<abstract xmlns="http://www.w3.org/1999/xhtml">

<p>An important area of interest in pharmaceutical technology is the issue of poorly soluble drugs and their formulation into drug dosage forms that ensure optimal bioavailability. One of the options to solve solubility is the development of nanodispersion systems. This work is focused on the preparation of microemulsion systems suitable for poorly soluble drugs, for example, nimodipine. The composition and structure of microemulsion enable solubilization of different drugs and make it a universal drug carrier. Microemulsions increased the solubility of the model drug 20-fold compared to solubility in water. The use of mucoadhesive polymers – hydroxyethyl cellulose and xanthan gum – improved the in vitro release significantly. The highest amount of nimodipine was released from the microemulsion gel system with hydroxyethyl cellulose (1% w/w) and this depended on the diffusion of dissolved molecules.</p>
</abstract>

An important area of interest in pharmaceutical technology is the issue of poorly soluble drugs and their formulation into drug dosage forms that ensure optimal bioavailability. One of the options to solve solubility is the development of nanodispersion systems. This work is focused on the preparation of microemulsion systems suitable for poorly soluble drugs, for example, nimodipine. The composition and structure of microemulsion enable solubilization of different drugs and make it a universal drug carrier. Microemulsions increased the solubility of the model drug 20-fold compared to solubility in water. The use of mucoadhesive polymers – hydroxyethyl cellulose and xanthan gum – improved the in vitro release significantly. The highest amount of nimodipine was released from the microemulsion gel system with hydroxyethyl cellulose (1% w/w) and this depended on the diffusion of dissolved molecules.


<div xmlns="http://www.w3.org/1999/xhtml">
<sec id="j_afpuc-2023-0004_s_001"><div>INTRODUCTION</div>
<p>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 (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_002">Huang et al., 2018</a>). From a physical point of view, NIM is a highly lipophilic drug (log <italic>P</italic> value of 3.05) and belongs to BCS class II, showing extremely poor aqueous solubility (2.30 µg/mL<sup>−1</sup>) and high permeability (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_004">Lee et al, 2021</a>). The major problem associated with NIM is extensive first-pass metabolism, low solubility, and low oral bioavailability (5%–10%) (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_006">Pathak et al, 2014</a>) caused by poor and erratic absorption (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_001">Heran et al. 2018</a>). 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 (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_003">Kiwilsza et al, 2015</a>), liposomes (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_007">Wang et al, 2006</a>), or ethosomes (<a ref-type="bibr" href="#j_afpuc-2023-0004_ref_005">Mohamed et al, 2022</a>).</p>
<p>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.</p>
</sec>
<sec id="j_afpuc-2023-0004_s_002"><div>MATERIALS AND METHODS</div>
<p>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).</p>
<sec id="j_afpuc-2023-0004_s_002_s_001"><div>Preparation and evaluation of microemulsions</div>
<p>Microemulsions (ME1 prepared from oleic acid, isopropyl alcohol, polysorbate 80, and water; ME2 composed of a mixture of olive oil and oleic acid (1:2), PEG-35 castor oil, ethanol, and water) were prepared by spontaneous emulsification. The mixture of surfactant and co-surfactant was homogenized with oil until a clear mixture was obtained and then titrated with the aqueous phase. Both microemulsions were characterized by particle size determination (λ = 632 nm, t = 25°C; Zeta Sizer Nano, Malvern Instruments), viscosity (t = 25°C; Ostwald viscosimeter), transmittance (λ = 650 nm, t = 25°C; Spectrophotometer Genesys 10S UV-VIS, Thermo Scientific), pH, and conductivity (t = 25°C; Phenomenal MU 6100L, VWR).</p>
</sec>
<sec id="j_afpuc-2023-0004_s_002_s_002"><div><italic>In vitro</italic> drug release</div>
<p>Microemulsion gel systems were prepared as a mixture of microemulsion and hydroxyethyl cellulose (ME HEC, 1% w/w) or microemulsion and xanthan (ME XG, 0.5% w/w) gels in a ratio of 1:4. These systems were characterized based on the rheological properties measured by a rotary viscometer (Rheolab QC, Anton Paar). NIM was added in a concentration of 1% w/w and dissolved in the microemulsion.</p>
<p>The influence of microemulsion gel systems on the model drug was evaluated by liberation <italic>in vitro</italic>. The release of NIM was determined by using Franz cells throughout the regenerated cellulose membrane (MWCO 12–14 kDa) into phosphate-buffered saline (pH 7.4) heated to 37 ± 0.5°C for 6 h. The released amount of NIM was determined spectrophotometrically at 210 nm (Spectrophotometer Genesys 10S UV-VIS, Thermo Scientific).</p>
</sec>
</sec>
<sec id="j_afpuc-2023-0004_s_003"><div>RESULTS AND DISCUSSION</div>
<p>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 “<italic>co-oil</italic>” (in our case, oleic acid). The physicochemical properties of the microemulsion are summarized in <a ref-type="table" href="#j_afpuc-2023-0004_tab_001">Table 1</a>.</p>
<table-wrap id="j_afpuc-2023-0004_tab_001" position="float"><label>Table 1.</label>
<caption><p>Physicochemical properties of microemulsions.</p></caption>
<table frame="box" rules="all">
<thead>
<tr>
<th align="center" valign="middle"><bold>Properties</bold></th>
<th align="center" valign="middle"><bold>ME1</bold></th>
<th align="center" valign="middle"><bold>ME2</bold></th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle">Particle size (nm) ± SD</td>
<td align="center" valign="middle">42.47 ± 11.25</td>
<td align="center" valign="middle">61.4 ± 6.043</td>
</tr>
<tr>
<td align="center" valign="middle">Viscosity (mPa s) ± SD</td>
<td align="center" valign="middle">33.036 ± 0.061</td>
<td align="center" valign="middle">31.281 ± 0.686</td>
</tr>
<tr>
<td align="center" valign="middle">Transmittance ± SD</td>
<td align="center" valign="middle">99.009 ± 0.434</td>
<td align="center" valign="middle">97.882 ± 0.168</td>
</tr>
<tr>
<td align="center" valign="middle">pH ± SD</td>
<td align="center" valign="middle">5.08 ± 0.10</td>
<td align="center" valign="middle">5.21 ± 0.10</td>
</tr>
<tr>
<td align="center" valign="middle">Conductivity (µs cm<sup>−1</sup>) ± SD</td>
<td align="center" valign="middle">33.9 ± 0.1</td>
<td align="center" valign="middle">40.6 ± 0.1</td>
</tr>
<tr>
<td align="center" valign="middle">Solubility of NIM (µg mL<sup>−1</sup>) ± SD</td>
<td align="center" valign="middle">73.65 ± 12.03</td>
<td align="center" valign="middle">247.55 ± 26.31</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn-group>
<fn><p>±<italic>SD calculated from three parallel measurements</italic></p></fn>
</fn-group>
</table-wrap-foot>
</table-wrap>
<p>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 <a ref-type="table" href="#j_afpuc-2023-0004_tab_001">Table 1</a> shows, the solubility of NIM increased more than 20 times in ME2 compared to solubility in water (12 µg mL<sup>−1</sup>). 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.</p>
<p>Based on the kinetic parameters, it can be concluded that the release from the microemulsion ME2 is described by the Higuchi model (<italic>r</italic><sup>2</sup> = 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 (<italic>r</italic><sup>2</sup> = 0.9403). The release rate was constant and independent of the drug concentration in the microemulsion.</p>
<p>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, <italic>P</italic> ˃ 0.05).</p>
<p>As shown in <a ref-type="fig" href="#j_afpuc-2023-0004_fig_001">Figure 1</a>, 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 (<sup>***</sup><italic>P</italic> ˂ 0.001). The cumulative amount of NIM from ME2 XG was 1511.40 ± 0.436 µg cm<sup>−2</sup> and from ME2 HEC was 3226.28 ± 0.486 µg cm<sup>−2</sup> (<a ref-type="table" href="#j_afpuc-2023-0004_tab_002">Table 2</a>).</p>
<figure id="j_afpuc-2023-0004_fig_001" position="float" fig-type="figure"><h2>Figure 1.</h2>
<figCaption><p>The released amount of NIM from microemulsions and microemulsion gel systems compared to a water solution of NIM.</p></figCaption>
<img xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="graphic/j_afpuc-2023-0004_fig_001.jpg" src="https://sciendo-parsed.s3.eu-central-1.amazonaws.com/6470851571e4585e08a9f136/j_afpuc-2023-0004_fig_001.jpg?X-Amz-Algorithm=AWS4-HMAC-SHA256&amp;X-Amz-Date=20240711T075442Z&amp;X-Amz-SignedHeaders=host&amp;X-Amz-Expires=18000&amp;X-Amz-Credential=AKIA6AP2G7AKP25APDM2%2F20240711%2Feu-central-1%2Fs3%2Faws4_request&amp;X-Amz-Signature=515542d0e380203cfbfe29826d313d24239d3ec2ad3bd8440de05d439ec069d3" class="mw-100"/>
</figure>
<table-wrap id="j_afpuc-2023-0004_tab_002" position="float"><label>Table 2.</label>
<caption><p>Drug release from microemulsion gel systems and their viscosity.</p></caption>
<table frame="box" rules="all">
<thead>
<tr>
<th align="center" valign="middle"><bold>Sample</bold></th>
<th align="center" valign="middle"><bold>Viscosity<a ref-type="table-fn" href="#j_afpuc-2023-0004_table-fn_001"><sup>a</sup></a> (mPa s)</bold></th>
<th align="center" valign="middle"><bold>The cumulative amount of NIM after 6 h (µg cm<sup>−2</sup>) ± SD<a ref-type="table-fn" href="#j_afpuc-2023-0004_table-fn_002"><sup>b</sup></a></bold></th>
</tr>
</thead>
<tbody>
<tr>
<td align="center" valign="middle">ME1 XG gel</td>
<td align="center" valign="middle">145.10</td>
<td align="center" valign="middle">556.20 ± 0.630</td>
</tr>
<tr>
<td align="center" valign="middle">ME1 HEC gel</td>
<td align="center" valign="middle">835.33</td>
<td align="center" valign="middle">2483.83 ± 0.795</td>
</tr>
<tr>
<td align="center" valign="middle">ME2 XG gel</td>
<td align="center" valign="middle">184.30</td>
<td align="center" valign="middle">1511.40 ± 0.436</td>
</tr>
<tr>
<td align="center" valign="middle">ME2 HEC gel</td>
<td align="center" valign="middle">194.60</td>
<td align="center" valign="middle">3226.28 ± 0.486</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn-group>
<fn id="j_afpuc-2023-0004_table-fn_001"><label>a</label><p><italic>Share rate D = 644.4 (s<sup>−1</sup>)</italic></p></fn>
<fn id="j_afpuc-2023-0004_table-fn_002"><label>b</label><p><italic>Calculated from six parallel measurements</italic></p></fn>
</fn-group>
</table-wrap-foot>
</table-wrap>
</sec>
<sec id="j_afpuc-2023-0004_s_004"><div>CONCLUSION</div>
<p>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 <italic>in vitro</italic> preformulation study showed the highest cumulative amount of released drug (57.80 ± 0.87%) after 6 h.</p>
<p>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.</p>
</sec>
</div>

Microemulsions as the Potential Delivery System for Nimodipine

Faculty of Pharmacy, Department of Galenic Pharmacy

European Pharmaceutical Journal

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

{"article-title":"Microemulsions as the Potential Delivery System for Nimodipine"}

An important area of interest in pharmaceutical technology is the issue of poorly soluble drugs and their formulation into drug dosage forms that ensure...

Microemulsions as the Potential Delivery System for Nimodipine

Article Category: Special Issue Article

Published Online: Aug 24, 2023

Page range: 34 - 36

Received: Jun 20, 2023

Accepted: Jun 22, 2023

DOI: https://doi.org/10.2478/afpuc-2023-0004

Keywords
microemulsion, nimodipine, hydroxyethyl cellulose, xanthan gum

© 2023 M. Čuchorová et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Microemulsions as the Potential Delivery System for Nimodipine

Article Category: Special Issue Article

Published Online: Aug 24, 2023

Page range: 34 - 36

Received: Jun 20, 2023

Accepted: Jun 22, 2023

DOI: https://doi.org/10.2478/afpuc-2023-0004

Keywordsmicroemulsion, nimodipine, hydroxyethyl cellulose, xanthan gum

© 2023 M. Čuchorová et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
microemulsion, nimodipine, hydroxyethyl cellulose, xanthan gum