Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies
ABSTRACT The bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was...
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description | ABSTRACT
The bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was used as the model drug. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies were used to prepare powders of danazol/PVP K-15 in a 1:1 ratio. The evaporative precipitation into aqueous solution (EPAS) and SFL compositions, physical mixture and commercial product were dosed by oral gavage to 28 male Swiss/ICR mice for each arm of the study. Samples were taken at time points ranging from 0.5 to 24 h. Pooled mouse serum was analyzed for danazol by high performance liquid chromatography (HPLC). Powders were analyzed for their ability to form supersaturated solutions through dissolution at concentrations of 1 mg/mL which was the dose delivered to the mouse models. Spray freezing into liquid (SFL) and EPAS compositions displayed higher Cmax at 392.5 ng/mL and 430.1 ng/mL, respectively, compared to the physical mixture (204.4 ng/mL) and commercially available danazol (199.3 ng/mL). The Tmax for all compositions studied was near the 1 h time point. The area under the curve (AUC) for the SFL composition was 2558 ng.h/mL compared to EPAS composition at 1534 ng.h/mL. The area under the curve (AUC) for the physical mixture and commercially available danazol were 672 ng.h/mL and 1519 ng.h/mL, respectively. The elimination rate constants for the EPAS composition, SFL composition, and physical mixture were similar at ∼0.15 h−1 where as the commercially available danazol capsules displayed an elimination rate constant of 0.103 h−1. The extent of danazol absorption in the mouse model was higher for SFL composition compared to the less amorphous EPAS composition, physical mixture, and commercially available danazol powders. Both EPAS and SFL compositions were able to form supersaturated solutions. However, the SFL composition displayed a supersaturation of 33% above control and was able to maintain supersaturation for 90 min compared to the EPAS composition (27% supersaturation above control for 60 min). Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercially available danazol capsules. Becaus |
doi_str_mv | 10.1080/03639040500529176 |
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The bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was used as the model drug. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies were used to prepare powders of danazol/PVP K-15 in a 1:1 ratio. The evaporative precipitation into aqueous solution (EPAS) and SFL compositions, physical mixture and commercial product were dosed by oral gavage to 28 male Swiss/ICR mice for each arm of the study. Samples were taken at time points ranging from 0.5 to 24 h. Pooled mouse serum was analyzed for danazol by high performance liquid chromatography (HPLC). Powders were analyzed for their ability to form supersaturated solutions through dissolution at concentrations of 1 mg/mL which was the dose delivered to the mouse models. Spray freezing into liquid (SFL) and EPAS compositions displayed higher Cmax at 392.5 ng/mL and 430.1 ng/mL, respectively, compared to the physical mixture (204.4 ng/mL) and commercially available danazol (199.3 ng/mL). The Tmax for all compositions studied was near the 1 h time point. The area under the curve (AUC) for the SFL composition was 2558 ng.h/mL compared to EPAS composition at 1534 ng.h/mL. The area under the curve (AUC) for the physical mixture and commercially available danazol were 672 ng.h/mL and 1519 ng.h/mL, respectively. The elimination rate constants for the EPAS composition, SFL composition, and physical mixture were similar at ∼0.15 h−1 where as the commercially available danazol capsules displayed an elimination rate constant of 0.103 h−1. The extent of danazol absorption in the mouse model was higher for SFL composition compared to the less amorphous EPAS composition, physical mixture, and commercially available danazol powders. Both EPAS and SFL compositions were able to form supersaturated solutions. However, the SFL composition displayed a supersaturation of 33% above control and was able to maintain supersaturation for 90 min compared to the EPAS composition (27% supersaturation above control for 60 min). Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercially available danazol capsules. Because of the greater extent of dissolution of the SFL composition, the bioavailability was enhanced in a mouse model.</description><identifier>ISSN: 0363-9045</identifier><identifier>EISSN: 1520-5762</identifier><identifier>DOI: 10.1080/03639040500529176</identifier><identifier>PMID: 16720411</identifier><language>eng</language><publisher>Colchester: Informa UK Ltd</publisher><subject>Algorithms ; Animals ; Biological and medical sciences ; Biological Availability ; Chemical Phenomena ; Chemistry, Physical ; Chromatography, High Pressure Liquid ; Danazol - administration & dosage ; Danazol - chemistry ; Danazol - pharmacokinetics ; Drug Compounding ; Estrogen Antagonists - administration & dosage ; Estrogen Antagonists - chemistry ; Estrogen Antagonists - pharmacokinetics ; Excipients ; Freezing ; General pharmacology ; Male ; Medical sciences ; Mice ; Mice, Inbred ICR ; Particle Size ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. Drug treatments ; Powders ; Solutions</subject><ispartof>Drug development and industrial pharmacy, 2006, Vol.32 (5), p.559-567</ispartof><rights>2006 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted 2006</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c434t-3d63989d7667eb957d0977eb45df4a073978f8fce9e7b3c006a8e901e3689b353</citedby><cites>FETCH-LOGICAL-c434t-3d63989d7667eb957d0977eb45df4a073978f8fce9e7b3c006a8e901e3689b353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/03639040500529176$$EPDF$$P50$$Ginformaworld$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/03639040500529176$$EHTML$$P50$$Ginformaworld$$H</linktohtml><link.rule.ids>314,780,784,4024,27923,27924,27925,59647,59753,60436,60542,61221,61256,61402,61437</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17758827$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16720411$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vaughn, Jason M.</creatorcontrib><creatorcontrib>McConville, Jason T.</creatorcontrib><creatorcontrib>Crisp, Matthew T.</creatorcontrib><creatorcontrib>Johnston, Keith P.</creatorcontrib><creatorcontrib>Williams, Robert O.</creatorcontrib><title>Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies</title><title>Drug development and industrial pharmacy</title><addtitle>Drug Dev Ind Pharm</addtitle><description>ABSTRACT
The bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was used as the model drug. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies were used to prepare powders of danazol/PVP K-15 in a 1:1 ratio. The evaporative precipitation into aqueous solution (EPAS) and SFL compositions, physical mixture and commercial product were dosed by oral gavage to 28 male Swiss/ICR mice for each arm of the study. Samples were taken at time points ranging from 0.5 to 24 h. Pooled mouse serum was analyzed for danazol by high performance liquid chromatography (HPLC). Powders were analyzed for their ability to form supersaturated solutions through dissolution at concentrations of 1 mg/mL which was the dose delivered to the mouse models. Spray freezing into liquid (SFL) and EPAS compositions displayed higher Cmax at 392.5 ng/mL and 430.1 ng/mL, respectively, compared to the physical mixture (204.4 ng/mL) and commercially available danazol (199.3 ng/mL). The Tmax for all compositions studied was near the 1 h time point. The area under the curve (AUC) for the SFL composition was 2558 ng.h/mL compared to EPAS composition at 1534 ng.h/mL. The area under the curve (AUC) for the physical mixture and commercially available danazol were 672 ng.h/mL and 1519 ng.h/mL, respectively. The elimination rate constants for the EPAS composition, SFL composition, and physical mixture were similar at ∼0.15 h−1 where as the commercially available danazol capsules displayed an elimination rate constant of 0.103 h−1. The extent of danazol absorption in the mouse model was higher for SFL composition compared to the less amorphous EPAS composition, physical mixture, and commercially available danazol powders. Both EPAS and SFL compositions were able to form supersaturated solutions. However, the SFL composition displayed a supersaturation of 33% above control and was able to maintain supersaturation for 90 min compared to the EPAS composition (27% supersaturation above control for 60 min). Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercially available danazol capsules. Because of the greater extent of dissolution of the SFL composition, the bioavailability was enhanced in a mouse model.</description><subject>Algorithms</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biological Availability</subject><subject>Chemical Phenomena</subject><subject>Chemistry, Physical</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Danazol - administration & dosage</subject><subject>Danazol - chemistry</subject><subject>Danazol - pharmacokinetics</subject><subject>Drug Compounding</subject><subject>Estrogen Antagonists - administration & dosage</subject><subject>Estrogen Antagonists - chemistry</subject><subject>Estrogen Antagonists - pharmacokinetics</subject><subject>Excipients</subject><subject>Freezing</subject><subject>General pharmacology</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred ICR</subject><subject>Particle Size</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Powders</subject><subject>Solutions</subject><issn>0363-9045</issn><issn>1520-5762</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EokvhAbggX-AWsJM4jgWXpXQp0kpU2nKOJo6zceW1UztZlD4WT4hDFlUIqSdbnu__Z_wPQq8peU9JST6QrMgEyQkjhKWC8uIJWlGWkoTxIn2KVnM9iQA7Qy9CuCWEpoKx5-iMFjwlOaUr9Gs39soHGEYPg3YWX3vXjFIFfKX3Hf6sHRxBG6i10cOEXYvXB-f7zo0BfwEL987ga_CDliZqNs4fVIPrCV8eoXez5VFFSyV1r4elgbaDw-u7Uc0WO2fGP69gG7zrPUx445W613a_gFt9N-oG3yjZWWfcXqvwEj1rwQT16nSeox-by5uLq2T7_eu3i_U2kXmWD0nWxHBK0fCi4KoWjDdE8HjLWdPmQHgmeNmWrVRC8TqThBRQKkGoyopS1BnLztG7xbf3Lo4bhuqgg1TGgJ1nr4qSkLlDBOkCSu9C8Kqteq8P4KeKkmpeVPXfoqLmzcl8rGNkD4rTZiLw9gRAkGBaD1bq8MBxzsoy5ZH7tHDatjF9-Om8aaoBJuP8X1H22Bwf_5F3CszQSfCqunWjtzHgR37xGwSrxGc</recordid><startdate>2006</startdate><enddate>2006</enddate><creator>Vaughn, Jason M.</creator><creator>McConville, Jason T.</creator><creator>Crisp, Matthew T.</creator><creator>Johnston, Keith P.</creator><creator>Williams, Robert O.</creator><general>Informa UK Ltd</general><general>Taylor & Francis</general><scope>IQODW</scope><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></search><sort><creationdate>2006</creationdate><title>Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies</title><author>Vaughn, Jason M. ; McConville, Jason T. ; Crisp, Matthew T. ; Johnston, Keith P. ; Williams, Robert O.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c434t-3d63989d7667eb957d0977eb45df4a073978f8fce9e7b3c006a8e901e3689b353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Algorithms</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biological Availability</topic><topic>Chemical Phenomena</topic><topic>Chemistry, Physical</topic><topic>Chromatography, High Pressure Liquid</topic><topic>Danazol - administration & dosage</topic><topic>Danazol - chemistry</topic><topic>Danazol - pharmacokinetics</topic><topic>Drug Compounding</topic><topic>Estrogen Antagonists - administration & dosage</topic><topic>Estrogen Antagonists - chemistry</topic><topic>Estrogen Antagonists - pharmacokinetics</topic><topic>Excipients</topic><topic>Freezing</topic><topic>General pharmacology</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred ICR</topic><topic>Particle Size</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Powders</topic><topic>Solutions</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vaughn, Jason M.</creatorcontrib><creatorcontrib>McConville, Jason T.</creatorcontrib><creatorcontrib>Crisp, Matthew T.</creatorcontrib><creatorcontrib>Johnston, Keith P.</creatorcontrib><creatorcontrib>Williams, Robert O.</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Drug development and industrial pharmacy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vaughn, Jason M.</au><au>McConville, Jason T.</au><au>Crisp, Matthew T.</au><au>Johnston, Keith P.</au><au>Williams, Robert O.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies</atitle><jtitle>Drug development and industrial pharmacy</jtitle><addtitle>Drug Dev Ind Pharm</addtitle><date>2006</date><risdate>2006</risdate><volume>32</volume><issue>5</issue><spage>559</spage><epage>567</epage><pages>559-567</pages><issn>0363-9045</issn><eissn>1520-5762</eissn><abstract>ABSTRACT
The bioavailability of high surface area danazol formulations was evaluated in a mouse model to determine what effect high supersaturation, as measured in vitro, has on the absorption of a poorly water soluble drug. Danazol, a biopharmaceutics classification system II (BCS II) compound, was used as the model drug. Evaporative precipitation into aqueous solution (EPAS) and spray freezing into liquid (SFL) technologies were used to prepare powders of danazol/PVP K-15 in a 1:1 ratio. The evaporative precipitation into aqueous solution (EPAS) and SFL compositions, physical mixture and commercial product were dosed by oral gavage to 28 male Swiss/ICR mice for each arm of the study. Samples were taken at time points ranging from 0.5 to 24 h. Pooled mouse serum was analyzed for danazol by high performance liquid chromatography (HPLC). Powders were analyzed for their ability to form supersaturated solutions through dissolution at concentrations of 1 mg/mL which was the dose delivered to the mouse models. Spray freezing into liquid (SFL) and EPAS compositions displayed higher Cmax at 392.5 ng/mL and 430.1 ng/mL, respectively, compared to the physical mixture (204.4 ng/mL) and commercially available danazol (199.3 ng/mL). The Tmax for all compositions studied was near the 1 h time point. The area under the curve (AUC) for the SFL composition was 2558 ng.h/mL compared to EPAS composition at 1534 ng.h/mL. The area under the curve (AUC) for the physical mixture and commercially available danazol were 672 ng.h/mL and 1519 ng.h/mL, respectively. The elimination rate constants for the EPAS composition, SFL composition, and physical mixture were similar at ∼0.15 h−1 where as the commercially available danazol capsules displayed an elimination rate constant of 0.103 h−1. The extent of danazol absorption in the mouse model was higher for SFL composition compared to the less amorphous EPAS composition, physical mixture, and commercially available danazol powders. Both EPAS and SFL compositions were able to form supersaturated solutions. However, the SFL composition displayed a supersaturation of 33% above control and was able to maintain supersaturation for 90 min compared to the EPAS composition (27% supersaturation above control for 60 min). Through the use of a testing method for supersaturation, it was found that EPAS and SFL compositions achieve higher apparent solubilities when compared to the physical mixture and commercially available danazol capsules. Because of the greater extent of dissolution of the SFL composition, the bioavailability was enhanced in a mouse model.</abstract><cop>Colchester</cop><pub>Informa UK Ltd</pub><pmid>16720411</pmid><doi>10.1080/03639040500529176</doi><tpages>9</tpages></addata></record> |
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subjects | Algorithms Animals Biological and medical sciences Biological Availability Chemical Phenomena Chemistry, Physical Chromatography, High Pressure Liquid Danazol - administration & dosage Danazol - chemistry Danazol - pharmacokinetics Drug Compounding Estrogen Antagonists - administration & dosage Estrogen Antagonists - chemistry Estrogen Antagonists - pharmacokinetics Excipients Freezing General pharmacology Male Medical sciences Mice Mice, Inbred ICR Particle Size Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Powders Solutions |
title | Supersaturation Produces High Bioavailability of Amorphous Danazol Particles Formed by Evaporative Precipitation into Aqueous Solution and Spray Freezing into Liquid Technologies |
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