影响红细胞生成素胶原蛋白双层微条体外释放度的处方及制备工艺因素研究

目的:考察影响红细胞生成素(EPO)胶原蛋白双层微条体外释放度的处方和制备工艺方面的因素。方法:采用单因素试验,以体外累积释放百分率为指标,考察胶原蛋白与EPO的含量比、硫酸软骨素钠的含量、喷嘴外管内径和微条长度对其体外释放度的影响。结果:胶原蛋白与EPO的含量比、硫酸软骨素钠的含量增加,喷嘴外管内径和微条长度减少均可提高EPO从双层微条中释放的速率。结论:4种因素对EPO胶原蛋白双层微条的体外释放度均有显著影响。     

促红细胞生成素双层微条的处方筛选与工艺优化研究

目的 对促红细胞生成素（EPO）胶原蛋白双层微条的处方及工艺进行筛选优化。方法 采用正交试验，以偏离度为评价指标，得到胶原蛋白与EPO含量比、硫酸软骨素钠（CS）含量、喷嘴外管内径和微条长度4个因素的最佳取值。结果 筛选得到胶原蛋白与EPO含量比为1000：1，CS含量为1％，喷嘴外管内径为1．4mm，微条长度为15mm。结论 根据得到的最优处方制备的双层微条释放缓慢、平稳。     

促红细胞生成素双层微条在家兔体内的药动学

目的：对促红细胞生成素胶原蛋白双层微条在家兔体内的药动学进行研究.方法：采用酶联免疫吸附测定（ELISA）法测定皮下注射给药后不同时间家兔血清中促红细胞生成素的量,计算药动学参数.结果：促红细胞生成素双层微条药-时曲线符合权重因子为1/C的一级吸收一室模型,主要药动学参数t1/2ke、t1/2ka、AUC、MRT、tmax以及CL分别为15.645 h,6.280 h,14 566.911 mIU·h·mL^-1,38.325 4 h,13.794 7 h,0.068 9 L·kg^-1·h^-1.结论：双层微条制剂能延长促红细胞生成素在体内的滞留时间,可能因此延长EPO的药理活性.     

重组人红细胞生成素胶原蛋白双层微条的制备及含量测定

目的:制备重组人红细胞生成素(rhEPO)胶原蛋白双层微条并建立其含量测定方法。方法:以胶原蛋白为包裹材料,以硫酸软骨素钠为释放调节剂,采用凝胶加压成型的方法制备双层微条;采用反相高效液相色谱法测定双层微条中rhEPO的含量。结果:rhEPO检测浓度线性范围为0 .25～20μg/ml(r=0 9998) ,平均回收率为96 .2% ,日内、日间精密度分别为0. 9%、2 .6%(n=3)。结论:rhEPO胶原蛋白双层微条制备方法简单可行,含量测定方法准确、可靠。     

促红细胞生成素胶原蛋白双层微条的处方筛选与工艺优化

目的:对促红细胞生成素胶原蛋白双层微条(EPO-DLMP)的处方及工艺进行筛选优化。方法:采用正交试验,以偏离度为评价指标,优选胶原蛋白与促红细胞生成素的含量比、硫酸软骨素钠的含量、喷嘴外管内径和微条的长度4个因素的最佳取值,并进行验证试验。结果:筛选得到上述4种因素的最佳取值分别为1000∶1、1%、1.4mm、15mm,偏离度值为7.59。结论:采用最优处方制备的EPO-DLMP经验证其释放较平稳,能够达到试验要求。     

红细胞生成素的生物特征和临床应用

红细胞生成素（erythropoietin）结合于细胞表面的红细胞生成素受体，能激发红细胞生成。重组人红细胞生成素，是由165种氨基酸构成的一种糖蛋白，含蛋白60辩，糖类40颁。其生物活性取决于糖基化作用（gbCO－sylation）：经肝迅速灭活并由循环廓清。卫红细胞生成素的调节血清红细胞生成素水平增加见于贫血、慢性肺实质疾病、心脏右至左分流等引起组织缺氧的情况；在组织缺氧被纠治后和红细胞密度增加前，血清红细胞生成素水平开始下降。红细胞生成素水平，上午高于下午Z茶碱阻滞腺着型受体，可降低其水平。单纯性缺铁时，如果血红蛋白＜11…     

左卡尼汀辅助红细胞生成素治疗血液透析贫血26例

目的：观察左卡尼汀辅助红细胞生成素治疗尿毒症血液透析贫血的疗效。方法：将尿毒症血液透析贫血患者52例随机分成两组各26例。治疗组于每次血液透析后静脉推注左卡尼汀1.0 g，而对照组不用该药。两组同时于血液透析后皮下注射红细胞生成素每周100～150 U·kg 1，若血红蛋白(Hb)≥100 g·L 1，红细胞压积(Hct)≥30%后减量。结果：治疗组Hb、Hct水平显著高于对照组(P＜0.05)，而血压升高发生率与对照组差异无显著性(P＞0.05)。结论：左卡尼汀能显著提高红细胞生成素对尿毒症血液透析患者的疗效，纠正贫血，减少红细胞生成素用量。     

红细胞生成素对慢性肾功能衰竭病人红细胞免疫功能的影响

目的：探讨红细胞生成素对慢性肾功能衰竭（肾衰）病人红细胞免疫功能的影响。方法：分别检测慢性肾衰病人和健康人的人红细胞Ｃ３ｂ受体花环率（ＲＣＲ）和红细胞免疫复合物花环率（ＲＩＣＲ）。结果：红细胞生成素治疗组慢性肾衰病人ＲＣＲ为９．２％±０．９％，高于非红细胞生成素治疗组２．６％±１．３％，低于健康人组１４．２９６±２．８％；前组肾衰病人ＲＩＣＲ为１１．２％±０．８％，低于后组１５．０％±１．５％，高于健康人组７．６％±１．１％。结论：慢性肾衰病人红细胞免疫功能低下，红细胞生成素治疗不仅增加红细胞数量，而且提高红细胞免疫功能。     

首个人体细胞株基因生成的红细胞生成素产品Epoetin Delta有望用于改善慢性肾脏病患者的贫血状况

据“新华美通”消息，欧洲血液协会（EHA）第11届大会于2006年6月首次公布的一项研究结果显示，采用一种新的人体细胞株内基因活化技术开发得到的红细胞生成素产品——Epoedn delta（Dynepo），可修复和维持采用透析治疗的慢性肾脏病患者的血红蛋白水平。慢性肾脏病患者出现贫血的主要原因是体内红细胞生成素缺乏。红细胞生成素是一种促进红细胞生成的特殊蛋白质，主要在肾脏中产生。随着肾脏功能的衰竭，其生成红细胞生成素的能力也相应减弱，进而造成人体血液内的红细胞数量减少，血红蛋白水平下降；此外，在肾脏病患者进行血液透析的过程中，也会引起红细胞数量的下降，加重了患者的贫血程度。     

国产促红细胞生成素治疗肾性贫血疗效观察

目的：观察国产重组人促红细胞生成素(rHuEPO)治疗肾性贫血的疗效。方法：选择24例血透慢性肾衰贫血病人，全部使用rHuEPO，每周150IU／kg，分3次皮下注射。观察用药12周后血生化的变化。结果：经治疗15例显效，7例进步，1例无效，总有效率为95．8％。病人血红蛋白、红细胞计数、红细胞压积和网织红细胞均显著增加，生活质量得到改善。结论：国产的促红细胞生成素能安全、有效地改善血透慢性肾衰病人贫血状态。     

The preparation of sustained release erythropoietin microparticle

PURPOSE: Protein microencapsulation in biodegradable polymers is a promising route to provide for sustained release. The erythropoietin (EPO) microparticles are using human serum albumin (HSA) and poly-L-lysine (PK) as the protection complex to increased EPO integrity, entrapped efficiency and active EPO release by w/o/w solvent evaporation techniques. The optimum formulation development process was also reported by using FITC-OVA as a model protein. METHODS: The model protein FITC-ovalbumin and EPO are protected by human serum albumin and poly-L-lysine complex and encapsulated in 50:50 poly(DL-lactide-co-glycolide) by a w/o/w solvent evaporation method. Protein active integrity and degradation compound is measured by size-exclusion chromatography. Protein-loaded microparticle physical properties and in vitro active and degradation compounds release profile are characterized. RESULTS: High active integrity protein loading efficiency and particle yield of EPO or OVA-HSA/PK-loaded PLG microparticles are successfully produced by a w/o/w solvent evaporation method. Varied protection protein complex formulations and encapsulation processes are investigated. The high OVA model protein loading efficiency (80.2%), FITC-OVA content (0.24 microg mg(-1)) and yield (72.4%) are obtained by adding 100 microg mL(-1) FITC-OVA complex with 10% HSA/0.05% PK (Mw 1.5-3 kD) in the initial solution to protect the model protein. In vitro release profiles show more active OVA release from HSA/PK OVA-loaded than OVA-loaded only microparticles and also the amount of degraded protein that comes out after 3 weeks incubated in the PBS medium for OVA-loaded only microparticles is observed. The same formulation and preparation process resulted in EPO loading efficiency (68.4%), EPO content (0.23 microg mg(-1)) and yield (76.1%) for HSA/PK EPO-loaded microparticles. In vitro release profiles show active EPO sustained release over 7 days. Using HSA/PK as carried in the primary emulsion of EPO-loaded microparticles resulted in less burst release% than EPO-loaded only microparticles.     

Dosing patterns, treatment costs, and frequency of physician visits in adults with cancer receiving erythropoietic agents in managed care organizations

OBJECTIVE: To investigate the dosing patterns and treatment costs of erythropoietic agents in adult (>or= 18 years of age) cancer patients newly initiated on epoetin alfa (EPO) or darbepoetin alfa (DARB) in managed care organizations. METHODS: An analysis of US medical claims (30 million lives in over 35 health plans) in the period July 1, 2002-February 28, 2005 was conducted. Patients with >or= 1 cancer claim within 90 days prior to initiating EPO or DARB, and who received at least two doses of the same erythropoietic agent, were included in this analysis. Weighted average weekly dosing, cumulative treatment dose, associated drug cost, dosing frequency patterns, and the frequency of outpatient visits were evaluated. The EPO:DARB dose ratio, based on average cumulative treatment doses, was assessed. RESULTS: 5639 EPO and 2166 DARB patients met the inclusion and exclusion criteria. The EPO group was older (EPO 59.1 years; DARB 57.6 years; p < 0.001) with a higher proportion of men (EPO 38.1%; DARB 33.1%; p < 0.001). Variable dosing frequency was observed with similar treatment durations for the two groups (days: EPO 55.6; DARB 57.7; p = 0.122). A dose ratio of 236:1 was observed (average cumulative dose: EPO 252 856 U; DARB 1072 mcg). Average drug cost was significantly higher in the DARB group (drug cost: EPO 3077 dollars; DARB 4674 dollars; p < 0.001). The average number of hematology/oncology outpatient visits per patient (visits: EPO 7.4; DARB 7.3; p = 0.676) and outpatient visits for hemoglobin determination (visits: EPO 6.7; DARB 6.4; p = 0.093) during treatment was similar between the two groups. LIMITATIONS: The results were based on medical claims only. The absence of information on actual injection dates in pharmacy claims prevented their incorporation in the analysis. CONCLUSIONS: Based on the average cumulative doses, the EPO:DARB dose ratio was 236:1 (Units EPO: mcg DARB) with 52% greater drug cost in the DARB group. Despite the variable administration frequency observed between the two agents, the number of hematology/oncology outpatient visits was not different.     

Controlled release of rhBMP-2 from collagen minipellet and the relationship between release profile and ectopic bone formation

The purpose of this study was to examine the effects of various additives on the profiles of rhBMP-2 release from minipellet, which is a sustained release formulation for protein drugs using collagen as a carrier, and to examine the influence of varying release profiles on ectopic bone formation. When the amount of rhBMP-2 remaining in the preparation after subcutaneous implantation to mice was examined, it was found that the addition of sucrose, glucose, PEG4000, alanine (Ala) or acacia in a concentration of 20% (w/w) to the minipellet with 5% (w/w) of rhBMP-2 did not accelerate the drug release in a noticeable manner, while the addition of sodium chondroitin sulfate, glutamic acid (Glu) or citric acid accelerated the release of rhBMP-2 markedly. When two types of minipellets (a fast release type added with 20% Glu and 20% Ala and a slow release type without additives) containing varying amounts of rhBMP-2 were implanted subcutaneously to mice, the soft X-ray observation, histological examination and measurement of calcium formation 3 weeks after implantation revealed extensive ectopic bone formation in mice implanted with the fast release type preparation. Ectopic bone formation was dose-dependent. The result of this study exhibited that the effects of controlled release formulation of rhBMP-2 on bone formation vary depending on their release profiles, and suggested that combination of initial burst and sustained release was effective for bone formation. It was also shown that minipellet is useful as a controlled release formulation which can release rhBMP-2 to areas around the implanted site with various release profiles.     

The preparation of sustained release erythropoietin microparticle

Purpose: Protein microencapsulation in biodegradable polymers is a promising route to provide for sustained release. The erythropoietin (EPO) microparticles are using human serum albumin (HSA) and poly-L-lysine (PK) as the protection complex to increased EPO integrity, entrapped efficiency and active EPO release by w/o/w solvent evaporation techniques. The optimum formulation development process was also reported by using FITC-OVA as a model protein.

Methods: The model protein FITC-ovalbumin and EPO are protected by human serum albumin and poly-L-lysine complex and encapsulated in 50:50 poly(DL-lactide-co-glycolide) by a w/o/w solvent evaporation method. Protein active integrity and degradation compound is measured by size-exclusion chromatography. Protein-loaded microparticle physical properties and in vitro active and degradation compounds release profile are characterized.

Results: High active integrity protein loading efficiency and particle yield of EPO or OVA-HSA/PK-loaded PLG microparticles are successfully produced by a w/o/w solvent evaporation method. Varied protection protein complex formulations and encapsulation processes are investigated. The high OVA model protein loading efficiency (80.2%), FITC-OVA content (0.24?µg?mg^?1) and yield (72.4%) are obtained by adding 100?µg?mL^?1 FITC-OVA complex with 10% HSA/0.05% PK (Mw 1.5–3?kD) in the initial solution to protect the model protein. In vitro release profiles show more active OVA release from HSA/PK OVA-loaded than OVA-loaded only microparticles and also the amount of degraded protein that comes out after 3 weeks incubated in the PBS medium for OVA-loaded only microparticles is observed. The same formulation and preparation process resulted in EPO loading efficiency (68.4%), EPO content (0.23?µg?mg^?1) and yield (76.1%) for HSA/PK EPO-loaded microparticles. In vitro release profiles show active EPO sustained release over 7 days. Using HSA/PK as carried in the primary emulsion of EPO-loaded microparticles resulted in less burst release% than EPO-loaded only microparticles.     

辛伐他汀-烟酸双层缓释片的制备及其体外质量评价

目的 制备辛伐他汀(SVT) -烟酸(NA)双层缓释片并进行体外质量评价.方法 分别通过正交实验和单因素实验,筛选NA缓释层与SVT常释层处方,确定最佳处方组成并制备SVT-NA双层缓释片,测定缓释片中NA与SVT的含量.以国内已上市NA缓释片为参比制剂,测定自制双层缓释片中NA的释放度,计算释放度相似因子(f2),并进行方程拟合.按照中国药典2010版中SVT普通片溶出度测定条件,测定自制双层缓释片常释层中SVT的溶出度.结果 自制双层缓释片中NA的释放度与市售NA缓释片相似(f2＞75),其释放行为符合Higuchi方程;常释层中SVT 30 min内的累积溶出度＞98％,符合中国药典有关规定.结论 SVT-NA双层缓释片处方组成合理,制备工艺稳定,重现性良好,有望开发成为新的复方制剂.     

法莫替丁胃内漂浮型双层缓释片的研究

目的研制法莫替丁胃内漂浮型双层缓释片并考察其体外释药行为。方法分别以湿法制粒的方法制备速释层和缓释层,压制胃内漂浮型双层片,紫外分光光度法测定法莫替丁的释放度,并记录起漂时间和持续漂浮时间。结果法莫替丁胃内漂浮型双层缓释片的释药曲线用Higuchi方程拟合,可维持24h持续释放,起漂时间〈5min,持续漂浮时间〉8h。结论研制的法莫替丁胃内漂浮型双层缓释片制备工艺简单,质量稳定,释药速度平稳,达到设计要求。