CN114376569B - Glucagon-carrying wearable device for treating hypoglycemia - Google Patents
Glucagon-carrying wearable device for treating hypoglycemia Download PDFInfo
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- CN114376569B CN114376569B CN202210062336.5A CN202210062336A CN114376569B CN 114376569 B CN114376569 B CN 114376569B CN 202210062336 A CN202210062336 A CN 202210062336A CN 114376569 B CN114376569 B CN 114376569B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14503—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14532—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring glucose, e.g. by tissue impedance measurement
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6801—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be attached to or worn on the body surface
- A61B5/6802—Sensor mounted on worn items
- A61B5/681—Wristwatch-type devices
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Abstract
The present invention provides a glucagon-loaded wearable device for the relief of hypoglycemia, 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 skin surface of a human body; control module, lifting module and the module of dosing inside arranging the casing in, wherein: the drug delivery module comprises a microneedle array fixed at the bottom of the lifting module, wherein 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, wherein the detection probe is fixed at the bottom of the shell and can be used for directly contacting human skin to detect 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 normal physiological index threshold values, if the relation is smaller than the threshold values, a control signal is sent to control the lifting module to descend, and the lifting module drives the microneedle array to descend and is used for releasing medicines. The invention also discloses a microneedle and a preparation method thereof.
Description
Technical Field
The invention relates to a wearable device, in particular to a glucagon-carrying wearable device which is used for monitoring the concentration of glucose in a body in real time and controllably delivering glucagon, and timely dosing, so as to realize quick treatment of hypoglycemia.
Background
Hypoglycemia is a limiting factor in the maintenance of normal blood glucose levels in diabetics over a long period of time. Minimization of the risk of hypoglycemia is an important issue to be addressed in diabetes management. Hypoglycemia refers to an adult human having a fasting blood glucose concentration of less than 2.8mmol/L. The blood sugar value of the diabetics is less than or equal to 3.9mmol/L, and the hypoglycemia can be diagnosed. Hypoglycemia is a group of syndromes caused by various causes and characterized by low concentration of venous plasma glucose (abbreviated as blood glucose), clinically by sympathetic excitation and cerebral hypoxia. Symptoms of hypoglycemia are usually manifested by sweating, hunger, palpitation, trembling, pale complexion, etc., and severe ones may also be manifested as mental confusion, agitation, irritability, even coma, etc.
The situation of hypoglycemia is serious and can not cause irreversible injury to the health when not obtaining timely treatment, in daily work life, people are difficult to accomplish and carry the medicine anywhere at any time, ordinary sugar thing can't timely carry out the treatment when the sudden severe hypoglycemia, can't effectual call for help when the sudden hypoglycemia takes place to fall simultaneously, this just increases the follow-up treatment degree of difficulty. If the treatment is not timely, continuous severe hypoglycemia can cause loss of consciousness, permanent nerve injury and even death. Many diabetics have difficulty in effectively self-blood glucose monitoring of diabetes and treatment-induced hypoglycemia, thereby increasing the occurrence of severe hypoglycemia and increasing the patient's illness and economic burden.
Microneedles are new drug delivery vehicles proposed in the 70 s of the last century. Microneedles can be classified into four types, i.e., solid microneedles, coated microneedles, soluble microneedles, and hollow microneedles, according to the manufacturing process and material properties. Among them, soluble microneedles are the most widely studied and hottest microneedle delivery systems. The ideal soluble microneedle would be one with a drug loaded needle tip and a drug free base. Powder core-shell microneedles are a drug delivery system in which a drug is filled in powder form into the microneedle shells. The microneedle has no basal layer and no medicine diffusion distribution problem, but the nanotechnology is combined with the soluble microneedle by matching with an instrument, so that the problem that the medicine cannot be concentrated on a needle point due to concentration diffusion can be solved. .
The Drug-device combination product combination product refers to a single entity which is formed by medicines and medical devices together and realizes a certain treatment function. With the rapid development of materials, electronics and digital networks, the integrated technology of medicine and machinery has also been significantly advanced. The intelligent wearable drug delivery system can integrate various functions of diagnosis, monitoring, drug delivery, treatment and the like together to form the intelligent wearable drug delivery system. Based on the outstanding advantages of the medicine equipment and the current research state, the development space of the wearable medicine administration equipment is quite large, but no report on an intelligent wearable medicine administration system for treating hypoglycemia exists so far.
Disclosure of Invention
Aiming at the defects of the prior art, the invention 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 skin surface of a human body; control module, lifting module and the module of dosing inside arranging the casing in, wherein: the drug delivery module comprises a microneedle array fixed at the bottom of the lifting module, wherein 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, wherein the detection probe is fixed at the bottom of the shell and can be used for directly contacting human skin to detect 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 normal physiological index threshold values, if the relation is smaller than the threshold values, a control signal is sent to control the lifting module to descend, and the lifting module drives the microneedle array to descend and is used for releasing medicines.
Preferably, each microneedle is bilayer, comprising a bottom end layer and a tip layer, wherein the bottom end layer carries a reducing agent and the tip layer carries glucagon redox clusters; and the physiological index is blood glucose concentration.
Preferably, the lifting module comprises: a driving gear driven by the speed reduction motor; the spiral lifting turntable is meshed with the driving gear and is of a cavity structure, and an inner threaded member 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 outer wall of the first lifting piece is provided with an outer threaded component meshed with an inner threaded component of the inner wall of the cavity of the spiral lifting turntable, the microneedle array is fixed at the bottom of the second lifting piece, and the lifting distance of the lifting assembly is larger than the sum of the thickness of the skin stratum corneum and the distance from the tip of the microneedle to the bottom shell.
Preferably, the internal thread member is a spiral bead and the external thread member is a trapezoidal spiral groove.
Preferably, the outer wall of the second lifting member is provided with a lifting assembly guide rib, the inner wall of the shell is provided with a shell guide groove, the lifting assembly guide rib is matched with the shell guide groove, so that the lifting assembly can only move up and down under the action of the guide groove,
preferably, an upper flange and a lower flange are provided in the housing for fixing the spiral lifting turntable between the upper flange and the lower flange, so that the spiral lifting turntable can only perform circular movement between the upper flange and the lower flange, and the vertical movement is restrained.
Preferably, the bottom case further includes a waterproof film coated on the microneedle array, and a waterproof film fixing plate for fixing the waterproof film is fixed on the bottom case.
Preferably, the waterproof membrane is composed of aluminum foil as a material, and has a thickness ranging from 1 μm to 100 μm, preferably from 1 μm to 50 μm.
Preferably, the signal processing module can be configured to acquire the current of the gear motor, when the lifting assembly runs to the uppermost end or the skin surface, the gear motor is blocked and the current rises, and when the signal processing module detects the current rise, the power supply of the gear motor is disconnected.
Preferably, the signal processing module is further provided with a 2.5GHz communication chip, and the signal processing module is used for sending the abnormal information obtained through judgment to external equipment and/or sending a distress signal.
Preferably, the control module further comprises a screen fixed below the upper cover of the shell, and the screen is used for displaying the detected blood glucose concentration of the human body in real time.
Preferably, the needle tip layer material of the microneedle array is composed of a polymer, and the polymer is a mixture of one or more of 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 prepared 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 selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
Preferably, the bottom layer material of the microneedle is selected from one or a mixture of more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylic acid mixed according to any proportion.
Preferably, the detection probes are platinum electrode probes of which the semipermeable membrane is coated with glucose oxidase, and the number of the detection probes is at least 2.
Preferably, the signal processing module comprises a PCB board, and the MCU is arranged on the PCB board.
According to another aspect of the present invention, there is provided a microneedle for use in a wearable device, the microneedle being bilayer comprising a bottom end layer and a tip layer, wherein the bottom end layer carries a reducing agent and the tip layer carries glucagon redox clusters.
Preferably, the glucagon redox cluster is prepared 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 selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
Preferably, the needle tip layer material of the microneedle comprises a polymer, and the polymer is a mixture of one or more of 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 material of the microneedle comprises a photo-curing material selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylic acid mixed according to any proportion.
Preferably, the needle tip layer material of the microneedle is composed of a polymer, and the polymer is a mixture of one or more of 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 prepared 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 selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide.
Preferably, the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
According to another aspect of the present invention, there is provided a method for preparing a microneedle, comprising the steps of:
preparing an aqueous solution containing glucagon with a certain concentration;
adding disulfide crosslinking agent, magnetically stirring at room temperature to obtain glucagon oxidation-reduction cluster;
weighing a proper amount of polymer and mixing with the glucagon oxidation-reduction 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;
preparing a reducer solution, dripping the reducer solution onto a microneedle mould containing the needle tip 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, thereby obtaining the final glucagon redox cluster microneedle.
Preferably, the aqueous solution is an aqueous solution of PBS having a pH of 9.
Preferably, the room temperature magnetic stirring time is 1 hour.
Preferably, the microneedle mould contains a plurality of conical holes.
Preferably, the conical holes have a hole depth of 1500-1800 μm, a hole maximum diameter of 850-1000 μm, and a hole spacing of 1000-1500 μm.
Preferably, the concentration ratio of the glucagon, the aqueous solution, and the disulfide crosslinking agent is: 100mg:50ml:50mg; and the concentration ratio of the polymer to the glucagon redox cluster solution is: 150mg:1ml.
Preferably, the glucagon redox cluster solution contains 100mg insulin per 1ml.
Preferably, the microneedle mould is made of polydimethylsiloxane.
Preferably, the disulfide crosslinking agent is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide; and the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
Preferably, the polymer is one or more of 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 end layer comprises a photo-curable material selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and methacrylated hyaluronic acid, mixed in any ratio.
The invention has the following beneficial effects.
1. The physiological indexes in the human body can be monitored in real time, and the medicine can be controllably delivered and administrated, so that the effect of rapid treatment is realized.
2. The device is particularly suitable for monitoring the blood sugar concentration in a human body, providing glucagon according to the blood sugar level and realizing the function of rapidly curing hypoglycemia.
Drawings
FIG. 1 shows the synthesis process (A) of glucagon redox clusters and the principle of glucagon release by reduction (B)
FIG. 2 shows a transmission electron micrograph (A), particle size distribution (B) and Zeta potential (C) of glucagon redox clusters
Figure 3 shows the route of preparation of glucagon-loaded redox cluster microneedle arrays.
Fig. 4 is an external appearance map of the microneedle robot.
Fig. 5 is a component view of the microneedle robot.
Fig. 6 is a schematic view of a lifting structure of the automatic microneedle device.
Fig. 7 is a schematic diagram of the operation of the spiral lifting turntable.
FIG. 8a is a schematic view of the engagement between the lifting assembly and the inside of the spiral lifting turntable.
Figure 8b shows a simplified elevation assembly.
Fig. 9 is a schematic view of a microneedle assembly installation.
Fig. 10 is an appearance of a glucagon-loaded redox cluster microneedle array.
FIG. 11 is a graph of displacement versus load capacity for glucagon-loaded redox cluster microneedle arrays.
Fig. 12 is a diagram of a skin pathology puncture of a glucagon-loaded redox cluster microneedle array.
Fig. 13 is an in vivo pharmacokinetic profile of a glucagon-loaded formulation.
Fig. 14 is a graph of blood glucose versus time for a glucagon-loaded wearable device.
Detailed Description
The following describes the specific embodiments of the present invention in detail, but the preparation process, the substances used and the amounts of the substances used according to the examples of the glucagon-carrying wearable device of the present invention are not limited to the text, and all the pharmaceutical compositions and pharmaceutical equipment provided by the present invention are included in the protection scope of the present invention.
Referring to fig. 4 and 5, the present invention is a wearable device for treating hypoglycemia, comprising a case 1 and watchbands 11 provided at both sides for fixing the wearable device on the skin surface of a human body; the inside control module 2, lifting module 3 and dosing module 4 that is provided with of casing 1. Wherein: the administration module 4 includes a microneedle array 41 fixed to the bottom of the elevation module 3, the microneedle array including a plurality of microneedles 410 each containing a drug for treating hypoglycemia.
The preparation of a particular drug and microneedle 410 is shown in figures 1-3.
I. Preparation and characterization of glucagon redox clusters
100mg of glucagon is dissolved in 50ml of PBS aqueous solution with pH of 9, 50mg of NHS-S-S-NHS is added, and the mixture is magnetically stirred at room temperature for 1 hour, and sephadex column separation and purification are carried out to obtain glucagon redox clusters (figure 1A). The cluster encounters glutathione solution and disulfide bonds are reduced and broken, a ring-closing reaction occurs, degrading and releasing glucagon (fig. 1B).
The size of the prepared clusters was shown to be about 60nm by dynamic light scattering (FIG. 2A), and the Zeta potential was-52.9 mV (FIG. 2B), indicating that the clusters had good thermodynamic stability. The transmission electron microscopy image shows that the clusters are spherical in shape (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 was dropped into a microneedle mould containing 100 conical holes with a pore depth of 1500-1800 μm, a maximum pore diameter of 850-1000 μm, and a pore spacing of 1000-1500 μm of polydimethylsiloxane, and centrifuged at high speed and air-dried to obtain the tip of the microneedle, i.e., the tip layer 412.
A500 mg/ml solution of glutathione vinyl pyrrolidone was prepared and dropped onto a mold containing a needle tip, vacuum-treated for 1 minute (min), and irradiated with ultraviolet light for 6 minutes to form a bottom layer 411 containing a reducing agent on the needle tip layer 412, to obtain the final glucagon redox cluster microneedle 410 (FIG. 3).
The microneedles 410 are attached to the bottom of the elevation assembly 32 of the microneedle array autoinjector (i.e., wearable device) by double-sided tape, and the waterproof membrane 42 is fixed to the bottom layer of the microneedle autoinjector by the waterproof membrane fixing plate 43. The specific structure of the wearable device is shown 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 material of the needle tip layer 412 of the microneedle array 41 is composed 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.
And the glucagon redox cluster is prepared 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 crosslinking agent may be one selected from the group consisting of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, and maleimide-disulfide-succinimide.
The reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol. And, the material of the bottom layer 411 of the microneedle array 41 is selected from one or a mixture of a plurality of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate and methacrylic acid in any proportion.
Design of automatic microneedle injector
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 wristband 11 provided on both sides for fixing the wearable device to the skin surface of a human body.
The inside control module 2, lifting module 3 and the module of dosing 4 of being provided with of casing, wherein: the administration module 4 comprises a microneedle array 41 fixed to the bottom of the lifting module 3, the microneedle array comprising a plurality of microneedles 410, each microneedle containing a drug. The bottom case 13 further includes a waterproof film 42 coated on the microneedle array 41, and a waterproof film fixing plate 43 for fixing the waterproof film 42. The waterproof film 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. Mu.m, preferably 1 μm to 50. Mu.m.
The control module 2 comprises a signal processing module 22, an OLED screen 21, a soft-pack battery 25 for providing power and a detection probe 24.
The detection probe 24 is fixed at the bottom of the casing 1, and can be used for directly contacting human skin to detect human physiological indexes in real time. In one embodiment, the detection probes 24 are platinum electrode probes coated with glucose oxidase by a semipermeable membrane, typically not less than 2, and are fixed on the bottom shell of the housing to directly contact 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 board, and the MCU is arranged on the PCB board and can detect the change of the potential of the probe so as to judge whether the glucose in the human body is at a normal level. When the glucose exceeds the normal range, the MCU sends out a signal to drive the turntable to rotate, and drives the lifting assembly 32 of the lifting module 3 to move downwards, and the micro needle 410 pierces the waterproof membrane 42 and enters the skin to release the medicine. To ensure drug release, the lifting distance of the lifting assembly 32 needs to be greater than the sum of the skin stratum corneum thickness and the distance from the microneedle tips to the bottom shell 13.
The OLED screen 21 is placed directly below the upper cover 12 of the housing for displaying the patient's real-time glucose level obtained by the detection probe 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 abnormal information obtained by the judgment to an external device and/or sending a distress signal.
As shown in fig. 6 to 7, the lifting module 3 includes a drive gear 30 driven by a gear motor 33, and a spiral lifting turntable 31 engaged with the drive 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 the 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 has a cavity structure, and an inner wall of the cavity is provided with an internal thread member 310, which in this embodiment is specifically a spiral rib.
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 lifting turntable 31, and the spiral lifting turntable 31 is embedded between the upper flange 34 and the lower flange 35, so that the spiral lifting turntable 31 can only perform circular movement between the upper flange and the lower flange, and the vertical movement is restrained.
The lifting module 3 further comprises a lifting assembly 32, wherein the lifting assembly 32 comprises a first lifting member 321 and a second lifting member 322 which are fixedly connected, and an external threaded member 325 meshed with the internal threaded member 310 of the cavity inner wall of the spiral lifting turntable 3 is arranged on the outer wall of the first lifting member 321, in this embodiment, a trapezoidal spiral groove is specifically formed. The microneedle array 41 is fixed at the bottom of the second lifter 322, and the lifter assembly 32 is lifted 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 shell 13, so that the microneedle 410 can penetrate the patient's skin 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 shell 1 is provided with a shell guide groove 14, and the lifting assembly guide rib 323 is matched with the shell 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 limiting position of the upward movement of the lifting assembly.
Fig. 8b shows a schematic view of a lifting assembly, in which a spiral lifting turntable 31 is connected to a lifting assembly 32 via a spiral 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 ribs 310 and the trapezoidal spiral grooves 325, thereby realizing the pressing and lifting actions. The lifting or descending height of the lifting assembly 32 is affected by the rotation angle of the spiral lifting turntable 31, and the lifting height can be controlled by controlling the rotation angle of the gear 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 the skin surface, the gear motor 33 is blocked and the current rises, and when the signal processing module 22 detects the current increase, the power supply of the gear motor 33 is disconnected.
As a preferred embodiment, as shown in fig. 8a, the second lifting member 322 is cylindrical, and a screw hole 324 is provided in the middle for fixedly connecting with the first lifting member 321. Meanwhile, the bottom shell 13 of the shell 1 is provided with a circular through hole, and the shell guide groove 14 is arranged in the through hole. Further, the bottom of the lifting assembly 32 is square flat bottom, which facilitates the fixation of the microneedle array 41.
As shown in fig. 9, a microneedle array 41 is mounted at the bottom end of the elevation assembly 32, and the tip of the microneedle is protected by a waterproof film 42. The waterproof membrane 42 is fixed below the microneedle array 41 by a waterproof membrane fixing plate 43, and the waterproof membrane fixing plate 43 is fixed on the bottom shell 13 of the housing 1 by screws (not shown) through screw holes 431, which has the effect that the waterproof membrane fixing plate can be conveniently detached, and the microneedle array 41 can be conveniently replaced from the lower end after being used.
The workflow of the wearable device of the invention is:
the device is fixed on the skin surface of a human body through a watchband, the detection probe 24 fixed on the bottom shell of the wearable device is directly contacted with the skin of the human body 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 speed exceeds the normal range, the MCU sends out a signal to control the gear motor 33 to rotate so as to drive the lifting assembly 32 to descend. The microneedle array 41 fixed to the bottom of the elevation assembly 32 descends, penetrates the waterproof membrane 42, and penetrates the skin of the human body. After the tips of the microneedles dissolve, the reducing agent of the microneedle bottom layer 411 reacts instantaneously with the glucagon redox clusters of the tip layer to release glucagon.
After the medicine is released, the speed reducing motor 33 is controlled to reversely rotate to enable the lifting assembly to ascend and restore to the original position. When the lifting assembly 32 runs to the uppermost end or the lowermost end, the speed reducing motor 33 is blocked, the current of the speed reducing motor is increased, and the MCU detects the increase of the current, namely, the power supply of the speed reducing motor is disconnected. Since the lifting assembly 32 is lowered and raised a distance greater than the sum of the thickness of the stratum corneum and the distance from the tip of the microneedle to the bottom shell, it is ensured that the microneedle penetrates the skin to release the drug. To ensure that the drug release is complete, control can be provided by controlling the time that the lifting assembly 32 is maintained after lowering, typically requiring 30 minutes.
The effects of the 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, and the morphology 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 needle height.
Figure 10 illustrates the morphology of one embodiment of a glucagon redox cluster microneedle array with a sharp needle tip. The tip width was 15 μm, the tip length was 1800 μm, and the tip distance was 1500 μm.
Experimental example 2 mechanical Strength of glucagon redox Cluster microneedle array
The backing layer of glucagon redox cluster microneedle array patch was attached using a double sided tape to a metal stand of a pressure-pull tester (SGL-8000, sulzer equipment limited) with the microneedle tips facing the probes of the instrument, the probe was pressed down against the microneedles, and the force and displacement applied by the instrument was 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.
Experimental example 3 skin insertion Performance of glucagon redox Cluster microneedle array
Using BALB/C mice as animal models, the hair of the mice was shaved using a razor and the exposed skin surface was rinsed with ethanol. Glucagon redox cluster microneedle array patches were each inserted vertically into the back skin of mice and left to stand for 5 minutes before peeling. Mice were sacrificed by cervical removal, skin was peeled off, microneedle insertion sites were embedded by cutting, and frozen in liquid nitrogen. Sections were cut to a thickness of 5 μm and placed on a silane coated slide. The skin sections were observed under an inverted microscope (IX-71, olympus, tokyo, japan).
As shown in fig. 12, glucagon redox cluster microneedle arrays were inserted at a depth of 231 μm, far deeper than the thickness of the skin stratum corneum (about 100 μm), which is the foremost barrier for transdermal drug delivery. Thus, the microneedle array facilitates percutaneous absorption of drugs.
Experimental example 4 pharmacokinetic Studies of glucagon wearable device
The microneedle array is placed in a microneedle automatic injection device and the glucagon wearable device is assembled. SD rats (200+ -10 g) were selected as model animals for a total of 12 animals. Rats were divided into subcutaneous and wearable groups using a razor to shave back hair of the rats. Wearable group: the wearable device was fixed to the back of the rat and the blood glucose trigger threshold was set to 0mmol/l. Subcutaneous injection group: 0.1ml of a 1mg/ml glucagon solution was subcutaneously injected. Plasma from two groups of rats was taken at a fixed time point at 100 μl and the concentration of glucagon in the plasma was determined by enzyme-linked immunosorbent assay.
The wearable system immediately activated group in vivo drug uptake (AUC) as shown in fig. 13 0～∞ 239+ -23.5 h.ng/ml, maximum blood concentration (C) max 18.9.+ -. 1.9. Mu.g/ml) and average residence time (MRT, 9.1.+ -. 0.5 h) with AUC of the subcutaneously injected group 0～∞ (226±34.1ng/ml)、C max (19.8±0.7μg/ml) And MRT (7.9+ -0.8 h) were not significantly different. The glucagon wearable system can quickly release medicine to the body, and is beneficial to the treatment of hypoglycemia.
Experimental example 5 pharmacodynamics study of glucagon wearable device
SD rats (200+ -10 g) were selected as model animals, and were divided into 12 model groups and wearable device administration groups (6 each). The back hair of the rats is shaved by using a shaver, 2IU of insulin is given to both groups of rats after initial blood sugar is measured, a model group is not treated, a glucagon wearable device is arranged on the back of each group of rats, and the administration threshold is set to be 2.8mmol. Blood glucose changes were measured at a time point. The model group showed that blood glucose level was reduced to 2.3.+ -. 0.9mmol after 60 minutes of insulin administration and the body reached a low blood glucose level as shown in FIG. 14. Blood glucose tended to decrease 60 minutes before the wearable group, but blood glucose rose back to 3.45±0.3mmol after 65 minutes. Thereafter, the blood glucose was raised 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.+ -. 0.4mmol. The results indicate that when the blood glucose level drops to the hypoglycemic threshold, the wearable device can immediately rescue administration.
Although the wearable device of the invention aims at curing hypoglycemia, a person skilled in the art can easily change the human physiological index monitored in the control module and the corresponding curing medicine, so that the wearable device of the invention can be suitable for curing other diseases, and therefore, the wearable device of the invention can be widely suitable for curing various diseases.
The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention by one of ordinary skill in the art without undue burden. Therefore, all technical solutions which can be obtained by logic analysis, reasoning or limited experiments based on the prior art by the person skilled in the art according to the inventive concept shall be within the scope of protection defined by the claims.
Claims (31)
1. A wearable device, the wearable device comprising:
a housing (1) comprising an upper cover (12), a bottom case (13) and watchbands (11) arranged on two sides, for fixing the wearing device on the skin surface of a human body;
a control module (2), a lifting module (3) and a drug delivery module (4) which are arranged in the shell, 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;
the control module at least comprises a detection probe (24) and a signal processing module (22), wherein the detection probe (24) is fixed at the bottom of the shell (1) and can be used for directly contacting human skin to detect human physiological indexes in real time, the signal processing module (22) is used for judging the relation between the human physiological indexes detected in real time and normal physiological index threshold values, if the relation is smaller than the threshold values, a control signal is sent to control the lifting module (3) to descend, and the lifting module (3) drives the microneedle array (41) to descend so as to release medicines;
each microneedle (410) is bilayer comprising a bottom end layer (411) and a tip layer (412), wherein the bottom end layer (411) carries a reducing agent and the tip layer (412) carries glucagon redox clusters; and the physiological index is blood glucose concentration; the glucagon redox cluster is prepared 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 glucagon redox cluster encounters glutathione solution, disulfide bond is reduced and broken, ring-closure reaction occurs, degradation is carried out, and glucagon is released;
the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
2. The wearable device according to claim 1, characterized in that the lifting module (3) comprises:
a drive gear (30) driven by a gear 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 inner threaded member (310) is arranged on the inner wall of the cavity;
lifting assembly (32), lifting assembly (32) are including fixed connection's first lifting part (321) and second lifting part (322), and wherein first lifting part (321) outer wall be equipped with screw thread component (325) of screw lift carousel (31) cavity inner wall's internal thread component (310) meshing, microneedle array (41) are fixed in the bottom of second lifting part (322), wherein the distance that lifting assembly (32) goes up and down is greater than skin stratum corneum thickness and microneedle tip to drain pan (13) distance sum.
3. The wearable device according to claim 2, characterized in that the internal threaded member (310) is a spiral bead and the external threaded member (325) is a trapezoidal spiral groove.
4. The wearable device according to claim 2, characterized in that the outer wall of the second lifting member (322) is provided with lifting assembly guide ribs (323), the inner wall of the housing is provided with a housing guide groove (14), and the lifting assembly guide ribs (323) are 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).
5. Wearable device according to claim 2, characterized in that an upper flange (34) and a lower flange (35) are provided in the housing for fixing the spiral lifting turntable (31) between the upper flange (34) and the lower flange (35) such that the spiral lifting turntable (31) can only perform a circular movement between the upper flange (34) and the lower flange (35), the vertical movement being constrained.
6. Wearable device according to claim 1 or 2, characterized in that the bottom shell (13) further comprises a waterproof membrane (42) coated on the microneedle array (41), a waterproof membrane fixing plate (43) for fixing the waterproof membrane (42) being fixed on the bottom shell (13).
7. The wearable device according to claim 6, characterized in that the waterproof membrane (42) is composed of aluminum foil as material, with a thickness ranging from 1 μm to 100 μm.
8. The wearable device according to claim 6, characterized in that the waterproof membrane (42) is composed of aluminum foil as material, with a thickness ranging from 1 μm to 50 μm.
9. The wearable device according to claim 2, characterized in that the signal processing module (22) is configurable to acquire the current of the gear motor (33), the gear motor (33) stalling and the current rising when the lifting assembly (32) is running to the uppermost or skin surface, and the power supply of the gear motor (33) being disconnected when the signal processing module (22) detects the current rising.
10. The wearable device according to claim 1, wherein the signal processing module (22) is further mounted with a 2.5GHz communication chip, and is configured to send the abnormal information obtained by the judgment to an external device and/or send a distress signal.
11. The wearable device according to claim 1, characterized in that 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 according to claim 11, wherein the disulfide cross-linker is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide.
13. The wearable device according to claim 1, characterized in that the needle tip layer (412) material of the microneedle array (41) is composed of a polymer, which 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, dextran mixed in any ratio.
14. The wearable device according to claim 1, wherein the bottom end layer (411) material of the microneedle (410) is selected from one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and a mixture of methacrylic acid and hyaluronic acid mixed in any ratio.
15. The wearable device according to claim 1, characterized in that the detection probes (24) are platinum electrode probes coated with glucose oxidase by a semi-permeable membrane, at least 2.
16. The wearable device according to claim 1, characterized in that the signal processing module (22) comprises a PCB board, on which the MCU is arranged.
17. A microneedle used in a wearable device, which is characterized in that the microneedle (410) is double-layered and comprises a bottom end layer (411) and a needle tip layer (412), wherein the bottom end layer (411) is loaded with a reducing agent, the needle tip layer (412) is loaded with glucagon redox clusters, and the glucagon redox clusters are generated by covalent reaction of glucagon serving as a raw material and a disulfide crosslinking agent under stirring at room temperature;
the glucagon redox cluster encounters glutathione solution, disulfide bond is reduced and broken, ring-closure reaction occurs, degradation is carried out, and glucagon is released;
the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
18. The microneedle of claim 17, wherein the disulfide cross-linking agent is selected from one of succinimide-disulfide-succinimide, dibenzocyclooctyne-disulfide-amino, diphenyl cyclooctyne-disulfide-succinimide, maleimide-disulfide-succinimide.
19. The microneedle according to claim 17, characterized in that the tip layer (412) material of the microneedle comprises a polymer being a mixture of one or more selected from the group consisting of dextran, chondroitin sulfate, polyvinyl alcohol, silk fibroin, sodium carboxymethyl cellulose, alginate, polylactic acid, hyaluronate, polyvinylpyrrolidone, chitosan, dextran, mixed in any ratio.
20. The microneedle according to claim 17, wherein the material of the bottom layer (411) of the microneedle (410) comprises a photo-curable material selected from the group consisting of a mixture of one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and methacrylic acid in any ratio.
21. A method of preparing a microneedle according to any one of claims 17 to 20, comprising the steps of:
preparing an aqueous solution containing glucagon with a certain concentration;
adding disulfide crosslinking agent, magnetically stirring at room temperature to obtain glucagon oxidation-reduction cluster;
weighing a proper amount of polymer and mixing with the glucagon oxidation-reduction 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;
preparing a reducer solution, dripping the reducer solution onto a microneedle mould containing the needle tip 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, thereby obtaining the final glucagon redox cluster microneedle.
22. The method of claim 21, wherein the aqueous solution is an aqueous solution of PBS having a pH of 9.
23. The method of claim 21, wherein the room temperature magnetic stirring time is 1 hour.
24. The method of making according to claim 21, wherein the microneedle mould comprises a plurality of conical holes.
25. The method of manufacturing according to claim 24, wherein: the hole depth of the conical holes is 1500-1800 mu m, the maximum diameter of the holes is 850-1000 mu m, and the hole spacing is 1000-1500 mu m.
26. The method of manufacturing according to claim 21, wherein: the concentration ratio of the glucagon, the aqueous solution and the disulfide bond crosslinking agent is as follows: 100mg:50ml:50mg; and the concentration ratio of the polymer to the glucagon redox cluster solution is: 150mg:1ml.
27. The method of manufacturing according to claim 26, wherein: the glucagon redox cluster solution contained 100mg insulin per 1ml.
28. The method of manufacturing according to claim 21, wherein: the microneedle mould is made of polydimethylsiloxane.
29. The method of manufacturing according to claim 21, wherein: the disulfide bond cross-linking agent is selected from one of succinimide-disulfide bond-succinimide, dibenzocyclooctyne-disulfide bond-amino, diphenyl cyclooctyne-disulfide bond-succinimide and maleimide-disulfide bond-succinimide; and the reducing agent is selected from one or more of glutathione, vitamin C, manganese dioxide, cerium oxide and tocopherol.
30. The method according to claim 21, 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 ratio.
31. The method of claim 21, wherein the bottom layer comprises a photocurable material selected from the group consisting of one or more of vinyl pyrrolidone, allyl methacrylate, hydroxypropyl methacrylate, and methacrylated hyaluronic acid, mixed in any ratio.
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| 微针阵列用于生物大分子药物的递送;黄颖聪；马凤森；占浩慧；章捷;《生物化学与生物物理进展》;全文 * |
| 新型光学核酸探针的制备及其在生化分析中的应用研究;卿志和;《 中国博士学位论文全文数据库 工程科技Ⅰ辑》;全文 * |
| 眼用微创布林佐胺可溶性微针;李敏姝；于翔；金义光；吴志鸿;《药学学报 》;全文 * |
| 眼用微创布林佐胺可溶性微针;李敏姝；于翔；金义光；吴志鸿;《药学学报》;全文 * |
| 胰岛素给药新剂型研究进展;王理群；詹晓平；陈少雄；毛振民;《中国医药工业杂志》;全文 * |
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| CN114376569A (en) | 2022-04-22 |
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