Controlled Release of an Antihypertensive Drug through Interpenetrating Polymer Network Hydrogel Tablets of Tamarind Seed Polysaccharide and Sodium Alginate

The application of interpenetrating polymer network (IPN) hydrogel tablets of tamarind seed polysaccharide and sodium alginate for controlled release of a water-soluble antihypertensive drug, propranolol HCl (PPL), was investigated. The IPN tablets loaded with PPL or PPL–resin complex (resinate) were prepared by a wet granulation/covalent cross-linking method. Fourier Transform Infrared Spectroscopic confirmed the cross-linking reaction and IPN formation, while X-ray Diffraction and Scanning Electron Microscopy studies confirmed the amorphous dispersion of the drug within the IPN tablets. The plain drug PPL showed complete release within 1 h, while drug release from the resinate was prolonged for 2.5 h and the IPN matrices showed drug release up to 24 h. The drug release rate from the IPN matrices was affected by polymer concentration and cross-linking time; the higher the cross-linking time, the slower was the drug release. The drug release mechanism was found to be of a non-Fickian type.     

药物小分子穿越磷脂双层膜输运过程中的时滞效应

本文基于扩散动力学,建立了一种新的药物小分子穿越磷脂双层膜输运的理论模型,研究药物小分子穿越磷脂双层膜输运的动态过程,考察药物小分子跨膜输运过程中的时间延迟(时滞)效应。研究发现,药物小分子在数分钟内穿越磷脂双层膜各区域进入细胞,由于时滞效应,穿膜过程呈现了周期性演化特性。当药物小分子数量增加到一定程度,磷脂分子层会出现微小孔,让积累的药物小分子快速通过。通过分析模型中各参数的敏感性,我们还发现,药物小分子在磷脂双层膜内不同区域的扩散特性,以及输运过程的时滞性,都会对药物小分子穿越磷脂双层膜的动力学有较大程度的影响。理论结果符合模拟、实验观测,进一步深刻揭示了药物小分子穿越磷脂双层膜的穿膜特性,可为设计确切的疗法药物提供必要的参考和新方案。     

六通道光纤传感药物溶出度监测仪的研制及应用

药物溶出度试验是药品检验的重要项目,在药物质量评价方面起着非常重要的作用。利用光纤传感技术可以实现药物溶出度的自动化、过程化监测。以氙灯、氘灯或卤钨灯作为荧光、紫外光及可见光的光源,以Y型分支光纤作为光路传输介质,紫外-可见吸收探头或荧光分子探头作为光响应器件,CCD作为检测器,通过自编软件实现紫外-可见吸收及荧光猝灭两种模式的检测。光纤传感药物溶出度监测仪不但解决了目前离线取样分析方法耗时、耗力的缺点,而且提供了药物溶出过程的实时信息,为药物质量控制提供了更好的评价手段。     

The characters of self-assembly core/shell nanoparticles of amphiphilic hyperbranched polyethers as drug carriers

The characters of self-assembly core/shell nanoparticles of amphiphilic hyperbranched polyethers (HP-g-PEO) as drug carriers were investigated. The HP-g-PEO consisting of hydrophobic HP-g-PEO core and hydrophilic poly(ethylene glycol) arms was prepared by the cation ring-opening polymerization. A series of HP-g-PEO samples with different degree of branching (DB) were synthesized under various reaction temperatures. Nanoparticles (NP) were obtained by self-assembly of HP-g-PEO in aqueous media. The structure of resulting HP-g-PEO was characterized by IR, ¹³CNMR and GPC. Dynamic light scattering and transmission electron microscopy were applied to characterize the sizes and size distributions of NP. The results demonstrated that the mean diameters of NP were less than 100 nm, which exhibited uniform spherical formations and narrow size distributions. Using hydrophobic drug Probucol (PRO) as model drug, the particle sizes of drug loaded NP were larger than relative blank NP. The drug loading efficiency (LE) and incorporation efficiency (IE) of these NP were achieved to 35 and 89%, respectively. The in vitro release of PRO from the NP exhibited a sustained release and the cumulative drugs released for more than 600 h. The most important factor to affect drug release was the value of DB of HP-g-PEO. With the DB of HP-g-PEO increasing, the size and size distribution of NP decreased as well as the release rate. However, the small DB was beneficial to the LE of NP. Nanoparticle size and size distribution, LE, IE, and drug release rate were slightly affected by the initial solution concentration of polyethers. The co-incorporated hydrophilic drug had influence slightly on the release of drug from drug loaded NP. The results of in vitro drug release suggested that the core/shell NP performed good controlled release behaviors with potential practice as novelty drug delivery vehicles.     

Template-directed hydrothermal synthesis of hydroxyapatite as a drug delivery system for the poorly water-soluble drug carvedilol

In order to improve the dissolution rate and increase the bioavailability of a poorly water-soluble drug, intended to be administered orally, the biocompatible and bioactive mesoporous hydroxyapatite (HA) was successfully synthesized. In the present study, mesoporous HA nanoparticles were produced using Pluronic block co-polymer F127 and cetyltrimethylammonium bromide (CTAB) as templates by the hydrothermal method. The obtained mesoporous HA was employed as a drug delivery carrier to investigate the drug storage/release properties using carvedilol (CAR) as a model drug. Characterizations of the raw CAR powder, mesoporous HA and CAR-loaded HA were carried out by the scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier transform infrared (FT-IR) spectroscopy, N₂ adsorption/desorption, thermogravimetric analysis (TGA), and UV-VIS spectrophotometry. The results demonstrated that CAR was successfully incorporated into the mesoporous HA host. In vitro drug release studies showed that mesoporous HA had a high drug load efficiency and provided immediate release of CAR compared with micronized raw drug in simulated gastric fluid (pH 1.2) and intestinal fluid (pH 6.8). Consequently, mesoporous HA is a good candidate as a drug carrier for the oral delivery of poorly water-soluble drugs.     

The impact of bubbles on measurement of drug release from echogenic liposomes

Echogenic liposomes (ELIP) encapsulate gas bubbles and drugs within lipid vesicles, but the mechanisms of ultrasound-mediated drug release from ELIP are not well understood. The effect of cavitation activity on drug release from ELIP was investigated in flowing solutions using two fluorescent molecules: a lipophilic drug (rosiglitazone) and a hydrophilic drug substitute (calcein). ELIP samples were exposed to pulsed Doppler ultrasound from a clinical diagnostic ultrasound scanner at pressures above and below the inertial and stable cavitation thresholds. Control samples were exposed to a surfactant, Triton X-100 (positive control), or to flow alone (negative control). Fluorescence techniques were used to detect release. Encapsulated microbubbles reduced the measured fluorescence intensity and this effect should be considered when assessing drug release from ELIP. The origin of this effect is not specific to ELIP. Release of rosiglitazone or calcein compared to the negative control was only observed with detergent treatment, but not with ultrasound exposure, despite the presence of stable and inertial cavitation activity. Release of rosiglitazone or calcein from ELIP exposed to diagnostic ultrasound was not observed, even in the presence of cavitation activity. Ultrasound-mediated drug delivery strategies with ELIP will thus rely on passage of the drug-loaded liposomes to target tissues.     

Functional and unmodified MWNTs for delivery of the water-insoluble drug Carvedilol - A drug-loading mechanism

The purpose of this study was to develop carboxyl multi-wall carbon nanotubes (MWNTs) and unmodified MWNTs loaded with a poorly water-soluble drug, intended to improve the drug loading capacity, dissolubility and study the drug-loading mechanism. MWNTs were modified with a carboxyl group through the acid treatment. MWNTs as well as the resulting functionalized MWNTs were investigated as scaffold for loading the model drug, Carvedilol (CAR), using three different methods (the fusion method, the incipient wetness impregnation method, and the solvent method). The effects of different pore size, specific surface area and physical state were systematically studied using scanning electron microscopy (SEM), thermogravimetric analysis (TGA), Fourier transformation infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), nitrogen adsorption, X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The functional MWNTs allowed a higher drug loading than the unmodified preparations. The methods used to load the drug had a marked effect on the drug-loading, dissolution, and physical state of the drug as well as its distribution. In addition, the solubility of the drug was increased when carried by both MWNTs and functional MWNTs, and this might help to improve the bioavailability.     

Spectroscopic studies of microenvironment dictated structural forms of piroxicam and meloxicam

Long acting non-steroidal anti-inflammatory drugs (NSAIDs) belonging to the oxicam group have attracted special interest because of their diverse biological functions. In this study we present the influence of microenvironment on the spectral properties of two oxicam drugs viz. piroxicam and meloxicam. For the two drugs, a high energy shift of the UV absorption maxima was observed with increasing drug concentrations both in protic solvent like ethanol and aprotic solvent like dimethyl sulfoxide (DMSO). Studies involving variation of percentage volume of water as well as pH, using absorption and steady state fluorescence spectroscopy, allow us to identify the principal species present at different concentrations of the drugs. It is found that even trace quantity of water present in the solvent becomes significant at low concentration of the drug making the water/drug ratio sufficiently large to support the formation of anion. As the concentration of the drug increases, the number of water molecules available per drug molecule decreases and most of the drug molecules face a relatively apolar environment in which zwitterionic/neutral species become predominant. This results in a concentration-dependent high-energy shift of the absorption maximum. This study demonstrates how microenvironments of these drugs guide the nature of the predominant form present in solution.     

THE EXPANDING ROLE OF NMR IN DRUG DISCOVERY AND DEVELOPMENT

The role of NMR in the pharmaceutical industry has changed dramatically over the last decade. Once thought of as an analytical technique used primarily to support synthetic chemistry, NMR now has an important role in the investigation of biochemical changes involved in clinical diseases and drug toxicity. It is also used extensively to elucidate the structures of drug metabolites. Data obtained using LC NMR MS and 19F NMR will be used to illustrate the utility of hyphenated methods in identifying xenobiotic metabolites as part of a drug development program. The application of NMR to the study of potential drug toxicity will also be described using the cationic, amphiphilic drugs chloroquine and amiodarone. These drugs are known to induce phospholipidosis characterized by lysosomal lamellar bodies and drug accumulation. Using a metabonomic approach, NMR spectroscopy of urine allowed the identification of a combination of urinary biomarkers of phospholipidosis.     

Ultrasound-triggered drug targeting of tumors in vitro and in vivo

The new modality of drug targeting of tumors that we are currently developing is based on drug encapsulation in polymeric micelles, followed by the localized release at the tumor site triggered by focused ultrasound. The rationale behind this approach is that drug encapsulation in micelles decreases systemic concentration of drug, diminishes intracellular drug uptake by normal cells, and provides passive drug targeting of tumors, thus reducing unwanted drug interactions with healthy tissues. Ultrasound irradiation is used to release drug from micelles at the tumor site and to enhance the intracellular drug uptake by tumor cells. An important advantage of ultrasound is that it is noninvasive, can penetrate deep into the interior of the body, can be focused and carefully controlled. Here we describe factors involved in the ultrasound interaction with viable cells in the absence and presence of drug carriers and anti-cancer drugs. We present in vivo effects of 1 MHz ultrasound on drug biodistribution, intratumoral distribution, and survival rates of immuno-compromised athymic nu/nu mice bearing ovarian carcinoma tumors.     

Drug release from various thicknesses of layered mats consisting of electrospun polycaprolactone and polyethylene oxide micro/nanofibers

A new drug delivery system (DDS) consisting of electrospun nanofibers is proposed. Layered mats of hydrophobic polycaprolactone (PCL) and polyethylene oxide (PEO) nanofibers were prepared successfully in a layer-by-layer manner using an electrospinning process. The PEO mat and drug were co-electrospun as a drug reservoir. Drug release rate was controlled physically by the thickness of the electrospun nanofibrous PCL layer, and its release behavior was examined over time. Release tests showed that the release behavior and the amount of initial burst of the drug were critically dependent on the thickness of the nanofibrous PCL mat. The release of drug showed a linear relationship with the thickness of the porous electrospun PCL mat. In addition, to demonstrate the feasibility of this type of DDS, the release behavior of the antimicrobial peptide HPA3NT3 from the nanofiber system was examined. The release of the peptide was easily controlled by the PCL nanofiber thickness and the released peptide did not lose biological activity.     

模型化研究药物小分子阻滞细胞周期

基于扩散动力学与细胞信号传导动力学,研究药物小分子对细胞周期的阻滞特性.理论模型考虑药物小分子穿越细胞膜输运的动力学特性,以及进入细胞内的药物分子对细胞周期的阻滞效应.研究发现,穿越细胞膜内层进入细胞内的药物分子,将会在很大程度上决定药物分子对相关的靶向基因、蛋白的阻滞功效.细胞膜对药物分子的输运特性,是影响药物分子阻滞细胞周期的关键因素.另外,药物分子的降解程度,将会改变药物分子与靶向基因、蛋白作用时间,进而改变对相关细胞生长增殖的抑制效应.通过对模型中各参数的敏感度分析,我们确认了药物分子穿越细胞膜、进入细胞内过程的多种因素对细胞周期的抑制效应.本文理论结果符合模拟、实验观测,进一步深刻揭示了药物小分子阻滞细胞周期的物理机制,可为设计确切的疗法药物提供必要的参考和新方案.     

Surfactant-assisted sonochemical synthesis of hollow calcium silicate hydrate (CSH) microspheres for drug delivery

Hollow calcium silicate hydrate (CSH) microspheres with diameters around 1 μm were synthesized by a surfactant-assisted sonochemical route, and the products were characterized by XRD, SEM, FETEM and BET techniques. The results suggested that the ultrasound radiation, surfactant and Ca source were important factors which affected the formation of hollow microspheres. Based on the observation of products in different reaction systems, the possible mechanism for the formation of hollow CSH spheres was discussed. Furthermore, gentamicin, a typical anti-inflammatory drug, was used to investigate the drug loading and release behavior of the hollow spheres. The results indicated that CSH hollow spheres had high drug loading capacity and favorable drug release behavior, and might be used for preparation of bone grafts with drug delivery properties.     

Pharmaceutical applications of photothermal beam deflection

We report the potential use of a noninvasive method of photothermal beam deflection (PBD) in pharmaceutical research exemplifying the determination of drug content in semisolid formulations and mapping the lateral drug diffusion into an artificial membrane. PBD exhibits a high sensitivity. The requirement of only minimal sample preparation makes this spectroscopic technique advantageous. PBD in conjunction with an appropriate scanner device and depth profiling is a promising technique for in vivo studies of three-dimensional drug diffusion into biological membranes. A short introduction to the basic principles of PBD is given.     

Transport properties of Chitosan-Amikacin films

The transport properties of films based on chitosan and a drug have been studied, and sorption and diffusion characteristics of the films have been examined. The calculated diffusion coefficients and the abnormal kinetic curves of amikacin release have been discussed. An analysis of the obtained data showed that the process of drug transport from chitosan films deviated from the classical Fick’s laws due to structural changes in the polymer matrix induced by its chemical modification because of interaction with the drug.     

Synthesis and characterization of microporous hollow core-shell silica nanoparticles (HCSNs) of tunable thickness for controlled release of doxorubicin

Hollow core-shell silica nanoparticles (HCSNs) are being considered as one of the most favorable drug carriers to accomplish targeted drug delivery. In the present study, we developed a simple two-step method, employing polystyrene (PS) nanoparticles (150?±?20 nm) as a sacrificial template for the synthesis of microporous HCSNs of size 230?±?30 nm. PS core and the wall structure directing agent cetyl trimethyl ammonium bromide (CTAB) were removed by calcination. Monodispersed spherical HCSNs were synthesized by optimising the parameters like water/ethanol volume ratio, PS/tetraethyl orthosilicate (TEOS) weight ratio, concentration of ammonia, and CTAB. Transmission electron microscopy (TEM) revealed the formation of hollow core-shell structure of silica with tunable thickness from 15 to 30 nm while tailoring the concentration of silica precursor. The results obtained from the cumulative release studies of doxorubicin loaded microporous HCSNs demonstrated the dependence of shell thickness on the controlled drug release behavior. HCSNs with highest shell thickness of 30 nm and lowest surface area of 600 m²/g showed delay in the doxorubicin release, proving their application as a drug carrier in targeted drug delivery systems. The novel concept of application of microporous HCSNs of pore size ~?1.3 nm with large specific surface area in the field of drug delivery is successful.     

In vitro and in vivo investigations of targeted chemotherapy with magnetic nanoparticles

Magnetic drug targeting is a local drug delivery system. Electromicroscopic pictures document the ferrofluid enrichment in the intracellular space in vitro. In vivo experiments were performed in VX2 tumor-bearing rabbits using magnetic nanoparticles bound to mitoxantrone. High-pressure liquid chromatography (HPLC) analyses after magnetic drug targeting showed an increasing concentration of the chemotherapeutic agent in the tumor region compared to regular systemic chemotherapy.     

Magnetic lipid nanoparticles loading doxorubicin for intracellular delivery: Preparation and characteristics

Tumor intracellular delivery is an effective route for targeting chemotherapy to enhance the curative effect and minimize the side effect of a drug. In this study, the magnetic lipid nanoparticles with an uptake ability by tumor cells were prepared dispersing ferroso-ferric oxide nanoparticles in aqueous phase using oleic acid (OA) as a dispersant, and following the solvent dispersion of lipid organic solution. The obtained nanoparticles with 200 nm volume average diameter and −30 mV surface zeta potential could be completely removed by external magnetic field from aqueous solution. Using doxorubicin (DOX) as a model drug, the drug-loaded magnetic lipid nanoparticles were investigated in detail, such as the effects of OA, drug and lipid content on volume average diameter, zeta potential, drug encapsulation efficiency, drug loading, and in vitro drug release. The drug loading capacity and encapsulation efficiency were enhanced with increasing drug or lipid content, reduced with increasing OA content. The in vitro drug release could be controlled by changing drug or lipid content. Cellular uptake by MCF-7 cells experiment presented the excellent internalization ability of the prepared magnetic lipid nanoparticles. These results evidenced that the present magnetic lipid nanoparticles have potential for targeting therapy of antitumor drugs.     

Ionic liquid-assisted synthesis of carbon nanotube/platinum nanocomposites

A novel solution-enhanced dispersion by supercritical CO₂ (SEDS) was employed to prepare silk fibroin (SF) nanoparticles. The resulting SF nanoparticles exhibited a good spherical shape, a smooth surface, and a narrow particle size distribution with a mean particle diameter of about 50?nm. The results of X-ray powder diffraction, thermo gravimetry-differential scanning calorimetry, and Fourier transform infrared spectroscopy analysis of the SF nanoparticles before and after ethanol treatment indicated conformation transition of SF nanoparticles from random coil to ??-sheet form and thus water insolubility. The MTS assay also suggested that the SF nanoparticles after ethanol treatment imposed no toxicity. A non-steroidal anti-inflammatory drug, indomethacin (IDMC), was chosen as the model drug and was encapsulated in SF nanoparticles by the SEDS process. The resulting IDMC?CSF nanoparticles, after ethanol treatment, possessed a theoretical average drug load of 20%, an actual drug load of 2.05%, and an encapsulation efficiency of 10.23%. In vitro IDMC release from the IDMC?CSF nanoparticles after ethanol treatment showed a significantly sustained release over 2?days. These studies of SF nanoparticles indicated the suitability of the SF nanoparticles prepared by the SEDS process as a biocompatible carrier to deliver drugs and also the feasibility of using the SEDS process to reach the goal of co-precipitation of drug and SF as composite nanoparticles for controlled drug delivery.