WO2014178216A1 - Formulation de solution aqueuse et son procede de production - Google Patents

Formulation de solution aqueuse et son procede de production Download PDF

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Publication number
WO2014178216A1
WO2014178216A1 PCT/JP2014/054036 JP2014054036W WO2014178216A1 WO 2014178216 A1 WO2014178216 A1 WO 2014178216A1 JP 2014054036 W JP2014054036 W JP 2014054036W WO 2014178216 A1 WO2014178216 A1 WO 2014178216A1
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aqueous solution
etanercept
buffer
concentration
solution
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PCT/JP2014/054036
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English (en)
Japanese (ja)
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健作 松田
里保 中井
恒彦 山根
範彦 山脇
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ニプロ株式会社
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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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1793—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
    • 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
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • 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
    • 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

Definitions

  • the present invention relates to an aqueous solution preparation and a method for producing the same, and more particularly to an aqueous solution preparation containing etanercept as an active ingredient and a method for producing the same.
  • the etanercept pharmaceutical composition is a glycoprotein comprising an extracellular domain portion of a human p75 tumor necrosis factor (Tumor Necrosis Factor (TNF)) receptor fused to the Fc region of human IgG1 (hereinafter referred to as “etanercept” in the present specification).
  • TNF Tumor Necrosis Factor
  • etanercept As an active ingredient, it captures TNF ⁇ / LT ⁇ produced excessively in the body (receptor binding reaction) and inhibits binding to receptors on the cell surface, thereby exhibiting anti-rheumatic and anti-inflammatory effects
  • Such an etanercept formulation is prepared, for example, as an aqueous solution formulation, and then sealed and stored in a syringe.
  • polypeptides such as etanercept are usually unstable in an aqueous solution and produce impurities composed of aggregates or cleaved bodies in the aqueous solution. These impurities can no longer capture TNF ⁇ / LT ⁇ , and no anti-rheumatic action or anti-inflammatory action is exhibited. Therefore, it is desired to develop a technique for suppressing the generation of impurities in an aqueous solution in an etanercept formulation.
  • Patent Document 1 In order to suppress the production of such impurities, it has been proposed that when L-arginine is contained as an aggregation inhibitor in an aqueous preparation containing etanercept, the production of aggregates which are one of the impurities of etanercept is suppressed.
  • the present inventors can improve the stability of an aqueous preparation containing etanercept by selecting a predetermined stabilizer and a buffer and adjusting the pH to a predetermined value.
  • the present invention was completed.
  • the present invention relates to an aqueous solution preparation containing etanercept, a stabilizer and a buffer, wherein the stabilizer is histidine or a salt thereof, the buffer is an organic acid or a salt thereof, and the pH is from 5.6. It is a formulation that is 6.4.
  • the organic acid or salt thereof is citric acid, citrate, acetic acid, acetate, tartaric acid, tartrate, and tris (hydroxymethyl) aminomethane, and tris (hydroxymethyl) aminomethane hydrochloride.
  • the buffer is contained at a concentration of 1 mM to 1 M with respect to the entire aqueous solution.
  • the stabilizer is contained at a concentration of 1 mM to 1 M with respect to the entire aqueous solution.
  • the aqueous solution formulation of the present invention further contains at least one isotonic agent selected from the group consisting of sodium chloride, sucrose, and glycine.
  • the present invention is also a method for producing an aqueous solution formulation, Preparing a buffer solution having a pH of 5.6 to 6.4 by dissolving histidine or a salt thereof and an organic acid or a salt thereof in water; Adding an etanercept stock solution to the buffer; Concentrating the stock solution to obtain a concentrate of the etanercept; and combining the concentrate with another buffer;
  • a method comprising
  • the organic acid or salt thereof is citric acid, citrate, acetic acid, acetate, tartaric acid, tartrate, and tris (hydroxymethyl) aminomethane, and tris (hydroxymethyl) aminomethane hydrochloride.
  • the isotonic agent is further dissolved in the step of preparing the buffer solution.
  • the tonicity agent is at least one compound selected from the group consisting of sodium chloride, sucrose, and glycine.
  • the present invention it is possible to suppress the generation of impurities composed of aggregates and / or cleaved bodies resulting from etanercept, which is an active ingredient, and improve the stability of the aqueous solution preparation itself. Due to the improved stability, the aqueous solution preparation of the present invention can be stored for a longer period of time.
  • FIG. 4 is a graph showing the ratio of aggregates and cleaved bodies to the total polypeptide at the start of storage when the pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 are stored in an incubator.
  • FIG. 5 is a graph showing the ratio of aggregates and cleaved bodies to the total polypeptide at one week after storage when the pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 are stored in an incubator. is there.
  • FIG. 2 is a graph showing the ratio of aggregates and cleaved bodies to total polypeptides at the time point after 2 weeks of storage when the pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 are stored in an incubator. is there.
  • FIG. 2 is a graph showing the ratio of aggregates and cleaved bodies to total polypeptides at the time point after 3 weeks of storage when the pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 are stored in an incubator. is there.
  • the aqueous solution preparation of the present invention is a pharmaceutical composition containing etanercept.
  • Etanercept constituting the present invention is an active ingredient in the present invention and is useful as an anti-rheumatoid arthritis drug, human IgG1 Fc region and human tumor necrosis factor type II receptor (TNFR-II) having a molecular weight of 75 kDa (p75) It is a glycoprotein (polypeptide) consisting of a dimer of subunits fused with the extracellular domain.
  • Etanercept can be produced by genetic recombination using Chinese hamster ovary cells (CHO). The etanercept subunit consists of 934 amino acids and has a molecular weight of about 150,000 daltons.
  • the content of etanercept in the aqueous solution preparation of the present invention is not particularly limited, but is, for example, 1 mg / mL to 150 mg / mL, preferably 5 mg / mL to 100 mg / mL. If the content of etanercept is less than 1 mg / mL, it may not function sufficiently as a pharmaceutical composition. If the content of etanercept exceeds 150 mg / mL, precipitation may occur in the preparation.
  • the aqueous solution preparation of the present invention contains a stabilizer and a buffer together with the etanercept.
  • the stabilizer in the present invention is histidine or a salt thereof.
  • histidine salts include, but are not limited to, histidine hydrochloride.
  • the stabilizer may be composed of such histidine or a salt thereof alone, or may be composed of a combination of two or more.
  • the concentration of the stabilizer in the aqueous solution preparation of the present invention is not necessarily limited, but is preferably 1 mM to 1 M, more preferably 10 mM to 100 mM, and even more preferably 25 mM to 50 mM, based on the entire aqueous solution. . If the concentration of the stabilizer is less than 1 mM, the generation of impurities of etanercept cannot be sufficiently suppressed, and there is a possibility that many aggregates and cleaved bodies are generated through storage of the aqueous solution preparation. When the concentration of the stabilizer exceeds 1M, the osmotic pressure is no longer too high and may not be suitable as a pharmaceutical composition.
  • the term “aggregate” used in the present specification refers to a high molecular weight polypeptide formed by aggregation of etanercept molecules.
  • the term “cleaved body” used in the present specification refers to a low molecular weight polypeptide consisting of a fragment obtained by cleaving a peptide bond at an arbitrary position in an etanercept molecule.
  • the buffer in the present invention is an organic acid or a salt thereof.
  • buffering agents include, but are not limited to, citric acid and its salts (eg, sodium citrate, sodium dihydrogen citrate, disodium citrate and potassium citrate), acetic acid and its salts (eg, ammonium acetate, Calcium acetate, potassium acetate and sodium acetate), tartaric acid and its salts (eg, sodium tartrate, sodium hydrogen tartrate and potassium sodium tartrate), tris (hydroxymethyl) aminomethane (Tris) and its salts (eg, tris (hydroxymethyl)) Aminomethane hydrochloride).
  • citric acid and its salts are particularly preferable.
  • the concentration of the buffering agent in the aqueous solution preparation of the present invention is not necessarily limited, but is preferably 1 mM to 1 M, more preferably 10 mM to 100 mM, and even more preferably 25 mM to 50 mM, based on the whole aqueous solution.
  • concentration of the buffering agent is less than 1 mM, the generation of impurities of etanercept cannot be sufficiently suppressed, and there is a possibility that many aggregates and cleaved bodies are generated through storage of the aqueous solution preparation. If the concentration of the buffer exceeds 1M, the osmotic pressure is no longer too high and may not be suitable as a pharmaceutical composition.
  • the aqueous solution preparation of the present invention is an aqueous solution in which the above etanercept, stabilizer and buffer are dissolved in water.
  • the aqueous solution preparation of the present invention can also be adjusted to a predetermined pH by adding sodium hydroxide, hydrochloric acid or the like to the aqueous solution of the buffer, stabilizer, tonicity agent and other additives as necessary. You may adjust.
  • the pH of the aqueous solution preparation of the present invention is 5.6 to 6.4, more preferably 5.7 to 6.3, and even more preferably 6.0.
  • the etanercept constituting the present invention greatly changes the production rate of aggregates and cleaved bodies as impurities, depending on the pH of the buffer solution to be dissolved. In particular, when it is tilted to a more basic side above pH 6.4, the formation of aggregates is promoted. On the other hand, when it is tilted to the acidic side from below pH 5.6, the formation of the cut body is promoted. Therefore, in the present invention, such a pH range is maintained.
  • the aqueous solution preparation of the present invention may also contain an isotonic agent as necessary.
  • isotonic agents include, but are not necessarily limited to, sodium chloride, sucrose and glycine, and combinations thereof.
  • the content of the tonicity agent is not necessarily limited, but is set so that the osmotic pressure of the entire aqueous solution is 140 mOsm to 780 mOsm.
  • aqueous solution preparation of the present invention may contain other pharmaceutically acceptable additives or excipients.
  • Additives and / or excipients are not necessarily limited, but include, for example, sugars or polyols (lactose, glycerol, xylitol, sorbitol, mannitol, maltose, inositol, trehalose, glucose); macromolecules (eg, serum albumin (bovine Serum albumin (BSA), human SA or recombinant HA), dextran, PVA, hydroxypropylmethylcellulose (HPMC), polyethyleneimine, gelatin, polyvinylpyrrolidone (PVP), polyoxyethylene (160) polyoxypropylene (30) glycol, Hydroxyethyl cellulose (HEC) lactic acid polymer); non-aqueous solvents (eg polyhydric alcohols such as polyethylene glycol, ethylene glycol, propylene glycol or glycerol) ), Dimethyl
  • the aqueous solution preparation of the present invention can be stored for a long time in the liquid itself or in a frozen state.
  • aqueous solution preparation of the present invention examples include rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Wegner's disease, Crohn's disease, chronic obstructive pulmonary disease (COPD), hepatitis C, endometriosis It can be used as a pharmaceutical composition for asthma, cachexia, psoriasis, atopic dermatitis and the like.
  • the dosage of the water-soluble preparation of the present invention depends on the kind and severity of the disease, the patient's age, weight and height, medical history, the degree of response to etanercept, etc. The administration period and the like can be appropriately selected.
  • histidine or a salt thereof and an organic acid or a salt thereof are dissolved in water to prepare a buffer solution having a pH of 5.6 to 6.4.
  • the mode of dissolution of histidine or a salt thereof (the stabilizer) and an organic acid or a salt thereof (the buffer) in water is not particularly limited. Further, the dissolution order of the stabilizer and the buffer is not particularly limited.
  • an isotonic agent in preparing this buffer solution, an isotonic agent, other additives, excipients and the like may be added as necessary in addition to the stabilizer and the buffer.
  • the pH of the buffer solution thus prepared is 5.6 to 6.4, more preferably 5.7 to 6.3, and even more preferably 6.0.
  • the osmotic pressure of the buffer solution is not necessarily limited, but is, for example, 140 mOsm to 780 mOsm, and preferably 250 mOsm to 315 mOsm.
  • the etanercept stock solution is added to the above-obtained buffer solution (one of them) to prepare a stock aqueous solution.
  • the addition mode of the etanercept stock solution to the buffer solution is not particularly limited, and any means commonly used by those skilled in the art can be used. Further, the temperature set at the time of addition is not particularly limited.
  • a concentrated solution in which etanercept is concentrated can be obtained by concentrating the raw aqueous solution.
  • Concentration of the raw aqueous solution is performed using means well known to those skilled in the art.
  • the conditions and temperature applied for the concentration are not particularly limited, and arbitrary conditions and temperatures are selected by those skilled in the art.
  • an ultrafiltration membrane having pores that cannot pass molecules having a certain molecular weight or more is used.
  • the raw aqueous solution is concentrated using, for example, a tangential flow type membrane cassette composed of a molecular filtration membrane having a fractional molecular weight of 30 kDa or less. If the amount is very small, a centrifugal filter unit composed of a tube provided with a desired molecular filtration membrane can be used. The filter unit may be further inserted into a filtrate tube to form a double-structure centrifugal ultrafiltration tube.
  • the concentration of etanercept increases without passing through the molecular filtration membrane, while unnecessary salts and buffer components originally contained in the etanercept stock solution can be efficiently filtered. In this way, a concentrated solution of etanercept in which the solution components constituting the etanercept stock solution are replaced with the buffer solution can be obtained.
  • Such an operation of concentration (substitution) may be repeated until the contents of the stabilizer and the buffering agent are set in advance in the concentrate.
  • the above buffer solution may be newly added to the obtained concentrated solution, and the concentration operation may be performed again.
  • the concentrated solution and the buffer solution may be mixed at a predetermined ratio so that the etanercept, the stabilizer, and the buffering agent have contents preset by those skilled in the art.
  • the aqueous solution obtained by combining may be filtered using a sterile filtration filter or the like as necessary.
  • the obtained aqueous solution is sealed in, for example, a sterilized vial, syringe, or screw cap tube.
  • Example 1 Histidine hydrochloride and glycine in a 50 mM citric acid monohydrate solution so that the concentration of histidine hydrochloride is 25 mM (4.79 g / L) and the concentration of glycine is 120 mM (9.0 g / L) Histidine hydrochloride and glycine were added to the dissolved solution and 50 mM trisodium citrate dihydrate solution, the concentration of histidine hydrochloride was 25 mM (4.79 g / L), and the concentration of glycine was 120 mM (9.0 g). / L) was mixed with an appropriate amount of each solution, and a buffer solution (liquid osmotic pressure 294 mOsm) adjusted to pH 6.0 by adding sodium hydroxide was prepared.
  • a buffer solution liquid osmotic pressure 294 mOsm
  • the buffer solution prepared above was added to the obtained etanercept concentrate, and the combined aqueous solution was frozen once and then melted. Thereafter, the solution is aseptically filtered using a 0.22 ⁇ m filter for aseptic filtration, and sealed in a 1.5 mL screw cap tube that has been sterilized by autoclaving at 121 ° C. for 20 minutes in advance, so that the concentration of etanercept is 47.
  • An aqueous solution of the pharmaceutical composition that was 1 mg / mL was obtained (Table 1).
  • pH of the pharmaceutical composition obtained by the present Example did not change with pH adjusted about the said buffer solution.
  • Example 2 Instead of the buffer prepared in Example 1, histidine hydrochloride and glycine were added to a 25 mM citrate monohydrate solution, the concentration of histidine hydrochloride was 25 mM (4.79 g / L), and the concentration of glycine was Histidine hydrochloride and glycine were added to a solution dissolved to 190 mM (14.25 g / L) and 25 mM trisodium citrate dihydrate solution, and the concentration of histidine hydrochloride was 25 mM (4.79 g / L).
  • a buffer solution liquid osmotic pressure 299 mOsm
  • sodium hydroxide adjusted to pH 6.0 by adding sodium hydroxide to each solution in an appropriate amount so that the glycine concentration is 190 mM (14.25 g / L).
  • a pharmaceutical composition having an etanercept concentration of 49.5 mg / mL was obtained in the same manner as in Example 1 except that was prepared and used (Table 1). In addition, it confirmed that pH of the pharmaceutical composition obtained by the present Example did not change with pH adjusted about the said buffer solution.
  • Example 3 Instead of the buffer solution prepared in Example 1, histidine hydrochloride, sodium chloride and sucrose were added to a 25 mM citric acid monohydrate solution, and the concentration of histidine hydrochloride was 25 mM (4.79 g / L).
  • histidine hydrochloride sodium chloride, and sucrose in a solution dissolved to a concentration of 80 mM (4.68 g / L) and a sucrose concentration of 10 mg / mL and a 25 mM trisodium citrate dihydrate solution was dissolved so that the concentration of histidine hydrochloride was 25 mM (4.79 g / L), the concentration of sodium chloride was 80 mM (4.68 g / L), and the concentration of sucrose was 10 mg / mL.
  • a suitable amount of the solution was mixed, and sodium hydroxide was added to adjust the pH to 6.0 (liquid osmotic pressure 294 mOsm).
  • the concentration of etanercept to obtain a pharmaceutical composition is 47.7 mg / mL (Table 1).
  • pH of the pharmaceutical composition obtained by the present Example did not change with pH adjusted about the said buffer solution.
  • Example 4 instead of the buffer prepared in Example 1, histidine hydrochloride, sodium chloride, and sucrose were added to a 50 mM citric acid monohydrate solution, and the concentration of histidine hydrochloride was 25 mM (4.79 g / L).
  • a solution in which the concentration of sodium is 40 mM (2.34 g / L) and the concentration of sucrose is 10 mg / mL and 50 mM trisodium citrate dihydrate solution are mixed with histidine hydrochloride, sodium chloride, And sucrose so that the concentration of histidine hydrochloride is 25 mM (4.79 g / L), the concentration of sodium chloride is 40 mM (2.34 g / L), and the concentration of sucrose is 10 mg / mL.
  • Buffer solution liquid osmotic pressure 288 mOsm
  • the concentration of etanercept to obtain a pharmaceutical composition is 47.7 mg / mL (Table 1).
  • pH of the pharmaceutical composition obtained by the present Example did not change with pH adjusted about the said buffer solution.
  • Example 1 (Comparative Example 1) Instead of the buffer prepared in Example 1, arginine hydrochloride, sodium chloride and sucrose were added to a 25 mM sodium dihydrogen phosphate solution, and the concentration of arginine hydrochloride was 25 mM (5.27 g / L). Arginine hydrochloride, sodium chloride and sucrose were added to a solution in which the concentration was 100 mM (5.84 g / L) and the sucrose concentration was 10 mg / mL and a 25 mM sodium monohydrogen phosphate dihydrate solution.
  • a buffer solution liquid osmotic pressure of 341 mOsm adjusted to pH 6.5 by adding sodium hydroxide was prepared.
  • the concentration of etanercept to obtain a pharmaceutical composition is 46.7 mg / mL (Table 1).
  • pH of the pharmaceutical composition obtained by this comparative example did not change with pH adjusted about the said buffer solution.
  • the eight types of pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were stored in an incubator for 3 weeks at a set temperature of 37 ° C. and protected from light.
  • SDS-PAGE Prepare etanercept reduced with 2-mercaptoethanol as a reducing agent and non-reduced (non-reduced) etanercept, and separate polypeptide fragments by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). And stained by silver staining.
  • the band near 75 kDa is the main band, the band with shorter migration distance (above) is cut with the aggregate band, and the band with longer migration distance (below) is cut. It was a body band.
  • the band near 150 kDa is the main band, the band having a shorter migration distance (located above) is the aggregate band, and the band having a longer migration distance (located below). The band was a cut band.
  • a high-intensity band was confirmed in the vicinity of the 75 kDa index, and a high-intensity band was also confirmed in the vicinity of 25 kDa to 37 kDa.
  • a high-intensity band was confirmed in the vicinity of the 150 kDa index, and a high-intensity band was also confirmed in the vicinity of 75 kDa to 100 kDa.
  • Size exclusion chromatography For the eight types of pharmaceutical compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 4, size exclusion was performed at 4 time points at the start of incubator storage, 1 week after storage, 2 weeks after storage, and 3 weeks after storage. Tested by chromatography. In the test, a sample solution (50 ⁇ L each) prepared by diluting the stored pharmaceutical composition with the buffer used in each Example or Comparative Example so that the etanercept concentration was about 0.2 mg / mL. Used as a test sample.
  • the area of the main peak of the obtained chromatography (A1), the total area of individual peaks eluting before the main peak (A2), and the total area of individual peaks excluding the solvent peak eluting after the main peak ( A3) was measured by an automatic integration method, and the amounts of aggregates and cut bodies, which are impurities of etanercept, were calculated by the following equation.
  • the liquidity of the buffer solution prepared in Comparative Example 3 was on the most acidic side (pH 5.5), and the obtained etanercept was cut most.
  • the buffer solution prepared in Comparative Example 4 was most basic (pH 6.5), and the resulting etanercept aggregate amount was the largest.
  • the storage stability of etanercept in the preparation was effectively improved by adjusting the liquidity of the buffer solution within the range of pH 5.6 to 6.4.
  • the stability of etanercept which is an active ingredient, can be increased.
  • long-term preservation as a pharmaceutical composition can be enhanced.
  • examples of the aqueous solution preparation of the present invention include rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Wegner's disease, Crohn's disease, chronic obstructive pulmonary disease (COPD), hepatitis C, endometriosis It is useful as a pharmaceutical composition for asthma, cachexia, psoriasis and atopic dermatitis.

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Abstract

L'invention concerne une formulation de solution aqueuse, qui comprend de l'étanercept comme principe actif, et son procédé de production. Dans cette formulation de solution aqueuse qui comprend de l'étanercept, un stabilisateur et un tampon, le stabilisateur est de l'histidine ou un sel de celui-ci, le tampon est un acide organique ou un sel de celui-ci, et le pH est compris entre 5,6 et 6,4. Cette formulation de solution aqueuse est stable pendant une longue période de temps et peut fournir une excellente durée de vie en éliminant la génération d'agrégat et de corps tronqué causée par l'étanercept.
PCT/JP2014/054036 2013-04-30 2014-02-20 Formulation de solution aqueuse et son procede de production WO2014178216A1 (fr)

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JP2016088897A (ja) * 2014-11-06 2016-05-23 持田製薬株式会社 エタネルセプトの凍結乾燥製剤
WO2016102328A1 (fr) * 2014-12-22 2016-06-30 Ares Trading S.A. Composition pharmaceutique liquide
CN108367094A (zh) * 2015-12-10 2018-08-03 株式会社目立康 肽组合物
CN112313727A (zh) * 2018-06-12 2021-02-02 瑞乐文特生物有限公司 用于药物溶解度体外试验的缓冲溶液的制备方法、用于制备缓冲溶液的包装以及用于临床状态试验的试剂盒

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CN112912100A (zh) * 2018-10-26 2021-06-04 诺和诺德股份有限公司 稳定的司美鲁肽组合物及其用途

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