Rational design and development of a stable liquid formulation of riluzole and its pharmacokinetic evaluation after oral and IV administrations in rats.
Eur J Pharm Sci
; 125: 1-10, 2018 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-30201516
ABSTRACT
Enterally administered riluzole is currently being investigated in a Phase II/III clinical trial for the treatment of acute spinal cord injury (SCI). Many SCI patients suffer from severe motor dysfunction and exhibit swallowing difficulties and cannot swallow riluzole tablets. The purpose of the present study was to develop a liquid solution formulation of riluzole, which can be administered more easily to this patient population with the capability to adjust the dose if needed. Riluzole was solubilized using water miscible organic solvents, namely, polyethylene glycol 400, propylene glycol and glycerin. A Central Composite Design (CCD) approach was used to develop an optimum co-solvent composition that can solubilize the entire 50â¯mg dose of riluzole in 5â¯ml. A three-factor five-level design was employed to investigate the effects of composition of co-solvents on riluzole solubility. The selected optimum formulation consists of 15% v/v PEG 400, 20% v/v propylene glycol and 10% v/v glycerin, with riluzole concentration of 10â¯mg/ml. The optimum composition was assessed for stability at different temperatures. Satisfactory stability was obtained at room temperature and 4⯰C (t90 of 17 and 35â¯months, respectively). The optimum formulation of riluzole was suitable for both oral and intravenous administrations. Single dose pharmacokinetic studies of the optimum formulation by oral and IV routes were evaluated in rats, using commercially available Rilutek® tablets as a reference. The co-solvent formulation was well tolerated both orally and intravenously. In comparison to the commercial tablet, the co-solvent formulation had a faster rate of absorption and more sustained plasma levels with a significantly longer elimination half-life. Higher concentrations of riluzole in brain and spinal cord were achieved from co-solvent formulation as compared to tablet. The riluzole solution formulation is stable and offers advantages of ease of administration, consistent dosing, rapid onset and longer duration of action, better availability at site of action which can be extremely beneficial for the therapy in SCI patients.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Antagonistas de Aminoácidos Excitatórios
/
Riluzol
/
Bloqueadores dos Canais de Sódio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2018
Tipo de documento:
Article