In Vivo Properties of an In Situ Forming Gel for Parenteral Delivery of Macromolecular Drugs |
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Authors: | Rajashree Joshi Vikram Arora John P. Desjardins Dennis Robinson Kenneth J. Himmelstein Patrick L. Iversen |
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Affiliation: | (1) Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska;(2) Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska;(3) Department of Pharmaceutical Sciences, University of Colorado Health Science Center, Denver, Colorado;(4) Omaha, Nebraska;(5) Antivirals, Inc., 4575 S. W. Research Way, Suite 200, Corvallis, Oregon, 97333 |
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Abstract: | Purpose. This study characterizes the in vivoproperties of an in situforming gel, comprising an 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. |
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Keywords: | in situgel poly(methacrylic acid) poly(ethylene glycol) macromolecular drugs sustained-delivery |
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