Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles

Chitosan-Ca-alginate microparticles for colon-specific delivery and controlled release of 5-aminosalicylic acid after peroral administration were prepared using spray drying method followed by ionotropic gelation/polyelectrolyte complexation. Physicochemical characterization pointed to the negatively charged particles with spherical morphology having a mean diameter less than 9 microm. Chitosan was localized dominantly in the particle wall, while for alginate, a homogeneous distribution throughout the particles was observed. (1)H NMR, FTIR, X-ray and DSC studies indicated molecularly dispersed drug within the particles with preserved stability during microencapsulation and in simulated in vivo drug release conditions. In vitro drug release studies carried out in simulated in vivo conditions in respect to pH, enzymatic and salt content confirmed the potential of the particles to release the drug in a controlled manner. The diffusional exponents according to the general exponential release equation indicated anomalous (non-Fickian) transport in 5-ASA release controlled by a polymer relaxation, erosion and degradation. Biodistribution studies of [(131)I]-5-ASA loaded chitosan-Ca-alginate microparticles, carried out within 2 days after peroral administration to Wistar male rats in which TNBS colitis was induced, confirmed the dominant localization of 5-ASA in the colon with low systemic bioavailability.     

Extrusion-spheronisation of highly loaded 5-ASA multiparticulate dosage forms

The aim of the current work was to develop an extrusion-spheronisation (E-S) route to manufacture pellets with a high loading (≥90wt%) of 5-aminosalicylic acid (5-ASA). Ram extrusion studies, supported by centrifuge testing, were employed to investigate the effect of the chemical (acidity) and physical (particle size and shape) characteristics of 5-ASA on the ability of microcrystalline cellulose (MCC)-based pastes to retain water when subjected to pressure. Liquid phase migration (LPM) within the paste during the extrusion, and hence variation in water content of extrudates and reproducibility of the final E-S product, was generally observed. The extent of LPM was found to be related to both the drug loading and its physical properties, most notably the particle shape (needle-like). A reduction in particle size, combined with a change in the shape of the 5-ASA particles, allowed LPM to be reduced considerably or eliminated. The performance of colloidal grades of MCC (Avicel RC591 and CL611) as alternative extrusion aids to the standard Avicel PH101 was also investigated: these proved to be superior aids for the highly loaded 5-ASA pastes as their greater water retention capacity mitigated LPM. Combining these results yielded a route for manufacturing pellets with 5-ASA loading ≥90wt%.     

Preparation and physicochemical characterization of supercritically dried insulin-loaded microparticles for pulmonary delivery.

In the search for non-invasive delivery options for the increasing number of therapeutic proteins, pulmonary administration is an attractive route. Supercritical fluid (SCF) drying processes offer the possibility to produce dry protein formulations suitable for inhalation. In this study, insulin-loaded microparticles suitable for pulmonary administration were prepared and characterized. N-Trimethyl chitosan (TMC), a polymeric mucoadhesive absorption enhancer and dextran, a non-permeation enhancer, were used as carriers for insulin. The particles were prepared by spraying an acidic water/DMSO solution of insulin and polymer into supercritical carbon dioxide. The mean size of the particles was 6-10microm (laser diffraction analysis) and their volume median aerodynamic diameter ca. 4microm (time-of-flight analysis). The particles had a water content of ca. 4% (w/w) (Karl-Fischer), and neither collapsed nor aggregated after preparation and storage. In the freshly prepared dried insulin powders, no insulin degradation products were detected by HPLC and GPC. Moreover, the secondary and tertiary structures of insulin as determined by circular dichroism and fluorescence spectroscopy were preserved in all formulations. After one-year storage at 4 degrees C, the particle characteristics were maintained and the insulin structure was largely preserved in the TMC powders. In conclusion, SCF drying is a promising, protein-friendly technique for the preparation of inhalable insulin-loaded particles.     

5-氟尿嘧啶共聚物纳米粒的制备及其药剂学性质

目的 以生物可降解材料Pluronic P105-PAGA共聚物制备5-氟尿嘧啶(5-FU)纳米粒,并考察纳米粒的药剂学特性.方法 采用透析法制备纳米粒,以包封率和载药量为指标,应用星点设计效应面优化法优化处方,并考察其表面特征、包封率、载药量、粒径、体外释放等性质.结果 5-FU-Pluronic P105-PAGA纳米粒为圆整的类球形实体粒子,平均粒径为175 nm,载药量为22.37%,包封率为95.26%,有突释现象,体外12 h累积释放率为80.4%.结论 所制纳米粒具有高包封率和载药量,粒径适宜,具有一定的缓控释作用.     

Melatonin loaded ethanolic liposomes: physicochemical characterization and enhanced transdermal delivery.

The current investigation aims to evaluate the transdermal potential of novel ethanolic liposomes (ethosomes) bearing Melatonin (MT), an anti-jet lag agent associated with poor skin permeation and long lag time. MT loaded ethosomes were prepared and characterized for vesicular shape and surface morphology, vesicular size, entrapment efficiency, stability, in vitro skin permeation and in vivo skin tolerability. Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM), and Dynamic Light Scattering (DLS) defined ethosomes as spherical, unilamellar structures having low polydispersity (0.032+/-0.011) and nanometric size range (122+/-3.5 nm). % Entrapment efficiency of MT in ethosomal carrier was found to be 70.71+/-1.4. Stability profile of prepared system assessed for 120 days revealed very low aggregation and growth in vesicular size (7.6+/-1.2%). MT loaded ethosomal carriers also provided an enhanced transdermal flux of 59.2+/-1.22 microg/cm2/h and decreased lag time of 0.9 h across human cadaver skin. Fourier Transform-Infrared (FT-IR) data generated to assess the fluidity of skin lipids after application of formulation revealed a greater mobility of skin lipids on application of ethosomes as compared to that of ethanol or plain liposomes. Skin permeation profile of the developed formulation further assessed by confocal laser scanning microscopy (CLSM) revealed an enhanced permeation of Rhodamine Red (RR) loaded formulations to the deeper layers of the skin (240 microm). Further, a better skin tolerability of ethosomal suspension on rabbit skin suggested that ethosomes may offer a suitable approach for transdermal delivery of melatonin.     

5-氨基水杨酸时控结肠定位控释微丸及其制剂的研制

目的制备5-氨基水杨酸微丸及其时控结肠定位控释释药系统的研究。方法首先采用挤出滚圆机制备了含药微丸,然后使用流化床包衣设备将微丸包衣,以羟丙甲纤维素和微粉硅胶的混合物包衣作为溶胀控释层,以乙基纤维素水分散体Surelease包衣作为时滞包衣层,并将包衣微丸装入肠溶胶囊。用释放度测定法研究微丸的释放行为。结果药物通过时滞层破裂开始释放,该层厚度增加可显著延长释药时滞。调节羟丙甲纤维素的型号、包衣增重及羟丙甲纤维素与微粉硅胶两者比例,可以控制药物释放速度。在模拟胃肠道pH情况下延迟5 h释药,之后的10 h内释药完全。结论可通过调整溶胀控释层包衣混合物的比例、型号、包衣厚度及时滞层的包衣厚度,制备5-氨基水杨酸时控结肠定位控释释药系统。     

茯苓多糖片剂的制备及理化性质的考察

目的:制备茯苓多糖片.方法:采用正交实验设计制备茯苓多糖片.结果:优化处方为崩解剂选择CMS-Na,粘和剂选择PVP10%,主药茯苓多糖含量10%.结论:实验表明,茯苓多糖片工艺简单、易于工业化操作,质量可控、具有生产和临床应用价值.     

Paclitaxel-loaded microparticles and implants for the treatment of brain cancer: preparation and physicochemical characterization

The aim of this study was to prepare different types of paclitaxel-loaded, PLGA-based microparticles and lipidic implants, which can directly be injected into the brain tissue. Releasing the drug in a time-controlled manner over several weeks, these systems are intended to optimize the treatment of brain tumors. The latter is particularly difficult because of the blood-brain barrier (BBB), hindering most drugs to reach the target tissue upon systemic administration. Especially paclitaxel (being effective for the treatment of ovarian, breast, lung and other cancers) is not able to cross the BBB to a notable extent since it is a substrate of the efflux transporter P-glycoprotein. Both, biodegradable microparticles as well as small, cylindrical, glycerol tripalmitate-based implants (which can be injected using standard needles) were prepared with different paclitaxel loadings. The effects of several formulation and processing parameters on the resulting drug release kinetics were investigated in phosphate buffer pH 7.4 as well as in a diethylnicotinamide (DENA)/phosphate buffer mixture. Using DSC, SEM, SEC and optical microscopy deeper insight into the underlying drug release mechanisms could be gained. The presence of DENA in the release medium significantly increased the solubility of paclitaxel, accelerated PLGA degradation, increased the mobility of the polymer and drug molecules and fundamentally altered the geometry of the systems, resulting in increased paclitaxel release rates.     

Preparation and characterization of spray-dried oxidized cellulose microparticles

The goal of this study was to investigate the feasibility of spray drying to produce microparticles of oxidized cellulose (OC), a biocompatible and bioresorbable polymer. OCs containing 7, 13, and 20 wt% carboxylic groups were converted into stable aqueous dispersions and then spray dried using a Yamoto G-32 spray dryer equipped with a standard fluid nozzle with an orifice of 406 microm. The following operating conditions were investigated: inlet temperature 140, 170, and 190 degrees C; feed rate 3, 6, and 9 mL/min; and atomization airpressure 0.5, 1, and 1.5 kg f/cm2. The amounts of OC used in feed were 1, 2.5, and 5%. OC microparticles produced under these conditions were shrunken spheres, ranging in size between 0.98+/-0.47 and 2.05+/-0.98 microm. The different operating conditions used had no significant effect on the size and shape of particles. The use of a water-soluble plasticizer (glycerin, polyethylene glycol 400, or polyethylene glycol 6000) in the dispersion yielded microparticles with a good sphericity and a smooth surface morphology, whereas no change in the shape or size of microparticles was noted with water-insoluble plasticizers, Triacetin and dibutyl phthalate. Powder X-ray diffraction and Fourier transform infrared spectral analyses of spray-dried microparticles showed no change in the solid-state structure of OC. In conclusion, results show that OC can be converted into stable aqueous dispersions and used to produce microparticles by spray drying.     

Preparation of amorphous carvedilol polymeric microparticles for improvement of physicochemical properties

The aim of the present study was to enhance the physicochemical properties of poorly aqueous soluble carvedilol (CRV) by preparing its microparticles in presence and/or in absence of a hydrophilic carrier. The polymeric microparticles of CRV were prepared with polyvinylpyrrolidone K30 with or without addition of adsorbents like Aerosil^?200 and/or Sylysia^?350 by using spray drying technique. The dissolution profiles revealed that the drug and polymer ratio and colloidal silica both played critical role in solubility enhancement. The spray dried microparticles and drug alone were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction, Fourier transformation infrared spectroscopy (FTIR), particle size analysis and scanning electron microscopy (SEM). DSC analysis showed that CRV transformed from the crystalline state to amorphous state by spray drying, confirmed by disappearance of its melting peak. The results of the X-ray analysis were in agreement with the thermal analysis data. It did not show characteristic crystalline drug peaks which confirmed that the amorphous form of CRV was present in the CRV loaded microparticles. FTIR analysis demonstrated hydrogen bonding interaction with an absence of significant chemical interaction between CRV and polymer. Spherical microparticles were yielded with smooth surfaces as observed by SEM. All in all, this work reveals that spray drying is a suitable technique for preparation of microparticles with improved physicochemical properties of CRV.     

Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

Purpose: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system.

Methods: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5?mg TS?g^?1. Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24?h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated.

Results: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7–95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM?<?5% GD?<?5% SA?<?5% GB?<?2.5% GM?<?2.5% SA?<?10% GD?<?10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB–2.5?mg TS?g^?1 SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB–2.5?mg TS?g^?1 stored at 5°C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation.

Conclusions: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

新型肺部吸入微球的制备及性质的研究

目的 制备并研究用于肺部给药的新型微球给药系统.方法 利用喷雾干燥技术干燥载药固体脂质纳米粒(SLNs)胶体溶液,制备成肺部吸入微球,并研究微球的基本粉体学性质及SLNs、模型药物胸腺五肽的稳定性.结果 微球表面呈多孔形,具有较小的粒径4.8±0.4μm、较低的堆密度0.48±0.02 g·cm~(-3)、实密度0.71±0.06 g·cm~(-3).微球具有良好的吸人特性,排空率为85.0%±2.8%,有效部位沉积率为61.6%±3.0%,且能有效地分布到肺泡内.制备过程中的SLNs和胸腺五肽能保持很好的稳定性.结论 新型微球具有适宜的吸入特性,是一种具有应用前景的肺部给药系统.     

Testosterone solid lipid microparticles for transdermal drug delivery. Formulation and physicochemical characterization

PURPOSE: The main objective of the study was to formulate and characterize testosterone (TS) solid lipid microparticles (SLM) to be applied as a transdermal delivery system. METHODS: Testosterone SLMs were formulated using an emulsion melt homogenization method. Various types and concentrations of fatty materials, namely glyceryl monostearate (GM), glyceryl distearate (GD), stearic acid (SA) and glyceryl behanate (GB) were used. The formulations contained 2.5 or 5 mg TS g(-1). Morphology, particle size, entrapment efficiency (EE), rheological properties and thermal behaviour of the prepared SLM were examined. In vitro release characteristics of TS from various prepared SLM were also evaluated over 24 h using a vertical Franz diffusion cell. In addition, the effect of storage and freeze-drying on particle size and release pattern of TS from the selected formulation was evaluated. RESULTS: The results indicated that the type of lipid affected the morphology and particle size of SLM. A relatively high drug percentage entrapment efficiency ranging from 80.7-95.7% was obtained. Rheological studies showed plastic flow characteristics of the prepared formulations. DSC examination revealed that TS existed in amorphous form in the prepared SLM. Release studies revealed the following rank order of TS permeation through cellophane membrane after application of various formulations: 5% GM < 5% GD < 5% SA < 5% GB < 2.5% GM < 2.5% SA < 10% GD < 10% GB. The drug permeation through excised abdomen rat skin after application of 10% GB-2.5 mg TS g(-1) SLM was lower than that permeated through cellophane membrane. Moreover, SLM containing 10% GB-2.5 mg TS g(-1) stored at 5 degrees C showed good stability as indicated by the release study and particle size analysis. Trehalose showed high potential as a cryoprotectant during freeze drying of the selected SLM formulation. CONCLUSIONS: The developed TS SLM delivery system seemed to be promising as a TS transdermal delivery system.     

Tretinoin-loaded nanocapsules: Preparation, physicochemical characterization, and photostability study

The aim of this study was to prepare and characterize tretinoin-loaded nanocapsules as well as to evaluate the influence of this nanoencapsulation on tretinoin photostability. Tretinoin-loaded nanocapsules (0.5 mg ml(-1)) were prepared by interfacial deposition of preformed polymer (poly-epsilon-caprolactone) using two different oily phases: capric/caprylic triglycerides and sunflower seed oil. Tretinoin-loaded nanocapsules presented drug content close to the theoretical value, encapsulation efficiencies higher than 99.9%, nanometric mean size with a polydispersity index below 0.25, and pH values between 5.0 and 7.0. Regarding photodegradation studies, tretinoin methanolic solution showed a half-life time around 40 min according to a first order equation, whereas tretinoin nanocapsule suspensions showed a half-life between 85 and 100 min (twofold higher than in methanolic solution) according to a zero order equation. Tretinoin-loaded nanocapsules improved tretinoin photostability, independently on the type of oily phase used in this study, and represent a potential system to be incorporated in topical or systemic dosage forms containing tretinoin.     

Preparation and in vitro release of zein microparticles loaded with prednisolone for oral delivery

Zein has been proposed as a polymer for targeted-drug delivery via the oral route. Zein microparticles were loaded with prednisolone and evaluated as an oral delivery system. Microparticles were formulated using phase separation. Starting quantities of zein and prednisolone, along with the agitation method and temperature were found to significantly impact drug loading and loading efficiency. Vortex mixing produced the highest drug loading and loading efficiency. Drug release was measured in simulated conditions of the stomach and small intestine using the microparticles made with the method that best improved drug loading. In simulated stomach and small intestine conditions, prednisolone release reached almost 70% over 3 and 4?h, respectively. While a clinically relevant dose may be delivered using c. 100?mg of zein microparticles, prednisolone release from the microparticles indicates that they may not be suited as a controlled- or targeted-delivery system.     

多功能载鲣鱼肽海藻酸钙微球的制备与表征

目的 通过制剂手段掩盖鲣鱼肽原料的不良嗅味,降低其吸湿性,提高在胃中的稳定性。方法 通过微胶囊造粒仪制备载鲣鱼肽海藻酸钙微球,分别对微球的外观、鲣鱼肽含量进行表征。在25 ℃、65%RH的环境下,检测所得微球吸湿增重。分别测定在模拟胃肠液中鲣鱼肽从微球中的释放。通过顶空进样GC-MS对在热水中孵育的载鲣鱼肽微球进行检测,使用面积归一化法对有异味的挥发性组分进行定量。结果 载鲣鱼肽海藻酸钙微球微球外观圆整且大小均一,鲣鱼肽含量为18.9%。在25 ℃、65%RH的环境下,制备所得微球吸湿增重显著低于鲣鱼肽原料粉末。在模拟胃肠液中,鲣鱼肽从微球中的释放达到了肠溶制剂的标准,预示微球口服后在生理条件严苛且吸收较差的胃部对鲣鱼肽起到保护作用。通过顶空进样GC-MS法发现所制备的海藻酸钙微球可在冲泡过程中掩盖80%的异味。结论 所制备的海藻酸钙微球同时解决了鲣鱼肽原料吸湿性强、在胃中易失活和感官刺激大的缺点,为活性肽保健食品制剂的开发提供了新的思路。     

胰岛素肠溶PLGA纳米粒的制备及体内外性质的评价

目的制备肠溶胰岛素PLGA纳米粒,并对其理化性质、体外释药以及在正常大鼠体内的降血糖效果进行研究。方法采用改良的乳化溶剂扩散法分别制备了胰岛素PLGA纳米粒和肠溶胰岛素纳米粒(PLGA HP55 NP、PLGA HP50 NP)。通过激光粒度测定仪测定粒径大小,系统考察了肠溶材料HP55的用量及类型对纳米粒性质的影响,以及各种纳米粒在人工胃液、人工肠液中的释药行为和其在正常大鼠体内的降血糖作用,并与PLGA HP50 NP进行了比较。结果制得的最终处方的肠溶纳米粒(PLGA HP55)的粒径为(169±16)nm,胰岛素的载药量为(3.17±0.24)%。肠溶纳米粒在人工胃液中的释药速率明显低于PLGA纳米粒。PLGA纳米粒和肠溶PLGA HP50、PLGA HP55纳米粒均能显著降低正常大鼠的血糖浓度,其在正常大鼠体内24 h相对于皮下注射给药的相对生物利用度分别为(5.46±0.7)%、(6.31±0.64)%和(8.72±0.5)%。结论胰岛素肠溶纳米粒可以有效抑制胰岛素在人工胃液中的释放,与PLGA纳米粒相比显著降低正常大鼠的血糖浓度。其中PLGA HP55纳米粒的降糖作用显著高于PLGA HP50纳米粒。pH值高的纳米粒有望成为胰岛素口服给药的有效载体。     

碳酸钙复合载药纳米粒的制备与表征

目的利用十六烷基三甲基溴化铵通过改变反应条件制备适当大小的碳酸钙空腔纳米球,碳酸钙复合纳米球进行海藻酸钠修饰。方法激光粒度分析仪、TEM对复合纳米球的性能进行表征,研究其制备条件对纳米粒径和纳米球质量的影响。结果在投料比固定的情况下,反应转速在1000r/min,碳酸钠和氯化钙的浓度为0.02mol/L,反应温度在20℃时空腔纳米球粒径最小,海藻酸钠修饰后的碳酸钙纳米球电位为(-27.20±0.75)mV,明显增加了复合纳米球的稳定性。结论最佳条件下制备的碳酸钙纳米粒粒径优良,可观察到明显的空腔结构,修饰后不仅增加了其稳定性,同时还实现了协同给药。