CN112237574A - Recombinant hirudin micro-needle drug delivery system and preparation method thereof - Google Patents
Recombinant hirudin micro-needle drug delivery system and preparation method thereof Download PDFInfo
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- CN112237574A CN112237574A CN201910666064.8A CN201910666064A CN112237574A CN 112237574 A CN112237574 A CN 112237574A CN 201910666064 A CN201910666064 A CN 201910666064A CN 112237574 A CN112237574 A CN 112237574A
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- microneedle
- recombinant hirudin
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- 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
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
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- A—HUMAN NECESSITIES
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- 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
- A61K47/36—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
- 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
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention belongs to the technical field of biological medicines, and relates to a recombinant hirudin micro-needle drug delivery system and a preparation method thereof. The recombinant hirudin microneedle drug delivery system comprises a backing patch and a microneedle body positioned at the bottom of the backing patch, wherein the microneedle body is internally loaded with recombinant hirudin, and the microneedle substrate is a water-soluble biodegradable high polymer material. Compared with the existing administration mode, the microneedle drug delivery system can remarkably relieve the pain caused by repeated injection, has stable drug activity and is convenient to store and transport.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a recombinant hirudin micro-needle drug delivery system and a preparation method thereof.
Background
Results of WHO surveys show that cardiovascular disease is the leading cause of death worldwide. At present, the main prevention and treatment measures for cardiovascular diseases are anticoagulant drug intervention, and the traditional anticoagulant drugs are mainly administered orally, intravenously and subcutaneously (as shown in fig. 1), but practice shows that clinical administration is limited due to certain defects. Wherein, the oral administration can cause gastrointestinal bleeding, the gastrointestinal patients have limited use, the degradation of the gastrointestinal tract can reduce the bioavailability of the medicament, the liver first-pass effect is still carried out even if the medicament is absorbed, and the bioavailability of the medicament is reduced again; in addition to the discomfort of pain and the like brought to patients by injection, a large amount of medical waste is generated, in addition, the risks of bleeding, infection, blood stasis and the like exist, the operation is inconvenient, the daily medication cannot be maintained, most of patients with cardiovascular and cerebrovascular diseases need to take anticoagulant drugs for all the life, and a safe and effective drug delivery mode which is convenient to administer is needed.
Studies have shown that thrombus (thrombosis) formation is a pathological hemostatic condition, and intravascular blood thrombosis can lead to vascular occlusion, organ damage and serious cardiovascular disease, including myocardial infarction and stroke; cardiovascular and cerebrovascular thrombotic diseases have become one of the main causes of cardiovascular death rate in the world; the anticoagulant drug can prevent and delay blood flow obstruction, reduce the occurrence rate of thrombus diseases and thrombus after thrombolytic therapy, and is the first line of prevention and treatment of thrombus.
The natural hirudin is a direct thrombin inhibitor, can be directly combined with an inactive substrate recognition site of thrombin, only has inhibition effect on the thrombin, and has no effect on other blood coagulation factors in plasma; has the advantages of strong anticoagulation effect, specific effect, small side effect and the like. Research reports that RGD in recombinant Hirudin (r-RGD-Hirudin) can antagonize the combination of platelet and fibrin and inhibit platelet aggregation; therefore, the medicine has the dual effects of anticoagulation and thrombus prevention, can prevent and treat venous thrombosis and arterial thrombosis simultaneously, has the dosage of only half of that of hirudin, and has small side effect, and stable and lasting effect.
In clinical practice, the protein/polypeptide anticoagulant antithrombotic agent is usually administered by intravenous injection, so that the compliance of patients is poor and the long-term administration is inconvenient; the drugs are also not suitable for oral administration, because the activity of the drugs is easily damaged by the acid environment of the gastrointestinal tract and digestive enzymes; subcutaneous injection is also the commonly selected administration route of the medicines, but subcutaneous injection has poor compliance to patients and has the defects of increased anticoagulation, high hemostasis difficulty and the like. In addition, the precise dosage control of anticoagulant antithrombotic agents is required, insufficient or excessive doses can lead to serious consequences, and timely and precise delivery of anticoagulant antithrombotic agents is critical for cardiovascular patients, and thus, the treatment of thrombotic diseases urgently requires a controlled and on-demand drug delivery system that can improve therapeutic efficacy while minimizing side effects and treatment time.
Microneedle transdermal delivery is increasingly being used. The structure of the skin is roughly divided into three layers: the injection is characterized by comprising a horny layer, an epidermal layer and a dermis layer, wherein the dermis layer is provided with abundant blood vessels and neurons, and the injection can bring discomforts such as pain and even cause infection; the existence of stratum corneum, a biological barrier, also limits the application range of the patch; for anticoagulant drugs, gastrointestinal side effects caused by oral administration are inevitable, and the problems can be well solved by the micro-needle which penetrates through the stratum corneum to touch the superficial epidermis but does not penetrate through the epidermis, and the administration mode combines the drug release advantages of two modes, namely injection and patch (as shown in figure 2).
The concept of microneedles was formally proposed in 1998, the technology is already basically mature after optimization processing, the delivery of microneedles of several drugs is realized, but most of them are mainly nucleic acid vaccines, only a few of them are low-molecular protein drugs such as low-molecular heparin, insulin, growth hormone and the like, and most of them stay in the in vitro experimental stage.
Based on the current situation of the prior art, the inventor of the application intends to provide a recombinant hirudin micro-needle drug delivery system and a preparation method thereof, so as to realize transdermal delivery of recombinant hirudin, avoid degradation or activity influence of a digestive system on the recombinant hirudin, realize relatively accurate anticoagulant regulation, have good patient compliance, realize autonomous drug delivery, and be suitable for patients with thrombotic diseases who need repeated long-term drug administration.
Disclosure of Invention
The invention aims to provide a recombinant hirudin micro-needle drug delivery system and a preparation method thereof based on the current situation of the prior art, so as to realize transdermal delivery of recombinant hirudin, avoid the degradation or activity influence of a digestive system on the recombinant hirudin, realize relatively accurate anticoagulant regulation, have good patient compliance, realize self-administration and be suitable for patients with thrombotic diseases who need to take drugs repeatedly for a long time.
The micro-needle drug delivery system of the recombinant hirudin can ensure that the recombinant hirudin is accurately delivered to the body through the skin to play the roles of anticoagulation and thrombosis prevention.
Specifically, the recombinant hirudin microneedle drug delivery system comprises a backing patch and a microneedle body positioned at the bottom of the backing patch, wherein the microneedle body has excellent mechanical strength and carries recombinant hirudin capable of meeting the clinical drug requirement;
in the invention, the microneedle substrate is a water-soluble biodegradable high molecular material.
Compared with the existing administration mode, the microneedle drug delivery system can remarkably relieve the pain caused by repeated injection, has stable drug activity and is convenient to store and transport.
The invention provides a preparation method of a recombinant hirudin microneedle drug delivery system, which comprises the following steps:
(1) mixing and dissolving the recombinant hirudin and a water-soluble polymer material solution with the mass concentration of 1-40% in a ratio of 1: 15-1: 1000 to obtain a drug-carrying solution;
(2) adding the drug-loaded solution onto a microneedle template, vacuumizing for 10-600 s, recovering the redundant drug-loaded solution, and continuously drying at 10-80 ℃ for 1-5 h to deposit the recombinant hirudin at the top end of a microneedle body;
(3) continuously adding the drug-loaded solution to the microneedle template, vacuumizing for 10-600 s, recovering the redundant drug-loaded solution, and drying at 10-80 ℃ for 1-5 h;
(4) and adding 0.1-1 ml of water-soluble polymer material solution with the mass concentration of 5-40% to the microneedle template, vacuumizing for 10-600 s, removing surface bubbles, and drying at 10-80 ℃ for 1-24 h to obtain the recombinant hirudin microneedle.
In the invention, the polymer material is preferably one or more of hyaluronic acid, chitosan, polyvinylpyrrolidone, polycarboxymethyl cellulose, polyvinyl alcohol and gelatin.
In the invention, the solvent of the water-soluble polymer material solution is preferably one or more of water, methanol, ethanol, acetonitrile and chloroform.
In the invention, the micro-needle is a lattice formed by micron-sized needle points with the length of 25-1000 μm, and the length of the micro-needle can be adjusted in the preparation process according to the treatment requirement.
Experiments show that the microneedle drug delivery system can realize transdermal delivery of macromolecules, particularly protein polypeptide drugs, by puncturing the stratum corneum of the skin; the micro-needle structure is tiny and hardly contacts nerve tissues in the dermis, so that pain can be avoided, the compliance of a patient is improved, the micro-needle structure is simple to use, the administration operation does not need training, and the self-administration can be realized.
Drawings
Figure 1 is a schematic representation of the clinical mode of administration.
Fig. 2 is a schematic illustration of a microneedle patch administration regime.
Figure 3 shows morphological characterization of the recombinant hirudin microneedles of example 1.
Figure 4 shows the skin rejuvenation following administration of recombinant hirudin microneedles.
Figure 5 shows the in vitro transdermal effect of recombinant hirudin microneedles.
Fig. 6 is a schematic view of the microneedle fabrication process.
Fig. 7 is a schematic view of the mode of microneedle administration.
Figure 8 shows a recombinant hirudin microneedle preparation.
FIG. 9 is a graph showing the identification of the subcutaneous injection of r-RGD-hirudin for 1h absorption.
Fig. 10 is drug absorption time for drug-loaded microneedles based on PVP material.
Fig. 11 is drug absorption time for drug-loaded microneedles based on HA materials.
Fig. 12 is drug absorption time for drug-loaded microneedles based on PVP material.
Detailed Description
The present invention is further illustrated by the following specific examples. The following examples will assist those skilled in the art to further understand the present invention, but are not intended to limit the invention in any way.
Example 1
Fully dissolving 1g of hyaluronic acid in 10ml of pure water, adding 10mg of recombinant hirudin, and mixing and dissolving to obtain a drug-loaded material solution;
fully dissolving 2g of hyaluronic acid in 10ml of pure water to obtain a blank material solution;
adding 100 mul of drug-loaded material solution to a microneedle template, standing for 20min under the vacuum degree of-0.06 MPa, recovering the redundant drug-loaded solution, and drying the microneedle template at 45 ℃ for 2h to deposit the drug-loaded hyaluronic acid on the top of a microneedle body;
adding 100 mul of drug-loaded material solution to a microneedle template, standing for 20min under the vacuum degree of-0.06 MPa, recovering the redundant drug-loaded solution, and drying the microneedle template at 45 ℃ for 2h to enable drug-loaded hyaluronic acid to fill a microneedle body;
and adding 200 mu l of blank material solution to the microneedle template, standing for 10min under the vacuum degree of-0.08 MPa, taking out the microneedle template, and drying at 45 ℃ for 6h to obtain the recombinant hirudin microneedle.
Example 2
Adding 0.1g of polyvinyl alcohol into 1ml of pure water, placing the mixture in a water bath shaking table at 60 ℃ overnight until the polyvinyl alcohol is completely dissolved, adding 10mg of recombinant hirudin, and mixing and dissolving to obtain a drug-carrying material solution;
adding 0.1g of polyvinylpyrrolidone into 1ml of ethanol, and stirring until the polyvinylpyrrolidone is completely dissolved to obtain a blank material solution;
adding 100 mul of drug-loaded material solution to a microneedle template, standing for 30s under the vacuum degree of-0.1 MPa, recovering the redundant drug-loaded material solution, and drying the microneedle template at 25 ℃ for 6h to deposit the drug-loaded polyvinyl alcohol on the top of a microneedle body;
adding 100 mul of drug-loaded material solution to a microneedle template, standing for 30s under the vacuum degree of-0.1 MPa, recovering the redundant drug-loaded material solution, and drying the microneedle template at 25 ℃ for 6h to enable drug-loaded polyvinyl alcohol to fill a microneedle body of the microneedle;
adding 150 mu l of blank material solution to the microneedle template, and drying at 25 ℃ for 12h to obtain the recombinant hirudin microneedle.
Example 3
Adding 0.04mg of polyvinyl alcohol and 0.16mg of polyvinylpyrrolidone into 1ml of pure water, placing the mixture in a water bath shaking table at 60 ℃, shaking the mixture overnight until the mixture is completely dissolved, adding 20mg of recombinant hirudin, and mixing and dissolving the mixture to obtain a drug-loaded material solution;
adding 0.2mg of polyvinyl alcohol into 1ml of pure water, placing the mixture in a water bath shaking table at 60 ℃, shaking overnight until the mixture is completely dissolved, and obtaining a blank material solution;
adding 200 mul of blank material solution onto a microneedle template, standing for 20min under the vacuum degree of-0.06 MPa, recovering the redundant drug-loaded material solution, and drying the microneedle template in a 45 ℃ drying oven for 5h to obtain a microneedle body;
and adding 50 mu l of blank material solution to the microneedle template, and drying the microneedle template in a drying oven at 45 ℃ for 5h to obtain the recombinant hirudin microneedle.
Example 4 skin rejuvenation experiments following recombinant hirudin microneedle administration
Unhairing the abdomen of the SD rat by using the unhairing ointment, and feeding the rat for one day after treatment until the skin surface layer is recovered; the recombinant hirudin microneedle is applied to the abdominal skin of a unhaired rat, stays for 20min, is taken down after the microneedle body is dissolved in the skin, and the skin condition of the administration part is observed at 0.5h, 1h, 3h and 16h respectively, and the result shows that the skin is basically recovered at 3h and completely recovered at 16 h.
Example 5 in vitro transdermal Effect of recombinant hirudin microneedles
After the in vitro pigskin is subjected to unhairing treatment, the prepared recombinant hirudin micro needle is applied to the surface of the in vitro pigskin by using a self-made administration device, the pigskin is fixed on a Franz diffusion cell, 0.9% of physiological saline is used as a receiving solution, the diffusion cell is placed in a transdermal diffusion instrument, the water bath temperature is set to be 37 ℃, the rotating speed is set to be 220r/min, 200 mu l of the receiving solution is respectively taken at different time points, and the anticoagulation activity of the receiving solution is detected. FIG. 3 shows morphological characterization of the recombinant hirudin microneedles of example 1; FIG. 4 shows the skin recovery after recombinant hirudin microneedles are administered; figure 5 shows the in vitro transdermal effect of recombinant hirudin microneedles.
Example 6
1) Experimental Material
Primary reagent
Main instrument
2) Method (as shown in fig. 6):
microneedle model fabrication:
i design model
II photoetching to obtain micro-needle mother template
Model III replication
Silanization reagent treatment microneedle mother template
Uniformly mixing PDMS and a curing agent according to a ratio of 10:1, removing bubbles by ultrasonic, pouring into a model, removing bubbles in vacuum to enable PDMS to be completely matched with the surface of a microneedle mould, drying at 57 ℃ for 2h, and demoulding to obtain the microneedle of the microneedle mould:
i, preparing a carrier solution: dissolving 10mg RGD-Hirudin in deionized water, mixing to a final concentration of 1mg/ml, adding 1g of low molecular HA/PVP to prepare a 10% carrier solution, and stirring with a glass rod to mix uniformly (a small amount of cross-linking agent can be added into the HA solution to increase the strength and drug-loading capacity of the microneedle);
and II, removing bubbles: carrying out water bath ultrasound on the stirred solution for 30min to remove bubbles, and putting the solution into a constant-temperature vacuum box to remove the rest bubbles in vacuum;
III, reversing the mold: pouring the carrier solution on a microneedle mould, covering the needle surface, repeatedly removing bubbles in vacuum to fill each pinhole with the carrier solution, and finally pouring a layer of carrier solution on the needle surface so as to facilitate the demolding of the microneedle;
IV, drying: drying the filled mold at room temperature or 37 ℃ overnight;
v, demolding: and (5) separating the microneedle from the mould after drying the microneedle to obtain the drug-loaded microneedle for later use.
In vitro experiments:
removing skin of pig skin, removing fat and connective tissue, detecting the permeation condition of the drug-loaded microneedle drug by using a transdermal diffusion tester, sampling at 0h, 0.5h, 1h, 2h, 3h, 4h, 6h and 8h respectively, and detecting the permeation time and the permeation rate of the drug by detecting the anticoagulant activity of the sample;
in vivo experiments:
carrying out animal experiments according to the permeation time and the permeation rate of the in vitro experiment medicine;
mode of administration (as shown in figure 7):
selecting about 25g ICR mice, removing hair on neck and back with depilatory cream 12-16h in advance, and washing with warm water; the mice are slightly numb the next day, the self-made administration device is used for pressing the micro-needles on the skin for about 15s, and then the micro-needles are sealed by an adhesive film to prevent the micro-needles from falling off; different groups are respectively set according to the permeation time of in vitro experimental drugs, abdominal aorta blood sampling is carried out on the mice at different time points, and anticoagulant sodium citrate is added according to the proportion of 1: 9; centrifuging at 4000rpm for 10-15min, and collecting supernatant.
And (3) blood coagulation index detection:
respectively detecting plasma aPTT, PT and TT of each group of mice, recording the coagulation time and analyzing the experimental data;
the results of in vitro transdermal experiments show that: the transdermal time of the PVP drug-loaded micro-needle is basically stabilized at about 2h
In vivo transdermal experiments: according to the results of the in vitro transdermal experiments, the following experiments were carried out:
early experiments show that the subcutaneous absorption time of the r-RGD-hirudin is about 1h, the subcutaneous absorption time of the r-RGD-hirudin is firstly identified, and the results are shown in figure 9: the drug absorption was detected at 1h in the subcutaneous administration group compared to the control group;
the starting point of transdermal absorption of the drug-loaded microneedle based on the PVP material is 3h by integrating the in vitro transdermal time and the subcutaneous injection absorption time of r-RGD-hirudin, and the following experiment is carried out, and the result is shown in FIG. 10: the absorption of the drug occurred at 3h and 7h, respectively; meanwhile, the transdermal absorption time of the drug-loaded microneedle based on the HA material is analyzed, and the result is shown in figure 11: the absorption time of the medicine is within 3-5 h;
because the absorption of the drug occurs at the expected initial point, two experimental groups of 1h and 2h are respectively added before the absorption of the drug is presumed to possibly occur 3h, and the absorption of the drug for 3h and 7h is further analyzed, and the result is shown in fig. 12, wherein the absorption of the drug occurs at 1h and is stabilized at 3 h;
experimental results show that the drug-loaded microneedle based on the HA and PVP is effective in drug delivery, but the absorption time is prolonged, and the blood concentration is obviously reduced compared with the equivalent subcutaneous injection drug delivery.
Claims (6)
1. A recombinant hirudin microneedle drug delivery system is characterized by comprising a backing patch and a soluble microneedle body; the soluble micro-needle body is positioned at the bottom of the micro-needle patch, the backing patch and the matrix of the micro-needle body are water-soluble biodegradable high polymer materials, and the micro-needle body is loaded with recombinant hirudin.
2. The system for micro-needle delivery of recombinant hirudin according to claim 1, wherein the water-soluble biodegradable polymer material is one or more of hyaluronic acid, chitosan, polyvinylpyrrolidone, polycarboxymethyl cellulose, polyvinyl alcohol and/or gelatin.
3. The recombinant hirudin microneedle drug delivery system according to claim 1, wherein the drug loading mode of the microneedle body containing recombinant hirudin is to uniformly disperse the recombinant hirudin in the microneedle body or to intensively distribute the recombinant hirudin at the needle tip of the microneedle or to contain the recombinant hirudin inside the microneedle body.
4. A method of preparing a recombinant hirudin microneedle delivery system according to claim 1, characterized in that it comprises the steps of:
(1) mixing and dissolving the recombinant hirudin and a water-soluble polymer material solution with the mass concentration of 1-40% in a ratio of 1: 15-1: 1000 to obtain a drug-carrying solution;
(2) adding the drug-loaded solution onto a microneedle template, vacuumizing for 10-600 s, recovering the redundant drug-loaded solution, and continuously drying at 10-80 ℃ for 1-24 h to deposit the recombinant hirudin at the top end of a microneedle body;
(3) continuously adding the drug-loaded solution to the microneedle template, vacuumizing for 10-600 s, recovering the redundant drug-loaded solution, and drying at 10-80 ℃ for 1-24 h;
(4) and adding 0.1-1 ml of water-soluble polymer material solution with the mass concentration of 5-40% to the microneedle template, vacuumizing for 10-600 s, removing surface bubbles, and drying at 10-80 ℃ for 1-24 h to obtain the recombinant hirudin microneedle.
5. The method according to claim 4, wherein the solvent of the 1-40% water-soluble polymer material solution and the 5-40% water-soluble polymer material solution is one or more of water, methanol, ethanol and/or acetonitrile.
6. The system for the micro-needle delivery of recombinant hirudin according to claim 1, wherein the soluble micro-needle body at the bottom of the backing patch is in the shape of a quadrangular pyramid, the length of the needle body is 200 to 1000 μm, and the distance between the needle bodies is 50 to 400 μm.
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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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| US20160271381A1 (en) * | 2015-03-18 | 2016-09-22 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Bioactive components conjugated to substrates of microneedle arrays |
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| US20180304062A1 (en) * | 2015-10-16 | 2018-10-25 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Multi-component bio-active drug delivery and controlled release to the skin by microneedle array devices |
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