Jiabi Zhu

Self-assembled liquid crystalline nanoparticles as a novel ophthalmic delivery system for dexamethasone: Improving preocular retention and ocular bioavailability

The object of this study was to design novel self-assembled liquid crystalline nanoparticles (cubosomes) as an ophthalmic delivery system for dexamethasone (DEX) to improve its preocular retention and ocular bioavailability. DEX cubosome particles were produced by fragmenting a cubic crystalline phase of monoolein and water in the presence of stabilizer Poloxamer 407. Small angle X-ray diffraction (SAXR) profiles revealed its internal structure as Pn3m space group, indicating the diamond cubic phase. In vitro, the apparent permeability coefficient of DEX administered in cubosomes exhibited a 4.5-fold (F1) and 3.5-fold (F2) increase compared to that of Dex-Na phosphate eye drops. Preocular retention studies revealed that the retention of cubosomes was significantly longer than that of solution and carbopol gel, with AUC(0-->180min) of Rh B cubosomes being 2-3-fold higher than that of the other two formulations. In vivo pharmacokinetics in aqueous humor was evaluated by microdialysis, which indicated a 1.8-fold (F1) increase in AUC(0-->240min) of DEX administered in cubosomes relative to that of Dex-Na phosphate eye drops, with about an 8-fold increase compared to that of DEX suspension. Corneal cross-sections after incubation with DEX cubosomes demonstrated an unaffected corneal structure and tissue integrity, which indicated the good biocompatibility of DEX cubosomes. In conclusion, self-assembled liquid crystalline nanoparticles might represent a promising vehicle for effective ocular drug delivery.

Novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of lipophilic cyclosporine A: In vitro and in vivo results

The objective of the present study was to design a novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of a lipophilic drug, cyclosporine A (CsA). A CsA-loaded microemulsion was prepared using castor oil, Solutol HS 15 (surfactant), glycerol and water. This microemulsion was then dispersed in a Kelcogel solution to form the final microemulsion in situ electrolyte-triggered gelling system. In vitro, the viscosity of the CsA microemulsion Kelcogel system increased dramatically on dilution with artificial tear fluid and exhibited pseudo-plastic rheology. In vivo results revealed that the AUC(0-->32 h) of corneal CsA for the microemulsion Kelcogel system was approximately three-fold greater than for a CsA emulsion. Moreover, at 32 h after administration, CsA concentrations delivered by the microemulsion Kelcogel system remained at therapeutic levels in the cornea. This CsA microemulsion in situ electrolyte-triggered gelling system might provide an alternative approach to deliver prolonged precorneal residence time of CsA for preventing cornea allograft rejection.

Self-double-emulsifying drug delivery system (SDEDDS): A new way for oral delivery of drugs with high solubility and low permeability

Water-in-oil-in-water (w/o/w) double emulsions are potential for enhancing oral bioavailability of drugs with high solubility and low permeability, but their industrial application is limited due to the instability. Herein, we developed a novel formulation, self-double-emulsifying drug delivery systems (SDEDDS) by formulating mixtures of hydrophilic surfactants and water-in-oil (w/o) emulsions, which were easier to be stable through formulations optimization. SDEDDS can spontaneously emulsify to water-in-oil-in-water (w/o/w) double emulsions in the mixed aqueous gastrointestinal environment, with drugs encapsulated in the internal water phase of the double emulsions. We employed SDEDDS to improve the oral absorption of pidotimod, a peptide-like drug with high solubility and low permeability. The optimized pidotimod-SDEDDS were found to be stable up to 6 months under 25°C. Plasma concentration-time profiles from pharmacokinetic studies in rats dosed with SDEDDS showed 2.56-fold (p<0.05) increased absorption of pidotimod, compared to the pidotimod solution. Histopathologic studies confirmed that SDEDDS exerted absorption promoting effect without serious local damages. These studies demonstrate that SDEDDS may be a promising strategy for peroral delivery of peptide and peptidomimetic drugs.

Preparation and evaluation of glyceryl monooleate-coated hollow-bioadhesive microspheres for gastroretentive drug delivery.

The purpose of this study was to produce hollow and bioadhesive microspheres to lengthen drug retention time in the stomach. In these microspheres, ethylcellulose was used as the matrix, Eudragit EPO was employed to modulate the release rate, and glyceryl monooleate (GMO) was the bioadhesive polymer in situ. The morphological characteristics of the microspheres were defined using scanning electron microscopy. The in vitro release test showed that the release rate of drug from the microspheres was pH-dependent, and was not influenced by the GMO coating film. The prepared microspheres demonstrated strong mucoadhesive properties with good buoyancy both in vitro and in vivo. Pharmacokinetic analysis indicated that the elimination half-life time of the hollow-bioadhesive microspheres was prolonged, and that the elimination rate was decreased. In conclusion, the hollow-bioadhesive synergic drug delivery system may be advantageous in the treatment of stomach diseases.

Novel NSAIDs ophthalmic formulation: flurbiprofen axetil emulsion with low irritancy and improved anti-inflammation effect.

The aim of this study was to design and formulate a novel low-irritant NSAIDs ophthalmic emulsion of flurbiprofen axetil (FBA), the prodrug of flurbiprofen (FB). FBA ophthalmic emulsion (FBA-EM) was prepared by high-pressure homogenization with caster oil as oil phase and tween 80 as emulsifying agent. Results from the stability evaluation suggested the protect effect of oil droplets on the stability of FBA. Compared with FBA-oil solution, the AUC(0→10h) of FB in aqueous humor administered in FBA-EMs exhibited 6.7-fold (F2), 4.5-fold (F3) and 4.6-fold (F4) increase. With the increment of oil content, the MRT also prolonged, which of FBA-EM F2-F4 were 5.14 ± 2.23, 5.73 ± 3.35 and 8.71 ± 0.94 h, respectively. No significant difference was found between the ocular bioavailability of FBA-EM F2 and 0.03% FB-Na eye drops. Ocular irritation evaluation revealed that FBA-EM F2 had better ocular biocompatibility than 0.03% FB-Na eye drops, even though the FBA concentration was up to 0.1%. Intraocular anti-inflammation effect evaluation showed that FBA-EM F2 had a quite good anti-inflammation effect. In conclusion, FBA-EM F2 with elevated FBA concentration to be 0.1% might represent a promising NSAIDs ophthalmic emulsion with low irritancy and improved anti-inflammation effect.

Water-In-Oil-In-Water Double Emulsions: An Excellent Delivery System for Improving the Oral Bioavailability of Pidotimod in Rats

The aims of this study were to prepare fine pidotimod-containing water-in-oil-in-water (W/O/W) double emulsions and to investigate the possibility of those emulsions as a delivery system for promoting the oral bioavailability of pidotimod. A modified two-step emulsification procedure was applied to prepare the double emulsions using medium-chain triglyceride as the oil phase, Tween 80 as the hydrophilic emulsifier, and Span 80 alone or in combination with different amount of phospholipids as the lipophilic emulsifiers. A fine W/O/W emulsion, with the encapsulation efficiency of 82 ± 3.4%, mean oil-droplet diameter of 3.93 ± 0.25 μm, and viscosity of 36.4 ± 0.93 mPa · s at 25 °C and 300 s(-1), was stable for 1 month at 4 °C. In addition, the oral bioavailability of pidotimod in rats, after intragastric administration of W/O/W double emulsions, was significantly higher than that of pidotimod control solution. Moreover, the maximum uptake time was significantly prolonged, suggesting an extra absorption pathway for W/O/W emulsions: a lymphatic circulation pathway. Those results demonstrated that W/O/W emulsions could become a potential formulation for improving the oral bioavailability of poorly absorbable drugs and suggested an important technology platform for the oral administration of peptide and peptidomimetic drugs.