WO2000015241A1 - Preparation d'une solution proteinique et son procede de stabilisation - Google Patents

Preparation d'une solution proteinique et son procede de stabilisation Download PDF

Info

Publication number
WO2000015241A1
WO2000015241A1 PCT/JP1999/004925 JP9904925W WO0015241A1 WO 2000015241 A1 WO2000015241 A1 WO 2000015241A1 JP 9904925 W JP9904925 W JP 9904925W WO 0015241 A1 WO0015241 A1 WO 0015241A1
Authority
WO
WIPO (PCT)
Prior art keywords
solution preparation
protein
protein solution
container
preparation according
Prior art date
Application number
PCT/JP1999/004925
Other languages
English (en)
Japanese (ja)
Inventor
Nobuyuki Suzuki
Naoki Mitsui
Takaya Hiraishi
Yoshirou Watanabe
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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 Chugai Seiyaku Kabushiki Kaisha filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to AU56492/99A priority Critical patent/AU5649299A/en
Publication of WO2000015241A1 publication Critical patent/WO2000015241A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • 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
    • A61K9/08—Solutions

Definitions

  • the present invention relates to a long-term stable protein solution preparation which is easy to handle. Furthermore, the present invention relates to a stable protein solution preparation pre-filled in a resin container. The invention further relates to a method for stabilizing a protein solution formulation. Background art
  • protein solution preparations contain diluents, solubilizers, isotonic agents, excipients, pH adjusters, buffers, sulfur-containing reducing agents, antioxidants, etc., in addition to the active ingredient protein. It is offered to the market in containers such as vials, ampoules or disposable syringes. Such containers should satisfy the following conditions: (1) the protein preparation is stable under long-term storage; (2) heat resistance and pressure resistance that can withstand the conditions used for sterilization; (4) that the container fragments do not mix into the solution preparation during use; (5) if the container is a syringe, the plunger has good sliding properties; (6) the solution It must be transparent so that turbidity can be detected, and (7) it is convenient for transportation.
  • Glass containers are excellent in terms of heat resistance, pressure resistance, chemical resistance, and transparency, but they require complicated work such as applying or baking a surface treatment agent such as silicon, which is costly. In addition, glass containers are heavy and fragile, which poses a transportation problem. Also, when protein is used as a solution formulation, it is especially important to store proteins at room temperature for a long time. A major problem was that the protein was degraded to lower the protein content. Therefore, the development of protein solution preparations that can be stored at room temperature for a long period of time is desired.However, none satisfying all of the above requirements has been developed, and at present, they are supplied to the market by filling them in resin containers in advance. No protein preparation has been identified.
  • the present inventors have examined the reactivity of proteins with glass surfaces, and found that polar residues such as silanol and silyloxy, which are originally present on the surface of glass materials, are the main causes of the degradation and association of proteins having biological activity.
  • Conventional methods for reducing the effects of these polar residues include the application of polysilicon or alkyl silicon to the glass surface, or the chemical masking of silanol residues. But it was not an essential means of improving stability.
  • the present inventors have found that, particularly when the protein is erythropoietin (EPO), the affinity of the protein solution with the container surface comes into contact, and the pure phase on the glass surface, that is, the stationary phase, has an affinity group. If filled, the hydrophilic portion of the protein would be distributed in large amounts, and this might lead to a decrease in stability. Based on this hypothesis, if the container surface is different from the glass surface and has a hydrophobic reversed phase with no polar residues, the fat-soluble residues of the protein will be distributed more, causing degradation and association. It was expected that the polar part of the protein in the opposite direction to the container surface would greatly contribute to the improvement of the stability of the protein.
  • EPO erythropoietin
  • the present inventors have discovered that by selecting a container having a hydrophobic and reversed phase, protein stability can be ensured without treating the container surface. That is, the present inventors have completed the present invention by finding that filling a resin solution preparation into a resin container of a specific material can hold a high content of protein for an extremely long time. Disclosure of the invention
  • the present invention provides a stable protein solution preparation, in which the material of at least a portion of the container for containing the protein solution preparation that comes into contact with the preparation is a hydrophobic resin.
  • the present invention provides the above protein solution preparation, wherein the container is a resin container.
  • the present invention provides the above-mentioned protein solution preparation, wherein the resin is selected from the group consisting of polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polyethyl methacrylate, and copolymers thereof.
  • the present invention provides the above protein solution preparation, wherein the resin is a cycloolefin copolymer which is a copolymer of cyclic olefin and Q! Olefin.
  • the present invention provides the above-mentioned protein solution preparation, wherein the cycloolefin copolymer is a ring-opening copolymer of norpolene or a derivative thereof with ethylene or propylene.
  • the present invention provides the above-mentioned protein solution preparation, wherein the cycloolefin copolymer is a ring-opening copolymer of norpolene and ethylene.
  • the present invention provides the above protein solution preparation, wherein the container shape is selected from the group consisting of vials, ampoules, syringes and bottles.
  • the present invention provides the above protein solution preparation, wherein the protein is a recombinant protein.
  • the present invention provides the above protein solution preparation, wherein the protein is erythropoietin.
  • the present invention provides the above protein solution preparation, wherein the protein is a granulocyte colony stimulating factor.
  • the present invention provides the above protein solution preparation, wherein the protein is a protein having a sugar chain.
  • the present invention provides a method for stabilizing a protein solution preparation, which comprises filling and storing a protein solution preparation in a container in which at least a portion of the material in contact with the preparation is a resin.
  • Resins suitable for the material of the container used in the present invention include known medical container materials such as polyethylene (PE), polypropylene (PP), polyethylene terephthalate (PET), polycarbonate, and polyethyl methacrylate.
  • PE polyethylene
  • PP polypropylene
  • PET polyethylene terephthalate
  • polycarbonate polycarbonate
  • polyethyl methacrylate Preferred is an example
  • COC cycloolefin copolymer
  • COC is characterized by heat resistance ⁇ chemical properties such as light resistance ⁇ chemical resistance is characteristic of polyolefin resin, and physical properties such as mechanical properties, melting, flow properties and dimensional accuracy are characteristics of amorphous resin This is the most preferable material because it shows.
  • the container for filling the protein solution preparation in the present invention can be selected according to the purpose of use, but it has a prescribed volume shape such as a vial, an ampoule or a syringe, and a large volume such as a bottle. Including shapes. Most preferred are syringes, especially disposable syringes.
  • Proteins used in the solution preparation of the present invention include, for example, monoclonal antibodies, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin (EPO), and inuichiferon Including interleukins such as IL-1 and IL-6, tissue plasminogen activator (TPA), thrombopoietin, perokinase, serum albumin, blood coagulation factor VHI, lebutin, stem cell growth factor (SCF), etc.
  • G-CSF granulocyte colony stimulating factor
  • GM-CSF granulocyte macrophage colony stimulating factor
  • EPO erythropoietin
  • interleukins such as IL-1 and IL-6, tissue plasminogen activator (TPA), thrombopoietin, perokinase, serum albumin, blood coagulation factor VHI, lebutin, stem cell growth factor (S
  • the protein used in the solution preparation of the present invention has substantially the same biological activity as that of a physiologically active protein of a mammal, particularly a human, and is obtained from a naturally occurring protein or by a genetic recombination method. Included Proteins obtained by genetic recombination include those having the same amino acid sequence as the natural protein, or those having one or more of the amino acid sequences deleted, substituted or added and having the biological activity described above. .
  • the protein used in the protein solution preparation of the present invention is preferably a protein having a sugar chain.
  • the origin of the sugar chain is not particularly limited, but a sugar chain added to a mammalian cell is preferable.
  • sugar chains added to Chinese hamster ovary cells, ⁇ cells, and cells of human origin can be mentioned.
  • EPO may be produced by any method, extracted from human urine by various methods, separated and purified, It is produced in Chinese hamster ovary cells, BHK cells, human-derived cells, etc. by an engineering method (for example, Japanese Patent Application Laid-Open No. 6-1-2288), and extracted and separated and purified by various methods.
  • the protein solution preparation of the present invention may contain a diluent, a solubilizing agent, a tonicity agent, an excipient, a pH adjuster, a soothing agent, a buffer, a sulfur-containing reducing agent, an antioxidant, and the like.
  • a diluent for example, polyethylene glycol; dextran, mannitol, sorbitol, inositol, glucose, fructos, lactose, xylose, mannose, maltos, sucrose, raffinos and the like Can be used.
  • sulfur-containing reducing agents include N-acetyl cysteine, N-acetyl homocysteine, thioctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, Examples thereof include daltathione and those having a sulfhydryl group such as thioalkanoic acid having 1 to 7 carbon atoms.
  • antioxidants include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, -tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbic acid palmitate, L-ascorbic acid stearate, and sodium hydrogen sulfite.
  • Chelating agents such as sodium sulfite, triamyl gallate, propyl gallate or disodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, and sodium metaphosphate.
  • inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate; and solution preparations such as organic salts such as sodium citrate, potassium citrate, and sodium acetate are usually used. It may contain added components.
  • the protein solution preparation of the present invention may further contain an appropriate stabilizer for each protein, and the stabilizer may include a surfactant (for example, sorbitan fatty acid ester which is a nonionic surfactant, glycerin).
  • Fatty acid ester polyglycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene glycerin fatty acid ester, Polyethylene glycol fatty acid ester, polyoxyethylene alkyl ether, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, polyoxyethylene beeswax derivative, polyoxyethylene lanolin derivative, Polyoxetylene fatty acid amide; alkyl sulfate as anionic surfactant, polyoxyethylene alkyl ether sulfate, alkyl sulfosuccinate; lecithin as natural surfactant, glycerol phospholipid, sphingophospholipid, Sugar fatty acid esters and the like, particularly polyoxyethylene sorbitan fatty acid esters
  • amino acids for example, D-, L- and DL- forms of leucine, tributofan, serine, glutamic acid, arginine, histidine, lysine, methionine, phenylalanine and acetyltributophan and salts thereof
  • amino acids for example, D-, L- and DL- forms of leucine, tributofan, serine, glutamic acid, arginine, histidine, lysine, methionine, phenylalanine and acetyltributophan and salts thereof
  • L-leucine, L-tributophane, L-dalminic acid L-arginine, L-histidine and L-lysine, and salts thereof
  • the stable protein solution preparation of the present invention is usually administered by a parenteral administration route, for example, injection (subcutaneous or intravenous injection), transdermal, transmucosal, nasal, etc., but oral administration is also possible.
  • a parenteral administration route for example, injection (subcutaneous or intravenous injection), transdermal, transmucosal, nasal, etc., but oral administration is also possible.
  • the amount of protein contained in the stable protein solution preparation of the present invention can be determined according to the protein used, the type of disease to be treated, the severity of the disease, the age of the patient, and the like.
  • the amount of EPO in the solution formulation is generally 100 to 500,000 IU / m1, preferably 200 to 1000001 UZm1, more preferably 750 to 720001 U / m1.
  • G—CSF it is generally 1 to 1000 , Preferably 10 to 800 ⁇ 8 1111, more preferably 50 to 500 xg / ml.
  • the solution formulation of the present invention can be prepared by dissolving these components in an aqueous buffer known in the field of solution formulation such as phosphate and Z or citrate buffers.
  • the phosphate buffer is preferably a sodium monohydrogen phosphate-sodium dihydrogen phosphate system
  • the citrate buffer is preferably a sodium citrate buffer.
  • the protein solution preparation of the present invention is an erythropoietin solution preparation
  • it includes EPO, a nonionic surfactant (eg, polysorbate 80, polysorbate 20), and an isotonic agent (eg, chloride).
  • a stabilizing agent eg, an amino acid, preferably L-histidine
  • the pH is preferably adjusted to 5.0-8.0, more preferably 5.5-7.0.
  • the protein solution preparation of the present invention is a G-CSF solution preparation
  • it contains G-CSF, a nonionic surfactant (eg, polysorbate 80, polysorbate 20), and necessary
  • a nonionic surfactant eg, polysorbate 80, polysorbate 20
  • the pH including diluents, solubilizers, tonicity agents, excipients, pH adjusters, soothing agents, buffers, sulfur-containing reducing agents, antioxidants, etc. 0, preferably 6-6.8.
  • the stable protein solution solution pre-filled in the resin container of the present invention was subjected to an accelerated test at 40 ° C. for 4 months, as shown in the examples described below, which were tested using EPO. Very good EPO residual ratio compared to glass containers.
  • the present invention also provides a method for stabilizing a protein solution preparation, which comprises filling and storing the protein solution preparation in the above-mentioned resin container.
  • the stabilization in the present invention differs depending on the type of protein to be filled.For example, in the case of an erythropoietin solution preparation, the stabilization is performed at 10 ° C for 2 years or more, or 25 at 6 months or more, preferably 1 year Above, more preferably for 2 years or more, or for 2 weeks or more at 40 ° C, which means that the erythropoietin residual rate is maintained at 90% or more, preferably 95% or more, and more preferably 98% or more. .
  • a protein solution preparation can be stably stored at room temperature for a long period of time.
  • EPO erythropoietin
  • Example 1 Long-term stability test in storage at 10 ° C and 25 ° C
  • erythropoietin solution preparation prepared as described above was placed in a glass container coated with silicone on its surface and a C ⁇ C container (manufactured from C ⁇ C, which is a copolymer of norbornene and ethylene).
  • the EP ⁇ solution was prepared by filling and subjected to a 3-month stability test at 10 ° C and 25 ° C.
  • EP ⁇ used in this example is a recombinant protein produced in CH ⁇ cells.
  • the EP0 solution preparation prepared by filling glass and COC containers in the same manner as in Example 1 was stored for 1, 2 and 3 months in an accelerated test at 50 ° C.
  • EP EP solution preparations prepared by filling in glass and COC containers in the same manner as in Example 1 were stored in an accelerated test at 60 ° C for 1, 2 and 3 weeks. ⁇ The results obtained are shown in Table 5 below.
  • the protein solution preparation pre-filled in the resin container of the present invention does not decrease the physiologically active content of protein for a long period of time, and is more stable than the solution preparation pre-filled in a conventional glass container. According to the present invention, a protein solution preparation can be stably stored at room temperature for a long period of time.
  • the protein solution preparation pre-filled in the resin container of the present invention simplifies the container manufacturing process (molding). Furthermore, resin containers are lighter in weight and less susceptible to breakage than glass containers, so they are suitable for transportation, and the industrial utility of the present invention is extremely large.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur une préparation d'une solution protéinique stable et sur un réceptacle, fabriqué dans une résine hydrophobe, destiné à contenir cette préparation et dont au moins une partie est en contact avec la préparation.
PCT/JP1999/004925 1998-09-11 1999-09-10 Preparation d'une solution proteinique et son procede de stabilisation WO2000015241A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU56492/99A AU5649299A (en) 1998-09-11 1999-09-10 Protein solution preparation and method for stabilizing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP25901398 1998-09-11
JP10/259013 1998-09-11

Publications (1)

Publication Number Publication Date
WO2000015241A1 true WO2000015241A1 (fr) 2000-03-23

Family

ID=17328146

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/004925 WO2000015241A1 (fr) 1998-09-11 1999-09-10 Preparation d'une solution proteinique et son procede de stabilisation

Country Status (2)

Country Link
AU (1) AU5649299A (fr)
WO (1) WO2000015241A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003533466A (ja) * 2000-05-18 2003-11-11 ツェンタリス アクチエンゲゼルシャフト ペプチドの薬剤適用形、その製造法及び使用
US6777052B2 (en) 2001-03-27 2004-08-17 Nipro Corporation Plastic container containing albumin solution
US7253142B1 (en) 1999-09-08 2007-08-07 Chugai Seiyaku Kabushiki Kaisha Protein solution preparation and method of stabilizing the same
JP2007528842A (ja) * 2003-06-10 2007-10-18 エルジー ライフサイエンス リミテッド 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液
WO2016051962A1 (fr) * 2014-10-02 2016-04-07 テルモ株式会社 Récipient médical pour recevoir une préparation de solution de protéine à l'intérieur de ce dernier

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6232A (ja) * 1985-02-06 1987-01-06 Chugai Pharmaceut Co Ltd 慢性関節リウマチ性貧血治療剤
JPS62252731A (ja) * 1986-01-22 1987-11-04 Chugai Pharmaceut Co Ltd 骨髄性白血病抑制剤
JPH05293159A (ja) * 1991-07-22 1993-11-09 Daikyo Seiko:Kk 衛生品用容器

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6232A (ja) * 1985-02-06 1987-01-06 Chugai Pharmaceut Co Ltd 慢性関節リウマチ性貧血治療剤
JPS62252731A (ja) * 1986-01-22 1987-11-04 Chugai Pharmaceut Co Ltd 骨髄性白血病抑制剤
JPH05293159A (ja) * 1991-07-22 1993-11-09 Daikyo Seiko:Kk 衛生品用容器

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7253142B1 (en) 1999-09-08 2007-08-07 Chugai Seiyaku Kabushiki Kaisha Protein solution preparation and method of stabilizing the same
JP2003533466A (ja) * 2000-05-18 2003-11-11 ツェンタリス アクチエンゲゼルシャフト ペプチドの薬剤適用形、その製造法及び使用
JP2011213733A (ja) * 2000-05-18 2011-10-27 Aeterna Zentaris Gmbh ペプチドの薬剤適用形、その製造法及び使用
US6777052B2 (en) 2001-03-27 2004-08-17 Nipro Corporation Plastic container containing albumin solution
JP2008259830A (ja) * 2001-03-27 2008-10-30 Nipro Corp アルブミン収容プラスチック容器
JP2007528842A (ja) * 2003-06-10 2007-10-18 エルジー ライフサイエンス リミテッド 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液
JP4871720B2 (ja) * 2003-06-10 2012-02-08 エルジー ライフサイエンス リミテッド 血清アルブミンを含まない、安定なヒトエリスロポエチン水溶液
WO2016051962A1 (fr) * 2014-10-02 2016-04-07 テルモ株式会社 Récipient médical pour recevoir une préparation de solution de protéine à l'intérieur de ce dernier

Also Published As

Publication number Publication date
AU5649299A (en) 2000-04-03

Similar Documents

Publication Publication Date Title
JP6076226B2 (ja) タンパク質溶液製剤およびその安定化方法
US7163671B2 (en) Long-term stabilized formulations
JP5490972B2 (ja) タンパク質注射製剤
JP4607336B2 (ja) 長期安定化製剤
AU2006235962A1 (en) Solution formulations having long-term stability
WO1997040850A1 (fr) Preparation de solution d'erythropoietine
JP2007204498A (ja) 長期安定化製剤
KR100389726B1 (ko) 안정한 과립구 콜로니-자극 인자 함유 제제
UA80331C2 (en) Human serum albumin-free stabilised interferon liquid formulations
JP5271481B2 (ja) タンパク質溶液製剤およびその安定化方法
WO2000015241A1 (fr) Preparation d'une solution proteinique et son procede de stabilisation
EP1663292A1 (fr) Formulation d'erythropoietine ne contenant pas d'albumine
JP4454571B2 (ja) 蛋白非添加製剤
WO2001047544A1 (fr) Preparation de seringue prealablement remplie de proteine et procede de stabilisation

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09786932

Country of ref document: US

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 569825

Kind code of ref document: A

Format of ref document f/p: F

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
CR1 Correction of entry in section i

Free format text: PAT. BUL. 08/2002 UNDER (30) ADD "09/930009, 20010815, US"