Peng Quan

A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability

In this study, chitosan, a cationic polymer with positive charge, was introduced to modify the nanocrystals of nitrendipine with negative charge. The nanocrystals were prepared via precipitation-high pressure homogenization method. Then the nanocrystals were dispersed into chitosan solution, and the free chitosan was removed by centrifugation to obtain the chitosan modified nanocrystals, which remained the same particle size. However, the zeta-potential changed to positive after modification. The physical stability of the chitosan modified nanocrystals was remarkably improved under ambient conditions. During the in vitro dissolution test, the modified nanocrystals showed a certain degree of slow-release property. In the in vivo study, the C(max) of nitrendipine remained the same, however, the T(max) delayed from 0.75 h to 1.5 h with the chitosan modified nanocrystals. The surface modification by chitosan improved the bioavailability compared with the initial nanocrystals, which had demonstrated significant improvement of bioavailability compared to the traditional coarse powder form. Based on the experimental results, modification of the nanocrystals with certain polymer was supposed to be a good method to control the in vitro and in vivo behaviors of the nanocrystals, which could further increase the bioavailability of the water insoluble drug.

In vitro–in vivo study of CoQ10-loaded lipid nanoparticles in comparison with nanocrystals

The present work described the effect of CoQ10 dissolution characteristics in nanocrystals and lipid nanoparticles (LNs) on its oral absorption in rats. Nanocrystals and LNs were prepared by melt-high pressure homogenization and sucrose monolaurate was used as a stabilizer in all formulations. Witepsol(®)W35 and medium-chain triglycerides (MCT) were selected as lipid additives to form LN(CoQ10+W35) and LN(CoQ10+MCT), respectively. From the results obtained, the particle size of CoQ10 nanocrystals was 285 nm, while it was reduced to 150 nm by mixture with an equal amount of lipid additives due to their lower melting points. In vitro dissolution results indicated that the drug release from two LNs was delayed compared with that from nanocrystals, and LN(CoQ10+W35) exhibited the highest drug release over 4h. Finally, in vivo evaluation demonstrated that the oral absorption of CoQ10 was markedly increased by using nanocrystals and LNs compared with a coarse suspension. A good relationship was found between the in vitro dissolution and in vivo evaluation. The enhanced oral absorption of CoQ10 by nanocrystals and LNs was due to improved dissolution. In conclusion, Witepsol(®)W35 was shown to be a better lipid additive for the preparation of LNs to increase the oral absorption of CoQ10.

Influence of drug physicochemical properties on absorption of water insoluble drug nanosuspensions

In order to investigate the influence of drug physicochemical properties on bioavailability of water insoluble drug nanosuspensions, five drug nanosuspensions were prepared using high pressure homogenization. These nanosuspensions were similar in particle size and same in stabilizer. Differential scanning calorimetry and powder X-ray diffraction analysis showed the crystalline state of the freeze dried nanocrystals did not change. In vitro dissolution test in fasted state simulated intestinal fluid (FaSSIF) and in vivo bioavailability study in rats demonstrated that the nanosuspensions had higher dissolution rate and higher AUC0-t and the ratios of dissolvednano/dissolvedmicro in 120 min were well correlated with the ratios of AUC0-t nano/AUC0-t micro. Correlation analysis between drug physicochemical properties and AUC0-t nano was performed and four-grid interpolation method was employed for interpolation and smooth surface fitting to give a visible trend. The results revealed that drug with smaller melting point, logP value around 5 and polar surface area value in the range of 50-60 would gain higher AUC0-t nano and accordingly better absorption of its nanosuspension. Melting point, logP and polar surface area were factors that influence the absorption of drug nanosuspensions in this study.

Probing the role of chemical enhancers in facilitating drug release from patches: Mechanistic insights based on FT-IR spectroscopy, molecular modeling and thermal analysis

In patches, a drug must release from patches prior to its percutaneous absorption. Chemical enhancers have been used for several decades, but their roles in drug release from patches are poorly understood. In this work, the roles of chemical enhancers in bisoprolol tartrate (BSP-T) release from patches were probed in vitro and in vivo. More importantly, an innovative mechanism insight of chemical enhancers in drug release process was provided at molecular level. FT-IR spectroscopy and molecular modeling were employed to investigate the influence of chemical enhancers on drug-adhesive interaction. The results showed chemical enhancers like Span 80, which had a strong ability forming hydrogen bonds, could decrease drug-adhesive interaction leading to the release of drug from adhesive of patches. Thermal analysis was conducted to research the influence of chemical enhancers on the thermodynamic properties of patch system. It showed that chemical enhancers promoted the formation of free volume of adhesive, which facilitated drug release process. By contrast, the influence on the thermodynamic properties of BSP-T was less effective in influencing BSP-T release process. In conclusion, chemical enhancers played an important role in facilitating BSP-T release from the adhesive DURO-TAK® 87-2287 of patches by decreasing drug-adhesive interaction and promoting the formation of free volume of adhesive. This work may be an important step in understanding the important roles of chemical enhancers in drug release process.

Time dependence of the enhancement effect of chemical enhancers: Molecular mechanisms of enhancing kinetics

Abstract Chemical enhancers are widely used for facilitating drug penetration in transdermal drug delivery system (TDDS). However, there is a lack of knowledge about how the enhancement effect changes over time. In this study, on the basis of kinetic parameters of enhancement effect, molecular details of the dynamic enhancement process was described and a new hypothesis of the recovery mechanism of the skin barrier function was proposed. Using pretreated skin and flurbiprofen patch, the effects of Azone (AZ) and menthyl decanoate (MT‐10) were evaluated with in vitro permeation experiment and further confirmed by confocal laser scanning microscopy (CLSM) and TEWL. The results showed that the enhancement ratio (ER) increased firstly, then reached a plateau and finally decreased. The enhancement effect of MT‐10 was slower (Tonset, MT‐10 > Tonset, AZ), weaker (ERmax, MT‐10 < ERmax, AZ) and shorter (Teff, MT‐10 < Teff, AZ) than that of AZ. According to the results of CLSM, ATR‐FTIR and molecular dynamic simulation, the dynamic enhancement effect was caused by the variation of the diffusion coefficient of intercellular lipid in the stratum corneum (SC), which was dependent on the affinity between enhancers and lipid. Moreover, the skin barrier function recovered although a large amount of enhancers still existed in the SC. Additionally, according to the results of ATR‐FTIR, molecular docking and skin retention study, the dynamic effect of AZ on the skin protein only induced skin irritation but showed no influence on drug penetration, so did the amount of the enhancer. In conclusion, dynamic enhancement effect was caused by the dynamic effect of the enhancer on the SC intercellular lipid, and the skin barrier function recovered by accepting the enhancer as a new component of the lipid bilayer. Graphical abstract Figure. No Caption available.

Saturated long-chain esters of isopulegol as novel permeation enhancers for transdermal drug delivery.

PurposeSaturated long-chain esters of isopulegol were synthesized and their activities as permeation enhancers for transdermal delivery of amlodipine and flurbiprofen were investigated, in contrast to the saturated fatty acids and isopulegol, as well as their physical mixtures.MethodsIn vitro permeation experiments, confocal laser scanning microscopy (CLSM) and attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy were introduced to investigate the regulation of enhancers in the skin permeability and biophysical properties. With in vitro cytotoxicity test and in vivo erythema model, the skin irritation of enhancers was evaluated.ResultsThe esters significantly increased the permeation of amlodipine and flurbiprofen, whereas saturated fatty acids and isopulegol had no such effect and even decreased the drug permeation when they were used alone or in combination. These results were supported by CLSM and ATR-FTIR studies, which revealed that only the esters could decrease the order of the alkyl chains in the skin lipids. Additionally, almost no skin irritation and cytotoxicity were observed for these esters.ConclusionsSaturated long-chain esters of isopulegol are shown to be suitable permeation enhancers for transdermal drug delivery. Covalent attachment of isopulegol and saturated fatty acids might represent a promising strategy to design novel and potent permeation enhancers.

Drug in adhesive patch of palonosetron: Effect of pressure sensitive adhesive on drug skin permeation and in vitro-in vivo correlation.

Palonosetron (PAL) is recommended for the prevention of chemotherapy-induced nausea and vomiting. The aim of this study was to develop a long-acting PAL transdermal patch to improve patient compliance. We were particularly concerned about the effect of pressure sensitive adhesives (PSAs) on PAL skin permeability. Formulation factors including PSAs, backing films and drug loadings were investigated in the in vitro skin permeation study using rabbit skin. Fourier transform infrared spectrometer study and thermal analysis were conducted to investigate the drug-PSA interaction and thermodynamic activity of PSAs, respectively. The results indicated that high drug skin permeation amount was obtained in PSA DURO-TAK(®)87-2516, which had low interaction potential with PAL and high thermodynamic activity. The optimized patch was composed of PAL of 8 %, DURO-TAK(®)87-2516 as PSA, CoTran™ 9700 as backing film and Scotchpak™ 9744 as release liner. The in vitro skin permeation amount of the optimized patch was 734.0±55.8μg/cm(2) during 3-day administration. The absolute bioavailability of the optimized patch was 43 % in rabbit and a good in vitro-in vivo correlation coefficient was obtained (R(2)=0.989). These results indicated the feasibility of PAL transdermal patch in the prevention of chemotherapy-induced nausea and vomiting.

A systemic evaluation of drug in acrylic pressure sensitive adhesive patch in vitro and in vivo: The roles of intermolecular interaction and adhesive mobility variation in drug controlled release

ABSTRACT Though acrylic pressure sensitive adhesives (PSAs) are widely used in transdermal drug delivery system, molecular details of drug‐PSA interactions, PSA molecular mobility variations and their influences on drug skin permeation are unclear. In this study, three classes of acrylic PSAs containing hydroxyl (AAOH), carboxyl (AACOOH) and non‐functional group (AAnone) were synthesized. Their abilities of controlling drug release were evaluated using propranolol (PRO) and zaltoprofen (ZAL) in vitro and in vivo. Interaction details were identified by FT‐IR, solid‐state NMR and molecular modeling. Thermodynamic activity of drug and strength of drug‐PSA interaction were characterized using miscibility study. PSA mobility was characterized using thermal analysis and rheology study. Thus, ionic interaction reduced the thermodynamic activity of PRO and mobility of AACOOH, which made PRO‐AACOOH obtain a significant lower bioavailability (11.8 ± 0.7%) than these of PRO‐AAnone (40.7 ± 2.5%) and PRO‐AAOH (42.3 ± 2.9%). Though thermodynamic activity of ZAL in AACOOH was lower than that in AAOH due to the hydrogen bonding, bioavailability of ZAL‐AAOH (19.0 ± 4.1%) exhibited no significant difference with ZAL‐AACOOH (15.4 ± 2.8%), mainly because AAOH mobility was decreased by ZAL. In conclusion, the strength, types and involved functional groups of drug‐PSA interactions were identified. On this basis, it was found that different control patterns of drug release were not only caused by the thermodynamic or kinetic hindrance effects of drug‐PSA interactions, but also influenced by the interactions introduced PSA mobility variations, which was an innovative mechanism of controlled release in transdermal patch. The conclusions extended our understanding about the mechanism of controlled drug release of drug‐in‐adhesive patch. In addition, they contributed to the design of TDDS and custom acrylic PSAs.

Mechanistic investigation and reversible effect of 2-isopropyl-5-methylcyclohexyl heptanoate on the in vitro percutaneous absorption of indomethacin.

Abstract In the present study, the enhancing effect of 2-isopropyl-5-methylcyclohexyl heptanoate (M-HEP) on the percutaneous absorption of indomethacin (IM) was evaluated by the in vitro penetration experiments using the rat abdominal skin as a barrier. Partition experiment, attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectrum and transepidermal water loss (TEWL), was employed to investigate the possible mechanisms of the action of M-HEP. Furthermore, the reversible effect of M-HEP on excised rat skin was also evaluated through in vitro permeation as a preliminary indicator of safety. The result of in vitro permeation experiment indicated that, 10% (w/w) M-HEP in combination with isopropyl palmitate (IPP) significantly increased (p < 0.05), the cumulative amount of IM in comparison with the control group (IPP only). The partition coefficient of IM between the stratum corneum (SC) and enhancer solution was also greater than that between the SC and IPP. A blue shift in the ATR-FTIR spectra of SC after treatment with M-HEP solution was observed at the CH2 band, which indicating that M-HEP disrupted the intercellular lipid structure of the SC. In addition, both M-HEP/IPP and L-menthol (MT)/IPP improved the TEWL value of rat abdominal skin. After removal of M-HEP, the skin barrier function would be restored in 8 h. In conclusion, M-HEP could reversibly enhance the percutaneous absorption of IM by increasing the partitioning of IM into the SC from enhancer solution and disturbing the organized structure of SC lipids and the reversibility of M-HEP was better than MT.

Effect of drug physicochemical properties on drug release and their relationship with drug skin permeation behaviors in hydroxyl pressure sensitive adhesive

The aim of this study was to investigate the influence of drug physicochemical properties on drug release behaviors and their relationship with skin permeation behaviors, which provided transdermal enhancement strategies for the design of transdermal drug delivery system. Six model drugs with different physicochemical properties were selected and hydroxyl pressure sensitive adhesive (PSA) was synthesized. Horizontal diffusion cell was used to evaluate drug release and skin permeation behaviors. The relationship between physicochemical properties and release behaviors was conducted with regression analysis. Release behavior of 0.25% drug loading was linear related with polar surface area, which represented the hydrogen bond. Release behavior of 2.0% drug loading was dependent on the polarizability and log P, which represented dipole-dipole interaction and lipophilicity, respectively. According to the results of Fourier transform infrared spectroscopy, it was inferred that hydrogen bond was limited in controlling release of drug due to the limited quantity of bonding site, thus dipole-dipole interaction and log P became dominate control factors. Combining the drug release study and drug skin permeation study, it was concluded that drugs with different physicochemical properties should be applied with different transdermal enhancement strategies, which was useful for the design of transdermal drug delivery system.