CN108430490A - Alimentation composition - Google Patents
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- CN108430490A CN108430490A CN201680070633.7A CN201680070633A CN108430490A CN 108430490 A CN108430490 A CN 108430490A CN 201680070633 A CN201680070633 A CN 201680070633A CN 108430490 A CN108430490 A CN 108430490A
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Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/30—Zinc; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/20—Milk; Whey; Colostrum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Developmental Biology & Embryology (AREA)
- Zoology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Cell Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Coloring Foods And Improving Nutritive Qualities (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
There is provided has good flavor and the physical property stablized and the alimentation composition for high heat.Alimentation composition contains protein sources.The protein sources of alimentation composition contain lactalbumin and whey peptides.Total ratio relative to protein sources total weight of lactalbumin weight and whey peptides weight in alimentation composition is 80 weight % or more.The protein-caloric ratio of alimentation composition is 16% or more and less than 50%.Alimentation composition is acidity.Alimentation composition has the heat density of 100kcal/100ml or more.
Description
Technical field
This disclosure relates to which alimentation composition is more specifically related to the alimentation composition of mobility.
Background technology
As the prior art, it is known to the various alimentation compositions for giving patient etc..Alimentation composition for example supplements
The nutritional ingredient that patient etc. is lacked contributes to the prevention or improvement of disease.
It is disclosed in Japanese Unexamined Patent Application Publication 2013-515718 bulletins for preventing or disposing the battalion with amyotrophic disease
Support composition.The alimentation composition contains at least about albumen of 12g (タ Application パ ク Quality) sample substance per 100kcal.Albumen sample object
Include the lactalbumin of about 80 weight % in matter.
The alimentation composition of Japanese Unexamined Patent Application Publication 2013-515718 bulletins consists of (カ ロ リ ー) low in calories and high egg
In vain.According to Japanese Unexamined Patent Application Publication 2013-515718 bulletins, if to providing food albumen in composition low in calories, and to high fever
The situation that food albumen is provided in amount composition is compared, and amino acid can arrive more quickly at blood circulation so that amino acid in blood
Horizontal increase.The synthesis of muscle protein is stimulated as a result,.
Invention content
Patient (rehabilitation (リ Ha ビ リ patient)) in medical rehabilitation (リ Ha ビ リ テ ー シ ョ Application) is usually mostly low nutrition
State.If rehabilitation maintains low nutrition state and do not absorb enough nutrition, physical function can not be improved, or even make body
Function deteriorates.It is therefore important that rehabilitation will maintain nutritional status appropriate (medical rehabilitation nutrition (rehabilitation nutrition)).
As the disease for needing rehabilitation nutrition, such as can enumerate：Chronic obstructive pulmonary disease (COPD), dyshepatia,
In rheumatoid arthritis, chronic cardiac insufficiency, chronic renal insufficiency, lower limb amputation, fracture of neck of femur, diabetes, brain
Wind, cancer, disuse syndrome, Parkinson's disease, aspiration pneumonia, bedsore etc..These diseases are sometimes with inflammation.If moreover,
It is inflamed, then the alienation of muscle protein can be made hyperfunction, become and cause to reduce (Secondary flesh lacks disease) or weight with muscle mass
The cachectic reason mitigated.If in addition, inflammation continue, loss of appetite, it is difficult to absorb enough nutrition.Therefore, for reality
Existing rehabilitation nutrition, must also control inflammation while carrying out alimentotheray.
In order to suitably maintain the nutritional status of rehabilitation, alimentation composition is given to rehabilitation.At this point, in order to make
Rehabilitation is easy constantly to absorb, and preferably alimentation composition has good flavor.Additionally, it is preferred that alimentation composition has surely
Fixed physical property also maintains good flavor during preservation.Moreover, in order to make easily to be absorbed in the rehabilitation of loss of appetite with
Required nutritional ingredient can be absorbed on a small quantity, and preferably alimentation composition is the liquid of high heat (high-energy).In the past, in this use
It has used on the way and the alimentation composition of lipid is mixed with using high concentration or is mixed with nutrition of the free amino acid as protein sources
Composition.However, these alimentation compositions have the following problems：Weak flavor and be difficult to lasting intake or with intake and
Diarrhea occurs.In addition, in order to promote the synthesis of muscle protein and inhibit alienation, it is desirable to which the albumen for improving fluid composition in advance contains
Amount, but there is problems with if increasing percent protein：The variation of physical property is easy to happen when modulating fluid composition.
The project of the disclosure is to provide alimentation composition, the physics which has good flavor and stablize
Property is high heat and can control inflammation.
The alimentation composition of the disclosure contains protein sources.Protein sources include lactalbumin and whey peptides.Lactalbumin weight
Total ratio relative to protein sources total weight with whey peptides weight is 80 weight % or more.The protein energy of alimentation composition
Than being 16% or more and less than 50%.Alimentation composition has the heat density of 100kcal/100ml or more.Alimentation composition is acid
Property.
Since the alimentation composition of the disclosure is acidity, so having good flavor.That is, patient can to alimentation composition
To experience tasty and refreshing flavor, can not repel the composition that absorbs nourishment.
In the alimentation composition of the disclosure, the 80 weight % or more in protein sources total weight are lactalbumin and whey peptides.With
Casein is compared, and lactalbumin and whey peptides are not easy to cure under acidity.Therefore, it can inhibit or prevent in alimentation composition
The generation etc. of precipitation, can be such that physical property stablizes.In addition, lactalbumin and whey peptides have anti-inflammatory effect.Therefore, battalion is utilized
Composition is supported, the inflammation of rehabilitation etc. can be controlled.
The alimentation composition of the disclosure has the heat density of 100kcal/100ml or more, consists of and compares ordinary nutritional
Composition has higher heat.Therefore, it according to the alimentation composition of the disclosure, can be supplemented needed for patient with less amount of intake
Nutritional ingredient.
In the alimentation composition of the disclosure, the ratio of lactalbumin weight and whey peptides weight can be 5：1~1：10.
Whey peptides have higher anti-inflammatory effect.However, if peptide is excessively increased, osmotic pressure is got higher, it is possible to cause abdomen
It rushes down.However, according to the above configuration, since the weight ratio of lactalbumin and whey peptides is 5：1~1：10 range, so whey peptides
Content will not be excessive.Accordingly it is possible to prevent the osmotic pressure of alimentation composition gets higher and causes diarrhea etc., at the same can have compared with
High anti-inflammatory effect.
In the alimentation composition of the disclosure, pH can be 3 or more and 5 or less.
According to the above configuration, for the patient for the composition that absorbs nourishment, it can be made to experience suitable tart flavour.Therefore,
Patient is easy the composition that constantly absorbs nourishment.
The alimentation composition of the disclosure can also contain lipid source.Lipid source can include n-3 systems aliphatic acid.
According to the above configuration, the inflammation that the disease of patient can be inhibited adjoint using n-3 systems aliphatic acid.It therefore, can be with
Prevent the alienation of the muscle protein caused by inflammation hyperfunction, (Secondary flesh is few as a result, can prevent adjoint muscle mass from reducing
Disease) or weight loss cachexia etc..Furthermore it is also possible to prevent the anorexia caused by inflammation continues.
The alimentation composition of the disclosure can also contain zinc.
In the alimentation composition of the disclosure, protein sources can also include leucine.
The alimentation composition of the disclosure can be used for medical rehabilitation nutrition.
The alimentation composition of the disclosure can be used for the prevention and/or improvement of chronic obstructive pulmonary disease.
The alimentation composition of the disclosure can be used for anti-inflammatory.
According to the disclosure, the physical property with good flavor and stabilization and the nutrition group for high heat can be obtained
Object is closed, and can be controlled inflammation.
Brief description
[Fig. 1] is the figure for the MCP-1 concentration for showing the alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1.
[Fig. 2] is the figure for the KC concentration for showing the alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1.
[Fig. 3] is the figure for the MMP-9 concentration for showing the alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1.
[Fig. 4] is the figure for the NE concentration for showing the alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1.
[Fig. 5] is the neutrophil cell number for showing the alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1
Figure.
[Fig. 6] is to show that the KC of the alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2 is dense
The figure of degree.
[Fig. 7] is the MMP-9 for showing the alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2
The figure of concentration.
[Fig. 8] be show alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2 it is thermophilic in
The figure of property granulocyte number.
[Fig. 9] is to show in embodiment 3 and comparative example 3 to give the plasma A ST after ConA after 24 hours to mouse tail vein
Active figure.
[Figure 10] is to show in embodiment 3 and comparative example 3 to give the plasma A LT after ConA after 24 hours to mouse tail vein
Active figure.
[Figure 11] is after show after giving ConA in embodiment 3 and comparative example 3 to mouse tail vein 2 hours and 4 hours
The figure of each Plasma TNF-α concentration afterwards.
[Figure 12] is after show after giving ConA in embodiment 3 and comparative example 3 to mouse tail vein 2 hours and 4 hours
The figure of -6 concentration of each plasma IL afterwards.
[Figure 13] is after show after giving ConA in embodiment 3 and comparative example 3 to mouse tail vein 2 hours and 4 hours
The figure of each blood plasma MCP-1 concentration afterwards.
[Figure 14] is that give after ConA 24 to mouse tail vein in display embodiment 4-1~embodiment 4-2 and comparative example 4 small
When after the active figures of plasma A ST.
[Figure 15] is that give after ConA 24 to mouse tail vein in display embodiment 4-1~embodiment 4-2 and comparative example 4 small
When after plasma ALT activity figure.
[Figure 16] is to show 2 given to mouse tail vein in embodiment 4-1~embodiment 4-2 and comparative example 4 after ConA
The figure of each Plasma TNF-α concentration after hour and after 4 hours.
[Figure 17] is to show 2 given to mouse tail vein in embodiment 4-1~embodiment 4-2 and comparative example 4 after ConA
The figure of -6 concentration of each plasma IL after hour and after 4 hours.
Specific implementation mode
For example, patient's (rehabilitation) in medical rehabilitation is usually mostly low nutrition state.Rehabilitation does not absorb enough
The situation of nutrition can not improve physical function, and have the situation for making physical function deteriorate.Therefore, easily for picture rehabilitation etc.
It is absorbed in the patient of low nutrition state, it is important to note that nutritional status simultaneously suitably maintains nutritional status.
As the disease that should pay attention to nutritional status, such as can enumerate：Chronic obstructive pulmonary disease (COPD), liver function are not
Entirely, rheumatoid arthritis, chronic cardiac insufficiency, chronic renal insufficiency, lower limb amputation, fracture of neck of femur, diabetes, brain
Apoplexy, cancer, disuse syndrome, Parkinson's disease, aspiration pneumonia and bedsore etc..These diseases are sometimes with inflammation.Moreover,
If being inflamed, the alienation of muscle protein can be made hyperfunction, cause to reduce (Secondary flesh lacks disease) or weight with muscle mass
The cachexia etc. of mitigation.If in addition, inflammation continue, anorexia, it is difficult to absorb enough nutrition.
[composition of alimentation composition]
Nutritional status of the alimentation composition of present embodiment for suitably maintaining patient.The alimentation composition of present embodiment
It is mainly used for the supplement of rehabilitation nutrition or rehabilitation nutrition.That is, the alimentation composition is used for rehabilitation, low battalion can help to
Foster prevention and/or improvement.The alimentation composition can be given as having the patient etc. of above-mentioned disease that should maintain battalion appropriate
The patient for the state of supporting.Prevention and/or improvement of the alimentation composition for example for chronic obstructive pulmonary disease (COPD).The nutrition group
It closes object and is additionally operable to the decomposition for promoting the synthesis of muscle protein, inhibiting muscle protein.It is scorching that the alimentation composition can also aid in inhibition
Disease.Hereinafter, the composition to the alimentation composition illustrates.
The alimentation composition of present embodiment is mobility.The alimentation composition is, for example, liquid.The alimentation composition has
There is acidity.Preferred pH is 3~5 in the alimentation composition.
It,, can for absorbing the patient of the alimentation composition if pH is 3~5 in the alimentation composition of present embodiment
To experience appropriate tart flavour.Therefore, patient is easy constantly to absorb the alimentation composition, can suitably maintain the battalion of patient
The state of supporting.
The alimentation composition of present embodiment has higher heat.That is, the alimentation composition preferably has 100kcal/
The heat density of 100ml or more, more preferably have 125kcal/100ml or more, it is further preferred with 150kcal/100ml with
On heat density.
The alimentation composition of present embodiment contains protein sources and lipid source.The alimentation composition can be preferably with 2~8g/
100kcal contains protein sources, more preferably contains protein sources with 3~6/100kcal, is further preferably contained with 4~6g/100kcal
There are protein sources.The alimentation composition preferably can contain lipid source with 1~4g/100kcal, more preferably with 2~3.5g/
100kcal contains lipid source, further preferably contains lipid source with 2~3g/100kcal.By reach above-mentioned protein sources or
The amount of lipid source, then the physical property for high heat (heat density is high) and after preserving is more preferable.
In the alimentation composition of present embodiment, protein sources peomote the synthesis of muscle protein.The protein sources packet
Whey protein and whey peptides.In the alimentation composition, lactalbumin weight and whey peptides weight it is total relative to albumen
The ratio of source total weight is preferably 80 weight % or more, more preferably 90 weight % or more.In the alimentation composition, lactalbumin
The ratio of weight and whey peptides weight is preferably 5：1~1：10, more preferably 3：1~1：7.
The alimentation composition of present embodiment, by the way that the weight ratio of lactalbumin and whey peptides is set in 5：1~1：10
Range, can prevent the content of whey peptides for increasing osmotic pressure from becoming excessive in the alimentation composition.Therefore, in the nutrition
In composition, can prevent osmotic pressure from getting higher and cause diarrhea etc., while can have anti-inflammatory effect.
Institute is residual when the whey of present embodiment refers to such as removing fat, casein, liposoluble vitamin from cow's milk
The water soluble ingredient stayed.Whey is typically the cheese breast obtained as by-product when manufacturing natural cheese or enzyme coagulates casein
Clear or enzyme curdled milk clear (or also referred to sweet whey), whens by skimmed milk manufacture acid casein, acidified milk or quark cheese etc. and
Casein whey, acid whey, the quark cheese whey of acquisition.Lactalbumin refers to the egg in addition to casein for example in cow's milk
White general name.Lactalbumin is made of Multiple components such as beta lactoglobulin, α-lactalbumin, lactoferrins, does not include lactose, dimension
Raw element, minerals etc..When the dairy milk starting material of cow's milk etc. is adjusted to acidity, the albumen of precipitation is casein, unprecipitated albumen
It is lactalbumin.
It should be noted that the whey of present embodiment also includes：By whey carry out concentration obtained by condensed whey,
The whey powder of processing gained is dried, by ultrafiltration (Ultrafiltration in whey：UF) method etc. is by the main of whey
Whey protein concentrate (the Whey Protein for handling gained are dried after carrying out concentration in albumen etc. again
Concentrate：Be also referred to below " WPC "), by microfiltration (Microfiltration：MF) method or centrifugal separation etc. will
Degreasing WPC (the high eggs of low fat obtained by handling are dried again after carrying out concentration using UF methods after whey removal fat
In vain), after major protein of whey etc. selectively being carried out fractionation processing using ion-exchange-resin process or gel filtration etc.
Lactalbumin isolate (the Whey Protein Isolate of processing gained are dried again：Be also referred to below " WPI "), utilize
Nanofiltration (Nanofiltration：NF) the de- of processing gained is dried after carrying out desalting processing in method or electrodialysis method etc. again
Salt whey is carried out using centrifugal separation etc. obtained by concentration after the mineral composition from whey to be carried out to precipitation process
Minerals condensed whey etc..
The whey peptides of present embodiment are such as can manufacture the hydrolysis with enzyme below of whey or lactalbumin.For
The enzyme of whey hydrolysis is pepsin, trypsase and chymotrypsin, but also have using plant-derived papain,
Protease from bacterium or mushroom research report (Food Technol., 48：68-71,1994；Trends Food Sci.
Technol., 7:120-125,1996；Food Proteins and Their Applications, the 443-472 pages,
1997).The enzymatic activity of hydrolyzing lactoalbumin can dramatically change.Pepsin decomposing alpha-La and α-the La being denaturalized, but do not decompose
Unmodified (natural) β-Lg (Neth. Milk dairy J., 47：15-22,1993).Although trypsase can slow water
Solve α-La, but β-Lg almost keep undecomposed state (Neth. Milk dairy J., 45：225-240,1991).Pancreas is solidifying
Although galactase fast decoupled α-La, β-Lg are slowly decomposed.Although papain hydrolyzes bovine serum albumin(BSA) (BSA)
With β-Lg, but α-La have repellence (Int. Dairy Journal 6:13-31,1996a).However, α-the La of unbonded Ca
Can completely be decomposed by papain at acidic (J. Dairy Sci., 76：311-320,1993).
The hydrolysis of peptide bond can cause charged group number and it is hydrophobic increase, the spatial configuration of low molecule quantization and molecule
Modification (J. Dairy Sci., 76：311-320,1993).The variation of its functional characteristic depends greatly on hydrolysis
Degree.Common visible maximum variation is the reduction of deliquescent increase and viscosity in the functionality of lactalbumin.Degree of hydrolysis is high
Situation, hydrolysate will not precipitate heating for multiple times, and in pH3.5~4.2, lower dissolubility is high.The viscosity of hydrolysate is far below
(intact) albumen that do not dispose.This difference is particularly significant in the highly concentrated situation of albumen.Other influences are the change of gel characteristic
Change, improve the reduction of the emulsification of thermal stability and enhancing, the emulsification and bubble stability of foaming characteristic.
The whey peptides used in present embodiment preferably have anti-inflammatory effect.LPS is inhibited to lure in vivo for example, confirming it
The effect that the property led TNF-α and IL-6 are generated.Whether have the function of that LPS inductivities TNF-α and IL-6 is inhibited to generate, can pass through
Well known measurement system (such as experimental medicine fascicle, " biological handbook UP experimentalists and technicians ", cell factor experimental method, palace island are sincere, mountain
This refined Knitting, (strain) Yang Tushe, 1997) confirm.Using LPS inductivities TNF-α and/or the inhibition of IL-6 generations as index,
Above-mentioned document (International Dairy Journal 12 can be referred to：813-820,2002) it tries to carry out lactalbumin
Hydrolysising condition (denaturation temperature, pH, temperature, hydrolysis time and enzyme/substrate ratio) optimization.It should be noted that this reality
It applies the whey peptides used in mode and includes the holding liquid or permeate (permeate) after whey peptides itself, ultrafiltration membrane treatment.
As the lactalbumin hydrolysate that can be used for present embodiment, such as following substance can be enumerated.Japanese Patent No.
No. 3183945 bulletins disclose：The lactalbumin isolate (WPI) of heated denaturation is hydrolyzed using endopeptidase and exopeptidase
Afterwards, adsorption treatment is carried out to the aromatic amino acid in the hydrolysate using ion exchange resin and the Fischer ratios that obtain are
10 or more, branched-chain amino acid be 15% or more, aromatic amino acid less than 2% lactalbumin hydrolysate (molecular weight is 200~3,
000 peptide mixer).
Japanese Kohyo 6-50756 bulletins disclose：Protein content is at least 65% at a temperature of more than 60 DEG C
After 12% aqueous solution of whey protein concentrate (WPC) is heat-treated, using from bacillus licheniformis (B. licheniformis) alkali protease and from bacillus subtilis (B. subtilis) neutral proteinase be hydrolyzed
To 15~35% DH, which is subjected to the ultrafiltration (Ultrafiltration with the cutoff value more than 10,000：UF)
Afterwards, pass through nanofiltration (Nanofiltration：NF it) is concentrated, then NF holding liquid is spray-dried and is obtained
Odorless and few bitter taste whey peptides.
The milk protein hydrolysate used in present embodiment as commercially available product, such as can be enumerated：Peptigen IF-
3080, Peptigen IF-3090, Peptigen IF-3091 and Lacprodan DI-3065 (Arla Foods), WE80BG
(DMV), Hyprol 3301, Hyprol 8361 and Hyprol 8034 (Kerry), Tatua2016, HMP406 (Tatua),
Whey Hydrolysate 7050 (Fonterra), Biozate3 (Davisco) etc., but it is not limited to these.As albumen water
Solve object modulator approach, such as can enumerate and include the following steps 1)~5) whey peptides manufacturing method.
1) lactalbumin and the water mixing including at least 65% albumen will be calculated with dried object, making, which has, reaches 20%
The slurries of protein content；
2) it is performed for more than the heat treatment until 60 DEG C of temperature；
3) will come from step 2) mixture, using can by bacillus licheniformis (B.licheniformis) make egg
White enzyme and/or using can by bacillus subtilis (B.subtilis) protease that makes, by the permanent steady methods of non-pH- into
Row proteolytic is hydrolyzed into the DH between 15 and 35%；
4) mixture from step 3) is divided on ultrafiltration/microfilter device with the cutoff value more than 10,000
From, pass it through object constitute protein hydrolysate (whey peptides)；And
5) hydrolysis is terminated by the inactivation of above-mentioned enzyme.
It is preferred that above-mentioned steps 1) in slurries have 7~12% protein content.It is preferred that above-mentioned steps 2) in heat treatment exist
It is carried out between 70 and 90 DEG C.It is preferred that above-mentioned steps 3) in hydrolysis carry out to the DH between 20~30%.It is preferred that above-mentioned ultrafiltration/micro-
The cutoff value of filter device is more than 50,000.
It is preferred that：Above-mentioned steps 3) or step 5) at the end of mixture with according between the 1 of dried object content calculation and 5%
Carbon corresponding to gauge, preferably at a temperature of between 50 with 70 DEG C during being longer than 5 minutes by activated carbon at
Reason, then removes the activated carbon.It is preferred that：In above-mentioned steps 5) after, preferably pass through nanometer at a temperature of between 50 and 70 DEG C
Filtering/ultrafiltration/reverse osmosis, and/or evaporation is concentrated, and recycles the holding object later as its protein hydrolysate (whey peptides)
Solution.
Be preferred from above-mentioned steps 5) protein hydrolysate (whey peptides) solution be spray-dried to aqueous less than 6.5%
Amount.
Therefore, the method for manufacturing lactalbumin hydrolysate is characterized in that：
1) lactalbumin and water that will be calculated with dried object including at least 65% albumen mix, and make to have and reach about 20%, preferably
Reach the slurries of 12% protein content；
2) it is performed for more than the heat treatment until 60 DEG C of temperature；
3) using can by bacillus licheniformis (B. licheniformis) make protease, preferably Alcalase
(registered trademark), and/or using can by bacillus subtilis (B. subtilis) protease, preferably that makes
Neutrase (registered trademark) will come from the stage 2 by the permanent steady methods of non-pH-) mixture carry out proteolytic and be hydrolyzed into
DH between 15 and 35%；
4) will come from the stage 3) mixture divided on ultrafiltration/microfilter device with the cutoff value more than 10,000
From making this constitute above-mentioned protein hydrolysate through object；And
5) hydrolysis is terminated by the inactivation of above-mentioned enzyme.
In the alimentation composition of present embodiment, protein sources can containing other than lactalbumin albumen, whey peptides with
Outer peptide, and/or amino acid.In the alimentation composition, protein sources can such as contain leucine.The alimentation composition can be with
It is preferred that containing leucine with 0.01~1.0g/100kcal, leucine is more preferably contained with 0.05~0.5g/100kcal.
In the alimentation composition of present embodiment, protein sources are substantially free of casein.With lactalbumin and whey peptides
It compares, casein is easy solidification.Casein is especially easy solidification under acidity.In the alimentation composition, protein sources essence
On not casein containing protein physical property can be made to stablize to inhibit or prevent generation etc. of precipitation in alimentation composition.
In the alimentation composition of present embodiment, protein-caloric ratio is preferably 16% or more and less than 50%, more preferably
20% or more and less than 30%.That is, the alimentation composition is high protein, promote the synthesis of muscle protein in patient's body.
In the alimentation composition of present embodiment, lipid source contains n-3 systems aliphatic acid.The alimentation composition can be preferred
Contain n-3 systems aliphatic acid with 10~100mg/100kcal, n-3 systems aliphatic acid is more preferably contained with 30~80mg/100kcal.
In the alimentation composition of present embodiment, n-3 systems aliphatic acid preferably comprise eicosapentaenoic acid (EPA) and/or
Docosahexaenoic acid (DHA).EPA and DHA has anti-inflammatory effect.In the alimentation composition of present embodiment, n-3 systems fat
Situation of the acid containing EPA is considered from the flavor angle of the alimentation composition, can preferably be contained with 1~100mg/100kcal
EPA more preferably contains EPA with 10~30mg/100kcal.In the alimentation composition, n-3 systems aliphatic acid contains the feelings of DHA
Shape considers from the flavor angle of the alimentation composition, preferably can contain DHA with 1~100mg/100kcal, more preferably with 10
~50mg/100kcal contains DHA.
In the alimentation composition of present embodiment, at least part of lipid source can use fish oil.Fish oil is rich in EPA
And DHA.In the alimentation composition, lipid source uses the situation of fish oil, which can be preferably with 0.05~0.5g/
100kcal contains fish oil, considers from flavor angle, more preferably contains fish oil with 0.1~0.3g/100kcal.
If being inflamed, the alienation of muscle protein can be hyperfunction, can cause to reduce (Secondary flesh lacks disease) with muscle mass
Or the cachexia etc. of weight loss.If in addition, inflammation continue, the anorexia of patient.However, in the battalion of present embodiment
It supports in composition, lipid source contains the situation of n-3 systems aliphatic acid, particularly EPA and/or DHA, can inhibit the disease institute of patient
Adjoint inflammation.Therefore, the disadvantage as described above generated by inflammation can be mitigated.
In the alimentation composition of present embodiment, lipid source can contain MCT Oil.Medium chain fatty
Acid glycerol three ester to digest and assimilate more common chain fatty acid triglycerides fast.The alimentation composition can preferably with 0.2~
2.0g/100kcal contains MCT Oil, and it is sweet more preferably to contain medium chain fatty acid with 0.4~0.8g/100kcal
Oily three esters.
The alimentation composition of present embodiment preferably comprises vitamin C and/or vitamin E.Vitamin C and vitamin E tool
Wheat Protein.The alimentation composition preferably can contain vitamin C with 1~1000mg/100kcal, more preferably with 10~
100mg/100kcal contains vitamin C.The alimentation composition preferably can contain vitamin E with 0.1~100mg/100kcal,
Vitamin E is more preferably contained with 1~10mg/100kcal.
The alimentation composition of present embodiment can contain the vitamins in addition to vitamin C and vitamin E.The nutrition
Composition can for example contain vitamin B1, vitamin B2, vitamin B6, vitamin B12, niacin, pantothenic acid, a kind in folic acid etc.
Or two or more.
The alimentation composition of present embodiment preferably comprises zinc.Zinc has the function of anti-inflammatory effect or improves muscle synthesis.
The alimentation composition preferably can contain zinc with 0.1~10mg/100kcal, more preferably contain zinc with 0.5~5mg/100kcal.
The alimentation composition of present embodiment can contain the minerals class other than zinc.The alimentation composition can for example contain
Have one kind or two or more in potassium, sodium, calcium, magnesium, iron etc..
In the alimentation composition of present embodiment, the content of potassium is preferably 20~500mg/100kcal, and more preferably 20
~300mg/100kcal.The content of sodium is preferably 20~500mg/100kcal, more preferably 20~300mg/100kcal.Calcium
Content be preferably 20~300mg/100kcal, more preferable 20~250mg/100kcal, further preferably 20~150mg/
100kcal.The content of magnesium be 5~300mg/100kcal, more preferable 10~200mg/100kcal, further preferably 10~
100mg/100kcal.By the way that the content of each minerals class is set as above range, the mine of appropriate amount can be supplemented rehabilitation etc.
Material class.Furthermore it is possible to which the adaptive (dispersion) when the manufacture of the alimentation composition of present embodiment is made to improve, while can protect
Inhibit the precipitation of the alimentation composition of mobility when depositing.
The alimentation composition of present embodiment can contain the ingredient other than mentioned component.The alimentation composition can be with institute
The concentration needed contains the ingredient of the disease for meeting patient or nutritional status etc..
The alimentation composition of present embodiment can contain the carbohydrate such as saccharic or food fiber.The alimentation composition
Such as isomaltulose and/or dextrin can be contained as saccharic.The content of the saccharics such as isomaltulose and/or dextrin is preferably 10~
16g/100kcal, more preferably 12~14g/100kcal.In the patient with the disease for needing rehabilitation nutrition, concurrent glycosuria
The patient of disease is quite a few.Therefore, it is preferable to use the 20 weight % or more of saccharic entirety in the alimentation composition of present embodiment
Sugar absorb slow isomaltulose.The usage amount of more preferable isomaltulose is the 50 weight % or more of saccharic entirety.
In the alimentation composition of present embodiment, as food fiber, it is preferable to use with blood glucose rising after meal is inhibited
Effect and while manufacturing be not likely to produce the indigestible dextrins of excessive viscosity.The content of the food fibers such as indigestible dextrins
Preferably 0.5~3.0g/100kcal, more preferably 1.0~2.0g/100kcal.
[manufacturing method of alimentation composition]
Next, illustrating the example of the manufacturing method of the alimentation composition of present embodiment.But the manufacturer of the alimentation composition
Method is not limited to manufacturing method described below.
First, the raw material of alimentation composition is concocted.Specifically, (input) 22 is added in blending tank (mixer),
000g dissolves water.The dissolving water is, for example, tap water, pure water, ion exchange water, by reverse osmosis (RO) film eliminates impurity
RO water etc..The temperature of the dissolving water may be set in 40~80 DEG C or so.Then, 169g dextrin (75 is added in blending tank
The dextrin solution of weight %), mixing (stirring) dissolving water and dextrin.
Next, addition 0.08g ferrous sulfate, 26g pH adjusting agents are mixed in blending tank, 2 are then added,
328g greases adjustment liquid (such as 2,200g vegetable fat, 128g animal fats etc.) is mixed.2,640g whey peptides are added again
(lactalbumin decomposition product), 3,000g whey protein concentrates, 750g food fibers, 3,360g isomaltuloses, 780g emulsifiers,
240g branched-chain amino acids, 3,360g stabilizers are mixed, and add 630g calcium preparations, 90g magnesium phosphates, 2g selenium yeasts, 7g later
Zinc gluconate, 0.36g Pu Tao Tang Suan Copper, 96g salt, 42g potassium chloride are mixed.
As long as pH adjusting agent can be edible, it is not particularly limited, pH adjusting agent can mix individually or with two or more
Use organic acid, inorganic acids.Organic acid can be used for example：Lactic acid, malic acid, citric acid, succinic acid, tartaric acid,
Ascorbic acid, gluconic acid, fumaric acid and their salt etc..Inorganic acids can be used for example：Hydrochloric acid, phosphoric acid and its salt
Deng.In addition, organic acid can use food additives, can also use from natural organic acid, such as lemon juice or apple
Juice etc..As long as grease adjust liquid can be edible, be not particularly limited, grease adjust liquid for example can individually or with 2 kinds with
On be used in mixed way rapeseed oil, palm oil, palm separation oil, rice bran oil, corn oil, fish oil etc..The temperature of grease adjustment liquid can be set
It is scheduled on 50~60 DEG C or so.
(stirring) mentioned component is mixed in blending tank on one side, is kept for 15 minutes or more for example at 50~60 DEG C on one side
(15~60 minutes).The raw material blending of alimentation composition is completed as a result,.
Next, carrying out the pre-heat treatment and heat sterilization processing to the blending liquid (raw material) concocted in blending tank.Pre-
In heat treatment, such as using heat-exchangers of the plate type, tubing heat exchanger etc., blending liquid is heated to 75~85 DEG C.It goes out in heating
In bacterium processing, such as using heat-exchangers of the plate type, tubing heat exchanger, steam jet type heater, steam injection heating device etc.,
Blending liquid after the pre-heat treatment is heated 1~10 second for example at 120~145 DEG C.
Next, the blending liquid to heated sterilization treatment carries out precooling treatment and pre- homogenize process.In precooling treatment
In, such as using heat-exchangers of the plate type, tubing heat exchanger etc., blending liquid is cooled to 70~80 DEG C.In pre- homogenize process
In, such as using homogenizer blending liquid is for example homogenized into (miniaturization) at 70~80 DEG C, 40~60MPa.Then, example
Heat-exchangers of the plate type, tubing heat exchanger are such as used, the blending liquid through pre- homogenize process is for example cooled to 5~25 DEG C,
It is stored in intermediate fluid reservoir.
(stirring) blending liquid is mixed in intermediate fluid reservoir on one side, is for example kept at 5~25 DEG C on one side.It is adjusted storing
Addition vitamins (such as 87g vitamin Cs, 9g vitamin Es etc.) in the intermediate fluid reservoir of liquid is closed to be mixed.Then, in
Between in fluid reservoir addition 258g fragrance, 18g sweeteners mixed.
Next, carrying out the pre-heat treatment and formal homogenize process to the blending liquid added with vitamins etc..It is preheating
In processing, such as using heat-exchangers of the plate type, tubing heat exchanger etc., blending liquid is heated to 70~80 DEG C.In formal homogeneous
In change processing, such as using homogenizer the blending liquid after the pre-heat treatment is for example subjected to homogeneous at 70~80 DEG C, 40~60MPa
Change (miniaturization).Then, such as using heat-exchangers of the plate type, tubing heat exchanger etc., by the blending through formal homogenize process
Liquid is for example cooled to 5~25 DEG C, is stored in final fluid reservoir.
Mix (stirring) blending liquid (alimentation composition, intermediate) in final fluid reservoir on one side, one side for example 5~
It is kept at 25 DEG C.Final fluid reservoir from storing blending liquid fills blending liquid into container appropriate.This implementation is completed as a result,
The alimentation composition (end article) of mode.
[effect]
Since the alimentation composition of present embodiment is acidity, so having tasty and refreshing excellent flavor.That is, patient etc. can be to battalion
Foster composition experiences tasty and refreshing excellent flavor, absorbs the alimentation composition with can not repelling.Thus, for example being easily in low battalion
The easy continuous ingestion alimentation compositions such as the rehabilitation for the state of supporting so that can suitably maintain the nutrition shape of rehabilitation etc.
State.
In the alimentation composition of present embodiment, the 80 weight % or more in protein sources total weight are lactalbumin and breast
Clear peptide.Compared with casein, lactalbumin and whey peptides are not easy to cure under acidity.Therefore, in alimentation composition, can press down
The generation etc. for making or preventing precipitation, can be such that physical property stablizes.
The alimentation composition of present embodiment has the heat density of 100kcal/100ml or more, is configured to than common
Alimentation composition has higher heat.Therefore, it even if patient etc. only absorb a small amount of alimentation composition, can also suitably maintain
The nutritional status of patient etc..Furthermore, it is possible to effectively improve the nutritional status of loss of appetite patient etc..
Since the alimentation composition of present embodiment is high heat, so the nutrition group can be inhibited in vivo in patient etc.
It closes protein sources contained in object and is used as energy source.Therefore, protein sources can more reliably be made to contribute to the synthesis of muscle protein,
It can inhibit the decomposition of muscle protein simultaneously.Thus, for example if the alimentation composition of present embodiment is used for rehabilitation
In, then medical rehabilitation can be effectively performed.At this point, the QOL (quality of life) of rehabilitation is improved, can expect to prevent to see
The increase of shield and the deterioration etc. for preventing the degree that need to be nursed.
More than, embodiment is illustrated, but the disclosure is not limited by the above embodiment, without departing from
Its purport, various modifications may be made.
Embodiment
Hereinafter, being illustrated to each embodiment.But the disclosure is not limited by following each embodiments.
[experiment 1. uses the evaluation test of the alimentation composition of the animal pattern of chronic obstructive pulmonary disease (COPD)]
(production method of the animal pattern of COPD)
Use 24 C57BL/6J systems male mices (3 week old).To mouse to food normal diet (standard concentrated feed (AIN93G))
(1 week) is raised and train within 7 days, is divided into 3 groups by index of weight later, is raised to tested feed 14 days (2 weeks) is eaten.
Tobacco smoke exposure group (Smoke)
Mouse is raised to tested feed 14 days (2 weeks) is eaten, mouse is made to be exposed in tobacco smoke for continuous 10 days later.
Mouse be exposed to tobacco smoke during in also to eating tested feed.It should be noted that the process for exposing of tobacco smoke is as follows.
Mouse is put into the chamber of exposure, uses tobacco mainstream smoke generation device (INH06-CIGR02A, strain formula
Commercial firm M I P S are manufactured) generate tobacco (Pease, Japan tobacco Inc's manufacture, tar：28mg/ roots, nicotine：
2.3mg/ roots) mainstream smoke (tobacco smoke：Air=1：5, flow velocity：1.05L/ minutes), the mainstream smoke of tobacco is sent into chamber
It is indoor.At this point, using about 1.5 hours daily, mouse is made to be exposed in 20 tobacco smokes.
Non-tobacco smog exposure group (air exposure group) (Air)
Mouse is raised to tested feed 14 days (2 weeks) is eaten, is later exposed to mouse in air within continuous 10 days.In mouse
It is also given in during being exposed to air and eats tested feed.It should be noted that the process for exposing of air is that mouse is put into air
In the chamber of exposure, air is sent into chamber using air pump.
(test method)
Embodiment 1
Allow the mouse of 8 tobacco smoke exposure groups at 24 days (during raising：During 14 days and tobacco smoke expose：10 days) in
Continuously freely absorb mobility alimentation composition as the disclosure of tested feed and common liquid food (Meibalance HP,
Meiji KK manufacture) mixture (alimentation composition：Liquid food=70：30 (weight ratios)) freeze-dried powder.Embodiment
The composition of the alimentation composition used in 1 is shown in Table 1.
[table 1]
The pH of alimentation composition shown in table 1 is 4.1.The heat density of the alimentation composition is 160kcal/100ml.The nutrition group
The protein-caloric ratio for closing object is 20%.The protein sources of the alimentation composition include the lactalbumin and 2.3g/ of 2.5g/100kcal
The whey peptides of 100kcal.The protein sources total weight of total weight of lactalbumin and whey peptides relative to the alimentation composition
Ratio is 96 weight %.EPA is 0.10g/100kcal.DHA is 0.04g/100kcal.
Comparative example 1
Allow the mouse of 8 tobacco smoke exposure groups at 24 days (during raising：During 14 days and tobacco smoke expose：10 days) in
The freezing for continuously freely absorbing the common liquid food (Meibalance HP, Meiji KK's manufacture) as tested feed is dry
Dry powder.
Reference examples 1
Allow the mouse of 8 non-tobacco smog exposure groups at 24 days (during raising：During 14 days and air exposure：10 days) in connect
Freely absorb the freeze-drying of the common liquid food (Meibalance HP, Meiji KK's manufacture) as tested feed in continuous ground
Powder.
(evaluation)
As the inflammation index of alveolar, using the monocyte chemotaxis factor (Monocyte Chemoattractant
Protein-1 (MCP-1)) concentration, as the Keratinocyte-derived of the neutrophil chemotactic factor
Chemokine (KC) concentration, matrix metalloproteinase 9 (Matrix metalloproteinase 9 (MMP-9)) concentration,
Neutrophil elastase (NE) concentration and neutrophil cell number.Here, with regard to the measured value of each index, according to average
Value ± standard error is evaluated.Then, in statistical analysis, as a control group with comparative example 1, using Dunnett examine or
Steel is examined.
In comparative example 1, compared with reference examples 1, the high situation of the measured value of each index has caused inflammation in comparative example 1
Disease.On the other hand, in embodiment 1, compared with comparative example 1, the low situation of the measured value of each index, inflammation in embodiment 1
It has been inhibited.
When measuring each index, after 24 hours, the whole blood of each mouse is acquired after terminating the exposure of tobacco smoke or air,
It is set to lose blood and dead.Here, it cleans alveolar 3 times (each 1mL) with PBS, recycles the cleaning solution of alveolar.Then, MCP-1 concentration,
In the measurement of KC concentration, MMP-9 concentration and NE concentration, the alveolar cleaning solution of these recycling is centrifuged, the lung is used
Steep the supernatant of cleaning solution.On the other hand, in the measurement of neutrophil cell number, the precipitation for the alveolar cleaning solution that suspended with PBS,
Use the suspension of the precipitation of the cleaning solution.
In the measurement of MCP-1 concentration, the Cytometric Bead of Japanese Becton Dickinson companies manufacture are used
Array (CBA) Mouse Inflammation kits.In the measurement of KC concentration, the Mouse of R ＆ D companies manufacture is used
KC Quantikine ELISA kits.In the measurement of MMP-9 concentration, the Mouse Total of R ＆ D companies manufacture are used
MMP-9 Quantikine ELISA kits.In the measurement of NE concentration, the Neutrophil that is manufactured using Cusabio companies
Elastase ELISA kits.
The MCP-1 concentration of alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1 is shown in Fig. 1.As shown in Figure 1：With it is right
It 1 compares as usual, a concentration of significantly high values of MCP-1 in comparative example 1.Compared with comparative example 1, MCP-1 is dense in embodiment 1
Degree is significantly low value.
The KC concentration of alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1 is shown in Fig. 2.As shown in Figure 2：With compare
Example 1 is compared, a concentration of significantly high values of KC in comparative example 1.Compared with comparative example 1, KC a concentration of low values in embodiment 1
Trend.
The MMP-9 concentration of alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1 is shown in Fig. 3.From the figure 3, it may be seen that with right
It 1 compares as usual, a concentration of significantly high values of MMP-9 in comparative example 1.Compared with comparative example 1, MMP-9 concentration in embodiment 1
For significantly low value.
The NE concentration of alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1 is shown in Fig. 4.As shown in Figure 4：With compare
Example 1 is compared, a concentration of significantly high values of NE in comparative example 1.Compared with comparative example 1, NE is a concentration of significantly low in embodiment 1
Value.
The neutrophil cell number of alveolar cleaning solution in embodiment 1, comparative example 1 and reference examples 1 is shown in Fig. 5.It can by Fig. 5
Know, compared with reference examples 1, neutrophil cell number is significantly high value in comparative example 1.Compared with comparative example 1, in embodiment
Neutrophil cell number is significantly low value in 1.
(investigation)
Compared with reference examples 1, the measured value of each index is high level in comparative example 1.It can thus be appreciated that：Pass through the exposure of tobacco smoke
It can cause inflammation.On the other hand, compared with comparative example 1, the measured value of each index is low value in embodiment 1.That is, if mouse is taken the photograph
Alimentation composition shown in table 1 is taken, although then mouse is exposed in tobacco smoke, each index value still shows low value.Thus may be used
Know：The alimentation composition of the disclosure can make to reduce by the concentration of the various inflammatory mediators caused by COPD, inhibit inflammatory cell
The increase of (neutrophil cell number).But also it understands：The nutritional composition in inhibiting of the disclosure becomes the original of alveolar tissue damage
The secretory volume of the various enzymes of cause.I.e., it is possible to which there is the alimentation composition for confirming the disclosure inflammation to improve (anti-inflammatory) effect.
[experiment 2. is commented using the lactalbumins of animal pattern of chronic obstructive pulmonary diseases (COPD), whey peptides, fish oil
Valence is tested]
(production method of the animal pattern of COPD)
Use 30 C57BL/6J systems female mices (6 week old).(standard concentrated feed (AIN93G)) is expected to common Feeding is eaten to mouse
(1 week) is raised and train within 7 days, is divided into 4 groups by index of weight later, is raised to tested feed 14 days (2 weeks) is eaten.
Tobacco smoke exposure group (Smoke)
Mouse is raised to tested feed 14 days (2 weeks) is eaten, is later exposed to mouse in tobacco smoke for three days on end.
It is also given in during mouse is exposed to tobacco smoke and eats tested feed.It should be noted that the process for exposing of tobacco smoke is such as
Under.
The mouse of tobacco smoke exposure group (Smoke) is put into the chamber of exposure, tobacco is generated using peristaltic pump
(Pease, Japan tobacco Inc's manufacture, tar：28mg/ roots, nicotine：2.3mg/ roots) mainstream smoke (tobacco
Smog：Air=1：5, flow velocity：600mL/ minutes), the mainstream smoke of tobacco is sent into chamber.At this point, small with 3 on day 1
When, with the 3rd day mouse was exposed in tobacco smoke with 4 hours on day 2.
Non-tobacco smog exposure group (air exposure group) (Air)
Mouse is raised to tested feed 14 days (2 weeks) is eaten, is later exposed to mouse in air for three days on end.Will be small
Mouse be exposed to air during in also to eating tested feed.It should be noted that the process for exposing of air is that mouse is put into sky
In the chamber of gas exposure, air is sent into chamber using air pump.
(test method)
Embodiment 2-1
The protein sources total amount of standard concentrated feed (AIN93G) is replaced with lactalbumin and whey peptides (lactalbumin：Whey peptides=1：
1 (weight ratio)), modulate whey food prod.The mouse of 6 tobacco smoke exposure groups is allowed (to switch to the feeding after whey food prod at 17 days
During supporting：During 14 days and tobacco smoke expose：3 days) in continuously freely absorb whey food prod as tested feed.
Embodiment 2-2
The half amount (50 weight %) of the lipid source of standard concentrated feed (AIN93G) is replaced with fish oil, modulates fish oil food.Allow 6
The mouse of tobacco smoke exposure group is at 17 days (during switching to the raising after fish oil food：14 days and tobacco smoke exposure period
Between：3 days) in continuously freely absorb fish oil food as tested feed.
Embodiment 2-3
The protein sources total amount of standard concentrated feed (AIN93G) is replaced with lactalbumin and whey peptides (lactalbumin：Whey peptides=1：
1 (weight ratio)), while the half amount of lipid source (50 weight %) is replaced with fish oil, modulate whey fish oil food.Allow 6 cigarettes
The mouse of tobacco smoke exposure group is at 17 days (during switching to the raising after whey fish oil food：14 days and tobacco smoke exposure period
Between：3 days) in continuously freely absorb whey fish oil food as tested feed.
Comparative example 2
Allow the mouse of 6 tobacco smoke exposure groups at 17 days (during the raising of standard concentrated feed：14 days and tobacco smoke exposure
Period：3 days) in continuously freely absorb standard concentrated feed (AIN93G) as tested feed.
Reference examples 2
Allow the mouse of 6 non-tobacco smog exposure groups at 17 days (during the raising of standard concentrated feed：14 days and air exposure phase
Between：3 days) in continuously freely absorb standard concentrated feed (AIN93G) as tested feed.
(evaluation)
As the inflammation index of alveolar, using the neutrophil chemotactic factor (KC) concentration, matrix metalloproteinase 9 (MMP-
9) concentration and neutrophil cell number.Here, it with regard to the measured value of each index, is evaluated according to mean+/-standard error.And
And in statistical analysis, as a control group with comparative example 2, is examined using Dunnett or Steel is examined.
In comparative example 2, compared with reference examples 2, the high situation of the measured value of each index has caused inflammation in comparative example 2
Disease.On the other hand, in embodiment 2-1~embodiment 2-3, compared with comparative example 2, the low situation of the measured value of each index,
Inflammation has been inhibited in embodiment 2-1~embodiment 2-3.It should be noted that being used in the measurement of each index and experiment 1
Identical method.
The KC concentration of alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2 is shown in Fig. 6.By scheming
Known to 6：Compared with reference examples 2, a concentration of significantly high values of KC in comparative example 2.Compared with comparative example 2, in embodiment 2-1
The trend of a concentration of low values of KC.Compared with comparative example 2, a concentration of significantly low values of KC in embodiment 2-2.With 2 phase of comparative example
Than the trend of a concentration of low values of KC in embodiment 2-3.In addition, compared with embodiment 2-2, KC is a concentration of in embodiment 2-3
The numerical value of same degree.
The MMP-9 concentration of alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2 is shown in Fig. 7.
As shown in Figure 7：Compared with reference examples 2, a concentration of significantly high values of MMP-9 in comparative example 2.Compared with comparative example 2, implementing
The trend of a concentration of low values of MMP-9 in example 2-1.Compared with comparative example 2, MMP-9 is a concentration of significantly low in embodiment 2-2
Value.Compared with comparative example 2, a concentration of significantly low values of MMP-9 in embodiment 2-3.
The neutrophil cell number of alveolar cleaning solution in embodiment 2-1~embodiment 2-3, comparative example 2 and reference examples 2 is shown in
Fig. 8.As shown in Figure 8：Compared with reference examples 2, neutrophil cell number is significantly high value in comparative example 2.With 2 phase of comparative example
Than neutrophil cell number is the trend of low value in embodiment 2-1.Compared with comparative example 2, neutrophilia in embodiment 2-2
Granulocyte number is notable low value.Compared with comparative example 2, neutrophil cell number is significantly low value in embodiment 2-3.
(investigation)
Compared with reference examples 2, the measured value of each index is high level in comparative example 2.It can thus be appreciated that：Pass through the sudden and violent of tobacco smoke
Dew, can cause inflammation.On the other hand, compared with comparative example 2, the measured value of each index is in embodiment 2-1~embodiment 2-3
Low value.That is, if mouse intake enhances the alimentation composition of lactalbumin and whey peptides and enhances the nutrient combination of fish oil
Object, although then mouse is exposed in tobacco smoke, each index value still shows low value.It can thus be appreciated that：The nutrient combination of the disclosure
Object can make to reduce by the concentration of the neutrophil chemotactic factor caused by COPD, and inhibiting inflammatory cell, (neutrophil(e) granule is thin
Born of the same parents' number) increase.But also it understands：The alimentation composition of the disclosure can inhibit to be discharged by inflammatory cell and as tissue damage original
The secretion of the enzyme of cause.Change with inflammation i.e., it is possible to confirm the alimentation composition of the disclosure, lactalbumin, whey peptides and fish oil
Kind (anti-inflammatory) effect.
[experiment 3. uses the evaluation test (1) of the alimentation composition of the animal pattern of hepatitis]
(production method of the animal pattern of hepatitis)
Use 17 C57BL/6J systems male mices (6 week old).
(test method)
Embodiment 3
8 mouse are allowed continuously freely to be absorbed in (2 weeks) at 14 days as tested feed and 1 identical alimentation composition of experiment
(table 1).Then, with 11mg/kg- weight (per 1kg mouse weights for 11mg) concanavalin A is given to mouse tail vein
(ConA), to induce hepatitis.
Comparative example 3
Allow 9 mouse continuously freely absorbed in (2 weeks) at 14 days as tested feed common liquid food (Meibalance HP,
Meiji KK manufactures).Then, with 11mg/kg- weight (per 1kg mouse weights for 11mg) companion is given to mouse tail vein
Con A (ConA), to induce hepatitis.
(evaluation)
It is living using Plasma aspartate transaminase (AST) activity and plasma alanine transaminase (ALT) as the index of hepatitis
Property.As the index of nutritional status, using plasma albumin and Total plasma protein.As the index of inflammation, using Plasma TNF-α
, plasma IL -6 and blood plasma MCP-1.With regard to the measured value of each index of hepatitis, nutritional status and inflammation, according to average value ± standard deviation
Difference is evaluated.In statistical analysis, as a control group with comparative example 3, the situation of dispersed phase etc. is examined using Student-t,
Disperse unequal situation, is examined using Mann-Whitney.
In embodiment 3, compared with comparative example 3, the low situation of the measured value of each index of hepatitis, liver in embodiment 3
Inflammation has been inhibited.On the other hand, in embodiment 3, compared with comparative example 3, the measured value of each index of nutritional status is high
The deterioration of nutritional status can be prevented and/or mitigate in embodiment 3 to situation.In embodiment 3, compared with comparative example 3, inflammation
Each index the low situation of measured value, inflammation has been inhibited.
In the measurement of Plasma TNF-α, plasma IL -6 and blood plasma MCP-1,2 after giving ConA to each mouse tail vein
After hour and after 4 hours, from the tail vein blood of each mouse, the blood is used.On the other hand, in plasma A ST activity, blood plasma
In ALT activity, the measurement of plasma albumin and Total plasma protein, each mouse tail vein is given after ConA after 24 hours, in second
It takes a blood sample from the abdominal vein of each mouse under ehterization, uses the blood.
In the measurement of plasma A ST activity, plasma ALT activity, plasma albumin and Total plasma protein, dedicated cunning is used
Dynamic chip (slide chip) (Fuji DRI-CHEM NX500, the manufacture of FILM Co., Ltd. of Fuji).In Plasma TNF-α, blood plasma
In the measurement of IL-6 and blood plasma MCP-1, the Cytometric Bead of Japanese Becton Dickinson companies manufacture are used
Array (CBA) Mouse Inflammation kits (Japanese Becton Dickinson companies).
The evaluation result of hepatitis
The plasma A ST activity given after ConA after 24 hours to mouse tail vein in embodiment 3 and comparative example 3 is shown in Fig. 9.By Fig. 9
Known to：Compared with comparative example 3, plasma A ST activity is significantly low value in embodiment 3.
The plasma ALT activity given after ConA after 24 hours to mouse tail vein in embodiment 3 and comparative example 3 is shown in Figure 10.
As shown in Figure 10：Compared with comparative example 3, plasma ALT activity is significantly low value in embodiment 3.
The evaluation result of nutritional status
The concentration and blood plasma of the plasma albumin after ConA after 24 hours are given in embodiment 3 and comparative example 3 to mouse tail vein
The concentration of total protein is shown in Table 2.As shown in Table 2：Compared with comparative example 3, the concentration of plasma albumin and blood plasma egg in embodiment 3
The trend of white a concentration of high level.
[table 2]
It should be noted that if giving ConA to mouse tail vein and mouse being made to induce pneumonia, then it has been generally acknowledged that plasma albumin
Concentration decline.
The evaluation result of inflammation
Give each Plasma TNF-α's behind 2 hours after ConA and after 4 hours in embodiment 3 and comparative example 3 to mouse tail vein
Concentration is shown in Figure 11.As shown in Figure 11：Compared with comparative example 3, a concentration of significantly low value of Plasma TNF-α in embodiment 3.
Mouse tail vein is given in embodiment 3 and comparative example 3 behind 2 hours after ConA and each plasma IL-after 4 hours
6 concentration is shown in Figure 12.As shown in Figure 12：Compared with comparative example 3, a concentration of significantly low value of plasma IL -6 in embodiment 3.
Mouse tail vein is given in embodiment 3 and comparative example 3 behind 2 hours after ConA and each blood plasma after 4 hours
The concentration of MCP-1 is shown in Figure 13.As shown in Figure 13：Compared with comparative example 3, blood plasma MCP-1's is a concentration of significantly low in embodiment 3
Value.
(investigation)
In embodiment 3 (mouse of alimentation composition shown in oral uptake table 1), with (1 institute of non-oral uptake table of comparative example 3
Show the mouse of alimentation composition) it compares, the measured value of each index is low value.It can thus be appreciated that：When the alimentation composition meeting of the disclosure
Prevent and/or mitigate to effect property the deterioration of hepatitis, the nutritional status caused by hepatitis, inflammation.I.e., it is possible to confirm the disclosure
There is alimentation composition inflammation to improve (anti-inflammatory) effect.
[experiment 4. uses the evaluation test (2) of the alimentation composition of the animal pattern of hepatitis]
Use 19 C57BL/6J systems male mices (6 week old).
(test method)
Embodiment 4-1
Allow 7 mouse continuously freely absorbed in 14 days mobility alimentation composition as the disclosure of tested feed with it is general
Mixture (the alimentation composition of through-flow food (Meibalance HP, Meiji KK's manufacture)：Liquid food=50：50 (weight
Than)).Then, with 12mg/kg- weight (per 1kg mouse weights for 12mg) concanavalin A is given to mouse tail vein
(ConA), to induce hepatitis.The composition of the alimentation composition used in embodiment 4-1 and embodiment 4-2 is shown in Table 3.
[table 3]
The pH of alimentation composition shown in table 3 is 4.1.The heat density of the alimentation composition is 159kcal/100ml.The nutrition group
The protein-caloric ratio for closing object is 20%.The protein sources of the alimentation composition include the lactalbumin and 0.6g/ of 4.2g/100kcal
The whey peptides of 100kcal.The lactalbumin of the alimentation composition and total weight of whey peptides are relative to protein sources total weight
Ratio is 96 weight %.EPA is 0.098g/100kcal.DHA is 0.035g/100kcal.
Embodiment 4-2
6 hepatitis mices are allowed continuously freely to be absorbed in 14 days as tested feed nutrition group identical with embodiment 4-1
Close object (table 3).
Comparative example 4
Allow 6 hepatitis mices continuously freely absorbed in 14 days as tested feed common liquid food (Meibalance HP,
Meiji KK manufactures).
(evaluation)
As the index of hepatitis, using plasma A ST activity and plasma ALT activity.It is white using blood plasma as the index of nutritional status
Albumen and Total plasma protein.As the index of inflammation, using Plasma TNF-α and plasma IL -6.Here, with regard to hepatitis, nutritional status
With the measured value of each index of inflammation, evaluated according to average value ± standard deviation.In statistical analysis, made with comparative example 4
For control group, the situation of dispersed phase etc. is examined using Student-t, is disperseed unequal situation, is examined using Mann-Whitney
It tests.It should be noted that being used in the measurement of each index and 3 identical methods of experiment.
The evaluation result of hepatitis
The plasma A ST given after ConA after 24 hours to mouse tail vein in embodiment 4-1~embodiment 4-2 and comparative example 4 lives
Property is shown in Figure 14.As shown in Figure 14：Compared with comparative example 4, plasma A ST activity is significantly low in embodiment 4-1 and embodiment 4-2
Value.
In embodiment 4-1~embodiment 4-2 and comparative example 4 blood plasma after ConA after 24 hours is given to mouse tail vein
ALT activity is shown in Figure 15.As shown in Figure 15：Compared with comparative example 4, plasma ALT activity is in embodiment 4-1 and embodiment 4-2
Significantly low value.
The evaluation result of nutritional status
In embodiment 4-1~embodiment 4-2 and comparative example 4 plasma albumin after ConA after 24 hours is given to mouse tail vein
Concentration and the concentration of Total plasma protein be shown in Table 4.As shown in Table 4：Compared with comparative example 4, the plasma albumin in embodiment 4-1
A concentration of high level trend.Compared with comparative example 4, a concentration of significantly high value of plasma albumin in embodiment 4-2.With
Comparative example 4 is compared, the trend of a concentration of high level of Total plasma protein in embodiment 4-1~embodiment 4-2.
[table 4]
The evaluation result of inflammation
Mouse tail vein is given in embodiment 4-1~embodiment 4-2 and comparative example 4 behind 2 hours after ConA and after 4 hours
The concentration of each Plasma TNF-α is shown in Figure 16.As shown in Figure 16：Compared with comparative example 4, the blood plasma in embodiment 4-1~embodiment 4-2
A concentration of significantly low value of TNF-α.
Mouse tail vein is given in embodiment 4-1~embodiment 4-2 and comparative example 4 behind 2 hours after ConA and 4 hours
The concentration of each plasma IL -6 afterwards is shown in Figure 17.As shown in Figure 17：Compared with comparative example 4, in embodiment 4-1~embodiment 4-2
A concentration of significantly low value of plasma IL -6.
(investigation)
In embodiment 4-1~embodiment 4-2 (mouse of alimentation composition shown in oral uptake table 3), (not with comparative example 4
The mouse of alimentation composition shown in oral uptake table 3) it compares, the measured value of each index is low.It can thus be appreciated that：The nutrition group of the disclosure
Closing object can prevent and/or mitigate to timeliness the deterioration of hepatitis, the nutritional status caused by hepatitis, inflammation.I.e., it is possible to confirm
There is the alimentation composition of the disclosure inflammation to improve (anti-inflammatory) effect.
[evaluation test of the delivered fresh of 5. alimentation compositions of experiment and the flavor and physical property of preservation product]
It has rated the delivered fresh of alimentation composition shown in table 5 and preserves the flavor and physical property of product.
[table 5]
The pH of alimentation composition shown in table 5 is 4.1.The heat density of the alimentation composition is 151kcal/100ml.The nutrition group
The protein-caloric ratio for closing object is 21%.The protein sources of the alimentation composition include the lactalbumin and 2.5g/ of 2.4g/100kcal
The whey peptides of 100kcal.The lactalbumin of the alimentation composition and total weight of whey peptides are relative to protein sources total weight
Ratio is 96 weight %.EPA is 0.157g/100ml.DHA is 0.056g/100ml.
The manufacturing condition of alimentation composition shown in table 5 is as follows：The solution temperature of blending liquid (raw material)：50~60 DEG C of (targets：
55℃)；The sterilising temp of blending liquid and time：124 DEG C, 5 seconds；The pressure that homogenizes of sterilized solution：40MPa (homogenizing in advance),
25MPa (formally homogenizes)；The shape and capacity of container：Rectangular paper container (manufacture of Tetra companies) is 125ml.It needs
Bright, each alimentation composition shown in table 1 and table 3 is also to be manufactured under identical manufacturing condition.
(test method)
It has rated the delivered fresh of alimentation composition shown in table 5 and preserves the flavor and physics of object (take care of 3 months, take care of 6 months)
Property.
Flavor
The flavor of delivered fresh and preservation product about alimentation composition, by 10 specialized review persons according to 5 grades (5：It is very good
Well, 4：Well, 3：Commonly, 2：It is slightly bad, 1：It is bad) carry out sensory evaluation.
Physical property
The physical property of delivered fresh and preservation product about alimentation composition, it is heavy according to proportion, pH, viscosity, size distribution, centrifugation
Shallow lake is measured and the floating upper rate of missible oil Floatation Rate (ク リ ー system) it is evaluated.
In the delivered fresh of alimentation composition and the gravity test of preservation product, sample is adjusted to 20 DEG C, is used later close
Spend densimeter (DA-130N, the manufacture of capital of a country Electronics Industry Company).
In the delivered fresh of alimentation composition and the pH of preservation product measure, sample is adjusted to 20 DEG C, uses pH meter later
(manufactured by F-53, the making of hole field).
In the delivered fresh of alimentation composition and the viscosimetric analysis of preservation product, sample is adjusted to 20 DEG C, uses Type B later
Rotational viscometer (manufacture of TVB10, Dong Ji industry companies).It should be noted that the operating condition is as follows：Revolution is 60rpm, protects
It is 60 seconds to hold the time.
In the delivered fresh of alimentation composition and the particle size distribution of preservation product, surveyed using laser refractive particle diameter distribution
Determine device (SALD-2200, Shimadzu Seisakusho Ltd.'s manufacture).It should be noted that the index takes median particle diameter (median).
In the delivered fresh of alimentation composition and the centrifugation sediment of preservation product measure, using following methods.First, it measures
(50ml, round bottom, central portion (at total high 1/2, the position away from top 5cm) are decorated with cross to glass centrifuge tube (Shen ガ ラ ス Far pipe)
The transparent centrifuge tube of line) weight, while each sample (sample size) of precision weighing 50g.Then, glass centrifuge tube (is contained into sample
Product) (1800g, 30 minutes) is centrifuged, liquid level is smoothly abandoned by decantation later.Glass centrifuge tube is fallen (containing precipitation) again
It sets, stands 30 minutes, wipe internal face with lens wiping paper until horizontal line from the upside of glass centrifuge tube later, measure glass later
The weight of glass centrifuge tube (containing residue).Then, centrifugation sediment is calculated by numerical expression below (1).
Centrifugation sediment [weight %]=(weight [g] of weight [g]-centrifuge tube (wind sleeve) of centrifuge tube (containing residue)) ÷
The weight [g] × 100 (1) of sample
In the delivered fresh of alimentation composition and the missible oil Floatation Rate of preservation product measure, using following methods.First, glass is measured
The weight of centrifuge tube (50ml, round bottom, central portion (at total high 1/2, the position away from top 5cm) are decorated with the transparent centrifuge tube of horizontal line)
Amount, while each sample (sample size) of precision weighing 50g.Then, glass centrifuge tube (containing sample) is centrifuged into (1800g, 30
Minute), use spatula to take out missible oil layer (top) into another glass centrifuge tube later.Glass centrifuge tube (is contained into missible oil again
Layer) it is inverted, 30 minutes are stood, wipes internal face with lens wiping paper until horizontal line from the upside of glass centrifuge tube later, later
Measure the weight of glass centrifuge tube (containing residue).Then, missible oil Floatation Rate is calculated by numerical expression below (2).
Missible oil Floatation Rate [weight %]=(weight [g] of weight [g]-centrifuge tube (wind sleeve) of centrifuge tube (containing residue)) ÷
The weight [g] × 100 (2) of sample
(evaluation)
The delivered fresh and preservation object of the alimentation composition (table 5) used in the evaluation criterion and experiment 5 of flavor and physical property
The evaluation of estimate of (take care of 3 months, take care of 6 months) is shown in Table 6.The delivered fresh of alimentation composition and the evaluation of estimate satisfaction for preserving object are respectively commented
The situation of price card standard, it is meant that the flavor and physical property of alimentation composition are good.
[table 6]
From taking from the point of view of a small amount of alimentation composition can absorb energy in large quantities, the proportion of alimentation composition is preferred
For 1.1~1.2g/cm3.From the point of view of it can gently set sterilising conditions while available appropriate tart flavour (flavor),
The pH of alimentation composition is preferably 3~5.From can inhibit or prevent manufacturing equipment from attaching burning etc. while good fluidity
From the point of view of, the viscosity of alimentation composition is preferably 10~100mPs s.From the point of view of emulsion stability raising, nutrition
The size distribution (median particle diameter) of composition is preferably 10μM or less.From the point of view of emulsion stability raising, nutrient combination
The centrifugation sediment of object is preferably 3 weight % or less.From the point of view of being well maintained physical property or quality, nutrient combination
The missible oil Floatation Rate of object is preferably 5 weight % or less.
Flavor
As shown in table 6, the delivered fresh of alimentation composition and preservation product (preservation condition：25 DEG C, keeping 3 months) flavor evaluation be
It is very good.Preservation product (the preservation condition of alimentation composition：25 DEG C, keeping 6 months) flavor evaluation be good.
Physical property
As shown in table 6, the delivered fresh of alimentation composition and preservation product (preservation condition：25 DEG C, 3 months and preservation condition：25
DEG C, 6 months) proportion, pH, viscosity, size distribution, centrifugation sediment, missible oil Floatation Rate be satisfied by evaluation criterion.That is, this public affairs
Even if the alimentation composition opened at normal temperatures the physical property of long-term preservation alimentation composition if having almost no change.
(investigation)
In alimentation composition shown in table 5, it is not only delivered fresh, even preserving product (preservation condition：25 DEG C, 3 months；And it protects
Deposit condition：25 DEG C, 6 months) also confirm flavor and physical property is good.That is, in the alimentation composition of the disclosure, although
Flavor and the ingredient of physical property are influenced whether containing such as fish oil (DHA and EPA) etc., at normal temperatures long-term preservation, it can also be true
Recognize excellent flavor, physical property is stablized.
Claims (9)
1. alimentation composition is the alimentation composition of mobility,
Containing protein sources, the protein sources include lactalbumin and whey peptides；
Total ratio relative to above-mentioned protein sources total weight of above-mentioned lactalbumin weight and above-mentioned whey peptides weight is 80 weights
Measure % or more；
Protein-caloric ratio is 16% or more and less than 50%；
Heat density with 100kcal/100ml or more；
The alimentation composition is acidity.
2. alimentation composition described in claim 1, wherein the ratio of above-mentioned lactalbumin weight and above-mentioned whey peptides weight is
5：1~1：10.
3. the pH of alimentation composition as claimed in claim 1 or 2, the alimentation composition is 3 or more and 5 or less.
4. the alimentation composition described in claim 3, wherein also contain zinc.
5. the alimentation composition described in claim 3, wherein above-mentioned protein sources also include leucine.
6. the alimentation composition described in claim 3, wherein also contain lipid source, the lipid source includes n-3 systems aliphatic acid.
7. any one of them alimentation composition of claim 1~6 is the alimentation composition of medical rehabilitation nutrition.
8. any one of them alimentation composition of claim 1~6 is the prevention and/or improvement of chronic obstructive pulmonary disease
Alimentation composition.
9. any one of them alimentation composition of claim 1~6 is anti-inflammatory alimentation composition.
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| JP2015236300 | 2015-12-03 | ||
| JP2015-236300 | 2015-12-03 | ||
| PCT/JP2016/085204 WO2017094669A1 (en) | 2015-12-03 | 2016-11-28 | Nutritional composition |
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| CN108430490A true CN108430490A (en) | 2018-08-21 |
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| JP (1) | JP7300243B2 (en) |
| CN (1) | CN108430490A (en) |
| HK (1) | HK1253384A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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- 2016-11-28 SG SG11201804602SA patent/SG11201804602SA/en unknown
- 2016-11-28 WO PCT/JP2016/085204 patent/WO2017094669A1/en active Application Filing
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Also Published As
| Publication number | Publication date |
|---|---|
| HK1253384A1 (en) | 2019-06-14 |
| WO2017094669A1 (en) | 2017-06-08 |
| SG11201804602SA (en) | 2018-06-28 |
| JPWO2017094669A1 (en) | 2018-09-20 |
| JP7300243B2 (en) | 2023-06-29 |
| TWI712367B (en) | 2020-12-11 |
| TW201731395A (en) | 2017-09-16 |
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