Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin
ABSTRACT The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between...
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| Veröffentlicht in: | Drug development and industrial pharmacy 2006-01, Vol.32 (3), p.327-334 |
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| creator | Karki, Shyam B. Treemaneekarn, Varaporn Ostovic, Drazen Nerurkar, Maneesh Almarsson, Örn |
| description | ABSTRACT
The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log kobsd on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described. |
| doi_str_mv | 10.1080/03639040500518997 |
| format | Article |
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The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log kobsd on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.</description><identifier>ISSN: 0363-9045</identifier><identifier>EISSN: 1520-5762</identifier><identifier>DOI: 10.1080/03639040500518997</identifier><identifier>PMID: 16556537</identifier><language>eng</language><publisher>Colchester: Informa UK Ltd</publisher><subject>Antibiotics, Antineoplastic - chemistry ; Antibiotics, Antineoplastic - therapeutic use ; Biological and medical sciences ; Calorimetry, Differential Scanning ; Chemistry, Pharmaceutical ; Degradation ; Doxorubicin - analogs & derivatives ; Doxorubicin - chemistry ; Doxorubicin - therapeutic use ; Doxorubicin peptide conjugate ; Drug Stability ; General pharmacology ; Humans ; Hydrogen-Ion Concentration ; Injections, Intravenous ; IV formulation ; Kinetics ; Lyophilization ; Male ; Medical sciences ; Oligopeptides - chemistry ; Oligopeptides - therapeutic use ; Pharmaceutical technology. Pharmaceutical industry ; Pharmacology. Drug treatments ; Preformulation ; Prodrug ; Prodrugs - chemistry ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Stability</subject><ispartof>Drug development and industrial pharmacy, 2006-01, Vol.32 (3), p.327-334</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-c465t-61ffeb5f858390b73b9b96a9a9cfc1fe1eb257a0afb209e00fdd834e199668b33</citedby><cites>FETCH-LOGICAL-c465t-61ffeb5f858390b73b9b96a9a9cfc1fe1eb257a0afb209e00fdd834e199668b33</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.tandfonline.com/doi/pdf/10.1080/03639040500518997$$EPDF$$P50$$Ginformahealthcare$$H</linktopdf><linktohtml>$$Uhttps://www.tandfonline.com/doi/full/10.1080/03639040500518997$$EHTML$$P50$$Ginformahealthcare$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,59647,59753,60436,60542,61221,61256,61402,61437</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17634142$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16556537$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Karki, Shyam B.</creatorcontrib><creatorcontrib>Treemaneekarn, Varaporn</creatorcontrib><creatorcontrib>Ostovic, Drazen</creatorcontrib><creatorcontrib>Nerurkar, Maneesh</creatorcontrib><creatorcontrib>Almarsson, Örn</creatorcontrib><title>Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin</title><title>Drug development and industrial pharmacy</title><addtitle>Drug Dev Ind Pharm</addtitle><description>ABSTRACT
The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log kobsd on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.</description><subject>Antibiotics, Antineoplastic - chemistry</subject><subject>Antibiotics, Antineoplastic - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Calorimetry, Differential Scanning</subject><subject>Chemistry, Pharmaceutical</subject><subject>Degradation</subject><subject>Doxorubicin - analogs & derivatives</subject><subject>Doxorubicin - chemistry</subject><subject>Doxorubicin - therapeutic use</subject><subject>Doxorubicin peptide conjugate</subject><subject>Drug Stability</subject><subject>General pharmacology</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Injections, Intravenous</subject><subject>IV formulation</subject><subject>Kinetics</subject><subject>Lyophilization</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Oligopeptides - chemistry</subject><subject>Oligopeptides - therapeutic use</subject><subject>Pharmaceutical technology. Pharmaceutical industry</subject><subject>Pharmacology. Drug treatments</subject><subject>Preformulation</subject><subject>Prodrug</subject><subject>Prodrugs - chemistry</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Stability</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>eNqFkcFu1DAQhi0EokvhAbigXEDlYLCT2IkLl2qhUKkCJFqu0cQZJ6mceLET0TwXL4i3u1WFkMrJ8sz3_5qZn5DnnL3hrGRvWSYzxXImGBO8VKp4QFZcpIyKQqYPyWrbpxEQB-RJCFeM8VQJ8ZgccCmEFFmxIr8_YOjbMXEmgTE5-5GcOj_MFqbe3RYvxzBBbTH55l3j5zZZw9j0DUyYGOe31diPn1jW6JMLjzANOE7HyXdn5xujdYdDHya_bC2_0KM21sEvlnbLhoIFGtBTvWjrOrxebGsXHZutHW8aFufXtHHXzs91r_vxKXlkwAZ8tn8PyeXpx4v1Z3r-9dPZ-uSc6lyKiUpuDNbClKKMV6qLrFa1kqBAaaO5QY51KgpgYOqUKWTMNE2Z5ciVkrKss-yQvNr5brz7OWOYqriERmthRDeHShZFoeKp_wtyJXlZlGUE-Q7U8WjBo6k2vh_iJSrOqm2k1T-RRs2LvflcD9jcKfYZRuDlHoCgwRofc-jDHRcHzHmeRu79juvHmNsAv5y3TTXBYp2_FWX3zfHuL3mHYKdOg8fqys1-jEncs8UfnCXRww</recordid><startdate>20060101</startdate><enddate>20060101</enddate><creator>Karki, Shyam B.</creator><creator>Treemaneekarn, Varaporn</creator><creator>Ostovic, Drazen</creator><creator>Nerurkar, Maneesh</creator><creator>Almarsson, Örn</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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>7X8</scope></search><sort><creationdate>20060101</creationdate><title>Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin</title><author>Karki, Shyam B. ; Treemaneekarn, Varaporn ; Ostovic, Drazen ; Nerurkar, Maneesh ; Almarsson, Örn</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c465t-61ffeb5f858390b73b9b96a9a9cfc1fe1eb257a0afb209e00fdd834e199668b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Antibiotics, Antineoplastic - chemistry</topic><topic>Antibiotics, Antineoplastic - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Calorimetry, Differential Scanning</topic><topic>Chemistry, Pharmaceutical</topic><topic>Degradation</topic><topic>Doxorubicin - analogs & derivatives</topic><topic>Doxorubicin - chemistry</topic><topic>Doxorubicin - therapeutic use</topic><topic>Doxorubicin peptide conjugate</topic><topic>Drug Stability</topic><topic>General pharmacology</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Injections, Intravenous</topic><topic>IV formulation</topic><topic>Kinetics</topic><topic>Lyophilization</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Oligopeptides - chemistry</topic><topic>Oligopeptides - therapeutic use</topic><topic>Pharmaceutical technology. Pharmaceutical industry</topic><topic>Pharmacology. Drug treatments</topic><topic>Preformulation</topic><topic>Prodrug</topic><topic>Prodrugs - chemistry</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Stability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Karki, Shyam B.</creatorcontrib><creatorcontrib>Treemaneekarn, Varaporn</creatorcontrib><creatorcontrib>Ostovic, Drazen</creatorcontrib><creatorcontrib>Nerurkar, Maneesh</creatorcontrib><creatorcontrib>Almarsson, Örn</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</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>Karki, Shyam B.</au><au>Treemaneekarn, Varaporn</au><au>Ostovic, Drazen</au><au>Nerurkar, Maneesh</au><au>Almarsson, Örn</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin</atitle><jtitle>Drug development and industrial pharmacy</jtitle><addtitle>Drug Dev Ind Pharm</addtitle><date>2006-01-01</date><risdate>2006</risdate><volume>32</volume><issue>3</issue><spage>327</spage><epage>334</epage><pages>327-334</pages><issn>0363-9045</issn><eissn>1520-5762</eissn><abstract>ABSTRACT
The chemical degradation of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin (henceforth referred to as doxorubicin peptide conjugate 1) was studied in buffered aqueous solution. The pH-rate profile of degradation shows that the doxorubicin conjugate is most stable between pH 5 and 6. The dependence of log kobsd on pH in acidic medium is characteristic of specific acid-catalysis of the sugar hemiaminal of 1 (as in the case of doxorubicin). Isolation of degradates and structural determination shows that the degradation at lower pH values yields the water-insoluble aglycone doxorubicinone, supporting the mechanism of acid-catalyzed loss of the amino sugar. At pH higher than 5, a more complicated degradation pattern is observed, including the loss of the amino sugar and the aromatization of the saturated ring to give 7,8-dehydro-9,10-desacetyldoxorubicinone as one of the major products. Around the pH of maximum stability in solution, the rate of degradation of 1 is significantly greater than that for doxorubicin, which rules out the formulation of a room temperature solution product with a sufficiently long shelflife for market use. Design of a stable lyophilized formulation for sterile reconstitution based on the physicochemical properties of 1 is described.</abstract><cop>Colchester</cop><pub>Informa UK Ltd</pub><pmid>16556537</pmid><doi>10.1080/03639040500518997</doi><tpages>8</tpages></addata></record> |
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| ispartof | Drug development and industrial pharmacy, 2006-01, Vol.32 (3), p.327-334 |
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| source | MEDLINE; EBSCOhost Business Source Complete; Taylor & Francis Medical Library - CRKN; Taylor & Francis Journals Complete |
| subjects | Antibiotics, Antineoplastic - chemistry Antibiotics, Antineoplastic - therapeutic use Biological and medical sciences Calorimetry, Differential Scanning Chemistry, Pharmaceutical Degradation Doxorubicin - analogs & derivatives Doxorubicin - chemistry Doxorubicin - therapeutic use Doxorubicin peptide conjugate Drug Stability General pharmacology Humans Hydrogen-Ion Concentration Injections, Intravenous IV formulation Kinetics Lyophilization Male Medical sciences Oligopeptides - chemistry Oligopeptides - therapeutic use Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Preformulation Prodrug Prodrugs - chemistry Prostate cancer Prostatic Neoplasms - drug therapy Stability |
| title | Design of an IV Formulation of an Unstable Prodrug Candidate for Prostate Cancer Treatment: Solution Chemistry of N-(glutaryl-hyp-ala-ser-cyclohexylglycyl-gln-ser-leu)-doxorubicin |
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