Capmul MCM/Solutol HS15-Based Microemulsion for Enhanced Oral Bioavailability of Rebamipide.

Rebamipide (RBP) is a potent anti-ulcer and anti-oxidative agent, which is a BCS class IV drug with a low oral bioavailability of less than 10%. Thus, the systemic absorption of RBP into the blood circulation is an essential prerequisite for exerting its pharmacological activities after oral dosing. Herein, we report on microemulsion (ME) systems for the enhancement of oral RBP bioavailability. In this study, MEs consisting of Capmul MCM (oil), Solutol HS15 (surfactant), and ethanol (co-surfactant) were prepared by the construction of pseudo-ternary phase diagram. The RBP-loaded MEs had spherical nano-sized droplets with narrow size distribution and neutral zeta potential. Moreover, the prepared MEs significantly enhanced the dissolution and oral bioavailability of RBP with no discernible intestinal toxicity. These results suggest that the present ME system could be further developed as an alternative oral formulation for RBP.

Aripiprazole-montmorillonite: a new organic-inorganic nanohybrid material for biomedical applications.

Poor aqueous solubility and the unpleasant taste of aripiprazole (APZ) have been recurring problems, owing to its low bioavailability and low patient tolerance, respectively. Herein, we prepared a nanohybrid system that was based on a bentonite clay material, montmorillonite (MMT), which could both mask the taste and enhance the solubility of APZ (i.e., APZ-MMT). To further improve the efficacy of this taste masking and drug solubility, APZ-MMT was also coated with a cationic polymer, polyvinylacetal diethylamino acetate (AEA). In vitro dissolution tests at neutral pH showed that the amount of drug that was released from the AEA-coated APZ-MMT was greatly suppressed (<1%) for the first 3 min, thus suggesting that AEA-coated APZ-MMT has strong potential for the taste masking of APZ. Notably, in simulated gastric juice at pH 1.2, the total percentage of APZ that was released within the first 2 h increased up to 95% for AEA-coated APZ-MMT. Furthermore, this in vitro release profile was also similar to that of Abilify®, a commercially available medication. In vivo experiments by using Sprague-Dawley rats were also performed to compare the pharmacokinetics of AEA-coated APZ-MMT and Abilify®. AEA-coated APZ-MMT exhibited about 20% higher systemic exposure of APZ and its metabolite, dehydro-APZ, compared with Abilify®. Therefore, a new MMT-based nanovehicle, which is coated with a cationic polymer, can act as a promising delivery system for both taste masking and for enhancing the bioavailability of APZ.

Physicochemical, pharmacokinetic and pharmacodynamic evaluations of novel ternary solid dispersion of rebamipide with poloxamer 407.

This study was conducted primarily to improve the solubility of rebamipide, a poorly water-soluble anti-ulcer drug, using novel ternary solid dispersion (SD) systems and secondly to evaluate the effect of solubility enhancement on its pharmacokinetic (PK) and pharmacodynamic (PD) profile. After dissolving the three components in aqueous medium, ternary SD containing the drug, sodium hydroxide (NaOH) and PVP-VA 64 was achieved by spray drying method, which was used as primary SD. Poloxamer 407, a surfactant polymer, was incorporated in this primary SD by four different methods: co-grinding, physical mixing, melting or spray drying. SD was then characterized by dissolution test, differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared spectroscopy (FT-IR). The spray dried SD of poloxamer 407 together with primary SD displayed highest dissolution rate of the drug of about 70% after 2 h. DSC, PXRD and FT-IR characterized the amorphous state and molecular dispersion of the drug in the SD. PK and PD studies in Sprague-Dawley rats revealed that the bioavailability of the drug using optimal SD was about twofold higher than that of reference product, and the irritation area of stomach was significantly reduced in the ulcer-induced rat model using optimal SD as compared to the reference product.

Effect of fixed aqueous layer thickness of polymeric stabilizers on zeta potential and stability of aripiprazole nanosuspensions.

The aim of this study was to evaluate the effect of the thickness of adsorbed polymer layer (also known as Fixed Aqueous Layer Thickness, FALT) of polymeric stabilizers on zeta potential and stability of nanoparticles in a suspension. Aripiprazole, a poorly water soluble drug was used as a model drug to evaluate rationale for increased FALT and to understand the effect of hydrophilicity and hydrophobicity of polymeric stabilizers on FALT of aripiprazole nanosuspensions. The nanosuspensions were prepared by media milling and Pluronic F68, Pluronic F127, Hydroxypropyl methylcellulose (HPMC) and Hydroxypropyl cellulose (HPC) were used as polymeric stabilizers. The particle size (immediately after preparation and after 1 week of storage at 25°C) and zeta potential of aripiprazole nanosuspensions were determined. For Pluronics, FALT was determined theoretically whereas for HPMC and HPC it was calculated as Debye Huckel parameter from the zeta potential dependence on the ionic strength. An increase in FALT resulted in reduced zeta potential. With an increase in FALT of polymers used, the stability of nanosuspensions showed improvement. Furthermore, a linear correlation was shown to exist between the FALT and length of hydrophilic chains in Pluronics.

Antitumor Efficacy of Ceranib-2 with Nano-Formulation of PEG and Rosin Esters.

Ceranib-2 is a recently discovered, poorly water-soluble potent ceramidase inhibitor, with the ability to suppress cancer cell proliferation and delay tumor growth. However, its poor water solubility and weak cellular bioavailability hinder its use as a therapeutic agent for cancer. PEGylated rosin esters are an excellent platform as a natural polymer for drug delivery applications, especially for controlling drug release due to their degradability, biocompatibility, capability to improve solubility, and pharmacokinetics of potent drugs. In this study, stable aqueous amphiphilic submicron-sized PEG400-rosin ester-ceranib-2 (PREC-2) particles, ranging between 100 and 350 nm in a 1:1 mixture, were successfully synthesized by solvent evaporation mediated by sonication.Conclusion: Stable aqueous PEGylated rosin ester nanocarriers might present a significant solution to improve solubility, pharmacokinetic, and bioavailability of ceranib-2, and hold promises for use as an anticancer adjacent drug after further investigations.

Anticoagulant-induced changes on antibiotic concentrations in the serum and bones.

The aim of this study was to determine whether the co-administration of acenocoumarin as anticoagulant and certain quinolones, i.e., cefapirin, pefloxacin and ciprofloxacin increased the levels of the given antibiotics and whether this resulted in a prolongation of prothrombin time. Seventy male albino Wistar rats aged 8-10 weeks and weighed 170 +/- 14 g were used and divided into seven groups (I, II, III, IV, V, VI, VII: n=10). The rats in group I received cefapirin via 1 g/kg/8h im injection. Group II received cefapirin via of 1 g/kg/8h im injection and 0.1 mg/kg/24h p.o. acenocoumarin. Group III received ciprofloxacin 0.18 mg/kg/24h im. Group IV received ciprofloxacin 0.18 mg/kg/24h im and 0.1 mg/kg/24h p.o. acenocoumarin. Group V received 10 mg/kg/24h pefloxacin im. Group VI received 10 mg/kg/24h pefloxacin im and 0.1 mg/kg/24h p.o. acenocoumarin while Group VII received only acenocoumarin 0.1 mg/kg/24h p.o. Drug administration was performed over a total of 5 doses in order to obtain steady state concentrations in the plasma and tissues. The animals were sacrificed by decapitation 2 h after the last antibiotic administration. Prothrombin time and antibiotic concentrations in the serum, femur and mandible were assessed. In the study, all the antibiotics were found to prolong prothrombine time following acenocoumarin administration. In addition, perfloxacin and ciproflaxin concentrations were increased in the serum and mandible after acenocoumarin treatment. Cepafirin levels remained unaffected after the administration of this anticoagulant. In conclusion, anticoagulant and quinolone co-administration led to significant pharmacokinetic interactions. Thus particular attention should be paid in the case of these drugs being used in combination in clinical practice.

Therapeutic efficacy of rebamipide-loaded PLGA nanoparticles coated with chitosan in a mouse model for oral mucositis induced by cancer chemotherapy.

Oral mucositis is one of the most common side effects induced by cancer therapy, and the prevention or rapid treatment of the symptoms of oral mucositis can improve patients' quality of life and reduce the need for treatment interruption. In this study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan hydroxypropyltrimonium chloride was used as a carrier of rebamipide, and its usefulness was evaluated using a mouse model for oral mucositis. The surface properties and particle size of this nanoparticle were considered to be advantageous for the treatment of oral mucositis. Positively charged nanoparticles with an average particle diameter of 97.0 ±â€¯36.7 nm were prepared. From the results of the mucin adsorption study using a periodic acid/Schiff colorimetric method, it was confirmed that the mucin adsorptive capacity of chitosan-coated nanoparticles was 2.3 times higher than that of bare nanoparticles. This result was consistent with the results of the oral retention study of chitosan-coated nanoparticles using an in vivo optical imaging system. Therapeutic efficacy of the nanoparticles on oral mucositis was evaluated using a mouse model for oral mucositis induced by cancer chemotherapy. The chitosan-coated nanoparticles administration group significantly decreased the ulcer area at day 9, 11, and 13 compared with the non-treated control group. Moreover, this group significantly shortened the treatment period by 3.6 days compared to the bare nanoparticles administration group. Therefore, it was suggested that rebamipide-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride were beneficial for the treatment of oral mucositis induced by cancer chemotherapy.

Comparison between immobilized artificial membrane (IAM) HPLC data and lipophilicity in n-octanol for quinolone antibacterial agents.

The membrane phospholipid affinity of ten quinolone antibacterial agents, including both acidic and zwitterionic compounds, was measured by HPLC on two different immobilized artificial membrane (IAM) stationary phases, namely IAM.PC.MG and IAM.PC.DD2; it is expressed as the logarithm of the retention factor measured with (or extrapolated to) 100% aqueous eluent at pH 7.0, logk(w)(IAM). Quinolones are a class of highly potent, orally active, broad-spectrum antibacterial agents. For these compounds, lipophilicity values in n-octanol found in the literature, either calculated or measured, are not consistent with each other and are too low to be compatible with their pharmacokinetic properties. The logk(w)(IAM) values obtained in this study showed no relation with any of the lipophilicity values in the literature (clogP(a), clogP(b), MLP, logD(7.4)). In contrast, they were collinear with a new lipophilicity scale we had previously obtained by an original ion-pair reversed-phase HPLC method set up to estimate the lipophilicity of the neutral forms, logP(N). Moreover, when comparing the retention of quinolones on IAM to the retention of structurally unrelated neutral compounds, we observed that they interact with phospholipids with the same affinity as neutral isolipophilic compounds. The use of an eluent at pH 5.5, instead of pH 7.0, increased the retention on IAM not only for acidic, but also for zwitterionic congeners, indicating that phospholipid affinity is enhanced in the experimental conditions that depress the ionization of the acidic function, even when the ionization of the amino function increases simultaneously. To gain an insight into the mechanism of quinolones/serum-protein interactions, we investigated about possible relationships between quinolones affinity data for serum proteins and IAM data. Quinolone affinity for both HSA and AGP was already demonstrated poorly related to n-octanol lipophilicity values, probably due to the occurrence of electrostatic interactions. Only poor relationships were found between IAM and HSA affinity data, whereas quite good relationships were found with AGP affinity data. However, IAM.PC.DD2 data correlated better than those on IAM.PC.MG with quinolone affinity for both serum-proteins, mainly due to the fact that IAM.PC.MG phase is scarcely discriminative for the compounds with the highest retention values. The results suggest that IAM retention can produce a lipophilicity scale that, unlike solvent/water partition coefficients, is consistent with the pharmacokinetic behaviour of zwitterionic quinolones.

Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 in Healthy Volunteers.

This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the ß2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 µg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 µg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.

Rebamipide delivered by brushite cement enhances osteoblast and macrophage proliferation.

Many of the bioactive agents capable of stimulating osseous regeneration, such as bone morphogenetic protein-2 (BMP-2) or prostaglandin E2 (PGE2), are limited by rapid degradation, a short bioactive half-life at the target site in vivo, or are prohibitively expensive to obtain in large quantities. Rebamipide, an amino acid modified hydroxylquinoline, can alter the expression of key mediators of bone anabolism, cyclo-oxygenase 2 (COX-2), BMP-2 and vascular endothelial growth factor (VEGF), in diverse cell types such as mucosal and endothelial cells or chondrocytes. The present study investigates whether Rebamipide enhances proliferation and differentiation of osteoblasts when delivered from brushite cement. The reactive oxygen species (ROS) quenching ability of Rebampide was tested in macrophages as a measure of bioactivity following drug release incubation times, up to 14 days. Rebamipide release from brushite occurs via non-fickian diffusion, with a rapid linear release of 9.70% ± 0.37% of drug per day for the first 5 days, and an average of 0.5%-1% per day thereafter for 30 days. Rebamipide slows the initial and final cement setting time by up to 3 and 1 minute, respectively, but does not significantly reduce the mechanical strength below 4% (weight percentage). Pre-osteoblast proliferation increases by 24% upon exposure to 0.4 uM Rebamipide, and by up to 73% when Rebamipide is delivered via brushite cement. Low doses of Rebamipide do not adversely affect peak alkaline phosphatase activity in differentiating pre-osteoblasts. Rebamipide weakly stimulates proliferation in macrophages at low concentrations (118 ± 7.4% at 1 uM), and quenches ROS by 40-60%. This is the first investigation of Rebamipide in osteoblasts.

Focus on aripiprazole.

This paper is an overview of recently published research concerning the neuroleptic drug aripiprazole. Aripiprazole is an antipsychotic drug with high affinity for D(2)- and D(3)-receptors and the dopamine autoreceptor. It also has serotonin 5-HT(1A)-receptor partial agonist and 5-HT(2A)-receptor antagonist properties. It is prescribed in the treatment of schizophrenia and is under the treatment of schizophrenia and schizoaffective investigation for treatment of bipolar disorder. The drug is given by mouth in an initial dose of 10 or 15 mg once daily. The dose may be adjusted at intervals of not less than 2 weeks up to a maximum of 30 mg daily. It appears to be useful in disorder and has a better side-effect profile than haloperidol.

Sustained release of liposome-encapsulated enrofloxacin after intramuscular administration in rabbits.

Enrofloxacin was encapsulated in multilamellar liposomes composed of phosphatidylcholine and cholesterol (molar ratio, 1:1), and its potential use as sustained release formulation was evaluated. The encapsulated drug was administered IM to rabbits (n = 6). Results indicated that absorption rate was slow, compared with previous studies; additionally, peak concentration was lower (0.5 +/- 0.1 microgram/ml), and the time to peak concentration was considerably longer for liposome-encapsulated enrofloxacin (1.5 +/- 1.08 hours) than for unencapsulated drug. Apparent elimination half-life of drug in the body was significantly (P < 0.05) increased (4.05 +/- 1.08 hours) when it was administered encapsulated in liposomes. Large-size liposomes containing enrofloxacin administered IM to rabbits gave sustained drug release from the injection site, providing therapeutic and prolonged plasma concentrations of drug in the body.

Lipid membrane interactions of indacaterol and salmeterol: do they influence their pharmacological properties?

This study compares the lipid membrane interactions of indacaterol, an ultra long acting beta-2 agonist that is given once a day, to salmeterol, a twice a day beta-2 agonist, in order to elucidate the potential mechanisms leading to their different pharmacological properties. Salmeterol but not indacaterol perturbed dimyristoyl-phosphatidylcholine membranes. While the liposome partitioning of the two compounds was similar, independent of the lipid composition, the membrane affinity of indacaterol was two-fold greater than that of salmeterol when rafts, i.e. detergent-insoluble membrane domains, were used as the partition phase. The observed association kinetics with immobilized liposomes at physiological pH were two times faster for indacaterol than for salmeterol. A new model to explain the relationships between the drug/membrane interactions and drug's pharmacological properties considering multiple factors is proposed. The synergy between the higher partitioning of indacaterol into the raft micro domains and the faster membrane permeation of indacaterol could explain the faster onset and longer duration of therapeutic effect of indacaterol. The higher fluidizing effect of salmeterol on membrane fluidity may contribute to its lower intrinsic efficacy compared to indacaterol.

Pharmacokinetics, safety, and tolerability of ascending single doses of moxifloxacin, a new 8-methoxy quinolone, administered to healthy subjects.

The pharmacokinetics of moxifloxacin were investigated in six studies after oral administration of 50, 100, 200, 400, 600, and 800 mg. Eight healthy male volunteers were included in each study. With doses of up to 200 mg the study was performed as a double-blind, randomized group comparison (n = 6 verum and n = 2 matched placebo); with the higher doses the study was conducted with a double-blind, randomized, crossover design. Safety and tolerability were assessed by evaluation of vital signs, electrocardiograms, electroencephalograms, clinical chemistry parameters, results of urinalysis, and adverse events. The drug was well tolerated. The concentrations of moxifloxacin in plasma, urine, and saliva were determined by a validated high-pressure liquid chromatography assay with fluorescence detection. In addition, plasma and urine samples were analyzed by a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of moxifloxacin in plasma (Cmax) ranged from 0.29 mg/liter (50-mg dose) to 4.73 mg/liter (800-mg dose) and were reached 0.5 to 4 h following drug administration. After reaching the Cmax, plasma moxifloxacin concentrations declined in a biphasic manner. Within 4 to 5 h they fell to about 30 to 55% of the Cmax, and thereafter a terminal half-life of 11 to 14 h accounted for the major part of the area under the concentration-time curve (AUC). During the absorption phase concentrations in saliva were even higher than those in plasma, whereas in the terminal phase a constant ratio of the concentration in saliva/concentration in plasma of between 0.5 and 1 was observed, indicating a correlation between unbound concentrations in plasma and levels in saliva (protein binding level, approximately 48%). AUC and Cmax increased proportionally to the dose over the whole range of doses investigated. Urinary excretion amounted to approximately 20% of the dose. Data on renal clearance (40 to 51 ml/min/1.73 m2) indicated partial tubular reabsorption of the drug. The pharmacokinetic parameters derived from compartmental and noncompartmental analyses were in good agreement. The kinetics could be described best by fitting the data to a two-compartment body model.

Concentrations of lomefloxacin in radicular cyst and oral tissues following single or multiple oral administration.

Concentrations of lomefloxacin in serum, the wall and fluid of radicular cyst, gingiva, and jawbone following single or multiple oral administration were measured. The highest concentrations of lomefloxacin in serum, cyst wall, cyst fluid, gingiva, and jawbone occurred at 3 h after multiple administration, and were 2.31 micrograms/ml, 4.06 micrograms/g, 1.54 micrograms/ml, 4.72 micrograms/g and 2.79 micrograms/g, respectively. The mean concentration ratios of wall/serum, fluid/serum, fluid/wall, gingiva/serum, and jawbone/serum at the highest concentrations were 1.74, 0.73, 0.47, 2.52 and 1.20, respectively. Although most lomefloxacin concentrations in cyst and oral tissues following single oral administration did not exceed the MICs for 80% of clinically isolated strains of alpha-hemolytic streptococci, Staphylococcus aureus and Niesseria spp., most of those obtained after multiple oral administration exceeded the MICs except in the case of fluid.

The effect of respiratory manoeuvres and pharmacological agents on the pharmacokinetics of nedocromil sodium after inhalation.

1. Eight healthy subjects inhaled nedocromil sodium from a metered-dose inhaler using a standardised inspiratory technique. Blood samples were taken for up to 270 min after inhalation for radioimmunoassay of plasma nedocromil sodium concentrations. 2. To investigate the possibility that respiratory manoeuvres can alter the absorption of the drug from the lungs, on the first (control) study day at 70 min after dosing, subjects performed nine forced expiratory manoeuvres over a 3 min period. At 110 min after dosing, subjects took a slow, full inspiration with a 30 s breath-hold, and at 150 min after dosing the subjects performed one single forced expiration. 3. On the second study day, subjects inhaled methoxamine, 0.15 mg kg-1 of a 20 mg ml-1 solution at 60 min after dosing, and the study continued as above. On the third day, subjects repeated the sequence of respiratory manoeuvres, after having taken phenoxymethyl penicillin and probenecid by mouth for 48 h. 4. Both multiple forced expirations and the deep inspiration with breath-hold produced significant increases in the absorption of nedocromil sodium. Inhaled methoxamine did not alter airway calibre or the response to the respiratory manoeuvres. Probenecid, but not penicillin, was detected in the subjects' plasma, and had the effect of increasing the rise in plasma nedocromil sodium concentrations after the multiple forced expirations when compared with the control day. 5. These data suggest that disruption of epithelial tight junctions induced by the respiratory manoeuvres leads to enhanced paracellular transport of nedocromil sodium into the draining circulation of the airways and alveoli.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics of enrofloxacin and tissue concentrations of parent drug and ciprofloxacin after intramuscular administrations of free and liposome-encapsulated enrofloxacin in rabbits.

Pharmacokinetic properties and tissue concentrations of enrofloxacin and ciprofloxacin were compared after intramuscular (i.m.) administrations of free and liposome-encapsulated enrofloxacin at the dose of 5 mg/kg body weight (bw). Twelve healthy adult New Zealand white rabbits were used in the experiment. Blood samples were obtained at 10, 20, 40, 60 and 90 min and 2, 4, 6, 8 and 12 h and tissue samples were collected 24 h after injection. Concentrations of drugs in serum were determined by high-performance liquid chromatography. Pharmacokinetics were best described by a two-compartment open model. Results indicated that absorption rate was slow, peak concentration was higher (P < 0.05), and the time to peak concentration (tmax congruent with 1.5 h) was significantly longer (P < 0.05) for liposome-encapsulated enrofloxacin (LEE) when compared with free enrofloxacin. Values of elimination half-life (t1/2beta = 12.9 h) and mean residence time (MRT = 17.6 h) of liposome-encapsulated enrofloxacin were longer (P < 0.05) and total clearance (Cl = 0.43 l/h/kg) was lower than those of free form. Moreover, the distribution volume at steady-state (Vd(ss) = 14.4 l/kg) of enrofloxacin administered encapsulated into liposomes was significantly higher (P < 0.05) than that of free enrofloxacin (FE). The tissue levels of enrofloxacin and ciprofloxacin after LEE injection were not different (P > 0.05) from FE. In conclusion, the result of present study suggest that LEE may be a beneficial and valuable formulation in the treatment of infectious diseases caused by sensitive pathogens in animals, providing sustained drug release from injection side and prolonged therapeutic serum concentrations after i.m. administration.

Pharmacokinetics of prulifloxacin. 1st communication: absorption, distribution and excretion in rats, dogs and monkeys after a single administration.

The pharmacokinetics of prulifloxacin ((+/-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-car boxylic acid. CAS 123447-62-1, NM441), a quinolone antibacterial prodrug, was investigated after i.v. (14C-NM394, CAS 112984-60-8) or oral (14C-NM441) administration to rats, dogs and monkeys. 1. 14C-NM441 was absorbed mainly from the upper small intestine and then metabolized to NM394 partly in the intestinal membrane but mainly in the portal blood and liver. Thus NM441 was not detected in the systemic circulation. 2. After i.v. administration of 14C-NM394 (5 mg/kg), the plasma concentration of radioactivity decreased biexponentially, and the elimination half-life in rats, dogs and monkeys was 4.2, 5.8 and 7.0 h, respectively. After oral administration of 14C-NM441 (20 mg/kg), the plasma concentration of radioactivity reached a maximum at 0.7-3.3 h, and thereafter decreased as observed after i.v. administration of 14C-NM394. An effect of food on the absorption of NM441 was found. No clear sex-related differences were observed in the plasma concentration profiles of rats. 3. The concentration of radioactivity in most tissues of rats reached a maximum within 1 h after oral administration of 14C-NM441 and thereafter decreased along with the plasma concentration. At 0.5 h, the radioactivity concentrations were highest in the liver and kidney, moderately high in the spleen, pancreas, lung and mandibular gland and extremely low in the cerebrum and cerebellum. 4. The radioactivity in the excreta collected over a 96-h period was 96-98% of the oral dose (urine, 22-32%; feces, 64-75%) in rats, dogs and monkeys, 35% of the radioactivity administered was excreted in the bile of rats during a 48-h period after oral administration, and only a small portion of the biliary radioactivity was reabsorbed. 5. The proportion of 14C-NM394 that bound to serum proteins in vitro in rats, dogs, monkeys and humans was 41-59% in a concentration range of 0.1-10 micrograms/ml.

Encapsulation of enrofloxacin in liposomes I: preparation and in vitro characterization of LUV.

Liposomes are effectively used in the treatment of microbial infections. Higher cellular uptake has been reported when antibiotics are encapsulated in liposomes. In this study, enrofloxacin (ENF) was encapsulated in large unilamellar vesicles (LUVs) and the effects of formulation variables on the liposome characteristics were investigated. Liposomes were prepared using dry lipid film method. A number of variables such as molar ratios of phospholipid (DPPC; DL-alpha-phosphatidylcholine dipalmitoyl), cholesterol, ENF and amount of alpha-tocopherol and the volumes of internal (chloroform) and external phases [phosphate buffered saline PBS (pH 7.4)] were studied. In vitro characterization of the liposomes including the encapsulation capacity, size and drug release properties were carried out. Using of this method, spherical LUV liposomes with high drug content could be produced. Particle size of liposomes changed between 3.12 and 4.95 microm. The molar ratios of DPPC, cholesterol and ENF affected the size of the liposome (p < 0.05). The drug encapsulation capacities were high and changed between 37.1% and 79.5%. The highest ENF encapsulation was obtained with the highest cholesterol content. An increase in the drug encapsulation capacity of the liposome was found with increasing molar ratios of DPPC, cholesterol and ENF (p < 0.05). Furthermore, the release of ENF from the liposomes decreased as the molar ratios of DPPC, cholesterol and ENF increased (p < 0.05). In conclusion, a convenient colloidal carrier for the controlled release of ENF can be prepared by changing the formulation parameters of LUVs.

Role of low-substituted hydroxypropylcellulose in dissolution and bioavailability of novel fine granule system for masking bitter taste.

Coated fine granules with water-insoluble film composed primarily of ethylcellulose, containing 20% of sparfloxacin (SPFX) and various amounts of low-substituted hydroxypropylcellulose (L-HPC) (0-52%) in the cores and which masked the bitter taste of SPFX, were orally administered to fasting rats to determine the effect of L-HPC on bioavailability. The release of SPFX in water from four kinds of these coated fine granules containing 0, 25, 40 and 52% of L-HPC showed the pseudo first order kinetics, followed by the second phase, with refractive points between 0.25 and 0.5 h. The rate constant (K1) up to 0.25 h increased with an increase [corrected] of the amount of L-HPC in the core, and the rate constant (K2) in subsequent release (the second phase) was lower than K1 in each fine granule. Areas under plasma concentration-time curves (AUC) of SPFX and the peak plasma SPFX levels (Cmax) after oral administration of coated fine granules lacking L-HPC to fasting rats were suppressed to one-eighth and one-ninth, respectively, of those obtained from the core granules that rapidly released SPFX. However, AUC and Cmax from the coated fine granules increased linearly with an increase in the amount of L-HPC in the cores, and nearly equaled those from the core fine granules when the content of L-HPC was 52%. These results confirmed that the addition of L-HPC to the cores increases not only the dissolution rate but also the bioavailability of SPFX.