JP2012051891A - 成長ホルモン製剤 - Google Patents
成長ホルモン製剤 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
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Abstract
【解決手段】等張リン酸緩衝液中の成長ホルモンから成る液体成長ホルモン製剤であり、該液体成長ホルモン製剤は、他の添加物を加えずに単独で成長ホルモンを生理的pH近くのリン酸緩衝液中で製剤することにより、2〜8℃の範囲内の温度で6ヵ月以上にわたって保存安定であり、約6.2又はそれ以上のpHを確保することにより、冷蔵温度又はそれ以上の温度での保存期間中、成長ホルモンの結晶化が回避又は低減される。
【選択図】図1
Description
図1は、pH5.6のリン酸緩衝液、塩化ナトリウム及びベンジルアルコールを付加的に含むhGH製剤に関する2〜8℃での比較安定性データのグラフである。これらの製剤のPluronic界面活性剤を含むものと含まないものを比較している。週単位の時間に対するhGHの対数%純度をプロットしている。
培養条件下でhGH蛋白を発現するようにhGH遺伝子で形質転換したCHO細胞の細胞培養において組換えhGHを作製する。どのようにして細胞を作製し、増殖させるかについての詳細は、参照してここに組み込まれるEP−A−0 217 822号(SCIOS NOVA)に記述されている。工業的又は商業的規模での培養物の増殖のための培養条件の改変は、十分に当業者の能力範囲内である。
種々の成分を一緒に混合することによってバルク製剤を調製する。成分を混合する順序は重要ではない。また、混合直前の種々の成分の正確な状態又は形態も重要ではない。製剤を調製する好ましい方法では、混合の前に、成分を混合のために最も都合のよい状態にし、また混合の順序及び様式も最も好都合であるように選択する。
1.必要な賦形剤をすべて注射用蒸留水に溶解し、モル塩酸又は水酸化ナトリウム溶液を用いて必要なpHに調整して、2倍の力価の賦形剤溶液を調製する。
製品のサンプルを2〜8℃の条件下で保存し、様々の時点で分析した。2つのHPLC法を使用して製品の安定性を調べ、どちらの方法も、参照してここに組み込まれる、「注射用ソマトトロピン」に関するヨーロッパ薬局方モノグラフに従った。最初の方法は、関連蛋白質、すなわち脱アミド化及び酸化によって形成される分解産物の測定のための逆相HPLC法である。第二の方法は、ダイマー及びより高い分子量の関連物質を測定するためのサイズ排除HPLC法である。
それぞれのリン酸緩衝液成分の量を調節することにより、製剤VIの一連のpH変異型(0.1単位ずつの増量)を作製した。ペン型注射器で使用するため、製剤を1.5mlずつ分取したものをそれぞれのカプセルに充填した。カプセルを3ヵ月間まで15℃で保存した。保存期間中を通じて、カプセル中に結晶が存在するか否かを肉眼で調べた。
Claims (34)
- 等張性を与える化合物が単糖類、二糖類及び糖アルコールの1つ又はそれ以上から選択される、等張性緩衝液中の成長ホルモンを含む液体成長ホルモン製剤。
- 緩衝液がリン酸緩衝液である、請求項1に記載の液体製剤。
- マンニトール及び/又はスクロース、任意にラクトースによって等張性が与えられる、請求項1又は請求項2に記載の液体製剤。
- 5.6〜6.5の範囲内のpHを持つ、請求項1〜3のいずれかに記載の液体製剤。
- 6.2又は約6.2より大きいpHを持つ、請求項1〜3のいずれかに記載の液体製剤。
- 6.15〜7.4の範囲内のpH、より好ましくは6.2〜6.5の範囲内のpHを持つ、請求項1〜4のいずれかに記載の液体製剤。
- 防腐剤をさらに含む、上記請求項のいずれかに記載の液体製剤。
- 防腐剤がフェノール、ベンジルアルコール、メタクレゾール、メチルパラベン、プロピルパラベン、塩化ベンザルコニウム及び塩化ベンゼトニウムの1つ又はそれ以上から選択される、請求項7に記載の液体製剤。
- 非イオン性界面活性剤をさらに含む、上記請求項のいずれかに記載の液体製剤。
- 非イオン性界面活性剤が0.05%〜5%(w/v)、好ましくは0.1〜1.0%(w/v)の範囲内の濃度で存在する、請求項9に記載の液体製剤。
- 基本的にリン酸緩衝液中の成長ホルモンから成る液体成長ホルモン製剤。
- 基本的にリン酸緩衝液中の成長ホルモンと防腐剤から成る液体成長ホルモン製剤。
- 基本的に等張リン酸緩衝液中の成長ホルモンと防腐剤から成る液体成長ホルモン製剤。
- 基本的に等張リン酸緩衝液中の成長ホルモンから成る液体成長ホルモン製剤。
- リン酸緩衝液中の成長ホルモンを含む液体成長ホルモン製剤。
- 0.05%未満、好ましくは0.04%未満、より好ましくは0.01%未満、さらに一層好ましくは0.001%(w/v)未満の濃度の非イオン性界面活性剤をさらに含む、請求項15に記載の液体製剤。
- リン酸緩衝液が等張性であり、任意に5.6〜6.5の範囲内のpHを持ち、好ましくは防腐剤をさらに含む、請求項15または請求項16に記載の液体製剤。
- 防腐剤がフェノール、ベンジルアルコール、メタクレゾール、メチルパラベン、プロピルパラベン、塩化ベンザルコニウム及び塩化ベンゼトニウムの1つ又はそれ以上から選択される、請求項17に記載の液体製剤。
- リン酸緩衝液の等張性が、中性の塩、例えばNaClによって、あるいは単糖類、例えばラクトース、二糖類、例えばスクロース、又は糖アルコール、例えばマンニトールから選択される化合物によって提供される、請求項13、14又は17のいずれかに記載の液体製剤。
- 成長ホルモンがヒトである、上記請求項のいずれかに記載の液体製剤。
- 成長ホルモンが0.01%未満の凝集、好ましくは0.1%未満、より好ましくは1%未満、さらに一層好ましくは10%未満の凝集を示す、上記請求項のいずれかに記載の液体製剤。
- 次の組成の液体成長ホルモン製剤:
hGH 3.33mg/ml(10IU/ml)
NaH2PO4.2H2O 0.85mg/ml
Na2HPO4.7H2O 0.31mg/ml
マンニトール 35mg/ml (3.5%w/v)
Pluronic F−68 2mg/ml (0.2%w/v)
ベンジルアルコール 9mg/ml (0.9%v/v)
注射用蒸留水 適量
pH6.2 - 保存時に検出可能な結晶化が生じない、上記請求項のいずれかに記載の液体製剤。
- 保存が少なくとも1ヵ月間、好ましくは6週間、より好ましくは約1ヵ月〜4ヵ月の範囲内の期間、最も好ましくは3ヵ月間である、請求項23に記載の液体製剤。
- 保存温度が約2℃又はそれ以上、好ましくは約4℃又はそれ以上、より好ましくは約2℃から40℃未満の範囲内の温度、さらに一層好ましくは約2℃〜25℃の範囲内の温度、最も好ましくは15℃である、請求項23又は請求項24に記載の液体製剤。
- 結晶化が成長ホルモンの結晶化である、請求項23〜25のいずれかに記載の液体製剤。
- 結晶化が肉眼によって、好ましくは5×の倍率の光学顕微鏡下で、より好ましくは10×の倍率の光学顕微鏡下で検出される、請求項23〜26のいずれかに記載の液体製剤。
- 液体を注射によって対象者に投与するための、請求項1〜27のいずれかの液体成長ホルモン製剤の少なくとも1回投与単位を使用のために充填した装置。
- ペン型注射器装置である、請求項28に記載の装置。
- 対象者がヒトである、請求項28又は請求項29に記載の装置。
- 注射装置と請求項1〜27のいずれかの液体成長ホルモン製剤の別個の容器を含むキット。
- 容器が、使用の際に容器内の液体製剤が注射装置の出口で液体と接触するように注射装置と接続するべく適合されている、請求項31に記載のキット。
- 注射装置がペン型注射器であり、容器がカートリッジである、請求項32に記載のキット。
- ペン型注射器装置と共に使用するための、請求項1〜27のいずれかの液体製剤を含むカートリッジ。
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GB9916252.1 | 1999-07-12 | ||
GBGB9916252.1A GB9916252D0 (en) | 1999-07-12 | 1999-07-12 | Growth hormone formulation |
GBGB9918902.9A GB9918902D0 (en) | 1999-08-12 | 1999-08-12 | Growth hormone formulation |
GB9918902.9 | 1999-08-12 |
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CA2491478A1 (en) * | 2002-07-09 | 2004-01-15 | Sandoz Ag | Liquid formulations with high concentration of human growth hormone (hgh) comprising phenol |
US20060252682A1 (en) * | 2003-03-18 | 2006-11-09 | Ares Trading S.A. | Liquid growth hormone formulation and process of preparation thereof |
EP1663296A4 (en) * | 2003-09-25 | 2009-11-25 | Cangene Corp | LIQUID FORMULATION OF HUMAN GROWTH HORMONE CONTAINING POLYETHYLENE GLYCOL |
CA2551510C (en) * | 2003-12-23 | 2013-07-30 | Pharmacia Corporation | Stable growth hormone liquid formulation |
DK1740213T3 (da) * | 2004-04-07 | 2012-04-10 | Ares Trading Sa | Væskeformulering til væksthormoner |
US8293532B2 (en) | 2009-03-26 | 2012-10-23 | Dow AgroSciences, L.L.C. | Method and apparatus for tissue transfer |
CA2780554C (en) * | 2009-11-17 | 2017-08-15 | Ipsen Pharma S.A.S. | Formulation for hgh and rhigf-1 combination |
WO2013014196A1 (en) | 2011-07-25 | 2013-01-31 | Sandoz Ag | Aqueous formulation comprising at least a neutral salt and a biopharmaceutical protein |
JP2013231030A (ja) * | 2012-04-30 | 2013-11-14 | Sun Pharmaceutical Industries Ltd | リュープロリド注射剤 |
JP6001401B2 (ja) * | 2012-09-28 | 2016-10-05 | ユニ・チャーム株式会社 | ウェットティッシュ用薬液及びウェットティッシュ |
JP6179690B1 (ja) | 2015-12-10 | 2017-08-16 | 三菱瓦斯化学株式会社 | 光硬化性組成物及び光学材料 |
JP6172880B1 (ja) * | 2017-02-01 | 2017-08-02 | 協和発酵キリン株式会社 | ダルベポエチンを含む液体医薬組成物 |
KR20210024082A (ko) | 2018-06-25 | 2021-03-04 | 제이씨알 파마 가부시키가이샤 | 단백질 함유 수성 액제 |
CN112494638B (zh) * | 2020-12-22 | 2023-12-19 | 深圳科兴药业有限公司 | 一种人生长激素注射剂组合物及其制备方法 |
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