Section 3 The absence of effect of the antirheumatic drug ibuprofen on Oral anticoagulation with phenprocoumon

Summary

Nineteen patients receiving oral anticoagulant therapy with phenprocoumon were treated concomitantly with 600?mg. ibuprofen daily for 2 weeks. Plasma concentrations of phenprocoumon, bleeding time, prothrombin time and the concentration of a number of coagulation factors were measured before, during and after ibuprofen treatment. No significant changes were noted in any of the parameters measured and no bleeding was reported in any patient. It is concluded that ibuprofen can be given safely to patients on long-term anticoagulant therapy.     

氟化钠缓释片人体药动学与体内外相关性研究

目的 :研究氟化钠缓释片在人体内药动学和体内外的相关性。方法 :采用氟离子选择电极 ,测定10名自愿者单剂量口服25mg氟化钠缓释片后的血清氟离子浓度 ,计算药动学参数 ;按照Wagner-Nelson法计算的药物吸收分数与体外释放度进行相关性研究。结果 :体内过程符合一室开放模型 ,AUC0→r为1216 03ng·h -1·ml -1,Ka为0 72h ,Tlag 为0 55h ,Ke为0 19h ,t12,Ke为3.75h ;药物体外释放与体内吸收具良好相关性。结论 :该研究可为氟化钠缓释片的内在质量评价和制剂开发提供一定科学依据。     

硝酸甘油口腔速崩片的研制及其药效学的初步评价

目的 研制及评价硝酸甘油口腔速崩片。方法 采用适宜的湿法制粒工艺制备硝酸甘油口腔速崩片,并对其性状、重量差异、崩解时限、含量、稳定性等进行检测。通过8例健康自愿受试者含服硝酸甘油舌下片0．5mg,比较了硝酸甘油口腔速崩片与市售片对受试者的心率（HR）、舒张压（DBP）的影响。结果 在性状、重量差异、含量等符合规定情况下,硝酸甘油口腔速崩片与市售片的崩解时间（分别为1．98s,74．0s）之间有显著性差异（P〈0．01）。服药后3min之内,硝酸甘油口腔速崩片的显效速度（对心率的增高和舒张压的降低）明显快于市售片,两者之间亦有显著性差异（P〈0．05）。结论 硝酸甘油口腔速崩片的速崩特性有利于药物的快速吸收,从而对急症冠心病心绞痛患者的自救具有显著性意义。     

Dissolution of a poorly water-soluble drug dry coated with magnesium and sodium stearate

The purpose of this research was to investigate the influence of dry coating micronized cohesive powders of a poorly water-soluble drug, indomethacin with force control agents, on its dissolution performance. A dry mechanical fusion method (mechanofusion) was used to coat indomethacin powders with magnesium stearate (0.25%, 1%, 5%) and sodium stearate (5%). After mechanofusion, significantly increased bulk and tapped densities and decreased intrinsic cohesion were observed for all samples. X-ray photoelectron spectroscopy analysis confirmed that a thicker magnesium stearate surface coating was achieved with increasing concentrations of the material. Dissolution was studied using the USP paddle method in buffer pH 5.0; several modelling approaches were used to explore the dissolution mechanisms. Whilst the bi-exponential equation represented dissolution of mechanofused indomethacin powders occurring from dispersed and agglomerated particles, it provided unrealistic parameter estimates for the two coating materials of contrasting properties. Initial increases in indomethacin dissolution were dependent on the concentration of magnesium stearate mechanofused onto the drug powders. The dissolution enhancing effect of indomethacin powders mechanofused with 5% sodium stearate was attributed to its surfactant properties that increased dispersion of indomethacin agglomerates. Initial drug release from the coated powders was described by a matrix-diffusion system according to the Higuchi model.     

Orally disintegrating tablet of novel salt of antiepileptic drug: Formulation strategy and evaluation

The aim of present research was to design and evaluate orally disintegrating tablet (ODT) of novel lamotrigine-cyclamate salt. Box–Behnken response surface methodology was selected to design the optimized formulation. The independent factors selected were tablet hardness (X₁), disintegrant (X₂) and lubricant (X₃) levels, and responses chosen were disintegration time (DT, Y₁), friability (Y₂), T₅₀ (Y₃), and T₉₀ (Y₄). The tablets were also characterized for drug uniformity by near infrared chemical imaging (NIR-CI) and taste masking evaluation by electronic tongue. All the selected independent variables were statistically (p < 0.05) effect the Y₁ while Y₂, Y₃, and Y₄ affected only by X₂. The optimized ODT was found to meet the regulatory requirement of DT and friability specification. The NIR-CI images indicated uniform distribution of active and inactive ingredients within the tablets. The electronic tongue results were analyzed by principle component analysis (PCA). It indicated that novel salt of lamotrigine and its ODT formulation have a taste similar to cyclamic acid which is indicated by close proximity on PCA score plot, lower Euclidean distance, and high discrimination index values. Furthermore, these parameters were very close to ODT placebo formulation. On the other hand, lamotrigine, its ODT, and placebo formulation were far from each other. In summary, lamotrigine salt provides another avenue for pediatric friendly formulation for children and will enhance patience compliance.     

In vitro effects of the nonsteroidal anti-inflammatory drug,ibuprofen, on the immune parameters of the colonial ascidian Botryllus schlosseri

In this study, in vitro effects of ibuprofen (IBU) on the immune parameters of the colonial ascidian Botryllus schlosseri were evaluated. Haemocytes were exposed for 1 h to 0 (control), 100 and 1000 μg IBU/L and the effects on haemocyte viability and morphology (shape factor), lysosomal membrane stability (Neutral Red Retention Assay), phagocytic activity, apoptosis (TUNEL reaction), hydrolytic (acid phosphatase) and oxidative (phenoloxidase and peroxidase) enzyme activities were evaluated. The exposure of haemocytes to IBU did not affect significantly their viability, but increased the percentage of cells with round shape. IBU caused a significant reduction in both phagocytic activity and lysosomal membrane stability. The percentage of haemocytes positive to TUNEL reaction (indicative of DNA fragmentation) increased significantly after IBU exposure. Significant decreases in the percentage of haemocytes positive to acid phosphatase were recorded at 1000 μg/L of IBU. Conversely, no significant variations were recorded in the percentage of haemocytes positive to phenoloxidase and peroxidase. Results obtained indicate that exposure of ascidian haemocytes to IBU induces marked alterations in cell functionality. Immunomarkers measured in this study are sensitive, rapid and reproducible. However, their responsiveness and biological relevance will need to be verified for in vivo exposure.     

The influence of stevia on the flow,shear and compression behavior of sorbitol,a pharmaceutical excipient for direct compression

Good flow and compaction properties are necessary for the manipulation of particulate material in the pharmaceutical industry. The influence of the addition of an alternative sweetener, rebaudioside A, in a concentration 0.2% w/w and 0.5% w/w on the flow, shear and compaction properties of sorbitol for direct compaction, Merisorb^® 200, was investigated in this work. Rebaudioside A worsened the flow properties of sorbitol: the Hausner ratio, the compressibility index and the mass flow rate through the aperture of a model hopper. Using a Jenike shear cell revealed a significant increase in cohesion leading to the decrease of the flow function; moreover, the addition of rebaudioside A increased the total energy for compression of tablets and plasticity estimated by the force–displacement method. Finally, the tablets showed a higher tensile strength and needed longer time to disintegrate compared to the tablets made of sorbitol itself. In view of the results for the free-flowable excipient, sorbitol, the effects of stevia even for a 0.2% w/w concentration have to be carefully considered, particularly whenever used in pharmaceutical formulations of poor flow properties.     

Analgesic efficacy of ibuprofen alone and in combination with codeine or caffeine in post-surgical pain: a meta-analysis

Objective: To estimate the analgesic effect of ibuprofen and to test whether codeine and caffeine enhance its effect on post-surgical pain. Method: Systematic overview of the literature and meta-analysis of published randomised, controlled trials. Results: Ibuprofen is effective in dental pain, episiotomy pain and other post-operative pain. There is a dose–response relationship over the range 50–400 mg. The difference in total pain-relief score relative to placebo was 19–31%. On average, patients were over three times more likely to obtain moderate to excellent pain relief with ibuprofen than with placebo (response-rate ratio = 3.45) and the number needed to treat was 2.44. Codeine 60 mg enhanced the analgesic effect of ibuprofen 400 mg by about 8% in the total pain-relief scale, but it also increased its adverse effects. The additive effect of caffeine was inconsistent. Conclusion: Ibuprofen is an effective analgesic in postoperative pain. Codeine 60 mg adds to the analgesic effect of ibuprofen 400 mg. Any additive caffeine effect requires validation. Received: 5 February 1997 / Accepted in revised form: 11 August 1997     

Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag,Tlow, Tmed,and a novel parameter,TCmaxRef

Objective: This study evaluated the early absorption characteristics of ibuprofen salt formulations and standard ibuprofen acid (the reference).

Methods: In this open-label, crossover, single-center study (NCT02452450) in 32 healthy, fasted adults receiving single oral doses (400?mg ibuprofen) of ibuprofen lysine, ibuprofen liquid capsule, ibuprofen sodium, ibuprofen acid, and paracetamol, intensive blood sampling was conducted for up to 6?h. Time between dosing and the start of absorption (T_lag); a novel parameter, time at which the test formulations (ibuprofen salts) reached the observed maximum plasma concentration (C_max) of the reference (standard ibuprofen acid) (T_CmaxRef); and time to achieve therapeutic plasma concentration were measured.

Results: Ibuprofen was absorbed more rapidly from the salt formulations than the reference; T_lag was 3.3–6.4?min for salt formulations compared with 10.9?min for the reference, and 100% of subjects had a T_lag ≤ 5?min for ibuprofen lysine, compared with 61% for ibuprofen liquid capsule, 21% for ibuprofen sodium, and 7% for the reference. T_CmaxRef was 3.22–5.74-times shorter for salt formulations than for the reference (all p?p?Conclusions: This study shows that ibuprofen salts are absorbed faster than ibuprofen acid. T_lag and T_CmaxRef demonstrated early start and increased speed of absorption of salts compared with the reference, and may predict more rapid onset of analgesia.     

塞来昔布分散片的制备及其体外溶出度研究

目的：制备塞来昔布分散片并考察其体外溶出度。方法：以微晶纤维素（MCC）为填充剂,采用湿法制粒法制备分散片;以MCC、羧甲基淀粉钠（CMS—Na）的处方用量及羟丙基甲基纤维素（HPMC）的浓度为因素,并采用正交实验设计优化处方;采用《中国药典》溶出度法第二法,以磷酸盐缓冲液为介质进行体外溶出度考察。结果：最佳处方为MCC30％、CMS—Na5％、HPMC3％;所制片剂呈白色、片面光洁,崩解时限20s,含量、分散均匀性均符合2010年版《中国药典》相关要求,30min内溶出度大于90％。结论：该分散片制备方法简单,分散均匀,溶出速度快且完全。     

The effect of the physicochemical properties of a drug on its release from chitosonium malate matrix tablets

The effect of the physico-chemical properties of an active compound (such as solubility and molecular size) on its release characteristics from chitosonium malate matrix tablets has been investigated. For this purpose, the release of 11 drugs of various solubilities (1 in < 1 to 1 in 10000) and molecular weights (138–375) through chitosonium malate matrix tablets was studied. It may be concluded that, in addition to the solubility, the molecular size of drug is of importance in the drug release characteristics from the chitosonium malate matrix. When the release data (< 60%) were fitted to the simple power law equation, the mode of drug release from the chitosonium malate matrix was generally non-Fickian and Super Case II type. These drugs (timolol maleate, ephedrine, propranolol hydrochloride, acetylsalicylic acid, naproxen, sulphadiazine, indomethacin and pindolol) can be released at a nearly zero-order rate through the matrix.     

Temperature effect of rheological parameters and pharmaceutical availability of diclofenak sodium salt from hydrogel products made on carbopol base for topical use

The aim of the carried out investigations was to state temperature effect of conventional carried out results of pharmaceutical availability valuation. Rheological parameters were tested in temperature of 32 and 37 degrees C in market hydrogel products for topical use made on carbopol base with diclofenac sodium salt. The kinetics of diclofenac sodium salt release with Hanson extraction cells through a dialysis membrane SpectraPor was tested in vitro. Viscosity parameters were determined with cone-plate digital rheometer.     

The effect of physico-chemical properties of the drug on the pharmaceutical availability of piroxicam from pellets

The aim of this study was to develop the formulation of pellets with solid dispersions of piroxicam, and determine the effect of physico-chemical properties of the drug on pharmaceutical availability from solid dispersions and pellets. Two types of piroxicam, varying in crystal size, were used in this study. Presence of the amorphous form in solid dispersions depended on the method of their formulation, and type of piroxicam used. Based on the results of piroxicam release rate from pellets, it was established that the extrusion and spheronization process caused change in the drug release profile in comparison to powder systems, because during the pelletization process, the amorphous form of the piroxicam present in the solid dispersion recrystallizes, and a low-solubility type forms. Better results were obtained using the method, where microcrystalline cellulose cores were coated with solid dispersion.     

Effects of sodium fluoride exposure on some biochemical parameters in mice: Evaluation of the ameliorative effect of royal jelly applications on these parameters

Forty eight male Balb/c mice, each weighing 30–35 g, were used in the present study. The animals were divided into four equal groups. The first group served as the control group, and the second group was administered royal jelly at a dose of 50 mg/kg bw by gavage for a period of 7 days. The third group received 200 ppm fluoride, as sodium fluoride, for a period of 7 days, in drinking water. Lastly, the fourth group was given 200 ppm fluoride in drinking water, in association with royal jelly at a dose of 50 mg/kg bw by gavage, for a period of 7 days. At the end of the seventh day, blood samples were collected from all groups into heparinised and dry tubes, and liver samples were taken concurrently. Erythrocyte and liver tissue malondialdehyde (MDA) levels and superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities were evaluated in the blood and tissue samples obtained. Furthermore, serum cholesterol, triglyceride, glucose, total protein and albumin levels, and aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alcaline phosphatase (ALP) activities were evaluated. In conclusion, fluoride was determined to cause adverse effects in mice, and the administration of royal jelly to these animals alleviated the adverse effects of fluoride.     

The effect of competitive and non-linear plasma protein binding on the stereoselective disposition and metabolic inversion of ibuprofen in healthy subjects

The stereoselective disposition and metabolic inversion of ibuprofen were studied in 12 healthy subjects under conditions of competitive and non-linear plasma protein binding. Each subject received each of four oral treatments according to a Latin-square design: 300 mg R(?)-ibuprofen, 300 mg S(+)-ibuprofen, 300 mg R(?)- + 300mg S(+)-ibuprofen, and 300 mg R(?)- + 600 mg S(+)-ibuprofen. For a given treatment, the partial clearance of S(+)-ibuprofen was greater than that of R(?)-ibuprofen for all stereoisomeric drug species. Likewise, the unbound partial clearances of S(+)-ibuprofen were greater for most stereoisomeric drug species. There was also less difference among treatment groups when partial clearances were referenced to unbound as opposed to total plasma concentrations of enantiomer. The unbound intrinsic clearance and fractional inversion of R(?)-ibuprofen were unchanged across the four treatments, and chiral inversion was systemic, averaging 69%. In conclusion, stereoselective differences exist for the partial and composite clearances of R(?)- and S(+)-ibuprofen even when corrected for differences in plasma protein binding. However, differences among treatment groups for a particular elimination pathway are largely due to ibuprofen's non-linear binding.     

Synthesis and evaluation of the structural and physicochemical properties of carboxymethyl pregelatinized starch as a pharmaceutical excipient

A pregelatinized starch (PGS) was derivatized with sodium chloroacetate (SCA) in alcoholic medium under alkaline condition to produce carboxymethyl pregelatinized starch (CMPGS) with various degrees of substitution (DS). Influence of the molar ratio of SCA to the glucopyranose units (SCA/GU), reaction time, temperature and the amount of sodium hydroxide on the degree of substitution (DS) and the reaction efficiency (RE) was studied. An optimal concentration of 30% of NaOH, for a reaction time of 1 h at 50 °C and molar ratio (SCA/GU) equal to 1.0, yielded an optimal DS of 0.55 and a RE of 55%. SEM micrographs revealed that the carboxymethylation assigned the structural arrangement of CMPGS and caused the granular disintegration. Wide angle diffraction X-ray (XRD) showed that the crystallinity of starch was obviously varied after carboxymethylation. New bands in FTIR spectra at 1417 and 1603 cm⁻¹ indicated the presence of carboxymethyl groups. The solubility and viscosity of CMPGS increased with an increase in the degree of modification. In order to investigate the influence of DS on physical and drug release properties, CMPGS obtained with DS in the range of 0.12–0.55 was evaluated as tablet excipient for sustained drug release. Dissolution tests performed in phosphate buffer (pH 6.8), with Ibuprofen as drug model (25% loading) showed that CMPGS seems suitable to be used as sustained release excipient since the drug release was driven over a period up to 8 h. The in vitro release kinetics studies revealed that all formulations fit well with Korsmeyer-Peppas model and the mechanism of drug release is non-Fickian diffusion.     

炔雌醇环丙孕酮片联合胰岛素增敏剂治疗多囊卵巢综合征的临床效果分析

目的 探讨炔雌醇环丙孕酮片联合胰岛素增敏剂治疗多囊卵巢综合征（PCOS）的临床效果及对促排卵结局的影响.方法 收集本院收治的PCOS患者50例作为本次研究对象,按照入院时间先后分成A、B两组,A组单纯使用炔雌醇环丙孕酮片治疗,B组采用炔雌醇环丙孕酮片联合二甲双胍和吡格列酮治疗,比较两组患者用药后糖代谢、生殖激素、促排卵结局及不良反应等情况.结果 A组患者治疗前后糖代谢各项指标差异无统计学意义（P＞0.05）;B组治疗前后糖代谢各项指标差异有统计学意义（P＜0.05）;A、B两组治疗后,T指标均明显下降（P＜0.05）;B组患者的周期取消率及OHSS发生率均低于A组,妊娠率高于A组,差异均有统计学意义（P＜0.05）.结论 炔雌醇环丙孕酮片联合胰岛素增敏剂治疗PCOS,可以有效促进患者内分泌及代谢平衡,促进排卵,提高妊娠率,值得推广应用.     

Voltammetric behavior and assay of the antibiotic drug cefazolin sodium in bulk form and pharmaceutical formulation at a mercury electrode

The electrochemical behavior of the antibiotic drug cefazolin sodium (CFZ) in Britton–Robinson buffers (pH 2–11) at the mercury electrode was studied by means of dc-polarography, cyclic voltammetry, controlled-potential coulometry and square-wave adsorptive stripping voltammetry techniques. A validated square-wave adsorptive cathodic stripping voltammetric procedure was described for the trace determination of cefazolin in bulk form up to limits of detection and quantitation of 2.6 × 10⁻¹⁰ M and 8.6 × 10⁻¹⁰ M, respectively. The method was successfully applied for determination of cefazolin in pharmaceutical preparation without the necessity for samples pretreatment or any time-consuming extraction or evaporation steps prior to the analysis.     

脉管复康片联合氯吡格雷治疗冠状动脉粥样硬化性心脏病的效果研究

目的 研究脉管复康片联合氯吡格雷治疗冠状动脉粥样硬化性心脏病的临床效果.方法 100例冠状动脉粥样硬化性心脏病患者,按照随机数字表法分为氯吡格雷组和两药联合组,各50例.氯吡格雷组患者使用氯吡格雷进行治疗,两药联合组采用脉管复康片联合氯吡格雷治疗.比较两组患者治疗前后心功能指标[左室射血分数(LVEF)、左室收缩末期内...