Development and Characterization of Eudragit® EPO-Based Solid Dispersion of Rosuvastatin Calcium to Foresee the Impact on Solubility, Dissolution and Antihyperlipidemic Activity

Abstract

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.

Keywords: Eudragit® EPO; anti-hyperlipidemic activity; docking; improved solubility; rosuvastatin calcium; solid dispersion.

Figure 1

Saturation solubility of pure drug (RoC) and formulations [mean ± S.d; n = 3].

Figure 2

FTIR spectra of (a) pure RoC, (b) EPO, (c) physical mixture, (d) RoC-3 and (e) RSE-2.

Figure 3

DSC of (a) pure RoC, (b) EPO, (c) RoC-3 and (d) RSE-2.

Figure 4

PXRD of (a) pure RoC, (b) EPO, (c) RoC-3 and (d) RSE-2.

Figure 5

SEM images of (a) pure RoC (b) physical mixture (c) RoC-3 and (d) RSE-2.

Figure 6

In vitro release profile from pure RoC and SDs prepared using the CG method.

Figure 7

In vitro release profile of pure RoC and SDs prepared using the SE method.

Figure 8

Molecular docking Of RoC with (a) PEG, (b) Kollidon and (c) EPO at the receptor site: 1(a–c) depict the bonding of monomers shown as yellow colored ligand at the RoC receptor (HMGCOA-reductase); 2(a–c) present magnified views of 1(a–c), respectively; and 3(a–c) depicts amino acids involved in H-bonding. The green dotted lines in 3(a–c) are symbolic of H-bonding, and pink dotted lines are indicators of hydrophobic interaction.

Figure 8

Molecular docking Of RoC with (a) PEG, (b) Kollidon and (c) EPO at the receptor site: 1(a–c) depict the bonding of monomers shown as yellow colored ligand at the RoC receptor (HMGCOA-reductase); 2(a–c) present magnified views of 1(a–c), respectively; and 3(a–c) depicts amino acids involved in H-bonding. The green dotted lines in 3(a–c) are symbolic of H-bonding, and pink dotted lines are indicators of hydrophobic interaction.

Figure 9

Impact on % body weight of hyperlipidemia-induced rat models (n = 6) after oral administration of DRF (6 weeks) and DRF + RoC-loaded SDs (4 weeks).

Figure 10

Influence of pure RoC and SDs on the liver index of rats (n = 6) fed DFR: α indicates statistically significant difference (p < 0.05) to NC group; β indicates statistically significant difference (p < 0.05) to HC group; and η indicates statistically significant difference (p < 0.05) to Group I (DRF + Pure RoC).

Figure 11

Influence of pure RoC and SDs on the serum lipid levels of rats (n = 6) fed DFR: α indicates statistically significant difference (p < 0.05) to NC group; β indicates statistically significant difference (p < 0.05) to HC group; η indicates statistically significant difference (p < 0.05) to Group I (DRF + Pure RoC); and ϕ indicates statistically significant difference (p < 0.05) to Group II (DRF + RoC-3).

Figure 12

Influence of pure RoC and SDs on the A.I and TG/HDL-C ratio of rats (n = 6) fed on DRF: where α indicates statistically significant difference (p < 0.001) to NC group; β indicates statistically significant difference (p < 0.05) to HC group; η indicates statistically significant difference (p < 0.05) to Group I (DRF + Pure RoC); and ϕ indicates statistically significant difference (p < 0.05) to Group II (DRF + RoC-3), (a) Effect of pure drug (RoC) and optimized SDs on the Atherogenic index (A.I), (b) Effect of pure drug (RoC) and optimized SDs on the TG/HDL-C ratio (an insulin resistance marker).

Figure 13

Influence of pure RoC and SDs on the levels of liver enzymes ALT and ALP in rats (n = 6) fed on DRF: where α indicates statistically significant difference (p < 0.001) to NC group; β indicates statistically significant difference (p < 0.05) to HC group and η indicates statistically significant difference (p < 0.05) to Group I (DRF + Pure RoC); (a) Effect of pure drug (RoC) and optimized SDs on the levels of liver functioning enzyme alanine transaminase (ALT), (b) Effect of pure drug (RoC) and optimized SDs on the levels of liver functioning enzyme alkaline phosphatase (ALP).

Figure 14

Visual appearance of the liver tissues: (a) NC group; (b) HC group; (c) Group I (DRF + RoC); (d) Group II (DRF + RoC-3); and (e) Group III (DRF + RSE-2).

Figure 15

Microscopic images of liver tissues at 40× magnification (H & E staining): (a) NC group; (b) HC group; (c) Group I (DRF + RoC); (d) Group II (DRF + RoC-3); and (e) Group III (DRF + RSE-2).

Figure 16

Percent cell viability of control, pure drug and optimized formulation (RSE-2).

Figure 17

Diagrammatic presentation for the manufacturing process of solid dispersion of RoC using SE technique.