DEVELOPMENT OF POLOXAMER MICELLE CONTAINING DOCETAXEL TO ENHANCE PERMEABILITY ACROSS BLOOD-BRAIN BARRIER AS AN EFFECTIVE AND SAFE BRAIN CANCER THERAPY

• Main Author: Harry Nugraha, Dwianto
• Format: Dissertations
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/70505
• Institution: Institut Teknologi Bandung

Nanotechnology-based drug delivery system, particularly micellar polymers, is an appropriate formulation approach for drug delivery to brain tissue. The use of polymers with a combination of hydrophilic and hydrophobic groups, such as poloxamer, can increase drug delivery through the blood brain barrier (BBB) selectively. Micellar polymer using freeze drying method is one of the approaches with great potential because it allows large-scale production to support the commercialization process. Docetaxel is the chemotherapy treatment of choice for cancer since it has a broad anti-cancer spectrum and has been demonstrated to be successful in treating brain cancer. It works as a cell microtubule inhibitor. A mixture of polysorbate 80 and alcohol is used as the nano-carrier of docetaxel in the formulation of Taxotere®, a commercial docetaxel product in the international market. The onset of adverse effects during use, which forces patients to get preventive measures (premedication) prior to receiving treatment, is the recipe for this weakness. This pretreatment causes severe patient inconvenience and may threaten patient safety. No products having safe docetaxel in water-based formulations have been reported as of yet. Poloxamer is a tri-block copolymer amphiphilic polymer that has been widely used in pharmaceutical products that have received marketing authorization. Micellar polymers based on poloxamer have been shown to improve drug distribution to brain tissue. A water-based docetaxel formula was successfully developed in this study using polymeric micellar technology derived from poloxamer via a freeze-drying manufacturing process. This formulation can increase the solubility of the docetaxel dose in water by more than 3000 times. Several tests were conducted to obtain an optimum formulation of polymeric micelles loaded with docetaxel, including the effect of polymer concentration, additional surfactant charge, stabilisers' impact on the physical, chemical, and anti-cancer effectiveness characteristics, and the ability to penetrate the BBB. iv The optimized polymer micelles from docetaxel had a particle size of 21.2 nm + 0.3 nm and a polydispersity index of 0.333+0.020, indicating that the micellar particles are nano-sized and have a homogeneous particle distribution. In-vitro testing revealed that polymer micelles containing docetaxel had higher anti-cancer activity and cross the blood-brain barrier more effectively than the commercial Taxotere ® product. Animal studies have shown that the concentration of docetaxel in the blood and brain delivered by polymer micelles containing docetaxel was higher than that of the commercial Taxotere® product. Despite having higher concentrations in the blood and brain, docetaxel loaded in polymeric micelles had a better safety profile than the commercial Taxotere® product. This study demonstrates that docetaxel formulated in polymeric micelles has better in vitro anti-cancer activity, can be delivered to brain tissue at higher concentrations, and has a better safety profile than current commercial products.