CN111450403A - Microneedle array for rapid transdermal delivery of protein drugs and preparation method thereof - Google Patents
Microneedle array for rapid transdermal delivery of protein drugs and preparation method thereof Download PDFInfo
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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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
- A61K38/212—IFN-alpha
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- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
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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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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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 provides a microneedle array for rapid transdermal delivery of protein drugs and a preparation method thereof, belonging to the technical field of biological medicines. The microneedle array prepared by the invention is simple and convenient to use, has short application time of only 10 s-1 min, can be taken away after application, is convenient for patients to self-administer, has the characteristics of minimal invasion and no pain, and can improve the compliance of the patients. The drug is released rapidly, and the pharmacokinetics and pharmacodynamics equivalent to those of common subcutaneous injection can be obtained.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a microneedle array for rapid transdermal delivery of protein medicines and a preparation method thereof.
Background
Many patients with disease require frequent injections or infusions of proteinaceous drugs to treat or alleviate symptoms. The traditional subcutaneous injection administration mode causes pain, thus reducing the compliance of patients and easily causing local adverse reactions; meanwhile, protein drugs are easy to degrade and difficult to absorb in the digestive system, and are not suitable for oral administration; and because of the higher molecular weight and stronger hydrophilicity of protein drugs, the traditional transdermal and transmucosal administration has extremely low administration efficiency. In the last two decades, the research on the transdermal drug delivery of the micro-needle has made great progress and is expected to replace the traditional injection administration mode. Microneedles, typically 200-4000 microns in length, can pierce the stratum corneum layer of the skin and deliver the proteinaceous agent to the more hydrophilic dermis layer and into the systemic circulation. The micro-needle has small size, can not cause obvious wound, can not touch nerves to cause pain, and is very simple and convenient to use.
The traditional coated microneedle has low drug load capacity and complex preparation process, and the drug delivery speed is slow, and the patent (application No. US: 201715437927: A) simply and conveniently carries the drug on the microneedle accurately and efficiently by a layer-by-layer self-assembly (L B L) technology.
Disclosure of Invention
In view of this, the present invention aims to provide a microneedle array for rapid transdermal delivery of protein drugs and a method for preparing the same, which can rapidly achieve transdermal delivery of protein drugs.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides a microneedle array for rapid transdermal delivery of protein drugs, which structurally comprises a microneedle array substrate and a drug-loaded release layer deposited on the surface of a microneedle, wherein the drug-loaded release layer is composed of a layer-by-layer self-assembled film formed by electrostatic interaction of protein drugs and anionic polyelectrolyte.
Preferably, the protein drug has an isoelectric point of less than 7.
Preferably, the protein drug comprises one or more of insulin, interferon α -2b, bovine serum albumin, carbonic anhydrase and adrenocorticotropic hormone.
Preferably, the anionic polyelectrolyte comprises one or more of polyglutamic acid, polyaspartic acid, hyaluronic acid, chondroitin sulfate, heparin, polyacrylic acid, polymethacrylic acid and polystyrene sulfonic acid.
The invention also provides a preparation method of the microneedle array in the technical scheme, which comprises the following steps: and alternately soaking the blank microneedle array in a protein drug solution and an anion polyelectrolyte solution, and drying to obtain the microneedle array.
Preferably, the concentration of the protein drug solution is 1 mu g/ml-1 g/ml, and the pH value is 2.5-4; the concentration of the anionic polyelectrolyte solution is 1 mu g/ml-1 g/ml, and the pH value is 2.5-4.
Preferably, the soaking temperature is 1-37 ℃, and the soaking time is 10 s-30 min each time.
The invention provides a microneedle array for rapid transdermal delivery of protein drugs, which structurally comprises a microneedle array substrate and a drug-loaded release layer deposited on the surface of a microneedle, wherein the drug-loaded release layer is composed of a layer-by-layer self-assembled film formed by electrostatic interaction of protein drugs and anionic polyelectrolyte.
The invention utilizes the electrostatic interaction between protein drugs and anion polyelectrolyte, and carries out layer-by-layer self-assembly of the protein drugs and the anion polyelectrolyte on the surface of a blank microneedle array by simple alternate soaking under the condition of low pH to form a layer-by-layer self-assembly film with pH sensitivity, namely a drug-loaded layer. After the microneedle array for rapidly and transdermally delivering protein drugs disclosed by the invention is inserted into skin, net charge of the loaded protein drugs is reversed due to the change of the pH value of the environment where the drug-loaded layer is located, so that the layer-by-layer self-assembled film is rapidly dissociated and the protein drugs are released, and the safe and rapid transdermal delivery of the protein drugs is realized.
The invention has the following beneficial effects:
the microneedle array prepared by the invention is simple and convenient to use, has short application time of only 10 s-1 min, can be taken away after application, and is convenient for patients to self-administer drugs.
Has the advantages of minimal invasion and no pain, and can improve compliance of patients.
After the microneedle array prepared by the invention is penetrated into the skin, the net charge of the protein drug is reversed electrically and is converted into mutual repulsion with the anionic polyelectrolyte from mutual attraction, so that the drug-loaded layer is instantaneously dissociated, and the protein drug is immediately released.
The protein drug administration is carried out by utilizing the microneedle array prepared by the invention, and the drug release is rapid. The pharmacokinetics are comparable to normal subcutaneous injection.
The protein drug administration is carried out by utilizing the microneedle array prepared by the invention, and the drug takes effect quickly. The pharmacodynamic curve is comparable to that of ordinary subcutaneous injection.
Drawings
Fig. 1 is a schematic diagram of transdermal delivery of protein drugs by a microneedle array prepared according to the present invention, wherein a in fig. 1 is a drug-loaded layer (layer-by-layer self-assembled film) formed by layer-by-layer self-assembly on microneedles in an acidic environment, wherein the protein drugs with positive net charges and polyelectrolytes with negative net charges are combined through electrostatic interaction; in fig. 1, B is a graph showing that after the microneedle array loaded with the drug-loaded layer (layer-by-layer self-assembled film) is inserted into the skin, the net charge of the protein drug is reversed, and the protein drug is repelled from the polyelectrolyte, so that the drug-loaded release layer dissociates rapidly and releases the protein drug into the skin;
FIG. 2 is a shape difference of a polymethyl methacrylate microneedle loaded with a drug-loaded release layer (insulin/poly-L-glutamic acid layer-by-layer self-assembled film) and a blank microneedle under the observation of a scanning electron microscope, wherein A in FIG. 2 is a surface shape of the blank polymethyl methacrylate microneedle array after being magnified by 100 times, B in FIG. 2 is a surface shape of the blank polymethyl methacrylate microneedle after being magnified by 1000 times, C in FIG. 2 is a surface shape of the polymethyl methacrylate microneedle array loaded with the insulin/poly-L-glutamic acid layer-by-layer self-assembled film after being magnified by 100 times, and D in FIG. 2 is a surface shape of the polymethyl methacrylate microneedle loaded with the insulin/poly-L-glutamic acid layer-by-layer self-assembled film after being magnified by 1000 times;
fig. 3 is a cumulative in vitro insulin release profile for a microneedle array loaded with a drug-loaded release layer ("insulin/poly-L-glutamate" layer-by-layer self-assembled film);
fig. 4 is a graph comparing the variation curve of blood concentration of rats after the drug-loaded release layer (insulin/poly-L-glutamic acid layer-by-layer self-assembled film) loaded polymethyl methacrylate microneedle array and subcutaneous injection are performed on type I diabetic SD rats, and the blank microneedle array is applied to the rats as a control.
Fig. 5 is a graph comparing the variation curve of blood glucose level of rats after the administration of insulin to type I diabetic SD rats by subcutaneous injection and a polymethyl methacrylate microneedle array loaded with a drug-loaded release layer ("insulin/poly-L-glutamic acid" layer-by-layer self-assembled film), and rats coated with a blank microneedle array are used as a control.
Detailed Description
The invention provides a microneedle array for rapid transdermal delivery of protein drugs, which structurally comprises a microneedle array substrate and a drug-loaded release layer deposited on the surface of a microneedle, wherein the drug-loaded release layer is composed of a layer-by-layer self-assembled film formed by electrostatic interaction of protein drugs and anionic polyelectrolyte.
In the invention, the isoelectric point of the protein drug is preferably less than 7. in the invention, the protein drug preferably comprises one or more of insulin, interferon α -2b, bovine serum albumin, carbonic anhydrase and adrenocorticotropic hormone.
In the present invention, the anionic polyelectrolyte preferably includes polyglutamic acid, polyaspartic acid, hyaluronic acid, chondroitin sulfate, heparin, polyacrylic acid, polymethacrylic acid, and polystyrene sulfonic acid.
In the present invention, the material of the microneedle array substrate preferably includes metal, silicon dioxide, glass, or a high molecular polymer. In the present invention, the metal preferably includes stainless steel, copper alloy, aluminum alloy, titanium alloy, nickel or nickel alloy. In the present invention, the high molecular polymer preferably includes polymethylmethacrylate, polystyrene, polylactic acid, or polylactic acid-glycolic acid copolymer.
The invention also provides a preparation method of the microneedle array in the technical scheme, which comprises the following steps: and alternately soaking the blank microneedle array in a protein drug solution and an anion polyelectrolyte solution, and drying to obtain the microneedle array.
In the invention, the concentration of the protein drug solution is preferably 1 mu g/ml-1 g/ml, and the pH value is preferably 2.5-4; the concentration of the anionic polyelectrolyte solution is preferably 1 mu g/ml-1 g/ml, and the pH value is preferably 2.5-4. In the present invention, the isoelectric point of the anionic polyelectrolyte solution is lower than that of the protein drug solution.
In the invention, the soaking temperature is preferably 1-37 ℃, more preferably 10-25 ℃, and most preferably 15-20 ℃; the time of each soaking is preferably 10 s-30 min, more preferably 4-20 min, and most preferably 5-6 min. In the invention, the drying time is preferably 10 s-48 h, and the drying temperature is preferably 1-37 ℃.
In the present invention, the method of using the microneedle array preferably includes: inserting the microneedle array into a subject. In the present invention, the time for the insertion is preferably 10s to 1 min. In the invention, after the micro-needle array is inserted into a subject, the net charge of the protein drug is reversed electrically, the layer-by-layer self-assembled film is rapidly dissociated, and the protein drug is released.
The technical solutions provided by the present invention are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Polymethyl methacrylate microneedle arrays loaded with a drug-loaded layer ("insulin/poly-L-glutamate" layer-by-layer self-assembled film) were prepared.
The preparation method comprises the specific steps of respectively dissolving insulin and poly-L-glutamic acid in glycine-hydrochloric acid buffer solution (pH is 3.5), wherein the concentrations are 1mg/m L, alternately soaking polymethyl methacrylate microneedle arrays (needle bodies 600 mu m long and 10 × 10 arrayed) in the two solutions for 5min each time, wherein the number of the cycles is 1, the temperature of the system is controlled to be 25 ℃, the cycles are repeated for 20 times, and the drug is obtained after drying.
Example 2
A polylactic acid-glycolic acid copolymer (P L GA) microneedle array loaded with a drug-loaded release layer ("interferon α -2 b/polyaspartic acid" layer-by-layer self-assembled film) was prepared.
The preparation method comprises dissolving interferon α -2b and polyaspartic acid in potassium chloride-hydrochloric acid buffer solution (pH 3.5) respectively, wherein the concentrations are 0.5mg/m L, alternately soaking P L GA microneedle arrays (700 μm long needle body, 15 × 15 array) in the two solutions for 4min each time, 1 cycle is 1 layer, controlling the temperature of the system at 20 deg.C, repeating the cycle for 15 times, and drying.
Example 3
A stainless steel microneedle array loaded with a drug-loaded release layer ("bovine serum albumin/hyaluronic acid" layer-by-layer self-assembled film) was prepared.
The preparation method comprises dissolving bovine serum albumin and hyaluronic acid in disodium hydrogen phosphate/citric acid buffer solution (pH 3.5) respectively at concentration of 2mg/m L, alternately soaking microneedle arrays (304 stainless steel, 800 μm long needle body, and 20 × 20 arranged) in the two solutions for 6min each time, 1 cycle for 1 layer, controlling system temperature at 30 deg.C, repeating the cycle for 10 times, and drying.
Example 4
An aluminum microneedle array was prepared loaded with a drug-loaded release layer ("carbonic anhydrase/heparin" layer-by-layer self-assembled film).
The preparation method comprises dissolving carbonic anhydrase and heparin in phthalic acid-hydrochloric acid buffer solution (pH 3.0) respectively at concentration of 5mg/m L, alternately soaking aluminum microneedle array (needle 500 μm long and 8 × 10 arranged) in the two solutions for 10min each time, 1 cycle for 1 layer, controlling system temperature at 15 deg.C, repeating the cycle for 30 times, and drying.
Example 5
Copper microneedle arrays loaded with a drug-loaded release layer ("corticotropin/polyacrylic acid" layer-by-layer self-assembled film) were prepared.
The preparation method comprises dissolving corticotropin and polyacrylic acid in acetic acid-sodium acetate buffer solution (pH 4.0) respectively at concentration of 8mg/m L, alternately soaking copper microneedle array (needle 900 μm long and 10 × 15 arranged) in the two solutions for 20min each time, 1 cycle for 1 layer, controlling system temperature at 25 deg.C, repeating the cycle for 50 times, and drying.
Example 6
Silica microneedle arrays were prepared loaded with a drug-loaded release layer ("interferon α 2 b/chondroitin sulfate" layer-by-layer self-assembled film).
The preparation method comprises dissolving interferon α 2b and chondroitin sulfate in citric acid-hydrochloric acid buffer solution (pH 2.5) respectively, wherein the concentration is 0.1mg/m L, alternately soaking silicon dioxide microneedle array (needle 400 μm long and 10 × 10 arranged) in the two solutions for 6min each time, 1 cycle is 1 layer, controlling the temperature of the system at 10 deg.C, repeating the cycle for 25 times, and drying.
Example 7
Polymethyl methacrylate microneedle arrays loaded with a drug-loaded release layer ("insulin/poly-L-glutamate" layer-by-layer self-assembled film).
After the surface of the microneedle array is dried, gold spraying is carried out for scanning electron microscope observation, the surface morphology of the microneedle array shown in figure 2 can be seen, and the cracked deposition layer shows that the drug-loaded release layer, namely the self-assembled membrane of the layers of the insulin/poly-L-glutamic acid, is successfully loaded on the polymethyl methacrylate microneedle array.
Example 8
In vitro release kinetics of drug-loaded release layer loaded microneedle arrays
The microneedle array (prepared by the same method as in example 1) loaded with the drug-loaded release layer ('insulin/poly-L-glutamic acid' layer-by-layer self-assembled film) was soaked in phosphate buffer (pH7.4), and the content of insulin in the soaking solution was detected by high performance liquid chromatography, the cumulative release amount of insulin is shown in FIG. 3, and it can be seen that the drug-loaded release layer ('insulin/poly-L-glutamic acid' layer-by-layer self-assembled film) on the microneedle array rapidly dissociates at pH7.4, and releases all insulin within 30 seconds.
The release kinetics of the drug-loaded release layers prepared in examples 2-7 were similarly determined in phosphate buffer at ph 7.4. As a result, the loaded protein was completely released in 30 seconds.
Example 9
Microneedle arrays loaded with a drug-loaded release layer ("insulin/poly-L-glutamate" layer-by-layer self-assembled film) delivered insulin transdermally to rats.
The transdermal administration effect of microneedle arrays loaded with drug-loaded release layers ("insulin/poly-L-glutamate" layer-by-layer self-assembled films) was evaluated in a type I diabetic SD rat model induced by Streptozotocin (STZ). type I SD rats (weighing around 300 g) were shaved off the back hair and fasted for 8h, randomized into three groups: 1) were administered with microneedle arrays (prepared in the same manner as in example 1) loaded with drug-loaded release layers ("insulin/poly-L-glutamate" layer-by-layer self-assembled films) to the skin for 1 min; 2) human recombinant insulin (0.25 IU/each) was subcutaneously injected with a blank polymethylmethacrylate microneedle array to the skin for 1min layer by layer after administration, 1min layer by layer after administration and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h after administration, each rat collected with ocular venous blood of 0.1m L, the blood glucose level of the rat was monitored layer by layer after layer by layer-layer upon layer rpm, the serum concentration of insulin loaded from the drug-loaded release layers ("insulin array after injection), the injection, the insulin loaded release layers was measured as well as the blood glucose concentration change after subcutaneous insulin-loaded from insulin-loaded microneedle arrays (" insulin-loaded self-assembled films) after injection, the injection of insulin-loaded microneedle arrays after the injection of insulin-loaded microneedle arrays showed the blood glucose concentration change in the subcutaneous insulin-loaded microneedle array after injection, as shown in the blood-loaded microneedle array after the blood-loaded microneedle array was synthesized blood-loaded insulin-loaded microneedle array after the blood-loaded microneedle array was synthesized blood-loaded insulin-loaded microneedle array was injected with the blood-loaded insulin-loaded microneedle array after the.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A microneedle array for rapid transdermal delivery of protein drugs structurally comprises a microneedle array substrate and a drug-loaded release layer deposited on the surface of microneedles, and is characterized in that the drug-loaded release layer is composed of a layer-by-layer self-assembled film formed by electrostatic interaction of protein drugs and anionic polyelectrolyte.
2. A microneedle array according to claim 1, wherein the protein drug has an isoelectric point of less than 7.
3. A microneedle array according to claim 1 or 2, wherein the protein drug comprises one or more of insulin, interferon α -2b, bovine serum albumin, carbonic anhydrase and corticotropin.
4. The microneedle array according to claim 1, wherein the anionic polyelectrolyte comprises one or more of polyglutamic acid, polyaspartic acid, hyaluronic acid, chondroitin sulfate, heparin, polyacrylic acid, polymethacrylic acid, and polystyrene sulfonic acid.
5. The microneedle array according to claim 1, wherein the material of the microneedle array substrate comprises one or more of metal, silicon, silica, glass, and high molecular polymer.
6. A method of preparing a microneedle array according to any one of claims 1 to 5, comprising: and alternately soaking the blank microneedle array in a protein drug solution and an anion polyelectrolyte solution, and drying to obtain the microneedle array.
7. The method according to claim 6, wherein the protein drug solution has a concentration of 1 μ g/ml to 1g/ml, a pH of 2.5 to 4; the concentration of the anionic polyelectrolyte solution is 1 mu g/ml-1 g/ml, and the pH value is 2.5-4.
8. The preparation method according to claim 6, wherein the soaking temperature is 1-37 ℃ and the time for each soaking is 10 s-30 min.
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| CN112494729A (en) * | 2020-12-02 | 2021-03-16 | 健诺维(成都)生物科技有限公司 | Drug-containing tissue graft and preparation method and application thereof |
| WO2021196546A1 (en) * | 2020-04-03 | 2021-10-07 | 南开大学 | Microneedle array for rapid transdermal delivery of protein drugs and preparation method therefor |
| CN113980093A (en) * | 2021-10-25 | 2022-01-28 | 河北工业大学 | Method for promoting protein medicine crystallization by polymer and application |
| CN114699510A (en) * | 2021-12-29 | 2022-07-05 | 浙江湃肽生物有限公司 | Simelide microneedle array and preparation method thereof |
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| CN114470170B (en) * | 2022-02-22 | 2023-09-19 | 广州新济药业科技有限公司 | Semiglutide soluble microneedle composition and preparation method thereof |
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| CN105078880A (en) * | 2015-09-12 | 2015-11-25 | 北京化工大学 | Macromolecular soluble microneedle used for cutaneous penetration of polypeptide and protein medicines and preparation method of macromolecular soluble microneedle |
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| CN107929810A (en) * | 2017-12-01 | 2018-04-20 | 浙江大学 | A kind of LBL self-assembly film and its preparation method and application |
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| WO2021196546A1 (en) * | 2020-04-03 | 2021-10-07 | 南开大学 | Microneedle array for rapid transdermal delivery of protein drugs and preparation method therefor |
| CN112494729A (en) * | 2020-12-02 | 2021-03-16 | 健诺维(成都)生物科技有限公司 | Drug-containing tissue graft and preparation method and application thereof |
| CN112494729B (en) * | 2020-12-02 | 2022-01-28 | 健诺维(成都)生物科技有限公司 | Drug-containing tissue graft and preparation method and application thereof |
| CN113980093A (en) * | 2021-10-25 | 2022-01-28 | 河北工业大学 | Method for promoting protein medicine crystallization by polymer and application |
| CN114699510A (en) * | 2021-12-29 | 2022-07-05 | 浙江湃肽生物有限公司 | Simelide microneedle array and preparation method thereof |
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