Formulation of self-nanoemulsifying drug delivery systems containing monoacyl phosphatidylcholine and Kolliphor® RH40 using experimental design

Abstract

The development of self-nanoemulsifying drug delivery systems (SNEDDS) to enhance the oral bioavailability of lipophilic drugs is usually based on traditional one-factor-at-a-time approaches. These approaches may be inadequate to analyse the effect of each excipient and their potential interactions on the emulsion droplet size formed when dispersing the SNEDDS in an aqueous environment. The current study investigates the emulsion droplet sizes formed from SNEDDS containing different levels of the natural surfactant monoacyl phosphatidylcholine to reduce the concentration of the synthetic surfactant polyoxyl 40 hydrogenated castor oil (Kolliphor^® RH40). Monoacyl phosphatidylcholine was used in the form of Lipoid S LPC 80 (LPC, containing approximately 80% monoacyl phosphatidylcholine, 13% phosphatidylcholine and 4% concomitant components). The investigated SNEDDS comprised of long-chain or medium-chain glycerides (40% to 75%), Kolliphor^® RH40 (5% to 55%), LPC (0 to 40%) and ethanol (0 to 10%). D-optimal design, multiple linear regression, and partial least square regression were used to screen different SNEDDS within the investigated excipient ranges and to analyse the effect of each excipient on the resulting droplet size of the dispersed SNEDDS measured by dynamic light scattering. All investigated formulations formed nano-emulsions with droplet sizes from about 20 to 200 nm. The use of medium-chain glycerides was more likely to result in smaller and more monodisperse droplet sizes compared to the use of long-chain glycerides. Kolliphor^® RH40 exhibited the most significant effect on reducing the emulsion droplet sizes. Increasing LPC concentration increased the emulsion droplet sizes, possibly because of the reduction of Kolliphor^® RH40 concentration. A higher concentration of ethanol resulted in an insignificant reduction of the emulsion droplet size. The study provides different ternary diagrams of SNEDDS containing LPC and Kolliphor^® RH40 as a reference for formulation developers.

Keywords: Cryogenic transmission electron microscopy; D-optimal design; Droplet size; Monoacyl phosphatidylcholine; Polyoxyl 40 hydrogenated castor oil (Kolliphor® RH40); Self-nanoemulsifying drug delivery systems.

Graphical abstract

Fig. 1

Cryo-TEM images of emulsions obtained from dispersing (A) LC7 (see Table 2) and (B) MC34 (see Table 6) in FastedM (at a ratio of 1:200).

Fig. 2

Factor effect plots showing the effect of each component on the nanoemulsion droplet size from (A) LC SNEDDS of DoE I and (B) MC SNEDDS of DoE I & II. The displayed droplet sizes are the predicted values obtained when varying one excipient concentration (KOL, LPC or ethanol) and maintaining the ratio of the other excipients as in a reference formulation. The reference formulation is the centre point, containing KOL:LPC:ethanol (at a ratio of 42.5:12.5:5 w/w for (A) and 35:20:5 w/w for (B)). A 40% glyceride concentration is fixed for all formulations.

Fig. 3

(A) Prediction plot of LC SNEDDS containing 40% LC glycerides (soybean oil:Maisine (1:1 w/w)), 30–55% KOL, 0–25% LPC, and 0–10% ethanol (DoE I). (B) Prediction plot of MC SNEDDS containing 40% MC glycerides (Captex:Capmul (1:1 w/w)), 15–55% KOL, 0–40% LPC, and 0–10% ethanol (DoE I & II). Excipient concentrations are presented as fractions.

Fig. 4

Factor effect plots showing the effect of each component on the nanoemulsion droplet size from MC SNEDDS – (A) DoE III and (B) DoE IV. The displayed droplet sizes are the predicted values obtained when varying one excipient concentration (KOL or LPC or ethanol) and maintaining the ratio of the other excipients as in a reference formulation. The reference formulation contains KOL:LPC:ethanol (at a ratio of 17.5:17.5:5 w/w for (A) and 13:8:4 w/w for (B)). A 60% glyceride concentration is fixed for all formulations of DoE III and a 75% glyceride concentration is fixed for all formulations of DoE IV.

Fig. 5

(A) Prediction plot of MC SNEDDS containing 60% glycerides (Captex:Capmul (1:1 w/w)), 5%–25% KOL, 5%–25% LPC, and 0–10% ethanol (DoE III). (B) Prediction plot of MC SNEDDS containing 75% glycerides (Captex:Capmul (1:1 w/w)), 5%–25% KOL, 0–20% LPC, and 0–10% ethanol (DoE IV). Excipient concentrations are presented as fractions.