Solid self-nanoemulsifying cyclosporin A pellets prepared by fluid-bed coating: preparation, characterization and in vitro redispersibility

Abstract

Background: The objective of this study was to evaluate fluid-bed coating as a new technique to prepare a pellet-based solid self-nanoemulsifying drug delivery system (SNEDDS) using cyclosporin A as a model of a poorly water-soluble drug.

Methods: The rationale of this technique was to entrap a Liquid SNEDDS in the matrix of the coating material, polyvinylpyrrolidone K30, by fluid-bed coating. Pseudoternary phase diagrams were used to screen the liquid SNEDDS formulations. The optimal formulation was composed of Labrafil M(®) 1944 CS, Transcutol P(®), and Cremophor(®) EL in a ratio of 9:14:7. To prepare solid SNEDDS pellets, liquid SNEDDS was first dispersed in an aqueous solution of polyvinylpyrrolidone and then sprayed onto the surface of non-pareil pellets. Upon evaporation of water, polyvinylpyrrolidone precipitated and formed tight films to entrap the liquid SNEDDS. Visual observation and scanning electron microscopic analysis confirmed good appearance of the solid SNEDDS pellets.

Results: Our results indicated that up to 40% of the liquid SNEDDS could be entrapped in the coating layer. Powder x-ray diffraction analysis confirmed nonexistence of crystalline cyclosporin A in the formulation. Solid SNEDDS pellets showed a slower redispersion rate than the liquid SNEDDS. An increase in the total liquid SNEDDS loading led to faster redispersion, whereas increased coating weight (up to 400%) significantly decreased the redispersion rate. Both cyclosporin A loading and protective coating with 5% polyvinylpyrrolidone K30 did not significantly affect the redispersion rate.

Conclusion: It is concluded that fluid-bed coating is a new technique with considerable potential for preparation of pellet-based solid SNEDDS formulations.

Keywords: cyclosporin A; fluid-bed coating; pellets; self-nanoemulsifying; solid.

Figure 1

A typical pseudoternary phase diagram with deionized water, Labrafil M^® 1944 CS (oil) and Cremophor^® EL/Transcutol P^® (surfactant/cosurfactant, K_m = 2) as three vertices. The dark region indicates area of self-nanoemulsifying (infinite dilution), whereas the gray region indicates an area of nanoemulsion that turns into a milky emulsion upon dilution with water. The red line shows the dilution profile of the liquid SNEDDS (F4 in Table 1) for the solid SNEDDS pellets study. The blue point indicates the nanoemulsion dispersion of the liquid SNEDDS after dilution with water. The particle size was 21.2 nm as measured by Zetasizer Nano. Abbreviation: SNEDDS, self-nanoemulsifying drug delivery system.

Figure 2

Optical photographs of the solid SNEDDS pellets, where the formulations are defined in Table 2. A–D) SF0–3 (liquid SNEDDS loading 0%, 20%, 30%, 40%); E, F) SF5, 6 (CWG 100%, 400%); G, H) SF7, 8 (cyclosporin A loading 6%, 10%). Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; CWG, coating weight gain.

Figure 3

Scanning electron microscopic photographs of the surface and cross-section view of solid SNEDDS pellets, where the formulations are defined in Table 2. Surface: A–D) SF1–3 (liquid SNEDDS loading 0%, 20%, 30%, 40%); E, F) SF5, 6 (CWG 100%, 400%); G, H) SF7, 8 (cyclosporin A loading 6%, 10%). Cross-section: A′–D′) SF1−3; E′, F′) SF5, 6; G′, H′) SF7, 8. Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; CWG, coating weight gain.

Figure 4

Powder x-ray diffraction patterns of cyclosporin A (A), PVP K30 (B), physical mixture (C) and solid SNEDDS powder (D). Abbreviations: PVP, polyvinylpyrrolidone; SNEDDS, self-nanoemulsifying drug delivery system.

Figure 5

Redispersion profiles of solid SNEDDS pellets, for which the formulations are defined in Table 2. A) SF1−3 (liquid SNEDDS loading 20%, 30%, 40%); B) SF5, 3, 6 (CWG 100%, 200%, 400%); C) SF7, 3, 8 (cyclosporin A loading: 6%, 8%, 10%); D) SF9 (protective PVP 30 coating at 5%). Abbreviations: SNEDDS, self-nanoemulsifying drug delivery system; CWG, coating weight gain; PVP, polyvinylpyrrolidone.