WO2022037362A1 - 一种治疗带状疱疹的注射剂 - Google Patents

一种治疗带状疱疹的注射剂 Download PDF

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WO2022037362A1
WO2022037362A1 PCT/CN2021/108239 CN2021108239W WO2022037362A1 WO 2022037362 A1 WO2022037362 A1 WO 2022037362A1 CN 2021108239 W CN2021108239 W CN 2021108239W WO 2022037362 A1 WO2022037362 A1 WO 2022037362A1
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injection
chlorogenic acid
freeze
drying
temperature
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PCT/CN2021/108239
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English (en)
French (fr)
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张洁
黄望
张雅
张飞
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四川九章生物科技有限公司
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Publication of WO2022037362A1 publication Critical patent/WO2022037362A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention specifically relates to an injection for treating herpes zoster.
  • VZV varicellazostervirus
  • HHV human herpesvirus
  • HSV-1 and type 2 HSV-2
  • the commonly used drugs for the treatment of herpes zoster are the nucleoside antiviral drug acyclovir (ACV) and the non-nucleoside antiviral drug foscamet (PFA).
  • ACCV nucleoside antiviral drug acyclovir
  • PFA non-nucleoside antiviral drug foscamet
  • Chlorogenic acid is widely found in various medicinal plants, such as honeysuckle and Eucommia leaves. At present, the chemical structure of chlorogenic acid has been clearly studied, and some people have carried out medicinal research on its antiviral effect. In vitro anti-herpes simplex virus effect [J]. China Natural Medicine, 2008 03, reported that chlorogenic acid can be used in the treatment of HSV-1 infection herpes, and the literature on chlorogenic acid used in the treatment of herpes zoster is mainly traditional Chinese medicine Preparations, such as Liu Weisu, Preparation and clinical application of compound Shuanghuanglian coating film [J]. Jiangsu Pharmacy and Clinical Research, 1999-02, the active ingredients in the disclosed drugs are complex. At present, there is no medicament for the treatment of herpes zoster which is prepared by adding pharmaceutically acceptable auxiliary materials or auxiliary components as the main drug with chlorogenic acid alone.
  • the present invention provides an injection for treating herpes zoster, which comprises chlorogenic acid, filler and antioxidant; the mass ratio of the chlorogenic acid, filler and antioxidant is 30:20-160 : 0.5 to 4.
  • the mass ratio of the chlorogenic acid, the filler and the antioxidant is 30:40-120:1-4.
  • mass ratio of chlorogenic acid, filler and antioxidant is 30:80:2
  • the filler is mannitol or lactose.
  • the filler is mannitol.
  • the antioxidant is sodium bisulfite, vitamin C or sodium metabisulfite.
  • the antioxidant is sodium bisulfite.
  • the present invention also provides a preparation method of the aforementioned injection, which comprises the following steps:
  • freeze-drying parameters are: pre-freezing temperature ⁇ -40°C, normal pressure, freezing; primary drying temperature ⁇ -13°C, negative pressure, drying until the product water line disappears; secondary drying temperature 20-30°C, Negative pressure, drying time ⁇ 2h.
  • the present invention finally provides an application of the aforementioned injection in preparing a medicine for treating herpes zoster.
  • the drug is a drug that has an inhibitory effect on varicella-zoster virus.
  • the injection for treating herpes zoster of the present invention is prepared by using an effective amount of chlorogenic acid as an active ingredient, adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients within a certain dosage range, and can effectively treat herpes zoster through injection and administration. , to provide a new and safe option for the clinical treatment of herpes zoster, and has a good application prospect.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the product water line disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation method weigh chlorogenic acid, mannitol, and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • chlorogenic acid 300g mannitol 1200g
  • sodium bisulfite 30g sodium bisulfite
  • Preparation method weigh chlorogenic acid, mannitol and sodium bisulfite according to the prescription, dissolve in water for injection, filter sterilize, freeze-dry (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C, normal pressure, freeze; once Drying: temperature ⁇ -13°C, negative pressure, dry until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30°C, negative pressure, drying time ⁇ 2h) to obtain freeze-dried powder injection.
  • Preparation formula 2 chlorogenic acid, mannitol, sodium bisulfite (30:40:2);
  • Formulation formulation 5 chlorogenic acid, mannitol, sodium bisulfite (30:160:2).
  • solubility of chlorogenic acid is 4%.
  • solubility of formulation prescription 1 in water is equivalent to that of chlorogenic acid, and the solubility of formulation prescriptions 2, 3, and 4 in water is better than that of chlorogenic acid.
  • the solubility in water is weaker than that of chlorogenic acid. It shows that the ratio of chlorogenic acid and filler mannitol is the optimal ratio in the range of 30:40-120.
  • Preparation formula 2 chlorogenic acid, mannitol, sodium bisulfite (30:80:1);
  • Formulation formulation 5 chlorogenic acid, mannitol, sodium bisulfite (30:80:4).
  • Test Example 3 The animal in vivo test of the drug of the present invention for the treatment of herpes zoster
  • Test drug 1 chlorogenic acid API
  • Test drug 2 chlorogenic acid for injection, prescription ratio: chlorogenic acid, mannitol, sodium bisulfite (30:40:1);
  • Test drug 3 chlorogenic acid for injection, prescription ratio: chlorogenic acid, mannitol, sodium bisulfite (30:80:2);
  • Test drug 4 chlorogenic acid for injection, prescription ratio: chlorogenic acid, mannitol, sodium bisulfite (30:120:3);
  • Test drug 5 chlorogenic acid granules, formula ratio: chlorogenic acid, filler (lactose), binder (sodium carboxymethylcellulose) (1000:500:5);
  • chlorogenic acid preparations for injection were weighed according to the prescription proportions, chlorogenic acid, mannitol and sodium bisulfite were dissolved in water for injection, filtered and sterilized, and freeze-dried (freeze-drying conditions: pre-freezing: temperature ⁇ -40°C , normal pressure, freezing; primary drying: temperature ⁇ -13 °C, negative pressure, drying until the water line of the product disappears; secondary drying: temperature 20 ⁇ 30 °C, negative pressure, drying time ⁇ 2h), get the labeled amount of chlorogenic acid It is 30mg/piece of lyophilized powder for injection.
  • chlorogenic acid granules For chlorogenic acid granules, weigh chlorogenic acid, fillers, and binders according to the prescribed proportions, mix, granulate, granulate, and package into granules.
  • VZV standard strain VZV-Ellen VR-1367, purchased from ATCC Company in the United States, was grown and passaged in MRC-5 cells.
  • BALB/c mice 48, half male and half male, weighing 18-22 g, purchased from the Experimental Animal Management Center of West China Medical Center.
  • mice Under sodium pentobarbital anesthesia, the backs of mice were depilated, cleaned, and disinfected by conventional methods, and VR-1367 virus strain was injected intradermally in the center of the hairless area. During sleep after anesthesia, mice were kept at 30°C for 2h. After the end of anesthesia, the cells were placed at room temperature of 25°C, and the surface changes were observed 24 hours after inoculation. Herpes Observation: Herpes grows and the herpes swells and becomes round, the blister wall is tight and shiny, and the inside is bright and clear, and then gradually becomes cloudy. New blister clusters appeared gradually, and the skin between the blister clusters was normal. General situation: animals infected with the virus have decreased appetite, slowed breathing, increased body temperature, decreased activity, and decreased feces.
  • mice were randomly divided into 8 groups, including:
  • Negative control group intraperitoneal injection of normal saline, once a day;
  • Oral chlorogenic acid API group Oral test drug 1, once a day, 30 mg/kg/time;
  • Oral chlorogenic acid granules group Oral test drug 5, once a day, 30 mg/kg/time;
  • Injection administration group 1 intraperitoneal injection of test drug 2, once a day, 30 mg/kg/time;
  • Injection administration group 2 intraperitoneal injection of test drug 3, once a day, 30 mg/kg/time;
  • Injection administration group 3 intraperitoneal injection of test drug 4, once a day, 30 mg/kg/time;
  • herpes zoster of the present invention uses an effective amount of chlorogenic acid as an active ingredient, and is prepared by adding pharmaceutically acceptable adjuvants or auxiliary ingredients within a certain dosage range, and can be effectively treated by injection.
  • Herpes zoster provides a new and high-safety option for the clinical treatment of herpes zoster, and has a good application prospect.

Abstract

公开了一种治疗带状疱疹的注射剂，其组成包括绿原酸、填充剂和抗氧化剂；所述绿原酸、填充剂和抗氧化剂质量比为30：20～160：0.5～4。所述治疗带状疱疹的注射剂以有效量的绿原酸为活性成分，添加药学上可接受的辅料或者辅助性成分制备的药剂，通过注射给药，能够有效治疗带状疱疹，为临床上带状疱疹的治疗提供一种新的，安全性高的选择，具有良好的应用前景。

Description

一种治疗带状疱疹的注射剂 技术领域
本发明具体涉及一种治疗带状疱疹的注射剂。
背景技术
水痘是儿童常见的一种急性、高传染性的呼吸道传染病，带状疱疹是患水痘后潜伏病毒的再激活所致，其病原为水痘-带状疱疹病毒(varicellazostervirus，VZV)。VZV又称人类疱疹病毒(human herpesvirus，HHV)3型(HHV-3)，与单纯疱疹病毒1型(herpes simplex virus l，HSV-1)和2型(HSV-2)同属HHV的α亚科，是具有最小双螺旋DNA的疱疹病毒，生长周期短，在多种细胞和组织中快速扩散，造成细胞间的感染。
目前临床上常用治疗带状疱疹的药物为核苷类抗病毒药物阿昔洛韦(acyclovir，ACV)和非核苷类抗病毒药物膦甲酸(foscamet，PFA)，但近年来有关VZV对ACV耐药以及耐药株感染者预后差的报告逐渐增多。尽管PFA可用于治疗ACV耐药株感染，但其肾脏毒性使临床应用受限。因此，研究新的抗VZV药物对临床上带状疱疹的治疗具有重要意义。
绿原酸广泛存在于各种药用植物，如金银花和杜仲叶等，目前对它的化学结构研究已经清楚，已有人对其的抗病毒作用进行药用研究，盛卸晃等,绿原酸体外抗单纯疱疹病毒作用[J].中国天然药物，2008年03期，报道了绿原酸可以应用于HSV-1感染疱疹的治疗，而绿原酸用于带状疱疹治疗的文献主要为中药制剂，如刘卫苏,复方双黄连涂膜剂的制备及临床应用[J].江苏药学与临床研究，1999年02期，其公开的药物中有效成分复杂。目前没有单纯绿原酸作为主药，添加药学上可接受的辅料或者辅助性成分制备而成的治疗带状疱疹的药剂。
发明内容
为解决上述问题，本发明提供了一种治疗带状疱疹的注射剂，其组成包括绿原酸、填充剂和抗氧化剂；所述绿原酸、填充剂和抗氧化剂质量比为30：20～160：0.5～4。
进一步地，所述绿原酸、填充剂和抗氧化剂质量比为30：40～120：1～4。
更进一步地，所述绿原酸、填充剂和抗氧化剂质量比为30：80：2
进一步地，所述填充剂为甘露醇或乳糖。
更进一步地，所述填充剂为甘露醇。
进一步地，所述抗氧化剂为亚硫酸氢钠、维生素C或焦亚硫酸钠。
更进一步地，所述抗氧化剂为亚硫酸氢钠。
本发明还提供了一种前述注射剂的制备方法，它包括如下步骤：
1)按前述配比称取原料；
2)原料溶解于注射用水，过滤除菌，冷冻干燥，即得。
进一步地，所述冷冻干燥参数为：预冻温度≤-40℃,常压，冻结；一次干燥温度≤-13℃，负压，干燥至制品水线消失；二次干燥温度20～30℃，负压，干燥时间≥2h。
本发明最后提供了一种前述注射剂在制备治疗带状疱疹的药物中的应用。
进一步地，所述药物是对水痘-带状疱疹病毒有抑制作用的药物。
本发明治疗带状疱疹的注射剂，以有效量的绿原酸为活性成分，添加一定剂量范围内药学上可接受的辅料或者辅助性成分制备的药剂，通过注射给药，能够有效治疗带状疱疹，为临床上带状疱疹的治疗提供一种新的，安全性高的选择，具有良好的应用前景。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
实施例1 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇400g、亚硫酸氢钠10g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例2 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇400g、亚硫酸氢钠20g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例3 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇400g、亚硫酸氢钠40g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例4 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇800g、亚硫酸氢钠10g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例5 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇800g、亚硫酸氢钠20g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例6 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇800g、亚硫酸氢钠40g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例7 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇1200g、亚硫酸氢钠10g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例8 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇1200g、亚硫酸氢钠20g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例9 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇1200g、亚硫酸氢钠40g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
实施例10 本发明药物注射制剂的制备
处方：绿原酸300g、甘露醇1200g、亚硫酸氢钠30g。
制备方法：按照处方称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得冻干粉针剂。
以下通过试验例来说明本发明的有益效果。
试验例1 药物注射制剂中填充剂筛选
1.材料
制剂处方各成分配比：
制剂处方1：绿原酸、甘露醇、亚硫酸氢钠(30:20:2)；
制剂处方2：绿原酸、甘露醇、亚硫酸氢钠(30:40:2)；
制剂处方3：绿原酸、甘露醇、亚硫酸氢钠(30:80:2)；
制剂处方4：绿原酸、甘露醇、亚硫酸氢钠(30:120:2)；
制剂处方5：绿原酸、甘露醇、亚硫酸氢钠(30:160:2)。
按以上处方配比称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得绿原酸标示量为30mg/支的冻干粉针剂。
2.试验方案
称取各上述冻干粉针剂样品适量，照《中国药典》2015年版附录中溶解度实验方法，分别加入定量的纯化水中，温度控制在25±2℃，每隔5分钟强力振摇30秒，观察30分钟内的溶解情况，记录数据，测定数据见表1。
表1 溶解性结果表
Figure PCTCN2021108239-appb-000001
3.实验结果
现有研究报道绿原酸的溶解度为4％，从表1结果可见，制剂处方1在水中的溶解度与绿原酸相当，制剂处方2、3、4在水中的溶解度优于绿原酸，处方5在水中的溶解度弱于绿原酸。说明绿原酸和填充剂甘露醇的配比在30:40～120范围为优选配比。
试验例2 药物注射制剂抗氧化剂筛选
1.材料
1.1制剂处方各成分配比
制剂处方1：绿原酸、甘露醇、亚硫酸氢钠(30:80:0.5)；
制剂处方2：绿原酸、甘露醇、亚硫酸氢钠(30:80:1)；
制剂处方3：绿原酸、甘露醇、亚硫酸氢钠(30:80:2)；
制剂处方4：绿原酸、甘露醇、亚硫酸氢钠(30:80:3)；
制剂处方5：绿原酸、甘露醇、亚硫酸氢钠(30:80:4)。
按以上处方配比称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得绿原酸标示量为30mg/支的冻干粉针剂。
1.2仪器设备
Agilent 1260高效液相色谱仪色谱仪，Sartorius BT 125D十万分之一电子天平
2.试验方案
将各上述冻干粉针剂溶于适量纯化水中，用加热煮沸的方式，采取HPLC法考察绿原酸的含量变化来确定最佳的抗氧剂亚硫酸氢钠的用量。结果见表2。
表2 亚硫酸氢钠对绿原酸溶液稳定性的影响
Figure PCTCN2021108239-appb-000002
3.实验结果
从表2可见，制剂处方1中的绿原酸在高温水溶液中含量减幅较大，稳定性较差；制剂处方2、3、4、5中的绿原酸含量减幅较缓，并随着亚硫酸氢钠含量的增加，绿原酸在高温水溶液中的稳定性较好，因此，绿原酸与亚硫酸氢钠的配比在30:1～4范围为优选配比。
试验例3 本发明药物治疗带状疱疹的动物体内试验
1.材料
1.1受试药物
受试药物1：绿原酸原料药；
受试药物2：注射用绿原酸，处方配比：绿原酸、甘露醇、亚硫酸氢钠(30:40:1)；
受试药物3：注射用绿原酸，处方配比：绿原酸、甘露醇、亚硫酸氢钠(30:80:2)；
受试药物4：注射用绿原酸，处方配比：绿原酸、甘露醇、亚硫酸氢钠(30:120:3)；
受试药物5：绿原酸颗粒剂，处方配比：绿原酸、填充剂(乳糖)、粘合剂(羧甲基纤维素钠)(1000：500：5)；
阳性药物：阿昔洛韦，武汉五景药业有限公司。
以上各注射用绿原酸制剂按处方配比称取绿原酸、甘露醇、亚硫酸氢钠，溶解于注射用水，过滤除菌，冷冻干燥(冷冻干燥条件：预冻：温度≤-40℃,常压，冻结；一次干燥：温度≤-13℃，负压，干燥至制品水线消失；二次干燥：温度20～30℃，负压，干燥时间≥2h)，得绿原酸标示量为30mg/支的冻干粉针剂。
绿原酸颗粒剂，按处方配比称取绿原酸、填充剂、粘合剂混合，制粒，整粒，分装成颗粒剂。
1.2受试病毒株
VZV标准菌株VZV-Ellen：VR-1367，购自美国ATCC公司，在MRC-5细胞中培养生长和传代。
1.3受试动物
BALB/c小鼠：48只，雌雄各半，体重18～22g，购自华西医学中心实验动物管理中心。
2试验方法
2.1实验动物带状疱疹模型的建立
在戊巴比妥钠麻醉下，将小鼠背部按常规方法脱毛、清洁、消毒，在无毛区的中心皮内注射VR-1367病毒株。在麻醉后的睡眠中，小鼠保存在30℃2h。待麻醉结束放置于25℃室温下，于接种24小时后观察表面变化。疱疹观察：长出疱疹且疱疹胀大、变圆，水疱疱壁紧张发亮内亮清澈，以后逐渐浑浊。新水疱群逐渐出现，各水疱群之间皮肤正常。一般情况：感染病毒的动物食欲减少、呼吸减慢、体温升高、活动度减少及粪便减少等。
2.2试验分组
将接种后的小鼠随机分成8组，包括：
(1)阴性对照组：腹腔注射生理盐水，一天一次；
(2)阳性药物组：腹腔注射阿昔洛韦，一天一次，100mg/kg/次；
(3)口服绿原酸原料药组：口服受试药物1，一天一次，30mg/kg/次；
(4)口服绿原酸颗粒组：口服受试药物5，一天一次，30mg/kg/次；
(5)注射给药组1：腹腔注射受试药物2，一天一次，30mg/kg/次；
(6)注射给药组2：腹腔注射受试药物3，一天一次，30mg/kg/次；
(7)注射给药组3：腹腔注射受试药物4，一天一次，30mg/kg/次；
(8)注射给药绿原酸原料药组：腹腔注射受试药物1，一天一次，30mg/kg/次。
2.3抗病毒作用评价
待各试验组痊愈后停止试验，为了定量药物的作用，按S Alenius和B Oberg的方法确立了一个记分系统(见表3)。在给小鼠接种VR-1367株后，接种的区域每天按症状记分1次。疮疹发生时的记分以阿拉伯数字显示。当疱疹开始变干并结痂时，记分改用罗马数字。所有记分均双盲进行，将感染过程中所有的阿拉伯及罗马记分数字加在一起得到累积的记分。并观察各组消肿时间、结痂时间及痊愈时间，对各试验结果进行统计学分析。
表3 小鼠VZV感染的计分系统
Figure PCTCN2021108239-appb-000003
3实验结果
各实验组对带状疱疹的治疗效果如下表。
表4 带状疱疹小鼠治疗观察情况
Figure PCTCN2021108239-appb-000004
Figure PCTCN2021108239-appb-000005
注：*与阴性对照组比较p＜0.01；△与阳性药物组比较p＜0.01。
4结论
由表4可知，(1)口服绿原酸原料药组和口服绿原酸颗粒剂组对带状疱疹治疗效果差，与阴性对照组没有显著性差异；(2)阳性药物组和各绿原酸注射剂组的累积记分均数、消肿时间、结痂时间及痊愈时间与阴性对照组均有显著性差异，但注射给药绿原酸原料药组对带状疱疹治疗效果差，与阴性对照组没有显著性差异，说明绿原酸注射剂组对带状疱疹治疗效果具有特异性；(3)绿原酸注射剂给药组1、组2及组3的累积记分均数与阳性药物组有显著性差异，说明绿原酸注射剂对带状疱疹治疗效果的显著；(4)各绿原酸注射剂组中，注射给药组2的治疗效果最佳，但绿原酸注射剂给药组1、组2及组3之间没有显著性差异，与直接注射给予绿原酸原料药组有显著性差异。
综上，本发明治疗带状疱疹的注射剂，以有效量的绿原酸为活性成分，添加一定剂量范围内药学上可接受的辅料或者辅助性成分制备的药剂，通过注射给药，能够有效治疗带状疱疹，为临床上带状疱疹的治疗提供一种新的，安全性高的选择，具有良好的应用前景。

Claims (10)

  1. 一种治疗带状疱疹的注射剂，其特征在于：其组成包括绿原酸、填充剂和抗氧化剂；所述绿原酸、填充剂和抗氧化剂质量比为30：(20～160)：(0.5～4)。
  2. 根据权利要求1所述的注射剂，其特征在于：所述绿原酸、填充剂和抗氧化剂质量比为30：(40～120)：(1～4)，优选，30：80：2。
  3. 根据权利要求1或2所述的注射剂，其特征在于：所述填充剂为甘露醇或乳糖。
  4. 根据权利要求3所述的注射剂，其特征在于：所述填充剂为甘露醇。
  5. 根据权利要求1或2所述的注射剂，其特征在于：所述抗氧化剂为亚硫酸氢钠、维生素C或焦亚硫酸钠。
  6. 根据权利要求5所述的注射剂，其特征在于：所述抗氧化剂为亚硫酸氢钠。
  7. 一种权利要求1～6任意一项所述注射剂的制备方法，其特征在于，它包括如下步骤：
    1)按权利要求1所述配比称取原料；
    2)原料溶解于注射用水，过滤除菌，冷冻干燥，即得。
  8. 根据权利要求5所述的注射剂，其特征在于：所述冷冻干燥参数为：预冻温度≤-40℃,常压，冻结；一次干燥温度≤-13℃，负压，干燥至制品水线消失；二次干燥温度20～30℃，负压，干燥时间≥2h。
  9. 权利要求1～6任意一项所述注射剂在制备治疗带状疱疹的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于：所述药物是对水痘-带状疱疹病毒有抑制作用的药物。
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