Lipospheres for Simultaneous Controlled Release and Improved Pharmacokinetic Profiles of Saxagliptin-Enalapril: Formulation, Optimization, and Comparative In Vitro-In Vivo Evaluation.
Identifieur interne : 000067 ( Main/Exploration ); précédent : 000066; suivant : 000068Lipospheres for Simultaneous Controlled Release and Improved Pharmacokinetic Profiles of Saxagliptin-Enalapril: Formulation, Optimization, and Comparative In Vitro-In Vivo Evaluation.
Auteurs : Safirah Maheen [Pakistan] ; Akhtar Rasul [Pakistan] ; Muhammad Hanif [Pakistan] ; Hafeez Ullah Khan [Pakistan]Source :
- AAPS PharmSciTech [ 1530-9932 ] ; 2020.
Descripteurs français
- KwdFr :
- Adamantane (administration et posologie), Adamantane (analogues et dérivés), Adamantane (pharmacocinétique), Administration par voie orale (MeSH), Animaux (MeSH), Antihypertenseurs (administration et posologie), Antihypertenseurs (pharmacocinétique), Biodisponibilité (MeSH), Cires (composition chimique), Dipeptides (administration et posologie), Dipeptides (pharmacocinétique), Humains (MeSH), Inhibiteurs de la dipeptidyl-peptidase IV (administration et posologie), Inhibiteurs de la dipeptidyl-peptidase IV (pharmacocinétique), Libération de médicament (MeSH), Préparations à action retardée (composition chimique), Période (MeSH), Taille de particule (MeSH), Énalapril (administration et posologie), Énalapril (pharmacocinétique).
- MESH :
- administration et posologie : Adamantane, Antihypertenseurs, Dipeptides, Inhibiteurs de la dipeptidyl-peptidase IV, Énalapril.
- analogues et dérivés : Adamantane.
- composition chimique : Cires, Préparations à action retardée.
- pharmacocinétique : Adamantane, Antihypertenseurs, Dipeptides, Inhibiteurs de la dipeptidyl-peptidase IV, Énalapril.
- Administration par voie orale, Animaux, Biodisponibilité, Humains, Libération de médicament, Période, Taille de particule.
English descriptors
- KwdEn :
- Adamantane (administration & dosage), Adamantane (analogs & derivatives), Adamantane (pharmacokinetics), Administration, Oral (MeSH), Animals (MeSH), Antihypertensive Agents (administration & dosage), Antihypertensive Agents (pharmacokinetics), Biological Availability (MeSH), Delayed-Action Preparations (chemistry), Dipeptides (administration & dosage), Dipeptides (pharmacokinetics), Dipeptidyl-Peptidase IV Inhibitors (administration & dosage), Dipeptidyl-Peptidase IV Inhibitors (pharmacokinetics), Drug Liberation (MeSH), Enalapril (administration & dosage), Enalapril (pharmacokinetics), Half-Life (MeSH), Humans (MeSH), Particle Size (MeSH), Waxes (chemistry).
- MESH :
- chemical , administration & dosage : Adamantane, Antihypertensive Agents, Dipeptides, Dipeptidyl-Peptidase IV Inhibitors, Enalapril.
- chemical , analogs & derivatives : Adamantane.
- chemical , chemistry : Delayed-Action Preparations, Waxes.
- chemical , pharmacokinetics : Adamantane, Antihypertensive Agents, Dipeptides, Dipeptidyl-Peptidase IV Inhibitors, Enalapril.
- Administration, Oral, Animals, Biological Availability, Drug Liberation, Half-Life, Humans, Particle Size.
Abstract
The current study aims at formulating and optimizing lipospheres (LS) by the Box-Behnken design (BBD) from safe biodegradable carnauba wax (CW) to co-administer saxagliptin (SG) and enalapril (EP) for co-existing chronic hypertensive diabetes in order to overcome inadequacies of conventional modes of drug administration. Optimized liposphere formulation (OLF) was selected by a numerical optimization procedure and a comparative in vivo pharmacokinetic study of OLF and commercial brands was also performed. Discrete, free-flowing, spherical, smooth-surface LS having a size range of 5-10 μm and zeta potential of - 20 to - 30 mV were successfully formulated. Compatibility studies by FTIR and DSC proved the lack of interaction of components while XRD suggested the transformation of crystalline drugs to amorphous form. Outcomes of dependent optimizing variables like percentage yield (30-90%), EP-release (32-92%), and SG-release (28-95%) followed a polynomial quadratic model. Pharmacokinetics studies indicated a significantly lower Cmax of EP (125.22 ± 6.32) and SG (75.63 ± 3.85) and higher mean Tmax values (9.4 h for EP and 10.73 h for SG) from OLF in comparison with reference brands of EP (257.54 ± 8.23 ng/mL) and SG (393.66 ± 2.97 ng/mL). Additionally, a potential rise in half-life and MRT of SG and EP was achieved reaching approximately 2- to 3-fold higher than noted for reference brands. Importantly, the enhanced Tmax and AUC0-24 specified the achievement of enhanced bioavailability of both drugs from LS. Consequently, such an innovative approach could not only control drug release in both in vitro and in vivo analyses but also maintain plasma drug concentration for a longer time without maximizing Cmax leading towards effective management of chronic illnesses.
DOI: 10.1208/s12249-020-01733-w
PubMed: 32651896
Affiliations:
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xml:lang="fr">Pakistan</country><wicri:regionArea>Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000</wicri:regionArea><wicri:noRegion>38000</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:affiliation>College of Pharmacy, University of Sargodha, Sargodha, Pakistan.</nlm:affiliation><country xml:lang="fr">Pakistan</country><wicri:regionArea>College of Pharmacy, University of Sargodha, Sargodha</wicri:regionArea><wicri:noRegion>Sargodha</wicri:noRegion></affiliation></author><author><name sortKey="Rasul, Akhtar" sort="Rasul, Akhtar" uniqKey="Rasul A" first="Akhtar" last="Rasul">Akhtar Rasul</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan. akhtar.rasul@gcuf.edu.pk.</nlm:affiliation><country xml:lang="fr">Pakistan</country><wicri:regionArea>Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000</wicri:regionArea><wicri:noRegion>38000</wicri:noRegion></affiliation></author><author><name sortKey="Hanif, Muhammad" sort="Hanif, Muhammad" uniqKey="Hanif M" first="Muhammad" last="Hanif">Muhammad Hanif</name><affiliation wicri:level="1"><nlm:affiliation>Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.</nlm:affiliation><country xml:lang="fr">Pakistan</country><wicri:regionArea>Faculty of Pharmacy, Bahauddin Zakariya University, Multan</wicri:regionArea><wicri:noRegion>Multan</wicri:noRegion></affiliation></author><author><name sortKey="Khan, Hafeez Ullah" sort="Khan, Hafeez Ullah" uniqKey="Khan H" first="Hafeez Ullah" last="Khan">Hafeez Ullah Khan</name><affiliation wicri:level="1"><nlm:affiliation>College of Pharmacy, University of Sargodha, Sargodha, Pakistan.</nlm:affiliation><country xml:lang="fr">Pakistan</country><wicri:regionArea>College of Pharmacy, University of Sargodha, Sargodha</wicri:regionArea><wicri:noRegion>Sargodha</wicri:noRegion></affiliation></author></analytic><series><title level="j">AAPS PharmSciTech</title><idno type="eISSN">1530-9932</idno><imprint><date when="2020" type="published">2020</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adamantane (administration & dosage)</term><term>Adamantane (analogs & derivatives)</term><term>Adamantane (pharmacokinetics)</term><term>Administration, Oral (MeSH)</term><term>Animals (MeSH)</term><term>Antihypertensive Agents (administration & dosage)</term><term>Antihypertensive Agents (pharmacokinetics)</term><term>Biological Availability (MeSH)</term><term>Delayed-Action Preparations (chemistry)</term><term>Dipeptides (administration & dosage)</term><term>Dipeptides (pharmacokinetics)</term><term>Dipeptidyl-Peptidase IV Inhibitors (administration & dosage)</term><term>Dipeptidyl-Peptidase IV Inhibitors (pharmacokinetics)</term><term>Drug Liberation (MeSH)</term><term>Enalapril (administration & dosage)</term><term>Enalapril (pharmacokinetics)</term><term>Half-Life (MeSH)</term><term>Humans (MeSH)</term><term>Particle Size (MeSH)</term><term>Waxes (chemistry)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adamantane (administration et posologie)</term><term>Adamantane (analogues et dérivés)</term><term>Adamantane (pharmacocinétique)</term><term>Administration par voie orale (MeSH)</term><term>Animaux (MeSH)</term><term>Antihypertenseurs (administration et posologie)</term><term>Antihypertenseurs (pharmacocinétique)</term><term>Biodisponibilité (MeSH)</term><term>Cires (composition chimique)</term><term>Dipeptides (administration et posologie)</term><term>Dipeptides (pharmacocinétique)</term><term>Humains (MeSH)</term><term>Inhibiteurs de la dipeptidyl-peptidase IV (administration et posologie)</term><term>Inhibiteurs de la dipeptidyl-peptidase IV (pharmacocinétique)</term><term>Libération de médicament (MeSH)</term><term>Préparations à action retardée (composition chimique)</term><term>Période (MeSH)</term><term>Taille de particule (MeSH)</term><term>Énalapril (administration et posologie)</term><term>Énalapril (pharmacocinétique)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Adamantane</term><term>Antihypertensive Agents</term><term>Dipeptides</term><term>Dipeptidyl-Peptidase IV Inhibitors</term><term>Enalapril</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Adamantane</term></keywords><keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Delayed-Action Preparations</term><term>Waxes</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacokinetics" xml:lang="en"><term>Adamantane</term><term>Antihypertensive Agents</term><term>Dipeptides</term><term>Dipeptidyl-Peptidase IV Inhibitors</term><term>Enalapril</term></keywords><keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Adamantane</term><term>Antihypertenseurs</term><term>Dipeptides</term><term>Inhibiteurs de la dipeptidyl-peptidase IV</term><term>Énalapril</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Adamantane</term></keywords><keywords scheme="MESH" qualifier="composition chimique" xml:lang="fr"><term>Cires</term><term>Préparations à action retardée</term></keywords><keywords scheme="MESH" qualifier="pharmacocinétique" xml:lang="fr"><term>Adamantane</term><term>Antihypertenseurs</term><term>Dipeptides</term><term>Inhibiteurs de la dipeptidyl-peptidase IV</term><term>Énalapril</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Administration, Oral</term><term>Animals</term><term>Biological Availability</term><term>Drug Liberation</term><term>Half-Life</term><term>Humans</term><term>Particle Size</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Administration par voie orale</term><term>Animaux</term><term>Biodisponibilité</term><term>Humains</term><term>Libération de médicament</term><term>Période</term><term>Taille de particule</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">The current study aims at formulating and optimizing lipospheres (LS) by the Box-Behnken design (BBD) from safe biodegradable carnauba wax (CW) to co-administer saxagliptin (SG) and enalapril (EP) for co-existing chronic hypertensive diabetes in order to overcome inadequacies of conventional modes of drug administration. Optimized liposphere formulation (OLF) was selected by a numerical optimization procedure and a comparative in vivo pharmacokinetic study of OLF and commercial brands was also performed. Discrete, free-flowing, spherical, smooth-surface LS having a size range of 5-10 μm and zeta potential of - 20 to - 30 mV were successfully formulated. Compatibility studies by FTIR and DSC proved the lack of interaction of components while XRD suggested the transformation of crystalline drugs to amorphous form. Outcomes of dependent optimizing variables like percentage yield (30-90%), EP-release (32-92%), and SG-release (28-95%) followed a polynomial quadratic model. Pharmacokinetics studies indicated a significantly lower C<sub>max</sub> of EP (125.22 ± 6.32) and SG (75.63 ± 3.85) and higher mean T<sub>max</sub> values (9.4 h for EP and 10.73 h for SG) from OLF in comparison with reference brands of EP (257.54 ± 8.23 ng/mL) and SG (393.66 ± 2.97 ng/mL). Additionally, a potential rise in half-life and MRT of SG and EP was achieved reaching approximately 2- to 3-fold higher than noted for reference brands. Importantly, the enhanced T<sub>max</sub> and AUC<sub>0-24</sub> specified the achievement of enhanced bioavailability of both drugs from LS. Consequently, such an innovative approach could not only control drug release in both in vitro and in vivo analyses but also maintain plasma drug concentration for a longer time without maximizing C<sub>max</sub> leading towards effective management of chronic illnesses.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" IndexingMethod="Curated" Owner="NLM"><PMID Version="1">32651896</PMID><DateCompleted><Year>2020</Year><Month>10</Month><Day>27</Day></DateCompleted><DateRevised><Year>2020</Year><Month>10</Month><Day>27</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">1530-9932</ISSN><JournalIssue CitedMedium="Internet"><Volume>21</Volume><Issue>5</Issue><PubDate><Year>2020</Year><Month>Jul</Month><Day>10</Day></PubDate></JournalIssue><Title>AAPS PharmSciTech</Title><ISOAbbreviation>AAPS PharmSciTech</ISOAbbreviation></Journal><ArticleTitle>Lipospheres for Simultaneous Controlled Release and Improved Pharmacokinetic Profiles of Saxagliptin-Enalapril: Formulation, Optimization, and Comparative In Vitro-In Vivo Evaluation.</ArticleTitle><Pagination><MedlinePgn>188</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1208/s12249-020-01733-w</ELocationID><Abstract><AbstractText>The current study aims at formulating and optimizing lipospheres (LS) by the Box-Behnken design (BBD) from safe biodegradable carnauba wax (CW) to co-administer saxagliptin (SG) and enalapril (EP) for co-existing chronic hypertensive diabetes in order to overcome inadequacies of conventional modes of drug administration. Optimized liposphere formulation (OLF) was selected by a numerical optimization procedure and a comparative in vivo pharmacokinetic study of OLF and commercial brands was also performed. Discrete, free-flowing, spherical, smooth-surface LS having a size range of 5-10 μm and zeta potential of - 20 to - 30 mV were successfully formulated. Compatibility studies by FTIR and DSC proved the lack of interaction of components while XRD suggested the transformation of crystalline drugs to amorphous form. Outcomes of dependent optimizing variables like percentage yield (30-90%), EP-release (32-92%), and SG-release (28-95%) followed a polynomial quadratic model. Pharmacokinetics studies indicated a significantly lower C<sub>max</sub> of EP (125.22 ± 6.32) and SG (75.63 ± 3.85) and higher mean T<sub>max</sub> values (9.4 h for EP and 10.73 h for SG) from OLF in comparison with reference brands of EP (257.54 ± 8.23 ng/mL) and SG (393.66 ± 2.97 ng/mL). Additionally, a potential rise in half-life and MRT of SG and EP was achieved reaching approximately 2- to 3-fold higher than noted for reference brands. Importantly, the enhanced T<sub>max</sub> and AUC<sub>0-24</sub> specified the achievement of enhanced bioavailability of both drugs from LS. Consequently, such an innovative approach could not only control drug release in both in vitro and in vivo analyses but also maintain plasma drug concentration for a longer time without maximizing C<sub>max</sub> leading towards effective management of chronic illnesses.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Maheen</LastName><ForeName>Safirah</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>College of Pharmacy, University of Sargodha, Sargodha, Pakistan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rasul</LastName><ForeName>Akhtar</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Government College University Faisalabad, Faisalabad, 38000, Pakistan. akhtar.rasul@gcuf.edu.pk.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Hanif</LastName><ForeName>Muhammad</ForeName><Initials>M</Initials><AffiliationInfo><Affiliation>Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Khan</LastName><ForeName>Hafeez Ullah</ForeName><Initials>HU</Initials><AffiliationInfo><Affiliation>College of Pharmacy, University of Sargodha, Sargodha, Pakistan.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><PublicationTypeList><PublicationType UI="D003160">Comparative Study</PublicationType><PublicationType UI="D016428">Journal Article</PublicationType></PublicationTypeList><ArticleDate DateType="Electronic"><Year>2020</Year><Month>07</Month><Day>10</Day></ArticleDate></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>AAPS PharmSciTech</MedlineTA><NlmUniqueID>100960111</NlmUniqueID><ISSNLinking>1530-9932</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D000959">Antihypertensive Agents</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D003692">Delayed-Action Preparations</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D004151">Dipeptides</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D054873">Dipeptidyl-Peptidase IV Inhibitors</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D014885">Waxes</NameOfSubstance></Chemical><Chemical><RegistryNumber>69PN84IO1A</RegistryNumber><NameOfSubstance UI="D004656">Enalapril</NameOfSubstance></Chemical><Chemical><RegistryNumber>9GB927LAJW</RegistryNumber><NameOfSubstance UI="C502994">saxagliptin</NameOfSubstance></Chemical><Chemical><RegistryNumber>PJY633525U</RegistryNumber><NameOfSubstance UI="D000218">Adamantane</NameOfSubstance></Chemical><Chemical><RegistryNumber>R12CBM0EIZ</RegistryNumber><NameOfSubstance UI="C026344">carnauba wax</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000218" MajorTopicYN="N">Adamantane</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000031" MajorTopicYN="Y">analogs & derivatives</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D000284" MajorTopicYN="N">Administration, Oral</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D000959" MajorTopicYN="N">Antihypertensive Agents</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D001682" MajorTopicYN="N">Biological Availability</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003692" MajorTopicYN="N">Delayed-Action Preparations</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D004151" MajorTopicYN="N">Dipeptides</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D054873" MajorTopicYN="N">Dipeptidyl-Peptidase IV Inhibitors</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="N">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D065546" MajorTopicYN="N">Drug Liberation</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D004656" MajorTopicYN="N">Enalapril</DescriptorName><QualifierName UI="Q000008" MajorTopicYN="N">administration & dosage</QualifierName><QualifierName UI="Q000493" MajorTopicYN="Y">pharmacokinetics</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006207" MajorTopicYN="N">Half-Life</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010316" MajorTopicYN="N">Particle Size</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D014885" MajorTopicYN="N">Waxes</DescriptorName><QualifierName UI="Q000737" MajorTopicYN="N">chemistry</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">Box-Behnken design</Keyword><Keyword MajorTopicYN="N">enalapril</Keyword><Keyword MajorTopicYN="N">lipospheres</Keyword><Keyword MajorTopicYN="N">pharmackinetics</Keyword><Keyword MajorTopicYN="N">saxagliptin</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="received"><Year>2020</Year><Month>03</Month><Day>22</Day></PubMedPubDate><PubMedPubDate PubStatus="accepted"><Year>2020</Year><Month>06</Month><Day>17</Day></PubMedPubDate><PubMedPubDate PubStatus="entrez"><Year>2020</Year><Month>7</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="pubmed"><Year>2020</Year><Month>7</Month><Day>12</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate PubStatus="medline"><Year>2020</Year><Month>10</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate></History><PublicationStatus>epublish</PublicationStatus><ArticleIdList><ArticleId IdType="pubmed">32651896</ArticleId><ArticleId IdType="doi">10.1208/s12249-020-01733-w</ArticleId><ArticleId IdType="pii">10.1208/s12249-020-01733-w</ArticleId></ArticleIdList></PubmedData></pubmed><affiliations><list><country><li>Pakistan</li></country></list><tree><country name="Pakistan"><noRegion><name sortKey="Maheen, Safirah" sort="Maheen, Safirah" uniqKey="Maheen S" first="Safirah" last="Maheen">Safirah Maheen</name></noRegion><name sortKey="Hanif, Muhammad" sort="Hanif, Muhammad" uniqKey="Hanif M" first="Muhammad" last="Hanif">Muhammad Hanif</name><name sortKey="Khan, Hafeez Ullah" sort="Khan, Hafeez Ullah" uniqKey="Khan H" first="Hafeez Ullah" last="Khan">Hafeez Ullah Khan</name><name sortKey="Maheen, Safirah" sort="Maheen, Safirah" uniqKey="Maheen S" first="Safirah" last="Maheen">Safirah Maheen</name><name sortKey="Rasul, Akhtar" sort="Rasul, Akhtar" uniqKey="Rasul A" first="Akhtar" last="Rasul">Akhtar Rasul</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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