WO2012037834A1 - 一种5α-雄甾（烷）-3β，5，6β-三醇注射剂及其制备方法 - Google Patents

一种5α-雄甾（烷）-3β，5，6β-三醇注射剂及其制备方法 Download PDF

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Publication number
WO2012037834A1
WO2012037834A1 PCT/CN2011/076968 CN2011076968W WO2012037834A1 WO 2012037834 A1 WO2012037834 A1 WO 2012037834A1 CN 2011076968 W CN2011076968 W CN 2011076968W WO 2012037834 A1 WO2012037834 A1 WO 2012037834A1
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Prior art keywords
injection
cyclodextrin
parts
hydroxypropyl
triol
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PCT/CN2011/076968
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English (en)
French (fr)
Inventor
颜光美
胡海燕
张静夏
邱鹏新
李玲
田宁
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中山大学
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Priority to JP2013527453A priority Critical patent/JP5750680B2/ja
Priority to ES11826361.5T priority patent/ES2677069T3/es
Priority to SI201131508T priority patent/SI2620153T1/en
Priority to RU2013105216/15A priority patent/RU2532354C1/ru
Priority to RS20180765A priority patent/RS57409B1/sr
Priority to KR1020137006176A priority patent/KR101468153B1/ko
Priority to LTEP11826361.5T priority patent/LT2620153T/lt
Application filed by 中山大学 filed Critical 中山大学
Priority to SG2013016126A priority patent/SG188393A1/en
Priority to AU2011304917A priority patent/AU2011304917B2/en
Priority to PL11826361T priority patent/PL2620153T3/pl
Priority to BR112013005763-7A priority patent/BR112013005763B1/pt
Priority to EP11826361.5A priority patent/EP2620153B1/en
Priority to DK11826361.5T priority patent/DK2620153T3/en
Priority to US13/821,849 priority patent/US9161985B2/en
Priority to CA2809646A priority patent/CA2809646C/en
Publication of WO2012037834A1 publication Critical patent/WO2012037834A1/zh
Priority to US14/839,869 priority patent/US9265837B1/en
Priority to HRP20181002TT priority patent/HRP20181002T1/hr
Priority to CY181100681T priority patent/CY1120724T1/el

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention relates to the field of pharmacy, and in particular to a 5?-androst(?:)-3?,5,6?-triol injection and a preparation method thereof.
  • 5 ⁇ -androstine ( ⁇ ) -3 ⁇ ,5,6 ⁇ -triol (hereinafter abbreviated as YC-6) is our newly discovered neuroprotective agent.
  • YC-6 5 ⁇ -androstine ( ⁇ ) -3 ⁇ ,5,6 ⁇ -triol
  • the treatment of acute ischemic stroke mainly through two ways: one is to dissolve thrombus, and the other is neuroprotection. Because neuroprotective agents can reduce the area of cerebral infarction, do not cause bleeding, and have no complications of thrombolysis and anticoagulation for bleeding, no detailed diagnosis of the cause is needed before use, which makes early treatment possible and has become a research hotspot in stroke treatment. .
  • neuroprotective agents have been found to be safe and effective so far.
  • Potential clinical applications for clinical trials include calcium channel blockers (CCB), calcium channel modulators, and glutamate release.
  • CB calcium channel blockers
  • Inhibitors GABA receptor agonists, free radical scavengers, anti-intercellular adhesion molecule antibodies, and the like.
  • neuroactive steroids have a widespread effect on neuroprotection and are receiving increasing attention.
  • YC-6 as a newly discovered neuroprotective agent, is not limited to neuroprotection. It is effective for both cerebral ischemia and spinal cord ischemia in vivo and in vitro, with a daily dose of 50-100 mg.
  • the present invention provides a YC-6 injection and a preparation method thereof.
  • the invention uses hydroxypropyl- ⁇ -cyclodextrin as a solubilizing agent, and successfully solves the problem of instability and irritation of the current YC-6 injection during use.
  • the YC-6 injection of the present invention comprises a liquid injection or a solid injection.
  • the soluble adjuvant of the injectable formulation contains hydroxypropyl- ⁇ -cyclodextrin.
  • the soluble adjuvant of the injection may also include an isotonicity adjusting agent or a lyophilized filler.
  • the preferred parts by weight of the weight of YC-6 and hydroxypropyl- ⁇ -cyclodextrin are: 1-20: 40-500
  • the weight percentage of each component in the injection can also be as follows: YC-6 1-20 parts, hydroxypropyl- ⁇ -cyclodextrin 40-500 parts, isotonicity adjusting agent 1-100 parts, lyophilized filler 0- 200 parts, solvent 0-2000 parts, were prepared.
  • the isotonicity adjusting agent may include one or more of sodium chloride, glucose, mannitol, lactose, xylitol, sorbitol or maltitol.
  • the lyophilized filler comprises one or more of sodium chloride, glucose, mannitol, lactose, xylitol, sorbitol or maltitol.
  • the solvent may be one or more selected from the group consisting of propylene glycol, ethanol, polyethylene glycol 400, polyethylene glycol 200, glycerin or water.
  • the injection solution of the invention can be obtained by the following preparation method: First, the hydroxypropyl- ⁇ -cyclodextrin solution, YC-6 and other soluble auxiliary materials are respectively dissolved in water for injection, sequentially decolorized, filtered, and sterilized. "Injection solution”.
  • the method for preparing the "lyophilized powder needle” is: filling the filtered filtrate into an ampoule, Freeze-dried, get “freeze-dried powder tl
  • the method for preparing the "sterile powder needle” is as follows: The above filtrate is spray-dried and dispensed to obtain a "bacterial powder needle”.
  • 0.1-0.3% of activated carbon may be used for decolorization, and the sterilization temperature and time are sterilized at 115 ° C for 30 minutes or 121 ° C for 15 minutes.
  • YC-6 can also be made into glucose injection, sodium chloride injection or glucose sodium chloride injection by the same principle.
  • the invention improves the solubility of YC-6 by using hydroxypropyl- ⁇ -cyclodextrin or a non-aqueous solvent/mixing solvent, so that YC-6 can be prepared by injection in water, non-aqueous solvent or mixed solvent.
  • YC-6 was used as a first-aid drug, and injection administration became possible. It has the advantages of stable solubility, no irritation, stable therapeutic effect and simple and easy preparation process.
  • Example 1 In this example, 200 YC-6 injections (size 5 ml: 50 mg) were prepared. The formula is:
  • Preparation process Take hydroxypropyl- ⁇ -cyclodextrin, soluble in Add YC-6 at room temperature and stir for 10-20 minutes to make it fully soluble. Add sodium chloride, stir to dissolve, add water for injection to a sufficient amount, add 0.1% activated carbon for 60 minutes at 60 ° C, let cool, and filter through a 0.22 ⁇ microporous membrane. The filtrate was potted into 5 ml injection and sterilized at 121 °C for 15 minutes.
  • Example 2 Preparation of this example 200 YC-6 injections (specification 10 ml: 80 mg)
  • Preparation process Take hydroxypropyl- ⁇ -cyclodextrin, dissolve in 80% of fresh water for injection, add YC-6 at room temperature and stir for 10-20 minutes to dissolve. Add glucose, stir to dissolve, add water for injection to a sufficient amount, add 0.1% activated carbon for 60 minutes at 60 ° C, let cool, and filter through 0.22 ⁇ microporous membrane. The filtrate was potted to obtain 10 ml of injection. Sterilize at 121 °C for 15 minutes.
  • Preparation process Take hydroxypropyl- ⁇ -cyclodextrin, dissolved in 80% of fresh water for injection, add YC-6, stir at room temperature for 10-20 minutes to fully dissolve, add water for injection to a sufficient amount, and add 0.1% activated carbon was incubated at 60 ° C for 15 minutes, allowed to cool, and filtered through a 0.22 ⁇ microporous membrane. The filtrate was potted to obtain 5 ml of injection. Sterilize at 115 ° C for 30 minutes. support)
  • Preparation process Take hydroxypropyl- ⁇ -cyclodextrin dissolved in 80% of fresh water for injection, dissolve it, add YC-6, stir at room temperature for 10-20 minutes to make it fully soluble. Sodium chloride was added, stirred to dissolve, and water for injection was added to 2000 ml. ⁇ Add 0.1% activated carbon at 60 ° C for 15 minutes, let cool, and filter through a 0.22 ⁇ microporous membrane. The filtrate was spray dried and divided into 200 pieces, which was obtained.
  • Example 5 In this example, 200 YC-6 freeze-dried powder needles were prepared (size 5 ml:
  • Preparation process Take hydroxypropyl- ⁇ -cyclodextrin dissolved in fresh water for injection with a prescription of 80%. After dissolving, add YC-6 and stir at room temperature for 10-20 minutes to dissolve. Sodium chloride was added, stirred to dissolve, and water for injection was added to 2000 ml. ⁇ Add 0.1% activated carbon at 60 ° C for 15 minutes, let cool, filter through 0.22 ⁇ microporous membrane, and dispense the filtrate into 5 ml/cild flask, freeze-dry, and obtain.
  • a colorless, clear, colorless, clear, colorless, clear, colorless, clear, colorless, clear, colorless, clear, colorless, clear, colorless, clear colorless, clear
  • mice were randomly divided into five groups, 10 in each group, half male and half female.
  • Different doses of YC-6 injection (20 mg/ml) in Example 3 were injected into the tail vein, and the phenomenon was recorded immediately. The surviving mice were sacrificed one week after observation, and the animal toxicity and death were recorded day by day, and 5Q was calculated. And 95% confidence limit.
  • Fresh New Zealand rabbit blood was taken, and blood cells were prepared according to a conventional method, and diluted with physiological saline to a 2% suspension, added to an injection, and incubated at 37 ° C for 3 hours, and the hemolysis rate was measured by colorimetry.

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Description

一种 5α-雄甾 (烷) -3ρ,5,6β-三醇注射剂
及其制备方法
技术领域
本发明涉及制药领域，具体涉及一种 5α-雄 (垸: )-3β,5,6β-三醇注 射剂及其制备方法。
背景技术
5α-雄甾 （垸） -3β,5,6β-三醇 （下面简称为 YC-6) 是我们新发现 的神经保护剂。 目前， 急性缺血性脑卒中的治疗主要通过两个途径： 一为溶解血栓， 二为神经保护。 由于神经保护剂可减少脑梗死面积， 不引发出血， 无溶栓、 抗凝治疗出血的并发症， 用前无需进行详细的 病因鉴别诊断， 使得早期治疗成为可能， 已成为脑卒中治疗的研究热 点。
然而， 迄今为止还没有发现已证明为安全有效的神经保护剂， 目 前正在进行临床试验的、具有潜在临床应用前景的药物有钙通道阻滞 剂（CCB)、 钙通道调节剂、 谷氨酸释放抑制剂、 GABA受体激动剂、 自由基清除剂、 抗细胞间黏附分子抗体等。在众多化合物中， 神经活 性甾体对神经保护具有广泛效应而日益受到关注。 特别是 YC-6, 作 为新发现的神经保护剂， 其作用不限于神经保护。在体内外对脑缺血 及脊髓缺血均有效， 日剂量为 50-100mg。但由于 YC-6在水中溶解度 小， 常用的非水溶剂及其混合溶剂虽然可提高其溶解度， 但均存在较 大的刺激性， 并且有经水稀释后析出的现象， 从而影响了该制剂的疗 效和安全性， 限制了注射剂的 YC-6的广泛应用。 发明内容
为了克服以上缺陷， 本发明提供了一种 YC-6注射剂及其制备 方法。 该发明使用羟丙基 -β-环糊精作为增溶剂， 成功地解决了目前 YC-6注射剂使用过程中澄明度不稳定和刺激性的问题。
为实现上述目的， 本发明的 YC-6注射剂， 包括液态注射液或固 态注射液。 注射液配方的可溶性辅料中含有羟丙基 -β-环糊精。 当然， 该注射液的可溶性辅料还可以包括等渗调节剂或冻干填充剂。
YC-6 与羟丙基 -β-环糊精重量的优选重量份数比为： 1-20 : 40-500
注射剂中各组分占的重量百分比也可按： YC-6 1-20份， 羟丙 基 -β-环糊精 40-500份，等渗调节剂 1-100份，冻干填充剂 0-200份， 溶剂 0-2000份， 进行配制。
所述的等渗调节剂可以包括氯化钠、 葡萄糖、 甘露醇、 乳糖、 木糖醇、 山梨醇或麦芽糖醇中的一种或几种。
所述的冻干填充剂包括氯化钠、 葡萄糖、 甘露醇、 乳糖、 木糖 醇、 山梨醇或麦芽糖醇中的一种或几种。
如果配制液态注射剂， 溶剂可以选用丙二醇、 乙醇、 聚乙二醇 400、 聚乙二醇 200、 甘油或水中的一种或几种。
本发明的注射液可以通过以下制备方法得到： 首先， 将羟丙基 -β-环糊精溶液、 YC-6和其他可溶性辅料按顺序分别溶于注射用水中， 经脱色、 过滤、 灭菌得 "注射液"。
制备"冻干粉针"的方法是：将上述过滤后的滤液灌装于安瓿中， 冷冻干燥， 得"冻干粉 tl
制备"无菌粉针"的方法是： 将上述滤液喷雾干燥， 分装得到"无 菌粉针"。
上述方法中， 可以使用 0.1-0.3%的活性炭进行脱色， 灭菌的温 度和时间为 115 °C灭菌 30分钟或 121 °C灭菌 15分钟。
当然， 也可以利用同原理将 YC-6制成葡萄糖注射液、 氯化钠 注射液或葡萄糖氯化钠注射液。
本发明与现有技术相比具有以下优越的技术效果：
本发明通过采用了羟丙基 -β-环糊精或非水溶剂 /混合溶剂，提高 了 YC-6的溶解度， 使 YC-6可以制成以水、 非水溶剂或混合溶剂为 溶剂的注射液、 注射用无菌粉末、 冻干粉针、 葡萄糖注射液、 氯化钠 注射液或葡萄糖氯化钠注射液。 使 YC-6作为急救用药， 注射给药成 为可能。 并具有溶解度稳定， 无刺激性、 疗效稳定和制备工艺简单易 得等优点。
具体实施方式
实施例 1：本实施例制备 200支 YC-6注射液（规格 5ml: 50mg)。 配方为：
YC-6
2-羟丙基 -β-环糊精
氯化钠
注射用水加至
制备工艺： 取羟丙基 -β-环糊精， 溶于处 加入 YC-6室温搅拌 10-20分钟， 使全溶。加入氯化钠， 搅拌使溶解， 添加注射用水至足量，遂加入 0.1%的活性碳 60°C保温 15分钟，放冷， 经 0.22 μιη微孔滤膜过滤。 滤液灌封为 5ml注射液， 121 °C灭菌 15分 钟， 即得。
实施例 2:本实施例制备 200支 YC-6注射剂（规格 10ml: 80mg)
YC-6 16 g
3-羟丙基 -β-环糊精 400 g
葡萄糖 13.9 g
注射用水加至 2000 ml
制备工艺： 取羟丙基 -β-环糊精， 溶于处方量 80%的新鲜注射用水中， 加入 YC-6室温搅拌 10-20分钟， 使全溶。加入葡萄糖， 搅拌使溶解， 添加注射用水至足量，遂加入 0.1%的活性碳 60°C保温 15分钟，放冷， 经 0.22μηι微孔滤膜过滤。 滤液灌封得 10ml注射液。 121 °C灭菌 15 分钟， 即得。
实施例 3:本实施例制备 200支 YC-6注射剂（规格 5ml: lOOmg)
YC-6 20 g
2-羟丙基 -β-环糊精 400 g
注射用水加至 1000 ml
制备工艺： 取羟丙基 -β-环糊精， 溶于处方量 80%的新鲜注射用水中， 加入 YC-6, 室温搅拌 10-20分钟使全溶，添加注射用水至足量，遂加 入 0.1%的活性碳 60°C保温 15分钟，放冷，经 0.22μηι微孔滤膜过滤。 滤液灌封得 5ml注射液。 115°C灭菌 30分钟， 即得。 支）
YC-6 16 g
2-羟丙基 -β-环糊精 400 g
氯化钠 2.5 g
分装成 200支
制备工艺： 取羟丙基 -β-环糊精溶于处方量 80%的新鲜注射用水中， 溶解后， 加入 YC-6, 室温搅拌 10-20分钟， 使全溶。 加入氯化钠， 搅拌使溶解， 添加注射用水至 2000ml。遂加入 0.1%的活性碳 60°C保 温 15分钟， 放冷， 经 0.22 μιη微孔滤膜过滤。 滤液喷雾干燥， 分装 成 200支， 即得。
实施例 5: 本实施例制备 200 支 YC-6冻干粉针 （规格 5ml:
60mg)
YC-6 12 g
-羟丙基 -β-环糊精 200 g
7 g
注射用水加至
制备工艺： 取羟丙基 -β-环糊精溶于处方量 80%的新鲜注射用水中， 溶解后， 加入 YC-6, 室温搅拌 10-20分钟， 使全溶。 加入氯化钠， 搅拌使溶解， 添加注射用水至 2000ml。遂加入 0.1%的活性碳 60°C保 温 15分钟， 放冷， 经 0.22 μιη微孔滤膜过滤， 滤液分装为 5 ml/西林 瓶， 冷冻干燥， 即得。 实施例 6 YC-6注射剂与常用输液配伍的稳定性研究
取实施例 1中所述的 YC-6注射液 2支 （5mlx2) 加入常用输液中， 考察 YC-6注射剂与常用输液 8h内的配伍稳定性。 考察项目包括色 泽、 澄明度、 pH及 YC-6含量， 结果如下表所示。
表 1 YC-6注射剂与常用输液配伍方案 样品号 配 伍 （ 25-30 °C )
A YC-6注射液 5ml*2支 +5%葡萄糖注射液 250ml
B YC-6注射液 5ml*2支 +0.9%氯化钠注射液 250ml
C YC-6注射液 5ml*2支 +葡萄糖氯化钠注射液 250ml
D YC-6注射液 5ml*2支 +复方氯化钠注射液 500ml
E YC-6注射液 5ml*2支 +5%碳酸氢钠注射液 250ml
表 2 常用输液与 YC-6注射液配伍后色泽与澄明度的变化
配伍后各时间点 （h)
样品号 配伍前 0 2 4 8
A 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明
B 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明
C 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明
D 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明
E 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明 无色、 澄明
表 3 常用输液与 YC-6注射液配伍后 pH的变化
样品 配伍后各时间点 （h)
号 配伍前 0 2 4 8
A 4.05 4.06 4.05 4.02 4.08
B 5.60 5.62 5.58 5.46 5.577 C 4.02 4.04 4.03 4.00 4.04
D 5.64 5.62 5.60 5.59 5.59
E 7.99 7.94 7.9 8.04 8.00
表 4 常用输液与 YC-6注射 '液配伍后输 〔中 YC-6的含 J t变化 g/ml) 样品号 Oh 2h 8h 24h
A 375.4 364.7 367.7 363.4
B 379.2 373.5 380.4 386.1
C 385.6 387.6 383.4 384.5
D 382.0 383.7 387.2 380.8
E 386.7 375.1 381.3 376.5
实施例 7 YC-6的初歩安全性评价
将昆明小鼠按体重分笼后， 随机分为五组， 每组 10只， 雌雄各 半。尾静脉注射不同剂量的实施例 3项下的 YC-6注射液（20 mg/ml) , 并立即记录现象， 存活小鼠观察一周后处死， 逐天记录动物毒性反应 情况及死亡数， 计算 5Q及 95%可信限。 YC-6 的 / )5Q > 400±121 mg/kg。 取新鲜新西兰兔血， 按常规方法制备血球， 并用生理盐水稀释成 2%的混悬液， 加入注射剂， 37°C温孵 3小时， 比色法测定溶血率。 结果表明， 注射剂溶血率小于 1%。 取白色豚鼠， 按常规方法进行过敏试验， 结果表明 YC-6注射液 不引起豚鼠过敏反应。
用新西兰兔进行静脉注射血管刺激性试验。结果表明用药组耳缘 静脉的组织变化与对照组相似， 各兔耳缘静脉血管壁完整， 未见内皮 损伤、 周围组织水肿等病理变化， 静脉血管结构正常。

Claims

权利要求书
1.5α-雄 (垸: )-3β,5,6β-三醇注射剂， 包括含有溶剂的液态注射液 或固态注射液， 注射剂的配方中包括可溶性辅料， 其特征在于： 所述 的可溶性辅料包括羟丙基 -β-环糊精。
2.如权利要求 1所述的注射剂，其特征在于， 5α-雄 (垸:) -3β,5,6β- 三醇与羟丙基 -β-环糊精的重量份数比为： 1-20: 40-500
3.如权利要求 1或 2所述的注射剂， 其特征在于， 所述的可溶性 辅料还包括等渗调节剂或冻干填充剂中的一种或两种。
4.如权利要求 3所述的注射剂， 其特征在于， 所述的等渗调节剂 包括氯化钠、 葡萄糖、 甘露醇、 乳糖、 木糖醇、 山梨醇或麦芽糖醇中 的一种或几种。
5.如权利要求 3所述的注射剂， 其特征在于， 所述的冻干填充剂 包括氯化钠、 葡萄糖、 甘露醇、 乳糖、 木糖醇、 山梨醇或麦芽糖醇中 的一种或几种。
6.如权利要求 1或 2所述的注射剂， 其特征在于， 所述液态注射 剂的溶剂为丙二醇、 乙醇、 聚乙二醇 400、 聚乙二醇 200、 甘油或水 中的一种或几种。
7.如权利要求 3所述的注射剂， 其特征在于， 该注射剂中各组分 占的重量百分比是： 5α-雄 (院) -3β,5,6β-三醇 1-20份， 羟丙基 -β-环 糊精 4-500份， 等渗调节剂 1-100份， 冻干填充剂 0-200份， 溶剂 0-2000份。
8.如权利要求 1所述的注射剂的制备方法， 其特征在于， 将羟丙 基 -β-环糊精溶液、 5α-雄 (垸:) -3β,5,6β-三醇和其他可溶性辅料按顺序 权利要求书
分别溶于注射用水中， 经脱色去热原、 过滤、 灭菌得 "注射液"； 或将 上述滤液灌装于安瓿中， 冷冻干燥， 得"冻干粉针"； 或将上述滤液喷 雾干燥， 分装得 "无菌粉针"
9.如权利要求 8所述的注射剂的制备方法， 其特征在于， 所述 的脱色吸附剂是活性炭， 用量为注射剂的质量百分比的 0.05-0.3%。
10. 如权利要求 8或 9所述的注射剂的制备方法， 其特征在于， 所述的灭菌歩骤的温度和时间分别是： 115 °C灭菌 30分钟或 121 °C灭 菌 15分钟。
PCT/CN2011/076968 2010-09-21 2011-07-08 一种5α-雄甾（烷）-3β，5，6β-三醇注射剂及其制备方法 WO2012037834A1 (zh)

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