Band 3, Heft 2 - Special Issue: Pediatric Formulations

Background Prednisone is a corticosteroid used in several inflammatory diseases and cancers. In France, no available prednisone drinkable formulation exists. Instead, an oral syrup of prednisone with ethanol, sodium benzoate and simple syrup is produced. However, sodium benzoate can induce neonatal icterus and alcohol is not authorized for children below 3 years of age. The aim of this study was to determine the stability of 5 mg/mL prednisone oral suspension in a commercial compounding excipient: Syrspend ® SF PH4. Methods Three batches of oral suspensions were prepared, using micronized prednisone and Syrspend ® SF PH4. They were packaged in amber glass vials and stored at room temperature. On day 0, 1, 4, 10, 30, 60 and 90, we observed physical and chemical stability (pH measurement, osmolality measurement, residual concentrations of prednisone and degradation product identification). A stability indicating method was developed using high performance liquid chromatography with Ultraviolet detection at 254 nm. Results Prednisone concentrations remained stable within ± 5 % of nominal values for 60 days. No degradation product and change of physicochemical properties were detected. Conclusion This study showed that 5 mg/mL prednisone oral suspension in Syrspend ® SF PH4 is stable for 60 days, at room temperature and protected from light.

Background Dexamethasone is used in pediatrics mainly for treatment of croup and bronchopulmonary dysplasia. Commercially available pediatric oral formulations include inadequate excipients for this population. When there are only commercially available oral dosage forms for adults, a formulation is prepared to reduce the dose by manipulation of authorized tablets or injectable dosage forms. This practice most of times is made without the quality and control that process requires. The aim of this study is to propose a formulation secure and suitable for pediatrics by the use of a Standard Operating Procedure that ensures its quality. Methods Design of two formulations was performed with lowest number and amount of excipients suitable for pediatrics, avoiding use of dexamethasone salts and preservatives. An accurate and precise analytical method and a methodology for analyzing uniformity of doses were developed. Physical, chemical and microbiological stability was tested. Results Stability of Dexamethasone was improved by acidification with citric/citrate buffer. Proposed suspension complies with quality criteria required for an oral non-sterile formulation using Dexamethasone as active pharmaceutical ingredient, and the minimum number and quantity of excipients suitable for pediatrics. Conclusions This formulation is physical, chemical and microbiologically stable during 15 days storage at 5 and 25 °C.

Background Viscous oral solutions of budesonide (dose range: 1 mg to 2 mg) have long been used to treat eosinophilic oesophagitis in children. The objective of the present study was to provide a convenient paediatric pharmaceutical formulation of a viscous budesonide solution at a dose level of 0.1 mg/mL, using cyclodextrin as a solubilizer. Methods Solubility studies were performed with γ-cyclodextrin and hydroxypropyl-β-cyclodextrin, and viscosity was tested with a Brookfield viscometer. The stability of the final formulation was tested in a climatic chamber. Levels of budesonide, budesonide impurities and degradation products were assayed using the HPLC–UV method described for the budesonide-related substance assay in the European Pharmacopoeia monograph. Results The solubility of budesonide increased linearly with both cyclodextrins. Gamma cyclodextrin (complexation efficiency: 0.147) was preferred to hydroxypropyl-β-cyclodextrin (complexation efficiency: 0.064) as a solubilizing agent. Hydroxypropylcellulose (1 % m/v) was added to increase viscosity, and sucralose was added to improve palatability. The sterilized, filtered, final formulation was stable for at least 3 months when packed aseptically in sterile 15 mL type 1 amber glass vials. Conclusions We have developed a convenient, stable, preservative-free, viscous formulation of a budesonide solution for the hospital- and home-based treatment of paediatric patients.

Background As many drugs are unavailable for paediatric use, hospital pharmacies are often required to develop suitable formulations themselves. Clonidine is commonly used in paediatrics (in severe hypertension, in opiate withdrawal syndrome, in tics and Gilles de la Tourette syndrome or in anaesthetic premedication) but no appropriate formulation has been drawn up. The aims of this work were to develop an oral solution of clonidine dedicated to children and to assess its physicochemical and microbiological stability. Methods Formulation of an oral solution of clonidine hydrochloride suitable for neonates and paediatrics was developed using the active pharmaceutical ingredient (API), with as few excipients as possible and without any complex excipient vehicle. A stability study was made according to GERPAC-SFPC guidelines. At each point in time (D0, D1, D7, D15, D29, D60 and D90), visual aspect (limpidity), pH and osmolality were established. Clonidine concentration was quantified using a stability-indicating HPLC-UV-DAD method previously developed from a forced degradation study and validated according to SFSTP Pharma. Microbiological stability was also tested according to the European Pharmacopeia monograph with the best adapted method (by comparing membrane filtration and inclusion). Solutions were stored in amber glass bottles with an oral adapter for up to 3 months in two different conditions: 5 °C +/– 3 °C and at 25 °C +/– 2 °C with 60 % residual humidity (climatic chamber). Results The formulated oral solution is composed of API at a concentration of 10 µg/mL and of potassium sorbate (0.3 %), citric acid, potassium citrate (pH 5 buffer) and sodium saccharine (0.025 %). Forced degradation highlighted six degradation products and the method was validated in the acceptance limits of ± 5 %. On D29, the mean percentages of the initial clonidine concentrations (+/–standard deviation) were 92.95+/–1.28 % in the solution stored at 25 °C +/– 2 °C and 97.44+/–1.21 % when stored at 5 °C +/– 3 °C. On D90, means were respectively 81.82+/–0.41 % and 93.66+/–0.71 %. The visual aspect did not change. Physical parameters remained stable during the study: pH varied from 4.94 to 5.09 and osmolality from 82 to 92 mOsm/kg in the two conditions tested here. Membrane filtration appeared to be the more sensitive method. Whatever the storage conditions,<1 micro-organism/mL was identified (only environmental) with no detected E.coli . Conclusions This formulation is stable for at least 3 months at 5 °C +/– 3 °C in amber glass bottles and for one month when stored at room temperature. Microbiological stability was proven in accordance with the European Pharmacopeia.

Background Eosinophilic Esophagitis is an increasing pathology which can cause stomach symptom like dysphagia, vomiting, food blockage. The treatment consists in dietary therapy and topical corticosteroid therapy to avoid the important number of side effects of the oral corticosteroids. There is presently no available topical form adapted for treating esophageal pathology. Methods The aim of this work was to develop an oral viscous budesonide gel (OVBG). A focus on palatability was made in order to use OVBG in children. A stability indicating HLPC method able to quantify budesonide contained in our OVBG has been developed. Results Previous work of Hefner and Al. showed that xanthan gum had a longer esophageal mucosal contact time than sucralose. This encouraged the development of a xanthan gum-based formulation. This OVBG has also the advantage to facilitate compliance thanks to its taste and pleasant texture. The stability length of the preparation can be extended over a 3-months period, stored in a refrigerator at 2–8 °C. Conclusions An adapted pediatric formulation with a 3-months stability was developed. Furthermore, the formulation can be easily reproduced in community pharmacy. Regarding the increasing number of patients concerned OVBG is a good answer to a real clinical need.

Background There is a lack of an age-appropriate formulation of fluconazole. The extemporaneous preparation of an oral suspension with an extended beyond-use-date may represent a good therapeutic alternative for the paediatric population. Methods A fluconazole 50 mg/mL oral suspension was prepared and evenly distributed into twenty amber plastic bottles: ten bottles were stored in controlled room temperature (25 °C) whereas the remainder ten bottles were stored in refrigerated temperature (5 °C). The physical characteristics (colour/appearance, odor, pH and density) and chemical characteristics [fluconazole concentration using Ultra High Performance Liquid Chromatography (UPLC)] of the oral suspension were tested at nine pre-determined time-points over a period of 182 days. Results The density, pH and mean concentration of the oral suspension did not change significantly. The recovery of fluconazole ranged from 92.67 % to 98.79 % (5 °C) and from 94.31 % to 100.02 % (25 °C), both within the specification limits. Conclusions A palatable, sugar-free formula was developed for fluconazole 50 mg/mL in the oral suspending vehicle SuspendIt™ to allow an easy and rapid extemporaneous preparation in the hospital setting. The beyond-use-date of the formula was determined using a valid, stability-indicating analytical method and it was concluded that the extemporaneously prepared oral suspension is stable for 6 months at refrigerated and controlled room temperature.

The preparation of liquid oral dosage forms for paediatric patients may pose a challenge on pharmacies. Marketed ready-to-use suspension vehicles do have advantages and disadvantages. In order to overcome the disadvantages a dedicated suspension vehicle, which can be prepared by every pharmacy, was cooperatively developed by pharmacist specialists on a national level in Germany. Marketed as well as pharmacy prepared suspension vehicles provide added value for pharmacy preparations for the special need of paediatric patients of different age groups.