查看更多>>摘要：The poor immunogenicity of peptide vaccines compared to conventional ones re usually improved by applying different adjuvants. As chemical or biological substances, adjuvants are added to vaccines to enhance and prolong the immune response. According to considerable investigations over the recent years in the context of finding new adjuvants, a handful of vaccine adjuvants have been licensed for human use. Recently, engineered nanoparticles (NPs) have been introduced as novel alternatives to traditional vaccine adjuvant. Metallic nanoparticles (MeNPs) are among the most promising NPs used for vaccine adjuvant as well as the delivery system that can improve immune responses against pathogens. Iron NPs, as an important class of MeNPs, have gained increasing attention as novel vaccine adjuvants. These particles have shown acceptable results in preclinical studies. Hence, understanding the physicochemical properties of iron NPs, including size, surface properties, charge and route of administration, is of substantial importance. The aim of this review is to provide an overview of the immunomodulatory effects of iron NPs as novel adjuvants. Furthermore, physicochemical properties of these NPs were also discussed.
查看更多>>摘要：Supersaturated lipid-based drug delivery systems are increasingly being explored as a bio-enabling formulation approach, particularly in preclinical evaluation of poorlywater-soluble drugs. While increasing the drug load through thermally-induced supersaturation resulted in enhanced in vivo exposure for some drugs, for others, such as cinnarizine, supersaturated lipid-based systems have not been found beneficial to increase the in vivo bioavailability. We hypothesized that incorporation of precipitation inhibitors to reduce drug precipitation may address this limitation. Therefore, pharmacokinetic profiles of cinnarizine supersaturated lipid-based drug delivery systems with or without precipitation inhibitors were compared. Five precipitation inhibitors were selected for investigation based on a high throughput screening of twenty-one excipients. In vivo results showed that addition of 5% precipitation inhibitors to long chain monoglyceride (LCM) or medium chain monoglyceride (MCM) formulations showed a general trend of increases in cinnarizine bioavailability, albeit only statistically significantly increased for Poloxamer 407 + LCM system (i.e. 2.7-fold increase in AUC(0-24h) compared to LCM without precipitation inhibitors). It appeared that precipitation inhibitors mitigated the risk of in vivo precipitation of cinnarizine from sLBDDS and overall, bioavailability was comparable to that previously reported for cinnarizine after dosing of non-supersaturated lipid systems. In summary, for drugs which are prone to precipitation from supersaturated lipid-based drug delivery systems, such as cinnarizine, inclusion of precipitation inhibitors mitigates this risk and provides the opportunity to maximize exposure which is ideally suited in early efficacy and toxicology evaluation.
查看更多>>摘要：Aligned with efforts to overcome shortcomings of conventional oral dosage forms, mucoadhesive oral thin films have been the focus of drug development. Transmucosal drug delivery through oral cavity is a popular alternative to deliver many drugs due to several advantages over conventional oral delivery including greater bioavailability due to bypassing the first-pass effect and avoiding enzymatic or acid-related degradation in the gastrointestinal tract, faster onset of action, and better patient compliance particularly in geriatric and pediatric patients. Furthermore, among solid transmucosal delivery platforms, buccal and sublingual strips or patches are more attractive due to their flexibility, ease of administration, high patient compliance, and fast dissolution. They are also more stable compared to oral gels making them a desirable candidate to deliver many small and large molecules locally or systemically. Mucoadhesion and mechanical properties of oral films are crucial in their performance, and therefore ways to measure these properties are also similarly important. Since they are relatively new to the pharmaceutical market, there are currently no FDA-recommended or USP standard methods available to characterize such dosage forms. This review intends to cover and discuss various methods cited in the literature to measure and evaluate mucoadhesive and mechanical properties of oral films.
查看更多>>摘要：Monoclonal antibodies (mAbs) display numerous structural attributes, some of them may impact their safety and/or efficacy profiles. C-terminal lysine clipping is a common phenomenon occurring during the bioproduction of mAbs and leads to variable amounts of final process-related charge variants. If Fc-glycosylation has been by far the most documented critical quality attribute (CQA), the potential impacts of mAb C-terminal lysine content is far less reported, particularly on the ability of these basic variants to bind human Fc receptors. To address this question, three charge variant species having zero (K0), one (K1) and two (K2) C-terminal lysine(s) were isolated with high purity from an in-house human IgG1 by preparative strong-cation exchange (SCX) chromatography. A comprehensive biophysical characterization of these three fractions was undertaken, demonstrating their high similarity in terms of structural homogeneity, with a particular attention paid on their respective N-glycosylation profiles. The binding affinity of the fractions to human Fc gamma RIIIa-Val(176) was assessed both by affinity chromatography and surface plasmon resonance (SPR), and to human neonatal Fc receptor (FcRn) by affinity chromatography. Results demonstrate that the three charge variants did not show any significant binding difference for the two tested human Fc receptors, translating certainly to comparable biological properties. As a consequence, C-terminal lysine clipping of the present therapeutic IgG1 should not impact both FcRn-dependent pharmacokinetic profiles and Fc gamma RIIIa-driven cytotoxic activities. The methods used in this study can be widely applied to other IgG1 to define criticality of the C-terminal lysine clipping as a CQA.
查看更多>>摘要：Rats are widely used to study ocular drug responses, whereas rabbits are the most widely used preclinical model of ocular pharmacokinetics. Despite their wide use in evaluation of intravitreally injected drugs, translational information about pharmacokinetics and dose scaling between rats and rabbits is missing. In this study, we investigated intravitreal pharmacokinetics in rats and rabbits using non-invasive ocular fluorophotometry. Fluorescein and fluorescently labeled molecules (dextrans) with different molecular weights (376 Da, 10, 150 and 500 kDa), were injected into the vitreous of rabbits and rats. Intravitreal concentrations of the compounds were determined and pharmacokinetic parameters were calculated. Overall, the elimination half-lives of the macromolecules in rat vitreous were 5-6 times shorter than in rabbits, and the half-lives were prolonged at increasing molecular weights. The apparent volumes of distribution for tested compounds in rats and rabbits were in the range of the anatomical vitreal volumes. In both species, anterior route of elimination was predominant for the dextrans, whereas fluorescein was mainly eliminated via posterior route. Rabbit-to-rat ratios for intravitreal clearance were in the range of 2 to 5 for dextrans. Therefore, 2-5 times higher doses are needed for similar drug exposure in rabbits than in rats. Also, the shorter half-lives of macromolecules in the rat vitreous must be taken into account in translation to rabbit and human studies. The scaling factors presented herein will augment translational drug development for eye diseases.
Lee, Wee BengWidjaja, EffendiHeng, Paul Wan SiaChan, Lai Wah...
15页
查看更多>>摘要：Background: Direct compression is potentially sensitive to particle size distribution (PSD) variability in pharmaceutical grade excipients. Yet, the impact is insufficiently studied. Furthermore, the use of force sensor as a process analytical technology (PAT) platform, to monitor the effect of PSD variations on compact tensile strength, is a readily available but underutilized strategy.
查看更多>>摘要：Rhein (RH) is a candidate for the treatment of kidney diseases. However, clinical application of RH is impeded by low aqueous solubility and oral bioavailability. Deoxycholic acid-conjugated nanoparticles (DNPs) were prepared by ionic interaction for enhancing intestinal absorption by targeting the apical sodium-dependent bile acid transporter in the small intestine. Resultant DNPs showed relatively high entrapment efficiency (90.7 +/- 0.73)% and drug-loading efficiency (6.5 +/- 0.29)% with a particle size of approximately 190 nm and good overall dispersibility. In vitro release of RH from DNPs exhibited sustained and pH-dependent profiles. Cellular uptake and apparent permeability coefficient (P-app) of the DNPs were 3.25and 5.05-fold higher than that of RH suspensions, respectively. An in vivo pharmacokinetic study demonstrated significantly enhanced oral bioavailability of RH when encapsulated in DNPs, with 2.40and 3.33-fold higher C-max and AUC(0-inf) compared to RH suspensions, respectively. DNPs are promising delivery platforms for poorly absorbed drugs by oral administration.
查看更多>>摘要：The resurgence of Cannabis therapeutic discoveries have led to the need for sensitive and selective analytical methods for the detection of cannabinoids and their metabolites in biological matrices. High resolution mass spectrometry (HRMS) enables good sensitivity and provides more selectivity due to its accurate mass measurement of the targeted compounds. The aim of this study was to develop and validate a sensitive liquid chromatography high resolution mass spectrometry (LC-HRMS) method for the quantitative analysis of cannabidiol (CBD), cannabinol (CBN), Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and its major metabolites 11-Hydroxy-Delta(9)-THC and 11-Nor-9-carboxy-Delta(9)-THC in human plasma. The method utilized a simple liquid-liquid extraction of the cannabinoids from plasma samples followed by an isocratic chromatographic separation and detection by ESI-HRMS Q-Exactive plus platform. The lower limit of quantification (LLOQ) was 0.2 ng/ mL for the targeted cannabinoids and its metabolites with sample volume of 0.5 mL plasma. The method was linear from 0.2 to 100.0 ng/mL with an average correlation coefficient of >0.995 using weighted (1/x) linear least-squares regression. No significant carry-over was noticed for all analytes and the extraction recovery ranged from 60.4 % to 85.4 %. Dilution results indicated no influence on the accuracy of analysis. The method's intra-day and inter-day precision (CV %) ranged from 2.90 to 10.80 % and accuracy within-0.9 to 7.0 from nominal. Matrix effect ranged from 1.1 % to 49.8 %. The analytes were stable in the autosampler for 6 and 12 h, respectively. This method was sensitive and can be applicable to cannabinoids pharmacokinetics study.
查看更多>>摘要：The purpose of this study was to investigate the effect of ultrasound combined with microbbules (SonoVue (TM)) on the potency of methylprednisolone in attenuating the renal injury induced by adriamycin in rats. Animal model was established by two intravenous injections of 4 mg/kg adriamycin with a 2-week interval in rats. One week later, the adriamycin injected rats were randomly divided into 7 groups, receiving various treatments daily for 2 weeks. Two doses of methylprednisolone (20 or 40 mg/kg) were administrated alone or 20 mg/kg methylprednisolone and 100 mu L SonoVue (TM) microbbules (1-5 x 10(8) bubbles/mL; mean diameter of bubbles: 2.5 mu m) was co-administrated by intravenous injections from the tail vein. The ultrasound was applied at a frequency of 0.8 MHz and a spatial average temporal average intensity of 2.79 W/cm(2) for 5 min at a 50% duty cycle (1 s on 1 s off) on the back skin of the anatomic position of the kidney in rats of two groups combined with ultrasound. Renal injury were analyzed using immunohistochemical staining, real-time PCR, light and transmission electron microcopies. The kidney function related biochemical indexes were measured by automatic biochemistry analyzer. The results showed that adriamycin induced a typical renal injury and 40 mg/kg methylprednisolone injection significantly ameliorated the abnormality of key parameters such as proteinuria, renal mRNA and protein expression levels of nephrin, collagens III and IV as well as podocyte impairment, glomerulosclerosis and tubulointerstitial injury indexes. However, a sub-dose of methylprednisolone at 20 mg/kg was ineffective when administered intravenously, but its potency at this dosage was enhanced by co-administration with 100 mu L SonoVue (TM) microbubbles plus ultrasound irradiation. In conclusion, ultrasound combined with microbubbles can significantly increase local renal drug delivery leading to enhanced therapeutic effect of low dose methylprednisolone in ameliorating adriamycin-induced nephropathy in rats.
查看更多>>摘要：Despite the widespread use of lipid excipients in both academic research and oral formulation development, rational selection guidelines are still missing. In the current study, we aimed to establish a link between the molecular structure of commonly used polar lipids and drug solubilization in biorelevant media.
NSTL
Elsevier