CN1287798C - 长效孕激素注射埋植剂制备方法和应用 - Google Patents
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Abstract
本发明介绍采用PLGA或PLA等生物可降解聚合物为骨架材料，以孕激素——孕三烯酮为模型药物，经溶媒蒸发法，制备可注射微球。微球可经注射于皮下或肌肉，药物可缓释15天以上时间。微球骨架材料在体内可逐渐降解成机体固有小分子物质而排出体外。孕三烯酮微球注射剂除可方便用药外，还可明显减少目前孕三烯酮常规剂型——片剂频繁口服导致的肝肾损害等不良反应。本新剂型经大鼠体内试验表明，可有效治疗子宫内膜异位等症。
Description
技术领域：
本发明涉及一种长效孕激素注射埋植剂制备方法和应用。
背景技术：
孕激素，如孕三烯酮(Gestrinone，R2323，三烯高诺酮，18-甲三烯炔诺酮)原为中等强度的孕激素，具有较强的抗孕激素和抗雌激素活性。实验证明，本品具有抗着床，抗早孕作用，在月经周期早期口服用尚有排卵抑制作用。其抗着床，抗早孕作用与改变宫颈粘液稠度，干扰子宫内膜发育，影响卵子运行速度及拮抗内膜孕酮受体有关。临床原用作探亲避孕药或事后避孕药。
近年国内外临床研究发现，口服某些孕激素，如孕三烯酮尚有治疗子宫内膜异位，子宫肌瘤等症的作用，疗效可靠(①Clin Exp Obstel Gynecol1996，23(4)：198-204)，(②中国医学杂志(台北)1996，58(2)：89-96)，(③Gynecol Obstel Invest 1997，43(3)：192-194)，(④J Med Assoc Thai 1999，82(1)：9-14)。
目前临床孕激素，如孕三烯酮剂型仅为片剂一种，剂量1.5mg，2.5mg。用于子宫内膜异位治疗，每周口服二次，每次2.5mg，一个疗程6个月。频繁给药给患者带来诸多不便。遗忘用药给治疗带来不良影响。更应注意的是，孕激素如孕三烯酮口服，经肝、肾代谢与排泄，长期使用，对人体肝肾有一定损害(陈新谦主编，新编药物学，第十五版，人民卫生出版社，P597)。
发明内容：
本发明需要解决的技术问题是公开一种长效孕激素注射埋植剂的制备方法和应用，以克服现有剂型存在的频繁给药给患者带来诸多不便以及对人体肝肾有一定损害的缺陷。
本发明的技术方案：
本发明的长效孕激素注射埋植剂为微粒、微球、纳米粒或纳米球中的一种，包括有效量的活性成分孕激素和作为骨架材料的生物降解聚合物，微球为直径为10～120微米的圆形实体，孕激素优选的重量百分比含量为1～70％。
所说的孕激素包括孕三烯酮，孕二烯酮(Gestrodene)，诺美孕酮(Nomegestrol)，普美孕酮(Promegestone)，炔诺酮(Norgestrol)，甲地孕酮(Megestrol)，炔诺孕酮(Norgestrel)，左炔诺孕酮(Levonorgestrel)，去氧孕酮(Desogestrol)，诺孕酯(Norgestimate)，炔酮肟(NorehisteroneOxime)，奎孕酮(Quingestanod)或双炔失碳酯(Anordrin)等中的一种，优选孕三烯酮。
所说的生物降解聚合物包括聚丙交酯-乙交酯，聚乳酸，聚乙醇酸，聚已内酯，聚酸酐，聚羟基丁酸酯-羟基戊酸酯共聚物，聚丙烯葡聚糖，聚乳酸-聚乙二醇的一种或一种以上，优选分子量范围从5,000至1,000,000的聚合物，其中所述聚丙交酯-乙交酯单体聚合比例在95∶5～5∶95之间，分子量在10,000-500,000间，聚乳酸分子量在5,000-300,000间。
本发明还涉及治疗有效量的上述制剂和生物相容性好且可降解的载体构成的药物组合物，将上述的制剂采用本领域公知的方法，即可方便地制备成皮下或肌肉注射剂、皮下植入剂如片剂，膜剂，棒剂，丸剂。
本发明的制剂可有效地用于治疗子宫内膜异位和子宫肌瘤等症。本发明长效孕激素微球注射剂的制备方法包括如下步骤：
将孕激素和生物降解聚合物溶解于有机溶媒中，经高速搅拌后，倒入搅拌着的含有助悬剂的水溶液中，制成乳液置于5～40℃的温度条件下，挥去有机溶媒，然后从该混合物中采用常规的方法收集微球，即为本发明的长效孕激素注射制剂。
可降解聚合物在有机溶媒中含量为1～500mg/ml；
所说的有机溶媒包括二氯甲烷，氯仿，乙酸乙酯，乙醚或一种或一种以上；
所说的助悬剂包括聚乙烯醇，CMC，PVP，天然胶体，如明胶，阿拉伯胶等的一种，助悬剂在水溶液中的含量为1～50mg/ml；
含有孕激素和生物降解聚合物的有机溶媒与含有助悬剂的水溶液的体积比为1∶1～500(v/v)。
本发明的制剂的使用方法为：将含有助悬剂的无菌水溶液注入所制备的微球中，混合振摇后，即可注射在皮下或肌肉内，剂量按不同药物制剂说明书标示量处理。
治疗子宫内膜异位，子宫肌瘤等症状可在起码15天间隔以上给予需要上述治疗的患者。
内包蔽药物可控制释放一段较长时间，骨架材料可自动降解成机体内固有的无毒的小分子物质，最终为机体所吸收。
本注射剂用药后可在体内缓释药物半个月以上时间。可减少患者用药次数，既可方便患者治疗，又减少片剂口服可能导致患者肝肾损害等不良反应。
具体实施方式：
实施例1
取20mg孕三烯酮，80mg聚丙交酯-乙交酯(丙交酯∶乙交酯＝75∶25)，溶解于3ml二氯甲烷中，在剧烈搅拌下(1000rpm)下将其滴入100ml 0.2％羧甲基纤维钠水溶液中，滴完后继续搅拌5-10分钟，然后降低搅拌速度至300rpm，于25℃蒸发约12h，离心，倒去上清液，沉淀经减压过滤，少量蒸馏水淋洗沉淀，室温减压干燥，微球直径40～120μm。
实施例2
取20mg孕三烯酮，80mg聚乳酸，溶解于1ml二氯甲烷中，在高速匀浆器内，加入5ml 0.5％PVA水溶液，以6000rpm转速剧烈搅拌2min，倒入100ml 0.5％PVA水溶液中，以300rpm于25℃蒸发约12h，离心，倒去上清液，沉淀经减压过滤，少量蒸馏水淋洗沉淀，室温减压干燥，微球直径30～80μm。
实施例3
大鼠动情周期的抑制试验：
方法：选择动情周期规则的大鼠分为2组，在大鼠的阴道分泌物图片显示动情后期(白细胞)的当天分别给予下列相应注射：
阴性对照组：皮下(s.c.)注射赋形剂(n＝5)。
实施例1的微球组：单剂量s.c.注射释药速度为0.5mg/周/kg的微球，粒径40～120μm，微球孕三烯酮含量25％(n＝5)。
注射后，每天定时观察记录阴道细胞涂片，大鼠阴道片持续显示白细胞，说明动情周期被抑制，如出现角质化细胞，则表明动情周期开始恢复，用阴道涂片方法可判断制剂药效持续时间。
结果：大鼠s.c.注射单剂量微球0.5mg/周/kg后，五只大鼠阴道涂片分别在15天，16天，16天，15天，15天内始终出现白细胞，随后出现园细胞和角化细胞。说明其动情周期被持续抑制了15天。阴性对照组未被抑制。
实施例4
大鼠子宫内膜异位疗效：
方法：参照Jones方法(Acta Endocrinol 1984，106：282-88)。用外科自体移植术建立子宫内膜异位的大鼠模型，将雌性大鼠子宫的一角剪下，移植至腹腔壁上。四周后，再次打开腹腔检查异位内膜生长状况。抑制处异位内膜生长良好且有黄色液体内容物者为模型建立成功者，测量体积后将动物随机分组进行以下处理：
阴性对照组：大鼠背部每天s.c.注射生理盐水(分10组，每组n＝3)。实施例2的微球组：大鼠背部一次性s.c.注射微球，剂量为0.5mg/周/kg，粒径30～80μm，微球孕三烯酮含量25％(分10组，每组n＝3)。
第2周末，麻醉处死大鼠，打开腹腔，测量异位内膜体积，计算抑制率。
抑制率％＝(1-V2/V1)×100％
V1：治疗前移植体积(mm2)
V2：治疗后移植体积(mm2)
其结果见表1。
从实验结果可见，阴性对照组注射前后体积分别从61.52增至63.15，抑制率为-2.65％，微球组注射后体积分别从49.80减至20.17，抑制率为59.50％，两者存在显著性差异(p＜0.05)，且用药后体重未见增加现象。
表1、孕三烯酮微球注射剂对大鼠子宫内膜异位抑制试验结果
| 组别 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
| 空对组 | 5.45 | 4.45 | 5.22 | 4.95 | 6.29 | 7.00 | 2.82 | 3.02 | 7.69 | 3.88 | 平均值 | SD | P值 |
| 5.01 | 4.42 | 5.14 | 5.04 | 4.72 | 5.27 | 2.83 | 3.02 | 6.89 | 2.88 | ||||
| 1.69 | 2.36 | 2.21 | 2.56 | 2.07 | 2.90 | 2.16 | 1.64 | 3.32 | 2.05 | ||||
| 药前体积 | 46.14 | 46.42 | 59.30 | 63.87 | 61.46 | 106.98 | 17.24 | 14.96 | 175.91 | 22.91 | 61.52 | 48.59 | |
| 2.82 | 3.78 | 6.21 | 3.72 | 5.29 | 7.19 | 5.94 | 5.22 | 4.87 | 5.99 | ||||
| 2.89 | 4.36 | 6.21 | 4.99 | 4.99 | 6.78 | 5.14 | 5.09 | 5.76 | 5.37 | ||||
| 1.09 | 4.36 | 1.62 | 1.00 | 3.36 | 2.89 | 2.94 | 2.05 | 1.19 | 1.94 | ||||
| 药后体积 | 8.88 | 71.86 | 62.47 | 18.56 | 88.69 | 140.88 | 89.94 | 54.47 | 33.38 | 62.40 | 63.15 | 38.56 | |
| 体积系数 | 0.19 | 1.55 | 1.05 | 0.29 | 1.44 | 1.32 | 5.22 | 3.64 | 0.19 | 2.72 | 1.76 | 1.64 | |
| 体重 | 246.60 | 249.30 | 251.10 | 266.60 | 215.00 | 276.70 | 267.60 | 240.40 | 274.40 | 258.50 | 254.62 | 18.51 | |
| R2323组 | 5.71 | 5.99 | 5.08 | 5.69 | 6.40 | 5.44 | 6.10 | 3.90 | 4.60 | 4.79 | 平均值 | SD | P值 |
| 5.38 | 5.99 | 5.09 | 5.49 | 5.69 | 3.53 | 6.18 | 3.90 | 6.34 | 5.12 | ||||
| 0.97 | 2.60 | 1.50 | 0.80 | 1.73 | 2.64 | 2.30 | 1.68 | 2.44 | 0.57 | ||||
| 药前体积 | 29.80 | 93.29 | 38.79 | 24.99 | 63.00 | 50.70 | 86.71 | 25.55 | 71.16 | 13.98 | 49.80 | 27.67 | |
| 4.15 | 4.45 | 5.78 | 4.58 | 3.83 | 3.48 | 4.59 | 3.63 | 5.92 | 3.13 | ||||
| 4.15 | 3.35 | 5.12 | 4.88 | 4.18 | 3.45 | 4.58 | 3.60 | 5.32 | 4.20 | ||||
| 0.23 | 0.85 | 1.27 | 0.80 | 0.76 | 0.73 | 0.50 | 0.63 | 2.63 | 0.54 | ||||
| 药后体积 | 3.96 | 12.67 | 37.58 | 17.88 | 12.17 | 8.76 | 10.51 | 8.23 | 82.83 | 7.10 | 20.17 | 23.93 | |
| 体积系数 | 0.13 | 0.14 | 0.97 | 0.72 | 0.19 | 0.17 | 0.12 | 0.32 | 1.16 | 0.51 | 0.44 | 0.38 | 0.0238029 |
| 体重 | 202.30 | 226.40 | 228.20 | 233.20 | 250.40 | 256.50 | 238.20 | 223.60 | 258.80 | 226.70 | 234.43 | 17.21 |
Claims (6)
1、一种孕激素注射埋植剂，其特征在于，包括活性成分孕激素和作为骨架材料的生物降解聚合物；
孕激素的重量百分含量为1～70％；所说的孕激素为孕三烯酮；
所说的生物降解聚合物为聚丙交酯-乙交酯，聚丙交酯-乙交酯单体聚合比例为75∶25，分子量为10,000-500,000。
2、根据权利要求1所述的孕激素注射埋植剂，其特征在于，该制剂为微粒，微球，纳米粒或纳米球中的一种。
3、根据权利要求2所述的孕激素注射埋植剂，其特征在于，微球为直径为10～120微米的圆形实体。
4、制备权利要求3所述孕激素注射埋植剂的方法，其特征在于包括如下步骤：将孕激素和生物降解聚合物溶解于有机溶媒中，倒入搅拌着的含有助悬剂的水溶液中，制成水包油乳液，挥去有机溶媒，然后从该混合物中采用常规的方法收集微球，即为本发明的制剂。
5、根据权利要求4所述的制备方法，其特征在于，可降解聚合物在有机溶媒中含量为1～500mg/ml；
所说的有机溶媒选自二氯甲烷、氯仿、乙酸乙酯或乙醚中的一种或一种以上；
所说的助悬剂选自聚乙烯醇、羧甲基纤维素、聚乙烯吡咯烷酮、或天然胶体，助悬剂在水溶液中的含量为1～50mg/ml；
含有孕激素和生物降解聚合物的有机溶媒与含有助悬剂的水溶液的体积比为1∶1～500。
6、根据权利要求1所述的孕激素注射埋植剂在制备治疗子宫内膜异位或子宫肌瘤症状药物中的应用。
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