Preparation and Pharmacokinetics Evaluation of Solid Self-Microemulsifying Drug Delivery System (S-SMEDDS) of Osthole.

The study was performed aiming to enhance the solubility and oral bioavailability of poorly water-soluble drug osthole by formulating solid self-microemulsifying drug delivery system (S-SMEDDS) via spherical crystallization technique. Firstly, the liquid self-microemulsifying drug delivery system (L-SMEDDS) of osthole was formulated with castor oil, Cremophor RH40, and 1,2-propylene glycol after screening various lipids and emulsifiers. The type and amount of polymeric materials, good solvents, bridging agents, and poor solvents in S-SMEDDS formulations were further determined by single-factor study. The optimal formulation contained 1:2 of ethyl cellulose (EC) and Eudragit S100, which served as matrix forming and enteric coating polymers respectively. Anhydrous ethanol and dichloromethane with a ratio of 5:3 are required to perform as good solvent and bridging agent, respectively, with the addition of 0.08% SDS aqueous solution as poor solvent. The optimized osthole S-SMEDDS had a high yield (83.91 ± 3.31%) and encapsulation efficiency (78.39 ± 2.25%). Secondly, osthole L-SMEDDS was solidified to osthole S-SMEDDS with no significant changes in terms of morphology, particle size, and zeta potential. In vitro release study demonstrated a sustained release of the drug from osthole S-SMEDDS. Moreover, in vivo pharmacokinetic study showed that the Tmax and mean residence time (MRT(0-t)) of osthole were significantly prolonged and further confirmed that osthole S-SMEDDS exhibited sustained release effect in rabbits. Comparing with osthole aqueous suspension and L-SMEDDS, osthole S-SMEDDS increased bioavailability by 205 and 152%, respectively. The results suggested that S-SMEDDS was an effective oral solid dosage form, which can improve the solubility and oral bioavailability of poorly water-soluble drug osthole.

Ultra-pH-sensitive nanoparticle of gambogenic acid for tumor targeting therapy via anti-vascular strategy plus immunotherapy.

Although the combination of anti-vascular strategy plus immunotherapy has emerged as the optimal first-line treatment of hepatocellular carcinoma, lack of tumor targeting leads to low antitumor efficacy and serious side effect. Here, we report an ultra-pH-sensitive nanoparticle of gambogenic acid (GNA) encapsulated by poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA) for tumor-targeting combined therapy of anti-vascular strategy plus immunotherapy. PEG-PAEMA-GNA nanoparticle was quite stable at pH 7.4 for 30 d. In contrast, it exerted size shrinkage, charge reversal and the release of GNA at pH 6.7 within 24 h. Moreover, PEG-PAEMA-GNA significantly enhanced the anti-vascular activity, membrane-disruptive capability and pro-apoptosis when pH changed from 7.4 to 6.7. Western blot analysis exhibits that PEG-PAEMA and its GNA nanoparticle facilitated the phosphorylation of STING protein. In vivo assays show that PEG-PAEMA-GNA not only displayed much higher tumor inhibition of 92 % than 37 % of free GNA, but also inhibited tumor vasculature, promoted the maturation of dendritic cells and recruited more cytotoxic t-lymphocytes for sufficient anti-vascular therapy and immunotherapy. All these results demonstrate that PEG-PAEMA-GNA displayed tumor-targeting combined treatment of anti-vascular therapy and immunotherapy. This study offers a simple and novel method for the combination of anti-vascular therapy and immunotherapy with high selectivity towards tumor.

[Real-time UV imaging of chloramphenicol intrinsic dissolution characteristics from ophthalmic in situ gel].

In this paper, chloramphenicol was selected as a model drug to prepare in situ gels. The intrinsic dissolution rate of chloramphenicol from in situ gel was evaluated using the surface dissolution imaging system. The results indicated that intrinsic dissolution rate of chloramphenicol thermosensitive in situ gel decreased significantly when the poloxamer concentration increased. The addition of the thickener reduced the intrinsic dissolution rate of chloramphenicol thermosensitive gel, wherein carbomer had the most impact. Different dilution ratios of simulated tear fluid greatly affected gel temperature, and had little influence on the intrinsic dissolution rate of chloramphenicol from the thermosensitive in situ gel. The pH of simulated tear fluid had little influence on the intrinsic dissolution rate of chloramphenicol thermosensitive in situ gel. For the pH sensitive in situ gel, the dissolution rates of chloramphenicol in weak acidic and neutral simulated tear fluids were slower than that in weak alkaline simulated tear fluid. In conclusion, the intrinsic dissolution of chloramphenicol from in situ gel was dependent on formulation and physiological factors. With advantages of small volume sample required and rapid detection, the UV imaging method can be an efficient tool for the evaluation of drug release characteristics of ophthalmic in situ gel.

Membrane-disruptive homo-polymethacrylate with both hydrophobicity and pH-sensitive protonation for selective cancer therapy.

The membrane-disruptive strategy, which involves host defense peptides and their mimetics, is a revolutionary cancer treatment based on broad-spectrum anticancer activities. However, clinical application is limited by low selectivity towards tumors. In this context, we have established a highly selective anticancer polymer, i.e. poly(ethylene glycol)-poly(2-azepane ethyl methacrylate) (PEG-PAEMA), that can mediate the membrane-disruptive activity via a subtle pH change between physiological pH and tumor acidity for selective cancer treatment. Specifically, the resulting PEG-PAEMA can assemble into neutral nanoparticles and silence the membrane-disruptive activity at physiological pH and disassemble into cationic free-chains or smaller nanoparticles with potent membrane-disruptive activity after the protonation of the PAEMA block due to tumor acidity, resulting in high selectivity towards tumors. Dramatically, PEG-PAEMA exhibited a >200-fold amplification in hemolysis and <5% in IC50 against Hepa1-6, SKOV3 and CT-26 cells at pH 6.7 as compared to those at pH 7.4, thanks to the selective membrane-disruptive mechanism. Moreover, mid- and high-dose PEG-PAEMA demonstrated higher anticancer efficacy than an optimal clinical prescription (bevacizumab plus PD-1) and, significantly, had few side effects on major organs in the tumor-bearing mice model, agreeing with the highly selective membrane-disruptive activity in vivo. Collectively, this work showcases the latent anticancer pharmacological activity of the PAEMA block, and also brings new hope for selective cancer therapy.

Dual-targeted enzyme-sensitive hyaluronic acid nanogels loading paclitaxel for the therapy of breast cancer.

In this study, a CD44 and biotin receptors dual-targeted enzyme-sensitive hyaluronic acid nanogel loading paclitaxel (PTX/Bio-NG) for targeting breast cancer was constructed. Spherical nanogels with a mean particle size of 149.1 ± 1.6 nm, higher entrapment efficiency (90.17 ± 0.52 %) and drug loading (15.28 ± 0.10 %) were obtained. PTX/Bio-NG quickly released drugs under the catalysis of hyaluronidase and/or lipase. Cell studies revealed that the uptake of Bio-NG by 4T1 cells was mediated by CD44 receptor and Bio-specific receptor. Compared with PTX-loaded biotin-free NG (PTX/NG), PTX/Bio-NG had higher cytotoxicity against breast cancer cells (4T1 cells). The rats pharmacokinetic profile indicated higher AUC0-t but lower clearance rates of PTX/NG (6.24 times and 15.96 %, respectively) and PTX/Bio-NG (6.66 times and 14.89 %, respectively) than control group (Taxol). In vivo studies showed that PTX/Bio-NG possessed excellent therapeutic efficacy in 4T1 tumor-bearing Balb/c mice, which suggest that PTX/Bio-NG could be an excellent candidate for the treatment of breast cancer.

Phosphatidylserine targeting peptide-functionalized pH sensitive mixed micelles for enhanced anti-tumor drug delivery.

In recent decades, targeted drug delivery systems (TDDS) have been widely used as an ideal method of improving therapeutic effects and reducing systemic side effects of chemotherapeutic agents. Historically, a handful of methods have been developed to further improve the targeting ability of delivery systems. Thus, in this study, two methods, taking advantage of tumor characteristics, were used for the creation of a multi-targeted delivery system. The first was the fabrication of pH-sensitive micelles, lending the ability to increase drug release by exploiting the acidic tumor environment. The second method was through utilization of the surface-exposed phosphatidylserine (PS) of tumors, which is normally found in the inner leaflet in healthy cells. Using PS as a target site, PS binding peptide (PSBP-6) was conjugated to pH-sensitive mixed micelles, (consisting of poly (ethylene glycol)-b-poly (D, L-lactide) (PEG-PDLLA) and poly (ethylene glycol)-b-poly (L-histidine) (PEG-PHIS)). After successful preparation of micelles, paclitaxel (PTX), a common chemotherapeutic agent, was selected to measure drug loading capacity and encapsulation efficiency, showing 7.9% and 83.5%, respectively. The in vitro release of PTX from mixed micelles at pH 5.0, 6.5, and 7.4 was 78.1, 56.8, and 51.4%, respectively, indicating acid-triggered drug release. The PSBP-6-modified, mixed micelles exhibited significantly enhanced in vitro cytotoxicity and demonstrated more efficient cellular uptake compared to unmodified mixed micelles in the HeLa cell line. Moreover, pharmacokinetic, in vivo biodistribution, and fluorescence imaging studies showed that PSBP-6-PEG-PDLLA/PEG-PHIS mixed micelles provide prolonged time in blood circulation and enhanced tumor accumulation. These results suggest that the use of PS as a novel targeting site is advantageous, and that these new multi-targeted mixed micelles show great potential for realization of broad prospects in the targeted treatment of tumors for chemotherapeutic delivery.

[Optimization of formulation of Fufang Danshen immediate release tablet by colligation score].

OBJECTIVE: To optimize the formulation of immediate release tablet. METHOD: The immediate release tablet was prepared by using dry granules. The preparation was optimized by using orthogonal design which took the flow property of granules, the hardness, the disintegrating time and the dissolution rate of the tablet as indices. RESULT: The optimized formulation contained 40% microcrystalline cellulose, 10% sodium carboxymethyl starch and 15% dextrin. The hardness disintegrating time and T50 of the tablet were 4.5 kg, 3 min, 5 min respectively. CONCLUSION: It is successful to prepare on immediate release tablet using the optimized formula above.