CN1687141A - 硫酸软骨素银及其治疗烧烫伤的应用 - Google Patents
硫酸软骨素银及其治疗烧烫伤的应用 Download PDFInfo
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Abstract
本发明包括一种硫酸软骨素银盐的制备方法及使用肝素银制备治疗烧烫伤用途的药物。硫酸软骨素银制备方法：在水溶液中使用硝酸银对可溶性硫酸软骨素盐进行离子置换，经浓缩，过滤，纯化，干燥等步骤得产品，其中银离子含量19％～33％，钠离子含量小于0.5％，硝酸根含量小于100ppm。应用硫酸软骨素银制备治疗烧烫伤的药物，经动物试验证明，其具有加快伤口愈合和减少瘢痕形成的作用。
Description
技术领域
本发明属于医疗技术领域，涉及硫酸软骨素银盐的制备方法及使用硫酸软骨素银制备治疗烧烫伤用途的药物。
背景技术
硫酸软骨素来源于动物组织，是一类硫酸糖胺聚糖，由糖醛酸和葡萄糖胺以糖苷键连接起来的重复二糖单位组成的多糖链的混合物，由D-葡萄糖醛酸和N-乙酰-D-氨基半乳糖组成二糖单位的多糖，其中由于硫酸基团位置不同，构成硫酸软骨素A、C、D、E、F和N等多种异构体，由艾杜糖醛酸和N-乙酰-D-氨基半乳糖硫酸酯组成二糖单位的多糖称为硫酸软骨素B，又称为硫酸皮肤素。硫酸软骨素分子量在2000～50000道尔顿之间，目前上市的产品为硫酸软骨素钠或硫酸软骨素钙的注射液、口服制剂和滴眼剂，临床主要用于治疗高血脂症、某些神经性头痛、神经痛、关节痛、冠心病、偏头痛、动脉粥样硬化等症及链霉素引起的听觉障碍及慢性肾炎、慢性肝炎、角膜炎以及角膜溃疡等的辅助治疗，此外还应用于化妆品、外伤创面的愈合剂和保健品，鲨鱼软骨中的软骨素还有抗肿瘤的作用。实验表明，皮肤创面使用硫酸软骨素可以改善血液循环，加速新陈代谢，促进渗出液的吸收及炎症的消除，鲜见不良反应发生。银盐应用于皮肤创面又具有收敛作用，可促进使创面干燥、结痂和早期愈合，硫酸软骨素银应用于烧烫伤创面，集硫酸软骨素和银盐的作用于一体，可明显加快愈合速度，减少感染和炎症发生，改善创面愈合质量。目前，硫酸软骨素的钠盐、钾盐、锌盐和钙盐的制备及应用已有资料公开报道，如专利CN96116057.8、JP01117812、US5696169和CN1296979等，而硫酸软骨素银盐的制备方法和应用，以及用于治疗烧烫伤的硫酸软骨素银的制剂还未见资料公开报道。
发明内容
本发明的目的是提供一种硫酸软骨素银盐的制备方法，和使用该方法制得的硫酸软骨素银制备治疗烧烫伤药物的应用。经动物试验证明，硫酸软骨素银用于烧烫伤的治疗，具有明显加快愈合速度、减少感染和炎症发生、改善创面愈合质量等作用。
本发明中硫酸软骨素银的制备方法如下：
①将可溶性硫酸软骨素盐溶于去离子水中，制得硫酸软骨素盐溶液；
②在步骤①得到的溶液中加入硝酸银，搅拌溶解；
③将步骤②得到的溶液进行减压浓缩，使硫酸软骨素银发生沉淀，过滤，收集沉淀；
④将步骤③得到的沉淀溶解于去离子水中，采用透析或超滤的方法进行纯化；
⑤将步骤④得到的溶液进行减压浓缩，制得硫酸软骨素银浓缩液；
⑥将步骤⑤得到的浓缩液进行冷冻干燥，或加入乙醇脱水，收集沉淀，常规减压干燥制得成品。
上述硫酸软骨素银的制备方法中，可溶性硫酸软骨素盐可以使用硫酸软骨素钠、硫酸软骨素钾、硫酸软骨素钙或硫酸软骨素锌。
上述硫酸软骨素银的制备方法中，硝酸银的加入量可以是溶液中可溶性硫酸软骨素盐重量的100％～500％。
上述硫酸软骨素银的制备方法中，步骤⑥中可以用丙酮或甲醇代替乙醇对浓缩液进行脱水。
硫酸软骨素盐的制备和提取一般使用乙醇、甲醇、丙酮等有机溶剂进行沉淀、脱水和干燥，在本发明硫酸软骨素银制备方法中，反应原料采用溶解度较高的硝酸银，在反应液中可以提供足够多的游离银离子，有利于硫酸软骨素银的生成和沉淀，同时由于反应液中存在大量的硝酸根离子，加入乙醇、甲醇、丙酮等有机溶剂则生成易爆的雷酸， 因此不能直接使用它们进行沉淀和脱水，本发明采用浓缩方法，使溶解度较小的硫酸软骨素银沉淀，过滤，滤液回收可以重复利用，所得沉淀再溶于去离子水中，使用透析或超滤的方法，除去沉淀中的杂质(包括残余的钠离子、吸附的银离子和硝酸根离子)之后，再次减压浓缩，使用乙醇脱水或冷冻干燥。
采用上述方法生产的硫酸软骨素银，产品纯度高、杂质含量少，其中银离子含量19％～33％，钠离子含量小于0.5％，硝酸根含量小于100ppm。
采用本发明制备的硫酸软骨素银经粉碎、灭菌之后，可以直接用于烧烫伤创面，也可以与其它药物和常用辅料组方，制成烧烫伤药物制剂施用于烧烫伤创面，达到加快愈合速度、减少感染和炎症发生、改善创面愈合质量等目的。
发明实施例：
实施例1：
将0.3公斤硫酸软骨素钠溶于10升去离子水中溶解，以下步骤在避光条件下操作：加入1公斤硝酸银，室温搅拌反应2小时，35℃～40℃减压浓缩至反应液体积约3升，用0.8微米的微孔滤膜过滤反应液，滤液保留用于回收，沉淀物溶解于0.3升去离子水中，搅拌溶解，用截断分子量2000的透析膜，去离子水流水透析24小时以上，再减压浓缩至溶液体积约0.2升，冷冻干燥后即得产物。将产物粉碎，过200目筛，用透气纸包装，环氧乙烷灭菌后，再用双层塑料袋包装，得成品。
实施例2：
将0.3公斤硫酸软骨素钠溶于10升去离子水中溶解，以下步骤在避光条件下操作：加入1公斤硝酸银，室温搅拌反应2小时，35℃～40℃减压浓缩至反应液体积约3升，用0.8微米的微孔滤膜过滤反应液，滤液保留用于回收，沉淀物溶解于0.5升去离子水中，搅拌溶解，使用截断分子量1800的超滤膜进行超滤，超滤过程中溶液体积减少至0.4升时，补加去离子水0.1升，补加3次后超滤至溶液体积约0.3升，再减压浓缩至溶液体积约0.2升，4倍乙醇脱水，过滤，沉淀于35℃～40℃真空干燥，即得产物。将产物于无菌环境用双层塑料袋包装，得成品。
硫酸软骨素银应用于烧烫伤治疗的动物实验：
①增生性瘢痕动物模型
在新西兰白兔兔耳腹面手术切除2cm×5cm全层皮肤缺损创面，作长期瘢痕模型〔具体操作方法参考Morris(1997)Acute and chronic animal models for excessive dermalscarring：quantitative studies〕。对照组创面用磺胺嘧啶银散剂外敷包扎至痊愈，换药1次/周，试验组创面用硫酸软骨素银散剂(本发明实施例1)外敷包扎至痊愈，亦换药1次/周。术后12个月内观察创面愈合情况，愈合标准为痂壳小于创面的5％。取瘢痕组织作Masson染色，光学显微镜下观察并测定创面上皮化后的真皮厚度(Da)及邻近正常组织中的真皮厚度(Db)，计算瘢痕指数＝(Da-Db)/Db。结果见下表。组别 对照组 试验组创面愈合时间(天) 26.5±2.59(n＝6) 22.9±2.74(n＝6)*瘢痕指数60天 2.83±0.46(n＝6) 2.97±0.27(n＝6)
180天 3.46±0.76(n＝6) 2.68±0.77n＝6)*
*与对照组比较，差异有显著性(p＜0.05)。
②烧伤动物模型
大鼠5％水合氯醛腹腔麻醉后背部脱毛，90℃水蒸气烫10秒，造成20％面积的深二度烫伤〔具体操作方法参考陆树良主编(2003)烧伤创面愈合机制与新技术〕，伤后1小时腹腔注射生理盐水1mL补充血容量。对照组创面涂磺胺嘧啶银散剂至痊愈，厚度0.5～1mm，换药1次/日，试验组创面涂硫酸软骨素银散剂(本发明实施例1)至痊愈，厚度0.5～1mm，亦换药1次/日。伤后间隔时间取样，用重量法测定创面组织湿重(Ga)和经80℃烘72小时的组织干重(Gb)，计算烧伤创面含水量W＝(Ga-Gb)/Ga×100％，W值表示水肿的程度；用氯胺T氧化法〔参考许志勤(1990)组织羟脯氨酸测定方法的改进〕测定创面羟脯氨酸含量，羟脯氨酸含量反映创面胶原的含量。
结果见下表。
| 组别 | 正常组 | 试验组 | 对照组 | |
| 愈合时间(d) | -- | 22.3±1.8(n＝8)# | 25.0±1.7(n＝8) | |
| 创面羟脯氨酸含量(ug/mL) | 1d2d3d5d7d10d14d21d | 18.37±1.27(n＝5)---------------- | --18.97±1.45(n＝5)20.69±1.89(n＝5)21.95±1.87(n＝5)23.11±2.05(n＝6)23.53±2.34(n＝6)26.59±3.67(n＝6)*#26.78±2.33(n＝6)*23.95±1.98(n＝7)* | --17.65±2.66(n＝5)18.37±2.41(n＝5)18.86±1.92(n＝5)21.71±2.05(n＝5)22.57±2.82(n＝5)22.12±2.65(n＝6)23.94±1.88(n＝6)25.63±2.95(n＝6) |
| 创面含水量(W) | 8h24h48h72h5d7d | 67.28±1.86(n＝5)------------ | --80.42±2.02(n＝6)*71.08±2.17(n＝6)*#70.25±1.76(n＝6)68.68±1.24(n＝5)68.11±2.64(n＝5)67.34±1.89(n＝5) | --80.37±1.56(n＝6)*76.15±3.21(n＝6)*72.23±2.37(n＝6)*68.75±2.89(n＝5)68.69±2.18(n＝5)68.05±2.23(n＝5) |
#与对照组比较，差异有显著性p＜0.05
*与正常组比较，差异有显著性p＜0.01。
Claims (7)
1.一种硫酸软骨素银盐的制备方法，其特征在于，该方法包括以下步骤：
①将可溶性硫酸软骨素盐溶于去离子水中，制得硫酸软骨素盐溶液；
②在步骤①得到的溶液中加入硝酸银，搅拌溶解；
③将步骤②得到的溶液进行减压浓缩，使硫酸软骨素银发生沉淀，过滤，收集沉淀；
④将步骤③得到的沉淀溶解于去离子水中，采用透析或超滤的方法进行纯化；
⑤将步骤④得到的溶液进行减压浓缩，制得硫酸软骨素银浓缩液；
⑥将步骤⑤得到的浓缩液进行冷冻干燥，或加入乙醇脱水，收集沉淀，常规减压干燥制得成品。
2.如权利要求1所述的方法，其特征在于，在所述的步骤①中，所述可溶性硫酸软骨素盐为硫酸软骨素钠、硫酸软骨素钾、硫酸软骨素钙或硫酸软骨素锌。
3.如权利要求1或2所述的方法，其特征在于，在所述的步骤②中：加入硝酸银的量为溶液中可溶性硫酸软骨素盐重量的100％～500％。
4.如权利要求1或2所述的方法，其特征在于，在所述步骤⑥中，用丙酮或甲醇代替乙醇对浓缩液进行脱水。
5.如权利要求3所述的方法，其特征在于，在所述步骤⑥中，用丙酮或甲醇代替乙醇对浓缩液进行脱水。
6.上述任意一一项权利要求所述制备方法制得的肝素银。
7.权利要求6所述肝素银在制备治疗烧烫伤药物中的应用。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1878754A4 (en) * | 2005-04-20 | 2012-12-26 | Ling Peixue | PREPARATION AND APPLICATION OF SILVER HEPARINE |
| WO2013121001A1 (en) | 2012-02-17 | 2013-08-22 | Kimflexor, S.L. | Partially depolymerized glycosaminoglycan silver and gold salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1878754A4 (en) * | 2005-04-20 | 2012-12-26 | Ling Peixue | PREPARATION AND APPLICATION OF SILVER HEPARINE |
| US8735363B2 (en) | 2005-04-20 | 2014-05-27 | Peixue Ling | Preparation and application of heparin silver |
| WO2013121001A1 (en) | 2012-02-17 | 2013-08-22 | Kimflexor, S.L. | Partially depolymerized glycosaminoglycan silver and gold salts |
| CN104125964A (zh) * | 2012-02-17 | 2014-10-29 | 金弗莱克瑟有限公司 | 部分解聚的糖胺聚糖银盐和金盐 |
| JP2015507070A (ja) * | 2012-02-17 | 2015-03-05 | キムフレクサー エセ．エレ． | 部分的に解重合したグリコサミノグリカン銀及び金塩 |
| CN104125964B (zh) * | 2012-02-17 | 2016-11-16 | 金弗莱克瑟有限公司 | 部分解聚的糖胺聚糖银盐和金盐 |
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