CN112494421B - Slow-release soluble microneedle, preparation method and application - Google Patents

Slow-release soluble microneedle, preparation method and application Download PDF

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CN112494421B
CN112494421B CN202011539854.9A CN202011539854A CN112494421B CN 112494421 B CN112494421 B CN 112494421B CN 202011539854 A CN202011539854 A CN 202011539854A CN 112494421 B CN112494421 B CN 112494421B
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drug
microneedle
carrier
slowly released
polymer
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CN112494421A (en
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朱锦涛
李沫
杜虹瑶
张连斌
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Huazhong University of Science and Technology
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    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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Abstract

The invention discloses a sustained-release soluble microneedle, a preparation method and application. The micro-needle comprises a substrate, a needle body and a carrier which is distributed in the needle body and is coated with a drug to be slowly released, wherein the carrier comprises a degradable high molecular material or inorganic nano-particles modified by a polymer. The method comprises the following steps: preparing a carrier coated with a drug to be slowly released by adopting one of an emulsion method, a dialysis method, a solvent volatilization method, a spray drying method and a polyelectrolyte protection method; the carrier comprises degradable high molecular materials or inorganic nanoparticles; dissolving or dispersing the carrier coated with the drug to be slowly released in a matrix solution, casting the matrix solution into a mold by a vacuum pumping method, drying and demolding to obtain the slowly released soluble microneedle. The invention slows down the release speed of the drug by taking the degradable high molecular material or the inorganic nano particles modified by the polymer as the carrier of the drug.

Description

Slow-release soluble microneedle, preparation method and application
Technical Field
The invention belongs to the field of microneedles, and particularly relates to a sustained-release soluble microneedle, a preparation method and application.
Background
When the microneedle is used for local administration on the skin, the microneedle can effectively pierce the stratum corneum of the skin and cannot touch nerves, so that adverse reactions caused by the drugs passing through the gastrointestinal tract are avoided, pain is not caused, the bioavailability of the drugs is increased, and the compliance of patients is improved. The micro-needles are of various types, and comprise hollow micro-needles and solid micro-needles, and the solid micro-needles are divided into tissue pretreatment micro-needles, soluble drug-carrying micro-needles and insoluble drug-coating micro-needles. The soluble microneedle constructed by the polymer material with good biocompatibility and in-vivo solubility has the advantages of simple preparation method, high drug loading capacity and high safety. However, when the drug-loaded dissolvable microneedle is locally used on the skin, the microneedle substrate can be quickly dissolved in the skin, so that the drug can be quickly released and absorbed by a large amount of partial blood vessels, a stable drug concentration can not be maintained locally on the skin, toxic and side effects can be brought, and the bioavailability of the drug is greatly reduced.
Disclosure of Invention
Aiming at the defects or the improvement requirements of the prior art, the invention provides a sustained-release soluble microneedle, a preparation method and application, aiming at reducing the release speed of a drug by using a degradable high molecular material or inorganic nanoparticles modified by a polymer as a carrier of the drug, thereby solving the technical problem that in the prior art, a microneedle matrix can be rapidly dissolved in skin, so that the drug is rapidly released and is absorbed by partial blood vessels in large quantity.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a sustained-release soluble microneedle, which comprises a substrate, a needle body and a carrier distributed in the needle body and coated with a drug to be sustained-released, wherein the carrier comprises a degradable high molecular material or inorganic nanoparticles modified by a polymer.
Preferably, the carrier coated with the drug to be slowly released is one or more of microspheres, microcapsules, nanoparticles, liposomes, micelles and slow release films.
Preferably, the inorganic nanoparticles comprise one of a nanocarbon material, gold nanoparticles, quantum dots, magnetic nanoparticles, hollow mesoporous silica, the polymer is a biodegradable and positively charged polymer, and preferably, the biodegradable and positively charged polymer is one of chitosan, polydopamine, polyetherimide, and poly N, N-dimethylaminoethyl methacrylate.
Preferably, the degradable polymer material includes a natural biodegradable polymer material, a semi-synthetic biodegradable polymer material or a synthetic biodegradable polymer material.
Preferably, the natural biodegradable high molecular material comprises gelatin, chitosan, sodium alginate, starch or cellulose; the semi-synthetic biodegradable high polymer material comprises carboxymethyl cellulose, methyl cellulose or cellulose acetate; the synthetic biodegradable high molecular material comprises aliphatic polyester polymer, polycarbonate polymer, polyanhydride or poly alpha-amino acid polymer or block polymer. For example, polylactic-co-glycolic acid (PLGA), polypropylene carbonate, polysebacic anhydride, polyserine, poly epsilon-caprolactone-polyethylene glycol copolymer (PCL-PEG), polyethylene glycol-polylactic acid, and the like.
Preferably, the polymer adopted by the substrate and the needle body comprises one or more of hyaluronic acid, chondroitin sulfate, sodium alginate, amylopectin, hydroxypropyl-beta-cyclodextrin and gelatin.
Preferably, the size of the carrier coated with the drug to be slowly released is 50-5000 nanometers, and the content of the drug to be slowly released coated in the slowly released soluble microneedle is 20-2000 micrograms.
Preferably, the length of the needle body of the slow release soluble microneedle is 200-1000 microns, the shape of the needle body is a triangular cone or a cone,
according to another aspect of the present invention, there is provided a method of preparing the sustained-release soluble microneedle described above, comprising the steps of:
(1) preparing a carrier coated with a drug to be slowly released by adopting one of an emulsion method, a dialysis method, a solvent volatilization method, a spray drying method and a polyelectrolyte protection method; the carrier comprises degradable high molecular materials or inorganic nano particles;
(2) dissolving or dispersing the carrier coated with the drug to be slowly released in a matrix solution, casting the matrix solution into a mold by a vacuum pumping method, drying and demolding to obtain the slowly released soluble microneedle.
Preferably, the polyelectrolyte protection method specifically comprises:
dissolving the hollow mesoporous silica nanoparticles and the drug to be slowly released in dimethyl sulfoxide, uniformly stirring, and removing the dimethyl sulfoxide by using a negative pressure method to obtain hollow mesoporous silica nanoparticles loaded with the drug to be slowly released;
dispersing the hollow mesoporous silica nano particles loaded with the drug to be slowly released in a biodegradable polymer with positive electricity, stirring, centrifuging and washing to obtain the carrier coated with the drug to be slowly released.
When the hollow mesoporous silica nanoparticles loaded with the drug to be slowly released are dispersed in the chitosan solution, as a preferable scheme, the concentration of the chitosan is 0.1-2% (mass-to-volume ratio), and the mass ratio of the hollow mesoporous silica nanoparticles loaded with the drug to be slowly released to the chitosan is 1 (1-4). The concentration and the mass ratio are strictly controlled, so that the maximum adsorption of the chitosan can be realized, and the carrier coated with the drug to be slowly released with the best performance can be obtained.
Wherein, when the carrier coated with the medicament to be slowly released is prepared by adopting an emulsion method, a dialysis method, a solvent volatilization method and a spray drying method, different medicament-carrying quantities can be obtained by adjusting the concentration of the polymer.
According to a further aspect of the present invention, there is provided a use of the sustained release soluble microneedle described above for sustained release of methotrexate, wherein the drug to be sustained released in the microneedle is methotrexate.
In general, at least the following advantages can be obtained by the above technical solution contemplated by the present invention compared to the prior art.
(1) The slow-release soluble microneedle provided by the invention can coat the drug to be slowly released by taking the degradable high polymer material or the inorganic nano particles modified by the polymer as the drug carrier, and can effectively slow down the release speed of the coated drug. The drug carrier can stay at the local part of the skin and slowly release the drug after the needle tip is dissolved, so that the concentration of the drug in the skin can be kept within a specific concentration range within a period of time, and a series of problems of low drug utilization efficiency, large side effect, frequent drug administration and the like caused by the direct and rapid drug release of the soluble microneedle in the skin are solved.
(2) According to the invention, the degradable high polymer material is used as a carrier to coat the drug to be slowly released, so that the release speed of the drug is limited by the dissolution speed of the degradable high polymer material, and the slow release of the drug is realized.
(3) According to the invention, the inorganic nanoparticles modified by the polymer are used as a carrier to coat the drug to be slowly released, for example, the biodegradable and positively charged polymer modified hollow mesoporous silica is used for loading the drug in the holes of the hollow mesoporous silica, and the biodegradable and positively charged polymer is adsorbed on the surface of the drug loaded hollow mesoporous silica through electrostatic adsorption because the hollow mesoporous silica is negatively charged, so that the drug is coated, and the rapid release of the drug is prevented.
Drawings
FIG. 1 is a transmission electron micrograph of a methotrexate drug carrier in example 5 of the present invention;
FIG. 2 is a graph showing the particle size distribution of the methotrexate drug carrier in example 5 of the present invention;
fig. 3A is a scanning electron micrograph of a sustained-release soluble microneedle prepared by example 5 of the present invention;
fig. 3B is a partial enlarged view of the extended release soluble microneedle of fig. 3A;
FIG. 4 is a graph showing in vitro release of hollow mesoporous silica nanoparticles loaded with methotrexate and a methotrexate-loaded drug carrier, which are prepared by example 5 of the present invention;
FIG. 5 is a graph of ear thickness variation for different groups of mice in characterization example 2 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the respective embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
The embodiment provides a preparation method of a sustained-release soluble microneedle, which specifically comprises the following steps:
(1) preparing the carrier coated with the methotrexate drug by a spray drying method: dissolving chitosan powder and methotrexate in 0.2% hydrochloric acid water solution, spraying into a dryer for drying after complete dissolution, and collecting the prepared methotrexate chitosan drug carrier.
(2) Preparing a microneedle mould: uniformly stirring polydimethylsiloxane raw material (PDMS, Sylgard 184) and a curing agent according to a mass ratio of 10:1, vacuumizing to remove bubbles, casting the liquid polydimethylsiloxane containing the curing agent into a plastic culture dish containing a polymethacrylic acid microneedle positive membrane (the length of a needle point of the positive membrane is 850 microns), heating for 2 hours at 80 ℃, after the PDMS is cured, carefully separating the microneedle positive membrane from the PDMS to obtain a microneedle PDMS mold, and carrying out plasma treatment on the PDMS microneedle mold for later use.
(3) Hyaluronic acid powder was dissolved in water at a concentration of 200mg/mL, and the solution was stirred overnight at room temperature to completely dissolve the hyaluronic acid powder.
(4) The prepared methotrexate chitosan drug carrier particles are dissolved or dispersed in a hyaluronic acid solution, and are carefully stirred to be uniformly dispersed to obtain a dispersion liquid.
(5) And (3) casting the dispersion into a PDMS microneedle mould, vacuumizing to enable the dispersion to fill the microneedle mould as much as possible, scraping off redundant solution on the surface of the mould, repeating the steps for three times to enable the methotrexate chitosan drug carrier to be gathered at the needle point of the mould, and finally casting the solution to form the microneedle substrate. And (3) putting the microneedle mould filled with the solution into a dryer overnight, and after drying, carefully demoulding the microneedle to obtain the microneedle patch loaded with the methotrexate chitosan drug carrier.
Example 2
The embodiment provides a preparation method of a sustained-release soluble microneedle, which specifically comprises the following steps:
(1) solvent volatilization method for preparing methotrexate drug carrier: dissolving a certain amount of polylactic-co-glycolic acid (PLGA) in dichloromethane, adding a proper amount of methotrexate to disperse uniformly, pouring into 1% polyvinyl alcohol (PVA) solution, stirring at high speed for 3 minutes at room temperature to form O/W emulsion, then continuously and slowly stirring at room temperature for 4 hours to volatilize the organic solvent, and washing and centrifuging to obtain the methotrexate drug carrier.
(2) Preparing a microneedle mould: uniformly stirring polydimethylsiloxane raw materials and a curing agent according to a mass ratio of 10:1, vacuumizing to remove bubbles, casting liquid polydimethylsiloxane containing the curing agent into a plastic culture dish containing a polymethacrylic acid microneedle positive membrane (the length of a needle point of the positive membrane is 650 microns), heating for 2 hours at 80 ℃, after curing PDMS, carefully separating the microneedle positive membrane from PDMS to obtain a PDMS microneedle mould, and carrying out plasma treatment on the PDMS microneedle mould for later use.
(3) Dissolving beta-cyclodextrin powder in water at a concentration of 100mg/mL, and stirring overnight in a water bath at 60 ℃ to completely dissolve the beta-cyclodextrin powder to obtain the microneedle matrix solution.
(4) And dispersing the prepared methotrexate drug carrier in a microneedle matrix solution to obtain a dispersion liquid.
(5) The dispersion was cast into a PDMS mold, and the use of centrifugation allowed the solution to completely fill the needle tip portion, with some aggregation of the methotrexate drug carrier at the needle tip portion due to the centrifugation. And (3) placing the microneedle patch in a dryer overnight, and after drying, carefully demoulding the microneedle to obtain the microneedle patch loaded with the methotrexate drug carrier.
Example 3
The embodiment provides a preparation method of a sustained-release soluble microneedle, which specifically comprises the following steps:
(1) solvent volatilization method for preparing methotrexate drug carrier: weighing 20mg of poly-epsilon-caprolactone-polyethylene glycol copolymer (PCL-PEG) and 4mg of methotrexate, dissolving in 10mL of dimethylformamide, slowly dripping the solution into deionized water under the condition of stirring, continuously stirring for ten minutes, dialyzing, washing after 24 hours of dialysis, and centrifuging to obtain the methotrexate drug carrier.
(2) Preparing a microneedle mould: uniformly stirring polydimethylsiloxane raw materials and a curing agent according to a mass ratio of 10:1, vacuumizing to remove bubbles, casting liquid polydimethylsiloxane containing the curing agent into a plastic culture dish containing a polymethacrylic acid microneedle positive membrane (the length of a needle point of the positive membrane is 650 microns), heating for 2 hours at 80 ℃, after curing the PDMS, carefully separating the microneedle positive membrane from the PDMS to obtain a PDMS microneedle mould, and carrying out plasma treatment on the PDMS microneedle mould for later use.
(3) The dextran powder was dissolved in water at a concentration of 150mg/mL, stirred well and bubbled through the solution. And dispersing the prepared methotrexate drug carrier into a glucan solution, and uniformly mixing.
(4) And (3) casting the solution into a prepared PDMS mold, using vacuum and centrifugation in a matching manner to enable the solution to completely fill the needle point of the mold, putting the mold into a dryer, drying overnight, taking out, and carefully peeling off the microneedle patch to obtain the microneedle patch loaded with the methotrexate drug carrier.
Example 4
The embodiment provides a preparation method of a sustained-release soluble microneedle, which specifically comprises the following steps:
(1) the double emulsion method is used for preparing the methotrexate drug carrier: firstly, the medicine methotrexate is dissolved in 0.4 percent sodium hydroxide solution to prepare a methotrexate sodium salt solution which is used as an internal water phase. Dissolving polyethylene glycol-polylactic acid in dichloromethane, stirring until the polyethylene glycol-polylactic acid is completely dissolved to be used as an oil phase, adding the internal water phase into the oil phase under a certain oil-water ratio, performing ultrasonic emulsification by using a probe type ultrasonic machine to obtain a stable primary emulsion, and then adding the primary emulsion into a certain volume of polyvinyl alcohol solution containing 0.6% to perform stirring to obtain a double emulsion. The double emulsion is placed in a room with a constant temperature of 30 ℃ overnight, and after dichloromethane in the double emulsion is completely volatilized, the medicine carrier coated with the methotrexate can be obtained by centrifugation and washing.
(2) Preparing a microneedle mould: uniformly stirring polydimethylsiloxane raw materials and a curing agent according to the mass ratio of 10:1, vacuumizing to remove bubbles, pouring liquid polydimethylsiloxane containing the curing agent into a plastic culture dish with a polymethacrylic acid microneedle positive membrane, heating at 80 ℃ for 2 hours, after curing PDMS, carefully separating the microneedle positive membrane from PDMS to obtain a PDMS microneedle mould, and carrying out plasma treatment on the PDMS microneedle mould for later use.
(3) Dissolving chitosan powder in 1% acetic acid solution, stirring overnight, and taking the solution as microneedle matrix solution after complete dissolution. And dispersing the methotrexate-loaded drug carrier prepared in the step into a microneedle matrix solution.
(4) And (3) casting the solution into a PDMS (polydimethylsiloxane) mold, vacuumizing to ensure that the microneedle mold can be filled with the solution as much as possible, scraping redundant solution on the surface of the mold, repeating for three times to ensure that the methotrexate drug carrier can be gathered at the needle point part of the mold, and finally casting the solution to form a microneedle substrate. And (3) putting the microneedle mould filled with the solution into a dryer overnight, and after drying, carefully demoulding the microneedle to obtain the microneedle patch loaded with the methotrexate drug carrier.
Example 5:
the present embodiment provides a method for preparing a sustained-release soluble microneedle, which specifically includes the following steps:
1. preparing a methotrexate drug carrier by a polyelectrolyte protection method:
(1) firstly, dissolving the prepared Hollow Mesoporous Silica Nanoparticles (HMSN) and the methotrexate drug in dimethyl sulfoxide (DMSO) and stirring overnight, and removing the DMSO solvent by using a negative pressure method to obtain the hollow mesoporous silica nanoparticles (marked as MTX @ HMSN) loaded with the methotrexate drug.
(2) Dissolving the hollow mesoporous silica nanoparticle MTX @ HMSN loaded with the methotrexate drug into a prepared 0.6% chitosan solution, stirring for 3 hours at the temperature of 30 ℃, and coating chitosan molecules on the surfaces of the MTX @ HMSN nanoparticles through electrostatic interaction. The obtained solution is centrifuged and washed for 3 times to obtain the methotrexate-loaded drug carrier (as MTX @ HMSN/CS). As shown in figure 1, is a transmission electron micrograph of the methotrexate drug carrier. As shown in figure 2, the particle size distribution diagram of the methotrexate drug carrier is shown, and the average particle size of the drug carrier is 464.8 +/-45.31 nm.
2. Preparing a microneedle mould: uniformly stirring polydimethylsiloxane raw materials and a curing agent according to the mass ratio of 10:1, vacuumizing to remove bubbles, casting the liquid polydimethylsiloxane containing the curing agent into a plastic culture dish containing a polymethacrylic acid microneedle positive membrane (the length of a needle point of the positive membrane is 850 mu m), heating for 2 hours at 80 ℃, after curing PDMS, carefully separating the microneedle positive membrane from the PDMS to obtain a PDMS microneedle mould, and carrying out plasma treatment on the PDMS mould for later use.
3. The chondroitin sulfate was dissolved in water, stirred overnight in the dark to be completely dissolved as a microneedle matrix solution, and the MTX @ HMSN/CS obtained in the above step was dispersed in the microneedle matrix solution.
4. And (3) casting the solution into a PDMS mold, vacuumizing to ensure that the microneedle mold can be filled with the solution as much as possible, removing excessive solution on the surface by using a scraper, and drying in a dryer for 24 hours. And after the needle point is completely dried, continuously casting a layer of PVP/PVA (1: 1) solution on the surface of the mould, and continuously putting the mould into a drying oven for drying for 24 hours to form the microneedle substrate layer. After drying, the microneedle is carefully demoulded, and the microneedle patch loaded with the MTX @ HMSN/CS can be obtained. Fig. 3A and 3B are scanning electron micrographs of the microneedle patch and partially enlarged views thereof.
Characterization example 1
The hollow mesoporous silica nanoparticles MTX @ HMSN loaded with the drug methotrexate and the drug carrier MTX @ HMSN/CS loaded with the drug methotrexate, which were prepared in example 5, were dissolved in 2mL of phosphate buffer solution (PBS, pH 7.4), and then the mixture was put into a centrifuge tube with a cover, incubated in a shaker at 37 degrees celsius and an oscillation speed of 200 rpm for fourteen days, and at appropriate time intervals, the centrifuge tube was removed and centrifuged to collect the whole supernatant, 2mL of fresh PBS was added, and the collected sample was subjected to uv detection. As shown in FIG. 4, which is an in vitro release diagram of MTX @ HMSN/CS and MTX @ HMSN, it can be seen that MTX @ HMSN coated with chitosan molecule has the ability to slowly release methotrexate.
Characterization example 2
The left ear of the mouse is induced to generate psoriasis-like dermatitis so as to establish a psoriasis mouse model. The mice were randomly divided into seven groups of five mice each, which were a control group (no treatment), a disease group, a blank microneedle group, a blank carrier microneedle group, an oral administration group, a methotrexate drug carrier microneedle group (experimental group), and a low-dose methotrexate microneedle group. Keeping the total drug dose of each group consistent, the microneedle treatment was performed every three days, and the low-dose methotrexate microneedle group was performed once a day (the experiment was performed for seven days in total). For example, fig. 5 is a graph of the variation of ear thickness of mice in different groups, which illustrates that the experimental group has better psoriasis treatment effect than the oral group, and the treatment effect is not significantly different from that of the low-dose methotrexate microneedle group, but the experimental group reduces the administration frequency and is more convenient than other groups.
Methotrexate is widely used in the treatment of psoriasis and rheumatoid arthritis as an immunosuppressant and antimetabolite. The methotrexate is coated in the drug carrier and is redistributed to the needle point of the microneedle, and a safer, more stable and more effective drug delivery way is developed through transdermal drug delivery.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (4)

1. The application of the slow-release soluble microneedle in preparing the drug is characterized in that the drug is methotrexate, the microneedle comprises a substrate, a needle body and a carrier which is distributed in the needle body and coated with the drug to be slow-released, and the carrier is polymer-modified inorganic nanoparticles; the inorganic nano particles are hollow mesoporous silica, the polymer is a biodegradable and positively charged polymer, and the biodegradable and positively charged polymer is chitosan; the polymer adopted by the matrix and the needle body is chondroitin sulfate; the hollow mesoporous silica is negatively charged, and the biodegradable and positively charged polymer is adsorbed on the surface of the hollow mesoporous silica loaded with the medicine through electrostatic adsorption, so that the medicine is wrapped, and the quick release of the medicine is prevented.
2. The use of claim 1, wherein the carrier coated with the drug to be sustained-released has a size of 50 to 5000 nm, and the microneedle has a content of the drug to be sustained-released of 20 to 2000 μ g; the structure of the carrier coated with the drug to be slowly released is one or more of microspheres, microcapsules, nano-particles, liposome, micelle and a slow release film.
3. The use of claim 1, wherein the microneedle is prepared by:
(1) preparing a carrier coated with a medicament to be slowly released by adopting one of an emulsion method, a dialysis method, a solvent volatilization method, a spray drying method and a polyelectrolyte protection method; the carrier is inorganic nano particles;
(2) dissolving or dispersing the carrier coated with the drug to be slowly released in a matrix solution, casting the matrix solution into a mold by a vacuum pumping method, drying and demolding to obtain the slowly-released soluble microneedle.
4. The use according to claim 3, wherein the polyelectrolyte protection method is in particular:
dissolving the hollow mesoporous silica nanoparticles and the drug to be slowly released in dimethyl sulfoxide, uniformly stirring, and removing the dimethyl sulfoxide by using a negative pressure method to obtain hollow mesoporous silica nanoparticles loaded with the drug to be slowly released;
dispersing the hollow mesoporous silica nanoparticles loaded with the drug to be slowly released in a biodegradable polymer with positive electricity, stirring, centrifuging and washing to obtain the carrier coated with the drug to be slowly released.
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