Investigation of Approval Trends and Benefits of New Fixed-Dose Combination Drugs in Japan

Kikuchi, Chikara; Ohno, Mifuyu; Izumo, Takafumi; Takahashi, Satoru; Aoki, Masayuki; Shimomura, Hitoshi; Kawano, Yoshinobu; Shimada, Shizuo; Aoyama, Takao

doi:10.1007/s43441-019-00046-w

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“…Fixed dose combinations (FDCs) are routinely used to achieve and improve complex medication regimens and to standardize prescribing practices. , Clinical guidelines underpin their use for treating chronic diseases such as tuberculosis, acquired immunodeficiency syndrome, and hypertension. − They improve patient compliance to medication and reduce dispensing and supervision costs in health care systems. The World Health Organization classifies many of them as essential medicinal products…”

Section: Introductionmentioning

confidence: 99%

Impact of Simulated Intestinal Fluids on Dissolution, Solution Chemistry, and Membrane Transport of Amorphous Multidrug Formulations

2021

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The solution behavior and membrane transport of multidrug formulations were herein investigated in a biorelevant medium simulating fasted conditions. Amorphous multidrug formulations were prepared by the solvent evaporation method. Combinations of atazanavir (ATV) and ritonavir (RTV) and felodipine (FDN) and indapamide (IPM) were prepared and stabilized by a polymer for studying their dissolution (under non-sink conditions) and membrane transport in fasted state simulated intestinal fluid (FaSSIF). The micellar solubilization by FaSSIF enhanced the amorphous solubility of the drugs to different extents. Similar to buffer, the maximum achievable concentration of drugs in combination was reduced in FaSSIF, but the extent of reduction was affected by the degree of FaSSIF solubilization. Dissolution studies of ATV and IPM revealed that the amorphous solubility of these two drugs was not affected by FaSSIF solubilization. In contrast, RTV was significantly affected by FaSSIF solubilization with a 30% reduction in the maximum achievable concentration upon combination to ATV, compared to 50% reduction in buffer. This positive deviation by FaSSIF solubilization was not reflected in the mass transport–time profiles. Interestingly, FDN concentrations remain constant until the amount of IPM added was over 1000 μg/mL. No decrease in the membrane transport of FDN was observed for a 1:1 M ratio of FDN-IPM combination. This study demonstrates the importance of studying amorphous multidrug formulations under physiologically relevant conditions to obtain insights into the performance of these formulations after oral administration.

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