Controlled Solvent Removal from Antiviral Drugs and Excipients in Solution Enables the Formation of Novel Combination Multi-Drug-Motifs in Pharmaceutical Powders Composed of Lopinavir, Ritonavir and Tenofovir

Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugsdwater-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = -1.6). DcNP powder, exhibiting repeating units of multi-drug-motifs (referred to as MDM), is made by dissolving all constituents in ethanolic solution, followed by controlled solvent removal. The DcNP powder intersperses chemically diverse drug molecules with lipid excipients to form repeating MDM units. The proposed MDM structure is consistent with data collected with X-ray diffraction, differential calorimetry, and time-of-flight secondary ion mass spectrometry. The successful assembly of chemically diverse drugs in MDM structure is likely due to a novel process of making drug combination powders. The method described here has successfully extended to formulating other clinically prescribed antiviral drug combinations, and thus may serve as a platform technology for developing drug combination nanoparticles for treating a wide range of chronic diseases. (C) 2020 Published by Elsevier Inc. on behalf of the American Pharmacists Association.