Preparation of Curcumin-Eudragit® E PO Solid Dispersions with Gradient Temperature through Hot-Melt Extrusion.

Hot-melt extrusion (HME) has great advantages for the preparation of solid dispersion (SD), for instance, it does not require any organic solvents. Nevertheless, its application to high-melting-point and thermosensitive drugs has been rarely reported. In this study, thermally unstable curcumin (Cur) was used as a drug model. The HME process was systematically studied by adjusting the gradient temperature mode and residence time, with the content, crystallinity and dissolution of Cur as the investigated factors. The effects of barrel temperature, screw speed and cooling rate on HME were also examined. Solubility parameters and the Flory-Huggins method were used to evaluate the miscibility between Cur and carriers. Differential scanning calorimetry, X-ray diffraction, Fourier transform infrared spectroscopy, equilibrium solubility and in vitro and in vivo experiments were used to characterize and evaluate the results. An amorphous Cur SD was successfully obtained, increasing the solubility and release of Cur. In the optimal process, the mass ratio of Cur to Eudragit® E PO (EPO) was 1:4 and the barrel temperature was set at a gradient heating mode (130 °C-135 °C-140 °C-145 °C-150 °C-155 °C-160 °C) at 100 rpm. Related pharmacokinetic test results also showed the improved bioavailability of the drug in rats. In a pharmacodynamic analysis of Sprague-Dawley rats, the Cmax and the bioavailability of the Cur-EPO SD were 2.6 and 1.5 times higher than those of Cur, respectively. The preparation of the amorphous SD not only provided more solubility but also improved the bioavailability of Cur, which provides an effective way to improve the bioavailability of BCS II drugs.

Optimization of the Preparation Conditions of Borneol-Modified Ginkgolide Liposomes by Response Surface Methodology and Study of Their Blood Brain Barrier Permeability.

Ginkgolides (GG), containing ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC), are mainly prescribed for ischemic stroke and cerebral infarction. However, the ginkgolides can hardly pass the blood-brain barrier (BBB) into the brain. The purpose of this study was to prepare borneol-modified ginkgolides liposomes (GGB-LPs) to study whether borneol could enhance the transport of ginkgolides across the BBB. The preparation conditions of GGB-LPs were optimized by a response surface-central composite design. Also, pharmacokinetics and biodistribution studies of GGB-LPs were conducted using UPLC-MS. The optimal preparation conditions for GGB-LP were as follows: ratio of lipid to drug (w/w) was 9:1, ratio of phospholipid to cholesterol (w/w) was 7:1, and hydrate volume was 17.5 mL. Under these conditions, the GGB-LP yield was 89.73 ± 3.45%. With GGB-LPs, borneol significantly promoted the transport of ginkgolide across the BBB. The pharmacokinetic parameters of GGB-LP were significantly improved too, with Tmax of 15 min and a high drug concentration of 3.39 µg/g in brain. Additionally, the drug targeting index and relative uptake rate of GGB-LP was increased. Borneol-modified ginkgolide liposomes can thus potentially be used to improve the BBB permeability of gingkolide formulations.

Targeted delivery of hybrid nanovesicles for enhanced brain penetration to achieve synergistic therapy of glioma.

Blood-brain barrier (BBB) obstructing brain drug delivery severely hampers the therapeutic efficacy towards glioma. An efficient brain delivery strategy is of paramount importance for the treatment of glioma. Inspired by brain targeting exosome, biomimetic BBB penetrated hybrid (pHybrid) nanovesicles, engineered by membrane fusion between blood exosome and tLyp-1 peptide modified liposome, is explored for brain targeting drug delivery. Transferrin receptor (TfR) on pHybrid nanovesicles facilitates the BBB transcytosis into brain parenchyma, and eventually endocytosed by glioma cells and diffusion to extra-vascular tumor tissues under the guidance of tLyp-1 peptide. pHybrid nanovesicles co-loaded with salvianolic acid B (SAB) and cryptotanshinone (CPT), which is constructed by membrane hybridization of blood exosome loaded with SAB and tLyp-1 modified liposome loaded with CPT, are explored for cytotoxic and anti-angiogenetic therapy towards glioma. Upon accumulation at tumor site, the loaded CPT and SAB shows synergistic effects towards glioma from cytotoxicity on cancer cells and anti-angiogenesis on tumor, respectively. Overall, this study provides a biomimetic nanoplatform for increased BBB transcytosis into brain parenchyma, which serves as a prospective strategy for delivering therapeutic agents against glioma through synergistic mechanisms.

Mucoadhesive improvement of alginate microspheres as potential gastroretentive delivery carrier by blending with Bletilla striata polysaccharide.

As polysaccharide from Bletilla striata (BSP) was anticipated with mucoadhesive improvement in sodium alginate (SA) microspheres, BSP was mixed with SA to construct a composite microsphere to retain in the gastrointestinal tract for a long time. The morphological properties, particle size and thermodynamic properties of the microspheres in combination with comprehensive evaluations in the swelling properties, mucin adsorption, ex vivo and in vivo gastric retention were determined to characterize the mucoadhesion of SA-BSP blend microspheres. Results showed that the prepared microspheres were discrete and spherical. The addition of BSP increased flexibility and reduced rigidity of SA microsphere. Furthermore, the swelling property, mucin adsorption ability and the retention rate on the gastric mucosa of SA matrix were increased after blending with BSP. Mucoadhesion tests showed the SA-BSP microspheres stayed much longer in rats' stomach than the SA microsphere did. Above all, the SA-BSP microspheres with the enhanced mucoadhesion suggested being a potential drug carrier in developing the gastroretentive drug delivery system.

Laser-triggered polymeric lipoproteins for precision tumor penetrating theranostics.

Natural particles ranging from various cell membranes to nascent proteins are highly optimized for their specific functions in vivo and possess features that are desired in drug delivery carriers. However, the current endeavor in research on bioparticles is still seeking the appropriate strategy to shield multiple agents and circumvent biological hurdles. These issues have propelled the advancement of lipid-polymer hybrid nanocarriers, which could be employed as drug reservoirs and strive to meet these expectations. We thereby proposed functionalized biopeptide-lipid hybrid particles, which were applied to encapsulating a PLGA polymeric core together with indocyanine green (ICG) and packaged by a lipoprotein-inspired structural shell. To initiate precision tumor-penetrating performance, tLyP-1-fused apolipoprotein A-I-mimicking peptides (D4F) were exploited to impart tumor-homing and tumor-penetrating biological functions. The sub-100 nm drug vehicle possessed a long circulation time with uniform mono-dispersity but was stable enough to navigate freely, penetrate deeply into tumors and deliver its cargoes to the targeted sites. Moreover, ICG-encapsulated penetrable polymeric lipoprotein particles (PPL/ICG) could realize real-time fluorescence/photoacoustic imaging for monitoring in vivo dynamic distribution. Upon near-infrared (NIR) laser irradiation, PPL/ICG demonstrated a highly efficient phototherapeutic effect to eradicate orthotopic xenografted tumors, resulting in an 88.77% decrease from the initial tumor volume and inhibited tumor metastasis with good biosafety. Therefore, the described bio-strategy opens new avenues for creating polymeric lipoproteins with varied hybrid functionalities, which may be applied to provide a basis and inspiration for improved nanoparticle-based precision theranostic nanoplatforms.

Rheological and mucoadhesive properties of polysaccharide from Bletilla striata with potential use in pharmaceutics as bio-adhesive excipient.

This study described the rheological and mucoadhesive properties of one natural water-soluble polysaccharide from Bletilla striata (BSP). The rheological characteristics of BSP in aqueous solutions and BSP mixed with other polymers were investigated under various conditions, including concentration, temperature, pH, and salt addition. Viscometric studies and ex vivo mucoadhesion tests were also conducted to examine the mucoadhesive properties of BSP. Results indicated that BSP behaved as a shear-thinning fluid at various concentrations, and its viscosity decreased at high temperatures. The viscous flow properties of the BSP mixtures changed at high pH (>5.0). Conversely, the viscosity of the BSP solutions was slightly affected by electrolytes. The viscosities of the BSP mixtures with four other commonly used polymers (sodium alginate, sodium carboxymethyl cellulose, hypromellose, and chitosan) were enhanced. The synergistic viscosity of BSP/mucin mixtures increased as BSP concentrations increased, and the maximum value was observed in the SIF medium without enzymes. The adhesive abilities of 5.0% and 10.0% BSP were almost equivalent to that of 0.5% sodium alginate, suggesting that BSP exhibited a certain mucoadhesive property, although it was weaker than that of the other commonly used mucoadhesive materials. BSP showed potential for pharmaceutical excipient applications in bioadhesive drug delivery systems.

High dispersed phyto-phospholipid complex/TPGS 1000 with mesoporous silica to enhance oral bioavailability of tanshinol.

Phenolic acids are widely distributed in the plant kingdom and possess a broad spectrum of pharmacological activity. However, low oral bioavailability restricts their application. In this study, a high dispersed phyto- phospholipid complex with mesoporous silica containing TPGS 1000 (TPC-SD) was fabricated using Tanshinol (Tan) as model drug. Phospholipid complex (PC) was employed to improve the n-octanol/water partition coefficient (log P) and apparent permeability coefficients (Papp) of Tan. Mesoporous silica was used to compensate for the negative effects of phospholipid on drug's dispersion and dissolution owing to its viscosity and poor water-solubility. TPGS 1000, a P-gp inhibitor, was used to block the efflux of Tan. Log P tests showed that the lipophilicity of Tan was significantly enhanced by Tanshinol phospholipid complex (TPC) formation. In vitro dissolution results showed that the cumulative dissolution percentage of Tan from TPC-SD was 4.33- fold of that from TPC in 120 min A Caco-2 permeability test confirmed that Papp (AP-BL) of TPC and TPC-SD increased approximately 2.22- and 3.53- fold compared to those of unformulated Tan, respectively (p < 0.01, p < 0.01). Pharmacokinetic studies demonstrated that the AUC0-∞ of TPC-SD was 2.23- and 1.47- fold compared with those of unformulated Tan and TPC, respectively (p < 0.01, p < 0.01). These results indicated that the high dispersed phyto- phospholipid complex/TPGS 1000 by mesoporous silica can be a promising drug delivery system to improve the oral bioavailability of free phenolic acids.

Orally delivered polycurcumin responsive to bacterial reduction for targeted therapy of inflammatory bowel disease.

Inflammatory bowel disease (IBD) such as Crohn's disease and ulcerative colitis is a chronic autoimmune disease affecting nearly five million people worldwide. Among all drug delivery system, oral administration is the most preferable route for colon-specific targeting and the treatment of IBD. Herein, an amphiphilic curcumin polymer (PCur) composed of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic curcumin (Cur) linked by disulfide bond was synthesized and characterized. The sufficient solubility, nano-scaled size and close to the neutral surface potential of PCur lead to preferential accumulation of the active drug in the inflamed regions of the gut. Moreover, PCur showed limited drug release and enhanced robustness under the physiological pH of the gastrointestinal tract (GIT), and a significantly elevated release was observed when responding to a bacterial reduction in the colon. Furthermore, cellular studies confirmed PCur had low cytotoxicity and increased transmembrane permeability, resulting in improved oral bioavailability evidenced by in vivo pharmacokinetics of rats. Finally, with DSS-induced murine model of IBD, we demonstrated that orally administered PCur ameliorated the inflammatory progression in the colon and could protect mice from IBD. In conclusion, it is illustrated that the developed PCur conjugate could potentially be employed as a colon-specific candidate for IBD treatment.

[Study of diffusion of muscone in different inclusion complexes and liposome through mouse (correction of rat) skin in vitro].

OBJECTIVE: To compare the penetrating rate of muscone in different inclusion complexes and liposome. METHOD: The transdermal effect of muscone in different inclusion complexes and liposome was studied comparatively on mouse [corrected] skin with 40% EtOH as the absorption solution and with an improved Franz diffuse cell. RESULT: Among the different inclusion complexes and liposome, the penetrating rate of muscone in the HP-beta-cyclodextrin inclusion and the liposome were higher than muscone, and that of muscone in the beta-cyclodextrin inclusion is the lowest. CONCLUSION: The HP-beta-cyclodextrin inclusion and the liposome can hence the muscone transdermal speed.

Preparation of osthole-polymer solid dispersions by hot-melt extrusion for dissolution and bioavailability enhancement.

The aim of this study was to investigate the potential of solid dispersion to improve the dissolution rate and bioavailability of osthole (Ost), a coumarin derivative with various pharmacological activities but with poor aqueous solubility. In present studies, the Ost solid dispersions were prepared with various polymers including Plasdone S-630, HPMC-E5, Eudragit EPO, and Soluplus by hot-melt extrusion method. In vitro characterizations were performed with differential scanning calorimetry (DSC), X-ray powder diffraction (XPRD), Fourier transform infrared (FT-IR) spectroscopy, and in vitro dissolution studies. In addition, in vivo pharmacokinetic studies of Ost solid dispersions were also conducted in rats after a single oral dose. In comparison to the untreated Ost coarse powder and the physical mixture with polymers, the solid dispersions prepared with Plasdone S-630 or HPMC-E5 (drug/polymer: 1:6) showed a significant enhancement of dissolution rate (∼3-fold higher D30). In addition, such preparations exhibited a significantly decreased Tmax, ∼5-fold higher Cmax and ∼1.4-fold higher AUC when comparing with Ost coarse powder. In conclusion, solid dispersion prepared with appropriate polymer could serve as a promising formulation approach to enhance the dissolution rate and hence oral bioavailability of Ost.