Development of digoxin dry elixir as a novel dosage form using a spray-drying technique

Abstract

A rapidly absorbed new novel oral dosage form for digoxin termed 'digoxin dry elixir' was developed by the spray-drying technique. Digoxin, dextrin and sodium lauryl sulphate were dissolved in a ethanol-water mixture (20:25 w/w) and therefore spray-dried to form the digoxin dry elixir. According to scanning electron micrographs, digoxin dry elixir is spherical in shape with a smooth surface. The geometric mean diameter of dry elixir determined by laser particle size analysis was about 13 microns. The appearance and flow properties were almost unchanged and about 10% of ethanol contents in the dry elixir decreased during 180 days in a sealed bottle at room temperature. Comparative studies on the in vitro dissolution and in vivo absorption of digoxin in the form of digoxin dry elixir, digoxin elixir and digoxin powder were carried out. Digoxin in the dry elixirs was completely dissolved within 2 min. On the other hand, only about 87% of digoxin powder dissolved in 60 min. The initial dissolution rates of digoxin in the dry elixirs markedly increased in distilled water at 37 degrees C, which were over 100 fold higher than that of digoxin powder alone. The maximal plasma concentration of digoxin (Cmax) and area under the digoxin concentration-time curve from zero to 6 h (AUC0-6h) after the oral administration of digoxin dry elixir were almost 3.8 and 5.5 fold increased compared to digoxin powder alone. No significant difference of AUC0-6 h between dry elixir and elixir was observed, but the Cmax of digoxin in the form of dry elixir was significantly reduced compared to the digoxin elixir (0.57 versus 0.83). Digoxin dry elixir might be a useful solid dosage form to improve the dissolution rate and bioavailability of poorly water-soluble digoxin compared to digoxin powder alone. It also indicates that dry elixir might reduce the side effects in oral digitalis glycoside therapy compared to the digoxin elixir due to the reduction of Cmax.

Development of a partially automated solubility screening (PASS) assay for early drug development

“…Fourth , PASS results might be used to identify appropriate surfactants for low solubility drugs for improving their dissolution rates or bioavailability. For example for digoxin and mefenamic acid, high solubility in surfactant solutions in this study correlated well with data from other studies showing that SDS improved the in vitro dissolution rate of digoxin in a spray‐dried formulation and that Tween 80 enhanced the bioavailability of mefenamic acid 16,17 . Finally , PASS results are used for rank ordering compounds in projects regarding ‘developability,’ as input parameters for modeling (GastroPlus®), and for the build‐up of an experimental database of high‐quality solubility data that can be used for the estimation of drug solubility in formulation excipients.…”

“…For example, based on the solubility results summarized in Table 2, high doses of digoxin may be formulated in cyclodextrins for parenteral or oral administration but not in medium‐ or long‐chain mono, di‐, and triglycerides, cosolvents or micellar solutions. In contrast, for danazol, cosolvents, Capmul MCM, and surfactants with high HLB12–16 may be a good starting point for oral formulation development. Second , knowledge of the order of magnitude of solubility in a given solvent, combined with other factors such as solvent toxicity and maximal dose volumes per route, helps to estimate if a given dose can be safely administered to an animal by the desired route or if a certain dosage form is feasible.…”