In vitro properties of an in situ forming gel for the parenteral delivery of macromolecular drugs.
The purpose of this research was to (i) formulate a solution of a water-insoluble interpolymeric complex (IPC) containing poly(methacrylic acid) (PMA), 15 kDa, and poly(ethylene glycol) (PEG), 20 kDa, in a biocompatible cosolvent system; (ii) demonstrate that the IPC solution can transform into a gel, in situ, at physiological pH; and (iii) determine the ability of the gel to entrap, protect, and control the release of macromolecular drugs such as proteins and oligonucleotides. Ternary phase diagrams were prepared to identify cosolvent composition containing N-methylpyrrolidone (NMP), ethanol, and water that dissolve the IPC. IPC solutions (40, 50, or 60% w/v) each containing 1 mg of either model proteins, fluorescein isothiocyanate (FITC)-insulin and FITC-albumin, or 24-mer phosphorothioate oligonucleotides, were placed in containers that were immersed in buffer, pH 7.4. Aliquots of the buffer were sampled periodically and analyzed for the macromolecular content. In addition, in vitro bioactivity of another model protein, alpha-amylase, contained in the IPC solution was also determined. The studies demonstrated that a cosolvent containing 1:1:2 ratio of NMP/ethanol/water was most suitable for dissolving the IPC. Concentrations > 30% w/v IPC were required to form the gel, however, those mixtures containing > 60% w/v IPC could not be easily injected via 18-22 gauge needle. The gel can entrap and control the release of the model macromolecules for up to 6 days, in vitro. In addition, the gel can maintain the bioactivity of the protein, alpha-amylase, for 6 days. Therefore, an IPC gel can entrap, protect, and control the release of macromolecular drugs over a period of 6 days, in vitro, and therefore can be considered for in vivo investigation.
Joshi
R
R
Supergen Pharmaceutical Research Institute, Pleasanton, California 94566, USA. rjoshi@supergen.com
Robinson
D H
DH
Himmelstein
K J
KJ
D000418:Albumins / Q000008:administration & dosage / Q000737:chemistry; D005079:Excipients; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage / Q000737:chemistry; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000737:chemistry; D005782:Gels; D007328:Insulin / Q000008:administration & dosage / Q000737:chemistry; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols; D011108:Polymers; D011109:Polymethacrylic Acids; D012995:Solubility; D012997:Solvents; D000516:alpha-Amylases / Q000378:metabolism
D000418:Albumins; D005079:Excipients; D005456:Fluorescent Dyes; D005782:Gels; D007328:Insulin; D020319:Oligodeoxyribonucleotides, Antisense; D011108:Polymers; D011109:Polymethacrylic Acids; D012997:Solvents; C030613:polymethacrylic acid; D011092:Polyethylene Glycols; D000516:alpha-Amylases; D016650:Fluorescein-5-isothiocyanate