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WO1999045953A1 - Compositions contenant un cofacteur ii de l'heparine et techniques de stabilisation - Google Patents

Compositions contenant un cofacteur ii de l'heparine et techniques de stabilisation Download PDF

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Publication number
WO1999045953A1
WO1999045953A1 PCT/JP1999/001102 JP9901102W WO9945953A1 WO 1999045953 A1 WO1999045953 A1 WO 1999045953A1 JP 9901102 W JP9901102 W JP 9901102W WO 9945953 A1 WO9945953 A1 WO 9945953A1
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WO
WIPO (PCT)
Prior art keywords
hcii
composition
heparin cofactor
nonionic surfactant
adjuster
Prior art date
Application number
PCT/JP1999/001102
Other languages
English (en)
Japanese (ja)
Inventor
Naomi Asahara
Takashi Goto
Akimasa Omizu
Yahiro Uemura
Original Assignee
Welfide Corporation
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 Welfide Corporation filed Critical Welfide Corporation
Priority to AU27463/99A priority Critical patent/AU2746399A/en
Publication of WO1999045953A1 publication Critical patent/WO1999045953A1/fr

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Classifications

    • 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
    • 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
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention relates to a stable composition containing heparin cofactor II (hereinafter, referred to as “HCII”) and a method for stabilizing an HCII-containing composition.
  • HCII heparin cofactor II
  • HCII like antithrombin III (hereinafter referred to as ⁇ ), is an important anticoagulant protein existing in the body (Matsuo et al .: Biomedical Perspectives, 2, 269-274 (1993)), and its molecular weight is According to SDS polyacrylamide gel electrophoresis (SDS-PAGE) analysis, it is a single-chain plasma glycoprotein of 72 kDa (Dougls M. Toll fsen et al .: J. Biol. Chemistry, 257, 2162-2169 (1982) ).
  • HCII As a physiological function of HCII, it is known that it inhibits proteases such as thrombin, but it has a different site of action from ⁇ and seems to function as a thrombin inhibitor outside the blood vessel rather than inside the blood vessel . Therefore, since HCII exhibits an anticoagulant effect in specific organs, tissues or cells, the present inventors have found that systemic administration of HCII to veins, arteries and the like may cause sepsis, diseases causing abnormal blood flow, They found that they were effective in preventing and treating diseases such as organ disorders such as liver, lung, kidney, and brain, and filed a patent application (Japanese Patent Application Laid-Open No. 9-176040).
  • HCII is also effective for the treatment of a disease caused by abnormal dysfunction of cells in a living body such as macrophages and the like, and is effective in treating the disease.
  • the application was filed on October 10, 19197 7, with a filing date of July 7, 1998).
  • a pharmaceutical composition containing HCII as an active ingredient is expected to be useful as a pharmaceutical.
  • an HCII-containing pharmaceutical composition actually suitable for use as a medicament has not yet been marketed.
  • the problems of the stability of the HCII-containing composition include a decrease in the activity of HCII, polymerization of HCII, and insolubility. It has been found that product formation can occur. Decreased activity of HC II is highly correlated with polymerization of HC II, but even when HC II activity is not reduced, production of polymerized HC II may be observed. Polymerized HCII is generally inactive and administration of HCII polymers may cause undesirable side effects such as shock and hypotension. In addition, shaking of the HCII-containing composition or the like may cause insolubles to be generated together with the decrease in the activity of HCII, which poses a problem as a pharmaceutical composition.
  • the HCII-containing composition it is desired to suppress the reduction of the activity of HCII, the polymerization of HCII, the generation of insolubles, and the like, and to stabilize the composition.
  • Such a problem relating to the stability of the HC II-containing composition has not been studied so far, and the present invention itself is novel.
  • the pH of the HCII-containing composition is 6 to 12, preferably 6 to 10, more preferably 6.5 to 10, and particularly preferably 6.5 to 10. ?
  • HC II activity reduction and HC II polymerization could be suppressed.
  • the present inventors have also found that by adding a nonionic surfactant to the HCII-containing composition, a decrease in the activity of HCII can be suppressed, and generation of insolubles can be suppressed.
  • the present inventors have found that by setting the storage temperature of the HCII-containing composition to 37 or lower, it is possible to suppress the decrease in HCII activity and the polymerization of HCII.
  • the present invention relates to the following.
  • An H C II-containing composition comprising a pH adjuster.
  • An HC II-containing composition comprising a nonionic surfactant.
  • An H C II-containing composition comprising a pH adjuster and a nonionic surfactant.
  • nonionic surfactant is at least one selected from the group consisting of polyalkylene glycol, polyoxyethylene-polyoxypropylene copolymer and polyoxyethylene sorbitan fatty acid ester.
  • the composition containing HC II according to any one of the above.
  • a method for stabilizing an HCII-containing composition comprising adding a pH adjuster to the HCII-containing composition.
  • a method for stabilizing an HCII-containing composition which comprises adding a nonionic surfactant to the HCII-containing composition.
  • a method for stabilizing an HCII-containing composition comprising adding a pH adjuster and a nonionic surfactant to the HCII-containing composition.
  • nonionic surfactant is at least one selected from the group consisting of polyalkylene glycols, polyoxyethylene-polyoxypropylene copolymers and polyoxyethylene sorbitan fatty acid esters. the method of.
  • a method for storing an HCII-containing composition comprising storing the HCII-containing composition according to any one of the above (1) to (14) at a temperature of 37 ° C or lower.
  • the present invention also provides an injection kit described in the following (i) to (iii) c
  • An injection kit comprising at least the following components (a) and (b):
  • a lyophilized composition comprising HCII and a pH adjuster, wherein the pH adjuster brings the pH of the solution to 6 to 10 when the composition is dissolved in an injectable aqueous solvent.
  • a lyophilized composition that can be adjusted,
  • an injection kit comprising at least the following components (c) and (d):
  • An injection kit comprising at least the following components (e) and (ii):
  • a lyophilized composition comprising a non-ionic surfactant and a pH adjuster, wherein the pH adjuster comprises a pH of the solution when the composition is dissolved in an injectable aqueous solvent.
  • a lyophilized composition capable of adjusting H to 6 to 10,
  • the method for stabilizing the HCII-containing composition includes a method for suppressing a decrease in the activity of HCII, a method for suppressing the polymerization of HCII, a method for suppressing the generation of insolubles in the composition, and the like. Is included.
  • HCII in the HCII-containing composition of the present invention shows a single band visually at a position of a molecular weight of about 72 kDa by SDS-PAGE, has an isoelectric point of about 5, and has thrombin, chymotrypsin and cathepsin.
  • a protein having a G inhibitory action Therefore, the HCII of the present invention is not necessarily limited to a full-length molecule as long as the above properties are satisfied.
  • the origin of HCII is not particularly limited, and includes both those derived from natural plasma and those derived from recombinant host cells genetically engineered to produce HCII.
  • plasma-derived substances include, for example, whole plasma, plasma fraction having high HCII activity, preferably purified from Eff.I, Eff.11 + III or Fr.IV, particularly waste fraction in ATIII purification. Things.
  • the biological origin of the plasma is not particularly limited, and may be derived from humans, but is preferably derived from humans.
  • HCII contained in HCII-containing fractions of cultures obtained by culturing host cells transformed with the transferred genes for example, those purified from culture solutions, cell extracts, culture supernatants and the like.
  • the host cell is not particularly limited, but preferably includes bacteria such as Escherichia coli, Bacillus subtilis, and lactic acid bacteria, fungi such as yeast, animal and plant cells, and insect cells.
  • HCII derived from a recombinant host cell examples include natural HCII (for example, Blinder et al., Biochemistry, 27: 752-759, 1988) or mutant HCII having retained or improved antithrombin activity (for example, Examples thereof include those produced by culturing host cells transformed with a recombinant vector containing DNA encoding the DNA encoding E. coli (see 3-139280).
  • the method of purifying HCII is not particularly limited.
  • the method of Blinder et al. J. Biol. Chem., Vol. 264, 5128-5133, 1989
  • the method described in JP-A-9-286797, international Application No. PC TZ JP 98/04939 filamenting date: October 30, 1998)
  • Method for obtaining HCII-containing composition from which depolymerizing factors Pla or host cell-derived protease, etc.
  • the method described in the Japanese patent application Japanese Patent Application No. 11-10911, filed on Jan. 19, 1999
  • the HCII crude product is brought into contact with an insoluble carrier having a hydrophobic group as a ligand to obtain a salt concentration.
  • an HCII-containing composition from which contaminating proteins derived from HCII have been removed by treating with a buffer solution having a different pH. Further, these purification methods can be appropriately combined.
  • the HCII-containing composition of the present invention may be any composition as long as it contains HCII, and may be in the form of a lyophilized composition or a liquid composition.
  • the HCII-containing composition of the present invention also includes a final preparation of an administrable drug, a composition during a manufacturing process of a pharmaceutical formulation, and a composition during a purification process of HC II.
  • HCII-containing composition of the present invention c present invention to provide an HC II containing composition characterized by containing a p H adjusting agent pH6 ⁇ l 2, preferably pH6 ⁇ l 0, favored more Or pH 6.5-1 to 10. Particularly preferably, the pH is adjusted to pH 7 to 10.
  • a suitable solvent such as an injectable aqueous solvent
  • the pH of the solution when dissolved in a suitable solvent is pH 6 to 12, preferably pH 6 to 10, and more preferably.
  • a suitable solvent such as an injectable aqueous solvent
  • Adjustment of pH can be performed using a pH adjusting agent.
  • the pH adjuster used in the present invention may be any as long as it can adjust the pH of the composition to pH 6 to 12.
  • the pH adjuster is capable of adjusting the pH of the composition to preferably pH 6 to 10, more preferably pH 6.5 to 10, and particularly preferably pH 7 to 10.
  • a buffer is usually used.
  • the buffer include a phosphate buffer (sodium phosphate buffer), a citrate buffer, a Tris-HCl buffer, a getylethanolamine chloride buffer, and the like.
  • a phosphate buffer (sodium phosphate buffer) and a tris-HCl buffer are used.
  • the concentration of the pH adjusting agent in the composition is usually 0.001 to 100 mM, preferably 0.1 to 10 OmM in the case of a liquid composition.
  • a suitable solvent such as an injectable aqueous solvent
  • suitable solvents for dissolving the lyophilized composition include sterile, injectable aqueous solvents free of pyrogenic substances, etc. Specifically, distilled water for injection, injection Physiological saline and the like.
  • the HC II-containing composition is a lyophilized composition
  • HC adjusted to 156 to 12, preferably pH 6 to 10, more preferably pH 6.5 to 10, and particularly preferably pH 7 to 10 with 11 regulators
  • the II-containing solution is prepared by lyophilization. When used, it is dissolved in a suitable solvent (for example, distilled water for injection, etc.) and the pH is adjusted to pH 6 to 12, preferably pH 6 to 10, more preferably pH 6.5 to 10, and particularly preferably pH 7 to 10.
  • a liquid composition is obtained.
  • the HC II-containing composition is a liquid composition
  • 15 15 (: 11 is about 0.01 to about 400 U
  • It can be prepared as a solution containing Zml, preferably from about 0.1 to about 100 UZml.
  • an appropriate solvent for example, distilled water for injection
  • the polymerized HCII means a polymer of HCII molecules. More specifically, it is a dimer or higher polymer.
  • the present invention also provides an H C II-containing composition comprising a nonionic surfactant.
  • a nonionic surfactant By including a nonionic surfactant, it is possible to suppress a decrease in the activity of HCII and to suppress the generation of insolubles.
  • nonionic surfactant examples include polyalkylene glycol [eg, polyethylene glycol (PEG), polypropylene glycol, etc.], polyoxyethylene-polyoxypropylene copolymer [eg, Poloxamer (trade name: Pluronic)], poly Oxyethylene sorbitan fatty acid esters [for example, polysorbate (trade name: Vienna)] and the like are exemplified.
  • the average molecular weight of these nonionic surfactants is preferably from 2,000 to 20,000.
  • Fatty acids of polyoxyethylene sorbitan fatty acid esters include fatty acids having 12 to 18 carbon atoms such as stearic acid, palmitic acid, myristic acid, lauric acid, and oleic acid.
  • nonionic surfactant examples include PEG having an average molecular weight of 4000 to 600 (for example, PEG4000, PEG6000), poloxamer 188 (trade name: Pull mouth nick F 68), polysorbate 80 ( Brand name Tween 80). More preferably, it is PEG (for example, PEG4000, PEG600).
  • the concentration of the nonionic surfactant in the composition is usually 0.001 to 2.0 w / v%, preferably 0.01 to: L. 0 w / v% for a liquid composition. More preferably, it is 0.02 to 5 w / v%.
  • a suitable solvent for example, distilled water for injection
  • the liquid composition is preferably pH 6 to l2, more preferably a pH adjuster as described above. It is adjusted to pH 6-10, particularly preferably pH 6.5-10, most preferably pH 7-10.
  • the H C II-containing composition is a lyophilized composition
  • it is prepared by lyophilizing an aqueous solution containing H C II and a nonionic surfactant.
  • HCII and non-hydrochloric acid are adjusted to pH 6 to 12, more preferably pH 6 to 10, particularly preferably pH 6.5 to 10, most preferably pH 7 to 10 with a pH adjusting agent as described above.
  • An aqueous solution containing an ionic surfactant is prepared by freeze-drying.
  • a liquid composition is obtained by dissolving in an appropriate solvent (for example, distilled water for injection).
  • the HC II-containing composition When the HC II-containing composition is a liquid composition, it can be prepared in the same manner as described above, as a solution containing 11 ⁇ 11 in an amount of about 0.01 to about 400 UZml, preferably about 0.11 to about 100 UZml. In the case of a lyophilized composition, it is prepared so that the HCII concentration in the solution when dissolved in an appropriate solvent (for example, distilled water for injection, etc.) at the time of use is in the same concentration range as the above liquid composition.
  • an appropriate solvent for example, distilled water for injection, etc.
  • the above-described HC II-containing composition of the present invention can maintain the stability of the HC II-containing composition, particularly when the storage temperature is 37 ° C. or less.
  • the storage temperature is preferably -20 to 37 ⁇ , more preferably 0 to 15.
  • the HCII-containing composition of the present invention may contain additives used in ordinary pharmaceutical compositions, for example, tonicity agents (eg, sucrose, sorbitol, mannitol, glycerin, glucose, sodium chloride, etc.), preservatives and disinfectants [For example, benzalkonium chloride, benzethonium chloride, paraoxybenzoic acid esters (eg, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate), benzyl alcohol, parachlorometoxylenol, -, Phenethyl alcohol, sorbic acid or its salt, thimerosal, black butanol, etc.), chelating agents (sodium edetate, etc.), thickeners (polyvinyl Loridone, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, sodium polyacryl
  • the H C II-containing composition of the present invention can be prepared by a method known per se. If desired, treatments such as heating, sterilization, virus inactivation, sterilization filtration, virus removal, aliquoting, and freeze-drying can be performed.
  • the HCII-containing composition of the present invention can also be provided as an injection kit comprising the above lyophilized composition and an injectable aqueous solution.
  • the HCII-containing composition of the present invention includes various diseases causing abnormal blood flow such as thrombosis, microcirculation failure, ischemic disease, sepsis, various organ dysfunctions such as liver, lung, kidney, and brain, glomerulonephritis, ⁇ It is useful for the prevention and treatment of various inflammations such as inflammation accompanied by inflammation and edema formation.
  • the HCII-containing composition of the present invention is preferably administered parenterally as an injection or infusion.
  • the administration method of the HCII-containing composition of the present invention includes a method of intravenous injection or intravenous drip infusion.
  • the dose of the HCII-containing composition of the present invention is generally 1 to 1000 OU / kg body weight, preferably 10 to 200 OUZ kg body weight per day for an adult, and this amount is administered once or divided into several times. be able to.
  • HCII of the purified product PD- 1 0 column (Pharmacia, Inc.) 5 mM tri scan HCl buffer with (pH 8. 0, 25) after desalting, the absorbance at 280 nm at each buffer (A 28 ) Force was adjusted to be 0, and the stability was examined.
  • HCII activity and polymerization HCII ratio was measured by the following method. (1) Measurement of HC II activity
  • the sample was diluted with 40 mM Tris buffer (pH 8.56) containing 60 mM EDTA, 0.2% human serum albumin (HSA) and 0.1 mg / mL dermatan sulfate.
  • the protein concentration of 0.1 mg mgZmL obtained from the above was defined as 1 U].
  • the HCII activity was calculated from the prepared calibration curve.
  • the ratio of the polymerized HC II is shown as a ratio (%) of the area of the peak detected on the polymer side from the peak of the full-length HC II in the gel filtration HPLC analysis to the total peak area.
  • pH 66 HCII is stable at I 0, since no increase in polymerized HCII and no decrease in HCII activity is observed.
  • HCII A 28 in 0.1 M Tris-HCl buffer (at pH 8.0, 25) containing 0.1 wZv% polyethylene glycol 4000. 1.0.
  • the HCII solution was horizontally shaken at 125 rpm for 1 hour at room temperature, and subsequently shaken for 1 minute at room temperature with a vortex mixer.
  • HCII solution was prepared with a 10 mM sodium phosphate buffer (pH 7.2) containing 0.15 M sodium chloride so that the HCII was 50 U / ml. 10 ml of this solution was dispensed into glass vials for pharmaceuticals and freeze-dried to prepare a freeze-dried preparation.
  • the HCII solution was prepared with 1 OmM sodium phosphate buffer (pH 7.2) containing 0.15 M sodium chloride so that HCII was 10 to 50 U / ml.
  • a liquid preparation was prepared by dispensing 10 ml of this solution into a glass vial for pharmaceuticals.
  • HCII solution with 1 OmM sodium phosphate buffer (pH 7.2) containing 0.15 M sodium chloride and 0.1 w / v% polyethylene glycol 4,000 so that HCII is 5 OU / m1.
  • 10 ml of this solution is Dispensed into glass vials and lyophilized to prepare a lyophilized formulation.
  • HCII solution 10 mM sodium phosphate buffer containing 0.15 M sodium chloride and 0.1 w / v% polyethylene glycol 4,000 so that HCII is 10-50 U / m1 (PH 7.
  • the HCII solution was prepared in 2).
  • a liquid preparation was prepared by dispensing 10 ml of this solution into a glass vial for pharmaceuticals.
  • An injection kit comprising the lyophilized preparation prepared in Preparation Example 1 and 10 ml of distilled water for injection was prepared.
  • An injection is prepared by dissolving the lyophilized formulation in distilled water for injection.
  • An injection kit comprising the lyophilized preparation prepared in Preparation Example 3 and 10 ml of distilled water for injection was prepared.
  • An injection is prepared by dissolving the lyophilized formulation in distilled water for injection.
  • 11 of the ⁇ 111-containing composition is adjusted to ⁇ 16 ⁇ 12, preferably pH 6 ⁇ : 10, more preferably pH 6.5 ⁇ 10, particularly preferably pH 7 ⁇ 10.
  • a nonionic surfactant added to the H C II-containing composition, a decrease in the activity of H C II can be suppressed, and the generation of insolubles can be suppressed.
  • HCII-containing composition of the present invention by setting the storage temperature of the HCII-containing composition of the present invention to 37X: or less, it is possible to suppress the decrease in HCII activity and the polymerization of HCII.
  • ADVANTAGE OF THE INVENTION According to this invention, HCII containing composition excellent in stability which suppressed HCII activity fall, polymerization of HCII, and generation

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Abstract

Cette invention, qui a trait à des compositions stables contenant un cofacteur II de l'héparine (HCII), concerne plus particulièrement des compositions contenant un cofacteur II de l'héparine refermant des agents régulateurs comme agents de stabilisation. Ces compositions contenant un cofacteur II de l'héparine se caractérisent par le fait que leur pH est ajusté de 6 à 12, de préférence de 6 à 10, et mieux encore de 6,5 à 10, par ledit agent de régulation du pH. Elle porte également sur des compositions contenant un cofacteur II de l'héparine qui renferment comme stabilisateur un tensioactif non ionique. On note, dans ces compositions contenant un cofacteur II de l'héparine, une diminution de l'activité HCII, une inhibition de la polymérisation de HCII et de la formation de substances insolubles, ce qui permet d'atteindre une stabilité élevée.
PCT/JP1999/001102 1998-03-09 1999-03-05 Compositions contenant un cofacteur ii de l'heparine et techniques de stabilisation WO1999045953A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27463/99A AU2746399A (en) 1998-03-09 1999-03-05 Heparin cofactor ii-containing compositions and method for stabilizing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/56445 1998-03-09
JP5644598 1998-03-09

Publications (1)

Publication Number Publication Date
WO1999045953A1 true WO1999045953A1 (fr) 1999-09-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003342193A (ja) * 2002-05-30 2003-12-03 Otsuka Pharmaceut Co Ltd 注射用製剤
WO2004075913A1 (fr) * 2003-02-28 2004-09-10 Chugai Seiyaku Kabushiki Kaisha Preparation stabilisee contenant une proteine
JP2005511520A (ja) * 2001-10-05 2005-04-28 ビスカム・アーゲー 組換え炭水化物結合ポリペプチドの安定型凍結乾燥生薬製剤

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03139280A (ja) * 1989-10-20 1991-06-13 Washington Univ 修飾へパリンコファクター２
WO1994022471A1 (fr) * 1993-04-05 1994-10-13 The Green Cross Corporation Preparation liquide d'antithrombine iii et procede pour sa stabilisation
JPH09176040A (ja) * 1995-12-27 1997-07-08 Green Cross Corp:The ヘパリンコファクターｉｉの医薬用途
JPH09286797A (ja) * 1996-04-18 1997-11-04 Green Cross Corp:The ヘパリンコファクターｉｉ及びその精製方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03139280A (ja) * 1989-10-20 1991-06-13 Washington Univ 修飾へパリンコファクター２
WO1994022471A1 (fr) * 1993-04-05 1994-10-13 The Green Cross Corporation Preparation liquide d'antithrombine iii et procede pour sa stabilisation
JPH09176040A (ja) * 1995-12-27 1997-07-08 Green Cross Corp:The ヘパリンコファクターｉｉの医薬用途
JPH09286797A (ja) * 1996-04-18 1997-11-04 Green Cross Corp:The ヘパリンコファクターｉｉ及びその精製方法

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005511520A (ja) * 2001-10-05 2005-04-28 ビスカム・アーゲー 組換え炭水化物結合ポリペプチドの安定型凍結乾燥生薬製剤
JP2003342193A (ja) * 2002-05-30 2003-12-03 Otsuka Pharmaceut Co Ltd 注射用製剤
JP4610154B2 (ja) * 2002-05-30 2011-01-12 大塚製薬株式会社 注射用製剤
WO2004075913A1 (fr) * 2003-02-28 2004-09-10 Chugai Seiyaku Kabushiki Kaisha Preparation stabilisee contenant une proteine
JPWO2004075913A1 (ja) * 2003-02-28 2006-06-01 中外製薬株式会社 タンパク質含有安定化製剤
AU2004216298B2 (en) * 2003-02-28 2009-04-23 Chugai Seiyaku Kabushiki Kaisha Stabilized protein-containing formulations
US8765124B2 (en) 2003-02-28 2014-07-01 Chugai Seiyaku Kabushiki Kaisha Stabilized preparation containing protein
US9968677B2 (en) 2003-02-28 2018-05-15 Chugai Seiyaku Kabushiki Kaisha Stabilized protein-containing formulations

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