JP7470376B2 - Submandibular gland atrophy inhibitor and wound healing promoter - Google Patents
Submandibular gland atrophy inhibitor and wound healing promoter Download PDFInfo
- Publication number
- JP7470376B2 JP7470376B2 JP2020062088A JP2020062088A JP7470376B2 JP 7470376 B2 JP7470376 B2 JP 7470376B2 JP 2020062088 A JP2020062088 A JP 2020062088A JP 2020062088 A JP2020062088 A JP 2020062088A JP 7470376 B2 JP7470376 B2 JP 7470376B2
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- Prior art keywords
- submandibular gland
- atrophy
- amino acids
- elental
- wound healing
- Prior art date
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Description
本発明は所定のアミノ酸を有効成分として含有する顎下腺の萎縮抑制剤や創傷治癒促進剤に関する。 The present invention relates to an agent for inhibiting atrophy of the submandibular gland and an agent for promoting wound healing that contain a specific amino acid as an active ingredient.
顎下腺は唾液腺の１つであり、唾液の分泌において重要な役目を果たしている。唾液の分泌が低下すると、口腔乾燥症や口腔粘膜炎を引き起こしてしまうため、顎下腺を正常な状態に維持して唾液の分泌を低下させないことが重要である。しかしながら、抗がん剤等の薬物によって顎下腺が萎縮することが知られている。 The submandibular gland is one of the salivary glands and plays an important role in the secretion of saliva. A decrease in saliva secretion can lead to xerostomia and oral mucositis, so it is important to maintain the submandibular gland in a normal state and prevent a decrease in saliva secretion. However, it is known that drugs such as anticancer drugs can cause the submandibular gland to atrophy.
炎症性腸疾患の患者に多用されているエレンタール（Elental:登録商標）は、デキストリン（Dextrin）及びアミノ酸を主成分とした経腸栄養剤である。かかるエレンタールは、胃ろう栄養患者用栄養組成物として提案されている（特許文献１参照）。また、近年食道がんに対する抗がん剤5-フルオロウラシル（5-FU）等の化学療法による口腔粘膜炎を抑制することや顎下腺の萎縮を抑制すること、さらには口腔がんに対する化学放射線療法時の口腔粘膜炎の増悪を阻止することが知られるようになった（非特許文献１参照）。しかしながら、その詳細なメカニズムは不明である。また、上記経腸栄養剤エレンタールの具体的な口腔粘膜炎等に対する効果効能、及びターゲットになる細胞のどの部位に作用しているのかという事についても全く不明であった。 Elental (registered trademark), which is widely used by patients with inflammatory bowel disease, is an enteral nutritional supplement whose main components are dextrin and amino acids. Such Elental has been proposed as a nutritional composition for patients receiving gastrostomy feeding (see Patent Document 1). In recent years, it has become known that Elental suppresses oral mucositis caused by chemotherapy using the anticancer drug 5-fluorouracil (5-FU) for esophageal cancer, suppresses atrophy of the submandibular gland, and prevents the worsening of oral mucositis during chemoradiotherapy for oral cancer (see Non-Patent Document 1). However, the detailed mechanism is unknown. In addition, the specific efficacy and efficacy of the above-mentioned enteral nutritional supplement Elental against oral mucositis, etc., and which part of the target cells it acts on are also completely unknown.
一方、唾液を分泌促進し、口腔乾燥を改善するものとして、たとえばピロカルピンを有効成分とする医薬組成物が開示されている(特許文献２参照)が、発汗、鼻汁等の副作用が生じるとの報告もある。また、D-,DL-メチオニン、D-, DL-アラニン、D-, L-, DL-プロリン、D-, L-, DL-スレオニン、D-, L-, DL-トリプトファン、及びこれらの塩からなる群から選択される１種以上のアミノ酸を有効成分として含有する唾液分泌促進剤が開示されている（特許文献３参照）。 On the other hand, a pharmaceutical composition containing pilocarpine as an active ingredient has been disclosed as a means for promoting saliva secretion and improving dry mouth (see Patent Document 2), but it has been reported that it causes side effects such as sweating and runny nose. In addition, a saliva secretion promoter containing one or more amino acids selected from the group consisting of D-, DL-methionine, D-, DL-alanine, D-, L-, DL-proline, D-, L-, DL-threonine, D-, L-, DL-tryptophan, and salts thereof as an active ingredient has been disclosed (see Patent Document 3).
本発明の課題は、アミノ酸を主成分とする顎下腺の萎縮抑制剤を提供することや、アミノ酸を主成分とする創傷治癒促進剤を提供することにある。 The objective of the present invention is to provide an agent for inhibiting atrophy of the submandibular gland that contains amino acids as its main component, and to provide an agent for promoting wound healing that contains amino acids as its main component.
本発明者は、マウスを用いて抗がん剤の単独投与群をコントロールとして、抗がん剤投与＋エレンタール併用投与群との比較試験を実施し、エレンタールが口腔内の、どの部位に、どの様に作用しているかという検討を試みた。その結果、肉眼的に唾液腺の一つである顎下腺に顕著な萎縮の低下を認めた。さらに、エレンタールに含まれる１７種類のアミノ酸に基づき、細胞増殖に特に影響のあるアミノ酸を見出し、本発明を完成した。 The inventors conducted comparative studies using mice in which a group administered anticancer drugs alone was used as a control, and a group administered both anticancer drugs and Elental, in an attempt to determine how and on which parts of the oral cavity Elental acts. As a result, a significant reduction in atrophy was macroscopically observed in the submandibular gland, which is one of the salivary glands. Furthermore, based on the 17 types of amino acids contained in Elental, they discovered amino acids that have a particular effect on cell proliferation, and completed the present invention.
すなわち、本発明は、以下のとおりである。
〔１〕アスパラギン酸、プロリン、アラニン及びこれらの塩からなる群から選択される２種以上のアミノ酸を有効成分として含有することを特徴とする、顎下腺の萎縮抑制剤。
〔２〕顎下腺の萎縮が抗がん剤による萎縮であることを特徴とする上記〔１〕記載の顎下腺の萎縮抑制剤。
〔３〕炭水化物源の含有量が０～３０質量％であることを特徴とする上記〔１〕又は〔２〕記載の顎下腺の萎縮抑制剤。
〔４〕イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、トレオニン、バリン、ヒスチジン、アルギニン、グルタミン、グリシン、セリン、チロシン及びこれらの塩からなる群から選択される１種又は２種以上のアミノ酸をさらに含有することを特徴とする上記〔１〕～〔３〕のいずれか記載の顎下腺の萎縮抑制剤。
〔５〕抗がん剤と組み合わせてがん患者に投与するための上記〔１〕～〔４〕のいずれか記載の顎下腺の萎縮抑制剤。
〔６〕抗がん剤が5-フルオロウラシルであることを特徴とする上記〔１〕～〔５〕のいずれか記載の顎下腺の萎縮抑制剤。
〔７〕アスパラギン酸、プロリン、アラニンから選択される２種以上のアミノ酸を有効成分として含有することを特徴とする創傷治癒促進剤。
〔８〕炭水化物源の含有量が０～３０質量％であることを特徴とする上記〔７〕記載の創傷治癒促進剤。
That is, the present invention is as follows.
[1] An agent for inhibiting atrophy of the submandibular gland, comprising as active ingredients two or more amino acids selected from the group consisting of aspartic acid, proline, alanine and salts thereof.
[2] The agent for inhibiting atrophy of submandibular gland according to [1] above, wherein the atrophy of submandibular gland is atrophy caused by an anticancer drug.
[3] The agent for inhibiting atrophy of the submandibular gland according to [1] or [2] above, characterized in that the content of the carbohydrate source is 0 to 30% by mass.
[4] The agent for inhibiting atrophy of the submandibular gland according to any one of [1] to [3] above, further comprising one or more amino acids selected from the group consisting of isoleucine, leucine, lysine, methionine, phenylalanine, threonine, valine, histidine, arginine, glutamine, glycine, serine, tyrosine, and salts thereof.
[5] The agent for suppressing atrophy of submandibular gland according to any one of [1] to [4] above, which is administered to a cancer patient in combination with an anticancer agent.
[6] The agent for suppressing atrophy of submandibular gland according to any one of [1] to [5] above, wherein the anticancer drug is 5-fluorouracil.
[7] A wound healing promoter comprising two or more amino acids selected from aspartic acid, proline, and alanine as active ingredients.
[8] The wound healing promoter according to [7] above, characterized in that the content of the carbohydrate source is 0 to 30 mass%.
本発明により、抗がん剤による顎下腺の萎縮の抑制や、創傷治癒促進が可能となる。 This invention makes it possible to inhibit atrophy of the submandibular gland caused by anticancer drugs and promote wound healing.
本発明の顎下腺の萎縮抑制剤は、アスパラギン酸、プロリン、アラニンから選択される２種以上のアミノ酸を有効成分として含有する顎下腺の萎縮抑制剤（以下、「本件顎下腺の萎縮抑制剤」ともいう）であればよく、ここで「顎下腺」とは頸部にある大唾液腺のうちの１つで下顎腺とも呼ばれ、顎二腹筋の２つの筋腹と下顎角により囲まれた空間内にあり、唾液の約65％を産生する組織である。 The submandibular gland atrophy inhibitor of the present invention may be an inhibitor of submandibular gland atrophy (hereinafter also referred to as the "submandibular gland atrophy inhibitor") that contains two or more amino acids selected from aspartic acid, proline, and alanine as active ingredients. Here, the "submandibular gland" is one of the major salivary glands in the neck, also known as the submandibular gland, and is a tissue that is located in the space surrounded by the two muscle bellies of the digastric muscle and the angle of the mandible, and produces approximately 65% of saliva.
本明細書において「顎下腺の萎縮」とは、上記顎下腺を構成する粘液細胞や漿液細胞の増殖が抑制され、顎下腺の体積が減少することを意味する。かかる顎下腺の萎縮は、抗がん剤、抗不安薬、降圧薬等の薬剤による副作用や、糖尿病、腎障害、貧血、脱水、シェーングレン症候群、サルコイドーシス、後天性免疫不全症候群等の全身性疾患や、ストレス、鬱等によって引き起こされる。顎下腺が萎縮すると、唾液の分泌が低下し、口腔乾燥症や口内炎の原因となるため、かかる疾患の予防や治療には顎下腺を正常な状態に維持することが肝要である。 In this specification, "atrophy of the submandibular gland" means that the proliferation of mucous cells and serous cells that compose the submandibular gland is inhibited, and the volume of the submandibular gland is reduced. Such atrophy of the submandibular gland is caused by side effects of drugs such as anticancer drugs, antianxiety drugs, and antihypertensive drugs, as well as systemic diseases such as diabetes, renal disorders, anemia, dehydration, Sjögren's syndrome, sarcoidosis, and acquired immune deficiency syndrome, as well as stress and depression. When the submandibular gland atrophies, saliva secretion decreases, which can cause xerostomia and stomatitis, so maintaining the submandibular gland in a normal state is essential for preventing and treating such diseases.
上記「抗がん剤」におけるがんとしては、固形がんでも血液がんでもよく、口腔がん、胃がん、食道がん、脾臓がん、咽頭がん、喉頭がん、上顎がん、皮膚がん、乳がん、前立腺がん、膀胱がん、膣がん、頸部がん、子宮がん、肝臓がん、腎臓がん、膵臓がん、肺がん、気管がん、気管支がん、結腸がん、小腸がん、胆嚢がん、精巣がん、卵巣がん等のがんや、骨組織、軟骨組織、脂肪組織、筋組織、血管組織及び造血組織のがんのほか、軟骨肉腫、ユーイング肉腫、悪性血管内皮腫、悪性シュワン腫、骨肉腫、軟部組織肉腫等の肉腫や、肝芽腫、髄芽腫、腎芽腫、神経芽腫、膵芽腫、胸膜肺芽腫、網膜芽腫等の芽腫や、胚細胞腫瘍や、リンパ腫や、白血病を挙げることができる。 The cancers in the above-mentioned "anticancer agents" may be solid cancers or blood cancers, and examples of such cancers include oral cancer, stomach cancer, esophageal cancer, spleen cancer, pharyngeal cancer, laryngeal cancer, maxillary cancer, skin cancer, breast cancer, prostate cancer, bladder cancer, vaginal cancer, cervical cancer, uterine cancer, liver cancer, kidney cancer, pancreatic cancer, lung cancer, tracheal cancer, bronchial cancer, colon cancer, small intestine cancer, gallbladder cancer, testicular cancer, and ovarian cancer, as well as cancers of bone tissue, cartilage tissue, adipose tissue, muscle tissue, vascular tissue, and hematopoietic tissue, as well as sarcomas such as chondrosarcoma, Ewing's sarcoma, malignant hemangioendothelioma, malignant schwannoma, osteosarcoma, and soft tissue sarcoma, blastomas such as hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatic blastoma, pleuropulmonary blastoma, and retinoblastoma, germ cell tumors, lymphomas, and leukemias.
上記「抗がん剤」としては顎下腺の萎縮を引き起こす抗がん剤である限り特に制限されないが、５－フルオロウラシル、ペントスタチン、フルダラビン、クラドリビン、メソトレキセート、６－メルカプトプリン、エノシタビン等の代謝拮抗薬、シクロホスファミド、ベンダムスチン、イオスファミド、ダカルバジン等のアルキル化薬、リツキシマブ、セツキシマブ、トラスツズマブ等の分子標的薬、イマチニブ、ゲフェチニブ、エルロチニブ、アファチニブ、ダサチニブ、スニチニブ、トラメチニブ等のキナーゼ阻害剤、ボルテゾミブ等のプロテアソーム阻害剤、シクロスポリン、タクロリムス等のカルシニューリン阻害薬、イダルビジン、ドキソルビシンマイトマイシンＣ等の抗がん性抗生物質、イリノテカン、エトポシド等の植物アルカロイド、シスプラチン、オキサリプラチン、カルボプラチン等のプラチナ製剤、タモキシフェン、ビカルダミド等のホルモン療法薬、インターフェロン、ニボルマブ、ペンブロリズマブ等の免疫制御薬を挙げることができる。 The above-mentioned "anticancer drug" is not particularly limited as long as it is an anticancer drug that causes atrophy of the submandibular gland, and examples thereof include metabolic antagonists such as 5-fluorouracil, pentostatin, fludarabine, cladribine, methotrexate, 6-mercaptopurine, and enocitabine, alkylating agents such as cyclophosphamide, bendamustine, iosphamide, and dacarbazine, molecular targeted drugs such as rituximab, cetuximab, and trastuzumab, imatinib, gefetinib, erlotinib, afatinib, dasatinib, and sunitinib. , kinase inhibitors such as trametinib, proteasome inhibitors such as bortezomib, calcineurin inhibitors such as cyclosporine and tacrolimus, anticancer antibiotics such as idarubicin, doxorubicin, and mitomycin C, plant alkaloids such as irinotecan and etoposide, platinum preparations such as cisplatin, oxaliplatin, and carboplatin, hormone therapy drugs such as tamoxifen and bicaldamide, and immunosuppressants such as interferon, nivolumab, and pembrolizumab.
上記本件顎下腺の萎縮抑制剤は、抗がん剤と組み合わせてがん患者に投与するために用いてもよい。かかる組み合わせて投与する抗がん剤としては、上記顎下腺の萎縮を引き起こす抗がん剤を挙げることができる。なお、「抗がん剤と組み合わせてがん患者に投与する」とは、抗がん剤をがん患者に投与して、その後本件顎下腺の萎縮抑制剤を投与する方法や、本件顎下腺の萎縮抑制剤をがん患者に投与して、その後抗がん剤を投与する方法や、本件顎下腺の萎縮抑制剤と抗がん剤を同時にがん患者に投与する方法を挙げることができる。 The above-mentioned submandibular gland atrophy inhibitor may be used for administration to a cancer patient in combination with an anticancer drug. An example of such an anticancer drug to be administered in combination is an anticancer drug that causes atrophy of the submandibular gland. "Administered to a cancer patient in combination with an anticancer drug" may include a method of administering an anticancer drug to a cancer patient and then administering the submandibular gland atrophy inhibitor, a method of administering the submandibular gland atrophy inhibitor to a cancer patient and then administering an anticancer drug, or a method of administering the submandibular gland atrophy inhibitor and an anticancer drug simultaneously to a cancer patient.
本発明の創傷治癒促進剤は、アスパラギン酸、プロリン、アラニンから選択される２種以上のアミノ酸を有効成分として含有する創傷治癒促進剤（以下、「本件創傷治癒促進剤」ともいう）であればよく、ここで創傷としては、体組織において生じる損傷であり、擦過傷、剥離、切開、裂創、刺創等を挙げることができる。 The wound healing promoter of the present invention may be any wound healing promoter (hereinafter, also referred to as the "wound healing promoter") that contains two or more amino acids selected from aspartic acid, proline, and alanine as active ingredients, and the wound here refers to damage that occurs in body tissue, such as an abrasion, avulsion, incision, laceration, puncture wound, etc.
本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤に有効成分として含有するアミノ酸としては、アスパラギン酸、プロリン、アラニンから選択される２種以上を含有していればよく、アスパラギン酸とプロリンの組み合わせ、アスパラギン酸とアラニンの組み合わせ、プロリンとアラニンの組み合わせ、及びアスパラギン酸とプロリンとアラニンの組み合わせのいずれでもよい。また、イソロイシン、ロイシン、リシン、メチオニン、フェニルアラニン、トレオニン、トリプトファン、バリン、ヒスチジン、アルギニン、グルタミン、グリシン、セリン、チロシンから選択される１種又は２種以上のアミノ酸、好ましくは５種以上、より好ましくは１０種以上、更に好ましくは１４種をさらに含有していてもよい。 The amino acids contained as active ingredients in the present submandibular gland atrophy inhibitor or the present wound healing promoter may contain two or more types selected from aspartic acid, proline, and alanine, and may be any combination of aspartic acid and proline, aspartic acid and alanine, proline and alanine, or aspartic acid, proline and alanine. The present invention may further contain one or more types of amino acids selected from isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, histidine, arginine, glutamine, glycine, serine, and tyrosine, preferably five or more types, more preferably ten or more types, and even more preferably fourteen types.
アスパラギン酸とアラニンを含有する場合には、好ましくはアスパラギン酸１００質量部に対してアラニン１０～１００質量部、より好ましくはアスパラギン酸１００質量部に対してアラニン３０～７０質量部を挙げることができる。アスパラギン酸とプロリンを含有する場合には、好ましくはアスパラギン酸１００質量部に対してプロリン１０～８０質量部、より好ましくはアスパラギン酸１００質量部に対してプロリン２０～５０質量部を挙げることができる。アラニンとプロリンを含有する場合には、好ましくはアラニン１００質量部に対してプロリン１０～１００質量部、より好ましくはアラニン１００質量部に対してプロリン３０～７０質量部を挙げることができる。 When aspartic acid and alanine are contained, preferably, 10 to 100 parts by mass of alanine per 100 parts by mass of aspartic acid, more preferably, 30 to 70 parts by mass of alanine per 100 parts by mass of aspartic acid. When aspartic acid and proline are contained, preferably, 10 to 80 parts by mass of proline per 100 parts by mass of aspartic acid, more preferably, 20 to 50 parts by mass of proline per 100 parts by mass of aspartic acid. When alanine and proline are contained, preferably, 10 to 100 parts by mass of proline per 100 parts by mass of alanine, more preferably, 30 to 70 parts by mass of proline per 100 parts by mass of alanine.
上記アミノ酸は、Ｄ体、Ｌ体のいずれでもよく、Ｄ体、Ｌ体の混合物でもよいが、Ｌ体であることが好ましい。 The above amino acids may be in the D- or L-form, or may be a mixture of the D- and L-forms, but are preferably in the L-form.
上記アミノ酸としては、その塩でもよく、かかる塩としては、薬理学的に許容されるものであれば特に制限されない。アミノ酸におけるカルボキシル基等の酸性基に対しては、ナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アンモニウム、テトラメチルアンモニウム等のアンモニウム塩が挙げられる。また、アミノ酸における塩基性基に対しては、塩酸、硫酸、リン酸、硝酸、臭化水素酸等の無機酸との塩、酢酸、クエン酸、安息香酸、マレイン酸、フマル酸、酒石酸、コハク酸、リンゴ酸等の有機カルボン酸との塩が挙げられる。 The above amino acids may be salts thereof, and such salts are not particularly limited as long as they are pharmacologically acceptable. For acidic groups such as carboxyl groups in amino acids, salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and ammonium salts such as ammonium and tetramethylammonium are listed. For basic groups in amino acids, salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, and hydrobromic acid, and salts with organic carboxylic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, and malic acid are listed.
本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤に有効成分として含有するアミノ酸としては、顎下腺の萎縮抑制効果若しくは創傷の治癒促進効果が得られる限り特に制限されないが、アミノ酸すべての含有量が３０質量％以上であっても、５０質量％以上であっても、６０質量％以上であっても、７０質量％以上であっても、８０質量％以上であっても、９０質量％以上であってもよい。さらに、本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤に含有するアミノ酸の中で、アスパラギン酸、プロリン、アラニン及びこれらの塩からなる群から選択される２種以上のアミノ酸の割合は特に制限されないが、本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤の全質量に対して１０質量％以上であっても、１７質量％以上であっても、１９質量％であっても、２５質量％以上であっても、５０質量％以上であっても、７０質量％以上であっても、９０質量％以上であっても、１００質量％であってもよい。なお、本件顎下腺の萎縮抑制剤に有効成分として含有するとは、顎下腺の萎縮抑制作用を有する成分として含有することを意味し、本件創傷治癒促進剤に有効成分として含有するとは、創傷治癒促進作用を有する成分として含有することを意味する。 The amino acids contained as active ingredients in the present submandibular gland atrophy inhibitor or the present wound healing promoter are not particularly limited as long as the effect of inhibiting atrophy of the submandibular gland or the effect of promoting wound healing can be obtained, but the content of all amino acids may be 30% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, or 90% by mass or more. Furthermore, the proportion of two or more amino acids selected from the group consisting of aspartic acid, proline, alanine, and salts thereof among the amino acids contained in the present submandibular gland atrophy inhibitor or the present wound healing promoter is not particularly limited, but may be 10% by mass or more, 17% by mass or more, 19% by mass or more, 25% by mass or more, 50% by mass or more, 70% by mass or more, 90% by mass or more, or 100% by mass relative to the total mass of the present submandibular gland atrophy inhibitor or the present wound healing promoter. In addition, containing it as an active ingredient in the present agent for inhibiting atrophy of the submandibular gland means containing it as an ingredient that has the effect of inhibiting atrophy of the submandibular gland, and containing it as an active ingredient in the present agent for promoting wound healing means containing it as an ingredient that has the effect of promoting wound healing.
また本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤の投与量は、たとえば有効成分として成人（体重６０ｋｇ）に対して１回あたり０．０２～２０gを挙げることができる。 The dosage of the present agent for inhibiting atrophy of the submandibular gland or the present agent for promoting wound healing can be, for example, 0.02 to 20 g of the active ingredient per dose for an adult (body weight 60 kg).
本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤にはデキストリン、デンプン、オリゴ糖、ブドウ糖、果糖、マンノース、ショ糖等の炭水化物源を含有してもよい。かかる炭水化物源の含有量としては、０～３０質量％、好ましくは０～１０質量％、より好ましくは０～５質量％、さらに好ましくは０～２質量％、特に好ましくは０～１質量％、中でも０質量％を挙げることができる。このほか、本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤には、ダイズ油、シソ油、トウモロコシ油等の脂質を含有してもよい。かかる脂質の含有量としては、好ましくは０～０．３質量％、より好ましくは０～０．１質量％、さらに好ましくは０質量％を挙げることができる。さらに、本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤には、さらにビタミン、ミネラル等の通常用いられる添加剤を含有してもよい。かかるビタミンとしては、ビタミンＡ、ビタミンＢ群、ビタミンＣ、ビタミンＤ、ビタミンＥ、ニコチン酸アミド、葉酸、パントテン酸、ビオチン、コリン等を挙げることができる。また、ミネラルとしては、塩化ナトリウム、塩化カリウム、グリセロリン酸カルシウム、硫酸マグネシウム、硫酸マンガン、硫酸亜鉛、硫酸鉄、硫酸銅等を挙げることができる。さらに必要に応じて、香料、甘味料、着色料、安定剤、保存剤、ｐＨ調整剤等を含有してもよい。 The atrophy inhibitor of the submandibular gland or the wound healing promoter of the present invention may contain a carbohydrate source such as dextrin, starch, oligosaccharide, glucose, fructose, mannose, or sucrose. The content of such carbohydrate source may be 0 to 30% by mass, preferably 0 to 10% by mass, more preferably 0 to 5% by mass, even more preferably 0 to 2% by mass, particularly preferably 0 to 1% by mass, and of these, 0% by mass. In addition, the atrophy inhibitor of the submandibular gland or the wound healing promoter of the present invention may contain lipids such as soybean oil, perilla oil, or corn oil. The content of such lipids may be preferably 0 to 0.3% by mass, more preferably 0 to 0.1% by mass, and even more preferably 0% by mass. Furthermore, the atrophy inhibitor of the submandibular gland or the wound healing promoter of the present invention may further contain commonly used additives such as vitamins and minerals. Examples of such vitamins include vitamin A, vitamin B group, vitamin C, vitamin D, vitamin E, nicotinamide, folic acid, pantothenic acid, biotin, choline, etc. Examples of minerals include sodium chloride, potassium chloride, calcium glycerophosphate, magnesium sulfate, manganese sulfate, zinc sulfate, ferrous sulfate, copper sulfate, etc. Furthermore, flavorings, sweeteners, coloring agents, stabilizers, preservatives, pH adjusters, etc. may be contained as necessary.
本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤は、薬学的に許容される通常の担体、結合剤、安定化剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、可溶化剤、溶解補助剤、等張剤等の各種調剤用配合成分を添加することができる。本件顎下腺の萎縮抑制剤又は本件創傷治癒促進剤は、経口的又は非経口的に投与することができ、例えば、粉末、顆粒、錠剤、カプセル剤、シロップ剤、懸濁液等の剤型で経口的に投与することができ、あるいは、例えば、軟膏剤、徐放型製剤、乳剤、懸濁液等の剤型にしたものを非経口投与することができる。 The present agent for inhibiting atrophy of the submandibular gland or the present agent for promoting wound healing may contain various compounding ingredients for preparation, such as pharma- ceutically acceptable ordinary carriers, binders, stabilizers, excipients, diluents, pH buffers, disintegrants, solubilizers, dissolution aids, and isotonic agents. The present agent for inhibiting atrophy of the submandibular gland or the present agent for promoting wound healing may be administered orally or parenterally, and may be administered orally in the form of, for example, powder, granules, tablets, capsules, syrup, suspension, or the like, or may be administered parenterally in the form of, for example, ointment, sustained-release preparation, emulsion, suspension, or the like.
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの
例示に限定されるものではない。
The present invention will be described in more detail below with reference to examples, but the technical scope of the present invention is not limited to these examples.
［実施例１］エレンタールに含有するアミノ酸による細胞増殖
エレンタールには、デキストリン、アミノ酸を主に含有している。そこで、エレンタールによる細胞増殖におけるアミノ酸の影響を検証した。なおエレンタールの組成を表１に示す。
Example 1: Cell proliferation by amino acids contained in Elental Elental mainly contains dextrin and amino acids. Therefore, the effect of amino acids on cell proliferation by Elental was examined. The composition of Elental is shown in Table 1.
（１)細胞増殖能
細胞の増殖は、3-(3,4-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (以下「MTT」と略記；Sigma Aldrich社)法を用いて測定した。すなわち、96ウェルマイクロプレート(Becton Dickinson社)にDulbecco's Modified Eagle Medium（DMEM）とHamF12を等量混合した培地（DMEM/HamF12: Thermo Fisher Scientific社）と共にエレンタール、デキストリンのみ、エレンタールに含有するアミノ酸１７種のみ（上記表１に示すエレンタールに含有する１７種のアミノ酸の配合比と同一となるように調整：EAファーマ社より入手）を所定の濃度となるように加え、かかる培地に3×103個の細胞を播種し、以降24(day1)、48(day2)、72(day3)時間培養した。次に、最終濃度が1 mg/mlとなるように MTT溶液を加え37℃、4時間反応させてMTT formazanを形成した。形成されたMTT formazanを100μlのジメチルスルホキシド(Dimethyl Sulfoxide; 以下「DMSO」と略記 ; Sigma Aldrich社)で溶解し、マイクロプレートリーダー(Bio-Rad Laboratories社)を用いて、OD 490 nmにて吸光度を測定することにより生細胞数（細胞増殖）を評価した。なお、細胞としては、不死化皮膚角化細胞であるHaCaT細胞、及び口腔がん細胞（HSC2細胞,HSC4細胞）を用いた。
(1) Cell proliferation The proliferation of cells was measured using the 3-(3,4-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (hereinafter abbreviated as "MTT"; Sigma Aldrich) method. That is, in a 96-well microplate (Becton Dickinson), a medium in which equal amounts of Dulbecco's Modified Eagle Medium (DMEM) and HamF12 were mixed (DMEM/HamF12: Thermo Fisher Scientific) was added together with Elental, dextrin only, and the 17 amino acids contained in Elental (adjusted to be the same as the composition ratio of the 17 amino acids contained in Elental shown in Table 1 above: obtained from EA Pharma) to a predetermined concentration, and 3 x 103 cells were seeded in the medium and cultured for 24 (day 1), 48 (day 2), and 72 (day 3) hours. Next, MTT solution was added to a final concentration of 1 mg/ml and reacted at 37°C for 4 hours to form MTT formazan. The formed MTT formazan was dissolved in 100 μl of dimethyl sulfoxide (hereinafter abbreviated as "DMSO"; Sigma Aldrich), and the number of live cells (cell proliferation) was evaluated by measuring the absorbance at OD 490 nm using a microplate reader (Bio-Rad Laboratories). The cells used were immortalized skin keratinocytes, HaCaT cells, and oral cancer cells (HSC2 cells, HSC4 cells).
（２）結果
HaCaT細胞における細胞増殖の結果を図１に、HSC2細胞における細胞増殖の結果を図２に、HSC4細胞における細胞増殖の結果を図３に示す。横軸は培地中のエレンタール、デキストリン、又はアミノ酸の終濃度を示し、縦軸は490nmの吸光度を示す。いずれの細胞においても、エレンタールを加えることによって細胞がより増殖することが確認された。また、いずれの細胞においてもデキストリンのみを加えた場合には、エレンタールを加えた場合と比較して細胞増殖が低かった。
(2) Results
The results of cell proliferation in HaCaT cells are shown in Figure 1, the results of cell proliferation in HSC2 cells in Figure 2, and the results of cell proliferation in HSC4 cells in Figure 3. The horizontal axis indicates the final concentration of Elental, dextrin, or amino acids in the medium, and the vertical axis indicates the absorbance at 490 nm. It was confirmed that the addition of Elental increased cell proliferation in all cells. Furthermore, when only dextrin was added in all cells, cell proliferation was lower than when Elental was added.
エレンタールに含有するアミノ酸１７種のみを加えた場合には、いずれの細胞においてもエレンタールを加えたときと同様に細胞が増殖していた。驚くべきことに、HaCaT細胞及びHSC2細胞においてはエレンタールに含有するアミノ酸１７種のみを8.8μg/mL以上加えた場合においてエレンタールを加えた場合以上に細胞が増殖していた。したがって、エレンタールによる細胞増殖はデキストリン、若しくは脂質電解質、ビタミンによる効果ではなくアミノ酸による効果であることが明らかとなった。 When only the 17 amino acids contained in Elental were added, the cells proliferated in both cases in the same way as when Elental was added. Surprisingly, in HaCaT cells and HSC2 cells, when only the 17 amino acids contained in Elental were added at 8.8 μg/mL or more, the cells proliferated more than when Elental was added. Therefore, it was revealed that the cell proliferation caused by Elental is due to the effect of amino acids, not dextrin, lipid electrolytes, or vitamins.
［実施例２］抗がん剤処理後のエレンタールによる細胞増殖能
エレンタールは、抗がん剤で処理した際の口腔粘膜炎の抑制に用いられている。そこで、抗がん剤処理後のエレンタールの細胞増殖能を調べた。
Example 2: Cell proliferation ability of Elental after anticancer drug treatment Elental is used to suppress oral mucositis caused by anticancer drug treatment. Therefore, the cell proliferation ability of Elental after anticancer drug treatment was investigated.
DMEM/HamF12培地に以下の(a)～(f)を加えた6つの区に分けて、3×103個の細胞を播種して細胞増殖を検証した。培養時間は(a)～(d)は48時間、(e)、(f)は抗がん剤である5-フルオロウラシル（5-FU）で24時間処理後にエレンタール又はデキストリンで24時間処理した。次に、実施例１と同様にMMT溶液を加えて生細胞数を評価した。
（ａ）0%FBS＋エレンタール５μg（48h）
（ｂ）0%FBS＋デキストリン4μg（48h）
（ｃ）10%FBS＋エレンタール5μg（48h）
（ｄ）10%FBS＋デキストリン4μg（48h）
（ｅ）10%FBS＋1.5μg/mL 5-FU（24h）→10%FBS＋エレンタール5μg（24h）
（ｆ）10%FBS＋1.5μg/mL 5-FU（24h）→10%FBS＋デキストリン5μg（24h）
DMEM/HamF12 medium was added to the following (a) to (f) and divided into six sections, and 3 x 103 cells were seeded to examine cell proliferation. The culture time was 48 hours for (a) to (d), and for (e) and (f), the cells were treated with the anticancer drug 5-fluorouracil (5-FU) for 24 hours, followed by treatment with Elental or dextrin for 24 hours. Next, MMT solution was added as in Example 1, and the number of viable cells was evaluated.
(a) 0% FBS + Elental 5 μg (48 h)
(b) 0% FBS + dextrin 4 μg (48 h)
(c) 10% FBS + Elenthal 5 μg (48 h)
(d) 10% FBS + dextrin 4 μg (48 h)
(e) 10% FBS + 1.5 μg/mL 5-FU (24 h) → 10% FBS + Elental 5 μg (24 h)
(f) 10% FBS + 1.5 μg/mL 5-FU (24 h) → 10% FBS + dextrin 5 μg (24 h)
図４に示すように、まず抗がん剤の処理がない場合においては、デキストリンと比較してエレンタールはより細胞増殖能を有していた。ただし、FBSを含有している場合におけるデキストリンとエレンタールとの差は、FBSを含有していない場合と比較して小さかった。つまり、エレンタールによる細胞増殖は栄養が存在している状況では、栄養が少ない場合よりも効果が低いと考えられた。一方、抗がん剤5-FUで処理した場合には、FBSを含有している場合でもデキストリンと比較してエレンタールにより細胞増殖がみられた。したがって、抗がん剤によって細胞にダメージがあるときには、栄養が存在している状況でもエレンタールは細胞増殖能が高いことが確認された。なお、エレンタールに含まれる組成物の約７９％はデキストリンであり、約１８％がアミノ酸であることや、デキストリンと比較してエレンタールはより細胞増殖能がみられたことから、図４におけるデキストリンとエレンタールによる効果の差はエレンタールに含有する１７種類のアミノ酸による効果であると推定される。 As shown in Figure 4, first, in the absence of anticancer drug treatment, Elental had a higher cell proliferation ability than dextrin. However, the difference between dextrin and Elental in the presence of FBS was smaller than in the absence of FBS. In other words, it was thought that cell proliferation caused by Elental was less effective in the presence of nutrients than in the absence of nutrients. On the other hand, in the treatment with the anticancer drug 5-FU, cell proliferation was observed with Elental compared to dextrin even in the presence of FBS. Therefore, it was confirmed that Elental has a higher cell proliferation ability even in the presence of nutrients when cells are damaged by anticancer drugs. Note that about 79% of the composition contained in Elental is dextrin and about 18% is amino acids, and Elental showed a higher cell proliferation ability than dextrin, so it is presumed that the difference in effect between dextrin and Elental in Figure 4 is due to the effect of the 17 types of amino acids contained in Elental.
［実施例３］エレンタールによる細胞浸潤能
創傷の治癒には細胞浸潤能が高いことが重要であるため、エレンタールによる細胞浸潤能を以下の方法により調べた。
Example 3 Cell Infiltration Ability Induced by Elental Since high cell infiltration ability is important for wound healing, the cell infiltration ability induced by Elental was examined by the following method.
細胞の浸潤転移能に対する評価方法の一つとしてMigration assayを用いて検索した。測定には48well Chemotaxis Chamber（Neuro Probe社）を用いた。48well Chemotaxis Chamberは、精密に加工された上下2枚の透明なアクリル板の間に25×80mmのフィルターメンブレンをセットし、上下の板を密着させるためのシリコンガスケットをフィルターの上に置きネジ止めができる構造となっており、底板（Bottom plate）には面積8mm2、容量25μlの丸底のlower wellが48個あり、上板（Top plate）のupper wellと合致するようになった細胞遊走試験装置である。エレンタール、デキストリンのみ、又はエレンタールに含有するアミノ酸１７種のみ（エレンタールに含有する１７種のアミノ酸の配合比と同一）を所定の濃度となるように添加した増殖培養液をBottom plateのLower wellに満たし、5mM Gelatin（Calbiochem-Novabiochem社）にて被覆したポアサイズ５μmのフィルター（Neuro Probe社）をセットしてTop plateを閉じ、6×105cell/mlの細胞浮遊液をUpper wellに充填、37℃で24時間静置した。その後、フィルターをChamberから取り出し、リン酸緩衝生食水（PBS）で非付着細胞を洗浄した後、フィルター付着細胞をメタノールにて固定し、ヘマトキシリンを用いて染色、Upper well sideの細胞を濾紙にて擦過除去したのち、フィルターをスライドガラス上にマウントし検鏡にて細胞数をカウントした。なお、細胞としては、HaCaT細胞、HSC2細胞及びHSC4細胞を用いた。 A migration assay was used to evaluate the invasive and metastatic potential of cells. A 48-well Chemotaxis Chamber (Neuro Probe) was used for the measurements. The 48-well Chemotaxis Chamber is a cell migration test device in which a 25 x 80 mm filter membrane is set between two precisely machined transparent acrylic plates, one above the other, and a silicon gasket is placed on top of the filter to tightly seal the two plates together, and then screwed into place. The bottom plate has 48 round-bottom lower wells with an area of 8 mm2 and a capacity of 25 μl, which match the upper wells of the top plate. The lower well of the bottom plate was filled with a growth culture medium containing only Elental, dextrin, or only 17 kinds of amino acids contained in Elental (same ratio as the 17 kinds of amino acids contained in Elental) at a predetermined concentration, a filter with a pore size of 5 μm (Neuro Probe) coated with 5 mM gelatin (Calbiochem-Novabiochem) was set, the top plate was closed, and a cell suspension of 6 × 10 5 cells/ml was filled into the upper well and left to stand at 37 ° C for 24 hours. Thereafter, the filter was removed from the chamber, non-adherent cells were washed with phosphate buffered saline (PBS), the cells attached to the filter were fixed with methanol and stained with hematoxylin, the cells on the upper well side were removed by rubbing with filter paper, and the filter was mounted on a slide glass and the number of cells was counted under a microscope. HaCaT cells, HSC2 cells, and HSC4 cells were used as cells.
図５に示すようにデキストリンのみでは浸潤効果がほとんどみられなかったが、エレンタールやアミノ酸のみでは浸潤効果がみられた。したがって、エレンタールに含有するアミノ酸に細胞浸潤能力を向上する作用があることが明らかとなった。細胞浸潤能力は創傷治癒につながることから、エレンタールに含有するアミノ酸は創傷治癒作用も有すると考えられる。 As shown in Figure 5, almost no infiltration effect was observed with dextrin alone, but an infiltration effect was observed with Elental or amino acids alone. This demonstrates that the amino acids contained in Elental have the effect of improving cell infiltration ability. Since cell infiltration ability is linked to wound healing, it is believed that the amino acids contained in Elental also have a wound healing effect.
［実施例４］細胞増殖能を有するアミノ酸の分析
実施例１～３ではエレンタールに含有する１７種類からなるアミノ酸を用いたが、どのアミノ酸により細胞増殖作用を生じるかを以下の方法で分析した。
Example 4 Analysis of Amino Acids Having Cell Proliferation Potential In Examples 1 to 3, 17 types of amino acids contained in Elental were used, and the amino acids that produce cell proliferation activity were analyzed using the following method.
アミノ酸としては、L-アスパラギン酸、L-アラニン、L-プロリンを選択し、それぞれ単独、及び２若しくは３つの組み合わせによるHaCaT細胞、HSC2細胞又はHSC4細胞の細胞増殖を実施例１と同様に調べた。 L-aspartic acid, L-alanine, and L-proline were selected as amino acids, and the cell proliferation of HaCaT cells, HSC2 cells, and HSC4 cells was examined in the same manner as in Example 1 when each was used alone and in combination of two or three of them.
図６にHaCaT細胞の結果を、図７にHSC2細胞の結果を、図８にHSC4細胞の結果を示す。図中、AspはL-アスパラギン酸、AlaはL-アラニン、ProはL-プロリン、17AAはエレンタールに含有する１７種類からなるアミノ酸を示す。驚くべきことに、L-アスパラギン酸、L-アラニン、L-プロリンの単独でもエレンタールに含有する１７種類からなるアミノ酸と同等の細胞増殖効果があった。また、L-アスパラギン酸、L-アラニン、L-プロリンから選択される２つの組み合わせ、特にプロリンとアスパラギン酸の組み合わせや、L-アスパラギン酸、L-アラニン、L-プロリンの３つの組み合わせではエレンタールに含有する１７種類からなるアミノ酸を用いた場合よりも細胞増殖作用を有すること、デキストリンやエレンタールに含有する脂質、電解質がなくても細胞増殖作用を有することが明らかとなった。 Figure 6 shows the results for HaCaT cells, Figure 7 shows the results for HSC2 cells, and Figure 8 shows the results for HSC4 cells. In the figures, Asp, Ala, Pro, and 17AA represent the 17 amino acids contained in Elental. Surprisingly, L-aspartic acid, L-alanine, and L-proline alone had the same cell proliferation effect as the 17 amino acids contained in Elental. It was also revealed that two combinations selected from L-aspartic acid, L-alanine, and L-proline, especially the combination of proline and aspartic acid, and the three combinations of L-aspartic acid, L-alanine, and L-proline, had a greater cell proliferation effect than the 17 amino acids contained in Elental, and that they had a cell proliferation effect even without dextrin or the lipids and electrolytes contained in Elental.
［実施例５］エレンタール又はアミノ酸による顎下腺の萎縮抑制
実施例１～４では細胞を対象として行ったが、マウスを用いてさらに解析を進めた。
Example 5 Inhibition of Submandibular Gland Atrophy by Elental or Amino Acids Although the studies in Examples 1 to 4 were carried out using cells, further analysis was carried out using mice.
ICRマウス（10週齢）雌、12匹を購入し、環境に慣れさせるため、1週間飼育した。その後下記の4群にグループ分けを行った。
(a)生理食塩水投与群
(b)アミノ酸＊１投与群
(c)デキストリン投与群
(d)エレンタール投与群
＊１：エレンタールに含有するアミノ酸１７種（エレンタールに含有する１７種のアミノ酸の配合比と同一）
Twelve female ICR mice (10 weeks old) were purchased and kept for one week to allow them to get used to the environment. After that, they were divided into the following four groups.
(a) Saline administration group
(b) Amino acid *1 administration group
(c) Dextrin administration group
(d) Elental administration group*1: 17 types of amino acids contained in Elental (same ratio as the 17 types of amino acids contained in Elental)
薬剤投与は、１日目から４日目まで連日5-FUを40mg/kg/日で腹腔内投与すると共に、生理食塩水、生理食塩水＋アミノ酸75.15μg/ml、生理食塩水＋デキストリン338.2μg/ml、又は生理食塩水＋エレンタール426.7μg/mlを投与した。さらに引き続き５日目から７日目まで連日生理食塩水、アミノ酸、デキストリン、又はエレンタールを投与した。そして8日目にマウスを屠殺し、顎下腺を摘出した。 Drug administration consisted of intraperitoneal administration of 40 mg/kg/day 5-FU every day from day 1 to day 4, along with saline, saline + amino acids 75.15 μg/ml, saline + dextrin 338.2 μg/ml, or saline + Elental 426.7 μg/ml. Furthermore, saline, amino acids, dextrin, or Elental were administered every day from day 5 to day 7. Mice were then sacrificed on day 8, and the submandibular glands were removed.
図９に示すように、生理食塩水で処理した場合には5-FUの影響で顎下腺が萎縮しているのに対し、アミノ酸やエレンタールで処理した場合には顎下腺の萎縮が抑制されており、特にアミノ酸で処理した場合に顎下腺の萎縮抑制効果が高いことが明らかとなった。したがって、エレンタールに含有するアミノ酸は抗がん剤処理による顎下腺の萎縮を抑制する効果を有することが明らかとなった。なお、顎下腺の萎縮は唾液の分泌低下をもたらし、結果として口腔乾燥症を引き起こすことが知られている。そのため、エレンタールに含有するアミノ酸は顎下腺を保護することにより口腔乾燥症の予防又は治療として用いることができる。また、実施例４の結果と合わせて検討すると、アスパラギン酸、アラニン、プロリンから選択される２つの組み合わせ、特にプロリンとアスパラギン酸の組み合わせや、アスパラギン酸、アラニン、プロリンの３つの組み合わせにより、顎下腺の萎縮を抑制できると考えられる。 As shown in FIG. 9, when treated with saline, the submandibular gland atrophied due to the effect of 5-FU, whereas when treated with amino acids or Elental, the atrophy of the submandibular gland was suppressed, and it was revealed that the effect of suppressing atrophy of the submandibular gland was particularly high when treated with amino acids. Therefore, it was revealed that the amino acids contained in Elental have the effect of suppressing atrophy of the submandibular gland caused by anticancer drug treatment. It is known that atrophy of the submandibular gland leads to a decrease in saliva secretion, which results in xerostomia. Therefore, the amino acids contained in Elental can be used to prevent or treat xerostomia by protecting the submandibular gland. In addition, when considered together with the results of Example 4, it is believed that atrophy of the submandibular gland can be suppressed by a combination of two selected from aspartic acid, alanine, and proline, particularly a combination of proline and aspartic acid, or a combination of three of aspartic acid, alanine, and proline.
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| JP2016175901A (en) | 2015-03-18 | 2016-10-06 | 第一三共ヘルスケア株式会社 | Composition for oral care comprising l-aspartic acid or salt thereof, and nicotinamide |
| JP2017141206A (en) | 2016-02-12 | 2017-08-17 | 株式会社らいむ | Wound-healing agent |
| JP2018127427A (en) | 2017-02-10 | 2018-08-16 | 味の素株式会社 | Saliva secretion promoter, food composition containing the same, and oral composition |
| JP2019530750A (en) | 2016-10-04 | 2019-10-24 | ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド | Amino acid composition and use thereof |
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| JP2016175901A (en) | 2015-03-18 | 2016-10-06 | 第一三共ヘルスケア株式会社 | Composition for oral care comprising l-aspartic acid or salt thereof, and nicotinamide |
| JP2017141206A (en) | 2016-02-12 | 2017-08-17 | 株式会社らいむ | Wound-healing agent |
| JP2019530750A (en) | 2016-10-04 | 2019-10-24 | ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド | Amino acid composition and use thereof |
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