title: Evaluation of exposure properties after injection of nanosuspensions and microsuspenions into the intraperitoneal space in rats.
abstract: In the present paper, BA99 and AC88 were used as model compounds for intraperitoneal (i.p.) administration to Sprague-Dawley rats. A major problem for the compounds, like many others newly developed pharmaceutical drugs, is the poor solubility in water. To solve solubility related problems, development of nanosuspensions is an attractive alternative. Both compounds are suitable for nanosuspensions, using the milling approach. After 2 weeks in freezer, the nanoparticles aggregated to form particles in the 400-2000 nm interval. However, following a 20 s ultrasonication step, the original particle sizes (about 200 nm) were obtained. Adding 5% mannitol before the samples were frozen abolished aggregation. It is also possible to freeze-dry the nanosuspension in the presence of 5% mannitol and re-disperse the formulation in water. Nanosuspensions of both compounds were injected i.p. to rats at 5 and 500 µmoL/kg. At the low dose, also a microsuspension was administered. I.p. administration resulted in overall improved C(max) for both AC88 and BA99 compared to s.c. and oral administration. I.p. is the preferred route of administration of tolerable drugs when a fast onset of action is desired and when a significant first passage metabolism occurs. The net charge of the active molecule appeared to affect the absorption kinetics. In the present work, the neutral molecule was favored over the negatively charged one.
authors.affiliation: Pharmaceutical Development, AstraZeneca R&D Mölndal , Mölndal , Sweden.
authors.forename: Kalle
authors.initials: K
authors.lastname: Sigfridsson
authors.forename: Anders
authors.initials: A
authors.lastname: Lundqvist
authors.forename: Marie
authors.initials: M
authors.lastname: Strimfors
mesh_terms: D000818:Animals; D055598:Chemical Phenomena; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics; D004339:Drug Compounding; D016503:Drug Delivery Systems; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000032:analysis / Q000737:chemistry / Q000493:pharmacokinetics*; D005079:Excipients / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007274:Injections, Intraperitoneal; D007700:Kinetics; D008958:Models, Molecular; D049329:Nanostructures / Q000737:chemistry*; D010316:Particle Size; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013010:Sonication; D013535:Suspensions
chemical_list: D004337:Drug Carriers; D015507:Drugs, Investigational; D005079:Excipients; D013535:Suspensions