Purpose: One of the main challenges in oral drug delivery is poor drug aqueous solubility, which frequently leads to low and variable oral absorption. Different enabling formulation approaches have been used to solve this problem e.g. lipid based formulations and amorphous dosage forms. Consequently, the purpose of this study was to compare the ability of a self-nanoemulsifying drug delivery system (SNEDDS) to amorphous solid dispersion (ASD) with regard to the ability to improve drug solubilization in an in vitro lipolysis model using danazol and fenofibrate as model drugs.
Methods: A self-nanoemulsifying drug delivery system (SNEDDS) composed of soybean oil (27.5% (w/w)), Maisine 35-1 (27.5% (w/w)), Kolliphor RH40 (35% (w/w)), and ethanol (10% (w/w)) was used in this work. For the solubility determination, drug in excess was added to 1g SNEDDS and the suspensions were kept in a rotator at 25ºC for up to 72h. Samples were withdrawn in 24h hours intervals and a clear supernatant was obtained by centrifugation at 13,300xg for 15min at 25ºC. The content of drug in the supernatant was determined by HPLC-UV. Equilibrium solubility in SNEDDS was achieved when values of two consecutive days varied by <5%. All the determinations were performed in triplicates. The SNEDDS preconcentrates were prepared by mixing soybean oil with Maisine 35-1 (heated to 50ºC) and adding Kolliphor RH40 (heated to 50ºC). Ethanol was added and the blend was mixed overnight at room temperature by magnetic stirring.
For the solubility determination in the polymers, physical mixtures (200mg) consisting of crystalline drug and polymer (Kollidon VA64 or Soluplus) in concentrations ranging from 70-90% drug (w/w) were prepared by gentle mixing using mortar and pestle. Samples of 2.5–3 mg were then analyzed by differential scanning calorimetry (DSC) at a heating rate of 1°C/min from ambient temperature to 20°C above the melting point of the pure crystalline drug to determine the onset of the (depressed) melting point. All the determinations were performed in duplicates. In order to predict the drug-polymer solubility at room temperature, the solubility data obtained at elevated temperatures was extrapolated to 25°C using the Flory-Huggins model. The final ADS formulations were prepared by ball milling Kollidon VA64 or Soluplus with danazol or fenofibrate for 180min at 30Hz.
In all cases, the formulations were loaded at 85% of the equilibrium solubility of the drug in the formulation (SNEDDS/ASD) to avoid precipitation during storage. Crystalline danazol and fenofibrate suspended in intestinal media were used as controls. Thus, the following formulations were used, for both danazol and fenofibrate:
1. SNEDDS containing drug at 85% of its equilibrium solubility
2. Kollidon VA64 containing drug at 85% of its equilibrium solubility
3. Soluplus containing drug at 85% of its equilibrium solubility
4. Crystalline drug suspended in intestinal media.
In vitro lipid digestion was initiated by the addition of 5mL of pancreatin solution to 25mL of intestinal medium simulating rat intestinal conditions. The composition of the intestinal media is given in Table 1. In vitro lipolysis was carried out for 120min and 1ml samples were withdrawn at 5, 15, 30, 60, 90 and 120min, centrifuged for 1min at 13,300xg at 25ºC and filtered using PVDF 0.45μm membranes. The drug content in the supernatant and the pellet was determined by HPLC-UV. As the total drug concentrations in the in vitro lipolysis were constant (735μg/mL for danazol and 960μg/mL for fenofibrate, corresponding to 10 times the solubility of the drug in the intestinal media), the lipid and polymer amounts in the lipolysis vessel varied.
Results: Solubility results for the different formulations and media are shown in Table 2. For both danazol and fenofibrate, SNEDDS showed higher capacity to dissolve danazol (92% dissolved) and fenofibrate (91% dissolved) than the amorphous solid dispersions. For danazol, Kollidon VA64 provided higher solubilization capacity (67% dissolved) than Soluplus (48% dissolved) during in vitro lipolysis. On the other hand, fenofibrate dosed in Soluplus as an ASD was better solubilized (60% dissolved) than the ASD prepared with Kollidon VA64 (51% dissolved). In vivo studies are being carried out to determine the correlation between in vivo and in vitro for fenofibrate.
Conclusion: The present work showed that SNEDDS is the best method to solubilize danazol and fenofibrate. On the contrary, the solubilization capacity of the polymers was compound specific. After the in vivo study we will be able to assess if the in vitro results for fenofibrate correlate with the in vivo outcome.
Ana Calduch-Arques1
– student, University of CopenhagenScheyla Siqueira Jørgensen
– post doc, University of Copenhagen
Frank Romanski
– Global Technical Marketing Manager, BASF SE, LudwigshafenThomas Rades
– Professor, University of CopenhagenMatthias Manne Knopp
– senior scientist, Bioneer A/SAnette Mullertz
– Professor, University of Copenhagen, CopenhagenAnette Mullertz
– Professor, University of Copenhagen, Copenhagen