CN111529489A - 一种含有地西泮的鼻腔喷雾剂 - Google Patents
一种含有地西泮的鼻腔喷雾剂 Download PDFInfo
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Abstract
本发明提供了一种含有地西泮的鼻腔喷雾剂，该喷雾剂由地西泮、溶剂、促渗透剂、抗氧剂和抑菌剂组成。通过鼻腔喷雾给药，用于治疗癫痫的反复发作。
Description
技术领域
本发明属于医药技术领域，具体的说涉及一种含有地西泮的鼻腔喷雾剂。
背景技术
癫痫是大脑神经元突发性异常放电，导致短暂的大脑功能障碍的一种慢性疾病。据中国最新流行病学资料显示，国内癫痫的总体患病率为7.0‰，年发病率为28.8/10万，1年内有发作的活动性癫痫患病率为4.6‰。据此估计中国约有900万左右的癫痫患者，其中500～600万是活动性癫痫患者，同时每年新增加癫痫患者约40万，在中国癫痫已经成为神经科仅次于头痛的第二大常见病。
癫痫可见于各个年龄段。儿童癫痫发病率较成人高，随着年龄的增长，癫痫发病率有所降低。进入老年期由于脑血管病、老年痴呆和神经系统退行性病变增多，癫痫发病率又见上升。
癫痫病做为一种慢性疾病，虽然短期内对患者没有多大的影响，但是长期频繁的发作可导致患者的身心、智力产生严重影响。主要包括：1、生命的危害：癫痫患者经常会在任何时间、地点、环境下且不能自我控制地突然发作，容易出现摔伤、烫伤、溺水、交通事故等。2、精神上的危害，癫痫患者经常被社会所歧视，在就业、婚姻、家庭生活等方面均遇到困难，患者精神压抑，身心健康受到很大影响。3、认知障碍，主要表现为患者记忆障碍、智力下降、性格改变等，最后逐渐丧失工作能力甚至生活能力。
癫痫发作特点有一下几点：1、大发作：约占癫痫发作的50％，多在1岁左右或14-17岁之间。大发作可分四个时期：(1)先兆期：有头晕、胃部不适。(2)强直期：突然意识丧失、倒地、头后仰、肢体强直，由于隔肌痉挛，病人发出"羊羔"样吼叫，面色青紫、瞳孔散大、呼吸暂停，持续数十秒不等。(3)阵挛期：全身肌肉有节律性抽动、常咬破舌头、口吐白沫、可伴有大小便失禁，一般持续1-3分钟。(4)恢复期：一般要数十分钟才能清醒，病人对发作过程不能回忆，全身疼痛、乏力。个别病人在恢复期有狂燥、乱跑乱叫、打人毁物等情况发生。2、小发作：痴痫小发作又称失神发作，典型的表现为病人有短暂意识丧失，大多数意识完全丧失，偶尔意识障碍较浅，对周围有所了解，能听见问话，但不能回答。意识障碍短暂而频发为其特点。多数每次发作2-15秒，不超过1分钟，每日数次至数十次。突然发生，突然终止。表现为言语及活动突然中断，两眼凝视，偶尔上翻，有时面色苍白，无先兆。手中持物落地，有时打碎饭碗，发作停止后，继续原来的活动。3、精神运动性发作：在意识障碍的背景上，常有错觉、幻觉及自动症等。因多由颞叶病变引起，故又称颞叶癫痫。发病年龄在各型癫痫中较晚，多在20岁左右首次发病。约有40％的病人发病时有先兆，感到胃部不适、幻听、幻味、眩晕、恶心、恐惧等。
目前癫痫的治疗包括药物治疗、手术治疗、神经调控治疗等。
目前国内外对于癫痫的治疗主要以药物治疗为主。癫痫患者经过正规的抗癫痫药物治疗，约70％的患者其发作是可以得到控制的，其中50％～60％的患者经过2～5年的治疗是可以痊愈的，患者可以和正常人一样地工作和生活。因此，合理、正规的抗癫痫药物治疗是关键。
选择抗癫痫药物时总的原则：对癫痫发作及癫痫综合征进行正确分类是合理选药的基础。此外还要考虑患者的年龄(儿童、成人、老年人)、性别、伴随疾病以及抗癫痫药物潜在的副作用可能对患者未来生活质量的影响等因素。如婴幼儿患者不会吞服药片，应用糖浆制剂既有利于患儿服用又方便控制剂量。儿童患者选药时应注意尽量选择对认知功能、记忆力、注意力无影响的药物。老年人共患病多，合并用药多，药物间相互作用多，而且老年人对抗癫痫药物更敏感，副作用更突出。因此老年癫痫患者在选用抗癫痫药物时，必须考虑药物副作用和药物间相互作用。对于育龄期女性癫痫患者应注意抗癫痫药对激素、性欲、女性特征、怀孕、生育以及致畸性等的影响。传统抗癫痫药物(如苯妥英钠、苯巴比妥)虽有一定临床疗效，但是副作用较多如齿龈增生、毛发增多、致畸率高、多动、注意力不集中等，患者不易耐受。
地西泮为苯二氮卓类抗焦虑药，具有抗焦虑、镇静、催眠、抗惊厥、抗癫痫及中枢性肌肉松弛作用。是目前临床上最常用的催眠药。此外还具有较好的抗癫痫作用，对癫痫持续状态极有效，静脉注射时可使70％～80％的癫痫得到控制，控制癫痫持续状态时应静脉注射。
发明内容
本发明提供了一种地西泮鼻腔喷雾剂，用于治疗癫痫的反复发作。鼻腔黏膜给药具有起效快、药物吸收完全、不受胃肠道首过效应的影响、用药方便的特点，与注射剂相比，鼻腔喷雾剂自带专用容器，不需要使用前的复杂操作，使用快速简便，尤其适用于癫痫的反复发作。因癫痫发作时起病急，病程长，易反复，长期住院和反复送急诊不太可行，因此，在反复发作的情况下及时给予快速有效的药物非常重要。本发明提供的地西泮鼻腔喷雾剂，给药方便，不需要专业的医护知识，按说明操作即可，鼻腔给药起效迅速，同时不受癫痫发作时身体强直、肌肉紧张的影响，具有比注射剂更好的给药操作。
本发明提供的地西泮鼻腔喷雾剂，一种含有地西泮的鼻腔喷雾剂，其特征在于，本品由地西泮、溶剂、促渗透剂、抗氧剂和抑菌剂组成。
鼻腔喷雾剂的溶剂可以使用醇类或纯化水或二者的组合，本发明选择的溶剂为75％乙醇，75％乙醇具有良好的黏膜穿透性，可以在保证药物溶解度的情况下促进药物的快速吸收。
鼻腔喷雾剂为液体制剂，一般需加入抑菌剂，本发明选择的抑菌剂为苯甲醇浓度为5％(V/V)～15％(V/V)，优选为10％。另外，苯甲醇还具有局部麻醉作用，可以减轻高浓度乙醇对鼻粘膜的刺激性。
为促进药物快速吸收，本发明的鼻腔喷雾剂加入了促渗透剂，促渗透剂为月桂酰基麦芽糖苷，含量为0.1％～2.0％，优选为1％。
为增强药物的稳定性，本发明在鼻腔喷雾剂中加入了抗氧剂，抗氧剂为维生素E，含量为10mg/ml～100mg/ml，优选为50mg/ml。
本发明所述的鼻腔喷雾剂的制备方法为：取75％乙醇，依次加入苯甲醇和维生素E，搅拌溶解，然后加入月桂酰基麦芽糖苷，搅拌溶解，最后加入地西泮搅拌溶解，经除菌过滤后，得澄清溶液，灌装到鼻腔喷雾剂专用瓶中。
具体实施方式
下面通过非限制性实施例描述本发明。
实施例一
| 成分 | 用量 |
| 地西泮 | 25g |
| 月桂酰基麦芽糖苷 | 10g |
| 苯甲醇 | 100ml |
| 维生素E | 50g |
| 75％乙醇 | 加至1000ml |
| 总量 | 1000ml |
制备方法：将月桂酰基麦芽糖苷、维生素E和苯甲醇溶解于无水乙醇中，搅拌均匀，加入地西泮，搅拌均匀，以0.22μm滤膜过滤除菌，灌装到定量鼻腔喷雾剂瓶中，每瓶10ml，每揿0.1ml给药。
实施例二
制备方法：将月桂酰基麦芽糖苷、维生素E和苯甲醇溶解于无水乙醇中，搅拌均匀，加入地西泮，搅拌均匀，以0.22μm滤膜过滤除菌，灌装到定量鼻腔喷雾剂瓶中，每瓶10ml，每揿0.1ml给药。
实施例三
| 成分 | 用量 |
| 地西泮 | 100g |
| 月桂酰基麦芽糖苷 | 10g |
| 苯甲醇 | 150ml |
| 维生素E | 100g |
| 75％乙醇 | 加至1000ml |
| 总量 | 1000ml |
制备方法：将月桂酰基麦芽糖苷、维生素E和苯甲醇溶解于无水乙醇中，搅拌均匀，加入地西泮，搅拌均匀，以0.22μm滤膜过滤除菌，灌装到定量鼻腔喷雾剂瓶中，每瓶10ml，每揿0.1ml给药。
实施例四
| 成分 | 用量 |
| 地西泮 | 50g |
| 月桂酰基麦芽糖苷 | 1g |
| 苯甲醇 | 50ml |
| 维生素E | 10g |
| 75％乙醇 | 加至1000ml |
| 总量 | 1000ml |
制备方法：将月桂酰基麦芽糖苷、维生素E和苯甲醇溶解于75％乙醇中，搅拌均匀，加入地西泮，搅拌均匀，以0.22μm滤膜过滤除菌，灌装到定量鼻腔喷雾剂瓶中，每瓶10ml，每揿0.1ml给药。
对比实施例
| 成分 | 用量 |
| 地西泮 | 100g |
| 苯甲醇 | 150ml |
| 维生素E | 100g |
| 75％乙醇 | 加至1000ml |
| 总量 | 1000ml |
制备方法：将维生素E和苯甲醇溶解于75％乙醇中，搅拌均匀，加入地西泮，搅拌均匀，以0.22μm滤膜过滤除菌，灌装到定量鼻腔喷雾剂瓶中，每瓶10ml，每揿0.1ml给药。
鼻腔黏膜渗透性试验
实验用鼻黏膜的处理将死亡1h内的猪鼻部取下，切开鼻腔，暴露出鼻中隔及两侧鼻甲骨，用圆头细玻璃棒及镊子小心剥离鼻腔薄膜，采用生理盐水洗除薄膜上残留的血迹，再将薄膜放在一片铝箔上，铺开，立即使用。
采用Franz扩散池法，有效扩散面积为3.14cm2，接收池容积为14mL。于接收室内加入电磁搅拌子和14mL生理盐水，并及时排出气泡。将猪鼻黏膜层固定在接收室和供给室之间，置于水浴温度37℃、3000r/min的恒温磁力搅拌器上，平衡20min。然后将地西泮鼻腔喷雾剂实施例3和对比实施例各取1mL加入供给室鼻黏膜上，分别于0、5、10、15、20、30min各取样1mL，每次取样后补加等量新鲜接收液，共取6个样品。将取得的样品经0.22μm滤膜滤过后，取20μL注入液相色谱仪测定峰面积，并计算其量。用十八烷基硅烷键合硅胶为填充剂；以甲醇-水(70:30)为流动；检测波长为254nm。计算累积渗透量(Qn)。
Cn和Ci分别代表第n、i个取样点测得的药物质量浓度(g/mL)，V和V0分别代表接收池体积和取样体积(mL)。
结果：
| 时间 | 5min | 10min | 15min | 20min | 30min |
| 实施例3 | 71.2％ | 88.5％ | 92.6％ | 99.3％ | 99.5％ |
| 对比实施例 | 46.8％ | 58.3％ | 69.8％ | 78.4％ | 85.2％ |
根据结果可知，实施例3的样品鼻粘膜渗透速率显著高于对比实施例，表明促渗透剂月桂酰基麦芽糖苷对地西泮的渗透起到显著作用。
本发明制剂(实施例3)稳定性试验结果
Claims (9)
1.一种含有地西泮的鼻腔喷雾剂，其特征在于，由地西泮、溶剂、促渗透剂、抗氧剂和抑菌剂组成。
2.根据权利要求1所述的鼻腔喷雾剂，其中地西泮的含量为2.5％-10％(W/V)。
3.根据权利要求1所述的鼻腔喷雾剂，其中溶剂为75％乙醇。
4.根据权利要求1所述的鼻腔喷雾剂，其中抗氧剂为维生素E。
5.根据权利要求1所述的鼻腔喷雾剂，其中抑菌剂为苯甲醇。
6.根据权利要求5所述的鼻腔喷雾剂，其中苯甲醇的浓度为5％～15％(V/V)，优选为10％。
7.根据权利要求4所述的鼻腔喷雾剂，其中维生素E的含量为1％-10％(W/V)，优选为5％(W/V)。
8.根据权利要求1所述的鼻腔喷雾剂，其中促渗透剂为月桂酰基麦芽糖苷。
9.根据权利要求8所述的鼻腔喷雾剂，其中月桂酰基麦芽糖苷的含量为0.1％～2.0％(W/V)，优选为1％(W/V)。
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