药学学报

Application type	505(b)(1)	505(b)(2)	505(j)
R&D time	10 years	5 years	3 years
Market share	Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months	Add new clinical trials -3 years	First generic drug-6 months

Application type

505(b)(1)

505(b)(2)

505(j)

R&D time

10 years

5 years

3 years

Market share

Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months

Add new clinical trials -3 years

First generic drug-6 months

Application type	505(b)(1)	505(b)(2)	505(j)
R&D time	10 years	5 years	3 years
Market share	Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months	Add new clinical trials -3 years	First generic drug-6 months

Application type

505(b)(1)

505(b)(2)

505(j)

R&D time

10 years

5 years

3 years

Market share

Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months

Add new clinical trials -3 years

First generic drug-6 months

Trade name	Launch date	Medication cycle	Component and dosage form	Indication
Risperdal	Dec. 1992	1-2 days	Risperidone tablets	Schizophrenia
Risperdal Consta	Aug. 2002	2 weeks	Risperidone injection microspheres	Schizophrenia and bipolar disorder
Invega Sustenua	Dec. 2009	1 month	Pembrolidone long-acting injection	Emotional stability and depression in schizophrenia and schizoaffective disorder
Invega Trinza	Jun. 2015	3-6 months	Pembrolidone long-acting injection

Trade name

Launch date

Medication cycle

Component and dosage form

Indication

Risperdal

Dec. 1992

1-2 days

Risperidone tablets

Schizophrenia

Risperdal Consta

Aug. 2002

2 weeks

Risperidone injection microspheres

Schizophrenia and bipolar disorder

Invega Sustenua

Dec. 2009

1 month

Pembrolidone long-acting injection

Emotional stability and depression in schizophrenia and schizoaffective disorder

Invega Trinza

Jun. 2015

3-6 months

Pembrolidone long-acting injection

Trade name	Launch date	Medication cycle	Component and dosage form	Indication
Risperdal	Dec. 1992	1-2 days	Risperidone tablets	Schizophrenia
Risperdal Consta	Aug. 2002	2 weeks	Risperidone injection microspheres	Schizophrenia and bipolar disorder
Invega Sustenua	Dec. 2009	1 month	Pembrolidone long-acting injection	Emotional stability and depression in schizophrenia and schizoaffective disorder
Invega Trinza	Jun. 2015	3-6 months	Pembrolidone long-acting injection

Trade name

Launch date

Medication cycle

Component and dosage form

Indication

Risperdal

Dec. 1992

1-2 days

Risperidone tablets

Schizophrenia

Risperdal Consta

Aug. 2002

2 weeks

Risperidone injection microspheres

Schizophrenia and bipolar disorder

Invega Sustenua

Dec. 2009

1 month

Pembrolidone long-acting injection

Emotional stability and depression in schizophrenia and schizoaffective disorder

Invega Trinza

Jun. 2015

3-6 months

Pembrolidone long-acting injection

Year	Dosage form	Pharmaceutical company
1955	Constant release tablets	Novartis
1982	Sustained release tablets	Novartis
2000	Osmotic pump tablet	ALZA/Johnson
2001	Dual phase sustained-release capsules (microspheres)	Elan
2006	Transdermal drug delivery systems	Hisamitsu
2012	Dual phase oral solution	Tris pharma
2015	Dual phase chewable tablets	Pfizer
2017	Dual phase sustained-release oral disintegrating tablets (microspheres)	Neos pharma

Year

Dosage form

Pharmaceutical company

1955

Constant release tablets

Novartis

1982

Sustained release tablets

Novartis

2000

Osmotic pump tablet

ALZA/Johnson

2001

Dual phase sustained-release capsules
(microspheres)

Elan

2006

Transdermal drug delivery systems

Hisamitsu

2012

Dual phase oral solution

Tris pharma

2015

Dual phase chewable tablets

Pfizer

2017

Dual phase sustained-release oral
disintegrating tablets (microspheres)

Neos pharma

Year	Dosage form	Pharmaceutical company
1955	Constant release tablets	Novartis
1982	Sustained release tablets	Novartis
2000	Osmotic pump tablet	ALZA/Johnson
2001	Dual phase sustained-release capsules (microspheres)	Elan
2006	Transdermal drug delivery systems	Hisamitsu
2012	Dual phase oral solution	Tris pharma
2015	Dual phase chewable tablets	Pfizer
2017	Dual phase sustained-release oral disintegrating tablets (microspheres)	Neos pharma

Year

Dosage form

Pharmaceutical company

1955

Constant release tablets

Novartis

1982

Sustained release tablets

Novartis

2000

Osmotic pump tablet

ALZA/Johnson

2001

Dual phase sustained-release capsules
(microspheres)

Elan

2006

Transdermal drug delivery systems

Hisamitsu

2012

Dual phase oral solution

Tris pharma

2015

Dual phase chewable tablets

Pfizer

2017

Dual phase sustained-release oral
disintegrating tablets (microspheres)

Neos pharma

Trade name	Pharmaceutical company	Launch date	Listed country	Technology
Paclitaxel	Shandong Luye Pharmaceutical	Jan. 2003	China	Paclitaxel liposome
Abraxane	Celgene	Feb. 2005	America	Paclitaxel liposome
Cynviloq	Samyang	Jan. 2007	Korea	Paclitaxel polymeric micelles
Nanoxel	Fresenius Kabi	Jan. 2007	India	Paclitaxel nanoparticles
PICN	SunPharma	May. 2014	India	Paclitaxel nanoparticles
Apealea/Paclical	Oasmia	Oct. 2015	Russia	Paclitaxel polymeric micelles
RMX3001 (R&D code)	Shanghai Haihe Biopharma	Sep. 2024	China	Lipid self emulsification delivery

Trade name

Pharmaceutical company

Launch date

Listed country

Technology

Paclitaxel

Shandong Luye Pharmaceutical

Jan. 2003

China

Paclitaxel liposome

Abraxane

Celgene

Feb. 2005

America

Paclitaxel liposome

Cynviloq

Samyang

Jan. 2007

Korea

Paclitaxel polymeric micelles

Nanoxel

Fresenius Kabi

Jan. 2007

India

Paclitaxel nanoparticles

PICN

SunPharma

May. 2014

India

Paclitaxel nanoparticles

Apealea/Paclical

Oasmia

Oct. 2015

Russia

Paclitaxel polymeric micelles

RMX3001 (R&D code)

Shanghai Haihe Biopharma

Sep. 2024

China

Lipid self emulsification delivery

Trade name	Pharmaceutical company	Launch date	Listed country	Technology
Paclitaxel	Shandong Luye Pharmaceutical	Jan. 2003	China	Paclitaxel liposome
Abraxane	Celgene	Feb. 2005	America	Paclitaxel liposome
Cynviloq	Samyang	Jan. 2007	Korea	Paclitaxel polymeric micelles
Nanoxel	Fresenius Kabi	Jan. 2007	India	Paclitaxel nanoparticles
PICN	SunPharma	May. 2014	India	Paclitaxel nanoparticles
Apealea/Paclical	Oasmia	Oct. 2015	Russia	Paclitaxel polymeric micelles
RMX3001 (R&D code)	Shanghai Haihe Biopharma	Sep. 2024	China	Lipid self emulsification delivery

Trade name

Pharmaceutical company

Launch date

Listed country

Technology

Paclitaxel

Shandong Luye Pharmaceutical

Jan. 2003

China

Paclitaxel liposome

Abraxane

Celgene

Feb. 2005

America

Paclitaxel liposome

Cynviloq

Samyang

Jan. 2007

Korea

Paclitaxel polymeric micelles

Nanoxel

Fresenius Kabi

Jan. 2007

India

Paclitaxel nanoparticles

PICN

SunPharma

May. 2014

India

Paclitaxel nanoparticles

Apealea/Paclical

Oasmia

Oct. 2015

Russia

Paclitaxel polymeric micelles

RMX3001 (R&D code)

Shanghai Haihe Biopharma

Sep. 2024

China

Lipid self emulsification delivery

改良型化学药研发案例和立项思考

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郑永刚 , 刘爱赟 , 张馨浓 , 靳文仙 ^* , 王伟 ^*

药学学报 | 综述 2026,61(2): 417-425

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药学学报 |综述 2026 , 61 (2) : 417 -425

改良型化学药研发案例和立项思考

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郑永刚, 刘爱赟, 张馨浓, 靳文仙^*, 王伟^*

作者信息

天津药物研究院有限公司技术创新研究中心, 天津 300301

通讯作者:

靳文仙, Tel: 13820106542, E-mail: jinwx@tjipr.com

王伟, Tel: 18622081595, E-mail: wangw@tjipr.com

作者简介:

作者贡献:

郑永刚负责文章内容的撰写; 刘爱赟、张馨浓负责文章内容的修改及格式的调整; 靳文仙、王伟负责文章的修订、审阅。

The development cases and proposal considerations of modified new drug

Yong-gang ZHENG, Ai-yun LIU, Xin-nong ZHANG, Wen-xian JIN^*, Wei WANG^*

Affiliations

Technology Innovation R&D Center, Tianjin Institute of Pharmaceutical Research Co., Ltd., Tianjin 300301, China

出版时间: 2026-02-12 doi: 10.16438/j.0513-4870.2025-0307

文章导航

摘要

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本文对比分析了美国505(b)(2) 药物与我国改良型新药的背景及二者本质差异, 着重介绍505(b)(2) 药物的成功案例, 阐述临床要求和发展趋势。从我国国情出发, 以制剂的角度进行改良新药的立项思考和举例。同时, 分析并讨论改良失败案例及原因, 为推动国内改良新药的研发提供重要借鉴。

关键词

改良型化学药 / 505(b)(2) 药物 / 制剂开发策略 / 临床需求 / 立项

Abstract

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This article conducted a comparative analysis of the background and fundamental differences between the 505(b)(2) drug and modified new drug, with a focus on successful case studies of 505(b)(2) drugs, discussing clinical requirements and development trends. Based on the national conditions of our country, the project initiation considerations and examples of improved new drugs were carried out from the perspective of preparations. Additionally, the causes of improvement failures and relevant cases were analyzed and discussed, providing critical insights to advance the development of modified new drug in China.

Key words

modified new drug / 505(b)(2) drug / formulation development strategy / clinical demand / project initiation

引用本文

郑永刚, 刘爱赟, 张馨浓, 靳文仙, 王伟. 改良型化学药研发案例和立项思考. 药学学报, 2026 , 61 (2) : 417 -425 . DOI: 10.16438/j.0513-4870.2025-0307

Yong-gang ZHENG, Ai-yun LIU, Xin-nong ZHANG, Wen-xian JIN, Wei WANG. The development cases and proposal considerations of modified new drug[J]. Acta Pharmaceutica Sinica, 2026 , 61 (2) : 417 -425 . DOI: 10.16438/j.0513-4870.2025-0307

正文

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2016年5月, 我国化学药品新注册分类申报要求, 首次提出药品注册分为创新药、改良型新药和仿制药。经过2020年6月对化学药品注册分类及申报资料要求的完善, 我国药品注册分类自此进入了新阶段, 改良型新药的概念逐步中国化。在我国现阶段, 改良型新药是在已知活性成分的基础上, 对其结构、剂型、给药途径、适应症、用法用量、规格等进行优化, 且具有明显临床优势的药品^[1]。2020年12月, 我国改良新药的临床试验技术指导原则指出, 改良的临床目标是提高安全性、有效性和临床顺应性^[2]。

在国外, 早在1984年的哈奇-瓦科特斯修正案, 将新药申请途径分为新药申请和简略新药申请, 其中505(b)(2) 药物(概念平行于改良型新药) 要求包含完整的安全性及有效性的研究报告, 但至少有部分信息来源于非申请人开展或申请人无权引用的研究数据^{[3, 4]}。对于新化学实体/新分子实体, 若申请资料并非来自申请人进行的研究, 并且申请人无权引用这部分数据, 则这类药物也属于505(b)(2) 药物的途径申请^{[5, 6]}。

在我国, 改良型新药主要提倡临床优势, 满足临床需求, 如提高疗效、改善毒性、优化给药方式。旨在敦促药物开发者辨识未满足的市场需求、将更多的创新药快速推向市场。505(b)(2) 药物注册申报的核心在于是否使用他人未注册的数据, 并未强调一定需要具备临床优势, 505(b)(2) 药物的申报范围较广。

随着国内仿制药研发的竞争日益激烈, 创新药的开发数量因新靶点的发现困难而逐步减少。改良型新药以研发周期短、竞品较少的优势成为研发的热门。在为患者带来高品质临床价值的同时, 改良新药具有投资少、时间短、成功率高的优势, 对于药企而言, 改良新药的研发对于延长药品的生命周期, 保护市场、抢占市场具有重要意义(表1)。近年来, 无论在我国国家药品监督管理局(National Medical Products Administration, NMPA), 还是美国食品药品监督管理局(Food and Drug Administration, FDA), 改良新药的获批均逐步增多^{[7, 8]}。

本文通过经典案例分析, 结合我国国情, 对改良型新药进行立项思考和分析, 旨在为改良新药立项提供参考。

1　经典案例分析

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1.1　利培酮

改良新药的经典药物之一——利培酮, 作为第二代精神分裂药物的一类新药, 1993年首先被FDA批准^[9], 其常规制剂(口崩片和口服液) 销售额于2007年达到巅峰34.20亿美元, 随着专利到期, 市场份额呈断崖式下滑。在此之前, 强生公司已通过对产品的升级进行应对, 从服药周期2天1次的口服片到口崩片, 再到2周1次的注射微球, 从给药顺应性角度进行改良, 延长产品生命周期。2006年12月, 强生公司以利培酮的主要活性代谢产物9-羟基利培酮, 即帕潘立酮, 进一步改良上市缓释制剂(商品名: Invega)。帕潘立酮具有与母体分子相似但不完全相同的受体药理学, 其主要代谢器官为肾脏, 同时具有较低的蛋白质结合率和P-糖蛋白抑制, 导致其药物相互作用的可能性更低, 安全性更高, 为目前全球唯一获批用于治疗分裂情感性精神病的口服缓释制剂^[10]。在制剂技术上, 口服缓释制剂Invega采用了制药界知名的渗透控释Push-Pull^TM输送系统(OROS平台技术)。与普通制剂相比, OROS技术可使该药的血药浓度更加稳定, 在提高顺应性的同时, 降低了不良反应^[11]。2009年12月在美国首次上市的帕利哌酮缓释注射液(商品名: Invega Sustenua) 是帕利哌酮与棕榈酸成酯后的混悬注射剂, 该药活性成分为棕榈酸帕利哌酮。帕利哌酮与棕榈酸成酯后溶解度变得极低, 结合纳米晶制剂技术可制备成混悬注射剂, 肌肉注射后, 在人体酯化酶的作用下缓慢释放出帕潘立酮起效, 释放周期延长至4周。疾病复发率能够控制在13%以下, 相较于利培酮长效注射液(商品名: Risperdal Consta) 用药后30%的复发率, Invega Sustenna对疾病复发率的控制有了更大的突破^[12]。后续以3个月和6个月给药周期的棕榈帕利哌酮酯注射液(商品名: Invega Trinza) 等产品, 更是开创了抗精神分裂药物治疗的新纪元, 复发率再次降低到4.9%和7.5%^[13], 成为全球首个也是目前唯一的用药次数最少的抗精神分裂药物^[14], 2019年销售额达到33.3亿美元。其研发重要里程碑见表2。

利培酮作为强生公司开发的重要抗精神病药物, 自1993年首次获批以来, 经历了多次技术升级和专利布局, 形成了从每日给药到每6个月给药的完整产品生命周期管理策略, 其清晰的研发目标、有力的技术布控, 都是值得国内医药公司借鉴的地方。利培酮的技术升级路径, 从常规制剂到超长效制剂形成了完整的技术迭代路线, 展现出系统性的产品生命周期管理策略。其遵循从化学实体改良到剂型创新, 从每日给药到超长效给药, 从母药到活性代谢物再到前药技术的核心逻辑, 逐步解决临床顺应性痛点, 延长产品生命周期, 创造了显著的商业价值, 阐释了新技术在药物研发的重要性, 以及合作互利的战略意义。

更重要的是, 每次技术升级都伴随着新的专利保护, 以基础化合物专利为锚点, 在该专利保护期内, 利培酮口服片剂(商品名: Risperdal) 全球销售额峰值达34亿美元, 累计贡献超300亿美元收入。专利到期前, 强生公司已启动迭代升级策略, 迭代专利覆盖丙交酯乙交酯共聚物(7525) 配比及粒径范围的缓释微球, 将活性代谢物开发为新分子实体进行代谢产物(帕利哌酮) 专利保护, 并拓展利培酮-丙戊酸复方缓释片等复方制剂专利, 通过剂型改良和代谢物开发构建专利护城河, 有效应对了专利悬崖的挑战, 延长了产品的市场独占期。临床需求虽是新药研发的初衷, 但知识产权是市场占有的保护伞, 是市场利润占有的关键因素。这提示应关注新技术, 注重技术创新, 从临床角度出发, 开发适用于临床的缓释制剂、靶向递送系统等, 并及时申请专利, 形成技术壁垒, 此外, 合作共赢也有助于企业突破新技术。在此同时, 研发企业应注重探索类似的策略, 如开发活性代谢物、前体药物、氘代药物等, 以改善药物的理化性质或药动学特征。

1.2　哌甲酯

哌甲酯是改良型新药开发中剂型改良的又一经典案例。最初由诺华公司于1955年开发速释片, 用于治疗小儿多动症。研发企业从改善临床顺应性出发, 考虑用药后的反弹效应、药物起效速度、吞咽问题, 以及孩子在校服用不方便等临床问题, 先后采用缓释、渗透泵、微丸包衣和口崩片等改良技术。通过不断的改良, 已使用60多年的哌甲酯仍作为儿童多动症的一线用药, 缔造了制剂改良的神话^[15], 其改良过程见表3^[16]。哌甲酯的剂型改良以用药频次高、血药浓度波动较大、特殊人群适配性不足等临床痛点为导向, 通过缓释剂型(如专注达) 通过渗透泵技术实现12 h平稳释放, 将给药频率从每日多次(2~3次) 降至每日1次, 显著提升注意缺陷多动障碍患儿依从性; 平稳血药浓度优化药代动力学减少不良反应, 满足儿童患者用药需求实现真正的年龄适应性治疗, 剂量灵活遵循个体化治疗推动精准医疗建设, 降低药品滥用同时提高了用药安全性, 解决了缺陷多动障碍患儿治疗中的关键问题。哌甲酯的改良历程展示了剂型创新如何深刻影响临床实践, 体现了“以患者为中心”的药物开发理念。对于制药企业, 改良型化药立项需遵循“临床痛点-技术方案-价值验证”闭环, 对现有药物的临床痛点进行精准突破, 通过剂型创新、适应症拓展或工艺优化, 实现从“仿制改良”到“临床价值重构”的升级, 挖掘现有药物的新剂型。

1.3　紫杉醇

紫杉醇的改良是载药系统优化的典型, 1992年12月首次登陆美国市场(紫杉醇注射液, 商品名: Taxol), 1997年专利到期, 2000年9月出现第一个仿制药, Taxol也在2000年达到了销售峰值(15.9亿美元)^[17]。Taxol存在一个非常明显的缺陷, 即溶媒中使用了聚氧乙烯蓖麻油, 能够刺激机体释放组胺, 引起周围神经病变及强烈的过敏反应。正是该缺陷限制了溶剂型紫杉醇的使用剂量和临床应用, 同时也给后期紫杉醇的开发留下了广阔的空间^[18]。2005年获得FDA批准的白蛋白结合型紫杉醇(商品名: Abraxane) 是一种新型紫杉醇纳米制剂^[19], 它将内源性人血白蛋白与紫杉醇以非共价形式结合, 所制得的纳米粒子完全克服了紫杉醇难溶于水的缺点, 具有安全无毒、生物相容性好、无需预处理等优点, 且具有一定的肿瘤靶向性。

然而, 白蛋白紫杉醇与溶剂型紫杉醇相比, 仅可增加客观缓解率, 并未改善平均无进展生存期和平均总生存期。因此, 白蛋白紫杉醇化疗方案仍不能满足临床需求。2007年韩国Samyang公司开发的紫杉醇聚合物胶束, 是一种由纳米粒子包裹的紫杉醇胶束组成的新型给药系统。粒径小(20~100 nm), 不易被网状内皮系统摄取。临床耐受剂量从175提高到300 mg·m^-2 (按体表面积计算), 同时并没有明显增加的毒性反应, 显示出更显著的高效低毒的抗癌效果^[20]。2020年, 绿叶公司以卵磷脂和胆固醇为辅料开发出紫杉醇脂质体药物力朴素^[21]。2024年, 紫杉醇口服溶液(商品名: RMX3001) 在国内获批上市, 成为首个基于脂质自乳化药物递送技术开发的口服制剂, 其在延长患者无进展生存期方面不劣于传统紫杉醇注射液, 而在总生存时间上则显著优于注射液, 中位总生存期延长了2.59个月, 紫杉醇口服溶液在疗效上的优效趋势。客观缓解率由注射液的9.8%提高至13.6%。在安全性方面, 紫杉醇口服溶液相较于紫杉醇注射液表现出更佳的安全性和耐受性。紫杉醇脂质体组在恶心呕吐、皮疹、肌痛、周围神经炎和呼吸困难等不良反应的发生率上, 置信区间(95%) 分别为0.48、0.17、0.23、0.41和0.18, 均显著低于紫杉醇(注射) 组。这些不良反应的差异均具有统计学意义(均P < 0.01), 显示出其临床可控的优势^[22]。其研发历程见表4。

口服紫杉醇溶液的成功改良, 是肿瘤治疗领域的重大突破, 为胃癌患者带来了新的治疗选择, 简化了治疗流程, 提高了患者的顺应性, 减轻患者在治疗过程中的痛苦, 并减少了不良反应的发生。紫杉醇的成功改良, 展示了“辅料革新-递送优化-安全性提升”的完整改良路径, 提示可通过结构修饰或制剂技术筛选降低已知不良反应, 提高药物安全性, 满足临床需求。

1.4　其他改良经典药物

改良型药物还包括从给药途径、适应症、新剂型、新技术、药械组合等多个角度的成功案例。

复方利多卡因/丁卡因局麻贴片(商品名: Synera) 为美国ZARS公司开发的加热局部贴片, 在2005年由FDA批准上市, 主要用于浅表静脉通路的镇痛、浅表皮肤切除术、电流干燥手术、皮肤刮除活检的麻醉等^[23]。Synera的成分为利多卡因和地卡因, 二者剂量均为70 mg, 其中利多卡因是早已批准的局部麻醉经典用药; 地卡因是之前FDA未正式批准的外用局部麻醉剂。Synera则是两种局部麻醉剂的组合, 适用于完整皮肤^[24]。与传统注射给药相比, 以透皮方式将局麻药物递送至手术部位, 可以克服传统注射给药带来的疼痛, 避免注射药物引起的组织水肿, 从而提高患者的依从性并有利于外科医生的操作^[25]。为老药设计新的给药途径以赋予其新的使用特点, 是差别化竞争的策略之一, 并可广泛借助已公开文献, 节约了资源和成本, 提高了申报效率, 同时易被市场接受。

格隆溴铵是改变适应症和剂型的典型药物, 其片剂和注射液分别于1961年和1975年上市, 用于治疗胃、十二指肠溃疡及慢性胃炎, 2010年上市的口服溶液用于治疗儿童重症流涎; 2015~2017年期间上市吸入制剂、复方气雾剂和吸入溶液用于治疗慢性阻塞性肺疾病; 2018年上市局部用药用于原发性腋窝多汗症^[26]。格隆溴铵的成功改良, 提示上市后新药应继续关注临床药理药效, 以开发新的适应症。

非诺贝特以工艺技术为着眼点进行了一系列改良, 旨在解决溶解性差、吸收差、剂量大、个体差异大、需与餐服用的问题。通过运用纳米晶、热熔分散、成盐加缓释技术等工艺, 服药量由400 mg·d^-1降低到240~290 mg·d^-1, 同时吸收差异变小, 血药浓度波动范围小, 临床优势明显^[27]。制剂工艺技术的改进可以有效解决临床用药的缺陷, 制剂研究应放眼于临床, 服务于临床。

肾上腺素通过药械方面的革新, 不断提高给药便利性, 由最早的人工注射到自动注射, 2003年上市带可视窗口的注射器, 患者可以在紧急状态下, 观察到是否真正将药品注射进体内, 2012年上市有语音提醒的注射装置, 患者可以根据语音的指导和辅助提醒, 正确、及时地用药^[28]。肾上腺素注射液从临床患者角度出发, 其注射器的革新, 为药械方面的发展提供重要的借鉴意义^[29]。

2　临床要求

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改良型新药在临床试验要求上, 相比创新药具有一定的优势, 在此, 中美两国要求基本一致。其中, 在临床设计上, 改良型新药需要完整的安全性、有效性数据, 但通过桥接试验可利用原研药品的安全性和有效性数据, 豁免部分临床研究^[30]。在具体技术上, 改良新药可以豁免部分临床研究, 比如生物药剂学分类系统(biopharmaceutics classification system, BCS) Ⅰ和Ⅲ类, 非活性成分对药物的吸收不显著, 可以豁免临床。但要求在安全性、有效性或依从性上具备明显的临床优势。Ⅰ期临床试验一般开展与原研药品相比的人体药代动力学研究, 以桥接与原研药品的安全有效性数据; Ⅱ期临床研究以探索药物治疗的有效性为主要目标, 为给药剂量的确定提供依据。按照改良型新药预期的临床优势, 达到非劣或者优效的要求; 通过Ⅲ期临床, 确证改良型新药在特定目标人群中存在有效性、安全性或依从性上的明显临床优势^[31]。

在临床评价上, 主要侧重于提高有效性; 或在不降低疗效、不增加新的重要安全性风险的前提下取得具有重要临床意义的安全性优势; 或改良后的新药更便于患者使用, 以上优势结果必须存在统计学差异。

3　发展趋势

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目前, 改良型新药呈多趋势发展态势。在剂型上, 朝着新口服制剂、新配方^[32]的方向迈进; 在适应症上, 由过去的中枢神经系统、传染病、心血管等, 逐步往癌症以及孤儿药方向发展; 同时, 解决患者不按时服药、依从性差问题也是改良新药发展的一项重要考量, 不按时服药成为影响疗效的主要原因, 造成巨大的医疗资源浪费, 导致重大的公众健康问题, 在慢性病、精神分裂症和阿尔茨海默病等精神和记忆疾病^[33]中尤为突出。减少用药次数、优化用药方式成为改良的重要方向。2017年, FDA批准的阿立哌唑数字化药片, 为患者开启药物的电子化、智能化的大门, 成为全球首例带有消化道电子跟踪系统的智能药物, 患者可根据药物的吸收情况, 实现用药可控^[34]。

随着前沿科学的发展, 改良新药也朝着再生医学^[35]、粪便移植药物^[36]、载体递送^[37]、细胞治疗药物^[38]等方向发展, 复杂纳米制剂^[39]研发受到越来越多的关注, 静脉注射乳剂有了非常广泛的应用^{[40, 41]}, 脂质体^{[42, 43]}、白蛋白纳米粒^{[44, 45]}等复杂制剂表现出巨大潜力, 创新佐剂的开发也成为当前的研究热点^[46]。

4　基于我国改良新药分类的立项思考

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我国改良新药的要求, 是基于我国国情出发, 主要的目的是满足临床需求、解决临床痛点, 或提高药物临床效果, 或减少用药次数, 增强患者顺应性, 或降低不良反应, 改善安全性, 以实现临床优效。

4.1　拆分光学异构体、成酯、成盐; 改变酸根碱基

根据现有药物, 临床上, 改良新药的目标体现在改善气味、口味、提高药效、减低毒副作用、减少刺激性、增加渗透性、改善生物利用度这些方面。对此, 改良的策略主要从改善溶解度、改善结晶性、吸湿性、提高理化稳定性、改变盐型晶型等方面展开。例如通过酸碱基团的改变, 可改善药物口味; 通过盐型晶型的改善, 可改善药物的理化性质和体内释放行为, 从而改善生物利用度; 通过光学异构体的拆分, 可降低毒副作用。比如奥硝唑氯化钠注射液改良成左奥硝唑氯化钠注射液, 对人体刺激性更低, 溶解性更好^[47]; 左亚叶酸钙改良成左亚叶酸钠后, 溶解性更好, 与其他药物或输液配伍时, 亚叶酸钠具有更好的相容性, 避免过多的钙离子进入体内而引发的代谢紊乱^{[48, 49]}。

4.2　改变药物剂型不改变给药途径

在药物剂型上, 高效、长效、低毒、缓释、使用方便、提高生物利用度、儿童用药成为改良的重要趋势。通过缓释、长效减少给药频率, 对于提高患者依从性有重大意义; 对于长期注射的产品, 可通过口服或者特殊注射装置, 使患者使用更加便捷; 另外, 目前儿童用药在市场上尚有很大的空缺, 当用到成人用药时, 临床医生对儿童剂量也凭感性经验判断, 因此, 开发儿童药具有关键意义。例如, 上市的醋酸亮丙瑞林注射混悬液, 用于治疗两岁及以上患有中枢性早熟的儿童, 用药周期延长至6个月^[50]; 睾酮十一醋酯自乳化胶囊为FDA首批口服睾酮胶囊, 促进肠道淋巴系统的吸收, 减少食物对药物吸收的影响^[51]; 儿童用口服氢化可的松颗粒, 填补儿科专用剂型的空白, 口服制剂临床灵活性更大, 实现个体化治疗^[52]。制药企业应该注重产品的市场定位和差异化特点, 如开发儿童专用剂型、罕见病用药等, 以提高产品的市场竞争力。

4.3　改变给药途径

传统给药需要跨越人体屏障, 往往生物利用度低, 伴随一定的毒副作用。通过给药途径的改变, 以实现高效、低毒。另外, 给药效率不高、依从性不强的必须药物, 可通过给药途径的改善, 延长作用时间, 改善患者的满意度。但是, 给药途径的改变, 需结合一定的临床研究, 关注适应症的差异。近些年, 舌下给药^[53]、皮下^[54]、眼部植入给药^[55]、鼻腔^[56]和肺部给药^[57]等也成为研究的热门。比如, 贝美前列素(PGF2α类似物) 滴眼液于2001年3月获FDA批准上市, 后续植入剂于2020年3月获批上市, 用于降低眼压的长效缓释植入剂一次性植入后, 疗效可维持12~16周, 便捷性和患者的顺应性显著提升。2004年上市的阿扎胞苷注射剂, 用于治疗骨髓增生异常、急性非淋巴细胞性白血病、乳腺癌症、肠癌、黑色素瘤等病症^[58]。2020年9月上市口服阿扎胞苷片, 用于经过高强度化疗后首次达到完全缓解或血细胞计数恢复的完全缓解, 而不适合再接受高强度痊愈性化疗的急性髓细胞白血病治疗^[59]。极大的改善用药便利性的同时, 提示给药途径的改变可能会对适应症产生影响, 需要对产品进行二次评估。药物研发没有终点, 上市后应继续关注临床需求, 通过新技术、新辅料或新设备实现给药途径的改变, 从而形成较强的专利壁垒。

4.4　复方药物

疾病有时伴随并发症, 或者多靶点、多激动剂互相作用, 复方药物克服了单一药物治疗范围的限制。复方药物的开发, 必须以临床需求为导向, 使临床受益成为改良的终点^[60], 要求复方药物之间配伍稳定性良好^[61], 或辅以双层片^[62]或包衣^[63]等技术优化。药理机制上应具有协同/相加或互补性, 药代动力学行为的吻合^[64]。当多个不同机制的分子专利到期后, 可以自行优化方案, 开发新的固定剂量组合物。常见的复方药物应用, 主要体现在感冒药^[65]、抗感染药^[66]、抗艾滋病药^[67]、心血管类药物^[68]等。2021年上市的维A酸过氧苯甲酰乳膏(商品名: Twyneo), 用于治疗成人与9岁及以上儿童患者的寻常痤疮。该药利用溶胶-凝胶的微囊化技术, 将维A酸和过氧化苯甲酰分别包封在微囊内, 稳定维A酸不被过氧化苯甲酰降解, 并缓慢释放各自的活性药物成分, 实现长效、减小刺激^[69]的临床效果。右美沙芬是常用的中枢镇咳药, 可被肝脏中的细胞色素P4502D6 (CYP2D6) 酶代谢, 5-羟色胺再摄取抑制剂, 如氟西汀、帕罗西汀和舍曲林, 是CYP2D6的抑制剂。因此, 当右美沙芬与此类药物同时服用时, CYP2D6活性会受到抑制, 导致右美沙芬在体内的清除率降低。药代动力学上, 选择性血清再吸收抑制剂抑制CYP2D6酶后, 会显著影响右美沙芬的药代动力学参数, 包括血浆浓度升高、清除率降低和剂量效应增强。美国Avanir Pharmaceuticals制药公司将右美沙芬与肝药酶抑制剂奎尼丁联用, 开发了用于治疗假性延髓影响的氢溴酸右美沙芬和硫酸奎尼丁复方制剂(商品名: Nuedexta)^[70], 是目前唯一获得FDA批准的情感失调治疗药物。它可以有效地减少患者的情感爆发次数和持续时间, 改善患者的生活质量和社会功能。添加酶抑制剂是常见的改良方法, 可以改变药物的药动学特征, 从而实现缓释效果或产生新的用途, 为开发新的复方制剂提供可能。

4.5　增加或改变适应症

药物适应症的改变, 需要结合临床、新型数据资源、靶点的再研究等。往往在临床中, 有的药物体现出新的适应症, 在关注药物临床疗效的同时, 其临床表现也至关重要。比如用于治疗Ⅱ型糖尿病药物利拉鲁肽, 通过临床得到启示, 改良成减肥药, 让老药有了新的价值体现^[71]。

5　改良失败原因和案例

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近些年, 国内改良新药的研发力度逐步增大, 但是企业耗时、耗资的投入却因市场不佳而进退两难, 主要有以下原因导致:

研发企业立项时, 不能精确把控临床的痛点, 比如患者的真实治疗难题、现有治疗方法在安全性、便捷性、疗效方面的不足等, 仅注重药学改良, 比如缓释制剂、临床依从性, 使得耗时研发的缓释制剂改良, 在临床上没有取代价值; 临床现有竞品, 比如长效注射剂、医疗创新器械等的竞争压力, 如果认知不足, 则无法占据有利市场。比如全球首个阿立哌唑“数字药物”因价格问题, 无法与长效注射剂抗衡, 市场不占优势, 反之, 肾上腺素鼻喷剂精准解决患者在急救场景下的需求。此外, 临床医生的处方习惯和思维认知, 也对新的改良制剂的市场影响举足轻重。

研发过程中, 药物的安全性和临床的有效性都影响着改良的结果, 比如Clovis Oncology公司研发的鲁卡帕尼(商品名: Rubraca), 用于治疗卵巢癌、输卵管癌和腹膜癌, 但因疗效不如阿斯利康的奥拉帕利(商品名: Lynparza) 等产品, 且对某些卵巢癌患者的潜在风险和危害, 最终不得不申请退市。

因此, 立项之初, 企业应注重真实的临床需求, 真正的填补临床空白, 才能获得医患双方认可; 另外, 注重差异化竞争策略, 构建自身的竞争优势, 比如技术壁垒、价格优势、应用场景更优、锁定特定目标患者等。对于处方药, 在立项时就需求权威医生的验证, 研发过程中充实的药学研究为医生提供信服的科学依据, 研发中后期需适时进行学术推广, 以便在上市后占据一席之地。

6　结语

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我国改良新药的立项, 需要关注临床急需、临床短缺、具有临床优势的药物, 做到真正以临床问题和需求为导向, 达到增效、减毒、改善顺应性的目的。目前, 神经系统用药、肿瘤用药的依从性和安全性仍需进一步的提高, 国内制药企业应重点关注。同时, 在技术上, 应关注新型制剂技术, 优化用药方式, 国内改良较多的剂型以注射剂、缓释片和口溶膜为主, 其中口溶膜剂型研发周期相对较短, 仅需完成生物等效性试验。“十四五”医药工业发展规划指出, 高选择性、长效缓控释等特点的复杂制剂技术, 如微球等注射剂、缓控释、多颗粒系统等口服制剂, 经皮、植入、吸入、口溶膜等给药系统等, 这也成为我国改良制剂的研发的风向标。随着医药技术的不断进步和患者需求的日益增加, 改良型新药在医药领域的重要性日益凸显, 研发经济优越性、显著的临床优势以及较高的患者依从性使其具有广阔的市场前景。

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2026年第61卷第2期

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doi: 10.16438/j.0513-4870.2025-0307

接收时间：2025-03-21
首发时间：2026-09-21
出版时间：2026-02-12

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收稿日期：2025-03-21
修回日期：2025-08-18

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天津药物研究院有限公司技术创新研究中心, 天津 300301

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靳文仙, Tel: 13820106542, E-mail: jinwx@tjipr.com

王伟, Tel: 18622081595, E-mail: wangw@tjipr.com

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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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Application type	505(b)(1)	505(b)(2)	505(j)
R&D time	10 years	5 years	3 years
Market share	Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months	Add new clinical trials -3 years	First generic drug-6 months

Application type

505(b)(1)

505(b)(2)

505(j)

R&D time

10 years

5 years

3 years

Market share

Orphan drug-7 years/NCE-5 years/Pediatric drugs - add an extra 6 months

Add new clinical trials -3 years

First generic drug-6 months

Trade name	Launch date	Medication cycle	Component and dosage form	Indication
Risperdal	Dec. 1992	1-2 days	Risperidone tablets	Schizophrenia
Risperdal Consta	Aug. 2002	2 weeks	Risperidone injection microspheres	Schizophrenia and bipolar disorder
Invega Sustenua	Dec. 2009	1 month	Pembrolidone long-acting injection	Emotional stability and depression in schizophrenia and schizoaffective disorder
Invega Trinza	Jun. 2015	3-6 months	Pembrolidone long-acting injection

Trade name

Launch date

Medication cycle

Component and dosage form

Indication

Risperdal

Dec. 1992

1-2 days

Risperidone tablets

Schizophrenia

Risperdal Consta

Aug. 2002

2 weeks

Risperidone injection microspheres

Schizophrenia and bipolar disorder

Invega Sustenua

Dec. 2009

1 month

Pembrolidone long-acting injection

Emotional stability and depression in schizophrenia and schizoaffective disorder

Invega Trinza

Jun. 2015

3-6 months

Pembrolidone long-acting injection

Year	Dosage form	Pharmaceutical company
1955	Constant release tablets	Novartis
1982	Sustained release tablets	Novartis
2000	Osmotic pump tablet	ALZA/Johnson
2001	Dual phase sustained-release capsules (microspheres)	Elan
2006	Transdermal drug delivery systems	Hisamitsu
2012	Dual phase oral solution	Tris pharma
2015	Dual phase chewable tablets	Pfizer
2017	Dual phase sustained-release oral disintegrating tablets (microspheres)	Neos pharma

Year

Dosage form

Pharmaceutical company

1955

Constant release tablets

Novartis

1982

Sustained release tablets

Novartis

2000

Osmotic pump tablet

ALZA/Johnson

2001

Dual phase sustained-release capsules
(microspheres)

Elan

2006

Transdermal drug delivery systems

Hisamitsu

2012

Dual phase oral solution

Tris pharma

2015

Dual phase chewable tablets

Pfizer

2017

Dual phase sustained-release oral
disintegrating tablets (microspheres)

Neos pharma

Trade name	Pharmaceutical company	Launch date	Listed country	Technology
Paclitaxel	Shandong Luye Pharmaceutical	Jan. 2003	China	Paclitaxel liposome
Abraxane	Celgene	Feb. 2005	America	Paclitaxel liposome
Cynviloq	Samyang	Jan. 2007	Korea	Paclitaxel polymeric micelles
Nanoxel	Fresenius Kabi	Jan. 2007	India	Paclitaxel nanoparticles
PICN	SunPharma	May. 2014	India	Paclitaxel nanoparticles
Apealea/Paclical	Oasmia	Oct. 2015	Russia	Paclitaxel polymeric micelles
RMX3001 (R&D code)	Shanghai Haihe Biopharma	Sep. 2024	China	Lipid self emulsification delivery

Trade name

Pharmaceutical company

Launch date

Listed country

Technology

Paclitaxel

Shandong Luye Pharmaceutical

Jan. 2003

China

Paclitaxel liposome

Abraxane

Celgene

Feb. 2005

America

Paclitaxel liposome

Cynviloq

Samyang

Jan. 2007

Korea

Paclitaxel polymeric micelles

Nanoxel

Fresenius Kabi

Jan. 2007

India

Paclitaxel nanoparticles

PICN

SunPharma

May. 2014

India

Paclitaxel nanoparticles

Apealea/Paclical

Oasmia

Oct. 2015

Russia

Paclitaxel polymeric micelles

RMX3001 (R&D code)

Shanghai Haihe Biopharma

Sep. 2024

China

Lipid self emulsification delivery