CN105285986A - Health food or pharmaceutical composition comprising chestnut shell extract - Google Patents
Health food or pharmaceutical composition comprising chestnut shell extract Download PDFInfo
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- CN105285986A CN105285986A CN201510750348.7A CN201510750348A CN105285986A CN 105285986 A CN105285986 A CN 105285986A CN 201510750348 A CN201510750348 A CN 201510750348A CN 105285986 A CN105285986 A CN 105285986A
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- Prior art keywords
- chestnut
- chestnut shell
- skin
- shell extract
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- Coloring Foods And Improving Nutritive Qualities (AREA)
Abstract
The present invention relates to a health food or pharmaceutical composition for alleviating or suppressing pruritus, comprising chestnut shell extract as an active ingredient. In one example of the present invention, the chestnut shell extract comprised in the health food or pharmaceutical composition of the present invention can suitably be used as the active ingredient of a health food or pharmaceutical composition for alleviating or suppressing pruritus as it has been confirmed that it can exhibit an outstanding effect in alleviating or suppressing pruritus by suppressing the activity of -2(proteinase-activated receptor-2:PAR-2) which is a source of stimulation in pruritus.
Description
Patent application of the present invention is the divisional application proposed for the application that the applying date is on 06 18th, 2010, application number is 201080035903.3, denomination of invention is " healthy food containing chestnut shell extract or pharmaceutical compositions ".
Technical field
The present invention relates to the healthy food containing chestnut shell extract or pharmaceutical compositions.
Background technology
Itch is defined as bringing out the offending dermal sensation of the desire wanting to scratch; as pain, sense of touch, cold or hot and so on physiological defence mechanism; time in the destructive stimulus that skin is exposed to from outside, cognition is carried out to it and plays the effect protecting skin.
Pruritus is the one in the common symptoms of often performance in various skin disease or general disease, actual conditions are, nettle rash, severe pruritus disease caused by various side effects of pharmaceutical drugs can easily be cured, but the treatment of the chronic pruritus of the severe of Biliary atresia, kidney trouble or atopic diseases and so on is very difficult.
Itch is brought out by many reasons such as inflammation, cancer, metabolic disease, infection, psychiatric condition, drug administration or pressure, in nearest some results of study, specify that skin and peripheral nervous system and central nervous system organic be connected with for bring out itch stimulation reaction, regulate closely related.
Recently, specify that specific sensory neurone and acceptor thereof react specifically to itch, receive the next state that itch is not pain, but as indivedual sensations of sensory nervous system, think mutually different itch medium and acceptor thereof and multiple disease association (Steinhoffetal., JournalofInvestigativeDermatology, 126 of bringing out itch, pp1705-1718,2006).
In the experiment for pruritus research up to now, main use histamine, but following opinion is proposed, namely the chronic pruritus of idiocrasy and so on is caused by histamine dependence path (pathway), not equal to be caused by nerve reason, this is illustrated as the pruritus not onset (Standeretal. of what antihistamine to atopic diseases, ExperimentalDermatology, 11, pp12-24,2002).
In addition, known 1st generation antihistaminic is mainly used in Formulations for systemic administration, but there is anti-parasympathetic effect and show sedation, as the antihistaminic chlorpheniramine of 1st generation when topical, the itch (Mundayetal. of atopic dermatitis patients cannot be suppressed, Dermatology, 205, pp40-45,2002), owing to there is the danger of cutaneous anaphylaxis, therefore do not encourage to use topical anti-histamines to atopic dermatitis.As when taking together with the medicine not having the antihistaminic Ebastine of contrastimulant 2nd generation, RMI 9918 with block cell pigment (cytochrome) P450 activity (ketoconazole, erythromycin), sometimes cardiac arrhythmia (Heyetal. is caused, Arzneimittelforschung, 46, pp159-163,1996), relative side effect is caused.
Therefore, at present in the urgent need to exploitation at the little and pruritus therapeutic agent of safety of effective side effect simultaneously, particularly to the effective curative of chronic pruritus of idiocrasy and so on.
Summary of the invention
Therefore, the object of the invention is to solve technical task to be solved all the time.Specifically, the object of one embodiment of the present of invention be to provide containing chestnut shell extract for relaxing or suppressing the healthy food of pruritus or pharmaceutical compositions, for improving the healthy food of skin barrier or pharmaceutical compositions and for the healthy food of Immunosuppression or pharmaceutical compositions.
According to such object, one embodiment of the invention relates to containing healthy food or the pharmaceutical compositions for relax or suppress pruritus of chestnut shell extract as active ingredient, and it had not only reduced side effect that pruritus curative in the past has, but also the effect having excellent suppression or relax pruritus.
One embodiment of the invention relates to containing healthy food or the pharmaceutical compositions for improve skin barrier function of chestnut shell extract as active ingredient.
One embodiment of the invention relates to containing chestnut shell extract as the healthy food for Immunosuppression of active ingredient or pharmaceutical compositions.
One embodiment of the present of invention relate to containing healthy food or the pharmaceutical compositions for improve or treat atopic dermatitis of chestnut shell extract as active ingredient.
Composition of the present invention contains chestnut shell extract as active ingredient, thus excellent pruritus suppression or alleviation effects is played by suppressing the activity as the proteolytic activity acceptor-2 (Proteinase-ActivatedReceptor-2:PAR-2) of itch stimulus, not only can improve the Skin barrier destruction brought out by pruritus significantly, but also can be treated to essence the immune hypersensitivity reaction that can become the reason of bringing out pruritus by the immunosuppressive activity of chestnut shell extract.
Accompanying drawing explanation
Fig. 1 is the chart of the measurement result of the active inhibition (trypsin treatment) of PAR-2 of the chestnut shell extract that one embodiment of the present of invention are shown.
Fig. 2 is the chart of the measurement result of the active inhibition (SLIGKV process) of PAR-2 of the chestnut shell extract that one embodiment of the present of invention are shown.
Fig. 3 is the chart of the measurement result of the active inhibition (trypsase, SLIGKV process) of PAR-2 of chestnut skin 1,3-BDO (BG) extract that one embodiment of the present of invention are shown.
Fig. 4 is the chart of pruritus (trypsin treatment) inhibition of chestnut skin 1,3-BDO (BG) extract that one embodiment of the present of invention are shown.
Fig. 5 is the chart of pruritus (SLIGRL process) inhibition of chestnut skin 1,3-BDO (BG) extract that one embodiment of the present of invention are shown.
Fig. 6 is the chart of pruritus (SLIGRL process) inhibition of the chestnut skin ethanol extract that one embodiment of the present of invention are shown.
Fig. 7 is the chart of pruritus (SLIGRL process) inhibition of the chestnut skin ethanol extract oral administration that one embodiment of the present of invention are shown.
Fig. 8 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect of TNF-α secretion.
Fig. 9 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect of IL-6 secretion.
Figure 10 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect of IL-1 α secretion.
Figure 11 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect of IL-8 secretion.
Figure 12 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect of GM-CSF secretion.
Figure 13 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect that IL-6 secretes caused by trypsase and active peptide (SLIGKV).
Figure 14 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect that IL-8 secretes caused by trypsase and active peptide (SLIGKV).
Figure 15 illustrates that the chestnut shell extract of one embodiment of the present of invention reduces the chart of the effect that GM-CSF secretes caused by trypsase and active peptide (SLIGKV).
Figure 16 is the chart of the measurement result of the skin moisturization of the chestnut skin ethanol extract that one embodiment of the present of invention are shown.
Figure 17 is the chart of the measurement result of the hyperkeratotic effect of improvement of the chestnut skin ethanol extract that one embodiment of the present of invention are shown.
Figure 18 illustrates that the pruritus of chestnut skin ethanol extract in NC/Nga model of one embodiment of the invention improves the chart of the measurement result of effect.
Figure 19 illustrates that the IgE of the chestnut skin ethanol extract of one embodiment of the invention in NC/Nga model reduces the chart of the measurement result of effect.
Figure 20 is the chart of the measurement result of the active inhibition of PAR-2 that the endothelium (tender skin) of the chestnut that one embodiment of the present of invention are shown and crust (shell) extract cause.
Detailed description of the invention
The present invention relates to containing healthy food or the pharmaceutical compositions for relax or suppress pruritus of chestnut shell extract as active ingredient.The target that proteolytic activity acceptor-2 (Proteinase-ActivatedReceptor-2:PAR-2) is treated as pruritus by present inventor etc., measure the degree of the PAR-2 activity suppression that chestnut shell extract causes, result as in aftermentioned embodiment confirm, confirm to demonstrate excellent PAR-2 antagonism in vitro, in addition, at the SLIGRL as the peptide making PAR-2 activate specifically, in SLIGKV or the itch Inhibition test that brings out as the trypsase (Trypsin) of protease, confirm the activity suppressing PAR-2 significantly, show very excellent itch inhibition.
Above-mentioned pruritus is also referred to as pruritus, induced factor or the form of this pruritus are not particularly limited, such as, by comprising struvite dermatitis, atopic dermatitis, skin chap in the dermatitis of caused dermatitis, prickly heat, ulcer, frostbite, contact dermatitis, seborrhea, psoriasis and parapsoriasis more than one bring out.
When pruritus, can wipe skin constantly due to continuity itch, scratch or pinch.Thus, bring out the Secondary skin injuries such as the ulcer of skin, scratch, lichen, pruigo, hyperpigmentation or pigmentation minimizing, the various materials of inflammatory reaction in secretion induced skin, such secretion increases itch again, and forms the circulation of itch-scratch.
But chestnut shell extract contained in healthy food of the present invention or pharmaceutical compositions shows effective skin barrier function and improves effect, and the Secondary skin injury that itch is brought out can be prevented or treat to result effectively.
Above-mentioned composition in the damage of mitigation skin barrier or improve in skin barrier restoring force and show significant effect, thus, can improve skin barrier to such as produced by the itch from atopic dermatitis 2 property skin injuries significantly.
Particularly, above-mentioned composition can by promoting skin moisture-keeping, preventing hyperkeratosis and improve skin barrier, and as confirmed by aftermentioned embodiment, present inventor etc. utilize and use hairless mouse (Hairlessmice)
the allergic model that oxazolone (oxazolon) carries out processing is tested, measure through transepidermal water loss (transepidermalwaterloss, TEWL) and skin thickness (skinthickness), chestnut shell extract display is effective promotes skin moisture-keeping or prevent its hyperkeratotic effect for results verification.
And then, the present invention relates to containing chestnut shell extract as the healthy food for Immunosuppression of active ingredient or pharmaceutical compositions.Above-mentioned composition can be used for the treatment of such as idiocrasy, the healthy food of rheumatoid arthritis (rheumatoidarthritis) or Crohn disease (Crohn ' sdisease) or pharmaceutical compositions, wherein, can be for preventing or treating the composition of atopic diseases as immune hypersensitivity reaction.
When atopic diseases is from the acute phase that skin injury etc. causes to chronic disease stage development, observe the change of the multiple secretor state of immune mediator, but in the injured skin of patient suffering from atopic diseases, the concentration of most interleukins (Interleukin) becomes increase.In addition, granulocyte-macrophage colony stimutaing factor (GM-CSF) is known in the injured skin of atopical skin Disease, its secretory volume increases, cause chronic inflammatory reaction, and unbalanced (Matsubaraetal., FEBSLetters, 566 of idiocrasy patient immune system can be caused, pp195-200,2004).
Related to this, present inventors etc. confirm chestnut shell extract and significantly can reduce and react relevant tumor necrosis factor-alpha (TumorNecrosisFactor-α: TNF-α) to immune hypersensitivity, interleukin-6 (IL-6), interleukin-1 alpha (IL-1 α), the expression of interleukin 8 (IL-8) or granulocyte-macrophage colony stimutaing factor (Granulocyte-MacrophageColonyStimulatingFactor:GM-CSF), result chestnut shell extract is suitable for as the healthy food of Immunosuppression or the active ingredient of pharmaceutical compositions.
Particularly, the present invention contains chestnut shell extract as active ingredient, is suitable for the active ingredient of the cosmetic combination improving or treat atopic dermatitis.
In addition, above-mentioned interleukin-6 (IL-6) and interleukin 8 (IL-8) also by known be the factor of bringing out itch in atopic diseases, chestnut shell extract can prevent for the pruritus of prevention and therapy from atopic diseases effectively.
Above-mentioned chestnut skin refers to the dark brown skin covering chestnut tree fruit, and the chestnut shell extract used in this description refers to more than one the extract in the endothelium (tender skin), crust and composition thereof being selected from chestnut.
Above-mentioned chestnut micromicro is with the skin being chestnut from arbitrary kind, be not particularly limited, can be such as be selected from chestnut (CastaneacrenataS.etZ., CastaneamollissimaBl., Castaneabulgaris), the skin of more than one chestnut in Chinese chestnut (CastaneaBungeanaBl.) and Korea's chestnut (Castaneacrenatafor.multicarpa (Uyeki) Chung).As chestnut skin, the endothelium of chestnut (tender skin) can be used, also can use the crust (shell) of chestnut, but confirm especially to present excellent PAR-2 antagonism in the group through chestnut crust (shell) extract-treated.
The extracting method of above-mentioned chestnut shell extract is not particularly limited, such as can by being selected from water, carbon number is the lower alcohol of 1 ~ 4, 1, more than one solvents in 3-butanediol and mixed solvent thereof extract, above-mentioned solvent can be such as be selected from water, methyl alcohol, ethanol, 1, 3-butanediol, more than one in butanols and composition thereof, such as, above-mentioned chestnut shell extract can by the alcohol solution of 10 ~ 100% or 10 ~ 100% 1, 3-butanediol extracts, specifically, it can be 20 ~ 90% ethanol water solution extracts of chestnut skin or 10 ~ 70% 1, 3-butanediol extract, more specifically, it can be 40 ~ 90% ethanol water solution extracts of chestnut skin or 10 ~ 50% 1, 3-butanediol extract, more specifically, it can be 60 ~ 90% ethanol water solution extracts of chestnut skin or 20 ~ 40% 1, 3-butanediol extract.
The content of chestnut shell extract contained in above-mentioned composition is not particularly limited, but with the gross weight of composition for benchmark, can contain with the content of 0.005 ~ 80 % by weight, preferably can contain with 0.01 ~ 30 % by weight.If the content of above-mentioned chestnut shell extract is very few, then effect becomes very micro-, if too much, then the stability of formulation can step-down.
According to circumstances, in order to relax or suppress pruritus, improve skin barrier and Immunosuppression, chestnut shell extract also can be used with one or more the material in antihistaminic, steroid dose, local anesthetic, immunodepressant.
In the past, take antihistaminic, anabolic agent is coated with as external preparation for relaxing the technology of atopic dermatitis and pruritus, even if but these preparations have and present temporary transient result for the treatment of and also recur such shortcoming very soon, and then, report the side effect such as central nervous disorders when taking these medicines, digestive organs obstacle.As the anabolic agent of cortex hormone of aadrenaline due to efficient antiinflammation and immunosuppressive action and excellent effect, but side effect is also serious, the treatment of tacrolimus hydrate ointment to atopic dermatitis reported as immunodepressant is effective, but may cutaneum carcinoma be brought out, or bring out nephropathy when skin lesion sites absorbs in body in a large number, actual conditions consider in security, is difficult to Long-Time Service.
Therefore, using containing chestnut shell extract as one or more in the composition of active ingredient and antihistaminic, steroid dose, local anesthetic, immunodepressant suitably and the used time, can improve the mitigation of pruritus or suppression, skin barrier and immunosupress etc. show significant effect safely without side effect.
Above-mentioned pharmaceutical compositions can also contain anticorrisive agent, stabilizing agent, hydrating agents or emulsification promoter, further for regulating the pharmaceutic adjuvants such as the salt of osmotic pressure and/or buffer and other materials useful in treatment, except conventional inorganic or organic carrier, oral administration can also be carried out with solid, semisolid or aqueous form, or with parenteral, rectum, locally, in skin, intravenous, muscle, in abdominal cavity, subcutaneous etc. carry out administration, particularly preferably oral administration.
Above-mentioned oral Preparation has such as tablet, pill, hard and soft capsules, liquid preparation, suspending agent, emulsion, syrup, granule etc., and these formulations can also contain diluent (example: lactose, glucose, sucrose, sweet mellow wine, D-sorbite, cellulose and glycine), lubricant (example: silica, talcum, stearic acid and magnesium thereof or calcium salt and polyethylene glycol) except active ingredient.Tablet can also contain the bonding agent of Magnesiumaluminumsilicate, gelatinized corn starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone and so on, according to circumstances, the pharmacy additives such as the disintegrant of starch, agar, alginic acid or its sodium salt and so on, absorbent, colouring agent, flavouring agent and sweetener can be contained.Above-mentioned tablet can be prepared by common mixing, granulating or coating process.
In addition, above-mentioned non-oral administration agent can be such as skin preparations for extenal use, also can be the formulation of lotion, ointment, gel, frost, patch or spray, but be not limited to these.
Above-mentioned health food composition is not particularly limited formulation, such as, can make the formulations such as tablet, granule, potus, molasses, meal rod (dietbar).To the health food composition of each formulation, except active ingredient, those skilled in the art can coordinate suitably selected according to formulation or application target for normally used for this field composition without difficulty, when using with other raw material, can play synergy simultaneously.
The dosage of above-mentioned active ingredient fixes in the level of those skilled in the art really, administration consumption on the 1st of medicine is different according to the many factors such as progress extent, occurrent time, age, health status, the complication difference of object to be administered, if but be benchmark with adult, then generally above-mentioned composition 1 ~ 500mg/kg, preferably 30 ~ 200mg/kg can be divided into 1 ~ 2 time according to 1 day and carry out administration, no matter above-mentioned dosage does not limit scope of the present invention by any method yet.
Below, further describe the present invention by embodiment, but following embodiment is for illustrating the present invention, scope of the present invention not limit by them.
The preparation of [embodiment 1] chestnut shell extract
1-1) the preparation of chestnut skin 1,3-BDO extract
Utilize the 1,3-BDO (1,3-buthyleneglycol) of 30%, make chestnut skin at room temperature leach 3 days.Then, filter successively with the filter of 250 orders, 3 μm, 1 μm, 0.5 μm sizes.Then, at 0 ~ 4 DEG C, place (Standing) after 3 days, filter successively with the filter of 0.5 μm, 0.3 μm, 0.2 μm size, obtain chestnut skin 1,3-BDO extract.
1-2) the preparation of chestnut skin ethanol extract
Utilize 70% ethanol, make chestnut skin at room temperature leach 3 days.Then, filter successively with the filter of 250 orders, 3 μm, 1 μm, 0.5 μm, 0.3 μm, 0.2 μm sizes.Then, at 60 DEG C after concentrated solution, at 30 DEG C, implement the vacuum drying of 18 hours, obtain the chestnut skin ethanol extract of powder morphology.
The active inhibition (external, trypsin treatment, HEK: people's epidermal keratinocyte) of PAR-2 of [test example 1] chestnut skin ethanol extract
Experiment the previous day, by keratinocyte (cell line name: HaCaT, obtain place: ATCC) in 96 holes (well) plate to become 4 × 10
4the mode of cells/well carries out plant division, then at 37 DEG C, 5%CO
2incubator (incubator) in cultivate 24 hours.After 24 hours, by 96 orifice plates with after HBSS (Hanks ' BalancedSaltsolution) buffer solution for cleaning (washing) 2 times, by reaction buffer (reactionbuffer:2uMFluo-4-AM, 20%Pluronic acid, 2.5mM probenecid) add in cell.At 37 DEG C, 5%CO
2incubator (incubator) in reaction 30 minutes, at room temperature react after 30 minutes, by HBSS buffer solution for cleaning (washing) 2 times, chestnut skin ethanol extract is processed with the concentration versus cell of 1ppm, 2ppm, 5ppm, 10ppm, 20ppm, 30ppm and 50ppm respectively.React after 10 minutes, process with 2U/ml trypsase (Trypsin), Ca in the cell measuring for 80 seconds
2+change in concentration.Ca in cell
2+the mensuration of change in concentration utilizes FlexStation3 (molecular device, the U.S.).After chestnut skin ethanol extract and trypsase (Trypsin) process, obtain the flexing (flex) in mensuration 80 second and after the difference of the minimum of a value in the value obtained and maximum, minimum of a value when this value and trypsase (Trypsin) being processed and the difference of maximum compare and obtain inhibiting rate.
With reference to Fig. 1, when can confirm to utilize trypsase at N-end cutting filament amino acid sequence (sequence) of PAR-2, PAR-2 to be activated, calcium ion flows in cell, but through the group of chestnut shell extract process when, PAR-2 activation is suppressed, and the inflow of calcium ion significantly reduces.
The active inhibition (external, SLIGKV process, HEK: people's epidermal keratinocyte) of PAR-2 of [test example 2] chestnut skin ethanol extract
Experiment the previous day, by keratinocyte (cell line name: HaCaT, obtain place: ATCC) in 96 holes (well) plate to become 4 × 10
4the mode of cells/well carries out plant division, then at 37 DEG C, 5%CO
2incubator (incubator) in cultivate 24 hours.After 24 hours, by 96 orifice plates with after HBSS (Hanks ' BalancedSaltsolution) buffer solution for cleaning (washing) 2 times, by reaction buffer (reactionbuffer:2uMFluo-4-AM, 20%Pluronic acid, 2.5mM probenecid) add in cell.At 37 DEG C, 5%CO
2incubator (incubator) in reaction 30 minutes, at room temperature react after 30 minutes, by HBSS buffer solution for cleaning (washing) 2 times, chestnut skin ethanol extract is processed with the concentration versus cell of 1ppm, 2ppm, 5ppm, 10ppm, 20ppm, 30ppm and 50ppm respectively.React after 10 minutes, process with 5uMPAR-AP (SLIGKV), Ca in the cell measuring for 80 seconds
2+change in concentration.Ca in cell
2+the mensuration of change in concentration utilizes FlexStation3 (molecular device, the U.S.).After chestnut skin ethanol extract and 5uMPAR-AP (SLIGKV) process, obtain the flexing (flex) in mensuration 80 second and after the difference of the minimum of a value in the value obtained and maximum, minimum of a value when this value and 5uMPAR-AP (SLIGKV) being processed and the difference of maximum compare and obtain inhibiting rate.
With reference to Fig. 2, can confirm if the SLIGKV (people) belonging to activated peptide plays a role as direct part and makes PAR-2 activate, then flow into calcium ion in cell, but through the group of chestnut shell extract process when, PAR-2 activation is suppressed, and the inflow of calcium ion significantly reduces.
The active inhibition (external, SLIGKV process, HEK: people's epidermal keratinocyte) of PAR-2 of [test example 3] chestnut skin 1,3-BDO (BG) extract
Experiment the previous day, by keratinocyte (cell line name: HaCaT, obtain place: ATCC) in 96 holes (well) plate to become 4 × 10
4the mode of cells/well carries out plant division, then at 37 DEG C, 5%CO
2incubator (incubator) in cultivate 24 hours.After 24 hours, by 96 orifice plates with after HBSS (Hanks ' BalancedSaltsolution) buffer solution for cleaning (washing) 2 times, by reaction buffer (reactionbuffer:2uMFluo-4-AM, 20%Pluronic acid, 2.5mM probenecid) add in cell.At 37 DEG C, 5%CO
2incubator (incubator) in reaction 30 minutes, at room temperature react after 30 minutes, by HBSS buffer solution for cleaning (washing) 2 times, chestnut skin 1,3-BDO (BG) extract is processed with the concentration versus cell of 0.1w/v%, 0.5w/v% and 1w/v% respectively.React after 10 minutes, process with 2U/ml trypsase (Trypsin) or 5uMPAR-AP (SLIGKV), Ca in the cell measuring for 80 seconds
2+change in concentration.Ca in cell
2+the mensuration of change in concentration utilizes FlexStation3 (MolecularDevice, USA).Through chestnut skin 1, after 3-butanediol (BG) extract and 2U/ml trypsase (Trypsin) or 5uMPAR-AP (SLIGKV) process, after obtaining the difference of the flexing (flex) in mensuration 80 second and the minimum of a value in the value that obtains and maximum, the difference of this value and the minimum of a value when 2U/ml trypsase or 5uMPAR-AP (SLIGKV) process and maximum is compared and obtains inhibiting rate.
With reference to Fig. 3, can confirm that the inflow of the intracellular calcium that trypsase or PAR-2 active peptide (SLIGKV) cause uprises along with the concentration of chestnut shell extract and significantly reduces.
[test example 4] chestnut skin 1,3-BDO (BG) extract is to the inhibition of the pruritus brought out by trypsase
Observe in hairless mouse (Hairlessmice), by chestnut skin 1,3-butanediol (BG) extract (in PBS buffer solution) injects with the concentration of 1w/v%, 10w/v% and 20w/v% respectively simultaneously, and the behavioral trait of scratching (scratchingbehavior) that intracutaneous (ID) is injected caused by trypsase (in PBS buffer solution) 200 μ g/ position is suppressed by concentration.Each measured value represents with the percentage change measuring mean value relative to 2 baselines (Baseline), the results are shown in Fig. 4.
With reference to Fig. 4,1,3-BDO (BG; Carrier) disposal group and 1% chestnut skin 1,3-butanediol (BG) extract disposal group is observed the effect not having to suppress the itch of being brought out by trypsase, but it is very large to observe inhibition in 10%, 20% chestnut skin 1,3-BDO (BG) extract disposal group.
[test example 5] chestnut skin 1,3-BDO (BG) extract is to the inhibition of the itch of being brought out by SLIGRL
Observe in hairless mouse (Hairlessmice), by chestnut skin 1,3-butanediol (BG) extract (in PBS buffer solution) injects with the concentration of 1%, 10% and 20% respectively simultaneously, and the behavioral trait of scratching (scratchingbehavior) making intracutaneous (ID) inject caused by SLIGRL (mouse PAR-2 active peptide, in PBS buffer solution) 50 μ g/ position is suppressed by concentration.Each measured value percentage change measuring mean value relative to 2 baselines (Baseline) represents, the results are shown in Fig. 5.
With reference to Fig. 5, can observe from 1% chestnut skin 1,3-butanediol (BG) extract disposal group starts to 10%, 20% chestnut skin 1,3-butanediol (BG) extract disposal group, along with the concentration of chestnut shell extract increases, the degree that the itch of being brought out by SLIGRL is suppressed increases.
The effect of the pruritus that the suppression that the skin application of [test example 6] chestnut skin ethanol extract causes is brought out by SLIGRL
The chestnut shell extract each test group being carried out to skin application process is all be dissolved in water, ethanol, 1,3 butanediols carry out with the ratio of 5:3:2 in the solution mixed and use, and experimental concentration is used with the concentration of 1,3 and 10w/v% by the chestnut skin ethanol extract of powder morphology.Carrier (vehicle) group uses the extract and the preparation that makes that do not add embodiment 1, as itch evocating substance, by PAR-2 active peptide (ActivatingPeptide (SLIGRL, peptide from rodent)) be dissolved in PBS buffer solution, carry out intracutaneous injection with the concentration at 50 μ g/ places.
Get each sample 200 μ l of chestnut skin ethanol extract, process in the mode extensively stretching coating at the position, back of hairless mouse.Be divided into the morning and afternoon, 1 day 2 times, process 4 days, the morning of the 5th day, before itch evocating substance injects 30 minutes, carry out last process.
In order to the presence or absence of the itch minimizing that the increase and chestnut skin ethanol extract of comparing the caused itch of itch evocating substance (PAR-2 active peptide, SLIGRL) cause, the skin application measuring chestnut skin ethanol extract measures the number of times of scratching of 40 minutes for first 2 days at every turn, the number of times of scratching that the value obtained by the calculating mean value of 2 days and stimulus inject latter 40 minutes compares, and represents with percent change value.
The experiment of itch loaded observation with in transparent hurdle giving 20 minutes adaptation times from by hairless mouse at injection itch evocating substance before 20 minutes.At the end of adaptation time, by itch evocating substance (PAR-2 active peptide; SLIGRL) intracutaneous injection (intradermalinjection) is carried out to the skin at the position, back adapting to the test hairless mouse terminated.At the end of injection, directly again loaded by hairless mouse after in observation hurdle, the hind leg measuring 40 minutes injection of scratching has the number of times at the position of itch evocating substance.The behavior of scratching with front foot or catch in its mouth is foreclosed, only the index of the behavior of injection site of scratching with metapedes as itch behavior is measured.
With reference to Fig. 6, after can confirming that chestnut skin ethanol extract (ChestnutInnerBarkExtract) is coated skin, when the concentration for 10%, even if do not giving under the usual state stimulated with itch, number of times of scratching also reduces, when give stimulates with itch, number of times of scratching from 1% concentration minimizing.
The effect of the pruritus that the suppression that the oral administration of [test example 7] chestnut skin ethanol extract causes is brought out by SLIGRL
The female hairless mice (Harilessmice) of extract to 8 week age obtained in embodiment 1 is carried out oral administration, observes itch inhibition.
Carry out chestnut shell extract equal the mixing with distilled water of oral administration process to each test group and use as suspension, experimental concentration is that the chestnut skin ethanol extract of powder morphology is carried out oral administration with the concentration of 200 and 500mg/Kg respectively.Carrier (vehicle) group is not added the extract of embodiment 1 and uses pure distilled water, as itch evocating substance, by PAR-2 active peptide (ActivatingPeptide (SLIGRL, peptide from rodent)) be dissolved in PBS buffer solution, carry out intracutaneous injection with the concentration at 50 μ g/ places.
Oral administration is the said sample of getting appropriate amount, with 1 administration on the 1st 5 days, the morning of the 5th day, before itch evocating substance injects 30 minutes, carries out last administration.
In order to the presence or absence of the itch minimizing that the increase and chestnut skin ethanol extract oral administration of comparing the caused itch of itch evocating substance (PAR-2 active peptide, SLIGRL) cause, the oral administration measuring chestnut skin ethanol extract measures the number of times of scratching of 40 minutes for first 2 days at every turn, the number of times of scratching that the value obtained by the calculating mean value of 2 days and stimulus inject latter 40 minutes compares, and represents with percent change value.
Itch experiment loaded observation with in transparent hurdle giving 20 minutes adaptation times from by hairless mouse at injection itch evocating substance before 20 minutes.After adaptation time terminates, by itch evocating substance (PAR-2 active peptide; SLIGRL) intracutaneous injection (intradermalinjection) is carried out to the skin at the position, back adapting to the test hairless mouse terminated.After injection terminates, directly hairless mouse is loaded again after in observation hurdle, measures 40 minutes scratch to inject with hind leg and have the number of times at the position of itch evocating substance.The behavior of scratching with front foot or catch in its mouth is foreclosed, only the index of the behavior of injection site of scratching with metapedes as itch behavior is measured.
With reference to Fig. 7, after can confirming that chestnut skin ethanol extract is carried out oral administration, chestnut skin reduces with concentration the inhibition that itch stimulates.
[test example 8] chestnut shell extract causes the secretion of TNF-α to reduce
Test the previous day, by Keratoderma epithelial cell (Normalhumanskinkeratinocyte, NHEK, distributors: Lonza) to become 5 × 10
4the mode of cells/well carries out plant division in 96 holes (well) plate, then at 37 DEG C, 5%CO
2incubator (incubator) in cultivate 24 hours.After 24 hours, clean 2 cells with PBS, change serum-free KBM (serumfreeKBM (keratinocyte hosqt media)) into.By concentration, (10,25,50ppm) are processed through chestnut skin to each hole (well), reacts after 30 minutes, use PGSA (10,50ppm), LPS (1ppm) process respectively.At 37 DEG C, 5%CO
2incubator (incubator) in cultivate after 24 hours, take out nutrient solution, carry out the ELISA to TNF-α.ELISA utilizes the experimental technique of manufacturing company (BDscience).
With reference to Fig. 8, the TNF-α secretion significantly minimizing that chestnut skin makes to increase because of PGSA and LPS can be observed.
[test example 9] chestnut shell extract causes the secretion of IL-6 to reduce
Carry out the ELISA to IL-6, in addition, utilize the method identical in fact with test example 8.
With reference to Fig. 9, the suppression that IL-6 secretion that chestnut skin makes to increase because of PGSA and LPS obtains great disparity can be observed.
[test example 10] chestnut shell extract causes the secretion of IL-1 α to reduce
Carry out the ELISA to IL-1 α, in addition, utilize the method identical in fact with test example 8.
With reference to Figure 10, can observe the IL-1 α secretory volume that chestnut skin makes to increase because of PGSA and LPS increases with concentration and reduces.
[test example 11] chestnut shell extract causes the secretion of IL-8 to reduce
Carry out the ELISA to IL-8, in addition, utilize the method identical in fact with test example 8.
With reference to Figure 11, the IL-8 secretion significantly minimizing that chestnut skin makes to increase because of PGSA and LPS can be observed.
[test example 12] chestnut shell extract causes the secretion of GM-CSF to reduce
Carry out the ELISA to GM-CSF, in addition, utilize the method identical in fact with test example 8.
With reference to Figure 12, the concentration can observed along with chestnut skin increases, and the amount of the GM-CSF secreted because of PGSA and LPS reduces.
The inhibition that [test example 13] chestnut shell extract is secreted trypsase and the caused IL-6 of active peptide (SLIGKV)
Test the previous day, by Keratoderma epithelial cell (Normalhumanskinkeratinocyte, NHEK obtain place: Lonza) to become 5 × 10
4the mode of cells/well carries out plant division in 96 holes (well) plate, then at 37 DEG C, 5%CO
2incubator (incubator) in cultivate 24 hours.After 24 hours, clean 2 cells with PBS, change serum-free KBM (serumfreeKBM (keratinocyte hosqt media)) into.With chestnut shell extract, by concentration, (10,50ppm) are processed to each hole (well), react after 30 minutes, use trypsase (10nM) or PAR-2 activated peptide (SLIGKV, 50uM) to process respectively.At 37 DEG C, 5%CO
2incubator (incubator) in cultivate after 24 hours, take out nutrient solution, carry out the ELISA to IL-6.ELISA utilizes the experimental technique of manufacturing company (BDscience).
Secrete with reference to Figure 13, the IL-6 suppressing while chestnut shell extract concentration dependent can be observed trypsase and active peptide (SLIGKV) to cause.
The inhibition that [test example 14] chestnut shell extract is secreted trypsase and the caused IL-8 of active peptide (SLIGKV)
Carry out the ELISA to IL-8, in addition, utilize the method identical in fact with test example 13.
Secrete with reference to Figure 14, the IL-8 suppressing while chestnut shell extract concentration dependent can be observed trypsase and active peptide (SLIGKV) to cause.
The inhibition that [test example 15] chestnut shell extract is secreted trypsase and the caused GM-CSF of active peptide (SLIGKV)
Carry out the ELISA to GM-CSF, in addition, utilize the method identical in fact with test example 13.
Secrete with reference to Figure 15, the GM-CSF suppressing while chestnut shell extract concentration dependent can be observed trypsase and active peptide (SLIGKV) to cause.
[test example 16] measures the skin moisturization of chestnut skin ethanol extract
The chestnut skin ethanol extract of Evaluation operation example 1 is to the skin barrier function recovery capability of long-time skin injury.First, 1 time is coated with through back (back) every day of the young hairless mouse (Orient, Korea S) of 7 ~ 8 weeks after birth
oxazolone (oxazolone), is periodically coated with 6 days, the skin barrier of animal used as test is sustained damage.Then, measure with atmidometer (Delfin, Finland) and divide loss amount (TransepidermalWaterLoss:TEWL) through the severe edema due to hypofunction of the spleen, display 50g/m per hour will be had
2animal used as test above through the skin of skin moisture loss divides into groups, by 1 and the chestnut shell extract of 5w/v% respectively with every 5cm
2skin area is the capacity of 100 μ l, every day 2 times, and continuously coating is after 10 days, determination experiment animal divide loss amount (TEWL) through the severe edema due to hypofunction of the spleen, the results are shown in Figure 16.
As shown in figure 16, known hairless mouse to be carried out
in the allergic model (Allergymodel) of oxazolone process, by coating chestnut shell extract, to by
what the dermatitis (atopic dermatitis, atopicdermatitis) of oxazolone induction and causing increased divides loss amount to have to make the barrier function of damage to recover through the severe edema due to hypofunction of the spleen and gets back to the function of normal skin.
[test example 17] measures chestnut skin ethanol extract and improves hyperkeratotic effect
In embodiment 1, the effect that chestnut skin ethanol extract improves hyperkeratosis is evaluated.First, 1 time is coated with through back (back) every day of the young hairless mouse (Orient, Korea S) of 7 ~ 8 weeks after birth
oxazolone (oxazolone), is periodically coated with 6 days, the skin barrier of animal used as test is sustained damage.Then, measure with atmidometer (Delfin, Finland) and divide loss amount (TransepidermalWaterLoss:TEWL) through the severe edema due to hypofunction of the spleen, display 50g/m per hour will be had
2animal used as test above through the skin of skin moisture loss divides into groups, by substances with every 5cm
2skin area is the capacity of 100 μ l, every day 2 times, continuous coating is after 10 days, about picking up the measurement site of back (back), (twofold is measured, two-foldingmeasurement), utilize micrometer (Mitsubishi, Japan) to measure skin thickness, the results are shown in Figure 17.
With reference to Figure 17, the powder by using chestnut shell extract can be confirmed, to by
the dermatitis that oxazolone (oxazolon) brings out and cause the skin thickness increased to demonstrate suppressing the effect of hyperkeratosis.
[test example 18] measures chestnut skin ethanol extract and in NC/Nga model, reduces IgE and improve the effect of pruritus
In embodiment 1, effect is improved by IgE minimizing and itch in the serum of NC/Nga mouse model evaluation chestnut skin ethanol extract.First, utilize shearing machine (clipper) to lose hair or feathers after birth through back (back) position of the young NC/Nga mouse of 7 ~ 8 weeks, the gross profit depilatory cream of remnants is removed completely.To the position, back of exposing and auricle position, Df (dust mite (dermatophagoidesfarinae)) 100mg was coated with 4 times with one week 2 times equably in 3 weeks, and brings out atopic diseases.After carrying out administration with 2 groups that chestnut shell extract to be divided into 100mg/kg and 250mg/kg for one week 5 times in 3 weeks, in order to measure pruritus, after NC/Nga mouse is loaded observation hurdle, be determined at the number of times at position, back of scratching with hind leg between 2 hours.The behavior of scratching with front foot or catch in its mouth is foreclosed, only the index of the behavior of scratching with metapedes as itch behavior is measured.The blood sample separation of serum be determined as from being undertaken taking a blood sample by eye socket veniplex of SERUM IgE, utilizes the OptIgE kit (OptIgEkit) of BD science (BDscience) implement ELISA and measure.Represent itch minimizing compared with non-process group in 250mg/kg administration group in Figure 18, with reference to Figure 19, the minimizing showing IgE in the administration group of 250mg/kg significantly can be confirmed.
Comparing (external, SLIGKV process, HEK: people's epidermal keratinocyte) of the active inhibition of PAR-2 of [test example 19] chestnut crust ethanol extract and chestnut endothelium ethanol extract
The crust of chestnut and endothelium are carried out being separated and after drying, according to embodiment 1-2) identical method prepares the outer bark extract of chestnut, in chestnut bark extract also according to embodiment 1-2) prepared by identical method.Use the method identical with test example 2 to measure the active inhibition of PAR-2 of chestnut crust ethanol extract and chestnut endothelium ethanol extract, and be shown in following table 2 and Figure 20.
Table 2
Comparing (external, SLIGKV process, HEK: people's epidermal keratinocyte) of the active inhibition of PAR-2 of [test example 20] chestnut crust ethanol extract and chestnut endothelium ethanol extract
The crust (shell) of chestnut and the concentration of endothelium (tender skin) extract are carried out process as described in Table 3, in addition, measure the active inhibition of PAR-2 according to the method identical with test example 19.
Table 3
Below, the formulation example of the present composition is described, pharmaceutical compositions or health food composition can be applied to various formulation, and this does not really want to limit the present invention, and just will illustrate the present invention.
Ointment in [formulation example 1] skin preparations for extenal use
According to the composition that following table 1 is recorded, prepare ointment by conventional method.
Table 1
| Gradation composition | Content (% by weight) |
| Embodiment 1 | 0.1 |
| Glycerine | 3.0 |
| Butanediol | 2.0 |
| Propane diols | 2.0 |
| Carboxyl ethylene polymer | 0.1 |
| PEG-12 nonylplenyl ether | 0.2 |
| Polysorbate 80 | 0.4 |
| Ethanol | 10.0 |
| Triethanolamine | 0.1 |
| Anticorrisive agent, pigment, spices | In right amount |
| Purified water | Surplus |
The preparation of [formulation example 2] powder
Embodiment 1.........................100mg
Lactose ... ... ... ... ... 100mg
Talcum ... ... ... ... ... 10mg
Grease ... ... ... ... ... 5mg
Mentioned component is mixed, is filled in sealed packet and prepares powder.
The preparation of [formulation example 3] tablet
Embodiment 1..........................50mg
Cornstarch ... ... ... ... 100mg
Lactose ... ... ... ... ... 100mg
Dolomol ... ... ... .2mg
Vitamin C ... ... ... ... .50mg
After mentioned component is mixed, carry out compressing tablet according to the method for preparing tablet thereof of routine and prepare tablet.
The preparation of [formulation example 4] capsule
Embodiment 1..........................50mg
Corn ... ... ... ... ..100mg
Lactose ... ... ... ... ... 100mg
Dolomol ... ... ... .2mg
Vitamin C ... ... ... ... .50mg
Serine ... ... ... ... ... 50mg
According to the capsule preparation method thereof of routine, mentioned component is mixed, be filled in gelatine capsule and prepare capsule.
The preparation of [formulation example 5] liquid preparation
Embodiment 1.........................100mg
Isomerized sugar ... ... ... ... ... 10g
Sweet mellow wine ... ... ... ... ..5g
Vitamin C ... ... ... ... .50mg
Serine ... ... ... ... ... 50mg
Grease ... ... ... ... ... appropriate
Purified water ... ... ... ... ... .. is appropriate
Utilize conventional liquid preparation preparation method to add various composition in purified water and make it to dissolve, after adding appropriate lemonene, after mixing mentioned component, add purified water, after overall adjustment to 100ml, be filled in brown bottle, carry out sterilizing, prepare liquid preparation.
The preparation of [formulation example 6] healthy food
Embodiment 1........................1000mg
Vitamin mixtures
Retinyl acetate ... ... ... ..70 μ g
Vitamin E ... ... ... ... 1.0mg
Vitamin B1 ... ... ... ... .0.13mg
Vitamin B2 ... ... ... ... .0.15mg
Vitamin B6 ... ... ... ... ..0.5mg
Vitamin B12 ... ... ... ... .0.2 μ g
Vitamin C ... ... ... ... .10mg
Biotin ... ... ... ... ..10 μ g
Niacinamide ... ... ... ... 1.7mg
Folic acid ... ... ... ... ... .50 μ g
Calcium pantothenate ... ... ... 0.5mg
Inanimate matter mixture
Ferrous sulfate ... ... ... ... ..1.75mg
Zinc oxide ... ... ... ... 0.82mg
Magnesium carbonate ... ... ... ..25.3mg
Potassium dihydrogen phosphate ... ... ... ... 15mg
Calcium monohydrogen phosphate ... ... ... ..55mg
Potassium citrate ... ... ... ... .90mg
Calcium carbonate ... ... ... ... .100mg
Magnesium chloride ... ... ... ..24.8mg
The ratio of components of the mixture of said vitamin and mineral matter carries out mixing composition by comparing the composition preferred embodiment being suitable for healthy food, but also its match ratio can be implemented modification arbitrarily, after mentioned component can being mixed by the healthy food preparation method of routine, prepare particle, utilize conventional method for the preparation of health food composition.
The preparation of [formulation example 7] healthy beverage
Embodiment 1........................1000mg
Citric acid ... ... ... ... 1000mg
Oligosaccharides ... ... ... ... ..100g
Plum concentrate ... ... ... ... ... 2g
Taurine ... ... ... ... ... .1g
It is overall after adding purified water ... ... ... ..900ml
After mixing mentioned component by the healthy beverage preparation method of routine, at 85 DEG C, agitating heating is after about 1 hour, filters the solution made, loads in 2 DEG C of containers of sterilizing, after sealing sterilizing, stored refrigerated, then for the preparation of healthy beverage composition of the present invention.
Ratio of components is suitable for having a liking for the composition preferred embodiment of beverage and carries out mixing by comparing and form, but also can the region such as stratum, demand country, use, national characteristic hobby degree and its match ratio is carried out modification arbitrarily according to demand.
Claims (13)
1. the purposes of chestnut shell extract in the healthy food preparing the activity suppressing PAR-2 and proteolytic activity acceptor-2 or pharmaceutical compositions,
Wherein, described chestnut shell extract is the outer bark extract of chestnut,
Wherein, with the cumulative volume of described composition for benchmark, contain the outer bark extract of described chestnut with the content of 0.5% to 20% (w/v%) by weight.
2. the purposes of chestnut shell extract according to claim 1, wherein, described composition relaxes or suppresses pruritus.
3. the purposes of chestnut shell extract according to claim 1, wherein, described composition relaxes or suppresses the pruritus that brought out by following at least one: struvite dermatitis, atopic dermatitis, skin are chapped caused dermatitis, prickly heat, ulcer, frostbite, contact dermatitis, seborrhea, psoriasis and parapsoriasis.
4. the purposes of chestnut shell extract according to claim 1, wherein, the pruritus that described composition relaxes or suppression is brought out by atopic dermatitis.
5. the purposes of chestnut shell extract according to claim 1, wherein, described composition is for improving skin barrier function.
6. the purposes of chestnut shell extract according to claim 5, wherein, described composition damages for the skin barrier relaxed from atopic dermatitis or improves the restoring force of skin barrier.
7. the purposes of chestnut shell extract according to claim 5, wherein, described composition is for promoting skin moisture-keeping or preventing hyperkeratosis.
8. the purposes of chestnut shell extract according to claim 1, wherein, described composition is used for Immunosuppression.
9. the purposes of chestnut shell extract according to claim 8, wherein, described composition is used for prevention or the treatment of atopic diseases.
10. the purposes of chestnut shell extract according to claim 8, wherein, described composition is used for atopic treatment.
The purposes of 11. chestnut shell extracts according to claim 1, wherein, described composition is used for improving or treatment atopic dermatitis.
The purposes of 12. chestnut shell extracts according to any one of claim 1 to 11, wherein, described chestnut shell extract be by being selected from water, carbon number is the lower alcohol of 1 ~ 4, more than one the solvent in 1,3-BDO and their mixed solvent carries out extracting.
The purposes of 13. chestnut shell extracts according to claim 12, wherein, described chestnut shell extract is undertaken extracting by more than one the solvent be selected from water, methyl alcohol, ethanol, butanols, 1,3-BDO and their mixture.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| KR20090054579 | 2009-06-18 | ||
| KR10-2009-0054579 | 2009-06-18 | ||
| CN2010800359033A CN102458156A (en) | 2009-06-18 | 2010-06-18 | Health food or pharmaceutical composition comprising chestnut shell extract |
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| CN2010800359033A Division CN102458156A (en) | 2009-06-18 | 2010-06-18 | Health food or pharmaceutical composition comprising chestnut shell extract |
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| CN201510750348.7A Pending CN105285986A (en) | 2009-06-18 | 2010-06-18 | Health food or pharmaceutical composition comprising chestnut shell extract |
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| JP (1) | JP2012530699A (en) |
| KR (1) | KR101338681B1 (en) |
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| JO3246B1 (en) | 2009-09-09 | 2018-03-08 | Regeneron Pharma | High affinity human antibodies to human protease-activated receptor-2 |
| KR101595959B1 (en) * | 2013-02-18 | 2016-02-19 | 재단법인 대구테크노파크 | Composition for preventing, improving or treating allergic dermatitis comprising hot water extract or ferment extract of chestnut inner shell |
| KR101643048B1 (en) * | 2014-10-23 | 2016-07-27 | 단국대학교 천안캠퍼스 산학협력단 | Composition for antiinflammatory and inflammatory neurodegenerative diseases comprising castanea crenata inner shell extract |
| CN104770644A (en) * | 2015-04-29 | 2015-07-15 | 唐凯 | Diabetes health care product based on affinal drugs and diet |
| JP6692905B2 (en) * | 2016-07-29 | 2020-05-13 | 株式会社 サティス製薬 | Chestnut skin extract manufacturing method |
| CN107686451B (en) * | 2017-09-29 | 2020-07-03 | 烟台新时代健康产业日化有限公司 | Preparation method of chestnut skin extract containing ceramide |
| KR102165675B1 (en) | 2018-10-17 | 2020-10-14 | 강진영 | A cosmetic manufacturing method comprising an extract extracted from chestnuts or a peptide fraction isolated therefrom and natural caffeine derived from coffee |
| JP7263538B2 (en) * | 2019-11-01 | 2023-04-24 | 株式会社 資生堂 | Skin condition evaluation method using active PAR-2 in skin as index, screening method for PAR-2 activation promoter or inhibitor, and PAR-2 activation inhibitor |
| FR3124947A1 (en) * | 2021-07-12 | 2023-01-13 | Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic | Ingestible composition (Ci) for use in the treatment of a skin disorder induced by an intestinal disorder |
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| KR20120027432A (en) | 2012-03-21 |
| CN102458156A (en) | 2012-05-16 |
| JP2012530699A (en) | 2012-12-06 |
| KR101338681B1 (en) | 2013-12-09 |
| WO2010147440A3 (en) | 2011-03-31 |
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