CN113318097A - 一种抗特发性肺纤维化的粉雾剂及制备方法 - Google Patents
一种抗特发性肺纤维化的粉雾剂及制备方法 Download PDFInfo
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Abstract
本发明涉及一种抗特发性肺纤维化的粉雾剂及制备方法,属于药物制剂领域。该粉雾剂包括以下重量份比的原料:80‑95份药物活性成分;2.5‑20份内源性肺表面活性剂;0‑10份钙盐。粉雾剂的颗粒体积几何直径为0.5μm‑6μm。该粉雾剂具有较小较窄的几何直径分布,可以直达病灶部位,其肺部沉积率FPF值>50%,FPF值(3.4)>30%,为肺深部沉积模式,具有递送到肺深部发挥抗肺纤维化的临床效果,能够降低药物有效成分的剂量,进而更大程度降低因有效成分剂量增加而引发的不良反应。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种抗特发性肺纤维化粉雾剂及制备方法。
背景技术
特发性肺纤维化(IPF)是一种局限于肺部的慢性进行性纤维化性间质性肺炎的一种特殊类型,好发于老年男性,组织学和/或影像学表现为普通型间质性肺炎(UIP)。特发性肺纤维化的病因不明,发病机制亦未完全阐明,但现有研究的证据表明与免疫炎症损伤有关,不同标本所显示的免疫炎症反应特征不尽一致,周围血所反映出的是免疫异常比较突出,而支气管肺泡灌洗液显示炎症反应为主,肺局部组织的异常又有所不同。目前认为,肺泡上皮细胞损伤和异常修复是导致肺纤维化的主要机制,损伤发生后,修复过程中不能完成正常的再上皮化过程,进而导致肺泡-毛细血管损伤,这一过程诱发细胞因子产生,成纤维细胞表面表达细胞因子受体,在细胞因子作用下聚集到损伤部位并增殖。
特发性肺纤维化具有渐进式的特征,表现为呼吸困难和肺功能的进行性恶化,预后不良,患者的中位生存期为2-3年,5年生存率低于30%,比大多数癌症(如白血病,乳腺癌,结肠癌,子宫癌和肾癌)的生存率都低。60%患者直接死于特发性肺纤维化,主要死亡原因包括特发性肺纤维化的急性恶化、急性冠状动脉、充血性心力衰竭、肺癌、感染和静脉血栓栓塞性疾病。特发性肺纤维化在全球范围内均有发生,且不分种族和性别,其自然病程变异较大,且无法预估。特发性肺纤维化虽为罕见病(发病率约14~43/10万),但近些年其发病率呈增加趋势。特发性肺纤维化的发病与患者年龄密切相关,75岁以上老年人特发性肺纤维化的发病率是35岁以下人群的100倍,男性发病率高于女性。特发性肺纤维化累及全球约300万人,美国约13万人。随着人口的老龄化,以及特发性肺纤维化诊断率的提高,预计特发性肺纤维化患病人群只增不少。
特发性肺纤维化的治疗手段有限,吡非尼酮是第一个获批用于治疗成人轻、中度特发性肺纤维化的药物,其在多项随机对照试验中表现出可延缓特发性肺纤维化患者病程进展,延长患者生存期。在2018年ATS/ERS/JRS/ALAT特发性肺间质纤维化指南中,吡非尼酮列入有条件推荐应用于特发性肺纤维化的临床治疗药物。吡非尼酮是一种非肽的合成分子,化学名称为5-甲基-l-苯基-2-(1H)-吡啶酮,分子量为185.23道尔顿,化学式为C12H11NO,结构已知。吡非尼酮可以抑制转化生长因子β(TGF-β),研发人员已发现BLM诱导的特发性肺纤维化仓鼠支气管肺泡灌洗液(BALF)中的TGF-β的含量比非纤维化对照组明显升高,给予吡非尼酮后,TGF-β含量显著下降,吡非尼酮抑制TGF-β基因表达,使表达水平下降33%。吡非尼酮还可以减少肿瘤坏死因子α(TNFα)的生成,抑制TNFα诱导的炎症反应,组织的损伤和坏死,抑制TNFα启动后续的组织修复和纤维化过程。此外,吡非尼酮能够减少血小板源生长因子(PDGF)等细胞因子的表达,减少细胞外基质沉积,刺激的肺成纤维细胞的有丝分裂,阻止成纤维细胞增殖,使胶原纤维Ⅰ和Ⅲ表达下降,抑制胶原合成并且促进胶原降解,但是作用靶点尚不明确(Khoo,J.K et al,A Randomized,Double-Blinded,Placebo-Controlled,Dose-Escalation Phase 1Study of Aerosolized Pirfenidone Deliveredvia the PARI Investigational eFlow Nebulizer in Volunteers and Patients withIdiopathic Pulmonary Fibrosis.Journal of Aerosol Medicine and Pulmonary DrugDelivery,2020,33(1):15-20)。
欧洲最近的一项安全性数据评估发现了数例与吡非尼酮有关的严重药物性肝损伤上市后报告,包括个别死亡病例。英国药品和健康产品管理局MHRA于2020年11月16日发布消息,警示吡非尼酮的严重肝损伤风险,报告的事件包括肝炎、肝损伤和肝衰竭。针对吡非尼酮的不良反应,沈俊等人检索中国学术期刊全文数据库(CNKI)、万方数据库、PubMed,Embas,Medline等,收集关于吡非尼酮致不良反应的个案报道,逐篇查阅全文并论述分析(沈俊,吴秋慧,葛卫红.吡非尼酮不良反应文献分析[J]中国药业,2019,28(15):81-84)。提取文献中患者性别、年龄、用法用量、不良反应发生时间、累及系统/器官及临床表现、治疗处理与转归等信息并进行回顾性分析(胡钟,张华,朱文莉等,氟康唑致不良反应文献分析[J],中国药业,2018,27(7):79-82;熊建群,高晓波,何珍等,碳酸锂致心血管系统不良反应文献分析[J],中国药业,2016,25(4):103-105)。分析结果表明,吡非尼酮不良反应表现为肝功能衰竭、皮肤光敏反应等,对不良反应因素进行调研发现,吡非尼酮经肝脏和肾脏代谢,老年人肝肾功能减退,免疫力下降,不良反应发生率增加;另外,剂量越高,发生不良反应的可能性越大,其不良反应的发生率与剂量呈正相关(CHO ME,KOPP JB,Pirfenidone:ananti-fibrotic therapy for progressive kidney disease[J],Expert Opin InvestigDrugs,2010,19(2):275-283)。
吡非尼酮常规以片剂和胶囊剂形式提供,主要用于口服,口服吡非尼酮后大鼠肝脏、肾脏、血浆、肺中吡非尼酮的结合率分别约为80.6%、69.6%、57.6%、22.2%(TogamiK,Kanehira Y,Tada H.Pharmacokinetic evaluation of tissue distribution ofpirfenidone and its metabolites for idiopathic pulmonary fibrosis therapy[J].Biopharm Drug Dispos,2015,36(4):205-215)。
现有研究显示,欧美人群口服吡非尼酮2403mg/d和亚洲人群口服吡非尼酮1200-1800mg/d能够在肺部达到有效的药物浓度,起到延缓肺纤维化进展的作用。吸入性吡非尼酮能够将药物直接送至肺部,较小剂量可能达到与口服吡非尼酮相似的肺脏血药浓度。药物动力学研究表明,应用吡非尼酮气雾剂100mg时,血药浓度-时间曲线下面积AUC是口服801mg剂量时的1/15,使肺泡上皮细胞衬液中最高药物浓度平均提高35倍,AUC增加20%。因此,与吸入给药相比,维持同等肺泡上皮细胞衬液中药物浓度,口服吡非尼酮给药是吸入给药的114倍,采用经口吸入给药可以显著降低吡非尼酮剂量。
专利ZL201280055619.1中公开了“吡非尼酮溶液暴露于模拟太阳光(250W/m2)的光强下,会导致吡非尼酮的降解”,表明吡非尼酮溶液存在不稳定性问题;该专利提供了一种粉雾剂的开发,通过局部靶向给药的方式,将粉末制剂通过吸入的方式输送到肺部,可以明显降低了吡非尼酮的用药量,也就相当于降低了吡非尼酮移行至皮肤的量,进而降低了由吡非尼酮引起的皮肤过敏反应。但通过对该专利实施,发现肺部沉积较差,导致药效不佳。
发明内容
针对上述技术问题,本发明提供一种抗特发性肺纤维化的粉雾剂及制备方法。所述粉雾剂包括以下重量份比的原料:
药物活性成分 80-95份;
内源性肺表面活性剂 2.5-20份;
钙盐 0-10份;
所述粉雾剂的颗粒几何直径为0.5μm-6μm。
本发明人对常规技术中吡非尼酮肺部沉积较差的原因进行了调查研究,发现由于吡非尼酮原料药在光学显微镜下呈现规则的鹅卵石状结晶,其边缘光滑,表面坚实无裂隙,故需多次对其进行粉碎,且所得微粉平均几何直径较大,在3μm-8μm,因而存在肺沉积率差的问题。
考虑到吡非尼酮如需沉积在肺病变部位,则吡非尼酮的空气动力学几何直径需要进一步缩小。在此基础上,本发明人通过反复试验尝试,制备得到了颗粒几何直径范围为0.5μm-6μm,平均几何直径为1.5-2.8μm的粉雾剂。
上述粉雾剂具有较小较窄的几何直径分布,可以直达病灶部位,其肺部沉积率FPF值>50%,FPF值(3.4)>30%,而现有研究已证实肺部沉积率FPF值与沉积在患者肺部的粉末的分数相关联,FPF(3.4)值与达到患者肺深部的粉末的分数相关联,FPF值(3.4)>30%为肺深部沉积模式,具有递送到肺深部发挥抗肺纤维化的临床效果,能够降低药物有效成分的剂量,进而更大程度降低因有效成分剂量增加而引发的不良反应。
在其中一个实施例中,所述粉雾剂包括以下重量份比的原料:
药物活性成分 80-90份;
内源性肺表面活性剂 2.5-5份;
钙盐 2.5-5份。
在其中一个实施例中,所述药物活性成分颗粒的几何直径为0.65μm-3.4μm,平均几何直径为1.4-2.0μm,根据空气动力学,所述颗粒体积几何直径进一步提高吡非尼酮在肺病变部位的沉积率。
在其中一个实施例中,所述药物活性成分为吡非尼酮和/或吡非尼酮类似物,所述内源性肺表面活性剂为磷脂。采用磷脂不仅能协助药物活性成分在肺部的吸收,且安全无毒,极大地降低了辅料对人体的副作用。
在其中一个实施例中,所述药物活性成分为吡非尼酮,所述磷脂为二硬脂酰磷脂酰胆碱。二硬脂酰磷脂酰胆碱是内源性肺表面活性物质中最丰富的成分,能进一步协助吡非尼酮在肺部的吸收,同时两者的结合具有良好的流动性和分散性,无需再加入大颗粒乳糖等赋形剂,减少后续工艺步骤,避免微米级粉末经过多操作步骤造成外泄。
在其中一个实施例中,所述钙盐为氯化钙。氯化钙中的钙离子能抗过敏,有利于肺炎渗出物的吸收,同时还能防潮,提高药品的储存稳定性。
吡非尼酮与二硬脂酰磷脂酰胆碱、氯化钙形成的球形度较高的颗粒,降低了颗粒间的内聚力,改善了气溶胶性能,并具有使得能够更有效的呼吸递送细颗粒。
本发明还提供了一种所述粉雾剂的制备方法,包括以下步骤:
含药乳化液制备:用有机溶剂和水分别溶解处方原料,并将得到的有机相溶液、水溶液混合乳化,即得含药乳化液;
微粉制备:将上述含药乳化液雾化成微乳滴,喷雾干燥,蒸发除去水和有机相后得到微粉并收集;
粉雾剂制备:将微粉填充入胶囊中,即得。
上述制备方法采用喷雾干燥工艺,通过粒子工程控制粒子表面特性,使吡非尼酮与二硬脂酰磷脂酰胆碱、氯化钙形成球形度较高的颗粒,降低颗粒间的内聚力,改善气溶胶性能,能更有效地呼吸递送直达肺部病灶,控制颗粒体积几何直径,使其能递送到肺深部。
在其中一个实施例中,将药物活性成分和内源性肺表面活性剂溶于有机溶剂中,将钙盐溶于水中,再将得到的有机相溶液、水溶液混合乳化。
在其中一个实施例中,所述有机溶剂为乙酸乙酯、乙酸丁酯、叔丁基甲醚、甲酸乙酯、正庚烷、乙酸异丁酯、乙酸异丙酯、乙酸甲酯、甲基异丁基酮、正戊烷、正戊醇、正丙醇、石油醚中的至少1种,能较好地溶解吡非尼酮和二硬脂酰磷脂酰胆碱。
在其中一个实施例中,所述有机溶剂和水的体积比例为20-50∶1,混合乳化后能得到几何直径较小,且均匀稳定的含药乳化液。
在其中一个实施例中,所述含药乳化液制备步骤中,乳化条件为:有机溶剂为乙酸乙酯,超声波乳化,振荡频率为40-100KHz。采用上述条件,不仅能使原料充分混合,超声波还能消除混合过程中产生的气泡,最终得到均匀的含药乳化液。
在其中一个实施例中,所述微粉制备步骤中,所述雾化和喷雾干燥条件为:采用蠕动泵将所述含药乳化液泵入,蠕动泵的流量范围为2-200ml/min;离心雾化,转速为10000-25000rpm;顶喷;进风温度为110-180℃,出风温度为70-90℃。采用上述雾化和喷雾干燥条件,能通过调节蠕动泵的流量、离心雾化中的转速来控制微乳滴的大小,进而获得不同几何直径分布的微粉,离心雾化成微乳滴后,通过顶喷的形式,能充分与热风接触,除去水和有机溶剂。
在其中一个实施例中,所述微粉制备步骤和粉雾剂制备步骤之间,还包括调理步骤,所述调理步骤中:将微粉放置于25±5℃、65±15%RH的环境内,放置调理时间≥240分钟。上述调理步骤能使微粉转变为稳定的结晶状态,避免在存储期因无定型的存在,容易复结的情况。
与现有技术相比,本发明具有以下有益效果:
本发明提供了一种抗特发性肺纤维化的粉雾剂,所述粉雾剂具有较小较窄的几何直径分布,可以直达病灶部位,其肺部沉积率FPF值>50%,FPF(3.4)值>30%,为肺深部沉积模式,具有递送到肺深部发挥抗肺纤维化的临床效果,能够降低药物有效成分的剂量,进而更大程度降低因有效成分剂量增加而引发的不良反应,降低肝肾毒性与光毒性。
具体实施方式
为了便于理解本发明,下面将参照相关实施例对本发明进行更全面的描述。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。本文所使用的术语“和/或”包括一个或多个相关的所列项目的任意的和所有的组合。
定义:
本发明所述的肺部沉积率FPF值对应于小于5.6μm的空气动力学直径的颗粒的百分比,FPF(3.4)值对应于具有小于3.4μm的空气动力学几何直径的颗粒的百分比,现有技术中用来表征肺部沉积情况。
本发明所述几何直径指以球的球径作为该不规则颗粒的几何当量径。本实施例中采用激光粒度仪进行测定。
设备采用:贝世德BET比表面及孔径分布仪(型号:BSD-PS1)、激光粒度仪(干法,Symptec GMBH,HELOS-RODOS型)、安德森阶式撞击器ACI(厂家:英国Copley)、药粉吸入器(生产商:意大利Plastiape S.p.A,规格型号:3#胶囊/RS01)、安捷伦高效液相仪、色谱柱(Diamonsil(钻石)c-s(250×4.6mm,5μm))、DP-4(Ina Research,Inc.)
本实施例所用试剂、材料如无特殊说明,均为市售来源;实验方法如无特殊说明,均为本领域的常规实验方法。
实施例1
制备微粉。
1、将吡非尼酮、二硬脂酰磷脂酰胆碱、卵磷脂在室温放置20分钟,按下表分别称取吡非尼酮、二硬脂酰磷脂酰胆碱、卵磷脂、氯化钙、水和乙酸乙酯,备用;
表1微粉配方表
2、按表1中的配方,将吡非尼酮、二硬脂酰磷脂酰胆碱、卵磷脂放入乙酸乙酯溶液中,搅拌使之溶解;将氯化钙溶解于水中,备用;
3、将步骤2得到的乙酸乙酯溶液倒入带有超声波功能的搅拌罐中,将溶有氯化钙的水加入其中,搅拌30min后,超声波震荡频率设置为20-130KHz,在本实施例中,设置超声波震荡频率为80KHz,超声30min后,即得含药乳化液;
4、将步骤3得到的含药乳化液采用蠕动泵泵入喷雾干燥机中,蠕动泵的流量设置为0.1-300ml/min,在本实施例中,蠕动泵的流量为10ml/min;离心喷雾头采用压缩空气转动,转速为10000-25000rpm,在本实施例中,离心喷雾头压缩空气转动速度为20000rpm,将含药乳化液雾化至较细的液滴;
5、设置喷雾干燥机的进风温度为110-180℃,出风温度为70-90℃,在本实施例中进风温度为170℃,出风温度为90℃,雾化的液滴接触干热空气,将其中的水和乙酸乙酯气雾化除去,即得微粉;
6、通过旋风分离器收集微粉;
7、对上述微粉进行调理,将微粉放置于25℃、75%RH的环境中,稳定360分钟,备用。
另按照配方三的各成分配比,在蠕动泵工作频率为500ml/min、离心喷雾头压缩空气转动速度为8000rpm的条件下,获得不同几何直径分布的微粉,将所得组别命名为配方三-2。
上述配方三-2组的制备过程中发现:将吡非尼酮、卵磷脂溶于乙酸乙酯溶液时,出现严重的泡沫,通过超声波处理亦无法消除或减缓;将有机相溶液与水溶液混合时,出现严重的乳化现象,并伴有严重气泡。
实施例2
测定微粉的各项数据指标。
对实施例1中得到的微粉进行各项数据指标测定,采用刻度量筒法测定堆积密度,采用圆角锥法测定休止角,采用比表面及孔径分布仪测定,结果如下表:
表2不同配比微粉的比表面积
组别 | 堆积密度g/ml | 休止角° | 比表面积m<sup>2</sup>/g |
配方一 | 0.082 | 62 | 12.7028 |
配方二 | 0.087 | 56 | 11.6099 |
配方三 | 0.089 | 50 | 13.928 |
配方三-2 | 0.12 | 48 | 6.2532 |
配方四 | 0.092 | 53 | 12.3025 |
配方五 | 0.085 | 58 | 7.9524 |
表3不同配比微粉的几何直径采用激光粒度仪对微粉的几何直径进行检测,结果如下:
结果表明:配方三-2与配方五颗粒偏大,且配方三-2和配方五在配制过程中出现严重的乳化现象,并伴有严重气泡,导致在喷雾干燥过程中,喷液不均匀,几何直径分布较宽,出现双峰。
实施例3
调理试验。
喷雾干燥所得微粉以无定型为主,需让其在温度和相对湿度结合的条件下转变成稳定地结晶状态。将实施例1第6步得到的微粉放置于25±5℃、65±15%RH的环境内,稳定时间≥240分钟。
在本实施例中,将所述微粉放置于25℃、75%RH的环境内,稳定360分钟,比较调理前和调理后的水分含量与晶型,另将配方三在实施例1中第6步中得到的微粉同步放于30℃,85%RH的环境内,稳定360分钟,将此份样品标记为配方三-3,进行结果比较,如下表:
表4各配方调理结果
组别 | 调理前水分含量% | 调理后水分含量% | 调理前晶型 | 调理后晶型 |
配方一 | 1.83 | 1.88 | 无定型 | 结晶 |
配方二 | 1.57 | 1.58 | 无定型 | 结晶 |
配方三 | 1.97 | 2.02 | 无定型 | 结晶 |
配方三-2 | 2.05 | 2.06 | 无定型 | 结晶 |
配方四 | 2.12 | 2.3 | 无定型 | 结晶 |
配方五 | 2.51 | 3.02 | 无定形 | 结晶 |
配方三-3 | 2.05 | 3.08 | 无定形 | 结晶 |
采用激光粒度仪对调理后的微粉进行几何直径检测,结果如下表:
表5各配方调理后几何直径
结果表明:配方一、配方二、配方三、配方三-2、配方四的微粉整体水分含量调理前后变化不大,调理前晶型以无定型为主,调理后以结晶形式为主,趋向于稳定状态,调理前后,微粉几何直径仅微微变化,说明调理过程未使微粉附聚抱团。配方五的微粉,因含有卵磷脂,几何直径分布比较大,存在较多的极细粉,在同样温湿度调理下,趋向于结团,几何直径增大明显。配方三-3也出现几何直径明显增加的现象。
实施例4
检测微粉调理前后稳定性的变化。
将实施例1中配方二、三未调理的微粉和已调理的微粉分别装入铝膜袋,热封,置于30℃、65%RH的恒温恒湿箱中检测微粉调理前后稳定性的变化,结果如下:
表6各配方调理前后稳定性的变化结果
注:D10表示累计10%点的几何直径,D50表示累计50%点的几何直径,D90表示累计90%点的几何直径。
结果表明:经过调理后的微粉,其几何直径稳定性更好,而未经调理的微粉因其主要为无定型存在,所以更容易在存储期发生复结。
实施例5
体外肺部沉积率试验与胶囊排空试验。
1、胶囊排空试验
将实施例1中配方一、配方二、配方三、配方三-2、配方四调理后的微粉,采用手工方式填充到3#绿色羟丙甲纤维素胶囊中,每粒胶囊含有5-50mg微粉,在本实施例中,每粒胶囊含有25mg微粉,热封到铝膜袋中,即得5种配方样品;
因上述胶囊中未加入大颗粒载体,且休止角均大于50°,所以需进行胶囊排空率测定,按照2015版《中国药典》四部通则中公开的方法,对上述5种配方样品进行排空率试验,结果如下:
表7各配方排空率试验结果
结果表明:排空率试验结果与休止角结果可对应,但排空率测定RSD值总体<5%,都处于可接受范围,尤其是配方三,其排空率试验结果最佳。
2、体外肺部沉积率试验
取实施例1调理后的微粉,采用手工方式填充到3#绿色羟丙甲纤维素空心胶囊中,每粒胶囊含有5-50mg微粉,在本实施例中,每粒胶囊含有25mg微粉,按照《中国药典》通则0951吸入制剂微细粒子空气动力学特性测定法测定粉雾剂的肺部沉积率,每组试验结果取平均值,测定条件为:采用阶式撞击器;泵流速:28.3L/min,2.7s;吸入装置采用药粉吸入器。
测定吡非尼酮含量,采用液相色谱法,色谱条件如下:
分析设备:高效液相分析设备;
色谱柱:C18色谱柱,规格为250×4.6mm,填料粒径为5μm;
流动相:0.05%三乙胺溶液(冰醋酸调pH为6.5)-甲醇,体积比为1:0.95;
流速:1.0ml/min;
检测波长:225nm;
柱温:30℃。
结果如下表:
表8体外肺部沉积率试验结果
注:MMAD值即质量中值空气动力学直径,表示气雾粒子喷出后,气雾群粒子的直径作对半分配后,取得的粒子直径,即有50%的粒子直径<MMAD和50%的粒子直径>MMAD。
结果表明:空气动力学几何直径不仅仅只与原料药本身的几何直径相关,原则上几何直径越小,分布越窄,肺部沉积量越多,但几何直径非常窄,有大量极细粉存在时,会出现微粉间范德华力增加,肺部沉积量反而降低的情况存在。
实施例6
检测本发明粉雾剂对百草枯导致的大鼠肺纤维化的治疗效果。
材料:百草枯、实施例1中配方三和配方三-2制得的粉雾剂、生理盐水、戊巴比妥钠注射液;
动物:体重为220-260g的Sprague-Dawley大鼠;
气道药物治疗工具:DP-4
1、肺纤维化造模:
将SD大鼠在常规实验室条件下以21±2℃和12/12明暗周期饲养,通过单次腹膜內(ip)注射百草枯(20mg/kg)诱导肺纤维化。
2、分组及给药:
诱导肺纤维化后两周,将大鼠随机分为四个实验组,每组16只大鼠:接受百草枯未经治疗的大鼠(PQ组)、吸入实施例1中配方三组、吸入实施例1中配方三-2组、均接受生理盐水的阴性对照组。经气道中插入DP-4发送压缩空气进行气管内给药。
单次给予粉雾剂后,通过腹膜注射麻醉剂将大鼠麻醉后,立即解剖,吸取肺泡上皮细胞衬液、肺泡表层组织,进行匀浆,建立吡非尼酮的高效液相色谱方法,测定大鼠深肺部吡非尼酮的药物浓度,检测结果如下表。具体检测方法如下:
分析设备:高效液相分析设备;
色谱柱:ZORBAX SB-C18色谱柱,规格为250×4.6mm,填料粒径为5μm;
流动相:乙腈-水-0.1%TFA(三氟乙酸);
流速:1.0ml/min;
检测波长:248nm;
柱温:30℃。
表9大鼠深肺部吡非尼酮的平均药物浓度
项目 | 配方三 | 配方三-2 | 阴性对照组 |
深肺部吡非尼酮的浓度 | 15632.17h*nmol/kg | 10425.43h*nmol/kg | 0h*nmol/kg |
结果表明:实施例1中配方三组的吡非尼酮浓度约为配方三-2的1.5倍。体内试验与体外试验结果相对应,药物几何直径在3.4μm以内的药物可以更集中分布在肺深部,预测可以起到更好的治疗效果。
实施例7
检测微粉胶囊的稳定性。
将实施例1所得微粉分别填充到绿色羟丙甲纤维素空心胶囊中,每粒25mg,将其装入铝铝泡罩包装中,并分别将其放入25℃,60%RH、30℃,65%RH与40℃,75%RH三个条件的恒温恒湿箱中,分别考察吡非尼酮含量、空气动力学几何直径分布在存储期的稳定性,取多次试验的平均值,结果如下:
1、25℃、60%RH温湿度条件下的稳定性情况如下表。
表10 5℃、60%RH温湿度条件下的稳定性
2、30℃、65%RH温湿度条件下的稳定性情况如下表。
表11 30℃、65%RH温湿度条件下的稳定性
3、40℃、75%RH温湿度条件下的稳定性情况:
表12 40℃、75%RH温湿度条件下的稳定性
结果表明:因微粉在高温高湿下都会有团聚存在,因此40℃,75%RH条件下存储期稳定性变差,尤其是在加速6个月,FPF值已经小于50%。
但现有研究显示,在肺部给药的范畴内,46%-50%的FPF值也可以起到良好的肺部递送效果。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种抗特发性肺纤维化的粉雾剂,其特征在于,包括以下重量份比的原料:
药物活性成分 80-95份;
内源性肺表面活性剂 2.5-20份;
钙盐 0-10份;
所述粉雾剂的颗粒几何直径为0.5μm-6μm。
2.根据权利要求1所述的粉雾剂,其特征在于,包括以下重量份比的原料:
药物活性成分 80-90份;
内源性肺表面活性剂 2.5-5份;
钙盐 2.5-5份。
3.根据权利要求2所述的粉雾剂,其特征在于,所述药物活性成分颗粒的几何直径为0.65μm-3.4μm。
4.根据权利要求1-3中任一项所述的粉雾剂,其特征在于,所述药物活性成分为吡非尼酮和/或吡非尼酮类似物,所述内源性肺表面活性剂为磷脂。
5.根据权利要求4所述的粉雾剂,其特征在于,所述药物活性成分为吡非尼酮,所述磷脂为二硬脂酰磷脂酰胆碱。
6.根据权利要求1所述的粉雾剂,其特征在于,所述钙盐为氯化钙。
7.权利要求1所述的粉雾剂的制备方法,其特征在于,包括以下步骤:
含药乳化液制备:用有机溶剂和水分别溶解处方原料,并将得到的有机相溶液、水溶液混合乳化,即得含药乳化液;
微粉制备:将上述含药乳化液雾化成微乳滴,喷雾干燥,蒸发除去水和有机相后得到微粉并收集;
粉雾剂制备:将微粉填充入胶囊中,即得。
8.根据权利要求8所述的制备方法,其特征在于,所述含药乳化液制备步骤中,乳化条件为:有机溶剂为乙酸乙酯,超声波乳化,振荡频率为40-100KHz。
9.根据权利要求8所述的制备方法,其特征在于,所述微粉制备步骤中,所述雾化和喷雾干燥条件为:
采用蠕动泵将所述含药乳化液泵入,蠕动泵的流量范围为2-200ml/min;离心雾化,转速为10000-25000rpm;顶喷;进风温度为110-180℃,出风温度为70-90℃。
10.根据权利要求8所述的制备方法,其特征在于,所述微粉制备步骤和粉雾剂制备步骤之间,还包括调理步骤,所述调理步骤中:将微粉放置于25±5℃、65±15%RH的环境内,放置调理时间≥240分钟。
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