In Vitro Properties of an In Situ Forming Gel for the Parenteral Delivery of Macromolecular Drugs*

Abstract

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.

Transdermal Delivery of Antisense Oligonucleotides Can Induce Changes in Gene ExpressionIn Vivo

“…A significant amount of the PS-ODN was broken down when it reached the urine. The fact that oligonucleotide is found intact in the small intestine but is not active is consistent with previous studies (Joshi et al, 1998).…”

The third evolution of ionic liquids: active pharmaceutical ingredients

“…21 Transdermal preparations of local anesthetics or analgesics depend on drugretaining layers that typically contain a water-soluble gel base that can release an active substance. 22 The IL-API strategy brings together the relatively hydrophobic lidocaine cation with a hydrophobic anion, docusate (an emollient) to produce a hydrophobic IL salt, which exhibits reduced or controlled water solubility and thus should exhibit extended residence time on the skin. DSC analysis of LD (Table 1) indicates no melting point, but a glass transition (T g ) at À29 1C and a liquid-liquid transition at 78 1C.…”

Self‐assembling cyclodextrin based hydrogels for the sustained delivery of hydrophobic drugs

“…Additionally, the administration of these systems is limited by absorption of the initiating radiation by tissue 12. The solvent exchange approach has been also proposed to design in situ forming gels 16, 17. In this case, a water‐insoluble polymer is dissolved in a water‐miscible, biocompatible solvent.…”