CN102655861A - 用于治疗放疗或化疗引起的粘膜炎的组合 - Google Patents
用于治疗放疗或化疗引起的粘膜炎的组合 Download PDFInfo
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Abstract
本发明涉及甘氨酸、脯氨酸和任选的天然或合成的形成薄膜的聚合物和/或赖氨酸和/或亮氨酸的组合用于制备治疗放疗或化疗引起的粘膜炎的组合物的应用。
Description
本发明涉及甘氨酸、脯氨酸和任选的天然或合成的形成薄膜的聚合物和/或赖氨酸和/或亮氨酸的组合，其用于治疗放疗或化疗引起的粘膜炎。
技术背景
口腔粘膜炎(OM)是非外科手术的抗肿瘤治疗的最常见和有潜在严重性的副作用之一(1,2)。在临床上，其特征为红斑、形成具有或不具有假膜的溃疡、出血、形成渗出物和/或位于较高水平的感染(3)，能够进展为使人虚弱的形式，严重地影响患者的生活质量。对粘膜的损伤可以从口腔延伸到咽部；因此，在本发明中，术语“口腔粘膜炎”包括咽的粘膜炎。
患者与OM有关的症状感受包括从口的疼痛感到各种口腔功能的损害(4)。OM可以与疼痛症状相关，例如味觉障碍、吞咽困难和难以说话、咀嚼或吞咽，并伴有进食能力的后续损害、体重减轻和需要通过经鼻胃管饲喂。
所有这些不仅对患者的生活质量产生不利影响，而且还可导致治疗中断或减少抗肿瘤药的剂量，并且使患者的生命期望随后下降(5)。在财政方面，患有OM的患者的频繁入院以及专业人员对其给药或进行胃肠外喂养的家庭护理，都导致了国家卫生机构的相当大的负担(6,7)。
尽管OM病例的严重性和出现频率以及对个体进行过的很多研究，但仍然没有普遍接受的用于预防和治疗这种潜在严重的并发症的标准策略。虽然一些试验已经证明OM的发生能够被预防或减少，但它们是在数量不足的参与者中进行的，并不符合能够形成临床医疗准则的足够标准(8-11)。
目前，对OM及其造成的疼痛的治疗包括：基本的局部麻醉药、系统的镇痛药、抗炎药、粘膜覆盖剂、漱口剂、常规的口腔卫生以及抗微生物剂(5,12-15)。也测试了许多其它物质，例如生长因子和细胞因子类、保护粘膜的生物学化合物、冷冻疗法和低强度激光治疗(13,16)。透明质酸(HA)在组织愈合中通过多种机制起到重要作用(17-19)；临床试验也已经证实其改善下肢溃疡的愈合过程(20)和手术后鼻粘膜的愈合(21)，并且在经过治疗头、颈、乳腺或盆腔癌的放疗患者中减少急性上皮炎(22)。
因此，研究关注的是口腔粘膜炎的新治疗策略及相应的制剂。
最近已经证明，局部应用的基于0.2%HA的凝胶不仅缓解与复发的口疮性口炎和萎缩性/糜烂性口腔扁平苔癣有关的疼痛/蜇刺感，而且有助于出现溃疡、糜烂或萎缩的区域的临床消退(23,24)。
WO 2007/048524描述了伤口愈合的药物组合物，其包含甘氨酸、赖氨酸、亮氨酸和脯氨酸以及透明质酸钠的组合，其在促进形成快速伤口愈合的基础的细胞更新过程中、促进结缔组织重建和随后的上皮细胞再生中特别有效。
WO 2008/027904公开了用于治疗口腔炎或粘膜炎的粘性聚合物例如透明质酸盐或PVP的制剂。
WO 02/39978公开了用于营养不良或慢性疾病患者的肠内营养补充剂，其包含谷氨酰胺、抗氧化剂和脂肪酸。可任选地存在作为钙拮抗剂的甘氨酸。
发明描述
现已发现，包含甘氨酸、脯氨酸和任选的天然或合成的形成薄膜的聚合物、赖氨酸和/或亮氨酸的组合产品在治疗放疗或化疗引起的口腔粘膜炎，尤其是疼痛控制方面是有效的。具体而言，已经发现，甘氨酸和脯氨酸的组合令人惊奇地增加e-NO合酶和VEGF的基因表达。而且，所述氨基酸控制和增强TGFβ的生成，在数量上控制成纤维细胞的胶原合成。这意味着甘氨酸和脯氨酸的组合，特别是与赖氨酸和亮氨酸组合时，也能有效抑制TGFβ的表达，因此当成纤维细胞的胶原生成速率最高时可阻止纤维化的胶原产生。单独使用的透明质酸在这方面绝对没有任何活性，因此不能观察到和获得对纤维化的瘢痕形成的预防。
本发明的组合物对伤口愈合具有明显的加速作用，和尤其是对疼痛控制的令人惊奇的作用，特别是在减少疼痛和即刻缓解(在给药后仅两小时)方面。因此，本发明的组合物的应用导致了对控制疼痛的实际帮助，提供了快速、有效的疼痛降低。
因此，本发明涉及口腔应用的制剂，其包含：
a)甘氨酸，
b)脯氨酸，
和任选的
c)天然或合成的形成薄膜的聚合物，和/或
d)赖氨酸，和/或
e)亮氨酸，
用于治疗放疗或化疗引起的口腔粘膜炎。
根据本发明，天然或合成的形成薄膜的聚合物选自透明质酸或其盐、聚乙烯吡咯烷酮和纤维素衍生物。
根据优选的方面，天然或合成的形成薄膜的聚合物是透明质酸或其盐。
根据本发明，所述氨基酸以L-型存在。
根据优选的方面，本发明的组合物含有以下的组合物重量比例的多种活性组分：
a)0.5-20%的甘氨酸，
b)0.2-15%的脯氨酸，
和任选的
c)0.5-5%的透明质酸或其盐，和/或
d)0.05-10%的赖氨酸，和/或
e)0.05%-3%的亮氨酸。
本发明组合物能够被配制为适合于局部给药的喷雾剂、气雾剂、漱口剂或凝胶形式，可根据药学领域熟知的常规方法制备，例如在Remington’sPharmaceutical Handbook,Mack Publishing Co.,N.Y.,USA中所述的方法，使用对于其最终用途而言可接受的赋形剂、增溶剂、润滑剂、稳定剂、乳化剂、pH调节剂和防腐剂。
药理学试验
该试验在27个患有OM的患者上进行，所述患者在近期(两周内)用放疗或化疗的每日剂量进行过治疗，表现出根据世界卫生组织(WHO)粘膜炎标准评估的至少一级的OM，并且他们的疼痛用扑热息痛/Co-codamol/乙酰水杨酸治疗未缓解。每个患者每天用喷雾剂形式的本发明组合物治疗3-4次，持续14天，所述喷雾剂必须在原位保持至少2分钟。这些患者被要求至少1小时不进食、饮水或清洗口腔。在整个试验期间，要求患者特别保持其口腔卫生，使用包含葡萄糖酸氯己定的非醇溶液的漱口液，并且不能吸烟、饮酒或进食刺激性食物。试验结果在下表I和II中说明。
表I显示在不同的评价阶段的疼痛评分。在时间T0(基线-在开始治疗之前)，评价以下参数：疼痛(使用1到100的线性直观类比标度)和OM的严重性(使用WHO的粘膜炎标准)。治疗的效力根据在T01(2小时之后)、T1(24小时之后)、T2(72小时之后)、T3(7天之后)和T4(14天之后)时的疼痛评分、临床消退指数和患者的顺应性进行评价。
表I.在不同的评价阶段用VAS评价的疼痛评分。
结果显示，在喷雾剂给药仅2小时之后与基线测量值相比疼痛症状显著降低(p<0.0001;z=-4.541)。在两周期间疼痛降低逐步进展(p<0.0001)。
表II显示治疗对临床消退指数的作用。所治疗的患者表现出在治疗仅72小时后伤口的显著临床改善(p=0.0051;z=-2.803;Wilcoxon检验)。具体而言，弗里德曼检验显示在多个测量阶段中与基线相比显著的临床改善(p<0.0001)。在两周的观察期间，所有患者显示与基线相比显著的改善(p<0.0001)，并且他们吞咽固体和液体的能力逐步改善。
表II.在治疗期间对临床消退指数的作用
所有的患者还表现出良好的顺应性，在试验结束时没有人抱怨副作用。没有患者被迫中断放疗或化疗。
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Claims (6)
1.口腔制剂，其包含：
a)甘氨酸，
b)脯氨酸，
和任选的
c)天然或合成的形成薄膜的聚合物，和/或
d)赖氨酸，和/或
e)亮氨酸，
用于治疗放疗或化疗引起的粘膜炎。
2.如权利要求1所述的制剂，其中所述天然或合成的形成薄膜的聚合物选自透明质酸或其盐、聚乙烯吡咯烷酮和纤维素衍生物。
3.如权利要求2所述的制剂，其中所述天然或合成的形成薄膜的聚合物是透明质酸或其盐。
4.如权利要求1所述的制剂，其中所述氨基酸是L-型。
5.如权利要求1和2所述的制剂，其中组合的各种组分按以下的组合物重量范围存在：
a)0.5-20%的甘氨酸，
b)0.2-15%的脯氨酸，
和任选的
c)0.5-5%的透明质酸或其盐，和/或
d)0.05-10%的赖氨酸，和/或
e)0.05%-3%的亮氨酸。
6.如权利要求1和2所述的制剂，其中组合物是喷雾剂、气雾剂、漱口剂或凝胶的形式。
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- 2010-11-25 EP EP10790906.1A patent/EP2504001B8/en active Active
- 2010-11-25 CN CN2010800531477A patent/CN102655861A/zh active Pending
- 2010-11-25 PL PL10790906T patent/PL2504001T5/pl unknown
- 2010-11-25 RU RU2012121562/15A patent/RU2570754C2/ru active
- 2010-11-25 SI SI201030933T patent/SI2504001T1/sl unknown
- 2010-11-25 WO PCT/EP2010/068216 patent/WO2011064297A1/en active Application Filing
- 2010-11-25 PT PT107909061T patent/PT2504001E/pt unknown
- 2010-11-25 DK DK10790906.1T patent/DK2504001T4/en active
- 2010-11-25 US US13/511,900 patent/US20130039881A1/en not_active Abandoned
- 2010-11-25 ES ES10790906.1T patent/ES2538349T5/es active Active
- 2010-11-25 BR BR112012012486A patent/BR112012012486A2/pt not_active Application Discontinuation
- 2010-11-25 CA CA2781820A patent/CA2781820C/en active Active
- 2010-11-25 KR KR1020127013470A patent/KR101767226B1/ko active IP Right Grant
- 2010-11-25 JP JP2012540428A patent/JP2013512220A/ja not_active Withdrawn
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- 2014-11-25 US US14/553,897 patent/US9220726B2/en active Active
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002039978A1 (de) * | 2000-11-17 | 2002-05-23 | Fresenius Kabi Deutschland Gmbh | Enteral zu verabreichendes supplement zur parenteralen ernährung oder partiellen enteralen/oralen ernährung bei kritisch kranken, chronisch kranken und mangelernährten |
| US20080261915A1 (en) * | 2005-10-26 | 2008-10-23 | Solartium Llc | Wound-Healing Pharmaceutical Compositions in the Form of a Sterile Powder Based on Amino Acids and Sodium Hyaluronate |
| WO2008027904A2 (en) * | 2006-08-28 | 2008-03-06 | Rexaderm, Inc. | Dry wound dressing and drug delivery system |
Also Published As
| Publication number | Publication date |
|---|---|
| HRP20150523T1 (hr) | 2015-06-05 |
| DK2504001T4 (en) | 2018-05-22 |
| EP2504001A1 (en) | 2012-10-03 |
| PL2504001T3 (pl) | 2015-10-30 |
| ZA201203808B (en) | 2013-08-28 |
| EP2504001B8 (en) | 2018-06-06 |
| PT2504001E (pt) | 2015-07-07 |
| NO2504001T3 (zh) | 2015-08-01 |
| US9220726B2 (en) | 2015-12-29 |
| RS54014B1 (en) | 2015-10-30 |
| DK2504001T3 (en) | 2015-05-11 |
| US20130039881A1 (en) | 2013-02-14 |
| EP2504001B2 (en) | 2018-03-21 |
| PL2504001T5 (pl) | 2019-06-28 |
| RU2012121562A (ru) | 2013-11-27 |
| CA2781820A1 (en) | 2011-06-03 |
| WO2011064297A1 (en) | 2011-06-03 |
| US20150079009A1 (en) | 2015-03-19 |
| ES2538349T5 (es) | 2018-06-18 |
| ES2538349T3 (es) | 2015-06-19 |
| IT1396935B1 (it) | 2012-12-20 |
| ITMI20092080A1 (it) | 2011-05-27 |
| CA2781820C (en) | 2018-05-08 |
| KR101767226B1 (ko) | 2017-08-10 |
| RU2570754C2 (ru) | 2015-12-10 |
| SI2504001T1 (sl) | 2015-06-30 |
| BR112012012486A2 (pt) | 2016-04-12 |
| KR20120105454A (ko) | 2012-09-25 |
| EP2504001B1 (en) | 2015-03-04 |
| JP2013512220A (ja) | 2013-04-11 |
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Application publication date: 20120905 |