WO2006115123A1 - Agent d'inactivation virale - Google Patents

Agent d'inactivation virale Download PDF

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Publication number
WO2006115123A1
WO2006115123A1 PCT/JP2006/308128 JP2006308128W WO2006115123A1 WO 2006115123 A1 WO2006115123 A1 WO 2006115123A1 JP 2006308128 W JP2006308128 W JP 2006308128W WO 2006115123 A1 WO2006115123 A1 WO 2006115123A1
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WO
WIPO (PCT)
Prior art keywords
inactivating agent
virus inactivating
virus
polyphenol
agent according
Prior art date
Application number
PCT/JP2006/308128
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English (en)
Japanese (ja)
Inventor
Kimitoshi Noda
Naoko Morinaga
Motoyuki Tagashira
Original Assignee
Asahi Breweries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Asahi Breweries, Ltd. filed Critical Asahi Breweries, Ltd.
Priority to JP2007514606A priority Critical patent/JPWO2006115123A1/ja
Publication of WO2006115123A1 publication Critical patent/WO2006115123A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • the present invention relates to a virus inactivating agent, which is a porcine anthocyanin-based polyphenol having an inactivating effect on a virus such as influenza virus, particularly preferably a polyphenol derived from an immature apple or hop koji. .
  • the power of research on natural substances having antiviral activity so far includes proanthocyanidin polymers (see Patent Document 1).
  • the polymer is a proanthocyanidin polymer having 2 to 30 flavonoid units that can also have a plant power of croton-recleri and is said to be effective in the treatment of respiratory virus infections such as influenza.
  • this document describes the therapeutic effect of broanthocyanine polymer A (having a degree of polymerization of 2 to 11 flavonoid units and an average of about 7) against influenza virus A virus.
  • tea catechins such as epicarocatechin gallate are listed as tea polyphenols.
  • Patent Document 1 Patent No. 3448052
  • Patent Document 2 JP-A-3-101623
  • the proanthocyanidin polymer described in the above-mentioned Patent Document 1 is effective for the treatment of respiratory viral infections, but the raw material is a croton-type tree that grows in a specific environment such as Amazon. Therefore, it is not suitable for simple and mass production. In recent years, the removal of such wood has been severely restricted for the purpose of protecting genetic resources. Further Easy take-off and breeding of non-native species other than the original habitat may disrupt the ecosystem.
  • polyphenol as used herein is a general term for compounds having a plurality of phenolic hydroxyl groups in a molecule mainly contained in a plant body.
  • “Proanthocyanin-based polyphenol” is a red pigment by hydrolysis. A compound that produces an anthocyanin (cyanidine, delphidin or pelargine)! Uh.
  • the first of the present invention is to provide a virus inactivating agent containing a proanthocyanidin-based polyphenol as an active ingredient that inactivates viruses.
  • the second of the present invention is to provide a virus inactivating agent in which the proanthocyanin-based polyphenol is a polyphenol obtained from an apple, particularly an unripe fruit of an apple.
  • the third of the present invention is to provide a virus inactivating agent, wherein the proanthocyanidin-based polyphenol is a polyphenol from which hops, in particular, hop cake is also obtained.
  • the Puroantoshia - Gin systems the preferred polyphenol 5-95 0/0, more preferably 20 to 95 weight 0/0, it is preferable to contain.
  • Puroantoshia - gin based polyphenol is also (from or contained in apples) obtained Ringoka when a polyphenol is preferably a virus inactivating agent is 20 to 80 wt%, more preferably 50 to 70 weight 0 / 0 , containing the polyphenol.
  • the proanthocyanidin-based polyphenol is a polyphenol that also has hopping power (derived from or contained in hops), it is preferably 20 to 70% by weight, more preferably 25 to 55% by weight as a virus inactivating agent %, The polyphenol is contained.
  • the proanthocyanidin-based polyphenol alcohol may be a proanthocyanine that does not permeate the membrane when treated with an ultrafiltration membrane having a molecular weight cut off of 1,000 or more. preferable.
  • the present invention provides a beverage or food product containing the above-mentioned virus inactivating agent, preferably in a final concentration range of 1 to 10, OOOppm.
  • the present invention also provides a therapeutic method in which, together with the above-mentioned medicine containing the virus inactivating agent, the medicine is administered as an oral or parenteral agent to a patient in a total daily dose of 2 mg to LOOO mg. To do.
  • the polyphenol provided by the present invention is stronger than the tea catechin described in JP-A-3-101623 in the strength of the virus growth inhibitory activity, and is applied to beverages and foods. It is excellent also in the taste which becomes important when doing.
  • the virus inactivating agent of the present invention has anti-influenza virus activity, it is effective against influenza virus.
  • the components that inactivate influenza virus are hops, especially hop koji, or polyphenols derived from or containing apples, especially apple immature fruits, there is an advantage that raw materials can be easily obtained.
  • FIG. 1 is a diagram in which the degree of growth of Sindbis virus in Example 10 is evaluated by viability of Vero cells. The higher the value on the vertical axis, the more cells are alive.
  • FIG. 2 shows the degree of proliferation of influenza virus in Example 11 evaluated by the hemagglutination activity of chorioallantoic fluid.
  • the vertical axis shows the maximum dilution factor showing hemagglutination activity, and the higher this value, the more influenza virus grows! /.
  • FIG. 3 is a graph showing an evaluation of the hemagglutination activity of chickens possessed by influenza virus in Example 12.
  • the vertical axis is a score of the degree of erythrocyte aggregation. The higher this value, the stronger the infectivity.
  • the unripe apple fruit used as the raw material of the present invention refers to an fruit that has been artificially picked before the fruit of the apple has matured, or that has fallen from the apple fruit tree naturally by dropping or the like.
  • the hop koji used as the raw material of the present invention is obtained by removing the rubulin portion from the hop koji, and in general, the hop koji is obtained by pulverizing the hop koji and removing the rubulin portion by sieving.
  • it is useful for beer brewing in order to save the trouble of hopping and removing the hop cake. It tends to be used for brewing beer as hop pellets. Accordingly, the raw material of the present invention is not particularly limited as long as it contains hop cake, and there is no problem even if hop fruit and hop pellets containing hop cake are used as raw materials.
  • the extracted liquid is an extract containing a virus inactive ingredient.
  • the virus-inactive component can be purified by using a column packed with granular resin having affinity for polyphenol, etc., and the degree of purification can be increased. However, this process is only to increase the degree of purification of the virus inactivating agent, and can be omitted if not necessary.
  • the virus inactive ingredient is a granular resin having affinity for polyphenol (hereinafter “In the purification process using a column packed with “fat” (t), etc.
  • the extract containing the virus inactivating component is passed through the column and the column is thoroughly washed. Thereafter, the virus inactivating agent adsorbed on the column may be eluted, or granular rosin may be immersed in an extract containing a virus inactivating component and batch-treated.
  • the virus inactivating agent on the sardine When adsorbing the virus inactivating agent on the sardine, if necessary, after cooling the extract containing the virus inactivating component to about 5 to 30 ° C in order to increase the adsorption efficiency, It is desirable to reduce the concentration of the organic solvent in the extract beforehand by concentration under reduced pressure.
  • the material of the resin hydroxypropylated dextran, hydrophilic bull polymer, styrene-dibutylbenzene polymer and the like can be used.
  • the scab can be washed to increase the degree of purification of the virus inactivating agent.
  • a solvent used for washing water or an aqueous ethanol solution of 1 to 10 wZw% (weight Z weight%) is suitable, and it is desirable to wash using a solvent amount of about 1 to 10 times the amount of greaves.
  • the virus inactivating agent is desorbed and eluted from the sorbate adsorbed with polyphenols.
  • the solvent to be used hydrous alcohol, hydrous acetone, hydrous acetonitrile or the like can be used. Particularly suitable examples include ethanol aqueous solution or ethanol of 10 wZw% or more. Desirably, the amount of elution solvent to be passed is about 2 to 6 times the amount of sallow.
  • the virus inactivating agent can be obtained as a powder by removing the solvent from the obtained eluate by a conventional method such as concentration, freeze-drying or spray-drying. Also, alcohol, acetone, acetonitrile, etc.
  • the synthetic resin used can be repeatedly used after being washed with an alcohol aqueous solution of 80 vZv% (capacity Z volume%) or more, an aqueous sodium hydroxide solution of about 0.05 N, and the like.
  • the virus inactivating agent obtained by force can be put to practical use as it is, but the degree of purification can be further increased by a method using an ultrafiltration membrane as described below. However, this process is only for increasing the purity of the virus inactivating agent and can be omitted if not necessary.
  • the step of purifying the virus inactive ingredient using an ultrafiltration membrane is performed by ultrafiltration with a molecular weight cut off of 1,000 or more from the solution containing the virus inactivating agent obtained by the above method. Treat with membrane.
  • the solution is preferably water or a solution of an organic solvent miscible with water.
  • a suitable example is a 5-50% aqueous ethanol solution.
  • the membrane material can be used without particular limitation as long as it is usually used as a material for an ultrafiltration membrane, such as cell mouth, cellulose acetate, polysanolefon, polypropylene, polyester, polyethersulfone, PVDF.
  • the molecular weight cut off is 1,000 or more, it can be used without any problem.
  • the yield will be drastically reduced. Since the time required for the treatment becomes long, an ultrafiltration membrane having a fractional molecular weight of about 3,000 to 50,000 is preferred. In addition, it is desirable that the treatment is performed until the amount of the remaining liquid is about iZio to iZioo at the start of the treatment, depending on the type of the extraction solvent and the ratio of the extraction solvent and hops or hops.
  • the pressure at that time is preferably about 0.1 to LO. OkgZcm 2 although it depends on the ultrafiltration membrane and the filtration device. If necessary, after the treatment, the remaining liquid can be diluted again with a suitable solvent such as water and retreated in the same manner to increase the degree of purification.
  • the solvent of the obtained upper liquid residue is concentrated by a usual method such as concentration, freeze drying, spray drying, or the like. Except, the virus inactivating agent can be obtained as a powder. Also, alcohol, acetone, acetonitrile, etc. can be recovered and reused during concentration under reduced pressure.
  • the virus inactivating agent thus obtained is an odorless skin-colored, brown or light yellow powder with a faint bitter taste, adsorbed on a synthetic resin having an affinity for polyphenol, and a molecular weight cut off. Proanthocyanidins that do not permeate the membrane when treated with more than 1,000 ultrafiltration membranes.
  • the yield is 0.5-20.
  • Ow / w% in terms of hop koji weight and 0.5-15.
  • OwZw% in terms of hop koji weight In the case of fruit, it is 0.5 to 15.
  • the content (rate) of the active ingredient, the proanthocyanin-based polyphenol, in the obtained virus inactivating agent varies depending on the difference in the purification process described above, and the content is small. However, depending on the amount of intake and dose, etc., a sufficient effect can be expected, and there is no limitation. More specifically, if proanthocyanidin-based polyphenols are contained in the virus inactivator in an amount of 2% by weight or more, the effect is exhibited as an active ingredient. In consideration of time and labor, it is preferably contained in the range of 5 to 95% by weight, more preferably 20 to 95% by weight.
  • the virus inactivating agent when the proanthocyanin-based polyphenol is a polyphenol obtained from apple strength, the virus inactivating agent preferably contains 20 to 80% by weight, more preferably 50 to 70% by weight. In addition, when the proanthocyanin-based polyphenol is a polyphenol obtained with a hopping force, the virus inactivating agent is preferably 20 to 70% by weight, more preferably 25 to 55% by weight. contains.
  • the content (% by weight) of the proanthocyanin-based polyphenol in the virus inactivating agent is generally determined by the method of Porter et al. (Porter et al., Phytochemistry 25, 223-230 (1986)). This method is a method in which proanthosidin-based polyphenol-specific interflavan bonds are hydrolyzed in the presence of alcohol, and the resulting red pigments such as pelargosine, cyadin, and delphidinidine are quantified at an absorbance of 550 nm. It is.
  • Proanthocyanidin-based polyphenols contain a variety of substances, so the light absorption usually obtained The degree can be converted to the absorbance of a relatively simple structure such as procyan-zine B1, such as procyan-zine B1, and expressed as the content of procyan-zine B1.
  • the content of proanthocyanidin-based polyphenol in the virus inactivating agent can be determined.
  • the virus inactivating agent obtained by force can be formulated with commonly used carriers, auxiliaries, additives, etc., and as a pharmaceutical product as an oral or parenteral product according to a conventional method. It can be used and mixed with food ingredients to make food and drink.
  • Pharmaceutical products include tablets, capsules, powders, granules, and syrups as oral preparations, and non-oral preparations such as ointments, creams, and liquids, and injections such as sterile solutions and suspensions. is there. It can also be made into mouth preparations such as mouthwash.
  • oral preparations such as oral preparations
  • non-oral preparations such as ointments, creams, and liquids
  • injections such as sterile solutions and suspensions. is there. It can also be made into mouth preparations such as mouthwash.
  • mouth preparations such as mouthwash.
  • the pharmaceutical containing the virus inactivating agent of the present invention is a physiologically recognized vehicle or carrier.
  • adjuncts mixed in tablets and capsules are as follows. Binders such as tragacanth, gum arabic, corn starch, gelatin, excipients such as microcrystalline cellulose, corn starch, total gelatinized starch, swelling agents such as alginic acid, lubricants such as magnesium stearate , Sweeteners such as sucrose, lactose, saccharin, peppermint, hard mono oil, flavoring such as cherry.
  • the above materials can further contain a liquid carrier such as fats and oils, and other materials can be used as coating agents or the physical form of the preparation can be changed by other methods. be able to. For example, tablets can be coated with shellac and sugar. Syrup or elixir is sucrose as a sweetener
  • methyl or propyl parabens As preservatives, methyl or propyl parabens, pigments and flavoring agents such as cherry or orange flavors can be included.
  • the content of the virus inactivating agent is preferably 3 to 50% by weight, more preferably 5 to 30% by weight. Range.
  • a sterile composition for injection comprises an active substance in a vehicle such as water for injection, a naturally occurring vegetable oil such as sesame oil, coconut oil, peanut oil, cottonseed oil, or a synthetic fat vehicle such as ethylolate. It can be formulated by conventional methods of dissolving or suspending. Moreover, a buffering agent, a preservative, an anti-oxidation agent, etc. can be mix
  • a buffering agent, a preservative, an anti-oxidation agent, etc. can be mix
  • vaseline, greaffin, oils and fats, lanolin, macrogol or the like is used as a base material, and an ointment, cream or the like can be obtained by an ordinary method.
  • the content of the virus inactivating agent is preferably in the range of 0.2 to 10% by weight, more preferably 0.5 to 5% by weight.
  • the beverage or food product containing the virus inactivating agent of the present invention may be in the form of the above-mentioned preparation, but in the form of candy, rice cracker, cookie, beverage, etc., the required amount is added to each raw material, It can also be processed and manufactured by a general manufacturing method. Ingestion as health food and functional food is used for disease prevention and health maintenance, so it can be divided into several times a day for oral consumption and taken as a daily product containing 5 mg to 500 mg. .
  • the virus inactivating agent When a virus inactivating agent is added to these beverages or foods, the virus inactivating agent may be added as a powder, but preferably the virus inactivating agent is added in an aqueous solution of 1 to 2% by weight or It is desirable to add an aqueous alcohol solution or an alcohol solution so that the final concentration is usually 1 to 10, OOOppm, preferably 100 to 5000 ppm, for beverages or foods.
  • apple immature fruit 400g was homogenized with 1% hydrochloric acid methanol and extracted with heating under reflux (3 times). The extract was concentrated under reduced pressure to distill off the methanol, In addition, it was distributed (twice), and the aqueous layer was collected. After filtration, it was diluted to 200 ml with distilled water. Furthermore, it was purified by solid phase extraction using Sep-pak C18 and freeze-dried to obtain 8.9 g of a virus inactivating agent. The yield of immature apple fruit was 2.2%.
  • this virus inactivating agent was added to size exclusion chromatography (Kurumatani et al., J. Liq. Chromatogr. Realt. Technol. 28, 1971-1983, (2005)), the average molecular weight of the virus inactivating agent was calculated to be about 1,500. This is equivalent to about a pentamer in terms of catechin.
  • hop koji 50 g was extracted with 1,000 ml of 40% ethanol aqueous solution with stirring at 50 ° C. for 60 minutes. After filtration, the solution was concentrated under reduced pressure until the volume reached 500 ml. The concentrated solution was passed through a column packed with 150 ml of styrene-dibulene benzoate (Separbeads 70 manufactured by Mitsubishi Chemical Co., Ltd.), and then with 500 ml of water. Washed. Further, 600 ml of 50% ethanol aqueous solution was passed through the same column, and the same eluate was collected and lyophilized to obtain 1.7 g of a virus inactive ingredient as a light yellow powder with an odorless faint bitterness. It was. The yield of hop repulsion was 3.4%.
  • Example 2 5 g of the virus inactivating component obtained in the same manner as in Example 2 was dissolved in 500 ml of a 20% aqueous ethanol solution and treated with an ultrafiltration membrane (YM10 manufactured by Millipore) having a molecular weight cut-off of 10,000. The remaining liquid that did not pass through this membrane was concentrated and lyophilized to obtain 2.2 g of a further purified virus inactivating agent as a yellow to brown powder.
  • the average molecular weight of the virus inactivating agent was calculated to be about 6,300. This corresponds to approximately 22-mer in terms of catechin.
  • the official food analysis method (HPLC method) for catechin determination can be measured, for example, according to the method described in the Ministry of Agriculture, Forestry and Fisheries of Vegetables, Tea Experiment Station “Tea Analysis Method” Tea Industry Research Report No. 71 (1990).
  • This powder (virus inactivating agent) was quantified with proanthocyanin using the Porter method, and as a result, it was 53% in terms of procyanin B1.
  • Each said weight part was mixed uniformly, and it was set as the powder and the granule according to the conventional method.
  • powders and granules to which the substance obtained according to Examples 1 and 2 was added were obtained in the same manner.
  • juice was prepared according to a conventional method.
  • a juice to which the substance obtained according to Examples 1 and 2 was added was obtained in the same manner.
  • a cookie was prepared according to a conventional method.
  • Example 3 As a control, cells with polyphenol and virus were used, and the cell activity indicated by the control was defined as 100%. The results are shown in Fig. 1.
  • the virus inactivating agent obtained in Example 3 was stronger and showed a virus inactivating effect as compared with epigallocatechin gallate, which is the main component of tea catechin.
  • Example 3 Growth of various concentrations of the virus inactivating agent obtained in Example 3 and influenza A virus (influenza A / Beijin / 352/89 (H3N2)) at 4 ° C for 30 minutes Were inoculated into the chorioallantoic cavity and incubated at 35 ° C for 48 hours.
  • the concentration of the virus inactivating agent of Example 3 was calculated based on the result of size exclusion chromatography with a molecular weight of 6300. After incubation, chorioallantoic fluid was collected and the amount of influenza virus was evaluated by erythrocyte aggregation activity. The result is shown in Fig.2.
  • the virus inactivating agent of Example 3 inhibited the growth of influenza virus depending on the concentration.
  • Example 1 and Example 3 The virus inactivating agent obtained in Example 1 and Example 3 at various concentrations and A-type influenza virus (influenza A / Beijin / 352/89 (H3N2)) were mixed and ink was used at 4 ° C for 30 minutes. Then, in addition to chicken erythrocytes, the infectivity of the virus was evaluated by its aggregation activity.
  • concentration of the virus inactivating agent obtained in Example 1 and Example 3 was calculated with molecular weights of 1500 and 6300, respectively, from the average molecular weight results of size exclusion chromatography. Figure 3 shows the results.
  • the virus inactivating agent obtained in Example 1 and Example 3 inhibited the hemagglutination activity of influenza A virus in a concentration-dependent manner and attenuated the infectivity of the virus.
  • the virus inactivating agent of the present invention has an effect of suppressing the growth of the virus, it has the effect of inhibiting the infection of the virus to the host, a pharmaceutical, a quasi-drug, a beverage or a food product, etc. Can be used effectively.

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Abstract

L'invention concerne un agent d'inactivation virale comprenant du polyphénol de proanthocyanidine, de façon particulièrement préférée un polyphénol obtenu à partir d'une pomme encore immature ou d'une bractée de houblon, ayant un effet d'inactivation (prévention d'une infection) contre les virus tel que le virus de la grippe. Dans l'utilisation de cet agent, l'effet d'inactivation (prévention d'une infection) contre le virus de la grippe est exercé efficacement par l'action du polyphénol dérivé des pommes, ou contenu dedans, ou bien dérivé du houblon, ou contenu dedans.
PCT/JP2006/308128 2005-04-19 2006-04-18 Agent d'inactivation virale WO2006115123A1 (fr)

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JP2005-121343 2005-04-19

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WO2011070970A1 (fr) * 2009-12-07 2011-06-16 北海道公立大学法人札幌医科大学 Inhibiteur de surexpression de lymphopoïétine stromale thymique
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Publication number Priority date Publication date Assignee Title
US20090035432A1 (en) * 2007-07-13 2009-02-05 Mantius Harold L Process for Producing a Proanthocyanidin Extract
EP2175731A1 (fr) * 2007-07-13 2010-04-21 Ocean Spray Cranberries, Inc. Procédé pour produire un extrait de proanthocyanidine
JP2010533648A (ja) * 2007-07-13 2010-10-28 オーシャン スプレー クランベリーズ インコーポレイテッド プロアントシアニジン抽出物を生成するためのプロセス
EP2175731A4 (fr) * 2007-07-13 2014-07-02 Ocean Spray Cranberries Inc Procédé pour produire un extrait de proanthocyanidine
US9023413B2 (en) 2007-07-13 2015-05-05 Ocean Spray Cranberries, Inc. Process for producing a proanthocyanidin extract
US9226520B2 (en) 2007-07-13 2016-01-05 Ocean Spray Cranberries, Inc. Process for producing a proanthocyanidin extract
US9420812B2 (en) 2007-07-13 2016-08-23 Ocean Spray Cranberries, Inc. Process for producing a proanthocyanidin extract
WO2011070970A1 (fr) * 2009-12-07 2011-06-16 北海道公立大学法人札幌医科大学 Inhibiteur de surexpression de lymphopoïétine stromale thymique
JPWO2011070970A1 (ja) * 2009-12-07 2013-04-22 北海道公立大学法人 札幌医科大学 胸腺間質性リンパ球新生因子過剰発現抑制剤
JP2013047196A (ja) * 2011-08-29 2013-03-07 Settsu Seiyu Kk 殺ノロウイルス組成物

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