JP3103588B2 - Lipoprotein (a) lowering agent - Google Patents
Lipoprotein (a) lowering agentInfo
- Publication number
- JP3103588B2 JP3103588B2 JP02312010A JP31201090A JP3103588B2 JP 3103588 B2 JP3103588 B2 JP 3103588B2 JP 02312010 A JP02312010 A JP 02312010A JP 31201090 A JP31201090 A JP 31201090A JP 3103588 B2 JP3103588 B2 JP 3103588B2
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- Prior art keywords
- acid
- icosapentic
- lowering agent
- lipoprotein
- lowering
- Prior art date
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Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は、有効成分としてイコサペント酸を含有する
リポプロテイン（ａ）（以下Lp（ａ）ということがあ
る。）低下剤に関するものである。イコサペント酸と
は、all−cis−5,8,11,14,17−icosapentaenoic acid
（遊離体）、その製薬学上許容しうる塩およびエステル
である。The present invention relates to a lipoprotein (a) (hereinafter sometimes referred to as Lp (a)) lowering agent containing icosapentic acid as an active ingredient. Eicosapentic acid is all-cis-5,8,11,14,17-icosapentaenoic acid
(Free form), its pharmaceutically acceptable salts and esters.
［従来の技術および発明が解決しようとする課題］ 血清Lp（ａ）はコレステロールに富み、カルシウム存
在下で凝集しやすく、グリコサミノグリカン等の結合織
成分と結合しやすいため動脈壁への脂質沈着を起こす可
能性が指摘されている（野間昭夫ら、動脈硬化、17巻、
639〜658頁、1989年）。また、グリコサミノグリカン等
の結合したLp（ａ）はマクロファージに取り込まれやす
くなり、泡沫細胞化の促進に働く可能性がある。さら
に、Lp（ａ）に特有なアポ蛋白のアポ（ａ）はプラスミ
ノーゲンとの相同性が高く（Karadi,I.ら、Biochemi.Bi
ophys.Acta.,960巻、91〜97頁、1988年）、線溶機構を
抑制することが示唆されている（Edelberg,J.M.ら,Bioc
hemistry,28巻、2370〜2374頁、1989年、Hajjar,K.A
ら、Nature,339巻、303〜305頁、1989年）。これらのこ
とは、Lp（ａ）が動脈硬化の発症、進展に働くことを示
唆すると考えられる。実際、Lp（ａ）は虚血性心疾患、
冠動脈バイパス手術後の再狭窄、脳梗塞、頚動脈硬化、
腹部大動脈瘤、血管性痴呆、糖尿病、糖尿病性網膜症お
よび血管障害性のパーキンソン病等に対して、従来の低
比重リポプロテインコレステロールや血小板凝集などと
は異なる独立した危険因子と考えられている（野間昭夫
ら、動脈硬化、17巻、639〜658頁、1989年）。[Problems to be Solved by Conventional Techniques and Inventions] Serum Lp (a) is rich in cholesterol, easily aggregates in the presence of calcium, and easily binds to connective tissue components such as glycosaminoglycan, so that lipids on the artery wall It has been pointed out that deposition may occur (Akio Noma et al., Atherosclerosis, Vol. 17,
639-658, 1989). Further, Lp (a) to which glycosaminoglycan or the like is bound is easily taken up by macrophages, and may work to promote foam cell formation. Furthermore, the apoprotein (a) specific to Lp (a) has high homology to plasminogen (Karadi, I. et al., Biochemi. Bi).
960, pp. 91-97, 1988), which has been suggested to suppress the fibrinolytic mechanism (Edelberg, JM et al., Bioc.
hemistry, Vol. 28, pp. 2370-2374, 1989, Hajjar, KA
Et al., Nature, 339, 303-305, 1989). These facts are considered to suggest that Lp (a) acts on the development and progression of arteriosclerosis. In fact, Lp (a) is ischemic heart disease,
Restenosis, cerebral infarction, carotid atherosclerosis after coronary artery bypass surgery,
It is considered to be an independent risk factor for abdominal aortic aneurysms, vascular dementia, diabetes, diabetic retinopathy, vasopathic Parkinson's disease, etc., different from conventional low-density lipoprotein cholesterol, platelet aggregation, etc. ( Noma, Akio et al., Atherosclerosis, 17, 639-658, 1989).
一方、従来の高脂血症治療剤は血漿脂質のうち、主に
低比重リポ蛋白コレステロールおよびトリグリセリドの
低下作用に着目された薬剤であり、Lp（ａ）への作用は
ほとんど注目されていなかった。近年、従来の高脂血症
治療剤のLp（ａ）に対する作用について以下のような報
告がある。高脂血症治療剤として公知であるプロブコー
ル（Maeds,S.ら、Atherosclerosis、79巻,267〜269頁、
1989年）、クロフィブレート（Albers,J.ら、Metabolis
m,24巻、1047〜1054頁,1975年）、コレスチラミン（Ler
en,T.P.ら、Atherosclerosis,73巻、135〜141頁、1988
年）、プラバスタチン（Jacob,B.G.ら、Ann.Intern.Me
d.,112巻、713〜714頁、1990年）、ロバスタチン、シン
バスタチン（Kostner,G.M.ら、Circulation,80巻、1313
〜1319頁、1989年）およびエプタスタチン（村井淳志
ら、動脈硬化、15巻、1461〜1464頁、1987年）等は血清
Lp（ａ）低下作用を有さず、むしろ上昇傾向を示す例す
らある。わずかにニコチン酸製剤（Carlson,L.A.ら、J.
Intern.Med.,226巻、271〜276頁、1989年）、ベザフィ
ブレート（Schwartzkopff,W.ら、Muench.Med.Wochensch
r.,130巻、422〜426頁、1988年）などに血清Lp（ａ）低
下作用が認められているにすぎない。また、ステロイド
剤であるスタノゾール（Albers,J.ら、Biochemica Biop
hysica Acta.,795巻、293〜296頁、1984年）、抗生物質
であるネオマイシン（Gurakar,A.ら、Atherosclerosis,
57巻、293〜301頁、1985年）に血清Lp（ａ）低下作用が
認められているが、副作用等の面で問題がある。On the other hand, conventional therapeutic agents for hyperlipidemia mainly focus on the lowering effect of low-density lipoprotein cholesterol and triglyceride in plasma lipids, and the effect on Lp (a) was hardly noticed. . In recent years, the following reports have been reported on the effects of a conventional therapeutic agent for hyperlipidemia on Lp (a). Probucol known as a therapeutic agent for hyperlipidemia (Maeds, S. et al., Atherosclerosis, 79, 267-269,
1989), clofibrate (Albers, J. et al., Metabolis
m, 24, 1047-1054, 1975), cholestyramine (Ler
en, TP et al., Atherosclerosis, 73, 135-141, 1988
Pravastatin (Jacob, BG et al., Ann. Intern. Me)
d., 112, 713-714, 1990), lovastatin, simvastatin (Kostner, GM et al., Circulation, 80, 1313)
Pp. 1319, 1989) and eptastatin (Atsushi Murai et al., Atherosclerosis, 15, 1461-1464, 1987)
There is even an example that has no Lp (a) lowering effect, but rather shows an upward trend. Slightly nicotinic acid preparations (Carlson, LA et al., J.
Intern. Med., 226, 271-276, 1989), bezafibrate (Schwartzkopff, W. et al., Muench. Med. Wochensch).
r., 130, 422-426, 1988), etc., only have an effect of lowering serum Lp (a). In addition, stanosol, a steroid drug (Albers, J. et al., Biochemica Biop.
hysica Acta., 795, 293-296, 1984), the antibiotic neomycin (Gurakar, A. et al., Atherosclerosis,
57, pp. 293-301, 1985), has an effect of lowering serum Lp (a), but has problems in side effects and the like.
魚油あるいはイコサペント酸およびドコサヘキサエン
酸を含む魚肝油等の健康食品の血清Lp（ａ）低下作用に
関する報告もされているが、Lp（ａ）を低下させたとす
る報告（Gavish,D.ら、Clin.Res.,38巻、250A頁、1990
年）、作用なしとする報告（Gries,A.ら、Thrombosis R
es.,58巻、667〜668頁、1990年）および運動負荷との併
用で一部の患者のLp（ａ）を低下させたとする報告（He
rrmann,W.ら、Med.Klin.,84巻、429〜433頁、1989年）
等、相反する結果が得られている。また、仮に魚油がLp
（ａ）低下作用をあらわすとしても、これまでの知見で
は有効成分が何であるのかまったくわかっておらず、脂
肪酸や他のビタミン等が作用している可能性もある。There have been reports on the serum Lp (a) lowering effect of health foods such as fish oil or fish liver oil containing icosapentic acid and docosahexaenoic acid, but reports that Lp (a) was reduced (Gavish, D. et al., Clin. Res. ., 38, 250A, 1990
Year), reported no effect (Gries, A. et al., Thrombosis R
es., 58, 667-668, 1990) and reports that Lp (a) of some patients was reduced in combination with exercise load (He
rrmann, W. et al., Med. Klin., 84, 429-433, 1989)
And other contradictory results. Also, if the fish oil is Lp
(A) Even if it shows a lowering effect, the findings so far do not at all know what the active ingredient is, and there is a possibility that fatty acids and other vitamins are acting.
さらに、魚油や健康食品についてはいずれもイコサペ
ント酸含有量が低く、血小板凝集作用等を有するトロン
ボキサンA2や白血球遊走作用を有するロイコトリエンB4
の前駆体であるアラキドン酸なども含まれる。また、魚
油や健康食品で有効性を高めるためにその投与量を上げ
ると、脂肪酸によるカロリー過多やビタミンA,Dを過剰
に摂取する等の危険性があり、さらに、悪心、嘔吐、下
痢、腹痛および体重増加等の副作用発現率も高い（Rei
s,G.J.,Lancet,Aug 31,2等、8656号、177〜181頁、1989
年）。Furthermore, the fish oils and health foods are both eicosapentaenoic acid content is low, leukotriene B 4 having a thromboxane A 2 and leukocyte migration action with platelet aggregation action and the like
Arachidonic acid, which is a precursor of In addition, increasing the dosage of fish oils and health foods to increase their effectiveness may lead to excessive calories due to fatty acids, excessive intake of vitamins A and D, etc., as well as nausea, vomiting, diarrhea, and abdominal pain. And high incidence of side effects such as weight gain (Rei
s, GJ, Lancet, Aug 31, 2 etc., 8656, pp. 177-181, 1989
Year).
魚油中のイコサペント酸に注目してみると、これは血
清総コレステロールおよびトリグリセリド低下作用を有
することが知られている。また、イコサペント酸、その
塩、エステルまたはアミドを高純度含有する血栓症治療
または予防のための処方物が特公昭62−57605に開示さ
れている。また、高純度イコサペント酸エチル製剤であ
るエパデール（持田製薬）投与による副作用発現率は
低いことが知られている（O.H.P.学術情報委員会、O.H.
P.news,32巻、205〜208頁、1990年）。しかし、イコサ
ペント酸、その塩もしくはエステルのLp（ａ）に対する
作用についての知見は現在までない。Looking at icosapentic acid in fish oil, it is known to have serum total cholesterol and triglyceride lowering effects. A formulation for treating or preventing thrombosis, which contains icosapentic acid, its salts, esters or amides in high purity, is disclosed in JP-B-62-57605. It is also known that the incidence of side effects due to the administration of epadel (Mochida Pharmaceutical), a high-purity ethyl icosapentate preparation, is low (OHP Academic Information Committee, OH
P. news, 32, 205-208, 1990). However, there is no knowledge about the action of icosapentic acid, its salt or ester on Lp (a).
以上のことからもわかるように、血清Lp（ａ）は食餌
や薬物の影響を受けにくいことが知られている。このた
め、血清Lp（ａ）低下作用を有し、かつ安全に投与でき
る薬剤の開発が切望されている。As can be seen from the above, it is known that serum Lp (a) is hardly affected by diet and drugs. Therefore, development of a drug that has a serum Lp (a) lowering effect and can be safely administered has been desired.
［課題を解決するための手段］ 本発明者らは、上記課題を解決するため鋭意研究を行
った結果、イコサペント酸に血清Lp（ａ）低下作用を見
いだし、本発明を完成した。[Means for Solving the Problems] The present inventors have conducted intensive studies to solve the above problems, and as a result, have found a serum Lp (a) lowering effect of icosapentic acid, thereby completing the present invention.
すなわち本発明は、有効成分としてイコサペント酸を
含有するリポプロテイン（ａ）低下剤である。That is, the present invention is a lipoprotein (a) lowering agent containing icosapentic acid as an active ingredient.
この有効成分にさらにイコサペント酸以外の脂肪酸を
含有してもよく、全脂肪酸中のイコサペント酸の含有量
は少なくとも50重量％であるのが好ましい。The active ingredient may further contain a fatty acid other than icosapentic acid, and the content of icosapentic acid in the total fatty acids is preferably at least 50% by weight.
また、有効成分として、イコサペント酸エチルエステ
ルが好ましい。Also, ethyl icosapentate is preferred as the active ingredient.
以下に本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
本発明のLp（ａ）低下剤は、有効成分としイコサペン
ト酸を含有する。The Lp (a) lowering agent of the present invention contains icosapentic acid as an active ingredient.
本発明のLp（ａ）低下剤中のイコサペント酸は、エチ
ルエステル等のアルキルエステルまたはグリセリド等の
製薬学上許容されるエステルとすることができる。ま
た、ナトリウム塩、カリウム塩等の無機塩基またはベン
ジルアミン塩、ジエチルアミン塩等の有機塩基あるいは
アルギニン塩、リジン塩等の塩基性アミノ酸との製薬学
上許容される塩を形成することもできる。The icosapentic acid in the Lp (a) -lowering agent of the present invention can be an alkyl ester such as an ethyl ester or a pharmaceutically acceptable ester such as glyceride. Also, a pharmaceutically acceptable salt can be formed with an inorganic base such as a sodium salt or a potassium salt, an organic base such as a benzylamine salt or a diethylamine salt, or a basic amino acid such as an arginine salt or a lysine salt.
本発明の低下剤は、さらに、イコサペント酸以外の脂
肪酸を含有してもよい。これらの脂肪酸は、ドコサヘキ
サエン酸、ドコサペンタエン酸、ドコサモノエン酸、ア
ラキドン酸、エイコサテトラエン酸、エイコサトリエン
酸、エイコサモノエン酸、オクタデカテトラエン酸、α
−リノレン酸、リノール酸、オレイン酸、パルミトオレ
イン酸、ヘキサデカテトラエン酸、ヘキサデカトリエン
酸およびヘキサデカジエン酸等の不飽和脂肪酸あるいは
ベヘン酸、アラキジン酸、ステアリン酸、パルミチン酸
およびミリスチン酸等の飽和脂肪酸等が例示される。The reducing agent of the present invention may further contain a fatty acid other than icosapentic acid. These fatty acids include docosahexaenoic acid, docosapentaenoic acid, docosamonoenoic acid, arachidonic acid, eicosatetraenoic acid, eicosatrienoic acid, eicosamonoenoic acid, octadecatetraenoic acid, α
-Unsaturated fatty acids such as linolenic acid, linoleic acid, oleic acid, palmitooleic acid, hexadecatetraenoic acid, hexadecatrienoic acid and hexadecadienoic acid or behenic acid, arachidic acid, stearic acid, palmitic acid and myristic acid And the like.
また、本発明でいうイコサペント酸をはじめとする脂
肪酸とは特に断らない限り、上述の例の脂肪酸の遊離体
のほか、それらのナトリウム塩等の無機塩基との塩また
はベンジルアミン塩等の有機塩基との塩、さらにはそれ
らのエチルエステル等のアルキルエステルまたはグリセ
リド等のエステル体を意味する。Unless otherwise specified, fatty acids such as icosapentic acid in the present invention include, in addition to the free form of the above-described fatty acids, salts thereof with inorganic bases such as sodium salts and organic bases such as benzylamine salts. And an alkyl ester such as ethyl ester or an ester such as glyceride thereof.
本発明のLp（ａ）低下剤の全脂肪酸中のイコサペント
酸は50重量％以上、好ましくは70重量％以上であり、さ
らに好ましくは90重量％以上であり、アラキドン酸含量
は少ないことが望まれる。The icosapentic acid in the total fatty acids of the Lp (a) lowering agent of the present invention is at least 50% by weight, preferably at least 70% by weight, more preferably at least 90% by weight, and it is desired that the arachidonic acid content is low. .
このようなイコサペント酸（遊離体）あるいはそのエ
ステルは、例えば魚油などの天然油脂より連続式蒸留法
や液体クロマトグラフィー法等により得ることができ
る。イコサペント酸（遊離体）は、イコサペント酸エス
テルを既知の方法により加水分解する事によって得る事
もできる。あるいは既存の市販品、例えば、純度約90％
のイコサペント酸（遊離体）、純度約98％のイコサペン
ト酸ナトリウム塩、純度約99％のイコサペント酸メチル
エステル（以上シグマケミカル社製）、純度90％以上の
イコサペント酸（遊離体）（アルドリッチケミカル社
製、ナカライテスク社製およびフルカケミカルバイオケ
ミカ社製）、純度95％以上のイコサペント酸（遊離体）
（フナコシ薬品社製）および純度90％のイコサペント酸
エチルエステル（東京化成工業社製）等を用いることが
できる。Such icosapentic acid (free form) or an ester thereof can be obtained from a natural fat or oil such as fish oil by a continuous distillation method or a liquid chromatography method. Eicosapentic acid (free form) can also be obtained by hydrolyzing icosapentic acid ester by a known method. Or an existing commercial product, for example, about 90% pure
Icosapentic acid (free form), icosapentic acid sodium salt of about 98% purity, icosapentic acid methyl ester of about 99% purity (manufactured by Sigma Chemical Co.), icosapentic acid (free form) of 90% or more purity (Aldrich Chemical Company) Manufactured by Nacalai Tesque and Fluka Chemical Biochemicals), icosapentic acid with a purity of 95% or more (free form)
(Manufactured by Funakoshi Pharmaceutical Co., Ltd.) and 90% pure icosapentic acid ethyl ester (manufactured by Tokyo Chemical Industry Co., Ltd.).
本発明のLp（ａ）低下剤の成人１日当たりの治療量
は、イコサペント酸として0.5ないし5.0gであるが、投
与経路あるいは症状により適宜増減することができ、全
量を一度に投与することや分割して投与することも可能
である。投与経路としては、経口投与が好ましいが、静
脈内、直腸内投与の他、外用剤としても使用可能であ
り、軟カプセル剤、錠剤および乳剤などの単位投与形態
を取り得る。The therapeutic amount of the Lp (a) lowering agent of the present invention per adult per day is 0.5 to 5.0 g as icosapentic acid, but can be appropriately increased or decreased depending on the administration route or symptoms. It is also possible to administer. The administration route is preferably oral administration, but can be used as an external preparation in addition to intravenous and rectal administration, and can take unit dosage forms such as soft capsules, tablets and emulsions.
以下、本発明のLp（ａ）低下剤の有効性、安全性、お
よび治療剤の製法について述べる。Hereinafter, the efficacy, safety, and method for producing a therapeutic agent of the Lp (a) lowering agent of the present invention will be described.
血清Lp（ａ）濃度に対する作用 正脂血症者および高脂血症者合わせて６名に、エパデ
ールを2.7g/日経口投与し、投与前、投与後４および1
2週目に採血し血清Lp（ａ）値をバイオプール社製のプ
レートを使用した酸素免疫測定法で測定した。Effect on Serum Lp (a) Concentration Epadale was orally administered at 2.7 g / day to a total of 6 patients with normolipidemia and hyperlipidemia before administration, and 4 and 1 after administration.
Blood was collected on the second week, and serum Lp (a) value was measured by an oxygen immunoassay using a BioPool plate.
第１表に結果を示す。 Table 1 shows the results.
以上のように、エパデール12週間連続経口投与によ
り、特に高いLp（ａ）値の人を含めて全例でLp（ａ）の
著しい低下作用が認められた。この作用はほとんどの人
で４週目から認められた。また、投与期間中顕著な副作
用は認められなかった。 As described above, a remarkable Lp (a) lowering effect was observed in all cases including those with particularly high Lp (a) values by continuous oral administration of epadale for 12 weeks. This effect was observed in most people from the fourth week. No remarkable side effects were observed during the administration period.
エパデールは安全性が高いことが知られており、毒
性試験に関しては、次の文献に記載がある。渋谷靖義
ら、医薬品研究、20巻、801〜844頁、1989年。また、イ
コサペント酸（遊離体）およびトリグリセリド型イコサ
ペント酸も同様に高い安全性を有する。Epadel is known to have high safety, and toxicity studies are described in the following literature. Yasuyoshi Shibuya et al., Pharmaceutical Research, 20, 801-844, 1989. In addition, icosapentic acid (free form) and triglyceride-type icosapentic acid also have high safety.
以上の説明および試験結果より明らかなように、本発
明Lp（ａ）低下剤は著名なLp（ａ）低下作用を有し、安
全性も高いことから、Lp（ａ）低下剤として有用であ
る。また、Lp（ａ）が危険因子と考えられている疾患、
例えば、虚血性心疾患、冠動脈バイパス手術後の再狭
窄、脳梗塞、頚動脈硬化、腹部大動脈瘤、血管性痴呆、
糖尿病、糖尿病性網膜症および血管障害性のパーキンソ
ン病等の予防および治療にも有効である。As is clear from the above description and the test results, the Lp (a) -lowering agent of the present invention has a remarkable Lp (a) -lowering effect and is highly safe, and thus is useful as an Lp (a) -lowering agent. . A disease in which Lp (a) is considered a risk factor;
For example, ischemic heart disease, restenosis after coronary artery bypass surgery, cerebral infarction, carotid atherosclerosis, abdominal aortic aneurysm, vascular dementia,
It is also effective for the prevention and treatment of diabetes, diabetic retinopathy, and vasculopathy Parkinson's disease.
また、本発明のLp（ａ）低下剤は、任意、慣用の製薬
用担体、基剤あるいは賦形剤とともに慣用の方法で、医
薬製剤に調製することができる。In addition, the Lp (a) -lowering agent of the present invention can be prepared into a pharmaceutical preparation by any conventional method together with any conventional pharmaceutical carrier, base or excipient.
次に製剤の実施例を示すが、本発明は以下の実施例に
限定されるものではない。Next, examples of the preparation are shown, but the present invention is not limited to the following examples.
実施例Ａ 軟カプセル剤 軟質ゼラチンカプセル（約0.5ml容）を滅菌し、エチ
ル化および精製した魚油、すなわちイコサペント酸エチ
ル90.6％、アラキドン酸エステル2.3％、オクタデカテ
トラエン酸エチル2.2％、ω−３イコサテトラエン酸エ
チル0.7％を含む組成物にビタミンＥを0.2％となるよう
に加えて、イコサペント酸エチルとして300mgとなるよ
うに満たし、次いで封じた。Example A Soft Capsules Soft gelatin capsules (about 0.5 ml volume) are sterilized, ethylated and purified fish oil, ie 90.6% ethyl icosapentate, 2.3% arachidonic ester, 2.2% ethyl octadecatetraenoate, ω- (3) Vitamin E was added to a composition containing 0.7% ethyl icosatetraenoate to a concentration of 0.2%, filled to 300 mg as ethyl icosapentate, and then sealed.
実施例Ｂ 乳剤 イコサペント酸エチル 11 流動パラフィン ９ ミリスチン酸イソプロピル ５ セタノール ５ モノステアリン酸ソルビタン 3.8 モノステアリン酸ポリオキシ エチレンソルビタン 6.2 ジブチルヒドロキシトルエン 0.2 パラオキシ安息香酸メチル 0.2 パラオキシ安息香酸プロピル 0.1 精製水 59.5 100重量％ 上記各成分のうち、精製水以外の成分を80℃にて加熱
溶解し、これに80℃に加熱した精製水を撹拌しながら徐
々に加え、10分間乳化させる。その後撹拌しながら35℃
まで冷却し、均一な乳化物を得る。Example B Emulsion Ethyl icosapentate 11 Liquid paraffin 9 Isopropyl myristate 5 Cetanol 5 Sorbitan monostearate 3.8 Polyoxyethylene sorbitan monostearate 6.2 Dibutylhydroxytoluene 0.2 Methyl parahydroxybenzoate 0.2 Propyl parahydroxybenzoate 0.1 Purified water 59.5 100% by weight Among the components, components other than purified water are heated and dissolved at 80 ° C., and purified water heated to 80 ° C. is gradually added thereto with stirring, and emulsified for 10 minutes. 35 ° C with stirring
Cool to obtain a uniform emulsion.
［発明の効果］ 本発明Lp（ａ）は低下剤は著明なLp（ａ）低下作用を
有し、また、トリグリセライドリッチリポプロテイン部
分に出現するLp（ａ）も低下させる。これらが危険因子
と考えられている疾患、例えば、虚血性心疾患、冠動脈
バイパス手術後の再狭窄、脳梗塞、頚動脈硬化、腹部大
動脈瘤、血管性痴呆、糖尿病、糖尿病性網膜症および血
管障害性のパーキンソン病等の予防剤および治療剤とし
て期待される。一方、本発明Lp（ａ）低下剤は高純度イ
コサペント酸を有効成分としたものであり、アラキドン
酸等の不純物含有量が少なく、魚油で認められるような
副作用がなく高い安全性を有することから、事実上Lp
（ａ）低下剤として使用し得る初めての製剤である。[Effect of the Invention] The Lp (a) of the present invention has a remarkable Lp (a) lowering effect, and also reduces Lp (a) appearing in the triglyceride-rich lipoprotein portion. Diseases for which these are considered risk factors, such as ischemic heart disease, restenosis after coronary artery bypass surgery, cerebral infarction, carotid atherosclerosis, abdominal aortic aneurysm, vascular dementia, diabetes, diabetic retinopathy and vascular disorders Is expected as a prophylactic and therapeutic agent for Parkinson's disease. On the other hand, the Lp (a) lowering agent of the present invention contains high-purity icosapentic acid as an active ingredient, has a low content of impurities such as arachidonic acid, and has high safety without side effects as observed in fish oil. , In effect Lp
(A) This is the first formulation that can be used as a reducing agent.
───────────────────────────────────────────────────── フロントページの続き (58)調査した分野(Int.Cl.7，ＤＢ名) A61K 31/202 A61K 31/232 A61P 3/06 ＣＡ（ＳＴＮ) ＥＭＢＡＳＥ（ＳＴＮ) ＭＥＤＬＩＮＥ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. 7 , DB name) A61K 31/202 A61K 31/232 A61P 3/06 CA (STN) EMBASE (STN) MEDLINE (STN)
Claims (4)
リポプロテイン（ａ）低下剤。A lipoprotein (a) lowering agent containing icosapentic acid as an active ingredient.
外の脂肪酸、その塩およびエステルを含有する請求項１
記載のリポプロテイン（ａ）低下剤。2. The active ingredient further comprises a fatty acid other than icosapentic acid, salts and esters thereof.
The lipoprotein (a) lowering agent according to the above.
エステル中の少なくとも50重量％である請求項２記載の
リポプロテイン（ａ）低下剤。3. The lipoprotein (a) lowering agent according to claim 2, wherein the active ingredient is at least 50% by weight of the total fatty acids, salts and esters thereof.
テルである請求項１ないし３のいずれかに記載のリポプ
ロテイン（ａ）低下剤。4. The lipoprotein (a) lowering agent according to claim 1, wherein the active ingredient is ethyl icosapentate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02312010A JP3103588B2 (en) | 1990-11-16 | 1990-11-16 | Lipoprotein (a) lowering agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02312010A JP3103588B2 (en) | 1990-11-16 | 1990-11-16 | Lipoprotein (a) lowering agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH04182426A JPH04182426A (en) | 1992-06-30 |
| JP3103588B2 true JP3103588B2 (en) | 2000-10-30 |
Family
ID=18024125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP02312010A Expired - Lifetime JP3103588B2 (en) | 1990-11-16 | 1990-11-16 | Lipoprotein (a) lowering agent |
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| Country | Link |
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| JP (1) | JP3103588B2 (en) |
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| WO2005046668A1 (en) * | 2003-11-14 | 2005-05-26 | Mochida Pharmaceutical Co., Ltd. | Preventive/therapeutic agent for speech disorder |
| EP1968402A2 (en) * | 2005-10-07 | 2008-09-17 | Ocean Nutrition Canada Limited | Salts of fatty acids and methods of making and using thereof |
| JPWO2009142242A1 (en) * | 2008-05-20 | 2011-09-29 | 持田製薬株式会社 | Composition for preventing cardiovascular events in high-risk patients |
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| RU2489145C1 (en) | 2009-04-29 | 2013-08-10 | АМАРИН КОРПОРЕЙШН ПиЭлСи | Pharmaceutical compositions containing epa and cardiovascular drug, and method for preparing them |
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| SI4056176T1 (en) | 2018-09-24 | 2024-09-30 | Amarin Pharmaceuticals Ireland Limited | Methods of reducing the risk of cardiovascular events in a subject |
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