TW201726111A - Liquid pharmaceutical agent comprising high concentration antibody - Google Patents

Abstract

The present invention can provide, at a low cost, a liquid formulation containing a high concentration of recombinant monoclonal antibodies comprising 150 mg/mL to 200 mg/mL of recombinant monoclonal antibodies, and 45 mM to 94 mM of an amino acid component in which the histidine component is less than 5 mM, and having a pH of 5.5 to 6.7. The liquid formulation containing a high concentration of recombinant monoclonal antibodies is stable, achieving limited dimer generation and limited deamidation during long-term storage, and exhibits a kinematic viscosity that allows for subcutaneous injection.

Description

Liquid preparation containing high concentration of antibody

The present invention relates to a liquid preparation containing a high concentration of antibodies.

A recombinant monoclonal antibody such as tocilizumab is currently used as an active ingredient of a pharmaceutical product. In order to obtain a sufficient therapeutic effect, the amount of the recombinant monoclonal antibody administered per time may be relatively large. However, for example, when a preparation for subcutaneous injection which can be administered by itself is used, the amount of the injection once is limited. Therefore, it is sometimes necessary to make the concentration of the recombinant monoclonal antibody contained in the preparation to a high concentration.

Heretofore, as a liquid preparation containing a high concentration of recombinant monoclonal antibodies, a formulation containing a specific amount of arginine, methionine, polysorbate (Patent Document 1), and a specific amount of spermine are known. A formulation formulation of a hydrochloride, a histidine, or a polysorbate (Patent Document 2).

Further, in these preparation formulations, when the recombinant monoclonal antibody content is 150 mg/mL or more, the content of the amino acid component such as arginine is 100 mM or more.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2009/084659

[Patent Document 2] International Publication No. 2004/091658

Conventionally, in order to prepare a liquid preparation containing a high concentration of a recombinant monoclonal antibody, it is generally considered to be necessary to add a high concentration of an amino acid component of 100 mM or more. Therefore, in order to provide a liquid preparation containing a high concentration of recombinant monoclonal antibody which inhibits dimer formation and inhibits deamikation during long-term storage and exhibits kinetic viscosity for subcutaneous injection at a low cost, further techniques are required. Development.

The present invention provides a stable high-concentration recombinant monoclonal antibody liquid preparation which can inhibit dimer formation and inhibit deamikation during long-term storage at low cost, and exhibits a high concentration recombination single sheet which can perform dynamic viscosity of subcutaneous injection. The liquid preparation of the strain antibody is a subject.

The invention is as follows.

<1> A liquid preparation containing a high concentration of recombinant monoclonal antibody, which comprises a recombinant monoclonal antibody of 150 mg/mL to 200 mg/mL, and an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM, and pH is 5.5~6.7.

<2> The liquid preparation according to <1>, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride, and methionine.

<3> The liquid preparation of <1> or <2>, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride.

<4> The liquid preparation according to any one of <1> to <3> which contains an amino acid component of 75 mM to 93 mM.

<5> The liquid preparation according to any one of <1> to <4> which contains 90 mM of an amino acid component.

<6> The liquid preparation according to any one of <1> to <5> which has a pH of 5.8 to 6.4.

<7> The liquid preparation according to any one of <1> to <6> which has a pH of 6.0 to 6.2.

<8> The liquid preparation according to any one of <1> to <7> which contains a recombinant monoclonal antibody of 170 mg/mL to 190 mg/mL.

<9> The liquid preparation according to any one of <1> to <8> which contains 180 mg/mL of recombinant monoclonal antibody.

<10> The liquid preparation according to any one of <1> to <9> which further contains a polyhydric alcohol.

<11> The liquid preparation according to <10>, wherein the recombinant monoclonal antibody is selected from the group consisting of Tocilizumab, Trastuzumab, Rituximab, and Palivizumab. (Palivizumab), Infliximab, Basiliximab, Gitutobe Monoclonal oxazolamide (Gemtuzumab ozogamicin), bevacizumab (Bevacizumab), tembutamomab tiuxetan, adalimumab, cetuximab, lei Ranibizumab, Omalizumab, Eculizumab, Panitumumab, Ustekinumab, Golimumab, Card That monoclonal antibody (Canakinumab), denosumab (Denosumab), mogamulizumab, Ofatumumab, Pertuzumab, trastuzumab, Itan New (Trastuzumab emtansine), Brentuximab vedotin, Natalizumab, Nivolumab, Alemtuzumab, Sukinimumab At least one of the group consisting of Ramucirumab and Ipilimumab.

According to the present invention, it is possible to provide a stable high-concentration recombinant monoclonal antibody liquid preparation which can inhibit dimer formation and inhibit deamikation during long-term storage at a low cost, and exhibits a high concentration of dynamic viscosity which can be subcutaneously injected. A liquid preparation of recombinant monoclonal antibodies.

[Formation of the Invention]

Hereinafter, the present invention will be described in detail.

The liquid preparation containing the high-concentration recombinant monoclonal antibody of the present invention (hereinafter also referred to as "liquid preparation") contains a recombinant monoclonal antibody of 150 mg/mL to 200 mg/mL, and a 45 mM to 94 mM having a histidine acid component of less than 5 mM. Amino acid components (total) and a pH of 5.5 to 6.7. Further, the liquid preparation may contain other ingredients.

The liquid preparation of the present invention transmits an amino acid component containing 45 mM to 94 mM of a histidine component of less than 5 mM, and adjusts the pH to a range of 5.5 to 6.7, even if the recombinant monomer contains a concentration of up to 150 mg/mL to 200 mg/mL. In the case of long-term storage in a liquid preparation, the antibody can inhibit the formation of dimer and inhibit the action of deamikamine, and the effect of exhibiting the dynamic viscosity of subcutaneous injection can be exhibited. Further, the liquid preparation of the present invention can be provided at a lower cost than the conventional liquid preparation containing a high concentration of recombinant monoclonal antibody because it contains a low amount of an amino acid component of an amino acid component of 45 mM to 94 mM.

In addition, the numerical range shown by "~" in this specification shows the range of the minimum value and the maximum value which are the values of the before and after the "~".

Further, the unit of the molar concentration is expressed by M (volume), and the mM is 10 ^-3 mol/L.

In the present specification, the term "long-term storage" is, for example, stored at 2 ° C to 8 ° C for one year or more, preferably at 2 ° C to 8 ° C for 2 years or more, and more preferably at 2 ° C. Store at ~8°C for 2 to 3 years.

(recombinant monoclonal antibody)

A recombinant monoclonal antibody system refers to an antibody produced by a cell transformed by recombinant DNA technology. The recombinant monoclonal antibody is preferably expressed or secreted as an animal cell, but the type of the recombinant monoclonal antibody is not particularly limited. Preferably, for example, a recombinant monoclonal antibody which can be used as a pharmaceutical product.

Further, the recombinant monoclonal antibody which can be contained in the liquid preparation of the present invention is not only a recombinant monoclonal antibody derived from an animal such as a human, a mouse or a rat, but also a recombinant monoclonal antibody such as a chimeric antibody or a humanized antibody. Further, the immunoglobulin type of the antibody is not particularly limited, and may be any of IgG, IgA, IgD, IgE, IgM, and the like such as IgG1, IgG2, IgG3, or IgG4.

Further, the recombinant monoclonal antibody further comprises an antibody fragment such as Fv, Fab or F(ab) ₂ or a variable region of the antibody which is conjugated to a linker such as a peptide linker, or a divalent or higher valence. A low molecular weight antibody such as a single-stranded Fv (Diabody such as scFv, sc(Fv) ₂ or scFv dimer) or the like.

Such recombinant monoclonal antibodies can be prepared according to the methods described in International Publication No. 92/019759 and International Publication No. 2005/090405.

Examples of the recombinant monoclonal antibody include, for example, Trastuzumab, Rituximab, Palivizumab, and Infliximab (for example, trastuzumab, rituximab, and rituximab). Infliximab), Basiliximab, Gemtuzumab ozogamicin, Bevacizumab, Ibritumomab tiuxetan, Tortoise Anti (Tocilizumab), Adalimumab (Adalimumab), Cetuximab, Ranibizumab, Omalizumab, Eculizumab, Panitumumab, Eudragit Usteninumab, Golimumab, Canakinumab, Denosumab, Mogamulizumab, Ofatumumab, Patux Pertuzumab, Trastuzumab emtansine, Brentuximab vedotin, Natalizumab, Nivolumab, Alemtuzumab, Secukinumab, Ramucirumab and Ipilimumab.

Further, in the case of a recombinant monoclonal antibody, Tocilizumab, Trastuzumab, Rituximab, Palivizumab, Inflix are preferred. Infliximab, Basiliximab, Bevacizumab, Adalimumab, Cetuximab, Ranibizumab, Omar Omalizumab, Eculizumab, Panitumumab, Ustekinumab, Golimumab, Canakinumab, Earth Noxumab, Mogamulizumab, Ofatumumab, Pertuzumab, Natalizumab, Navolumab ), alemtuzumab, sulkinumab, remomitum (Ramucirumab) or Ipilimumab, preferably trastuzumab, Tocilizumab, Infliximab, Bevacizumab, Adalimumab, Ustekinumab, Golimumab or Denosumab, more preferably tocilizumab, infliximab ( Infliximab), Bevacizumab, Adalimumab or Denosumab.

Furthermore, it is most preferable to betuzumab in terms of recombinant monoclonal antibodies.

The tocilizumab is an amino acid sequence (Gln1-Gly448) having a heavy chain of a commercially available ACTEMRA (registered trademark) and an amino acid sequence (Asp1-Cys214) of a light chain, and the same amino acid sequence. Yes. Further, the amino acid sequence (Glu1-Gly448) of the heavy chain of ACTEMRA and the amino acid sequence (Asp1-Cys214) of the light chain are described in the Sequence Listing attached to International Publication No. 2005/090405.

Further, the N-terminal residue of the heavy chain may also be pyroglutamic acid (pGlu) instead of glutamic acid. The C-terminal residue of the heavy chain may also be a 447 amino acid (Pro) or a 449 amino acid residue added to the 448th glycine acid (Gly) with an amino acid (Lys) instead of 448. Amino acid residue.

The liquid preparation of the present invention contains a recombinant monoclonal antibody of 150 mg/mL to 200 mg/mL. Further, from the viewpoint of sufficiently exerting the effects of the present invention, it is preferred to contain a recombinant monoclonal antibody of 170 mg/mL to 190 mg/mL, and more preferably a recombinant monoclonal antibody of 180 mg/mL. The invention The recombinant monoclonal antibody to be used is preferably not freeze-dried and reconstituted in the production method.

(amino acid component)

The liquid preparation of the present invention contains an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM.

The amino acid component other than the histidine component is not limited, and examples thereof include arginine, arginine hydrochloride, methionine, glycine, phenylalanine, aspartic acid, and bran. Aminic acid, lysine, aspartame, tryptophan, cysteine and cysteamine. Further, the amino acid component other than the histidine component is preferably selected from the group consisting of arginine and arginine hydrochloride, from the viewpoint of suppressing the formation of dimer and inhibiting the action of deamikation during long-term storage. At least one of the group consisting of methionine. Further, the amino acid component other than the histidine component preferably contains arginine, arginine hydrochloride and methionine, and more preferably contains arginine hydrochloride and methionine. .

The histidine component is preferably at least one selected from the group consisting of histidine and histamine hydrochloride, more preferably histamic acid and histamine hydrochloride.

The liquid preparation of the present invention may contain a histamic acid of less than 5 mM in a liquid preparation, and preferably contains a histidine component of 1 mM or more and 4 mM or less, from the viewpoint of adjusting the pH to a preferred range. It is preferred to contain a histidine component of 2 mM or more and 4 mM or less.

In the case of the amino acid component, it is preferred to contain an amino acid component of 45 mM to 94 mM having a histidine component of less than 5 mM in the liquid preparation. Further, it preferably contains an amino acid component of 75 mM to 93 mM, and more preferably contains 90 mM of an amino acid component.

(Polyol)

The liquid preparation may further contain a polyol.

Examples of the polyhydric alcohol include propylene glycol, glycerin (glycerol), threose, threitol, erythritol, erythritol, ribose, arabinose, arabitol, sucrose, maltitol, and sorbose. Alcohol, sorbose, glucose, mannose, mannitol, levulose, dextrose, maltose, trehalose, fructose, xylitol, inositol, galactose, xylose, fructose, sucrose, 1,2,6 - hexanetriol. Among them, the polyhydric alcohol is preferably sucrose, trehalose or the like, and is preferably sucrose.

One or two or more kinds of these polyols may be combined in the liquid preparation.

Further, when the content of the amino acid component is less than 70 mM, it is preferred to use a polyol in combination from the viewpoint of suppressing the formation of a dimer.

The content of the polyhydric alcohol is not particularly limited, and may be appropriately determined depending on the viewpoint of the osmotic pressure of the liquid preparation. For example, it may be 30 mg/mL to 80 mg/mL, 40 mg/mL to 70 mg/mL, or 50 mg/mL to 60 mg/mL.

(other ingredients)

The liquid preparation may contain, in addition to the recombinant monoclonal antibody and the amino acid component, other components required for formulation of the liquid preparation. As other components, it may contain, for example, a solubilizing agent, an isotonic agent, a preservative, an anti-adsorbent, and the like. The sulfur reducing agent and the antioxidant are preferably solubilizers.

The solubilizing agent may, for example, be a surfactant, particularly a nonionic surfactant, specifically polyoxyethylene hardened castor oil, polysorbate (polysorbate 80, polysorbate 40, polysorbate) Alcohol ester 20, etc.), polyoxyethylene sorbitan monolaurate, castor oil fatty acid ethyl ester, and nicotinic acid decylamine.

As the isotonic agent, for example, in addition to the polyhydric alcohol, salts such as sodium chloride, potassium chloride, and calcium chloride may be mentioned.

Examples of the preservative include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid, phenol, cresol, m-cresol, and chlorocresol.

Examples of the anti-adsorbing agent include human serum albumin, lecithin, dextran, hydroxypropylcellulose, methylcellulose, and polyethylene glycol.

Examples of the sulfur-containing reducing agent include N-acetylcysteine, N-ethinylcysteine, lipoic acid, thiodiglycol, thioethanolamine, thioglycerol, and thio Sorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione.

Examples of the antioxidant include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and salts thereof, L-ascorbyl palmitate, and L-ascorbic acid. Stearic acid ester, sodium hydrogen sulfite, sodium sulfite, triamyl gallate, propyl gallate, disodium edetate (EDTA‧2Na), sodium pyrophosphate, sodium metaphosphate.

In addition, when preparing a liquid preparation containing a recombinant monoclonal antibody containing a recombinant monoclonal antibody of 150 mg/mL or less, for example, 100 mg/mL, an amino acid component containing 45 mM to 94 mM of a histidine component of less than 5 mM may be prepared. And a liquid preparation containing a recombinant monoclonal antibody having a pH of 5.5 to 6.7.

(pH)

The pH of the liquid preparation is 5.5 to 6.7. Further, in the range in which subcutaneous injection can be carried out, the pH is preferably from 5.8 to 6.4, more preferably from 6.0 to 6.2, from the viewpoint of adjusting the dynamic viscosity of the liquid preparation. The pH can be measured, for example, by a pH meter (Model: HM-30G, manufactured by DKK-TOA Co., Ltd.). In addition, the measurement of the pH may be carried out according to the method described in the 16th revision of the Japanese Pharmacopoeia, and may be carried out, for example, at normal temperature (15 ° C to 25 ° C).

The pH of the liquid preparation can be adjusted by the histidine component contained in the liquid preparation, but other buffers can be used to adjust the pH of the liquid preparation, as needed. Examples of other buffering agents include phosphate (sodium or potassium), sodium hydrogencarbonate, citrate (sodium or potassium), sodium acetate, sodium succinate, phosphoric acid, carbonic acid, citric acid, succinic acid, and malic acid. , gluconic acid, glycine.

The liquid preparation of the present invention can be administered, for example, by injection (subcutaneous injection, intravenous injection, intramuscular injection, etc.), transdermal, transmucosal, nasal, and transpulmonary.

When subcutaneous injection is performed, the amount of recombinant antibody administered per antibody is 150 mg/mL to 200 mg/mL, but the amount of the injection is limited. this The liquid preparation of the invention exhibits a dynamic viscosity which can be administered subcutaneously even if it contains a high concentration of recombinant monoclonal antibody of 150 mg/mL to 200 mg/mL. Therefore, the liquid preparation of the present invention is preferably used for subcutaneous injection from the viewpoint of exerting the effects of the present invention. In the case of subcutaneous injection, not only the doctors who are headed by doctors, but also the patients who are self-injected by themselves, the patients who are uncomfortable with self-injection are also in the country. Mostly, it is preferred that the dynamic viscosity is low and the stability over time is excellent.

The dynamic viscosity of the liquid preparation of the present invention is, for example, preferably 6 mm ² /s to 15 mm ² /s, more preferably 7 mm ² /s to 14 mm ² /s, more preferably 8 mm ² / after the liquid preparation has just been prepared. s~12mm ² /s.

The dynamic viscosity can be measured by an Ubbel-type viscometer (16th revision Japanese Pharmacopoeia general test method 2.53 viscosity measurement method 1).

The dimer product and the low molecular weight decomposed product can be measured by, for example, a high performance liquid chromatography system (Prominence, manufactured by Shimadzu Corporation) by size exclusion chromatography.

The amidoxime can be measured by ion exchange chromatography using, for example, a high performance liquid chromatography system (Prominence, manufactured by Shimadzu Corporation).

The invention is further described in detail in the following examples, but the invention should not be construed as limited. In the present specification, unless otherwise specified, % is expressed as % by mass.

[Examples] (Example 1) Confirmation of stabilization effect of liquid preparation

For a liquid preparation containing a high concentration of recombinant monoclonal antibody (180 mg/mL in terms of tocilizumab), the stabilization of the preparation of the present invention containing 94 mM of the amino acid component and having a pH of 5.5 to 6.7 was evaluated. The impact.

In the present study, in order to confirm the stabilization effect of the liquid preparation, the evaluation samples of No. 1 to No. 5 were prepared. The formulations of the respective evaluation samples are as follows. Further, "-" in the compositions in Tables 1 and 5 indicates that it was not blended. Further, the tocilizumab used in the examples can be subjected to the methods described in International Publication No. 92/019759, International Publication No. 2005/090405, International Publication No. 99/063058, and International Publication No. 2002/072615. modulation.

In order to evaluate the stability of the liquid preparation, each evaluation sample was filled in a 2 mL glass vial with 0.5 mL, and the thermal acceleration test of each of the evaluation samples was carried out (60 ° C - 2 weeks, 50 ° C - 2 weeks, and 40 ° C - 4 weeks). save). Thereafter, it was confirmed by size exclusion chromatography (SEC) and ion exchange chromatography (IEX). Purity of recombinant monoclonal antibodies before and after thermal acceleration. Further, the usability of the liquid preparation was evaluated based on the dynamic viscosity. The analytical conditions for size exclusion chromatography (SEC), ion exchange chromatography (IEX), and dynamic viscosity are as follows.

[size exclusion chromatography]

The evaluation sample was diluted with a mobile phase to a protein concentration of 1 mg/mL to prepare an evaluation sample solution.

20 μL of the sample solution was evaluated by liquid chromatography according to the following conditions, and the peak area of the polymer division, the main division, and the low molecular division was measured by an automatic analysis method, and the amount (%) was determined.

Analysis condition

Column: TSKgel G3000SWx1 7.8mm I.D.×30cm (manufactured by TOSOH)

Protection column: TSKgel guard column SW _XL 6.0mm ID × 4cm (manufactured by TOSOH)

Mobile phase: pH 6.8 phosphate buffer (20 mmol/L phosphate buffer containing 300 mmol/L sodium chloride pH 6.8)

Evaluation of sample injection amount: about 20 μg based on recombinant monoclonal antibody

Flow rate: 0.5mL/min

Detection wavelength: 280nm

Computational

Total area of each peak = peak area of main division + peak area of high molecular division Peak area of product + low molecular differentiation

Polymer classification (%) = (total of each peak area of the polymer division / total area of each peak) × 100

Low molecular discrimination (%) = (total of each peak area of low molecular division / total area of each peak) × 100

[Dynamic Viscosity Measurement]

The evaluation sample is directly adjusted to the evaluation sample solution.

The tension generated by the pusher when the test solution is aspirated while the injection needle is attached to the glass syringe is measured. The obtained tension is fitted to a calibration curve obtained by measuring the tension and dynamic viscosity obtained by measuring the dynamic viscosity of 2 mm ² /s to 20 mm ² /s, which is a standard solution for viscosity meter calibration (NIPPON GREASE). Dynamic viscosity. The measurement temperature of the dynamic viscosity was set to 20 °C.

The evaluation results of the size exclusion chromatography obtained in the present example are shown in Table 2. The evaluation results of the ion exchange chromatography are shown in Table 3. The evaluation results of the dynamic viscosity are shown in Table 4.

A formulation containing 94 mM amino acid component and having a pH adjusted to 6 (assessment sample No. 5), although the total amount of amino acid and the content of histidine component were small, it was stored at 60 ° C. In the thermal acceleration test in which the product was stored at 50 ° C for 2 weeks and stored at 40 ° C for 4 weeks, the amount of the polymer and the low molecular weight were used, and the total amount of the amino acid and the content of the histidine component were used. The evaluation sample No. 1 was equivalent to the same degree.

In addition, the sample No. 5 was evaluated, and it was confirmed that the increase in the acidity of the deamidated body contained in the ion exchange chromatography was suppressed to the same level as the evaluation sample No. 1.

Further, the formulation having the pH adjusted to 5 (evaluation sample No. 2) and the formulation having the pH adjusted to 6.8 (evaluation sample Nos. 3 and 4) were evaluated in comparison with the polymer No. 5 containing the polymer of the dimer. Can be seen to increase the tendency, and the package The acidic differentiation of the deaminating amine can also be seen as an increasing tendency, so it is clear that the pH range is an important control item.

From the viewpoint of the evaluation of the presence or absence of the addition of histidine (evaluation samples No. 3 and 4), it is apparent that the histidine component is an important component from the viewpoint of adjusting the pH of the liquid preparation to a desired pH range.

Further, the dynamic viscosity of the sample No. 5 was evaluated to be lower than that of the evaluation sample No. 1, and the change was small, so that the usability for subcutaneous injection can be improved.

As described above, even when the content of the amino acid component is 94 mM or less, it is possible to prepare a liquid preparation exhibiting the dynamic viscosity of subcutaneous injection by adjusting the pH to a range of 5.5 to 6.7.

(Example 2)

In the liquid preparation containing the recombinant monoclonal antibody (180 mg/mL in terms of Tocilizumab) when the content of the amino acid component was further lower than 94 mM, the stability of the amino acid component was further evaluated. effect.

In the present study, in order to evaluate the possibility of further lowering the concentration of the amino acid component, the samples No. 6-1 to No. 8 were prepared. The formulations of the respective evaluation samples are as follows.

In order to evaluate the stability of the liquid preparation, each of the evaluation samples was filled in a 2 mL glass vial with 0.5 mL, and a thermal acceleration test of each of the evaluation samples was carried out (at 60 ° C - 1 week, 50 ° C - 2 weeks, 40 ° C - 8 weeks). And 25 ° C -4 months to save). The purity of the recombinant monoclonal antibody before and after thermal acceleration was evaluated by size exclusion chromatography and ion exchange chromatography; and the usability was evaluated based on the dynamic viscosity. The analysis conditions are as shown in Example 1.

The evaluation results of the size exclusion chromatography obtained in the present example are shown in Table 6. The evaluation results of the ion exchange chromatography are shown in Table 7, and the evaluation results of the dynamic viscosity are shown in Table 8.

Any of the formulations is shown in Table 6, and the size exclusion chromatography was compared with the evaluation sample (evaluation sample No. 1) in which the amino acid content was higher than that of the amino acid component shown in Example 1 (evaluation sample No. 1). In the evaluation of 50 ° C - 2 weeks from the test in which the thermal stability was the same condition, it was confirmed that the increase in the molecular division was suppressed.

From this result, it is understood that the formation of the dimer in the liquid preparation can be suppressed by setting the content of the amino acid component to 93 mM or less.

Further, as shown in Table 7, compared with the evaluation sample No. 1, the production suppression effect of the acid separation including the deamination body was evaluated by the evaluation of 50 ° C - 2 weeks in which the thermal stability was the same condition. Further improvements can be confirmed. In addition, in terms of dynamic viscosity, no significant increase was observed in any of the evaluated samples. Add, confirmation shows that there is no problem in the use of subcutaneous injection.

From the evaluation results of the formulations (evaluation samples No. 7 and 8) which further lowered the concentration of the amino acid component by 90 mM, by further reducing the concentration of the amino acid component from 90 mM, under accelerated conditions, it can be seen that the size was In the evaluation of the exclusion chromatography, the tendency of the polymer of the dimer to be increased is increased, but by adding sucrose (refined white sugar), it is confirmed that the effect of the increase can be suppressed.

Further, even when 55.66 mg/mL of sucrose was added, no significant increase in dynamic viscosity was observed, and it was confirmed that the useability was not problematic in subcutaneous injection. Obviously, by combining the amino acid component with sucrose, volatilization can suppress the effect of dimer formation.

[Industrial availability]

The preparation of the present invention can provide a stable high-concentration recombinant monoclonal antibody liquid preparation which can inhibit the formation of dimer and inhibit the action of deamikamine during long-term storage at a low cost, and exhibits a dynamic viscosity which can be subcutaneously injected. The liquid preparation of high concentration recombinant monoclonal antibody is extremely useful in industry.

Claims (11)

A liquid preparation containing a high concentration of recombinant monoclonal antibody, comprising a recombinant monoclonal antibody of 150 mg/mL to 200 mg/mL, and an amino acid component having a histidine component of less than 5 mM of 45 mM to 94 mM, and having a pH of 5.5 ~6.7. The liquid preparation according to claim 1, wherein the amino acid component other than the histidine component is at least one selected from the group consisting of arginine, arginine hydrochloride and methionine. The liquid preparation according to claim 1 or claim 2, wherein the histidine component is at least one selected from the group consisting of histidine and histidine hydrochloride. The liquid preparation according to any one of claims 1 to 3, which contains an amino acid component of 75 mM to 93 mM. The liquid preparation according to any one of claims 1 to 4, which contains a 90 mM amino acid component. The liquid preparation according to any one of Claims 1 to 5, which has a pH of 5.8 to 6.4. The liquid preparation according to any one of Claims 1 to 6, which has a pH of 6.0 to 6.2. The liquid preparation according to any one of claims 1 to 7, which comprises a recombinant monoclonal antibody of 170 mg/mL to 190 mg/mL. The liquid preparation according to any one of claims 1 to 8, which contains 180 mg/mL of recombinant monoclonal antibody. A liquid preparation according to any one of claims 1 to 9, wherein It further contains a polyol. The liquid preparation of claim 10, wherein the recombinant monoclonal antibody is selected from the group consisting of Tocilizumab, Trastuzumab, Rituximab, and Palivizumab. Infliximab, Basiliximab, Gemtuzumab ozogamicin, Bevacizumab, Tiemozumab tilbutam Ibritumomab tiuxetan), Adalimumab, Cetuximab, Ranibizumab, Omalizumab, Eculizumab, Panitumumab (Panitumumab), Ustekinumab, Golimumab, Canakinumab, Denosumab, Mogamulizumab, Alphamu Oftamumab, Pertuzumab, Trastuzumab emtansine, Brentuximab vedotin, Natalizumab, Nivolumab, Alemtuzumab, Secukinumab, Removumab (Ramucir) At least one of the group formed by umab) and Ipilimumab.