Hongyu Piao

Preparation of stable nitrendipine nanosuspensions using the precipitation–ultrasonication method for enhancement of dissolution and oral bioavailability

The aim of this study was to prepare and characterize nitrendipine nanosuspensions to enhance the dissolution rate and oral bioavailability of this drug. Nanosuspensions were prepared by the precipitation-ultrasonication method. The effects of five important process parameters, i.e. the concentration of PVA in the anti-solvent, the concentration of nitrendipine in the organic phase, the precipitation temperature, the power input and the time length of ultrasonication on the particle size of nanosuspensions were investigated systematically, and the optimal values were 0.15%, 30 mg/ml, below 3 degrees C, 400 W and 15 min, respectively. The particle size and zeta potential of nanocrystals were 209 nm (+/- 9 nm) and -13.9 mV (+/-1.9 mV), respectively. The morphology of nanocrystals was found to be flaky in shape by scanning electron microscopy (SEM) observation. The X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) analysis indicated that there was no substantial crystalline change in the nanocrystals compared with raw crystals. The in vitro dissolution rate of nitrendipine was significantly increased by reducing the particle size. The in vivo test demonstrated that the C(max) and AUC(0-->12) values of nanosuspension in rats were approximately 6.1-fold and 5.0-fold greater than that of commercial tablets, respectively.

A solid-in-oil nanodispersion for transcutaneous protein delivery.

Transcutaneous delivery attracts much attention but remains a challenging strategy for hydrophilic macromolecular drug administration. In the present study, we demonstrated that a solid-in-oil (S/O) nanodispersion, an oil-based nanodispersion of hydrophilic drugs, effectively enhanced the permeation of proteins into the skin. All of the different model proteins, FITC-labeled insulin (MW ca. 6 kDa), enhanced green fluorescent protein (EGFP, MW ca. 27 kDa) and horseradish peroxidase (HRP, MW ca. 40 kDa), permeated through the stratum corneum of Yucatan micropig skin in vitro by forming a S/O nanodispersion. The penetrated EGFP and HRP exhibited green fluorescence and catalytic activity, respectively, suggesting that these proteins can permeate into the skin in a functional form. The results indicated the potential utility of the S/O nanodispersion as a novel vehicle for transcutaneous protein delivery.

α-Tocopherol succinate-modified chitosan as a micellar delivery system for paclitaxel: Preparation, characterization and in vitro/in vivo evaluations

α-Tocopherol succinate hydrophobically modified chitosan (CS-TOS) containing 17 α-tocopherol groups per 100 anhydroglucose units was synthesized by coupling reaction. The formation of CS-TOS was confirmed by (1)H NMR and FT-IR analysis. In aqueous medium, the polymer could self-aggregate to form micelles, and the critical micelle concentration (CMC) was determined to be 5.8 × 10(-3) mg/ml. Transmission electron microscopy (TEM) observation revealed that both bare and paclitaxel-loaded micelles were near spherical in shape. The mean particle size and zeta potential of drug-loaded micelles were about 78 nm and +25.7 mV, respectively. The results of DSC and XRD analysis indicated that paclitaxel was entrapped in the micelles in molecular or amorphous state. In vitro cytotoxicity and hemolysis study revealed the effectiveness and safety of this delivery system, which was further confirmed by the in vivo antitumor evaluations. It can be concluded that the CS-TOS was a potential micellar carrier for paclitaxel.

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.

Preparation of a solid-in-oil nanosuspension containing L-ascorbic acid as a novel long-term stable topical formulation.

L-Ascorbic acid (AA, vitamin C) easily decomposes into inactive compounds in aqueous solutions and this has limited its topical use. This work reports the preparation of a solid-in-oil nanosuspension (SONS) containing AA and validation of its basic storage stability. Although AA itself is water-soluble, it can readily be nanosuspended in squalane via complex formation involving a combination of sucrose erucate (i.e. lipophilic surfactant) and sucrose monolaureate (i.e. hydrophilic surfactant) to yield SONS with a very low moisture content (<500 ppm). To extract encapsulated AA, a lipase-based enzymatic degradation technique was used to degrade a formulation phase making it easier for AA to distribute into an extraction solution. Our results demonstrate that almost all the encapsulated AA (95.3%) was readily extracted from the SONS upon addition of medium-chain triglyceride, which offers the possibility of degrading the formulation phase using lipase. Finally, its storage stability study was investigated at 25°C over 90 days under protection from light. An aqueous solution containing AA was used as a control. Compared with the control, the SONS markedly increased the stability of AA due to its low moisture content and, thus, the potential usefulness SONSs as a novel long-term stable topical formulation of AA has been proved.

Characterization and Pharmacokinetic Study of Aprepitant Solid Dispersions with Soluplus

Solid dispersions are a useful approach to improve the dissolution rate and bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). The aim of this study was to improve the physicochemical properties and bioavailability of a poorly water-soluble aprepitant by preparation of solid dispersions. The solid dispersions were characterized by dissolution, FTIR, XRPD, DSC, SEM and pharmacokinetic studies in rats. The dissolution rate of the aprepitant was significantly increased by solid dispersions, and XRD, DSC, and SEM analysis indicated that the aprepitant existed in an amorphous form within the solid dispersions. The result of dissolution study showed that the dissolution rate of SDs was nearly five-fold faster than aprepitant. FTIR spectrometry suggested the presence of intermolecular hydrogen bonds between the aprepitant and polymer. Pharmacokinetic studies in rats indicated that the degree drug absorption was comparable with that of Emend®. Aprepitant exists in an amorphous state in solid dispersions and the solid dispersions can markedly improve the dissolution and oral bioavailability of the aprepitant. The AUC0–t of the SDs was 2.4-fold that of the aprepitant. In addition, the method and its associated techniques are very easy to carry out.

Reduction of Gastric Ulcerogenicity During Multiple Administration of Diclofenac Sodium by a Novel Solid-in-Oil Suspension

This article reports a significant reduction of gastric ulcerogenicity by complex formation of a nonsteroidal anti-inflammatory drug with surfactants. Diclofenac sodium (DFNa) was suspended in medium chain triglyceride (MCT) by forming a complex with an edible lipophilic surfactant. Two types of suspensions, prepared through a membrane emulsification with different pore sizes, were evaluated according to the degree of gastric damage following multiple oral administration in rats. It was shown that gastric ulcerogenicity of DFNa was reduced by the surfactant–drug complexes, at doses up to 12 mg/kg, whereas severe gastric damage was observed upon oral administration of the aqueous solution at doses of 6 mg/kg. Comparable blood levels of DFNa were observed after administration of solution and suspension formulations.

Development of an osmotically-driven pellet coated with acrylic copolymers (Eudragit® RS 30 D) for the sustained release of oxymatrine, a freely water soluble drug used to treat stress ulcers (I): in vitro and in vivo evaluation in rabbits

Purpose: To develop an osmotically-driven pellet coated with polymeric film for sustained release of oxymatrine (OMT), a freely water soluble drug. Methods: Pellet containing OMT and sodium chloride (NaCl), an osmotically active agent, were prepared by extrusion/spheronization and then coated with acrylic copolymers (Eudragit® RS 30 D) by the fluidized bed coating process. In vitro release and swelling behavior studies were employed to optimize and to evaluate the sustained-release behavior from the osmotically-driven pellets with film coated. Finally, in vivo evaluation in rabbits was employed to investigate the sustained plasma level of OMT and its active metabolite matrine. Results: It was found that the F3 formulation, prepared with 20% NaCl and an 8% coating level, showed a continuous NaCl-induced water influx into the pellets providing a gradual sustained release of OMT for over 12 h. Finally, we confirmed that oral OMT with sustained release led to a gradual sustained plasma profile of both OMT, with a reduction in its bioavailability, and MT with an increase in the bioavailability compared with that of oral OMT with immediate release. Conclusions: The pharmaceutical parameters obtained suggested the potential usefulness of oral OMT with sustained release for the treatment of stress ulcers, as well as reducing the risk of MT-induced side effects.

Polymer-Mediated Anti-solvent Crystallization of Nitrendipine: Monodispersed Spherical Crystals and Growth Mechanism

ABSTRACTPurposeTo investigate anti-solvent crystallization and growth mechanism of nitrendipine spherical crystals in an aqueous solution containing polymeric additives.MethodsSize and shape of crystals were investigated using laser diffractometry, optical microscopy and scanning electron microscopy (SEM). Crystalline form was determined by X-ray powder diffractometer (XRPD). During crystal growth, morphological changes at different time points were observed using SEM.ResultsMorphology of nitrendipine crystals was affected by polymers and temperature. Monodispersed micro-spherical crystals were obtained when polyvinyl alcohol (PVA) and PEG 200 were present in crystallization medium at 2°C. During crystallization, large number of amorphous nanoparticles was first observed, followed by aggregation into a core for spherical crystals. Once crystalline state was achieved, rapid growth on core surface was observed with amorphous particles acting as a reservoir allowing formation of star-like particles with needle-like subunits. Spherical crystals were formed by filling the gap between needle-like distinct crystalline units of star-like templates with molecules from dissolved amorphous particles.ConclusionsMonodispersed nitrendipine spherical crystals were obtained using carefully controlled conditions. A mechanism for the nitrendipine spherical crystal growth is suggested. These findings provide a new insight into spherulitic crystallization of active pharmaceutical ingredients.