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Titre du document / Document title

Powder for reconstitution of the anti-HIV-1 drug TMC278 -Formulation development, stability and animal studies

Auteur(s) / Author(s)

VAN GYSEGHEM Elke (1) ; PENDELA Murali (2) ; BAERT Lieven (3) ; ROSIER Jan (3) ; VAN 'T KLOOSTER Gerben (4) ; DE MAN Hilde (5) ; BOUCHE Marie-Paule (6) ; SCHUELLER Laurent (3) ; VAN REMOORTERE Pieter (3) ; WIGERINCK Piet (7) ; ADAMS Erwin (2) ; HOOGMARTENS Jos (2) ; VAN DEN MOOTER Guy (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Laboratorium voor Farmacotechnologie en Biofarmacie, Katholieke Universiteit Leuven, Leuven, BELGIQUE
(2) Laboratodum voor Farmaceutische Analyse, Katholieke Universiteit Leuven, Leuven, BELGIQUE
(3) Chem-Pharm Development, Tibotec BVBA, Mechelen, BELGIQUE
(4) Preclinical Development, Tibotec BVBA, Mechelen, BELGIQUE
(5) Drug Metabolism and Pharmacokinetics, Johnson &Johnson Pharmaceutical Research & Developmen, Beerse, BELGIQUE
(6) Bioanalysis, Jolinson & Johnson Pharmaceutical Research & Development, Beerse, BELGIQUE
(7) Galapagos NV, Mechelen, BELGIQUE

Résumé / Abstract

Powders for reconstitution of the next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 with low water solubility were developed by using a spray-dry technology. Their flexible dosing ability makes them suitable for patients looking for a different approach for antiretroviral (ARV) therapy. The selection of formulation excipients was based on their potential to create and maintain supersaturation solubility of TMC278 in 0.01 M HCl. Suitable water-soluble carriers for TMC278 were selected by a supersaturation screening to formulate powders for reconstitution by spray-drying. The selected powders for reconstitution were compared to clinical tablets of TMC278.HCl, in vitro using dissolution and stability testing, and in vivo through administration to beagle dogs, fed immediately after dosing. The spray-dried powders for reconstitution made up of TMC278/PVP-VA 64 1:9 (w/w) and TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w) showed ease of suspendability, nearly complete dissolution of the drug and acceptable stability after one month storage at 25 and 40 °C. In dogs, TMC278 was more slowly absorbed from tablets than from the suspended powders for reconstitution. Compared to the tablet, the relative bioavailability obtained with the powders ranged between 69% and 89% for TMC278/PVP-VA 64 1:9 (w/w) and between 85% and 157% for TMC278/PVP-VA 64/Cremophor EL 1:8.5:0.5 (w/w/w). The absence of differences in vivo and in vitro between the powders made an eventual choice very difficult, yet their advantageous in vivo behaviour and flexible dosing possibility may provide a starting point for paediatric formulations.

Revue / Journal Title

European journal of pharmaceutics and biopharmaceutics    ISSN  0939-6411 

Source / Source

2008, vol. 70, no3, pp. 853-860 [8 page(s) (article)] (14 ref.)

Langue / Language

Anglais
Revue : Anglais

Editeur / Publisher

Elsevier, Amsterdam, PAYS-BAS  (1991) (Revue)

Mots-clés anglais / English Keywords

Physicochemical properties

;

Virus

;

Retroviridae

;

Lentivirus

;

Human immunodeficiency virus

;

Pharmaceutical technology

;

Pharmacokinetics

;

Bioavailability

;

Oral administration

;

Dissolution

;

Screening

;

Supersaturation

;

Animal

;

Stability

;

Formulation

;

Drug

;

Research and development

;

HIV-1 virus

;

Antiretroviral agent

;

Antiviral

;

Powder

;

Mots-clés français / French Keywords

Propriété physicochimique

;

Virus

;

Retroviridae

;

Lentivirus

;

Virus immunodéficience humaine

;

Technologie pharmaceutique

;

Pharmacocinétique

;

Biodisponibilité

;

Voie orale

;

Dissolution

;

Criblage

;

Sursaturation

;

Animal

;

Stabilité

;

Formulation

;

Médicament

;

Recherche et développement

;

Virus HIV1

;

Antirétroviral

;

Antiviral

;

Poudre

;

Mots-clés espagnols / Spanish Keywords

Propiedad fisicoquímica

;

Virus

;

Retroviridae

;

Lentivirus

;

Human immunodeficiency virus

;

Tecnología farmacéutica

;

Farmacocinética

;

Biodisponibilidad

;

Vía oral

;

Disolución

;

Cernido

;

Sobresaturación

;

Animal

;

Estabilidad

;

Formulación

;

Medicamento

;

Investigación desarrollo

;

HIV-1 virus

;

Antiretroviral

;

Antiviral

;

Polvo

;

Mots-clés d'auteur / Author Keywords

TMC278

;

Powder for reconstitution

;

Supersaturation screening

;

Dissolution

;

Oral bioavailability

;

Localisation / Location

INIST-CNRS, Cote INIST : 17483, 35400018452467.0210

Nº notice refdoc (ud4) : 20873566



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