CN108245482B - Polymer composite microneedle capable of releasing drugs in programmed manner and preparation method thereof - Google Patents
Polymer composite microneedle capable of releasing drugs in programmed manner and preparation method thereof Download PDFInfo
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- CN108245482B CN108245482B CN201810115096.4A CN201810115096A CN108245482B CN 108245482 B CN108245482 B CN 108245482B CN 201810115096 A CN201810115096 A CN 201810115096A CN 108245482 B CN108245482 B CN 108245482B
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- microneedle
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- polymer composite
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- 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
- A61M2037/0046—Solid microneedles
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- 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
- A61M2037/0053—Methods for producing microneedles
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Abstract
The invention discloses a polymer composite microneedle capable of releasing medicaments in a programmed manner and a preparation method thereof, wherein the polymer composite microneedle comprises a soluble biocompatible polymer needle body, a biodegradable indissolvable polymer needle point embedded with a first medicament and positioned on the needle body, and a medicament coating which is positioned on the surface layer of the polymer composite microneedle and contains a second medicament; wherein the first drug corresponds to a drug that requires slow release and the second drug corresponds to a drug that requires rapid release. According to the invention, by improving the composition and structure of the polymer composite microneedle, the whole process flow design of the corresponding preparation method, the conditions and parameters (including the type of the polymer, the type of the medicine and the like) of each step, compared with the prior art, the problem that the microneedle can not release the medicine in a programmed manner can be effectively solved.
Description
Technical Field
The invention belongs to the field of drug delivery, and particularly relates to a polymer composite microneedle capable of releasing drugs in a programmed manner and a preparation method thereof.
Background
When some diseases are clinically treated, a plurality of medicines are often required to be combined for treatment. Because the action mechanisms and the metabolism conditions in vivo of the medicines are different, the medicines are often required to be firstly and rapidly released to exert the drug effect; then gradually releasing the other drug, thereby playing a role in enhancing or consolidating the therapeutic effect of the former. For example, in tumor immunodetection point therapy, it is first necessary to allow a CpG oligonucleotide (a nucleic acid drug) to act, causing immunosuppression; then aPD-1 is slowly released and acts gradually, so that the immunotherapy effect of aPD-1 can be better exerted. However, it is difficult to achieve programmed release of multiple drugs in a simple and effective manner by both conventional oral administration and injection administration. In recent years, with the development of micro-electro-mechanical processing technology, microneedles have received attention as a novel drug delivery method. The micro-needle generally refers to a needle composed of metal, silicon, polymer and other materials and having a micron-sized three-dimensional array structure, and the micro-needle can penetrate through the epidermis layer of the skin after being loaded with a target drug so as to achieve the purpose of positioning and drug delivery in the skin. The microneedle can overcome the barrier effect of the skin stratum corneum to the drug, and has high administration efficiency. The length of the micro needle is generally 25-2000 mu m, and the micro needle can not touch nerve tissues and blood vessels after penetrating into the skin, so that a patient can not feel pain generally and the damage degree to the body is small. Meanwhile, the microneedle administration does not need special medical care personnel to operate, the patient can administer the drug by oneself, the use is convenient, and the patient can interrupt the administration at any time by combining the actual condition of the patient, so the compliance of the patient can be greatly improved by the microneedle administration mode. Therefore, the microneedle administration mode has great application prospect in the field of drug delivery.
Microneedles can be generally classified into four types, coated microneedles, solid microneedles, hollow microneedles, and soluble microneedles. The micro-needles of the types such as solid micro-needles and hollow micro-needles have the defects of harsh preparation conditions, high preparation technical requirements, low dosage, complex operation, easy infection and the like due to the defects of the structure and the preparation method. In contrast, the soluble microneedle is generally prepared from a biodegradable or biodegradable polymer material with good biocompatibility, and has the advantages of large drug loading, mild preparation conditions, simplicity and convenience in operation, high biological safety and the like. The drug embedded in the soluble micro-needle is gradually released along with the dissolution of the soluble material in the skin, so that the drug is absorbed and metabolized by human tissues. The soluble microneedle has high dissolving speed and short microneedle application time, but the prior art can not control the release speed of the carried drug according to different requirements of different drugs. Meanwhile, the existing soluble polymer microneedle can realize the synchronous release of a plurality of medicaments, but cannot realize the programmed release of the plurality of medicaments, thereby greatly limiting the application of the soluble microneedle in the field of medicament delivery.
Disclosure of Invention
Aiming at the defects or improvement requirements of the prior art, the invention aims to provide a polymer composite microneedle capable of releasing medicaments in a programmed manner and a preparation method thereof, wherein the composition and the structure of the polymer composite microneedle, the whole process flow design of the corresponding preparation method, and the conditions and parameters (including the types of polymers, the types of medicaments and the like) of each step are improved, compared with the prior art, the problem that the microneedle cannot release a plurality of medicaments in a programmed manner can be effectively solved, the polymer composite microneedle can load a plurality of types of medicaments with different release rate requirements (or simultaneously requires the same medicament with two or more release rate requirements), the programmed sequential control release of the medicaments can be realized by one-time needle application, the programmed release of the medicaments is realized, the application time of the microneedle is short, and the compliance of a patient is high, the polymer composite microneedle body material is a degradable material with good biological safety, can be digested and absorbed by tissues, is harmless to human bodies, and is suitable for the field of drug delivery; in addition, the polymer composite microneedle capable of releasing the drugs in the programmed manner is simple in preparation process and high in mechanical strength.
In order to achieve the above object, according to one aspect of the present invention, there is provided a polymer composite microneedle capable of releasing a drug in a programmed manner, the polymer composite microneedle is characterized in that the polymer composite microneedle comprises a biocompatible polymer needle body capable of dissolving, a biodegradable insoluble polymer needle tip embedded with a first drug on the needle body, and a drug coating layer on the surface layer of the polymer composite microneedle and containing a second drug; wherein the first drug corresponds to a drug that requires slow release and the second drug corresponds to a drug that requires rapid release.
As a further preferred aspect of the present invention, the dissolvable biocompatible polymer used for the dissolvable biocompatible polymer needle body specifically includes one or more of hyaluronic acid, carboxymethyl cellulose, hydroxypropyl methyl cellulose, dextran, sodium chondroitin sulfate, sodium alginate, pullulan, gelatin, silk fibroin, hyaluronic acid, dextrin, poly-gamma-glutamic acid, polyvinylpyrrolidone, and derivatives thereof.
In a further preferred embodiment of the present invention, the biodegradable slightly soluble polymer used for the biodegradable slightly soluble polymer needle tip in which the first drug is embedded includes one or more of chitosan, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycarbonate, polycaprolactone, polyglycolide, polycarboxyacetic acid, chitin, and derivatives thereof.
As a further preferred aspect of the present invention, the first drug comprises one or more of monoclonal antibodies, epidermal growth factor, aPD1, interferon, growth hormone, bovine serum albumin, insulin, vaccines, hypotensive agents, doxorubicin, paclitaxel, and the like, and derivatives thereof.
As a further preference of the present invention, the second medicament includes one or more of phenobarbital, interleukin, lidocaine, analgesic, ela, nucleic acid, and the like, and derivatives thereof; or the components and the proportion of the components of the second medicament and the first medicament are the same.
As a further preferred embodiment of the present invention, the polymer composite microneedle is a three-dimensional shape formed by continuously decreasing the cross-sectional area from the bottom surface of the needle body to the tip of the needle point, the polymer composite microneedle is preferably in a pyramid shape or a cone shape, the distance from the bottom surface of the needle body to the tip of the needle point of the polymer composite microneedle is 25 to 2000 μm, and the maximum width of the bottom surface of the needle body satisfies 50 to 800 μm; preferably, the polymer composite microneedle is a polymer composite microneedle array, the distance between adjacent tips in the polymer composite microneedle array is 100-.
According to another aspect of the present invention, there is provided a method for preparing a polymer composite microneedle capable of releasing a drug in a programmed manner, the method comprising the steps of:
(1) injecting the degradable slightly soluble polymer solution or melt mixed with the first drug into a microneedle mould, and filling the degradable slightly soluble polymer solution or melt mixed with the first drug into the tip of the microneedle mould through vacuum treatment or centrifugal treatment;
(2) then, injecting a solution of a soluble polymer into the microneedle mould treated in the step (1), filling the solution of the soluble polymer into the microneedle mould through vacuum treatment or centrifugal treatment, drying and then stripping the microneedle mould to obtain the polymer microneedle loaded with the first drug;
(3) covering a drug solution containing a second drug on the surface of the polymer microneedle obtained in the step (2) by dipping or spraying, and drying to obtain the polymer composite microneedle capable of releasing the drug in a programmed manner;
the first drug corresponds to a drug that requires slow release and the second drug corresponds to a drug that requires rapid release.
In a further preferred aspect of the present invention, in the step (1), in the solution or the melt of the degradable slightly soluble polymer mixed with the first drug, the mass percentage concentration of the degradable slightly soluble polymer is 1% to 99.99%, and the mass percentage concentration of the first drug is 0.01% to 50%;
in the step (2), the mass percentage concentration of the soluble polymer in the solution of the soluble polymer is 1-60%;
in the step (3), the mass percentage concentration of the second medicament in the medicament solution containing the second medicament is 0.01-50%.
As a further preferred aspect of the present invention, in the step (1), the ratio of the height of the degradable slightly soluble polymer solution or melt mixed with the first drug filled into the microneedle mould tip to the height of the whole microneedle mould is 1: 99-99: 1.
Through the technical scheme, compared with the prior art, two types of polymers with different dissolving capacities in tissue fluid (mainly containing water) are selected, namely the soluble biocompatible polymer (the polymer has high solubility in water) and the biodegradable insoluble polymer (the polymer has low solubility in water), the solubility of the soluble biocompatible polymer is higher than that of the biodegradable insoluble polymer, the needle point of the microneedle is formed by embedding the first drug in the biodegradable insoluble polymer, the needle body is formed by the soluble biocompatible polymer, the drug coating containing the second drug is directly arranged on the surface layer of the microneedle, the release of the second drug is faster than that of the first drug, so the first drug can correspond to the drug needing to be slowly released, and the second drug can correspond to the drug needing to be quickly released, thereby realizing programmed release of various medicaments by the polymer composite microneedle; of course, the first drug and the second drug can be identical, and the application situation that the same drug simultaneously requires two or more release rates can be satisfied.
The invention integrates a plurality of technologies such as dissoluble microneedles, degradable microneedles and coating microneedles, and the polymer composite microneedles obtained by design can realize programmed controlled release of a plurality of medicaments clinically. The polymer composite microneedle mainly comprises the following parts: a biocompatible polymer needle body capable of being dissolved rapidly (the polymer composite microneedle also comprises a base, the base is positioned below the needle body, and the needlepoint is positioned above the needle body; the base is also a biocompatible polymer capable of being dissolved, in particular a biocompatible polymer capable of being dissolved rapidly); a biodegradable insoluble polymer needle tip embedded with a drug; a drug coating formed of another drug; the medicine embedded in the needle tip is the medicine which needs to be slowly released, and the medicine of the coating is the medicine which needs to be quickly released. The polymer composite microneedle can realize programmed sequential release of different drugs, after the polymer composite microneedle penetrates into the skin, the needle body is quickly dissolved, the indissolvable needle point is continuously remained in the skin, the coating drug is quickly dissolved and released, and the drug embedded in the needle point is gradually released along with the degradation of the indissolvable polymer needle point, so that various drugs are released in a programmed manner.
The invention also controls the morphological parameters of the polymer compound micro-needle and the micro-needle array (such as the height of a single polymer compound micro-needle, the maximum width of the bottom surface, the distance between adjacent micro-needles in the micro-needle array, and the like), the type of the polymer, the concentration of the polymer solution or melt, the concentration of the first drug, the type of the polymer and the concentration of the polymer solution, which are adopted when preparing the biocompatible polymer needle body which can be dissolved, and the concentration of the drug solution, which is adopted when preparing the drug coating layer containing the second drug, and the height ratio of the biodegradable insoluble polymer needle tip embedded with the first drug to the whole polymer composite microneedle, thereby further regulating and controlling the programmed release behaviors of the first medicament carried by the microneedle tip and the second medicament carried by the coating.
Drawings
Fig. 1 is a schematic view of a polymer composite microneedle.
Fig. 2 is a schematic view of a method for preparing a polymer composite microneedle.
Fig. 3 is a photomicrograph of a solid polymer composite microneedle.
Fig. 4 is an optical microscope image of the polymer composite microneedle after penetrating the pigskin.
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 embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
As shown in fig. 1, the polymer composite microneedle capable of releasing a drug in a programmed manner according to the present invention has the following structure: the base and the needle body of the micro-needle are composed of biocompatible polymers capable of being dissolved quickly, the tip of the micro-needle is composed of biodegradable insoluble polymers carrying drugs (namely first drugs) needing to be released slowly, and the surface coating of the micro-needle is composed of drug (namely second drugs) needing to be released quickly.
After the polymer composite microneedle capable of releasing the drugs in the programmed way is pricked into the skin, the second drug in the surface coating is quickly dissolved and released under the action of tissue fluid to play a role; then, in a short time, the needle body of the microneedle, which can be quickly dissolved, is quickly dissolved under the action of tissue fluid, so that the degradable insoluble needle tip embedded with the medicine (namely the first medicine) needing to be slowly released is separated from the base and is continuously remained in the skin; with the gradual degradation of the degradable insoluble polymer in the needle tip, the embedded medicine is slowly released from the needle tip and plays a role, thereby realizing the programmed release of a plurality of medicines or the same medicine.
The following are specific examples:
example 1
This embodiment comprises the steps of:
1. uniformly mixing PDMS (polydimethylsiloxane, Sylgard 184) and a curing agent according to a mass ratio of 10:1, removing bubbles by ultrasonic treatment for several minutes, injecting the liquid PDMS containing the curing agent, from which the bubbles are removed, into a watch glass with a microneedle male mold, heating the watch glass in an oven at 80 ℃ for 2-3 hours, and separating the PDMS from the microneedle male mold after the PDMS is completely cured, thereby obtaining the PDMS microneedle mold. Wherein the height of the used micro-needle is 25 μm, the width of the bottom is 50 μm, the distance between the needle points is 100 μm, the side length of the array is 1mm, and the number of the micro-needles is 1 multiplied by 1.
2. Dissolving chitosan in 1% acetic acid solution, dialyzing in water for about 48 hr to remove excessive acetic acid molecules to obtain chitosan solution with pH of about 6, heating, and concentrating to obtain chitosan concentrated solution with mass concentration of 8%. Adding bovine serum albumin into the chitosan concentrated solution and mixing uniformly. Adding a chitosan concentrated solution (the mass fraction of bovine serum albumin is 50%) embedded with bovine serum albumin into a PDMS microneedle mould, filling the solution into the tip of a microneedle under the assistance of vacuum (the filling height can be adjusted by controlling the vacuum degree/centrifugal force and the acting time), and then centrifuging for several minutes to enable the polymer solution embedded with bovine serum albumin to completely fill the tip part.
3. Dissolving hyaluronic acid powder in water, and magnetically stirring for half an hour to obtain a uniformly mixed hyaluronic acid solution. And adding a hyaluronic acid solution with the mass fraction of 30% to the PDMS mould with the drug-containing chitosan solution loaded at the tip, and completely filling the rest part of the mould with the aid of vacuum.
4. And (3) placing the PDMS mould carrying the polymer solution in a dryer, drying overnight, and then separating the microneedle from the template to obtain the polymer microneedle with the bovine serum albumin embedded at the tip, wherein the ratio of the height of the tip of the obtained microneedle to the height of the whole microneedle mould is 1: 99.
5. Dipping the obtained polymer microneedle in a solution of another drug interleukin (the mass fraction of the interleukin is 15 percent), and drying to obtain the polymer composite microneedle of which the tip is embedded with the drug bovine serum albumin and the coating is the interleukin.
Example 2
This embodiment comprises the steps of:
1. uniformly mixing PDMS (polydimethylsiloxane, Sylgard 184) and a curing agent according to a mass ratio of 10:1, removing bubbles by ultrasonic treatment for several minutes, injecting the liquid PDMS containing the curing agent, from which the bubbles are removed, into a watch glass with a microneedle male mold, heating the watch glass in an oven at 80 ℃ for 2-3 hours, and separating the PDMS from the microneedle male mold after the PDMS is completely cured, thereby obtaining the PDMS microneedle mold. Wherein the height of the used micro-needle is 1000 μm, the width of the bottom is 400 μm, the distance between the needle points is 2500 μm, the side length of the array is 30mm, and the number of the micro-needles is 15 multiplied by 15.
2. Mixing and melting paclitaxel and polycaprolactone at 70 ℃ to obtain a polycaprolactone melt containing paclitaxel (the mass fraction of the paclitaxel is 0.01%, and the mass fraction of the polycaprolactone is 99.99%), adding the melt into a PDMS microneedle mould, and filling the melt into the tip of the microneedle under the assistance of vacuum to enable the polycaprolactone melt embedded with the paclitaxel to completely fill the tip of the polycaprolactone melt.
3. Dissolving carboxymethyl cellulose powder in water, and magnetically stirring for half an hour to obtain a uniformly mixed carboxymethyl cellulose solution. And adding a 30% carboxymethyl cellulose solution on the PDMS mould with the tip loaded with the polycaprolactone melt embedded with the paclitaxel, and completely filling the rest part of the mould with the carboxymethyl cellulose solution under the assistance of vacuum.
4. And (3) placing the PDMS mould carrying the polymer solution in a dryer, drying overnight, and then stripping the microneedle from the template to obtain the polymer microneedle with the tip embedded with the paclitaxel, wherein the ratio of the height of the tip of the obtained microneedle to the height of the whole microneedle mould is 99: 1.
5. Spraying another drug-Euler aqueous solution (Euler mass fraction is 50%) on the surface of the obtained polymer microneedle, and drying to obtain the polymer composite microneedle with the tip embedded with paclitaxel and the coating of Euler.
Example 3
This embodiment comprises the steps of:
1. uniformly mixing PDMS (polydimethylsiloxane, Sylgard 184) and a curing agent according to a mass ratio of 10:1, removing bubbles by ultrasonic treatment for several minutes, injecting the liquid PDMS containing the curing agent, from which the bubbles are removed, into a watch glass with a microneedle male mold, heating the watch glass in an oven at 80 ℃ for 2-3 hours, and separating the PDMS from the microneedle male mold after the PDMS is completely cured, thereby obtaining the PDMS microneedle mold. Wherein the height of the used micro-needle is 2000 μm, the width of the bottom is 800 μm, the distance between the needle points is 5000 μm, the side length of the array is 60mm, and the number of the micro-needles is 30 multiplied by 30.
2. Dissolving chitin in 1% acetic acid solution, dialyzing in water for about 48 hr to remove excessive acetic acid molecules to obtain chitin solution with pH of about 6, heating, and concentrating to obtain chitin concentrated solution with mass concentration of 8%. Adding aPD-1 antibody into chitin concentrated solution (aPD1 mass fraction is 20%), and mixing. The chitin concentrate with the aPD-1 antibody embedded was added to a PDMS microneedle mold and the solution was filled into the microneedle tips with vacuum assistance. The tip portion was then completely filled with the chitin solution embedded with aPD1 antibody by centrifugation for several minutes.
3. Dissolving polyvinylpyrrolidone in water, and magnetically stirring for half an hour to obtain uniformly mixed polyvinylpyrrolidone solution. A60% solution of polyvinylpyrrolidone was added to the PDMS mold with the tip already loaded with a chitin solution of aPD-1 antibody, and the mold was completely filled with the remainder under vacuum assistance.
4. And (3) placing the PDMS mould carrying the polymer solution in a dryer, drying overnight, and then peeling the microneedle and the template to obtain the polymer microneedle with the aPD-1 antibody embedded at the tip, wherein the ratio of the height of the tip of the obtained microneedle to the height of the whole microneedle mould is 50: 50.
5. And (2) spraying a CpG oligonucleotide (a nucleic acid medicament) solution (the CpG mass fraction is 0.01%) on the surface of the microneedle, and drying to obtain the polymer composite microneedle with the tip embedded with aPD-1 antibody and the surface coated with CpG.
Example 4
This embodiment comprises the steps of:
1. uniformly mixing PDMS (polydimethylsiloxane, Sylgard 184) and a curing agent according to a mass ratio of 10:1, removing bubbles by ultrasonic treatment for several minutes, injecting the liquid PDMS containing the curing agent, from which the bubbles are removed, into a watch glass with a microneedle male mold, heating the watch glass in an oven at 80 ℃ for 2-3 hours, and separating the PDMS from the microneedle male mold after the PDMS is completely cured, thereby obtaining the PDMS microneedle mold. Wherein the height of the used micro-needle is 800 μm, the width of the bottom is 300 μm, the distance between the needle points is 500 μm, the side length of the array is 10mm, and the number of the micro-needles is 10 multiplied by 10.
2. Dissolving carboxymethyl chitosan in water to obtain a carboxymethyl chitosan solution with the mass concentration of 1%. Adding adriamycin into the chitosan concentrated solution and mixing uniformly. The carboxymethyl chitosan solution embedded with adriamycin (the mass fraction of adriamycin is 15%) is added into a PDMS microneedle mould, the solution is filled into the tip of the microneedle under the assistance of vacuum (the filling height can be adjusted by controlling the vacuum degree/the centrifugal force and the acting time), and then the solution is centrifuged for a plurality of minutes, so that the polymer solution embedded with bovine serum albumin completely fills the tip part.
3. Dissolving the amylopectin powder in water, and magnetically stirring for half an hour to obtain a uniformly mixed amylopectin solution. And adding a pullulan solution with the mass fraction of 1% into the PDMS mould with the drug-containing chitosan solution loaded at the tip, and completely filling the rest part of the mould with the assistance of vacuum.
4. And (3) placing the PDMS mould carrying the polymer solution in a dryer, drying overnight, and then separating the microneedle from the template to obtain the polymer microneedle with the tip embedded with the adriamycin, wherein the ratio of the height of the tip of the obtained microneedle to the height of the whole microneedle mould is 20: 80.
5. Dipping the obtained polymer microneedle with another drug solution of lidocaine (the mass fraction of lidocaine is 10%), and drying to obtain the polymer composite microneedle with the tip embedded with the drug adriamycin and the coating of lidocaine.
Example 5
In-vitro transdermal test of polymer composite microneedle with tip embedded with bovine serum albumin and coating of interleukin
Taking fresh pig skin which is unhaired and cleaned, aligning the tip end of the polymer composite microneedle with the tip embedded with bovine serum albumin and the coating of interleukin in the embodiment 1 to the surface layer of the pig skin for vertical penetration, pressing the base part of the polymer composite microneedle by fingers for about 5 minutes until the needle body part of the soluble microneedle is completely dissolved, and only the tip end of the degradable microneedle is left in the skin. The pigskin with the microneedle is observed under an optical microscope, as shown in figure 4, the pigskin part with the microneedle has clear holes, and the puncture rate reaches 100 percent, which shows that the polymer composite microneedle has enough mechanical strength and can effectively puncture the surface layer of the pigskin.
Example 6
Release rate testing of two drugs with paclitaxel embedded at tip and polymer composite microneedle coated with ela
The polymer composite microneedle with the tip embedded with paclitaxel and the coating of ela described in example 2 was placed in a centrifuge tube containing 10mL of phosphate buffered saline (PBS solution, pH 7.4), placed in a water bath shaker at 37 ℃, 1mL of the solution was taken out at certain time intervals, 1mL of fresh PBS solution was added, the content of paclitaxel and ela in the taken-out solution was measured, and the release rate of paclitaxel and ela at different time points was calculated. The experimental results show that the ela is released completely rapidly within ten minutes, while the paclitaxel maintains a slow release rate within one week. The polymer composite microneedle capable of releasing the medicament in the programmed way realizes the programmed medicament release of the medicament.
The micro-needle in the invention is in a three-dimensional shape formed by continuously reducing the cross-sectional area from the bottom surface of the needle body to the tip end of the needle point, the cross section can be in a circular shape, a polygonal shape (such as a triangle, a quadrangle and the like) or an irregular shape (such as a petal shape, a cross shape and the like), and the corresponding micro-needle mould can also be provided with a corresponding shape.
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 (6)
1. A preparation method of a polymer composite microneedle capable of releasing drugs in a programmed manner is characterized in that the polymer composite microneedle comprises a biocompatible polymer needle body capable of dissolving, a biodegradable insoluble polymer needle point embedded with a first drug and positioned on the needle body, and a drug coating which is positioned on the surface layer of the polymer composite microneedle and contains a second drug; wherein the first drug corresponds to a drug that needs to be slowly released and the second drug corresponds to a drug that needs to be rapidly released; the polymer composite micro-needle loads several types of medicines with different release rate requirements, or loads the same medicine with more than two release rate requirements, and the programmed sequential controlled release of the medicines is realized by one-time needle application;
the soluble biocompatible polymer adopted by the soluble biocompatible polymer needle body specifically comprises one or more of hyaluronic acid, carboxymethyl cellulose, hydroxypropyl methyl cellulose, dextran, sodium chondroitin sulfate, sodium alginate, amylopectin, gelatin, silk fibroin, hyaluronic acid, dextrin, poly-gamma-glutamic acid, polyvinylpyrrolidone and derivatives thereof;
the biodegradable slightly-soluble polymer used by the biodegradable slightly-soluble polymer needle tip embedded with the first medicine comprises one or more of chitosan, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, polycarbonate, polycaprolactone, poly (glycolide-co-lactide), polycarboxyacetic acid, chitin and derivatives thereof;
the polymer composite microneedle is in a three-dimensional shape formed by continuously reducing the cross-sectional area from the bottom surface of the needle body to the tip of the needle point;
the preparation method comprises the following steps:
(1) injecting the degradable slightly soluble polymer solution or melt mixed with the first drug into a microneedle mould, and filling the degradable slightly soluble polymer solution or melt mixed with the first drug into the tip of the microneedle mould through vacuum treatment or centrifugal treatment;
(2) then, injecting a solution of a soluble polymer into the microneedle mould treated in the step (1), filling the solution of the soluble polymer into the microneedle mould through vacuum treatment or centrifugal treatment, drying and then stripping the microneedle mould to obtain the polymer microneedle loaded with the first drug;
(3) covering a drug solution containing a second drug on the surface of the polymer microneedle obtained in the step (2) by dipping or spraying, and drying to obtain the polymer composite microneedle capable of releasing the drug in a programmed manner;
the first drug corresponds to a drug that requires slow release and the second drug corresponds to a drug that requires rapid release.
2. The method for preparing a polymer composite microneedle capable of releasing a programmed drug according to claim 1, wherein in the step (1), the mass percentage concentration of the degradable slightly soluble polymer in the solution or the melt mixed with the first drug is 1% to 99.99%, and the mass percentage concentration of the first drug is 0.01% to 50%;
in the step (2), the mass percentage concentration of the soluble polymer in the solution of the soluble polymer is 1-60%;
in the step (3), the mass percentage concentration of the second medicament in the medicament solution containing the second medicament is 0.01-50%.
3. The method for preparing a polymer composite microneedle capable of releasing a programmed drug according to claim 1, wherein the ratio of the height of the degradable slightly soluble polymer solution or melt mixed with the first drug filled into the tip of the microneedle mold to the height of the entire microneedle mold in the step (1) is 1: 99-99: 1.
4. The method of manufacturing a polymer composite microneedle for releasing a drug in a programmed manner according to claim 1, wherein the first drug includes one or more of monoclonal antibody, epidermal growth factor, aPD1, interferon, growth hormone, bovine serum albumin, insulin, vaccine, antihypertensive, doxorubicin, paclitaxel, and derivatives thereof.
5. A method of fabricating a polymer composite microneedle for releasing a programmed drug according to claim 1, wherein the second drug includes one or more of phenobarbital, interleukin, lidocaine, analgesic, ela, nucleic acid and its derivatives; or the components and the proportion of the components of the second medicament and the first medicament are the same.
6. The method for preparing a polymer composite microneedle capable of releasing drugs in a programmed manner according to claim 1, wherein the polymer composite microneedle is in a pyramid shape or a cone shape, the distance between the bottom surface of the polymer composite microneedle and the tip of the needle tip is 25-2000 μm, and the maximum width of the bottom surface of the polymer composite microneedle meets 50-800 μm; the polymer composite microneedle array is a polymer composite microneedle array, the distance between adjacent needlepoints in the polymer composite microneedle array is 100-5000 microns, the side length of the whole polymer composite microneedle array is 1-60 mm, and the number of microneedles is (1-30) × (1-30).
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| CN110870943A (en) * | 2018-08-31 | 2020-03-10 | 中科微针（北京）科技有限公司 | Implantable two-section type microneedle patch and preparation method thereof |
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| CN113332589B (en) * | 2021-05-26 | 2023-05-09 | 四川大学 | Polymer microneedle for loading double medicines for oral mucosa administration and preparation method thereof |
| CN113648528A (en) * | 2021-08-20 | 2021-11-16 | 天津大学 | Multiple-administration core-shell microneedle patch and preparation method thereof |
| CN113952318B (en) * | 2021-09-08 | 2023-12-15 | 北京宝理泰科技有限公司 | Preparation method of multi-layer microneedle patch for relieving pain |
| CN114404352A (en) * | 2021-12-21 | 2022-04-29 | 浙江德清娃哈哈科技创新中心有限公司 | Microneedle with surface loaded with fat-soluble active substances and preparation method thereof |
| CN114796091A (en) * | 2022-03-12 | 2022-07-29 | 四川大学 | Microneedle array for subcutaneous slow release of calcitonin and preparation method thereof |
| CN115120552B (en) * | 2022-06-22 | 2024-06-04 | 华中科技大学 | Polypeptide drug-loaded microneedle patch capable of responding to drug release in microenvironment, preparation and application |
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