[Recent development of natural and reconstituted lipoprotein based nano drug delivery vehicles].

Lipoproteins are biological lipids carriers. The natural and reconstituted lipoprotein based drug delivery systems have been extensively developed in recent years. This article reviews the development of natural and reconstituted low-density lipoprotein and high-density lipoprotein based vehicles in the antitumor area.

Solidified mPEG-PDLLA micelles as a novel oral delivery system of indomethacin.

In this study, indomethacin (IND) loaded solidified-polymeric micelles (IND-SPM) were prepared. Their in vitro characteristics were investigated. Methoxy-poly(ethylene glycol) poly(D, L-lactide) copolymer (mPEG-PDLLA) was used as IND carrier. The preparation of IND-SPM was conducted by solution-absorption method and evaporation by rotary evaporator. Polyplasdone XL-10 was used as adsorbent. The solution-absorption method was conducted by the following procedure; IND and mPEG-PDLLA were dissolved in acetone, followed by addition of polyplasdone XL-10 and stirred to obtain a suspension. The powder of IND-SPM was simply obtained after the organic solvent was completely evaporated. More than 90% (w/w) of IND (20 mg) in the powder was dissolved in 250 mL PBS within 30 min. DSC, 1H NMR and SEM results proved that IND was encapsulated within mPEG-PDLLA. The solubility of IND in the system increased 4.6 times with the highest amount of copolymer. The solidified particles were found to be suitable for the formulation of tablets or capsules.

[Water in oil microemulsions containing NaCl for transdermal delivery of fluorouracil].

This study is to prepare the W/O microemulsion containing NaCl and fluorouracil (5-Fu) as a model drug to investigate the transdermal characteristics and skin irritation of the microemulsion in vitro. Isopropylmyristate (IPM) acting as oil phase, Aerosol-OT (AOT) as surfactant, Tween 85 as cosurfactant, NaCl solution was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, and then 5-Fu powder was added. According to the area of microemulsion based on the pseudo-tertiary phase diagrams, the optimum formulation was screened initially. And the permeation flux of fluorouracil across excised mice skin was determined in vitro using Franz diffusion cells to study the influence of the amount of water and the drug loading capacity and optimize the formulation further. Refer to 5-Fu cream, the irritation of microemulsion on the rat skin was studied. The optimum formulation was composed of 0.7% (w/v) 5-Fu, 50% NaCl solution (0.05 mol x L(-1)), 20% mix-surfactant (AOT/Tween 85, K(m) = 2) and 29.3% oil (IPM). The cumulative amount of fluorouracil permeated in 12 h was (2 013.4 +/- 41.6) microg x cm(-2), 20.23 folds and 10.38 folds more than 0.7% fluorouracil aqueous solution and 2.5% (w/w) fluorouracil cream, respectively. Microemulsion exhibited some irritation, but could be reversed after drug withdrawal. The addition of NaCl significantly increased the content of water and the drug loading in microemulsion systems. The NaCl/AOT-Tween 85/IPM microemulsion system promoted the permeation of fluorouracil greatly, which may be a promising vehicle for the transdermal delivery of fluorouracil and other hydrophilic drug.

[Microemulsion-based gel of fluorouracil for transdermal delivery].

This study is to prepare the microemulsion-based gel based on the W/O microemulsion and fluorouracil (5-Fu) as a model drug to study the transdermal characterization and observe its skin irritation of the microemulsion-based gel in vitro. IPM acted as oil phase, AOT as surfactant, Tween 85 as cosurfactant, water was added dropwise to the oil phase to prepare W/O microemulsion at room temperature using magnetic stirring, then 5-Fu powder was added. The gelatin was used as substrate to prepare 5-Fu microemulsion-based gel. The permeation flux of 5-Fu from 5-Fu microemulsion-based gel across excised mice skin was determined in vitro using Franz diffusion cell to study the influence of the amount of gelatin and the drug loading capacity. Refer to 5-Fu cream, the irritation of microemulsion and microemulsion-based gel on the rat skin was studied. Based on the water/AOT/Tween 85/IPM microemulsion, only the gelatin can form the microemulsion-based gel. At 25 degrees C, 32 degrees C and 40 degrees C, the amount of gelatin required for the formation of microemulsion-based gel were 7%, 14% and more than 17%, respectively. The 12 h transdermal cumulated permeation amount of 5-Fu from microemulsion-based gel containing 14% gelatin and 0.5% drug loading were (876.5 +/- 29.1) microg x cm(-2), 12.3 folds and 4.5 folds more than 0.5% 5-Fu aqueous solution and 2.5% (w/w) 5-Fu cream, respectively. Microemulsion-based gel exhibited some irritation, but could be subsided after drug withdrawal. Microemulsion-based gel may be a promising vehicle for transdermal delivery of 5-Fu and other hydrophilic drug.

[Water in oil microemulsions for transdermal delivery of fluorouracil].

An Aersol-OT (AOT) included microemulsion containing fluorouracil was prepared by using appropriate proportion of oil, co-surfactant and water for increasing the drug transdermal delivery ability. According to the area of microemulsion basing on the pseudo-tertiary phase diagrams, the optimum formulation was screened initially. And the permeation flux of fluorouracil across excised mice skin was determined in vitro using Franz diffusion cell to optimize the formulation further. The effect of the kind of co-surfactant, the content of water, the content of mixed surfactant, the mass ratio of surfactant/cosurfactant (Km) and the drug load on skin permeation of fluorouracil were evaluated. The optimum formulation was composed of 0.5% (w/v) fluorouracil, 30% water, 20% mix-surfactant (AOT/Tween 85, Km = 2) and 49.5% oil (IPM). The cumulative amount permeated of fluorouracil in 12 hour was 1 355.5 microg x cm(-2), 19.1 folds and 7 folds more than 0.5% fluorouracil aqueous solution and 2.5% (w/w) fluorouracil cream, respectively. The permeation of this microemulsion accorded with first-order model. The water/AOT/Tween 85/IPM microemulsion system promoted the permeation of fluorouracil greatly, which may be a promising vehicle for the transdermal delivery of fluorouracil and other hydrophilic drug.

Distribution of nobiletin chitosan-based microemulsions in brain following i.v. injection in mice.

The purpose of this study was to characterize the in vitro properties of a number of chitosan-based microemulsions containing nobiletin and determine its distribution in mice brain following i.v. administration. The phase behavior and properties of chitosan-based microemulsions were investigated in a pseudo-ternary system composed of polyoxyethylene 35 castor oil/benzyl alcohol/medium-chain triglyceride/tea oil/water with the chitosan. The droplet sizes were found to be smaller than 25 nm by photo correlation spectrometer. The nobiletin-loaded hyaluronic acid chitosan-based microemulsion (HAC-ME) carried negative charge and nobiletin-loaded hydrochlorate chitosan-based microemulsion (HCC-ME) carried positive charge. The concentrations of nobiletin in tissues were determined by HPLC after i.v. administration of HAC-ME, nobiletin-loaded microemulsion (ME), HCC-ME and nobiletin solution. Based on AUC(0-t), MRT and C(max), HAC-ME delivered more nobiletin to the brain compared to nobiletin solution, ME and HCC-ME. The long-circulation effect might contribute to the higher AUC(0-t) for HAC-ME in brain. On the other hand, the AUC(0-t) in plasma and brain after i.v. administration of HCC-ME were not significantly increased relative to ME. These results indicate that HAC-ME may be presented as potential candidates for delivering more drugs into the brain.

[Distribution behavior of lipophilic drugs in the oil-in-water microemulsions].

Distribution behavior of lipophilic drugs in the oil-in-water (O/W) microemulsions was studied. Fluorescence spectra analysis was performed to investigate the effect of the compositions of microemulsions on the fluorescence spectra of armillarisin and ofloxacin which were used as the model drugs. The fluorescence spectra of the model drugs in the microemulsions with various amount of the compositions were compared. The results showed that the armillarisin were both localized in the interfacial film of microemulsion systems with both phenylmethanol and PEG 400 as the co-surfactants, separately. Ofloxacin was localized in the interfacial film of microemulsion systems with Gradamol GTCC as the oil phase, but in the oil pool of microemulsion systems with oleic acid/olive oil (OA/OO) (1:1) as the oil phase. Besides, it was found that the drug would have the tendency to locate in the microenvironment where the composition with the largest solubility to model drug is located, and its actual localized position would be dependent on the amount of this composition. The results indicate that the localized region of lipophilic drug in the O/W microemulsion systems is related with the solubility of the model drug in various compositions.

[Free amino groups on the surface of chitosan nanoparticles and its characteristics].

The relationship of free amino groups on the surface and the characteristics of chitosan nanoparticles (CS-NPs) prepared by ionic gelation method was investigated. Free amino groups on the surface of CS-NPs were determined by colloidal titration, and the effects of the amount of free amino groups and its ionizable level on the particle size, zeta potential, appearance, drug entrapment efficiency and drug release profile in vitro of CS-NPs were investigated. The result showed that the surface free amino groups reduced, the average size, zeta potential, stability of nanoparticles, and the drug release rate and degree all decreased while the drug entrapment efficiency was not affected with the increase of tripolyphosphate (TPP) concentration. With the increase of pH, the free amino groups could be deprotonated and the ionizable level was stepped down, correspondingly the particle size and zeta potential of CS-NPs decreased. Additionally, the drug release rate and degree were elevated in acid medium while descended in neutral or base medium. The amount and ionizable level of free amino groups on the surface are affected by the gelation degree and pH, which further affected the volume phase transitions (swelling/shrinking processes) of CS-NPs. The properties of CS-NPs have correlation with the surface free amino groups.

[The simultaneous determination of laetrile, paeoniflorin and paeonol in Jingzhi Guizhi Fuling capsule by HPLC].

OBJECTIVE: To establish an HPLC method for the simultaneous determination of three major bioactive components in Jingzhi Guizhi Fuling capsules namely laetrile, paeoniflorin and paeonol. METHOD: A LiChrospher C18 column (4.6 mm x 250 mm, 5 microm) was used. The chromatography was carried out with a stepwise gradient programming. The mobile phase was acetonitrile-water (containing 0.1% phosphorous acid) and the flow rate was 1.0 mL x min. RESULT: The linear range of laetrile was 12.87-102.94 micron x mL(-1), r = 0.999 9, paeoniflorin 24.84 - 198.7 microg x mL(-1), r = 0.9999 and paeonol 12.57-100.56 microg x mL(-1), r = 0.999 9. The method is accurate with variation less than 1.5 % and recovery more than 95 %. CONCLUSION: The method was successfully applied to analyze three major bioactive components in Jingzhi Guizhi Fuling capsules.

[Mechanisms of action of transportation of liposomes and chitosan-coated liposomes containing leuprolide across intestine and Caco-2 cell].

AIM: To investigate the mechanisms of action of transportation of liposomes and chitosan-coated liposomes containing leuprolide across rat intestine and Caco-2 cell. METHODS: Everted-gut technique and Caco-2 cell were used to study the transport properties of free leuprolide, liposomes and chitosan-coated liposomes containing leuprolide. Caco-2 cell was used to study the effect of chitosan concentration and the order of addition on the permeation of liposomes. RESULTS: The transport of leuprolide was passive diffusion. Probably because the entrapment by liposomes prevents the transport of leuprolide across the rat intestine and Caco-2 cell, the permeation amount of leuprolide from liposomes was lower than that of the free drug. However, liposomes protected the leuprolide from degradation. Chitosan promoted the transport of leuprolide from liposomes and there was no obvious difference in enhancement effect from the concentration of 0.1% to 0.5%. On the other hand, the incubation of chitosan with liposomes may weak the enhancement effect of chitosan. CONCLUSION: Chitosan-coated liposomes showed both protection and enhancement effect, therefore, they may promote the oral absorption of leuprolide.

[In vitro and in vivo stability of 9-nitrocamptothecin lactone form in rats].

AIM: To investigate the in vitro and in vivo stability of 9-nitrocamptothecin lactone form in rat plasma. METHODS: The specific and accurate HPLC method was developed for quantifying 9-nitrocamptothecin lactone form and the total lactone and carboxylate forms simultaneously. By using of this method, the ratios of lactone form to the total in rat plasma at different time were determined in vitro and in vivo. The results were compared to determine which was the main factor influencing the stability of 9-nitrocamptothecin lactone form in rat plasma in vivo. RESULTS: The stability of lactone form in rat plasma was much higher in vivo than that in vitro. CONCLUSION: Blood cells help to increase the stability of 9-nitrocamptothecin lactone form. Clearance from blood in vivo is the primary factor which influences the plasma stability of 9-nitrocamptothecin lactone form. The kinetic process of 9-nitrocamptothecin lactone form and total drug in rats were both best fitted to a two-compartment model. However, the process of 9-nitrocamptothecin carboxylate form in vivo was best fitted to a one-compartment model.