(W1230-09-56) Application of Precipitation Inhibitors in Lipid-Based Simvastatin Formulations to Prepare Simvastatin Amorphous Granules

Purpose: Lipid-based drug delivery systems (LBDDD) are promising strategies for water-insoluble drugs. However, drugs are dissolved in lipids and surfactants in supersaturated conditions in the preparation of these lipid-based formulations. After preparation, during storage and upon contact with water, drugs could precipitate. Precipitation inhibitors, e.g. polymers, have been applied to prevent drug precipitation in solid dispersion, but they were rarely used in LBDDD. Binary lipid system (BLS) is a new type of LBDDD. BLS utilized a single lipid and water-soluble surfactant to formulate solid drug granules which would enhance the oral absorption of water-insoluble drugs. Simvastatin (SIM) is a statin medication that is used to lower cholesterol. As a BCS class II compound, SIM has low solubility (30 mg/ml), leading to low dissolution and low bioavailability. In this study, we used SIM as a model drug to develop a BLS composition to dissolve SIM and identified polymers that inhibited SIM precipitation during preparation, achieving increased dissolution.

Methods: SIM granules were prepared by mixing SIM with a lipid (Campul MCM C8), a water-soluble surfactant (TPGS) and Aeroperl 300 at 36°C with 8% drug loading. Precipitate inhibitors including HPMC, PVP, Eudragit S100 and Eudragit L100P were tested to prevent SIM precipitation during and after granule preparation. Physical states of SFN measured by differential scanning calorimetry (DSC) from 10 to 240°C with an increase of 10°C/min and powder X-ray diffraction (PXRD) scanned over a 2 θ range of 8-25° with a scan rate of 1.0 sec. Dissolution of SIM granules was measured in mouse simulated gastric fluid (pH = 3.5) for 60 min (n=3).

Results: SIM was fully dissolved in Campul MCM C8 and TPGS at 8% drug loading. However, when formulations were cooling down, SIM precipitated out during granule preparation. DSC failed to identify crystal SIM in the granules, but XRD showed SIM crystal peaks. Adding Eudragit S100 and Eudragit L100 at a 1:1 ratio (polymer/drug, w/w) did not prevent SIM precipitation as measured by XRD. Adding HPMC or PVP successfully prevented SIM precipitation and XRD demonstrated amorphous SIM in the granules with HPMC or PVP. SIM granules containing PVP increased drug dissolution over 8-fold compared to SIM powder.

Conclusion: SIM amorphous granules with 8% drug loading were successfully prepared. Solid SIM granules with precipitate inhibitor PVP increased solubility by over 8-fold compared to SIM powder. Further studies are warranted to evaluate SIM amorphous granules in in vivo studies. Overall, solid SIM granules created using BLS and precipitate inhibitors show potential to increase oral bioavailability of SIM.

References: [1] X. Dong, N. Nguyen, Exploring novel type of lipid-bases drug delivery systems that contain one lipid and one water-soluble surfactant only, International Journal of Pharmaceutics 661 (2024) 124447

Acknowledgements: This work was supported by the National Institutes of General Medical Sciences [1R35GM138225] to Dong, X. and by the Cancer Prevention Research Institute of Texas (CPRIT) Summer Undergraduate Program Award # RP210046 (PI: Vishwanatha).

Figure 1: PXRD of SIM granules and SIM powders. SIM powder showed major SIM crystal peaks at 9.5, 11.2, 17-18 and 22.7°. Without precipitation inhibitor, SIM showed crystal form in the granule (SIM G no inhibitor) although SIM fully dissolved in the binary lipid systems. Addition of Eudragit E100 (SIM G ES100) and Eudragit L100 (SIM G EL100) did not prevent SIM precipitation showing SIM crystal peaks. Addition of HPMC (SIM G HPMC) or PVP (SIM G PVP) prevented SIM crystal formation showing no major SIM crystal peaks.

Figure 2. Dissolution of SIM granules and SIM powders. SIM amorphous granules with PVP as a precipitation inhibitor increased drug release over 8-fold after 30 min compared to SIM powder. Dissolution was measured at pH 3.5 to mimic mouse stomach pH. Experiments were triplicated for each formulation(n=3).