Your browser doesn't support javascript.
loading
Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.
Alhalaweh, Amjad; Bergström, Christel A S; Taylor, Lynne S.
Afiliação
  • Alhalaweh A; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN, 47907, United States.
  • Bergström CAS; Department of Pharmacy, Uppsala University, Uppsala Biomedical Centre, P.O. Box 580, SE-751 23 Uppsala, Sweden.
  • Taylor LS; Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, West Lafayette, IN, 47907, United States. Electronic address: lstaylor@purdue.edu.
J Control Release ; 229: 172-182, 2016 05 10.
Article em En | MEDLINE | ID: mdl-27006280
ABSTRACT
Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 11 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 111 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores da Protease de HIV / Ritonavir / Lopinavir / Sulfato de Atazanavir Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Control Release Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Inibidores da Protease de HIV / Ritonavir / Lopinavir / Sulfato de Atazanavir Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: J Control Release Ano de publicação: 2016 Tipo de documento: Article