WO2010075663A1 - 一种水飞蓟素高效长效制剂及其制法 - Google Patents

一种水飞蓟素高效长效制剂及其制法 Download PDF

Info

Publication number
WO2010075663A1
WO2010075663A1 PCT/CN2009/001298 CN2009001298W WO2010075663A1 WO 2010075663 A1 WO2010075663 A1 WO 2010075663A1 CN 2009001298 W CN2009001298 W CN 2009001298W WO 2010075663 A1 WO2010075663 A1 WO 2010075663A1
Authority
WO
WIPO (PCT)
Prior art keywords
silymarin
release
sustained
add
solid dispersion
Prior art date
Application number
PCT/CN2009/001298
Other languages
English (en)
French (fr)
Inventor
徐希明
余江南
童珊珊
朱源
曹霞
Original Assignee
江苏大学
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 江苏大学 filed Critical 江苏大学
Priority to US13/126,071 priority Critical patent/US8962017B2/en
Publication of WO2010075663A1 publication Critical patent/WO2010075663A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/70—Nanostructure
    • Y10S977/773—Nanoparticle, i.e. structure having three dimensions of 100 nm or less
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/84—Manufacture, treatment, or detection of nanostructure
    • Y10S977/888—Shaping or removal of materials, e.g. etching
    • 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
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S977/00—Nanotechnology
    • Y10S977/902—Specified use of nanostructure
    • Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
    • Y10S977/906—Drug delivery

Definitions

  • the invention relates to a sustained-release high-efficiency long-acting pharmaceutical preparation and a preparation method thereof, in particular to a 72-hour sustained-release silymarin high-efficiency long-acting preparation and a preparation method thereof.
  • Silymari SLM is a new type of flavonoid extracted from the seeds of milk thistle. It is a light yellow powdery substance.
  • the main components are silybin: and isolilybin. , silydianin, silychristin, etc. Among them, the highest content of silybin and the strongest activity. It has physiological functions such as liver protection, hypolipidemic, anti-oxidation, prevention of diabetes, protection of the myocardium, anti-platelet aggregation and anti-tumor. [See: Flora, Hahn M, Rahn H, et al. Milk thisle (silybum marianum) for the therapy of live disease. Am J Gastroenterol, 1998, 93 (13): 139.; Yan Yufeng, Yu Jiandong.
  • Solid dispersion technology is widely used due to its simple preparation method and remarkable solubilization effect.
  • the controlled release preparation has the advantages of reducing the total dose and the number of medications, avoiding the phenomenon of blood concentration and peaks, reducing toxic side effects, improving patient compliance, etc., and is increasingly used in clinical practice [see: Kathy WY Lee, Tri-Hung Nguyen, Tracey Hanley, et al.
  • Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs.
  • the solubilized drug is solubilized to prepare a sustained-release preparation, which can make up for the disadvantages of large fluctuations in blood concentration and frequent administration after drug solubilization.
  • the Mesopore material is a porous material with a pore diameter of 2-50 nm. According to whether the mesopores are ordered, they can be classified into two types: disordered and ordered.
  • the ordered mesoporous material structure has the following characteristics: 1. The long-range structure is ordered; 2. The pore size distribution is narrow and can be adjusted and controlled between 1. 5- lOnm; 3. The specific surface is as high as lOOmmVg; 4. The porosity is high; The surface is rich in unsaturated groups and the like.
  • the ordered mesoporous material has the following advantages as a drug carrier: 1.
  • the invention is based on the quick release of the solid dispersion, the ordinary slow release of the hydrophilic gel skeleton material, and the long-acting sustained release "triple release" mechanism of the ordered mesoporous material, and the preparation of a combination of immediate release and double sustained release.
  • a 72-hour sustained-release silymarin high-efficiency long-acting formulation with the dual advantages of features, efficiency and long-lasting.
  • the above-described silymarin high-efficiency long-acting preparation is a tablet or a capsule.
  • the method for preparing the above-described silymarin high-efficiency long-acting preparation which is basically composed of the following steps: Step 1. Weighing silymarin lg, PVP-K30 l-3g, soybean phospholipid 0. 3- 0. 8g, acrylic resin IV No. 0 2- 0.
  • Step 2 Take 20_80ml of cyclohexane, add NP-10 4- 8ml, mix; add 1- 3ml n-hexanol, 25. 6% ammonia l_3ml, stir at room temperature for lh ; slowly add tetraethyl orthosilicate 3- 5ml , stirring at room temperature for 24 h; adding anhydrous ethanol 40-80 ml, ultrasonic lh; centrifugation at 15000 rpm for 15 min, the precipitate was washed three times with distilled water; adding appropriate amount of water to freeze-dry, to obtain silica nanoparticle powder 8g-32g ;
  • Step 2 after mixing, the sirolimus solid dispersion lg, and the hypromellose K4M 0. 2-0. 3g, low-substituted hydroxypropyl cellulose 0. 1-0. 2g, after mixing, add An appropriate amount of 70% syrup is used to prepare soft materials. After 16 mesh sieves, wet granules are obtained. After drying at 60 ° C for 30 minutes, the granules are taken out and sieved through a 16 mesh sieve to obtain a sustained release granule 1 ;
  • Step 2 Take the silibinin solid dispersion lg prepared in the first step, and hypromellose K4M0. 1- 0. 2g, Low-substituted hydroxypropyl cellulose 0. 2-0. 3g, Step 2 prepared by carrying silymarin silica nanoparticles 1. 25-2. 5g After mixing, add appropriate amount of 70% sugar paddle to prepare soft material, 16 mesh sieve to obtain wet granules, after 6 minutes of drying at 6CTC, take out, through 16 mesh sieve granules, to obtain sustained release granules 2;
  • the invention is based on the immediate release of a solid dispersion, the general sustained release of a hydrophilic gel matrix material, and the long-acting sustained-release "triple release" mechanism of ordered mesoporous materials, combined with immediate release and ordinary sustained release.
  • the ordered mesoporous material Based on the preparation technology of "double release drug" sustained-release preparation, the ordered mesoporous material has high specific surface area and large pore volume, which is beneficial to adsorbing drugs, and can release the drug slowly for a long time.
  • Porous silica nanoparticles are used as carrier materials, combining solid dispersion technology, ordered mesoporous nanoparticle preparation technology and hydrophilic gel matrix material preparation technology to prepare first-time release, post-release, and long-lasting Released SLM long-acting sustained-release preparations with immediate release and double sustained release characteristics.
  • the prepared SLM high-efficiency long-acting preparations and control preparations were studied by Beagle dogs in vivo. The results showed that: SLM high-efficiency long-acting preparations extended the half-life in vivo by 2. 3 times, 3 ⁇ 411 ⁇ extended 7.94 times, and SLM was released in Beagle dogs.
  • the drug curve showed a smooth release and a long-term sustained release of 72 hours.
  • Figure 3 The results are shown in Figure 3.
  • the invention adopts the combination of solid dispersion technology and nano technology.
  • soybean phospholipid is added in the preparation of SLM immediate release solid dispersion, which can promote the absorption of SLM in vivo; on the other hand, due to the application of nanoparticles, SLM nanocrystallization After significantly increasing the speed and extent of absorption of SLM in the body, it is also beneficial to improve the bioavailability of SLM long-acting sustained-release preparations. Therefore, the SLM sustained-release preparation prepared by the invention is not only a long-acting sustained-release preparation, but also a high-efficiency preparation, and is a novel sustained-release preparation having both the advantages of "high efficiency and long-acting effect".
  • the prepared SLM long-acting sustained-release preparations and control preparations were studied by Beagle dogs in vivo.
  • the results showed that the relative bioavailability of SLM long-acting sustained-release preparations was 3017%. It can be used for the development of modern high-efficiency long-acting sustained-release preparations administered once a day for 3 days.
  • Silica is biocompatible, safe and non-toxic, and has a wide range of sources; the preparation of silica nanoparticles by the method of the invention has the advantages of simple preparation method, no special equipment, less influence factors in the preparation process, good reproducibility, etc. advantage.
  • DRAWINGS 1 is a transmission electron micrograph of mesoporous silica nanoparticles prepared according to the present invention
  • Fig. 3 is a diagram showing the pharmacokinetic curve of the high-efficiency long-acting sustained-release preparation of silymarin prepared by the present invention. detailed description
  • silica nanoparticles were added to 0.6 M Na 2 C0 3 2000 ml, 60 ° C, 200 W respectively for 4 min, 15000 rpm, centrifuged for 15 min, washed three times with distilled water; 10 ml of distilled water was added, freeze-dried to obtain mesoporous silica nanoparticles (See Figures 1 and 2).
  • sustained-release granules 1 and the sustained-release granules 2 are mixed in a ratio of 1:2, tableted, and the pressure is controlled at 40-60 N to prepare a silymarin high-efficiency long-acting tablet.
  • Embodiment 2
  • silica nanoparticles were added to 0. 6M Na 2 C0 3 3000ml, 60 ° C, 200W respectively for 4min, 15000rpm, centrifuged for 15min, washed three times with distilled water; 10ml distilled water was added, freeze-dried to obtain mesoporous silica nanoparticles .
  • the soft material was passed through a 16 mesh sieve to obtain wet granules, which were taken out after drying for 30 minutes at 60 Torr, and sieved through a 16 mesh sieve to obtain a sustained release granule 2.
  • the sustained-release granules 1 and the sustained-release granules 2 are mixed in a ratio of 2:3, and then filled with capsules to prepare a silymarin high-efficiency long-acting capsule.
  • Embodiment 3
  • the lg silica nanoparticles were added to 0. 6M Na 2 C0 3 1000ml, 65 ° C, 200W respectively ultrasonic 4. 5min, 15000rpm, centrifuged for 15min, washed three times with distilled water; added 10ml distilled water, freeze-dried to obtain mesoporous silica Hollow nanoparticles.
  • sustained-release granules 1 and the sustained-release granules 2 are mixed in a ratio of 2:3, tableted, and the pressure is controlled at 40-60 N to prepare a high-efficiency long-acting tablet of silybin.
  • the lg silica nanoparticles were added to 0. 6M Na 2 C0 3 1000ml, 65 ° C, 200W respectively ultrasonic 4. 5min, 15000rpm, centrifuged for 15min, washed three times with distilled water; added 10ml distilled water, freeze-dried to obtain mesoporous silica Hollow nanoparticles.
  • sustained-release granules 1 and the sustained-release granules 2 are mixed in a ratio of 2:3, tableted, and the pressure is controlled at 40-60 N to prepare a high-efficiency long-acting tablet of silybin.
  • silica nanoparticles 2 g were added to 0.6 M N3 ⁇ 4C0 3 2000 ml, 70 ° C, 200 W respectively for 5 min, 15000 rpm, centrifuged for 15 min, washed three times with distilled water; 10 ml of distilled water was added, and lyophilized to obtain mesoporous silica hollow nanoparticles.
  • the soft material was passed through a 16 mesh sieve to obtain wet granules, which were baked at 60 ° C for 30 minutes, taken out, and sieved through a 16 mesh sieve to obtain a sustained release granule 2 .
  • sustained-release granules 1 and the sustained-release granules 2 are mixed in a ratio of 1:1, tableted, and the pressure is controlled at 40-60 N to prepare a high-efficiency long-acting tablet of silybin.
  • Embodiment 6
  • silica nanoparticles were added to 0.6 M Na 2 C0 3 2000 ml, 70 ° C, 200 W respectively for 5 min, 15000 rpm, centrifuged for 15 min, washed three times with distilled water; 10 ml of distilled water was added, freeze-dried to obtain mesoporous silica hollow nano grain.
  • Slg solid dispersion 2 lg, with hypromellose K4M 0. 42g, low-substituted hydroxypropyl cellulose 0. 48g, 2g of drug-loaded silica nanoparticles, after adding an appropriate amount of 70% syrup preparation
  • the soft material was passed through a 16 mesh sieve to obtain wet granules, which were baked at 60 ° C for 30 minutes, taken out, and sieved through a 16 mesh sieve to obtain a sustained release granule 2 .
  • the sustained-release granules 1 and the sustained-release granules 2 were mixed in a ratio of 1:1, tableted, and the pressure was controlled at 40-60 N to prepare a silybin high-efficiency long tablet.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Nanotechnology (AREA)
  • Physics & Mathematics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Optics & Photonics (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Virology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biochemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Toxicology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

一种水飞蓟素高效长效制剂及其制法 技术领域
本发明涉及缓释的高效长效药物制剂及其制法， 特别是一种 72 小时缓释的水飞蓟 素高效长效制剂及其制法。 背景技术
水飞蓟素（silymari SLM)是从水飞蓟种子中提取的一种新型黄酮类化合物， 是 一种淡黄色粉末状物质， 主要成分有水飞蓟宾 （silybin：)、 异水飞蓟宾 （isosilybin)、 水飞蓟宁 （silydianin)、 水飞蓟亭 （silychristin) 等。 其中， 以水飞蓟宾含量最高， 活性也最强。 它具有保肝、 降血脂、 抗氧化、 防止糖尿病、 保护心肌、 抗血小板聚集和 抗肿瘤等生理作用。 [参见: Flora , Hahn M, Rahn H, et al. Milk thisle (silybum marianum) for the therapy of live disease. Am J Gastroenterol, 1998， 93 (13)： 139.； 闫玉峰， 于建东. 水飞蓟化学成分及药理研究进展 [J] . 中国药事， 2000, 14 (5) ： 335. ]。 由于 SLM难溶于水， 普通口服制剂生物利用度较低， 近期有关 SLM新剂型与新 制剂研究集中于提高其口服制剂的生物利用度， 如， 制成卵憐脂复合物、 固体分散体、 环糊精包合物等 [参见： Giacomelli S, Gallo D, Apollonio P, et al. Silybin and its bioavailable phospholipid complex (IdB1016) potentiate in vitro and in vivo the activity of cisplatin. Life Sci, 2002, 70 (12)： 1447 ; 李凤前， 胡晋红， 朱全刚. 水飞蓟宾固体分散,体中总黄酮的测定. 中草药， 2002, 33 (1) : 31 ; 李凤前， 胡晋红， 王 慧， 等. PEG6000 固体分散体系对难溶性药物水飞蓟素的增溶作用与晶格变化的关系. 药学学报， 2002, 37 (4) : 294 ; Lirussi F, Beccarello A, Zanette G, et al. Silybin-beta-cyclodextrin in the treatment of patients with diabetes mellitus and alcoholic liver disease. Efficacy study of a new preparation of an anti-oxidant agent. Di abets Nutr Me tab, 2003, 15 (4) : 222. ]
固体分散技术由于其制备方法简单， 增溶效果显著等优点， 应用较为广泛 [参见： 邓莉等. 水飞蓟素固体分散体的制备及体外溶出研究. 第二军医大学学报. 2000, 21 ( 10 ) : 961.； Zhen-ping Wei, Shi-rui Mao, Dian-zhou Bi, et al. Dissolution improvement of cisapride by solid dispersion with HPMC. Journal of Chinese Pharmaceutical Science, 2004, 13 (4) : 254.； Fude Cui, Mingshi Yang, Yanyan Jiang. Design of sustained-release nitrendipine microspheres having solid dispersion structure by quetsi- emulsion solvent diffusion method. Journal of Controlled Release, 2003, 97 (3) : 375. ]。 难溶性药物制备成固体分散体后， 可以增加药物的溶 解度与溶出速率， 改善药物的吸收， 提高生物利用度， 但仍存在频繁给药、 峰谷浓度波 动较大等缺点。 缓控释制剂具有减少用药总剂量和用药次数、 避免血浓峰谷现象、 降低 毒副作用、 提高病人顺应性等优点， 在临床上应用日益广泛 [参见： Kathy W. Y. Lee, Tri-Hung Nguyen, Tracey Hanley, et al. Nanostructure of liquid crystalline matrix determines in vitro sustained release and in vivo oral absorption kinetics for hydrophilic model drugs. International Journal of Pharmaceutics, 2009, 365 (1-2)： 190.； Jie-Xin Wang, Zhi-Hui Wang, Jian-Feng Chen, et al. Direct encapsulation of water-soluble drug into silica microcapsules for sustained release applications. Materials Research Bulletin, 2008, 43 (12)： 3374. ]。 将 难溶性药物增溶后制备成缓释制剂， 可以弥补药物增溶后产生的血药浓度波动较大、 频 繁给药等缺点。
近年来， 具有特殊结构和特殊形貌的介孔材料研究备受关注。 介孔 （Mesopore) 材 料是孔径为 2-50nm的多孔材料， 根据介孔是否有序， 可分为无序和有序两类。 有序介 孔材料结构具有以下特点： 1.长程结构有序； 2.孔径分布窄并可在 1. 5- lOnm之间调节 和控制； 3.比表面高达 lOOOmVg; 4.孔隙率高； 5.表面富含不饱和基团等。 有序介孔材 料作为药物载体具有以下优点： 1.本身无毒、 无生理活性， 生物相容； 2.具有均匀可调 的孔道， 丰富的硅烷基可作为和有机客体分子反应的新的活性位点， 有利于结合在活性 位点上的药物均匀地分散在孔道内， 使有序介孔材料吸附药物并具有缓释作用； 3. 能 够保持药物结构的完整性。 有序介孔材料作为疏水性药物的控释载体， 能够获得理想的 控释效果， 不同孔道结构的有序介孔材料， 控释效果不同。
本发明基于固体分散体的速释、 亲水凝胶骨架材料的普通缓释、 有序介孔材料的长 效缓释 "三重释药"机理， 制备了一种兼具速释与双重缓释特征、 高效与长效双重优点 的 72小时缓释的水飞蓟素高效长效制剂。
发明内容 将固体分散技术、 有序介孔纳米粒制备技术、 亲水凝胶骨架材料制备技术三者相结 合， 制备了一种生物利用度高、 体内释药平稳、 72小时缓释的水飞蓟素高效长效制剂。
本发明的技术方案如下：
一种水飞蓟素高效长效制剂， 它由水飞蓟素的固体分散体、 水飞蓟素二氧化硅纳米 粒、 缓释骨架材料及促释放剂组成， 它们之间的质量比为： 水飞蓟素固体分散体： 载水 飞蓟素二氧化硅纳米粒： 缓释骨架材料： 促释放剂 = 1 : 0. 5-1. 25 ： 0. 1-0. 3 ： 0. 1-0. 3， 其中载水飞蓟素二氧化硅纳米粒的载药量为 51. 95%~52. 87%， 水飞蓟素固体 分散体中包含聚维酮 K30、 大豆磷脂、 丙烯酸树脂 IV号， 水飞蓟素与其它辅料的质量比 为水飞蓟素 ： 聚维酮 Κ30 ： 大豆磷脂 ： 丙烯酸树脂 iv号 = 1： 1-3 ： 0. 3-0. 8 ： 0. 2~0. 5。
上述的水飞蓟素高效长效制剂为片剂或胶囊。
一种制备上述水飞蓟素高效长效制剂的方法， 它基本上由下列步骤组成： 步骤 1. 称取水飞蓟素 lg， PVP-K30 l-3g, 大豆磷脂 0. 3- 0. 8g， 丙烯酸树脂 IV号 0. 2- 0. 5g， 加入 20- 40ml 无水乙醇溶解 （必要时可置于 70°C水浴中加速溶解） 后， 于 6(TC水浴， 90rpm旋转蒸发至近干， 于 70°C水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60Ό烘箱 12h， 粉碎， 过 80目筛， 得水飞蓟素固体分散体， 备用；
步骤 2. 取 20_80ml环己垸， 加入 NP- 10 4- 8ml， 混匀； 加入 1- 3ml正己醇， 25. 6 %氨水 l_3ml, 室温搅拌 lh; 缓慢滴加正硅酸四乙酯 3- 5ml， 室温搅拌 24h; 加入无水 乙醇 40-80ml， 超声 lh; 在 15000rpm， 离心 15min， 沉淀用蒸熘水洗三次； 加入适量水 冷冻干燥， 得到二氧化硅纳米粒粉末 8g-32g;
取 lg上述二氧化硅纳米粒加入 0. 6mol/L N¾C03溶液 1000ml， 60-70 °C , 200W分别 超声 4-5min, 15000rpm， 离心 15min, 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻千燥， 得到介孔二氧化硅纳米粒；
取 2g水飞蓟素， 溶于 10-20ml无水乙醇， 加入 lg介孔二氧化硅纳米粒浸润 24小 时， 15000rpm离心 15min, 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载水 飞蓟素纳米粒 2g， 载药量为 51. 95%~52. 87%；
步骤 3. 取步骤 1制得的水飞蓟素固体分散体 lg， 与羟丙甲纤维素 K4M 0. 2-0. 3g、 低取代羟丙基纤维素 0. 1-0. 2g， 混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得 到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 1 ;
步骤 4. 取步骤 1制得的水飞蓟素固体分散体 lg， 与羟丙甲纤维素 K4M0. 1- 0. 2g、 低取代羟丙基纤维素 0. 2-0. 3g， 步骤 2制得的载水飞蓟素二氧化硅纳米粒 1. 25-2. 5g 混勾后， 加入适量 70%的糖桨制备软材， 过 16目筛得到湿颗粒， 于 6CTC烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 2;
步骤 5.取步骤 3制得的缓释颗粒 1和步骤 4制得的缓释颗粒 2， 按照缓释颗粒 1 : 缓释颗粒 2 = 1 : 2. 75-1 : 4的比例混合后， 压片， 压力控制在 40-60N, 制得本发明的 水飞蓟素高效长效片剂。
上述的水飞蓟素高效长效制剂的制备方法， 它可以将步骤 3制得的缓释颗粒 1和步 骤 4制得的缓释颗粒 2按照缓释颗粒 1 :缓释颗粒 2 = 1 : 2. 75-1 : 4的比例混合后灌装 胶囊， 制得本发明的水飞蓟素高效长效胶囊。 有益效果
1. 本发明基于固体分散体的速释、 亲水凝胶骨架材料的普通缓释、 有序介孔材料 的长效缓释 "三重释药"机理， 以速释与普通缓释相结合的 "双释药"缓释制剂制备技 术为基础， 又充分利用有序介孔材料具有高的比表面和大的孔体积， 有利于吸附药物， 能够长时间缓慢释放药物的优点， 选择有序介孔二氧化硅纳米粒为载体材料， 将固体分 散技术、 有序介孔纳米粒制备技术、 亲水凝胶骨架材料制备技术三者相结合， 制备先速 释、 后缓释、 再长效缓释的 SLM长效缓释制剂， 使其具有速释与双重缓释特征。 所制备 的 SLM高效长效制剂及对照制剂经 Beagle犬体内药动学研究，结果表明： SLM高效长效 制剂体内半衰期延长 2. 3倍， ¾11^延长7. 94倍， SLM在 Beagle犬体内释药曲线显示其 释放平稳， 实现了 72小时的长效缓释效果， 结果见图 3。
2. 本发明采用固体分散技术与纳米技术的结合， 一方面在制备 SLM速释固体分散 体时加入了大豆磷脂， 可促进 SLM的体内吸收； 另一方面， 由于纳米粒的运用， SLM纳 米化后显著增加了 .SLM在机体内吸收的速度和程度， 同样有利于提高 SLM长效缓释制剂 的生物利用度。 因此， 本发明制备的 SLM缓释制剂既是一种长效缓释制剂， 也是一种高 效制剂， 是兼具 "高效与长效"双重优点的新型缓释制剂。 所制备的 SLM长效缓释制剂 及对照制剂经 Beagle犬体内药动学研究，结果表明： SLM长效缓释制剂相对生物利用度 为 3017%。 可用于 3天给药 1次的现代高效长效缓释制剂的开发。
3.二氧化硅生物相容，安全无毒，来源广泛；用本发明的方法制备二氧化硅纳米粒， 具有制备方法简单、 不需要特殊设备、 制备过程中影响因素少、 重现性好等优点。
附图说明 图 1为本发明制备的介孔二氧化硅纳米粒的透射电镜图；
图 2为本发明制备的介孔二氧化硅纳米粒的粒径分布图；
图 3 为本发明制备的水飞蓟素高效长效缓释制剂 Beagle犬体内药时曲线。 具体实施方式
以下实施例所用材料和仪器
实验材料： 聚维酮 K30 (上海胜浦新型材料有限公司）； 大豆磷脂（上海太伟药业有 限公司）； IV号丙烯酸树脂（淮南山河药用辅料有限公司）； 正硅酸四乙酯（国药集团化 学试剂有限公司）； 羟丙甲纤维素 K4M (上海卡乐康包衣技术有限公司）； 低取代羟丙基 纤维素 （上海卡乐康包衣技术有限公司）； NP-10 (上海嘉芳贸易有限公司）。
实验仪器： 旋转蒸发仪 （Heidolph公司， 德国）； H66025超声清洗机 （无锡超声电 子设备厂）； ADP单冲压片机 （上海天祥健台制药机械有限公司）。 实施例一
称取 SLM lg， PVP-K30 lg， 大豆磷脂 0. 2g， IV号丙烯酸树脂 0. lg, 加入 20ml无水 乙醇溶解（必要时可置于 70°C水浴中加速溶解）后， 于 60Ό水浴， 90rpm旋转蒸发至近 干， 于 70Ό水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得固体分散体， 备用。
取 30ml环己垸， 加入 NP-10 4ml, 混匀； 加入 lml正己醇， 25. 6%氨水11111， 室温 搅拌 lh; 缓慢滴加正硅酸四乙酯 3ml， 室温搅拌 24h; 加入无水乙醇 40ml， 超声 lh; 在 15000rpm, 离心 15min， 沉淀用蒸馏水洗三次； 加入适量水冷冻干燥， 得到二氧化硅纳 米粒粉末。
取 2g二氧化硅纳米粒加入 0. 6M Na2C03 2000ml， 60°C , 200W分别超声 4min， 15000rpm, 离心 15min， 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧化硅纳米粒 (见图 1和图 2)。
取 3gSLM，溶于 20ml无水乙醇，加入 1. 5g介孔二氧化硅纳米粒浸润 24小时， 15000rpm 离心 15min，沉淀用无水乙醇洗三次,加入 10ml蒸馏水冷冻干燥得载药二氧化硅纳米粒。
取 SLM固体分散体 lg， 与羟丙甲纤维素 K4M 0. 2g、 低取代羟丙基纤维素 0. 2g， 混 匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取 出， 过 16目筛整粒， 得缓释颗粒 1。 取取 SLM固体分散体 1. 8g，与羟丙甲纤维素 K4M 0. 36g、低取代羟丙基纤维素 0. 4g， 载药二氧化硅纳米粒 2g混匀后，加入适量 70%的糖桨制备软材，过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。
缓释颗粒 1和缓释颗粒 2按照 1 : 2的比例混合后， 压片， 压力控制在 40-60N, 制 得水飞蓟素高效长效片剂。 实施例二
称取 SLM lg, PVP-K30 3g, 大豆磷脂 0. 8g， 丙烯酸树脂 IV号 0. 5g， 加入 40ml无水 乙醇溶解（必要时可置于 70°C水浴中加速溶解）后， 于 60°C水浴， 90rpm旋转蒸发至近 干， 于 70°C水浴完全挥去溶剂， 置一 20Ό冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得固体分散体， 备用。
取 80ml环己垸， 加入 NP-10 8ral , 混匀； 加入 3ml正己醇， 25. 6%氨水31111， 室温 搅拌 lh; 缓慢滴加正硅酸四乙酯 5ml， 室温搅拌 24h; 加入无水乙醇 80ml， 超声 lh; 在 15000rpm, 离心 15min， 沉淀用蒸熘水洗三次； 加入适量水冷冻干燥， 得到二氧化硅纳 米粒粉末。
取 3g二氧化硅纳米粒加入 0. 6M Na2C03 3000ml， 60 °C， 200W分别超声 4min， 15000rpm, 离心 15min，蒸馏水洗涤三次；加入 10ml蒸馏水，冷冻干燥，得到介孔二氧化硅纳米粒。
取 3gSLM，溶于 20ml无水乙醇，加入 1. 5g介孔二氧化硅纳米粒浸润 24小时， 15000rpm 离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载药纳米粒。
取 SLM固体分散体 1. 8g, 与羟丙甲纤维素 K4M 0. 4g、 低取代羟丙基纤维素 0. 4g, 混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60°C烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 1。
取 SLM固体分散体 1. 8g， 与羟丙甲纤维素 K4M 0. 36g、 低取代羟丙基纤维素 0. 4g， 载药二氧化硅纳米粒 3g混匀后，加入适量 70%的糖浆制备软材，过 16目筛得到湿颗粒， 于 60Ό烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。
缓释颗粒 1和缓释颗粒 2按照 2 : 3的比例混合后， 灌装胶囊， 制得水飞蓟素高效 长效胶囊。 实施例三
称取 SLM lg, PVP-K30 1. 2g, 大豆磷脂 0. 4g， 丙烯酸树脂 IV号 0. 3g， 加入 25ml无 水乙醇溶解（必要时可置于 70Ό水浴中加速溶解）后， 于 60°C水浴， 90rpm旋转蒸发至 近干， 于 70°C水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得固体分散体， 备用。
取 30ml环己垸， 加入 NP- 10 5ml , 混匀； 加入 1. 2ml正己醇， 25. 6%氨水 1. 5ml， 室温搅拌 lh; 缓慢滴加正硅酸四乙酯 3. 5ml， 室温搅拌 24h; 加入无水乙醇 50ml， 超声 lh; 在 15000rpm， 离心 15min， 沉淀用蒸馏水洗三次； 加入适量水冷冻干燥， 得到二氧 化硅纳米粒粉末。
取 lg 二氧化硅纳米粒加入 0. 6M Na2C03 1000ml， 65°C， 200W分别超声 4. 5min, 15000rpm, 离心 15min， 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧 化硅空心纳米粒。
取 2gSLM， 溶于 20ml无水乙醇， 加入 lg介孔二氧化硅空心纳米粒浸润 24小时， 15000rpm离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载药纳米 粒。
取 SLM固体分散体 lg， 与羟丙甲纤维素 K4M 0. 2g、 低取代羟丙基纤维素 0. 2g， 混 匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60Ό烘 30分钟后取 出， 过 16目筛整粒， 得缓释颗粒 1。
取 SLM固体分散体 lg， 与羟丙甲纤维素 K4M 0. lg, 低取代羟丙基纤维素 0. 3g， 载 药二氧化硅纳米粒 2g混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。
缓释颗粒 1和缓释颗粒 2按照 2 : 3的比例混合后， 压片， 压力控制在 40-60N, 制 得水飞蓟宾高效长效片剂。
实施例四
称取 SLMlg, PVP-K30 1. 5g， 大豆磷脂 0. 5g， 丙烯酸树脂 IV号 0. 4g， 加入 30ml无 水乙醇溶解（必要时可置于 70Ό水浴中加速溶解）后， 于 60°C水浴， 90rpm旋转蒸发至 近干， 于 7(TC水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得固 ^分散体， 备用。
取 50ral环己垸， 加入 NP-10 6ml , 混匀； 加入 2. 2ml正己醇， 25. 6%氨水 1. 8ml, 室温搅拌 lh; 缓慢滴加正硅酸四乙酯 4. 2ml， 室温搅拌 24h; 加入无水乙醇 60ml， 超声 lh; 在 15000rpm， 离心 15min， 沉淀用蒸馏水洗三次； 加入适量水冷冻干燥， 得到二氧 化硅纳米粒粉末。
取 lg 二氧化硅纳米粒加入 0. 6M Na2C03 1000ml , 65°C， 200W分别超声 4. 5min, 15000rpm, 离心 15min， 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧 化硅空心纳米粒。
取 2gSLM，溶于 20ml无水乙醇，加入 lg介孔二氧化硅纳米粒浸润 24小时， 15000rpm 离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻千燥得载药纳米粒。
取 SLM固体分散体 lg， 与羟丙甲纤维素 K4M 0. 22g、 低取代羟丙基纤维素 0. 22g, 混勾后， 加入适量 70%的糖浆制备软材， 过 16 目筛得到湿颗粒， 于 60°C烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 1。
取 SLM固体分散体 lg， 与羟丙甲纤维素 K4M 0. 15g、 低取代羟丙基纤维素 0. 25g， 载药二氧化硅纳米粒 2g混匀后，加入适量 70%的糖浆制备软材，过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。
缓释颗粒 1和缓释颗粒 2按照 2 : 3的比例混合后， 压片， 压力控制在 40-60N, 制 得水飞蓟宾高效长效片剂。 ' 实施例五
称取 SLM lg, PVP-K30 2. 5g， 大豆磷脂 0. 7g， 丙烯酸树脂 IV号 0. 4g， 加入 40ml无'. 水乙醇溶解（必要时可置于 70Ό水浴中加速溶解）后， 于 60Ό水浴， 90r~pm旋转蒸发至. 近干， 于 70°C水浴完全挥去溶剂， 置一 2CTC冰箱中 2h后， 放置 60Ό烘箱 12h， 粉碎， 过 80目筛， 得固体分散体， 备用。
取 70ml环己烷， 加入 NP-10 6ml , 混匀； 加入 lml正己醇， 25. 6%氨水 1. 5ml， 室 温搅拌 lh; 缓慢滴加正硅酸四乙酯 6ml， 室温搅拌 24h; 加入无水乙醇 60ml， 超声 lh; 在 15000rpm， 离心 15min, 沉淀用蒸馏水洗三次； 加入适量水冷冻干燥， 得到二氧化硅 纳米粒粉末。
取 2g二氧化硅纳米粒加入 0. 6M N¾C03 2000ml, 70 °C， 200W分别超声 5min， 15000rpm, 离心 15min， 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧化硅空心纳 米粒。
取 2gSLM， 溶手 15ml无水乙醇， 加入 lg介孔二氧化硅空心纳米粒浸润 24小时， 15000rpm离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载药纳米 粒。 取 SLM固体分散体 1. 2g， 与羟丙甲纤维素 K4M 0. 3g、 低取代羟丙基纤维素 0. 3g， 混勾后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60Ό烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 1。
取 SLM固体分散体 1. 8g， 与羟丙甲纤维素 K4M 0. 36g、 低取代羟丙基纤维素 0. 32g， 载药二氧化硅纳米粒 2g混匀后，加入适量 70%的糖浆制备软材，过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。
缓释颗粒 1和缓释颗粒 2按照 1 : 1的比例混合后， 压片， 压力控制在 40-60N, 制 得水飞蓟宾高效长效片剂。 实施例六
称取 SLM lg， PVP- 30 2g， 大豆磷脂 0. 8g， 丙烯酸树脂 IV号 0. 2g， 加入 40ml无水 乙醇溶解（必要时可置于 70°C水浴中加速溶解）后， 于 60°C水浴， 90rpm旋转蒸发至近 干， 于 70°C水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得固体分散体， 备用。
取 60ml环己垸， 加入 NP- 10 5ml， 混匀； 加入 lml正己醇， 25. 6%氨水 1. 5ml， 室 温搅拌 lh;缓慢滴加正硅酸四乙酯 5. 5ml ,室温搅拌 24h;加入无水乙醇 70ml，超声 lh; 在 15000rpm， 离心 15min， 沉淀用蒸馏水洗三次； 加入适量水冷冻干燥， 得到二氧化硅 纳米粒粉末。
取 2g二氧化硅纳米粒加入 0. 6M Na2C03 2000ml， 70 °C， 200W分别超声 5min， 15000rpm， 离心 15min， 蒸馏水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧化硅空心纳 米粒。
取 2gSLM， 溶于 15ml无水乙醇， 加入 lg介孔二氧化硅空心纳米粒浸润 24小时， 15000rpm离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载药纳米 粒。
取 SLM固体分散体 1. 4g， 与羟丙甲纤维素 K4M 0. 3g、 低取代羟丙基纤维素 0. 3g， 混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60'C烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 1。
取 SLM固体分散体 2. lg, 与羟丙甲纤维素 K4M 0. 42g、 低取代羟丙基纤维素 0. 48g， 载药二氧化硅纳米粒 2g混匀后，加入适量 70%的糖浆制备软材，过 16目筛得到湿颗粒， 于 60°C烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 2。 缓释颗粒 1和缓释颗粒 2按照 1 : 1的比例混合后， 压片， 压力控制在 40-60N， 制 得水飞蓟宾高效长 片剂。

Claims

权 利 要 求
1. 一种水飞蓟素高效长效制剂， 其特征是： 它由水飞蓟素的固体分散体、 水飞蓟 素二氧化硅纳米粒、 缓释骨架材料及促释放剂组成， 它们之间的质量比为： 水飞蓟素固 体分散体： 载水飞蓟素二氧化硅纳米粒： 缓释骨架材料： 促释放剂 = 1： 0. 5-1. 25 ： 0. 1-0. 3 ： 0. 1-0. 3， 其中载水飞蓟素二氧化硅纳米粒的载药量为 51. 95%~52. 87%, 水 飞蓟素固体分散体中包含聚维酮 K30、 大豆磷脂、 丙烯酸树脂 IV号， 水飞蓟素与其它辅 f斗的质量比为水飞蓟素 ： 聚维酮 K30 ： 大豆磷脂 ： 丙烯酸树脂 iv号 = 1： 1-3 ： 0. 3-0. 8 ： 0· 2~0· 5。
2. 根据权利犟求 1所述的水飞蓟素高效长效制剂， 其特征是： 为片剂或胶囊。 3. 一种制备权利要求 1 所述的水飞蓟素高效长效制剂的方法， 其特征是它基本上 由下列步骤组成：
步骤 1. 称取水飞蓟素 lg， PVP-K30 l-3g, 大豆磷脂 0.
3- 0. 8g， 丙烯酸树脂 IV号 0. 2-0. 5g, 加入 20-40ml无水乙醇溶解后， 于 60°C水浴， 90rpm旋转蒸发至近干， 于 70 °C水浴完全挥去溶剂， 置一 20°C冰箱中 2h后， 放置 60°C烘箱 12h， 粉碎， 过 80目筛， 得水飞蓟素固体分散体， 备用；
步骤 2. 取 20-80ml环己烷， 加入 NP- 10 4-8ml, 混勾； 加入 1- 3ml正己醇， 25. 6 %氨水 1- 3ml， 室温搅拌 lh; 缓慢滴加正硅酸四乙酯 3- 5ml， 室温搅拌 24h; 加入无水 乙醇 40-80ml， 超声 lh; 在 15000rpm， 离心 15min， 沉淀用蒸馏水洗三次； 加入适量水 冷冻干燥， 得到二氧化硅纳米粒粉末 8g-32g;
取 lg上述二氧化硅纳米粒加入 0. 6mol/L N¾C03溶液 1000ml , 60-70 °C , 200W分别 超声 4-5min， 15000rpm, 离心 15min， 蒸熘水洗涤三次； 加入 10ml蒸馏水， 冷冻干燥， 得到介孔二氧化硅纳米粒； .
取 2g水飞蓟素， 溶于 10-20ml无水乙醇， 加入 lg介孔二氧化硅纳米粒浸润 24小 时， 15000rpm离心 15min， 沉淀用无水乙醇洗三次， 加入 10ml蒸馏水冷冻干燥得载水 飞蓟素二氧化硅纳米粒 2g， 载药量为 51. 95%~52. 87%;
步骤 3. 取步骤 1制得的水飞蓟素固体分散体 lg， 与羟丙甲纤维素 K4M 0. 2-0. 3g、 低取代羟丙基纤维素 0. 1-0. 2g， 混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得 到湿颗粒， 于 60Γ烘 30分钟后取出， 过 16目筛整粒， 得缓释颗粒 1 ;
步骤 4. 取步骤 1制得的水飞蓟素固体分散体 lg， 与羟丙甲纤维素 K4M0. 1- 0. 2g、 低取代羟丙基纤维素 0.2-0.3g， 步骤 2制得的载水飞蓟素二氧化硅纳米粒 1.25-2: 5g 混匀后， 加入适量 70%的糖浆制备软材， 过 16目筛得到湿颗粒， 于 60°C烘 30分钟后 取出， 过 16目筛整粒， 得缓释颗粒 2;
步骤 5.取步骤 3制得的缓释颗粒 1和步骤 4制得的缓释颗粒 2， 按照缓释颗粒 1: 缓释颗粒 2 = 1: 2.75-1: 4的比例混合后， 压片， 压力控制在 40- 60N， 制得本发明的 水飞蓟素高效长效片剂。
4. 根据权利要求 3所述的水飞蓟素高效长效制剂的制备方法， 其特征是： 将步骤 3 制得的缓释颗粒 1和缓释颗粒 2按照缓释颗粒 1:缓释颗粒 2 = 1: 2.75-1: 4的比例混 合后灌装胶囊， 制得本发明的水飞蓟素高效长效胶囊。
PCT/CN2009/001298 2008-12-31 2009-11-23 一种水飞蓟素高效长效制剂及其制法 WO2010075663A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/126,071 US8962017B2 (en) 2008-12-31 2009-11-23 Formulation of silymarin with high efficacy and prolonged action and the preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008102429887A CN101439025B (zh) 2008-12-31 2008-12-31 一种水飞蓟素高效长效制剂及其制法
CN200810242988.7 2008-12-31

Publications (1)

Publication Number Publication Date
WO2010075663A1 true WO2010075663A1 (zh) 2010-07-08

Family

ID=40723725

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/001298 WO2010075663A1 (zh) 2008-12-31 2009-11-23 一种水飞蓟素高效长效制剂及其制法

Country Status (3)

Country Link
US (1) US8962017B2 (zh)
CN (1) CN101439025B (zh)
WO (1) WO2010075663A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4023246A4 (en) * 2019-08-30 2023-10-04 San-Ei Gen F.F.I., INC. SOLID COMPOSITION CONTAINING AN AMORPHOUS MATERIAL, POORLY SOLUBLE IN WATER, AND METHOD FOR PRODUCING SAME

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101444494B (zh) * 2008-12-31 2011-03-30 江苏大学 难溶性药物高效长效缓释制剂及其制法
CN101785759B (zh) * 2010-03-09 2012-01-25 湖南大学 包埋药物阿霉素的纳米颗粒及其制备方法和应用
US8877259B2 (en) 2012-02-09 2014-11-04 Mary Kay Inc. Cosmetic formulation
CN102657598B (zh) * 2012-05-09 2014-03-12 上海交通大学 一种基于多孔无机材料二次分散难溶性药物的口服制剂及其制备方法
KR102662912B1 (ko) * 2015-10-09 2024-05-03 산에이겐 에후.에후. 아이. 가부시키가이샤 폴리페놀 함유 고체 조성물
CN114948910B (zh) * 2022-06-21 2024-04-09 武汉工程大学 一种小肠靶向释放的板栗壳多酚缓释材料及其制备和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1543943A (zh) * 2003-11-26 2004-11-10 沈阳药科大学 口服水飞蓟素缓释制剂及其制备方法
CN1561201A (zh) * 2001-09-28 2005-01-05 诺瓦提斯公司 包含胶态二氧化硅的药物组合物
EP1774963A1 (en) * 2005-10-14 2007-04-18 S.I.I.T. S.r.l.-Servizio Internazionale Imballaggi Termosaldanti Galactogenic compositions based on silymarin
CN101164537A (zh) * 2006-10-16 2008-04-23 江苏大学 高效口服水飞蓟宾缓释制剂及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699900B2 (en) * 2001-04-07 2004-03-02 Jan E. Zielinski Hydrophilic and lipophilic silibinin pro-forms
WO2003089906A2 (en) * 2002-04-22 2003-10-30 University Of Florida Functionalized nanoparticles and methods of use
EP2535042A1 (en) * 2003-06-16 2012-12-19 ANDRX Pharmaceuticals LLC. Oral sustained-release composition comprising a macrolide
KR20070043894A (ko) * 2004-08-19 2007-04-25 알자 코포레이션 제어 방출형 나노입자 활성제 제제 제형 및 방법
US20060068022A1 (en) * 2004-09-29 2006-03-30 Playford Raymond J Bioactive agent compositions for repair of cell injuries
US20070166255A1 (en) * 2004-11-22 2007-07-19 Gupta Shyam K Treatment of Topical Discomforts Including Acne, Sunburn, Diaper Rash, Wound, Wrinkles and Dandruff/Hair Loss by Natural Lignans via Fatty Acid Desaturase Inhibition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1561201A (zh) * 2001-09-28 2005-01-05 诺瓦提斯公司 包含胶态二氧化硅的药物组合物
CN1543943A (zh) * 2003-11-26 2004-11-10 沈阳药科大学 口服水飞蓟素缓释制剂及其制备方法
EP1774963A1 (en) * 2005-10-14 2007-04-18 S.I.I.T. S.r.l.-Servizio Internazionale Imballaggi Termosaldanti Galactogenic compositions based on silymarin
CN101164537A (zh) * 2006-10-16 2008-04-23 江苏大学 高效口服水飞蓟宾缓释制剂及其制备方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4023246A4 (en) * 2019-08-30 2023-10-04 San-Ei Gen F.F.I., INC. SOLID COMPOSITION CONTAINING AN AMORPHOUS MATERIAL, POORLY SOLUBLE IN WATER, AND METHOD FOR PRODUCING SAME

Also Published As

Publication number Publication date
US20110201680A1 (en) 2011-08-18
CN101439025B (zh) 2011-05-11
CN101439025A (zh) 2009-05-27
US8962017B2 (en) 2015-02-24

Similar Documents

Publication Publication Date Title
WO2010075664A1 (zh) 难溶性药物高效长效缓释制剂及其制法
WO2010075663A1 (zh) 一种水飞蓟素高效长效制剂及其制法
CN102579350B (zh) 右旋布洛芬脂质体固体制剂
US9023388B2 (en) Formulation of silibinin with high efficacy and prolonged action and the preparation method thereof
CN101548994A (zh) 一种银杏酮酯口服前体脂质体及其制备方法
CN106983734B (zh) 一种布洛芬缓释胶囊及其制备方法
CN112245399B (zh) 一种二氢杨梅素胃漂浮丸剂及其制备方法
WO2014090174A1 (zh) 纳米级卡培他滨及其制备方法
CN1762341A (zh) 治疗心脑血管疾病、肝脏疾病的丹参酚酸复合物及其应用
CN104288141A (zh) 一种辛伐他汀固体药物组合物及其制备方法
CN102406620B (zh) 一种骨架型洛伐他汀缓释微丸及其制备方法
CN110960491A (zh) 一种负载丹参酮ⅡA的水溶性壳聚糖/γ-聚谷氨酸纳米复合物的制备方法及应用
CN101301476A (zh) 一种疏水性环糊精包合物及其制备方法和应用
CN101040850A (zh) 秋水仙碱缓释微丸及制备方法
CN102552358B (zh) 一种水飞蓟素组合物及其制备方法
CN102440959B (zh) 一种匹多莫德脂质体固体制剂
CN102327226B (zh) 一种头孢丙烯脂质纳米粒固体制剂
CN102526110B (zh) 一种用于强心急救的蟾酥粉末注射剂及其制备方法
CN103040745B (zh) 一种环磷腺苷葡胺脂质体注射剂
CN102133192B (zh) 一种坎地沙坦酯脂质纳米粒固体制剂
ONGED et al. i, United States Patent (10) Patent No.: US 9.023. 388 B2
CN1969861A (zh) 一种氯氮平固体脂质微颗粒控制释放体系
CN102366407B (zh) 盐酸克林霉素棕榈酸酯脂质体固体制剂
CN102429869B (zh) 包裹度可控的负载药物的硬脂酸载药微纳米粒的制备方法
CN103040749A (zh) 盐酸沙格雷酯脂质体固体制剂

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: 09835950

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 13126071

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09835950

Country of ref document: EP

Kind code of ref document: A1