred until transparent to form an oil phase.

[0092] The preparation of PVA aqueous solution is the same as in Example 1.

[0093] 10.5 g of the oil phase was slowly dropped into 10.5 g of a 2 wt % PVA aqueous solution at 60° C., with shearing performed at 8000 rpm during the dropping process. After the dropping was completed, the solution was sheared at 8000 rpm for 15 min to obtain an O / W emulsion.

[0094] At 60° C., 5 g of 7 wt % propylene glycol aqueous solution was added dropwise to 21 g of the O / W emulsion. After the addition was completed, the mixture was reacted at 60° C. for 1.5 h and cooled to room temperature to obtain polyurethane-epoxycarbamimidone oil-in-water microcapsules.

[0095] Weigh 1 g NIPAAm, 50 mg azobisisobutyronitrile (AIBN), 50 mg 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide (TMO), 50 mg triallyl isocyanurate (TAIC) and 10 g deionized water and mix them. 2 Under protection, the reaction was stirred at 60°C for 3 h to obtain PNIPAAm thermosensitive hydrogel.

[0096] 26 g of polyurethane-epoxicillin oil-in-water microcapsules were mixed with 11.15 g of PNIPAAm thermosensitive hydrogel and stirred at 300 rpm for 1 h to obtain a temperature-responsive epoxicillin controlled-release system.

[0097] The polyurethane microcapsules prepared in Example 1 were scanned by SEM at different sizes. The results are as follows: Figure 1 shown. Figure 1 The middle a is intercepted Figure 1 A fragment of b in the figure is enlarged and processed. Figure 1 In b, it can be seen that the diameter of most microcapsules is less than 2.5 μm, and the particle size distribution is relatively uniform. Figure 1 From a, we can see that the surface of the microcapsule is not smooth, which proves that the two monomers reacted on the surface of the microcapsule.

[0098] The temperature-responsive cycloheximide controlled-release system prepared in Example 1 was subjected to sustained-release tests at different temperatures. The test method was dialysis, and the results were plotted as follows: Figure 2 .from Figure 2It can be seen that at three different temperatures, rapid release is shown in the initial stage of the experiment, and it can be clearly seen that with the increase of temperature, the release rate and the total release amount will increase. The increase of the sample at 31°C is the most obvious, which is in line with the expected effect of temperature response, indicating that the temperature-responsive cycloheximide controlled-release system prepared by the present invention has good thermal stability and temperature-sensitive properties.

[0099] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A temperature-responsive cycloheximide controlled-release system, characterized in that: It comprises poly N-isopropylacrylamide thermosensitive hydrogel and polyurethane-epoxypridon oil-in-water microcapsules, wherein the poly N-isopropylacrylamide hydrogel and polyurethane-epoxypridon oil-in-water microcapsules form a semi-interpenetrating network structure; The mass ratio of the poly (N-isopropylacrylamide) thermosensitive hydrogel to the polyurethane-epoxycycloheximide oil-in-water microcapsules is 1:5 to 10:1; The poly N-isopropylacrylamide thermosensitive hydrogel is obtained by polymerizing N-isopropylacrylamide in water under the action of a crosslinking agent and an initiator; The polyurethane-epoxycycloheximide oil-in-water microcapsules include an aqueous phase and polyurethane-epoxycycloheximide microcapsules dispersed in the aqueous phase, the polyurethane-epoxycycloheximide microcapsules include a capsule wall and a capsule core, the capsule core includes epoxycycloheximide and an organic solvent, the capsule wall is polyurethane, and the polyurethane is cross-linked by isocyanate and a curing agent; The curing agent is an alcohol monomer and / or an amine monomer.

2. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The mass ratio of cycloheximide to isocyanate is 1:1 to 10:1; The isocyanate includes one or more of isophorone diisocyanate, toluene diisocyanate, diphenylmethane diisocyanate, dicyclohexylmethane diisocyanate, hexamethylene diisocyanate, tetramethylxylylene diisocyanate and lysine diisocyanate.

3. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The mass ratio of the N-isopropylacrylamide to the cross-linking agent is 5:500 to 30:100; The crosslinking agent is one or more of N,N'-methylenebisacrylamide, dicumyl peroxide, triallyl isocyanurate and butanediol diglycidyl ether.

4. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The mass ratio of N-isopropylacrylamide to initiator is 5:2 to 30:2; The initiator is any two of sodium persulfate, dibenzoyl peroxide, azobisisobutyronitrile, azobisisoheptanenitrile, N,N,N',N'-tetramethyl-1,2-ethylenediamine, tetramethylethylenediamine and 2,4,6-trimethylbenzoyl-di(p-tolyl)phosphine oxide.

5. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The alcohol monomer includes one or more of ethylene glycol, glycerol, polyether polyol and polyester polyol; The amine monomers include one or more of ethylenediamine, hexamethylenediamine, polyetheramine, 1,2-propylenediamine, butanediamine, diethylenetriamine, triethylenetetramine and tetraethylenepentamine.

6. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The mass ratio of cycloheximide to the organic solvent is 1:5 to 1:40; The organic solvent is one or more of cyclohexanone, butyl acetate, cyclohexanone, decanoic acid amide, methyl acetate, dimethyl carbonate, octanol and diethyl carbonate.

7. The temperature-responsive cycloheximide controlled-release system according to claim 1, characterized in that: The aqueous phase includes a surfactant aqueous solution; the mass fraction of the surfactant in the surfactant aqueous solution is 0.5-10 wt %.

8. The method for preparing the temperature-responsive cycloheximide controlled-release system according to any one of claims 1 to 7, characterized in that: The following steps are involved: Mix cycloheximide and an organic solvent, heat to a molten state, cool to 55-65° C., add isocyanate and mix to obtain an oil phase; The oil phase is added dropwise to the water phase for emulsification to obtain an O / W emulsion; Adding the curing agent aqueous solution dropwise into the O / W emulsion to carry out a cross-linking reaction to obtain polyurethane-epoxycyclan oil-in-water microcapsules; N-isopropylacrylamide, a crosslinking agent, an initiator and water are mixed, and a polymerization reaction is carried out under the protection of an inert gas to obtain a poly-N-isopropylacrylamide thermosensitive hydrogel; The polyurethane-epoxycycladim oil-in-water microcapsules and the poly (N-isopropylacrylamide) thermosensitive hydrogel are mixed to obtain the temperature-responsive epoxycycladim controlled-release system.

9. The preparation method according to claim 8, characterized in that: The mass ratio of the oil phase to the water phase is 1:6 to 10:

1.

10. The preparation method according to claim 8, characterized in that: The mass ratio of the O / W emulsion to the curing agent is 10 to 100:1; The mass fraction of the curing agent in the curing agent aqueous solution is 1 to 20%.

Images