CN1202111A - 依匹斯汀在治疗疼痛中的用途 - Google Patents
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Abstract
本发明是关于使用依匹斯汀作为治疗疼痛,尤其是偏头痛,宾－霍顿(Bing－Horton)综合症,紧张性头疼,肌肉痛,炎性疼痛或神经痛的药物。
Description
本发明是关于依匹斯汀(Epinastine)用于治疗和预防疼痛，尤其是慢性或发炎引起的疼痛，及特别是偏头痛的新用途。
依匹斯汀(3-氨基-9，13b-二氢-1H-二苯并[c，f]-咪唑[1，5-a]-氮杂盐酸盐)由Fugner等人在药剂研究(Arzneimittelforschung)38(1988)：1446-1453中有说明。该有效物质可以以其消旋体形式或纯对映体形式或以不同比例的这两种对映体的混合物形式被使用。就治疗性而言，依匹斯汀是以盐酸盐的型式使用。然而，本发明并不限于盐酸，而是关于任何具有药理学上可接受的酸的加成盐，以及游离态碱本身。
依匹斯汀及其酸加成盐对治疗哮喘的用途是已知的。欧洲专利EP-B-0 035 749揭示该物质也适用于治疗过敏性疾病，如过敏性鼻炎，过敏性结膜炎，及过敏性支气管炎。
头痛是一种普遍发生的症状。在大多数情况下，头痛具有短时限，且易于用弱的镇痛药，如阿斯匹灵扑热息痛或异丁苯丙酸控制。这种头痛虽然令人烦厌，但是并不会导致任何明显的健康伤害。相反地，慢性再发性的头痛(如偏头痛)可以导致严重的伤害，以致必需找医生。使用弱的镇痛药治疗这种严重的头痛通常不能令人满意。
另一方面，并没有普遍可接受的分类头痛的***；本发明的意义，慢性再发性头痛主要是指偏头痛及宾-霍顿(Bing-Horton)综合症。偏头痛本身包含几种不同亚型[见J.Olesen与R.B.Lipto，神经学44(1944)第6-10页，分类]。虽然偏头痛和紧张性头痛是两种不同型式，一些科学家将它们视作以偏头痛在谱的一端，而紧张性头痛在谱的另一端的临床连续谱[K.L.Kumar和T.G.Cooney：“北美的医学临床(Medical Clinics of North America”中的；头痛”第79卷，第2期(1995)261页至286页]。因此，假定许多患有紧张性头痛的病人对偏头痛的治疗也有反应，似乎很合理。一些其它与慢性疼痛有关连的疾病，如神经痛，肌肉痛，及炎症痛(例如在晒斑后或骨关节炎或在运动伤害后)都具有慢性再发性疼痛的共同特征[A.Dray，L.Urban及A.Dickenson，药理科学的趋势(Trends in Pharmacololcal Sciences)15(1994)：190-197页]。
现有治疗偏头痛的方法包括使用麦角生物碱，如麦角胺，及5HT1D激动剂，如舒马坦(sumatriptan)。虽然许多病人受利于这些药物，但是，并非所有病人都有反应。此外，有许多副作用，如眩晕及恶心。预防处理偏头痛的药物包括二甲麦角新碱与苯噻啶，β-阻断剂如心得安，及钙沟阻断剂如氟苯桂嗪。这些药物的慢性使用可能具有会伤害病人的生活品质的副作用，且这些药物通常只会减少偏头痛侵袭的次数，而不会消除它们[见H.C.Diener，欧洲神经学(Eur.Neurol).34(增补2)(1994)：18-25.]。
因此，本发明的任务是提供一种用于治疗偏头痛的药物，该药物不仅有效，而且也没有明显的副作用。本发明的另一个任务是提供一种对于特殊病人团体如儿童，及患有肝或肾功能衰退，或心脏血管性疾病的病人，具高度安全性的药物。
令人惊异的是，发现依匹斯汀符合这些要求至异常程度。这可由下述研究结果表示：
在实验动物中，通过电刺激三叉神经节以诱导硬脑膜的发炎，它会引起神经肽如物质P，从感觉神经末端中释放。血浆外渗可以由标记物，如伊凡斯(Evans)蓝监测。该动物模式广泛用于试验治疗偏头痛的药物。令人惊讶的是，在该模式中，依匹斯汀呈现极优异的活性。
对炎性疼痛，广泛使用的动物模式首先由Randall和Selitto(L.O.Randall，和J.J.Selitto，国际药物学文献(Arch.Int Phrmacodyn.)。111(1957)：409-419)所描述。通过足底内注射酵母细胞以诱导鼠足掌的发炎，且测量炎症诱发的痛觉过敏。在该模式中，依匹斯汀也呈现令人惊讶的良好作用。
依匹斯汀作为抗组胺药是周知的。配位体(例如药物)和受体间的相互作用可以由亲和力常数(Ki)定量。亲和力常数的值愈小，药物与受体间的结合力愈强。这种显示较小Ki值的化合物受到特别的重视，因为它表明在标的组织(或血浆)中的浓度比预期的药物浓度小或有相同数量级。该5HT7受体是一种5-羟基色胺结合受体的特别亚型[为了分类方便，见`药理科学′(Pharmacological Sciences)1994受体及离子道命名法附刊`(Receptor & IonChannel Nomenclature Supplement)]。令人惊讶的是，发现依匹斯汀对于5HT7受体有良好的结合力。依匹斯汀和两种比较抗组胺药的Ki值列于表1。
所述的发明现在参考实施例予以说明。从本发明书中，熟悉本专业的人对其它方案是明显的。必需明确地指出，这些实例只是说明，而并不限制本发明。实例：依匹斯汀在5HT7受体上的结合力的研究
以CHO细胞表达的2.0nM[3H]LSD对鼠5HT7受体的结合力是在37℃下、pH7.4、含有10mM MgCl2与0.5mM EDTA的50mM Tris-HCl缓冲液中测定60分钟。在经0.1％聚亚乙基亚胺予处理的玻璃纤维滤纸上，快速真空过滤而停止该反应。在没有和有在3nM及10μM之间的6与8个浓度之间的依匹斯汀存在下进行重复测定。在各浓度存在下，测量在滤纸上沉积的放射性，且与对照值比较，以便确定该药物和克隆(cloned)的5-HT7受体的互相作用。在有5-羧基酰氨基色胺(5-CT)存在下测定非-特异性结合力。有放射性标记的配位体置换的IC50由图解外推法测定，且在由Cheng和普鲁索夫(Prusoff)方程式校正放射性配位体占有变化后，计算Ki值(见生化药理学(Biochem.Pharmacol.)22.(1973)：3099-3108)。进行三次实验。在各实验中，发现依匹斯汀明显良好地结合5HT7受体。所发现的依匹斯汀的平均Ki值为33nM，(+)对映体的平均Ki为28nM，而(-)对映体的平均Ki为189nM。在进行的三次实验中所发现的依匹斯汀及其对映体的各个Ki值与两种对照的抗组胺药的Ki一起列于表1中：表1：依匹斯汀(消旋体和对映体)和两种对照的抗组胺药(甲哌噻庚酮和甲氧苄二胺)对5HT7受体的结合力
| 化合物 | 完整的化学名字 | 测量的Ki值，nM |
| 依匹斯汀 | 3-氨基-9，13b-二氢-1H-二苯并-[c，f]-咪唑[1，5a]-氮杂-盐酸盐(消旋体) | 27，41，30 |
| 依匹斯汀(+)对映体 | (+)-3-氨基-9，13b-二氢-1H-二苯并-[c，f]-咪唑[1，5a]-氮杂-盐酸盐 | 45，18，22 |
| 依匹斯汀(-)对映体 | (-)-3-氨基-9，13b-二氢-1H-二苯并-[c，f]-咪唑[1，5a]-氮杂-盐酸盐 | 155，204，207 |
| 甲哌噻庚酮 | 406，572，331 | |
| 甲氧苄二胺 | 2660，747，1330 |
依匹斯汀对于由电刺激三叉神经节所诱导的
鼠硬脑膜的血浆外渗的影响的研究
用戊巴比妥(nembutal)50毫克/公斤腹腔内注射(i.p.)以麻醉重达175-190克的Wistar雄鼠，且使颈静脉***套管，以便注射药物。将该动物放置在趋实体性框中。从前囟对称地侧向钻孔3.0毫米，且在后面钻孔3.2毫米，然后从前囟降低电极9.5毫米。在电刺激右三叉神经节前10分钟，静脉内供给试验化合物依匹斯汀或对照物溶液(5分钟；2.0mA，5Hz，5ms持续期)，且在电刺激前5分钟，提供依凡斯蓝作为血浆蛋白质外渗的标记。在刺激期结束后15分钟，经由左心室，以50毫升生理盐液灌注该动物，以洗去血管内的伊凡斯蓝。分离硬脑膜，吸干，并称重。于50℃下，用0.3毫升甲酰胺萃取组织中的伊凡斯蓝24小时。使用分光光度计，于620nm波长测定染料浓度，在标准曲线上内推，且以每毫克组织重量的纳克(ng)伊凡斯蓝含量表示。数据计算：
外渗是以该刺激位置的伊凡斯蓝含量除以未经刺激的位置的伊凡斯蓝含量所计算而得的商表示。结果以平均值表示。该结果示于表2中。表2依匹斯汀在偏头痛的动物模式中的效果用1毫升/公斤的0.9％氯化钠溶液处理对照组(i.v.)
注：EB＝伊凡斯蓝 平均1.25以每公斤体重静脉注射10μg依匹斯汀在1ml0.9％氯化钠的溶液处理动物组
| 动物号 | 体重 | 经刺激位置的硬膜湿重 EB-含量 EB/湿重[mg] [μg/ml] [μg/ml] | 非经刺激位置的硬膜湿重 EB-含量 EB/湿重[mg] [μg/ml] [μg/ml] | 商经刺激/非经刺激位置 | ||||
| 1 | 180g | 4.24 | 0.85 | 0.060 | 5.58 | 0.73 | 0.039 | 1.54 |
| 2 | 185g | 5.34 | 0.76 | 0.043 | 5.13 | 0.60 | 0.035 | 1.23 |
| 3 | 185g | 5.06 | 0.47 | 0.028 | 4.60 | 0.38 | 0.025 | 1.12 |
| 4 | 190g | 6.05 | 1.33 | 0.066 | 6.23 | 1.03 | 0.050 | 1.32 |
| 5 | 185g | 4.22 | 0.72 | 0.051 | 5.77 | 0.67 | 0.035 | 1.46 |
| 6 | 185g | 4.81 | 0.57 | 0.036 | 5.03 | 0.54 | 0.032 | 1.13 |
| 7 | 185g | 7.62 | 1.35 | 0.053 | 6.53 | 1.22 | 0.056 | 0.95 |
| 动物号 | 体重 | 经刺激位置的硬膜湿重 EB-含量 EB/湿重[mg] [μg/ml] [μg/ml] | 非经刺激位置的硬膜湿重 EB-含量 EB/湿重[mg] [μg/ml] [μg/ml] | 商经刺激/非经刺激位置 | ||||
| 1234567 | 175g175g170g165g190g190g190g | 6.634.964.636.527.976.246.87 | 1.200.740.530.541.230.700.60 | 0.0540.0460.0340.0250.0460.0340.026 | 6.014.787.686.299.326.527.29 | 1.280.801.010.531.390.830.48 | 0.0640.0500.0390.0250.0450.0380.020 | 0.840.920.871.001.020.891.30 |
平均0.98
表2表示在偏头痛的动物模式中，经依匹斯汀的治疗显著地减少由电刺激三叉神经节所诱导的伊凡斯蓝外渗。
依匹斯汀对经酵母诱导的鼠足掌的痛觉过敏的影响的研究
Randall和Selitto的方法是通过使用米兰Basile的止痛计而进行修饰。
以含有0，0.3，1.0，3.0或10毫克/公斤的依匹斯汀(消旋体混合物)的1％Natrosol 250 HX，以每100克体重1毫升经口服喂10只已断食的Chbb：THOM种的鼠组(重量110-140克，5雄5雌)。1小时后，以0.1毫升体积的酵母细胞悬浮液足底注射入该鼠组的右后足掌。酵母悬浮液注射3小时后，增加该已发炎足掌的压力、直到产生疼痛迹象为止，以测定疼痛限值。从在不同剂量的依匹斯汀所测得的疼痛限值、使用直线回扫分析以决定ED50。如表3所示，依匹斯汀增加该疼痛限值。需要增加疼痛限值50％的依匹斯汀剂量经计算为1.1毫克/公斤。表3：依匹斯汀对已发炎鼠足掌的疼痛限值的影响。
表4：根据Randall Selitto的止痛作用的试验动物：雄/雌鼠重量：110至140克哺养法：断食用药法：1.0毫米/100克(p.o.)赋形剂：1％Natrosol90分钟值
| 物质 | 剂量毫克/公斤p.o. | 鼠数 | 疼痛限值的平均值，克/后爪 | 标准偏差 | 增加％ |
| 对照物依匹斯汀依匹斯汀依匹斯汀依匹斯汀 | 0.00.31.03.010.0 | 1010101010 | 150.4164.8235 2259.4272.8 | 30.441.851.560.760.9 | 9.656.472.581.4 |
| 物质 | 剂量mg/kg | N | 平均值 | 效应％ | SD | VK％ |
| 对照物 | 0/0 | 10 | 150 | 46.188 | 30.792 | |
| 依匹斯汀/异丁苯丙酸 | 0/3.0 | 10 | 153 | 2.00 | 20.028 | 13.090 |
| 依匹斯汀/异丁苯丙酸 | 0/10.0 | 10 | 202.00 | 34.67 | 29.740 | 14.723 |
| 依匹斯汀/异丁苯丙酸 | 0.3/0 | 10 | 216.00 | 44.00 | 44.020 | 20.380 |
| 依匹斯汀/异丁苯丙酸 | 0.3/3.0 | 10 | 252.00 | 68.00 | 57.116 | 22.665 |
| 依匹斯汀/异丁苯丙酸 | 0.3/10.0 | 10 | 277.00 | 84.67 | 81.792 | 29.528 |
| 依匹斯汀/异丁苯丙酸 | 1.0/0 | 10 | 232.00 | 54.67 | 57.889 | 24.952 |
| 依匹斯汀/异丁苯丙酸 | 1.0/3.0 | 10 | 295.00 | 96.67 | 70.593 | 23.930 |
| 依匹斯汀/异丁苯丙酸 | 1.0/10.0 | 10 | 369.00 | 146.00 | 107.233 | 29.060 |
依匹斯汀或其对映体可以以水溶液方式、经由适当途径，如静脉内注射，肌肉内注射或皮下注射，以片剂，栓剂，乳剂，经皮肤使用的膏剂，吸入肺部用药的气溶胶，或鼻内喷雾剂，以治疗疼痛。
一个片剂或一个栓剂的有效物质的含量为5-200毫克之间，优选的剂量为介于10与50毫克之间。对于吸入给药而言，单次剂量为介于0.05与20毫克之间，优选为介于0.2与5毫克之间。对于非经肠的注射给药，单次剂量为介于0.1与50毫克之间，优选剂量为介于0.5与20毫克之间。若有必要，上述剂量可以一天提供几次。
特别优选的是依匹斯汀和其它治疗剂，例如阿斯匹灵，或扑热息痛，或非-类脂醇的抗发炎药物(NSAID)如异丁苯丙酸(ibuprofen)，美洛昔康(meloxicam)，消炎痛(indomethacin)或纳普生(naproxen)；5HT1D激动剂如舒马坦(sumatriptan)，MK-462，纳拉里坦(naratriptan)或311C；CP-122,288；UK 116,044；多巴胺D2受体拮抗剂如灭吐灵(metoclopram)；麦角生物碱如麦角胺，二氢麦角胺或麦角苄酯(metergoline)；可乐宁(clonidine)；二甲麦角新碱(methysergide)；多他利嗪(dotarizine)；麦角乙脲(lisuride)；苯噻啶(pizotifen)；丙戊酸；氨基他特灵(aminotryptiline)；β阻断剂如心得安(propanolol)或甲氧乙心安(metoprolol)；钙通道拮抗剂如氟苯桂嗪(flunarizine)或乐美里辛(lomerizine)，或神经激肽拮抗剂，的组合。
以下为含有有效成份的药物配方的实例：片剂：依匹斯汀 20毫克硬脂酸镁 1毫克玉米淀粉 62毫克乳糖 83毫克聚乙烯基吡咯烷酮 1.6毫克可注射溶液：依匹斯汀 0.3克氯化钠 0.9克注射用水至100毫升该溶液可以使用标准方法灭菌。鼻内或吸入用药的溶液：依匹斯汀 0.3克氯化钠 0.9克氯苄烷胺 0.01毫克纯水至100毫升。
上述溶液适于以喷药方式鼻内施药，或与能够产生具有优选大小分布为2至6微米的颗粒的气溶胶的装置相结合，以便肺部给药。吸入剂的胶囊：
以微粉化形式(粒子大小介于2与6微米之间)使用的依匹斯汀通常添加有微粉化的载体物质(如乳糖)，并装入硬明胶的胶囊中。为用于吸入，一般用于粉末吸入给药的装置都可以使用。每个胶囊含有0.2与20毫克之间的依匹斯汀，及0与40毫克的乳糖。吸入性气溶胶依匹斯汀 1份大豆卵磷脂 0.2份推进剂气体混合物至100份。
该混合物最好装入具有计量阀的气溶胶容器，各次喷出量经测量是要供应0.5毫克剂量。对于所建议剂量范围中的其它剂量则使用具有较大或较少有效成份量的适当制剂。软膏
组合物，克/100克软膏
依匹斯汀 2
浓盐酸 0.011
焦亚硫酸钠 0.050
等份量的鲸蜡醇和硬脂醇的混合物 20
白色凡士林 5
合成香柠檬油 0.075
蒸馏水至 100
以一般方法混合各成份以便制造乳剂。
Claims (13)
1.依匹斯汀在治疗疼痛中的用途，它以其对映体、对映体混合物，或消旋体形式存在。
2.根据权利要求1的依匹斯汀的用途，它用于治疗偏头痛，宾-霍顿综合症，紧张性头痛，肌肉痛，炎性疼痛或神经痛。
3.以其消旋体或对映体形式存在的依匹斯汀在制造医疗性治疗疼痛的药物中的用途，它以游离态碱或和药理学上可接受的酸所形成的加成盐的形式存在。
4.根据权利要求3的以其消旋体或对映体形式的依匹斯汀的用途，它以游离态碱或和药理学上可接受的酸所形成的加成盐形式而用于制造用于医疗性治疗偏头痛，宾-霍顿综合症，紧张性头痛，肌肉痛，炎性疼痛或神经痛的药物。
5.根据权利要求1或2的以其消旋体或其对映体形式存在的依匹斯汀的用途，它是和另外的镇痛药组合使用。
6.根据权利要求5的以其消旋体或其对映体形式存在的依匹斯汀的用途，其特征在于，结合所用的另外镇痛剂为NSAID，5HT1D激动剂，多巴胺D2受体拮抗剂，麦角生物碱，β-阻断剂，钙通道阻断剂或神经激肽拮抗剂。
7.根据权利要求6的用途，其特征在于，该NSAID是异丁苯丙酸，美洛黄康，消炎痛或纳普生。
8.根据权利要求6的用途，其特征在于，该5HT1D激动剂是舒马坦，MK-462，纳拉里坦或311C。
9.根据权利要求6的用途，其特征在于，多巴胺D2受体拮抗剂是灭吐灵。
10.根据权利要求6的用途，其特征在于，麦角生物碱是麦角胺，二氢麦角胺或麦角苄酯。
11.根据权利要求6的用途，其特征在于，该β-阻断剂是心得安或甲氧乙心安。
12.根据权利要求6的用途，其特征在于，该钙通道阻断剂是氟苯桂嗪或乐美里辛。
13.根据权利要求6的用途，其特征在于，组合用的镇痛剂是阿斯匹灵，扑热息痛，可乐亭。二氢麦角新碱，多他利嗪，麦角乙脲，苯噻啶，丙戊酸，氨基他特灵，CP-122,288或UK 116,044。
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| Application Number | Priority Date | Filing Date | Title |
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| DE19542281A DE19542281C2 (de) | 1995-11-14 | 1995-11-14 | Verwendung von Epinastin für die Behandlung der Migräne |
| DE19542281.3 | 1995-11-14 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105708840A (zh) * | 2014-12-01 | 2016-06-29 | 重庆安格龙翔医药科技有限公司 | 一种盐酸依匹斯汀组合物 |
| CN115448927A (zh) * | 2022-10-20 | 2022-12-09 | 重庆瑞泊莱医药科技有限公司 | 一种氢溴酸依匹斯汀晶型ii及其制备方法 |
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