WO2015056613A1 - Préparation aqueuse de polypeptide stabilisée - Google Patents

Préparation aqueuse de polypeptide stabilisée Download PDF

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Publication number
WO2015056613A1
WO2015056613A1 PCT/JP2014/076898 JP2014076898W WO2015056613A1 WO 2015056613 A1 WO2015056613 A1 WO 2015056613A1 JP 2014076898 W JP2014076898 W JP 2014076898W WO 2015056613 A1 WO2015056613 A1 WO 2015056613A1
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Prior art keywords
creatinine
pharmaceutical composition
etanercept
macrogol
preparation
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PCT/JP2014/076898
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English (en)
Japanese (ja)
Inventor
惇也 辻井
充成 藤田
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Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
ドン ア ソシオホールディングス シーオー．，エルティディー．
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Publication of WO2015056613A1 publication Critical patent/WO2015056613A1/fr

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    • 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
    • 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
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the present invention relates to an aqueous pharmaceutical composition suitable for long-term storage of a polypeptide, a method for producing the pharmaceutical composition, and a kit containing the pharmaceutical composition. More specifically, the present invention relates to a method for improving the stability of an aqueous pharmaceutical composition containing etanercept, a storage form, and an aqueous etanercept preparation coexisting with a stabilizer.
  • polypeptide pharmaceuticals are prone to physical changes such as various chemical changes and aggregation during the manufacturing process and storage due to the complex structure of the polypeptide. It is generally known that these changes not only reduce the pharmacological action but also greatly affect safety such as immunogenicity.
  • Non- Patent Document 1 In the preparation of polypeptide pharmaceuticals, a pharmaceutical formulation capable of stably storing the polypeptide used as an active ingredient is required (Nat. Rev. Drug. Discov. 2005 4 (4) 298-306 (non- Patent Document 1)).
  • degradation of polypeptides includes degradation accompanied by chemical modification such as hydrolysis, deamidation, and methionine oxidation (Int. J. Pharm. 1999 185, 129-188 (Non-patent Document 2)), aggregation, and fragmentation. And degradation associated with physical association such as denaturation (Int. J. Pharm. 2005 289 1-30 (non-patent document 3)).
  • the method includes selection of dosage form; optimization of solution pH; optimization of the type and concentration of buffers, salts, and stabilizers.
  • a polypeptide used for the treatment of collagen diseases and autoimmune diseases such as rheumatoid arthritis is physically and chemically caused by temperature, humidity, light, etc. It is assumed that the activity is reduced, resulting in decreased activity.
  • freeze-drying As one method for providing a stable polypeptide at the time of use, freeze-drying is widely used. Solidification by lyophilization suppresses the mobility of the polypeptide and surrounding molecules, and greatly reduces the rate of physical and chemical changes during storage.
  • freeze-drying sometimes causes aggregation associated with irreversible conformational change of a polypeptide and decreases storage stability due to moisture absorption or oxidation.
  • the freeze-dried preparation requires an additional step of dissolving with a solvent at the time of use, it can be a burden on the user.
  • liquid preparations are excellent in convenience.
  • additives such as stabilizers.
  • Patent Document 1 L-arginine is used, and International Publication No. 2012/165917 (Patent Document 2) uses methionine, lysine, and histidine.
  • Patent Document 3 shows the effect of an etanercept stabilizer containing 25 to 120 mM glutamic acid, sucrose and sodium phosphate in the Examples.
  • stabilizers suitable for certain proteins are extremely difficult to predict without actually trying this, and the combinations are enormous.
  • An object of the present invention is to provide a new aqueous polypeptide preparation in which etanercept is thermodynamically stable and can be stored for a long period of time.
  • the present inventors have reached the present invention. That is, the present inventors have newly found that creatinine and macrogol 400 are particularly effective as stabilizers for etanercept among various stabilizers, and etanercept in an aqueous preparation by taking the following constitution. It has been found that the stability of etanercept can be improved, and a stable etanercept formulation can be obtained.
  • the present invention provides: (1) A pharmaceutical composition which is an aqueous liquid preparation containing etanercept and at least one stabilizer selected from creatinine and macrogol 400. (2) Further, among buffer, sugar and osmotic pressure regulator.
  • the pharmaceutical composition according to (1) comprising at least one additive selected from the above (3)
  • a composition and a pharmaceutical preparation according to (5) At least the one is a kit formulation comprising a Specifications Manual of the pharmaceutical composition.
  • etanercept By taking the constitution of the present invention, etanercept can be stabilized, and a stable etanercept aqueous preparation that can be stored for a long period of time can be obtained. As a result, an increase in the components other than the active body of etanercept is suppressed, and the stability of the pharmaceutical composition containing etanercept is expected to be improved, and the decrease in pharmacological action is expected.
  • the present invention aims to stabilize an aqueous preparation containing etanercept which is a polypeptide (hereinafter sometimes referred to as “aqueous preparation of etanercept” or “aqueous preparation of etanercept”) by adding creatinine as a stabilizer. It is.
  • the concentration of creatinine to be added is not particularly limited, but the lower limit is preferably 5 mM in the pharmaceutical composition of the present invention, more preferably 10 mM, and even more preferably 25 mM.
  • the upper limit value of the creatinine concentration is not particularly limited, but is preferably 200 mM, more preferably 150 mM, still more preferably 100 mM, particularly preferably 89 mM, most preferably in the pharmaceutical composition of the present invention. Preferably it is 50 mM.
  • the upper limit value and the lower limit value can be independently selected, and it is particularly preferably 25 to 50 mM.
  • the present invention also aims to stabilize an aqueous preparation of etanercept, which is a polypeptide, by adding macrogol 400, that is, polyethylene glycol 400, as a stabilizer.
  • macrogol 400 that is, polyethylene glycol 400
  • the concentration of macrogol 400 is not particularly limited, but the lower limit is selected from 0.01, 0.05, 0.1 in weight / volume% (W / V%) in the pharmaceutical composition of the present invention, and the upper limit thereof.
  • the value is selected from 0.1, 0.25, 0.5, 1.0 in weight / volume%.
  • the concentration of the macrogol 400 the upper limit value and the lower limit value can be independently selected, but it is particularly preferably 0.1 to 1.0% by weight / volume. In the present invention, for example, 0.1% by weight / volume corresponds to 1 mg / ml.
  • creatinine and macrogol 400 may be added not only individually but also in combination.
  • creatinine and Macrogol 400 by using creatinine and Macrogol 400 in combination, a further excellent etanercept stabilization effect is exhibited.
  • etanercept means a fusion protein of an extracellular domain of a TNF receptor (TNFR p75 protein) and an IgG1 Fc domain, which is an active ingredient of a pharmaceutical preparation marketed as “Emblel (registered trademark)”, and a pharmaceutical.
  • Emblel registered trademark
  • etanercept refers to polypeptides that are equivalent in nature and have the same sequence as the TNF receptor.
  • monomer and “monomer” of etanercept refer to an active protein of about 150 kDa.
  • the term “pharmaceutical composition” is understood to refer to a preparation (pharmaceutical preparation) containing a peptide prepared so as to be suitable for injection and / or administration to a patient in need of treatment.
  • the pharmaceutical composition may further contain a buffer, a tonicity adjusting agent, and an excipient.
  • aqueous pharmaceutical composition and “aqueous preparation” are understood to refer to a preparation using water as a solvent among the above-mentioned pharmaceutical preparations, and “etanercept aqueous preparation” contains at least water and etanercept. And may contain additives such as buffers, tonicity modifiers, excipients and the like in addition to the stabilizers.
  • the “aqueous liquid formulation” is understood to refer to a liquid formulation using water as a solvent in the form of the pharmaceutical formulation, and the “frozen pharmaceutical composition” means that the aqueous liquid formulation is frozen. It is understood to refer to the formulation that has been made.
  • aqueous liquid preparation in the present invention is preferably used as an injection or an infusion
  • the “frozen pharmaceutical composition” is preferably used as an injection or an infusion after thawing, such as a prefilled sterile syringe. It is preferably stored in a syringe or in an infusion pack.
  • the “kit formulation” is understood to refer to a formulation comprising the pharmaceutical composition and specifications of the pharmaceutical composition, and the pharmaceutical composition includes the aqueous liquid formulation and the frozen pharmaceutical composition. It may be.
  • the pH of the pharmaceutical composition in the present invention may be in the range of 4.0 to 8.0, preferably 5.0 to 7.0, and more preferably 6.1 to 6.5.
  • Preferred buffers in the present invention are sodium phosphate, histidine, potassium phosphate, sodium citrate, potassium citrate, maleic acid, ammonium acetate, sodium acetate, acetic acid, tris- (hydroxymethyl) -aminomethane (Tris), acetate.
  • a tonicity regulator (osmotic pressure regulator) preferred in the present invention is at least selected from the group consisting of sodium chloride, potassium chloride, sodium citrate, sucrose, glucose, mannitol, sorbitol, xylitol, arginine, cysteine, histidine, and glycine.
  • One tonicity regulator more preferably sodium chloride.
  • Preferred excipients in the present invention are sorbitol, mannitol, sucrose, xylitol, trehalose, glucose, lactose, glycerol, maltose, inositol, bovine serum albumin (BSA), dextran, PVA, hydroxypropyl methylcellulose (HPMC), polyethyleneimine, Gelatin, polyvinylpyrrolidone (PVP), hydroxyethyl cellulose (HEC), polyethylene glycol, ethylene glycol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), proline, sodium L-serine glutamate, potassium glutamate, alanine, glycine, lysine hydrochloride , Sarcosine, ⁇ -aminobutyric acid, Tween 20, Tween 80, SDS, polyoxyethylene copolymer Potassium phosphate, sodium acetate, ammonium sulfate, magnesium sulfate,
  • “stable” or “stable and can be stored for a long time” means that it can be used as a pharmaceutical preparation for 2 years under storage conditions of 2 to 8 ° C. Further, in the present invention, even when it is marketed as a pharmaceutical product and exhibits a stability equivalent to or higher than that of Embrel (registered trademark) having an expiration date of 24 months or more, it is "stable” or “stable and can be stored for a long time” Suppose there is. Further, in the present invention, when at least 70% of the active substance contained immediately after preparation after storage at 50 ° C. for 7 days remains, “stable” or “stable and long-term storage” is similarly applied. It is possible.
  • the “active body” refers to a monomer of etanercept, and is understood to refer to a normally folded intact monomer that can be confirmed by hydrophobic interaction chromatography (HIC).
  • the monomer of etanercept can also be confirmed by size exclusion chromatography (SEC).
  • SEC size exclusion chromatography
  • a normally folded intact monomer that can be confirmed by HIC and a monomer that can be confirmed by SEC In any case, it is more preferable that 70% or more remain under the above conditions.
  • HIC is a technique for separation based on the difference in surface hydrophobicity of proteins and the like, and separates and detects polypeptide-related species. Assuming that peak 1, peak 2, and peak 3 from the earliest retention time, peak 1 contains a truncated body, peak 2 contains a normally folded active body, and peak 3 is a mistake that is folded into an abnormal form. Includes fold bodies.
  • HMW high molecular weight species
  • monomer monomer
  • LMW low molecular weight species
  • FIG. 1 shows the remaining ratio of active body (Active Ingredient Residual (%)) by HIC.
  • active body Active Ingredient Residual (%)
  • creatinine and macrogol 400 showed a higher stabilizing effect than other stabilizers, and particularly creatinine showed a higher stabilizing effect (FIG. 1).
  • the residual ratio when the stabilizer was not added was 47%.
  • FIG. 2 shows the remaining ratio of active body by SEC (Active Ingredient Residual (%)). Also in the analysis by SEC, creatinine and macrogol 400 showed a high stabilizing effect, and creatinine showed the most excellent stabilizing effect (FIG. 2). In the test, the residual ratio when the stabilizer was not added was 53%.
  • Each sample contains etanercept about 50 mg / ml, NaCl 6.0 mg / ml, sodium phosphate buffer about 32 mM, sorbitol 10.2 mg / ml, and creatinine at the above-mentioned concentration, and the pH is 6.1 to Prepared as a 6.5 aqueous solution.
  • Fig. 3 shows the remaining ratio (%) of active body by HIC
  • Fig. 4 shows the remaining ratio (%) of active body by SEC.
  • the effect of stabilizing etanercept was observed depending on the creatinine concentration (FIGS. 3 and 4). Further, even when the creatinine concentration was 100 mM or 150 mM, a high stabilizing effect was observed.
  • Each sample contains creatinine 50 mM, etanercept about 50 mg / ml, NaCl 5.5 mg / ml, phosphate buffer 66 mM, sorbitol 1.0 mg / ml, and macrogol 400.
  • Fig. 5 shows the remaining ratio (%) of active body by HIC. Stabilization by further addition of macrogol 400 was observed by HIC, and the stabilization effect of etanercept by addition of creatinine was higher than that of the known embrel formulation regardless of whether macrogol 400 was used or not (FIG. 5). Also in SEC, the stabilization effect of etanercept was improved by adding Macrogol 400.
  • Each sample consists of etanercept approximately 50 mg / ml, NaCl 5.7 mg / ml, sodium phosphate buffer approximately 32 mM, sorbitol 9.8 mg / ml, macrogol 400 0.1 W / V%, and each of the above concentrations. It was prepared as an aqueous solution containing an agent and having a pH of 6.1 to 6.5 (Table 2). The sample was stored at 50 ° C. for 7 days, then analyzed by HIC and SEC, and the residual ratio (%) of the active body was determined by the above formulas (1) and (2) and evaluated.
  • Fig. 6 shows the residual ratio (%) of active body by HIC.
  • a clear improvement in the stabilizing effect was recognized (FIG. 6).
  • the residual ratio when the macrogol 400 and the other stabilizers were not added was 48%.
  • the combination with creatinine showed the highest stabilization effect.
  • the stability at 5 ° C. and 25 ° C. of the formulation to which creatinine was added was compared with that of the emblem formulation.
  • the formulation with added creatinine (Example 13) contains about 50 mg / mL etanercept, 25 mM creatinine, 2.92 mg / mL NaCl, about 32 mM sodium phosphate buffer, and 20.22 mg / mL sorbitol. Prepared as an aqueous solution of 6.1-6.5. Samples were stored at 5 ° C. or 25 ° C.
  • the present invention shows that creatinine and macrogol 400 are effective as stabilizers for etanercept. According to the present invention, it is possible to provide a stable and highly convenient etanercept aqueous preparation. Surprisingly, the combination formulation of creatinine and Macrogol 400 showed an unexpectedly high stabilizing effect as compared with L-arginine known as another stabilizer.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une préparation aqueuse d'étanercept stable comprenant de la créatinine et/ou du macrogol 400 en tant que stabilisant. La décomposition et l'agrégation de l'étanercept peuvent être prévenues en ajoutant ces stabilisants à la préparation aqueuse.
PCT/JP2014/076898 2013-10-15 2014-10-08 Préparation aqueuse de polypeptide stabilisée WO2015056613A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114324882A (zh) * 2020-10-12 2022-04-12 广东菲鹏生物有限公司 蛋白稳定剂及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63130536A (ja) * 1986-11-19 1988-06-02 Mohan Yakuhin Kenkyusho:Kk 安定なコカルボキシラ−ゼ凍結乾燥製剤の製造法
JP2007269793A (ja) * 2006-03-10 2007-10-18 Shionogi & Co Ltd 安定化されたインターフェロン−γ組成物
WO2012165917A1 (fr) * 2011-06-03 2012-12-06 Lg Life Sciences Ltd. Formulation liquide stable d'étanercept
WO2013006454A1 (fr) * 2011-07-01 2013-01-10 Biogen Idec Ma Inc. Compositions de polypeptide de fusion tnfr:fc exempt d'arginine et leurs procédés d'utilisation
WO2013059412A1 (fr) * 2011-10-18 2013-04-25 Coherus Biosciences, Inc. Préparations d'étanercept stabilisées avec des combinaisons de sucres et de polyols

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63130536A (ja) * 1986-11-19 1988-06-02 Mohan Yakuhin Kenkyusho:Kk 安定なコカルボキシラ−ゼ凍結乾燥製剤の製造法
JP2007269793A (ja) * 2006-03-10 2007-10-18 Shionogi & Co Ltd 安定化されたインターフェロン−γ組成物
WO2012165917A1 (fr) * 2011-06-03 2012-12-06 Lg Life Sciences Ltd. Formulation liquide stable d'étanercept
WO2013006454A1 (fr) * 2011-07-01 2013-01-10 Biogen Idec Ma Inc. Compositions de polypeptide de fusion tnfr:fc exempt d'arginine et leurs procédés d'utilisation
WO2013059412A1 (fr) * 2011-10-18 2013-04-25 Coherus Biosciences, Inc. Préparations d'étanercept stabilisées avec des combinaisons de sucres et de polyols

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IYAKUHIN TENKABUTSU JITEN 2007, 25 July 2007 (2007-07-25), pages 91 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114324882A (zh) * 2020-10-12 2022-04-12 广东菲鹏生物有限公司 蛋白稳定剂及其应用

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