Etodolac/cyclodextrin formulations: physicochemical characterization and in vivo pharmacological studies.
BACKGROUND
The formulation of nonsteroidal anti-inflammatory drugs with cyclodextrins (CDs) has demonstrated to be a suitable strategy to increase drug aqueous solubility, dissolution rate, and gastric tolerance.


OBJECTIVE
We investigated the effects of the CDs on the physicochemical and pharmacological properties of Etodolac (ET), a practically water-insoluble nonsteroidal anti-inflammatory drug, to individuate a drug formulation with optimized pharmacokinetics and pharmacodynamics.


METHODS
The interactions in solution of ET with beta-CD, hydroxypropyl-beta-CD (HP-beta-CD), and gamma-CD were studied by (13)C-NMR spectroscopy and phase solubility method. Solid binary systems, prepared by physical mixing and freeze-drying, were characterized by differential scanning calorimetry, X-ray analysis and Fourier transform infrared spectroscopy, and dissolution studies. An in vivo pharmacological investigation (analgesic activity and gastric tolerance studies) was performed on freeze-dried ET/CD formulations.


RESULTS
(13)C-NMR and phase solubility studies demonstrated the ability of CDs to complex with ET and increase drug solubility. ET/CD interactions at the solid state occurred at the molecular level only for freezed-dried samples. All binary systems, mainly those containing HP-beta-CD and gamma -CD, showed a significantly improved dissolution profile of ET. In vivo pharmacological studies evidenced an improvement of analgesic activity and a reduction of gastrolesivity of ET/CD-tested formulations with respect to ET alone.


CONCLUSIONS
The formulation of ET with CDs demonstrates relevant pharmaceutical potential in view of decreasing dose and side effects of ET. For industrial applications, HP-beta-CD appears to be the best partner for ET, as it is less expensive than gamma-CD and gives rise to higher drug solubilization than beta-CD.
Cappello
Brunella
B
Dipartimento di Chimica Farmaceutica e Tossicologica, Università degli Studi di Napoli Federico II, Napoli, Italy. cappello@unina.it
di Maio
Clelia
C
Iervolino
Maria
M
Miro
Agnese
A
Calignano
Antonio
A
D000818:Animals; D055598:Chemical Phenomena; D002626:Chemistry, Pharmaceutical; D003505:Cyclodextrins / Q000737:chemistry* / Q000494:pharmacology*; D017308:Etodolac / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
D003505:Cyclodextrins; D017308:Etodolac