No abstract

An interesting multicomponent crystal consisting of drug–drug combination was synthesized. The multidrug crystals consisted of antidiabetic drugs glicalzide and metformin. Single crystal X-ray structure analysis revealed that this multicomponent crystal is salt-type multicomponent crystal. The physicochemical properties of this crystal were significantly different from those of the parent drugs. The multicomponent crystal showed impressive solubility and dissolution rate compared to that of the raw material of gliclazide. Also, the hygroscopicity issue in metformin was tackled by the formation of multicomponent crystal. These physicochemical property alterations were associated with the existence of hydrophilic channel structure, which was confirmed by microscopic analysis. Therefore, the weaknesses of each component were mutually solved.

Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood-brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [(3)H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5 microM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, K(t), was 2.99+/-0.71 mM; the maximum uptake rate, J(max), was 0.477+/-0.083 micromol/min/g brain; and the nonsaturable first-order rate constant, K(d), was 0.160+/-0.044 ml/min/g brain. The uptake of [(3)H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H(1)-antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [(3)H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L-carnitine or substrates for organic anion transport systems such as p-aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH-dependent and saturable influx transport system that is a selective transporter for cationic H(1)-antagonists is involved in the BBB transport of naloxone in the rat.