JP7411983B2 - Anti-inflammatory agents, prefilled syringes, and kits - Google Patents

Description

The present invention relates to an anti-inflammatory agent, a prefilled syringe, and a kit.

In Japan, which has entered a super-aging society, the development of treatments for acute and chronic inflammatory diseases is even more desired. While the inflammatory response is a biological defense system against external factors such as infection, it is known to be associated with diseases such as arthritis, arteriosclerosis, pressure ulcers, and cancer.

Steroids, nonsteroidal drugs, and antibody drugs are used as drugs to suppress inflammation, but side effects such as adrenal insufficiency, infection, osteoporosis, and autoimmune diseases are a problem. In addition, there were problems with drug stability, development costs, and manufacturing costs.

Therefore, research is underway into drugs that are safer and have anti-inflammatory properties. For example, hydrogels containing steroids (Non-Patent Document 1), polysaccharides that exhibit anti-inflammatory properties (Non-Patent Document 2), and high molecular weight hyaluronic acid that exhibits anti-inflammatory effects (Non-Patent Document 3) have been proposed. ing.

Uri Soiberman, Siva P. Kambhampati, Tony Wu, Manoj K. Mishra, Yumin Oh, Rishi Sharma, Jiangxia Wang, Abdul Elah Al Towerki, Samuel Yiu, Walter J. Stark, Rangaramanujam M. Kannan, Subconjunctive injectable dendrimer-dexamethasone gel for the treatment of corneal inflammation. Biomaterials, 125, 38-53 (2017). Hong Chen, JiAN SUN, JUN LIU, YARUN GOU, XIN ZHANG, XIAONAN WU, RUI SUN, SIXUE TANG, JUAN KAN, CHUNLU QIAN, CHUNLU QIANG, C HANGHAI JIN, STRUCTURAL CHARACTERIZATION And and INFLAMMATY ACTIVITY OF ALKALI -SOLUBLE POLYSACCHARIDES FROM PURPLE PURPLE sweet potato. International Journal of Biological Macromolecules, 131, 484-494 (2019) Jamie E. Rayahin, Jason S. Buhrman, Yu Zhang, Timothy J. Koh, Richard A. Gemeinhart, High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomaterials Science and Engineering, 1, 481-493 (2015).

In the steroid-encapsulating hydrogel described in Non-Patent Document 1, it is difficult to control the sustained release rate of the steroid, and side effects originating from the steroid are a problem.
Although some polysaccharides isolated from natural products such as those described in Non-Patent Document 2 exhibit anti-inflammatory properties, their effects are weak and it is difficult to mass produce them.
Although the high molecular weight hyaluronic acid described in Non-Patent Document 3 exhibits anti-inflammatory properties compared to low molecular weight hyaluronic acid, its effect is weak and insufficient.

Therefore, an object of the present invention is to provide an anti-inflammatory agent that exhibits a sufficient anti-inflammatory effect without containing a steroid compound, in other words, has excellent safety and anti-inflammatory properties. Another object of the present invention is to provide a prefilled syringe and a kit.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that the above-mentioned problems can be achieved by the following configuration.

[1] An anti-inflammatory agent containing as an active ingredient at least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000.
[2] The anti-inflammatory agent according to [1], wherein the polyethyleneimine has a molecular weight of 100 to 1200.
[3] The anti-inflammatory agent according to [1], wherein the polyethyleneimine has a molecular weight of 200 to 1,000.
[4] The anti-inflammatory agent according to [1], which contains polyethyleneimine having a molecular weight of 200 to 1000.
[5] The anti-inflammatory agent according to any one of [1] to [4], wherein the polyethyleneimine is branched.
[6] The anti-inflammatory agent according to any one of [1] to [5], further containing a gelling agent.
[7] The anti-inflammatory agent according to [6], wherein the gelling agent is hyaluronic acid or a derivative thereof.
[8] The anti-inflammatory agent according to [7], further containing a crosslinking agent.
[9] The anti-inflammatory agent according to [8], wherein the crosslinking agent is sulfonated cellulose.
[10] The anti-inflammatory agent according to any one of [1] to [9], further containing water.
[11] The anti-inflammatory agent according to any one of [1] to [10], which acts on macrophages to suppress the production of inflammatory cytokines.
[12] A prefilled syringe comprising the anti-inflammatory agent according to any one of [1] to [10] and a syringe containing the anti-inflammatory agent.
[13] At least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000, and a gelling agent, and mixed at the time of use to prepare a gel containing the above compound. kit for.
[14] The kit according to [13], further comprising water.

According to the present invention, an anti-inflammatory agent having excellent safety and anti-inflammatory properties can be provided. Further, according to the present invention, a prefilled syringe and a kit can also be provided.

This is the measurement result of the anti-inflammatory effect of polyethyleneimine of various molecular weights.

The present invention will be explained in detail below.
Although the description of the constituent elements described below may be made based on typical embodiments of the present invention, the present invention is not limited to such embodiments.
In this specification, a numerical range expressed using "~" means a range that includes the numerical values written before and after "~" as the lower limit and upper limit.

[Anti-inflammatory agent]
The anti-inflammatory agent according to the embodiment of the present invention contains at least one compound selected from the group consisting of ethylenediamine and polyethyleneimine having a molecular weight of 100 to 2000 (hereinafter also referred to as "specific polyethyleneimine"). It is an anti-inflammatory agent that contains it as an active ingredient.

The content of the above-mentioned compound in the anti-inflammatory agent may be determined as appropriate depending on the usage and dosage, and is not particularly limited as long as the effect can be obtained, but it is generally 0.00000% based on the total mass of the anti-inflammatory agent. 001 to 99.999% by mass is preferred. Note that the anti-inflammatory agent may contain one kind of the above-mentioned compounds alone, or two or more kinds thereof. When the anti-inflammatory agent contains two or more of the above compounds, the total content is preferably within the above numerical range.

As used herein, polyethyleneimine refers to a compound having a repeating unit consisting of an amine and -CH ₂ CH ₂ - bonded to the amine, and the repeating unit is represented by the following formula 1.

In Formula 1, X ¹ represents a hydrogen atom or a group represented by A1. In formula A1, X ² and X ³ each independently represent a hydrogen atom or a group represented by A1, and * represents a bonding position.
Polyethyleneimine may be linear, that is, composed only of repeating units represented by -CH ₂ CH ₂ -NH-, or may be branched, but the more excellent polyethyleneimine of the present invention A branched chain is preferred in that an effective anti-inflammatory agent can be obtained.

Although the polyethyleneimine is not particularly limited, examples thereof include compounds represented by the following formulas.

The above polyethyleneimine can be synthesized by a known synthesis method. Specifically, for example, ethylenediamine and/or diethylenetriamine may be reacted with ethyleneimine under an acid catalyst such as hydrochloric acid, sulfuric acid, or para-toluenesulfonic acid.
Moreover, commercially available products can also be used as polyethyleneimine. Commercially available products include Epomin (registered trademark) SP series (manufactured by Nippon Shokubai), Lupasol series (manufactured by BASF), and LUGALVAN-G15000 (manufactured by BASF).

Polyethyleneimine has at least a primary amino group and a secondary amino group in its molecule. When polyethyleneimine further has a tertiary amino group, it becomes branched. Note that in this specification, branched polyethyleneimine also includes polyethyleneimine in the form of a dendrimer consisting of a primary amino group and a tertiary amino group.

The content of primary amino groups in polyethyleneimine is not particularly limited, but it is preferably 1 to 99 mol% based on the total of primary amino groups, secondary amino groups, and tertiary amino groups.
Note that the ratio of primary amino groups, secondary amino groups, and tertiary amino groups in polyethyleneimine is measured by, for example, ¹³ C-NMR (Nuclear Magnetic Resonance) method or infrared spectroscopy. Desired.
Further, such branched polyethyleneimine can be obtained by ring-opening polymerization of ethyleneimine using a known method.

The specific polyethyleneimine has a molecular weight of 100 to 2,000, preferably 100 to 1,200, and preferably 200 to 1,000. In addition, in this specification, the molecular weight of polyethyleneimine means an average molecular weight, and means the molecular weight measured by the boiling point elevation method or the viscosity method. If the molecular weight of polyethyleneimine is 2000 or more, the desired anti-inflammatory properties cannot be obtained, if it is 1200 or less, a better anti-inflammatory effect can be obtained, and if it is 1000 or less, an even better anti-inflammatory effect can be obtained. Further, when the molecular weight of polyethyleneimine is 200 or more, a more excellent anti-inflammatory effect can be obtained.

The molecular weight dispersity of the specific polyethyleneimine is not particularly limited, but is generally preferably from 1.1 to 1.5.

The anti-inflammatory agent according to the embodiment of the present invention only needs to contain at least one compound selected from the group consisting of ethylenediamine and specific polyethyleneimine, and an anti-inflammatory agent with better effects can be obtained. In this respect, it is more preferable to contain polyethyleneimine having a molecular weight of 200 to 1000, and even more preferable to contain branched polyethyleneimine having a molecular weight of 200 to 1000.

The anti-inflammatory agent according to the embodiment of the present invention has the effect of acting on macrophages and suppressing the production of inflammatory cytokines, as shown in the Examples described below.

The anti-inflammatory agent according to the embodiment of the present invention can be used as an external preparation for the skin, and may be formulated into a dosage form containing a medium or base material acceptable for the above uses. It includes all dosage forms suitable for topical application, such as solutions, gels, solids, kneaded anhydrous products, emulsions obtained by dispersing an oil phase in an aqueous phase, suspensions, microemulsions, It may be provided in the form of microcapsules, fine granulocytes, etc., as creams, skins, lotions, powders, ointments, sprays, concealer sticks, etc.

The anti-inflammatory agent according to the embodiment of the present invention includes a solvent, a solubilizing agent, a concentrating agent, a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, a fragrance, a surfactant, It may also contain emulsifiers, fillers, sequestrants, chelating agents, preservatives, vitamins, blocking agents, wetting agents, essential oils, dyes, pigments, and hydrophilic or lipophilic active agents.

Furthermore, the anti-inflammatory agent according to the embodiment of the present invention may be formulated into a pharmaceutical composition for oral or parenteral administration. Parenteral administration may include rectal, topical, transdermal, intravenous, intramuscular, intraperitoneal, and subcutaneous administration.

Dosage forms for parenteral administration include injection preparations, fillers, drops, ointments, lotions, sprays, suspensions, oils, suppositories, and the like. The anti-inflammatory agent according to the embodiment of the present invention includes a gelling agent, a crosslinking agent, a surfactant, an excipient, a coloring agent, a spice, a preservative, a stabilizer, a buffering agent, a suspending agent, and others. It may also contain adjuvants.

The anti-inflammatory agent according to the embodiment of the present invention may contain a gelling agent. Containing a gelling agent improves the ease of handling when used as an injection preparation. Gelling agents are not particularly limited, but include, for example, guar gum, locust bean gum, queen seed, carrageenan, galactan, gum arabic, tara gum, tamarind, farcellan, gum karaya, tragacanth, carra gum, gum tragacanth, pectin, pectic acid, and sodium salt. salts such as alginic acid and sodium salts, mannan; starches such as rice, corn, potato, wheat, etc.; xanthan gum, dextran, succinoglucan, curdlan, hyaluronic acid and its derivatives and salts thereof, xanthan gum, pullulan, gellan gum , chitin, chitosan, agar, cassow extract, chondroitin sulfate, casein, collagen, gelatin, albumin; methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and its salts such as sodium, methylhydroxypropylcellulose, Cellulose and its derivatives such as sodium cellulose sulfate, dialkyldimethylammonium cellulose sulfate, crystalline cellulose, and cellulose powder; starch-based polymers such as soluble starch, carboxymethyl starch, methylhydroxypropyl starch, and methyl starch; hydroxypropyltrimonium chloride starch; Starch derivatives such as corn starch aluminum octenyl succinate; alginic acid derivatives such as sodium alginate and propylene glycol alginate; polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), vinylpyrrolidone/vinyl alcohol copolymer, polyvinyl methyl ether; polyethylene glycol, polypropylene Glycol, polyoxyethylene/polyoxypropylene copolymer; Amphoteric methacrylate ester copolymer such as (methacryloyloxyethyl carboxybetaine/alkyl methacrylate) copolymer, (acrylates/stearyl acrylate/ethylamine oxide methacrylate) copolymer; ( dimethicone/vinyl dimethicone) crosspolymer, (alkyl acrylate/diacetone acrylamide) copolymer, (alkyl acrylate/diacetone acrylamide) copolymer AMP; partially saponified polyvinyl acetate, maleic acid copolymer; vinylpyrrolidone/dialkyl methacrylate Aminoalkyl copolymers; acrylic resin alkanolamines; polyesters, water-dispersible polyesters; polyacrylamides; polyacrylic acid ester copolymers such as polyethyl acrylate, carboxyvinyl polymers, polyacrylic acids and their salts such as sodium salts; Acrylic acid/methacrylic acid ester copolymer; acrylic acid/alkyl methacrylate copolymer; cationized cellulose such as polyquaternium-10, diallyldimethylammonium chloride/acrylamide copolymer such as polyquaternium-7, polyquaternium-22, etc. acrylic acid/diallyldimethylammonium chloride copolymer such as polyquaternium-39, acrylic acid/diallyldimethylammonium chloride/acrylamide copolymer such as polyquaternium-39, acrylic acid/cationized methacrylate ester copolymer, acrylic acid/cationized methacrylic Acid amide copolymer, acrylic acid/methyl acrylate/methacrylamidopropyltrimethylammonium chloride copolymer such as polyquaternium-47, chlorinated methacrylic acid choline ester polymer; cationized oligosaccharide, cationized dextran, guar hydroxypropyltrimonium Cationized polysaccharides such as chloride; polyethyleneimine; cationic polymers; copolymers of 2-methacryloyloxyethylphosphorylcholine such as polyquaternium-51 and butyl methacrylate copolymers; acrylic resin emulsions, polyethyl acrylates Polymer emulsions such as emulsions, polyacrylalkyl ester emulsions, polyvinyl acetate resin emulsions, natural rubber latex, synthetic latex; nitrocellulose; polyurethanes and various copolymers; various silicones; acrylic-silicone graft copolymers, etc. Various silicone copolymers; Various fluorinated polymers; 12-hydroxystearic acid and its salts; Dextrin fatty acid esters such as dextrin palmitate and dextrin myristate; silicic anhydride, fumed silica (ultrafine silicic anhydride), Examples include aluminum magnesium silicate, sodium magnesium silicate, metal soap, dialkyl phosphate metal salt, bentonite, hectorite, organically modified clay mineral, sucrose fatty acid ester, fructooligosaccharide fatty acid ester, and the like.

Among them, as shown in the examples below, hyaluronic acid or its derivatives are preferred as gelling agents, from the viewpoint that the resulting anti-inflammatory agent has lower toxicity to cells or has a better anti-inflammatory effect. preferable.

Furthermore, when the anti-inflammatory agent in the embodiment of the present invention contains a gelling agent, it may further contain a crosslinking agent. A crosslinking agent can improve the mechanical strength of the resulting gel.

Although the crosslinking agent is not particularly limited, for example, sulfonated cellulose represented by the following formula may be used.

In the above formula, k, m, and n represent mol% of each repeating unit, and are not particularly limited, but k is preferably 25 to 95 mol%, more preferably 40 to 90 mol%. m is preferably 4 to 70 mol%, more preferably 7 to 60 mol%. n is preferably 1 to 70 mol%, more preferably 10 to 30 mol%.

The above-mentioned sulfonated cellulose is a cellulose containing a sulfonated structure in which a ring is opened between the 3rd and 4th positions of a glucose unit shown in the following formula.

The above formula shows a state in which the sulfone group (-SO ₃ H) is dissociated in water or the like, and the counter cation is not limited to Na ⁺ but may be a proton, K ⁺ or the like.

Sulfonated cellulose can be synthesized, for example, by the route shown in the following formula described in Henrikki Liimatainen et al., Cellulose (2013) 20:741-749.

First, raw cellulose is dispersed in water to obtain a dispersion. To the above dispersion, 50 to 200 mol% of sodium periodate (NaIO ₄ ) was added when the amount (k) of glucose units in cellulose was 100 mol%, and the mixture was heated at 40 to 60°C while shielding from light. By stirring for 2 to 6 hours, aldehyde cellulose is produced.

Next, the aqueous solution containing unreacted substances is removed by vacuum filtration, and the procedure of washing with ultrapure water is repeated several times, followed by freeze-drying to obtain a dry powder of aldehyde cellulose. In the above formula, when the initial value of k is 100 mol%, m is 1 to 80 mol%, preferably 10 to 50 mol%.

The amount of aldehyde groups can be determined by neutralization titration using conductivity measurement using an aqueous sodium hydroxide solution, and is 0.5 to 8 mmol/g, preferably 1 to 7 mmol/g, more preferably 1 to 5 mmol/g. mmol/g.

As the raw material cellulose, for example, cellulose obtained from plants, animals, etc. such as softwood pulp, hardwood pulp, and cotton pulp, paper using these, waste paper, etc. can be used.

Next, the aldehyde cellulose is dispersed in ultrapure water, and sodium pyrosulfite (Na ₂ S ₂ O ₅ ) is added in an amount of 20 to 200 mol%, preferably 50 to 150 mol%, with the aldehyde group amount being 100 mol%. and react at room temperature for 12 to 24 hours with stirring. The product is collected by centrifugation, purified by washing with ultrapure water etc. to remove unreacted substances, and then homogenized for about 10 to 30 minutes using an ultrasonic homogenizer to obtain sulfonated cellulose nanofibers ( (sometimes abbreviated as "sCNF") can be obtained. Yield is approximately 80-90%.

sCNF is biodegradable. In the present invention, "biodegradability" was confirmed by decomposition of 1% by mass or more in 1 day in phosphate buffered saline (PBS) of p7.4 at 37°C. This biodegradability is determined when m+n, that is, ring-opened units, is at least 1 mol%, preferably 10 to 50 mol%, when the initial value of the amount (k) of glucose units in the raw material cellulose is 100 mol%. This is thought to be due to certain reasons. Furthermore, since sCNF has a ring-opening unit, the degree of crystallinity measured by X-ray diffraction is 20 to 70%, which is lower than the raw material cellulose, which has a degree of crystallinity of about 90%.

Moreover, the anti-inflammatory agent according to the embodiment of the present invention may contain a solvent. The solvent is not particularly limited, but water, organic solvents that are miscible with water in any proportion, and mixed solvents thereof are preferred, and water is more preferred. Examples of the organic solvent include alcohols (including polyhydric alcohols).

In addition, when the anti-inflammatory agent according to the embodiment of the present invention contains a gelling agent, it may further contain other ingredients, and various drugs to be delivered, proteins, etc. are blended, and these local It may be used as a delivery carrier or a sustained release delivery carrier.
Examples of the drug include anti-inflammatory drugs, antithrombotic drugs, antibiotics, growth factors such as fibroblast growth factor, vascular endothelial cell growth factor, and hepatocyte growth factor.
Furthermore, it may be used as a vaccine carrier by supporting a virus or cancer antigen protein.

The method for producing the anti-inflammatory agent according to the embodiment of the present invention is not particularly limited, and the components described above may be mixed. The mixing method is not particularly limited, but other solid components may be dispersed or dissolved in the solvent, or solids may be mixed together. When mixing solids, the solids of each component may be pulverized before mixing. The method of pulverization is not particularly limited, but includes, for example, a wet pulverization method. Examples of the wet pulverization method include ball milling and homogenizer pulverization.

Further, by filling a syringe with the anti-inflammatory agent according to the embodiment of the present invention and leaving it to stand, a pre-filled syringe pre-filled with the anti-inflammatory agent can be manufactured.

The prefilled syringe obtained in this way exhibits fluidity by simply pushing the plunger rod of the syringe and expelling the injection preparation (anti-inflammatory agent) contained therein from the needle. Not only can it be excreted, but the anti-inflammatory agent also has excellent storage stability. Note that the present invention also includes a kit including the prefilled syringe.

The dosage of the active ingredient (already explained compound) of the anti-inflammatory agent according to the embodiment of the present invention is determined by the age, sex, weight, disease status and severity of the subject to be administered, the route of administration, or the judgment of the prescriber. It depends. Determination of appropriate doses based on such factors is within the level of those skilled in the art, and the daily dose may be, for example, from 0.1 mg/kg/day to 100 mg/kg/day, more specifically. can be, but is not limited to, 5 mg/kg/day to 50 mg/kg/day.

The present invention will be explained in more detail below based on Examples. The materials, usage amounts, proportions, processing details, processing procedures, etc. shown in the following examples can be changed as appropriate without departing from the spirit of the present invention. Therefore, the scope of the present invention should not be construed as being limited by the Examples shown below.

(Suppression of TNF-α production)
3 × 10 ⁴ mouse bone marrow-derived macrophages (BMDM) were seeded in a 96-well plate and precultured for 24 hours. LPS (lipopolysaccharide) was added to polyethyleneimine, which was adjusted to 100 μg/mL in a medium, to 100 ng/mL. 100 μL of this solution was added to each well and cultured for 24 hours. The samples include ethylenediamine (indicated as "PEI60" in the figure), "PEI150" with a molecular weight of 150 (tris(2-aminoethyl)amine purity of 90% or more), and "PEI300" with a molecular weight of 300. , "PEI600" with a molecular weight of 600, "PEI1200" with a molecular weight of 1200, and "PEI10000" with a molecular weight of 10,000 were used.
Furthermore, as controls, a sample to which only the medium was added (control) and a sample to which LPS was added at 100 ng/mL were used.

After culturing, the supernatant was collected, and the concentration of tumor necrosis factor (TNF-α), a type of inflammatory cytokine, contained in the supernatant was determined by enzyme-linked immunosorbent assay (ELISA). As a result, when only LPS was added, 346 pg/mL of TNF-α was produced, whereas by adding PEI300 at the same time, the production of TNF-α could be suppressed more than twice. PEI1200 also showed high anti-inflammatory effects. On the other hand, TNF-α was below the detection limit in PEI10000.

Since the cytotoxicity of PEI10,000 was thought to be the cause of this, cell viability was evaluated by WST-8 assay. As a result, PEI10000 was found to have high cytotoxicity. The results are summarized in Figure 1.

From the results in Figure 1, PEI600 with a molecular weight of 100 to 2000 has a better anti-inflammatory effect compared to PEI10000, and PEI600 with a molecular weight of 200 to 1200 has an even better anti-inflammatory effect compared to PEI150. PEI600, which has an inflammatory effect and has a molecular weight of 200-1000, was found to have a particularly good anti-inflammatory effect compared to PEI1200.

In Figure 1, Table A represents the production amount of TNF-α (unit: pg/mL), Table B represents the cell survival rate by WST-8 assay, and Table C represents the amount of TNF-α produced (unit: pg/mL). It represents the amount of TNF-α produced per 1×10 ⁴ cells (unit: pg/1×10 ⁴ cells) calculated from the results in Table B. In addition, "-" in FIG. 1 indicates that it was below the detection limit (no anti-inflammatory effect was obtained).

(Suppression of IL-6 production)
3 × 10 ⁴ mouse bone marrow-derived macrophages (BMDM) were seeded in a 96-well plate and precultured for 24 hours. LPS was added to polyethyleneimine ("PEI300" with a molecular weight of 300) adjusted to 100 ng/mL in a medium to 100 ng/mL. 100 μL of this solution was added to each well and cultured for 24 hours. As controls, a sample to which only the medium was added (control) and a sample to which LPS was added at 100 ng/mL were used.
After culturing, the supernatant was collected, and the concentration of interleukin-6 (IL-6), an inflammatory cytokine, contained in the supernatant was determined by ELISA. As a result, compared to the control, when polyethyleneimine was used, the amount of IL-6 produced was reduced by more than half, confirming an excellent anti-inflammatory effect.

Claims (14)

It is an anti-inflammatory agent,
An anti-inflammatory agent having a molecular weight of 300 to 2000 and containing polyethyleneimine having a tertiary amino group as an active ingredient. The anti-inflammatory agent according to claim 1, wherein the polyethyleneimine has a molecular weight of 300 to 1,200. The anti-inflammatory agent according to claim 1, wherein the polyethyleneimine has a molecular weight of 300 to 1,000. The anti-inflammatory agent according to claim 1, wherein the polyethyleneimine has a molecular weight of 300 to 600. The anti-inflammatory agent according to any one of claims 1 to 4, wherein the polyethyleneimine is branched. The anti-inflammatory agent according to any one of claims 1 to 5, further comprising a gelling agent. The anti-inflammatory agent according to claim 6, wherein the gelling agent is hyaluronic acid or a derivative thereof. The anti-inflammatory agent according to claim 7, further comprising a crosslinking agent. The anti-inflammatory agent according to claim 8, wherein the crosslinking agent is sulfonated cellulose. The anti-inflammatory agent according to any one of claims 1 to 9, further comprising water. The anti-inflammatory agent according to any one of claims 1 to 10, which acts on macrophages to suppress the production of inflammatory cytokines. A prefilled syringe comprising the anti-inflammatory agent according to any one of claims 1 to 10, and a syringe containing the anti-inflammatory agent. It is a kit,
polyethyleneimine having a molecular weight of 300 to 2000 and having a tertiary amino group;
and a gelling agent,
A kit for preparing a gel containing the polyethyleneimine by mixing at the time of use. 14. The kit of claim 13, further comprising water.