Zhe Li

Ethyl oleate-containing nanostructured lipid carriers improve oral bioavailability of trans-ferulic acid ascompared with conventional solid lipid nanoparticles.

trans-Ferulic acid (TFA) has antioxidative, anti-inflammatory, and cardioprotective effects, but its poor solubility in water results in unsatisfactory oral bioavailability when administered conventionally at a standard dosage. However, the limited bioavailability of TFA can be overcome by delivering it in nanostructured lipid carriers (NLCs). In this study, a microemulsion (ME)-based method was used to prepare NLCs with ethyl oleate as the liquid lipid component and glyceryl behenate as the solid lipid component. These NLCs and solid lipid nanoparticles (SLNs) were then used as vehicles for TFA. Their entrapment efficiencies (EE), stability during storage, in vitro release profiles, and in vivo pharmacokinetics were compared. The NLC formulation afforded a drug entrapment efficiency that was significantly greater than that of the SLN formulation, which was made using a single solid lipid. Furthermore, the TFA that was dispersed in the disordered binary lipid matrix of the NLC formulation was more stable than that in the SLN formulation, and thus showed less expulsion from the vehicle during storage. In in vivo pharmacokinetic studies, the NLC TFA formulation yielded a greater Cmax and AUC than that produced by the SLN formulation and an aqueous TFA suspension. This showed that the oral bioavailability of TFA was markedly improved by packaging in NLCs. NLCs are thus a promising vehicle for oral TFA administration, with significant advantages over SLNs.

Composite particles based on particle engineering for direct compaction

Direct compaction (DC) is the preferred method for tablet production. However, only a minority of the active pharmaceutical ingredients (APIs) can be truly manufactured into tablets by DC so far due to that most of APIs lack sufficient functional properties required for DC. Particle engineering with co-processing provides a promising way to obtain various composite API and/or excipient particles with markedly improved functional properties, which makes successful tableting of them by DC possible. This review, as an informative update and supplement, covers the improvement of functional properties of composite API and/or excipient particles via co-processing based on recent developments and researches in the area of particle engineering for DC. The improved functionality of co-processed particles and corresponding mechanisms were summarized and discussed from the perspective of structure characteristics (Crystal level and Particle level) as the properties of particles are markedly affected by their structure.

Direct compaction: An update of materials, trouble-shooting, and application

Direct compaction (DC) is the preferred choice for tablet manufacturing; however, only less than 20% of active pharmaceutical ingredients could be compacted via DC as its high requirement for functional properties of materials. Materials with improper functionalities could lead to serious troubles during DC manufacturing, such as content non-uniformity, sticking, and capping, all of which profoundly affect the properties of final products and, thus, severely restrict the practical application of DC. With undoubted importance, these seem to be unexpectedly ignored by reviewers but not researchers in terms of many original research articles published recently. Therefore, as an informative supplement and update, this review mainly focused on trouble-shooting and application situation of DC, together with several newly reported materials.

Co-delivery of evodiamine and rutaecarpine in a microemulsion-based hyaluronic acid hydrogel for enhanced analgesic effects on mouse pain models

The aim of this study was to improve the analgesic effect of evodiamine and rutaecarpine, using a microemulsion-based hydrogel (ME-Gel) as the transdermal co-delivery vehicle, and to assess hyaluronic acid as a hydrogel matrix for microemulsion entrapment. A microemulsion was formulated with ethyl oleate as the oil core to improve the solubility of the alkaloids and was loaded into a hyaluronic acid-structured hydrogel. Permeation-enhancing effects of the microemulsion enabled evodiamine and rutaecarpine in ME-Gel to achieve 2.60- and 2.59-fold higher transdermal fluxes compared with hydrogel control (p<0.01). The hyaluronic acid hydrogel-containing microemulsion exhibited good skin biocompatibility, whereas effective ME-Gel co-delivery of evodiamine and rutaecarpine through the skin enhanced the analgesic effect in mouse pain models compared with hydrogel. Notably, evodiamine and rutaecarpine administered using ME-Gel effectively down-regulated serum levels of prostaglandin E2, interleukin 6, and tumor necrosis factor α in formaldehyde-induced mouse pain models, possibly reflecting the improved transdermal permeability of ME-Gel co-delivered evodiamine and rutaecarpine, particularly with hyaluronic acid as the hydrogel matrix.

Essential oil-mediated glycerosomes increase transdermal paeoniflorin delivery: optimization, characterization, and evaluation in vitro and in vivo

In this study, a novel glycerosome carrier containing essential oils was prepared for topical administration of paeoniflorin (PF) to enhance its transdermal drug delivery and improve drug absorption in the synovium. The formulation of glycerosomes was optimized by a uniform design, and the final vehicle was composed of 5% (w/v) phospholipid, 0.6% (w/v) cholesterol, and 10% (v/v) glycerol, with 2% (v/v) Speranskia tuberculata essential oil (STO) as the transdermal enhancer. The in vitro transdermal flux of PF loaded in the STO-glycerosomes was 1.4-fold, 1.6-fold, and 1.7-fold higher than those of glycerosomes, liposomes, and tinctures, respectively. In vivo studies showed that the use of STO-glycerosomes was associated with a 3.1-fold greater accumulation of PF in the synovium than that of common glycerosomes. This finding was confirmed by in vivo imaging studies, which found that the fluorescence intensity of Cy5.5-loaded STO-glycerosomes in mice knee joints was 1.8-fold higher than that of the common glycerosomes 5 h after administration. The glycerosomes mediated by STO exhibited considerable skin permeability as well as improved drug absorption in the synovium, indicating that STO-glycerosomes may be a potential PF transdermal delivery vehicle for the treatment of rheumatoid arthritis caused by synovium lesions.

Microneedle-mediated transdermal delivery of nanostructured lipid carriers for alkaloids from Aconitum sinomontanum

Abstract A combination method using microneedle (MN) pretreatment and nanostructured lipid carriers (NLCs) was developed to improve the transdermal delivery of therapeutics. The MN treatment of the skin and co-administration of NLCs loaded with total alkaloids isolated from Aconitum sinomontanum (AAS–NLCs) significantly increased the skin permeation of the drugs. Fluorescence imaging confirmed that MNs could provide microchannels penetrating the stratum corneum, and delivery of NLCs through the channels led to their deeper permeation. In vivo studies showed that combination of AAS–NLCs with MNs (AAS–NLCs–MN) in transdermal delivery could improve the bioavailability and maintain stable drug concentrations in the blood. Moreover, AAS–NLCs–MN showed benefits in eliminating paw swelling, decreasing inflammation and pain, and regulating immune function in adjuvant arthritis rats. After administration of AAS–NLCs–MN, no skin irritation was observed in rabbits, and electrocardiograms of rats showed improved arrhythmia. These results indicated that the dual approach combining MN insertion and NLCs has the potential to provide safe transdermal delivery and to improve the therapeutic efficacy through sustained release of AAS.

Chitosan-functionalized lipid-polymer hybrid nanoparticles for oral delivery of silymarin and enhanced lipid-lowering effect in NAFLD

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a chronic disease that causes excessive hepatic lipid accumulation. Reducing hepatic lipid deposition is a key issue in treatment and inhibition of NAFLD evolution. Silymarin is a potent hepatoprotective agent; however, it has low oral bioavailability due to its poor aqueous solubility and low membrane permeability. Unfortunately, few studies have addressed the development of convenient oral nanocarriers that can efficiently deliver silymarin to the liver and enhance its lipid-lowering effect. We designed silymarin-loaded lipid polymer hybrid nanoparticles containing chitosan (CS-LPNs) to improve silymarin bioavailability and evaluated their lipid-lowering effect in adiponutrin/patatin-like phospholipase-3 I148M transgenic mice, an NAFLD model.ResultsCompared to chitosan-free nanoparticles, CS-LPNs showed 1.92-fold higher uptake by fatty liver cells. Additionally, CS-LPNs significantly reduced TG levels in fatty liver cells in an in vitro lipid deposition assay, suggesting their potential lipid-lowering effects. The oral bioavailability of silymarin from CS-LPNs was 14.38-fold higher than that from suspensions in rats. Moreover, compared with chitosan-free nanoparticles, CS-LPNs effectively reduced blood lipid levels (TG), improved liver function (AST and ALT), and reduced lipid accumulation in the livers of mice in vivo. Reduced macrovesicular steatosis in pathological tissue after CS-LPN treatment indicated their protective effect against liver steatosis in NAFLD.ConclusionsCS-LPNs enhanced oral delivery of silymarin and exhibited a desirable lipid-lowering effect in a mouse model. These findings suggest that CS-LPNs may be a promising oral nanocarrier for NAFLD therapeutics.

Improved oral bioavailability of notoginsenoside R1 with sodium glycocholate-mediated liposomes: Preparation by supercritical fluid technology and evaluation in vitro and in vivo

&NA; Schematic diagram of a process for preparing bile salt liposomes by ISCRPE method to increase oral bioavailability. ABSTRACT The chief objective of this research was to appraise liposomes embodying a bile salt, sodium glycocholate (SGC), as oral nanoscale drug delivery system to strengthen the bioavailability of a water‐soluble and weakly penetrable pharmaceutical, notoginsenoside R1 (NGR1). NGR1‐loaded liposomes were prepared with the improved supercritical reverse evaporation (ISCRPE) method and the preparation conditions were optimized with response surface methodology (RSM). The mean encapsulation efficiency (EE), particle size, and polydispersity index (PDI) of the optimized liposomal formulation (NGR1@Liposomes) were 49.49%, 308.3nm, and 0.229, respectively. SGC‐mediated liposomes (NGR1@SGC‐Liposomes) were formulated based on the optimal preparation conditions and the mean EE, particle size, and PDI were 41.51%, 200.1nm, and 0.130, respectively. The in vitro Caco‐2 cellular uptake of fluorescent marker was increased by loading into NGR1@SGC‐Liposomes as compared with the conventional liposomes. Furthermore, the intestinal permeability as well as the intestinal absorption of NGR1 were both significantly improved with NGR1@SGC‐Liposomes as the nanovesicles. The in vivo pharmacokinetic study results showed that AUC0‐t value of NGR1@SGC‐Liposomes and NGR1@Liposomes was 2.68‐ and 2.03‐fold higher than that of NGR1 aqueous solution, respectively. The AUC0‐t of the NGR1@SGC‐Liposomes group was significantly higher than that of NGR1@Liposomes. Thus, ISCRPE method is a feasible method for the preparation of water‐soluble drug‐loaded liposomes and bile salt‐mediated liposomes may enhance the oral absorption of water‐soluble and poorly permeable drugs.

DOC-LS, a new liposome for dermal delivery, and its endocytosis by HaCaT and CCC-ESF-1 cells

The main objective of this work was to investigate the uptake channels of skin cells through which coumarin 6, transported by deoxycholate-mediated liposomes (DOC-LS), was internalised; this was also compared against the action of conventional LS. Coumarin 6-loaded DOC-LS and LS were characterised for size distribution, zeta potential, and shape, and analysed in vitro in human epidermal immortal keratinocyte (HaCaT) (epidermal) and human embryonic skin fibroblast (CCC-ESF-1) (dermal) cell lines. Various endocytosis inhibitors were incubated with cells treated with the nanocarriers. Flow cytometry results indicated that HaCaT and CCC-ESF-1 cells internalise the tested preparations through pinocytotic vesicles, macropinocytosis, clathrin-mediated endocytic pathways, and via lysosomes, which consume a considerable amount of energy. The endocytosis pathways of DOC-LS and LS showed no difference. This study provides a basis for the application of LS being combined with a microneedle system for efficient intracellular drug delivery, targeting cutaneous histocyte disorders.

Biotinylated-lipid bilayer coated mesoporous silica nanoparticles for improving the bioavailability and anti-leukaemia activity of Tanshinone IIA

Abstract The oral bioavailability and anti-leukaemia activity of Tanshinone IIA (TanIIA) were enhanced by using biotinylated-lipid bilayer coated mesoporous silica nanoparticles (Bio-LB-MSNs) as a vehicle. The in vitro release of TanIIA from TanIIA@MSNs was significantly higher than that of the TanIIA powder (pu2009<u2009.05). The in vitro cellular uptake of TanIIA by Caco-2 was increased by loading drug into the Bio-LB-MSNs more than those of the compared nanovehicles without biotin modification. The apparent in situ permeability coefficient (Papp) of TanIIA@Bio-LB-MSNs showed nearly 2.5-, 1.6- and 1.3-fold improvement compared with the TanIIA powder, TanIIA@MSNs and TanIIA@LB-MSNs. Following oral administration of TanIIA@Bio-LB-MSNs in rats, the area under the plasma concentration–time curves (AUC) of TanIIA was 3.4-, 1.9- and 2.4-fold larger than those in the groups received a pure TanIIA powder, TanIIA@MSNs or TanIIA@LB-MSNs, indicating that drug bioavailability was enhanced by using MSNs as a vehicle, and further improved significantly through biotin modification. The in vitro anti-leukaemia activity of TanIIA was also enhanced after being loaded into nanoparticles and modification, with 50% inhibitive concentration (IC50) of NB4 cells at 6.5u2009μM for TanIIA@Bio-LB-MSN. In conclusion, Bio-LB-MSNs are a promising vehicle to improve the oral bioavailability and anti-leukaemia activity of the poorly water-soluble drug TanIIA.