CN1239436A - 用于将肽药物引入生物体的局部制剂 - Google Patents
用于将肽药物引入生物体的局部制剂 Download PDFInfo
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- CN1239436A CN1239436A CN97180273A CN97180273A CN1239436A CN 1239436 A CN1239436 A CN 1239436A CN 97180273 A CN97180273 A CN 97180273A CN 97180273 A CN97180273 A CN 97180273A CN 1239436 A CN1239436 A CN 1239436A
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Abstract
本发明涉及能通过透皮吸收将肽药物引入生物体的可局部施用的药物制剂。这些制剂包含(i)肽药物，(ii)辣椒素、组胺和/或斑蝥提取物，以及(iii)上皮形成剂，并混合有常用于局部药物制剂的载体和/或稀释剂，其任选被加入到能黏附于皮肤的载体上。
Description
本发明涉及能通过透皮吸收将肽药物引入生物体中的可局部施用的药物制剂。根据本发明的可局部施用的药物制剂可为例如软膏剂、乳油剂、凝胶剂、洗剂、溶液、悬浮液以及在局部治疗中通常使用的类似制剂，其中它们可被任选以在载体中的形式施用至皮肤表面。它们尤其优选的代表为其中可局部施用的制剂被施加到能黏附到皮肤的载体上的那些，即硬膏(膏药)，其中这些载体使得能安全给药并易于处理。
根据对病人的治疗舒适性，可局部施用的药物制剂显然为优选的制剂。与胃肠外制剂相反，如针剂，它的采用是疼痛或至少是不愉快的，并需要医生或护士的帮助，或当自己给药时，病人需要实践和技术，局部制剂甚至可由病人很容易并且无疼痛地给药于治疗部位。对于患有下咽困难或对药物味道厌恶的病人来说，局部制剂也比口服制剂更为优选。局部制剂的一个特有的优点是病人可一看就知道或通过抚摸其皮肤很容易地判断他是否施用了该药物，从而显著降低了疏忽过量给药或给药不足的危险。
尽管有这些优点，可局部施用的制剂被在相当窄的范围内用于医学实践，通常仅用于对外伤以及局部炎症的治疗。这一情况的原因主要在于活性剂吸收的生理特性。为了促使可局部施用的活性剂以适宜浓度到达靶器官，活性剂应不仅透过皮肤而且透过真皮下血管壁。由于其物理结构(多孔性和半透膜性质)，甚至皮肤和血管壁均具有高度限制的渗透性。其它明显的障碍来自所谓角质层的屏障功能，其中后者主要起保护生物免于外源物质接触皮肤的作用。
已研究出一些可成功代替用于引入相关活性剂的口服制剂的局部制剂。其中之一为在匈牙利出售了约15年、商品名为MOTTO(R)的抗风湿膏药，它包含与Unguentum emulsificans(一种包含非离子表面活性剂的乳油，PH.Hg.V.)形成的甲酸(作为抗风湿剂)、水杨酸和任选的缓解疼痛剂的乳剂，其中它被施加到能黏附于皮肤的载体上。NITRODERM(R)，由Ciba-Geigy公司(德国联邦共和国)销售的组合物，包含与甲基或羧甲基纤维素形成的硝基甘油(作为强心剂)的凝胶剂，其中它被施加到能黏附于皮肤的小的聚氨基甲酸乙酯海绵上。SALONPAS(R)，由Hisamitsu药物公司(日本)销售的组合物，包含与聚乙烯醇形成的水杨酸甲酯(作为抗炎剂)和甲醇的大丸块，其中它被施加到能黏附于皮肤的小的聚氨基甲酸乙酯海绵上。这些已知组合物中的活性剂为具有相对低的分子量的强极性物质，因此它们比较高分子量的极性较小的物质具有更多的吸收机会。
肽化合物形成一类重要的药物活性物质。在说明书和权利要求书中，术语“肽化合物”或“肽药物”通常指任何其分子包含至少两个通过肽键连接在一起的氨基酸的药物活性物质。其中一小类具有突出药物重要性的为多肽类，其中天然激素和其人工类似物和衍生物尤其令人感兴趣。从公众健康来看，具有突出重要性的后面一组的一个成员是胰岛素。调节生物体良好平衡的激素和激素类似物是非常危险的物质，因此对于这些物质，尤其需要降低疏忽过量服用或过少服用的危险。激素和激素类似物的一些代表，尤其是胰岛素仅可经胃肠外引入。因此，非常希望能局部将这些活性剂引入生物体。然而，以前没有公开可用于将肽药物引入生物体的局部制剂。
根据研究结果，我发现在使用特定的辅助剂时，可使肽药物成为能透皮吸收的形式。这种认识使得能制备包含肽药物的可局部施用的药物制剂。
因此，本发明涉及用于将肽药物引入生物体的可局部施用的制剂。根据本发明的制剂包含：(i)肽药物，(ii)辣椒素、组胺和/或斑蝥提取物，以及(iii)上皮形成剂，并混合有局部药物制剂中常用的载体和/或稀释剂，其任选被加到能黏附于皮肤的载体上。
根据本发明的制剂可优选包含作为肽药物的天然激素或其合成类似物或其衍生物，尤其优选胰岛素。包含在本发明的制剂单剂(即一次治疗的剂量)中的肽药物的量(如在一个硬膏中)可与存在于常规口服或胃肠外单剂型中的大致相同。因此，例如根据本发明的可用于治疗糖尿病的硬膏可包含0.1-50IU胰岛素/硬膏或一个单位硬膏块(例如对于1cm2的硬膏表面)。
形成根据本发明制剂成分(ii)的辣椒素、组胺和斑螯提取物(斑蝥酊活性剂)为使皮肤发红的局部血管舒张药。这些物质长期以来被作为刺激皮下循环的外部摩擦物用于例如治疗冻疮、肢端疼痛、风湿病等的治疗中[Kiray，Racz，Torok：Bor-es nemibetegsegek(皮肤和性病，匈牙利)；第1927页以及后面的页(Medicina Konyvkiado，布达佩斯，1986)]。作为本发明制剂成分(iii)的上皮形成剂，可使用任何已知在治疗中使用以使皮肤上皮层松弛的物质。这些物质特征性的代表被列在如上面提到的教科书中。水杨酸、氯化钠、脲和间苯二酚为具有很好效果可用于本发明制剂中的上皮形成剂的实例。
虽然，从上述教科书中看出，本发明制剂成分(ii)和(iii)在以前已单独用于局部治疗的组合物中，但是在文献中没有发现关于它们的联合使用以及它们预期的联合效果的资料。在文献中也未能发现成分(ii)或成分(iii)被与肽药物结合使用用于局部治疗的目的。
在根据本发明的制剂中，成分(i)和(ii)相互作用，这通过观察到当辣椒素被加入到胰岛素悬液(例如加入到由Novo Nordisk销售的，商品名为Insulin lente MC)中时，形成透明溶液而得以证实。这种相互作用的准确性质仍未得到阐明，然而，最有可能的是在两种成分的疏松的含氢基团与局部氢受体中心之间(如辣椒素的HO-和HOOC-基团与胰岛素的-NH2基团之间)形成氢键。我的观点是本发明制剂肽药物的透皮吸收可能基本上是由于这种相互作用引起的结果。
根据本发明的制剂必须包含至少能发生上述相互作用的量的成分(ii)，然而优选制剂含有比该最少量多的成分(ii)。对于任何各种肽药物/成分(ii)对，最小以及适宜的比例可很容易地通过属于药物制剂学领域技术人员常规知识的的试验确定。作为参考，例如根据本发明的含有胰岛素的制剂可包含0.001-0.3g，优选0.003-0.1g，尤其优选0.005-0.05g的成分(ii)/10IU胰岛素。
根据本发明的制剂可包含重量比为1∶(0.01-10)，优选重量比为1∶(0.03-3)，尤其优选重量比为1∶(0.05-2)的成分(ii)和(iii)。
我观察到根据本发明的制剂中的成分(ii)和(iii)的量越高，活性剂的吸收越快。
根据本发明的制剂包含成分(i)-(iii)以及混合有用于局部制剂的常规的载体和/或稀释剂，后者的实例列举如下：水、醇(还包括甘油)、二元醇、胶凝剂(如甲基纤维素、羧甲基纤维素、聚乙烯醇和聚乙烯乙酸酯)、软膏基质(如羊毛脂)、离子性和非离子性表面活性剂等。
根据本发明的制剂还可包含被包囊形式的肽药物(如密封在环状淀粉中或胶囊包封)。从药物制剂学考虑，使用这种包囊可能是必须的，例如当有关肽药物与选择的载体或稀释剂不相容时。例如，当被密封至具有疏水性表面的膜中时，可让亲水性药物变得与油状载体相容。在这种情况下，成分(i)和(ii)之间的相互作用以成分(i)从膜中释放的速率进行。
如果需要，根据本发明的制剂还可包含其它与肽药物一起被引入的药物活性剂或活性增强剂。这些成分的实例为有时与胰岛素一起加入的锌化合物。
如果需要，根据本发明的制剂还可包含一种适用于检测肽药物存在的指示剂。以肉眼可观察的变化(最适合的是颜色反应)对相关药物的存在或不存在产生反应的物质可被用作指示剂。通过蓝色显色表明肽物质存在的茚三酮是一种非常适宜的显示肽物质存在的指示剂。这种含有指示剂的制剂的一个很大的优点是对吸收发生与否，病人可很容易地从施用的组合物的颜色变化(例如从茚三酮蓝色的消逝)得出结论，并且如果需要，可以适宜的时间间隔更换已经消耗的硬膏。根据本发明的制剂可包含提供良好可观察性量的指示剂。这些量对分析领域的技术人员是熟知的或可很容易地通过常规试验确定。
下面的实施例用于说明本发明制剂的组成和制备。实施例1
将0.28ml斑蝥酊(Ph.Hg.V.，含斑蝥的70％醇溶液)和0.05g水杨酸加入到10ml可经肌肉内给药的含有40IU/ml胰岛素(由Novo Nordisk销售，商品名为Insulin rapitard)的水悬液。在加入辣椒素后，由胰岛素悬液形成透明溶液。将0.01％(重量计)茚三酮加入到溶液中，随后，溶液的颜色变为蓝色。通过加入15％(重量计)甲基纤维素使产生的溶液凝胶化，并将产生的凝胶加到具有20cm2活性表面的聚氨基甲酸乙酯海绵硬膏上。将施加的凝胶剂用铝箔覆盖。实施例2
将10g Unguentum nonionicum emulsificans(Ph.Hg.V.，用非离子表面活性剂形成的油状凝胶)与10g(400IU)结晶胰岛素、0.05g结晶水杨酸和0.28ml斑蝥酊混合。将产生的油性软膏加到具有20cm2活性表面的聚氨基甲基乙酯海绵硬膏上，将施加的软膏剂用铝箔覆盖。
Claims (12)
1. 用于将肽药物引入生物体中的可局部施用的制剂，它包含：(i)肽药物，(ii)辣椒素、组胺和/或斑蝥提取物，以及(iii)上皮形成剂，并混合有局部药物制剂中常用的载体和/或稀释剂，其任选被加到能黏附于皮肤的载体上。
2. 如权利要求1的制剂，它包含作为肽药物的天然激素或其合成类似物或衍生物。
3. 如权利要求2的制剂，它包含胰岛素作为肽药物。
4. 如权利要求3的制剂，它包含0.001-0.3g成分(ii)/10IU胰岛素。
5. 如权利要求4的制剂，它包含0.003-0.1g成分(ii)/10IU胰岛素。
6. 如权利要求5的制剂，它包含0.005-0.05g成分(ii)/10IU胰岛素。
7. 如前述任一项权利要求所述的制剂，它包含重量比为1∶(0.01-10)的成分(ii)和(iii)。
8. 如权利要求7所述的制剂，它包含重量比为1∶(0.03-3)的成分(ii)和(iii)。
9. 如权利要求8所述的制剂，它包含重量比为1∶(0.05-2)的成分(ii)和(iii)。
10. 如前述任一项权利要求所述的制剂，它包含水杨酸、氯化钠、间苯二酚或脲作为成分(iii)。
11. 如前述任一项权利要求所述的制剂，它还包含以肉眼可观察到的变化对肽药物的存在或不存在产生反应的指示剂。
12. 如权利要求所述11的制剂，它包含茚三酮作为指示剂。
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| HU225734B1 (en) * | 1999-07-28 | 2007-07-30 | Zoltan Dardai | Multilayer plaster for introducing peptidaceous pharmacons in living organisms and process for producing thereof |
| EP1229939A1 (en) * | 1999-07-30 | 2002-08-14 | Maxim Pharmaceuticals, Inc. | Use of histamine as a drug delivery enhancing compound for use in transmucosal or transdermal delivery |
| US7176278B2 (en) | 2001-08-30 | 2007-02-13 | Biorexis Technology, Inc. | Modified transferrin fusion proteins |
| WO2004069180A2 (en) | 2003-01-31 | 2004-08-19 | Smithkline Beecham Corporation | Solid dispersion compositions |
| US8637096B2 (en) | 2009-12-04 | 2014-01-28 | Curtis C. Stojan | Compositions and method for enhancing insulin activity |
| KR101457263B1 (ko) * | 2012-02-03 | 2014-11-07 | 단국대학교 산학협력단 | 파스의 제조방법 |
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| CA2079900A1 (en) * | 1990-04-05 | 1991-10-06 | Richard C. Potter | Film-forming proteinaceous emulsion |
| CH687053A5 (fr) * | 1993-10-05 | 1996-09-13 | Crina | Additifs pour l'alimentation animale et procédé pour leur préparation. |
| US5686100A (en) | 1994-11-22 | 1997-11-11 | E.R. Squibb & Sons, Inc. | Prophylactic and therapeutic treatment of skin sensitization and irritation |
| AUPN089295A0 (en) * | 1995-02-02 | 1995-03-02 | International Diabetes Institute | Treatment of diabetic neuropathy |
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Owner name: DIAPETTIC TELASTE STOCK COMPANY Free format text: FORMER OWNER: ZOLTAN DARDAI Effective date: 20020621 |
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