CN1915215A - 一种口腔崩解制剂 - Google Patents
一种口腔崩解制剂 Download PDFInfo
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- CN1915215A CN1915215A CN 200510090503 CN200510090503A CN1915215A CN 1915215 A CN1915215 A CN 1915215A CN 200510090503 CN200510090503 CN 200510090503 CN 200510090503 A CN200510090503 A CN 200510090503A CN 1915215 A CN1915215 A CN 1915215A
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- oral disintegrated
- disintegrated preparation
- preparation according
- oral
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Abstract
本发明涉及一种口腔崩解制剂,详细地说,涉及一种包含双组分作为粘合剂的口腔崩解制剂;本发明涉及的口腔崩解制剂,表面平整,光滑,色泽均匀,既保持一定的韧性又具有必要的硬度,防止了药品在运输过程中的损坏。
Description
技术领域
本发明涉及一种崩解制剂,特别涉及一种包含双组分作为粘合剂的口腔崩解制剂。
背景技术
口腔崩解制剂指的是能在口腔内迅速崩解或溶解的制剂,此类制剂在口腔中遇到唾液能迅速崩解并大部分溶解,无需水就可以服用。口腔崩解制剂出现于20世纪70年代后期,Gregory等采用冷冻干燥技术制造了高孔隙率的药物载体,该载体在口腔遇到唾液后崩解。口腔崩解制剂以其独特的优越性越来越受到患者的喜爱。这种制剂不需水送服,在口腔内遇到唾液迅速崩解,给一些吞咽功能不好和取水不便的病人服药提供了方便。
目前,口腔崩解制剂的制备方法,主要有直接压片法(Orasolv)和冷冻干燥法(Zydis),直接压片法是采取先以明胶作为粘合剂、羧甲基淀粉钠、低取代羟丙纤维素、交联羧甲纤维素钠、交联聚乙烯吡咯烷酮等作为崩解剂,另加入少量泡腾剂、崩解剂、矫味剂以及润滑剂,以较小压力直接压片而成。该方法工艺设备简单、生产周期短、因此目前市场上出售的口腔崩解制剂大部分是采用该技术制备的,但由于该方法中主要是通过使用崩解剂而使得制剂在口腔中迅速崩解,但是由于大多数的崩解剂不溶于水,因此采用该方法制备的口腔崩解制剂在患者口腔中崩解后,由于崩解剂只是崩解成小的颗粒,所以常常会有砂砾的感觉,急需要用水将其冲下;而在冷冻干燥法中,由于不使用崩解剂、所采用的辅料全部是水溶性的,崩解的原理是通过制剂中溶剂干燥后留下的多空隙性,使得制剂在口腔中崩解后,药物以及辅料能快速且完全分散于唾液中,从而克服了直接压片法制备的口腔崩解剂在口腔中砂砾感的缺陷,因此从长远前景来看,采用该方法制备口腔崩解制剂具有十分广泛的市场前景,但目前采用冷冻干燥法制备口腔崩解制剂时均采用单一辅料作为粘合剂来使用,例如US4305502公开了一种采用明胶作为粘合剂制备口腔崩解片的方法,明胶多来源于动物胶原组织的蛋白水解物,像皮、腱、韧带和骨骼,水解明胶作为药物的载体或骨架支持剂是常规技术。由于近年来,疯牛病、口蹄疫和羊骚病等动物源性疾病的出现,使水解明胶的安全性受到了越来越多的置疑;来源于猪的明胶替代品在穆斯林和其他一些宗教信仰人群中很难得到认同;而来源于动物的明胶制品是素食者所难以接受的。
以水解明胶为辅料的制剂加工工艺也有难度,首先表现为水解明胶必须加热才能充分溶解,使用水解明胶为辅料的生产工艺须有加热工序,这样的加热过程不但延长了口腔崩解制剂的制备时间,而且增加了生产成本;在传统的加工过程中需要将含有水解明胶的混合液放置较长时间以使液体体系分散均匀,但是随着放置时间的延长,以水解明胶为辅料的混合液粘度也随之增加,从而造成加工工艺难度的增加。水解明胶在升华干燥过程之中,易在未完全干燥的制剂表面形成一层致密的薄膜,阻碍水份从制剂内部的进一步升华干燥,从而造成产品的后续干燥更为困难,延长生产周期,提高生产成本;提高生产温度,还会造成不稳定的主药成分受到破坏。
水解明胶的另一个问题是其可应用的药物范围因此缩小。因水解明胶保留有蛋白和多肽的一些性质而不适用于制备易与蛋白、多肽发生反应的药物崩解制剂,因此水解明胶在含有酚羟基较多的化合物药物、中药及其有效成分中的应用受到了限制,例如水溶性丹酚酸盐,以及其他的含有鞣质的水溶性中药成分等。
为了克服明胶存在的问题,WO00/50013公开的采用单一辅料普鲁兰代替明胶,作为粘合剂来制备口腔崩解制剂,虽然该方法能克服了明胶存在的缺陷,而且也能在口腔迅速崩解,但使用该方法制备的口腔崩解制剂的外观比较粗糙,尤其是对于亲水性较好,能够溶解在水中的药物,使得产品在制备过程中成品率比较低,而且由单一的粘合剂普鲁兰制备的口腔速溶片剂,在片剂强度方面,虽然能够表现良好的弹性,但缺乏必要的硬度,使得运输过程中表面极易受到压迫而变形,进而影响片剂崩解。
因此,本发明的发明者为了克服上述的缺陷,进行了深入地研究,从而完成了本发明。
发明内容
本发明的目的就是提供一种不仅能在口腔中迅速崩解、而且制备的产品外观光滑平整,色泽均匀的口腔崩解制剂。
本发明的发明者经过长年的研究,现已研究出符合以上要求的口腔崩解制剂及其制备方法,从而完成了本发明。
本发明涉及的口腔崩解制剂,包含有效剂量的药物活性成分、骨架支持剂、粘合剂,上述的粘合剂包含至少两种高分子辅料;所述的高分子辅料选自选自右旋糖酐、普鲁兰、海藻酸钠、透明质酸、魔芋胶、明胶、改性淀粉和他们的混合物,优选右旋糖酐和普鲁兰,更优选右旋糖酐70和普鲁兰。
对于本发明涉及的口腔崩解制剂,作为对人体发挥作用的药物含量不受特别的限定,普通技术人员可以根据所要制备的药物活性成分的种类、特性以及市场的需求进行合适的选择。
本发明涉及的口腔崩解制剂中,各种辅料的比例,以各种辅料占据成型产品总的重量百分比计,普鲁兰重量比为1-40%,优选15-25%,更优选17%;右旋糖酐重量比为1-50%,优选20-40%,更优选36.7%;骨架支持剂重量比为10-40%,优选20-30%,更优选28.2%。
作为以上所述的骨架支持剂,选自糖、糖醇、无机盐、氨基酸和他们的混合物;其中氨基酸优选甘氨酸、丝氨酸、精氨酸和他们的混合物;更优选甘氨酸;所述的糖醇选自甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇和他们的混合物,更优选甘露醇;所述的糖选自木糖、棉籽糖、麦芽糖、葡萄糖、半乳糖、海藻糖、糊精、羟丙基倍他环糊精和他们的混合物。
作为本发明涉及的药物活性成分,水溶性药物或者脂溶性药物均可以,但优选能溶解于水的药物;而当药物表现为脂溶性时,进一步加入增稠助悬剂。
以上所述的加入增稠助悬剂的目的是以促进药物在溶剂中的均匀分布。所述的增稠助悬剂选自黄原胶、魔芋胶、天然来源胶、合成高分子化合物、多肽、多糖或它们的组合,更优选黄原胶、魔芋胶或它们的组合。所述的天然来源胶选自海藻胶、阿拉伯胶、瓜儿豆胶、琼脂、羟甲基纤维素、角叉菜胶、或果胶。所述的合成高分子优选聚乙烯吡咯烷酮。
本发明涉及的口腔崩解制剂,根据需要,进一步包含其它药学上可以接受的其它辅料,例如增稠稳定剂、表面活性剂、抗氧化剂、甜味剂、掩味剂、矫味剂、着色剂、透皮吸收促进剂、pH调节剂、抑菌剂等成分。
作为本发明涉及的口腔崩解制剂的制备方法,可以采用常规的冷冻干燥方法。所述的冷冻干燥方法就是将药物活性成分、所有的辅料分散于溶剂中,然后在低温下冷冻成固体,随后置于冻干机中真空冷冻干燥,除去制剂中的溶剂,形成固体制剂。低温冷冻的方法包括液氮冷冻、制冷剂冷冻等常规的方法,优选液氮冷冻。
用于本发明涉及的口腔崩解制剂的药物活性成分没有特别的限定,可以是一种或多种选自下组的药物:
化学药物:
止痛和抗炎药,例如吗啡、丁丙诺啡、罗痛定、丙磺舒、咖啡因等。
抗偏头痛药,例如佐米曲普坦、舒马普坦、双氢麦角胺等。
其他镇痛药,例如盐酸曲马多等。
抗抑郁药,例如盐酸氟西汀、文拉法辛、帕罗西汀等。
抗焦虑药、镇静剂、催眠药、安神药、抗癫痫药,例如奥氮平、五氟利多、利培酮等。
抗帕金森氏症药,例如左旋多巴、培高利特、溴隐亭等。
胆碱酯酶抑制药,例如东莨菪碱等。
其他神经系统用药,例如石杉碱甲、脑活素等。
拟肾上腺素药,例如多米君、多巴胺等。
肾上腺受体阻断剂,例如醋丁洛尔、阿普洛尔等。
抗心律失常药,例如胺碘酮、丙吡胺、黄杨宁等。
强心药,例如地高辛、C毛花甙。
抗高血压药,例如氨氯地平、比尼地平等。
脂调节剂,例如洛伐他汀等。
抗心绞痛药,例如硝酸甘油、单硝酸异山梨酯等。
其他心血管药,例如芦丁、磷酸肌酸等。
内分泌系统用药:
皮质甾类药,例如倍他米松、醋酸可的松等。
抗糖尿病药,例如瑞格列奈等。
抗甲状腺药,例如丙硫氧嘧啶、卡比马唑、甲巯咪唑等。
抗组织胺药,例如盐酸西替利嗪、氯雷他定等。
自体活性物质,例如地诺前列酮、前列地尔、倍他司汀等。
蛋白质、肽类和重组药物,例如胰岛素、胰高血糖素、生长激素多肽及其衍生物等。
麻醉用药,例如地氟烷、恩氟烷等。
营养药,例如各种氨基酸、各种维生素。
呼吸系统用药,例如枸橼酸喷托维林、硫酸沙丁胺醇、孟鲁司特钠、扎鲁司特等。
消化系统用药,例如丁溴东莨菪碱、盐酸格拉司琼等。
血液系统药,例如EPO、腺苷钴胺等。
泌尿系统药,例如阿佐塞米、呋塞米等。
生殖系统药,例如雌激素、苯丙酸诺龙等。
抗寄生虫药,例如阿苯达唑、坎苯达唑等。
抗肿瘤药,例如氨鲁米特、安吖啶等。
抗微生物药,例如氨苄西林、磺苄西林钠等。
其他如枸橼酸西地那非等。
口服疫苗,例如流感、结核病的疫苗。
用于预防和减轻由弧菌属、沙门菌属等微生物引起的疾病的疫苗。
用于非传染性免疫调节疾病的疫苗,如:枯草热、哮喘、类风湿关节炎、癌症等,
直接用于以下兽医的疫苗,如:新城病、猫白血病、萎缩性鼻炎、丹毒、口蹄疫、肺炎等
中药有效成分单体,如:灯盏花素、青蒿素等。
单味中药材提取物,如:丹参酮、丹参酚酸等。
复方中药提取物,如:复方丹参滴丸提取物、牛黄上清丸复方提取物等。
本发明涉及的口腔崩解制剂,在口中就可以完全崩解,无须用水辅助给药,特别适合于某些特殊人群(如高龄老人、长期卧床病人以及呕吐厉害的病人);
附图说明
图1是比较例1制备的口腔崩解制剂放大10倍的扫描电镜图片。
图2是比较例1制备的口腔崩解制剂局部放大100倍的扫描电镜图片。
图3是比较例1制备的口腔崩解制剂局部放大500倍的扫描电镜图片。
图4是比较例2制备的口腔崩解制剂放大10倍的扫描电镜图片。
图5是比较例2制备的口腔崩解制剂局部放大100倍的扫描电镜图片。
图6是比较例2制备的口腔崩解制剂局部放大500倍的扫描电镜图片。
图7是实施例1制备的口腔崩解制剂放大10倍的扫描电镜图片。
图8是实施例1制备的口腔崩解制剂局部放大100倍的扫描电镜图片。
图9是实施例1制备的口腔崩解制剂局部放大500倍的扫描电镜图片。
具体实施方式
以下通过实施例和比较例进一步详细地说明本发明,但这些实施例只是本发明的举例,本发明并不仅仅限于此。
根据表1所示的成分及其数量制备口腔崩解制剂,其具体方法如下:
将表1中所述的骨架支持剂和普鲁兰(Hayashibara Co.Ltd.,Japan)和根据需要而加入的助悬剂以及其他辅料,混匀,加入适量的纯化水,室温充分搅拌至全部溶解;加入表1所示数量的药物活性成分混匀,加适量的纯化水,使得以上全部加入的纯化水的总量为表中所示的纯化水的总量,制得药液;将药液真空脱气,然后使用电子移液枪(北京吉诺斯科贸有限公司、720110\710040)精确注入到0.4毫升模具中,经液氮(北京普莱克斯实用气体有限公司、XL-45)喷淋制冷在-110℃冷冻5分钟后,转入冻干机(北京速原中天科技有限公司,GLZ-0.8)中,在0.5毫巴压力、-20℃至25℃的条件下冻干5小时,即得到本发明的口腔崩解制剂。
表1
药物活性成分 | 骨架支持剂 | 粘合剂 | 纯化水 | 助悬剂 | 其他辅料 | ||
普鲁兰 | 右旋糖酐70 | ||||||
实施例1 | 10mg的单硝酸异山梨酯 | 20mg的甘氨酸 | 12mg | 26mg | 332mg | ||
实施例2 | 5mg的盐酸倍他司汀 | 6mg的甘露醇 | 4mg | 6mg | 179mg | ||
实施例3 | 25mg的盐酸阿米替林 | 16mg的甘露醇 | 12mg | 24mg | 321.7mg | 0.8mg的薄荷醇0.5mg的安赛密 | |
实施例4 | 5mg的佐米曲普坦 | 5mg的甘氨酸 | 5mg | 6mg | 178.9mg | 0.1mg黄原胶 | |
比较例1 | 10mg的单硝酸异山梨酯 | 20mg的甘氨酸 | 12mg | 0 | 358mg | ||
比较例2 | 10mg的单硝酸异山梨酯 | 20mg的甘氨酸 | 0 | 26mg | 344mg |
注:甘氨酸:北京精求化工有限责任公司,
甘露醇:北京精求化工有限责任公司
薄荷醇:苏州禾田香料有限公司
安赛密:张家港浩波化学品有限公司
右旋糖酐70:黑龙江完达山制药厂
从图1-9可以看出,当采用普鲁兰或者右旋糖酐作为独立粘合剂制备口腔崩解制剂时,会出现花边,碎边,表层龟裂,轻度萎缩等缺陷(见说明书附图1-6),由于这些缺陷,使得采用比较例2和比较例3的处方制备的片剂在运输过程或者消费者服用的实施容易受到损害从而使得服用的剂量不够,因此必须对这两种片剂进行额外的包装使其免于受到外界的损害,而这无疑会大大增加了产品的成本。而当采用本发明涉及辅料普鲁兰和右旋糖酐以适当比例作为复合粘合剂使用时,制备的口腔崩解制剂外观色泽均匀、致密、完整,无任何塌陷等缺陷,完全符合国家有关部门要求的上市标准。
应该注意的是,对于本发明的各种细节可以进行任意的修改,但毫无疑问,这些修改都将落入本发明的保护范围之内。
Claims (19)
1.一种口腔崩解制剂,包含有效剂量的药物活性成分、骨架支持剂、粘合剂,所述的粘合剂包含至少两种高分子辅料。
2.根据权利要求1所述的口腔崩解制剂,其中,所述的高分子辅料选自右旋糖酐、普鲁兰、海藻酸钠、透明质酸、魔芋胶、明胶、改性淀粉和他们的混合物。
3.根据权利要求2所述的口腔崩解制剂,其中,所述的高分子辅料包含右旋糖酐和普鲁兰。
4.根据权利要求3所述的口腔崩解制剂,其中,普鲁兰重量比为1-40%,右旋糖酐重量比为1-50%,骨架支持剂重量比为10-40%。
5.根据权利要求4所述的口腔崩解制剂,其中,普鲁兰重量比为15-25%,右旋糖酐重量比为20-40%,骨架支持剂重量比为20-30%。
6.根据权利要求5所述的口腔崩解制剂,其中,普鲁兰重量比为17%,右旋糖酐重量比为36.7%,骨架支持剂重量比为28.2%。
7.根据权利要求1-6任意一项所述的口腔崩解制剂,其中,所述的骨架支持剂选自糖、糖醇、无机盐、氨基酸和他们的混合物。
8.根据权利要求7所述的口腔崩解制剂,其中,氨基酸选自甘氨酸、丝氨酸、精氨酸和他们的混合物。
9.根据权利要求7所述的口腔崩解制剂,其中,糖醇选自甘露醇、山梨醇、麦芽糖醇、木糖醇、乳糖醇、赤藓糖醇、异麦芽糖醇和他们的混合物,糖选自木糖、棉籽糖、麦芽糖、葡萄糖、半乳糖、海藻糖、糊精、羟丙基环糊精和他们的混合物。
10.根据权利要求8所述的口腔崩解制剂,其中,氨基酸为甘氨酸。
11.根据权利要求9所述的口腔崩解制剂,其中,糖醇为甘露醇。
12.根据权利要求1-6、8-11任意一项所述的口腔崩解制剂,其中,药物活性成分优选易溶于水的药。
13.根据权利要求7所述的口腔崩解制剂,其中,药物活性成分优选易溶于水的药。
14.根据权利要求1-6、8-11任意一项所述的口腔崩解制剂,其中,药物活性成分不溶于水时,加入增稠助悬剂。
15.根据权利要求7所述的口腔崩解制剂,其中,药物活性成分不溶于水时,加入增稠助悬剂。
16.根据权利要求1-6、8-11、13、15任意一项所述的口腔崩解制剂,还可以包含增稠稳定剂、表面活性剂、抗氧化剂、甜味剂、掩味剂、矫味剂、着色剂、透皮吸收促进剂、pH调节剂、抑菌剂。
17.根据权利要求7所述的口腔崩解制剂,还可以包含增稠稳定剂、表面活性剂、抗氧化剂、甜味剂、掩味剂、矫味剂、着色剂、透皮吸收促进剂、pH调节剂、抑菌剂。
18.根据权利要求12所述的口腔崩解制剂,还可以包含增稠稳定剂、表面活性剂、抗氧化剂、甜味剂、掩味剂、矫味剂、着色剂、透皮吸收促进剂、pH调节剂、抑菌剂。
19.根据权利要求14所述的口腔崩解制剂,还可以包含增稠稳定剂、表面活性剂、抗氧化剂、甜味剂、掩味剂、矫味剂、着色剂、透皮吸收促进剂、pH调节剂、抑菌剂。
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