Category: Formulation and Quality
Purpose: This study describes a continuous process for the production of Raloxifene Hydrochloride (RX-HCl) loaded Nanostructured Lipid Carriers (NLC) for enhanced oral bioavailability utilizing Hot-Melt Extrusion (HME) Technology and Probe Sonication.
Methods: Solid lipids were selected by checking the solubility of RX-HCl in melted solid lipid by means of visual observation with the naked eyes under normal light. This was further characterized with HPLC analysis. Solid lipids such as Glyceryl monostearate, Compritol® 888ATO, Precirol® ATO5, and Dynasan® 118 were screened for their potential to solubilize RX-HCl. Liquid lipids, Capmul® MCM C8, Castor Oil, and Labrafil® M 1944 CS, were screened for their potential to solubilize RX-HCl. RX-HCl compatibility with various 1% surfactant solutions, Polysorbate 80, Polysorbate 20, and Cremophor EL® was assessed. After the screening studies, two solid lipids, two liquid lipids, and two surfactants were selected for further preliminary studies. Twenty-four NLC blank formulations were prepared by the conventional probe sonication method. Composition of the 24 blank NLC formulations is as shown in Table 1. All the prepared formulations were stored at 25°C/60% RH to check for stability. Based on the stability results, six formulations; F4-1, F4-2, F4-3, F8-1, F8-2, and F8-3 were selected for the preparation of RX-HCl loaded NLC formulations using conventional probe sonication and HME methods. Particle size, polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE), and drug loading were then evaluated.
Results: Four solid lipids, three liquid lipids, and three surfactants were assessed for RX-HCl solubility and compatibility. Based on these studies, solid lipids; Glyceryl Monostearate and Compritol® 888ATO, liquid lipids; Capmul® MCM C8 and Castor Oil, and surfactants; Polysorbate 80 and Cremophor EL®, were selected for further studies. Figures 1 shows particle size, PDI, and ZP results for the assessment of formulation variables of the 24 NLC blank formulations. Selection of formulations for further studies was based on stability results and the physical properties (e.g. gelling) of the formulations. Six formulations; F4-1, F4-2, F4-3, F8-1, F8-2, and F8-3 were selected for further assessment of formulation variables of RX-HCl loaded NLCs using conventional probe sonication and HME methods. Percent EE and drug loading results for RX-HCl loaded NLCs prepared by conventional method are as shown in Figure 2. When F4-3 was prepared conventionally, particle size, PDI, and ZP results were 344.5 ± 4.70 nm, 0.347 ± 0.057, and 14.5 ± 0.200 mV, respectively. On the other hand, when F4-3 was prepared using HME conjugated with probe sonication, particle size, PDI, ZP, EE, and percent drug loading results were 199.9 ± 28.7 nm, 0.264 ± 0.112, 19.5 ± 9.5 mV, 88.2 ± 3.2%, 14.7 ± 0.5%, respectively. The feeding rates for the volumetric feeder and peristaltic pumps were optimized before starting HME. A screw speed of 100 rpm and a barrel temperature of 85° C, were used in the extrusion process.
Conclusion: HME technology and probe sonication were successfully utilized to prepare RX-HCl loaded NLC formulation as a continuous manufacturing process with shorter processing times as compared to the conventional methods. Results from this study suggest an efficient method that can be used to prepare RX-HCl loaded NLC formulation that will have enhanced oral bioavailability and offer a better option for the prevention and treatment of postmenopausal osteoporosis.
Eman Ashour– Oxford, Mississippi
Mashan Almutairi– Grad Student, University of Mississippi, Oxford, Mississippi
Poorva Joshi– Ms, University of Mississippi, Oxford, Mississippi
Michael Repka– Professor, University of Mississippi, Oxford, Mississippi