CN102665701A - Ceramide and collagen synthesis promoter and collagen saccharification inhibitor - Google Patents

Ceramide and collagen synthesis promoter and collagen saccharification inhibitor Download PDF

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Publication number
CN102665701A
CN102665701A CN2010800498036A CN201080049803A CN102665701A CN 102665701 A CN102665701 A CN 102665701A CN 2010800498036 A CN2010800498036 A CN 2010800498036A CN 201080049803 A CN201080049803 A CN 201080049803A CN 102665701 A CN102665701 A CN 102665701A
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collagen
xylitol
skin
ceramide
saccharifying
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市川智也
吉田圭司郎
志村进
大石祐一
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Lotte Co Ltd
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Lotte Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/16—Emollients or protectives, e.g. against radiation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/007—Preparations for dry skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Abstract

Disclosed is an oral preparation that is capable of enhancing skin barrier functions such as moisture retention by accelerating the synthesis of ceramide in the skin, and furthermore increases the level of collagen in the skin, prevents skin wrinkles and sagging by inhibiting the saccharification of collagen, and can be safely ingested. Specifically disclosed are a ceramide synthesis promoter, a collagen synthesis promoter, and a collagen saccharification inhibitor, which involve the oral ingestion of xylitol, that have an excellent ceramide synthesis promoting effect, collagen level increasing effect, and collagen saccharification inhibiting effect, and can be safely ingested.

Description

The saccharifying inhibitor of the synthesis accelerant of ceramide and collagen and collagen
Technical field
The present invention relates to the synthesis accelerant of ceramide and collagen and the saccharifying inhibitor of collagen.
Background technology
In the past, the deterioration of known aging and cortex along with skin can produce dry skin (dry skin), wrinkle, problem such as lax.
Dry skin is meant that the moisture of skin keeps function reduction, xerosis cutis, and its surface is in wizened state.Dry skin is to receive stimulation from the outside easily, cause and therefore require pachylosis, inflammation, macule, eczema, the state of chapping etc. it is improved easily.
As the drying that prevents skin, improve the method for dry skin, be employed in the method for coating external agent on the skin, be mixed with the composition that vaseline, mineral oil, ceramide etc. suppress moisture transpirations in this external agent.In addition, as preventing that skin from producing wrinkle and lax method, is employed in the method for coating collagen on the skin.But,, be difficult to give play to the moisture maintenance function equal technically with original skin only through these external agent of coating.In addition, also have following problem: its effect is temporary, and people still have suspection to its persistence effect, can't essence ground solve dry skin and wrinkle, lax problem.
As the method that does not have the problems referred to above, the interior ceramide of oral promotion Skin Cell and the method for the synthetic composition of collagen have been studied.
Ceramide is sphingosine and the fatty acid complex lipid through the amido link be combined into, is the main component of lipid between the horn cell of epidermis.Lipid plays an important role aspect the barrier function that skin stimulates moisture penetration, chemical irritation, physical property keeping between horn cell, and ceramide helps barrier function that moisture is seen through especially.Therefore, the amount of contained ceramide is an important index in the moisture maintenance function aspects of assessing skin in the skin.It is thus clear that in the dry skin of atopic dermatitis and old people's the xeroderma, think that the minimizing of ceramide is one of reason (non-patent literature 1).
As the rate-limiting enzyme in the ceramide biosynthesis, known serine palmitoyltransferase (SPT).SPT is the enzyme by the synthetic 3-ketone group dihydrosphingosine of serine and palmitin acyl-CoA, is to be the enzyme of the initial reaction of catalysis in the biosynthesis of sphingolipid of representative with the ceramide.
On the other hand, be as the unitary fibrous proteins of basic comprising with the helical structure that constitutes by 3 polypeptide chains as the collagen of one of extracellular matrix.The aminoacid that constitutes collagen mainly contains glycine, proline, hydroxyproline and alanine etc., and wherein, hydroxyproline is the characteristic aminoacid in the collagen, therefore is used as collagen quantity is carried out the index when quantitative.
Known collagen has important function aspect the elasticity of skin keeping, and the minimizing of skin collagen quantity and the qualitative change of collagen and the naturally-aged that is caused by age growth, the light decay uneducated person that is caused by ultraviolet etc. are closed, and become wrinkle and lax reason.As the saccharifying of the collagen of one of qualitative change be with age and the phenomenon of aggravation is considered to one of aging phenomenon of skin in recent years.
As ceramide synthesis accelerators, phospholipid (non-patent literature 3), Janpanese sake composition (non-patent literature 4), nicotiamide (non-patent literature 5) of nicotinic acid derivates (patent documentation 1), plant extract (patent documentation 2～4), Chinese medicine (non-patent literature 2), milk etc. have been disclosed.
As collagen synthesis promoter, fermentation sporangium fermentating metabolism liquid (non-patent literature 10), plant extract (patent documentation 5～9), collagen peptide appearance dipeptides and tripeptides (patent documentation 10～11), gamma oryzanol catabolite (patent documentation 12) etc. have been disclosed.
But, strong material of the zest of pair skin etc. is also arranged in these materials, insufficient material aspect safety is arranged.In addition; Also have and make effective ingredient directly act on the situation that cultured cell comes evaluation effect; But when desire is used the human or animal; The problem that whether effective ingredient is absorbed in the body, whether effective ingredient also can be brought into play effect by metabolism in vivo it be unclear that, and still indeterminately whether can obtain enough effects.That is, it is enough good aspect effect and safety hardly.
The prior art document
Patent documentation
Patent documentation 1: No. 3508042 communique of Japanese Patent Laid
Patent documentation 2: Japanese Patent Laid is opened the 2006-111560 communique
Patent documentation 3: Japanese Patent Laid is opened the 2004-210743 communique
Patent documentation 4: Japanese Patent Laid is opened the 2002-370998 communique
Patent documentation 5: Japanese Patent Laid is opened the 2007-230917 communique
Patent documentation 6: Japanese Patent Laid is opened the 2006-273756 communique
Patent documentation 7: Japanese Patent Laid is opened the 2006-265120 communique
Patent documentation 8: Japanese Patent Laid is opened the 2005-139141 communique
Patent documentation 9: Japanese Patent Laid is opened the 2005-120108 communique
Patent documentation 10: Japanese Patent Laid is opened the 2010-024200 communique
Patent documentation 11: Japanese Patent Laid is opened the 2006-056904 communique
Patent documentation 12: Japanese Patent Laid is opened the 2005-263677 communique
Non-patent literature
Non-patent literature 1: the good tree in ground, palace etc., cosmetic dermatology,, 8～18 pages, Nan Shantang in 2005
Non-Patent Document 2: Hino Takayuki, MOROHASHI Masaaki, flavor magazine (フ Ritz bag Lance ji ya a naru), 2004, 3, 26 to 30, "Adjusting skin lipid metabolism research in Chinese medicine (skin Full lipid metabolism を adjusted す ru-Han Jian Fang Sheng Pharmaceutical Full review). "
Non-patent literature 3:Haruta Y. etc., bioscience, biotechnology and biochemistry (Bioscience, Biotechnology; And Biochemistry); 2008,72 volumes, No. 8; 2151～2157 pages, improve the epidermis function (Dietary phospholipid concentrate from bovine milk improves epidermal function in hairless mice) of hairless mouse from phospholipid concentration in the meals of milk
Non-patent literature 4:Nakahara M. etc.; Bioscience, biotechnology and biochemistry (Bioscience; Biotechnology, and Biochemistry), 2007; 71 volumes; No. 2, the 427-434 page or leaf, Janpanese sake concentration is to the influence of Aged Mice epidermis and as the checking (Effect of a sake concentrate on the epidermis of aged mice and confirmation of ethyl alpha-D-glucoside as its active component) of the ethyl α-D-glucoside of its active component
Non-Patent Document 5: Tanno repair, flavor magazine (フ Ritz bag Lance ji ya a naru), 1999, 10, 23 to 28, "by the ceramide de novo synthesis promoter induced epidermal barrier function improvement (De Novo ceramide synthesis promoter Proceeds from the epidermis perfect re ア Full function improvement). "
Non-patent literature 6:Knuuttila M.L. etc.; Life sciences (Life Sciences); 2000,67 volumes, No. 3; 283～290 pages, the xylitol in the meals is to the influence (Effects of dietary xylitol on collagen content and glycosylation in healthy and diabetic rats) of healthy and intravital collagen content of diabetes rat and saccharifying
Non-patent literature 7:Mattila P.T. etc.; Presbyatrics (Gerontology); 2005,51 volumes, No. 3; 166～169 pages, long-term meal supplement xylitol is to the influence (Effects of a long-term dietary xylitol supplementation on collagen content and fluorescence of the skin in aged rats) of intravital collagen content of senile rat and SF
Non-patent literature 8:J.F.Woessner, Jr., Arch Biochem Biophys., 93,440-447 (1961)
Non-patent literature 9:I.Bergman and R.Loxley, Anal Chem., 35,1961-1965 (1963)
Non-Patent Document 10: Tian Zhonghao, flavor magazine (フ Ritz bag Lance ji ya a naru), 2006, 12, 29 to 35, "UV-induced dermal constituent injury and improvement (UV affiliates dermal constituents Full double メ a zip と Other improvements). "
Non-patent literature 11:Philip G. etc.; Threpsology's magazine (The Journal of Nutrition); 1993; 123 volumes; No. 11,1936～1951 pages, the rodentine AIN-93 purification of laboratory recipe: U.S. threpsology institute is write the Final Report (AIN-93 purified diets for laboratory rodents:final report of the American Institute of Nutrition ad hoc writing committee on the reformulation of the AIN-76A rodent diet) of committee to the new regulation of AIN-76A rodent recipe especially
Summary of the invention
Invent technical problem to be solved
Based on above-mentioned problem; The object of the present invention is to provide a kind of oral agents; This oral agents can be synthesized the moisture that improves skin through the ceramide that promotes skin and kept barrier functions such as function; The wrinkle that collagen quantity that can also be through increasing skin and the saccharifying that suppresses collagen prevent skin can absorb with lax safely.
The means that the technical solution problem is adopted
The inventor has carried out conscientiously research to above-mentioned problem, and the result finds, the administered through oral xylitol, and synthetic the obtaining of ceramide promotes, and the mRNA expression of serine palmitoyltransferase raises.In addition, the inventor finds, the administered through oral xylitol, and the collagen quantity of skin increases, and the saccharifying of collagen is inhibited.Based on these discoveries, the inventor has accomplished the present invention.
That is, the present invention relates to a kind of oral ceramide and the synthesis accelerant of collagen and saccharifying inhibitor of collagen that contains xylitol as effective ingredient.
The effect of invention
The administered through oral xylitol can increase the collagen quantity in ceramide synthetic quantity and the skin, and can reduce saccharifying collagen level.
In addition, xylitol is used as the sweeting agent of dessert etc. all the time, even oral, its safety is also no problem.
The simple declaration of accompanying drawing
Fig. 1 is the summary of the testing program among the embodiment.
Fig. 2 is the figure of the expression of the serine palmitoyltransferase gene (Spt) in 3 months Testing Team in the expression Test Example 1.
Fig. 3 is the figure of the expression of the serine palmitoyltransferase gene (Spt) in 6 months Testing Team in the expression Test Example 1.
Fig. 4 is the mensuration result's of the ceramide levels in 3 months Testing Team in the expression Test Example 2 figure.
Fig. 5 is the mensuration result's of the ceramide levels in 6 months Testing Team in the expression Test Example 2 figure.
Fig. 6 is the extraction in the Test Example 3, isolating process chart.
Fig. 7 is the figure of the hydroxyproline amount in 3 months Testing Team in the expression Test Example 3.
Fig. 8 is the figure of the hydroxyproline amount in 6 months Testing Team in the expression Test Example 3.
Fig. 9 is the figure of the fluorescence intensity of the per unit collagen quantity in 3 months Testing Team in the expression Test Example 3.
Figure 10 is the figure of the fluorescence intensity of the per unit collagen quantity in 6 months Testing Team in the expression Test Example 3.
The mode that carries out an invention
Xylitol (xylitol) is that carbon number is 5 a sugar alcohol, also claims xylit.Xylitol generates through xylose is carried out hydrogenation, is widely used in dessert such as chewing gum and confection as the sweeting agent that does not have cariogenicity.
Xylitol is a kind of of polyalcohols such as glycerol, propylene glycol, and water holding capacity is high, and through coating skin, the moisture that can expect to improve skin keeps the effect of function, therefore mixes as the composition of preserving moisture of external agent sometimes.But above-mentioned effect is the effect that can expect of time spent outside, even oral xylitol also can't arrive skin with original state, can't give play to above-mentioned effect.
During about oral xylitol to the effect of skin; Reported following effect: in the experiment of the rat of the xylitol mixed fodder of containing xylitol for the higher dosage give 5.0 weight % and 10.0 weight %; The collagen quantity of skin increases, and also suppresses the saccharifying (non-patent literature 6, non-patent literature 7) of collagen.But, about the synthetic effect of the ceramide of skin is not found.In addition, about effect to collagen, when the disposable picked-up of people a large amount of be the sugar alcohol of representative with the xylitol time, may produce side effect such as diarrhoea, therefore hope whether can expect that to xylitol content still less this problem of same effect estimates.
To this, the inventor finds, the administered through oral xylitol, and synthetic the obtaining of the ceramide of skin promotes, and the mRNA expression of the rate-limiting enzyme serine palmitoyltransferase (SPT) in the ceramide biosynthesis raises.The inventor finds that also the administered through oral ratio is the xylitol of less amount in the past, and the collagen quantity of skin increases, and the saccharifying of collagen is inhibited.Through these discoveries that newly obtains, the inventor has accomplished the saccharifying inhibitor of ceramide synthesis accelerators of the present invention, collagen synthesis promoter and collagen.
The saccharifying inhibitor of ceramide synthesis accelerators of the present invention, collagen synthesis promoter and collagen better is the xylitol that contains the amount that satisfies following condition as effective ingredient: the dosage of every day is 0.4g～1.35g with respect to the heat 100kcal that in one day diet, is absorbed by administration person.Be more preferably the xylitol that contains the amount that satisfies following condition as effective ingredient: the dosage of every day is 0.4g～0.67g with respect to the heat 100kcal that in one day diet, is absorbed by administration person.In addition; The saccharifying inhibitor of ceramide synthesis accelerators of the present invention, collagen synthesis promoter and collagen better is that the ratio with 0.1 weight %～99 weight % contains xylitol as effective ingredient, and the ratio that is more preferably with 1 weight %～90 weight % contains xylitol as effective ingredient.
In addition, the saccharifying inhibitor of ceramide synthesis accelerators of the present invention, collagen synthesis promoter and collagen is characterised in that the administered through oral picked-up.
The saccharifying inhibitor of ceramide synthesis accelerators of the present invention, collagen synthesis promoter and collagen can be as for example medicine, quasi drug or diet article etc.
During for medicine, with the form administration of oral agents.As the dosage form of oral agents, can give an example tablet, capsule, powder, syrup, potus etc.During for quasi drug, use with dosage forms such as tablet, capsule, potus.During for the diet article, except beverages such as beverage and confection, cracknel, cookies etc. the food, the preferences such as Nicotiana tabacum L. and chewing gum of can giving an example, feedstuff and toiletrieses such as feedstuff class, collutory and toothpaste etc.These are just given an example, as long as the oral xylitol of ability, the present invention can be used for any article.
During for medicine or quasi drug, can contain the pharmacology and go up acceptable one or more carrier, can also contain the effective ingredient that other is used to treat as required.In addition, can also contain excipient, binding agent, disintegrating agent, lubricant, dispersant, surfactant, plasticizer, suspensoid, emulsifying agent, diluent, buffer agent, antioxidant, bacterial inhibitor etc.
In addition, the diet article also can contain acceptable base material, carrier, excipient, additive, extender, coloring agent, spice etc. in the food manufacturing.
Composition beyond the xylitol does not receive the qualification of preceding text yet, and the present invention can at random contain known any composition.
The saccharifying inhibitor that contains ceramide synthesis accelerators, collagen synthesis promoter and the collagen of xylitol of the present invention can be made through the known any means in the technical field separately.In its manufacture process, can add xylitol through known any method.
The saccharifying inhibitor that contains ceramide synthesis accelerators, collagen synthesis promoter and the collagen of xylitol of the present invention not only can use the people, also can use the animal (being designated hereinafter simply as the non-human animal) beyond the people.As the non-human animal, the animal beyond the people such as mammals, reptiles, amphibian, Fish that can give an example.
Through above formation, the present invention can expect the synthetic facilitation effect of ceramide with the ceramide synthesis accelerators equal extent of the picked-up of administered through oral in the past.The moisture that therefore, can be used to improve skin keeps the purposes of function, the improvement of dry skin etc.In addition, the present invention also can expect to promote synthetic effect of collagen and the effect that suppresses the collagen saccharifying.Therefore, can be used to prevent the wrinkle and lax purposes of skin.
Embodiment
The present invention will be described below to utilize embodiment, but these embodiment do not cause any qualification to scope of the present invention.
Supply the raising of examination animal, animal
(male, in 11 ages in week, body weight when leaving feed lot: 350～400g) are used for experiment to buy 40 SD rats from Japanese Emilio Correa company (Network レ ア).Animal in the regular grade animal feeding room in 23 ± 1 ℃, the circulation of humidity 50 ± 10%, light and shade 12 hours (the environment raising down of bright phase 8:00～20:00).Carry out body weight determination after the domestications in 2 weeks are raised, rat is grouped into 4 test group shown in the table 1, make that average weight of each group is impartial, then, during giving as test feed, carry out the raising in 11 weeks.According to the body weight through 11 whens week be divided into 3 with 7 group, make average weight equalization in each test group.For the group that is divided into 3, raise lucky 1 week again, dissect (amounting to for 12 weeks, 3 months Testing Team).For the group that is divided into 7, raised for 13 weeks again, dissect (amounting to for 24 weeks, 6 months Testing Team).Shown in Figure 1 is the summary of testing program.
[table 1]
I matched group (CO) : 3 (3 months)+7 (6 months)
II 1.5% xylitol mixed fodder group (Xyl 1.5%) : 3 (3 months)+6 (6 months)
III 2.5% xylitol mixed fodder group (Xyl 2.5%) : 3 (3 months)+7 (6 months)
IV 5.0% xylitol mixed fodder group (Xyl 5.0%) : 3 (3 months)+6 (6 months)
Feedstuff basic composition is AIN-93G standard refined feedstuff.Preparation is replaced as the feedstuff (with reference to table 2) of the composition of xylitol with sucrose, is used for test.In the domestication feeding process, give the feedstuff same with matched group.About the heat of xylitol, any value among 2.40kcal/g and the 3.00kcal/g generally can both be accepted, thus table 2 to be depicted as with two kinds of values be the result that basic calculation goes out.
[table 2]
Figure BPA00001546864900091
Annotate 1: quote from non-patent literature 11
Annotate 2: sucrose is made as 3.87 (kcal/g), xylitol is made as 2.40 (kcal/g) calculates
Annotate 3: sucrose is made as 3.87 (kcal/g), xylitol is made as 3.00 (kcal/g) calculates
Freely absorb feedstuff and water, all 16:30～next day 10:30 was decided to be ingest time in these 18 hours, fasting during 10:30～16:30 from dissecting preceding 1.Carried out the mensuration of 1 body weight determination and feed supply amount and feedstuff surplus in 2 days, with both difference as food ration.In addition, also observe, write down the having or not of abnormal conditions such as state and diarrhoea of feces.
After test raised for 2～3 weeks; In 1 rat of xylitol 5% mixed fodder group, observe the wound that causes by the scratching behavior at back; Though treat subsequently, think and can the analysis of skin be impacted, therefore this animal is got rid of from analytic target.In addition, test raised for the 10th week, in 1 rat of xylitol 1.5% mixed fodder group, observed hematuria, and body weight subsequently is unstable, therefore this animal was got rid of from analytic target.
The correlated results of raising
From beginning to give test feed 1～2 day, 1 merely hitting and observe soft stool (the tangible feces that water quantities is many) in 10 rats of xylitol 5.0% mixed fodder group, but be temporary symptom, recover subsequently.In addition, about variation, the variation of the grand mean food ration in 1 week and the accumulative total food ration in 3 months of the average weight of the rat in each group between 3 months feeding periods,, each does not see the significant difference of food ration between whole feeding period between organizing.
Dissection, each sample collecting
When dissected gives arcotic somunopentyl (upright altogether drugmaker (upright altogether pharmacy)) with the amount of every 100g body weight 0.1mL in the abdominal cavity.After the anesthesia, pick the hair of rat back with clippers, the microscope slide that will be coated with instant adhesive (Aron Alpha) then was pasted on back surfaces 1 minute, gathered the sebum of skin surface.Then, gather skin of back (downcutting the part of skin with the puncher of φ=1.8cm with circle), blood plasma (heart blood sampling), liver, epididymal adipose tissues.
The mensuration of the expression of [Test Example 1] ceramide synzyme
Total RNA from skin extracts and the cDNA preparation
The skin histology of gathering is pulverized under freezing state, about 350mg pulverizing pieces of skin is made for sample.Extraction from total RNA of skin is carried out with the total RNA purification system of SV (SV Total RNA Isolation System) (Pu Luomaige company (Promega)).(high power capacity cDNA reverse transcription test kit (High Capacity cDNA Reverse Transcription Kit) ABI) prepares cDNA through reverse transcription reaction by the total RNA of 2 μ g.The cDNA that makes will be used for the PCR in real time analysis, therefore with 5 times of aquesterilisa dilutions.
Adopt the range gene expression analysis of PCR in real time
In 96 orifice plates (ABI), add 5 times of dilute samples of cDNA, the 1 μ L that processes in the real-time PCR reactions liquid 24 μ L that (ABI) mix by the primer of serine palmitoyltransferase (Spt) and probe and the general prefabricated mixed liquor I I of TaqMan (registered trade mark) (Universal Master Mix II) and the preceding text; (7300 types ABI) carry out gene expression analysis with PCR in real time.Sequence shown in primer and probe use hereinafter.5 ' end of the oligo DNA that uses in the probe is combined with FAM, and 3 ' end is combined with TAMRA.After the expression that mRNA amount is used as the beta-actin (Beta-actin) of house-keeping gene is proofreaied and correct, try to achieve with form with respect to the relative value of matched group.
Forward primer: 5 '-CAG TGC AGC CTG CTT TGC TA-3 ' (sequence numbering 1)
Reverse primer 5 '-GCC TTT CGA GGA TTC TTT TGA TC-3 ' (sequence numbering 2)
Probe (rat SPT): 5 '-CCA GAA AGG ACT ACA GGC ATC ACG CAG-3 ' (sequence numbering 3)
The mensuration result of the expression of serine palmitoyltransferase gene (Spt)
The expression of the serine palmitoyltransferase gene (Spt) in 3 months Testing Team is shown in Fig. 2, and the expression of the serine palmitoyltransferase gene (Spt) in 6 months Testing Team is shown in Fig. 3.
Though do not see significant difference and remarkable tendency on the statistics between each group, each xylitol administration group is compared expression with matched group all have rising.
The mensuration of [Test Example 2] cutaneous nerve amide amount
The extraction of cutaneous nerve amide
The sebum sample of when dissected from the skin of back acquisition surface to microscope slide impregnated in hexane: the solvent of ethanol to mix at 95: 5, extract lipid components through ultrasonic Treatment.The lipid components that extracts is transferred in the test tube after filtering with hydrophobicity filter (Millex (registered trade mark)-FH, φ=0.45 μ m, Millipore Corp. (ミ リ Port ア)),, drying and consolidating concentrated with nitrogen.The lipid components of drying and consolidating is dissolved with chloroform once more, be transferred in the umbrinaceous microtubule,, drying and consolidating concentrated once more with nitrogen.At this moment, measure the weight of microtubule in advance, with its with concentrate with nitrogen, the difference of weight behind the drying and consolidating is as the TL amount.
TL with respect to every 1mg gained adds 10 μ L chloroforms, makes lipid components dissolving, with it as the TL sample that is conducted to the TCL method.
Quantizing of the cutaneous nerve amide amount of employing TLC method
5 μ L TL sample (amount that is equivalent to the 0.5mg TL) point samples in silica gel plate (HPTLC, Merck & Co., Inc.'s (メ Le Network)), are used and launched solvent (chloroform: methanol: acetic acid=192: 7: 1) launch.After launch finishing, make the silica gel plate intensive drying after, spraying is according to copper sulfate (the II)-phosphoric acid solution (colour reagent) of the formulated shown in the table 3, in 150 ℃ of heating about 10 minutes.As standard substance, use the ceramide (ceramide (Ceramide), natural mixed liquor (Natural Mixture), ship are got over company (Off Na コ シ)) that derives from Medulla Bovis seu Bubali.The speckle that appears on the silica gel plate quantizes with image analyzer (LAS-3000, Fuji Photo Film Co Ltd.'s (Off ジ Off イ Le system)).
[table 3]
Copper sulfate (II) pentahydrate 7.815g
Phosphoric acid 4.0g
Pure water Be settled to 50mL
Amount to 50mL
The mensuration result of cutaneous nerve amide level
The mensuration result of the ceramide levels in 3 months Testing Team is shown in Fig. 4.Though do not see significant difference and remarkable tendency on the statistics between each group, xylitol administration group is compared with matched group and demonstrated higher value on the whole, particularly the value of xylitol 2.5% mixed fodder group is higher than matched group.
The mensuration result of the ceramide levels in 6 months Testing Team is shown in Fig. 5.Xylitol 1.5% mixed fodder group is compared with matched group with 5.0% mixed fodder group has increased by 1.4～1.5 times, remarkable on statistics.Though xylitol 2.5% mixed fodder group is not seen significant difference and remarkable tendency on the statistics, its value is higher than matched group.
The evaluation of [Test Example 3] skin collagen quantity, the mensuration of the mass commercial weight in the collagen
Extraction, the separation of total collagen
Extract, separate (with reference to Fig. 6) according to non-patent literature.
The skin freezing of gathering is pulverized, carried out the defat processed, use the dissecting scissors cutting with acetone.Then, with ball mill (Lay speed company (Retsch)) freezing and pulverizing, after lyophilization, obtain the skin powder sample.In 30mg skin powder sample, add the 0.5M acetic acid of 9mL, in 4 ℃ of concussion extractions after 16 hours,, be divided into cleer and peaceful deposition with 30000G, 4 ℃ condition centrifugalize 30 minutes.
In supernatant, add 1: 10000 (the pure medicine of biochemistry usefulness and light company (with the pure medicine of light)) of pepsin, make final concentration reach 100mg/mL,, non-collagenic structure protein matter is decomposed in 22 ℃ of reactions 16 hours.Then, add sodium chloride, make final molar concentration reach 1.8M, carry out centrifugally once more with 30000G, 4 ℃ condition, the gained precipitate is dissolved with 0.1M acetic acid, with products therefrom as the acid-solubility component.
On the other hand, for the precipitate behind the 0.5M acetic acid extraction, use collagenase buffer washing precipitation once according to the preparation of the composition of table 4 after, add 3mL and be mixed with the collagenase liquid of 200 units/mL concentration, in 37 ℃ of reactions 22 hours according to the composition of table 5.Then, carry out with 30000G, 30 minutes, 4 ℃ condition centrifugal, with supernatant as the collagenase soluble component.
[table 4]
Sodium chloride 5.844g
Calcium chloride 1.665g
Ultrapure Tris 6.057g
Pure water Be settled to 1L
1N hydrochloric acid The pH adjustment
The 1N sodium hydroxide The pH adjustment
Amount to 1L
[table 5]
VII Collagen Type VI enzyme (Sigma company (シ グ マ)) 15000 units
Collagenase buffer (pH=7.4/37 ℃) ? 75mL
Amount to ?75mL
Hydroxyproline (Hyp) quantitatively
Carry out the quantitative of hydroxyproline according to non-patent literature 8 and non-patent literature 9.
In 20 μ L acid soluble components or collagenase soluble component, add the 6N hydrochloric acid of 500 μ L, after the mixing, in 130 ℃ of acid hydrolysis that carry out 3 hours.After the cooling,, add the 0.04% C.I. 13020. solution of 2 μ L, add the 2.5N sodium hydroxide of 1150 μ L as the pH indicator.Suitably add the dilute aqueous solution of hydrochloric acid and sodium hydroxide, be adjusted to pH=6～7, make the color of solution be the color of pink colour and lurid Neutral colour.
Then, mix the 50mM toluene-sodium-sulfonchloramide solution that 1mL prepares according to the composition of record in table 6, the table 7, after room temperature reacts 20 minutes down, mix 18.9% high chloro acid solution of 1mL, reacted 5 minutes down in room temperature.Then, mix the 20% paradime thylaminobenzaldehyde solution of 1mL according to the composition preparation of record in the table 8, reaction is 20 minutes in 60 ℃ hot bath.Then, with flowing water cooling 5 minutes, after leaving standstill more than 1 hour under the room temperature,, obtain the hydroxyproline amount according to calibration trace with the absorbance of spectrophotometer (U-3900H, Hitachi) mensuration 557nm.The hydroxyproline amount that obtains thus multiply by conversion coefficient 7.25, with the value of gained as the collagen scaled value.
[table 6]
The citric acid monohydrate compound 50g
Acetic acid 12mL
Sodium acetate trihydrate 120g
Sodium hydroxide 34g
Pure water Be settled to 1L
1N hydrochloric acid The pH adjustment
The 1N sodium hydroxide The pH adjustment
Amount to 1L
[table 7]
The toluene-sodium-sulfonchloramide trihydrate 1.41g
Methyl cellosolve 30mL
Hyp quantitatively uses buffer (pH=6.0, table 6) 50mL
Pure water 20mL
Amount to 100mL
[table 8]
Paradime thylaminobenzaldehyde 20g
Methyl cellosolve ? Be settled to 100mL
Amount to 100mL
The evaluation of the mensuration of fluorescence intensity and mass commercial weight
Carry out fluorescent strength determining according to non-patent literature 6.For acid-solubility component and collagen soluble component, suitably dilute, measure fluorescence intensity with spectrofluorophotometer (RF-5000, Shimadzu Seisakusho Ltd.) with the condition of excitation wavelength Ex:370nm, mensuration wavelength Em:440nm.According to the fluorescence intensity of the collagen quantity unit of the calculating collagen quantity of calculating, as the index of mass commercial weight by the hydroxyproline amount of each component.
The mensuration result of hydroxyproline amount
Hydroxyproline amount in 3 months Testing Team is shown in Fig. 7, and the hydroxyproline amount in 6 months Testing Team is shown in Fig. 8.
For 3 months Testing Team; Acid-solubility component, collagenase soluble component are not all seen the significant difference on the statistics and significantly are inclined between each group; And for 6 months Testing Team; Hydroxyproline amount in each component all increases to some extent, and particularly in the collagenase soluble component, all xylitol mixed fodder groups are compared with matched group all has remarkable rising on statistics.Because the amount of the characteristic aminoacid hydroxyproline of collagen increases, can think that therefore the synthetic quantity of the collagen in the xylitol mixed fodder group increases.
The mensuration result of saccharifying collagen level
The fluorescence intensity (saccharifying collagen level) of the unit collagen quantity of calculating according to the hydroxyproline amount in 3 months Testing Team is shown in Fig. 9, and the fluorescence intensity (saccharifying collagen level) of the unit collagen quantity of calculating according to the hydroxyproline amount in 6 months Testing Team is shown in Figure 10.
The minimizing of all visible saccharifying collagen level in each component, particularly for 3 months Testing Team, xylitol 2.5% mixed fodder group is compared with matched group, and the value of collagenase soluble component is significantly lower.In addition, for 6 months Testing Team, the acid-solubility of all xylitol mixed fodder groups (1.5%, 2.5%, 5.0%) and the value of these two kinds of components of collagenase solubility were compared all significantly lower with matched group.
As stated, xylitol administration group is compared with the matched group that does not give xylitol, the synthetic facilitation effect of visible ceramide.Can confirm in addition, with disclose oral xylitol beyond composition the result technical literature formerly, be that patent documentation 1～4, non-patent literature 2～5 are compared the synthetic effect with equal extent.
In addition, xylitol administration group is compared with matched group, the synthetic facilitation effect of also visible collagen and the effect that suppresses the collagen saccharifying.
[embodiment 4]
According to following formulated tablet.
Figure BPA00001546864900151
With the mentioned component uniform mixing,, process tablet with this mixed-powder tabletting.
[embodiment 5]
According to following formulated tablet.
Xylitol 80%
Lactose 8%
Hydroxypropyl cellulose 10%
Magnesium stearate 2%
With the mentioned component uniform mixing,, process tablet with this mixed-powder tabletting.
[embodiment 6]
According to following formulated syrup.
Simple syrup 30%
Xylitol 20%
Pure water 50%
[embodiment 7]
According to following formulated capsule.
Xylitol 99%
Magnesium stearate 1%
With the mentioned component uniform mixing, this mixed-powder is filled in the hard capsule.
[embodiment 8]
According to following formulated capsule.
Xylitol 90%
Lactose 8%
Magnesium stearate 2%
With the mentioned component uniform mixing, this mixed-powder is filled in the hard capsule.
[embodiment 9]
According to following formulated powder.
Xylitol 65%
Corn starch 9.9%
Hydroxypropyl cellulose 25%
L-menthol 0.1%
[embodiment 10]
According to following formulated potus.
Figure BPA00001546864900161
Figure BPA00001546864900171
[embodiment 11]
According to following formulated potus.
Figure BPA00001546864900172
[embodiment 12]
According to following formulated potus.
Figure BPA00001546864900173
The application requires the priority based on the japanese patent application No. 2009-262951 that filed an application on November 18th, 2009, quotes the part of its content as the application.
Figure IPA00001546864300011

Claims (9)

1. ceramide synthesis accelerators for oral use is characterized in that, contains xylitol as effective ingredient.
2. ceramide synthesis accelerators for oral use as claimed in claim 1 is characterized in that, contains the xylitol of 0.1 weight %～99 weight %.
3. ceramide synthesis accelerators for oral use as claimed in claim 1; It is characterized in that the xylitol that contains the amount that satisfies following condition is as effective ingredient: the dosage of every day is 0.4g～1.35g with respect to the heat 100kcal that in one day diet, is absorbed by administration person.
4. collagen synthesis promoter for oral use is characterized in that, contains xylitol as effective ingredient.
5. collagen synthesis promoter for oral use as claimed in claim 4 is characterized in that, contains the xylitol of 0.1 weight %～99 weight %.
6. collagen synthesis promoter for oral use as claimed in claim 4; It is characterized in that the xylitol that contains the amount that satisfies following condition is as effective ingredient: the dosage of every day is 0.4g～1.35g with respect to the heat 100kcal that in one day diet, is absorbed by administration person.
7. collagen saccharifying inhibitor for oral use is characterized in that, contains xylitol as effective ingredient.
8. collagen saccharifying inhibitor for oral use as claimed in claim 7 is characterized in that, contains the xylitol of 0.1 weight %～99 weight %.
9. collagen saccharifying inhibitor for oral use as claimed in claim 7; It is characterized in that the xylitol that contains the amount that satisfies following condition is as effective ingredient: the dosage of every day is 0.4g～1.35g with respect to the heat 100kcal that in one day diet, is absorbed by administration person.
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