CN113784703A - 经鼻施予用粉末制剂及其制造方法 - Google Patents
经鼻施予用粉末制剂及其制造方法 Download PDFInfo
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- CN113784703A CN113784703A CN202080032083.6A CN202080032083A CN113784703A CN 113784703 A CN113784703 A CN 113784703A CN 202080032083 A CN202080032083 A CN 202080032083A CN 113784703 A CN113784703 A CN 113784703A
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- composite particles
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- insoluble polysaccharide
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Abstract
本发明的课题为提供高效地发挥药效的经鼻施予用粉末制剂等。前述课题可通过含有有效成分与水不溶性多糖类附着于彼此而成的复合粒子的经鼻施予用粉末制剂来解决。
Description
技术领域
本发明涉及经鼻施予用粉末制剂及其制造方法。
背景技术
一直以来,经鼻施予主要以鼻炎治疗等局部治疗作为目的。然而,最近,尝试了出于预防或治疗全身疾病、中枢神经系统疾病、感染症等的目的来利用经鼻施予,报道了各种经鼻施予用制剂。例如,专利文献1公开了“含有非肽·蛋白质性药物和作为它们的载体的结晶纤维素聚集体而成的粉末状经鼻施予用组合物”。
现有技术文献
专利文献
专利文献1:国际公开第2006/016530号
发明内容
发明所要解决的课题
专利文献1公开了将药物和结晶纤维素使用乳钵进行混合的方法作为粉末状经鼻施予用组合物的制造方法。然而,该制造方法中,存在下述问题:从施予装置喷射得到的组合物时,药物和结晶纤维素分离,可能无法充分利用结晶纤维素所具有的粘膜附着性效果,结果,所期待的药效得不到发挥。
本发明的课题为提供高效地发挥药效的经鼻施予用粉末制剂及其制造方法。
用于解决课题的手段
本申请发明人发现,通过将含有有效成分和水不溶性多糖类的混合物进行搅拌造粒、流化床造粒、或冷冻干燥,能够得到高效地发挥药效的复合粒子。
本发明包含以下的实施方式。
[1]
经鼻施予用粉末制剂,其含有有效成分与水不溶性多糖类附着于彼此而成的复合粒子。
[2]
如[1]所述的粉末制剂,其中,所述复合粒子的平均一次粒径为20~350μm。
[3]
如[1]或[2]所述的粉末制剂,其中,所述复合粒子的比表面积为0.20~2.3m2/g。
[4]
如[1]~[3]中任一项所述的粉末制剂,其中,所述复合粒子的Hausner比为1.8以下。
[5]
如[1]~[4]中任一项所述的粉末制剂,其中,所述水不溶性多糖类包含结晶纤维素。
[6]
如[1]~[5]中任一项所述的粉末制剂,其中,所述复合粒子还含有粘结剂。
[7]
如[1]~[6]中任一项所述的粉末制剂,其中,所述复合粒子还含有吸收促进剂。
[8]
如[7]所述的粉末制剂,其中,所述吸收促进剂为羟丙基β环糊精、十二烷基硫酸钠或正十二烷基-β-D-麦芽糖苷。
[9]
经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行搅拌造粒,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
[10]
经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行流化床造粒,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
[11]
经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行冷冻干燥,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
[12]
如[9]~[11]中任一项所述的制造方法,其中,所述水不溶性多糖类包含结晶纤维素。
[13]
如[9]~[12]中任一项所述的制造方法,其中,所述混合物还含有粘结剂。
[14]
如[9]~[13]中任一项所述的制造方法,其中,所述混合物还含有吸收促进剂。
[15]
如[14]所述的制造方法,其中,所述吸收促进剂为羟丙基β环糊精、十二烷基硫酸钠或正十二烷基-β-D-麦芽糖苷。
发明效果
根据本发明,可提供高效地发挥药效的经鼻施予用粉末制剂及其制造方法。
附图说明
[图1]示出实施例7的试验制剂的电子显微镜照片。
[图2]示出实施例10的试验制剂的电子显微镜照片。
[图3]示出实施例15的试验制剂的电子显微镜照片。
[图4]示出实施例16的试验制剂的电子显微镜照片。
[图5]示出比较例1的试验制剂的电子显微镜照片。
[图6]示出比较例2的试验制剂的电子显微镜照片。
具体实施方式
<粉末制剂>
本发明的一个实施方式涉及含有有效成分与水不溶性多糖类附着于彼此而成的复合粒子的经鼻施予用粉末制剂。
本说明书中的所谓“复合粒子”是有效成分与水不溶性多糖类附着于彼此而形成的粒子(凝聚物)。因此,本说明书中的“复合粒子”可与例如专利文献1中所公开的药物与结晶纤维素的单纯混合物明确区分。
本实施方式中,有效成分与水不溶性多糖类形成了复合粒子,因此,粉末制剂被施予至鼻腔内时,有效成分与水不溶性多糖类成为一体而附着于鼻粘膜。由于水不溶性多糖类具有粘膜附着效果,因此,有效成分利用该效果而附着于鼻粘膜,可高效地发挥有效成分带来的药效。
仅将有效成分与水不溶性多糖类单纯地混合时,存在有效成分得不到均匀混合、粉末制剂间的有效成分的量产生差异的可能性。另一方面,本实施方式中,由于有效成分与水不溶性多糖类形成了复合粒子,因此能够抑制这样的差异。
本实施方式中,由于有效成分与水不溶性多糖类形成了复合粒子,因此粉末制剂的流动性提高。由此,能够将粉末制剂均匀且容易地填充至容器中,并且,粉末制剂自施予装置的喷射率提高。
将含有粒径小的粒子的粉末制剂施予至鼻腔内时,存在从鼻腔中通过而到达肺的可能性。另一方面,本实施方式中,有效成分与水不溶性多糖类形成复合粒子从而粒径增大,因此能够抑制通过鼻腔的情况。
本实施方式的复合粒子是复合粒子的构成成分附着于彼此而形成的,因此具有比各构成成分更大的粒径。
作为本实施方式的复合粒子的平均一次粒径的下限,例如,可举出20μm、25μm、30μm、35μm、40μm等,作为上限,例如,可举出350μm、300μm、250μm、200μm、150μm、100μm等。可将前述下限及前述上限适当组合而划定特定的范围。例如,可设为20~350μm、25~300μm、30~250μm、35~200μm、40~150μm的范围。平均一次粒径按照以下的实施例中记载的方法进行测定。
需要说明的是,平均一次粒径在2bar的分散压力下进行测定,因此,如果复合粒子的构成成分没有附着于彼此,则复合粒子会由于分散压力而分解为各构成成分。例如为专利文献1中所公开那样的药物与结晶纤维素的单纯混合物时,即使一部分构成成分聚集而形成大的粒子,在平均一次粒径的测定条件下,该粒子也会分解,因此与本实施方式的复合粒子的平均一次粒径有很大不同。
作为本实施方式的复合粒子的比表面积的下限,例如,可举出0.10m2/g、0.15m2/g、0.20m2/g、0.25m2/g、0.30m2/g等,作为上限,例如,可举出2.3m2/g、2.0m2/g、1.8m2/g、1.6m2/g、1.4m2/g等。可将前述下限及前述上限适当组合而划定特定的范围。例如,可设为0.10~2.3m2/g、0.15~2.0m2/g、0.20~1.8m2/g、0.25~1.6m2/g、0.30~1.4m2/g的范围。比表面积按照以下的实施例中记载的方法进行测定。
作为本实施方式的复合粒子的Hausner比的上限,例如,可举出1.8、1.7、1.6、1.5、1.4、1.3、1.2等,下限没有特别限定。Hausner比按照以下的实施例中记载的方法进行测定。
第十七版日本药典针对Hausner比与流动性的关系记载了下述内容。
Hausner比:流动性的程度
1.00~1.11:极其良好
1.12~1.18:良好
1.19~1.25:稍微良好
1.26~1.34:普通
1.35~1.45:稍微不良
1.46~1.59:不良
>1.60:极其不良
作为本实施方式的粉末制剂所诊断、预防或治疗的疾病,例如,可举出脑出血、脑梗塞、中枢神经系统的感染症、脑瘤、帕金森病、癫痫、肌萎缩侧索硬化症、阿尔茨海默病、路易小体型痴呆症、进行性核上性麻痹、大脑皮质基底节变性症、皮克氏病、额颞痴呆症、多发性硬化症、精神分裂症、抑郁症、双相障碍(bipolar disorder)、情绪障碍症(dysthymicdisorder)、适应障碍、社交焦虑障碍、惊恐障碍、强迫症、自闭症谱系障碍、注意缺陷·多动障碍、睡眠障碍、失眠症、创伤性脑损伤、疼痛、偏头痛、头痛、退烧、炎症、风湿病、癫痫、脑循环代谢症、肌肉松弛症、自主神经症、晕眩、高血压症、心绞痛、心率失常、过敏、支气管扩张·哮喘、其他呼吸器官疾病(镇咳、去痰等)、消化性溃疡、其他消化器官疾病(止泻、调节肠道功能、健胃、促进消化、通便等)、痛风·高尿酸血症、脂质异常症、糖尿病、激素相关疾病(与垂体激素、肾上腺皮质激素、性激素、其他激素等相关的疾病)、子宫相关疾病、骨质疏松症·骨代谢疾病、维生素缺乏、营养不足、中毒(包括解毒)、癌症、免疫过度、耳鼻咽喉相关疾病、口腔相关疾病、泌尿·生殖器官疾病、痔疮、皮肤疾病、造血·血液凝固相关疾病、麻药依赖症、麻醉、生活习惯病等。
本实施方式的有效成分可以单独使用1种,也可以组合使用多种有效成分。作为有效成分,例如,可举出低分子化合物、中分子药(例如肽药)、蛋白质医药(例如抗体医药)、核酸医药、细胞医药、再生医疗、疫苗抗原(例如肽抗原)等。
作为更具体的有效成分,例如,可举出组织纤溶酶原激活物、依达拉奉、奥扎格雷钠、选择性凝血酶抑制剂、阿糖腺苷、阿昔洛韦、更昔洛韦、缬更昔洛韦、齐多夫定、去羟肌苷、扎西他滨、奈韦拉平、地拉韦啶、沙喹那韦、利托那韦、茚地那韦、奈非那韦、万古霉素、头孢他啶、氨苄青霉素、帕尼培南-倍他米隆、地塞米松、顺铂、卡铂、长春新碱、环磷酰胺、异环磷酰胺、替莫唑胺、依托泊苷、L-多巴、卡比多巴、苄丝肼、恩他卡朋、肾上腺素、安非他命、阿扑吗啡、金刚烷、卡麦角林、唑尼沙胺、屈昔多巴、比哌立登、苯巴比妥、苯妥英、扑米酮、乙琥胺、唑尼沙胺、氯硝西泮、咪达唑仑、瑞米唑仑、氟马西尼、丙戊酸钠、卡马西平、加巴喷丁、托吡酯、大麻素、多奈哌齐、卡巴拉汀、加兰他敏、美金刚、富马酸二甲酯、那他珠单抗、氟哌啶醇、螺环哌丁苯、氟奋乃静、氯丙嗪、利司培酮、布南色林、喹硫平、奥氮平、阿立哌唑、依匹哌唑、三唑仑、佐匹克隆、唑吡坦、依替唑仑、氯甲西泮、溴异戊酰脲、水合氯醛、戊巴比妥、利马扎封、催产素、后叶加压素、去氨加压素、格拉司琼、昂丹司琼、托烷司琼、帕洛诺司琼、吲地司琼、三唑仑、褪黑素、左乙拉西坦、大麻素、氯硝西泮、地西泮、硝基安定、唑吡坦、多奈哌齐、美金刚、硫必利、头孢克洛、依诺沙星、阿昔洛韦、齐多夫定、去羟肌苷、奈韦拉平、茚地那韦、丹曲林、地高辛、苯海索、比哌立登、右美沙芬、纳洛酮、倍他司汀、萘甲唑林、地尔硫卓、曲尼司特、洛哌丁胺、倍氯米松、氯苯那敏、西地那非、他达拉非、伐地那非、氰钴胺素、非那雄胺、肾上腺素、奥昔布宁、丙哌维林、索非那新、托特罗定、咪达那新、弗斯特罗定、米拉贝隆、坦索罗辛、赛洛多辛、5-FU、特拉匹韦、利巴韦林、西咪匹韦(simeprevir)、胍法新、哌甲酯、托莫西汀、孕酮、舒马曲坦、佐米曲普坦、双氢麦角胺、利扎曲普坦、卡莫司他、萘莫司他、厄瑞奴单抗、加那珠单抗、瑞玛奈珠单抗、福米韦生、米泊美生、诺西那生、环孢菌素、他克莫司、氟脱氧葡萄糖、氟胸苷、碘帕醇(iopamidol)、铊、锰、锝、胰岛素、生长激素、生长激素释放肽、胃饥饿素、胰高血糖素、降钙素、干扰素、促红细胞生成素、白细胞介素、PTH(1-84)、PTH(1-34)、PTH相关肽、GLP-1、后叶加压素、亮丙瑞林、粒细胞集落刺激因子、催乳素、垂体促性腺激素、胎盘促性腺激素Snbl2600、促卵泡激素、黄体化激素、瘦素、神经生长因子(NGF)、干细胞生长因子(SCGF)、角质细胞生长因子(KGF)、低分子肝素、他克莫司、过敏原提取物粉末、人抗体(例如,阿达木单抗、帕尼单抗、戈利木单抗、卡那单抗(canakinumab)、奥法木单抗、地诺单抗、伊匹单抗(ipilimumab)、贝利木单抗、瑞西巴库单抗(raxibacumab)、雷莫芦单抗、纳武单抗(nivolumab)、苏金单抗、依洛尤单抗(evolocumab)、阿利库单抗、耐昔妥珠单抗、纳武单抗、帕博利珠单抗(pembrolizumab)等)、嵌合抗体(例如阿昔单抗(abciximab))、人源化抗体(例如贝伐单抗)、小鼠抗体(例如博纳吐单抗)等。
作为更具体的有效成分,例如,可举出针对以下的病毒或病原体的疫苗抗原。
腺病毒、AIDS病毒、杆状病毒、HCMV(人巨细胞病毒)、出血热病毒、肝炎病毒、B疱疹病毒、免疫缺陷病毒、人免疫缺陷病毒、人T细胞白血病病毒、婴儿肠胃炎病毒、传染性造血器官坏死病毒、传染性胰腺坏死病毒、流感病毒、日本脑炎病毒、白血病病毒、腮腺炎病毒、正粘病毒、肺炎病毒、脊髓灰质炎病毒、多分DNA病毒、轮状病毒、SARS病毒、牛痘病毒、RS病毒、志贺氏菌属菌种、伤寒沙门氏菌(Salmonella enterica serovar Typhi)、结核杆菌、破伤风杆菌、白喉杆菌、脑膜炎球菌(meningococcus)、百日咳杆菌、肺炎链球菌、炭疽杆菌、肉毒杆菌、艰难梭状芽胞杆菌、产气荚膜梭菌、粪肠球菌、屎肠球菌、流感嗜血杆菌、幽门螺旋杆菌、麻风分枝杆菌、淋病奈瑟菌、脑膜炎球菌、伤寒沙门氏菌、金黄色葡萄球菌、梅毒螺旋体、霍乱弧菌、恶性疟原虫(Plasmodium falciparum)。
本说明书中的所谓“水不溶性多糖类”是指1000ml的水(20℃)中溶解0.001g以下的多糖类。水不溶性多糖类可以单独使用1种,也可以组合使用多种水不溶性多糖类。
作为水不溶性多糖类,例如可以举出纤维素、半纤维素、脱乙酰壳多糖、壳多糖等,优选为纤维素或半纤维素,更优选为纤维素,特别优选为结晶纤维素。通过使用结晶纤维素,能够进一步提高粉末制剂的流动性。作为市售的结晶纤维素,例如,可举出CEOLUS(注册商标)的PH系列、AVICEL(注册商标)的PH系列等,更具体而言,可举出CEOLUS(注册商标)PH-F20JP、AVICEL(注册商标)PH-105、CEOLUS(注册商标)PH-UF702等。
本实施方式的复合粒子可还含有粘结剂。通过使复合粒子含有粘结剂,能够提高有效成分与水不溶性多糖类的附着强度,或调节复合粒子的一次粒径、崩解性。粘结剂可以单独使用1种,也可以组合使用多种粘结剂。
作为粘结剂,例如,可举出纯化水、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、甲基纤维素、羧甲基纤维素、α化淀粉、部分α化淀粉、它们的盐等,优选为羟丙基甲基纤维素或α化淀粉。
本实施方式的复合粒子可还含有添加剂。作为添加剂,例如,可举出吸收促进剂、助溶·增溶剂、稳定剂、流化剂、崩解剂、掩蔽剂、矫味剂、防腐剂、免疫赋活剂等。
作为吸收促进剂,例如,可举出表面活性剂、螯合剂、环糊精、透膜肽等。作为表面活性剂,例如,可举出十二烷基硫酸钠、癸酸钠等阴离子性表面活性剂、正十二烷基-β-D-麦芽糖苷、四(十二烷基)-β-D-麦芽糖苷等非离子性表面活性剂、二棕榈酰磷脂酰胆碱、牛磺胆酸钠等双离子性表面活性剂。作为螯合剂,可举出EDTA、柠檬酸盐、焦磷酸盐等。作为环糊精,可举出β-环糊精、2-羟丙基-β-环糊精、甲基-β-环糊精等。作为透膜肽,可举出穿透素(penetratin)、HIV-1Tat、HIV-1Rev、精氨酸八聚体(arginine octamer)、精氨酸十二聚体(arginine dodecamer)、pVEC、Ems、RRL helix、PRL4等。
作为助溶·增溶剂,例如,可举出环糊精、癸酸、卵磷脂、二棕榈酰甘油磷脂酰胆碱、十二烷基麦芽糖苷、十二烷基磷酸胆碱、聚乙二醇等。
作为稳定剂,例如,可举出二糖类(例如,蔗糖、乳果糖、乳糖、麦芽糖、海藻糖、纤维二糖、木二糖、麦芽酮糖、半乳蔗糖、它们的衍生物)、维生素类(例如,抗坏血酸、生育酚)、氨基酸类(例如,甘氨酸)、柠檬酸盐、焦磷酸盐等。
作为流化剂,例如,可举出结晶纤维素、磷酸三钙等。
作为崩解剂,例如,可举出纤维素、淀粉、交联聚维酮等。
作为掩蔽剂,例如,可举出甘露糖醇等。
作为矫味剂,例如,可举出阿斯巴甜、薄荷醇等。
作为防腐剂,例如,可举出硫柳汞等。
作为免疫赋活剂,例如,可举出环糊精、铝盐、CpG寡核苷酸等。
<粉末制剂的制造>
本发明的一个实施方式涉及经鼻施予用粉末制剂的制造方法,其包括下述工序:将含有有效成分和水不溶性多糖类的混合物进行搅拌造粒、流化床造粒或冷冻干燥,形成前述有效成分与前述水不溶性多糖类附着于彼此而成的复合粒子。以下,将基于搅拌造粒的方法、基于流化床造粒的方法、及基于冷冻干燥的方法分别称为“搅拌造粒法”、“流化床造粒法”、及“冷冻干燥法”。对于复合粒子的构成成分,与前述<粉末制剂>的项目中所说明的相同。
作为搅拌造粒法中的粘结剂的添加液量,造粒槽内的粉末合计重量每100g,优选为5mL~150mL,更优选为15mL~100mL,进一步优选为20mL~75mL。通过以这样的粘结剂的添加液量进行搅拌造粒,能够得到理想的性质的复合粒子。
作为流化床造粒法中的粘结剂的喷雾速度,造粒槽内的粉末合计重量每50g,优选为0.001g/分钟~0.4g/分钟,更优选为0.005g/分钟~0.3g/分钟,进一步优选为0.01g/分钟~0.25g/分钟。作为流化床造粒法中的粘结剂的总添加量,造粒槽内的粉末合计重量每50g,优选为0.01g~4.0g,更优选为0.05g~3.0g,进一步优选为0.1g~2.5g。通过以这样的条件进行流化床造粒,能够得到理想的性质的复合粒子。
冷冻干燥法中的冷冻温度优选为-100℃~-10℃,更优选为-80℃~-15℃,进一步优选为-60℃~-20℃。通过以这样的温度进行冷冻,能够得到理想的性质的复合粒子。
实施例
以下,使用实施例及比较例来更详细地说明本发明,但本发明的技术范围不限于此。
<材料>
(有效成分)
·L-多巴(Cayman Chemical Company)
·吲哚美辛(和光纯药工业株式会社)
·睾酮(和光纯药工业株式会社)
·佐米曲普坦(东京化成工业株式会社)
·布洛芬(和光纯药工业株式会社)
(水不溶性多糖类)
·结晶纤维素(Ceolus(注册商标)PH-F20JP,Asahi Kasei ChemicalsCorporation)
(粘结剂)
·羟丙基纤维素(HPC-H,日本曹达株式会社)
·羟丙基甲基纤维素(HPMC TC-5E,信越化学工业株式会社)
·α化淀粉(Asahi Kasei Chemicals Corporation)
(添加剂)
·羟丙基β环糊精(和光纯药工业株式会社)
·抗坏血酸(和光纯药工业株式会社)
·海藻糖(株式会社林原)
·结晶纤维素(Ceolus(注册商标)PH-301,Asahi Kasei ChemicalsCorporation)
·磷酸三钙(ICL Performance Products LP)
·十二烷基硫酸钠(和光纯药工业株式会社)
·正十二烷基-β-D-麦芽糖苷(和光纯药工业株式会社)
<制造方法>
(搅拌造粒法)
向搅拌造粒机(high-speed mixer FS-GS-5,Fukae Powtec Kk)的造粒槽内投入有效成分、水不溶性多糖类、及添加剂,在搅拌器(agitator)旋转速度为400rpm及切碎器(chopper)旋转速度为1500rpm的搅拌条件下将造粒槽内的粉体进行搅拌混合。然后,一边向造粒槽内滴入粘结剂,一边在同搅拌条件下搅拌混合6~8分钟左右。将从造粒槽取出的混合物在棚式干燥机内(NO607C,岩黑制作所)于50℃干燥2小时以上。将得到的干燥混合物通过32μm及180μm的筛(JIS Z 8801,饭田制作所),将残留于32μm的筛上的干燥混合物作为试验制剂。
(流化床造粒法)
向流化床造粒机(FL-LABO,Freund Corporation)的腔室内投入有效成分、水不溶性多糖类、及添加剂,在70℃的空气中对腔室内的粉体进行流动混合。然后,一边将已溶于纯化水的粘结剂以3.6g(作为粘结溶液的量)/分钟的喷雾速度向腔室内喷雾10分钟,一边进行流动混合。将从腔室中取出的干燥混合物通过32μm及180μm的筛(JIS Z 8801,饭田制作所),将残留于32μm的筛上的干燥混合物作为试验制剂。
(冷冻干燥法)
事先将200mL超纯水装入铝盘中,于-20℃将铝盘内底部冷冻后,将有效成分、水不溶性多糖类、粘结剂、及添加剂与磷酸缓冲液混合,装入铝盘中,于-20℃事先冷冻2小时,置于棚式冷冻干燥机内(FreeZone Triad Freeze Dry System,Labconco Corp.),在以下条件下得到冷冻干燥品。作为冷冻干燥条件,在105mTorr的减压条件下,于-25℃进行30小时的一次干燥,然后于30℃进行37小时的二次干燥。将制得的冷冻干燥品使用玻璃乳钵粉碎,作为试验制剂。
(乳钵混合法)
向玻璃乳钵中添加结晶纤维素进行填隙(日文:目溃し),除去多余的结晶纤维素。向该玻璃乳钵中投入有效成分、水不溶性多糖类、及添加剂,使用玻璃研杵混合10分钟,作为试验制剂。
各实施例及比较例的详细信息示于表1。
[表1-1]
表1.试验制剂的组成及制法
[表1-2]
表1.试验制剂的组成及制法
HPMC:羟丙基甲基纤维素
HPC:羟丙基纤维素
磷酸Ca:磷酸三钙
<利用电子显微镜的观察>
将试验制剂置于电子显微镜(Miniscope TM3000,Hitachi High-TechnologiesCorporation),使用真空泵实施减压后观察。图1~6分别示出实施例7、10、15及16以及比较例1及2的试验制剂的电子显微镜照片。实施例的试验制剂中,不同于比较例的试验制剂,观察到各种成分凝聚而形成了复合粒子的状态。
<平均一次粒径的测定>
将干式自动分散单元(Scirocco 2000,Malvern公司)连接至基于激光衍射法的粒度分布测定装置(Mastersizer 2000,Malvern公司),在2bar的分散压力下测定试验制剂的平均一次粒径。基于利用体积换算法的粒度分布分析算出平均一次粒径,结果示于表2。实施例的试验制剂的平均一次粒径与比较例的试验制剂相比优越性地更大,这表明各种成分形成了复合粒子。
<平均含量及含量均匀度>
(含有L-多巴的试验制剂)
利用反相色谱进行了测定。具体而言,将pH2.8乙腈/0.05%三氟乙酸(5/95)作为流动相,使用流动相对试验制剂进行稀释以使得成为适当的浓度,使用0.45μm的注射式过滤器进行过滤,将滤液使用高效液相色谱仪(LC-2010或LC-2030C 3D plus,株式会社岛津制作所)进行测定,算出试验制剂中的L-多巴含量。针对1种试验制剂实施3次该操作,算出相对于用于测定的试验制剂量中所含的理论L-多巴含量而言的实测L-多巴含量的平均值及相对标准偏差,分别作为含量(%)及含量均匀度(%)。
(含有吲哚美辛的试验制剂)
利用反相色谱进行了测定。具体而言,将甲醇/0.1%磷酸(28/12)作为流动相,使用流动相对试验制剂进行稀释以使得成为适当的浓度,使用0.45μm的注射式过滤器进行过滤,将滤液使用高效液相色谱仪(LC-2030C 3D plus,株式会社岛津制作所)进行测定,算出试验制剂中的吲哚美辛含量。针对1种试验制剂实施3次该操作,算出相对于用于测定的试验制剂量中所含的理论吲哚美辛含量而言的实测吲哚美辛含量的平均值及相对标准偏差,分别作为含量(%)及含量均匀度(%)。
结果示于表2。该结果显示,实施例的复合粒子中均匀地包含了各种成分。
[表2]
表2.试验制剂的平均粒径、含量及含量均匀度
平均粒径(μm) | 含量(%) | 含量均匀度(%) | |
实施例1 | 42.9 | 100.8 | 2.6 |
实施例2 | 36.0 | 98.2 | 5.6 |
实施例3 | 42.6 | 101.6 | 0.2 |
实施例4 | 40.6 | 102.2 | 5.2 |
实施例5 | 55.6 | - | - |
实施例6 | 31.6 | 90.4 | 3.5 |
实施例7 | 37.7 | 102.6 | 5.2 |
实施例8 | 31.6 | 107.1 | 1.8 |
实施例9 | 32.8 | 96.9 | 1.5 |
实施例10 | 34.2 | 103.3 | 3.2 |
实施例11 | 124.1 | 97.8 | 3.2 |
实施例12 | 120.6 | 96.3 | 3.3 |
实施例13 | 35.4 | - | - |
实施例14 | 37.1 | - | - |
实施例15 | 45.6 | 104.6 | 2.7 |
实施例16 | 35.9 | 92.6 | 1.0 |
实施例17 | 41.6 | 83.9 | 0.7 |
实施例18 | 37.6 | - | - |
实施例19 | 43.2 | - | - |
实施例20 | 34.8 | 96.3 | 2.0 |
实施例21 | 35.8 | 98.7 | 0.2 |
实施例22 | 34.7 | 110.2 | 0.7 |
实施例23 | 34.1 | 99.2 | 0.7 |
比较例1 | 16.2 | 103.3 | 1.9 |
比较例2 | 17.6 | 102.4 | 1.1 |
<比表面积的测定>
将试验制剂在抽吸减压条件下于100℃干燥1小时,然后,通过使用了基于气体吸附法(其利用了氮气)的比表面积测定仪(Autosorb-iQ-MP,Quantachrome)的BET法对比表面积进行测定。结果示于表3。实施例的试验制剂的比表面积显著小于比较例的试验制剂,这表明各种成分形成了复合粒子。
[表3]
表3.试验制剂的比表面积
比表面积(m<sup>2</sup>/g) | |
实施例1 | 0.453 |
实施例2 | 0.521 |
实施例3 | 0.582 |
实施例4 | 0,302 |
实施例5 | 0.483 |
实施例6 | 1.218 |
实施例7 | 0.753 |
实施例8 | 1.069 |
实施例9 | 0.668 |
实施例10 | 0.550 |
实施例11 | 0.213 |
实施例12 | 0.335 |
实施例13 | 0.956 |
实施例14 | 0.809 |
实施例15 | 0.772 |
实施例16 | 1.221 |
实施例17 | 1.019 |
实施例18 | 0.971 |
实施例19 | 0.718 |
实施例20 | 0.674 |
实施例21 | 1.368 |
实施例22 | 0.946 |
实施例23 | 0.853 |
比较例1 | 2.391 |
比较例2 | 2.388 |
<Hausner比的测定>
基于日本药典一般试验法中的粉体物性测定方法,测定将已知质量的试验制剂装入量筒内时的体积,将质量除以体积而算出堆密度。
基于日本药典一般试验法中的粉体物性测定方法,将已知质量的试验制剂装入量筒内后,敲击量筒,测定不再观察到试验制剂的体积变化时的体积,将质量除以体积而算出振实密度。
将堆密度除以振实密度而算出Hausner比。结果示于表4。实施例的试验制剂的Hausner比显著小于比较例的试验制剂,这表明实施例的试验制剂的流动性是优异的。
[表4]
表4.试验制剂的Hausner比
Hausner比 | |
实施例1 | 1.44 |
实施例2 | 1.40 |
实施例3 | 1.31 |
实施例4 | 1.38 |
实施例5 | 1.35 |
实施例6 | 1.65 |
实施例7 | 1.35 |
实施例8 | 1.57 |
实施例9 | 1.48 |
实施例10 | 1.33 |
实施例11 | 1.08 |
实施例12 | 1.14 |
实施例13 | 1.33 |
实施例14 | 1.26 |
实施例15 | 1.41 |
实施例16 | 1.65 |
实施例17 | 1.25 |
实施例18 | 1.59 |
实施例19 | 1.62 |
实施例20 | 1.79 |
实施例21 | 1.56 |
实施例22 | 1.39 |
实施例23 | 1.39 |
比较例1 | 1.89 |
比较例2 | 1.86 |
<喷射率的测定>
将20mg的试验制剂填充至胶囊(HPMC胶囊,Size2,Qualicaps)中,置于小型喷射器(Publizer,日文:パブライザ一)(FORTE GROW MEDICAL co.,ltd.)后,测定小型喷射器的重量。仅按下1次小型喷射器的泵,喷射试验制剂后,再次测定小型喷射器的重量,将喷射前后的重量之差作为喷射量。算出以所填充的试验制剂的重量作为100%的情况下的喷射量(喷射率)。结果示于表5。显示实施例的试验制剂以与比较例的试验制剂相比显著更高的比例进行了喷射。
[表5]
表5.试验制剂的来自喷射器的喷射率
来自喷射器的喷射率(%) | |
实施例1 | 68.2 |
实施例2 | 59.0 |
实施例3 | 76.9 |
实施例4 | 91.5 |
实施例5 | 70.1 |
实施例6 | 57.3 |
实施例7 | 68.0 |
实施例8 | 52.7 |
实施例9 | 78.0 |
实施例10 | 70.6 |
实施例11 | 66.9 |
实施例12 | 69.5 |
实施例13 | 60.2 |
实施例14 | 72.9 |
实施例15 | 69.0 |
实施例16 | 64.7 |
实施例17 | 57.8 |
实施例18 | 72.9 |
实施例19 | 76.6 |
实施例20 | 64.0 |
实施例21 | 57.6 |
实施例22 | 82.1 |
实施例23 | 79.9 |
比较例1 | 12.5 |
比较例2 | 17.1 |
Claims (15)
1.经鼻施予用粉末制剂,其含有有效成分与水不溶性多糖类附着于彼此而成的复合粒子。
2.如权利要求1所述的粉末制剂,其中,所述复合粒子的平均一次粒径为20~350μm。
3.如权利要求1或2所述的粉末制剂,其中,所述复合粒子的比表面积为0.20~2.3m2/g。
4.如权利要求1~3中任一项所述的粉末制剂,其中,所述复合粒子的Hausner比为1.8以下。
5.如权利要求1~4中任一项所述的粉末制剂,其中,所述水不溶性多糖类包含结晶纤维素。
6.如权利要求1~5中任一项所述的粉末制剂,其中,所述复合粒子还含有粘结剂。
7.如权利要求1~6中任一项所述的粉末制剂,其中,所述复合粒子还含有吸收促进剂。
8.如权利要求7所述的粉末制剂,其中,所述吸收促进剂为羟丙基β环糊精、十二烷基硫酸钠或正十二烷基-β-D-麦芽糖苷。
9.经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行搅拌造粒,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
10.经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行流化床造粒,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
11.经鼻施予用粉末制剂的制造方法,其包括下述工序:
将含有有效成分和水不溶性多糖类的混合物进行冷冻干燥,形成所述有效成分与所述水不溶性多糖类附着于彼此而成的复合粒子。
12.如权利要求9~11中任一项所述的制造方法,其中,所述水不溶性多糖类包含结晶纤维素。
13.如权利要求9~12中任一项所述的制造方法,其中,所述混合物还含有粘结剂。
14.如权利要求9~13中任一项所述的制造方法,其中,所述混合物还含有吸收促进剂。
15.如权利要求14所述的制造方法,其中,所述吸收促进剂为羟丙基β环糊精、十二烷基硫酸钠或正十二烷基-β-D-麦芽糖苷。
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CN101668544A (zh) * | 2006-12-26 | 2010-03-10 | 株式会社新日本科学 | 经鼻投用制剂 |
CN101428009A (zh) * | 2008-04-09 | 2009-05-13 | 上海医药工业研究院 | 胰岛素经鼻吸入粉雾剂 |
CN102905717A (zh) * | 2010-03-19 | 2013-01-30 | 第一三共株式会社 | 经鼻投与用组合物及其制造方法 |
WO2017223566A1 (en) * | 2016-06-24 | 2017-12-28 | Opiant Pharmaceuticals, Inc. | Compositions, devices, and methods for the treatment of alcohol use disorder |
Cited By (1)
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CN117503703A (zh) * | 2023-11-09 | 2024-02-06 | 广州新济药业科技有限公司 | 一种左旋多巴鼻喷雾剂及其制备方法及应用 |
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JPWO2020230676A1 (zh) | 2020-11-19 |
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AU2020273810A1 (en) | 2021-11-18 |
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