JP3070980B2 - Lecithinated superoxide dismutase and drug containing the same as active ingredient - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a lecithinated superoxide dismutase and a medicament containing the same as an active ingredient.

[0002]

2. Description of the Related Art A drug delivery system (DDS) has been used for a long time to enhance the effect of a drug and reduce side effects. DDS is an attempt to move a drug to a site in need thereof, as selectively as possible, for the required time, thereby enhancing the effect of the drug and greatly reducing systemic side effects.

[0003] There are various carriers used for DDS, for example, liposomes and lipid microspheres. Liposomes are obtained by dissolving naturally occurring lipids such as lecithin and cholesterol in an organic solvent, diffusing them into water by sonication or the like, and encapsulating the drug therein. On the other hand, lipid microspheres are suspensions of soybean oil and lecithin in water, with lecithin on the surface and a drug encapsulated inside.

[0004] In both cases, the drug is encapsulated mainly by physical bonding. Liposomes have poor stability, and lipid microspheres require that the drug to be encapsulated is fat-soluble, and furthermore, a special production apparatus must be used.

On the other hand, superoxide dismutase (hereinafter, abbreviated as SOD) is a superoxide anion which is widely distributed in living organisms such as animals, plants, and microorganisms, and is a free (free) reactive oxygen. It is known as an enzyme that decomposes radicals. In terms of drugs, anti-rheumatic drugs, use during myocardial infarction or organ transplantation,
It is expected to be applied to various inflammations such as removal of radicals generated after the use of antithrombotic agents (for antiinflammatory agents, see Pharmacia, Vol. 17, p. 411 (1981)).

[0006]

When SOD is administered intravenously, its cell affinity is low, its half-life in blood is only 4 to 6 minutes, and SOD is rapidly excreted in urine. . To increase the blood half-life of SOD,
Has been modified with ficoll, polyethylene glycol, rat albumin, and dextran to produce macromolecules.

[0007] However, it has been reported that SOD modified with ficoll or polyethylene glycol significantly reduces the enzyme activity of SOD and has low cell affinity, and that SOD modified with rat albumin has antigenicity. ing. In the modification with dextran, SOD
Has an enhanced anti-inflammatory effect, but has no effect of suppressing immunogenicity.

[0008] Various conventionally known modified SODs have practical problems in view of the above-mentioned reasons already reported, and a decrease in tissue permeability due to macromolecularization. Therefore, at present, none of the modified SODs has reached clinical application.

[0009]

DISCLOSURE OF THE INVENTION The present inventors have studied the conversion of SOD into DDS, which is completely different from these conventional ones and can provide excellent effects. As a result, the following specific lecithinated superoxide dismutase was obtained. I found The present invention is this particular lecithinated superoxide dismutase. That is, the present invention is a specific superoxide dismutase bound to lecithin via the following specific chemical crosslinking, and a drug containing the same as an active ingredient.

A lecithinated superoxide dismutase represented by the following formula [1]: A- [C (O)-(CH ₂ ) _n C (O) -B] _m ··· [1] where A is derived from a human coordinated with copper and / or zinc and having the 111-position represented by serine B: Residue of lysolecithin having a hydroxyl group at position 2 of glycerol, excluding the hydrogen atom of the hydroxyl group at position 2 m: an integer of 1 or more n: integer of 2 or more

[0011] The lecithinated superoxide dismutase of the present invention has a very uniform distribution in the living body and cell affinity from conventional SOD, and has a very uniform activity with a residual activity of 90% or more. It can be expected to enhance the pharmacological activity of SOD, reduce side effects, and promote absorption.

The lecithinated superoxide dismutase of the present invention is usually a lecithin derivative in which a chemical crosslinking agent is bound to the residue of lysolecithin, in which copper and / or zinc is coordinated, and the 111-position is represented by serine. Human-derived superoxide dismutase (hereinafter referred to as Cu-Zn Ser
¹¹¹ h-SOD).

B is a residue of lysolecithin having a hydroxyl group at the 2-position of glycerol represented by the following formula [2], except for the hydrogen atom of the 2-position hydroxyl group. _{-O-CH (CH 2 OR)} [CH 2 OP (O) (O -) (OCH 2 CH 2 N + (CH 3) 3)] ··· [2] In the above formula [2], R is a fatty acid And a saturated (unsaturated) fatty acid residue having 8 to 30 carbon atoms. Particularly preferred R 1 is a myristoyl group, palmitoyl group, stearoyl group, or other saturated fatty acid residue having 14 to 22 carbon atoms.

In the above formula [1], -C (O)-(CH ₂ ) _n C (O)-represents a residue of a chemical crosslinking agent. The residue of this chemical crosslinking agent is a linear dicarboxylic acid represented by HO-C (O)-(CH ₂ ) _n C (O) -OH, and its anhydride, its ester, and other dicarboxylic acids. This is a residue obtained by removing both hydroxyl groups of a chemical crosslinking agent comprising a reactive derivative of an acid. Hereinafter, this residue is referred to as chemical crosslinking.

[0015] This chemical crosslinking is linked to the lysolecithin residue through an ester bond. It is considered that the other end of the chemical bridge is directly bonded to the amino group of Cu-Zn type Ser ¹¹¹ h-SOD by an amide bond or the like. In this formula, n is an integer of 2 or more, and — (CH ₂ ) _n — represents a straight-chain alkylene group, particularly preferably a straight-chain alkylene group having 2 to 10 n.

The lecithinated Cu- represented by the above formula [1]
Zn-type Ser ¹¹¹ h-SOD is produced, for example, by using Cu-Zn-type recombinant h-SOD and a lysolecithin derivative of the formula [3]. Z-C (O) - ( CH 2) n C (O) -B ··· [3]

In the above formula, B and n are the same as in the case of formula [1]. In the formula [3], Z represents a hydroxyl group or a group obtained by removing an carbonyl group from a group forming an active ester. For example, p-nitrophenol, 1,3,5-trichlorophenol, pentafluorophenol, 2,4-dinitrophenol, N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxy-5-norbornene-2,3-dicarboxylic It is a group obtained by removing a hydrogen atom of a hydroxyl group of a hydroxyl group-containing compound such as acid imide, 8-hydroxyquinoline and 2-hydroxypyridine. A known method can be used for the method of synthesizing the active ester (see Izumiya et al., “Basic and Experimental Peptide Synthesis” (1985) published by Maruzen Co., Ltd.).

Examples of the method for bonding the lysolecithin derivative represented by the formula [3] and Cu-Zn type Ser ¹¹¹ h-SOD include the following.

When Z is a hydroxyl group in the formula [3], the reaction is carried out by a carbodiimide method. Carbodiimides include diethylcarbodiimide, diisopropylcarbodiimide, dicyclohexylcarbodiimide, 1-ethyl-3
-(3-dimethylaminopropyl) carbodiimide and the like. For example, a 1 to 10 wt% aqueous solution of the compound [3] is adjusted to pH 4 to 6 with hydrochloric acid, and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide is added at room temperature or 0 ° C., and the pH is adjusted to 4 again. Adjust to ~ 6. SOD was added and the pH was kept at 4 to 6 at room temperature or 0 ° C. for 1 hour, followed by stirring for 5 to 20 hours to obtain lecithinated Cu-Zn type Ser ¹¹¹ h-SOD.

In the formula [3], when Z represents a group obtained by removing an carbonyl group from a group forming an active ester,
It can bind directly to u-Zn type Ser ¹¹¹ h-SOD. The reaction is carried out by mixing the lecithin derivative and the Cu-Zn type Ser ¹¹¹ h-SOD in an aqueous solution of a salt such as sodium borate, sodium phosphate, potassium phosphate, sodium bicarbonate and the like.

If necessary, an organic solvent such as N, N-dimethylformamide, N-methylpyrrolide, N, N-dimethylacetamide, sulfolane, dimethylsulfoxide, acetone, 1,4-dioxysan or methanol may be added. it can. The reaction temperature is preferably -20 to 50 ° C, and 0 to 20 ° C.
Is more preferred. The reaction time varies depending on the reaction temperature and the mixing method, but is usually 2 to 24 hours.

The charged amount of the lecithin derivative represented by the formula [3] is 0.2 to the amino group of Cu-Zn type Ser ¹¹¹ h-SOD.
A molar amount of up to 8 times is appropriate. Cu-
The number of molecules of the lecithin derivative (formula [3]) to be bound to Zn-type Ser ¹¹¹ h-SOD can be adjusted.

The reaction solution thus obtained contains lecithinated Cu-Zn-type Ser ¹¹¹ h-SOD and unreacted Cu-Zn-type Ser ¹¹¹ h-SOD
, And unreacted lecithin derivative coexist, but the reaction solution is subjected to gel filtration and ion exchange column chromatography to obtain the desired lecithinated Cu-Zn Ser ¹¹¹ h-SOD.
Can be obtained. The thus obtained lecithinized Cu-Zn-type Ser ¹¹¹ h-SOD is a mixture that obtained by combining lecithin derivatives of various molecular number in Cu-Zn-type Ser ¹¹¹ h-SOD.

As an active ingredient compound, Cu-Zn type Ser ¹¹¹ h-SO
If a lecithin-Cu-Zn-type Ser ¹¹¹ h-SOD is desired such that the number of molecules of the lecithin derivative bound to D is uniform, the lecithin-Cu-Zn-type Ser obtained by the above-described method is desired.
^The desired lecithinated Cu-Zn-type Ser ¹¹¹ h-SOD can be obtained by subjecting ¹¹¹ h-SOD to further operations such as gel filtration and ion exchange column chromatography. C
The number of lecithin bonds per molecule of u-Zn type Ser ¹¹¹ h-SOD (m 1 in the formula [1]) is not particularly limited, but is preferably 1 to 16, and particularly preferably 1 to 10.

As a method for producing the compound of the formula [3], a method of reacting an acid anhydride represented by the following formula [4] with lysolecithin represented by H—B or a dicarboxylic acid represented by the following formula [5] It is obtained by a method in which a half ester anhydride is reacted with lysolecithin represented by H-B. [-C (O)-(CH ₂ ) _n C (O)-] = O ··· [4] [Z'-OC (O)-(CH ₂ ) _n C (O)-] ₂ = O ·・ ・ [5]

Here, B and n are the same as in the case of equation [1]. Z ′ is a protecting group for a carboxyl group, for example, an alkyl group, a methoxymethyl group, a benzyl group, a phenacyl group, a t-
Represents a butyldimethylsilyl group, a triethylsilyl group, a trimethylsilyl group, or the like.

The reaction for producing the compound of the formula [3] using these acid anhydrides and half ester anhydrides is usually carried out in a solvent, and if necessary, in the presence of an organic base. As a reaction solvent, for example, a halogenated hydrocarbon such as chloroform is used, and as an organic base, for example, pyridine, piperidine, triethylamine, 4-dimethylaminopyridine, 4-piperidinopyridine and the like are used.
The reaction temperature is preferably from 20 to 80 ° C, more preferably from 40 to 60 ° C. The reaction time is usually 2 to 24 hours.

The production method of the formula [5] is obtained by mixing the carboxylic acid half ester with carbodiimide in a solvent such as benzene, toluene, chloroform, dichloromethane, tetrahydrofuran and the like. As the carbodiimide, for example, diethylcarbodiimide, diisopropylcarbodiimide, dicyclohexcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and the like are used. The reaction temperature can be in the range of −20 ° C. to the reflux temperature of the solvent, but preferably a temperature of 0 ° C. to about room temperature is used.

The Cu-Zn type Ser ¹¹¹ h-SOD used in the present invention is
For example, a nucleotide sequence encoding the amino acid sequence of human-derived superoxide dismutase can be obtained by converting a cysteine residue at position 111 to a serine residue based on site-directed mutagenesis (Japanese Patent Laid-Open No. 62-130684). .

The form of the preparation in the present invention includes an injection, a rectal absorbent, a nasal absorbent and the like. Injectables include, for example, a buffer, an isotonicity agent, a pH adjuster,
Dissolve in stabilizing agent and appropriate amount of distilled water for injection and disinfect through sterilization filter and dispense into ampoules, or dissolve this active ingredient in distilled water for injection together with bulking agent and stabilizer It is prepared by dispensing the sterilized product through an antibacterial filter into ampoules or dispensing into vials and freeze-drying.

The present invention will be specifically described below, but the present invention is not limited to these examples.

[0032]

【Example】

[Synthesis Example 1] Synthesis of 9-benzyloxycarbonyl-1-nonanoic anhydride 15 g (51 mmo) of 9-benzyloxycarbonyl-1-nonanoic acid
l) was dissolved in 50 ml of benzene, cooled to 0 ° C, and DCC
(5.8 g (28 mmol) of 1,3-dicyclohexylcarbodiimide
Was added and stirred at room temperature for 15 hours. The insolubles were filtered through celite and concentrated under reduced pressure to give the title compound.

[Synthesis Example 2] Synthesis of 2- (9-benzyloxycarbonylnonanoyl) lysolecithin 3 g of lysolecithin in which the 2-position of glycerol is a hydroxyl group
(5.9 mmol) in a chloroform-pyridine (80 ml / 20 ml) suspension was added to DMAP (N, N-dimethylaminopyridine) 2.16.
g (17.7 mmol) and 10.0 g (17.7 mmol) of 9-benzyloxycarbonyl-1-nonanoic anhydride were added, and the mixture was stirred at 60 ° C. for 15 hours. Thereafter, the reaction solution was concentrated under reduced pressure, and chloroform:
Methanol: water = 4: 5: 1 (10 ml) was added and dissolved.
Ion exchange column equilibrated with the same solution (Dowex 50W-X8)
Passed.

After fractionating the target compound by TLC and concentrating the solvent under reduced pressure, the residue was purified by a silica gel column to obtain 3.91 g (5.0 mmol, 85%) of the title compound. 1H-NMR (CDCl3) 0.84 (t, 3H), 1.20 (brs), 1.50-1.70 (brs, 6H), 2.20-2.40 (b
rs, 6H), 3.38 (s, 9H), 3.80-4.00 (m, 4H), 4.20-4.40 (m, 4H),
5.10 (s, 2H), 5.20 (m, 1H), 7.30 (m, 5H).

Synthesis Example 3 Synthesis of 2- (9-hydroxycarbonylnonanoyl) lysolecithin 3.91 g (5.00 mmol) of 2- (9-benzyloxycarbonylnonanoyl) lysolecithin obtained in Synthesis Example 2 was dissolved in methanol-water. (225ml / 25ml) and palladium hydroxide 3.0
g was added. After hydrogen replacement, the mixture was stirred at 1 atm and room temperature for 15 hours. After filtration through celite and concentration under reduced pressure, the residue was purified by a silica gel column to give 2.37 g of the title compound (3.41 mmol,
61%).

[Synthesis Example 4] Synthesis of an active ester of 2- (9-hydroxycarbonylnonanoyl) lysoleticin 2.0 g (2.98 mmol) of the carboxylic acid obtained in Synthesis Example 3 was dissolved in 50 ml of dichloromethane and heated to 0 ° C. After cooling, 343 mg (2.98 mmol) of N-hydroxysuccinimide, 209 m of tetrazole
g (2.98 mmol) was added in this order. Next, 769 mg of DCC (3.73
mmol) was dissolved in 8 ml of dichloromethane. The solution was slowly added dropwise and stirred at room temperature for 15 hours. The insoluble material was filtered through Celite to obtain a dichloromethane solution of the active ester.

[Synthesis Example 5] Synthesis of 11-benzyloxycarbonyl-1-undecanoic anhydride In the same manner as in Synthesis Example 1, it was synthesized from 11-benzyloxycarbonyl-1-undecanoic acid.

[Synthesis Example 6] Synthesis of 2- (11-benzyloxycarbonylundecanoyl) lysolecithin Synthesized from the acid anhydride obtained in Synthesis Example 5 in the same manner as in Synthesis Example 2.

[Synthesis Example 7] Synthesis of 2- (11-hydroxycarbonylundecanoyl) lysolecithin It was synthesized from the benzyl ester obtained in Synthesis Example 6 in the same manner as in Synthesis Example 3.

Synthesis Example 8 Synthesis of Active Ester of 2- (11-Hydroxycarbonylundecanoyl) lysolecithin Synthesis was performed from carboxylic acid obtained in Synthesis Example 7 in the same manner as in Synthesis Example 4.

[Synthesis Example 9] Synthesis of 6-benzyloxycarbonyl-1-hexanoic anhydride The same as in Synthesis Example 1, it was synthesized from 6-benzyloxycarbonyl-1-hexanoic acid.

Synthesis Example 10 Synthesis of 2- (6-benzyloxycarbonylhexanoyl) lysolecithin Synthesized from the acid anhydride obtained in Synthesis Example 9 in the same manner as in Synthesis Example 2.

[Synthesis Example 11] Synthesis of 2- (6-hydroxycarbonylhexanoyl) lysolecithin Synthesized from the benzyl ester obtained in Synthesis Example 10 in the same manner as in Synthesis Example 3.

Synthesis Example 12 Synthesis of Active Ester of 2- (6-Hydroxycarbonylhexanoyl) lysolecithin Synthesized from the carboxylic acid obtained in Synthesis Example 11 in the same manner as in Synthesis Example 4.

[Synthesis Example 13] Synthesis of 2- (4-hydroxycarbonylbutyroyl) lysolecithin In the same manner as in Synthesis Example 3, it was synthesized from glutaric anhydride. Purification was performed using a column packed with ODS (octadecylsilane). 1H-NMR (CDCl3) 0.84 (t, 3H), 1.20 (brs), 1.52-1.60 (brs, 2H), 1.80-1.95
(m, 2H), 2.20-2.42, (m, 6H), 3.35 (s, 9H), 3.78 (m, 4H), 3.90
-4.35 (m, 4H), 5.20 (m, 1H).

Synthesis Example 14 Synthesis of Active Ester of 2- (4-Hydroxycarbonylbutyroyl) lysolecithin Synthesis was performed from carboxylic acid obtained in Synthesis Example 13 in the same manner as in Synthesis Example 4.

[Examples] Using the compounds prepared in the above synthesis examples, lecithinated Cu-Zn type Ser ¹¹¹ h-SOD was prepared using the following A to C
It was manufactured using the method described above.

Method A: Dichloromethane of the active ester solution was distilled off, and Cu-dissolved in 50 mM borate buffer (pH 8.5) was dissolved.
Zn-type Ser ¹¹¹ h-SOD, copper and zinc coordinated, 111
A human-derived superoxide dismutase (hereinafter referred to as rh-SOD) whose position is represented by serine is added at 0 ° C. for 1 hour,
Further react at room temperature for 2 hours. The reaction solution is filtered and applied to a gel filtration column using Sephacryl S-300 (Pharmacia) as a carrier, and eluted with the same buffer as the reaction buffer. The lecithinated r-h-SOD eluted fractions are then collected and concentrated by ultrafiltration.

Method B: The dichloromethane in the active ester solution was distilled off and dissolved in DMF. This is added to a 50 mM borate buffer (pH 8.5), and the insoluble matter is filtered, dissolved in the same buffer, and added dropwise to an r-h-SOD solution cooled to 0 ° C. At this time, 50% of DMF is added to the rh-SOD solution. After stirring at 0 ° C. for 15 hours, purification is carried out as in Method A.

Method C: 20% DMF was added to an r-h-SOD solution dissolved in a 50 mM borate buffer (pH 8.5), the mixture was cooled to 0 ° C., and the active ester DMF prepared in the same manner as in Method B was used. The solution is slowly added dropwise. After stirring at 0 ° C. for 15 hours, purification is carried out as in Method A.

Example 1 Synthesis of lecithin-r-h-SOD having an average of two lecithin derivatives bound to one molecule of r-h-SOD r-h-SOD dissolved in 50 mM borate buffer (pH 8.5) SOD and r
According to Method A, the active ester synthesized in Synthesis Example 4 was reacted in a 0.4-fold molar amount with respect to all amino groups of -h-SOD.
The reaction solution was purified by gel filtration and ion exchange chromatography. The protein concentration was determined by the Lowry method (Lowry, O.
H. et al., (1951). J. Biol. Chem., 193, 265), TNBS method (trinitrobenzene sulfonate, Goodwin, JF et al., (1970) Clin. Chem. , 16, 24), the number of lecithin derivatives bonded per r-h-SOD molecule was determined to be 2.0 on average.

Example 2 Synthesis of lecithin-r-h-SOD having an average of four lecithin derivatives bound to one molecule of r-h-SOD r-h-SOD dissolved in 50 mM borate buffer (pH 8.5) SOD and r
Synthesis Example 14 in a 0.8-fold molar amount with respect to all amino groups of -h-SOD
Was reacted according to Method B. Purification was carried out in the same manner as in Example 1, and the number of lecithin derivatives bonded per r-h-SOD molecule was determined.

Example 3 Synthesis of lecithin-r-h-SOD having an average of eight lecithin derivatives bound to one molecule of r-h-SOD r-h-SOD dissolved in 50 mM borate buffer (pH 8.5) SOD and r
The active ester synthesized in Synthesis Example 8 was reacted in a 2.0-fold molar amount with respect to all amino groups of -h-SOD according to Method C.
Purification was performed in the same manner as in Example 1, and the number of lecithin derivatives bonded per r-h-SOD molecule was determined.

Example 4 Effect of Lecithinated rh on Respiratory Resistance by Forssman Antiserum
-SOD inhibitory effect Hartley female guinea pigs (body weight: 280 g to 390 g) were purchased from the Japan Institute of Animal Science and Animal Materials and used for experiments.

The respiratory resistance was measured using a guinea pig respiratory resistance measuring device (Type PMR), which was partially modified from the oscillation method of Mead et al.
-2, Shizume Medical), under anesthesia and spontaneous respiration. That is, put the guinea pig in the plastic chamber box, put the head out of the box,
After closing the box, a 20 Hz sine wave was applied to the body surface with an amplifier and speakers. The air flow velocity (ΔV) generated at this time is obtained by recording the pressure difference generated through the 400 mesh screen at the tip of the conical rubber mask on a polygraph, and at the same time, the difference (ΔP) between the box internal pressure and the oral cavity pressure is obtained. Respiratory resistance value (Rrs) from ΔP / ΔV
Was calculated. The indicated values were expressed as the rate of increase from the respiratory resistance before the induction of Forssman antiserum.

As a inducer, forssman antiserum (anti-sheep erythrocyte serum, cappel) diluted 1/40 was administered from the ear vein at 1 ml / kg, and respiratory resistance was measured over time for 30 minutes. As test drugs, physiological saline for injection (control group) and each were dissolved in physiological saline for injection to make 3000 U / ml, and rh-SOD was adjusted to 3 U / ml.
Mixed solution containing 000 U / kg, lecithin synthesized in Example 2
Mixed solution containing 3000U / kg of -h-SOD and r-h-SOD 3000U / k
g and a compound (123-g / kg of 2- (4-hydroxycarbonylbutyroyl) lysolecithin) synthesized in Synthesis Example 13 were administered from the ear vein at 3 ml / kg 5 minutes before the induction.

As a statistical treatment, a significance test was performed using the Mann-Whitney U test. P <0.05 was determined to be significant (see FIG. 1). FIG. 1 shows the test results. From the results, the lecithin-r-h-SOD 300 of Example 2 was obtained.
0 U / kg administration group was P <0.01 relative to control (non-administration group).
Was found to be effective. Also, r-hS
Even when compared with the OD 3000 U / kg administration group, a difference was observed at P <0.05 at all measurement points, and the lecithinated r-hS of Example 2 was observed.
OD was determined to be effective because it significantly reduced free radicals over r-h-SOD.

As described above, the lecithinated rh of Example 2
-SOD showed a significant inhibitory effect on respiratory resistance of guinea pigs by forssman antiserum. In addition, lecithinization
As a result of intravenous injection of -h-SOD into guinea pigs (5 animals per group) at 6000 U / kg, no deaths were found.

[0059]

According to the present invention, the lecithinated superoxide dismutase of the present invention is bound to lecithin via chemical crosslinking with superoxide dismutase. It can be expected that the biodistribution and the cell affinity are significantly different from those of the conventional modified product, which has the effect of enhancing pharmacological activity.

[Brief description of the drawings]

FIG. 1 is a graph showing test results of Example 4.

Continuation of the front page (72) Inventor Yasuda Shin 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Asahi Glass Co., Ltd. Examiner at the Central Research Laboratory Mayumi Saito (58) Field surveyed (Int.Cl. ⁷ , DB name) C12N 9 / 00-9/99 BIOSIS (DIALOG) WPI (DIALOG)

Claims (3)

(57) [Claims] 1. A lecithinated superoxide dismutase represented by the following formula [1]. A- [C (O)-(CH ₂ ) _n C (O) -B] _m ... [1] where A is a human-derived compound in which copper and / or zinc is coordinated and 111 is serine. Residue of superoxide dismutase B: Residue of lysolecithin having a hydroxyl group at position 2 of glycerol, excluding the hydrogen atom of the hydroxyl group at position 2 m: an integer of 1 or more n: an integer of 2 or more 2. The lecithinated superoxide dismutase of claim 1, wherein n is an integer from 2 to 10. 3. The lecithinated superoxide dismutase according to claim 1, wherein m is 1 to 16 on average.