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.
Désévaux
Cyril
C
Faculty of Pharmacy, University of Montreal, C.P. 6128, Quebec, H3C 3J7, Montreal, Canada. cyril.desevaux@umontreal.ca
Girard
Christiane
C
Lenaerts
Vincent
V
Dubreuil
Pascal
P
D000818:Animals; D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D004343:Drug Implants; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D013213:Starch / Q000008:administration & dosage / Q000009:adverse effects*; D013552:Swine
D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D004343:Drug Implants; D007334:Insulin-Like Growth Factor I; D013213:Starch; D013007:Growth Hormone-Releasing Hormone