CN110538136A - preparation of micelle composite gel microneedle for transdermal delivery of insoluble drug - Google Patents
preparation of micelle composite gel microneedle for transdermal delivery of insoluble drug Download PDFInfo
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Abstract
the invention discloses a preparation method of micelle composite gel micro-needle for delivering insoluble drugs through skin. Can simultaneously entrap one or more insoluble drugs to achieve the effects of treatment and cooperative treatment. The method is simple to prepare, and according to the characteristics of the material, the needle body material can absorb water to swell after the soluble micro-needle penetrates into the skin, and gel is formed in situ on the skin. The two amphiphilic materials Soluplus and F127 can be assembled with insoluble drugs to form nano micelles with uniform particle sizes after contacting tissue fluid, and the nano micelles can be better identified and absorbed by cells.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a preparation method of a micelle composite gel microneedle for transdermal delivery of an insoluble drug.
Background
in the 20 th century and the 70 th century, the Transdermal Drug Delivery System (TDDS) became a hot spot in drug delivery systems due to its stable blood concentration after administration, no liver first-pass effect and no gastrointestinal irritation, convenient and safe administration, and easy operation. However, due to the existence of the natural stratum corneum (the thickness is about 15-20 μm) of a human body, the transdermal delivery of the existing drugs has high selectivity, and most drugs hardly or rarely penetrate through the stratum corneum of the skin to reach the concentration required by treatment. So that the development of the preparation falls into the bottleneck of more research and less products. Therefore, how to make drugs, especially insoluble drugs, rapidly penetrate into the skin through the stratum corneum to form a research focus, and after more than 30 years of development, new technologies for transdermal permeation promotion of various drugs continuously appear, such as traditional subcutaneous injection, electroporation, ion introduction, ultrasonic introduction, laser, microneedles, chemical permeation promoters, nano-scale delivery carriers and the like, so that the drug range for TDDS is greatly widened.
the micro needle (micro needle) is a needle-shaped micron-scale fine structure which is processed by inorganic and organic materials through micro-electro-mechanical technology, the length of the micro needle is generally between 25 and 1000 mu m, and most of the micro needle is made of silicon, metal, polymer and the like. The mechanism of the microneedle transdermal drug delivery system is that drugs enter the skin through tiny pores formed after microneedles penetrate the stratum corneum of the skin and enter the skin, so that the effects of promoting transdermal penetration and reaching the specific depth of the skin are achieved.
according to the difference of preparation materials of the micro-needles and distribution and release modes of the medicines, the micro-needles are mainly divided into the following categories: solid microneedles, hollow microneedles, coated microneedles, and soluble microneedles. Solid microneedles are the first type of microneedle used for transdermal drug delivery and were made primarily of metal. Firstly, the metal micro-needle is utilized to puncture the hole formed by the stratum corneum, and then the medicine is applied to the damaged part of the skin to realize the delivery of the medicine. Because the microneedle body is smaller, the microneedle body can be broken during the skin penetrating process, so that the risk of metal staying in the skin is caused; the hollow microneedle is similar to a miniaturized syringe needle, and can continuously or discontinuously administer the medicine by conveying the medicine into the skin through an internal pore passage under pressure driving after penetrating into the skin, and the speed of medicine conveying can be adjusted. Transdermal drug delivery experiments show that the use of the hollow microneedle can promote the transdermal efficiency of the drug, but still has some problems, such as the front end of the hollow microneedle is easily blocked by skin tissues in the skin piercing process, and in addition, the needle body is fragile and easy to break; the coated microneedle is formed by coating a water-soluble drug preparation on the surface of a solid microneedle by using acting forces such as electrostatic adsorption or non-covalent bond and the like to form a drug film. After the microneedles penetrate into the skin, the surface-coated drugs are dissolved from the microneedles into the skin, and then the microneedles are removed to complete drug release. However, the preparation technology has complex operation and limited drug-loading rate, and the effective treatment amount of the drug is difficult to achieve.
In recent years, soluble microneedles have shown significant advantages in the delivery of water-soluble small molecule, antibody, protein, and polypeptide drugs, but still have significant problems with poorly soluble drugs.
By poorly soluble drug is meant a drug solute that is hardly soluble or insoluble in a particular solvent, i.e. 1g (ml) of solute cannot be completely dissolved in 10000ml of solvent.
As the micro-needle which directly punctures the stratum corneum to reach the epidermis layer to absorb the tissue fluid to dissolve, firstly, the selection of the material needs to have safety, no toxicity and biodegradability, and secondly, the prepared soluble micro-needle needs to have enough mechanical property to ensure that the prepared soluble micro-needle can not break and deform in the process of puncturing the skin when in administration. At present, materials for preparing the soluble microneedles are mainly biological high-molecular degradable materials, such as one or more of water-soluble macromolecules, such as polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), Hyaluronic Acid (HA), Dextran (DEX), trehalose (Tre), chondroitin sulfate (Chs), Chitosan (CS), fibroin and the like. Since these materials are mainly polysaccharides, proteins and their derivatives. In the preparation process, water is often used as a solvent to prepare the soluble microneedle patch containing water-soluble biological macromolecules and small molecules. For the slightly soluble drugs, because the solubility in water is low, the method of adding a cosolvent (such as N-methylformamide, Tween, acetone and the like) is mainly adopted to improve the solubility of the drugs, so that the drug loading of the microneedles is improved. However, the added organic solvent has certain toxicity and skin irritation, cannot be metabolized and discharged out of the body after penetrating into the skin to be dissolved, and is easy to cause the accumulation of the organic solvent in the body after long-term use, so that great potential safety hazard exists. Insoluble drugs are also prepared into liposome to be encapsulated in the soluble microneedle, but the soluble microneedle prepared by the method has low drug-loading rate and is difficult to enable the drug to be above the effective treatment concentration, and meanwhile, the liposome preparation materials are mainly fat-soluble macromolecules which are added too much to cause the reduction of the mechanical strength of the microneedle. High drug loading and strong mechanical properties of soluble microneedles cannot be achieved simultaneously. Therefore, soluble microneedles still have a big problem in the field of delivery of poorly soluble drugs, and a safe and efficient preparation method for realizing effective delivery of soluble microneedles in poorly soluble drugs is not available for the moment.
disclosure of Invention
The invention aims to solve the technical problem of the prior microneedle technology in delivering insoluble drugs and provides a preparation method of a micelle composite gel microneedle for delivering the insoluble drugs through skin.
Another object of the present invention is to provide micellar composite gel microneedles for transdermal delivery of poorly soluble drugs, prepared by the above method.
The technical scheme adopted by the invention is as follows:
The preparation method of the micelle composite gel microneedle for transdermal delivery of the insoluble drug is provided, and comprises the following steps:
S1, adding PAV into distilled water, heating to dissolve to obtain a solution A, dissolving Soluplus and/or F127 and an insoluble drug in absolute ethyl alcohol, and stirring to uniformly distribute the Soluplus and/or F127 and the insoluble drug in the absolute ethyl alcohol to obtain a mixed solution B;
S2, pressurizing to volatilize and remove the ethanol in the solution B, dripping distilled water after the Soluplus and/or F127 and the insoluble drug form a layer of film on the inner surface of the container, and uniformly stirring to obtain a solution C;
S3, slowly adding the solution A obtained in the step S1 into the solution C obtained in the step S2, stirring under pressure, adding PVPK30 after the solution A and the solution C are uniformly mixed, and stirring to obtain a mixed needle body solution;
S4, placing the mixed needle body solution obtained in the step S3 into a microneedle pore channel of a microneedle mould through centrifugation, removing redundant mixed needle body solution, freezing the centrifuged mould, taking out the mould, standing the mould at room temperature (15-35 ℃) for thawing, repeatedly freezing and thawing for 3 times, and drying the mould containing the mixed needle body solution until the needle body solution is solidified to form a microneedle;
S5, dissolving PVPK90 in absolute ethyl alcohol to prepare a microneedle substrate layer solution, centrifugally placing the microneedle substrate layer solution into a substrate layer cavity of a microneedle mould, drying, solidifying and demoulding to obtain the micelle composite gel microneedle for transdermal delivery of the insoluble drug.
More specifically, the specific operation of step S1 is: weighing PVA, dissolving in distilled water, heating in water bath at 80 deg.C for dissolving, and stirring at high speed for about 10min to obtain solution A; dissolving Soluplus and/or F127 and the insoluble drug in absolute ethyl alcohol, and stirring at room temperature (15-35 ℃) to uniformly disperse the Soluplus and/or F127 and the insoluble drug in the absolute ethyl alcohol solution to obtain a mixed solution B.
More specifically, the specific operation of step S2 is: and (2) standing at room temperature (15-35 ℃) for about 30min under low pressure to remove the organic solvent ethanol, dripping distilled water at the speed of 8-12 seconds/drop after the ethanol is volatilized and the mixture of the Soluplus and/or F127 and the insoluble drug forms a layer of film on the inner surface of the container, and stirring at the room temperature of 500rpm for about 30min to obtain the nano micelle solution of the Soluplus and/or F127 and the insoluble drug, namely solution C.
The method is adopted to prepare the Soluplus and/or F127 and the insoluble drug into the nano micelle, so that the insoluble drug is dissolved in the distilled water under the condition of not damaging the molecular structure of the insoluble drug, and the original molecular form is maintained.
More specifically, the specific operation of step S3 is: slowly adding the solution A obtained in the step S1 into the solution C obtained in the step S2, uniformly stirring at 500rpm, adding PVPK30 after the solution A and the solution C are uniformly mixed, and stirring at room temperature for 1h to obtain a mixed needle body solution;
More specifically, the specific operation of step S4 is: and (4) placing the mixed needle body solution obtained in the step S3 into a microneedle pore channel of a microneedle mould through centrifugation, removing redundant mixed needle body solution, placing the mould after centrifugation at-20 ℃ for freezing for about 2 hours, then taking out the mould, placing the mould at room temperature for thawing, repeatedly freezing and thawing for 3 times, and drying the mould containing the mixed needle body solution for about 24 hours until the needle body solution is solidified to form the microneedle. In order to maintain the sustained release of the slightly soluble drug delivered by the micro-needle in vivo for a long time, the curative effect is further improved.
More specifically, the specific operation of step S5 is: dissolving PVPK90 in absolute ethyl alcohol to prepare a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a solution microneedle substrate layer, centrifugally placing the solution microneedle substrate layer into a substrate layer cavity of a microneedle mould, drying, solidifying and demoulding to obtain the micelle composite gel microneedle for transdermal delivery of the insoluble drug.
Providing the micelle composite gel microneedle for transdermal delivery of the insoluble drug prepared by the method, which comprises a microneedle substrate and a microneedle body arranged on the microneedle substrate, wherein the material of the microneedle body comprises PVA, PVPK30, the insoluble drug, Soluplus and/or F127; the substrate material is PVPK 90.
The needle body material is selected from PVA, PVPK30, Soluplus or F127 with biocompatibility. Among them, polyvinyl alcohol (PVA) has good hydrophilic properties as the only water-soluble high molecular polymer in nature.
After the PVA is prepared into the micro-needle, the PVA in a dry state has high toughness but large brittleness and is easy to break; the defects of poor elasticity, low hardness and the like of PVA hydrogel in a swelling state limit the PVA hydrogel to be used as a medicinal dressing independently, so that PVPK30 with certain viscosity is selected as an additive, the toughness of the PVA in a microneedle state is improved, the brittleness of the PVA is reduced, and the elasticity and the water absorption swelling capacity of the PVA which is penetrated into the skin to form hydrogel are improved.
Preferably, the PVA content in the needle body material part is 10-20%; the content of PVPK30 is 15-30%; the content of Soluplus and/or F127 is 5-10%; the content of the insoluble drug is 0.1-1%.
More preferably, the content of PVA in the needle material portion is 15%; the content of PVPK30 is 15 percent; the content of Soluplus is 10 percent; the content of the poorly soluble drug is 1%.
More preferably, the content of PVA in the needle material portion is 15%; the content of PVPK30 is 15 percent; the content of F127 is 5%; the content of the poorly soluble drug was 0.5%.
the invention has the beneficial effects that:
1. The micelle composite gel microneedle for delivering the insoluble drug through the skin, provided by the invention, carries the water-soluble biological polymer and the insoluble drug together, and simultaneously wraps one, two or more than two therapeutic drugs, so that the insoluble drug is delivered by the soluble microneedle, the application of the insoluble drug in the soluble microneedle is expanded, and the therapeutic effect of the soluble microneedle in the insoluble drug is improved. On the other hand, the simultaneous delivery of different physicochemical properties of the drugs can be realized, and the purpose of synergistic treatment is achieved.
2. The microneedle provided by the invention is simple in preparation method, and fully utilizes the characteristics of the material, and the needle body material can absorb water and swell after the soluble microneedle is penetrated into the skin, so that gel is formed in situ on the skin. The two amphiphilic materials Soluplus and F127 can be assembled with the insoluble drug to form nano-micelles with uniform particle sizes after contacting interstitial fluid, and the solubility of the insoluble drug in the aqueous solution is greatly increased under the condition of not damaging the molecular structure of the insoluble drug. In addition, the insoluble drug can be better identified and absorbed by cells, and the micelle particles are highly dispersed in a gel pore channel formed after the needle body material swells, so that the drug can be sustained and released for a long time, and the curative effect is improved.
3. The micro-needle provided by the invention uses PVA and PVPK30 as needle body materials, on one hand, the micro-needle penetrates into the skin due to higher mechanical strength in a dry state, on the other hand, the micro-needle can absorb water to expand to form hydrogel after penetrating into the skin, and the micelle is highly dispersed in a gel pore channel to realize the sustained release of the drug.
Drawings
Fig. 1 is a schematic flow chart of a preparation method of micelle composite gel microneedles for transdermal delivery of poorly soluble drugs.
fig. 2 is a schematic diagram of a micelle complex gel microneedle structure for transdermal delivery of a poorly soluble drug. A: a schematic diagram of a structure of a soluble microneedle of the paclitaxel-loaded micelle; b: a structural schematic diagram of a gel microneedle carrying FITC and IR780 micelles together; c: schematic structure of soluble microneedle carrying paclitaxel and IR780 micelle.
Fig. 3 is a scanning electron microscope image of the paclitaxel-loaded nano-micelle microneedle prepared in example 1.
Fig. 4 shows the particle size and distribution of the paclitaxel-loaded nanomicelle before and after preparation into soluble microneedles in example 1. A: the particle size and distribution before preparing the microneedle; b: particle size and distribution of re-dissolved after preparation into microneedles.
figure 5 skin staining before and after dorsal puncture of rats of the soluble microneedle patch of example 1. A. B is retention and distribution of trypan blue staining on skin for 5 min and 30min, respectively.
Fig. 6 example 7 confocal laser mapping of water-soluble FITC and fat-soluble Cy5 micellar microneedles. A: carrying only water-soluble FITC microneedles; b: carrying only liposoluble Cy5 nano micelle microneedles; c: water-soluble FITC and lipid-soluble Cy5 micelles were mixed to co-load microneedles.
Detailed Description
The invention is further described with reference to the following detailed description of embodiments in conjunction with the accompanying drawings. The following examples are for illustrative purposes only and are not to be construed as limiting the invention. Unless otherwise specified, the raw materials used in the following examples, raw materials for reagents, were raw materials conventionally commercially available or commercially available. The apparatus used in the following examples is an apparatus conventionally used in the art unless otherwise specified.
Example 1 Soluplus/PVA micellar gel microneedle of paclitaxel
preparing a gel microneedle patch carrying paclitaxel, with a base layer of 1cm × 1cm × 0.2cm and pyramid microneedles of 100, length of 800 μm and regular arrangement of microneedles at intervals, according to the process shown in figure 1.
Paclitaxel is white crystal powder, odorless, tasteless, insoluble in water, and soluble in organic solvents such as methanol, acetonitrile, chloroform, and acetone.
Preparing a mould: the mould is prepared conventionally by adopting polydimethylsiloxane according to the mould, the mould is internally provided with microneedle channels and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle channels are all pyramid cavities, the diameter of the bottom of each pyramid channel is 100 micrometers, the height of each pyramid channel is 800 micrometers, and each microneedle channel is vertical to the base layer cavity and is uniformly distributed at intervals.
Soluplus/PVA micelle gel microneedles of paclitaxel were prepared according to the following steps:
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); weighing appropriate amount of Soluplus and paclitaxel, dissolving in 200 μ L of anhydrous ethanol, and stirring at room temperature to uniformly disperse paclitaxel and Soluplus in anhydrous ethanol solution (solution B).
S2, placing the mixed solution of the Soluplus and the paclitaxel in a vacuum drying oven, placing the mixed solution at room temperature for 30min under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the ethanol is completely dried and the paclitaxel and the Soluplus form a layer of colorless transparent film on the bottom surface of a penicillin bottle, and stirring the solution at the room temperature of 500rpm for 30min to prepare the 1% paclitaxel-containing nano micelle solution (solution C).
s3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30, adding into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v) and 1% of paclitaxel (w/v).
s4, placing the mixed needle body solution into a microneedle pore channel of a mold by adopting a centrifugal method, after removing excessive needle body fluid, placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, repeatedly freezing and thawing for 3 times in the way, and placing the mold containing the needle body fluid in a dryer for warm drying for 24h until the needle body fluid is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into 32% (w/v) of high-molecular absolute ethyl alcohol solution, namely substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the Soluplus/PVA micelle gel microneedle patch containing paclitaxel.
the structural schematic diagram of the Soluplus/PVA micelle gel microneedle of paclitaxel is shown in figure 2A, the scanning electron microscope image is shown in figure 3, and it can be seen from the figure that the prepared micelle gel microneedle is orderly arranged, the surface is regular, the microneedle is in a quadrangular shape, and the microneedle has good mechanical properties.
And determining the size and distribution condition of the water flow dynamics particle size of the nano micelle formed in the preparation process of the Soluplus/PVA micelle gel microneedle of the paclitaxel by adopting a Malvern particle size analyzer before and after the nano micelle is prepared into a soluble microneedle.
the result is shown in figure 4, and the particle size and distribution of the micelle in the figure show that the particle size of the paclitaxel-loaded Soluplus/PVA micelle gel microneedle is close to that of a simple micelle, and is not greatly changed. The micro-needle can not change the particle size of the micelle and influence the physiological process of the micelle in vivo.
Subsequently, the Soluplus/PVA micelle gel microneedle of paclitaxel is subjected to puncture test on the back of a rat, and retention and distribution of the microneedle on the skin are observed by trypan blue staining. The rats after the experiment were euthanized, the abdominal skin was removed, the abdominal hair was removed with depilatory cream, and after soaking in PBS, the moisture on the skin surface was removed with absorbent paper. The prepared paclitaxel Soluplus/PVA micelle gel microneedle is pressed on the abdominal skin of a rat, after 2 minutes, the microneedle is taken down, trypan blue dye containing 1 percent is dripped on the punctured part of the microneedle for dyeing for 30 seconds, and the dye remained on the surface of the skin is sucked off. The retention and diffusion of the dye in the skin pores was observed.
the results are shown in fig. 5, from which it can be seen that the Soluplus/PVA micelle gel microneedles of paclitaxel successfully penetrated into the abdominal skin of rats and trypan blue dye could smoothly penetrate into the skin. The Soluplus/PVA micelle gel microneedle of paclitaxel is shown to have sufficient mechanical properties to penetrate into the skin.
Example 2F 127/PVA micellar gel microneedles for paclitaxel
Preparing a gel microneedle patch carrying paclitaxel, with a base layer of 1cm × 1cm × 0.2cm and pyramid microneedles of 100, length of 800 μm and regular arrangement of microneedles at intervals, according to the process shown in figure 1.
Paclitaxel is white crystal powder, odorless, tasteless, insoluble in water, and soluble in organic solvents such as methanol, acetonitrile, chloroform, and acetone.
preparing a mould: the mould is prepared conventionally by adopting polydimethylsiloxane according to the mould, the mould is internally provided with microneedle channels and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle channels are all pyramid cavities, the diameter of the bottom of each pyramid channel is 100 micrometers, the height of each pyramid channel is 800 micrometers, and each microneedle channel is vertical to the base layer cavity and is uniformly distributed at intervals.
F127/PVA micelle gel microneedle of paclitaxel was prepared according to the following procedure
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); an appropriate amount of F127 and paclitaxel were weighed, dissolved in 200. mu.L of absolute ethanol, and stirred at room temperature to disperse paclitaxel and F127 uniformly in the absolute ethanol solution (solution B).
S2, placing the mixed solution of the F127 and the paclitaxel in a vacuum drying oven, placing the mixed solution at room temperature for 30min under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the ethanol is completely dried and the paclitaxel and the F127 form a colorless transparent film on the bottom surface of a penicillin bottle, and stirring the solution at the room temperature of 500rpm for 30min to prepare a 1% paclitaxel-containing nano micelle solution (solution C).
s3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30, adding into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 5% of F127(w/v) and 0.5% of paclitaxel (w/v).
S4, placing the needle body solution into a microneedle pore channel of a mold by adopting a centrifugal method, after removing excessive needle body solution, placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, repeatedly freezing and thawing for 3 times, and placing the mold containing the needle body solution in a dryer for drying at room temperature for 24h until the needle body solution is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into 32% (w/v) of high-molecular absolute ethyl alcohol solution, namely substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the F127/PVA micelle gel microneedle patch of the paclitaxel. The schematic structure of the microneedle is shown in fig. 2A.
Example 3 Soluplus/PVA micellar gel microneedles of IR780
Preparing an IR 780-loaded gel microneedle patch with a cubic base layer of 1cm multiplied by 0.2cm and pyramid-shaped microneedles of 100 in number, 800 microns in length and regularly arranged at intervals according to the process shown in figure 1;
Preparing a mould: the method comprises the following steps of (1) manufacturing a conventional preparation mold by adopting polydimethylsiloxane according to the mold, wherein the mold is internally provided with microneedle pore passages and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle pore passages are all pyramid-shaped cavities, the diameter of the bottom of each pyramid-shaped pore passage is 100 micrometers, the height of each pyramid-shaped pore passage is 800 micrometers, and each microneedle pore passage is vertical to the base layer cavity and is mutually and uniformly distributed at intervals;
The Soluplus/PVA micellar gel microneedles for IR780 were prepared according to the following procedure:
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); an appropriate amount of Soluplus and IR780 was weighed, dissolved in 200 μ L of absolute ethanol, and stirred at room temperature to uniformly disperse IR780 and Soluplus in the absolute ethanol solution (solution B).
S2, placing the mixed solution of Soluplus and IR780 in a vacuum drying oven, placing at room temperature for 30min under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, after the ethanol is completely dried, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the IR780 and Soluplus form a layer of colorless transparent film on the bottom surface of a penicillin bottle, and stirring at room temperature of 500rpm for 30min to prepare a nano micelle solution (solution C) containing 0.5% of IR 780.
S3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30, adding the PVPK30 into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v) and 0.5% of IR780(w/v)
S4, placing the needle body solution into a microneedle pore channel of a mold by adopting a centrifugal method, removing redundant needle body solution, then placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, and after repeated freezing and thawing for 3 times, placing the mold containing the needle body solution in a dryer for warm drying for 24h until the needle body solution is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into 32% (w/v) of high-molecular absolute ethyl alcohol solution, namely substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the Soluplus/PVA micelle gel microneedle of the IR 780.
Example 4 Soluplus/PVA micellar gel microneedles of coumarin
Preparing a coumarin-loaded gel microneedle patch with a cubic base layer of 1cm multiplied by 0.2cm and pyramid-shaped microneedles according to the process shown in the attached drawing 1, wherein the number of the microneedles is 100, the length of the microneedles is 800 micrometers, and the microneedles are regularly arranged at intervals;
Preparing a mould: the method comprises the following steps of (1) manufacturing a conventional preparation mold by adopting polydimethylsiloxane according to the mold, wherein the mold is internally provided with microneedle pore passages and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle pore passages are all pyramid-shaped cavities, the diameter of the bottom of each pyramid-shaped pore passage is 100 micrometers, the height of each pyramid-shaped pore passage is 800 micrometers, and each microneedle pore passage is vertical to the base layer cavity and is mutually and uniformly distributed at intervals;
Soluplus/PVA micelle gel microneedles of coumarin were prepared according to the following steps:
s1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); appropriate amounts of Soluplus and coumarin were weighed, dissolved in 200 μ L of absolute ethanol, and stirred at room temperature to disperse IR780 and Soluplus uniformly in the absolute ethanol solution (solution B).
S2, placing the mixed solution of the Soluplus and the coumarin in a vacuum drying oven, placing the vacuum drying oven at room temperature for 30min under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the ethanol is completely dried and the coumarin and the Soluplus form a colorless transparent film on the bottom surface of a penicillin bottle, and stirring the solution at the room temperature of 500rpm for 30min to prepare a nano micelle solution (solution C) containing 0.5% of coumarin.
s3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30, adding into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v) and 0.5% of coumarin (w/v).
S4, placing the needle body fluid into a microneedle pore channel of a mold by adopting a centrifugal method, after removing excessive needle body fluid, placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, and after repeated freezing and thawing for 3 times, placing the mold containing the needle body fluid in a drier for room temperature drying for 24h until the needle body fluid is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the coumarin gel microneedle patch.
Example 5 Soluplus/PVA mixed micelle gel microneedles of coumarin and paclitaxel
preparing a gel microneedle patch which is cubic with a base layer of 1cm multiplied by 0.2cm and is loaded with coumarin and paclitaxel together, wherein the microneedle number is 100, the microneedle length is 800 micrometers, and the microneedles are regularly arranged at intervals, according to the process shown in the attached drawing 1:
Preparing a mould: the method comprises the following steps of (1) manufacturing a conventional preparation mold by adopting polydimethylsiloxane according to the mold, wherein the mold is internally provided with microneedle pore passages and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle pore passages are all pyramid-shaped cavities, the diameter of the bottom of each pyramid-shaped pore passage is 100 micrometers, the height of each pyramid-shaped pore passage is 800 micrometers, and each microneedle pore passage is vertical to the base layer cavity and is mutually and uniformly distributed at intervals;
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); weighing appropriate amount of Soluplus, coumarin and paclitaxel, dissolving in 200 μ L anhydrous ethanol, and stirring at room temperature to uniformly disperse coumarin, paclitaxel and Soluplus in anhydrous ethanol solution (solution B).
s2, placing the mixed solution of coumarin, paclitaxel and Soluplus in a vacuum drying oven, placing for 30min at room temperature under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, after the ethanol is completely dried, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the coumarin, paclitaxel and Soluplus form a layer of colorless transparent film on the bottom surface of a penicillin bottle, and stirring for 30min at the room temperature of 500rpm to prepare the mixed nano micelle solution (solution C) containing 0.5% of coumarin and 0.5% of paclitaxel.
s3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution B are uniformly mixed, weighing a proper amount of PVPK30, adding the PVPK30 into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v), 0.5% of coumarin (w/v) and 0.5% of paclitaxel (w/v).
S4, placing the needle body solution into a microneedle pore channel of the mold prepared in the step (1) by adopting a centrifugal method, removing redundant needle body solution, placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for thawing for 30min, repeatedly freezing and thawing for 3 times in the way, and placing the mold containing the needle body solution in a dryer for drying for 24 hours at room temperature until the needle body solution is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the mixed gel microneedle patch loaded with coumarin and paclitaxel.
Example 6 Soluplus/PVA Mixed micelle gel microneedles of fat-soluble Cy5 and IR780
preparing a gel microneedle patch which has a cubic base layer of 1cm multiplied by 0.2cm and pyramid-shaped microneedles, is loaded with fat-soluble Cy5 and IR780, and has the following steps of preparing the gel microneedle patch according to the process shown in the attached drawing 1, wherein the number of the microneedles is 100, the length of the microneedles is 800 micrometers, and the microneedles are regularly arranged at intervals:
Preparing a mould: the method comprises the following steps of (1) manufacturing a conventional preparation mold by adopting polydimethylsiloxane according to the mold, wherein the mold is internally provided with microneedle pore passages and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle pore passages are all pyramid-shaped cavities, the diameter of the bottom of each pyramid-shaped pore passage is 100 micrometers, the height of each pyramid-shaped pore passage is 800 micrometers, and each microneedle pore passage is vertical to the base layer cavity and is mutually and uniformly distributed at intervals;
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); appropriate amounts of solubles, fat-soluble Cy5 and IR780 were weighed and dissolved in 200. mu.L of absolute ethanol, and stirred at room temperature to uniformly disperse fat-soluble Cy5, IR780 and solubles in the absolute ethanol solution (solution B).
S2, then placing the mixed solution of the fat-soluble Cy5, the IR780 and the Soluplus in a vacuum drying oven, placing the mixed solution at room temperature under the vacuum pressure of 1.0bar for 30min to remove the organic solvent ethanol, after the ethanol is completely dried, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the fat-soluble Cy5, the IR780 and the Soluplus form a colorless transparent film on the bottom surface of a penicillin bottle, and stirring the mixture at the room temperature of 500rpm for 30min to prepare a mixed nano micelle solution (solution C) containing 0.5% of fat-soluble Cy5 and 0.5% of IR 780.
s3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30, adding the PVPK30 into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v), 0.5% of fat-soluble Cy5(w/v) and 0.5% of IR780 (w/v).
S4, placing the needle body solution into a microneedle pore channel of a mold by adopting a centrifugal method, removing redundant needle body solution, then placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, and after repeated freezing and thawing for 3 times, placing the mold containing the needle body solution in a dryer for warm drying for 24h until the needle body solution is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the mixed gel microneedle patch loaded with the fat-soluble Cy5 and the IR 780.
Example 7 Soluplus/PVA micellar gel microneedles for FITC (Water soluble) and IR780 (poorly soluble)
Preparing an IR 780-loaded gel microneedle patch with a cubic base layer of 1cm multiplied by 0.2cm and pyramid-shaped microneedles of 100 in number, 800 microns in length and regularly arranged at intervals according to the process shown in the attached drawing 1:
preparing a mould: the method comprises the following steps of (1) manufacturing a conventional preparation mold by adopting polydimethylsiloxane according to the mold, wherein the mold is internally provided with microneedle pore passages and a base layer cavity which are mutually independent, the base layer cavity is a rectangular cavity with the length and width of 1cm and the height of 0.2cm, 100 microneedle pore passages are all pyramid-shaped cavities, the diameter of the bottom of each pyramid-shaped pore passage is 100 micrometers, the height of each pyramid-shaped pore passage is 800 micrometers, and each microneedle pore passage is vertical to the base layer cavity and is mutually and uniformly distributed at intervals;
S1, weighing a proper amount of PVA (polyvinyl alcohol) in 1mL of distilled water at room temperature, heating and dissolving in a water bath at 80 ℃, and stirring at a high speed for 10min to prepare a PVA high molecular solution (solution A); an appropriate amount of Soluplus and IR780 was weighed, dissolved in 200 μ L of absolute ethanol, and stirred at room temperature to uniformly disperse IR780 and Soluplus in the absolute ethanol solution (solution B).
s2, placing the mixed solution of Soluplus and IR780 in a vacuum drying oven, placing at room temperature for 30min under the vacuum pressure of 1.0bar to remove the organic solvent ethanol, after the ethanol is completely dried, slowly adding 1mL of distilled water (the dropping speed is about ten seconds per drop) after the IR780 and Soluplus form a layer of colorless transparent film on the bottom surface of a penicillin bottle, and stirring at room temperature of 500rpm for 30min to prepare a nano micelle solution (solution C) containing 0.5% of IR 780.
S3, slowly adding the solution A into the solution C, uniformly stirring at room temperature under the condition of 500rpm, after the solution A and the solution C are uniformly mixed, weighing a proper amount of PVPK30 and FITC, adding into the mixed solution of the solution A and the solution C, and stirring at room temperature for 1h to obtain a mixed needle body solution containing 15% of PVA (w/v), 15% of PVPK30(w/v), 10% of Soluplus (w/v), 0.5% of IR780(w/v) and 0.5% of FITC (w/v).
S4, placing the needle body solution into a microneedle pore channel of a mold by adopting a centrifugal method, removing redundant needle body solution, then placing the mold after centrifugation at-20 ℃ for freezing for 2h, then taking out the mold, placing the mold at room temperature for 30min for thawing, and after repeated freezing and thawing for 3 times, placing the mold containing the needle body solution in a dryer for warm drying for 24h until the needle body solution is solidified to form a microneedle;
S5, preparing PVPK90 and solvent absolute ethyl alcohol into a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a substrate solution, placing the substrate solution into a substrate cavity of a mold by adopting a centrifugal method, drying until the substrate solution is solidified, and demolding to obtain the gel microneedle patch carrying the IR780 and the FITC together. The schematic structure of the microneedle is shown in fig. 2B.
carrying out laser confocal detection on the gel microneedle which carries the IR780 and the FITC together to qualitatively reflect the distribution condition of the drug in the microneedle, and the result is shown in figure 6, wherein a picture A is the color of the gel microneedle which only carries the water-soluble FITC under a confocal microscope; the B picture is the color of the microneedle which only carries fat-soluble Cy5 nano micelle under a confocal microscope; and the C picture is the color of the water-soluble FITC and fat-soluble Cy5 micelle mixed microneedle under laser confocal. It can be seen that in the C diagram, water-soluble FITC is mainly distributed at the needle tip and periphery of the micelle microneedle, and fat-soluble Cy5 is uniformly distributed on the needle body, which indicates that the Soluplus/PVA micelle gel microneedle can simultaneously entrap water-soluble small molecules represented by FITC and fat-soluble micelles represented by Cy 5.
EXAMPLE 8 poorly soluble drug dissolution test
TABLE 1 exploration of poorly soluble drugs in the dissolution process
Claims (10)
1. a preparation method of micelle composite gel microneedles for transdermal delivery of poorly soluble drugs comprises the following steps:
S1, adding PAV into distilled water, heating to dissolve to obtain a solution A, dissolving Soluplus and/or F127 and an insoluble drug in absolute ethyl alcohol, and stirring to uniformly distribute the Soluplus and/or F127 and the insoluble drug in the absolute ethyl alcohol to obtain a mixed solution B;
S2, pressurizing to volatilize and remove the ethanol in the solution B, dripping distilled water after the Soluplus and/or F127 and the insoluble drug form a layer of film on the inner surface of the container, and uniformly stirring to obtain a solution C;
s3, slowly adding the solution A obtained in the step S1 into the solution C obtained in the step S2, stirring, adding PVPK30 after the solution A and the solution C are uniformly mixed, and stirring to obtain a mixed needle body solution;
S4, placing the mixed needle body solution obtained in the step S3 into a microneedle pore channel of a microneedle mould through centrifugation, removing redundant mixed needle body solution, freezing the centrifuged mould, taking out the mould, standing and thawing at room temperature, repeatedly freezing and thawing for 3 times, and drying the mould containing the mixed needle body solution until the needle body solution is solidified to form a microneedle;
S5, dissolving PVPK90 in absolute ethyl alcohol to prepare a microneedle substrate layer solution, centrifugally placing the microneedle substrate layer solution into a substrate layer cavity of a microneedle mould, drying, solidifying and demoulding to obtain the micelle composite gel microneedle for transdermal delivery of the insoluble drug.
2. The method according to claim 1, wherein the specific operation of step S1 is: weighing PVA, dissolving in distilled water, heating in water bath at 80 deg.C for dissolving, and stirring to obtain solution A; dissolving Soluplus and/or F127 and the insoluble drug in absolute ethyl alcohol, and stirring to uniformly disperse Soluplus and/or F127 and the insoluble drug in the absolute ethyl alcohol solution to obtain a mixed solution B.
3. the method according to claim 1, wherein the specific operation of step S2 is: and (3) placing the container to remove the organic solvent ethanol, after the ethanol is volatilized, dripping distilled water at the speed of 8-12 seconds per drop after the mixture of the Soluplus and/or F127 and the insoluble medicine forms a layer of film on the inner surface of the container, and stirring at 500rpm to obtain the nano-micelle solution of the Soluplus and/or F127 and the insoluble medicine, namely solution C.
4. The method according to claim 1, wherein the specific operation of step S3 is: slowly adding the solution A obtained in the step S1 into the solution C obtained in the step S2, uniformly stirring at 500rpm, adding PVPK30 after the solution A and the solution C are uniformly mixed, and stirring at room temperature for 1h to obtain a mixed needle body solution.
5. the method according to claim 1, wherein the specific operation of step S4 is: and (4) placing the mixed needle body solution obtained in the step S3 into a microneedle pore channel of a microneedle mould through centrifugation, removing redundant mixed needle body solution, placing the mould after centrifugation into a temperature of-20 ℃ for freezing, taking out the mould after centrifugation, placing the mould at room temperature for thawing, repeatedly freezing and thawing for 3 times, and drying the mould containing the mixed needle body solution until the needle body solution is solidified to form the microneedle.
6. the method according to claim 5, wherein the specific operation of step S5 is: dissolving PVPK90 in absolute ethyl alcohol to prepare a 32% (w/v) high-molecular absolute ethyl alcohol solution, namely a solution microneedle substrate layer, centrifugally placing the solution microneedle substrate layer into a substrate layer cavity of a microneedle mould, drying, solidifying and demoulding to obtain the micelle composite gel microneedle for transdermal delivery of the insoluble drug.
7. The micelle composite gel microneedle for transdermal delivery of a poorly soluble drug prepared by the method of any one of claims 1 to 6, comprising a microneedle substrate and a microneedle body disposed on the microneedle substrate, wherein the needle body material comprises PVA, PVPK30, the poorly soluble drug, Soluplus and/or F127; the substrate material is PVPK 90.
8. The micelle composite gel microneedle according to claim 7, wherein the content of PVA in the needle body material portion is 10-20%; the content of PVPK30 is 15-30%; the content of Soluplus and/or F127 is 5-10%; the content of the insoluble drug is 0.1-1%.
9. the micellar composite gel microneedle according to claim 8, wherein the amount of PVA in said needle material portion is 15%; the content of PVPK30 is 15 percent; the content of Soluplus is 10 percent; the content of the poorly soluble drug is 1%.
10. The micellar composite gel microneedle according to claim 8, wherein the amount of PVA in said needle material portion is 15%; the content of PVPK30 is 15 percent; the content of F127 is 5%; the content of the poorly soluble drug was 0.5%.
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Application publication date: 20191206 |