Shuangshuang Zhang

Pharmacokinetics and atherosclerotic lesions targeting effects of tanshinone IIA discoidal and spherical biomimetic high density lipoproteins

High density lipoproteins (HDL) have been successfully reconstructed to deliver a large number of lipophilic drugs. Here, discoidal and spherical recombinant HDL loaded with cardiovascular drug tanshinone IIA (TA) were constructed (TA-d-rHDL and TA-s-rHDL), respectively. And next their in vitro physiochemical and biomimetic properties were characterized. Furthermore, pharmacokinetics, atherosclerotic lesions targeting effects and antiatherogenic efficacies were elaborately performed and compared in atherosclerotic New Zealand White (NZW) rabbits. In vitro characterizations results showed that both TA-d-rHDL and TA-s-rHDL had nano-size diameter, high entrapment efficiency (EE) and drug-loading capacity (DL). Additionally, similar to their native counterparts, TA-d-rHDL maintained remodeling behaviors induced by lecithin cholesterol acyltransferase (LCAT), and TA leaked during remodeling behaviors. Pharmacokinetic studies manifested that both TA-d-rHDL and TA-s-rHDL markedly improved pharmacokinetic behaviors of TA in vivo. Ex vivo imaging demonstrated that both d-rHDL and s-rHDL bound more avidly to atherosclerotic lesions than to normal vessel walls, and s-rHDL had better targeting effect than d-rHDL. Pharmacodynamic tests illustrated that both TA-d-rHDL and TA-s-rHDL had much stronger antiatherogenic efficacies than conventional TA nanostructured lipid carriers (TA-NLC), TA liposomes (TA-L) and commercially available preparation Sulfotanshinone Sodium Injection (SSI). Moreover, TA-s-rHDL had more potent antiatherogenic efficacies than TA-d-rHDL. Collectively our studies indicated that rHDL could be exploited as potential delivery vehicles of TA targeting atherosclerotic lesions as well as synergistically improving efficacies, especially for s-rHDL.

Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets.

The present study aimed to develop and optimize the wax based floating sustained-release dispersion pellets for a weakly acidic hydrophilic drug protocatechuic acid to achieve prolonged gastric residence time and improved bioavailability. This low-density drug delivery system consisted of octadecanol/microcrystalline cellulose mixture matrix pellet cores prepared by extrusion-spheronization technique, coated with drug/ethyl cellulose 100cp solid dispersion using single-step fluid-bed coating method. The formulation-optimized pellets could maintain excellent floating state without lag time and sustain the drug release efficiently for 12h based on non-Fickian transport mechanism. Observed by SEM, the optimized pellet was the dispersion-layered spherical structure containing a compact inner core. DSC, XRD and FTIR analysis revealed drug was uniformly dispersed in the amorphous molecule form and had no significant physicochemical interactions with the polymer dispersion carrier. The stability study of the resultant pellets further proved the rationality and integrity of the developed formulation.

Enhanced dissolution and oral bioavailability of lurasidone hydrochloride nanosuspensions prepared by antisolvent precipitation–ultrasonication method

In order to improve the dissolution rate and oral bioavailability of lurasidone hydrochloride (LH), LH nanosuspensions (LH-NSP) were prepared by an antisolvent precipitation–ultrasonication method and characterized in this study. Three important formulation factors including the concentration of LH in the solvent, the amount of sodium dodecyl sulfonate (SDS) and poloxamer 188 (F68) in the antisolvent were optimized by the central composite design response surface methodology. Besides, the impacts of three important process parameters, namely the precipitation temperature, the power input and the duration of ultrasonication, on the particle size and polydispersity index (PDI) of LH-NSP were also investigated. The optimal values of these formulation factors were 0.21% (w/v) LH, 0.06% (w/v) SDS and 0.16% (w/v) F68, respectively, while for the process parameters, the precipitation temperature, power input and duration of ultrasonication were 5 °C, 100 W and 10 min, respectively. The particle size and PDI of the optimized LH-NSP were 124.6 ± 11.9 nm and 0.097 ± 0.0024, respectively. There was no crystalline change in the LH-NSP compared with LH raw material on the basis of powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) analysis results. With the reduced particle size, the solubility and in vitro dissolution rate of LH in the LH-NSP were significantly improved. Pharmacokinetic studies showed that the Cmax and AUC0–24 of the group with oral administration of the LH-NSP were both 1.5 times higher than that of raw LH.

Development of cryptotanshinone-loaded pellets for angina chronotherapy: In vitro/in vivo prediction and evaluation

The clinical manifestations of variant angina is unevenly distributed during the 24 h, thus the in vivo performance of drugs should be tailored according to the angina circadian rhythm. Cryptotanshinone (CTN) is one of the representative bioactive lipid-soluble components of Danshen which has been commonly used for cardiovascular diseases such as angina pectoris. The aim of this study was to develop a novel CTN sustained-released pellets (CTN-SRPs) to precisely synchronize the CTN plasma concentrations with predicted occurrence of angina pectoris for angina chronotherapy. A deconvolution-based method was applied to develop and optimize the CTN-SRPs. The plasma concentration-time curve of CTN immediate-released formulation after oral administration in rats was used as the weight function. The predicted plasma concentration-time curve of CTN-SRPs simulated according to the incidence of variant angina during 24 h was used as the response function. Then the desired drug release profile of CTN-SRPs was calculated based on deconvolution using weight function and response function, and subsequently used for guiding the formulation optimization. CTN-SRPs were prepared with the combinations of PVP, poloxamer 127 and EC as matrix using fluidized bed technology. An orthogonal design was employed to obtain the optimal formulation with its release profile similar with the desired one. Pharmacokinetic studies validated that the actual plasma concentration-time curve of these optimized CTN-SRPs was similar with the predicted one. In addition, the percent errors (%PE) of CTN plasma concentrations in 8–12 h were less than 10%. In conclusion, this deconvolution-based method could be applied to adjust the in vivo performance of drugs for angina chronotherapy.

Tanshinol sustained-release pellets with absorption enhancer: optimization, characterization, pharmacokinetics and pharmacodynamics.

Abstract The objective of this study was to develop tanshinol sustained-release pellets (TS–SRPs) for the treatment of angina. Considering the poor intestinal absorption of TS, sodium caprate (SC) was used as an absorption enhancer for bioavailability improvement. Single-pass intestinal perfusion in rats demonstrated that the permeability of TS was remarkably enhanced, when the weight ratio of TS to SC was 1:3. Then, the cores were prepared with TS, SC and MCC at a weight ratio of 1:3:16 via extrusion–spheronization, followed by coating with Eudragit® RS30D/RL30D dispersion (9:1, w/w). In vitro release studies revealed that release methods and rotation rates had no significant effects on the drug release of optimized TS–SC–SRPs except for the dissolution media. The release behavior was characterized as non-Fick diffusion mechanism. The pellets possessed a dispersion-layered spherical structure and were stable during three months of storage at 40 °C/75% RH. Compared with TS immediate-release pellets, the AUC0–24 in healthy rabbits was increased by 1.97-fold with prolonged MRT (p < .05). Pharmacodynamic studies in rabbits with angina showed that the optimized TS–SC–SRPs had a steady and improved efficacy with synchronous drug concentration–efficacy. Consequently, preparation of sustained-release pellets with absorption enhancer provides a potential strategy to prolong the release and enhance the efficacy for hydrophilic drugs with poor intestinal absorption.

Development of protocatechualdehyde proliposomes-based sustained-release pellets with improved bioavailability and desired pharmacokinetic behavior for angina chronotherapy.

The present study was aimed to develope a proliposomal formulation to decrease the hepatic first-pass metabolism of protocatechualdehyde (PD), followed by pellet coating to modify the drug release for angina chronotherapy. PD proliposomes were prepared by depositing PD-phospholipid complex on mannitol powders to improve the drug encapsulation. Afterwards, the PD proliposomes were prepared into pellet cores via extrusion-spheronization using 10% κ-carrageenan as pelletization aid prior to the development of PD sustained-release pellets (PD-SRPs). Eudragit® NE 30D was chosen as coating material and the desired drug release profile of PD-SRPs was calculated for formulation optimization by deconvolution based on the circadian rhythm of variant angina. A high similarity factor (f2=85.72) was achieved when the coating weight was 30% and the sustained release behavior also prevented the destruction of liposomes by gastric fluids. Pharmacokinetic studies revealed a basically consistent trend between the actual and the predicted plasma concentration-time curve with absolute percent errors (%PE) of concentrations <10% in 2-12h. Meanwhile, a relative bioavailability of 200% was achieved compared with pure PD. Therefore, the development of proliposomes-based PD-SRPs was an effective strategy to provide both improved oral bioavailability and desired drug plasma concentration-time course for angina chronotherapy.

Suppression of Remodeling Behaviors with Arachidonic Acid Modification for Enhanced in vivo Antiatherogenic Efficacies of Lovastatin-loaded Discoidal Recombinant High Density Lipoprotein.

ABSTRACTPurposeA series of in vitro evaluation in our previous studies had proved that arachidonic acid (AA) modification could suppress the remodeling behaviors of lovastatin-loaded discoidal reconstituted high density lipoprotein (LT-d-rHDL) by restraining the reactivity with lecithin cholesterol acyltransferase (LCAT) for reducing undesired drug leakage. This study focuses on the investigation of AA-modified LT-d-rHDL (AA-LT-d-rHDL) in atherosclerotic New Zealand White (NZW) rabbit models to explore whether AA modification could enhance drug targeting delivery and improve antiatherogenic efficacies in vivo.MethodsAfter pharmacokinetics of AA-LT-d-rHDL modified with different AA amount were investigated in atherosclerotic NZW rabbits, atherosclerotic lesions targeting property was assessed by ex vivo imaging of aortic tree and drug distribution. Furthermore, their antiatherogenic efficacies were elaborately evaluated and compared by typical biochemical indices.ResultsWith AA modification amount augmenting, circulation time of AA-LT-d-rHDL was prolonged, and drug accumulation in the target locus was increased, eventually the significant appreciation in antiatherogenic efficacies were further supported by lower level of bad cholesterol, decreased atherosclerotic lesions areas and mean intima-media thickness (MIT), markedly attenuated matrix metalloproteinase-9 (MMP-9) protein expression and macrophage infiltration.ConclusionThis proof-of-concept study demonstrated that AA-LT-d-rHDL could enhance drug accumulation in atherosclerotic lesion and impede atherosclerosis progression more effectively.