Disclosure of Invention
An object of the present application is to provide a novel method of fabricating a polymer microneedle, and a polymer microneedle fabricated thereby.
The following technical scheme is adopted in the application:
one aspect of the present application discloses a method of preparing a polymer microneedle, including the steps of,
(1) a polymer solution preparation step, which comprises the steps of carrying out vacuum decompression treatment to remove bubbles in the polymer solution when stirring and dispersing the polymer solution;
(2) the polymer array microneedle mould processing step comprises the steps of carrying out plasma processing on the polymer array microneedle mould, wherein the plasma processing condition is that the power is 10-200W, and the processing time is 5-90 s;
(3) and (3) a polymer microneedle preparation step, which comprises the steps of pouring the polymer solution prepared in the step (1) into the polymer array microneedle mould treated by the plasma in the step (2), standing for 3-10min to ensure that the polymer solution fully flows into the bottom of the cavity of the polymer array microneedle mould, removing the redundant polymer solution, curing and molding, and demoulding to obtain the polymer microneedle.
The key point of the method for preparing a polymer microneedle of the present application is that first, bubbles are removed by vacuum decompression during stirring and dispersion; second, the polymer array microneedle mold is previously subjected to plasma treatment. For bubbles in a polymer solution, the existing preparation method is to perform vacuum degassing treatment after adding the polymer solution into a polymer array microneedle mould; however, after the polymer solution is prepared, the polymer solution is not completely added into the mold to prepare the microneedle, and especially in the mass production process, a large amount of polymer solution is usually prepared in advance and then mass produced in a large scale, and in the process, the polymer solution is left for a long time; so that the time for the bubbles to exist in the polymer solution is relatively long, and in the process, the existence of the bubbles can cause the polymer solution to be solidified to different degrees, thereby affecting the quality of the polymer microneedle; therefore, the invention creatively provides that the bubbles are removed by vacuum decompression in the preparation process of the polymer solution, and the problem of polymer solution solidification caused by the long-term existence of the bubbles is avoided. Under the condition of ensuring the quality of the polymer solution, the polymer array microneedle mould is further and creatively subjected to plasma treatment, so that the polymer array microneedle mould has better affinity to the polymer, the polymer solution can automatically flow into the bottom of the cavity of the polymer array microneedle mould without using vacuum or negative pressure, and the quality of the polymer microneedle is improved. It can be understood that the manufacturing method of the present application, which is the key to the improvement of the above two steps, can refer to the existing manufacturing process for the subsequent polymer microneedle preparation, such as curing molding, demolding and the like.
It should be further noted that in the preparation method of the present application, the plasma treatment time is 5s to 90s, wherein the treatment time is too short, the affinity improvement effect is weak, and the effect of the polymer solution automatically filling the bottom of the cavity of the polymer array microneedle mould is poor; the treatment time is too long, which can result in difficult release of the polymeric microneedles. Therefore, the preferred plasma treatment time in this application is 5s to 90s, and more preferably 5s to 30s, in which the affinity improvement effect is achieved to facilitate both the automatic filling of the polymer solution to the bottom of the mold and the mold release.
Preferably, the polymer material used in the polymer solution is at least one of polyvinylpyrrolidone, polyvinyl alcohol, poloxamer, chitosan, dextran, cellulose, heparin, hyaluronic acid, alginate, inulin, starch, glycogen, polyester, polyhydroxyalkanoate, poly α -hydroxy acid, poly β -hydroxy acid, 3-hydroxybutyrate-3-hydroxyvalerate copolymer, poly 3-hydroxypropionate, poly 3-hydroxyhexanoate, poly 4-hydroxy acid, phosphocreatine, polyhydroxyalkanoate-polyethylene glycol copolymer, ethylene-vinyl alcohol copolymer, acrylonitrile-butadiene-styrene copolymer, ethylene-vinyl acetate copolymer, poly 4-hydroxybutyrate, poly 4-hydroxyvalerate, poly 4-hydroxyhexanoate, polyesteramide, polycaprolactone, polylactide, polyglycolide, polylactic acid-glycolic acid copolymer, polydioxanone, polyorthoester, polyetherester, polyanhydride, glycolic acid-methyl carbonate copolymer, polyvinyl chloride, polyvinyl ether, polyvinyl methyl ether, polyvinylidene fluoride, polyvinylidene chloride, polyalkylene fluoride, polystyrene, polyvinyl chloride-co-acrylate, polyvinyl chloride, polyvinyl fluoride, polyvinyl acetate copolymer, polyvinyl chloride-acrylonitrile, polyvinyl chloride-co-styrene-co-acrylate, polyvinyl alcohol, polyvinyl chloride-co-polyvinyl chloride, polyvinyl chloride-co-polyvinyl chloride, polyacrylonitrile, polyvinyl chloride-co-polyvinyl chloride, polyvinyl chloride-co-polyvinyl chloride.
It should be noted that the above polymer materials are conventional materials for preparing polymer microneedles, and the polymer solution may further include some drugs or other active ingredients to be administered transdermally, which is not limited herein. It is understood that the key of the present application lies in the improvement of the preparation method, and in principle, the existing polymer microneedle materials and drugs can be prepared by the preparation method of the present application.
Preferably, the rotation speed of the stirring dispersion treatment is 25 to 1000 rpm/min.
Preferably, the degree of vacuum of the vacuum decompression treatment is 0.001MPa to 0.1 MPa.
It should be noted that the vacuum decompression treatment of the present application aims to remove bubbles in the polymer solution, and therefore, 0.001MPa to 0.1MPa is sufficient to remove bubbles efficiently, although it is not excluded that a higher vacuum degree may be used depending on the use requirements.
Preferably, the polymer array microneedle mould is made of Polydimethylsiloxane (PDMS).
It should be noted that after being subjected to plasma treatment, the polymer array microneedle mould prepared from polydimethylsiloxane can improve the affinity between the polymer array microneedle mould and the polymer, so that the polymer and the PDMS can be well adhered to each other, and thus the polymer array microneedle mould can automatically flow and fill the polymer array microneedle mould to the bottom of the micro-pit.
Preferably, the curing and forming mode is at least one of freeze drying, vacuum drying, air drying, constant temperature drying and initiator ultraviolet crosslinking polymerization.
Preferably, the demolding comprises the step of adhering a supporting substrate with good skin biocompatibility and air permeability to the polymer microneedles in the polymer array microneedle mould after curing and forming, and the demolding is carried out through the adhesion of the supporting substrate.
Preferably, the supporting substrate is made of at least one material selected from polyvinyl alcohol, polyvinylpyrrolidone, polylactic acid, polyglycolic acid, dacron, polypropylene, chitin, fiber, polylactic acid-glycolic acid copolymer, polydioxanone, polymethyl methacrylate, styrene-acrylonitrile copolymer, polyamide, polyethylene, polyester fiber, polyacrylonitrile, teflon, polyvinyl chloride, polyurethane, sulfonamide resin, epoxy resin, ceramic, and semiconductor material.
Preferably, the preparation method further comprises the steps of cutting and packaging, namely cutting the support substrate adhered with the polymer microneedle into the size of the product specification, sterilizing and packaging to obtain the polymer microneedle product.
The application also discloses a polymer micro-needle prepared by the preparation method.
It should be noted that, with the polymer microneedle of the present application, due to the preparation method of the present application, firstly, the polymer solution does not have the problem of partial solution solidification caused by air bubbles due to long-term standing, and the quality problem of the polymer microneedle caused thereby; secondly, the problem of inferior quality or product quality caused by the fact that the polymer solution cannot effectively reach the bottom of the polymer array microneedle mould micro-pit is solved; thirdly, after the polymer solution is added into the polymer array micro-needle mould, the polymer solution is automatically filled to the bottom of the micro-pit, vacuum decompression is not needed, and the production cost is reduced. In general, the polymer microneedle prepared by the preparation method has high quality, low defective rate and low cost, and is particularly suitable for large-scale batch industrial production.
The beneficial effect of this application lies in:
according to the preparation method of the polymer microneedle, bubbles are removed in the preparation process of the polymer solution, so that the influence of the bubbles on the quality of the polymer solution is avoided, and the quality problem of the polymer microneedle caused by the bubbles is avoided; and moreover, the polymer array microneedle mould is subjected to plasma treatment, so that the polymer solution can be automatically filled to the bottom of the cavity, and the quality of the polymer microneedles is guaranteed.
Examples
First, prepare reation kettle of polymer solution
The polymer solution reaction kettle 100 comprises a reaction cavity, wherein a feeding port 102 is formed in the upper part of the reaction cavity, and a thermometer 101 extending into the reaction cavity is arranged and used for monitoring the temperature inside the reaction kettle; a constant temperature circulating system is arranged on the outer wall of the reaction kettle and used for ensuring the temperature inside the reaction kettle, water or oil of the constant temperature circulating system enters from a water inlet 104, then flows out from a water outlet 103 after surrounding the outer wall of the reaction kettle for a circle, and the whole constant temperature circulating system is powered by a constant temperature water oil pump 107; a stirrer 105 for stirring and dispersing the polymer solution is arranged in the reaction kettle; a vacuum pump connecting hole is formed in the side wall of the reaction kettle, and the inside of the reaction kettle is vacuumized through a vacuum pump 108 to realize vacuum pressure reduction and remove bubbles in the polymer solution; the bottom of the reaction kettle is provided with a feed opening 106 for releasing the prepared polymer solution.
The reaction kettle of the example is used as follows:
1) adding polymer powder and medicine through a feeding port 102, and adding a solvent;
2) starting a constant-temperature water oil pump 107, adjusting the temperature, generally speaking, adjusting the temperature to 0-100 ℃ according to requirements, inputting constant-temperature water into the reaction kettle through a water inlet 104, refluxing through a water outlet 103 to realize constant-temperature circulation, and monitoring the actual temperature of the reaction system in real time through a thermometer 101;
3) starting the stirrer 105, wherein the rotating speed range is 25-1000rpm/min, and accelerating the dispersion and dissolution of the polymer and the medicine in the solvent;
4) simultaneously, the vacuum pump 108 is started, the vacuum degree range is adjusted to be 0.001MPa-0.1MPa, and bubbles are quickly removed;
5) after the polymer solution is uniformly dispersed, the constant-temperature water oil pump 107 and the vacuum pump 108 are closed, and after the polymer solution is cooled at room temperature, the valve of the feed opening 106 is opened for feeding to obtain the prepared polymer solution.
Wherein the polymer solution is prepared from polyvinyl pyrrolidone, polyvinyl alcohol, poloxamer, chitosan, dextran, cellulose, heparin, hyaluronic acid, alginate, inulin, starch, glycogen, polyester, polyhydroxyalkanoate, poly α -hydroxy acid, poly β -hydroxy acid, 3-hydroxybutyrate-3-hydroxyvalerate copolymer, poly 3-hydroxypropionate, poly 3-hydroxyhexanoate, poly 4-hydroxy acid, poly creatine phosphate, poly hydroxyalkanoate-polyethylene glycol copolymer, ethylene-vinyl alcohol copolymer, acrylonitrile-butadiene-styrene copolymer, ethylene-vinyl acetate copolymer, poly 4-hydroxybutyrate, poly 4-hydroxyvalerate, poly 4-hydroxyhexanoate, polyesteramide, polycaprolactone, polylactide, polyglycolide, polylactic acid-glycolic acid copolymer, polydioxanone, polyorthoester, polyether ester, polyanhydride, glycolic acid-trimethylene carbonate copolymer, ethylene, polyvinyl ether, polyvinyl methyl ether, polyvinylidene fluoride, polyalkylene fluoride, polyvinyl chloride, polyvinyl fluoride, polyvinyl acetate copolymer, polyvinyl chloride-co-methacrylate, polyvinyl acetate, polyvinyl alcohol copolymer, polyvinyl chloride-acrylonitrile copolymer, polyvinyl acetate copolymer, polyvinyl alcohol copolymer, polyvinyl chloride-acrylonitrile copolymer, polyvinyl chloride-co-styrene copolymer, polyvinyl chloride.
Second, polymer array microneedle mould treatment
In order to enable the viscous polymer solution to rapidly enter the bottom of each micro groove of the polymer array microneedle mould, as shown in fig. 2, the polymer array microneedle mould 201 is subjected to plasma treatment, so that the polymer array microneedle mould has a hydrophilic surface 202, and the affinity of the polymer array microneedle mould to the polymer solution is enhanced. The polymer array microneedle mould of this example was prepared using Polydimethylsiloxane (PDMS).
The plasma treatment in this example can be a chamber type plasma cleaning apparatus, such as a corona machine, a showerhead plasma, and the like. The adjustment of power and time can be optimized according to different instruments; generally, the power is 10-200W, and the time is 5-90 s. The polymer array microneedle mould was shown in figure 2, panels a and b, before and after processing.
Preparation of polymer microneedle
The polymer solution prepared in this example was added to the polymer array microneedle mold after the plasma treatment, and the excess polymer solution was scraped off by a squeegee and recovered again, as shown in fig. 2 c, so that the polymer solution formed an array of microneedle structures 203 in each microtank.
The polymer solution is solidified and formed in various ways, and the ways can be selected according to the physicochemical properties of the polymer solution and the solvent, such as freeze drying, vacuum drying, air drying, constant temperature drying, ultraviolet crosslinking polymerization by adding an initiator and the like. The cured and molded polymer 204 obtained after the treatment is adhered to a supporting substrate 205 as shown in d of fig. 2, and the supporting substrate 205 has a function of easily peeling off the array microneedles and can be easily taken and placed by a user. The material of the supporting substrate in this example can be biodegradable and non-degradable polymers, and is required to have good biocompatibility with skin, be breathable, and not cause irritation such as allergy to the skin.
The supporting substrate material in this embodiment may be polyvinyl alcohol, polyvinyl pyrrolidone, polylactic acid, polyglycolic acid, polyester, polypropylene, chitin, fiber, polylactic acid-glycolic acid copolymer, polydioxanone, polymethyl methacrylate, styrene-acrylonitrile copolymer, polyamide, polyethylene, polyester fiber, polyacrylonitrile, teflon, polyvinyl chloride, polyurethane, sulfonamide resin, epoxy resin, ceramic, semiconductor material, or the like.
Separating the polymer microneedles from the mold to obtain a final product 206, as shown in e of fig. 2, if a plurality of polymer array microneedles are arranged simultaneously, adhering the microneedles to a large-area supporting substrate, separating the microneedles from the mold, and then cutting, sterilizing and packaging the microneedles.
Test 1: preparation of silk fibroin-polyvinylpyrrolidone array microneedle
Preparation of polyvinylpyrrolidone high-molecular polymer solution containing silk fibroin
The high molecular polymer used in the test is polyvinylpyrrolidone (PVP), the molecular weight is 130 thousands, the abbreviation PVP-K90, the concentration of the polymer is 300mg/mL, wherein, the mass fraction of the contained silk fibroin is 1%, the functions of the test are moisturizing, anti-wrinkle and anti-inflammatory, and the test has wide application in the aspects of beauty treatment and skin care.
The preparation method of PVP-K90 containing silk fibroin comprises the following steps:
1) PVP-K90150g, 5g of silk fibroin powder and 500mL of ultrapure water are put into the device through a feeding port 102;
2) starting a constant-temperature water oil pump 107, adjusting the temperature, setting the temperature to be 30 ℃, inputting constant-temperature water into the reaction kettle through a water inlet 104, realizing constant-temperature water circulation through backflow of a water outlet 103, and monitoring the actual temperature of the reaction system in real time through a thermometer 101;
3) starting the stirrer 105, wherein the rotating speed range is 500rpm/min, and accelerating the dispersion and dissolution of the polymer and the medicine in the solvent;
4) simultaneously starting the vacuum pump 108, and adjusting the vacuum degree range to be 0.03 MPa;
5) after about 30min, the PVP solution containing the drug is uniformly dispersed without any air bubbles, at this time, the constant-temperature water oil pump 107 and the vacuum pump 108 are closed, after cooling at room temperature, the valve of the feed opening 106 is opened for feeding, and the polyvinylpyrrolidone high polymer solution containing the silk fibroin of the test is obtained.
Preparation of silk fibroin-polyvinylpyrrolidone array microneedle
The prepared polyvinylpyrrolidone high molecular polymer solution containing silk fibroin is used for preparing polymer microneedles. The polymer array microneedle mould used in this test was provided by singapore Micropoint Technologies pte. ltd. the dimensions of each microneedle were 1000 μm high, 300 μm wide, 1cm overall2The mould can prepare 15X 15 needles; firstly, carrying out plasma treatment on a mould, and then preparing a polymer microneedle, wherein the preparation method comprises the following steps:
1. carrying out surface modification on the polymer array microneedle mould by using a corona machine, and treating for 60s under the power of 50 w;
2. adding the prepared polyvinylpyrrolidone high-molecular polymer solution containing silk fibroin into a polymer array microneedle mould treated by corona machine plasma, standing for 5min to ensure that the high-molecular polymer solution fully enters the bottom of the cavity, scraping the redundant high-molecular polymer solution by using a scraper and recovering again, wherein the high-molecular polymer solution forms an array microneedle structure in each microgroove;
3. drying and curing the high molecular polymer solution, wherein the test specifically adopts a constant-temperature air-blast drying oven to treat the high molecular polymer solution, the temperature is set to be 50 ℃, and the time is 8 hours; the polymer obtained after curing and molding is treated to adhere to a whole supporting substrate, and the test specifically adopts a polyvinyl alcohol film with the mass fraction of 10%.
4. And separating the array microneedle from the mould to obtain the final polymer microneedle finished product.
Test 2: production of bulk sodium hyaluronate array microneedles
The embodiment utilizes a mould with 100 polymer micro-needles to simultaneously produce 100 hyaluronic acid array micro-needles in a short time, the sodium hyaluronate has the functions of moisturizing, wrinkle resistance, inflammation diminishing and the like, can be used as a polymer for forming the array micro-needles and also can be used as a material for beautifying and skin care, has very good biocompatibility, and is one of the most commonly used polymers for beautifying and skin care.
The sodium hyaluronate used in the test is divided into two types, one type is macromolecular sodium hyaluronate, which helps polymer formation, has good moisturizing effect and can promote collagen regeneration, and the molecular weight of the sodium hyaluronate is 100-200 ten thousand, and the concentration of the sodium hyaluronate is 30 mg/mL; the second one is micromolecular sodium hyaluronate with good anti-inflammatory function, the molecular weight is 20-30 ten thousand, and the concentration is 50 mg/mL.
The preparation method comprises the following steps:
1. preparation of hyaluronic acid high molecular polymer solution
1) 3g of macromolecular sodium hyaluronate, 5g of micromolecular sodium hyaluronate and 100mL of ultrapure water are fed through a feeding port;
2) starting a constant-temperature water oil pump, adjusting the temperature, setting the temperature to be 50 ℃, inputting constant-temperature water into the reaction kettle through a water inlet, realizing constant-temperature water circulation through backflow of a water outlet, and monitoring the actual temperature of the reaction system in real time through a thermometer;
3) starting a stirring device, wherein the rotating speed range is 200rpm/min, and accelerating the dispersion and dissolution of the polymer in the solvent;
4) simultaneously starting a vacuum pump, and adjusting the vacuum degree range to be 0.07 MPa;
5) and after about 30min, uniformly dispersing the sodium hyaluronate solution without any bubbles, closing the constant-temperature water oil pump and the vacuum pump, cooling at room temperature, and opening a feed opening valve for feeding to obtain the hyaluronic acid high polymer solution for the test.
2. Preparation of sodium hyaluronate array microneedle
The 100 polymer array microneedle moulds are placed in order without gaps, placed on a tray, and simultaneously placed into a cavity type plasma cleaning instrument for treatment for 30s under the power of 100W. The polymer array microneedle mould used in this test was the same as test 1.
And taking out the polymer array microneedle mould tray treated by the plasma cleaning instrument, adding the hyaluronic acid high molecular polymer solution prepared in the test, standing for 5min to allow the hyaluronic acid high molecular polymer solution to fully enter the bottom of the cavity, scraping off the redundant high molecular polymer solution by using a scraper, and recovering again to allow the high molecular polymer solution to form an array microneedle structure in each microgroove.
The polymer solution was dried and cured, and the test was carried out by vacuum drying at room temperature under 20000Pa for 10 hours. The polymer obtained after curing and molding through treatment is adhered to a whole supporting substrate, and the experiment uses the high-flexibility non-woven fabric made of breathable polyester as the supporting substrate.
And (3) separating the whole polymer array microneedle containing 100 units from the mould, and then cutting, sterilizing and packaging according to the required shape and size to obtain the final polymer microneedle finished product.
The polymer microneedles prepared in the tests 1 and 2 are observed by a microscope, and the results show that the two polymer microneedles prepared in the tests have no microneedle defect caused by bubbles, the microneedles are highly uniform, and the microneedle defect caused by the fact that the polymer solution cannot reach the bottom of the micropore of the mold is avoided.
The mechanical properties that every micropin can bear are detected to application universal tester: the mechanical properties which can be borne by the microneedles of the tests 1 and 2 are tested by using a universal testing machine, the testing and detecting method is a compression test, and the set area is 1cm2The speed was 300 μm/min. The detection result shows that the strength of each needle can reach more than 0.1N, which indicates that the microneedle can pierce the skin and meet the use requirement.
The foregoing is a more detailed description of the present application in connection with specific embodiments thereof, and it is not intended that the present application be limited to the specific embodiments thereof. It will be apparent to those skilled in the art from this disclosure that many more simple derivations or substitutions can be made without departing from the spirit of the disclosure.