Nasal Administration: A Tool for Tomorrow's Systemic Administration of Drugs

Abstract

By its anatomy and physiology, due to the great amount of air treated there, the nasal route represents a very interesting possibility for the administration of products degraded in the gastro-intestinal tract or inhibited by the first hepatic pass. The nasal dosage forms most studied are bioadhesive hydrogels and microspheres, especially for the systemic administration of peptides.     

The Relationship Between the Rigidity of the Liposomal Membrane and the Absorption of Insulin After Nasal Administration of Liposomes Modified with an Enhancer Containing Insulin in Rabbits

The relationship between the rigidity of the liposomal membrane and the absorption of insulin after nasal administration of liposomes modified with an enhancer containing insulin was investigated for the nasal delivery of peptide drugs in rabbits. The rigid liposomal membrane makes liposomes stable, protecting insulin from enzymatic degradation. Soybean-derived sterol (SS) or its sterylglucoside (SG) was used as an enhancer. Dipalmitoylphosphatidylcholine (DPPC) liposomes modified with SG had increased fluidity of the hydrophobic group of the liposome bilayer compared with the liposomes modified with cholesterol (Ch) or SS, as shown by measurements of the steady-state fluorescence anisotropy of 1,6-diphenyl-1,3,5,-hexatriene (DPH); however, the fluidity of the polar group of the liposome bilayer was decreased according to measurements of steady-state fluorescence anisotropy of dansylhexadecylamine (DSHA) at 37°C. These findings suggest that the fluidity of the hydrophobic group of the liposome bilayer is responsible for the increase of liposomal leakage and instability of the liposomes. When insulin was administered nasally to rabbits as a solution, no hypoglycemic effect was observed. The administration of insulin contained in DPPC/SG (7/4, mole) liposomes with high fluidity caused a high glucose reduction of long duration (8 hr). DPPC/SS and DPPC/Ch (7/4) liposomes with low fluidity caused low glucose reductions. These results demonstrated that liposomes modified with SG can be useful as carriers of insulin administered nasally.     

Pharmacodynamic Comparison of a Nasal Formulation of Verapamil and Intravenous and Oral Dosage Forms

The nasal route has been shown to be effective for the administration of numerous drugs in order to improve drug bioavailability. A nasal gel of verapamil hydrochloride was formulated and evaluated pharmacodynamically in humans, using electrocardiographic results, with comparison to oral and IV routes. Seven volunteers were involved in the study and the pharmacodynamic parameters were evaluated statistically. Experimental nasal gel showed similar pharmacodynamic results with the intravenous route, which is a hint to the reduction in verapamilinduced first-pass metabolism. However, oral route of administration showed a tendency of less efficacy. No reasonable effect of verapamil could be obtained with the placebo group.     

Ondansetron-loaded chitosan microspheres for nasal antiemetic drug delivery: an alternative approach to oral and parenteral routes

Background: The aim of this study was to develop chitosan microspheres for nasal delivery of ondansetron hydrochloride (OND). Method: Microspheres were prepared with spray-drying method using glutaraldehyde as the crosslinking agent. Microspheres were characterized in terms of morphology, particle size, zeta potential, production yield, drug content, encapsulation efficiency, and in vitro drug release. Results: All microspheres were spherical in shape with smooth surface and positively charged. Microspheres had also high encapsulation efficiency and the suitable particle size for nasal administration. In vitro studies indicated that all crosslinked microspheres had a significant burst effect, and sustained drug release pattern was observed until 24 hours following burst drug release. Nasal absorption of OND from crosslinked chitosan microspheres was evaluated in rats, and pharmacokinetic parameters of OND calculated from nasal microsphere administration were compared with those of both nasal and parenteral administration of aqueous solutions of OND. In vivo data also supported that OND-loaded microspheres were also able to attain a sustained plasma profile and significantly larger area under the curve values with respect to nasal aqueous solution of OND. Conclusion: Based on in vitro and in vivo data, it could be concluded that crosslinked chitosan microspheres are considered as a nasal delivery system of OND.     

看板管理在企业的应用

借鉴实施丰田生产方式准时化的一种重要手段——看板管理的原理和方法等技术，结合实践形成了适合成批多品种生产，满足市场需求的新看板管理模式，论述了在生产现场中的具体运作方法，阐述了看板管理系统的构筑思路。     

我国民政事业标准化问题分析与政策建议

作为现代民政的重要构成,近年来民政事业标准化工作受到了广泛关注和高度重视。文章在现状梳理和问题分析的基础上,参考国内外标准化管理先进做法和良好经验,从管理机制、顶层设计、标准研制、标准宣贯实施和队伍建设五维度提出了民政事业标准化工作政策建议,为落实民政事业标准化战略任务、提升民政事业标准化整体水平探索现实路径,可为民政部门制定民政事业标准化相关法规、政策和决策提供参考依据。     

COMPARISON OF NASAL INSULIN POWDERS PREPARED BY SUPERCRITICAL FLUID AND FREEZE-DRYING TECHNIQUES

In this study, the effect of drug loading on the nasal absorption of insulin was determined. Human insulin was loaded into different drug carriers by two methods: supercritical fluid processing and freeze-drying. The powder formulations were characterized and then evaluated after nasal administration to alloxan induced diabetic rabbits at a dose of 5U/kg and 7.5U/kg. The blood glucose levels and serum insulin levels were monitored for five hours after administration of insulin formulations. The drug carriers evaluated were: ammonium glycyrrhizinate (AG), polyacrylic acid (PAA), cross-linked polyacrylic acid (CPAA), polyethylene oxide (PEO) and chitosan (CHTN).

Nasal administration of AG infused with insulin by carbon dioxide resulted in absolute bioavailability of 9.81% as compared to 2.86% observed with same powder loaded with insulin by freeze-drying. 8.05% bioavailability was obtained with PAA powder loaded with insulin by carbon dioxide as compared to much lower absorption seen with freeze-dried formulation. Similarly a two fold increase in absolute bioavailability was observed when carbon dioxide infused CPAA powder formulation was compared to the lyophilized powder. Nasal administration of PEO and CHTN loaded with insulin by carbon dioxide resulted in bioavailabilities of 1.55% and 1. 18% respectively.

The drug-loading process seems to have a significant effect on nasal absorption of insulin. The powders loaded with insulin by carbon dioxide infusion resulted in significantly higher absorption. The exact mechanism is still not known and a possible explanation for increased absorption may be due to improved stability of insulin in carbon dioxide infused formulations. Among the powders evaluated, polyacrylic acid and ammonium glycyrrhizinate prepared by carbon dioxide infusion as drug-loading method seem to offer good potential for development of nasal powder dosage forms for insulin.     

论公共行政的伦理基础

文章主要论述了公共行政中蕴含的伦理学意义及价值追求，权力的两重性和权力的道德约束，以及构建道德体制的实现途径等若干问题。通过对这些问题的探讨，试图对解决目前中国面临的公共管理危机问题提供一个新的视角。     

COMPARISON OF NASAL INSULIN POWDERS PREPARED BY SUPERCRITICAL FLUID AND FREEZE-DRYING TECHNIQUES

ABSTRACT

In this study, the effect of drug loading on the nasal absorption of insulin was determined. Human insulin was loaded into different drug carriers by two methods: supercritical fluid processing and freeze-drying. The powder formulations were characterized and then evaluated after nasal administration to alloxan induced diabetic rabbits at a dose of 5U/kg and 7.5U/kg. The blood glucose levels and serum insulin levels were monitored for five hours after administration of insulin formulations. The drug carriers evaluated were: ammonium glycyrrhizinate (AG), polyacrylic acid (PAA), cross-linked polyacrylic acid (CPAA), polyethylene oxide (PEO) and chitosan (CHTN).

Nasal administration of AG infused with insulin by carbon dioxide resulted in absolute bioavailability of 9.81% as compared to 2.86% observed with same powder loaded with insulin by freeze-drying. 8.05% bioavailability was obtained with PAA powder loaded with insulin by carbon dioxide as compared to much lower absorption seen with freeze-dried formulation. Similarly a two fold increase in absolute bioavailability was observed when carbon dioxide infused CPAA powder formulation was compared to the lyophilized powder. Nasal administration of PEO and CHTN loaded with insulin by carbon dioxide resulted in bioavailabilities of 1.55% and 1. 18% respectively.

The drug-loading process seems to have a significant effect on nasal absorption of insulin. The powders loaded with insulin by carbon dioxide infusion resulted in significantly higher absorption. The exact mechanism is still not known and a possible explanation for increased absorption may be due to improved stability of insulin in carbon dioxide infused formulations. Among the powders evaluated, polyacrylic acid and ammonium glycyrrhizinate prepared by carbon dioxide infusion as drug-loading method seem to offer good potential for development of nasal powder dosage forms for insulin.     

A Simplified Rat Model for Studying Nasal Drug Absorption

Abstract

A simple and rapid rat model for studying nasal drug absorption was developed. In this model, a solution of the test drug, propranolol hydrochloride, was gradually deposited into the nasal cavity of an anesthetized rat through a PE-20 polyethylene catheter connected to a tuberculin syringe via a 30 gauge needle. The extent of drug bioavailability was assessed by measuring propranolol blood levels and the changes in heart rate. For comparative purposes, identical experiments were repeated using the intravenous route of administration, an established rat model requiring surgery, and the proposed model after tracheal cannulation and esophageal li-gation. Although the pharmacokinetic parameters for the various models tested indicated bioavailabilities that were quite similar to that obtained by the intravenous route of administration, the drop in heart rates appeared to be more pronounced with the proposed model than with any of the other two models. In addition to its simplicity, the proposed rat model represents a less stressful and more physiological means of delivering a drug by the nasal route.     

A Simplified Rat Model for Studying Nasal Drug Absorption

A simple and rapid rat model for studying nasal drug absorption was developed. In this model, a solution of the test drug, propranolol hydrochloride, was gradually deposited into the nasal cavity of an anesthetized rat through a PE-20 polyethylene catheter connected to a tuberculin syringe via a 30 gauge needle. The extent of drug bioavailability was assessed by measuring propranolol blood levels and the changes in heart rate. For comparative purposes, identical experiments were repeated using the intravenous route of administration, an established rat model requiring surgery, and the proposed model after tracheal cannulation and esophageal li-gation. Although the pharmacokinetic parameters for the various models tested indicated bioavailabilities that were quite similar to that obtained by the intravenous route of administration, the drop in heart rates appeared to be more pronounced with the proposed model than with any of the other two models. In addition to its simplicity, the proposed rat model represents a less stressful and more physiological means of delivering a drug by the nasal route.     

Nasal absorption of sulfobromophthalein and amaranth

Abstract

Nasal absorption of sulfobromophthalein (BSP) and amaranth (AM) was investigated and compared with oral absorption in the rat. Bioavailability of BSP and AM after nasal administration was about 26% and 30% respectively. Oral absorption of them was not detected. Nasal route was considered more effective than oral route for these anionic model drugs, but their nasal bioavailability was not so good as expected from the reports for other drugs. High nasal mucus binding of BSP and AM were implied by their high binding to plasma protein (97% and 94%) or to intestinal mucus (78% and 81%). They seemed to have very low lipophilicity since their apparent partition coefficient(APC) between phosphate buffer of various pH and n-octanol were almost zero. They have too large molecular size to pass through the pore (<0.4nm) of nasal mucus membrane. Therefore it was concluded that the low nasal bioavailability of these anionic model drugs might be due to either nonspecific binding to nasal mucus, or low lipophilicity to pass the nasal mucus membrane, or their large molecular size to pass through the pore route of the nasal mucus. Possibility of nasal metabolism in the mucus membrane was excluded since the reported enzymes in the nasal mucus may not affect the metabolism of them.     

地方开展监狱执法管理标准化建设的分析和思考

本文分析了我国监狱执法管理标准化建设的实践情况,分析了监狱执法管理标准化的概念和内涵,提出了地方开展监狱执法管理标准化建设的工作路径、重点内容和措施建议。     

Intraduodenal Administration of Biocarrier-Insulin Systems

Successful oral administration of insulin for systemic therapeutic effects has long been a major pharmaceutical challenge. Intraduodenal administration of insulin to rats, free or in a form of carrier-insulin, was the subject of this study. Several erythrocyte-membrane carrier systems (ghosts, vesicles, liposomes-ghosts, and liposomes-vesicles) were tested. Insulin (100 U) was incubated with each of the carriers at 37°C for 24 hr. The carrier-insulin system, insulin solution, sodium chloride solution, or carrier-free insulin was then introduced into the duodenum of anesthetized male Wistar diabetic rats. Blood samples were collected from the tail at different time intervals and then analyzed for glucose content using an o-toluidine method. There was no significant difference in blood glucose concentrations among the control groups. However, ghosts-insulin, vesicles-insulin, and liposomes-vesicles-insulin all showed a statistically significant difference in lowering blood glucose levels when compared to control groups. Liposomes-ghosts-insulin did not show any significant difference from its control group. The results indicate that liposomes-vesicles-insulin was the most efficient in delivering insulin into the circulation in its pharmacologically active form of any other carrier tested. The findings of this study may be of significance in the search for a suitable oral carrier for insulin or perhaps other proteinaceous substances.     

Preparation and evaluation of carfentanil nasal spray employing cyclodextrin inclusion technology

Carfentanil (CFTN), a derivative of fentanyl, is highly effective as an analgesic, but its relatively poor solubility in water has limited its nasal application. The objective of this study was to develop the new CFTN-CD inclusion technology to increase the solubility of CFTN. The inclusion compound CFTN–DM-β-CD was prepared by the ultrasonic method and characterized using X-ray powder diffraction and morphological shapes analysis (the scanning electron microscopy). The in vitro dissolution profiles of CFTN–DM-β-CD were assessed in hydrochloric acid and phosphate buffer. Nasal ciliotoxicity studies were carried out using isolated toad palate. Rats were treated with CFTN–DM-β-CD (250?µg/kg) by intravenous, intramuscular injection, oral, or nasal drops. The results showed that CFTN was successfully enveloped by DM-β-CD. The in vitro cumulative dissolution of CFTN–DM-β-CD was obviously enhanced compared to free CFTN in two buffers. Nasal ciliotoxicity studies have shown that the CFTN–DM-β-CD does not exhibit higher nasal ciliotoxicity than that of free CFTN. Pharmacokinetic studies demonstrated that CFTN–DM-β-CD by nasal administration was absorbed more rapidly and has higher C_max and bioavailability than that of either intramuscular injection or oral administration. In conclusion, the CFTN–DM-β-CD nasal spray was shown to be a relatively safe dosage form for the rapid and effective intranasal delivery of CFTN.     

Nanoneurotherapeutics approach intended for direct nose to brain delivery

Abstract

Context: Brain disorders remain the world's leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood–brain barrier (BBB), thus impeding treatment of these conditions.

Objective: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain.

Methods: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown.

Result and conclusion: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles.     

电子政务安全中常用网络技术

结合电子政务网的性质和电子政务安全的特点,分析了电子政务安全系统可能遇到的威胁,在此基础上针对电子政务安全出现的问题分别在防恶意攻击、信息存储与传输、防病毒、操作系统和灾难恢复五个方面提出了相应的网络技术解决方案。     

Thermoreversible mucoadhesive in situ nasal gel for treatment of Parkinson’s disease

Abstract

Parkinson’s disease is a degenerative disorder of the central nervous system (CNS). The most obvious symptoms are movement-related such as shaking, rigidity, slowness of movement and difficulty with walking, rigid muscular movements and difficulty in chewing and swallowing especially solid dosage forms. Ropinirole is an anti-Parkinson drug that has low oral bioavailability which is primarily due to first-pass metabolism. The objective of proposed work was to increase bioavailability of ropinirole and avoid patient discomfort by formulating thermoreversible in situ nasal gel. Thermoreversible nasal gels were prepared by cold method using Pluronic F-127 and hydroxy methyl propyl cellulose (HPMC K4M) as gelling agents. Formulations were evaluated for various parameters such as drug content, pH, gelling time, gelling temperature, gel strength, mucoadhesive force, ex vivo diffusion, histological studies and in vivo bioavailability. Formulations displayed gelation at nasal temperature and the gelation time was found to be less than mucociliary clearance time. The nasal residence time was seen to be increased due to mucoadhesion and increased gel strength. The nasal gel formulations showed ex vivo drug release between 56–100% in 5?h. Histological study of sheep nasal mucosa revealed that the gel had a protective effect on the mucosa unlike plain ropinirole which showed evidence of moderate cellular damage. A fivefold increase in bioavailability in brain was observed on nasal administration as compared to IV route. Thermoreversible in situ nasal gel was found to a promising drug delivery for Parkinsonian patients.     

关于我国标准化管理立法完善的思考

标准化管理立法是促进标准化工作深入开展的法律保障。随着经济的发展,标准化管理的立法也应不断得到完善。本文在总结、分析我国标准化管理立法现状的基础上,指出了我国标准化管理立法存在的问题,提出了我国标准化管理立法完善的建议。     

工业工程在政府组织行政管理中的应用

将政府组织视为一个广义的生产系统,由输入、输出和内部结构活动组成,在此基础上,根据政府组织行政管理的特质性,应用工业工程的系统展开原理,把政府组织的行政管理分解为4个单元,共计16个模块;其次,基于政府组织机构设立、行政管理资源两条线路,对行政管理的单元结构、模块结构进行了优化,并通过对行政管理模块的分解,建立了每个模块的行政要素系列,给出要素应用工业工程的基本方法与要求.