JP2004285079A - 徐放性タンパク質製剤 - Google Patents
徐放性タンパク質製剤 Download PDFInfo
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- JP2004285079A JP2004285079A JP2004206098A JP2004206098A JP2004285079A JP 2004285079 A JP2004285079 A JP 2004285079A JP 2004206098 A JP2004206098 A JP 2004206098A JP 2004206098 A JP2004206098 A JP 2004206098A JP 2004285079 A JP2004285079 A JP 2004285079A
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- Prior art keywords
- triacetin
- somatotropin
- composition
- bovine somatotropin
- concentration
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Classifications
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K9/0012—Galenical forms characterised by the site of application
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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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Dermatology (AREA)
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- Gynecology & Obstetrics (AREA)
- Pregnancy & Childbirth (AREA)
- Reproductive Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
【解決手段】 実質的に、トリアセチン中に懸濁させた治療上有効量の生物学的活性タンパク質からなる組成物の提供。
【選択図】なし
Description
米国特許第3,966,962号、第4,301,175号、第4,680,312号には、トリアセチン、エタノールを含むトリアセチン、コロイド状の二酸化ケイ素を含むトリアセチン中の安定なおよび/または水混和性処方としてのプロスタグランジン様化合物の溶液が開示されている。
ザ・メルク・インデックス(The Merck Index)の第11版では、水14に対しトリアセチン1の程度で水に可溶であることを報告している。
ザ・メルク・インデックス(The Merck Index)の第11版、第1204頁では、水溶性の潤滑油、食品の包装において、頭髪用品および化粧品の調製において、および医薬上での軟膏および坐薬の主成分としての使用を含むPEG類の種々の使用がリストされている。
(PEG)中組成物に関する。さらに詳しくは、本発明はホルモン、特に具体的には成長ホルモンまたはソマトトロピンおよび成長ホルモン放出ホルモンの持続性放出を提供する。
本発明の本態様の特別な具体例は、約5〜約50%(W/V)の濃度でトリアセチン中に懸濁したウシ・ソマトトロピンを提供する。
本発明の本態様の別の具体例は、約5〜約50%(W/V)の濃度でPEG400に懸濁したウシ・ソマトトロピンを提供する。
より具体的には、本発明の本態様は雌牛での牛乳の生産を増大させるための、トリアセチンまたはポリエチレングリコール400中に懸濁したソマトトロピンの使用に関する。
最も具体的には、本発明の本態様は牛乳の生産を増大させるため雌牛に注射するための約10〜約30%の濃度でトリアセチンまたはPEGに懸濁させたソマトトロピンの使用に関する。
この明細書および請求の範囲を通じて使用される一定の単語および熟語は以下の意味を持つ:
「生物学的活性」とは、関心のある種での生物学的活性を持つタンパク質を意味する。
「重量/体積」とは、投与される懸濁液の体積の単位当たりの、グラムで表わされるタンパク質の重量を意味する。
25.01gのトリアセチンを6.85gの生物学的に活性な組換えウシ・ソマトトロピン(ソマブボーブ(Somavubove)、ジ・アップジョン・カンパニー
(The Upjohn Company))に添加し、終濃度200mg組換えウシ・ソマトトロピン/ml懸濁液になるようスパチュラで混合する。この処方はSR−SbV/TACと名付けられ、使用するまで栓のついた20mlのバイアル中で保存される。
実施例1で調製された懸濁液の一部を、妊娠しておらず、乳を分泌していない若雌ウシへの投与のため取り出す。15匹の、妊娠しておらず、乳を分泌していないホルスタインの若雌ウシを、南西ミシガンの乾燥した敷地に飼う。アルファルファ/芝の干し草および水を自由に摂取させる;若雌ウシにはまた一頭当たり一日15kgのとうもろこしの貯蔵生牧草を投与する。若雌ウシをランダムに以下のグループに割り当てる: (1)対照 (注入なし); (2)150mgのSR−SbV/TAC (トリアセチン中の150mgの組換えウシ・ソマトトロピン); (3)および300mgのSR−SbV/TAC (トリアセチン中の300mgの組換えウシ・ソマトトロピン)。
(Endocrinol.),第84巻,第1166頁 (1969年)の方法に従うラジオイムノアッセイによる分析まで−20℃で保存する。
し、用量にかかわらず血清中のウシ・ソマトトロピンの最大量は注射後12ないし30時間後に現れ、少なくとも84時間の間上昇したままであることは明らかである。
最後的に安定性の研究により、本発明のトリアセチン懸濁液は経済的に実行可能な、商業的生産物として必要とされるような生物学的活性のあるタンパク質の、十分な安定性をもたらすことが示される。
21.8gのPEG400(シグマ・ケミカル(Sigma Chemical))を、6.00グラムの生物学的活性組換えウシ・ソマトトロピン(rbSt)(ソマブボーブ,ジ・アップジョン・カンパニー(Somavubove, The Upjohn Company))に添加し、終濃度200mg組換えウシ・ソマトトロピン/ml懸濁液となるように、スパチュラで混合する。この処方はSR−SbV/PEGと名付けられ、使用するまで20mlの栓付きバイアルに保存される。
実施例3で調製された懸濁液の一部分を、妊娠していない、乳を分泌していない若雌ウシへの投与のために取り出す。15匹の、妊娠しておらず、乳を分泌していないホルスタインの若雌ウシを、南西ミシガンの乾燥した敷地に飼う。アルファルファ/芝の干し草および水を自由に摂取させる;若雌ウシにはまた一頭当たり一日15kgのとうもろこしの貯蔵生牧草を与える。若雌ウシをランダムに以下のグループに割り当てる: (1)対照 (注入なし); (2)150mgのSR−SbV/PEG(PEG400中の150mgの組換えウシ・ソマトトロピン);および (3)300mgのSR−SbV/PEG (PEG400中の300mgの組換えウシ・ソマトトロピン)。
し、用量にかかわらず、血清中のウシ・ソマトトロピンの最大量は注射後12ないし30時間後に現れ、少なくとも72時間(150mg)、および84時間(300mg)の間上昇したままであることは明らかである。
最後的に、本発明のPEG400懸濁液は経済的に実行可能な、商業的生産物として必要とされるような生物学的活性のあるタンパク質の、十分な安定性をもたらす。
10.3ミリグラムの生物学的に活性な、凍結乾燥したウシ・成長ホルモン放出ホルモンのアナログをはかりとり、穏やかな振盪によって、0.5mlのトリアセチン中に懸濁し、約20.6mg/mlの濃度で成長ホルモン放出ホルモンを含む、分散可能な懸濁液を得た。この処方はSR−GRF/TACと名付けられ、ガラスのバイアルに保存される。安定性の研究により、トリアセチン/成長ホルモン放出ホルモン懸濁液は、室温で10日間の保存の後も、容易に再分散できたことが示される。
10.3ミリグラムの生物学的に活性な、凍結乾燥したウシ・成長ホルモン放出ホルモンのアナログをはかりとり、穏やかな振盪によって、0.5mlのPEG400(シグマ・ケミカル(Sigma Chemical))中に懸濁し、約20.6
mg/mlの濃度で成長ホルモン放出ホルモンを含む、分散可能な懸濁液を得た。この処方はSR−GRF/PEGと名付けられ、ガラスのバイアルに保存される。安定性の研究により、PEG400/成長ホルモン放出ホルモン懸濁液は、室温で10日間の保存の後も、容易に再分散できたことが示される。
nsこの上付き文字のついた平均値は、全体の対照の平均値(3.7ngウシ・ソマトトロピン/ml 血清)と有意には異ならない(P>.05)。
対照の平均値は、全ての血液を採取する時間に対するウシ・ソマトトロピンの平均の濃度である(144時間を通して)。
Claims (10)
- 実質的に、トリアセチン中に懸濁させた治療上有効量の生物学的活性タンパク質からなる組成物。
- 生物学的活性タンパク質がウシ・ソマトトロピンである請求項1記載の組成物。
- 生物学的活性タンパク質がブタ・ソマトトロピンである請求項1記載の組成物。
- 生物学的活性タンパク質が成長ホルモン放出ホルモンである請求項1記載の組成物。
- ウシ・ソマトトロピン濃度が約5〜約50%(W/V)である請求項2記載の組成物。
- 濃度が約10〜30%(W/V)である請求項2記載の組成物。
- 請求項1記載の組成物を皮下または筋肉内注射することを特徴とする非ヒト動物において生物学的活性タンパク質の長期の放出を達成する方法。
- トリアセチンおよび治療上有効量のウシ・ソマトトロピンからなる組成物を乳牛に皮下または筋肉内注射することを特徴とする乳牛での牛乳の生産量を増大させる方法。
- ウシ・ソマトトロピンが組成中に約5〜約50%の濃度(W/V)で存在している請求項8記載の方法。
- ウシ・ソマトトロピンが組成中に約10〜30%の濃度(W/V)で存在している請求項9記載の方法。
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1993
- 1993-08-23 ES ES93920157T patent/ES2107051T3/es not_active Expired - Lifetime
- 1993-08-23 DE DE69312947T patent/DE69312947T2/de not_active Expired - Fee Related
- 1993-08-23 JP JP50808394A patent/JP3756512B2/ja not_active Expired - Fee Related
- 1993-08-23 EP EP93920157A patent/EP0661989B1/en not_active Expired - Lifetime
- 1993-08-23 AT AT93920157T patent/ATE156361T1/de not_active IP Right Cessation
- 1993-08-23 AU AU50186/93A patent/AU5018693A/en not_active Abandoned
- 1993-08-23 WO PCT/US1993/007756 patent/WO1994006452A1/en active IP Right Grant
- 1993-08-23 DK DK93920157.0T patent/DK0661989T3/da active
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-
1995
- 1995-03-20 US US08/407,327 patent/US6011011A/en not_active Expired - Fee Related
-
1997
- 1997-09-04 GR GR970402270T patent/GR3024632T3/el unknown
-
2004
- 2004-07-13 JP JP2004206098A patent/JP2004285079A/ja not_active Ceased
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11291636B2 (en) | 2011-11-18 | 2022-04-05 | Regeneron Pharmaceuticals, Inc. | Polymer protein microparticles |
US11951216B2 (en) | 2011-11-18 | 2024-04-09 | Regeneron Pharmaceuticals, Inc. | Polymer protein microparticles |
JP2018538243A (ja) * | 2015-10-16 | 2018-12-27 | リジェネロン・ファーマシューティカルズ・インコーポレイテッド | 安定なタンパク質組成物 |
Also Published As
Publication number | Publication date |
---|---|
TW224055B (ja) | 1994-05-21 |
JP3756512B2 (ja) | 2006-03-15 |
DE69312947D1 (de) | 1997-09-11 |
ATE156361T1 (de) | 1997-08-15 |
DK0661989T3 (da) | 1998-03-02 |
WO1994006452A1 (en) | 1994-03-31 |
EP0661989B1 (en) | 1997-08-06 |
DE69312947T2 (de) | 1998-01-08 |
AU5018693A (en) | 1994-04-12 |
GR3024632T3 (en) | 1997-12-31 |
MX9305729A (es) | 1994-03-31 |
EP0661989A1 (en) | 1995-07-12 |
ES2107051T3 (es) | 1997-11-16 |
JPH08501305A (ja) | 1996-02-13 |
US6011011A (en) | 2000-01-04 |
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