CN109010295A - 一种左甲状腺素钠冻干口腔崩解片 - Google Patents
一种左甲状腺素钠冻干口腔崩解片 Download PDFInfo
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- CN109010295A CN109010295A CN201810997165.9A CN201810997165A CN109010295A CN 109010295 A CN109010295 A CN 109010295A CN 201810997165 A CN201810997165 A CN 201810997165A CN 109010295 A CN109010295 A CN 109010295A
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- Prior art keywords
- levothyroxine sodium
- gelatin
- oral disnitegration
- disnitegration tablet
- drying
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Abstract
提供一种左甲状腺素钠口腔崩解片制备方法。该口腔崩解片采用冻干工艺,左甲状腺素钠稳定性获得充分的保障,解决了诸多病患服药不便的困难。
Description
技术领域
本发明涉及一种左甲状腺素钠口腔崩解片的制备方法。该口腔崩解片采用冻干工艺,左甲状腺素钠稳定性获得充分的保障,大幅改善了喉颈部手术、无意识、没有自理能力或抗拒服药的甲状腺素缺乏病患人群的服药顺应性。属于医药领域。
背景技术
甲状腺素是人体自身产生的一种内源性激素,对身体的健康和各项机能至关重要。左甲状腺素钠又称四碘甲状腺原氨酸钠(L-T4),是人体内源性甲状腺素的左旋同分异构体的单钠盐。甲状腺功能的亢进,降低或摘除会直接导致人体内甲状腺素水平过高,过低或缺失。甲状腺功能亢进造成机体代谢亢进和交感神经兴奋,引起心悸、心动过速、出汗、进食增多和体重减少等。多数患者还伴有突眼、眼睑水肿、视力减退等症状。而甲状腺功能降低将造成机体代谢减弱、容易疲乏、虚胖、畏寒、智力和记忆力减退等等。左甲状腺素钠可以有效调节人体内甲状腺素水平。临床上无论甲亢、甲减还是甲状腺摘除,左甲状腺素钠都是至关重要的治疗药物。
左甲状腺素钠对光、热、湿均表现出不稳定,且与大量辅料存在相容性问题,所以药品制剂中所使用辅料越少,药品潜在稳定性风险可能也更少。
左甲状腺素钠目前以片剂形式上市,规格为50μg、100μg。然而,在病患服用片剂的时候,经常会遇到一些服用不方便的情况。例如喉颈部手术、无意识、没有自理能力或抗拒服药的甲状腺素缺乏病患人群用药时。片剂的给药形式并不能满足所有的患者需求。
美国药品监管机构FDA要求左甲状腺素钠片中左甲状腺素钠在效期内效价应为标示的95%~105%,中国药品标准中相关要求与此接近。左甲状腺素钠公认的稳定性不良,其口服固体片剂在较高的光、热、空气和湿度的条件下都不甚稳定。CN200480019774中葛兰素公司通过将微晶纤维素和预胶化淀粉进行微粉化的方式进行制备,以使产品能符合要求。CN201380042787默克公司解决左甲状腺素钠稳定性的方式是,将左甲状腺素钠溶解于明胶水溶液中,然后以特定设备将其喷干与其他辅料表面。此外再提到加入柠檬酸和丁羟甲苯进一步改善稳定性。CN200810172608中,柏林化学公司提出了一种固定物料组合方式尝试解决左甲状腺素钠的稳定性问题,其中包含了磷酸氢钙及淀粉羟乙酸钠。这些技术都是将左甲状腺素钠制成了普通的压制片。这种常规的湿法或干法口服固体制剂的共同缺陷,它们都具有。
由于左甲状腺素钠的治疗剂量非常小、制剂规格非常小、常规的湿法或干法口服固体制剂工艺难以很好地保障小规格产品的均匀性是共知的。左甲状腺素钠治疗指数非常窄的特点,则预示着目前口服片剂经常需要通过手动掰片后服下的服用方式以调整患者服药剂量,这些有比其他药品更高的使用风险。
美国食药监管理部门FDA明确规定,口腔崩解片是在口腔内能够迅速崩解(限度不超过1分钟,通常为30秒)的制剂。以前人们以口腔片、速溶片、口腔速溶片、速崩片、速液化咀嚼片等作为此类制剂的名称,为避免名称的混淆,我国国家食品药品监督管理总局药品审评中心将在口腔中快速崩解(或溶解)的片剂,统一规定为“口腔崩解片(OrallyDisintegrating Tablets,ODT)”,其定义为一种在口腔内不需水即能崩解或溶解的片剂。
发明者通过冻干工艺将左甲状腺素钠制成冻干口腔崩解片后,惊喜地发现解决了目前市面上多数口服左甲状腺素钠产品所遇到的问题。冻干口腔崩解片制备过程中,将左甲状腺素钠溶解于明胶水溶液中,冻干后产品完全均一,没有不匀的风险。
本发明工艺,将左甲状腺素钠溶解于含明胶的水溶液中,迅速深度冻结,固体状态下,通过升华,除掉水分。这些工序可以有效规避水分、热、光等因素对稳定性的不利影响。本发明制成产品,左甲状腺素钠稳定性得到了充分保障,优于传统工艺口服固体制剂。
本发明制成的冻干左甲状腺素钠口腔崩解片,进入人体口腔后会在唾液的作用下迅速融化,然后流入消化道中,显著降低吞咽依赖。
发明内容
本发明的基本组成包括左甲状腺素钠、明胶和支撑剂。左甲状腺素钠为活性成分,在本发明中拥有很宽的用量适用范围,确切的说,从0~10mg都能做成口腔崩解片。考虑到药物本身狭窄治疗窗的特性,卫计委推荐的左甲状腺素钠常规的治疗用药范围为50~175μg,本发明选择的用药范围为10μg ~200μg。推荐将25μg、50μg、100μg、150μg四种不同量的左甲状腺素钠制成口腔崩解片,如此可以非常便利临床上对药物的使用,避免常规口服药物需要小剂量调解用药时只能以手掰片的窘境。
本发明中明胶如果不使用并不影响冻干口腔崩解片的制成,但是使用了明胶,则会大幅度改善口腔崩解片的性状,提升左甲状腺素钠的稳定性。明胶对本发明口腔崩解片性状的改善体现在,片剂强度增加方便取用,韧性增强不易破碎。明胶可以选自普通生物源明胶,也可以选自经水解或部分水解的明胶。考虑到明胶的溶解特性,制备过程中,往往首先将明胶进行溶解、溶胀。为了加速这个进程,加热是常用的工艺手段。本发明中,明胶在水溶液中的浓度为0.5%~20%,优选使用的浓度为1%~10%。具体在本发明的口腔崩解片中明胶的含量范围是2mg~40mg/片。
本发明中使用的支撑剂,原则上可以使任何安全的,可以药用的,水溶性固体物质。然而考虑到最终产品的味觉效果和片形的好坏,发明者将支撑剂的选择范围定在糖类、糖醇类、氨基酸类、水溶性纤维素类、聚维酮类。
糖类中如蔗糖、葡萄糖、果糖、木糖、乳糖、麦芽糖、甘露糖、山梨糖等等,也可以是低聚糖或高聚糖。低聚糖如低聚麦芽糖、低聚果糖,高聚糖如葡聚糖(右旋糖酐)等。糖醇类中如木糖醇、山梨糖醇、异山梨醇、甘露醇、赤藓糖醇、麦芽糖醇、异麦芽糖醇、乳糖醇等等。氨基酸类中如甘氨酸、甘氨酸钠也可以作为支撑剂使用,但考虑到成本并不推荐。小分子盐,小分子有机酸也可以作为支撑剂,例如氯化钠,磷酸钠盐,枸橼酸盐,枸橼酸,酒石酸等等。但这些材料作为支撑剂,较大量使用时往往有不良的口味,或酸或苦或咸或涩等,并不适于口腔崩解片的制备。
聚维酮及水溶性纤维素中如羟丙基纤维素,羟丙基甲基纤维素等。对冻干工艺成片可以起到片剂性状改良的作用,但这些产品经常有比较明显的致黏效应。片剂产品进入水中后,黏度增长,并不利于迅速溶化和其中活性成分的迅速释放。
本发明中,支撑剂在水溶液中的浓度为1%~20%,优选使用的浓度为2%~10%。具体在本发明的口腔崩解片中支撑剂的含量范围是5mg~40mg/片。
本发明除了左甲状腺素钠、明胶、支撑剂外,还可以加入一些辅助成分以改善口腔崩解片的特性。例如加入适量pH调节剂以平衡左甲状腺素钠略显碱性的pH表现,pH调节剂可以选择枸橼酸、乳酸等等。例如可以加入适量抗氧剂以进一步改良左甲状腺素钠可能被氧化的特性,抗氧剂可以选择加入生育酚、抗坏血酸钠、没食子酸丙酯、丁羟甲苯等。
本发明推荐的工艺过程是先以温或热水化开溶解明胶,然后将明胶水溶液溶解支撑剂,制成空白溶液。将空白溶液温度降至室温,加入左甲状腺素钠,溶解完全。溶液迅速分装至片形模具中,低温冻结。进入真空状态,冻干。在此基本程序中,溶解明胶与溶解支撑剂互相之间的顺序,并非关键,即便是同时溶解,也是可以的。但是左甲状腺素钠在溶解过程中的最后加入是必要的。最后加入左甲状腺素钠,既可以使明胶提前进入体系以起到保护左甲状腺素钠的作用,也可以缩短左甲状腺素钠在液体水溶液中的停留时间,这对左甲状腺素钠的稳定性具有积极的作用。如果溶解过程中,进行了加热,则溶解左甲状腺素钠前必须将温度降低,本发明建议将温度降低至30℃以下,以保障左甲状腺素钠在水溶液中,可承受的暴露时间更长。溶液配置过程中,如发现或怀疑有气泡产生,有必要对溶液进行脱气处理。因为气泡的存在容易破坏冻干产品的形态。
溶液中固形物的含量范围为5%~30%(w/v),优选的固形物含量范围为8%~20%,其中包含左甲状腺素钠、明胶、支撑剂和其他可能加入的成分。更低的固形物含量将使口腔崩解片冻干状态变差,例如太松,不结实等。更高的固形物含量则会影响冻干效率,产品过于致密,也会影响产品最终的溶化速率。
左甲状腺素钠溶液,从溶解到冻实的时间越短越好。一般被分装至片形模具包材中的溶液量有限,所以冻实的时间往往较短,例如在低温通道中2~10分钟即可。溶液存在的时间,主要取决于溶液的体积以及分装的速度,而分装的速度取决于分装头的多少以及分装的效率。将溶解到完成分装的总时长控制在3小时以内较好,更低的溶液温度能支持的溶液暴露时间更长。
溶液分装至片形模具的量范围为0.05ml~0.5ml,优选的体积为0.1ml~0.4ml。更大的片可能限制入口的便利性,而更小的片则会显著提升对溶液分装的效率要求。综合规划溶液分装量及5%~30%的固形物含量,较优的口腔崩解片经冻干后质量会在15~100mg,更优的质量范围为20~50mg。
本发明中溶液迅速冻结的方式,实验室经常通过低温冰箱或低温冷阱实现,实验室和生产中都可以通过低温通道得以实现。低温通道即溶液在分装至片形模具后的传送途中迅速降温的方式,这种通道的降温方式较为剧烈,需要使用较多的冷媒,例如液氮,氢氟烷烃,氟氯烷烃等制冷剂。如使用液氮是通过液氮流转进行快速降温,如使用烷烃类制冷剂则是通过压缩泵原理进行工作。速冻完成后,一般不再储存而是直接转移或传送至干燥箱进行冻干,除非能保障超低温状态得以一直持续,而这将给液氮的用量或制备线上的耗能带来严重的负荷。一旦冻结状态化开,左甲状腺素钠的稳定性将会受到影响,这种影响由所受影响的时间和温度决定。片形物中的温度要求低于-40℃,优选为低于-50℃。这个过程经常被称为冻干前的预冻。
干燥箱是冻干机重要的组成部分,冻干开始后,设备进行抽真空,真空程度≤10bar,优选的真空度为≤1bar。预冻的物料在真空状态下,持续以升华的形式除去水分,而这个过程中,水分升华吸热维持物料的低温状态,此为一级干燥。冻干机自带的温度调剂功能,可以加热或降低物料容器的温度,以保障产品物料温度一直在设定的范围内。所以冻干机带有温度调节功能在口腔崩解片的制备过程中是重要的。整个一级干燥时间,以水分控制为准,控制水分≤5%,优化的控制指标是水分≤3%,生产中进行了必须的验证后,可以以时间进行参数设定。更低的水分,降低了其后二级干燥的时间和难度。为了达到这个水分控制水平,一级干燥可以在20小时以内。优秀的工艺可以将一级干燥时间控制在8小时以内。
一级干燥完成后,冻干机持续保持真空状态,逐渐升温以除去极少量的初始未能升华除去的水分,此为二级干燥。二级干燥温度最终可以升高至不超过40℃。二级干燥,产品仍以水分为控制指标,最终干燥至产品水分含量≤3%。二级干燥时需要的时间与一级干燥的效果有关,越短越好,越长的时间越不利于左甲状腺素钠的稳定,一般控制在3小时以内。
完成二级干燥,口腔崩解片即算完成了制备,接下来需要转移出冻干机进行包装。
左甲状腺素钠口腔崩解片中各物料均是水溶性材料,冻干完成后,片剂结构较为疏松,这些都加大了产品的引湿特性。所以,承载左甲状腺素钠溶液并进行冻干的模具包装不仅需要具有优良的抗形变能力,更需要有较好的水分隔绝能力。包装材质一般选择金属材质为基本结构,如不锈钢、铝等,加以特殊膜层隔离金属与药物的直接接触。膜材选用可以药用的材质,例如聚乙烯、聚氯乙烯、聚偏二氯乙烯、聚四氟乙烯、聚对苯二甲酸乙二醇酯、环氧树脂等等。
待完成冻干,承载冻干口腔崩解片的包材移出冻干机后,需及时覆上封闭材料,如覆铝箔,覆含铝层纸膜等。所附材料必须满足产品与外界完全隔离的要求。
冻干左甲状腺素钠口腔崩解片的质量控制,最重要的是左甲状腺素含量的降低,即控制活性成分的降解。其次是优良的冻干成型效果,需要冻干片形完整,有一定物理强度和韧性,便于从包材中取出,便于患者或护理人员拿住而不会出现破碎、散塌等。然后是快速的溶化特性,口腔崩解片1分钟溶化或崩散的要求相对是低的,左甲状腺素钠冻干口腔崩解片可以在≤30秒时间内完全或几近完全溶化。
两年内,左甲状腺素钠普通压制片与左甲状腺素钠冻干口腔崩解片的稳定性比较,以相对于标示的百分含量评价。
可见两年后压制普通片的含量比标示出现一定幅度下降,虽然也符合相关要求,但相对于出厂的含量其实已降低达5%。本发明所制成的口腔崩解片在两年的时间内,含量变化不明显,稳定性优势明显。
实施例1
将处方量明胶加入300ml水中,加热至80℃,搅拌,使完全溶清。加入处方量甘露醇,搅拌,使完全溶解。溶液降温至约25℃,加入左甲状腺素钠,搅拌,使完全溶解。分装溶液至铝塑泡眼中,300μl/片。快速冷冻,使左甲状腺素钠溶液迅速降低温度至-50℃~-80℃,完全冻结。保障冻结品温度在原范围,将预冻片转运至冻干机。抽真空,启动冻干,真空要求<1bar。持续冻干6小时,时间达到,停止冻干制冷,维持真空,待样品自然升温至25℃,持续20分钟,即可出柜。如无法达到25℃,启动冻干机制热功能,加热至样品温度25℃,维持20分钟即可。
左甲状腺素钠普通压制片与左甲状腺素钠冻干口腔崩解片溶化性评价比较。
实施例2
实施例3
Claims (8)
1.一种左甲状腺素钠口腔崩解片,特征在于含有左甲状腺素钠、明胶和支撑剂,各组分在每片中的用量为:
左甲状腺素钠 10μg~200μg
明胶 2mg~40mg
支撑剂 5mg~40mg 。
2.权利要求1所述支撑剂,选自可用于制药领域的水溶性固体物质。
3.权利要求2所述水溶性固体物质,选自糖类、糖醇类、氨基酸类、水溶性纤维素类、聚维酮类。
4.权利要求2、3所述水溶性固体物质,优选为甘露醇、木糖醇、葡聚糖。
5.权利要求1所述明胶,可选自明胶、水解明胶、部分水解明胶。
6.权利要求1所述口腔崩解片,采用冻干的工艺方式进行制备。
7.权利要求1中所述左甲状腺素钠口腔崩解片,应用于治疗由甲状腺素缺乏引起的各种疾病。
8.权利要求7中所述治疗由甲状腺素缺乏引起的各种疾病,更适用于喉颈部手术、无意识、没有自理能力或抗拒服药的甲状腺素缺乏病患人群。
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