CN117298071A - 一种用于治疗口腔溃疡的口腔贴膜及其制备方法 - Google Patents
一种用于治疗口腔溃疡的口腔贴膜及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种用于治疗口腔溃疡的口腔贴膜,其含有丁卡因和曲安奈德的组合作为活性成分。该贴膜由包含无定形盐酸丁卡因和无定形曲安奈德的载药层以及不含药物的水溶性背衬层组成的双层膜制剂,具有药物组合的口腔贴膜比单独的药物具有更好的疗效,且双层膜结构使得药物有良好的疗效维持时间和良好的口感。载药层包含3‑20%(w/w)的无定形盐酸丁卡因或其药学可接受的盐、0.1‑2.0%(w/w)的无定形曲安奈德或其药学可接受的盐、20‑95%(w/w)的第一成膜材料、1‑12%(w/w)的粘合剂、1‑20%(w/w)的一种或多种清凉剂、以及可选的1‑12%(w/w)的增塑剂。背衬层包含70‑95%(w/w)的一种或多种成膜材料、2‑10%(w/w)的增塑剂和可选的1‑8%(w/w)的矫味剂。
Description
技术领域
本发明涉及的是医药领域中的药物制剂,具体涉及一种用于治疗口腔溃疡的药物组合物及其制备方法。
背景技术
口腔溃疡是是一种常见的发生于口腔黏膜的溃疡性损伤病症,多见于唇内侧、舌头、舌腹、颊黏膜、前庭沟、软腭等部位。口腔溃疡的特点是口腔内黏膜层的溃疡,包括急性的或慢性的、局部的或弥漫性的。口腔溃疡是最常见的口腔问题之一,可能由多种疾病引起,其中一些与口咽周围的问题有关,但多种全身性疾病也可能引起这些病变。口腔溃疡的主要原因是外伤、复发性口疮性口炎、微生物感染、皮肤粘膜疾病、全身性疾病、鳞状细胞癌等。
口腔溃疡涉及黏膜上皮的破损,暴露出下面的固有层,而糜烂代表上皮层的不完全破裂,并表现为红斑,发作时疼痛剧烈,局部灼痛明显,严重者还会影响饮食、说话,对日常生活造成极大不便。
广泛用于缓解口腔溃疡局部疼痛的治疗方法是冲洗剂和凝胶制剂。漱口剂是含有抑菌剂的漱口水,凝胶制剂为含有活性药物的口服软膏。然而,由于药物在溃疡局部的停留时间很短,药效维持时间短,这些治疗需要频繁给药。
治疗口腔溃疡的常用药物有软膏或凝胶形式的苯佐卡因或氨来呫诺、苯达明漱口水、胶囊或粉末形式的盐酸多西环素。所有广泛使用的制剂都是凝胶、软膏或漱口水的形式,需要频繁给药。
盐酸丁卡因是一种局部麻醉剂,用于暂时缓解疼痛,将其涂抹在受影响的部位,可以快速暂时缓解疼痛。目前市场上销售的盐酸丁卡因有外用乳膏、喷雾剂或溶液形式;但这种形式单独治疗口腔溃疡,药效维持时间短,且单独使用效果不佳。
曲安奈德是一种合成糖皮质激素,用于治疗皮肤的炎症、肿胀、瘙痒等例如湿疹、皮炎、过敏和皮疹等。该药还用于治疗关节炎,以减轻疼痛和炎症。目前,曲安奈德在市场上有外用乳膏、混悬剂、注射剂、外用洗剂、外用软膏、口服片剂、鼻喷雾剂的形式。
临床需要一种有效治疗口腔溃疡的药物组合物,该组合物应具有较长的停留时间,以避免频繁给药并增加疗效。
发明内容
本发明提供了适合局部给药以治疗口腔溃疡的药物组合物,该药物组合物含有活性成分丁卡因和曲安奈德。该药物组合物为口腔膜剂或口腔贴膜的形式,其使用时与口腔溃疡直接接触并且具有缓释效果,延长药物的释放。本发明的口腔贴膜粘附在溃疡病灶的黏膜上,然后在2.5-4小时的时间内被唾液缓慢崩解或溶解,以减轻疼痛和炎症。该口腔贴膜制剂直接作用于溃疡病灶,可避免口服的胃肠道降解并绕过肝脏首过效应。口腔贴膜克服了通过漱口水、软膏或凝胶给药时药物停留时间短的问题。本发明的口腔贴膜可有效减少口腔溃疡的数量和大小以及红斑水平,同时可有效减轻口腔溃疡引起的疼痛。
本发明的口腔贴膜包含两种药物的组合:麻醉药物丁卡因和抗炎药物曲安奈德,用于治疗口腔溃疡。丁卡因可有效缓解疼痛,曲安奈德可减轻溃疡引起的炎症。本发明的口腔贴膜是缓释剂型,可直接附着于溃疡处,并持续释放药物达2.5-4小时。药物的缓释作用避免了频繁给药,克服了凝胶或漱口水给药作用时间短的缺点,且膜剂可以使药物集中在溃疡上,增加疗效,减小扩散到正常组织引起的副作用。
本发明口腔膜剂中使用的活性成分为丁卡因或其药学上可接受的盐、和曲安奈德或其药学上可接受的盐。
如本文所用,“药学上可接受的盐”是保留母体化合物的所需生物活性并且不赋予不期望的毒理作用的盐。
例如丁卡因的药学上可接受的盐包括盐酸丁卡因和二盐酸丁卡因等,曲安奈德的药学上可接受的盐包括曲安奈德、曲安奈德二乙酸酯、曲安奈德六丙酮和曲安奈德磷酸钠等。在本申请中,除非另有说明,术语“丁卡因”与丁卡因的药学上可接受的盐可互换使用。在本申请中,除非另有说明,术语“曲安奈德”与曲安奈德的药学上可接受的盐可互换使用。
丁卡因,化学名称为4-(丁氨基)-苯甲酸2-(二甲氨基)乙酯,是一种脂类局部麻醉剂,通过阻断参与神经元冲动启动和传导的钠离子通道产生局部麻醉。盐酸丁卡因是一种白色、结晶性粉末,可溶于水和乙醇。
曲安奈德的化学名称为9-氟-11β,21-二羟基-16α,17[(1-甲基亚乙基)双(氧)]-孕甾-1,4-二烯-3,20-二酮,是肾上腺皮质激素类药物,具有抗炎和免疫调节特性。曲安奈德为白色至类白色结晶粉末,具有轻微气味,几乎不溶于水,易溶于乙醇。
丁卡因是一种麻醉药物,如果丁卡因释放到患者口中,会导致口腔内舌头麻木,从而导致患者的依从性问题。本发明的口腔贴膜为双层形式,其具有包含丁卡因和曲安奈德的黏膜粘附载药层和包含聚合物的背衬层。背衬层有效防止口服给药时药物扩散到口腔,从而防止舌头麻木,提高患者的依从性。
本发明的丁卡因和曲安奈德口腔贴膜为包含载药层和背衬层的双层膜形式。载药层厚度约100-250μm,背衬层厚度约100-200μm。载药层层提供麻醉和抗炎的治疗作用,背层通过减少给药过程中舌头的麻木感来解决患者的依从性。
载药层包含约3%-20%(w/w)的无定形丁卡因或其药学上可接受的盐、0.1%-2.0%(w/w)的无定形曲安奈德或其药学上可接受的盐、20-95%(w/w)的第一成膜材料、约1-12%(w/w)的粘附剂、以及约1-20%(w/w)的清凉剂。背衬层包含约70-95%(w/w)的第二成膜材料和2-10%(w/w)的增塑剂。
载药层中丁卡因的量为0.2-8mg,优选0.5-8mg、1-8mg、0.5-6mg或1-6mg。载药层中丁卡因的重量百分比一般为3-20%w/w。载药层中曲安奈德的量为0.01-1.0mg,优选0.02-0.8mg、0.02-0.7mg、0.03-0.7mg或0.03-0.65mg。载药层中曲安奈德的重量百分比一般为0.1-2.0%w/w。
本申请中使用的“大约”是指所引用值的±10%。
除非另有说明,“%”在本申请中指的是重量百分比%(w/w)。
适合于载药层的第一成膜材料选自以下的一种或多种材料:醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、羟丙甲纤维素(HPMC)、乙基纤维素、蔗糖月桂酸酯、聚乙烯醇(PVA)、聚维酮(PVP)、聚乙二醇、羧甲基纤维素(CMC)、羟丙基纤维素(HPC)、甲基丙烯酸甲酯类共聚物、高直链淀粉和聚环氧乙烷(PEO)。优选的第一成膜材料为HPMCAS、HPMC、乙基纤维素、蔗糖月桂酸酯、PVA、聚维酮、聚乙二醇和羧甲基纤维素(CMC)中的一种或多种。
第一成膜材料与丁卡因、曲安奈德具有良好的相容性,使载药层具有足够高的载药量,形成的贴膜具有良好的力学性能和柔韧性。活性成分丁卡因和曲安奈德在贴膜中保持无定形状态,不发生重结晶或晶型转化。载药层中成膜材料的重量百分比一般为约20-95%w/w、30-95%w/w、20-95%w/w、25-90%w/w,或30-90%w/w。
载药层包含粘附剂,以提供贴膜与黏膜的良好粘附性并最大化功效。药物的局部作用通过贴膜对溃疡部位长达2.5-4小时粘附时间,以延长作用。如果口腔贴膜不能有效粘附并且贴膜贴的部位易受影响而移动或脱落,则口腔贴膜的功效会降低。适用于本发明的粘附剂包括聚丙烯酸、海藻酸钠、丙烯酸乙酯与甲基丙烯酸甲酯的共聚物、瓜尔胶、羧甲基纤维素钠、5-甲基吡咯烷酮壳聚糖、聚谷氨酸、聚卡波非、硫酸葡聚糖等中的一种或多种材料。优选的粘附剂是聚丙烯酸、海藻酸钠、丙烯酸乙酯和甲基丙烯酸甲酯的共聚物、瓜尔胶、羧甲基纤维素钠。口腔贴膜中粘附剂的用量为1-12%w/w;优选1-8%w/w。
大多数口腔溃疡都有烧灼感,本发明的口腔贴膜在载药层中包括一种或多种清凉剂,以减少药物使用期间的初始灼烧感和患者不适。清凉剂包括樟脑、薄荷醇、薄荷油、丁香油、乙酸薄荷酯、木糖醇、山梨醇、百里酚和薄荷油中的一种或多种。贴膜中使用的清凉剂为约1-20%w/w,优选1-18%w/w或1-15%w/w。
在一个实施方案中,贴膜在载药层中还包含一种或多种增塑剂以提高耐折性和制造加工性能。载药层中适合的增塑剂包括聚乙二醇(PEG)、甘油、聚山梨醇酯、聚乙二醇、丙二醇、己二醇和聚丙二醇,或柠檬酸三乙酯。载药层中增塑剂的含量为1-15%w/w,优选1-12%w/w。
背衬层是水溶性的,背衬层防止在使用口腔贴膜期间丁卡因和曲安奈德扩散到患者的口腔中,并防止麻醉剂丁卡因引起的麻木。
可用于背衬层的第二成膜材料选自以下一种或多种材料:HPMC、HPC、羟乙基纤维素(HEC)、羟丙基化高直链淀粉、甲基丙烯酸甲酯共聚物、聚维酮、胶原蛋白、明胶、果胶、邻苯二甲酸醋酸纤维素(CAP)、聚乙烯醇(PVA)和邻苯二甲酸聚乙烯醇酯(PVAP)。优选的成膜材料是HPMC、HPC、HEC、羟丙基化高直链淀粉、甲基丙烯酸甲酯共聚物和聚维酮。这些成膜材料提供了良好的阻隔作用,有效防止药物从载药层扩散到口腔中。背衬层中成膜材料的用量为70-95%w/w。
背衬层还包含一种或多种增塑剂以改善口腔贴膜的耐折性和制造加工性。合适的增塑剂包括聚乙二醇(PEG)、甘油、聚山梨醇酯、聚乙二醇、丙二醇、己二醇和聚丙二醇、或柠檬酸三乙酯。背衬层中增塑剂的用量为2-10%w/w。
当背衬层的厚度为100μm至200μm时,由盐酸丁卡因引起的麻木感明显减轻。当背衬层的厚度<100μm时,患者观察到舌头麻木,当背衬层厚度>200μm时,药物释放速率慢,背衬层的优选厚度为100-200μm。
在一个实施例中,可以将一种或多种矫味剂添加到载药层和/或背衬层中以改善口腔贴膜的味道并改善患者使用的顺应性。矫味剂提供风味和/或甜味,适用于载药层和背衬层的调味剂包括但不限于阿斯巴甜、蔗糖、葡萄糖、果糖、木糖醇、甜叶菊、三氯蔗糖、纽甜、糖精钠、安赛蜜、薄荷油、薄荷醇、橙子香料、菠萝香料、樱桃香精、苹果香精、香蕉香精、蓝莓香精、桃子香精、芒果香精、葡萄香精。载药层和背衬层中矫味剂的量为约0.5-15%w/w,优选约1-8%w/w。
可以将一种或多种着色剂例如二氧化钛、FD&C颜色、D&C颜色及其组合添加到载药层和/或背衬层中。
本发明的口腔贴膜柔韧且有弹性可给患者提供舒适感。口腔贴膜的强度足以抵抗口腔运动造成的破损。给药过程将贴膜的载药层贴于溃疡创面,覆盖溃疡面并适当粘附于黏膜。
本发明提供了一种用于治疗口腔溃疡的丁卡因和曲安奈德贴膜。给药后,药物直接与溃疡接触,药物在第1小时释放约25-50%,1.5小时累计约释放51-70%,2.5小时累积释放80%以上。口腔贴膜中的药物在3-4时的较长时间内缓慢释放,并提供长期、有效的局部治疗。
丁卡因是一种局部麻醉剂,可以在几分钟内减轻疼痛,曲安奈德是一种抗炎药,可减轻疼痛、炎症、红斑等,结合两种药物可提供快速有效的治疗。该口腔贴膜外观、厚度、颜色均匀,稳定性好。药物直接施用于溃疡部位进行局部治疗,避免了药物的首过代谢,提高了治疗效果降低副作用。本发明的口腔贴膜可以与口腔黏膜直接接触进行局部给药,并延长药物释放,减少给药频次。
本发明还提供一种丁卡因、曲安奈德口腔贴膜的制备方法。该方法包括以下步骤:(a)将丁卡因或其药学上可接受的盐和曲安奈德或其药学上可接受的盐、一种或多种第一成膜材料、一种或多种粘附剂、以及一种或多种清凉剂在第一溶剂中混合,形成澄清的载药层成膜液;(b)将载药层成膜液涂布在基材上并干燥,形成载药层;(c)将一种或多种第二成膜材料和一种或多种增塑剂在第二溶剂中混合以形成背衬层成膜液;(d)将背衬层成膜液涂布在载药层上并干燥,以在基底上形成双层贴膜;(e)从基底上取下双层贴膜以形成丁卡因和曲安奈德的双层口腔贴膜。
在步骤(a)中,第一溶剂是20-100%w/w的有机溶剂的水溶液。有机溶剂选自:乙醇、二甲基亚砜、二甲基甲酰胺及其任意组合,优选的有机溶剂为乙醇。
在步骤(b)中,第二溶剂由乙醇、水或其组合。在一个实施例中,第二溶剂是水。
在步骤(a)和(b)中,所有材料完全溶解并形成均匀成膜液,这导致口腔贴膜中盐酸丁卡因和曲安奈德呈无定形。
在步骤(b)和(d)中,干燥温度为约40℃-100℃,优选约60-90℃。
用于形成双层贴膜的基材包括聚对苯二甲酸乙二醇酯、聚丙烯树脂和聚甲基戊烯树脂。
在步骤(e)之后,任选地将双层贴片切割成合适的尺寸和形状,然后进一步包裹或包装。
本发明的口腔贴膜的长度约为1-2cm,宽度约为1-2cm;优选长度为约1-1.5cm,宽度为约1-1.5cm;更优选地,长度为约1cm,宽度为约1cm。
本发明还提供了向受试者施用口腔贴膜以局部治疗口腔溃疡的方法。该方法包括识别有需要的受试者,并将贴膜粘附到受试者的溃疡黏膜上。
本发明制备的口腔贴膜给药制剂,用于哺乳动物,例如人,马,狗和猫。以人的治疗为最优。
具体实施方式
下面将结合实施例进一步的详细说明本发明。需要指出的是,以下说明仅仅是对本发明要求保护的技术方案的举例说明,并非对这些技术方案的任何限制。本发明的保护范围以所附权利要求书记载的内容为准。
实施例1:单层贴膜(无定型膜)
在本实施例中,根据以下配方和工艺制备盐酸丁卡因和曲安奈德口腔贴膜:
处方:
制备工艺:
·在持续搅拌下将盐酸丁卡因和曲安奈德溶解到溶剂中;
·添加其他赋形剂并继续搅拌直至完全溶解;
·抽真空/静置消泡;
·将消泡后的成膜液均匀地涂在基材上;
·在约60℃至90℃的温度下干燥形成薄膜;
·成膜后,将薄膜裁剪成合适的尺寸、形状,装入小袋或合适的包装容器中。
按上述配方和工艺制备的口腔贴膜成膜性好,易于从基材上撕下,外观平整,色泽均一。X射线粉末衍射测定显示,盐酸丁卡因和曲安奈德处于无定形状态。溶出试验中,释放缓慢,3小时内释放不到80%的药物。
表1实施例1溶出结果
口腔贴膜的口感良好,但是,在使用后,释放到口腔中的盐酸丁卡因的麻醉作用影响了舌头,受试者的舌头感到麻木。
实施例2:双层口腔贴膜(无定型膜)
在本实施例中,制备双层贴膜以改善药物的溶出并避免药物释放到口腔中。
处方:
备注:工艺过程使用的溶剂在干燥工艺过程中被除去
制备的口腔贴膜外观平整,色泽均一,贴膜的X射线粉末衍射测试结果表明,两种活性药物均处于无定形状态。实施例2-1和实施例2-2的溶出实验显示2.5小时内释放超过80%。实施例2-3在3.5小时时释放缓慢且不完全。
表2:实施例2溶出结果
选取两名患有口腔溃疡的志愿者,对实施例2-1和实施例2-3的制剂进行试验,以检测口腔中药物的释放以及对舌头麻木的影响。将载药层一侧贴在溃疡黏膜上,观察5分钟。志愿者报告与实施例1的贴膜相比,贴膜最初有烧灼感并且膜有从施用部位轻微移动。使用实施例2-3的贴膜的患者在2小时后表现出口腔中有轻微肿胀,结果表明聚环氧乙烷不适合作为载药层成膜材料。
在类似的实验中,使用了不同浓度的乙醇溶液(20%和100%)作为第一溶剂;贴膜的所有机械性能参数均令人满意,口腔贴膜的XRD研究表明活性成分均呈无定形形式。
实施例3:双层口腔贴膜(无定型膜,粘附剂,清凉剂)
在本实施例中,添加粘合剂以提高贴片对溃疡粘膜的粘附力,并添加清凉剂以起到缓解溃疡灼烧感。制备工艺与实施例2相同。
处方:
备注:工艺过程使用的溶剂在干燥工艺过程中被除去
按照上述配方制备的双层贴膜外观平整,色泽均一,盐酸丁卡因和曲安奈德口服贴膜的X射线粉末衍射研究表明,两种药物在膜中均呈无定形状态。
通过重复实施例3-2,将贴片切割成长×宽:1cm×1cm、1cm×1.5cm、1.5cm×1.5cm、2.0cm×2.0cm、2.0cm×3.0cm和3.0cm×3.0cm来进行贴片尺寸评价。溶出结果显示,2.0cm×3.0cm和3.0cm×3.0 cm尺寸的贴膜厚度较薄,释放速度太快,2小时内几乎100%释放。从1cm×1cm到2.0cm×2.0 cm的贴片尺寸显示出可接受的结果。
可接受的背衬层厚度被确定为100-200μm。当背衬层厚度小于100μm时,药物在口腔中释放并感到舌头麻木。溶出研究表明,当背衬层厚度超过200μm时,药物释放缓慢。
表3:实施例3溶出结果
对3名患有口腔溃疡的志愿者进行了非临床研究,发现贴膜与溃疡充分贴合,口腔内没有感觉到药物的释放而引起的麻木感。志愿者没有感觉到最初的灼烧感,并且口腔贴膜的味道是可以接受的。
在类似的实验中,使用羟丙甲纤维素ER级、羧甲基纤维素和甲基丙烯酸甲酯共聚物作为成膜材料及释放控制聚合物。在所有试验中,药物在贴膜中保持其无定形形式,外观均匀,并在2.5小时内溶出度超过80%。
重复实施例3-2的配制以进行背衬层评估。载药层配方保持不变,在背衬层中,使用具有相同重量百分比的相同赋形剂,但背衬层的总重量分别从25mg变为15mg、20mg、30mg、35mg和40mg。溶出结果显示,背衬层重量范围为20-35mg,2.5小时内释放率超过80%,可接受。背衬层重量为15mg的测试口腔贴膜的溶出速度太快,2小时内约100%释放。背衬层重量为40mg的测试口腔贴膜的溶出速度太慢,在2.5小时内只有约70%释放。
在类似的实验中,木糖醇、山梨糖醇和丁香油分别被评估为清凉剂和矫味剂,所有试验均显示出可接受的结果。
实施例4:双层口腔贴膜(无定型膜,组成比例试验)
在这些实验中,评估了成膜材料和其他赋形剂的用量,制备工艺与实施例2相同。
处方:
备注:工艺过程使用的溶剂在干燥工艺过程中被除去
根据上述配方制备的双层贴膜具有光滑的外观、均匀的颜色以及所有可接受的膜剂性能。
在类似的实验中,测试了背衬层中按2%w/w、5%w/w、10%w/w、15%w/w的不同浓度的甘油。15%w/w的贴膜非常柔软,并且难以干燥。
实施例5:曲安奈德贴膜(单药)
本实施例制备曲安奈德贴膜(单药),制备工艺与实施例2相似,不同之处在于本实施例中载药层制备采用80%乙醇。
处方:
备注:工艺过程使用的溶剂在干燥工艺过程中被除去
根据上述配方制备的贴膜具有光滑的外观、均匀的颜色以及所有可接受的膜特性。溶出实验表明,2.5小时内药物释放量超过80%。实施例5的贴膜用于临床试验,实验结果参见实施例8。
实施例6:盐酸丁卡因贴膜(单药)
本实施例制备了盐酸丁卡因贴膜(单药),制备工艺与实施例2相似,不同之处在于本实施例中载药层制备采用20%乙醇。
处方:
备注:工艺过程使用的溶剂在干燥工艺过程中被除去
按上述配方制备的贴膜外观光滑、色泽均匀。溶出实验表明,2.5小时内药物释放量超过80%。实施例6的贴膜用于临床试验,实验结果参见实施例8。
实施例7:盐酸丁卡因和曲安奈德双层贴膜
在本实施例中,使用不同浓度的盐酸丁卡因和曲安奈德,制备工艺与实施例2相似。配方如下表所示。
处方:
所有批次的溶出实验均显示缓释效果,2.5小时内释放80%以上的药物。各实施例贴膜均用于临床试验,实验结果参见实施例8。
此外,还对其他不同类型的背衬成膜材料如羟丙基纤维素(HPC)、羟乙基纤维素(HEC)、聚维酮(PVP)、羟丙基化高直链淀粉、羟丙甲纤维素(HPMC)进行了评价,结果均显示出良好的效果。
实施例8:临床试验
在此示例中,对30名自愿受试者进行了临床研究。采用随机、双盲、单一研究以评价和比较实施例5、实施例6和实施例7-1、7-2、7-3在减轻疼痛、数量和炎症方面的临床效果。
受试者被分为5组,每组包含6名受试者。所选受试者有已知的口腔溃疡病史,并且有单个或多个直径小于10毫米的溃疡。用双盲方法,研究者和患者都不知道每个患者接受了哪种治疗。所有参数均由主要研究者测量,所有数据均计算为平均值。
入组后,主要研究者在第0、3、5和6天测量溃疡的大小、数量、疼痛和红斑。溃疡大小使用William校准牙科探针测量,最长直径作为测量值,疼痛由受试者在治疗前(0天)和随后的天(1、3和5)根据视觉模拟量表进行评估,红斑级别分类如下所示:
分级 | 红斑级别 |
0 | 无红斑 |
1 | 浅红色或粉色 |
2 | 红色但不深 |
3 | 深红色 |
指导患者在治疗过程中不要进食。对于每位患者,最多使用3个贴膜。如果患者有两个溃疡在同一位置或距离较近,则用2.0×2.0cm的贴片覆盖两个溃疡。对于单个溃疡,使用1.0×1.0cm的贴膜。将贴膜轻轻贴在溃疡上并保持3-5秒以达到适当的粘附效果。每30分钟间隔观察一次结果,持续3小时。患者每天早上和晚上各给药1次。
结果:所有30名患者均完成了研究,总体缓解率为100%。这项研究表明,所有测试中与溃疡相关的数量、大小、红斑和疼痛均有所减少。
结果表明,与实施例5和实施例6(单药)的结果相比,实施例7-1至7-3(含有两种药物)在减小溃疡尺寸、疼痛缓解和红斑减少方面拥有更好的效果。
表4溃疡尺寸的治疗比较
表5溃疡数量的治疗比较
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表6疼痛缓解的治疗比较
表7红斑水平的治疗比较
表8疼痛缓解的起效和持续时间的比较
组别 | 疼痛缓解的起效时间 | 疼痛缓解的维持时间 |
实施例5 | 128S | 2.50h–3.20h |
实施例6 | 90S | 2.40h–3.10h |
实施例7-1 | 82S | 3.15h–3.45h |
实施例7-2 | 94S | 3.20h–4.30h |
实施例7-3 | 100S | 3.00h–4.20h |
上述实施例仅例示性说明本发明的原理及其功效,而非用于限制本发明。任何熟悉此技术的人士皆可在不违背本发明的精神及范畴下,对上述实施例进行修饰或改变。因此,举凡所属技术领域中具有通常知识者在未脱离本发明所揭示的精神与技术思想下所完成的一切等效修饰或改变,仍应由本发明的权利要求所涵盖。
Claims (17)
1.一种用于治疗口腔溃疡的口腔贴膜,包括:
(a)载药层:包含3-20重量份的无定形丁卡因或药学上可接受的盐、0.1-2.0重量份的无定形曲安奈德或药学上可接受的盐、20-95重量份的第一成膜材料、1-12重量份的粘附剂、以及1-20重量份的清凉剂;
(b)背衬层:包括70-95重量份的第二成膜材料和2-10重量份的增塑剂,背衬层可防止丁卡因或其药学可接受的盐、曲安奈德或其药学可接受的盐扩散到口腔中;
所述第一成膜材料选自:醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、羟丙甲纤维素(HPMC)、乙基纤维素(EC)、蔗糖月桂酸酯、聚乙烯醇(PVA)、聚维酮(PVP)、聚乙二醇,羧甲基纤维素(CMC)、羟丙基纤维素(HPC)、甲基丙烯酸甲酯共聚物、高直链淀粉、聚环氧乙烷(PEO)中的一种或多种;
所述粘附剂选自:聚丙烯酸、海藻酸钠、丙烯酸乙酯与甲基丙烯酸甲酯的共聚物、瓜尔豆胶、羧甲基纤维素钠、5-甲基吡咯烷酮壳聚糖、聚谷氨酸、聚卡波非、硫酸葡聚糖中的一种或多种;
所述清凉剂选自:樟脑、薄荷醇、薄荷油、丁香油、乙酸薄荷酯、木糖醇、山梨糖醇、百里酚中的一种或多种;
第二成膜材料选自:HPMC、HPC、羟乙基纤维素(HEC)、羟丙基化高直链淀粉、甲基丙烯酸甲酯共聚物、聚维酮、胶原蛋白、明胶、果胶、邻苯二甲酸醋酸纤维素(CAP)、聚乙烯醇(PVA)、邻苯二甲酸聚乙烯醇酯(PVAP)中的一种或多种。
2.根据权利要求1所述的口腔贴膜,其特征在于:所述第一成膜材料为醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、羟丙甲纤维素(HPMC)、乙基纤维素(EC)、聚乙烯醇(PVA)、聚维酮(PVP)、聚乙二醇、羧甲基纤维素(CMC)中的一种或多种。
3.根据权利要求1所述的口腔贴膜,其特征在于:所述第二成膜材料为HPMC、HPC、HEC、羟丙基化高直链淀粉、甲基丙烯酸甲酯共聚物、聚维酮中的一种或多种。
4.根据权利要求1所述的口腔贴膜,其特征在于:所述载药层还包含1-12重量份的增塑剂。
5.根据权利要求1所述的口腔贴膜,其特征在于:所述载药层中的增塑剂和所述背衬层中的增塑剂可分别选自:甘油、柠檬酸三乙酯、丙二醇中的一种或多种。
6.根据权利要求1所述的口腔贴膜,其特征在于:所述背衬层的厚度为100-200μm。
7.根据权利要求1所述的口腔贴膜,其特征在于:所述丁卡因或其药学可接受的盐的量为1-6mg。
8.根据权利要求1所述的口腔贴膜,其特征在于:所述曲安奈德或其药学可接受的盐的量为0.03-0.65mg。。
9.根据权利要求1所述的口腔贴膜,其特征在于:所述载药层还含有1-8重量份的一种或多种矫味剂。
10.根据权利要求1所述的口腔贴膜,其特征在于:所述背衬层还含有1-8重量份的一种或多种矫味剂。
11.根据权利要求1所述的口腔贴膜,其特征在于:所述载药层包含盐酸丁卡因和曲安奈德。
12.根据权利要求11所述的口腔贴膜,其特征在于:
(a)载药层包含3-20重量份的无定型盐酸丁卡因、0.1-2.0重量份的无定形曲安奈德、30-90重量份的第一成膜剂材料、1-8重量份的粘附剂、1-15重量份的清凉剂和1-12重量份的增塑剂;
(b)背衬层,其包含80-95重量份的第二成膜材料和2-8重量份的增塑剂。
13.根据权利要求1所述的口腔贴膜,其特征在于:其尺寸为1cm×1cm至2cm×2cm。
14.根据权利要求1所述的口腔贴膜,其制备方式为:
(a)将丁卡因或其药学上可接受的盐、曲安奈德或其药学上可接受的盐、一种或多种第一成膜材料、粘附剂、清凉剂混合,形成载药层成膜液;
(b)将载药层成膜液均匀涂布、干燥成膜,得到载药层;
(c)将一种或多种第二成膜材料和一种或多种增塑剂在第二溶剂中混合以形成背衬层成膜液;
(d)将背衬层成膜液涂布在载层上并干燥,并干燥成膜,得到含背衬层和载药层的双层膜;
(e)从基材取下双层膜得到双层口腔贴膜。
15.根据权利要求14所述的口腔贴膜制备方法,其特征在于:所述第一溶剂为浓度20-100%(w/w)的有机溶剂的水溶液,其中所述有机溶剂选自乙醇、二甲基亚砜、二甲基甲酰胺中的一种或多种。
16.根据权利要求15所述的方法,其特征在于:所述有机溶剂是乙醇。
17.一种治疗受试者口腔溃疡的方法,包括以下步骤:
确定有需要的患者;
将权利要求1的贴膜粘附于患者的口腔溃疡黏膜上。
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