JP2009286745A - Oil-in-water type emulsion composition - Google Patents

Abstract

An oil-in-water emulsified composition containing a metal oxide, with suppressed liquid separation and good usability.
In an oil-in-water emulsion composition containing zinc oxide or titanium oxide as a metal oxide, polyalkylene glycol (average molecular weight: 600 to 20000) is further contained to suppress liquid separation. An oil-in-water emulsion composition in which liquid separation is suppressed. The polyalkylene glycol is preferably polyethylene glycol.
[Selection figure] None

Description

  The present invention relates to an oil-in-water emulsion composition containing a metal oxide such as zinc oxide and having suppressed liquid separation.

  Conventionally, metal oxides such as zinc oxide and titanium oxide have been used in the fields of pharmaceuticals, cosmetics, etc. due to their drying, sebum resistance, UV shielding, deodorization, etc. Etc. are widely used. As these skin external preparations, water-in-oil type emulsion compositions are mainly used from the viewpoint of the dispersion stability of metal oxides, but there are many cases where a strong feeling of oil and a good feeling of use cannot be obtained. . On the other hand, since the oil-in-water emulsion composition has a fresh feeling of use, it can impart a good feeling of use to cosmetics and pharmaceuticals.

  However, in an oil-in-water emulsion composition, a phenomenon in which an aqueous component oozes from the composition over time, so-called liquid separation (Syneresis) may occur. Generally, an oil-in-water emulsion composition is an aqueous phase having a low viscosity unlike a water-in-oil emulsion composition, so that oil droplets aggregate over time and the composition aggregates into an aqueous phase. Although exudation is thought to occur, the details of the cause of the occurrence are unknown, and the influence of the blending components and the like is also considered. The liquid separation causes deterioration of the quality of the oil-in-water emulsion composition over time. In particular, in the pharmaceutical field, the uniformity of medicinal ingredients is impaired by liquid separation, which can be a problem from the viewpoint of safety.

  As means for suppressing liquid separation in such an oil-in-water emulsion composition, for example, means for improving the viscosity of an aqueous phase that is a continuous phase is known. Such means suppresses liquid separation by improving the dispersibility of oil droplets by improving the viscosity of the aqueous phase (see Patent Documents 1, 2, 3, and 4).

Further, as means for suppressing liquid separation in a system of an oil-in-water emulsion composition containing zinc oxide whose surface may be hydrophobized, for example, it is known to add citric acid or a salt thereof ( (See Patent Document 5).
Japanese translation of PCT publication No. 2003-502356 JP-T-2004-522751 Special table 2003-518010 gazette Special table 2003-518008 gazette JP 2007-277191 A

  Accordingly, an object of the present invention is to provide an oil-in-water emulsion composition containing a metal oxide such as zinc oxide and having suppressed liquid separation.

In order to suppress the liquid separation that occurs in an oil-in-water emulsion composition containing a metal oxide such as zinc oxide or titanium oxide, the present inventors first examined the cause of the occurrence. As a result, in an oil-in-water emulsion composition containing a metal oxide, it was found that liquid separation occurs due to the addition of the metal oxide. That is, in the state where particles such as metal oxide are not added, liquid separation does not occur, but gel aggregation occurs due to the addition of metal oxide, and liquid separation occurs (see the reference example described later). In order to suppress such liquid separation, the present inventors have attempted to suppress liquid separation by improving the viscosity of the composition in view of the prior art. However, in oil-in-water emulsion compositions containing metal oxides such as zinc oxide and titanium oxide, consistency is improved by blending thickeners such as water-soluble polymers that are commonly used to improve viscosity. It was difficult to suppress the liquid separation only by making it happen. Moreover, excessive improvement in viscosity also causes stickiness during use of the composition and causes a decrease in the feeling of use, so that there is inevitably a limit to the blending of the thickener.
Accordingly, the present inventors have conducted further diligent studies, and found that polyalkylene glycol can suppress liquid separation of an oil-in-water emulsion composition containing a metal oxide while maintaining a good feeling of use. The headline and the present invention were completed.

That is, the present invention relates to the following [1] to [18].
[1] An oil-in-water emulsion composition containing a metal oxide and a polyalkylene glycol.
[2] An oil-in-water emulsion composition containing polyalkylene glycol as a component for suppressing metal oxide and liquid separation.
[3] An oil-in-water emulsion composition containing a metal oxide, further comprising a polyalkylene glycol as a component for suppressing liquid separation.
[4] An oil-in-water emulsion composition comprising a metal oxide and further containing a polyalkylene glycol in order to suppress liquid separation.
[5] The oil-in-water emulsion composition according to any one of [1] to [4], wherein the metal oxide is zinc oxide or titanium oxide.
[6] The oil-in-water emulsion composition according to any one of [1] to [5], wherein the polyalkylene glycol has an average molecular weight of 600 to 20000.
[7] The oil-in-water emulsion composition according to any one of [1] to [6], wherein the polyalkylene glycol is polyethylene glycol.
[8] The oil-in-water emulsion composition according to any one of [1] to [7], wherein the oil-in-water emulsion composition is a pharmaceutical or a cosmetic.
[9] A method for suppressing liquid separation of an oil-in-water emulsion composition containing a metal oxide by blending a polyalkylene glycol.
[10] The method according to [9], wherein the metal oxide is zinc oxide or titanium oxide.
[11] The method according to [9] or [10], wherein the polyalkylene glycol has an average molecular weight of 600 to 20,000.
[12] The method according to any one of [9] to [11], wherein the polyalkylene glycol is polyethylene glycol.
[13] The method according to any one of [9] to [12], wherein the oil-in-water emulsion composition is a pharmaceutical or a cosmetic.
[14] A liquid separation inhibitor for suppressing liquid separation of an oil-in-water emulsion composition containing a metal oxide and containing a polyalkylene glycol.
[15] The liquid separation inhibitor according to [14], wherein the metal oxide is zinc oxide or titanium oxide.
[16] The liquid separation inhibitor according to [14] or [15], wherein the polyalkylene glycol has an average molecular weight of 600 to 20,000.
[17] The liquid separation inhibitor according to any one of [14] to [16], wherein the polyalkylene glycol is polyethylene glycol.
[18] The liquid separation inhibitor according to any one of [14] to [17], wherein the oil-in-water emulsion composition is a pharmaceutical or a cosmetic.

  According to the present invention, an oil-in-water emulsified composition containing a metal oxide such as zinc oxide, which is suppressed in liquid separation and has a good feeling in use can be obtained.

  Specific examples of the “metal oxide” used in the oil-in-water emulsion composition of the present invention include zinc oxide and titanium oxide. A preferred metal oxide is zinc oxide. In the present invention, the shape of the metal oxide (spherical, rod-like, needle-like, plate-like, indeterminate, scaly, spindle-like, etc.) and particle structure (porous, nonporous, etc.) are not particularly limited. Further, the surface of the metal oxide may be subjected to a hydrophobic treatment. Here, as the hydrophobization treatment of the surface, it can be used without particular limitation as long as it is made of powders such as ordinary pharmaceuticals and cosmetics, for example, hydrogen methylpolysiloxane baking, dimethylpolysiloxane baking, etc. , Perfluoroalkylsilylating agent treatment, fatty acid aluminum soap coating treatment, polyethylene coating treatment, lecithin coating treatment, acylglutamate aluminum coating treatment, and the like. In the present invention, these may be used in combination. As the metal oxide in the present invention, zinc oxide or titanium oxide is preferable, more preferably zinc oxide, and zinc oxide when formulated as a pharmaceutical is zinc oxide described in the 15th revision Japanese Pharmacopoeia. preferable. Commercially available products can be used as the metal oxide of the present invention. Specific examples of commercially available products include zinc oxide (manufactured by Sakai Chemical Industry Co., Ltd.), titanium oxide A-HR (manufactured by Freund Sangyo Co., Ltd.), and the like. It is done.

  The average primary particle diameter of the metal oxide is not particularly limited, but is preferably 0.01 to 1 μm, particularly preferably 0.01 to 0.5 μm from the viewpoint of dispersion stability. The average primary particle diameter of zinc oxide can be measured with a laser diffraction / scattering particle size distribution measuring apparatus.

  The content of the metal oxide such as zinc oxide or titanium oxide in the oil-in-water emulsion composition of the present invention is not particularly limited, but from the viewpoints of dispersion stability, pharmacological effect, etc., the total mass of the oil-in-water emulsion composition On the other hand, the total amount is preferably 1 to 40% by mass, particularly preferably 3 to 20% by mass.

The “polyalkylene glycol” used in the present invention has the following general formula (1):
HO- (A-O) n-H (1)
(In the formula, A represents a linear or branched alkylene group having 2 to 4 carbon atoms, and n represents an average added mole number of 2 to 1000, preferably 5 to 1000. The n A's are the same. However, when A is different, the polymerization mode of the plurality of A may be random copolymerization, alternating copolymerization, periodic copolymerization, or block copolymerization.)
In the present invention, the compound represented by the general formula (1) can be used alone or in combination of two or more.
Specific examples of the polyalkylene glycol suitable in the present invention include polyethylene glycol and polypropylene glycol, and among these, polyethylene glycol is preferable from the viewpoint of the effect of inhibiting liquid separation. In the present invention, commercially available products and the like can be used. Specific examples of commercially available products include macro goal 200, macro goal 300, macro goal 400, macro goal 600, macro goal 1000, macro goal 1500, macro goal. 1540, Macrogol 4000, Macrogol 6000, Macrogol 20000, Macrogol 35000 (above, manufactured by Nippon Oil & Fats Co., Ltd.), New Pole PP2000 (above, manufactured by Sanyo Chemical Industries, Ltd.) and the like.

  The average molecular weight of the polyalkylene glycol used in the present invention is not particularly limited, and two or more polyalkylene glycols having different average molecular weights can be used in combination as appropriate. From the viewpoint of the effect, the average molecular weight of the blended polyalkylene glycol is preferably in the range of 600 to 20000, more preferably in the range of 800 to 15000, and in the range of 1000 to 10,000. Particularly preferred. The average molecular weight of polyalkylene glycol was determined by back titration using phthalic anhydride and sodium hydroxide solution (average molecular weight test shown in the section of “15th revised Japanese Pharmacopoeia Pharmaceuticals,“ Macrogol 400 ””). Can be measured.

  The content of the polyalkylene glycol in the oil-in-water emulsion composition of the present invention is not particularly limited, but from the viewpoint of the effect of inhibiting liquid separation of the oil-in-water emulsion composition, the total amount with respect to the total mass of the oil-in-water emulsion composition 0.01 to 10% by mass is preferable, and 0.1 to 5% by mass is particularly preferable.

  The content ratio of the metal oxide such as zinc oxide and titanium oxide and the polyalkylene glycol in the oil-in-water emulsion composition of the present invention is not particularly limited, but from the viewpoint of the liquid separation inhibiting effect of the oil-in-water emulsion composition, oxidation 0.001-10 mass parts of polyalkylene glycol is preferable with respect to 1 mass part of metal oxides, such as zinc, 0.01-10 mass parts is more preferable, and 0.1-10 mass parts is especially preferable.

  In the present invention, the “oil-in-water type emulsion composition” means a generic name of an emulsifier form in which the continuous phase is an aqueous phase, and even if it is a complex emulsifier form such as water-in-oil-in-water, an aqueous phase exists as a continuous phase. As long as it is included, it is included in the “oil-in-water emulsion composition”.

  The water content in the oil-in-water emulsion composition of the present invention is not particularly limited, but from the viewpoint of the stability of the emulsion system, it is contained in an amount of 30 to 99 parts by mass with respect to the total mass of the oil-in-water emulsion composition of the present invention. It is preferable to contain 50 to 95 parts by mass, and it is particularly preferable to contain 70 to 95 parts by mass.

  The oily component constituting the oil phase of the oil-in-water emulsion composition of the present invention is not particularly limited as long as it is a component used in pharmaceuticals, cosmetics, and the like. Specifically, for example, hydrocarbons (white petrolatum, Liquid paraffin, squalane, etc., waxes (salax beeswax, carnauba wax, candelilla wax, lanolin, etc.), fats and oils (soybean oil, hard fat, castor oil, olive oil, etc.), alcohols (cetanol, stearyl alcohol, oleyl alcohol, Cholesterol, etc.), fatty acids (palmitic acid, stearic acid, oleic acid, etc.), silicone oil (methylpolysiloxane, etc.), vitamin derivatives (retinol palmitate, tocopherol acetate, etc.) and the like. , Or a combination of two or more. The content of these oil components is not particularly limited, but from the viewpoint of stability of the emulsion system, it is preferable to contain 1 to 50 parts by mass in total with respect to the total mass of the oil-in-water emulsion composition of the present invention. It is more preferable to contain -30 mass parts, and it is especially preferable to contain 10-20 mass parts.

  The emulsifier used in the oil-in-water emulsion composition of the present invention is not particularly limited as long as it is a component used in pharmaceuticals, cosmetics, etc. Specifically, for example, polyoxyethylene alkyl ether (polyoxyethylene cetyl) Ether, polyoxyethylene stearyl ether, etc.), polyoxyethylene alkylphenyl ether (polyoxyethylene nonylphenyl ether, polyoxyethylene octylphenyl ether, etc.), polyoxyethylene polyoxypropylene alkyl ether (polyoxyethylene polyoxypropylene cetyl ether) Etc.), polyoxyethylene sorbite fatty acid esters (monolauric acid polyoxyethylene sorbite, etc.), polyoxyethylene sorbitan fatty acid esters (monooleic acid polyoxyethylene sorbate) Tan, polyoxyethylene sorbitan tristearate, polysorbate, etc.), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbit beeswax, sucrose fatty acid ester, monoacylglycerol (eg glyceryl monostearate), diacyl Glycerol (glyceryl distearate, etc.), polyglycerol fatty acid ester (diglyceryl monostearate, etc.), polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene sterol, polyoxyethylene fatty acid amide (polyoxyethylene stearic acid amide, etc.) ), Lecithin, polyethylene glycol fatty acid esters (polyethylene glycol monolaurate, etc.), propylene glycol fatty acid esters (mono Propylene glycol teatate), sorbitan fatty acid ester (sorbitan monostearate, etc.), sodium alkyl sulfate (sodium lauryl sulfate, etc.), polyoxyethylene alkyl ether phosphate (polyoxyethylene cetyl ether sodium phosphate, polyoxyethylene lauryl) Ether sodium phosphate etc.) can be mentioned, and these can be used alone or in combination of two or more. The content of these emulsifiers is not particularly limited, but from the viewpoint of the stability of the emulsion system, it is preferable to contain 0.5 to 10 parts by mass in total with respect to the total mass of the oil-in-water emulsion composition of the present invention. The content is more preferably 1 to 10 parts by mass, and particularly preferably 2 to 10 parts by mass.

  In the oil-in-water emulsion composition of the present invention, the mass ratio of the water phase and the oil phase is not particularly limited, but from the viewpoint of the stability of the emulsion system, the water phase / oil phase is preferably 1/1 to 100/1, 2/1 to 20/1 is more preferable, and 3/1 to 10/1 is particularly preferable.

  In addition to the above components, the oil-in-water emulsion composition of the present invention may contain an aqueous component, preservative, antioxidant, other medicinal component, etc., if necessary, depending on various conditions such as purpose of use and form. Can do.

  Examples of the aqueous component include lower alcohols (ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, glycerin, propylene glycol, etc.), water-soluble polymers (methylcellulose, ethylcellulose, carboxyvinyl polymer). , Xanthan gum, polyvinyl pyrrolidone, water-soluble collagen, hyaluronic acid, etc.), amino acids (glycine, alanine, etc.) and others (citric acid, phosphoric acid, lactic acid, sodium lactate, sodium chloride, etc.), etc. It can be used alone or in combination of two or more.

  Examples of the preservative include methyl paraben, ethyl paraben, propyl paraben, butyl paraben and the like, and these can be used alone or in combination of two or more.

  Examples of the antioxidant include dibutylhydroxytoluene and tocopherol. These can be used alone or in combination of two or more.

  Other medicinal ingredients can be appropriately selected according to the purpose of use of the oil-in-water emulsion composition of the present invention. Specifically, for example, anti-inflammatory agents (hydrocortisone, prednisolone, dexamethasone, triamcinolone, betamethasone, actarit, acemetacin, Ampiroxicam, ibuprofen, indomethacin, etodolac, ketoprofen, zaltoprofen, diclofenac, sulindac, celecoxib, thiaprofenic acid, tenoxicam, naproxen, piroxicam, felbinac, pranoprofen, flurbiprofen, mefenamic acid, medicoxib, meloxicamo Loxoprofen, lobenzalit, lornoxicam, bufexamac, antipyrine, glycyrrhetinic acid, glycyrrhizic acid, salicy Acid, methyl salicylate, glycol salicylate, ethylene glycol salicylate, arnica tincture, horse chestnut seed extract, dried shrimp extract, camphor, menthol, etc.), antibacterial agents (clotrimazole, miconazole, econazole, croconazole, isoconazole, pyrrolnitrin, Butenafine, terbinafine, omoconazole, ranoconazole, itraconazole, fluconazole, sulconazole, bifonazole, riranaphthate, tolnaftate, thianthol, isopropylmethylphenol, homosulfamine, chlorhexidine, sulfadiazine, trichlorocarbanilide, etc., antihistaminic acid, diphenhydramine acid Lamin), local anesthetics (ethyl aminobenzoate, Lido) In, dibucaine, tesitdecitine, etc.), decongestants (ephedrine, methylephedrine, etc.), wound healing agents (allantoin, aluminum chlorohydroxy allantoate, etc.), humectants (1,3-butylene glycol, glycerin, propylene glycol, Glycine, alanine, etc., hyaluronic acid, heparin-like substance, sorbitol, trehalose, urea, lactic acid, sodium lactate, pyrrolidone carboxylate, etc.) can be blended, and these can be used alone or in combination of two or more.

  The consistency of the oil-in-water emulsion composition of the present invention is not particularly limited, but is preferably 3 to 30 g, more preferably 5 to 20 g, and particularly preferably 5 to 10 g from the viewpoint of feeling of use such as stickiness. Here, the consistency represents the maximum value of stress when a metal sphere having a diameter of 1 cm enters at a speed of 30 mm / min at 25 ° C., and is measured by, for example, a rheometer (3002D-L, manufactured by FUDOH). be able to.

  The pH of the oil-in-water emulsion composition of the present invention is preferably from 3 to 9, more preferably from 4 to 8, from the viewpoint of skin irritation.

  The oil-in-water emulsified composition of the present invention can be made into a dosage form such as cream, emulsion, lotion, ointment and the like according to the purpose of use, and is not particularly limited as long as it is an emulsifier form having a continuous phase as an aqueous phase.

  The oil-in-water emulsion composition of the present invention can be produced according to a conventional method according to a specific dosage form or the like.

  The oil-in-water emulsified composition of the present invention has a dry action, an anti-sebum action, an ultraviolet shielding effect, a deodorizing action, etc. of the affected part based on the oil absorption property of zinc oxide. It can be used as a skin external preparation for treatment and relaxation; sunscreen cosmetics; deodorant cosmetics and the like.

  EXAMPLES Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

[Example 1]
1 g of hydroxyethyl cellulose (Natrozole 250HHR: manufactured by HERCULES), 2 g of polyethylene glycol (Macrogol 4000: manufactured by Nippon Oil & Fats) and 0.2 g of citric acid hydrate are added to purified water corresponding to an amount of 100 g, What was heated at 0 degreeC was made into the water phase. Meanwhile, 4 g of stearic acid, 2.5 g of cetanol, 6 g of octyldodecyl myristate, 5 g of light liquid paraffin, 1.5 g of polyoxyl stearate 40, 1.5 g of polysorbate 20 and 0.5 g of sorbitan monooleate and heated to 80 ° C. The mixture was used as the oil phase. The oil phase was added to the aqueous phase, and the mixture was stirred and mixed at 80 ° C. to emulsify, and then cooled to 50 ° C. or lower, added with 10 g of zinc oxide and stirred, and cooled to room temperature to produce a cream.

[Examples 2-3]
In Example 1, a cream was prepared by setting the blending amount of polyethylene glycol (Macrogol 4000) to 3 g as Example 2, and similarly 5 g as Example 3.

Example 4
A cream was prepared as Example 4 by blending 3 g of polyethylene glycol (Macrogol 6000: manufactured by NOF Corporation) instead of polyethylene glycol (Macrogol 4000) in Example 1.

[Reference Example 1]
In Example 1, a cream preparation was prepared as Reference Example 1 containing no zinc oxide.

[Comparative Example 1]
A cream preparation was prepared as Comparative Example 1 in which polyethylene glycol was not blended in Example 1.
[Comparative Example 2]
A cream was prepared as Comparative Example 2 in which the amount of octyldodecyl myristate was 7.5 g in Comparative Example 1.
[Comparative Example 3]
A cream was prepared as Comparative Example 3 by blending 0.3 g of xanthan gum which is generally used as a thickener instead of polyethylene glycol in Example 1.
[Comparative Example 4]
A cream was prepared as Comparative Example 4 by further blending 0.1 g of xanthan gum in Comparative Example 2.

[Test Example 1]
For the creams of Examples 1 to 4, Reference Example 1 and Comparative Examples 1 to 4, the consistency immediately after preparation, the presence or absence of liquid separation after storage at 60 ° C. for 1 month, and the feeling of use were evaluated.
The consistency was measured using a rheometer (3002D-L, manufactured by FUDOH) as the maximum value of stress when a metal sphere having a diameter of 1 cm was entered at 25 ° C. at a speed of 30 mm / min for 1 cm.
Presence or absence of liquid separation was determined by filling the cream with a glass sealed container and storing it at 60 ° C. for 1 month, and then visually evaluating the appearance. The thing was made into x.
The feeling of use was evaluated by a sensory test. The sensory test was conducted by five panelists. The evaluation of the feeling of use was evaluated as “Good” when more than half of the panelists answered “I did not feel stickiness and the feeling was good” and “No” when they answered “I feel stickiness”.
The results of Test Example 1 are shown in Table 1.

In the cream of Reference Example 1 that does not contain zinc oxide, liquid separation occurred in the creams of Comparative Examples 1 to 4 that contained zinc oxide even though no liquid separation occurred. It was confirmed that the liquid separation after high-temperature and long-term storage of the emulsified composition was caused by the blending of zinc oxide.
In addition, the creams of Examples 1 to 4 were oxidized because the liquid separation was specifically suppressed even though the consistency was equal to or less than that of Comparative Examples 1 to 4. In the system in the oil-in-water emulsion composition containing zinc, the liquid separation cannot be suppressed even if the viscosity of the composition is simply improved, and the liquid separation in the oil-in-water emulsion compositions of Examples 1 to 4 It has been clarified that the inhibitory action is not simply due to the improvement of the viscosity of the composition but based on the addition of polyethylene glycol.
Furthermore, it became clear that the creams of Examples 1 to 4 had no stickiness and good usability.

  Based on the above test results, the oil-in-water emulsion composition containing a metal oxide such as zinc oxide and containing a polyalkylene glycol further suppresses liquid separation and is easy to use. It became clear that things could be obtained.

Claims (13)

  In the oil-in-water emulsion composition containing a metal oxide, an oil-in-water emulsion composition further comprising polyalkylene glycol in order to suppress liquid separation.   The oil-in-water emulsion composition according to claim 1, wherein the metal oxide is zinc oxide or titanium oxide.   The oil-in-water emulsion composition according to claim 1 or 2, wherein the polyalkylene glycol has an average molecular weight of 600 to 20,000.   The oil-in-water emulsion composition according to any one of claims 1 to 3, wherein the polyalkylene glycol is polyethylene glycol.   The oil-in-water emulsion composition according to any one of claims 1 to 4, wherein the oil-in-water emulsion composition is a pharmaceutical or a cosmetic.   A liquid separation inhibitor for an oil-in-water emulsion composition containing a metal oxide, comprising polyalkylene glycol.   The liquid separation inhibitor according to claim 6, wherein the metal oxide is zinc oxide or titanium oxide.   The liquid separation inhibitor according to claim 6 or 7, wherein the polyalkylene glycol has an average molecular weight of 600 to 20,000.   The liquid separation inhibitor according to any one of claims 6 to 8, wherein the polyalkylene glycol is polyethylene glycol.   A method of suppressing liquid separation of an oil-in-water emulsion composition containing a metal oxide by blending polyalkylene glycol.   The method according to claim 10, wherein the metal oxide is zinc oxide or titanium oxide.   The method according to claim 10 or 11, wherein the polyalkylene glycol has an average molecular weight of 600 to 20,000.   The method according to any one of claims 10 to 12, wherein the polyalkylene glycol is polyethylene glycol.