AIMTo study the enhancement effect and mechanism of sodium N-[8-(2-hydroxybenzyl) amino] caprylate (SNAC--a kind of synthetic enhancer) to insulin (INS) solution in gastrointestine.

METHODSTo determine the enhancement effect of SNAC on INS absorption by oral administration to rats and mice; To study the enhancement mechanism of SNAC by three kinds of methods: Delivering SNAC and INS solution to different parts of rats' intestines, adding energy inhibitor 2,4-dinitrophenol (DNP) or P-glycoprotein (P-gp) inhibitor verapamil (Ver) into SNAC and INS solution.

RESULTSSNAC was shown to enhance the gastrointestinal absorption of INS, the intensity of absorption enhancement corresponded to the doses of SNAC. The enhancement of SNAC to INS in different parts of the rat intestine was different (jejunum > colon > ileum). The effect of SNAC on INS absorption increased accordingly.

CONCLUSIONThe enhancement of SNAC to INS absorption presented dose dependence on SNAC; the absorption process needed energy and related to P-gp efflux.

2,4-Dinitrophenol ; pharmacology ; Animals ; Caprylates ; administration & dosage ; pharmacology ; Colon ; metabolism ; Dose-Response Relationship, Drug ; Ileum ; metabolism ; Insulin ; metabolism ; Intestinal Absorption ; drug effects ; Jejunum ; metabolism ; Male ; Mice ; Rats ; Rats, Sprague-Dawley ; Verapamil ; pharmacology

The purpose of this study was to prepare the nobiletin-loaded nanoemulsions (NOB-NE) and study its in vivo distribution in mice. The characteristics and stability of the unloaded and drug-loaded nanoemulsions were investigated. The size, apparent viscosity and pH value of NOB-NE were respectively (15.5 +/- 2.9) nm, (3.10 +/- 0.33) mPa x s and 6.56 +/- 0.05, which were all higher than those of unloaded nanoemulsions. The zeta potential of unloaded and drug-loaded nanoemulsions carried negative charge. The NOB-NE after diluted by 5% glucose solution was stable in 8 h, and there was no significant difference in the size, content and diluted stability of its preconcentrate in long-term storage. The concentration of nobiletin in plasma and tissues was determined by HPLC after intravenous administration of NOB-NE. Based on AUC(0-t), MRT and C(max), the nanoemulsions delivered more nobiletin into the brain and kidney compared to those of nobiletin solution. The brain and kidney targeting efficiency was improved. In addition, the results fitting using SAAM II software show that the higher drug concentration of the NOB-NE in the brain might be owed to the quicker transport rate from the blood to the brain, and that in the kidney relate to the probable accumulation effect. These results indicate that the in vivo distribution of NOB-NE with consistent quality in mice could be changed and its brain and kidney targeting absorption capability was enhanced comparing with nobiletin solution.
Animals ; Drug Stability ; Emulsions ; Female ; Flavones ; administration & dosage ; pharmacokinetics ; Male ; Mice ; Nanoparticles ; administration & dosage ; Tissue Distribution

AIMTo study the protection of casein and protamine against degradation of insulin (INS) by proteolysis enzymes and the effect of these two kinds of protein on the hypoglycemic action of INS solution and enteric-microspheres after administrated orally to rats.

METHODSHPLC was used to determine the remained INS in the solution of alpha-chymotrypsin and trypsin with or without casein or protamine; INS solution and enteric-microspheres were prepared and adiministrated orally to rats together with the absorption enhancer sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). At the same time, casein or protamine or both of these two kinds of protein were administrated together in order to study their influence on the hypoglycemic effect of INS and microspheres.

RESULTSCasein had a good protection against degradation of INS by alpha-chymotrypsin, but protamine had no protection effect. However, the degradation of INS by trypsin is concerned, the protection effect of protamine on INS was better that of casein. Both of protamine and casein can increase the hypoglycemic effect of INS solution and enteric-microspheres. Co-administrated these two kinds of protein had a better effect. In addition, co-administrated with SNAC, casein and protamine, INS enteric-microspheres had a longer and more potent hypoglycemic effect than that of the solution.

CONCLUSIONCasein and protamine can increase the stability of INS in the intestinal fluid by the mechanism of competition and combine with proteolysis enzymes, which will benefit to INS oral administration.

Administration, Oral ; Animals ; Blood Glucose ; metabolism ; Caprylates ; Caseins ; pharmacology ; Chymotrypsin ; antagonists & inhibitors ; Drug Delivery Systems ; Hypoglycemic Agents ; administration & dosage ; pharmacokinetics ; Insulin ; administration & dosage ; pharmacokinetics ; Male ; Microspheres ; Protamines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Solutions ; Trypsin ; pharmacology

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.
Animals ; Antineoplastic Agents ; administration & dosage ; chemistry ; Apolipoproteins B ; administration & dosage ; chemistry ; Drug Carriers ; administration & dosage ; chemistry ; Humans ; Lipoproteins ; administration & dosage ; chemistry ; Lipoproteins, HDL ; administration & dosage ; chemistry ; Lipoproteins, LDL ; administration & dosage ; chemistry ; Nanoparticles ; Neoplasms ; drug therapy ; Peptides ; administration & dosage ; chemistry ; Pharmaceutical Vehicles ; chemistry

Prodrug is an effective way to improve the oral absorption of the drugs which belong to Biopharmaceuticals Classification System (BCS) class III and IV. This review addresses the progress of the oral prodrugs in recent years, mainly including classical prodrug design and targeted prodrug design. Classical prodrug design is focused on modification of oil-water partition coefficient or decrease the metabolism of parent drugs. Targeted prodrug design is actively concerned with the physiological characteristics of the gastrointestinal tract to target tissues, enzymes and influx transporters. Intestinal influx transporter, the peptide transporter-targeted prodrug design is a growing field of the research of oral prodrugs recently. Challenges of prodrug strategy, design and investigation in vivo are also discussed.
Administration, Oral ; Animals ; Biological Transport ; Drug Delivery Systems ; Drug Design ; Humans ; Intestinal Absorption ; Prodrugs ; administration & dosage ; pharmacokinetics ; Solubility

OBJECTIVETo establish an HPLC method for the simultaneous determination of three major bioactive components in Jingzhi Guizhi Fuling capsules namely laetrile, paeoniflorin and paeonol.

METHODA 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.

RESULTThe 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 %.

CONCLUSIONThe method was successfully applied to analyze three major bioactive components in Jingzhi Guizhi Fuling capsules.

Acetophenones ; analysis ; Amygdalin ; analysis ; Benzoates ; analysis ; Bridged-Ring Compounds ; analysis ; Capsules ; Chromatography, High Pressure Liquid ; methods ; Cinnamomum ; chemistry ; Drug Combinations ; Drugs, Chinese Herbal ; administration & dosage ; chemistry ; isolation & purification ; Glucosides ; analysis ; Monoterpenes ; Paeonia ; chemistry ; Plants, Medicinal ; chemistry ; Polyporales ; chemistry ; Reproducibility of Results

AIMTo investigate the enhancing effect on insulin absorption through GI. tract in mice by using the Ulex europaeus agglutinin I (UEA1) modified liposomes as the carrier.

METHODSUEA1 modified phosphatidylethanolamine (PE) was prepared by conjugating method of 1-ethyl-3-(3'-dimethylaminopropyl) carbodiimide (EDC), then the modified compound (PE-UEA1) was incorporated into the conventional liposomes of insulin to obtain UEA1 modified liposomes. The agglutination test was performed to examine the UEA1 biological activities after synthesis and modification. When liposomes were applied to healthy mice or diabetic mice at insulin dose of 350 u x kg(-1) orally, the hypoglycemic effect was investigated according to the blood glucose level determination.

RESULTSThe blood glucose levels of the healthy mice reduced by UEA1 modified liposomes were (84 +/- 15)% at 4 h, (78 +/- 11)% at 8 h and (90 +/- 12)% at 12 h after oral administration. The conventional liposomes and saline showed no effect. The blood glucose levels of the diabetic mice reduced by UEA1 modified liposomes were (73 +/- 7)% at 4 h, (74 +/- 9)% at 8 h, (86 +/- 9)% at 12 h after oral administration.

CONCLUSIONThe UEA1 modified liposomes promote the oral absorption of insulin due to the specific-site combination on M cell membrane.

Administration, Oral ; Animals ; Blood Glucose ; metabolism ; Diabetes Mellitus, Experimental ; blood ; Drug Carriers ; Drug Delivery Systems ; Hypoglycemic Agents ; administration & dosage ; pharmacokinetics ; Insulin ; administration & dosage ; pharmacokinetics ; Intestinal Absorption ; drug effects ; Liposomes ; Mice ; Phosphatidylethanolamines ; chemistry ; Plant Lectins ; chemistry ; isolation & purification ; pharmacology ; Plants, Medicinal ; chemistry ; Ulex ; chemistry

AIMTo investigate the enhancing effect on insulin absorption through GI tract in mice by using tomato lectin (TL) modified liposomes as the carrier.

METHODSTL-phosphatidylethanolamine (PE) conjugate (TL-PE) was synthesized by using carbodiimide cross-linking method, then the compound was incorporated into the conventional liposomes of insulin. The agglutination test was performed to examine TL biological activities after synthesis and incorporation. When TL modified liposomes were administrated orally to the normal mice or diabetic mice at insulin dose of 350 u x kg(-1), the hypoglycemic effect was determinated according to the blood glucose level.

RESULTSThe blood glucose levels of the normal mice were reduced by modified liposomes. The glucose levels were (85 +/- 5)% at 4 h, (54 +/- 11)% at 8 h, (57 +/- 6)% at 12 h postdose compared with the glucose levels prior to oral administration respectively. However, the conventional liposomes and saline have no hypoglycemic effect. The blood glucose levels of the diabetic mice were obviously reduced by TL modified liposomes, the glucose levels were (38 +/- 13)% at 4 h, (50 +/- 15)% at 8 h, (50 +/- 16)% at 12 h respectively.

CONCLUSIONTL modified liposomes promote the oral absorption of insulin due to the specific-site combination on GI cell membrane.

Administration, Oral ; Animals ; Blood Glucose ; metabolism ; Delayed-Action Preparations ; Diabetes Mellitus, Experimental ; blood ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Hypoglycemic Agents ; administration & dosage ; pharmacokinetics ; pharmacology ; Insulin ; administration & dosage ; pharmacokinetics ; pharmacology ; Intestinal Absorption ; drug effects ; Intestine, Small ; metabolism ; Liposomes ; Mice ; Phosphatidylethanolamines ; chemistry ; Plant Lectins ; chemistry ; pharmacology ; Technology, Pharmaceutical ; methods

AIMTo study the effect of hyaluronic acid chitosan-based microemulsion (HAC-ME) on the permeability of blood brain barrier( BBB) by using Evans blue (EB) as the indicator.

METHODSA formamide extraction-ultraviolet spectrophotometry method was employed to determine the concentrations of EB in each of the tissues. The in vivo distribution of HAC-ME groups containing EB in mice and the fluorescence intensity and diffusion domain of brain slices were all studied.

RESULTSContrasting to the common microemulsion (ME), HAC-ME at the lower concentration of HAC (<5 mg x mL(-1)) could further improve the transporting of EB across the BBB while EB concentration in other tissues decreased, and Tmax was delayed about 30 min.

CONCLUSIONHAC-ME could facilitate the transporting of EB across the BBB and it was concentration dependent. While the brain targeting absorptive capability of HAC-ME was enhanced.

Animals ; Blood-Brain Barrier ; drug effects ; metabolism ; Brain ; metabolism ; Chitosan ; chemistry ; pharmacology ; Dose-Response Relationship, Drug ; Emulsions ; Evans Blue ; chemistry ; pharmacokinetics ; Female ; Hyaluronic Acid ; chemistry ; pharmacokinetics ; pharmacology ; Male ; Mice ; Particle Size ; Tissue Distribution

To explore the mechanism of the absorption enhancement of borneol, the effect of borneol on the intestinal absorption and the pharmacokinetics of tetramethylpyrazine phosphate after oral administration were investigated. In situ intestinal recirculation was performed to study the effect of various concentrations of borneol on the absorption of tetramethylpyrazine phosphate at duodenum, jejunum, ileum and colon. After oral administration of tetramethylpyrazine phosphate, the mixture of tetramethylpyrazine phosphate and borneol and the mixture of tetramethylpyrazine phosphate and verapamil in rats, the concentrations of tetramethylpyrazine phosphate in plasma were determined by RP-HPLC at predesigned time. The pharmacokinetic parameters were compared based on the results of the three animal experiments, and analyzed with software program 3p97. The result showed that tetramethylpyrazine phosphate could be absorbed at all of the four intestinal segments with increasing absorption amount per unit as follows: colon > duodenum > jejunum > ileum, but without saturation, which demonstrated that tetramethylpyrazine phosphate was absorbed via simple diffusion. Borneol could enhance the intestinal absorption of tetramethylpyrazine phosphate, however, not in proportion. There was no obvious difference between the test group and the control group when 10 microg x mL(-1) borneol was added (P > 0.05), while when the concentration comes to 25 microg x mL(-1) and 50 microg x mL(-1), significant differences were observed (P < 0.05). Borneol and verapamil did enhance the bioavailability of tetramethylpyrazine phosphate after oral administration in rats. The enhancing effect of borneol showed only when the concentration came to a certain level but with no specific sites existed in the intestine. One of the mechanisms of borneol on the enhancing effect on absorption of tetramethylpyrazine phosphate might be the inhibition of the metabolism of CYP 3A and exocytosis of P-gp.
Animals ; Biological Availability ; Bornanes ; pharmacokinetics ; Herb-Drug Interactions ; Intestinal Absorption ; drug effects ; Male ; Pyrazines ; pharmacokinetics ; Rats ; Rats, Sprague-Dawley