经鼻给药的机遇与挑战

作为一种非侵入给药方式,鼻腔给药具有快速起效、使用方便、依从性高、无首过效应、不良反应较小、黏膜免疫等诸多优点,且提供了鼻脑递送途径,鼻用制剂日益成为研发热点,以着力解决未被满足的临床需求。但是,因鼻腔结构和生理学上的特殊性,鼻用制剂的开发和评价还存在诸多挑战。     

鼻腔给药新制剂的研究进展

目的介绍国内鼻腔给药新制剂的研究进展。方法系统查阅国内1999-2004年有关鼻腔给药制剂的研究报道及文献，并进行综合分析。结果鼻腔用药具有吸收起效快、生物利用度高、使用方便等优点。结论鼻腔给药治疗全身性疾病具有广阔的前景。     

用于全身治疗的鼻腔给药系统研究概况

目的介绍用于全身治疗的鼻腔给药系统研究概况。方法综述了鼻腔给药的特点、手段、制剂方法、要求、影响因素及研究状况。结果与讨论鼻腔给药可以产生全身作用,可以代替静脉给药,有广泛的应用前景。     

鼻腔给药系统的鼻粘膜毒性及解决途径

就鼻腔给药系统可能导致的鼻粘膜毒性的评价方法、易产生毒性的制剂组分及解决毒性的方法进行简要的综述。     

The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.     

Chitosan as a Novel Nasal Delivery System for Peptide Drugs

A nasal solution formulation of the cationic material chitosan was shown to greatly enhance the absorption of insulin across the nasal mucosa of rat and sheep. The absorption promoting effect was concentration dependent with the optimal efficacy obtained for concentrations higher than 0.2% and 0.5% in rats and sheep, respectively. The absorption promoting effect was reversible with time in a pulse-chase study. Histological examination of the nasal mucosa of rats exposed to a chitosan solution for 60 minutes showed little change.     

环糊精在鼻腔给药系统中的应用

综述了环糊精作为鼻腔给药系统赋形剂的应用及安全性.     

Cyclodextrins: Their Future in Drug Formulation and Delivery

Pharmaceutical Research - Since their discovery, cyclodextrins and their ability to form inclusion complexes have fascinated chemists, formulators and recently, entrepreneurs. This mini-review has...     

栀子环烯醚萜苷鼻腔给药的吸收特性

目的研究栀子环烯醚萜苷类成分鼻腔给药的吸收特性,为其鼻腔给药制剂设计提供依据。方法采用Franz扩散池,选用新鲜猪鼻黏膜为渗透屏障,以栀子苷为测定指标,HPLC测定含量,进行渗透试验;采用大鼠鼻腔循环灌流实验,以PBS溶液(pH7.4)作为鼻腔循环液,HPLC测定栀子苷,进行在体鼻黏膜吸收试验。结果栀子苷表观渗透系数Papp为(2.01±0.23)×10 5cm 2.s 1;药物稳态流量Jss为(1.61±0.18)×10 4μg.cm 2.s 1,透黏膜扩散属于以膜两侧浓度差为动力的被动扩散。栀子苷大鼠在体鼻黏膜吸收动力学方程lnC=1.165 7 0.001 6t,r=0.991 4,k=(1.6±0.021)×10 3min 1。结论栀子环烯醚萜苷可经鼻吸收,可制成经鼻给药的新制剂用于脑部疾病的防治。     

扎那米韦鼻用粉雾剂粉体性质研究

目的 考察3种方法制备扎那米韦鼻用粉雾剂粉体的性质。方法 分别采用研磨法、气流粉碎法和喷雾干燥法制备不同粒径扎那米韦的粉体,并与吸入乳糖混合,对混合粉体的粒径、微观形态、流动性、堆密度和吸湿性进行考察。结果 研磨法、喷雾干燥法和气流粉碎法得到的扎那米韦原料粉末粒径依次减小;与乳糖相比,3种混合粉体松密度逐渐减小,振实密度依次增加,流动性仅喷雾干燥略增加,研磨法和气流粉碎法无影响; 3种方式得到的混合粉末均没有明显的吸湿性。结论 研磨筛分法比较适合扎那米韦鼻用粉雾剂的进一步开发。     

The Influence of Blood Sampling Site in Nasal Drug Delivery Studies in Rats

Pharmaceutical Research -     

Self-Emulsifying Drug Delivery Systems: Formulation and Biopharmaceutic Evaluation of an Investigational Lipophilic Compound

Self-emulsifying drug delivery systems (SEDDSs) represent a possible alternative to traditional oral formulations of lipophilic compounds. In the present study, a lipophilic compound, WIN 54954, was formulated in a medium chain triglyceride oil/nonionic surfactant mixture which exhibited self-emulsification under conditions of gentle agitation in an aqueous medium. The efficiency of emulsifi-cation was studied using a laser diffraction sizer to determine particle size distributions of the resultant emulsions. An optimized formulation which consisted of 25% (w/w) surfactant, 40% (w/w) oil, and 35% (w/w) WIN 54954 emulsified rapidly with gentle agitation in 0.1 N HCl (37°C), producing dispersions with mean droplet diameters of less than 3 µm. The self-emulsifying preparation was compared to a polyethylene glycol 600 (PEG 600) solution formulation by administering each as prefilled soft gelatin capsules to fasted beagle dogs in a parallel crossover study. Pharmacokinetic parameters were determined and the absolute bioavailability of the drug was calculated by comparison to an i.v. injection. The SEDDS improved the reproducibility of the plasma profile in terms of the maximum plasma concentration (C _max) and the time to reach the maximum concentration (t _max). There was no significant difference in the absolute bioavailability of WIN 54954 from either the SEDDS or the PEG formulations.     

氢溴酸高乌甲素鼻用原位凝胶剂的制备及其处方评价

目的：制备氢溴酸高乌甲素（LH）鼻用原位凝胶剂,并进行处方考察以提高其鼻腔给药的镇痛效果。方法：采用在体蟾蜍上腭纤毛法考察不同LH处方对鼻黏膜纤毛的毒性、大鼠在体鼻腔循环实验考察处方中3种吸收促进剂（β-环糊精、吐温-80和冰片）对LH的鼻黏膜吸收的促进作用以及小鼠扭体法实验考察不同LH处方的镇痛药效,从而确定LH鼻用原位凝胶剂的最佳处方工艺。结果：处方中LH和所选用的辅料对鼻黏膜纤毛均无显著毒性;3种吸收促进剂对LH的鼻黏膜吸收速率常数无显著影响（P〉0．05）;在所有受试处方中,结冷胶和β-环糊精联用处方制剂的镇痛效果最佳,其药效与腹腔注射相同剂量的LH注射液无显著差异（P〉0．05）。结论：结冷胶和β-环糊精联用是制备LH鼻用原位凝胶剂的最佳处方组合。     

鲑降钙素经鼻干粉吸入剂的制备及评价

采用冷冻干燥法制备鲑降钙素生物黏附附聚物，研究表面活性剂泊洛沙姆用量对容器吸附降钙素的作用；用改进的Twin-impinger进行体外模拟试验，并测定家兔静脉和经鼻腔给药后的血钙降低情况。结果表明，当泊洛沙姆188浓度为0．25％时，具良好的抗容器吸附主药能力，与溶液型喷雾剂和胶囊干粉吹入剂相比，主动吸入的泡囊型干粉吸入剂较溶液型喷雾剂更易在具治疗意义的部位沉积；家兔试验表明，鼻腔给药后，其降血钙作用相当于静注给药的72％，达峰时间为3．5h（静注为1．5h），作用时间可持续约10h（静注约为7h）。     

Optimization of an Alum-Adsorbed Vaccine Powder Formulation for Epidermal Powder Immunization

Purpose. To develop stable and effective aluminum salt (alum)-adsorbed vaccine powder formulations for epidermal powder immunization (EPI) via a spray freeze-drying (SFD) process. Methods. Powder properties were determined using particle size analysis, tap density, and scanning electron microscopy. Alum coagulation was monitored via optical microscopy and particle sedimentation. Protein analysis was determined by the BCA protein assay, SDS-PAGE, and an enzyme immunoassay. In vivo immunogenicity and skin reactogenicity were performed on hairless guinea pigs and pigs, respectively. Results. SFD of hepatitis B surface antigen (HBsAg) adsorbed to aluminum hydroxide or aluminum phosphate using an excipient combination of trehalose/mannitol/dextran produced vaccine powders of dense particles and satisfactory powder flowability and hygroscopicity. This formulation also offered excellent long-term stability to the powder and the antigen. The two most important factors influencing alum particle coagulation are the freezing rate and the concentration of aluminum in the liquid formulation for SFD. The SFD vaccines, when delivered to hairless guinea pigs by EPI or injected intramuscularly after reconstitution, were as immunogenic as the original liquid vaccine. A further study showed that EPI with SFD alum-adsorbed diphtheria-tetanus toxoid vaccine was well tolerated, whereas needle injection of the liquid formulation caused persistent granuloma. Conclusions. Stabilization of alum-adsorbed vaccine by SFD has important implications in extending vaccination to areas lacking a cold chain for transportation and storage and may also accelerate the development of new immunization technologies such as EPI.     

疫苗微粒鼻腔给药系统的研究进展

疫苗微粒鼻腔给药作为一种新型非侵入性疫苗给药系统,具有能延长免疫时间、增强免疫效果、提高病人顺应性等优点。综述疫苗鼻腔免疫诱导机制、常用的微粒系统、免疫效果影响因素及其评价方法及目前该给药系统存在的问题,旨在为研究开发疫苗微粒鼻腔给药系统提供新的思路和方法。     

复方链呋油滴鼻剂透膜扩散考察

目的：考察复方链呋油滴鼻剂透膜扩散效果。方法：采用改良型Franz扩散池（垂直式）,接收液为pH5．0的磷酸盐缓冲液,用HPLC法同时测定呋喃西林、麻黄碱的透膜浓度,计算其累积透膜量、累积透膜率和单位面积平均透膜率。结果：呋喃西林和麻黄碱透过速度分别为0．9948、11．8750μg·cm^-2·h^-1,其透膜扩散行为符合Fick’s第一定律。结论：复方链呋油滴鼻剂有较好的透膜扩散能力。     

Smart Polymers in Nasal Drug Delivery

Nasal drug delivery has now been recognized as a promising route for drug delivery due to its capability of transporting a drug to systemic circulation and central nervous system. Though nasal mucosa offers improved bioavailability and quick onset of action of the drug, main disadvantage associated with nasal drug delivery is mucocilliary clearance due to which drug particles get cleared from the nose before complete absorption through nasal mucosa. Therefore, mucoadhesive polymeric approach can be successfully used to enhance the retention of the drug on nasal mucosal surface. Here, some of the aspects of the stimuli responsive polymers have been discussed which possess liquid state at the room temperature and in response to nasal temperature, pH and ions present in mucous, can undergo in situ gelation in nasal cavity. In this review, several temperature responsive, pH responsive and ion responsive polymers used in nasal delivery, their gelling mechanisms have been discussed. Smart polymers not only able to enhance the retention of the drug in nasal cavity but also provide controlled release, ease of administration, enhanced permeation of the drug and protection of the drug from mucosal enzymes. Thus smart polymeric approach can be effectively used for nasal delivery of peptide drugs, central nervous system dugs and hormones.     

水飞蓟素自乳化给药系统处方设计及溶出度评价

目的: 设计水飞蓟素自乳化系统处方并评价其溶出度.方法: 采用正交设计进行水飞蓟素自乳化系统处方设计,以溶解状况、乳化速度及透光率为指标进行综合评价,确定最佳处方.结果: 水飞蓟素自乳化系统除主药外,主要由吐温85、橄榄油、甘油组成.结论: 按最佳处方制备的水飞蓟素自乳化系统在人工胃液及人工肠液的溶出度均与德国的对照胶囊基本相同.     

Respiratory Drug Delivery X

There were ～ 700 delegates who attended Respiratory Drug Delivery X (RDD-X) at the Boca Raton Resort and Club in Boca Raton, Florida, between the 24th and 27th April 2006. Participants from North America, Europe and many other parts of the world came together to hear a series of invited podium presentations covering the latest scientific developments in pulmonary and nasal drug delivery, along with regulatory and quality control issues. A total of 150 proffered posters were also presented, and a Technology Exhibition involved the products of 78 companies. The conference also provided unparalleled networking opportunities. The proceedings of RDD-X will prove to be an invaluable resource for years to come.