University of Mississippi Oxford, Mississippi, United States
Purpose: Raloxifene Hydrochloride (RLH) is used to treat and prevent post-menopausal osteoporosis; however, it is known to have low relative bioavailability of less than 2% owing to its poor solubility and extensive degradation by metabolic enzymes. This study aimed at formulating amorphous solid dispersion of RLH with polyvinylpyrrolidone K30 (PVP), and Polyox™ WSR N80 (PEO) by hot-melt extrusion (HME). The selected polymers will not only enhance the apparent solubility, and dissolution rate of RLH through amorphization and polymer hydrophilic properties but will also inhibit the metabolic enzymes leading to potential improvement of RLH efficiency and bioavailability. Methods: PVP K30 was used as the main polymer to fabricate RLH filaments due to its high solubilizing efficiency and high compatibility with the drug. PEO was added as a co-polymer. Four different formulations were investigated for extrudability (90%PVP:10%RLH), (60%PVP:30%PEO:10%RLH), (45%PVP:45%PEO:10%RLH) and (30% PVP:60% PEO:10% RLH) w/w. The ingredients were mixed and extruded with 11mm-twin screw extruder (11 mm Process 11™, Thermo Fisher Scientific, Waltham, MA, USA) at 160 °C and 150 RPM. Differential Scanning Calorimetry (DSC) was used for thermal characterization of the drug, polymers, physical mixture (RLH-M1-PM), and the extrudate ((RLH-M1) using (TA DSC 25) with a heating rate of 10 °C/min from 25 °C to 300 °C. Potential interactions between RLH, PVP K30, PEO, and extrudate were examined using FTIR (Agilent Technologies Cary 630, Santa Clara, CA). Drug content of the formulation was determined, and an amount equivalent to 60 mg RLH of the milled extrudate was filled into gelatin capsules and dissolution study was performed to compare the in vitro drug release profile to pure drug using dissolution apparatus II, 1000 mL of 0.1% polysorbate 80 solution. A 1 mL sample was withdrawn at 15,30, 45, 60, 90, 120 and 180 minutes) and RLH was quantified using Waters HPLC-UV system (Waters Corporation, Milford, MA, USA). Results: The extrusion trials with PVP K30 solely were not successful due to the increased viscosity of the polymer. It was found that the maximum amount of PVP that was extrudable was 45% w/w. The higher ratios of PVP led to increasing torque and equipment shutdown. The optimized batch included 10% RLH, 45% PVP and 45% PEO w/w. The extrusion temperature and speed were also optimized to compromise increasing process torque and ingredients’ degradation points. DSC thermograms showed a characteristic RLH endothermic peak at 269.98 °C and confirmed amorphization of RLH in the polymers where the melting peak completely disappeared after extrusion (Figure 1). Drug content was equal to 96.83% ± 0.54. FTIR studies illustrated RLH characteristic C=O stretching at 1640 cm-1, however, the disappearance of the peak for RLH-M1 spectrum suggested the potential hydrogen bonding between RLH and PVP (Figure 2). In vitro release studies confirmed enhanced release of RLH from the formulation (RLH-M1) since 91.45% ± 4.83 was released in 120 minutes versus 51.87% ± 0.02 from the pure drug (Figure 3). Conclusion: In this study, RLH with enhanced release properties using PVP K30 and PEO N80 by HME was produced. The extrudates had a significant improved release profile, and it is expected to have higher bioavailability due to metabolism inhibitors included in the formula. References: 1. Elsheikh, M. A., Elnaggar, Y. S., Gohar, E. Y., & Abdallah, O. Y. (2012). Nanoemulsion liquid preconcentrates for raloxifene hydrochloride: optimization and in vivo appraisal. International journal of nanomedicine, 7, 3787. 2. Kim, A. R., Lim, S. J., & Lee, B. J. (2009). Metabolic inhibition and kinetics of raloxifene by pharmaceutical excipients in human liver microsomes. International Journal of Pharmaceutics, 368(1-2), 37-44. 3. Tran, T. H., Poudel, B. K., Marasini, N., Chi, S. C., Choi, H. G., Yong, C. S., & Kim, J. O. (2013). Preparation and evaluation of raloxifene-loaded solid dispersion nanoparticle by spray-drying technique without an organic solvent. International journal of pharmaceutics, 443(1-2), 50-57.
Figure 1. DSC of (1) RLH (2) PVP K30 (3) PEO N80 (4) RLH-M1-PM, and (5) RLH-M1
Figure 2. FTIR (a) RLH, (b) RLH-M1, (c) RLH-M1, RLH, PVP K30, PEO bottom to top
Figure 3. Drug release studies of pure drug and optimized formulation RLH-M1
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