Novel drug formulation technology for water-insoluble drugs
Oral delivery is the most favorable and preferred route of drug administration, but poor water solubility, low oral absorption and non-targeted delivery limit drug concentrations in the action site in order to produce an effective therapy. Although previous studies have used nanoparticles (NPs) to formulate oral drugs, these NPs were prepared in liquid forms, raising significant issues of instability as well as manufacturing and storage difficulties. Conversion of liquid NPs into solid forms resulted in complicated drying processes, increased particle size, low entrapment efficiency (EE) and low drug loading (DL) in solid forms, making this conversion strategy unsuitable for oral medications. To overcome the difficulties in use of NPs in oral solid forms, we developed the novel NPs and named these in situ self-assembly nanoparticles (ISNPs). As illustrated in the figure, water is completely removed from the NP preparation, which fundamentally solves the issue of instability caused by water. Drugs are mixed with lipid and surfactant followed by a solid carrier to produce drug ISNP granules. Once drug ISNP granules are introduced into liquids (e.g. water during oral administration or the fluid in the gastrointestinal (GI) tract after oral administration), lipid and surfactant form a lipid-based ISNP (~150 nm) by a self-assembly process. We have developed drug granules for several water-insoluble drugs with high drug loading and entrapment efficiency.
In addition, the ISNP nanotechnology also can be used to prepare injections. As shown in the figure, if we do not add solid carrier, we will get a mixture of drug and excipients that will form drug-loaded ISNPs upon reconstitution with saline. The mixture does not have water so that the particle stability is not a concern for long-term storage. We used this approach to develop long-acting injections of drugs.
Cancer treatment with low doses of chemotherapy drugs by oral administration
Metronomic chemotherapy, giving low doses of chemotherapeutics (e.g., docetaxel) on a frequent schedule over a long time, may improve outcomes and reduce side effects for cancer patients. Oral medications are vital for applying metronomic chemotherapy. However, low solubility, low absorption, low drug availability in the targeted tissue, and side effects limit the development of oral chemotherapeutics. Many chemotherapeutics are intravenously delivered. In this work, we developed a new docetaxel granule that produces docetaxel-loaded in situ self-assembled nanoparticle (180 nm) upon contact with water. The process of manufacturing docetaxel granules is scalable in industrial settings. Docetaxel granule (5 mg/kg twice per week) can profoundly inhibit the tumor growth of lung-metastatic cancer xenograft model over 24 days. The oral nanoformulation provides an opportunity for conventionally intravenous chemotherapy drugs to be easily applied in oral administration for metronomic chemotherapy for cancer patients with cancers.