查看更多>>摘要：The polymorphism of apremilast has been investigated. Two polymorphs have been identified and characterized by differential scanning calorimeter, fourier transform infrared spectroscopy, and powder X-ray diffractometer. Solubilities of apremilast forms B and E in three binary solvents of methanol-water, acetonitrile-water, and acetonitrile-methanol have been measured using the static method at a temperature ranging from 288.15 K to 328.15 K under standard atmospheric pressure. Subsequently, the solubility data have been analyzed using the Wilson, NRTL, and UNIQUAC thermodynamic models, respectively. Furthermore, the Gibbs energy of solution and the radial distribution function have been calculated using the molecular simulation method to evaluate the dissolution mechanism. The Gibbs energy of solution reveals that the rank of solute-solvent interaction correlated well with solubility order in binary solvent mixtures, and the radial distribution function indicates that weakening of solvent-solvent interaction led to an increase in solubility.
查看更多>>摘要：The circadian timing system controls many biological functions in mammals including drug metabolism and detoxification, cell cycle events, and thus may affect pharmacokinetics, target organ toxicity and efficacy of medicines. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is effective against several cancers. The aim of this study was to investigate dosing-time dependent testicular toxicity of subacute everolimus administration in mice. C57BL/6 J male mice were syn-chronized with Light-Dark (12h:12 h) cycle, with Light-onset at Zeitgeber Time (ZT)-0. Everolimus (5 mg/kg/ day) was administered orally to mice at ZT1rest-span or ZT13activity-span for 4 weeks. Body weight loss, clinical signs, changes in testicular weights, testis histology, spermatogenesis and proliferative activity of germinal epithelium of seminiferous tubules were examined. Steady-state everolimus concentrations in testes were determined with validated HPLC method. Everolimus toxicity was less severe following dosing at ZT13 compared to ZT1, as shown with least body weight loss (p<0.001), least reductions in testes weights (p<0.001) and least histopathological findings. Everolimus-induced histological changes on testes included vacuolisation and atrophy of germinal epithelium, and loss of germinal cell attachment. The severity of everolimus-induced histological toxicity on testes was significantly more evident in mice treated at ZT1 than ZT13 (p<0.001). Spermatogenic cell population significantly decreased when everolimus administered at ZT1 compared to ZT13 (p<0.001). Prolif-erative activity of germinal epithelium was significantly decreased due to treatment at ZT1 compared to ZT13 (p<0.001). Everolimus concentrations in testes indicated a pronounced circadian variation, which was greater in mice treated at ZT1 compared to ZT13 (p<0.05). Our study revealed dosing-time dependent testicular toxicity of everolimus in mice, which was greater in severity when everolimus administered at early rest-span (daytime-ZT1) than early activity-span (nighttime-ZT13). These findings support the concept of everolimus chronotherapy for minimizing reproductive toxicity and increasing the tolerability of everolimus, as a clinical advantage.
Sousa, Andre Luiz Moreira Domingues deSantos, Widson Michael dosSouza, Myla Lobo deSilva, Laysa Creusa Paes Barreto Barros...
11页
查看更多>>摘要：Layered Double Hydroxides (LDH) have received great attention in the development of drug carrier systems. LDHs have become intelligent excipients of high technological potential for the pharmaceutical industry due to their ability to intercalate biomaterials in the interlayer region, adsorb substances on its vast surface area, have flexible structure, swelling properties, high chemical and thermal stability, modulate drug release, have high biocompatibility and be easily synthesized. This article, using typical examples, mainly addresses the systems formed between LDHs and antimicrobial, antineoplastic and anti-inflammatory agents, which constitute the main pharmacological classes of wide interest due to the problems encountered with low solubility, control in administration, stability in body fluids and toxicity, among others. Additionally, the article also reports on the recent development of ternary or quaternary (multicomponent systems) compounds based on LDH, bringing the advantages of targeted therapy, improving the aqueous stability of nanohybrids and the performance of these inorganic carriers.
查看更多>>摘要：Forced degradation tests are studies used to assess the stability of active pharmaceutical ingredients (APIs) and their formulations. These tests are performed submitting the API under extreme conditions in order to know the main degradation products in a short period of time. The results of these studies are used to assess the degradation susceptibility of APIs and to validate chromatographic analytical methods. However, most of degradation studies are performed using one-factor-at-the-time (OFAT) which does not consider the interactions between degradation variables. This work proposes the use of Design of Experiment (DoE) approach in forced degradation of albendazole (ABZ). It was used a central composite design (CCD) to evaluate the forced degradation in a multivariate way. Experiments were performed taking into account the variables pH, temperature, oxidizing agent (H2O2) and UV radiation. It was verified the influence of the variables and their interactions on the ABZ degradation. The ABZ oxidation showed to be the main degradation route for ABZ, which is strongly influenced by the temperature. The hydrolysis was relevant at alkaline medium and high temperature. LC-IT-MSn was used to identify the degradation products. It was found three known degradation products (albendazole-2-amino, albendazole sulfoxide and albendazole sulfone) and a new derivate of albendazole molecule (albendazole sulfoxide with a chlorine). This last one was isolated and characterized by UPLC-QToF-MS and NMR analyses.
查看更多>>摘要：This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNF alpha) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Interoccasion variability and the pharmacokinetics of two test compounds have been added to this secondgeneration model, and the goal is to produce a framework of how to model TNF alpha response in LPS challenge studies in vivo and demonstrate its general applicability regardless of occasion or type of test compound. Model improvements based on experimental data were successfully implemented and provided a robust model for TNF alpha response after LPS provocation, as well as reliable estimates of the median pharmacodynamic parameters. The two test compounds, Test Compound A and roflumilast, showed 81.1% and 74.9% partial reduction of TNF alpha response, respectively, and the potency of Test Compound A was estimated to 0.166 mu mol/L. Comparing this study with previously published work reveals that our model leads to biologically reasonable output, handles complex data pooled from different studies, and highlights the importance of accurately distinguishing the stimulatory effect of LPS from the inhibitory effect of the test compound.
查看更多>>摘要：Albeit the preparation of liquisolid systems represents an innovative approach to enhance the dissolution of poorly soluble drugs, their broader utilization is still limited mainly due to the problematic conversion of the liquid into freely flowing and readily compressible powder. Accordingly, the presented study aims to determine the optimal carrier/coating material ratio (R value) for formulations based on magnesium aluminometasilicate (NUS2) loaded with polyethylene glycol 400. Four commercially available colloidal silica were used as coating materials in nine different R values (range of 5 - 100). The obtained results suggested that the higher R value leads to the superior properties of powder mixtures, such as better flowability, as well as compacts with higher tensile strength and lower friability. Moreover, it was observed that the type of coating material impacts the properties of liquisolid systems due to the different arrangement of particles in the liquisolid mixture. To confirm the noted dependency of R value and coating material type, the one-and two-way ANOVA, linear regression and principal component analysis (PCA) techniques were performed. In addition, a comparison of results with the properties of loaded NUS2 itself revealed that LSS with sufficient properties may be prepared even without the coating material.
Bonner, Jennifer J.Burt, HowardJohnson, Trevor N.Whitaker, Martin J....
10页
查看更多>>摘要：The goal of hormone replacement is to mirror physiology. Hydrocortisone granules and modified release formulations are being developed to optimise cortisol replacement in the rare disease of adrenal insufficiency. To facilitate clinical development, we built and verified a physiologically based pharmacokinetic (PBPK) model for the endogenous hormone cortisol (hydrocortisone) in healthy adults, and children and adults with adrenal insufficiency. The model predicted immediate-release hydrocortisone pharmacokinetics in adults across the dose range 0.5 to 20 mg, with predicted/observed AUCs within 0.8 to 1.25-fold. The model also tightly predicted pharmacokinetic parameters for modified-release formulations, with AUCs within 0.8 to 1.25-fold after single and multiple dosing. Predicted modified-release formulation pharmacokinetics (PK) in 12 to 18-year olds showed PK to be similar to adults. This hydrocortisone PBPK model is a useful tool to predict adult and paediatric pharmacokinetics of both immediate- and modified-release hydrocortisone formulations, and develop clinical dosing regimens.
查看更多>>摘要：Poorly absorbable sugar alcohols (e.g., mannitol, sorbitol, and maltitol) are the excipients frequently contained in pediatric dosage forms. Due to their osmotically active properties, certain amount of sugar alcohols reportedly reduces oral bioavailability of concomitant drugs. This fact implies the possible pharmacokinetic interaction between orally administered drug and sugar alcohols which are present in other concomitant medications. The purpose of this study was to identify the possibility and likeliness of the osmotically active excipient-induced pharmacokinetic interaction in pediatric polypharmacy. Previously developed in silico model that captured the osmotic effect of sugar alcohols in adults was expanded to pediatric population. This mathematical model successfully explained the impaired bioavailability of lamivudine by the co-administered sorbitol in other dosage forms. In the meantime, sugar alcohol contents in marketed pediatric dosage forms were investigated by reverse engineering technology. Considering the critical administration dose of sugar alcohols estimated by in silico model, it was revealed that 25 out of 153 pediatric dosage forms were identified as possible perpetrators even under the approved administration and dosage in Japan. This study shed light on the potential pharmacokinetic interaction that cannot be dismissed throughout the pediatric pharmaceutical dosage form design and development.
查看更多>>摘要：Tizanidine hydrochloride (TIZ) is a skeletal muscle relaxant used to treat spasms, a sudden involuntary muscle contraction. The currently available oral dosage forms exhibit low oral bioavailability due to high first-pass metabolism. Frequent administration of the drug is thus necessary because of the short half-life of the drug. Transdermal delivery is an excellent alternative, but the skin's outer stratum corneum barrier prevents most drugs from being effectively delivered into the bloodstream. Here we present a pre-clinical investigation of derma roller mediated delivery of TIZ invasome gel as a potential approach for treating muscle spasm. Further, specific terpenes namely limonene and pinene in different concentrations and their impact on the properties of the prepared TIZ invasomes, including particle size, drug entrapment, and ex vivo drug release, were investigated. TIZ invasomes were incorporated into a gel and delivered to rats with and without pre-treatment of the skin with a derma roller. Pre-treated skin achieved maximum drug plasma concentrations within 3 +/- 0.00 h of gel application and maintained for 24 h. In the untreated skin the maximum plasma drug levels was achieved at the end of 6 +/- 0.00 h. The findings were further supported by in vivo efficacy studies conducted using rotarod and actophotometer. Overall, the study indicates that derma roller mediated transdermal delivery of TIZ loaded invasomes is a promising strategy for enhancing the bioavailability of TIZ.
NSTL
Elsevier