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Article(id=1201124484787954320, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0972, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1692028800000, receivedDateStr=2023-08-15, revisedDate=1704729600000, revisedDateStr=2024-01-09, acceptedDate=null, acceptedDateStr=null, onlineDate=1764299992987, onlineDateStr=2025-11-28, pubDate=1710172800000, pubDateStr=2024-03-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764299992987, onlineIssueDateStr=2025-11-28, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764299992987, creator=13701087609, updateTime=1764299992987, updator=13701087609, issue=Issue{id=1201124478286786612, tenantId=1146029695717560320, journalId=1189982191388893191, year='2024', volume='59', issue='3', pageStart='493', pageEnd='788', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764299991434, creator=13701087609, updateTime=1764300490467, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1201126571420639892, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1201126571420639893, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1201124478286786612, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=574, endPage=580, ext={EN=ArticleExt(id=1201124485719089866, articleId=1201124484787954320, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Preparation modification strategies for clinical treatment drugs of Parkinson's disease, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Parkinson's disease (PD) is a chronic neurodegenerative disease. At present, levodopa and other drugs are mainly used for dopamine supplementation therapy. However, the absorption of levodopa in the gastrointestinal tract is unstable and its half-life is short, and long-term use of levodopa will lead to the end-of-dose deterioration, dyskinesia, the "ON-OFF" phenomenon and other symptoms. Therefore, new preparations need to be developed to improve drug efficacy, reduce side effects or improve compliance of patients. Based on the above clinical needs, this review briefly introduced the preparation modification strategies for the treatment of PD through case analysis, in order to provide references for the research and development of related preparations.

, correspAuthors=Qian CHEN, Chun-meng SUN, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2024 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Meng-jiao HE, Yi-fang XIAO, Xiang-an-ni KONG, Zhi-hao LIU, Xiao-guang WANG, Hao FENG, Jia-sheng TU, Qian CHEN, Chun-meng SUN), CN=ArticleExt(id=1201124487556195074, articleId=1201124484787954320, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=帕金森病临床治疗药物的制剂改良策略, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

帕金森病(Parkinson's disease, PD) 是一种慢性神经退行性疾病, 目前主要以左旋多巴等药物进行多巴胺补充治疗, 但左旋多巴在胃肠道吸收不稳定且半衰期短, 长期服用会导致剂末现象、异动症、开关效应等症状的发生, 因此需要研发新型制剂以提高药效、降低不良反应或提高患者用药依从性, 基于以上临床需求, 本文通过案例分析介绍了用于帕金森病治疗的制剂改良策略, 以期为相关制剂的研发提供思路。

, correspAuthors=陈芊, 孙春萌, authorNote=null, correspAuthorsNote=
*陈芊, Tel: 15298366219, E-mail:
孙春萌, Tel: 86-25-83271305, E-mail:
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Dosage formMedicationActive pharmaceutical ingredientStage of developmentApproved year
TabletSinemetCarbidopa, levodopaApproved by FDA1975
TabletMadoparLevodopa, benserazideApproved by Swissmedic1973
TabletStalevoCarbidopa, entacapone, levodopaApproved by FDA2003
TabletWD-1603Carbidopa, levodopaPhase Ⅱ-
TabletWD-1804Carbidopa, levodopaPre-IND-
TabletWD-1905Carbidopa, levodopaPhase Ⅰ-
CapsuleAP 09004Carbidopa, levodopaPhase Ⅲ-
CapsuleRytaryCarbidopa, levodopaApproved by FDA2015
CapsuleIPX203Carbidopa, levodopaPhase Ⅲ-
SuspensionDuopaCarbidopa, levodopaApproved by FDA2015
InhalantInbrijaLevodopaApproved by FDA2018
PatchNeuproRotigotineApproved by FDA2007
MicrosphereLY03003RotigotinePhase Ⅲ-
), ArticleFig(id=1201124494795563293, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124484787954320, language=CN, label=Table 1, caption=

New formulations for Parkinson's disease (PD)

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Dosage formMedicationActive pharmaceutical ingredientStage of developmentApproved year
TabletSinemetCarbidopa, levodopaApproved by FDA1975
TabletMadoparLevodopa, benserazideApproved by Swissmedic1973
TabletStalevoCarbidopa, entacapone, levodopaApproved by FDA2003
TabletWD-1603Carbidopa, levodopaPhase Ⅱ-
TabletWD-1804Carbidopa, levodopaPre-IND-
TabletWD-1905Carbidopa, levodopaPhase Ⅰ-
CapsuleAP 09004Carbidopa, levodopaPhase Ⅲ-
CapsuleRytaryCarbidopa, levodopaApproved by FDA2015
CapsuleIPX203Carbidopa, levodopaPhase Ⅲ-
SuspensionDuopaCarbidopa, levodopaApproved by FDA2015
InhalantInbrijaLevodopaApproved by FDA2018
PatchNeuproRotigotineApproved by FDA2007
MicrosphereLY03003RotigotinePhase Ⅲ-
), ArticleFig(id=1201124494887837990, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124484787954320, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
MedicationActive pharmaceutical ingredientDosage formDoseFrequency of administrationApproved year
Sinemet CRCarbidopa, levodopaTablet25, 50, 100, 200 mgTwice a day1991
NeuproRotigotinePatch1, 2, 3, 4, 6, 8 mg (24 h)Once a day2007
Requip XLRopinirole hydrochlorideTablet2, 3, 4, 6, 8, 12 mgThree times a day2009
Mirapex ERPramipexole hydrochlorideTablet0.375, 0.75, 1.5, 2.25, 3, 3.75, 4.5 mgOnce a day2009
RytaryCarbidopa, levodopaCapsule23.75/95, 36.25/145, 48.75/195, 61.25/245 mgThree times a day2015
GocovriAmantadine hydrochlorideCapsule137, 274 mgOnce a day2017
), ArticleFig(id=1201124495013667116, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1201124484787954320, language=CN, label=Table 2, caption=

Sustained release preparations for PD treatment that have been marketed domestically and internationally

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MedicationActive pharmaceutical ingredientDosage formDoseFrequency of administrationApproved year
Sinemet CRCarbidopa, levodopaTablet25, 50, 100, 200 mgTwice a day1991
NeuproRotigotinePatch1, 2, 3, 4, 6, 8 mg (24 h)Once a day2007
Requip XLRopinirole hydrochlorideTablet2, 3, 4, 6, 8, 12 mgThree times a day2009
Mirapex ERPramipexole hydrochlorideTablet0.375, 0.75, 1.5, 2.25, 3, 3.75, 4.5 mgOnce a day2009
RytaryCarbidopa, levodopaCapsule23.75/95, 36.25/145, 48.75/195, 61.25/245 mgThree times a day2015
GocovriAmantadine hydrochlorideCapsule137, 274 mgOnce a day2017
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帕金森病临床治疗药物的制剂改良策略
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何梦娇 1 , 肖伊芳 1 , 孔祥安妮 1 , 刘智昊 1 , 王孝广 2 , 冯浩 2 , 涂家生 1 , 陈芊 1, * , 孙春萌 1, *
药学学报 | 综述 2024,59(3): 574-580
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药学学报 | 综述 2024, 59(3): 574-580
帕金森病临床治疗药物的制剂改良策略
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何梦娇1, 肖伊芳1, 孔祥安妮1, 刘智昊1, 王孝广2, 冯浩2, 涂家生1, 陈芊1, * , 孙春萌1, *
作者信息
  • 1.国家药品监督管理局药物制剂及辅料研究与评价重点实验室, 中国药科大学药学院, 江苏 南京 210009
  • 2.南京兰铭生物医疗科技有限公司, 江苏 南京 210028

通讯作者:

*陈芊, Tel: 15298366219, E-mail:
孙春萌, Tel: 86-25-83271305, E-mail:
Preparation modification strategies for clinical treatment drugs of Parkinson's disease
Meng-jiao HE1, Yi-fang XIAO1, Xiang-an-ni KONG1, Zhi-hao LIU1, Xiao-guang WANG2, Hao FENG2, Jia-sheng TU1, Qian CHEN1, * , Chun-meng SUN1, *
Affiliations
  • 1. NMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and Excipients, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China
  • 2. Nanjing Lanming Biomedical Technology Co., Ltd., Nanjing 210028, China
出版时间: 2024-03-12 doi: 10.16438/j.0513-4870.2023-0972
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摘要
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帕金森病(Parkinson's disease, PD) 是一种慢性神经退行性疾病, 目前主要以左旋多巴等药物进行多巴胺补充治疗, 但左旋多巴在胃肠道吸收不稳定且半衰期短, 长期服用会导致剂末现象、异动症、开关效应等症状的发生, 因此需要研发新型制剂以提高药效、降低不良反应或提高患者用药依从性, 基于以上临床需求, 本文通过案例分析介绍了用于帕金森病治疗的制剂改良策略, 以期为相关制剂的研发提供思路。

帕金森病  /  左旋多巴  /  卡比多巴  /  多巴胺受体激动剂  /  剂型

Parkinson's disease (PD) is a chronic neurodegenerative disease. At present, levodopa and other drugs are mainly used for dopamine supplementation therapy. However, the absorption of levodopa in the gastrointestinal tract is unstable and its half-life is short, and long-term use of levodopa will lead to the end-of-dose deterioration, dyskinesia, the "ON-OFF" phenomenon and other symptoms. Therefore, new preparations need to be developed to improve drug efficacy, reduce side effects or improve compliance of patients. Based on the above clinical needs, this review briefly introduced the preparation modification strategies for the treatment of PD through case analysis, in order to provide references for the research and development of related preparations.

Parkinson's disease  /  levodopa  /  carbidopa  /  dopamine agonist  /  dosage form
何梦娇, 肖伊芳, 孔祥安妮, 刘智昊, 王孝广, 冯浩, 涂家生, 陈芊, 孙春萌. 帕金森病临床治疗药物的制剂改良策略. 药学学报, 2024 , 59 (3) : 574 -580 . DOI: 10.16438/j.0513-4870.2023-0972
Meng-jiao HE, Yi-fang XIAO, Xiang-an-ni KONG, Zhi-hao LIU, Xiao-guang WANG, Hao FENG, Jia-sheng TU, Qian CHEN, Chun-meng SUN. Preparation modification strategies for clinical treatment drugs of Parkinson's disease[J]. Acta Pharmaceutica Sinica, 2024 , 59 (3) : 574 -580 . DOI: 10.16438/j.0513-4870.2023-0972
正文
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帕金森病(Parkinson's disease, PD) 是一种仅次于阿尔茨海默病的第二大老年慢性神经退行性疾病, 其临床特征主要表现为运动迟缓、震颤麻痹、运动平衡失调、肌肉强直等运动症状[1], 且有研究表明, PD也是一种复杂的精神障碍性疾病[2], 有些患者伴有记忆力衰退、认知睡眠障碍、抑郁[3]等精神类非运动症状, 极大地影响了患者的工作和生活。据流行病学统计, 自1990至2015年, PD患病率呈指数级增长, 其增长速率几乎快于其他神经系统疾病, 全球PD患者数超过600万, 涉及到全球1%~2%的65岁以上的老年人, 且男性发病率高于女性[4, 5]。
对于PD的病理生理学机制, 目前比较公认的是黑质纹状体多巴胺能神经-胆碱能神经功能失衡学说, 该学说认为, PD患者由于黑质中多巴胺能神经元变性死亡, 多巴胺(dopamine, DA) 含量显著减少, 使胆碱能神经功能占优势, 继而导致一系列病理改变和PD症状的发生[5]。
基于以上PD病理学说, 当前PD临床治疗的药物大都围绕促进DA能神经功能或抑制胆碱能神经功能而研发, 如左旋多巴类药物[6, 7]、DA受体激动剂[8, 9]、单胺氧化酶(monoamine oxidase-B, MAO-B) 抑制剂[10, 11]、儿茶酚-O-甲基转移酶(catechol-O-methyl transferase, COMT) 抑制剂[12]及其他辅助治疗药物[13]等。其中左旋多巴类药物已被证明是治疗PD最基本、最有效的药物, 可以有效转化为DA作为补充, 对于震颤、强直、运动迟缓等症状均有较好的疗效, 被称为PD治疗的首选药, 除单用外, 还可与酶抑制剂联合使用以降低左旋多巴外周代谢, 在临床上广泛使用。
但这些药物仅在一定程度上改善PD症状, 延缓PD进程, 并不能逆转或治愈PD, 疗效有限, 且左旋多巴存在药物半衰期短、剂末现象、开关效应、用药频率高、患者顺应性差等问题; 另外基于PD神经退行性病变不断进展的自然病程特点与发病机制的复杂性, 新靶点及药物的发现仍然较为困难, 因此当前研究大多致力于已有PD治疗药物的新型递药系统研发, 如对左旋多巴相关制剂类型不断改进, 制成缓释胶囊或渗透泵片、胃滞留制剂、肠道泵入剂、吸入粉雾剂, 或研发其他药物透皮贴剂或长效复杂注射剂等。通过对原研制剂的剂型、给药途径、活性成分结构进行优化以凸显临床优势, 提高疗效, 增加药物的胃肠道吸收, 提高左旋多巴等药物的生物利用度; 延迟剂末效应的发生, 缩短PD患者“OFF”期时间; 降低给药频率, 改善患者用药依从性等。本文结合案例, 以左旋多巴类药物为代表的相关制剂(表 1), 综述基于临床需求的PD治疗用新型制剂设计及制剂改良目标, 以期为PD治疗相关制剂的研发提供研究思路与理论依据。
1 延长单剂量口服左旋多巴作用时间
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自20世纪70年代以来, 左旋多巴(levodopa, LD) 一直是治疗PD最有效的药物, 对于PD早期患者, LD可以在短期内有效地控制PD运动症状, 并且其不良反应低于其他类药物[14]。LD给药入血后, 经芳香族氨基酸转运载体进入脑内, 并在脱羧酶的作用下转化为DA, 以补充脑内缺失的DA, 从而发挥其药理作用。但LD具有酶不稳定性, 外周多巴脱羧酶的广泛分布及细胞周围存在的COMT使其代谢较快, 半衰期较短(1~3 h), 导致最终进入脑内的LD仅约1%, 因此早在1973年, 临床上就已经将LD与多巴脱羧酶抑制剂如卡比多巴(carbidopa, CD)、苄丝肼联用并制备成复方制剂, 以减少LD的外周代谢。
目前常用的复方LD片剂有3种, 即息宁(Sinemet)、美多巴(Madopar) 和达灵复(Stalevo)。这3种复方制剂与单一的LD片剂相比, 可以有效地减少外周DA的生成, 使LD用药剂量显著降低约60%~80%。
但传统的LD复方制剂由于药物释放较快, 导致LD血浆半衰期较短, 患者长期服用后容易出现运动波动, 而将传统常释复方片剂改良成缓控释复方片剂或胶囊是克服上述不足的有效手段。
1.1 卡左双多巴缓释胶囊(IPX066和IPX203)
IPX066 (即Rytary) 是一种新型卡比多巴/左旋多巴(carbidopa/levodopa, CD/LD) 缓释胶囊, 于2015年在FDA获批上市, 用于PD运动并发症的治疗。其制剂规格有4种, 即CD/LD: 23.75/95 mg、36.25/145 mg、48.75/195 mg和61.25/245 mg, 每6 h服用1次。该缓释胶囊与仅含CD-LD速释颗粒的普通胶囊不同, 其内部不仅含有CD-LD速释颗粒, 通过加入聚维酮、交联羧甲基纤维素钠等崩解剂促使药物快速释放, 还含有释放速率不同的CD-LD肠溶包衣微丸, 以乙基纤维素及羟丙甲纤维素等控释材料、不同含量的酒石酸及甲基丙烯酸共聚物等肠溶包衣材料共同控制LD的释放和吸收[15, 16]。该制剂既能速释又能缓释药物, 因此给药后可以快速达到治疗所需的LD血浆浓度并在4 h内维持在Cmax的50%以上, 维持时间约为速释左旋多巴/卡比多巴制剂(immediate-release carbidopa/levodopa, IR-CD/LD) 的两倍[17], 对于PD中晚期患者, 能显著缩短其“OFF”期时间[18], 这对需要缓解运动障碍并快速进入“ON”期的患者尤为重要。
IPX203在适用症、给药途径及剂型上与IPX066相似, 每8 h服用1次。IPX203缓释胶囊中含有速释颗粒和缓释包衣微丸, 速释颗粒含处方中100%的CD、处方中25%的LD及促使药物快速释放的崩解剂; 缓释包衣微丸有4层结构, 从内到外依次为含处方中剩余75% LD的药物丸芯、控制药物缓慢释放的聚合物材料层、可使微丸黏附在生物膜上以便吸收的黏膜黏附材料层及微丸外的肠溶包衣层[19], 相比于IPX066和IR-CD/LD, 这种设计使IPX203在给药后易于被黏附滞留在小肠上部并以既定速率释放药物, LD血浆浓度更高且维持时间更长, 在药效上, 患者“ON”期显著延长, 有利于患者运动症状的改善[20, 21]。
缓释胶囊的优点在于其可设计并调节药物释放的速率, 将速释颗粒与缓释包衣微丸相结合, 维持稳定的LD血浆浓度, 且适用范围广、便于携带, 但和普通胶囊一样, 不适用于存在吞咽困难问题的患者。
1.2 卡左双多巴渗透泵片(WD-1603)
当前已上市的渗透泵制剂较少, 并且载药量较低, 最高约100 mg, 而PD患者所需LD剂量从250~6 000 mg不等, 已有的前3代渗透泵技术限制了LD渗透泵制剂的发展。
目前, 上海汉都医药研究出一种“高载量高通量”第4代渗透泵技术, 并以此技术研制出了全球首个卡左双多巴渗透泵片(WD-1603), 用于PD早中期的治疗。该渗透泵片由渗透助推层、高载药量含药层、释药孔、高通量控释包衣层及含药速释外包衣层构成。其中外包衣层含有处方中25%的LD、处方中100%的CD和羟丙基纤维素及其他矫味剂, 形成一种速释组合物; 控释包衣层中含有醋酸纤维膜和高比例水溶性的流量促进剂共聚维酮, 便于水渗透进入助推层和高剂量药物的释放[22]; 渗透助推层主要包括渗透剂、亲水聚合物和黏合剂, 便于吸水后将处方中75%的LD缓慢推出。给药后, 该制剂被可个性化定制的滞留平台固定在口腔中, 外包衣层快速释放药物, 随后控释层维持药物释放数小时并经上消化道持续吸收[23], 弥补了普通卡左双多巴片剂释药速度较快, 容易引发不良反应的缺陷, 同时, 解决了前3代渗透泵技术载药量低的不足, 具有良好的应用前景。
WD-1603的临床Ⅱ期研究已经顺利完成, 该研究设置低、中、高剂量及安慰剂4个治疗组, 结果表明, WD-1603不同剂量组的血药浓度波动指数均低于已上市制剂, LD浓度较为平稳, 且患者的统一帕金森病评定量表(unified Parkinson's disease rating scale, UPDRS) 第Ⅱ和Ⅲ部分评分与基线相比显著降低。
此外, 汉都医药尚有处于临床Ⅰ期的WD-1804 (卡左双多巴片/左旋多巴口腔控释片) 和处于临床Ⅱ期的WD-1905 (卡左双多巴控释片-夜片) 两条研发管线, 分别用于PD晚期治疗和患者晨僵现象的缓解, 相关产品从尚未满足的临床用药需求出发, 有望进一步改善帕金森患者的生活质量。
2 提高口服左旋多巴生物利用度
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LD口服后在消化道上部吸收, 但生物利用度较低, 仅约40%, 其原因主要在于胃排空、胃液成分与pH、食物等因素均会对LD的吸收率产生较大影响, 而PD患者常常伴有胃排空减慢、胃轻瘫、便秘等不利于LD吸收的症状[24]。因此, 有必要通过改剂型等方式对LD进行制剂改良, 以增加LD在胃肠道的滞留时间, 提高其生物利用度。
胃滞留技术是解决上述问题的一种很有前景的方法, 其中手风琴药丸(Accordion Pill, AP) 是由以色列Intec Pharma公司开发的一种可延长药物在胃内滞留时间的药物递送平台, 该平台通过对制剂结构进行构建, 将药物保留在消化道上部, 使其定时定位释放, 从而延长药物滞留时间, 使药物实现持续稳定的胃肠道吸收, 并且该技术能够提高药物的表观溶解度, 避免难溶性药物的析出, 适用于吸收窗窄、治疗窗窄或溶解度低的药物(BCS Ⅱ类或BCS Ⅳ类)。
以LD为例, 由于LD胃肠道吸收不稳定, 且吸收部位局限, 因此可利用该技术制备CD/LD手风琴药丸胶囊(AP 09004, AP-CD/LD), 其内部含有折叠似手风琴的波浪形多层生物可降解聚合物膜, 该膜由控制药物释放速率的控释层、载有LD和CD的含药层及便于在胃内充分展开且防止被排空的支撑层构成, 并且可根据需要设计单层或多层聚合物膜及膜的结构、形状和力学性能。如图 1所示, AP-CD/LD胶囊经口服后, 胶囊壳在胃部溶解, 膜结构在支撑材料的作用下逐渐展开, 在渗透压与溶蚀双重作用下, 药物通过外膜膜孔于上消化道缓慢释放, 胃滞留时间可达12 h[25]。
AP-CD/LD胶囊具有较好的生物相容性、释药速率可控性及胃部可滞留性, 与传统的IR-CD/LD胶囊相比, AP-CD/LD使LD吸收段显著延长[26], 受胃排空及食物等因素影响较小, 且血浆浓度更为稳定, 峰浓度降低了约60%, 在PD治疗中表现出一定的潜力。
遗憾的是, AP-CD/LD未能显著降低患者的“OFF”期时间, 其Ⅲ期临床未达到主要临床终点。
3 克服长期服用左旋多巴产生的剂末效应
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在PD患者治疗早期, LD的少量服用就可使患者的震颤、僵直、运动迟缓等症状有明显改善, 患者的生活质量相对较高, 这一段时期常被称为PD治疗的“蜜月期”。但随着PD病程的发展和LD的长期使用, 会出现剂末效应等现象[27, 28]。出现这种现象的原因之一是LD在胃肠道吸收不稳定、吸收部位较为局限、半衰期较短, 使得血药浓度不稳定, 对纹状体中的DA受体产生了非生理性的脉冲样刺激, 导致疗效下降。而大量临床研究表明, 持续多巴胺能刺激可以降低或延迟运动并发症的发生, 是PD治疗的核心理念[29]。因此, 实现持续高效的药物肠道吸收以使血药浓度平稳并克服剂末效应是研究者们不断追求的重要目标。
Duopa是由AbbVie公司研发的CD/LD肠凝胶(levodopa/carbidopa intestinal gel, LCIG), 于2015年在FDA获批上市, 用于PD晚期患者的治疗。该制剂在给药前是一种以羧甲基纤维素为基质制备的混悬液, 含20 mg·mL-1 LD和4.63 mg·mL-1 CD。给药时须将经皮PEG导管连接到便携式输液泵上, 经患者胃部将药物凝胶混悬液持续输送至空肠近端, 在该部位形成原位凝胶, 并控制药物缓慢释放约16 h。
与口服LD相比, LCIG的输送流速和给药剂量可以灵活调节, 从而实现个性化、持续、平稳给药, 并且这种借助胃造瘘术的给药方式可避免胃排空、胃液、酶等对LD吸收的影响, 延缓剂末效应, 使UPDRS运动评分显著降低[30]。
但是Duopa的贮存条件及稳定性、悬浮液粒径与黏度、降解杂质和溶出度会影响制剂质量, 在生产过程中需要严格控制。并且由于该制剂采用特殊的肠内输液系统, 需要进行外科手术, 容易导致给药不便、创口感染、器械脱位等问题, 因此医生应结合患者病情进展考虑是否需要采用该方式进行治疗。
4 提升左旋多巴起效速度
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口服LD会与其他中性氨基酸竞争胃肠道及血脑屏障转运载体, 且PD患者大多伴随胃肠道症状, 这些因素导致LD体内有效浓度较低, 因此可将LD制备成吸入型粉雾剂, 从而绕过胃肠道使药物直达肺部, 吸收起效更快[31], 有利于快速缓解PD患者的“OFF”期症状。
Inbrija (CVT-301) 是Acorda Therapeutics公司基于其创新的ARCUS技术平台研发的一款LD吸入粉雾剂, FDA于2018年批准其用于接受CD/LD治疗的“OFF”期间歇性治疗。Inbrija的主要辅料为二棕榈酰磷脂酰胆碱和氯化钠, 利用ARCUS平台的喷雾干燥技术制备出低密度、易于分散的微粉化药物与载体, 并将其贮存在胶囊中, 每个胶囊内含42 mg的LD。患者通过呼吸驱动的干粉吸入装置自行给药, 研究表明, 干粉的空气动力学直径约3 μm, 可到达肺部更深处并快速吸收, 从而避免了肝首过效应, 且以胶囊形式作为LD贮库, 使给药剂量更为准确。
在Lipp等[32]的研究中, CVT-301组峰浓度和前10 min内的血药浓度-时间曲线下面积要远大于相同剂量下的口服LD组, 且CVT-301组的健康志愿者LD血浆浓度都要比口服LD组增长更快, 表明CVT-301吸收更迅速。在给药后30 min内, CVT-301组使处于“OFF”期的PD患者的UPDRS运动评分较安慰剂组显著改善[33], 在60 min后患者仍能保持“ON”状态, 且经52周长期CVT-301治疗后, 依然有与短期药效研究一致的结果, 有利于PD患者“OFF”期发作症状的治疗。
由此可见, LD吸入剂有助于产生快速的治疗效果, 且患者可自行用药, 使用方便, 是一种可用于及时缓解PD患者“OFF”期发作的优良给药方案。
5 开发长效制剂, 降低给药频率
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PD是一种老年慢性疾病, 病程较长, 需要长期服药以控制运动症状。但LD存在半衰期短、需要多次服药、容易多服漏服错服、长期服用易导致运动障碍、对脑内DA受体产生脉冲样多巴胺能刺激等缺点。而多巴胺受体激动剂具有相对较长的半衰期, 可直接作用于DA受体且产生持续性多巴胺能刺激, 因此开发多巴胺受体激动剂长效缓释制剂不仅可以降低服药频率, 改善患者顺应性, 而且有助于延迟LD的应用, 对LD导致的异动症也有治疗作用。
当前国内外已上市的PD治疗用缓释制剂种类比较少(表 2), 且大多是LD类药物缓释片、缓释胶囊。此外尚有一些其他新型缓释制剂正在研发中, 如罗匹尼罗贴剂、雷沙吉兰贴剂、罗替戈汀注射用微球等。
注射用微球近年来发展非常迅速, 该制剂是一种粒径范围在1~300 μm, 溶解或分散于高分子材料中经固化而形成的微小球体, 具有生物相容性好、可长期缓慢释药等优势, 尤其适用于PD这种需要患者长期不间断服药以改善症状的疾病治疗。
以罗替戈汀为例, 罗替戈汀是一种非麦角类多巴胺受体激动剂, 可选择性作用于D1/D2/D3受体以发挥疗效[34]。罗替戈汀的log P值为4.03, 具有较好的脂溶性[35]。此外, 罗替戈汀经大鼠口服后, 在胃肠道代谢迅速, 最终从门静脉进入肝脏的药量仅约1%[36], 首过效应明显, 导致其生物利用度很低。
基于以上因素, 罗替戈汀更适合经非胃肠道途径给药。Neupro贴剂是罗替戈汀目前唯一上市的制剂, 每日1片, 降低了PD患者的用药频率[37]。Neupro已被证明具有较好的缓释作用, 但其存在局部刺激、个体吸收差异大等问题, 且每日1次, 贴敷不便。针对上述不足, 山东绿叶制药集团研发了一款以聚乳酸-羟基乙酸共聚物[poly(lactic-co-glycolic acid), PLGA] 为载体的注射用罗替戈汀长效缓释微球(LY03003), 通过调节高分子材料的组成及处方比例可以控制微球的载药量、包封率、粒径及粒径分布, 并降低药物突释效应。罗替戈汀缓释微球的制剂规格包括每支14、28、42和56 mg, 每周肌肉注射1次, 适用于胃肠道功能紊乱、吞咽困难、记忆功能减退的PD患者。LY03003在中国的Ⅲ期临床试验已顺利达到预设终点, 结果表明, LY03003能显著降低UPDRS运动评分, 给药周期长, 将给药频率从每日1次降低到每周1次, 能极大地提高患者用药依从性。
但微球容易存在突释现象, 究其原因可能为微球表面药物快速溶解、药物分布不均、内部孔道疏松导致药物快速释放, 针对上述问题, 可通过优化制备工艺、调整或更换聚合物材料、加入添加剂等措施解决。
由于微球等长效制剂技术门槛较高, 具有较为特殊的制备工艺, 因此不易被仿制, 产品生命周期较长, 可持续占有市场份额。所以开发用于PD治疗的长效制剂, 包括微球、脂质体、纳米粒、可注射原位凝胶、注射用混悬液、植入剂等, 不仅临床优势突出, 利于PD患者用药顺应性的提高, 而且可以带动老药新用的研发趋势, 发挥出药物的最佳疗效, 并延长产品的市场生命周期。
6 总结和展望
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目前PD是一种无法逆转或治愈的慢性疾病, LD是经典的治疗药物, 为降低其外周代谢, 常与酶抑制剂(如CD、苄丝肼) 联用制备成复方片剂或胶囊, 第一代CD/LD制剂释药速度较快, 且LD生物利用度很低, 而IPX066、WD-1603这类缓释胶囊或渗透泵片的研发实现了LD口服后缓控释释药, 并有研究通过胃滞留技术增加LD胃肠道吸收, 提高LD生物利用度。
尽管口服LD存在方便给药、易于携带的优点, 但吞咽困难、给药频率高、易产生间歇性多巴胺能刺激, 因此持续输送LD是一种同样具有临床价值的给药方式, 如CD/LD肠凝胶、长效制剂等, 可使血药浓度稳定并缓解剂末效应; 口服LD起效较慢, 对处于“OFF”期且运动障碍的患者, 吸入给药更具优势。
每一类剂型都有其优缺点, 新制剂的研发也并不意味着已有制剂的淘汰, 而是为了解决当前制剂在临床应用中的某些问题, 为处于不同PD病程的患者提供最佳的治疗方式。因此制剂改良的总原则应是从临床需求出发, 提高安全性、有效性或顺应性, 如采用更改剂型、给药途径等方式, 提高LD等药物的生物利用度、延缓剂末效应、缓解“OFF”期运动障碍或降低给药频次, 提高患者用药依从性。随着研究者们不断的探索和相关靶点的发现, 及国家改良型新药相关政策法规的完善, 将有更多的新药出现, 为PD治疗带来曙光。
作者贡献: 何梦娇、肖伊芳、孔祥安妮、刘智昊负责文献检索及文稿撰写; 王孝广、冯浩、涂家生、孙春萌负责修改及审核文章; 陈芊、孙春萌负责文章选题与写作思路的指导。
利益冲突: 本文所有作者声明不存在利益冲突关系。
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2024年第59卷第3期
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doi: 10.16438/j.0513-4870.2023-0972
  • 接收时间：2023-08-15
  • 首发时间：2025-11-28
  • 出版时间：2024-03-12
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  • 收稿日期：2023-08-15
  • 修回日期：2024-01-09
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作者信息
    1.国家药品监督管理局药物制剂及辅料研究与评价重点实验室, 中国药科大学药学院, 江苏 南京 210009
    2.南京兰铭生物医疗科技有限公司, 江苏 南京 210028

通讯作者:

*陈芊, Tel: 15298366219, E-mail:
孙春萌, Tel: 86-25-83271305, E-mail:
参考文献
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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2023-0972
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2种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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