2 research outputs found
Exploration and Pharmacokinetic Profiling of Phenylalanine Based Carbamates as Novel Substance P 1–7 Analogues
The
bioactive metabolite of Substance P, the heptapeptide SP<sub>1–7</sub> (H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-OH), has been shown
to attenuate signs of hyperalgesia in diabetic mice, which indicate
a possible use of compounds targeting the SP<sub>1–7</sub> binding
site as analgesics for neuropathic pain. Aiming at the development
of drug-like SP<sub>1–7</sub> peptidomimetics we have previously
reported on the discovery of H-Phe-Phe-NH<sub>2</sub> as a high affinity
lead compound. Unfortunately, the pharmacophore of this compound was
accompanied by a poor pharmacokinetic (PK) profile. Herein, further
lead optimization of H-Phe-Phe-NH<sub>2</sub> by substituting the
N-terminal phenylalanine for a benzylcarbamate group giving a new
type of SP<sub>1–7</sub> analogues with good binding affinities
is reported. Extensive <i>in vitro</i> as well as <i>in vivo</i> PK characterization is presented for this compound.
Evaluation of different C-terminal functional groups, i.e., hydroxamic
acid, acyl sulfonamide, acyl cyanamide, acyl hydrazine, and oxadiazole,
suggested hydroxamic acid as a bioisosteric replacement for the original
primary amide
Solid dispersions enhance solubility, dissolution, and permeability of thalidomide
<p>Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire<sup>®</sup> 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor<sup>®</sup> TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several <i>in vitro</i> techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2–3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.</p