JP2005060377A - Freeze-dried preparation containing interleukin-11 - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a stable freeze-dried preparation containing IL (interleukin)-11, without having such an anxiety that the freeze-dried preparation becomes cloudy when redissolved. <P>SOLUTION: A method for preventing the freeze-dried preparation from becoming cloudy when redissolved comprises adding a nonionic surfactant to a preparation solution for the freeze-dried preparation and/or adding saccharides thereto for dealing with various problems of the freeze-dried preparation containing the IL-11, particularly, a problem of becoming cloudy when redissolved, namely, solubility (turbidity) of the preparation when reconstructed. The method solves the problem that the freeze-dried preparation containing the IL-11 becomes cloudy when redissolved, and further is effective for stabilizing the preparation. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for preventing white turbidity of a freeze-dried preparation containing interleukin-11 and a freeze-dried preparation containing interleukin-11 (hereinafter referred to as IL-11) which has achieved prevention of white turbidity upon re-dissolution.

Bioactive proteins are used in various fields as pharmaceuticals, and include various interferons, hematopoietic factors, TPA, urokinase, various CSFs, and various interleukins (IL). When these are administered parenterally, the preparation is generally liquefied at the time of administration. Physiologically active proteins have poor storage stability, and there are many difficulties in preparing liquid formulations. In general, the prepared preparation is lyophilized, liquefied with a solution at the time of use, and administered parenterally.
In lyophilized preparations, various stabilizers have been studied, and a combination of useful proteins and surfactants (Patent Document 2), mixing of IL-12 and surfactants (Patent Document 3), non-use of IL-6 There are reports of addition of reducing sugar (Patent Document 4), addition of various sugars to G-CSF (Patent Document 5), addition of a water-soluble heterocyclic compound to human growth hormone (Patent Document 6), and the like. Patent Documents 2, 3, and 4 have a problem of avoiding a decrease in the activity of the proteins described therein, and Patent Documents 5 and 6 have a problem of avoiding irreversible aggregate formation.

  IL-11, a physiologically active protein, is a protein produced by a recombinant gene manipulation method and stimulates various hematopoiesis and immune functions. Genetics Institute (currently Wyeth) developed "Neumega (product name)" consisting of recombinant human IL-11 (rhIL-11), an N-terminal proline deletion, For the prevention of severe thrombocytopenia and improvement in avoidance of platelet transfusion seen after bone marrow prevention chemotherapy in Japan. This preparation is a freeze-dried preparation described in Patent Document 1, and contains IL-11 as a concentration after re-dissolution of the preparation, 5 mg / ml, 10 mM sodium phosphate (pH 7.0), and 300 mM glycine.

International Publication No. WO95 / 28951 (corresponding US Pat. No. 6,270,757) JP 2001-192343 A JP 2002-275197 A JP-T 8-502722 Publication JP-T 8-504784 Japanese Patent Laid-Open No. 10-265404

As described in detail below, the object of the present invention is to provide a method for preventing white turbidity at the time of re-dissolution of an IL-11-containing lyophilized preparation, and a stable product comprising IL-11 that does not cause white turbidity prevention at the time of re-dissolution. It is to provide a lyophilized formulation.
Since IL-11 is relatively stable in a pH range near neutral in an aqueous solution, it is desirable to formulate it in the form of a liquid preparation for injection that is conventionally advantageous in various ways. However, since it hydrolyzes depending on the temperature, it is difficult to store the liquid preparation for a long period of time, which is practically required. In practice, it must be a lyophilized preparation. In order to obtain a lyophilized preparation, the IL-11 solution is rapidly cooled to -30 ° C. or lower, frozen by breaking the supercooling of the solution, and then dried. A cloudiness was observed.
In general, some lyophilized preparations containing physiologically active proteins are observed to be slightly soluble and cloudy in part of the lyophilized cake upon re-dissolution. The lyophilized preparation of bioactive protein is prepared by re-dissolving with water for injection during clinical use. At that time, it is quickly re-dissolved so that the presence or absence of abnormalities in the preparation, such as contamination with foreign substances, can be easily confirmed. It is necessary to Therefore, lyophilized preparations that cause white turbidity at the time of re-dissolution even if transient are considered difficult to handle in the clinical field, and a method for preventing such white turbidity at the time of re-dissolution has been desired. .

  The present inventor has conducted various studies to solve the above-mentioned problems such as transient cloudiness, and as a result, the problem of cloudiness at the time of re-dissolution of IL-11-containing lyophilized preparation, that is, solubility at the time of reconstitution (turbidity) On the other hand, by adding a nonionic surfactant and / or a saccharide to the preparation solution, the problem of cloudiness at the time of re-dissolution of IL-11-containing lyophilized preparation can be solved, It has been found that there is an effect on the improvement and stability of the preparation, and the present invention has been completed.

That is, this invention consists of the following.
1. In a production process of an interleukin 11-containing freeze-dried preparation comprising interleukin 11 and a buffer, at least one selected from the following is introduced as a means for improving the solubility of interleukin 11: How to prevent white turbidity during re-dissolution
1) Add a nonionic surfactant to the preparation solution.
2) Add sugars to the preparation.
2. 2. The method for preventing white turbidity at the time of re-dissolution of a freeze-dried preparation according to the above 1, wherein the nonionic surfactant is a polyoxysorbitan fatty acid ester.
3. 3. The method for preventing white turbidity at the time of re-dissolution of a lyophilized preparation according to 1 or 2 above, wherein the nonionic surfactant is polysorbate 80.
4). 4. The method for preventing white turbidity at the time of re-dissolution of a freeze-dried preparation according to the above 3, wherein the concentration of polysorbate 80 is about 0.0001% to 0.01% by weight in the solution at the time of preparation.
5). 2. The method for preventing cloudiness at the time of re-dissolution of a lyophilized preparation according to the above 1, wherein the saccharide is purified sucrose and / or lactose.
6). 6. The method for preventing white turbidity at the time of re-dissolution of the lyophilized preparation according to 1 to 5 above, wherein the buffer is sodium phosphate and / or histidine.
7). A method for producing a freeze-dried preparation containing interleukin 11 comprising the method according to any one of 1 to 6 above.
8). A freeze-dried preparation containing interleukin 11 prepared by the production method described in 7 above.
9. A freeze-dried pharmaceutical composition for parenteral administration containing interleukin-11, glycine, a buffer, and one or two saccharides selected from polyoxyethylene sorbitan fatty acid ester and / or purified sucrose and lactose.
10. 10. The lyophilized pharmaceutical composition for parenteral administration according to 9 above, wherein the polyalkylene glycol of the aliphatic alcohol is polysorbate 80.

The present invention is characterized by adding a nonionic surfactant and / or adding a saccharide to a preparation solution at the time of producing an IL-11-containing lyophilized preparation containing at least IL-11 and a buffer. 11-containing freeze-dried preparation and freeze-dried pharmaceutical composition for parenteral administration.
In addition, IL-11 in the present invention may be a natural derivative or a modified form obtained by a gene recombination technique or the like, or a modified form thereof (for example, a chemically modified form such as polyethylene glycol). These may be used as monomers or as homo or hetero multimers.

Examples of IL-11 selected as the most suitable embodiment of the present invention include proteins described in US Pat. No. 5,215,895, US Pat. No. 5,270,181, and US Pat. No. 5,292,646. Also included are proteins produced by recombinant gene manipulation methods, proteins purified from cell sources producing IL-11, proteins synthesized by chemical methods, or proteins obtained by combinations of the above, and in particular N-terminal proline Recombinant human IL-11 (rhIL-11), which is a deletion, can be selected as suitable. Any other IL-11 can be selected as long as the object of the present invention can be achieved.
In this specification, IL-11 includes not only natural IL-11 but also the sequence of natural IL-11 or a sequence in which several amino acid sequences are substituted, deleted and / or inserted. Means a protein exhibiting IL-11 activity (hematopoietic action).

  In the present invention, the concentration of IL-11 at the time of preparation prior to lyophilization is preferably adjusted to a concentration of 0.1 to 20 mg / ml, more preferably 1 to 10 mg / ml, more preferably 3 to 8 mg / ml. Adjusted. If desired, a stabilizer or / and a solubilizing agent for each protein can be selected and added within a range to achieve each target effect. For example, in the case of IL-11, the protein concentration at the time of preparation prior to lyophilization is preferably in the range of 0.1 mg / ml to 20.0 mg / ml, more preferably 1 mg / ml to 10 mg / ml, most preferably about 5 mg / ml. It is. An amino acid, preferably glycine, is added as a solubilizing agent, and the optimum concentration is preferably in the range of 100 mM to 400 mM, more preferably 150 mM to 350 mM, and most preferably about 300 mM.

In the present invention, the buffer means a pH stabilizer of an aqueous solution, and those generally used in the field of pharmaceutical production can be selected.
In the case of formulation of IL-11, it is possible to select a phosphate buffer containing sodium phosphate. In this case, it is necessary to add a stabilizer for the purpose of the present invention. As other buffering agents, histidine, Tris buffer, hepes buffer, and the like can be selected. It is also possible to use a combination of sodium phosphate and histidine.
The concentration of a suitable buffer at the time of preparation before lyophilization is in the range of 5 mM to 40 mM, more preferably 7 to 30 mM, particularly preferably about 10 to 20 mM. When IL-11 is selected and sodium phosphate is used, it is in the range of 5 mM to 40 mM, preferably 10 mM, and in the case of histidine, it is in the range of 5 mM to 40 mM, preferably about 20 mM.

The main means of the present invention is to add a nonionic surfactant and / or a saccharide to a preparation solution at the time of producing a lyophilized preparation.
In freeze-drying, the drug solution-filled product is stored in a freeze-drying chamber and left on a shelf. Next, the shelf of the freeze-drying cabinet is cooled to −30 ° C. or lower to freeze the filled product. After freezing, the inside of the freeze-drying chamber is depressurized, and the shelf temperature is raised to a temperature at which the filled product does not melt to sublimate the water to perform primary drying. Then, secondary drying is performed by raising shelf temperature and removing adhering water.
In order to produce such a freeze-dried preparation, a means selected from the following procedures can be specifically introduced in the present invention.
1) Add a nonionic surfactant to the preparation solution.
2) Add sugars to the preparation.
3) Crystallize the buffer.
4) Perform pre-treatment at a temperature condition of -20 ° C to 0 ° C before freeze-drying.
Introducing at least one selected from the above provides a method for preventing white turbidity at the time of re-dissolution of a freeze-dried preparation.

In the present invention, the addition of a nonionic surfactant to the preparation means that a nonionic surfactant is added to the aqueous solution (preparation solution) used for the preparation before lyophilization of IL-11. To do.
As the nonionic surfactant used in the present invention, a surfactant that does not exhibit ionic properties such as polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, and polyoxyethylene sorbitan fatty acid ester can be selected. Preferably, polyoxyethylene sorbitan fatty acid ester can be selected, more preferably polysorbate 80 and polysorbate 20, more preferably polysorbate 80, and most preferably plant-derived polysorbate 80. The nonionic surfactant of the present invention can be blended alone or in combination of two or more.

  In the present invention, the concentration of the nonionic surfactant is preferably in the range of about 0.0001% to 0.01% by weight, more preferably 0.0005 to 0.001% by weight in the solution. When such a concentration is less than 0.0001% by weight, there is a concern that white turbidity may occur when the freeze-dried cake is re-dissolved. On the other hand, when the content is higher than 0.01% by weight, there is a concern about an increase in oxidant in the preparation due to specific promotion of protein oxidation by impurities in the nonionic surfactant or a modified substance (degraded product). Therefore, the concentration of the nonionic surfactant in the present invention can be determined, for example, by selecting a concentration at which the increase in the oxidized form of IL-11 is not a concern. In addition, the nonionic surfactant of this invention also has the effect which improves the re-dissolution property of a freeze-dried cake.

  In the present invention, adding a saccharide to a preparation solution means adding a saccharide to an aqueous solution (preparation solution) used for preparation of IL-11 before lyophilization treatment. Specific examples of such saccharides include monosaccharides such as glucose, xylose, galactose, and fructose, disaccharides such as lactose, maltose, purified white sugar, and sucrose, and sugar alcohols such as mannitol, sorbitol, xylitol, and inositol. . Preferred are purified sucrose and lactose. The saccharides of the present invention can be blended alone or in combination of two or more. Note that the saccharide of the present invention also has a function of improving the stability of a preparation containing IL-11 and a function of improving the disintegration property of a freeze-dried cake upon re-dissolution.

In the present invention, the concentration of the saccharide to be added is preferably 0.1 to 50% by weight, more preferably 0.5 to 5% by weight. If the concentration is less than 0.1% by weight, there is a concern that the titer of the protein will decrease and the related substances will increase. On the other hand, when the concentration is higher than 50% by weight, there is a concern about precipitation of sugars and the like.
By selecting glycine, a buffer, and a nonionic surfactant and / or saccharide in combination with IL-11, it becomes possible to achieve the object effect of the present invention, and a phosphate buffer as a buffer. , Preferably sodium phosphate, polyoxyethylene sorbitan fatty acid ester as nonionic surfactant (more preferably, polysorbate 80, polysorbate 20, more preferably polysorbate 80, most preferably plant-derived polysorbate 80) Further effects can be achieved by selecting purified sucrose and / or lactose as the saccharide.

  The present invention provides a means for avoiding the surface of IL-11 from becoming hydrophobic during the freeze-drying process by selecting the above procedure. In addition to the present invention, there is a method for controlling lyophilization conditions as means for avoiding that the surface of IL-11 becomes hydrophobic during lyophilization treatment. Specifically, 1) a buffer is crystallized. Or 2) performing a pretreatment under a temperature condition of −20 ° C. to 0 ° C. before the freeze-drying treatment. Of course, it is possible to adopt and apply two or more of these simultaneously.

  Thus, the parenteral pharmaceutical preparation produced by introducing the method for preventing white turbidity at the time of re-dissolution of the lyophilized preparation is not particularly limited as long as it is usually a pharmaceutically acceptable dosage form. In addition, the lyophilization conditions at the time of manufacturing the lyophilized preparation can be appropriately set as known per se, except for the conditions related to the pretreatment conditions.

  An example of a method for producing the IL-11 freeze-dried preparation of the present invention is as follows. A solution is prepared by mixing an aqueous solution containing a protein at a high concentration with a dilution buffer in which glycine, a nonionic surfactant, and / or a saccharide, etc. are mixed and dissolved to a final desired concentration. The prepared liquid is filled in a container and frozen at −30 ° C. or lower. Thereafter, the lyophilized preparation of the present invention can be prepared by drying under reduced pressure.

  The parenteral pharmaceutical composition of the IL-11-containing lyophilized preparation of the present invention contains pharmaceutical additives that are usually added to the parenteral pharmaceutical composition (eg, solubilizers, preservatives, stabilizers, emulsifiers, painlessness). Agents, isotonic agents, buffers, excipients, colorants, thickeners). For example, L-arginine, cyclodextrins, etc. are mentioned as a solubilizing agent. Examples of the preservative include sodium benzoate and methyl paraoxybenzoate. Examples of the emulsifier include lecithin. Examples of soothing agents include benzyl alcohol and chlorobutanol. Examples of isotonic agents include sodium chloride. Examples of the excipient include maltose which is also used as the saccharide of the present invention. Examples of the thickener include hyaluronic acid.

  In the present invention, an IL-11-containing freeze-dried preparation having good re-dissolvability upon re-dissolution of the freeze-dried preparation was provided, and the convenience of clinical use of the IL-11-containing freeze-dried preparation was achieved. The IL-11-containing lyophilized preparation of the present invention exhibits excellent stability in a solution state or a lyophilized state. In particular, in a lyophilized state, it can be stored at room temperature, and the lyophilized preparation exhibits excellent resolubility and white turbidity prevention effect upon reconstitution.

  Hereinafter, the present invention will be described with reference to Examples, Reference Examples, Experimental Examples, and the like, but the present invention is not limited thereto.

The test methods used in the examples are described below. Test method 1 was used for measuring turbidity.
[Test method 1] Evaluation of turbidity of redissolved solution by measuring absorbance As a turbidity evaluation of redissolved solution, water for injection (1.2 mL) was injected into a freeze-dried preparation containing 5 mg of IL-11, and 3, 5, Measure the absorbance of the redissolved solution after 7 minutes at OD650 nm. In addition, regarding the turbidity evaluation method of the solution by the absorbance measurement, the following two reports were referred.
(1) Pharmaceutical Research 26 (4) 223-230 (1955) “Examination of Turbidity Evaluation Method in Pharmaceutical Solution Testing”
(2) J. Pharm. Sci. Tech., 48 (2) 64-70 (1994) “A turbidimetric method to determine visual appearance of protein solutions”
[Test Method 2] Confirmation of related substances by SDS-PAGE (silver staining)
For confirmation of related substances by SDS-PAGE (silver staining), dimers and degradation products due to covalent bonds are to be measured. As the gel, a polyacrylamide gel (large gel format) having an acrylamide concentration gradient of 10 to 20% is used. Add 50 μg of sample to each lane and perform electrophoresis under a constant current of 45 mA. For staining, use a silver staining kit (2D-silver staining reagent II “Daiichi”, manufactured by Daiichi Chemicals) and perform staining according to the attached instructions. In addition, about evaluation, only qualitative evaluation by visual confirmation is performed.

[Test Method 3] Quantification of related substances by high performance liquid chromatography (RP-HPLC)
For the determination of the amount of related substances by high-performance liquid chromatography, degradation products, Met122 oxidants, and covalently bonded multimers are measured. Test 100 μL of a solution containing 0.65 mg of IL-11 by liquid chromatography under the following conditions. The area percentage of peak areas other than IL-11 is measured by the automatic integration method.
Detector: Ultraviolet absorptiometer column: A stainless steel tube with an inner diameter of about 4.6 mm and a length of about 10 cm is filled with a 10 μm styrene-divinylbenzene copolymer for liquid chromatography.
Column temperature: constant temperature around 25 ° C.
Mobile phase A: A solution prepared by adding water to 1.0 g of trifluoroacetic acid to make 1000 mL.
Mobile phase B: A solution prepared by adding 800 mL of acetonitrile for liquid chromatography and water to 1.0 g of trifluoroacetic acid to make 1000 mL.
Mobile phase feeding: Concentration gradient control by changing the mixing ratio of mobile phase A and mobile phase B as follows.

流量：毎分0.5 mL

Flow rate: 0.5 mL per minute

[Test Method 4] Quantification of multimer mass by high performance liquid chromatography (SE-HPLC)
For quantification of the amount of multimers, non-covalent and covalent multimers are used as measurement targets. Test 50 μL of a solution containing 0.6 mg of IL-11 by liquid chromatography under the following conditions. The area percentage of the peak area with a retention time smaller than that of IL-11 is measured by the automatic integration method.
Detector: Ultraviolet absorptiometer column: A stainless steel tube with an inner diameter of about 7.8 mm and a length of about 30 cm is filled with 5 μm of porous silica gel for liquid chromatography.
Column temperature: constant temperature around 4 ° C.
Mobile phase: 7.5 mg of glycine, 29.2 g of sodium chloride, 9.75 g of 2-morpholinoethanesulfonic acid in 750 mL of water, adjust the pH to 6.0 by adding sodium hydroxide test solution, and add water to make 1000 mL .
Flow rate: Adjusted so that the retention time of IL-11 is about 9 minutes.

  The effects of adding a nonionic surfactant and a saccharide as stabilizers were confirmed by preparing the preparations of Examples 1 to 9 and Comparative Examples 1 and 2.

  Based on an IL-11 concentration of 5 mg / mL, a sodium phosphate buffer concentration of 10 mM, and a glycine concentration of 300 mM, a sample solution to which saccharides described in Table 2 were added was prepared.

A sample solution was prepared in the same manner as in Example 1 except for the saccharides listed in Table 2.

A sample solution was prepared in the same manner as in Example 1 except for the saccharides listed in Table 2.

(Comparative Example 1)
A sample solution was prepared in the same manner as in Example 1 except that no saccharide was added.

After aseptic filtration of the sample solutions of Examples 1 to 3 and Comparative Example 1, each vial was preliminarily sterilized in an aseptic environment by 1 mL, freeze-dried, capped and capped to obtain the preparation of the present invention. . The preparation of the present invention and the comparative preparation were stored at 5 ° C. and 40 ° C., and the stability was compared. The test results are shown in Table 2. As is clear from Table 2, in the preparation without a sugar of the comparative example, an increase in the amount of multimers and a decrease in the residual titer rate were remarkably observed particularly under high temperature (40 ° C.) conditions, In the sugar-added preparations of Examples 1 to 3, the effect of preventing the increase in the amount of multimers and the decrease in the residual titer rate were observed. In particular, in the preparation to which the purified sucrose of Example 3 was added, no clear fluctuations in the amount of multimer and the residual titer rate were observed under any storage conditions. Therefore, it can be said that the preparation of the present invention is a preparation having very high stability.

  Based on the IL-11 concentration of 5 mg / mL, the sodium phosphate buffer concentration of 10 mM, and the glycine concentration of 300 mM, sample solutions were prepared in which the addition amounts of purified sucrose and polysorbate 80 listed in Table 3 were varied.

A sample solution was prepared in the same manner as in Example 4 except that the amounts of purified sucrose and polysorbate 80 listed in Table 3 were varied.

A sample solution was prepared in the same manner as in Example 4 except that the amounts of purified sucrose and polysorbate 80 listed in Table 3 were varied.

A sample solution was prepared in the same manner as in Example 4 except that the amounts of purified sucrose and polysorbate 80 listed in Table 3 were varied.

---：測定せず (Comparative Example 2)
A sample solution was prepared in the same manner as in Example 4 except that purified sucrose and polysorbate 80 were not added.

---: Not measured

The sample solutions of Examples 4 to 7 and Comparative Example 2 were aseptically filtered, filled into vials that had been sterilized 1 mL at a time in an aseptic environment, freeze-dried, capped and capped to obtain the preparation of the present invention. . The preparation of the present invention and the comparative preparation were stored at 40 ° C., and the stability was compared. The test results are shown in Table 3 and FIGS. The analytical sample is 50 μg / Lane. As is clear from Table 3, the preparation of Comparative Example without purified sucrose and polysorbate 80 (Comparative Example 2) increased the number of related substances and multimers under high temperature (40 ° C.) conditions. In the purified sucrose-containing preparations (Examples 4 to 6), no increase was observed in the amount of related substances and multimers. From FIG. 1 to FIG. 3, in the comparative example, a marked increase in covalent dimer (SDS-Stable Dimer) and an increase in low molecular weight degradation products were observed. Only the band of books was slightly increased. Therefore, it can be said that the formulation of the present invention is a very stable formulation. The meaning of each lane in FIGS. 1 to 3 is as shown in Table 4 below.

  Sample solutions were prepared by varying the amounts of purified sucrose and polysorbate 80 listed in Table 5 based on IL-11 concentration 5 mg / mL, sodium phosphate buffer concentration 10 mM, and glycine concentration 300 mM.

A sample solution was prepared in the same manner as in Example 8 except that the amount of polysorbate 80 listed in Table 5 was varied.

実施例４〜９及び比較例２の試料溶液を無菌濾過後無菌環境下で1 mLずつ予め滅菌処理したバイアル瓶に充填し、凍結乾燥後打栓閉塞を行い本発明製剤を得た。本発明製剤および比較製剤の注射用水による再溶解性について比較検討した。試験結果を表５に示す。比較例の製剤では比較的高い吸光度（すなわち高い濁度または低い澄明度）を示したのに対し、実施例で調製された本発明製剤では低い吸光度（すなわち低い濁度または高い澄明度）を示した。

The sample solutions of Examples 4 to 9 and Comparative Example 2 were aseptically filtered and filled in vials that had been sterilized in advance by 1 mL each in a sterile environment. The re-solubility of the preparation of the present invention and the comparative preparation with water for injection was compared. The test results are shown in Table 5. The comparative formulation showed a relatively high absorbance (ie high turbidity or low clarity), whereas the inventive formulation prepared in the examples showed a low absorbance (ie low turbidity or high clarity). It was.

It is an analysis result of SDS-PAGE (silver staining) of a sample stored at 40 ° C./one month at the start of the test of the sample. It is an analysis result of SDS-PAGE (silver staining) of a sample stored at 40 ° C./one month at the start of the test of the sample. It is an analysis result of SDS-PAGE (silver staining) of a sample stored at 40 ° C./one month at the start of the test of the sample.

Claims (10)

In a production process of an interleukin 11-containing freeze-dried preparation comprising interleukin 11 and a buffer, at least one selected from the following is introduced as a means for improving the solubility of interleukin 11: How to prevent white turbidity during re-dissolution
1) Add a nonionic surfactant to the preparation solution.
2) Add sugars to the preparation. The method for preventing cloudiness at the time of re-dissolution of a lyophilized preparation according to claim 1, wherein the nonionic surfactant is a polyoxysorbitan fatty acid ester. The method for preventing cloudiness at the time of re-dissolution of a lyophilized preparation according to claim 1 or 2, wherein the nonionic surfactant is polysorbate 80. The method for preventing cloudiness at the time of re-dissolution of a lyophilized preparation according to claim 3, wherein the concentration of polysorbate 80 is about 0.0001% to 0.01% by weight in the solution at the time of preparation. The method for preventing cloudiness at the time of re-dissolution of a lyophilized preparation according to claim 1, wherein the saccharide is purified sucrose and / or lactose. The method for preventing cloudiness at the time of re-dissolution of a freeze-dried preparation according to any one of claims 1 to 5, wherein the buffer is sodium phosphate and / or histidine. A method for producing a freeze-dried preparation containing interleukin 11 comprising the method according to any one of claims 1 to 6. A freeze-dried preparation containing interleukin 11 prepared by the production method of claim 7. A freeze-dried pharmaceutical composition for parenteral administration containing interleukin-11, glycine, a buffer, and one or two saccharides selected from polyoxyethylene sorbitan fatty acid ester and / or purified sucrose and lactose. The lyophilized pharmaceutical composition for parenteral administration according to claim 9, wherein the polyalkylene glycol of the aliphatic alcohol is polysorbate 80.

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