CN104940943B - 喷雾用凝胶型皮肤·粘膜附着型制剂及使用它的给药系统 - Google Patents
喷雾用凝胶型皮肤·粘膜附着型制剂及使用它的给药系统 Download PDFInfo
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- CN104940943B CN104940943B CN201510214262.2A CN201510214262A CN104940943B CN 104940943 B CN104940943 B CN 104940943B CN 201510214262 A CN201510214262 A CN 201510214262A CN 104940943 B CN104940943 B CN 104940943B
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Abstract
本发明提供一种由在含有皮肤·粘膜附着剂的凝胶基质中含有药物活性物质的凝胶制剂构成的喷雾用凝胶型皮肤·粘膜附着型制剂及使用该喷雾用凝胶型皮肤·粘膜附着型制剂的给药系统。
Description
本申请是申请日为2007年4月20日、申请号为200780014284.8、发明名称为“喷雾用凝胶型皮肤·粘膜附着型制剂及使用它的给药系统”的发明专利申请的分案申请。
技术领域
本发明涉及含有药物活性物质的凝胶型皮肤·粘膜附着制剂、及使用含有药物活性物质的粘性凝胶型皮肤·粘膜附着制剂的给药系统,其中,使用凝胶制剂用喷雾容器(上方排压真空式喷雾容器),可以任意设定喷雾容器的给药方向。特别是涉及一种作为喷鼻用的、将喷雾容器的给药方向设定为任意方向、使用鼻腔喷雾容器将该制剂喷雾到鼻腔内、可以使凝胶基质分布并滞留在大范围的鼻腔内的制剂及使用该制剂的给药系统。
背景技术
作为以往的药物的给药方式,将液体制剂填充到喷雾容器中,然后将其喷雾到内腔、体表上的粘膜及皮肤来进行给药的方法被广泛利用。特别是鼻腔内给药型制剂被广泛利用。在此所使用的药物局限于用于鼻炎治疗等以局部作用为目标的药物,最近,以全身作用为目标的药物的给药途径备受瞩目。目前已有的以全身作用为目标的鼻腔内给药型制剂的市售品有:布托啡诺及舒马曲坦等低分子药物、以及降钙素及去氨加压素等肽类药物,并且一直在大量尝试期待吸收改善及速效性的药物的经鼻给药应用。
作为用于粘膜的喷雾给药型制剂、尤其是鼻腔内给药型制剂的优点,例如有:(1)可以迅速吸收,从而可以期待速效性、(2)可以避免肝脏的首过效应引起的药物的分解、(3)可以避免胃酸及消化道酶等引起的消化道中的药物分解、(4)可以提高生物利用度,从而使药物的用量减少、(5)和注射相比为无创(非侵袭性)给药途径、(6)可以自己对患处进行治疗、(7)可以使药物直接进入血液循环或中枢神经系统等,另一方面,作为鼻腔内给药型制剂的缺点,例如有:(1)可以给予鼻腔的给药量被限定在1次25~200μL、(2)1kD以上的高分子量的化合物通过该给药途径难以被吸收、(3)鼻腔的病理状态会影响吸收、(4)鼻腔的状态具有个体差异、(5)作为粘膜纤毛清除系统的异物排除系统会影响药物吸收、(6)鼻腔内存在酶屏障、(7)药物对鼻粘膜有刺激等。
鼻腔是与口腔一同与外界接触的初始部位,具有非常优良的异物排除功能和抗感染功能。这些功能的异常活性化或由此导致的功能消失会导致鼻炎、鼻过敏等。特别是花粉症,已成为深刻的社会问题。为了治疗这些鼻局部疾病,含有血管收缩剂、抗过敏剂、类固醇剂等的点鼻剂被广泛销售。
另一方面,含有分子量1000~3000的生理活性肽或水溶性肽的经鼻吸收型制剂也有市售品。这些水溶性高分子药物通过经口给药是无效的,只有做成注射剂来给药才是有效的给药方法,但是在经鼻给药中,可以获得几%~数十%左右的高生物利用度。其主要原因是:作为水溶性高分子药物的吸收路径的鼻粘膜上皮层的透过性比消化道及其它粘膜的透过性高很多。由此,以全身作用为目标的水溶性高分子药物的经鼻吸收型制剂作为替代注射剂的无创给药剂型是非常有用的。
近年来,一直在利用鼻粘膜上皮层的透过性比其它部位的粘膜透过性好的特点来设计和开发用于缓和剧烈疼痛的麻药性镇痛药及偏头痛药的经鼻吸收制剂。这样的含有中枢神经作用型药物的经鼻吸收制剂由于可以比口服给药制剂更迅速的发挥其药效、且可以自己给药,因此可以显著地提高患者的QOL。鼻腔存在与淋巴类组织类似的NALT(鼻咽相关淋巴组织)。目前,作为利用鼻子的免疫应答性高的特点的流感疫苗或白喉疫苗等针对可通过空气传染的病毒的疫苗的给药途径,正在设计和开发鼻腔内给药型制剂。由此,利用鼻腔的解剖生理学的特点来进行鼻腔内给药型制剂的开发被寄予了很大的希望,为了设计和开发鼻腔内给药型制剂,必须理解鼻粘膜和其周边组织的解剖生理学特征,从而进行制剂设计。
鼻腔内给药型制剂中,由于鼻腔的清除率很大,因此需要下很多功夫。以往的制剂剂型包括鼻腔软膏型制剂、液滴型制剂、喷雾型制剂、粉末型制剂等。这些制剂以达到如下所述的目的来进行设计和开发:谋求通过提高制剂在鼻腔内的分散性从而使活性药物与鼻粘膜的接触时间增大,或谋求通过提高药物在鼻腔内的滞留性(附着性)从而使活性药物与鼻粘膜的接触时间增大,由此来使活性药物在鼻腔内有效地发挥其效果、使鼻腔吸收药物(专利文献1)。
鼻腔软膏型制剂由于通常通过手指进行涂敷,因此不卫生,并且仅通过手指进行涂敷不能使药物到达鼻腔深部的粘膜,从而难以给予固定量的活性药物。
液滴型制剂在过去是最简单而简便的方法,但由于其不仅无法给药正确的量,而且会通过粘膜纤毛清除而迅速地从鼻腔向咽喉一侧被除去。
喷雾型制剂通过泵将药液制剂吸上来,之后以雾状喷到鼻腔内,因此比液滴型制剂具有更好的分散性。
粉末型制剂用于在溶液中易分解的药物及可以确保其在鼻腔内的滞留性的情况。但是,在对鼻腔给药时,有时出现不适感或粘膜障碍性、且粒子的均匀化等的制剂设计难。
在这些鼻腔内给药型制剂中,由于喷雾型制剂使用方便且使用感良好,因此是最常用的剂型。喷雾型制剂中,通过扩大活性药物与鼻粘膜的接触面积、延长接触时间,即改善滞留性的方式,进行了各种提高药效和吸收性的尝试。
通常的喷雾型制剂中,为了避免药物被鼻前庭捕获或从鼻孔流出,广泛地建议在喷雾操作时用鼻子吸气,然而认为,实际上,在吸气时,鼻腔瓣的弹性组织进一步变窄,大部分药物从鼻子被运送到口腔而咽下。
此处通常所使用的液体喷雾装置是利用泵将内装药液通过管吸上来的液体喷雾型制剂,该使用通常在角度0~25°的范围内广泛应用(参照图3)。这是由于:由于通常需要使用于将装在容器中的液体吸上来的管的顶端与药液接触,因此需要将头往前倾以使喷雾容器的给药角度接近于0°的方式来使用并给药。但是,该给药方法中,没有粘度和附着性的通常的液体制剂或低粘度的液体制剂会直接流到鼻孔外,另一方面,在将头向后仰、喷雾容器的给药角度为约65°~90°的状态下使用时,通常的液体喷雾型制剂中,药液冲击到鼻腔内的被称为鼻甲或鼻中隔的壁上,由于没有附着性,因而从下鼻道流出,大部分流入口腔中而被吞下。从下鼻道流出的缺点认为可以通过添加后述的附着性高分子作为制剂基质而得到一定程度的改善,但是使用附着性高分子时,由于喷雾制剂粒子的粒径变大、喷雾容器的喷射角度变窄,因而不能使药物广范围地分散,并且由于鼻腔内的粒子之间的碰撞,药物成为更大粒子并与壁碰撞,结果使相当的部分被运送到口腔而被咽下。通过进一步提高给药角度进行喷雾,有望使药物分散到鼻甲的广范围内,但是会使通常的喷雾型制剂中的用于将药液吸上来的管的顶端不能与药液接触,在将头倾斜来给药的给药角度的调整方面有一定的限度。
此外,上述液体喷雾装置由于制成了会吸入外界空气的系统,因此必须使用一定量的防腐剂等。
并且,鼻腔喷雾装置喷出的制剂的粒径在谋求药物的清除率的改善上是需要考虑的因素之一。即,人的鼻腔具有约150~180cm2的面积,直线测定从外鼻孔到鼻咽的距离为12~14cm,为了保护鼻腔的下呼吸道,鼻腔成为最优化的狭窄的、复杂的几何结构,鼻腔内的鼻腔瓣的狭小间隙相当于鼻腔的空气阻力整体的一半。并且,鼻腔瓣的后部具有被鼻甲分隔成狭缝状的空间,在此,被喷雾的制剂粒子速度下降,和鼻粘膜接触而分散。但是,在弯曲复杂的鼻腔内,被喷雾出的制剂粒子直接碰撞到鼻腔内的壁上而被捕获、沉积。也就是说,将制剂喷射到鼻腔内时,几乎所有粒径5μm以上的制剂粒子都被鼻腔捕获,碰撞到鼻腔内的鼻甲粘膜并被捕获而沉积的制剂粒子由于覆盖粘膜的纤毛细胞的纤毛运动而被运送到后方,经过后鼻腔、咽喉最终被咽下或从口腔排出。对该纤毛和粘液的将活性药物当作异物除去(粘膜纤毛清除)的对策在鼻腔内给药型制剂的设计上是极其重要的方面,鼻粘膜中的药物的效果和吸收性主要通过鼻粘膜的捕获部位的药物的滞留性(制剂的附着性)和透过性来决定。给予到鼻腔内的有效捕获部位的药物,主要是通过粘膜纤毛清除而向食管、气管方向被除去、和通过鼻粘膜向鼻粘膜细胞侧的吸收方向被除去,由此,作为它们的并发反应而从给药捕获部位消失。从有效捕获部位向食管、气管方向的除去速度快时,向吸收方向的清除率降低,生物利用率减少。另一方面,通过使被喷雾出的制剂的粒径变小,可以使鼻腔内药物到达部位的范围变广,但提高了药物到达肺的危险性,因此需要考虑它们之间的平衡性,这是本领域技术人员所知道的事实。因此,为了增大向吸收方向的清除率,使喷出制剂以最优选的粒径、适当的喷射角度、均匀的密度进行喷射且附加药物的滞留性即制剂的鼻粘膜附着性,在改善吸收上是很重要的,并且有必要添加附着性高分子作为制剂基质来改善吸收。
喷鼻制剂的喷雾中,理论上可以使用喷雾容器将喷雾制剂粒子控制在50μm以下、边吸入喷雾边使用喷雾将药物送达到鼻腔瓣的后部,但是,使用50μm以下的微粒时,一半以上的微粒被送达到支气管、肺,鼻腔内捕获的药物损失,同时出现不良的副作用。并且喷雾容器之类的机器价格昂贵,没有廉价且可以简便地使制剂覆盖整个鼻腔内的粒径的有效系统。
本发明人等为了改善喷雾型制剂的药物在鼻腔内的滞留性,发明了适用于粘膜或皮肤的可进行喷雾的喷雾用凝胶基质,并提案有可作为适用于粘膜部位即鼻腔的、展开性优良的鼻腔喷雾型制剂使用的喷雾用凝胶基质及在该基质中混合活性药物而成的喷雾用凝胶剂(专利文献1)。
但是,即使配制用于提高滞留性的高粘度的喷雾用凝胶剂,也存在由喷雾操作引起的其粘度降低的问题,这是已知的问题点。
此外,该喷雾用凝胶制剂由于具有高粘度,因此在作为喷雾型制剂使用时附着在喷雾容器中的侧壁上而不被喷射到容器的外面,从而容器内制剂残留的残留率比通常的液体制剂高,并且由于内装制剂的液体不容易迅速地在喷雾容器内流动,因此喷射角度急剧变化等时,有时难以确保固定量的稳定的喷雾量。并且,还具有以下缺点:从其粒度分布出发,制剂粒子通过喷雾难以到达鼻腔深部;及不能调节喷射角度,难以以均匀的密度喷雾出药物。
此外,在通过将药物喷雾到皮肤上进行给药的制剂中,对于其制剂的滞留性、喷雾容器的给药角度等,存在和上述喷鼻制剂类似的问题。
专利文献1:日本特许第2011069号
发明内容
发明要解决的课题
如上所述,关于针对鼻腔、眼、耳、口腔、直肠、阴道、尿道等的粘膜的喷雾给药型制剂、特别是点鼻喷雾型制剂,为了改善药液的滞留性,通过将药液做成喷雾用凝胶基质,可以一定程度地改善药液的滞留性,但如果使用以往的鼻腔喷雾容器来喷出药液,由于其滞留性,从容器喷出的喷雾则伴随有如上所述的高残存率及不稳定的喷雾量等障碍,并且药液自身通过喷雾操作粘度会降低,需要对其进行改善。此外,以往的鼻腔喷雾装置由于会吸入外界空气,因此需要使用一定量的防腐剂等,在安全性及制造成本等方面需要得到改善。
进而,针对复杂的鼻腔内结构,为了使喷雾制剂覆盖鼻甲的大范围,使喷雾容器的给药角度符合鼻腔内的结构进行给药等的方法被认为是有效的,但是,目前的鼻腔喷雾型制剂中,给药的角度也有一定限度,需要开发可以以有效的角度进行给药且使喷雾制剂覆盖鼻甲的大范围的给药系统以及使该给药系统成为可能的喷鼻制剂。
此外,对手、手指、足、体部、腿部、头皮、肛门周围、性器官周围等的皮肤的喷雾给药制剂中,也存在和上述喷鼻制剂类似的问题点。
解决课题的方法
本发明人等鉴于上述情况进行了潜心的研究,结果发现了通过将凝胶型皮肤·粘膜附着制剂填充到与通常的喷鼻制剂等所使用的喷雾容器不同的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)中,可以任意设定喷雾容器的给药方向而使用的给药系统,由此完成了本发明。具体而言,通过含有一定量的羧基乙烯基聚合物和/或结冷胶作为皮肤·粘膜附着剂,可以制备达到上述目标的凝胶型皮肤·粘膜附着制剂。发现特别是通过加入结冷胶,可以明显地改善由鼻涕等引起的本制剂的粘度降低。
而且发现,通过从外部赋予上述制剂剪切力来调节相对高粘度(例如10000mPa·s~50000mPa·s)的制剂的粘度,可以使喷雾均匀,并且可以完全抑制由喷雾操作引起的粘度降低。并且惊人地发现,通过粘度调节剂及从外部赋予剪切力来调节粘度,可以使喷雾容器的喷射角度、喷射密度以符合目标的方式进行管理。即发现,在通过施加剪切力来调节粘度的凝胶型粘膜附着制剂中,喷雾容器的喷射角度有变窄的倾向,添加粘度调节剂、施加剪切力时,喷射角度有变广的倾向。利用该原理,即使为同一喷雾容器,也可以以符合目标的方式对喷射角度进行调节。此外,对于喷雾密度,同样发现,在不施加剪切力而仅通过粘度调节剂调节的凝胶型粘膜附着制剂中,从喷雾容器喷出的喷雾具有向外周偏移的倾向,但通过施加剪切力可以使喷雾均匀,因此,通过利用这些因素,也可以以符合目标的方式对该喷射密度进行管理。
并且发现,这类凝胶型皮肤·粘膜附着制剂具有粘性·附着性,难以以稳定的喷雾量进行喷雾,并且难以用尽容器内的制剂,但是通过使用凝胶制剂用喷雾容器(上方排压真空式喷雾容器),可以以稳定的喷雾量大幅度地改善使用后的残留率。
特别是在使用了该制剂及系统的喷鼻制剂中,在将给药体位(头部的角度)和喷雾容器以有效的角度进行设定并将药物喷雾到鼻腔时,可以使制剂覆盖鼻甲的大范围。
具体而言,本发明提供一种由在含有皮肤·粘膜附着剂的凝胶基质中含有药物活性物质的凝胶制剂构成的喷雾用凝胶型皮肤·粘膜附着型制剂。
此外,本发明提供一种上述的喷雾用凝胶型皮肤·粘膜附着制剂,其中,适用的粘膜为鼻腔、眼、耳、口腔、直肠、阴道或尿道,或者适用的皮肤为手、手指、足、体部、腿部、头皮、肛门周围或性器官周围。本发明特别提供一种作为喷鼻用的、由在含有粘膜附着剂的凝胶基质中含有药物活性物质的凝胶制剂构成的点鼻用凝胶型粘膜附着型制剂。
此外,本发明还提供一种含有羧基乙烯基聚合物和/或结冷胶作为皮肤·粘膜附着剂的上述喷雾用凝胶型皮肤·粘膜附着型制剂。并且,本发明还提供一种在含有羧基乙烯基聚合物和/或结冷胶作为皮肤·粘膜附着剂时,其重量%为0.1%~2.0%;在含有羧基乙烯基聚合物及结冷胶两者作为皮肤·粘膜附着剂时,其重量合计为0.2%~4.0%的上述喷雾用凝胶型皮肤·粘膜附着型制剂。
此外,本发明还提供一种含有0.1重量%~2.0重量%的羧基乙烯基聚合物作为皮肤·粘膜附着剂的、从外部施加剪应力来调节粘度的上述喷雾用凝胶型皮肤·粘膜附着型制剂。粘度通常调节为50mPa·s~5000mPa·s,优选为100mPa·s~4000mPa·s,更优选为500mPa·s~3000mPa·s,最优选为2000mPa·s~2500mPa·s。
进一步,本发明还提供一种含有0.1重量%~2.0重量%的羧基乙烯基聚合物作为皮肤·粘膜附着剂的、通过粘度调节剂及从外部施加剪应力来调节相对高粘度的制剂(例如10000mPa·s~50000mPa·s)的粘度的、以符合目标的方式对喷雾容器的喷射角度及喷射密度进行管理的上述喷鼻用凝胶型皮肤·粘膜附着型制剂。通过从外部施加剪切力,喷射角度具有变狭窄的倾向。由于该变窄的喷射角度可以通过添加粘度调节剂来变大,因此通过调节这2个因素可以以符合目标的方式来管理喷射角度。此外,通过从外部施加剪切力,可以将仅调节粘度调节剂时引起的偏向外周的喷雾密度变均匀,并且通过从外部施加剪切力可以以符合目标的方式对喷射密度进行管理。
此处的粘度调节剂优选选自氯化钠、氯化钾及氯化钙。粘度通常调节为50mPa·s~5000mPa·s,优选为100mPa·s~4000mPa·s,更优选为500mPa·s~3000mPa·s,最优选为2000mPa·s~2500mPa·s。
此外,本发明还提供一种以对羧基乙烯基聚合物的重量比在1:0.5~1:3(优选为1:1~1:2)范围含有选自中性或碱性水溶性氨基酸的羧基乙烯基聚合物的增粘剂的上述喷雾用凝胶型皮肤·粘膜附着型制剂。并且该羧基乙烯基聚合物的增粘剂优选为精氨酸、赖氨酸、和/或鸟氨酸。
此外,本发明还提供一种作为含有0.001~10重量%药物活性物质的凝胶制剂的、上述喷雾用凝胶型皮肤·粘膜附着型制剂。
此外,本发明还提供一种药物活性物质为溶解状态、混悬状态或乳化状态的上述喷雾用凝胶型皮肤·粘膜附着型制剂。
本发明提供一种给药系统,其特征在于,将上述喷雾用凝胶型皮肤·粘膜附着型制剂填充到凝胶制剂用喷雾容器(上方排压真空式喷雾容器)中,任意设定喷雾容器的给药方向并将制剂喷雾到患部,可以将凝胶基质以所有的角度喷雾。特别是提供这样一种给药系统,其特征在于,将上述鼻腔喷雾用凝胶型粘膜附着型制剂填充到凝胶制剂用喷雾容器(上方排压真空式喷雾容器)中,任意设定喷雾角度而将制剂喷雾到鼻腔内,可以使凝胶基质分布并滞留在大范围的鼻腔内。
此外,本发明还提供一种凝胶制剂的粘度在50mPa·s~5000mPa·s(优选为100mPa·s~4000mPa·s)的范围、通过喷雾操作得到的喷雾制剂粒子的粘度保持率为50%以上的上述给药系统。
此外,本发明还提供一种含有凝胶制剂的粘度被从外部施加的剪切力调节为50mPa·s~5000mPa·s范围的凝胶制剂的、通过喷雾操作得到的喷雾制剂粒子的粘度保持率为90%以上的上述给药系统。
此外,本发明还提供一种被喷雾出的制剂粒子的平均粒径在10μm~100μm(优选为50μm~100μm)范围的上述给药系统。
此外,本发明还提供一种含有利用从外部施加的剪切力(适当添加粘度调节剂)将凝胶制剂的粘度调节到50mPa·s~5000mPa·s范围的凝胶制剂的、以符合使用目标的方式进行管理从而使喷雾容器的喷射角度设定在10°~70°范围、将喷射密度调节为均匀乃至(或)集中于外周的上述给药系统。
此外,本发明还提供一种通过使用来完全地进行喷雾,至不能喷雾时的容器中凝胶制剂的残存率为20%以下(优选为15%以下、更优选为10%以下)、在设定量的±10%以内的范围的喷雾率为70%以上(更优选为80%以上)的上述给药系统。
此外,本发明还提供一种喷雾容器的给药角度为0°~360°中任意的角度或角度范围的上述给药系统。本发明进一步提供一种给药角度为45°~180°中的任意喷雾容器的给药角度或角度范围的上述喷鼻用给药系统。
此外,本发明还提供上述的给药系统,其特征在于,不配合防腐剂或保存剂、或者防腐剂或保存剂的配合量被减量为通常的配合量的50%以下。
此外,本发明还提供上述的给药系统,其中,在凝胶制剂用喷雾容器(上方排压真空式喷雾容器)的容器内安装除去多余空间的环,并使滑动底盖本体维持5~30°(优选为15~25°)的角度,同时该环也具有相同的角度。
附图说明
图1表示本发明所使用的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)。图的右半面表示内部结构的剖面图。
图2表示图1所示的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)的剖面图的主要部分的扩大图。其中,右半面表示作为本发明特征的、滑动底盖本体维持一定角度(本图中作为一个例子为20°)的容器,左半面表示以往的上方排压真空式喷雾容器。
图3表示向人的鼻甲(鼻道)中插入本发明的点鼻(喷鼻)喷雾制剂并以一定角度进行给药的方式。将点鼻喷雾制剂垂直的状态设定为0°,图3示出了以0°、25°、45°、65°、90°、135°及180°的角度进行给药的7种方式。
图4表示粘度为1000mPa·s(喷射角度0°)的制剂由各喷雾容器的喷雾量的稳定性。
图5表示粘度为2000mPa·s(喷射角度0°)的制剂由各喷雾容器的喷雾量的稳定性。
图6表示粘度为3600mPa·s(喷射角度0°)的制剂由各喷雾容器的喷雾量的稳定性。
图7表示喷射角度45°(粘度2000mPa·s)时的各喷雾容器的喷雾量的稳定性。
图8表示喷射角度65°(粘度2000mPa·s)时的各喷雾容器的喷雾量的稳定性。
图9表示喷射角度90°(粘度2000mPa·s)时的各喷雾容器的喷雾量的稳定性。
图10表示实施例5(通过0%的氯化钠、外部施加的剪切力将粘度调节为2500mPa·s的制剂)的喷射密度分布图。
图11表示实施例6(通过0.125%的氯化钠、外部施加的剪切力将粘度调节为2500mPa·s的制剂)的喷射密度分布图。
图12表示实施例7(通过0.25%的氯化钠、外部施加的剪切力将粘度调节为2500mPa·s的制剂)的喷射密度分布图。
图13表示实施例8(通过0.50%的氯化钠但不从外部施加剪切力而将粘度调节为2500mPa·s的制剂)的喷射密度分布图。
图14表示实施例4~实施例10及比较例的人工鼻涕的粘度变化。
具体实施方式
本发明中,凝胶基质是指由作为粘膜附着剂的水溶性高分子化合物和水和/或醇类构成的具有粘稠性的基质。凝胶基质中,还可以含有药品中通常使用的防腐剂、保存剂、等渗剂、pH调节剂、着色剂等。
本发明中使用的作为皮肤·粘膜附着剂(附着性高分子)使用的水溶性高分子化合物,例如有:阿拉伯胶、海藻酸钠、海藻酸丙二醇酯、羧基乙烯基聚合物、羧甲基纤维素钠、黄原胶、结冷胶、明胶、羟乙基纤维素、羟丙基纤维素、羟丙甲基纤维素、聚乙烯醇、甲基纤维素等。也可以使用它们的组合物。进一步,为了同时满足以下条件:具有皮肤·粘膜附着性、喷雾操作不引起制剂的粘度变化、可以以高粘度到达要处理的患部(点鼻用时为鼻腔内)、喷雾后的制剂的平均粒径为10~100μm(优选为50~100μm),非常细微,因此,优选使用同时使用羧基乙烯基聚合物或结冷胶、或者羧基乙烯基聚合物和结冷胶作为附着性高分子的凝胶基质。作为使用羧基乙烯基聚合物的基质,也可以使用本发明人另外发明的“喷雾用凝胶基质及使用该基质的凝胶剂”(专利文献1)。
此外,也可以配制成这样的凝胶基质:通过从外部对羧基乙烯基聚合物赋予剪切力来调节粘度、或通过对羧基乙烯基聚合物添加粘度调节剂和从外部赋予其剪切力来调节粘度,使从喷雾容器的喷射角度、喷射密度以符合目标的方式进行管理。
关于此处的赋予剪切力的操作,可以以本领域技术人员公知的方法来进行,具体而言,赋予剪切力的操作可以使用高速旋转型乳化装置、胶体磨型乳化装置、高压乳化装置、轧制(roll mill)型乳化装置、超声乳化装置及膜乳化装置。特别优选高速搅拌机型、梳型及间断射流发生型的高速旋转型乳化装置。
将此处的粘度通常调节为50mPa·s~5000mPa·s,优选为100mPa·s~4000mPa·s,更优选为500mPa·s~3000mPa·s,最优选为2000mPa·s~2500mPa·s。
此外,这里,喷射角度是指将从喷射口笔直地喷出的制剂设为0°时,由此扩展喷射的凝胶制剂的角度。此外,喷射密度是指表示喷射的凝胶制剂在扩散(扩展)中的均匀性的指标。具体而言,表示均匀地喷雾、偏向外周等。予以说明,该喷射密度的评价是通过目测观察从喷射口向板进行喷雾时附着在板上的凝胶制剂进行判断的。
本发明的作为附着性高分子使用的羧基乙烯基聚合物是以丙烯酸为主要成分聚合而得的亲水性聚合物,可以使用通常的羧基乙烯基聚合物,例如美国Noveon公司销售的カーボポール(注册商标)等。羧基乙烯基聚合物的使用浓度通常可以为约0.1~2.0重量%。结冷胶是被称为少动鞘脂单胞菌(Sphingomonas elodea)的微生物产生于菌体外的多糖类,其被广泛应用于各种食品等。特别优选使用作为低乙酰化型结冷胶的商品名Gelrite(注册商标)等。结冷胶的使用浓度通常为0.1~2.0重量%。在同时使用该羧基乙烯基聚合物和结冷胶的情况下,由于在与鼻涕(鼻粘液)接触时,对其离子的敏感度降低,因此通过利用离子强度(离子浓度)该基质被喷雾到鼻腔,最初粘度较低,但是一旦基质覆盖大范围的鼻腔之后,由于粘度维持(上升),基质长时间地滞留在鼻腔而显示出理想的分布。羧基乙烯基聚合物和结冷胶的总使用浓度通常使用0.2~4.0重量%,其配合比率根据含有活性药物的制剂与鼻涕(鼻粘液)接触时的粘度变化进行调节。
所谓用于使羧基乙烯基聚合物增粘的增粘剂,是指通过中和酸性物质羧基乙烯基聚合物,使羧基乙烯基聚合物离子化而立体地增大,由此使羧基乙烯基聚合物增粘化的水溶性碱物质,作为其具体例,例如有:氢氧化钠、氢氧化钾等无机碱;二异丙醇胺、三乙醇胺、三丙醇胺等胺类,精氨酸、赖氨酸、鸟氨酸等氨基酸等有机碱,优选为精氨酸、赖氨酸、鸟氨酸。在此,所含的氨基酸增粘剂相对羧基乙烯基聚合物的通常的重量比在1:0.5~1:3的范围,优选为1:1~1:2。这些水溶性碱物质通过中和羧基乙烯基聚合物可以调节到所希望的pH范围。增粘剂也可以组合使用多个上述物质。
本发明中的溶解于凝胶基质的“药物活性物质”是指通常使用于皮肤和/或粘膜部位的药物,例如有:通过局部作用来治疗炎症、过敏的药物、期望通过经皮及经鼻等经粘膜吸收来作用于全身的药物,但并不限定于此。具体而言,作为本发明的可对皮肤和/或粘膜部位给药的药物活性物质的例子,例如有:硝酸萘甲唑啉、盐酸四氢唑啉、盐酸羟甲唑啉、盐酸曲马唑啉等局部血管收缩药;氢化可的松、氢化泼尼松、曲安奈德、磷酸地塞米松、氟尼缩松、磷酸倍他米松、丙酸倍氯米松钠、丙酸氟替卡松、糠酸莫米松、糠酸氟替卡松、布地奈德、环索奈德、倍他米松丁酸丙酸酯、二氟可龙戊酸酯等类固醇药;阿斯匹林、甲灭酸、布洛芬吡啶甲醇、舒洛芬、丁苯羟酸、苄达酸、乌芬那酯、双氯芬酸钠、吲哚美辛、联苯乙酸、酮洛芬、氟比洛芬、奈普生、普拉洛芬、洛索洛芬钠、阿米洛芬、扎托布洛芬、吡罗昔康、美洛昔康、氯诺昔康、塞来昔布、罗非考昔等非甾体类镇痛消炎药;苯海拉明、富马酸氯马斯丁、盐酸曲普利啶、盐酸氮异丙嗪、酒石酸异丁嗪、马来酸氯苯那敏、盐酸异丙嗪等抗组胺药;色甘酸钠、曲尼司特、富马酸酮替芬、氨来呫诺、盐酸氮斯汀、奥沙米特、盐酸左卡巴斯汀、盐酸非索非那定、盐酸依匹斯汀、依巴斯汀、盐酸西替利嗪、苯磺酸贝他斯汀、盐酸奥洛他定、氯雷他定、盐酸奥扎格雷、塞曲司特、普仑司特、扎鲁司特、孟鲁司特钠、甲磺司特等抗过敏药;那氟沙星、克林霉素磷酸酯、左氧氟沙星、盐酸匹伏头孢卡品水合物、克拉霉素、头孢妥仑匹伏酯、盐酸万古霉素、美罗培南水合物、氟氧头孢钠、盐酸头孢替安、奥比沙星等抗菌剂;阿昔洛韦、伐昔洛韦、阿糖腺苷等抗疱疹病毒药;更昔洛韦、膦甲酸钠水合物等抗巨细胞病毒药、磷酸奥司他韦、扎那米韦水合物等抗流感病毒药;两性霉素B、氟康唑、伊曲康唑、米卡芬净钠、盐酸特比萘芬、盐酸奈康唑、拉诺康唑、卢立康唑、利拉萘酯、盐酸布替萘芬、盐酸阿莫洛芬等抗真菌药、聚维酮碘、苯扎氯铵、苄索氯铵、葡萄糖酸氯己定等消毒药;利多卡因、地布卡因等局部麻醉药;环孢霉素、他克莫司水和物等免疫抑制药、他卡西醇、卡泊三醇、阿法骨化醇、骨化三醇、马沙骨化醇等活性型维生素D3制剂、米诺地尔、卡普氯铵等脱毛治療药,铝克洛沙(Aluminum Chlorohydroxy Allantoinate)、托可维A酸、布拉地新、阿法环糊精前列地尔、曲弗明等皮肤溃疡治疗药;氰钴胺、甲钴胺等维生素B12制剂;植物甲萘醌、四烯甲萘醌等维生素K制剂;ε-氨基己酸、氨甲环酸等抗血纤蛋白溶酶药;氯硝西泮、卡马西平、唑尼沙胺等抗癫痫药;三唑仑、溴替唑仑、唑吡旦半酒石酸盐、夸西泮、硝西泮、地西泮等催眠镇静药;盐酸帕罗西汀水合物、依替唑仑、马来酸氟伏沙明、盐酸米那普仑、盐酸丙米嗪等抗抑郁药;奥氮平、利培酮、富马酸奎硫平等综合失调症治疗药;盐酸多奈哌齐、尼麦角林等痴呆症治疗药;阿扑吗啡、卡麦角林、甲磺酸培高利特、甲磺酸溴隐亭、盐酸金刚烷胺、屈昔多巴等帕金森病治疗药;依达拉奉等脑保护药;吗啡、羟考酮、芬太尼、盐酸丁丙诺啡、酒石酸布托诺啡等镇痛药;尼古丁等禁烟辅助药;酒石酸麦角胺、舒马曲坦、佐米曲普坦、氢溴酸依来曲普坦、苯甲酸利扎曲坦、那拉曲坦、夫罗曲坦、阿莫曲坦、阿维曲坦等偏头疼药;氰钴胺、甲钴胺等维生素剂;雌二醇、雌三醇、孕酮、睾酮等性甾体类激素药;甲磺酸去铁胺等金属解毒药;磷酸可待因、盐酸异丙肾上腺素等镇咳去痰药;盐酸恩丹西酮、盐酸雷莫司琼、盐酸托烷司琼、盐酸格拉司琼、甲氧氯普胺、多潘立酮、枸橼酸莫沙必利等止吐药;醋酸戈舍瑞林、比卡鲁胺、替加氟、紫杉醇、枸橼酸他莫昔芬、盐酸吉西他滨、去氧氟尿苷、卡培他滨、甲磺酸伊马替尼、利妥昔单抗、吉非替尼、曲妥珠单抗、紫杉醇、多烯紫杉醇水合物等抗癌药;坎地沙坦酯、缬沙坦、洛沙坦钾、替米沙坦、奥美沙坦酯、苯磺酸氨氯地平、硝苯地平、盐酸贝尼地平、盐酸尼卡地平、尼伐地平、阿折地平、盐酸马尼地平、盐酸地尔硫马来酸依那普利、盐酸咪达普利、盐酸替莫普利、培哚普利叔丁胺盐、卡维地洛、富马酸比索洛尔、盐酸普萘洛尔、阿替洛尔等降压药;盐酸坦索罗辛、萘哌地尔等排尿障碍治疗药;西咪替丁、盐酸雷尼替丁、法莫替丁、尼扎替丁等抗溃疡药;盐酸多巴胺、盐酸多巴酚丁胺等强心药;氢溴酸非诺特罗、异丙托溴铵、氧托溴铵等支气管扩张药;吗吲哚、YY肽等肥胖治疗药;甲硫酸新斯的明等自律神经作用药;硝酸甘油、硝酸异山梨酯、尼可地尔等心绞痛用药;盐酸噻氯匹定、西洛他唑、盐酸沙格雷酯、贝前列素钠等抗血小板凝集药;伏格列波糖、阿卡波糖、格列美脲、那格列奈、盐酸甲福明、盐酸吡格列酮、格列齐特等糖尿病药;普伐他丁钠、辛伐他汀、氟伐他汀钠、阿托伐他汀水合物、匹伐他汀钙、罗素伐他汀钙、苯扎贝特等高血脂症治疗药物;盐酸吡西卡尼、盐酸美西律、磷酸丙吡胺等抗心律失常药;巴氯芬、吡拉西坦、盐酸乙哌立松、盐酸替扎尼定等肌肉松驰药;布西拉明、氨甲喋呤、英夫利昔单抗、法呢酸泼尼松龙酯、阿克他利等抗风湿药;以及,作为肽/蛋白质性药物,例如有:LHRH(黄体生成素释放激素)类;生长激素释放因子类;生长抑素衍生物类;加压素、醋酸去氨加压素等脑下垂体后叶激素;催产素类;水蛭素衍生物类;脑啡肽类;ACTH(副肾上腺皮质激素)衍生物类;缓激肽衍生物类;胰岛素类;胰高血糖素衍生物类;生长激素类;生长激素释放激素类;黄体生成激素类;类胰岛素生长因子类;降钙素基因相关肽类;心房利尿钠肽衍生物类;干扰素类;白介素类;促红细胞生成素;粒细胞集落形成刺激因子;巨噬细胞形成刺激因子;副甲状腺激素类;副甲状腺激素释放激素;催乳素;甲状腺刺激激素释放激素;及血管紧张素类等;降钙素类;醋酸亮丙瑞林;醋酸布舍瑞林、醋酸那法瑞林等Gn-RH(促性腺素释放激素)衍生物类;替索激酶、阿替普酶、孟替普酶、帕米普酶、那沙普酶等血栓溶解药;流感HA疫苗、肺炎球菌疫苗、重组乙肝疫苗等疫苗类。该医药活性物质的含量没有特别限定,可以含有0.001~10重量%。此外,凝胶制剂中还可以含有多种该医药活性成分。
在水中使用不溶性活性药物时,得到的本发明的制剂为白色浑浊,但是活性药物不沉积,对于通常的给药是没有障碍的。但是,在活性药物溶解于水时更有利于要处理的患部(点鼻用时为鼻粘膜)的吸收的情况下,优选使用溶解剂、或预先将活性药物溶解于水溶性有机溶剂中进行制剂化。作为该水溶性有机溶剂,例如有:乙醇、异丙醇等低级醇,丙二醇,1,3-丁二醇,分子量300~500的聚乙二醇等醇类。此外,作为溶解剂,可以根据活性药物的溶解性使用各种表面活性剂等。
此外,可以添加适当的助悬剂使活性药物混悬,作为该助悬剂,例如有:蔗糖脂肪酸酯、聚氧乙烯(40)硬脂酸酯、聚氧乙烯(60)氢化蓖麻油、吐温80、单硬脂酸甘油酯、山梨聚糖单硬脂酸酯、山梨聚糖单棕榈酸酯等各种表面活性剂等。
此外,还可以添加适当的乳化剂使该凝胶基质乳化再在其中配合活性药物、及使活性药物自身乳化,作为该乳化剂,可以使用各种表面活性剂等。
本发明所说的术语“粘膜”,是指被上皮细胞覆盖的来自外胚叶的上皮层。具体而言,例如为:鼻腔、眼、耳、口腔、直肠、阴道、性器官、尿道、肛门等。此外,本发明中使用的术语“皮肤”,是指覆盖体表的皮层,具体而言,例如为:手、手指、足、体部、腿部、头皮、肛门周围、性器官周围等的皮肤。
本发明所说的“皮肤·粘膜”,是指“皮肤和/或粘膜”的意思,其含义也包括例如,肛门周围或性器官周围之类的皮肤和粘膜共存而难以区分开的患部。
本发明规定的粘度,可通过例如日本药局方一般试验法的粘度测定法中举出的毛细管粘度计法、旋转粘度计法等进行测定。
本发明的凝胶制剂中,粘度通常为50mPa·s~5000mPa·s,优选为100mPa·s~4000mPa·s,更优选为500mPa·s~3000mPa·s,最优选为2000mPa·s~2500mPa·s。
本发明规定的粘度保持率是指相对于喷雾前的凝胶制剂的粘度,刚喷雾完后的喷雾粒子的粘度的比例。
本发明中通过喷雾操作得到的喷出的制剂粒子的粘度保持率优选为50%以上。
本说明书中所说的喷出的制剂粒子的平均粒径可以使用例如激光散射方式的粒径测定装置进行测定。
在此,平均粒径优选在10μm~100μm范围,更优选在50μm~100μm的范围。
本发明中规定的残留率是指,使用凝胶制剂用喷雾容器(上方排压真空式喷雾容器),将喷鼻用凝胶型粘膜附着型制剂完全喷出,直至不能进行喷雾时容器中残留的凝胶制剂的量相对于使用前的总量的比例。
本发明中,上述残留率通常为20%以下,优选为15%以下,更优选为10%以下。
本发明中规定的设定值是指通过上述点鼻喷雾容器的1次喷雾操作而喷出的内装制剂的预先设定好的量的值或量的范围,具体而言,例如,将通过1次喷雾操作喷出的内装制剂设为约100mg时,则100mg即为设定值。
本发明中,上述设定值的±10%以内范围的喷雾率优选为70%以上,更优选为80%以上。
作为本发明中规定的防腐剂的具体例,例如有:苯扎氯铵、苄索氯铵等,但并不限定于此。此外,作为保存剂,例如有:对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等对羟基苯甲酸酯类,但并不限定于此。在此,通常的配合量是指例如药品所批准的添加量,通常如果是本领域技术人员,就可以容易地从在已批准的药品中的添加量和化合物的结构等进行推论。
本发明中使用的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)是指例如如附图1所示的容器。在此,该喷雾容器是这样的带泵真空容器:取下容器的盖子,通过按压安装在容器头部的泵的环状操作部,将从容器内抽吸到泵的抽吸室中的内容物通过喷射孔喷到外部,同时,为了排出容器内的空气而进行连续抽吸,具有向上方滑动的滑动底盖本体,该滑动底盖本体的周围形成有压接在容器的内周面的、以密封状态移动的环状外周面部分。
具有如上所述机制的喷雾容器的用途特别是在用作喷鼻用容器等方面没有明确记载,但已记载了带泵的真空容器(日本特开2003-212262)。但是,作为如本发明的凝胶制剂用(上方排压真空式)喷雾容器,需要尽可能地排除不能供给喷雾的多余的空间,使制剂填充时容器内的空气和制剂可以顺利地置换。特别是本发明中使用的滞留性凝胶制剂的流动性差,可以预料使用结束后残存的凝胶制剂的量比通常的制剂多。因此,本发明对以往的真空式喷雾容器进行了进一步改良,发现,通过填装图2的右半面所示的用于除去多余空间的环,并进一步使通常为平坦的滑动底盖本体具有一定的角度,由此可以容易地除掉容器内的空气,进一步通过使环也具有同样的角度,在使用结束时,滑动底盖本体和环几乎完全配合,几乎将无用的体积完全除去,由此可以使使用结束时的残存量非常小。并且,具有这些特征的图1及图2所示的本专利使用的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)可以确保作为通常的药品的喷雾量精度。该滑动底盖本体的一定的角度小时,填充制剂时容器本体的肩部分残留空隙,角度大时,滑动底盖的支撑(裾野)部分残留空隙,都不合适。该角度优选为5~30°,更优选为15~25°。
此外,本专利使用的凝胶制剂用喷雾容器(上方排压真空式喷雾容器)由于是不吸入外界空气的系统,因此具有不易被外界空气的微生物污染的特性,该特性对药物制剂是极其有利的,从不需要添加必要量以上的防腐剂及保存剂的安全性及制造成本方面考虑,也是极其优良的经鼻给药系统。
本发明中,喷雾容器的给药角度可以为0°~360°的任意角度或角度范围。例如在点鼻用时,使用上述喷雾型喷鼻制剂时,可以使给药体位(头部的角度)和喷雾容器的给药角度进行如附图3所示的多种变化。即,本发明的喷雾容器,在以往的鼻腔喷雾容器能够进行喷雾的0°附近、难以进行喷雾的45°~90°、及不能进行喷雾的180°,都能进行喷雾。
在此,通过将头向后仰,以容器给药角度为65~180°的方式使用,使鼻甲(鼻道)从平行方向向垂直方向变化,认为刚开始时制剂被可靠地分散并附着到鼻甲的顶端部分,鼻甲所捕获、沉积的制剂通过重力引起的流动和覆盖粘膜的纤毛细胞的纤毛运动而被运送到后方,从而使制剂覆盖鼻甲的大范围。
因此,作为给药体位和喷雾容器的给药角度,为0°~180°的任意角度即可,优选为45°~180°,更优选为65°~180°,最优选为135°附近的鼻甲(鼻道)为垂直方向,制剂广范围地覆盖鼻甲大范围的角度是最有利而优选的。此外,给药时的姿势可以为站立、坐、仰卧、侧卧等任意姿势,本发明的点鼻制剂也可以以任意的给药角度来使用。
实施例
下面基于实施例及试验例对本发明进行更详细的说明,但本发明并不限定于此。对于实际中配合药物活性物质的本发明的制剂,作为制剂例在本说明书的后部分示出实施例,对于与物性有关的各种试验,从特别是认为对物理化学性质没有影响方面出发,不配合药物活性物质,使用下述成分制做粘度等不同的下述9种凝胶型皮肤·粘膜附着制剂,用于与各种物性有关的试验。
予以说明,以下的实施例及试验例的粘度使用C形粘度计于20℃下进行测定。
在实施例1~3的不施加剪切力,添加相同量的氯化钠作为粘度调节剂制得的凝胶制剂中,具有分别为1000、2000及3000mPa·s的粘度。(在实施例1~3不添加粘度调节剂氯化钠时,实施例1中粘度为31000mPa·s、实施例2中粘度为35000mPa·s、实施例3中粘度为36000mPa·s。)
在实施例4~7的施加剪切力制得的凝胶制剂中,实施例6及7进一步添加氯化钠作为粘度调节剂,并施加剪切力。粘度均调节为2500mPa·s。(实施例4中,在不施加剪切力时,其粘度为23000mPa·s,实施例5~7中,不施加剪切力时(实施例5)、或既不添加粘度调节剂氯化钠也不施加剪切力时(实施例6、实施例7)的粘度为34000mPa·s。)
实施例8的组成和实施例4~7相同,不施加剪切力,仅添加粘度调节剂,是粘度调节为2500mPa·s的制剂。(在不添加粘度调节剂氯化钠时,其粘度为34000mPa·s。)
此外,作为实施例4~8的对照,不添加粘度调节剂也不从外部施加剪切力,制成了粘度为2500mPa·s的制剂,将其作为比较例。
作为试验容器,使用安装有1次操作可喷雾出约100mg的泵的以下喷雾容器。
本发明容器:凝胶制剂用喷雾容器(上方排压真空式喷雾容器)(100mg泵、填充量5g)
对照容器(1):本体容器为双重结构的、内侧具有研钵型的形状,考虑了容器内残留量的市售品的喷雾容器(100mg泵、填充量5g)
对照容器(2):通用型喷雾容器(100mg泵、填充量5g)
与容器内残留量、规定范围内喷雾量及次数有关的试验
在测定为空的重量的本发明容器、对照容器(1)及对照容器(2)这3种喷雾容器中,分别准确地填充实施例1~实施例8的制剂约5.0g,如表1及表2所示将给药角度从0°~180°变化,每进行1次喷雾,由前后质量差求出1次的喷雾量,反复进行喷雾操作直至内容物几乎被完全喷雾出,本发明容器的测定结果示于表1,对照容器的测定结果示于表2。
作为此时的容器内填充制剂的使用分布(%),利用下式求出从泵不能再喷雾出制剂时的容器内残留量(%)、表示在作为容器的喷雾量所规定的设定量(100mg)的范围内(±10%以内)喷出的总喷雾量相对于总量(5.0g)的比例的“100±10mg范围内的量(%)”、及表示在设定量的范围外喷出的总喷雾量相对于总量(5.0g)的比例的“100±10mg范围外的量(%)”,将各自求出的值也示于表1及表2。
容器内残留量(%)=容器内残留量(g)/初始填充量(g)×100
100±10mg范围内(%)=100±10mg范围内总喷雾量(g)/初始填充量(g)×100
100±10mg范围外(%)=100±10mg范围外总喷雾量(g)/初始填充量(g)×100
还示出了在100±10mg范围内可以使用的次数。
表1:本发明容器的试验结果
表2:对照容器(1)及对照容器(2)的试验结果
只要是使用本发明容器的本发明的系统,对于具有高粘度的制剂来说,就与制剂的粘度无关、与喷射角度无关,容器内填充制剂的使用分布(%)几乎都为一定的值,容器内制剂残留量(%)显示低的值(约7.1%),设定值的范围内的量(%)也显示出高的值(约87.7%)。相对于此,对照容器(1)及对照容器(2)中,如下表2所示粘度,粘度越高容器内制剂残留量(%)越增加,规定范围内的量越(%)减少。
下面,基于上述表1及表2的结果,根据给药角度及制剂的种类进行分类,将更换的结果一并示于表3~表8。
首先,将给药角度设为0°,将使用各粘度的制剂的各喷雾容器的使用分布(%)汇总示于表3、表4及表5。可知使用了本发明容器的本发明的系统是极其优良的。此外,对于各个喷雾容器的粘度和喷雾量的稳定性,从将表3~表5的结果分别作成图显示出来的图4、图5及图6可以看出,本发明的系统是优良的。
表3:粘度(1000mPa·s)的不同的各喷雾容器的容器内填充制剂的使用分布(%)
表4:粘度(2000mPa·s)的不同的各喷雾容器的容器内填充制剂的使用分布(%)
表5:粘度(3600mPa·s)的不同的各喷雾容器的容器内填充制剂的使用分布(%)
此外,从实施例2和实施例7的制剂中选择内容制剂,使喷射角度发生各种变化,将各喷雾容器的使用分布(%)汇总示于表6~表11。以任意的喷射角度进行喷射时,使用了本发明容器的本发明的系统中,残留率都低,可以进行极其稳定的喷雾。此外,对于各个喷雾容器的喷射角度和喷雾量的稳定性而言,从将表6~表8的结果分别制图显示出来的图7~图9可知,可以在喷射角度65°及90°下使用的只有本发明的系统。
表6:粘度(2000mPa·s)、喷射角度45°下的各喷雾容器的容器内填充制剂的使用
分布(%)
表7:粘度(2000mPa·s)、喷射角度65°下的各喷雾容器的容器内填充制剂的使用
分布(%)
表8:粘度(2000mPa·s)、喷射角度90°下的各喷雾容器的容器内填充制剂的使用
分布(%)
表9:粘度(2500mPa·s)、喷射角度45°下的各喷雾容器的容器内填充制剂的使用
分布(%)
表10:粘度(2500mPa·s)、喷射角度65°下的各喷雾容器的容器内填充制剂的使用
分布(%)
表11:粘度(2500mPa·s)、喷射角度90°下的各喷雾容器的容器内填充制剂的使用
分布(%)
平均粒径的比较
利用激光散射方式的粒径测定装置测定本发明的凝胶型皮肤·粘膜附着制剂和其它的凝胶型皮肤·粘膜附着制剂的喷雾的平均粒径,并进行比较(表12)。容器均使用同一凝胶制剂用喷雾容器(上方排压真空式喷雾容器)。本发明的凝胶型皮肤·粘膜附着制剂即使是高粘度,也可以显示出小的粒径,是作为鼻腔内给药型制剂的特别理想的平均粒径(50μm~100μm)。
表12:平均粒径的比较
制剂 | 粘度(mPa·s) | 容器的给药角度 | 平均粒径(μm) |
实施例1 | 1000 | 0° | 74.8 |
实施例2 | 2000 | 0° | 75.3 |
实施例3 | 3600 | 0° | 87.5 |
实施例4 | 2500 | 0° | 71.1 |
实施例5 | 2500 | 0° | 233.4 |
实施例6 | 2500 | 0° | 69.8 |
实施例7 | 2500 | 0° | 66.6 |
实施例8 | 2500 | 0° | 77.3 |
比较例 | 2500 | 0° | 77.5 |
羟丙基纤维素 | 1000 | 0° | 294.1 |
羟丙基纤维素 | 2000 | 0° | 531.6 |
羧甲基纤维素钠 | 400 | 0° | 88.4 |
羧甲基纤维素钠 | 1000 | 0° | 192.5 |
羧甲基纤维素钠 | 2000 | 0° | 254.9 |
喷雾的粘度保持的比较
通过测定喷雾前和刚喷雾后的本发明的凝胶型皮肤·粘膜附着制剂和其它的凝胶型皮肤·粘膜附着制剂的喷雾的粘度变化,并进行比较(表13)。容器均使用同一凝胶制剂用喷雾容器(上方排压真空式喷雾容器)。发现只有本发明的凝胶型皮肤·粘膜附着制剂具有极高的粘度保持率。特别是,在通过施加剪切力调节粘度的制剂的实施例4~实施例7中,喷射前后的浓度完全没有变化,具有极高的粘度保持率。
表13:喷雾的粘度保持的比较
喷雾的喷射角度和喷射密度的比较
对由上述制得的、粘度和制备方法不同的各凝胶型皮肤·粘膜附着制剂的喷雾的喷射角度和喷射密度进行测定、比较(表14)。容器均使用同一凝胶制剂用喷雾容器(上方排压真空式喷雾容器)。
粘度的不同不会使喷射角度受到影响(例如,对实施例1~3进行比较),但对于作为通过施加剪切力来调节粘度的凝胶型粘膜附着制剂的实施例4~7,喷射角度有变小的倾向,此外,这些实施例的制剂中,对于添加氯化钠作为粘度调节剂的实施例6及7,和不添加氯化钠的具有同一组成的实施例5相比,喷射角度有变大的倾向。
此外,喷射密度也受附加的剪切力的影响。即,不施加剪切力的实施例1~3及实施例8的制剂中,喷雾偏向外周,但施加剪切力的实施例4~7的制剂中,喷雾的喷射密度均匀(参照图10~13)。
由此可知,本发明的凝胶型皮肤·粘膜附着制剂中,通过添加粘度调节剂和从外部施加剪切力对凝胶制剂的粘度进行调节,可以将喷雾容器的喷射角度、喷射密度控制为符合目标的喷射角度、喷射密度,例如,由于药物活性物质为离子性并处于溶解状态时,由于具有和粘度调节剂相同的作用,因此仅通过外部施加的剪切力,就可以调节喷雾容器的喷射角度并使喷射密度均匀。
表14:喷雾引起的喷射角度和喷射密度的比较
人工鼻涕引起的制剂的粘度变化的比较
制备使用下述成分的、配合结冷胶的凝胶型皮肤·粘膜附着制剂,将实施例4~实施例8及比较例的制剂均用于人工鼻涕(组成如下)引起的制剂的粘度变化的比较试验。
人工鼻涕是将和人的鼻涕相同的离子以相同浓度配合而成的调配液,添加后进行均化,约5分钟后测定粘度。(人工鼻涕的添加量以相对制剂10g而添加的量(g)来表示)
[人工鼻涕的组成]
NaCl | 6.81g |
KCl | 1.91g |
CaCl<sub>2</sub>·2H<sub>2</sub>O | 0.59g |
MgCl<sub>2</sub>·6H<sub>2</sub>O | 0.13g |
总1000mL |
上述人工鼻涕是根据佐分利保雄等著的“鼻汁によるスギ花粉の破裂(鼻涕引起的杉花粉的破坏)”(日本公众卫生志,1992年,第39卷,第6号,P341~P346记载的组成进行制备的。
本发明的凝胶型皮肤·粘膜附着制剂的由人工鼻涕引起的制剂的粘度变化如图14所示。容器均使用同一凝胶制剂用喷雾容器(上方排压真空式喷雾容器)。即,在既不添加粘度调节剂进行粘度调节、也不从外部施加剪切力进行粘度调节的比较例中,观察到人工鼻涕的添加使粘度明显下降,与此相比,在添加粘度调节剂和从外部施加剪切力进行粘度调节的实施例4~10中,粘度的降低得到良好的抑制。特别值得注意的是,配合了结冷胶的实施例9及10与不配合结冷胶的其它实施例相比,随着人工鼻涕的添加量的增加,粘度的变化也不易不受影响。
对微生物的稳定性的比较
加热灭菌0.2%结冷胶溶液,将其作为内容制剂,在EOG灭菌处理过的制剂用喷雾容器(上方排压真空式喷雾容器)及对照容器(2)中填充5g制剂,喷雾2.5g使内容制剂量变为50%,在37℃的恒温器、室温下进行保存,经时观察,对微生物的稳定性进行比较(表15)。本发明的凝胶制剂用喷雾容器与以往的喷鼻用容器相比,对微生物的稳定性更优良。
表15:对微生物的稳定性的比较
使用糖精制剂的鼻腔内滞留性的比较
制备在实施例2的制剂中浓度添加具有甜味的糖精钠浓度为0.5%的制剂、和0.5%糖精钠水溶液,使用安装有可喷雾出100mg上述制剂或0.5%糖精钠水溶液的泵的喷鼻用凝胶制剂用喷雾容器(上方排压真空式喷雾容器),以各种角度对受试者(3名:A、B、C)进行喷鼻给药(两鼻孔各一次,共喷200mg),给药一定时间后,使头部垂直,测定给药后受试者感觉到甜味时的时间,并进行比较(表16~19)。在任意一种情况下,与非凝胶型的通常的水溶液相比,实施例2的凝胶型皮肤·粘膜附着剂感觉到甜味所需的时间更长,因此意味着凝胶型制剂在鼻腔内的滞留性足够高。
表16:使用了糖精制剂的鼻腔内滞留性的比较
(给药后立即将头垂直的情况)
表17:使用了糖精制剂的鼻腔内滞留性的比较
(给药15秒后将头垂直的情况)
表18:使用了糖精制剂的鼻腔内滞留性的比较
(给药30秒后将头垂直的情况)
表19:使用了糖精制剂的鼻腔内滞留性的比较
(以仰卧姿势(135°)给药,将仰卧姿势维持5分钟的情况)
下面对实际中含有药物活性物质的本发明的制剂,作为制剂例,示出实施例。但本发明并不限定于此。
[表20]
制剂例01(实施例11):羟甲唑啉鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为1000mPa·s。
[表21]
制剂例02(实施例12):四氢唑啉鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为2000mPa·s。
[表22]
制剂例03(实施例13):丙酸氟替卡松鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2200mPa·s。
[表23]
制剂例04(实施例14):丙酸氟替卡松鼻腔用制剂
[表24]
制剂例05(实施例15):糠酸莫米松鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2500mPa·s。
[表25]
制剂例06(实施例16):胰岛素鼻腔用制剂(50U/g)
预先在10重量份的精制水中混合胰岛素,混合搅拌残余的成分,按照以下的方法进行粘度调节,在该调制物中添加胰岛素,并使其均匀化。
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为750mPa·s。
[表26]
制剂例07(实施例17):左卡巴斯汀鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为2700mPa·s。
[表27]
制剂例08(实施例18):色甘酸钠鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2000mPa·s。
[表28]
制剂例09(实施例19):芬太尼鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2500mPa·s。
[表29]
制剂例10(实施例20):芬太尼鼻腔用制剂
[表30]
制剂例11(实施例21):芬太尼鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2500mPa·s。
[表31]
制剂例12(实施例22):舒马曲坦鼻腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2500mPa·s。
[表32]
制剂例13(实施例23):布舍瑞林鼻腔用制剂
预先在10重量份的精制水中混合醋酸布舍瑞林,混合搅拌残余的成分,按照以下的方法进行粘度调节,在该调制物中添加醋酸布舍瑞林,并使其均匀化。
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为1500mPa·s。
[表33]
制剂例14(实施例24):去氨加压素鼻腔用制剂
预先在10重量份的精制水中混合醋酸去氨加压素,混合搅拌残余的成分,按照以下的方法进行粘度调节,在该调制物中添加醋酸去氨加压素溶液,并使其均匀化。
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为2000mPa·s。
[表34]
制剂例15(实施例25):洛索洛芬钠皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3500mPa·s。
[表35]
制剂例16(实施例26):洛索洛芬钠皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3000mPa·s。
[表36]
制剂例17(实施例27):马来酸氯苯那敏皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为5000mPa·s。
[表37]
制剂例18(实施例28):阿昔洛韦皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为2500mPa·s。
[表38]
制剂例19(实施例29):利多卡因皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3500mPa·s。
[表39]
制剂例20(实施例30):特比萘芬皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3000mPa·s。
[表40]
制剂例21(实施例31):拉诺康唑皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以10000rmp的转数施加剪切力,将粘度调节为3000mPa·s。
[表41]
制剂例22(实施例32):拉诺康唑皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3500mPa·s。
[表42]
制剂例23(实施例33):倍他米松丁酸丙酸酯皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为4500mPa·s。
[表43]
制剂例24(实施例34):马沙骨化醇皮肤用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为3000mPa·s。
[表44]
制剂例25(实施例35):泼尼松龙肛门周围用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为4000mPa·s。
[表45]
制剂例26(实施例36):二氟可龙戊酸酯肛门周围用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为3000mPa·s。
[表46]
制剂例27(实施例37):米诺地尔头皮用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为4000mPa·s。
[表47]
制剂例28(实施例38):酮替芬眼用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以15000rmp的转数施加剪切力,将粘度调节为100mPa·s。
[表48]
制剂例29(实施例39):曲安奈德口腔用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为4000mPa·s。
[表49]
制剂例30(实施例40):动物用奥比沙星体部用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为5000mPa·s。
[表50]
制剂例31(实施例41):动物用奥比沙星耳用制剂
粘度调节:使用间断射流发生型高速旋转型乳化装置(型号CLM-0.8S),边冷却边以20000rmp的转数施加剪切力,将粘度调节为500mPa·s。
产业实用性
如上所述,本发明的喷雾用凝胶型皮肤·粘膜附着型制剂与以往的药液相比,滞留性得到改善,并且,使用的容器不是以往一直广泛使用的用吸管抽吸类型的喷雾容器,而是通过使用上方排压真空式喷雾容器,做成了也适合于本发明的凝胶制剂的喷雾制剂。特别适用于点鼻剂,可以以对以往的喷鼻制剂来说很难或不可能的45°以上的角度进行鼻腔喷雾容器的给药。
并且,在上方排压真空式喷雾容器中,通过改良容器内的滑动底盖本体,设计可以使残留率降低且喷雾量稳定的喷雾容器,可以制造安全且制造成本方面较经济的凝胶型皮肤·粘膜附着型鼻腔喷雾容器制剂。
因此,通过使用本发明的鼻腔喷雾用凝胶型皮肤·粘膜附着型制剂及使用了该凝胶型皮肤·粘膜附着型制剂的给药系统,具有以下优点:可以谋求对以往的鼻炎治疗等的吸收及清除率的改善、且可以以使用时所需要的角度进行给药、并且最后,在稳定的喷雾量的前提下基本将制剂用完,因此可以成为更有效且有用的鼻腔制剂等。此外,在作为以全身作用为目标的药物的给药途径的鼻腔内给药型制剂的开发中,可以成为具有很大作用的给药系统。
Claims (14)
1.一种给药系统,其特征在于,在上方排压真空式喷雾容器中填充在含有皮肤·粘膜附着剂的凝胶基质中含有药物活性物质的凝胶制剂,
其中,凝胶制剂含有羧基乙烯基聚合物作为皮肤·粘膜附着剂,任选含有结冷胶,皮肤·粘膜附着剂含有0.1重量%~2.0重量%的羧基乙烯基聚合物,
凝胶制剂通过将粘度调节剂与使用高速旋转型乳化装置、胶体磨型乳化装置、高压乳化装置、轧制型乳化装置、超声乳化装置或膜乳化装置从外部施加剪切力的方法并用,将粘度调节为50mPa·s~5000mPa·s的范围,
任意设定喷雾容器的给药方向对要处理的患部进行喷雾,能将凝胶制剂以所有的角度进行喷雾,
通过喷雾操作得到的被喷雾的制剂粒子的粘度保持率为约100%,被喷雾的制剂的平均粒径在50μm~100μm的范围。
2.权利要求1所述的给药系统,其中,适用的粘膜为鼻腔、眼、耳、口腔、直肠、阴道或尿道、或者适用的皮肤为手、手指、足、体部、腿部、头皮、肛门周围或性器官周围。
3.权利要求1所述的给药系统,其中,适用的粘膜为鼻腔。
4.权利要求1~3中任一项所述的给药系统,其中,作为皮肤·粘膜附着剂,含有合计为0.2重量%~4.0重量%的羧基乙烯基聚合物及结冷胶。
5.权利要求1~3中任一项所述的给药系统,其中,粘度调节剂选自氯化钠、氯化钾及氯化钙。
6.权利要求1~3中任一项所述的给药系统,其中,以相对羧基乙烯基聚合物的重量比为1:0.5~1:3的范围含有选自中性或碱性的水溶性氨基酸的羧基乙烯基聚合物的增粘剂。
7.权利要求6所述的给药系统,其中,增粘剂为精氨酸、赖氨酸和/或鸟氨酸。
8.权利要求1~3中任一项所述的给药系统,其中,凝胶制剂为含有0.001~10重量%的药物活性物质的凝胶制剂。
9.权利要求1~3中任一项所述的给药系统,其中,药物活性物质为溶解状态。
10.权利要求1~3中任一项所述的给药系统,其中,药物活性物质为混悬状态。
11.权利要求1~3中任一项所述的给药系统,其中,药物活性物质为乳化状态。
12.权利要求1~3中任一项所述的给药系统,其中,由于使用而完全地进行喷雾,使得不能喷雾时的容器中的凝胶制剂的残留率为20%以下,在设定量的±10%以内的范围的喷雾率为70%以上。
13.权利要求12所述的给药系统,其中,由于使用而完全地进行喷雾,使得不能喷雾时的容器中的凝胶制剂的残留率为15%以下,在设定量的±10%以内的范围的喷雾率为80%以上。
14.权利要求1~3中任一项所述的给药系统,其中,喷雾容器的给药角度为0°~360°之间的任意角度或角度范围。
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