The development of an injection-molding process for a polyanhydride implant containing gentamicin sulfate

A production-scale manufacturing process has been developed for polyanhydride/gentamicin sulfate implants for the treatment of osteomyelitis. Gentamicin sulfate was first dried to an acceptable moisture level by using a tumble vacuum dryer. Dried gentamicin sulfate powder and polyanhydride granules were separately fed into the twin-screw extruder at a pre-determined metering rate using a gravimetric feeding device. The extruded molten mixture was solidified to form strands which were subsequently cut into pellets by using a pelletizer. The pellets were characterized with respect to copolymer molecular weight and drug content uniformity. The pellets were later fed into production-scale injection-molding equipment for implant fabrication. The injection-molding cycle was developed and evaluated in terms of cycle reproducibility. Implants were tested and shown to yield an oriented skin-core structure exhibiting a desirable in-vitro drug release profile.     

Mucoadhesive microspheres containing gentamicin sulfate for nasal administration: preparation and in vitro characterization

In this study, suitable microsphere formulations were designed in order to provide the absorption of a high polar drug through nasal mucosa. For this purpose, gentamicin sulfate (GS) was chosen as a model drug and used at different drug/polymer ratios in the microsphere formulations. The microspheres were prepared by spray drying technique. Hydroxypropyl methylcellulose was used as a mucoadhesive polymer in the formulations to increase the residence time of the microspheres on the mucosa. Sodium cholate was added into the formulations for increasing the absorption of GS through nasal mucosa. The in vitro characteristics of the microspheres were determined. The microspheres were evaluated with respect to the particle size, production yield, encapsulation efficiency, shape and surface properties, drug-polymer interaction, mucoadhesive property, in vitro drug release and suitability for nasal drug delivery.     

硫酸庆大霉素/壳聚糖纳米球的制备及其释药性能

目的 制备具有预防和降低硫酸庆大霉素耳毒性的壳聚糖纳米球.方法 采用离子交联法,以三聚磷酸钠为离子交联剂,制备了硫酸庆大霉素/壳聚糖纳米球,用透射电子显微镜,X-射线衍射仪和紫外分光光度计考察了其理化性质和释药性能.结果 纳米球的粒径为50～80nm,载药包封率为39.8%,载药量为18.3%,体外60h释药90%左右,释放过程符合双相动力学方程.结论 这可能预示硫酸庆大霉素/壳聚糖纳米球缓释效果可降低硫酸庆大霉素的耳毒性.     

硫酸皮肤素的生物学功能

硫酸皮肤素是一类结构复杂的糖胺聚糖,与此相对应的是其生物功能的多样性。硫酸皮肤素除了具有抗血栓作用外,还具有抗炎症、抗肿瘤、抗感染和损伤修复等作用,并且这些作用与其结构密切相关。此文综述了硫酸皮肤素的多种生物学功能、作用机制及其结构与功能的关系     

The in vivo and in vitro comparative nephrotoxicity of cefazolin and gentamicin.

Biochemical, histopathological and cell culture evaluations compared the nephrotoxicity of cefazolin with that of gentamicin. New Zealand rabbits were dosed with 250 mg cefazolin/animal i.m. twice daily, 3 mg gentamicin/kg i.m. twice daily, or 0.9% NaCl solution for 10 d. The rabbits in drug-treated groups had necrosis of proximal kidney tubules and elevated urinary-gamma glutamyl transferase (uGGT) levels. The results of the histopathological examinations, uGGT analyses and effects in cell culture indicated the nephrotoxicities of both antibiotics were similar.     

Propranolol analogs containing natural monoterpene structures: synthesis and pharmacological properties.

A few derivatives of natural, bicyclic monoterpenes, which are propranolol analogs, were synthetized. Those compounds were studied pharmacologically in order to determine their toxicity, antiarrhythmic activity in selected experimental models of arrhythmia, the local anesthetic effect and influence on the cardiovascular system. The tested compounds showed a less potent or similar toxicity towards reference drugs, were devoid of an antiarrhythmic activity in the model of barium arrhythmia, yet some of them (compounds 9 and 12) increased the arrhythmogenic dose of strophanthin. All the compounds studied had a local anesthetic effect stronger than lidocaine in infiltration anesthesia, and compound 8--also in surface anesthesia.     

脆性组氨酸三联体表达与多西紫杉醇敏感性的关系

目的探讨胃癌组织中脆性三联体（FHIT）表达水平与多西紫杉醇敏感性的关系。方法对52例胃癌组织标本用免疫组化法检测标本中FHIT的表达水平,行ATP-TCA法检测多西紫杉醇药敏,比较分析FHIT表达水平与多西紫杉醇疗效的相关性。结果 4例FHIT强阳表达组中多西紫杉醇体外敏感者1例（25.00%）,10例阳性表达组中敏感者4例（40.00%）,12例弱阳性表达组中敏感者10例（83.33%）,26例阴性表达组中敏感者19例（73.08%）。两者差异有统计学意义（P〈0.05）,即FHIT表达水平与多西紫杉醇体外药敏呈负相关。结论 FHIT表达水平可能成为胃癌患者多西紫杉醇药物敏感性的预测指标。     

柱切换HPLC-ELSD法测定硫酸庆大霉素颗粒中庆大霉素C组分的研究

目的 建立柱切换高效液相色谱-蒸发光散射检测法(HPLC-ELSD)测定硫酸庆大霉素颗粒中庆大霉素C组分含量,并对2017年国家评价性抽验190批次样品进行检测。方法 采用配置切换六通阀的高效液相色谱仪,GRACE Apollo C18色谱柱( 250mm×4.6mm, 5μm),流动相为0.2mol/L三氟乙酸溶液:甲醇(96:4, V/V),柱温35℃,流速0.6mL/min,进样量25μL,ELSD漂移管温度110℃,载气流量2.5L/min,增益1。结果 采用新建的柱切换HPLC-ELSD法可有效去除辅料蔗糖等对测定的干扰,庆大霉素C组分(C1、C1a、C2、C2a)的平均回收率分别为98.9%、102.0%、100.1%和98.6%,RSD(n=9)分别为0.5%、0.4%、0.3%和0.6%,线性范围分别为0.0517~0.6465、0.0538~0.6729、0.0651~0.8136和0.0299~0.3738mg/mL。190批次样品中12批次样品的庆大霉素C1偏低,2批次样品的庆大霉素总C组分含量偏低,3批次样品的庆大霉素总C组分含量偏高。结论     

柱切换HPLC-ELSD法测定硫酸庆大霉素颗粒中庆大霉素C组分的研究

目的 建立柱切换高效液相色谱-蒸发光散射检测法(HPLC-ELSD)测定硫酸庆大霉素颗粒中庆大霉素C组分含量,并对2017年国家评价性抽验190批次样品进行检测。方法 采用配置切换六通阀的高效液相色谱仪,GRACE Apollo C18色谱柱( 250mm×4.6mm, 5μm),流动相为0.2mol/L三氟乙酸溶液:甲醇(96:4, V/V),柱温35℃,流速0.6mL/min,进样量25μL,ELSD漂移管温度110℃,载气流量2.5L/min,增益1。结果 采用新建的柱切换HPLC-ELSD法可有效去除辅料蔗糖等对测定的干扰,庆大霉素C组分(C1、C1a、C2、C2a)的平均回收率分别为98.9%、102.0%、100.1%和98.6%,RSD(n=9)分别为0.5%、0.4%、0.3%和0.6%,线性范围分别为0.0517~0.6465、0.0538~0.6729、0.0651~0.8136和0.0299~0.3738mg/mL。190批次样品中12批次样品的庆大霉素C1偏低,2批次样品的庆大霉素总C组分含量偏低,3批次样品的庆大霉素总C组分含量偏高。结论 新建方法准确简便,专属性良好,可为硫酸庆大霉素颗粒中庆大霉素C组分的控制提供参考。     

Regression analysis of the relationship between physical properties and the in vitro inhibition of monoamine oxidase by propynylamines.

Regression analysis of the potency of inhibition of monoamine oxidase by 47 propynylamines revealed that there are three determinants of inhibitory potency: (1) the smallest substituent on the nitrogen must be methyl or hydrogen in order for any activity to be observed; (2) potency is parabolically related to pKa-the optimum pKa is 6.2; and (3) ortho-substituted benzylamine analogs are ten times more potent than predicted on the basis of pKa values. The optimum pKa cannot be explained by differences in fraction ionized but rather in terms of the multistep sequence whereby these compounds inhibit MAO. A very slight positive effect of hydrophobicity on potency was found. The potency of several analogs not included in the original analysis was predicted.     

Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates

Population pharmacokinetic parameter estimates were calculated from 725 routine plasma gentamicin concentrations obtained in 177 neonates of 24 to 42 weeks' gestational age in their first week of life. Kel increases and V/W decreases with increasing gestational age. Almost identical results were obtained with iterative two-stage Bayesian fitting (MW\PHARM 3.30) as with a non-parametric maximization algorithm (NPEM2). The effect of various covariates on drug disposition was investigated retrospectively using multiple regression analysis. Predictive power for Kel increases with rising gestational age. For neonates 28.5 weeks and 30.9 weeks (r2 = 0.482), with gestational age, postnatal age, and Apgar score at 5 minutes being predictors. A very strong correlation existed between volume of distribution and weight (r2 = 0.83). Volume as a function of weight could be described with low predictivity by gestational age and to a lesser degree by Apgar score at 5 minutes (r2 = 0.298). The developed models need appropriate prospective clinical validation.     

In vitro and in vivo studies of sustained-release floating dosage forms containing salbutamol sulfate

Peroral sustained-release floating capsules containing salbutamol sulfate were formulated using different combinations of hydrocolloids of natural and semi-synthetic origin. The floating properties and release rate characteristics were determined for the capsules in simulated gastric fluid USP XXI and HCl (0.1 mol.l-1) as dissolution media. Also, a marketed sustained-release non-floating capsule containing salbutamol sulfate was studied for its release rate characteristics. The floating capsule formulated showed a Higuchian release profile while the marketed product released only about 80% of the total dose in the stipulated 12 h in the dissolution medium. In vivo X-ray studies of the abdomen were carried out to locate the floating and non-floating (fabricated) dosage forms at various time intervals of uniform duration. The floating capsule definitely indicated a residence time (up to 8-9 h) in the stomach greater than for the non-floating capsule.     

Sterilization of gentamicin containing collagen/PLGA microparticle composites.

In order to achieve implants which provide sustained release of gentamicin, microparticles based on a 50/50 Resomer 503/Resomer 502H blend were combined with collagen in order to achieve their fixation and to utilize the favorable effect of collagen on wound healing. Ethylene oxide treatment as well as beta- and gamma-irradiation were tested for sterilization of the collagen/PLGA-microparticle composite. All methods resulted in a decrease of molecular weight and glass transition temperature of polymer raw material and microparticles. In addition, ethylene oxide treatment yielded aggregation of microparticles leading to a substantial increase in the initially liberated gentamicin dose. Furthermore, chemical changes of gentamicin after ethylene oxide sterilization could be identified using NMR spectroscopy. Despite a decrease in the molecular weight and glass transition temperature after irradiation, neither morphological changes of the composites nor changes regarding the gentamicin release profile from beta- and gamma-sterilized material were observed. Free radicals, which could only be detected in gentamicin drug substance and at marginal level in gentamicin-loaded MPs, disappeared within 4 weeks. Additional microbiological testing verified the microbiological activity of gentamicin liberated from beta-sterilized composites. Storage of beta-sterilized composite at 4 degrees C/35% r.h. for 3 months did not influence morphology, molecular weight, glass transition temperature, and release profiles of microparticles and composites. However, at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. a marked decrease in molecular weight and glass transition temperature resulted. This effect was due to a higher humidity, water uptake into polymers, and subsequent hydrolysis of polymers and microparticles, which was more pronounced for RG 502H because of its hydrophilicity. Upon storage at 25 degrees C/60% r.h. and 40 degrees C/75% r.h. particles collapsed resulting in an increased gentamicin liberation. Thus, all sterilization techniques have their pros and cons, but based on drug release profile and chemical changes of gentamicin irradiation treatment appears to be more suitable for collagen/gentamicin-loaded PLGA microparticle composites.     

消草磷同类物使P450失活的能力与其理化性质间的定量关系(英文)

十四种消草磷结构类似物与经苯巴比妥预处理大鼠肝匀浆S9悬液一起温育,在有NADPH存在时,可不同程度地使P450失活.若温育10 min后P450丢失量用Y表示,化合物的疏水性和电性分别用P_(gc)和μ_(gc)表示,可建立如下相关性: logY=4.106logP_(gc)-0.575(logP_(gc))~2-5.822 (n=14,r=0.954,s=0.054);logY=3.678 logP_(gc)-0.520(logP_(gc))~2-0.037μ_(gc)-4.877 (n=14,r=0.965,S=0.049) 上述两方程表明,消草磷同类物体外使P450失活的能力与其疏水性呈良好的抛物线型相关,化合物的电性对此能力也有影响,但贡献较小.     

硫酸庆大霉素盐酸林可霉素注射液细菌内毒素检查法的建立

目的 建立硫酸庆大霉素盐酸林可霉素注射液细菌内毒素检查方法。方法 按照2015版《中国兽药典》附录1143“细菌内毒素检查法”项下凝胶法的要求，根据干扰试验确定样品成分最小不干扰稀释倍数，并进行方法学验证及3批中试产品细菌内毒素检查。结果 供试品最小不干扰倍数为100倍，3批中试产品细菌内毒素检查均符合要求。结论 建立的方法能够用于硫酸庆大霉素盐酸林可霉素注射液细菌内毒素检查，其细菌内毒素限制为37.5EU/mL。     

Stability of gentamicin sulfate and tobramycin sulfate in extemporaneously prepared ophthalmic solutions at 8 degrees C

The stability of gentamicin sulfate and tobramycin sulfate in fortified ophthalmic solutions stored under refrigeration was studied. Fortified gentamicin ophthalmic solution and fortified tobramycin ophthalmic solution were prepared to a final theoretical concentration of 13.6 mg/mL by using commercially available ophthalmic and injectable solutions. Volumes of each solution were packaged in plastic bottles and refrigerated at 4-8 degrees C. Samples of each solution were analyzed by fluorescence polarization immunoassay on days 0 (before refrigeration), 1, 2, 3, 4, 7, 14, 28, 63, and 91. To validate the method, identical solutions were prepared, stored under refrigeration at 4-8 degrees C, and analyzed by a stability-indicating high-performance liquid chromatographic assay on days 0 (before refrigeration), 9, 28, 56, and 91. Fluorescence polarization immunoassay showed the mean concentrations of gentamicin and tobramycin on day 91 to be 104.4% and 97.4%, respectively, of the time 0 concentrations; the difference was not significant in either case. HPLC validated these results; the mean concentration of gentamicin and tobramycin on day 91 was 103.3% and 101.2%, respectively, of the mean day 0 concentrations. Gentamicin and tobramycin in ophthalmic solutions prepared by mixing ophthalmic and injectable products and stored in plastic bottles at 4-8 degrees C were stable for three months.     

The relationship between cytotoxic drug exposure and tumour cell kill, in vitro and in vivo.

Doxorubicin has been shown to be more effective against MGH-U1 bladder carcinoma cells grown in monolayer than spheroid. In vitro clonogenic cell survival curves have been replotted against the area under the concentration-time curve (AUC) for drug exposure and fitted to a Hill plot to derive the parameters E max (maximum possible cell kill) and C50 (drug exposure resulting in half the maximum cell kill). The plasma AUC following intraperitoneal administration of doxorubicin to nude mice was measured using a sensitive and specific HPLC assay and combined with the in vitro cell survival parameters to predict the clonogenic cell survival in MGH-U1 xenografts. The Hill parameters from the spheroid model are better predictors of xenograft clonogenic cell survival than the monolayer parameters. It is possible to predict clonogenic cell survival in solid tumours on the basis of the pharmacokinetics of cytotoxic drug exposure, using a mathematical model based on clonogenic cell kill in vitro.