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Objective: The aim of this study was to develop a drug-in-adhesive patch for transdermal delivery of daphnetin (DA), which is a coumarin derivative in Girald Daphne, and to investigate the role of Transcutol P (TP) in the release and percutaneous permeation processes of DA., Methods: Backing films, permeation enhancers and enhancer content in the transdermal patch were investigated through in vitro experiments using rat skin. Anti-inflammatory and analgesic effects of the optimized formulation were evaluated using the adjuvant arthritis model and the pain model induced by acetic acid, respectively. In addition, the enhancement effect of TP was investigated using differential scanning calorimetry (DSC), FTIR, and molecular dynamic simulation., Results: The optimal formulation, composed of DURO-TAK ® 87-2852, CoTran TM 9680, 1% DA, and 10% TP showed anti-inflammatory and analgesic effects. It was found that TP only promoted the release process of DA from its transdermal patch. Furthermore, the decrease of interaction between drug and pressure sensitive adhesive (PSA) as well as the improvement of PSA mobility due to TP addition were the main factors that enhanced the release of DA from patch., Conclusions: This study successfully used TP to develop a DA patch with good anti-inflammatory and analgesic effects, proving that TP promotes the release of DA by reducing the interaction between DA and PSA and increasing the mobility of PSA.

Objective: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability., Methods: Liquid SNEDDS (L-SNEDDS) composed of Capryol™ 90 (oil), Cremophor ® RH40 (surfactant), and Transcutol ® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits., Results: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in t max , AUC (0-12) , and AUC (0-∞) at p < .05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product., Conclusions: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.

Background: Peptide-mediated drug delivery system (DDS) has been increasingly used to promote on-demand treatment efficacy of cancers. Herein, LTLRWVGLMS (LS10) peptide is selected as the functional ligand for specific glioma-targeting drug delivery. LS10 peptide selectively binds to NG2 proteins that are widely overexpressed in the glioma cells and restricted in normal tissue. LS10 peptide-decorated DDS is expected to hold vast promises in glioma therapy and decrease unwanted side effects., Methods: LS10 peptide was conjugated on the surface of poly(ethylene glycol)-poly(ɛ-caprolactone) (PEG-PCL) nanoparticles via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N-hydroxysulfosuccinimide coupling reaction. Using U87MG cells as the glioma cell model, cellular uptake, internalization mechanism, cellular cytotoxicity and apoptosis were investigated. 1,1'-Dioctadecyl-3,3,3',3'-tetramethyl indotricarbocyanine iodide were used as fluorescence probes to investigated in vivo glioma targeting capability of LS10-NP. The glioma therapeutic efficacy of paclitaxel-loaded LS10-NP was studied on glioma-bearing nude mice., Results: The LS10-NP with size of 119 nm enhanced cellular uptake on U87MG cells, increased cytotoxicity of the loaded paclitaxel (PTX), and improved penetration in 3D U87MG glioma spheres. In vivo biodistribution experiments showed that LS10-NP exhibited the enhanced drug localization at glioma site, which resulted in prolonged survival time of glioma-bearing mice., Conclusion: Our results indicated that LS10 peptide-modified nanoparticulate DDS could significantly improve the anti-glioma efficacy.

The aim of this work is to improve the oral bioavailability of poorly water soluble drug, simvastatin (SV) through combining the advantages of self-nanoemulsifying systems (SNEs) and tablets. Ternary phase diagram was constructed using Labrafil, Tween 80 and Transcutol, in order to evaluate self-nanoemulsification domain. The particle size distribution and zeta potential of the prepared systems were evaluated using Malvern Zetasizer. Liquisolid powders were prepared using Aeroperl(®) as a coating material and Avicel(®) or Starch 1500 as carrier materials, the powder flow properties were then evaluated. Compressed SV SNE based tablets were evaluated regarding their physical characteristics, in-vitro release properties as well as in-vivo pharmacokinetic evaluation in six healthy human volunteers using a validated LC/MS/MS method. The in-vitro release results revealed that the developed SNE based tablets improved the release of SV significantly, compared to commercially available SV tablets (Zocor(®)). The optimal SV SNE tablet formulation was S3St10 (10% Labrafil, 60% Tween 80, and 30% Transcutol). The in-vivo evaluation of S3St10 revealed that rapid and enhanced absorption of SV could be obtained from the SNE based tablet, with a 1.5 fold increase in bioavailability than that obtained after administration of Zocor(®). Hence such an approach could be promising in improving the bioavailability of SV.

Introduction: Diethylene glycol (DEG) is a clear, colorless, practically odorless, viscous, hygroscopic liquid with a sweetish taste. In addition to its use in a wide range of industrial products, it has also been involved in a number of prominent mass poisonings spanning back to 1937. Despite DEG's toxicity and associated epidemics of fatal poisonings, a comprehensive review has not been published., Methods: A summary of the literature on DEG was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material., Aim: The aim of this review is to summarize all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, toxicity of DEG, diagnosis, and management., Epidemiology: Most of the documented cases of DEG poisoning have been epidemics (numbering over a dozen) where DEG was substituted in pharmaceutical preparations. More often, these epidemics have occurred in developing and impoverished nations where there is limited access to intensive medical care and quality control procedures are substandard., Toxicokinetics: Following ingestion, DEG is rapidly absorbed and distributed within the body, predominantly to regions that are well perfused. Metabolism occurs principally in the liver and both the parent and the metabolite, 2-hydroxyethoxyacetic acid (HEAA), are renally eliminated rapidly., Mechanisms of Toxicity: Although the mechanism of toxicity is not clearly elucidated, research suggests that the DEG metabolite, HEAA, is the major contributor to renal and neurological toxicities., Clinical Features: The clinical effects of DEG poisoning can be divided into three stages: The first phase consists of gastrointestinal symptoms with evidence of inebriation and developing metabolic acidosis. If poisoning is pronounced, patients can progress to a second phase with more severe metabolic acidosis and evidence of emerging renal injury, which, in the absence of appropriate supportive care, can lead to death. If patients are stabilized, they may then enter the final phase with various delayed neuropathies and other neurological effects, sometimes fatal. TOXICITY OF DEG: Doses of DEG necessary to cause human morbidity and mortality are not well established. They are based predominantly on reports following some epidemics of mass poisonings, which may underestimate toxicity. The mean estimated fatal dose in an adult has been defined as approximately 1 mL/kg of pure DEG., Management: Initial treatment consists of appropriate airway management and attention to acid-base abnormalities. Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite HEAA; hemodialysis can also be critical, and assisted ventilation may be required., Conclusions: DEG ingestion can lead to serious complications that may prove fatal. Prognosis may be improved, however, with prompt supportive care and timely use of fomepizole or ethanol.

1. Ethylene glycol monobutyl ether (EGBE) causes forestomach hyperplasia and neoplasia in mice when administered chronically by inhalation. 2. The study was initiated to test the physiologically based pharmacokinetic (PBPK) model prediction that 2-butoxyacetaldehyde (BAL), a transient, labile intermediate in the oxidation of EGBE to butoxyacetic acid (BAA), is unlikely to achieve concentrations sufficient to cause DNA damage in target tissues. 3. Male and female B6C3F1 mice were administered a high oral dose of EGBE (600mgkg(-1)), and tissues were collected at 5, 15, 45 and 90min following the dose. The tissues were processed for determination of EGBE, BAL and BAA by gas chromatography-mass spectrometry. 4. BAL was detected at low concentrations in all tissues sampled and at all time points following EGBE administration (about 0.3-33 microM). BAL concentrations were highest in the initial samples (5 min) in all tissues and declined from that point. 5. BAL concentrations in liver and forestomach tissues corresponded to the peak concentrations predicted by an already published PBPK model, and are higher than BAL concentrations that could be achieved by inhalation exposure to EGBE. 6. Mouse inhalation exposure to EGBE is therefore unlikely to generate BAL concentrations in tissues sufficient to initiate a carcinogenic response.

Current literature indicates that an in vitro release test (IVRT) can serve as a research tool during the course of developing topical formulations. The purpose of this study was therefore to investigate the ability of an IVRT to select the topical semisolid formulations with the most rapid release rate of the model drug ketoprofen from two closely related hydrogels in a simulated product development process. Two glycols with distinct differences in their physical-chemical properties, Transcutol P (ethoxydiglycol) and propylene glycol, were incorporated into Carbopol 980 and Poloxamer 407 formulations. The release rate of ketoprofen was determined utilizing different receptor media and conditions, i.e., phosphate buffer pH 7.4, isopropyl myristate (IPM), and a combination of an IPM soaked membrane and phosphate buffer (pH 7.4) as receptor fluid. The results indicated that the conditions chosen could affect greatly the conclusions concerning the formulations. The only observable trend was that Transcutol P-containing formulations tended to permit a faster ketoprofen release than propylene glycol-containing formulations when utilizing IPM as a receptor component. This was attributed to the mutual miscibility of Transcutol P in IPM. It can be concluded that, for the purpose of formulation screening in the early phases of product development, an IVRT will only be useful for predicting the amount of drug available for absorption if the receptor medium has properties that closely mimic human skin. These results illustrate the importance of selecting suitable receptor components and indicate that it may be necessary to consider alternatives to the commonly used synthetic membranes.

Ethylene glycol monomethyl ether (EGME) and its acetate ester (EGMEA) are highly flammable, colorless, moderately volatile liquids with very good solubility properties. They are used in paints, lacquers, stains, inks and surface coatings, silk-screen printing, photographic and photo lithographic processes, for example, in the semiconductor industry, textile and leather finishing, production of food-contact plastics, and as an antiicing additive in hydraulic fluids and jet fuel. EGME and EGMEA are efficiently absorbed by inhalation as well as via dermal penetration. Dermal absorption may contribute substantially to the total uptake following skin contact with liquids or vapours containing EGME or EGMEA. EGMEA is rapidly converted to EGME in the body and the two substances are equally toxic in animals. Therefore, the two substances should be considered as equally hazardous to man. Effects on peripheral blood, testes, and sperm have been reported at occupational exposure levels ranging between 0.4 and 10 ppm EGME in air, and with additional, possibly substantial, dermal exposure. Severe malformations and disturbed hematopoiesis have been linked with exposure to EGME and EGMEA at unknown, probably high, levels. Embryonic deaths in monkeys and impaired spermatogenesis in rabbits have been reported after daily oral doses of 12 and 25 mg per kg body weight, respectively. In several studies, increased frequency of spontaneous abortions, disturbed menstrual cycle, and subfertility have been demonstrated in women working in the semiconductor industry. The contribution of EGME in relation to other exposure factors in the semiconductor industry is unclear.

1. [1,2]-14C-Ethylene glycol (EG) was given to female CD (Sprague-Dawley) rats and CD-1 mice in order to determine tissue distribution and metabolic fate after intravenous (iv), peroral (po), and percutaneous (pc) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional pc doses of 400, 600 or 800 mg/kg. Mice were also given iv and po doses of 10 or 1000 mg/kg, and intermediate po doses of 100, 200 or 400 mg/kg. Mice were given po doses of 100 or 1000 mg/kg, and both species were given a 50% (w/w) aqueous po dose to simulate antifreeze exposure. 2. For both species, EG is very rapidly and almost completely adsorbed after po doses. Perorally administered EG doses produced similar dose-dependent relationships described in prior studies for the disposition and excretion of iv doses. 3. The tissue distribution of EG following either iv or po routes was essentially the same, with similar percentages recovered for each dose by both routes and for either species. 4. Cutaneously-applied EG was slowly and rather poorly adsorbed in both species, in comparison with po-dose administration, and urinalysis after undiluted po doses indicated that EG probably penetrates rat skin in the parent form. There was an absence in both species of dose-dependent changes in disposition and elimination following the pc application of EG. 5. 14C-labelled EG, glycolic acid and/or oxalic acid accounted for the majority of the detectable radioactivity in the urine samples from all dose routes in the rat, while glycoaldehyde and glyoxylic acid were not detected in any of the urine fractions evaluated. Similar increases in glycolate production with increasing dose were also observed in mouse urine samples from iv and po dosing. Also, glyoxylate and oxalate were absent from mouse urine. 6. Oxidative metabolic pathways appeared to be saturated at high po doses in both species, resulting in a shift from principally 14CO2 exhalation to urinary 14C excretion, while the onset of capacity-limited metabolic changes appears to occur at lower doses for mice than for rats. 7. In summary, rats and mice displayed several similarities in the manner in which low doses of EG by several routes are distributed, metabolized, and excreted, but the onset of capacity-limited changes in metabolism occurs at lower doses for mice than for rats. Such differences in the disposition of EG may provide important interpretive information to help explain differences observed in developmental toxicity and nephrotoxic responses between these two rodent species.

1. The pharmacokinetic fate of [1,2-14C]-ethylene glycol (EG) was evaluated in the male Sprague-Dawley rat in order to characterize its overall uptake and elimination. Doses of 10 and 1000 mg/kg were administered by the intravenous (i.v.), peroral (p.o.), or percutaneous (p.c.) route; additional doses of 400, 600 and 800 mg/kg were evaluated by the p.o route. 2. Baseline data obtained by the i.v. route for bioavailability comparisons showed that while plasma radioactivity concentrations declined in a biexponential manner with t1/2 beta of 26-37 h, the disappearance of unmetabolized EG from the plasma was quite rapid (t1/2 beta of 0.8-1.2 h). Peroral doses were rapidly and almost completely absorbed, showing t1/2 abs in the order of minutes, and a bioavailable fraction for unmetabolized EG of 92-100%. Conversely, EG applied to rat skin was slowly and rather poorly absorbed, showing t1/2 abs which were an order of magnitude longer than for comparable p.o. and i.v. doses, and a bioavailability of approximately 22%. 3. The major route of elimination for the 10 mg/kg dose by any route was by metabolism to 14CO2 and exhalation, while urinary elimination of 14C was the secondary excretion pathway. 4. Plasma clearance of 14C was linear with increases in p.o. doses over the 400-800 mg/kg range, with AUC proportional to dose for these and the 10 mg/kg p.o. dose levels. However, a dose-dependent shift in excretion routes was observed following the p.o. 1000 mg/kg dose, with urine becoming the major excretion route, and similar capacity limited pharmacokinetics were observed for the i.v. 1000 mg/kg dose. Plasma pharmacokinetic data for unchanged EG after i.v. and p.o. doses demonstrated an apparent first-order kinetic behaviour between the 10 and 1000 mg/kg dose levels for the disappearance of EG. 5. Following both i.v. and p.o doses, dose-independent relationships were seen in the values obtained for the area under the plasma curve (AUC infinity), the total clearance of EG (CltotalEG), mean residence time (MRT infinity), apparent volume of distribution at steady state (Vdss), the terminal half-life (t1/2 beta) and the renal and metabolic clearance values. However, this dose-linear plasma time course was not apparent from the dose-dependent excretion profiles for these two exposure routes. 6. Increases in urinary 14C-glycolate were also observed when the i.v. or p.o. doses were increased from 10 to 1000 mg EG/kg, indicating that metabolism of EG makes a substantial contribution to AUC infinity in the beta disposition phase of the plasma curves for this high dose. Oxalate, a metabolite found in man after EG exposure, was detected at very low levels after both the 10 and 1000 mg/kg dose levels and by either i.v or p.o. routes. 7. Thus, EG given by three different routes demonstrated apparent first-order pharmacokinetic behaviour for disposition in and the elimination from plasma in the male rat, but dose-dependent changes occurred for the elimination of metabolites in urine and as 14CO2 after single i.v. and p.o. doses, but not for the p.c. routes.

During a period of 10 years 18 men were treated for severe ethylene glycol (EG) intoxication. All patients received supportive measures and ethanol infusion. Hemodialysis (HD) was applied in 11 patients (Group I) whereas 7 patients, who exhibited more advanced toxicity symptoms, received peritoneal dialysis (PD) simultaneously with HD (Group II). Patients in Group II showed more advanced acidosis on admission than in Group I (Base excess -27.1 mmol/l versus -16.8 mmol/l, p < 0.0075). The results of treatment in these two groups of patients were compared. All patients in Group I survived and one patient in Group II died. The patients in Group II were discharged with higher serum creatinine and follow up time to improve renal function was longer than in Group I (252 versus 149 mumol/l, p < 0.015 and 23 versus 7.9 weeks, p < 0.05 respectively). No correlations were found between serum EG and grade of acidosis on admission or serum EG and subsequent increase of serum creatinine but acidosis on admission was highly correlated to the rise of serum creatinine after the 72 hours of observation time (p < 0.0001). It is concluded, that combined HD and PD treatment was beneficial in the presented patients as it corrected acidosis earlier and could eliminate EG and its toxic metabolites faster, improving prognosis.

1. 14C-Diethylene glycol (DEG), administered orally to rats at 1, 5, and 10 ml/kg, gave elimination half-lives of 6, 6, and 10 h, respectively, from urinary excretion data. Half-logarithmic plots of urinary 14C excretion rates versus time indicated zero-order elimination for the first 9 and 18 h after oral doses of 5 and 10 ml of 14C-DEG/kg, respectively. 14C-DEG urinary elimination kinetics changed into first-order 6, 9, and 18 h after oral doses of 1, 5, and 10 ml/kg, with a half-life of 3 h. 2. After oral doses of 3 and 5 ml ethylene glycol (EG)/kg, half-lives of 4.5 and 4.1 h were estimated from cumulative urinary excretion data for non-metabolized EG. A half-life of 2 h was determined from half-logarithmic plots of urinary excretion rates of non-metabolized EG after the same oral doses of EG. 3. The urinary concentrations of non-metabolized DEG and its metabolite, 2-hydroxyethoxyacetic acid (2-HEAA), determined by high-resolution n.m.r. spectroscopy in the urine of rats doses with DEG were 61-68% and 16-31% dose, respectively. 4. Urinary concentrations of non-metabolized EG and its metabolite, glycolic acid (GA), determined by n.m.r., gave 62-67% for non-metabolized EG and 28.7% for GA following oral doses of EG. 5. Oxidation of DEG and EG in rats was accompanied by a change of urinary pH, reflecting metabolic acidosis. 6. Comparison of the KM for DEG oxidation in vitro by ADH with that of ethanol oxidation, showed a 680-fold difference in substrate affinity. DEG inhibited ethanol oxidation non-competitively, the Ki being 0.44 M.