Cyclosporin A osmotic pump tablets which can form supersaturated micelles / 药学学报

The poor solubility of cyclosporine A (CsA) in water limits its oral absorption. We prepared CsA/ Soluplus/SDS complex, which can form CsA/Soluplus/SDS supersaturated micelles (CSS-SM) after hydration. Then, We further prepared CSS-SM osmotic pump tablets (CSS-SM-T). CSS-SM had a particle size of 156 nm, where in encapsulation efficiency and drug loading efficiency of CsA were 89.0% and 17.5%, respectively. CSS-SM-T achieved zero-level drug release in vitro. Pharmacokinetic data from Beagle dogs (all animal experiments were conducted under the guidelines approved by the Institutional Animal Care and Use Committee of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences) indicated that CsA in the ordinary osmotic pump tablets was hardly absorbed after orally administered; despite slightly lower bioavailability [relative bioavailability: (85.1 ± 47.4) %] than that of Sandimmum Neoral, CSS-SM-T displayed lower fluctuations in CsA plasma concentration and obvious sustained-release characteristics in vivo, implying lower toxicity. Therefore, CSS-SM-T provides a new research idea for the design and development of oral sustained- and controlled-release preparations of poorly water-soluble drugs.

Absorption-enhancing mechanisms and advances of polymer-based supersaturated drug delivery system / 药学学报

Supersaturated drug delivery systems (SDDS) are defined as systems that are able to generate and maintain a sustained drug supersaturation in the gastrointestinal tract, facilitating the oral absorption of drugs with poor water solubility. Supersaturated drug solution is generated from a higher energy form of the drug or rapid dissolution through various formulation options. However, supersaturated solution is a thermodynamically unstable system that can easily lead to drug precipitation, missing the aim of improving the absorption. Therefore, maintenance of the supersaturated state is essential for the development of SDDS. Polymer-based SDDS take polymers as the precipitation inhibitor,which can effectively prevent the precipitation of drugs, generating an excellent effect on maintenance of the stability of supersaturated solution. However, different polymers have distinct anti-precipitation ability, and the mechanisms of such activity supported by the polymer remain unrevealed. In this review, we summarize the research advances in the absorption-enhancing mechanisms and in vitro evaluations of polymers-based SDDS. This review provides a reference for the design of rational SDDS.

Ion-sensitive nanoemulsion-in situ gel system for ophthalmic delivery of flurbiprofen axetil / 药学学报

The aim of the study is to prepare flurbiprofen axetil nanoemulsion-in situ gel system (FBA/NE-ISG) and observe its ocular pharmacokinetics, rheological behavior, TEM images, irritation and cornea retention. Production of nanoemulsion was based on high-speed shear and homogenization process, and then mixed with gellan gum to prepare FBA/NE-ISG. Rheological study showed that FBA/NE-ISG possesses strong gelation capacity and its viscosity and elastic modulus increases by 2 Pa*s and 5 Pa respectively when mixed with artificial tear at the ratio of 40 : 7. TEM images suggested no significant changes in particle morphology of the pre and post gelation. Good ocular compatibility of FBA/NE-ISG was testified by the irritation test based on histological examination. In vivo fluorescence imaging system was applied to investigate the characteristics of cornea retention, and the results indicated that the nanoemulsion-in situ gel (NE-ISG) prolonged the cornea retention time significantly since K(NE-ISG) (0.008 5 min(-1) was much lower compared with flurbiprofen sodium eye drops (FB-Na, 0.03% w/v) of which the K(Eye drops) was 0.105 2 min(-1), indicated that the cornea retention time of NE-ISG was prolonged significantly. Pharmacokinetics of FBA/NE-ISG in rabbit aqueous humor was studied by cornea puncture, the MRT (12.3 h) and AUC(0-12h) (126.8 microg x min x mL(-1)) of FBA/NE-ISG was 2.7 and 2.9 times higher than that of the flurbiprofen sodium eye drops respectively, which meant that the ocular bioavailability was improved greatly by the novel preparation. Therefore, FBA/NE-ISG can enhance the ocular bioavailability by prolonging drug corneal retention significantly. What's more, encapsulated by emulsion droplets prodrug flurbiprofen (FBA) instead of flurbiprofen (FB) can reduce the ocular irritation.

Preparation of PEG-modified nanostructured lipid carriers loaded with hydroxycamptothecin and tissue distribution in mice / 药学学报

Hydroxycamptothecin (HCPT) loaded PEG modified nanostructured lipid carriers (HCPT-PEG-NLC) and nanostructured lipid carriers (HCPT-NLC) were prepared by melt emulsification and homogenization method. The morphology, particle size and encapsulation efficiency of them were investigated. HCPT concentrations in plasma, heart, liver, spleen, lung, kidney and ovary were determined after iv of HCPT injection, HCPT-PEG-NLC and HCPT-NLC in mice. The targeting indexes of HCPT-PEG-NLC and HCPT-NLC were calculated. The transmission electron microscope imaging showed that HCPT-PEG-NLC and HCPT-NLC exhibited a spherical shape. The particle sizes of them were (88.6 +/- 22.5) and (127.2 +/- 43.4) nm. The encapsulation efficiency were (90.51 +/- 3.29)% and (84.37 +/- 2.81)%, respectively. After iv injection into the tail vein of mice, HCPT plasma concentrations of HCPT-PEG-NLC and HCPT-NLC were higher than that of HCPT injection at each sampling time. They also showed longer elimination time in every tissue. HCPT-NLC accumulated in endothelial system (RES), Re and Ce of it in liver and spleen were significantly higher than HCPT-PEG-NLC. HPCT-PEG-NLC prolonged circulation time and increased bioavailability of HCPT. MRT and AUC0-24 h of it were 19.80 and 17.02 times higher than those of HCPT injection. It also significantly reduced phagocytosis of RES, and showed lung targeting effect (Re and Ce were 14.51 and 41.35). To summarize, HCPT-PEG-NLC could prolong the circulation time of HCPT in vivo, and had the lung targeting effect. It was a promising carrier to increase therapeutic effect of HCPT in treating lung cancer.

Preparation and in vitro corneal retention behavior of novel cationic microemulsion/in situ gel system / 药学学报

The aim was to prepare a novel ocular cationic microemulsion-in situ gel (CM-ISG) system with vitamin A palmitate (VAP) as model drug, and investigate the corneal retention behavior and corneal irritation of the system. VAP/CM was prepared by a process based on supply of energy, and the before-and-after gelation rheology of VAP/CM-ISG was investigated. In vitro VAP release and gel dissolution of both VAP/CM-ISG and Oculotect Gel was determined. And in vitro corneal retention behavior of both formulations was evaluated by captive bubble technique. Ocular irritation test was carried out based on the Draize method. Images of TEM showed that homogenous VAP/CM was made, and no significant differences of particle size were found between the VAP/CM and VAP/CM in Poloxamer 407 gel. Rheology study illustrated that VAP/CM reduced the phase transition temperature of Poloxamer 407 gel by 1.5 degrees C, and the elastic modulus increased about 15.7 times. The in vitro release and gel dissolution profile of both formulations exhibited the characteristics of zero order kinetics. Comparing with Oculotect Gel, desorption kinetics study of VAP/CM-ISG exhibited longer corneal retention time and smaller contact angle. Irritation test showed a good ocular compatibility of VAP/CM-ISG. Therefore, VAP/CM-ISG combined both advantages of the cationic microemulsion and in situ gel system, provided better wettability and longer ocular retention time. It might be a promising ocular drug delivery system.

Optimization and evaluation of a new antischistosomal drug QH917 self-microemulsifying drug delivery system / 药学学报

To screen a new poorly water-soluble antischistosomal drug QH917 self-microemulsifying drug delivery system which has steady release in vitro and absorption in situ separately. The formulation was optimized using central composite design-response surface methodology. Independent variables were oil content (%) and the weight ratio of surfactant and cosurfactant (Km), while response variables were self-microemulsifying time (t), mean particle size (PS) and polydispersity index (PI). The effects of ionic strength, food, pH, rotation speed and medium volume on drug release of the optimized formulation were evaluated under conditions simulating in vivo physiological situations. The absorption of the optimized formulation was studied using in situ intestinal permeability technique of rats. The optimized formulation was as follows: the content of media chain triglyceride (MCT) was 30%-34% (w/w); and the weight ratio of surfactant polyoxyl 40 hydrogenated castor oil (Cremophor RH40) and co-surfactant ethanol was 4.8-5.2. Release of QH917 from the optimized formulation was nearly unaffected by ionic strength, food, pH, rotation speed and medium volume. There was no marked difference of the absorption rate between rats with and without ligated bile duct in rat intestinal permeability technique. Inter-individual variability in absorption of the optimized formulation was negligible. Central composite design-response surface methodology is an efficient approach for optimizing formulations of self-microemulsifying drug delivery system; drug release in vitro and absorption behavior in situ of the optimized formulation is steady.