Drug Formulations for Microcontainers

Research output: Book/ReportPh.D. thesisResearch

Abstract

The purpose of this PhD thesis was to investigate the potential of microcontainers as an oral drug delivery system with mucoadhesive properties for poorly water soluble drugs.

Microcontainers are small polymeric devices consisting of a flat base with a walled reservoir. In the studies described in this thesis the microcontainers were either fabricated from SU-8, or from the biopolymer, poly-L-lactic acid (PLLA). The microcontainers were to be filled with a poorly soluble drug/formulation. In early work, the solubility and dissolution rate of furosemide, a poorly soluble drug intended for use with the microcontainers, was improved by employing the strategy of converting the drug into an amorphous salt form. Amorphous furosemide sodium salt was prepared by spray drying and characterised in vitro and in vivo. The amorphous salt was found to exhibit a high physical stability at ambient storage conditions, as well as a significantly greater biorelevant apparent solubility and dissolution rate compared to both amorphous and crystalline acid of furosemide. However, the amorphous salt demonstrated instability during biorelevant dissolution, and converted immediately at the point of drug wetting to a trihydrate form of furosemide. Following oral dosing of amorphous salt, and amorphous and crystalline acid forms of furosemide to rats, the amorphous salt was found to exhibit a faster Tmax compared to the two other forms. In an attempt to improve the stability of amorphous furosemide during storage and dissolution, solid dispersions containing hydroxypropyl methylcellulose (HPMC) were prepared by spray drying. It was found that 20 w/w% HPMC was sufficient for stabilising amorphous furosemide during storage, but from a dissolution point of view, 80 w/w% HPMC was required for stabilising the amorphous furosemide form during biorelevant dissolution. Following characterisation and optimisation, furosemide drug powder was filled into the microcontainers by direct filling. The furosemide-filled microcontainers were spray coated with a protective lid of the pH-sensitive polymer, Eudragit L100 (dissolution at pH > 6), and the release of furosemide from sealed microcontainers was investigated in biorelevant gastric (pH 1.6-2) and intestinal (pH 6.5) media. Either no furosemide or very small amounts of drug were released in the gastric media, whereas an immediate release was observed in the intestinal media. For evaluation of the microcontainers as a mucoadhesive system for attachment to the mucus in the small intestine, the microcontainers were spray coated with a lid of chitosan. A thickness of the chitosan layer of 5.4 µm was found to show mucoadhesive properties, by using the tensile force model; however, the chitosan layer did result in hindrance of the release of furosemide from the microcontainers. The permeability of furosemide loaded in microcontainers through a Caco-2 cell layer was evaluated, but as the integrity of the cell layer was not maintained during the cell studies, such permeability investigations are currently inconclusive. The microcontainers were furthermore investigated for their ability to stabilise amorphous drugs by spatial confinement, with the aim being for the microcontainers to restrict the progression of crystal growth to distances corresponding to the diameter of the microcontainers. For these studies, the amorphous form of a second poorly soluble drug, indomethacin, was prepared in the microcontainers. It was found that the degree of crystallisation of amorphous indomethacin was decreased by confinement of the drug into 174 µm and 223 µm diameter microcontainers compared to amorphous bulk indomethacin. Moreover, it was discovered that the stability of amorphous indomethacin could be improved further by slow cooling of the indomethacin melt, without influencing the dissolution behaviour of amorphous indomethacin.

In conclusion, the microcontainers were found to show promise for utilisation as an oral drug delivery system with mucoadhesive properties for poorly water soluble drugs. Further characterisation and optimisation of the microcontainer system is however still required in order to improve their efficacy and efficiency in drug delivery.
Original languageEnglish
Place of PublicationCopenhagen
PublisherUniversity of Copenhagen
Publication statusPublished - 2014
Externally publishedYes

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