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Purpose: To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties., Methods: Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters., Results: The generation of new, single and pure crystal forms was characterized by DSC and PXRD. The crystal structure determination from PXRD revealed the existence of both cocrystals in triclinic (P-1) crystal system. The hydrogen bonded network, determined by material studio was well supported by shifts in FTIR and SSNMR. Both the new solid forms displayed improved solubility, IDR, antidiabetic activity and pharmacokinetic parameters as compared to GL., Conclusions: The improvement in these physicochemical and biopharmaceutical properties corroborated the fact that the supramolecular cocrystallization may be useful in the development of pharmaceutical crystalline materials with interesting network and properties.

Purpose: For the rational design of nanovaccines against respiratory pathogens, careful selection of optimal particle size and chemistry is paramount. This work investigates the impact of these properties on the deposition, biodistribution, and cellular interactions of nanoparticles within the lungs., Method: In this work, biodegradable poly(sebacic anhydride) (poly(SA)) nanoparticles of multiple sizes were synthesized with narrow particle size distributions. The lung deposition and retention as well as the internalization by phagocytic cells of these particles were compared to that of non-degradable monodisperse polystyrene nanoparticles of similar sizes., Results: The initial deposition of intranasally administered particles in the lungs was dependent on primary particle size, with maximal deposition occurring for the 360-470 nm particles, regardless of chemistry. Over time, both particle size and chemistry affected the frequency of particle-positive cells and the specific cell types taking up particles. The biodegradable poly(SA) particles associated more closely with phagocytic cells and the dynamics of this association impacted the clearance of these particles from the lung., Conclusions: The findings reported herein indicate that both size and chemistry control the fate of intranasally administered particles and that the dynamics of particle association with phagocytic cells in the lungs provide important insights for the rational design of pulmonary vaccine delivery vehicles.

Purpose: This paper presents a three-dimensional patient-specific simulation of carmustine delivery to brain tumor. The simulation investigates several crucial factors, particularly the role of convective flow, affecting drug delivery efficacy., Methods: The simulation utilizes a complete three-dimensional tissue geometry constructed from magnetic resonance images (MRI) of a brain tumor patient in whom commercially available Gliadel wafers were implanted for sustained delivery of carmustine following excision of the tumor. This method permits an estimation of the convective flow field (in the irregularly shaped anatomical region) which can be used for prediction of drug penetration into the domain of interest, i.e. remnant tumor. A finite volume method is utilized to perform all simulations., Results: Drug exposure exceeds its threshold therapeutic concentration (approximately 15 microM) but for only a limited time (i.e. less than a week) and only in the immediately adjacent tissue (i.e. less than 2 mm). A quasi-steady transport process is established within 1 day following treatment, in which the drug is eliminated rapidly by transcapillary exchange, while its penetration into the tumor is mainly by diffusion. Convection appears to be crucial in influencing the drug distribution in the tumor: the remnant tumor near the ventricle is, by one to two orders of magnitude, less exposed to the drug than is the distal remnant tumor., Conclusions: Carmustine penetration from Gliadel wafers implanted in brain is limited by rapid elimination via transcapillary exchange. Therefore, it could be useful to consider other therapeutic agents such as paclitaxel. In addition, local convective flow within the cavity appears to be a crucial factor in distributing the drug so that the tumor domain near the ventricle is prone to minimal drug exposure. Thus, complete removal of the tumor from this region is of particular concern.

Purpose: To demonstrate that polyanhydride copolymer chemistry affects the uptake and intracellular compartmentalization of nanospheres by THP-1 human monocytic cells., Methods: Polyanhydride nanospheres were prepared by an anti-solvent nanoprecipitation technique. Morphology and particle diameter were confirmed via scanning election microscopy and quasi-elastic light scattering, respectively. The effects of varying polymer chemistry on nanosphere and fluorescently labeled protein uptake by THP-1 cells were monitored by laser scanning confocal microscopy., Results: Polyanhydride nanoparticles composed of poly(sebacic anhydride) (SA), and 20:80 and 50:50 copolymers of 1,6-bis-(p-carboxyphenoxy)hexane (CPH) anhydride and SA were fabricated with similar spherical morphology and particle diameter (200 to 800 nm). Exposure of the nanospheres to THP-1 monocytes showed that poly(SA) and 20:80 CPH:SA nanospheres were readily internalized whereas 50:50 CPH:SA nanospheres had limited uptake. The chemistries also differentially enhanced the uptake of a red fluorescent protein-labeled antigen., Conclusions: Nanosphere and antigen uptake by monocytes can be directly correlated to the chemistry of the nanosphere. These results demonstrate the importance of choosing polyanhydride chemistries that facilitate enhanced interactions with antigen presenting cells that are necessary in the initiation of efficacious immune responses.

Purpose: This study was carried out to show the effect of particle size reduction and bioadhesion on the dissolution and relative bioavailability of dicumarol., Methods: Formulations were produced by a variety of methods including a novel technique to reduce particle size as well as phase inversion with poly(fumaric-co-sebacic)anhydride p(FA:SA) to create nanospheres. Drug was administered to groups of pigs and rats via oral gavage of a suspension, and dicumarol concentration in the blood was measured using a double extraction technique., Results: In vitro results showed improved dissolution in both the micronized formulation and the encapsulated p(FA:SA) nanospheres. In vivo, relative bioavailability of a spray-dried formulation was increased by 17% in the rat and 72% in the pig by further reduction in particle size. The bioadhesive p(FA:SA) formulation also improved relative bioavailability over the spray-dried drug, increasing it by 55% in the rat and 96% in the pig. Additionally, the p(FA:SA) formulation prolonged Tmax and decreased Cmax in both species., Conclusion: This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.

Purpose: Water-in-oil (w/o) microemulsions have been developed which, in addition to non-ionic medium-chain glycerides, incorporate ionic lipids, primarily medium-chain fatty acids, such as caprylic (C8) capric (C10) and lauric (C12) acids and their corresponding sodium salts. The absorption enhancing activity of w/o microemulsions incorporating these lipids was evaluated in the rat using Calcein (MW = 623) a water-soluble and poorly absorbed marker molecule., Methods: Phase diagrams were constructed where C8/C10 or C12 fatty acids were treated as lipophilic surfactants and their sodium salts as hydrophilic ones. The anesthetised rat model was employed to evaluate Calcein absorption upon a single intraduodenal administration from a solution and the various w/o microemulsions., Results: A wide range of clear and transparent w/o microemulsions were obtained at ambient temperature either in liquid or solid form when a fixed blend of medium chain fatty acid/salt was titrated by a fixed ratio of the oil containing the oil-soluble mono- and diglycerides and deionized water or physiological saline. Upon intraduodenal administration in the anesthetised rat, the absorption of Calcein was improved from about 2% in aqueous solution up to about 37% in w/o microemulsions. Solid and liquid formulations were equally effective in improving bioavailability. The absorption enhancement activity of the fatty acids/salts followed the order C8 approximately C10 > C12. Absorption enhancement of Calcein was significantly reduced in the absence or presence of low levels of C8/C10 mono-/diglycerides., Conclusions: These results further support the use of medium-chain glycerides and fatty acids/salts in microemulsion formulations to improve intestinal absorption of water-soluble compounds.