CN114376569A - Glucagon-carrying wearable device for treating hypoglycemia - Google Patents

Glucagon-carrying wearable device for treating hypoglycemia Download PDF

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CN114376569A
CN114376569A CN202210062336.5A CN202210062336A CN114376569A CN 114376569 A CN114376569 A CN 114376569A CN 202210062336 A CN202210062336 A CN 202210062336A CN 114376569 A CN114376569 A CN 114376569A
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microneedle
wearable device
glucagon
lifting
module
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CN114376569B (en
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郑超
于翔
谷卫
张亦凯
王声遥
叶舒
胡叶鹏
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Zhejiang University ZJU
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Zhejiang University ZJU
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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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Abstract

The invention provides a glucagon-carrying wearable device for treating hypoglycemia, which comprises: the shell comprises an upper cover, a bottom shell and watchbands arranged on two sides and is used for fixing the wearing equipment on the surface of the skin of a human body; arrange inside control module, the lift module of casing and the module of dosing in, wherein: the drug delivery module comprises a microneedle array fixed at the bottom of the lifting module, the microneedle array comprises a plurality of microneedles, and each microneedle contains a drug; the control module at least comprises a detection probe and a signal processing module, the detection probe is fixed at the bottom of the shell and can be used for directly contacting human skin, detecting human physiological indexes in real time, the signal processing module is used for judging the relation between the human physiological indexes detected in real time and a normal physiological index threshold value, if the relation is smaller than the threshold value, a control signal is sent to control the lifting module to descend, and the lifting module drives the microneedle array to descend to release drugs. The invention also discloses the microneedle and a preparation method thereof.

Description

Glucagon-carrying wearable device for treating hypoglycemia
Technical Field
The invention relates to wearable equipment, in particular to glucagon-carrying wearable equipment which is used for monitoring the concentration of glucose in a body in real time, controllably delivering glucagon and timely administering medicine to realize the quick treatment of hypoglycemia.
Background
Hypoglycemia is a limiting factor in the long-term maintenance of normal blood glucose levels in diabetic patients. Minimizing the risk of hypoglycemia is an important issue that needs to be addressed in diabetes management. Hypoglycemia refers to the condition that the concentration of fasting blood glucose of an adult is lower than 2.8 mmol/L. The blood sugar value of the diabetic patient is less than or equal to 3.9mmol/L, so that hypoglycemia can be diagnosed. Hypoglycemia is a group of syndromes caused by various causes and mainly characterized by low concentration of venous plasma glucose (blood glucose for short) and excitation of sympathetic nerves and hypoxia of brain cells in clinic. The symptoms of hypoglycemia usually include sweating, hunger, palpitation, tremor, pale complexion, etc., and the serious patients may also have mental confusion, restlessness, irritability, even coma, etc.
The hypoglycemia condition is serious, irreversible damage can be caused to the body when the hypoglycemia condition is not timely relieved, people are difficult to carry medicines anytime and anywhere in daily work and life, ordinary sugar cannot be timely relieved when sudden severe hypoglycemia occurs, and meanwhile, effective help calling cannot be achieved when sudden hypoglycemia occurs, so that the subsequent difficulty in relief is increased. If the treatment is not timely, the continuous severe hypoglycemia can cause consciousness loss, cause permanent nerve damage and even death. Many diabetics have difficulty in effectively self-monitoring their blood sugar for diabetes and treatment-induced hypoglycemia, thereby increasing the incidence of severe hypoglycemia and exacerbating the patient's condition and economic burden.
Microneedles have been a new drug delivery vehicle proposed in the last 70 th century. Microneedles can be classified into four categories, namely, solid microneedles, coated microneedles, soluble microneedles and hollow microneedles, according to the preparation process and material properties. Among them, soluble microneedles are the most widely studied and hottest microneedle drug delivery system. An ideal dissolvable microneedle would be one with the tip loaded with drug and the base holder without drug. The powder core-shell type microneedle is a drug delivery system formed by filling a drug in a microneedle shell in a powder form. The micro-needle has no basal layer and does not have the problem of drug diffusion distribution, but the nano technology and the soluble micro-needle are combined by matching with an instrument, so that the problem that the drug cannot be concentrated on the needle point due to the concentration diffusion effect of the drug can be solved. .
Drug-device combination products (Drug-device combination products) refer to a single entity that is composed of drugs and medical devices together to achieve a certain therapeutic function. With the rapid development of materials, electronics and digital networks, the technology of drug-mechanical integration is also remarkably improved. The intelligent wearable drug delivery system can integrate multiple functions of diagnosis, monitoring, drug delivery, treatment and the like to form an intelligent wearable drug delivery system. Based on the outstanding advantages of the medical apparatus and the current research state, wearable drug delivery devices have a large development space, but no intelligent wearable drug delivery system for treating hypoglycemia is reported so far.
Disclosure of Invention
The invention aims at overcoming the defects of the prior art and provides a wearable device for treating hypoglycemia.
According to one aspect of the invention, there is provided a wearable device comprising: the shell comprises an upper cover, a bottom shell and watchbands arranged on two sides and is used for fixing the wearing equipment on the surface of the skin of a human body; arrange inside control module, the lift module of casing and the module of dosing in, wherein: the drug delivery module comprises a microneedle array fixed at the bottom of the lifting module, the microneedle array comprises a plurality of microneedles, and each microneedle contains a drug; the control module at least comprises a detection probe and a signal processing module, the detection probe is fixed at the bottom of the shell and can be used for directly contacting human skin, detecting human physiological indexes in real time, the signal processing module is used for judging the relation between the human physiological indexes detected in real time and a normal physiological index threshold value, if the relation is smaller than the threshold value, a control signal is sent to control the lifting module to descend, and the lifting module drives the microneedle array to descend to release drugs.
Preferably, each microneedle is a bilayer comprising a bottom layer and a tip layer, wherein the bottom layer carries a reducing agent and the tip layer carries a glucagon redox cluster; and the physiological index is blood glucose concentration.
Preferably, the lifting module comprises: a drive gear driven by a reduction motor; the spiral lifting turntable is meshed with the driving gear and is of a cavity structure, and an internal thread component is arranged on the inner wall of the cavity; the lifting assembly comprises a first lifting piece and a second lifting piece which are fixedly connected, wherein an external thread component meshed with an internal thread component of the inner wall of the cavity of the spiral lifting turntable is arranged on the outer wall of the first lifting piece, the microneedle array is fixed at the bottom of the second lifting piece, and the lifting distance of the lifting assembly is greater than the sum of the distance between the thickness of a skin cuticle layer and the distance between the tip of a microneedle and the bottom shell.
Preferably, the internally threaded member is a helical bead, and the externally threaded member is a trapezoidal helical groove.
Preferably, the outer wall of the second lifting part is provided with a lifting component guide rib, the inner wall of the shell is provided with a shell guide groove, and the lifting component guide rib is matched with the shell guide groove, so that the lifting component can only move up and down under the action of the guide groove,
preferably, an upper flange and a lower flange are arranged in the shell and used for fixing the spiral lifting turntable between the upper flange and the lower flange, so that the spiral lifting turntable can only do circular motion between the upper flange and the lower flange, and the vertical motion is restricted.
Preferably, the bottom case further comprises a waterproof membrane coated on the microneedle array, and a waterproof membrane fixing plate for fixing the waterproof membrane is fixed on the bottom case.
Preferably, the waterproof membrane is made of aluminum foil, and the thickness of the waterproof membrane ranges from 1 μm to 100 μm, and preferably ranges from 1 μm to 50 μm.
Preferably, the signal processing module can be configured to obtain the current of the speed reduction motor, when the lifting assembly is operated to the uppermost end or the skin surface, the speed reduction motor is locked and the current is increased, and when the signal processing module detects the current increase, the power supply of the speed reduction motor is disconnected.
Preferably, the signal processing module is further equipped with a 2.5GHz communication chip, and is configured to send the determined abnormal information to an external device and/or send a distress signal.
Preferably, the control module further comprises a screen fixed below the upper cover of the housing for displaying the detected blood glucose concentration of the human body in real time.
Preferably, the tip layer material of the microneedle array is composed of a polymer, and the polymer is a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan and dextran mixed according to any proportion.
Preferably, the glucagon redox cluster is generated by taking glucagon as a raw material, adding a disulfide bond cross-linking agent, and carrying out covalent reaction under stirring at room temperature.
Preferably, the disulfide crosslinking agent is one selected from the group consisting of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion.
Preferably, the bottom layer material of the microneedle is selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylated hyaluronic acid mixed according to any proportion.
Preferably, the detection probes are platinum electrode probes with glucose oxidase coated on a semi-permeable membrane, and the number of the platinum electrode probes is at least 2.
Preferably, the signal processing module comprises a PCB board, and the MCU is disposed on the PCB board.
According to another aspect of the present invention, the present invention provides a microneedle for use in a wearable device, the microneedle being a bilayer comprising a bottom layer and a tip layer, wherein the bottom layer carries a reducing agent and the tip layer carries a glucagon redox cluster.
Preferably, the glucagon redox cluster is generated by taking glucagon as a raw material, adding a disulfide bond cross-linking agent, and carrying out covalent reaction under stirring at room temperature.
Preferably, the disulfide crosslinking agent is one selected from the group consisting of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion.
Preferably, the tip layer material of the microneedle comprises a polymer, wherein the polymer is a mixture formed by mixing one or more of dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan and dextran in any proportion.
Preferably, the bottom layer material of the microneedle comprises a light-cured material selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylated hyaluronic acid mixed in any proportion.
Preferably, the tip layer material of the microneedle is composed of a polymer, and the polymer is a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan and dextran mixed according to any proportion.
Preferably, the glucagon redox cluster is generated by taking glucagon as a raw material, adding a disulfide bond cross-linking agent, and carrying out covalent reaction under stirring at room temperature.
Preferably, the disulfide crosslinking agent is one selected from the group consisting of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion.
According to another aspect of the present invention, there is provided a method of preparing a microneedle, comprising the steps of:
preparing a glucagon water solution with a certain concentration;
adding a disulfide bond cross-linking agent, and magnetically stirring at room temperature to obtain a glucagon redox cluster;
weighing a proper amount of polymer and mixing with the glucagon redox cluster solution to prepare a microneedle tip solution;
injecting the microneedle tip solution into a microneedle mould, centrifuging at a high speed, and drying overnight to prepare a microneedle tip layer;
and (3) preparing a reducing agent solution, dropwise adding the reducing agent solution onto a microneedle mould containing the needle point layer, carrying out vacuum treatment for 1 minute, and carrying out ultraviolet irradiation for 6 minutes to form a bottom end layer of the microneedle so as to obtain the final glucagon redox cluster microneedle.
Preferably, the aqueous solution is a PBS aqueous solution with pH 9.
Preferably, the room temperature magnetic stirring time is 1 hour.
Preferably, the microneedle mould contains a plurality of conical shaped holes.
Preferably, the conical holes have a hole depth of 1500-.
Preferably, the concentration ratio of the glucagon, the aqueous solution and the disulfide cross-linker is: 100 mg: 50 ml: 50 mg; and the concentration ratio of the polymer to the glucagon redox cluster solution is: 150 mg: 1 ml.
Preferably, the glucagon redox cluster solution contains 100mg of insulin per 1 ml.
Preferably, the microneedle mould is made of polydimethylsiloxane.
Preferably, the disulfide cross-linking agent is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide; and the reducing agent is one or a mixture of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion.
Preferably, the polymer is a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan and dextran mixed according to any proportion.
Preferably, the bottom layer comprises a light-cured material selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylated hyaluronic acid mixed in any proportion.
The present invention has the following advantageous effects.
1. Physiological indexes in a human body can be monitored in real time, and drug delivery can be controlled, so that the effect of quick treatment is realized.
2. The glucagon-like glucose sensor is particularly suitable for monitoring the blood glucose concentration in a human body, providing glucagon according to the blood glucose level and realizing the function of quickly treating hypoglycemia.
Drawings
FIG. 1 shows the synthesis process (A) and the principle (B) of the redox-release of glucagon
FIG. 2 shows a transmission electron micrograph (A), particle size distribution (B) and Zeta potential (C) of glucagon redox clusters
Figure 3 shows a route for preparation of glucagon-loaded redox cluster microneedle arrays.
Fig. 4 is an appearance and appearance map of the microneedle automatic device.
Fig. 5 is a device composition diagram of the microneedle automatic apparatus.
Fig. 6 is a schematic view of the lifting structure of the microneedle robot.
Fig. 7 is a working principle diagram of the spiral lifting turntable.
FIG. 8a is a schematic view of the inner connection between the lifting assembly and the spiral lifting turntable.
Figure 8b shows a simplified schematic of the lifting assembly.
Fig. 9 is a schematic view of microneedle assembly installation.
Fig. 10 is an appearance of the glucagon-loaded redox cluster microneedle array.
Fig. 11 is a displacement versus load curve for a glucagon-loaded redox cluster microneedle array.
Fig. 12 is a diagram of pathological skin punctures by glucagon-loaded redox cluster microneedle arrays.
Figure 13 is an in vivo pharmacokinetic profile of glucagon-loaded formulations.
Figure 14 is a plot of blood glucose versus time for a glucagon-loaded wearable device.
Detailed Description
The following describes in detail specific embodiments of the present invention, but the preparation process, the substances used, and the amount of the substances used in the examples of the glucagon-carrying wearable device according to the present invention are not limited to the words, and all the devices containing the pharmaceutical composition and the pharmaceutical-mechanical combination provided by the present invention are within the scope of the present invention.
Referring to fig. 4 and 5, the wearable device of the present invention for treating hypoglycemia includes a case 1 and a band 11 disposed on both sides for fixing the wearable device on the skin surface of a human body; the inside of the housing 1 is provided with a control module 2, a lifting module 3 and a drug delivery module 4. Wherein: the drug delivery module 4 includes a microneedle array 41 secured to the bottom of the lifting module 3, the microneedle array containing a plurality of microneedles 410, each containing a drug for treating hypoglycemia.
The specific drug and the preparation of the microneedles 410 are shown in fig. 1-3.
I. Preparation and characterization of glucagon redox clusters
Dissolving 100mg glucagon in 50ml PBS water solution with pH of 9, adding 50mg NHS-S-S-NHS, magnetically stirring at room temperature for 1 hr, separating and purifying with Sephadex column to obtain glucagon redox cluster (FIG. 1A). When the cluster meets glutathione solution, the disulfide bond is reduced and broken, a ring-closing reaction occurs, and glucagon is released through degradation (figure 1B).
The cluster prepared was shown to have a particle size of about 60nm (FIG. 2A) and a Zeta potential of-52.9 mV (FIG. 2B) by using dynamic light scattering, indicating that the cluster has good thermodynamic stability. The transmission electron micrograph shows that the cluster is spherical (fig. 2C).
Preparation of glucagon redox cluster microneedles
150mg of polyvinylpyrrolidone K90 was dissolved in 1ml of the above glucagon redox cluster solution (containing 100mg of insulin). The solution is dripped into a micro-needle mold containing 100 conical holes and polydimethylsiloxane with the hole depth of 1500-.
Preparing a 500mg/ml glutathione vinyl pyrrolidone solution, dripping the solution on a mold containing a needle point, carrying out vacuum treatment for 1 minute (min), carrying out ultraviolet irradiation for 6 minutes, and forming a bottom layer 411 containing a reducing agent on a needle point layer 412 to obtain the final glucagon redox cluster microneedle 410 (fig. 3).
The micro-needle 410 is attached to the bottom of the lifting component 32 of the micro-needle array automatic injector (i.e. wearable device) through a double-sided adhesive tape, and the waterproof film 42 is fixed to the bottom layer of the micro-needle automatic injector through the waterproof film fixing plate 43. The specific structure of the wearable device is described below.
The above is one preferred embodiment of the glucagon redox cluster microneedle of the present invention, but the present invention is not limited thereto. For example, the needle tip layer 412 of the microneedle array 41 is made of a polymer, and the polymer may be a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan, and dextran mixed in any ratio.
The glucagon redox cluster is generated by taking glucagon as a raw material, adding a disulfide bond cross-linking agent, and carrying out covalent reaction under stirring at room temperature.
The disulfide cross-linking agent may be one selected from succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
The reducing agent is one or a mixture of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion. And, the material of the bottom layer 411 of the microneedle array 41 is selected from one or more of vinylpyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and methacrylated hyaluronic acid mixed in any ratio.
Design of microneedle auto-injectors
As shown in fig. 4 to 5, the wearable device comprises a housing 1 including an upper cover 12, a bottom case 13, and a band 11 disposed on both sides for fixing the wearable device on the skin surface of a human body.
Inside control module 2, the lifting module 3 and the module 4 of dosing of being provided with of casing, wherein: the administration module 4 includes a microneedle array 41 secured to the bottom of the lifting module 3, the microneedle array comprising a plurality of microneedles 410, each containing a drug. The bottom case 13 further includes a waterproof film 42 covering the microneedle array 41, and a waterproof film fixing plate 43 for fixing the waterproof film 42. The waterproof membrane fixing plate 43 is fixed to the bottom case 13. The waterproof film 42 is preferably made of aluminum foil, and has a thickness in the range of 1 μm to 100 μm, preferably 1 μm to 50 μm.
The control module 2 comprises a signal processing module 22, an OLED screen 21, a soft package battery 25 for supplying power and a detection probe 24.
The detection probe 24 is fixed at the bottom of the shell 1 and can be used for directly contacting human skin and detecting human physiological indexes in real time. In one embodiment, the detection probes 24 are platinum electrode probes coated with glucose oxidase through a semi-permeable membrane, generally not less than 2, and are fixed on the bottom shell of the shell to directly contact with the human body.
The detection probe is sensitive to glucose in a human body, when the glucose in the human body changes, the potential of the detection probe changes, the signal processing module 22 comprises a PCB, and the MCU is arranged on the PCB and can detect the potential change of the probe, so that whether the glucose in the human body is in a normal level or not is judged. When the glucose exceeds the normal range, the MCU sends a signal to drive the turntable to rotate, so as to drive the lifting assembly 32 of the lifting module 3 to move downwards, and the microneedles 410 pierce the waterproof membrane 42 and enter the skin to release the drug. In order to ensure the drug release, the lifting distance of the lifting assembly 32 needs to be greater than the sum of the thickness of the stratum corneum layer of the skin and the distance from the tip of the microneedle to the bottom case 13.
The OLED screen 21 is placed directly under the upper cover 12 of the housing and is used to display the real-time glucose level of the patient obtained by the detection probes 24. The upper cover of the shell is made of transparent materials.
The signal processing module 22 is further equipped with a 2.5GHz communication chip (not shown) for sending the determined abnormal information to an external device and/or sending a distress signal.
As shown in fig. 6 to 7, the lifting module 3 includes a driving gear 30 driven by a reduction motor 33, and a spiral lifting turn table 31 engaged with the driving gear. The outer wall of the spiral lifting turntable 31 is provided with a gear ring which is meshed with the driving gear 30, and the spiral lifting turntable 31 is pushed to rotate by the driving gear 30. The driving gear 30 is fixed on an output shaft of the gear motor 33, and the gear motor 33 drives the driving gear to rotate when rotating. The spiral lifting turntable 31 is of a cavity structure, and an internal thread member 310, specifically a spiral rib, is arranged on the inner wall of the cavity.
Further, as shown in fig. 7, the side wall of the housing 1 is provided with an upper flange 34 and a lower flange 35 for fixing the spiral elevating turntable 31, and the spiral elevating turntable 31 is embedded between the upper flange 34 and the lower flange 35, so that the spiral elevating turntable 31 can only perform circular motion between the upper flange and the lower flange, and the vertical motion is restricted.
The lifting module 3 further comprises a lifting assembly 32, the lifting assembly 32 comprises a first lifting member 321 and a second lifting member 322 which are fixedly connected, wherein an external thread member 325, in this embodiment, specifically, a trapezoidal spiral groove, which is engaged with the internal thread member 310 on the inner wall of the cavity of the spiral lifting turntable 3 is arranged on the outer wall of the first lifting member 321. The bottom of the second lifting piece 322 fixes the microneedle array 41, and the lifting assembly 32 lifts by a distance greater than the sum of the thickness of the stratum corneum of the patient's skin and the distance from the tip of the microneedle 410 to the bottom case 13, so as to ensure that the microneedle 410 can penetrate into the skin of the patient to release the drug.
The outer wall of the second lifting member 322 is further provided with a lifting assembly guide rib 323, the inner wall of the housing 1 is provided with a housing guide groove 14, and the lifting assembly guide rib 323 is matched with the housing guide groove 14, so that the lifting assembly 32 can only move up and down under the action of the guide groove 14. The shell 1 is also provided with a fixed layer positioned at the top of the spiral lifting turntable and used for limiting the limit position of the upward movement of the lifting assembly.
Fig. 8b shows a simplified structure of the lifting assembly, in which the spiral lifting turntable 31 and the lifting assembly 32 are connected by a screw pair. When the spiral lifting turntable 31 rotates, the lifting assembly 32 can move in the vertical direction under the action of the engaged spiral rib 310 and the trapezoidal spiral groove 325, so as to realize the pressing and lifting actions. The ascending or descending height of the ascending and descending component 32 is influenced by the rotation angle of the spiral ascending and descending turntable 31, and the ascending and descending height can be controlled by controlling the rotation angle of the speed reducing motor 33.
In addition, the signal processing module 22 can be configured to obtain the current of the gear motor 33, when the lifting assembly 32 is operated to the uppermost end or skin surface, the gear motor 33 is locked and the current is increased, and when the signal processing module 22 detects the increase of the current, the power supply of the gear motor 33 is cut off.
Preferably, as shown in fig. 8a, the second lifting member 322 is cylindrical, and a screw hole 324 is formed in the middle for fixedly connecting with the first lifting member 321. Meanwhile, a circular through hole is formed in a bottom shell 13 of the shell 1, and the shell guide groove 14 is formed in the through hole. Further, the bottom of the lifting assembly 32 is a square flat bottom, which facilitates fixing the microneedle array 41.
As shown in fig. 9, a microneedle array 41 is mounted at the bottom end of the lifting assembly 32, and the microneedle tips are protected by a waterproof film 42. The waterproof membrane 42 is fixed below the microneedle array 41 by a waterproof membrane fixing plate 43, the waterproof membrane fixing plate 43 is fixed on the bottom case 13 of the housing 1 by a screw (not shown) through a screw hole 431, and the waterproof membrane fixing plate is used for being convenient to detach, and the microneedle array 41 can be conveniently replaced from the lower end after being used.
The work flow of the wearable device is as follows:
the device is fixed on the surface of human skin through a watchband, a detection probe 24 fixed on the bottom shell of the wearable device is directly contacted with the human skin and starts to detect the blood glucose concentration of the human body in real time, and the blood glucose concentration is displayed on the OLED screen 21 in real time. Meanwhile, the MCU arranged on the PCB of the signal detection module 22 compares the blood glucose concentration fed back by the detection probe 24 with a set normal blood glucose concentration threshold value. When the normal range is exceeded, the MCU sends a signal to control the speed reduction motor 33 to rotate to drive the lifting assembly 32 to descend. The microneedle array 41 fixed to the bottom of the lifting assembly 32 is lowered to penetrate the waterproof film 42 and then to pierce the skin of the human body. After the microneedle tips are dissolved, the reducing agent on the bottom layer 411 of the microneedle and the glucagon redox cluster on the tip layer are instantaneously reacted to release glucagon.
After the medicine is released, the speed reducing motor 33 is controlled to rotate reversely to enable the lifting assembly to ascend and return to the original position. Wherein, when lifting unit 32 moved to the top or when the lower extreme, gear motor 33 locked rotor, gear motor electric current risees, and MCU detects the electric current increase, cuts off the gear motor power supply promptly. Because the distance of descending and ascending of the lifting component 32 is greater than the sum of the thickness of the cutin layer of the skin and the distance from the tip of the microneedle to the bottom shell, the microneedle can be ensured to penetrate into the skin to release the drug. To ensure that the drug is released, the time for the lifting assembly 32 to descend is controlled, which generally takes 30 minutes.
The effects of the present invention are further illustrated below in connection with specific tests:
experimental example 1 appearance of glucagon redox cluster microneedle array
The prepared glucagon redox cluster microneedle array patches were fixed with a conductive tape, respectively, and the topography of the microneedles was observed with a scanning electron microscope (SEM, JSM-6330F, japan) at a voltage of 5kV to obtain fig. 10 and measure the dimensions of the tip and the height of the needles.
Figure 10 illustrates the topography of one embodiment of a glucagon redox cluster microneedle array with a sharp tip. The width of the needle tip is 15 μm, the length of the needle tip is 1800 μm, and the distance between the needle tips is 1500 μm.
Experimental example 2 mechanical Strength of glucagon Redox Cluster microneedle array
The glucagon redox cluster microneedle array patch is attached to the backing layer of the glucagon redox cluster microneedle array patch by using a double-sided adhesive tape, and is fixed on a metal table of a pressure-tension tester (SGL-8000, Suzhou Shanghai detection equipment Co., Ltd.), the tip of the microneedle faces to a probe of the instrument, the probe is pressed downwards towards the microneedle, and the force and displacement applied by the instrument can be recorded.
As shown in fig. 11, the resulting microneedle had a load bearing capacity of 0.19N, indicating that the microneedle had sufficient mechanical strength to pierce the stratum corneum of the skin.
Experimental example 3 skin insertion Performance of glucagon redox cluster microneedle array
BALB/C mice were used as an animal model, and the hair of the mice was shaved using a razor, and the exposed skin surface was cleaned with ethanol. The glucagon redox cluster microneedle array patches were inserted vertically into the dorsal skin of mice, respectively, and peeled off after 5 minutes of holding. The mice were sacrificed by decapitation, the skin was peeled off, the microneedle insertion sites were cut embedded, and frozen in liquid nitrogen. Cut to a thickness of 5 μm and placed on a silane-coated glass slide. The skin sections were observed under an inverted microscope (IX-71, Olympus, Tokyo, Japan).
As shown in fig. 12, the glucagon redox cluster microneedle array was inserted to a depth of 231 μm far deeper than the thickness of the stratum corneum (about 100 μm), which is the most important barrier for transdermal delivery of drugs. Therefore, the microneedle array facilitates percutaneous absorption of the drug.
EXAMPLE 4 pharmacokinetic Studies of glucagon wearable device
And (3) placing the microneedle array in a microneedle automatic injection device, and assembling the glucagon wearable device. SD rats (200 +/-10 g) were selected as model animals, and 12 animals were selected. The rats were divided into a subcutaneous injection group and a wearable group by shaving their back hairs using a razor. Wearable group: the wearable device was fixed to the back of the rat and the blood glucose trigger threshold was set to 0 mmol/l. Subcutaneous injection group: 0.1ml of a 1mg/ml glucagon solution was injected subcutaneously. Two groups of rats, 100 μ l plasma, were taken from the tail vein at fixed time points and the glucagon concentration in the plasma was determined by enzyme linked immunosorbent assay.
In vivo drug uptake (AUC) in wearable System immediate Start group as shown in FIG. 130～∞239 +/-23.5 h.ng/ml) and maximum blood concentration (C)max18.9. + -. 1.9. mu.g/ml) and mean residence time (MRT, 9.1. + -. 0.5h) versus AUC for the subcutaneous injection group0～∞(226±34.1ng/ml)、Cmax(19.8 +/-0.7 mu g/ml) and MRT (7.9 +/-0.8 h) have no significant difference. The wearable system of glucagon can quickly release medicine to body, and is beneficial to treating hypoglycemia。
EXAMPLE 5 pharmacodynamic study of glucagon wearable device
SD rats (200 +/-10 g) are selected as model animals, 12 animals are selected, and the model animals and the wearable device administration groups (6 animals in each group) are divided. The rats were shaved using a razor on their backs, 2IU of insulin was administered to both groups of rats after the initial blood glucose measurement, no treatment was applied to the model group, a glucagon wearable device was mounted on the backs of both wearable group rats, and the dosing threshold was set at 2.8 mmol. Blood glucose changes were measured at certain time points. As shown in FIG. 14, the blood glucose level of the model group decreased to 2.3. + -. 0.9mmol after 60 minutes of insulin administration, and the body reached a low blood glucose level. Blood glucose declined before 60 minutes in the wearable group, but rose back to 3.45 ± 0.3mmol after 65 minutes. Thereafter, blood glucose rose all the way back, and after 180 minutes the blood glucose value was 5.45. + -. 1.1mmol, whereas the model group blood glucose value was 1.85. + -. 0.4 mmol. This result indicates that the wearable device can immediately rescue medication when the blood glucose value drops below the hypoglycemic threshold.
Although the wearable device is aimed at treating hypoglycemia, a person skilled in the art can easily change the human body physiological indexes monitored in the control module and corresponding treatment medicines, and other diseases can be treated, so that the wearable device can be widely applied to treating various diseases.
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations could be devised by those skilled in the art in light of the present teachings without departing from the inventive concepts. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.

Claims (35)

1. A wearable device, characterized in that the wearable device comprises:
the shell (1) comprises an upper cover (12), a bottom shell (13) and watchbands (11) arranged on two sides and is used for fixing the wearing equipment on the surface of the skin of a human body;
locate control module (2), lift module (3) and dosing module (4) inside the casing, wherein:
the drug delivery module comprises a microneedle array (41) fixed at the bottom of the lifting module (3), wherein the microneedle array comprises a plurality of microneedles (410), and each microneedle contains a drug;
control module includes detecting probe (24) and signal processing module (22) at least, and detecting probe (24) are fixed in casing (1) bottom, can be used for the human skin of direct contact, the human physiology index of real-time detection, and signal processing module (22) are used for judging the relation of the human physiology index of real-time detection and normal physiology index threshold value, if be less than the threshold value, then send control signal control lifting module (3) descend, lifting module (3) drive micropin array (41) descend and are used for releasing the medicine.
2. The wearable device according to claim 1, wherein each microneedle (410) is a bilayer comprising a bottom layer (411) and a tip layer (412), wherein the bottom layer (411) carries a reducing agent and the tip layer (412) carries a glucagon redox cluster; and the physiological index is blood glucose concentration.
3. Wearable device according to claim 1 or 2, characterized in that the lifting module (3) comprises:
a drive gear (30) driven by a reduction motor (33);
the spiral lifting turntable (31) is meshed with the driving gear, the spiral lifting turntable (31) is of a cavity structure, and an internal thread component (310) is arranged on the inner wall of the cavity;
the lifting assembly (32) comprises a first lifting piece (321) and a second lifting piece (322) which are fixedly connected, wherein an external thread component (325) meshed with an internal thread component (310) on the inner wall of a cavity of the spiral lifting turntable (31) is arranged on the outer wall of the first lifting piece (321), the microneedle array (41) is fixed at the bottom of the second lifting piece (322), and the lifting distance of the lifting assembly (32) is greater than the sum of the thickness of a skin cutin layer and the distance from a microneedle tip to the bottom shell (13).
4. The wearable device according to claim 3, wherein the internally threaded member (310) is a helical rib and the externally threaded member (325) is a trapezoidal helical groove.
5. The wearable device according to claim 3, wherein the outer wall of the second lifting member (322) is provided with a lifting assembly guide rib (323), the inner wall of the housing is provided with a housing guide groove (14), and the lifting assembly guide rib (323) is matched with the housing guide groove (14) so that the lifting assembly (32) can only move up and down under the action of the guide groove (14).
6. Wearable device according to claim 3, wherein an upper flange (34) and a lower flange (35) are provided in the housing for securing the spiral lifting rotor (31) between the upper flange (34) and the lower flange (35) such that the spiral lifting rotor (31) can only move in a circular motion between the upper flange (34) and the lower flange (35), the vertical motion being restricted.
7. The wearable device according to claim 1 or 2, wherein the bottom case (13) further comprises a waterproof membrane (42) covering the microneedle array (41), and a waterproof membrane fixing plate (43) for fixing the waterproof membrane (42) is fixed to the bottom case (13).
8. Wearable device according to claim 1 or 2, wherein the waterproof membrane (42) is made of aluminium foil, with a thickness in the range of 1 μm to 100 μm, preferably 1 μm to 50 μm.
9. The wearable device according to claim 3, wherein the signal processing module (22) is configurable to obtain the current of the deceleration motor (33), wherein when the lifting assembly (32) is operated to the uppermost or skin surface, the deceleration motor (33) stalls and the current rises, and wherein when the signal processing module (22) detects an increase in current, the power supply to the deceleration motor (33) is disconnected.
10. The wearable device according to claim 1, wherein the signal processing module (22) is further equipped with a 2.5GHz communication chip for sending the determined abnormal information to an external device and/or sending a distress signal.
11. Wearable device according to claim 1, wherein the control module (2) further comprises a screen (21) fixed under the upper cover (12) of the housing (1) for displaying the detected blood glucose concentration of the human body in real time.
12. The wearable device of claim 2, wherein the glucagon redox cluster is formed by a covalent reaction of glucagon with a disulfide cross-linker at room temperature under stirring.
13. The wearable device according to claim 12, wherein the disulfide cross-linker is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
14. The wearable device according to claim 2, wherein the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide, and tocopherol, mixed in any proportion.
15. The wearable device according to claim 2, wherein the needle tip layer (412) material of the micro-needle (410) is composed of a polymer, and the polymer is a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan, and dextran mixed in any ratio.
16. The wearable device according to claim 2, wherein the bottom layer (411) of the micro-needle (410) is made of a mixture of one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylated hyaluronic acid in any proportion.
17. Wearable device according to claim 1, wherein the detection probes (24) are platinum electrode probes coated with glucose oxidase by a semi-permeable membrane, at least 2.
18. Wearable device according to claim 1, wherein the signal processing module (22) comprises a PCB board on which the MCU is arranged.
19. A microneedle for use in a wearable device, characterized in that the microneedle (410) is a bilayer comprising a bottom layer (411) and a tip layer (412), wherein the bottom layer (411) carries a reducing agent and the tip layer (412) carries glucagon redox clusters.
20. The microneedle according to claim 19, wherein the glucagon redox cluster is produced by adding a disulfide cross-linking agent to glucagon as a raw material and stirring the mixture at room temperature to cause a covalent reaction.
21. A microneedle according to claim 20, wherein said disulfide cross-linker is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenylcyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
22. A microneedle according to claim 19, wherein the reducing agent is selected from glutathione, vitamin C, manganese dioxide, cerium oxide, tocopherol, or a mixture thereof mixed in any proportion.
23. A microneedle according to claim 19, wherein the material of the tip layer (412) of the microneedle comprises a polymer selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethylcellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan, dextran, or a mixture thereof, mixed in any ratio.
24. A microneedle according to claim 19, wherein the material of the base layer (411) of the microneedle (410) comprises a light-curable material selected from one or more of vinylpyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylated hyaluronic acid in any proportion.
25. A method of producing a microneedle according to any one of claims 19 to 24, comprising the steps of:
preparing a glucagon water solution with a certain concentration;
adding a disulfide bond cross-linking agent, and magnetically stirring at room temperature to obtain a glucagon redox cluster;
weighing a proper amount of polymer and mixing with the glucagon redox cluster solution to prepare a microneedle tip solution;
injecting the microneedle tip solution into a microneedle mould, centrifuging at a high speed, and drying overnight to prepare a microneedle tip layer;
and (3) preparing a reducing agent solution, dropwise adding the reducing agent solution onto a microneedle mould containing the needle point layer, carrying out vacuum treatment for 1 minute, and carrying out ultraviolet irradiation for 6 minutes to form a bottom end layer of the microneedle so as to obtain the final glucagon redox cluster microneedle.
26. The method of claim 25, wherein the aqueous solution is a PBS aqueous solution having a pH of 9.
27. The method of claim 25, wherein the magnetic stirring is carried out at room temperature for 1 hour.
28. The method of manufacturing of claim 25, wherein the microneedle mold contains a plurality of conical shaped holes.
29. The method of claim 28, wherein: the depth of the conical hole is 1500-.
30. The method of claim 25, wherein: the concentration ratio of the glucagon, the aqueous solution and the disulfide cross-linker is: 100 mg: 50 ml: 50 mg; and the concentration ratio of the polymer to the glucagon redox cluster solution is: 150 mg: 1 ml.
31. The method of claim 30, wherein: the glucagon redox cluster solution contained 100mg of insulin per 1 ml.
32. The method of claim 24, wherein: the microneedle mould is made of polydimethylsiloxane.
33. The method of claim 24, wherein: the disulfide bond cross-linking agent is selected from one of succinimide-disulfide bond-succinimide, dibenzocyclooctyne-disulfide bond-amino, diphenylcyclooctyne-disulfide bond-succinimide and maleimide-disulfide bond-succinimide; and is
The reducing agent is one or a mixture of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol which are mixed according to any proportion.
34. The method for preparing the silk fibroin of the claim 24, wherein the polymer is a mixture of one or more selected from dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan and dextran mixed in any proportion.
35. The method of claim 24, wherein the bottom layer comprises a light-curable material selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and methacrylated hyaluronic acid mixed in any proportion.
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