Potent dried drug nanosuspensions for oral bioavailability enhancement of poorly soluble drugs with pH-dependent solubility

• Published in: International journal of pharmaceutics 2011-07, Vol.413 (1), p.237-244
• Main Authors: Mou, Dongsheng, Chen, Huabing, Wan, Jiangling, Xu, Huibi, Yang, Xiangliang
• Format: Article
• Language: English
• Subjects: Acid–base neutralization; Administration, Oral; adsorption; Animals; Antifungal Agents - administration & dosage; Antifungal Agents - blood; Antifungal Agents - chemistry; Antifungal Agents - pharmacokinetics; bioavailability; Biological and medical sciences; Biological Availability; Desiccation; Dried drug nanosuspensions; Drug Compounding - methods; Drug Delivery Systems - methods; drugs; Excipients - chemistry; food intake; General pharmacology; Hydrogen-Ion Concentration; Hypromellose Derivatives; itraconazole; Itraconazole - administration & dosage; Itraconazole - blood; Itraconazole - chemistry; Itraconazole - pharmacokinetics; Mannich Bases - chemistry; Medical sciences; Methylcellulose - analogs & derivatives; Methylcellulose - chemistry; Nanoparticles - chemistry; Nanosuspensions; neutralization; oral administration; Oral bioavailability enhancement; Particle Size; pellets; Ph-dependent solubility; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Poloxamer - chemistry; Poorly soluble drugs; Rats; Rats, Wistar; small intestine; Solubility; spray drying; stabilizers; Suspensions - chemistry
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2011.04.034

The objective of this study was to enhance the oral bioavailability of itraconazole (ITZ) with dried drug nanosuspensions. The feasibility of using poloxamer 407 or HPMC (50 cp) as stabilizers for preparing ITZ nanosuspensions by facile acid–base neutralization was investigated. Dried ITZ nanosuspensions were prepared by spray drying. The effect of matrix former on the dissolution rate of dried ITZ nanosuspensions was investigated. Results from dissolution test revealed that spray-dried ITZ nanosuspensions (ITZ:HPMC:mannitol 1:0.5:2, w/w) preserved the high dissolution rate from nanosuspensions. After oral administration in rats, the AUC 0–36 from dried ITZ nanosuspensions was 1.5-fold and 1.8-fold higher than the AUC 0–36 from sporanox pellets (commercial product) in the fed and fasted states, respectively ( p < 0.05). More importantly, the AUC 0–36 from dried ITZ nanosuspensions showed no difference between fed/fasted states, because this formulation could enhance the adsorption of ITZ in target site (small intestine) regardless of food intake. In addition, dried ITZ nanosuspensions showed a lower inter-individual variability in terms of bioavailability. Positive results demonstrate that dried drug nanosuspensions formulation prepared by acid–base neutralization combined with spray drying may be a promising method for enhancing the oral bioavailability of poorly soluble drugs with pH-dependent solubility.