Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective.

The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals. It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system.

Polymeric particulate technologies for oral drug delivery and targeting: a pathophysiological perspective.

The oral route for delivery of pharmaceuticals is the most widely used and accepted. Nanoparticles and microparticles are increasingly being applied within this arena to optimize drug targeting and bioavailability. Frequently the carrier systems used are either constructed from or contain polymeric materials. Examples of these nanocarriers include polymeric nanoparticles, solid lipid nanocarriers, self-nanoemulsifying drug delivery systems and nanocrystals. It is the purpose of this review to describe these cutting edge technologies and specifically focus on the interaction and fate of these polymers within the gastrointestinal system.

Novel quartz crystal microbalance based biosensor for detection of oral epithelial cell-microparticle interaction in real-time.

Recent applications of quartz crystal resonant sensor technology to monitor cell adhesion and specific ligand interaction processes has triggered the development of a new category of quartz crystal microbalance (QCM) based biosensors. In this study human oral epithelial cells (H376) were cultured on quartz sensors and their response to microspheres investigated in situ using the QCM technique. The results demonstrated that this novel biosensor was able to follow cell-microsphere interactions in real-time and under conditions of flow as would occur in the oral cavity. Unique frequency profiles generated in response to the microspheres were postulated to be due to phases of mass addition and altered cellular rigidity. Supporting microscopic evidence demonstrated that the unique frequency responses obtained to these interactions were in part due to binding between the cell surface and the microspheres. Furthermore, a cellular uptake process, in response to microsphere loading was identified and this, by influencing the rigidity of the cellular cytoskeleton, was also detectable through the frequency responses obtained.

Ring-B functionalized androst-4-en-3-ones and ring-C substituted pregn-4-en-3-ones undergo differential transformation in Aspergillus tamarii KITA: ring-A transformation with all C-6 substituted steroids and ring-D transformation with C-11 substituents.

The fungus Aspergillus tamarii transforms progesterone 1 into testololactone 5 in high yield through a four-step enzymatic pathway which is flexible to a range of steroidal substrates. To date, no studies have investigated the fate of C-6 (ring-B) and C-11 (ring-C) functionalized steroidal substrates on metabolism. Remarkably all of the C-6 functionalized substrates underwent reductive metabolism on ring-A in contrast to C-11 functionalized steroids where only ring-D oxidative or reductive transformation occurred. In order to discern the precise role of the functional groups in directing metabolism 6-ketoprogesterone 10 with functionality at C-6 and the ring-D methyl ketone underwent reductive and oxidative transformation on both terminal A and D rings showing that this functionality was directing metabolism. Androst-4-en-3,6-dione 12 devoid of ring-D functionality underwent reductive metabolism on ring-A proving that the C-6 functionality was directing metabolism to this ring with the ring-D methyl ketone responsible for generating transformation at this position. Functionality at C-11 exclusively controlled entry into and degree of metabolism on the lactonization pathway. These novel findings may have important bearing in the future understanding of structure activity relationships in revealing new metabolic pathways and further affords a unique opportunity for generation of novel bioactive steroidal compounds.

Fate of novel Quasi reverse steroidal substrates by Aspergillus tamarii KITA: bypass of lactonisation and an exclusive role for the minor hydroxylation pathway.

The fungus Aspergillus tamarii transforms progesterone to testololactone in high yield through a flexible four-step enzymatic pathway. To date no studies have investigated the effect of transposition of steroidal functionality between ring-A and ring-D in order to determine the effect on steroidal metabolism. A series of novel quasi reverse steroids (7-9) were synthesised through Linz and Schafer oxidation where 14-en-16-one functionality is generated on ring-D of the steroid. To retain parity with the normal series ring-D functionality was substituted onto ring-A of the analogues. All of the analogues (7-9) were handled through a minor 11beta-hydroxylation pathway with no lactones being formed. In previous studies testololactone is produced within the first 12 h of metabolism. A time course experiment demonstrated that the transformation of these steroids initiated with the formation of a 3beta-hydroxy group after which (48-96 h) hydroxylation through a minor pathway occurred, indicating that this hydroxylase was only then being induced. This is in contrast to the normal fungal metabolism of xenobiotic steroidal substrates where they are primarily hydroxylated. Furthermore, ring-D hydrogenation is reported for the first time as is reverse metabolism on this pathway. All metabolites were isolated by column chromatography and were identified by 1H and 13C NMR spectroscopy, DEPT analysis and other spectroscopic and crystallographic data.