Furosemide ethanol-free oral solutions for paediatric use: formulation, HPLC method and stability study.

BACKGROUND: Oral liquid solutions of the diuretic active ingredient furosemide (FUR) marketed across Europe do not comply with recent requirements for paediatric preparation owing to their ethanol content and, moreover, in some countries only tablet or injection dosage forms of furosemide are available. OBJECTIVES: To formulate extemporaneous paediatric ethanol-free solutions of FUR (2 mg/mL) with suitable solubility in the aqueous vehicle and an acceptable taste and to evaluate their stability under two different storage conditions during a 9-month study period. METHODS: Our work presents two developed formulations of FUR ethanol-free paediatric oral solutions 2 mg/mL for easy extemporaneous compounding in a pharmacy. FUR solubility avoiding the use of ethanol was achieved using sodium hydroxide (formulation F1) or disodium hydrogen phosphate dodecahydrate (formulation F2). The preparations were stored at 25°C±3°C or at 40°C±0.5°C and protected from light. For FUR and preservative, methylparaben (MP), a stability assay was conducted by a high-performance liquid chromatography validated method and determination of pH stability. RESULTS: The remaining FUR concentration was >90% of the initial concentration after 270 days in both formulations at both storage conditions, 25°C and 40°C. The concentration of MP decreased significantly in the formulation F2 stored at 40°C. CONCLUSIONS: Both formulations were stable when stored at room temperature for up to 9 months; formulation F1 was stable even at 40°C. MP used as an antimicrobial agent fully satisfied the recommended criteria for preservative efficacy in oral preparations according to the European Pharmacopoeia 9.0 (5.1.3).

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans.

RATIONALE: Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. OBJECTIVES: We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. METHODS: We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. RESULTS: Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. CONCLUSIONS: In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

Extemporaneous sotalol hydrochloride oral solutions for use in paediatric cardiology: formulation and stability study.

OBJECTIVES: Sotalol hydrochloride (SOT) is an antiarrhythmic ß-blocker which is highly effective for the treatment of supraventricular tachycardia in children. However, a licensed paediatric dosage form with sotalol is not currently available in Europe. The aim of this work was to formulate paediatric oral solutions with SOT 5 mg/mL for extemporaneous preparation in a hospital pharmacy with the lowest possible amount of excipients and to determine their stability. METHODS: Three aqueous solutions were formulated. One preparation without any additives for neonates and two preparations for children from 1 month of age were compounded using citric acid to stabilise the pH value, potassium sorbate 0.1% w/v as a preservative, and simple syrup or sodium saccharin as a sweetener. The samples were stored at room temperature and in a refrigerator, respectively, and the content of SOT and potassium sorbate was determined simultaneously using a validated high performance liquid chromatography method at different time points over 180 days. RESULTS: At least 95% of the initial sotalol concentration remained throughout the 180-day study period in all three preparations at both temperatures. The content of potassium sorbate decreased by 17% with sodium saccharin stored at room temperature. CONCLUSIONS: The three proposed oral aqueous solutions of SOT for neonates and infants were stable for 180 days. Storage in a refrigerator is preferred, particularly with sodium saccharin. The additive-free solution of SOT can be autoclaved to ensure microbiological stability and used particularly for neonates and in emergency situations.

Development of a gradient HPLC method for the simultaneous determination of sotalol and sorbate in oral liquid preparations using solid core stationary phase.

A selective and sensitive gradient HPLC-UV method for quantification of sotalol hydrochloride and potassium sorbate in five types of oral liquid preparations was developed and fully validated. The separation of an active substance sotalol hydrochloride, potassium sorbate (antimicrobial agent), and other substances (for taste and smell correction, etc.) was performed using an Ascentis Express C18 (100 × 4.6 mm, particles 2.7 µm) solid core HPLC column. Linear gradient elution mode with a flow rate of 1.3 mL min(-1) was used, and the injection volume was 5 µL. The UV/Vis absorbance detector was set to a wavelength of 237 nm, and the column oven was conditioned at 25°C. A sodium dihydrogen phosphate dihydrate solution (pH 2.5; 17.7 mM) was used as the mobile phase buffer. The total analysis time was 4.5 min (+2.5 min for reequilibration). The method was successfully employed in a stability evaluation of the developed formulations, which are now already being used in the therapy of arrhythmias in pediatric patients; the method is also suitable for general quality control, that is, not only just for extemporaneous preparations containing the mentioned substances.

Pediatric oral solutions with propranolol hydrochloride for extemporaneous compounding: the formulation and stability study.

UNLABELLED: The aim of this study is to formulate an extemporaneous pediatric oral solution of propranolol hydrochloride (PRO) 2 mg/ml for the therapy of infantile haemangioma or hypertension in a target age group of 1 month to school children and to evaluate its stability. A citric acid solution and/or a citrate-phosphate buffer solution, respectively, were used as the vehicles to achieve pH value of about 3, optimal for the stability of PRO. In order to mask the bitter taste of PRO, simple syrup was used as the sweetener. All solutions were stored in tightly closed brown glass bottles at 5 ± 3 °C and/or 25 ± 3 °C, respectively. The validated HPLC method was used to evaluate the concentration of PRO and a preservative, sodium benzoate, at time intervals of 0-180 days. All preparations were stable at both storage temperatures with pH values in the range of 2.8-3.2. According to pharmacopoeial requirements, the efficacy of sodium benzoate 0.05 % w/v was proved (Ph.Eur., 5.1.3). The preparation formulated with the citrate-phosphate buffer, in our experience, had better palatability than that formulated with the citric acid solution. KEYWORDS: propranolol hydrochloride pediatric preparation extemporaneous preparation solution stability testing HPLC.