title: Development of a long-acting injectable formulation with nanoparticles of rilpivirine (TMC278) for HIV treatment.
abstract: Long-acting parenteral formulations of antiretrovirals could facilitate maintenance and prophylactic treatment in HIV. Using the poorly water- and oil-soluble non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC278 (rilpivirine) as base or hydrochloride (HCl), nanosuspensions were prepared by wet milling (Elan NanoCrystal technology) in an aqueous carrier. Laser diffraction showed that the average particles size were (1) close to the targeted size proportionality (200-400-800 nm), with increasing distributions the larger the average particle size, and (2) were stable over 6 months. Following single-dose administration, the plasma concentration profiles showed sustained release of TMC278 over 3 months in dogs and 3 weeks in mice. On comparison of intramuscular and subcutaneous injection of 5mg/kg (200 nm) in dogs, the subcutaneous route resulted in the most stable plasma levels (constant at 25 ng/mL for 20 days, after which levels declined slowly to 1-3 ng/mL at 3 months); 200 nm nanosuspensions achieved higher and less variable plasma concentration profiles than 400 and 800 nm nanosuspensions. In mice, the pharmacokinetic profiles after a single 20mg/kg dose (200 nm) were similar with two different surfactants used (poloxamer 338, or d-alpha-tocopheryl polyethylene glycol 1000 succinate). In conclusion, this study provides proof-of-concept that 200-nm sized TMC278 nanosuspensions may act as long-acting injectable.
authors.affiliation: Tibotec bvba, Gen. De Wittelaan L11B 3, 2800 Mechelen, Belgium. lbaert@its.jnj.com
authors.forename: Lieven
authors.initials: L
authors.lastname: Baert
authors.forename: Gerben
authors.initials: G
authors.lastname: van 't Klooster
authors.forename: Willy
authors.initials: W
authors.lastname: Dries
authors.forename: Marc
authors.initials: M
authors.lastname: François
authors.forename: Alfons
authors.initials: A
authors.lastname: Wouters
authors.forename: Esther
authors.initials: E
authors.lastname: Basstanie
authors.forename: Koen
authors.initials: K
authors.lastname: Iterbeke
authors.forename: Fred
authors.initials: F
authors.lastname: Stappers
authors.forename: Paul
authors.initials: P
authors.lastname: Stevens
authors.forename: Laurent
authors.initials: L
authors.lastname: Schueller
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Remoortere
authors.forename: Guenter
authors.initials: G
authors.lastname: Kraus
authors.forename: Piet
authors.initials: P
authors.lastname: Wigerinck
authors.forename: Jan
authors.initials: J
authors.lastname: Rosier