CN108742718A - It is a kind of can Fast-swelling from adherency microneedle patch and preparation method thereof - Google Patents
It is a kind of can Fast-swelling from adherency microneedle patch and preparation method thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0045—Devices for taking samples of body liquids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B10/00—Other methods or instruments for diagnosis, e.g. instruments for taking a cell sample, for biopsy, for vaccination diagnosis; Sex determination; Ovulation-period determination; Throat striking implements
- A61B10/0035—Vaccination diagnosis other than by injuring the skin, e.g. allergy test patches
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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
- 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
- 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 present invention relates to it is a kind of can Fast-swelling from adherency microneedle patch and preparation method thereof, by the way that the first dressing agent (one or two kinds of mixture in acrylic anhydride and methacrylic anhydride) is modified hydrophilic polymer, synthesize the hydrophilic polymer of acroleic acid esterification;Then, the hydrophilic polymer of catechol and acroleic acid esterification is subjected to secondary response, synthesize the hydrophilic polymer of the acroleic acid esterification of catechol modification, and the hydrophilic polymer has good biocompatibility, when the hydrophilic polymer is prepared into microneedle patch, the microneedle patch has good biocompatibility, simultaneously, the microneedle patch can quickly absorb liquid and is swollen, it will not be blocked by skin histology in suction process, further, due to the effect of catechol group, skin surface can be adhered to, it does not need additional adhesive plaster or adhesive tape is fixed, time saving and energy saving cost-saving.
Description
Technical field
The present invention relates to chemistry, materialogy, biomedical device and product technical fields, and in particular to one kind can be fast instant
Swollen microneedle patch of adherency certainly and preparation method thereof.
Background technology
It is using across the master transmitted as transdermal drug in the medical practice that microneedle devices are more and more applied
Multiple micropins of the cuticula of the skin of barrier layer are wanted to come the primary many channels for forming perforation fur portion.By above-mentioned channel,
An adequate amount of drug reaches epidermis or skin corium, and later, drug is absorbed by blood vessel and lymph gland, to be introduced into people
In the circulatory system of body.As other application, above-mentioned multiple micropins are also used for cosmetic purpose.Although utilizing above-mentioned multiple micropins
The percutaneous delivery mode of active principle is useful, still, is applicable in order to which it is convenient, it is preferable that be applicable in the patch type of microneedle devices.
Total micropin and microneedle patch, the micropin include the life of micropin shape after being disclosed such as Chinese patent literature CN105581975A
Object compatible matrix and multiple porous particles, the porous particles are formed on the surface of the biocompatible matrix
Or at least part of the inside of the biocompatible matrix, wherein the biocompatible matrix is essentially polymerizable aqueous
Object and its derivative or mixture, the porous particles are smoothing wrinkle filler.
With micropin and the application development of microneedle patch, in addition to being widely used in percutaneous delivery drug and vaccine inoculation etc.
Aspect, recent years, microneedle patch is already used to carry out the extraction of the interstitial fluid of skin, still, when above-mentioned microneedle patch
Piece or existing microneedle patch above have the following problems in the application:1, the hole of the micropin of traditional structure can be by skin histology
It blocks;2, the broken risk for leading to skin there are interior residue;3, micropin is needed after being inserted into skin with adhesive plaster or adhesive tape
It is fixed, either adhesive tape comes sense of discomfort or allergic reaction to adhesive plaster to skin tape;4, the interstitial fluid of micropin extraction skin
Overlong time.
Invention content
In order to solve the above technical problems, the present invention provides it is a kind of can Fast-swelling from adhere to microneedle patch preparation side
Method comprising:
(1) hydrophilic polymer is dissolved in formation hydrophilic polymer solution, a concentration of 0.1mg/mL- in the first solvent
The first dressing agent progress esterification is then added in above-mentioned solution and obtains mixture A by 200mg/mL;Wherein, reaction condition
For:PH=8-9, temperature are 1-37 degree, time 12-48h;Speed of agitator is 100-10000rpm;First dressing agent with it is hydrophilic
Property polymer molar ratio be 1:1-100:1, the hydrophilic polymer is hyaluronic acid, collagen, alginic acid, chitosan, liver
One or more of mixture in element, poly arginine, poly-aspartate, polylysine, polyacrylic acid;First solvent is water
Or the mixture of water and dimethylformamide;First dressing agent is one kind or two in acrylic anhydride and methacrylic anhydride
The mixture of kind;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First precipitating reagent is added in mixture A and is carried out
Precipitation obtain sediment, reuse water and dissolve sediment, be subsequently placed into renewable fiber dialysis bag in deionized water into
Row dialysis finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the precipitating reagent
For methanol, ethyl alcohol, one kind in propyl alcohol or ether;As for the condition of freeze-drying, as long as using common freeze dryer, not
Particular provisions are lyophilized under vacuum as long as can reach, and the temperature range of general freeze dryer is -80 degree to -30 degree;
The molecular cut off of the renewable fiber dialysis bag is in 1-200kda;
(3) esterification hydrophilic polymer is dissolved into the second solvent, a concentration of 0.1mg/mL-200mg/mL then adds
Enter 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS)
Solvent reaction;Wherein, reaction condition is:PH=2-5, temperature are in 1-50 degree, time in 30min-12h, the range of speeds of stirring
It is 100rpm-10000rpm;Catechol is then added and carries out amidation process, generates mixture B;Wherein, it reacts
Condition is:In 12min-48h, the range of speeds of stirring is 100rpm-10000rpm in 1-50 degree, time for pH=2-5, temperature;
The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, N- hydroxies succinyl are sub-
Amine sodium salt, catechol molar ratio be 1:0.5:0.5:0.5-1:100:100:100;The catechol
For dopamine or tannic acid;Second solvent is deionized water or buffer solution;The buffer solution be PBS buffer solution,
Tris buffer solutions or 2- (N- morpholines) ethanesulfonic acid (MES) buffer solution;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
It dialyses in the deionized water of pH=4 in fiber dialysis bag, then freeze-drying can be obtained amidation esterification hydrophilic polymer
Object;Wherein, as the condition of freeze-drying, as long as using common freeze dryer, not particular provisions, as long as can reach true
It is lyophilized under empty condition, the temperature range of general freeze dryer is -80 degree to -30 degree;The renewable fiber dialysis bag is cut
Stay molecular weight in 1-200kda;
(5) amidation esterification hydrophilic polymer prepares microneedle patch:Amidation esterification hydrophilic polymer is dissolved in
In third solvent, a concentration of 10mg/mL-500mg/mL is then added in template, is then dried, and finally demoulding can obtain
To microneedle patch.The preferred dimethyl silicone polymer of template (PDMS) template, the third solvent is deionized water, PBS is slow
Fliud flushing, Tris buffer solutions or 2- (N- morpholines) ethanesulfonic acid (MES) buffer solution.
Further, in step (5), the microneedle patch after demoulding carries out ultraviolet light, and the time of irradiation is 1min-
30min;The intensity of ultraviolet light is 10.0mW/cm2-30mW/cm2。
It should be noted that in the present invention, pH value is adjusted using sodium hydroxide and hydrochloric acid;1- ethyls-(3- diformazans
Base aminopropyl) carbodiimide hydrochloride/N- hydroxy thiosuccinimide sodium salt solvents are referred to as EDC/NHS solvents;Temperature
For degree Celsius;Water pays the utmost attention to selection deionized water.
Further, in step (5), before it is dried, so that solution is further filled up completely template using centrifuge and exclude gas
Bubble;The condition of centrifugation is:Centrifugal rotational speed is 500-10000rpm, centrifugation time 1-30min;And drying temperature is 20-70
Degree, drying time is 20-28h, uses drying box.
The present invention also provides the microneedle patch being prepared according to above-mentioned preparation method, can quickly draw liquid into
Row Fast-swelling also has adhesiveness;The microneedle patch can be applied to percutaneous dosing, injection of insulin, gene delivery, inoculation epidemic disease
Seedling, medical diagnosis on disease, biosensor and wearable device.
The above technical solution of the present invention has the following advantages over the prior art:
(1) it is of the invention can Fast-swelling from the preparation method for adhering to microneedle patch, by by the first dressing agent (propylene
One or two kinds of mixture in acid anhydrides and methacrylic anhydride) modification hydrophilic polymer, synthesize the parent of acroleic acid esterification
Waterborne polymeric;Then, the hydrophilic polymer of catechol and acroleic acid esterification is subjected to secondary response, synthesized
The hydrophilic polymer of the acroleic acid esterification of catechol modification, and the hydrophilic polymer has good biocompatibility,
When the hydrophilic polymer is prepared into microneedle patch, which has good biocompatibility, meanwhile, the microneedle patch
Liquid can quickly be absorbed to be swollen, will not be blocked by skin histology in suction process, further, due to catechu phenolic group
The presence of group there is substances, the two such as protein, polypeptide can generate chelatropic reaction in skin, so skin can be adhered to
Surface, does not need additional adhesive plaster or adhesive tape is fixed, time saving and energy saving cost-saving.
(2) it is of the invention can Fast-swelling the microneedle patch obtained from the preparation method of adherency microneedle patch, due to adopting
It is the hydrophilic polymer of the acroleic acid esterification of catechol modification, it can be fast instant when encountering Skin tissue fluid
It is swollen, rapidly by body fluid inspiration micropin, extra means or instrument are not needed, greatly reduces the time of body fluid extraction;Meanwhile by
The irradiation for also needing to carry out ultraviolet light in preparation process in microneedle patch makes the hydrophily of the acroleic acid esterification of catechol modification
Polymer is crosslinked, and not will produce the broken risk of micropin, be will not leave in skin, less will produce blocking skin histology
Risk.
(3) microneedle patch of the invention is in addition to that can extract body fluid, additionally it is possible to be used for other application, such as drug gene passes
It passs, vaccine inoculation, injection of insulin, biosensor and wearable device.
Description of the drawings
It, below will be in specific implementation mode in order to illustrate more clearly of the technical solution in the specific embodiment of the invention
Required attached drawing does simple introduction, it should be apparent that, the accompanying drawings in the following description is some embodiment party of the present invention
Formula without creative efforts, can also obtain according to these attached drawings for those of ordinary skill in the art
To other attached drawings.
Fig. 1 is the shape graph of microneedle patch;
Fig. 2 is the synthesis mechanism procedure chart that hydrophilic polymer is esterified hydrophilic polymer to amidation;
Fig. 3 is the weight chart that microneedle patch is inserted into that nude mice skin different time extracts body fluid;
Fig. 4 is the recovery figure of skin after microneedle patch is taken out from nude mice skin;
Fig. 5 is hydrophilic polymer in embodiment 1, esterification hydrophilic polymer and amidation esterification hydrophilic polymer
Nuclear magnetic resonance figures spectrogram.
Specific implementation mode
Clear, complete description is carried out to present disclosure below in conjunction with the accompanying drawings, it is clear that described embodiment is this
A part of the embodiment of invention, instead of all the embodiments.Occupy the embodiment in the present invention, those of ordinary skill in the art
The other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
Embodiment 1
(1) hyaluronic acid is dissolved and forms hydrophilic polymer solution in deionized water, a concentration of 20mg/mL, then
Methacrylic anhydride progress esterification is added in above-mentioned solution and obtains mixture A;Wherein, reaction condition is:PH=8, temperature
Degree is 4 degree, and the time is for 24 hours;Speed of agitator is 300rpm;The molar ratio of methacrylic anhydride and hyaluronic acid is 2:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag and carries out in deionized water
Dialysis 5 days finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the item of freeze-drying
Part is:Temperature is:- 60 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 20mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=5, temperature 20 degree, the time, the range of speeds of stirring was 300rpm in 1h;DOPA is then added
Amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5, temperature, for 24 hours, are stirred in 20 degree, time
The range of speeds be 300rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:2:2:2;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 5 days is carried out in fiber dialysis bag in the deionized water of pH=4, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D1;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 1pa.
Embodiment 2
(1) collagenolysis is formed to hydrophilic polymer solution, a concentration of 50mg/mL, then upper in deionized water
It states addition methacrylic anhydride progress esterification in solution and obtains mixture A;Wherein, reaction condition is:PH=9, temperature are
10 degree, time 36h;Speed of agitator is 1000rpm;The molar ratio of methacrylic anhydride and collagen is 50:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag and carries out in deionized water
Dialysis 3 days finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the item of freeze-drying
Part is:Temperature is:- 60 degree, pressure 10pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 50mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=4, temperature 30 degree, the time, the range of speeds of stirring was 100rpm in 3h;DOPA is then added
Amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=2, temperature are in 20 degree, time in 12h, stirring
The range of speeds be 2000rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:10:10:10;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 3 days is carried out in fiber dialysis bag in the deionized water of pH=3, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D2;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 5pa.
Embodiment 3
(1) alginic acid dissolving is formed into hydrophilic polymer solution in deionized water, a concentration of 80mg/mL then exists
Methacrylic anhydride progress esterification is added in above-mentioned solution and obtains mixture A;Wherein, reaction condition is:PH=8, temperature
It is 10 degree, time 30h;Speed of agitator is 5000rpm;The molar ratio of methacrylic anhydride and alginic acid is 60:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First methanol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses deionized water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag in deionized water
In carry out dialysis 7 days, finally from renewable fiber dialysis bag take out freeze-drying can be obtained esterification hydrophilic polymer;Wherein, freeze
Dry condition is:Temperature is:- 60 degree, pressure 5pa;
(3) esterification hydrophilic polymer is dissolved into PBS buffer solution, 1- ethyls-are then added in a concentration of 80mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=3, temperature 40 degree, the time, the range of speeds of stirring was 5000rpm in 5h;It is then added more
Bar amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=3, temperature, for 24 hours, are stirred in 40 degree, time
The range of speeds mixed is 5000rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide salt
Hydrochlorate, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:0.5:0.5:0.5;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 7 days is carried out in fiber dialysis bag in the deionized water of pH=4, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D3;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 10pa.
Embodiment 4
(1) formation hydrophilic polymer solution, a concentration of 100mg/mL in deionized water is dissolved chitosan in then to exist
Methacrylic anhydride progress esterification is added in above-mentioned solution and obtains mixture A;Wherein, reaction condition is:PH=9, temperature
It is 30 degree, time 48h;Speed of agitator is 100rpm;The molar ratio of methacrylic anhydride and chitosan is 100:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First propyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag and carries out in deionized water
Dialysis 4 days finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the item of freeze-drying
Part is:Temperature is:- 60 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into Tris buffer solutions, 1- second is then added in a concentration of 100mg/mL
Base-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent is anti-
It answers;Wherein, reaction condition is:PH=2, temperature 50 degree, the time, the range of speeds of stirring was 10000rpm in 30min;Then
Dopamine is added and carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=4, temperature exist in 50 degree, time
The range of speeds of 12min, stirring are 8000rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbon
Diimmonium salt hydrochlorate, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:20:20:20;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 4 days is carried out in fiber dialysis bag in the deionized water of pH=5, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D4;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 1pa.
Embodiment 5
(1) heparin dissolving is formed into hydrophilic polymer solution, a concentration of 150mg/mL, then upper in deionized water
It states addition methacrylic anhydride progress esterification in solution and obtains mixture A;Wherein, reaction condition is:PH=8, temperature are
37 degree, time 12h;Speed of agitator is 8000rpm;The molar ratio of methacrylic anhydride and heparin is 10:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ether is added in mixture A and is sunk
Shallow lake obtains sediment, reuses deionized water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag in deionized water
In carry out dialysis 5 days, finally from renewable fiber dialysis bag take out freeze-drying can be obtained esterification hydrophilic polymer;Wherein, freeze
Dry condition is:Temperature is:- 60 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into 2- (N- morpholines) ethanesulfonic acid (MES) buffer solution, it is a concentration of
1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy ambers are then added in 150mg/mL
Acid imide sodium salt (NHS) solvent reaction;Wherein, reaction condition is:PH=5, temperature are in 20 degree, time in 12h, the rotating speed of stirring
Range is 1000rpm;Dopamine is then added and carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5,
Temperature 20 degree, the time, the range of speeds of stirring was 10000rpm in 48h;The esterification hydrophilic polymer, 1- ethyls-(3- bis-
Dimethylaminopropyl) carbodiimide hydrochloride, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:10:10:
10;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 5 days is carried out in fiber dialysis bag in the deionized water of pH=6, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D5;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 1pa.
Embodiment 6
(1) poly arginine is dissolved in dimethylformamide and forms hydrophilic polymer solution, a concentration of 0.1mg/mL,
The mixture progress esterification that methacrylic anhydride and acrylic anhydride are then added in above-mentioned solution obtains mixture A;Its
In, reaction condition is:PH=8, temperature are 1 degree, time 48h;Speed of agitator is 10000rpm;Methacrylic anhydride and propylene
The sum of mole of acid anhydrides is 1 with the molar ratio of poly arginine:1;The ratio between mole of the methacrylic anhydride and acrylic anhydride be
1:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses deionized water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag in deionized water
In carry out dialysis 1 day, finally from renewable fiber dialysis bag take out freeze-drying can be obtained esterification hydrophilic polymer;Wherein, freeze
Dry condition is:Temperature is:- 30 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 0.1mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=5, temperature 1 degree, the time, the range of speeds of stirring was 8000rpm in 12h;It is then added single
Peaceful acid carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5, temperature are in 1 degree, time in 48h, stirring
The range of speeds be 6000rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, tannic acid molar ratio be 1:100:100:100;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 1 day is carried out in fiber dialysis bag in the deionized water of pH=2, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D6;Wherein, the condition of freeze-drying is:Temperature is:- 40 degree, pressure 1pa.
Embodiment 7
(1) poly-aspartate is dissolved in the mixture of deionized water and dimethylformamide and forms hydrophilic polymer
The volume ratio of solution, a concentration of 30mg/mL, wherein deionized water and dimethylformamide is 1:1, then add in above-mentioned solution
Enter acrylic anhydride progress esterification and obtains mixture A;Wherein, reaction condition is:PH=8, temperature are 10 degree, and the time is for 24 hours;
Speed of agitator is 2000rpm;The molar ratio of acrylic anhydride and poly-aspartate is 2:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag and carries out in deionized water
Dialysis 4 days finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the item of freeze-drying
Part is:Temperature is:- 50 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into PBS buffer solution, 1- ethyls-are then added in a concentration of 30mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=4, temperature 10 degree, the time, the range of speeds of stirring was 2000rpm in 3h;It is then added single
Peaceful acid carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=4, temperature, in 48h, are stirred in 10 degree, time
The range of speeds mixed is 100rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:50:50:50;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 4 days is carried out in fiber dialysis bag in the deionized water of pH=4, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D7;Wherein, the condition of freeze-drying is:Temperature is:- 30 degree, pressure 1pa.
Embodiment 8
(1) polylysine is dissolved in water to form hydrophilic polymer solution, a concentration of 50mg/mL, then above-mentioned
Methacrylic anhydride progress esterification is added in solution and obtains mixture A;Wherein, reaction condition is:PH=8, temperature 20
Degree, time 20h;Speed of agitator is 1000rpm;The molar ratio of methacrylic anhydride and polylysine is 10:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses deionized water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag in deionized water
In carry out dialysis 5 days, finally from renewable fiber dialysis bag take out freeze-drying can be obtained esterification hydrophilic polymer;Wherein, freeze
Dry condition is:Temperature is:- 50 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 50mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=5, temperature 20 degree, the time, the range of speeds of stirring was 300rpm in 1h;DOPA is then added
Amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5, temperature, for 24 hours, are stirred in 20 degree, time
The range of speeds be 300rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:1:1:1;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 5 days is carried out in fiber dialysis bag in the deionized water of pH=4, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D8;Wherein, the condition of freeze-drying is:Temperature is:- 80 degree, pressure 1pa.
Embodiment 9
(1) polyacrylic acid is dissolved and forms hydrophilic polymer solution in deionized water, a concentration of 200mg/mL, then
Methacrylic anhydride progress esterification is added in above-mentioned solution and obtains mixture A;Wherein, reaction condition is:PH=8, temperature
Degree is 15 degree, time 30h;Speed of agitator is 1000rpm;The molar ratio of methacrylic anhydride and polyacrylic acid is 30:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag and carries out in deionized water
Dialysis 5 days finally takes out freeze-drying from renewable fiber dialysis bag and can be obtained esterification hydrophilic polymer;Wherein, the item of freeze-drying
Part is:Temperature is:- 80 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 150mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=5, temperature 10 degree, the time, the range of speeds of stirring was 300rpm in 10h;It is then added more
Bar amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5, temperature, for 24 hours, are stirred in 10 degree, time
The range of speeds mixed is 400rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:2:2:2;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
Dialysis 5 days is carried out in fiber dialysis bag in the deionized water of pH=3, then takes out and is lyophilized from renewable fiber dialysis bag
Obtain amidation esterification hydrophilic polymer D9;Wherein, the condition of freeze-drying is:Temperature is:- 50 degree, pressure 1pa.
Embodiment 10
(1) dissolving of the mixture of hyaluronic acid and collagen is formed into hydrophilic polymer solution, concentration in deionized water
For 150mg/mL, methacrylic anhydride progress esterification is then added in above-mentioned solution and obtains mixture A;Wherein, it reacts
Condition is:PH=8, temperature are 4 degree, and the time is for 24 hours;Speed of agitator is 300rpm;Methacrylic anhydride and hyaluronic acid and glue
The molar ratio of former the sum of mole is 5:1;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First ethyl alcohol is added in mixture A and is sunk
Shallow lake obtains sediment, reuses deionized water and dissolves sediment, is subsequently placed into renewable fiber dialysis bag in deionized water
In carry out dialysis 5 days, finally from renewable fiber dialysis bag take out freeze-drying can be obtained esterification hydrophilic polymer;Wherein, freeze
Dry condition is:Temperature is:- 60 degree, pressure 1pa;
(3) esterification hydrophilic polymer is dissolved into deionized water, 1- ethyls-are then added in a concentration of 200mg/mL
(3- dimethylaminopropyls) carbodiimide hydrochloride (EDC)/N- hydroxy thiosuccinimides sodium salt (NHS) solvent reaction;
Wherein, reaction condition is:PH=5, temperature 20 degree, the time, the range of speeds of stirring was 300rpm in 1h;DOPA is then added
Amine carries out amidation process, generates mixture B;Wherein, reaction condition is:PH=5, temperature, for 24 hours, are stirred in 20 degree, time
The range of speeds be 300rpm;The esterification hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride
Salt, N- hydroxy thiosuccinimides sodium salt, dopamine molar ratio be 1:5:5:5;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable
It dialyses in the deionized water of pH=4 in fiber dialysis bag, then taking out freeze-drying from renewable fiber dialysis bag can obtain
To amidation esterification hydrophilic polymer D10;Wherein, the condition of freeze-drying is:Temperature is:- 60 degree, pressure 1pa.
It should be noted that the molecular cut off of the renewable fiber dialysis bag used in above-described embodiment 1-10 is
3.5kda。
Embodiment 11
The preparation of microneedle patch:
It is molten that the amidation esterification hydrophilic polymer D1-D10 that embodiment 1- embodiments 10 are prepared is dissolved in third
In agent, wherein D1-D3 dissolves in deionized water, and D4-D5 is dissolved in PBS buffer solution, and D6-D8 is dissolved in 2- (N- morphines
Quinoline) in ethanesulfonic acid (MES) buffer solution, D9-D10 is dissolved in Tris buffer solutions, is then added in PDMS templates, then use from
The mode of the heart is by solution filling mold and excludes bubble, is finally dried using drying machine, and finally demoulding can be obtained micropin
Patch W1-W10.Concentration, centrifugal condition and drying condition about amidation esterification hydrophilic polymer D1-D10 refer to table
1。
As for the shape for the microneedle patch being prepared, it is arranged in fact according to purpose is used, such as most common shape,
As shown in Figure 1 comprising bottom plate and the several micropins being arranged on the bottom plate.Wherein, the A in Fig. 1 and B does not originally pass through
What scanning electron microscope (A) and light microscope (B) obtained.
Embodiment 12
The microneedle patch W1-W10 that embodiment 11 is prepared is subjected to ultraviolet light and obtains microneedle patch W11-W20.
Condition about ultraviolet light refers to table 1.
Table 1
Test case
1, synthesis mechanism process
Explanation is esterified the synthesis mechanism mistake of hydrophilic polymer by hydrophilic polymer to amidation by taking embodiment 1 as an example
Journey refers to Fig. 2.
2, modification rate
Esterification hydrophilic polymer is obtained to embodiment 1-10 and amidation esterification hydrophilic polymer passes through nuclear magnetic resonance
Instrument is characterized, and it is poly- that methacrylate group or acrylate group and catechol group group successfully modify hydrophily
It closes on object, by analysis of spectra, methacrylate modification rate or acrylate modification rate are in 40%-80%, catechol collection
Group's modification rate is in 5%-19%.Wherein, hydrophilic polymer, esterification hydrophilic polymer and amidation esterification parent in embodiment 1
Shown in nuclear magnetic resonance figures spectrogram Fig. 5 of waterborne polymeric.The modification rate of above-mentioned group illustrates esterification hydrophilic polymer and acyl
Amination is esterified the successful synthesis of hydrophilic polymer.Simultaneously as the presence with catechol group, has skin adherence,
It shows and microneedle patch is prepared by the method for the present invention has the function of that skin can be adhered to.
3, it is quickly restorative quickly to draw fluid and skin
Microneedle patch W11-W20 is inserted into the surface of hydrogel (1.4wt% agar gels) respectively, it is disconnected by optical coherence
Layer scanning imagery art (OCT) show (when scale is 1000 microns, can clear view) 1min or so microneedle patch micropin just
It can swell to utmostly, show have the characteristics that quickly to draw liquid.Meanwhile above-mentioned microneedle patch is inserted into nude mice skin
When upper, within the 1min times, the body fluid of about 1.4mg can be extracted from mouse skin, as shown in figure 3, the body of this amount
Liquid carries out the analysis of the metabolin of next step enough.
When above-mentioned microneedle patch is taken out from nude mice skin, skin can restore in 30 minutes, as shown in figure 4, table
The bright microneedle patch can be with ordinary normal use without causing skin problem.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or
It changes still within the protection scope of the invention.
Claims (10)
1. it is a kind of can Fast-swelling from adhere to microneedle patch preparation method, which is characterized in that including:
(1) hydrophilic polymer is dissolved in formation hydrophilic polymer solution in the first solvent, then added in above-mentioned solution
Enter the first dressing agent progress esterification and obtains mixture A;
(2) extraction of hydrophilic polymer is esterified in the mixture A:First precipitating reagent is added in mixture A and is precipitated
Sediment is obtained, then sediment is dissolved, is subsequently placed into renewable fiber dialysis bag and dialyses in deionized water, finally
Freeze-drying can be obtained esterification hydrophilic polymer;
(3) esterification hydrophilic polymer is dissolved into the second solvent, 1- ethyls-(3- dimethylaminopropyls) carbon is then added
Diimmonium salt hydrochlorate/N- hydroxy thiosuccinimide sodium salt solvents are reacted, and catechol is then added and carries out
Amidation process generates mixture B;
(4) in the mixture B amidation esterification hydrophilic polymer extraction:The mixture B is put into renewable fiber
It dialyses in deionized water in bag filter, then freeze-drying can be obtained amidation esterification hydrophilic polymer;
(5) amidation esterification hydrophilic polymer prepares microneedle patch:Amidation esterification hydrophilic polymer is dissolved in third
In solvent, a concentration of 10mg/mL-500mg/mL is then added in template, is then dried, and finally demoulds.
2. preparation method according to claim 1, which is characterized in that in step (5), the microneedle patch after demoulding carries out purple
The time of outer light irradiation, irradiation is 1min-30min;The intensity of ultraviolet light is 10.0mW/cm2-30mW/cm2。
3. preparation method according to claim 1 or 2, which is characterized in that in step (1), reaction condition is:PH=8-
9, temperature is 1-37 degree, time 12-48h, speed of agitator 100-10000rpm;First dressing agent and hydrophilic polymer
Molar ratio is 1:1-100:1, the hydrophilic polymer is hyaluronic acid, collagen, alginic acid, chitosan, heparin, poly- smart ammonia
One or more of mixture in acid, poly-aspartate, polylysine, polyacrylic acid;First solvent be water or water with
The mixture of dimethylformamide;First dressing agent is mixing one or two kinds of in acrylic anhydride and methacrylic anhydride
Object;A concentration of 0.1mg/mL-200mg/mL of the hydrophilic polymer in the first solvent.
4. preparation method according to claim 1 or 2, which is characterized in that in step (2), the precipitating reagent is methanol, second
One kind in alcohol, propyl alcohol or ether.
5. preparation method according to claim 1 or 2, which is characterized in that in step (3), reaction condition is:PH=2-5,
In 1-50 degree, time, in 30min-12h, the range of speeds of stirring is 100rpm-10000rpm to temperature;Amidation reaction condition
For:In 12min-48h, the range of speeds of stirring is 100rpm-10000rpm in 1-50 degree, time for pH=2-5, temperature;It is described
It is esterified hydrophilic polymer, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, N- hydroxy thiosuccinimides
Sodium salt, catechol molar ratio be 1:0.5:0.5:0.5-1:100:100:100;The catechol is
Dopamine either tannic acid;Second solvent is deionized water or buffer solution;The esterification hydrophilic polymer exists
A concentration of 0.1mg/mL-200mg/mL in second solvent.
6. preparation method according to claim 1 or 2, which is characterized in that in step (4), the pH=1-6 of dialysis procedure.
7. preparation method according to claim 1 or 2, which is characterized in that further include in step (5), before dry using from
The mode of the heart is by solution filling mold and excludes bubble.
8. a kind of microneedle patch that any preparation methods of claim 1-7 are prepared, which is characterized in that the microneedle patch
Piece can quickly draw liquid and carry out Fast-swelling.
9. a kind of microneedle patch that any preparation methods of claim 1-8 are prepared, which is characterized in that the microneedle patch
Piece has adhesiveness.
10. a kind of microneedle patch that any preparation methods of claim 1-9 are prepared, which is characterized in that the micropin
Patch can be used for percutaneous dosing, injection of insulin, gene delivery, vaccine inoculation, medical diagnosis on disease, biosensor and wearable set
It is standby.
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