ABSTRACT
This paper reports the use of two crystalline polymers, an amphiphilic Pluronic® F-127 (PF-127) and a hydrophilic poly(ethylene glycol) (PEG6000) as drug delivery carriers for improving the drug release of a poorly water-soluble drug, fenofibrate (FEN), via micelle formation and formation of a solid dispersion (SD). In 10% PF-127 (aq.), FEN showed an equilibrium solubility of ca. 0.6 mg/mL, due to micelle formation. In contrast, in 10% PEG6000 (aq.), FEN only exhibited an equilibrium solubility of 0.0037 mg/mL. FEN-loaded micelles in PF-127 were prepared by direct dissolution and membrane dialysis. Both methods only yielded a highest drug loading (DL) of 0.5%. SDs of FEN in PF-127 and PEG6000, at DLs of 5-80%, were prepared by solvent evaporation. In-vitro dissolution testing showed that both micelles and SDs significantly improved FEN's release rate. The SDs of FEN in PF-127 showed significantly faster release than crystalline FEN, when the DL was as high as 50%, whereas SDs of PEG6000 showed similar enhancement in the release rate when the DL was not more than 20%. The DSC thermograms of SDs of PF-127 exhibited a single phase transition peak at ca. 55-57 °C when the DL was not more than 50%, whereas those in PEG6000 exhibited a similar peak at ca. 61-63 °C when the DL was not more than 35%. When the DL exceeded 50% for SDs of PF-127 and 35% for SDs of PEG6000, DSC thermograms showed two melting peaks for the carrier polymer and FEN, respectively. FT-IR studies revealed that PF-127 has a stronger hydrophobic-hydrophobic interaction with FEN than PEG6000. It is likely that both dispersion and micelle formation contributed to the stronger effect of PF-127 on enhancing the release rate of FEN in its SDs.
Subject(s)
Pharmaceutical Preparations/chemistry , Polymers/chemistry , Water/chemistry , Chemistry, Pharmaceutical/methods , Drug Carriers/chemistry , Drug Delivery Systems/methods , Drug Liberation , Hydrophobic and Hydrophilic Interactions , Micelles , Polyethylene Glycols/chemistry , Solubility , Spectroscopy, Fourier Transform Infrared/methodsABSTRACT
In formulating an orodispersible film (ODF), it is important for polymer choice to strike a balance between mechanical properties and release rates. Studies have been done to study polymer combinations. However, there is a lack of a systematic study to determine key factors affecting these properties. We studied the effect of varying the ratios of a solubilising polymer (Kollidon(®) VA 64 or Soluplus(®)) to a film forming polymer, hydroxypropyl cellulose (HPC), on mechanical properties and release rates of hot-melt extruded ODFs using a 2(3) factorial design. The two drugs evaluated were chlorpheniramine and indomethacin. The main effects impacting mechanical properties were the drug and two-way interaction between drug and solubilising polymer. For dissolution, the main effects were the solubilising polymer; the drug; and the two-way interaction between solubilising polymer and ratio of solubilising to film forming polymer. Both drugs exhibited plasticising effects on the polymer matrix and had higher film ductility and lower film stiffness. Kollidon(®) VA 64-containing films performed better in terms of drug release whereas Soluplus(®)-containing films had better mechanical properties. The dissolution rate can be improved by decreasing film thickness. The findings of our study will be crucial to forming a robust ODF formulation.
