CN116916890A - 包含劳拉西泮的膜剂中固体口分散性药物组合物 - Google Patents
包含劳拉西泮的膜剂中固体口分散性药物组合物 Download PDFInfo
- Publication number
- CN116916890A CN116916890A CN202280018531.6A CN202280018531A CN116916890A CN 116916890 A CN116916890 A CN 116916890A CN 202280018531 A CN202280018531 A CN 202280018531A CN 116916890 A CN116916890 A CN 116916890A
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- Prior art keywords
- lorazepam
- oil
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- film
- percentage
- Prior art date
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Classifications
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Abstract
公开了用于口服施用劳拉西泮的膜剂形式的固体口分散性药物组合物,其特征在于在产品的整个贮存期限的自始至终具有高度稳定性。所公开的组合物甚至适用于无意识或吞咽困难的患者。
Description
本发明涉及用于口服施用劳拉西泮的膜剂形式的固体口分散性药物组合物。特别地,本发明描述了包含劳拉西泮的口分散性膜剂,其为一种即用型药物形式,可不用水而使用,适用于将活性成分施用至甚至无意识或吞咽困难的患者,其不仅可以以已经批准的各种剂量制备,而且可以以适合于患者治疗要求的剂量制备,并且在产品的整个贮存期限自始至终保持稳定。
现有技术
劳拉西泮(7-氯-5-(2′-氯苯基-)-1,3-二氢-3-羟基-2H-1,4-苯二氮卓-2-酮,式I)属于苯二氮卓家族,这是一类药物,几十年来已用于治疗由抑郁或神经官能症引起的焦虑、失眠和各种起因的睡眠障碍、治疗心身障碍和作为治疗癫痫和神经性疼痛的佐剂。
1,4-苯二氮卓环上的取代基的性质对药理学效能有影响。氯原子在2′位的存在使劳拉西泮在药理学上具有高度活性,但电子-受体原子的存在使劳拉西泮不稳定,使其成为化学稳定性最低的苯二氮卓类之一。存在于7-原子环上的羟基引起分子结构上的张力调整,这导致朝向6-原子环的重排,所述6-原子环更稳定且应变更小,同时消除了水分子(方案1)。这种劳拉西泮重排/脱水过程受到温度升高的促进,并且负责喹唑啉醛的形成,在USP专论中被鉴定为杂质C(M.S.Siddegowda等人“Facile Thermal Rearrangement ofLorazepam and Oxazepam”,Indian Journal of Chemistry Section B 51(11):1628-1632,2012)。
市场上没有劳拉西泮的即用型口服溶液,仅有设计为在使用前通过在施用前立即将劳拉西泮溶解在溶剂混合物中而重构的溶液。重构溶液具有限于一个月的贮存期限,优选在低温下。
WO2004004783公开了劳拉西泮的即用型液体口服制剂,其不需要重构。该制剂通过从制剂中除去水并使用三醋精(三乙酰甘油)(药典中描述的无色、无味溶剂)与二甘醇单乙醚(商业上称作)组合来克服劳拉西泮的稳定性问题。WO2004004783不使用多元醇,多元醇与包含羟基的所有溶剂一样被认为是劳拉西泮的不稳定性的原因。
WO2008/019109已经描述了将劳拉西泮配制成口分散性药物形式(例如口分散性片剂(ODT))的问题。WO2008/019109规定,使用用于这种类型的药物形式的常用赋形剂(例如甘露醇或聚乙烯吡咯烷酮(PVP))降低劳拉西泮在成品中的稳定性。在这种情况下,通过用制粒方法保护劳拉西泮或用具有超过65℃的玻璃化转变温度(Tg)的聚合物包衣劳拉西泮来保证活性成分的稳定性,优选纤维素衍生物或PVP。
US2016/0000803公开了一种用于经鼻施用苯二氮卓类(包括劳拉西泮)的液体制剂。它没有提及劳拉西泮的差的化学稳定性,而是旨在克服劳拉西泮的差的溶解性,其导致劳拉西泮在水和疏水性溶剂中沉淀。因此,不可能获得可以以适合于小尺寸鼻腔的小体积施用的浓缩溶液。US2016/0000803通过在乳液中包含与苯二氮卓类(薄荷醇、麝香草酚)形成低共熔混合物的物质来克服该问题。
即用型口服溶液和ODT是非常便利的药物形式,其可用于苯二氮卓类、特别是劳拉西泮的特定临床应用,例如治疗患有癫痫发作的患者,对其需要尽可能快的施用。
在速溶的口服形式中,口分散性膜剂(ODF)最近引起了越来越多的兴趣。所述膜剂是设计用于引入口腔的薄片,包含分散或溶解的活性成分,并且由成膜聚合物和用于获得适于口服施用的剂型的其他赋形剂组成。口腔膜剂通常通过将成膜聚合物(例如纤维素、麦芽糖糊精或藻酸盐)溶解在合适的溶剂(例如水或乙醇)中来制备。除了成膜聚合物之外,还必须引入增塑剂,以便获得坚固且柔性的膜并保证足够的机械性能。增塑剂通常属于多元醇的化学类别,其也被认为是极性溶剂。
与必须在使用时制备和给药的口服溶液相比,膜剂是即用型的并且确保精确和宽范围的剂量。与常规固体形式不同,它们可以在不吞咽和不用水的情况下服用,在其非常快速的崩解后在口中不留下残留物,因此不涉及不合作的患者将排出任何碎片的风险,如不能吞咽或不能完全崩解的片剂可能发生的那样。当引入口腔并置于舌头上时,它们与唾液接触迅速崩解,从而使得活性成分能够在没有另外的液体的情况下施用。与ODT不同,源自膜崩解的碎片非常小并且难以排出。这在癫痫发作发生时紧急施用的情况下构成了优点。
劳拉西泮的特别不稳定的性质使得难以配制保持其物理化学稳定性并且还可通过工业过程再现的口腔膜剂。从药物的观点来看,如果产品满足药典的要求,保证在合适的时间段内符合质量标准,并且允许实际的储存条件,例如在室温下,则认为产品是稳定的并且适合于销售。
常用于口腔膜剂制备的赋形剂是负责劳拉西泮降解的物质,特别是极性溶剂如水或乙醇、亲脂性溶剂和增塑剂如甘油多元醇和丙二醇。
WO2005039543和WO2014049548公开了其中劳拉西泮快速降解的口腔膜剂,如将在发明详述中列出的实施例中证明的。
发明详述
本发明克服了上述问题,允许将劳拉西泮配制成速崩膜剂,其随时间稳定并且能够提供具有足够机械性能的产品。
已经发现,与从已知水和亲脂性溶剂的去稳定作用导出的预期相反,可以通过将用水作为溶剂制备的成膜剂与在室温下为固体的增塑剂和药用级油合并而将劳拉西泮配制成稳定的口分散性膜剂。
因此,本发明的第一方面涉及速崩膜剂形式的固体口分散性药物组合物,其包含劳拉西泮、至少一种选自麦芽糖糊精、共聚维酮、藻酸钠或其混合物的成膜聚合物和至少一种增塑剂,其特征在于增塑剂仅为在室温下为固体形式的那些,并且组合物包含水和药用级非精油。
“速崩”在本文中是指膜剂在口腔中分散以快速释放活性成分(Ph.Eur.最新版,1807 Oromucosal Preparations,orodispersible films),即在3分钟内(Ph.Eur.0478,Tablets,Orodispersible Tablets),优选在施用后1分钟内(Ph.Eur.Current Edition,1807 Oromucosal Preparations,orodispersible films)。
本发明的组合物可以通过如下方法制备,该方法包含将劳拉西泮在药用级油中的分散体加入到亲水性成分(成膜剂和固体增塑剂)的水溶液中,连续干燥该混合物并将所得膜切割成一定尺寸。
在室温下为固体的增塑剂选自多元醇(例如山梨醇、甘露醇、麦芽糖醇和木糖醇)和甜菜碱。固体增塑剂以5-50%重量,优选10-30%重量的百分比存在。
成膜聚合物以40-80%重量的百分比存在。
本发明的膜剂中的水以5-30%重量的百分比存在。
“非精油”在本文中是指不属于精油类别的油,其被定义为通常具有复杂组成的有气味的产品,其通过蒸汽蒸馏、干馏、干燥或合适的机械方法而不加热并且任选地进行进一步处理以改变其化学组成而得自植物学确定的植物原材料(Ph.Eur.最新版,2098Essential Oils)。
非精油选自植物油或动物油或中链甘油三酯,并且以1-15%重量的百分比存在。
优选使用橄榄油、芝麻油、向日葵油、大豆油、花生油、玉米油、红花油或鱼油。
劳拉西泮以0.25-10%重量的百分比存在。
本发明的组合物还可以包含其他赋形剂,例如表面活性剂和改善膜剂的感官特性所需的其他成分,例如矫味剂、甜味剂、着色剂等。可以不存在在室温下为液体的增塑剂,例如甘油。
令人惊讶的是,尽管膜剂中存在残留水,但本发明的膜剂随时间推移更稳定。劳拉西泮在膜剂中是均匀的,即使使用溶解性差的溶剂也是如此,例如水或药用级油。
在以下实施例中更详细地示例本发明。
对比例1
根据WO2014049548制备实施例的口腔膜剂即制剂1。制剂1如表1所示。
表1.制剂1,表示为%w/w
成分 | 功能 | 组成(%) |
劳拉西泮 | 活性成分 | 2.00 |
麦芽糖糊精 | 成膜聚合物 | 63.798 |
甘油 | 增塑剂 | 15.00 |
水 | 溶剂残留物 | 10.00 |
甘露醇 | 增塑剂 | 5.00 |
共聚维酮 | 成膜聚合物 | 2.00 |
单亚油酸甘油酯 | 表面活性剂 | 1.12 |
聚山梨醇酯80 | 表面活性剂 | 0.38 |
三氯蔗糖 | 甜味剂 | 0.20 |
二氧化钛 | 着色剂 | 0.50 |
亮蓝FCF E133 | 着色剂 | 0.002 |
简言之,为了制备制剂1,将劳拉西泮预分散在甘油中;然后将所述混合物加入到预溶于水中的其他成分中,并将该物质混合直至完全均匀。将该混合物涂覆并连续干燥,直至获得均匀、无气泡的膜卷。将卷切割成合适的尺寸以获得具有所需剂量的膜剂。
通过HPLC分析测定值和降解产物。柱是ACE Equivalence C18(250mm X 4.6mm),粒度为5μm,恒温至10℃。使用0.24%乙酸水溶液和乙腈的50:50混合物作为流动相,流速为1.0mL/分钟。将DAD-UV检测器设定为230nm,并注入10μl样品。
长期稳定性研究(25℃,60%R/H)、中间稳定性研究(30℃,65%R/H)和加速稳定性研究(40℃,75%R/H)证实劳拉西泮是高度不稳定的,如表2中所概括的。在仅仅三个月内,测定值在25℃下降7.5%,在30℃下降12.4%,在40℃下降55.4%。测定值的急剧降低伴随着杂质C含量的显著增加,其在40℃下在三个月内达到35.97%。在25℃和30℃下,杂质C的百分比低得多,但仍高于USP关于劳拉西泮片剂的专论中设定的3.0%限值。
表2.稳定性测试中制剂1中劳拉西泮和杂质C含量的测定值
这些数据表明,根据WO2014049548获得的具有劳拉西泮的口腔膜剂不满足USP专论中所述的质量标准,因为杂质C的百分比超过3.0%的质量标准。因此,该制剂即使在室温下也是不稳定的。
实施例2
本发明的制剂如表3中所示。
表3.劳拉西泮膜剂制剂,表示为%w/w。
为了制备本发明的膜剂,将劳拉西泮分散在药用级橄榄油中;同时,制备亲水性成分的水溶液,并在连续搅拌下加入包含劳拉西泮的油性混合物。将所得物质混合直至完全均匀,然后涂覆并连续干燥直至获得均匀、无气泡的膜卷。将卷切割成合适的尺寸以获得具有所需剂量的膜剂。
使用根据欧洲药典(Ph.Eur.,2.9.1)对于固体口服形式的崩解测试,膜剂显然是塑性的、坚固的并且快速崩解(10秒)。
通过实施例1中所述的方法分析测定值和降解产物。
长期稳定性研究(25℃,60%R/H)、中间稳定性研究(30℃,65%R/H)和加速稳定性研究(40℃,75%R/H)的结果如表4中所示。
与对比例1的制剂观察到的结果不同,本发明令人惊讶地产生了随时间具有足够稳定性的包含劳拉西泮的口腔膜剂。表4显示了根据本发明获得的制剂2和3的至多3个月的稳定性数据。
衰4.稳定性测试中制剂2和3中劳拉西泮和杂质C含量的测定值
ND=低于可检测限的百分比
如果比较稳定性研究期间劳拉西泮和杂质C的测定值的变化,则可以看出,本发明的膜剂显著更稳定,特别是当与对比例1的结果相比时。在25℃和30℃下,制剂2和3中劳拉西泮的测定值实际上没有改变。在40℃下,观察到显著降低,但与对比例1相比较低:在后一种情况下,3个月后,降低超过50%,而在实施例2的处方中,降低约为15%。
测定值的这些有限变化的结果是杂质C的不太显著的增加,特别是在25℃和30℃下。在这些储存条件下,该值低于作为参考的3.0%限值。在40℃下,3个月后,杂质C的值超出质量标准,但在本发明的两种制剂中,该百分比令人惊讶地比在对比例中发现的百分比低约10倍(35.97%)。
实施例3
本发明的其他制剂如表5中所示。
表5.劳拉西泮膜剂制剂,表示为%w/w。
为了制备本发明的膜剂,将劳拉西泮分散在药用级橄榄油中;同时,制备亲水性成分的水溶液,并在连续搅拌下加入包含劳拉西泮的油性混合物。将所得物质混合直至完全均匀。将混合物连续铺展并干燥,直至获得均匀、无气泡的膜卷。将卷切割成合适的尺寸以获得具有所需剂量的膜剂。例如,1mg劳拉西泮膜具有的尺寸为20mm x15mm,重量为50mg;2.5mg劳拉西泮膜具有的尺寸为30mm x25mm,重量为125mg。
使用根据欧洲药典(Ph.Eur.,2.9.1)有关固体口服形式的崩解测试,膜剂显然是塑性的、坚固的并且快速崩解(10秒)。
通过对比例1中所述的方法进行测定值和降解产物的分析。
表6中显示了制剂4和5至多3个月的长期稳定性研究(25℃,60%R/H)、中间稳定性研究(30℃,65%R/H)和加速稳定性研究(40℃,75%R/H)的结果。与用实施例1的制剂获得的结果不同,本发明的制剂随时间表现出足够的稳定性。
表6.稳定性测试中制剂4和5中劳拉西泮和杂质C含量的测定值
ND=低于可检测限的百分比
Claims (11)
1.速崩膜剂形式的固体口分散性药物组合物,其包含劳拉西泮、一种或多种选自麦芽糖糊精、共聚维酮、藻酸钠或其混合物的成膜聚合物和一种或多种增塑剂,其特征在于所述增塑剂仅是在室温下为固体形式的增塑剂,并且所述组合物包含水和药物级非精油。
2.根据权利要求1的组合物,其中所述增塑剂选自多元醇和甜菜碱。
3.根据权利要求2的组合物,其中所述多元醇选自山梨醇、甘露醇、麦芽糖醇和木糖醇。
4.根据权利要求1-3的一项或多项的组合物,其中所述固体增塑剂以重量计5-50%、优选10-30%的百分比存在。
5.根据权利要求1-4的一项或多项的组合物,其中所述成膜聚合物为麦芽糖糊精与共聚维酮或藻酸钠的混合物。
6.根据权利要求1-5的一项或多项的组合物,其中所述成膜聚合物以40-80%重量的百分比存在。
7.根据权利要求1-6的一项或多项的组合物,其中水以5-30%重量的百分比存在。
8.根据权利要求1-7的一项或多项的组合物,其中所述非精油为植物或动物来源的或为中链甘油三酯。
9.根据权利要求1-8的一项或多项的组合物,其中所述油选自橄榄油、芝麻油、向日葵油、大豆油、花生油、玉米油、红花油和鱼油。
10.根据权利要求8和9的组合物,其中所述油以1-15%重量的百分比存在。
11.根据权利要求1-10的一项或多项的组合物,其中劳拉西泮以0.25-10%重量的百分比存在。
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US (1) | US20240156725A1 (zh) |
EP (1) | EP4301338A1 (zh) |
CN (1) | CN116916890A (zh) |
CA (1) | CA3210430A1 (zh) |
IT (1) | IT202100004880A1 (zh) |
WO (1) | WO2022185201A1 (zh) |
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GB1548022A (en) * | 1976-10-06 | 1979-07-04 | Wyeth John & Brother Ltd | Pharmaceutial dosage forms |
US4671953A (en) * | 1985-05-01 | 1987-06-09 | University Of Utah Research Foundation | Methods and compositions for noninvasive administration of sedatives, analgesics, and anesthetics |
ITRM20020357A1 (it) | 2002-07-03 | 2004-01-05 | Foscama Biomed Chim Farma | Composizione liquida per la somministrazione orale di lorazepam. |
ITMI20032087A1 (it) | 2003-10-27 | 2005-04-28 | Pharmafilm S R L | Film autosupportanti per uso farmaceutico ed alimentare. |
US20080031944A1 (en) | 2006-08-04 | 2008-02-07 | Cima Labs Inc. | Stabilization of lorazepam |
ITMI20121628A1 (it) | 2012-09-28 | 2014-03-29 | Pharmafilm Srl | Film orodisperdibili autosupportanti a rapida dissoluzione per uso terapeutico o alimentare |
WO2014127458A1 (en) | 2013-02-22 | 2014-08-28 | Eastgate Pharmaceuticals Inc. | Pharmaceutical composition for transmucosal administration of benzodiazepines |
US20140335153A1 (en) * | 2013-05-09 | 2014-11-13 | Cure Pharmaceutical Corporation | Thin film with high load of active ingredient |
US11033493B2 (en) * | 2013-12-02 | 2021-06-15 | Intelgenx Corp. | Film dosage form with extended release mucoadhesive particles |
JP2017537127A (ja) * | 2014-12-09 | 2017-12-14 | モノソル アールエックス リミテッド ライアビリティ カンパニー | 線状多糖をベースとするフィルム製品 |
US20180243207A1 (en) * | 2017-02-27 | 2018-08-30 | Padmakshi Singh | Dual-release flexible formulation useful in palliative and hospice cares of elderly patients |
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- 2022-03-01 US US18/548,338 patent/US20240156725A1/en active Pending
- 2022-03-01 CA CA3210430A patent/CA3210430A1/en active Pending
- 2022-03-01 CN CN202280018531.6A patent/CN116916890A/zh active Pending
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WO2022185201A1 (en) | 2022-09-09 |
IT202100004880A1 (it) | 2022-09-02 |
CA3210430A1 (en) | 2022-09-09 |
EP4301338A1 (en) | 2024-01-10 |
US20240156725A1 (en) | 2024-05-16 |
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