JP3636480B2 - Freeze-dried preparation - Google Patents
Freeze-dried preparation Download PDFInfo
- Publication number
- JP3636480B2 JP3636480B2 JP13925293A JP13925293A JP3636480B2 JP 3636480 B2 JP3636480 B2 JP 3636480B2 JP 13925293 A JP13925293 A JP 13925293A JP 13925293 A JP13925293 A JP 13925293A JP 3636480 B2 JP3636480 B2 JP 3636480B2
- Authority
- JP
- Japan
- Prior art keywords
- freeze
- growth factor
- gluconate
- dried preparation
- protein
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【０００１】
【産業上の利用分野】
本発明は、グルコン酸塩を含有することを特徴とするペプチドまたはタンパク質の凍結乾燥製剤に関するものである。
【０００２】
【従来の技術】
ペプチドおよびタンパク質は溶液状態では不安定であり、安定なペプチド製剤またはタンパク質製剤を提供するには、凍結乾燥などの操作が必要となる。しかし、凍結乾燥時にペプチドおよびタンパク質は種々の要因によって分解や変性を起こし失活や不溶化することが知られている。
【０００３】
【発明が解決しようとする課題】
凍結乾燥する際に、従来から知られているマンニトール、マルトース、グルコース、ラクトースなどの糖類やグリシンやアルギニンなどの親水性アミノ酸の安定化基剤を用いても、ペプチドまたはタンパク質の一部には満足する結果を得られず、本発明者らは、さらに安定化基剤について鋭意検討を進めてきた。
【０００４】
【課題を解決するための手段】
本発明はペプチドまたはタンパク質の凍結乾燥製剤の調製において、安定化基剤としてグルコン酸塩を加え、長期に安定な凍結乾燥製剤を提供することに特徴を有する。
本発明で用いられるグルコン酸塩としては、グルコン酸カルシウム、グルコン酸マグネシウム、グルコン酸ナトリウム、グルコン酸塩カリウムなどがあげられる。特に好ましくはグルコン酸マグネシウムである。
グルコン酸塩は単独、もしくは２種以上の混合物として用いることができ、また従来より使用されてきた他の安定化基剤と配合使用してもよい。
本発明で用いられるグルコン酸塩の添加量は、ペプチドまたはタンパク質１重量部に対し１０分の１重量部から１０万重量部であり、凍結乾燥するペプチドまたはタンパク質溶液中に加えられるグルコン酸塩の濃度としては０．５〜１０％が好ましい。
本発明の凍結乾燥製剤を調製する際の溶液のｐＨは４．０〜７．５が好ましく、場合によってはｐＨ調整剤、さらに生理的に許容される添加剤、希釈剤、賦形剤などを混合することができる。
本発明の凍結乾燥製剤は、グルコン酸塩を含有するペプチドまたはタンパク質溶液を−１５℃〜−６０℃にて、凍結し、次いで減圧乾燥することにより調製できる。
本発明におけるペプチドまたはタンパク質としては、特に生理活性ペプチドまたは生理活性タンパク質であり、例えばタフトシン、バゾプレッシン、黄体形成ホルモン放出ホルモン、ヒト成長ホルモン、成長ホルモン放出因子、サブスタンス−Ｐ、インスリン、テトラガストリン、塩基性線維芽細胞成長因子、酸性線維芽細胞成長因子、肝細胞増殖因子、上皮細胞増殖因子、骨形成因子、コロニー刺激因子、インスリン様成長因子、神経成長因子、幹細胞増殖因子、腫瘍壊死因子、血管内皮細胞増殖因子、各種インターロイキンなどがあげられる。
【０００５】
【実施例】
実施例１
２．５％のグルコン酸マグネシウムを含む注射用水に、タフトシン、バゾプレッシン、黄体形成ホルモン放出ホルモン、サブスタンスーＰ、インスリン、上皮細胞増殖因子または塩基性線維芽細胞成長因子をそれぞれ５０μｇ／ｍｌとなるように添加し、１バイアルに１ｍｌを充填し、−４０℃にて２時間保持し凍結後、減圧乾燥して、凍結乾燥製剤を調製した。
【０００６】
実施例２
３．０％のグルコン酸カリウムを含む注射用水に、タフトシン、バゾプレッシン、黄体形成ホルモン放出ホルモン、サブスタンスーＰ、インスリン、上皮細胞増殖因子または塩基性線維芽細胞成長因子をそれぞれ５０μｇ／ｍｌとなるように添加し、１バイアルに１ｍｌを充填し、−２０℃にて２時間保持し凍結後、減圧乾燥して、凍結乾燥製剤を調製した。
【０００７】
実施例３
２．０％のグルコン酸ナトリウムを含む注射用水に、タフトシン、バゾプレッシン、黄体形成ホルモン放出ホルモン、サブスタンスーＰ、インスリン、上皮細胞増殖因子または塩基性線維芽細胞成長因子をそれぞれ５０μｇ／ｍｌとなるように添加し、１バイアルに１ｍｌを充填し、−５０℃にて１時間保持し凍結後、減圧乾燥して、凍結乾燥製剤を調製した。
【０００８】
試験例１
実施例１で調製した凍結乾燥製剤を６０℃の苛酷条件下に２週間保存し、生理活性ペプチドまたはタンパク質の安定性を比較した。なお、対照としては実施例１における２．５％のグルコン酸マグネシウムの代わりに、２．５％のグリシンあるいは２．５％のマンニトールを用い、比較対照製剤とした。
結果を表１に示した。
【０００９】
【発明の効果】
これらの試験から、本発明の凍結乾燥製剤は優れた安定性を示した。[0001]
[Industrial application fields]
The present invention relates to a freeze-dried preparation of a peptide or protein characterized by containing gluconate.
[0002]
[Prior art]
Peptides and proteins are unstable in a solution state, and operations such as lyophilization are required to provide stable peptide preparations or protein preparations. However, it is known that peptides and proteins are degraded or denatured by various factors to be inactivated or insolubilized during lyophilization.
[0003]
[Problems to be solved by the invention]
When freeze-drying, some of the peptides or proteins are satisfactory even if the conventionally known saccharides such as mannitol, maltose, glucose and lactose and the stabilizing bases of hydrophilic amino acids such as glycine and arginine are used. As a result, the present inventors have further intensively investigated a stabilizing base.
[0004]
[Means for Solving the Problems]
The present invention is characterized in that, in the preparation of a freeze-dried preparation of a peptide or protein, gluconate is added as a stabilizing base to provide a freeze-dried preparation that is stable for a long time.
Examples of the gluconate used in the present invention include calcium gluconate, magnesium gluconate, sodium gluconate, potassium gluconate and the like. Particularly preferred is magnesium gluconate.
Gluconate may be used alone or as a mixture of two or more, and may be used in combination with other stabilizing bases conventionally used.
The addition amount of the gluconate used in the present invention is 1/10 to 100,000 parts by weight per 1 part by weight of the peptide or protein. The concentration is preferably 0.5 to 10%.
The pH of the solution when preparing the lyophilized preparation of the present invention is preferably 4.0 to 7.5. In some cases, a pH adjuster, further physiologically acceptable additives, diluents, excipients and the like are added. Can be mixed.
The freeze-dried preparation of the present invention can be prepared by freezing a peptide or protein solution containing gluconate at −15 ° C. to −60 ° C. and then drying under reduced pressure.
The peptide or protein in the present invention is particularly a bioactive peptide or bioactive protein, such as tuftsin, vasopressin, luteinizing hormone-releasing hormone, human growth hormone, growth hormone-releasing factor, substance-P, insulin, tetragastrin, base Fibroblast growth factor, acidic fibroblast growth factor, hepatocyte growth factor, epithelial cell growth factor, osteogenic factor, colony stimulating factor, insulin-like growth factor, nerve growth factor, stem cell growth factor, tumor necrosis factor, blood vessel Examples thereof include endothelial cell growth factor and various interleukins.
[0005]
【Example】
Example 1
Water for injection containing 2.5% magnesium gluconate so that tuftsin, vasopressin, luteinizing hormone-releasing hormone, substance P, insulin, epidermal growth factor or basic fibroblast growth factor are 50 μg / ml each. 1 ml was added, 1 ml was filled, kept at −40 ° C. for 2 hours, frozen, and dried under reduced pressure to prepare a freeze-dried preparation.
[0006]
Example 2
Water for injection containing 3.0% potassium gluconate so that tuftsin, vasopressin, luteinizing hormone-releasing hormone, substance P, insulin, epidermal growth factor or basic fibroblast growth factor are each 50 μg / ml 1 ml was added, 1 ml was filled, kept at −20 ° C. for 2 hours, frozen, and dried under reduced pressure to prepare a freeze-dried preparation.
[0007]
Example 3
Injectable water containing 2.0% sodium gluconate so that tuftsin, vasopressin, luteinizing hormone-releasing hormone, substance P, insulin, epidermal growth factor or basic fibroblast growth factor are 50 μg / ml each. 1 ml was added, 1 ml was filled, kept at −50 ° C. for 1 hour, frozen, and then dried under reduced pressure to prepare a freeze-dried preparation.
[0008]
Test example 1
The freeze-dried preparation prepared in Example 1 was stored for 2 weeks under severe conditions at 60 ° C., and the stability of the bioactive peptide or protein was compared. As a control, instead of 2.5% magnesium gluconate in Example 1, 2.5% glycine or 2.5% mannitol was used as a comparative control preparation.
The results are shown in Table 1.
[0009]
【The invention's effect】
From these tests, the freeze-dried preparation of the present invention showed excellent stability.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13925293A JP3636480B2 (en) | 1993-05-19 | 1993-05-19 | Freeze-dried preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP13925293A JP3636480B2 (en) | 1993-05-19 | 1993-05-19 | Freeze-dried preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH06321800A JPH06321800A (en) | 1994-11-22 |
| JP3636480B2 true JP3636480B2 (en) | 2005-04-06 |
Family
ID=15240986
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP13925293A Expired - Fee Related JP3636480B2 (en) | 1993-05-19 | 1993-05-19 | Freeze-dried preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3636480B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10024451A1 (en) * | 2000-05-18 | 2001-11-29 | Asta Medica Ag | Pharmaceutical dosage form for peptides, process for their preparation and use |
| JP5357424B2 (en) | 2005-07-20 | 2013-12-04 | 協和メデックス株式会社 | Method for stabilizing peptides in biological samples |
| JP6165986B2 (en) * | 2013-08-23 | 2017-07-19 | シントン・ビー．ブイ．Ｓｙｎｔｈｏｎ Ｂ．Ｖ． | Pharmaceutical composition comprising bortezomib |
-
1993
- 1993-05-19 JP JP13925293A patent/JP3636480B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06321800A (en) | 1994-11-22 |
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