Valproic acid-hydrophilic cyclodextrin complexes and valproic acid-solid dispersions: evaluation of their potential pharmaceutical use.
The purpose of this study was to evaluate the potential use of two novel solid formulations of valproic acid (VPA) prepared by complexation with hydrophilic cyclodextrins (CDs) as hydroxypropyl-beta- and sulfobutylether-beta-cyclodextrin and by solid dispersion (SD) in hydrophilic carriers as polyethylene glycol 6000 (PEG 6000) and polyvinylpyrrolidone K-30 (PVP K-30). The corresponding cyclodextrin-based complexes were prepared by the freeze-drying method while the solid dispersions were obtained by the solvent method. Valproic acid solubility improved by CDs complexation and solid dispersion techniques. Comparison of dissolution profiles with that of VPA sodium salt (NaVP) was made by using release parameters such as dissolution efficiency, percent of drug dissolved after 60 min, and difference and similarity factors. Based on difference and similarity factors, it can be concluded that all the VPA formulations possess dissolution profiles essentially equivalent to those of NaVP at pH 6. However, this conclusion is not confirmed by using the analysis of variance (ANOVA) approach, indicating some significant differences between some SD-based formulations and NaVP at that pH value. Preliminary pharmacological studies in the pentylenetetrazole test in rats showed some important differences among the SD-based formulations, NaVP, and VPA as oil/water emulsion. Some implications and limitations of the investigated formulations are discussed.
Trapani
G
G
Dipartimento Farmaco-Chimico, Facoltà di Farmacia, Università degli Studi di Bari, Bari, Italy. xtrapani@farmchim.uniba.it
Cutrignelli
A
A
Latrofa
A
A
Franco
M
M
Serra
M
M
Pisu
M G
MG
Biggio
G
G
Liso
G
G
D000465:Algorithms; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D002152:Calorimetry, Differential Scanning; D002851:Chromatography, High Pressure Liquid; D003292:Convulsants; D003505:Cyclodextrins / Q000737:chemistry*; D004337:Drug Carriers; D005079:Excipients; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010433:Pentylenetetrazole; D011092:Polyethylene Glycols; D011205:Povidone; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014635:Valproic Acid / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology
D000927:Anticonvulsants; D003292:Convulsants; D003505:Cyclodextrins; D004337:Drug Carriers; D005079:Excipients; D011092:Polyethylene Glycols; D014635:Valproic Acid; D011205:Povidone; D010433:Pentylenetetrazole