Sascha General

Evaluation of the in vitro release and pharmacokinetics of parenteral injectable formulations for steroids.

The aim of this study was to investigate the pharmacokinetics of injectable conventional dosage forms containing steroids. First, the in vitro release of drospirenone (DRSP) microcrystal suspensions (MCSs) was studied. Next, the pharmacokinetics of selected subcutaneously injected DRSP MCSs was analyzed in female Wistar rats and Cynomolgus monkeys. Furthermore, in vivo and in vitro results were fitted to mathematical models. Although the in vitro-in vivo correlation was partially good, the predictability of the in vitro test was assumed to be restricted. Nevertheless, mathematical calculations and in vitro results allow the interpretation of in vivo results and the identification of parameters influencing the drug release. DRSP microcrystal size had a marginal influence on the pharmacokinetics. The drug absorption was slower from aqueous MCSs than from peanut oil MCSs. Absorption profiles of aqueous DRSP MCSs correlated best with Hixson-Crowell model, whereas absorption profiles of oil-based DRSP MCSs showed a good fit to the Higuchi model. The established assumptions were used to interpret the pharmacokinetics of subcutaneously injected oil-based formulations of the steroid ZK28. In summary, low drug solubility in the vehicle and a high vehicle viscosity were assumed to result in slower and constant drug release.

Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release

Our aim was to investigate the in vitro release and combination of ethinyl estradiol (EE) and drospirenone (DRSP) drug-delivery systems. DRSP poly(lactic-co-glycolic acid) (PLGA) microparticles and organogels containing DRSP microcrystals were prepared and characterized with regard to properties influencing drug release. The morphology and release kinetics of DRSP PLGA microparticles indicated that DRSP is dispersed in the polymer. The in vitro release profiles correlated well with in vivo data. Although DRSP degradation is known to be acid-catalyzed, DRSP was relatively stable in the PLGA matrix. Aqueous DRSP PLGA microparticle suspensions were combinable with EE PLGA microparticles and EE poly(butylcyanoacrylate) (PBCA) microcapsules without interacting. EE release from PLGA microparticles was faster than DRSP release; EE release is assumed to be primarily controlled by drug diffusion. Liquid-filled EE PBCA microcapsules were shown to be more robust than air-filled EE PBCA microcapsules; the bursting of microcapsules accelerating the drug delivery was therefore delayed. The drug release profile for DRSP organogels was fairly linear with the square root of time. The system was not combinable with EE PBCA microcapsules. In contrast, incorporation of EE PLGA microparticles in organogels resulted in prolonged EE release. The drug release of EE and DRSP was thus approximated.

Parenteral oil-based drospirenone microcrystal suspensions—Evaluation of physicochemical stability and influence of stabilising agents

Drospirenone (DRSP) is a contraceptive drug substance with challenging physicochemical properties, due to insufficient solubility in aqueous and oil-based vehicles as well as low chemical stability in aqueous fluids. Although it is one of the most popular orally used progestins, no parenteral long-acting contraceptive containing the drug substance is marketed. An oil-based DRSP microcrystal suspension (MCS) might be an attractive formulation option. The main focus of this study was to investigate the physicochemical stability of such preparations. Moreover, syringeability and injectability via autoinjector were analysed using a materials testing machine. A high chemical stability of DRSP was found in oil-based vehicles. Span(®) 83, cholesteryl oleate, lecithin, methyl cholate, Aerosil(®) R972 and 200 Pharma were tested for increasing the physical stability of DRSP dispersions. Changes in viscosity, rheological properties, and solubility were analysed. The intention was to show a stabilising effect of the excipients without increasing viscosity and solubility. To evaluate the physical stability of DRSP MCS with and without addition of stabilising agents, sedimentation and particle growth after storage were examined. Especially, the silica derivatives Aerosil(®) 200 and R972 Pharma influenced the physical stability positively.