JPH0977680A - Liquid formulation containing haptoglobin - Google Patents
Liquid formulation containing haptoglobinInfo
- Publication number
- JPH0977680A JPH0977680A JP7260911A JP26091195A JPH0977680A JP H0977680 A JPH0977680 A JP H0977680A JP 7260911 A JP7260911 A JP 7260911A JP 26091195 A JP26091195 A JP 26091195A JP H0977680 A JPH0977680 A JP H0977680A
- Authority
- JP
- Japan
- Prior art keywords
- liquid preparation
- haptoglobin
- containing liquid
- ionic strength
- sugar
- 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.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
(57)【要約】
【課題】保存時の安定性にさらに優れたＨＰ含有液状製
剤を提供すること。
【解決手段】 ｐＨ６〜８で塩濃度が低イオン強度で
あることを特徴とするＨＰ含有液状製剤、 糖、糖ア
ルコールまたは非イオン系界面活性剤を配合してなるハ
プトグロビン含有液状製剤、 ３７℃で２時間振盪時
に不溶性異物を生じないハプトグロビン含有液状製剤。
【効果】ＨＰの長期保存時の安定性が改善すると共に特
に、重合による高分子および分解による低分子体の生成
を抑えた製剤を調製することができる。(57) Abstract: To provide a HP-containing liquid preparation having further excellent stability during storage. SOLUTION: A HP-containing liquid preparation characterized by having a low ionic strength in salt concentration at pH 6-8, a haptoglobin-containing liquid preparation containing sugar, sugar alcohol or a nonionic surfactant, at 37 ° C. A haptoglobin-containing liquid preparation that does not produce insoluble foreign matter when shaken for 2 hours. [Effect] It is possible to prepare a preparation in which the stability of HP during long-term storage is improved and, in particular, the formation of a polymer by polymerization and a low-molecular substance due to decomposition is suppressed.
Description
【０００１】[0001]
【発明の属する技術分野】本発明はハプトグロビン（以
下、「ＨＰ」とも略す）の液状製剤に関する。TECHNICAL FIELD The present invention relates to a liquid preparation of haptoglobin (hereinafter also abbreviated as “HP”).
【０００２】[0002]
【従来の技術】ＨＰは、分子量８万５千〜４０万の血漿
糖蛋白質であり、血中に遊離するヘモグロビンの代謝に
重要な役割を演ずる。ＨＰはヘモグロビンと特異的に結
合し、ＨＰ−ヘモグロビン複合体を形成する特性を有す
る。血漿中のＨＰは、溶血により生じたヘモグロビンと
複合体を形成し、ヘモグロビンの正常な代謝経路である
肝に運ばれるが、ヘモグロビン量がＨＰとの結合量を上
回ったときは、余剰のヘモグロビンは遊離の状態で血漿
中に存在し、ヘモグロビン血症及び腎を経てヘモグロビ
ン尿症を引き起こす。従って、ＨＰは、熱傷、火傷、輸
血、対外循環下開心術などの溶血反応に伴うヘモグロビ
ン血症、ヘモグロビン尿症の治療に有効とされている。2. Description of the Related Art HP is a plasma glycoprotein having a molecular weight of 85,000 to 400,000, and plays an important role in the metabolism of hemoglobin released into the blood. HP has the property of specifically binding to hemoglobin and forming an HP-hemoglobin complex. HP in plasma forms a complex with hemoglobin produced by hemolysis and is transported to the liver, which is a normal metabolic pathway of hemoglobin.When the amount of hemoglobin exceeds the amount bound to HP, the excess hemoglobin becomes It is present in plasma in its free state and causes hemoglobinemia and hemoglobinuria via the kidneys. Therefore, HP is said to be effective in treating hemoglobinemia and hemoglobinuria associated with hemolytic reactions such as burns, burns, blood transfusion, and open-heart surgery under external circulation.
【０００３】現在、ＨＰは液状製剤として発売中であ
り、商品名ハプトグロビン注−ミドリ（（株）ミドリ十
字社製）等がある。[0003] Currently, HP is on sale as a liquid preparation, such as Haptoglobin Injection-Midori (manufactured by Midori Cross).
【０００４】[0004]
【発明が解決しようとする課題】本発明者らは上記の事
情を考慮して研究を重ねた結果、保存時の安定性にさら
に優れたＨＰの液状製剤を調製し、本発明を完成した。DISCLOSURE OF THE INVENTION As a result of repeated studies in view of the above circumstances, the inventors of the present invention have completed the present invention by preparing a liquid HP formulation having further excellent stability during storage.
【０００５】[0005]
【課題を解決するための手段】本発明は ｐＨ６〜８
で塩濃度が低イオン強度であることを特徴とするＨＰ含
有液状製剤、 糖、糖アルコールまたは非イオン系界
面活性剤を配合してなるハプトグロビン含有液状製剤、
および ３７℃で２時間振盪時に不溶性異物を生じな
いハプトグロビン含有液状製剤である。The present invention has a pH of 6-8.
An HP-containing liquid preparation characterized in that the salt concentration is low ionic strength, a haptoglobin-containing liquid preparation containing sugar, sugar alcohol or a nonionic surfactant,
And a liquid preparation containing haptoglobin that does not generate insoluble foreign matter when shaken at 37 ° C. for 2 hours.
【０００６】ＨＰ 本発明に用いられるＨＰは血漿由来、細胞培養由来、遺
伝子工学由来のいずれにも限定されない。また、医薬品
として適用可能な程度にまで精製されていればよい。血
漿由来の場合は、コーンの上清II＋III 、沈澱IV、沈澱
IV−１等の画分から調製できる。ＨＰの精製法として
は、硫安分画、アクリノール分画、陰イオン交換体処理
（特開昭５０−７７５１６）、加熱処理（同５０−７７
５２７）、コロイド珪酸処理（特開昭６３−１７８９
９）、ポリエチレングリコール分画、固定化ヘパリンに
よるアフィニティ処理等が挙げられる。HP The HP used in the present invention is not limited to that derived from plasma, cell culture, or genetic engineering. Further, it may be purified to such an extent that it can be applied as a medicine. If derived from plasma, corn supernatant II + III, precipitation IV, precipitation
It can be prepared from fractions such as IV-1. As a method for purifying HP, ammonium sulfate fractionation, acrinol fractionation, anion exchanger treatment (JP-A-50-77516), and heat treatment (the same 50-77).
527), colloidal silicic acid treatment (JP-A-63-1789)
9), polyethylene glycol fractionation, affinity treatment with immobilized heparin, and the like.
【０００７】液状製剤 本発明の液状製剤におけるＨＰの濃度は１〜１００単位
／ｍｌ程度、好ましくは１０〜５０単位／ｍｌ程度が例
示される。なお、１単位は１ｍｇのヘモグロビンを結合
することを意味する。ｐＨは、６〜８、好ましくは６．
０〜７．５である。Liquid formulation The concentration of HP in the liquid formulation of the present invention is, for example, about 1 to 100 units / ml, preferably about 10 to 50 units / ml. In addition, 1 unit means that 1 mg of hemoglobin is bound. The pH is 6-8, preferably 6.
It is 0 to 7.5.
【０００８】塩濃度が低イオン強度であるとは具体的に
は塩濃度が０．１Ｍ以下、好ましくは０．０１Ｍ以下の
濃度を意味する。すなわち、緩衝能を有しない塩濃度を
意味する。添加剤としては、糖、糖アルコール、非イオ
ン系界面活性剤等が挙げられる。糖としては単糖類、二
糖類等が挙げられる。単糖類としてはブドウ糖、マンノ
ース、ガラクトース等が例示される。二糖類としてはシ
ョ糖、乳糖、麦芽糖等が例示される。糖アルコールとし
てはマンニトール、ソルビトール等が例示される。非イ
オン系界面活性剤としてはポリオキシエチレンソルビタ
ン脂肪酸エステル（Ｔｗｅｅｎ）、ポリオキシエチレン
−ポリオキシプロピレン共重合体等が挙げられる。添加
量としては糖、糖アルコールでは、１〜２０％（ｗ／
ｖ）程度、好ましくは５〜１０％（ｗ／ｖ）程度、非イ
オン系界面活性剤では０．０１〜１％（ｗ／ｖ）程度、
好ましくは０．０５〜０．５％（ｗ／ｖ）程度が例示さ
れる。ｐＨおよび塩濃度が規定されたＨＰ含有溶液に必
要に応じて添加剤を配合し、通常の製剤化技術により、
例えば、加熱処理、除菌濾過、小分け分注等の処理を施
して、液状製剤として臨床に供与できる。本製剤は注射
剤等として患者に投与される。The low ionic strength salt concentration specifically means a salt concentration of 0.1 M or less, preferably 0.01 M or less. That is, it means a salt concentration having no buffering capacity. Examples of the additive include sugar, sugar alcohol, nonionic surfactant and the like. Examples of sugars include monosaccharides and disaccharides. Examples of monosaccharides include glucose, mannose and galactose. Examples of the disaccharide include sucrose, lactose, maltose and the like. Examples of sugar alcohols include mannitol and sorbitol. Examples of the nonionic surfactant include polyoxyethylene sorbitan fatty acid ester (Tween) and polyoxyethylene-polyoxypropylene copolymer. The added amount of sugar and sugar alcohol is 1 to 20% (w /
v), preferably about 5 to 10% (w / v), about 0.01 to 1% (w / v) for nonionic surfactants,
A preferable range is about 0.05 to 0.5% (w / v). If necessary, an additive is added to an HP-containing solution having a specified pH and salt concentration, and a conventional formulation technique is used.
For example, it can be clinically provided as a liquid preparation after being subjected to heat treatment, sterilization filtration, subdivision and the like. This preparation is administered to patients as an injection or the like.
【０００９】[0009]
【発明の効果】本発明によれば、ＨＰの長期保存時の安
定性が改善される。特に、重合による高分子および分解
による低分子体の生成を抑えた製剤を調製することがで
きる。According to the present invention, the stability of HP during long-term storage is improved. In particular, it is possible to prepare a preparation in which formation of a polymer by polymerization and a low-molecular substance due to decomposition is suppressed.
【００１０】[0010]
【実施例】本発明をさらに詳細に説明するために実施例
を挙げるが、本発明はこれらにより何ら限定されるもの
ではない。 実施例１ ｐＨ、イオン強度と液状製剤の安定化効果の関係につい
て検討した。EXAMPLES Examples will be given to explain the present invention in more detail, but the present invention is not limited thereto. Example 1 The relationship between pH, ionic strength and the stabilizing effect of a liquid preparation was examined.
【００１１】特開昭５０−７７５１６により調製した精
製ＨＰを注射用水で透析して、濃度２０単位／ｍｌ、ｐ
Ｈ７、イオン強度０．００１Ｍ以下に調整した溶液を３
７℃で２時間の振盪を行い、不溶性異物の生成を肉眼観
察した。一方、対照では添加剤として、塩化ナトリウム
を配合し、イオン強度０．１５Ｍ（０．９％（ｗ／
ｖ））としたものを用いて同様に実施した。結果を表１
に示す。Purified HP prepared according to JP-A-50-77516 was dialyzed against water for injection to give a concentration of 20 units / ml, p.
H7, ionic strength 0.001M or less solution adjusted to 3
Shaking was performed at 7 ° C. for 2 hours, and generation of insoluble foreign matter was visually observed. On the other hand, in the control, sodium chloride was added as an additive, and the ionic strength was 0.15 M (0.9% (w /
v)) was used and the same operation was carried out. Table 1 shows the results
Shown in
【００１２】[0012]
【表１】 [Table 1]
【００１３】低イオン強度である実施例のＨＰ含有液状
製剤は、イオン強度０．１５Ｍの対照に比べ不溶性異物
の量が顕著に減少した。 実施例２ 添加剤の種類と液状製剤の安定化効果の関係について検
討した。特開昭５０−７７５１６により調製した精製Ｈ
Ｐを注射用水で透析して、濃度２０単位／ｍｌ、ｐＨ
７、イオン強度０．００１Ｍ以下に調整した溶液に各種
添加剤を配合し、３７℃で２時間の振盪を行い、不溶性
異物の生成を肉眼観察した。結果を表２に示す。The HP-containing liquid preparations of Examples having a low ionic strength showed a marked reduction in the amount of insoluble foreign matter as compared with the control having an ionic strength of 0.15M. Example 2 The relationship between the type of additive and the stabilizing effect of the liquid preparation was examined. Purified H prepared by JP-A-50-77516
P is dialyzed against water for injection to give a concentration of 20 units / ml, pH
7. Various additives were added to the solution adjusted to an ionic strength of 0.001 M or less, and shaken at 37 ° C. for 2 hours, and the generation of insoluble foreign matter was visually observed. Table 2 shows the results.
【００１４】[0014]
【表２】 [Table 2]
【００１５】ｐＨ７、低イオン強度で、かつ各種添加剤
を所定の濃度で含有すると不溶性異物の生成を防止する
か、もしくは前記対照に比べその生成は減少した。When the pH was 7, low ionic strength, and various additives were contained at a predetermined concentration, the formation of insoluble foreign matter was prevented, or the production thereof was reduced as compared with the control.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 三宅 正一 大阪府大阪市都島区都島中通３−５−44 株式会社ミドリ十字都島工場内 (72)発明者 西槇 秀雄 大阪府枚方市招提大谷２丁目25番１号 株 式会社ミドリ十字中央研究所内 (72)発明者 上村 八尋 大阪府枚方市招提大谷２丁目25番１号 株 式会社ミドリ十字中央研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shoichi Miyake 3-5-44, Miyajima Shimadori, Miyakojima-ku, Osaka City, Osaka Prefecture Midori Cross Miyakojima Plant (72) Hideo Nishimaki Invited Otani, Hirakata City, Osaka Prefecture 2-25-1 Incorporated Midori Cross Central Research Institute (72) Inventor Yahiro Uemura Invited Hirakata, Osaka Prefecture 2-25-1 Otani Incorporated Midori Cross Central Research Institute
Claims (3)
ることを特徴とするハプトグロビン含有液状製剤。1. A liquid preparation containing haptoglobin, which has a low salt concentration and a low ionic strength at pH 6-8.
活性剤を配合してなるハプトグロビン含有液状製剤。2. A haptoglobin-containing liquid preparation containing sugar, sugar alcohol or a nonionic surfactant.
じないハプトグロビン含有液状製剤。3. A haptoglobin-containing liquid preparation that does not produce insoluble foreign matter when shaken at 37 ° C. for 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7260911A JPH0977680A (en) | 1995-09-14 | 1995-09-14 | Liquid formulation containing haptoglobin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7260911A JPH0977680A (en) | 1995-09-14 | 1995-09-14 | Liquid formulation containing haptoglobin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0977680A true JPH0977680A (en) | 1997-03-25 |
Family
ID=17354472
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7260911A Pending JPH0977680A (en) | 1995-09-14 | 1995-09-14 | Liquid formulation containing haptoglobin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0977680A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9937229B2 (en) | 2012-10-03 | 2018-04-10 | Csl Behring Ag | Methods of treatment using hemopexin compositions |
-
1995
- 1995-09-14 JP JP7260911A patent/JPH0977680A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9937229B2 (en) | 2012-10-03 | 2018-04-10 | Csl Behring Ag | Methods of treatment using hemopexin compositions |
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