JP2006160672A - Allergy inhibitor, food, allergy-inhibiting method using the same, immunosuppressed animal and method for making the same - Google Patents
Allergy inhibitor, food, allergy-inhibiting method using the same, immunosuppressed animal and method for making the same Download PDFInfo
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本発明は、IgE抗体抑制、特にI型アレルギー疾患発症防止ならびに抗炎症などの作用が期待できる、アレルギー抑制剤及び食品素材の提供に関するものである。更に、本発明は該アレルギー抑制剤が投与された免疫抑制動物及びその作製方法に関するものである。 The present invention relates to the provision of an allergy inhibitor and food material that can be expected to suppress IgE antibodies, in particular, prevent the onset of type I allergic diseases and anti-inflammatory. Furthermore, the present invention relates to an immunosuppressed animal to which the allergy inhibitor is administered and a method for producing the same.
アレルギー疾患の罹患率および死亡率は、食生活や居住環境の変化などに伴い、ここ10年間で世界的にも増加傾向にある。民間調査(新薬開発の現状と将来展望 91年度版、(株)シードプランニング)によると、現在、我国で3人に1人は、アトピー性皮膚炎、気管支喘息、アレルギー性鼻炎などの典型的なI型アレルギー疾患の症状を示しており、このデータは、厚生省保健福祉動向調査(1991年)でも裏付けられている。アレルギー疾患は、直接生命に関わることがない反面、ごく若い世代に突然現れ、早い時期での自然治癒はまず期待できず慢性に経過することによって、本人や家族の負担は勿論のこと、長期に亘って社会的活動にも大きな影響を及ぼしていると考えられる。 The morbidity rate and mortality rate of allergic diseases have been increasing worldwide over the past 10 years due to changes in diet and living environment. According to a private survey (present state and future prospects of new drug development, 1991 edition, Seed Planning Co., Ltd.), one in three people in Japan is typical of atopic dermatitis, bronchial asthma, allergic rhinitis, etc. It shows the symptoms of type I allergic disease, and this data is supported by the Ministry of Health and Welfare Health and Welfare Trend Survey (1991). Although allergic diseases are not directly related to life, they suddenly appear in the very young generation, and natural healing at an early stage cannot be expected. It is thought that it has a great influence on social activities.
I型アレルギー疾患は、室内塵、ダニ、花粉類、真菌類などの抗原を吸入することで感作、発症し、次のような機序が考えられている。感作は、Th2型のサイトカインを生産するCD4陽性T細胞によってメディエートされ、一般的免疫反応を経由し、B細胞が遊離したIgE抗体がそのFc部分で肥満細胞上のレセプターと結合することにより成立する。再侵入抗原がIgEのFab部分を架橋するとヒスタミン、ロイコトリエンなどのケミカルメディエータが遊離され、これらの物質が、組織の炎症、血管透過性亢進、平滑筋収縮、粘液分泌亢進などに働き、アレルギー疾患の病像を引き起こす。 Type I allergic diseases are sensitized and developed by inhaling antigens such as house dust, mites, pollens, and fungi, and the following mechanism is considered. Sensitization is established when IgE antibody released by B cells is mediated by CD4-positive T cells that produce Th2-type cytokines and through general immune responses, and binds to receptors on mast cells at its Fc portion. To do. When the re-entry antigen crosslinks the Fab part of IgE, chemical mediators such as histamine and leukotriene are released, and these substances act on tissue inflammation, increased vascular permeability, smooth muscle contraction, increased mucus secretion, etc. Causes a illness.
アレルギー疾患の治療に最も有効な方法は、抗原との接触を避けることであるが、居住環境の至る所に遊離して存在する抗原で感作発症している患者では、抗ヒスタミン剤などの副作用もある、対症療法剤を用いた一般的な解決策に依存せざるを得ないのが実状である。このため、薬剤を飲み続けるあるいは塗布し続けない限り発症を繰り返すことになり、財政的にも、肉体的にも大きな負担を強いられ、使用を中止するとリバウンドによる症状の悪化も懸念されるという問題を抱えている。 The most effective way to treat allergic diseases is to avoid contact with antigens, but there are side effects such as antihistamines in patients who are sensitized with antigens that are free and present throughout the living environment The reality is that we have to rely on general solutions using symptomatic treatments. For this reason, unless you continue to drink or apply the drug, the onset will be repeated, and you will be burdened financially and physically, and if you stop using it, you may be worried about worsening symptoms due to rebound Have
なお、特許文献1には、こんにゃく精粉から得られた精製グルコマンナン(食物繊維含量90%以上)を、粉砕処理を施すことによって平均粒子径を100μm以下にしたものが、こんにゃく精粉の場合に比べ著しく高いIgE抗体抑制能を持ち、アレルギー抑制作用があることが開示されている。 In addition, in patent document 1, what refine | purified glucomannan (dietary fiber content 90% or more) obtained from the konjac refined powder, and made the average particle diameter 100 micrometers or less by giving a grinding | pulverization process is the case of konjac refined powder. It has been disclosed that it has a significantly higher IgE antibody-inhibiting ability and has an allergy-inhibiting action.
上述のような従来技術に鑑み、本発明は生体内におけるIgE産生を抑制し、アトピー性皮膚炎、気管支喘息、アレルギー性鼻炎などのアレルギー疾患の発症を予防し、改善できる安全で摂取しやすいアレルギー抑制剤及び食品素材を提供しようとするものである。 In view of the prior art as described above, the present invention suppresses IgE production in the living body, prevents the development of allergic diseases such as atopic dermatitis, bronchial asthma, and allergic rhinitis, and is a safe and easy to take allergy It intends to provide an inhibitor and a food material.
本発明者らは、こんにゃく精粉から得られた精製グルコマンナン(食物繊維含量90%以上)を、粉砕処理を施すことによって平均粒子径を100μm以下にしたものが、こんにゃく精粉の場合に比べ著しく高いIgE抗体抑制能を持ち、アレルギー抑制作用があることを見出している(特開2003−55233)。本発明者等は、その他のIgE抗体抑制剤についても鋭意研究を続け、その後の研究において、微細化処理を施した多糖類の影響を幅広く調査した結果、キトサンおよびキサンタンガムの微細粉末においても類似の抗アレルギー作用ならびに抗炎症作用があることを見出し、本発明を完成するに至った。
本発明は、上記の目的を達成するために下記の構成からなるものである。
The inventors of the present invention have refined glucomannan (dietary fiber content of 90% or more) obtained from konjac refined powder to give an average particle size of 100 μm or less by pulverization, compared with konjac refined powder. It has been found that it has a remarkably high IgE antibody inhibitory activity and has an allergic inhibitory effect (Japanese Patent Laid-Open No. 2003-55233). The inventors of the present invention have continued intensive studies on other IgE antibody inhibitors, and in the subsequent studies, as a result of extensive investigation of the effects of polysaccharides subjected to micronization treatment, similar results were obtained in chitosan and xanthan gum fine powders. It has been found that it has antiallergic action and anti-inflammatory action, and has completed the present invention.
In order to achieve the above object, the present invention comprises the following constitution.
(1)多糖類の微細粉末を含有することを特徴とするアレルギー抑制剤。
(2)前記多糖類の微細粉末が、平均粒子径が50μm以下のキトサンであることを特徴とする前記(1)記載のアレルギー抑制剤。
(3)前記多糖類の微細粉末が、平均粒子径が50μm以下のキサンタンガムであることを特徴とする前記(1)記載のアレルギー抑制剤。
(4)粉末、カプセル製剤、錠剤、または顆粒剤の形態であることを特徴とする前記(1)〜(3)のいずれかに記載のアレルギー抑制剤。
(1) An allergy suppressor comprising a polysaccharide fine powder.
(2) The allergy inhibitor according to (1), wherein the polysaccharide fine powder is chitosan having an average particle size of 50 μm or less.
(3) The allergy inhibitor according to (1), wherein the polysaccharide fine powder is xanthan gum having an average particle size of 50 μm or less.
(4) The allergy suppressor according to any one of (1) to (3) above, which is in the form of powder, capsule preparation, tablet, or granule.
(5)多糖類の微細粉末を含有することを特徴とするアレルギー抑制食品。
(6)前記多糖類の微細粉末が、平均粒子径が50μm以下のキトサンであることを特徴とする前記(5)記載のアレルギー抑制食品。
(7)前記多糖類の微細粉末が、平均粒子径が50μm以下のキトサンであることを特徴とする前記(5)記載のアレルギー抑制食品。
(8)粉末、カプセル製剤、錠剤、または顆粒剤の形態であることを特徴とする前記(5)〜(7)のいずれかに記載のアレルギー抑制食品。
(5) An allergy-suppressing food comprising fine polysaccharide powder.
(6) The allergy-suppressing food according to (5), wherein the polysaccharide fine powder is chitosan having an average particle size of 50 μm or less.
(7) The allergy-suppressing food according to (5), wherein the polysaccharide fine powder is chitosan having an average particle size of 50 μm or less.
(8) The allergy-suppressing food according to any one of (5) to (7), which is in the form of powder, capsule preparation, tablet, or granule.
(9)前記(1)〜(4)のいずれかに記載のアレルギー抑制剤を経口投与することを特徴とするアレルギーの抑制方法。
(10)前記(5)〜(8)のいずれかに記載のアレルギー抑制食品を経口投与することを特徴とするアレルギーの抑制方法。
(9) A method for suppressing allergy comprising orally administering the allergy suppressor according to any one of (1) to (4).
(10) A method for suppressing allergy comprising orally administering the allergy-suppressing food according to any one of (5) to (8).
(11)前記(1)〜(4)のいずれかに記載のアレルギー抑制剤を動物に投与したことを特徴とする免疫抑制動物。
(12)前記(1)〜(4)のいずれかに記載のアレルギー抑制剤を動物に投与することを特徴とする工程を含む免疫抑制動物の作製方法。
(13)前記(5)〜(8)のいずれかに記載のアレルギー抑制食品を動物に投与したことを特徴とする免疫抑制動物。
(14)前記(5)〜(8)のいずれかに記載のアレルギー抑制食品を動物に投与する工程を含むことを特徴とする免疫抑制動物の作製方法。
(11) An immunosuppressed animal, wherein the allergy suppressing agent according to any one of (1) to (4) is administered to the animal.
(12) A method for producing an immunosuppressed animal comprising the step of administering to the animal the allergy suppressing agent according to any one of (1) to (4).
(13) An immunosuppressed animal, wherein the allergy-suppressing food according to any one of (5) to (8) is administered to an animal.
(14) A method for producing an immunosuppressed animal, comprising a step of administering the allergy-suppressing food according to any one of (5) to (8) to an animal.
本発明によれば、多糖類の微細粉末を含有するアレルギー抑制剤を継続的に経口投与することによって、生体内におけるIgE抗体の高産生を抑制し、アレルギー疾患を防止することが可能である。 According to the present invention, by continuously orally administering an allergy inhibitor containing a fine polysaccharide powder, high production of IgE antibodies in vivo can be suppressed and allergic diseases can be prevented.
本発明におけるI型アレルギーの抑制方法は、平均粒子径を50μm以下に加工処理を施したキトサン、またはキサンタンガムの微細粉末を継続的に経口投与することを特徴とするものである。
本発明で使用する多糖類の原料であるキトサンまたはキサンタンガムは、それぞれ食品素材、食品添加物として永年の使用実績もあり、安全性が高く、継続的な服用によって、過剰なIgE抗体の産生を抑制し、アレルギー疾患を防止することができる。
The method for suppressing type I allergy according to the present invention is characterized by continuously orally administering chitosan or xanthan gum fine powder processed to an average particle size of 50 μm or less.
The polysaccharide raw materials used in the present invention, chitosan or xanthan gum, have been used for many years as food materials and food additives, respectively, are highly safe, and suppress excessive IgE antibody production through continuous use. And allergic diseases can be prevented.
本発明は、微細化処理を施した多糖類の粉末の特定の用途に関するものである。本発明で使用する多糖類は、それ自身公知であり、その物理化学的特性などについては、例えば、辻 啓介・森 文平編著「食物繊維の科学 1997年刊」や、國崎直道・佐野征男編著「食品多糖類−乳化・増粘・ゲル化の知識 2001年刊」などに記載されている。 The present invention relates to a specific use of a polysaccharide powder that has been subjected to a refinement treatment. The polysaccharides used in the present invention are known per se, and their physicochemical properties and the like are described, for example, by Keisuke Tsuji and Bunpei Mori “Science of Dietary Fiber 1997” and edited by Naomichi Kunizaki and Sadao Sano. "Food polysaccharides-Knowledge of emulsification, thickening, and gelation, 2001".
本発明で使用する多糖類の微細粉末は、それ自身の粉末、またはカプセル製剤あるいは打錠製剤として具体化されるばかりでなく、それを食品に含有させた形態、すなわちアレルギー抑制食品の形態としても具体化される。また、アレルギー疾患が複雑な免疫系のバランス破綻(過剰なIgE抗体産生)から炎症を生じるものであることからすれば、本発明で使用するアレルギー抑制剤は、免疫調節剤(IgE抗体抑制剤)もしくは抗炎症剤として考えることもできる。 The polysaccharide fine powder used in the present invention is not only embodied as its own powder, capsule formulation or tableting formulation, but also in a form containing it in a food product, that is, as a form of an allergy-suppressing food product. Embodied. In addition, allergic inhibitors used in the present invention are immunomodulators (IgE antibody inhibitors) because allergic diseases cause inflammation due to a complicated balance of the immune system (excess IgE antibody production). Alternatively, it can be considered as an anti-inflammatory agent.
IgE抗体抑制剤の摂取量は、通常、経口にて1〜50g/60kg体重・日で有効である。
過剰なIgE抗体産生によるアレルギー疾患については、本発明によるIgE抗体抑制剤はアレルギー疾患防止剤またはアレルギー疾患予防剤として用いることもできる。
The intake of an IgE antibody inhibitor is usually effective at 1-50 g / 60 kg body weight / day orally.
For allergic diseases caused by excessive IgE antibody production, the IgE antibody inhibitor according to the present invention can also be used as an allergic disease preventing agent or allergic disease preventing agent.
本発明のアレルギー抑制剤は、平均粒子径を50μm以下に加工処理したキトサンまたはキサンタンガムの微細粉末であるが、抑制剤としての機能を損なわない限り補助成分を含んでいてもよい。 The allergy inhibitor of the present invention is a fine powder of chitosan or xanthan gum processed to an average particle size of 50 μm or less, but may contain an auxiliary component as long as the function as an inhibitor is not impaired.
本発明において含有しても良いその他の補助成分としては、人体に無害なものであればあらゆるものが使用できる。また、本発明の抑制剤の形態はあらゆるものが考えられ、例えば、粉末そのもの、ゼラチンカプセルなどによるカプセル製剤、錠剤および顆粒剤としても良く、また通常の食品に混入させても良いことは言うまでもない。 Any other auxiliary component that may be contained in the present invention can be used as long as it is harmless to the human body. Any form of the inhibitor of the present invention is conceivable, for example, powder itself, capsule preparations such as gelatin capsules, tablets and granules, and it goes without saying that they may be mixed in ordinary foods. .
本発明に用いるアレルギー抑制食品を得るには、キトサンまたはキサンタンガムの微細粉末を食品の性状に合せて、例えばビスケット様の食品には、粉末状で配合すればよい。本発明において、それぞれの効果が発現する食品中の最低濃度は、通常、多糖類の微細粉末量として1重量%以上である。 In order to obtain an allergy-suppressing food used in the present invention, a fine powder of chitosan or xanthan gum may be blended in the form of a food, for example, in a biscuit-like food, in a powder form. In this invention, the minimum density | concentration in the foodstuff which each effect expresses is 1 weight% or more normally as the amount of fine powder of a polysaccharide.
以下に実施例を挙げて、本発明を更に詳しく説明する。なお、本発明は下記の実施例に限定されるものではない。
実施例1 アレルギー疾患モデルマウスの病状変化の観察
<実験方法>
供試動物として、自然発症アトピー性皮膚炎モデル動物であるNC/Ngaマウス[Matsuda H、et al;Int.Immunol 9、461(1997)]を用いた。NC/Ngaマウスは、4週齢の雄性を日本SLC株式会社より購入した。基礎飼料は、オリエンタル酵母工業株式会社製の飼育用MF(固形飼料)を用いた。試験飼料は、基礎飼料に5重量%の微細化多糖粉末1〜3をそれぞれ添加した固形飼料を用いた。
Hereinafter, the present invention will be described in more detail with reference to examples. In addition, this invention is not limited to the following Example.
Example 1 Observation of pathological changes in allergic disease model mice <Experimental method>
As test animals, NC / Nga mice [Matsuda H, et al; Int. Immunol 9, 461 (1997)] was used. NC / Nga mice purchased 4-week-old males from Japan SLC Co., Ltd. As the basic feed, breeding MF (solid feed) manufactured by Oriental Yeast Co., Ltd. was used. As the test feed, a solid feed obtained by adding 5% by weight of the refined polysaccharide powders 1 to 3 to the basic feed was used.
それぞれの飼料に添加する微細多糖粉末1〜3は以下のものを用いた。
試験飼料1;こんにゃくグルコマンナン(平均粒子径:17μm)
試験飼料2;キトサン(平均粒子径:10μm)
試験飼料3;キサンタンガム(平均粒子径:46μm)
The following were used for the fine polysaccharide powders 1-3 added to each feed.
Test feed 1; Konjac glucomannan (average particle size: 17 μm)
Test feed 2; chitosan (average particle size: 10 μm)
Test feed 3; xanthan gum (average particle size: 46 μm)
NC/Ngaマウス5匹を1群とし、各供試動物群に基礎飼料、各試験飼料を8週間自由給餌させた。2週間ごとに皮膚病変の状態を目視で観察し、症状をスコア化した。皮膚炎症状は、痒み(掻痒行動)、出血・紅斑、浮腫、擦過傷、乾燥の程度をそれぞれスコア化した。スコアは、0;無症状、1;軽度、2;中程度、3;強度とし、皮膚炎症状は、その合計値で示した。 A group of 5 NC / Nga mice was used, and each test animal group was allowed to freely feed the basic feed and each test feed for 8 weeks. The state of skin lesions was visually observed every two weeks, and the symptoms were scored. Skin inflammation was scored for itching (pruritus behavior), bleeding / erythema, edema, abrasion, and dryness. The score was 0; asymptomatic, 1; mild, 2; moderate, 3; intensity, and skin inflammation was shown as the total value.
また、掻痒行動については、12週齢において各群ごとにビデオ撮影を30分間行い、20分間あたりにマウスが後足で、耳介、背部、腹部、顔面を引っ掻く回数を測定した。 For pruritus behavior, video shooting was performed for 30 minutes for each group at 12 weeks of age, and the number of times the mouse scratched the auricle, back, abdomen, and face with the hind legs was measured every 20 minutes.
<実験結果>
上記実施例1において、マウスの皮膚炎症状をスコア化によって評価した結果を、図1に示す。12週齢における皮膚病変の外観写真を図2に示す。図2において、Aは基礎飼料投与群、Bは試験飼料1投与群、Cは試験飼料2投与群、Dは試験飼料3投与群を示す。また、12週齢において、マウスの掻痒行動に及ぼす影響を評価した結果を図3に示す。
<Experimental result>
FIG. 1 shows the results of scoring the skin inflammation in mice in Example 1 above. An appearance photograph of a skin lesion at 12 weeks of age is shown in FIG. In FIG. 2, A is a basic feed administration group, B is a test feed 1 administration group, C is a test feed 2 administration group, and D is a test feed 3 administration group. Moreover, the result of having evaluated the influence which acts on pruritus behavior of a mouse | mouth at 12 weeks of age is shown in FIG.
上記実施例1において、基礎飼料投与群では、9週齢頃から頭部、頸部および耳介部に脱毛、出血が観られ、皮膚炎スコアは顕著に上昇した(図1参照)。しかしながら、試験飼料2の微粒子キトサン投与群および試験飼料3の微粒子キサンタンガム投与群では、試験飼料1のグルコマンナン群と同様にそれらの病変の著明な緩和が観られ、スコアを有意に抑制した。図3からも明らかなように、12週齢において基礎飼料投与群では、痒みによって誘発される引っ掻き行動が頻繁に観られたが、試験飼料1〜3の微粒子多糖投与群で著しい抑制が観察された。 In Example 1 above, in the basal diet administration group, hair loss and bleeding were observed in the head, neck and auricle from around the age of 9 weeks, and the dermatitis score significantly increased (see FIG. 1). However, in the test feed 2 particulate chitosan-administered group and the test feed 3 particulate xanthan gum administration group, as in the glucomannan group of the test feed 1, significant relaxation of those lesions was observed, and the score was significantly suppressed. As apparent from FIG. 3, scratching behavior induced by itch was frequently observed in the basic feed administration group at 12 weeks of age, but significant suppression was observed in the test polysaccharides 1 to 3 administration group. It was.
実施例2 血清中の抗体量および急性期蛋白量の分析
<実験方法>
実施例1で用いた各供試動物群から、2週間ごとに採血を行い、この血液を1800rpm、10分間、遠心分離し、血清を得た。血清中の総IgE量をサンドイッチELISA法により分析した。また、12週齢における総IgG1量を同様にサンドイッチELISA法によって分析した。さらに、12週齢において、炎症状態で血中濃度に上昇がみられる血清アミロイドA蛋白(SAA)量を、競合的ELISA法によって分析した。
Example 2 Analysis of Serum Antibody Level and Acute Phase Protein Level <Experimental Method>
Blood was collected from each group of test animals used in Example 1 every two weeks, and the blood was centrifuged at 1800 rpm for 10 minutes to obtain serum. The total amount of IgE in the serum was analyzed by sandwich ELISA. Moreover, the total amount of IgG1 at 12 weeks of age was similarly analyzed by sandwich ELISA. Furthermore, the amount of serum amyloid A protein (SAA) at which the blood concentration was increased in the inflammatory state at 12 weeks of age was analyzed by a competitive ELISA method.
<実験結果>
上記実施例2において、2週間ごとにNC/Ngaマウスから採血を行い、血清中の総IgE量を分析した結果を図4に示す。図4からも明らかなように、基礎飼料投与群では12週齢までの間にIgEの顕著な上昇が確認された。本発明による微細化キトサンおよびキサンタンガム粉末を投与した群では、試験飼料1の微粒子グルコマンナン投与群と同様に、著しく高いIgE抗体抑制能が認められた。
<Experimental result>
In Example 2 above, blood was collected from NC / Nga mice every two weeks, and the result of analyzing the total amount of IgE in the serum is shown in FIG. As is clear from FIG. 4, a marked increase in IgE was confirmed in the basal diet administration group up to 12 weeks of age. In the group administered with the finely divided chitosan and xanthan gum powder according to the present invention, a remarkably high IgE antibody suppressing ability was observed as in the group of test feed 1 administered with the fine particle glucomannan.
12週齢において、血清中の総IgG1量について分析した結果を図5に示す。また、SAA量を分析した結果を図6に示す。 FIG. 5 shows the results of analyzing the total IgG1 level in serum at 12 weeks of age. Moreover, the result of having analyzed the amount of SAA is shown in FIG.
基礎飼料投与群と比較して、微細化キトサンおよびキサンタンガム粉末を投与した群では、試験飼料1の微粒子グルコマンナン投与群と同様に、血清中の総IgG1量が減少していることが明らかになった。また、図6に示したように、炎症マーカーであるSAA量が試験飼料1〜3の微粒子多糖投与群で著しく抑制されることが明らかになった。 Compared with the basic feed administration group, in the group administered with fine chitosan and xanthan gum powder, it became clear that the total amount of IgG1 in the serum was decreased, as in the fine feed glucomannan administration group of test feed 1. It was. Moreover, as shown in FIG. 6, it became clear that the amount of SAA which is an inflammatory marker is remarkably suppressed in the group of microparticulate polysaccharides of test feeds 1 to 3.
Claims (14)
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JP2019127472A (en) * | 2018-01-26 | 2019-08-01 | 国立大学法人鳥取大学 | Agents for treating allergic diseases |
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JPH0748278A (en) * | 1992-06-10 | 1995-02-21 | Taiho Yakuhin Kogyo Kk | Powdery pharmaceutical preparation for nasal cavity |
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JPH11346711A (en) * | 1998-06-15 | 1999-12-21 | Kurebusu:Kk | Healthy food |
JP2003055233A (en) * | 2001-08-06 | 2003-02-26 | Nishikawa Rubber Co Ltd | IgE ANTIBODY-SUPPRESSING AGENT AND FOOD |
JP2004002582A (en) * | 2002-06-03 | 2004-01-08 | Miyazaki Prefecture | Fine particle containing natural polysaccharides and method for producing the same |
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JPS58212750A (en) * | 1983-02-22 | 1983-12-10 | San Ei Chem Ind Ltd | Instant solid drink |
JPH0748278A (en) * | 1992-06-10 | 1995-02-21 | Taiho Yakuhin Kogyo Kk | Powdery pharmaceutical preparation for nasal cavity |
JPH11279050A (en) * | 1998-03-28 | 1999-10-12 | Hiroaki Kuroki | Bathing agent |
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