WO2003090767A1 - Injection a base d'ixeris sonchifolia pour le traitement des maladies vasculaires cardio-cerebrales et des maladies du fond de l'oeil, et procede de production associe - Google Patents

Injection a base d'ixeris sonchifolia pour le traitement des maladies vasculaires cardio-cerebrales et des maladies du fond de l'oeil, et procede de production associe Download PDF

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WO2003090767A1
WO2003090767A1 PCT/CN2003/000290 CN0300290W WO03090767A1 WO 2003090767 A1 WO2003090767 A1 WO 2003090767A1 CN 0300290 W CN0300290 W CN 0300290W WO 03090767 A1 WO03090767 A1 WO 03090767A1
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injection
add
hours
filter
sodium
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PCT/CN2003/000290
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English (en)
French (fr)
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Ruixiang Zhang
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Wang, Maoxiang
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Priority to US10/511,902 priority Critical patent/US7163704B2/en
Priority to JP2003587400A priority patent/JP4521192B2/ja
Priority to BR0309595-9A priority patent/BR0309595A/pt
Priority to EP03720106A priority patent/EP1502595B1/en
Priority to MXPA04010579A priority patent/MXPA04010579A/es
Priority to CA002487245A priority patent/CA2487245A1/en
Priority to AU2003236145A priority patent/AU2003236145B2/en
Priority to DE60312505T priority patent/DE60312505T2/de
Priority to KR1020047016965A priority patent/KR100897656B1/ko
Publication of WO2003090767A1 publication Critical patent/WO2003090767A1/zh

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • 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 traditional Chinese medicine injection and a preparation method thereof, and more particularly to a disc vein spirit frozen Qianfen injection and a preparation method thereof, which are suitable for treating cardio-cerebral vascular disease and fundus disease.
  • Background technique :
  • the traditional Chinese medicine injection for treating cardio-cerebral vascular disease and fundus disease is Diemailing injection.
  • the clinically used Diemailing injection is a brown-yellow clear liquid, which is derived from the plant Asteraceae (Ixeris Sonchifolia Hance), Extracted from whole grass as raw material to produce intravenous injection, its main medicinal ingredients are flavonoids and adenosine. Because the phytoadenosine and flavonoids contained in bitter sauce coexist, it has very significant complementarity for the treatment of cardiovascular and cerebrovascular diseases, and has been confirmed through pharmacodynamics and clinical.
  • the pharmacological effects of Diemailing injection are: 1.
  • Increase coronary flow reduce cardiac vascular resistance, resist myocardial infarction, increase collateral circulation, reduce myocardial oxygen consumption, improve cardiac microcirculation, and apply to coronary heart disease, angina pectoris, shortness of breath, and myocardium Infarction treatment.
  • Reduce platelet aggregation function increase fibrinolytic enzyme activity, inhibit thrombosis, reduce plasma serum viscosity, increase red blood cell electrophoresis speed, reduce cerebrovascular resistance, increase cerebral blood volume, promote neural function recovery, apply to cerebral infarction (cerebral thrombosis Formation) treatment.
  • microcirculation disorders caused by bacteria improve microcirculation disorders caused by high-molecular dextran, improve fundus microcirculation, and dilate blood vessels of the fundus artery, and be used to treat fundus diseases such as central retinitis, optic nerve atrophy, retinal pigment degeneration Treatment.
  • Diemailing injection has poor stability and short storage time.
  • the content of adenosine and flavonoids was determined by high performance liquid chromatography and derivatization. The adenosine was reduced from 15. 0ug / ml to before and after completion of the injection. 6.
  • Flavonoid 0.133mg / ml can also be tested by taking the flavone and adenosine content of 5.07mg / ml, 24.37 ig / nil Diemailing injection in an 80 ° C oven for accelerated destruction for 10 days, Then measure the flavonoid and adenosine content. At this time, the flavonoid and adenosine content are left.
  • the maps are quite different. Randomly sample the stability of similar water injections (batch numbers 20000303, 20000503, 20010120).
  • the flavonoid content is 0.27 mg / ml, 0.51 mg / ml, 0.30 mg / ml, and adenosine content 1.1 lug / ml. , 0. 147ug / ml, 0. OOug / ml;
  • Diemailing injection is susceptible to many factors such as production, storage, etc. It is difficult to control the quality of the water injection product, which greatly affects the Diemailing injection. Effect of treatment. Summary of the invention:
  • the purpose of the present invention is to provide a traditional Chinese medicine injection for treating cardio-cerebral vascular and fundus diseases and a preparation method thereof, which can not only overcome the shortcomings of Diemailing injection water injection, but also have stable and easy-to-control product quality, adenosine and flavonoids.
  • the ingredients are not easy to lose, which ensures the safety and effectiveness of clinical medication, and is conducive to product storage.
  • the purpose of the present invention is to realize a Chinese medicine injection for treating cardio-cerebral vascular disease and fundus disease, which is characterized in that the injection is Diemailing lyophilized powder injection, and the flavonoid and adenosine content ratio in the lyophilized powder injection is 5mg. : 15ug or 5mg: 30ug.
  • the traditional Chinese medicine injection preparation method is as follows: take a clean bitter dish and cook with 25 ⁇ 30 times the amount of water for 3 hours, coarse filtration, microfiltration, and concentrate to 0.5g per lml equivalent to the native medicine; cool the concentrated decoction To below 40 ° C, add 10% calcium oxide milk to adjust pH1 (Ml, filter, and weigh the precipitate under stirring); suspend the above precipitate in 5.3 times ethanol, and add 25% sulfuric acid solution to adjust pH 3 ⁇ 4, and then fully stirred and filtered; the filtrate was added 40% sodium hydroxide solution, adjusted to pH 7 ⁇ 7.5, filtered, ethanol was recovered from the filtrate and ethanol was evaporated, and 4 g of equivalent native medicine per 1 ml was added with water for injection; Refrigerate below -8 ° C for 12 hours and filter; add 0.1 ⁇ 0.2% activated carbon and boil for 15 minutes, and then leave at -5 ° C for more than 24 hours, filter, Regulated 1) ⁇ 17.
  • the advantage of the present invention is that, because the Chinese herbal medicine of bitter dish containing flavonoids and adenosine is made into discoid spirit freeze-dried powder injection, it not only overcomes the unstable product quality, adenosine and flavonoids of the discoid spirit injection water injection.
  • the disadvantage of easy loss, and easy to control the quality of the product, the adenosine and flavonoid components are not easy to lose, which ensures the safety and effectiveness of clinical medication and is conducive to product storage.
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Table 1 is a comparison table of the stability test of flavonoids and adenosine in freeze-dried powder injections and injections against high fever: No. Formulation Flavones (Before Test) Flavones (After Test) Adenosine (Before Test) Adenosine (After Test) Exterior
  • discoidin lyophilized powder injections can be dissolved in water for injection, and then 250ml of sodium chloride injection or glucose injection can be added for intravenous drip.

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Description

一种治疗心脑血管和眼底病的中药针剂及其制备方法 技术领域：
本发明涉及一种中药针剂及其制备方法，更具体地说是涉及一种 碟脉灵冻千粉针剂及其制备方法， 适合于治疗心脑血管病和眼底病。 背景技术：
目前， 治^心脑血管病和眼底病的中药针剂有碟脉灵注射剂， 临 床所用碟脉灵注射剂为棕黄色澄明液体，来源于菊科植物苦碟子（抱 茎苦荬菜 Ixeris Sonchifolia Hance)，以全草为原料提取制成静脉 注射液，其主要的药用成分为黄酮和腺苷。 由于苦碟子中所含的植物 腺苷与黄酮共存，所以对于心脑血管疾病的治疗具有非常显著的互补 性， 并通过药效学和临床得到证实。碟脉灵注射剂的药理作用是： 1. 增加冠脉流量、 降低心脏血管阻力、抗心肌梗塞、 增加侧枝循环、 降 低心肌耗氧、 改善心脏微循环， 应用于冠心病、 心绞痛、 胸闷气短、 心肌梗塞治疗。 2.降低血小板聚集功能、 增加纤维蛋白溶解酶活性、 抑制血栓形成、 降低血浆血清粘度、增加红细胞电泳速度、 降低脑血 管阻力、 增加脑血容量、促进神经功能恢复， 应用于脑梗塞（脑血栓 形成）治疗。 3.改善细菌所致微循环障碍、 改善高分子右旋糖酐所致 全身微循环障碍、改善眼底微循环、扩张眼底动脉血管， 应用于治疗 眼底病，如中心视网膜炎、视神经萎缩、视网膜色素变性等病的治疗。 但是， 碟脉灵注射剂稳定性能差、储存时间短， 用高效液相色谱法和 衍生化法测定腺苷和黄酮的含量， 在水针剂完成前和完成后腺苷由 15. 0ug/ml降为 6. 7ug/ml， 黄酮由 0. 25mg/ml降为 0. 169mg/ml, 分别损 失投药量的 55. 3%和 32. 4%， 6个月后腺苷为 6. 5ug/ml， 黄酮 0. 133mg/ml； 还可以通过取黄酮和腺苷含量分别为 5. 07mg/ml、 24. 37 ig/nil的碟脉灵注射液置于 80°C烘箱中进行加速破坏 10天检验， 然后再测定黄酮和腺苷含量， 这时， 则黄酮和腺苷含量只剩下
1
确 认 本 3. 16mg/ml、 12. 18ug/ml (表 1)， 由于黄酮与腺苷两种有效成份在生 产和存储中的大量损失， 严重影响了药品的治疗效果。 同时， 碟脉灵 注射液溶液的色泽变化明显，由原料提取物配制成水针剂的过程中用 紫外分光光度计在 400nm处测试吸收度， 其值由灭菌前的 0. 338变为 灭菌后的 0. 423， 放置 6个月变为 0. 443， 色泽加深； 还有制剂的高效 液相图谱相似度差， 相同原料所制的提取物配制的不同批号的水针 剂，其高效液相图谱存在较大差异。随机抽样市售同类水针剂的稳定 性情况 (批号 20000303 , 20000503 , 20010120 ) 黄酮含量分别为 0. 27mg/ml、 0. 51mg/ml、 0. 30mg/ml，腺苷含量 1. 1 lug/ml、 0. 147ug/ml、 0. OOug/ml ; 综上所述， 碟脉灵水针剂易受制作、 储存等诸多因素的 影响，很难控制水针剂的产品质量，大大影响了碟脉灵注射剂的治疗 效果。 发明内容：
本发明的目的是提供一种治疗心脑血管和眼底病的中药针剂及 其制备方法， 它不仅能克服碟脉灵注射液水针剂存在的不足，而且产 品质量稳定易于控制、腺苷及黄酮的成份不易损失、保证了临床用药 的安全、 有效， 有利于产品储存。
本发明的目的是这样实现的，一种治疗心脑血管病和眼底病的中 药针剂，其特征在于针剂为碟脉灵冻干粉针剂，冻干粉针剂中黄酮与 腺苷的含量比为 5mg: 15ug或 5mg: 30ug。
本发明中药针剂的制备方法是：取洁净的苦碟子加 25〜30倍量水 煎煮 3小时， 粗滤， 微滤， 浓缩至每 lml相当于原生药 0.5g; 将浓缩 的煎煮液冷却至 40°C以下，在搅拌下加入 10%的氧化钙乳调 pHl (Ml， 过滤， 沉淀物称重； 将上述沉淀物悬浮于 5.3倍乙醇中， 加入浓度为 25%的硫酸溶液调 pH3~4， 再充分搅拌过滤； 将滤液中加入 40%氢氧 化钠溶液， 调 pH至 7〜7.5， 过滤， 从滤液中回收乙醇并挥尽乙醇， 加 注射用水制成每 lml相当原生药 4g; 置于 -8°C以下冷藏 12小时， 过滤; 加 0. 1〜0. 2%活性炭煮沸 15分钟， 再于 -5°C下放置 24小时以上， 过滤， 调1)}17. 0〜7. 5， 再用纸板、 垂熔漏斗、 微孔滤膜 (孔径 0. 45um)过滤， 灌封，灭菌（115°C30分钟），制成提取物；取上述提取物加入稳定剂、 或再加入支持剂，搅拌使之完全溶解，再加入针用活性炭处理，过滤， 得无热源澄明溶液， 分装于西林瓶或安瓿中， 于 -40〜- 60 °C预冻广 3小 时，随后抽真空 (真空度为 l~20pa) ，升温干燥，最终温度为 25〜40°C、 干燥 20~40小时， 即可制成碟脉灵冻干粉针剂制品。
本发明的优点是，由于将含有黄酮和腺苷的苦碟子中草药制成了 碟脉灵冻干粉针剂，不仅克服了上述碟脉灵注射液水针剂存在的产品 质量不稳定、腺苷及黄酮易损失的缺点，而且实现了产品质量易于控 制， 腺苷及黄酮成份不易损失， 保证了临床用药的安全、 有效， 有利 于产品储存。 具体实施方式：
实施例一：
取洁净的苦碟子（抱茎苦荬菜） 1kg置入煎煮锅内， 加 25〜30倍 量水煎煮 3小时， 粗滤， 微滤， 置于浓缩罐中进行浓缩处理至每 lml 相当于原生药 0.5g;将浓缩液放冷至 39°C， 搅拌、加含量为 10%的氧 化钙乳调 pH至 10, 过滤， 取沉淀物称重， 再放入沉淀物重量的 5.3倍 的乙醇中悬浮， 再加入浓度为 25%硫酸溶液调节 pH至 3; 充分搅拌过 滤， 再向滤液中加入含量为 40%氢氧化钠溶液， 调 pH至 7， 过滤， 滤 液回收乙醇并挥尽乙醇， 加注射用水使每 lml相当原生药 4g， 置 -9°C 冷藏 12小时， 过滤， 加 0. 1%活性炭煮沸 15分钟， 再于 -5Ό下放置 24小 时， 过滤， 调 pH至 7， 再用纸板、 垂熔漏斗、 微孔滤膜 (孔径 0. 45um) 过滤， 灌封， 灭菌（115Ό30分钟）， 制成提取物； 取上述提取物加入 0.05%的乙二胺四乙酸二钠或柠檬酸钠稳定剂， 搅拌使之完全溶解， 再加入 0.1%针用活性炭处理， 过滤，得无热源澄明溶液， 分装于西林 瓶或安瓿中， 每支 2ml， 于 -40°C预冻 3小时， 随后抽真空（真空度为 15pa) ， 升温干燥， 最终温度为 25°C、 干燥 20小时， 即可制成碟脉灵 冻干粉针剂制品。 实施例二：
取洁净的苦碟子 （抱茎苦荬菜） 1kg置入煎煮锅内， 加 25〜30倍 量水煎煮 3小时， 粗滤， 微滤， 置于浓缩罐中进行浓缩处理至每 lml 相当于原生药 0.5g; 将浓缩液放冷至 35°C，搅拌、加含量为 10%的氧 化鈣乳调至 pH10， 过滤， 将沉淀物称重， 再放入沉淀物重量的 5.3倍 的乙醇中悬浮， 再加入浓度为 25%硫酸溶液调节至 pH3.5; 充分搅拌 过滤，再向滤液中加入含量为 40%氢氧化钠溶液，调 pH至 7.3，过滤， 滤液回收乙醇并挥尽乙醇， 加注射用水使成每 lml相当原生药 4g， 置 -10°C冷藏 12小时， 过滤， 力 Π0. 12%活性炭煮沸 15分钟， 再于 -5°C下放 置 25小时， 过滤， 调 11至7. 2， 再用纸板、 垂熔漏斗、 微孔滤膜 (孔径 0. 45um)过滤， 灌封， 灭菌 （115Ό30分钟）， 制成提取物； 取上述提 取物加入 0.1%的亚硫酸氢钠或焦亚硫酸钠稳定剂或其混合物、 3%的 甘露醇支持剂， 搅拌使之完全溶解， 再加入 0.05%针用活性炭处理， 过滤， 得无热源澄明溶液， 分装于西林瓶或安瓿中， 每支 3ml， 于 -45 °C预冻 2. 5小时， 随后抽真空 (真空度为 18pa)， 升温干燥， 最终温度 为 30°C、 干燥 30小时， 即可制成碟脉灵冻干粉针剂制品。
实施例三：
取洁净的苦碟子 （抱茎苦荬菜） 1kg置入煎煮锅内， 加 25〜30倍 量水煎煮 3小时， 粗滤， 微滤， 置于浓縮罐中进行浓缩处理至每 lml 相当于原生药 0.5g; 将浓缩液放冷至 20°C， 搅拌、加含量为 10%的氧 化钙乳调 pH至 10.5， 放置 12小时， 滤出沉淀物， 将沉淀物称重， 再放 入沉淀物重量的 5.3倍的乙醇中悬浮，再加入浓度为 25%硫酸溶液调节 pH至 4; 充分搅拌过滤， 再向滤液中加入含量为 40%氢氧化钠溶液， 调 pH至 7， 过滤， 滤液回收乙醇并挥尽乙醇， 加注射用水使成每 lml 相当原生药 4g， 置 -HO冷藏 12小时， 过滤， 力 Π0. 15%活性炭煮沸 15分 钟， 再于 -5Ό下放置 24小时， 过滤， 调 }¾7. 4， 再用纸板、 垂熔漏 斗、 微孔滤膜 (孔径 0.45um)过滤， 灌封， 灭菌（115°C30分钟）， 制成 提取物；取上述提取物加入 0.05%的稳定剂亚硫酸钠或维生素 C或其混 合物、 或充氮气， 再加入 3%的右旋糖苷支持剂， 搅拌使之完全溶解， 加 0.05%针用活性炭处理， 过滤， 得无热源澄明溶液， 分装于西林瓶 或安瓿中， 每支 nl， 于 -50°C预冻 2小时， 随后抽真空（真空度为 10pa) ， 升温干燥， 最终温度为 35Ό干燥 25小时， 即可制成碟脉灵冻 干粉针剂制品。
实施例四：
取洁净的苦碟子 （抱茎苦荬菜） 1kg置入煎煮锅内， 加 25〜30倍 量水煎煮 3小时， 粗滤， 微滤， 置于浓缩罐中进行浓缩处理至每 lml 相当于原生药 0.5g; 将浓縮液放冷至 10Ό，搅拌、加含量为 10%的氧 化钙乳调 ρΗ至 11， 过滤， 将沉淀物称重， 放入沉淀物重量的 5.3倍的 乙醇中悬浮， 加入浓度为 25%硫酸溶液调节 ρΗ至 3; 充分搅拌过滤， 再向滤液中加入含量为 40%氢氧化钠溶液，调 ρΗ至 7， 过滤，滤液回 收乙醇并挥尽乙醇， 加注射用水使成每 lml相当原生药 4g， 置 -12°C冷 藏 12小时，过滤，加 0. 2%活性炭煮沸 15分钟，再于 -5°C下放置 24小时， 过滤， 调 pH7. 5， 再用纸板， 垂熔漏斗， 微孔滤膜 (孔径 0. 45um)过滤， 灌封， 灭菌（115°C30分钟）， 制成提取物； 取上述提取物加入 0.02% 硫代硫酸钠稳定剂和加入支持剂 5%的乳糖或葡萄糖或其混合物，搅 拌使之完全溶解， 加 0.01%针用活性炭处理， 过滤， 得无热源澄明溶 液， 分装于西林瓶或安瓿中， 每支 4ml或 5ml， 于 -60Ό预冻 1小时， 随 后抽真空 (真空度为 20pa) ， 升温干燥， 最终温度为 40°C干燥 40小时， 即可制成碟脉灵冻干粉针剂制品。
表 1是冻干粉针剂与注射液内的黄酮和腺苷含量对高热的稳定性 试验对照表： 序号 剂型 黄酮（试验前） 黄酮（试验后） 腺苷 (试验前） 腺苷（试验后） 外观
(mg/ml) (mg/ml) (ug/ml) (ug/ml)
1 冻干粉针 5. 07 5. 03 24. 37 23. 88 加水溶解后 呈黄棕色
2 注射液 5. 07 3. 16 24. 37 12. 18 呈深棕黄色 取碟脉灵冻干粉针剂配制成黄酮和腺苷含量分别为 5. 07mg/ml、 24. 37ug/ml的碟脉灵冻干粉针剂注射液，置于 80°C烘箱中进行加速破 坏 10天试验， 然后再测定黄酮和腺苷含量， 这时， 则黄酮和腺苷含量 分别为 5. 03mg/ml、 23. 88ug/ml, 黄酮与腺苷的含量几乎未发生改变。 而注射液却降至原含量的 62. 33%和 49. 99%。
临床使用时，根据患者病情的要求，可取不同规格的碟脉灵冻干 粉针剂加入注射用水溶解， 然后加入 250ml氯化钠注射液或葡萄糖注 射液中， 进行静脉点滴。

Claims

利 要 求
1、 一种治疗心脑血管病和眼底病的中药针剂， 其特征在于针剂 为碟脉灵冻干粉针剂，冻干粉针剂中黄酮与腺苷的含量比为 5mg: 15ug 或 5mg: 30ug。
2、一种权利要求 1中药针剂的制备方法， 其特征是： 取洁净的苦 碟子加 25〜30倍量水煎煮 3小时，粗滤， 微滤， 滤液浓缩至每 lml相当 于原生药 0.5g;将浓缩的煎煮液冷却至 40 °C以下，在搅拌下加入 10% 的氧化钙乳调 pH10〜ll， 过滤， 沉淀物称重； 将沉淀物悬浮于 5.3倍乙 醇中， 加入浓度为 25%的硫酸溶液调 pH3〜4， 再充分搅拌过滤； 将滤 液中加入 40%氢氧化钠溶液， 调 pH至 7〜7.5， 过滤， 从滤液中回收 乙醇并挥尽乙醇， 加注射用水制成每 lml相当原生药 4g; 置于 -8°C以 下冷藏 12小时， 过滤； 力 Π0. 1〜0. 2%活性炭煮沸 15分钟， 再于 -5°C下 放置 24小时以上， 过滤， 调 PH7. 0〜7. 5 再用纸板、 垂熔漏斗、 微孔 滤膜 (孔径 0. 45um)过滤， 灌封， 灭菌（Π5 30分钟）， 制成提取物； 取上述提取物加入稳定剂、或再加入支持剂， 搅拌使之完全溶解， 再 加入针用活性炭处理， 过滤， 得无热源澄明溶液， 分装于西林瓶或安 瓿中， 于 -40— 60°C预冻; Γ3小时， 随后抽真空 (真空度为广 20pa) ， 升 温干燥， 最终温度为 25〜40°C、干燥 20~40小时， 即可制成碟脉灵冻干 粉针剂制品。
3、根据权利要求 2所述的制备方法，其特征在于所说的稳定剂是 乙二胺四乙酸二钠、 柠檬酸 (钠） 、 亚硫酸氢钠、 亚硫酸钠、 焦亚硫 酸钠、 硫代硫酸钠、 维生素 C或氮气。
4、根据权力要求 2所述的制备工艺，其特征在于所说的支持剂是 甘露醇、 右旋糖苷、 乳糖或葡萄糖。
5、 根据权利要求 2或 3所述的制备方法， 其特征在于加入的稳定 剂为一种或两种以上的混合物。
6、 根据权利要求 2或 4所述的制备方法， 其特征在于加入的支持 剂为一种、 或两种以上的混合物。
PCT/CN2003/000290 2002-04-23 2003-04-21 Injection a base d'ixeris sonchifolia pour le traitement des maladies vasculaires cardio-cerebrales et des maladies du fond de l'oeil, et procede de production associe WO2003090767A1 (fr)

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JP2003587400A JP4521192B2 (ja) 2002-04-23 2003-04-21 心・脳血管病および眼底病の治療のための漢方薬注射剤ならびにその製造方法
BR0309595-9A BR0309595A (pt) 2002-04-23 2003-04-21 Injeção produzida a partir de ixeris sonchifolia hance para o tratamento de doenças vasculares cardiocerebrais e doenças de fundo, e método para a produção da mesma
EP03720106A EP1502595B1 (en) 2002-04-23 2003-04-21 An injection made from ixeris sonchifolia for treatment of cardio-cerebral vascular disease and fundus diseases and method of producing thereof
MXPA04010579A MXPA04010579A (es) 2002-04-23 2003-04-21 Una inyeccion hecha de lxeris sonchifolia hance para el tratamiento de las enfermedades cardio-cerebrales vasculares y enfermedades del fundus y metodo para producir la misma.
CA002487245A CA2487245A1 (en) 2002-04-23 2003-04-21 An injection made from ixeris sonchifolia hance for treatment of cardio-cerebral vascular diseases and fundus diseases and method of producing thereof
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DE60312505T DE60312505T2 (de) 2002-04-23 2003-04-21 Injektion aus ixeris sonchifolia zur behandlung von kardiozerebralen gefässerkrankungen und funduserkrankungen sowie herstellungsverfahren dafür
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