CN116549827A - Microneedle for delivering drug to stomach wall, preparation method thereof and drug delivery system - Google Patents
Microneedle for delivering drug to stomach wall, preparation method thereof and drug delivery system Download PDFInfo
- Publication number
- CN116549827A CN116549827A CN202310701003.7A CN202310701003A CN116549827A CN 116549827 A CN116549827 A CN 116549827A CN 202310701003 A CN202310701003 A CN 202310701003A CN 116549827 A CN116549827 A CN 116549827A
- Authority
- CN
- China
- Prior art keywords
- microneedle
- drug
- needle
- stomach wall
- delivering
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
-
- 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
-
- 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
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
- B29C33/38—Moulds or cores; Details thereof or accessories therefor characterised by the material or the manufacturing process
- B29C33/3835—Designing moulds, e.g. using CAD-CAM
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
- B29C33/38—Moulds or cores; Details thereof or accessories therefor characterised by the material or the manufacturing process
- B29C33/3842—Manufacturing moulds, e.g. shaping the mould surface by machining
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/02—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor for making articles of definite length, i.e. discrete articles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/42—Casting under special conditions, e.g. vacuum
-
- 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
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Mechanical Engineering (AREA)
- Inorganic Chemistry (AREA)
- Hematology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Manufacturing & Machinery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nutrition Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Zoology (AREA)
- Organic Chemistry (AREA)
- Physiology (AREA)
- Diabetes (AREA)
- Child & Adolescent Psychology (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
Abstract
The invention relates to the technical field of stomach wall injection, in particular to a microneedle for delivering medicines to a stomach wall, a preparation method thereof and a medicine delivery system. The microneedle comprises a base part and a plurality of needle parts which are arranged on the base part and are loaded with medicines, each needle part is of a conical structure with the length-diameter ratio of 1.25-3:1, the height of each needle part is 250-350 mu m, and the bottom diameter of each needle part is 100-200 mu m. According to different conditions of patients, the injection layer is customized individually, the medicine is accurately delivered to a specific layer of the stomach wall, the target is a muscle layer, the medicine can be uniformly distributed, and meanwhile, the unpredictable tissue damage and uncertain curative effect in the injection process of the traditional injector can be avoided.
Description
Technical Field
The invention relates to the technical field of stomach wall injection, in particular to a microneedle for delivering medicines to a stomach wall, a preparation method thereof and a medicine delivery system.
Background
Obesity increases the risk of onset of type 2 diabetes, hypertension, hyperlipidemia, metabolic-related fatty liver disease, atherosclerosis cardiovascular and cerebrovascular disease, gout, gall stones, polycystic ovary syndrome, amenorrhea/infertility, sleep apnea, bone joint disorders, anxiety, depression, and certain specific tumors, which in turn severely affect longevity. Therefore, the aim of weight reduction is not only to beautify, but also to treat diseases and improve the health state.
Among the therapeutic measures for obesity, there are many new therapeutic methods in addition to traditional drug therapy, exercise therapy and surgical therapy. Among them, stomach wall injection treatment is convenient to be concerned by the academic community because of its minimally invasive. For example, injection of botulinum toxin (BTX-a), a protease consisting of a heavy chain and a light chain, into the stomach wall prevents release of the neurotransmitter acetylcholine, and inhibits muscle contraction and gland secretion. Current studies indicate that injection of BTX-a into the antrum of the rat results in reduced ingestion, delayed gastric emptying, and weight loss in the rat. Subsequent studies on multiple clinical cohorts of this formula have been conducted sequentially, and a number of studies have shown that BTX-a can effectively control appetite, delay gastric emptying, and reduce body weight, with significant advantages in the treatment of obesity. However, there are some central clinical data showing that this regimen is not effective in controlling body weight, and that the patient's weight loss effect, glycemic control, is not significantly different from that of the placebo group. The analysis may be present because: (1) The traditional injection mode has great randomness, so that medicines in the stomach wall, such as BTX-A, are unevenly distributed, and the gastric emptying inhibition effect is poor: (2) The injection depth is uncertain and the stomach wall mainly comprises a mucous membrane layer, a submucosa layer, a myolayer and a serosa layer. The nerve regulation and function of each layer are different, and the drug is delivered to different layers, so that different treatment effects can be generated. Meanwhile, the stomach wall is very thin, the stomach wall of an adult is only about 6mm, the traditional injection mode has the danger of perforation, and meanwhile, submucosal hemorrhage is often caused, so that a certain medical risk is provided. There is therefore an urgent need for a new delivery strategy to achieve an effective and safe therapeutic effect.
In view of this, the present invention has been made.
Disclosure of Invention
The present invention aims to provide a microneedle for delivering a drug to a stomach wall, a preparation method thereof and a drug delivery system. The microneedle provided by the embodiment of the invention can definitely inject the layer, accurately deliver the drug to the muscular layer of the stomach wall, uniformly distribute the drug, and simultaneously avoid unpredictable tissue damage in the injection process of the traditional injector.
The invention is realized in the following way:
in a first aspect, the present invention provides a microneedle for delivering a drug to a stomach wall comprising a base portion and a plurality of drug-loaded needle portions disposed on the base portion, each of the needle portions having a conical structure with an aspect ratio of 1.25-3:1, each of the needle portions having a height of 250-350 μm and a bottom diameter of 100-200 μm.
In an alternative embodiment, each cubic centimeter of microneedle contains 90-110 of the needle portions;
preferably, each cubic centimeter of microneedle contains 2-15U of drug;
preferably, each cubic centimeter of microneedle contains 6-7U of drug;
preferably, each needle portion contains 0.06-0.07U of medicament;
preferably, each needle portion contains 0.02-0.15U of medicament.
In an alternative embodiment, each needle body part comprises a needle tip loaded with a drug and a needle seat with two ends respectively connected with the base part and the needle tip, and the material for forming the needle seat is the same as that for forming the base part.
In alternative embodiments, the materials forming the needle tip include PVP, PVA, and a drug;
preferably, the mass ratio of PVP to PVA is 1:0.5-1.5.
In alternative embodiments, the materials forming the hub and the base portion include PVP, PVA, and hyaluronic acid (abbreviated HA);
preferably, the mass ratio of PVP, PVA and HA is 1:0.5-1.5:0.5-1.5.
In an alternative embodiment, the drug is selected from drugs that inhibit gastric emptying, reduce ingestion, preferably a botulinum toxin, e.g., botulinum toxin type a for injection.
In a second aspect, the present invention provides a method for preparing a microneedle for delivering a drug to a stomach wall according to the foregoing embodiment, comprising: microneedles for delivering drugs to the stomach wall are formed using a step-and-mold process.
In an alternative embodiment, the method comprises: preparing a microneedle model;
adding the raw material forming the needle tip into the microneedle mould, and then carrying out first incomplete drying;
adding the raw materials for forming the needle seat and the substrate part into the microneedle model, and then carrying out secondary incomplete drying; demolding and then completely drying.
In an alternative embodiment, the step of adding the material forming the tip to the microneedle mould comprises: adding the raw material forming the needle tip into the microneedle mould by using a pipetting gun, vacuumizing the microneedle mould, centrifuging, and removing redundant solution;
preferably, the conditions of the first partial drying include: the drying temperature is 35-37 ℃ and the drying time is 5-15 minutes;
preferably, the conditions of the second partial drying include: the drying temperature is 35-37 ℃ and the drying time is 10-12 hours.
In a third aspect, the present invention provides a drug delivery system comprising a microneedle according to the previous embodiments for delivering a drug to the stomach wall.
The invention has the following beneficial effects: according to the embodiment of the invention, the microneedle can accurately act on the myometrium of the stomach wall by controlling the height, the bottom diameter and the length-diameter ratio of each needle body part, so that the medicine is accurately delivered into the stomach wall, and the treatment effect is improved. And the medicines can be uniformly distributed on the muscular layer of the stomach wall and cannot be concentrated on a certain part, so that the treatment effect is further improved. Further, the use of microneedles to deliver drugs to the stomach wall avoids unpredictable tissue damage, such as perforation or submucosal bleeding, that occurs during conventional syringe injection, enhancing the safety of the treatment.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing the results of the test provided in test example 1 of the present invention;
FIG. 2 is a graph showing the results provided in test example 2 of the present invention;
FIG. 3 is a graph showing the detection results provided in Experimental example 1 of the present invention;
FIGS. 4-5 are graphs showing the detection results provided in Experimental example 2 of the present invention;
FIG. 6 is a graph showing the results of the test provided in Experimental example 3 of the present invention;
FIG. 7 is a graph showing the results of the test provided in Experimental example 4 of the present invention;
FIG. 8 is a graph showing the results of the test provided in Experimental example 5 of the present invention;
FIG. 9 is a graph showing the results of the test provided in Experimental example 6 of the present invention;
FIG. 10 is a graph showing the results of the test provided in Experimental example 7 of the present invention;
FIG. 11 is a graph showing the results of the test provided in Experimental example 8 of the present invention;
FIG. 12 is a graph showing the results of the test provided in Experimental example 9 of the present invention;
FIG. 13 is a graph showing the results of the test provided in Experimental example 10 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
In a first aspect, the present invention provides a microneedle for delivering a drug to the stomach wall, which applies the microneedle technology to peristaltic gastrointestinal tissue for the first time, and can achieve the treatment of obesity, and provides a new technical means for the treatment of obesity.
Meanwhile, it should be noted that the embodiments of the present invention are not limited to the treatment of obesity, and other diseases that can be treated by gastric administration, including inflammatory diseases, diabetes, neoplastic diseases, etc., can be accurately delivered by using the microneedles provided by the embodiments of the present invention.
Further, the needle comprises a base part and a plurality of needle parts which are arranged on the base part and are loaded with medicines, each needle part is in a conical structure with the length-diameter ratio of 1.25-3:1, for example, any value or range of values between any two values, preferably 2.2-2.5:1, of 1.25:1, 1.5:1, 2:1, 2.5:1, 3:1 and the like, of 1.25-3:1, and the like of each needle part is formed by the needle parts. The height of each needle portion is 250-350 μm, for example, any value or range of values between any two values, preferably 310-330 μm, between 250-350 μm, such as 250 μm, 260 μm, 370 μm, 280 μm, 290 μm, 300 μm, 310 μm, 320 μm, 330 μm, 340 μm, 350 μm, etc. The bottom diameter is 100 to 200. Mu.m, for example, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm or the like, or a range between any two values or values of 100 to 200. Mu.m, preferably 140 to 160. Mu.m. The length-diameter ratio, the height and the bottom diameter of each needle part are limited, so that the structure of the needle part is more stable, the muscle layer of the stomach wall is easier to penetrate, and the delivery effect of the medicine is improved.
Further, each cubic centimeter of the microneedle contains 90-110 needle portions; for example, there are any number between 90 and 110, such as 90, 95, 100, 105, and 110. The microneedles contain 2-15U of drug per cubic centimeter, e.g., 2U, 5U, 6U, 7U, 8U, 9U, 10U, 11U, 13U, and 15U, etc., any value or range between any two values, e.g., 6-7U of drug is preferred. Each needle portion contains a drug of any value or range of values between any two values, e.g. 0.02-0.15U, such as 0.02U, 0.05U, 0.06U, 0.07U, 0.1U, 0.12U, 0.14U, 0.15U, etc. 0.02-0.15U, preferably 0.06-0.0U.
The dosage of the medicine is further limited, so that the uniform distribution of the medicine after being delivered to the stomach wall can be improved, and the problem of nonuniform distribution of the medicine caused by a conventional injection mode is solved.
The drug used may be one that is capable of acting on the stomach wall, and the present invention is merely intended to treat obesity, so that the drug selected to inhibit gastric emptying and reduce ingestion is exemplified by a botulinum toxin (e.g., botulinum toxin type A for injection). But is not limited thereto, and is more not limited to a medicament for treating obesity. Also included are medicaments for the treatment of other diseases, such as inflammatory diseases, diabetes, neoplastic diseases, and the like.
Further, each needle body part comprises a needle point for loading medicine and a needle seat with two ends respectively connected with the base part and the needle point, and the material for forming the needle seat is the same as that for forming the base part. The needle seat and the base part are made of the same material, so that the connection between the base part and the needle body part is more stable, and the stability of the micro needle is improved.
Further, the raw materials for forming the needle tip comprise PVP, PVA and medicines; preferably, the mass ratio of PVP to PVA is 1:0.5-1.5. For example, the mass ratio is 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1: any value or range of values between 1:0.5 and 1.5, such as 0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, and 1:1.5.
The embodiment of the invention specifically adopts PVP and PVA as the materials of the needle tip, thereby ensuring that the micro needle has enough mechanical strength to pierce the stomach wall and ensuring that the micro needle can quickly release the medicine after acting on the stomach wall.
Further, the materials forming the hub and the base portion include PVP, PVA and HA in a mass ratio of 1:0.5-1.5:0.5-1.5, e.g. mass ratio 1:1:1. 1:0.5:1, 1:1:0.5, 1:1.5:1.5, 1:1:1.5, 1:0.5:1.5, 1:1.5: any value between 0.5 and 1:1.5:1, etc. 1:0.5-1.5:0.5-1.5, or a range of values between any two values.
In a second aspect, the present invention provides a method for preparing a microneedle for delivering a drug to a stomach wall according to the foregoing embodiment, comprising:
s1, forming a microneedle model;
firstly, the 3D printing microneedle male die is utilized, the existing 3D printing technology can be utilized, the invention is exemplified, and the embodiment of the invention adopts high-precision (2 mu m) 3D printing based on the surface projection three-dimensional photo-curing technology. The specific process is as follows: firstly, designing a needle body part and a base part with the required structure size by utilizing SolidWorks design software, wherein the needle tip of the needle tip part of the needle body part is of a platform structure of 10-20 mu m. And importing the designed model into BMF slicing software for digital processing. To ensure smoothness of the needle tip surface, the preparation is performed with a minimum layer thickness of 5 μm during the preparation process.
And forming a microneedle female die by using PDMS, namely a microneedle model required by the embodiment of the invention, wherein the microneedle model can be repeatedly used.
S2, preparing a solution:
PVA solution was prepared, as examples: PVA and water are mixed and dissolved at 40-70 ℃ to form 10-30% PVA solution, such as 10%, 15%, 20%, 25%, 30% and the like, any value between 10-30% or a range of values between any two values.
Preparing PVP solution, by way of example: PVP and water are mixed and dissolved at normal temperature, for example, 30 ℃, to form 10-30% PVP solution, for example, 10%, 15%, 20%, 25%, 30% and the like, 10-30% or any value or any range between any two values.
HA solutions were prepared, examples: HA and water are mixed and dissolved at 40-70 ℃ to form a 2-10% HA solution, e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, etc., of any value or range of values between any two values between 2-10%.
A drug solution is formulated and the drug is dissolved in a solvent, such as water, on an ultra clean bench.
It should be noted that (1) the temperature of the prepared solution is merely an example of an embodiment of the present invention, and only at this temperature the raw material can be dissolved faster, and the dissolution temperature does not affect the performance of the raw material.
(2) The concentration of the formulation solution is also an example of the embodiment of the present invention and is not limited to the above-described example concentration.
S3, forming:
and quantitatively taking out the PVP solution, the PVA solution and the drug solution, oscillating, stirring and mixing, wherein the mass ratio of PVP to PVA is 1:0.5-1.5, and the dosage of the drug is that 6-7U of the drug is contained in each cubic centimeter of microneedle.
And quantitatively taking out the mixed solution into the microneedle female die by using a liquid-transferring gun, and slightly stirring the mixed solution back and forth by using the liquid-transferring gun to ensure that the mixed solution is completely paved on the surface of the die. And then placing the mould in a vacuum box for vacuumizing, centrifuging in a centrifuge to fill the cavity of the microneedle female mould, taking out, and scraping off and storing the redundant solution by using a scraper. Then, carrying out first incomplete drying; incomplete drying avoids the situation that the drug-carrying layer is not connected with the basal layer, and is easy to break in the demolding process. Wherein, the conditions of the first incomplete drying include: the drying temperature is 35-37deg.C, such as 35 deg.C, 36 deg.C, 37 deg.C, etc., and the drying time is 5-15 min; for example, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, etc., and any number between 5 and 15 minutes.
Mixing the PVP solution, the PVA solution and the HA solution, wherein the mass ratio of PVP to PVA to HA is 1:0.5-1.5:0.5-1.5, then pouring the mixture on a first incompletely dried die, and then carrying out second incompletely dried; avoiding the breakage of the micro-needles caused by demoulding after complete drying.
The conditions for the second partial drying include: the drying temperature is any value between 35 and 37 ℃, for example 35 ℃,36 ℃, 37 ℃ and the like, and the drying time is any value between 10 and 12 hours, for example 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours and the like.
Demolding, removing the microneedle after the second incomplete drying from the mold, shearing off the redundant part of the surrounding circle by using scissors, and continuing to dry at the same temperature until the microneedle is completely molded (avoiding warping and retraction).
In a third aspect, the present invention provides a drug delivery system comprising a microneedle according to the previous embodiments for delivering a drug to the stomach wall.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment of the invention provides a preparation method of a microneedle, which comprises the following steps:
s1, preparing a microneedle model;
referring to fig. 1, model number is designed first by using SolidWorks design software: the needle body part with the bottom diameter of 150 mu m (aiming at the stomach wall muscle layer) is 300 mu m, and the adopted micro needle tip is of a platform structure of 10 mu m according to the preparation requirement. And importing the designed model into BMF slicing software for digital processing. In order to ensure the smoothness of the surface of the needle tip, the preparation is carried out by adopting a minimum layer thickness of 5 mu m in the preparation process, and a high-precision (2 mu m) 3D printing microneedle male die based on a surface projection three-dimensional photo-curing technology is adopted, wherein the microneedle male die is formed by curing HTL Yellow-5 resin under 405nm ultraviolet light, and a female die required by PDMS preparation is adopted.
S2, preparing a solution:
a20% PVA solution was prepared at 60℃and stirred every 30min to accelerate dissolution of PVA molecules while avoiding dissolution of PVA lumps. A20% PVP solution was prepared at room temperature (30 ℃).
Preparing a base solution: a5% HA solution was prepared at 60℃and PVP and PVA were prepared as described above.
S3, a forming process:
referring to FIG. 1, the PVP and PVA solutions dissolved in S2 above were quantitatively removed and mixed, (PVP and PVA mass ratio 1:1), and BTX-A was dissolved in an ultra clean bench, in which a 33ul tip solution was added to 6.7U BTX-A solution, 1cm 3 The microneedle of (a) contains 100 needle points and BTX-A6.7U. Quantitatively taking out the mixed solution into the PDMS microneedle female die by using a liquid-transferring gun, and slightly stirring the mixed solution back and forth by using the liquid-transferring gun to enable the mixed solution to be completely paved on the surface of the die. The mold was then placed in a vacuum box and evacuated, and the cavity filled with microneedles was centrifuged in a centrifuge (1000 r), removed and the excess solution scraped off with a spatula and stored. The first time of incomplete drying, the temperature is controlled at 36 ℃ and the time is 10min.
Mixing PVP solution, PVA solution and HA solution, wherein PVA: PVP: ha=1: 1:1, casting on a dried mould, drying for 10 hours at 36 ℃, taking off the prepared micro needle from the mould (the drying completely causes brittleness, the needle point of the medicine carrier is broken in the mould), cutting off the redundant part around a circle by scissors, and continuing drying at the same temperature until the micro needle is completely formed (avoiding warping and retraction).
Example 2
The microneedle was prepared by the preparation method provided in reference to example 1, except that each needle portion had a height of 250 μm and a bottom diameter of 100. Mu.m.
Example 3
The microneedle was prepared by the preparation method provided in reference to example 1, except that each needle portion had a height of 350 μm and a bottom diameter of 200. Mu.m.
Example 4
The microneedle was prepared by the preparation method provided in reference to example 1, except that each needle portion had a height of 250 μm and a bottom diameter of 200. Mu.m.
Example 5
The microneedle was prepared by the preparation method provided in reference to example 1, except that each needle portion had a height of 300 μm and a bottom diameter of 200. Mu.m.
Example 6
The microneedles were prepared according to the preparation method provided in example 1, except that the mass ratio of PVP to PVA was 1:0.5.
Example 7
The microneedles were prepared according to the preparation method provided in example 1, except that the mass ratio of PVP to PVA was 1:1.5.
Example 8
The microneedles were prepared according to the preparation method provided in example 1, except that the mass ratio of PVP, PVA and HA was 1:0.5:0.5.
Example 9
The microneedles were prepared according to the preparation method provided in example 1, except that the mass ratio of PVP, PVA and HA was 1:0.5:1.5.
Example 10
The microneedles were prepared according to the preparation method provided in example 1, except that the mass ratio of PVP, PVA and HA was 1:1:0.5.
Detection example 1
The mechanical property of the microneedle prepared in example 1 was measured, and a force tester was used to apply a force gradually increasing vertically downward to the tip of the microneedle, and the degree of displacement of the tip of the microneedle was analyzed to determine whether the mechanical strength was sufficient to pierce the stomach wall. Force is applied to the microneedle substrate, and deformation and fracture of the substrate are detected to evaluate the deformability of the substrate.
As a result, referring to fig. 1, it can be seen from fig. 1 that the needle tip is displaced only about 35um under a pressure of 0.56N (corresponding to a skin piercing force of 3.183 MPa), which proves to be sufficient to pierce the stomach wall. The base portion of the microneedle has a maximum curvature of about 30% sufficient to meet the surface curvature of the stomach wall.
Test example 2 in vitro and in vivo dissolution experiments were performed on the microneedles prepared in example 1, and as a result, referring to fig. 2, it can be seen from fig. 2 that they can be dissolved within 120s, thereby achieving rapid drug delivery.
Experimental example
(1) Constructing a rat model:
male SD rats of 4 weeks old are selected as model animals, the control group is fed with basic feed, the experimental group is fed with high-fat and high-nutrition feed, and the two groups of rats are free to enter water, and the room temperature limit range is as follows: modeling feeding is carried out for 8 weeks at 18-20 ℃ and relative humidity of 30% -70%. Record food intake, body weight, lee's index, blood lipid, etc. Model evaluation: the body weight is 20% higher than that of the control group, and the rats are judged to be obese.
(2) The treatment process comprises the following steps: under 2% isoflurane inhalation anesthesia, the rat abdomen was disinfected and a 3-4 cm surgical incision was made in the middle of the abdomen. The stomach wall was exposed and gently rubbed with gauze. Injection operation: 0.3mL of BTX-A (20 IU) solution was injected through a 30G needle to multiple points of the stomach wall (including the antrum, fundus and body), each point at a dose of 0.1mL. Microneedle administration procedure: using forceps, 3 LGP-MN patches (i.e., microneedle patches) (each containing 6.7U BTX-A) were placed in the stomach wall at the indicated location (same as the injection site) and immediately pressurized to pierce the microneedles into the stomach tissue and dissolve for about 120 seconds. After the operation was completed, abdominal incisions were sutured layer by layer, and the rats were removed from anesthesia.
Experimental example 1
Three specifications of microneedles were prepared with reference to the preparation method of example 1, respectively: 3, the microneedle of the specification does not contain a drug, and the drug is changed into fluorescein sodium capable of being displayed in a fluorescent manner.
(a) A height of 300 μm and a bottom diameter of 150 μm, and can deliver drugs to the parietal layer of the stomach;
(b) A height of 600 μm and a bottom diameter of 300 μm, and can deliver drugs to the submucosa of the stomach wall;
(c) The height is 1000 μm, the bottom diameter is 500 μm, and the medicine can be delivered to the mucosa layer of the gastric wall.
The microneedle administration was performed according to the above procedure, and the microneedles of the above 3 specifications were inserted into the stomach wall to completely dissolve and release the drug, and then the stomach wall tissue was frozen and sectioned, and the area of sodium fluorescein distribution was observed under a fluorescence microscope to determine the site of drug delivery.
As a result, referring to fig. 3, it can be seen from fig. 3 that different specifications of microneedles can deliver drugs to different areas, including a mucosal layer, a submucosal layer, and a muscularis layer, which proves that the microneedles provided by the embodiment of the present invention can perform accurate delivery for the parietal musculature of the stomach. In vivo experiments show that after 300 mu m microneedle drug delivery, the drug is uniformly distributed in the muscular layer; after 600 mu m microneedle delivery, the drug is uniformly distributed on submucosa; after the 1000 μm microneedle delivery, the drug was uniformly distributed on the mucosal layer.
Experimental example 2
The microneedle administration and injection procedures were performed on the microneedle provided in example 1 according to the above procedure.
The appearance of the administration point was observed after administration, and referring to fig. 4, it is understood from fig. 4 that bleeding of local stomach wall tissue easily occurs after injection with a normal needle, whereas the microneedle delivery group has almost no bleeding, and the intraoperative bleeding score is significantly lower than that of the control group.
Meanwhile, whether the micro-needle on the stomach wall of the rat can be effectively penetrated is observed, and as a result, referring to fig. 5, it can be known from fig. 5 that the micro-needle can be effectively penetrated, and the needle pitch after penetration is relatively uniform.
Experimental example 3
The microneedles provided in example 1 were subjected to the microneedle dosing procedure as described above, and the body weight of the rats was measured every 3 days after the treatment of the injection procedure until the period was free-running (i.e., food was given to the feet, and the rats were free-fed) after 30 days from the dosing, and the results were shown in fig. 6. Wherein the grouping is as follows: I-NC represents normal needle injection saline (this is a control group); I-B represents a normal needle injection BTX-A; MN-NC represents a microneedle-carried physiological saline (this is a control group); MN-Mus represents that the microneedle carries BTX-A for administration of gastric wall muscle layer; MN-Sub represents that the microneedle carries BTX-A for administration of stomach wall submucosa; MN-Muc represents the administration of gastric wall mucosal layer by carrying BTX-A on a microneedle.
As can be seen from FIG. 6, compared with the injection of BTX-A (I-B group) with a common needle, the weight of rats with BTX-A (MN-Mus group) delivered by the muscle layer of the microneedle group is obviously reduced by about 3.35 times, which indicates that the administration of the muscle layer of the microneedle group provided by the embodiment of the invention can effectively reduce the weight and treat obesity.
Experimental example 4
The rats of experimental example 3 were administered for 30 days and then examined for indices related to systemic metabolic disorders by taking venous blood from each group, see fig. 7.
As can be seen from FIG. 7, the delivery of triglycerides and low density lipoproteins (LDL-C) by the muscle layer of the microneedle group was significantly reduced in both BTX-A (MN-Mus) compared to the injection of BTX-A (I-B) group by a conventional needle.
Experimental example 5
During the treatment of experimental example 3, the feeding amount of each group of rats was measured, and the gastric emptying rate of the two groups of rats after administration for 14 days was measured by means of color Doppler ultrasound. The results are shown in FIG. 8.
From fig. 8, it can be seen that the transient feeding rate rapidly decreases after gastric wall administration, and then slowly recovers, and the delivery of BTX-a by the microneedles (MN-Sub group and MN-Mus group) is significantly slower than that of the normal needle injection BTX-a group (I-B group). With the help of color Doppler ultrasonic measurement, compared with the gastric emptying rate of a control group, the gastric emptying rate of a BTX-A group (I-B) injected by a common needle is reduced by 66.3 percent, and the reduction of BTX-A (MN-Mus) delivered by a micro-needle muscle layer is more obvious and is 80.1 percent, which suggests that the phenomenon of delayed gastric emptying of the BTX-A (MN-Mus) delivered by the micro-needle muscle layer is obviously superior to the former although the gastric emptying can be inhibited to a certain extent by the common needle injection group.
Experimental example 6
Color doppler ultrasound evaluation the liver of each group of rats was modified in degree of fat and liver elasticity 30 days after administration. Meanwhile, rats were sacrificed 30 days after administration, and fresh liver tissue was obtained and subjected to staining analysis. The results are shown in FIG. 9.
Referring to FIG. 9, it is understood from FIG. 9 that the ratio of liver to kidney was 2.47 for the general control group (I-NC group) and 2.64 for the micro control group (MN-NC group). The general needle injection BTX-A group (I-B group) was 1.71, while the microneedle myolayer delivery BTX-A group (MN-Mus group) was 1.06, suggesting that liver steatosis was relieved in both the I-B group and the MN-Mus group, while the later was more pronounced. Meanwhile, pathological staining also proves that compared with the group I-B, the small oil drops in liver cells are obviously reduced, and the adipose-derived cells are reduced, so that the liver adipose-derived degeneration is obviously improved.
Experimental example 7
Rats were sacrificed 30 days after administration, adipose tissues including perirenal fat, epididymal fat and inguinal fat were obtained, their ratios with body weight were compared, and fat rates were calculated. Visceral fat ratio = (bilateral perirenal fat weight + bilateral epididymal fat weight) g/body weight g 100%. Subcutaneous fat rate = bilateral inguinal fat weight g/body weight g 100%.
Results referring to fig. 10, it can be seen from the results of fig. 10 that the visceral fat rate and the subcutaneous fat rate of the microneedle muscle layer delivery BTX-a group (MN-Mus group) were both the lowest, demonstrating the strongest therapeutic effect.
Experimental example 8
After 30 days of administration, rats were individually raised, and rat fecal samples were collected, and the Short Chain Fatty Acid (SCFA) content therein was detected by gas chromatography mass spectrometry.
As a result, referring to fig. 11, it can be seen from the results of fig. 11 that the microneedle muscular layer delivers short chain fatty acids of the stool of the BTX-a group (MN-Mus group) rats, which have been demonstrated to play an important role in maintaining intestinal health, preventing and improving various non-infectious diseases including cancer, with a stronger therapeutic effect, compared to the micropin-control group (MN-NC) and the general needle injection BTX-a group (I-B group).
Experimental example 9
Rats were sacrificed 30 days after dosing, the intestinal contents were taken and 16sRNA genomic sequencing was performed to analyze the changes in the flora.
Results referring to fig. 12, it can be seen from the results of fig. 12 that the ratio (F/B value) of Firmics to Bactoides decreases for the microneedle muscle layer delivery BTX-A group (MN-Mus group) (3.30%) and for the microneedle submucosal delivery BTX-A group (MN-Sub group) (1.48%) compared to the microneedle irradiation group (MN-NC) (15.44%). Whereas at the flora level the relative abundance of bacteria in all treatment groups was much higher than in the control group, showing the advantage of BTX-a treatment. In particular, microneedle muscle layer delivery BTX-a group (MN-Mus group) exhibited higher relative abundance of lactic acid bacteria than all other groups, which is beneficial for weight loss and metabolic improvement.
Experimental example 10
Glucose tolerance was measured 30 days after administration. Rats were fasted for 12 hours prior to testing, and then were bled and empty of blood. Rats were then perfused with 50% dextrose solution at 2g/kg, and blood was collected at 15, 30, 60, 90 and 120 minutes after the lavage, and blood glucose levels were measured at each time point and an oral glucose tolerance curve (OGTT) was drawn.
Results referring to fig. 13, it can be seen from the results of fig. 13 that in all treatment groups, only the microneedle muscle layer delivered BTX-a group (MN-Mus group) showed a significant decrease in area under the glucose tolerance curve compared to the micro-control group (MN-NC group), suggesting that this group showed a significant improvement in glucose tolerance compared to the micro-control group (MN-NC group). The micro-needle intramuscular injection BTX-A (MN-Mus group) is indicated to have a strong weight reduction effect and can effectively improve blood sugar.
In summary, the microneedle provided by the embodiment of the invention can accurately deliver the drug to the muscular layer of the stomach wall, so that the adverse conditions such as bleeding caused by common intragastric injection are reduced, and meanwhile, the operation is simple by using the microneedle, the gastric emptying can be more effectively inhibited, the weight is effectively controlled, the fatty liver degree is reduced, and the blood fat is reduced. While reducing gastric motility, regulate partial endocrine function, and achieve the effects of controlling weight and improving blood sugar. The novel safe, efficient and low-cost weight and blood glucose reducing mode has wide application prospect and extremely high application value and social and economic benefits. The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A microneedle for delivering a drug to the stomach wall, comprising a base portion and a plurality of drug-loaded needle portions disposed on the base portion, each of the needle portions having a conical structure with an aspect ratio of 1.25-3:1, each of the needle portions having a height of 250-350 μm and a bottom diameter of 100-200 μm.
2. The microneedle for delivering a drug to the stomach wall according to claim 1, wherein the microneedle contains 90-110 of said needle body portions per cubic centimeter;
preferably, each cubic centimeter of microneedle contains 2-15U of drug;
preferably, each cubic centimeter of microneedle contains 6-7U of drug;
preferably, each needle portion contains 0.06-0.07U of medicament;
preferably, each needle portion contains 0.02-0.15U of medicament.
3. The microneedle for delivering a drug to the stomach wall according to claim 1 or 2, wherein each needle body portion comprises a needle tip carrying the drug and a needle holder having both ends connected to the base portion and the needle tip, respectively, the needle holder being formed of the same material as the base portion.
4. A microneedle for delivering a drug to the stomach wall according to claim 3, wherein the raw materials forming the needle tip comprise PVP, PVA and a drug;
preferably, the mass ratio of PVP to PVA is 1:0.5-1.5.
5. A microneedle for delivering a drug to the stomach wall according to claim 3, wherein the material forming the hub and the base portion comprises PVP, PVA and hyaluronic acid,
preferably, the mass ratio of PVP, PVA and hyaluronic acid is 1:0.5-1.5:0.5-1.5.
6. Microneedle for delivering a drug to the stomach wall according to claim 1, characterized in that the drug is selected from drugs that inhibit gastric emptying, reduce ingestion, preferably botulinum toxin.
7. A method of preparing a microneedle for delivering a drug to the stomach wall according to claim 1, comprising: microneedles for delivering drugs to the stomach wall are formed using a step-and-mold process.
8. The method of manufacturing according to claim 7, comprising: preparing a microneedle model;
adding the raw material forming the needle tip into the microneedle mould, and then carrying out first incomplete drying;
adding the raw materials for forming the needle seat and the substrate part into the microneedle model, and then carrying out secondary incomplete drying; demolding and then completely drying.
9. The method of preparing according to claim 8, wherein the step of adding the raw material for forming the tip to the microneedle mould comprises: adding the raw material forming the needle tip into the microneedle mould by using a pipetting gun, vacuumizing the microneedle mould, centrifuging, and removing redundant solution;
preferably, the conditions of the first partial drying include: the drying temperature is 35-37 ℃ and the drying time is 5-15 minutes;
preferably, the conditions of the second partial drying include: the drying temperature is 35-37 ℃ and the drying time is 10-12 hours.
10. A drug delivery system comprising the microneedle for delivering a drug to the stomach wall of claim 1.
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