Abstract
Docetaxel (DTX) has clinical efficacy in the treatment of breast cancer, but it is difficult to develop a product for oral administration, due to low solubility and permeability. This study focused on preparing a self-microemulsifying drug delivery system (SME) loaded with DTX-phospholipid complex (DTX@PLC), to improve the dissolution and gastrointestinal (GI) permeability of DTX. A dual technique combining the phospholipid complexation and SME formulation described as improving upon the disadvantages of DTX has been proposed. We hypothesized that the complexation of DTX with phospholipids can improve the lipophilicity of DTX, thereby increasing the affinity of the drug to the cell lipid membrane, and simultaneously improving permeability through the GI barrier. Meanwhile, DTX@PLC-loaded SME (DTX@PLC-SME) increases the dissolution and surface area of DTX by forming a microemulsion in the intestinal fluid, providing sufficient opportunity for the drug to contact the GI membrane. First, we prepared DTX@PLC-SME by combining dual technologies, which are advantages for oral absorption. Next, we optimized DTX@PLC-SME with nanosized droplets (117.1 nm), low precipitation (8.9%), and high solubility (33.0 mg/g), which formed a homogeneous microemulsion in the aqueous phase. Dissolution and cellular uptake studies demonstrated that DTX@PLC-SME showed 5.6-fold higher dissolution and 2.3-fold higher DTX uptake in Caco-2 cells than raw material. In addition, an ex vivo gut sac study confirmed that DTX@PLC-SME improved GI permeability of DTX by 2.6-fold compared to raw material. These results suggested that DTX@PLC-SME can significantly overcome the disadvantages of anticancer agents, such as low solubility and permeability.
Highlights
Docetaxel (DTX), an anticancer agent, is one of the second generation taxoids
DTX is widely known as an effective anticancer agent for breast, ovarian, lung, and hormonal refractory prostate cancers, but is limited in clinical use, due to several side effects such as hypersensitivity responses, bone marrow suppression, alopecia, stomatitis, and mucositis [2,3]
The commercial product (Taxotere®) is an intravenous formulation, which is generally used for clinical use, but the parenteral route can cause infection, phlebitis, infiltration, extravasation, fluid overload, hypothermia, electrolyte imbalance, etc. [4,5]
Summary
Docetaxel (DTX), an anticancer agent, is one of the second generation taxoids. It leads to apoptosis of malignant cells by inducing cell death [1]. DTX is widely known as an effective anticancer agent for breast, ovarian, lung, and hormonal refractory prostate cancers, but is limited in clinical use, due to several side effects such as hypersensitivity responses, bone marrow suppression, alopecia, stomatitis, and mucositis [2,3]. The commercial product (Taxotere®) is an intravenous formulation, which is generally used for clinical use, but the parenteral route can cause infection, phlebitis, infiltration, extravasation, fluid overload, hypothermia, electrolyte imbalance, etc. The formulation may lower patient compliance, due to the inconvenience of administration. Oral formulations can be a suitable alternative to intravenous formulations, as they reduce multiple side effects including pain, allergic reactions, and infections and promote patient compliance
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