JP6584745B2 - A method for producing a composition for improving the effect of an anti-obesity drug. - Google Patents
A method for producing a composition for improving the effect of an anti-obesity drug. Download PDFInfo
- Publication number
- JP6584745B2 JP6584745B2 JP2014080531A JP2014080531A JP6584745B2 JP 6584745 B2 JP6584745 B2 JP 6584745B2 JP 2014080531 A JP2014080531 A JP 2014080531A JP 2014080531 A JP2014080531 A JP 2014080531A JP 6584745 B2 JP6584745 B2 JP 6584745B2
- Authority
- JP
- Japan
- Prior art keywords
- composition
- obesity
- administration
- weeks
- administered
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
Images
Landscapes
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Plant Substances (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
本発明は抗肥満薬の抗肥満作用促進効果を有する、アマニリグナンを有効成分として含む組成物に関する。 The present invention relates to a composition comprising linalignan as an active ingredient, which has an effect of promoting anti-obesity action of an anti-obesity drug.
肥満症の治療には、食事療法及び運動療法が行われるが、それで十分な改善が見られない場合は、抗肥満薬による薬物療法も行われる。抗肥満薬の中でも中枢神経性抗肥満薬は、食欲中枢への直接作用や脳内でのアドレナリン、ドパミン、セロトニン等のモノアミンの神経細胞による再取り込み抑制などの機序により、消費エネルギーを促進するとともに食欲を抑制する。中枢神経性抗肥満薬は肥満症の治療において基礎となる食事療法及び運動療法の導入並びにそれらを習慣として維持、継続するための動機づけに非常に有用であるとされている。しかしながらその有効性の反面、非常に短期間で依存性や精神疾患への影響、耐性が発現するという問題点がある。
マジンドール（Mazindol）は、現在、中枢神経性抗肥満薬としては日本で唯一承認されている薬剤である。マジンドールは臨床において高い有効性を示す反面、上記のような中枢神経性抗肥満薬特有の問題点から、連続投与の期間は最長で１２週間と限定され、ＢＭＩ（ボディマス指数、体重（ｋｇ）/（身長（ｍ）×身長（ｍ）））＝３５以上の高度肥満患者にのみ保険適用可とされるなど、使用に制限がある。
Diet and exercise therapy are used to treat obesity, but drug therapy with anti-obesity drugs is also used if sufficient improvement is not observed. Among anti-obesity drugs, central nervous system anti-obesity drugs promote energy consumption through mechanisms such as direct action on the appetite center and suppression of reuptake of monoamines such as adrenaline, dopamine, and serotonin by neurons in the brain. Also suppresses appetite. Central nervous system anti-obesity drugs are considered to be very useful for the introduction of dietary and exercise therapies that are fundamental in the treatment of obesity and for motivating them to maintain and continue as a habit. However, on the other hand, there is a problem that dependency, influence on mental illness, and tolerance develop in a very short time.
Mazindol is currently the only approved drug in Japan as a central nervous system anti-obesity drug. Although mazindol is highly effective in the clinic, the continuous administration period is limited to a maximum of 12 weeks due to the problems inherent in the above-mentioned central nervous system anti-obesity drugs. BMI (body mass index, body weight (kg) / kg) (Height (m) × height (m))) = Limited use, such as insurance is available only for highly obese patients over 35.
リグナンは植物に含まれている化合物群の一種であり、エストロゲン様作用を示すことから植物エストロゲンとも呼ばれる。リグナンは他にも抗がん作用、抗酸化作用、脂質代謝改善作用などを示すことが知られており（例えば特許文献１参照）、その健康機能への多大な効用が着目されている。
アマニはリグナン源として最も知られている植物のひとつであり、アマニリグナンとしてセコイソラリシレジノールグルコシドが多量に含まれている他、マタイレシノール、ピノレシノール、イソラレシレジノール及びこれらの配糖体などが少量含まれている。
アマニリグナンは女性ホルモンバランスの乱れを原因とする諸症状、例えば、閉経期における更年期障害や閉経後の骨粗鬆症、高血圧症、高脂血症、肥満症、鬱、ほてりなどに対して有効であることが知られている（例えば特許文献２参照）。
アマニリグナンの効果として脂肪蓄積抑制作用、例えば、動物において高脂肪食と同時に摂取させると同時摂取しない群と比較して脂肪の蓄積を抑制することが出来ることが知られているが（例えば特許文献３参照）、一旦蓄積された脂肪の代謝を促進し、その量を減らす蓄積脂肪低減促進作用、すなわちすでに肥満の状態にあるものの体重を軽減させる効果については報告がない。また、既知の抗肥満薬との併用に関する報告もされていない。
また、アマニはα-リノレン酸源としても良く知られている植物であり、アマニ油中の脂肪酸含量としては50〜60％がα-リノレン酸である。α-リノレン酸の効果は、炎症改善、脂質代謝改善、美容効果などが知られている（例えば非特許文献１及び２参照）。
Lignans are a group of compounds contained in plants and are also called phytoestrogens because of their estrogenic action. In addition, lignan is known to exhibit anticancer action, antioxidant action, lipid metabolism improving action, and the like (see, for example, Patent Document 1), and its great utility for health functions has attracted attention.
Linseed is one of the most well-known plants for lignans, and it contains a large amount of secoisolaricylesinol glucoside as flax lignans, as well as matailesinol, pinoresinol, isolaresirinol and their glycosides. A small amount is included.
Amani lignans are effective against symptoms caused by disturbances in female hormone balance, such as menopause in menopause and postmenopausal osteoporosis, hypertension, hyperlipidemia, obesity, depression, and hot flashes. Is known (see, for example, Patent Document 2).
It is known that fat accumulation can be suppressed as an effect of flax lignan, for example, fat accumulation can be suppressed in animals compared with a group that does not consume simultaneously when consumed at the same time as a high fat diet (for example, patent document) 3), there is no report on the action of promoting the reduction of accumulated fat, which promotes the metabolism of fat once accumulated, that is, the effect of reducing the body weight of an already obese state. In addition, there has been no report on the combined use with known anti-obesity drugs.
Linseed is a plant well known as an α-linolenic acid source, and 50 to 60% of the fatty acid content in linseed oil is α-linolenic acid. As the effect of α-linolenic acid, inflammation improvement, lipid metabolism improvement, cosmetic effect and the like are known (for example, see Non-Patent Documents 1 and 2).
近年、肥満は糖尿病、高血圧症、動脈硬化、脂肪肝、癌などに代表される生活習慣病の主要な原因とされていることにより、肥満症の治療薬の開発が望まれている。しかしながら上記のように現在使用可能な肥満症治療薬は限られ、さらにその使用にも制限がある。
また一旦蓄積した脂肪の代謝を促進する蓄積脂肪低減促進作用を有するような有効な治療薬は報告されていない。従ってより有効でかつ安全な抗肥満症薬の開発、既存の抗肥満薬の効果を促進するための補助薬の開発が望まれている。
In recent years, obesity has been a major cause of lifestyle-related diseases represented by diabetes, hypertension, arteriosclerosis, fatty liver, cancer and the like, and therefore development of therapeutic drugs for obesity is desired. However, as described above, the currently available anti-obesity drugs are limited and their use is also limited.
In addition, no effective therapeutic agent has been reported that has an action of promoting the reduction of accumulated fat that promotes the metabolism of fat once accumulated. Therefore, development of more effective and safe anti-obesity drugs and development of adjuvants for promoting the effects of existing anti-obesity drugs are desired.
本発明者等は、アマニリグナンが抗肥満薬の抗肥満作用を促進する効果を有すること、具体的には抗肥満薬の投与期間中にアマニリグナンを有効成分として含む組成物を投与することで、より高い体重減少効果を示すこと及び抗肥満薬単独治療における抗肥満作用耐性を軽減することができること、抗肥満薬の投与期間後にアマニリグナンを有効成分として含む組成物を投与することで、抗肥満薬による治療の中止後のリバウンド現象を防ぐことができることを見出し、本発明を完成するにいたった。 The present inventors have the effect that flax lignan has an effect of promoting the anti-obesity action of an anti-obesity drug, specifically, by administering a composition containing flax lignan as an active ingredient during the administration period of the anti-obesity drug. Anti-obesity action resistance in anti-obesity drugs alone treatment can be reduced, administration of a composition containing linagignan as an active ingredient after the administration period of anti-obesity drugs, It has been found that the rebound phenomenon after discontinuation of treatment with an obesity drug can be prevented, and the present invention has been completed.
すなわち本発明は以下の通りである。
（１）アマニリグナンを有効成分として含む、抗肥満薬の抗肥満作用を促進するための組成物。
（２）抗肥満薬の投与期間中に投与されることにより、蓄積された脂肪の低減を促進する、前記（１）に記載の組成物。
（３）抗肥満薬の投与期間中に投与されることにより、抗肥満薬の投与による抗肥満作用耐性を軽減する、前記（１）に記載の組成物。
（４）抗肥満薬投与期間後のリバウンド現象を抑制する、前記（１）に記載の組成物。
（５）１日あたり、成人に対し１０〜６０００ｍｇの量のアマニリグナンが摂取されるように投与される、前記（１）〜（４）のいずれか一項に記載の組成物。
（６）少なくとも１週間にわたり投与される、前記（１）〜（５）のいずれか一項に記載の組成物。
（７）さらにα‐リノレン酸を含む前記（１）〜（６）のいずれか一項に記載の組成物。
That is, the present invention is as follows.
(1) A composition for promoting the anti-obesity action of an anti-obesity drug, comprising linalignan as an active ingredient.
(2) The composition according to (1), wherein the composition is administered during the administration period of the anti-obesity drug to promote the reduction of accumulated fat.
(3) The composition according to (1), wherein the anti-obesity drug resistance by administration of the anti-obesity drug is reduced by being administered during the administration period of the anti-obesity drug.
(4) The composition according to the above (1), which suppresses a rebound phenomenon after an anti-obesity drug administration period.
(5) The composition according to any one of (1) to (4), wherein the composition is administered such that linagnan is ingested in an amount of 10 to 6000 mg per day for an adult.
(6) The composition according to any one of (1) to (5), which is administered for at least one week.
(7) The composition according to any one of (1) to (6), further comprising α-linolenic acid.
本発明の組成物により、抗肥満薬の抗肥満作用を促進することが出来る。
具体的には、抗肥満薬の投与期間中に本発明の組成物を投与することにより、より高い体重減少効果を示すことが出来る。また、抗肥満薬の投与期間中に本発明の組成物を投与することにより、抗肥満薬単独治療における抗肥満作用耐性を軽減することができる。さらに抗肥満薬の投与期間後に本発明の組成物を投与することにより、抗肥満薬による治療の中止または中断後のリバウンドを防ぐことができる。
With the composition of the present invention, the anti-obesity action of an anti-obesity drug can be promoted.
Specifically, a higher weight loss effect can be shown by administering the composition of the present invention during the administration period of the anti-obesity drug. Further, by administering the composition of the present invention during the administration period of the anti-obesity drug, it is possible to reduce the anti-obesity action resistance in the anti-obesity drug alone treatment. Furthermore, by administering the composition of the present invention after the administration period of the anti-obesity drug, rebound after the discontinuation or interruption of the treatment with the anti-obesity drug can be prevented.
アマニ(亜麻仁)は、欧州の地中海地方原産の自生植物である亜麻科植物アマ（亜麻、学名：Ｌｉｎｕｍ ｕｓｉｔａｔｉｓｓｉｍｕｍ）の種子(仁)のことであり、英名 Ｆｌａｘ Ｓｅｅｄ (フラックスシード)、学名 Ｌｉｎｕｍ Ｕｓｉｔａｔｉｓｓｉｍｕｍと呼ばれる。
本発明におけるアマニリグナンとしてはアマニから公知の方法で抽出したアマニ抽出物を用いても良く、更に、精製して得たものを用いても良い。さらにアマニリグナンを多く含有するアマニをそのまま又は加工して使用してもよい。例えばアマニには、１０ｇあたり約１００ｍｇのアマニリグナンが含まれるので、これを粉砕して組成物に添加することが出来る。
本発明において、アマニは、国内産、外国産などの産地や栽培用、搾油用の品種を問わず使用でき、焙煎、非焙煎の処理の有無に関係なく原料として使用できる。また、搾油工程で産生するアマニ粕を原料としてもよい。
アマニリグナンのアマニからの抽出方法としては、例えばまずアマニをミキサー、ホモジナイザーなどの粉砕機で粉砕する。粉砕物をｎ−ヘキサン等の脂溶性有機溶媒で油分を除去し、脱脂物としてもよい。次に得られた粉砕物又は脱脂物をアマニリグナンを抽出可能な低級アルコール（エタノール、メタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノールなど）、またはその含水アルコールで抽出し、必要であればケン化処理、中和を行い、吸着剤としてオクタデシルシリカ（ＯＤＳ）、シリカゲルなどを使用して、分画、精製することができる。
Linseed (flaxseed) is a seed of the flax family flax (flax, scientific name: Linum usitatissimum), an indigenous plant native to the Mediterranean region of Europe, and the English name Flax Seed (fluxseed), scientific name Linum Usitissimum and be called.
As the linseed lignan in the present invention, a linseed extract extracted from linseed by a known method may be used, or a linseed extract obtained by purification may be used. Furthermore, flax containing a large amount of flax lignan may be used as it is or after being processed. For example, flaxseed contains about 100 mg flax lignan per 10 g, which can be crushed and added to the composition.
In the present invention, flaxseed can be used regardless of whether it is a domestic or foreign production area, a variety for cultivation or oil extraction, and can be used as a raw material regardless of whether it is roasted or non-roasted. Alternatively, flaxseed meal produced in the oil extraction process may be used as a raw material.
As a method for extracting flaxseed lignan from flaxseed, flaxseed is first pulverized by a grinder such as a mixer or a homogenizer. The pulverized product may be degreased by removing oil with a fat-soluble organic solvent such as n-hexane. Next, the obtained pulverized product or defatted product is extracted with a lower alcohol (ethanol, methanol, n-propanol, isopropanol, n-butanol, etc.) from which linseignan can be extracted, or its hydrous alcohol, and if necessary, saponified Treatment, neutralization, and fractionation and purification can be performed using octadecyl silica (ODS), silica gel, or the like as an adsorbent.
本発明において、抗肥満薬としては、マジンドール、フェンフルラミン、シブトラミン等の中枢性抗肥満薬、オルリスタット、セチリスタット等の膵リパーゼ阻害薬、β３作動薬、レプチン、ＣＮＴＦ（毛様体神経栄養因子）等のペプチド性食欲抑制薬、ロルカセリンなどのセロトニン受容体作動薬、リンチトリプト等のコレシストキニン受容体作動薬が挙げられる。
本発明において、抗肥満薬は中枢神経性抗肥満薬であることが好ましい。中枢神経性抗肥満薬としては、食欲中枢への直接作用や脳内でのアドレナリン、ドパミン、セロトニン等のモノアミンの神経細胞による再取り込み抑制などの機序により抗肥満効果を有する薬物であれば特に限定されないが、例えばマジンドール、フェンフルラミン、シブトラミン、デクスフェンフルアミン、フェンテルミン、シブトラミン、アンフェプラモン、デキサンフェタミン、フェニルプロパノールアミン、クロベンゾレックス、フルオキセチンが挙げられる。最も好ましくはマジンドールである。
In the present invention, anti-obesity agents include central anti-obesity agents such as mazindol, fenfluramine and sibutramine, pancreatic lipase inhibitors such as orlistat and cetiristat, β3 agonists, leptin and CNTF (ciliary neurotrophic factor). Peptide anorectic agents such as serotonin receptor agonists such as lorcaserine, and cholecystokinin receptor agonists such as lynchtrypto.
In the present invention, the anti-obesity drug is preferably a central nervous system anti-obesity drug. As a central nervous system anti-obesity agent, any drug that has an anti-obesity effect by a mechanism such as a direct action on the appetite center or suppression of reuptake of monoamines such as adrenaline, dopamine, and serotonin by nerve cells in the brain can be used. Examples include, but are not limited to, mazindol, fenfluramine, sibutramine, dexfenfluamine, phentermine, sibutramine, ampifepramon, dexamphetamine, phenylpropanolamine, clobenzorex, fluoxetine. Most preferred is mazindol.
抗肥満薬の投与量及び投与方法は各抗肥満薬の種類によって異なるが、例えば抗肥満薬がマジンドールである場合、一般的には１日あたり０．５〜１．５ｍｇを２〜３回に分けて食前に経口投与する。連続投与は１２週間を限度とし、１２週間の連続投与による治療期間を１クールとする。各クール間には１週間〜３ヶ月の休薬期間を設ける事が一般的である。
本発明において「抗肥満薬の投与期間中に投与する」とは、抗肥満薬の投与期間中に、抗肥満薬と本発明の組成物とを同時又は順次のいずれかで実質的に同時期に組み合わせ投与することを意味する。例えば、抗肥満薬の連続投与が認められている１２週間のうち、抗肥満薬の投与後２週間目から本発明の組成物の投与を開始し、その後８〜１０週間にわたって抗肥満薬と本発明の組成物の組み合わせ投与を行う事が出来る。組み合わせ投与の期間は少なくとも１週間にわたることが好ましく、２週間を超えることがより好ましく、４週間を超えることがさらに好ましく、８週間を超えることがもっとも好ましい。
The dose and administration method of the anti-obesity drug vary depending on the type of each anti-obesity drug. For example, when the anti-obesity drug is mazindol, generally 0.5 to 1.5 mg per day is increased to 2 to 3 times. Separately orally before meals. The continuous administration is limited to 12 weeks, and the treatment period by continuous administration for 12 weeks is one course. It is common to provide a drug holiday of 1 week to 3 months between each course.
In the present invention, “administered during the administration period of an anti-obesity drug” means that the anti-obesity drug and the composition of the present invention are substantially simultaneously or either simultaneously or sequentially during the administration period of the anti-obesity drug. Means combined administration. For example, the administration of the composition of the present invention is started from the second week after the administration of the anti-obesity drug among the 12 weeks in which continuous administration of the anti-obesity drug is permitted, and then the anti-obesity drug and the main drug are administered for 8 to 10 weeks. Combination administration of the compositions of the invention can be performed. The duration of the combined administration is preferably at least 1 week, more preferably more than 2 weeks, more preferably more than 4 weeks and most preferably more than 8 weeks.
ここで「抗肥満薬による治療による抗肥満作用耐性」とは、１２週間の連続投与を１クールとする抗肥満薬による治療期間を１回又は複数回行うことにより、有意な体重減少が得られなくなることをいう。 Here, “resistance to anti-obesity action by treatment with anti-obesity drugs” means that a significant weight loss can be obtained by performing one or more treatment periods with anti-obesity drugs with 12 weeks of continuous administration as one course. It means disappearing.
本発明の組成物は抗肥満薬の投与期間中に投与されることにより、抗肥満薬による治療による抗肥満作用耐性を軽減することが出来る。例えば、抗肥満薬による治療を数クール経験した患者に対して、新たなクールとしてマジンドールの投与後２週間目から本発明の組成物の投与を開始しその後８〜１０週間にわたって抗肥満薬と本発明の組成物を組み合わせ投与することで、そのクールにおいて有意な体重減少を得ることが出来る。組み合わせ投与の期間は少なくとも１週間にわたることが好ましく、２週間を超えることがより好ましく、４週間を超えることがさらに好ましく、８週間を超えることがもっとも好ましい。 By administering the composition of the present invention during the administration period of the anti-obesity drug, it is possible to reduce the resistance to anti-obesity action by the treatment with the anti-obesity drug. For example, for a patient who has undergone several courses of treatment with an anti-obesity drug, the administration of the composition of the present invention is started from the second week after the administration of mazindol as a new course, and then the anti-obesity drug and By administering the compositions of the invention in combination, significant weight loss can be obtained in that course. The duration of the combined administration is preferably at least 1 week, more preferably more than 2 weeks, more preferably more than 4 weeks and most preferably more than 8 weeks.
本発明において、「抗肥満薬による治療の中止後のリバウンド」とは抗肥満薬による治療により一旦減少した体重が、抗肥満薬の投与期間の終了後再び増加する現象をいう。リバウンド抑制作用を得るために、本発明組成物は、抗肥満薬の投与期間後に投与される。好ましくは抗肥満薬の投与期間終了時点において抗肥満薬と組み合わせ投与しており、抗肥満薬の投与期間終了後に投与を続けることが好ましい。抗肥満薬の投与期間終了時点での抗肥満薬と本発明の組成物の組み合わせ投与の期間は、少なくとも１週間にわたることが好ましく、２週間を超えることがより好ましく、４週間を超えることがさらに好ましく、８週間を超えることがもっとも好ましい。 In the present invention, “rebound after discontinuation of treatment with an anti-obesity agent” refers to a phenomenon in which the weight once reduced by treatment with an anti-obesity agent increases again after the end of the administration period of the anti-obesity agent. In order to obtain a rebound suppressing action, the composition of the present invention is administered after the administration period of the anti-obesity drug. Preferably, it is administered in combination with an anti-obesity drug at the end of the administration period of the anti-obesity drug, and the administration is preferably continued after the end of the administration period of the anti-obesity drug. The period of administration of the combination of the anti-obesity drug and the composition of the present invention at the end of the anti-obesity drug administration period is preferably at least 1 week, more preferably more than 2 weeks, and more preferably more than 4 weeks. Preferably, more than 8 weeks are most preferable.
本発明の組成物は、助剤とともに任意の形態に製剤化して、経口または非経口投与が可能な医薬品とすることができる。経口用の剤形としては、例えば、錠剤、口腔内速崩壊錠、カプセル、顆粒、細粒などの固形投薬形態、シロップ及び懸濁液のような液体投薬形態で投与される。非経口の剤形としては、注射剤、点眼剤、点鼻剤、貼付剤、坐剤、皮膚外用剤の形態で投与される。なお、医薬品には医薬部外品も含まれる。 The composition of the present invention can be formulated into an arbitrary form together with an auxiliary agent into a pharmaceutical that can be administered orally or parenterally. Examples of oral dosage forms include solid dosage forms such as tablets, intraoral quick disintegrating tablets, capsules, granules and fine granules, and liquid dosage forms such as syrups and suspensions. The parenteral dosage form is administered in the form of injections, eye drops, nasal drops, patches, suppositories, and external preparations for skin. Pharmaceutical products include quasi-drugs.
固形投薬形態とする場合、一般製剤の製造に用いられる種々の添加剤を適当量含んでいてもよい。このような添加剤として、例えば賦形剤、結合剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、安定化剤、ｐＨ調整剤、界面活性剤などが挙げられる。 In the case of a solid dosage form, it may contain an appropriate amount of various additives used for the production of general preparations. Examples of such additives include excipients, binders, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, pH adjusters, and surfactants.
液体投薬形態とする場合、本発明の組成物は必要に応じてｐＨ調製剤、緩衝剤、溶解剤、懸濁剤等、張化剤、安定化剤、防腐剤などの存在下、常法により製剤化することができる。 In the case of a liquid dosage form, the composition of the present invention is prepared by a conventional method in the presence of a pH adjusting agent, a buffering agent, a solubilizing agent, a suspending agent, etc., a tonicity agent, a stabilizing agent, a preservative, and the like. It can be formulated.
皮膚外用剤の形態には、特に限定されず、例えば、乳液、クリーム、化粧水、パック、分散液、洗浄料、メーキャップ化粧料、頭皮・毛髪用品等の化粧品や、軟膏剤、クリーム剤、外用液剤等の医薬品などとすることができる。上記成分以外に、通常化粧品や医薬品等の皮膚外用剤に用いられる成分、例えば、美白剤、保湿剤、各種皮膚栄養成分、紫外線吸収剤、酸化防止剤、油性成分、界面活性剤、増粘剤、アルコール類、色剤、水、防腐剤、香料等を必要に応じて適宜配合することができる。 There are no particular limitations on the form of the external preparation for skin, for example, cosmetics such as emulsions, creams, lotions, packs, dispersions, cleaning agents, makeup cosmetics, scalp / hair products, ointments, creams, and external use. It can be a pharmaceutical such as a liquid. In addition to the above components, components commonly used in skin external preparations such as cosmetics and pharmaceuticals, such as whitening agents, moisturizers, various skin nutritional components, ultraviolet absorbers, antioxidants, oily components, surfactants, thickeners , Alcohols, coloring agents, water, preservatives, fragrances and the like can be appropriately blended as necessary.
本発明の組成物の投与量は、投与される患者の年齢、体重、性別、症状の程度、投与形態によって異なるが、成人では１日あたり、アマニリグナンの量として好ましくは１０〜６０００ｍｇ、より好ましくは２０〜３００ｍｇである。小児では１日あたり、アマニリグナンの量として好ましくは１０〜３０００ｍｇ、より好ましくは２０〜１５０ｍｇである。 The dose of the composition of the present invention varies depending on the age, weight, sex, symptom level, and administration form of the patient to be administered, but in adults, the amount of linalignan is preferably 10 to 6000 mg per day, more preferably Is 20 to 300 mg. In children, the amount of flax lignan is preferably 10 to 3000 mg, more preferably 20 to 150 mg per day.
本発明の組成物は、さらに任意の成分として公知の脂質代謝改善効果を有する成分を含むことが出来る。このような成分としては、例えばα-リノレン酸、ステアリドン酸、エイコサテトラエン酸、エイコサペンタエン酸、ドコサヘキサエン酸等のω３系高度不飽和脂肪酸が挙げられ、好ましくはα-リノレン酸である。これらは単離して単独で配合することも、また、混合物として使用することもでき、さらにこれらを多く含有する油脂をそのまま使用することができる。α-リノレン酸はエゴマ油、アブラナ（キャノーラ）油、ダイズ油、アマニ油などの種油に多く含まれ、好ましくは食用アマニ油として添加される。食用アマニ油は例えば原料のアマニを低温圧搾製法により搾油し、水分、ガム質、遊離脂肪酸、色素、臭い等不純物を取り除く精製工程を経て得ることが出来る。
本発明の組成物は、成人に対し１日あたり、α-リノレン酸が１０〜４０００ｍｇの量で好ましくは１００〜３０００ｍｇの量で摂取されるように投与される。またが小児に対し１日あたり、α-リノレン酸が好ましくは１０〜３０００ｍｇ、より好ましくは２０〜２５００ｍｇの量で摂取されるように投与される。
The composition of the present invention can further contain a known component having an effect of improving lipid metabolism as an optional component. Examples of such components include ω3 highly unsaturated fatty acids such as α-linolenic acid, stearidonic acid, eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid, and preferably α-linolenic acid. These can be isolated and blended alone or used as a mixture, and fats and oils containing a large amount of these can be used as they are. α-Linolenic acid is contained in a large amount in seed oils such as sesame oil, rape (canola) oil, soybean oil, and linseed oil, and is preferably added as edible linseed oil. The edible linseed oil can be obtained, for example, through a purification process in which raw linseed is squeezed by a low-temperature pressing method to remove impurities such as moisture, gum, free fatty acids, pigments and odors.
The composition of the present invention is administered to an adult so that α-linolenic acid is ingested in an amount of 10 to 4000 mg, preferably 100 to 3000 mg per day. However, α-linolenic acid is preferably administered to a child in an amount of 10 to 3000 mg, more preferably 20 to 2500 mg per day.
以下本発明を具体的に説明する為に実施例を示すが、本発明は以下の実施例のみに限定されるものではない。
試験例１：アマニ抽出物の製造例
カナダ産アマニの乾燥種子１ｋｇをホモジナイザーで粉砕した。粉砕物をヘキサンで洗浄して油分を分離し、脱脂物を得た。次に得られた脱脂物に含水アルコールを加えて常法により抽出した。前記抽出物をアルカリでケン化処理し、酸で中和後、吸着剤としてシリカゲルなどの樹脂を使用してアマニリグナンを精製した。精製画分を減圧下に濃縮し、凍結乾燥及び粉砕し、アマニ抽出物粉末を得た。得られたアマニ抽出物粉末に賦形剤としてαシクロデキストリンを加え、アマニ抽出物含有粉末２０ｇを得た。この粉末は、ＨＰＬＣ分析したところ、アマニリグナンを４１．３％含むものであった。
EXAMPLES Examples will be shown below for specifically explaining the present invention, but the present invention is not limited to the following examples.
Test Example 1: Manufacture of flaxseed extract 1 kg of dried flaxseed from Canada was pulverized with a homogenizer. The pulverized product was washed with hexane to separate oil, and a defatted product was obtained. Next, hydrous alcohol was added to the obtained defatted product and extracted by a conventional method. The extract was saponified with alkali, neutralized with acid, and purified linalignan using a resin such as silica gel as an adsorbent. The purified fraction was concentrated under reduced pressure, freeze-dried and pulverized to obtain flaxseed extract powder. Α-cyclodextrin was added as an excipient to the obtained linseed extract powder to obtain 20 g of linseed extract-containing powder. This powder was found to contain 41.3% of flax lignan when analyzed by HPLC.
試験例２：アマニ成分サプリメント（ソフトカプセル剤）の製造例
常法によりソフトカプセル剤皮１５０ｍｇ（ゼラチン９５重量％、グリセリン脂肪酸エステル５重量％）に下記成分からなるカプセル内容物２５０ｍｇを混練してから充填し、１粒４００ｍｇのソフトカプセルを得た。配合量は重量％である。なお、本試験例で得られたアマニ成分サプリメント３粒あたりアマニリグナンが１００ｍｇ含まれる。
（カプセル内容物組成）
アマニ抽出物含有粉末 34％
食用アマニ油 60％
ビタミンＥ含有植物油 １％
ミツロウ １％
乳化剤 ４％
１００％
Test Example 2: Manufacture example of flaxseed component supplement (soft capsule) In a conventional manner, 150 mg of soft capsule skin (95% by weight of gelatin, 5% by weight of glycerin fatty acid ester) was kneaded with 250 mg of the capsule contents consisting of the following ingredients and then filled. One capsule of 400 mg was obtained. The blending amount is% by weight. In addition, 100 mg of linseed lignan is contained per 3 linseed component supplements obtained in this test example.
(Capsule content composition)
Linseed extract-containing powder 34%
Edible linseed oil 60%
Vitamin E-containing vegetable oil 1%
Beeswax 1%
Emulsifier 4%
100%
試験例３：肥満外来通院中の肥満患者における評価
試験例２で製造したアマニ成分サプリメントを用いて以下の試験を行った。
なお、以下の試験においてアマニ成分サプリメントは１日３粒（アマニリグナン１００ｍｇ含有）、特に時間を決めずに経口投与した。また抗肥満薬としてマジンドールを使用し、マジンドールは１日あたり０．５〜１．５ｍｇの投与量を１日２〜３回食前に経口投与した。
Test Example 3: Evaluation of obese patients in obesity outpatient clinics The following tests were conducted using the flaxseed component supplement produced in Test Example 2.
In the following tests, linseed component supplements were orally administered 3 times a day (containing 100 mg of linseed lignans) without particular time. Moreover, mazindol was used as an anti-obesity drug, and mazindol was orally administered at a dose of 0.5 to 1.5 mg per day 2 to 3 times a day before meals.
［アマニ成分サプリメント単独投与］
肥満外来通院中の肥満患者５名について、アマニ成分サプリメントを上記投与量で投与し、８週間後体重及びＢＭＩ値の変化を評価した。表１に結果を示す。
この結果、アマニ成分サプリメント単独投与では患者の体重変化に有意差はなかった（ｐ＞０．５）。
[Flame component supplement alone]
For five obese patients in obesity outpatient clinics, flaxseed component supplements were administered at the above doses, and changes in body weight and BMI values were evaluated after 8 weeks. Table 1 shows the results.
As a result, there was no significant difference in the change in body weight of patients when flaxseed component supplements were administered alone (p> 0.5).
［マジンドール単独投与］
肥満外来通院中の肥満患者８名（男性４名、女性４名）について、マジンドールを上記投与量で投与し、１２週間の連続投与を１クールとし、２クールにわたる投与を行い、各クールにおいて４週ごとの体重及びＢＭＩ値の変化を評価した。被験者の年齢は３４歳から６１歳であった。表２及び表３に結果を示す。なお表中、変化率は各クール開始時の体重に対する各クール終了後に変化した体重の％を示す。
この結果から、マジンドール単独投与により、第１クール開始時に対し、第１クール終了時における体重の変化率は平均で-４．６％であり有意な減少を示した（ｐ＜０．０５）。
またマジンドール単独投与により、第２クール開始時に対し第２クール終了時における体重の変化率は平均で-１．１％であり、有意な減少（ｐ＜０．５）を示したが、第１クールにおける変化率よりも少なかった。
[Mazindol alone]
For 8 obese patients (4 males and 4 females) in obesity outpatient clinics, mazindol is administered at the above dose, 12 weeks of continuous administration is 1 course, and 2 courses are administered. Changes in body weight and BMI values from week to week were evaluated. The age of the subjects was 34 to 61 years. Tables 2 and 3 show the results. In the table, the rate of change indicates the percentage of the weight changed after the end of each cool with respect to the weight at the start of each cool.
From these results, the rate of change in body weight at the end of the first course was -4.6% on average with the administration of mazindol alone, showing a significant decrease (p <0.05).
In addition, administration of mazindol alone showed a significant decrease (p <0.5) in the rate of change in body weight on average at the end of the second course relative to the start of the second course, which was -1.1%. Less than the rate of change in cool.
［マジンドール及びアマニ成分サプリメントの組み合わせ投与］
（１）第１クールのみ組み合わせ投与した場合
肥満外来通院中の肥満患者５名（男性２名、女性３名）について、マジンドールを上記投与量で投与し、マジンドールの投与開始後２週間後から１０週間、マジンドールとアマニ成分サプリメントの組み合わせ投与を行った（図１（a）参照）。マジンドールの投与開始から２週後、６週後、１０週後及び１２週後の体重及びＢＭＩ値の変化を評価した。被験者の年齢は３１歳から７０歳であった。表４に結果を示す。なお表中、変化率は第１クール開始時の体重に対する第１クール終了後に変化した体重の％を示す。
[Combination administration of mazindol and flaxseed ingredient supplements]
(1) Combined administration of only the first course For 5 obese patients (2 males and 3 females) in obesity outpatient clinic, mazindol was administered at the above dose, and 10 weeks after the start of mazindol administration Weekly, mazindol and flaxseed component supplements were administered (see FIG. 1 (a)). Changes in body weight and BMI values were evaluated 2 weeks, 6 weeks, 10 weeks and 12 weeks after the start of administration of mazindol. The age of the subjects was 31 to 70 years. Table 4 shows the results. In the table, the rate of change indicates the percentage of the weight that has changed after the end of the first cool with respect to the weight at the start of the first cool.
マジンドールの投与期間中にアマニ成分サプリメントを投与することにより、第１クール開始時に対し、第１クール終了時における体重の変化率は平均で-６．５％であり、有意な減少を示した（ｐ＜０．０５）。またマジンドールを単独投与した第１クールの結果よりも大きい変化率を示した。
By administering the linseed component supplement during the administration period of mazindol, the rate of change in body weight at the end of the first course was -6.5% on average compared to the start of the first course, indicating a significant decrease ( p <0.05). Moreover, the rate of change was larger than the result of the first course in which mazindol was administered alone.
（２）第１クールにおいてマジンドール単独投与した後、第２クールにおいて組み合わせ投与した場合
肥満外来通院中の肥満患者５名（女性５名）について、マジンドールを上記投与量で１２週間の連続投与し（第1クール）、第２クールのマジンドール投与開始から２週間後から４名については１０週間、１名については８週間、マジンドールとアマニ成分サプリメントとの組み合わせ投与を行った（図１（ｂ）参照）。被験者の年齢は４３歳から６７歳であった。表５及び表６に結果を示す。なお表中、変化率は各クール開始時の体重に対する各クール終了後に変化した体重の％を示す。
(2) In the case where mazindol is administered alone in the first course and then in combination in the second course, mazindol is administered continuously for 12 weeks at the above doses for 5 obese patients (5 women) in an obese outpatient clinic ( The first course), 2 weeks after the start of the second course of mazindol, four patients were administered for 10 weeks, and one person was administered for 8 weeks in combination with mazindol and flaxseed component supplements (see FIG. 1 (b)) ). The age of the subjects was 43 to 67 years. Tables 5 and 6 show the results. In the table, the rate of change indicates the percentage of the weight changed after the end of each cool with respect to the weight at the start of each cool.
この結果より、第１クール及び第２クール共にマジンドール単独投与群では、第１クールにおいて有意な体重減少を示しても第２クールで有意な減少を示さなかったところ、第１クールにおいてマジンドール単独投与した後、第２クールにおいてマジンドールとアマニ成分サプリを組み合わせ投与したところ第２クール終了時における体重の変化率は平均で-５．６％であり、有意な減少を示した（ｐ＜０．０５）。
従って、マジンドールの投与期間中にアマニ成分サプリメントを投与すると、マジンドールによる治療による抗肥満作用耐性を軽減することが示された。
From these results, in both the first and second courses, the mazindol alone administration group showed significant weight loss in the first course, but no significant decrease in the second course. Thereafter, when the mazindol and linseed component supplement were administered in the second course, the rate of change in body weight at the end of the second course was -5.6% on average, indicating a significant decrease (p <0.05). ).
Therefore, it was shown that administration of flaxseed component supplement during the administration period of mazindol reduces the anti-obesity effect resistance by treatment with mazindol.
［マジンドールを休薬した場合のリバウンドへのアマニ成分サプリメントの影響］
マジンドール投与期間後もアマニ成分サプリメントの投与を続けた場合と何も投与しなかった場合について体重のリバウンドへの影響を観察した。
（１）マジンドールの投与期間終了時にアマニ成分サプリメントの投与を終了した場合
肥満外来通院中の肥満患者４名（男性２名、女性２名）について、マジンドールを上記投与量で１２週間の連続投与し、マジンドール投与開始から２週間後から１０週間、マジンドールとアマニ成分サプリメントの組み合わせ投与を行った（図１（ｃ）参照）。マジンドール投与開始から２週間、１０週間、１２週間、１８週間、２２週間、２６週間における体重及びＢＭＩの変化を評価した。表７に結果を示す。なお表中、変化率はマジンドール投与開始時の体重に対する各時点において変化した体重の％を示す。
この結果から、マジンドールの投与開始から１２週後にマジンドール及びアマニ成分サプリメントの投与を終了した後も１８週までは投与終了時の体重よりもさらに体重が減少することが観察されたが、２２週後は投与終了時の体重よりも体重が増加することが観察され、２６週において開始時の体重に対する平均変化率は-２．８％にまで減少した。
[Effects of flaxseed supplements on rebound when mazindol is withdrawn]
The effect on body weight rebound was observed when linseed component supplements were administered even after administration of mazindol and when nothing was administered.
(1) When administration of flaxseed ingredient supplement is terminated at the end of the administration period of mazindol For 4 obese patients (2 males and 2 females) in an obese outpatient clinic, mazindol is administered continuously for 12 weeks at the above dosage. Then, combination administration of mazindol and flaxseed component supplement was performed for 2 weeks from the start of mazindol administration for 10 weeks (see FIG. 1 (c)). Changes in body weight and BMI at 2 weeks, 10 weeks, 12 weeks, 18 weeks, 22 weeks and 26 weeks from the start of mazindol administration were evaluated. Table 7 shows the results. In the table, the rate of change indicates the percentage of body weight changed at each time point relative to the body weight at the start of mazindol administration.
From this result, it was observed that the body weight was further decreased from the body weight at the end of the administration until 18 weeks after the administration of mazindol and flaxseed component supplements was completed 12 weeks after the start of the administration of mazindol. Was observed to increase in body weight compared to the body weight at the end of the administration, and at 26 weeks, the average rate of change relative to the body weight at the start decreased to -2.8%.
（２）マジンドールの投与期間終了後もアマニ成分サプリメントを継続投与した場合
肥満外来通院中の肥満患者３名（女性３名）について、マジンドールを上記投与量で１２週間の連続投与し、マジンドール投与開始から２週間後から１０週間、マジンドールとアマニ成分サプリメントの組み合わせ投与を行った（図１（ｄ）参照）。マジンドールの投与開始から１２週間以降はアマニ成分サプリメントの単独投与を行い、マジンドール投与開始から２週間、１０週間、１２週間、１８週間、２２週間、２６週間における体重及びＢＭＩの変化を評価した。表８に結果を示す。なお表中、変化率はマジンドール投与開始時の体重に対する各時点において変化した体重の％を示す。
(2) Continuous administration of flaxseed ingredient supplements even after the end of the administration period of mazindol For 3 obese patients (3 women) in an obese outpatient clinic, mazindol was administered continuously for 12 weeks at the above dose, and mazindol administration started Two weeks later and 10 weeks later, mazindol and linseed component supplements were administered in combination (see FIG. 1 (d)). From 12 weeks after the start of administration of mazindol, linseed component supplements were administered alone, and changes in body weight and BMI at 2 weeks, 10 weeks, 12 weeks, 18 weeks, 22 weeks and 26 weeks from the start of administration of mazindol were evaluated. Table 8 shows the results. In the table, the rate of change indicates the percentage of body weight changed at each time point relative to the body weight at the start of mazindol administration.
マジンドールの投与開始から１２週後にマジンドールの投与を終了した後もアマニ成分サプリメントを継続投与した場合、１８週から２６週後においていずれも投与終了時の体重よりもさらに体重が減少することが観察され、２６週において開始時の体重に対する平均変化率は-１２．５％であった。 It was observed that when linseed component supplements were continuously administered even after mazindol administration was completed 12 weeks after the start of mazindol administration, the body weight was further reduced from the body weight at the end of administration after 18 to 26 weeks. At 26 weeks, the average rate of change relative to starting weight was -12.5%.
以上より、マジンドールの投与期間後に、何も投与しなかった場合、体重の増加（リバウンド）が観察されたのに対し、マジンドールの投与期間後もアマニ成分サプリメントの投与を続けた場合、さらなる体重の減少が認められ、本発明の組成物はマジンドールによる治療の中止後のリバウンドを抑制する事が示された。 Based on the above, when nothing was administered after the administration period of mazindol, an increase in body weight (rebound) was observed, whereas when administration of flaxseed supplements was continued after the administration period of mazindol, A decrease was observed, indicating that the composition of the present invention inhibits rebound after cessation of treatment with mazindol.
Claims (6)
前記ソフトカプセル剤からなる組成物は、前記中枢神経性抗肥満薬の連続投与期間中に、前記中枢神経性抗肥満薬の一日当たりの投与重量に対して一日当たり６６倍以上２００倍以下の投与重量で連続投与される組合せ投与期間を、８週間を超え１０週間までの間にわたる組合せ投与期間の日数だけ連続させることにより、蓄積された脂肪の低減を促進する組成物の製造方法。 Linseed lignans as an active ingredient, and purified on the basis of the extracts alcoholic extract from defatted of pulverized dry seed of linseed, a purified product of the flax lignan due to soft capsules of, in the central nervous antiobesity drugs A method for producing a composition comprising a soft capsule for promoting the anti-obesity effect of a certain mazindol ,
Composition comprising the soft capsule, the central nervous resistance during continuous administration period antiobesity agent, the central nervous daily dose weight of 200 times or less per day 66 times or more for administration by weight of anti-obesity drugs The method for producing a composition that promotes the reduction of accumulated fat by continuing the combination administration period continuously administered for a period of days of the combination administration period ranging from 8 weeks to 10 weeks .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014080531A JP6584745B2 (en) | 2014-04-09 | 2014-04-09 | A method for producing a composition for improving the effect of an anti-obesity drug. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2014080531A JP6584745B2 (en) | 2014-04-09 | 2014-04-09 | A method for producing a composition for improving the effect of an anti-obesity drug. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2015199687A JP2015199687A (en) | 2015-11-12 |
| JP6584745B2 true JP6584745B2 (en) | 2019-10-02 |
Family
ID=54551324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2014080531A Active JP6584745B2 (en) | 2014-04-09 | 2014-04-09 | A method for producing a composition for improving the effect of an anti-obesity drug. |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP6584745B2 (en) |
-
2014
- 2014-04-09 JP JP2014080531A patent/JP6584745B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| JP2015199687A (en) | 2015-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5165894B2 (en) | Body fat percentage reducing drug | |
| WO2019155337A1 (en) | Compositions comprising a cannabinoid and punicalagin and methods of use thereof | |
| US20160243185A1 (en) | Bioactive-rich concentrates and nutritive and therapeutic products containing same | |
| US20060083700A1 (en) | Use of a novel phytonutrient rich bioactive concentrate (Ri-ActiveTM) for the prevention and treatment of cardiovascular disease, diabetes and other health disorders | |
| JP2006342286A (en) | Oil and fat composition | |
| JP6966206B2 (en) | Composition for improving menopausal symptoms or osteoporosis | |
| KR101964841B1 (en) | Composition for relieving menopausal symptom | |
| JP2006062984A (en) | Antiaging composition, cosmetic containing the same, and food and drink containing the same | |
| JP2006063038A (en) | Antiaging composition, cosmetic containing the same, and food and drink containing the same | |
| WO2015163316A1 (en) | Composition for preventing or improving peripheral neuropathy | |
| JP2019513693A (en) | Composition for amelioration of female menopausal symptoms comprising mandala mochi extract | |
| JP6584745B2 (en) | A method for producing a composition for improving the effect of an anti-obesity drug. | |
| JP2007314475A (en) | Agent for suppressing triacylglycerol synthesis | |
| AU2012228213B2 (en) | Treatment of vaginal atrophy as novel indication for myrrh | |
| EP2397136A1 (en) | Anti-inflammatory composition | |
| JP2017209108A (en) | Composition for improving climacteric symptom or osteoporosis | |
| WO2007120144A1 (en) | Bioactive-rich concentrates and nutritive and therapeutic products containing same | |
| US20220105107A1 (en) | Bioidentical progesterone cream infused with nanoemulsified cbd | |
| US20240207348A1 (en) | Herbal composition for cancer | |
| US8758840B2 (en) | Method of treating areas of osteoarthritis in animals and human beings with milkweed seed oil | |
| EP3380092A1 (en) | Composition of olivetol and method of use reduce or inhibit the effects of tetrahydrocannabinol in the human body | |
| US10933109B2 (en) | Compositions and methods for sleep disorders and restless leg syndromes | |
| KR20230143155A (en) | Supplements for Arthritis and Psoriasis | |
| JP2006131572A (en) | Emollient for menstruation-related symptom | |
| JP2016050202A (en) | Composition for anti-stress or homeostasis containing lactobionate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A80 | Written request to apply exceptions to lack of novelty of invention |
Free format text: JAPANESE INTERMEDIATE CODE: A80 Effective date: 20140425 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20170313 |
|
| A711 | Notification of change in applicant |
Free format text: JAPANESE INTERMEDIATE CODE: A711 Effective date: 20170324 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20170313 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170410 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170409 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20170411 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20170327 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180130 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180330 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180814 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20181013 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20181213 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190122 |
|
| A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190320 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190523 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190625 |
|
| R155 | Notification before disposition of declining of application |
Free format text: JAPANESE INTERMEDIATE CODE: R155 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190904 |
|
| R150 | Certificate of patent or registration of utility model |
Ref document number: 6584745 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |