Evaluation of orntide microspheres in a rat animal model and correlation to in vitro release profiles

Abstract

Orntide acetate, a novel luteinizing hormone-releasing hormone (LHRH) antagonist, was prepared and evaluated in vivo in 30-day and 120-day sustained delivery formulations using a rat animal model. Orntide poly(d,l-lactide-co-glycolide) (PLGA) and poly(d,l-lactide) (PLA) microspheres were prepared by a dispersion method and administered subcutaneously in a liquid vehicle to rats at 2.2 mg Orntide/kg of body weight (30-day forms) or 8.8 mg Orntide/kg (120-day forms). Serum levels of Orntide and testosterone were monitored by radioimmunoassays, and a dose-response study at 4 doses (3, 2.25, 1.5, and 1.75 mg Orntide/kg) was conducted to determine the effective dose of Orntide. Microspheres with diameters between 3.9 and 14 µ were prepared. The onset and duration of testosterone suppression varied for different microsphere formulations and were influenced both by polymer properties and by microsphere characteristics. Microspheres prepared with 50:50 and 75:25 copolymers effectively sustained peptide release for 14 to 28 days, whereas an 85:15 copolymer and the PLA microspheres extended the pharmacological response for more than 120 days. Increase in drug load generally accelerated peptide release from the microspheres, resulting in higher initial serum levels of Orntide and shorter duration of the release. In general, apparent release was faster in vivo than under in vitro conditions. Orntide microspheres effectively suppressed testosterone in rats, providing rapid onset of release and extended periods of chemical castration. Testosterone suppression occurred immediately after microsphere administration without the initial elevation seen with LHRH superagonists.

Evaluation of mucoadhesive properties of chitosan microspheres prepared by different methods

“…[1][2][3][4][5][6] Mucoadhesive polymers may fulfill the desirable features of a prolonged residence time at the site of drug absorption owing to increased contact with the absorbing mucosa, resulting in a steep concentration gradient to favor drug absorption, and localization in specified regions to improve and enhance the bioavailability of the drug. 7 Factors such as cross-linking status, ionic modification, and salt formation can significantly influence the ability of a material to show substantial mucoadhesion in an in vitro system.…”

Microspheres in cancer therapy

“…Various microspheres are now available, and are used in various cancer treatments, such as, orntide poly(d,llactide-co-glycolide) and poly(d,l-lactide) microspheres, [59] a biodegradable poly(lactic acid) microsphere formulation for in-vivo cytokine immunotherapy of cancer, [60] paclitaxel loaded in PLGA microspheres, [61] polylactic co-glycolic acid microspheres in nanofibrous scaffolds have been shown to control the release of rhPDGF-BB (platelet-derived growth factor) in-vitro, [62] ethylcellulose microspheres containing 5-fluorouracil, [63] paclitaxel-sodium alginate microsphere, [64] yttrium silica sol-gel microspheres, [65] and microspheres labeled with holmium-166. [66] Drug eluting microspheres Chemoembolization with drug-eluting particles has been recently introduced in the field of interventional oncology.…”

Methods to Assess in Vitro Drug Release from Injectable Polymeric Particulate Systems

“…These include proteins such as lysozyme (75), bovine-derived superoxide dismutase (124), and peptides such as orntide (116,117), vapreotide (41), TRH (125,126), and small molecules such as methadone (74). SpragueYDawley (SYD) or Wistar species of the rat are the most commonly used models for in vivo experiments.…”

“…In these studies, the authors believed that in vivo release was faster because of higher solubility of the drug in serum than in a buffer system, presence of hydrolytic enzymes in vivo along with formation of acidic microenvironment, and effect of plasma proteins on degradation of polyesters (75,117). However, slower in vitro release with orntide PLGA microspheres could be due to use of a small dialysis membrane surface area, which would increase equilibration time and would be responsible for lower peptide diffusion rates (116,117). In the study with lysozyme PLGA microspheres and bSOD microspheres (Figs.…”