Abstract
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.
Highlights
Fixed dose combinations (FDCs) are routinely used to achieve and improve complex medication regimens and to standardize prescribing practices.[1,2] Clinical guidelines underpin their use for treating chronic diseases such as tuberculosis, acquired immunodeficiency syndrome, and hypertension.[3−5] They improve patient compliance to medication and reduce dispensing and supervision costs in health care systems
Despite similarities in their ionization and chemical structures, ATV and RTV had significantly different The onset of melting (Tm) and ΔHf values: ATV had a Tm of 483 K(39an9dKΔ) Hanf dofΔ5H2.f8(k4J9·m.7oklJ−·1m, wolh−e1)re. aTshReTrVesuhlatdingboftohrmlouwlaetrioTnms containing ATV and/or RTV were amorphous as no melting endotherm was observed by Differential scanning calorimetry (DSC) (Supporting Information, Figure S3).[12]
For ATV and IPM from equimolar combination formulations, concentration and membrane transport were reduced roughly by 50% in both buffer and fasted state simulated intestinal fluid (FaSSIF)
Summary
Fixed dose combinations (FDCs) are routinely used to achieve and improve complex medication regimens and to standardize prescribing practices.[1,2] Clinical guidelines underpin their use for treating chronic diseases such as tuberculosis, acquired immunodeficiency syndrome, and hypertension.[3−5] They improve patient compliance to medication and reduce dispensing and supervision costs in health care systems. It has been suggested that this is a result of their mixing in the drug-rich phase, which leads to a decrease in the bulk solution concentrations. The presence of an ionizable drug (diclofenac) with ritonavir results in no reduction in the bulk solution concentration of either drug.[13] it was shown that excipients in the formulation may partition into the colloidal phase and lead to a reduced supersaturation of drugs and thereby membrane transport.[15,16] the size of the colloidal precipitate may impact the membrane transport of the drug and its bioavailability.[15,17,18]
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