Formulation and stability study of an oral paediatric phenobarbital 1% solution containing hydroxypropyl-ß-cyclodextrins.

OBJECTIVES: Phenobarbital is a barbiturate, used to treat focal and generalised epilepsy. Since the end of marketing of the oral solution KANEURON in 2017, phenobarbital tablets remain the only available dosage form. Development of an oral phenobarbital solution for paediatric use is therefore essential to fulfil clinical needs. A new formulation of phenobarbital with hydroxypropyl-ß-cyclodextrins (HPBCD) was developed, and the physicochemical stability of the solution was evaluated. METHODS: Different excipients have been selected to formulate a solution of phenobarbital. Samples were dosed by High Performance Liquid Chromatography (HPLC) at 216 nm with a LiChroCART C18 endcapped column and mobile phase composed of phosphate buffer pH 3 and methanol (50:50 v/v). Linearity, accuracy, sensibility and specificity of the method were tested, and a forced degradation study was carried out. During stability study, content of phenobarbital, pH, osmolality of the phenobarbital solution and degradation products were followed up for 6 months in line with GERPAC guidelines. RESULTS: The stability indicating the character of the assay method has been validated. The physicochemical stability study shows that the phenobarbital solution formulated is stable for 6 months, in line with International Conference of Harmonisation (ICH) recommendations Q1A and Q3B (R2) regarding the content of phenobarbital and levels of degradation products (no degradation products >0.01%). Phenobarbital concentration was 101.59±2.6% of initial concentration in refrigerated samples and 101.14±0.5% at 20±5°C. No phenobarbital degradation products (>0.01%) were observed throughout the 6 months. No significant variation of pH or osmolality was observed. CONCLUSIONS: HPBCD solubilise phenobarbital and create a homogeneous solution. These stability data set the shelf life of this new phenobarbital solution at up to 6 months. A microbiological stability study will be carried out to ensure the possibility of using this solution in children.

Role of Daily Milk Volume and Period of Lactation in Nutrient Content of Human Milk: Results from a Prospective Study.

Most studies assessing the macronutrient content of human milk are published retrospectively using analyzers that fail to determine sodium content and do not take into account the role of volume in milk composition. We aimed to describe macronutrient content and sodium content in human milk over time, observe any associations between them, and determine the factors associated with the evolution of milk composition. A prospective, longitudinal, monocentric study was undertaken. Contents of protein, fat, and lactose of 102 milk samples from 40 mothers were determined using a human milk analyzer and that of sodium with a flame spectrophotometer. Milk volumes along with clinical data were recorded. Protein content in the fourth quartile of volume was significantly lower than that in the first three, suggesting the existence of a volume threshold for protein content at approximately 445 mL. After multivariate analysis, it was found that maternal age, average volume, and lactation period remained significantly associated with protein content, maternal age remained significantly associated with fat content, and only average volume with sodium content. In consideration of previous findings along with our data, we suggest that extra care should be taken with fortification for feeding preterm infants when the mother's milk volume is greater than 400-450 mL.

Residual gravimetric method to measure nebulizer output.

The aim of this study was to assess a residual gravimetric method based on weighing dry filters to measure the aerosol output of nebulizers. This residual gravimetric method was compared to assay methods based on spectrophotometric measurement of terbutaline (Bricanyl, Astra Zeneca, France), high-performance liquid chromatography (HPLC) measurement of tobramycin (Tobi, Chiron, U.S.A.), and electrochemical measurements of NaF (as defined by the European standard). Two breath-enhanced jet nebulizers, one standard jet nebulizer, and one ultrasonic nebulizer were tested. Output produced by the residual gravimetric method was calculated by weighing the filters both before and after aerosol collection and by filter drying corrected by the proportion of drug contained in total solute mass. Output produced by the electrochemical, spectrophotometric, and HPLC methods was determined after assaying the drug extraction filter. The results demonstrated a strong correlation between the residual gravimetric method (x axis) and assay methods (y axis) in terms of drug mass output (y = 1.00 x -0.02, r(2) = 0.99, n = 27). We conclude that a residual gravimetric method based on dry filters, when validated for a particular agent, is an accurate way of measuring aerosol output.