Two kinds of ketoprofen enteric gel beads(CA and CS-SA) using biopolymer alginate

To obtain expected rapid-release and sustained-release of ketoprofen gel beads, this paper adopted biopolymer alginate to prepare alginate beads and chitosan-alginate gel beads. Formulation factors were investigated and optimized by the single factor test. The release of ketoprofen from calcium alginate gel beads in pH 1.0 hydrochloric acid solution was less than 10% during 2 h, then in pH6.8 was about 95% during 45 min, which met the requirements of rapid-release preparations. However, the drug release of chitosan-alginate gel beads in pH1.0 was less than 5% during 2 h, then in pH6.8 was about 50% during 6 h and reached more than 95% during 12 h, which had a good sustained-release behavior. In addition, the release kinetics of keteprofen from the calcium alginate gel beads fitted well with the Korsmeyer–Peppas model and followed a case-II transport mechanism. However, the release of keteprofen from the chitosan-alginate gel beads exhibited a non-Fickian mechanism and based on the mixed mechanisms of diffusion and polymer relaxation from chitosanalginate beads. In a word, alginate gel beads of ketoprofen were instant analgesic, while chitosan-alginate gel beads could control the release of ketoprofen during gastrointestinal tract and prolong the drug's action time.

The characterization and dissolution performances of spray dried solid dispersion of ketoprofen in hydrophilic carriers

Solid dispersion is one of the most promising strategies to improve oral bioavailability of poorly soluble API.However,there are inconsistent dissolution performances of solid dispersion reported which entails further investigation.In this study,solid dispersions of ketoprofen in three hydrophilic carriers,i.e.PVP K30,PVPVA 6:4 and PVA were prepared and characterized.Physical characterization of the physical mixture of ketoprofen and carriers shows certain extent of amorphization of the API.This result is coinciding to evaluation of drug-polymer interaction using ATR-FTIR whereby higher amorphization was seen in samples with higher drug-polymer interaction.XRPD scanning confirms that fully amorphous solid dispersion was obtained for SD KTP PVP K30 and PVPVA system whereas partially crystalline system was obtained for SD KTP PVA.Interestingly,dissolution profiles of the solid dispersion had shown that degree of amorphization of KTP was not directly proportional to the dissolution rate enhancement of the solid dispersion system.Thus,it is concluded that complete amorphization does not guarantee dissolution enhancement of an amorphous solid dispersion system.

Effects of Ginsenosides and Ketoprofen on Smoke Inhalation Injury in Rabbits and Rats

Six hours after smoke inhalation injury in rabbits, the permeability of pulmonary vesselsand the aggregation of circulating platelets increased markedly accompanied with apparent patholog-ical changes in the trachea and lungs. Fifteen minutes after smoke inhalation injury in rabbits, an intravenous dose of ginsenosides or ketoprofenwas given to the animals respectively. 6 hours after medication, it was found that both the drugscould significantly alleviate the platelet aggregation, but only ginsenosides could alleviate theaugmentation of pulmonary vascular permeability and the pathological lesions in the trachea andlungs. In those rats injured by smoke inhalation, l hour after an intravenous dose of ginsenosides, theplasma PGI2 level was elevated and TXA2/PGI2 ratio decreased significantly.

Investigation on the Percutaneous Enhancing Permeation Mechanism of Azone for Ketoprofen Based on the Intermolecular Hydrogen-bonding Interaction

The permeation enhancing activity of Azone for ketoprofen through excised cavia skins was investigated using Franz diffusion cell. The possible hydrogen-bonded complexes formed between ketoprofen and the model molecule of Azone as azacyclopentane-2-one were fully optimized at the B3LYP/6-311＋＋G＊＊ level. The intermolecular hydrogen-bonding interactions were calculated using the B3LYP/6-311＋＋G＊＊, B3LYP/6-311＋＋G（2df, 2p）, MP2（full）/6-311＋＋G＊＊ and MP2（full）/6-311＋＋G（2df, 2p） methods, respectively. The results show that the steady-state permeation rate of ketoprofen through excised cavia skins enhances over 9 times in the solvent with 2% Azone as compared with the solvent without Azone. The stable O–H…O=C and N–H…O=C hydrogen-bonded complexes could exist between azacyclopentane and ketoprofen. The hydrogen-bonding interaction energy follows the order of（a） 〉（b） 〉（c） 〉（d） 〉（g）〉（e） 〉（h） 〉（f）. The formation of the complexes leads to the change of the conformation and molecular polarity of ketoprofen, and thus causes a better percutaneous permeation for the drug. The analyses of AIM（atom in molecule） and shift of electron density were used to further reveal the nature of the enhancing permeation activity of Azone for ketoprofen. The investigations of the temperature and solvent effects confirm that ketoprofen might enter into the skin by means of the Azone complex.

Effects of Ketoprofen, Ketamine, Lidocaine and Propofol on Fentanyl-Induced Hyperalgesia in Rats

Opioid-induced hyperalgesia negatively affects physiological pain management and presents a complex causal mechanism, involving, pharmacodynamic and pharmacokinetic factors of interactions with receptors, opioid-independent ascending systems and with pro-nociceptive systems. After approval by the CEUA, 42 male Wistar rats were divided into 7 groups: In group 1 (GCSSL) the animals received 1 ml of 0.9% saline solution intraperitoneally (IP);in group 2 (GFTSL), they received fentanyl at a dose of 100 ug·kg-1 IP;in the remaining groups (3, 4, 5, 6 and 7) the animals received IP, fentanyl at a dose of 100 ug·kg-1 followed also by IP route of: group 3 (GFTKP) ketoprofen at a dose of 5 mg·kg-1;group 4 GFTKT), ketamine up to a dose of 10.0 mg·kg-1;group 5 (GFTLI), incisional lidocaine up to a dose of 10 mg·kg-1;group 6 (GFTLP), intraperitoneal lidocaine up to a dose of 10 mg·kg-1 and group 7 (GFTPP), propofol up to a dose of 60 mg·kg-1. Under general anesthesia, all animals with a plantar surgical incision. Hyperalgesia was evaluated by applying Von Frey filaments on the 2nd, 1st, 3rd and 5th days after treatment. In the 2nd hour and on the 5th day after the procedure, there was no hyperalgesia associated with the use of fentanyl, however, on the 1st and 3rd postoperative days there was hyperalgesia that was attenuated by ketoprofen, ketamine, lidocaine infiltrated in the incision and intraperitoneally, an effect not observed with the use of propofol. The results suggest fentanyl-induced hyperalgesia and the efficacy of ketoprofen, ketamine, incisional lidocaine and intraperitoneal lidocaine in reducing this effect.

Determination of Ketoprofen in Human Plasma by RP-HPLC

For in vivo pharmacokinetic studies, it is pre-requisite to quantify drug concentrations in plasma. In the present study a RP-HPLC procedure was developed and validated for the assessment of ketoprofen in human plasma. For this purpose mobile phase consisting of methaol:water (70:30) adjusted to pH 3.3 with phosphoric acid was used, and chromatography was carried out on Discovery HS C18 column, 5 μm (25 cm × 4.6 mm). The flow rate was 1 mL·min-1 and quantitative assessment was performed at 260 nm. The retention time was found to be was found to be accurate and illustrated linearity from 0.2441 to 125 μg·mL-1 with the determination coefficient (r2) of 0.9999, also accuracy and precision were found to be <2 (%RSD). The intraday accuracy for concentrations 62.5 μg·mL-1, 15.625 μg·mL-1, 7.812 μg·mL-1 and 1.953 μg·mL-1 were found to be 99.747%, 99.475%, 98.457% and 99.824% respectively where as for interday accuracy consecutive values for days 1, 2 and 3 were 99.104%, 99.091%, 98.96% and 99.385% in plasma. All validation parameters were assessed and were found to be within the limits. The proposed method was accurate, specific, quick (retention time < 10 min), selective (showed no interference with excipients), cost effective and a good resolution which gave this method an advantage over the different other reported methods for the estimation of ketoprofen in human plasma.

The Extent of Solubilization of Flurbiprofen and Ketoprofen by Cetyltrimethylammonium Micelles Using Semi-Equilibrium Dialysis

The partitioning of two non-steroidal anti-inflammatory drugs (NSAIDs), flurbiprofen and ketoprofen, into cationic cetyltrimethylammonium micelles was investigated using semi-equilibrium dialysis at 37℃ in phosphate buffered saline. The micellar-water solubilization equilibrium constants for both NSAIDs, in their deprotonated forms, were observed to decrease linearly with increasing mole fraction of drug in micelles. For flurbiprofen, the solubilization constant in the limit as mole fraction of drug in micelles approaches zero was found to be 11,200 (co = 1 M), while for ketoprofen the value was 1950 (co = 1 M). Using 1H-NMR and UV spectroscopic techniques, the locus of solubilization for ketoprofen was found to be towards the charged exterior of the micelles, in the Stern layer, whereas flurbiprofen was found to solubilize more in the micellar interior.

Chiral extraction of ketoprofen enantiomers with chiral selector tartaric esters

Distribution behavior of ketoprofen enantiomers was examined in methanol aqueous and organic solvent mixture containing tartaric esters. The influence of length of alkyl chain of tartaric esters, concentration of L-tartaric esters and methanol aqueous, kind of organic solvent on partition ratio and separation factors was investigated. The results show that L-tartaric and D-tartaric esters have different chiral recognition abilities. S-ketoprofen is easily extracted by L-tartaric esters, and R-ketoprofen is easily extracted by D-tartaric esters. L-tartaric esters form more stable diastereomeric complexes with S-enantiomer than that with R-enantiomer. This distribution behavior is consistent with chiral recognition mechanism. With the increase of the concentration of tartaric ester from 0 to 0.3 molL, partition coefficient K and separation factor α increase. Also, the kind of organic solvent and the concentration of the methanol aqueous have significant influence on K and α.

Resolving Ketoprofen Using n-Octyl-d-glucamine as an Optical Resolution Agent

The process of resolution of racemic ketoprofen using n-octyl-d-glucamine as an optical resolution agent was investigated. The process consists of preparation of the diastereomer salt of ketoprofen with n-octyl-d-glucamine, liberation of S-(+)-ketoprofen from its diastereomer salt and recovery of the remaining ketoprofen and n-octyl-d- glucamine. The suitable conditions for preparation of the diastereomer salt were methanol and ethyl acetate (1.1 by volume) as the solvent, the ratio of solvent volume to ketoprofen mass at 8ml:1g, and the molar ratio of ketoprofen to n-octyl-d-glucamine at 1:1. The preferred approach to liberate S-(+)-ketoprofen from its diastereomer salt was alkali dissolution, acid adjustment and ethyl acetate extraction. Racemization of the recovered ketoprofen could be achieved by reacting the recovered ketoprofen with 10% NaOH at 507 kPa for 6h. The recovered n-octyl-d- glucamine could be refined by acid dissolution and alkali adjustment. S-(+)-ketoprofen can be obtained with high optical purity and yield, showing that the present process is a practical and efficient one which can be used in industrial scale for preparation of S-(+)-ketoprofen.

Co_(3)O_(4)催化臭氧氧化降解水中酮基布洛芬的研究

以Co(NO_(3))_(2)·6H_(2)O和尿素为原料制备了9种Co_(3)O_(4)催化材料,考察了其对水中酮基布洛芬(KTP)的催化臭氧氧化降解效能。结果表明,与单独臭氧氧化相比,所制备的Co_(3)O_(4)对水中KTP的催化臭氧氧化降解率提高了12.0%~63.8%,且在n〔Co(NO_(3))_(2)·6H_(2)O〕∶n(尿素)=4∶1、煅烧温度400℃下制备得到的Co_(3)O_(4)催化剂催化活性最高。SEM、XRD、FTIR、XPS、BET等表征分析显示,该Co_(3)O_(4)催化剂表面呈覆盖细小微粒的球状颗粒,晶相为立方相,且表面含有丰富的羟基,表面羟基密度为1.075×10^(-5) mol/m^(2)。机理研究证实,Co_(3)O_(4)对水中KTP的非均相催化臭氧氧化降解遵循羟基自由基(·OH)氧化机理,表面羟基作为催化剂活性位点促进了臭氧分解,提高了臭氧转移率和利用率,强化了新生活性物种·OH的生成,增强了对KTP的去除。KTP的氧化降解经历了芳环的羟基化、苯环裂解、双键加成及脂肪族链式化合物的氧化,最终被矿化为CO_(2)和H_(2)O。

过硫酸盐协同g-C_(3)N_(4)光催化降解酮洛芬的研究

以尿素为原料,采用热聚合法合成光催化剂石墨相氮化碳(g-C_(3)N_(4)),并研究其光催化剂性能。通过X射线衍射仪(XRD)、自带能谱分析的扫描电镜(SEM-EDS)、傅里叶红外光谱仪(FT-IR)、热重分析仪(TG/DTG)和紫外-可见分光光度计(UV-Vis DRS)等对光催化剂的结构、形貌、表面官能团、热稳定和光学性能进行表征分析。考察了g-C_(3)N_(4)的合成温度、g-C_(3)N_(4)质量浓度、过硫酸钠(SPS)质量浓度、酮洛芬(KTP)初始质量浓度、溶液初始pH、降解时间及催化剂循环使用次数等因素对光催化降解KTP的影响。结果表明,500℃合成的g-C_(3)N_(4)呈片状多孔纳米结构,具有最佳的光催化性能;在光照功率为35 W、pH为9、SPS初始质量浓度为1.20 g/L、g-C_(3)N_(4)质量浓度为1.00 g/L、降解时间为150 min时,初始质量浓度为2 mg/L的KTP的降解率为96.84%;催化剂经回收连续使用5次,可将初始质量浓度为2 mg/L的KTP溶液光催化降解至100μg/L,可满足回用水要求。

非甾体抗炎药联合抗菌药治疗奶牛临床型乳房炎的临床试验

选取临床型乳房炎患牛30头,分为3组,每组10头,试验组用酮洛芬注射液加硫酸头孢喹肟乳房注入剂治疗,对照组用美洛昔康注射液加硫酸头孢喹肟乳房注入剂治疗,阴性对照组用硫酸头孢喹肟乳房注入剂治疗,比较患牛临床精神状况、乳房局部症状、乳汁性状,直肠温度、奶产量及体细胞数、病原菌清除率、治疗效果等。结果显示,试验组与对照组的各项指标相当,均好于阴性对照组,非甾体抗炎药与抗菌药物联合可更有效地恢复泌乳期奶牛的产奶性能,增加牧场的经济效益,该两组的治疗方法可在临床中推广使用。

酮洛芬异丙酯在皮肤细胞中的代谢

目的 :研究酮洛芬异丙酯在皮肤细胞中的代谢作用 ,为进一步研究利用酯类前体药物方法改善药物的经皮吸收特性提供实验依据。方法 :将人包皮的第 3代角质形成细胞或成纤维细胞超声破碎制成匀浆 ,加入不同量的酮洛芬异丙酯进行37℃温孵实验 ,通过高效液相色谱法分别在不同时间测定细胞匀浆中酮洛芬异丙酯及酮洛芬的浓度。结果 :酮洛芬异丙酯在表皮角质形成细胞和真皮成纤维细胞的匀浆中存在代谢现象 ,且前者的代谢能力明显大于后者。结论

高效液相色谱法测定人血浆中酮洛芬浓度

目的 :采用高效液相色谱法测定人血浆中酮洛芬浓度。方法 :用石油醚 -乙醚 ( 1∶1)提取血浆样品中酮洛芬及萘普生 (内标 ) ,在SpherisorbC18柱上 ,以甲醇 - 5 0mmol·L-1磷酸二氢钠 ( 63∶3 7)为流动相进行分离 ,于 2 5 5nm检测。结果 :线性范围为 0 0 4～ 12 μg·mL-1,萃取回收率为 85 2 %～ 89 9% ,加样回收率为 97 0 %～ 10 0 1% ,日内RSD为 0 4 5 %～ 2 72 % ,日间RSD为 1 3 1%～ 4 4 0 %。结论 :本法简便 ,准确 ,重现性好 ,用于测定

用乙基纤维素制备酮洛芬缓释固体分散体的研究

为评价以水不溶性聚合物EC 为载体,用固体分散技术( 溶剂法) 制备难溶性药物酮洛芬缓释固体分散体,并进行DSC 和体外释放度研究。DSC 结果表明:药物与EC 比例为1∶2 和1∶3 时药物以非晶态存在于载体中。体外释放度试验结果表明,药物体外释药行为均符合Higuchi 方程;缓释效果与EC 量和固体分散体的粒径有主要关系,药物释放速率随EC 用量和粘度增加而减小;固体分散体粒径越小药物体外释放速率越快;在pH 6 .8 介质中的体外释放速率高于在pH1 .2 介质。

酮洛芬前体药物皮肤渗透代谢的立体选择性研究

目的 :研究酮洛芬前体药物 (酮洛芬甲酯、乙酯和异丙酯 )经离体SD大鼠皮肤渗透代谢的立体选择性 ,为利用前体药物方法促进透皮吸收提供依据。方法 :Valia Chien水平扩散池上进行大鼠皮肤渗透代谢研究。应用α 酸性糖蛋白手性柱 (AGP)拆分、测定透皮接受液中酮洛芬对映体的含量。结果 :消旋酮洛芬经离体SD大鼠皮肤渗透没有选择性 ,但其稳态渗透速率显著小于S 酮洛芬的稳态渗透速率 (P <0 0 5 )。酮洛芬前体药物经离体SD大鼠皮肤渗透被完全代谢成酮洛芬 ,其稳态形成速率大于酮洛芬本身经皮渗透的速率 (P <0 0 5 ) ,且所形成的酮洛芬具有立体选择性。结论 :酮洛芬前体药物能够促进酮洛芬的透皮吸收 ,其经皮渗透代谢具有立体选择性。

右旋酮洛芬氨丁三醇和酮洛芬双盲对照治疗类风湿关节炎

目的 :比较右旋酮洛芬氨丁三醇和酮洛芬治疗类风湿关节炎的疗效和安全性。方法 :采用随机、双盲、平行对照的方法治疗类风湿关节炎 12 0例。试验组 6 1例予右旋酮洛芬氨丁三醇 2 5mg ,po,tid ;对照组 5 9例予酮洛芬 5 0mg ,po ,tid ,疗程均为 4周。 结果 :右旋酮洛芬氨丁三醇能明显改善患者的临床症状和体征 ,治疗有效率6 3.9% ,与对照组 (5 5 .9% )相比无显著差异。右旋酮洛芬氨丁三醇的不良反应少且轻微 ,其中胃不适症状发生率两药相比有显著差异 (分别为 4 .9%和 18.6 % )。结论 :右旋酮洛芬治疗类风湿关节炎疗效与酮洛芬相近 ,耐受性优于酮洛芬。

酮洛芬不同透皮制剂的体外透皮性和释放性

分别制备含1%、3%、5%酮洛芬的混合型巴布剂、交联型巴布剂、透皮贴剂,以同浓度的酮洛芬凝胶剂作为对照组,采用改良Franz透皮扩散池,以离体小鼠皮肤为透皮屏障,考察酮洛芬在不同制剂中的体外透皮和释放性能。结果表明,同浓度酮洛芬在不同受试制剂的透皮速率依序为交联型巴布剂>混合型巴布剂>凝胶剂>透皮贴剂;3%酮洛芬在不同贴膏剂中的释放速率依序为混合型巴布剂>交联型巴布剂>透皮贴剂。

酮洛芬β-CD包合物的结构研究

对自制酮洛芬βＣＤ包合物的结构进行了研究。用红外光谱、Ｘ衍射、核磁共振技术研究了酮洛芬βＣＤ包合物的波谱学性质，比较了酮洛芬与βＣＤ形成包合物前后的波谱变化。结果表明：综合图谱解析结果，证实了酮洛芬有部分芳环进入了βＣＤ分子内腔；同时，从酮洛芬分子结构上异丙酸部分的甲基信号产生明显的低场位移（核磁共振谱）的结果，证明是酮洛芬分子的异丙酸及其相连的苯环部分进入βＣＤ分子内腔，形成了包合物。