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Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System
The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for...
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Published in: | Journal of pharmacy & pharmaceutical sciences 2018-01, Vol.21 (1s), p.335s-348s |
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creator | Trepanier, Daniel J Ure, Daren R Foster, Robert Thomas |
description | The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use.
The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).
The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats.
The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma. |
doi_str_mv | 10.18433/jpps30245 |
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The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).
The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats.
The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.</description><identifier>ISSN: 1482-1826</identifier><identifier>EISSN: 1482-1826</identifier><identifier>DOI: 10.18433/jpps30245</identifier><identifier>PMID: 30472978</identifier><language>eng</language><publisher>Canada: Frontiers Media S.A</publisher><subject>Administration, Oral ; Adolescent ; Adult ; Animals ; Chromatography, Liquid ; Cyclosporins - administration & dosage ; Cyclosporins - chemistry ; Cyclosporins - pharmacokinetics ; Drug Delivery Systems ; Emulsions - administration & dosage ; Emulsions - chemistry ; Emulsions - pharmacokinetics ; Healthy Volunteers ; Humans ; Liver - chemistry ; Liver - metabolism ; Middle Aged ; Molecular Conformation ; Particle Size ; Rats ; Rats, Sprague-Dawley ; Small Molecule Libraries - administration & dosage ; Small Molecule Libraries - chemistry ; Small Molecule Libraries - pharmacokinetics ; Solubility ; Spectrometry, Mass, Electrospray Ionization ; Surface Properties ; Tissue Distribution ; Young Adult</subject><ispartof>Journal of pharmacy & pharmaceutical sciences, 2018-01, Vol.21 (1s), p.335s-348s</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c353t-55d5985dbd89b1dbc0dbf77e9523555728a53089ec9f71141f5172832817b1a83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30472978$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Trepanier, Daniel J</creatorcontrib><creatorcontrib>Ure, Daren R</creatorcontrib><creatorcontrib>Foster, Robert Thomas</creatorcontrib><title>Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System</title><title>Journal of pharmacy & pharmaceutical sciences</title><addtitle>J Pharm Pharm Sci</addtitle><description>The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use.
The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).
The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats.
The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.</description><subject>Administration, Oral</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Animals</subject><subject>Chromatography, Liquid</subject><subject>Cyclosporins - administration & dosage</subject><subject>Cyclosporins - chemistry</subject><subject>Cyclosporins - pharmacokinetics</subject><subject>Drug Delivery Systems</subject><subject>Emulsions - administration & dosage</subject><subject>Emulsions - chemistry</subject><subject>Emulsions - pharmacokinetics</subject><subject>Healthy Volunteers</subject><subject>Humans</subject><subject>Liver - chemistry</subject><subject>Liver - metabolism</subject><subject>Middle Aged</subject><subject>Molecular Conformation</subject><subject>Particle Size</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Small Molecule Libraries - administration & dosage</subject><subject>Small Molecule Libraries - chemistry</subject><subject>Small Molecule Libraries - pharmacokinetics</subject><subject>Solubility</subject><subject>Spectrometry, Mass, Electrospray Ionization</subject><subject>Surface Properties</subject><subject>Tissue Distribution</subject><subject>Young Adult</subject><issn>1482-1826</issn><issn>1482-1826</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNpNUV1v1DAQjBCIfsALPwD5EaEGvHYcO4_o2kKlQyDa8mo59rr4SOJgJycd_Hmiu3LiZXY1O5rV7hTFK6DvQFWcv9-MY-aUVeJJcQqVYiUoVj_9rz8pznLeUMo4a-jz4oTTSrJGqtPizyVusYtjj8N0QVY_TDJ2whR-mynE4YKYwZGvC9sbG3-GAadgydXWdPN-TqInhqy-fa84kHU0Dh25xc6Xn4NNEfu5y8HvwvBALtO8AHZhi2lHbnd5wv5F8cybLuPLx3pe3F9f3a0-lesvH29WH9al5YJPpRBONEq41qmmBdda6lovJTaCcSGEZMoITlWDtvESoAIvYCE5UyBbMIqfFzcHXxfNRo8p9CbtdDRB74mYHrRJy2EdalYDVRYslYxWwNpGGVYrxKoGVksPi9ebg9eY4q8Z86T7kC12nRkwzlkz4IqKBetF-vYgXV6Rc0J_XA1U74PTx-AW8etH37nt0R2l_5LifwH8O5Jo</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Trepanier, Daniel J</creator><creator>Ure, Daren R</creator><creator>Foster, Robert Thomas</creator><general>Frontiers Media S.A</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>7X8</scope><scope>DOA</scope></search><sort><creationdate>20180101</creationdate><title>Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System</title><author>Trepanier, Daniel J ; Ure, Daren R ; Foster, Robert Thomas</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c353t-55d5985dbd89b1dbc0dbf77e9523555728a53089ec9f71141f5172832817b1a83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Administration, Oral</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Animals</topic><topic>Chromatography, Liquid</topic><topic>Cyclosporins - administration & dosage</topic><topic>Cyclosporins - chemistry</topic><topic>Cyclosporins - pharmacokinetics</topic><topic>Drug Delivery Systems</topic><topic>Emulsions - administration & dosage</topic><topic>Emulsions - chemistry</topic><topic>Emulsions - pharmacokinetics</topic><topic>Healthy Volunteers</topic><topic>Humans</topic><topic>Liver - chemistry</topic><topic>Liver - metabolism</topic><topic>Middle Aged</topic><topic>Molecular Conformation</topic><topic>Particle Size</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Small Molecule Libraries - administration & dosage</topic><topic>Small Molecule Libraries - chemistry</topic><topic>Small Molecule Libraries - pharmacokinetics</topic><topic>Solubility</topic><topic>Spectrometry, Mass, Electrospray Ionization</topic><topic>Surface Properties</topic><topic>Tissue Distribution</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Trepanier, Daniel J</creatorcontrib><creatorcontrib>Ure, Daren R</creatorcontrib><creatorcontrib>Foster, Robert Thomas</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Directory of Open Access Journals</collection><jtitle>Journal of pharmacy & pharmaceutical sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Trepanier, Daniel J</au><au>Ure, Daren R</au><au>Foster, Robert Thomas</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System</atitle><jtitle>Journal of pharmacy & pharmaceutical sciences</jtitle><addtitle>J Pharm Pharm Sci</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>21</volume><issue>1s</issue><spage>335s</spage><epage>348s</epage><pages>335s-348s</pages><issn>1482-1826</issn><eissn>1482-1826</eissn><abstract>The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use.
The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS).
The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats.
The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.</abstract><cop>Canada</cop><pub>Frontiers Media S.A</pub><pmid>30472978</pmid><doi>10.18433/jpps30245</doi><oa>free_for_read</oa></addata></record> |
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subjects | Administration, Oral Adolescent Adult Animals Chromatography, Liquid Cyclosporins - administration & dosage Cyclosporins - chemistry Cyclosporins - pharmacokinetics Drug Delivery Systems Emulsions - administration & dosage Emulsions - chemistry Emulsions - pharmacokinetics Healthy Volunteers Humans Liver - chemistry Liver - metabolism Middle Aged Molecular Conformation Particle Size Rats Rats, Sprague-Dawley Small Molecule Libraries - administration & dosage Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacokinetics Solubility Spectrometry, Mass, Electrospray Ionization Surface Properties Tissue Distribution Young Adult |
title | Development, Characterization, and Pharmacokinetic Evaluation of a CRV431 Loaded Self-Microemulsifying Drug Delivery System |
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