Loading…
In vivo screening of subcutaneous tolerability for the development of novel excipients
To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be requ...
Saved in:
Published in: | Journal of Toxicologic Pathology 2022, Vol.35(4), pp.355-360 |
---|---|
Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
cited_by | cdi_FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73 |
---|---|
cites | cdi_FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73 |
container_end_page | 360 |
container_issue | 4 |
container_start_page | 355 |
container_title | Journal of Toxicologic Pathology |
container_volume | 35 |
creator | Takai, Yuichi Powlin, Stephanie Awasaki, Yasuyuki Yamauchi, Toshiaki Sano, Tomoya Takahashi, Haruyuki Ranneh, Abdul-Hackam Arai, Yuta |
description | To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase. |
doi_str_mv | 10.1293/tox.2022-0035 |
format | article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9647210</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2738497268</sourcerecordid><originalsourceid>FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73</originalsourceid><addsrcrecordid>eNpdUU1v1DAQjRBILKVH7pG4cEnxVxL7goRW0FaqxAVQb5ZjT3a98trBdlbtv8dpqq3gMjP2vPdmRq-qPmB0hYmgn3N4uCKIkAYh2r6qNphz3Ajc3r-uNkhgVmrB31bvUjogRHrU0k31-9bXJ3sKddIRwFu_q8NYp3nQc1YewpzqHBxENVhn82M9hljnPdQGTuDCdASfF4IP5VnDg7aTLV_pffVmVC7B5XO-qH59__Zze9Pc_bi-3X69a3QnUG4IZYYwrowBxY0iuhsAcNt3I--MJnTsiCCqhZK5Lstr3gMd9ABUjNSonl5UX1bdaR6OYHSZHZWTU7RHFR9lUFb-2_F2L3fhJEXHeoJREfj0LBDDnxlSlkebNDi3Hi9JTzkTPel4gX78D3oIc_TlvAWFCW4JogXVrCgdQ0oRxvMyGMnFJllskotNcrGp4K9XfFnSauWCd9bDi7QxtBAm9UJBrCQuS9WW0CGGeMe4KErbVemQstrBea6K2WoHT3NpK9kSzmLnrt6rKMHTv-44tyg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2731215203</pqid></control><display><type>article</type><title>In vivo screening of subcutaneous tolerability for the development of novel excipients</title><source>NCBI_PubMed Central(免费)</source><creator>Takai, Yuichi ; Powlin, Stephanie ; Awasaki, Yasuyuki ; Yamauchi, Toshiaki ; Sano, Tomoya ; Takahashi, Haruyuki ; Ranneh, Abdul-Hackam ; Arai, Yuta</creator><creatorcontrib>Takai, Yuichi ; Powlin, Stephanie ; Awasaki, Yasuyuki ; Yamauchi, Toshiaki ; Sano, Tomoya ; Takahashi, Haruyuki ; Ranneh, Abdul-Hackam ; Arai, Yuta ; Drug Safety Research and Evaluation ; Takeda Pharmaceutical Company Limited ; Pharmaceutical Sciences ; Takeda Pharmaceutical International Co</creatorcontrib><description>To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase.</description><identifier>ISSN: 0914-9198</identifier><identifier>EISSN: 1881-915X</identifier><identifier>EISSN: 1347-7404</identifier><identifier>DOI: 10.1293/tox.2022-0035</identifier><language>eng</language><publisher>Tokyo: JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY</publisher><subject>Degeneration ; Dosage ; Evaluation ; Excipients ; Formulations ; in vivo screening ; Injection ; Irritation ; Lipids ; Necrosis ; novel excipient ; Optimization ; Pharmaceuticals ; Physicochemical properties ; Polymers ; rat ; Risk reduction ; Safety ; Screening ; Technnical Report ; ubcutaneous</subject><ispartof>Journal of Toxicologic Pathology, 2022, Vol.35(4), pp.355-360</ispartof><rights>2022 The Japanese Society of Toxicologic Pathology</rights><rights>Copyright Japan Science and Technology Agency 2022</rights><rights>2022 The Japanese Society of Toxicologic Pathology 2022</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73</citedby><cites>FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647210/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9647210/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>Takai, Yuichi</creatorcontrib><creatorcontrib>Powlin, Stephanie</creatorcontrib><creatorcontrib>Awasaki, Yasuyuki</creatorcontrib><creatorcontrib>Yamauchi, Toshiaki</creatorcontrib><creatorcontrib>Sano, Tomoya</creatorcontrib><creatorcontrib>Takahashi, Haruyuki</creatorcontrib><creatorcontrib>Ranneh, Abdul-Hackam</creatorcontrib><creatorcontrib>Arai, Yuta</creatorcontrib><creatorcontrib>Drug Safety Research and Evaluation</creatorcontrib><creatorcontrib>Takeda Pharmaceutical Company Limited</creatorcontrib><creatorcontrib>Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Takeda Pharmaceutical International Co</creatorcontrib><title>In vivo screening of subcutaneous tolerability for the development of novel excipients</title><title>Journal of Toxicologic Pathology</title><addtitle>J Toxicol Pathol</addtitle><description>To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase.</description><subject>Degeneration</subject><subject>Dosage</subject><subject>Evaluation</subject><subject>Excipients</subject><subject>Formulations</subject><subject>in vivo screening</subject><subject>Injection</subject><subject>Irritation</subject><subject>Lipids</subject><subject>Necrosis</subject><subject>novel excipient</subject><subject>Optimization</subject><subject>Pharmaceuticals</subject><subject>Physicochemical properties</subject><subject>Polymers</subject><subject>rat</subject><subject>Risk reduction</subject><subject>Safety</subject><subject>Screening</subject><subject>Technnical Report</subject><subject>ubcutaneous</subject><issn>0914-9198</issn><issn>1881-915X</issn><issn>1347-7404</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNpdUU1v1DAQjRBILKVH7pG4cEnxVxL7goRW0FaqxAVQb5ZjT3a98trBdlbtv8dpqq3gMjP2vPdmRq-qPmB0hYmgn3N4uCKIkAYh2r6qNphz3Ajc3r-uNkhgVmrB31bvUjogRHrU0k31-9bXJ3sKddIRwFu_q8NYp3nQc1YewpzqHBxENVhn82M9hljnPdQGTuDCdASfF4IP5VnDg7aTLV_pffVmVC7B5XO-qH59__Zze9Pc_bi-3X69a3QnUG4IZYYwrowBxY0iuhsAcNt3I--MJnTsiCCqhZK5Lstr3gMd9ABUjNSonl5UX1bdaR6OYHSZHZWTU7RHFR9lUFb-2_F2L3fhJEXHeoJREfj0LBDDnxlSlkebNDi3Hi9JTzkTPel4gX78D3oIc_TlvAWFCW4JogXVrCgdQ0oRxvMyGMnFJllskotNcrGp4K9XfFnSauWCd9bDi7QxtBAm9UJBrCQuS9WW0CGGeMe4KErbVemQstrBea6K2WoHT3NpK9kSzmLnrt6rKMHTv-44tyg</recordid><startdate>20220101</startdate><enddate>20220101</enddate><creator>Takai, Yuichi</creator><creator>Powlin, Stephanie</creator><creator>Awasaki, Yasuyuki</creator><creator>Yamauchi, Toshiaki</creator><creator>Sano, Tomoya</creator><creator>Takahashi, Haruyuki</creator><creator>Ranneh, Abdul-Hackam</creator><creator>Arai, Yuta</creator><general>JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY</general><general>The Japanese Society of Toxicologic Pathology</general><general>Japan Science and Technology Agency</general><general>Japanese Society of Toxicologic Pathology</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20220101</creationdate><title>In vivo screening of subcutaneous tolerability for the development of novel excipients</title><author>Takai, Yuichi ; Powlin, Stephanie ; Awasaki, Yasuyuki ; Yamauchi, Toshiaki ; Sano, Tomoya ; Takahashi, Haruyuki ; Ranneh, Abdul-Hackam ; Arai, Yuta</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Degeneration</topic><topic>Dosage</topic><topic>Evaluation</topic><topic>Excipients</topic><topic>Formulations</topic><topic>in vivo screening</topic><topic>Injection</topic><topic>Irritation</topic><topic>Lipids</topic><topic>Necrosis</topic><topic>novel excipient</topic><topic>Optimization</topic><topic>Pharmaceuticals</topic><topic>Physicochemical properties</topic><topic>Polymers</topic><topic>rat</topic><topic>Risk reduction</topic><topic>Safety</topic><topic>Screening</topic><topic>Technnical Report</topic><topic>ubcutaneous</topic><toplevel>online_resources</toplevel><creatorcontrib>Takai, Yuichi</creatorcontrib><creatorcontrib>Powlin, Stephanie</creatorcontrib><creatorcontrib>Awasaki, Yasuyuki</creatorcontrib><creatorcontrib>Yamauchi, Toshiaki</creatorcontrib><creatorcontrib>Sano, Tomoya</creatorcontrib><creatorcontrib>Takahashi, Haruyuki</creatorcontrib><creatorcontrib>Ranneh, Abdul-Hackam</creatorcontrib><creatorcontrib>Arai, Yuta</creatorcontrib><creatorcontrib>Drug Safety Research and Evaluation</creatorcontrib><creatorcontrib>Takeda Pharmaceutical Company Limited</creatorcontrib><creatorcontrib>Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Takeda Pharmaceutical International Co</creatorcontrib><collection>CrossRef</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of Toxicologic Pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takai, Yuichi</au><au>Powlin, Stephanie</au><au>Awasaki, Yasuyuki</au><au>Yamauchi, Toshiaki</au><au>Sano, Tomoya</au><au>Takahashi, Haruyuki</au><au>Ranneh, Abdul-Hackam</au><au>Arai, Yuta</au><aucorp>Drug Safety Research and Evaluation</aucorp><aucorp>Takeda Pharmaceutical Company Limited</aucorp><aucorp>Pharmaceutical Sciences</aucorp><aucorp>Takeda Pharmaceutical International Co</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>In vivo screening of subcutaneous tolerability for the development of novel excipients</atitle><jtitle>Journal of Toxicologic Pathology</jtitle><addtitle>J Toxicol Pathol</addtitle><date>2022-01-01</date><risdate>2022</risdate><volume>35</volume><issue>4</issue><spage>355</spage><epage>360</epage><pages>355-360</pages><artnum>2022-0035</artnum><issn>0914-9198</issn><eissn>1881-915X</eissn><eissn>1347-7404</eissn><abstract>To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase.</abstract><cop>Tokyo</cop><pub>JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY</pub><doi>10.1293/tox.2022-0035</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 0914-9198 |
ispartof | Journal of Toxicologic Pathology, 2022, Vol.35(4), pp.355-360 |
issn | 0914-9198 1881-915X 1347-7404 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9647210 |
source | NCBI_PubMed Central(免费) |
subjects | Degeneration Dosage Evaluation Excipients Formulations in vivo screening Injection Irritation Lipids Necrosis novel excipient Optimization Pharmaceuticals Physicochemical properties Polymers rat Risk reduction Safety Screening Technnical Report ubcutaneous |
title | In vivo screening of subcutaneous tolerability for the development of novel excipients |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T17%3A19%3A42IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=In%20vivo%20screening%20of%20subcutaneous%20tolerability%20for%20the%20development%20of%20novel%20excipients&rft.jtitle=Journal%20of%20Toxicologic%20Pathology&rft.au=Takai,%20Yuichi&rft.aucorp=Drug%20Safety%20Research%20and%20Evaluation&rft.date=2022-01-01&rft.volume=35&rft.issue=4&rft.spage=355&rft.epage=360&rft.pages=355-360&rft.artnum=2022-0035&rft.issn=0914-9198&rft.eissn=1881-915X&rft_id=info:doi/10.1293/tox.2022-0035&rft_dat=%3Cproquest_pubme%3E2738497268%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c690t-234d248addea8da2c6bee1576f86dc23f6292a5ef628c198c87e3bcbe39f3da73%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2731215203&rft_id=info:pmid/&rfr_iscdi=true |