Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.
Mol Pharm
; 19(11): 3846-3857, 2022 11 07.
Article
em En
| MEDLINE
| ID: mdl-36047719
ABSTRACT
Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Esquizofrenia
/
Antipsicóticos
/
Pró-Fármacos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Mol Pharm
Assunto da revista:
BIOLOGIA MOLECULAR
/
FARMACIA
/
FARMACOLOGIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China