WO2024109829A1 - 抑制交感神经的医疗器械及其制备方法 - Google Patents
抑制交感神经的医疗器械及其制备方法 Download PDFInfo
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- WO2024109829A1 WO2024109829A1 PCT/CN2023/133417 CN2023133417W WO2024109829A1 WO 2024109829 A1 WO2024109829 A1 WO 2024109829A1 CN 2023133417 W CN2023133417 W CN 2023133417W WO 2024109829 A1 WO2024109829 A1 WO 2024109829A1
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- 230000002889 sympathetic effect Effects 0.000 title claims abstract description 74
- 210000005036 nerve Anatomy 0.000 title claims abstract description 62
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 38
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000013268 sustained release Methods 0.000 claims abstract description 97
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- 238000004891 communication Methods 0.000 claims abstract description 3
- DIVDFFZHCJEHGG-UHFFFAOYSA-N oxidopamine Chemical compound NCCC1=CC(O)=C(O)C=C1O DIVDFFZHCJEHGG-UHFFFAOYSA-N 0.000 claims description 28
- 239000000463 material Substances 0.000 claims description 18
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- 239000001506 calcium phosphate Substances 0.000 claims description 8
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 8
- 229940078499 tricalcium phosphate Drugs 0.000 claims description 8
- 229910000391 tricalcium phosphate Inorganic materials 0.000 claims description 8
- 235000019731 tricalcium phosphate Nutrition 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 4
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- 230000003187 abdominal effect Effects 0.000 description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
- A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- 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
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
Definitions
- the present invention relates to the field of biotechnology, and in particular to a medical device for inhibiting sympathetic nerves and a preparation method thereof.
- the current mainstream method of inhibiting peripheral nerves is intraperitoneal injection of 6-hydroxydopamine. This method is easy to operate, but lacks precision. The sympathetic nerves in the abdominal cavity will be killed, resulting in the loss of function of the sympathetic nerves in the entire abdominal nervous system, and its safety is poor.
- a medical device for inhibiting sympathetic nerves comprising:
- the sustained-release particles carrying denervation drugs are contained in the accommodating cavity.
- the particle size of the sustained-release particles is larger than the pore size of the sustained-release holes.
- the denervation drugs can be separated from the sustained-release particles and pass through the sustained-release holes.
- the sustained-release particles containing denervation drugs are contained in the containing cavity, and the denervation drugs can be separated from the sustained-release particles and pass through the sustained-release holes connected to the containing cavity, so that the medical device can be accurately targeted at the treatment site to accurately release the denervation drugs to the treatment site to avoid irritation to other tissues that do not need to be treated, and the medical device only needs to be sutured to the epithelium around a specific area, or implanted in a specific tissue, without the need for additional surgical operations, while reducing damage to achieve experimental effects, and has high safety.
- the medical device for inhibiting sympathetic nerves can be implanted into the stomach to inhibit the sympathetic nerve innervation of the stomach.
- the immunohistochemistry results show that the sympathetic nerves of the stomach are killed, while the sympathetic nerve fibers of the surrounding tissues (spleen, pancreas and small intestine) remain intact, and the direct intraperitoneal injection of 6-OHDA causes all sympathetic neurons in the abdominal cavity to be killed, and the sympathetic nerve innervation is lost.
- the above-mentioned medical device can accurately target and inhibit sympathetic nerves and has high safety.
- the denervating drug comprises 6-hydroxydopamine.
- the material of the sustained-release particles is a degradable material.
- the material of the sustained-release particles includes poly(lactic acid-co-glycolic acid).
- the sustained-release granules contain 1 mg - 2 mg of 6-hydroxydopamine.
- the sustained-release particles have a particle size of 5 ⁇ m-10 ⁇ m.
- the pore size of the sustained-release pore is 1 ⁇ m-3 ⁇ m.
- the material of the shell includes tricalcium phosphate.
- the shell is spherical in shape.
- the shell includes two detachably connected hemispherical shells, and the two hemispherical shells are arranged opposite to each other and cooperate to form the spherical shell.
- a method for preparing a medical device for inhibiting sympathetic nerves comprising the following steps:
- the sustained-release particles loaded with the drug are arranged in the containing cavity of the shell to obtain a medical device for inhibiting sympathetic nerves;
- the shell is provided with a plurality of sustained-release holes, each of which is connected to the accommodating cavity; the particle size of the sustained-release particles is larger than the pore size of the sustained-release holes, the drug can be separated from the sustained-release particles and pass through the sustained-release holes, and the drug includes 6-hydroxydopamine.
- the following step is also included: preparing the sustained-release particles loaded with the drug by a centrifugal shaking method.
- FIG1 is a schematic structural diagram of a medical device for inhibiting sympathetic nerves according to an embodiment
- FIG. 2 is a side schematic diagram of the medical device for inhibiting sympathetic nerves shown in FIG. 1 .
- an embodiment of the present invention provides a medical device for inhibiting sympathetic nerves, which can accurately target and inhibit sympathetic nerves and has high safety.
- the medical device for inhibiting sympathetic nerves comprises a shell having a receiving cavity 7 and sustained-release particles 6 carrying a denervation drug.
- the shell is provided with a plurality of sustained-release holes 3, each of which is connected to the receiving cavity 7.
- the sustained-release particles 6 are received in the receiving cavity 7.
- the particle size of the sustained-release particles 6 is larger than the pore size of the sustained-release holes 3.
- the denervation drug can be separated from the sustained-release particles 6 and pass through the sustained-release holes 3.
- the slow-release particles 6 carrying the denervation drug are contained in the accommodating cavity 7, and the denervation drug can be separated from the slow-release particles 6 and pass through the slow-release hole 3 connected to the accommodating cavity 7, so that the medical device can be accurately targeted at the site to be treated, so as to accurately release the denervation drug to the site to be treated, avoid irritation to other tissues that do not need to be treated, and only need to suture the medical device to the epithelium around the specific area, or implant it in a specific tissue, no additional surgical operation is required, and the experimental effect is achieved while reducing damage, and the safety is relatively high.
- the medical device for inhibiting sympathetic nerves can be implanted in the stomach to inhibit the sympathetic nerve control of the stomach.
- the immunohistochemical results show that the sympathetic nerves of the stomach are killed, while the sympathetic nerve fibers of the surrounding tissues (spleen, pancreas and small intestine) remain intact, and the direct intraperitoneal injection of 6-OHDA causes all sympathetic neurons in the abdominal cavity to be killed, and the sympathetic nerve control is lost.
- the above-mentioned medical device can accurately target and inhibit the sympathetic nerves and has high safety.
- the denervation drug includes 6-hydroxydopamine.
- 6-hydroxydopamine (6-OHDA) is a neurotoxic organic compound that can selectively destroy dopaminergic and noradrenergic neurons in the nervous system. This is mainly because the chemical structure of 6-OHDA is similar to dopamine and noradrenalin, so 6-ODHA can selectively enrich and kill dopaminergic and noradrenergic neurons.
- sympathetic nerves are all noradrenergic neurons, so 6-OHDA can be used as an inhibitor of the sympathetic nervous system of the peripheral nervous system.
- the denervating drug is not limited to 6-hydroxydopamine, and may be other denervating drugs.
- the material of the sustained-release particles 6 is a degradable material. Based on the degradability of the sustained-release particles 6, the drug can be released from the sustained-release particles 6 during the degradation process of the sustained-release particles 6, and pass through the sustained-release holes 3 to enter the tissue to exert a therapeutic effect, thereby achieving local tissue treatment.
- the material of the sustained-release particles 6 includes polylactic acid-glycolic acid copolymer.
- Polylactic acid-glycolic acid copolymer is a degradable, non-toxic polymer material with good biocompatibility and is included as a pharmaceutical excipient by the FDA.
- this study uses polylactic acid-glycolic acid copolymer as a sustained-release material, so that the sustained-release process can be controlled and efficient by adjusting the shape and composition of the sustained-release particles 6.
- the sustained-release particles 6 contain 1 mg - 2 mg of 6-hydroxydopamine, which is beneficial to drug release so as to accurately target and inhibit sympathetic nerves.
- the drug loading is not limited to the above-mentioned range, and the drug loading can be adjusted according to the type, age, experimental purpose, etc. of the treatment object, for example, the required drug dosage per kilogram of body weight per day is 1 mg - 5 mg.
- the treatment object may be, for example, a human or an experimental animal.
- the experimental animal may be, for example, a rat, a mouse, etc.
- the medical device for inhibiting sympathetic nerves can inhibit the local sympathetic nerves of the rodent organ.
- the particle size of the sustained-release particles 6 is 5 ⁇ m - 10 ⁇ m.
- the sustained-release particles 6 of this particle size are beneficial to the release of the drug, so as to accurately target and inhibit the sympathetic nerves.
- sustained-release holes 3 are evenly distributed on the shell.
- the pore size of the sustained-release hole 3 is 1 ⁇ m-3 ⁇ m.
- the sustained-release hole 3 of this pore size is conducive to drug release, so as to accurately target and inhibit sympathetic nerves.
- the material of the shell includes tricalcium phosphate.
- Tricalcium phosphate has good bio-tissue compatibility and biomechanical properties, so that the shell has both good bio-tissue compatibility and biomechanical properties.
- the shell is spherical in shape.
- the spherical structure is conducive to the targeting and fixed-point effect of the medical device.
- the shell includes two detachably connected hemispherical shells 5.
- the two hemispherical shells 5 are arranged relative to each other and cooperate to form a spherical shell.
- the shell is also provided with a fixing member 4.
- the fixing member 4 can detachably fix and connect the two hemispherical shells 5.
- the fixing member 4 is a lock.
- the fixing member 4 is arranged on the outer surface of the shell.
- the shell is also provided with a mounting hole 1.
- the mounting hole 1 is used to fix the above-mentioned medical device for inhibiting sympathetic nerves to the place to be treated.
- a support plate 2 is provided at the cross-sectional edge of the hemispherical shell 5.
- the mounting hole 1 is arranged on the support plate 2.
- the support plate 2 is annular and surrounds the cross-sectional edge of the hemispherical shell 5.
- the medical device for inhibiting sympathetic nerves can be sutured and fixed to the place to be treated by surgical sutures. Among them, the surgical sutures are non-absorbable sutures.
- the multiple mounting holes 1 are evenly distributed on the support plate 2 .
- the shape of the shell is not limited to being spherical, and may also be other shapes and may be set as required.
- the slow-release particles 6 carrying the denervation drug are contained in the accommodating cavity 7, and the denervation drug can be separated from the slow-release particles 6 and pass through the slow-release hole 3 connected to the accommodating cavity 7, so that the medical device can be accurately targeted at the site to be treated, so as to accurately release the denervation drug to the site to be treated, avoid irritation to other tissues that do not need to be treated, and only need to suture the medical device to the epithelium around the specific area, or implant it in a specific tissue, no additional surgical operation is required, and the experimental effect is achieved while reducing damage, and the safety is relatively high.
- the medical device for inhibiting sympathetic nerves can be implanted in the stomach to inhibit the sympathetic nerve control of the stomach.
- the immunohistochemical results show that the sympathetic nerves of the stomach are killed, while the sympathetic nerve fibers of the surrounding tissues (spleen, pancreas and small intestine) remain intact, and the direct intraperitoneal injection of 6-OHDA causes all sympathetic neurons in the abdominal cavity to be killed, and the sympathetic nerve control is lost.
- the above-mentioned medical device can accurately target and inhibit the sympathetic nerves and has high safety.
- the mainstream method of inhibiting peripheral nerves is intraperitoneal injection of 6-hydroxydopamine.
- This method is convenient to operate, but lacks precision, and the sympathetic nerves in the abdominal cavity will be killed.
- the medical device for inhibiting sympathetic nerves in this study aims to use tricalcium phosphate to construct a cavity structure containing micropores, and the cavity can contain a sustained-release material with polylactic acid-glycolic acid copolymer as a sustained-release matrix, which contains 6-hydroxydopamine to form sustained-release particles 6 to locally release the drug.
- the sustained-release process of the medical device for inhibiting sympathetic nerves in this study is more controllable and efficient, and can improve the efficiency of hexahydroxydopamine (6-ODAH) in inhibiting peripheral sympathetic nerves.
- 6-OHDA injected intraperitoneally will cause the sympathetic nerves in the entire abdominal nervous system to lose their function.
- 6-OHDA was encapsulated in polylactic acid-glycolic acid copolymer to form sustained-release particles 6, and these sustained-release particles 6 were encapsulated in a fixing material composed of tricalcium phosphate, which was specifically adhered to the target tissue, so as to inhibit the local sympathetic nervous system that specifically controls a specific organ, but would not cause interference with surrounding non-target tissues.
- the medical device for inhibiting sympathetic nerves of the present invention can avoid extensive killing stimulation caused by intraperitoneal injection, protect animals from unnecessary damage, and reduce interference factors and errors in experiments; the polylactic acid-glycolic acid copolymer supported by a tricalcium phosphate sustained-release microsphere structure with bioaffinity can maintain the experimental effect for a long time after one experiment until the material is degraded and absorbed; and 6-OHDA can be released in a targeted and quantitative manner to accurately control the experimental dosage and range.
- the medical device for inhibiting sympathetic nerves of the present invention can specifically encapsulate specific sustained-release compounds, release them stably over a long period of time, and reduce stimulation to surrounding non-target tissues; the installation operation is simple, and the device can be fixed around the target organ, for example, by suturing the epithelium around a specific area, or implanted into a specific tissue, without the need for additional surgical operations, thereby achieving experimental effects while reducing damage and avoiding animal death; it can be easily installed and removed, and the inhibition site can be replaced or the inhibition can be terminated according to experimental needs.
- One embodiment of the present invention also provides a method for preparing the above-mentioned medical device for inhibiting sympathetic nerves, comprising the following steps: placing sustained-release particles 6 loaded with drugs in a receiving cavity 7 of a shell to obtain a medical device for inhibiting sympathetic nerves; wherein the shell is provided with a plurality of sustained-release holes 3, each of which is connected to the receiving cavity 7; the particle size of the sustained-release particles 6 is larger than the pore size of the sustained-release holes 3, and the drug can be separated from the sustained-release particles 6 and pass through the sustained-release holes 3, and the drug includes 6-hydroxydopamine.
- a step of preparing the drug-loaded sustained-release particles 6 is included before the step of installing the drug-loaded sustained-release particles 6 in the housing cavity 7. Specifically, the drug-loaded sustained-release particles 6 are prepared by centrifugal shaking.
- a step of preparing the shell is also included.
- the shell is prepared by using 3D printing technology.
- the method for preparing the above-mentioned medical device for inhibiting sympathetic nerves includes S110-S130:
- 6-OHDA polylactic acid-co-glycolic acid sustained-release particles 6 are constructed by centrifugal shaking method.
- the release rate can be adjusted according to the animal weight, age, and experimental objectives, such as 1, 5 or 5 mg/kg per day.
- the medical device obtained by the preparation method of the above-mentioned medical device for inhibiting sympathetic nerves can gradually release 6-OHDA in a specific area, only affecting the sympathetic neurons around the fixed position, while the neurons far away from the fixed position will not be affected, thereby achieving the function of specifically killing sympathetic neurons without damaging non-target areas.
- the reagents and instruments used in the examples are all conventionally selected in the art.
- the experimental methods without specific conditions in the examples are usually carried out according to conventional conditions, such as the conditions described in the literature, books, or the methods recommended by the kit manufacturer.
- the reagents used in the examples are all commercially available.
- mice C57/6J wild-type mice were anesthetized, the outer skin was cut along the midline of the abdomen, and a surgical window of about 5 cm was cut along the midline of the peritoneum.
- the prepared shell device containing 1 mg of 6-OHDA polylactic acid-co-glycolic acid copolymer sustained-release particles was sutured to the peritoneum corresponding to the right stomach with non-absorbable sutures to achieve a fixation effect.
- the peritoneum was sutured with non-absorbable sutures and the epidermis was sutured with absorbable sutures. Wait for two weeks.
- mice were then killed by dragging the neck, the epidermis and peritoneum were cut along the midline of the abdomen, the abdominal organs (stomach, spleen, pancreas, etc.) were removed, fixed with paraformaldehyde, and frozen sections were 30 microns.
- the sympathetic nerve inhibitory medical device in this study can inhibit the sympathetic nerve innervation of the stomach.
- the immunohistochemical results showed that the sympathetic nerves of the stomach were killed, while the sympathetic nerve fibers of the surrounding tissues (spleen, pancreas and small intestine) remained intact.
- the experimental results are compared with direct intraperitoneal injection of 6-OHDA, which will lead to the killing of all sympathetic neurons in the abdominal cavity and the loss of sympathetic nerve innervation.
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Abstract
一种抑制交感神经的医疗器械及其制备方法，该抑制交感神经的医疗器械，包括：具有容置腔（7）的壳体，壳体设有多个缓释孔（3），各个缓释孔（3）均与容置腔（7）连通；载有去神经支配药物的缓释颗粒（6），缓释颗粒（6）收容于容置腔（7）中，缓释颗粒（6）的粒径大于缓释孔（3）的孔径，去神经支配药物能够从缓释颗粒（6）上分离并穿过缓释孔（3）。该抑制交感神经的医疗器械能够精准靶向在待治疗处，以向待治疗处精准释放去神经支配药物，避免对其他无需治疗的组织产生刺激，且仅需将该医疗器械缝合在特定区域周围上皮即可，或者植入特定组织内，不需要额外手术操作，在减少损伤的同时达到实验效果，安全性较高。
Description
本发明涉及生物技术领域，特别是涉及一种抑制交感神经的医疗器械及其制备方法。
目前主流抑制外周神经方法为腹腔注射6-羟基多巴胺，这种方法操作便捷，但缺乏精确性，腹腔内的交感神经都会被杀死，导致整个腹腔神经***内交感神经丧失功能，安全性较差。
基于此，有必要提供一种安全性较高、能够精准靶向抑制交感神经的医疗器械及其制备方法。
一种抑制交感神经的医疗器械，包括：
具有容置腔的壳体，所述壳体设有多个缓释孔，各个所述缓释孔均与所述容置腔连通；
载有去神经支配药物的缓释颗粒，所述缓释颗粒收容于所述容置腔中，所述缓释颗粒的粒径大于所述缓释孔的孔径，所述去神经支配药物能够从所述缓释颗粒上分离并穿过所述缓释孔。
上述抑制交感神经的医疗器械中，通过载有去神经支配药物的缓释颗粒收容于所述容置腔中，去神经支配药物能够从缓释颗粒上分离并穿过与容置腔连通的缓释孔，使得该医疗器械能够精准靶向在待治疗处，以向待治疗处精准释放去神经支配药物，避免对其他无需治疗的组织产生刺激，且仅需将该医疗器械缝合在特定区域周围上皮即可，或者植入特定组织内，不需要额外手术操作，在减少损伤的同时达到实验效果，安全性较高。经试验验证，将该抑制交感神经的医疗器械植入胃部，能够抑制胃部交感神经支配，免疫组化结果显示胃部交感神经被杀死，而周围组织（脾脏、胰腺和小肠）的交感神经纤维仍然保持完好，且直接腹腔注射6-OHDA导致腹腔内所有交感神经元被杀死，交感神经支配丧失。上述医疗器械能够精准靶向抑制交感神经、安全性较高。
在其中一个实施例中，所述去神经支配药包括6-羟基多巴胺。
在其中一个实施例中，所述缓释颗粒的材料为可降解材料。
在其中一个实施例中，所述缓释颗粒的材料包括聚乳酸-羟基乙酸共聚物。
在其中一个实施例中，所述缓释颗粒含有1 mg - 2 mg 的6-羟基多巴胺。
在其中一个实施例中，所述缓释颗粒的粒径为5 µm- 10 µm。
在其中一个实施例中，所述缓释孔的孔径为1 µm -3 µm。
在其中一个实施例中，所述壳体的材料包括磷酸三钙。
在其中一个实施例中，所述壳体的形状为球形。
在其中一个实施例中，所述壳体包括两个可拆卸连接的半球壳，两个所述半球壳相对设置而配合形成球形的所述壳体。
一种抑制交感神经的医疗器械的制备方法，包括如下：
将载有药物的缓释颗粒设置于壳体的容置腔中，得到抑制交感神经的医疗器械；
其中，所述壳体设有多个缓释孔，各个所述缓释孔均与所述容置腔连通；所述缓释颗粒的粒径大于所述缓释孔的孔径，所述药物能够从所述缓释颗粒上分离并穿过所述缓释孔，所述药物包括6-羟基多巴胺。
在其中一个实施例中，所述将载有药物的缓释颗粒安装于壳体的容置腔中的步骤之前，还包括如下步骤：采用离心震荡法制备载有所述药物的所述缓释颗粒。
图1为一实施方式的抑制交感神经的医疗器械的结构示意图；
图2为图1所示的抑制交感神经的医疗器械的侧面示意图。
附图标记说明：1-安装孔；2-支撑板；3-缓释孔；4-固定件；5-半球壳；6-缓释颗粒；7-容置腔。
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实施例及附图对本发明的具体实施方式做详细的说明。在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
如图1和图2所示，本发明一实施方式提供一种抑制交感神经的医疗器械，能够精准靶向抑制交感神经、安全性较高。
该抑制交感神经的医疗器械包括具有容置腔7的壳体和载有去神经支配药物的缓释颗粒6。壳体设有多个缓释孔3，各个缓释孔3均与容置腔7连通。缓释颗粒6收容于容置腔7中。缓释颗粒6的粒径大于缓释孔3的孔径。去神经支配药物能够从缓释颗粒6上分离并穿过缓释孔3。
上述抑制交感神经的医疗器械中，通过载有去神经支配药物的缓释颗粒6收容于所述容置腔7中，去神经支配药物能够从缓释颗粒6上分离并穿过与容置腔7连通的缓释孔3，使得该医疗器械能够精准靶向在待治疗处，以向待治疗处精准释放去神经支配药物，避免对其他无需治疗的组织产生刺激，且仅需将该医疗器械缝合在特定区域周围上皮即可，或者植入特定组织内，不需要额外手术操作，在减少损伤的同时达到实验效果，安全性较高。经试验验证，将该抑制交感神经的医疗器械植入胃部，能够抑制胃部交感神经支配，免疫组化结果显示胃部交感神经被杀死，而周围组织（脾脏、胰腺和小肠）的交感神经纤维仍然保持完好，且直接腹腔注射6-OHDA导致腹腔内所有交感神经元被杀死，交感神经支配丧失。上述医疗器械能够精准靶向抑制交感神经、安全性较高。
在其中一个实施例中，去神经支配药包括6-羟基多巴胺。6-羟基多巴胺（6-OHDA）是一种具有神经毒性的有机化合物，可选择性破坏神经***中多巴胺能和去甲肾上腺素能神经元，这主要是6-OHDA化学结构类似多巴胺和去甲肾上腺素，因此6-ODHA可以选择性在多巴胺能和去甲肾上腺素能神经元富集并杀死这些神经元。外周神经***中，交感神经都是去甲肾上腺素能的神经元，因此6-OHDA可以作为外周神经***交感神经***的抑制剂。
需要说明的是，去神经支配药不限于为6-羟基多巴胺，也可以为其他去神经支配药。
在其中一些实施例中，缓释颗粒6的材料为可降解材料。基于缓释颗粒6的可降解性，药物能够在缓释颗粒6的降解过程中从缓释颗粒6上释放出来，并穿过缓释孔3而进入组织中发挥治疗作用，以实现组织局部治疗。
进一步地，缓释颗粒6的材料包括聚乳酸-羟基乙酸共聚物。聚乳酸-羟基乙酸共聚物是一种可降解的无毒性高分子材料，具有良好的生物相容性，被FDA收录为药用辅料。相比已有等利用聚碳酸酯或含氟聚合物作为缓释材料，本研究采用聚乳酸-羟基乙酸共聚物作为缓释材料，使得能够通过调整缓释颗粒6形状和成分来实现缓释过程的可控、高效。
在其中一些实施例中，缓释颗粒6含有1 mg - 2 mg 的6-羟基多巴胺，该载药量有利于药物释放，以能够精准靶向抑制交感神经。需要说明的是，载药量不限于上述指出范围，可根据治疗对象的类型、年龄、实验目的等来调整载药量，例如每天每千克体重的所需药量为1毫克-5毫克。
其中，治疗对象例如可以为人或者实验动物。实验动物例如可以为大鼠、小鼠等。进一步地，上述抑制交感神经的医疗器械能够抑制啮齿类动物器官局部交感神经。
在其中一些实施例中，缓释颗粒6的粒径为5 µm - 10 µm。该粒径的缓释颗粒6有利于药物释放，以能够精准靶向抑制交感神经。
其中，多个缓释孔3均匀分布于壳体上。
在其中一些实施例中，缓释孔3的孔径为1 µm- 3 µm。该孔径的缓释孔3有利于药物释放，以能够精准靶向抑制交感神经。
在其中一些实施例中，壳体的材料包括磷酸三钙。磷酸三钙具有良好生物组织相容性与生物力学特性，使得壳体兼具良好生物组织相容性与生物力学特性。
在其中一个实施例中，壳体的形状为球形。球形结构有利于该医疗器械靶向定点作用。进一步地，壳体包括两个可拆卸连接的半球壳5。两个半球壳5相对设置而配合形成球形的壳体。更进一步地，壳体还设有固定件4。固定件4能够将两个半球壳5可拆卸地固定连接。具体地，固定件4为锁扣。固定件4设置在壳体的外表面上。
壳体还设有安装孔1。安装孔1用于将上述抑制交感神经的医疗器械固定在待治疗处。进一步地，半球壳5的截面边缘设有支撑板2。安装孔1设置在支撑板2上。支撑板2为环形，环绕半球壳5的截面边缘。可通过手术缝合线将该抑制交感神经的医疗器械缝合固定在待治疗处。其中，手术缝合线为不可吸收缝合线。
进一步地，安装孔1为多个。多个安装孔1均匀分布在支撑板2上。
需要说明的是，壳体的形状不限于为球形，也可以为其他形状，可根据需要进行设置。
上述抑制交感神经的医疗器械中，通过载有去神经支配药物的缓释颗粒6收容于所述容置腔7中，去神经支配药物能够从缓释颗粒6上分离并穿过与容置腔7连通的缓释孔3，使得该医疗器械能够精准靶向在待治疗处，以向待治疗处精准释放去神经支配药物，避免对其他无需治疗的组织产生刺激，且仅需将该医疗器械缝合在特定区域周围上皮即可，或者植入特定组织内，不需要额外手术操作，在减少损伤的同时达到实验效果，安全性较高。经试验验证，将该抑制交感神经的医疗器械植入胃部，能够抑制胃部交感神经支配，免疫组化结果显示胃部交感神经被杀死，而周围组织（脾脏、胰腺和小肠）的交感神经纤维仍然保持完好，且直接腹腔注射6-OHDA导致腹腔内所有交感神经元被杀死，交感神经支配丧失。上述医疗器械能够精准靶向抑制交感神经、安全性较高。
目前主流抑制外周神经方法为腹腔注射6-羟基多巴胺，这种方法操作便捷，但缺乏精确性，腹腔内的交感神经都会被杀死。本研究的抑制交感神经的医疗器械，旨在利用磷酸三钙构造一个含有微孔的腔体结构，其腔体内可以包含以聚乳酸-羟基乙酸共聚物作为缓释基质得缓释材料，后者内含有6-羟基多巴胺，形成缓释颗粒6，局部释放药物。相比已有等利用聚碳酸酯或含氟聚合物作为缓释材料，本研究的抑制交感神经的医疗器械缓释过程更加可控、高效，能够提高六羟多巴胺（6-ODAH）抑制外周交感神经的效率。
进一步地，现有的交感神经抑制方法中范围较大，通过腹腔注射的6-OHDA会导致整个腹腔神经***内交感神经丧失功能。本研究将6-OHDA包裹在聚乳酸-羟基乙酸共聚物中，构成缓释颗粒6，将这些缓释颗粒6包裹在磷酸三钙构成的固定材料中，将其特定粘附在目标组织旁，达到抑制特定支配特定器官的局部交感神经***，但不会导致干扰周围非靶标组织。
本发明的抑制交感神经的医疗器械，可以避免腹腔注射的广泛杀伤刺激，保护动物免受不必要的损伤，减少实验的干扰因素以及误差；使用具备生物亲和性的磷酸三钙缓释微球结构支撑的聚乳酸-羟基乙酸共聚物，一次实验后能够长期保持实验效果，直到材料被降解吸收；能够靶向定量释放6-OHDA，精准控制实验剂量和范围。
本发明抑制交感神经的医疗器械，可以特定的包裹特定缓释化合物，长期稳定释放，并减少对周围非目标组织的刺激；安装操作简单，将装置固定在目标器官周围，例如缝合在特定区域周围上皮即可，或者植入特定组织内，不需要额外手术操作，在减少损伤的同时达到实验效果，避免动物死亡；可以易于安装和移除，根据实验需要可以更换抑制位点或者终止抑制。
本发明一实施方式还提供上述抑制交感神经的医疗器械的制备方法，包括如下：将载有药物的缓释颗粒6设置于壳体的容置腔7中，得到抑制交感神经的医疗器械；其中，壳体设有多个缓释孔3，各个缓释孔3均与容置腔7连通；缓释颗粒6的粒径大于缓释孔3的孔径，药物能够从缓释颗粒6上分离并穿过缓释孔3，药物包括6-羟基多巴胺。
上述抑制交感神经的医疗器械的具体介绍详见上文，此处不再赘述。
具体地，壳体包括两个可拆卸连接的半球壳5，将载有药物的缓释颗粒6设置于壳体的容置腔7中的步骤包括：将载有药物的缓释颗粒6放入两个半球壳5中，然后将两个半球壳5相对设置，且用固定件4固定，形成球形的壳体。
在其中一些实施例中，将载有药物的缓释颗粒6安装于壳体的容置腔7中的步骤之前，还包括制备载有药物的缓释颗粒6的步骤。具体地，采用离心震荡法制备载有药物的缓释颗粒6。
在其中一些实施例中，将载有药物的缓释颗粒6安装于壳体的容置腔7中的步骤之前，还包括制备壳体的步骤。具体地，采用3D打印技术制备壳体。
在一个具体示例中，上述抑制交感神经的医疗器械的制备方法，包括S110-S130：
S110、6-OHDA作为去神经支配剂，通过离心震荡法构建6-OHDA聚乳酸-羟基乙酸共聚物缓释颗粒6，可以根据动物体重、年龄、实验目标调节释放速率，例如1、5或者5毫克每千克每天。
S120、将含有缓释颗粒6装载聚乳酸-羟基乙酸共聚物放入3D打印的磷酸三钙缓释固定器中。随后将两个半圆形固定器扣紧，形成一个完整的结构，将缓释颗粒6完全包裹起来。
S130、将装置安放在动物特定器官周围（如腹腔内肾上腺、肝脏、肾脏、胃部等）。利用不可吸收缝线将装置缝合在特定器官周围的***上，达到固定效果。
上述抑制交感神经的医疗器械的制备方法得到的医疗器械能够在特定区域内逐步释放6-OHDA，仅影响固定位置周围的交感神经元，而远离固定位置的神经元则不会受到影响，从而达到特异性杀死交感神经元，但又不损伤非目标区域的功能。
以下为具体实施例部分。
实施例中采用试剂和仪器如非特别说明，均为本领域常规选择。实施例中未注明具体条件的实验方法，通常按照常规条件，例如文献、书本中所述的条件或者试剂盒生产厂家推荐的方法实现。实施例中所使用的试剂均为市售。
实施例1
将C57/6J野生型小鼠麻醉沿着腹部中线剪开外表皮，并且沿着腹膜中线剪开大约5厘米手术窗。将制备好的含有1毫克的6-OHDA聚乳酸-羟基乙酸共聚物缓释颗粒的壳体装置，用不可吸收缝线绕一周缝合在靠右侧胃部对应的腹膜上，以达到固定效果。接下来，利用不可吸收缝线缝合腹膜，采用可吸收缝线缝合表皮。等待两周时间。随后将小鼠拖颈处死，沿腹部中线剪开表皮和腹膜，将腹部器官（胃、脾脏、胰腺等）取出，多聚甲醛固定，冰冻切片30微米。组织免疫荧光染色标记酪氨酸羟化酶，胃部染色结果显示阳性信号减少，表明装置起到了抑制效果，胃部交感神经元被杀死，而周围器官仍能观察到完好的交感神经纤维。
综上，本研究的抑制交感神经的医疗器械可以抑制胃部交感神经支配，免疫组化结果显示胃部交感神经被杀死，而周围组织（脾脏、胰腺和小肠）的交感神经纤维仍然保持完好。实验结果与直接腹腔注射6-OHDA相比，直接注射会导致腹腔内所有交感神经元被杀死，交感神经支配丧失。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
- 一种抑制交感神经的医疗器械，其特征在于，包括：具有容置腔的壳体，所述壳体设有多个缓释孔，各个所述缓释孔均与所述容置腔连通；载有去神经支配药物的缓释颗粒，所述缓释颗粒收容于所述容置腔中，所述缓释颗粒的粒径大于所述缓释孔的孔径，所述去神经支配药物能够从所述缓释颗粒上分离并穿过所述缓释孔。
- 根据权利要求1所述的医疗器械，其特征在于，所述去神经支配药包括6-羟基多巴胺。
- 根据权利要求1所述的医疗器械，其特征在于，所述缓释颗粒的材料为可降解材料。
- 根据权利要求3所述的医疗器械，其特征在于，所述缓释颗粒的材料包括聚乳酸-羟基乙酸共聚物。
- 根据权利要求1所述的医疗器械，其特征在于，所述缓释颗粒含有1 mg - 2 mg 的6-羟基多巴胺；及/或，所述缓释颗粒的粒径为5 µm - 10 µm；及/或，所述缓释孔的孔径为1 µm- 3 µm。
- 根据权利要求1所述的医疗器械，其特征在于，所述壳体的材料包括磷酸三钙。
- 根据权利要求1所述的医疗器械，其特征在于，所述壳体的形状为球形。
- 根据权利要求7所述的医疗器械，其特征在于，所述壳体包括两个可拆卸连接的半球壳，两个所述半球壳相对设置而配合形成球形的所述壳体。
- 一种抑制交感神经的医疗器械的制备方法，其特征在于，包括如下：将载有药物的缓释颗粒设置于壳体的容置腔中，得到抑制交感神经的医疗器械；其中，所述壳体设有多个缓释孔，各个所述缓释孔均与所述容置腔连通；所述缓释颗粒的粒径大于所述缓释孔的孔径，所述药物能够从所述缓释颗粒上分离并穿过所述缓释孔，所述药物包括6-羟基多巴胺。
- 根据权利要求9所述的制备方法，其特征在于，所述将载有药物的缓释颗粒安装于壳体的容置腔中的步骤之前，还包括如下步骤：采用离心震荡法制备载有所述药物的所述缓释颗粒。
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| CN105025974A (zh) * | 2013-03-12 | 2015-11-04 | 普西维达公司 | 包含硅基载体粒子的药物递送装置 |
| KR20160105168A (ko) * | 2015-02-27 | 2016-09-06 | 서울대학교산학협력단 | 약물 방출 나노 구조체를 함유하는 생체내 이식가능한 생흡수성 의료 장치 |
| CN109432020A (zh) * | 2019-01-02 | 2019-03-08 | 中国人民解放军第四军医大学 | 多孔磷酸钙支架负载微球复合材料及其制备方法和应用 |
| CN109689032A (zh) * | 2016-08-17 | 2019-04-26 | 优普顺药物公司 | 包括抗生素在内的药物的持续局部递送 |
| US20200289250A1 (en) * | 2017-09-06 | 2020-09-17 | Children's National Medical Center | Porous implantable devices |
| CN115135306A (zh) * | 2020-01-24 | 2022-09-30 | W.L.戈尔及同仁股份有限公司 | 用于外膜或外膜周神经消融的缓释基质及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105025974A (zh) * | 2013-03-12 | 2015-11-04 | 普西维达公司 | 包含硅基载体粒子的药物递送装置 |
| KR20160105168A (ko) * | 2015-02-27 | 2016-09-06 | 서울대학교산학협력단 | 약물 방출 나노 구조체를 함유하는 생체내 이식가능한 생흡수성 의료 장치 |
| CN109689032A (zh) * | 2016-08-17 | 2019-04-26 | 优普顺药物公司 | 包括抗生素在内的药物的持续局部递送 |
| US20200289250A1 (en) * | 2017-09-06 | 2020-09-17 | Children's National Medical Center | Porous implantable devices |
| CN109432020A (zh) * | 2019-01-02 | 2019-03-08 | 中国人民解放军第四军医大学 | 多孔磷酸钙支架负载微球复合材料及其制备方法和应用 |
| CN115135306A (zh) * | 2020-01-24 | 2022-09-30 | W.L.戈尔及同仁股份有限公司 | 用于外膜或外膜周神经消融的缓释基质及其用途 |
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