Biodegradable microspheres of ketorolac tromethamine for parenteral administration

Ketorolac tromethamine loaded microspheres were prepared using two different polyesters, namely poly (lactic acid) and poly (glycolic acid) by solvent evaporation technique. The morphology of microspheres was analysed by scanning electron microscopy. In vitro release profiles of these microspheres were studied in phosphate buffered saline pH 7.4. The release kinetics of ketorolac tromethamine from the microspheres was evaluated by fitting the release data to the zero-order, Higuchi and korsemeyer-peppas equations. All microspheres showed initial burst release, followed by fickian diffusion of drug through microspheres. These microspheres were formulated as parenterals to have controlled release system.     

酮咯酸氨丁三醇致过敏性休克

1例26岁男性患者因腹痛给予酮咯酸氨丁三醇30mg肌内注射。注射完毕后约5min,患者感头晕、乏力,并出现全身出汗、晕厥。血压65／40mmHg（1mmHg=0．133kPa）,心率108次／min。立即予吸氧、静脉给予肾上腺素、地塞米松、间羟胺及肌内注射异丙嗪等治疗。约30min后,患者神志恢复正常,症状逐渐好转,血压105／75mmHg,心率80次／min。其后未再出现不适。     

Evaluation of ketorolac tromethamine microspheres by chitosan/gelatin B complex coacervation

Microspheres (MS) of Ketorolac Tromethamine (KT) for oral delivery were prepared by complex coacervation (method-1) and simple coacervation (method-2) methods without the use of chemical crossalinking agent (glutaraldehyde) to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate (Na-TPP) as cross linking agent. Chitosan and gelatin B were used as polymer and copolymer respectively. All the prepared microspheres were subjected to various physico-chemical studies, such as drug-polymer compatibility by Thin Layer Chromatography (TLC) and Fourier Transform Infra Red Spectroscopy (FTIR), surface morphology by Scanning Electron Microscopy (SEM), frequency distribution, encapsulation efficiency, in-vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by Differential Scanning Calorimetry (DSC) and X-ray powder Diffractometry (XRD). TLC and FTIR studies indicated no drug-polymer incompatibility. All the MS showed release of drug by a fickian diffusion mechanism. DSC and XRD analysis indicated that the KT trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. It is possible to design a controlled drug delivery system for the prolonged release of KT, improving therapy by possible reduction of time intervals between administrations.     

Comparative bioavailability of two oral formulations of ketorolac tromethamine: Dolac® and Exodol®

The bioavailability of ketorolac after administration of two oral formulations containing 10 mg of ketorolac tromethamine, Exodol^® and Dolac^®, to 12 healthy Mexican volunteers was compared. Subjects received both formulations according to a randomized crossover design and blood samples were drawn at selected times during 24 h. Ketorolac plasma concentrations were determined by HPLC and individual plasma-concentration-against-time curves were constructed. Maximal plasma concentration and AUC_0-24. values were compared by analysis of variance followed by Westlake's confidence interval test. 90% confidence limits ranged from 80 to 125% for C_max and from 85 to 118% for AUC_0-24. It is concluded that the two assayed formulations are bioequivalent.     

国产酮咯酸氨丁三醇分散片的人体相对生物利用度研究

目的评价酮咯酸氨丁三醇分散片剂的人体相对生物利用度,并与胶囊剂比较其生物等效性。方法 18名男性健康受试者随机、自身对照交叉单剂量口服酮咯酸氨丁三醇分散片和胶囊,采用RP-HPLC法测定血浆中酮咯酸氨丁三醇的浓度。结果单剂量口服含酮咯酸氨丁三醇20 mg的受试和参比制剂,其达峰时间Tmax分别为(0.68±0.30)、(0.80±0.38)h;血药浓度峰值Cmax分别为(3 124.44±382.96)、(3 170.28±289.03)ng/mL;药时曲线下面积AUC(0→24)分别为(13 939.32±2 471.53)、(14 312.29±2 268.26)ng.h/mL。两种制剂的药物动力学参数比较差异无统计学意义(P>0.05),受试制剂的相对生物利用度(F)为97.86%±11.62%。结论两种制剂具有生物等效性。     

术前静滴酮咯酸氨丁三醇预防小儿全麻苏醒期躁动的临床观察

目的观察预先静脉滴注酮咯酸氨丁三醇对小儿全麻苏醒期躁动的影响。方法选择60例择期静吸复合全麻下行骨折内固定物取出术患儿,随机分为试验组和对照组,每组30例。全麻诱导前10 min试验组静脉滴注酮咯酸氨丁三醇0.5 mg/kg,对照组静脉滴注相同容量的生理盐水。记录两组患儿手术时间、麻醉时间、拔除喉罩时间、苏醒室停留时间,患者在入室及拔除喉罩时(T1)、到达苏醒室后5 min(T2)、15 min(T3)、30 min(T4)各时点的心率(HR)、平均动脉压(MAP)、血氧饱和度(SpO2)值以及T1～T4的疼痛、躁动和镇静评分(分别为FLACC评分、PAED评分和Ramsay评分),并观察恶心呕吐、低氧血症、呼吸抑制、反流误吸、瘙痒等不良反应发生情况。结果试验组在T1、T2、T3时点HR低于对照组,在T1、T2时点MAP低于对照组;试验组的疼痛评分在T1、T2、T3时点均低于对照组,躁动评分在4个时点均低于对照组,镇静评分在T1、T2、T3时点均高于对照组,差异有统计学意义(P<0.05)。结论在骨折内固定物取出术患儿全麻诱导前预先静脉滴注酮咯酸氨丁三醇0.5 mg/kg,可获得良好的镇痛效果,减少苏醒期躁动,无明显不良反应的发生。     

酮咯酸氨丁三醇与地佐辛用于妇科腹腔镜手术后镇痛效果比较

目的 探讨酮咯酸氨丁三醇与地佐辛在妇科腹腔镜手术中镇痛效果.方法 120例妇科腹腔镜手术患者按照随机数字表法分为A组(60例)和B组(60例),A组术前给予酮咯酸氨丁三醇,B组术前给予地佐辛,观察两组镇痛效果.结果 A组拔管时间和意识恢复时间均明显的低于B组(P<0.05);A组不良反应发生率为6.7%,明显低于B组,差异有统计学意义(P<0.05).结论 妇科腹腔镜手术预先给予酮咯酸氨丁三醇与地佐辛均具有较好的镇痛效果,但地佐辛不良反应较多,术后苏醒时间延长.     

酮咯酸氨丁三醇注射液急诊治疗肾绞痛的临床观察

目的探讨肌内注射酮咯酸氨丁三醇注射液急诊治疗肾绞痛的效果。方法将肾绞痛患者108例随机分为两组,观察组56组例,对照组52例,观察组采用酮咯酸氨丁三醇注射液30mg肌内注射;对照组强痛定50mg肌内注射。结果观察组的临床总有效率明显比对照组（P〈0．01）,起效及显效时间快差异有统计学意义（P〈0．01）,不良反应小。结论采用肌内注射酮咯酸氨丁三醇注射液能有效提高止痛效果,起效快,不良反应小,值得临床推广。     

酮咯酸氨丁三醇联合山莨菪碱治疗肾绞痛的疗效观察

目的：探讨酮咯酸氨丁三醇联合山莨菪碱治疗肾绞痛的疗效。方法选取2011—2013年沧州市中心医院急诊科收治的肾绞痛患者457例,随机分为治疗组（228例）与对照组（229例）。治疗组患者予以酮咯酸氨丁三醇联合山莨菪碱治疗,对照组患者予以盐酸哌替啶联合山莨菪碱治疗。观察两组患者临床疗效及不良反应（如恶心、呕吐、头晕、尿潴留、低血压、过敏等）发生情况。结果两组患者总有效率比较,差异无统计学意义（ P ＞0.05）;治疗组患者不良反应发生率低于对照组,差异有统计学意义（P ＜0.05）。结论酮咯酸氨丁三醇联合山莨菪碱治疗肾绞痛的疗效显著,且不良反应少,安全性高。     

Porous Biodegradable Microspheres for Controlled Drug Delivery. I. Assessment of Processing Conditions and Solvent Removal Techniques

Microspheres containing methylene blue and prednisolone acetate were prepared by one of three methods: freeze-drying, evaporation, and solvent-extraction-precipitation. An extremely porous structure was obtained by the freeze-dry and solvent-extraction-precipitation procedures. The specific surface area of 6.33-µm particles was 20.6 m²/g, or 35 times that of a particle devoid of pores, and the void space was 59–61%. The sphericity, size, and yields of the microspheres were influenced by the preparation procedure, surfactant type and concentration, temperature of the continuous phase, polymer concentration in the dispersed phase, and ratio of marker to polymer. The most suitable processing conditions were a polymer concentration of 5–10%, a marker loading of 10%, 0.1% sorbitan sesquioleate as the surfactant, and temperature adjustment of the continuous phase from 15 to 50°C following the addition of the dispersed phase. Complete release of the highly water soluble methylene blue occurred within 72 hr, while the less soluble prednisolone acetate released much more slowly, i.e., 90% after 7 days. The microspheres remained relatively intact during the in vitro release of methylene blue, confirming that the incorporated agent was confined to the walls of the porous network. Collapse of the polymer structure was evident after 7 days. The release therefore was believed to be governed principally by the solubility of the drug and the porosity of the matrix.     

酮咯酸氨丁三醇超前镇痛对扁桃体切除术患者血流动力学的影响

目的观察酮咯酸氨丁三醇超前镇痛对扁桃体切除术患者气管拔管期血流动力学的影响及术后的镇痛效果。方法选择择期行双侧扁桃体切除术的全麻患者60例,随机分为2组:观察组(酮咯酸氨丁三醇30 mg),对照组(生理盐水)。手术开始前15 min,观察组静注酮咯酸氨丁三醇30 mg,对照组静注等剂量生理盐水。记录两组患者的一般资料,入室、拔管即刻、拔管后5 min、拔管后10 min患者的收缩压、舒张压、心率、血氧饱和度,苏醒期躁动评分,拔管后5 min、10 min、1 h时的OAA/S评分和拔管后1、4、6、12 h的VAS评分,记录患者的手术时间、麻醉时间、拔管时间及术后不良反应。结果拔管即刻及拔管后5、10 min,观察组的SBP为(124.9±7.7)、(120.3±9.2)、(118.9±9.3)mm Hg,DBP为(73.8±5.9)、(71.8±8.1)、(69.5±8.0)mm Hg;对照组的SBP为(138.0±9.4)、(134.9±11.0)、(132.7±10.8)mm Hg,DBP为(82.3±8.5)、(80.6±9.6)、(79.8±8.5)mm Hg,观察组各时点的血压均低于对照组,差异有统计学意义(P<0.05)。拔管后1、4、6、12 h,观察组的VAS评分为1.0±0.8、1.4±0.7、2.2±1.0、2.8±0.6,对照组为2.7±1.0、3.5±1.1、4.1±1.0、3.2±1.1,观察组评分低于对照组(P<0.05)。结论酮咯酸氨丁三醇30 mg超前镇痛用于成人双侧扁桃体切除术患者气管拔管期血流动力学波动小,镇痛效果良好。     

酮咯酸氨丁三醇联合曲马多超前镇痛预防小儿全麻苏醒期躁动的临床观察

目的探讨酮咯酸氨丁三醇联合曲马多超前镇痛预防小儿全麻苏醒期躁动的作用。方法选择40例择期在全麻下行骨折闭合复位的患儿,随机分为联合用药组和对照组,每组20例。对照组在全麻诱导前静注曲马多0.8 mg/kg,联合用药组在全麻诱导前静注酮咯酸氨丁三醇0.5 mg/kg和曲马多0.8 mg/kg。术中监测血压、心率、血氧饱和度、呼吸末气体浓度,记录手术时间、麻醉时间、拔管时间及术后躁动情况。结果两组患儿手术时间、麻醉时间、拔管时间、术后低氧血症、恶心呕吐发生率的差异均无统计学意义(P>0.05),联合用药组术后躁动发生情况优于对照组(P<0.05)。结论酮咯酸氨丁三醇联合曲马多预防小儿全麻苏醒期躁动的疗效优于单用曲马多,值得临床借鉴。     

Determinants of Release Rate of Tetanus Vaccine from Polyester Microspheres

Controlled-release formulations based on poly(lactic) (PLA) and poly(lactic/glycolic) acid (PLGA) microspheres containing tetanus vaccine were designed. The polymers forming the microspheres were L-PLA of different molecular weights and DL-PLGA, 50:50. These microspheres were prepared by two solvent elimination procedures, both using a double emulsion, and were characterized for size, morphology, and toxoid release kinetics. The influence of formulation variables such as polymer type, vaccine composition, and vaccine/polymer ratio was also investigated. Both techniques yielded microspheres with similar size, morphology, and release properties. Microsphere size was dependent on the type of polymer and the presence of the surfactant L--phosphatidylcholine, which led to a reduction in microsphere size. On the other hand, the release kinetics of encapsulated protein were affected by the polymer properties (ratio lactic/glycolic acid and molecular weight) as well as by the vaccine composition, vaccine loading, and microsphere size. Moreover, for some formulations, a decrease in microsphere size occurred simultaneously, with an increase in porosity leading to an augmentation of release rate. The changes in the PLA molecular weight during in vitro release studies indicated that release profiles of tetanus toxoid from these microspheres were only marginally influenced by polymer degradation. A significant fraction of protein (between 15 and 35%) was initially released by diffusion through water-filled channels. In contrast, the decrease in the PLGA molecular weight over the first 10 days of incubation suggested that erosion of the polymer matrix substantially affects protein release from these microspheres. Among all formulations developed, two differing in microsphere size, polymer hydrophobicity, and release profile were selected for in vivo administration to mice. Administration of both formulations resulted in tetanus neutralizing antibody levels that were higher than those obtained after administration of the fluid toxoid.     

Controlled Delivery Systems for Proteins Based on Poly(Lactic/Glycolic Acid) Microspheres

This paper describes an investigation of the use of poly(lactic/glycolic acid) polymers for long-term delivery of high molecular weight, water-soluble proteins. Poly(lactic/glycolic acid) (PLGA) microspheres, containing (fluorescein isothiocyanate)-labeled bovine serum albumin and (fluorescein isothiocyanate)-labeled horseradish peroxidase, were prepared by a modified solvent evaporation method using a double emulsion. The microspheres were spherical with diameters of 55–95 µm and encapsulated more than 90% of the protein. The preparation method was gentle and maintained enzyme activity and protein solubility. Stability studies showed that the encapsulation of an enzyme inside PLGA microspheres can protect them from activity loss. When not placed inside PLGA microspheres, (fluorescein isothiocyanate)-labeled horseradish peroxidase lost 80% of its activity in solution at 37°C in a few days, whereas inside the PLGA microspheres it retained more than 55% of its activity after 21 days of incubation at 37°C. In vitro release studies revealed that different release profiles (i.e., near-constant or biphasic) and release rates can be achieved by simply modifying factors in the preparation procedure such as mixing rate and volume of inner water and organic phases. Degradation studies by scanning electron microscopy and gel-permeation chromatography suggested that the mechanism responsible for protein release is mainly through matrix erosion.     

静脉注射小剂量酮咯酸氨丁三醇联合间苯三酚治疗肾绞痛的观察

目的探讨静脉注射小剂量酮咯酸氨丁三醇联合间苯三酚解除肾绞痛的临床疗效。方法将140例肾绞痛患者随机分为三组,I组46例静脉注射酮咯酸氨丁三醇30mg,II组47例肌注酮咯酸氨丁三醇60mg,同时两组均静脉滴注间苯三酚80mg;III组47例在肌注哌替啶100mg的同时静脉滴注山莨菪碱10mg,观察比较各组给药后10、20、40min的疼痛缓解效果、不良反应等情况。结果给药后10minI组患者疼痛解除率及总有效率（19．56％,76．9％）明显高于Ⅱ组（0,40．42％）、III组（8．51％,55．31％）,差异有统计学意义（P=0．005,P=0．002）,给药后40min各组间比较差异无统计学意义（P=0．861,P=0．869）;I组患者的平均疼痛解除时间为（14．3±9．5）min,短于Ⅱ组（23．8±5．4）min、Ⅲ组（18．2±8．3）min,差异有统计学意义（F=46．32,P〈0．05）;I、Ⅱ组的不良反应率（8．69％,14．89％）低于Ⅲ组（82．97％）,差异有统计学意义（P=0．000）。结论小剂量（30mg）酮咯酸氨丁三醇静脉注射联合间苯三酚静脉滴注对肾绞痛疗效好,起效快,不良反应少。     

Evaluation of poly(lactic acid) as a biodegradable drug delivery system for parenteral administration

Poly(lactic acid) (PLA) microspheres of 1–10 μm diameter prepared by emulsion deposition and containing entrapped prednisolone released the drug rapidly into an aqueous medium. Similarly sized microparticles prepared by a fusion process exhibited a more prolonged drug release profile and may have potential as a long-acting parenteral delivery system. Both methods of fabricating the polymer produced material which was cytotoxic when phagocytosed by mouse peritoneal macrophages. The intracellular toxicity and hence potential irritancy in vivo was only partially overcome by incorporating anti-inflammatory drug. Compressed implants of the same polymers containing prednisolone 10% w/w (100 mg·cm⁻³) and weighing 12 mg were readily administered and sustained the delivery of the drug for over 30 days without complications at the implantation site.     

反相高效液相色谱法测定酮咯酸氨丁三醇滴眼液的含量

目的 采用反相高效液相色谱法测定酮咯酸氨丁三醇滴眼液的含量.方法 采用RP-HPLC法,色谱柱为C8柱(4.6mm×250 mm,5μm);流动相为磷酸盐缓冲液-四氢呋喃(70 ∶ 30);流速为1.2 mL·min-1;检测波长313 nm.结果 酮咯酸氧丁三醇在0.24～0.56 mg·mL-1 (r=0.999 7)与峰面积呈良好线性关系,其平均回收率为100.3％,RSD=0.34％(n=9);仪器精密度RSD=0.23％(n=6);方法重复性RSD=0.43％(n=6).结论 该分析方法灵敏、准确,专属性强,重现性好,可以作为酮咯酸氨丁三醇滴眼液的质量控制方法.     

酮咯酸氨丁三醇与曲马多对小儿七氟醚全麻术后躁动的影响

目的观察酮咯酸氨丁三醇与曲马多对小儿七氟醚全麻术后躁动的影响。方法选择全麻下行扁桃体和腺样体切除术的患儿80例,年龄2⁷岁、ASAⅠ7岁、ASAⅠ^Ⅱ级。根据手术结束前静脉注入的药物分为4组,每组20例,曲马多组(T组,手术结束前30 min静注曲马多1 mg/kg),酮咯酸氨丁三醇组(K组,手术结束前30 min静注酮咯酸氨丁三醇0.5 mg/kg),曲马多+酮咯酸氨丁三醇组(T+K组,手术结束前30 min静注曲马多1mg/kg和酮咯酸氨丁三醇0.5 mg/kg),对照组(C组,手术结束前30 min静注盐水5 mL)。记录各组手术时间、术后拔管时间,拔管后5 min(T5)、10 min(T10)的躁动评分,入PACU后记录疼痛和镇静评分,以及术后恶心呕吐的情况。结果各组间患儿手术时间、拔管时间比较差异无统计学意义(P>0.05);T5和T10 2个时点的躁动发生率排序:C组>T组>T+K组,C组>K组>T+K组,差异有统计学意义(P<0.05)。K组躁动发生率高于T组,但差异无统计学意义(P>0.05);入PACU后患儿疼痛评分排序:C组>T组>T+K组,C组>K组>T+K组,差异有统计学意义(P<0.05)。K组疼痛评分高于T组,但差异无统计学意义(P>0.05);术后恶心呕吐发生率T组和T+K组明显高于C组和K组(P<0.05)。结论酮咯酸氨丁三醇和曲马多可减轻术后疼痛,减少小儿七氟醚麻醉后躁动的发生。两种药物联合应用降低术后躁动的效果更显著。     

缓释微球抗肿瘤研究进展

目的介绍聚乳酸-羟基乙酸共聚物缓释微球在抗肿瘤研究方面的进展。方法查阅国内外近年来的期刊。结果国外学者的研究热点是通过在聚乳酸-羟基乙酸共聚物缓释微球外包裹小分子、外加保护剂或黏附壳聚糖达到靶向肿瘤组织的作用,降低抗肿瘤药物对正常组织的毒副作用。国内学者将聚乳酸-羟基乙酸共聚物缓释微球技术应用于一些半衰期短但疗效明显的抗癌药物,通过包裹到微球中延长其抗肿瘤作用。结论以聚乳酸-羟基乙酸共聚物为微球骨架材料,能提高药物疗效,降低抗肿瘤药物对正常组织的毒副作用,在体内达到缓释、长效的目的。     

Preparation and evaluation of ketorolac tromethamine gel containing genipin for periodontal diseases

Ketorolac tromethamine gel (KT gel) and ketorolac tromethamine gel containing genipin (KTG gel) were prepared and their therapeutic effects on periodontitis were evaluated. The skin permeation rate of ketorolac from the KT gel and KTG gel was 5.75+/-0.53 and 5.82 +/- 0.74 microg/cm2/ h, respectively. The skin permeation rate of genipin from the KTG gel was 10.13 +/- 1.47 microg/ cm2/h. The tensile strength of the KTG gel was larger than the KT gel. After 4 weeks, the periodontal pocket depth of the KTG gel group (3.22 +/- 0.20 mm) significantly decreased compared with the non-treated group (4.50 +/- 0.25 mm) and the KT group (3.84 +/- 00.26 mm). The KTG gel did not induce separation of the stratum corneum and subcutaneous tissue, and the collagen layers of the corium were closer, more fibrous, and showed longer connections than in the other groups. The KTG gel appears to be effective against gingivitis in the periodontal pocket through its increased anti-inflammatory activity and the crosslinking of genipin with the biological tissue.