Pharmacokinetics and Tolerability of a Novel 17β-Estradiol and Progesterone Intravaginal Ring in Sheep

J Pharm Sci. 2019 Aug;108(8):2677-2684. doi: 10.1016/j.xphs.2019.03.032. Epub 2019 Apr 5.

Abstract

This study reports the preparation, in vitro release, pharmacokinetics, and local tolerability of novel ethylene-vinyl acetate intravaginal rings (IVRs) delivering 17β-estradiol (E2) and progesterone (P), in drug-naïve ovariectomized female Dorset crossbred sheep. After preparation and assessment of in vitro release of E2 and P, animals were randomized to treatment groups 1 or 2 (comparator rings releasing 50 or 100 μg/d E2, respectively), groups 3 or 4 (ethylene-vinyl acetate IVRs, 160 μg/d E2 with 4 [160/4 IVR] or 8 mg/d P [160/8 IVR], respectively), or group 5 (160 μg E2 and 10 mg P administered intravenously). IVRs were placed on day 1 and remained in place through day 29. Animals underwent daily examinations to confirm ring placement, and vaginal irritation was scored from 0 (none) to 4 (severe). Blood samples were taken at scheduled times for pharmacokinetic analysis. Postmortem examinations performed on groups 1-4 were macroscopic and microscopic evaluations, including irritation scoring and histopathology. IVRs were retained over 28 days in all but 1 animal (group 4). In all animal groups, clinical observations showed no significant abnormal findings. Pharmacokinetic analysis in the animals showed sustained release of E2 and P over a 28-day period. Irritation scores and microscopic assessments were consistent with foreign object placement. A novel 2-drug IVR delivery system was well tolerated in a sheep model and pharmacokinetic release was as expected over a 28-day release period. These results will guide future human clinical studies.

Keywords: 17β-estradiol; intravaginal ring; pharmacokinetics; progesterone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravaginal
  • Animals
  • Drug Delivery Systems / adverse effects
  • Drug Delivery Systems / methods
  • Estradiol / administration & dosage
  • Estradiol / pharmacokinetics*
  • Estrogens / administration & dosage
  • Estrogens / pharmacokinetics*
  • Ethylenes / chemistry
  • Female
  • Progesterone / administration & dosage
  • Progesterone / pharmacokinetics*
  • Progestins / administration & dosage
  • Progestins / pharmacokinetics*
  • Sheep
  • Vinyl Compounds / chemistry

Substances

  • Estrogens
  • Ethylenes
  • Progestins
  • Vinyl Compounds
  • Progesterone
  • Estradiol
  • ethylene
  • vinyl acetate