WO2007068212A1 - Emulsion intraveineuse de butylbenzene phtaleine et son application - Google Patents

Emulsion intraveineuse de butylbenzene phtaleine et son application Download PDF

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Publication number
WO2007068212A1
WO2007068212A1 PCT/CN2006/003434 CN2006003434W WO2007068212A1 WO 2007068212 A1 WO2007068212 A1 WO 2007068212A1 CN 2006003434 W CN2006003434 W CN 2006003434W WO 2007068212 A1 WO2007068212 A1 WO 2007068212A1
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Prior art keywords
oil
butylphthalide
weight
emulsion according
phase
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PCT/CN2006/003434
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English (en)
French (fr)
Inventor
Chunshun Zhao
Zhanqi Niu
Zhen Chen
Haibo Guo
Original Assignee
Shijiazhuang Pharma Group Nbp Pharmaceutical Co., Ltd.
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Filing date
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Application filed by Shijiazhuang Pharma Group Nbp Pharmaceutical Co., Ltd. filed Critical Shijiazhuang Pharma Group Nbp Pharmaceutical Co., Ltd.
Priority to BRPI0619915-1A priority Critical patent/BRPI0619915B1/pt
Priority to CA2633170A priority patent/CA2633170C/en
Priority to EA200870060A priority patent/EA014518B1/ru
Priority to JP2008544744A priority patent/JP5571311B2/ja
Priority to KR1020087016969A priority patent/KR101061268B1/ko
Priority to AU2006324219A priority patent/AU2006324219B2/en
Priority to EP06828348.0A priority patent/EP1970050B1/en
Priority to US12/086,665 priority patent/US20090281177A1/en
Publication of WO2007068212A1 publication Critical patent/WO2007068212A1/zh
Priority to IL192169A priority patent/IL192169A/en
Priority to US13/112,180 priority patent/US10463614B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/365—Lactones
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a formulation of butylphthalide, and in particular to a butylphthalide intravenous emulsion and use thereof.
  • NBP 3-n-butyl benzoquinone
  • H 3-butyl-1 (H)-isobenzofuranone
  • celery is a racemate extracted from the seed of celery. It can also be artificially synthesized.
  • NBP acts on multiple aspects of cerebral ischemic pathology and can be used to reduce infarcts after focal cerebral ischemia, increase cerebral blood flow in ischemic areas, improve microcirculation in cerebral ischemic areas, protect mitochondrial function, and reduce neurological impairment. The extent to which the brain's energy metabolism is improved after global cerebral ischemia.
  • Chinese patents 98126618.X, 03137457.3, 200310100222.2 and 200410001748.X respectively disclose anti-thrombotic and anti-platelet aggregation of butylphthalide, and prevention and treatment of dementia, cerebral infarction and preparation of cerebral ischemic drugs in levo-n-butylphthalide Application in .
  • butylphthalide formulations are only soft gelatin. Since butylphthalide is an oily liquid, it can be dissolved in hard gelatin or soft gelatin after it is dissolved in the oil phase or directly into an emulsion. It can also be directly orally administered. However, butylphthalide has a strong first-pass effect, resulting in low bioavailability, and the stroke often causes dysphagia or coma in patients, so capsules cannot meet the clinical needs of these patients. For stroke patients, time is the brain, so it is particularly important or urgent to study new drug delivery systems that are fast-acting and more clinically suitable.
  • butylphthalide is an oily liquid which is hardly soluble in water
  • the present invention prepares an emulsion for intravenous administration using a specific preparation technique.
  • the butylphthalide intravenous emulsion of the invention has the advantages that: the drug directly enters the systemic circulation, and the onset of action is rapid; increasing the solubility of the butylphthalide and reducing the dosage can increase the targeting of the butylphthalide brain tissue and reduce the side effects.
  • the emulsion prepared by the invention has a particle diameter of 10 to 2000 nm and can be intravenously injected or instilled. N2006/003434
  • the butylphthalide intravenous emulsion of the present invention comprises 0.01 to 50% by weight, preferably 0.01 to 20% by weight, more preferably 0.01 to 10% by weight, of butylphthalide or a derivative thereof as an active ingredient and 50 to 99.99% by weight, preferably 80 - 99.9% by weight, more preferably 90 to 99.5% by weight of the excipient, based on the total weight of the emulsion.
  • the excipients contain an oil phase, an aqueous phase, an emulsifier, a stabilizer, and/or an osmotic pressure regulator.
  • the butylphthalide or its derivative may be either a butylphthalide racemate or a derivative thereof, or a levobyrylphthalide or a derivative thereof.
  • the auxiliary material may comprise 0 to 50% by weight, preferably 0.1 to 40% by weight of the oil phase, 50 to 98% by weight, preferably 60 to 97% by weight of the aqueous phase, 0.01 to 50% by weight, preferably 0.5 to 10% by weight of the emulsifier. 0 to 50% by weight, preferably 0 to 15% by weight of stabilizer, 0 to 10% by weight of osmotic pressure adjusting agent, based on the total weight of all excipients.
  • the preparation method of the butylphthalide intravenous emulsion of the invention comprises the steps of preparing a primary emulsion, sieving, sterilizing and quality control.
  • Preparation of the primary emulsion by ultrasonic or high-speed shear method (FA25 laboratory high shear ⁇ emulsifier, Shanghai Fluke Mechanical and Electrical Equipment Co., Ltd.).
  • Homogenization was carried out using a two-step high-pressure emulsion homogenizer (Niro-Soavi NS1001L high-pressure homogenizer and Avestin EmulsiFlex-C5 high-pressure homogenizer) or microfluidic technology.
  • Sterilization is carried out by rotary autoclaving. Quality control mainly takes particle size measurement.
  • the mass fraction (w/v) of the oil phase in the emulsion of the present invention is generally 0 to 50%, and in the present invention, it is required to dissolve a therapeutically effective amount of the drug with less oil phase, and to store in a low temperature condition. There will be no drug precipitation (or stratification with the drug), and a stable emulsion can be formed with the aqueous phase under the action of the emulsifier.
  • the oil phase used in the present invention is a natural vegetable oil containing long-chain fatty acid ester groups or a vegetable oil or fatty acid ester after structural modification and hydrolysis, such as soybean oil (including injection grade), castor oil, tea oil, One or more of peanut oil, cottonseed oil, sesame oil, vegetable oil, safflower oil, olive oil, coconut oil, palm oil, cocoa butter; or chain length at C 6 ⁇ C 12 Medium-chain glyceride (MCT), such as Arlacel 80 ⁇ Arlacel 86, Capmul MCM, Captex 200 (oil), Captex 355 (oil) > Miglyol 812 (oil), Myvacet (oil) , Myverol 18-92, oleic acid glyceride, linoleic acid glyceride, polyethylene glycol lauric acid glyceride, ethyl oleate, ethyl linoleate, octyl/capric t
  • oils are also useful in the present invention:
  • the emulsifier used in the present invention is a mixture of one or more of a nonionic surfactant and an ionic surfactant. Preference is given to using soy lecithin or a modification thereof (natural or synthetic), egg yolk egg yolk or a modification thereof (natural or synthetic), Ophase 31, poloxamer 108, poloxamer 188, poloxamer 407, Polyoxyethylene (hydrogenated) castor oil, water soluble VE (TPGS), Solutol HS-15, PEG400 monostearate, PEG1750 monostearic acid One of ester, Tween 80, Tween20 Span20, or a mixture of two or more. Preferably, one or several emulsifiers are used in combination.
  • a purified emulsifier having a small hemolysis effect is preferred.
  • the following emulsifiers are also suitable for use in the butylphthalide emulsions of the present invention:
  • Stabilizers suitable for use in the present invention include oleic acid, sodium oleate, sodium octanoate, cholesterol, cholic acid, deoxycholic acid and sodium salts thereof, vitamin A, vitamins (:, vitamin E or a mixture thereof in any ratio. Selection of osmotic pressure regulator
  • the osmotic pressure adjusting agent to which the present invention is applied includes one of sodium chloride, glucose, sorbitol, xylitol, mannitol, glycerin, or a mixture of two or more kinds.
  • butyphthalide oil phase: emulsifier: 7J phase: stabilizer: the ratio of the osmotic pressure adjusting agent is 0.01 to 50% by weight: 0 to 50% by weight: 0.01 - 50 Weight%: 50 to 98% by weight: 0 to 50% by weight: Any ratio (by weight) in the range of 0 to 10% by weight.
  • composition of the butylphthalide intravenous emulsion of the present invention is as follows: Butylphthalide 10g
  • Emulsifier 50g Emulsifier 50g
  • the aqueous phase is added to 1000ml.
  • Example 1 Preparation of butylphthalide intravenous emulsion Formulation composition ( g )
  • Preparation method Weigh butylphthalide, vitamin E, soybean oil and mix to form oil phase, preheat the oil phase in a 60 ° C water bath; weigh soy lecithin and sorbitol and disperse in water to form water Phase, preheated water phase in a 60 ° C water bath; slowly pour the oil phase into the water phase, disperse the mixture at 1000 rpm for 5 min with a high speed shear dispersing emulsifier, and then cycle 5 times on a high pressure homogenizer, one of which The pressure was 100 MPa, the secondary pressure was 10 MPa, then the pH was adjusted to 8, filtered, and packaged and sterilized at 121 ° C for 15 min. The entire process should be filled with nitrogen.
  • Example 2 Preparation of butylphthalide intravenous emulsion
  • Preparation method Weigh butylphthalide, soybean lecithin, oleic acid, castor oil and mix to form an oil phase, preheat the oil phase in a water bath at 60 ° C; weigh poloxamer 188, glycerol and Forming an aqueous phase in water, preheating the water phase in a 60 Torr water bath; slowly pouring the oil phase into the aqueous phase, dispersing the mixture at 1000 rpm for 5 min using a high speed shear dispersing emulsifier, and then circulating 5 times on a high pressure homogenizer, one of which The stage pressure was 100 MPa, the secondary pressure was 10 MPa, then the pH was adjusted to 8, filtered and sterilized at 121 ° C for 15 min. The entire process should be filled with nitrogen.
  • Example 3 Preparation of butylphthalide intravenous emulsion
  • Water for injection is added to 1000ml.
  • Preparation method Weigh butylphthalide, egg yolk lecithin, sodium oleate, cottonseed oil and mix to form oil phase, preheat the oil phase in 60 ° C water bath; weigh poloxamer 188, glycerin And forming an aqueous phase in water, preheating the water phase in a 60 ° C water bath; slowly pouring the oil phase into the aqueous phase, dispersing the mixture at 1000 rpm for 5 min with a high speed shear emulsifier, and then circulating 5 times on a high pressure homogenizer.
  • Example 5 Preparation of butylphthalide intravenous emulsion Formula composition ( g )
  • Preparation method Weigh butylphthalide, Tween 80, vitamin E, soybean oil and mix to form oil phase, preheat the oil phase in a water bath at 60 ° C; weigh soybean egg fat and xylitol Disperse in water to form an aqueous phase, preheat the phase in a 60 ° C water bath; slowly pour the oil phase into the aqueous phase, disperse the mixture at 1000 rpm for 5 min with a high speed shear emulsifier, and then cycle it 5 times on a high pressure homogenizer.
  • the first stage pressure is 100 MPa
  • the second stage pressure is 10 MPa
  • the pH is adjusted to 8
  • the mixture is filtered and sterilized at 121 ° C for 15 min.
  • the entire process should be filled with nitrogen.
  • Example 6 Preparation of butylphthalide intravenous emulsion
  • Preparation method Weigh butyl benzoquinone, soybean lecithin, oleic acid, octane/capric triglyceride and mix to form an oil phase at 60. Preheating the oil phase in the C water bath; weigh poloxamer 188, glycerin and disperse in water to form an aqueous phase, preheat the water phase in a 60 ° C water bath; slowly pour the oil phase into the water phase, and disperse it with high speed shear The emulsifier disperses the mixture at 100 rpm for 5 min, and then circulates 5 times on a high-pressure homogenizer, wherein the first-stage pressure is 100 MPa, the second-stage pressure is 10 MPa, the pH is adjusted to 8, and the mixture is filtered and sterilized at 121 ° C for 15 min. . The entire process should be filled with nitrogen.
  • Example 7 Preparation of butylphthalide intravenous emulsion Formulation composition ( g )
  • Preparation method Weigh butylphthalide, vitamin E, sesame oil and weigh them to form an oil phase, preheat the oil phase in a 60 ° C water bath; weigh soy lecithin and glycerin and disperse in water to form an aqueous phase.
  • Glycerin 25 Water for injection to 1000ml Preparation method: Weigh butylphthalide, egg yolk lecithin, sodium oleate, soybean oil and mix to form oil phase, preheat the oil phase in a water bath at 60 ° C; weigh poloxamer 188 , glycerol and ⁇ : form an aqueous phase in water, pre-heated the phase in a 60-inch water bath; slowly pour the oil phase into the aqueous phase, disperse the mixture at 1000 rpm for 5 min with a high-speed shear emulsifier, and then cycle on a high-pressure homogenizer.
  • Example 9 Preparation of butylphthalide intravenous emulsion Formulation composition ( g )
  • Water for injection is added to 1000ml.
  • Preparation method Weigh butylphthalide, egg yolk lecithin, sodium oleate, soybean oil and mix to form oil phase, preheat the oil phase in 60 ⁇ water bath; weigh poloxamer 188 and disperse in water The aqueous phase was formed, and the hot water phase was preheated in a 60 ° C water bath; the oil phase was slowly poured into the water phase, and the mixture was dispersed at 1000 rpm for 5 min with a high speed shear dispersing emulsifier, and then cycled 5 times on a high pressure uniform shield, one of which The stage pressure is 100 MPa, the secondary pressure is 10 MPa, the pH is adjusted to 8, filtered, and packaged and sterilized at 121 °C for 15 min. The entire process should be filled with nitrogen.

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Description

丁苯酞静脉乳剂及其应用 技术械
本发明涉及丁苯酞的制剂， 具体而言涉及一种丁苯酞静脉乳剂及其 应用。
背景技术
3-正丁基苯酞（筒称 NBP ), 化学名 3-丁基 -1 ( H ) -异苯并呋喃酮， 又名芹菜甲素， 是从芹茱籽中提取出来的消旋体， 也可人工合成。 NBP 作用于脑缺血病理的多个环节， 可用于缩小局灶性脑缺血后的梗死灶， 增加缺血区脑血流量和改善脑缺血区微循环， 保护线粒体功能， 减轻神 经功能损伤的程度，改善全脑缺血后脑的能量代谢。中国专利 98125618.X、 03137457.3, 200310100222.2和 200410001748.X分别公布了丁苯酞在抗血 栓形成及抗血小板聚集， 左旋正丁基苯酞在预防和治疗痴呆、 脑梗塞及 用于制备脑缺血药物中的应用。
目前上市的丁苯酞制剂只有软胶嚢。 由于丁苯酞为油状液体， 将其 溶于油相或直接制成乳剂后， 可以装入硬胶嚢或软胶嚢， 也可以直接口 服。 但丁苯酞有较强的首过效应， 导致生物利用度低， 加之脑卒中常导 致患者吞咽困难或昏迷， 因此胶嚢剂无法满足这部分患者的临床需求。 对于脑卒中患者来说， 时间就是大脑， 因此研究起效快、 更适于临床的 新的给药系统， 就显的特别重要或迫切。
发明概述
由于丁苯酞为难溶于水的油状液体， 本发明采用特定的制备技术将 其制备成静脉给药的乳剂。 本发明的丁苯酞静脉乳剂的优点在于： 药物 直接进入体循环， 起效迅速； 增加丁苯酞的溶解度， 减少用量， 可增加 丁苯酞脑组织的靶向性， 降低毒副作用。
本发明制备的乳剂的粒径在 10 ~ 2000nm之间，可以静脉注射或滴注 N2006/003434
-2- 给药， 以达到速效和脑靶向作用。
本发明的丁苯酞静脉乳剂包含 0.01 - 50重量％、 优选 0.01 - 20重量 %、 更优选 0.01 ~ 10重量％的丁苯酞或其衍生物作为有效成分和 50 ~ 99.99重量％、 优选 80 - 99.9重量％、 更优选 90 ~ 99.5重量％的辅料， 基于乳剂的总重量。 辅料含有油相、 水相、 乳化剂、 稳定剂和 /或渗透压 调节剂。 丁苯酞或其衍生物既可以是丁苯酞消旋体或其衍生物， 也可以 是左旋丁苯酞或其衍生物。
辅料可以包含 0 ~ 50重量％、 优选 0.1 - 40重量％的油相， 50 ~ 98 重量％、 优选 60 ~ 97重量％的水相， 0.01 ~ 50重量％、 优选 0.5 ~ 10重 量％的乳化剂， 0 ~ 50重量％、 优选 0 ~ 15重量％的稳定剂， 0 ~ 10重量 %的渗透压调节剂， 基于所有辅料的总重量。
本发明的丁苯酞静脉乳剂的制备方法包括制备初级乳液、 均盾化、 灭菌和质量控制等步骤。 制备初级乳液利用超声法或高速剪切法进行 ( FA25型实验室高剪切^乳化机， 上海弗鲁克机电设备有限公司）。 均质化采用二步高压乳匀机 ( Niro-Soavi NS1001L 型高压均质机和 Avestin EmulsiFlex-C5型高压均质机）或微射流技术进行。 灭菌采用旋 转高压灭菌进行。 质量控制主要采取粒径测定。
发明详述
(―)油相的选择
油相在本发明所涉及的乳剂中的质量分数 (w/v)—般为 0〜50%， 在本 发明中要求能以较少的油相溶解治疗有效量的药物， 并在低温储藏条件 下不会有药物析出 （或与药物分层）， 同时在乳化剂的作用下能与水相生 成稳定的乳剂。 在本发明中所应用的油相是含长链脂肪酸酯基团的天然 植物油或经过结构改造和水解后的植物油或脂肪酸酯， 如大豆油 （含注 射级）、 蓖麻油、 茶油、 花生油、 棉籽油、 芝麻油、 菜油、 红花油、 橄榄 油、 椰子油、 棕榈油、 可可豆油中的一种或多种； 或者是链长在 C6 ~ C12 之间的中等链长脂肪酸甘油酯 （medium-chain glyceride , MCT ), 如 Arlacel 80 ^ Arlacel 86, Capmul MCM, Captex 200(oil), Captex 355(oil)> Miglyol 812(oil), Myvacet(oil), Myverol 18-92、 油酸甘油酯、 亚油酸甘 油酯、 聚乙二醇月桂酸甘油酯、 油酸乙酯、 亚油酸乙酯、 辛^/癸酸甘油 三酯中的一种或多种； 还可以是上述长链脂肪酸酯和中等链长脂肪酸酯 的混合物。
在制备注射用乳剂时， 优选溶血作用小的、 经过精制的油相。 除常 用的植物油外， 还有下列油类可用于本发明中：
Arlacel 80 (HLB=4.3) 油酸山梨醇酯
Arlacel 86 (HLB=2.8) 油酸甘油酯： 丙二醇（90: 10 )
Capmul MCM (HLB=5.5~6.0)椰子油 C8 / C10甘油单酯或双酯
Captex 200(oil) 椰子油 C8 / CIO丙二醇双酯
Captex 355(oil) 椰子油 C8 / CIO甘油三酯
Miglyol 812(oil) 椰子油 C8 / C10甘油三酯
Myvacet(oil) 纯化乙酰化的单甘油酯
Myverol 18-92 (HLB=3~7) 纯化向日葵油单甘油酯（含 90 %亚油酸甘油酯） Peceol (HLB=3) 油酸甘油酯
Maisine (HLB=3) 亚油酸甘油酯
Gelucire 44/14 (HLB=14) 聚乙二醇月桂酸甘油酯
(二）乳化剂的选择
本发明中采用的乳化剂是非离子型表面活性剂和离子型表面活性剂 中的一种或一种以上的混合物。 优选使用大豆卵磷脂或其修饰物 （天然 或合成）、 蛋黄卵碑脂或其修饰物（天然或合成）、 Ophase 31、 泊洛沙姆 108、 泊洛沙姆 188、 泊洛沙姆 407、 聚氧乙烯（氢化） 蓖麻油、 水溶性 VE ( TPGS ), Solutol HS-15, PEG400单硬脂酸酯、 PEG1750单硬脂酸 酯、 Tween 80、 Tween20 Span20中的一种， 或者两种或两种以上的混 合物。 优选一种或几种乳化剂混合使用。 在制备注射用乳剂时， 优选溶 血作用小的， 经过精制的乳化剂。 除此， 以下乳化剂在本发明所涉及的 丁苯酞乳剂中也适用：
Ophase 31(HLB=4) 液态卵磷脂
Soybean lecithin ( HLB = 4/7/9 ) 大豆卵磷脂
Cremophor EL(HLB=13.5) 聚氧乙烯蓖麻油
Poloxamerl08(HLB=30.5) 聚氧乙烯聚氧丙稀醚 F - 38
Poloxamerl88(HLB=29) 聚氧乙烯聚氧丙稀醚 F - 68
Poloxamer407(HLB=21.5) 聚氧乙烯聚氧丙稀醚 F - 127
Tween 80(HLB=15) 聚氧乙烯失水山梨醇单油酸酯
Tween 20(HLB=16.7) 聚氧乙烯失水山梨醇单月桂酸酯
Span20(HLB=8.6) 失水山梨醇单月桂酸酯 (三）稳定剂的选择
本发明所适用的稳定剂包括油酸、 油酸钠、 辛酸钠、 胆固醇、 胆酸、 脱氧胆酸及其钠盐、 维生素 A、 维生素（：、 维生素 E或其任意比例的混 合物。 (四）渗透压调节剂的选择
本发明所适用的渗透压调节剂包括氯化钠、 葡萄糖、 山梨醇、 木糖 醇、 甘露醇、 甘油中的一种， 或者两种或两种以上的混合物。
(五）丁苯酞静脉乳剂的基本配方
在本发明的丁苯酞静脉乳剂中， 丁苯酞： 油相： 乳化剂： 7J相： 稳 定剂： 渗透压调节剂的比例为 0.01〜50重量％： 0 ~ 50重量％： 0.01 - 50 重量％: 50 ~ 98重量％: 0 ~ 50重量％: 0 ~ 10重量％范围内的任何 比例（以重量计）。
在一个示例实施方案中， 本发明的丁苯酞静脉乳剂的组成如下： 丁苯酞 10g
油相 100g
乳化剂 50g
稳定剂 50g
水相 加至 1000ml 具体实施方式
实施例一： 丁苯酞静脉乳剂的制备 配方組成 ( g )
丁苯酞 10
大豆卵磷脂 12
大豆油 100
维生素 E 1
山梨醇 25
注射用水 加至 1000ml 制备方法：称取丁苯酞、维生素 E、大豆油并混合形成油相，在 60°C 水浴中预热油相； 称取大豆卵磷脂和山梨醇并分散于水中形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相中， 用高速剪切分散乳化机 于 lOOOOrpm下分散混合物 5min, 然后在高压均质机上循环 5次， 其中 一级压力为 100MPa， 二级压力为 10MPa， 然后调整 pH到 8, 过滤后分 装并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例二： 丁苯酞静脉乳剂的制备
配方组成 （ g )
丁苯酞 15
蓖麻油 100
大豆卵磷脂 12
泊洛沙姆 188 6
甘油 25
油酸 10
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 大豆卵磷脂、 油酸、 蓖麻油并混合形成油 相， 在 60°C水浴中预热油相； 称取泊洛沙姆 188、 甘油并 于水中形 成水相， 在 60Ό水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切分 散乳化机于 lOOOOrpm下分散混合物 5min, 然后在高压均质机上循环 5 次， 其中一级压力为 lOOMPa, 二级压力为 10MPa， 然后调整 pH到 8, 过滤并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例三： 丁苯酞静脉乳剂的制备
配方组成 （ g )
丁苯酞 20
大豆卵鱗脂 12
橄榄油 100
胆酸 1
甘露醇 30
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 胆酸、 橄榄油并混合形成油相， 在 60°C水 浴中预热油相；称取大豆卵磷脂、甘露醇并分散于水中形成水相，在 60°C 水浴中预热水相； 将油相緩慢倒入水相， 将混合物超声 10次（每次 10 秒，功率 400W ) , 然后在高压均质机上循环 5次， 一级压力为 lOOMPa, 二级压力为 lOMPa,调整 pH到 8，过滤后分装并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例四： 丁苯酞静脉乳剂的制备
配方组成 ( g )
丁苯酞 25
棉籽油 100
蛋黄卵磷脂 12
泊洛沙姆 188 20
甘油 25
油酸钠 10
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 蛋黄卵磷脂、 油酸钠、 棉籽油并混合形成 油相， 在 60°C水浴中预热油相； 称取泊洛沙姆 188、 甘油并 于水中 形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切 乳化机于 lOOOOrpm下分散混合物 5min， 然后在高压均质机上循环 5次， 其中一级压力为 100MPa， 二级压力为 10MPa， 调整 pH到 8, 过 滤后分装并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例五： 丁苯酞静脉乳剂的制备 配方组成 （ g )
丁苯酞 30
大豆卵磷脂 12
大豆油 200
Tween 80 6
维生素 E 8
^ 1醇 100
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 Tween 80、 维生素 E、 大豆油并混合形成 油相， 在 60°C水浴中预热油相； 称取大豆卵碑脂和木糖醇并分散于水中 形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切 乳化机于 lOOOOrpm下分散混合物 5min， 然后在高压均质机上循环 5次， 其中一级压力为 100MPa， 二级压力为 10MPa， 调整 pH到 8， 过 滤后分装并在 121 °C下灭菌 15min。 整个过程要充氮气保护。 实施例六： 丁苯酞静脉乳剂的制备
配方组成 （ g )
丁苯酞 40
辛^/癸酸甘油三酯 200
大豆卵磷脂 12
泊洛沙姆 188 20
甘油 25
油酸 10
注射用水 加至 1000ml N2006/003434 一 9一
制备方法： 称取丁苯酞、 大豆卵磷脂、 油酸、 辛^/癸酸甘油三酯并 混合形成油相， 在 60。C水浴中预热油相； 称取泊洛沙姆 188、 甘油并分 散于水中形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用 高速剪切分散乳化机于 lOOOOrpm下分散混合物 5min， 然后在高压均质 机上循环 5次， 其中一级压力为 100MPa， 二级压力为 lOMPa, 调整 pH 到 8, 过滤后分装并在 121 °C下灭菌 15min。 整个过程要充氮气保护。 实施例七： 丁苯酞静脉乳剂的制备 配方组成 ( g )
丁苯酞 50
大豆卵磚脂 15
¾ 油 100
维生素 E 8
甘油 22.5
注射用水 加至 1000ml 制备方法： 称取丁苯酞、维生素 E、芝麻油并混合形成油相，在 60°C 水浴中预热油相；称取大豆卵磷脂和甘油并分散于水中形成水相，在 60 °C 水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切分散乳化机于 lOOOOrpm下分散混合物 5min, 然后在高压均 ^：机上循环 5次， 其中一 级压力为 100MPa， 二级压力为 10MPa， 调整 pH到 8， 过滤后分装并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例八： 丁苯酞静脉乳剂的制备 配方组成 （g )
丁苯酞 20
大豆油 100
蛋黄卵磷脂 12
泊洛沙姆 188 20
甘油 25 注射用水 加至 1000ml 制备方法： 称取丁苯酞、 蛋黄卵磷脂、 油酸钠、 大豆油并混合形成 油相， 在 60°C水浴中预热油相； 称取泊洛沙姆 188、 甘油并^：于水中 形成水相， 在 60Ό水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切 乳化机于 lOOOOrpm下分散混合物 5min, 然后在高压均质机上循环 5次， 其中一级压力为 100MPa， 二级压力为 lOMPa, 调整 pH到 8， 过 滤后分装并在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例九： 丁苯酞静脉乳剂的制备 配方组成 （ g )
丁苯酞 100
蛋黄卵磷脂 20
泊洛沙姆 188 20
甘油 25
油酸钠 30
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 蛋黄卵磷脂、 油酸納并混合形成油相， 在
60°C水浴中预热油相； 称取泊洛沙姆 188、 甘油并分散于水中形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切分散乳化机 于 lOOOOrpm下分散混合物 5min, 然后在高压均质机上循环 5次， 其中 一级压力为 100MPa， 二级压力为 10MPa， 调整 pH到 8, 过滤后分装并 在 121°C下灭菌 15min。 整个过程要充氮气保护。 实施例十： 丁苯酞静脉乳剂的制备 配方组成 （g )
丁苯酞 0.1
大豆油 100
蛋黄卵磷脂 19
泊洛沙姆 188 25
甘油 25
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 蛋黄卵磷脂、 大豆油并混合形成油相， 在 60°C水浴中预热油相； 称取泊洛沙姆 188、 甘油并分散于水中形成水相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切分散乳化机 于 lOOOOrpm下分散混合物 5min, 然后在高压均质机上循环 5次， 其中 一级压力为 lOOMPa, 二级压力为 lOMPa, 调整 pH到 8， 过滤后分装并 在 121 °C下灭菌 15mhi。 整个过程要充氮气保护。 实施例十一： 丁苯酞静脉乳剂的制备 配方组成 （ g )
丁苯酞 5
大豆油 100
蛋黄卵磷脂 12
泊洛沙姆 188 20
油酸钠 3
注射用水 加至 1000ml 制备方法： 称取丁苯酞、 蛋黄卵磷脂、 油酸钠、 大豆油并混合形成 油相， 在 60Ό水浴中预热油相； 称取泊洛沙姆 188并分散于水中形成水 相， 在 60°C水浴中预热水相； 将油相緩慢倒入水相， 用高速剪切分散乳 化机于 lOOOOrpm下分散混合物 5min , 然后在高压均盾机上循环 5次， 其中一级压力为 100MPa， 二级压力为 10MPa， 调整 pH到 8， 过滤后分 装并在 121 °C下灭菌 15min。 整个过程要充氮气保护。

Claims

权 利 要 求
1、一种丁苯酞静脉乳剂， 包含 0.01 ~ 50重量％丁苯酞或其衍生物作 为有效成分和 50 ~ 99.99重量％辅料， 基于乳剂的总重量。
2、 根据权利要求 1的丁苯酞静脉乳剂， 其中所述丁苯酞或其衍生物 选自丁苯酞消旋体或其衍生物和左旋丁苯酞或其衍生物。
3、 根据权利要求 1或 2的丁苯酞静脉乳剂， 其中所述辅料包含 0 ~ 50重量％油相、 50 ~ 98重量％水相、 0.01 ~ 50重量％乳化剂、 0 ~ 50重 量％稳定剂和 0 ~ 10重量％渗透压调节剂 , 基于辅料的总重量。
4、 根据权利要求 3的丁苯酞静脉乳剂， 其中所述油相包括含长链脂 肪酸酯基团的天然植物油或经过结构改造和水解后的植物油或脂肪酸 酯、 链长在 C6 ~ C12之间的中等链长脂肪酸甘油酯、 以及它们的混合物。
5、 根据权利要求 4的丁苯酞静脉乳剂， 其中所述油相选自大豆油、 蓖麻油、 茶油、 花生油、 棉籽油、 芝麻油、 菜油、 红花油、 橄榄油、 椰 子油、棕榈油、可可豆油、 Arlacel 80、 Arlacel 86、 Capmul MCM、 Captex 200(oil)、 Captex 355(oiI), Miglyol 812(oil)、 Myvacet(oil), Myverol 18-92、 油酸甘油酯、 亚油酸甘油酯、 聚乙二醇月桂酸甘油酯、 油酸乙酯、 亚油 酸乙酯、 辛^/癸酸甘油三酯及其混合物。
6、 根据权利要求 3的丁苯酞静脉乳剂， 其中所述乳化剂包含非离子 表面活性剂和离子型表面活性剂的一种或多种。
7、 根据权利要求 6的丁苯酞静脉乳剂， 其中所述乳化剂选自大豆卵 磷脂或其修饰物、 蛋黄卵磷脂或其修饰物、 Ophase 31、 泊洛沙姆 108、 泊洛沙姆 188、泊洛沙姆 407、聚氧乙烯（氢化）蓖麻油、7 溶性 VE( TPGS )、 Solutol HS-15> PEG400单硬脂酸酯、 PEG1750单硬脂酸酯、 Tween 80、 Tween20、 Span20及其混合物。
8、 根据权利要求 3的丁苯酞静脉乳剂， 其中所述稳定剂选自油酸、 油酸钠、 辛酸钠、 胆固醇、 胆酸、 脱氧胆酸及其钠盐、 维生素 A、 维生 素（、 维生素 E及其混合物。
9、 根据权利要求 3的丁苯酞静脉乳剂， 其中所述渗透压调节剂选自 氯化钠、 葡萄糖、 山梨醇、 木糖醇、 甘露醇、 甘油及其混合物。
10、 根据权利要求 1的丁苯酞静脉乳剂， 通过静脉注射或滴注给药。
PCT/CN2006/003434 2005-12-16 2006-12-15 Emulsion intraveineuse de butylbenzene phtaleine et son application WO2007068212A1 (fr)

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