中国药学杂志

Strategy	Common name of drug	Comments	Dosage form	Indication	Status	Company
Add excipients	Parathyroid hormone	Excipients contain penetration enhancer SNAC and soybean trypsin inhibitor	Tablet	Hypoparathyroidism; Osteoporosis	Phase Ⅱ NCT03516773	Entera Bio. Ltd.
	Exenatide	Enteric coating; The excipients contain penetration enhancers: EDTA and bile salt; Protease inhibitor: aprotinin and soybean enzyme inhibitor	Capsule	Type 2 diabetes mellitus	Phase Ⅱ NCT04564846	Oramed
	Octreotide	Application of TPETM technology: enteric coating, compounded with sodium octanoate as penetration enhancer	Capsule	Acromegaly; systemic childbirth, psoriasis and gastrointestinal disorders	Approved in 2020	Chiasma
	Insulin	POD^TM Technology: combination of penetration enhancer EDTA, bile salt, peptidase inhibitor and soybean trypsin inhibitor	Capsule	Type 1 diabetes mellitus	Phase Ⅲ	University of Texas Health Science Center San Antonio/Oramed Pharmaceuticals
	Salmon calcitonin	Peptelligence^TM technology: combination of penetration enhancer SNAC and protease inhibitor	Tablet	Osteoporosis; Postmenopausal osteoporosis	Phase Ⅲ	Enteris Biopharma and Tarsa Therapeutics
	Semaglutide	Eligen^TM technology: the excipient contains the penetration enhancer SNAC	Tablet	Type 2 diabetes mellitus	Approved in 2019	Novo Nordisk
Nanotechnology	Oshadi Icp	Silicon dioxide nanocarriers	unknown	Diabetes	Phase Ⅱ	Oshadi Drug Administration
The “robot” pill RaniPill^TM	Octreotide	Enteric coating; Micro-needle technology; Add local pH regulator citric acid into the excipients	Capsule	Acromegaly	Phase I NCT03798912	Rani Therapeutics
Self-emulsifying drug delivery system	Cyclosporine A	It forms a self-emulsifying system with oil phase, surfactant and cosurfactant to increase intestinal permeability and inhibit P-glycoprotein efflux and P450 metabolism	Soft capsule	Immunosuppression	Approved in 1995	Novatis AG
Acts locally	Vancomycin	Play a local role in the gastrointestinal tract	Capsule	Gram-positive infection; pseudomembranous colitis	Approved in 1986	ANI Pharmaceuticals
	Colistin sul- fate	Locally acting on the site of bacterial infection	Tablet	Infected	Approved	Biocon Ltd
	Tyrosine	Local action on the throat	Tablet	Pharyngitis	Approved	Sanofi/STADA/The Boots Company PLC
	Pancreatic lipase	Local action on gastrointestinal tract	Capsule	Exocrine Pancreatic Insufficiency	Approved in 2015	AbbVie
Chemical modification	Taltirelin	Amino acid replacement	Capsule	Spinocerebellar degeneration; systemic delivery	Approved in 2000	Mitsubishi Tanabe Pharma Co.
	Linaclotide	Cyclization	Hard capsule	Irritable bowel syndrome; chronic idiopathic constipation	Approved in 2022	Actavis
	Desmopressin acetate	Cyclization	Capsule	Central diabetes insipidus; primary nocturnal enuresis	Approved in 1995	Ferring Pharmaceuticals
	Plecanatide Impurtiy	Amino acid replacement	Capsule	Chronic idiopathic constipation (CIC)	Approved in 2017	Synergy Pharmaceuticals

Strategy	Common name of drug	Comments	Dosage form	Indication	Status	Company
Add excipients	Parathyroid hormone	Excipients contain penetration enhancer SNAC and soybean trypsin inhibitor	Tablet	Hypoparathyroidism; Osteoporosis	Phase Ⅱ NCT03516773	Entera Bio. Ltd.
	Exenatide	Enteric coating; The excipients contain penetration enhancers: EDTA and bile salt; Protease inhibitor: aprotinin and soybean enzyme inhibitor	Capsule	Type 2 diabetes mellitus	Phase Ⅱ NCT04564846	Oramed
	Octreotide	Application of TPETM technology: enteric coating, compounded with sodium octanoate as penetration enhancer	Capsule	Acromegaly; systemic childbirth, psoriasis and gastrointestinal disorders	Approved in 2020	Chiasma
	Insulin	POD^TM Technology: combination of penetration enhancer EDTA, bile salt, peptidase inhibitor and soybean trypsin inhibitor	Capsule	Type 1 diabetes mellitus	Phase Ⅲ	University of Texas Health Science Center San Antonio/Oramed Pharmaceuticals
	Salmon calcitonin	Peptelligence^TM technology: combination of penetration enhancer SNAC and protease inhibitor	Tablet	Osteoporosis; Postmenopausal osteoporosis	Phase Ⅲ	Enteris Biopharma and Tarsa Therapeutics
	Semaglutide	Eligen^TM technology: the excipient contains the penetration enhancer SNAC	Tablet	Type 2 diabetes mellitus	Approved in 2019	Novo Nordisk
Nanotechnology	Oshadi Icp	Silicon dioxide nanocarriers	unknown	Diabetes	Phase Ⅱ	Oshadi Drug Administration
The “robot” pill RaniPill^TM	Octreotide	Enteric coating; Micro-needle technology; Add local pH regulator citric acid into the excipients	Capsule	Acromegaly	Phase I NCT03798912	Rani Therapeutics
Self-emulsifying drug delivery system	Cyclosporine A	It forms a self-emulsifying system with oil phase, surfactant and cosurfactant to increase intestinal permeability and inhibit P-glycoprotein efflux and P450 metabolism	Soft capsule	Immunosuppression	Approved in 1995	Novatis AG
Acts locally	Vancomycin	Play a local role in the gastrointestinal tract	Capsule	Gram-positive infection; pseudomembranous colitis	Approved in 1986	ANI Pharmaceuticals
	Colistin sul- fate	Locally acting on the site of bacterial infection	Tablet	Infected	Approved	Biocon Ltd
	Tyrosine	Local action on the throat	Tablet	Pharyngitis	Approved	Sanofi/STADA/The Boots Company PLC
	Pancreatic lipase	Local action on gastrointestinal tract	Capsule	Exocrine Pancreatic Insufficiency	Approved in 2015	AbbVie
Chemical modification	Taltirelin	Amino acid replacement	Capsule	Spinocerebellar degeneration; systemic delivery	Approved in 2000	Mitsubishi Tanabe Pharma Co.
	Linaclotide	Cyclization	Hard capsule	Irritable bowel syndrome; chronic idiopathic constipation	Approved in 2022	Actavis
	Desmopressin acetate	Cyclization	Capsule	Central diabetes insipidus; primary nocturnal enuresis	Approved in 1995	Ferring Pharmaceuticals
	Plecanatide Impurtiy	Amino acid replacement	Capsule	Chronic idiopathic constipation (CIC)	Approved in 2017	Synergy Pharmaceuticals

无机载体在蛋白多肽类药物口服给药系统中的应用进展

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宋小丹 ¹ , 丛可心 ¹ , 周秀婷 ¹ , 曹德英 ¹ , 宋玉品 ¹^,²^,^* , 高健 ¹^,³^,^* , 向柏 ¹

中国药学杂志 | 综述 2024,59(11): 953-960

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中国药学杂志 | 综述 2024, 59(11): 953-960

无机载体在蛋白多肽类药物口服给药系统中的应用进展

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宋小丹¹, 丛可心¹, 周秀婷¹, 曹德英¹, 宋玉品¹^,²^,^*, 高健¹^,³^,^*, 向柏¹

作者信息

¹ 河北医科大学药学院,石家庄 050017

² 石家庄学院,石家庄 050035

³ 华北制药股份有限公司, 石家庄 050015

宋小丹,女,硕士研究生研究方向:新型纳米药物递送系统

通讯作者:

*宋玉品,女,硕士,讲师研究方向:新型纳米药物递送系统 Tel:(0311)86265591;

高健,男,硕士,正高级工程师研究方向:新型纳米药物递送系统 Tel:(0311)87173829

Research Progress in the Application of Inorganic Carriers in the Oral Delivery System of Protein and Peptide Drugs

Xiaodan SONG¹, Kexin CONG¹, Xiuting ZHOU¹, Deying CAO¹, Yupin SONG¹^,²^,^*, Jian GAO¹^,³^,^*, Bai XIANG¹

Affiliations

¹ College of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China

² Shijiazhuang University, Shijiazhuang 050035, China

³ North China Pharmaceutical Company. Ltd, Shijiazhuang 050015, China

出版时间: 2024-06-08 doi: 10.11669/cpj.2024.11.001

文章导航

摘要

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由于蛋白多肽类药物本身的理化性质,以及口服给药后复杂的pH和酶环境,黏液层屏障及肠上皮组织屏障等原因,致使其口服生物利用度低的难题长期未得到解决。无机纳米粒载体具有多孔刚性结构、载药量大、稳定性强等特点。对其表面进行修饰后能够提高穿黏液能力和跨膜转运能力,从而克服胃肠道生理屏障。本文介绍了蛋白多肽类药物口服给药系统的研究现状,生理屏障限制其口服吸收的机制及应对策略,以及无机材料作为载体在蛋白多肽类药物口服给药系统中的应用。

关键词

无机载体 / 蛋白多肽类药物 / 口服给药

Abstract

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The development of oral delivery systems for protein and peptide drugs has long been the goal of the pharmaceutical field. However, extremely low bioavailability has been an unsolved problem in this research. This is related to the physical and chemical properties of the protein and peptides, as well as the three physiological barriers: the complex pH and enzyme environment after oral administration, the mucus barrier and the intestinal epithelial tissue barrier. With its porous rigid structure and high drug loading and strong stability, inorganic particle carrier has the ability to penetrate mucus and transport intestinal epithelia after surface modification, thus overcoming the three physiological barriers. This study introduces the current clinical application of protein and peptide drugs for oral administration, and the mechanism and coping strategies of physiological barrier that limit their oral absorption. Additionally, the application of inorganic materials as carriers in the oral delivery system of protein and peptide drugs are summarized.

Key words

inorganic carriers / protein and peptide drug / oral delivery

引用本文

宋小丹, 丛可心, 周秀婷, 曹德英, 宋玉品, 高健, 向柏. 无机载体在蛋白多肽类药物口服给药系统中的应用进展. 中国药学杂志, 2024 , 59 (11) : 953 -960 . DOI: 10.11669/cpj.2024.11.001

Xiaodan SONG, Kexin CONG, Xiuting ZHOU, Deying CAO, Yupin SONG, Jian GAO, Bai XIANG. Research Progress in the Application of Inorganic Carriers in the Oral Delivery System of Protein and Peptide Drugs[J]. Chinese Pharmaceutical Journal, 2024 , 59 (11) : 953 -960 . DOI: 10.11669/cpj.2024.11.001

正文

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近年来,低毒高效的蛋白多肽类药物(protein and peptide drugs,PPDs)在临床上的应用日趋增加。由于具有相对分子质量大、亲水性和对酶及pH值敏感等特性,大部分PPDs通过注射给药。这既降低了患者的顺应性,又增加了用药风险,不利于药物的广泛应用。相比之下,口服给药途径能够避免注射引起的疼痛与不适,消除因使用不当或重复注射而引发的感染。然而PPDs的口服递送一直是制药领域的难点问题。胃肠道中存在多种生理障碍^[1](图1):复杂的pH环境、多种蛋白酶的存在造成蛋白多肽的稳定性差;PPDs吸收需要穿过黏液层、肠上皮组织等生理屏障,这使得目前已上市PPDs的口服生物利用度均较低^[2]。

对PPDs进行衍生化,将其包载在纳米粒给药系统中,或加入吸收促进剂均能在一定程度上提高口服生物利用度。将其包载在纳米粒给药系统中的方法既能增加稳定性,又能促进吸收,具有良好的应用前景。构建纳米粒给药系统的关键之一是载体材料的选择。性质稳定,生物相容性好,易于进行化学修饰,强大的载药能力是选择载体材料的重要依据。无机载体具有性质稳定,尺寸、形状和表面能够定制等优势,使其成为构建PPDs口服纳米粒给药系统的优质载体。本文将系统总结PPDs口服吸收机制和研究现状,及近年来无机载体在该领域的应用,以期为PPDs口服纳米粒给药系统的开发提供参考。

1 PPDs口服吸收的研究

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1.1 PPDs的特点

随着生物技术和基因工程的发展,PPDs呈现爆发式增长。BCC Research的统计数据显示,到2026年,全球蛋白药物市场会从2021年的265.0亿美元增加到394.2亿美元,复合年增长率为8.3%^[3]。同样,据Verified Market Research报道,口服蛋白和肽市场规模在2022年为12亿美元,预计到2030年将达到78亿美元,从2023年到2030年的复合年增长率为11.5%^[4]。

PPDs大部分通过注射途径给药。但是注射剂使用安全性低,患者依从性差,尤其对于需要长期用药的疾病,如糖尿病,频繁注射胰岛素可能会引起疼痛、局部组织坏死、皮下注射部位感染、发生硬结等反应,还可能出现低血糖、高胰岛素血症、脂肪营养不良、体重增加等副作用^[5]。相比之下,通过口服途径给药的胰岛素从肠腔吸收后,经过门静脉循环运输到肝脏^[6],模拟内源性胰岛素分泌途径,降低了全身胰岛素的水平^[7],也减少了低血糖和体重增加的问题^[8],因此,开发PPDs的口服制剂成为国内外研究的热点。

1.2 PPDs口服给药系统的研究现状

增加PPDs的口服生物利用度的相关研究,已有很多报道。针对药物本身方面,可以采用化学修饰的方法。例如聚乙二醇修饰^[9]、长链脂肪酸修饰^[10]、非天然氨基酸^[11]修饰以及生物素化^[12]。这些方法的困难在于,进行化学修饰时如何保证药物的安全性、有效性以及活性。制剂技术方面包括加入吸收促进剂^[13]、酶抑制剂^[14],开发口服纳米粒递送系统^[15]、口腔纳米粒给药系统^[16],黏膜黏附给药系统^[17]以及将肽与细胞穿膜肽组合^[18]等方法。上述技术通过保护PPDs免受胃肠道内酶促降解,以及促进其穿过肠上皮组织屏障这2种机制,来提高口服生物利用度^[19]。目前已有几种口服制剂进入临床试验阶段或批准上市,相关药物种类,制剂技术等信息见表1^[5,20-26]。然而即使PPDs口服制剂的研究已有百年历史^[1],人类仍然没有找到一种行之有效的办法解决其生物利用度低的难题。其中的原因可以从药物经口服到进入血液循环的吸收过程进行分析。

2 PPDs口服吸收的生理屏障及促吸收策略

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2.1 胃肠液破坏

为了吸收营养,胃肠道作为人体的消化器官有将进入体内的蛋白分解成氨基酸的使命。胃肠道不同区域pH值差异很大。胃pH值为1.0~4.0,十二指肠pH值约上升为5.5,空肠pH值约为6.0,回肠pH值为7.2~8.0,结肠pH值约为6.5。这些pH环境可能会引起肽键断裂,氧化、脱酰胺、水解等一系列反应,导致蛋白多肽类药物的结构和功能发生变化^[27]。另外,胃肠液中含有多种消化酶。蛋白质进入胃中刺激胃黏膜通过胃内壁细胞分泌胃蛋白酶。胃蛋白酶水解肽键,将蛋白质降解成多肽片段^[28]。多肽在肠道中被由胰腺分泌的大量胰蛋白酶、胰凝乳蛋白酶、弹性蛋白酶降解,丧失功效。蛋白质的其余部分最终被刷状缘膜中的各种肽酶,如氨肽酶或二肽基肽酶,降解成能够被肠上皮细胞摄取进入血液循环的三肽、二肽和相应的氨基酸^[29]。因此,保护PPDs在胃肠道内不被降解,是口服PPDs研发成功的重要前提之一。

为提高PPDs在胃肠道中的稳定性,通常采取调节胃内pH值、使用蛋白酶抑制剂、开发纳米粒给药系统、肠溶包衣、对肽进行聚乙二醇化或环化修饰等手段。

2.2 黏液层的双刃剑作用

黏液是由杯状细胞分泌的亲水凝胶,覆盖在肠上皮组织上,保护胃肠道免受消化酶、酸碱物质及外源性微生物的侵害。黏液主要成分是黏蛋白^[30]。黏蛋白单体通过二硫键结合,形成相对分子质量为(0.5~40)×10⁶的大分子黏蛋白纤维。黏蛋白纤维分为细胞相关蛋白纤维和分泌蛋白纤维,前者长约100~500 nm,后者长达微米级^[30]。这些纤维相互缠绕形成平均孔径为100 nm^[31]的网状结构。黏蛋白纤维中含有大量的丝氨酸、苏氨酸和脯氨酸残基,通过羟基或氨基与低聚糖相连形成糖基化黏蛋白。糖基化黏蛋白上的羧基和硫酸盐基团使得黏液带负电。黏蛋白非糖基化的区域通过吸附或共价结合的方式与脂质相连,形成疏水区。这些脂质覆盖的疏水区域是黏液层捕获外来物质的区域。为了保护肠上皮组织,黏液层平均50~270 min更新1次^[32],可将饮食中引入体内的有害物质排出体外。黏液的网状结构、静电作用、疏水作用和不断更新的特性,均不利于亲水性大分子蛋白多肽到达肠上皮组织。

在给药系统的设计中黏液层发挥着双刃剑的作用(图2)。普通的黏膜黏附纳米粒(mucoadhesive conventional particles,MCP)通过静电作用或疏水作用与黏液层发生吸附,延长药物在胃肠道黏膜的停留时间,增加药物吸收。虽然MCP在一定程度上促进了吸收,但由于该设计是基于微粒与黏液层的吸附作用,大部分微粒被束缚在黏液层中,随着黏液层更新排出体外。因此,其促进药物吸收的作用有限。穿黏液微粒(mucus penetrating particles,MPP)是另一种针对黏液层设计的给药系统,但其与黏液层的作用与MCP完全相反。MPP具有表面接近电中性,亲水性和粒径较小的特点,以克服黏液层的静电作用,疏水作用和黏蛋白纤维的物理缠绕。MPP能够快速穿过黏液层,到达肠上皮组织,而不随黏液的更新排出,增加到达肠上皮组织的量,促进吸收。

2.3 肠上皮组织屏障

肠上皮组织位于黏液层下方,是由一系列分化的细胞通过紧密连接形成的连续的单细胞层。它是药物吸收的又一个生理屏障。肠上皮组织主要由4种细胞组成。其中,普通肠上皮细胞作为药物吸收的主要细胞,数量最多。杯状细胞是分泌黏液的细胞,约占肠细胞总量的16%。M细胞仅占肠细胞总量的1%,但其承担着抗原和微生物吸收的重要功能,是摄取PPDs的主要细胞。还有一种激素分泌细胞,数量较少,能够分泌与消化功能相关的激素^[33]。作为肠上皮细胞层重要组成部分的紧密连接,是两个相邻上皮细胞密切相连的区域,在防止大分子物质穿过肠屏障过程中发挥着重要的作用。它是由多种蛋白及分子复合形成,包括ZO-1,ZO-2等外周膜蛋白、紧密连接蛋白、连接黏附分子、调节蛋白和跨膜整合蛋白^[34]。

药物只有穿过肠上皮组织后才能吸收进入血液循环。根据Lipinksi规则,蛋白多肽相对分子质量大于500,油水分配系数低于-1,并且具有大量的氢键供体或受体,难以直接通过跨膜转运吸收。药物口服吸收的另一条途径是细胞旁路转运。细胞旁路是充满水的紧密连接孔。该孔的直径在3~10Å之间。PPDs相对分子质量大,直径远高于该孔径,难以通过细胞旁路途径被吸收。

针对肠上皮组织的PPDs口服给药系统的设计,通常从跨细胞途径和细胞旁路途径两方面进行(图3)。主动靶向给药系统通过受体介导的胞吞作用促进药物跨膜转运,是提高PPDs口服生物利用度的有效手段。维生素、转铁蛋白、凝集素等是常用的靶向性配体。肠道吸收促进剂通过打开紧密连接促进细胞旁路吸收,或增加细胞膜的通透性促进药物跨膜转运。目前已有超过250种吸收促进剂应用于PPDs口服给药系统的研究。例如,N-(8-[2-羟基苯甲酰基]-氨基)辛酸钠(SNAC)与肽形成疏水离子对,增加了肽的亲脂性,促进跨膜转运,改善了索马鲁肽在胃肠道上皮细胞的吸收^[35]。还有研究发现SNAC显著降低Caco-2细胞单层的跨膜电阻值,使得放射性标记甘露醇的渗透性增加了36倍^[1,36],促进药物的细胞旁路转运。

3 应用于PPDs口服纳米粒给药系统中的无机载体

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纳米粒给药系统广泛应用于提高PPDs的口服生物利用度。载体材料的选择是建立纳米粒给药系统的关键之一。载体材料分为有机材料和无机材料。使用有机材料构建纳米粒给药系统时,往往需要用到有机溶剂。有机溶剂存在增大了封装于其中的PPDs变性的风险,在应用于人体的时候容易产生毒性^[37-39]。有机载体载药量低,稳定性差,药物在胃肠道吸收之前容易发生泄漏^[37-38,40]。无机载体一般具有稳定的刚性结构,在胃肠道中不易坍塌,且具有多孔,比表面积大,载药量大,表面易于功能化等优点。无机载体如硅和二氧化硅、氧化铁、碳、金属有机框架等(图4)已成为替代有机材料的潜力股^[41]。以下将对用于PPDs口服给药系统中的无机载体进行综述。

3.1 二氧化硅

近年来,二氧化硅纳米颗粒因具有易于合成,易于进行表面修饰,生物相容性好,对胃肠道中不同pH环境和酶稳定的特点而受到广泛关注。特别是介孔二氧化硅纳米颗粒,在孔隙率、孔隙形态、颗粒尺寸、孔径大小和形貌可调方面具有更大的优势。

将肽类药物加载到不同形态的介孔二氧化硅中,能降低胃肠道的破坏,提高其生物利用度。吸附在树突状介孔二氧化硅中的胰岛素,在胃中的释放或降解水平降低至5%,而向肠道的运输则有所增强^[42]。将胰岛素包载到球形介孔泡沫硅中后,胰岛素释放过程更加可控^[43]。然而,仅介孔二氧化硅并不能完全克服口服给药后的多重生理屏障。用聚合物、靶向肽等对介孔二氧化硅进行化学修饰,能够进一步提高PPDs的口服生物利用度。Zhang等^[44]在介孔二氧化硅表面修饰了阳离子细胞穿透肽和阴离子戊二酸酐。该纳米粒内部孔径6 nm,胰岛素的大小为2.5 nm×2.7 nm×3.3 nm^[45],载药量为18%,满足了高载药量的要求;表面阴阳离子的修饰使其表面电荷近中性,且具有亲水性,能快速穿过黏液层到达肠上皮细胞表面;穿膜肽通过小窝蛋白介导的胞吞作用,增加纳米粒在肠上皮组织的跨膜转运。最终使得胰岛素的口服相对生物利用度达2.48%。Tan等^[46]在介孔二氧化硅表面修饰了亲水性的聚乳酸-聚乙二醇嵌段聚合物,再在共聚物表面修饰穿膜肽,用于包载胰岛素。该纳米粒同样具有亲水性和近中性的表面性质,在黏液中的滞留量减少了36%。通过硫酸肝素蛋白聚糖受体和小窝蛋白介导的胞吞作用,该纳米粒的细胞摄取量是胰岛素溶液的9.1倍。除此之外,Araújo等^[47]同时用壳聚糖(CS)和细胞穿膜肽(CPP)修饰多孔硅纳米颗粒(PSi)和聚乳酸-羟基乙酸共聚物(PLGA),包载胰高血糖素样肽-1(GLP-1)。胃肠道中存在二肽基肽酶4(DPP4)能够在2 min内使GLP-1迅速降解。该研究通过微流控技术分别将上述纳米粒与DPP4的抑制剂同时包载在肠溶性材料羟丙基甲基纤维素中,形成复合纳米粒。PSi对应的体系中GLP-1的包封率和载药量分别为75%和7.5%,PLGA对应的体系中GLP-1的包封率和载药量分别为59.7%和0.07%,前者细胞摄取的荧光强度高于后者,前者的跨膜转运量是后者的2倍。数据表明,在该体系中无机载体比有机载体更有优势。

除了改善胰岛素的口服给药外,国内外学者还开展了大量有关介孔二氧化硅口服递送疫苗的研究。Xi等^[48]以牛血清白蛋白(BSA)为抗原模型药物,构建了壳聚糖修饰的介孔二氧化硅纳米颗粒,用于保护抗原在胃肠道复杂的生理环境不降解。结果表明,纳米粒在体外12 d的释放量仅50%,且释放出的BSA结构完整。Kumeria等^[49]用PSi负载免疫球蛋白A-2(IgA2)抗体,并将其装载在明胶胶囊中,在胶囊外包裹pH值响应聚合物丙烯酸树脂。体外释放结果表明该体系在人工肠液中释放的抗体保存了45%~54%的活性。此外,还有人将二氧化硅纳米颗粒用于口服万古霉素的研究。研究中合成了不同孔径的二氧化硅,并通过修饰不同的官能团来改变其表面电荷和极性,以提高纳米粒的控释能力和渗透性能。结果发现与万古霉素原料药相比,带负电荷的大孔二氧化硅可使万古霉素在肠上皮细胞单层的通透性提高6倍,渗透性显著增强^[50]。

3.2 碳纳米材料

碳纳米材料在生物医学纳米技术领域已成为研究热点,它的碳碳键使碳纳米材料具有出色的化学、热、机械、光学和电子性能。碳碳键的灵活性使碳原子可与其他原子形成各种类型的键^[51]。因此碳纳米材料被认为是药物递送领域杰出的载体材料。常见的碳纳米材料有纳米管、富勒烯、石墨烯、碳纳米球等^[52]。

在糖尿病的治疗领域,碳纳米材料包载胰岛素表现出强大的降血糖作用,为设计高效的胰岛素口服递送系统开辟了新的途径。Ganeshkumar等^[53]开发了涂有壳聚糖和丙烯酸树脂L-100的中空碳纳米球用于包载胰岛素。该中空碳纳米球载体具有两亲性,能够通过疏水作用促进药物跨膜转运。丙烯酸树脂L-100为肠溶衣,使药物在胃的pH条件下不释放。结果显示,糖尿病大鼠在给药4 h后血糖水平降低到给药前的33%,且降血糖效果持续了6 h。

家蝇天蚕素(Musca domestica cecropin,MDC)是一种治疗溃疡性结肠炎的蛋白类药物。为提高MDC的口服生物利用度,Zhang等^[54]开发了一种由MDC和介孔碳纳米颗粒(mesoporous carbon nanoparticles,MCNs)组成的新型结肠靶向口服药物递送平台(MDC@MCNs)。与MDC相比,MDC@MCNs表现出更优异的抗胰蛋白酶破坏能力,更易被结肠上皮细胞NCM460摄取。同时在结肠炎区域,阳离子蛋白表达上调,使得肠上皮组织表面正电荷增加。MDC@MCNs与肠上皮组织的静电作用增强,黏附性增强,口服生物利用度提高^[55]。

碳纳米粒在疫苗的口服递送中也有所应用。Wang等^[56]合成了一种疏水性碳纳米颗粒(C1),用于包载BSA。该碳纳米粒子具有大孔或大中孔结构,载药量高。BSA被分散在不同的孔道中,蛋白之间的聚集性降低,稳定性增加,活性增强。纳米粒的疏水性使其对M细胞亲和力增加,促进了M细胞的摄取。Balb/c小鼠口服负载BSA的碳纳米颗粒后,IgG滴度与肌内注射的BSA基本一致,在肠道、唾液和阴道分泌物中均可以检测到IgA,且辅助性T细胞介导的反应均被诱导。这项研究证实了碳纳米颗粒作为口服疫苗载体的潜力。Bavandpour^[57]将霍乱毒素抗原(Cholera toxin subunit B,CTB)加载到介孔碳纳米粒子中,口服给药。结果发现兔子首次免疫后第4周产生显著的抗CTB IgG。该纳米粒子可以保护抗原免受酸性和蛋白水解酶的影响,是口服疫苗的良好载体。

3.3 碳酸钙

碳酸钙作为金属氧化物,具有无机载体的优势,如较好的化学稳定性、热稳定性和多孔结构,适合包载药物。而作为天然矿物,它具有生物相容性好、制备条件温和、可生物降解等优点。

在口服疫苗开发中,碳酸钙纳米粒能够利用自身独特的优势对抗恶劣的胃肠道吸收屏障,且碳酸钙本身具有亲水性和电中性的特点,符合MPP的要求^[58]。Snook等^[58]通过将碳酸钙沉淀在含有自组装肽KFE8纳米纤维的水缓冲液中,合成了KFE8纳米纤维-碳酸钙复合纳米粒。该研究以卵清蛋白(ovalbumins,OVA)为模型抗原,将其包载在KFE8纳米纤维-碳酸钙复合纳米粒中。与口服接种OVA-KFE8纳米纤维、PBS或OVA的对照组小鼠相比,在口服了OVA-KFE8纳米纤维-碳酸钙复合纳米粒的小鼠粪便提取物中检测到更高水平的抗体。口服胰岛素研发中,碳酸钙也发挥了较好的作用。Liu等^[14]利用反相微乳共沉淀法制备了含透明质酸涂层的碳酸钙复合纳米载体,并将其用来包载胰岛素。透明质酸可以减缓碳酸钙在酸性环境中的分解速度,提高胰岛素的稳定性。大鼠口服上述纳米粒后,血糖能够降到与皮下注射胰岛素相同的水平。

3.4 金纳米粒

金纳米粒具有生物相容性好,比表面积大,容易与生物分子结合等特性^[59],同时还具有氧化还原活性、表面等离子共振、表面拉曼散射和荧光猝灭效应^[60-61],这些多功能性已使其在生物传感、药物递送以及疾病诊断等领域发挥重要作用^[62-63]。金纳米粒具有多种形态,包括金纳米球、金纳米笼、金纳米线等。

与介孔二氧化硅纳米颗粒相同,金纳米粒已被广泛探索用作胰岛素的口服递送载体。Cho等^[64]利用被硫酸软骨素覆盖的金纳米粒包裹胰岛素。口服2 h后,血浆中胰岛素的平均质量浓度比胰岛素溶液处理组高出6.61倍,4 h后血糖水平显著低于胰岛素溶液处理组。Bhumkar等^[65]合成了一种壳聚糖还原的金纳米粒,促进胰岛素在黏膜上的渗透和摄取。Kang等^[66]开发出一种口服递送Akt siRNA的金纳米偶联物,用于治疗结直肠癌肝转移。该纳米粒通过在金纳米粒表面修饰乙二醇壳聚糖-牛磺胆酸偶联物,促进顶端膜离子依赖型胆汁酸转运体介导的吸收。体外细胞实验表明,游离Akt siRNA导致24%肝癌细胞凋亡,加载到金纳米偶联物中的Akt siRNA导致67%的肝癌细胞凋亡。

除此之外,金纳米粒易于与抗原结合,它在口服疫苗的研究中引发关注。Barhate等^[67]制备了壳聚糖功能化的金纳米粒同时包载破伤风疫苗(tetanus toxoid,TT)和免疫增强剂皂树提取物。体外研究显示,CsGNPs可以保护TT免受胃中酸性环境的水解。口服给药后,纳米粒诱导的免疫反应是TT的28倍。Esteban-Fernandez de Avila等^[68]将半胱氨酸蛋白酶加载到涂有pH值响应聚合物涂层的金纳米线中,形成纳米马达。体外研究表明,该纳米马达可以在5min内实现80%的人胃腺癌细胞凋亡,显著优于其他半胱氨酸蛋白酶递送方法。

3.5 其他

除了上述常见的载体外,还有很多无机载体被用于PPDs口服递送的研究,如硒纳米粒子、羟基磷灰石、金属有机框架、磷酸钙、磷酸锆等。

研究表明,糖尿病患者经常表现出强烈的氧化应激反应,硒具有良好的抗氧化作用。因此糖尿病患者对硒的摄取量高。硒能够改善胰岛功能,提高葡萄糖的利用率,具有与胰岛素相似的降糖作用。因此将硒作为胰岛素载体制备纳米粒,对糖尿病的治疗具有很好的协同作用。Deng等^[69]采用离子交联和原位还原技术制备了负载胰岛素的硒纳米粒。胰岛素口服相对生物利用率高达9.15%,且降血糖效果可以持续10h。羟基磷灰石具有生物相容性和多孔性,是一种理想的药物载体。Zhang等^[70]制备了聚乙二醇(PEG)包裹的羟基磷灰石纳米颗粒,PEG与胰岛素和没食子酸偶联。羟基磷灰石具有多孔结构,比表面积大,载药量高。PEG的修饰增加了纳米粒的亲水性,提高了胰岛素和没食子酸的稳定性。口服该纳米粒后,空腹血糖水平明显下降,7 h后血糖水平仍能维持在最高血糖值的50%。Zhou等^[71]设计了两性离子水凝胶包被的金属有机框架(MOF)纳米颗粒,用于包载艾塞那肽,并将其装载在肠溶胶囊中。MOF具有孔径大、比表面积大的特点,有利于蛋白多肽的高效载药。两性离子水凝胶层使纳米粒既有穿黏液能力,又有利于肠细胞摄取。糖尿病大鼠模型口服胶囊后,血浆中艾塞那肽水平显著增强,持续时间超过8 h,内源性胰岛素分泌显著增加,降糖效果明显。Chen等^[72]设计了一种用于胰岛素口服递送的耐酸介孔MOF。该体系能够在30 min内完成胰岛素的包载,载药量高达40%,且在模拟胃液中1h的释放量低于10%,在模拟肠液中释放量约为90%。在模拟胃液中释放出来的胰岛素能够保持84%的活性,在模拟肠液中释放出胰岛素的活性高达100%。

4 总结与展望

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PPDs具有高选择性和有效性,被开发用于治疗多种疾病。口服作为PPDs的给药途径,展现出非常广阔的应用前景。但是复杂的胃肠道生理环境,黏液层和肠上皮组织的吸收屏障对该应用提出了巨大挑战。对PPDs结构进行修饰,加入pH值调节剂和吸收促进剂,构建纳米粒给药系统是提高口服生物利用度的有效方法。与有机纳米粒载体相比,无机载体在载药量和稳定性方面具有更大的优势。二氧化硅、碳纳米材料、碳酸钙、金、硒、羟基磷灰石、磷酸钙、磷酸锆等均在该领域有所应用。但相关研究仍处于基础研究阶段。无机载体在体内环境中不可降解,而有些PPDs需要长期给药,这会导致载体在人体中蓄积从而产生毒性^[73]。另外,制造技术的可重复性、储存条件的可行性以及在人体中可重复的治疗效果都是开发无机纳米载体重点解决的问题^[74]。

设计能在肠上皮组织及时释放药物,协助药物安全地被肠上皮组织吸收,而载体本身不吸收的智能纳米粒,能够在一定程度上解决无机载体在体内蓄积毒性的问题。结合有机化合物的多功能性和无机载体的稳定性,合成无机-有机杂化复合物,作为PPDs的载体,这将成为未来研究的热点。

基金

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国家自然科学基金项目资助(81973251)

参考文献

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文献

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2024年第59卷第11期

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doi: 10.11669/cpj.2024.11.001

接收时间：2023-02-22
首发时间：2025-11-25
出版时间：2024-06-08

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收稿日期：2023-02-22

基金

国家自然科学基金项目资助(81973251)

作者信息

¹ 河北医科大学药学院,石家庄 050017

² 石家庄学院,石家庄 050035

³ 华北制药股份有限公司, 石家庄 050015

通讯作者:

*宋玉品,女,硕士,讲师研究方向:新型纳米药物递送系统 Tel:(0311)86265591;

高健,男,硕士,正高级工程师研究方向:新型纳米药物递送系统 Tel:(0311)87173829

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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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TxT

Strategy	Common name of drug	Comments	Dosage form	Indication	Status	Company
Add excipients	Parathyroid hormone	Excipients contain penetration enhancer SNAC and soybean trypsin inhibitor	Tablet	Hypoparathyroidism; Osteoporosis	Phase Ⅱ NCT03516773	Entera Bio. Ltd.
	Exenatide	Enteric coating; The excipients contain penetration enhancers: EDTA and bile salt; Protease inhibitor: aprotinin and soybean enzyme inhibitor	Capsule	Type 2 diabetes mellitus	Phase Ⅱ NCT04564846	Oramed
	Octreotide	Application of TPETM technology: enteric coating, compounded with sodium octanoate as penetration enhancer	Capsule	Acromegaly; systemic childbirth, psoriasis and gastrointestinal disorders	Approved in 2020	Chiasma
	Insulin	POD^TM Technology: combination of penetration enhancer EDTA, bile salt, peptidase inhibitor and soybean trypsin inhibitor	Capsule	Type 1 diabetes mellitus	Phase Ⅲ	University of Texas Health Science Center San Antonio/Oramed Pharmaceuticals
	Salmon calcitonin	Peptelligence^TM technology: combination of penetration enhancer SNAC and protease inhibitor	Tablet	Osteoporosis; Postmenopausal osteoporosis	Phase Ⅲ	Enteris Biopharma and Tarsa Therapeutics
	Semaglutide	Eligen^TM technology: the excipient contains the penetration enhancer SNAC	Tablet	Type 2 diabetes mellitus	Approved in 2019	Novo Nordisk
Nanotechnology	Oshadi Icp	Silicon dioxide nanocarriers	unknown	Diabetes	Phase Ⅱ	Oshadi Drug Administration
The “robot” pill RaniPill^TM	Octreotide	Enteric coating; Micro-needle technology; Add local pH regulator citric acid into the excipients	Capsule	Acromegaly	Phase I NCT03798912	Rani Therapeutics
Self-emulsifying drug delivery system	Cyclosporine A	It forms a self-emulsifying system with oil phase, surfactant and cosurfactant to increase intestinal permeability and inhibit P-glycoprotein efflux and P450 metabolism	Soft capsule	Immunosuppression	Approved in 1995	Novatis AG
Acts locally	Vancomycin	Play a local role in the gastrointestinal tract	Capsule	Gram-positive infection; pseudomembranous colitis	Approved in 1986	ANI Pharmaceuticals
	Colistin sul- fate	Locally acting on the site of bacterial infection	Tablet	Infected	Approved	Biocon Ltd
	Tyrosine	Local action on the throat	Tablet	Pharyngitis	Approved	Sanofi/STADA/The Boots Company PLC
	Pancreatic lipase	Local action on gastrointestinal tract	Capsule	Exocrine Pancreatic Insufficiency	Approved in 2015	AbbVie
Chemical modification	Taltirelin	Amino acid replacement	Capsule	Spinocerebellar degeneration; systemic delivery	Approved in 2000	Mitsubishi Tanabe Pharma Co.
	Linaclotide	Cyclization	Hard capsule	Irritable bowel syndrome; chronic idiopathic constipation	Approved in 2022	Actavis
	Desmopressin acetate	Cyclization	Capsule	Central diabetes insipidus; primary nocturnal enuresis	Approved in 1995	Ferring Pharmaceuticals
	Plecanatide Impurtiy	Amino acid replacement	Capsule	Chronic idiopathic constipation (CIC)	Approved in 2017	Synergy Pharmaceuticals

Strategy

Common name of drug

Comments

Dosage form

Indication

Status

Company

Add excipients

Parathyroid hormone

Excipients contain penetration enhancer SNAC and soybean trypsin inhibitor

Tablet

Hypoparathyroidism; Osteoporosis

Phase Ⅱ NCT03516773

Entera Bio. Ltd.

Exenatide

Enteric coating; The excipients contain penetration enhancers: EDTA and bile salt; Protease inhibitor: aprotinin and soybean enzyme inhibitor

Capsule

Type 2 diabetes mellitus

Phase Ⅱ NCT04564846

Oramed

Octreotide

Application of TPETM technology: enteric coating, compounded with sodium octanoate as penetration enhancer

Capsule

Acromegaly; systemic childbirth, psoriasis and gastrointestinal disorders

Approved in 2020

Chiasma

Insulin

POD^TM Technology: combination of penetration enhancer EDTA, bile salt, peptidase inhibitor and soybean trypsin inhibitor

Capsule

Type 1 diabetes mellitus

Phase Ⅲ

University of Texas Health Science Center San Antonio/Oramed Pharmaceuticals

Salmon calcitonin

Peptelligence^TM technology: combination of penetration enhancer SNAC and protease inhibitor

Tablet

Osteoporosis; Postmenopausal osteoporosis

Phase Ⅲ

Enteris Biopharma and Tarsa Therapeutics

Semaglutide

Eligen^TM technology: the excipient contains the penetration enhancer SNAC

Tablet

Type 2 diabetes mellitus

Approved in 2019

Novo Nordisk

Nanotechnology

Oshadi Icp

Silicon dioxide nanocarriers

unknown

Diabetes

Phase Ⅱ

Oshadi Drug Administration

The “robot” pill
RaniPill^TM

Octreotide

Enteric coating; Micro-needle technology; Add local pH regulator citric acid into the excipients

Capsule

Acromegaly

Phase I NCT03798912

Rani Therapeutics

Self-emulsifying drug
delivery system

Cyclosporine A

It forms a self-emulsifying system with oil phase, surfactant and cosurfactant to increase intestinal permeability and inhibit P-glycoprotein efflux and P450 metabolism

Soft capsule

Immunosuppression

Approved in 1995

Novatis AG

Acts locally

Vancomycin

Play a local role in the gastrointestinal tract

Capsule

Gram-positive infection;
pseudomembranous colitis

Approved in 1986

ANI Pharmaceuticals

Colistin sul-
fate

Locally acting on the site of bacterial infection

Tablet

Infected

Approved

Biocon Ltd

Tyrosine

Local action on the throat

Tablet

Pharyngitis

Approved

Sanofi/STADA/The Boots Company PLC

Pancreatic
lipase

Local action on gastrointestinal tract

Capsule

Exocrine Pancreatic Insufficiency

Approved in 2015

AbbVie

Chemical modification

Taltirelin

Amino acid replacement

Capsule

Spinocerebellar degeneration; systemic delivery

Approved in 2000

Mitsubishi Tanabe Pharma Co.

Linaclotide

Cyclization

Hard capsule

Irritable bowel syndrome; chronic idiopathic constipation

Approved in 2022

Actavis

Desmopressin acetate

Cyclization

Capsule

Central diabetes insipidus; primary nocturnal enuresis

Approved in 1995

Ferring Pharmaceuticals

Plecanatide
Impurtiy

Amino acid replacement

Capsule

Chronic idiopathic constipation (CIC)

Approved in 2017

Synergy Pharmaceuticals