CN101380320B - 胆碱酯酶抑制剂的制药用途 - Google Patents
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Abstract
本发明涉及用胆碱酯酶抑制剂治疗口腔干燥症，在此提供了以胆碱酯酶抑制剂配制局部给药的药剂，用于治疗口腔干燥症的用途。本发明还提供了胆碱酯酶抑制剂在制备用于治疗口腔干燥症的对口腔粘膜局部给药的药物方面的用途。
Description
本申请是申请号为96199706.0、申请日为1996年11月25日、发明名称为“用胆碱酯酶抑制剂治疗口腔干燥症”的专利申请的分案申请。
发明领域
本发明是关于一类已知化合物的新用途，即将胆碱酯酶抑制剂对口腔粘膜局部给药，用于治疗口腔干燥症，以及一种治疗口腔干燥症的方法。
发明背景
口腔干燥症，或口腔发干，是一种普遍的感受性病症，其特点是唾液分泌减少或停止。
唾液是由许多唾液腺分泌的，只要有腮腺，颔下腺和舌下腺等唾液腺，以及许多恰好位于口腔粘膜下的微小副唾液腺。
唾液的只要功能是保持口腔粘膜湿润，在咀嚼过程中湿润食物，保护牙齿，以及有助于淀粉的初步消化。
因此，口腔干燥的直接后果包括咀嚼，吞咽，说话困难，以及睡眠过程中断。但是，更严重的情况是，已发现口腔干燥症可导致口腔粘膜溃疡，包括龋齿的牙科疾病，念珠菌发生率增加，葡萄株菌感染，以及由后者引起的口臭。
口腔干燥症的病因有多种，按病因学系可对此病症作进一步分类。
原发性口腔干燥症，是由导致唾液腺机能减退的病理性过程(例如萎缩或疾病)的后果而引起的。患有风湿病(如Sjogren氏综合症)的病人，以及正在经受头部和颈部癌症放射治疗的病人，也普遍存在原发性口腔干燥症。
已知原发性口腔干燥症的发病率随年龄增加。例如在瑞典，有15％50岁以上的人诉说口腔干燥之苦。这种情况在70岁以上的人增加到25％，而80岁以上的人增加到33％。瑞典住院的老年人群中，多达40％的人患有口腔干燥症。
继发性口腔干燥症是服用某些药剂的病人遇到的特别普遍的副作用。据认为，所有药剂中的大约半数会引起某种程度的口腔干燥症， 而且这种问题对于服用抗抑郁药和精神仰制药的病人特别普遍。
目前，口腔干燥症现有的治疗剂非常少，仅包括一些合成粘蛋白(例如羧甲基纤维素钙，羟甲基纤维素(hypromellose)和甲基纤维素)，和通过降低病人口腔唾液粘度而起作用的药剂(例如硫氰酸钙，1，6-己二胺， 
).
最近已将盐酸毛果芸香碱用于对放射治疗引起的口腔干燥症进行全身性治疗。但是，也发现毛果芸香碱会引起一些涉及心脏，血压和消化功能的不利的副作用。即使每日小剂量的毛果芸香碱也会引起大量出汗。
美国专利5,387,614号公开了用Sigma受体的配体，即N，N-二取代的烷基苯胺，对病人进行口腔干燥症的全身性治疗。
已知胆碱酯酶抑制剂(此后称为CEIs)特别可用于治疗重症肌无力，青光眼和肠道麻痹等疾病。
一种胆碱酯酶抑制剂吡啶斯的明已被用于患有口腔干燥症的病人，参见例如，Ferguson，M.M.，Oral Surg.Oral Med.Oral Pathol.，1993：75，191。给病人口服其缓释片剂可引起唾液流量增加，并引起眼泪增加，对不同的病人个体之间有不同的反应。
因此，仍然需要一种有效的，并且不产生明显副作用的口腔干燥症治疗剂。
现在我们已令人惊奇地发现，CEIs对治疗口腔干燥症是高效的，并且，为刺激唾液分泌，消除口腔干燥症，针对口腔粘膜，特别是对副唾液腺位置直接给药同时，不引起任何明显的副作用。
发明内容
因此，本发明在此提供了CEI在配制对口腔粘膜局部给药的药剂，用于治疗口腔干燥症方面的用途。
有关名词“口腔干燥症”本领域技术人员可理解为包括常见于人或动物患者，不论病因如何的所有形式的原发性和继发性口腔干燥症。所以，该名词将被理解包括表现为口腔干燥和/或唾液分泌减少或停止的任何病症。
特别是我们已发现，当以CEI对患有，或易患口腔干燥症的患者作口腔粘膜局部给药时，可增加唾液分泌量。
因此，根据本发明的另一方面，在此提供一种治疗口腔干燥症的 方法，它包括对患有，或易患这种病症的哺乳动物患者的口腔粘膜，局部给予治疗有效剂量的CEI。
所述的CEIs包括毒扁豆碱，溴化新斯的明，硫酸新斯的明，吡啶斯的明，(3aS-顺式)-1，2，3，3a，8，8a，-六氢-1，3a，8-三甲基吡咯并[2，3-b]吲哚-5-基-3，4-二氢-2(1H)异喹啉羧酸盐(见InternationalPatent Application NO.SE92/00873的实施例54)，以及(3aS-顺式)-1，2，3，3a，8，8a，-六氢-1，3a，8-三甲基吡咯并[2，3-b]吲哚-5-醇(见US Patent NO.5,187,165)，或者它们的组合物。
根据本发明，在此提供了一种治疗口腔干燥症的方法，它包括对患有，或易患这种病症的哺乳动物患者的口腔粘膜，局部给予治疗有效剂量的CEI。
我们已发现，对口腔粘膜使用CEI，可刺激口腔“副”唾液腺产生唾液，正如本领域的技术人员所知道的，这些“副”唾液腺恰好位于口腔粘膜下面。进而我们还发现，对口腔粘膜局部使用CEIs将导致足以缓解口腔干燥症的唾液分泌，而不会引起明显的副作用，如出汗。
CEIs可以按已知技术与通常用于药物活性化合物局部给药的其它成分共同配制。
适合于局部给药的制剂包括溶液，特别是水溶液。活性化合物还可以配制成用于局部给药的缓释片剂，可将这种片剂置于(例如通过粘贴)紧靠各种唾液腺的位置。可能提到的其它局部给药剂型包括口香糖，糖锭，漱口剂，和膏药片。
优选的局部给药剂型是缓释片剂。
可被用于局部制剂的其它成分将取决于具体的CEI和所采用的局部给药方式。
在局部制剂中，一种或几种药物活性化合物的含量主要取决于所包含的一种或几种具体CEI，以及所采用的局部给药方式而定。例如，当给药剂型是借助于水溶液时，一般药物活性成分含量为0.01-100mg/ml，优选0.05-25mg/ml，而特别优选0.1-10mg/ml。一般CEI日剂量可以在0.1-100mg活性成分的范围内，例如0.2-25mg，优选0.5-10mg。
CEIS可以和被指定用于治疗口腔干燥症的其它活性成分共同配制，例如合成粘蛋白，降低粘度的药剂(如Mucidan)，如毛果芸香碱。
据本发明的治疗方法，其优点是CEIS对缓解口腔干燥症症状特别有效，而不显示出明显的副作用。本发明的治疗方法还具有可根据需要将CEIS局部用于口腔粘膜的优点。
本发明的治疗方法与以前用于治疗口腔干燥症的给药方法相比较，还具有如下优点：CEIS能更快地，以更高的浓度到达其口腔副唾液腺中的靶细胞，并且可在更长的时间内保持活性。
本发明的治疗方法中，与以前用于治疗口腔干燥症的活性成分相比较，CEIS毒性更低，或者还可能有其它有用的药理特性的优点。
附图说明
图1是颊部使用毒扁豆碱(1mg/ml；n＝5)后，颊唾液腺的分泌情况。
试验
试验A
雪貂唾液腺的唾液分泌：
使雪貂(从瑞典Mr Stig Held，Bjarshog获得)禁食过夜，然后作全身麻醉。将主唾液腺的所有唾液管结扎或插导管。对插导管唾液腺的唾液分泌进行监测。
为了获得本底值，将一片预先称重的干燥滤纸片置于动物一侧面颊的内面，5分钟后取出，并随即称重，此程序被重复二次。
将待测物质以水溶液的形式局部涂抹于面颊粘膜5分钟以上。在预先称重的新鲜滤纸片上收集面颊部的唾液，每5分钟更换滤纸片一次，直至其唾液分泌回到预先测定的本底值为止。
持续地记录心率和血压。
试验B
人志愿者副唾液腺的唾液分泌：
为了获得本底值，将一片预先称重的干燥滤纸片置于健康志愿者的下唇内侧。在固定的时间内收集唾液。
随后将几滴待测物质以水溶液形式抹于下唇内侧面，并用一片预先称重的滤纸在相等的一段时间内收集该部位的唾液。
将各种情况下收集的唾液量进行比较。
在此试验过程之后，询问患者是否在使用该活性物质的过程中或 使用活性物质之后，他或她感受到任何不良副反应。
可通过下面的实施例对本发明进行说明：
实施例1
按上述试验A试验毒扁豆碱(水溶液，0.1-10mg/ml)。
最低剂量(0.1mg/ml)在5分钟时间内产生13μl的最大分泌量，最高剂量(10mg/ml)产生90μl的最大分泌量。
以最低剂量使用毒扁豆碱15分钟之后，分泌返回到本底值(5分钟内3μl)，以最高剂量则100分钟后分泌返回到本底值。
仅在给予最高剂量后观察到血压和心率轻度降低。
按1mg/ml剂量给药后以颊腺唾液分泌量对时间作图，示于图1中。
实施例2
按上述试验A试验溴化新斯的明(水溶液，0.1-10mg/ml)。最高剂量(10mg/ml)在5分钟的时间内产生60μl的最大分泌量，分泌反应持续约20分钟。
实施例3
按上述试验法A试验硫酸新斯的明(水溶液，0.1-10mg/ml)。最高剂量(10mg/ml)在5分钟的时间内产生130μl的最大分泌量，分泌反应持续约20分钟。
实施例4
按上述试验法B，对二名健康人以毒扁豆碱(水溶液，0.1-1mg/ml)进行试验。用药后观察到局部唾液分泌增加到大约本底值的2倍，持续增加大约15分钟。未观察到任何副作用。
Claims (1)
1.胆碱酯酶抑制剂毒扁豆碱在制备用于治疗口腔干燥症的对口腔粘膜局部给药的药物方面的用途。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE95042677 | 1995-11-29 | ||
| SE9504267A SE9504267D0 (sv) | 1995-11-29 | 1995-11-29 | New therapeutic use |
| SE9504267-7 | 1995-11-29 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199706A Division CN1207679A (zh) | 1995-11-29 | 1996-11-25 | 用胆碱酯酶抑制剂治疗口腔干燥症 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101380320A CN101380320A (zh) | 2009-03-11 |
| CN101380320B true CN101380320B (zh) | 2010-12-29 |
Family
ID=20400405
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199706A Pending CN1207679A (zh) | 1995-11-29 | 1996-11-25 | 用胆碱酯酶抑制剂治疗口腔干燥症 |
| CN2008101459688A Expired - Fee Related CN101380320B (zh) | 1995-11-29 | 1996-11-25 | 胆碱酯酶抑制剂的制药用途 |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96199706A Pending CN1207679A (zh) | 1995-11-29 | 1996-11-25 | 用胆碱酯酶抑制剂治疗口腔干燥症 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5962503A (zh) |
| EP (1) | EP0866699B1 (zh) |
| JP (1) | JP4113257B2 (zh) |
| CN (2) | CN1207679A (zh) |
| AR (1) | AR004330A1 (zh) |
| AT (1) | ATE216235T1 (zh) |
| AU (1) | AU718661B2 (zh) |
| DE (1) | DE69620786T2 (zh) |
| DK (1) | DK0866699T3 (zh) |
| ES (1) | ES2175153T3 (zh) |
| PT (1) | PT866699E (zh) |
| SE (1) | SE9504267D0 (zh) |
| WO (1) | WO1997019685A1 (zh) |
| ZA (1) | ZA969586B (zh) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1401481A1 (en) * | 2001-06-14 | 2004-03-31 | Novo Nordisk A/S | Mucosal repair by tff dimer peptides |
| JP2006070027A (ja) * | 2004-08-06 | 2006-03-16 | Dai Ichi Seiyaku Co Ltd | 口腔粘膜投与剤 |
| US20060263414A1 (en) * | 2005-05-19 | 2006-11-23 | Pauline Pan | Confectionery products for the treatment of dry mouth |
| US20070077300A1 (en) * | 2005-09-30 | 2007-04-05 | Wynn David W | Oral compositions containing a salivation inducing agent |
| US20090053309A1 (en) * | 2007-08-24 | 2009-02-26 | Axiomedic Ltd., Gibraltar | Adhesive compositions for the treatment of xerostomia |
| US9161909B2 (en) * | 2007-08-24 | 2015-10-20 | Axiomedic Ltd. | Adhesive compositions for the treatment of xerostomia |
| CN114010575A (zh) * | 2021-10-22 | 2022-02-08 | 江苏谛奇医药科技有限公司 | 新斯的明及其衍生物的新制剂 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5187165A (en) * | 1987-05-15 | 1993-02-16 | Hoechst-Roussel Pharmaceuticals Inc. | Memory enhancing and analgesic 1,2,3a,8,8a-hexahydro-3a,8(and 1,3a,8)-di(and tri)methylpyrrolo[2,3-b]indoles |
| SE9103752D0 (sv) * | 1991-12-18 | 1991-12-18 | Astra Ab | New compounds |
| US5387614A (en) * | 1993-07-27 | 1995-02-07 | University Of Iowa Research Foundation | Use of sigma receptor ligands as salivary gland stimulants |
-
1995
- 1995-11-29 SE SE9504267A patent/SE9504267D0/xx unknown
-
1996
- 1996-11-14 ZA ZA969586A patent/ZA969586B/xx unknown
- 1996-11-18 AR ARP960105229A patent/AR004330A1/es unknown
- 1996-11-25 ES ES96940220T patent/ES2175153T3/es not_active Expired - Lifetime
- 1996-11-25 JP JP52040697A patent/JP4113257B2/ja not_active Expired - Fee Related
- 1996-11-25 DK DK96940220T patent/DK0866699T3/da active
- 1996-11-25 US US08/750,825 patent/US5962503A/en not_active Expired - Fee Related
- 1996-11-25 WO PCT/SE1996/001531 patent/WO1997019685A1/en active IP Right Grant
- 1996-11-25 CN CN96199706A patent/CN1207679A/zh active Pending
- 1996-11-25 CN CN2008101459688A patent/CN101380320B/zh not_active Expired - Fee Related
- 1996-11-25 AU AU77160/96A patent/AU718661B2/en not_active Ceased
- 1996-11-25 DE DE69620786T patent/DE69620786T2/de not_active Expired - Lifetime
- 1996-11-25 PT PT96940220T patent/PT866699E/pt unknown
- 1996-11-25 EP EP96940220A patent/EP0866699B1/en not_active Expired - Lifetime
- 1996-11-25 AT AT96940220T patent/ATE216235T1/de not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| Mahvash Navazesh et al.Xerostomia: Diagnosis and Treatment.Am J Otolaryngol.1983,4(4),283-292. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101380320A (zh) | 2009-03-11 |
| EP0866699A1 (en) | 1998-09-30 |
| AU718661B2 (en) | 2000-04-20 |
| ZA969586B (en) | 1997-05-29 |
| DE69620786D1 (de) | 2002-05-23 |
| DK0866699T3 (da) | 2002-08-12 |
| DE69620786T2 (de) | 2002-11-21 |
| SE9504267D0 (sv) | 1995-11-29 |
| AR004330A1 (es) | 1998-11-04 |
| JP4113257B2 (ja) | 2008-07-09 |
| US5962503A (en) | 1999-10-05 |
| CN1207679A (zh) | 1999-02-10 |
| ATE216235T1 (de) | 2002-05-15 |
| PT866699E (pt) | 2002-08-30 |
| ES2175153T3 (es) | 2002-11-16 |
| EP0866699B1 (en) | 2002-04-17 |
| AU7716096A (en) | 1997-06-19 |
| JP2000508618A (ja) | 2000-07-11 |
| WO1997019685A1 (en) | 1997-06-05 |
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