(T1530-12-79) Dissolution Technology Using HPMCAS Solid Dispersion Targeting the Upper Small Intestine

Purpose: Hypromellose acetate succinate (HPMCAS) is highly effective as a carrier for solid dispersions. On the other hand, since HPMCAS is enteric polymer, the dissolution of the solid dispersion using HPMCAS may be slightly delayed at the absorption site of relatively low pH in the upper small intestine. In this study, we developed a technology to control the enteric property of HPMCAS by adding an alkaline component as a neutralizer during the production of solid dispersion, and to improve the dissolution in the upper small intestine at low pH.

Methods: We used nifedipine as a model drug and HPMCAS (Shin-Etsu AQOAT^® AS-LG, Shin-Etsu Chemical Co., Ltd., Japan) as a carrier. After dissolving nifedipine and HPMCAS in an organic solvent, Sodium hydrogen carbonate (NaHCO₃) was dispersed or dissolved in the organic solvent as an alkaline component, and a solid dispersion was produced by a spray drying method. Dissolution profiles in phosphate buffer pH5.0 and pH6.8 were evaluated. In addition, we evaluated the effect of NaHCO3 addition amount and dissolution state on the dissolution properties of solid dispersions and the stability of HPMCAS.

Results: The dissolution of nifedipine in pH5.0 at 30 minutes was greatly improved by adding NaHCO3, which acts as a neutralizer for HPMCAS, into the solution to produce a solid dispersion. The dissolution rate of nifedipine varied depending on the amount of NaHCO₃. Addition of 0.2 molar equivalent or more of NaHCO₃ to the succinyl group of HPMCAS improves dissolution of nifedipine in pH5.0 by approximately 1.6 times. In pH6.8, it showed a high dissolution improvement effect equivalent to Control that does not contain alkaline component. Furthermore, the solid dispersion prepared by dispersing NaHCO₃ in acetone as the solvent could suppress the degradation of HPMCAS during storage (40℃, 75%RH, closed-bottles) compared with the solid dispersion prepared by dissolving NaHCO3 in Ethanol / water mixture (80 / 20 wt%).

Conclusion: It was found that the dissolution rate in the upper small intestine can be improved even when an enteric polymer is used as a carrier by adding an alkaline component during spray drying. This technology is expected to contribute to the improvement of bioavailability of solid dispersion using enteric polymers.

Table 1. Formulations of spray-drying solution

Figure 1. Maximum dissolution amount of Nifedipine in pH5.0 and pH6.8

Figure 2. Degradability of HPMCAS by storage under 40℃/75%RH in closed bottles