JPH04504253A - Formulations for the stabilization of IgM antibodies - Google Patents

Formulations for the stabilization of IgM antibodies

Info

Publication number
JPH04504253A
JPH04504253A JP50510090A JP50510090A JPH04504253A JP H04504253 A JPH04504253 A JP H04504253A JP 50510090 A JP50510090 A JP 50510090A JP 50510090 A JP50510090 A JP 50510090A JP H04504253 A JPH04504253 A JP H04504253A
Authority
JP
Japan
Prior art keywords
formulation
paragraph
igm
formulation according
sodium
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
Application number
JP50510090A
Other languages
Japanese (ja)
Inventor
ボルマー，サリイ
マテイス，ジエフリイ・エイ
フイリツプス，クリストフアー・ピー
Original Assignee
セントカー・インコーポレーテツド
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by セントカー・インコーポレーテツド filed Critical セントカー・インコーポレーテツド
Publication of JPH04504253A publication Critical patent/JPH04504253A/en
Pending legal-status Critical Current

Links

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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39591—Stabilisation, fragmentation
    • 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
    • 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
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Inorganic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

【発明の詳細な説明】 ＩｇＭ抗体の安定化のための配合物 発明の背景 人間に投与するための多くの蛋白質配合物が、配合物の使用前の蛋白質の変性、 凝集、及び他の変化を防ぐための安定剤を必要とすることは周知である。多くの 蛋白質は希薄溶液の状態が特に適していない。この不安定性は不溶粒子の形成に より現れ、蛋白質配合物を保存、又は輸送する時に増加する。蛋白質薬剤の分野 における主な挑戦は蛋白質の溶解性、及び活性の両方を保持する配合物の開発で ある。[Detailed description of the invention] Formulations for the stabilization of IgM antibodies Background of the invention Many protein formulations for human administration require denaturation of the protein prior to use of the formulation. The need for stabilizers to prevent agglomeration and other changes is well known. many A dilute solution is not particularly suitable for proteins. This instability leads to the formation of insoluble particles. It appears more frequently and increases when protein formulations are stored or transported. Field of protein drugs The main challenge in protein development is the development of formulations that preserve both protein solubility and activity. be.

特に免疫グロブリンは溶液中で粒子を形成する傾向を持ち、配合物を静脈注射に 使用する前に濾過が必要であることが認められている。蛋白質凝集物、及び粒子 の形成は、非経口用免疫グロブリン生成物の開発において、長い間問題であった 。例えば最近の化学的、及び酵素的処理を施した免疫グロブリンＧの発展までは 、凝集免疫グロブリンによる内因性抗補体活性のために、免疫グロブリンＧ（Ｉ ｇＧ）の投与は筋肉内設ロブリンＧ配合物の改良は問題の軽減に役立った。Ｊ、 Ｐ、ＭｃＣｕｅ等、Ｒｅｖ、Ｉｎｆ、Ｄｉｓ、、８　（４）：５３７４　５３８ １　（１９８６）。しかし現在使用されているほとんどの商業的に入手できる配 合物は、これらの不溶凝集物、又は粒子を除去するために、注射の前に生成物を 濾過する必要がある。Immunoglobulins in particular have a tendency to form particles in solution, making formulations difficult to administer intravenously. It is recognized that filtration is necessary before use. protein aggregates and particles has long been a problem in the development of parenteral immunoglobulin products. . For example, until the recent development of chemically and enzymatically treated immunoglobulin G, , immunoglobulin G (I Administration of gG) was administered intramuscularly. Improvements in Robulin G formulations helped alleviate the problem. J. P. McCue et al., Rev. Inf. Dis, 8(4):5374 538 1 (1986). However, most commercially available arrangements currently in use The product may be pre-injected to remove these insoluble aggregates, or particles. Needs to be filtered.

免疫グロブリン（ＩｇＭ）同位体が最も大きい免疫グロブリンであり、分子量は 約９００．０００ダルトンである。１ｇＭ分子は本来不安定な傾向があり、種々 の形で物理的、及び化学的圧迫を与えると容易に沈澱を形成する。この性質のた め、非経口的投与のためのＩｇＭを含む安定な配合物の調製が困難である。Immunoglobulin (IgM) is the immunoglobulin with the largest isotope, and the molecular weight is It is approximately 900,000 Daltons. 1 gM molecules tend to be inherently unstable, and various It easily forms precipitates when subjected to physical and chemical pressure in the form of Because of this property This makes it difficult to prepare stable formulations containing IgM for parenteral administration.

発明の要約 本発明はＩｇＭ抗体のための安定化配合物を含む。本配合物は緩衝液、ヒト血清 アルブミン、塩化ナトリウム、及びＩｇＭ抗体、又は抗体フラグメントを含む。Summary of the invention The present invention includes stabilizing formulations for IgM antibodies. This formulation contains buffer solution, human serum Includes albumin, sodium chloride, and IgM antibodies or antibody fragments.

配合物は静脈注射用の溶液におけるＩｇＭ抗体の安定性を増加させる。The formulation increases the stability of IgM antibodies in intravenous solutions.

本配合物は凍結真空乾燥して乾燥粉末とすることができる。凍結真空乾燥はＩｇ Ｍ抗体の生物活性を保持し、物理的、及び化学的圧迫下の液体調剤中で起こり得 る粒子の形成を最小にする。凍結真空乾燥生成物は容易に粒子を含まない溶液に 再生することができ、それは生物活性の損失を示さず、予備的濾過を行わずに投 与することができる。The formulation can be freeze-vacuum dried into a dry powder. Freeze-vacuum drying is Ig Retains biological activity of M antibodies and can occur in liquid preparations under physical and chemical pressure Minimize the formation of particles. Freeze-vacuum dried products are easily converted into particle-free solutions can be regenerated, it shows no loss of biological activity and can be poured without preliminary filtration. can be given.

本発明の液体、及び凍結真空乾燥調剤は蛋白質粒子の形成が最小であり、高温、 びんへの充填、及び輸送などの圧迫下で長期間免疫活性を保持するという点で優 れた安定性を示す。The liquid and lyophilized formulations of the present invention have minimal formation of protein particles, It is superior in that it maintains immune activity for a long time even under pressure during bottle filling and transportation. It shows stable stability.

本発明の液体、及び凍結真空乾燥配合物は両方ともＩｇＭ抗体の安定化に成功し た。配合物は注射用のモノクロナール抗体のための、粒子を含まない安定な溶液 を保ち、投与の前に濾過をする必要がない。特に凍結真空乾燥生成物は免疫活性 の損失なしに輸送、及び保存することができる。調剤は冷蔵、又は他の特別な扱 いを必要としない。Both the liquid and lyophilized formulations of the invention successfully stabilize IgM antibodies. Ta. The formulation is a stable particle-free solution for injectable monoclonal antibodies. , and there is no need for filtration before administration. In particular, freeze-vacuum dried products are immunoactive. can be transported and stored without loss. Dispensing must be refrigerated or otherwise specially handled. does not require

図の簡単な説明 図１は非凍結真空乾燥、及び凍結真空乾燥／再生ＩｇＭ調剤、及びプラシーボを 含むゲル濾過ＨＰＬＣの結果を示す。Brief description of the diagram Figure 1 shows non-lyophilized vacuum-dried and freeze-vacuum-dried/regenerated IgM preparations, and placebo. The results of gel filtration HPLC are shown.

図２は非凍結真空乾燥、及び凍結真空乾燥／再生１ｇＭ調剤の固相脂質Ａに結合 する能力を比較した免疫活性分析の結果を示す図である。Figure 2 shows non-lyophilized and lyophilized/reconstituted 1 gM formulations bound to solid phase lipid A. FIG. 3 is a diagram showing the results of an immune activity analysis comparing the ability to

本発明の詳細な説明 本発明の配合物は、免疫グロブリンＭ（ＩｇＭ）を含む試薬中で蛋白質凝集物、 及び粒子の形成を最小にし、溶液中の抗体が長期間その免疫活性を保持するのを 確実にする。配合物は中性、又は塩基性のｐＨ（例えば６．８又はそれ以上）の トロメタミン又はリン酸塩緩衝液、塩化ナトリウム、ＩｇＭ抗体、及びヒト血清 アルブミンを含む無菌の、製薬上許容できる溶液から成る。Detailed description of the invention The formulations of the invention contain protein aggregates in a reagent containing immunoglobulin M (IgM). and minimize particle formation, allowing antibodies in solution to retain their immunological activity for long periods of time. Assure. The formulation has a neutral or basic pH (e.g. 6.8 or higher). Tromethamine or phosphate buffer, sodium chloride, IgM antibodies, and human serum Consists of a sterile, pharmaceutically acceptable solution containing albumin.

緩衝液は非経口的注射のための抗体生成物のｐＨの安定化に長い間使用されてき た。緩衝液中の蛋白質の溶解度はイオン強度、及び溶液のｐＨなどの多くの因子 に依存する。この調剤に使用できる緩衝液には中性、又は塩基性ｐＨのトロメタ ミン、及びリン酸塩緩衝液が含まれる。それより低いｐＨの調剤は安定性が低く 、すなわち、凝集物を形成する傾向が高い。トロメタミンはＭｅｒｃｋ　Ｉｎｄ ｅｘ、１０版、Ｍｅｒｃｋａｎｄ　Ｃｏ、、Ｉｎｃ、、Ｒａｈｗａｙ、Ｎ、Ｊ、 ｊ：記載されティる。トロメタミンの濃度は約５−約１００ｍＭで、ｐＨは約８ −約１０であることができる。Buffers have long been used to stabilize the pH of antibody products for parenteral injection. Ta. The solubility of proteins in buffers depends on many factors such as ionic strength and pH of the solution. Depends on. Buffers that can be used in this preparation include Trometas, which has a neutral or basic pH; and phosphate buffer. Preparations with lower pH are less stable. , that is, there is a high tendency to form agglomerates. Tromethamine is manufactured by Merck Ind. ex, 10th edition, Merckand Co, Inc., Rahway, N.J. j: Described. The concentration of tromethamine is about 5 to about 100 mM, and the pH is about 8. - can be about 10.

リン酸ナトリウムなどのリン酸塩緩衝液も使用することができる。本配合物では 約８−約２０ｍＭの濃度、及び約６．８−約７．４のｐＨを使用することができ る。Phosphate buffers such as sodium phosphate can also be used. In this formulation A concentration of about 8 to about 20 mM and a pH of about 6.8 to about 7.4 can be used. Ru.

安定化蛋白質を調剤に添加する。安定化蛋白質は水溶液における免疫グロブリン の溶解度、及び／又は安定性を増加させる蛋白質である。例えば免疫グロブリン の水溶液に添加するとこれらの蛋白質は免疫グロブリンが溶液から析出するのを 防ぎ、その結果より高い濃度で免疫グロブリンを溶解することができる。本配合 物の場合、ヒト血清アルブミン（ＨＳＡ）が液体、及び凍結真空乾燥調剤の両方 においてＩｇＭのための特に有用な安定剤であることがわかった。ＩＳＡは調剤 中で約２．５−約１０％（ｗ／ｖ）の量で存在する。約２．５％（ｗ／ｖ）から 約５％（Ｗ／Ｖ）の量のＩＳＡがＩｇＭの安定な溶液を保持するのに特に有効で ある。Add stabilizing proteins to the formulation. Stabilizing proteins are immunoglobulins in aqueous solution A protein that increases the solubility and/or stability of For example, immunoglobulin When added to an aqueous solution, these proteins prevent immunoglobulins from precipitating out of solution. prevention and, as a result, higher concentrations of immunoglobulin can be dissolved. This formulation In the case of human serum albumin (HSA), both liquid and lyophilized preparations are available. It has been found to be a particularly useful stabilizer for IgM. ISA is dispensing present in an amount of about 2.5% to about 10% (w/v). From about 2.5% (w/v) An amount of ISA of about 5% (w/v) is particularly effective in maintaining a stable solution of IgM. be.

本発明のひとつの具体化において、ＨＳＡのための安定化試薬、例えばカプリル 酸ナトリウム、及びＮ−アセチルトリプロファネートが調剤中に存在する。ＩＳ Ａはこれらの化合物が存在しないと安定性が低い（すなわちより凝集し易い）。In one embodiment of the invention, stabilizing reagents for HSA, such as caprylic Sodium acid, and N-acetyl triprophanate are present in the formulation. IS A is less stable (ie, more likely to aggregate) in the absence of these compounds.

例えばＨＳＡの２５％（Ｗ／Ｖ）溶液は２０ｍＭのカプリル酸ナトリウム、及び ２０ｍＭのＮ−アセチルトリプトファネートを含み、従って調剤に添加した２、 ５％（ｗ／ｖ）ＩＳＡは２ｍＭのカプリル酸ナトリウム、及び２ｍＭのＮ−アセ チルトリプトファネートを含む。Ｎ−アセチルトリプロファネート、及びカプリ ル酸ナトリウム以外の安定化試薬も使用することができ、それは説明のために上 記に挙げられている。For example, a 25% (w/v) solution of HSA contains 20 mM sodium caprylate, and 2, containing 20mM N-acetyltryptophanate and thus added to the preparation. 5% (w/v) ISA contains 2mM sodium caprylate and 2mM N-acetate. Contains tiltptophanate. N-acetyl triprophanate, and capri Stabilizing reagents other than sodium sulfate can also be used and are mentioned above for illustration. It is listed in the book.

塩化ナトリウムは１ｇＭ蛋白質の溶解性のために必要なイオン強度の上昇のため に本配合物に加える。ＩｇＭは水のみの場合より塩の水溶液の場合の方がより溶 解し易い。添加する塩化ナトリウムの量は約２００−約３５０ｍＭである。この 場合の目的には約２７０−３００ｍＭの塩化ナトリウムが特に有効である。Sodium chloride increases the ionic strength required for 1 gM protein solubility. to this formulation. IgM is more soluble in an aqueous salt solution than in water alone. Easy to understand. The amount of sodium chloride added is about 200 to about 350 mM. this About 270-300 mM sodium chloride is particularly effective for this purpose.

本発明の液体、及び凍結真空乾燥配合物はＩｇＭと同様にすべてのサブクラスの ＩｇＭ抗体の安定化に使用することができる。本配合物は特にヒトのモノクロナ ールＩｇＭ抗体の安定化に有用である。The liquid and lyophilized formulations of the present invention are suitable for all subclasses as well as IgM. It can be used to stabilize IgM antibodies. This formulation is particularly suitable for human monoclonal It is useful for stabilizing IgM antibodies.

本発明のひとつの具体化は約５ｍＭ−約１００ｍＭのトロメタミン（ｐＨ８−１ ０）　、約２００ｍＭ−約３００ｍＭの塩化ナトリウム、約２゜５−約５％（ｗ ／ｖ）のＩＳＡ、及び約２．５−約１０．０ｍｇ／ｍｌのＩｇＭ抗体を含む配合 物から成る。ＨＳＡの安定化のために、約２ｍＭ−約４ｍＭのカプリル酸ナトリ ウム、及び約２ｍＭ−約４ｍＭのＮ−アセチルトリプロファネートを任意に含む ことができる。本発明の好ましい具体化は約４．５ｍＭのトロメタミン（ｐＨ８ ，５）　、約２７０ｍＭの塩化ナトリウム、約２．　５　（ｗ／ｖ）のＨＳＡ、 約５ｍｇ／ｍｌのＩｇＭ抗体、又は抗体フラグメント、及びそれぞれ約２ｍＭの Ｎ−アセチルトリプロファネート及びカプリル酸ナトリウムを含む。この調剤は モノクロナール抗体の免疫活性の安定性を増強し、人間の患者への静脈注射用の 溶液中の免疫グロブリンが最終的生成物のびん中で沈澱して粒子を形成するのを 防ぐ。One embodiment of the invention is about 5mM to about 100mM tromethamine (pH 8-1). 0), about 200mM - about 300mM sodium chloride, about 2°5 - about 5% (w /v) of ISA and about 2.5 to about 10.0 mg/ml of IgM antibody. consists of things. For stabilization of HSA, about 2mM to about 4mM sodium caprylate and optionally about 2mM to about 4mM N-acetyl triprophanate. be able to. A preferred embodiment of the invention is about 4.5 mM tromethamine (pH 8). , 5), about 270 mM sodium chloride, about 2. 5 (w/v) HSA, about 5 mg/ml of IgM antibody, or antibody fragment, and about 2 mM of each Contains N-acetyl triprophanate and sodium caprylate. This preparation Enhances the stability of monoclonal antibody immunoreactivity and makes it suitable for intravenous injection into human patients. Allow immunoglobulins in solution to precipitate and form particles in the final product bottle. prevent.

本発明の他の具体化は約８ｍＭ−約２０ｍＭの無菌の、発熱物質を含まないリン 酸ナトリウム（ｐＨ６，８−７，４）　、約２５０ｍＭ−約３５ＱｍＭの塩化ナ トリウム、約２．５−約５％（ｗ／ｖ）のＨＳＡ、及び約２．５−約１０．０ｍ ｇ／ｍｌのＩｇＭ抗体、又は抗体フラグメントを含む配合物から成る。カプリル 酸ナトリウム、及びＮ−アセチルトリプロファネートをそれぞれ約２ｍＭ−約４ ｍＭの量で調剤中に含むことができる。この調剤の好ましい具体化は約８ｍＭの リン酸ナトリウム（ｐＨ７，２Ｌ約２７０ｍＭの塩化ナトリウム、約５．０％（ ｗ／ｖ）のヒト血清アルブミン、約５ｍｇ／ｍｌのＩｇＭ抗体、又は抗体フラグ メント、及びそれぞれ約２ｍＭのカプリル酸ナトリウム、及びＮ−アセチルトリ プロファネートから成る。Other embodiments of the invention include about 8mM to about 20mM sterile, pyrogen-free phosphorus. Sodium chloride (pH 6,8-7,4), about 250mM - about 35QmM sodium chloride thorium, about 2.5 to about 5% (w/v) HSA, and about 2.5 to about 10.0 m g/ml of IgM antibodies, or formulations containing antibody fragments. Capril sodium acid and N-acetyl triprophanate at about 2 mM to about 4 It can be included in the formulation in an amount of mM. A preferred embodiment of this formulation is about 8mM Sodium phosphate (pH 7, 2L approx. 270mM sodium chloride, approx. 5.0%) w/v) human serum albumin, approximately 5 mg/ml IgM antibodies, or antibody flag and about 2mM of sodium caprylate and N-acetyltritrichloride, respectively. Consisting of prophanate.

本発明の他の具体化において、上記の調剤を凍結真空乾燥し、乾燥した保存用粉 末を形成することができ、それは容易に再生して静脈注射に適した粒子を含まな い溶液とすることができる。凍結真空乾燥は製薬品の製造においてその生物活性 の保持のために良く使用されるフリーズドライ法である。液体配合物を製造し、 その後凍結真空乾燥して乾燥した塊状の生成物とする。この方法は一般に水を除 去し、非水成分をそのまま完全に粉末状、又は塊状物質として残すために前以て 凍結した試料を真空中で乾燥する段階を含む。凍結真空乾燥生成物は高温で、生 物活性の損失なしに長期間保存することができ、適した希釈剤を加えることによ り容易に再生して粒子を含まない溶液とすることができる。適した希釈剤は生物 学的に許容でき、凍結真空乾燥粉末が完全に溶解するどんな液体であることもで きる。水、特に無菌の発熱性物質を含まない水が、抗体の安定性に影響する塩、 又は他の物質を含まないので好ましい希釈剤である。凍結真空乾燥の利点は、生 成物の不安定性を招く種々の分子の現象を非常に減少させる量まで含水量を減ら すことである。凍結真空乾燥生成物は又、輸送による物理的圧迫を十分耐えるこ とができる。再生生成物は粒子を含まず、従って予備的濾過を行わずに静脈注射 により投与することができる。In another embodiment of the invention, the preparation as described above is freeze-vacuum dried and the dried preservative powder is prepared. can form a particle-free substance that is easily regenerated and suitable for intravenous injection. It can be made into a clear solution. Freeze-vacuum drying improves its biological activity in the manufacture of pharmaceutical products This is a freeze-drying method that is often used to preserve producing a liquid formulation; It is then lyophilized and vacuum dried to form a dry mass product. This method generally removes water. to completely remove the non-aqueous components as a powder or lump material. It involves drying the frozen sample in vacuum. Freeze-vacuum-dried products are produced at high temperatures and It can be stored for long periods of time without loss of biological activity and by adding a suitable diluent. It can be easily regenerated into a particle-free solution. Suitable diluents are biological Any liquid that is biologically acceptable and in which the freeze-dried powder completely dissolves can be used. Wear. Water, especially sterile, pyrogen-free water, contains salts that affect antibody stability. or other substances, it is a preferred diluent. The advantage of freeze-vacuum drying is that The water content can be reduced to an amount that greatly reduces the various molecular phenomena that lead to product instability. It is to do so. Freeze-vacuum dried products are also well suited to withstand the physical stress of transportation. I can do it. The regenerated product is particle-free and therefore can be injected intravenously without preliminary filtration. It can be administered by

本発明をさらに以下の実施例により説明するが、これはいずれにも本発明を制限 するものではない。The invention is further illustrated by the following examples, which in no way limit the invention. It's not something you do.

実施例１ トロメタミンに基づ＜ＩｇＭ液体、及び凍結真空乾燥調剤の製造液体調剤 Ｃｅｎｔｒｉｐｒｅｐ３０Ｃｏｎｃｅｎｔｒａｔｏｒ　（Ａｍｉｃｏｎ）を用い てＩｇＭ（ＨＡ−ＩＡ　ＩｇＭ、ｏット番号０１２５６７、Ｃｅｎｔｏｃｏｒ、 Ｉｎｃ、、Ｍａｌｖｅｒｎ、ＰＡ）を５．５ｍｇ／ｍｌに濃縮した。濃縮した蛋 白質（２０ｍｌ）を２５ｍ１のメスシリンダー中に入れ、カプリル酸ナトリウム 、及びＮ−アセチルトリプロファネートを含む２ｍｌのＨ３Ａ　（Ｕ、Ｓ、Ｐ、 ２０ｍＭのカプリル酸ナトリウム、及び２０ｍＭのＮ−アセチルトリプロファネ ート中の２５％Ｈ３Ａ。Example 1 Manufacture of <IgM liquids and lyophilized preparations based on tromethamineLiquid preparations Using Centriprep 30 Concentrator (Amicon) IgM (HA-IA IgM, ot number 012567, Centocor, Inc., Malvern, PA) was concentrated to 5.5 mg/ml. concentrated protein Place the white matter (20 ml) in a 25 ml graduated cylinder and add sodium caprylate. , and 2 ml of H3A containing N-acetyl triprophanate (U, S, P, 20mM sodium caprylate and 20mM N-acetyltryprophane 25% H3A in the solution.

Ａｒｍｏｕｒ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｃｏ、）、トロメタミン（５０ ｍＭ、ｐＨ８，５０）　、及び３００ｍＭの塩化ナトリウム（Ｎａｃｌ）を加え た。溶液を０．２μのシリンジフィルターを用いて５０ｍ１の遠心管に濾過した 。ナトリウムアジド（１０％溶液を０．２２ｍ１）を加え、最終濃度０．１％と した。最終溶液は透明の明黄色の液体で、４．９５ｍｇ／ｍｌのＩｇＭ、４５ｍ Ｍのトロメタミン（ｐＨ３゜３５）　、２７０ｍＭの塩化ナトリウム、２．５％ のＨ３Ａ、２ｍＭのカプリル酸ナトリウム、及び２ｍＭのＮ−アセチルトリプロ ファネートを含む。Armor Pharmaceutical Co.), Tromethamine (50 Add 300 mM sodium chloride (NaCl) and 300 mM sodium chloride (NaCl). Ta. The solution was filtered into a 50ml centrifuge tube using a 0.2μ syringe filter. . Add sodium azide (0.22 ml of 10% solution) to give a final concentration of 0.1%. did. The final solution was a clear light yellow liquid with 4.95 mg/ml IgM, 45 m M Tromethamine (pH 3°35), 270mM Sodium Chloride, 2.5% H3A, 2mM sodium caprylate, and 2mM N-acetyl tripro Including fanate.

ＩｇＭを除く以外は上記調剤と全く同一の”ブラシーポ”調剤も製造した。従っ てプラシーポ調剤は４５ｍＭのトリス緩衝液（ｐＨ８，３５）、２７０ｍＭのＮ ａＣＬ　２．５％のＨ８Ａ、２ｍＭのカプリル酸ナトリウム、及び２ｍＭのＮ− アセチルトリプロファネートを含む。A "Brasipo" formulation was also prepared which was identical to the above formulation except for the IgM. follow The placebo preparation consisted of 45mM Tris buffer (pH 8.35), 270mM N aCL 2.5% H8A, 2mM sodium caprylate, and 2mM N- Contains acetyl triprophanate.

凍結真空乾燥 液体ＩｇＭ調剤を２ｍｌのタイプｌＴｕｂｉｎｇびん（ＷｅｓｔＣＯｌ）中に１ ｍｌづつ増量しながら分配した。合計２０本のびんに入れた。びんを１°　ｘ１ ′の棚を持つ凍結真空乾燥機（ＦＴＳ）に置いた。Freeze vacuum drying Liquid IgM preparation was placed in a 2 ml Type I Tubing bottle (West COl). It was distributed in increasing amounts in ml increments. A total of 20 bottles were placed. Bottle 1° x 1 The sample was placed in a freeze vacuum dryer (FTS) with a shelf.

十分な熱を負荷するために棚の残り空間にブラシーボのびんを置いた。A bottle of Brasibo was placed in the remaining space on the shelf to load sufficient heat.

びんを１３ｍＭのグレイブチル凍結真空乾燥クロージヤー（＃２２４１４２、Ｗ ｈｅａｔｏｎ）を用いてふたをした。凍結真空乾燥機の棚は約５℃±２℃に予備 冷却した。試験びん、及びブラシーボびんを盆に載せて棚に置き、ドアの良い密 閉性を保持するために室を少し減圧にした。The bottle was sealed with a 13mM Gray Butyl Freeze Vacuum Drying Closure (#224142, W heaton) and covered with a lid. Freeze-vacuum dryer shelves are kept at approximately 5℃±2℃ Cooled. Place the test bottles and Brushbo bottles on a tray and place them on a shelf, making sure the door is tightly closed. A slight vacuum was applied to the chamber to keep it closed.

合計２０本の生成物のびん、及び３５５本のブラシーボのびんで棚の全空間を占 めるように置いた。A total of 20 product bottles and 355 Brasibo bottles occupy the entire shelf space. I placed it so that it would fit.

びんを５℃とし、少なくとも１時間保持した後、棚の表面の温度を約−４０℃に 設定した。びんは−４０℃に少なくとも１時間保った。コンデンサーを約−７０ ℃に冷却した。室内の圧力を機械によるポンプを用いて５０トール以下に下げた 。生成物の温度が一４７℃から一４２℃を保つように棚の表面温度を調節した。After the bottles are brought to 5°C and held for at least 1 hour, the shelf surface temperature is reduced to approximately -40°C. Set. Bottles were kept at -40°C for at least 1 hour. Capacitor about -70 Cooled to ℃. The pressure in the room was lowered to below 50 Torr using a mechanical pump. . The shelf surface temperature was adjusted to maintain the product temperature between 147°C and 142°C.

生成物の温度が棚の温度に達し、少なくとも１時間保持した後、室内の残留気体 の質量スペクトルを記録した。その後棚の表面温度を約＋２０℃に設定した。温 度が＋２０℃に達し、少な（とも２時間保った後、室内の残留気体の分圧を記録 した。After the product temperature reaches the shelf temperature and has been maintained for at least 1 hour, any residual gas in the room A mass spectrum was recorded. Thereafter, the surface temperature of the shelf was set to approximately +20°C. warm After the temperature reaches +20°C and remains for 2 hours, record the partial pressure of the residual gas in the room. did.

その後室に乾燥窒素を逆充填し、圧力を約６００トールとした。生成物を乾燥機 から除去し、びんにクリンプシールを適用した。調製蛋白質は凍結すると非常に 密度の高い塊を形成する。The chamber was then backfilled with dry nitrogen to a pressure of approximately 600 Torr. Dryer the product and applied a crimp seal to the bottle. Prepared proteins are very Forms dense clumps.

形成した凍結真空乾燥機は表面上に殻も、つやも持たず、びん中全体が均一であ った。The formed freeze-vacuum dryer has no shell or gloss on its surface, and is uniform throughout the bottle. It was.

凍結真空乾燥ＩｇＭの再生 びんからクリンプシールを除き、クロージヤーを露出し、生成物を含むびん１本 、及びブラシーボびん１本からクロージヤーを除去した。無菌のピペットにＬ　 Ｏｍｌの無菌／発熱物質を含まない（ｓ／ｐ　ｆ）水（ＭｃＧａｗ）を満たし、 凍結真空乾燥した生成物を入れたびんに分配した。水を全部注入してから、視覚 で観察できる物質がすべて溶解するのに要する時間を測定した。Regeneration of freeze-vacuum dried IgM Remove the crimp seal from the bottle, expose the closure, and remove one bottle containing the product. , and the closure was removed from one Brushbo bottle. L into a sterile pipette Fill with Oml sterile/pyrogen-free (s/pf) water (McGaw); The lyophilized product was dispensed into bottles. After injecting all the water, visually The time required for all the observable substances to dissolve was measured.

０．５分　領３分 再生後の視覚検査 視覚検査のためにびんを黒い背景の直前に置いた。その後光線が液体を通って上 方に進むようにびんの下に光源を置いた。色の変化、濁り、凝集、微細沈澱又は 他の粒子を調べた。非凍結真空乾燥調剤、及び凍結真空乾燥して再生した調剤の 間に認識可能な差はなかった。結果を以下の表に示す： ブラシーポ（非凍結真空乾燥）　透明、黄色液体生成物（非凍結真空乾燥）　透 明、黄色液体プラシーボ（凍結真空乾燥）　透明、黄色液体生成物（凍結真空乾 燥）　透明、黄色液体ＨＰ　Ｌ　Ｃゲル濾過 凍結真空乾燥生成物、及びプラシーポをＨＰＬＣ（Ｗａ　ｔ　ｅ　ｒ　ｓ）ゲル 濾過により測定した。非凍結真空乾燥生成物、及びブラシーポも同様に行ったｏ Ｄｕｐｏｎｔ　Ｚｏｒｖａｘ　ＧＦ−４５０ゲルカラムを０゜２Ｍのリン酸ナト リウム緩衝液（ｐＨ６，８）　、及び０．３ＭのＮａＣ１の混合物を用い、１ｍ ｌ／分の流量で平衡化した。吸収波長を２１４ｎｍに設定した。0.5 minutes 3 minutes Visual inspection after playback The bottle was placed directly in front of a black background for visual inspection. The light beam then travels up through the liquid. A light source was placed under the bottle so that it would move in the opposite direction. Color change, turbidity, flocculation, fine sediment or Other particles were investigated. Non-freeze vacuum-dried preparations and preparations regenerated by freeze-vacuum drying There was no discernible difference between them. The results are shown in the table below: Brashipo (non-freezing vacuum drying) Clear, yellow liquid product (non-freezing vacuum drying) Transparent Bright, yellow liquid placebo (freeze-vacuum dried) Clear, yellow liquid product (freeze-vacuum dried) Drying) Transparent, yellow liquid HP L C gel filtration The freeze-vacuum dried product and the placebo were analyzed on HPLC (Waterrs) gel. Measured by filtration. The non-freeze vacuum-dried product and Brachypo were also treated in the same way. Dupont Zorvax GF-450 gel column with 0.2M sodium phosphate 1 m Equilibration was carried out at a flow rate of l/min. The absorption wavelength was set at 214 nm.

１μｌの非希釈試料（凍結真空乾燥、及び凍結真空乾燥前生成物、ならびにブラ シーボ）を自動インジェクターを通してカラムに注入し、１５分運転した。図１ に示す結果は凍結真空前ブラシーボ、及び生成物と、凍結真空プラシーボ、及び 生成物の間に差がないことを示した。1 μl of undiluted sample (freeze-vacuum dried and pre-freeze-vacuum dried product, and blank) Sebo) was injected into the column through an automatic injector and run for 15 minutes. Figure 1 The results shown are for frozen vacuum pre-brasibo and product, frozen vacuum placebo, and It showed that there was no difference between the products.

免疫活性分析 それぞれの調剤中のＩｇＭの免疫活性を、酵素結合イムノアッセイ法を用い、固 相脂質Ａへの結合を測定して決定した。Immune activity analysis IgM immunoreactivity in each preparation was determined using an enzyme-linked immunoassay method. It was determined by measuring the binding to phase lipid A.

１びんのサルモネラ　ミネソタ（Ｓａ　１ｍｏｎｅ　Ｉ　］　ａ　ｍ１ｎｎｅｓ ｏｔａ）Ｒ５９５脂質Ａ（Ｌｉｓｔ　Ｂｉｏｌｏｇｉｃａｌ　Ｌａｂｏｒａｔｏ ｒｉｅｓ、Ｉｎｃ、、Ｃａｍｐｂｅｌ］、ＣＡ；カタログ番号４０１）をｓ／ｐ ｆ水中で０．５％ＴＥＡ　（１−リエチルアミン）を用いて１ｍｇ／ｍｌに再生 した。１０ｍＭのＨＥＰＥＳ、及び無菌／発熱物質を含まない鉤　９％のＮａＣ ］　（ｓ／ｐｆ食塩水、ＭｃＧｒ−ａｗ）から成る緩衝溶液、ｐＨ７，２（緩衝 液＃１）中で脂質Ａの１０Ｍｇ／ｍｌの溶液を作った。この調剤をＰｖＣミクロ タイタープレート（Ｄｙｎａｔｅｃｈ　Ｌａｂｏｒａｔｏｒｉｅｓ、Ｉｎｃ、、 Ｃｈａｎｔｉｌｉｙ、ＶＡカタＯグ番号＃０１１−０１０−２１０１）　、５０ μ！／ウエルに分配し、プレートに覆いをして４℃で１夜培養した。1 bottle of Salmonella Minnesota (Sa 1mone I) a m1nnes ota) R595 Lipid A (List Biological Laborato ries, Inc., Campbell], CA; catalog number 401) s/p f Regenerate to 1 mg/ml using 0.5% TEA (1-ethylamine) in water did. 10mM HEPES, and sterile/pyrogen-free hook 9% NaC ] (s/pf saline, McGr-aw), pH 7.2 (buffered A 10 Mg/ml solution of Lipid A was made in solution #1). Add this preparation to PvC Micro Titer plate (Dynatech Laboratories, Inc.) Chantiliy, VA catalog number #011-010-2101), 50 μ! The plate was covered and cultured overnight at 4°C.

プレートを培養器から除去し、ｓ／ｐｆ食塩水で３回洗浄し、ＬＯｍＭのＨＥＰ ＥＳ、ｓ／ｐｆ食塩水、及び２％の熱−不活性化ＦＢＳから成る緩衝液（緩衝液 ＃２）の２００μｌ／ウエルに分配した。プレートに覆いをし、３７℃にて１時 間培養した。培養後、プレートをｓ／ｐｆ食塩水で３回洗浄した。The plate was removed from the incubator, washed three times with s/pf saline, and LOmM of HEP. A buffer consisting of ES, s/pf saline, and 2% heat-inactivated FBS (buffer #2) was distributed into 200 μl/well. Cover the plate and incubate at 37°C for 1 hour. It was cultured for a period of time. After incubation, the plates were washed three times with s/pf saline.

５．０Ｍｇ／ｍｌの濃度で試験調剤、ＩｇＭ標準、及びヒト骨髄腫■ｇＭの負の 標準（Ｃｈｒｏｍｐｕｒｅ　Ｈｕｍａｎ　ＭｙｅｌｏｍａＩｇＭ、Ｊａｃｋｓｏ ｎ　Ｉｍｍｕｎｏ　Ｒｅ５ｅａｒｃｈ　Ｌａｂ。test preparation, IgM standard, and human myeloma gM negative at a concentration of 5.0 Mg/ml. Standard (Chrompure Human MyelomaIgM, Jackso n　Immuno　Re5search　Lab.

ｒａｔｏｒｉｅｓ、Ｗｅｓｔ　Ｇｒｏｖｅ、ＰＡ）の溶液を準備した。rations, West Grove, PA).

緩衝液＃２をＢ−Ｈの列のウェルに分配した。ＩｇＭ標準を列Ａの段１−３に分 配した（１００μｍ／ウェル）。試験調剤を列Ａの段４−１２に３重に分配した （１００μｍ／ウェル）。プレート中の列Ｈに向かって順に５０μｌづつの希釈 を行った。列Ｈの１００　ｔｔ　１のうち５０μ夏を捨て、負の標準を加えた。Buffer #2 was dispensed into wells in rows B-H. Separate the IgM standards into rows 1-3 of column A. (100 μm/well). The test formulation was distributed in triplicate to rows 4-12 of row A. (100 μm/well). Dilute in 50 μl increments toward column H in the plate. I did it. Out of 100 tt1 in column H, 50μ summers were discarded and a negative standard was added.

プレートを覆い、３７℃にて２時間培養し、ｓ／ｐｆ食塩水で３回洗浄した。Plates were covered, incubated for 2 hours at 37°C, and washed three times with s/pf saline.

１　：　５００希釈のアルカリ性緩衝液（Ｓｉｇｍａ　ＣｈｅｍｉｃａｌＳ、カ タログ番号＃０１４−１０５）を含む５ｍｌのｓ／ｐｆ水にホスファターゼ基質 １錠剤を加えて、基質溶液を調製し、２０分培養した。1: 500 dilution alkaline buffer (Sigma Chemical S, chemical Phosphatase substrate in 5 ml s/pf water containing (Talog Number #014-105) A substrate solution was prepared by adding 1 tablet and incubated for 20 minutes.

３ＭのＮａＯＨ５０μｌを加えることより反応を止めた。The reaction was stopped by adding 50 μl of 3M NaOH.

プレートリーダーを用い、４１４ｎｍにて溶液の光学濃度を測定した。The optical density of the solution was measured at 414 nm using a plate reader.

濃度に対するＯＤの４パラメーターフイツトを用いてデータを分析した。Data were analyzed using a four-parameter fit of OD to concentration.

図２に示す結果は凍結真空乾燥前、及び凍結真空乾燥生成物の活性に差がないこ とを示した。The results shown in Figure 2 indicate that there is no difference in the activity of the pre-lyophilized and freeze-vacuum dried products. and showed.

温度ストレス試験 凍結真空乾燥生成物試料を４℃、２２℃、及び４０℃にて保存した。temperature stress test Freeze-vacuum dried product samples were stored at 4°C, 22°C, and 40°C.

試料を活性、及び外観（すなわち粒子の形成）に関して周期的に評価した。試料 は評価の前に再生した。結果を以下の表に示す・温度／時間　活性　外観 ４℃７２力月　変化なし　透明 ２２℃／２カ月　変化なし　透明 ４０℃／２カ月　少し減少　少量の粒子４℃１５力月　変化なし　透明 ２２℃１５力月　変化なし　透明 ４℃／７カ月　変化なし　透明 同等例 同業者は１種類以上の日常的実験を用いて、ここに記載した本発明の特別な具体 化の多くの同等例を認める、又は確認することができるであろう。これらの、及 び他のすべての同等例は以下のフレイムに含まれるものとする。Samples were periodically evaluated for activity and appearance (ie, particle formation). sample was played before evaluation. The results are shown in the table below: Temperature/Time Activity Appearance 4°C 72 months, no change, transparent 22℃/2 months, no change, transparent 40℃/2 months Slight decrease Small amount of particles 4℃ 15 months No change Transparent 22℃ 15 months, no change, transparent 4℃/7 months No change Transparent Equivalent example Those skilled in the art will be able to determine, using one or more routine experiments, specific embodiments of the invention described herein. One may recognize or identify many equivalent examples of . These and all other equivalent examples shall be included in the frames below.

標　準　０１２５６７　凍結真空乾燥前　凍結真空乾燥後４１４ｎｍにおける吸 収 負の対数希釈 ＦＩＧ、　２ 国際調査報告 国際調査報告Standard 012567 Before freeze vacuum drying After freeze vacuum drying Absorption at 414 nm Collection negative log dilution FIG. 2 international search report international search report

Claims (1)

【特許請求の範囲】 １．緩衝液、ヒト血清アルブミン、塩化ナトリウム、及びＩｇＭ抗体から成るＩ ｇＭ抗体の配合物。 ２．第１項に記載の配合物において、緩衝液がリン酸塩緩衝液、又はトロメタミ ンから成ることを特徴とする配合物。 ３．第２項に記載の配合物において、リン酸塩緩衝液が約８ｍＭ−約２０ｍＭの 濃度、及び６．８−７．４のｐＨのリン酸ナトリウムから成ることを特徴とする 配合物。 ４．第２項に記載の配合物において、トロメタミンの濃度が約５−約１００ｍＭ であり、ｐＨが約８−約１０であることを特徴とする配合物。 ５．第１項に記載の配合物において、塩化ナトリウムの濃度が約２７０ｍＭであ ることを特徴とする配合物。 ６．第１項に記載の配合物において、さらにＮ−アセチルトリプトファネート、 及びカプリル酸ナトリウムを含むことを特徴とする配合物。 ７．第７項に記載の配合物において、Ｎ−アセチルトリプロファネートの濃度が 約２ｍＭ−約４ｍＭであり、カプリル酸ナトリウムの濃度が約２ｍＭ−約４ｍＭ であることを特徴とする配合物。 ８．第１項に記載の配合物において、ＩｇＭ抗体の濃度が約５．０ｍｇ／ｍｌで あることを特徴とする配合物。 ９．第８項に記載の配合物において、ＩｇＭ抗体がヒトの免疫グロブリンである ことを特徴とする配合物。 １０．第１項に記載の配合物において、ＩｇＭ抗体がモノクロナール抗体である ことを特徴とする配合物。 １１．第１項に記載の配合物において、約２．５％−約５％（ｗ／ｖ）のヒト血 清アルブミンを含むことを特徴とする配合物。 １２．凍結真空乾燥した第１項に記載の配合物。 １３．第１２項に記載の配合物において、乾燥粉末から成り、再生して注射用の ＩｇＭの溶液を与えることができることを特徴とする配合物。 １４．ＩｇＭの注射用配合物において：ａ．ｐＨが約８から約１０のトロメタミ ン約５ｍＭ−約１００ｍＭ；ｂ．約２００−約３００ｍＭの塩化ナトリウム；ｃ ．約２．５−約５％（ｗ／ｖ）のヒト血清アルブミン；及びｄ．約２．５−約１ ０．０ｍｇ／ｍｌのＩｇＭ抗体から成ることを特徴とする配合物。 １５．第１４項に記載の注射用配合物において、さらに２ｍＭ−４ｍＭのＮ−ア セチルトリプトファネート、及び２ｍＭ−４ｍＭのカプリル酸ナトリウムを含む ことを特徴とする配合物。 １６．第１５項に記載の配合物において：ａ．４５ｍＭのトロメタミン、ｐＨ８ ．５；ｂ．２７０ｍＭの塩化ナトリウム； ｃ．２．５％（ｗ／ｖ）のヒト血清アルブミン；ｄ．５ｍｇ／ｍｌのＩｇＭ抗体 ： ｅ．２ｍＭのカブリル酸ナトリウム；及びｆ．２ｍＭのＮ−アセチルトリプロフ ァネートを含むことを特徴とする配合物。 １７．凍結真空乾燥した第１６項に記載の配合物。 １８．第１７項に記載の配合物において、乾燥粉末から成り、再生して注射用の ＩｇＭの溶液を与えることができることを特徴とする配合物。 １９．ＩｇＭの注射用配合物において：ａ．ｐＨが約６．８から約７．４のリン 酸ナトリウム約８ｍＭ−約２００ｍＭ； ｂ．約２５０−約３５０ｍＭの塩化ナトリウム；ｃ．約２．５−約５％（ｗ／ｖ ）のヒト血清アルブミン；及びｄ．約２．５−約１０．０ｍｇ／ｍｌのＩｇＭ抗 体から成ることを特徴とする配合物。 ２０．第１９項に記載の注射用配合物において、さらに２ｍＭ−４ｍＭのＮ−ア セチルトリプトファネート、及び２ｍＭ−４ｍＭのカプリル酸ナトリウムを含む ことを特徴とする配合物。 ２１．第２０項に貴記載の配合物において：ａ．８ｍＭのリン酸ナトリウム、ｐ Ｈ７．２；ｂ．２７０ｍＭの塩化ナトリウム； ｃ．５．０％（ｗ／ｖ）のヒト血清アルブミン：ｄ．５ｍｇ／ｍｌのＩｇＭ抗体 ； ｅ．２ｍＭのカブリル酸ナトリウム；及びｆ．２ｍＭのＮ−アセチルトリプロフ ァネートを含むことを特徴とする配合物。 ２２．凍結真空乾燥した第２１項に記載の配合物。 ２３．第２２項に記載の配合物において、乾燥粉末から成り、再生して注射用の ＩｇＭの溶液を与えることができることを特徴とする配合物。 ２４．緩衝液、蛋白質、及びＩｇＭを含むＩｇＭ配合物において、ＩｇＭ抗体を リン酸塩、又はトロメタミン緩衝液、塩化ナトリウム、及びヒト血清アルブミン と組み合わせることから成ることを改良点とする配合物。 ２５．第２４項に記載の改良配合物において、ヒト血清アルブミンをＮ−アセチ ルトリプトファネート、及びカプリル酸ナトリウムにより安定化することを特徴 とする配合物。 ２６．第２４項に記載の改良配合物において：ａ．ｐＨが約８から約１０のトロ メタミン約５ｍＭ−約１００ｍＭ；ｂ．約２００−約３００ｍＭの塩化ナトリウ ム；ｃ．約２．５−約５％（ｗ／ｖ）のヒト血清アルブミン；ｄ．約２．５−約 １０．０ｍｇ／ｍｌのＩｇＭ抗体；ｅ．約２ｍＭ−約４ｍＭのカプリル酸ナトリ ウム；及びｆ．約２ｍＭ−約４ｍＭのＮ−アセチルトリプロファネートから成る ことを特徴とする配合物。 ２７．第２４項に記載の改良配合物において：ａ．リン酸ナトリウム約８ｍＭ− 約２００ｍＭ；ｂ．約２５０−約３５０ｍＭの塩化ナトリウム；ｃ．約２．５− 約５．０％（ｗ／ｖ）のヒト血清アルブミン；ｄ．約２．５−約１０．０ｍｇ／ ｍｌのＩｇＭ抗体；ｅ．約２ｍＭ−約４ｍＭのカプリル酸ナトリウム；及びｆ． 約２ｍＭ−約４ｍＭのＮ−アセチルトリプロファネートから成ることを特徴とす る配合物。 ２８．第２６項に記載の改良配合物において、凍結真空乾燥して乾燥粉末とし、 その粉末を再生してＩｇＭの注射用溶液とすることができることを特徴とする配 合物。 ２９．２７項に記載の改良配合物において、凍結真空乾燥して乾燥粉末とし、そ の粉末を再生してＩｇＭの注射用溶液とすることができることを特徴とする配合 物。[Claims] 1. I consisting of buffer, human serum albumin, sodium chloride, and IgM antibodies. gM antibody formulation. 2. In the formulation according to paragraph 1, the buffer is phosphate buffer or trometamide. A formulation characterized in that it consists of: 3. In the formulation according to paragraph 2, the phosphate buffer is about 8mM to about 20mM. and a pH of 6.8-7.4. compound. 4. In the formulation of paragraph 2, the concentration of tromethamine is from about 5 to about 100 mM. and a pH of about 8 to about 10. 5. In the formulation according to paragraph 1, the concentration of sodium chloride is about 270mM. A compound characterized by: 6. In the formulation according to paragraph 1, further N-acetyltryptophanate, and sodium caprylate. 7. In the formulation according to paragraph 7, the concentration of N-acetyl triprophanate is about 2mM to about 4mM, and the concentration of sodium caprylate is about 2mM to about 4mM. A formulation characterized in that: 8. In the formulation according to paragraph 1, the concentration of IgM antibody is about 5.0 mg/ml. A formulation characterized by: 9. In the formulation according to paragraph 8, the IgM antibody is a human immunoglobulin. A compound characterized by: 10. In the formulation according to paragraph 1, the IgM antibody is a monoclonal antibody. A compound characterized by: 11. In the formulation of paragraph 1, about 2.5% to about 5% (w/v) human blood. A formulation characterized in that it contains clear albumin. 12. 2. A formulation according to paragraph 1 which has been freeze-vacuum dried. 13. A formulation according to paragraph 12, consisting of a dry powder, which can be reconstituted for injection. A formulation characterized in that it is capable of giving a solution of IgM. 14. In an injectable formulation of IgM: a. Trometami with a pH of about 8 to about 10 about 5mM to about 100mM; b. about 200-about 300mM sodium chloride; c ．． about 2.5-about 5% (w/v) human serum albumin; and d. about 2.5 - about 1 A formulation characterized in that it consists of 0.0 mg/ml IgM antibodies. 15. In the injectable formulation according to paragraph 14, further 2mM-4mM N-A Contains cetyltryptophanate and 2mM-4mM sodium caprylate A compound characterized by: 16. In the formulation according to paragraph 15: a. 45mM tromethamine, pH 8 ．． 5; b. 270mM sodium chloride; c. 2.5% (w/v) human serum albumin; d. 5mg/ml IgM antibody : e. 2mM sodium cabrylate; and f. 2mM N-acetyltriprof A formulation characterized in that it contains a phanate. 17. 17. A formulation according to paragraph 16 which has been freeze-vacuum dried. 18. A formulation according to paragraph 17, consisting of a dry powder, which can be reconstituted for injection. A formulation characterized in that it is capable of giving a solution of IgM. 19. In an injectable formulation of IgM: a. Phosphorus with a pH of about 6.8 to about 7.4 sodium acid about 8mM - about 200mM; b. about 250-about 350 mM sodium chloride; c. About 2.5-about 5% (w/v ) of human serum albumin; and d. about 2.5 to about 10.0 mg/ml IgM anti- A formulation characterized in that it consists of the body. 20. In the injectable formulation according to paragraph 19, further 2mM-4mM N-A Contains cetyltryptophanate and 2mM-4mM sodium caprylate A compound characterized by: 21. In the formulation described by you in Section 20: a. 8mM sodium phosphate, p H7.2;b. 270mM sodium chloride; c. 5.0% (w/v) human serum albumin: d. 5mg/ml IgM antibody ; e. 2mM sodium cabrylate; and f. 2mM N-acetyltriprof A formulation characterized in that it contains a phanate. 22. 22. A formulation according to paragraph 21 which has been freeze-vacuum dried. 23. A formulation according to paragraph 22, consisting of a dry powder and reconstituted for injection. A formulation characterized in that it is capable of giving a solution of IgM. 24. IgM antibodies in an IgM formulation containing buffer, protein, and IgM. Phosphate, or tromethamine buffer, sodium chloride, and human serum albumin A compound whose improvement is that it consists of being combined with. 25. In the improved formulation described in paragraph 24, human serum albumin is Stabilized by tryptophanate and sodium caprylate A compound that 26. In the improved formulation according to paragraph 24: a. Toro with a pH of about 8 to about 10 Methamine about 5mM - about 100mM; b. about 200-about 300mM sodium chloride M;c. about 2.5-about 5% (w/v) human serum albumin; d. approx. 2.5 - approx. 10.0 mg/ml IgM antibody; e. About 2mM - about 4mM Sodium Caprylate um; and f. Consisting of about 2mM - about 4mM N-acetyl triprophanate A compound characterized by: 27. In the improved formulation according to paragraph 24: a. Sodium phosphate approx. 8mM approximately 200mM; b. about 250-about 350 mM sodium chloride; c. Approximately 2.5- Approximately 5.0% (w/v) human serum albumin; d. About 2.5-about 10.0mg/ ml of IgM antibody; e. about 2mM to about 4mM sodium caprylate; and f. characterized by consisting of about 2mM to about 4mM N-acetyl triprophanate formulation. 28. In the improved formulation according to paragraph 26, freeze-vacuum drying to a dry powder; A composition characterized in that the powder can be regenerated into an injectable solution of IgM. Compound. 29. In the improved formulation described in paragraph 27, freeze-vacuum drying to a dry powder; A formulation characterized in that the powder can be regenerated into an injectable solution of IgM. thing.
JP50510090A 1989-03-27 1990-03-13 Formulations for the stabilization of IgM antibodies Pending JPH04504253A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US32857989A 1989-03-27 1989-03-27
US328,579 1989-03-27

Publications (1)

Publication Number Publication Date
JPH04504253A true JPH04504253A (en) 1992-07-30

Family

ID=23281559

Family Applications (1)

Application Number Title Priority Date Filing Date
JP50510090A Pending JPH04504253A (en) 1989-03-27 1990-03-13 Formulations for the stabilization of IgM antibodies

Country Status (4)

Country Link
EP (1) EP0465513A1 (en)
JP (1) JPH04504253A (en)
CA (1) CA2049342A1 (en)
WO (1) WO1990011091A1 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008303176A (en) * 2007-06-07 2008-12-18 Kobayashi Pharmaceut Co Ltd Protein-containing composition
JP2014520535A (en) * 2011-07-05 2014-08-25 ノボザイムス バイオファーマ デーコー アクティーゼルスカブ Albumin preparation and use
JP2017527531A (en) * 2014-10-06 2017-09-21 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Composition comprising carrier and antibody and method for producing and using the same
JP2018523670A (en) * 2015-08-18 2018-08-23 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Carrier binder composition and methods of making and using the same
US10279035B2 (en) 2012-10-01 2019-05-07 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, trastuzumab, and albumin
US10300016B2 (en) 2014-10-06 2019-05-28 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
US10561726B2 (en) 2015-10-06 2020-02-18 Vavotar Life Sciences LLC Methods of treating cancer using compositions of antibodies and carrier proteins with antibody pretreatment
US10618969B2 (en) 2016-04-06 2020-04-14 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
US10765741B2 (en) 2011-05-09 2020-09-08 Mayo Foundation For Medical Education And Research Methods for treating VEGF-expressing cancer using preformed nanoparticle complexes comprising albumin-bound paclitaxel and bevacizumab
US11160876B2 (en) 2016-09-01 2021-11-02 Mayo Foundation For Medical Education And Research Methods and compositions for targeting t-cell cancers
US11241387B2 (en) 2015-08-18 2022-02-08 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
US11285221B2 (en) 2014-06-16 2022-03-29 Mayo Foundation For Medical Education And Research Treating myelomas
US11305020B2 (en) 2016-03-21 2022-04-19 Mayo Foundation For Medical Education And Research Methods for reducing toxicity of a chemotherapeutic drug
US11311631B2 (en) 2016-09-06 2022-04-26 Mayo Foundation For Medical Education And Research Paclitaxel-albumin-binding agent compositions and methods for using and making the same
US11351254B2 (en) 2016-02-12 2022-06-07 Mayo Foundation For Medical Education And Research Hematologic cancer treatments
US11427637B2 (en) 2016-09-06 2022-08-30 Mayo Foundation For Medical Education And Research Methods of treating PD-L1 expressing cancer
US11548946B2 (en) 2016-09-01 2023-01-10 Mayo Foundation For Medical Education And Research Carrier-PD-L1 binding agent compositions for treating cancers
US11571469B2 (en) 2016-01-07 2023-02-07 Mayo Foundation For Medical Education And Research Methods of treating cancer with interferon wherein the cancer cells are HLA negative or have reduced HLA expression
US11590098B2 (en) 2016-09-06 2023-02-28 Mayo Foundation For Medical Education And Research Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins
US11878061B2 (en) 2016-03-21 2024-01-23 Mayo Foundation For Medical Education And Research Methods for improving the therapeutic index for a chemotherapeutic drug

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUT63343A (en) * 1990-07-03 1993-08-30 Akzo Nv Process for producing immunereactive compounds
JPH0565233A (en) * 1991-03-08 1993-03-19 Mitsui Toatsu Chem Inc Monoclonal antibody-containing lyophilized preparation
WO1993006862A1 (en) * 1991-10-11 1993-04-15 Toray Industries, Inc. Antibody composition
ATE146359T1 (en) * 1992-01-21 1997-01-15 Stanford Res Inst Int IMPROVED METHOD FOR PRODUCING MICRONIZED POLYPEPTIDE DRUGS
US6267958B1 (en) 1995-07-27 2001-07-31 Genentech, Inc. Protein formulation
US6171586B1 (en) 1997-06-13 2001-01-09 Genentech, Inc. Antibody formulation
US6991790B1 (en) 1997-06-13 2006-01-31 Genentech, Inc. Antibody formulation
AU2444899A (en) * 1998-01-22 1999-08-09 Astrazeneca Ab Pharmaceutical formulation comprising an antibody and a citrate buffer
IL155002A0 (en) 2000-10-12 2003-10-31 Genentech Inc Reduced-viscosity concentrated protein formulations
US8703126B2 (en) 2000-10-12 2014-04-22 Genentech, Inc. Reduced-viscosity concentrated protein formulations
EP1428537B1 (en) 2001-08-29 2008-11-19 Chugai Seiyaku Kabushiki Kaisha Stabilized preparations containing antibody
WO2003039485A2 (en) 2001-11-08 2003-05-15 Protein Design Labs Stable liquid pharmaceutical formulation of igg antibodies
US20040033228A1 (en) 2002-08-16 2004-02-19 Hans-Juergen Krause Formulation of human antibodies for treating TNF-alpha associated disorders
EP3178492A1 (en) 2003-04-04 2017-06-14 Genentech, Inc. High concentration antibody and protein formulations
US8883146B2 (en) 2007-11-30 2014-11-11 Abbvie Inc. Protein formulations and methods of making same
BRPI1006519A2 (en) 2009-03-06 2016-08-09 Genentech Inc antibody formulation
SG10201903166PA (en) 2010-03-01 2019-05-30 Bayer Healthcare Llc Optimized monoclonal antibodies against tissue factor pathway inhibitor (tfpi)
KR20210128021A (en) 2010-08-23 2021-10-25 얀센 바이오테크 인코포레이티드 Treatment for neoplastic diseases
CN108404127A (en) 2011-09-23 2018-08-17 埃克斯生物科技公司 Cachexia is treated
US9592297B2 (en) 2012-08-31 2017-03-14 Bayer Healthcare Llc Antibody and protein formulations

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1546177A (en) * 1976-11-19 1979-05-16 Biokema Sa Process for the preparation of a stable injectable solution
JPS5822085B2 (en) * 1977-07-19 1983-05-06 株式会社ミドリ十字 Intravenous gamma globulin preparations
DE3875852T2 (en) * 1987-08-10 1993-03-18 Miles Inc CLEANED IGM.

Cited By (54)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008303176A (en) * 2007-06-07 2008-12-18 Kobayashi Pharmaceut Co Ltd Protein-containing composition
US10765741B2 (en) 2011-05-09 2020-09-08 Mayo Foundation For Medical Education And Research Methods for treating VEGF-expressing cancer using preformed nanoparticle complexes comprising albumin-bound paclitaxel and bevacizumab
US10844349B2 (en) 2011-07-05 2020-11-24 Albumedix Ltd. Albumin formulation and use
JP2014520535A (en) * 2011-07-05 2014-08-25 ノボザイムス バイオファーマ デーコー アクティーゼルスカブ Albumin preparation and use
US10376580B2 (en) 2012-10-01 2019-08-13 Mayo Foundation For Medical Education And Research Methods of treating cancer with antibody-albumin nanoparticle complexes comprising albumin, trastuzumab, and paclitaxel
US10376579B2 (en) 2012-10-01 2019-08-13 Mayo Foundation For Medical Education And Research Nanoparticle complexes of albumin, paclitaxel, and anti-VEGF antibody for treatment of cancer
US10279035B2 (en) 2012-10-01 2019-05-07 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, trastuzumab, and albumin
US10493150B2 (en) 2012-10-01 2019-12-03 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, alemtuzumab, and albumin
US10307482B2 (en) 2012-10-01 2019-06-04 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, cetuximab, and albumin
US10668151B2 (en) 2012-10-01 2020-06-02 Mayo Foundation For Medical Education And Research Nanoparticle complexes of albumin, paclitaxel, and panitumumab for treatment of cancer
US10507243B2 (en) 2012-10-01 2019-12-17 Mayo Foundation For Medical Education And Research Nanoparticle complexes of rituximab, albumin and pacltaxel
US10279036B2 (en) 2012-10-01 2019-05-07 Mayo Foundation For Medical Education And Research Antibody-albumin nanoparticle complexes comprising albumin, bevacizumab, and paclitaxel, and methods of making and using the same
US11648311B2 (en) 2012-10-01 2023-05-16 Mayo Foundation For Medical Education And Research Cancer treatments
US10406224B2 (en) 2012-10-01 2019-09-10 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, trastuzumab, and albumin
US10413606B2 (en) 2012-10-01 2019-09-17 Mayo Foundation For Medical Education And Research Methods for treating cancer with nanoparticle complexes of albumin-bound paclitaxel and anti-VEGF antibodies
US10420839B2 (en) 2012-10-01 2019-09-24 Mayo Foundation For Medical Education And Research Methods for treating CD52-expressing cancers using compositions comprising nanoparticle complexes of paclitaxel, alemtuzumab, and albumin
US10441656B2 (en) 2012-10-01 2019-10-15 Mayo Foundation For Medical Education And Research Nanoparticle complexes of paclitaxel, cetuximab, and albumin, and methods of making the same
US10471145B2 (en) 2012-10-01 2019-11-12 Mayo Foundation For Medical Education And Research Methods for treating cancer using nanoparticle complexes of paclitaxel, rituximab, and albumin
US10478495B2 (en) 2012-10-01 2019-11-19 Mayo Foundation For Medical Education And Research Methods for treating cancer using nanoparticle complexes of paclitaxel, cetuximab, and albumin
US11285221B2 (en) 2014-06-16 2022-03-29 Mayo Foundation For Medical Education And Research Treating myelomas
US10624846B2 (en) 2014-10-06 2020-04-21 Mayo Foundation For Medical Education And Research Lyophilized compositions comprising albumin-antibody paclitaxel nanoparticle complexes
US11433023B2 (en) 2014-10-06 2022-09-06 Mayo Foundation For Medical Education And Research Albumin-PD-1 paclitaxel nanoparticle complex compositions and methods of making and using the same
US10596111B2 (en) 2014-10-06 2020-03-24 Mayo Foundation For Medical Education And Research Methods of making lyophilized compositions comprising albumin-VEGF paclitaxel nanoparticle complexes
US10596112B2 (en) 2014-10-06 2020-03-24 Mayo Foundation For Medical Education And Research Methods of using albumin-antibody nanoparticle complex compositions for treating cancer
US10610484B2 (en) 2014-10-06 2020-04-07 Mayo Foundation For Medical Education And Research Methods of using albumin-CD20 paclitaxel nanoparticle complex compositions for treating cancer
JP2017527531A (en) * 2014-10-06 2017-09-21 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Composition comprising carrier and antibody and method for producing and using the same
US10391055B2 (en) 2014-10-06 2019-08-27 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
US10322084B2 (en) 2014-10-06 2019-06-18 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
JP2019081768A (en) * 2014-10-06 2019-05-30 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Compositions comprising carriers and antibodies, methods of making and using the same
US10772833B2 (en) 2014-10-06 2020-09-15 Mayo Foundation For Medical Education And Research Albumin-CTLA-4 paclitaxel nanopartilce complex compositions and methods of making and using the same
US10780049B2 (en) 2014-10-06 2020-09-22 Mayo Foundation For Medical Education And Research Lyophilized compositions comprising albumin-rankl or albumin-GD2 paclitaxel nanoparticle complexes
US10780050B2 (en) 2014-10-06 2020-09-22 Mayo Foundation For Medical Education And Research Lyophilized compositions comprosing albumin-EGFR paclitaxel nanoparticle complexes
US10300016B2 (en) 2014-10-06 2019-05-28 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
US10966923B2 (en) 2014-10-06 2021-04-06 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
JP2021059593A (en) * 2014-10-06 2021-04-15 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Carrier-antibody compositions and methods of making and using the same
US10993912B2 (en) 2014-10-06 2021-05-04 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
US10993911B2 (en) 2014-10-06 2021-05-04 Mayo Foundation For Medical Education And Research Carrier-antibody compositions and methods of making and using the same
US11241387B2 (en) 2015-08-18 2022-02-08 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
JP2018523670A (en) * 2015-08-18 2018-08-23 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Carrier binder composition and methods of making and using the same
JP2021075579A (en) * 2015-08-18 2021-05-20 マヨ ファウンデーション フォー メディカル エデュケーション アンド リサーチＭａｙｏ Ｆｏｕｎｄａｔｉｏｎ Ｆｏｒ Ｍｅｄｉｃａｌ Ｅｄｕｃａｔｉｏｎ Ａｎｄ Ｒｅｓｅａｒｃｈ Carrier-binding agent compositions and methods for making and using same
US10561726B2 (en) 2015-10-06 2020-02-18 Vavotar Life Sciences LLC Methods of treating cancer using compositions of antibodies and carrier proteins with antibody pretreatment
US11660339B2 (en) 2015-10-06 2023-05-30 Mayo Foundation For Medical Education And Research Methods of treating cancer using compositions of antibodies and carrier proteins with antibody pretreatment
US11571469B2 (en) 2016-01-07 2023-02-07 Mayo Foundation For Medical Education And Research Methods of treating cancer with interferon wherein the cancer cells are HLA negative or have reduced HLA expression
US11351254B2 (en) 2016-02-12 2022-06-07 Mayo Foundation For Medical Education And Research Hematologic cancer treatments
US11305020B2 (en) 2016-03-21 2022-04-19 Mayo Foundation For Medical Education And Research Methods for reducing toxicity of a chemotherapeutic drug
US11878061B2 (en) 2016-03-21 2024-01-23 Mayo Foundation For Medical Education And Research Methods for improving the therapeutic index for a chemotherapeutic drug
US10618969B2 (en) 2016-04-06 2020-04-14 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
US11655301B2 (en) 2016-04-06 2023-05-23 Mayo Foundation For Medical Education And Research Carrier-binding agent compositions and methods of making and using the same
US11548946B2 (en) 2016-09-01 2023-01-10 Mayo Foundation For Medical Education And Research Carrier-PD-L1 binding agent compositions for treating cancers
US11160876B2 (en) 2016-09-01 2021-11-02 Mayo Foundation For Medical Education And Research Methods and compositions for targeting t-cell cancers
US11427637B2 (en) 2016-09-06 2022-08-30 Mayo Foundation For Medical Education And Research Methods of treating PD-L1 expressing cancer
US11311631B2 (en) 2016-09-06 2022-04-26 Mayo Foundation For Medical Education And Research Paclitaxel-albumin-binding agent compositions and methods for using and making the same
US11590098B2 (en) 2016-09-06 2023-02-28 Mayo Foundation For Medical Education And Research Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins
US11872205B2 (en) 2016-09-06 2024-01-16 Mayo Foundation For Medical Education And Research Methods of treating triple-negative breast cancer using compositions of antibodies and carrier proteins

Also Published As

Publication number Publication date
CA2049342A1 (en) 1990-09-28
EP0465513A1 (en) 1992-01-15
WO1990011091A1 (en) 1990-10-04

Similar Documents

Publication Publication Date Title
JPH04504253A (en) Formulations for the stabilization of IgM antibodies
JP6952019B2 (en) Immunoglobulin single variable domain stable preparation and its use
Garratty Immune hemolytic anemia associated with drug therapy
RU2322980C2 (en) Piperacillin and tazobactam-containing compositions used for injection
EP0417193B1 (en) Freeze-dried formulation for antibody products
JP4948407B2 (en) Stabilization formula
US6900184B2 (en) Compositions containing pipercillin and tazobactam useful for injection
UA82685C2 (en) Stable aqueous pharmaceutical formulation of natalyzumab and method for its obtaining
JPS6191131A (en) Method and composition for preventing adsorption of pharmaceutical
US4276050A (en) Method for systemic endotoxin detection
EP0417191A1 (en) Formulation for antibody reagents.
JPH11510170A (en) Protein Formula
BR112016008576B1 (en) STABLE AQUEOUS FORMULATIONS OF ANTIBODIES AND PHARMACEUTICAL UNIT DOSAGE FORM
US4439421A (en) Stabilized gamma globulin concentrate
CN111110638B (en) Protein-coupled microsphere freeze-dried preparation and preparation method and storage mode thereof
WO2004098643A1 (en) Compositions containing piperacillin and tazobactam useful for injection
Pressman et al. The nature of the combining sites of antibodies: the specific protection of the combining site by hapten during iodination
CN113521018B (en) Freeze-dried composition containing anti-HER 2-drug conjugate, freeze-dried preparation, preparation method and application thereof
Garratty et al. Positive direct antiglobulin tests and haemolytic anaemia following therapy with beta‐lactamase inhibitor containing drugs may be associated with nonimmunologic adsorption of protein onto red blood cells
Linkuvienė et al. Effects of transportation of IV bags containing protein formulations via hospital pneumatic tube system: particle characterization by multiple methods
CZ2004189A3 (en) The title is not available
Van Furth et al. Opsonic and physicochemical characteristics of intravenous immunoglobulin preparations
Walter et al. Membrane surface properties of reticulocytes from rats rendered severely anemic with phenylhydrazine as determined by partition in aqueous phase systems
Arvinte et al. The formulation of biological molecules
Williams et al. Vancomycin‐induced red cell aggregation