CN112494639A - Temperature-sensitive microneedle array patch and preparation method thereof - Google Patents
Temperature-sensitive microneedle array patch and preparation method thereof Download PDFInfo
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- CN112494639A CN112494639A CN202110040600.0A CN202110040600A CN112494639A CN 112494639 A CN112494639 A CN 112494639A CN 202110040600 A CN202110040600 A CN 202110040600A CN 112494639 A CN112494639 A CN 112494639A
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- temperature
- microneedle
- sensitive
- hydrophilic monomer
- microneedle array
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract
The invention discloses a temperature-sensitive microneedle array patch and a preparation method thereof, belonging to the field of pharmaceutical preparations. The temperature-sensitive microneedle takes N-isopropyl acrylamide (NIPAm) as a temperature-sensitive material, adopts ultraviolet irradiation to copolymerize the temperature-sensitive material with a hydrophilic monomer, and improves the low critical solution temperature of the NIPAm by introducing the hydrophilic monomer, so that the temperature-sensitive microneedle is more suitable for application. The preparation method of the microneedle is simple and easy to repeat, the array structure is regular, the mechanical strength is good, the microneedle can effectively penetrate through the stratum corneum of the skin, so that the drug is delivered into the body through rich capillary vessels of the dermis layer to play the drug effect; the microneedle has sensitive temperature responsiveness, can adjust the temperature according to the severity of diseases so as to adjust the release dosage of the drug, and effectively avoids weak drug effect or adverse reaction caused by insufficient or excessive drug release.
Description
Technical Field
The invention belongs to the technical field of medicinal preparations, and particularly relates to a temperature-sensitive microneedle array patch for protein polypeptide medicament delivery and a preparation method thereof.
Background
Diabetes mellitus is a chronic metabolic disorder disease characterized by elevated blood sugar, is caused by insufficient insulin produced by pancreatic islets or the body cannot effectively utilize insulin, and is now a serious non-infectious disease worldwide. According to statistics, diabetes affects more than 4.25 million people all over the world, and in 2045 years, the number of diabetic patients reaches 7 million, while 9700 million diabetic patients in China are more than about 1.5 million people in the early stage of diabetes, which are the first in the world.
Insulin is a 51 amino acid peptide secreted by pancreatic islet beta cells that regulates blood glucose levels by stimulating the absorption of glucose from the blood by the liver and muscle cells. Type i diabetics require lifelong insulin therapy and are also commonly used in type ii diabetics with impaired islet beta cell function. Insulin is mainly administered by subcutaneous injection at present, but long-term administration causes inconvenience and pain to patients, may cause infection at injection sites, tissue necrosis and the like, and often induces acute hypoglycemia due to excessive insulin use and is accompanied by fatal risk due to inaccurate control of administration dosage, so timely supply of glucagon is required. In contrast to the hypoglycemic effect of insulin, glucagon promotes glycogenolysis and thus blood glucose elevation.
The transdermal administration mode can avoid gastrointestinal side effects and enzymolysis brought by oral administration, and liver first-pass metabolism, and has the advantages of interrupting administration at any time, but the protein polypeptide drug is difficult to penetrate the stratum corneum of the skin, so the curative effect is very little. The array micro-needle as a novel transdermal drug delivery mode has the advantages of no pain, minimal invasion and the like, and becomes a research hotspot in recent years, and is used for treating diseases such as tumors, diabetes and the like. The length of the membrane is 10-2000 mu m, and the membrane can effectively penetrate through the stratum corneum of the skin, so that biological macromolecules such as hydrophilic drugs, protein polypeptides and the like can be efficiently delivered. Microneedles are largely classified into the following 4 classes: the drug delivery system comprises a solid microneedle, a hollow microneedle, a coated microneedle and a polymer microneedle, wherein the polymer microneedle has the advantages of good biocompatibility, safe drug delivery, low cost and the like, so the drug delivery system has the best application prospect.
Stimulus-responsive drug delivery systems have been receiving attention, which effectively avoid side effects caused by drug overdose by releasing a corresponding dose of drug as needed in response to a specific stimulus at a lesion site or under an applied external stimulus. Endogenous stimulation mainly comprises pH, oxidation-reduction potential, enzyme activity, glucose concentration and the like; the external stimuli are mainly temperature, light, electric field, magnetic field, etc. The advantage of external stimulation over endogenous stimulation is that it does not require consideration of physiological differences between patients and allows precise spatio-temporal control. Of the external stimuli, temperature is the most commonly studied stimulus to control the responsive release of the drug. Poly (N-isopropylacrylamide) (PNIPAm) and its derivatives have received much attention in thermo-responsive materials, have a Low Critical Solution Temperature (LCST) of about 32 ℃, close to the physiological temperature of the human body, and can be improved by copolymerization with hydrophilic monomers (e.g., N-vinyl pyrrolidone NVP) to make them more suitable for use.
Disclosure of Invention
The invention aims to provide a temperature-sensitive microneedle array patch for delivering protein polypeptide drugs, which is prepared by copolymerizing N-isopropylacrylamide (NIPAm) serving as a temperature-sensitive material with hydrophilic monomers and drugs under ultraviolet irradiation to prepare the temperature-sensitive microneedle array patch with temperature responsiveness, so that the diseases such as diabetes and the like are effectively treated.
In order to achieve the purpose, the invention adopts the following technical scheme:
a temperature-sensitive micro-needle array patch comprises a micro-needle array and a backing;
the microneedle array is formed by copolymerizing N-isopropyl acrylamide, hydrophilic monomers, a photoinitiator, a cross-linking agent and a medicament under ultraviolet irradiation;
the back lining is formed by copolymerizing a hydrophilic monomer, a photoinitiator and a cross-linking agent under the irradiation of ultraviolet light.
Further, the hydrophilic monomer is acrylic acid, acrylamide, N-vinyl pyrrolidone, preferably acrylic acid and N-vinyl pyrrolidone.
Further, the photoinitiator is 2-hydroxy-2-methyl-1-phenyl-1-acetone, 1-hydroxycyclohexyl phenyl ketone, 2-methyl-1- (4-methylthiophenyl) -2-morpholine-1-acetone, diphenyl- (2,4, 6-trimethylbenzoyl) oxyphosphorus, 2-hydroxy-4 '- (2-hydroxyethoxy) -2-methyl propiophenone, preferably 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone; the cross-linking agent is ethylene glycol dimethacrylate or N, N-methylene bisacrylamide.
Further, the medicine is protein polypeptides such as insulin, glucagon-like peptide-1, human serum albumin, interleukin, interferon, growth factor, heparin, enzyme, antibody and vaccine, preferably insulin and glucagon.
The preparation method of the temperature-sensitive microneedle array patch comprises the following steps:
step 3, dissolving a cross-linking agent and a photoinitiator in an aqueous solution of a hydrophilic monomer, adding the solution into the microneedle mould in the step 2, and copolymerizing under the irradiation of ultraviolet light to prepare a backing;
and 4, demolding the microneedle array and the backing obtained in the step 3, removing unreacted monomers, and drying to obtain the temperature-sensitive microneedle array patch.
In the invention, the specification of the microneedle array mould is 10 multiplied by 10 to 20 multiplied by 20; the microneedle body in the microneedle array is conical or quadrangular pyramid, the height of the microneedle is preferably 400-.
In the invention, the material is filled into the mould by centrifugation, the centrifugation speed is 1000-10000rpm, and the time is 5-120 min.
Further, in the step 1, the mass ratio of the N-isopropylacrylamide to the hydrophilic monomer is 1:50-5:1, the mass ratio of the hydrophilic monomer to the water in the aqueous solution of the hydrophilic monomer is 1:5-50:1, the mass of the crosslinking agent is 0.01-5% of the total mass of the N-isopropylacrylamide, the hydrophilic monomer and the water, and the mass of the photoinitiator is 0.01-5% of the total mass of the N-isopropylacrylamide, the hydrophilic monomer and the water.
Further, the conditions for copolymerization under ultraviolet irradiation in step 2 are 254-365nm of ultraviolet wavelength, 5-100W of power and 10-60min of time.
Further, in the step 3, the mass ratio of the hydrophilic monomer to the water in the aqueous solution of the hydrophilic monomer is 1:5-50:1, the mass of the cross-linking agent is 0.01-5% of the total mass of the hydrophilic monomer and the water, and the mass of the photoinitiator is 0.01-5% of the total mass of the hydrophilic monomer and the water.
Further, the conditions for copolymerization under ultraviolet irradiation in step 3 are 254-365nm of ultraviolet wavelength, 5-100W of power and 10-60min of time.
Further, in step 4, an impurity removing solution is used to remove unreacted monomers, and the impurity removing solution is selected from deionized water, PBS buffer solution with pH7.4 or normal saline.
Further, the impurity removal solution also comprises ethanol, and the addition amount of the ethanol is 0-20% v/v.
Further, the drying temperature in step 4 is 0 to 25 ℃.
In the invention, the temperature-sensitive microneedle array patch for delivering protein polypeptide drugs is prepared by a simple and easily-repeated method. Hydrophilic monomers in the microneedle material are copolymerized with N-isopropyl acrylamide (NIPAm) under ultraviolet irradiation so as to improve the low critical solution temperature of the NIPAm, and the NIPAm is slightly higher than the body temperature and is more suitable for application. The prepared temperature-sensitive microneedle array has a regular structure and good mechanical strength, can effectively penetrate through the stratum corneum of the skin, so that the drug is delivered into the body through rich capillary vessels of the dermis layer to play a drug effect; the microneedle has sensitive temperature responsiveness, can adjust the temperature according to the severity of diseases so as to adjust the release dosage of the drug, and effectively avoids weak drug effect or adverse reaction caused by insufficient or excessive drug release; in addition, the microneedle has the characteristic of swelling only and insolubility, so that the microneedle has no defects such as residual in vivo polymer and the like. The temperature-sensitive microneedle array patch has good biocompatibility and high loaded drug content, and has wide application prospect in treatment of diabetes and other diseases.
Drawings
FIG. 1 is a schematic diagram of preparation and structure of temperature-sensitive microneedle NIPAm-NVP.
FIG. 2 is a morphological diagram of the prepared temperature-sensitive microneedle NIPAm-NVP loaded with insulin.
FIG. 3 is a prepared temperature-sensitive microneedle NIPAm-NVP fluorescence picture loaded with insulin-FITC.
FIG. 4 shows in vitro release data of prepared insulin-FITC-loaded temperature-sensitive microneedle NIPAm-NVP and non-temperature-sensitive microneedle NVP.
FIG. 5 shows temperature cycle data of prepared temperature-sensitive microneedles NIPAm-NVP loaded with insulin-FITC and non-temperature-sensitive microneedles NVP.
FIG. 6 is a picture of the prepared temperature-sensitive microneedle NIPAm-NVP skin puncture loaded with insulin.
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
Preparation of temperature-sensitive microneedle NIPAm-NVP loaded with insulin
And 3, carefully demolding the microneedle array patch crude product prepared in the step 2, and soaking the microneedle array patch crude product in PBS (phosphate buffer solution) with the pH value of 7.4 for 24 hours to remove unreacted monomers. The gel was then placed in a low temperature desiccator, preferably allochroic silica gel, and dried overnight for subsequent experiments.
Example 2
Preparation of temperature-sensitive microneedle NIPAm-AAc loaded with insulin
And 3, carefully demolding the microneedle array patch crude product prepared in the step 2, and soaking the microneedle array patch crude product in PBS (phosphate buffer solution) with the pH value of 7.4 for 24 hours to remove unreacted monomers. The gel was then placed in a low temperature desiccator, preferably allochroic silica gel, and dried overnight for subsequent experiments.
Example 3
Preparation of glucagon-loaded temperature-sensitive microneedle NIPAm-NVP
And 3, carefully demolding the microneedle array patch crude product prepared in the step 2, and soaking the microneedle array patch crude product in PBS (phosphate buffer solution) with the pH value of 7.4 for 24 hours to remove unreacted monomers. The gel was then placed in a low temperature desiccator, preferably allochroic silica gel, and dried overnight for subsequent experiments.
FIG. 1 is a schematic diagram of the preparation and structure of temperature-sensitive microneedle NIPAm-NVP.
FIG. 2 is a morphological diagram of the prepared temperature-sensitive microneedle NIPAm-NVP loaded with insulin.
Example 4
In-vitro release experiment of temperature-sensitive microneedle NIPAm-NVP loaded with insulin-FITC
Step 3, the microneedle array prepared in step 2 was placed in 1mL of PBS buffer solution of ph7.4, and placed in water baths at 25, 33, and 39 ℃ for in vitro release experiments. At preset time points (0, 2,4,6, 8, 10, 12 h) 50 μ L was sampled and an equal volume of release medium was made up.
And 4, taking 20 mu L of the sample obtained in the step 3, putting the sample into a 96-well plate, supplementing the sample to 200 mu L by adopting PBS (phosphate buffer solution) with pH7.4, and putting the sample into a microplate reader for fluorescence quantitative detection. Detection conditions are as follows: the excitation wavelength is 485nm and the emission wavelength is 528 nm.
FIG. 3 is a prepared temperature-sensitive microneedle NIPAm-NVP fluorescence picture loaded with insulin-FITC.
FIG. 4 shows in vitro release data of prepared insulin-FITC-loaded temperature-sensitive microneedle NIPAm-NVP and non-temperature-sensitive microneedle NVP. As can be seen from the data in the figure, when the mass ratio of NIPAm to NVP is 5:4, the rate and dose of release of insulin-FITC in the 39 ℃ water bath are higher than those of the other groups, and the NVP group has no temperature-sensitive release characteristic.
Example 5
Temperature cycle experiment of temperature-sensitive microneedle NIPAm-NVP loaded with insulin-FITC
And 3, taking 20 mu L of the sample obtained in the step 2, putting the sample into a 96-well plate, supplementing the sample to 200 mu L by adopting PBS (phosphate buffer solution) with pH7.4, and putting the sample into a microplate reader for fluorescence quantitative detection. Detection conditions are as follows: the excitation wavelength is 485nm and the emission wavelength is 528 nm.
FIG. 5 shows temperature cycle data of prepared temperature-sensitive microneedles NIPAm-NVP loaded with insulin-FITC and non-temperature-sensitive microneedles NVP. The data in the figure show that the NIPAm-NVP group releases more rapidly in the water bath at 39 ℃ and releases more slowly in the water bath at 35 ℃, which indicates that the NIPAm-NVP group has good temperature sensitivity.
Example 6
Skin puncture experiment of temperature-sensitive microneedle NIPAm-NVP loaded with insulin
FIG. 6 is a picture of the prepared temperature-sensitive microneedle NIPAm-NVP skin puncture loaded with insulin. The regular array formed after the skin is punctured by the microneedles can be clearly seen from the picture, which shows that the microneedle has good mechanical strength, can effectively puncture the stratum corneum of the skin, and has application prospect.
The above is only a preferred embodiment of the present invention and is not intended to limit the present invention, and it should be noted that modifications or substitutions made to the method, steps or conditions of the present invention are within the scope of the present invention without departing from the technical principle of the present invention.
Claims (10)
1. A temperature-sensitive micro-needle array patch is composed of a micro-needle array and a backing, and is characterized in that:
the microneedle array is formed by copolymerizing N-isopropyl acrylamide, hydrophilic monomers, a photoinitiator, a cross-linking agent and a medicament under ultraviolet irradiation;
the back lining is formed by copolymerizing a hydrophilic monomer, a photoinitiator and a cross-linking agent under the irradiation of ultraviolet light.
2. The temperature-sensitive microneedle array patch according to claim 1, wherein: the hydrophilic monomer is selected from acrylic acid, acrylamide or N-vinyl pyrrolidone.
3. The temperature-sensitive microneedle array patch according to claim 1, wherein: the photoinitiator is selected from 2-hydroxy-2-methyl-1-phenyl-1-acetone, 1-hydroxycyclohexyl phenyl ketone, 2-methyl-1- (4-methylthiophenyl) -2-morpholine-1-acetone, diphenyl- (2,4, 6-trimethylbenzoyl) oxyphosphorus or 2-hydroxy-4' - (2-hydroxyethoxy) -2-methyl propiophenone; the cross-linking agent is ethylene glycol dimethacrylate or N, N-methylene bisacrylamide.
4. The temperature-sensitive microneedle array patch according to claim 1, wherein: the drug is selected from insulin, glucagon-like peptide-1, human serum albumin, interleukins, interferons, growth factors, heparin, enzymes, antibodies or vaccines.
5. The method for preparing a temperature-sensitive microneedle array patch according to claim 1, wherein: the method comprises the following steps:
step 1, dissolving N-isopropyl acrylamide, a cross-linking agent and a photoinitiator in an aqueous solution of a hydrophilic monomer, dissolving a drug in a benign solvent, and uniformly mixing the two;
step 2, filling the mixed solution obtained in the step 1 into a microneedle array mould, and carrying out copolymerization under the irradiation of ultraviolet light to obtain a microneedle array;
step 3, dissolving a cross-linking agent and a photoinitiator in an aqueous solution of a hydrophilic monomer, adding the solution into the microneedle mould in the step 2, and copolymerizing under the irradiation of ultraviolet light to prepare a backing;
and 4, demolding the microneedle array and the backing obtained in the step 3, removing unreacted monomers, and drying to obtain the temperature-sensitive microneedle array patch.
6. The production method according to claim 3, characterized in that: in the step 1, the mass ratio of the N-isopropyl acrylamide to the hydrophilic monomer is 1:50-5:1, the mass ratio of the hydrophilic monomer to water in the aqueous solution of the hydrophilic monomer is 1:5-50:1, the mass of the cross-linking agent is 0.01-5% of the total mass of the N-isopropyl acrylamide, the hydrophilic monomer and the water, and the mass of the photoinitiator is 0.01-5% of the total mass of the N-isopropyl acrylamide, the hydrophilic monomer and the water.
7. The production method according to claim 3, characterized in that: the copolymerization condition under the ultraviolet irradiation in the step 2 is that the ultraviolet wavelength is 254-.
8. The production method according to claim 3, characterized in that: in the step 3, the mass ratio of the hydrophilic monomer to the water in the aqueous solution of the hydrophilic monomer is 1:5-50:1, the mass of the cross-linking agent is 0.01-5% of the total mass of the hydrophilic monomer and the water, and the mass of the photoinitiator is 0.01-5% of the total mass of the hydrophilic monomer and the water.
9. The production method according to claim 3, characterized in that: the copolymerization in the step 3 under the irradiation of ultraviolet light is carried out under the conditions of the ultraviolet wavelength of 254-.
10. The production method according to claim 3, characterized in that: in step 4, removing unreacted monomers by using an impurity removal solution, wherein the impurity removal solution is selected from deionized water, PBS buffer solution with pH7.4 or normal saline.
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| CN115120552A (en) * | 2022-06-22 | 2022-09-30 | 华中科技大学 | Polypeptide drug-loaded microneedle patch capable of releasing drug in microenvironment response manner, preparation and application |
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| US20160045720A1 (en) * | 2014-08-18 | 2016-02-18 | Noven Pharmaceuticals, Inc. | Microneedle device and methods |
| CN109011131A (en) * | 2018-07-03 | 2018-12-18 | 华中科技大学 | A kind of temperature-responsive discharges soluble micropin and its application of drug |
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| US20160045720A1 (en) * | 2014-08-18 | 2016-02-18 | Noven Pharmaceuticals, Inc. | Microneedle device and methods |
| CN109011131A (en) * | 2018-07-03 | 2018-12-18 | 华中科技大学 | A kind of temperature-responsive discharges soluble micropin and its application of drug |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115120552A (en) * | 2022-06-22 | 2022-09-30 | 华中科技大学 | Polypeptide drug-loaded microneedle patch capable of releasing drug in microenvironment response manner, preparation and application |
| 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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