CN102724963B - 液体前体组合物及其用于口腔病的pH-依赖的缓释治疗的用途 - Google Patents
液体前体组合物及其用于口腔病的pH-依赖的缓释治疗的用途 Download PDFInfo
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Abstract
本发明公开了适用于施用在口腔中的硬表面上的液体前体组合物,其包含至少一种适于治疗口腔病的治疗剂、至少一种对酸性pH敏感的聚合物、至少一种疏水聚合物,以及药学上可接受的挥发性载体,其中所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的重量比大于1。本发明还公开了由这些组合物的固化形成的制剂,以及通过将这些组合物施用在口腔中的硬表面上或放置于口腔中而治疗口腔病的方法。
Description
口腔是非常脆弱的环境。在口腔卫生、饮食、药剂或年龄上的任何变化都可导致口腔病,如龋齿、牙周疾病、龈炎、恶臭、牙齿染色(toothstaining)、细菌和真菌感染。
此外,牙本质过敏症(dentalhypersensitivity)是牙科中经常遇到的问题,并且是非常麻烦的临床病症,其发生于牙齿的牙本质或牙骨质由于磨损或磨耗而暴露的任何地方,或发生在牙齿的细根表面由于牙周疾病或任何齿龈有关的治疗而暴露时。对于牙本质过敏的人而言,日常刺激如刷牙或吃喝冷和/或热和/或甜和/或苦和/或酸的食物或饮料可为痛苦的。
使用了若干种治疗剂和药物递送装置以尝试治疗、预防或改善这些疾病:水氟化、片剂、凝胶、滴剂和牙膏是使用的最普通的药物施用方式。这些药物递送系统的主要缺点是它们在目标器官中的低直接性(substantivity)。特别地,注意到如下:
在许多情况下,广泛使用的途径是机械清洁方法,例如在使用或不使用各种牙膏组合物的情况下刷牙。虽然已经证明这种方法在治疗个体方面相当成功,但其具有高的复发率(recurrencerate)。还存在推动人们养成他们会终生保持的良好口腔卫生习惯的问题。此外,智力迟钝的、有缺陷的、残疾的或就医的患者或者具有肌肉运动问题的任何受试者由于不能适当地护理他们的牙齿而对牙病更易感。
而且,在一些情况中,例如在本质过敏症的治疗中,牙膏中一些活性成分(例如锶盐)的使用,由于在口中的不愉快的盐味或金属味,而为患者所厌恶。
在一些情况中,例如用于抗真菌剂时,活性成分形成漱口水、洁牙剂、溶液和凝胶的一部分。这些技术的主要问题是所述抗真菌药物不在口腔中以有效水平保持足够长的时间。
已经表明治疗剂如抗生素或抗真菌剂的全身给药是控制口腔感染的有用方法;然而,治疗的中断将导致潜在病原体的可能的恢复。而进一步地,当使用长期抗生素治疗时,其产生发展耐受性菌株和重复感染的潜在危险。
缓释递送(SRD)系统是其中活性试剂以受控的速率从赋形剂释放的药物施用方式。
SRD的使用产生若干药理学优势:药物在目标部位的受控的持续时间和浓度;减少的施用药物量和最小的副作用(如苦味、牙齿染色、耐受性菌株的发展、和口腔感染的复发)。这些优势反过来又导致更好的临床改善和更好的患者顺从性。
实际上已经报导缓释递送系统在一些情况中对于牙周疾病的局部治疗和在佩戴正畸器械的患者中噬斑预防的治疗中是有用的(参见例如Friedman,M.等人,J.Dent.Res.64:1319-1321,1985)。在这种系统中,活性成分嵌入乙基纤维素聚合物中以形成膜。本发明人的美国专利US5,330,746公开了用于噬斑预防或用于治疗和/或预防牙本质过敏症的牙科液体前体组合物,但抗细菌剂或本质过敏症试剂是嵌入缓释载体,如亲水聚合物、丙烯酸类聚合物或这两者的组合中的。
本发明人中一些的美国专利US5,160,737显示可使用丙烯酸类聚合物作为用于试剂如氯化十六烷基吡啶(CPC)的缓释的基体。
似乎在许多病理性口腔病(如本文描述的那些)期间,口腔的pH从7.2-6.8的正常pH降低至低得多的值。例如,在碳水化合物存在下的口腔细菌如变形链球菌(mutansstreptococci)群将口腔pH值降低至pH=4.0(WolinskyLE,Cariesandcardiology,InOralMicrobiologyandImmunology.Eds;NisengardandNewman,第2版,W.B.SaundersCompany,第7章,第341-359页,1994)。在另一个实例中,口腔真菌如白念珠菌(Candidaalbicans)在48小时的发酵周期内,将口腔pH值从7.5降低至3.8(Samaranayake等人,GrowthandacidproductionofCandidaspeciesinhumansalivasupplementedwithglucose.J.OralPathol.1986年5月;15(5):251-4)。
此外,与pH的下降有关的生物膜形成也与其它口腔病如牙本质过敏和牙齿染色以及口腔溃疡形成有关。
WO2010/0264333公开了包含主体结构的装置(如支架),其具有由对pH敏感的层组成的一个或多个表面,其在pH触发物下具有变化的水溶性。这种装置用于在该装置周围的生理学pH例如由于细菌感染而改变时预防感染。
本发明人现已成功地开发了缓释制剂(配方,formulation),其在酸性pH下提高释放速率,从而当需要时,即当存在与pH降低有关的疾病时,或当病症(condition)恶化时(通过降低的pH证实),释放更大量的治疗剂;而在缓解时,所述释放速率将恢复至基本的释放速率。
此外,已经显示在口腔中,酸性条件对于一些药物的给药是优选的。例如,酸化的氟化物制剂显示出在氟化物穿透、结合到龋齿损伤中具有优势(Murakami等人,ArchOralBiol.2009年11月;54(11):997-1001.Epub2009年9月1日;Effectoffluoridevarnishandgelondentalerosioninprimaryandpermanentteeth)。药物(如氟化物)仅在低pH值下对pH敏感的缓释具有增强的生物利用性和因此的药理学优势。
所提出的系统是独特的,因为其具有在酸性pH下提高释放速率的“内置”pH传感器。
具体而言,本发明描述了适用于施用在口腔中的硬表面上的液体前体组合物,包含:
a)至少一种适于治疗口腔病的治疗剂,
b)至少一种对酸性pH敏感的聚合物,
c)至少一种疏水聚合物,和
d)药学上可接受的挥发性载体,
其中所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的重量比大于1。
术语“液体”是指当存在于容器中时在室温下为流体的组合物。
术语“液体前体”是指虽然本发明的组合物最初为液体,但当施用到硬表面时其固化(主要是由于所述药学上可接受的挥发性载体或溶剂的蒸发)。
所述溶剂(有时称为“载体”)通常是生物相容和挥发性的(在体温下)溶剂。
适于用作本发明的液体前体组合物的一部分的所述载体应能够在正常存在于口腔中的条件下蒸发,任选地能够在施加主动干燥条件下(如在热空气流下)蒸发。
优选地,所述载体为醇或醇与水的组合(水-醇类或醇类溶剂)。
更优选地,所述载体选自乙醇或者乙醇与水或生物相容且无毒的任何其它溶剂的组合。
术语“适用于施用到口腔中的硬表面”是指如下事实:将所述液体前体组合物(通过擦涂(brushing)、浸渍、喷雾等)施用在硬表面上,且不意图施用在口腔的软表面,如齿龈、舌头、上腭等上。然而,应该澄清的是随着治疗剂逐渐分散到口腔中,它们也可分散在与所述硬表面相邻的区域如软组织和齿龈中。
术语“口腔中的硬表面”包括但不限于牙齿或放置于口中的装置如假牙、植入物、正畸器械、固位体、护口器、牙托或放置于口内的任何其它潜在的口装置或器械。
术语“对酸性pH敏感的聚合物”是指在酸性pH下提高其降解的生物相容聚合物。本文使用的术语“酸性pH”是指降低到低于7.2-6.8的正常pH的口腔中的pH。更优选地,所述对酸性pH敏感的聚合物在约pH6.0下或低于pH6.0下具有增强的降解。
对酸性pH敏感的聚合物的实例为甲基丙烯酸二甲氨基乙酯共聚物(胃溶型丙烯酸树脂(EudragitE))。尤特奇(Eudragit)系列的其它丙烯酸酯聚合物和/或包含伯、仲或叔胺基的其它聚合物可用于该目的。
术语“疏水聚合物”是指具有疏水性质的生物相容聚合物,其进一步不溶于口腔环境中。具体而言,所述疏水聚合物应不溶于唾液中。
疏水聚合物的非限制性实例包括但不限于以下聚合物,以及它们的交联形式(如醛或极性化合物)和化学衍生物:甲基丙烯酸羟甲酯(HEMA)与甲基丙烯酸甲酯(MMA)的共聚物水凝胶、乙基纤维素(EC)、硅橡胶、聚乙烯、聚(亚乙基氧)、聚(丙烯酸)、聚乳酸、聚甲基丙烯酸甲酯、聚(甲基乙烯基醚共-马来酸酐)、聚(甲基丙烯酸羟乙酯)、聚氯乙烯、聚氨酯、聚乙酸乙烯酯、硝酸纤维素、卡拉牙胶(karyagum)、乙酸乙基乙烯酯、聚苯乙烯、聚酰胺和蛋白质。
优选地,所述疏水聚合物选自甲基丙烯酸羟甲酯(HEMA)与甲基丙烯酸甲酯(MMA)的共聚物水凝胶、乙基纤维素(EC)、聚(丙烯酸)、聚(甲基乙烯基醚共-马来酸酐)、聚(亚乙基氧)、卡拉牙胶、聚(甲基丙烯酸羟乙酯)、硅橡胶、聚乙烯、聚乳酸、聚甲基丙烯酸甲酯、聚氯乙烯、聚乙酸乙烯酯和聚氨酯。
更优选地,所述至少一种疏水聚合物选自:聚合物如乙基纤维素、硅橡胶、聚乙烯、聚乳酸、聚甲基丙烯酸甲酯、聚氯乙烯、聚氨酯的交联聚合物和衍生物。
在本发明的优选实施方式中,所述组合物包含作为所述疏水聚合物的乙基纤维素和作为所述对酸性pH敏感的聚合物的胃溶型丙烯酸树脂。
通常,所述疏水聚合物的范围为约30%-约80%,所述对pH敏感的聚合物的范围为约10%-约30%,且所述活性试剂的范围为约5%-约40%,所有这些均在干燥膜中。
然而,为了实现本发明组合物的有益性能,重要的是所述疏水聚合物与所述对酸性pH敏感的聚合物之间的比例保持大于1。这将保证在所述液体前体组合物固化时,所述疏水聚合物将形成基体且所述对酸性pH敏感的聚合物将成为嵌入所述疏水基体中的成分。
典型地,所述疏水聚合物与所述“对pH敏感的”聚合物(如胃溶型丙烯酸树脂)之间的比例为约5:1至约1.5:1,进一步优选为约3:1至约2:1。
重要的是应注意术语所述疏水聚合物与所述对pH敏感的聚合物之间的重量比在所述液体前体组合物中与在所述干燥膜中是相同的。
术语“口腔病”包括任何口腔相关的病症和疾病,包括与口腔生物膜直接相关和有关的病症、牙科和牙周疾病(如噬斑、龋齿、龈炎、牙周疾病、牙根管感染、拔牙、牙本质过敏症、病毒感染、口干燥症、灼口症、溃疡、念珠菌病、肿瘤、口疮(aphthous)、溃疡形成、脓肿(absecsss)、口炎、口臭、口干(drymouse)、唾液腺功能障碍)以及包括牙科美容(牙齿增白)。
术语“适于治疗口腔病的治疗剂”是指旨在预防、治疗、改善或减轻总之任何上述口腔病的试剂。
具体而言,所述治疗剂选自抗生素剂、抗细菌剂、防腐剂、抗真菌剂、抗病毒剂、骨和/或组织生长因子剂、抗肿瘤剂、抗炎剂、抗恶臭剂、牙齿增白剂、漂白剂、牙本质过敏症试剂、噬斑治疗剂、口干治疗剂、生物膜治疗剂、龋齿治疗剂、牙周疾病治疗剂、龈炎治疗剂、牙齿染色治疗剂、口疮或溃疡治疗剂、抗原生动物剂和口炎剂。
抗生素剂的实例包括但不限于四环素衍生物、青霉素衍生物、红霉素衍生物、头孢菌素衍生物、林可霉素(Lindomycin)衍生物和糖肽衍生物。
术语“抗细菌剂”包括能够杀灭细菌的任何试剂。
防腐剂的实例包括但不限于杀菌的季铵盐如氯化十六烷基吡啶或苯扎氯铵或氯己定,或三氯生,或苯酚衍生物,或防腐的挥发性油,草本防腐剂或其它杀菌剂如含樟脑的对氯苯酚(CPK)。
抗真菌剂的实例包括但不限于多烯类化合物、制霉菌素、两性霉素、咪唑、克霉唑、对氯苯咪唑(moconazole)、酮康唑(ketonazole)、三唑、氟康唑(fluconazole)和伊曲康唑(itraconazole)。在本发明的上下文中,术语“抗真菌剂”也包括口炎试剂。
抗病毒剂的实例包括但不限于阿昔洛韦、金刚烷胺(amamatadine)、diolamosine、泛昔洛韦、磷卡萘替(foscaruet)、更昔洛韦(gamciclovir)、利巴韦林、金刚乙胺、司他夫定、扎西他宾和叠氮胸苷(zioloudine)。
骨和/或组织生长因子剂的实例包括但不限于骨形态发生蛋白质(BMP)、细胞活素、IGF和FGF。
抗炎剂的实例包括但不限于甾族和非甾族抗炎剂。
抗恶臭剂的实例包括但不限于充当抗细菌剂/防腐剂或抗酶剂的那些。
牙齿增白剂、漂白剂和牙齿染色治疗剂的实例包括但不限于过氧化物试剂、过氧化脲、过氧化氢。
牙本质过敏症试剂的实例包括但不限于锶盐(如氯化锶或硝酸锶)、钾盐(如氯化钾、酒石酸氢钾或硝酸钾)、氟化盐(如氟化亚锡)、锑或草酸盐(oxylate)(如草酸氢钾),且还可包括氨基酸和肽。
噬斑治疗剂的实例包括但不限于抗细菌剂/防腐剂、抗生物膜剂。
生物膜治疗剂的实例包括但不限于低于最小抑菌浓度的抗细菌剂;草药提取物如大蒜、呋喃酮、高丝氨酸内酯类似物、群体感应抑制剂、表面活性剂和亲水试剂。
龋齿治疗剂的实例包括但不限于例如氟化物化合物如钠、胺、亚锡、磷酸盐。
牙周疾病治疗剂的实例包括但不限于抗生素、抗细菌剂、抗炎剂、生长激素和血管收缩剂。
龈炎治疗剂的实例包括但不限于抗细菌防腐剂。
口疮或溃疡治疗剂的实例包括但不限于四环素、二甲胺四环素、去炎松、地塞米松、酞胺哌啶酮、氨来占司、利多卡因、锌盐、赖氨酸、作为B族复合物和C族的维生素。
口干治疗剂的实例包括但不限于葡糖氧化酶、薄荷醇、薄荷、柠檬和柠檬酸、乳铁蛋白、乳过氧化物酶、溶菌酶和毛果芸香碱。
根据具体的优选实施方式,如可在以下实施例中看到的,所述治疗剂为抗细菌剂和/或抗真菌剂。
更具体地,所述治疗剂选自三氯生、二醋酸氯己定(CHX)、克霉唑和氯化十六烷基吡啶(CPC)。
本发明的组合物可另外包含任何数量的生物相容的添加剂。这些可包括但不限于增塑剂(如聚乙二醇、邻苯二甲酸二丁酯、丙三醇或三乙酸甘油酯),示味剂或遮味剂,如薄荷、薄荷醇、替代糖类的挥发性提取物,以及增稠剂如羟丙基纤维素、羟丙基甲基纤维素。
本文所述的液体前体组合物在其固化时能够形成由所述至少一种疏水聚合物制成的基体,其具有嵌入在内的所述至少一种对酸性pH敏感的聚合物和所述至少一种治疗剂。
本发明的液体前体向固体基体膜的固化可通过使溶剂蒸发而自然地发生或可通过向口施加温和的加热的空气流而促进。
通过所述液体前体组合物的固化而形成的所得基体形成适于治疗多种口腔病的缓释制剂。
因此,根据本发明的另一个方面,提供了缓释制剂,其包含由至少一种疏水聚合物制成的基体,该基体具有嵌入在内的至少一种对酸性pH敏感的聚合物和至少一种适于治疗口腔病的治疗剂,使得所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的重量比大于1。
如在上文详述的,优选该比例为约5:1至约1.5:1,进一步优选为约3:1至约2:1。
本发明的制剂可采取许多形式,如膜、凝胶、泡沫、涂膜(varnish)、剂量计喷雾,以及牙膏或牙刷内药筒的一部分。
在施用到口腔的硬表面上之后,其在所述硬表面上固化后,在该硬表面上形成非常薄的涂层,该层为几微米至几百微米。优选地,所述涂层厚度应为约30微米至约150微米。
术语“缓释制剂”是指允许其中包含的活性试剂以延长的时间(典型地为至少一天)转移至口腔的制剂(在处于固体形式的情况中)。
即使在这些薄涂层的情况下,本发明的制剂的缓释性能也得以保持,范围为。
由于释放速率随着SRD涂层的厚度而变化,如上所述,取决于厚度和环境,其可为数小时至数天。本发明的液体前体组合物由与对酸性pH敏感的聚合物相比足够的疏水聚合物(即疏水聚合物与对酸性pH敏感的聚合物之间的重量比大于1)组成,以使得能够形成疏水基体,在该疏水基体中嵌入所述对pH敏感的聚合物和所述治疗剂。
然后,取决于上述比例和环境以及口腔中的位置(例如,正畸器械和假牙),这种基体即使在相对薄的涂层的情况下,也能够在口腔中的硬表面上保持其缓释性能数小时和数天。
典型地,对于30微米-150微米的涂层,所述释放速率相应为3-12小时。
然而,取决于其上施用所述组合物的表面、厚度和在口腔中的位置,所述释放速率可调节为至少3天。
当pH为中性时,本发明的制剂保持治疗剂的逐渐变慢的释放速率。如上文中解释的,当牙病或口腔病发展时(例如当细菌感染影响口腔时),发生pH降低至约为pH6.0或低于pH6.0。在口腔中形成的酸性pH环境中,所述对酸性pH敏感的聚合物(例如胃溶型丙烯酸树脂)降解,从而提高所述治疗剂从基体中的释放速率,该治疗剂也嵌入在所述基体中。应注意即使在极端酸性的pH下,由于所述疏水聚合物的恒定降解速率,不是所有的治疗剂都会立即释放(“爆裂”)。所述治疗剂的较快的释放速率将持续,直至pH由于病态的停止(例如由于细菌感染的停止)而再次增大。这种“传感器”效果远优于经典的缓释递送系统,在该递送系统中释放表现为恒定概况(profile),而与环境反馈无关。
典型地,固体形式的制剂在一定程度上耐受由正常活动如吃、喝、刷牙等而引起的磨蚀。应强调,根据本发明,所述释放速率不是恒定的,而是响应环境的变化(特别是由于pH变化)而变化。pH越低(指示疾病或病症的存在/恶化),所述释放速率越快,且反之亦然,这使得所述释放取决于疾病或病症的严重性/存在。
鉴于这些优点,即,“感知”与低pH有关的口腔病的能力、所述治疗剂的缓释和延长释放,以及所述系统对于治疗成功(和pH的上升)的敏感性,本文所述的制剂尤其适于口腔病和病症的治疗。
因此,根据本发明的又一个方面,提供用于治疗、预防、改善或消除总之至少一种口腔病的方法,这种方法包括将本发明的液体前体组合物局部施用至口腔中的硬表面,或意欲放置于口腔中的表面,以及使所述组合物在该表面上固化,从而形成膜。
因此所述硬表面可为牙齿、假牙、固位体、植入物、护口器、护圈和正齿器械。其也可为经由口腔插入身体中的任何管道或气道器械或装置,如饲管、通气管、气管和吸管。
术语“膜”包括涂层(或包覆层)和涂膜两者。
通过施用到邻面(inter-proximal)部位中,在牙周袋中施用,或施用到牙根管中来影响这种治疗方法。
如上文中详述的,其可通过擦涂、浸渍、浸泡、喷雾施用在牙齿、口腔组织植入物、或者用于牙科或非牙科用途的任何口腔器械或装置上。
在一个具体实施方式中,本发明的液体前体组合物施用在口腔中的或口腔外部的牙科或口腔装置上。
因此,根据本发明的另一个方面,提供用于将其中所述治疗剂为抗感染(抗细菌、抗病毒、抗原生动物、抗真菌)剂的本发明上述液体前体组合物施用在任何待放置于口中的装置(例如假牙、固位体、植入物等)上,以及使所述液体组合物固化,从而形成缓释用膜的方法。所述施用可为将所述组合物施用到假牙(通过擦涂、喷雾等)或将所述假牙浸渍在本发明的液体前体组合物中。
本发明的所述液体前体组合物和所述方法适用于人类或兽医使用。
试验
材料和方法
活性试剂
二醋酸氯己定(CHX)、氯化十六烷基吡啶(CPC)、克霉唑和三氯生均获自Sigma-Aldrich,St.Louis,美国。
赋形剂
尤特奇EPO(RohmGmbh,德国)
十二烷基硫酸钠(SLS)(RiedeldeHaen,Sigma-AldrichGmbh,德国)
乙基纤维素-(EC)(EthocelPremiumN100,DowChemicalCompanyRusselville,美国)
乙醇(J.T.BakerDeventerHolland)
聚乙二醇400(PEG400)(SchuchardtHohenbrunnGermany)
乙酸钠三水合物
1-庚烷磺酸钠盐(J.T.BakerNJUSA)
附加成分
氨基丁三醇碱(2-氨基-2-(羟甲基)-1,3-丙二醇)-(Sigma-Aldrich,St.Louis,美国)
磷酸盐缓冲液USPpH=6.8
磷酸盐缓冲液USPpH=5.0
实施例1:包含克霉唑的对pH敏感的液体前体组合物的制备及其施用
I.液体前体组合物的制备:
称重PEG400置于乙醇中。然后,向乙醇中缓慢加入作为干粉末的疏水聚合物(乙基纤维素)和对pH敏感的聚合物(胃溶型丙烯酸树脂)的干粉末,并剧烈搅拌约30分钟直至完全溶解。然后,在连续搅拌的同时加入克霉唑(活性试剂)。
II.由液体前体组合物制备膜:
在干燥室中,将部分I中获得的液体前体组合物倾倒(15ml)在Teflon盘(10.5厘米直径)上,并干燥约4小时。获得的膜为0.230mm厚。
下表1显示了制备的克霉唑样品,显示了其以干燥膜形式的和以液体前体组合物形式的组成。
表1
III.测定克霉唑从部分II的膜中的释放速率:
基于PeterdeBruijn等人,2001(LiquidchromatographicdeterminationofKetoconazole,apotentinhibitorofCYP3A-mediatedmetabolism,JournalofChromatographyB,753(2001)395-400)如下通过HPLC使用已知的克霉唑浓度标定曲线来测定释放的克霉唑浓度:
将100微升样品自动注入HPLC(HP1090型)中,该HPLC装有InertsilODS-80A柱(5μm150×4.6mmGLScience,Tokyo,日本)并通过MetaGuard4.6mmInertsilODS-3柱(5μm)保护。
流动的缓冲液为pH6.0的45:50.2:2.5:0.1:0.1比例的水、乙腈、THF、三乙胺和氢氧化铵的混合物。流速为1ml/分钟。
根据参考曲线,在206nm波长下测量UV吸收。
释放速率试验:
通过首先将膜放置在包含氨基丁三醇碱缓冲液(50mM)和0.2%SLS(十二烷基硫酸钠)的350ml玻璃容器中,在pH=5.0和6.8以及50cpm下于37℃进行克霉唑从该膜中的释放速率的测定。
然后,以预定的时间间隔(1-8小时的每个小时)从所述玻璃容器中取出1cc样品。通过分光光度计(Uvikon933:KontronInstruments)在206nm下测量释放的克霉唑浓度。根据参考曲线计算所述CHX的浓度。
图1显示了对于两个不同的pH:5.0和6.8,随时间(1-8小时)的克霉唑释放速率(作为膜中初始量的%)。如从图中清楚的是,pH5.0下的释放速率比pH6.8下的释放速率快得多。
在不同的试验中,将该膜在pH5.0的缓冲液中保持2小时,然后在pH6.8的缓冲液中保持2小时,然后在pH5.0的缓冲液中保持2小时并再在pH6.8的缓冲液中保持2小时。以类似间隔取出样品。结果示于图2中,其显示了对于这种pH变化概况的随时间(1-8小时)的克霉唑释放速率(作为膜中初始量的%)。其再次证明6.8的pH延迟了从对pH敏感的SRD中的释放速率。
实施例2:包含二醋酸氯己定(CHX)的对pH敏感的液体前体组合物的制备及其施用
I.液体前体组合物的制备:
以二醋酸氯己定(CHX)代替克霉唑,如实施例1(部分I)中所述制备液体前体组合物。
II.由所述液体前体组合物制备膜:
在干燥室(37℃)中,将部分I中获得的所述液体前体组合物倾倒(21ml)在Teflon盘(10.5厘米直径)上,并干燥约4小时。获得的膜为0.120mm厚。
下表2显示了制备的CHX样品,显示了其以干燥膜形式的和以液体前体组合物形式的组成。
表2
III.测定CHX从部分II的膜中的释放速率:
基于Y.W.FrancisLam等人,1993(Sensitivehighperformanceliquidchromatographicassayforthedeterminationofchlorhexidineinsaliva,JournalofChromatogrPHY,612(1993)166-171)如下采用HPLC使用已知的CHX浓度的标定曲线测定释放的CHX浓度:
将50微升样品自动注入HPLC(HP1090型)中,所述HPLC装有InertsilODS-80A柱(5μm150×4.6mmGLScience,Tokyo,日本)并通过MetaGuard4.6mmInertsilODS-3柱(5μm)保护。
流动的缓冲液为pH=5.0的40%ACN、60%0.05M乙酸钠、0.05M庚烷磺酸。
流动速率为1ml/分钟。
在260nm波长下测量UV吸收,并通过参考曲线确定CHX浓度。
释放速率试验:
通过首先将膜放置在包含磷酸盐缓冲液的100ml玻璃容器中,在pH=5.0和6.8以及50cpm下于37℃进行CHX从所述膜中的释放速率的测定。
然后,以预定的时间间隔(1-8小时的每个小时)从所述玻璃容器中取出1cc样品。
通过分光光度计(Uvikon933:KontronInstruments)在260nm下测量释放的CHX浓度。根据参考曲线计算所述CHX的浓度。图3显示了在两个不同的pH:5.0和6.8下,随时间(1-8小时)的CHX释放速率(作为膜中初始量的%),再次显示出在pH5.0下的更高的释放速率。
在不同的试验中,将该膜在pH5.0的缓冲液中保持2小时,然后在pH6.8的缓冲液中保持2小时,然后在pH5.0的缓冲液中保持2小时并再在pH6.8的缓冲液中保持2小时。以类似的时间间隔取出样品。结果示于图4中,其显示了对于这种pH变化概况的随时间(1-8小时)的CHX-1释放速率(作为膜中初始量的%)。如图4中各取样时间间隔处所示,CHX在pH5.0下的释放速率快于在pH6.8下的释放速率,这也证明了6.8的pH延迟从对pH敏感的SRD中的释放速率。
实施例3:包含三氯生的对pH敏感的液体前体组合物的制备及其施用
I.液体前体组合物的制备:
以三氯生代替克霉唑,如实施例1(部分I)中所述制备液体前体组合物。
II.由所述液体前体组合物制备膜:
在干燥室中,将部分I中获得的液体前体组合物倾倒(15ml)在Teflon盘(10.5厘米直径)上,并干燥约4小时。获得的膜为0.177mm厚。
下表3显示了制备的三氯生样品,显示了其以干燥膜形式的和以液体前体组合物形式的组成。
表3
III.测定三氯生从部分II的膜中的释放速率:
通过首先将膜放置在包含氨基丁三醇碱缓冲液(50mM)+10%SLS(十二烷基硫酸钠)的100ml玻璃容器中,在pH=5.0和6.8以及50rpm下于37℃进行三氯生从该膜中的释放速率的测定。
然后,以预定的时间间隔(1-8小时的每个小时)从所述玻璃容器中取出2cc样品。通过分光光度计(Uvikon933:KontronInstruments)在280nm下测量释放的三氯生浓度。根据参考曲线计算所述三氯生的浓度。图5显示了在两个不同的pH:5.0和6.8下,随时间(1-8小时)的所述三氯生(Tric-1)释放速率(作为在膜中初始量的%)。
在不同的试验中,将该膜在pH5.0的缓冲液中保持2小时,然后在pH6.8的缓冲液中保持2小时,然后在pH5.0的缓冲液中保持2小时并再在pH6.8的缓冲液中保持2小时。以类似的时间间隔取出样品。结果示于图6中,其显示了对于这种pH变化概况的随时间(1-8小时)的Tric-1释放速率(作为膜中初始量的%)。
如图6的各取样时间间隔处所示,三氯生在pH5.0下的释放速率显著快于在pH6.8下的释放速率。
实施例4:包含氯化十六烷基吡啶(CPC)的对pH敏感的液体前体组合物的制备及其施用
I.液体前体组合物的制备:
以氯化十六烷基吡啶(CPC)代替克霉唑,如实施例1(部分I)中所述制备液体前体组合物。
II.由所述液体前体组合物制备膜:
在干燥室中,将部分I中获得的液体前体组合物倾倒(15ml)在Teflon盘(10.5厘米直径)上,并干燥约4小时。获得的膜为100-150微米厚。
下表4显示了制备的三氯生样品,显示了其以液体前体组合物形式的组成。
表4
实施例5:具有和没有对pH敏感的聚合物的样品的抗细菌活性的比较
分别如以上在实施例2和4中详述的,制备具有抗微生物剂氯己定(CHX)和氯化十六烷基吡啶(CPC)的基于乙基纤维素的制剂,其具有或没有对酸性pH敏感的聚合物(胃溶型丙烯酸树脂)。对变异链球菌(S.mutans)ATCC27351细菌的抗细菌生物测定活性的持续时间通过如下测试:测量所述制剂周围的每日生长抑制区域,随后将所述制剂转移到新制成平板的琼脂培养基中,直至观察不到抑制作用。
不同的测试液体前体组合物的组成在下表5中给出。
表5
结果
图7显示了以上详述的配方1-3的CHX制剂对临床分离的链球菌属的持续抗微生物活性随时间(天)的变化。如在图7中可看出的,包含作为抗微生物剂的CHX与对pH敏感的聚合物胃溶型丙烯酸树脂的SRD显示出对变异链球菌最好的延长的体外抗细菌活性(超过79天)。
实施例6:本发明SRD系统的人药物动力学
为了进行临床人药物动力学试验,制备并使用根据实施例1-4(分别为部分I)制备的液体前体组合物。
例如,通过将1.2克克霉唑、0.9克乙基纤维素、0.2克胃溶型丙烯酸树脂溶解在10mL乙醇中制备克霉唑缓释型对酸性pH敏感的制剂。所述组合物对应于包含30%羟丙基纤维素的膜剂型。包含10mg克霉唑和903.5mg葡萄糖的Oralten锭剂(AgisIndustries,Yeruham,Israel)用作商业对照。
将本发明的液体前体组合物和锭剂施用于十四位健康的志愿者。当研究所述锭剂时,要求志愿者将该锭剂在口腔中溶解。在两种情况(本发明的液体前体组合物或锭剂给药)下,在施用前5分钟以及在克霉唑给药后5、30、60、120、180、240和300分钟收集未受刺激的唾液样品(2ml于刻度管中)。使用HPLC分析所述唾液样品。使用WinNonlin5.0.1软件(PharsightCorporation,MountainView,CA,美国)进行所有的药物动力学和药效动力学计算。由浓度-时间曲线确定所述曲线下的面积(AUC)、终末半衰期(terminalhalf-life)和在克霉唑对于白念珠菌的最低抑制浓度之上的时间(T>MIC)。所有的数据作为平均值±SD给出。通过配对的双尾学生t检验评价各组之间的差异的统计显著性。
基线唾液流动速率在两者中非常相似。在本发明液体前体组合物的施用以及锭剂给药之前的第一个五分钟的唾液流动速率分别为3.9±2.5ml和4.3±2.0ml。作为本发明液体前体组合物施用的克霉唑的量为9.21±2.27mg(平均值±SD),且将所述唾液浓度数据归一化以允许与10mg锭剂比较。
图8显示了在给药后的不同时间间隔(分钟)唾液中的克霉唑浓度(平均值±SD),两者之一为根据本发明的优选实施方式(在图中标记为“涂膜”)且另一为对照的锭剂组合物(在图中标记为“Oralten”)。如可从这张图中看出的,在所有的时间点,液体前体组合物组中的唾液克霉唑浓度均高于锭剂组中的浓度。在两个组中均观察到浓度在初始(至~60分钟)非常快速的下降,随后处于慢得多的消除期。在所述两组之间,动力学速率的终末期显著不同。在所述试验期间,本发明的液体前体组合物组显示出所述锭剂组的两倍以上的面积曲线(AUC0→300)(p<0.001)。
药效动力学:可通过计算超出在唾液中获得的克霉唑的最低抑制浓度(MIC)的时间而模拟所述两种制剂的药效动力学比较。来自所述液体前体的克霉唑的浓度高于典型的MIC值(0.5-3mg/ml),且与锭剂组相比,其超出所述MIC的持续时间延长。例如,对于锭剂,克霉唑在治疗窗下的持续时间为60分钟,与之相比对于所述液体前体,在MIC3mg/ml下的持续时间为240分钟。因此,施用本发明的液体前体组合物之后的超出MIC的时间比给药所述锭剂之后的长3倍以上。
Claims (14)
1.适用于施用在口腔中的硬表面上的液体前体组合物,包含:
a.至少一种适于治疗口腔病的治疗剂,
b.至少一种对酸性pH敏感的聚合物,其在低于pH6.0下具有增强的降解,
c.至少一种疏水聚合物,其不溶于唾液中,和
d.药学上可接受的挥发性载体,
其中所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的重量比大于1。
2.权利要求1所述的组合物,其中所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的所述重量比为5:1至1.5:1。
3.权利要求1所述的组合物,在其固化时,能够形成由所述至少一种疏水聚合物制成的基体,所述基体具有嵌入在内的所述至少一种对酸性pH敏感的聚合物和所述至少一种治疗剂。
4.权利要求1所述的组合物,其中所述疏水聚合物选自:甲基丙烯酸羟甲酯(HEMA)和甲基丙烯酸甲酯(MMA)的共聚物水凝胶、乙基纤维素、聚(丙烯酸)、聚(甲基乙烯基醚共-马来酸酐)、聚(亚乙基氧)、卡拉牙胶、聚(甲基丙烯酸羟乙酯)、硅橡胶、聚乙烯、聚乳酸、聚甲基丙烯酸甲酯、聚氯乙烯、聚乙酸乙烯酯和聚氨酯。
5.权利要求1所述的组合物,其中所述治疗剂选自抗生素剂、抗细菌剂、防腐剂、抗真菌剂、抗病毒剂、骨和/或组织生长因子剂、抗肿瘤剂、抗炎剂、抗恶臭剂、牙齿增白剂、漂白剂、牙本质过敏症试剂、噬斑治疗剂、口干治疗剂、生物膜治疗剂、龋齿治疗剂、牙周疾病治疗剂、龈炎治疗剂、牙齿染色治疗剂、口疮或溃疡治疗剂、和抗原生动物剂。
6.权利要求5所述的组合物,其中所述治疗剂选自三氯生、二醋酸氯己定(CHX)、克霉唑和氯化十六烷基吡啶(CPC)。
7.权利要求1所述的组合物,其中所述对酸性pH敏感的聚合物选自胃溶型丙烯酸树脂或包含伯、仲或叔胺基的任何化合物。
8.权利要求1所述的组合物,其中所述对酸性pH敏感的聚合物选自丙烯酸类化合物。
9.权利要求1所述的组合物,其中所述治疗剂为抗口炎剂。
10.缓释制剂,包含由至少一种疏水聚合物制成的基体,所述基体具有嵌入在内的至少一种对酸性pH敏感的聚合物和至少一种适于治疗口腔病的治疗剂,使得所述至少一种疏水聚合物与所述至少一种对酸性pH敏感的聚合物之间的重量比大于1,其中所述对酸性pH敏感的聚合物在pH6.0下或低于pH6.0下具有增强的降解。
11.权利要求10所述的制剂,其中所述对酸性pH敏感的聚合物形成所述基体的总重量的10重量%-40重量%。
12.权利要求10所述的制剂,其为具有30微米至150微米的宽度的膜形式。
13.权利要求12所述的制剂,其具有3-12小时的所述治疗剂的释放速率。
14.权利要求1-9中任一项所述的液体前体组合物用于制造在治疗、预防、改善或消除至少一种口腔病的方法中使用的药物的用途,所述方法包括将所述液体前体组合物局部施用到口腔中的硬表面或待放置于所述口腔中的硬表面上,使所述组合物固化,从而在所述硬表面上形成膜。
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