CN100402020C - 特别用于椎间盘突出治疗的药物制剂 - Google Patents
特别用于椎间盘突出治疗的药物制剂 Download PDFInfo
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Abstract
本发明涉及一种产品，以注射剂药物制剂的形式存在，含有至少一种能提供粘稠制剂的化合物、乙醇和至少一种能使所述制剂不透X射线的化合物以控制其给药和发挥作用。所述制剂尤其对于治疗突出的脊椎间盘有效，而且也能用于已经证明了纯乙醇有效的介入治疗，如对肝细胞肿瘤或骨样骨瘤、肾囊肿和动静脉血管瘤进行治疗。
Description
发明领域
本发明涉及一种含有乙醇和不透X射线化合物的、粘稠的、可注射的药物制剂。
该制剂尤其但不唯独用于间盘突出的治疗，还用于已经发现纯乙醇有效的介入手术：对肝细胞肿瘤或骨样骨瘤、肾囊肿和动静脉血管瘤的治疗是有效的。
发明背景
间盘突出是引起背痛和坐骨神经痛的主要原因。它们通常涉及多个人类环境改造学和解剖学因素，例如姿势不正确、腹部和脊柱两侧肌肉衰弱等。
在很多情况下，传统治疗和外科治疗是选择的疗法。然而，对于某些具有明确的临床和放射线学标准的患者来说，可以进行经皮治疗。
通过注射一种酶、木瓜凝乳蛋白酶(核溶解(nucleolysis)：椎间盘的酶改造)来经皮治疗腰椎间盘突出的效果是得到了公认的。然而，有过敏史的患者或已经接受过核溶解治疗的患者不能利用这一方法。
由于乙醇使生物组织发生坏死的效果，纯乙醇(无水乙醇)已经在很多介入手术，例如神经节和神经硬化；肝肿瘤和肾肿瘤部分切除；脊椎肿瘤的手术前治疗；动静脉、外周、内脏和脑畸形等中用作有效的治疗剂。
最近，一个团队考虑将这种治疗性质用在背部疾病的治疗中。他们用纯乙醇对腰椎间盘突出进行间盘内注射，取得了很有希望的结果。这种经皮手术有很多优点：
-没有过敏并发症，
-没有局部腐败并发症，
-治疗后疼痛少，
-间盘间空隙不收缩，
-没有炎症并发症，
-临床痊愈时间缩短。
尽管如此，由于乙醇的性质，它能在离靶位的一定距离内扩散，引起健康细胞坏死。这就是为什么这个团队使用纯乙醇进行间盘突出治疗时，椎间盘造影术显示出治疗不当造成硬膜外渗漏，就像颈间盘突出治疗所渗漏的那样。
而且，由于产品扩散到静脉系统，使用乙醇治疗肝细胞肿瘤会引起门静脉血栓形成。
发明内容
申请人的一个目的是避免乙醇在这种疾病治疗中的副作用，换句话说，避免健康组织坏死，这通常发生在离靶位的一定距离内扩散以后，以及增强乙醇的效力。
为此，申请人试验了数种增稠剂，最后，主张一种可注射的药物制剂，它包含至少一种用于使制剂粘稠的化合物、乙醇和至少一种使所述制剂不透X射线的化合物以控制其给药和起作用。
有利地，粘性限制制剂扩散到特定的区域，增强了它的治疗效果。
因此，该制剂具有双重优点：提供可受限扩散的活性成分，提供使治疗学家进行手术时可以更好地监控注射的指示剂，最重要的是，在扫描仪的帮助下，治疗后监控注射产品的确切位置。
用于使制剂不透X射线的化合物可以是惰性化合物，如氧化钨或氧化钽。
这些化合物可以例如以粉末的形式在制剂制造过程的最后加入，也可以在注射前立即加入。
选择乙基纤维素作为用于实现所需粘度的化合物(赋形剂)。该选择基于几项标准：
-它的亲水性，假定制剂用于注射；
-它的增稠能力，即使只存在很少量，也要足以增加混合物的粘度；
-纤维素衍生物在体外是水溶性的，因此避免需要对治疗部位进行外科切除；
-为了不稀释乙醇，它应是粉末形式而不是液体形式；
-在乙醇中要有适当的溶解度，以获得均一的制剂；
-为了不必破坏对该制剂的耐受性，全身毒性和/或局部毒性要降到最低，优选不存在毒性。
因此，本发明的制剂满足需要的标准--使用过程的所有阶段都是安全的，能产生稳定的和选择性的硬化。
本发明的一个实施方式，并不作为限制，将在下文进行描述：
附图说明
图1代表的是用药物单位表示的粘度度量是浓度(用乙基纤维素重量相对于总重量的百分数表示)的函数；
图2代表的是用药物单位表示的粘度度量是温度(用摄氏度表示)的函数。
具体实施方式
用在制剂中的赋形剂的选择
选择欧洲药典第3版(1999)登记的、符合上述标准的六个产品作为赋形剂进行评价(表I)。测试每个产品在热/冷乙醇中的溶解度。另外，还要检查物质相互之间的物理-化学相容性(视觉评价)和混合物的大概粘度。
表I：用于凝胶制备所试验的产品
各种试验的结果总结在表II中。所有试验产品在热乙醇中都是可溶的。只有乙基纤维素或多或少还溶于冷乙醇中。此外，混合物的物理-化学相容性(没有沉淀)都很好，粘度也令人满意。这就是为什么乙基纤维素被认为是最合适的产品。
表II：试验产品的特性
制剂的制备
将0.15、0.45和0.75g乙基纤维素溶解在纯度为70到99％体积、优选95％体积(d＝0.8)的15mL乙醇中，制备含有不同浓度乙基纤维素的几种制剂，也就是说，按重量计占制剂总重量的1.22、3.61和5.88％。
选择乙基纤维素浓度最高的制剂。观察到2.5％分布在瓶子上的损失，那是205mL 95°乙醇(％体积)和10.25g乙基纤维素在每40个瓶子中的比例。*
通常地，乙基纤维素的使用浓度按重量计是制剂总重量的0.5到15％，优选5.88％。
依照药品生产质量管理规范(1998)，按三个阶段制造制剂：凝胶制备、无菌分装和最后包装的产品的灭菌。刚开始，在无菌的圆形玻璃颈烧瓶中通过磁力搅拌将赋形剂(乙基纤维素)与热乙醇混和并回流至完全溶解。混合物被搅拌并回流15分钟，然后搅拌直至它完全冷却，以使乙醇在烧瓶中浓缩。然后在水平层流通风橱中将它分装到5mL的灭菌瓶(bioblock 42065)中。最后，依照欧洲药典的建议，在高压灭菌器中用121℃的饱和水蒸汽灭菌20分钟。
制剂制造过程的最后一步是按不同比例加入使制剂不透明的粉末状化合物如氧化钽或氧化钨，并以获得良好的不透明性。可以在制造过程的最后、包装以前加入或仅仅在注射前加入。
由于这些化合物是惰性的，以很小的量使用，它们没有显著地改变下述试验的结果，在加入之前对制剂进行试验。
进行的试验
依据无菌试验和化学及物理化学试验证实制剂的一致性。
依照欧洲药典的建议，将4mL制剂在250mL tryticase-大豆肉汤中培养来调查任何可能存在的污染物，如需氧菌，在thioglycate中培养来调查厌氧菌，在Sabouraud中培养来调查酵母菌。
无菌试验的结果证实制剂中不存在任何污染物。
样品稀释以后，掺入内标丙醇-1，通过气相色谱法用火焰电离检测来测定乙醇含量。用Porapak Q柱(80-100目，长度3m)、用氮气作为载气(1.2bar)、在Delsi DN200装置上进行分离。
乙醇分析值为802g·L-1。
不进行粘性添加剂的特殊分析，而是用干燥残渣法(在槽中蒸发乙醇，保持温度在110℃，直至样品达到恒重的方法)估计浓度。
干燥残渣法使得乙基纤维素的理论浓度和实验测量浓度之间有相关性，更确切的说，按重量计占样品总重量的5.88％。
用Baum é毛细管粘度计(Prolabo)测量制剂粘度。在不同温度下、不同的增稠剂浓度下进行一系列测量。粘度测量显示，在恒温下，作为乙基纤维素含量的函数，制剂粘度成指数地增加(图1)。然而，当温度增加时，它也成指数地降低(图2)。
最后，通过分析用参数定义的制剂，换句话说，粘度、乙醇含量和粘度剂随时间变化的函数，进行物理-化学稳定性研究。在第1天(D1)、第8天(D8)、第15天(D15)和第30天(D30)重复进行测量。
结果在表III中给出。变异系数低于3％证明了混合物直到D30都是稳定的，这也允许制剂的有效期能被测定。
表III：物理-化学参数对时间的函数
| 数据 | C<sub>乙醇</sub>(g·L<sup>-1</sup>) | V<sub>éch</sub>(mL) | W<sub>ech</sub>(g) | D<sub>ech</sub>(g·mL<sup>-1</sup>) | 干燥残渣DR(g) | DR/W<sub>ech</sub>比率(％) | 粘度(cp)* |
| D1 | 784 | 2 | 1.650 | 0.825 | 0.101 | 6.10 | 320 |
| D8 | 821 | 2 | 1.720 | 0.850 | 0.103 | 5.97 | 339.5 |
| D15 | 783 | 2 | 1.610 | 0.800 | 0.097 | 6.00 | - |
| D30 | 820 | 2 | 1.670 | 0.830 | 0.099 | 5.92 | 332 |
| 平均 | 802 | - | 1.663 | 0.826 | 0.100 | 5.998 | 330.5 |
| 标准偏差 | 21.370 | - | 0.046 | 0.021 | 0.002 | 0.076 | 9.836 |
| 变异系数 | 2.665 | - | 2.751 | 2.489 | 2.458 | 1.265 | 2.976 |
*cp：药学单位
将制剂注射到腰椎间盘导致降低的间盘内压力，从而减轻了由间盘突出引起的背痛。
Claims (6)
1.用于治疗椎间盘突出的粘稠的可注射制剂，其特征在于其含有至少一种浓度为制剂总重量的0.5-15％重量的乙基纤维素、纯度为70％-90％体积的乙醇和极少量至少一种能使所述制剂不透X射线的化合物，使得乙醇浓度实质上为制剂总重量的94.12％-98.78％，所述乙基纤维素用于提供粘稠制剂并在冷乙醇中是可溶解的。
2.根据权利要求1的制剂，其特征在于所述纤维素衍生物的使用浓度按重量计占制剂总重量的5.88％。
3.根据权利要求1的制剂，其特征在于所述的使所述制剂不透X射线的化合物是惰性化合物。
4.根据权利要求3的制剂，其特征在于所述的使所述制剂不透X射线的化合物是氧化钽。
5.根据权利要求3的制剂，其特征在于所述的使所述制剂不透X射线的化合物是氧化钨。
6.根据权利要求1的制剂，其特征在于所述乙醇的纯度是95％体积。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR02/05819 | 2002-05-07 | ||
| FR0205819A FR2839450B1 (fr) | 2002-05-07 | 2002-05-07 | Preparation medicamenteuse notamment pour le traitement des hernies discales |
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| Publication Number | Publication Date |
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| CN1665546A CN1665546A (zh) | 2005-09-07 |
| CN100402020C true CN100402020C (zh) | 2008-07-16 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB038129361A Expired - Fee Related CN100402020C (zh) | 2002-05-07 | 2003-05-07 | 特别用于椎间盘突出治疗的药物制剂 |
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| Country | Link |
|---|---|
| US (3) | US20070116647A1 (zh) |
| EP (1) | EP1503803B1 (zh) |
| CN (1) | CN100402020C (zh) |
| AT (1) | ATE402719T1 (zh) |
| AU (1) | AU2003262617A1 (zh) |
| CA (1) | CA2498976C (zh) |
| CY (1) | CY1108413T1 (zh) |
| DE (1) | DE60322530D1 (zh) |
| DK (1) | DK1503803T3 (zh) |
| ES (1) | ES2309334T3 (zh) |
| FR (1) | FR2839450B1 (zh) |
| HK (1) | HK1081849A1 (zh) |
| PT (1) | PT1503803E (zh) |
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| WO (1) | WO2003097108A1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2839450B1 (fr) * | 2002-05-07 | 2006-04-07 | Aboville Marc D | Preparation medicamenteuse notamment pour le traitement des hernies discales |
| FR2891461B1 (fr) * | 2005-09-30 | 2010-09-03 | Jacques Theron | Preparation medicamenteuse visqueuse injectable comprenant de l'ethanol et un compose liposoluble opaque aux rayons x. |
| EP3679140B1 (en) | 2017-09-08 | 2022-11-16 | MiNA Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
| TW201920669A (zh) | 2017-09-08 | 2019-06-01 | 英商美納治療公司 | ＨＮＦ４ａ ｓａＲＮＡ組成物和使用方法 |
| EP4017539A1 (en) | 2019-08-19 | 2022-06-29 | MiNA Therapeutics Limited | Oligonucleotide conjugate compositions and methods of use |
| CN117222405A (zh) * | 2021-03-04 | 2023-12-12 | 苏州医本生命科技有限公司 | 一种含乙醇的药物组合物及其用途 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071170A1 (en) * | 1999-05-21 | 2000-11-30 | Micro Therapeutics, Inc. | Novel high viscosity embolizing compositions |
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| US2162028A (en) * | 1938-06-25 | 1939-06-13 | Pittsburgh Plate Glass Co | Cellulose ether coating composition |
| US2903396A (en) * | 1957-05-08 | 1959-09-08 | Ciba Pharm Prod Inc | Therapeutic compositions and method for treating parkinsonism |
| EP0304403A3 (de) * | 1987-08-21 | 1990-12-12 | Ciba-Geigy Ag | Kunststoffzusammensetzung mit Supraleitern |
| JPH02157029A (ja) * | 1988-12-09 | 1990-06-15 | Dainippon Pharmaceut Co Ltd | アニオン系界面活性剤含有組成物の安定化 |
| US5830178A (en) * | 1996-10-11 | 1998-11-03 | Micro Therapeutics, Inc. | Methods for embolizing vascular sites with an emboilizing composition comprising dimethylsulfoxide |
| US6476070B2 (en) * | 1997-09-11 | 2002-11-05 | Provasis Therapeutics Inc. | Compositions useful for remodeling body spaces |
| US6015541A (en) * | 1997-11-03 | 2000-01-18 | Micro Therapeutics, Inc. | Radioactive embolizing compositions |
| US6150022A (en) * | 1998-12-07 | 2000-11-21 | Flex Products, Inc. | Bright metal flake based pigments |
| EP1180051A4 (en) * | 1999-05-21 | 2004-06-30 | Micro Therapeutics Inc | METHODS FOR EMBOLIZING BLOOD VESSELS WITH AN EMBOLIZING CONNECTION |
| US6355058B1 (en) * | 1999-12-30 | 2002-03-12 | Advanced Cardiovascular Systems, Inc. | Stent with radiopaque coating consisting of particles in a binder |
| US20020115904A1 (en) * | 2001-02-21 | 2002-08-22 | Brooke Ren | Magnetically controllable embolic materials |
| FR2839450B1 (fr) * | 2002-05-07 | 2006-04-07 | Aboville Marc D | Preparation medicamenteuse notamment pour le traitement des hernies discales |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000071170A1 (en) * | 1999-05-21 | 2000-11-30 | Micro Therapeutics, Inc. | Novel high viscosity embolizing compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1665546A (zh) | 2005-09-07 |
| US20130143970A1 (en) | 2013-06-06 |
| FR2839450A1 (fr) | 2003-11-14 |
| WO2003097108A1 (fr) | 2003-11-27 |
| CA2498976A1 (fr) | 2003-11-27 |
| CY1108413T1 (el) | 2014-02-12 |
| DK1503803T3 (da) | 2008-11-10 |
| EP1503803A1 (fr) | 2005-02-09 |
| EP1503803B1 (fr) | 2008-07-30 |
| FR2839450B1 (fr) | 2006-04-07 |
| ATE402719T1 (de) | 2008-08-15 |
| CA2498976C (fr) | 2011-09-06 |
| US20070116647A1 (en) | 2007-05-24 |
| HK1081849A1 (en) | 2006-05-26 |
| DE60322530D1 (de) | 2008-09-11 |
| ES2309334T3 (es) | 2008-12-16 |
| PT1503803E (pt) | 2008-10-16 |
| AU2003262617A1 (en) | 2003-12-02 |
| US20100329991A1 (en) | 2010-12-30 |
| US8153696B2 (en) | 2012-04-10 |
| SI1503803T1 (sl) | 2008-12-31 |
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