JP2014198721A - External composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an external composition containing pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof, being excellent in preservation stability of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof.SOLUTION: In an external composition with pH of 4 to 6, pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof is contained in a range of 0.00001 to 1 wt.% to a total amount of a composition, and at least one of surfactants with HLB values of 8 or more is contained in a range of 0.001 to 10 wt.% to the total amount of the composition (except provided that lecithin is contained as a liposome).

Description

  The present invention relates to a composition for external use that contains pyrroloquinoline quinone and is used as a cosmetic, quasi-drug, or pharmaceutical product.

Pyrroloquinoline quinone (hereinafter sometimes abbreviated as “PQQ”) is widely present in the living world such as plants, organisms, and microorganisms, and functions as a redox coenzyme essential for energy acquisition.
PQQ is known to have many physiological activities and is expected to be used as an active ingredient in pharmaceuticals, quasi drugs, cosmetics, or supplements. As such physiological activities, active oxygen and radical removal action, cell growth promotion action, ultraviolet absorption action, nerve growth factor production promotion action, brain function improvement action, hair growth action, facial color improvement action, melanin production suppression and whitening action, Mitochondrial activation and anti-fatigue effects are known.
Attempts have also been made to improve the stability of PQQ in formulations. For example, in Patent Document 1, oxazopyrroloquinoline, a salt thereof, or an ester thereof, which is a compound similar to PQQ, has physiological activities such as an active oxygen scavenging action, a melanin synthesis inhibitory action, and a lipid peroxide production inhibitory action. At the same time, it teaches excellent stability in the preparation.
Patent Documents 2 and 3 show that a specific ester of PQQ has physiological activities such as a melanin production inhibitory action, a melanin deposition inhibitory action, and an ultraviolet absorption action, as well as stability and safety in the preparation. Also teaches that it is excellent.

JP-A-6-100428 JP-A-8-20512 JP-A-8-20585

  The present invention is a composition for external use containing pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as “a salt thereof”), which is excellent in the storage stability of PQQ or a salt thereof. The issue is to provide goods.

  The present inventor repeated researches to solve the above problems, and obtained the knowledge that when a surfactant is added to a composition containing PQQ or a salt thereof, the stability of PQQ or a salt thereof becomes very poor. Moreover, it discovered that the storage stability of PQQ or its salt improved by adjusting the pH of the composition containing PQQ or its salt and surfactant to 4-6.

This invention is completed based on the said knowledge, and provides the following external compositions.
Item 1. A composition for external use comprising pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof and a surfactant, and having a pH of 4-6.
Item 2. Item 2. The external composition according to Item 1, wherein the concentration of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof is 1% by weight or less based on the total amount of the composition.
Item 3. Item 3. The topical composition according to Item 1 or 2, wherein the concentration of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof is 0.00001% by weight or more based on the total amount of the composition.
Item 4. Item 4. The composition for external use according to any one of Items 1 to 3, wherein the surfactant is a surfactant having an HLB of 8 or more.
Item 5. Item 5. The external composition according to any one of Items 1 to 4, wherein the surfactant is a nonionic surfactant.
Item 6. The nonionic surfactant is selected from the group consisting of sorbitan fatty acid ester, polyglycerin fatty acid ester, hydrogenated castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl ether, and alkyl glucoside. Item 6. The composition for external use according to Item 5, which is at least one selected from the group consisting of:
Item 7. Item 5. The external composition according to any one of Items 1 to 4, wherein the surfactant is an anionic surfactant.
Item 8. Item 8. The composition for external use according to Item 7, wherein the anionic surfactant is glycerophospholipid.
Item 9. The external composition in any one of claim | item 1 -8 which contains 0.001 to 10weight% of surfactant with respect to the whole quantity of a composition.
Item 10. Furthermore, the external composition in any one of claim | item 1 -9 containing at least 1 sort (s) chosen from the group which consists of C2-C6, a C2-C4 polyhydric alcohol, and its monoether.
Item 11. At least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and monoethers thereof is propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, Item 11. The external composition according to Item 10, which is at least one selected from the group consisting of diglycerin and diethylene glycol monoethyl ether (ethoxy glycol).
Item 12. The concentration of at least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and monoethers thereof is 0.01 to 70% by weight based on the total amount of the composition. Item 12. The composition for external use according to Item 10 or 11.
Item 13. Furthermore, the external composition in any one of claim | item 1 -12 containing at least 1 sort (s) chosen from the group which consists of a C2-C5 monohydric alcohol.
Item 14. Item 14. The external composition according to Item 13, wherein at least one selected from the group consisting of monohydric alcohols having 2 to 5 carbon atoms is at least one selected from the group consisting of ethanol, propanol, and isopropyl alcohol.
Item 15. Item 15. The external composition according to Item 13 or 14, wherein the concentration of the monohydric alcohol having 2 to 5 carbon atoms is 0.01 to 50% by weight based on the total amount of the composition.
Item 16. The external composition according to any one of Items 1 to 15, further comprising EDTA or a pharmaceutically acceptable salt thereof.
Item 17. Item 17. The external composition according to Item 16, wherein the concentration of EDTA or a pharmaceutically acceptable salt thereof is 0.0001 to 1% by weight based on the total amount of the composition.
Item 18. Item 18. The topical composition according to Item 16 or 17, comprising 0.001 to 1000 parts by weight of EDTA or a pharmaceutically acceptable salt thereof per 1 part by weight of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof. .

Item 19. Stability of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof in this composition, wherein the pH of the composition comprising pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof and a surfactant is 4-6 How to improve.
Item 20. Item 20. The method according to Item 19, wherein the concentration of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof in the composition is 1% by weight or less based on the total amount of the composition.
Item 21. Item 21. The method according to Item 19 or 20, wherein the concentration of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof in the composition is 0.00001% by weight or more based on the total amount of the composition.
Item 22. Item 22. The method according to any one of Items 19 to 21, wherein the surfactant is a surfactant of HLB8 or higher.
Item 23. Item 23. The method according to any one of Items 19 to 22, wherein the surfactant is a nonionic surfactant.
Item 24. The nonionic surfactant is selected from the group consisting of sorbitan fatty acid ester, polyglycerin fatty acid ester, hydrogenated castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene monococonut oil fatty acid glyceryl, glycerin alkyl ether, and alkyl glucoside. Item 24. The method according to Item 23, which is at least one selected from the group consisting of:
Item 25. Item 23. The method according to any one of Items 19 to 22, wherein the surfactant is an anionic surfactant.
Item 26. Item 26. The method according to Item 25, wherein the anionic surfactant is glycerophospholipid.
Item 27. Item 27. The method according to any one of Items 19 to 26, wherein the concentration of the surfactant in the composition is 0.001 to 10% by weight based on the total amount of the composition.
Item 28. Item 28. The method according to any one of Items 19 to 27, wherein the composition further comprises at least one selected from the group consisting of a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and a monoether thereof.
Item 29. At least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and monoethers thereof is propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, Item 29. The method according to Item 28, which is at least one selected from the group consisting of diglycerin and diethylene glycol monoethyl ether (ethoxy glycol).
Item 30. The concentration of at least one selected from the group consisting of 2 to 6 carbon atoms, polyhydric alcohols having 2 to 4 hydroxyl groups, and monoethers thereof in the composition is 0.01 to 70 with respect to the total amount of the composition. Item 30. The method according to Item 28 or 29, wherein the method is% by weight.
Item 31. Item 31. The method according to any one of Items 19 to 30, wherein the composition further comprises at least one selected from the group consisting of monohydric alcohols having 2 to 5 carbon atoms.
Item 32. Item 32. The method according to Item 31, wherein at least one selected from the group consisting of monohydric alcohols having 2 to 5 carbon atoms is at least one selected from the group consisting of ethanol, propanol, and isopropyl alcohol.
Item 33. Item 33. The method according to Item 31 or 32, wherein the concentration of the monohydric alcohol having 2 to 5 carbon atoms in the composition is 0.01 to 50% by weight with respect to the total amount of the composition.
Item 34. Item 34. The method according to any one of Items 19 to 33, wherein the composition further comprises EDTA or a pharmaceutically acceptable salt thereof.
Item 35. Item 35. The method according to Item 34, wherein the concentration of EDTA or a pharmaceutically acceptable salt thereof in the composition is 0.0001 to 1% by weight relative to the total amount of the composition.
Item 36. Item 34 or 35, wherein the composition comprises 0.001 to 1000 parts by weight of EDTA or a pharmaceutically acceptable salt thereof with respect to 1 part by weight of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof. the method of.

In cosmetics, quasi-drugs, and external preparations for pharmaceutical use, a surfactant may be added in order to improve the familiarity with the skin or improve the permeability of other components to the skin. The present inventor has found that when a surfactant is added to a composition containing PQQ or a salt thereof, the storage stability of PQQ or a salt thereof becomes very poor.
Although the composition of the present invention has a pH of 4 to 6, PQQ or a salt thereof is stably maintained even though the composition includes a surfactant. According to the present invention, PQQ or a salt thereof can be practically used as a component of cosmetics, quasi drugs, and pharmaceutical external preparations.

It is a figure which shows stability of PQQ in the composition which does not contain surfactant. It is a figure which shows stability of PQQ in the composition containing surfactant, a polyhydric alcohol, and a lower alcohol. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant, a polyhydric alcohol, and a lower alcohol. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant and a polyhydric alcohol. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant and a polyhydric alcohol. It is a figure which shows the influence of pH which acts on stability of PQQ in the composition containing surfactant and a polyhydric alcohol.

Hereinafter, the present invention will be described in detail.
The composition for external use of the present invention is a composition having a pH of 4 to 6 containing PQQ or a salt thereof and a surfactant.

Since PQQ or its salt PQQ exists in various organisms such as animals, plants, and bacteria, it can be extracted from various organisms. Moreover, PQQ can purchase a commercial item.
Examples of pharmaceutically acceptable salts of PQQ include alkali metal salts such as sodium salt, potassium salt, and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt. Among the salts, sodium salt, potassium salt, lithium salt, calcium salt, and magnesium salt are preferable.

  The content of PQQ or a salt thereof in the composition is preferably 0.00001% by weight or more, more preferably 0.0001% by weight or more, and still more preferably 0.001% by weight or more with respect to the total amount of the composition. . Moreover, 1 weight% or less is preferable, 0.3 weight% or less is more preferable, and 0.1 weight% or less is still more preferable. If it is the said range, the physiological activity of PQQ or its salt will fully be obtained by the normal usage-amount of cosmetics, a quasi-drug, and a pharmaceutical external preparation. Moreover, if it is the said range, the solubility in a formulation will be favorable and it will be excellent in the point of the external appearance as a composition for external use.

Surfactants Surfactants are often used for the purpose of assisting penetration of other components into the skin and improving the familiarity of the composition with the skin. Moreover, it may be used as a cleaning component.
As the surfactant, any of a nonionic surfactant, an anionic surfactant, a cationic surfactant, and an amphoteric surfactant can be used.
Nonionic surfactants include, for example, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, diglycerol sorbitan penta-2-ethylhexylate, and di-2-ethylhexyl diate. Sorbitan fatty acid esters such as glycerol sorbitan;
Glyceryl fatty acid esters such as glyceryl monostearate and glyceryl monostearate malate;
Polyglyceryl fatty acid esters such as polyglyceryl monostearate, polyglyceryl monoisostearate, polyglyceryl diisostearate, polyglyceryl monolaurate, polyglyceryl monooleate, polyglyceryl monomyristate;
Polyglyceryl fatty acids such as polyglyceryl monostearate, polyglyceryl monoisostearate, polyglyceryl diisostearate, polyglyceryl monolaurate, polyglyceryl monooleate, and glyceryl fatty acid esters;
Propylene glycol fatty acid esters such as propylene glycol monostearate;
Polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 Hydrogenated castor oil derivatives such as oxyethylene hydrogenated castor oil;
Polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyisostearate Polyoxyethylene sorbitan fatty acid esters such as ethylene (20) sorbitan;
Polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether;
Alkyl glucosides;
Polyoxyalkylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene behenyl ether; and polyoxyethylene-methylpolysiloxane copolymer; Examples thereof include silicone surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone and PEG-9 polydimethylsiloxyethyl dimethicone.

Further, for example, glycerophospholipid such as lecithin (including hydrogenated lecithin), polyoxyalkylene alkyl (or alkenyl) ether sulfate, alkyl (or alkenyl) sulfate, higher fatty acid salt, ether carboxylate, amide ether carboxyl Anionic surfactants such as acid salts, alkyl phosphate ester salts, N-acyl amino acid salts, polyoxyalkylene fatty acid amide ether sulfates, acylated isethionates, and acylated taurates; And cationic surfactants such as mono- or di-long chain alkyl quaternary ammonium salts having a linear or branched long chain alkyl group; and, for example, carbobetaine, sulfobetaine, imidazolinium betaine, and Amphoteric surface activity such as amide betaine It can also be used.

A surfactant having a HLB of 8 or more, particularly 10 or more, and especially 12 or more is preferable in that the composition is well adapted to the skin. The upper limit of HLB is usually about 20. Examples of the surfactant having an HLB of 8 or more include the following.
Examples of nonionic surfactants include sorbitan fatty acid esters such as sorbitan monolaurate, sorbitan monopalmitate, diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitan tetra-2-ethylhexylate;
Polyglyceryl fatty acid esters such as polyglyceryl monostearate, polyglyceryl monoisostearate, polyglyceryl diisostearate, polyglyceryl monolaurate, polyglyceryl monooleate, polyglyceryl monomyristate;
Polyoxyethylene hydrogenated castor oil 40 (HCO-40), polyoxyethylene hydrogenated castor oil 50 (HCO-50), polyoxyethylene hydrogenated castor oil 60 (HCO-60), and polyoxyethylene hydrogenated castor oil 80 Hydrogenated castor oil derivatives such as oxyethylene hydrogenated castor oil;
Polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene monostearate (20) sorbitan (polysorbate 60), polyoxyethylene (20) sorbitan monooleate (polysorbate 80), and polyoxyisostearate Polyoxyethylene sorbitan fatty acid esters such as ethylene (20) sorbitan;
Polyoxyethylene monococonut oil fatty acid glyceryl; glycerin alkyl ether;
Alkyl glucosides;
Polyoxyalkylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, and polyoxyethylene behenyl ether; and polyoxyethylene-methylpolysiloxane copolymers , Silicone surfactants such as lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone.

Anionic surfactants include lecithin and glycerophospholipids such as hydrogenated lecithin, polyoxyalkylene alkyl (or alkenyl) ether sulfate, alkyl (or alkenyl) sulfate, higher fatty acid salt, ether carboxylate, amide Ether carboxylates, alkyl phosphate esters, N-acyl amino acid salts, polyoxyalkylene fatty acid amide ether sulfates, acylated isethionates, acylated taurates, and the like.
Examples of the cationic surfactant include mono- or di-long alkyl quaternary ammonium salts having a linear or branched long-chain alkyl group to which alkylene oxide may be added.
Examples of amphoteric surfactants include carbobetaine, sulfobetaine, imidazolinium betaine, and amide betaine.
Among these, nonionic surfactants are preferable, hydrogenated castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, and sorbitan fatty acid esters are more preferable, and among these, hydrogenated castor oil derivatives and polyoxyethylene sorbitan fatty acid esters are preferable. . Anionic surfactants are also preferable, and among them, glycerophospholipid, particularly lecithin (for example, soybean-derived lecithin) and hydrogenated lecithin (for example, hydrogenated to soybean-derived lecithin) are more preferable.
Surfactant can be used individually by 1 type or in combination of 2 or more types.

The content of the surfactant in the composition is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, and still more preferably 0.1% by weight or more based on the total amount of the composition. If it is the said range, the effect | action of surfactant will be fully acquired.
Further, the content of the surfactant in the composition is preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 3% by weight or less, and even more preferably 2% by weight or less based on the total amount of the composition. Is even more preferred. If it is the said range, PQQ or its salt will be kept stable, while fully exhibiting the function as a surfactant, deterioration of feeling of use such as stickiness and irritation to the skin can be suppressed.

Polyhydric alcohol / monoether thereof The composition of the present invention preferably contains a polyhydric alcohol and / or a monoether thereof. Polyhydric alcohols or monoethers thereof are generally added to cosmetics and pharmaceutical external preparations as moisturizers. However, the present inventors also reduced the storage stability of polyhydric alcohols or monoethers of PQQ or salts thereof. I found out that Therefore, in addition to PQQ or a salt thereof, and a surfactant, a composition containing a polyhydric alcohol and / or a monoether thereof is also a suitable subject of the present invention.
As the polyhydric alcohol, for example, a polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups can be used.
Specifically, for example, ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, 1,4- Butanediol (tetramethylene glycol), 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol, isoprene glycol (isopentyldiol), hexylene glycol, diethylene glycol And dihydric alcohols such as dipropylene glycol; trihydric alcohols such as glycerin and trimethylolpropane; and tetrahydric alcohols such as diglycerin, pentaerythritol, and 1,2,6-hexanetriol. .
Examples of monoethers of polyhydric alcohols include methyl ethers or ethyl ethers of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups (for example, those exemplified above).
Among these, propylene glycol, 1,3-butylene glycol, dipropylene glycol, glycerin, isoprene glycol, diglycerin, and diethylene glycol monoethyl ether (ethoxy glycol) are preferable, and propylene glycol, 1,3-butylene glycol, glycerin, and di Glycerin is more preferred.
A polyhydric alcohol or its monoether can be used individually by 1 type or in combination of 2 or more types.

The content of the polyhydric alcohol having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups and / or its monoether in the composition is preferably 0.01% by weight or more based on the total amount of the composition, % By weight or more is more preferable, and 1% by weight or more is even more preferable. If it is the said range, the effect | action of a polyhydric alcohol or its monoether will fully be acquired.
The content of the polyhydric alcohol and / or monoether thereof in the composition is preferably 70% by weight or less, more preferably 50% by weight or less, and further preferably 30% by weight or less, based on the total amount of the composition. More preferred. If it is the said range, PQQ or its salt will be kept stable, and it will become a composition of the favorable usability | use_condition without stickiness.

Lower alcohol The composition of the present invention preferably contains a lower alcohol. Generally, it is added to cosmetics and pharmaceutical external preparations, but the present inventor has found that lower alcohols also lower the storage stability of PQQ or a salt thereof. Therefore, a composition containing a lower alcohol in addition to PQQ or a salt thereof and a surfactant is also a suitable subject of the present invention.
As the lower alcohol, for example, a linear or branched monovalent alcohol having 2 to 5 carbon atoms can be used. Examples of monovalent lower alcohols include ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, t-butyl alcohol, 1-pentanol (n-amyl alcohol), 2-pentanol (sec-amyl alcohol), 2 Pentanol, 2-methyl-1-butanol, 3-methyl-1-butanol, 2-methyl-2-butanol, 3-methyl-2-butanol, and 2,2-dimethyl-1-propanol (neopentyl alcohol) ). Of these, ethanol, propanol, and isopropyl alcohol are preferable.
A lower alcohol can be used individually by 1 type or in combination of 2 or more types.

The content of the lower alcohol in the composition is preferably 0.01% by weight or more, more preferably 0.1% by weight or more, and still more preferably 1% by weight or more based on the total amount of the composition. If it is the said range, the effect | action of a lower alcohol will fully be acquired.
The content of the lower alcohol in the composition is preferably 50% by weight or less, more preferably 30% by weight or less, and still more preferably 10% by weight or less based on the total amount of the composition. If it is the said range, PQQ or its salt will be kept stable, and it will become a composition of the favorable usability | use_condition without a skin irritation.

EDTA or a pharmaceutically acceptable salt thereof The composition of the present invention preferably comprises EDTA or a pharmaceutically acceptable salt thereof. EDTA or a salt thereof is generally added as a chelating agent to cosmetics and pharmaceutical external preparations. By adding EDTA or a salt thereof to the composition of the present invention, the stability of PQQ or a salt thereof is further improved.
Examples of the EDTA salt include Na salt (2Na salt, 3Na salt, 4Na salt), K salt (2K salt, 3K salt, 4K salt), and Ca · Na salt (Ca · 2Na salt). It is done. These may be hydrates. Among them, EDTA salt is preferable due to high chelating action, and Na salt or K salt of EDTA is more preferable.
EDTA or its salt can be used individually by 1 type or in combination of 2 or more types.

The content of EDTA or a salt thereof in the composition for external use of the present invention is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, and more preferably 0.01% by weight or more based on the total amount of the composition. Is even more preferred. Moreover, 1 weight% or less is preferable, 0.7 weight% or less is more preferable, and 0.5 weight% or less is still more preferable.
The ratio of the content of PQQ or a salt thereof to the content of EDTA or a salt thereof (PQQ or a salt thereof: EDTA or a salt thereof) is preferably 1: 0.001 to 1000 in terms of a weight ratio. 0.01 to 700 is more preferable, and 1: 0.1 to 100 is even more preferable.
When the content of EDTA or a salt thereof is in the above range, a sufficient stability of PQQ or a salt thereof can be obtained, and a skin irritation hardly occurs.

pH
The pH of the composition of the present invention is 4 or higher. Moreover, the pH of the composition of this invention is 6 or less, Preferably it is 5.5 or less, More preferably, it is 5 or less.
The pH of the composition of this invention is 4-6, for example, Preferably it is 4-5.5, More preferably, it is 4-5. If it is the said range, PQQ or its salt will be kept stable.

Formulation Form The composition for external use of the present invention usually contains PQQ or a salt thereof, a surfactant, and, if necessary, the above polyhydric alcohol or monoether or lower alcohol thereof in a pharmaceutical, quasi-drug or cosmetic. It can be mixed with the base or carrier to be used and, if necessary, an additive to prepare a skin external composition for pharmaceuticals, quasi drugs, or cosmetics.

The form of the external composition for skin for pharmaceuticals is not particularly limited, and examples thereof include solutions, suspensions, emulsions, creams, ointments, gels, liniments, lotions, and aerosols. These preparations can be produced according to the method described in the 15th revised Japanese Pharmacopoeia General Rules for Preparations. Of these, liquids, suspensions, emulsions, creams, ointments, gels, lotions, and aerosols are preferable, and creams, emulsions, and gels are more preferable.
Also when it is set as the composition for external use on the skin for quasi drugs or cosmetics, it can be made into the same form as said pharmaceutical. In addition, a stick agent, a sheet agent obtained by impregnating a non-woven fabric with a chemical solution, and the like can be given. Among these, a liquid agent, a suspension agent, an emulsion, a cream agent, an ointment, a gel agent, a lotion agent, and a sheet agent are preferable, and a cream agent, an emulsion, and a gel agent are more preferable.
When an oily base and an aqueous base are included, such as creams and emulsions, they may be W / O type or O / W type, but O / W type is preferred.
In the case of a base not containing water, an ointment and a liquid containing the lower alcohol described above and / or the polyhydric alcohol described above as a base are preferable.

  Specifically, the use in the case of a quasi-drug or cosmetic composition for external use in skin includes, for example, lotion, emulsion, gel, cream, cosmetic liquid, sunscreen cosmetic, pack, mask, hand cream And basic cosmetics such as body lotions and body creams; and cleansing cosmetics such as facial cleansers, makeup removers, body shampoos, shampoos, rinses, and treatments.

As a base or carrier base or carrier, for example, liquid paraffin, squalane, vaseline, hydrocarbon gel (such as Plastibase), ozokerite, alpha-olefin oligomers, and hydrocarbons such as light liquid paraffin; methylpolysiloxane, Cross-linked methylpolysiloxane, highly polymerized methylpolysiloxane, cyclic silicone, alkyl-modified silicone, cross-linked alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, cross-linked polyether-modified silicone, cross-linked alkylpoly Ether-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin-modified Silicone oils such as silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, and behenyl alcohol; celluloses such as ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose Derivatives; polyvinylpyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, penta-2-ethylhexanoate Elyslit and esters like jojoba oil; Dextri And polysaccharides such as maltodextrin; ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, propylene glycol monoethyl Glycol ethers such as ether, propylene glycol monopropyl ether, dipropylene glycol monoethyl ether, and dipropylene glycol monopropyl ether; polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups as described above; Lower alcohols; and aqueous bases such as water.

Among these, polyhydric alcohols, higher alcohols, hydrocarbons, esters, and silicone oils are preferable, and polyhydric alcohols are more preferable.
Preferable examples of the composition of the present invention include creams, gels, and emulsions containing the above-described polyhydric alcohol as a base.
A base or a support | carrier can be used individually by 1 type or in combination of 2 or more types.

Additives In the composition for external use of the present invention, known additives that are added to pharmaceuticals, quasi drugs, or cosmetics within a range not impairing the effects of the present invention, for example, antioxidants, thickeners, storage An agent, a pH adjuster, a stabilizer, an irritation reducing agent, an antiseptic, a coloring agent, a fragrance, and / or a pearly luster imparting agent can be added.

  Examples of the antioxidant include dibutylhydroxytoluene, butylhydroxyanisole, sorbic acid, sodium sulfite, ascorbic acid, ascorbic acid derivative, tocopherol, tocopherol derivative, erythorbic acid, and L-cysteine hydrochloride.

  Examples of the thickener include guar gum, locust bean gum, carrageenan, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, macrogol, chondroitin sulfate sodium And cellulose-based thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, and carboxyethylcellulose.

  Examples of the preservatives and preservatives include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoate Examples include benzyl benzoate, methyl paraoxybenzoate, phenoxyethanol, benzyl alcohol, chlorobutanol, sorbic acid and its salts, chlorhexidine gluconate, and alkanediol.

  Examples of pH adjusters include inorganic acids (such as hydrochloric acid and sulfuric acid), organic acids (such as lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, and sodium succinate), inorganic bases (potassium hydroxide, And sodium hydroxide), and organic bases (such as triethanolamine, diisopropanolamine, and triisopropanolamine).

Examples of the stabilizer include sodium polyacrylate, dibutylhydroxytoluene, and butylhydroxyanisole.
Examples of the irritation reducing agent include licorice extract and sodium alginate.

  An additive can be used individually by 1 type or in combination of 2 or more types.

Other active ingredients The composition for external use of this invention can contain another active ingredient in the range which does not impair the effect of this invention. Specific examples of active ingredients include, for example, moisturizing ingredients, anti-inflammatory ingredients, antibacterial ingredients, vitamins, amino acids or derivatives thereof, cell activation ingredients, anti-aging ingredients, blood circulation promoting ingredients, keratin softening ingredients, whitening ingredients, and astringents. Ingredients and the like.

  Examples of moisturizing ingredients include sodium hyaluronate, heparin-like substance, chondroitin sulfate sodium, collagen, elastin, keratin, chitin, and chitosan polymer compounds; amino acids such as glycine, aspartic acid, arginine; sodium lactate, Natural moisturizing factors such as urea and sodium pyrrolidone carboxylate; lipids such as ceramide, cholesterol, and phospholipids; and plant extract extracts such as chamomile extract, hamamelis extract, tea extract, and perilla extract.

  Examples of the anti-inflammatory component include a component derived from a plant (for example, Comfrey), allantoin, glycyrrhizic acid or a derivative thereof, zinc oxide, pyridoxine hydrochloride, tocopherol acetate, salicylic acid or a derivative thereof, and ε-aminocaproic acid. It is done.

  Antibacterial or bactericidal components include, for example, chlorhexidine, salicylic acid, benzalkonium chloride, acrinol, sulfur, resorcin, ethanol, benzethonium chloride, adapalene, benzoyl peroxide, clindamycin, cresol, gluconic acid and its derivatives, popidone iodine, iodine Potassium iodide, iodine, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol, 1,2-pentanediol, alkyldiaminoglycine hydrochloride, chlorhexidine gluconate, and zinc paraphenolsulfonate Etc.

  Vitamins include, for example, retinol derivatives (retinol, retinol acetate, retinol palmitate, etc.), retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, d-δ-tocopheryl retinoate, α-tocotic acid. Vitamins such as ferryl retinoate and β-tocopheryl retinoate; vitamins such as dl-α-tocopherol, dl-α-tocopherol acetate, dl-α-tocopherol succinate, and dl-α-tocopherol calcium succinate E: Riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, and riboflavin tetranicotinate Nicotinic acids such as dl-α-tocopherol nicotinate, benzyl nicotinate, methyl nicotinate, β-butoxyethyl nicotinate, and 1- (4-methylphenyl) ethyl nicotinate; ascorbigen-A Vitamin C such as ascorbic acid stearate, ascorbyl palmitate, and L-ascorbyl dipalmitate; Vitamin D such as methyl hesperidin, ergocalciferol, and cholecalciferol; vitamin K such as phylloquinone and farnoquinone Γ-oryzanol, dibenzoyl thiamine, and dibenzoyl thiamine hydrochloride; thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine Vitamin B1 such as amine lysine salt, thiamine triphosphate, thiamine monophosphate phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, and thiamine triphosphate monophosphate Vitamin B6 such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5′-phosphate pyridoxal hydrochloride, pyridoxamine hydrochloride; vitamin B12 such as cyanocobalamin, hydroxocobalamin, and deoxyadenosylcobalamin; folic acid, pteroylglutamic acid, etc. Nicotinic acids such as folic acid; nicotinic acid and nicotinamide; pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantheine, D-pan Pantothenic acids such as tin, coenzyme A, and pantothenyl ethyl ether; biotins such as biotin and biotisin; ascorbic acid, sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, and magnesium ascorbate phosphate And vitamin Cs such as carnitine, ferulic acid, α-lipoic acid, and orotic acid, and the like.

  Examples of amino acids or derivatives thereof include betaine (trimethylglycine), proline, hydroxyproline, arginine, lysine, serine, glycine, alanine, phenylalanine, β-alanine, threonine, glutamic acid, glutamine, asparagine, aspartic acid, cysteine, cystine. Methionine, leucine, isoleucine, valine, histidine, taurine, γ-aminobutyric acid, γ-amino-β-hydroxybutyric acid, carnitine, carnosine, creatine and the like.

Cell activation components include, for example, amino acids such as γ-aminobutyric acid and ε-aminoproic acid; vitamins such as retinol, thiamine, riboflavin, pyridoxine hydrochloride, and pantothenic acids; α- such as glycolic acid and lactic acid Hydroxy acids; Tannins; Flavonoids; Saponins; Allantoins;
Examples of anti-aging components include pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivatives, silicon, silicic acid, N-methyl-L-serine, and mevalonolactone.

  Examples of the blood circulation promoting component include plants (e.g., ginseng, ashitaba, arnica, ginkgo, fennel, enmelio, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shiitake, hawthorn, prunus, Senkyu, assembly, thyme, clove, chimpi, spruce, spruce, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpi, spruce, spruce, peach, apricot , Walnuts, and corn); and glucosyl hesperidin.

Examples of the keratin softening component include urea, salicylic acid, glycolic acid, fruit acid, phytic acid, and sulfur.
Examples of the whitening component include ascorbic acid and its derivatives, arbutin, and tocopherol.
Examples of the astringent component include zinc paraphenol sulfonate, zinc oxide, menthol, and ethanol.

  Other active ingredients can be used alone or in combination of two or more.

The composition of the present invention, which is excellent in storage stability of the container PQQ or a salt thereof, can be stored and used in a container having an appropriately selected shape and material according to the intended purpose and application. Examples of the container shape include a bottle type, a tube type, a jar type, a spoid type, a dispenser type, a stick type, a pouch bag, and a cheer pack. Examples of the material include polyethylene terephthalate, polypropylene, polyethylene (such as HDPE, LDPE, and LLDPE), ABS resin, ethylene vinyl alcohol resin, polystyrene, glass, and metal (such as aluminum). In addition, these materials are subjected to various coating treatments in consideration of strength, flexibility, weather resistance, component stability, etc., and these materials are combined or laminated, for example, by mixing them. It can be used as a container material. Further, those skilled in the art can select the diameter and material of the nozzle of the container and the elution part of the preparation in order to limit the discharge amount from the container and reduce the adhesion to the container.

Method of Use The composition for external use of the present invention varies depending on the skin condition, age, sex, etc. of the subject of use, but may be the following method, for example. That is, an appropriate amount (for example, about 0.05 to 5 g) may be applied to the skin several times a day (for example, about 1 to 5 times, preferably 1 to 3 times). In addition, the composition is used so that the daily use amount of PQQ or a salt thereof is, for example, about 0.0005 to 0.05 g, preferably 0.001 to 0.02 g, more preferably about 0.002 to 0.01 g. May be applied.
The application period may be, for example, about 2 weeks to 6 months, preferably about 1 to 6 months.
The composition for external use of the present invention can be suitably used for people having various skin diseases and skin troubles, expecting the physiological activity of PQQ or a salt thereof. In particular, people who have wrinkles and tarmi, people whose skin texture is disturbed, and people with sensitive skin are suitable targets. Moreover, the person who has normal skin also becomes a suitable use object for prevention of a skin trouble.

Others The present invention includes a method for improving the stability of PQQ or a salt thereof, wherein the pH of the composition containing PQQ or a salt thereof and a surfactant is adjusted to 4-6.
The type of PQQ or a salt thereof, a preferable one thereof, and the content of PQQ or a salt thereof in the composition; the type of surfactant, a preferable one thereof, and the content of a surfactant in the composition; The preferred pH of the composition is the same as that of the external composition of the present invention.
The composition for external use is at least one selected from the group consisting of polyhydric alcohols and monoethers thereof, at least one selected from the group consisting of lower alcohols, and / or at least selected from the group consisting of EDTA or a salt thereof. It is the same as the case of the composition for external use of this invention that it is preferable to include 1 type. The types of polyhydric alcohols and monoethers thereof, lower alcohols, and EDTA or salts thereof, preferred ones thereof, and the content of these components in the composition are the same as in the case of the composition for external use of the present invention. .
In the method of the present invention, the composition can be a skin external composition for pharmaceuticals, quasi drugs, or cosmetics. The formulation form of the external composition for skin is the same as that of the external composition of the present invention. In addition, usable bases or carriers, additives, active ingredients other than PQQ or a salt thereof, and preferred ones thereof are the same as in the case of the external composition of the present invention.
Moreover, the container which accommodates a composition, and the usage method of a composition are the same as the case of the composition for external use of this invention.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these Examples.
(1) Evaluation of stability of PQQ in a composition containing no surfactant An aqueous solution containing 0.01 w / w% PQQ-2Na was added to a succinate buffer (succinic acid-succinate disodium) and Test solutions of various pHs were prepared using dilute hydrochloric acid or sodium hydroxide. The pH of each test solution was adjusted to 3.67, 3.04, 3.96, 4.85, 6.63, 7.80, 9.50.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the residual ratio (%) of PQQ-2Na after storage was determined.
The results are shown in FIG. As is clear from FIG. 1, when no surfactant was contained, the storage stability of PQQ-2Na was good and was not affected by pH.

(2) Effect of Surfactant on PQQ Stability PQQ-2Na solutions of Reference Test Examples 1 and 2 having the compositions shown in Table 1 below were prepared, filled into glass vials 10 mL each, and sealed 60 Stored for 1 week at ° C. The PQQ-2Na content before and after storage was quantified by HPLC, and the residual ratio (%) of PQQ-2Na after storage was determined. The results are shown in FIG.
As is apparent from FIG. 2, it is understood that PQQ-2Na became very unstable by adding a surfactant, a polyhydric alcohol, and a lower alcohol.

(3) Effect of pH on the stability of PQQ in the presence of surfactants / polyhydric alcohols or monoethers / lower alcohols
Test 1
Each composition of the Example and comparative example which have a composition of following Table 2 was prepared.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the residual ratio (%) of PQQ-2Na after storage was determined. The results are shown in FIG.
HCO-60: manufactured by NIKKOL, polyoxyethylene (60) hydrogenated castor oil

Ingredients such as surfactants, polyhydric alcohols or their monoethers, and lower alcohols are formulated to improve the skin fit of the preparation, improve the skin permeability of other ingredients, and obtain moisturizing and antiseptic effects. The The solution of Comparative Example 1 not containing these components was not preferable as an external preparation because the formulation was generally repelled when applied to the skin.
However, as is clear from FIG. 3, the stability of PQQ-2Na in the test solution was significantly lowered by the blending of these components. That is, when Comparative Example 1 and Comparative Example 2 in FIG. 3 are compared, Comparative Example 2 containing a surfactant, a polyhydric alcohol, and a lower alcohol as compared with the test solution of Comparative Example 1 while having a comparable pH. In the test solution, the stability of PQQ-2Na was very low. Moreover, the stability of PQQ-2Na in the test solutions of Comparative Examples 3 and 4 having a pH exceeding 6 was very low.
On the other hand, the test liquids of Examples 1 and 2 that contain a surfactant, a polyhydric alcohol, and a lower alcohol but in the range of pH 4 to 6 contain a surfactant, a polyhydric alcohol, and a lower alcohol. PQQ-2Na was as stable as the test solution of Comparative Example 1 that was not present.
Moreover, the test liquid of Example 2 containing EDTA-2Na was more stable than the test liquid of Example 1 not containing EDTA-2Na.

Test 2
The composition of the Example and comparative example which have a composition of following Table 3 was prepared.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the component residual ratio (%) after storage was determined. The results are shown in FIG.

HCO-60: manufactured by NIKKOL, polyoxyethylene (60) hydrogenated castor oil

As is apparent from FIG. 4, the stability of PQQ-2Na in the test solution was significantly reduced by the addition of the surfactant. That is, when Comparative Example 5 and Comparative Example 6 in FIG. 4 are compared, the test solution of Comparative Example 6 to which a surfactant is added compared to the test solution of Comparative Example 5 while having the same pH is PQQ-2Na. Stability was very low. In addition, the stability of PQQ-2Na in the test solution of Comparative Example 7 having a pH exceeding 6 was very low.
On the other hand, even when the surfactant was included, PQQ-2Na was stable in the test solutions of Examples 3 and 4 that were in the range of pH 4 to 6.

Test 3
The composition of the Example and comparative example which have a composition of following Table 4 was prepared.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the component residual ratio (%) after storage was determined. The results are shown in FIG. 5 and FIG.
TS-10MV: manufactured by NIKKOL, polysorbate 60
(Polyoxyethylene sorbitan monostearate
(20E.O.))
Resinol S-10: manufactured by NIKKOL, hydrogenated lecithin

As is clear from FIG. 5, the stability of PQQ-2Na in the test solution was significantly reduced by the combination of the surfactant and the polyhydric alcohol. That is, when Comparative Example 8 and Comparative Example 9 in FIG. 5 are compared, the test of Comparative Example 9 in which a surfactant and a polyhydric alcohol were added as compared with the test solution of Comparative Example 8 while having the same pH. The liquid had very low stability of PQQ-2Na.
On the other hand, PQQ-2Na was stable in the test solution of Example 5 that contained a surfactant and a polyhydric alcohol within the pH range of 4-6.

As is apparent from FIG. 6, the stability of PQQ-2Na in the test solution was significantly reduced by the addition of the anionic surfactant. That is, when comparing Comparative Example 8 and Comparative Example 10 in FIG. 6, the test solution of Comparative Example 10 to which an anionic surfactant was added compared to the test solution of Comparative Example 8 while having the same pH was The stability of PQQ-2Na was very low.
On the other hand, even when an anionic surfactant was included, PQQ-2Na was stable in the test solution of Example 6 in the pH range of 4-6.

Test 4
The compositions of Examples and Comparative Examples having the compositions shown in Table 5 below were prepared.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the component residual ratio (%) after storage was determined. The results are shown in FIG.
TI-10V: manufactured by NIKKOL, PEG-20 sorbitan isostearate
(Polyoxyethylene sorbitan isostearate
(20E.O.))
TO-10MV: manufactured by NIKKOL, polysorbate 80
(Polyoxyethylene sorbitan monooleate (20E.O.))

As is clear from FIG. 7, the stability of PQQ-2Na in the test solution was significantly reduced by the combination of the surfactant and the polyhydric alcohol. That is, when Comparative Example 11 and Comparative Example 12 in FIG. 7 are compared, the test of Comparative Example 12 in which a surfactant and a polyhydric alcohol were added as compared with the test solution of Comparative Example 11 while having a similar pH. The liquid had very low stability of PQQ-2Na.
On the other hand, PQQ-2Na was stable in the test solution of Example 7 that was in the range of pH 4 to 6 even if it contained a surfactant and a polyhydric alcohol.

Moreover, when the comparative example 11 of FIG. 7 and the comparative example 13 are contrasted, compared with the test liquid of the comparative example 11, compared with the test liquid of the comparative example 11, the test of the comparative example 13 which added surfactant and polyhydric alcohol. The liquid had very low stability of PQQ-2Na.
On the other hand, even though the surfactant and polyhydric alcohol were included, PQQ-2Na was stable in the test solution of Example 8 in the range of pH 4-6.

Test 5
Compositions of Examples and Comparative Examples having the compositions shown in Table 6 below were prepared.
These test solutions were filled in 10 mL glass vials, sealed, and stored at 60 ° C. for 1 week. The PQQ-2Na content before and after storage was quantified by HPLC, and the component residual ratio (%) after storage was determined. The results are shown in FIG.
Decaglyn1-SV: manufactured by NIKKOL, polyglyceryl stearate-10
(Polyglyceryl monostearate)

As is clear from FIG. 8, the stability of PQQ-2Na in the test solution was significantly lowered by the combination of the surfactant and the polyhydric alcohol. That is, when Comparative Example 8 and Comparative Example 14 in FIG. 8 are compared, the test of Comparative Example 14 in which a surfactant and a polyhydric alcohol were added as compared with the test solution of Comparative Example 8 while having the same pH. The liquid had very low stability of PQQ-2Na. Moreover, the stability of PQQ-2Na was also very low in the test solution of Comparative Example 15 containing a surfactant and a polyhydric alcohol and having a pH exceeding 6.
On the other hand, PQQ-2Na was stable in the test solution of Example 9, which contained a surfactant and a polyhydric alcohol, and was in the range of pH 4-6.

Formulation Example A formulation example of the external preparation of the present invention is shown below. The unit of the content of each component is% by weight.

Example 1 (milky lotion)
PQQ2Na 0.01
Acrylic acid / alkyl methacrylate copolymer 0.4
Hydroxyethyl cellulose 0.2
1,3-butylene glycol 3
Glycerin 2
Polyoxyethylene (60) hydrogenated castor oil (HLB14) 0.5
Sodium edetate 0.05
Methylphenylpolysiloxane 3
pH adjuster
(Adjust so that pH is 5.5)
Preservative appropriate amount
Purified water remaining
100%
The prepared preparation is filled into a pump bottle made of polypropylene.

Example 2 (cream)
PQQ2Na 0.02
Liquid paraffin 10
Isopropyl palmitate 10
Glycerin 5
Polyoxyethylene (60) hydrogenated castor oil (HLB14) 2
Glycerin stearate 1
Carboxyvinyl polymer 0.5
Xanthan gum 0.3
pH adjuster
(Adjust to pH 6.0)
Preservative appropriate amount
Purified water remaining
100%
The prepared preparation is filled into a polyethylene tube container.

Example 3 (lotion)
PQQ2Na 0.01
Dipropylene glycol 5
Glycerin 5
Polyoxyethylene (80) hydrogenated castor oil (HLB15) 0.2
Sodium edetate 0.05
pH adjuster
(Adjust to pH 4.0)
Preservative appropriate amount
Purified water remaining
100%

Example 4 (Cosmetic liquid)
PQQ2Na 0.02
Acrylic acid / alkyl methacrylate copolymer 0.3
1,3-butylene glycol 3
Dipropylene glycol 2
Sodium edetate 0.05
Squalane 5
Glyceryl stearate (HLB12) 0.2
pH adjuster
(Adjust so that pH is 5.0)
Preservative appropriate amount
Purified water remaining
100%

Example 5 (cleansing agent)
PQQ2Na 0.001
Acrylic acid / alkyl methacrylate copolymer 0.3
Carboxyvinyl polymer 0.4
1,3-butylene glycol 5
Glycerin 5
Tetraoleic acid polyoxyethylene sorbit (HLB14) 1
Dialkyl carbonate (C14,15) 5
Triethylhexanoin 10
Liquid paraffin 15
pH adjuster
(Adjust so that pH is 5.5)
Preservative appropriate amount
Purified water remaining
100%

  Since the composition for external use of the present invention contains PQQ or a salt thereof and is excellent in storage stability, it has a high commercial value.

Claims (6)

  A pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof is contained in an amount of 0.00001 to 1% by weight based on the total amount of the composition, and at least one HLB8 or higher surfactant is added to the total amount of the composition. An external composition containing 0.001 to 10% by weight and having a pH of 4 to 6 (except when lecithin is contained as a liposome).   Furthermore, the composition for external use of Claim 1 containing at least 1 sort (s) chosen from the group which consists of C2-C6, a C2-C4 polyhydric alcohol, and its monoether.   The composition according to claim 2, comprising 0.01 to 70% by weight based on the total amount of the composition of at least one selected from the group consisting of polyhydric alcohols having 2 to 6 carbon atoms and 2 to 4 hydroxyl groups, and monoethers thereof. The external composition as described.   Furthermore, the composition for external use in any one of Claims 1-3 containing at least 1 sort (s) chosen from the group which consists of a C2-C5 monohydric alcohol.   Furthermore, the external composition in any one of Claims 1-4 containing at least 1 sort (s) chosen from the group which consists of EDTA or its pharmaceutically acceptable salt.   A pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof is contained in an amount of 0.00001 to 1% by weight based on the total amount of the composition, and at least one HLB8 or higher surfactant is added to the total amount of the composition. A method for improving the stability of pyrroloquinoline quinone or a pharmaceutically acceptable salt thereof in this composition, wherein the pH of the composition for external use containing 0.001 to 10% by weight is 4 to 6 (provided that lecithin is used as a liposome) Unless included).