Investigating phase separation in amorphous solid dispersions via Raman mapping

The bioavailability of poorly-water-soluble active pharmaceutical ingredients (APIs) can be significantly improved by so-called amorphous solid dispersions (ASDs). However, the long-term stability of ASDs might be impaired by API recrystallization and/or amorphous phase separation (APS). So far, no methods have been reported to quantify APS in ASDs. In this work, phase-separation kinetics as well as the compositions of the two amorphous phases evolving due to APS were quantitatively determined for the first time using confocal Raman spectroscopy. Raman spectra were evaluated via non-linear multivariate Indirect Hard Modeling and verified by differential scanning calorimetry and hot-stage microscopy. APS in water-free ASDs of ibuprofen and poly (DL-lactic-co-glycolic acid) was investigated considering the influence of temperature and polymer architecture (linear vs. star-shaped). Water absorbed at 40?°C and 75% relative humidity (RH) promotes APS which was quantified for formulations of felodipine/poly(vinyl pyrrolidone) and ibuprofen/poly(vinyl pyrrolidone).     

布洛芬缓释胶囊单剂量与多剂量给药的人体药动学及生物等效性研究

目的：建立高效液相色谱法测定人血浆中布洛芬浓度,并应用于两种布洛芬缓释制剂的人体生物等效性研究。方法：采用双周期自身随机交叉试验设计,24名男性健康志愿者分别单剂量、多剂量口服布洛芬缓释胶囊受试制剂和参比制剂300mg,采用高效液相色谱法测定人血浆中布洛芬浓度,利用DAS 2.0程序计算主要药动学参数,并对两种制剂进行生物等效性评价。结果：单剂量口服受试制剂和参比制剂后血浆中布洛芬的Cmax分别为（12.7±5.4）和（13.5±5.9）μg/mL,tmax分别为（5.5±1.4）和（5.1±1.0）h,AUC0→24分别为（96.8±50.2）和（95.7±45.4）μg·h·mL^-1。多剂量口服受试制剂和参比制剂后血浆中布洛芬的Cmax分别为（14.1±5.3）和（14.9±6.4）μg/mL,tmax分别为（4.8±1.0）和（4.6±0.9）h,Cav分别为（8.3±3.4）和（8.6±4.3）μg/mL,DF值分别为（117.2±35.3）%和（131.7±35.1）%。经统计学检验,两种制剂主要药动学参数间无统计学差异（P〉0.05）。结论：所建立的高效液相色谱法适合用于人体血浆中布洛芬测定。布洛芬受试制剂和参比制剂具有生物等效性。     

Biodegradation of L-Valine Alkyl Ester Ibuprofenates by Bacterial Cultures

Nowadays, we consume very large amounts of medicinal substances. Medicines are used to cure, halt, or prevent disease, ease symptoms, or help in the diagnosis of illnesses. Some medications are used to treat pain. Ibuprofen is one of the most popular drugs in the world (it ranks third). This drug enters our water system through human pharmaceutical use. In this article, we describe and compare the biodegradation of ibuprofen and ibuprofen derivatives—salts of L-valine alkyl esters. Biodegradation studies of ibuprofen and its derivatives have been carried out with activated sludge. The structure modifications we received were aimed at increasing the biodegradation of the drug used. The influence of the alkyl chain length of the ester used in the biodegradation of the compound was also verified. The biodegradation results correlated with the lipophilic properties (log P).     

Efficacy and Safety of an Intravenous Acetaminophen/Ibuprofen Fixed-dose Combination After Bunionectomy: a Randomized,Double-blind,Factorial, Placebo-controlled Trial

PurposeMultimodal analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs is recommended for the treatment of postoperative pain. Although oral fixed-dose combinations (FDCs) are available, parenteral administration may be clinically justified. The goal of this study was to investigate the clinical efficacy and safety of an intravenous FDC of ibuprofen and acetaminophen after bunionectomy.MethodsThis study was a prospective, randomized, double-blind, multicenter, placebo-controlled factorial clinical trial conducted at 2 clinical research centers in the United States between November 2016 and June 2017. Eligible patients (male and female subjects, aged 18–65 years, reporting pain intensity levels ≥40 mm on a 100-mm visual analog scale (VAS) after distal, first metatarsal bunionectomy) were randomized (3:3:3:2) to receive the FDC (ibuprofen 300 mg + acetaminophen 1000 mg), ibuprofen 300 mg, acetaminophen 1000 mg, or placebo (vehicle), administered as 15-minute intravenous infusions every 6 hours for 48 hours. The primary efficacy end point was the time-adjusted sum of pain intensity differences from baseline over 48 hours (SPID₄₈). In addition to VAS pain intensity scores, pain relief scores, time to perceptible and meaningful pain relief, the use of rescue medication, and participant's global evaluations of the study drug were recorded. Adverse events occurring during the 48-hour treatment period were included in the safety analysis.FindingsA total of 276 participants were enrolled; most were female (82%), the mean age was 42.4 years, and the median baseline VAS was 67 mm, indicating moderate to severe pain. SPID₄₈ was significantly higher for the FDC (23.4 [2.5] mm) than for ibuprofen (9.5 [2.5] mm), acetaminophen (10.4 [2.5] mm), and placebo (−1.3 [3.1] mm; all, P < 0.001). The superior analgesic effect of the FDC was supported by a range of secondary end points, including reduced opioid usage rates (75% for FDC, 92% for ibuprofen, 93% for acetaminophen, and 96% for placebo; all, P < 0.005). The safety profile of the FDC was comparable to that of intravenous ibuprofen or acetaminophen alone. Three participants withdrew from the study due to adverse events: 2 in the ibuprofen group and 1 in the acetaminophen group.ImplicationsThe study found that repeated administration of an intravenous FDC of ibuprofen and acetaminophen provided statistically significant improvement in SPID₄₈ over comparable doses of either monotherapy without an increase in adverse events. ClinicalTrials.gov identifier: NCT02689063.     

载布洛芬的PLGA/PLA电纺纳米纤维GTR膜的实验研究

目的:通过静电纺丝技术制备载不同含量布洛芬(IPF)的聚乳酸-羟基乙酸共聚物(PLGA)/聚乳酸(PLA)纳米纤维引导组织再生(GTR)膜,评价其生物学性能。方法:使用静电纺丝技术制备PLA纳米纤维膜,扫描电镜观察其表面形貌,与EMT-6细胞复合培养,检测其生物相容性及机械阻挡功能;制备载不同含量布洛芬的PLGA/PLA纳米纤维膜,观察其表面形貌、MTT法检测人牙龈成纤维细胞(HGFs)在其上的增殖情况,同时检测其载药率及药物缓释情况。结果:PLA以及载入不同量IPF的电纺纤维的直径均为300 nm~5μm,载入布洛芬后,纳米纤维仍表面光滑、均一、连续;绝大多数的EMT-6细胞均黏附在PLA膜的表面,膜内部几乎没有细胞;HGFs与不同载药量的IPF-PLG/PLA电纺膜复合培养1、3、5、7 d时,各载药实验组在各时间点的OD值与空白对照组相比P>0.05;5%、10%、15%3种载药量的电纺膜的载药率均可达85%以上,在1周内的突释量分别为30%、60%、85%,突释较小,药物释放时间可持续10~28 d。结论:本实验所制备的载布洛芬PLGA/PLA电纺纳米纤维膜具有良好生物相容性、优异的阻挡功能及缓慢释药功能。     

口服布洛芬对早产儿PDA的疗效及消化道症状的观察

目的 观察口服布洛芬对早产儿动脉导管未闭(PDA)的疗效及不同奶量喂养下消化道症状的发生率.方法 收集2012年1月至2015年12月在金华市中心医院新生儿重症监护室(NICU)住院的283例胎龄≤32周出生48小时确诊为PDA的早产儿行布洛芬治疗者为布洛芬组,并选取同期入院胎龄≤32周、出生48小时床旁超声多普勒证实存在PDA,且PDA直径>1.5mm,CVD评分总分≥3分的早产儿78例作为对照组.布洛芬组又根据第1剂布洛芬口服时的奶量喂养情况,将283例患儿分为禁食组(a)、10~<20mL·kg-1·d-1组(b)、20~<50mL·kg-1·d-1组(c)、50~<80mL·kg-1·d-1组(d)、≥80mL·kg-1·d-1组(e),并根据第1剂布洛芬口服时不同的奶量喂养情况,分析布洛芬口服后1周内消化道症状,如消化道出血、新生儿坏死性小肠结肠炎(NEC)、喂养不耐受等的发生率.结果 经过1、2、3个疗程布洛芬口服治疗后,有效率分别为50.5%(143例))、20.1%(57例)和4.6%(13例),第1个疗程PDA的关闭率和有效率明显高于第2、3疗程(χ2值分别为3.87、4.17和10.14、18.60,均P<0.05).对照组于生后第14天时复查心脏彩超,PDA关闭16例(20.5%),好转12例(15.4%),手术38(48.7%).布洛芬组与对照组比较,在PDA关闭率(χ2=18.13)、好转率(χ2=20.23)、手术率(χ2=29.17)方面的差异均有统计学意义,均P<0.05.布洛芬口服后,消化道症状总发生率禁食组(a组)分别与各不同奶量喂养组(b、c、d、e组)间比较,差异均有统计学意义(χ2=5.71~40.00,均P<0.05).结论 早产儿出生1周内发现并予布洛芬第1个疗程口服后,PDA关闭率明显高于第2、3个疗程.早期喂养,喂养量大的早产儿布洛芬口服后1周内,消化道出血、NEC的发生率较少.     

布洛芬丁香酚酯微乳的镇痛作用及大鼠体内药动学研究

目的:研究布洛芬丁香酚酯微乳剂的镇痛作用及其在大鼠体内的药动学.方法:采用小鼠热板法考察布洛芬丁香酚酯微乳的镇痛作用.大鼠尾静脉给药后,分别于给药后5,10,25,40 min和1,1.5,2,3,4,5,7和9 h取血.采用高效液相色谱法测定血浆中布洛芬的浓度.结果:布洛芬丁香酚酯微乳可剂量依赖性延长小鼠热板痛阀时间,且效果等同于同剂量布洛芬.布洛芬丁香酚酯微乳及布洛芬溶液组静脉注射后的消除半衰期(t1/2)分别为(6.30±0.56)和(2.79±0.29)h,清除率(CL)分别为(94.93±12.09)和(112.17±7.00)mL·h-1·kg-1,稳态表观分布容积(Vss)分别为(543.62±64.68)和(243.12±6.87)mL·kg-1,两组存在显著性统计学差异(P＜0.05).结论:布洛芬丁香酚酯微乳与布洛芬溶液剂镇痛作用相当,静脉注射后消除时间较布洛芬明显延长.     

高效液相色谱法测定布洛芬片中布洛芬含量

目的建立高效液相色谱法测定布洛芬片中布洛芬的含量。方法色谱柱为Zorbax—Extend C18柱（150mm×4．6mm，5μm），甲醇-0．01m01／L磷酸二氢钾一磷酸（700：300：0．1）为流动相，流速为1．0mL／min，检测波长为263nm。结果布洛芬质量浓度线性范围是100～800μg／mL，r=0．9999，其低、中、高3个量级的平均回收率分别为99．4％，98．8％，100．2％，RSD分别为0．8％，0．7％，1．0％。结论该法测定布洛芬中布洛芬的含量，结果可靠、简便、准确。     

布洛芬缓释胶囊的生物利用度和药代动力学

 本文比较研究了布洛芬缓释胶囊（Fenbid）和普通市售片的药代动力学和生物利用度，并分析了生物利用度与体外溶出度的相关性。在5位受试者一次口服900mg药物后，Fenbid的半衰期比市售片长，前者为4．875h，后者为2．236h，Fenbid的相对生物利用度（F）为150％。在10位受试者连续给药，测定谷浓度，Fenbid的谷浓度变化范围小（9．3～13．5μg／ml），而市售片的变化范围大（2．7～17．3μg／ml）。结果表明Fenbid具有较理想的缓释特性。体外溶出度与体内生物利用度相关性分析证明Fen－bid的AUC与溶出度显示良好的相关性（r＝0．9964）。