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Article(id=1218263313499210541, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263312425468717, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2016-0953, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1474992000000, receivedDateStr=2016-09-28, revisedDate=1480348800000, revisedDateStr=2016-11-29, acceptedDate=null, acceptedDateStr=null, onlineDate=1768386208176, onlineDateStr=2026-01-14, pubDate=1486828800000, pubDateStr=2017-02-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1768386208176, onlineIssueDateStr=2026-01-14, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1768386208176, creator=13701087609, updateTime=1768386208176, updator=13701087609, issue=Issue{id=1218263312425468717, tenantId=1146029695717560320, journalId=1189982191388893191, year='2017', volume='52', issue='2', pageStart='181', pageEnd='338', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1768386207920, creator=13701087609, updateTime=1768386467475, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1218264401140962014, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263312425468717, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1218264401140962015, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1218263312425468717, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=181, endPage=188, ext={EN=ArticleExt(id=1218263313901863732, articleId=1218263313499210541, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=The progress of novel drug delivery systems, columnId=1190335349059588909, journalTitle=Acta Pharmaceutica Sinica, columnName=PROFESSIONALS FORUM, runingTitle=null, highlight=null, articleAbstract=

The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.

, correspAuthors=Xin-guo JIANG, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2017 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=Hui-le GAO, Xin-guo JIANG), CN=ArticleExt(id=1218263314182882102, articleId=1218263313499210541, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=新型药物递释系统的研究进展, columnId=1190335349206389552, journalTitle=药学学报, columnName=专家论坛, runingTitle=null, highlight=null, articleAbstract=

新型药物递释系统对提高药物的治疗效果、降低毒副反应具有重要作用，是药剂学领域的重要研究方向，目前已有诸多新型递药系统上市或正在研发中。根据其性质主要可以分为速效递药系统、长效递药系统和高效递药系统。本文拟对目前热点关注的新型递药系统进行综述，并对其中存在的问题进行分析和讨论。

, correspAuthors=蒋新国, authorNote=null, correspAuthorsNote=
* 蒋新国, Tel:86-21-51980067, E-mail:
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Nanopharmaceuticals (part 1):products on the market[J]. Int J Nanomedicine, 2014, 9:4357-4373., articleTitle=null, refAbstract=null), Reference(id=1218968399556825948, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=[32], rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Ruan S, Yuan M, Zhang L, et al. Tumor microenvironment sensitive doxorubicin delivery and release to glioma using angiopep-2 decorated gold nanoparticles[J]. 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Trade name Active drug Indication Company Time-to-market
Feldene fast melt Piroxicam Rheumatoid arthritis Pfizer Inc. 1993
Pepcid RPD Famotidine Enterelcosis, gastrohelcosis Merck 1998
Zofran ODT Ondansetron Chemotherapy and radiotherapy caused nausea and vomiting Glaxo Wellcome 1999
Maxalt MLT Rizatriptan Migraine Merck 1998
Zelapar Selegiline Parkinson’s disease Valeant Pharmaceuticals 2005
Imodium (instant melts) Loperamide hydrochloride Diarrhea Janssen 2008
Klonopin wafers Clonazepam Epilepsy Solvay Pharmaceutical 2003
Zyprexa ZYDIS Olanzapine Schizophrenia, bipolar depression Lilly 2000
--- Nisoldipine Primary hypertension Jiangxi Herbisky 2014
Kangershuning Nisoldipine Bronchial asthma Chongqing Conquer 2015
Yilian Enalapril maleate Hypertension Qingdao Guohai 2013
Youheng Nimesulide Chronic arthritis NCPC 2013
Weiboan Glimepiride Diabetes Wuhan Weihao 2013
), ArticleFig(id=1218968391797362997, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, language=CN, label=Table 1, caption=

Clinical available orally disintegrating tablets

, figureFileSmall=null, figureFileBig=null, tableContent=
Trade name Active drug Indication Company Time-to-market
Feldene fast melt Piroxicam Rheumatoid arthritis Pfizer Inc. 1993
Pepcid RPD Famotidine Enterelcosis, gastrohelcosis Merck 1998
Zofran ODT Ondansetron Chemotherapy and radiotherapy caused nausea and vomiting Glaxo Wellcome 1999
Maxalt MLT Rizatriptan Migraine Merck 1998
Zelapar Selegiline Parkinson’s disease Valeant Pharmaceuticals 2005
Imodium (instant melts) Loperamide hydrochloride Diarrhea Janssen 2008
Klonopin wafers Clonazepam Epilepsy Solvay Pharmaceutical 2003
Zyprexa ZYDIS Olanzapine Schizophrenia, bipolar depression Lilly 2000
--- Nisoldipine Primary hypertension Jiangxi Herbisky 2014
Kangershuning Nisoldipine Bronchial asthma Chongqing Conquer 2015
Yilian Enalapril maleate Hypertension Qingdao Guohai 2013
Youheng Nimesulide Chronic arthritis NCPC 2013
Weiboan Glimepiride Diabetes Wuhan Weihao 2013
), ArticleFig(id=1218968391898026309, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Trade name Active drug Formulation Indication Company Time-to-market
Emend Aprepitant Capsule Antiemetics Merck 2003
Rapamune Sirolimus Tablet Immunosuppression Pfizer 2000
TriCor Fenofibrate Tablet Hypercholesterolemia Abbott Laboratories 2001
Megace ES Megestrol Suspension Antianorexia, cachexia Par Phamaceutical Inc 2005
Triglide Fenofibrate Tablet Hypercholesterolemia First Horizon Pharmaceutical 2005
Gris-PEG Griseofulvin Tablet Mycotic infection Novartis 1975
Cesamet Nabilone Capsule Chemotherapy caused nausea and vomitting Lilly 2006
), ArticleFig(id=1218968392007078228, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, language=CN, label=Table 2, caption=

Clinical available nanocrystals

, figureFileSmall=null, figureFileBig=null, tableContent=
Trade name Active drug Formulation Indication Company Time-to-market
Emend Aprepitant Capsule Antiemetics Merck 2003
Rapamune Sirolimus Tablet Immunosuppression Pfizer 2000
TriCor Fenofibrate Tablet Hypercholesterolemia Abbott Laboratories 2001
Megace ES Megestrol Suspension Antianorexia, cachexia Par Phamaceutical Inc 2005
Triglide Fenofibrate Tablet Hypercholesterolemia First Horizon Pharmaceutical 2005
Gris-PEG Griseofulvin Tablet Mycotic infection Novartis 1975
Cesamet Nabilone Capsule Chemotherapy caused nausea and vomitting Lilly 2006
), ArticleFig(id=1218968392128713058, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Drug delivery system Drug/trade name Indication Company Time-to-market
Liposomes Amphotericin B/AmBisome Fungal infection Gilead 1990
Liposomes Daunorubicin/DaunoXome Kaposi’s sarcoma Gilead 1996
Liposomes Influenza virus antigen/Inflexal V Influenza Crucell 1997
Liposomes Cytarabine/DepoCyt Central nervous system leukemia Skye Pharma 1999
Liposomes Doxorubicin/Doxil Ovarian cancer, breast cancer ALZA 1999
Liposomes Doxorubicin/Myocet Breast cancer Teva 2000
Liposomes Verteprofin/Visudyne Wet age-related macular degeneration QLT 2000
Liposomes Amphotericin B/FengKeSong Fungal infection New Asia Pharmacuetical 2003
Liposomes Morphine sulfate/DepoDur Pain Skye Pharma 2004
Liposomes Mifamurtide/Mepact Osteosarcoma IDM 2009
Liposomes Paclitaxel/LiPuSu Breast cancer Luye Pharma 2010
Liposomes Doxorubicin Ovarian cancer, breast cancer Fudan Zhangjiang 2011
Liposomes Vincristine/Marqibo Acute lymphatic leukemia Talon Therapeutics 2012
Liposomes Irinotecan/Onivyde MM-398 Metastatic prostatic cancer Merrimack 2015
PLGA nanoparticls Leuproprelin/Eligard Prostatic cancer Atrix Laboratories 2002
Albumin nanoparticles Paclitaxel/Abraxane Breast cancer AM Bio Science 2005
Solid lipid nanoparticles Paclitaxel/Opaxio Glioblastoma Cell Therapeutics 2012
Polymer micelle Paclitaxel/Genexol Breast cancer, lung cancer Samyang Biopharmaceuticals 2006
), ArticleFig(id=1218968392233570673, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1218263313499210541, language=CN, label=Table 3, caption=

Clinical available passive targeting nanomedicines

, figureFileSmall=null, figureFileBig=null, tableContent=
Drug delivery system Drug/trade name Indication Company Time-to-market
Liposomes Amphotericin B/AmBisome Fungal infection Gilead 1990
Liposomes Daunorubicin/DaunoXome Kaposi’s sarcoma Gilead 1996
Liposomes Influenza virus antigen/Inflexal V Influenza Crucell 1997
Liposomes Cytarabine/DepoCyt Central nervous system leukemia Skye Pharma 1999
Liposomes Doxorubicin/Doxil Ovarian cancer, breast cancer ALZA 1999
Liposomes Doxorubicin/Myocet Breast cancer Teva 2000
Liposomes Verteprofin/Visudyne Wet age-related macular degeneration QLT 2000
Liposomes Amphotericin B/FengKeSong Fungal infection New Asia Pharmacuetical 2003
Liposomes Morphine sulfate/DepoDur Pain Skye Pharma 2004
Liposomes Mifamurtide/Mepact Osteosarcoma IDM 2009
Liposomes Paclitaxel/LiPuSu Breast cancer Luye Pharma 2010
Liposomes Doxorubicin Ovarian cancer, breast cancer Fudan Zhangjiang 2011
Liposomes Vincristine/Marqibo Acute lymphatic leukemia Talon Therapeutics 2012
Liposomes Irinotecan/Onivyde MM-398 Metastatic prostatic cancer Merrimack 2015
PLGA nanoparticls Leuproprelin/Eligard Prostatic cancer Atrix Laboratories 2002
Albumin nanoparticles Paclitaxel/Abraxane Breast cancer AM Bio Science 2005
Solid lipid nanoparticles Paclitaxel/Opaxio Glioblastoma Cell Therapeutics 2012
Polymer micelle Paclitaxel/Genexol Breast cancer, lung cancer Samyang Biopharmaceuticals 2006
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新型药物递释系统的研究进展
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高会乐 1 , 蒋新国 2, *
药学学报 | 专家论坛 2017,52(2): 181-188
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药学学报 | 专家论坛 2017, 52(2): 181-188
新型药物递释系统的研究进展
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高会乐1, 蒋新国2, *
作者信息
  • 1.四川大学华西药学院, 靶向药物与传递系统教育部重点实验室, 四川 成都 610041
  • 2.复旦大学药学院, 智能化递药教育部重点实验室, 上海 201203

通讯作者:

* 蒋新国, Tel:86-21-51980067, E-mail:
The progress of novel drug delivery systems
Hui-le GAO1, Xin-guo JIANG2, *
Affiliations
  • 1. Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
  • 2. Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China
出版时间: 2017-02-12 doi: 10.16438/j.0513-4870.2016-0953
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摘要
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新型药物递释系统对提高药物的治疗效果、降低毒副反应具有重要作用，是药剂学领域的重要研究方向，目前已有诸多新型递药系统上市或正在研发中。根据其性质主要可以分为速效递药系统、长效递药系统和高效递药系统。本文拟对目前热点关注的新型递药系统进行综述，并对其中存在的问题进行分析和讨论。

药物递释系统  /  药物释放  /  药物靶向  /  药物载体  /  难溶性药物  /  生物药物  /  靶向递药系统

The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.

drug delivery system  /  drug release  /  drug targeting  /  drug carrier  /  insoluble drug  /  biopharmaceutics  /  targeting drug delivery system
高会乐, 蒋新国. 新型药物递释系统的研究进展. 药学学报, 2017 , 52 (2) : 181 -188 . DOI: 10.16438/j.0513-4870.2016-0953
Hui-le GAO, Xin-guo JIANG. The progress of novel drug delivery systems[J]. Acta Pharmaceutica Sinica, 2017 , 52 (2) : 181 -188 . DOI: 10.16438/j.0513-4870.2016-0953
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随着越来越多的药物被发现, 新型化学实体药物的研发难度逐年加大, 研发周期和成本逐年上升。许多新发现的小分子化学实体药物属于生物药剂学分类系统(biopharmaceutical classification system, BCS) Ⅱ或Ⅳ类, 其溶解性或膜穿透性差、生物利用度低, 很大程度上影响其成药性; 而生物药物(如蛋白、多肽和核酸等)则存在体内外稳定性差、应用困难等问题。新型药物递释系统的研发有助于克服药物自身的问题, 提高溶解度、稳定性和靶向性; 相对而言, 其研发周期短, 投入低, 且具有一定的普适性。医学、药学、材料科学等学科的快速发展以及人民生活水平的不断提高, 传统药物制剂难以满足高效化、个性化的用药需求, 新型药物递释系统得到广泛关注, 成为药物研发领域的热点, 并有多种新型递药系统上市。
新型药物递释系统可以在不改变药物化学结构的前提下, 通过递药系统的合理选择和设计, 提高药物的治疗效果, 降低毒副作用, 改善用药的顺应性, 具有很高的临床意义和发展前景。根据药效特点主要分为速效递药系统、长效递药系统和高效递药系统。
1 速效递药系统
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普通药物制剂如片剂、胶囊口服后起效较慢, 无法满足一些疾病的急性发作, 由此, 研究者研发了速效递药系统, 代表性的如某些口腔崩解片(orally disintegrating tablets)和鼻喷剂(nasal spray)等。
口腔崩解片依靠口腔中的少许唾液即可迅速崩解, 进而吸收, 达到快速发挥疗效的目的, 适用于心绞痛、哮喘和偏头痛的急性发作; 不需整片吞咽, 适于吞咽困难的患者、老人和儿童使用, 顺应性良好[1]。理想的口腔崩解片应具有以下特点:无需水、进入口腔后几秒钟即可分散、较高的载药量、适宜的口感。然而, 口腔崩解片的制备也面临很多挑战, 如片剂本身的强度需要足够大、分散非常快、能够遮掩药物本身的味道。为了满足这些要求, 研究者开发了多种技术, 如Orasolv®、Durasolv®、Wowtab®、Flashtab®、Zydis®、Flashdose®、Oraquick®、Lyoc®、Advatab®、Frosta®、Quick-Disc®和Nanomelt®等[2]。利用这些技术, 已有多种药物上市(表 1), 目前国家食品药品监督管理总局(CFDA)受理了31项相关药品, 正在进行各期临床试验[3], 更值得一提的是口腔崩解片已被载入2015年版中国药典, 如利培酮口腔崩解片。
鼻喷剂主要指通过鼻黏膜吸收发挥全身性治疗作用的制剂。鼻腔的黏膜层较薄, 黏膜下毛细血管和淋巴管丰富, 吸收迅速、完全; 鼻黏膜吸收后直接入血, 能够避免肝首过效应, 从而提高某些药物的生物利用度。由于鼻腔具有鼻脑通路, 部分药物可经嗅黏膜、三叉神经吸收直接入脑, 适用于脑部疾病和神经系统疾病的治疗[4-6]。吸毒是美国的重大社会问题, 2010年海洛因/阿片类药物滥用导致的死亡人数比1999年升高了4倍, 达到16 651人[7]。纳洛酮作为阿片受体拮抗剂, 长期用于逆转阿片类药物滥用导致的症状, 具有明确的效果[8]。然而纳洛酮注射剂的应用不便, 易引起继发性感染, 难以满足突发急症尤其是非医疗部门的应用[9]。鉴于鼻喷剂迅速起效的优势, 美国FDA于2015年11月18日通过快速通道4个月即批准纳洛酮鼻喷剂用于救治阿片类药物中毒, 使其成为世界上第1个非注射的纳洛酮制剂。纳洛酮鼻喷剂给药后2.5 min即可在血液中检出, 20 min后血药浓度达到峰值, 与肌注的起效时间相近[9]。在急性偏头痛患者的临床研究中, 相比安慰剂, 佐米曲普坦鼻喷剂具有良好的耐受性, 给药后2~5 min即可在血液中检测到药物, 15 min后大多数患者的疼痛消失, 且在随后更长时间点达到无疼痛期的患者比例显著提高[10, 11]。但由于鼻纤毛的清除作用, 药物在鼻腔的滞留半衰期仅30 min, 一定程度上影响了药物的吸收; 而很多药物或辅料都存在不同程度的纤毛毒性; 且鼻腔体积较小, 因此只适合于低剂量药物使用[12]。此外, 鼻喷剂给药的个体差异很大, 因此不适于治疗窗窄的药物。
2 长效递药系统
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某些药物的生物半衰期短, 血药浓度存在明显的峰谷现象。而制备长效递药系统可使药物缓慢、持续甚至智能化释放, 能够保持血药浓度平稳, 延长药物作用时间, 减少药物毒性并提高患者顺应性。目前应用的长效递药系统主要为口服缓控释系统(oral controlled release drug delivery systems, OCRDDS)、脉冲释药系统(pulsatile drug delivery system, PDDS)和经皮递药系统(transdermal drug delivery system, TDDDS)等。
口服缓控释系统能够缓慢甚至接近恒速释放药物, 从而避免药物浓度波动、延长作用时间。目前缓控释系统的发展已经比较成熟, 根据其作用机制可分为骨架型缓控释制剂、膜控型缓控释制剂和渗透泵型缓控释制剂等。关于此类制剂的释药原理及应用已经多有介绍, 本文不再赘述。
某些疾病的发病呈明显的时间节律性和周期性, 如哮喘容易在深夜发作, 心绞痛容易在凌晨发作。为满足这些疾病的用药需求, 研究者开发了脉冲释药系统, 即在给药一定时间后, 能够单次或多次以脉冲的形式快速释药。脉冲释药系统主要依靠两种机制, 一种为外界因素刺激, 包括生物化学信号刺激和物理信号刺激; 另一种为依靠制剂本身触发, 如体系溶蚀或膨胀爆破后释药[13]。该原理主要依靠制剂本身设定的程序, 在口服后随着水分的接触, 控制释药的脉冲塞不断膨胀或溶蚀, 一定时间后涨破制剂外膜或冲开脉冲塞而释放药物。该类系统原理简单, 应用较广。如人体胆固醇合成具有明显的昼夜节律性, 在深夜和凌晨较高。辛伐他汀能抑制羟甲基戊二酰辅酶A还原酶(hydroxymethylglutaryl coenzyme A reductase)的活性, 从而抑制胆固醇合成。Taha EI将其制备为脉冲释药系统, 与上市片剂Zocor相比, 药物吸收的时间显著延后, 并且口服后3~10 h的血药浓度显著提高[14]。
经皮递药系统是指药物通过皮肤经由毛细血管吸收进入体循环起到全身治疗作用的一类制剂。与传统递药系统相比, 经皮递药系统有其独特的优势:避免药物口服后肝脏和胃肠道的首过效应; 可以缓慢释放药物, 防止药物吸收过快而造成过高的血药浓度, 既能维持较长时间的疗效, 又可减少不良反应的发生等。尽管如此, 经皮递药系统必须使药物有效透过皮肤进入血液方能发挥药效。目前研究者已开发出多种新型促进皮肤渗透的方法, 如将离子型药物制备为渗透性更好的离子对复合物; 采用微晶磨皮去除角质层; 采用微针技术直接透过角质层和皮肤; 采用无针高速注射技术; 采用纳米技术改善药物和皮肤的渗透性[15]。经皮递药系统不仅能够缓释药物, 而且通过设计还可赋予其响应性释放特性, 如将微针系统头部的储药库设计为包含葡萄糖酶和胰岛素的小室, 小室的外壳由缺氧环境敏感的透明质酸交联物构成[16]。当血液中葡萄糖浓度升高时, 葡萄糖酶氧化葡萄糖并消耗氧, 使得局部成为缺氧环境, 导致透明质酸交联物被还原而去交联, 从而释放胰岛素。当葡萄糖浓度降低时, 葡萄糖酶需氧量下降, 使得局部含氧量上升, 透明质酸被氧化而交联, 从而抑制胰岛素释放。通过改变微针的材料还可以赋予其他响应特性, 如将微针填充具有光热转换能力的LaB6@SiO2纳米结构并将药物储库用热敏材料制备, 当红外线照射时LaB6@SiO2吸收光能将其转变为热能, 使得药物储库融化而释药[17]。这些新材料虽然赋予递药系统良好的性质, 但其生物安全性仍需进一步考察。
3 高效递药系统
收起
3.1 难溶性药物递药系统
难溶性药物是制剂学一大挑战。生物药剂学分类系统Ⅱ药物由于溶解度差, 口服后在胃肠道溶出较慢, 易受食物的影响, 生物利用度低, 而溶解度较差难以制备为注射液。目前上市药物中约40%溶解性很差, 而研发中的活性分子更是约90%水溶性很差[18]。采用表面活性剂增溶是药剂学最常用的方法, 如紫杉醇注射液采用聚氧乙烯蓖麻油(Cremorphor CL)为增溶剂, 多西紫杉醇采用Tween 80为增溶剂。但是表面活性剂的应用普遍增加药物制剂的毒副作用, 如Cremophor EL会产生高脂血症、红细胞聚集和周围神经系统伤害等不良反应[19]。因此研究者将目光转向采用药剂学手段改善药物的溶解性, 提高活性分子的成药性。目前的研究策略主要分为三类: ①采用离子对、两亲性材料等增加溶解度; ②采用纳米粉碎、纳米结晶等方式改变药物的物理状态; ③采用纳米载体包载药物[20]。
据统计约70%药物能够电离, 且多数为弱碱性, 将分子型药物制备为离子型或盐的形式可以一定程度改善药物的溶解度, 如拉帕替尼磺酸盐。但有些药物的盐溶解度仍然很差, 因此有研究者开发了离子对技术和磷脂复合物技术, 即采用溶解度较好、且与药物带电荷相反的辅料与药物通过静电结合为离子对, 或将药物与溶解性较好的磷脂形成复合物, 从而改善药物自身的溶解度和口服生物利用度。如将姜黄素和磷脂一起形成磷脂复合物后, 在同样口服剂量(1.0 g·kg-1)下, 复合物的血浆最高浓度为单纯姜黄素口服的2.4倍[21]。该策略还可制备为纳米制剂, 从而进一步改善其生物利用度和治疗效果。如将石蒜碱与油酸形成离子对复合物后进一步制备成脂质纳米乳, 能有效提高其抗肿瘤效果[22]。
药物的物理形态会极大影响药物的溶解速度和程度。纳米尺度的微粒比表面积大, 且表面药物分子活跃, 因此将药物颗粒粉碎至纳米尺度, 或直接将其制备为纳米结晶, 能够有效改善其溶出效率, 从而提高其生物利用度, 并能有效降低食物对药物吸收的影响[23]。纳米晶体药物具有多种优点: ①不受包封率、载药量制约, 药物剂量范围宽; ②无需特殊的纳米材料, 利于新药研发; ③制备方法通用、简便, 易于工业化大生产。制备纳米晶体药物的方法主要分为由小到大(bottom-up)和由大到小(top-down)两种[24]。由小到大主要是通过控制结晶的方式, 药物溶液中加入药物的不良溶剂, 促使药物快速形成大量晶核, 进而形成尺度较小的纳米结晶。而由大到小则主要通过湿法研磨、高压均质和微射流等方式将较大颗粒的药物粉碎为较小颗粒。目前已有多种药物上市和正在研发中(表 2)。如盐酸瑞伐拉赞制备为纳米结晶后, 相比普通混悬液, 其药时曲线下面积(AUC)提高45%, 血浆最高浓度提高87%, 血药浓度达峰时间提前了185 min[25]。但是纳米颗粒静脉注射可能引起一定程度的免疫反应, 且纳米尺度物质在体内、细胞内的转运、毒性都具有特殊性, 因此需要深入系统的研究。
将难溶性药物包载于纳米载体而制备的纳米载体药物具有更大的通用性, 且随着纳米技术的不断完善、纳米材料的不断涌现, 纳米载体药物得到越来越多的关注, 并有越来越多的药品上市。一般而言, 可以将难溶性药物溶于适当有机溶剂中, 并与纳米材料混合后制备纳米载体药物。将有机溶剂除去后, 药物可以非结晶的形式包裹在纳米系统的疏水内腔或嵌在纳米材料的疏水结构之间。如Genexol为紫杉醇与聚乙二醇-聚乳酸(PEG-PLA)形成的纳米胶束, 紫杉醇包载于胶束的疏水内核中, 胶束外层的亲水性聚乙二醇则赋予纳米药物良好的水分散性。较含有Cremophor EL的紫杉醇注射液, Genexol的最大耐受剂量从230 mg·m2提高到390 mg·m2, 同时不良反应显著降低[26]。除物理包裹外, 也可将药物通过一定的化学键(如酯键、腙键等)偶联在纳米材料上, 形成的纳米药物可以在特定部位释放药物, 从而在解决其难溶性问题的同时赋予其控释能力。如紫杉醇固体脂质纳米粒Opaxio则将紫杉醇通过共价键连接在纳米材料上, 进入肿瘤内部, 依靠高表达的Cathepsin B使其断裂而释放药物[27]。
3.2 生物药物递送系统
生物药物包括多肽、蛋白质、抗体、疫苗与核酸等, 多用于治疗肿瘤、艾滋病、心脑血管疾病和神经退行性疾病等重大疾病。生物药物以其作用的高度专属性和多样性, 在重大疾病治疗中发挥极其重要的作用, 被全球公认为21世纪药物研发最具前景的高端领域之一。2014年全球十大畅销药物中, 生物药物占7个, 其全球年销售总额已超600亿美元。尽管生物药物具有显著优势, 但药效发挥的前提是递药系统能够将其高效递送至作用靶点; 同时生物药物的生物活性依赖于特定的三维结构、结晶等, 其体内外稳定性极差, 因此如何保持生物药物的活性并将其高效递送至靶细胞、靶细胞器是发挥药物作用的关键[28]。
生物药物递送系统(biopharmaceutical delivery system, BPDS)的研究重点可以分为两方面: ①提高体内外稳定性和生物利用度; ②提高靶向性。目前较为成熟的策略有两种:第一种策略是改变生物药物的序列, 从药物的氨基酸或核酸组成出发, 通过修饰等方法, 提高药物自身的稳定性和安全性。如制备人源化抗体, 目前上市的抗体药物多数为人源化抗体, 相比动物来源的抗体, 人源化抗体免疫原性小、安全性高。对生物药物进行化学修饰则能进一步提高其稳定性和生物利用度, 常用的方式包括PEG修饰、透明质酸修饰、唾液酸修饰、叶酸(Fc)配体融合及白蛋白化等, 如Enzon公司开发的用于治疗急性淋巴细胞白血病的PEG化门冬酰胺酶(Oncaspa)、罗氏公司开发的PEG化的α-干扰素-2a (Pegasys)。但是传统修饰的位点专一性差, 一定程度上影响其生物活性, 因此目前的重点是专一化修饰技术的开发[29]; 第二种策略为采用药物载体包裹的方式提高生物药物的稳定性和生物利用度。载体包裹能够在不影响生物药物本身结构的同时避免其与周围环境中的酶等接触, 并保持药物所在微环境的稳定, 从而维持其活性并提高生物利用度和药效。如生物相容性好、无毒和可降解的聚乳酸羟基乙酸(PLGA)已作为促黄体激素释放激素(LHPH)类似物、胰高血糖素样肽(GLPs)和人体生长激素(HGH)等蛋白多肽类药物的载体成功上市。而对于核酸类药物, 目前的研究重点集中在以高分子聚合物为主的非病毒载体[30]。相比病毒载体, 非病毒载体安全性更好, 但目前受限于可注射载体材料的缺乏和非病毒载体较低的转染效率, 上市基因药物仍采用病毒载体。
3.3 靶向递药系统
鉴于纳米药物普遍具有一定的靶向性, 在此重点阐述。多数药物需要进入特定部位、组织、细胞和细胞器, 或与特定靶点结合才能发挥其药理作用。然而普通药物制剂经口服、静脉注射等方式吸收入血后, 其体内分布受药物自身性质的极大影响, 难以专属性分布于特定靶部位。尤其是对于毒副作用较大的药物, 如抗肿瘤药物和抗感染药物等, 非选择性分布使其治疗窗窄, 疗效差。靶向递药系统(targeting drug delivery system, TDDS)可改变药物的体内行为, 依靠递药系统本身的性质, 将药物递送至特定靶部位, 从而达到增效减毒的作用。同时, 靶向递药系统还能提高药物透过组织屏障和跨细胞膜转运的能力, 甚至提高药物在特定细胞器的分布, 从而有效增强药物疗效。
目前的靶向递药系统以纳米载体为主, 即将药物包载于纳米载体内部或修饰于纳米载体表面, 依靠纳米载体的理化性质, 达到靶向的目的。一般而言, 靶向策略可以分为被动靶向和主动靶向。被动靶向系指依靠靶部位的生理、病理特点及纳米递药系统本身的性质, 使纳米递药系统能够有效蓄积在靶部位; 而主动靶向则是指依靠纳米系统表面的特定分子与靶部位的特定分子间、蛋白间的主动识别而结合, 达到靶组织、细胞选择性浓集药物的目的。如肿瘤和炎症部位均具有增强的渗透和滞留效应(enhanced permeability and retention effect, EPR), 因此具有一定尺度(一般粒径为几百纳米)的纳米递药系统则可被动分布并蓄积在肿瘤和炎症部位, 从而提高药物在该部位的浓度。
由于被动靶向策略对递药系统的要求较低, 因此得到广泛的研究和发展, 并已有多种药物上市(表 3)[31], 其中以脂质体为载体的纳米药物最多。此外尚有多种药物的白蛋白纳米粒在进行临床前及临床Ⅰ/Ⅱ期研究。
由于机体病灶的生理、病理特征具有较大的异质性, 被动靶向递药系统往往无法达到良好的靶向递药效果。鉴于此, 研究者设计了多种主动靶向递药系统, 通过靶向分子特异性识别病灶部位的特定靶点, 并介导细胞内吞, 从而有效提高递药系统的靶向性。
在基础研究领域, 主动靶向递药系统受到广泛关注, 研究者从多个方面入手提高递药系统的靶向性: ①筛选合适的靶向分子。通常研究者主要采用靶部位已知受体或转运体的天然配体作为靶向分子, 如转铁蛋白可以靶向肿瘤部位高表达的转铁蛋白受体。为避免内源性配体的干扰, 提高靶向分子的稳定性和靶向能力, 降低其免疫原性, 进一步采用多种技术, 如噬菌体展示技术和SELEX技术从多肽库和核酸库中筛选具有更好靶点特异性的分子。采用计算机辅助设计技术从已知配体蛋白出发设计分子量小、亲和性好的多肽; ②设计具有病灶微环境响应性的纳米系统。病灶部位往往具有特殊的微环境, 如肿瘤和炎症部位的pH较低, 血管微小血栓形成时血流的剪切力改变等。通过设计具有环境响应性的递药系统能使得递药系统更加智能地聚集在病灶部位, 并将药物专属性释放, 从而更好的达到增效、减毒的目的。
主动靶向递药系统的功能强大, 但制备也变得繁琐而难以规模化和产业化。截止目前, 尚无主动靶向递药系统被批准上市。随着相关技术的发展, 主动靶向递药系统正越来越多地进入临床研究, 如谷胱甘肽修饰的脂质体被用来主动靶向脑部, 转铁蛋白修饰的脂质体则被用于肿瘤靶向递药。
为了进一步降低药物的药源性毒副作用并提高治疗效果, 开发了病变组织定位释放递药系统(on-demand release drug delivery system, ORDDS), 即该递药系统能在血液循环中携带药物, 进入病变组织后特异性释放药物, 从而提高药物在病变部位的浓度, 降低药物在正常组织的分布。病变部位定位释放一般依靠病变部位的特殊生理病理特征, 如多种病变组织的酶表达异常, 肿瘤组织的低pH、高表达谷胱甘肽、高内压、缺氧和温度较高, 以及外部给予的磁场、温度、光照和超声等。腙键是一种常用的pH敏感键, 将抗肿瘤药物多柔比星通过腙键修饰在纳米载体表面, 其在肿瘤环境pH (约6.0)的药物释放速度和程度显著高于生理pH (7.4), pH 6.0时多柔比星在48 h内累积释放82.1%, 而在pH 7.4累积释放仅21.9%, 从而表现出更好的抗肿瘤效果和较低的心脏毒性[32]。又如热敏脂质体(thermosensitive liposomes)主要通过选择具有合适相变温度的磷脂使脂质体在低于相变温度时呈现固态, 包载药物; 高于相变温度时呈现液态或半固态, 释放药物。为了进一步提高敏感性, 可以采用外部加热的方式提高肿瘤部位的温度[33]。Celsion公司开发的多柔比星热敏脂质体ThermoDox, 在40 ℃时5 min内即可释放60%~70%, 而在37 ℃时30 min仅能释放约20%[34]。在体内, 静脉给予5 mg·kg-1药物后, 将肿瘤组织加热到42 ℃, 肿瘤中药物浓度达到约25 ng·mg-1, 而普通脂质体在肿瘤部位的浓度仅为7~8 ng·mg-1。经过60天ThermoDox治疗后, 85%荷鳞状细胞癌皮下瘤小鼠的肿瘤完全消失, 而普通脂质体仅能延缓肿瘤生长[35]。在2015年的Ⅱ期临床试验中, ThermoDox联合放射热疗(radiofrequency thermal ablation)将患者的整体生存期从单独进行放射热疗的53.6个月提高到79个月。
纳米递药系统在取得诸多成绩的同时, 仍然面临多种瓶颈问题: ①纳米材料的安全性。目前仅有少数材料获准注射, 极大限制了纳米递药系统的产业化和临床应用, 因此设计生物相容性良好、可降解的纳米材料成为本领域的重要课题; ②靶向递药系统的体内行为仍然有待探索。靶向递药系统的尺度为纳米级, 其体内吸收、分布转运和代谢等过程均具有特殊性。如部分纳米材料代谢和排泄很慢, 从而容易发生蓄积, 产生毒性。只有全面阐释靶向递药系统的体内行为才能更好的指导其设计; ③靶向递药系统的规模化生产。许多新型纳米递药系统的制备流程过于复杂而难以规模化生产, 因此如何优化新型纳米递药系统的制备流程, 设计更精密的工业化生产设备, 是纳米递药系统产业化必须克服的屏障。
4 展望
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随着医学、药学和材料学等发展, 新型递药系统层出不穷, 能够不断满足人们越来越高的用药需求。总体而言, 新型递药系统的研究目的均在于不断提高用药顺应性和增效、减毒。但许多新型递药系统仍然有待完善, 尤其是制剂辅料的安全性、制剂工艺的可操作性和可控性、制剂应用的普适性。目前, 速效递药系统、缓控释递药系统已有扎实的理论基础, 已经进入临床应用阶段并有较多品种上市, 制剂的难度也较低。但针对重大疾病的响应性递药系统、生物药物递药系统及靶向递药系统仍面临诸多问题, 需要深入开展应用基础研究并逐步走向临床应用。生物药物递药系统的研究意义重大、涉及面广, 但目前的研究水平较低, 无法充分满足临床需求, 仍然存在巨大的发展空间。靶向递药系统的研究得到广泛关注, 但仍面临众多问题, 尤其是产业化问题亟待解决。对疾病特征的深入研究、对药物制剂体内行为的全面了解及个性化医疗的开展有助于对症用药, 进一步提高新型递药系统的应用价值。
基金
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  • 国家自然科学基金资助项目(31571016)
  • 国家自然科学基金资助项目(81402866)
文献
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2017年第52卷第2期
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doi: 10.16438/j.0513-4870.2016-0953
  • 接收时间：2016-09-28
  • 首发时间：2026-01-14
  • 出版时间：2017-02-12
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  • 收稿日期：2016-09-28
  • 修回日期：2016-11-29
基金
国家自然科学基金资助项目(31571016)
国家自然科学基金资助项目(81402866)
作者信息
    1.四川大学华西药学院, 靶向药物与传递系统教育部重点实验室, 四川 成都 610041
    2.复旦大学药学院, 智能化递药教育部重点实验室, 上海 201203

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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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
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