The Use of Polymers to Inhibit Crystal Growth and Nucleation of a Supersaturated Hydrophobic Compound -RESCRIPTOR™
Nielsen, L. Cartsen
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Ai; part of the Supersaturation project, an in vitro study indicates that tri-block copolymers (Pluronic®) and a homopolymer (hydroxypropylmethyl cellulose, HPMC) used in conjunction can provide substantial improvement in the precipitation inhibition of a poorly soluble drug (RESCRIPTORTM). These two excipients were chosen because Pluronic block copolymers were found to be effective in suppressing drug precipitation at early times, whereas HPMC proved to be effective at later times. The rank order of the observed concentration profile for RESCRIPTORTM is F87 > F127 > L44 > F68-Fl08 when only the block copolymers were used. Considerable precipitation suppression was observed when both HPMC K3cp and Pluronic copolymers were used and the rank-order became F68 > F87> Fl08 > F127> L44. Furthermore, higher concentration profiles were observed when a more hydrophobic homopolymer (HPMC E5) was utilized. The best concentration profiles were obtained with HPMC E5 and the Pluronic block copolymer F68. These two polymers, in a ratio of 3 E5 to 1 F68, yielded the highest degree of supersaturation for 1 RESCRIPTORTM. More importantly, it was found that micelle formation was not the primary determinant for the improved precipitation retardation of drug, since the concentration used was well below the critical micelle concentration of F68. Based on the above finding, the key to formulations design for poorly soluble compounds may lie in identifying excipients that have complementary functions, such as being effective in suppressing precipitation at different times. The data suggest that HPMC E5 with F68 could provide an effective drug delivery system, perhaps not only with RESCRIPTORTM, but also with other poorly soluble drugs.