Highly loaded nanoparticulate formulation of progesterone for emergency traumatic brain injury treatment.

BACKGROUND: Progesterone (PG), a promising therapeutic for treating traumatic brain injury, has been difficult to formulate into a high-dose/low-volume form for emergency intravenous administration due to its hydrophobicity and crystallinity. RESULTS: This work demonstrates the use of Flash NanoPrecipitation to produce 300-nm PG-loaded polymeric nanoparticles with approximately 24 wt% drug loading using only components that are classified by the US FDA as generally recognized as safe. Approximately 80% of the encapsulated PG is in dissolved, rather than crystalline form. For prolonged stability, the nanoparticles are freeze-dried with Pluronic F68 and can be reproducibly reconstituted by hand agitation for 1 min without particle aggregation to produce injectable formulations with approximately 30-mg/ml PG, which is more than ten-times higher than has been previously reported. CONCLUSION: This formulation can allow for administration of therapeutically viable concentrations of PG, which has been impossible with all previously reported nanoparticulate formulations because of low drug loadings and concentrations.

Spontaneous assembly of a polymeric helicate of sodium with LVO(2) units forming the strand: photoinduced transformation into a mixed-valence product.

The anionic cis-dioxovanadium(V) complex species LVO(2)(-) of a tridentate ONS ligand (H(2)L) can bind sodium ion in a bis-monodentate fashion like a bridging carboxylate group. The product [LVO(2)Na(H(2)O)(2)](infinity) (1) is a water soluble polymeric compound in which the complementary units are held together by the simultaneous use of hydrogen bonding and Coulombic interactions. Crystallographic characterization reveals that 1 is a single stranded helicate with LVO(2)(-) units forming the strand which surrounds the labile sodium ions that occupy the positions on the axis. In solution of protic solvents, viz. water and methanol, 1 is quite stable as indicated by electrical conductivity and (1)H NMR measurements. In aprotic solvents, viz. CH(3)CN, DMF, or DMSO, however, the extended hydrogen bonded network in 1 breaks apart and the helical structure collapses when irradiated with visible light. The product is a mixed-oxidation vanadium(IV/V) species obtained by photoinduced reduction as confirmed by EPR, time dependent (1)H NMR, and electronic spectroscopy. Compound 1 is a rare example of a nonnatural helix where hydrogen bonding interactions play a crucial role in stabilizing the single stranded polymeric structure such as that frequently observed in the biological world.

Mixed-Oxidation Divanadium(IV,V) Compound with Ligand Asymmetry: Electronic and Molecular Structure in Solution and in the Solid State.

Reaction of [V(IV)OL(1)(Im)] (H(2)L(1) = S-methyl-3-((2-hydroxyphenyl)methyl)dithiocarbazate) with [V(V)OL(OCH(3))] allows isolation of (ImH)[L(1)OV-(&mgr;-O)-VOL] complexes 2 (H(2)L = H(2)L(2) = S-methyl-3-((5-bromo-2-hydroxyphenyl)methyl)dithiocarbazate) and 3 (H(2)L = H(2)L(1)), one of which (2) has ligand asymmetry not previously known in this type of complex. In the solid state, (ImH)[L(1)OV-(&mgr;-O)-VOL(2)] (2) provides an example of a divanadium(IV,V) compound with a syn angular [V(2)O(3)](3+) core structure that exhibits crystallographically imposed mirror symmetry due to static disorder. Crystals of 2 are orthorhombic, space group Pnma, with a = 10.740(2) Å, b = 18.912(4) Å, c = 17.163(4) Å, and Z = 4. In toluene at room temperature, both 2 and 3 have 8-line EPR spectra, characteristic of trapped-valence structure. When acetonitrile is added to these solutions, the spectra reveal 15-line features with asymmetric distortions that smooth out with the lowering of temperature. This probably has its origin in a solvent-dependent equilibrium involving two magnetically inequivalent structural forms of the divanadium(IV,V) compound, with syn angular and anti linear structures of the [V(2)O(3)](3+) core. Variable temperatures (298-220 K) (51)V NMR spectroscopic studies in solution also support this view. In acetonitrile, both 2 and 3 exhibit an intervalence transfer band in the near-IR region at ca. 970 nm (epsilon, 1600 and 1480 M(-)(1) cm(-)(1) for 2 and 3, respectively) and they undergo one-electron reversible oxidation at ca. 0.40 V (vs SCE) due to the V(IV)V(V)/V(V)V(V) couple.