CN107638381A - Containing the microneedle array for being soaked with nucleic acid - Google Patents
Containing the microneedle array for being soaked with nucleic acid Download PDFInfo
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- CN107638381A CN107638381A CN201710605841.9A CN201710605841A CN107638381A CN 107638381 A CN107638381 A CN 107638381A CN 201710605841 A CN201710605841 A CN 201710605841A CN 107638381 A CN107638381 A CN 107638381A
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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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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/042—Polysaccharides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/044—Collagen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/043—Proteins; Polypeptides; Degradation products thereof
- A61L31/045—Gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/048—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
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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
- A61M2037/0023—Drug applicators using microneedles
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Abstract
The present invention relates to containing microneedle array for being soaked with nucleic acid and preparation method thereof, the microneedle array using nucleic acid as separate constituent is prepared for, and confirm prepared microneedle array through skin and dissolved in skin.Thus, and few side effects high using biocompatibility, containing the microneedle array for being soaked with the nucleic acid that can be used in mixed way with other polymer substances or medicine, more effectively to skin transmission and release medicine, so as to improve treatment or improve the effect of skin.
Description
Technical field
The present invention relates to containing microneedle array for being soaked with nucleic acid and preparation method thereof.
Background technology
According to the difference to the internal method for transmitting medicine, the problems such as being agonized there is inefficiency or patient.Example
Such as, oral administration methods are most commonly used drug administration formulations due to convenient and stably, but be decomposed because of digestion or
Degree of absorption reduces, and therefore, drug delivery efficiency is very low.As other medicines transmission method, injection type is most basic
Method, but the pain that patient is experienced is big, the help of expert is needed during use, and in the case where carrying out 1 administration,
Lasting one week is at least needed to some months, so as to be made troubles to patient.
According to drug delivery mode as described above, by the medicine moment to be put into is to internal transmission, therefore, pass through
Internal metabolism, drug concentration can be reduced gradually., can be to human body when the drug concentration of body absorption is higher than suitable concentration
Adverse reaction is produced, is then difficult the effect for playing medicine when lower than suitable concentration.Therefore a kind of medicine is needed to keep suitable
When concentration and can be to the effective drug delivery method of vivo medicine-feeding.
Transdermal administration process can prevent the medicine caused by digestion point due to transmitting medicine by skin
Solution, and the pain brought to patient is lacked.But the skin of people (skin) plays and prevents internal material from being flowed out to outside skin, and hinder
Extracutaneous harmful substance of breaking is to the important function flowed into vivo, thus it is not easy to form drug delivery.Due to skin outermost layer
Thickness be about 10~20 μm cuticula (startum corneum) will not pass through hydrophily or the big medicine of molecular weight,
Allow to the medicine passed through, its penetration speed is also very small, therefore be transmit medicine to internal big barrier (Kim Y.C.,
Et al., 2012；Bariya S.H., et al., 2012).In addition, skin by epidermis (epidermis), corium (dermis),
Subcutaneous fat (subcutaneous fat) forms, and passes through path between Skin Cell with the material of skin contact
(intercellular route) is very small through the possibility of cuticula (startum corneum), therefore is difficult to be absorbed
In to skin (Piao Zhengxian, et al., 2013).
Micropin (microneedle) as a kind of new active transdermal drug delivery system, by be pierced into skin and
Passage is formed on cutin, so as to increase transmitance of the medicine to skin, is capable of painless transmission more than 500Da hydrophilic medicament
(Prausnitz M.R., 2004).In addition, when micropin is impregnated into skin corium, Skin Cell plays the work that nature heals a wound
With inducing skin cells generation self collagen albumen, so as to show improvement wrinkle and elasticity in Skin Cell, shrink hair
Hole, alleviate pigementation, improve wrinkle of skin and other effects (Piao Zhengxian, et al., 2013).
Micropin can be substantially categorized as：Solid microneedles (solid microneedles), coating micropin (coated
Microneedles), soluble micropin (dissolving microneedles) and empty micropin (hollow
Microneedles) (S. Korea and the USA are beautiful, et al., and 2013；Kim Y.C., et al., 2012；Jin Youtian, 2013).
Generally, solid microneedles pre-process available for skin.It is inoculated with after solid microneedles and forms micron (μm) greatly in skin surface
Small hole, by smearing medicine or the patch using drug containing on the hole, so that medicine is absorbed into body via the hole
It is interior, so as to be transmitted into skin.But it is restricted in terms of accurate dose is transmitted, and therefore, is not suitable for price
In the medicine of costliness, the medicine or vaccine of ormal weight (Jin Youtian, 2013).
Coating micropin be it is a kind of using water soluble preparations such as tackifier and surface conditioning agents in microneedle surface painting medicine and
After the medicine is equipped on into micropin, when being inoculated into skin, micropin that the medicine that is coated with dissolves and transmitted in skin.It is logical
Often, coating micropin can be effectively inoculated with using the sharp micropin of metal material, but the amount that can be carried is few, no
It is adapted to the big medicine of dose demand, and suitable for only with (Kim Y.C., et a small amount of vaccine carrying that can also show effect
Al., 2012；Gill H.S., et al., 2007；Jin Youtian, 2013).
Soluble micropin is that medicine is equipped on to the form inside pin using Biodegradable polymer or carbohydrate, transdermal to connect
During kind, it is completely dissolved in inoculation position, there is the advantages of being inoculated with after micropin without otherwise processed.But due to micropin itself
Comprising medicine, therefore, mechanical strength is associated with medication amount, and there is be difficult to transmit high amount of drug into skin to reach effective
The shortcomings that inoculation (Jin Youtian, 2013).
Generally, empty micropin is the hollow micropin of injector type, easily transmits liquid preparation, substantial amounts of medicine or epidemic disease
Seedling, but its preparation process is complicated, therefore, the commercialization of micropin has limitation.In addition, also there is the injection institute with liquid
The distress level brought is more than the shortcomings that other types of micropin (Jin Youtian, 2013).
In view of the foregoing, the present inventor is constantly ground to effectively transmit medicine to skin to micropin
Study carefully, as a result prepared containing being soaked with the micropin of nucleic acid, and confirm prepared micropin have can transdermal intensity, from
And complete the present invention.
As prior art, a kind of micropin is disclosed in Korean granted patent the 1582314th, but do not record completely
It is disclosed in this invention to contain the micropin for being soaked with nucleic acid.In addition, though recorded in Korean granted patent the 1221192nd a kind of micro-
Pin array, but it is the microneedle array being made up of carboxymethyl cellulose or agarose mix, with the present invention's in structure
Had differences containing the microneedle array for being soaked with nucleic acid.Recorded in US granted patent the 8708966th a kind of comprising biodegradation
Property polymer micropin, although to the present invention microneedle configuration it is similar, nucleic acid is not the constituent of micropin, but
The composition of medicine, therefore, had differences in structure with impregnation nucleic acid as the present invention of the constituent of micropin.
Prior art literature
Patent document
Korean granted patent the 1582314th, micropin and preparation method thereof, 2015.12.28. are authorized.
Korean granted patent the 1221192nd, microneedle array and preparation method thereof, 2013.01.04. are authorized.
US granted patent the 8708966th, Microneedle devices and methods of
Manufacture and use thereof, 2014.04.29. mandates.
Non-patent literature
Jin Youtian, new drug delivery techniques：The application of micropin and prospect, NICE, 31 (5), 602-605,2013.
Piao Zhengxian, et al., the network research of drug delivery system：Micropin and skin, Korean Intellectual information technology association
Periodical, 8 (2), 127-135,2013.
S. Korea and the USA are beautiful, et al., the characteristic and hair tonic efficiency of the soluble high-molecular micropin length based on interior bag minoxidil
Observation, Polymer (Korea), 37 (3), 393-398,2013.
Bariya S.H., et al., Microneedles：an emerging transdermal drug delivry
System, J.Pharm and Pharmcol., 64 (1), 11-29,2012.
Gill H.S., et al., Coated microneedles for transdermal delivery,
J.Control.Rel., 117 (2), 227-237,2007.
Kim Y.C., et al., Microneedles for drug and vaccine delivery, Adv.Drug
Deli.Rev., 64 (14), 1547-1568,2012.
Prausnitz M.R., Microneedles for transdermal drug delivery, Adv.Drug
Deli.Rev., 56 (5), 581-587,2004.
The content of the invention
Problems to be solved by the invention
It is an object of the present invention to provide a kind of containing microneedle array for being soaked with nucleic acid and preparation method thereof.
The means used to solve the problem
The present invention relates to containing the microneedle array for being soaked with nucleic acid, above-mentioned microneedle array is to contain to be soaked with the more than one micro- of nucleic acid
Pin is formed at the microneedle array of substrate surface.
On the basis of micropin gross weight, the content of the nucleic acid can be the weight % of 40 weight %~100.
The molecular weight of the nucleic acid can be 10kDa~100,000kDa.
The molecular weight of the nucleic acid can be 10kDa~10,000kDa.
The molecular weight of the nucleic acid can be 50kDa~3,500kDa.
The microneedle array, which can also contain, is soaked with water soluble polymer as supplementary element.
On the basis of micropin gross weight, the content of the water soluble polymer can be the weight % of 0 weight %~60.
The water soluble polymer, hyaluronic acid (hyaluronic acid), chondroitin sulfate can be selected from
(chondroitin sulfate), glycogen (glycogen), dextrin (dextrin), glucan (dextran), dextran sulfate
(dextran sulfate), hydroxypropyl methyl cellulose (hydroxypropyl methylcellulose), alginic acid
(alginic acid), chitin (chitin), chitosan (chitosan), pulullan polysaccharide (pullulan), collagen
(collagen), gelatin (gelatin) and their hydrolysate, polyvinyl alcohol (polyvinyl alcohol), polyethylene pyrrole
Pyrrolidone (polyvinyl pyrrolidone), polyacrylic acid (polyacrylic acid) and carboxy vinyl polymer
One or more of (carboxylvinyl polymer).
The water soluble polymer, can be selected from hyaluronic acid, glucan, chitosan, collagen and polyethylene pyrrole
One or more of pyrrolidone.
The water soluble polymer, can be selected from one or more of hyaluronic acid and chitosan.
The length of the micropin can be 50 μm~5000 μm.
Below, the present invention will be described in detail.
The present invention relates to containing the microneedle array for being soaked with nucleic acid.
Impregnation in the present invention refers to that material is evenly dispersed in the state in microneedle array.
In the microneedle array, the content of nucleic acid can be the weight % of 40 weight %~100 on the basis of micropin gross weight.
The content of the nucleic acid refers to, micropin is poured into by nucleic acid solution or by the mixed solution of nucleic acid and water soluble polymer
The nucleic acid content being impregnated with array mold and the micropin for being allowed to dry in baking box (oven) and preparing.
Nucleic acid concentration in the mixed solution of the nucleic acid solution or nucleic acid and water soluble polymer, using total solution weight as
Benchmark, can be the weight % of 0.1 weight %~3.The weight % of preferably 1 weight %~2.
If above-mentioned nucleic acid solution or nucleic acid are less than 0.1 weight % with the nucleic acid concentration in water soluble polymer mixed solution,
The nucleic acid distributed degrees deficiency of array surface when then due to drying micropin, the intensity of prepared micropin can be weakened, if nucleic acid concentration
More than 3 weight %, then due to preparing solution when nucleic acid can not fully dissolve, so as to which when being applied to array mold, solution will not be equal
Spread evenly and cause coacervation, it is impossible to micropin is equably prepared, therefore it is not preferred.
The molecular weight of the nucleic acid can be 10kDa~100,000kDa, preferably 10kDa~10,000kDa, most preferably
For 50kD~3,500kDa.When the molecular weight of nucleic acid is less than 10kDa, intermolecular adhesion is weak, it is difficult to reaches composition micropin
Required sufficient intensity is long the time required to dissolving, it is difficult to applied to industry when the molecular weight of nucleic acid is more than 100,000kDa
On.
The nucleic acid, can be DNA (deoxyribonucleic acid, DNA), ribonucleic acid
(ribonucleic acid, RNA) or their mixture.
In addition, the DNA can be oligonucleotides (oligonucleotide), polynucleotides
And polydeoxyribonucleotide (polydeoxyribonucleotide) (polynucleotide).
The microneedle array, which can also contain, is soaked with water soluble polymer as supplementary element.
In the microneedle array, the content of water soluble polymer can be 0 weight %~60 on the basis of micropin gross weight
Weight %.
The content of the water soluble polymer refers to, the mixed solution of nucleic acid and water soluble polymer is poured into microneedle array
The content for the water soluble polymer being impregnated with mold and the micropin for being allowed to dry in an oven and preparing.
In the mixed solution of the nucleic acid and water soluble polymer, water soluble polymer concentration is on the basis of total solution weight
Can be the weight % of 0.001 weight %~3.
In the mixed solution of the nucleic acid and water soluble polymer, nucleic acid and water soluble polymer can be with 5000:1~1:
5000 weight ratio is mixed.Preferably 100:1~1:100.The weight ratio of mixed water soluble polymer, can be according to institute
The water soluble polymer of selection and be adjusted.
The water soluble polymer can dissolve or decompose in vivo, can be used：Hyaluronic acid, chondroitin sulfate
Element, glycogen, dextrin, glucan, dextran sulfate, hydroxypropyl methyl cellulose, alginic acid, chitin, chitosan, Propiram are more
The polysaccharides such as sugar；The protein such as collagen, gelatin and their hydrolysate；Polyvinyl alcohol, polyvinylpyrrolidone, poly- third
The synthetic macromolecular compounds such as olefin(e) acid, carboxy vinyl polymer, preferably hyaluronic acid, glucan, chitosan (chitosan),
Collagen and polyvinylpyrrolidone, most preferably hyaluronic acid and chitosan, but it is not limited to this.
The micropin length of the microneedle array, it is the institute that corium, epidermis, hypodermis can be reached through keratoderma
The length of position is needed, can be 50 μm~5000 μm.Preferably 50 μm~2000 μm, more preferably 50 μm~500 μm.
The microneedle array can also include active medicine.
The active medicine, skin or certain transdermal beneficial compound can be acted on including all.Make
To be adapted to the exemplary agents of the object of the invention, can enumerate such as physiologically active peptides (peptide) and its derivative, various antigens
Protein, bacterium, virion etc..As the physiologically active peptides and its derivative, such as calcitonin can be enumerated, promoted on kidney
Gland cortin, parathyroid hormone (parathyroid hormone, PTH), hPTH (1 → 34), insulin, the clear excretion peptide of poison
(Exendin), secretin, oxytocins, angiotensin, beta-endorphin, hyperglycemic factor, antidiuretic hormone, growth hormone suppression
Make element, gastrins, luteinizing hormone releasing hormone, enkephalins, neurotensin, atrial natriuretic peptide, growth hormone, growth hormone
Releasing hormone, bradykinin, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, dynorphin, thyrotropic hormone, prolactin, interferon, interleukins, granular leukocyte colony
Stimulating factor (G-CSF, granulocyte colony stimulating factor), glutathione peroxidase, super oxygen
Compound mutase, minirin, somatomedin, Endothelin and their salt etc..As antigen protein, can enumerate such as stream
Row sexuality emits antigen, hepatitis B surface antigen (HBs), hepatitis B virus e antigen (HBe) etc..In addition, it can include using in the active medicine
In the medicine of cosmetics.
The effect of invention
The present invention relates to microneedle array comprising nucleic acid and preparation method thereof, more specifically, using nucleic acid as individually into
Divide and be prepared for micropin.
The new material that can be used in the microneedle array that insertion skin uses of the present invention, its biocompatible
High, few side effects, and can mix and use with other polymer substances or medicine, therefore, by more effectively being passed to skin
Pass and discharge medicine, it is possible to increase treatment or the effect for improving skin.
Brief description of the drawings
Figure 1A -1~1D-2 represents the result of the microneedle array by the electron microscope confirmation present invention, wherein, Figure 1A -1
It is the result for the microneedle array for observing embodiment 1-2-1 with Figure 1A -2, Figure 1B -1 and Figure 1B -2 are the micropins for observing embodiment 2-1
The result of array, Fig. 1 C-1 and Fig. 1 C-2 are that the result for the microneedle array for observing embodiment 3-1, Fig. 1 D-1 and Fig. 1 D-2 are observations
The result of embodiment 4-1 microneedle array.
Fig. 2A and Fig. 2 B represent to confirm the result of transdermal rate using embodiment 1-2-1 microneedle array.
Embodiment
Hereinafter, the preferred embodiment of the invention is described in detail.But the present invention is not limited to illustrate herein
Embodiment, can specifically be realized in a manner of other shapes.The following examples are in order that the content introduced herein more adds
It is whole, and provided to fully transmit the thought of the present invention to those of ordinary skill in the art.
<Embodiment 1. includes the preparation of the microneedle array of nucleic acid>
The preparation of embodiment 1-1. microneedle arrays mold (mold)
From dimethyl silicone polymer (PDMS, polydimethylsiloxane, Sylgard 184Silicone
elastomer base:Sylgard R 184Silicone elastomer curing agent=10:1) in mixed solution
After removing bubble removing completely, it is dried in 70 DEG C of baking boxs and makes its solidification.It is right using laser printer (Laser Writer)
PDMS after solidification is etched (etching), and etch depth is 230 μm, is then washed, so as to make microneedle array
Mold.
Embodiment 1-2. includes the preparation of the micropin of nucleic acid
It is slow that nucleic acid is added to 200mM disodium hydrogen phosphates (sodium phosphate dibasic dodecahydrate)
Rush in solution, stirred more than 2 hours in 75 DEG C of heating stirrer, it is molten so as to be prepared for the nucleic acid of concentration shown in table 1 below
Liquid.Prepared nucleic acid solution is poured into the microneedle array mold of above-described embodiment 1-1 preparations, under conditions of 3000rpm
Centrifuge 3 minutes, to remove bubble removing and nucleic acid solution is entered the end of mold.The mold of nucleic acid solution will be poured into
Place 1 hour or so under vacuum conditions, it is secondary to remove bubble removing, and it is dried overnight in 60 DEG C of baking boxs after, separated from mold
Go out microneedle array, so as to be prepared for the microneedle array of the present invention.Using micro- in the microneedle array prepared by observation by light microscope
The preparation situation of pin, the results are shown in Figure 1A -1 and Figure 1A -2.Hereinafter, embodiments of the invention are carried out referring to the drawings detailed
Carefully illustrate.
Table 1
| Form | Nucleic acid concentration (weight %) |
| Embodiment 1-2-1 | 1.5 |
| Embodiment 1-2-2 | 0.1 |
| Embodiment 1-2-3 | 3 |
As shown in Figure 1A -1, in the case of the micropin comprising nucleic acid, it is thus identified that on array formed with length be 80~
90 μm of micropin.
Now, if above-mentioned nucleic acid solution concentration is less than 0.1 weight %, in dry compositions, due to array surface
Nucleic acid distributed degrees deficiency, the intensity of micropin can be weakened；If the concentration of nucleic acid is more than 3 weight %, in nucleic acid solution process
Nucleic acid dissolving can not be successfully carried out, during so as to be applied to array mold, solution can not equably spread and produce coacervation,
Micropin can not be equably prepared, thus it is not preferred.
<Embodiment 2. includes the preparation of the microneedle array of nucleic acid and hyaluronic acid>
Nucleic acid is added in 200mM disodium hydrogen phosphate buffer solution, stirred 2 hours in 75 DEG C of heating stirrer
Nucleic acid solution is prepared for above.Further mixed transparent matter acid and the heating stirring at 60 DEG C in prepared nucleic acid solution
After being stirred 1 hour in device, stir 3 hours at normal temperatures, so as to be prepared for the nucleic acid of concentration described in table 2 below and hyaluronic acid
Mixed solution.
Prepared nucleic acid and hyaluronic acid mixed solution are poured into above-described embodiment 1-1 to the microneedle array casting prepared
Mould, centrifuged 3 minutes under the conditions of 3000rpm, to remove bubble removing and mixed solution is entered the end of mold.It will fall
The mold for having entered mixed solution is placed 1 hour or so under vacuum conditions, secondary to remove bubble removing, dried overnight in 60 DEG C of baking boxs
Afterwards, microneedle array is isolated from mold, so as to be prepared for the microneedle array of the present invention.It is made using observation by light microscope
The preparation situation of micropin, the results are shown in Figure 1B -1 and Figure 1B -2 in standby microneedle array.
Table 2
As shown in figure ib-i, in the case of the micropin comprising nucleic acid and hyaluronic acid, it is thus identified that：With embodiment 2-1's
When prepared by condition, formed with the micropin that length is 100~110 μm or so on array, core is only included with what is prepared under the same terms
The micropin (Figure 1A -1) of acid is compared, it was observed that the micropin that end is sharper.
<Embodiment 3. includes the preparation of the microneedle array of nucleic acid and chitosan>
Nucleic acid is added in 200mM disodium hydrogen phosphate buffer solutions, stirred in 75 DEG C of heating stirrer 2 hours with
Above it is prepared for nucleic acid solution.Dissolve the chitosan in 90mM acetic acid (acetic acid) and be prepared for chitosan solution.Will
After prepared nucleic acid solution and chitosan solution are to provide ratio mixing and stirred 30 minutes in 70 DEG C of heating stirrer,
Stirred 3 hours under normal temperature, so as to be prepared for the nucleic acid of concentration shown in Table 3 below and chitosan mixed solution.
Prepared nucleic acid and chitosan mixed solution are poured into above-described embodiment 1-1 to the microneedle array mold prepared,
Centrifuged 3 minutes under the conditions of 3000rpm, to remove bubble removing and mixed solution is entered the end of mold.It will pour into
The mold of mixed solution is placed 1 hour or so under vacuum conditions, secondary to remove bubble removing, dried overnight in 60 DEG C of baking boxs
Afterwards, microneedle array is isolated from mold, so as to be prepared for the microneedle array of the present invention.It is made using observation by light microscope
The preparation situation of micropin in standby microneedle array, the results are shown in Fig. 1 C-1 and Fig. 1 C-2.
Table 3
As shown in Fig. 1 C-1, in the case of the micropin comprising nucleic acid and chitosan, it is thus identified that：With embodiment 3-1 bar
When prepared by part, formed with the micropin that length is 120~150 μm or so on array, nucleic acid is only included with what is prepared under the same terms
Micropin (Figure 1A -1), compared with the micropin (Figure 1B -1) of hyaluronic acid comprising nucleic acid, observed the main part of cone
Keep micropin hard and that end is sharper.
<Embodiment 4. includes the preparation of the microneedle array of nucleic acid, hyaluronic acid and chitosan>
Nucleic acid is added in 200mM disodium hydrogen phosphate buffer solution, stirred 2 hours in 75 DEG C of heating stirrer
Nucleic acid solution is prepared for above.Dissolve the chitosan in 150mM acetic acid and be prepared for chitosan solution.Will be prepared
After nucleic acid solution and chitosan solution are mixed and stirs 30 minutes in 70 DEG C of heating stirrer, go back mixed transparent matter it is sour and
After being stirred 1 hour in 60 DEG C of heating stirrer, stir 3 hours at normal temperatures, so as to be prepared for the core of concentration shown in table 4 below
Acid, hyaluronic acid and chitosan mixed solution.
Prepared nucleic acid, hyaluronic acid and chitosan mixed solution are poured into above-described embodiment 1-1 to the micropin prepared
Array mold, centrifuged 3 minutes under the conditions of 3000rpm, to remove bubble removing and nucleic acid solution is entered the end of mold
End.The mold for having poured into nucleic acid solution is placed 1 hour or so under vacuum conditions, it is secondary to remove bubble removing, in 60 DEG C of baking boxs
After dried overnight, microneedle array is isolated from mold, so as to be prepared for the microneedle array of the present invention.Seen using light microscope
The preparation situation of micropin in prepared microneedle array has been examined, the results are shown in Fig. 1 D-1 and Fig. 1 D-2.
Table 4
As shown in Fig. 1 D-1, in the micropin comprising nucleic acid, hyaluronic acid and chitosan, it is thus identified that with embodiment 4-1's
When prepared by condition, it is 161 μm or so of micropin formed with length on array, also, core is only included with what is prepared under the same terms
Micropin (Figure 1A -1), the micropin (Figure 1B -1) comprising nucleic acid and hyaluronic acid and the micropin comprising nucleic acid and chitosan of acid
(Fig. 1 C-1) is compared, and the intensity of micropin is improved because the adhesion between each composition is strengthened, so as to the micropin length of cone
Degree keeps longer, and end is formed as more sharp sharp keen and exquisite.
<It is prepared by the microneedle array of the comparison other of comparative example 1.>
The mixed proportion of composition and content according to corresponding to table 5 below, it is prepared for the microneedle array of comparison other.System
Preparation Method make use of and the identical method of 1~embodiment of above-described embodiment 4.
Table 5
For the microneedle array prepared by the constituent concentration according to above-mentioned table 5 and mixed proportion, confirm due to mixing
The composition of composition does not dissolve in course of dissolution, or because the amount of nucleic acid is not enough to smear dried substrate entirety, therefore,
The micropin formed does not have sufficient intensity, it is difficult to be used as micropin.
<The transdermal rate of the micropin of experimental example 1. confirms>
Using porcine skin (porcine skin), the microneedle array that is prepared in 1~embodiment of above-described embodiment 4 is implemented
Transdermal is tested.Porcine skin be at -80 DEG C take care of, also, use before thawed more than 2 hours at -4 DEG C after at normal temperatures
Use.Before being pierced into microneedle array, each angle for stretching porcine skin is drawn skin is kept tight state, and make it have and actual skin
The similar engineering properties of skin.After microneedle array is pierced into skin, 0.01% trypan blue (trypan is smeared in skin surface
Blue after) solution dyes skin, the hole count that microneedle array is formed in skin surface is identified through, so as to confirm transdermal
Rate, it the results are shown in table 6 and Fig. 2A and Fig. 2 B.
In table 6, transdermal rate is the percentage relative to the micropin number in microneedle array with transdermal micropin number
Rate represents that Fig. 2 represents the transdermal result of embodiment 1-2-1 microneedle array.
Table 6
| Form | Transmitance (%) |
| Embodiment 1-2-1 | 85 |
| Embodiment 1-2-2 | 64 |
| Embodiment 1-2-3 | 73 |
| Embodiment 2-1 | 87 |
| Embodiment 2-2 | 66 |
| Embodiment 2-3 | 69 |
| Embodiment 2-4 | 75 |
| Embodiment 2-5 | 77 |
| Embodiment 3-1 | 88 |
| Embodiment 3-2 | 67 |
| Embodiment 3-3 | 70 |
| Embodiment 3-4 | 76 |
| Embodiment 3-5 | 78 |
| Embodiment 4-1 | 92 |
| Embodiment 4-2 | 71 |
| Embodiment 4-3 | 73 |
| Embodiment 4-4 | 72 |
| Embodiment 4-5 | 74 |
| Embodiment 4-6 | 80 |
| Embodiment 4-7 | 82 |
| Embodiment 4-8 | 81 |
| Embodiment 4-9 | 83 |
As above-mentioned table 6 understands that the microneedle array of 1~embodiment of above-described embodiment 4 shows skin more than specified degree
Transmitance, confirm with the intensity for being adapted to actual use.
In addition, as shown in Fig. 2 embodiment 1-2-1 microneedle array is pierced into (Fig. 2 B) in the case of skin, with piercing
Preceding skin (Fig. 2A) differently, is expected by micropin is inserted into the bore portion that skin formed and is not applied to the platform of stained tissue
Blue solution dyeing, therefore it is viewed as white states.That is, observed in fig. 2b multiple not by the white hole of Trypan Blue
(arrow meaning part), is able to confirm that the micropin of embodiment 1-2-1 microneedle array has passed through skin.
Thus, it is thus identified that the micropin comprising nucleic acid of the invention, which has, is enough transdermal intensity, and confirms to lead to
Addition water soluble polymer is crossed, micropin sharper, that intensity is higher can be obtained.
<The dissolubility of the micropin of experimental example 2. confirms>
Confirm the dissolubility of the microneedle array of 1~embodiment of above-described embodiment 4.
Using with the above-mentioned identical method of experimental example 1, microneedle array piercing porcine skin is made it fully through utilizing belt
(band) microneedle array is fixed on skin.Microneedle array is removed after the scheduled time, and pin is put into normal temperature state
Taken care of more than 24 hours in drier, so as to remove moisture removal.Confirm the weight change of microneedle array after drying and have rated dissolving
Property.Now, the weight of the microneedle array before and after measure piercing skin, and using the weight before piercing as 100, with hundred
Divide rate to represent the weight after being pierced into, the results are shown in table 7.
Table 7
As shown in Table 7 above, it is able to confirm that after microneedle array is pierced into skin, with the increase micropin battle array of standing time
The weight of row is reduced.
Thus, it is known that microneedle array of the invention is impregnated into skin and dissolved.
<Preparation example 1. includes the microneedle array of nucleic acid and water soluble polymer>
1-1. the microneedle array comprising nucleic acid and glucan
Nucleic acid is added in 200mM disodium hydrogen phosphate buffer solutions, stirred in 75 DEG C of heating stirrer 2 hours with
Above it is prepared for nucleic acid solution.Glucan is dissolved in distilled water, is prepared for dextran solution.By prepared nucleic acid solution
And dextran solution, mixed in a manner of making nucleic acid be 1 weight % and glucan is 2 weight %, and in 70 DEG C of heating
After being stirred 30 minutes in agitator, stir 3 hours at normal temperatures, so as to be prepared for nucleic acid and glucan mixed solution.
Prepared nucleic acid and glucan mixed solution are poured into above-described embodiment 1-1 to the microneedle array mold prepared,
Centrifuged 3 minutes under the conditions of 3000rpm, to remove bubble removing and mixed solution is entered the end of mold.It will pour into
The mold of mixed solution is placed 1 hour or so under vacuum conditions, secondary to remove bubble removing, dried overnight in 60 DEG C of baking boxs
Afterwards, microneedle array is isolated from mold, so as to be prepared for the microneedle array of the present invention.
1-2. includes the microneedle array of nucleic acid and collagen
The preparation of microneedle array comprising nucleic acid and collagen, it is to implement with above-mentioned preparation example 1-1 identicals method
.Collagen solution is that collagen is dissolved in 5% acetic acid (w/v) and prepared.By prepared nucleic acid solution and glue
Former protein solution, mixed in a manner of making nucleic acid be 1 weight % and collagen is 1 weight %, so as to be prepared for micropin
Array.
1-3. includes the microneedle array of nucleic acid and polyvinyl alcohol
The preparation of microneedle array comprising nucleic acid and polyvinyl alcohol, it is to implement with above-mentioned preparation example 1-1 identicals method.
Poly-vinyl alcohol solution is that polyvinyl alcohol is dissolved in into distilled water and prepared.By prepared nucleic acid solution and poly-vinyl alcohol solution,
Mixed in a manner of making nucleic acid be 1.5 weight % and polyvinyl alcohol is 0.5 weight %, so as to be prepared for microneedle array.
Claims (11)
- A kind of 1. microneedle array, it is characterised in thatIt is formed at by the more than one micropin for being impregnated with nucleic acid to prepare on substrate surface.
- 2. microneedle array according to claim 1, it is characterised in thatOn the basis of micropin gross weight, the content of the nucleic acid is the weight % of 40 weight %~100.
- 3. microneedle array according to claim 1 or 2, it is characterised in thatThe molecular weight of the nucleic acid is 10kDa~100,000kDa.
- 4. microneedle array according to claim 3, it is characterised in thatThe molecular weight of the nucleic acid is 10kDa~10,000kDa.
- 5. microneedle array according to claim 4, it is characterised in thatThe molecular weight of the nucleic acid is 50kDa~3,500kDa.
- 6. microneedle array according to claim 1 or 2, it is characterised in thatThe microneedle array, which also contains, is soaked with water soluble polymer as supplementary element.
- 7. microneedle array according to claim 6, it is characterised in thatOn the basis of micropin gross weight, the content of the water soluble polymer is the weight % of 0 weight %~60.
- 8. microneedle array according to claim 7, it is characterised in thatThe water soluble polymer is selected from hyaluronic acid, chondroitin sulfate, glycogen, dextrin, glucan, dextran sulfate, hydroxypropyl Ylmethyl cellulose, alginic acid, chitin, chitosan, pulullan polysaccharide, collagen, gelatin and their hydrolysate, gather One or more of vinyl alcohol, polyvinylpyrrolidone, polyacrylic acid and carboxy vinyl polymer.
- 9. microneedle array according to claim 8, it is characterised in thatThe water soluble polymer in hyaluronic acid, glucan, chitosan, collagen and polyvinylpyrrolidone one More than kind.
- 10. microneedle array according to claim 9, it is characterised in thatThe water soluble polymer is selected from one or more of hyaluronic acid and chitosan.
- 11. microneedle array according to claim 1 or 2, it is characterised in thatThe length of the micropin is 50 μm~5000 μm.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020160093311A KR101779393B1 (en) | 2016-07-22 | 2016-07-22 | Microneedle array comprising nucleic acid and manufacture method thereof |
| KR10-2016-0093311 | 2016-07-22 |
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| CN107638381A true CN107638381A (en) | 2018-01-30 |
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|---|---|---|---|
| CN201710605841.9A Withdrawn CN107638381A (en) | 2016-07-22 | 2017-07-24 | Containing the microneedle array for being soaked with nucleic acid |
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| KR (1) | KR101779393B1 (en) |
| CN (1) | CN107638381A (en) |
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|---|---|---|---|---|
| CN112716885A (en) * | 2021-01-13 | 2021-04-30 | 上海行渝生物科技有限公司 | Nucleic acid micro needle and preparation method and application thereof |
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| KR20240059023A (en) * | 2022-10-26 | 2024-05-07 | 재단법인대구경북과학기술원 | Method for Manufacturing Polymer-based Microneedle Patch and Microneedle Patch Using the Same |
| WO2024122989A1 (en) * | 2022-12-05 | 2024-06-13 | 한양대학교 산학협력단 | Microstructure containing water-soluble and fat-soluble immunomodulator |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8708966B2 (en) * | 1998-06-10 | 2014-04-29 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
| CN104066475A (en) * | 2012-02-17 | 2014-09-24 | 考司美德制药株式会社 | Microneedle of short-time dissolution type |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2683359T3 (en) * | 2011-03-07 | 2015-07-20 | 3M Innovative Properties Co | MICROWAVE DEVICES AND METHODS |
| KR20150016356A (en) | 2012-06-29 | 2015-02-11 | 이엘씨 매니지먼트 엘엘씨 | Dissolvable microneedles comprising one or more encapsulated cosmetic ingredients |
-
2016
- 2016-07-22 KR KR1020160093311A patent/KR101779393B1/en active IP Right Grant
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2017
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8708966B2 (en) * | 1998-06-10 | 2014-04-29 | Georgia Tech Research Corporation | Microneedle devices and methods of manufacture and use thereof |
| CN104066475A (en) * | 2012-02-17 | 2014-09-24 | 考司美德制药株式会社 | Microneedle of short-time dissolution type |
Non-Patent Citations (2)
| Title |
|---|
| YUQIN QIU ET AL.: ""Dissolving microneedle arrays for intradermal immunization of hepatitis B virus DNA vaccine"", 《PROCEDIA IN VACCINOLOGY》 * |
| 李朝等: ""壳聚糖生物微针的制备"", 《2015年全国高分子学术论文报告会》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112716885A (en) * | 2021-01-13 | 2021-04-30 | 上海行渝生物科技有限公司 | Nucleic acid micro needle and preparation method and application thereof |
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