CN1269846C - 肝素银的制备及其应用 - Google Patents
肝素银的制备及其应用 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
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- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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Abstract
本发明包括一种肝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。肝素银制备方法：在水溶液使用硝酸银对可溶性肝素盐进行离子置换，经浓缩，过滤，纯化，干燥等步骤得产品，其中银离子含量25%～45%，钠离子含量小于0.5%，硝酸根含量小于100ppm。应用肝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，涉及肝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。
背景技术：
肝素来源于动物组织，是一类硫酸糖胺聚糖，结构复杂，其基本骨架是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，其中糖醛酸有艾杜糖醛酸和葡萄糖醛酸，各单糖残基硫酸化和乙酰化情况变化较多，有N-硫酸基、N-乙酰基和不同位置的O-硫酸基(酯)。未分级肝素分子量3000～30000道尔顿，平均分子量12000～15000道尔顿，分子量为3000～8000道尔顿的产品称为低分子肝素。抗凝血和抗血栓是肝素最主要的生理活性，同时有引起血小板减少和出血的副作用，低分子肝素由于抗凝血酶活性降低，在抗血栓形成的同时减少了出血的危险，另外它还有生物利用度高，体内半衰期长等优点，成为目前肝素产品开发的热点。目前上市的肝素产品为肝素钠和肝素钙，有注射液、乳膏和***片等，其它的肝素盐临床还未见使用。肝素应用于临床已有近70年的历史，主要用于抗凝血、防治血栓性疾病及改善局部微循环。动物实验证明，肝素应用于烧伤治疗可以缓解疼痛、抗凝、抑制炎症反应、促进血管再生、恢复局部供血，并能影响胶原的合成和降解，创面愈合后皮肤光滑、减少瘢痕和瘢痕挛缩，还能保护肠道屏障功能，保护及改善肺和肾的功能，提高肌体免疫力，预防感染。众所周知，银盐应用于皮肤创面具有收敛作用，可使创面干燥、结痂和促进愈合。肝素银应用于烧烫伤创面，集肝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。肝素最主要的不良反应是出血，有活动性出血及溃疡、有肝素过敏史或血小板减少、有出血体质等情况为肝素的禁忌症。实验证明，大剂量肝素用于烧伤后早期(缺血、酸中毒期)，每天使用前测凝血时间15～30min为安全范围，烧伤后早期采用局部用药直到创面愈合，未发现明显的抗凝阳性结果。目前，临床皮肤使用的肝素为钠盐，主要用于浅表性静脉炎、静脉曲张性静脉炎、静脉曲张和硬化术后的辅助治疗、血肿、挫伤、肿胀和水肿、血栓性静脉炎，由静脉输液和注射引起的渗出、软组织挫伤、冻疮、皱裂、湿疹、抑制疤痕形成和软化疤痕。然而，肝素银盐的制备方法和应用，以及用于治疗烧烫伤的肝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肝素银盐的制备方法，和使用该方法制得的肝素银制备治疗烧烫伤药物的应用。经动物试验证明，该肝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。
本发明中肝素银的制备方法如下：
①将可溶性肝素盐溶于去离子水中，制得肝素盐溶液；
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，使肝素银发生沉淀，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，制得肝素银浓缩液；
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。
上述肝素银的制备方法中，可溶性肝素盐可以使用肝素钠、肝素钾、肝素钙或肝素锌。
上述肝素银的制备方法中，硝酸银的加入量可以是溶液中可溶性肝素盐重量的150％～600％。
上述肝素银的制备方法中，步骤⑥中可以用丙酮或甲醇代替乙醇对浓缩液进行脱水。
肝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，在本发明肝素银的制备方法中，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，有利于肝素银的生成和沉淀，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，使溶解度较小的肝素银沉淀，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。
采用本发明方法制备生产的肝素银，产品纯度高、杂质含量少，其中银离子含量25％～45％，钠离子含量小于0.5％，硝酸根含量小于100ppm。
采用本发明制备的肝素银经粉碎、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。
具体实施方式：
实施例1：
将0.3公斤肝素钠[平均分子量小于8000Da的重量为60～70％，按中国药监局试行标准WS-487(X-423)-2001规定的方法，照羊血浆法测定抗凝(FIIa)效价，照COATEST试剂盒法测定抗FXa效价，抗FXa活性为抗FIIa活性的2.3倍。]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1.2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3000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公斤肝素钠(平均分子量12000～15000Da，按中国药典2000年版二部附录XIID肝素生物检定法测定，效价为156单位/毫克。)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1.1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2000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，3.5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。
肝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，试验组创面用肝素银散剂(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) | 21.4±2.16(n＝6)* | |
| 瘢痕指数 | 60天 | 2.83±0.46(n＝6) | 2.06±0.83(n＝6) |
| 180天 | 3.46±0.76(n＝6) | 1.85±0.52(n＝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。对照组创面撒涂磺胺嘧啶银散剂至痊愈，厚度0.5～1mm，换药1次/日，试验组创面撒涂肝素银散剂(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) | -- | 21.5±2.2(n＝8)# | 25.0±1.7(n＝8) | |
| 创面羟脯氨酸含量(ug/mL) | 18.37±1.27(n＝5) | -- | -- | |
| 1d | -- | 18.55±2.13(n＝5) | 17.65±2.66(n＝5) | |
| 2d | -- | 20.45±2.12(n＝5) | 18.37±2.41(n＝5) | |
| 3d | -- | 22.04±1.35(n＝5) | 18.86±1.92(n＝5) | |
| 5d | -- | 23.27±2.11(n＝6) | 21.71±2.05(n＝5) | |
| 7d | -- | 23.96±2.54(n＝6) | 22.57±2.82(n＝5) | |
| 10d | -- | 26.87±2.36(n＝6)*# | 22.12±2.65(n＝6) | |
| 14d | -- | 26.91±2.14(n＝6)* | 23.94±1.88(n＝6) | |
| 21d | -- | 24.05±1.74(n＝7)* | 25.63±2.95(n＝6) | |
| 创面含水量(W) | 67.28±1.86(n＝5) | -- | -- | |
| 8h | -- | 80.25±2.78(n＝6)* | 80.37±1.56(n＝6)* | |
| 24h | -- | 70.82±3.56(n＝6)*# | 76.15±3.21(n＝6)* | |
| 48h | -- | 70.16±2.64(n＝6) | 72.23±2.37(n＝6)* | |
| 72h | -- | 68.44±1.32(n＝5) | 68.75±2.89(n＝5) | |
| 5d | -- | 67.61±2.85(n＝5) | 68.69±2.18(n＝5) | |
| 7d | -- | 67.52±1.36(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、一种肝素银盐的制备方法，其特征在于，该方法包括以下步骤：
①将可溶性肝素盐溶于去离子水中，制得肝素盐溶液；
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，使肝素银发生沉淀，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，制得肝素银浓缩液；
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、权利要求1所述的方法，其特征在于，在所述的步骤①中，所述可溶性肝素盐为肝素钠、肝素钾、肝素钙或肝素锌。
3、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肝素盐重量的150％～600％。
4、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、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、上述任一一项权利要求所述制备方法制得的肝素银，其中银离子含量为25％～45％，钠离子含量小于0.5％，硝酸根含量小于100ppm。
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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| PCT/CN2006/000742 WO2006111092A1 (en) | 2005-04-20 | 2006-04-20 | Preparation and application of heparin silver |
| US11/912,123 US8735363B2 (en) | 2005-04-20 | 2006-04-20 | Preparation and application of heparin silver |
| EP06741691.7A EP1878754B1 (en) | 2005-04-20 | 2006-04-20 | Preparation and application of heparin silver |
| JP2008506905A JP5078875B2 (ja) | 2005-04-20 | 2006-04-20 | ヘパリン銀の調製及び用途 |
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| CN100335506C (zh) | 2004-05-20 | 2007-09-05 | 汕头市金丰医疗器械科技有限公司 | 一种肝素化合物及其制备方法和应用 |
| CN1269845C (zh) * | 2005-04-29 | 2006-08-16 | 凌沛学 | 硫酸软骨素银及其治疗烧烫伤的应用 |
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