Pharmacokinetics of two types of dipropofol crystal tablets in Beagle dogs / 药学学报

A method for determining dipropofol in the plasma of Beagle dogs was established by HPLC-MS/MS. We also studied the pharmacokinetic characteristics of two different forms of crystal tablets of dipropofol in Beagle dogs. All animal experiments were approved by the Animal Experimental Management, Welfare and Ethics Committee of Pharmacology Evaluation Research Center, Shanghai Institute of Pharmaceutical Industry. The results indicate that the maximum plasma concentration (Cmax) of dipropofol was 69.02 ± 20.16 μg·L-1 after 20 mg·kg-1 crystal form Ⅰ tablet taken orally, and the AUC0-t was 160.49 ± 55.26 μg·L-1·h. After 20 mg·kg-1 crystal form Ⅱ tablet taken, the Cmax of dipropofol was 92.58 ± 60.26 μg·L-1, and the AUC0-t was 243.59 ± 148.36 μg·L-1·h. The AUC0-t and Cmax of crystal form Ⅱ were significantly different from that of crystal form Ⅰ (P<0.05). Crystal form Ⅱ was the dominant crystal form. The results suggest that we should control crystal form during the development of dipropofol oral tablets.

Construction and evaluation of non-specific targeting cationic polymer lipid liposomes / 药学学报

A new class of dendrimer polylysine poly(ethylene glycol)-lipid was designed and synthesized. The cationic polymer liposomes were prepared by the lipid film-extrusion and post-insertion two methods with these dendrimer polylysine poly(ethylene glycol)-lipid and other lipids. The structural properties of obtained cationic polymer liposomes were studied by laser light scattering and fluorescence spectrometer. It was demonstrated that the nano sized liposomes with different density of surface cationic charges can be prepared by either lipid film-extrusion or post-insertion methods, but post-insertion process did not affect drug loading, did not influence drug loading capacity and did not induce liposomal morphology and particle size. The density of positive charge does not affect the size and distribution of different liposomes size and distribution. It was the better choice for manufacture because post-insertion method did not cause early release of drug and size changes. Cell binding experiments show that cationic polymer liposomes, especially dendrimer polymer liposomes had higher local charge density, and therefore have dramatic non specific cell targeting ability.

Acid-sensitive liposomes prepared with poly(ethylene glycol)-POPA derivatives / 药学学报

The poly(ethylene glycol)-lipid derivatives were synthesized for constructing pH-sensitive liposomes. The polyethylene glycol polymer MePEG2000-NH2 and phospholipids POPA were connected by phosphorus-amide linkage. The poly(ethylene glycol)-lipid derivatives acidic sensitive liposomes were prepared. Factor effects on polymer insertion into liposomes were evaluated and the pH-sensitivity of the polymer associated liposomes were studied by calcein release assay. The poly(ethylene glycol)-lipid derivatives acidic sensitive liposomes were prepared successfully by the extruding linkage device. The liposomes constructing by poly(ethylene glycol)-lipid derivatives was stable at pH 6.5-7.5, the stability was closely related to phospholipid types and cholesterol content of the preparation of liposomes. At pH 5.0 occurred when divulging fluorescence occurred obviously, the leakage rate and the strength was with a positive correlation between time of in the acidic environment and intensity of acid. The acidic sensitive liposomes prepared by poly(ethylene glycol)-lipid derivatives were developed as a potential pH sensitive delivery system.

Preparation and thermo-sensitivity behavior of polymer liposomes made of poly(2-ethylacrylic acid) alkylamide derivatives / 药学学报

The temperature-sensitive liposomes were constructed by poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives that were synthesized for partially modification of carboxylic groups. The thermal characteristics of liposomes were investigated by using fluorescent indicator, particle size device and fluorescence spectrophotometer system. The results showed that the liposome made of fatty amine-modified poly(2-ethylacrylate) had a marked thermal sensitive release of drugs, which is correlated with the structure of molecular of polymer and the initial ratio of composition of phospholipid. The PEAA-associated-liposomes were also shown pH-sensitive drug release under acidic condition. The poly (2-ethylacrylate) for the preparation of medium-induced thermal liposomes in vitro experiments showed a good thermal characteristics and the methods of preparing temperature-sensitive liposomes were convenient and stability.

Property of liposomal fusion induced by acid-sensitive polymer / 药学学报

The fusion between liposome-liposome, liposome-biomembarnes induced by acid-sensitive polymers has been systematically investigated. The polymer-liposomes were constructed by post-insertion method with the poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives. The liposomal fusion was studied by use of fluorescence resonance energy transfer assay, particle size, fluorescent-photometer. The results indicated that the poly (2-ethylacrylic acid)-liposomes has very strong acidic induced fusion capability. Under acidic conditions, acid-sensitive polymer liposomes fused each other, the fusion closely related to the molecular weight of acid sensitivity polymer on the surface of liposomes. The acidic fusion of polymer-liposomes was dependent upon the lipids composition, the degree of fusion was reversely related to the cholesterol contents. Acid-en ci-nsitive polymer liposomes fused with erythrocyte ghosts. The liposomal fusion induced by acid-sensitive polymer associated with the increase of membrane permeability. The good acid-sensitivity of PEAA has been further demonstrated by membrane fusion in current experiments, and the liposomes prepared with lipid anchored-poly (2-ethylacrylic acid) were developeds s a potential pH sensitive delivery system.

Acid-sensitive polymer liposomes prepared by poly(2-ethylacrylic acid) alkylamide derivatives / 药学学报

Poly (2-ethylacrylic acid) (PEAA) alkylamide derivatives were synthesized for constructing pH-sensitive liposomes by partially modification of carboxylic groups of PEAA with chemical reaction. These lipid derivatives of PEAA were synthesized by partially modification of carboxylic groups of PEAA with alkylamines. The acid-sensitive polymer associated liposomes were obtained by the method of polymer self-insertion in aqueous solutions through inserting hydrophobic lipid anchors of the polymer PEAA derivatives into the outer layer of vesicles. Factor effects on polymer insertion into liposomes were evaluated and the pH-sensitivity of the polymer associated liposomes was studied by calcein release assay. The PEAA-assoeiated-liposomes were prepared successfully by the methods of self-insertion. The PEAA-associated-liposomes are shown to be stable at neutral pH. (1) There was no correlate of anchor density of PEAA with length of the alkyl chain, but was positively correlated with the degree of PEAA modification. (2) Polymer insertion increased with initial ratio of polymer to lipid. (3) Unerting hydrophobic lipidr acidic conditions the associated polymer induces membrane disruption and fusion. (4) The PEAA-associated-liposomes shown pH-sensitive drug release property under acidic conditions. The anchored-poly (ethylacrylic acid) lipid derivatives can be useful in developing a potential pH sensitive drug delivery system.

Biliary excretion of genistein and its metabolite at different doses in rats / 药学学报

<p><b>AIM</b>To study the biliary excretion of genistein and its metabolite at different doses in rats.</p><p><b>METHODS</b>Suspended in 0.5% CMC-Na solution, genistein was orally administered to rats at the dose of 6.25, 12.5 and 50 mg x kg(-1), separately. At various time intervals, the bile was collected. The bile was treated with beta-glucuronidase. The genistein in bile was extracted twice by vortexing with 2.0 mL mixture of methyl tert-tubtyl ether and pentane (8:2). The organic phase was removed into the tubes and then evaporated in ventilation cabinet. The residue was dissolved in 50 microL of methanol. Twenty microL solution was drawn and detected by high-performance liquid chromatography.</p><p><b>RESULTS</b>The accumulative biliary excretion of genistein was (42.56 +/- 6.54) , (75.17 +/- 18.87) and (126.60 +/- 34.78) microg at the dose of 6.25, 12.5 and 50 mg x kg(-1), respectively. The total drug (genistein plus glucuronidated genistein) excreted from bile was (108.46 +/- 35.23), (423.46 +/- 158.31) and ( 853.74 +/- 320. 84) microg, and the ratio of glucuronidated genistein was 60.76% , 82.25% and 85.17% at the dose of 6.25, 12.5 and 50 mg x kg(-1), respectively.</p><p><b>CONCLUSION</b>The genistein was excreted mainly in the form of glucuronidated genistein in rat bile. The genistein and glucuronidated genistein were excreted in a nonlinear dose-dependent manner.</p>

Dose-dependent pharmacokinetic study of genistein in Beagle dogs / 药学学报

<p><b>AIM</b>To study the pharmacokinetics of genistein at different doses in Beagle dogs.</p><p><b>METHODS</b>Suspended in 0.5% CMC-Na solution, genistein was orally administered to Beagle dogs at doses of 2.67, 5.34 and 10.68 mg.kg(-1). At various time intervals, 1.5 mL of blood was drawn from the femoral vein of dogs in their front legs. The plasma was treated with beta-glucuronidase. The genistein in plasma was extracted twice by vortexing with 2.0 mL mixture of methyl tert-tubtyl ether and pentane (v/v = 8:2). The organic phase was removed into the tubes and then evaporated in ventilation cabinet. The residue was dissolved in 50 microL of methanol. 20 microL solution was drawn and detected by high-performance liquid chromatography. The pharmacokinetic parameters were calculated by 3P97 software.</p><p><b>RESULTS</b>The plasma drug concentration-time data were fitted to the two-compartment model. When the dose was 2.67 mg.kg(-1), the MRT and AUC of parent compound were 52.9 min and 6.7 mg.min. L(-1), respectively. When the dose rose to 5.34 mg.kg(-1), the MRT and AUC of parent compound became 224.8 min and 26.1 mg.min.L(-1), respectively. However, when the dose increased to 10.68 mg .kg(-1), the MRT and AUC of parent compound increased to 267.7 min and 33.2 mg.min L(-1), respectively. The AUC of glucuronidated genistein was 33.9, 70.1 and 140.5 mg.min.L(-1) at the dose of 2.67, 5.34 and 10.68 mg.kg(-1), respectively.</p><p><b>CONCLUSION</b>Due to significant first pass metabolism, the drug was mainly existed in the form of glucuronidated genistein in the plasma. With the increase of dose, the absorption of genistein became saturated and the half life prolonged.</p>