The Effect of Polymer Blends on the In Vitro Release/Degradation and Pharmacokinetics of Moxidectin-Loaded PLGA Microspheres.

To investigate the effect of polymer blends on the in vitro release/degradation and pharmacokinetics of moxidectin-loaded PLGA microspheres (MOX-MS), four formulations (F1, F2, F3 and F4) were prepared using the O/W emulsion solvent evaporation method by blending high (75/25, 75 kDa) and low (50/50, 23 kDa) molecular weight PLGA with different ratios. The addition of low-molecular-weight PLGA did not change the release mechanism of microspheres, but sped up the drug release of microspheres and drastically shortened the lag phase. The in vitro degradation results show that the release of microspheres consisted of a combination of pore diffusion and erosion, and especially autocatalysis played an important role in this process. Furthermore, an accelerated release method was also developed to reduce the period for drug release testing within one month. The pharmacokinetic results demonstrated that MOX-MS could be released for at least 60 days with only a slight blood drug concentration fluctuation. In particular, F3 displayed the highest AUC and plasma concentration (AUC0-t = 596.53 ng/mL·d, Cave (day 30-day 60) = 8.84 ng/mL), making it the optimal formulation. Overall, these results indicate that using polymer blends could easily adjust hydrophobic drug release from microspheres and notably reduce the lag phase of microspheres.

Physicochemical Characterization and Pharmacokinetics of Agomelatine-Loaded PLGA Microspheres for Intramuscular Injection.

PURPOSE: The aim of this study was to design agomelatine loaded long acting injectable microspheres, with an eventual goal of reducing the frequency of administration and improving patient compliance in treatment of depression. METHODS: AGM-loaded microspheres were prepared by an O/W emulsion solvent evaporation method. The physicochemical properties and in vitro performance of the microspheres were characterized. The pharmacokinetics of different formulations with various particle sizes and drug loadings were evaluated. RESULTS: AGM-loaded microspheres with drug loading of 23.7% and particle size of 60.2 µm were obtained. The in vitro release profiles showed a small initial burst release (7.36%) followed by a fast release, a period of lag time and a second accelerated release. Pore formation and pore closure were observed in vitro, indicating that the release of drug from microspheres is dominated by water-filled pores. Pharmacokinetic studies showed that AGM microspheres could release up to 30 days in vivo at a steady plasma concentration. As well, particle size and drug loading could significantly influence the in vivo release of AGM microspheres. CONCLUSIONS: AGM-loaded microspheres are a promising carrier for the treatment of major depressant disorder.

Drug-Polymer Interaction, Pharmacokinetics and Antitumor Effect of PEG-PLA/Taxane Derivative TM-2 Micelles for Intravenous Drug Delivery.

PURPOSE: A novel polymer micelle was prepared with a high drug loading, good stability, high tolerance and better anti-tumor effect. METHODS: TM-2 was encapsulated in poly-block-poly (D, L-lactic acid) self-assembled micelles by the thin-film hydration method. From the critical micelle concentrations of the copolymers, particle size, drug loading and encapsulation efficiency of drug-loading micelles, the appropriate polymer material could be assessed. Comparisons between TM-2 solution and TM-2 micelles were done to evaluate the pharmacokinetics and toxicity in rats, compared with Taxol to evaluate the anti-tumor effect in mice. RESULTS: The optimized TM-2 micelles achieved a high drug loading (~20%) with the polymer material of PEG2k-PLA2.5k, with a particle size of 30 nm and no significant change in particle size after lyophilization. The result of pharmacokinetic experiment displayed that the half-life in vivo was obviously prolonged. The maximum tolerated dose of TM-2 micelles was approximately 25 mg/kg in rats, and the relative tumor growth rate of Taxol (15 mg/kg), TM-2 (10 mg/kg), TM-2 (15 mg/kg) and TM-2 (40 mg/kg) in mice were 49.35%, 49.14%, 36.44 and 9.98% respectively. CONCLUSIONS: TM-2 micelles with high drug loading increased drug solubility, improved tolerance, antitumor effects and reduced toxicity.

In Vitro-In Vivo Relationship of Amorphous Insoluble API (Progesterone) in PLGA Microspheres.

PURPOSE: The mechanism of PRG release from PLGA microspheres was studied and the correlation of in vitro and in vivo analyses was assessed. METHODS: PRG-loaded microspheres were prepared by the emulsion-evaporate method. The physical state of PRG and microstructure changings during the drug release period were evaluated by powder X-ray diffraction (PXRD) and scanning electron microscopy (SEM) respectively. Pharmacokinetic studies were performed in male Sprague-Dawley rats, and the in vivo-in vitro correlation (IVIVC) was established by linear fitting of the cumulative release (%) in vitro and fraction of absorption (%) in vivo. RESULTS: PXRD results indicated recrystallization of PRG during release. The changes of microstructure of PRG-loaded microspheres during the release period could be observed in SEM micrographs. Pharmacokinetics results performed low burst-release followed a steady-released manner. The IVIVC assessment exhibited a good correlation between vitro and in vivo. CONCLUSIONS: The burst release phase was caused by diffusion of amorphous PRG near the surface, while the second release stage was impacted by PRG-dissolution from crystal depots formed in microspheres. The IVIVC assessment suggests that the in vitro test method used in this study could predict the real situation in vivo and is helpful to study the release mechanism in vivo.

Molecularly imprinted polymers based on SBA-15 for selective solid-phase extraction of baicalein from plasma samples.

Highly selective molecularly imprinted mesoporous silica polymer (SBA-15@MIP) for baicalein (BAI) extraction was synthesized using a surface molecular imprinting technique on the SBA-15 supporter. Computational simulation was used to predict the optimal functional monomer for the rational design of SBA-15@MIP. Meanwhile, high adsorption capacity was obtained when a suitable yield of molecularly imprinted polymers (MIPs) layer was grafted onto the surface of SBA-15. Characterization and performance tests of the obtained polymer revealed that SBA-15@MIP possessed a highly ordered mesoporous structure, reached saturated adsorption within 60 min, and exhibited higher sorption capacity to the target molecule BAI compared with non-imprinted mesoporous silica polymer (SBA-15@NIP) and SBA-15. Finally, SBA-15@MIP was successfully applied to solid-phase extraction (SPE) coupled with high-performance liquid chromatography and ultraviolet detection (HPLC-UV) for the determination of trace BAI in plasma samples. Mean recoveries of BAI through the molecularly imprinted solid-phase extraction (MISPE) sorbent, non-imprinted solid-phase extraction (NISPE) sorbent, and SBA-15 solid-phase extraction (SBA-15-SPE) sorbent were 94.4, 22.7, and 10.7 %, respectively, and the relative standard deviations were 2.9, 2.6, and 3.6 %, respectively. These results reveal that SBA-15@MIP as a SPE sorbent has good applicability to selectively separate and enrich trace BAI from complex samples.

Evaluating supersaturation in vitro and predicting its performance in vivo with Biphasic gastrointestinal Simulator: A case study of a BCS IIB drug.

This study aimed to develop an evaluation approach for supersaturation by employing an in vitro bio-mimicking apparatus designed to predict in vivo performance. The Biphasic Gastrointestinal Simulator (BGIS) is composed of three chambers with absorption phases that represent the stomach, duodenum, and jejunum, respectively. The concentration of apatinib in each chamber was detected by fiber optical probes in situ. The dissolution data and the pharmacokinetic data were correlated by GastroplusTM. The precipitates were characterized by polarizing microscope, Scanning Electron Microscopy, Powder X-ray diffraction and Differential scanning calorimetry. According to the results, Vinylpyrrolidone-vinyl acetate copolymer (CoPVP) prolonged supersaturation by improving solubility and inhibiting crystallization, while Hydroxypropyl methylcellulose (HPMC) prolonged supersaturation by inhibiting crystallization alone. Furthermore, a predictive in vitro-in vivo correlation was established, which confirmed the anti-precipitation effect of CoPVP and HPMC on in vitro performance and in vivo behavior. In conclusion, CoPVP and HPMC increased and prolonged the supersaturation of apatinib, and then improved its bioavailability. Moreover, BGIS was demonstrated to be a significant approach for simulating in vivo conditions for in vitro-in vivo correlation in a supersaturation study. This study presents a promising approach for evaluating supersaturation, screening precipitation inhibitors in vitro, and predicting their performances in vivo.

Functional modification of cellulose fabrics with phthalocyanine derivatives and the UV light-induced antibacterial performance.

Cellulose fabrics were modified with a derivative of copper phthalocyanine (Reactive Blue C.I. 21) by dyeing method. The modified cellulose fabrics exhibited important photoactive property, such as the hydroxyl radicals-generating ability. The UV-vis spectrum, exhaustion rate, fixation rate and grafting quantity of Reactive Blue 21 on the cellulose fabrics were measured and calculated. The chemical structure and morphology of the modified cellulose were characterized. The amount of the produced hydroxyl radicals was measured and the photoactive mechanism was discussed. The UV light-induced antibacterial performance of the modified materials was measured. The modified cellulose exhibited photo-induced antibacterial activity against both Staphylococcus aureus and Escherichia coli.

Silica nanoparticles on the oral delivery of insulin.

INTRODUCTION: When intravenous or subcutaneous administration of insulin, various side effects or possible risks have been reported. Oral administration of insulin has significant advantages of convenience, painless and mimetic endogenous insulin pathway, and thus it presents patients compliance, protects pancreatic ß cells and lessens adverse effects caused by long-term injection. This challenging oral delivery of insulin can be achieved by promising silica nanoparticles (SNs), especially mesoporous silica nanoparticles (MSNs), with controllable morphology and high loading efficiency. This review presents the synthesis and physiological behaviors of SNs such as in vivo and in vitro degradation, absorption, distribution, and excretion, as well as preparations of oral insulin based on SNs. As well, this review will provide insights for innovative oral delivery of SNs and insulin. AREAS COVERED: Promising SNs and MSNs have gained interests for application in oral drug delivery of insulin. EXPERT OPINION: After synthesis under proper conditions and methods, promising SNs with controllable structure and suitable stability can be synthesized. By improving permeability and penetration, achieving controlled release and adjusting physiological processes, functionalization on SNs by active groups, molecules, or polymers is necessary for oral delivery of insulin.

Self-assembly and characterization of paclitaxel-loaded N-octyl-O-sulfate chitosan micellar system.

N-octyl-O-sulfate chitosan micellar system loaded paclitaxel was prepared by using dialysis method. The critical micelle concentration (CMC) of the modified chitosan was found to be 0.45 mg/ml. Compared with the amount of N-octyl-O-sulfate chitosan, the paclitaxel loading amount in the system was up to 25% (w/w), depending on both of the solvents used in dialysis and the feed weight ratio of paclitaxel to the derivative. The polymeric micelles forming and loading occurred simultaneously in the dialysis process when ethanol and water were utilized as the solvents for paclitaxel and the polymer, respectively. Paclitaxel-loaded micellar system of N-octyl-O-sulfate chitosan was characterized by DSC, WXRD and TEM. TEM photograph revealed that paclitaxel existed as the colloid particulates in ethanol before loading and in the cores of the spherical polymeric micelles after loading. The results of DSC and WXRD indicated that paclitaxel was transferred from the crystalline state to amorphous state after loading. The lyophilized powder of micellar system (25% (w/w) loading) could be reconstituted easily in aqueous media even after 2 months storage at 4 degrees C without the change of paclitaxel entrapment and micelle size. The reconstituted solution (2.1 mg paclitaxel/ml) also showed good stability. The dilution with saline may decrease the loading and physical stability based on the dilution times which was related with CMC of the polymer. In vitro tests showed that paclitaxel was slowly released from micellar solution and the release lasted up to 220 h by means of the dialysis method.

Mutation analysis of p63 gene in the first Chinese family with ADULT syndrome.

BACKGROUND: ADULT syndrome (acro-dermato-ungual-lacrimal-tooth syndrome) is a rare ectodermal dysplasia disorder known as autosomal dominant inheritance. Recent studies have linked p63 gene mutation to the development of this disease. However, the genetic characteristics of ADULT syndrome were still not well understood. METHODS: Mutation analysis of p63 gene in the first Chinese ADULT syndrome family was performed using direct DNA sequencing. RESULTS: The sequence analysis of exon 8 of p63 gene disclosed a heterozygous G>A substitution at nucleotide 893 (R298Q) in the proband. In addition, a single nucleotide polymorphism (SNP) rs16864880 in the downstream flanking region (DFR) of p63 exon 8 was also identified in this family. The proband and the paternal side including her father exhibited the C/G genotype at this position. The C/G variant frequency in the paternal was significantly higher as compared with the maternal (6/10 vs 0/6, P = 0.034). CONCLUSIONS: ADULT syndrome may be caused by the p63 gene mutation, and it might have closer genetic association with the paternal side in this family.