Stability of frozen 1% voriconazole eye-drops in both glass and innovative containers.

PURPOSE: To assess the physico-chemical stability of Voriconazole Eye-Drops (VED), when stored frozen and refrigerated once thawed, in 3 containers: Amber glass with a Low-Density PolyEthylene (LDPE) eyedropper, and two types of LDPE bottles: one classical and one with an innovative insert that maintains sterility after opening (Novelia® from Nemera). METHODS: Three batches of 1% VED (10 mL) were aseptically compounded from marketed injectable voriconazole (Vfend®) diluted in sterile water for injection. VEDs were stored for three months at -20 °C in amber glass (n = 32), classical LDPE (n = 32) or innovative LDPE (n = 31) bottles. Stability-indicating (HPLC-UV-DAD) and chiral chromatography methods were developed. The stability study was conducted according to GERPAC-SFPC guidelines. At each study time, the following parameters were controlled: visual aspect, voriconazole concentration, pH and osmolality. In addition, non-visible particle count, sterility and absence of racemisation (impurity D - (2S,3R)-voriconazole) were assessed at the beginning and end of the study. Results are expressed as mean ± standard deviation. Statistical analyses were performed using non-parametric tests (α < 5%) to compare containers. RESULTS: When stored frozen, concentration was between 95.2 ±â€¯1.4% and 103.6 ±â€¯1.3% of the initial concentration (C0) with no difference between the three containers (p = 0.564; non-significant). Fifteen days after thawing, concentration was between 97.1 ±â€¯1.6% and 98.6 ±â€¯0.8% of C0 with no difference between containers (p = 0.278 and 0.368 for VED thawed at room temperature and at 2-8 °C, respectively). pH remained stable between each time. Osmolality was slightly higher in glass (533.17 ±â€¯8.93 mOsm/Kg) than in plastic containers (522.17±3.31mOsm/Kg, classical LDPE; 517.5 ±â€¯12.42 mOsm/Kg, innovative LDPE) (p = 0.022). Sterility was preserved. Degradation product areas increased slightly but remained below the limit of quantification. Impurity D was never detected. CONCLUSION: We have demonstrated that the ability of the innovative container Novelia® to maintain VED physicochemical and microbiological stability does not differ from that of amber glass and classical LDPE containers. Real life studies are required to find out if there is a potential difference between Novelia® and other containers in terms of sterility preservation.

Quality control and stability of ketamine, remifentanil, and sufentanil syringes in a pediatric operating theater.

BACKGROUND: Transforming a drug from its commercial form into a ready-to-use drug is common practice, especially in pediatrics. However, the risk of compounding error is real and data on drug stability in practice are not always available. AIMS: The aim of this study was to assess, in real conditions, both the error rate and stability of three drugs: ketamine, remifentanil, and sufentanil. METHODS: A new rapid and easy-to-use high-performance liquid chromatography method with a diode array detector has been developed and validated to quantify these drugs and detect their degradation products. Over a 1-month period, 151 syringes were collected in the postanesthesia care unit. Seventy-three were stock solution syringes containing a 10-fold dilution of commercial drugs and 78 were serial dilution syringes made from successive dilutions of stock solutions. A comparison between real and expected concentrations as well as the detection of possible degradation products was carried out on these samples. RESULTS: All stock solution syringes had good chemical stability throughout the working day. A 4-µg/mL remifentanil serial dilution syringe, however, had to be discarded as a degradation peak was detected. Overall, 15.3% (95% CI, 9.5-21.1%) of syringes had a drug concentration outside the ±10% acceptability range, that is, 11.0% (95% CI, 3.7-18.2%) and 19.5% (95% CI, 10.6%-28.4%) of stock and diluted syringes respectively, with drug amounts ranging from -25.3% to 22.0%. The highest error rates were observed with sufentanil syringes: 20% and 28% for stock solution and serial dilution, respectively. CONCLUSION: The study shows that stock solution syringes prepared in advance are chemically stable throughout the day, unlike certain serial dilution syringes, indicating that the latter should be prepared just before administration to ensure chemical stability. Our results show that the error rate for serial dilution syringes is twice that of stock solution. Different safety measures are under discussion and have to be further studied.

Pharmacokinetic evaluation of a novel benzopyridooxathiazepine derivative as a potential anticancer agent.

BACKGROUND/AIMS: The in vivo metabolic profile of a benzopyridooxathiazepine (BPT) derivative, a potent tubulin polymerization inhibitor with a promising in vitro activity, was investigated. METHODS: The quantification of the BPT derivative and the identification of metabolites in the plasma of Wistar rats after i.p. and oral administration of 10 mg/kg were performed by the HPLC-mass spectrometry method. RESULTS: Following a single i.p. dose of the BPT derivative, the plasma concentrations showed a biexponential decay (with a rapid decline) followed by a slow decay with a terminal half-life of 77.90 min. The area under the concentration-time curve from time 0 to infinity (AUC0-∞) was 18.90 µg/ml·min. After oral administration, the plasmatic concentrations reached a peak of 0.06 µg/ml at 35 min and then decayed with a half-life of 108 min. The AUC0-∞ was 10.25 µg/ml·min, representing 54.2% of the relative bioavailability. The compound was well distributed in the body, and its elimination seemed to be fast, regardless of the administration route. The major metabolic pathways were demethylation and hydroxylation reactions, both followed by conjugation with glucuronic acid. CONCLUSION: In rats, the BPT derivative is well distributed and undergoes extensive metabolism, leading to several metabolites. With promising in vitro activity and very good oral bioavailability, this compound seems to be an attractive candidate for further development as an anticancer agent.

A validated micellar electrokinetic chromatography method for the quantitation of dexamethasone, ondansetron and aprepitant, antiemetic drugs, in organogel.

A micellar electrokinetic chromatography (MEKC) method was developed for the determination of three anti-vomiting drugs (aprepitant, dexamethasone and ondansetron) in pharmaceutical formulations. The method was optimized using a central composite design (CCD). Four main factors (borate buffer concentration, pH, methanol content and sodium dodecyl sulfate concentration) were optimized in order to obtain best resolutions and peak efficiencies in a minimum runtime. The separation was performed in a fused-silica capillary. After optimization, the background electrolyte consisted of a borate buffer (62.5mM, pH 8.75) containing sodium dodecyl sulfate (77.5mM) and methanol (3.75%). Under these conditions, a complete separation of each antiemetic drug and its respective internal standards was achieved in 38min. The method was validated with trueness values from 94.9 to 107.2% and precision results (repeatability and intermediate precision) lower than 5.9%. MEKC-UV was the first method allowing the separation of aprepitant, dexamethasone and ondansetron and was suitable for the quantitation of these three antiemetic drugs in organogel formulations. The rapid sample preparation coupled with an automated separation technique make this method convenient for quality control of extemporaneous magistral ready-to-use formulation.

In vitro pharmacokinetic profile of a benzopyridooxathiazepine derivative using rat microsomes and hepatocytes: identification of phases I and II metabolites.

In the present study, the in vitro metabolic behavior of a benzopyridooxathiazepine (BZN), a potent tubulin polymerization inhibitor, was investigated by liquid chromatography-UV detection (LC-UV). First, simple and fast LC-UV methods have been optimized and validated to evaluate the pharmacokinetic profile of BZN using rat liver microsomes or hepatocytes primary cultures suspensions. Whatever the medium investigated, baseline resolution between the internal standard and BZN was achieved in a run time less than 15min using a Symmetry ODS column (150mm×4.6mm i.d., 5µm) and a mobile phase consisting of acetonitrile/water/formic acid 60:40:0.1 (v/v/v). Linearity was assessed in the 0.1-50µM and in the 0.05-5µM concentration ranges, respectively, in microsomal and hepatocyte matrix. According to the novel strategy based on the build of the accuracy profile, total error of the developed methods was included within the ±10% limits of acceptance. Then, from incubation of BZN with both liver microsomes and or hepatocytes, structural informations on phase I and phase II metabolites were acquired using liquid chromatography coupled to electrospray orbitrap mass spectrometer (LC-MS). Mass spectrum, double bond equivalent and elemental composition were useful data to access to the chemical structure of each metabolite. In microsomal suspension, four main metabolites were observed including monohydroxylation and dihydroxylation of the benzopyridooxathiazepine core, demethylation of the methoxyphenyl moiety, as well as their combinations. The phase II metabolites detected in hepatocytes suspension were the glucuronide adducts of both demethylated BZN and mono-oxygenated BZN. Based on the structural elucidation of the metabolites detected, we proposed an in vitro metabolic pathway of BZN, a new tubulin polymerization inhibitor.