药物的长效化设计策略

doi:10.12122/j.issn.1673-4254.2025.01.24

摘要/Abstract

摘要：

随着药物设计和制剂技术的进步，长效药物的开发已成为精准医疗与慢病管理的重要研究方向。此类药物通过延长体内有效浓度的维持时间，减少用药频率达到改善患者依从性与生活质量的目的。小分子药物、单克隆抗体及核酸药物在实现长效化方面各有难点，特别是后两者因其结构的复杂性，存在更多挑战。本文将对小分子药物、单克隆抗体及核酸药物的长效化设计策略进行综述。

关键词: 长效药物, 药物设计, 小分子药物, 单克隆抗体, 核酸药物

Abstract:

With advances of drug design and preparation technology, the development of long-acting drugs has become an important research focus in precision medicine and chronic disease management. These drugs are designed to improve the patients' compliance and quality of life by achieving prolonged maintenance of an effective drug concentration in the body with a reduced dosing frequency. Small molecule drugs, monoclonal antibodies and nucleic acid drugs all have their own difficulties in achieving long actions, which can be especially challenging for the latter two because of their structural complexity. This review provides an overview of the strategies for designing long-acting small molecule drugs, monoclonal antibodies, and nucleic acid drugs.

Key words: long-acting drugs, drug design, small molecule drugs, monoclonal antibodies, nucleic acid drugs

黄慕齐, 蔡铮, 刘叔文. 药物的长效化设计策略[J]. 南方医科大学学报, 2025, 45(1): 206-212.

Muqi HUANG, Zheng CAI, Shuwen LIU. Strategies for long-acting drug design[J]. Journal of Southern Medical University, 2025, 45(1): 206-212.

图/表 1

参考文献 46

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Drug type	Generic name (trade name)		Indication	Long acting strategy	Plasma half-life	Dosing method	FDA approval date
Small molecule drug	Paliperidone Palmitate (Invega Sustenna)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	25-49 d	qm, im	2009.7
	Paliperidone Palmitate (Invega Trinza)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	84-95 d	q3m,im	2015.5
	Aripiprazole Lauroxil (Aristada Initio)	Alkermes Inc	Schizophrenia	Nanocrystals	15-18 d	s, im	2018.6
	Risperidone (Perseris)	Indivior PLC	Schizophrenia	ATRIGEL delivery system	9-11 d	qm, sc	2018.7
	Baloxavir marboxil (Xofluza)	Shionogi	Influenza A and B	Prodrug technique	80-100 h	s, po	2018.10
	Cabotegravir/Rilpivirine (Cabenuva)	Viiv Healthcare Co	Treatment of HIV-1 infection	Nanocrystals	Cabotegravir:5.6-11.5w;Rilpivirine:13-28 w	qm or q2m, im	2021.1
	Paliperidone Palmitate (Invega Hafyera)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	148-159 d	q6m,im	2021.8
	Cabotegravir (Apretude)	Viiv Healthcare Co	Prophylaxis for HIV-1	Nanocrystals	25-54 d	q2m, im	2021.12
	Lenacapavir (Sunlenca)	Gilead Sciences	Treatment/Prevention of HIV-1 infection	10 Fluoride substituted, PEG solvent, subcutaneous extended-release	8-12 w	q6m, sc	2022.12
	Risperidone Microspheres for Injection(II) (Rykindo)	Luye Pharma Group	Acute and chronic schizophrenia and bipolar disorder type I	Microsphere technique	3-6 d, stable release:4-5 w	q2w, im	2023.1
Monoclonal antibody	Ravulizumab (Ultomiris)	Alexion	Paroxysmal nocturnal hemoglobinuria	Increased extent of terminal sialylation on N-glycosylation Fc: LS modification, two histidine substitutions in complementarity determining region	50 d	q8w, iv	2018.12
	Sotrovimab (Xevudy)	GSK/Vir Biotechnology	COVID-19 treatment	Fc: LS modification	61 d	s, im	2021.5
	Tixagevimab/Cilgavimab (Evusheld)	AstraZeneca	Prophylaxis for COVID-19	Fc: TM and YTE modification	Tixagevimab:87.9 d,Cilgavimab:77.9-92.0 d	s, im	2022.12
	Nirsevimab (Beyfortus)	AstraZeneca/Sanofi	RSV induced lower respiratory tract infection	Fc: YTE modification	63-73 d	s, im	2023.7
Nucleic acid drug	Nusinersen (Spinraza)	Ionis/Biogen	Spinal muscular atrophy(SMA)	PS, 2′⁃MOE	plasma:63-87 d,cerebrospinal fluid:135-177 d	q4w, it	2016.12
	Patisiran (Onpattro)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	2′⁃OH/2′⁃OMe/2′⁃H; LNP delivery	2-4 d, 12-20 d(elimination)	q3w, iv	2018.8
	Givosiran (Givlaari)	Alnylam	Acute hepatic porphyria	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	6 h, CL= 0.50 L·h^-1·kg^-1	qm, sc	2019.11
	Lumasiran (Oxlumo)	Alnylam	Primary hyperoxaluria type 1(PH1)	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	5.2 h, CL= 0.38 L·h^-1·kg^-1, liver: not detected	q3m, sc	2020.11
	Inclisiran (Leqvio)	Novartis	Heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease	Advanced ESC, PS, 2′-OMe/2′-F; GalNAc delivery	9 h, liver: 80-90 d	q6m, sc	2020.12
	Vutrisiran (Amvuttra)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	ESC, PS, 2′-OMe/2′-F; GalNAc delivery	5.2 h, CL= 0.30 L·h^-1·kg^-1, liver: not detected	q3m, sc	2022.6
	Tofersen (Qalsody)	Ionis/Biogen	Amyotrophic lateral sclerosis with SOD1 gene mutation	PS, 2′-MOE	Cerebrospinal fluid:4 w	q4w, it	2023.4
	Nedosiran (Rivfloza)	Novo Nordisk	Primary hyperoxaluria type 1(PH1)	PS, 2′-OMe/2′-F; GalXc technique	15 h, CL=0.08 L·h^-1·kg^-1 liver: not detected	qm, sc	2023.9
	Eplontersen (Wainua)	Ionis/AstraZeneca	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	PS/PO, 2′-MOE; GalNAc delivery	3 w	qm, sc	2023.12

Drug type	Generic name (trade name)		Indication	Long acting strategy	Plasma half-life	Dosing method	FDA approval date
Small molecule drug	Paliperidone Palmitate (Invega Sustenna)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	25-49 d	qm, im	2009.7
	Paliperidone Palmitate (Invega Trinza)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	84-95 d	q3m,im	2015.5
	Aripiprazole Lauroxil (Aristada Initio)	Alkermes Inc	Schizophrenia	Nanocrystals	15-18 d	s, im	2018.6
	Risperidone (Perseris)	Indivior PLC	Schizophrenia	ATRIGEL delivery system	9-11 d	qm, sc	2018.7
	Baloxavir marboxil (Xofluza)	Shionogi	Influenza A and B	Prodrug technique	80-100 h	s, po	2018.10
	Cabotegravir/Rilpivirine (Cabenuva)	Viiv Healthcare Co	Treatment of HIV-1 infection	Nanocrystals	Cabotegravir:5.6-11.5w;Rilpivirine:13-28 w	qm or q2m, im	2021.1
	Paliperidone Palmitate (Invega Hafyera)	Janssen Pharmaceuticals Inc	Schizophrenia	Nanocrystals	148-159 d	q6m,im	2021.8
	Cabotegravir (Apretude)	Viiv Healthcare Co	Prophylaxis for HIV-1	Nanocrystals	25-54 d	q2m, im	2021.12
	Lenacapavir (Sunlenca)	Gilead Sciences	Treatment/Prevention of HIV-1 infection	10 Fluoride substituted, PEG solvent, subcutaneous extended-release	8-12 w	q6m, sc	2022.12
	Risperidone Microspheres for Injection(II) (Rykindo)	Luye Pharma Group	Acute and chronic schizophrenia and bipolar disorder type I	Microsphere technique	3-6 d, stable release:4-5 w	q2w, im	2023.1
Monoclonal antibody	Ravulizumab (Ultomiris)	Alexion	Paroxysmal nocturnal hemoglobinuria	Increased extent of terminal sialylation on N-glycosylation Fc: LS modification, two histidine substitutions in complementarity determining region	50 d	q8w, iv	2018.12
	Sotrovimab (Xevudy)	GSK/Vir Biotechnology	COVID-19 treatment	Fc: LS modification	61 d	s, im	2021.5
	Tixagevimab/Cilgavimab (Evusheld)	AstraZeneca	Prophylaxis for COVID-19	Fc: TM and YTE modification	Tixagevimab:87.9 d,Cilgavimab:77.9-92.0 d	s, im	2022.12
	Nirsevimab (Beyfortus)	AstraZeneca/Sanofi	RSV induced lower respiratory tract infection	Fc: YTE modification	63-73 d	s, im	2023.7
Nucleic acid drug	Nusinersen (Spinraza)	Ionis/Biogen	Spinal muscular atrophy(SMA)	PS, 2′⁃MOE	plasma:63-87 d,cerebrospinal fluid:135-177 d	q4w, it	2016.12
	Patisiran (Onpattro)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	2′⁃OH/2′⁃OMe/2′⁃H; LNP delivery	2-4 d, 12-20 d(elimination)	q3w, iv	2018.8
	Givosiran (Givlaari)	Alnylam	Acute hepatic porphyria	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	6 h, CL= 0.50 L·h^-1·kg^-1	qm, sc	2019.11
	Lumasiran (Oxlumo)	Alnylam	Primary hyperoxaluria type 1(PH1)	ESC, PS, 2′⁃OMe/2′⁃F; GalNAc delivery	5.2 h, CL= 0.38 L·h^-1·kg^-1, liver: not detected	q3m, sc	2020.11
	Inclisiran (Leqvio)	Novartis	Heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease	Advanced ESC, PS, 2′-OMe/2′-F; GalNAc delivery	9 h, liver: 80-90 d	q6m, sc	2020.12
	Vutrisiran (Amvuttra)	Alnylam	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	ESC, PS, 2′-OMe/2′-F; GalNAc delivery	5.2 h, CL= 0.30 L·h^-1·kg^-1, liver: not detected	q3m, sc	2022.6
	Tofersen (Qalsody)	Ionis/Biogen	Amyotrophic lateral sclerosis with SOD1 gene mutation	PS, 2′-MOE	Cerebrospinal fluid:4 w	q4w, it	2023.4
	Nedosiran (Rivfloza)	Novo Nordisk	Primary hyperoxaluria type 1(PH1)	PS, 2′-OMe/2′-F; GalXc technique	15 h, CL=0.08 L·h^-1·kg^-1 liver: not detected	qm, sc	2023.9
	Eplontersen (Wainua)	Ionis/AstraZeneca	The polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults	PS/PO, 2′-MOE; GalNAc delivery	3 w	qm, sc	2023.12

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