In vitro and in vivo release of dinalbuphine sebacate extended release formulation: Effect of the oil ratio on drug release.

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Dinalbuphine sebacate (DNS) is a prodrug of nalbuphine for which we have developed long-acting lipophilic formulations in a benzyl benzoate/sesame oil mixture for intramuscular (IM) injection. In this study, we found that the in vitro release profile of DNS could be affected by adjusting the weight ratio of benzyl benzoate to sesame oil (the solvent/oil ratio). A longer release period could be attained by increasing the solvent/oil ratio in the formulation. A pharmacokinetic study was conducted in beagle dogs to verify the relationship between the in vitro release and the drug release from the formulations in vivo. The pharmacokinetic study confirmed that the formulation with a higher benzyl benzoate to oil ratio exhibits a longer drug release profile with a lower maximum concentration (Cmax) and a longer time to peak blood concentration level (Tmax) than the formulation with a lower benzyl benzoate to oil ratio.

Pharmacokinetics of dinalbuphine sebacate and nalbuphine in human after intramuscular injection of dinalbuphine sebacate in an extended-release formulation.

Nalbuphine is a semi-synthetic opioid indicated for the relief of moderate to severe pain. Its short half-life requires frequent injections in clinical practice, resulting in a greater incidence of adverse events. A prodrug of nalbuphine has been developed, dinalbuphine sebacate (DNS), dissolved in a simple oil-based injectable formulation, which could deliver and maintain an effective blood level of nalbuphine. An open-label, prospective, two-period study was performed in healthy volunteers to verify the extended blood concentration profile of nalbuphine. Twelve healthy Taiwanese were randomized to receive an intramuscular injection of 20 mg nalbuphine HCl and 150 mg DNS sequentially with a washout period of 5 days. To prevent DNS hydrolysis during sample analysis, the effect of four esterase inhibitors was evaluated in the quantitation of DNS in human whole blood and thenoyltrifluoroacetone was chosen. The bioavailability of nalbuphine from intramuscularly injected DNS relative to that from nalbuphine HCl was 85.4%. The mean absorption time of nalbuphine from DNS was 145.2 h. It took approximately 6 days for the complete release of DNS into the blood stream where DNS was rapidly hydrolysed to nalbuphine; suggesting a single injection of 150 mg DNS in our extended-release formulation could provide long-lasting pain relief.

Pharmacokinetics and protein binding of MPT0B292.

MPT0B292 was identified through screening of compounds able selectively to acetylate α-tubulins in cells and it exhibited potent anti-tumor, anti-angiogenesis and anti-metastatic effects in vitro and in vivo. Because of its poor water solubility, MPT0B292 is difficult to formulate with conventional approaches and hence difficulties are experienced in research practices. MPT0B292 was mixed with albumin in an aqueous solvent to form drug albumin nanoparticles with a size range around 333 nm. Unbound fractions of these nanoparticles were investigated in different or the same albumin concentration solutions. Unlike most drugs, the binding of MPT0B292 in human serum albumin increased with increasing drug concentrations. An analytical method was also developed and validated to determine MPT0B292 in rat plasma. This analytical method was applied successfully to the intravenous pharmacokinetic study of MPT0B292 in rats. A single dose study was regularly done to characterize the pharmacokinetic properties of the drug. Additionally, a novel i.v. infusion study was carried out to verify the extraction ratio of MPT0B292. The pharmacokinetic analysis revealed that MPT0B292 was a high extraction ratio drug with high systemic clearance, a high volume of distribution and a short half-life in rats. Copyright © 2017 John Wiley & Sons, Ltd.

Studies on pharmacokinetic mechanism of phenytoin resistance in refractory epilepsy.

P-glycoprotein (P-gp) is a drug efflux pump in many organs, including the intestine and liver. Two single nucleotide polymorphisms (SNPs) of P-gp gene, 2677G>T and 3435C>T, were reported to influence function and expression of P-gp and have the controversial effects on drug disposition. Phenytoin is one substrate of P-gp. Persistent low phenytoin levels in plasma and P-gp overexpression in brain in several refractory epilepsy patients were reported. P-gp polymorphisms may also affect phenytoin efficacy by altering its bioavailability (F). Because two P-gp SNPs, 2677G>T and 3435C>T, may affect P-gp expression in tissue, we examined phenytoin disposition in patients of different P-gp haplotypes, G/G2677C/C3435 and T/T2677T/T3435. We found that the mean absolute F of phenytoin in T/T2677T/T3435 subjects (91%) is slightly higher than in G/G2677C/C3435 subjects (82%). There was no difference in the maximum concentration (Cmax ) and the area under the serum concentration-time curve of phenytoin administered orally between two genotypic groups. However, the time of maximum concentration was higher in T/T2677T/T3435 subjects (10 h) than in G/G2677C/C3435 subjects (6 h). The study ruled out the possibility that genetic polymorphisms of P-gp may affect phenytoin efficacy through the decreased absorption or the increased elimination. P-gp SNPs could affect phenytoin efficacy in refractory epilepsy patients probably because of central nervous system.