Ovulation inhibition with a new vaginal ring containing trimegestone.

OBJECTIVES: The primary objective was to determine the lowest trimegestone (TMG) dose, administered via a vaginal ring, that effectively inhibited ovulation. STUDY DESIGN: Single-centre, open-label, single-dose, parallel-group clinical trial with adaptive design. Eighty healthy female volunteers with proven ovulatory cycles were allocated to treatment with a vaginal ring during 28 days, with an average daily release rate of either 46 µg, 94 µg, 147 µg, or 184 µg TMG (20 women/group). Ultrasound measurements of follicular growth and endometrial thickness, and blood sampling for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone determinations were performed every 3rd (±1) day from treatment day 4 (±1) until day 28 (±1), and in a follow-up phase after ring removal, until study day 39 (±1). Trimegestone concentrations were measured at each visit in the treatment phase. RESULTS: Mean age and body mass index were 28.8 years and 23.15 kg/m2. One subject in the lowest dose group (46 µg/day) ovulated, no ovulations were seen in the higher dose groups. The degree of ovarian suppression increased with the dose. Median estradiol levels were 119, 36.5, 33.2 and 27.2 pg/mL in the 46, 94, 147 and 184 µg/day groups, respectively. Ovarian activity was resumed in the follow-up phase. Plasma TMG levels gradually declined over the treatment period and showed dose proportionality. The study treatment was safe and well tolerated. CONCLUSION: The release rate of 94 µg TMG per day was the lowest effective dose for ovulation inhibition. The study results justify further development of the TMG-ring as progestogen-only contraceptive. IMPLICATIONS: The vaginal ring releasing TMG seems to be an effective new progestogen-only contraceptive preparation, having the advantage of once-a-month vaginal insertion.

Establishment of a Molding Procedure to Facilitate Formulation Development for Co-extrudates.

Co-extrusion offers a number of advantages over conventional manufacturing techniques. However, the setup of a co-extrusion line is cost- and time-intense and formulation development is challenging. This work introduces a novel procedure to test the applicability of a co-extruded reservoir-type system at an early product development stage. We propose vacuum compression molding (VCM), a fast procedure that requires only small material amounts, for the manufacturing of cylindrical reservoir-type system. To this end, the commercially available co-extruded product NuvaRing® and variations thereof were used as test systems. All VCM systems showed a homogeneous skin thickness that adhered well to the core, thereby providing a precise core/skin interface. As drug release is a key criterion for pharmaceutical products, a modified in vitro dissolution method was set up to test the VCM systems. The drug release from the VCM systems was in the same order of magnitude as the corresponding co-extruded strands and followed the same release kinetics. Moreover, the VCM systems were capable of indicating the relative effect of formulation-related modifications on drug release. Overall, this shows that this system is a powerful tool that facilitates formulation tailoring and co-extrusion process setup at the earliest stage.

Long-term dietary high protein intake up-regulates tissue specific gene expression of uncoupling proteins 1 and 2 in rats.

BACKGROUND: The consequences of chronic high protein (HP) diets are discussed controversially and are not well understood. Rats adapted to HP exposure show an increased amino acid and fat oxidation and lower feed energy efficiency. We hypothesized that the dietary protein level can affect gene expression of uncoupling protein (UCP) homologues which is suggested to be involved in thermogenesis, substrate oxidation, and energy expenditure. AIM OF THE STUDY: To assess the mRNA expression of UCP homologues in various tissues of rats fed HP diets and to relate UCP gene expression to various parameters of substrate and energy metabolism. To obtain further indications for the possible involvement of UCP in reducing feed energy efficiency under conditions of HP exposure. METHODS: Adult rats were adapted to casein based diets containing either 13.8% (adequate, AP), 25.7% (medium, MP), or 51.3 % (high, HP) crude protein. Rats were fed for 8 wk and killed in the postabsorptive state. Energy expenditure and mRNA expression were measured using indirect calorimetry and Northern blot analysis, respectively. Pearson correlation coefficients were calculated to determine relationships between UCP mRNA expression and metabolic parameters. RESULTS: Hepatic UCP2 mRNA expression was increased by MP and HP diets compared to AP diet. In skeletal muscle UCP2 mRNA expression was lowest under MP conditions. UCP1 mRNA expression in brown adipose tissue (BAT) was significantly increased by HP exposure. The values were inversely associated with feed energy efficiency and positively with energy expenditure and oxygen consumption in the dark period. Skeletal muscle UCP2 and -3 mRNA expression strongly correlated with the plasma free fatty acid concentration, whereas BAT UCP1 and hepatic UCP2 gene expression did not. CONCLUSIONS: Our results indicate that hepatic UCP2 and BAT UCP1 mRNA expression is related to the level of dietary protein intake. This suggests a role of UCPs in substrate oxidation and in thermogenesis under conditions of HP exposure.