Effect of phospholipid composition on characterization of liposomes containing 9-nitrocamptothecin.

9-Nitrocamptothecin (9-NC), a newly developed camptothecin derivative, had poor solubility in any pharmaceutically acceptable solvents. One way of improving the solubility is to formulate the drug into liposomes. However, 9-NC has low affinity to lipid membranes resulting in a very low drug-to-liposome entrapment. We developed a novel liposome-based 9-NC formulation which was composed of soybean phosphatidylcholine (SPC), hydrogenated soybean phosphatidylcholine (HSPC), and cholesterol. Compared with conventional liposomes composed of only SPC and cholesterol, 9-NC/lipid molar ratio increased from 1:72 to 1:18 while incorporation efficiency was still maintained about 80%. In addition, after 9-NC was encapsulated into novel liposomes, pharmacokinetic results revealed an increase in area under the plasma concentration-time curve (AUC) and a decrease in distribution volume of 9-NC following intravenous administration to rats. Increased stability in plasma may account for the improved pharmacokinetic behavior of the novel liposomes. Effect of HSPC/SPC molar ratio on characterization of the novel liposomes was also investigated. Except for drug/lipid molar ratio and encapsulation efficiency, HSPC/SPC molar ratio had only a little effect on other properties of novel liposomes. In conclusion, the study suggests that the novel liposomes can act as promising carriers for hydrophobic substances such as 9-NC.

Gastrointestinal absorption enhancement of insulin by administration of enteric microspheres and SNAC to rats.

The preparation and characteristics of insulin enteric microspheres (EMS) were studied and the gastrointestinal absorption enhancement of insulin by co-administering EMS with sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) was determined. The w/o/w and o(1)/o(2) emulsion solvent evaporation methods were used to prepare insulin-hydroxypropyl methylcellulose phthalate (HPMCP) EMS. High-performance liquid chormatography determined the drug loading, entrapment efficiency, stability to pepsin, and drug dissolution rate in hydrochloric acid solution (pH 1.2) and phosphate buffer solution (pH 6.8). The hypoglycaemic effect was studied by orally administrating the insulin EMS and SNAC to rats. The particle size of EMS (o(1)/o(2)) and EMS (w/o/w) was about 500 and 30 micro m respectively, and drug loading was 7 and 3% respectively. After being incubated with 18 micro g/mL pepsin solution (pH 1) at 37 degrees C, only 20% of insulin in EMS (o(1)/o(2)) was digested within 4 h, while 60% of the insulin in EMS (w/o/w) was digested within 1 h. In hydrochloric acid solution (pH 1.2), EMS (o(1)/o(2)) had less drug dissolution than EMS (w/o/w). In phosphate buffer solution (pH 6.8), the entire drug release time of EMS (o(1)/o(2)) and EMS (w/o/w) was 75 and 10 min, respectively. After orally administering with SNAC, EMS (o(1)/o(2)) could decrease the blood glucose level of rats remarkably and maintain the hypoglycaemic effect for 4 h, while EMS (w/o/w) had just a weakly hypoglycaemic effect. The results showed that the characteristics-optimized EMS, i.e. EMS (o(1)/o(2)) incorporating SNAC, could enhance insulin absorption significantly in the gastrointestional tract by taking advantage of both protection from enzyme degradation and improvement of drug permeability.

[Transdermal delivery of cyclosporin A solubilized in mixed micelles through mice skin].

AIM: To investigate the transdermal delivery effects of cyclosporine A solubilized in mixed micelles composed of phospholipid and different surfactants. METHODS: When applied onto the excised abdominal skin of the mice occlusively, the enhancing effects of various mixed micelles on the penetration of cyclosporin A were assessed by an in vitro permeation technique. In vivo study was carried out by topical application of sodium cholate-phospholipid mixed micelles onto the mice skin and drug blood concentration was detected. RESULTS: In vitro, mixed micelles containing different surfactants displayed distinct permeability and corresponded to the following order: sodium cholate > sodium deoxycholate > Trition X-100 > Tween-20. In vivo, peak drug concentration was detected at 5 h and after that the concentration fell down slowly. CONCLUSION: Mixed micelles were shown to be efficient carrier for the transdermal delivery of the lipophilic polypeptide when kept in solution during the application process.

[Permeation of buspirone hydrochloride across animal buccal mucosa and its mechanism].

AIM: To study the permeation of busprione hydrochloride across animal buccal mucosa and its permeation mechanism. METHODS: The in vitro penetration model was designed to investigate drug buccal mucosa permeability, and the influence factors (different animal oral mucosa, such as rabbit, guinea pig, pig, sheep and cow, drug concentrations and solution pH values) were measured. RESULTS: The permeability of rabbit buccal mucosa for busprione hydrochloride was the largest. The permeation rate was increased with solution pH and directly to the drug concentration. CONCLUSION: The transport way of busprione hydrochloride was passive diffusion and the transport channel was through cells.

Microencapsulation and characterization of tramadol-resin complexes.

Tramadol was complexed with a sulfonic acid cation-exchange resin by a column method. Microencapsulation of tramadol-resin complexes (TRC) was carried out by the spray-drying method. The effect of ethylcellulose (EC) of various viscosities, different solvent systems and addition of plasticizers on microencapsulation were investigated. The morphology of microcapsules was characterized by scanning electron microscopy (SEM). Selected solvents having similar toxicity levels while various physico-chemical properties resulted in greatly different microcapsules. Regular particle morphology and sustained-release behavior were obtained when dichloromethane or ethyl acetate was used as the solvent system, whereas ethanol produced a substantial number of coalesced microcapsules and acetone produced apparently surface-smooth monomicrocapsules with faster release behavior. Three kinds of plasticizers affected the drug release rate similarly. On the addition of plasticizer (DEP), the drug release rate from the microcapsule obtained from low viscosity-grade EC reduced, while there was no alternation for those obtained from middle viscosity-grade EC. Compared to EC with a viscosity of 100 cP, which produced multi-microcapsules and released 60% of the drug within 1 h, microcapsules prepared with 10, 20 and 45 cP viscosity-grade EC showed slower drug release and regular and smooth morphology.

[Transdermal delivery mechanisms of lecithin nanoparticles with cyclosporin A through mice skin].

AIM: To investigate the transdermal delivery mechanisms of the flexible nano-liposomes, conventional nano-liposomes and lecithin-cholate mixed micelles through mouse skin. METHODS: Liposomes and micelles were applied onto the mouse skin non-occlusively in vitro and in vivo, then the drug concentrations in the skin, receiver and blood were determined. RESULTS: In vitro permeation studies showed that flexible nano-liposomes and mixed micelles transported measurable amount of cyclosporin A through the skin. Conventional liposomes precluded drugs permeate through the skin while deposited it in the skin. In vivo studies indicated that blood concentration reached peak value at 8 h after the application of flexible nano-liposomes. Both conventional nano-liposomes and mixed micelles failed to deliver measurable amount of drug into the blood. CONCLUSION: Liposomes fuse with the skin. Flexible nano-liposomes penetrate through the skin under the pressure of hydration force. Mixed micelles promote transfer in state of solution.

Enhancing effect of essential oils on the penetration of 5-fluorouracil through rat skin.

Three essential oils as penetration enhancers for 5-fluorouracil (5-FU) were studied using excised rat skin. The oils used were eucalyptus, peppermint and turpentine. Azone was used for comparison. The enhancing effect of the oils was found to be less than that of azone, but all the oils used enhanced the permeation of 5-FU. Eucalyptus oil was found to be the most active, causing about 60 fold increase, while peppermint and turpentine caused 46 and 28 fold increase, respectively. Eucalyptus oil was further studied by grading it into 5 fractions according to difference in boiling points. It was found that their activities increased as their boiling point increased. With all enhancers increased partition coefficients were observed but the diffusion coefficient values obtained were comparatively higher. The mode of action of these accelerants may be described by combined processes of partition and diffusion, the diffusion process being dominant.

[The bioavailability of transdermal therapeutic system of timolol].

A matrix-type transdermal therapeutic system of timolol (TTS-timolol) was well prepared. The patch consisted of backing membrane layer, timolol reservoir layer, pressure sensitive adhesive layer and protective layer. A sensitive and reliable HPLC-UV method for the determination of plasma level of timolol in healthy volunteers was developed. Effective therapeutic plasma level of timolol (4 ng/ml) was attained 4 h after application of the timolol patches and was maintained within 32 h while the patch was removed at 24 h. The pharmacokinetic behavior of this transdermal therapeutic system (TTS)-timolol in human showed zero order absorption and well fitted to a one compartment model. The pharmacokinetic parameters are: Tmax = 18.8 h; Cmax = 11.2 ng/ml; AUC = 265.7 ng/ml.h; Vss = 120.0 L; K = 0.084 h-1. In comparison with the results of oral administration of timolol tablets, TTS-timolol possesses some advantages: stable plasma level, long effective time and convenient administration.

[Role of stratum corneum and its lipids in permeability of 5-fluorouracil through human skin].

The role of stratum corneum (SC) and its lipid constituents in skin permeability was assessed in vitro in diffusion system combined with the determination of partition coefficients (PC) and DSC technique. 5-Fu and 1,8-CN were used as the hydrophilic drug and penetration enhancer, respectively. The results showed that the PCs of 5-Fu were the same in SC, delipid SC, full skin and SC-stripped full skin, but the diffusion coefficients (D) of 5-Fu were different from each other. They were 1.32 +/- 0.37 x 10(-7), 13.71 +/- 5.12 x 10(-7), 1.01 +/- 0.31 x 10(-7) and 540.85 +/- 50.99 x 10(-7) cm2/h, respectively. When the skin membranes were pretreated with 1,8-CN for 12 h, the PCs were reduced to similar extent. However, the D was increased significantly in SC and in full skin, there was a small increase for delipid SC. No change was found in the D of stripped skin. DSC analysis indicated that 1,8-CN might change the thermal behaviour of SC lipid and the influence disappeared when SC was extracted with organic solvent. These results suggest that SC was the main barrier for 5-Fu diffusion through human skin, and the intercellular lipids played an important role for the hydrophilic drug penetration regardless of the presence of the enhancer in SC.