蛋白多肽类药物非注射给药途径的研究

目的:概述近年来蛋白多肽类药物各种非注射给药途径的特点及研究进展。方法:通过比较蛋白多肽类药物口服、鼻腔、口腔粘摸、肺部吸入、透皮吸收等给药途径的特点及研究进展,剖析各种给药途径的优劣势及存在的问题。结果:由于蛋白多肽类药物本身的化学性质及人体各个部位的生理结构特点不同,各种非注射给药途径存在的问题也各不相同。结论:针对口服、鼻腔、口腔粘膜、肺部、皮肤等吸收途径的特点,选择适合蛋白多肽类药物特点的给药途径,能为人类防治疾病取得更好的治疗效果。     

蛋白和多肽药物的透粘膜吸收

随着蛋白和多肽药物的增多，其非注射给药剂型的研究受到了越来越多的重视，本文综述了国外对鼻腔、口腔、口服、直肠和阴道几种主要透粘膜吸收给药途径的研究。蛋白和多肽药物的透粘膜给药剂型的研究推进了蛋白和多肽药物的临床应用。     

生化药物鼻腔给药的研究进展

鼻腔给药系统 (nasaldraydeliverysystem ,NDDS)是指在鼻腔内使用 ,经鼻粘膜吸收而发挥局部或全身治疗作用的制剂。鼻腔给药是传统的给药方式 ,在耳鼻喉科应用极为广泛 ,一般用来治疗各种鼻腔和鼻窦疾病。随着新辅料和治疗新技术的应用 ,发挥全身治疗作用的鼻腔给药制剂的研究越来越受到人们的广泛关注。研究发现许多药物的鼻腔给药生物利用度高于口服给药 ,尤其是随着生物技术的发展 ,越来越多的生化药物 (蛋白质和多肽 )用于治疗各种疾病 ,而这些药物一般不能口服给药 ,因此越来越多的制剂专家把注意力转向鼻腔给药系统。1 鼻腔给药的…     

蛋白质及多肽药物的药剂学研究进展

蛋白质及多肽类药物的体内过程存在的特殊情况，因而为制剂与生物药剂学研究提出了新课题，新给药途径的研究，本文重点介绍了鼻腔给给与肺部给药，长效脂质本，蛋白质及多肽类药物的吸收促进剂以及一些符合时辰节律的药物释放系统如按需给药系统，脉冲释药系统与自我调节系统等。     

蛋白质和肽类药物的口服胃肠道吸收机理

随着生物技术的发展 ,出现了许多用于预防和治疗疾病的多肽和蛋白质药物。蛋白质类药物目前市场总值逾 1 5 0多亿美元。其中肽类药物的销售额超过 2 0亿美元。因此 ,几家公司正重点开发蛋白质和肽类药物新的给药系统。开发给药系统是人们最乐于接受的一种给药方式 ,然而由于多肽与蛋白质类药物特殊的理化性质 ,此类药物口服后吸收差 ,生物利用度低。加之此类药物的t1/2 较短 ,故需频繁注射给药 ,给病人带来极大的痛苦和不便 ,因此 ,蛋白质和肽类药物新的给药途径的研究成为热点。其中口服给药途径的研究尤其重要 ,研究口服后胃肠吸收障碍及…     

提高难透膜水溶性药物口服生物利用度的方法研究进展

难透膜水溶性药物多为基因工程药物或传统中药中水溶性活性成分,近年来该类药物发展迅速,但由于口服生物利用度低,在临床上往往需要注射给药,开发此类药物的口服制剂是近年来药剂学领域关注的热点和难点问题之一。本文综述了改善此类药物口服吸收的方法,包括利用化学修饰、载体主动转运吸收、吸收促进剂、微粒给药系统、生物黏附给药系统和酶抑制剂等方法。部分药物通过此类方法已经成功进入临床试验,个别药物已经上市。     

吸收促进剂的作用机制及其在鼻腔给药中的研究进展

随着新的蛋白质及肽类治疗药物的开发,非侵入性给药途径-鼻腔给药日益受到关注。与口服给药和注射给药相比,鼻腔给药既可避免注射给药带来的生理和心理创伤,也可消除口服给药过程中肝脏的首过效应;且鼻腔黏膜下血管丰富,有助于药物的吸收,也更加便于患者的抢救和自救。然而,由于鼻黏膜屏障的存在,药物很难达到理想的治疗效果,因此需要加入鼻黏膜吸收促进剂来增强药物的吸收。该文主要探讨鼻黏膜吸收促进剂的作用机制及分类,并对FDA已上市鼻腔制剂中的吸收促进剂进行汇总,同时对新型黏膜吸收促进剂在鼻腔给药制剂中的应用进行阐述,以期为鼻腔给药制剂的开发提供依据。     

鼻腔给药系统的研究新进展

近年来药物的鼻腔给药系统受到了越来越多的关注.全球众多制药行业都在致力于基因和多肽类药物新型鼻腔给药系统的研发.现阐述了鼻腔生理特点和药物鼻黏膜转运机制及其影响因素,并对近年来鼻腔给药系统的促吸收途径和发展动向作一概述.     

蛋白质和多肽类药物口服给药研究进展

蛋白质和多肽类药物具有良好的选择性和生物活性,已成为治疗众多疾病的首选药物。由于胃肠道内酶的降解作用以及肠道粘膜的低通透性,蛋白质和多肽类药物口服生物利用度极低,其常规给药一直以注射为主。为了使蛋白质和多肽类药物能够广泛应用于临床,研究人员对蛋白质和多肽类药物口服给药系统做了大量研究。目前用于提高蛋白质和多肽类药物口服生物利用度的方法主要有微粒给药系统、内源性细胞转运系统、应用酶抑制剂和黏附给药系统等。文章就这些方法在蛋白质和多肽类药物口服给药中的应用进行了综述。     

鼻黏膜给药剂型的研究进展

鼻黏膜给药以往多用于局部作用,如杀菌、抗病毒、血管收缩、抗过敏等,通过将药物制成溶液剂滴入鼻腔或制成气雾剂喷入鼻腔。近年来,研究发现一些甾体激素类、抗高血压、镇痛、抗生素类以及抗病毒药物,在鼻腔内用药,通过鼻黏膜吸收,生物利用度比口服更高。某些很难从鼻腔吸收的多肽和蛋白质类药物,当选用合适的黏膜促透剂或制成生物降解性微球等新剂型给药时,能提高鼻腔吸收的生物利用度[1]。近年对鼻黏膜给药达到全身作用的研究报道较多,成为药物新剂型研究的重要领域。本文对近年来有关鼻黏膜给药新剂型、新技术进行了综述。1优点与不足鼻…     

Nasal route and drug delivery systems

Nasal drug administration has been used as an alternative route for the systemic availability of drugs restricted to intravenous administration. This is due to the large surface area, porous endothelial membrane, high total blood flow, the avoidance of first-pass metabolism, and ready accessibility. The nasal administration of drugs, including numerous compound, peptide and protein drugs, for systemic medication has been widely investigated in recent years. Drugs are cleared rapidly from the nasal cavity after intranasal administration, resulting in rapid systemic drug absorption. Several approaches are here discussed for increasing the residence time of drug formulations in the nasal cavity, resulting in improved nasal drug absorption. The article highlights the importance and advantages of the drug delivery systems applied via the nasal route, which have bioadhesive properties. Bioadhesive, or more appropriately, mucoadhesive systems have been prepared for both oral and peroral administration in the past. The nasal mucosa presents an ideal site for bioadhesive drug delivery systems. In this review we discuss the effects of microspheres and other bioadhesive drug delivery systems on nasal drug absorption. Drug delivery systems, such as microspheres, liposomes and gels have been demonstrated to have good bioadhesive characteristics and that swell easily when in contact with the nasal mucosa. These drug delivery systems have the ability to control the rate of drug clearance from the nasal cavity as well as protect the drug from enzymatic degradation in nasal secretions. The mechanisms and effectiveness of these drug delivery systems are described in order to guide the development of specific and effective therapies for the future development of peptide preparations and other drugs that otherwise should be administered parenterally. As a consequence, bioavailability and residence time of the drugs that are administered via the nasal route can be increased by bioadhesive drug delivery systems. Although the majority of this work involving the use of microspheres, liposomes and gels is limited to the delivery of macromolecules (e.g., insulin and growth hormone), the general principles involved could be applied to other drug candidates. It must be emphasized that many drugs can be absorbed well if the contact time between formulation and the nasal mucosa is optimized.     

Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles

The clinical development of therapeutic peptides has been restricted to peptides for non-CNS diseases and parenteral dosage forms due to the poor permeation of peptides across the gastrointestinal mucosa and the blood-brain barrier. Quaternary ammonium palmitoyl glycol chitosan (GCPQ) nanoparticles facilitate the brain delivery of orally administered peptides such as leucine(5)-enkephalin, and here we examine the mechanism of GCPQ facilitated oral peptide absorption and brain delivery. By analyzing the oral biodistribution of radiolabeled GCPQ nanoparticles, the oral biodistribution of the model peptide leucine(5)-enkephalin and coherent anti-Stokes Raman scattering microscopy tissue images after an oral dose of deuterated GCPQ nanoparticles, we have established a number of facts. Although 85-90% of orally administered GCPQ nanoparticles are not absorbed from the gastrointestinal tract, a peak level of 2-3% of the oral GCPQ dose is detected in the blood 30 min after dosing, and these GCPQ particles appear to transport the peptides to the blood. Additionally, although peptide loaded nanoparticles from low (6 kDa) and high (50 kDa) molecular weight GCPQ are taken up by enterocytes, polymer particles with a polymer molecular weight greater than 6 kDa are required to facilitate peptide delivery to the brain after oral administration. By examining our current and previous data, we conclude that GCPQ particles facilitate oral peptide absorption by protecting the peptide from gastrointestinal degradation, adhering to the mucus to increase the drug gut residence time and transporting GCPQ associated peptide across the enterocytes and to the systemic circulation, enabling the GCPQ stabilized peptide to be transported to the brain. Orally administered GCPQ particles are also circulated from the gastrointestinal tract to the liver and onward to the gall bladder, presumably for final transport back to the gastrointestinal tract.     

Drug delivery via the buccal mucosa

A candidate drug has entered the development phase but there are problems in drug delivery. The oral bioavailability is low or provides the wrong plasma profile. It is usual that other routes of administration are proposed such as nasal, pulmonary, transdermal, buccal or rectal drug delivery. These routes offer advantages but they also require some development time. The situation regarding patents has to be examined, specific formulations must be manufactured—which can require a large amount of the active drug—and sometimes new excipients are used and these have to be documented, and other animal species may need to be chosen for appropriate evaluation. The buccal mucosa is one of the administration sites that might provide an alternative for peroral administration. This review will provide an insight into this route of drug delivery and the formulations that are, or can be, used, and it will also describe the challenges or possibilities of this route of administration.     

Nasal mucosal versus gastrointestinal absorption of nasally administered cocaine

Objective: Several xenobiotics, including cocaine, are dosed by the nasal route for systemic effects. The aim of this study was to estimate and compare cocaine input into the systemic circulation after oral and nasal dosing, and to determine the relevance of local absorption through the nasal mucosa. Methods: Cocaine was administered to healthy volunteers through the intravenous, oral, and nasal routes. Cocaine serum concentrations were measured at frequent intervals. From these data, the gastrointestinal, nasal, and nasal mucosa input rate functions were determined using nonparametric, subject-specific population deconvolution. Results: After oral dosing, cocaine input into systemic circulation increased slowly and peaked around 45 min after ingestion. The median systemic bioavailability after oral dosing was 33%. After nasal dosing, drug input was substantial even during the first minute and showed two peaks at 10 min and 45 min after ingestion. Since the second peak after nasal dosing closely resembled drug input after oral administration, we hypothesized that, after nasal administration, a part of the dose is swallowed and thereafter absorbed gastrointestinally. The data from the sessions with nasal cocaine administration were reanalyzed assuming the same shape for gastrointestinal drug input as after oral dosing. The fraction absorbed through the nasal mucosa was estimated to be 19% (95% CI: 11–26%). The fraction absorbed through the nasal mucosa contributed 31% (95% CI: 23–37%) of total systemic cocaine exposure. Conclusions: Our data suggest that the main reason addicts prefer nasal to oral cocaine dosing is faster absorption, enhancing the subjective effects rather than higher bioavailability. Received: 28 December 1999 / Accepted in revised form: 23 March 2000     

Drug development of intranasally delivered peptides

Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug-development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies.     

Hydrogel nanoparticles and nanocomposites for nasal drug/vaccine delivery

Over the past few years, nasal drug delivery has attracted more and more attentions, and been recognized as the most promising alternative route for the systemic medication of drugs limited to intravenous administration. Many experiments in animal models have shown that nanoscale carriers have the ability to enhance the nasal delivery of peptide/protein drugs and vaccines compared to the conventional drug solution formulations. However, the rapid mucociliary clearance of the drug-loaded nanoparticles can cause a reduction in bioavailability percentage after intranasal administration. Thus, research efforts have considerably been directed towards the development of hydrogel nanosystems which have mucoadhesive properties in order to maximize the residence time, and hence increase the period of contact with the nasal mucosa and enhance the drug absorption. It is most certain that the high viscosity of hydrogel-based nanosystems can efficiently offer this mucoadhesive property. This update review discusses the possible benefits of using hydrogel polymer-based nanoparticles and hydrogel nanocomposites for drug/vaccine delivery through the intranasal administration.     

Intranasal absorption of flurazepam, midazolam, and triazolam in dogs.

Intranasal delivery of flurazepam, midazolam, and triazolam was studied in a dog model as a possible alternate route of drug administration for treatment of insomnia. Four beagles received each hypnotic by both intranasal and oral routes on two separate occasions. Plasma concentrations for each hypnotic after dosing were measured by electron-capture gas-liquid chromatography. The mean intranasal absorption rates (tmax) of flurazepam, midazolam, and triazolam were 1.7, 2.0, and 2.6 times faster, respectively, compared with oral dosing. The mean dose-normalized peak concentrations (Cmax) after intranasal delivery were 16.4, 2.9, and 3.4 times higher, respectively, versus oral administration. The mean dose-normalized AUCs estimated for these compounds after nasal administration were 2.4-, 2.5-, and at least 2-fold larger than after oral administration for midazolam, triazolam, and flurazepam, respectively. If these observations can be extrapolated to humans, the faster absorption achieved by the intranasal route would appear to benefit insomniacs characterized by difficulty in falling asleep because of an anticipated faster sedative effect onset. The higher peak concentrations and larger amounts absorbed in the case of intranasal midazolam and triazolam delivery may lead to dose reduction.     

Liposomes and micro/nanoparticles as colloidal carriers for nasal drug delivery

The use of the nasal route for drug delivery has attracted much interest in recent years in the pharmaceutical field. Local and principally systemic drug delivery can be achieved by this route of administration. But the nasal route of delivery is not applicable to all drugs. Polar drugs and some macromolecules are not absorbed in sufficient concentration due to poor membrane permeability, rapid clearance and enzymatic degradation into the nasal cavity. Thus, alternative means that help overcome these nasal barriers are currently in development. Absorption enhancers such as phospholipids and surfactants are constantly used, but care must be taken in relation to their concentration. Drug delivery systems including liposomes, cyclodextrins, micro- and nanoparticles are being investigated to increase the bioavailability of drugs delivered intranasally. This review article discusses recent progress and specific development issues relating to colloidal drug delivery systems in nasal drug delivery.