PURPOSE: This study characterizes the in vivo properties of an in situ forming gel, comprising of IPC of water-soluble polymers, PMA and PEG, for sustained release of macromolecular drugs. METHODS: 40, 50, or 60% w/v formulations were injected subcutaneously in a rat model either alone, or containing model macromolecules, 3A2-ATG-psODN or REV-psODN, to (i) determine the approximate gelling and residence time of the gel at the site of injection (ii) assess the biological efficacy of the formulation using a MZ sleep time model and (iii) demonstrate specificity of the sequence and selectivity of the psODNs by measuring changes in microsomal enzyme levels and urine volumes. RESULTS: A sol to gel transition requires 15 min in vivo, and the 60% w/v IPC gel remains at the site of injection for up to 72 hr. The MZ sleep times and CYP3A2 expression due to 3A2-ATG-psODNs released from the gel are significantly different compared to that of REV-psODNs. CONCLUSIONS: The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .
PURPOSE: This study characterizes the in vivo properties of an in situ forming gel, comprising of IPC of water-soluble polymers, PMA and PEG, for sustained release of macromolecular drugs. METHODS: 40, 50, or 60% w/v formulations were injected subcutaneously in a rat model either alone, or containing model macromolecules, 3A2-ATG-psODN or REV-psODN, to (i) determine the approximate gelling and residence time of the gel at the site of injection (ii) assess the biological efficacy of the formulation using a MZ sleep time model and (iii) demonstrate specificity of the sequence and selectivity of the psODNs by measuring changes in microsomal enzyme levels and urine volumes. RESULTS: A sol to gel transition requires 15 min in vivo, and the 60% w/v IPC gel remains at the site of injection for up to 72 hr. The MZ sleep times and CYP3A2 expression due to 3A2-ATG-psODNs released from the gel are significantly different compared to that of REV-psODNs. CONCLUSIONS: The IPC solutions exhibit phase transformation in vivo. and demonstrate no evidence of toxicity. The pharmacological effects observed from the of release of 3A2-ATG-psODNs suggest that the formulation can entrap, protect, and sustain the delivery of macromolecules. .
Authors: J P Desjardins; B S Sproat; B Beijer; M Blaschke; M Dunkel; W Gerdes; J Ludwig; V Reither; T Rupp; P L Iversen Journal: J Pharmacol Exp Ther Date: 1996-09 Impact factor: 4.030
Authors: K E Thummel; D O'Shea; M F Paine; D D Shen; K L Kunze; J D Perkins; G R Wilkinson Journal: Clin Pharmacol Ther Date: 1996-05 Impact factor: 6.875
Authors: M F Paine; D D Shen; K L Kunze; J D Perkins; C L Marsh; J P McVicar; D M Barr; B S Gillies; K E Thummel Journal: Clin Pharmacol Ther Date: 1996-07 Impact factor: 6.875