CN108837299A - A kind of intelligence adjusts the microneedle patch and preparation method thereof of blood glucose - Google Patents
A kind of intelligence adjusts the microneedle patch and preparation method thereof of blood glucose Download PDFInfo
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- CN108837299A CN108837299A CN201810792842.3A CN201810792842A CN108837299A CN 108837299 A CN108837299 A CN 108837299A CN 201810792842 A CN201810792842 A CN 201810792842A CN 108837299 A CN108837299 A CN 108837299A
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- 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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- 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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- 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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- 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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- 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
- A61M2037/0061—Methods for using microneedles
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Abstract
The invention discloses the microneedle patch and preparation method thereof that a kind of intelligence adjusts blood glucose, belong to field of biomedicine.The micropin that the present invention adjusts the microneedle patch intelligence of blood glucose is filled partially with the drug that intelligence adjusts blood glucose, the drug carrier material, the sentive switch factor of glucose responding, drug molecule.Using the method for vacuumizing and being centrifuged, the hydrogel solution of drug containing is filled into the micropin of microneedles template；And the method by being centrifuged again carries out the solidification of hydrogel material by suitable method with the substrate of the hydrogel solution preparation microneedle patch of not drug containing, after dry, microneedle patch is removed from template and obtains the microneedle patch that intelligence adjusts blood glucose.Microneedle patch of the present invention can puncture skin, and intelligently release contained insulin according to blood sugar concentration in vivo, and intelligence adjusts blood glucose level.Through the invention, the blood glucose-control for realizing painless intelligent response type is expected to instruct the diagnosis and treatment integration of diabetes.
Description
Technical field
The present invention relates to fields of biomedicine, and in particular to a kind of intelligence adjusts microneedle patch and its preparation side of blood glucose
Method.
Background technique
Diabetes are a kind of since internal hypoinsulinism or biological insulin effect are impaired, lead to internal high grape
The metabolic disease of sugar.Wherein, type 1 diabetes be since autoimmune destruction pancreatic beta cell leads to hypoinsulinism,
Diabetes B is then the combination of insulin resistance and impaired insulin secretion.Diabetes endanger the world with getting worse in recent years
Publilc health safety.According to statistics, 2017, the whole world shared 1 type and diabetes B adult patients there are about 4.25 hundred million, and China with
1.144 hundred million adult patients become the whole world and suffer from the most populous country of diabetes.
For type 1 diabetes patient and middle and advanced stage type 2 diabetic patient, traditional therapeutic modality be using finger blood-taking,
Blood glucose is detected, and carries out subcutaneous insulin injection to treat.However, traditional blood sugar test needs the acupuncture treatment at finger to take blood,
Pricker blood sampling repeatedly.This blood sugar test and the mode of drug injection are not only made troubles to patient and pain, and patient
Need long-term compliance.Importantly, the not direct-coupled conventional therapy of glucose sensing and drug therapy, Wu Fashi
Now strictly adjust the glucose level of patient.The patient for lacking strict glycemic control level can often cause correlation and cut including limbs
The illnesss such as limb, blindness, renal failure and mortality hypoglycemia.Therefore, one kind can mitigate patient's physiology and mental anguish, can
By according to the concentration of glucose in blood and intelligent response is passed to release and urgently be studied in a manner of the painless diagnosis and treatment of insulin.
Summary of the invention
The purpose of this invention is to solve the problems associated with the prior art, provides a kind of microneedle patch of intelligence adjusting blood glucose
And preparation method thereof.Microneedle patch of the invention be it is a kind of it is intelligent, can blood sugar concentration release insulin in real-time response body, adjust
Save the minimally-invasive microneedle array patch that internal blood glucose reaches normal level.
The purpose of the invention is achieved by the following technical solution：
A kind of intelligence adjusts the microneedle patch of blood glucose, and the drug that intelligence adjusts blood glucose, the intelligence are contained in micropin part
The drug for adjusting blood glucose includes carrier material, the sentive switch factor of glucose responding, drug molecule, and surfaces of carrier materials connects
The sentive switch factor surface grafting drug molecule of the branch sentive switch factor of glucose responding, glucose responding.Wherein, carrier
Material is gold nanoclusters particle or the coated gold nanoclusters particle of BSA (bovine serum albumin(BSA)), the sentive switch of glucose responding
The factor is phenyl boric acid or derivatives thereof, and drug molecule is insulin.
The intelligence adjusts the preparation method of the microneedle patch of blood glucose, includes the following steps：
(1) biocompatible hydrogel solution is prepared.Preferably, the biocompatible hydrogel includes gelatin/shallow lake
Flour hydrogel, Sodium Alginate Hydrogel Films, hyaluronic acid gel, polyvinyl alcohol hydrogel etc..
(2) drug that above-mentioned intelligence adjusts blood glucose is added into hydrogel solution and obtains the hydrogel solution of drug containing.
(3) hydrogel solution of drug containing is filled into the micropin of microneedles template.Preferably, the step can pass through by
The hydrogel solution of drug containing, which is added on microneedles template surface, makes it be deposited directly to microneedles template surface, then makes to contain by centrifugation
The hydrogel solution of drug is filled into micropin.After the hydrogel solution of drug containing is added to microneedles template surface, in order to avoid molten
The influence of bubble can further remove bubble removing in liquid.
(4) hydrogel solution of not drug containing is added to the base part that microneedle patch is prepared on microneedles template surface.It is excellent
Choosing, the base part of microneedle patch is prepared by the method for centrifugation.After hydrogel solution is added to microneedles template surface, in order to keep away
The influence for exempting from bubble in solution can further remove bubble removing.
(5) water-setting adhesive curing is made by suitable method according to the difference of hydrogel material.Preferably, hydrogel material is
Gelatin/starch is solidified by drying；Hydrogel material is sodium alginate by the way that calcium ion (Ca is added2+) solidified；Water
Gel rubber material is that hyaluronic acid is solidified by ultraviolet irradiation；Hydrogel material be polyvinyl alcohol by circulating frozen thaw into
Row solidification.
(6) drying is carried out after water-setting adhesive curing to strip down microneedle patch from microneedles template after the completion of dry, obtain
The microneedle patch of blood glucose is adjusted to intelligence.
Microneedle patch of the invention uses the integration of biocompatible hydrogel material using gold nanoclusters particle as the intelligence of carrier
It is adjustable the drug of blood glucose, obviously increases the mechanical strength of the microneedle array of patch, skin can be punctured, according to internal blood glucose
Horizontal respone discharges insulin, intelligence adjusts blood glucose level, realizes minimally invasive detection and administration.The present invention realizes painless, intelligence
The blood glucose-control of energy response type is expected to instruct the diagnosis and treatment integration of diabetes.
The present invention realizes minimally invasive percutaneous dosing mode, and realizes the blood glucose-control of response type.The present invention have with
Lower advantages and beneficial effects：
(1) it is conducive to MEMS (MEMS) technology and prepares microneedle patch, is advantageously implemented and the painless of skin minimally invasive is worn
Thorn.Microneedle array patch is made of biocompatible hydrogel material, using nontoxic in vivo；Microneedle patch is included with Jenner
Rice cluster particle is that the intelligence of carrier adjusts the drug of blood glucose, on the one hand can increase substantially the mechanical strength of microneedle patch, promote
It is with better skin-piercing effect, and on the other hand the drug delivery amount is high, and can intelligent response concentration of glucose release pancreas
Island element, intelligence adjust blood glucose.
(2) in the microneedle patch system energy controllable adjustment diabetes hyperglycemia effect, with its distinctive Drug loading capacity with
Minimally invasive characteristic greatly improves the diagnosis and treatment therapeutic effect of diabetes, mitigates the pain of patient.
(3) preparation method is simple, and reaction condition is very mild (room temperature, normal pressure, water phase), greatly protects the work of drug
Property.
Detailed description of the invention
Fig. 1 is the structure chart of microneedles template.(a) design and parameter of microneedles template, template contain the circular cone of 11 × 11 arrays
The hole configurations of shape, wherein the upper bottom surface diameter d1 of each conical bore is 300-400 μm, high h is 600-800 μm, adjacent circular cone
The distance between hole d2 is 600 μm；(b) the light microscopic figure of microneedles template；(c) the 3D profile scan figure of microneedles template.
Fig. 2 is the preparation process schematic diagram of microneedle patch.Using the method for vacuumizing and being centrifuged, by the hydrogel of drug containing
Solution is filled into the micropin of microneedles template；And the method by being centrifuged again, it is prepared with the hydrogel solution of not drug containing micro-
The substrate of needle patch is carried out the solidification of hydrogel material by suitable method and shells microneedle patch from template after dry
From.
Fig. 3 is the influence result figure of different hydrogel materials and curing method to the insulin active of drug.(a) it simulates not
Insulin active is influenced when synthermal lower gelatin solidification plastic；(b) insulin active is influenced when simulating sodium alginate cross-linking；
(c) insulin active is influenced when simulating ultraviolet curing transparent matter acid；(d) to insulin active when simulating polyvinyl alcohol crosslinked
It influences；Dotted line indicates the glucose initial concentration (7.4mM) in the glucose solution of control group in figure.
Fig. 4 is the microneedle patch figure prepared.(a) photo in kind of microneedle array；(b-d) the scanning electricity of microneedle array patch
Sub- microscope (SEM) photo, (b) 11 × 11 microneedle array, (c) 4 × 4 microneedle array, (d) single micropin.
Fig. 5 is the mechanical property figure of microneedle patch.
Fig. 6 is microneedle patch to the puncture experiment signal of skin and result figure.(a) skin penetrating tests schematic diagram, (b) skin
Light microscopic figure after skin puncture, (c) trypan blue dyeing effect figure after skin penetrating.
Fig. 7 is puncture effect and skin recovery effects test result figure of the microneedle patch to skin.(a-d) microneedle patch is moved
Except the light microscopic picture of rear different time skin recovery effects, the H&E dyeing of skin after (e) microneedle patch is applied to skin 1 hour
Picture, the H&E of skin dyes picture after (f) microneedle patch removes 30 minutes, and (g) microneedle patch punctures the depth and skin of skin
The statistical result of paracentesis depth after recovery.
Fig. 8 is comparison result figure of the different disposal to the internal blood sugar regulation ability to type 1 diabetes mouse.
Specific embodiment
Following embodiment should not be construed as limiting the invention for further illustrating the present invention.If not referring in particular to
Conventional means bright, that technological means used in embodiment is well known to those skilled in the art.
1 intelligence of embodiment adjusts the preparation of the drug of blood glucose
(1) according to the earlier patent application of applicant《A kind of intelligence release insulin adjusts the gold nanoclusters particle of blood glucose
And preparation method thereof》The method recorded in (application number 201810075085.8,108079282 A of publication number CN) prepares intelligence
Discharge the gold nanoclusters particle (GNC-FPBA-Insulin or GNC-PBA-Insulin) that insulin adjusts blood glucose.
(2) preparation of the gold nanoclusters particle (BSA-GNC-PBA-Insulin) of response type blood glucose-control
1) the coated gold nanoclusters particle (BSA-GNCs) of BSA is prepared
Containing HAuCl4, BSA mixed solution 35-40 DEG C of reaction 10-18h under conditions of pH >=12 obtain the coated gold of BSA
Nano-cluster particle (BSA-GNCs).
2) amino on the surface BSA is converted into carboxyl
Glutaraldehyde is first added in BSA-GNCs solution, 24-26 DEG C of reaction 3-5h makes the amino and glutaraldehyde on the surface BSA
On an aldehyde radical reaction；The glycine of pH=8 is added, 24-26 DEG C of reaction 20-40min makes the amino on glycine and penta
Another aldehyde radical reaction on dialdehyde, obtains surface without amino, only carboxylic gold nanoclusters particle (BSA-GNCs).
3) carboxyl on the surface activated b SA-GNCs
BSA-GNCs is added in the solution containing EDC, NHS and MES, 24-26 DEG C of reaction 15min-30min, is activated
Carboxyl on BSA-GNCs.
4) 4- amino phenyl boric acid (PBA) is grafted to the BSA-GNCs after activated carboxylic
4- amino phenyl boric acid is added in BSA-GNCs solution after activated carboxylic, 24-26 DEG C of reaction 12-18h is obtained
The gold nanoclusters particle (BSA-GNC-PBA) of PBA modification.
5) glycosylated insulin is grafted on BSA-GNC-PBA
Glycosylated insulin (Insulin) is added in BSA-GNC-PBA solution, 24-26 DEG C of reaction 18-30h is obtained
The gold nanoclusters particle (BSA-GNC-PBA-Insulin) of response type blood glucose-control.Under the same conditions, BSA-GNC-PBA-
Insulin is more preferable relative to GNC-FPBA-Insulin and GNC-PBA-Insulin hypoglycemic effect.
Above-mentioned intelligence adjusts drug GNC-FPBA-Insulin, GNC-PBA-Insulin, BSA-GNC-PBA- of blood glucose
Insulin can respond release insulin according to blood glucose level, intelligence adjusts blood glucose level.GNC-FPBA-Insulin,GNC-
PBA-Insulin, BSA-GNC-PBA-Insulin are by carrier material, the sentive switch factor of glucose responding, drug molecule
Composition, the sentive switch factor, the sentive switch factor of glucose responding of surfaces of carrier materials grafting and modifying glucose responding
Surface grafting drug molecule.Wherein, the carrier material of GNC-FPBA-Insulin, GNC-PBA-Insulin are gold nanoclusters
Grain, the sentive switch factor of glucose responding are 4- carboxyl 3- fluorobenzoic boric acid (FPBA) or 4- Carboxybenzeneboronic acid (PBA), drug point
Son is glycosylated insulin；The carrier material of BSA-GNC-PBA-Insulin is BSA (bovine serum albumin(BSA)) coated gold nano
Cluster particle (BSA-GNCs), the sentive switch factor of glucose responding are 4- amino phenyl boric acid (PBA), and drug molecule is glycosylation
Insulin.
2 intelligence of embodiment adjusts the preparation of the microneedle patch of blood glucose
(1) microneedles template
Microneedles template is purchased from Ireland Blueacre Technology company, and microneedles template is made of silicone material,
Design and size are as shown in Figure 1：Template contains the hole configurations of the cone of 11 × 11 arrays, wherein the upper bottom of each conical bore
Face diameter is 300-400 μm, and a height of 600-800 μm, the distance between adjacent conical bore is 600 μm.
(2) preparation of microneedle patch
The preparation of microneedle patch includes the following steps：
1) biocompatible hydrogel solution is prepared.If biocompatible hydrogel includes gelatin/starch hydrogel, seaweed
Sour sodium hydrogel, hyaluronic acid gel, polyvinyl alcohol hydrogel etc..
2) be added into hydrogel solution intelligence adjust blood glucose drug (GNC-FPBA-Insulin in embodiment 1,
GNC-PBA-Insulin or BSA-GNC-PBA-Insulin) obtain the hydrogel solution of drug containing.
3) hydrogel solution of drug containing is filled into the micropin of microneedles template.It such as can be by by the water-setting of drug containing
Sol solution, which is added on microneedles template surface, makes it be deposited directly to microneedles template surface, then makes the hydrogel of drug containing by centrifugation
It is molten to be filled into micropin (Fig. 2 a-c)；After the hydrogel solution of drug containing is added to microneedles template surface, in order to avoid gas in solution
The influence of bubble can further remove bubble removing.
4) hydrogel solution of not drug containing is added to the base part that microneedle patch is prepared on microneedles template surface.Such as may be used
To prepare the base part (Fig. 2 c-e) of microneedle patch by the method for centrifugation.After hydrogel solution is added to microneedles template surface,
In order to avoid the influence of bubble in solution can further remove bubble removing.
5) water-setting adhesive curing (Fig. 2 f) is made by different methods according to the difference of hydrogel material.Such as：Hydrogel material
Solidified for gelatin/starch by drying；Hydrogel material is sodium alginate by the way that calcium ion (Ca is added2+) solidified；
Hydrogel material is that hyaluronic acid is solidified by ultraviolet irradiation；Hydrogel material is that polyvinyl alcohol is thawed by circulating frozen
Solidified.
6) drying is carried out after water-setting adhesive curing to strip down microneedle patch from microneedles template after the completion of dry, obtain
Intelligence adjusts the microneedle patch (Fig. 2 g-h) of blood glucose.
Embodiment 3 prepares the microneedle patch that intelligence adjusts blood glucose using different hydrogel materials
Intelligence, which is prepared, using different hydrogel materials according to the method in embodiment 2 adjusts blood glucose.
(1) using gelatin/starch as hydrogel material
It is 1 by mass ratio:1 starch and gelatin is dissolved in deionized water respectively, is heated to 60 DEG C, and stirring 30 minutes sufficiently molten
Solution, gelatin is prepared, starch concentration be 5% (w/v) (gelatin+starch total concentration 10%) gelatin/starch solution.
The drug that suitable intelligence adjusts blood glucose is added in gelatin/starch solution, gelatin/starch of drug containing is obtained
Solution.
It takes gelatin/starch solution of 50 μ L drug containing to be deposited directly on microneedles template surface with liquid-transfering gun, is placed in vacuum
(400mmHg) lower 15 minutes removes the bubble in gelatin/starch solution.Then template is transferred in centrifuge,
20 minutes are centrifuged under 4000rpm so that gelatin/starch solution of drug containing to be distributed in the chamber of micropin.It is (molten to repeat the process
Liquid is deposited on template surface, vacuum placement removes bubble, is centrifuged again) 2~3 times, so that micropin part is by gelatin/starch of drug containing
Solution is fully filled with.
After filling full micropin part, respectively applies one piece of glass baffle plate around microneedles template and prepare miniature storage tank.Use liquid relief
Rifle takes gelatin/starch solution of 200 μ L not drug containing to be added in miniature storage tank, then using vacuumizing bubble, and with
4000rpm is centrifuged 20 minutes, prepares the base part of microneedle patch.
After preparing base part, template is put into 37 DEG C of baking oven, after one day, gelatin solidification, from template
Microneedle patch is stripped down, is obtained based on gelatin/starch hydrogel material microneedle patch.
(2) using sodium alginate as hydrogel material
Preparation concentration is the sodium alginate aqueous solution of 1%-3% (w/v) (preferably 2%), the side shaken using water bath sonicator
Method accelerates the dissolution of sodium alginate, and sodium alginate soln is prepared.
The drug that suitable intelligence adjusts blood glucose is added in sodium alginate aqueous solution, the sodium alginate of drug containing is obtained
Aqueous solution.
It takes the sodium alginate soln of 50 μ L drug containing to be deposited directly on microneedles template surface with liquid-transfering gun, is placed in vacuum
(400mmHg) lower 15 minutes removes the bubble in sodium alginate soln.Then template is transferred in centrifuge, in 4000rpm
Lower centrifugation 20 minutes the sodium alginate soln of drug containing to be distributed in the chamber of micropin.It repeats the process 2~3 times, so that
Micropin part is fully filled with by the sodium alginate soln of drug containing.
After filling full micropin part, respectively applies one piece of glass baffle plate around microneedles template and prepare miniature storage tank.By 200 μ L
The sodium alginate soln of drug containing is not added in miniature storage tank, then using vacuumizing bubble, and is centrifuged 20 points with 4000rpm
Clock prepares the base part of microneedle patch.
After preparing base part, by 10% (w/v) calcium salt soln (CaSO of 150 μ L4Or CaCl2) it is added to miniature storage
In slot, Ca2+Ionization is allowed to be cured reaction in sodium alginate.Then it dries 24 hours at normal temperature, after the completion of dry,
Microneedle patch is stripped down from template, obtains the microneedle patch based on Sodium Alginate Hydrogel Films material.
(3) using hyaluronic acid as hydrogel material
It weighs 0.3g hyaluronic acid to be dissolved in 10mL deionized water, prepares the hyaluronic acid solution of 3% (w/v).
The drug that suitable intelligence adjusts blood glucose is added in hyaluronic acid solution, the hyaluronic acid for obtaining drug containing is molten
Liquid.
It takes the hyaluronic acid solution of 50 μ L drug containing to be deposited directly on microneedles template surface with liquid-transfering gun, is placed in vacuum
(400mmHg) lower 15 minutes removes the bubble in hyaluronic acid solution.Then template is transferred in centrifuge, in 4000rpm
Lower centrifugation 20 minutes the hyaluronic acid solution of drug containing to be distributed in the chamber of micropin.It repeats the process 2~3 times, so that
Micropin part is fully filled with by the hyaluronic acid solution of drug containing.
After filling full micropin part, respectively applies one piece of glass baffle plate around microneedles template and prepare miniature storage tank.Use liquid relief
Rifle takes the hyaluronic acid solution of 200 μ L not drug containing to be added in miniature storage tank, then using vacuumizing bubble, and with
4000rpm is centrifuged 20 minutes, prepares the base part of microneedle patch.
After preparing base part, template is placed under the ultraviolet lamp of 365nm and irradiates 5min, hyaluronic acid occurs solid
Change.Then it dries 24 hours, after the completion of dry, strips down microneedle patch from template at normal temperature, obtain based on transparent
The microneedle patch of matter acid hydrogel material.
(4) using polyvinyl alcohol as hydrogel material
Polyvinyl alcohol is add to deionized water, 90 DEG C is heated to and dissolves 30 minutes, prepare the polyethylene of 3% (w/v)
Alcoholic solution.
The drug that suitable intelligence adjusts blood glucose is added in poly-vinyl alcohol solution, the polyvinyl alcohol for obtaining drug containing is molten
Liquid.
It takes the poly-vinyl alcohol solution of 50 μ L drug containing to be deposited directly on microneedles template surface with liquid-transfering gun, is placed in vacuum
(400mmHg) lower 15 minutes removes the bubble in poly-vinyl alcohol solution.Then template is transferred in centrifuge, in 4000rpm
Lower centrifugation 20 minutes the poly-vinyl alcohol solution of drug containing to be distributed in the chamber of micropin.It repeats the process 2~3 times, so that
Micropin part is fully filled with by the poly-vinyl alcohol solution of drug containing.
After filling full micropin part, respectively applies one piece of glass baffle plate around microneedles template and prepare miniature storage tank.Use liquid relief
Rifle takes the poly-vinyl alcohol solution of 200 μ L not drug containing to be added in miniature storage tank, then using vacuumizing bubble, and with
4000rpm is centrifuged 20 minutes, prepares the base part of microneedle patch.
After preparing base part, template passes through 5 freeze-thaw circulations (- 20 DEG C of refrigerator freezing 1h, 25 DEG C of room temperature defrostings
0.5h, so circulation 5 times) so that poly-vinyl alcohol solution solidifies.Then it dries 24 hours at normal temperature, after the completion of dry, from mould
Microneedle patch is stripped down on plate, obtains the microneedle patch based on polyvinyl alcohol hydrogel material.
The influence of the different materials and curing method of micropin to the insulin active of drug is evaluated, specific experiment process is such as
Under：Under room temperature, by the aqueous solution (11.11mM) and GNC-FPBA-Insulin of glucose, (glycosylated insulin concentration is
1.5mM) with 1mL:0.5mL volume mixture, as a control group (wherein glucose concentration is 7.4mM).(a) not equality of temperature is simulated
Insulin active is influenced when spending lower gelatin solidification plastic：Glucose is dissolved in 10% (w/v) gelatin/starch solution (to obtain
Concentration of glucose is 11.11mM), it respectively takes in 1mL glucose solution, it is at different temperatures, each that 0.5mL 1.5mM GNC- is added
FPBA-Insulin solution is uniformly mixed.Concentration of glucose is detected using blood glucose meter, is evaluated at different temperatures when gelatin solidifies
Manage the influence to insulin active in drug；(b) insulin active is influenced when simulating sodium alginate cross-linking：Glucose is dissolved in
2% (w/v) sodium alginate aqueous solution (obtained concentration of glucose is 11.11mM), by the 1mL solution and 0.5mL GNC-
FPBA-Insulin mixing, adds a small amount of Ca2+Solution (50 μ L) makes sodium alginate soln crosslinking curing form sodium alginate water
Gel.Using blood glucose meter measure glucose concentration, influence of the sodium alginate solidification process to insulin active in drug is evaluated；
(c) insulin active is influenced when simulating ultraviolet curing transparent matter acid：The hyaluronic acid that glucose is dissolved in 3% (w/v) is molten
The 1mL solution is mixed with 0.5mL GNC-FPBA-Insulin, uses 365nm by liquid (obtained concentration of glucose be 11.11mM)
Ultraviolet lamp under irradiate different time, make hyaluronic acid be cured to form hyaluronic acid gel.Portugal is measured using blood glucose meter
Grape sugar concentration, evaluation ultraviolet light irradiation solidify influence of the process of hyaluronic acid to insulin active in drug；(d) poly- second is simulated
Insulin active is influenced when enol is crosslinked：Glucose is dissolved in the poly-vinyl alcohol solution of 3% (w/v), and (obtained glucose is dense
Degree is 11.11mM), the 1mL solution is mixed with 0.5mL GNC-FPBA-Insulin, is made by 5 freeze-thaw circulations
Poly-vinyl alcohol solution is formed by curing polyvinyl alcohol hydrogel.Using blood glucose meter measure glucose concentration, polyvinyl alcohol solidification is evaluated
Form influence of the process of hydrogel to insulin active in drug.As a result see Fig. 3, it is solid to show that above-mentioned each hydrogel material passes through
After change, the insulin active of drug will not influence, it is specific as follows：Carrier material using gelatin/starch hydrogel as micropin,
During hydrogel dissolves and is cured, the glucose regulating power (Fig. 3 a) of drug is not influenced；Using sodium alginate water-setting
Glue as micropin carrier material and carry out cured process, do not influence the glucose regulating power (Fig. 3 b) of drug；Using saturating
Bright matter acid hydrogel as micropin carrier material and carry out cured process with ultraviolet light, do not influence the glucose tune of drug
Energy saving power (Fig. 3 c)；It is carried out using polyvinyl alcohol hydrogel as the carrier material of micropin and with circulating frozen defrosting cured
Process does not influence the glucose regulating power (Fig. 3 d) of drug.
4 intelligence of embodiment adjusts the application of the microneedle patch of blood glucose
By taking the preparation of embodiment 3 is based on gelatin/starch hydrogel material microneedle patch as an example.
(1) pattern of microneedle patch
Appearance of the camera shooting based on gelatin/starch hydrogel material microneedle patch is shown in Fig. 4 a, scanning electron microscope
(SEM) pattern for observing microneedle patch is shown in Fig. 4 b-d.The result shows that microneedle patch shape is complete, it is micro- containing 11 × 11 cones
The appearance of needle, micropin is smooth, structural integrity.
(2) mechanical strength test of microneedle patch
With the mechanical strength of nano-indenter test method measurement micropin, Fig. 5 is as a result seen, the blank micropin relative to not drug containing
(micropin is filled with the gelatin of not drug containing/starch solution in preparation process) array, drug containing (drug that intelligence adjusts blood glucose)
The mechanical performance of microneedle array significantly improve.
(3) skin penetrating and the test of skin restorability
1) it will be pressed and be attached on back of mice skin (Fig. 6 a) based on gelatin/starch hydrogel material microneedle patch.
After microneedle patch is applied to skin 1 hour, microneedle patch is taken off, with skin pattern of the cameras record microneedle patch after processed
(Fig. 6 b).Trypan Blue then is carried out 30 minutes to skin with 0.4% trypan blue solution, observes skin with optical microscopy
The Trypan Blue effect (Fig. 6 c) of sample.Can be seen that microneedle patch from Fig. 6 b-c result can effectively pierce through skin, puncture
Skin part dyes blue by trypan blue.
2) after skin surface application gelatin/starch microneedle patch, microneedle patch is taken off, and with cameras record different time points
The recovery situation of skin.The results show that over time, the skin after puncture can be gradually recovered after taking micropin off,
After about 30 minutes, the trace that micropin punctures can almost completely disappear (Fig. 7 a-d).
(Fig. 7 e) is dyed with the skin that H&E colouring method corresponds to used microneedle patch.Microneedle patch 1 is applied on skin
After as a child, the mean depth that micropin is pierced into skin is 305 ± 31 μm (Fig. 7 e, g).Microneedle patch is removed, skin restores 30min
Afterwards, to only 31 ± 8 μm (Fig. 7 g), the trace that micropin punctures almost disappears for the depth recovery of micropin piercing skin, and skin can be extensive
It restores looks (Fig. 7 f).
(4) the internal blood glucose-control measure of merit of microneedle patch
Diabetic mice modeling：C57 male mice, four week old, 1% (w/v) streptozotocin-citric acid of intraperitoneal injection are slow
Fliud flushing, injection dosage 50mg/kg are injected for continuous 5 days one time a day.Survey blood glucose after a week, mouse average blood sugar 15mM with
Upper (15-25mM), type 1 diabetes mouse model construct successfully.
Prepare different experimental groups, first three groups microneedle patch group, respectively micropin (blank group), micropin are (containing free pancreas islet
Plain group), micropin (group containing GNC-FPBA-Insulin), that is, during preparing microneedle patch, the solution for filling micropin is respectively
Gelatin/starch solution, gelatin/starch solution of insulin-containing, gelatin/starch solution containing GNC-FPBA-Insulin, the 4th
Group is insulin injection group.Microneedle patch is applied to the surface of mouse skin by first three groups experimental group, and the 4th group by insulin medicine
Object is subcutaneously injected, and the insulin dose in each experimental group for mouse is 10 μm of ol/kg.Point in different times, it is right
Mouse carries out docking and takes blood, with the intracorporal blood sugar concentration of glucose meter test record mouse.
As a result see Fig. 8：Using micropin (group containing GNC-FPBA-Insulin), blood glucose is rapid in 0.75 hour in Mice Body
It is reduced to 11.35mM, and is always held at normal glycemic levels (lower than 12mM) in 4 hours, subsequent blood glucose level is gradually
Rise.Using micropin (group containing free insulin) and subcutaneous insulin injections group, under blood glucose is rapid in 0.5 hour in Mice Body
Drop, gradually gos up later to elevated blood glucose levels.After micropin (blank group) is applied to the skin of mouse, microneedle patch cannot reduce small
The intracorporal blood glucose level of mouse, the blood sugar concentration of mouse are constantly in highest level (Fig. 8).
The above embodiment is a preferred embodiment of the present invention, but embodiments of the present invention are not by above-described embodiment
Limitation, other any changes, modifications, substitutions, combinations, simplifications made without departing from the spirit and principles of the present invention,
It should be equivalent substitute mode, be included within the scope of the present invention.
Claims (8)
1. the microneedle patch that a kind of intelligence adjusts blood glucose, it is characterised in that：Contain intelligent tune in the micropin part of the microneedle patch
Save the drug of blood glucose；It includes carrier material, the sentive switch factor of glucose responding, drug that the intelligence, which adjusts the drug of blood glucose,
Molecule, surfaces of carrier materials are grafted the sentive switch factor surface of the sentive switch factor of glucose responding, glucose responding
It is grafted drug molecule；Wherein, carrier material be gold nanoclusters particle or the coated gold nanoclusters particle of BSA, glucose responding
The sentive switch factor is phenyl boric acid or derivatives thereof, and drug molecule is insulin.
2. the preparation method that intelligence described in claim 1 adjusts the microneedle patch of blood glucose, it is characterised in that：Including following step
Suddenly：
(1) biocompatible hydrogel solution is prepared；
(2) drug for intelligently adjusting blood glucose described in addition claim 1 into hydrogel solution obtains the hydrogel of drug containing
Solution；
(3) hydrogel solution of drug containing is filled into the micropin of microneedles template；
(4) hydrogel solution of not drug containing is added to the base part that microneedle patch is prepared on microneedles template surface；
(5) water-setting adhesive curing is made by suitable method according to the difference of hydrogel material；
(6) drying is carried out after water-setting adhesive curing to strip down microneedle patch from microneedles template after the completion of dry, obtain intelligence
It is adjustable the microneedle patch of blood glucose.
3. the preparation method that intelligence according to claim 1 adjusts the microneedle patch of blood glucose, it is characterised in that：The biology
Biocompatible hydrogel includes gelatin/starch hydrogel, Sodium Alginate Hydrogel Films, hyaluronic acid gel, polyvinyl alcohol hydrogel.
4. the preparation method that intelligence according to claim 1 adjusts the microneedle patch of blood glucose, it is characterised in that：Step (3)
For：Crossing for the hydrogel solution of drug containing to be added on microneedles template surface makes it be deposited directly to microneedles template surface, then passes through
Centrifugation is filled into the hydrogel solution of drug containing in micropin.
5. the preparation method that intelligence according to claim 4 adjusts the microneedle patch of blood glucose, it is characterised in that：Drug containing
After hydrogel solution is added to microneedles template surface, bubble removing need to be removed.
6. the preparation method that intelligence according to claim 1 adjusts the microneedle patch of blood glucose, it is characterised in that：Step (4)
For：The hydrogel solution of not drug containing is added on microneedles template surface, the substrate of microneedle patch is prepared by the method for centrifugation
Part.
7. the preparation method that intelligence according to claim 6 adjusts the microneedle patch of blood glucose, it is characterised in that：Not drug containing
Hydrogel solution be added to microneedles template surface after, bubble removing need to be removed.
8. the preparation method that intelligence according to claim 1 adjusts the microneedle patch of blood glucose, it is characterised in that：Step (5)
In be directed to different hydrogel materials, curing method is：Hydrogel material is that gelatin/starch is solidified by drying；Water
Gel rubber material is that sodium alginate is solidified by the way that calcium ion is added；Hydrogel material is that hyaluronic acid is carried out by ultraviolet irradiation
Solidification；Hydrogel material is that polyvinyl alcohol is solidified by circulating frozen defrosting.
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| CN114814084A (en) * | 2022-03-24 | 2022-07-29 | 武汉大学 | Method for detecting pH by using microneedle |
| CN114601918A (en) * | 2022-04-22 | 2022-06-10 | 沈阳药科大学 | Glucose-responsive insulin microneedle patch and preparation method thereof |
| CN114601918B (en) * | 2022-04-22 | 2024-01-30 | 沈阳药科大学 | Glucose-responsive insulin microneedle patch and preparation method thereof |
| CN114849052A (en) * | 2022-04-24 | 2022-08-05 | 浙江理工大学 | Microneedle patch for repairing diabetic skin wounds and preparation method thereof |
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