CN103561721A - 包含氟替卡松的鼻用药物配制剂 - Google Patents
包含氟替卡松的鼻用药物配制剂 Download PDFInfo
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Abstract
本发明涉及包含鼻内皮质类固醇作为活性物质的鼻用配制剂以及用于预防或治疗季节性或常年性的过敏性和非过敏性鼻炎和鼻炎结膜炎。
Description
本发明涉及包含鼻内皮质类固醇作为活性物质的鼻用配制剂。在优选的实施方式中，本发明涉及包含氟替卡松或其制药可接受的酯或盐的鼻用配制剂。在特别地优选的实施方式中，本发明涉及包含丙酸氟替卡松的鼻用药物配制剂。
本发明还涉及用包含鼻内皮质类固醇（优选氟替卡松或其制药可接受的酯或盐）作为活性物质的鼻用配制剂预防或治疗季节性或常年性的过敏性和非过敏性鼻炎和鼻炎结膜炎以及治疗鼻息肉，预防外科手术去除鼻息肉后的息肉复发，在急性和慢性窦炎、睡眠呼吸暂停、打鼾或炎症-相关的阻塞性睡眠病症的情况下作为辅助治疗的方法。在特别地优选的实施方式中，本发明涉及用包含丙酸氟替卡松的鼻用药物配制剂预防或治疗季节性或常年性过敏性鼻炎和鼻炎结膜炎的方法。
本发明还涉及用于制备包含鼻内皮质类固醇（优选氟替卡松或其制药可接受的酯或盐）作为活性物质的鼻用配制剂的方法。在优选的实施方式中，本发明涉及用于制备包含丙酸氟替卡松的鼻用药物配制剂的方法。
过敏性鼻炎是患病率升高的全球性健康问题。目前世界范围内约5亿人罹患该病。过敏性鼻炎的症状影响社交生活、睡眠、学习和工作能力并由此成为实质性负担（Bousquet等人，Allergy.2008Apr;63Suppl86:8-160）。
对于具有较强症状、特别是堵塞的鼻子的患者，鼻内皮质类固醇是所选择的治疗（LaForce J Allergy Clin Immunol1999;103;pp.388-94;Brozek等人，J Allergy Clin Immunol2010;126:466-76,Wallace J Allergy Clin Immunol.2008Aug;122(2Suppl):pp.1-84）。
氟替卡松是出自皮质类固醇类的活性物质并用于治疗季节性或常年性过敏性鼻炎。市场上的鼻用配制剂例如Flutide、丙酸氟替卡松（Flonase或Fluticasone Propionate）鼻用喷雾剂50μg（RoxaneLaboratories）。在悬浮液中，活性物质氟替卡松细微分散于液体中。
然而分析表明，多于60％的过敏性鼻炎患者对他们当前的治疗不满意，特别是因为不足的有效性（Bousquet,J Allergy Clin Immunol.2009Sep;124(3):428-33）。因此对用于治疗过敏性鼻炎的改良药物存在需求。
本发明的任务是提供用于治疗过敏性鼻炎具有改良效果的包含皮质类固醇的药物。该任务通过氟替卡松、特别是丙酸氟替卡松的鼻用配制剂解决，其包含微晶纤维素+羧甲基纤维素钠（Avicel CL611）、依地酸二钠、聚山梨酯80、甘油、苯扎氯铵和苯乙醇作为助剂。丙酸氟替卡松的标称剂量为50μg。
局部应用和局部作用的物质的有效性的关键参数是所施用的活性物质的标称剂量。通常假设具有同一活性物质的相同标称剂量的药物显示可比的效果（LeSouef,Allergy1999,54,pp.93-96）。
根据本发明的配制剂相对于现有技术具有如下优点，尽管是相同标称剂量的肾上腺皮质激素氟替卡松将在鼻中更好地被利用（Derendorf等人，2012Br J Clin Pharmacol accepted）且在那里能够施展更强的效果：
根据实施例1，表1显示具有相同标称剂量的根据本发明的配制剂与现有技术的配制剂（丙酸氟替卡松鼻用喷雾剂50μg（RoxaneLaboratories））之间的对比。在此，若无其它表征，结果作为与基线的差给出（rTNSS：反射的总鼻症状评分（reflective Total NasalSymptom Score）；iTNSS：瞬时的总鼻症状评分（instantaneous TotalNasal Symptom Score)；TOSS：总的可见症状评分（Total OcularSymptom Score））。
表1
| 参数 | 本发明的配制剂 | 对比（Roxane的氟替卡松50μg） |
| rTNSS | -5.1 | -3.8 |
| iTNSS | -4.60 | -3.46 |
| rTOSS | -2.71 | -2.17 |
| 鼻堵塞 | -1.10 | -0.86 |
| 鼻瘙痒 | -1.10 | -0.91 |
| 眼瘙痒 | -0.96 | -0.70 |
| 泪眼 | -0.96 | -0.82 |
| rTNSS（基线>18.9） | -5.42 | -4.76 |
| rTNSS（blocker） | -4.95 | -3.92 |
| 鼻充血（blocker） | -1.26 | -0.90 |
与治疗之前相比，鼻和眼症状评分以及各种不适相比使用相同标称剂量的常规氟替卡松鼻用喷雾剂明显减少。出自四种相关鼻症状（鼻堵塞、喷嚏、流涕、鼻瘙痒）的0至24标度的总评分，常规氟替卡松在14天的治疗下平均仅变化3.8个点（Hampel等人Ann AllergyAsthma Immunol.2010;105:S168-73），而在新配制剂的治疗下以5.1个点明显改善（Carr等人，J Allergy Clin Immunol129(5)2012pp.1282-1289）。
如上所提及的，所述改良的有效性源于活性物质的改善的局部利用性，其反映了改善的全身性生物利用率。所述全身性可用的氟替卡松必须是基本上通过鼻粘膜吸收，因为口腔吸收仅占约1%。所述改善的生物利用率在Derendorf等人，2012的研究中表明。
在一个二随机、三期、六顺序、三治疗的交叉研究中，19名健康志愿者分别一次性鼻内施用200μg氟替卡松（标称50μg，每个鼻孔2喷剂），作为常规标准（丙酸氟替卡松鼻用喷雾剂50μg(RoxaneLaboratories)）和以根据实施例1的本发明的配制剂（新）。经历24小时测量血清氟替卡松。平均氟替卡松值以[pg/ml]在附图1中相对于时间作图并显示出在可利用性方面改善的程度。
本发明进一步的实施方式包括，用选自下组鼻内皮质类固醇的一种或多种活性物质取代氟替卡松或其制药可接受的酯或盐：布地奈德、倍氯米松、莫米松、曲安西龙、地塞米松、环索奈德或其制药可接受的盐或酯。
所述配制剂任选地包含一种或多种选自下组的助剂：抗沉降剂/增稠剂，如羧甲基纤维素、羟甲基纤维素、甲基纤维素、明胶、聚乙烯吡咯烷酮、聚乙二醇、聚乙烯醇，优选微晶纤维素+羧甲基纤维素钠（Avicel CL611），螯合剂，优选依地酸二钠，润湿剂如脂肪酸的聚氧乙烯衍生物或山梨糖醇酐（优选聚山梨酯80）的部分脂肪酸酯的聚氧乙烯衍生物，渗透活性物质如蔗糖、葡萄糖、山梨醇、丙二醇、NaCl，优选甘油，以及保藏剂如硫柳汞、苄醇、烷铵盐和苯扎铵盐、葡萄糖酸氯己定，优选苯扎氯铵和苯乙醇。
根据本发明的配制剂的制备，例如通过将纯化水加温至30至40℃，然后相续地加入依地酸二钠和甘油并各自混合5分钟。将微晶纤维素和羧甲基纤维素钠通过40目的筛过筛并随后加入且再搅拌约30分钟。
在一个分开的容器中将聚山梨酯80与纯净水搅拌约5分钟。在进一步的搅拌下加入丙酸氟替卡松并且再搅拌约30分钟。
将这两种分散液合并并继续混合约10分钟。加入苯扎氯铵溶液10%(w/v)并在约10分钟的搅拌下混合。
加入苯乙醇并在约10分钟的搅拌下混合。在加入纯净水之后将该悬浮液均化约30分钟，并通过200目筛。
所述配制剂的使用通过具有商购可得的泵的喷雾瓶进行，所述泵如已知于Aptar或MeadWestvaco Corporation的那些。Aptar的VP3/140F CS20-AG泵是特别优选的。
根据本发明的配制剂以在施用剂量单位中一半的小液滴不超过150μm、优选介于50μm和100μm、特别优选介于75μm和95μm的小液滴施用。
剂量单位包含介于10和200μg，优选介于25和100μg，特别优选介于40和60μg的鼻内皮质类固醇。剂量单位包含例如50μg的丙酸氟替卡松。
鼻内皮质类固醇的剂量单位以介于50和250μl，优选介于100和150μl的量施用。丙酸氟替卡松的剂量单位例如以每喷一下137μl施用。
每天一次或两次每个鼻孔喷1至2下，由此每天总共喷2至8下；特别优选的是每个鼻孔早晨喷一下且晚上喷一下，由此每天总共喷四下。
实施例:
示范性例举以下组合物，而非将本发明局限于此。
实施例1:
| 内容物 | 量[g/100g] |
| 丙酸氟替卡松 | 0.0365 |
| MCC+NaCMC**(Avicel CL611) | 2.00 |
| 依地酸二钠 | 0.01 |
| 聚山梨酯80 | 0.005 |
| 甘油 | 2.30 |
| 苯扎氯铵 | 0.01 |
| 苯乙醇 | 0.25 |
| 纯净水 | 至100 |
实施例2:
| 内容物 | 量[g/100g] |
| 丙酸氟替卡松 | 0.025 |
| MCC+NaCMC**(Avicel CL611) | 2.00 |
| 依地酸二钠 | 0.01 |
| 聚山梨酯80 | 0.005 |
| 甘油 | 2.30 |
| 苯扎氯铵 | 0.01 |
| 苯乙醇 | 0.25 |
| 纯净水 | 至100 |
Claims (10)
1.鼻用药物配制剂，其包含氟替卡松或其制药可接受的酯或盐和任选地包含一种或多种助剂。
2.根据权利要求1的配制剂，其特征在于，使用丙酸氟替卡松。
3.根据权利要求1或2的配制剂，其特征在于，所述一种或多种助剂选自下组：抗沉降剂、螯合剂、润湿剂、渗透活性物质和保藏剂。
4.根据权利要求3的配制剂，其特征在于，包含微晶纤维素和羧甲基纤维素钠（Avicel CL611）作为抗沉降剂。
5.根据权利要求3的配制剂，其特征在于，包含依地酸二钠作为螯合剂。
6.根据权利要求3的配制剂，其特征在于，包含聚山梨酯80作为润湿剂。
7.根据权利要求3的配制剂，其特征在于，包含甘油作为渗透活性物质。
8.根据权利要求3的配制剂，其特征在于，包含选自苯扎氯铵和苯乙醇的至少一种作为保藏剂。
9.根据前述权利要求任一项的配制剂，其特征在于，其通过喷雾泵使用。
10.前述权利要求任一项的配制剂的用途，其用于预防或治疗过敏性的季节性或常年性鼻炎或鼻炎结膜炎。
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| DE102011103347.9A DE102011103347B4 (de) | 2011-05-27 | 2011-05-27 | Nasale pharmazeutische Formulierung |
| DE102011103347.9 | 2011-05-27 | ||
| PCT/EP2012/002222 WO2012163501A1 (de) | 2011-05-27 | 2012-05-24 | Nasale pharmazeutische formulierung enthaltend fluticason |
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| CN103893120A (zh) * | 2012-12-27 | 2014-07-02 | 重庆华邦制药有限公司 | 提高了稳定性的丙酸氟替卡松喷雾剂 |
| JP6675974B2 (ja) * | 2013-03-26 | 2020-04-08 | オプティノーズ アズ | 経鼻投与 |
| US11554229B2 (en) | 2013-03-26 | 2023-01-17 | OptiNose Inc. | Nasal administration |
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| US20020165211A1 (en) * | 2000-08-05 | 2002-11-07 | Keith Biggadike | Formulation containing anti-inflammatory androstane derivative |
| US20040208830A1 (en) * | 2003-04-16 | 2004-10-21 | Imtiaz Chaudry | Nasal pharmaceutical formulations and methods of using the same |
| CN101443018A (zh) * | 2006-01-27 | 2009-05-27 | 伊兰制药国际有限公司 | 灭菌纳米微粒糖皮质激素制剂 |
| WO2010141834A1 (en) * | 2009-06-05 | 2010-12-09 | Aciex Therapeutics, Inc. | Ophthalmic formulations of fluticasone and methods of use |
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| EP1981476A2 (en) * | 2006-02-09 | 2008-10-22 | Schering Corporation | Pharmaceutical formulations |
| DK2035004T3 (en) * | 2006-06-09 | 2013-01-02 | Parion Sciences Inc | Phenylsubstituerede pyrazinoylguanidin-natriumkanalblokkere med beta-agonistaktivitet |
| JP2010195716A (ja) * | 2009-02-25 | 2010-09-09 | Takeda Chem Ind Ltd | 点鼻睡眠導入剤 |
| AU2010324596A1 (en) * | 2009-11-30 | 2012-06-14 | Wisconsin Alumni Research Foundation | 2-methylene-19,26-nor-(20S)-1alpha-hydroxyvitamin D3 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020165211A1 (en) * | 2000-08-05 | 2002-11-07 | Keith Biggadike | Formulation containing anti-inflammatory androstane derivative |
| US20040208830A1 (en) * | 2003-04-16 | 2004-10-21 | Imtiaz Chaudry | Nasal pharmaceutical formulations and methods of using the same |
| CN101443018A (zh) * | 2006-01-27 | 2009-05-27 | 伊兰制药国际有限公司 | 灭菌纳米微粒糖皮质激素制剂 |
| WO2010141834A1 (en) * | 2009-06-05 | 2010-12-09 | Aciex Therapeutics, Inc. | Ophthalmic formulations of fluticasone and methods of use |
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| GEP201606577B (en) | 2016-11-25 |
| US20140194400A1 (en) | 2014-07-10 |
| IL229497A0 (en) | 2014-01-30 |
| CA2836025A1 (en) | 2012-12-06 |
| EA025203B1 (ru) | 2016-11-30 |
| AU2012265231B2 (en) | 2016-09-08 |
| DE102011103347A1 (de) | 2012-11-29 |
| EP2714005A1 (de) | 2014-04-09 |
| NZ616149A (en) | 2015-11-27 |
| EA201391686A1 (ru) | 2014-03-31 |
| DE102011103347B4 (de) | 2014-10-30 |
| ZA201308905B (en) | 2015-03-25 |
| MX2013013879A (es) | 2014-01-23 |
| BR112013030260A2 (pt) | 2016-12-06 |
| WO2012163501A9 (de) | 2013-03-07 |
| JP2014515360A (ja) | 2014-06-30 |
| WO2012163501A1 (de) | 2012-12-06 |
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