Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)
Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time prop...
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| Veröffentlicht in: | Drug delivery and translational research 2020-08, Vol.10 (4), p.919-944 |
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| creator | Yadav, Monika Schiavone, Nicola Guzman-Aranguez, Ana Giansanti, Fabrizio Papucci, Laura Perez de Lara, Maria J. Singh, Mandeep Kaur, Indu Pal |
| description | Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time propose and investigate local application of atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles (SLNs), as self-administrable eye drops. Insolubility, instability, and high molecular weight > 500 of ATS, and ensuring that SLNs reach posterior eye were the challenges to be met. ATS-SLNs, developed (2339/DEL/2014) using suitable components, quality-by-design (QBD) approach, and scalable hot high-pressure homogenization, were characterized and evaluated comprehensively for ocular suitability. ATS-SLNs were 8 and 12 times more bioavailable (AUC) in aqueous and vitreous humor, respectively, than free ATS. Three-tier (in vitro, ex vivo, and in vivo) ocular safety, higher corneal flux (2.5-fold), and improved stability (13.62 times) including photostability of ATS on incorporation in ATS-SLNs were established. Autoclavability and aqueous nature are the other highlights of ATS-SLNs. Presence of intact fluorescein-labeled SLNs (F-SLNs) in internal eye tissues post–in vivo application as eye drops provides direct evidence of successful delivery. Perinuclear fluorescence in ARPE-19 cells confirms the effective uptake of F-SLNs. Prolonged residence, up to 7 h, was attributed to the mucus-penetrating nature of ATS-SLNs.
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| doi_str_mv | 10.1007/s13346-020-00733-4 |
| format | Article |
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Graphical abstract</description><subject>Animals</subject><subject>Apoptosis - drug effects</subject><subject>Atorvastatin - administration & dosage</subject><subject>Atorvastatin - chemistry</subject><subject>Atorvastatin - pharmacokinetics</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Proliferation - drug effects</subject><subject>Cells, Cultured</subject><subject>Cornea - metabolism</subject><subject>Drug Liberation</subject><subject>Epithelial Cells - drug effects</subject><subject>Humans</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry</subject><subject>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</subject><subject>Lipids - administration & dosage</subject><subject>Lipids - chemistry</subject><subject>Lipids - pharmacokinetics</subject><subject>Macular Degeneration - drug therapy</subject><subject>Male</subject><subject>Nanoparticles - administration & dosage</subject><subject>Nanoparticles - chemistry</subject><subject>Ophthalmic Solutions - administration & dosage</subject><subject>Ophthalmic Solutions - chemistry</subject><subject>Ophthalmic Solutions - pharmacokinetics</subject><subject>Original</subject><subject>Original Article</subject><subject>Permeability</subject><subject>Pharmaceutical Sciences/Technology</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Swine</subject><issn>2190-393X</issn><issn>2190-3948</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9UT1PHDEQtVBQQMAfSBG5JIVh_HHrvRSRTiRAJFCaREpnzXlnL4v27JXtQ6Ljp2M4ciJNpvCMPe892_MY-yDhTALY8yy1No0ABaJutRZmjx0qOQeh56Z9t6v17wN2kvMd1DCNtHP7nh1opSwYPT9kj4sS0z3mgmUIYozYUcdzHIeOj8NU14AhTpjK4EfKHDOnB-JdilP-zKeaYq6EkgjLmkLhcSpDDLyPieOKRKIRSwWs0W9GTLyjFQVK-AI6Xdx-_XTM9nscM5285iP26_Lbz4trcfPj6vvF4kZ4Y5oiZKuWNLPQGyvBwswDKE1KzsBi_b2CzvdedW2zRNAIM1KqaVskWc8leq-P2Jet7rRZrqnz9bEJRzelYY3pwUUc3L-dMPxxq3jvrFJaGVUF1FbAp5hzon7HleCeLXFbS1y1xL1Y4kwlfXx7647y14AK0FtArq2wouTu4iaFOon_yT4BIoCaRw</recordid><startdate>20200801</startdate><enddate>20200801</enddate><creator>Yadav, Monika</creator><creator>Schiavone, Nicola</creator><creator>Guzman-Aranguez, Ana</creator><creator>Giansanti, Fabrizio</creator><creator>Papucci, Laura</creator><creator>Perez de Lara, Maria J.</creator><creator>Singh, Mandeep</creator><creator>Kaur, Indu Pal</creator><general>Springer US</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20200801</creationdate><title>Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)</title><author>Yadav, Monika ; Schiavone, Nicola ; Guzman-Aranguez, Ana ; Giansanti, Fabrizio ; Papucci, Laura ; Perez de Lara, Maria J. ; Singh, Mandeep ; Kaur, Indu Pal</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-182be570f4710705c0023e21507a73320dcfc2d86ba03a05e22688ae1dcf1acc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Apoptosis - drug effects</topic><topic>Atorvastatin - administration & dosage</topic><topic>Atorvastatin - chemistry</topic><topic>Atorvastatin - pharmacokinetics</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cell Proliferation - drug effects</topic><topic>Cells, Cultured</topic><topic>Cornea - metabolism</topic><topic>Drug Liberation</topic><topic>Epithelial Cells - drug effects</topic><topic>Humans</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry</topic><topic>Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics</topic><topic>Lipids - administration & dosage</topic><topic>Lipids - chemistry</topic><topic>Lipids - pharmacokinetics</topic><topic>Macular Degeneration - drug therapy</topic><topic>Male</topic><topic>Nanoparticles - administration & dosage</topic><topic>Nanoparticles - chemistry</topic><topic>Ophthalmic Solutions - administration & dosage</topic><topic>Ophthalmic Solutions - chemistry</topic><topic>Ophthalmic Solutions - pharmacokinetics</topic><topic>Original</topic><topic>Original Article</topic><topic>Permeability</topic><topic>Pharmaceutical Sciences/Technology</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Swine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yadav, Monika</creatorcontrib><creatorcontrib>Schiavone, Nicola</creatorcontrib><creatorcontrib>Guzman-Aranguez, Ana</creatorcontrib><creatorcontrib>Giansanti, Fabrizio</creatorcontrib><creatorcontrib>Papucci, Laura</creatorcontrib><creatorcontrib>Perez de Lara, Maria J.</creatorcontrib><creatorcontrib>Singh, Mandeep</creatorcontrib><creatorcontrib>Kaur, Indu Pal</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Drug delivery and translational research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yadav, Monika</au><au>Schiavone, Nicola</au><au>Guzman-Aranguez, Ana</au><au>Giansanti, Fabrizio</au><au>Papucci, Laura</au><au>Perez de Lara, Maria J.</au><au>Singh, Mandeep</au><au>Kaur, Indu Pal</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD)</atitle><jtitle>Drug delivery and translational research</jtitle><stitle>Drug Deliv. and Transl. Res</stitle><addtitle>Drug Deliv Transl Res</addtitle><date>2020-08-01</date><risdate>2020</risdate><volume>10</volume><issue>4</issue><spage>919</spage><epage>944</epage><pages>919-944</pages><issn>2190-393X</issn><eissn>2190-3948</eissn><abstract>Statins, widely prescribed for cardiovascular diseases, are also being eyed for management of age-related macular degeneration (AMD). Poor bioavailability and blood-aqueous barrier may however limit significant ocular concentration of statins following oral administration. We for the first time propose and investigate local application of atorvastatin (ATS; representative statin) loaded into solid lipid nanoparticles (SLNs), as self-administrable eye drops. Insolubility, instability, and high molecular weight > 500 of ATS, and ensuring that SLNs reach posterior eye were the challenges to be met. ATS-SLNs, developed (2339/DEL/2014) using suitable components, quality-by-design (QBD) approach, and scalable hot high-pressure homogenization, were characterized and evaluated comprehensively for ocular suitability. ATS-SLNs were 8 and 12 times more bioavailable (AUC) in aqueous and vitreous humor, respectively, than free ATS. Three-tier (in vitro, ex vivo, and in vivo) ocular safety, higher corneal flux (2.5-fold), and improved stability (13.62 times) including photostability of ATS on incorporation in ATS-SLNs were established. Autoclavability and aqueous nature are the other highlights of ATS-SLNs. Presence of intact fluorescein-labeled SLNs (F-SLNs) in internal eye tissues post–in vivo application as eye drops provides direct evidence of successful delivery. Perinuclear fluorescence in ARPE-19 cells confirms the effective uptake of F-SLNs. Prolonged residence, up to 7 h, was attributed to the mucus-penetrating nature of ATS-SLNs.
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| subjects | Animals Apoptosis - drug effects Atorvastatin - administration & dosage Atorvastatin - chemistry Atorvastatin - pharmacokinetics Biomedical and Life Sciences Biomedicine Cell Proliferation - drug effects Cells, Cultured Cornea - metabolism Drug Liberation Epithelial Cells - drug effects Humans Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage Hydroxymethylglutaryl-CoA Reductase Inhibitors - chemistry Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacokinetics Lipids - administration & dosage Lipids - chemistry Lipids - pharmacokinetics Macular Degeneration - drug therapy Male Nanoparticles - administration & dosage Nanoparticles - chemistry Ophthalmic Solutions - administration & dosage Ophthalmic Solutions - chemistry Ophthalmic Solutions - pharmacokinetics Original Original Article Permeability Pharmaceutical Sciences/Technology Rabbits Rats Swine |
| title | Atorvastatin-loaded solid lipid nanoparticles as eye drops: proposed treatment option for age-related macular degeneration (AMD) |
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