Liquid Growth Hormone: Preservatives and Buffers
Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients re...
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Veröffentlicht in: | Hormone research 2004-01, Vol.62 (Suppl 3), p.98-103 |
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description | Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin ® SimpleXx ® , has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin ® SimpleXx ® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance. |
doi_str_mv | 10.1159/000080507 |
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For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin ® SimpleXx ® , has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin ® SimpleXx ® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.</description><identifier>ISSN: 1663-2818</identifier><identifier>ISSN: 0301-0163</identifier><identifier>ISBN: 9783805578332</identifier><identifier>ISBN: 3805578334</identifier><identifier>EISSN: 1663-2826</identifier><identifier>EISBN: 9783318011548</identifier><identifier>EISBN: 3318011541</identifier><identifier>DOI: 10.1159/000080507</identifier><identifier>PMID: 15539807</identifier><language>eng</language><publisher>Basel, Switzerland</publisher><subject>Buffers ; Chemistry, Pharmaceutical ; Convenience and Compliance ; Growth Hormone - administration & dosage ; Growth Hormone - chemistry ; Growth Hormone - therapeutic use ; Human Growth Hormone - deficiency ; Humans ; Injections - adverse effects ; Pain - chemically induced ; Pain - etiology ; Pain - prevention & control ; Patient Compliance ; Preservatives, Pharmaceutical - adverse effects ; Steroid Metabolism, Inborn Errors - drug therapy</subject><ispartof>Hormone research, 2004-01, Vol.62 (Suppl 3), p.98-103</ispartof><rights>2004 S. Karger AG, Basel</rights><rights>2004 S. Karger AG, Basel.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c330t-f692dc0fcd868d4c531b65e4fcc89a0486901f15edf99beb6bc8333a34a5a2343</citedby><cites>FETCH-LOGICAL-c330t-f692dc0fcd868d4c531b65e4fcc89a0486901f15edf99beb6bc8333a34a5a2343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2422,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15539807$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kappelgaard, Anne-Marie</creatorcontrib><creatorcontrib>Bojesen, Anders</creatorcontrib><creatorcontrib>Skydsgaard, Karsten</creatorcontrib><creatorcontrib>Sjögren, Ingrid</creatorcontrib><creatorcontrib>Laursen, Torben</creatorcontrib><title>Liquid Growth Hormone: Preservatives and Buffers</title><title>Hormone research</title><addtitle>Horm Res Paediatr</addtitle><description>Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin ® SimpleXx ® , has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin ® SimpleXx ® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.</description><subject>Buffers</subject><subject>Chemistry, Pharmaceutical</subject><subject>Convenience and Compliance</subject><subject>Growth Hormone - administration & dosage</subject><subject>Growth Hormone - chemistry</subject><subject>Growth Hormone - therapeutic use</subject><subject>Human Growth Hormone - deficiency</subject><subject>Humans</subject><subject>Injections - adverse effects</subject><subject>Pain - chemically induced</subject><subject>Pain - etiology</subject><subject>Pain - prevention & control</subject><subject>Patient Compliance</subject><subject>Preservatives, Pharmaceutical - adverse effects</subject><subject>Steroid Metabolism, Inborn Errors - drug therapy</subject><issn>1663-2818</issn><issn>0301-0163</issn><issn>1663-2826</issn><isbn>9783805578332</isbn><isbn>3805578334</isbn><isbn>9783318011548</isbn><isbn>3318011541</isbn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0D1PwzAQBmDzJVqVDsxIKGJjCNi52LHZoCoNUiUQgjly_AEB2qR2UsS_JyUlLNzi4X18ujuEjgm-IISKS9wWxxQnO2gsEg5AOG6DmO-iIWEMwohHbK_LWkc3JNrvM8IHaOz926YN8ESQ5BANCKUgOE6GCM-LVVPoYObKz_o1SEu3KJfmKnhwxhu3lnWxNj6QSx3cNNYa54_QgZUf3oy37wg9306fJmk4v5_dTa7noQLAdWiZiLTCVmnOuI4VBZIzamKrFBcSx5wJTCyhRlshcpOzXLVzg4RYUhlBDCN03vVVrvTeGZtVrlhI95URnG0Ok_WHae1pZ6smXxj9J7drtuCkA-_SvRjXg9_vZ_-m6eP0B2SVtvANJ_Brng</recordid><startdate>20040101</startdate><enddate>20040101</enddate><creator>Kappelgaard, Anne-Marie</creator><creator>Bojesen, Anders</creator><creator>Skydsgaard, Karsten</creator><creator>Sjögren, Ingrid</creator><creator>Laursen, Torben</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20040101</creationdate><title>Liquid Growth Hormone: Preservatives and Buffers</title><author>Kappelgaard, Anne-Marie ; Bojesen, Anders ; Skydsgaard, Karsten ; Sjögren, Ingrid ; Laursen, Torben</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c330t-f692dc0fcd868d4c531b65e4fcc89a0486901f15edf99beb6bc8333a34a5a2343</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Buffers</topic><topic>Chemistry, Pharmaceutical</topic><topic>Convenience and Compliance</topic><topic>Growth Hormone - administration & dosage</topic><topic>Growth Hormone - chemistry</topic><topic>Growth Hormone - therapeutic use</topic><topic>Human Growth Hormone - deficiency</topic><topic>Humans</topic><topic>Injections - adverse effects</topic><topic>Pain - chemically induced</topic><topic>Pain - etiology</topic><topic>Pain - prevention & control</topic><topic>Patient Compliance</topic><topic>Preservatives, Pharmaceutical - adverse effects</topic><topic>Steroid Metabolism, Inborn Errors - drug therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kappelgaard, Anne-Marie</creatorcontrib><creatorcontrib>Bojesen, Anders</creatorcontrib><creatorcontrib>Skydsgaard, Karsten</creatorcontrib><creatorcontrib>Sjögren, Ingrid</creatorcontrib><creatorcontrib>Laursen, Torben</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Hormone research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kappelgaard, Anne-Marie</au><au>Bojesen, Anders</au><au>Skydsgaard, Karsten</au><au>Sjögren, Ingrid</au><au>Laursen, Torben</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Liquid Growth Hormone: Preservatives and Buffers</atitle><jtitle>Hormone research</jtitle><addtitle>Horm Res Paediatr</addtitle><date>2004-01-01</date><risdate>2004</risdate><volume>62</volume><issue>Suppl 3</issue><spage>98</spage><epage>103</epage><pages>98-103</pages><issn>1663-2818</issn><issn>0301-0163</issn><eissn>1663-2826</eissn><isbn>9783805578332</isbn><isbn>3805578334</isbn><eisbn>9783318011548</eisbn><eisbn>3318011541</eisbn><abstract>Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropin ® SimpleXx ® , has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3–9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3–4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin ® SimpleXx ® showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.</abstract><cop>Basel, Switzerland</cop><pmid>15539807</pmid><doi>10.1159/000080507</doi><tpages>6</tpages></addata></record> |
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subjects | Buffers Chemistry, Pharmaceutical Convenience and Compliance Growth Hormone - administration & dosage Growth Hormone - chemistry Growth Hormone - therapeutic use Human Growth Hormone - deficiency Humans Injections - adverse effects Pain - chemically induced Pain - etiology Pain - prevention & control Patient Compliance Preservatives, Pharmaceutical - adverse effects Steroid Metabolism, Inborn Errors - drug therapy |
title | Liquid Growth Hormone: Preservatives and Buffers |
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