Preparation and Evaluation of a Self-Nanoemulsifying Drug Delivery System Loaded with Heparin Phospholipid Complex

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the absorption of heparin after oral administration, in which heparin was compounded with phospholipids to achieve better fat solubility in the form of heparin-phospholipid (HEP-Pc) complex. HEP-Pc complex was prepared using the solvent evaporation method, which increased the solubility of heparin in n-octanol. The successful preparation of HEP-Pc complex was confirmed by differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR) spectroscopy, NMR, and SEM. A heparin lipid microemulsion (HEP-LM) was prepared by high-pressure homogenization and characterized. HEP-LM can enhance the absorption of heparin after oral administration, significantly prolong activated partial thromboplastin time (APTT) and thrombin time (TT) in mice, and reduce fibrinogen (FIB) content. All these outcomes indicate that HEP-LM has great potential as an oral heparin formulation.     

Vitrification of aqueous suspensions from a controlled environment for electron microscopy: An improved plunge-cooling device

In the process of vitrifying aqueous suspensions for cryotransmission electron microscopy, water is solidified without crystallization. Vitrification can be achieved by rapidly plunging an aqueous thin film into a liquid cryogen. The preparation of aqueous thin films prior to vitrification must be performed in an environmental cabinet at controlled temperature and humidity in order to prevent evaporation and temperature-induced phase changes in the thin film. The device described here incorporates several important features which make the apparatus simpler and more convenient to use than similar devices described in the literature. One of these features includes the use of a totally enclosed environmental cabinet in which the grid, sample, micropipette and absorbent paper are equilibrated before thin-film preparation. Other features include a cryogen dewar on a swing arm for easy refilling, a guillotine shutter which is used to trigger the plunger electrically and a semiautomatic system which facilitates rapid transfer of the vitrified specimen from liquid propane to liquid nitrogen for storage and reduces handling of the specimen. To demonstrate the utility of the device, results showing the influence of temperature on the morphology of phospholipid vesicles are presented. A commercial cryotransfer apparatus (which is used for transportation of the vitrified specimen to the electron microscope cold-stage) has been modified to reduce the possibility of reversion of the vitreous phase to the crystalline ice phases.     

HPP－1型皮革加脂剂的研制和应用

本文概述了以磷酸化蓖麻油和羟化磷脂为基础的皮革加脂剂的研制，讨论了合成反应、产品配伍、应用试验等工艺过程。     

Solubilization of unilamellar liposomes by betaine-type zwitterionic/anionic surfactant systems

The mechanisms governing the solubilizing interactions between zwitterionic/anionic mixed surfactant systems at different molar fractions of the zwitterionic surfactant (X_zwitter) and neutral or electrically charged unilamellar liposomes were investigated. The mixed systems were formed by N-dodecyl-N,N-dimethylbetaine and sodium dodecyl sulfate in the presence of piperazine-1,4-bis-(2-ethanesulfonic acid) buffer at pH 7.20. Unilamellar liposomes formed by egg phosphatidylcholine, in some cases together with stearylamine or phosphatidic acid, were used. Solubilization was detected as a decrease in static light-scattering of liposomes. Two parameters were regarded as corresponding to the effective surfactant/lipid molar ratios (Re) at which the surfactant system (i) saturated the liposomes, Re_sat, and (ii) led to a total solubilization of liposomes, Re_sol. From these parameters the bilayer/aqueous medium surfactant partition coefficients for the saturation (K_sat) and complete bilayer solubilization (K_sol) were determined. When X_zwitter was 0.40, The Re and K parameters showed a maximum, whereas the critical micellar concentration (CMC) of these systems exhibited a minimum, regardless of the electrical charge of bilayers. Given that the ability of the surfactant systems to saturate or solubilize liposomes is inversely related to the Re_sat and Re_sol parameters, these capacities appear to be directly correlated with the CMC of the mixed systems. The similarity of both K_sat and K_sol (particularly for X_zwitter=0.2–0.8) suggests that a similar partition equilibrium governs both the saturation and the complete solubilization of bilayers, the free surfactant concentration (S_a,S_b), remaining almost constant with similar values to the CMC for each mixed system studied.     

Effect of pH on a gossypol complex with phospholipids: Gossypol-PE

PE, one of the major phospholipids in oilseed soapstock, may react with gossypol to form Schiff bases. PE amounts to 20–30% of the phosphorus compounds in soap-stock. In this report, the dependence on pH of the Schiff base products between PE and gossypol was investigated using a spectrophotometer, an HPLC equipped with an ELSD, and an LC-MS system. We observed that at pH 7 the Schiff reaction product and reactants were clearly detected by ELSD, absorption, and LC-MS spectra. The absorption spectra displayed the characteristic peak for the Schiff bases around 430–440 nm. The absorption spectra also indicated that the reaction was pH dependent. The reaction temperatures were 60 and 90°C. The LC-MS spectra supported the formation of Schiff bases as well as methyl ether derivatives of gossypol in alcohol at the elevated temperatures. The implications of these experimental findings are presented in this paper.     

Diffuse reflectance fourier transform infrared spectroscopy of phospholipid adsorption onto silicic acid

Diffuse reflectance Fourier transform infrared spectroscopy was used to study the mode of adsorption of phosphatidylcholine (PC) in hexane onto silicic acid (SA). PC adsorption was mainly through the charged phosphate group with minimal binding through the ester carbonyl. When the SA surface with adsorbed PC is washed with hexane, containing a small concentration of isopropanol, the desorbed PC is recovered without structural change, i.e., there is no evidence of PC hydrolysis in the adsorption process. Adsorbent misture probably promotes PC adsorption due to the increased availability of surface water hydroxyl groups for interaction with the PC phosphate groups. Isopropanol promoted PC binding by destabilizing PC reverse miscelles in solution, thus promoting its adsorption.     

Sorafenib delivery nanoplatform based on superparamagnetic iron oxide nanoparticles magnetically targets hepatocellular carcinoma

Currently,sorafenib is the only systemic therapy capable of increasing overall survival of hepatocellular carcinoma patients.Unfortunately,its side effects,particularly its overall toxicity,limit the therapeutic response that can be achieved.Superparamagnetic iron oxide nanoparticles (SPIONs) are very attractive for drug delivery because they can be targeted to specific sites in the body through application of a magnetic field,thus improving intratumoral accumulation and reducing adverse effects.Here,nanoformulations based on polyethylene glycol modified phospholipid micelles,loaded with both SPIONs and sorafenib,were successfully prepared and thoroughly investigated by complementary techniques.This nanovector system provided effective drug delivery,had an average hydrodynamic diameter of about 125 nm,had good stability in aqueous medium,and allowed controlled drug loading.Magnetic analysis allowed accurate determination of the amount of SPIONs embedded in each micelle.An in vitro system was designed to test whether the SPION micelles can be efficiently held using a magnetic field under typical flow conditions found in the human liver.Human hepatocellular carcinoma (HepG2) cells were selected as an in vitro system to evaluate tumor cell targeting efficacy of the superparamagnetic micelles loaded with sorafenib.These experiments demonstrated that this delivery platform is able to enhance sorafenib's antitumor effectiveness by magnetic targeting.The magnetic nanovectors described here represent promising candidates for targeting specific hepatic tumor sites,where selective release of sorafenib can improve its efficacy and safety profile.     

A lyophilized etoposide submicron emulsion with a high drug loading for intravenous injection: preparation,evaluation, and pharmacokinetics in rats

Objective: To develop a submicron emulsion for etoposide with a high drug loading capacity using a drug–phospholipid complex combined with drug freeze-drying techniques. Methods: An etoposide–phospholipid complex (EPC) was prepared and its structure was confirmed by X-ray diffraction and differential scanning calorimetry analysis. A freeze-drying technique was used to produce lyophilized etoposide emulsions (LEPE), and LEPE was investigated with regard to their appearance, particle size, and zeta potential. The pharmacokinetic study in vivo was determined by the UPLC/MS/MS system. Results: It showed that EPC significantly improved the liposolubility of etoposide, indicating a high drug loading intravenous emulsion could be easily prepared by EPC. Moreover, the obtained loading of etoposide in the submicron emulsion was 3.0 mg/mL, which was three times higher than that of the previous liquid emulsions. The optimum cryoprotectant was trehalose (15%) in freeze-drying test. The median diameter, polydispersity index, and zeta potential of the optimum formulation of LEPE were 226.1 ± 5.1 nm, 0.107 ± 0.011, and ?36.20 ± 1.13 mV, respectively. In addition, these parameters had no significant change during 6 months storage at 4 ± 2°C. The main pharmacokinetic parameters exhibited no significant differences between LEPE and etoposide commercial solution except for area under the concentration–time curve and clearance. Conclusions: The stable etoposide emulsion with a high drug loading was successfully prepared, indicating the amount of excipients such as the oil phase and emulsifiers significantly decreased following administration of the same dose of drug, effectively reducing the metabolism by patients while increasing their compliance. Therefore, LEPE has a great potential for clinical applications.