CN110876711B - Method for preparing multilayer polymer microneedle - Google Patents
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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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
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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
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- 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 method for preparing a multilayer polymer microneedle, belonging to the field of transdermal drug release of microneedles. Firstly, preparing an insoluble hard substrate microneedle by using a micro-hot stamping process, and then drying a medicinal solution on the surface of a microneedle body in a multi-time spraying mode to realize a multi-layer medicinal structure. And coating sodium hyaluronate on the outer layer to obtain the polymer microneedle with a basal layer, a drug layer and a quick release layer. Compared with the existing microneedle, the microneedle provided by the invention can be stacked in a multilayer manner within a certain range of the length of the microneedle, so that the types of the drug-carrying substances are increased. Meanwhile, the micro-hot stamping process is utilized to prepare the insoluble substrate micro-needle, the process operation is simple, the micro-processing precision is high, and the preparation period is greatly shortened. And the aim of controlling the dissolution speed of the medicine is achieved by changing the thickness of the outer sodium hyaluronate layer.
Description
Technical Field
The invention relates to a medical microneedle drug delivery system, in particular to a method for preparing a multilayer polymer microneedle.
Background
The micro-needle is a new transdermal drug delivery formulation, generally consists of a group of 25-2000 μm long needle points arranged on a base, and achieves the purpose of minimally invasive painless drug delivery by puncturing the stratum corneum of the skin. Microneedles are currently classified primarily as silicon, metal or polymer microneedles, from a material perspective. The polymer micro-needle has good biocompatibility, biodegradability, low toxicity, low processing cost and enough strength, is expected to replace silicon and metal micro-needles, and has great development potential. Currently, polymer microneedles are mostly used in a single type. Although the single polymer microneedle has the advantages of good biocompatibility and simple manufacturing process, and overcomes the defect that some protein drugs cannot be absorbed by oral administration, the single polymer microneedle still has the defects of drug release and drug-loading diversity.
Before the application of the patent, the Chinese invention patent (CN105617526A) discloses a swelling type fibroin protein microneedle drug delivery system and a preparation method thereof, wherein a fibroin protein solution and a micromolecule swelling agent are compounded and then are mixed with a model drug, the mixture is poured in a PDMS mold, and a high drug loading system with high swelling, no loss and high drug activity for the whole fibroin microneedle drug loading is obtained through vacuum drying, constant temperature and humidity drying and balancing. But such microneedles may be loaded with too single a type and number of drugs. The Chinese invention patent (CN108392728A) discloses a silk fibroin multilayer composite microneedle and a preparation method thereof, which adopts a layer-by-layer composite curing mode to dip a microneedle into a silk fibroin solution, then dry and cure the microneedle, and repeat the dipping and curing steps to obtain the multilayer composite microneedle. The multilayer microneedle can realize the superposition of different layers in a single needle body, increases the species capable of carrying drugs, but needs a complex preparation process, and has longer preparation period and higher preparation cost.
Disclosure of Invention
Aiming at the defects of the existing polymer micro-needle, the invention provides a method for preparing a multilayer polymer micro-needle, which can load different kinds of medicines in the same needle body simultaneously, has simple process operation and high micro-processing precision and greatly shortens the preparation period.
The technical scheme adopted by the invention is a method for preparing a multilayer polymer microneedle, which is characterized by comprising the following steps: the method comprises the following steps:
step (1) preparation of microneedle substrate layer: placing a microstructure mould and a polymer sheet between an upper mould frame and a lower mould frame of micro-hot stamping equipment, and then heating the mould and the polymer sheet to a hot stamping temperature of 70-200 ℃; loading to press the die into the softened polymer sheet, adjusting the pressure to be 0-20 MPa, and keeping the pressure for a certain time to ensure that the polymer is fully filled; and (3) maintaining the pressure for 20-80 s after self-loading, cooling until the temperature of the polymer sheet and the mould is reduced to 10 ℃ below the glass transition temperature of the polymer, unloading, and finally demoulding to obtain the microneedle product, wherein the microneedle product is a conical microneedle.
Step (2) preparation of microneedle drug layer: and (2) placing the base layer microneedle sheet obtained in the step (1) in a rotating chamber with the needle point facing downwards by adopting a spraying method, uniformly spraying the prepared medicinal solution on the surface of the microneedle, and drying in a vacuum drying oven at the temperature of 30-120 ℃ for 2-8 hours. And spraying a curing inducer to the dried drug layer, wherein the curing inducer comprises a methanol or ethanol aqueous solution with the volume concentration of 70-90%, so as to obtain the polymer microneedle carrying the substrate layer and the drug layer.
Preparing a microneedle quick release layer: and (3) downwards pointing the microneedle which is loaded with the inner layer and the drug layer and is obtained in the step (2), preparing a sodium hyaluronate solution with the mass fraction of 1% -20%, dipping the sodium hyaluronate solution in the prepared sodium hyaluronate solution for 1-10 s, lifting, and drying for 2-8 h under the condition of air blowing at the temperature of 30-120 ℃. And coating sodium hyaluronate on the outermost layer of the needle body to obtain the polymer microneedle with a basal layer, a drug layer and a quick release layer.
The spraying method comprises the steps of placing the obtained substrate layer microneedle in a rotating chamber with the needle tip facing downwards, uniformly spraying the prepared drug solution on the surface of the microneedle, and drying in a vacuum drying oven at 30-120 ℃ for 2-8 hours.
After the spraying process is finished, a curing inducer is sprayed on the dried medicine layer, wherein the curing inducer comprises a methanol or ethanol aqueous solution with the volume concentration of 70-90%, and the medicine layer is insoluble in water after volatilization, so that the dissolution and diffusion of the medicine are prevented.
The spraying method is repeated for 1-4 times, and the polymer microneedle containing multiple drug layers is obtained after solidification after each spraying and drying process.
The spraying method can spray different kinds of medicines, and can repeatedly spray to obtain medicine layers with different thicknesses, thereby controlling the release speed of the medicines.
The middle layer is 1-5 layers.
The outer sodium hyaluronate achieves the aim of controlling the dissolution speed of the medicine by changing the thickness of the outer sodium hyaluronate.
The micro-hot stamping process is characterized in that a micro-structure mold and a polymer sheet are placed between an upper mold frame and a lower mold frame of micro-hot stamping equipment, and then the mold and the polymer sheet are heated to a hot stamping temperature of 70-200 ℃; loading to press the die into the softened polymer sheet, adjusting the pressure to be 0-20 MPa, and keeping the pressure for a certain time to ensure that the polymer is fully filled; and (3) maintaining the pressure for 20-80 s after self loading, cooling until the temperature of the polymer sheet and the mold is reduced to 10 ℃ below the glass transition temperature of the polymer, unloading, and finally demolding to obtain the microneedle product.
The mass fraction of the sodium hyaluronate solution is 1-20%.
The drying temperature of the sodium hyaluronate solution is 30-120 ℃, and the drying time is 2-8 hours.
The micro-hot stamping process is simple to operate, high in micro-processing precision and relatively low in cost.
The medicine is lidocaine, isosorbide mononitrate, hydrochlorothiazide, efletirizine, salbutamol, acetylsalicylic acid, imipramine, gentamicin, amoxicillin, ampicillin, roxithromycin, norfloxacin or acetylspiramycin and the like.
The microneedle body is of a layered structure and comprises a basal layer, a drug layer and a quick release layer.
Compared with the existing preparation method of the polymer microneedle, the invention adopts a multilayer assembly mode, firstly prepares the insoluble hard substrate microneedle by using a micro-hot stamping process, and then dries the drug solution on the surface of the microneedle body by a multi-time spraying method to realize a multilayer drug structure. And coating sodium hyaluronate on the outer layer to obtain the polymer microneedle with a basal layer, a drug layer and a quick release layer. The novel polymer microneedle can be stacked in multiple layers within a certain range of the length of the microneedle, and the types of the drug-carrying substances are increased. And the insoluble substrate is prepared by utilizing the micro-hot stamping process, the process operation is simple, the micro-processing precision is high, and the preparation period is greatly shortened. And the aim of controlling the dissolution speed of the medicine can be achieved by changing the thickness of the outer sodium hyaluronate layer.
Drawings
FIG. 1 is a schematic view of a single layer-by-layer assembled polymer microneedle
Fig. 2 is a schematic view of a layer-by-layer assembled polymer microneedle array.
In the figure: 1-basal layer 2-drug layer 3-quick release layer 4-PDMS micro needle mould
Detailed Description
The invention will be further described with reference to the drawings and the detailed description, but the scope of the invention is not limited thereto.
Example 1
The embodiment provides a preparation method of a four-layer composite microneedle loaded with a lidocaine drug and an acetylspiramycin drug, and the preparation method comprises the following steps:
(1) preparation of microneedle substrate layer: the experimental die is made of stainless steel materials, a 7 multiplied by 7 microneedle concave truncated cone array is distributed on the die, the distance between adjacent taper holes of the die is 2mm, the diameter of the bottom of a microneedle counter bore (the large diameter of the truncated cone) is 0.25mm, the diameter of the top of the microneedle counter bore (the small diameter of the truncated cone) is 0.05mm, and the depth of the microneedle counter bore is 0.55 mm. The polymer material is polylactic acid (PLA), and the glass transition temperature of the PLA is 56 ℃. Placing the microstructure mould and the PLA sheet between an upper mould frame and a lower mould frame of a micro-hot stamping device, and then heating the mould and the PLA sheet to a hot stamping temperature of 112 ℃; loading to press the die into the softened PLA sheet, adjusting the pressure to be 4.10MPa, and keeping the pressure for a certain time to ensure that the PLA is fully filled; and (3) maintaining the pressure for 60s after self loading, cooling until the temperature of the PLA sheet and the mould is reduced to below the PLA glass transition temperature by 10 ℃, unloading, and finally demoulding to obtain the insoluble hard substrate microneedle.
(2) Preparation of microneedle drug layer: and (2) placing the base layer microneedle sheet obtained in the step (1) in a rotating chamber with the tip facing downwards by adopting a spraying method, uniformly spraying the prepared lidocaine medicinal solution on the surface of the microneedle, and drying in a vacuum drying oven at 65 ℃ for 4.5 hours. Spraying methanol water solution with volume concentration of 75% to the dried medicine, volatilizing to obtain the microneedle loaded with the lidocaine medicine, spraying acetylspiramycin medicine solution by using the method, drying and curing to obtain the three-layer composite microneedle loaded with the lidocaine medicine and the acetylspiramycin medicine.
(3) Preparing a microneedle quick release layer: preparing a sodium hyaluronate solution with the mass fraction of 2%, dipping the multi-layer composite microneedle slice obtained in the step (2) with the needle tip downwards in the prepared sodium hyaluronate solution for 5s, lifting, and drying for 4.5h under the condition of air blast at the temperature of 65 ℃ to obtain the four-layer composite microneedle loaded with the lidocaine medicine and the acetylspiramycin medicine.
Example 2
The embodiment provides a preparation method of a four-layer composite microneedle loaded with an ibuprofen drug and a gentamicin drug, and the preparation method comprises the following steps:
(1) preparation of microneedle substrate layer: the experimental die is made of stainless steel materials, a 7 multiplied by 7 microneedle concave truncated cone array is distributed on the die, the distance between adjacent taper holes of the die is 2mm, the diameter of the bottom of a microneedle counter bore (the large diameter of the truncated cone) is 0.25mm, the diameter of the top of the microneedle counter bore (the small diameter of the truncated cone) is 0.05mm, and the depth of the microneedle counter bore is 0.55 mm. The polymer material is polymethyl methacrylate (PMMA), and the glass transition temperature of PMMA is 105 ℃. Placing the microstructure mould and the PMMA sheet between an upper mould frame and a lower mould frame of a micro-hot stamping device, and then heating the mould and the PMMA sheet to a hot stamping temperature of 116 ℃; loading to press the mold into the softened PMMA sheet, adjusting the pressure to 7.08MPa, and keeping the pressure for a certain time to ensure that PMMA is fully filled; and (3) maintaining the pressure for 60s after self loading, cooling until the temperature of the PMMA sheet and the mold is reduced to be below the PMMA glass transition temperature by 10 ℃, unloading, and finally demolding to obtain the insoluble hard substrate microneedle.
(2) Preparation of microneedle drug layer: and (2) placing the base layer microneedle sheet obtained in the step (1) in a rotating chamber with the needle point facing downwards by adopting a spraying method, uniformly spraying the prepared ibuprofen medicinal solution on the surface of the microneedle, and drying in a vacuum drying oven at 66 ℃ for 5.0 h. Spraying an ethanol water solution with the volume concentration of 80% to the dried drug, volatilizing to obtain the microneedle loaded with the ibuprofen drug, spraying the gentamicin drug solution by using the method, drying and curing to obtain the three-layer composite microneedle loaded with the ibuprofen drug and the gentamicin drug.
(3) Preparing a microneedle quick release layer: preparing a sodium hyaluronate solution with the mass fraction of 3%, dipping the multi-layer composite microneedle slice obtained in the step (2) with the needle tip downwards in the prepared sodium hyaluronate solution for 6s, lifting, and drying for 5.0h under the condition of air blast at the temperature of 66 ℃ to obtain the four-layer composite microneedle loaded with ibuprofen and gentamicin.
Example 3
The embodiment provides a preparation method of a four-layer composite microneedle carrying a salbutamol drug and a norfloxacin drug, which comprises the following steps:
(1) preparation of microneedle substrate layer: the experimental die is made of stainless steel materials, a 7 multiplied by 7 microneedle concave truncated cone array is distributed on the die, the distance between adjacent taper holes of the die is 2mm, the diameter of the bottom of a microneedle counter bore (the large diameter of the truncated cone) is 0.25mm, the diameter of the top of the microneedle counter bore (the small diameter of the truncated cone) is 0.05mm, and the depth of the microneedle counter bore is 0.55 mm. The polymer material is Polycarbonate (PC), and the glass transition temperature of the PC is 150 ℃. Placing the microstructure mould and the PC sheet between an upper mould frame and a lower mould frame of micro-hot stamping equipment, and then heating the mould and the PC sheet to a hot stamping temperature of 120 ℃; loading to press the die into the softened PC sheet, adjusting the pressure to 10.00MPa, and keeping the pressure for a certain time to ensure that the PC is fully filled; and (3) maintaining the pressure for 60s after self loading, cooling until the temperature of the PC sheet and the mould is reduced to 10 ℃ below the glass transition temperature of the PC, unloading, and finally demoulding to obtain the insoluble hard substrate microneedle.
(2) Preparation of microneedle drug layer: and (2) placing the base layer microneedle sheet obtained in the step (1) in a rotating chamber with the tip facing downwards by adopting a spraying method, uniformly spraying the prepared salbutamol medicinal solution on the surface of the microneedle, and drying in a vacuum drying oven at 68 ℃ for 5.5 hours. Spraying methanol water solution with volume concentration of 85% on the dried medicine, volatilizing to obtain the microneedle loaded with the salbutamol medicine, spraying norfloxacin medicine solution by using the method, drying and curing to obtain the three-layer composite microneedle loaded with the salbutamol medicine and the norfloxacin medicine.
(3) Preparing a microneedle quick release layer: preparing a sodium hyaluronate solution with the mass fraction of 4%, dipping the multi-layer composite microneedle slice obtained in the step (2) with the needle tip downwards in the prepared sodium hyaluronate solution for 7s, lifting, and drying for 5.5h under the condition of air blast at the temperature of 68 ℃ to obtain the four-layer composite microneedle carrying the salbutamol drug and the norfloxacin drug.
In the embodiment, the prepared polymer microneedle can be stacked in multiple layers within a certain range of the length of the microneedle, so that the types of the drug-loaded substances are increased. And the insoluble substrate is prepared by utilizing the micro-hot stamping process, the process operation is simple, the micro-processing precision is high, and the preparation period is greatly shortened. And the aim of controlling the dissolution speed of the medicine can be achieved by changing the thickness of the outer sodium hyaluronate layer.
Claims (7)
1. A method of making a multilayered polymeric microneedle, comprising the steps of:
step (1) preparation of microneedle substrate layer: placing a microstructure mould and a polymer sheet between an upper mould frame and a lower mould frame of micro-hot stamping equipment, and then heating the mould and the polymer sheet to a hot stamping temperature of 70-200 ℃; loading to press the die into the softened polymer sheet, adjusting the pressure to be 0-20 MPa, and keeping the pressure for a certain time to ensure that the polymer is fully filled; maintaining the pressure for 20-80 s after self loading, cooling until the temperature of the polymer sheet and the mold is reduced to 10 ℃ below the glass transition temperature of the polymer, unloading, and finally demolding to obtain the microneedle product, wherein the microneedle product is a conical microneedle;
step (2) preparation of microneedle drug layer: placing the base layer microneedle sheet obtained in the step (1) in a rotating chamber with the tip facing downwards by adopting a spraying method, uniformly spraying the prepared drug solution on the surface of the microneedle, and drying in a vacuum drying oven at 30-120 ℃ for 2-8 h; spraying a curing inducer to the dried drug layer, wherein the curing inducer comprises a methanol or ethanol aqueous solution with the volume concentration of 70-90% to obtain a polymer microneedle carrying the substrate layer and the drug layer;
preparing a microneedle quick release layer: downwards pointing the microneedle tip of the microneedle sheet loaded with the inner layer and the drug layer obtained in the step (2), preparing a sodium hyaluronate solution with the mass fraction of 1% -20%, dipping the sodium hyaluronate solution in the prepared sodium hyaluronate solution for 1-10 s, lifting, and drying for 2-8 h under the condition of air blowing at the temperature of 30-120 ℃; coating sodium hyaluronate on the outermost layer of the needle body to obtain a polymer microneedle;
the spraying method comprises the steps of placing the obtained substrate layer microneedle in a rotating chamber with the needle tip facing downwards, uniformly spraying the prepared drug solution on the surface of the microneedle, and drying in a vacuum drying oven at 30-120 ℃ for 2-8 hours;
after the spraying process is finished, spraying a curing inducer to the dried medicine layer, wherein the curing inducer comprises a methanol or ethanol aqueous solution with the volume concentration of 70-90%, and the medicine layer is insoluble in water after being volatilized so as to prevent the medicine from being dissolved and diffused;
the spraying method is repeated for 1-4 times, and the polymer microneedle containing multiple drug layers is obtained after solidification after each spraying and drying process.
2. The method of claim 1, wherein the spraying method sprays different kinds of drugs and can be repeated to obtain drug layers with different thicknesses, and the drug layer is an intermediate layer; the intermediate layer is 1-5 layers; the outer sodium hyaluronate layer can control the dissolution speed of the medicine by changing the thickness of the outer sodium hyaluronate layer.
3. The method for preparing a multilayer polymer microneedle according to claim 1, wherein the micro-hot stamping process comprises placing a micro-structure mold and a polymer sheet between an upper mold frame and a lower mold frame of a micro-hot stamping device, and then heating the mold and the polymer sheet to a hot stamping temperature of 70-200 ℃; loading to press the die into the softened polymer sheet, adjusting the pressure to be 0-20 MPa, and keeping the pressure for a certain time to ensure that the polymer is fully filled; and (3) maintaining the pressure for 20-80 s after self loading, cooling until the temperature of the polymer sheet and the mold is reduced to 10 ℃ below the glass transition temperature of the polymer, unloading, and finally demolding to obtain the microneedle product.
4. The method of claim 3, wherein the sodium hyaluronate solution is present in an amount of 1 to 20% by weight.
5. The method of claim 3, wherein the drying temperature of the sodium hyaluronate solution is 30-120 ℃ and the drying time is 2-8 hours.
6. A method of fabricating a multilayered polymer microneedle according to claim 3, wherein the drug is lidocaine, isopyriproxyfen mononitrate, hydrochlorothiazide, efletirizine, salbutamol, acetylsalicylic acid, imipramine, gentamicin, amoxicillin, ampicillin, roxithromycin, norfloxacin or acetylspiramycin.
7. A method of fabricating multilayered polymer microneedles in claim 3, wherein the polymer microneedles are layered structures comprising a base layer, a drug layer and a fast release layer.
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| CN113144273B (en) * | 2021-03-30 | 2022-08-26 | 嘉兴学院 | Drive response composite material and preparation method and application 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 |
| CN114272510B (en) * | 2021-12-27 | 2022-11-01 | 广州纳丽生物科技有限公司 | Soluble microneedle capable of carrying medicine in layered and segmented manner and preparation method thereof |
| CN114712696B (en) * | 2022-04-08 | 2023-06-23 | 北京化工大学 | Method for preparing three-section sustained-administration polymer microneedle |
| CN114834066B (en) * | 2022-04-25 | 2023-09-29 | 武汉纺织大学 | Preparation method of composite multilayer microneedle |
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| CN108392728A (en) * | 2018-02-12 | 2018-08-14 | 南通纺织丝绸产业技术研究院 | A kind of compound micropin of silk fibroin multilayer and preparation method thereof |
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