Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy
Identifieur interne : 000E02 ( Ncbi/Merge ); précédent : 000E01; suivant : 000E03Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy
Auteurs : Célia Faustino ; Lídia PinheiroSource :
- Pharmaceutics [ 1999-4923 ] ; 2020.
Abstract
Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.
Url:
DOI: 10.3390/pharmaceutics12010029
PubMed: 31906268
PubMed Central: 7023008
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy</title><author><name sortKey="Faustino, Celia" sort="Faustino, Celia" uniqKey="Faustino C" first="Célia" last="Faustino">Célia Faustino</name></author><author><name sortKey="Pinheiro, Lidia" sort="Pinheiro, Lidia" uniqKey="Pinheiro L" first="Lídia" last="Pinheiro">Lídia Pinheiro</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31906268</idno><idno type="pmc">7023008</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023008</idno><idno type="RBID">PMC:7023008</idno><idno type="doi">10.3390/pharmaceutics12010029</idno><date when="2020">2020</date><idno type="wicri:Area/Pmc/Corpus">000A99</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000A99</idno><idno type="wicri:Area/Pmc/Curation">000A99</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000A99</idno><idno type="wicri:Area/Pmc/Checkpoint">000113</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000113</idno><idno type="wicri:Area/Ncbi/Merge">000E02</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy</title><author><name sortKey="Faustino, Celia" sort="Faustino, Celia" uniqKey="Faustino C" first="Célia" last="Faustino">Célia Faustino</name></author><author><name sortKey="Pinheiro, Lidia" sort="Pinheiro, Lidia" uniqKey="Pinheiro L" first="Lídia" last="Pinheiro">Lídia Pinheiro</name></author></analytic><series><title level="j">Pharmaceutics</title><idno type="eISSN">1999-4923</idno><imprint><date when="2020">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bongomin, F" uniqKey="Bongomin F">F. Bongomin</name></author><author><name sortKey="Gago, S" uniqKey="Gago S">S. Gago</name></author><author><name sortKey="Oladele, R O" uniqKey="Oladele R">R.O. Oladele</name></author><author><name sortKey="Denning, D W" uniqKey="Denning D">D.W. Denning</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vallabhaneni, S" uniqKey="Vallabhaneni S">S. Vallabhaneni</name></author><author><name sortKey="Mody, R K" uniqKey="Mody R">R.K. Mody</name></author><author><name sortKey="Walker, T" uniqKey="Walker T">T. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Pharmaceutics</journal-id><journal-id journal-id-type="iso-abbrev">Pharmaceutics</journal-id><journal-id journal-id-type="publisher-id">pharmaceutics</journal-id><journal-title-group><journal-title>Pharmaceutics</journal-title></journal-title-group><issn pub-type="epub">1999-4923</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31906268</article-id><article-id pub-id-type="pmc">7023008</article-id><article-id pub-id-type="doi">10.3390/pharmaceutics12010029</article-id><article-id pub-id-type="publisher-id">pharmaceutics-12-00029</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4599-8404</contrib-id><name><surname>Faustino</surname><given-names>Célia</given-names></name></contrib><contrib contrib-type="author"><name><surname>Pinheiro</surname><given-names>Lídia</given-names></name><xref rid="c1-pharmaceutics-12-00029" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-pharmaceutics-12-00029">Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;<email>cfaustino@ff.ulisboa.pt</email></aff><author-notes><corresp id="c1-pharmaceutics-12-00029"><label>*</label>Correspondence: <email>lpinheiro@ff.ulisboa.pt</email>; Tel.: +351-21-7946-400; Fax: +351-21-7946-470</corresp></author-notes><pub-date pub-type="epub"><day>01</day><month>1</month><year>2020</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2020</year></pub-date><volume>12</volume><issue>1</issue><elocation-id>29</elocation-id><history><date date-type="received"><day>27</day><month>11</month><year>2019</year></date><date date-type="accepted"><day>19</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>© 2020 by the authors.</copyright-statement><copyright-year>2020</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Amphotericin B (AmB), a broad-spectrum polyene antibiotic in the clinic for more than fifty years, remains the gold standard in the treatment of life-threatening invasive fungal infections and visceral leishmaniasis. Due to its poor water solubility and membrane permeability, AmB is conventionally formulated with deoxycholate as a micellar suspension for intravenous administration, but severe infusion-related side effects and nephrotoxicity hamper its therapeutic potential. Lipid-based formulations, such as liposomal AmB, have been developed which significantly reduce the toxic side effects of the drug. However, their high cost and the need for parenteral administration limit their widespread use. Therefore, delivery systems that can retain or even enhance antimicrobial efficacy while simultaneously reducing AmB adverse events are an active area of research. Among those, lipid systems have been extensively investigated due to the high affinity of AmB for binding lipids. The development of a safe and cost-effective oral formulation able to improve drug accessibility would be a major breakthrough, and several lipid systems for the oral delivery of AmB are currently under development. This review summarizes recent advances in lipid-based systems for targeted delivery of AmB focusing on non-parenteral nanoparticulate formulations mainly investigated over the last five years and highlighting those that are currently in clinical trials.</p></abstract><kwd-group><kwd>amphotericin B</kwd><kwd>fungal diseases</kwd><kwd>drug delivery</kwd><kwd>lipid systems</kwd><kwd>nanoparticles</kwd><kwd>infection</kwd></kwd-group></article-meta></front><floats-group><fig id="pharmaceutics-12-00029-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Chemical structure of amphotericin B.</p></caption><graphic xlink:href="pharmaceutics-12-00029-g001"></graphic></fig><table-wrap id="pharmaceutics-12-00029-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-12-00029-t001_Table 1</object-id><label>Table 1</label><caption><p>Properties and clinical pharmacokinetic parameters of commercial amphotericin B parenteral formulations.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Formulation</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Composition (Molar Ratio)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Structure</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Size (nm)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Population (<italic>n</italic>)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Dose (mg/kg/day)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Duration </th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"><italic>C</italic><sub>max</sub> (μg/mL)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">AUC<sub>0–24 h</sub> (μg/h/mL)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"><italic>t</italic><sub>1/2</sub> (h)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">CL (mL/h/kg)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"><italic>V</italic><sub>d</sub> (L/kg)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">AmB-DOC (Fungizone<sup>®</sup>)</td><td align="center" valign="middle" rowspan="1" colspan="1">DOC:AmB (2:1)</td><td align="center" valign="middle" rowspan="1" colspan="1">Micellar dispersion</td><td align="center" valign="middle" rowspan="1" colspan="1">35</td><td align="center" valign="middle" rowspan="1" colspan="1">Mucocutaneous<break></break>leishmaniasis (<italic>n</italic> = 5)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.6 (i.v. 0.25 mg/kg/h), 42 days</td><td align="center" valign="middle" rowspan="1" colspan="1">Day 42</td><td align="center" valign="middle" rowspan="1" colspan="1">1.06 ± 0.14</td><td align="center" valign="middle" rowspan="1" colspan="1">17.06 ± 5.03</td><td align="center" valign="middle" rowspan="1" colspan="1">91.1 ± 40.9</td><td align="center" valign="middle" rowspan="1" colspan="1">29.2 ± 12.2 <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" rowspan="1" colspan="1">5.17 ± 2.6</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B97-pharmaceutics-12-00029" ref-type="bibr">97</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neutropenic with fungal infection (<italic>n</italic> = 8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Day 1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.83 ± 1.17</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28.98 ± 15.46</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15.23 ± 5.25</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">33.01 ± 14.33</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.56 ± 0.15</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B98-pharmaceutics-12-00029" ref-type="bibr">98</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-DOC in Intralipid<sup>®</sup> 20% (admixture)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Soybean oil 20% <italic>w</italic>/<italic>v</italic>, egg yolk PLs 1.2% <italic>w</italic>/<italic>v</italic>, glycerin 2.25% <italic>w</italic>/<italic>v</italic>, AmB 1 mg/mL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fat emulsion</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><1000</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neutropenic with fungal infection (<italic>n</italic> = 8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Day 1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.46 ± 0.61</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">17.22 ± 11.15</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11.44 ± 5.18</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">62.97 ± 35.51</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.04 ± 0.51</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B98-pharmaceutics-12-00029" ref-type="bibr">98</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ABLC (Abelcet<sup>®</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DMPC:DMPG (7:3)-AmB (1:1)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ribbons</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1600–11,000</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mucocutaneous<break></break>leishmaniasis (<italic>n</italic> = 8)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 (2 h-inf.), 5 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Day 5</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.70 ± 0.83</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9.50 ± 1.36</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">173.4 ± 78.0</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">408.2 ± 61.9 <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">131.0 ± 57.7</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B97-pharmaceutics-12-00029" ref-type="bibr">97</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fungal infections (<italic>n</italic> = 17)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5 (2-h inf.), 10–17 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Last day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.39 ± 1.58</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">19.17 ± 4.43</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">393 ± 486</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">270 ± 70</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">147 ± 144</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B99-pharmaceutics-12-00029" ref-type="bibr">99</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">ABCD (Amphotec<sup>®</sup>, Amphocil<sup>®</sup>)</td><td align="center" valign="middle" rowspan="1" colspan="1">Cholesteryl sulfate:AmB (1:1)</td><td align="center" valign="middle" rowspan="1" colspan="1">Disks</td><td align="center" valign="middle" rowspan="1" colspan="1">(122 ± 48) × 4.3</td><td align="center" valign="middle" rowspan="1" colspan="1">Critically ill patients (<italic>n</italic> = 5)</td><td align="center" valign="middle" rowspan="1" colspan="1">4 (4 h-inf.), 5 days</td><td align="center" valign="middle" rowspan="1" colspan="1">Single dose</td><td align="center" valign="middle" rowspan="1" colspan="1">0.65 ± 0.26</td><td align="center" valign="middle" rowspan="1" colspan="1">4.24 ± 1.14</td><td align="center" valign="middle" rowspan="1" colspan="1">28.54 ± 18.97</td><td align="center" valign="middle" rowspan="1" colspan="1">320 ± 230</td><td align="center" valign="middle" rowspan="1" colspan="1">8.89 ± 2.64</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B100-pharmaceutics-12-00029" ref-type="bibr">100</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">Day 5</td><td align="center" valign="middle" rowspan="1" colspan="1">1.24 ± 0.53</td><td align="center" valign="middle" rowspan="1" colspan="1">14.22 ± 7.54</td><td align="center" valign="middle" rowspan="1" colspan="1">19.56 ± 8.44</td><td align="center" valign="middle" rowspan="1" colspan="1">190 ± 130</td><td align="center" valign="middle" rowspan="1" colspan="1">4.65 ± 2.01</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B100-pharmaceutics-12-00029" ref-type="bibr">100</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bone marrow transplant recipients (<italic>n</italic> = 51)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4 (4 h-inf.), 10 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Steady state <italic><sup>(b)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">42</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">29.8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">112</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4.08</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B101-pharmaceutics-12-00029" ref-type="bibr">101</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">L-AmB (AmBisome<sup>®</sup>)</td><td align="center" valign="middle" rowspan="1" colspan="1">HSPC:DSPG:cholesterol:AmB (2:0.8:1:0.4)</td><td align="center" valign="middle" rowspan="1" colspan="1">SUV</td><td align="center" valign="middle" rowspan="1" colspan="1">60–80</td><td align="center" valign="middle" rowspan="1" colspan="1">Critically ill patients (<italic>n</italic> = 16)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.0 (1 h-inf.)</td><td align="center" valign="middle" rowspan="1" colspan="1">Steady state</td><td align="center" valign="middle" rowspan="1" colspan="1">14.4 (6.4–89.0)</td><td align="center" valign="middle" rowspan="1" colspan="1">171 (53.1–1380)</td><td align="center" valign="middle" rowspan="1" colspan="1">13.05 (8.70–41.40)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.311 (0.031–0.807) <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" rowspan="1" colspan="1">0.421 (0.055–0.932)</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B102-pharmaceutics-12-00029" ref-type="bibr">102</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">Neutropenic with fungal infection (<italic>n</italic> = 12)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 (1 h-inf.), 8 days</td><td align="center" valign="middle" rowspan="1" colspan="1">Day 1</td><td align="center" valign="middle" rowspan="1" colspan="1">57.6 ± 21.0</td><td align="center" valign="middle" rowspan="1" colspan="1">269 ± 96</td><td align="center" valign="middle" rowspan="1" colspan="1">6.4 ± 2.1</td><td align="center" valign="middle" rowspan="1" colspan="1">21 ± 14</td><td align="center" valign="middle" rowspan="1" colspan="1">0.22 ± 0.17</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B103-pharmaceutics-12-00029" ref-type="bibr">103</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">Last day</td><td align="center" valign="middle" rowspan="1" colspan="1">83.0 ± 35.2</td><td align="center" valign="middle" rowspan="1" colspan="1">555 ± 311</td><td align="center" valign="middle" rowspan="1" colspan="1">6.8 ± 2.1</td><td align="center" valign="middle" rowspan="1" colspan="1">11 ± 6</td><td align="center" valign="middle" rowspan="1" colspan="1">0.11 ± 0.08</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B103-pharmaceutics-12-00029" ref-type="bibr">103</xref>]</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1"></td><td align="center" valign="middle" rowspan="1" colspan="1">Immuno-compromised patients with IFI (<italic>n</italic> = 8)</td><td align="center" valign="middle" rowspan="1" colspan="1">7.5 (2 h-inf.), 23 days</td><td align="center" valign="middle" rowspan="1" colspan="1">Day 1</td><td align="center" valign="middle" rowspan="1" colspan="1">75.9 ± 58.4 </td><td align="center" valign="middle" rowspan="1" colspan="1">692 ± 834</td><td align="center" valign="middle" rowspan="1" colspan="1">6.8 ± 1.9</td><td align="center" valign="middle" rowspan="1" colspan="1">23 ± 14</td><td align="center" valign="middle" rowspan="1" colspan="1">0.22 ± 0.18</td><td align="center" valign="middle" rowspan="1" colspan="1">[<xref rid="B104-pharmaceutics-12-00029" ref-type="bibr">104</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Last day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">144.3 ± 61.6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1286 ± 973</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6.5 ± 3.4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11 ± 13</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.08 ± 0.08</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B104-pharmaceutics-12-00029" ref-type="bibr">104</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Indian L-AmB (Fungisome<sup>TM</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SPC:cholesterol (7:3)-AmB (1:45) 2.2% <italic>w</italic>/<italic>w</italic> in normal saline</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MLV</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2743–3454</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Systemic fungal infections (<italic>n</italic> = 12)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1 (1 h-inf.), 3 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Last day</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.01 ± 0.06</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11.43 ± 0.91</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">17.2 ± 1.8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">91.7 ± 8.9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.28 ± 0.30</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B105-pharmaceutics-12-00029" ref-type="bibr">105</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p>ABCD, amphotericin B colloidal dispersion; ABLC, amphotericin B lipid complex; AmB, amphotericin B; AmB-DOC amphotericin B deoxycholate; AUC, area under the concentration–time curve; CL, total body clearance; <italic>C</italic><sub>max</sub>, peak plasma concentration; DMPC, dimyristoyl phosphatidylcholine; DMPG, dimyristoyl phosphatidylglycerol; DOC, deoxycholate; DSPG, distearoyl phosphatidylglycerol; HSPC, hydrogenated soy phosphatidylcholine; IFI, invasive fungal infection; inf., infusion; i.v., intravenous; L-AMB, liposomal amphotericin B; MLV, multilamellar vesicles; <italic>n</italic>, number of subjects; PL, phospholipid; SPC, soy phosphatidylcholine; SUV, small unilamellar vesicles; <italic>t</italic><sub>1/2</sub>, half-life; <italic>V</italic><sub>d</sub>, apparent volume of distribution; <italic>w</italic>/<italic>w</italic>, weight/weight; <italic><sup>(a)</sup></italic>assuming mean body weight of 70.0 kg; <italic><sup>(b)</sup></italic> Predicted values obtained from population modeling. Data presented as mean ± standard deviation or mean (range).</p></fn></table-wrap-foot></table-wrap><table-wrap id="pharmaceutics-12-00029-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-12-00029-t002_Table 2</object-id><label>Table 2</label><caption><p>Lipid-based systems for delivery of amphotericin B currently under development.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Delivery System</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Adm. Route</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Size, nm (PI)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">EE, %</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Formulation Composition and Preparation Method</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Main Outcomes and Limitations</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref.</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oleic acid (OA) conjugate (amide prodrug)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-OA conjugate.<break></break>Synthesis via CDI chemistry.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Conjugation to OA improved AmB stability at gastric pH and permeability in Caco-2 monolayer model with cell viability >90% and reversible TEER reduction.<break></break>Metabolism of AmB-OA into AmB > 80% in liver homogenate.<break></break>AmB-OA showed differential aggregation behavior with no evidence of hemolytic or kidney (HEK 293 cells) toxicity in vitro.<break></break>Oral AmB-OA given to rats (10 mg/kg in PBS as gavage vehicle) significantly increased <italic>C</italic><sub>max</sub> and AUC compared to AmB i.v. and AmB-OA admixture. Histopathological studies did not show kidney or liver damage in animals treated with oral AmB-OA conjugate.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B161-pharmaceutics-12-00029" ref-type="bibr">161</xref>,<xref rid="B162-pharmaceutics-12-00029" ref-type="bibr">162</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Molecular umbrella conjugate (amide prodrug)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-di-walled molecular umbrella (cholic acid walls and spermidine scaffold) conjugate.<break></break>Synthesis via CDI chemistry.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Conjugation reduced hemolytic activity and in vitro cytotoxicity to kidney (HEK 293) cells.<break></break>The conjugate retained in vitro antifungal efficacy against <italic>C. albicans</italic>, <italic>Candida glabrata</italic>, <italic>Cryptococcus neoformans,</italic> and <italic>Cryptococcus gatti</italic> with MIC and MFC values in the range of 1–2 μM and 2–4 μM, respectively.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B163-pharmaceutics-12-00029" ref-type="bibr">163</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SDCS micelles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pulmonary</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">73 ± 0.9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB:SDCS (1:2 molar ratio).<break></break>Lyophilized dry powder.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Jet nebulization of anionic SDCS micelles (ζ –40 mV) produced aerosols suitable for inhaler use (MMAD 1.0 μm, FPF 81.4%, and GSD 2.1).<break></break>Enhanced in vitro antifungal activity against <italic>C. albicans</italic>, <italic>C. neoformans,</italic> and <italic>Saccharomyces cerevisiae</italic>, antileishmanial against <italic>Leishmania tropica</italic> promastigotes (IC<sub>50</sub> 0.021 μM).<break></break>Not cytotoxic in vitro (MTT assay) to kidney (HK-2, 293T/17), bronchial epithelial (HBE1), lung cancer (A549, Calu-3), and macrophage (NR8383, RAW 267.4) cell lines at conc. up to 8 μg/mL (cell viability > 90%).<break></break>In vitro phagocytosis by alveolar macrophages (NR8383).<break></break>Not nephrotoxic in vivo after 7 days of regular dosing (1.5 mg/kg/day) to rats by intratracheal instillation.<break></break>Higher drug conc. in lung (7.5 μg/g) and lower in kidney (0.06 μg/g).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B124-pharmaceutics-12-00029" ref-type="bibr">124</xref>,<xref rid="B164-pharmaceutics-12-00029" ref-type="bibr">164</xref>,<xref rid="B165-pharmaceutics-12-00029" ref-type="bibr">165</xref>,<xref rid="B166-pharmaceutics-12-00029" ref-type="bibr">166</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LAA micelles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">63.4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-loaded LAA micelles.<break></break>Self-assembly in PBS (pH 7.4) at r.t.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LAA micelles (CMC 0.612 mM) deaggregated AmB in a concentration-dependent manner with a more pronounced effect at higher LAA conc.<break></break>In vitro activity against <italic>C. albicans</italic> (ATCC 10231), MIC 3.12 μg/mL.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B167-pharmaceutics-12-00029" ref-type="bibr">167</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LAA-BS mixed micelles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral, topical <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">49–61</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">LAA-BS mixed micelles (1:1 molar ratio) loaded with AmB.<break></break>Self-assembly in PBS (pH 7.4) at r.t.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The presence of LAA with dimeric structure in LAA-NaC (CMC 1.05 mM) and LAA-NaDC (CMC 1.74 mM) improved AmB solubilization compared to pure BS micelles.<break></break>In vitro activity against <italic>C. albicans</italic> (ATCC 10231), MIC (μg/mL) 2.50 (LAA-NaC) and 6.25 (LAA-NaDC).<break></break>UV spectroscopy showed monomeric AmB in LAA-BS mixed micelles at 10 mM.<break></break>LAA-NaDC formed shear-shinning gels at higher NaDC conc. (>10 mM) that can provide interesting topical DDS.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B168-pharmaceutics-12-00029" ref-type="bibr">168</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Surface-modified liposomes (SML)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">204.4 ± 0.34 (0.22)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">95</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Unsaturated SPC:saturated SPC:cholesterol (1:1:1 molar ratio) with modified ligand (3% <italic>w</italic>/<italic>w</italic>) and AmB (105 μg/mg lipid).<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Alginate hydrophobized by conjugation with Sta produced anionic SML (ζ –19.21 mV) with enhanced cellular uptake in macrophage (RAW 264.7) cells attributed to receptor-mediated endocytosis.<break></break>In healthy mice, SML (5 mg/kg single i.v. dose) resulted in improved PK profile, higher accumulation in liver and spleen (with no histopathological damage to the organs), and lower accumulation in kidney compared to conventional (unmodified) liposomes and AmB solution.<break></break>SML displayed enhanced anti-leishmanial activity against both promastigotes (IC<sub>50</sub> 39.7 nM) and amastigotes (IC<sub>50</sub> 29.1 nM) of <italic>Leishmania donovani</italic> (Dd8) compared to conventional liposomes and AmB solution.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B169-pharmaceutics-12-00029" ref-type="bibr">169</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Magnetic liposomes (MLP)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Intracarotid</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">240 ± 11 (0.092)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">79.32</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SPC:cholesterol (5:1 weight ratio) and AmB:Fe<sub>3</sub>O<sub>4</sub> (1:2 weight ratio).<break></break>Film dispersion-ultrasonication method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Good magnetic responsiveness (saturation magnetization 32.54 memu/g at r.t.).<break></break>AmB-MLP crossed the BBB enhancing AmB conc. in the brain under an applied magnetic field after carotid artery injection to rats (1 mg/kg).<break></break>AmB-MLP may be used for simultaneous MRI and AmB delivery in brain fungal infections.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B170-pharmaceutics-12-00029" ref-type="bibr">170</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stigmasterol-based liposomes (DSHemsPC)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">111.6 ± 1.0 (0.21)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DSHemsPC:DMPC:DMPG:AmB (1.25:5:1.5:1 molar ratio).<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anionic liposomes (ζ –25.3 mV) were less hemolytic (IC<sub>50</sub> 42.6 mg/mL) than AmBisome<sup>®</sup> (IC<sub>50</sub> 11.6 mg/mL).<break></break>In vitro antifungal activity (MIC 0.07–2.3 μg/mL) against <italic>C. albicans</italic> (PTCC 5027), <italic>C. glabrata</italic> (PTCC 5297), <italic>A. fumigatus</italic> (PTCC 5009), <italic>A. terreus</italic> (PTCC 5021), and <italic>A. flavus</italic> (PTCC 5006), anti-leishmanial against <italic>Leishmania major</italic> promastigotes (ED<sub>50</sub> 1.4 μg/mL) and amastigotes (ED<sub>50</sub> 0.14 μg/mL).<break></break>Biodistribution studies in mice showed higher AmB conc. in liver and spleen and lower in kidney.<break></break>In mouse models of both acute and established lesions (<italic>L. major</italic> MRHO/IR/75/ER), multiple doses (5 mg/kg i.v.) of AmB-DSHemsPC cleared parasites from liver and spleen but less effectively from footpad, suggesting more suitability for VL treatment than CL.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B171-pharmaceutics-12-00029" ref-type="bibr">171</xref>,<xref rid="B172-pharmaceutics-12-00029" ref-type="bibr">172</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Transfersomes, UDL</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">106 ± 6 (0.14)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SPC:Tween 80:AmB (86:43:0.1 weight ratio).<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-UDL encapsulated AmB in its monomeric form.<break></break>In vitro antifungal activity (MIC 0.06–0.25 μg/mL) against ATCC <italic>Candida</italic> strains (<italic>C. albicans</italic> 10231, <italic>C. tropicalis</italic> 750, <italic>C. glabrata</italic> 90030, <italic>C. krusei</italic> 6258, <italic>C. parapsilosis</italic> 22019) and clinical isolates of <italic>C. albicans</italic> at conc. not toxic to human keratinocyte (HaCaT) and murine monocyte/macrophage (J774) cells.<break></break>AmB-UDL at 1.25 μg/mL exhibited 100% and 75% activity against promastigote and amastigote forms of <italic>L. braziliensis</italic>, respectively.<break></break>Non-occlusive incubation (1 h) of human skin explants with AmB-UDL revealed drug penetration into deep epithelial layers and much higher drug accumulation in skin (1.8 ± 0.1 μg/cm<sup>2</sup>) compared to AmBisome<sup>®</sup> (0.045 ± 0.002 μg/cm<sup>2</sup>).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B173-pharmaceutics-12-00029" ref-type="bibr">173</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nanoethosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">258 ± 2 (0.261)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">89.1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SPC:ethanol:AmB (3:30:0.1 weight ratio) in Carbopol<sup>®</sup> gel (1.5% <italic>w</italic>/<italic>w</italic>).</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nanoethosomes containing 30% (<italic>w</italic>/<italic>w</italic>) ethanol showed enhanced skin permeability compared to a marketed gel formulation (AmB 0.1% <italic>w</italic>/<italic>w</italic>).<break></break>Enhanced in vitro activity against <italic>C. albicans</italic>.<break></break>No skin irritation observed in vivo (Draize test).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B174-pharmaceutics-12-00029" ref-type="bibr">174</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ergosterol-based liposomes (Kalsome<sup>TM</sup>10)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">119.5 ± 14.85</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PC:ergosterol:AmB (5:2:1.8 molar ratio) in 0.9% saline.<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mixed lamellarity liposomes, require sonication before administration to reduce particle size.<break></break>Kalsome<sup>TM</sup>10-mediated anti-leishmanial effect is dependent on endocytosis by host macrophages.<break></break>Kalsome<sup>TM</sup>10 induced apoptosis in both promastigote and intracellular amastigote forms of <italic>L. donovani</italic> but not on mammalian host macrophages.<break></break>Mechanistic studies showed increased ROS production, caspase-like activity, and DNA fragmentation in Kalsome<sup>TM</sup>10-treated promastigotes and amastigotes.<break></break>In <italic>L. donovani</italic>-infected mice, Kalsome<sup>TM</sup>10 to (7.5 mg/kg triple i.v. dose) suppressed parasite burden, shifting immune response from Th2 (IL-10 and TGFβ production) to Th1-type (IL-12 and IFNγ production).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B175-pharmaceutics-12-00029" ref-type="bibr">175</xref>,<xref rid="B176-pharmaceutics-12-00029" ref-type="bibr">176</xref>,<xref rid="B177-pharmaceutics-12-00029" ref-type="bibr">177</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEGylated cationic liposomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vaginal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">400–500</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50–60</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DOPE:DOTAP:cholesterol (4:5:1 molar ratio) and 6 mol% DSPE-PEG2k in thermosensitive poloxamer gel composed of P407:P188 (15:15 <italic>v</italic>/<italic>v</italic>).</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEGylation enhanced AmB solubility and encapsulation efficiency.<break></break>The formulation showed a sol-to-gel transition at body temperature of 37 °C.<break></break>PEGylated cationic liposomes (ζ 40–60 mV) were more stable and less toxic to kidney (HEK 293) cells than the free drug.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B178-pharmaceutics-12-00029" ref-type="bibr">178</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sophorolipid (SL) niosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">80</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">63.20</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acidic SL:cholesterol:DCP (10:0.9:0.64 molar ratio) and AmB in 0.9% saline.<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Affordable SLs produced by <italic>S. bombicola</italic> from renewable low-cost substrates (rice bran and cottonseed oil).<break></break>Higher <italic>C. albicans</italic> (clinical strain SC5314) anti-biofilm effect of AmB-SL niosomes after 24 h incubation (BEC<sub>50</sub> 0.195 μg/mL) compared to AmB alone (BEC<sub>50</sub> 0.390 μg/mL).<break></break>Absence of pseudohyphae on mature biofilms treated with niosomal AmB but not with marketed liposomal AmB (Phosome<sup>®</sup>).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B179-pharmaceutics-12-00029" ref-type="bibr">179</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cholesterol-based NEs </td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">169 ± 0 (0.11 ± 0.02)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">99 ± 1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5% MCT, 1.5% polysorbate 80, 0.5% cholesterol, 0.2% Sta, 0.01% α-tocopherol, 2.25% glycerol, AmB (1.99 ± 0.01 mg/mL); pH 7.44.<break></break>Hot homogenization method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cytotoxicity studies on J774 (ATCC/TIB-67TM) murine macrophages (24 h exposure) CC<sub>50</sub> 1.8 ± 0.8 μg/mL.<break></break>In vitro efficacy against intracellular amastigotes of <italic>L. amazonensis</italic> (IFLA/BR/67/PH8), IC<sub>50</sub> 0.11 ± 0.03 μg/mL.<break></break>Stability (ζ 53 ± 2 mV) for at least 180 days.<break></break>Increase of Sta conc. enhanced cytotoxicity and antifungal activity. NEs less toxic than conventional AmB (reduced of self-associated AmB in lipid nanocarrier). Selectivity index was significantly higher than that of conventional AmB.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B180-pharmaceutics-12-00029" ref-type="bibr">180</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sefsol 218-based NEs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">67.32 ± 0.8 (0.23)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sefsol-218 (12.5% <italic>w</italic>/<italic>w</italic>), Tween 80:PEG400 S<sub>mix</sub> 2:1 (33.45% <italic>w</italic>/<italic>w</italic>) AmB; pH 7.4.<break></break>Slow spontaneous titration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cumulative amount of AmB permeated (24 h): 425.36 ± 1.9 μg. Permeation flux rate 17.8 ± 0.5 μg/cm<sup>2</sup>/h (higher than AmB solution and Fungisome<sup>®</sup>).<break></break>AmB deposition in abdominal albino rat skin, after first 6 h: 35.6 ± 2.0%.<break></break>AmB undecomposed in NE (ζ –37.3 mV), after 90 days of storage: 99.3% (5 °C), 96.7% (25 °C), 87.1% (40 °C).<break></break>Minimal aggregation behavior at pH 6.8 and pH 7.4.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B181-pharmaceutics-12-00029" ref-type="bibr">181</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Capmul-based NEs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">49.5 ± 1.5 (0.33)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Capmul PG8 (15% <italic>w</italic>/<italic>w</italic>), LAB-PEG400 S<sub>mix</sub> 1:2 (24% <italic>w</italic>/<italic>w</italic>), AmB; pH 7.4.<break></break>Slow spontaneous titration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ZOI: 19.1 ± 1.4 mm (<italic>Aspergillus niger</italic>, MTCC 282), 22.8 ± 2.0 mm (<italic>C. albicans</italic>, MTCC 4748).<break></break>AmB-NE (ζ –24.59 mV) in vitro release (slow and sustained release): 46.1 ± 3.7% (60 min).<break></break>Ex vivo skin permeation flux rate: 22.88 ± 1.7 μg/cm<sup>2</sup>/h.<break></break>AmB deposited in abdominal albino rat skin, after first 6 h: 74 ± 5.6%.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B182-pharmaceutics-12-00029" ref-type="bibr">182</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NEs with antifungal excipients</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">74.8 ± 4.1 (0.21)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Peceol (19.4% <italic>w</italic>/<italic>w</italic>), LAB:PG S<sub>mix</sub> 1:3 (14.9% <italic>w</italic>/<italic>w</italic>), AmB; pH 6.8.<break></break>Slow spontaneous titration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ZOI: 21.8 ± 1.5 mm (<italic>A. fumigatus</italic>), 19.7 ± 1.2 mm (<italic>C. albicans</italic>).AmB-NE (ζ –33.2 mV) in vitro sustained release: 19.8 ± 1.1% (90 min).<break></break>Enhanced ex vivo rat skin permeation-deposition (skin permeation flux rate: 21.62 ± 1.6 μg/cm<sup>2</sup>/h; AmB deposition: 84.7 ± 9.3 μg).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B183-pharmaceutics-12-00029" ref-type="bibr">183</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Castor oil-based NEs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">128.40 ± 12.71 (0.27 ± 0.05)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">95 ± 2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5% castor oil, 55% LAB:Plurol<sup>®</sup> oleique (5:1), 40% Transcutol<sup>®</sup> P, 0.50% (<italic>w</italic>/<italic>w</italic>) AmB; pH 7.42 ± 0.53.<break></break>Aqueous titration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Newtonian behavior, viscosity 12.20 ± 0.28 mPa·s.<break></break>In vitro sustained release (without burst effect): 100% of AmB after 75 h.<break></break>AmB retention 17.76 μg/g/cm<sup>2</sup> after 36 h of skin application.<break></break>Antifungal activity against <italic>C. albicans</italic> (ATCC 10231), <italic>C. glabrata</italic> (ATCC 66032), <italic>C. parapsilosis</italic> (ATCC 22019), <italic>A. brasiliensis</italic> (ATCC 16404), with MICs of 0.78, 0.39, 0.19, 0.13, respectively.<break></break>Ex vivo permeation studies on women skin suggests no theoretical systemic absorption: all participants exhibited TEWL values in the normal range (except after 2 h, possibly caused by the effect of Transcutol<sup>®</sup> P on skin).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B184-pharmaceutics-12-00029" ref-type="bibr">184</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SEDDS (iCo-010)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">≈200</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">60/40 (<italic>v</italic>/<italic>v</italic>) mono- and diglycerides (Peceol/Gelucire 44/14, lauroyl macrogol-32-glycerides) with vitamin E-TPGS.<break></break>Mixing, mild heating and stirring (45 °C for 1–2 h).</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stability: >75% (over 60 days, 30 °C and 43 °C); >95% (4 h in SIF).<break></break>In vivo antileishmanial activity in murine model of VL (BALB/c mice infected with <italic>L. donovani</italic> promastigotes): <99% inhibition (10 mg/kg orally, twice daily, 5 days); 95% inhibition (20 mg/kg orally, once daily, 5 days).<break></break>Efficacy in a mouse model of systemic candidiasis (<italic>C. albicans</italic> ATCC 18804): 69–96% reduction of fungal burden in mouse tissues with oral iCo-010 at 5, 10, and 20 mg/kg daily for 5 days, when compared to untreated animals.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B185-pharmaceutics-12-00029" ref-type="bibr">185</xref>,<xref rid="B186-pharmaceutics-12-00029" ref-type="bibr">186</xref>,<xref rid="B187-pharmaceutics-12-00029" ref-type="bibr">187</xref>,<xref rid="B188-pharmaceutics-12-00029" ref-type="bibr">188</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SNEDDS</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical, oral <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">FA: 27.70 ± 0.5 (0.187); FB: 30.17 ± 0.7 (0.171)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Formulation A (FA): 35% DMSO, 20% Captex 300, 45% Cremophor EL; Formulation B (FB): 35% DMSO, 20% Captex 300, 35% Cremophor RH, 10% Tween 80.<break></break>Vortex mixing and sonication.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diffusion ability on porcine GIT mucus in up to 8 mm of mucus: FA, 1.45%; FB, 1.37%.<break></break>In vitro permeation across Caco-2 cells monolayer (0.5% AmB-loaded SNEDDS): FA, 10%; FB, 11%.<break></break>In vitro evaluation of cytotoxicity (Caco-2 cell lines): FA, 89%; FB, 86.9%.<break></break>Spreading efficiency: on 12 cm<sup>2</sup> of buccal mucosa, FA, 45 min; FB, 50 min; on 14 cm<sup>2</sup> of ulcerated skin model, FA, 55 min; FB, 60 min.<break></break>In vitro anti-leishmanial activity against <italic>L. tropica</italic>, IC<sub>50</sub>: FA, 0.017 ± 0.005 μg/mL (promastigote), 0.025 ± 0.003 μg/mL (amastigote); FB, 0.031 ± 0.006 μg/mL (promastigote), 0.056 ± 0.004 μg/mL (amastigote).<break></break>At 0.1 μg/ml concentration, FA and FB formulations successfully released AmB in infected macrophages and killed 100% of <italic>Leishmania</italic> parasites.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B189-pharmaceutics-12-00029" ref-type="bibr">189</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PHY cubosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">206.31 ± 4.66 (0.12)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">91</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PHY, Pluronic F127 (20% <italic>w</italic>/<italic>w</italic>), AmB (7% <italic>w</italic>/<italic>w</italic>). Hydrotrope (methanol) dilution method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stable in SGF and SIF, enhanced uptake by Caco-2 cells without cytotoxicity to the Caco-2 monolayer.<break></break>In vitro sustained AmB release (PBS pH 7.4, 37 °C), with slower release from PHY than from GMO cubosomes (80% vs. 90% release after 120 h).<break></break>Oral administration to rats (10 mg/kg) enhanced oral bioavailability (increased <italic>C</italic><sub>max</sub> and AUC) in the order AmB-PHY > AmB-GMO >> AmB due to PHY higher acid resistance.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B190-pharmaceutics-12-00029" ref-type="bibr">190</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMO cubosomes</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">192.3 ± 10.8 (0.20)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">94</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMO:poloxamer P407 (18:1 weight ratio), AmB.<break></break>O/W emulsion technology.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stable in SGF and SIF, enhanced uptake by Caco-2 cells via clathrin- and caveolae-mediated endocytosis.<break></break>Plasma drug profile showed a sustained release of AmB over 5 days with no differences found in serum creatinine and BUN levels prior to and 24 h after oral administration of AmB-GMO (10 and 20 mg/kg single dose) to rats.<break></break>In a rat model of systemic candidiasis (<italic>C. albicans</italic> ATCC 18804), oral administration of AmB-GMO (1, 5, and 10 mg/kg thrice daily for 5 days) reduced fungal burden only in kidneys, consistent with dose-dependent response in kidney tissue.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B191-pharmaceutics-12-00029" ref-type="bibr">191</xref>,<xref rid="B192-pharmaceutics-12-00029" ref-type="bibr">192</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMO cubic phase gel</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Intra-articular</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMO 55%, soybean oil 5%, hyaluronic acid 0.75%, water 15%, ethanol 10%, PG 15%, AmB 0.1% <italic>w</italic>/<italic>w</italic>.<break></break>Dispersion method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The hydrolipid formulation showed good syringeability forming a shear-shinning gel.<break></break>In vitro drug release profile (PBS, pH 7.4) at 37 °C showed long-term sustained release lasting several weeks.<break></break>Intra-articular administration to rabbits corroborated long-term sustained release of AmB with no signs of inflammation at the injected joint.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B193-pharmaceutics-12-00029" ref-type="bibr">193</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cochleates (CAmB)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">407.3 ± 233.8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Soy lecithin (enriched with 50% <italic>w</italic>/<italic>w</italic> PS-CaCl<sub>2</sub>): AmB (1:10 molar ratio).<break></break>Aqueous-aqueous hydrogel binary system.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral CAmB + flucytosine more effective than oral fluconazole against <italic>C. neoformans</italic> H99 (ATCC 208821) in a murine model of cryptococcal meningoencephalitis without toxic side effects.<break></break>Fluorescence imaging demonstrated brain transport and accumulation of CAmB.<break></break>Oral CAmB (25 mg/kg/day) and AmB-DOC (5 mg/kg/day i.p.) plus oral flucytosine (250 mg/kg/day) for 3 weeks had similar efficacy and immunological profile in treated mice.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B194-pharmaceutics-12-00029" ref-type="bibr">194</xref>,<xref rid="B195-pharmaceutics-12-00029" ref-type="bibr">195</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cochleates modified with adjuvant Finlay (AFCo3)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Intra-peritoneal</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5000–10,000</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Detoxified LPS from <italic>Neissera meningitides</italic> B (87% <italic>w</italic>/<italic>w</italic>), CaCl<sub>2</sub>, AmB. Resuspension-sedimentation method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro activity against <italic>Sporothrix schenckii</italic> (ATCC 16345) with MIC 0.25 μg/mL and MFC 0.5 μg/mL.<break></break>Enhanced intracellular fungicidal activity in peritoneal macrophages with stimulation of TNF-α, IL-1β, and NO release in vitro and ex vivo in mouse splenocytes.<break></break>Reduced spleen and liver fungal burden after 5-day treatment (5 mg/kg/day i.p.) in a mouse model of systemic sporotrichosis and induced Th1/Th17 response with no significant changes in BUN and serum creatinine levels.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B196-pharmaceutics-12-00029" ref-type="bibr">196</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nanodisk (ND)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sinonasal <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">44–80</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">DMPC:DMPG (7:3 weight ratio), ApoA-I, AmB.<break></break>Thin film method; sonication and dialysis after addition of AmB and ApoA-I.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HSNE exposed to toxic conc. of AmB-ND (18 h): apical membranes permeable to K<sup>+</sup> ions at 10 μg/mL AmB; reduction of apical cell K<sup>+</sup> permeability at 75 μg/mL AmB with 85% reduction of LDH and no increase in LDH release at 150 μg/mL AmB.<break></break>In vitro expression of <italic>A. fumigatus</italic> (ATCC 13073) conidia after 4 h exposure to AmB-ND (10 μg/mL) smaller than exposure to AmB; AmB-ND (50 μg/mL) RNA expression without statistical significance between AmB and AmB-ND.<break></break>AmB-ND protected human nasal epithelia membranes from AmB toxicity.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B197-pharmaceutics-12-00029" ref-type="bibr">197</xref>,<xref rid="B198-pharmaceutics-12-00029" ref-type="bibr">198</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SLN gel</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Skin</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">111.1 ± 2.2 (0.13 ± 0.04)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">93.8 ± 1.8</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB:lipid (1:10 weight ratio), Pluronic F127 (0.25% <italic>w</italic>/<italic>v</italic>).<break></break>Solvent diffusion method in aqueous system.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Antifungal activity against <italic>Trichophyton rubrum</italic> (ATCC 28188, KWIK-STIK 0444P), ZOI (72 h) 2.81 ± 0.13 mm.<break></break>Stability (ζ –23.98 ± 1.36 mV) at 2–8 °C and 25 ± 2 °C, for 3 months.<break></break>AmB in aqueous phase: 90.2 ± 1.1% (compritol ATO 888), 96.5 ± 1.4% (Precirol ATO 5, selected for preparation of SLNs gel), and 72.1 ± 2.7% (stearic acid).<break></break>Ex vivo permeation studies on abdomen skin of female albino Wistar rats: AmB efflux 22.34 μg/cm<sup>2</sup>.<break></break>PII (SLN gel) 0.11 ± 0.19<break></break>Higher skin deposition, lower skin irritation, high antifungal activity, localized delivery with minimal side effects.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B199-pharmaceutics-12-00029" ref-type="bibr">199</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Glyceride dilaurate-based SLN (AmbiOnp)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">392.8 ± 6.97</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GDL, PC-enriched lecithin, PEG-660-12-hydroxystearate, AmB.<break></break>Probe sonication-assisted nanoprecipitation technique.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Easy redispersion of AmbiOnp in water (3 months, 2–8 °C).<break></break>Significant increase in particle size at 25 and 40 °C after 3 months.<break></break>AmB content in AmbiOnp (ζ –27.9 ± 0.2 mV) ≈ 100% (after 1 month), showing significant reduction after 3 months when stored at 25 °C and 40 °C.<break></break>In vitro antifungal activity against <italic>C. albicans</italic> in SGF, MIC 7.812 μg/mL.In vivo PK studies (adult female Sprague-Dawley rats): C<sub>máx</sub> 1109.31 ± 104.79 ng/mL, AmbiOnp (3.6 mg/kg of AmB) oral, 24 h, comparable to C<sub>máx</sub> 1417.49 ± 85.52 ng/mL Fungizone<sup>®</sup> (0.8 mg/kg of AmB), i.v.<break></break>Low renal tissue levels of AmB in AmbiOnp at 8 h: 84.50 ± 22.896 ng/mL; without detectable levels post 8 h.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B200-pharmaceutics-12-00029" ref-type="bibr">200</xref>,<xref rid="B201-pharmaceutics-12-00029" ref-type="bibr">201</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sesame oil-based NLCs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-NLC: 79.5 ± 2.7 (0.26 ± 0.01); LYO-AmB-NLC: 179.7 ± 2.1 (0.23 ± 0.00)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-NLC: 98.1 ± 1.3; LYO-AmB-NLC: 96.9 ± 2.1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GMS:sesame oil (7:3 weight ratio), Pluronic F68 (3% <italic>w</italic>/<italic>w</italic>), AmB.<break></break>Ultrasonic cavitation homogenization method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-NLC (ζ –14.8 ± 1.9 mV): LC 0.196 ± 0.003; LYO-AmB-NLC (ζ –14.6 ± 2.6 mV): LC 0.194 ± 0.004.<break></break>AmB-NLC in vitro release profile (24 h after particle preparation), fitted the Baker–Lonsdale model; AmB controlled release for 72 h.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B202-pharmaceutics-12-00029" ref-type="bibr">202</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sta-OA NLCs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pulmonary</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">659.7 ± 1.20 (0.27 ± 0.12)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">77.10 ± 5.50</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sta:OA (6:4 weight ratio), AmB.<break></break>Solvent diffusion method followed by AmB loading and spray-drying.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro sustained drug release (88.2% up to 40 h) and reduced dose dumping.<break></break>Better in vitro antifungal activity over control against <italic>A. fumigatus</italic> (MTCC 5186).<break></break>PK, histopathology, hematological, and in vivo biodistribution studies demonstrated localized AmB delivery for prolonged period after pulmonary administration to rats and reduced nephrotoxicity.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B203-pharmaceutics-12-00029" ref-type="bibr">203</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PEG-DSPE micelles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">23.2 nm</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-DOC:PEG-DSPE micelles (1:20, 1:40, and 1:90 molar ratio) in 0.9% saline.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reconstitution of Fungizone<sup>®</sup> with PEG-DSPE micelles in saline facilitated co-delivery of monomeric AmB and sodium supplementation.<break></break>More extensive AmB deaggregation achieved with AmB-DOC:PEG-DSPE at 1:90 molar ratio, decreasing the size of AmB-DOC aggregates from 3310 nm (in saline) to 23.2 nm in mixed DOC-PEG-DSPE micelles.<break></break>Reduced in vitro hemolytic activity (bovine RBCs) and in vivo renal toxicity in rats after 1.5-h infusion (2 mg/kg/day) for 3 days compared to conventional formulation. Similar in vitro fungicidal activity against <italic>S. cerevisiae</italic> (ATCC 9763) and <italic>C. albicans</italic> (K1 strain).<break></break>Simple preparation from commercially available AmB-DOC and FDA-approved PEG-DSPE excipients.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B204-pharmaceutics-12-00029" ref-type="bibr">204</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lecithin-based polymeric hybrid micelles (Ambicelles)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral, parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">187.20 ± 10.15 (0.51)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">90.14</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB:lecithin:DSPE-PEG2k (1:1:10 weight ratio).<break></break>Thin film hydration method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ambicelles improved AmB solubility from 0.001 to 5 mg/mL.<break></break>Increased bioavailability in rats compared to Fungizone<sup>®</sup> after single i.v. (0.8 mg/kg) and oral (10 mg/kg) doses. Reduced in vitro cytotoxicity against human colon adenocarcinoma (HT29) cells.<break></break>Organic solvent (methanol:dichloromethane 19:1) required to dissolve AmB, lecithin and polymer.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B205-pharmaceutics-12-00029" ref-type="bibr">205</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MPEG-CS-LNA hybrid micelles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Parenteral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">257.94 ± 10.42 (0.181 ± 0.028)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">82.3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB:MPEG-CS-LNA (1:7 weight ratio).<break></break>Dialysis method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cationic hybrid micelles (ζ 17.53 ± 0.15 mV) with low CMC (0.2138 mg/mL) enhanced drug solubilization up to 1.64 mg/mL.<break></break>Reduced hemolytic effect in vitro and decreased nephrotoxicity in vivo compared to i.v. AmB, with improved PK profile.<break></break>Enhanced in vivo fungal cellular uptake due to combined inducement of LNA and CS.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B206-pharmaceutics-12-00029" ref-type="bibr">206</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hybrid NE with lipo-polymeric nanoparticles</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50 ± 10</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tween 80: canola oil (1.18 weight ratio), Carbopol<sup>®</sup> (1% <italic>w</italic>/<italic>w</italic>), HPMC (0.03% <italic>w</italic>/<italic>w</italic>).<break></break>Solvent evaporation-emulsion technique.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro antifungal activity against <italic>A. fumigatus</italic> (FCBP 66), <italic>Aspergillus flavus</italic> (FCBP 0064), <italic>A. niger</italic> (FCBP 0198), <italic>Fusarium solani</italic> (FCBP 0291): ZOI 14 mm, 8 mm, 10 mm, 19,5 mm, respectively.<break></break>In vitro anti-leishmanial activity (<italic>L. tropica</italic> promastigotes): 50% killing rate at 0.2 μg/mL AmB; 100% mortality at 20 μg/mL AmB.<break></break>LC<sub>50</sub> against <italic>L. tropica</italic>: 0.743 μg/m (AmB emulsion in water); 0.190 μg/m (AmB emulsion in DMSO).<break></break>Physical stability for more than three months; AmB proved to be undamaged in the nanoformulation.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B207-pharmaceutics-12-00029" ref-type="bibr">207</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cationic Sta lipid–polymer hybrid NPs (LPNPs)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">198.3 ± 3.52 (0.135 ± 0.03)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">96.1 ± 2.01</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLGA, AmB (10% <italic>w</italic>/<italic>w</italic>), Sta (1% <italic>w</italic>/<italic>v</italic>), TPGS.<break></break>Modified W/O/W double emulsification method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cationic hybrid NPs (ζ 31.6 ± 1.91 mV) provided sustained AmB release.<break></break>Antileishmanial activity against <italic>L. donovani</italic> (MHOM/IN/80/Dd8):<break></break>in vitro (J774A.1 intra-macrophage amastigotes) IC<sub>50</sub> 0.16 ± 0.04 μg AmB/mL); in vivo (Syrian golden male hamsters), 89.41 ± 3.58% parasite inhibition against VL models.<break></break>Antileishmanial activity enhancement due to macrophage targeting potential, Th-1 biased immune-alteration mediated by drug-free LPNPs and synergistic activity of Sta lipid component.<break></break>Reduced level of nephrotoxicity markers and minimal distribution to kidney tissues.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B208-pharmaceutics-12-00029" ref-type="bibr">208</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Palmitoyl-modified chitosan NPs (GCPQ)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">35 and 216</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">GCPQ (16.9 mol% palmitoylated, 16.5 mol% quaternized, HI 1.02; 5 mg/mL), AmB (1 mg/mL).<break></break>Polyelectrolyte complex formation.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">The bimodal size formulation is due to an equilibrium between AmB loaded NPs and empty micelles formed by self-assembly of amphiphilic GCPQ.<break></break>AmB-GCPQ NPs delivered the drug specifically to liver, lung, and spleen while sparing the kidney. Mucoadhesive GCPQ NPs were taken up by the gut enterocytes with bioavailability of 24.7%.<break></break>AmB-GCPQ NPs (5 mg/kg/day orally for 10 days) cleared spleen and liver fungal load in a systemic murine model of candidiasis and were as effective as parenteral AmBisome<sup>®</sup> in a murine model of VL.<break></break>Oral AmB-GCPQ NPs (7.5 or 15 mg/kg/day for 7 days) reduced fungal burden in a murine model of disseminated aspergillosis and was statistically similar to AmBisome<sup>®</sup> (5 mg/kg/day i.v.).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B209-pharmaceutics-12-00029" ref-type="bibr">209</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chitosan-modified NLCs (CH-NLC)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ocular</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">185.4 ± 5.9 (0.20 ± 0.08)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">90.9 ± 3.9</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-chitosan NLC.<break></break>Emulsion evaporation-solidification method.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cationic chitosan-modified NLC (ζ 27.1 ± 2.9 mV) provided in vitro sustained drug release.<break></break>Improved bioavailability of AmB-CH-NLC suggested by in vivo ocular PK study (<italic>t</italic><sub>1/2</sub> 2.37 h vs. 1.24 h and 0.16 h for uncoated formulation and AmB eye drops, respectively).<break></break>In vivo corneal penetration study showed successful penetration into the cornea with no obvious irritation to the ocular mucosa of rabbits’ eyes.<break></break>AmB-CH-NLC may be a promising system for ocular delivery of AmB in fungal keratitis-targeted therapy.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B210-pharmaceutics-12-00029" ref-type="bibr">210</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chitosan-coated NLCs</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral <italic><sup>(a)</sup></italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">394.4 ± 6.4 (0.44 ± 0.03)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">86.0 ± 3.0</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Beeswax, coconut oil, Tween 80, lecithin, AmB.<break></break>Homogenization-ultrasonication technique and further coating with chitosan (1:40 <italic>v</italic>/<italic>v</italic>).</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In vitro slow release profile (26.1% drug release in 5 h).<break></break>Prevention of AmB expulsion upon exposure to simulated GI pH media (63.9% drug retention vs. 56.1% in the uncoated formulation).<break></break>Chitosan-coated NLCs showed mucoadhesive properties in vitro and ex vivo on excised rat intestinal tissue; higher retention time within the small intestine (84.2 ± 5.1% adhesion vs. 55.8 ± 16.1% with the uncoated formulation).<break></break>Coated formulation was less cytotoxic than the free drug to RBCs and HT-29 cells, but with comparable in vitro antifungal activity against <italic>C. albicans</italic> (ATCC 90028).</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B211-pharmaceutics-12-00029" ref-type="bibr">211</xref>,<xref rid="B212-pharmaceutics-12-00029" ref-type="bibr">212</xref>]</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Acetylated <italic>Sterculia striata</italic> polysaccharide (ASSP) NCs(DS 1.68 and DS 1.35)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NC1.68: 274.1 ± 8.6 (0.181); NC1.35: 277.3 ± 9.5 (0.149)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NC1.68: 99.2 ± 1.3; NC1.35: 80.5 ± 1.6</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ASSP (1.0 mg/mL), Miglyol812<sup>®</sup>, AmB (0.25 mg/mL).<break></break>Spontaneous emulsification.</td><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NC1.68 (ASSP concentration, 0.5 mg/mL) and NC1.35 (ASSP concentration, 1.0 mg/mL) loaded AmB in a monomeric form.<break></break>AmB-NC1.68: MIC 0.25 μg/mL against 5 strains of <italic>C. albicans</italic> (ATCC 90028, LABMIC 0104, LABMIC 0105, LABMIC 0106).<break></break>In vitro controlled release of AmB: 3.6 ± 0.5% after 1 h; 49.1 ± 0.4% after 72 h; complete release after 212 h.<break></break>NC1.68 showed potential to be employed as AmB DDS.</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B213-pharmaceutics-12-00029" ref-type="bibr">213</xref>]</td></tr></tbody></table><table-wrap-foot><fn><p><italic><sup>(a)</sup></italic> intended; AmB, amphotericin B; AmB-DOC, amphotericin B deoxycholate; ApoA-I, apolipprotein A-I; ASSP, acetylated <italic>Sterculia striata</italic> polysaccharide; AUC, area under the concentration-time curve; BBB, blood–brain barrier; BEC<sub>50</sub>, minimum biofilm eradication concentration; BS, bile salt; BUN, blood urea nitrogen; CAmB, cochleated amphotericin B; CC<sub>50</sub>, 50% cytotoxic concentration; CDI, carbodiimide; CH, chitosan; CMC, critical micelle concentration; <italic>C</italic><sub>max</sub>, peak plasma concentration; CS, oligochitosan; DCP, dicetyl phosphate; DDS, drug delivery system; DMPC, dimyristoyl phosphatidylcholine; DMPG, dimyristoyl phosphatidylglycerol; DMSO, dimethylsulfoxide; DNA, deoxyribonucleic acid; DOPE, dioleoyl phosphatidylethanolamine; DOTAP, dioleoyl-3-trimethylammonium propane; DS, degree of substitution; DSHemsPC, distigmasterylhemisuccinyl phosphatidylcholine; DSPE, distearoyl phosphatidylethanolamine; EE, encapsulation efficiency; FDA, Food and Drug Administration; FPF, fine particle fraction; GCPQ, <italic>N</italic>-palmitoyl-<italic>N</italic>-methyl-<italic>N</italic>,<italic>N</italic>-dimethyl-<italic>N</italic>,<italic>N</italic>,<italic>N</italic>-trimethyl-6-<italic>O</italic>-glycol chitosan; GDL, glyceride dilaurate; GIT, gastrointestinal tract; GMO, glyceryl monooleate; GMS, glyceryl monostearate; GSD, geometric standard deviation; HI, hydrophobicity index; HPMC, hydroxypropylmethylcellulose; HSNE, human septonasal epithelial cells; IC<sub>50</sub>, half-maximal inhibitory concentration; IFNγ, interferon γ; IL, interleukin; i.v., intravenous; LAA, lipoamino acid; LAB, Labrasol<sup>®</sup>; LC<sub>50</sub>, 50% lethal concentration; LDH, lactate dehydrogenase; LNA, linolenic acid; LPNP, lipid–polymer nanoparticle; LPS, lipopolysaccharide; LYO, lyophilized; MCT, medium chain triglycerides; MFC, minimum fungicidal concentration; MIC, minimum inhibitory concentration; MLP, magnetic liposomes; MMAD, mass median aerodynamic diameter; MPEG, methoxy-poly(ethylene glycol); MRI, magnetic resonance imaging; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; N/A, not available; NaC, sodium cholate; NaDC, sodium deoxycholate; NC, nanocapsule; ND, nanodisk; NE, nanoemulsion; NLC, nanostructured lipid carrier; OA, oleic acid; O/W, water-in-oil; PBS, phosphate buffered saline; PC, phosphatidylcholine; PEG, poly(ethylene glycol); PG, propylene glycol; PHY, phytantriol; PI, polydispersion index; PII, primary irritation index; PK, pharmacokinetic; PLGA, poly(D,L-lactide-co-glycolic acid); PS, phosphatidylserine; RBC, red blood cell; SDCS, sodium deoxycholate sulfate; SEDDS, self-emulsifying drug delivery system; SGF, simulated gastric fluid; SIF, simulated intestinal fluid; SL, sophorolipid; SLN, solid lipid nanoparticle; S<sub>mix</sub>, surfactant/co-surfactant ratio; SML, surface-modified liposomes; SNEDDS, self-nanoemulsifying drug delivery system; SPC, soy phosphatidylcholine; Sta, stearylamine; TEER, transepithelial electrical resistance; TEWL, transepidermal water loss; TGFβ, transforming growth factor β; TNF-α, tumor necrosis factor α; TPGS, D-α-tocopheryl polyethylene glycol succinate; UDL, ultradeformable liposomes; UV, ultraviolet; VL, visceral leishmaniasis; ZOI, zone of inhibition; ζ, zeta potential.</p></fn></table-wrap-foot></table-wrap><table-wrap id="pharmaceutics-12-00029-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">pharmaceutics-12-00029-t003_Table 3</object-id><label>Table 3</label><caption><p>Recently completed, on-going and expected clinical trials evaluating amphotericin B (AmB) safety and efficacy against antifungal and antiparasitic diseases.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Formulation</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Phase</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Trial Identifier (Acronym)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Population (<italic>n</italic>)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment Regimen</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Status, (Expected) Start Date–(Estimated) Completion Date</th></tr></thead><tbody><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical AmB solution (2 mg/mL in 30% DMSO)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03814343</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Non-dermatophytes onychomycosis (<italic>n</italic> = 20)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1–3 drops of AmB solution (2 mg/mL in 30% DMSO) once daily vs. placebo (30% DMSO solution) for 12 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, January 2019–June 2020</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical 3% AmB cream (Anfoleish<sup>®</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1b/2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT01845727</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Uncomplicated CL in Colombia (<italic>n</italic> = 80)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical 3% AmB cream twice or thrice daily for 4 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Completed, February 2014–July 2016</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical 0.4% L-AmB gel</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02656797</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CL due to <italic>L. major</italic> or <italic>L. tropica</italic> (<italic>n</italic> = 108)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Topical AmB 0.4% liposomal gel vs. placebo gel</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, January 2018–January 2021</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB (AmBisome<sup>®</sup>) aerosol plus oral itraconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03656081</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chronic pulmonary aspergillosis (<italic>n</italic> = 224)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral itraconazole (200 mg tablet twice daily) and inhaled L-AmB (25 mg) or inhaled placebo (isotonic saline) twice a week, for 24 weeks</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, December 2018–July 2023</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nebulized L-AmB (AmBisome<sup>®</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02273661 (NEBULAMB)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Allergic broncho pulmonary aspergillosis, excluding cystic fibrosis (<italic>n</italic> = 174)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Aerosol of L-AmB at 25 mg once a week for 6 months vs. placebo (isotonic saline)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Active (not recruiting), November 2014–July 2019</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02686853</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cryptococcal meningitis without AIDS (<italic>n</italic> = 40)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Intrathecal administration of L-AmB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Unknown, January 2016–January 2018</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB(AmBisome<sup>®</sup>) plus fluconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2/3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03945448 (ACACIA)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Asymptomatic cryptococcal antigenemia in Uganda (<italic>n</italic> = 600)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmBisome<sup>®</sup> single i.v. dose (10 mg/kg) and/or fluconazole 800 mg for 2 weeks, 400 mg for 8 weeks and 200 mg up to 6 months</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not yet recruiting, May 2019–November 2023</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB and follow-up oral itraconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT04059770</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Disseminated histoplasmosis in AIDS patients (<italic>n</italic> = 99)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Induction therapy with L-AmB i.v. as single dose (10 mg/kg), two doses (10 mg/kg on day 1 and 5 mg/kg on day 3) or 3 mg/kg for 2 weeks, followed by oral itraconazole capsules (400 mg daily) for 1 year</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not yet recruiting, November 2019–October 2021</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB (AmBisome<sup>®</sup>) monotherapy or plus miltefosine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02011958</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">VL in HIV patients in Ethiopia (<italic>n</italic> = 59)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB i.v. (5 mg/kg/day on day 1, 3, 5, 7, 9 and 11) combined with oral miltefosine (one or two 50 mg capsules daily for 28 days) or alone (5 mg/kg/day on days 1 to 5, 10, 17 and 24)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Completed, July 2014–September 2017</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB for injection 50 mg/vial (generic and AmBisome<sup>®</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03636659</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bioequivalence study in VL patients under fed condition (<italic>n</italic> = 140)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB for injection (generic or AmBisome<sup>®</sup>) 50 mg/vial at 3 mg/kg/day i.v. infusion once daily for 5 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Completed, May 2018–April 2019</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB (AmBisome<sup>®</sup>)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03311607</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PKDL in Bangladesh (<italic>n</italic> = 280)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmBisome<sup>®</sup> 15 mg/kg over 15 days in 5 biweekly 3 mg/kg infusions</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Completed, April 2014–October 2015</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">L-AmB (AmBisome<sup>®</sup>) plus oral miltefosine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT03399955</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PKDL in Sudan (<italic>n</italic> = 110)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmBisome<sup>®</sup> 5 mg/kg/day i.v. infusion at day 1, 3, 5 and 7 combined with oral miltefosine twice daily (allometric dosing) for 28 days</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, May 2018–May 2022</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-DOC (Fungizone<sup>®</sup>) and follow-up voriconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02283905 (BLASTO)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pulmonary blastomycosis requiring mechanical ventilation (<italic>n</italic> = 6)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Continuously infused AmB-DOC (1 mg/kg/day) up to a total dose of 1 g, then stepped down to oral or i.v. voriconazole</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, June 2015–December 2020</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-DOC plus flucytosine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT04140461</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HIV-associated cryptococcal meningitis (<italic>n</italic> = 40)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB (0.5 or 0.7 mg/kg IVGTT once daily) plus flucytosine (100 mg/kg orally once daily for 4 or 2 weeks)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not yet recruiting, January 2020–April 2022</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">AmB-DOC plus flucytosine</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT04072640<break></break>(TITOC)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cryptococcal meningitis in HIV patients (<italic>n</italic> = 120)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Induction therapy with AmB-DOC (0.4–0.5 or 0.7–1.0 mg/kg/day i.v.) plus flucytosine (100 mg/kg/day) for 28 or 14 days, then fluconazole for consolidation (400 mg/day for 2 months) and maintenance (200 mg/day)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Not yet recruiting, January 2020–December 2022</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral cochleate AmB (CAmB/MAT2203)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT04031833 (EnACT)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cryptococcal meningitis in HIV patients in Uganda (<italic>n</italic> = 176)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral CAmB vs. standard i.v. AmB</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Recruiting, October 2019–December 2021</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral cochleate AmB (CAmB/MAT2203)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2a</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02629419 (CAmB)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mucocutaneous candidiasis refractory or intolerant to standard non-intravenous therapies (<italic>n</italic> = 16)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral CAmB (200 mg, 400 mg or 800 mg)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Active (not recruiting), September 2016–December 2021</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral cochleate AmB (CAmB/MAT2203)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NCT02971007</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vulvovaginal candidiasis (<italic>n</italic> = 137)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Oral CAmB (200 mg or 400 mg for 5 days) vs. oral fluconazole (150 mg single dose)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Completed, November 2016–May 2017</td></tr></tbody></table><table-wrap-foot><fn><p>AIDS, acquired immunodeficiency syndrome; AmB, amphotericin B; AmB-DOC, amphotericin B deoxycholate; CAmB, cochelate amphotericin B; CL, cutaneous leishmaniasis; DMSO, dimethylsulfoxide; HIV, human immunodeficiency virus; i.v., intravenous; IVGTT, intravenous glucose tolerance test; L-AmB, liposomal amphotericin B; PKDL, post-kala-azar dermal leishmaniasis; VL, visceral leishmaniasis (kala-azar).</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list></list><tree><noCountry><name sortKey="Faustino, Celia" sort="Faustino, Celia" uniqKey="Faustino C" first="Célia" last="Faustino">Célia Faustino</name><name sortKey="Pinheiro, Lidia" sort="Pinheiro, Lidia" uniqKey="Pinheiro L" first="Lídia" last="Pinheiro">Lídia Pinheiro</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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