Microemulsions as the Potential Delivery System for Nimodipine

Nimodipine (NIM), a dihydropyridine calcium channel blocker, is used in the treatment of mild or moderate hypertension, sudden hearing loss, and mainly ischemic cerebrovascular disease (Huang et al., 2018). From a physical point of view, NIM is a highly lipophilic drug (log P value of 3.05) and belongs to BCS class II, showing extremely poor aqueous solubility (2.30 µg/mL) and high permeability (Lee et al, 2021). The major problem associated with NIM is extensive first-pass metabolism, low solubility, and low oral bioavailability (5%–10%) (Pathak et al, 2014) caused by poor and erratic absorption (Heran et al. 2018). One of the solutions to ensure bioavailability of NIM is the preparation of alternative application forms such as microspheres, solid microemulsions, drug-loaded type systems based on cyclodextrins, lipids, phospholipid micelles (Kiwilsza et al, 2015), liposomes (Wang et al, 2006), or ethosomes (Mohamed et al, 2022).

This work is focused on the preformulation studies of microemulsions as delivery systems for NIM. The specific properties of microemulsions, such as thermodynamic stability, high solubilizing capacity, and enhanced penetration through the biological membranes, could be promising systems for intranasal or transdermal application of NIM.

NIM was kindly supplied by VULM Modra (Slovakia); PEG-35 castor oil, xanthan gum, and hydroxyethyl cellulose were obtained from Sigma Aldrich Chemie GmbH (Germany); xanthan gum was purchased from Merck KGaA (Germany); and olive oil, oleic acid, isopropyl alcohol, and ethanol (96% w/w) were obtained from Centralchem s.r.o. (Slovakia).

The prepared O/W microemulsion contained natural oils (oleic acid and olive oil), the nature of which largely determines the formation of an oil microemulsion. The preparation of an O/W microemulsion from such oil is possible either through a high concentration of surfactant or by adding the “co-oil” (in our case, oleic acid). The physicochemical properties of the microemulsion are summarized in Table 1.

The composition and properties affect the incorporation of drugs. Clear and transparent solutions with appropriate sizes were prepared. Other properties were very similar in both cases, while they were probably most affected by the proportion of the aqueous phase. As Table 1 shows, the solubility of NIM increased more than 20 times in ME2 compared to solubility in water (12 µg mL⁻¹). It is evident that the low solubility of the drug in water caused uneven release. Compared to microemulsions, only 2.31% of the drug was released from the aqueous solution. The microemulsion was able to encapsulate the drug in its internal phase and thus improve the diffusion coefficient of the drug, which ultimately increased the release.

Based on the kinetic parameters, it can be concluded that the release from the microemulsion ME2 is described by the Higuchi model (r² = 0.9232). In this case, the diffusion coefficient of the drug in the microemulsion was constant, and the permeation of the drug through the membrane occurred depending on the diffusion of dissolved drug molecules. However, the zero-order model is more suitable for the release of NIM from ME1 (r² = 0.9403). The release rate was constant and independent of the drug concentration in the microemulsion.

The use of microemulsions themselves is often limited by their low viscosity due to the reduced time of action. Despite a wide selection of gelling agents and polymers, the choice of the microemulsion system is more difficult due to its influence on the thermodynamic stability of the system. The selected gels – xanthan gum (0.5%, w/w) as well as hydroxyethyl cellulose (1%, w/w) gel – were characterized based on rheological parameters. In both systems, the non-Newtonian character with the time-independent flow was observed. The increase in the viscosity and the preparation of gels with mucoadhesive polymers significantly increased the amount of released drug, except for the sample ME1 XG gel where no significant differences in the drug concentration were observed (NS, P ˃ 0.05).

As shown in Figure 1, in both gel systems – ME2 XG and ME2 HEC – there was a significant increase in the released drug compared to the reference sample, which was a microemulsion (^***P ˂ 0.001). The cumulative amount of NIM from ME2 XG was 1511.40 ± 0.436 µg cm⁻² and from ME2 HEC was 3226.28 ± 0.486 µg cm⁻² (Table 2).

Figure 1.

As the results indicate, the most suitable formulation for NIM was a mixture of microemulsion 2 containing a mixture of oleic acid and olive oil, and hydroxyethyl cellulose gel (1%, w/w). This system had appropriate solubilizing capacity due to the presence of microemulsion, and in vitro preformulation study showed the highest cumulative amount of released drug (57.80 ± 0.87%) after 6 h.

Microemulsion, together with mucoadhesive polymers, could play an important role in the drug delivery of NIM. By increasing the contact between the drug forms and the skin (transdermal application) or mucus membrane (nasal application), the absorption of the drug and thereby its bioavailability increase by minimizing the impact of physiological factors on the elimination of the drug.