CN1604777A - 治疗方法 - Google Patents
治疗方法 Download PDFInfo
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- CN1604777A CN1604777A CNA028249364A CN02824936A CN1604777A CN 1604777 A CN1604777 A CN 1604777A CN A028249364 A CNA028249364 A CN A028249364A CN 02824936 A CN02824936 A CN 02824936A CN 1604777 A CN1604777 A CN 1604777A
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- 238000000034 method Methods 0.000 title claims description 7
- 206010020853 Hypertonic bladder Diseases 0.000 claims abstract description 42
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims abstract description 42
- 208000020629 overactive bladder Diseases 0.000 claims abstract description 42
- HXGBXQDTNZMWGS-RUZDIDTESA-N darifenacin Chemical compound C=1C=CC=CC=1C([C@H]1CN(CCC=2C=C3CCOC3=CC=2)CC1)(C(=O)N)C1=CC=CC=C1 HXGBXQDTNZMWGS-RUZDIDTESA-N 0.000 claims abstract description 32
- 229960002677 darifenacin Drugs 0.000 claims abstract description 31
- 239000003814 drug Substances 0.000 claims abstract description 4
- 230000027939 micturition Effects 0.000 claims description 28
- 241001597008 Nomeidae Species 0.000 claims description 16
- 239000002552 dosage form Substances 0.000 claims description 6
- 239000011159 matrix material Substances 0.000 claims description 3
- 150000003839 salts Chemical group 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims description 3
- 239000012730 sustained-release form Substances 0.000 claims description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 2
- 238000007599 discharging Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000902 placebo Substances 0.000 description 15
- 229940068196 placebo Drugs 0.000 description 15
- 238000011160 research Methods 0.000 description 11
- 206010046543 Urinary incontinence Diseases 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 230000003203 everyday effect Effects 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 230000000007 visual effect Effects 0.000 description 2
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- -1 acid-addition salts Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/402—1-aryl substituted, e.g. piretanide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
- Chemical Treatment Of Metals (AREA)
- Pyridine Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Processing Of Meat And Fish (AREA)
- Document Processing Apparatus (AREA)
- Inorganic Insulating Materials (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Diaphragms For Electromechanical Transducers (AREA)
Abstract
本发明提供了达非那新或其可药用衍生物在制备用于减轻患有膀胱过动症的患者尿急的药物中的用途。
Description
本发明涉及达非那新和其可药用衍生物的新用途。
达非那新是(S)-2-{1-[2-(2，3-二氢苯并呋喃-5-基)乙基]-3-吡咯烷基}-2，2-二苯基-乙酰胺，公开于欧洲专利No 0388054的实施例1B和8中。在其中它被称为3-(S)-(-)-(1-氨基甲酰基-1，1-二苯基甲基)-1-[2-(2，3-二氢-苯并呋喃-5-基)乙基]吡咯烷。据称它可以治疗尿失禁和肠易激综合征，其具有以下结构：
膀胱过动症(overactive bladder，OAB)的症状包括尿频和尿急，伴有或不伴有无局部病理学或系统病症的尿失禁。尿急在草拟的ICS术语报告[国际抗尿失禁协会术语报告；草案6，2001年8月15日]中被描述为难以控制的突然的强烈的排尿愿望。
最近，术语湿OAB(OAB Wet)和干OAB(OAB Dry)已被建议分别用于描述伴有或不伴有尿失禁的OAB患者。湿和干OAB在男性和女性中的总患病数相似，在美国患病率为16.6％[Stewart等人，在美国膀胱过动症的患病数：高贵活动的结果；2001年7月于法国巴黎举行的第二届国际尿失禁评议会上提交的摘要]。直到最近，人们一直认为OAB的主要症状是尿失禁。但是，随着新术语的出现，对于大量没有尿失禁的患病者(即干OAB患者)这显然没有意义。因此，Liberman等人的近期研究[在具有膀胱过动症症状的成年人中与健康相关的生活质量：以美国社区为基础的调查结果；Urology 57(6)，1044-1050，2001]调查了所有OAB症状对以社区为基础的美国人口样本的生活质量的影响。该研究证明：与对照相比较，患有无任何明显失尿的OAB的人生活质量受损。另外，与对照相比较，单有尿急的人生活质量受损。
因此，现在认为尿急是OAB的首要症状，但迄今为止尚未在临床研究中以定量方式对其进行评价。
现已发现达非那新和其可药用衍生物可用于减轻患有膀胱过动症的患者的尿急。
该发现令人惊讶，因为无法预测已知用于治疗尿失禁(即不自愿的且经常是不自主的漏出尿液)的化合物能减轻尿急感(即突然的强烈的排尿愿望)。甚至更令人惊讶的是达非那新和其可药用衍生物能减轻没有尿失禁的患者(即干OAB患者)的尿急感。
因此，根据本发明，提供了达非那新或其可药用衍生物在制备用于减轻患有膀胱过动症(OAB)的患者尿急的药物中的用途。
达非那新的可药用衍生物包括溶剂合物和盐，特别是酸加成盐，如氢溴酸盐。
待治疗的患者可以患有湿膀胱过动症(湿OAB)或干膀胱过动症(干OAB)。
达非那新或其可药用衍生物可以单独施用或以任何方便的药物形式施用，包括欧洲专利No 388054中所提及的那些形式。优选口服施用。在本适应症中，对于70kg的人，达非那新或其可药用衍生物中活性达非那新部分的适宜剂量为每天3.75-40mg，例如每天7.5-30mg。所述剂量可以以例如3个分剂量或以单一的控释制剂施用。
但是，优选达非那新或其可药用衍生物以适合于在患者的胃肠道下段释放至少10％达非那新或其可药用衍生物的剂型施用。所述剂型在美国专利No 6,106,864(其教导在此引入作为参考)中述及。优选的所述剂型是缓释骨架片(具体可参见美国专利No 6,106,864的实施例3)。
本发明还提供了用于减轻患有膀胱过动症的患者尿急的达非那新或其可药用衍生物。
本发明还提供了减轻患有膀胱过动症的患者尿急的方法，其包括将达非那新或其可药用衍生物施用于需要所述治疗的患者。
用以下实施例阐述本发明。
实施例
有膀胱过动症的对象的尿急的临床研究
使用了两种新方法评价尿急。第一种方法用于大规模临床试验，第二种方法用于临床实验室研究。
在这两项研究中，达非那新均以其氢溴酸盐形式施用。其剂型为美国专利No 6,106,864，特别是实施例3中所述的那种缓释骨架片。该片剂每天施用一次(o.d.)。
临床研究1
在本研究中，湿OAB患者在日志中记录每天的每次尿急发作以及每天尿急的总体严重性。使用其中定位点为轻度和重度的视觉模拟量表(visual analogue scale，VAS)记录尿急的严重性。
在多中心试验中，在诊断为膀胱过动症的对象中评价达非那新(为氢溴酸盐；7.5mg、15mg和30mg活性部分，o.d.)和安慰剂，并在基线和研究结束时(12周治疗)用VAS评估尿急症状。
108名患者(14名男性，94名女性)接受7.5mg；107名患者(15名男性，92名女性)接受15mg；114名患者(16名男性，98名女性)接受30mg；108名患者(18名男性，90名女性)接受安慰剂。
结果
达非那新(7.5-30mg)剂量相关性地降低临床研究中OAB对象所经历的尿急发作次数和尿急的总体严重性。其效应显著大于安慰剂所产生的效应。数据列于以下的表1和2中。
表1
达非那新和安慰剂对OAB患者的尿急频率和严重性的作用
| 尿急发作次数/天 | 安慰剂 | 7.5mg | 15mg | 30mg |
| 基线 | 8.1 | 8.5 | 8.6 | 8.4 |
| 与基线相比的中位数变化 | -1.2 | -1.8 | -2.3* | -3*** |
| 与基线相比的中位数百分比变化 | -15.7 | -29.2 | -26.9 | -33.1 |
| 尿急严重性/天 | 安慰剂 | 7.5mg | 15mg | 30mg |
| 基线 | 53.5 | 53.2 | 56.2 | 53.5 |
| 与基线相比的中位数变化 | -3.9 | -7 | -7* | -9.4* |
| 与基线相比的中位数百分比变化 | -8.0 | -14.2 | -11.6 | -19.9 |
*P＜0.05，**P＜0.01，***P＜0.001
表2
经安慰剂校正的达非那新对OAB患者尿急频率&严重性的作用
| 尿急发作次数/天 | 7.5mg | 15mg | 30mg |
| 基线 | 8.5 | 8.6 | 8.4 |
| 与安慰剂的中位数之差 | -0.5 | -1.1* | -1.4*** |
| 尿急严重性/天 | 7.5mg | 15mg | 30mg |
| 基线 | 53.2 | 56.2 | 53.5 |
| 与安慰剂的中位数之差 | -2.5 | -3.8* | -5.5* |
*P＜0.05，**P＜0.01，***P＜0.001
临床研究2
本研究使用了新方法测定尿急首次出现和需要排尿之间的时间，其被称为“警告时间”。使用了改进的秒表，要求所述对象在强烈愿望出现时按下按钮，且当他们感觉需要排尿时按下第二个按钮。
在具有尿急症状的对象中评价达非那新(为氢溴酸盐；30mg o.d.)和安慰剂。所述对象是湿OAB和干OAB患病者的混合体。在基线和治疗2周后用改进的秒表估算“警告时间”。
36名患者(29名女性，7名男性)接受达非那新；36名患者(22名女性，14名男性)接受安慰剂。
结果
与用安慰剂治疗的对象相比较，用达非那新治疗有尿急的对象使警告时间显著延长。数据列于表3中。
应注意的是湿OAB和干OAB对象均对治疗有反应。
表3
达非那新和安慰剂对有尿急和尿频的患者的警告时间的作用
| 警告时间(分钟) | 达非那新 | 安慰剂 |
| 基线(中位数) | 4.7 | 9.4 |
| 2周(中位数) | 8.4** | 4.1 |
*P＜0.05，**P＜0.01，***P＜0.001
与安慰剂的中位数之差为4.3分钟
结论
结果表明达非那新使患有膀胱过动症的患者的尿急症状临床上显著减轻。
Claims (9)
1.达非那新或其可药用衍生物在制备用于减轻患有膀胱过动症的患者尿急的药物中的用途。
2.权利要求1的用途，其中达非那新是可药用的酸加成盐形式。
3.权利要求1的用途，其中达非那新是其氢溴酸盐形式。
4.以上权利要求中任意一项的用途，其中待治疗的患者患有湿膀胱过动症。
5.权利要求1至3中任意一项的用途，其中待治疗的患者患有干膀胱过动症。
6.以上权利要求中任意一项的用途，其中达非那新或其可药用衍生物以适合于在患者的胃肠道下段释放至少10％达非那新或其可药用衍生物的剂型施用。
7.权利要求6的用途，其中剂型是缓释骨架片。
8.用于减轻患有膀胱过动症的患者尿急的达非那新或其可药用衍生物。
9.减轻患有膀胱过动症的患者尿急的方法，其包括将达非那新或其可药用衍生物施用于需要所述治疗的患者。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0129962.7A GB0129962D0 (en) | 2001-12-14 | 2001-12-14 | Method of treatment |
| GB0129962.7 | 2001-12-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1604777A true CN1604777A (zh) | 2005-04-06 |
| CN100488505C CN100488505C (zh) | 2009-05-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB028249364A Expired - Lifetime CN100488505C (zh) | 2001-12-14 | 2002-03-05 | 达非那新及其盐的用途 |
Country Status (28)
| Country | Link |
|---|---|
| US (3) | US20030130338A1 (zh) |
| EP (1) | EP1458376B1 (zh) |
| JP (3) | JP2005516925A (zh) |
| KR (1) | KR100889086B1 (zh) |
| CN (1) | CN100488505C (zh) |
| AT (1) | ATE341323T1 (zh) |
| AU (1) | AU2002236141B2 (zh) |
| BR (1) | BR0214925A (zh) |
| CA (1) | CA2469702C (zh) |
| CY (1) | CY1105814T1 (zh) |
| CZ (1) | CZ301283B6 (zh) |
| DE (1) | DE60215219T2 (zh) |
| DK (1) | DK1458376T3 (zh) |
| ES (1) | ES2276910T3 (zh) |
| GB (1) | GB0129962D0 (zh) |
| HK (1) | HK1073779A1 (zh) |
| HU (1) | HU229908B1 (zh) |
| IL (2) | IL162391A0 (zh) |
| MX (1) | MXPA04005760A (zh) |
| NO (1) | NO20042586L (zh) |
| NZ (1) | NZ533421A (zh) |
| PL (1) | PL206034B1 (zh) |
| PT (1) | PT1458376E (zh) |
| RU (1) | RU2321398C2 (zh) |
| SI (1) | SI1458376T1 (zh) |
| SK (1) | SK287510B6 (zh) |
| WO (1) | WO2003051354A1 (zh) |
| ZA (1) | ZA200404289B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101332178B (zh) * | 2007-06-29 | 2010-12-15 | 江苏正大天晴药业股份有限公司 | 一种用于口服的达非那新或其药用盐的药物制剂 |
| CN102048706A (zh) * | 2011-01-12 | 2011-05-11 | 山东创新药物研发有限公司 | 一种氢溴酸达非那新缓释片及制备方法 |
| CN102307579B (zh) * | 2009-02-04 | 2013-10-16 | 安斯泰来制药株式会社 | 经口给药用医药组合物 |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007109142A2 (en) * | 2006-03-17 | 2007-09-27 | Oregon Health & Science University | M3 muscarinic receptor antagonists for treating tumors |
| CZ300895B6 (cs) * | 2008-01-28 | 2009-09-02 | Zentiva, A. S. | Zpusob prípravy Darifenacinu |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8906166D0 (en) * | 1989-03-17 | 1989-05-04 | Pfizer Ltd | Therapeutic agents |
| GB9518953D0 (en) * | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
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2001
- 2001-12-14 GB GBGB0129962.7A patent/GB0129962D0/en not_active Ceased
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- 2002-03-05 CZ CZ20040719A patent/CZ301283B6/cs not_active IP Right Cessation
- 2002-03-05 CN CNB028249364A patent/CN100488505C/zh not_active Expired - Lifetime
- 2002-03-05 DK DK02702623T patent/DK1458376T3/da active
- 2002-03-05 WO PCT/IB2002/000664 patent/WO2003051354A1/en active IP Right Grant
- 2002-03-05 EP EP02702623A patent/EP1458376B1/en not_active Expired - Lifetime
- 2002-03-05 CA CA2469702A patent/CA2469702C/en not_active Expired - Lifetime
- 2002-03-05 BR BR0214925-7A patent/BR0214925A/pt active Search and Examination
- 2002-03-05 SI SI200230464T patent/SI1458376T1/sl unknown
- 2002-03-05 ES ES02702623T patent/ES2276910T3/es not_active Expired - Lifetime
- 2002-03-05 RU RU2004121780/15A patent/RU2321398C2/ru active
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101332178B (zh) * | 2007-06-29 | 2010-12-15 | 江苏正大天晴药业股份有限公司 | 一种用于口服的达非那新或其药用盐的药物制剂 |
| CN102307579B (zh) * | 2009-02-04 | 2013-10-16 | 安斯泰来制药株式会社 | 经口给药用医药组合物 |
| CN102048706A (zh) * | 2011-01-12 | 2011-05-11 | 山东创新药物研发有限公司 | 一种氢溴酸达非那新缓释片及制备方法 |
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