HPLC法测定甲磺酸培氟沙星及其注射剂有关物质

目的：建立HPLC法测定甲磺酸培氟沙星及其注射剂有关物质。方法：C18色谱柱,流动相为乙腈-2.70g/十六烷基三甲基溴化铵与6.18g硼酸溶液的混合溶液（用1mol/L氢氧化钠溶液调pH值至8.30）-硫二甘醇（30∶70∶0.2）,检测波长为273nm。结果：培氟沙星与同系物及相关杂质分离良好。结果：本方法结果准确、专属性强,更适用于甲磺酸培氟沙星有关物质的检测。     

化学发光法快速检测甲磺酸培氟沙星的含量

目的 建立快速检测痕量甲磺酸培氟沙星注射液的化学发光方法 .方法 利用Ce4+-Na2SO3-H2SO4氧化还原体系在加入甲磺酸培氟沙星后发光强度明显增强的现象,建立了一种测定痕量甲磺酸培氟沙星的化学发光分析方法 .结果 线性范围为0.2～20mg/L(r=0.9974),检测限为0.02mg/L,RSD=2.39%(n=11).结论 本方法 快速,简便,灵敏度高,可以用于甲磺酸培氟沙星注射液含量的测定.     

Gel-forming erodible inserts for ocular controlled delivery of ofloxacin

A new application of high molecular weight (400 kDa) linear poly(ethylene oxide) (PEO) in gel-forming erodible inserts for ocular controlled delivery of ofloxacin (OFX) has been tested in vitro and in vivo. Inserts of 6 mm diameter, 20 mg weight, medicated with 0.3 mg OFX, were prepared by powder compression. The in vitro drug release from inserts was mainly controlled by insert erosion. The erosion time scale was varied by compounding PEO with Eudragit L100 (EUD) 17% neutralized (EUDNa17) or 71% neutralized (EUDNa71). The insert erosion rate depended on the strength of interpolymer interactions in the compounds, and on the hydrophilic-hydrophobic balance of compounds. Immediately after application in the lower conjunctival sac of the rabbit eyes, the inserts based on plain PEO, PEO-EUDNa17 or PEO-EUDNa71 formed mucoadhesive gels, well tolerated by the animals; then the gels spread over the corneal surface and eroded. The gel residence time in the precorneal area was in the order PEO-EUDNa71 < PEO < PEO-EUDNa17. Compared to commercial OFX eyedrops, drug absorption into the aqueous humor was retarded by the PEO-EUDNa71 inserts, and both retarded and prolonged by the PEO-EUDNa17 inserts, while C(max) (maximal concentration in the aqueous) and AUC(eff) (AUC in the aqueous for concentrations > MIC) were barely altered by either insert type. On the other hand, C(max), AUC(eff) and t(eff) (permanence time in the aqueous at concentrations > MIC) were strikingly increased by plain PEO inserts with respect to commercial eyedrops (5.25 +/- 0.56 vs. 1.39 +/- 0.05 microg ml(-1); 693.6 vs. 62.7 microg ml(-1) min; and 290 vs. 148 min, respectively). Bioavailability increase has been ascribed to PEO mucoadhesion and/or increased tear fluid viscosity.     

Evaluation of carbopol-methyl cellulose based sustained-release ocular delivery system for pefloxacin mesylate using rabbit eye model

The major purpose of this study was to develop and characterize a series of carbopol- and methyl cellulose-based solutions as the in situ gelling vehicles for ophthalmic drug delivery. The rheological properties, in vitro release as well as in vivo pharmacological response of a combination of polymer solutions, including carbopol and methyl cellulose, were evaluated. It was found that the optimum concentration of carbopol solution for the in situ gel-forming delivery systems was 0.3% (w/w), and that for methyl cellulose solution was 1.5% (w/w). The mixture of 0.3% carbopol and 1.5% methyl cellulose solutions showed a significant enhancement in gel strength in the physiological condition; this gel mixture was also found to be free flowing at pH 4.0 and 25 degrees C. The rheological behaviors of carbopol/methyl cellulose solution were not affected by the incorporation of the drug. Drug levels in the aqueous humor of the rabbits were well above the MIC-values of relevant bacteria after 12 hours, the results of an optimized formulation containing 0.18% of pefloxacin mesylate compared well with the 0.3% marketed eye drop formulation, indicating our formulation to be significantly better considering that a similar effect was obtained at half the concentration. Both the in vitro release and in vivo pharmacological studies indicated that the carbopol/methyl cellulose solution had better ability to retain drug than did the carbopol or methyl cellulose solutions alone. The results demonstrated that the carbopol/methyl cellulose mixture can be used as an in situ gelling vehicle to enhance the ocular bioavailability of pefloxacin mesylate.     

Spectrophotometric determination of pefloxacin mesylate in pharmaceuticals

A spectrophotometric method is described for assay of pefloxacin mesylate (PFM) in bulk drug and in tablets. The method is based on back extraction of the bromophenol blue dye at pH 5.2 from the dye-drug ion pair followed by measurement of the dye absorbance at 590 nm. The working conditions of the method were investigated and optimized. Beer's law plot showed a good correlation in the concentration range of 0.15-1.25 microg mL(-1). Sensitivity indices such as molar absorptivity, limits of detection and quantification are reported. Intra-day and inter-day precision, and accuracy of the methods were established according to the ICH guidelines, and the er values were in the range of -1.7 to 1.8% with RSD values ranging from 1.0 to 1.1%. The method was successfully applied to the assay of PFM in tablet preparations with recoveries varying from 97.5 to 101.9%, with standard deviation in the range of 0.6 to 1.9. The results were statistically compared with those of the reference method by applying Student's t-test and F-test. Accuracy evaluated by means of the spike recovery method, range from 97.0 to 106.0%, with precision better than 3%.     

Novel nanostructured lipid carrier-based inserts for controlled ocular drug delivery: evaluation of corneal bioavailability and treatment efficacy in bacterial keratitis

Objectives: The aim of the present study was to develop novel ofloxacin (OFX)-loaded nanostructured lipid carrier (NLC)-based inserts for ocular application for treatment of bacterial keratitis.

Methods: NLC loaded with 0.3% OFX was prepared by means of high shear homogenization and 0.75% chitosan oligosaccharide lactate (COL) was added. Glycerin or PEG 400 at the range of 1 – 15% was added to NLCs as plasticizers and inserts were developed by solvent casting evaporation. Characterization, in vitro release, microbiological, ex vivo and in vivo studies were performed.

Results: The inserts developed with the addition of glycerin (Ins3_OFX) was found as optimal. The kinetic studies revealed that the release of Ins3_OFX was a combination of diffusion and swelling. Ins3_OFX was more bioadhesive in texture profile analysis studies. In the in vivo studies performed with rabbits, the pre-ocular retention time was enhanced up to 24 h and C_max was increased almost six times in comparison with commercial. The rabbits were infected with Staphylococcus aureus and keratitis was confirmed. This group was treated with Ins3_OFX and they recovered in 7 days with no significant sign of conjunctival redness and corneal opacity.

Conclusion: NLC-based inserts developed with COL and glycerin may be offered as appropriate vehicles for ocular delivery.     

甲磺酸培氟沙星胶囊的人体药代动力学及相对生物利用度

８名受试者交叉口服甲磺酸培氟沙星片剂和胶囊各４００ｍｇ，用ＨＰＬＣ法测定血药浓度，灵敏度高，准确度好。测定血药浓度的时间曲线（除２例口服片剂符合一室模型外）均符合二室模型。片剂和胶囊的药动学参数，Ｃｍａｘ为５．７±１．５和６．８±１．７ｍｇ／Ｌ；Ｔ＿ｍａｘ为２．１±１．１和２．１±１．１ｈ；消除半衰期为１６±４和１５±６ｈ；胶囊的相对生物利用度１１４±１１％。关键词     

培氟沙星临床评价

培氟沙星治疗１０９３例细菌感染，包括男性６４９例，女性４４４例，平均年龄４３．４岁。病种包括呼吸系统感染、泌尿系统感染、肠道感染、皮肤软组织感染、外科及其它部位感染。服药剂量为０．４～１．２ｇ／ｄ，其中０．４ｇ／ｄ４９８例，０．６ｇ／ｄ９８例，０．８ｇ／ｄ４６８例，平均疗程８ｄ。痊愈率为６５．３％，有效率为９０．８％，细菌清除率为７６．９％。不良反应发生率为９．５％（１０４／１０９３），其中消化系统６２例，神经系统２４例，皮疹、搔痒共１０例，早搏１例，ＡＬＴ升高７例。本试验中６５岁以上患者１５１例，其临床疗效与不良反应发生率与总体相似。培氟沙星不同剂量有效性与安全性分析结果显示，随药物剂量增加，临床疗效和不良反应发生率均增高，统计学分析无明显性差异（Ｐ＞０．０５）。     

Chitosan-based hydrogels for nasal drug delivery: from inserts to nanoparticles

Importance of the field: Chitosan represents a multifunctional polymer, featuring both mucoadhesive and permeation-enhancing properties and therefore is a widely studied excipient for mucosal drug delivery. As regards nasal administration, chitosans have been used for the preparation of gels, solid inserts, powders and nanoparticles in which a three-dimensional network can be recognized.

Areas covered in this review: This review provides a discussion of the different nasal dosage forms based on chitosan hydrogels. In the first section intranasal delivery is discuss as a useful tool for non-invasive administration of drugs intended for local or systemic treatments. Then chitosan-based hydrogels are described with a focus on their mucoadhesive and permeation-enhancing ability as well as their capacity of controlled drug release. Finally, a detailed discussion regarding several examples of the different nasal dosage forms is reported, including considerations on in vitro, ex vivo and in vivo studies.

What the reader will gain: Summary and discussion of recent data on the different pharmaceutical forms based on chitosan hydrogels could be of interest to researchers dealing with nasal drug delivery.

Take home message: The aim of this review is to stimulate further investigations in order to achieve the collection of harmonized data and concrete clinical perspectives.     

Proliposomes for oral delivery of dehydrosilymarin: preparation and evaluation in vitro and in vivo

Aim:

To formulate proliposomes with a polyphase dispersed system composed of soybean phospholipids, cholesterol, isopropyl myristate and sodium cholate to improve the oral bioavailability of dehydrosilymarin, an oxidized form of herbal drug silymarin.

Methods:

Dehydrosilymarin was synthesized from air oxidation of silymarin in the presence of pyridine, and proliposomes were prepared by a film dispersion-freeze drying method. Morphological characterization of proliposomes was observed using a transmission electron microscope. Particle size and encapsulation efficiency of proliposomes were measured. The in vitro release of dehydrosilymarin from suspension and proliposomes was evaluated. The oral bioavailability of dehydrosilymarin suspension and proliposomes was investigated in rabbits.

Results:

The proliposomes prepared under the optimum conditions were spherical and smooth with a mean particle size in the range of 7 to 50 nm. Encapsulation efficiency was 81.59%±0.24%. The in vitro accumulative release percent of dehydrosilymarinloaded proliposomes was stable, which was slow in pH 1.2, and increased continuously in pH 6.8, and finally reached 86.41% at 12 h. After oral administration in rabbits, the relative bioavailability of proliposomes versus suspension in rabbits was 228.85%.

Conclusion:

Proliposomes may be a useful vehicle for oral delivery of dehydrosilymarin, a drug poorly soluble in water.     

Ocular tolerability of Eudragit RS100 and RL100 nanosuspensions as carriers for ophthalmic controlled drug delivery

Polymeric nanoparticle suspensions were prepared from inert polymer resins (Eudragit RS100, RS, and RL100, RL). When loaded with drugs, these resins have been recently proposed as delivery systems to prolong the release and improve ocular availability of the drug. To verify the absence of toxicity toward the ocular structures, blank RS and RL nanosuspensions were applied to rabbit eye and a modified Draize test was performed. Polymer nanoparticles appeared to be avoiding of any irritant effect on cornea, iris, and conjunctiva up to 24 h after application, thus appearing to be a suitable inert carrier for ophthalmic drug delivery.     

Ion-activated, Gelrite-based in situ ophthalmic gels of pefloxacin mesylate: comparison with conventional eye drops

The purpose of our work was to develop an ophthalmic delivery system of a flouroquinolone antibiotic, pefloxacin mesylate, based on the concept of ion-activated in situ gelation. Gelrite gellan gum, a novel ophthalmic vehicle, that gels in the presence of mono- or divalent-cations present in the lacrimal fluid, was used as the gelling agent. The developed formulation was compared with marketed eye drops in efficacy of treatment of bacterial conjunctivitis that was induced artificially in rabbits. The formulations were evaluated for rheological characteristics, in vitro release behavior, antimicrobial efficacy, and efficacy against bacterial conjunctivitis.We found that in situ gelling formulations passed the test for sterility. The formulations exhibited a first-order release pattern over 12 hr in in vitro release studies. The developed formulation was effective against selected micro-organisms in antimicrobial efficacy studies. The shelf lives of formulation was >2 years. The formulation demonstrated better therapeutic efficacy compared with standard eye drops because it improved the clinical parameters monitored for prolonged periods. The developed formulations can be considered as a viable alternative to conventional eye drops.     

Montmorillonite Poly-L-Lactide Microcomposites of Procainamide for controlled drug delivery: In vitro and In vivo evaluation

The research work reported in this paper is extension of our previous findings related to intercalation of procainamide hydrochloride, an antiarrythmia drug in interlayer gallery of Na⁺-clay (montmorillonite). The microcomposite particles prepared from procainamide-montmorillonite hybrid and poly L-lactide were characterised by scanning electron microscope and atomic force microscopy analysis. In vitro drug release study in simulated intestinal fluid showed controlled release pattern up to ~72 h and significant reduction in the drug release in gastric environment. In vivo pharmacokinetics and biodistribution in rats showed that the plasma/tissue drug levels were within therapeutic window as compared with free drug. The data from toxicity biomarker estimations and clinical biochemistry/haematological parameters showed significant reduction in drug toxicity when formulated in montmorillonite/poly L-lactide as compared with free drug, which is of considerable value in achieving improved therapy with reduced side effects.     

甲磺酸酚妥拉明泡腾片的处方及制备工艺研究

目的:利用普通制剂技术制备起效快、服用方便的甲磺酸酚妥拉明泡腾片。方法:通过实验优化筛选甲磺酸酚妥拉明泡腾片的辅料及其配比,并对制剂进行初步的质量评价。结果:优化处方的甲磺酸酚妥拉明泡腾片的崩解时限、片重差异、硬度等指标均符合或优于中国药典2005版附录的相关要求。结论:本品处方和制备方法有效可行,可作为甲磺酸酚妥拉明的一种新剂型开发。     

In vitro evaluation of novel polymer-coated magnetic nanoparticles for controlled drug delivery

Previously uncharacterized poly(N-isopropylacrylamide-acrylamide-allylamine)-coated magnetic nanoparticles (MNPs) were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Properties of these nanoparticles such as size, biocompatibility, drug loading efficiency, and drug release kinetics were evaluated in vitro for targeted and controlled drug delivery. Spherical core-shell nanoparticles with a diameter of 100 nm showed significantly lower systemic toxicity than did bare MNPs, as well as doxorubicin encapsulation efficiency of 72%, and significantly higher doxorubicin release at 41°C compared with 37°C, demonstrating their temperature sensitivity. Released drugs were also active in destroying prostate cancer cells (JHU31). Furthermore, the nanoparticle uptake by JHU31 cells was dependent on dose and incubation time, reaching saturation at 500 μg/mL and 4 hours, respectively. In addition, magnetic resonance imaging capabilities of the particles were observed using agarose platforms containing cells incubated with nanoparticles. Future work includes investigation of targeting capability and effectiveness of these nanoparticles in vivo using animal models.From the Clinical EditorIn this paper, previously uncharacterized magnetic nanoparticles were synthesized using silane-coated MNPs as a template for radical polymerization of N-isopropylacrylamide, acrylamide, and allylamine. Various properties of these nanoparticles were evaluated in vitro for targeted drug delivery.     

薄荷脑鼻腔原位凝胶剂的制备及安全性研究

目的 制备薄荷脑鼻用原位凝胶剂,并对其进行安全性考察。方法 采用去乙酰结冷胶为材料制备离子敏感性原位凝胶。考察鼻腔原位凝胶对蟾蜍鼻黏膜纤毛的毒性及大鼠鼻黏膜的影响;并进行家兔皮肤刺激实验和豚鼠皮肤过敏实验,观察皮肤反应并评分。结果 薄荷脑鼻用原位凝胶剂对蟾蜍鼻黏膜纤毛无显著毒性,对大鼠鼻黏膜形态及细胞分化无显著影响;对家兔完整皮肤无刺激作用,豚鼠皮肤无过敏反应。结论 薄荷脑鼻用原位凝胶剂具有制备工艺简便、纤毛毒性低、生理相容性好的优点,开发为经鼻给药系统可行性良好。     

Development and biopharmaceutical evaluation of osmotic pump tablets for controlled delivery of diclofenac sodium

Based on the principles of an elementary osmotic pump (OP), OP tablets were designed and evaluated with the aim to deliver diclofenac sodium (DS) in a controlled manner. In vitro evaluation was done in various release media and kinetics was evaluated using the regression coefficient analysis. Effects of orifice size, coating membrane type, coating thickness, static and stirred conditions and pH variation were studied. In vivo evaluation was performed on six healthy human volunteers and various pharmacokinetic parameters (c(max), t(max), AUC(0-24), MRT) and relative bioavailability were calculated. The results were compared with the performance of two commercial tablets of DS. The drug release from OP tablets was dependent on the type and thickness of the coating membrane, but was independent of the orifice size and static and stirred conditions of the release medium. The OP tablets provided a prolonged and controlled DS release compared to commercial sustained-release and conventional tablets of DS.     

Chitosan phthalate microspheres for oral delivery of insulin: preparation, characterization, and in vitro evaluation

Chitosan phthalate polymer was synthesized and its microspheres were prepared by emulsion phase separation technique. The characterization of microspheres was determined by means of FTIR spectroscopy, electron microscopy, particle size, and zeta potential. The insulin was loaded to the microspheres by passive absorption technique. The peptic and tryptic enzymes degradation of insulin in microspheres was investigated. The in vitro release behavior of the microspheres was investigated under different pH conditions (pH 2.0 and pH 7.4). The degree of phthalate substitution in the synthesized polymer was 20%. The prepared microspheres were spherical with an average diameter 46.34 μ m. The insulin-loading capacity was 62%. Chitosan phthalate microspheres protect the insulin from gastric enzymes degradation that may enhance the oral stability of insulin. The encapsulated insulin was quickly released in a phosphate buffer saline (pH 7.4), whereas a small amount of insulin was released under acidic condition (0.1N HCl; pH 2.0) because under acidic conditions, carboxylic groups present in the system exist in nonionized form and are poorly hydrophilic. However, in alkaline conditions, it exists in ionized form and is considerably hydrophilic. The results suggest that chitosan phthalate microspheres may be used as a potential carrier for oral insulin delivery.     

Thiomers: preparation and in vitro evaluation of a mucoadhesive nanoparticulate drug delivery system

It was the aim of this study to develop a mucoadhesive nanoparticulate delivery system. Nanoparticles were generated by in situ gellation of the thiomer chitosan-4-thiobutylamidine (chitosan-TBA) with tripolyphosphate (TPP) followed by stabilization via the formation of inter- and intrachain disulfide bonds by oxidation with H(2)O(2) in various concentrations. Afterwards TPP was removed by exhaustive dialysis at pH 1-2. Incorporation of the model compound fluorescein diacetate (FDA) was achieved by incubation of this fluorescence marker, dissolved in acetonitrile, with aqueous particle suspensions for 1h at room temperature. Mucoadhesion studies were performed on porcine intestinal mucosa. Results showed that the preparation method described above leads to nanoparticles of a mean diameter of 268+/-15 nm and a FDA load of 2%. Due to the removal of the anionic crosslinker TPP, the zeta potential of the nanoparticles was raised from 4+/-1 up to 19+/-2 mV without loosing stability of the nanoparticles. The more H(2)O(2) was added to the particles, the more inter- and intrachain disulfide bonds were formed. The more thiol groups were oxidized within the particles, however, the lower was the improvement in mucoadhesive properties. Nevertheless, even when 91% of all thiol groups on the nanoparticles were oxidized, their mucoadhesive properties were still twice as high as the mucoadhesive properties of unmodified nanoparticles. Thiolated chitosan nanoparticles show a two-fold higher zeta potential (I), improved stability (II) and more than doubled mucoadhesive properties (III) than corresponding unmodified chitosan nanoparticles. Therefore, they seem to be advantageous over ionically crosslinked chitosan nanoparticles.     

Nasal in-situ gels for delivery of rasagiline mesylate: improvement in bioavailability and brain localization

Abstract

Intranasal thermosensitive gel for rasagiline mesylate (RM) was developed for effective treatment of Parkinson’s disease. Intranasal gels were prepared by combination of poloxamer 407 and poloxamer 188 (1:1) with mucoadhesive polymers (carbopol 934?P and chitosan). The formulations were evaluated for sol–gel transition temperature, in-vitro drug release and in-vivo mucociliary transit time. Further, optimal intranasal gel formulations were tested for in-vivo pharmacokinetic behavior, nasal toxicity studies and brain uptake studies. It was found that optimal formulations had acceptable gelation temperature (28–33?°C) and adequate in-vitro drug release profile. Pharmacokinetic study in rabbits showed significant (p?<?0.05) improvement in bioavailability (four- to six-folds) of the drug from intranasal gels than oral solution. Chronic exposure studies in Wistar rats showed that these intranasal gels were non-irritant and non-toxic to rat nasal mucosa. Estimation of RM in rat brain tissue showed significant (p?<?0.01) improvement in uptake of RM form intranasal gel formulations than nasal solution.