An accelerated stability study of 5‐flucytosine in intravenous solution

The stability of the antimycotic drug flucytosine (5FC) and the extent of 5fluorouracil (5FU) formation in 5FC intravenous solution was studied in an accelerated stability experiment. 5FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5FC and 5FU were determined using a newly developed, stability indicating HPLCUV method. Heating the 5FC intravenous solution at 40, 60, 70, 80 and 90 C lead to 5FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5FC decomposition is described by: Lnk5-FC decomposition = 80.1892 * 1/T 0.2396 and the 5FU formation is described by Lnk5FU formation = 13087 * 1/T + 34.4028. It is concluded that 5FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5FC is reached. However, the toxic and teratogen degradation product 5FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5FC upon sterilisation and storage.     

Physical stability of albinterferon-α(2b) in aqueous solution: effects of conformational stability and colloidal stability on aggregation

Controlling aggregation in protein therapeutics is a significant challenge. In this study, the aggregation behavior of albinterferon-α(2b) , a genetic fusion protein combining human serum albumin and α-interferon, was examined as a function of solution conditions. The stability was monitored during agitation and during storage at elevated temperature, where the extent of aggregation was determined using size-exclusion chromatography. The osmotic second virial coefficient and the free energy of unfolding were measured for each sample. This study demonstrates that both increasing conformational stability and maximizing colloidal stability help to maintain the physical stability of albinterferon-α(2b).     

Light effect on the stability of β-lapachone in solution: pathways and kinetics of degradation

Objectives The purpose of this work was to study the chemical stability of the new antitumoral β‐lapachone (βLAP) to determine the degradation pathway/s of the molecule and the degradation kinetics in addition to identifying several degradation products. Method Samples of βLAP in solution were stored under conditions of darkness and illumination at 40°C at which the pseudo‐first order rate constants for the βLAP degradation were determined. Furthermore, drug degraded solutions were concentrated and purified using Sephadex LH‐20 and preparative thin‐layer chromatography and degradation products were identified by nuclear magnetic resonance spectroscopy. Key findings The results revealed that βLAP shows two different degradation routes: hydrolysis in the dark and photolysis under the light. The βLAP exposure to light accelerated the drug degradation about 140 fold, compared with the samples stored in the absence of light. The hydrolysis produced hydroxylapachol as the main degradation product. The photolysis yielded phthalic acid, 6‐hydroxy‐3methylene‐3H‐isobenzofuran‐1‐one and a benzomacrolactone together with a complex mixture of other phthalate‐derivatives such as 2‐(2‐carboxy‐acetyl)‐benzoic acid. Conclusions This study provides useful information for the development of βLAP dosage forms, their storage, manipulation and quality control.     

Assessing the physical–chemical properties and stability of dapivirine-loaded polymeric nanoparticles

Nanocarriers may provide interesting delivery platforms for microbicide drugs and their characterization should be addressed early in development. Differently surface-engineered dapivirine-loaded, poly(epsilon-caprolactone) (PCL)-based nanoparticles (NPs) were obtained by nanoprecipitation using polyethylene oxide (PEO), sodium lauryl sulfate (SLS), or cetyltrimethylammonium bromide (CTAB) as surface modifiers. Physical–chemical properties of NP aqueous dispersions were evaluated upon storage at −20–40 °C for one year. NPs presented 170–200 nm in diameter, roundish-shape, low polydispersity index (≤0.18), and high drug association efficiency (≥97%) and loading (≥12.7%). NPs differed in zeta potential, depending on surface modifier (PEO: −27.9 mV; SLS: −54.7 mV; CTAB: +42.4 mV). No interactions among formulation components were detected by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), except for SLS–PCL NPs. Colloidal properties of NPs were lost at −20 °C storage. Negatively charged NPs were stable up to one year at 5–40 °C; as for CTAB–PCL NPs, particle aggregation was observed from 30 to 90 days of storage depending on temperature. Colloidal instability affected the in vitro drug release of CTAB–PCL NPs after 360 days. In any case, no degradation of dapivirine was apparent. Overall, PEO–PCL and SLS–PCL NPs presented suitable properties as nanocarriers for dapivirine. Conversely, CTAB–PCL NPs require additional strategies in order to increase stability.     

Continuous infusion of chemotherapy: focus on 5‐fluorouracil and fluorodeoxyuridine.

Continuous infusion of chemotherapy is one of the developments to try to improve the treatment of metastic cancer. There is a sound theoretical rationale to deliver cytotoxic drugs as a continuous infusion. Furthermore, the development of reliable venous access devices and portable infusion pumps enables patients to be treated in an ambulatory setting. This review focuses on the continuous infusion of the most frequently used drugs: 5fluorouracil (5FU) and fluorodeoxyuridine (FUDR). An overview is given of both preclinical studies and studies in humans. Continuous infusion of 5FU and FUDR has proven to be feasible in all studies. However, the results (response rate and especially survival) are rather disappointing. So far, continuous infusion of cytostatic drugs can stil be considered as an experimental procedure. Whether protracted, intermittent or circadian modulated continuous infusion is the optimal treatment schedule has still to be proven in future studies. Furthermore, studies are needed to demonstrate whether dose intensity for most tumours is important for treatment outcome. Also, studies are needed to investigate quality of life and economic issues.     

Influence of temperature and pH on the stability of dimethoxy biphenyl monocarboxylate·HCl solutions

The accelerated stability of dimethoxy biphenyl monocarboxylate x HCl (DDB-S) was investigated in 6 mg/mL water solution in the pH ranging 2-10 and the temperature of 45-85 degrees C. The observed rate of degradation followed first-order kinetics. The energy of activation for DDB-S degradation was calculated to be 14.1 and 16.5 Kcal/mole at pH 5 and in distilled water, respectively. The degradation rate constant (K(25 degrees C)) obtained by trending line analysis of Arrhenius plots for DDB-S was 5.3 x 10(-6) h(-1). The times to degrade 10% (t10) and 50% (t50) at 25 degrees C were 829 and 5,416 days, respectively. DDB-S exhibited the fastest degradation at pH 10 and the slowest rate at pH 5. In addition, at 65 degrees C, degradation rate constants of DDB-S were 0.066, 0.059, 5.460, 32.171, and 1.41 x 10(6) h(-1) at pH 2, 5, 8, 10 and in distilled water, respectively. These observations indicated that the rate-pH profile of DDB-S showed general acid-base catalysis reaction in the range of pH 2-10.     

Long‐term stability of morphine and bupivacaine mixture for spinal use

From clinical studies it has been proven that morphine in combination with bupivacaine is applicable in cancer pain. The availability of a ready to use parental dosage form of morphine and bupivacaine is comfortable for health care workers. Stability of a morphine or a bupivacaine preparation or a combination of both in a PVC cassette or polypropylene syringe for spinal use is examined in several studies. Apart from one study no data on longterm stability of morphinebupivacaine mixture is available. A forced degradation study and a shelflife study at room temperature (2025 °C) were started on morphine hydrochloride 0.2 mg/ml and bupivacaine hydrochloride 7.5 mg/ml in 50 ml sterilized glass bottles type II. The results of the stability study showed that this mixture was stable up to 18 months at room temperature, whereafter morphine showed a slight degradation (5 %) and bupivacaine remained stable.     

Lyophilised liposome‐based formulations of α‐tocopheryl succinate: Preparation and physico‐chemical characterisation

α‐Tocopheryl succinate (α‐TOS) is a semisynthetic analogue of α‐tocopherol with selective toxicity to the cancer cells and anticancer activity in vivo. Yet, no suitable formulation of α‐TOS for medical application has been reported. Various formulations, for example, solutions in organic solvents, oil emulsions and vesicules prepared by spontaneous vesiculation, polyethylene glycol conjugates and liposomes of various compositions have been tested. We developed and characterised a stable lyophilised liposome‐based α‐TOS formulation. α‐TOS (15 mol%) was incorporated into large oligolamellar vesicles (OLVs) composed of soy phosphatidylcholine (SPC) by the method of lipid film hydration followed by extrusion through polycarbonate filters. Stabilised liposomal formulation was prepared by lyophilisation in the presence of sucrose (molar ratio lipid/sucrose, 1:5). The size distribution of the liposomes (130–140 nm, polydispersity index 0.14) as well as the stable lipid and α‐TOS contents were preserved during storage in the lyophilised form at 2–8°C for at least 6 months. The data indicate good physical and chemical stability of the lyophilised preparation of α‐TOS liposomes that can be used in clinical medicine. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2434–2443, 2010     

Long-term stability of temocillin in dextrose 5% and in sodium chloride 0.9% polyolefin bags at 5 ± 3°C after freeze-thaw treatment

Introduction

The aim of this study was to investigate the stability of a mixture of temocillin 20 mg/ml in 5% dextrose and in 0.9% sodium chloride polyolefin bags after freezing, microwave thawing and long-term storage at 5 ± 3 °C.

Methods

The stability of ten polyolefin bags containing 20 mg/ml of temocillin, five bags in 5% dextrose and five bags in 0.9% sodium chloride, prepared under aseptic conditions was studied after freezing for 1 month at –20 °C, thawing in a microwave oven with a validated cycle, and stored at 5 ± 3 °C. Over 30 days, temocillin concentrations were measured by high-pressure liquid chromatography. Visual inspections, microscope observation, spectrophotometric measurements and pH measurements were also performed.

Results and discussion

No precipitation occurred in the preparations but minor colour change was observed. No microaggregate was observed with optical microscopy or revealed by a change of absorbance. Based on a shelf life of 95% residual potency, temocillin infusions were stable at least 11 days in 5% dextrose and 14 days in 0.9% sodium chloride after freezing and microwave thawing (corresponding at the period where 95% lower confidence limit of the concentration-time profile remained superior to 95% of the initial concentration). During this period, the pH values of drug solutions have been observed to decrease without affecting chromatographic parameters.

Conclusion

Within these limits, temocillin in 5% dextrose and in 0.9% sodium chloride infusions may be prepared and frozen in advance by a centralized intravenous admixture service then thawed before use in clinical units.     

Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.     

Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-β-cyclodextrin vehicles

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9+/-0.24 degrees C and 7249+/-217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees C. In HCl-NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPbetaCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT.     

Plasma dopamine-β-hydroxylase activity and the pressor effect of dopamine infusion in man

Summary In order to study the function of dopamine--hydroxylase (DBH) in human plasma, dopamine, its natural substrate, was infused intravenously in 22 healthy volunteers. Their plasma DBH activities showed great interindividual variations (31–301 units/ml). The infusion rates of dopamine required to increase systolic blood pressure (BP) by 30 mm Hg differed considerably between the subjects, and ranged from 3,0 to 11,6 µg/kg/min. No correlation could be shown between the various dopamine doses and individual plasma levels of DBH. It was concluded, therefore, that plasma DBH in the blood stream was enzymatically inactive. Experiments with human plasma DBH in vitro also support this interpretation. Consequently, interindividual differences in the effects on BP during dopamine infusion cannot be due to pressor effects of noradrenaline synthesized by plasma DBH.The study was supported by the Deutsche Forschungsgemeinschaft     

Recombinant factor VIII SQ—influence of oxygen,metal ions,pH and ionic strength on its stability in aqueous solution

Recombinant factor VIII SQ (r-VIII SQ) is a derivative of human factor VIII in which the B-domain has been deleted. It corresponds to the smallest active form, a metal ion-linked 80+90 kDa heterodimer, present in therapeutic factor VIII concentrates. The stability of r-VIII SQ was investigated in aqueous solution, without albumin (human) as a stabiliser. Activity assay (VIII:C), visual inspection and gel filtration were performed after storage at different temperatures. The influence of oxygen, metal ions, pH and ionic strength was studied. The thermal stability was investigated using differential scanning calorimetry (DSC). There was a rapid loss of activity when r-VIII SQ was stored in solution in vials containing air in the headspace. The stability was markedly improved by reducing the oxygen content. pH 6.5–7.0 was optimal for stability at both low and high ionic strengths. The best results were obtained at high ionic strengths, since r-VIII SQ precipitated at sodium chloride concentrations below 5 mg/ml. The loss of VIII:C correlated with dissociation of the light (80 kDa) and heavy (90 kDa) chain complex. The separation of these chains was partly prevented by addition of calcium or strontium ions in the concentration range 1–10 mM. The transition point for heat denaturation (T_m′) was 64±0.2°C in a formulation containing 9500 IU r-VIII SQ/ml, 18 mg/ml sodium chloride, 0.5 mg/ml calcium chloride dihydrate, 3 mg/ml l-histidine and 0.2 mg/ml polysorbate 80. The stability results presented here show promise and prompt further investigations into the development of a stable solution of r-VIII SQ.     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

The safety,stability, and compatibility of fragrances in skin and hair products†

Abstract

The efforts of the formulating chemist, perfumer, and toxicologist represent the creative forces that ultimately merge to accomplish a finished formulation. Because the ingredients in a compounded fragrance are proprietary to the company that produces them, the formulating chemist must add a mixture of unknown substances to his basic formulation with the hope that they will be compatible in functionality, stability, and safety. A well-controlled stability and safety testing program is needed to assure complete compatibility between the base formulation and the fragrance.

Potential stability problems include changes in viscosity, color, odor, clarity of transparent systems, and emulsion stability. These changes may be caused by hydrolysis, oxidation, reaction to light, reaction to metals, insolubilities, reaction to processing conditions, and packaging materials. The interactions which occur during these changes can cause the formation of new materials that may have irritation or sensitization potential. We recommend that samples of product that have successfully passed shelf-life testing be furnished to the toxicologist for a complete battery of safety tests, including controlled use testing. This procedure should help to assure that untoward reactions do not occur during consumer use.     

Cadmium-induced disruption of environmental exploration and chemical communication in matrinxã, Brycon amazonicus

The effects of cadmium exposure on both environment exploration and behavioral responses induced by alarm substance in matrinx? (Brycon amazonicus), a fish species endemic to the Amazon basin, were investigated. Fish exposed to 9.04+/-0.07 microg/L waterborne cadmium for 96h followed by 24h depuration period in clean water, were video-recorded for 15 min, followed by immediate introduction of conspecific skin extract to the tank and a new 30 min period of fish video-recording. Cd-exposed matrinx? showed a significantly lowered locomotor activity (t-test t(12)=2.7; p=0.025) and spatial distribution (t-test t(12)=2.4; p=0.03) relative to the unexposed control fish prior to the alarm substance introduction, and did not present any significant reaction when the skin extract was introduced. The control fish, in opposite, showed a higher level of activity and spatial distribution prior the skin extract contact and significantly decreased their response after the chemical stimulus (locomotion-repeated-measure ANOVA F(1,11)=5.6; p=0.04; spatial distribution F(1,11)=19.4; p=0.001). In conclusion, exposure to a low level of cadmium affects both the environment exploration performance and the conspecific chemical communication in matrinx?. If the reduced environmental exploration performance of Cd-exposed fish is an adjustment to the compromised chemical communication or an independent effect of cadmium is the next step to be investigated.     

Is there a trigger role of peroxynitrite in the anti-arrhythmic effect of ischaemic preconditioning and peroxynitrite infusion?

This study has examined whether peroxynitrite (PN), generated during the preconditioning (PC) procedure or administered by brief intracoronary infusions, plays a trigger role in the anti-arrhythmic effects of preconditioning and peroxynitrite in anaesthetized dogs. To achieve this we infused the peroxynitrite scavenger uric acid (UA; 0.2 mg/kg/min, i.v.) over a 30 min period, just prior to a 25 min occlusion of the left anterior descending coronary artery, in preconditioned (UA+PC, n=8), peroxynitrite-treated (UA+PN, n=8) and in control (UAC; n=9) dogs. The effects were compared to those obtained from groups (PC, n=10; PN, n=10; C1, n=14) without uric acid administration. Severities of ischaemia (ST-segment elevation, inhomogeneity of electrical activation) and ventricular arrhythmias (VPBs, VT, VF), plasma nitrate/nitrite levels, as well as myocardial superoxide and nitrotyrosine productions were determined. Both preconditioning and the infusion of peroxynitrite increased nitrotyrosine formation which was abolished by the simultaneous administration of urate. Despite this, the protective effects of preconditioning (i.e. reductions in arrhythmias, superoxide and nitrotyrosine productions, as well as the increase in nitric oxide availability), occurring during the prolonged period of occlusion and reperfusion were still present. In contrast, urate completely abolished the protection resulted from peroxynitrite administration. This effect is most probably due to the fact that urate has already scavenged peroxynitrite during the infusion. Interestingly, urate itself, given prior to ischaemia and reperfusion, was also protective. We conclude that peroxynitrite in nanomolar concentrations can induce an anti-arrhythmic effect but peroxynitrite, generated during the preconditioning stimulus, is not necessary for the preconditioning-induced anti-arrhythmic protection.     

First‐in‐human,phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel,in patients with advanced or metastatic solid malignancies

Investigational New Drugs - Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle...     

Pharmacokinetics of paracetamol and its metabolites in women at delivery and post‐partum

Aim

A recent report on intravenous (i.v.) paracetamol pharmacokinetics (PK) showed a higher total clearance in women at delivery compared with non‐pregnant women. To describe the paracetamol metabolic and elimination routes involved in this increase in clearance, we performed a population PK analysis in women at delivery and post‐partum in which the different pathways were considered.

Methods

Population PK parameters using non‐linear mixed effect modelling were estimated in a two‐period PK study in women to whom i.v. paracetamol (2 g loading dose followed by 1 g every 6 h up to 24 h) was administered immediately following Caesarean delivery and in a subgroup of the same women to whom single 2 g i.v.loading dose was administered 10–15 weeks post‐partum.

Results

Population PK analysis was performed based on 255 plasma and 71 urine samples collected in 39 women at delivery and in eight of these 39 women 12 weeks post‐partum. Total clearance was higher in women at delivery compared with 12th post‐partum week (21.1 vs. 11.7 l h⁻¹) due to higher clearances to paracetamol glucuronide (11.6 vs. 4.76 l h⁻¹), to oxidative metabolites (4.95 vs. 2.77 l h⁻¹) and of unchanged paracetamol (1.15 vs. 0.75 l h⁻¹). In contrast, there was no difference in clearance to paracetamol sulphate.

Conclusion

The increased total paracetamol clearance at delivery is caused by a disproportional increase in glucuronidation clearance and a proportional increase in clearance of unchanged paracetamol and in oxidation clearance, of which the latter may potentially limit further dose increase in this patient group.