JP2015098464A - Agent for enhancing dpp-4 inhibitor - Google Patents
Agent for enhancing dpp-4 inhibitor Download PDFInfo
- Publication number
- JP2015098464A JP2015098464A JP2013251496A JP2013251496A JP2015098464A JP 2015098464 A JP2015098464 A JP 2015098464A JP 2013251496 A JP2013251496 A JP 2013251496A JP 2013251496 A JP2013251496 A JP 2013251496A JP 2015098464 A JP2015098464 A JP 2015098464A
- Authority
- JP
- Japan
- Prior art keywords
- dpp
- inhibitor
- glp
- action
- arginine
- 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.)
- Pending
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Abstract
Description
本発明は、血糖低下剤ＤＰＰ−４阻害剤の作用を増強する化合物の使用法、およびＤＰＰ−４阻害剤とその化合物を含有する医薬組成物に関する。 The present invention relates to a method of using a compound that enhances the action of a hypoglycemic agent DPP-4 inhibitor, and a pharmaceutical composition containing the DPP-4 inhibitor and the compound.
ＤＰＰ−４（ジペプチジルペプチダーゼ４）阻害剤は、インクレチン経路の増強作用を主な作用機序とした、２型糖尿病に対する薬剤であり、現在、シタグリプチン、ビルダグリプチン、アログリプチン、リナグリプチン、テネリグリプチン、アナグリプチン、オキサグリプチンなどが臨床に供されている。 DPP-4 (dipeptidyl peptidase 4) inhibitor is a drug for type 2 diabetes whose main mechanism of action is to enhance the incretin pathway. Currently, sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, Oxagliptin and the like are used in clinical practice.
インクレチンは、食事摂取に反応して消化管の上皮細胞から分泌されるぺプチドホルモンであり、血糖値に依存してインスリン分泌を増強させ、肝臓や末梢の筋肉、脂肪組織への糖の取り込みを促進させる。代表的なインクレチンホルモンとしてＧＬＰ−１（グルカゴン様ペプチド１）およびＧＩＰ（Ｇｌｕｃｏｓｅ−ｄｅｐｅｎｄｅｎｔ ｉｎｓｕｌｉｎｏｔｒｏｐｉｃ ｐｏｌｙｐｅｐｔｉｄｅ）が知られており、これらのホルモンは血糖値に依存してインスリンの生合成および分泌を促進することが知られている。糖尿病患者を対象とした臨床試験で、ＧＬＰ−１を静脈内持続投与した結果、インスリンの分泌量が増加し、血漿中グルコース濃度、並びに血糖コントロールの指標であるＨｂＡ１ｃが低下することが明らかになった。しかしながら、ＧＬＰ−１およびＧＩＰはともにＤＰＰ−４により迅速に代謝され不活化される。このＤＰＰ−４を阻害することによりインクレチンホルモンであるＧＬＰ−１およびＧＩＰの不活化を阻害し、その生物活性を持続させるために開発されたのがＤＰＰ−４阻害剤である。 Incretin is a peptide hormone that is secreted from epithelial cells of the gastrointestinal tract in response to dietary intake. It increases insulin secretion depending on blood glucose levels, and uptakes sugar into the liver, peripheral muscles, and adipose tissue. To promote. As typical incretin hormones, GLP-1 (glucagon-like peptide 1) and GIP (Glucose-dependent insulinopolypeptide) are known, and these hormones promote insulin biosynthesis and secretion depending on blood glucose level. It is known. As a result of continuous intravenous administration of GLP-1 in a diabetic clinical trial, insulin secretion increased and plasma glucose concentration and HbA1c, an index of blood glucose control, decreased. It was. However, both GLP-1 and GIP are rapidly metabolized and inactivated by DPP-4. A DPP-4 inhibitor has been developed to inhibit the inactivation of GLP-1 and GIP, which are incretin hormones, by maintaining this biological activity by inhibiting DPP-4.
一方、ＧＬＰ−１と同様にＧＬＰ−１受容体に結合し、ＧＬＰ−１様作用を示すＧＬＰ−１受容体作動薬が開発されている。現在、リラグルチド、エキセナチド、リキシセナチドなどが臨床使用されている。これらの薬剤はＧＬＰ−１と異なりＤＰＰ−４によって分解されにくい構造となっているために、投与した場合に作用が強力で持続する。 On the other hand, GLP-1 receptor agonists that bind to the GLP-1 receptor and exhibit a GLP-1-like action like GLP-1 have been developed. Currently, liraglutide, exenatide, lixisenatide and the like are in clinical use. Unlike GLP-1, these drugs have a structure that is difficult to be decomposed by DPP-4, and therefore, when administered, the action is strong and lasts.
このように、ＤＰＰ−４阻害剤とＧＬＰ−１受容体作動薬はその作用は同様にＧＬＰ−１受容体を介して示されるが、ＤＰＰ−４阻害剤が食事摂取に反応して分泌されるＧＬＰ−１の分解を抑えてＧＬＰ−１の体内濃度を高めて間接的に作用を示すのに対し、ＧＬＰ−１受容体作動薬はそのものがＧＬＰ−１受容体に作用して直接的に作用するものである。そのために両者の作用に大きな違いが現れる可能性がある。実際、ＤＰＰ−４阻害剤とＧＬＰ−１受容体作動薬は臨床試験において抗糖尿病作用を含むＧＬＰ−１作用に違いが見られることが明らかにされている。すなわち、ＤＰＰ−４阻害薬であるシタグリプチンとＧＬＰ−１受容体作動薬であるリラグルチドとを２型糖尿病患者を対象に５２週間にわたって効果や副作用を比較検討したところ、リラグルチドを投与された患者ではＨｂＡ１ｃが１．５１％低下したのに対し、シタグリプチンでは０．８８％の低下であった（この差は統計的に有意であった）。体重への影響は、リラグルチド投与患者では３．６８ｋｇ減少したのに対し、シタグリプチンでは１．１６ｋｇの減少にとどまった（この差は統計的に有意であった）。両薬の副作用はほぼ同等であった。この作用の強さの差は他の薬剤でも同様であった。すなわち、ＧＬＰ−１受容体作動薬では一般的にＨｂＡ１ｃの低下率が１％以上であるのに対し、ＤＰＰ−４阻害薬では１％未満であった。また、体重に関しても、ＧＬＰ−１受容体作動薬では明らかに体重減少が見られたが、ＤＰＰ−４阻害薬では体重減少効果はほとんど見られないかわずかといわれている。 Thus, DPP-4 inhibitors and GLP-1 receptor agonists are similarly shown to act via GLP-1 receptors, but DPP-4 inhibitors are secreted in response to food intake GLP-1 receptor agonists act indirectly by acting on GLP-1 receptor, while suppressing degradation of GLP-1 to increase the in-vivo concentration of GLP-1 and exhibit an indirect effect. To do. For this reason, there is a possibility that a big difference appears between the actions of the two. In fact, it has been shown that DPP-4 inhibitors and GLP-1 receptor agonists show differences in GLP-1 action including antidiabetic action in clinical trials. That is, when sitagliptin, which is a DPP-4 inhibitor, and liraglutide, which is a GLP-1 receptor agonist, were compared for 52 weeks in patients with type 2 diabetes, HbA1c was administered to patients who received liraglutide. Was 1.51%, compared to 0.88% for sitagliptin (this difference was statistically significant). The effect on body weight was reduced by 3.68 kg in patients receiving liraglutide, compared to a reduction of 1.16 kg in sitagliptin (this difference was statistically significant). The side effects of both drugs were almost the same. The difference in the strength of this action was the same for other drugs. That is, the decrease rate of HbA1c was generally 1% or more for GLP-1 receptor agonists, whereas it was less than 1% for DPP-4 inhibitors. Regarding the body weight, the GLP-1 receptor agonist clearly showed a weight loss, but the DPP-4 inhibitor is said to have little or no weight reduction effect.
ではＧＬＰ−１受容体作動薬とＤＰＰ−４阻害薬の作用の差はどこに原因があるのであろうか。ＧＬＰ−１受容体作動薬は化合物そのものがＧＬＰ−１受容体に結合しＧＬＰ−１作用を示すのに対し（理論的には１００％以上のＧＬＰ−１作用を示すことができる）、ＤＰＰ−４阻害薬では体内で分泌されるＧＬＰ−１の分解を抑えて間接的にＧＬＰ−１作用を示すために、その強さは体内で分泌されるＧＬＰ−１の量に大きく依存すると考えられる。実際、ＤＰＰ−４のノックアウトマウスのデータより、ＤＰＰ−４を１００％阻害しても血中の活性ＧＬＰ−１濃度の上昇は２倍程度が限度である。また、臨床的にも例えばシタグリプチンによってＤＰＰ−４がほぼ完全に阻害されている状況での活性ＧＬＰ−１の濃度上昇は約２倍であった。 So where is the difference in the action of GLP-1 receptor agonists and DPP-4 inhibitors? In contrast to GLP-1 receptor agonists, the compound itself binds to the GLP-1 receptor and exhibits GLP-1 action (theoretically can exhibit 100% or more GLP-1 action), whereas DPP- Since the 4 inhibitor suppresses the degradation of GLP-1 secreted in the body and indirectly exhibits GLP-1 action, its strength is considered to largely depend on the amount of GLP-1 secreted in the body. In fact, from the data of DPP-4 knockout mice, even if DPP-4 is inhibited by 100%, the increase in the concentration of active GLP-1 in the blood is limited to about twice. Also, clinically, for example, the increase in the concentration of active GLP-1 in a situation where DPP-4 was almost completely inhibited by sitagliptin was about twice.
本発明で解決しようとする課題は、ＤＰＰ−４阻害剤の弱い抗糖尿病作用（血糖低下作用）を増強する成分を見出し、これをＤＰＰ−４阻害剤の増強剤として糖尿病の治療用に提供することである。具体的には、安全性の極めて高い成分の併用によって、ＤＰＰ−４阻害剤の弱い抗糖尿病作用（血糖低下作用）が増強される、安全性の高い優れた医薬組成物を提供することが本発明の課題である。 The problem to be solved by the present invention is to find a component that enhances the weak anti-diabetic action (blood glucose lowering action) of a DPP-4 inhibitor, and to provide this as a DPP-4 inhibitor enhancer for the treatment of diabetes. That is. Specifically, the present invention provides an excellent highly safe pharmaceutical composition in which the weak anti-diabetic action (blood sugar lowering action) of a DPP-4 inhibitor is enhanced by the combined use of extremely safe ingredients. It is a subject of the invention.
本発明者は、かかる成分を探索すべく長年にわたって鋭意研究を行ってきた。その結果、ＤＰＰ−４阻害剤にＬ−アルギニンを併用することにより、ＤＰＰ−４阻害剤単独よりさらに強い抗糖尿病作用（血糖低下作用）を示す（すなわちＤＰＰ−４阻害剤の抗糖尿病作用（血糖低下作用）の増強作用）ことを見出した。このＬ−アルギニンによるＤＰＰ−４阻害剤の抗糖尿病作用（血糖低下作用）の増強作用は本発明者によって初めて見出されたものである。 The inventor has conducted extensive research for many years to search for such components. As a result, when L-arginine is used in combination with the DPP-4 inhibitor, the anti-diabetic action (blood glucose lowering action) stronger than that of the DPP-4 inhibitor alone is exhibited (that is, the anti-diabetic action of the DPP-4 inhibitor (blood glucose It was found that the potentiating action of the lowering action). This potentiation of the anti-diabetic action (blood glucose lowering action) of a DPP-4 inhibitor by L-arginine was first discovered by the present inventors.
ＤＰＰ−４阻害剤の血糖低下作用を、Ｌ−アルギニンが増強するメカニズムとして種々考えられるが、その一つとして、食物成分の一部（アミノ酸を含む）がＧＬＰ−１の分泌を促進することが知られているので、恐らくＬ−アルギニンによって分泌促進されたＧＬＰ−１の分解をＤＰＰ−４阻害剤が阻害することでＧＬＰ−１の働きが増強され、ＤＰＰ−４阻害剤の抗糖尿病作用（血糖低下作用）が増強されたものと考えられる。 Various mechanisms of L-arginine enhance the blood glucose lowering action of DPP-4 inhibitors, and one of them is that a part of food components (including amino acids) promotes secretion of GLP-1. Since it is known, the action of GLP-1 is enhanced by inhibiting the degradation of GLP-1 secreted by L-arginine by the DPP-4 inhibitor, and the anti-diabetic action of the DPP-4 inhibitor ( It is considered that the blood glucose lowering action was enhanced.
すなわち、本発明は以下の通りである。
（１）ＤＰＰ−４阻害剤の抗糖尿病作用を増強するためのＬ−アルギニンまたはその塩、およびその使用法。
（２）ＤＰＰ−４阻害剤とＬ−アルギニンまたはその塩とを含有する医薬組成物。
（３）糖尿病の治療用である上記（２）に記載の医薬組成物。
（４）ＤＰＰ−４阻害剤が、例えば、シタグリプチン、ビルダグリプチン、アログリプチン、リナグリプチン、テネリグリプチン、アナグリプチン、オキサグリプチンなどから選ばれる上記（１）〜（３）に記載の医薬組成物。That is, the present invention is as follows.
(1) L-arginine or a salt thereof for enhancing the antidiabetic effect of a DPP-4 inhibitor, and a method for using the same.
(2) A pharmaceutical composition comprising a DPP-4 inhibitor and L-arginine or a salt thereof.
(3) The pharmaceutical composition according to the above (2), which is used for treating diabetes.
(4) The pharmaceutical composition according to the above (1) to (3), wherein the DPP-4 inhibitor is selected from, for example, sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, oxagliptin and the like.
本発明により、ＤＰＰ−４阻害剤の弱い抗糖尿病作用（血糖低下作用）を増強し、より強い抗糖尿病作用（血糖低下作用）と高い安全性を兼ね備えた医薬組成物を提供することができる。 According to the present invention, it is possible to provide a pharmaceutical composition that enhances the weak antidiabetic action (blood sugar lowering action) of a DPP-4 inhibitor and has a stronger antidiabetic action (blood sugar lowering action) and high safety.
本発明におけるＤＰＰ−４阻害剤は、ＤＰＰ−４を阻害する薬剤であれば特に限定されないが、例えば、シタグリプチン、ビルダグリプチン、アログリプチン、リナグリプチン、テネリグリプチン、アナグリプチン、オキサグリプチンなどがあげられる。 The DPP-4 inhibitor in the present invention is not particularly limited as long as it is a drug that inhibits DPP-4, and examples thereof include sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and oxagliptin.
本発明における、上記のＤＰＰ−４阻害剤は国内にて販売されており、容易に入手できる。なお、各薬剤の用法用量は各薬剤の添付文書に記載されているためにここでは省くが、本発明における各薬剤の用法用量はこれに準拠する。 The above-mentioned DPP-4 inhibitor in the present invention is sold domestically and can be easily obtained. In addition, since the dosage of each drug is described in the package insert of each drug, it is omitted here, but the dosage of each drug in the present invention conforms to this.
本発明で使用されるＬ−アルギニンは、動物あるいは植物由来の天然タンパク質の加水分解から得られたもの、発酵法あるいは化学合成法によって得られたものいずれでも良い。アルギニンは光学異性体として、Ｄ体とＬ体が存在するが、本発明に使用するには、生体タンパク成分であるＬ体（Ｌ−アルギニン）を用いるのが望ましい。Ｌ−アルギニンはそのままあるいは種々の塩の形で用いても良い。Ｌ−アルギニンの塩としては、Ｌ−アルギニンが塩基性を示すために主に酸との塩が用いられる。酸としては、無機酸、有機酸いずれでも良い。無機酸の例としては、塩酸、硫酸、硝酸、燐酸、臭化水素酸、ヨー化水素酸などがあげられる。有機酸の例としては、蟻酸、酢酸、プロピオン酸、蓚酸、コハク酸、マレイン酸、フマル酸、クエン酸、グルタミン酸、アスパラギン酸などがあげられる。 The L-arginine used in the present invention may be either one obtained by hydrolysis of natural protein derived from animals or plants, or one obtained by fermentation or chemical synthesis. Arginine has D-form and L-form as optical isomers. For use in the present invention, it is desirable to use L-form (L-arginine) which is a biological protein component. L-arginine may be used as it is or in the form of various salts. As a salt of L-arginine, a salt with an acid is mainly used because L-arginine shows basicity. The acid may be either an inorganic acid or an organic acid. Examples of inorganic acids include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydriodic acid and the like. Examples of organic acids include formic acid, acetic acid, propionic acid, succinic acid, succinic acid, maleic acid, fumaric acid, citric acid, glutamic acid, aspartic acid and the like.
本発明のＬ−アルギニンまたはＬ−アルギニン塩の医薬組成物としての投与量は、本発明の病気の状態、病人の体重、年齢、体質、体調等によって調整されるべきであるが、一般に１日あたり、Ｌ−アルギニンに換算して、０．００１ｇ〜３０ｇ、好ましくは０．０１ｇ〜２０ｇの範囲で適宜選択することができる。これを病気の状態や医薬組成物の形態によって１日１ないし数回にわけて投与することができる。 The dose of the L-arginine or L-arginine salt of the present invention as a pharmaceutical composition should be adjusted according to the disease state of the present invention, the weight, age, constitution, physical condition, etc. of the sick person, In terms of L-arginine, it can be appropriately selected within the range of 0.001 g to 30 g, preferably 0.01 g to 20 g. This can be administered once to several times a day depending on the disease state and the form of the pharmaceutical composition.
本発明の医薬組成物には、本発明の効果が阻害されない限り、添加物として、賦形剤、結合剤、滑沢剤、コーティング剤、防腐剤、着色剤、安定剤、ｐＨ調節剤、溶解補助剤、清涼剤、香料、などを配合することができる。 In the pharmaceutical composition of the present invention, as long as the effects of the present invention are not inhibited, additives, excipients, binders, lubricants, coating agents, preservatives, colorants, stabilizers, pH regulators, dissolution agents An adjuvant, a refreshing agent, a fragrance | flavor, etc. can be mix | blended.
本発明の医薬組成物の剤形は、固形剤が望ましく、その具体的な剤形としては、例えば、錠剤、顆粒剤、散剤、カプセル剤等があげられる。 The dosage form of the pharmaceutical composition of the present invention is preferably a solid preparation. Specific examples of the dosage form include tablets, granules, powders, capsules and the like.
本発明の医薬組成物の製剤は、当該分野で公知の方法で製造することができる。 The preparation of the pharmaceutical composition of the present invention can be produced by a method known in the art.
本発明の医薬組成物は、糖尿病または糖尿病に起因する疾患（糖尿病合併症）の治療に有効である。さらに、本発明の医薬組成物は、優れた血糖低下作用を示し、有効性と安全性を兼ね備えていることを特徴とする。 The pharmaceutical composition of the present invention is effective for the treatment of diabetes or diseases caused by diabetes (diabetic complications). Furthermore, the pharmaceutical composition of the present invention exhibits an excellent blood glucose lowering action and is characterized by having both effectiveness and safety.
本発明の医薬組成物を上記疾患に投与する場合には、経口的に投与することが好ましい。その場合、上記の一日あたりの投与量を１日１回または数回に分けて投与する。 When the pharmaceutical composition of the present invention is administered to the above diseases, it is preferably administered orally. In that case, the above-mentioned daily dose is administered once or several times a day.
以下、本発明をさらに具体的に説明するが、本発明はこれに限定されるものではない。 Hereinafter, the present invention will be described more specifically, but the present invention is not limited thereto.
Ａは糖尿病を患っていた。血糖低下剤としてＤＰＰ−４阻害剤を処方され、それを摂取していたがその効果は満足のいくものでなかった。そこでＡは、Ｌ−アルギニンを、ＤＰＰ−４阻害剤と共に、１日あたり４ないし１２ｇ摂取したところ、血糖値はより低下し、その効果は満足すべきものであった。副作用はほとんど見られなかった。 A suffered from diabetes. DPP-4 inhibitor was prescribed as a hypoglycemic agent and was ingested, but the effect was not satisfactory. Therefore, when A took 4 to 12 g of L-arginine together with the DPP-4 inhibitor per day, the blood glucose level was further lowered, and the effect was satisfactory. There were almost no side effects.
本発明の医薬組成物は、高い抗糖尿病作用（血糖低下作用）と安全性を兼ね備えた医薬組成物である。従って、本発明は、糖尿病患者への予防または治療剤として有用である。 The pharmaceutical composition of the present invention is a pharmaceutical composition having both high antidiabetic action (blood sugar lowering action) and safety. Therefore, the present invention is useful as a preventive or therapeutic agent for diabetic patients.
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| JP (1) | JP2015098464A (en) |
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2013
- 2013-11-18 JP JP2013251496A patent/JP2015098464A/en active Pending
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