No abstract

By modulating polymer MW, it was possible to vary the physical properties of beads. Dissolution/swelling characteristics were dependent on the MW of the polymer. Such unique dissolution/swelling properties are useful for delivering drugs to different sites in the intestine.

N-isopropylacrylamide (NIPAAm) polymers exhibit a lower critical solution temperature (LCST). Aqueous solutions of these polymers are soluble below their LCST and precipitate above their LCST. The LCST is dependent on pH for polymers with ionizable groups because of a change in hydrophilicity with ionization and electrostatic repulsion that cause a shift in the LCST. We have designed a novel polymeric delivery system that utilizes linear, pH/temperature-sensitive terpolymers of NIPAAm, butyl methacrylate (BMA) and acrylic acid (AA). This system allows the aqueous loading of drugs in polymeric beads with high loading efficiency while preserving the bioactivity of the protein drug. Furthermore, the unique properties of the pH/temperature-sensitive polymeric bead make it a potential system for oral drug delivery of peptide and protein drugs to different regions of the intestinal tract. This study aims at investigating the effect of polydispersity and molecular weight (MW) of terpolymers of poly(NIPAAm-co-BMA-co-AA) with feed mol ratio of NIPAAm/BMA/AA 85/5/10 on the polymer dissolution rate and on the release kinetics of a model protein, namely insulin. Varying the weight average MW (Mw) and polydispersity of the polymer modulated the polymer dissolution rate and the release rate of insulin from pH/temperature-sensitive polymeric beads. An increase in the polydispersity of the polymer through the addition of high MW polymer chains caused a decrease in the release rate of insulin and in the polymer dissolution rate. High MW polymer chains impose a certain degree of interaction between polymer chains due to chain entanglement. There is a limiting value of MW above which chain entanglement has no effect on drug release rate.

In this report, the effect of ionic strength on the loading efficiency of three model polypeptide/protein drugs, namely angiotensin II, insulin, and cytochrome c, in pH- and temperature-sensitive terpolymers of poly(NIPAAm-co-butylmethacrylate-co-acrylic acid) (poly(NIPAAm-co-BMA-co-AA)) has been investigated. Loading efficiency of polypeptides in pH-/temperature-sensitive beads composed of poly(NIPAAm-co-BMA-co-AA) terpolymer is predominantly governed by hydrophobic interactions, both nonspecific surface interactions and/or specific interactions (binding pockets) between the protein and the polymer molecules. Thus, loading efficiency increases with ionic strength. However, as ionic strength increases further, polymer deswelling (collapse), which is also controlled by hydrophobic forces, becomes more pronounced, and consequently, a higher fraction of water is squeezed out during bead formation and the loading efficiency starts to decrease.

pH-and temperature-sensitive terpolymers of N-isopropylacrylamide (NIPAAm), butylmethacrylate (BMA), and acrylic acid (AA) were used to prepare polypeptide releasing beads via loading in aqueous solution. Insulin was protected and not released from the beads at low pH, such as that in the stomach. Linear polymers with NIPAAm/BMA/AA mol feed ratio of 85/5/10 were prepared by free radical polymerization. Molecular weight (M.Wt.) of the polymers was varied using different volume percentages of benzene/tetrahydrofuran (THF) as solvent. The weight average M.Wt. of the polymer synthesized in THF was 33,000 and 990,000 for the polymer synthesized in benzene. The lower critical solution temperature (LCST) was determined by cloud point measurement and was 22 °C at pH 2.0 and 85 °C at pH 7.4 for the polymers. Beads were loaded with the polypeptide by preparing a 10% polymer, 0.2% polypeptide solution in 20 mM glycine/HCl buffer, pH 2.0, 0.15 M NaCl at 4 °C and adding the solution dropwise into an oil bath at 35 °C. Loading efficiency was between 20 to 100% depending on the M. Wt. of the polymer and M. Wt. of the polypeptide. Release studies were performed at pH 2.0 and pH 7.4, and 37 °C, simulating in vivo conditions. Low M.Wt. polymer beads displayed a dump-like release profile and high M. Wt. polymer beads released drug slowly over a period of eight hours. The loaded and released polypeptide drugs were bioactive as shown by in vivo studies. These polymers allow aqueous phase loading of proteins in beads, protect polypeptides from the harsh acidic environment in the stomach, and can provide oral controlled release of polypeptide drugs. The low M.Wt. polymer beads can be used for immediate release of polypeptide in the duodenum while the high M. Wt. polymer beads can be used for slow release of polypeptide in the colon. 322