Degradation of fenprostalene in polyethylene glycol 400 solution

The kinetics of degradation of fenprostalene (I) in polyethylene glycol 400 solution was examined using HPLC. The degradation of I at 80 degrees C was shown to depend on the presence of oxygen and a large number of polar products were produced, as evidenced by using 3H-labeled I. Evidence that autoxidation of the polyethylene glycol 400 was concurrent with degradation of I was found from a drop in the apparent pH. Antioxidants were very effective in retarding the rate of degradation in the presence of oxygen. Degradation of I in polyethylene glycol 400 appears to arise from a reaction between the drug and reactive peroxide intermediates formed through air-oxidation of polyethylene glycol 400. This is supported by the finding that I reacts exclusively by a slow transesterification reaction in diethylene glycol, a solvent that is stable to autoxidation.     

Formation of reactive impurities in aqueous and neat polyethylene glycol 400 and effects of antioxidants and oxidation inducers

A 2,4-dinitrophenylhydrazine (DNPH) precolumn derivatization high-performance liquid chromatography-ultraviolet detection (HPLC-UV) method was developed to quantify levels of formaldehyde and acetaldehyde in polyethylene glycol (PEG) solutions. Formic acid and acetic acid were quantified by HPLC-UV. Samples of neat and aqueous PEG 400 solutions were monitored at 40°C and 50°C to determine effects of excipient source, water content, pH, and trace levels of hydrogen peroxide or iron metal on the formation of reactive impurities. The effects of antioxidants were also evaluated. Formic acid was the major degradation product in nearly all cases. The presence of water increased the rate of formation of all impurities, especially formic acid as did the presence of hydrogen peroxide and trace metals. Acidic pH increased the formation of acetaldehyde and acetic acid. A distribution of unidentified degradation products formed in neat PEG 400 disappeared upon addition of HCl with corresponding increase of formic acid, indicating they were likely to be PEG-formyl esters. Other unidentified degradation products reacted with DNPH to form a distribution of derivatized products likely to be PEG aldehydes. Antioxidants butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate d-alpha tocopheryl polyethylene glycol-1000 succinate, and sodium metabisulfite were effective in limiting reactive impurity formation, whereas ascorbic acid and acetic acid were not.     

Nitroglycerin stability in polyethylene glycol 400 and povidone solutions.

The stability of solutions of nitroglycerin in several common pharmaceutical solvents and compounds used as tablet excipients was investigated using a UV spectrophoto metric assay. Included in the study were povidone (I), polyethylene glycol 400 (II), and solvents such as absolute alcohol, propylene glycol, and glycerol. At the elevatted temperatures of the accelerated stability studies, only II demonstrated a considerable adverse effect on the stability of the nitroglycerin solution. It is postulated that a "reaction compound" was formed between nitroglycerin and II which regenerated nitroglycerin depending on hydrolysis conditions. Based on the Arrhenius equation and with initial rates of up to 6 hr of degradation, the predicted stability for a II solution of nitroglycerin in terms of its 10% decomposition at 25 degrees was approximately 7 days.     

聚乙二醇400对黄芩苷在大鼠体内药动学的影响

目的 考察聚乙二醇400 (PEG400)对黄芩苷在大鼠体内药动学的影响.方法 将大鼠随机分为黄芩苷组和PEG400组,黄芩苷组大鼠单独灌胃给予黄芩苷,PEG400组的灌胃给予黄芩苷和PEG400混合物,于不同时间点取静脉血,用HPLC法检测血浆中的黄芩苷,绘制药时曲线,用DAS 2.0计算药动学参数.结果 黄芩苷的线性范围为0.3203 ～ 10.25 μg·mL-1,定量下限为0.3203 μg· mL-1,日内、日间RSD均＜10％,提取回收率＞85％,PEG400组的AUC0-t明显高于黄芩苷组.结论 PEG400可促进黄芩苷在大鼠体内的吸收.     

Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine

Purpose. To investigate the effect of co-administered polyethylene glycol 400 (PEG 400), a pharmaceutical excipient previously shown to accelerate small intestinal transit, on the absorption characteristics of ranitidine from the gastrointestinal tract. Methods. Ten healthy male volunteers each received, on two separate occasions, an immediate-release pellet formulation of ranitidine (150 mg) encapsulated within a hard gelatin capsule and a liquid preparation consisting of 150 ml orange juice (control) or 150 ml orange juice containing 10 g PEG 400 (test). The liquid preparations were also radiolabelled with indium-111 to allow their transit through the gastrointestinal tract to be followed using a gamma camera. On a further occasion an intravenous injection of ranitidine (50 mg) was administered. Blood samples were taken over a 12 h period on each study day to allow a ranitidine plasma and subsequent absorption rate profile to be generated for each oral formulation. Urine was collected for 24 h and assessed for PEG 400 concentration. Results. The absolute bioavailability of ranitidine from the pellet formulation was significantly reduced by 31% (from 51% to 35%) and small intestinal liquid transit time was significantly shortened by 37% (from 226 min to 143 min) as a consequence of PEG 400 in the test preparation. PEG 400 also affected the rate of ranitidine absorption, with major differences noted in the mean absorption time and C_max parameters. The appearance of double peaks were less evident in the ranitidine pharmacokinetic profiles in the presence of PEG 400, and little or no correlation was observed between the absorption of ranitidine and PEG 400. Conclusions. These results clearly demonstrate that PEG 400 adversely influences the gastrointestinal absorption of ranitidine. This in turn has ramifications for the use of PEG 400 as a pharmaceutical excipient in oral formulations.     

Enhanced oral bioavailability of paclitaxel by D-alpha-tocopheryl polyethylene glycol 400 succinate in mice

Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of D-alpha-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18mg/kg) or oral (100mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77+/-0.17 and 3.39+/-0.49microg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40-47min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1mM did not inhibit testosterone 6beta-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel.     

Gastric mucosal changes induced by polyethylene glycol 400 administered by gavage in rats

Polyethylene glycol 400 (PEG 400) is widely used with a variety of pharmaceutical formulations, and is often added to dosing formulations in preclinical toxicity studies. The aim of the present study was to characterize the effects of PEG 400 on the rat gastrointestinal tract. Three dosage levels (5, 50 or 100 v/v%) of PEG 400 were administered at a volume of 5 ml/kg/day by gavage for 15 days to the rats (5 males and 5 females in each group). At the end of the treatment, the whole lengths of gastrointestinal tracts were examined pathologically. Although there were no gross abnormalities at necropsy, the histopathological examination revealed several changes localized to the stomach mucosa, but not in the intestine. The changes consisted of infiltration of eosinophils and globule leukocytes, increased in the height of the entire mucosal layer, elongation of the surface mucous epithelial and mucous neck cell layers with increased intracellular mucous in the glandular stomach, and the spongiosis (intercellular edema) of the squamous epithelium in the forestomach. These changes near the limiting ridge tended to increase in severity and extent in a dose-dependent manner. These results suggest that repeated oral administration of concentrated PEG 400 can easily induce the mucosal changes in the stomach of the rats.     

The effect of glycerol, propylene glycol and polyethylene glycol 400 on the partition coefficient of benzophenone-3 (oxybenzone)

Sunscreen products are widely used to protect the skin from sun-related deleterious effects. The objective of the study was to investigate the potential effect of glycerol, propylene glycol and polyethylene glycol 400 on dermal absorption of oxybenzone by studying their effects on its partition coefficient. The partition coefficient was evaluated in a chloroform-water system at room temperature. It was found that glycerol and propylene glycol decreased the partition coefficient of oxybenzone, while an increase in partition coefficient was observed with polyethylene glycol 400. The findings suggest that polyethylene glycol 400 in contrast to glycerol and propylene glycol has the potential of increasing the vehicle-skin partition coefficient of oxybenzone when cosmetic products containing such an UV absorber are topically applied to the skin.     

Effect of drug solubility on in vitro availability rate from suppositories with polyethylene glycol excipients

Factors involved in the availability mechanism of different drugs from suppositories with polyethylene glycol (PEG) excipients were studied using an in vitro model of the rectal compartment with a porous membrane simulating the rectal barrier. Different from lipophilic excipients, the drug is released as a consequence of the progressive dissolution of PEG into the intrarectal aqueous phase. Drug concentration in this small intrarectal phase produces the gradient against the large volume of the plasmatic phase, which regulates the diffusion rate through the barrier. As with lipophilic excipients, drug solubility in water was found to be an important factor influencing suppository release rate. Nevertheless, PEG influenced in vitro drug availability considerably, by increasing both drug solubility and dissolution rate. The osmotic effect of PEG in the intrarectal compartment influenced the increase in volume of the aqueous phase. The results, compared with those obtained from suppositories with a lipophilic excipient, show a higher dissolution rate from PEG excipient, but a higher diffusion rate across the barrier did not always correspond. Drugs less soluble in water showed a greater availability from PEG suppositories. On the contrary the more soluble drugs were less available.     

Solubilization of valsartan by aqueous glycerol, polyethylene glycol and micellar solutions

To increase the solubility of valsartan in aqueous solutions was considered of interest. This study therefore investigated the solubilization of valsartan by cosolvency and micellization. Of the solubilization agents used, sodium lauryl sulfate was found to be the most effective. The increase in solubility at the maximum concentration studied was in the following order: sodium lauryl sulfate > polysorbate-80 > polyethylene glycol 400 > glycerol. The effect of propylene glycol on the solubility of valsartan in a 2% w/v polysorbate-80 solution was also investigated and was found that propylene glycol decreased the solubilizing power of polysorbate-80 at the concentrations studied.     

Effect of polyethylene glycol 400 on the penetration of drugs through human cadaver skin in vitro

The effect of polyethylene glycol 400 on the penetration of drugs through human cadaver skin is reported. Polyethylene glycol 400 was used in various concentrations in the donor and the receptor compartments. It was observed that polyethylene glycol 400 had significant effects on the penetration rates of compounds, both when used in the donor as well as in the receptor solutions. These effects were barrier specific and are related to the alteration of the skin structure and the mass flow of water.     

Mechanisms of vasorelaxation to 17beta-oestradiol in rat arteries

We have investigated the involvement of the endothelium, K+ channels, oestradiol receptors, and Ca2+ influx in 17beta-oestradiol-induced vasorelaxation in rat mesenteric arterial beds and aortae. 17beta-Oestradiol (10 pM-1 mM) caused acute vasorelaxations in mesenteric arterial beds and aortae from male and female rats. In male rat mesenteric vessels and aortae, the vasorelaxations were mostly independent of the endothelium and nitric oxide (NO). However, indomethacin (10 microM) enhanced the relaxant responses to 17beta-oestradiol. In male rat mesenteric beds, 60 mM KCl, tetrabutylammonium chloride (300 microM), 4-aminopyridine (1 mM), and barium chloride (30 microM), charybdotoxin (100 nM), but not glibenclamide (10 microM) and tamoxifen (10 microM), inhibited vasorelaxation to 17beta-oestradiol. In male rat aortae, 60 mM KCl did not affect vasorelaxation to 17beta-oestradiol. However, in the presence of indomethacin, vasorelaxation to 17beta-oestradiol was enhanced but this was sensitive to 60 mM KCl. Pre-treatment with 17beta-oestradiol (100 microM) inhibited CaCl2-induced contraction. The present findings indicate that, in rat mesenteric beds and aortae, 17beta-oestradiol causes acute and potent vasorelaxation which may be enhanced in the presence of a cyclooxygenase inhibitor. In mesenteric arterial bed, 17beta-oestradiol-induced vasorelaxation occurs primarily via activation of K+ channels. In the aorta, vasorelaxations involved activation of K+ efflux when the cyclooxygenase pathway was inhibited, and also inhibition of Ca2+ influx.     

Systemic toxicity and toxicokinetics of a high dose of polyethylene glycol 400 in dogs following intravenous injection

Polyethylene glycol 400 (PEG-400) has been used in injections. However, limited data are available concerning the toxicity of a high dose of PEG-400 following intravenous (i.v.) injection. The aim of the present study was to estimate the systemic toxicity and toxicokinetics of a high dose of PEG-400 in dogs following i.v. injection. Twenty-four dogs were divided into four groups: a control group receiving normal saline and three test groups receiving 4.23, 6.34, and 8.45 g/kg of PEG-400, respectively, by i.v. injection once a day for 30 days. The repeated-dose toxicity of PEG-400 was assessed. Toxicokinetic parameters of PEG-400 in dogs were estimated on days 1 and 30. Dry mouth and dry nasal mucus membrane were observed in dogs treated with 6.34 and 8.45 g/kg of PEG-400. Cloudy swelling of kidney cell and increased glomerular volume were observed in dogs treated with 8.45 g/kg of PEG-400 when the animals were sacrificed 24 hours after the last injection. No significant histological changes were found 21 days later. Repeated dosing did not affect the toxicokinetic profile of PEG-400 in dogs. This study has shown that the toxicity of a high dose of PEG-400 following repeated intravenous injections is low, and alterations produced are reversible.     

Systemic toxicity and toxicokinetics of a high dose of polyethylene glycol 400 in dogs following intravenous injection

Polyethylene glycol 400 (PEG-400) has been used in injections. However, limited data are available concerning the toxicity of a high dose of PEG-400 following intravenous (i.v.) injection. The aim of the present study was to estimate the systemic toxicity and toxicokinetics of a high dose of PEG-400 in dogs following i.v. injection. Twenty-four dogs were divided into four groups: a control group receiving normal saline and three test groups receiving 4.23, 6.34, and 8.45?g/kg of PEG-400, respectively, by i.v. injection once a day for 30 days. The repeated-dose toxicity of PEG-400 was assessed. Toxicokinetic parameters of PEG-400 in dogs were estimated on days 1 and 30. Dry mouth and dry nasal mucus membrane were observed in dogs treated with 6.34 and 8.45?g/kg of PEG-400. Cloudy swelling of kidney cell and increased glomerular volume were observed in dogs treated with 8.45?g/kg of PEG-400 when the animals were sacrificed 24 hours after the last injection. No significant histological changes were found 21 days later. Repeated dosing did not affect the toxicokinetic profile of PEG-400 in dogs. This study has shown that the toxicity of a high dose of PEG-400 following repeated intravenous injections is low, and alterations produced are reversible.