WO2023226136A1 - 一种用于脑部疾病诊断和治疗的微针系统及其制备方法 - Google Patents

一种用于脑部疾病诊断和治疗的微针系统及其制备方法 Download PDF

Info

Publication number
WO2023226136A1
WO2023226136A1 PCT/CN2022/101279 CN2022101279W WO2023226136A1 WO 2023226136 A1 WO2023226136 A1 WO 2023226136A1 CN 2022101279 W CN2022101279 W CN 2022101279W WO 2023226136 A1 WO2023226136 A1 WO 2023226136A1
Authority
WO
WIPO (PCT)
Prior art keywords
active drug
microneedle
liposomes
parts
treatment
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.)
Ceased
Application number
PCT/CN2022/101279
Other languages
English (en)
French (fr)
Inventor
盛宗海
郑海荣
胡德红
高笃阳
刘新
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenzhen Institute of Advanced Technology of CAS
Original Assignee
Shenzhen Institute of Advanced Technology of CAS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shenzhen Institute of Advanced Technology of CAS filed Critical Shenzhen Institute of Advanced Technology of CAS
Publication of WO2023226136A1 publication Critical patent/WO2023226136A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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 or needleless injectors
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • 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
    • 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
    • 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
    • A61M2037/0061—Methods for using microneedles

Definitions

  • the present application relates to the technical field of medical drug delivery, and more specifically, it relates to a microneedle system for diagnosis and treatment of brain diseases and a preparation method thereof.
  • Brain diseases are a heterogeneous group of neurological and mental disorders that occur in the brain and can cause severe personal suffering and economic losses to patients.
  • brain tumors represented by glioblastoma multiforme
  • brain neurodegenerative diseases represented by Alzheimer's disease and Parkinson's disease have attracted particular attention.
  • the number of patients worldwide is high, and the consequences of the disease are serious.
  • the current drug diagnosis and treatment effects are not ideal.
  • the reason is that the brain's natural defense system, the blood-brain barrier (BBB), while protecting the brain from harmful substances, also restricts the entry of most imaging probes and drug molecules, seriously affecting brain gliomas. diagnosis and treatment.
  • BBB blood-brain barrier
  • the lymphatic system is another liquid reticular circulatory system that is independent of the blood circulation system. It is spread throughout most tissues of the human body and helps remove metabolic waste from the interstitium to maintain body fluid homeostasis and play an immune response and immune surveillance role. Although meningeal lymphatic vessels have certain specificities in development time and morphology, similar to peripheral lymphatic vessels, they are highly expressed markers of mature lymphatic endothelial cells. The function of the cerebral lymphatic system is not only limited to the removal of metabolites, but its impact on cerebrospinal fluid circulation cannot be ignored.
  • VEGF-C vascular endothelial growth factor C
  • Microneedles can overcome stratum corneum obstacles in a minimally invasive and painless way, and can effectively promote the transdermal penetration of drug molecules, especially in the transdermal delivery of macromolecular drugs.
  • experiments gradually demonstrated that microneedles can significantly improve the transdermal delivery of insulin.
  • materials With the increasing abundance of materials, more and more materials are being developed for the preparation of insulin microneedles.
  • soluble insulin microneedles have received widespread attention because they can achieve drug delivery effects similar to those of injections.
  • This microneedle patch can carry three kinds of drugs at the same time.
  • the release sequence and cycle of the drugs can match the different requirements of clinical medication standards. It has the functions of rapid intraoperative hemostasis, long-term postoperative chemotherapy to inhibit tumor cells, and timely start of targeted blood vessel inhibition as needed. key functions such as generation.
  • the patch is implanted in situ into the tumor cavity.
  • this application provides a microneedle system for the diagnosis and treatment of brain diseases and a preparation method thereof.
  • this application provides a microneedle system for diagnosis and treatment of brain diseases, using the following technical solutions:
  • a microneedle system for the diagnosis and treatment of brain diseases including the following raw materials in parts by weight:
  • Active drug liposome 0.1-10 parts
  • the active drug liposome includes the following raw materials:
  • microneedles loaded with active drug liposomes can successfully deliver active drug liposomes to the brain through deep cervical lymph nodes to exert therapeutic effects. It can avoid the interference of the gastrointestinal environment on drug efficacy and the "first-pass effect" of the liver, maintain a constant optimal blood drug concentration or physiological effect, prolong the effective action time, reduce the number of medication times, and allow patients to self-administer drugs with better compliance.
  • the microneedle system for diagnosis and treatment of brain diseases also includes NK cell membrane proteins.
  • NK cells are natural killer cells (NK), which are important immune cells in the body. They are not only related to anti-tumor, anti-viral infection and immune regulation, but also participate in hypersensitivity reactions in some cases. and the occurrence of autoimmune diseases; using its membrane protein for bionics can effectively increase the rate at which active drug liposomes enter brain cells, thereby quickly exerting effects.
  • NK natural killer cells
  • the mass ratio of the active drug liposome to the NK cell membrane protein is 300:1.
  • the active drug liposomes and NK cell membrane proteins are prepared through a homogenization method to produce imitated active drug liposomes.
  • the specific operations of the homogenization method are:
  • active drug liposomes and NK cell membrane proteins are mixed with high-pressure homogenization method, so that the final particle size of the biomimetic active drug liposome is suitable, uniform, and the surface is smooth and free of crystals.
  • the active drug includes a water-soluble active drug and a fat-soluble active drug; when the active drug is a fat-soluble active drug, the preparation of the liposome of the fat-soluble active drug includes the following steps:
  • the pretreatment method for fat-soluble drugs is as follows: take 0.1-10 parts of fat-soluble active drugs and dissolve them in anhydrous methanol or ether to obtain a mixed solution II for later use;
  • the preparation of the water-soluble active drug liposome includes the following steps:
  • S1 water-soluble active pharmaceutical carrier Take 10-100 parts of phospholipids and 10-100 parts of cholesterol, dissolve them in chloroform to obtain a mixed solution I for later use;
  • the active drug includes a water-soluble active drug and a fat-soluble active drug; when the active drug is a fat-soluble active drug, the preparation of the liposome of the fat-soluble active drug includes the following steps:
  • the pretreatment method for fat-soluble drugs is as follows: take 0.25 parts of fat-soluble active drugs and dissolve them in anhydrous methanol or ether to obtain a mixed solution II for later use;
  • the preparation of the water-soluble active drug liposome includes the following steps:
  • S1 water-soluble active drug carrier Take 50 parts of phospholipids and 25 parts of cholesterol, dissolve them in chloroform to obtain a mixture I for later use;
  • the phospholipid is soy lecithin.
  • the extrusion operation in step 2) in S3 is specifically: repeatedly extruding 20 times using a liposome extruder equipped with filter membranes of different pore sizes, and the pore sizes of the filter membranes are successively reduced.
  • the filter membrane is a polycarbonate membrane, and the pore diameters of the polycarbonate membrane are 200 nm, 100 nm and 50 nm.
  • the extrusion operation in step 2) in S3 is to sequentially use a liposome extruder equipped with polycarbonate membranes with pore diameters of 200nm, 100nm and 50nm for extrusion filtration.
  • the number of extrusion filtrations is 20 times respectively.
  • the particles in the liposomes are crushed and passed through 200nm, 100nm and 50nm filter membranes in sequence to make the particle size of the liposomes uniform, and finally obtain active drugs with a particle size of 50nm. Liposomes.
  • the dispersing agent is one or a combination of sodium hyaluronate, hyaluronic acid, dextran or polyethylene glycol (PEG).
  • the dispersing agent is sodium hyaluronate and dextran.
  • the active drugs are curcumin, nimodipine, flunarizine, betahistine, ligustrazine, butylphthalide, papaverine, ginkgo leaf extract, vinpocetine, quintiaphen fumarate Citalopram, olanzapine, citalopram, alprazolam, oxazepam (norazepam), lorazepam (Lola), triazolam (Hyloshen), Madopar, Taserda , Senfurol, Xining, Antam, Selegiline, Rasagiline, Tolcapone, Ropinirole, Antam, Ambroxol, Codan, Amantadine, Carbamazepine, Valpro Sodium phenytoin, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, topiramate, vigabatrin, levetiracetam, clonazepam, di
  • this application provides a method for preparing a microneedle system for diagnosis and treatment of brain diseases, adopting the following technical solution: a method for preparing a microneedle system for diagnosis and treatment of brain diseases, including Following preparation steps:
  • a method for preparing a microneedle system for diagnosis and treatment of brain diseases includes the following preparation steps:
  • the drying temperature is 4°C and the drying time is 1-100h; preferably, the drying time is 24h.
  • the microneedle system used in the diagnosis and treatment of brain diseases does not require surgery, is simple in process, highly safe, and does not require long-term application.
  • Implantable sustained-release microneedles Implantable sustained-release microneedles.
  • Transdermal drug delivery attached to the head or neck) allows the drug to pass through the deep cervical lymph nodes and meningeal lymphatic vessels, bypassing the blood-brain barrier and reaching the brain tissue to exert therapeutic effects.
  • Figure 1 is a TEM image of curcumin liposomes of a microneedle system disclosed in the present application for diagnosis and treatment of brain diseases;
  • Figure 2 is a particle size diagram of curcumin liposomes of a microneedle system disclosed in the present application for diagnosis and treatment of brain diseases;
  • Figure 3 is a distribution diagram of curcumin in mouse brain slices in Example 1 of the present application.
  • Figure 4 is a comparison table of the efficiency of curcumin entering the brain at different time points in Application Examples 1-3 of the present application.
  • the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an in vitro brain or neck microneedle patch for treating brain diseases.
  • This method loads active drugs for treating brain diseases into microneedles, and explores the transdermal delivery effect of microneedles loaded with active drugs (attached to the head or neck).
  • the active drug in the embodiments of this application takes curcumin as an example.
  • the active drug can also be nimodipine, flunarizine, betahistine, ligustrazine, butylphthalide, papaverine, Ginkgo biloba extract, vinpocetine, quetiapine fumarate, olanzapine, citalopram, alprazolam, oxazepam (norazepam), lorazepam (lorola), triazole Lun (Helena), Madopar, Taserta, Senfuluo, Xining, Antam, Selegiline, Rasagiline, Tolcapone, Ropinirole, Antam, Ambroxol , Codan, amantadine, carbamazepine, sodium valproate, phenytoin, gabapentin, lamotrigine, oxcarbazepine, phenobarbital, topiramate, vigabatrin, levetiracetam, chloride Nitrazepam, di
  • microneedles loaded with curcumin liposomes could successfully deliver curcumin liposomes to the brain through deep cervical lymph nodes, exerting therapeutic effects.
  • the present invention is of great significance in promoting the application transformation of microneedle in clinical treatment of brain diseases, and provides new methods and new technologies for the treatment of brain diseases.
  • curcumin carrier Dissolve 50 mg of phospholipid and 25 mg of cholesterol in 2 ml of chloroform to obtain a mixture I for later use;
  • Curcumin pretreatment Take 0.25 mg curcumin and dissolve it in 2 ml of anhydrous methanol to obtain a mixed solution II for later use;
  • Preparation Example 2-3 is different from Preparation Example 1 in that the amounts of raw materials used are different, as shown in the table below.
  • Example 2-3 The difference between Example 2-3 and Example 1 is that the amounts of raw materials used are different, as shown in the table below.
  • Example 1 The difference between this example and Example 1 is that the bionic curcumin liposome prepared in Preparation Example 4 is used.
  • the obtained bionic curcumin liposomes were scanned under an electron microscope to obtain the TEM image of the biomimetic curcumin liposomes as shown in Figure 1. From the TEN image, it can be seen that the particle size of the biomimetic curcumin liposomes is approximately 50 nm. , the dispersion is better.
  • the particle size distribution of bionic curcumin liposomes was measured using a particle size analyzer. As shown in Figure 2, the hydrated particle size of bionic curcumin liposomes is approximately 50 nm, and the particles are relatively uniform.
  • Application Example 1 First, take the experimental mouse and remove the hair on the mouse's neck and head; then stick the curcumin liposome microneedle patch prepared in Example 1 on the mouse's neck (curcumin liposome group); finally, the small animal in vivo imaging system (IVIS) was used to track the distribution of curcumin in the mouse brain, as shown in Figures 3 and 4.
  • IVIS small animal in vivo imaging system
  • Application Example 2 The difference from Application Example 1 is that the bionic curcumin liposome microneedle patch prepared in Example 4 was applied to the neck of mice (biomimetic curcumin liposome group).
  • IVIS In vivo imaging system
  • Application Example 3 Using the curcumin liposome obtained in Preparation Example 1, injecting it into the tail vein of mice (tail vein group), and then using a small animal in vivo imaging system (IVIS) to track the movement of curcumin in the mouse brain The distribution of parts is shown in Figure 4.
  • IVIS in vivo imaging system
  • curcumin liposomes or bionic curcumin liposomes prepared by the preparation method of the present application can also be made into a gel and applied to the head or neck, or introduced into the head or neck using methods such as ultrasound and subcutaneous injection. neck.
  • the microneedle patch prepared using the preparation method of the microneedle system provided in this application shows that the curcumin liposomes or bionic curcumin are loaded Liposome microneedles can successfully deliver curcumin liposomes or bionic yellowstone liposomes to the brain through deep cervical lymph nodes to exert therapeutic effects.
  • the present invention is of great significance in promoting the clinical application and transformation of microneedles of curcumin liposomes, and provides new methods and technologies for the treatment of brain diseases. Compared with traditional treatment methods for brain diseases, it does not require surgery and reduces treatment risks. It is an implantable sustained-release microneedle with a simple process, high safety, and no need for long-term application.
  • the principle uses transdermal administration (attached to the head or neck), allowing the drug to pass through the deep cervical lymph nodes and meningeal lymphatic vessels, bypassing the blood-brain barrier and reaching the brain tissue to exert its therapeutic effect.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dispersion Chemistry (AREA)
  • Medical Informatics (AREA)
  • Anesthesiology (AREA)
  • Biomedical Technology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种用于脑部疾病诊断和治疗的微针系统及其制备方法。一种用于脑部疾病诊断和治疗的微针系统包括活性药物脂质体0.1-10份；分散剂1-10份；其中，所述活性药物脂质体包括以下原料制成：活性药物0.1-10份；磷脂10-100份；胆固醇10-100份。其制备方法为：通过薄膜水化-冻融-均质法制得。一种用于脑部疾病诊断和治疗的微针系统，其具有改变现有用于脑部疾病治疗的微针需要手术植入的方式，采用经皮给药，无需手术且治疗效果良好的优点。

Description

一种用于脑部疾病诊断和治疗的微针系统及其制备方法 技术领域
本申请涉及医学给药的技术领域，更具体地说，它涉及一种用于脑部疾病诊断和治疗的微针系统及其制备方法。
背景技术
脑部疾病是一类发生在脑部的异质性神经和精神障碍，会引起患者严重的个人痛苦和经济损失。在各类脑部疾病中，以多形胶质母细胞瘤为代表的脑部肿瘤和以阿尔茨海默病及帕金森病为代表的脑部神经退行性疾病，尤其受到人们的关注。其全球患病人数较高，且病情造成的后果较严重，而现有的药物诊断和治疗效果并不理想。究其原因，大脑的天然防御系统血脑屏障(Blood Brain Barrier,BBB)在保护大脑免受有害物质侵害的同时，也限制了大部分成像探针和药物分子进入，严重影响了脑胶质瘤的诊断和治疗。
淋巴系统是独立于血液循环系统的另一套液体网状循环系统，它遍布人体大部分组织，协助清除间质中的代谢废物，以维持体液稳态，并发挥免疫应答及免疫监视作用。虽然脑膜淋巴管在发育时间和形态上存在一定的特殊性，但与外周淋巴管类似，它们是高表达成熟淋巴内皮细胞的标志物。脑淋巴系统，其功能不仅仅局限于对代谢产物的清除，对于脑脊液循环的影响同样不可忽视。2020年1月15日耶鲁大学医学院Akiko Iwasaki教授团队在Nature杂志上发表文章揭示血管内皮生长因子C(VEGF-C)促进颈深淋巴结中CD8T细胞引流至大脑中，并促进CD8T细胞启动，迁移至肿瘤部位，快速清除胶质母细胞瘤，发挥持久的抗肿瘤免疫记忆反应。但是在将颈深淋巴结进行结扎后，VEGF-C的这种抗肿瘤作用就消失了，这就表明VEGF-C对胶质母细胞瘤的清除作用需要淋巴引流至颈深部淋巴结。因此，开发安全高效的新型经颈深淋巴结的脑部药物递送策略，成为中枢神经系统领域的重要研究目标。
微针能够以微创无痛的方式克服角质层障碍，可有效促进药物分子的经皮渗透，尤其是在大分子药物的经皮递送方面有着显著的效果。在21世纪初，逐渐有实验证明微针可大幅度提高胰岛素的经皮递送。随着材料的日益丰富，越来越多的材料被开发用于胰岛素微针的制备。其中，可溶胰岛素微针因可达到与注射相近的给药效果，而得到了广泛的关注。中科院上海微系统所陶虎研究员团队与复旦大学附属华山医院神经外科毛颖教授团队合作，针对脑胶质瘤治疗，开发出基于蚕丝蛋白的异质、异构、可降解微针贴片。该微针贴片可同时携带三种药物，药物的释放顺序和周期能够匹配临床用药规范的差异性要求，具备术中快 速止血、术后长期化疗抑制肿瘤细胞、按需定时启动靶向抑制血管生成等关键功能。在切除肿瘤的手术过程中，将该贴片原位植入到瘤腔内，待其释放药物后可完全降解消失，无需二次手术取出，且降解产物不会引起免疫炎症反应。这种颅内局部给药的方式不仅解决了血脑屏障对药物分子的阻碍问题，还降低了常规全身大剂量给药的毒副作用。在动物实验中，与空白组和注射组相比，采用蚕丝蛋白载药微针贴片的治疗组有效抑制了肿瘤体积，显著延长了小鼠生存时间。美国约翰霍普金斯大学李兴德教授报告了一种超小型(外径580μm)治疗性深部脑微针，与800nm光学相干断层成像与激光切除相结合。通过小鼠脑显微结构的体内超高分辨率(轴向1.7μm，横向5.7μm)、高速(每秒20帧)容积成像和光衰减系数的测定，证明了该方法的有效性。通过在小鼠深部脑的体内肿瘤可视化(成像深度为1.23mm)和有效的组织切除(350mw功率的1448nm连续波激光)进一步证明了其转化潜能。
然而以上的这些方法都需要将微针通过手术的方式植入脑组织，众所周知，手术无论大小均存在一定风险，更何况是对于脑部手术，风险更是增加了不少。故发明人认为相关技术中关于脑部疾病治疗位置的给药方式单一，且风险较高的缺陷。
发明内容
为了改善相关技术中对于脑部疾病诊断和治疗的微针给药方式单一，以及手术风险高的缺陷，本申请提供一种用于脑部疾病诊断和治疗的微针系统及其制备方法。
第一方面，本申请提供一种用于脑部疾病诊断和治疗的微针系统，采用如下的技术方案：
一种用于脑部疾病诊断和治疗的微针系统，包括以下重量份原料制成：
活性药物脂质体0.1-10份；
分散剂1-10份；
其中，所述活性药物脂质体包括以下原料制成：
活性药物0.1-10份；
磷脂10-100份；
胆固醇10-100份。
通过采用以上技术方案，负载有活性药物脂质体的微针可成功的将活性药物脂质体通过颈深淋巴结递送到脑部，发挥治疗效果。可以避免肠胃环境对药效的干扰和肝脏“首过效应”，维持恒定的最佳血药浓度或生理效应，延长有效作用时间，减少用药次数，患者可自主给药，依从性较好。
可选的，所述一种用于脑部疾病诊断和治疗的微针系统还包括NK细胞膜蛋白。
通过采用上述技术方案，NK细胞为自然杀伤细胞(Natural Killer cell，NK)，是机体重要的免疫细胞，不仅与抗肿瘤、抗病毒感染和免疫调节有关，而且在某些情况下参与超敏反应和自身免疫性疾病的发生；采用其膜蛋白进行仿生，能够有效提高活性药物脂质体进入脑部细胞的速率，从而快速发挥效果。
可选的，所述活性药物脂质体与NK细胞膜蛋白的质量比为300:1。
可选的，所述活性药物脂质体与NK细胞膜蛋白通过均质法制得仿生活性药物脂质体，所述均质法的具体操作为：
1)在20psi的气压下，进行3-10次均质操作；
2)调节气压至40psi，继续3-10次均质操作即得仿生活性药物脂质体。
通过采用上述技术方案，通过高压均质法使得活性药物脂质体与NK细胞膜蛋白，使得最终得到的仿生活性药物脂质体的粒径大小合适，且均匀，表面光滑无结晶。
可选的，所述活性药物包括水溶性活性药物和脂溶性活性药物；当活性药物为脂溶性活性药物时，所述脂溶性活性药物脂质体的制备包括以下步骤：
S1脂溶性活性药物前处理以及脂溶性活性药物载体的制备，
脂溶性活性药物载体的制备：取10-100份的磷脂和10-100份的胆固醇，溶于氯仿中得混合液I备用；
脂溶性药物前处理方法为：取0.1-10份的脂溶性活性药物，溶于无水甲醇或者乙醚中得混合液II备用；
S2旋蒸混合液，
将混合液I和混合液II混合，然后蒸干得混合物；
S3活性药物脂质体的制备，
1)使用PBS缓冲液冲洗混合物，然后在液氮-65℃下进行冻融，循环4-8次得到活性药物脂质体溶液；
2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存；
当活性药物为水溶性活性药物时，所述水溶性活性药物脂质体的制备包括以下步骤：
S1水溶性活性药物载体的制备：取10-100份的磷脂和10-100份的胆固醇，溶于氯仿中得混合液I备用；
S2旋蒸混合液：将混合液I旋蒸蒸干得混合物；
S3活性药物脂质体的制备，
1)使用PBS缓冲液冲洗混合物并加入0.1-10份的水溶性活性药物，使其充分溶解，然后在液氮-65℃下进行冻融，循环4-8次得到活性药物脂质体溶液；
2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存。
通过采用上述技术方案，先使用氯仿将磷脂和胆固醇进行溶解，使用无水甲醇和乙醚溶解活性药物，然后混合，能够使得活性药物充分与磷脂、胆固醇混合，使得活性药物能够均匀分布在脂质体中，其次使用PBS冲洗混合物，是为了将混合物从容器壁上冲洗脱落，S3的最后一步进行透析是为了将游离的活性药物去除；其中脂溶性药物如姜黄素、尼莫地平、氟桂利嗪、川芎嗪、罂粟碱、长春西汀等，需要使用无水甲醇进行溶解，然后使其充分分散在脂质体内，如水溶性药物如，倍他司汀、丙戊酸钠、苯妥英钠等，则直接使用PBS缓冲液进行溶解即可。
优选的，所述活性药物包括水溶性活性药物和脂溶性活性药物；当活性药物为脂溶性活性药物时，所述脂溶性活性药物脂质体的制备包括以下步骤：
S1脂溶性活性药物前处理以及脂溶性活性药物载体的制备，
脂溶性活性药物载体的制备：取50份的磷脂和25份的胆固醇，溶于氯仿中得混合液I备用；
脂溶性药物前处理方法为：取0.25份的脂溶性活性药物，溶于无水甲醇或者乙醚中得混合液II备用；
S2旋蒸混合液，
将混合液I和混合液II混合，然后蒸干得混合物；
S3活性药物脂质体的制备，
1)使用PBS缓冲液冲洗混合物，然后在液氮-65℃下进行冻融，循环6次得到活性药物脂质体溶液；
2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存；
当活性药物为水溶性活性药物时，所述水溶性活性药物脂质体的制备包括以下步骤：
S1水溶性活性药物载体的制备：取50份的磷脂和25份的胆固醇，溶于氯仿中得混合液I备用；
S2旋蒸混合液：将混合液I旋蒸蒸干得混合物；
S3活性药物脂质体的制备，
1)使用PBS缓冲液冲洗混合物并加0.25份水溶性活性药物，使水溶性活性药物充分溶解，然后在液氮-65℃下进行冻融，循环5次得到活性药物脂质体溶液；
2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存。
可选的，所述磷脂为大豆卵磷脂。
可选的，所述S3中的步骤2)中的挤压操作具体为：依次采用装有不同孔径的滤膜的脂质体挤压器反复挤压20次，且滤膜孔径依次减小。
可选的，所述滤膜为聚碳酸酯膜，所述聚碳酸酯膜的孔径为200nm，100nm和50nm。
具体的，所述S3中的步骤2)中的挤压操作为，依次采用装有孔径为200nm，100nm和50nm的聚碳酸酯膜的脂质体挤压器进行挤压过滤，挤压过滤次数分别为20次。
通过采用上述技术方案，通过反复的挤压过滤，使得脂质体内的颗粒粉碎，依次通过200nm、100nm以及50nm的滤膜，使得脂质体的粒径均一，最终得到粒径为50nm的活性药物脂质体。
可选的，所述分散剂为透明质酸钠、透明质酸、葡聚糖或者聚乙二醇(PEG)中的一种或多种的组合。
优选的，所述分散剂为透明质酸钠和葡聚糖。
可选的，所述活性药物为姜黄素、尼莫地平、氟桂利嗪、倍他司汀、川芎嗪、丁苯酞、罂粟碱、银杏叶提取物、长春西汀、富马酸喹硫平、奥氮平、西酞普兰、阿普唑仑、奥沙西泮(去甲羟安定)、劳拉西泮(罗拉)、三唑仑(海乐神)、美多芭、泰舒达、森福罗、息宁、安坦、司来吉兰、雷沙吉兰、托卡朋、罗匹尼罗，安坦、氨溴索，珂丹，金刚烷胺，卡马西平、丙戊酸钠、苯妥英钠、加巴喷丁、拉莫三嗪、奥卡西平、苯巴比妥、托吡酯、氨己烯酸、左乙拉西坦、氯硝西泮、地西泮、马来酸咪达唑仑、乙琥胺、扑痫酮、唑尼沙胺、普瑞巴林、瑞替加滨中的一种。
第二方面，本申请提供一种用于脑部疾病诊断和治疗的微针系统的制备方法，采用如下的技术方案：一种用于脑部疾病诊断和治疗的微针系统的制备方法，包括以下制备步骤：
1)取以上制得的活性药物脂质体或者仿生活性药物脂质体进行冻干，得到白色粉末；
2)取1)中0.1-10份的活性药物脂质体或仿生活性药物脂质体以及1-10份的分散剂分散于水中，搅拌至充分溶解得基质液；
3)将2)中得到的基质液注入微针模具中，进行离心倒转使得基质液均匀分布在模具中，并充满模具中的微针针尖部分；
4)再取1-10份的分散剂分散于水中，得分散液；然后将分散液加入步骤3)中微针针尖中，离心后干燥，得活性药物脂质体微针或者仿生活性药物脂质体微针；
5)在微针基底背面贴上压敏胶被衬，脱模，即得活性药物脂质体微针贴片或仿生活性药物脂质体微针贴片。
优选的，一种用于脑部疾病诊断和治疗的微针系统的制备方法，包括以下制备步骤：
1)取以上制得的活性药物脂质体或者仿生活性药物脂质体进行冻干，得到白色粉末；
2)取1)中2份的活性药物脂质体或仿生活性药物脂质体以及4份的分散剂分散于水中，搅拌至充分溶解得基质液；
3)将2)中得到的基质液注入微针模具中，进行离心倒转使得基质液均匀分布在模具中，并充满模具中的微针针尖部分；
4)再取1份的葡聚糖和2份的透明质酸钠分散于水中，得分散液；然后将分散液加入步骤3)中微针针尖中，离心后干燥，得活性药物脂质体微针或者仿生活性药物脂质体微针；
5)在微针基底背面贴上压敏胶被衬，脱模，即得活性药物脂质体微针贴片或仿生活性药物脂质体微针贴片。
可选的，所述步骤4)中干燥温度为4℃，干燥时间为1-100h；优选的，干燥时间为24h。
综上所述，本申请具有以下有益效果：本申请提高的一种用于脑部疾病诊断和治疗的微针系统无需动手术，是一种工艺简单，安全性高，无需长期贴敷的可植入型缓释微针。采用经皮给药(贴于头部或颈部)，使药物经过颈部深层淋巴结及脑膜淋巴管，绕过血脑屏障到达脑组织，发挥治疗效果。
附图说明
图1是本申请公开的一种用于脑部疾病诊断和治疗的微针系统的姜黄素脂质体的TEM图；
图2是本申请公开的一种用于脑部疾病诊断和治疗的微针系统的姜黄素脂质体的粒径图；
图3是本申请实施例1中小鼠脑切片的姜黄素分布图；
图4是本申请应用例1-3的关于不同时间点姜黄素入脑的效率对比表。
具体实施方式
本发明的目的是为了克服现有技术的上述不足，提供一种体外脑部或颈部微针贴片，用于治疗脑部疾病。该方法将治疗脑部疾病的活性药物负载于微针中，并探究了负载有活性药物的微针的经皮给药效果(贴于头部或颈部)。本申请实施例中的活性药物以姜黄素为例，在其他的实施例中，活性药物还可以是尼莫地平、氟桂利嗪、倍他司汀、川芎嗪、丁苯酞、罂粟碱、银杏叶提取物、长春西汀、富马酸喹硫平、奥氮平、西酞普兰、阿普唑仑、奥沙西泮(去甲羟安定)、劳拉西泮(罗拉)、三唑仑(海乐神)、美多芭、泰舒达、森福罗、息宁、安坦、司来吉兰、雷沙吉兰、托卡朋、罗匹尼罗，安坦、氨溴索，珂丹，金刚烷胺，卡马西平、丙戊酸钠、苯妥英钠、加巴喷丁、拉莫三嗪、奥卡西平、苯巴比妥、托吡酯、氨己烯酸、左乙拉西坦、氯硝西泮、地西泮、马来酸咪达唑仑、乙琥胺、扑痫酮、唑尼沙胺、普瑞巴林、瑞替加滨等治疗脑部疾病的药物。
结果显示，负载有姜黄素脂质体的微针可成功的将姜黄素脂质体通过颈深淋巴结递送到脑部，发挥治疗效果。本发明对于推动临床治疗脑部疾病的微针的应用转化具有重要意义，为脑部疾病的治疗提供新方法和新技术。
以下结合附图1至附图4和实施例对本申请作进一步详细说明。予以特殊说明的是：以下实施例中未注明具体条件者按照常规条件或制造商建议的条件进行，以下实施例中所用原料除特殊说明外均可来源于普通市售。
姜黄素脂质体的制备例
制备例1
S1姜黄素溶解以及姜黄素载体的制备，
姜黄素载体的制备：取50mg磷脂和25mg胆固醇，溶于2ml的氯仿中得混合液I备用；
姜黄素前处理：取0.25mg姜黄素，溶于2ml的无水甲醇中得混合液II备用；
S2旋蒸混合液，
将混合液I和混合液II混合于圆底烧瓶中，然后置于旋蒸仪(型号是IKA-RV10)上进行旋蒸，旋蒸仪的转速为60rpm,温度为27℃，蒸干圆底烧瓶瓶壁上形成薄膜混合物；
S3姜黄素脂质体的制备，
1)使用5ml的PBS冲洗烧瓶壁上的薄膜混合物，使其完全脱落，然后在液氮-65℃下进行冻融，循环5次得到脂质体溶液；
2)使用装有聚碳酸酯膜的脂质体挤压器(型号是Avanti脂质体挤出器610023)反复挤压20次,并且依次过滤；其中聚碳酸酯膜的孔径为200nm、100nm和50nm；挤压过滤时所使用的滤膜孔径依次减小，以便得到的粒径均一的脂质体
3)最后透析制得姜黄素脂质体，置于4℃下避光保存。
制备例2-3，与制备例1的不同之处在于，所使用的原料用量不同，具体见下表。
Figure PCTCN2022101279-appb-000001
仿生姜黄素脂质体的制备例
制备例4
取30mg制备例1所制得的姜黄素脂质体放入注射器中，然后向注射器中加入0.1mg的NK细胞膜蛋白。
打开高压均质机气泵，设置压力为20psi，打开均质阀填充压力；将装有样品的注射器装入均质机中，均质操作重复5次，然后将压力设置为40psi，继续进行均质操作，并重复5次，最后得到仿生姜黄素脂质体。
实施例
实施例1
1)取制备例1制得的姜黄素脂质体进行冻干，得到白色粉末；
2)取1)中2g的姜黄素脂质体或仿生姜黄素脂质体以及4g的透明质酸钠分散于4ml水中，搅拌至充分溶解得基质液；
3)将2)中得到的基质液注入微针模具中，进行离心倒转6次使得基质液均匀分布在模具中，并充满模具中的微针针尖部分；
4)再取1g的葡聚糖和2g的透明质酸钠分散于7ml的水中，得分散液；然后将分散液加入步骤3)中微针针尖中，离心后干燥24h，得姜黄素脂质体微针；
5)在微针基底背面贴上压敏胶被衬，脱模，即得姜黄素脂质体微针贴片。
实施例2-3
实施例2-3与实施例1的不同之处在于，所使用的原料的用量不同，具体如下表所示。
Figure PCTCN2022101279-appb-000002
实施例4
本实施例与实施例1的不同之处在于，所使用的是制备例4制得的仿生姜黄素脂质体。将所得到的仿生姜黄素脂质体进行电镜扫描，得如图1所示的仿生姜黄素脂质体的TEM图，从TEN图可以看出，仿生姜黄素脂质体的粒径大约是50nm，分散性比较好。另外通过粒径分析仪，测定仿生姜黄素脂质体的粒径分布，如图2所示，仿生姜黄素脂质体的水合粒径大约是50nm，颗粒比较均匀。
应用例
应用例1：首先取实验小鼠，并脱掉小鼠颈部和头部的毛；然后将实施例1制备的姜黄素脂质体微针贴片贴于小鼠颈部(姜黄素脂质体组)；最后采用小动物活体成像系统(IVIS)跟踪了姜黄素在小鼠脑部的分布，如图3和图4所示。
应用例2：与应用例1的不同之处在于，是将实施例4制备的仿生姜黄素脂质体微针贴片贴于小鼠颈部(仿生姜黄素脂质体组)，采用小动物活体成像系统(IVIS)跟踪了姜黄素在小鼠脑部的分布，如图4所示。
应用例3：采用制备例1所得的姜黄素脂质体，将其注射至小鼠的尾部静脉中(尾静脉组)，然后采用小动物活体成像系统(IVIS)跟踪了姜黄素在小鼠脑部的分布，如图4所示。
其他应用，还可以将采用本申请的制备方法制备的姜黄素脂质体或仿生姜黄素脂质体做成凝胶贴于头部或颈部，或采用超声和皮下注射等方法导入头部或颈部。
结合实施例以及应用例，图1-图4，可以看出采用本申请提供的一种微针系统的制备方法制备的微针贴片，结果显示，负载有姜黄素脂质体或仿生姜黄素脂质体的微针可成功的将姜黄素脂质体或仿生将黄石脂质体通过颈深淋巴结递送到脑部，发挥治疗效果。本发明对于推动临床姜黄素脂质体的微针的应用转化具有重要意义，为脑部疾病的治疗提供新方法和新技术。相比于传统的脑部疾病治疗方法，无需动手术，降低了治疗风险，是一种工艺简单，安全性高，无需长期贴敷的可植入型缓释微针。可以避免肠胃环境对药效的干扰和肝脏“首过效应”，维持恒定的最佳血药浓度或生理效应，延长有效作用时间，减少用药次数，患者可自主给药，依从性较好其原理是采用经皮给药(贴于头部或颈部)，使药物经过颈部深层 淋巴结及脑膜淋巴管，绕过血脑屏障到达脑组织，发挥治疗效果。
本具体实施例仅仅是对本申请的解释，其并不是对本申请的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本申请的权利要求范围内都受到专利法的保护。

Claims (10)

  1. 一种用于脑部疾病诊断和治疗的微针系统，其特征在于，包括以下重量份的原料制成：
    活性药物脂质体0.1-10份；
    分散剂1-20份；
    其中，所述活性药物脂质体包括以下重量份的原料制成：
    活性药物0.1-10份
    磷脂10-100份；
    胆固醇10-100份。
  2. 根据权利要求1所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述一种用于脑部疾病诊断和治疗的微针系统还包括NK细胞膜蛋白。
  3. 根据权利要求2所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述活性药物脂质体与NK细胞膜蛋白的质量比为300:1。
  4. 根据权利要求2-3所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述活性药物脂质体与NK细胞膜蛋白通过均质法制得仿生活性药物脂质体，所述均质法的具体操作为：1)在20psi的气压下，进行3-10次均质操作；2)调节气压至40psi，继续3-10次均质操作即得仿生活性药物脂质体。
  5. 根据权利要求1-3任一项所述的部疾病诊断和治疗的微针系统，其特征在于，所述活性药物包括水溶性活性药物和脂溶性活性药物；当活性药物为脂溶性活性药物时，所述脂溶性活性药物脂质体的制备包括以下步骤：
    S1脂溶性活性药物前处理以及脂溶性活性药物载体的制备，
    脂溶性活性药物载体的制备：取10-100份的磷脂和10-100份的胆固醇，溶于氯仿中得混合液I备用；
    脂溶性药物前处理方法为：取0.1-10份的脂溶性活性药物，溶于无水甲醇或者乙醚中得混合液II备用；
    S2旋蒸混合液，
    将混合液I和混合液II混合，然后蒸干得混合物；
    S3活性药物脂质体的制备，
    1)使用PBS缓冲液冲洗混合物，然后在液氮-65℃下进行冻融，循环4-8次得到活性药物脂质体溶液；
    2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存；当活性药物为水溶性活性药物时，所述水溶性活性药物脂质体的制备包括以下步骤：
    S1水溶性活性药物载体的制备：取10-100份的磷脂和10-100份的胆固醇，溶于氯仿中得混合液I备用；
    S2旋蒸混合液：将混合液I旋蒸蒸干得混合物；
    S3活性药物脂质体的制备，
    1)使用PBS缓冲液冲洗混合物并加0.1-10份水溶性活性药物，使水溶性活性药物充分溶解，然后在液氮-65℃下进行冻融，循环4-8次得到活性药物脂质体溶液；
    2)进行透析或先进行挤压过滤后再进行透析制得活性药物脂质体，置于4℃下避光保存。
  6. 根据权利要求5所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述S3还包括挤压过滤，所述挤压过滤操作具体为：依次采用装有不同孔径滤膜的脂质体挤压器反复挤压20次，且滤膜孔径依次减小。
  7. 根据权利要求5所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述滤膜为聚碳酸酯膜，所述聚碳酸酯膜的孔径为200nm，100nm和50nm。
  8. 根据权利要求1所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述分散剂为透明质酸钠、透明质酸、葡聚糖或者PEG中的一种或多种的组合。
  9. 根据权利要求1所述的一种用于脑部疾病诊断和治疗的微针系统，其特征在于，所述活性药物为治疗脑部疾病的药物，具体为姜黄素、尼莫地平、氟桂利嗪、倍他司汀、川芎嗪、丁苯酞、罂粟碱、银杏叶提取物、长春西汀、富马酸喹硫平、奥氮平、西酞普兰、阿普唑仑、奥沙西泮(去甲羟安定)、劳拉西泮(罗拉)、三唑仑(海乐神)、美多芭、泰舒达、森福罗、息宁、安坦、司来吉兰、雷沙吉兰、托卡朋、罗匹尼罗，安坦、氨溴索，珂丹，金刚烷胺，卡马西平、丙戊酸钠、苯妥英钠、加巴喷丁、拉莫三嗪、奥卡西平、苯巴比妥、托吡酯、氨己烯酸、左乙拉西坦、氯硝西泮、地西泮、马来酸咪达唑仑、乙琥胺、扑痫酮、唑尼沙胺、普瑞巴林、瑞替加滨中的一种。
  10. 权利要求1-9所述的一种用于脑部疾病诊断和治疗的微针系统的制备方法，其特征在于，包括以下制备步骤：
    1)取以上制得的活性药物脂质体或者仿生活性药物脂质体进行冻干，得到白色粉末；
    2)取1)中0.1-10份的活性药物脂质体或仿生活性药物脂质体以及1-10份的分散剂分散于水中，搅拌至充分溶解得基质液；
    3)将2)中得到的基质液注入微针模具中，进行离心倒转使得基质液均匀分布在模具中，并充满模具中的微针针尖部分；
    4)再取1-10份的分散剂分散于水中，得分散液；然后将分散液加入步骤3)中微针针尖中， 离心后干燥，得活性药物脂质体微针或者仿生活性药物脂质体微针；
    5)在微针基底背面贴上压敏胶被衬，脱模，即得活性药物脂质体微针贴片或仿生活性药物脂质体微针贴片。
PCT/CN2022/101279 2022-05-26 2022-06-24 一种用于脑部疾病诊断和治疗的微针系统及其制备方法 Ceased WO2023226136A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210589807.8 2022-05-26
CN202210589807.8A CN114948852B (zh) 2022-05-26 2022-05-26 一种用于脑部疾病诊断和治疗的微针系统及其制备方法

Publications (1)

Publication Number Publication Date
WO2023226136A1 true WO2023226136A1 (zh) 2023-11-30

Family

ID=82955668

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/101279 Ceased WO2023226136A1 (zh) 2022-05-26 2022-06-24 一种用于脑部疾病诊断和治疗的微针系统及其制备方法

Country Status (2)

Country Link
CN (1) CN114948852B (zh)
WO (1) WO2023226136A1 (zh)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117919254A (zh) * 2024-01-12 2024-04-26 中国医学科学院药用植物研究所 一种三唑类化合物在制备防治缺血性脑卒中药物中的应用
CN120022343A (zh) * 2025-03-05 2025-05-23 沈阳丽都麦恩综合门诊部有限公司 一种中西结合气血养护组合物及其制备方法
CN120437033A (zh) * 2025-05-09 2025-08-08 黑龙江中医药大学 一种多靶点神经修复的导电水凝胶微针及其制备方法

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116036004A (zh) * 2023-01-29 2023-05-02 广东药科大学 一种载纳米粒的可溶性微针及其制备方法与应用
CN116019785A (zh) * 2023-02-15 2023-04-28 中国药科大学 一种抗菌纳米透皮递送系统及其制备方法
CN117224506A (zh) * 2023-10-07 2023-12-15 广西大学 一种苯巴比妥钠递送系统制备方法以及其应用
CN121041199B (zh) * 2025-09-22 2026-03-17 北京农学院 可溶性加巴喷丁微针贴片及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110195124A1 (en) * 2008-10-07 2011-08-11 Tuo Jin Phase-transition polymeric microneedles
US20180021559A1 (en) * 2006-12-22 2018-01-25 Nanomed Skincare, Inc. Microdevice and method for transdermal delivery and sampling of active substances
CN108478521A (zh) * 2018-05-02 2018-09-04 苏宇雄 一种载有脂质体顺铂纳米颗粒的可溶解微针及其制备方法
CN110662532A (zh) * 2017-04-03 2020-01-07 加利福尼亚大学董事会 用于跨血脑屏障、透粘膜和经皮药物递送的可变形的纳米级媒介物(dnvs)
CN111759794A (zh) * 2020-07-14 2020-10-13 中山大学 一种治疗黑色素瘤的微针及其制备方法
CN112823811A (zh) * 2019-11-18 2021-05-21 深圳先进技术研究院 一种跨越血脑屏障和特异性靶向脑胶质瘤治疗药物的投递系统的制备方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103637988A (zh) * 2013-09-11 2014-03-19 浙江中医药大学 一种姜黄素长循环脂质体的制备方法
CN106176609B (zh) * 2016-08-22 2019-10-15 南通大学 一种nk细胞膜仿生脂质体药物载体、制作方法及其应用
CN107050465A (zh) * 2017-01-17 2017-08-18 中国药科大学 一种用于脑部疾病诊疗的功能性姜黄素纳米药物及其应用
CN110604821A (zh) * 2018-06-14 2019-12-24 复旦大学 一种淀粉样蛋白β短肽介导的脑靶向递送系统
CN109077994B (zh) * 2018-09-04 2021-11-30 南京工业大学 小分子水凝胶-纳米粒复合药物载体及其在皮肤/粘膜给药系统中的应用
CN112716899B (zh) * 2019-10-11 2022-03-18 复旦大学 一种防治主动脉夹层的仿生纳米药物及其制备方法
CN114432230B (zh) * 2022-02-28 2024-03-22 浙江工业大学 一种经皮递送脂质体治疗银屑病的微针及其制备方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180021559A1 (en) * 2006-12-22 2018-01-25 Nanomed Skincare, Inc. Microdevice and method for transdermal delivery and sampling of active substances
US20110195124A1 (en) * 2008-10-07 2011-08-11 Tuo Jin Phase-transition polymeric microneedles
CN102202720A (zh) * 2008-10-07 2011-09-28 金拓 相转化聚合物微针
CN110662532A (zh) * 2017-04-03 2020-01-07 加利福尼亚大学董事会 用于跨血脑屏障、透粘膜和经皮药物递送的可变形的纳米级媒介物(dnvs)
CN108478521A (zh) * 2018-05-02 2018-09-04 苏宇雄 一种载有脂质体顺铂纳米颗粒的可溶解微针及其制备方法
CN112823811A (zh) * 2019-11-18 2021-05-21 深圳先进技术研究院 一种跨越血脑屏障和特异性靶向脑胶质瘤治疗药物的投递系统的制备方法
CN111759794A (zh) * 2020-07-14 2020-10-13 中山大学 一种治疗黑色素瘤的微针及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutics", 31 January 2005, PEKING UNIVERSITY MEDICAL PRESS, CN, ISBN: 7-81071-641-7, article ZHANG, QIANG ET AL.: "The Application of Liposomes in Medicine", pages: 504, XP009550846 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117919254A (zh) * 2024-01-12 2024-04-26 中国医学科学院药用植物研究所 一种三唑类化合物在制备防治缺血性脑卒中药物中的应用
CN120022343A (zh) * 2025-03-05 2025-05-23 沈阳丽都麦恩综合门诊部有限公司 一种中西结合气血养护组合物及其制备方法
CN120437033A (zh) * 2025-05-09 2025-08-08 黑龙江中医药大学 一种多靶点神经修复的导电水凝胶微针及其制备方法

Also Published As

Publication number Publication date
CN114948852A (zh) 2022-08-30
CN114948852B (zh) 2024-05-17

Similar Documents

Publication Publication Date Title
WO2023226136A1 (zh) 一种用于脑部疾病诊断和治疗的微针系统及其制备方法
CN109528695B (zh) 一种治疗类风湿性关节炎的微针透皮给药贴片及其制备方法
Morrow et al. Innovative strategies for enhancing topical and transdermal drug delivery
CA2795995C (en) Microneedle assembly formulation for skin treatment
CN111195230B (zh) 一种制备柔性脂质体的方法
CN108653754A (zh) 一种透明质酸靶向聚多巴胺包覆相变型液态氟碳纳米超声造影剂
WO2019029154A1 (zh) 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN115590774A (zh) 透明质酸脂质体组装体及其制备方法和应用
Rajendran et al. Transferosome formulations as innovative carriers for transdermal drug delivery: composition, properties, and therapeutic applications
CN114146050B (zh) 一种可溶性微针基质材料及其制备方法和应用
WO2004067012A1 (fr) Liposomes contenant de l'asiaticoside et leurs utilisations
CN118490615A (zh) 含有脱氧胆酸的可溶性微针贴片及其制备方法和应用
Yi et al. Visually controlled pulsatile release of insulin from chitosan poly-acrylic acid nanobubbles triggered by focused ultrasound
CN108697639A (zh) 一种经皮吸收组合物及其在制备经皮吸收制剂中的用途
CN101933897A (zh) 注射用重组人血管内皮抑制素温度敏感性凝胶组合物
Konatham et al. A critical analysis of the vesicular drug delivery system: recent advancements and prospects for the future
CN103664936A (zh) 一类治疗创伤性脑损伤疾病的化合物及其用途
CN108587998A (zh) 一种外泌体、外泌体的制备方法及其在制备皮肤浅表性肿瘤的药物中的应用
CN109925297A (zh) 含乌头碱的经皮给药系统及其制备方法和应用
Kagalkar et al. Approach on novel drug delivery system
CN116712665A (zh) 一种光热-化疗联合治疗剂及其制备方法和应用
Joseph et al. Transferosomes: novel delivery system for increasing Theskin permeation of drugs
Kurhe et al. Transferosome: a vesicular transdermal delivery system for enhanced drug permeation
CN115844828B (zh) 一种氟比洛芬酯脂质体及其制备和应用
Shende et al. Transferosomes: A promising vesicular-based skin-oriented drug delivery system: https://doi. org/10.54037/WJPS. 2021.91009

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22943328

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22943328

Country of ref document: EP

Kind code of ref document: A1