Critical Aspects in the Preparation of Extemporaneous Flecainide Acetate Oral Solution for Paediatrics.

The availability of liquid oral preparations compounded by pharmacists is essential to meet paediatric needs which remain unanswered by the pharmaceutical industry. Unfortunately, compendial monographs are often not available and, in many cases, pre-formulation studies (e.g., compatibility with other excipients and solubility evaluations) are not performed in-depth, leading, in some rare cases, to the inadvertent administration of a toxic dose. In this study, the preparation of an oral liquid formulation for paediatric use, containing flecainide acetate at different strengths, was considered, taking into account the possible effects of conventionally used excipients. First, the optimal vehicle was selected based on a solubility study, evidencing some unexpected formations of precipitates. As a matter of fact, the buffers commonly used for oral solutions significantly reduced flecainide solubility, and the concomitant presence of citrate buffer and methylparaben even caused the formation of non-resuspendable crystals. Then, chemical, physical, and microbiological stability were assessed. Solutions at strengths of 10 and 20 mg/mL flecainide acetate were stable up to 8 weeks when compounded by using a 40% sucrose solution as a vehicle. Microbiological data showed that the use of methylparaben was not necessary over this time period.

Stability of high concentrated triple intrathecal therapy for pediatrics and mitigation strategies.

Stringent formulation requirements are defined to intrathecally administer drug substances, avoiding neurological complications. In case of pediatric patients, these are further complicated due to the limited volumes of the celebrospinal fluid and, therefore, high concentrated solutions of methotrexate (MTX), cytarabine and corticosteroids (i.e., methylprednisolone or hydrocortisone) are prepared based on the patient's age. This work aims to assess the chemical and physical stability of triple intrathecal mixtures differing in volume and composition by a bracketing approach and to identify possible stress causes and mitigation strategies. Low solubility of MTX was the main factor limiting the physical stability of triple mixtures. Regarding solutions containing methylprednisolone, the amount of MTX remaining was about 95% in the solution at highest concentrations with the concomitant formation of a visible particulate sizing bigger than 1 µm after 24 h of storage at 25 °C. This behavior was mainly driven by the pH reduction due to the pH value of the cytarabine solution used; the shear stress also induced drug precipitation. In the case of the hydrocortisone based mixtures, the precipitate formation occurred at a slow rate. To improve the physical stability, a better control of the mixture pH (optimal value ≈ 7) is required or, as an alternative, the addition of the cytarabine solution to a pre-mixed binary mixture containing MTX and a corticosteroid should be preferred.

Topical Administration of Cannabidiol: Influence of Vehicle-Related Aspects on Skin Permeation Process.

Cannabidiol (CBD) is a non-psychoactive cannabinoid isolated from Cannabis sativa which, given its claimed beneficial properties and therapeutic potential, has lately aroused considerable attention from the scientific community. Starting from the little literature evidence, the main purpose of this study was to investigate the topical administration of CBD, with particular focus on the influence of vehicle-related aspects on the skin permeation process. This could provide useful information for the design of suitable drug delivery systems which could be used in developing topical medicines and cosmetics. In vitro human skin permeation studies were conducted using modified Franz diffusion cells to compare the performance of four solutions and two semisolid formulations. The Hildebrand solubility parameter was used to better understand the thermodynamic aspects implied in the partitioning process of the cannabinoid compound into the skin. It was interestingly found that a hydrophilic gel, mostly consisting of propylene glycol (79%, w/w), can be an optimal choice for the topical administration of CBD. Moreover, the feasibility of the preparation of CBD-loaded (trans)dermal patches, made with new printing technology, was also demonstrated.