CN110404161A - A kind of transdermal accurate drug delivery device and preparation method thereof based on micropin formula ion nestocalyx part - Google Patents
A kind of transdermal accurate drug delivery device and preparation method thereof based on micropin formula ion nestocalyx part Download PDFInfo
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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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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Abstract
The invention belongs to medical drug delivery device technical fields, the specific open transdermal accurate drug delivery device based on micropin formula ion nestocalyx part, the compound micropin being connected including passing sequentially through conducting wire, DC power supply and lagging electrode slice, compound micropin includes microneedle patch and regulatable load medicine substrate, microneedle patch is the hydrogel micropin with grid gap by being formed after polyethylene glycol-cross-linked poly methyl vinethene-maleic acid crosslinking, the medicine substrate that carries includes by the polyethyleneglycol diacrylate (PEGDA) after photocuring and being enclosed with the composite hydrogel of insulin, the back side of the composite hydrogel is equipped with microneedle electrodes piece.The drug delivery device efficiently realizes the macromoleculars cutaneous penetration such as insulin, the percutaneous permeation rate of insulin is greatly improved by ionophoresis technology, the present invention is by changing the voltage of ionophoresis, electric current, time being capable of more accurate, controllable drug delivery, it realizes the intelligent release of insulin and terminates, adjust blood glucose more accurately.
Description
Technical field
It is the invention belongs to medical drug delivery device technical field, in particular to a kind of based on the transdermal of micropin formula ion nestocalyx part
Accurate drug delivery device and preparation method thereof.
Background technique
In the prior art, diabetes be it is a kind of by blood glucose level adjustment mechanism failure characterized by metabolic disease, be after
The third-largest Chronic Non-Communicable Diseases of human health is endangered after cardiovascular and cerebrovascular disease and tumour.Newest world diabetes connection
The analysis report that alliance announces shows that diabetes adult patient (20-79 years old) had reached from 1.51 hundred million in 2000 by 2017
4.25 hundred million, increase nearly 2 times, directly or indirectly dies of diabetes, and cumulative year after year per year over 5100000 people.Expect 2045
Year, diabetic will break through 600,000,000, and harmfulness has caused the worry of various circles of society.The research of biological medicine is endeavoured always
In disclose diabetes mechanism, develop diabetes Clinics and control prece.Wherein, new insulin administration mode is developed
And it is very crucial to realize that drug intelligentized control method has the function of the novel therapeutic for developing diabetes.
Diabetes are largely divided into two types, i.e. type 1 diabetes and diabetes B according to pathogenesis.Wherein 1 type glycosuria
Disease is autoimmune disease, can not effective excreting insulin, it is necessary to adjust blood glucose by exogenous insulin and sustain life；2
Patients with type Ⅰ DM is in morning, mid-term energy excreting insulin, but since type 2 diabetic patient's body is to insulin insensitivity (i.e. insulin
Resist), it needs frequently to detect blood sugar concentration, insulin is replenished in time and carries out blood glucose-control.Also, diabetes B develops to late
Phase also can only could maintain the normal of blood glucose by insulin injection.
Insulin is the hormone that uniquely can reduce blood glucose in human body, and how exogenous insulin effectively enters diabetes patient
In vivo and maintain functionalization be the key that insulin carry medicine transport.The molecular weight of insulin can not be directed through 5800 or so
Keratoderma enters subcutaneous.Currently, clinically insulin mainly passes through injection or infusion enters in vivo.However, continually
Injection and infusion can bring the risk of the initiation inflammation such as pain and bacterial infection, virus and related complication to patient.In addition,
Insulin can not be entered in vivo via gastrointestinal tract again by oral, this is because stronger acidity is presented in gastrointestinal tract, more rich in more
Kind can attack microbial components and digestive ferment with protein degradation matter, and high molecular weight protein parahormone drug is caused to be easy to be divided
Solution.Moreover, fine and close inner wall of intestine can more hinder protein drug to enter in vivo.Therefore, needing to develop one kind can be effective
Ground avoids patient pain and no inflammation from reacting the treatment technology for being able to achieve the macromolecular drugs transdermal release such as insulin again.
In recent years, micropin administration is suggested as a kind of novel percutaneous dosing mode.The general diameter of micropin is about 200
Micron, cone of the length at 500-800 microns can be improved the useful load of drug by array.Micropin can effectively by
Macromolecular drug reaches subcutaneous tissue, and the pain sensation that will not be damaged veins beneath the skin, touch skin corium through keratoderma delivering
Nerve has without pain, bloodless advantage.Recently, the Robert Langer professor seminar of Massachusetts Institute Technology opens
Issuing a micropin capsule for loading insulin can be realized the percutaneous dosing of enteron aisle, and micropin capsule shell is similar to leopard tortoise shape
Shape has the stomach wall that capsule is attached to animal body that unique mechanical characteristic can orient, and micropin capsule is by insulin
Support disk three parts made of the micropin of cladding, stainless steel spring and sugar are constituted, when sugared rounding disk by the corrosion of gastric acid and
Dissolution touches stainless steel spring and loses the restraining force of disk and micropin is pushed to puncture stomach wall release insulin, realizes percutaneous dosing
Effect.Micropin has advantage in addition to the cutaneous penetration in insulin, equally plays a role in the administration of other macromolecular drugs.
For example, the flexible eye that Nanyang Technological University Chen Peng professor seminar develops a kind of biodegradable polymer preparation is micro-
Needle patch.Compared with traditionally topical eye drops method, this microneedle patch loads macromolecular drug (monoclonal antibody DC101)
Carrying out cornea rebirth blood vessel treatment applied to mouse model has significantly more effect.
To sum up, microneedle patch can be used for the cutaneous penetration of various types drug, it is especially big in polypeptide protein, vaccine etc.
There is very big advantage on the transdermal delivery of molecular drug, be expected to become the novel therapeutic mode of substitution conventional injection administration.
Summary of the invention
The purpose of the present invention is overcome the deficiencies in the prior art, the specific open transdermal essence based on micropin formula ion nestocalyx part
True drug delivery device, the drug delivery device efficiently realize the macromoleculars cutaneous penetration such as insulin, significantly by ionophoresis technology
Improve the percutaneous permeation rate of insulin, the present invention by change the voltage of ionophoresis, electric current, the time can it is more accurate,
Controllable drug delivery is realized the intelligent release of insulin and is terminated, adjusts blood glucose more accurately.
In order to reach above-mentioned technical purpose, the present invention is realized by following technical scheme:
A kind of transdermal accurate drug delivery device based on micropin formula ion nestocalyx part of the present invention, including pass sequentially through and lead
Compound micropin, DC power supply and the lagging electrode slice that line is connected, the compound micropin include microneedle patch and regulatable load
Medicine substrate, the microneedle patch are by being formed after polyethylene glycol-cross-linked poly methyl vinethene-maleic acid crosslinking between grid
The hydrogel micropin of gap, the load medicine substrate includes by the polyethyleneglycol diacrylate (PEGDA) after photocuring and being enclosed with
The back side of the composite hydrogel of insulin, the composite hydrogel is equipped with microneedle electrodes piece.
As the further improvement of above-mentioned technology, the lagging electrode slice and microneedle electrodes piece are platinum electrode piece.
The invention also discloses the preparation method of the above-mentioned transdermal accurate drug delivery device based on micropin formula ion nestocalyx part,
It comprises the concrete steps that:
(1) microneedle patch is prepared；
(2) preparation carries medicine substrate；
(3) compound micropin is prepared；
(4) cathode that medicine substrate back installation platinum electrode connecting wire connects DC power supply is carried, a lagging electrode is separately taken
The anode of piece connection DC power supply.
As the further improvement of above-mentioned technology, the specific steps of preparation microneedle patch described in above-mentioned steps (1) include:
(11) firstly, weighing 0.6-1.2g ethylene methacrylic ether-maleic acid powder, 0.3-O.6g molecular weight be 10000 second
Glycol is added in the deionized water of 6-12ml, after 90 DEG C of water-bath, magnetic agitation 30 minutes, can prepare slightly clear viscous
Thick precursor liquid, it is spare；
(12) secondly, precursor liquid to be imported into a certain number of micropin molds as required, micropin mold uses poly- diformazan
Radical siloxane PDMS solidifies with corresponding curing agent heat cross-linking to be prepared, and 4000rpm/min is centrifuged 5 minutes, to guarantee to form micropin
Needle point position；
(13) microneedle patch with " wall " can be prepared finally, being transferred to 80 DEG C of baking ovens and taking out after 24 hours.
As the further improvement of above-mentioned technology, preparation described in above-mentioned steps (2) carries the specific steps packet of medicine substrate
It includes:
(21) polyethyleneglycol diacrylate (PEGDA) of 1.65g molecular weight 20000 is weighed, 1.1g molecular weight 700 is added
Polyethyleneglycol diacrylate (PEGDA) in, wherein the mass ratio of 20000 molecule PEGDA and 700 molecule PEGDA are 6:4,
Then, 1.8ml deionized water is added under stirring, lasting stirring ultrasound each 20 minutes, obtains uniform liquid, consolidating for solution contains
Amount is 60%, spare, can prepare different cross-linked polyethylene glycol dipropyls by adjusting the quality proportioning of PEGDA of two kinds of molecular weight
Olefin(e) acid ester (PEGDA) hydrogel sized molecules link network, realization are administered various sizes of drug molecule；
(22) the 140 above-mentioned dispersion liquids of μ l are taken, DNA solution and 0.0035g that the concentration of 80 μ g is 10mg/ml is added
2- hydroxyl -4'- (2- hydroxy ethoxy) -2- methyl phenyl ketone is as light-fixing agent.
As the further improvement of above-mentioned technology, the specific steps packet of compound micropin is prepared described in above-mentioned steps (3)
It includes: will be centrifuged behind the microneedle patch back for carrying the injection preparation of medicine substrate, after five minutes by 4000rpm/min centrifugation, 70%
The UV illumination of intensity 30 seconds can prepare the compound micropin for being mounted with pharmaceutical hydrogel.
As the further improvement of above-mentioned technology, the voltage range 1-10V of the DC power supply in above-mentioned steps (4).
Compared with prior art, the beneficial effects of the present invention are:
(1) the transdermal accurate drug delivery device of the present invention based on micropin formula ion nestocalyx part can efficiently realize insulin
Etc. macromoleculars cutaneous penetration, the percutaneous permeation rate of insulin is greatly improved by ionophoresis technology.
(2) the transdermal accurate drug delivery device of the present invention based on micropin formula ion nestocalyx part is by changing ionophoresis
Voltage, electric current, the time can more accurate, controllable drug delivery, realize the intelligent release of insulin and terminate, more accurately
Adjust blood glucose.
(3) material being related to of the invention is biocompatible materials, and process nonhazardous intermediate generates.
Detailed description of the invention
The present invention is described in detail in the following with reference to the drawings and specific embodiments:
Fig. 1 is the transdermal accurate drug delivery device structural schematic diagram of the present invention based on micropin formula ion nestocalyx part；
Fig. 2 is the transdermal accurate drug delivery device working principle signal of the present invention based on micropin formula ion nestocalyx part
Figure；
Fig. 3 is drug release comparison diagram of the ion swimming microneedle patch under 30 minutes different voltages；
Fig. 4 is that ion swimming microneedle patch is powered in 10V respectively and cold drug release changes with time relational graph.
Specific embodiment
As shown in Figure 1 and Figure 2, a kind of transdermal accurate drug delivery device based on micropin formula ion nestocalyx part of the present invention,
Compound micropin 10, DC power supply 30 and the lagging electrode slice 40 being connected including passing sequentially through conducting wire 20, the compound micropin 10
Including microneedle patch 11 and regulatable load medicine substrate 12, the microneedle patch 11 is by polyethylene glycol-cross-linked poly methyl ethylene
The hydrogel micropin with grid gap formed after ether-maleic acid crosslinking, the load medicine substrate 12 includes by after photocuring
Polyethyleneglycol diacrylate (PEGDA) 1211 and the composite hydrogel 121 for being enclosed with insulin 1212, the composite hydrogel
121 back side is equipped with microneedle electrodes piece 13, and the lagging electrode slice 40 and microneedle electrodes piece 13 are platinum electrode piece, electric conductivity
It is good, and chemical stability is high.
The invention also discloses the preparation method of the above-mentioned transdermal accurate drug delivery device based on micropin formula ion nestocalyx part,
It comprises the concrete steps that:
(1) microneedle patch 11 is prepared, the specific steps of the preparation microneedle patch 11 include:
(11) firstly, weighing 0.6-1.2g ethylene methacrylic ether-maleic acid powder, 0.3-O.6g molecular weight be 10000 second
Glycol is added in the deionized water of 6-12ml, after 90 DEG C of water-bath, magnetic agitation 30 minutes, can prepare slightly clear viscous
Thick precursor liquid, it is spare；
(12) secondly, precursor liquid to be imported into a certain number of micropin molds as required, micropin mold uses poly- diformazan
Radical siloxane PDMS solidifies with corresponding curing agent heat cross-linking to be prepared, and 4000rpm/min is centrifuged 5 minutes, to guarantee micropin needle point
Position；
(13) microneedle patch with " wall " can be prepared finally, being transferred to 80 DEG C of baking ovens and taking out after 24 hours.
(2) prepare and carry medicine substrate 12: the specific steps that the preparation carries medicine substrate 12 include:
(21) polyethyleneglycol diacrylate (PEGDA) of 1.65g molecular weight 20000 is weighed, 1.1g molecular weight 700 is added
Polyethyleneglycol diacrylate (PEGDA) in, wherein the mass ratio of 20000 molecule PEGDA and 700 molecule PEGDA are 6:4,
Then, 1.8ml deionized water is added under stirring, lasting stirring ultrasound each 20 minutes, obtains uniform liquid, consolidating for solution contains
Amount is 60%, spare, can be prepared by adjusting the quality proportioning of polyethyleneglycol diacrylate (PEGDA) of two kinds of molecular weight
Different cross-linked polyethylene glycol diacrylate (PEGDA) hydrogel sized molecules link networks are realized to various sizes of drug molecule
It is administered；
(22) the 140 above-mentioned dispersion liquids of μ l are taken, DNA solution and 0.0035g that the concentration of 80 μ g is 10mg/ml is added
2- hydroxyl -4'- (2- hydroxy ethoxy) -2- methyl phenyl ketone is as light-fixing agent.
(3) it prepares compound micropin 10: will be centrifuged, pass through behind the back for carrying the microneedle patch 11 of the injection preparation of medicine substrate 12
After crossing 4000rpm/min centrifugation 5min, the UV illumination 30s of 70% intensity can be prepared and is mounted with the compound micro- of pharmaceutical hydrogel
Needle 10；
(4) the negative of DC power supply 30 is connected by conducting wire 20 again after carrying 12 back of medicine substrate installation microneedle electrodes piece 13
Pole separately takes a lagging electrode slice 13 to connect the anode of DC power supply 30, the voltage range 1-10V of the DC power supply
The working principle of detailed description below drug delivery device of the present invention:
For the release process of aids drug, as shown in Fig. 2, one container 50 of setting, loads onto 500 microlitres in container 50
PBS buffer solution 60 adjusts the release of electric current, voltage and time progress drug (DNA70), and concentration is by microplate reader Nano Quant
Plate progress quantitative analysis results are as shown in Figure 3, Figure 4, the release conditions under 30 minutes, different voltages: in the electricity of 0V-10V
It presses under gradient, with the increase of voltage, release amount of medicine is also with incremental.Likewise, under 10V voltage, with conduction time
Increase, incremental rule is also presented in drug concentration, by adjusting voltage and time, can accurately control the release of drug.
By change the voltage of ionophoresis, electric current, the time can more accurate, controllable drug delivery, realize the intelligent release of insulin
With termination, blood glucose is adjusted more accurately.
It is all that the present invention is not departed to various changes or modifications of the invention the invention is not limited to above embodiment
Spirit and scope, if these modification and variations belong within the scope of claim and equivalent technologies of the invention, then this hair
It is bright to also imply that comprising these modification and variations.
Claims (7)
1. a kind of transdermal accurate drug delivery device based on micropin formula ion nestocalyx part, it is characterised in that: including passing sequentially through conducting wire
Compound micropin, DC power supply and the lagging electrode slice being connected, the compound micropin include microneedle patch and regulatable load medicine
Substrate, the microneedle patch are that have grid gap by what is formed after polyethylene glycol-cross-linked poly methyl vinethene-maleic acid crosslinking
Hydrogel micropin, the load medicine substrate includes by the polyethyleneglycol diacrylate (PEGDA) after photocuring and being enclosed with pancreas
The back side of the composite hydrogel of island element, the composite hydrogel is equipped with microneedle electrodes piece.
2. the transdermal accurate drug delivery device according to claim 1 based on micropin formula ion nestocalyx part, it is characterised in that: institute
It states lagging electrode slice and microneedle electrodes piece is platinum electrode piece.
3. the preparation method of the transdermal accurate drug delivery device based on micropin formula ion nestocalyx part according to right 1 or 2, tool
Body step is:
(1) microneedle patch is prepared；
(2) preparation carries medicine substrate；
(3) compound micropin is prepared；
(4) cathode that medicine substrate back installation platinum electrode connecting wire connects DC power supply is carried, a lagging electrode slice is separately taken to connect
The anode of logical DC power supply.
4. the preparation method of the transdermal accurate drug delivery device according to claim 3 based on micropin formula ion nestocalyx part,
Be characterized in that: the specific steps of preparation microneedle patch described in above-mentioned steps (1) include:
(11) firstly, weighing 0.6-1.2g ethylene methacrylic ether-maleic acid powder, the ethylene glycol that 0.3-O.6g molecular weight is 10000,
It is added in the deionized water of 6-12ml, after 90 DEG C of water-bath, magnetic agitation 30 minutes, slightly clear sticky forerunner can be prepared
Liquid, it is spare；
(12) secondly, precursor liquid to be imported into a certain number of micropin molds as required, micropin mold uses poly dimethyl silicon
Oxygen alkane PDMS solidifies with corresponding curing agent heat cross-linking to be prepared, and 4000rpm/min is centrifuged 5 minutes, to guarantee to form micropin needle point
Position；
(13) microneedle patch with " wall " can be prepared finally, being transferred to 80 DEG C of baking ovens and taking out after 24 hours.
5. the preparation method of the transdermal accurate drug delivery device according to claim 3 based on micropin formula ion nestocalyx part,
Be characterized in that: preparation described in above-mentioned steps (2) carries the specific steps of medicine substrate and includes:
(21) polyethyleneglycol diacrylate (PEGDA) of 1.65g molecular weight 20000 is weighed, the poly- of 1.1g molecular weight 700 is added
In glycol diacrylate (PEGDA), wherein the mass ratio of 20000 molecule PEGDA and 700 molecule PEGDA are 6:4, then,
1.8ml deionized water is added under stirring, lasting stirring ultrasound each 20 minutes, obtains uniform liquid, the solid content of solution is
60%, it is spare；
(22) the 140 above-mentioned dispersion liquids of μ l are taken, the concentration that 80 μ g are added is the DNA solution of 10mg/ml and the 2- hydroxyl of 0.0035g
Base -4'- (2- hydroxy ethoxy) -2- methyl phenyl ketone is as light-fixing agent.
6. the preparation method of the transdermal accurate drug delivery device according to claim 3 based on micropin formula ion nestocalyx part,
Be characterized in that: the specific steps that compound micropin is prepared described in above-mentioned steps (3) include: that will carry medicine substrate to inject the micropin prepared
Patch is centrifuged behind back, and after five minutes by 4000rpm/min centrifugation, the UV illumination of 70% intensity 30 seconds can prepare dress
It is loaded with the compound micropin of pharmaceutical hydrogel.
7. the preparation method of the transdermal accurate drug delivery device according to claim 3 based on micropin formula ion nestocalyx part,
It is characterized in that: the voltage range 1-10V of the DC power supply in above-mentioned steps (4).
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110812688A (en) * | 2019-11-20 | 2020-02-21 | 广州中医药大学(广州中医药研究院) | Transdermal drug delivery microneedle and preparation method thereof |
| CN111643447A (en) * | 2020-06-10 | 2020-09-11 | 赵超超 | Drug-loaded microneedle, drug-loaded microneedle patch, electrically controlled drug release microneedle system and preparation method of drug-loaded microneedle |
| CN111956951A (en) * | 2019-12-17 | 2020-11-20 | 中山大学·深圳 | Iontophoresis micro-needle medicine patch and preparation method thereof |
| CN112587790A (en) * | 2020-11-25 | 2021-04-02 | 中山大学 | Transdermal drug pressing/ion electrophoresis controlled release device based on 3D printing hollow microneedle array |
| CN112827061A (en) * | 2021-02-26 | 2021-05-25 | 中山大学 | Drug release control device, control method thereof, and computer-readable storage medium |
| CN113171090A (en) * | 2021-03-12 | 2021-07-27 | 中山大学 | Diabetes monitoring and treating device and system based on mesoporous microneedle |
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| CN111956951B (en) * | 2019-12-17 | 2022-09-09 | 中山大学·深圳 | Iontophoresis micro-needle medicine patch and preparation method thereof |
| CN111643447A (en) * | 2020-06-10 | 2020-09-11 | 赵超超 | Drug-loaded microneedle, drug-loaded microneedle patch, electrically controlled drug release microneedle system and preparation method of drug-loaded microneedle |
| CN111643447B (en) * | 2020-06-10 | 2024-02-09 | 赵超超 | Drug-loaded microneedle, drug-loaded microneedle patch, electrically-controlled drug release microneedle system and drug-loaded microneedle preparation method |
| CN112587790A (en) * | 2020-11-25 | 2021-04-02 | 中山大学 | Transdermal drug pressing/ion electrophoresis controlled release device based on 3D printing hollow microneedle array |
| CN112827061A (en) * | 2021-02-26 | 2021-05-25 | 中山大学 | Drug release control device, control method thereof, and computer-readable storage medium |
| CN113171090A (en) * | 2021-03-12 | 2021-07-27 | 中山大学 | Diabetes monitoring and treating device and system based on mesoporous microneedle |
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| CN113171090B (en) * | 2021-03-12 | 2023-09-26 | 中山大学 | Diabetes monitoring and treatment device and system based on mesoporous microneedle |
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