CN113416292B - Hydrogel capable of loading high-hydrophobicity drugs and preparation method and application thereof - Google Patents

Hydrogel capable of loading high-hydrophobicity drugs and preparation method and application thereof Download PDF

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CN113416292B
CN113416292B CN202110484021.5A CN202110484021A CN113416292B CN 113416292 B CN113416292 B CN 113416292B CN 202110484021 A CN202110484021 A CN 202110484021A CN 113416292 B CN113416292 B CN 113416292B
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cyclodextrin
polyurethane
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侯昭升
毕晶晶
李雪静
刘常琳
高伟伟
文正
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Changsha Jingyi Pharmaceutical Technology Co ltd
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Shandong Normal University
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Abstract

The invention provides a hydrogel capable of loading a high-hydrophobicity drug, and a preparation method and application thereof, and belongs to the technical field of preparation of high polymer materials. The invention firstly prepares the cyclodextrin-terminated polyurethane (DPU) with a side chain containing double bonds, and utilizes the click chemistry crosslinking of a multi-sulfhydryl compound and the double bonds to form the polyurethane hydrogel. The cyclodextrin hydrogel has hydrophobic inner cavity and hydrophilic outer edge and can provide a hydrophobic binding site, so that the cyclodextrin molecular cavity in the polyurethane hydrogel can be non-covalently bound with the high-hydrophobicity medicine, the high-hydrophobicity medicine is loaded, the gel is very stable in vitro, and the cyclodextrin polysaccharide is gradually degraded under the action of in vivo enzyme, so that the bound medicine is released, and the hydrogel capable of loading the high-hydrophobicity medicine is successfully prepared, so that the hydrogel has good practical application value.

Description

Hydrogel capable of loading high-hydrophobicity medicine and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of high polymer materials, and particularly relates to a hydrogel capable of loading a high-hydrophobicity drug, and a preparation method and application thereof.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
The hydrogel is a polymer with a three-dimensional network structure and formed by covalent bond and non-covalent bond interaction crosslinking, can absorb a large amount of water in water to swell, can continuously keep the original structure after swelling without being dissolved, and can achieve the purpose of controlling and releasing the drug by chemical crosslinking or physical acting force or shrinkage and relaxation of the crosslinked network under specific conditions. The prior art discloses a photosensitive hydrogel, which is prepared by taking azobenzene and compounds of acid radical ions such as tetrafluoroborate, hexafluorophosphate, sulfate and the like as cross-linking agents.
In the prior art, a novel polyurethane hydrogel is also disclosed, which is prepared by using Polycaprolactone (PCL), diphenylmethane diisocyanate (MDI) and the like as main raw materials, respectively using diethylene glycol (DEG), 2-dimethylolpropionic acid (DMPA) and N-Methyldiethanolamine (MDEA) as chain extenders to synthesize a polyurethane prepolymer, and then adding a cross-linking agent Benzoyl Peroxide (BPO) to carry out free radical polymerization. The polyurethane hydrogel prepared by taking DMPA with carboxyl and MDEA with tertiary amino functional groups as chain extenders has strong hydrophilicity, a microporous structure on the surface and large chloramphenicol drug-loading capacity.
Generally speaking, hydrogel is a three-dimensional network constructed by hydrophilic macromolecular chains, can be highly swollen in water, and retains a large amount of water in a network structure, when the hydrogel is used as a drug carrier, drug molecules can be protected, adverse effects of external adverse environmental conditions on drugs are isolated, and a stimulus-responsive structural unit is introduced into the hydrogel network structure, so that the release speed and mode of the drug molecules can be adjusted through the change of structure and performance after the hydrogel receives external signals or stimulus, and the controllability of drug release is achieved.
When the polymer hydrogel is used as a drug carrier, drug molecules can be protected, and adverse effects of external adverse environmental conditions on drugs can be isolated. Since the hydrogel can contain a large amount of hydrophilic drug per volume, while the size and physicochemical properties between polymer chains can be adjusted, a highly tunable release profile from hours to days can be provided. However, due to the inherent incompatibility, it remains a challenge how to encapsulate hydrophobic drugs into hydrogels. The inventors have found that the field of delivery and controlled release of hydrophobic drugs currently faces two urgent problems: one is how to make the hydrophilic carrier material capable of loading sufficient hydrophobic drug molecules have difficulty in playing a role in loading highly hydrophobic drugs (such as anticancer anti-inflammatory drugs, such as nobiletin, hesperetin, curcumin and the like); and how to effectively release the loaded hydrophobic drug molecules into the surrounding environment.
Disclosure of Invention
Aiming at the defects of the prior art, the inventor provides a hydrogel capable of loading a high-hydrophobicity medicament, a preparation method and application thereof through long-term technical and practical exploration. The invention firstly prepares the cyclodextrin-terminated polyurethane (DPU) with a side chain containing double bonds, and utilizes the click chemistry crosslinking of a multi-sulfhydryl compound and the double bonds to form the polyurethane hydrogel. The cyclodextrin hydrogel has hydrophobic inner cavity and hydrophilic outer edge and can provide a hydrophobic binding site, so that the cyclodextrin molecular cavity in the polyurethane hydrogel can be non-covalently bound with the high-hydrophobicity medicine, the high-hydrophobicity medicine is loaded, the gel is very stable in vitro, and the cyclodextrin polysaccharide is gradually degraded under the action of in vivo enzyme, so that the bound medicine is released, and the hydrogel capable of loading the high-hydrophobicity medicine is successfully prepared, so that the hydrogel has good practical application value.
Specifically, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a cyclodextrin terminated polyurethane (DPU) having a double bond in a side chain, which has a molecular structural formula shown below:
Figure BDA0003049600890000021
wherein m and n are natural numbers different from 0;
preferably, n is 1 to 2; and m is 65-270.
In a second aspect of the present invention, there is provided a method for producing the above cyclodextrin terminated polyurethane (DPU) having a double bond in a side chain, the method comprising:
the preparation method comprises the steps of firstly reacting isocyanate-terminated polyethylene glycol with 1, 5-hexadiene-3, 4-diol to prepare an isocyanate-terminated polyurethane prepolymer with a side chain containing double bonds, and then reacting the isocyanate-terminated polyurethane prepolymer with mono-6-O-amino-beta-cyclodextrin to carry out end capping to obtain the DPU.
In a third aspect of the invention, the application of the cyclodextrin terminated polyurethane with double bonds in side chains is provided for preparing cyclodextrin-containing polyurethane hydrogel.
In a fourth aspect of the present invention, there is provided a cyclodextrin-containing polyurethane hydrogel prepared by a method comprising: dissolving DPU in organic solvent, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain polyurethane gel (DPU-G), soaking the gel in deionized water, and periodically changing water to obtain the polyurethane hydrogel (DPU-WG).
In a fifth aspect of the invention, there is provided a use of a cyclodextrin-containing polyurethane hydrogel in the medical field.
Specifically, the application comprises the application of the polyurethane hydrogel containing cyclodextrin as a drug carrier.
More particularly, the drug is a highly hydrophobic drug.
In a sixth aspect of the present invention, there is provided a drug-loaded polyurethane hydrogel, which comprises the cyclodextrin-containing polyurethane hydrogel described above, and a drug loaded on the cyclodextrin-containing polyurethane hydrogel.
The drug is a highly hydrophobic drug, which can be specifically used for antibacterial, anti-inflammatory, anticancer, etc., including but not limited to doxorubicin, paclitaxel, and curcumin.
In a seventh aspect of the present invention, there is provided a preparation method of the drug-loaded polyurethane hydrogel, the preparation method including: dissolving DPU in an organic solvent in which a medicine is dissolved, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain medicine-carrying polyurethane gel (DPU-DG), soaking the gel in deionized water, and periodically changing water to obtain the medicine-carrying polyurethane hydrogel (DPU-DWG).
In an eighth aspect of the present invention, a method for sustained release of a drug is provided, the method comprising administering the drug-loaded polyurethane hydrogel, wherein the cyclodextrin is decomposed under the action of an enzyme to release the drug, thereby achieving the purpose of sustained release of the drug.
Wherein the enzyme comprises an enzyme capable of degrading cyclodextrin, such as an alpha-amylase.
The beneficial technical effects of one or more technical schemes are as follows:
(1) the hydrogel provided by the technical scheme has good biocompatibility, and the degradation product is nontoxic and easy to absorb by a human body and has good physiological acceptability to the human body;
(2) the hydrogel provided by the technical scheme contains cyclodextrin molecules, and the cyclodextrin cavity can be stably combined with the hydrophobic drug, so that the hydrophobic drug is loaded, and the defect that the traditional hydrogel cannot load the hydrophobic drug is overcome;
(3) the loading capacity of the hydrogel for the hydrophobic drug provided by the technical scheme is determined by the cyclodextrin content in the hydrogel, and the drug loading capacity of the hydrogel can be controlled by adjusting the dosage of the cyclodextrin.
(4) The click chemical reaction adopted by the technical scheme is a reaction condition which is mild, the product yield is high, the selectivity is good, the byproducts are few, and the separation is easy;
(5) the drug-loaded hydrogel provided by the technical scheme can decompose cyclodextrin to release the drug only under the action of the enzyme, so that the hydrogel has stable drug-loading capacity, and has good practical application value.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are included to illustrate an exemplary embodiment of the invention and not to limit the invention.
FIG. 1 shows a DPU-DWG hydrogel prepared according to example 1 of the present invention1Drug release in PBS solution with alpha-amylase.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As previously mentioned, the field of delivery and controlled release of hydrophobic drugs currently faces two urgent problems: one is how to make the hydrophilic carrier material capable of loading sufficient hydrophobic drug molecules have difficulty in playing a role in loading highly hydrophobic drugs (such as anticancer anti-inflammatory drugs, such as nobiletin, hesperetin, curcumin and the like); and how to effectively release the loaded hydrophobic drug molecules into the surrounding environment.
In view of the above, in one embodiment of the present invention, there is provided a cyclodextrin terminated polyurethane (DPU) having a double bond in a side chain, which has a molecular structural formula as shown below:
Figure BDA0003049600890000051
wherein m and n are natural numbers different from 0, and in one embodiment of the invention, n is 1-2; and m is 65-270.
In another embodiment of the present invention, there is provided a method for producing the above cyclodextrin terminated polyurethane (DPU) having a double bond in a side chain, the method comprising:
firstly, reacting the isocyanate-terminated polyethylene glycol with 1, 5-hexadiene-3, 4-diol to prepare an isocyanate-terminated polyurethane prepolymer with a side chain containing double bonds, and then reacting with mono-6-O-amino-beta-cyclodextrin to carry out end capping to obtain DPU;
wherein, the molecular structural formula of the end isocyanate polyethylene glycol is as follows:
Figure BDA0003049600890000052
in another embodiment of the present invention, the molecular weight of the isocyanato-terminated polyethylene glycol is controlled to 3000 to 12000;
in another embodiment of the present invention, the molar ratio of 1, 5-hexadiene-3, 4-diol to the isocyanatopolyethylene glycol is controlled to be 1:1 to 3, and further controlled to be 1:1.5 to 2;
in another embodiment of the present invention, the isocyanato-terminated polyethylene glycol is reacted with 1, 5-hexadiene-3, 4-diol in a solvent system, wherein the solvent is an organic solvent, and more preferably N, N-Dimethylformamide (DMF); the concentration of the isocyanato-terminated polyethylene glycol and 1, 5-hexadiene-3, 4-diol in DMF is controlled to be 0.3-0.5 g/mL; in order to improve the reaction rate and the reaction yield, a catalyst is added in the reaction, and the catalyst is a tin catalyst, including but not limited to dibutyltin dilaurate, stannous octoate and dibutyltin diacetate; the adding amount is controlled to be 0.1-0.5 percent of the total mass of the reactants, namely the end isocyanate polyethylene glycol and the 1, 5-hexadiene-3, 4-diol;
in another embodiment of the invention, the temperature in the reaction process for preparing the isocyanate-terminated polyurethane prepolymer with the side chain containing double bonds is controlled to be 60-85 ℃; further preferably 70-80 deg.C, such as 70 deg.C, 72 deg.C, 75 deg.C, 78 deg.C or 80 deg.C; controlling the reaction time to be 3-5 h; specifically, the reaction end point of the reaction of the terminal isocyanate group polyethylene glycol and the 1, 5-hexadiene-3, 4-diol can be judged when the-NCO content is determined to reach a theoretical value by a di-n-butylamine method.
The adding amount of the mono-6-O-amino-beta-cyclodextrin in the reaction is controlled as follows: -NH2The molar ratio of the compound to-NCO is 1: 0.5-2, and the preferable ratio is 1: 1;
in another embodiment of the invention, before adding the mono-6-O-amino-beta-cyclodextrin in the reaction, the temperature is reduced to 10-15 ℃, the organic solution of the mono-6-O-amino-beta-cyclodextrin is dropwise added under a stirring state, and after the dropwise addition is finished, the temperature is maintained for reaction until the characteristic absorption peak of infrared detection-NCO disappears, which takes about 1.5-2.5 hours;
in another embodiment of the present invention, the solvent in the organic solution is preferably N, N-Dimethylformamide (DMF), and the concentration of the mono-6-O-amino- β -cyclodextrin is controlled to be 0.2 to 0.3g/mL, preferably 0.25 g/mL.
In another embodiment of the present invention, DPU is obtained by separation and purification; wherein, the purification method comprises the following steps: diluting the DPU solution with DMF; then, the mixture is settled by using glacial ethyl ether (-6-1 ℃), filtered, and dried in vacuum at normal temperature to constant weight.
In another embodiment of the present invention, there is provided a use of the cyclodextrin terminated polyurethane having double bonds in side chains as described above in the preparation of a cyclodextrin-containing polyurethane hydrogel.
In another embodiment of the present invention, there is provided a cyclodextrin-containing polyurethane hydrogel prepared by a method comprising: dissolving DPU in organic solvent, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain polyurethane gel (DPU-G), soaking the gel in deionized water, and periodically changing water to obtain the polyurethane hydrogel (DPU-WG).
In another embodiment of the present invention, the organic solvent is DMF, and the concentration of DPU in the DMF solution is 0.03-0.05 g/mL;
in another embodiment of the present invention, the multi-mercapto compound may be pentaerythritol tetrakis (3-mercaptopropionate), and the amount added is controlled as follows: the molar ratio of the mercapto group to the double bond is 1: 0.5-2, preferably 1:1.
In another embodiment of the present invention, in order to improve the reaction rate and yield, a catalyst is used in the click chemistry reaction, wherein the catalyst is an organic base catalyst, and more preferably N, N-diisopropylethylamine, and the amount of the catalyst is 0.05 to 0.5%, preferably 0.1%, of the total mass of the reactants;
in another embodiment of the present invention, the click reaction may be performed at normal temperature, and thus the reaction temperature may be 20 to 35 ℃; judging the reaction end point by detecting the disappearance of the characteristic absorption peak of the double bond in the infrared spectrum, and controlling the reaction time to be 3-6 h;
in another embodiment of the invention, the DPU-G is soaked in 10 times volume of deionized water at room temperature of about 20-25 ℃;
in another embodiment of the present invention, the water changing period in the above process is once every 10h at the beginning and once every 24h at the later stage, and it takes about 5 to 7 days until no characteristic absorption peak of DMF exists in the infrared detection deionized water.
In yet another embodiment of the present invention, there is provided a use of a cyclodextrin-containing polyurethane hydrogel in the medical field.
In yet another embodiment of the present invention, the use comprises the use of the cyclodextrin-containing polyurethane hydrogel described above as a drug carrier.
In yet another embodiment of the present invention, the drug is a highly hydrophobic drug.
In another embodiment of the present invention, a drug-loaded polyurethane hydrogel is provided, which includes the cyclodextrin-containing polyurethane hydrogel described above, and a drug loaded on the cyclodextrin-containing polyurethane hydrogel.
The drug is a highly hydrophobic drug which can be specifically used for antibiosis, antiphlogosis, anticancer and the like, including but not limited to doxorubicin, paclitaxel and curcumin.
In another embodiment of the present invention, there is provided a method for preparing the drug-loaded polyurethane hydrogel, the method comprising: dissolving DPU in an organic solvent dissolved with a drug, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain drug-loaded polyurethane gel (DPU-DG), soaking the gel in deionized water, and periodically changing water to obtain the drug-loaded polyurethane hydrogel (DPU-DWG).
In still another embodiment of the present invention, the DPU-DG and DPU-DWG are produced under the same conditions as the DPU-G and DPU-DWG.
In another embodiment of the present invention, the organic solvent is DMF, such that the concentration of DPU in DMF containing dissolved drug is 0.03-0.05 g/mL.
In yet another embodiment of the present invention, the drug is a highly hydrophobic drug that is particularly useful for antibacterial, anti-inflammatory, anticancer, and the like, including but not limited to doxorubicin, paclitaxel, and curcumin.
In another embodiment of the present invention, the concentration of the drug in the DMF solution containing the drug dissolved therein is 3-20 mg/mL.
The hydrogel disclosed by the invention not only has good biocompatibility, but also can realize effective loading on a high-hydrophobicity medicament, and the cyclodextrin is a polysaccharide compound, so that the cyclodextrin can be decomposed under the action of enzyme in vivo to release the medicament, and the aim of slowly releasing the medicament is fulfilled.
Therefore, in still another embodiment of the present invention, there is provided a method for sustained release of a drug, which comprises administering the above drug-loaded polyurethane hydrogel, and decomposing the cyclodextrin under the action of an enzyme to release the drug.
Wherein the enzyme comprises an enzyme capable of degrading cyclodextrin, such as an alpha-amylase.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1:
preparation of polyurethane: 90.00g of isocyanatopolyethylene glycol-terminated at the molecular weight of 3000g/mol, 1.71g of 1, 5-hexadiene-3, 4-diol and 0.18g of stannous octoate were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ for reaction at a constant temperature until the reaction was detected by the di-N-butylamine methodThe NCO content reached the theoretical value, about 3.5 h. After cooling to 15 ℃, 34.02g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, when the system is recovered to the room temperature, adding DMF solution to dilute the cyclodextrin-terminated polyurethane with the double bond in the side chain to 0.05g/mL, then using ten times of volume of glacial ethyl ether (-6-1 ℃) to carry out sedimentation, suction filtration and vacuum drying at the room temperature to constant weight, thus obtaining the cyclodextrin-terminated polyurethane (DPU) with the double bond in the side chain1)。
Preparation of hydrogel: 20g of DPU1Dissolving in 400mL DMF solution, adding 0.59G pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G N, N-diisopropylethylamine, reacting at room temperature until the characteristic absorption peak of double bond in infrared spectrum disappears, and obtaining polyurethane gel (DPU-G) after about 4h1) DPU-G1Soaking in 500ml deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain polyurethane hydrogel (DPU-WG)1)。
Preparing a drug-loaded hydrogel: 20g of DPU1Dissolving in 400mL of paclitaxel DMF solution with concentration of 10.00mg/mL, adding 0.59g of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02g N, N-diisopropylethylamine, reacting at normal temperature until the characteristic absorption peak of double bond in the infrared spectrum of detection disappears, and obtaining drug-loaded polyurethane gel (DPU-DG) after about 4 hours1) Soaking the drug-loaded polyurethane gel in 500mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the drug-loaded polyurethane hydrogel (DPU-DWG)1)；
Example 2:
preparation of polyurethane: 90g of isocyanatopolyethylene glycol having a molecular weight of 3000g/mol, 2.05g of 1, 5-hexadiene-3, 4-diol and 0.18g of dilauryl diisobutyltin were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ to a constant temperature to react until the-NCO content determined by the di-N-butylamine method reached the theoretical value for about 3.5 hours. After cooling to 15 ℃, 27.22g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, the system is recoveredCooling to room temperature, adding DMF solution to dilute the cyclodextrin terminated polyurethane with double bonds in side chains to 0.05g/mL, then using ten times of volume of glacial ethyl ether (-6-1 ℃) to carry out sedimentation, carrying out suction filtration, and drying in vacuum at room temperature to constant weight to obtain the cyclodextrin terminated polyurethane (DPU) with double bonds in side chains2)。
Preparation of hydrogel: 20g of DPU2Dissolving in 400mL DMF solution, adding 0.74G pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G N, N-diisopropylethylamine, reacting at room temperature until the characteristic absorption peak of double bond in infrared spectrum disappears, and obtaining polyurethane gel (DPU-G) after about 4h2) Soaking the polyurethane gel in 300mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the polyurethane hydrogel (DPU-WG)2)。
Preparing a drug-loaded hydrogel: 20g of DPU2Dissolving in 400mL of paclitaxel DMF solution with concentration of 8.59mg/mL, adding 0.74G of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G of N, N-diisopropylethylamine, reacting at normal temperature until the characteristic absorption peak of double bond in the infrared spectrum disappears, and obtaining drug-loaded polyurethane gel (DPU-G) after about 4h2) Soaking the drug-loaded polyurethane gel in 500mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the drug-loaded polyurethane hydrogel (DPU-WG)2)；
Example 3
Preparation of polyurethane: 90g of isocyanatopolyethylene glycol having a molecular weight of 3000g/mol, 2.28g of 1, 5-hexadiene-3, 4-diol and 0.18g of dilauryl diisobutyltin were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ to a constant temperature to react until the-NCO content determined by the di-N-butylamine method reached the theoretical value for about 3.5 hours. After cooling to 15 ℃, 22.68g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, the system is recovered to the room temperature, DMF solution is added to dilute the cyclodextrin end-capped polyurethane with the double bond on the side chain to 0.05g/mL, then glacial ethyl ether (-6-1 ℃) with ten times of volume is used for settling, suction filtration and vacuum drying at the normal temperature to constant weight, and the cyclodextrin end-capped polyurethane with the double bond on the side chain is obtainedPolyurethane (DPU)3)。
Preparation of hydrogel: 20g of DPU3Dissolving in 400mL DMF solution, adding 1.49G pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G N, reacting at room temperature under catalysis of N-diisopropylethylamine, detecting infrared spectrum until the characteristic absorption peak of double bond disappears, and obtaining polyurethane gel (DPU-G) after about 4h3) Soaking the polyurethane gel in 500ml of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the polyurethane hydrogel (DPU-WG)3)。
Preparing a drug-loaded hydrogel: 20g of DPU3Dissolving in 400mL of paclitaxel DMF solution with concentration of 7.45mg/mL, adding 1.49G of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.03G of N, N-diisopropylethylamine, reacting at normal temperature until the characteristic absorption peak of double bond in the infrared spectrum disappears, and obtaining drug-loaded polyurethane gel (DPU-G) after about 4h3) Soaking the drug-loaded polyurethane gel in 500mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the drug-loaded polyurethane hydrogel (DPU-WG)3)；
Example 4
Preparation of polyurethane: 150.00g of isocyanatopolyethylene glycol (molecular weight 5000g/mol), 2.30g of 1, 5-hexadiene-3, 4-diol and 0.18g of stannous octoate were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ to react at a constant temperature until the-NCO content determined by the di-N-butylamine method reached the theoretical value for about 3.5 hours. After cooling to 15 ℃, 31.75g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, the system is recovered to the room temperature, DMF solution is added to dilute the cyclodextrin-terminated polyurethane with double bonds in the side chain to 0.05g/mL, then ethyl glacial ether (-6-1 ℃) with ten times of volume is used for settling, suction filtration and vacuum drying at the room temperature to constant weight, and the cyclodextrin-terminated polyurethane (DPU) with double bonds in the side chain is obtained4)。
Preparation of hydrogel: 20g of DPU4Dissolved in 400mL of DMF solution, and 0.53g of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02g ofReacting under the catalysis of N, N-diisopropylethylamine at normal temperature until the characteristic absorption peak of double bonds in the infrared spectrum disappears, and obtaining polyurethane gel (DPU-G) after about 4h4) DPU-G4Soaking in 500mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain polyurethane hydrogel (DPU-WG)4)。
Preparing a drug-loaded hydrogel: 20g of DPU4Dissolving in 400mL paclitaxel DMF solution with concentration of 2.60mg/mL, adding 0.53g pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02g N, N-diisopropylethylamine, reacting at room temperature until the characteristic absorption peak of double bond in infrared spectrum disappears, and obtaining drug-loaded polyurethane gel (DPU-DG) after about 4h4) Soaking the drug-loaded polyurethane gel in 500ml of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the drug-loaded polyurethane hydrogel (DPU-DWG)4)；
Example 5
Preparation of polyurethane: 90.00g of isocyanatopolyethylene glycol having a molecular weight of 3000g/mol, 1.71g of 1, 5-hexadiene-3, 4-diol and 0.18g of stannous octoate were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ to a constant temperature for reaction until the-NCO content determined by the di-N-butylamine method reached the theoretical value for about 3.5 hours. After cooling to 15 ℃, 34.02g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, the system is recovered to room temperature, DMF solution is added to dilute the cyclodextrin end-capped polyurethane with double bonds on the side chain to 0.05g/mL, then ethyl glacial ether (-6-1 ℃) with ten times of volume is used for settling, suction filtration and vacuum drying at normal temperature to constant weight, and the cyclodextrin end-capped polyurethane (DPU) with double bonds on the side chain is obtained5)。
Preparation of hydrogel: 20g of DPU5Dissolving in 400mL DMF solution, adding 0.59G pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G N, reacting at normal temperature under the catalysis of N-diisopropylethylamine until the characteristic absorption peak of double bond in the infrared spectrum of detection disappears, and obtaining polyurethane gel (DPU-G) after about 4h5) DPU-G5Soaking in 500ml of deionized waterChanging water every 10h for the first three days and every 24h for the last three days to obtain the polyurethane hydrogel (DPU-WG)5)。
Preparing a drug-loaded hydrogel: 20g of DPU5Dissolving in 400mL of paclitaxel DMF solution with concentration of 5mg/mL, adding 0.59g of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02g N, N-diisopropylethylamine, reacting at normal temperature until the characteristic absorption peak of double bond in the infrared spectrum of detection disappears, and obtaining drug-loaded polyurethane gel (DPU-DG) after about 4 hours5) Soaking the drug-loaded polyurethane gel in 500ml of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain the drug-loaded polyurethane hydrogel (DPU-DWG)5)；
Example 6
Preparation of polyurethane: 90.00g of isocyanatopolyethylene glycol having a molecular weight of 3000g/mol, 1.71g of 1, 5-hexadiene-3, 4-diol and 0.18g of stannous octoate were dissolved in 200mL of N, N-Dimethylformamide (DMF), and the mixture was heated in an oil bath to 75 ℃ to a constant temperature for reaction until the-NCO content determined by the di-N-butylamine method reached the theoretical value, which was about 3.5 hours. After cooling to 15 ℃, 34.02g of mono-6-O-amino-beta-cyclodextrin is added, the temperature is maintained for reaction, until the infrared absorption peak of the isocyanic acid radical in the detection system disappears, and about 2 hours are needed. After the reaction is finished, the system is recovered to the room temperature, DMF solution is added to dilute the cyclodextrin-terminated polyurethane with double bonds in the side chain to 0.05g/mL, then ethyl glacial ether (-6-1 ℃) with ten times of volume is used for settling, suction filtration and vacuum drying at the room temperature to constant weight, and the cyclodextrin-terminated polyurethane (DPU) with double bonds in the side chain is obtained6)。
Preparation of hydrogel: 20G of DPU6 is dissolved in 400mL of DMF solution, and then 0.59G of pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02G N, N-diisopropylethylamine are added to react at normal temperature under the catalysis of the reaction until the characteristic absorption peak of double bonds in the infrared spectrum of detection disappears, and the polyurethane gel (DPU-G) is obtained after about 4 hours6) DPU-G6Soaking in 500mL of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain polyurethane hydrogel (DPU-WG)6)。
Preparing a drug-loaded hydrogel: 20g of DPU6Dissolving in 400mL of 20.00mg/mL paclitaxel DMF solution is added with 0.59g pentaerythritol tetrakis (3-mercaptopropionate) (cas:7575-23-7) and 0.02g N, N-diisopropylethylamine for reaction at normal temperature until the characteristic absorption peak of double bonds in the infrared spectrum disappears and about 4 hours are detected to obtain the drug-loaded polyurethane gel (DPU-DG)6) Soaking the medicine-carrying polyurethane gel in 500ml of deionized water, changing water every 10h for the first three days, and changing water every 24h for the last three days to obtain medicine-carrying polyurethane hydrogel (DPU-DWG)6)；
Effect verification
In vitro release of drug-loaded hydrogel: respectively immersing the hydrogel carrying the drugs in 50mL of PBS solution containing alpha-amylase and not containing alpha-amylase, placing the solution on a shaking table with the rotating speed of 35r/min, adjusting the temperature to 37 ℃, taking out 2mL of solution containing the released drugs every 4 hours, simultaneously adding 2mL of solution not containing the drugs, measuring the drug content in the solution at a specific wavelength by an ultraviolet-visible spectrophotometer, and calculating the cumulative release amount of the drugs according to a standard curve;
TABLE 1 hydrogel DPU-DWG1、DPU-DWG2、DPU-DWG3、DPU-DWG4、DPU-DWG5、DPU-DWG6Actual drug loading after soaking, wherein DPU-DWG1、DPU-DWG5、DPU-DWG6Respectively representing the hydrogel prepared by the hydrogel with the cyclodextrin content equal to, more than or less than the total content of the medicine. It can be found that the drug loading is closely related to the content of cyclodextrin in the gel, and the drug loading of the hydrogel is gradually increased along with the increase of the content of cyclodextrin in the gel. It has also been found that when the drug is used in a high DMF content, a portion of the drug is released with DMF during the preparation of the drug-loaded hydrogel, and the amount of the drug contained in the final gel and the amount of cyclodextrin are substantially stabilized at a molar ratio of about 1:1, because the drug content is higher than the cyclodextrin content, so that a portion of the drug is not coated in the cavity of cyclodextrin, and is released along with the swelling effect of the hydrogel in PBS solution. When the number of moles of the drug contained is smaller than that of the cyclodextrin contained in the gel, no drug is released. This indicates that highly hydrophobic drugs can be subjected to cyclodextrinsIn the hydrophobic cavity, the medicament wrapped by the cyclodextrin can not be released along with the soaking of an external solvent (organic solvent or water), and the wrapping of the medicament is stable. Therefore, the content of the cyclodextrin plays a decisive role in the loading of the drug, and the drug loading of the hydrogel can be controlled by adjusting the content of the cyclodextrin in the hydrogel so as to meet different requirements on the drug dosage.
Table 1: drug loading of different hydrogels
Figure BDA0003049600890000131
FIG. 1 shows the drug release of hydrogel DPU-DWG1 in α -amylase-containing PBS. It was found that in the PBS solution without alpha-amylase, the hydrogel-loaded drug was hardly released. In the PBS solution containing the alpha-amylase, the drug is gradually released along with the change of time, and the drug release amount can be close to 100 percent after 5 days. This is because the drug coated with cyclodextrin is not released as the hydrogel swells, but the cyclodextrin molecules (polysaccharides) are degraded by the action of an enzyme, and the drug is released by breaking the internal cavity. The hydrogel drug prepared by the invention is stable in release, can be released only under the action of enzyme, and is gradually degraded and absorbed by enzyme in a human body along with the continuous extension of time, so that the purpose of drug slow release is achieved.
The above description is only a preferred embodiment of the present application and is not intended to limit the present application, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims (34)

1. A cyclodextrin-terminated polyurethane having a double bond in a side chain, characterized in that it has the following molecular structural formula:
Figure 98854DEST_PATH_IMAGE001
wherein m and n are natural numbers different from 0.
2. The cyclodextrin terminated polyurethane having double bonds in its side chains according to claim 1, wherein n = 1-2; m =65~ 270.
3. The method for producing cyclodextrin terminated polyurethane having a double bond in a side chain according to claim 1 or 2, comprising:
the end isocyanate group polyethylene glycol reacts with 1, 5-hexadiene-3, 4-diol to prepare an end isocyanate group polyurethane prepolymer with a side chain containing double bonds, and then the end isocyanate group polyethylene glycol reacts with mono-6-O-amino-beta-cyclodextrin to carry out end capping to obtain the DPU.
4. The method of claim 3, wherein the isocyanatopolyethylene glycol has the following molecular structure:
Figure 347432DEST_PATH_IMAGE002
wherein m =65~ 270.
5. The method of claim 3, wherein the molecular weight of the isocyanato-terminated polyethylene glycol is controlled to 3000 to 12000.
6. The method according to claim 3, wherein the molar ratio of 1, 5-hexadiene-3, 4-diol to the isocyanatopolyethylene glycol is controlled to be 1:1 to 3.
7. The method according to claim 6, wherein the molar ratio of 1, 5-hexadiene-3, 4-diol to the isocyanatopolyethylene glycol is controlled to be 1:1.5 to 2.
8. The method of claim 3, wherein the isocyanato terminated polyethylene glycol is reacted with 1, 5-hexadiene-3, 4-diol in a solvent system, wherein the solvent is an organic solvent.
9. The method of claim 8, wherein the organic solvent is N, N-dimethylformamide DMF; the concentration of the isocyanato-terminated polyethylene glycol and 1, 5-hexadiene-3, 4-diol in DMF is controlled to be 0.3-0.5 g/mL.
10. The method of claim 3, wherein a catalyst is added to the isocyanate terminated polyethylene glycol and 1, 5-hexadiene-3, 4-diol, and the catalyst is a tin catalyst comprising dibutyltin dilaurate, stannous octoate and dibutyltin diacetate.
11. The method of claim 10, wherein the amount of the catalyst added is controlled to be 0.1 to 0.5% by mass of the sum of the isocyanatopolyethylene glycol and 1, 5-hexadiene-3, 4-diol.
12. The method according to claim 3, wherein the reaction temperature is controlled to be 60 to 85 ℃ during the preparation of the isocyanate-terminated polyurethane prepolymer having double bonds in the side chain; the reaction time is controlled to be 3-5 h.
13. The method of claim 12, wherein the temperature is 70-80 ℃.
14. The method according to claim 3, wherein the amount of the mono-6-O-amino- β -cyclodextrin added in the reaction is controlled to be: the molar ratio of-NH 2 to-NCO is 1: 0.5-2.
15. The method of claim 14, wherein the molar ratio of-NH 2 to-NCO is 1:1.
16. The preparation method according to claim 3, wherein the temperature is reduced to 10-15 ℃ before the mono-6-O-amino-beta-cyclodextrin is added in the reaction, the organic solution of the mono-6-O-amino-beta-cyclodextrin is dropwise added under the stirring state, the temperature is maintained after the dropwise addition is finished, the reaction is carried out until the characteristic absorption peak of the infrared detection-NCO disappears, and the reaction time is controlled to be 1.5-2.5 h.
17. The method according to claim 16, wherein the solvent in the organic solution is N, N-dimethylformamide DMF, and the concentration of the mono-6-O-amino- β -cyclodextrin is controlled to be 0.2 to 0.3 g/mL.
18. The method of claim 17, wherein the concentration of the mono-6-O-amino- β -cyclodextrin is controlled to be 0.25 g/mL.
19. The method according to claim 3, wherein the DPU is obtained by separation and purification.
20. Use of a cyclodextrin-terminated polyurethane having double bonds in the side chains as claimed in claim 1 or 2 for the preparation of a cyclodextrin-containing polyurethane hydrogel.
21. A polyurethane hydrogel containing cyclodextrin, which is prepared by a method comprising: dissolving the cyclodextrin-terminated polyurethane DPU with a double bond in a side chain in an organic solvent, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain a polyurethane gel DPU-G, soaking the gel in deionized water, and periodically changing water to obtain the polyurethane hydrogel DPU-WG.
22. The polyurethane hydrogel according to claim 21, wherein the organic solvent is DMF, and the concentration of DPU in the DMF solution is 0.03-0.05 g/mL.
23. The polyurethane hydrogel of claim 21, wherein said polymercapto compound is pentaerythritol tetrakis (3-mercaptopropionate) and the amount added is controlled to: the molar ratio of the sulfydryl to the double bonds is 1: 0.5-2.
24. The polyurethane hydrogel of claim 23, wherein the molar ratio of thiol groups to double bonds is 1:1.
25. The polyurethane hydrogel of claim 21, wherein a catalyst is used in the click chemistry reaction, and wherein the catalyst is an organic base catalyst.
26. The polyurethane hydrogel according to claim 25, wherein the organic base catalyst is N, N-diisopropylethylamine in an amount of 0.05 to 0.5% based on the total mass of the reactants.
27. The polyurethane hydrogel according to claim 26, wherein the amount is 0.1% by mass of the total mass of the reactants.
28. The polyurethane hydrogel according to claim 21, wherein the click chemistry reaction is performed at a normal temperature and the reaction time is controlled to be 3 to 6 hours.
29. Use of a cyclodextrin-containing polyurethane hydrogel of any one of claims 21-28 in the preparation of a pharmaceutical carrier.
30. The use of claim 29, wherein the drug is a highly hydrophobic drug.
31. A drug-loaded polyurethane hydrogel comprising the cyclodextrin-containing polyurethane hydrogel of any one of claims 21 to 28, and a drug loaded on the cyclodextrin-containing polyurethane hydrogel.
32. The drug-loaded polyurethane hydrogel of claim 31, wherein the drug is a highly hydrophobic drug for antibacterial, anti-inflammatory, and anticancer uses, including doxorubicin, paclitaxel, and curcumin.
33. A method for preparing the drug-loaded polyurethane hydrogel of claim 31 or 32, which comprises: the preparation method comprises the steps of dissolving the cyclodextrin-terminated polyurethane DPU with a double bond-containing side chain in DMF solution dissolved with a medicament, adding a multi-sulfhydryl compound, performing cross-linking through a click chemical reaction to obtain medicament-carrying polyurethane gel DPU-DG, soaking the gel in deionized water, and periodically changing water to obtain the medicament-carrying polyurethane hydrogel DPU-DWG.
34. The method of claim 33, wherein the concentration of the drug in the DMF solution with the dissolved drug is 3-20 mg/mL.
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