Cyril Désévaux

Characterization of crosslinked high amylose starch matrix implants: 1. In vitro release of ciprofloxacin

The objective of this study was to characterize in vitro the potential of crosslinked high amylose starch (CLHAS) as an implant matrix for the delivery of ciprofloxacin (CFX). Direct compression of dry blends of four different matrices: control CLHAS; CLHAS with 1% hydrogenated vegetable oil (HVO); and CLHAS with 10 or 20% hydroxypropylmethylcellulose (HPMC), each of them with three CFX loadings (2.5, 5.0 and 7.5%) was performed to prepare twelve implant formulations. All CLHAS implants were used for 24-h dissolution tests to evaluate swelling, erosion, water uptake and CFX release. Additionally, 1%-HVO- CLHAS implants were used for an extended dissolution test. The presence of HPMC in the matrix increased CFX release rate, swelling, erosion and water uptake in a concentration-dependent manner whereas HVO had no effect. With increasing drug loading, a decrease of cumulative CFX percent release was observed in both 24-h and extended dissolution tests. Of the different formulations tested, CLHAS implants with 1% HVO and 7.5% CFX provided the longest period of drug delivery without any initial burst effect.

Characterization of subcutaneous Contramid® implantation: host response and delivery of a potent analog of the growth hormone-releasing factor

Cross-linked high amylose starch (Contramid) was investigated as a solid implant for evaluation of host response in mice and as a possible delivery system for a human growth hormone-releasing factor analog (Hex-hGRF) release profile in pigs. Seventy mice were administered subcutaneously one 3 mm diameter Contramid pellet and host reaction was evaluated over 6 months. Thirty pigs were divided into four groups. All animals of the three implanted groups were administered subcutaneously 15 mg Hex-hGRF, (1) one pure Hex-hGRF implant; (2) four 30/70 w/w Hex-hGRF/Contramid implants; or (3) eight 15/85 w/w Hex-hGRF/Contramid implants. The fourth group (n=6) was injected subcutaneously twice daily with 10 microg/kg of Hex-hGRF over 5 consecutive days. Serum insulin-like growth factor-I (IGF-I) was monitored over 1 month. In mice, no adverse reaction occurred after implantation. Macroscopic and microscopic inflammatory reactions were always localized. Polymorphonuclear cells (PMNs) and macrophages predominated within and around the pellets, respectively. Thin fibrovascular septas eventually subdivided Contramid pellets which were progressively phagocytosed by macrophages. In pigs, serum IGF-I concentrations were increased over a 10 day period in all implanted groups. The initial IGF-I peak observed in the daily injected group was avoided in both Contramid implant groups but not in the pure Hex-hGRF implant group. These encouraging results warrant the development of Contramid implants as a sustained delivery system for peptidic drugs.

Growth Hormone-Releasing Factor: Structural Modification or Protection for More Potent Analogs

Growth hormone-releasing factor was discovered in 1982 by Guillemin and has been subjected to intense investigations because of its huge potential applications. The major concerns encountered with the native molecules were their short half-lives in vivo in many species including man, precluding the practical use of these peptides for medical or production purposes. Many efforts to produce analogs of shorter length, more resistant to degradation and having higher affinity to the receptors have been made during the last decades. The present paper presents a quick review of the work done to produce such analogs.