Physicochemical Stability Study of Oral Suspension Containing Ruxolitinib in Children with Steroid-Refractory Acute Graft-Versus-Host Disease.

Ruxolitinib, used in children with steroid-refractory acute graft-versus-host (GVH) disease, is currently commercially available only as a tablet adult dosage. For the paediatric population, an oral liquid would be an adapted dosage formulation. The aim of this study was to develop ruxolitinib compounded oral suspensions at 2 mg/mL by using commercial tablets in available aqueous vehicle (Inorpha) and to measure its stability at both room temperature and under refrigeration. Chemical stability of suspensions containing ruxolitinib was evaluated for 60 days based on pH, degradation, and drug content. Physical stability of the drug suspension was evaluated by visual aspect and odour. The remaining ruxolitinib concentration of the suspension was at least 95% of the initial concentration after 60 days at both temperatures. The pH, colour, and odour of the suspensions throughout the study remained unchanged with respect to the initial time point.

External contamination of antineoplastic drug vials: an occupational risk to consider.

Risk management for workers involved in the handling and preparation of cytotoxic drugs is challenging. This study aims to investigate drug contamination of the exterior surfaces of cytotoxic drug vials. Two batches of commercially available cytotoxic drugs in unprotected vials (ifosfamide, etoposide phosphate and cyclophosphamide) and plastic shrink wrap vials (doxorubicin, cytarabine and busulfan) were tested without removing the flip-off cap or the plastic wrap, and without prewashing. The results showed significant trace amounts of cytotoxic drugs on the exterior surfaces in both unprotected (eg, cyclophosphamide, ifosfamide) and protected plastic shrink wrap vials (eg, cytarabine), indicating that the secondary packaging of protected vials does not systematically prevent exposure to the handlers. These results focus on the need for guidelines to prevent cytotoxic vial contamination and safety recommendations for staff in the handling and storage of these vials.

Stability of pemetrexed diarginine concentrates for solution in vials and diluted in 0.9% sodium chloride and dextrose 5% polyolefin infusion bags.

OBJECTIVES: To determine the physicochemical stability of pemetrexed diarginine in original vials, and after dilution in two commonly used infusion fluids (0.9% sodium chloride, 5% dextrose) in polyolefin bags, stored under refrigeration (2-8°C) or at ambient temperature (22-25°C) exposed to light. METHODS: Stability of pemetrexed diarginine injection concentrate was determined in the original glass vials with closed-system transfer device. Diluted pemetrexed diarginine infusion solutions were aseptically prepared by dilution of pemetrexed diarginine concentrate with either 0.9% sodium chloride or dextrose 5% in polyolefin bags, in amounts yielding pemetrexed diarginine concentrations of 4, 9 and 12 mg/mL. Test solutions were stored under refrigeration (2-8°C) or at ambient temperature (22-25°C) exposed to light. Pemetrexed diarginine concentrations were determined throughout a 14-day storage period using a stability-indicating HPLC assay. In addition, test solutions were visually examined for colour change and precipitation. RESULTS: Pemetrexed diarginine injection concentrate with closed-system transfer device is shown to be physicochemically stable for up to 4 days when stored under refrigeration and for 1 day at room temperature. A browning of the pemetrexed diarginine concentrate solutions appeared 0n day 2 when stored at ambient temperature and on day 5 under refrigeration. Pemetrexed diarginine diluted in dextrose 5% and 0.9% sodium chloride was physicochemically stable for up to 4 days when stored under refrigeration and for 1 day at room temperature. A browning of the diluted solutions appeared on day 2 when stored at room temperature and on day 5 when stored under refrigeration. CONCLUSIONS: Pemetrexed diarginine concentrate for solution stored under refrigeration with closed-system transfer device can be retained as a residual to reduce product losses. The analytical stability of pemetrexed diarginine in dextrose 5% and 0.9% sodium chloride under refrigeration enables our centralised unit to prepare this drug in advance.

Stability of Pentobarbital Hydrogel for Rectal Administration in Pediatric Procedural Sedation.

Purpose: Pentobarbital is a sedative agent to limit children motion during computed tomography or magnetic resonance imaging (MRI) and ensures the successful completion of the imaging procedure. However, data on rectal drug formulation and its stability in practice are not available. The aim of this study was to formulate and evaluate the stability of a ready-to-use rectal pentobarbital gel. Methods: The formulation consisted of a hydrated gel containing 25 mg/mL of pentobarbital sodium, packaged in 10-mL amber glass bottles and stored at either 22°C to 25°C or 2°C to 8°C. At each predetermined time point, samples were taken for visual inspection, pH measurement, and analysis by a validated stability-indicating high-performance liquid chromatography (HPLC) method. The viscosity parameters of the hydrogel formulation were assessed. Results: The freshly prepared rectal formulations appeared clear, colorless, and particular-free with pH readings of 9.75 to 9.83. Over the 90 days of the study period, there was no significant change in appearance or pH values for all stability samples. The HPLC results confirmed the chemical stability when stored at 2°C to 8°C or at 22°C to 25°C. Conclusion: Pentobarbital hydrogel 25 mg/mL are stable chemically at least 90 days and can be administered to children for an effective and fast sedation.

Stability of 10-mg/mL and 50-mg/mL ketamine oral solutions.

PURPOSE: Ketamine is an anesthetic agent commonly used for the induction of anesthesia. Ketamine is also given to control pain, for treatment of posttraumatic stress disorder, and to induce bronchodilation in refractory asthma. Moreover, ketamine therapy is gaining ground as an intervention for patients with treatment-resistant depression and individuals who have depression with serious suicidal ideation. Recently, the drug has been used to disrupt maladaptive reward memories in individuals with harmful alcohol consumption behaviors. The stability of 10-mg/mL and 50-mg/mL ketamine solutions stored at ambient and refrigeration temperatures was assessed over 90 days. METHODS: Three batches of 10-mg/mL and 50-mg/mL ketamine solutions were stored for 90 days under two temperature conditions (2°C-8°C and 22°C-25°C) in amber plastic bottles. Chemical stability was assessed using a stability-indicating high-performance liquid chromatography assay. At each study time, visual inspection and pH assessments of ketamine concentration and pH were conducted. RESULTS: For all solutions tested at each condition, the ketamine concentration remaining was at least 98% of the initial concentration over 90 days of storage. Throughout the study period, solution pH remained stable and the color and odor of the suspensions remained unchanged. CONCLUSION: Extemporaneously compounded 10-mg/mL and 50-mg/mL oral solutions of ketamine prepared in a flavored suspending excipient and stored in amber polypropylene plastic bottles were stable for at least 90 days at both ambient and refrigeration temperatures.

Formulation and Stability of Ataluren Eye Drop Oily Solution for Aniridia.

Congenital aniridia is a rare and severe panocular disease characterized by a complete or partial iris defect clinically detectable at birth. The most common form of aniridia occurring in around 90% of cases is caused by PAX6 haploinsufficiency. The phenotype includes ptosis, nystagmus, corneal limbal insufficiency, glaucoma, cataract, optic nerve, and foveal hypoplasia. Ataluren eye drops aim to restore ocular surface PAX6 haploinsufficiency in aniridia-related keratopathy (ARK). However, there are currently no available forms of the ophthalmic solution. The objective of this study was to assess the physicochemical and microbiological stability of ataluren 1% eye drop in preservative-free low-density polyethylene (LDPE) bottle with an innovative insert that maintains sterility after opening. Because ataluren is a strongly lipophilic compound, the formulation is complex and involves a strategy based on co-solvents in an aqueous phase or an oily formulation capable of totally dissolving the active ingredient. The visual aspect, ataluren quantification by a stability-indicating chromatographic method, and microbiological sterility were analyzed. The oily formulation in castor oil and DMSO (10%) better protects ataluren hydrolysis and oxidative degradation and permits its complete solubilization. Throughout the 60 days period, the oily solution in the LDPE bottle remained clear without any precipitation or color modification, and no drug loss and no microbial development were detected. The demonstrated physical and microbiological stability of ataluren 1% eye drop formulation at 22-25 °C might facilitate clinical research in aniridia.

Assessment of practices for suspended oral drugs by tablet crushing in pediatric units.

The aim of this study was to assess the impact of suspended drug by tablet crushing in our pediatric hospital in term of targeted dose and to identify parameters involved in the potential variability. Four usually crushed pediatric drug substances were selected: amiodarone, warfarin, hydrocortisone and captopril. Each tablet was crushed in a bag using a crusher device. Once crushed, a pre-determined volume of water was added using oral syringes before taking the necessary volume to obtain the targeted drug amount. For each drug, operators among pharmacy technicians and nurses investigated 2 targeted doses (high and low). Each suspension was assayed 3 times using the corresponding validated HPLC procedure. Statistical analysis was performed (GraphPad Prism®) to evaluate the impact of operators, the level of suction in bag, and actual drug doses. To investigate the impact of formulation change on syringe drug content, five generic drugs of amiodarone were selected. Syringes contents were compared using one-way ANOVA. Drug loss in syringe ranged from 8.1% to 54.1%. The drug loss represented 18.9% to 30.5% for amiodarone, 0.1% to 5.5% for captopril, 5.6% to 19.7% for warfarin and 5.0% to 30.7% for hydrocortisone. The comparison of level sampling of suspensions presented significant differences for amiodarone, hydrocortisone, and warfarin. Comparison of operators demonstrated significant difference between pharmacy technician and nurse (p = 0.0251). Finally, comparison of 5 generic drugs for amiodarone showed some statistical difference between the syringes content obtained when using the original medicine as compared to the generics. The physicochemical properties of each drug substance and the formulation of the drug product may both factor that should be considered. As a result, crushing tablets in water for oral administration needs a case by case assessment. Although appropriate pediatric formulations are lacking, suspend the crushed material in a given volume of water should be discouraged and not recommended because far from good practice.

Voriconazole topical cream formulation: evidence for stability and antifungal activity.

Systemic use of voriconazole (VCZ) might be restricted by adverse events, such as hepatotoxicity and neurotoxicity, or drug-drug interactions. Topical VCZ application to skin may help to treat local infection more effectively and limit unwanted whole-body exposure. Topical VCZ cream was stable for 90 days when refrigerated. A patient with cutaneous Fusarium solani infection on his right forearm was successfully treated with topical 1% VCZ cream after failure of oral VCZ treatment.

Physicochemical and microbiological stability of azathioprine in InOrpha suspending agent studied under various conditions.

Azathioprine is an antineoplastic antimetabolite drug currently used as an immunosuppressive agent after organ transplantation and for several dysimmunitary diseases. The usual daily dose ranges from 1 to 5 mg/kg orally. Azathioprine is marketed in France under the trade name Imurel in tablet form for oral administration that contains either 25 mg or 50 mg of the active ingredient. This Galenic formulation is not suitable for pediatric use and often requires a grinding operation or a dose fractionation to facilitate administration. In addition to a potential risk of imprecision in the administered dose, tablet grinding might unnecessarily expose nurses and families to a toxic compound. To overcome this problem, the objective of this study was to develop and evaluate the physicochemical and microbiological stabilities of azathioprine in a sugar-free, alcohol-free, and paraben-free InOrpha suspending agent. The studied samples were formulated into a 10-mg/mL suspension and stored in 24 plastic bottles of 60 mL at two different temperature conditions (between 2 degrees C to 8 degrees C and room temperature). Two series of 12 samples were tested for physicochemical stability using high-performance liquid chromatography as well as for a microbiological status for 35 days (daily opening of the bottles from day 0 of compounding) and for 56 days, upon daily flask opening (first opening at day 28 from compounding and daily opening for 28 consecutive days). The high-performance liquid chromatography method developed is linear, accurate, precise, and robust. In addition, a forced degradation study validated the selectivity and the specificity requirements of the method validated as stability indicating. At room temperature storage, high-performance liquid chromatography analysis showed that tested samples had concentrations ranging from 90% to 110% of the initial concentration throughout the course of the study. Microbiological status remained stable during the 56 days of investigation. Based on the data collected, the study led to the development of a new Galenic formulation of azathioprine that is suitable for pediatric use and can be safely stored at room temperature for 28 days (before and after opening for a maximum of 56 consecutive days).

First on-sky SCAO validation of full LQG control with vibration mitigation on the CANARY pathfinder.

Adaptive optics provides real time correction of wavefront disturbances on ground based telescopes. Optimizing control and performance is a key issue for ever more demanding instruments on ever larger telescopes affected not only by atmospheric turbulence, but also by vibrations, windshake and tracking errors. Linear Quadratic Gaussian control achieves optimal correction when provided with a temporal model of the disturbance. We present in this paper the first on-sky results of a Kalman filter based LQG control with vibration mitigation on the CANARY instrument at the Nasmyth platform of the 4.2-m William Herschel Telescope. The results demonstrate a clear improvement of performance for full LQG compared with standard integrator control, and assess the additional improvement brought by vibration filtering with a tip-tilt model identified from on-sky data, thus validating the strategy retained on the instrument SPHERE at the VLT.

Routine application of Raman spectroscopy in the quality control of hospital compounded ganciclovir.

This study compares the performance of a reference method of HPLC to Raman spectroscopy (RS) for the analytical quality control (AQC) of therapeutic objects. We assessed a model consisting of a widely used antiviral drug, i.e., ganciclovir, which was compounded in a medical device and then transferred in a vacuum glass vial prior to analyses. As the aim of the alternative RS method is to replace the destructive, time-consuming HPLC method, requiring sample preparation, it needs to be demonstrated that RS performs at least as good as the HPLC method. Therefore, the two methods were validated by calculating the accuracy profile and provided excellent results for the analytical validation key criteria, i.e., trueness, precision and accuracy, ranging from 0.8 to 10mg/mL. The Spearman and Kendall correlation tests (p-value<1.10-15) and the statistical studies performed on the graphs confirm a strong correlation in the results between RS and the standard HPLC under the experimental conditions. These results confirmed the potential of this option for future applications, owing to its analytical and practical quality and its contributions to the safety of the medication circuit. This method also greatly contributes to the protection of caregivers and their working environment.

The contribution of Raman spectroscopy to the analytical quality control of cytotoxic drugs in a hospital environment: eliminating the exposure risks for staff members and their work environment.

The purpose of the study was to perform a comparative analysis of the technical performance, respective costs and environmental effect of two invasive analytical methods (HPLC and UV/visible-FTIR) as compared to a new non-invasive analytical technique (Raman spectroscopy). Three pharmacotherapeutic models were used to compare the analytical performances of the three analytical techniques. Statistical inter-method correlation analysis was performed using non-parametric correlation rank tests. The study's economic component combined calculations relative to the depreciation of the equipment and the estimated cost of an AQC unit of work. In any case, analytical validation parameters of the three techniques were satisfactory, and strong correlations between the two spectroscopic techniques vs. HPLC were found. In addition, Raman spectroscopy was found to be superior as compared to the other techniques for numerous key criteria including a complete safety for operators and their occupational environment, a non-invasive procedure, no need for consumables, and a low operating cost. Finally, Raman spectroscopy appears superior for technical, economic and environmental objectives, as compared with the other invasive analytical methods.

Comparison of Raman spectroscopy vs. high performance liquid chromatography for quality control of complex therapeutic objects: model of elastomeric portable pumps filled with a fluorouracil solution.

This study compares the performance of a reference method of HPLC to Raman spectroscopy (RS) for the analytical quality control (AQC) of complex therapeutic objects. We assessed a model consisting of a widely used anticancer drug, i.e., 5-fluorouracil, which was compounded in a complex medical device, i.e., an elastomeric portable infusion pump. In view of the main objective, the two methods provided excellent results for the analytical validation key criteria, i.e., trueness, precision and accuracy, ranging from 7.5 to 50mg/mL and in either isotonic sodium or 5% dextrose. The Spearman and Kendall correlation tests (p-value<1×10(-15)) and the statistical studies performed on the graphs confirm a strong correlation in the results between RS and the standard HPLC under the experimental conditions. The selection of a spectral interval between 700 and 1400cm(-1) for both the characterization and quantification by RS was the result of a gradual process optimization, combining matrix and packaging responses. In this new application, we demonstrate at least eight benefits of RS: (a) operator safety, (b) elimination of disposables, (c) elimination of analysis waste, which contributes to the protection of the environment, (d) a fast analytical response of less than 2min, (e) the ability to identify the solubilizing phase, (f) reduction of the risk of errors because no intrusion or dilution are needed, (g) negligible maintenance costs and (h) a reduction in the budget dedicated to technician training. Overall, we indicate the potential of non-intrusive AQC performed by RS, especially when the analysis is not possible using the usual techniques, and the technique's high potential as a contributor to the safety of medication.

Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis.

We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5µL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5µm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The ß-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin.

Physicochemical and microbiological stabilities of hydrocortisone in InOrpha suspending agent studied under various conditions.

Hydrocortisone is principally used as replacement therapy in adrenocortical deficiency states. In pediatric practice, posology ranges from 10 to 20 mg/m2 per day, divided in three doses, for the purpose of mimicking the nycthemeral cycle. Hydrocortisone is marketed in France in tablet form that contains 10 mg of the active ingredient. This galenic formulation is not suitable for pediatric use, and often requires a grinding operation or a dose fractionation to facilitate administration. To overcome this difficulty, the objective of this study was to develop and evaluate the physicochemical and microbiological stabilities of hydrocortisone in a sugar-free, alcohol-free, and paraben-free InOrpha suspending agent. The studied samples were formulated into a 2-mg/mL suspension and stored in glass bottles at two temperature conditions, between 2 degrees C to 8 degrees C and at room temperature). Two series of twelve samples were tested for physicochemical stability using high-performance liquid chromatography as well as for a microbiological status for 28 days (daily opening of the bottles from day 0 of compounding) and for 56 days (first opening at day 28 from compounding and daily opening for 28 consecutive days). The high-performance liquid chromatography method developed is linear, accurate, precise, and robust. On the other hand, a forced degradation study has demonstrated the selectivity and specificity of the method validated as stability indicating. In both storage conditions, high-performance liquid chromatography analysis showed that tested samples had concentrations ranging within 90% to 110% of the initial concentration for 28 consecutive days upon daily bottle opening and, for a maximum of 42 days with a first opening at day 28 from the compounding time. Microbiological status remained stable throughout the course of the study. Based on the data collected, the study led to the development of a new galenic formulation of hydrocortisone suitable for pediatric use which can be safely stored under refrigerated conditions or at room temperature for a maximum of 42 consecutive days.

[A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations]. / Modèle de coopération médico-pharmaceutique comme contributeur au succès du conditionnement de la greffe allogénique de cellules souches hématopoïétiques chez l'adulte : un regard croisé sur nos organisations.

Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.

Tomography approach for multi-object adaptive optics.

Multi-object adaptive optics (MOAO) is a solution developed to perform a correction by adaptive optics (AO) in a science large field of view. As in many wide-field AO schemes, a tomographic reconstruction of the turbulence volume is required in order to compute the MOAO corrections to be applied in the dedicated directions of the observed very faint targets. The specificity of MOAO is the open-loop control of the deformable mirrors by a number of wavefront sensors (WFSs) that are coupled to bright guide stars in different directions. MOAO calls for new procedures both for the cross registration of all the channels and for the computation of the tomographic reconstructor. We propose a new approach, called "Learn and Apply (L&A)", that allows us to retrieve the tomographic reconstructor using the on-sky wavefront measurements from an MOAO instrument. This method is also used to calibrate the registrations between the off-axis wavefront sensors and the deformable mirrors placed in the science optical paths. We propose a procedure linking the WFSs in the different directions and measuring directly on-sky the required covariance matrices needed for the reconstructor. We present the theoretical expressions of the turbulence spatial covariance of wavefront slopes allowing one to derive any turbulent covariance matrix between two wavefront sensors. Finally, we discuss the convergence issue on the measured covariance matrices, we propose the fitting of the data based on the theoretical slope covariance using a reduced number of turbulence parameters, and we present the computation of a fully modeled reconstructor.