Effect of beta-cyclodextrin on the degradation rate of amoxicillin in acidic solution.

The formation of an inclusion complex of amoxicillin (AMX) with beta-cyclodextrin (beta-CD) in aqueous solution was confirmed by a solubility method and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The apparent stability constant for the inclusion complex was 10.72 M(-1) in water at 25 degrees C. The effect of alpha-CD, beta-CD, and gamma-CD on the degradation of AMX in a pH 1.2 solution at 37 degrees C was investigated. beta-CD and gamma-CD reduced the rate of degradation. alpha-CD had no effect. These results were consistent with those of 1H-NMR spectroscopy. The effect of beta-CD on the degradation rate was studied in more detail. The apparent first order rate constant for the degradation of AMX in the pH 1.2 solution at 37 degrees C was 0.1121 h(-1) (t(1/2)=6.18 h), which decreased with the addition of beta-CD. The rate constants and t(1/2) values for the concentrations of beta-CD added, corresponding to molar ratios of AMX to beta-CD of 1:0.5, 1:1, 1:2, 1:5, and 1:10, were 0.1051 h(-1) and 6.59 h, 0.0992 h(-1) and 6.98 h, 0.0893 h(-1) and 7.76 h, 0.0697 h(-1) and 9.95 h, and 0.0509 h(-1) and 13.61 h, respectively. The activation energy for the degradation of AMX in the pH 1.2 solution was increased from 6.9 x 10(4) J/mol (AMX alone) to 8.0 x 10(4) J/mol (AMX:beta-CD=1:10).

PEG-PLA diblock copolymer micelle-like nanoparticles as all-trans-retinoic acid carrier: in vitro and in vivo characterizations.

The purpose of this study was to characterize the properties in vitro, i.e. release, degradation, hemolytic potential and anticancer activity, and in vivo disposition of all-trans-retinoic acid (ATRA) in rats after administration of ATRA-loaded micelle-like nanoparticles. The amphiphilic block copolymers consisted of a micellar shell-forming mPEG block and a core-forming PLA block. The mPEG-PLA nanoparticles prepared by an acetone volatilization dialysis procedure were identified as having core-shell structure by (1)H NMR spectroscopy. Critical association concentration, drug contents, loading efficiency, particle size and xi potential were evaluated. The release of ATRA from the nanoparticles and the degradation of PLA were found to be mostly associated with the compositions of the nanoparticles. ATRA release was faster at smaller molecular weight of copolymer and lower drug contents. In vitro, the incorporation of ATRA in mPEG-PLA nanoparticles reduced the hemolytic potential of ATRA. Furthermore, anticancer activity of ATRA against HepG2 cell was increased by encapsulation, which showed an enhancement of tumor treatment of ATRA. In vivo, after intravenous injection to rats, the levels of ATRA in the blood stream and the bioavailability were higher for ATRA-loaded mPEG-PLA nanoparticles than those for ATRA solution. In conclusion, the structure of the mPEG-PLA diblock copolymer could be modulated to fit the demand of in vitro and in vivo characterizations of nanoparticles. The mPEG-PLA nanoparticles' loading ATRA have a promising future for injection administration.

Superparamagnetic iron oxide nanoparticles stabilized by alginate: pharmacokinetics, tissue distribution, and applications in detecting liver cancers.

The objectives of this study were to describe the pharmacokinetics and tissue distribution of superparamagnetic iron oxide nanoparticle (SPIO) stabilized with alginate (SPIO-alginate), and investigate its potential in detecting liver cancers as a newly developed magnetic resonance (MR) contrast agent. Pharmacokinetics and tissue distribution of SPIO-alginate were investigated in Sprague-Dawley rats. The results showed that SPIO-alginate was eliminated rapidly from serum with the half-life of 0.27 h at 109.5 micromol Fe/kg and accumulated dominantly in liver and spleen with a total percentage of more than 90% of dose after intravenous injection. The studies of pharmacokinetics and distribution of SPIO-alginate in rats indicated the MR contrast agent, based on SPIO, mainly accumulating in targeting organs that contain phagocytosing cells, i.e. liver and spleen. The efficacies in detecting hepatocellular carcinoma (HCC) of rat with primary liver cancer and xenograft liver cancers of rabbit were investigated before and after injection of SPIO-alginate. The signal intensity of liver parenchyma in rabbit with VX2 tumor after injection of SPIO-alginate was reduced sharply resulting in a significant contrast between liver parenchyma and tumor. Detection of the HCC in rat model was also demonstrated. The present study provides evidence that SPIO-alginate might have the ability to improve the detection of liver tumors as an MR contrast agent, and the efficacy is associated with the SPIO specifically located in Kupffer cells in hepatic sinusoid.

Mechanisms of co-modified liver-targeting liposomes as gene delivery carriers based on cellular uptake and antigens inhibition effect.

In order to deliver antisense oligonucleotides (asODN) into hepatocytes orientedly in the treatment of hepatitis B virus (HBV) infection, the liver-targeting cationic liposomes was developed as a gene carrier, which was co-modified with the ligand of the asialoglycoprotein receptor (ASGPR), beta-sitosterol-beta-d-glucoside (sito-G) and the nonionic surfactant, Brij 35. Flow cytometry (FCM) analysis and enzyme-linked immunosorbent assay (ELISA) showed that the asODN-encapsulating cationic liposomes exhibited high transfection efficiency and strong antigens inhibition effect in primary rat hepatocytes and HepG2.2.15 cells, respectively. With the help of several inhibitors acting on different steps during the targeting lipofection, the cellular uptake mechanisms of the co-modified liver-targeting cationic liposomes were investigated through antigens inhibition effect assay and confocal laser scanning microscopy (CLSM) analysis. The cellular uptake with high transfection efficiency seemed to involve both endocytosis and membrane fusion. The ligand sito-G was confirmed to be able to enhance ASGPR-mediated endocytosis, the nonionic surfactant Brij 35 seemed to be able to facilitate membrane fusion, and the co-modification resulted in the most efficient transfection but no enhanced cytotoxicity. These results suggested that the co-modified liver-targeting cationic liposomes would be a specific and effective carrier to transfer asODN into hepatocytes infected with HBV orientedly.

Preparation and characterization of superparamagnetic iron oxide nanoparticles stabilized by alginate.

SPION with appropriate surface chemistry have been widely used experimentally for numerous in vivo applications. In this study, SPION stabilized by alginate (SPION-alginate) were prepared by a modified coprecipitation method. The structure, size, morphology, magnetic property and relaxivity of the SPION-alginate were characterized systematically by means of XRD, TEM, ESEM, AFM, DLS, SQUID magnetometer and MRI, respectively, and the interaction between alginate and iron oxide (Fe(3)O(4)) was characterized by FT-IR and AFM. The results revealed that typical iron oxide nanoparticles were Fe(3)O(4) with a core diameter of 5-10 nm and SPION-alginate had a hydrodynamic diameter of 193.8-483.2 nm. From the magnetization curve, the Ms of a suspension of SPION-alginate was 40 emu/g, corresponding to 73% of that of solid SPION-alginate. This high Ms may be due to the binding of Fe(3)O(4) nanoparticles to alginate macromolecule strands as visually confirmed by AFM. SPION-alginate of several hundred nanometers was stable in size for 12 months at 4 degrees C. Moreover, T1 relaxivity and T2 relaxivity of SPION-alginate in saline (1.5 T, 20 degrees C) were 7.86+/-0.20 s(-1) mM(-1) and 281.2+/-26.4 s(-1) mM(-1), respectively.

Pharmaceutical and immunological evaluation of a single-dose hepatitis B vaccine using PLGA microspheres.

The objective of the study was to investigate the feasibility of a single-dose hepatitis B vaccine based on three kinds of poly (D, L)-lactide-co-glicolide acid (PLGA) microspheres. PLGA microspheres loaded with recombinant hepatitis B surface antigen (HBsAg) were formulated using a double emulsion microencapsulation technique. The pharmaceutical characteristics of size, surface morphology, protein loading efficiency, antigen integrity, release of HBsAg-loaded PLGA microspheres and degradation of the polymer in vitro were evaluated. The degradation of the polymer corresponded with the composition of the polymer (lactide/glycolide ratio), molecular weight of the polymer (viscosity) and morphology of the microspheres. These PLGA microspheres were able to continuously release antigen under conditions that mimic the environment in vivo. The single subcutaneous injection of HBsAg-loaded PLGA50/50 microspheres, PLGA75/25 microspheres and a mixture of PLGA50/50, PLGA75/25, and PLGA50/50-COOH microspheres in mice resulted in comparable serum antibody titers to those of three injections of the conventional aluminum adjuvant formulated HBsAg vaccine. Based on these findings in vitro and in vivo, it was concluded that HBsAg was successfully loaded into the PLGA microspheres, which can auto-boost an immune response, and the HBsAg-loaded PLGA microsphere is a promising candidate for the controlled delivery of a vaccine.

Enhanced intracellular delivery and improved antitumor efficacy of doxorubicin by sterically stabilized liposomes modified with a synthetic RGD mimetic.

While sterically stabilized liposomes (SSL) can passively accumulate into tumor tissue due to the effect of enhanced permeability and retention (EPR), the intracellular uptake of the entrapped anticancer drugs by the tumor cells should be a determinant step for their antitumor activities. Therefore, strategies that can enhance the intracellular uptake of SSL into tumor cells could lead to an improved therapeutic efficacy for the drugs. To check this possibility, RGD-mimetic-modified SSL (RGDm-SSL) were constructed aimed to achieve tumor accumulation as well as enhanced intracellular delivery, and were loaded with doxorubicin (DOX), an anticancer drug. Flow cytometry and confocal microscopy reveal that RGDm-SSL facilitated the DOX uptake into the melanoma cells via integrin-mediated endocytosis. DOX-loaded RGDm-SSL (RGDm-SSL-DOX) displayed higher cytotoxicity on melanoma cells than DOX-loaded SSL (SSL-DOX). Tissue distribution and therapeutic experiments were examined in C57BL/6 mice carrying melanoma B16 tumors. RGDm-SSL-DOX displayed similar DOX accumulation in tumor tissue to that of SSL-DOX but showed significantly lower DOX level in blood and remarkably higher DOX level in spleen than SSL-DOX. Administration of RGDm-SSL-DOX at a dose of 5 mg DOX/kg resulted in effective retardation of tumor growth and prolonged survival times compared with SSL-DOX. These results suggest that RGDm-modified SSL may be a promising intracellular targeting carrier for efficient delivery of chemotherapeutic agents into tumor cells.

Transport of nerve growth factor encapsulated into liposomes across the blood-brain barrier: in vitro and in vivo studies.

A nerve growth factor (NGF) was encapsulated into liposomes in order to protect it from the enzyme degradation in vivo and promote it permeability across the blood-brain barrier (BBB). RMP-7, a ligand to the B2 receptor on brain microvascular endothelial cells (BMVEC), was combined with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-n-[poly(ethylenegly-col)]-hydroxy succinamide (DSPE-PEG-NHS) to obtain DSPE-PEG-RMP-7. Then DSPE-PEG-RMP-7 was incorporated into the liposomes' surface to target sterically stabilized liposomes (SSL-T) to the brain. The highest percent of NGF encapsulated into liposomes was about 34%, and the average size of liposomes was below 100 nm. A primary model of BBB was established and evaluated by morphological, permeability, and transendothelial electrical resistance (TEER). The BBB model was employed to study the permeability of NGF liposomes in vitro. The results indicated that the liposomes could enhance transport of NGF across the BBB. The best transport rate was received with NGF-SSL-T. The brain distribution of NGF liposomes was studied in vivo, the amount of NGF in the brain was increased in the order: NGF-SSL-T>NGF-SSL+RMP-7>NGF-SSL>NGF-L. The maximum concentration of NGF was recorded in 30 min following the intravenous injection. In particular, a majority of NGF was distributed in striatum, hippocampus and cortex, and the concentration of NGF was relatively lower in olfactory bulb, cerebellum and brain stem. There was a close relationship between P(e) (permeability coefficient on in vitro BBB model) and T(e) (brain targeted coefficient in vivo) for NGF encapsulated into the liposomes.

Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy: in vitro and in vivo.

Passive targeting by sterically stabilized liposomes (SSL), once combined with efficient intracellular delivery, may be a very useful strategy to improve the antitumor efficacy for the anticancer agents. The arginine-glycine-aspartic acid tripeptide (RGD) is known to serve as a recognition motif for several different integrins located on cell surface. In this study, the RGD tripeptide was coupled to the distal end of the poly (ethylene glycol)-coated liposomes (RGD-SSL) aimed to achieve increased tumor accumulation and enhanced intracellular uptake. DOX-loaded RGD-SSL (RGD-SSL-DOX), DOX-loaded SSL (SSL-DOX), and free DOX were compared with respect to their in vitro uptake and cytotoxicity and their in vivo biodistribution and therapeutic efficacy in tumor-bearing mice. Flow cytometry and confocal microscopy studies revealed that RGD-SSL could facilitate the DOX uptake into melanoma cells by integrin-mediated endocytosis. RGD-SSL-DOX displayed higher cytotoxicity on melanoma cells than SSL-DOX. While RGD-SSL-DOX demonstrated prolonged circulation time and increased tumor accumulation as SSL-DOX did, it showed remarkably higher splenic uptake than SSL-DOX. Mice receiving RGD-SSL-DOX (5 mg DOX/kg) showed effective retardation in tumor growth compared with those receiving same dose of SSL-DOX, free DOX solution, or saline. These results suggest that RGD-modified SSL may be a feasible intracellular targeting carrier for efficient delivery of chemotherapeutic agents into tumor cells.

Cholesteryl hemisuccinate as a membrane stabilizer in dipalmitoylphosphatidylcholine liposomes containing saikosaponin-d.

In the present study, cholesteryl hemisuccinate (CHEMS) was evaluated for use as a membrane stabilizer in dipalmitoylphosphatidylcholine (DPPC) liposomes. Differential scanning calorimetry (DSC) and a calcein release study showed that CHEMS was more effective than cholesterol (CHOL) in increasing DPPC membrane stability. The findings of Fourier transform infrared spectroscopy (FT-IR) also suggested that CHEMS interacts with DPPC via both hydrogen bonding and electrostatic interaction. More importantly, CHEMS did not interact with saikosaponin-d (SSD), a triterpene saponin from Bupleurum species, unlike CHOL. SSD-containing liposomes with DPPC, CHEMS and DSPE-PEG could greatly decrease the hemolytic activity of SSD. This study demonstrated that CHEMS has more stabilization ability than CHOL since CHEMS may exhibit both hydrogen bond interaction and electrostatic interaction with DPPC membrane while CHOL only has hydrogen bond interaction, resulting in stable and low-hemolytic SSD-liposomes.

Ultra-deformable liposomes containing bleomycin: in vitro stability and toxicity on human cutaneous keratinocyte cell lines.

Formulations of ultra-deformable liposomes containing bleomycin (Bleosome) have previously been described and proposed for topical treatment of skin cancer [Lau, K.G., Chopra, S., Maitani, Y., 2003. Entrapment of bleomycin in ultra-deformable liposomes. S. T. P. Pharm. Sci. 13, 237-239]. In this study, the stability of various Bleosome formulations was characterised and a purification process was established to isolate Bleosome for testing on cultures of either human cutaneous keratinocytes (NEB-1) immortalised by human papilloma virus (HPV)-type 16, or a spontaneously immortalised human squamous cell carcinoma (SCC) from a primary tumour. Bleosome facilitated entrapment of high concentrations of active bleomycin and samples purified by gel-filtration chromatography remained stable during 7 days of storage at 4 degrees C or at room temperature. Serially-diluted samples of this purified, high-strength product, 'high dose' were applied onto keratinocyte cell cultures to elucidate Bleosome LD50 profiles. In vitro data revealed that the LD50 of bleomycin encapsulated in Bleosome was approximately three-fold higher than free bleomycin solution for SCC cells, and nearly 30 times higher for NEB-1 cells. However, Bleosome containing 30 microg/ml of active bleomycin killed more than twice as many SCC cells than NEB-1 cells. At that concentration, the potency of liposomal bleomycin on causing cell death of SCC cells was found to be similar to that of free bleomycin solution. This effect was not seen on NEB-1 cells. It seems that SCC cells were particularly susceptible to Bleosome containing high levels of bleomycin. Results from these experiments promote the development of a novel product for the topical treatment of skin cancer.

Characteristics and biodistribution of soybean sterylglucoside and polyethylene glycol-modified cationic liposomes and their complexes with antisense oligodeoxynucleotide.

A novel cationic liposome modified with soybean sterylglucoside (SG) and polyethylene glycol-distearoylphosphatidylethanolamine (PEG-DSPE) as a carrier of antisense oligodeoxynucleotide (ODN) for hepatitis B virus (HBV) therapy was constructed. Characteristics of the cationic liposomes modified with SG and PEG (SG/PEG-CL) and their complexes with 15-mer phosphorothioate ODN (SG/PEG-CL-ODN complex) were investigated by incorporation efficiency, morphology, electrophoresis, zeta potentials, and size analysis. Antisense activity of the liposomes and ODN complexes was determined as hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) in HepG2 2.2.15 cells by ELISA. Their tissue and intrahepatic distribution were evaluated following intravenous injection in mice. The complexes gained high incorporation efficiency and intact vesicular structure with mean size at approximately 200 nm. The SG/PEG-CL-ODN complexes enhanced the inhibition of both HBsAg and HBeAg expression in the cultured HepG2 2.2.15 cells relative to free ODN. The uptake of SG/PEG-CL and nonmodified cationic liposomes (CL) was primarily by liver, spleen, and lung. Furthermore, the concentration of SG/PEG-CL was significant higher than that of CL in hepatocytes at 0.5 hr postinjection. The biodistribution of SG/DSPE-CL-ODN complex compare with free ODN showed that liposomes enhanced the accumulation of ODN in the liver and spleen, while decreasing its blood concentration. SG/PEG-CL-mediated ODN transfer to the liver is an effective gene delivery method for cell-specific targeting, which has a potential for gene therapy of HBV infections. SG and PEG-modified cationic liposomes have proven to be an alternative carrier for hepatocyte-selective drug targeting.

The effect of polyion complex formation on in vitro/in vivo correlation of hydrophilic matrix tablets.

The aim of this study was to investigate the effects of polyion complex formation on in vivo performance of hydrophilic matrix tablets. Three kinds of controlled release theophylline tablets were prepared by direct compression using carboxymethyldextran (CMD), a mixture of CMD and [2-(diethylamino)ethyl]dextran (EA), and a mixture of dextran sulfate (DS) and EA. According to a conventional dissolution test, in vitro drug release profiles of these tablets were similar to each other. In vivo absorption profiles of theophylline after oral administration to beagle dogs, however, were quite different and were not consistent with in vitro release profiles. Thus, we applied a modified in vitro release test considering destructive forces. An excellent in vitro/in vivo correlation was obtained in the cases of CMD/EA- and DS/EA-tablets. The results suggested that the drug was released constantly in the overall gastrointestinal tract, and even in the colon. Then, hydrophilic matrices were characterized by swelling rate, matrix density and strength in a wet state. DS/EA-tablets showed limited swelling, higher density and a larger value of wet strength than the others. These findings indicated that polyion complex formation in gel layer contributes to prevent over-swelling and strengthen the wetted matrices.

Release phenomena of insulin from an implantable device composed of a polyion complex of chitosan and sodium hyaluronate.

An implant controlled-release system for protein drug delivery based on a polyion complex device composed of chitosan (CS) and sodium hyaluronate (HA) was investigated. The conditions which generated the greatest amount of the polyion solid complex were studied to ascertain the formation of polyion complex between CS and HA. The greatest amount of the polyion complex was formed at the weight ratio of 3 to 7 (CS:HA) at pH 3.5. Furthermore, the CS-HA pellets were prepared and then drug release from CS-HA pellets was evaluated using insulin as a model drug. The results demonstrated that the insulin release from CS-HA pellets was markedly influenced by both the change in the polymer mixing ratio and the total pellet weight, whereas the compression pressure did not affect the release significantly. An artificial neural network (ANN) and biharmonic spline interpolation (HSI) were employed to predict the actual relation between causal factors and the release rate constant of insulin. Although both the ANN and HSI successfully represented a non-linear relationship between the formulation factors and the release rate constant, HSI methodology gave a better estimation than that of the ANN.

Elucidation of the mechanism of incorporation of insulin in controlled release systems based on complexation polymers.

The objective of this study was to investigate the insulin incorporation and release properties of poly(methacrylic acid-g-ethylene glycol) P(MAA-g-EG) microparticles as a function of copolymer composition. These microparticles exhibited unique pH-responsive characteristics in which interpolymer complexes were formed in acidic media and dissociated in neutral/basic environments. The microparticles containing equimolar amounts of MAA and PEG were capable of efficient insulin loading using equilibrium partitioning (>90%). Additionally, insulin release from the gel was significantly retarded in acidic media while rapid release occurred under neutral/basic conditions. In contrast, as the amount of MAA of the polymer was increased, the entrapment efficiency of insulin within the gel greatly reduced and the insulin was readily released from the polymer network in the acidic and neutral/basic media. In addition, in order to evaluate the potential application of the microparticles to other drugs, theophylline, vancomycin, fluorescein-isothiocyanate-labeled dextrans (FITC-Ds) with average molecular weights of 4400 (FITC-D-4), 12,000 (FITC-D-10) and 19,500 (FITC-D-20) were utilized as model hydrophilic drugs. The incorporation profiles showed that the uptake of theophylline and vancomycin to the microparticles was lower than that of insulin. Additionally, polymer microparticles loaded with theophylline and vancomycin exhibited pH-sensitive release behavior, however, the oscillatory behavior is less pronounced than those of insulin. The values of drug incorporation ratio showed that the microparticles were capable of incorporating almost 90% of insulin and 15% of vancomycin from solution. On the other hand, the other hydrophilic drugs showed very low incorporation efficiency to the microparticles. These data suggest that gels containing equimolar amounts of MAA:EG have the potential to be used as an oral carrier of peptide drugs, especially for insulin.

Regional intestinal absorption of FITC-dextran 4,400 with nanoparticles based on beta-sitosterol beta-D-glucoside in rats.

Nanoparticles (NP) are potential carriers for drug delivery to the targeted intestine. NP based on beta-sitosterol beta-D-glucoside (Sit-G) enhanced the colon-specific absorption of FITC-dextran 4,400 (FD-4), because the concentration-dependent increase of bioavailability appeared in only the colon. In a permeation study, the absorption enhancement in the colon was suppressed in the following conditions: (1) the addition of Sit-G NP to serosa; (2) a permeation study at 4 degrees C; (3) the addition of endocytosis inhibitor, cytochalasin B. NP based on sitosterol, the aglycon of Sit-G, did not increase the FD-4 colonic permeation. The addition of Sit-G NP to the mucosal side induced a decrease of transepithelial resistance (TEER), but this phenomenon was suppressed by an inhibitor of Na(+)-dependent specific glucose transporter, phrolidzin, which did not affect FD-4 permeation. These findings suggested that absorption enhancement by Sit-G NP may not be due to opening of a tight junction, but might be related to endocytosis via glucose residue of Sit-G.

Sustained release of cisplatin from multivesicular liposomes: potentiation of antitumor efficacy against S180 murine carcinoma.

Cisplatin was encapsulated into multivesicular liposomes (MVLs) and the entrapment efficiency, size distribution, and in vitro drug release characteristics of the cisplatin-MVLs were studied. Pharmacokinetics, tissue distribution, and therapeutic efficacy of cisplatin-MVLs were compared against injection of cisplatin solution into mice inoculated with the murine carcinoma 180 (S180) tumor. The results showed that the cisplatin-MVLs were capable of high drug loading (0.148:1 mg cisplatin/mg lipid) and high encapsulation efficiency (>80%). The mean diameter of cisplatin-MVLs was 17 microm. In vitro studies of cisplatin-MVLs in saline solution showed that they sustained release of encapsulated drug for >7 days. Cisplatin-MVLs showed higher drug accumulation in the liver, spleen, and tumor regions than cisplatin solution, as well as higher plasma concentrations and a longer circulation time. The therapeutic efficacy of the cisplatin-MVL preparation against S180 tumor-bearing mice is significantly higher than that of cisplatin solution.

Preparation and pharmacokinetics of pirarubicin loaded dehydration-rehydration vesicles.

Liposomes entrapped pirarubicin (THP, L-THP) were prepared by the modified dehydration-rehydration vesicle (DRV) method, and their pharmacokinetics and antitumor effects were evaluated in mice bearing M5076 liver metastasis tumor. After small unilamellar vesicles (SUVs) composed of egg lecithin, cholesterol (Ch), beta-sitosterol beta-D-glucoside (Sit-G) and oleic acid (OA) were freeze-dried with THP and sugars, rehydration of the lyophilized powders led to form the larger vesicles entrapping drugs, but the proper amounts of sugars and OA to lipids (sucrose/lipid=8 (w/w)) maintained the small particle size (about 340nm) with high entrapment (80.7%) of THP. After intravenous injection of L-THP, the accumulations of THP in the liver and heart were approximately 4-fold higher and half lower, respectively, than those of free THP (F-THP). L-THP had superior antitumor effect in 10mg/kg intravenous administration without significant body weight loss. L-THP is a potential drug dosage form of liver cancer treatment since the liposomes carry THP to the liver.

Pharmacokinetics and antitumor effects of vincristine carried by microemulsions composed of PEG-lipid, oleic acid, vitamin E and cholesterol.

In this study, injectable microemulsions of vincristine (M-VCR) were prepared and its pharmacokinetics, acute toxicity and antitumor effects were evaluated. In M-VCR, the surfactants were PEG-lipid and cholesterol, the oil phase was a vitamin E solution of oleic acid and VCR. The particle size distribution and zeta potential of M-VCR were measured by the laser light dynamic scattering method. The VCR-loading efficiency was measured by Sephadex G50 column chromatography. The stability of M-VCR was monitored by particle size, VCR-loading efficiency and VCR content changes of M-VCR stored at 7 degrees C. The pharmacokinetics, acute toxicity and antitumor effects of M-VCR were studied in C57BL/6 mice bearing mouse murine histocytoma M5076 tumors. When stored at 7 degrees C in the dark for 1 year, the average diameter and VCR-loading efficiency of M-VCR changed from 138.1+/-1.2 nm and 94.6+/-4.7% to 127.1+/-2.4 nm and 91.3+/-4.8% (n=3), respectively, while 7.4+/-0.3% VCR decomposition was observed (n=3). The plasma AUC of M-VCR was significantly greater than that of free VCR (F-VCR). The heart, spleen and liver AUC(0.08-12 h) of M-VCR were significantly smaller than those of F-VCR while the kidney AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. The tumor AUC(0.08-12 h) of M-VCR was significantly greater than that of F-VCR. M-VCR had lower acute toxicity and greater potential antitumor effects than F-VCR in M5076 tumor-bearing C57BL/6 mice. M-VCR is a useful tumor-targeting microemulsion drug delivery system.

Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea-pigs.

The buccal administration of ergotamine tartrate (ET) combined with polyvinyl alcohol (PVA) gel brought about higher plasma concentration of ET compared with that of oral administration of capsules in guinea-pigs. T(max) of ET in plasma of buccal administration was significantly smaller than that of oral administration. For the buccal dosage form of ET, the bioadhesive tablet system (BTS) was newly developed. It consisted of a reservoir of drug and an adhesive region. BTS showed better absorption of ET compared with PVA gel in guinea pigs. Among several pharmaceutical bases in the reservoir of BTS, Witepsol W-35 was most effective. It is likely that the high lipophilic property of Witepsol W-35 in which ET was dissolved facilitated the drug release by its relatively low melting point (around 35 degrees C), consequently a rapid absorption. In addition, the enhancing activity of the cod-liver oil extract (CLOE) in hydrophilic ointment on the in vivo buccal ET absorption was clarified to be comparable to that in the in vitro study utilizing the keratinized epithelial-free membrane (KEF-membrane) of the hamster cheek pouch.