HPLC法测定布洛芬颗粒的含量

目的:建立布洛芬颗粒中布洛芬的含量测定方法。方法:用Diamonsil C_(18)(25cm×4.6mm×5μm)色谱柱,以0.01mol/L磷酸溶液～乙腈(37:63)为流动相,流速为1.5ml/min,检测波长220nm。结果:在0.04968～0.4968mg/ml范围内,色谱峰面积与对照品浓度呈良好的线性关系,r=0.9999,平均回收率为99.52％(RSD=0.32％,n=18)。结论:该法快速、简便、重现性好,可用于布洛芬颗粒中布洛芬的质量控制。     

反相高效液相色谱法测定布洛芬片的含量

目的建立布洛芬片中布洛芬含量的HPLC测定法。方法采用十八烷基硅烷键合硅胶柱,流动相:醋酸钠缓冲液(取醋酸钠6.13 g,加水750 m l,振摇使溶解,用冰醋酸调节pH值至2.5)-乙腈(40∶60),流速为1.0 m l.m in-1,检测波长为263 nm。结果线性范围:10.22~102.2 mg.L-1(r=0.99999)。精密度:RSD为0.18%(n=5)平均回收率为99.5%。结论试验表明,该方法简便,快速,结果准确,重现性     

高效液相色谱法测定苦荞籽壳中芦丁和槲皮素的含量

目的:建立高效液相色谱法测定苦荞籽壳中芦丁和槲皮素的含量。方法:采用 Zorbax SB-C_(18)(4.6 mm×150 mm,5μm)色谱柱;流动相为甲醇-0.4%磷酸(50:50);流速1.0 mL·min~(-1);检测波长254 nm。结果:芦丁进样量在0.024～0.963mg·mL~(-1)范围内(r=0.9996),槲皮素进样量在0.0132～0.528 mg·mL~(-1)范围内(r=0.9990)线性关系良好,平均回收率芦丁为100.1%(RSD=1.15%),槲皮素为99.9%(RSD=1.04%)。结论:该方法操作简便,分离度高,重复性好,可同时测定苦荞籽壳中芦丁和槲皮素的含量。     

Assay of topically administered ibuprofen using a model of post-injury hypersensitivity

Objective: To develop a reliable assay for quantifying the analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) using a model that is accepted as a paradigm of clinical pain. Subjects: Fifteen normal subjects, all of whom were volunteers from medical school staff, took part in the study. Methods: Capsaicin (20 μl) in solution (0.03 mg/ml) was applied to the volar surface of the forearm, and the skin was maintained at a constant temperature using a thermal stimulator. The magnitude of the surrounding area of mechanical allodynia to a brush stimulus (i.e. a clinical correlate of tenderness to touch) was assessed. Under double-blind, placebo-controlled conditions, the test was repeated using skin previously treated with ibuprofen gel or placebo. Results: A close linear relationship was observed between skin temperature over a range of 30 °C to 40 °C and the area of capsaicin-induced allodynia. Ibuprofen gel significantly reduced (P < 0.004) the area of touch-evoked allodynia at a constant skin temperature of 40 °C. Conclusions: The thermal-facilitated adaptation of the capsaicin model described in this study represents an inexpensive and reliable assay for the effects of topical formulations of NSAID upon mechanical sensitivity. As such, it is a potential alternative to many clinical studies in which inherent confounding and bias can preclude a meaningful conclusion. Received: 13 September 1999 / Accepted in revised form: 14 March 2000     

Pharmacokinetics and absolute bioavailability of ibuprofen after oral administration of ibuprofen lysine in man

The lysine salt of d,l-2-(4-isobutylphenyl)-propionic acid (ibuprofen lysine) was administered as a single oral dose of 500 mg by means of commercially available coated tablets (Imbun).* To assess the absolute bioavailability of ibuprofen after its oral application as a lysine salt, intravenous injections of ibuprofen solutions containing 200 mg and 400 mg of the drug served as reference application. In a partially randomized cross-over design, 8 healthy male volunteers received three different single dose administrations which were separated by wash-out periods of 4 days each. Ibuprofen plasma concentrations were determined by HPLC using direct injection, pre-column enrichment and column switching techniques. From the results of intravenous injections one can deduce linear ibuprofen pharmacokinetics within the considered dosage range, with corresponding AUC0-infinity values of 3786 micrograms * min ml-1 and 7260 micrograms * min ml-1 for the 200 mg and 400 mg doses, respectively. The values of plasma clearances as well as those of different volumes of distribution showed remarkable constancy after evaluation from both intravenous injections. The absorption of orally administered ibuprofen lysine proved to be rapid, resulting in a mean peak plasma level (Cmax) of 31 micrograms ml-1 ibuprofen and in a mean time to peak (tmax) of 45 min. The absolute bioavailability of ibuprofen amounts to 102.7 per cent, indicating a complete absorption of ibuprofen when administered as its lysine salt. Drug tolerability was excellent for the oral administration of ibuprofen lysine as well as for the intravenous treatments with ibuprofen free acid. Only mild and transient adverse drug reactions such as mild burning or dragging sensation during injection or mild redness at the site of injection were reported.     

Comparative human study of ibuprofen enantiomer plasma concentrations produced by two commercially available ibuprofen tablets

Twelve healthy male subjects participated in a two-way Latin square crossover study in which the treatments were a single 400 mg generic ibuprofen tablet (Tablet A) or a single 400 mg MOTRIN Tablet (Tablet B). Blood samples were drawn at various times through 12 h after dosing and plasma samples were assayed for ibuprofen enantiomers with a stereospecific capillary gas chromatographic procedure. Concentration-time data for both enantiomers were in agreement and indicated that drug was absorbed much more quickly from Tablet B than from the Tablet A; enantiomer Tmax values were less than 1.3 h from Tablet B but longer than 4 h from the Tablet A (p less than 0.001). Also, maximum enantiomer plasma concentrations from the Tablet B were about 50 per cent of the peak concentrations observed from Tablet A (p less than 0.001). The total extent of drug absorption appeared to be the same in both products. These data clearly indicate that the two tablets are not bioequivalent with respect to either ibuprofen enantiomer.     

Enhanced dissolution of ibuprofen using solid dispersion with poloxamer 407

To improve its dissolution, ibuprofen solid dispersions (SDs) were prepared, characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and Fourier transform infrared spectroscopy (FTIR), and evaluated for solubility, and in-vitro ibuprofen release. Loss of individual surface properties during melting and re-solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. FTIR spectra showed the presence of drug crystalline in SDs. The effect of improved dissolution on the oral absorption of ibuprofen in rats was also studied. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C_max, and a significant decrease in T_max over pure ibuprofen. Comparison of the enhanced solubility, dissolution, AUC, and C_max of ibuprofen from different poloxamers suggested that the preparation of ibuprofen SDs using P 407 as a meltable hydrophilic polymer carrier could be a promising approach to improve its solubility, dissolution and absorption rate.     

Optimization of ibuprofen gel formulations using experimental design technique for enhanced transdermal penetration

The aims of this study were to develop a transdermal gel formulation for ibuprofen using experimental design techniques and to evaluate its pharmacokinetic properties. The three factors chosen for factorial design were the concentrations of drug, polyoxyethylene(5)cetyl/oleyl ether and ethanol and the levels of each factor were low, medium and high. Skin permeation rates and lag times of ibuprofen were evaluated using the Franz-type diffusion cell in order to optimize the gel formulation. The permeation rate of ibuprofen significantly increased in proportion to the drug concentration, but significantly decreased in proportion to POE(5)cetyl/oleyl ether concentration. Ethanol concentration was inversely proportional to the lag time. The pharmacokinetic properties of the optimized formulation were compared with those of two marketed products in rats. The relative bioavailability of ibuprofen gel compared to the two marketed products was 228.8% and 181.0%. In conclusion, a transdermal ibuprofen gel was formulated successfully using the technique of experimental design and these results helped in finding the optimum formulation for transdermal drug release.     

Safety profile of ibuprofen suspension in young children

The Children’s Analgesic Medicine Project (CAMP) was a multicenter, all-comers, openlabel, prospective study to compare the safety of ibuprofen suspension with acetaminophen suspension in children with fever and/or pain. Four hundred and twenty four (424) pediatricians enrolled 41 810 children (aged 1 month to 18 years old) at 69 US clinics. Safety data included information concerning medication use and adverse events (AEs) summarized by severity and analyzed by age groups (younger and older than 2 years). Among 30 144 children who took at least one dose of ibuprofen or acetaminophen, 14 281 were younger (< 2 yrs) and 15 863 were older (⩾ 2 to < 12 yrs). Within both age groups, the incidence rates for specific AEs, including abdominal pain, insomnia, and hyperkinesia were rare and generally < 1% for both treatments. For younger children, fever, vomiting, diarrhea, rhinitis, rash and otitis media were the only AEs with an incidence rate > 1% (in either treatment group). For older children, the only AEs with an incidence rate > 1% in either group were rhinitis, pharyngitis and otitis media. AEs were generally mild to moderate for both treatments within the two age groups. There were no serious AEs, including anaphylaxis, Reye’s syndrome, renal failure, GI bleeding/perforation or necrotizing fasciitis. There was a slightly higher overall incidence of side effects in the ibuprofen group (17.6% vs. 15.0%) for the younger children; and similar results were seen in the older children (11.9% vs. 10.7%). This may have been due to the preference of physicians to treat the sicker children with ibuprofen. There were four deaths, all unrelated to study medication, all occurring in children < 2 yrs (herpes encephalitis, sepsis due to 5. pneumoniae, medulloblastoma, and sudden infant death syndrome). The safety of ibuprofen suspension in children < 2 yrs was demonstrated in this study. The safety profile in children < 2 yrs is consistent with the excellent profile observed in children ⩾ 2 yrs. Overall, ibuprofen exhibited an AE profile similar to acetaminophen in both younger and older children.     

Accelerated degradation of ibuprofen in tablets

The forced degradation of 11 ibuprofen tablet brands was carried out according to current industry best practices. The results indicated an incompatibility between ibuprofen and two common tablet excipients (polyethylene glycol and polysorbate 80) that were observed to accelerate the degradation of ibuprofen in tablets stored for three weeks at 70°C/75% RH. Studies of binary drug/excipient samples supported the conclusion. One degradant that was observed at increased levels was 4-isobutylacetophenone (4-IBAP), which is a known toxin.     

布洛芬生产中缩酮工艺改进

目的改进布洛芬生产中的缩酮反应工艺。方法新工艺使用浓硫酸替代对甲苯磺酸为缩酮催化剂,使用季戊四醇替代新戊二醇反应底物,并且通过正交实验对工艺进行优化设计。结果工艺改进路线可行。结论该工艺路线有生产成本下降等优点。     

布洛芬颗粒溶出度测定方法研究

目的建立布洛芬颗粒溶出度测定方法。方法采用紫外分光光度法测定。测定波长为：220nm。溶出介质为pH7．2磷酸盐缓冲液。结果布洛芬溶液在3．0-15．0μg／ml范围内,吸收度与浓度呈良好的线性关系,r=0．9993。样品精密度试验RSD为0．85％,样品供试液在12h内稳定,样品加样回收率为99．9％,RSD为0．22％。结论该法操作简便,稳定可靠,专属性强,可以有效测定布洛芬颗粒溶出度,为控制布洛芬颗粒质量提供了依据。     

儿科各种退热疗法临床效果比较

目的:探讨不同退热药物的退热效果,总结各种措施的副作用及儿科医生首选用药。方法:对210例病毒性呼吸道感染所致861例次高热(>39℃)患儿,分别予不同的退热药物及各自联合物理降温治疗,观察用药1h后的退热效果。结果:安乃近、复方阿斯匹林、对乙酰氨基酚糖浆与布洛芬混悬液退热总有效率分别为78%、76%、81%与89%(χ2为6.81、8.64、3.97,P<0.05)。布洛芬混悬液退热效果显著优于安乃近、复方阿斯匹林、对乙酰氨基酚糖浆,且不良反应最少,联合物理降温有协同效应。结论:布洛芬混悬液退热效果肯定,不良反应少,值得临床应用。     

Absorption kinetics of rectally and orally administered ibuprofen

The bioavailability of rectally administered sodium ibuprofen solution and aluminum ibuprofen suspension was determined in eight normal subjects relative to the same treatments administered orally. The results indicate that the suspension was less bioavailable than the solution irrespective of the route of administration. Although not bioequivalent, rectally administered ibuprofen solution compared favourably with orally administered ibuprofen solution. The mean AUC and Cmax from rectal administration were 87 per cent and 62 per cent of the corresponding values achieved after oral administration. Mean residence times and peak times were 1-3 h longer with the rectal solution, indicating a slower rate of absorption. Absorption after rectal administration was zero order in some subjects while absorption after oral administration was first order. This may be due to the large differences in surface area between absorption sites. Since sodium ibuprofen solution is absorbed when given rectally, this route of administration could be used in patients unable to take oral ibuprofen.     

布洛芬混悬液与片剂的临床药理学比较

目的 :比较研究布洛芬混悬液和市售布洛芬片的生物利用度和药代动力学。方法 :选择20名健康男性志愿者 ,随机分为两组 ,进行单次混悬液或片剂交叉给药600mg后 ,利用HPLC法测定血浆中布洛芬浓度。结果 :两组血浆的布洛芬浓度分别在(1 12±0 23)和 (1 76±0 48)小时达到峰值 (14 46±1 85)和 (13 56±2 98)μg/ml。血药浓度曲线下面积 (AUC)分别达 (46 76±3 65)和 (44 13±5 01)μg/ml ,混悬液的相对生物利用度 (F)为 (104 3±10 7) %。结论 :布洛芬混悬液和市售布洛芬片两种制剂具有生物等效性。     

Optimization of thein vitro glucuronidation of ibuprofen using factorial design

Ibuprofen was chosen as a test compound to perform a multivariate design in order to determine the highest yield of thein vitro glucuronidation reaction in relation to the concentration of reacting and activating substances. Preliminary studies with a univariate design indicated that the concentration of Mg²⁺ had no significant effect on the glucuronidation and that Triton X-100 could be omitted as it appeared to inhibit the glucuronidation. In a 3³ factorial design the influence of concentrations of ibuprofen, UDP glucuronic acid and enzyme, respectively, on the yield of ibuprofen glucuronide was established. It was concluded that the highest amount of ibuprofen glucuronide formed (within the limits of this design) was achieved with an ibuprofen concentration of 486 M, a UDP-glucuronic acid concentration of 3 mM and an enzyme concentration of 3.57 mg/ml. Using this methodology it is possible to optimize the glucuronidation yield in a more rational way, which can be useful in the upscaling of enzymatic reactions.     

The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans

Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)-enantiomer. However, a portion of R(-)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)-enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(-)-ibuprofen which was metabolically inverted to S(+)-ibuprofen, was independent of the administered dose.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Determination of ibuprofen and naproxen in tablets

Ibuprofen and naproxen have been quantified in tablets by capillary isotachophoresis. Hydrochloric acid (10 mmol/l) adjusted with creatinine to pH 5.0 plus 0.1% polyvinylpyrrolidone was used as the leading electrolyte and 10 mmol/l 4-morpholineethanesulfonic acid as the terminating electrolyte. Linearity was observed from 40.0 to 200.0 mg/l of ibuprofen (naproxen), with a coefficient of determination (r²) of 0.999. Good quantitation was obtained in short analysis time. The isotachophoretic results were compared with those obtained by the fluorescence spectrometry. Experimental parameters for ibuprofen were: λ_EX=224 nm and λ_EM=290 nm. Experimental parameters for naproxen were: λ_EX=230 nm and λ_EM=355 nm. The calibration plot was found to be linear in the range 0.4–2.4 mg/l for ibuprofen and 5.0–20.0 μg/l for naproxen. The minimal sample pretreatment and relatively low running cost make isotachophoresis a good alternative to existing methods.     

Pharmacokinetics of ibuprofen enantiomers after single and repeated doses in man.

The pharmacokinetic parameters of ibuprofen enantiomers after a single 600 mg dose and repeated 3 x 400 mg doses of Nurofen were determined in 12 healthy volunteers. Terminal half-lives were similar for both enantiomers, but plasma levels of S-ibuprofen were higher than those of R-ibuprofen, due to the chiral inversion and differences in distribution and metabolism. Comparison of maximal concentrations and areas under the concentration vs time curves between the first and last doses for each enantiomer indicated linear pharmacokinetics with no time-dependency. A large inter-individual variability in the ratio of S- to R-ibuprofen average concentrations at steady-state was observed (mean +/- SD 1.89 +/- 0.89) and probably accounts for the known lack of correlation between racemic ibuprofen concentrations and therapeutic efficacy.