JP5450508B2 - タンパク質溶液製剤およびその安定化方法 - Google Patents
タンパク質溶液製剤およびその安定化方法 Download PDFInfo
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- JP5450508B2 JP5450508B2 JP2011108579A JP2011108579A JP5450508B2 JP 5450508 B2 JP5450508 B2 JP 5450508B2 JP 2011108579 A JP2011108579 A JP 2011108579A JP 2011108579 A JP2011108579 A JP 2011108579A JP 5450508 B2 JP5450508 B2 JP 5450508B2
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- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
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- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
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- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
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- 229940042585 tocopherol acetate Drugs 0.000 description 1
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Classifications
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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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- 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
- A61K47/02—Inorganic compounds
-
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
- Physical Or Chemical Processes And Apparatus (AREA)
- Distillation Of Fermentation Liquor, Processing Of Alcohols, Vinegar And Beer (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Non-Alcoholic Beverages (AREA)
Description
従って、常温で長期保存できるタンパク質溶液製剤の開発が望まれているが、上記の要件を全て満足するものは開発されておらず、樹脂製容器に予め充填して市場に供給されている安定なタンパク質製剤はなかった。
本発明者らは、疎水性の逆相をもつ容器を選択することにより容器表面を処理することなく、タンパク質の安定性が確保できることを発見した。すなわち、本発明者らは、特定材料の樹脂容器中にタンパク質溶液製剤を充填すると長期にわたって凝集、変性、分解が抑えられ、高含量のタンパク質を保持できることを見いだして本発明を完成した。
(1)タンパク質溶液製剤を収納する容器の少なくとも該製剤と直接接触する部分の容器材質が疎水性の樹脂であって、前記タンパク質が糖鎖を有する遺伝子組換えタンパク質であって、前記疎水性樹脂が以下のものから選択される常温で長期間保存することができる安定したタンパク質溶液製剤:
1)環状オレフィンとオレフィンの共重合体であるシクロオレフィンコポリマー、
2)シクロオレフィン類開環重合体、
3)シクロオレフィン類開環重合体に水素添加したもの。
(2)容器が樹脂製容器である前記(1)記載のタンパク質溶液製剤。
(3)シクロオレフィン類開環重合体がノルボルネンもしくはテトラシクロドデセンの開環重合体である前記(1)又は(2)記載のタンパク質溶液製剤。
(4)シクロオレフィン類開環重合体に水素添加したものがノルボルネンもしくはテトラシクロドデセンの開環重合体に水素添加したものである前記(1)又は(2)記載のタンパク質溶液製剤。
(5)シクロオレフィンコポリマーがノルボルネンもしくはテトラシクロドデセンまたはその誘導体と、エチレンまたはプロピレンとの共重合体である前記(1)又は(2)記載のタンパク質溶液製剤。
(6)シクロオレフィンコポリマーがノルボルネンもしくはテトラシクロドデセンとエチレンとの共重合体である前記(5)記載のタンパク質溶液製剤。
(7)樹脂が熱可塑性ノルボルネン系樹脂または熱可塑性テトラシクロドデセン系樹脂である前記(1)又は(2)記載のタンパク質溶液製剤。
(8)容器形状が、バイアル、アンプル、注射器および瓶からなる群より選択される前記(1)〜(7)のいずれかに記載のタンパク質溶液製剤。
(9)プレフィルドシリンジ溶液製剤である前記(8)記載のタンパク質溶液製剤。
(10)タンパク質がエリスロポエチンである前記(1)〜(9)のいずれかに記載のタンパク質溶液製剤。
(11)タンパク質が顆粒球コロニー刺激因子である前記(1)〜(9)のいずれかに記載のタンパク質溶液製剤。
(12)常温で長期間保存することができる前記(1)〜(11)のいずれかに記載のタンパク質溶液製剤。
(13)タンパク質溶液製剤を、少なくとも該製剤と直接接触する部分の容器材質が疎水性の樹脂である容器に充填して保存することからなるタンパク質溶液製剤を常温で長期間安定化させる方法であって、前記タンパク質が糖鎖を有する遺伝子組換えタンパク質であって、前記疎水性樹脂が以下のものから選択される前記方法:
1)環状オレフィンとオレフィンの共重合体であるシクロオレフィンコポリマー、
2)シクロオレフィン類開環重合体、
3)シクロオレフィン類開環重合体に水素添加したもの。
本発明の安定なタンパク質溶液製剤中に含まれるタンパク質の量は、使用するタンパク質、治療すべき疾患の種類、疾患の重症度、患者の年齢などに応じて決定できる。
実施例1:EPO溶液製剤の10℃、25℃保存における長期安定性試験
EPO溶液製剤の調製
調剤溶液1ml中に以下の成分:
EPO 1500国際単位
ポリオキシエチレンソルビタンモノオレエート
(ポリソルベート80) 0.05mg
塩化ナトリウム 8.5mg
L−ヒスチジン 1.35mg
を含み、10mMリン酸緩衝溶液にてpH6.0に調整した。
試験方法
前記のようにして調製したエリスロポエチン溶液製剤0.5mLを、表面にシリコンを塗布したガラス製容器、およびCOP製容器(ノルボルネンの開環重合体の水素添加物であるCOPから製造:大協精工製、Daikyo Resin CZ(登録商標))にそれぞれ充填してEPO溶液製剤を調製し、10℃で3ヶ月および9ヶ月、ならびに25℃で3ヶ月、6ヶ月、12ヶ月および24ヶ月の安定性試験を行った。
得られた結果を以下の表1(10℃保存)、および表2(25℃保存)に示す。数字はRP−HPLC分析法で測定したEPOの含量を示し、カッコ内の数字は充填時(Initial)の残存率を100%としたときの残存率を示す。
実施例2:EPO溶液製剤の40℃加速試験
実施例1と同様にしてガラス製およびCOP製容器に充填して調製したEPO溶液製剤を、40℃の加速試験で2ヶ月、4ヶ月および6ヶ月保存した。
実施例3:EPO溶液製剤の50℃加速試験
実施例1と同様にしてガラス製およびCOP製容器に充填して調製したEPO溶液製剤を、50℃の加速試験で1ヶ月、2ヶ月および3ヶ月保存した。
実施例4:EPO溶液製剤の60℃加速試験
実施例1と同様にしてガラス製およびCOP製容器に充填して調製したEPO溶液製剤を、60℃の加速試験で1週間、2週間および3週間保存した。
実施例5:G−CSF溶液製剤の40℃加速試験
G−CSF溶液製剤の調製
調剤溶液1ml中に以下の成分:
G−CSF 125μg
ポリオキシエチレンソルビタンモノラウレート
(ポリソルベート20) 0.1mg
塩化ナトリウム 7.5mg
を含み、1mol/L塩酸にてpH6.5に調整した。
試験方法
前記のようにして調製したG−CSF溶液製剤0.5mLを、表面にシリコンオイルを塗布しないガラス製容器、シリコンオイルを塗布したガラス製容器、およびCOP製容器(ノルボルネンの開環重合体の水素添加物であるCOPから製造:大協精工製、Daikyo Resin CZ(登録商標))にそれぞれ充填してG−CSF溶液製剤を調製し、40℃の加速試験で2週間保存した。
得られた結果を以下の表6に示す。数字はRP−HPLC分析法で測定したG−CSFの含量を示し、カッコ内の数字は充填時(Initial)の残存率を100%としたときの残存率を示す。
実施例6:不純物の溶出試験ならびに容器への吸着性試験
調剤溶液1ml中にEPOを1500国際単位又は48000国際単位含むエリスロポエチン溶液製剤を調製した。1500国際単位含む製剤は実施例1に記載するようにして調製した。また48000国際単位含む製剤は、以下のように調製した。
EPO 48000国際単位
ポリオキシエチレンソルビタンモノオレエート
(ポリソルベート80) 0.05mg
塩化ナトリウム 7.0mg
L−ヒスチジン 1.35mg
を含み、25mMリン酸緩衝溶液にてpH6.0に調整した。
不純物の溶出試験
各容器中に調製したEPO溶液製剤の残存率をRP−HPLC分析法を用いて定量するときに、EPOのピーク以外の、容器から溶出した不純物のピークが観察されるかを試験した。全てのサンプルについて不純物のピークは観察されず、容器からの不純物の溶出はないことが確認された。
容器への吸着性試験
各容器中のEPOを回収して、EPO調製液に対する回収率(%)を測定した。結果(3回の試験から得られた平均)を表7に示す。
実施例7:種々の樹脂製容器中のEPO溶液製剤の長期安定性試験及び加速度試験
調剤溶液1ml中にEPOを1500国際単位含むエリスロポエチン溶液製剤(実施例1と同様に調製)0.5mlを、ガラス製容器、COP製容器(ノルボルネンの開環重合体の水素添加物であるCOPから製造:大協精工製、Daikyo Resin CZ(登録商標))、COC製容器(テトラシクロドデセンとエチレン等のオレフィンを原料とした共重合体:三井化学製、アペル(登録商標))にそれぞれ充填してEPO溶液製剤を調製した。
Claims (11)
- タンパク質溶液製剤を収納する容器の少なくとも該製剤と直接接触する部分の容器材質が疎水性の樹脂であって、容器形状がバイアルであるか、もしくはプレフィルドシリンジ溶液製剤であって、前記タンパク質が糖鎖を有する遺伝子組換えタンパク質であって、前記疎水性樹脂が以下のものから選択される、常温で長期間保存することができる安定したタンパク質溶液製剤:
1)環状オレフィンとオレフィンの共重合体であるシクロオレフィンコポリマー、
2)シクロオレフィン類開環重合体、
3)シクロオレフィン類開環重合体に水素添加したもの。 - 容器が樹脂製容器である請求項1記載のタンパク質溶液製剤。
- シクロオレフィン類開環重合体がノルボルネンもしくはテトラシクロドデセンの開環重合体である請求項1又は2記載のタンパク質溶液製剤。
- シクロオレフィン類開環重合体に水素添加したものがノルボルネンもしくはテトラシクロドデセンの開環重合体に水素添加したものである請求項1又は2記載のタンパク質溶液製剤。
- シクロオレフィンコポリマーがノルボルネンもしくはテトラシクロドデセンまたはその誘導体と、エチレンまたはプロピレンとの共重合体である請求項1又は2記載のタンパク質溶液製剤。
- シクロオレフィンコポリマーがノルボルネンもしくはテトラシクロドデセンとエチレンとの共重合体である請求項5記載のタンパク質溶液製剤。
- 樹脂が熱可塑性ノルボルネン系樹脂または熱可塑性テトラシクロドデセン系樹脂である請求項1又は2記載のタンパク質溶液製剤。
- 常温で長期間保存することができる請求項1〜7のいずれかに記載のタンパク質溶液製剤。
- タンパク質溶液製剤が非イオン界面活性剤、等張化剤および安定化剤を含み、かつpHが5.0〜8.0である請求項1〜8のいずれかに記載のタンパク質溶液製剤。
- 安定化剤がアミノ酸である請求項9に記載のタンパク質溶液製剤。
- タンパク質溶液製剤を、少なくとも該製剤と直接接触する部分の容器材質が疎水性の樹脂である容器に充填して保存することからなるタンパク質溶液製剤を常温で長期間安定化させる方法であって、前記タンパク質が糖鎖を有する遺伝子組換えタンパク質であって、前記疎水性樹脂が以下のものから選択される前記方法:
1)環状オレフィンとオレフィンの共重合体であるシクロオレフィンコポリマー、
2)シクロオレフィン類開環重合体、
3)シクロオレフィン類開環重合体に水素添加したもの。
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2000
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- 2000-09-08 TW TW089118513A patent/TWI245645B/zh not_active IP Right Cessation
- 2000-09-08 AU AU68759/00A patent/AU6875900A/en not_active Abandoned
- 2000-09-08 WO PCT/JP2000/006144 patent/WO2001017542A1/ja active IP Right Grant
- 2000-09-08 US US09/720,757 patent/US7253142B1/en not_active Expired - Lifetime
- 2000-09-08 DE DE60038386T patent/DE60038386T2/de not_active Expired - Lifetime
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2014051502A (ja) * | 1999-09-08 | 2014-03-20 | Chugai Pharmaceut Co Ltd | タンパク質溶液製剤およびその安定化方法 |
Also Published As
Publication number | Publication date |
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AU6875900A (en) | 2001-04-10 |
JP2016056176A (ja) | 2016-04-21 |
DE60038386D1 (de) | 2008-04-30 |
JP2014051502A (ja) | 2014-03-20 |
WO2001017542A1 (fr) | 2001-03-15 |
TWI245645B (en) | 2005-12-21 |
JP6134370B2 (ja) | 2017-05-24 |
JP6076226B2 (ja) | 2017-02-08 |
EP1232753A4 (en) | 2004-08-11 |
EP1232753B1 (en) | 2008-03-19 |
ATE389414T1 (de) | 2008-04-15 |
US7253142B1 (en) | 2007-08-07 |
JP2011168610A (ja) | 2011-09-01 |
DE60038386T2 (de) | 2009-04-23 |
EP1232753A1 (en) | 2002-08-21 |
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