Tian Yin

Hydroxyethyl starch conjugates for improving the stability, pharmacokinetic behavior and antitumor activity of 10-hydroxy camptothecin

10-Hydroxy camptothecin (10-HCPT)-hydroxyethyl starch (HES) conjugates were prepared to improve the water solubility, prolong the half-life in plasma and increase the antitumor efficacy of 10-HCPT, and the structures of the conjugates were confirmed by NMR and infrared spectroscopy. The 10-HCPT conjugates showed good sustained release effect in phosphate-buffered saline (PBS), rat plasma and liver homogenate. Meanwhile, 10-HCPT-HES conjugates achieved much lower IC50 and higher cytotoxicity effects than the free 10-HCPT on Hep-3B and SMMC-7721 cell lines. The pharmacokinetics results of 10-HCPT-HES conjugates demonstrated that the biological half-life of 10-HCPT was increased from 10 min to 2.94 h and 3.76 h, respectively, in comparison with the commercial 10-HCPT injection. The pharmacodynamics results indicated that 10-HCPT-HES conjugate had a better antitumor efficiency against nude mouse with Hep-3B tumor than the commercial 10-HCPT injection, and the inhibition ratio of tumor was 78.3% and 31.5%, respectively, at the dose of 1.0 mg/kg. These findings suggest that 10-HCPT-HES conjugate is a promising drug delivery system providing improved long circulating effect, greater stability and better antitumor effect.

Modified PLGA–PEG–PLGA thermosensitive hydrogels with suitable thermosensitivity and properties for use in a drug delivery system

PLGA-PEG-PLGA (PPP) triblock copolymer is the most widely studied thermosensitive hydrogel owing to its non-toxic, biocompatible, biodegradable, and thermosensitive properties. PPP thermosensitive hydrogels are being investigated as in situ gels because, at a low temperature, PPP solutions with drugs can be injected at the target site, and converted into a gel without surgical procedures. To meet the requirements of different therapeutic applications, PPP hydrogels with different properties need to be synthesized. The adjustable properties include the sol-gel transition temperature, gel window width, retention time and drug release time. Furthermore, thermo- and pH-, thermo- and electro-, and thermo- and photo-dual sensitive hydrogels are needed for some special therapies. Thus, this review examines the methods of modification of PPP thermosensitive hydrogels used to obtain desired drug delivery systems with appropriate physicochemical and pharmaceutical properties.

Improved oral bioavailability of core-shell structured beads by redispersion of the shell-forming nanoparticles: preparation, characterization and in vivo studies.

In order to increase the dissolution rate and oral bioavailability of bifendate, coated beads with core-shell structure were prepared via a combination use of wet media milling method and bead layering process. Hydroxypropyl cellulose (HPC-SL) and sodium lauryl sulfate (SLS) were found to be the best pair to stabilize the nanosuspension during milling process. A 10:1 ratio of mixture of mannitol and SLS was chosen as most suitable coating matrix to maintain the redispersability of dried nanoparticles in the shell of beads. The mean particle size of the nanosuspension was 139 nm and the zeta potential was -20.2 mV. Nanoscale bifendate particles with a mean diameter of 360 nm could be generated when redispersing the prepared beads in water. The differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analysis indicated that the crystalline state of the drug was not changed. The stability test confirmed that coated beads showed no distinct difference in particle size and dissolution velocity during 6 month storage while liquid nanosuspension was stable no more than 3 weeks. Dissolution rate of coated beads was increased significantly compared with commercially available pills. Likewise, the Cmax and AUC (0→24) of nanosuspension based beads in beagle dogs were 2.40-fold and 1.66-fold greater than that of commercially available pills, respectively. The present work is a reliable approach to stabilize nanosuspension based product, and improve dissolution velocity and bioavailability of poor soluble drugs.

Simultaneous determination by LC-MS/MS of 25-methoxydammarane-3β,12β,20-triol epimers and active metabolites in rat plasma after intravenous administration.

Abstract 1. The pharmacokinetics of the 25-OCH3-PPD epimers and active metabolites in rat plasma after a single intravenous (i.v.) administration were studied by a rapid, selective and sensitive UPLC-MS/MS method. 2. Chromatographic separation was performed on an Acquity UPLC with Agela C18 column, and the solvents of 5 mM ammonium acetate (pH 7.8) – acetonitrile (65: 35, v/v) were used as mobile phase for elution. The quantification was performed with the transitions of m/z 493.5 → 475.5 for 20(R,S)-25-OCH3-PPD, m/z 479.5 → 461.5 for 20(R,S)-25-OH-PPD. The Lower Limit Of Quantitation (LLOQ) was 20.0 ng mL−1 for 20(R,S)-25-OCH3-PPD, 2.0 ng mL−1 for 20(R,S)-25-OH-PPD in the plasma samples assay. 3. The pharmacokinetic parameters of AUC, t1/2 and MRT had no difference between 20(R)- and (S)-25-OCH3-PPD, but S-epimer has a lower plasma clearance compared to the R-isomer. The active metabolite 20(S)-25-OH-PPD showed significantly higher AUC, MRT and a longer half-life than that of 20(R)-25-OH-PPD. These assay results are necessary for the evaluation of the pharmacokinetic behavior of 25-methoxydammarane-3β,12β,20-triol in vivo.

Improved tumor tissue penetration and tumor cell uptake achieved by delayed charge reversal nanoparticles

The high affinity of positively charged nanoparticles to biological interfaces makes them easily taken up by tumor cells but limits their tumor permeation due to non-specific electrostatic interactions. In this study, polyion complex coated nanoparticles with different charge reversal profiles were developed to study the influence of charge reversal profile on tumor penetration. The system was constructed by polyion complex coating using micelles composed of poly (lysine)-b-polycaprolactone (PLys-b-PCL) as the cationic core and poly (glutamic acid)-g- methoxyl poly (ethylene glycol) (PGlu-g-mPEG) as the anionic coating material. Manipulation of charge reversal profile was achieved by controlling the polymer chain entanglement and electrostatic interaction in the polyion complex layer through glutaraldehyde-induced shell-crosslinking. The delayed charge reversal nanoparticles (CTCL30) could maintain negatively charged in pH 6.5 PBS for at least 2h and exhibit pH-responsive cytotoxicity and cellular uptake in an extended time scale. Compared with a faster charge reversal counterpart (CTCL70) with similar pharmacokinetic profile, CTCL30 showed deeper penetration, higher in vivo tumor cell uptake and stronger antitumor activity in vivo (tumor inhibition rate: 72.3% vs 60.2%, compared with CTCL70). These results indicate that the delayed charge reversal strategy could improve therapeutic effect via facilitating tumor penetration. STATEMENT OF SIGNIFICANCE Here, the high tumor penetration capability of PEG-coated nanoparticles and the high cellular uptake of cationic nanoparticles were combined by a delayed charge reversal drug delivery system. This drug delivery system was composed of a drug-loading cationic inner core and a polyion complex coating. Manipulation of charge reversal profile was realized by varying the crosslinking degree of the shell of the cationic inner core, through which changed the strength of the polyion complex layer. Nanoparticles with delayed charge reversal profile exhibited improved tumor penetration, in vivo tumor cell uptake and in vivo tumor growth inhibition effect although they have similar pharmacokinetic and biodistribution behaviors with their instant charge reversal counterpart.

Dry state microcrystals stabilized by an HPMC film to improve the bioavailability of andrographolide

OBJECTIVE The main purpose of this study was to improve the in-vitro dissolution and the in-vivo bioavailability of a poorly water-soluble drug, andrographolide (ADG). METHODS A wet-milled suspension was prepared using a Lab basket mill in the presence of a hydrophilic carrier solution and then it was layered on to MCC beads with a fluidized bed coater to obtain solidified pellets. Optical microscopy, particle size distribution investigation, differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) were used to characterize the wet-milled suspension. In addition, the ADG pellets were subjected to investigations involving scanning electron microscopy (SEM), as well as dissolution, accelerated stability and bioavailability measurements. RESULTS The particle size was significantly reduced (from 31.6 μm to 2.17 μm), however, the ADG in suspension retained its crystallinity as shown by the results of the DSC and PXRD investigations. The dissolution of the new pellets and commercial dripping pills was 95.6% and 48%, respectively, in pure water over 60 min. After a 6 month accelerated test (40°C and RH 75%), although the initial dissolution rate declined slightly, the overall dissolution of the new pellets within 60 min was almost as high as the freshly prepared pellets. In the in-vivo evaluation, the Cmax (87.54 ± 54.82 μg/L) and AUC(0-t) of the new pellets (495.86 ± 281.05 μg/Lh) were clearly higher than those of the dripping pills (30.88 ± 12.02 μg/L, 301.07 ± 133.85 μg/Lh), while the Tmax of the test preparation was shorter than that of the reference (1.38 h vs 3.29 h). CONCLUSION These results showed that the new core-shell structured pellets consisting of ADG microcrystalline particles and stabilized by HPMC alone, markedly improved the dissolution and bioavailability of andrographolide.

Clarithromycin ion pair in a liposomal membrane to improve its stability and reduce its irritation caused by intravenous administration

ABSTRACT Objective: The aim of this study was to improve the drug loading (DL) and stability of clarithromycin (CLA)-loaded liposomes, and reduce the irritation caused by intravenous administration of CLA. Methods: A CLA–cholesteryl hemisuccinate (CHEMS) ion pair (CIP) was prepared by the solvent evaporation method and confirmed by fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance, differential scanning calorimetry and X-ray powder diffraction. Subsequently, CIP liposomes (CIP-Lip) were prepared by the thin-film dispersion method and evaluated in terms of their size, zeta-potential, in vitro release, stability, in vitro antimicrobial activity and irritation. Results: The CIP-Lip exhibited a homogeneous round shape, and their size, ζ-potential, encapsulation efficiency (EE) and DL were 71.89 ± 2.6 nm, −9.91 ± 0.82 mV, 95.1 ± 1.5% and 7.8 ± 0.3%, respectively. The physical appearance and drug content of CIP-Lip over a three-month storage remained almost unchanged. The release of CLA in CIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4. Although the in vitro antimicrobial activity of CIP-Lip was comparable with free CLA, the irritation produced by CIP-Lip was significantly reduced compared with CLA solution. Conclusions: These findings suggest that CIP-Lip is a promising intravenous drug delivery system, especially on account of its high DL and reduced irritation.

A parenteral docetaxel-loaded lipid microsphere with decreased 7-epidocetaxel conversion in vitro and in vivo

&NA; The purpose of the study was to develop a parenteral docetaxel lipid microsphere to inhibit its 7‐epidocetaxel conversion in vitro and in vivo. 7‐epidocetaxel conversion as the main indicator was investigated to optimize the formulation and process. 10% medium‐chain triglyceride/long‐chain triglyceride (3:1) as the oil phase, egg lecithin E80 as the emulsifier and 0.02% NaHSO3 as the acidity regulator were selected to prepare docetaxel lipid microsphere. This study found that pH and temperature were dominant factors on the epimerization of docetaxel in lipid microsphere, and that optimum conditions were a pH of 5.3 and thermal sterilization conditions of 121°Cautoclaving for 8 min. According to the degradation kinetics, docetaxel lipid microsphere had a wider pH range where 7‐epidocetaxel(%) stayed at low levels than Docetaxel for Injection, and might improve the docetaxel stability by loading drug in lecithin layer instead of altering the degradation mechanism. Docetaxel lipid microsphere decreased epimerization in plasma in vitro obviously. Pharmacokinetics of docetaxel and 7‐epidocetaxel were investigated to quantify the 7‐epidocetaxel conversion in vivo. The resulrs indicated that there was less conversion of docetaxel in lipid microspheres than in Docetaxel for Injection. The convert ratios were 0.61% and 3.04% respectively. In conclusion, lipid microsphere is a promising delivery system for intravenous administration of docetaxel with decreased 7‐epidocetaxel conversion. Graphical abstract Figure. No caption available.

Vincristine-loaded liposomes prepared by ion-paring techniques: Effect of lipid, pH and antioxidant on chemical stability

ABSTRACT In the present study, vincristine (VCR)‐loaded liposomes were designed by ion‐pairing techniques and the model could be applied to investigate the effect of lipids on the degradation of vinca alkaloids, and how to weaken their influence by adjusting pH and adding antioxidants. It was found that there was a positive correlation between degree of degradation and the unsaturation extent of the phospholipids. In the phospholipid with the lowest oxidation index, only 6% of VCR was degraded in 6 days at 37 °C, whereas for the phospholipids with highest oxidation index, the degradation reached above 95% over the same time. At pH 6.8 and 7.4, the degradation rate of VCR in the lipid membrane was significantly faster than that in aqueous solution, instead, at pH 5.0. After the addition of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tocopherol, ascorbate and tocopherol with ascorbate, the residual content of VCR after 6 days was 79.9%, 78.1%, 7.1%, 89.6% and 94.6% respectively. It was speculated that VCR could be oxidized by hydrated peroxyl radicals, which formed from lipid peroxidation as well as nucleophilic substitution with peroxyl radicals in the dry state. Also, the antioxidants were shown to have different eliminating capacity on the peroxyl radicals whether hydrated or not, and the phenoxyl radicals generated from fat‐soluble antioxidants may be potentially destabilizing to VCR. Therefore, for these two crucial reasons, the degradation of VCR was quite different when used with a combination of water and fat‐soluble antioxidants, and thus provides the best protection for VCR. &NA; Graphical abstract Figure. No Caption available.

Polyester–Solid Lipid Mixed Nanoparticles with Improved Stability in Gastro-Intestinal Tract Facilitated Oral Delivery of Larotaxel

The objective of this study was to investigate the role of core stability of nanoparticles on their performances in oral drug delivery. Solid lipids (Geleol Mono and Diglycerides Nf) were incorporated into nanoparticles composed of mPEG-b-PCL by the dialysis method. The prepared solid lipid loaded nanoparticles were found to be spherical nanoparticles with a core state and size distribution dependent on the amount of solid lipid incorporated. The critical aggregation concentrations of lipid-loaded nanoparticles were determined using pyrene fluorescence. Then, the stability of block copolymer in nanoparticles with different solid lipid contents was studied in simulated gastric fluid and simulated intestinal fluid. Solid lipids were found to stabilize nanoparticle cores by improving not only the thermodynamic stability (lowered CAC) of the nanoparticle but also the chemical stability of the block copolymer in the gastrointestinal environment. The stability of the loaded drug (larotaxel, LTX) in nanoparticles with different solid lipid contents was challenged by intestinal homogenate and rat liver microsome, and solid lipid loaded nanoparticles showed superior drug-protecting capability. Solid lipid incorporation exhibited limited influence on the cytotoxicity and cellular uptake but improved the transcytosis of nanoparticles in Caco-2 monolayers. The results of pharmacokinetic study indicated that core stabilization was helpful in promoting oral larotaxel absorption as the absolute bioavailability of LTX delivered by solid lipid loaded nanoparticles was found to be 13.17%, compared with that by the lipid-free nanoparticles (6.264%) and LTX solution (2.435%). Additionally, the results of biodistribution study indicated relatively higher particle integrity of solid lipid loaded nanoparticles, shown by slower liver and spleen accumulation rate, compared with its lipid-free counterpart. Overall, incorporation of solid lipids made the nanoparticles more suitable for oral drug delivery.