CN108742718B - Self-adhesive microneedle patch capable of swelling rapidly and preparation method thereof - Google Patents
Self-adhesive microneedle patch capable of swelling rapidly and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a self-adhesive microneedle patch capable of swelling rapidly and a preparation method thereof, wherein a hydrophilic polymer is modified by a first modifier (one or a mixture of two of acrylic anhydride and methacrylic anhydride) to synthesize an acrylated hydrophilic polymer; then, the catechol compound and the acrylic acid esterified hydrophilic polymer are subjected to secondary reaction to synthesize the catechol-modified acrylic acid esterified hydrophilic polymer, the hydrophilic polymer has good biocompatibility, when the hydrophilic polymer is prepared into the microneedle patch, the microneedle patch has good biocompatibility, and meanwhile, the microneedle patch can quickly absorb liquid to swell and cannot be blocked by skin tissues in the suction process.
Description
Technical Field
The invention relates to the technical field of chemical, material science, biomedical equipment and articles, in particular to a self-adhesive microneedle patch capable of swelling rapidly and a preparation method thereof.
Background
In medical practice in which microneedle devices are increasingly used, many channels are formed through the fur portion at a time by using a plurality of microneedles which pass through the stratum corneum layer of the skin as a main barrier layer for transdermal drug delivery. Through the above-mentioned passages, a sufficient amount of the drug can reach the epidermal layer or the dermal layer, and thereafter, the drug is absorbed through blood vessels and lymph glands, thereby being introduced into the circulatory system of the human body. As other applications, the above-mentioned plurality of microneedles are also used for cosmetic purposes. Although the transdermal delivery system of an active substance using a plurality of microneedles is useful, a patch type of microneedle device is preferably used for its convenience. For example, chinese patent document CN105581975A discloses a microneedle and a microneedle patch, wherein the microneedle comprises a biocompatible matrix in a shape of a microneedle and a plurality of porous particles formed on a surface of the biocompatible matrix or at least in a part of an interior of the biocompatible matrix, the biocompatible matrix is substantially an aqueous polymer, a derivative thereof, or a mixture thereof, and the porous particles are a wrinkle-removing filler.
With the development of microneedles and microneedle patches, in addition to the wide application in transdermal drug delivery and vaccination, microneedle patches have been used in recent years to extract interstitial fluid from skin tissues, but the above microneedle patches or existing microneedle patches have the following problems in the application: 1. the holes of the microneedles of conventional structures can be blocked by skin tissue; 2. the risk of fragile skin with internal residues; 3. after the microneedle is inserted into the skin, an adhesive tape or an adhesive tape is required to be used for fixing, and the adhesive tape or the adhesive tape brings discomfort or anaphylactic reaction to the skin; 4. the microneedles extract interstitial fluid from the skin for too long.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of a self-adhesive microneedle patch capable of swelling rapidly, which comprises the following steps:
(1) dissolving a hydrophilic polymer in a first solvent to form a hydrophilic polymer solution with the concentration of 0.1mg/mL-200mg/mL, and then adding a first modifier into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH value is 8-9, the temperature is 1-37 ℃, and the time is 12-48 h; the stirring speed is 100 and 10000 rpm; the molar ratio of the first modifier to the hydrophilic polymer is 1: 1-100: 1, the hydrophilic polymer is one or a mixture of more of hyaluronic acid, collagen, alginic acid, chitosan, heparin, polyarginine, polyaspartic acid, polylysine and polyacrylic acid; the first solvent is water or a mixture of water and dimethylformamide; the first modifier is one or a mixture of two of acrylic anhydride and methacrylic anhydride;
(2) extraction of the esterified hydrophilic polymer in the mixture a: firstly, adding a precipitator into the mixture A for precipitation to obtain a precipitate, dissolving the precipitate by using water, then putting the precipitate into a renewable fiber dialysis bag for dialysis in deionized water, and finally taking out the renewable fiber dialysis bag for freeze-drying to obtain an esterified hydrophilic polymer; wherein the precipitant is one of methanol, ethanol, propanol or diethyl ether; as for the freeze-drying conditions, a common freeze-drying machine is adopted, and the freeze-drying conditions are not particularly specified as long as the freeze-drying under vacuum condition can be achieved, and the temperature range of the common freeze-drying machine is-80 ℃ to-30 ℃; the molecular weight cut-off of the renewable fiber dialysis bag is 1-200 kda;
(3) dissolving the esterified hydrophilic polymer into a second solvent at a concentration of 0.1mg/mL to 200mg/mL, and then adding a 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxythiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: pH 2-5, temperature 1-50 deg.C, time 30min-12h, stirring speed range of 100rpm-10000 rpm; then adding a catechol compound to perform amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 2-5, the temperature is 1-50 ℃, the time is 12min-48h, and the stirring rotating speed range is 100rpm-10000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the catechol compound is 1: 0.5: 0.5:0.5-1: 100:100: 100, respectively; the catechol compound is dopamine or tannic acid; the second solvent is deionized water or buffer solution; the buffer solution is PBS buffer solution, Tris buffer solution or 2- (N-morpholine) ethanesulfonic acid (MES) buffer solution;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 4, and then freeze-drying to obtain the amidated esterified hydrophilic polymer; wherein, the freeze-drying condition only needs to adopt a common freeze-drying machine, is not specially specified, as long as the freeze-drying under the vacuum condition can be achieved, and the temperature range of the common freeze-drying machine is-80 ℃ to-30 ℃; the molecular weight cut-off of the renewable fiber dialysis bag is 1-200 kda;
(5) preparing a microneedle patch by amidating and esterifying a hydrophilic polymer: dissolving the amidated esterified hydrophilic polymer in a third solvent with the concentration of 10mg/mL-500mg/mL, then adding the amidated esterified hydrophilic polymer into a template, then drying, and finally demoulding to obtain the microneedle patch. The template is preferably a Polydimethylsiloxane (PDMS) template, and the third solvent is deionized water, a PBS buffer solution, a Tris buffer solution or a 2- (N-morpholine) ethanesulfonic acid (MES) buffer solution.
Further, in the step (5), ultraviolet irradiation is carried out on the demoulded microneedle patch, and the irradiation time is 1-30 min; the intensity of the ultraviolet light is 10.0mW/cm2-30mW/cm2。
In the invention, the pH value is adjusted by sodium hydroxide and hydrochloric acid; 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxythiosuccinimide sodium salt solvent is abbreviated as EDC/NHS solvent; the temperature is centigrade; water deionized water is preferred.
Further, in the step (5), before drying, a centrifuge is used for enabling the solution to further completely fill the template and remove air bubbles; the conditions of centrifugation were: the centrifugal speed is 500 plus 10000rpm, and the centrifugal time is 1-30 min; and the drying temperature is 20-70 ℃, the drying time is 20-28h, and a drying oven is used.
The invention also provides the microneedle patch prepared by the preparation method, which can quickly absorb liquid for quick swelling and has adhesiveness; the microneedle patch can be applied to transdermal drug delivery, insulin injection, gene delivery, vaccination, disease diagnosis, biosensors, and wearable devices.
Compared with the prior art, the technical scheme of the invention has the following advantages:
(1) the preparation method of the self-adhesive microneedle patch capable of swelling rapidly comprises the steps of modifying a hydrophilic polymer by a first modifier (one or a mixture of two of acrylic anhydride and methacrylic anhydride) to synthesize an acrylated hydrophilic polymer; then, the catechol compound and the acrylic acid esterified hydrophilic polymer are subjected to secondary reaction to synthesize the catechol-modified acrylic acid esterified hydrophilic polymer, the hydrophilic polymer has good biocompatibility, when the hydrophilic polymer is prepared into the microneedle patch, the microneedle patch has good biocompatibility, and meanwhile, the microneedle patch can rapidly absorb liquid to swell and cannot be blocked by skin tissues in the suction process, furthermore, due to the existence of the catechol group, substances such as protein and polypeptide are contained in the skin, and the two substances can generate chelation reaction, so that the microneedle patch can be adhered to the surface of the skin, and does not need additional adhesive tapes or adhesive tapes for fixation, thereby saving time, labor and cost.
(2) The microneedle patch prepared by the preparation method of the self-adhesive microneedle patch capable of swelling rapidly disclosed by the invention adopts the catechol-modified acrylated hydrophilic polymer, so that the microneedle patch can swell rapidly when encountering skin tissue fluid, and can rapidly absorb body fluid into microneedles, and no additional device or instrument is needed, so that the time for extracting the body fluid is greatly shortened; meanwhile, because the microneedle patch is irradiated by ultraviolet light in the preparation process, the catechol-modified acrylated hydrophilic polymer is crosslinked, the risk of microneedle breakage is avoided, the microneedle patch is not left in the skin, and the risk of blocking skin tissues is avoided.
(3) The microneedle patch of the present invention can be used for other applications such as drug gene delivery, vaccination, insulin injection, biosensor and wearable device, in addition to being capable of extracting body fluids.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to derive other drawings without creative efforts.
Fig. 1 is a shape diagram of a microneedle patch;
FIG. 2 is a process diagram of the mechanism of synthesis of a hydrophilic polymer to an amidated esterified hydrophilic polymer;
FIG. 3 is a weight graph of body fluid extracted from the microneedle patch inserted into the skin of a nude mouse at different times;
fig. 4 is a view showing recovery of the skin of a microneedle patch after being removed from the skin of a nude mouse;
FIG. 5 is a NMR chart of the hydrophilic polymer, the esterified hydrophilic polymer and the amidated esterified hydrophilic polymer in example 1.
Detailed Description
The present invention now will be described more fully hereinafter with reference to the accompanying drawings, in which some, but not all embodiments of the invention are shown. The embodiments in the present invention, other embodiments obtained by persons skilled in the art without any inventive work, belong to the protection scope of the present invention.
Example 1
(1) Dissolving hyaluronic acid in deionized water to form a hydrophilic polymer solution with the concentration of 20mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 4 ℃, and the time is 24 h; the stirring speed is 300 rpm; the molar ratio of methacrylic anhydride to hyaluronic acid is 2: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in deionized water for 5 days, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water with the concentration of 20mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH is 5, the temperature is 20 ℃, the time is 1h, and the stirring speed range is 300 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 20 ℃, the time is 24h, and the stirring rotating speed range is 300 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxythiosuccinimide sodium salt to the dopamine is 1: 2: 2: 2;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 4 for 5 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D1; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and a pressure of 1 pa.
Example 2
(1) Dissolving collagen in deionized water to form a hydrophilic polymer solution with the concentration of 50mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 9, the temperature is 10 ℃, and the time is 36 h; the stirring speed is 1000 rpm; the molar ratio of methacrylic anhydride to collagen is 50: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in deionized water for 3 days, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 10 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water with the concentration of 50mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH is 4, the temperature is 30 ℃, the time is 3h, and the stirring speed range is 100 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 2, the temperature is 20 ℃, the time is 12h, and the stirring rotating speed range is 2000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the dopamine is 1: 10: 10: 10;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 3 for 3 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D2; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and 5 pa.
Example 3
(1) Dissolving alginic acid in deionized water to form a hydrophilic polymer solution with the concentration of 80mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 10 ℃, and the time is 30 h; the stirring speed is 5000 rpm; the molar ratio of the methacrylic anhydride to the alginic acid is 60: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding methanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with deionized water, putting the precipitate into a renewable fiber dialysis bag to dialyze in the deionized water for 7 days, and taking out the renewable fiber dialysis bag and freeze-drying to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 5 pa;
(3) dissolving the esterified hydrophilic polymer into PBS buffer solution with the concentration of 80mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy-thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH is 3, the temperature is 40 ℃, the time is 5h, and the stirring speed range is 5000 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH is 3, the temperature is 40 ℃, the time is 24h, and the stirring speed range is 5000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxythiosuccinimide sodium salt to the dopamine is 1: 0.5: 0.5: 0.5;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 4 for 7 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D3; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and a pressure of 10 pa.
Example 4
(1) Dissolving chitosan in deionized water to form a hydrophilic polymer solution with the concentration of 100mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 9, the temperature is 30 ℃, and the time is 48 h; the stirring speed is 100 rpm; the molar ratio of the methacrylic anhydride to the chitosan is 100: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: firstly, adding propanol into the mixture A for precipitation to obtain a precipitate, dissolving the precipitate by using water, then putting the precipitate into a renewable fiber dialysis bag for dialysis in deionized water for 4 days, and finally taking out the renewable fiber dialysis bag and freeze-drying to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into Tris buffer solution with the concentration of 100mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: pH 2, temperature at 50 deg.C, time at 30min, stirring speed range is 10000 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH is 4, the temperature is 50 ℃, the time is 12min, and the rotating speed range of stirring is 8000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the dopamine is 1:20:20: 20;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 5 for 4 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D4; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and a pressure of 1 pa.
Example 5
(1) Dissolving heparin in deionized water to form a hydrophilic polymer solution with the concentration of 150mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 37 ℃, and the time is 12 h; the stirring speed is 8000 rpm; the molar ratio of methacrylic anhydride to heparin is 10: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: firstly, adding diethyl ether into the mixture A for precipitation to obtain a precipitate, dissolving the precipitate by using deionized water, then putting the precipitate into a renewable fiber dialysis bag for dialysis in the deionized water for 5 days, and finally taking out the renewable fiber dialysis bag for freeze-drying to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into 2- (N-morpholine) ethanesulfonic acid (MES) buffer solution with the concentration of 150mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 20 ℃, the time is 12h, and the stirring rotating speed range is 1000 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 20 ℃, the time is 48h, and the stirring rotating speed range is 10000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the dopamine is 1: 10: 10: 10;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 6 for 5 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D5; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and a pressure of 1 pa.
Example 6
(1) Dissolving poly-arginine in dimethylformamide to form a hydrophilic polymer solution with the concentration of 0.1mg/mL, and then adding a mixture of methacrylic anhydride and acrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 1 ℃, and the time is 48 h; the stirring speed is 10000 rpm; the molar ratio of the sum of the moles of methacrylic anhydride and acrylic anhydride to the moles of polyarginine is 1: 1; the molar ratio of the methacrylic anhydride to the acrylic anhydride is 1: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with deionized water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in deionized water for 1 day, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 30 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water at the concentration of 0.1mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy-thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 1 ℃, the time is 12h, and the rotating speed range of stirring is 8000 rpm; subsequently, tannic acid is added for amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 1 ℃, the time is 48h, and the stirring rotating speed range is 6000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the tannic acid is 1: 100: 100: 100;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 2 for 1 day, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D6; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 40 degrees and a pressure of 1 pa.
Example 7
(1) Dissolving polyaspartic acid in a mixture of deionized water and dimethylformamide to form a hydrophilic polymer solution with the concentration of 30mg/mL, wherein the volume ratio of the deionized water to the dimethylformamide is 1:1, and then adding acrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 10 ℃, and the time is 24 h; the stirring speed is 2000 rpm; the molar ratio of acrylic anhydride to polyaspartic acid is 2: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in deionized water for 4 days, taking out the renewable fiber dialysis bag, and freeze-drying to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: -50 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into PBS buffer solution with the concentration of 30mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy-thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH value is 4, the temperature is 10 ℃, the time is 3h, and the stirring rotating speed range is 2000 rpm; subsequently, tannic acid is added for amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 4, the temperature is 10 ℃, the time is 48h, and the stirring rotating speed range is 100 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxythiosuccinimide sodium salt to the dopamine is 1: 50: 50: 50;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 4 for 4 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D7; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 30 ℃ below zero and a pressure of 1 pa.
Example 8
(1) Dissolving polylysine in water to form a hydrophilic polymer solution with the concentration of 50mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 20 ℃, and the time is 20 h; the stirring speed is 1000 rpm; the molar ratio of methacrylic anhydride to polylysine is 10: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with deionized water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in the deionized water for 5 days, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: -50 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water with the concentration of 50mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH is 5, the temperature is 20 ℃, the time is 1h, and the stirring speed range is 300 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 20 ℃, the time is 24h, and the stirring rotating speed range is 300 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the dopamine is 1: 1: 1;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 4 for 5 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D8; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 80 degrees and a pressure of 1 pa.
Example 9
(1) Dissolving polyacrylic acid in deionized water to form a hydrophilic polymer solution with the concentration of 200mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 15 ℃, and the time is 30 h; the stirring speed is 1000 rpm; the molar ratio of methacrylic anhydride to polyacrylic acid is 30: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in deionized water for 5 days, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: -80 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water with the concentration of 150mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 10 ℃, the time is 10h, and the stirring rotating speed range is 300 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 10 ℃, the time is 24h, and the stirring rotating speed range is 400 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxythiosuccinimide sodium salt to the dopamine is 1: 2: 2: 2;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water with the pH value of 3 for 5 days, taking out the mixture from the renewable fiber dialysis bag, and freeze-drying to obtain the amidated esterified hydrophilic polymer D9; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 50 ℃ below zero and a pressure of 1 pa.
Example 10
(1) Dissolving a mixture of hyaluronic acid and collagen in deionized water to form a hydrophilic polymer solution with the concentration of 150mg/mL, and then adding methacrylic anhydride into the solution to perform esterification reaction to obtain a mixture A; wherein the reaction conditions are as follows: the pH is 8, the temperature is 4 ℃, and the time is 24 h; the stirring speed is 300 rpm; the molar ratio of methacrylic anhydride to the sum of the moles of hyaluronic acid and collagen is 5: 1;
(2) extraction of the esterified hydrophilic polymer in the mixture a: adding ethanol into the mixture A to precipitate to obtain a precipitate, dissolving the precipitate with deionized water, putting the precipitate into a renewable fiber dialysis bag, dialyzing the precipitate in the deionized water for 5 days, and taking out the renewable fiber dialysis bag and freeze-drying the dialyzed precipitate to obtain an esterified hydrophilic polymer; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees, pressure 1 pa;
(3) dissolving the esterified hydrophilic polymer into deionized water at the concentration of 200mg/mL, and then adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC)/N-hydroxy thiosuccinimide sodium salt (NHS) solvent for reaction; wherein the reaction conditions are as follows: the pH is 5, the temperature is 20 ℃, the time is 1h, and the stirring speed range is 300 rpm; then adding dopamine to carry out amidation reaction to generate a mixture B; wherein the reaction conditions are as follows: the pH value is 5, the temperature is 20 ℃, the time is 24h, and the stirring rotating speed range is 300 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxythiosuccinimide sodium salt to the dopamine is 1: 5: 5: 5;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag to be dialyzed in deionized water with the pH value of 4, and then taking out the mixture B from the renewable fiber dialysis bag to be freeze-dried to obtain the amidated esterified hydrophilic polymer D10; wherein, the freeze-drying conditions are as follows: the temperature is as follows: 60 degrees and a pressure of 1 pa.
It is noted that the regenerable fiber dialysis bags used in examples 1-10 above had a molecular weight cut-off of 3.5 kda.
Example 11
Preparation of microneedle patch:
the amidated esterified hydrophilic polymer D1-D10 prepared in example 1-example 10 was dissolved in a third solvent, wherein D1-D3 was dissolved in deionized water, D4-D5 was dissolved in PBS buffer, D6-D8 was dissolved in 2- (N-morpholino) ethanesulfonic acid (MES) buffer, D9-D10 was dissolved in Tris buffer, and then added to PDMS template, and then the solution was filled into a mold and air bubbles were removed by centrifugation, and finally dried by using a dryer, and finally released from the mold to obtain microneedle patches W1-W10. Details of the concentration of amidated esterified hydrophilic polymers D1-D10, centrifugation conditions, and drying conditions are shown in Table 1.
As for the shape of the microneedle patch prepared, it is set according to the purpose of use, as the most common shape, as shown in fig. 1, and it includes a base plate and a plurality of microneedles arranged on the base plate. In fig. 1, a and B are obtained by a scanning electron microscope (a) and an optical microscope (B), respectively.
Example 12
The microneedle patches W1-W10 prepared in example 11 were irradiated with ultraviolet light to obtain microneedle patches W11-W20. The conditions for ultraviolet irradiation are detailed in table 1.
TABLE 1
Test example
1. Mechanism of synthesis process
The mechanism of the synthesis from hydrophilic polymer to amidated esterified hydrophilic polymer is illustrated by example 1 and shown in FIG. 2.
2. Rate of modification
The esterified hydrophilic polymer and the amidated esterified hydrophilic polymer obtained in examples 1 to 10 were characterized by a nuclear magnetic resonance apparatus, and a methacrylate group or an acrylate group and a catechol group were successfully modified on the hydrophilic polymer, and by analyzing the spectra, the methacrylate modification rate or the acrylate modification rate was 40% to 80%, and the catechol group modification rate was 5% to 19%. Wherein, the NMR spectra of the hydrophilic polymer, the esterified hydrophilic polymer and the amidated esterified hydrophilic polymer in example 1 are shown in FIG. 5. The modification ratios of the above groups illustrate the successful synthesis of esterified hydrophilic polymers and amidated esterified hydrophilic polymers. Meanwhile, the microneedle patch has skin adhesion due to the existence of the catechol group, which shows that the microneedle patch prepared by the method has the effect of adhering to the skin.
3. Rapid absorption of liquid and rapid recovery of skin
The microneedle patches W11-W20 were inserted into the surface of the hydrogel (1.4 wt% agar gel) respectively, and Optical Coherence Tomography (OCT) (clearly observable when the scale was 1000 microns) showed that the microneedles of the microneedle patches swelled to the maximum extent at about 1min, indicating that they had the characteristic of rapidly sucking liquid. Meanwhile, when the microneedle patch was inserted into the skin of a nude mouse, about 1.4mg of body fluid could be extracted from the skin of the mouse within 1min, which is sufficient for the next analysis of metabolites, as shown in fig. 3.
When the microneedle patch was removed from the skin of a nude mouse, the skin was restored within 30 minutes, as shown in fig. 4, indicating that the microneedle patch could be used normally without causing skin problems.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. A preparation method of a self-adhesive microneedle patch capable of swelling rapidly is characterized by comprising the following steps:
(1) dissolving a hydrophilic polymer in a first solvent to form a hydrophilic polymer solution, and then adding a first modifier into the solution to perform esterification reaction to obtain a mixture A;
(2) extraction of the esterified hydrophilic polymer in the mixture a: firstly, adding a precipitator into the mixture A for precipitation to obtain a precipitate, dissolving the precipitate, then putting the precipitate into a renewable fiber dialysis bag for dialysis in deionized water, and finally freeze-drying to obtain an esterified hydrophilic polymer;
(3) dissolving an esterified hydrophilic polymer into a second solvent, then adding a 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxy thiosuccinimide sodium salt solvent for reaction, and then adding a catechol compound for amidation reaction to generate a mixture B;
(4) extraction of amidated esterified hydrophilic polymer in the mixture B: putting the mixture B into a renewable fiber dialysis bag, dialyzing in deionized water, and freeze-drying to obtain the amidated esterified hydrophilic polymer;
(5) preparing a microneedle patch by amidating and esterifying a hydrophilic polymer: dissolving the amidated esterified hydrophilic polymer in the third solvent in the concentration of 10-500 mg/mL, adding the amidated esterified hydrophilic polymer to the template, drying, and demolding.
2. The manufacturing method according to claim 1, wherein in the step (5), the microneedle patch after being released from the mold is irradiated with ultraviolet light for 1min to 30 min; the intensity of the ultraviolet light is 10.0mW/cm2-30mW/cm2。
3. The production method according to claim 1 or 2, wherein in the step (1), the reaction conditions are: the pH value is 8-9, the temperature is 1-37 ℃, the time is 12-48h, and the stirring speed is 100-10000 rpm; the molar ratio of the first modifier to the hydrophilic polymer is 1: 1-100: 1, the hydrophilic polymer is one or a mixture of more of hyaluronic acid, collagen, alginic acid, chitosan, heparin, polyarginine, polyaspartic acid, polylysine and polyacrylic acid; the first solvent is water or a mixture of water and dimethylformamide; the first modifier is one or a mixture of two of acrylic anhydride and methacrylic anhydride; the concentration of the hydrophilic polymer in the first solvent is 0.1mg/mL-200 mg/mL.
4. The method according to claim 1 or 2, wherein in the step (2), the precipitant is one of methanol, ethanol, propanol or diethyl ether.
5. The production method according to claim 1 or 2, wherein in the step (3), the reaction conditions are: pH 2-5, temperature 1-50 deg.C, time 30min-12h, stirring speed range of 100rpm-10000 rpm; the amidation reaction conditions are as follows: the pH value is 2-5, the temperature is 1-50 ℃, the time is 12min-48h, and the stirring rotating speed range is 100rpm-10000 rpm; the molar ratio of the esterified hydrophilic polymer to the 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to the N-hydroxy thiosuccinimide sodium salt to the catechol compound is 1: 0.5: 0.5:0.5-1: 100:100: 100, respectively; the catechol compound is dopamine or tannic acid; the second solvent is deionized water or buffer solution; the concentration of the esterified hydrophilic polymer in the second solvent is from 0.1mg/mL to 200 mg/mL.
6. The method according to claim 1 or 2, wherein in the step (4), the dialysis process has a pH of 2 to 6.
7. The method of claim 1 or 2, wherein the step (5) further comprises filling the mold with the solution by centrifugation and removing air bubbles before drying.
8. A microneedle patch prepared according to any one of the preparation methods of claims 1 to 7, wherein the microneedle patch can rapidly absorb liquid to rapidly swell.
9. A microneedle patch produced by the production method according to any one of claims 1 to 7, wherein the microneedle patch has adhesiveness.
10. A microneedle patch prepared according to any one of the preparation methods of claims 1 to 7, wherein the microneedle patch can be used for transdermal drug delivery, insulin injection, gene delivery, vaccination, disease diagnosis, biosensor, and wearable device.
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| CN110090044B (en) * | 2019-04-23 | 2021-01-19 | 西安交通大学 | Hydrogel microneedle patch for collecting interstitial fluid of skin and preparation method and use method thereof |
| CN110664439B (en) * | 2019-09-05 | 2021-07-27 | 华中科技大学 | Microneedle capable of extracting skin tissue fluid and preparation method thereof |
| CN111349551B (en) * | 2020-03-06 | 2023-05-09 | 华中科技大学同济医学院附属协和医院 | Microneedle patch capable of extracting microorganisms in skin tissue fluid and preparation method thereof |
| CN111329528A (en) * | 2020-03-26 | 2020-06-26 | 清华大学 | Patch for chronic wound pathology sampling and preparation and use methods |
| CN111437444B (en) * | 2020-04-12 | 2021-03-12 | 南方医科大学 | Preparation method of intestinal adhesion-resistant double-layer biogel and double-layer biogel |
| CN111388407B (en) * | 2020-04-17 | 2021-02-12 | 南京鼓楼医院 | Microneedle array based on dopamine gel and preparation and application thereof |
| CN113995444B (en) * | 2021-11-03 | 2024-05-07 | 深圳大学 | Hydrogel microneedle patch and preparation method and application thereof |
| CN114984435A (en) * | 2022-05-20 | 2022-09-02 | 杭州诺莘科技有限责任公司 | Coating-modified sponge spicule percutaneous absorption composition and preparation method thereof |
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