The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol(R), sodium cholate, sodium caprate, hydroxypropyl beta-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and Papp of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC0-24 h of ZMR in the lungs following oral administration of PO-SC was 125.22 +/- 27.25 ng hr ml(-1) with a Cmax of 156.00 +/- 24.00 ng/ml reached at 0.50+/-0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC50 concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.
Administration, Oral ; Animals ; Biological Availability* ; Caco-2 Cells ; Humans ; Influenza, Human ; Inhibitory Concentration 50 ; Lung* ; Orthomyxoviridae ; Permeability ; Plasma* ; Rats* ; Sodium ; Sodium Cholate ; Zanamivir*

OBJECTIVETo prepare tanshinone transfersome (TTs) and evaluate its deformability.

METHODSThe transfersomes were prepared by film dispersion method followed by sonication, and their physical properties, morphology, content, entrapment efficiency, particle size, polydispersity, and Zeta potential were investigated. The stability and deformability of TTs were studied. Liposomes with different molar ratios of cholate and lecithin were compared for their permeability under external pressure.

RESULTSThe prepared TF were spherical vesicles with content of 1.0192+/-0.075 mg/ml, entrapment efficiency of (62.3+/-0.08)%, particle size of 110 nm, polydispersity of 0.19 and Zate potential of -15.0 mV. The TTs remained stable during light-proof preservation for 3 months at 4 degrees C, and sodium cholate contributed to the flexibility of the lecithin vesicles.

CONCLUSIONTTs prepared by film dispersion method has good entrapment efficiency and stability. The vesicles possess high deformability in relation to the molar ratio of sodium cholate to lecithin and the external pressure.

Diterpenes, Abietane ; Drug Compounding ; methods ; Lecithins ; chemistry ; Liposomes ; chemistry ; Microscopy, Electron, Transmission ; Particle Size ; Phenanthrenes ; chemistry ; Sodium Cholate ; chemistry ; Technology, Pharmaceutical ; methods ; Temperature

Animals ; Blood Glucose ; metabolism ; Colon ; metabolism ; ultrastructure ; Hypoglycemic Agents ; pharmacokinetics ; Immunohistochemistry ; Insulin ; pharmacokinetics ; Intestinal Absorption ; drug effects ; Male ; Microscopy, Electron ; Rats ; Rats, Sprague-Dawley ; Sodium Cholate ; pharmacology

This study investigated that the antioxidative effect of freeze-dried cranberry powder against protein and lipid oxidation and ameliorative effect of serum lipid profile in rat fed atherogenic diet. Six weeks old male Sprague-Dawley rats were divided into the following four groups: normal diet group with 5% corn oil (control), atherogenic diet group with 5% corn oil, 10% lard, 1% cholesterol, and 0.5% sodium cholate (HFC), atherogenic plus 2% cranberry powder diet group (HFC + C2), and atherogenic plus 5% cranberry powder diet group (HFC + C5), and respective diet and water were fed daily for 6 weeks. After the experimental period, the serum lipid profile, such as total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride, ferric reducing ability of plasma (FRAP), plasma phenolics content, superoxide dismutase (SOD) activity, serum protein carbonyl and thiobarbituric acid reactive substances (TBARS) levels were examined. Total phenolic compound and total flavonoid levels in freeze-dried cranberry powder were 9.94 mg/g and 8.12 mg/g, respectively. Serum total cholesterol and LDL-cholesterol levels were not significantly different for cranberry powder treatment, but serum HDL-cholesterol level was significantly increased in HFC + C5 group compared with HFC group. Plasma FRAP value tended to be increased by cranberry powder treatment though there was no significant difference. Plasma total phenol concentrations and SOD activities were not significantly different among all groups. Serum protein carbonyl and TBARS levels were significantly decreased in HFC + C5 group compared with HFC group. Overall results suggested that freeze-dried cranberry powder might have the serum lipid improving effect, as well as antioxidative effect demonstrated by its protective effect against protein and lipid oxidation.
Animals ; Biomarkers ; Cholesterol ; Corn Oil ; Diet ; Diet, Atherogenic ; Dietary Fats ; Humans ; Male ; Oxidative Stress ; Phenol ; Plasma ; Rats ; Rats, Sprague-Dawley ; Sodium Cholate ; Superoxide Dismutase ; Thiobarbiturates ; Thiobarbituric Acid Reactive Substances ; Vaccinium macrocarpon ; Water

AIMTo prepare capsaicin transfersomes and evaluate them in vitro and in vivo.

METHODSCapsaicin transfersomes were prepared by high shear dispersing machine and evaluated by entrapment efficiency, release rate, in vitro skin permeation and distribution in different tissues in vivo.

RESULTSCapsaicin transfersomes were composed of single unilamellar vesicles with an average diameter of 150.6 nm. Capsaicin entrapment efficiency increased distinctly with increasing of concentration of lecithin and entrapment efficiency is 96.7% while concentration of lecithin to 8%. Cumulative release amount of capsaicin is in direct proportion to the ethanol concentration in the receptor medium. In vitro capsaicin cumulative penetration amount showed higher levels in transfersomes than cream and suspension in rat abdominal skin. Abdominal skin cumulative penetration amount in vitro of capsaicin transfersomes in mouse was significantly higher than that from rat and men. In the same way, abdominal skin epidermal membrane cumulative penetration amount in vitro of capsaicin transfersomes was significantly higher than that from derma and full skin in human abdominal skin. The capsaicin tissue distribution of capsaicin injection by multiple celiac injections in rats is different: bone > plasma > skin > muscle. There is a similar result by multiple thigh topical application of capsaicin transfersomes: bone > skin > plasma > muscle.

CONCLUSIONEntrapment efficiency of capsaicin transfersomes reached the criterion of China Pharmacopoeia (> 80%) and capsaicin skin penetration can be increased by capsaicin transfersomes. It should be noted that the diverse characters and levels of skin may probably affect the permeating capability of capsaicin. Capsaicin tissue distribution in bone and muscle is similar and is different in plasma and skin by multiple injections and topical skin apply.

Administration, Cutaneous ; Animals ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; pharmacokinetics ; Capsaicin ; administration & dosage ; pharmacokinetics ; Drug Carriers ; Drug Delivery Systems ; Humans ; Lecithins ; chemistry ; Male ; Mice ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Skin Absorption ; Sodium Cholate ; chemistry ; Tissue Distribution

AIMTo study the relationship between cellular membrane fluidity and relative bioavailability (Fr) of protein and peptide drugs combined with absorption enhancers after pulmonary administration in rats.

METHODSA series of model drug salmon calcitonin (sCT) solutions with 6 absorption enhancers (Brij78, sodium cholate, sodium caprylate, 2-hydroxypropyl-beta-cyclodextrin, lecithin and chitosan) were prepared and then delivered to rats by pulmonary route. Serum drug concentration was determined by radioimmunoassay method. Using the techniques of electron spin resonance and fluorescence polarography, the effects of enhancers on pulmonary cellular membrane fluidity were investigated.

RESULTSFr values of sCT solution with some absorption enhancers (Brij78, sodium cholate, sodium caprylate, lecithin and chitosan) were significantly higher than those without enhancers. Brij78, lecithin and sodium caprylate, not only increased membrane lipid fluidity but also loosed the constitution of membrane protein. The effect of sodium cholate on membrane protein was low. Lipid fluidity was reduced and protein constitution was changed markedly, after pulmonary cellular membrane was treated by 0.5% chitosan solution. This result showed that the absorption enhancing of chitosan mainly came from its effects on membrane protein. Corresponded with lower Fr after pulmonary administration, 2-hydroxypropyl-beta-cyclodextrin (0.5% and 3%) had not significant effects on both lipid fluidity and protein constitution.

CONCLUSIONThe effects of enhancers on pulmonary absorption of peptide drugs in vivo might be investigated on the grounds of determination of cellular membrane fluidity in vitro.

Absorption ; Animals ; Biological Availability ; Calcitonin ; administration & dosage ; pharmacokinetics ; Caprylates ; pharmacology ; Cell Membrane ; metabolism ; Chitin ; analogs & derivatives ; pharmacology ; Chitosan ; Drug Synergism ; Lung ; metabolism ; Male ; Membrane Fluidity ; drug effects ; Membrane Proteins ; drug effects ; Molecular Conformation ; Phosphatidylcholines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Sodium Cholate ; pharmacology