Amorphous solid dispersions (ASD) of a poorly soluble water-soluble VR1 antagonist (AMG 517) were explored for improving physical stability and in vivo exposure. AMG 517 was incorporated at 15 or 50 wt % into polymeric microparticles of hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose (HPMC) by spray-drying. Solid particles having a collapsed, corrugated structure were observed by SEM. Median particle size ranged from 29 to 40 microm by laser light scattering, and residual solvent levels were below 2% by thermal gravimetric analysis. ASD powders exhibited single glass transition temperatures (Tg) in the range of 98-117 degrees C by modulated DSC and were amorphous by XRPD. Amorphous stability, characterized at 40 degrees C/75% RH (open dish) by XRPD, was at least six months for ASD formulations. Drug dissolution and supersaturation testing in a USP-2 apparatus indicated superior performance of ASD formulations over micronized AMG 517. PK of an ASD formulation in capsule (15 wt % AMG 517 in HPMCAS blended with 5 wt % SDS) in cynomolgus monkeys (n = 6, crossover) increased AUC 163% and Cmax 145% in comparison to an OraPlus suspension control. The study demonstrates the ASD approach provides improved amorphous physical stability and oral bioavailability for a poorly soluble development-stage molecule.

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Microfluidic networks is a powerful tool for aligning one-dimensional materials over a large area on solid substrates. Here we show that lipid nano- and microtubules can be assembled into two-dimensional (2-D) parallel arrays with controlled separations by combining fluidic alignment with dewetting, which occurs within microchannels. We also demonstrate that lipid tubules can be bent into a well-defined shape at the entrance of the channels by the capillary force. Atomic force microscopy is used to study the structure and stability of the aligned lipid tubules on substrates. The deposition experiments with silica colloidal particles show that the 2-D parallel-aligned tubules can be used as a template to synthesize silica films with controlled morphologies and patterns on substrates in a single-step process.

Self-assembled cylindrical tubules of chiral phospholipids are interesting supramolecular structures. Understanding the moleculartilt order is a key step in controlling the size and shape of the tubules and designing new functional materials. The current theories based on the chiral interactions, coupled with molecular tilt, have predicted that the tubules could have both uniform and modulated tilt states. Here, we image the molecular-tilt order in the self-assembled tubules of a chiral phospholipid by using liquid crystals as an optical amplification probe. We demonstrate that the organization of the molecular-tilt azimuth in the lipid tubules can induce an azimuthal orientation in the liquid crystals. Both uniform and modulated tilt states of the lipid tubules are observed after liquid-crystal optical amplification.liquid-crystal amplification ͉ molecular ordering ͉ self-assembly ͉ optical amplification ͉ supramolecular structure T he self-assembled cylindrical tubules have attracted considerable attention because of their interesting supramolecular structures and technological applications (1, 2). It has been found that a variety of amphiphilies, including alkylaldonamides (3), diacetylenic phospholipids (4, 5), amino acid-based surfactants (6, 7), and multicomponent mixtures in bile (8, 9), selfassemble into cylindrical tubules in solutions. Recently, advances have been made in controlling the sizes and shapes of tubules by adjusting the chemical compositions and the conditions under which self-assembly occurs (10-16).Theoretical models based on the chiral interactions, coupled with molecular tilt, have been used to explain the formation of the cylindrical tubules (17)(18)(19). In these models, the chiral molecules do not pack parallel to their neighbors but, rather, at a nonzero angle with respect to their neighbors. This chiral packing causes the twisting of a bilayer stripe, which leads to the formation of cylindrical tubules. The model by Selinger et al. (19) suggests that the tubules can have both uniform and modulated tilt states. In the uniform tilt state, the tubule has a constant orientation of the molecule tilt with respect to the equator of the cylinder (Fig. 1a). In the modulated tilt state, the tubule has a periodic modulated structure by helical stripes in the molecular tilted direction winding around the cylinder. The direction of the molecular tilt smoothly varies across the stripes and jumps at the edges of the stripes (Fig. 1b). These stripes in the tubules are suggested to be analogous to the tilted stripes seen in the Langmuir monolayers (20) but in a cylindrical rather than a planar geometry. To our knowledge, there has been no experimental test of the theoretical predictions because of the difficulty in probing the local direction of the molecular tilt in the tubules.In recent years, there has been an increased interest in developing an imaging technique based on liquid-crystal optical amplification for studying the structures and physical properties of organic and biological interfac...