Goserelin/PLGA solid dispersion used to prepare long-acting microspheres with reduced initial release and reduced fluctuation of drug serum concentration in vivo.

To prepare Goserelin (GOS) loaded long-acting microspheres with reduced initial release and prolonged drug release time of GOS, GOS/PLGA solid dispersion (by hot-melt extrusion, HME) was dissolved/dispersed in dichloromethane (DCM) to prepare microspheres by O/W method. From results of molecular dynamics simulation, PLGA and GOS molecules completely and uniformly dissolved and dispersed in DCM, respectively. In F5 microspheres (prepared by HME-O/W method), GOS existed as molecular or amorphous state, but not aggregation. Burst release of F5 microspheres (2.75%) was similar with Zoladex™ implant (0.39%) and less than F10 microspheres (prepared by S/O/W method, 25.92%). After lag phase, GOS released rapidly from F5 microspheres and the cumulative release on the 45th days was 95.14%. After injection of F5 microspheres, GOS serum concentration was relative steady at the range of 27.64-175.27 ng/mL for nearly 35 days. AUC(0-35 day) of F5 microspheres was almost 2 times that of F10 microspheres. Pharmacodynamics study also showed potential effect of F5 microspheres on inhibiting the secretion of testosterone in male rats. HME-O/W method is potential to establish long-acting PLGA microspheres (loading water-soluble drug), exhibiting stable drug serum concentration in vivo, and without large concentration fluctuation or serious pain/side effects.

Bioadhesive poly(methyl vinyl ether-co-maleic anhydride)-TPGS copolymer modified PLGA/lipid hybrid nanoparticles for improving intestinal absorption of cabazitaxel.

A bioadhesive nanocarrier, PTNP, was constructed by utilizing a novel poly(methyl vinyl ether-co-maleic anhydride)- D-α-Tocopheryl polyethylene glycol succinate (PVMMA-TPGS) copolymer in the PLGA/lipid hybrid nanoparticles (PLGA NPs) for improving oral delivery of cabazitaxel (CTX). The PVMMA-TPGS was synthesized by the ring-opening polymerization of the anhydride groups with the hydroxyl groups, combining the bioadhesive property of PVMMA with P-glycoprotein (P-gp) inhibitory effect of TPGS. The CTX-loaded PTNPs (CTX-PTNPs) were prepared by an emulsification-solvent evaporation method and performed a spherical appearance with a uniform particle size of 192.2 nm. The CTX-PTNPs were surface negatively charged, and exhibited good drug loading (10.2%) and encapsulation efficiency (92.1%). A sustained drug release and high stability in simulated gastrointestinal environment were confirmed in in vitro studies. The in vitro mucin adhesion and in vivo intestinal retention experiments indicated that the PTNPs had a stronger bioadhesive effect and a notably longer intestinal retention than the control PLGA NPs, due to the interaction of PVMMA on the PTNP surface with the intestinal mucosa. Moreover, an enhanced intestinal permeability of the PTNPs was also verified in in vivo and ex vivo intestinal permeation studies, which was probably attributed to the extended retention of PTNPs in intestinal mucosa and the P-gp inhibitory effect of TPGS. As respected, in in vivo pharmacokinetic study, the Tmax and oral bioavailability of CTX were dramatically improved to 1.08 h and 28.84% by the PTNPs, respectively, obviously superior to the CTX solution and the PLGA NPs, further demonstrating the high-efficiency in oral delivery of CTX. Hence, this bioadhesive carrier is proposed to be a potential and promising strategy for increasing oral absorption of small molecule insoluble drugs.

Utilization of PLGA nanoparticles in yeast cell wall particle system for oral targeted delivery of exenatide to improve its hypoglycemic efficacy.

Oral delivery of exenatide (EXE), a high-efficiency therapeutic peptide, is urgently needed for long-term treatment of diabetes. In this study, a polylactide-co-glycoside (PLGA) nanoparticles (NPs) in yeast cell wall particle (YCWP) system was built to improve the intestinal absorption of EXE by efficient protection of EXE against gastrointestinal degradation and intestinal phagocytic cell targeted delivery. The EXE-loaded PLGA NPs were prepared by a double emulsion solvent diffusion method and exhibited a uniformly spherical appearance, a nano size (92.4 ± 4.6 nm) and a positive surface charge (+32.3 ± 3.8 mV). And then, the NPs were successfully loaded into the YCWPs by a solvent hydration - lyophilization cycle method to obtain the EXE-PLGA NPs @YCWPs, which was verified by scanning electron microscope and confocal laser scanning microscopy. An obvious sustained drug release and a reduced burst release were achieved by this nano-in-micro carrier. Moreover, the gastrointestinal stability of EXE in PLGA NPs @YCWPs was significantly higher than that in PLGA NPs in the simulated gastrointestinal environment, which were useful in enhancing the intestinal absorption of EXE. In biodistribution study, the EXE-PLGA NPs @YCWPs could quickly reached the root of the villi, and even partly entered the inner of the villi, especially in ileum and Peyer's patches. In vitro cell evaluation demonstrated an efficient ß-glucan receptor mediated endocytosis and transport of EXE-PLGA NPs @YCWPs by the macrophage RAW 264.7 cells, suggesting a potential intestinal macrophage targeted absorptive pathway. The in vivo pharmacokinetic study showed a preferred hypoglycemic effect and an increased pharmacological availability (13.7 ± 4.1%) after oral administration of the EXE-PLGA NPs @YCWPs. It is believed that the PLGA nanoparticles in YCWP system could become an efficient strategy to orally deliver therapeutic peptide drugs.

Toxicity Reduction and Efficacy Promotion of Doxorubicin in the Treatment of Breast Tumors Assisted by Enhanced Oral Absorption of Curcumin-Loaded Lipid-Polyester Mixed Nanoparticles.

Curcumin (CUR), a polyphenol derived from turmeric, exhibits anticancer and anti-inflammatory properties. However, it has poor water solubility, stability, and oral bioavailability. To overcome these limitations, lipid-polyester mixed nanoparticles (NPs) embedded in enteric polymer-EudragitL100-55(Eu) were formulated (CUR-NPs-Eu). NPs composed of mPEG-b-PCL have a hybrid core made up of middle chain triglyceride (MCT) and poly(ε-caprolactone) (PCL) for enhancing drug loading. The CUR-NPs with MCT content of 10% had a particle size of 121.2 ± 16.8 nm, ζ potential of -16.25 ± 1.38 mV, drug loading of 9.8%, and encapsulation efficiency of 87.4%. The transport of the CUR-NPs-Eu across Caco-2 monolayers is enhanced compared with CUR alone (1.98 ± 0.94 × 10-6 of curcumin versus 55.43 ± 6.06 × 10-6 cm/s of curcumin-loaded NPs) because of the non-disassociated nanostructure during absorption. The absolute bioavailability of CUR-NPs-Eu was 7.14%, which was drastically improved from 1.08% of the CUR suspension (CUR-Sus). Therefore, in the xenograft 4T1 tumor-bearing mice, increased drug accumulation in heart and tumor was noticed because of enhanced oral bioavailability of CUR. The chemosensitizing effect of CUR was attributed to its NF-κB reduction effect (148 ± 11.83 of DOX alone versus 104 ± 8.71 of combined therapy, ng/g tissue). The cardioprotective effect of CUR was associated with maintenance of cardiac antioxidant enzyme activity and down-regulation of NF-κB. This study provided a partial illustration of the mechanisms of chemosensitizing and cardioprotective effects of CUR utilizing the oral availability promotion effect brought by the NPs-Eu formulation. And these results further demonstrated that the capability of this NPs-Eu system in oral delivery of poorly soluble and poorly permeable drugs.

Cell-penetrating peptide together with PEG-modified mesostructured silica nanoparticles promotes mucous permeation and oral delivery of therapeutic proteins and peptides.

Poor permeation across intestinal mucous barriers often limits the oral delivery of prospective therapeutic proteins and peptides (TPPs). In order to address this issue, cell penetrating peptide (CPP) together with PEG modified and pore-enlarged mesostructured silica nanoparticle (NP) were constructed to form the mucus-penetrating electrostatic particle-complexes, CPP/TPP/NP. Alone, CPP and TPP often present with poor stability, and their traditional electrostatic complex shows reduced pharmacodynamics. To provide satisfactory protection, silica NPs were loaded with CPP and TPP (CPP@NP and TPP@NP), respectively, and then CPP@NP and TPP@NP could together form CPP/TPP/NP via electrostatic interaction. As a result, CPP involvement with PEG modification showed an 8.45-, 1.62- and 5.09-fold increase in cellular uptake, exocytosis and final transcellular permeation in mucous conditions, respectively. It was found that CPP involvement mainly affected transport and exocytosis, and the PEG polymer significantly influenced mucous penetration and cellular uptake, which could further promote CPP ability for uptake and exocytosis. Additionally, NP-mediated CPP/TPP/NP showed a similar uptake mechanism with supporting carriers (clathrin-mediated endocytosis), and could strengthen transcellular routes (the endoplasmic reticulum-Golgi apparatus pathway and the lysosome route). Utilizing recombinant growth hormone (RGH) as a model TPP, oral administration of the RGH-loaded CPP/TPP/LMSN-PEG10k with hydrophilic and electroneutral properties induced 5.41- and 4.91-fold increases in pharmacodynamics in vitro and in vivo, respectively. Thus, CPP/TPP/NP significantly promoted mucous permeation and shows promising potential for oral delivery of TPPs.

Encapsulation of Azithromycin Ion Pair in Liposome for Enhancing Ocular Delivery and Therapeutic Efficacy on Dry Eye.

The aim of this work was to design a novel ocular delivery carrier based on liposomes loaded with azithromycin (AZM) for the treatment of dry eye (DE) disease. To improve the drug loading efficiency, an AZM-cholesteryl hemisuccinate (CHEMS) ion pair (ACIP) was first prepared, and the successful formation of the ACIP was characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray powder diffraction (XRD), which demonstrated a stable interaction between CHEMS and AZM. The ACIP-loaded liposome (ACIP-Lip) appeared as spherical particles under TEM, with a uniform particle size of 60 ± 2 nm and zeta potential of -20.3 ± 4.6 mV. The entrapment efficiency (EE) and drug loading (DL) of ACIP-Lip were greatly improved to 95.6 ± 2.0 and 9.2 ± 0.7%, respectively, which was attributed to the enhanced loading capacity of the liposomes through use of the ion pair and addition of MCT. ACIP-Lip also exhibited a high stability during a 3 month storage period at both 4 and 25 °C. In vitro release of AZM from ACIP-Lip was pH-dependent, with a more rapid release at pH 6.0 than at pH 7.4, which is beneficial for ocular therapy. Furthermore, the corneal permeation of AZM was enhanced by ACIP-Lip, demonstrating an apparent permeability coefficient ( Papp × 106) of 8.92 ± 0.56 cm/s, which was approximately 2-fold greater that of the AZM solution. Finally, an in vivo pharmacodynamical study showed that the essential symptoms of DE rats were significantly improved by ACIP-Lip, as it was highly efficient and superior compared to hyaluronic acid sodium eye drops available on the market. Hence, ACIP-Lip is a promising formulation for DE treatment.

Folate-modified carboxymethyl-chitosan/polyethylenimine/bovine serum albumin based complexes for tumor site-specific drug delivery.

A ternary core/shell based nanoparticulate complex was designed for the sequential and site-specific drug delivery. First, bovine serum albumin nanoparticles (BSA NPs) were served as the core for loading gambogic acid (GA). Subsequently, the BSA NPs were adsorbed by polyethylenimine and then shielded with carboxymethyl chitosan-folate (CMCS-FA) as the outer shell for encapsulating tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), forming the GA/TRAIL co-delivery BSA (GTB) NPs. In normal tissues, the GTB NPs were negatively charged; in acidic tumor tissues, the shielding CMCS-FA was detached, allowing the release of TRAIL, which binds to the cell death receptor on the plasma membrane. The resulting positively charged complex promoted cellular internalization and escaped from lysosomes, producing a rapid release of GA, which exerted the combined tumor therapy by regulating both intrinsic and extrinsic apoptotic pathways. In vitro and in vivo studies confirmed that GTB NPs could enhance antitumor efficacy and reduce adverse effects.

Entrapping of Nanoparticles in Yeast Cell Wall Microparticles for Macrophage-Targeted Oral Delivery of Cabazitaxel.

In this work, a nano-in-micro carrier was constructed by loading polymer-lipid hybrid nanoparticles (NPs) into porous and hollow yeast cell wall microparticles (YPs) for macrophage-targeted oral delivery of cabazitaxel (CTX). The YPs, primarily composed of natural ß-1,3-d-glucan, can be recognized by the apical membrane receptor, dectin-1, which has a high expression on macrophages and intestinal M cells. By combining electrostatic force-driven self-deposition with solvent hydration/lyophilization methods, the positively charged NPs loaded with CTX or fluorescence probes were efficiently packaged into YPs, as verified by scanning electron microscope (SEM), atomic force mircoscope (AFM), and confocal laser scanning microscopy (CLSM) images. NP-loaded YPs (NYPs) showed a slower in vitro drug release and higher drug stability compared with NPs in a simulated gastrointestinal environment. Biodistribution experiments confirmed a widespread distribution and extended retention time of NYPs in the intestinal tract after oral administration. Importantly, a large amount of NYPs were primarily accumulated and transported in the intestinal Peyer's patches as visualized in distribution and absorption site studies, implying that NYPs were mainly absorbed through the lymphatic pathway. In vitro cell evaluation further demonstrated that NYPs were rapidly and efficiently taken up by macrophages via receptor dectin-1-mediated endocytosis using a mouse macrophage RAW 264.7 cell line. As expected, in the study of in vivo pharmacokinetics, the oral bioavailability of CTX was improved to 32.1% when loaded in NYPs, which is approximately 5.7 times higher than that of the CTX solution, indicating the NYPs are efficient for oral targeted delivery. Hence, this nano-in-micro carrier is believed to become a hopeful alternative strategy for increasing the oral absorption of small molecule drugs.

Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles.

Combination therapy with different functional chemotherapeutic agents based on nano-drug delivery systems is an effective strategy for the treatment of breast cancer. However, co-delivery of drug molecules with different physicochemical properties still remains a challenge. In this study, an amphiphilic poly (ε-caprolactone)-b-poly (l-glutamic acid)-g-methoxy poly (ethylene glycol) (PCL-b-PGlu-g-mPEG) copolymer was designed and synthesized to develop a nanocarrier for the co-delivery of hydrophilic doxorubicin (DOX) and hydrophobic disulfiram (DSF). The amphiphilic copolymer self-assembled into core-shell-corona structured nanoparticles with the hydrophobic PCL core for DSF loading (hydrophobic interaction) and anionic poly (glutamic acid) shell for DOX loading (electrostatic interaction). DSF and DOX co-loaded nanoparticles (Co-NPs) resulted in high drug loading and precisely controlled DSF/DOX ratio via formulation optimization. Compared with free drug solutions, DSF and DOX delivered by the Co-NPs were found to have improved intracellular accumulation. Results of cytotoxicity assays showed that DSF/DOX delivered at the weight ratio of 0.5 and 1 could achieve a synergistic cytotoxic effect on breast cancer cell lines (MCF-7 and MDA-MB-231). In vivo imaging confirmed that the core-shell-corona nanoparticles could efficiently accumulate in tumors. In vivo anti-tumor effect results indicated that Co-NPs showed an improved drug synergistic effect on antitumor activity compared with the free drug combination. Therefore, it can be concluded that core-shell-corona nanoparticles prepared by PCL-b-PGlu-g-mPEG could be a promising co-delivery system for drug combination therapy in the treatment of breast cancer.

Enhanced oral absorption and anticancer efficacy of cabazitaxel by overcoming intestinal mucus and epithelium barriers using surface polyethylene oxide (PEO) decorated positively charged polymer-lipid hybrid nanoparticles.

Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2±5.7nm, zeta potential of +40.90±3.05mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.

Poly(vinyl methyl ether/maleic anhydride)-Doped PEG-PLA Nanoparticles for Oral Paclitaxel Delivery To Improve Bioadhesive Efficiency.

Bioadhesive nanoparticles based on poly(vinyl methyl ether/maleic anhydride) (PVMMA) and poly(ethylene glycol) methyl ether-b-poly(d,l-lactic acid) (mPEG-b-PLA) were produced by the emulsification solvent evaporation method. Paclitaxel was utilized as the model drug, with an encapsulation efficiency of up to 90.2 ± 4.0%. The nanoparticles were uniform and spherical in shape and exhibited a sustained drug release compared with Taxol. m-NPs also exhibited favorable bioadhesive efficiency at the same time. Coumarin 6 or DiR-loaded nanoparticles with/without PVMMA (C6-m-NPs/DiR-m-NPs or C6-p-NPs/DiR-p-NPs) were used for cellular uptake and intestinal adhesion experiments, respectively. C6-m-NPs were shown to enhance cellular uptake, and caveolae/lipid raft mediated endocytosis was the primary route for the uptake of the nanoparticles. Favorable bioadhesive efficiency led to prolonged retention in the intestine reflected by the fluorescence in isolated intestines ex vivo. In a ligated intestinal loops model, C6-m-NPs showed a clear advantage for transporting NPs across the mucus layer over C6-p-NPs and free C6. The apparent permeability coefficient (Papp) of PTX-m-NPs through Caco-2/HT29 monolayers was 1.3- and 1.6-fold higher than PTX-p-NPs and Taxol, respectively, which was consistent with the AUC0-t of different PTX formulations after oral administration in rats. PTX-m-NPs also exhibited a more effective anticancer efficacy, with an IC50 of 0.2 ± 1.4 µg/mL for A549 cell lines, further demonstrating the advantage of bioadhesive nanoparticles. The bioadhesive nanoparticles m-NPs demonstrated both mucus permeation and epithelial absorption, and thus, this bioadhesive drug delivery system has the potential to improve the bioavailability of drugs that are insoluble in the gastrointestinal environment.

Strategies for improving the payload of small molecular drugs in polymeric micelles.

In the past few years, substantial efforts have been made in the design and preparation of polymeric micelles as novel drug delivery vehicles. Typically, polymeric micelles possess a spherical core-shell structure, with a hydrophobic core and a hydrophilic shell. Consequently, poorly water-soluble drugs can be effectively solubilized within the hydrophobic core, which can significantly boost their drug loading in aqueous media. This leads to new opportunities for some bioactive compounds that have previously been abandoned due to their low aqueous solubility. Even so, the payload of small molecular drugs is still not often satisfactory due to low drug loading and premature release, which makes it difficult to meet the requirements of in vivo studies. This problem has been a major focus in recent years. Following an analysis of the published literature in this field, several strategies towards achieving polymeric micelles with high drug loading and stability are presented in this review, in order to ensure adequate drug levels reach target sites.

Modified PLGA-PEG-PLGA thermosensitive hydrogels with suitable thermosensitivity and properties for use in a drug delivery system.

PLGA-PEG-PLGA (PPP) triblock copolymer is the most widely studied thermosensitive hydrogel owing to its non-toxic, biocompatible, biodegradable, and thermosensitive properties. PPP thermosensitive hydrogels are being investigated as in situ gels because, at a low temperature, PPP solutions with drugs can be injected at the target site, and converted into a gel without surgical procedures. To meet the requirements of different therapeutic applications, PPP hydrogels with different properties need to be synthesized. The adjustable properties include the sol-gel transition temperature, gel window width, retention time and drug release time. Furthermore, thermo- and pH-, thermo- and electro-, and thermo- and photo-dual sensitive hydrogels are needed for some special therapies. Thus, this review examines the methods of modification of PPP thermosensitive hydrogels used to obtain desired drug delivery systems with appropriate physicochemical and pharmaceutical properties.

Effects of Pluronic F127-PEG multi-gel-core on the release profile and pharmacodynamics of Exenatide loaded in PLGA microspheres.

Pluronic F127 and PEG as a multi-gel-core were used to prepare Exenatide-loaded microspheres and store the drug within the microspheres. Also, the sol-gel transition and novel functions of the Pluronic F127-PEG gel core were investigated.Microspheres with a multi-gel-core (GCMs) and without a multi-gel-core (Ms) were compared in terms of the rate of PLGA degradation, therelease kinetics in vitro and the efficacy in KKAy mice. The drug release of GCMs was at a constant rate, and slower than Ms. In addition, after the KKAy mice were given Exenatide for 55days, the blood glucose concentration and HbA1c concentration in the GCMs group were lower than that in the Ms group. The obtained results demonstrated that a single injection of GCMs allowed the mice to maintain a stable blood glucose concentration for two weeks and their body weight was reduced more effectively than that in the Ms group. In addition, GCMs had a longer interval between dosing (two weeks) and a lower dosage(2.4µg/kg) than Bydureon(®) (one week, 33µg/kg). The bioactivity and release of macromolecular Exenatide was improved by the multi-gel-core structure:(1)The hydrophilic Exenatide tended to partition into the PEG chains of F127 and PEG homopolymer, and so it was protected from the organic solvent and vigorous stirring; (2)The macromolecular Exenatide was released both by diffusing through the hydrophilic F127-PEG chains and hydrophobic PLGA.

Evaluating the safety of phytosterols removed perilla seed oil-based lipid emulsion.

OBJECTIVES: The aim of this study was to ascertain the potential toxicity of perilla seed oil-based lipid emulsion (POLE) caused by phytosterols and confirm the efficacy of the technique for removing phytosterols from perilla seed oil, and evaluate the safety of a low phytosterol POLE in a long-term tolerance study in dogs. METHODS: A comparison between a soybean oil lipid emulsion (Intralipid group A) and POLE with high (group B) versus low (group C) levels of phytosterols was made with regard to their effects on the general condition, hematological and biochemical parameters, urinalysis and histopathological changes in nine dogs receiving daily infusions for four weeks at dosage levels of 6, 6, 9 g fat /kg. RESULTS: Dogs in group A and group C remained in good condition and gained weight during the infusion period and no diarrhea or gastrointestinal bleeding occurred. Only a moderate degree of anemia was observed, the biochemical parameters changed only slightly and returned to normal after treatment had ceased. However, the dogs in group B exhibited significant symptoms of 'fat overload syndrome'. Vomiting, diarrhoea and blood in the faeces were observed. Moreover, triglyceridemia, cholesteremia, and dark urine as well as microscopic signs of liver and gastrointestinal tract damage and generalized jaundice were clearly seen. CONCLUSIONS: Phytosterols promote 'fat overload syndrome' in long-term tolerance studies of POLE in dogs by producing cholestatic liver injury and interfering with fat metabolism. And the toxicity of POLE was reduced by removing phytosterols.

A bufadienolide-loaded submicron emulsion for oral administration: stability, antitumor efficacy and toxicity.

The purpose of this study was to develop an alternative submicron emulsion containing three bufadienolides for oral administration and evaluate its preclinical stability, efficacy, and toxicity. The bufadienolide-loaded oral submicron emulsion (BU-OE) was prepared by high-pressure homogenization. The storage stability, in vitro cytotoxicity, in vivo antitumor efficacy, acute toxicity, and long-term toxicity of BU-OE were investigated in detail to evaluate the formulation. The stability study suggested that BU-OE was stable at room temperature and could be stored for at least 18 months at 6±2 °C. The cytotoxicity test revealed that BU-OE had marked cytotoxic activities against cancer cells, but no evident inhibitory effects on normal cells. Likewise, BU-OE exhibited significant antitumor efficacy against Hep G2, HCT-8, and EC9706 cell lines and a slight inhibitory effect on BGC 803 cell line in nude mice, while comparable antitumor activity with fluorouracil injection. The LD50 of BU-OE in mice was 29.4 mg/kg (male) and 22.8 mg/kg (female), respectively. As for the long-term toxicity, BU-OE showed no apparent toxic effects except minor cardiotoxic effects which were reversible. In conclusion, submicron emulsion is a suitable delivery system for oral administration of bufadienolides, with satisfactory stability, superior antitumor efficacy and low toxicity.

A highly stable norcantharidin loaded lipid microspheres: preparation, biodistribution and targeting evaluation.

The purpose of this study was to prepare norcantharidin (NCTD)-loaded lipid microspheres (LMs) with a high encapsulation efficiency (EE) and stability during sterilization. The NCTD-phospholipid complex (NPC) was produced and characterized to increase the lipophilic properties of NCTD and a novel concentrated homogenization method was applied for the preparation of LMs. The results of the UV, DSC and IR investigations confirmed the formation of NPC. The oil-water partition coefficient (log P) of NPC was significantly increased with a value of -1.34 ± 0.06 at pH 7.4, nearly 224 times higher than that of NCTD. A concentrated emulsion was prepared based on a homogenization method and then diluted with water. After optimization of the NPC formation and emulsion preparation process, the EE was dramatically increased from 21.6% to 84.6%, and a highly sterilization stability was achieved with only a minor change in particle size from 168.2 ± 39.4 nm to 173.4 ± 43.5 nm. The tissue distribution of NPCLM was measured after intravenous administration to rats of a dose of 3.9 mg/kg with NCTD injection (NI) as the reference. Considerably increased concentrations of NCTD in the liver, spleen and lung were detected with NPCLM and the values were 1.67, 1.49 and 1.06 times higher than in the NI group, respectively while, in the kidney, the concentration was slightly reduced 0.96-fold. Overall, based on these techniques, this NPCLM with an improved EE and stability offers great promise in clinical applications and industrial-scale production along with a potentially increased targeting effect on the liver and reduced toxicity in the kidney.

Development and application of a UPLC-MS/MS method for the pharmacokinetic study of 10-hydroxy camptothecin and hydroxyethyl starch conjugate in rats.

With the purpose to carry out the pharmacokinetic studies of 10-hydroxy camptothecin (10-HCPT) and hydroxyethyl starch (10-HCPT-HES) conjugate, an ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method has been developed and validated. The analytes, 10-HCPT and the internal standard, Diphenhydramine hydrochloride were extracted with ethyl acetate-isopropanol (95:5, v/v) and separated on an ACQUITY UPLC™ BEH C18 column using a mobile phase composed of acetonitrile and water (containing 0.1% formic acid) with a linear gradient program. With positive ion electrospray ionization (ESI), the analytes were monitored on a triple quadrupole mass spectrometer in the multiple reaction monitoring (MRM) mode. Linear calibration curves were obtained over the concentration ranges of 0.5-2500ng/mL. The intra- and inter-day precisions were less than 9.8% and 10.8%, respectively. The accuracy was within 12.1%. The mean recoveries of 10-HCPT at three concentrations of 2.5, 100, 2000ng/mL were higher than 87.2%. Commercial 10-HCPT injection and 10-HCPT-HES conjugate were administered intravenously at an equal dose of 10-HCPT at 0.5mg/kg. The biological half-life of conjugate was increased significantly from 10min to 3.15h and the bioavailability was 40 times higher than 10-HCPT injection. Consequently, the proposed UPLC-ESI-MS/MS method was proved to be sensitive, specific and reliable to analyze 10-HCPT in biological samples; 10-HCPT and HES conjugate is a promising strategy for delivery of 10-HCPT with prolonged half time and improved bioavailability.

Lipid emulsions in parenteral nutrition: current applications and future developments.

INTRODUCTION: A parenteral lipid emulsion (LE), used as a key source of energy, essential fatty acids (FAs), and fat-soluble vitamins, is an integral part of a parenteral nutrition (PN) regimen. The conventional LEs, such as soybean oil (SO)-based emulsions, have caused concerns about the potential adverse effects involving oxidative stress, inflammation, and immune response probably because of undesirable FA composition. AREAS COVERED: Recently, alternative LEs, optimizing the FA composition with partial substitution of SO with medium-chain triglyceride (MCT), olive oil (OO), and fish oil (FO), have been developed and applied in clinical practice. This review summarizes the characteristics and beneficial clinical effects of alternative parenteral LEs in critically ill, pediatric, and long-term PN patients. EXPERT OPINION: More clinical data from sufficiently high-powered studies are required to characterize the integral biological properties of alternative LEs for further selection to fit individual needs and disease characteristics. Simultaneously, potential lipid sources with desirable FA compositions and biological properties should be selected to develop new therapeutic LEs. As supplements to current parenteral lipids, the new LEs with different therapeutic effects are expected to fit specified subpopulations of patients with different diseases. Great efforts should be devoted to the development of parenteral LEs.

Increased absorption of mangiferin in the gastrointestinal tract and its mechanism of action by absorption enhancers in rats.

The therapeutic efficiency of mangiferin is restricted by its low intestinal permeability. In order to improve the oral absorption of mangiferin, potential of enhancers, including TPGS, sodium deoxycholate and Carbopol 974P, were investigated in a series of in vivo experiments. After administration of mangiferin at a dose of 30 mg/kg combining with sodium deoxycholate, the bioavailability of mangiferin increased four-fold, and this may be due to sodium deoxycholate weakening the compactness between lecithin molecules and increased the paracellular permeability. When Carbopol 974P (100 mg/kg) was combined with mangiferin, the oral bioavailability of it increased seven-fold compared with the control group, and this may be related to the mucoadhesive properties of Carbopol 974P and paracellular drug permeation. However, following coadministration of TPGS (50 mg/kg), the oral absorption of mangiferin increased slightly compared with that of the control group (p > 0.05). The increased oral absorption by the three coexcipients was in the order of Carbopol 974P > sodium deoxycholate > TPGS. The absolute bioavailability of mangiferin in the three different doses following oral administration were evaluated based on the AUC(0-t) of the intravenous dose and there was no increase from low doses to high doses (25 mg/kg to 100 mg/kg). The above results show that the low absorption of mangiferin was due to presence of a narrow absorption window, which may also exist in these compounds, which have structures similar to mangiferin including three fused aromatic rings with polyphenolic hydroxyl groups. Bioadhesion polymers are effective enhancers of the absorption of mangiferin in the gastrointestinal tract.