Novel Formulation Technology to Enhance Oral Absorption of Water-insoluble Drugs

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Project Summary/Abstract Bioavailability enhancement technologies for insoluble drugs represent incremental progress, but no breakthrough oral drug technologies have been identified in the past three decades. Lipid-based drug delivery systems (LBDDS) are considered as a well-established, very important strategy for insoluble compounds. According to the previous knowledge, a stable binary lipid system (BLS) composed of one lipid and one water- soluble surfactant seems impossible. Another key tenet of LDBBS is that a drug must completely dissolve in a LBDDS to increase its dissolution and oral bioavailability. While co-excipients are added to increase drug solubility, drug loading in the final LBDDS is decreased. The stability of liquid formulations, compatibility of liquid excipients and capsule shell, and manufacturing liquid-filed soft gelatin capsules are also limiting the applications of LBDDS. Nanoparticles are the other alternatives for insoluble drugs. However, the liquid forms of nanoparticles lead to particle instability during storage. To address these limitations, incorporation of liquid LBDDS or NPs into a solid dosage form is highly desirable. However, low drug loading is the major issue for this conversion strategy. In addition, although lipids and surfactants in colloidal particles alter the biodistribution, the influence of individual excipient on biodistribution is unclear. The long-term goal of our research program is to advance formulation technologies for insoluble drugs. Our laboratory has recently developed novel in situ self-assembly nanoparticle (ISNP) granules that in contact with water produce drug-loaded ISNPs. Drug ISNP granules not only improved oral absorption but also showed the potential for tissue-targeted oral solid formulations. More importantly, we recently discovered that our ISNPs, composed of one lipid and one water-soluble surfactant, create a new stable BLS. Our results further demonstrated that completely dissolving the drug in our formulations and the formation of ISNPs are not mandatory for absorption enhancement. Building on these recent breakthrough findings, the goal of this proposal is to develop a novel formulation technology by bringing our unique findings of new colloidal binary lipid system into solid dosage forms to improve oral absorption of insoluble drugs. We propose to identify the relationship of excipients’ structure and the formation of BLS and build a library of BLS. The library will provide guidance for selecting appropriate compositions when formulators use the BLS. We will develop new BLS-based formulations for two model drugs, Olmesartan medoxomil and Amphotericin B, in order to establish a new technology of oral solid dosage forms for absorption enhancement. We will use sorafenib to prepare drug granules to dissect the influence of lipid or surfactant on biodistribution as well as identify the mechanism of absorption enhancement. Our studies will provide a strong foundational resource for BLS and represent a possibly game-changing approach for the use of lipids and surfactants in formulations. We expect these contributions will positively impact oral drug development and will lead to a breakthrough in oral drug delivery technologies. This work also can be extended to future studies of other drugs in other administration routes.