JPH04182426A - Agent for suppressing lipoprotein (a) - Google Patents

Agent for suppressing lipoprotein (a)

Info

Publication number
JPH04182426A
JPH04182426A JP31201090A JP31201090A JPH04182426A JP H04182426 A JPH04182426 A JP H04182426A JP 31201090 A JP31201090 A JP 31201090A JP 31201090 A JP31201090 A JP 31201090A JP H04182426 A JPH04182426 A JP H04182426A
Authority
JP
Japan
Prior art keywords
acid
icosapent
agent
ester
lipoprotein
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.)
Granted
Application number
JP31201090A
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Japanese (ja)
Other versions
JP3103588B2 (en
Inventor
Yuichiro Goshima
五島 雄一郎
Yasuhiko Honma
本間 康彦
Hisami Oshima
大島 久美
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mochida Pharmaceutical Co Ltd
Original Assignee
Mochida Pharmaceutical Co Ltd
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Filing date
Publication date
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Priority to JP02312010A priority Critical patent/JP3103588B2/en
Publication of JPH04182426A publication Critical patent/JPH04182426A/en
Application granted granted Critical
Publication of JP3103588B2 publication Critical patent/JP3103588B2/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Abstract

PURPOSE:To provide an agent for suppressing lipoprotein (a) level, containing eicosapentanoic acid or its salt or ester as an active component, free from side effect and having high safety. CONSTITUTION:The objective agent contains at least one kind of substance selected from eicosapentanoic acid, its pharmacologically permissible salt and ester as an active component. The active component may contain fatty acids other than eicosapentanoic acid and, in such a case, the content of eicosapentanoic acid is >=50wt.% (especially >=90wt.%) based on the total fatty acid and the content of arachidonic acid is preferably as small as possible. The lowering agent is effective for the prevention and therapeutic treatment of ischemic cardiopathy, restenosis after bypass operation of coronary artery, cerebral infarction, carotid arteriosclerosis, abdominal aneurysm, vascular dementia, diabetes. angiopathic Parkinson's disease, etc.

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、その製薬学
上許容しうる塩およびエズテルからなる群から選ばれる
少なくとも1つ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。
Detailed Description of the Invention [Industrial Application Field] The present invention provides a lipoprotein (a ) (hereinafter sometimes referred to as Lp (a)) relates to a lowering agent.

イコサペント酸とは、all−cis−5,8,11,
14,17−icosapentaenoic aci
dである。
Icosapentoic acid is all-cis-5,8,11,
14,17-icosapentaenoic aci
It is d.

[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冨み、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
ミノグリカン等と結合した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((Ka
radi、 I 、ら、Biochemi。
[Prior Art and Problems to be Solved by the Invention] Serum Lp(a) is rich in cholesterol, tends to aggregate in the presence of calcium, and easily binds to connective tissue components such as glycosaminoglycans, so it does not reach the arterial wall. It has been pointed out that there is a possibility of causing lipid deposition (Akio Noma et al., Arteriosclerosis, 17
Vol., pp. 639-658, 1989). Furthermore, Lp(a) bound to glycosaminoglycan etc. is easily taken up by macrophages and may work to promote foam cell formation. Furthermore, apo(a), an apoprotein unique to Lp(a), has high homology with plasminogen ((Ka
radi, I., et al., Biochemi.

Biophys、  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、
 Biochemistry、 28巻、2370〜2
374頁、1989年、Hajjar、 K、A、ら、
Nature、 339巻、303〜305頁、198
9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、L
p (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、6
39〜658頁、1989年)。
Biophys, Acta, Volume 960, 91
~97, 1988) and has been suggested to suppress the fibrinolytic mechanism (Edelberg, J. M., et al.
Biochemistry, Volume 28, 2370-2
374 pages, 1989, Hajjar, K. A. et al.
Nature, vol. 339, pp. 303-305, 198
9 years). These results are considered to suggest that Lp(a) acts on the onset and progression of arteriosclerosis. In fact, L
p (a) is for ischemic heart disease, restenosis after coronary artery bypass surgery, cerebral infarction, carotid artery sclerosis, abdominal aortic aneurysm, vascular dementia, diabetes, diabetic retinopathy, and vasculopathic Parkinson's disease, etc. It is considered to be an independent risk factor different from conventional low-density lipoprotein cholesterol and platelet aggregation (Akio Noma et al., Arteriosclerosis, Vol. 17, 6).
39-658, 1989).

一方、従来の高脂血症治療剤は血漿脂質のうち、主に低
比重リボ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(Maeda、 S 、ら、Atherosc
lerosis 、79巻、  267〜269 頁、
1989年)、クロフィブレート(Albers、  
J。
On the other hand, conventional antihyperlipidemia drugs have focused on lowering low-density riboprotein cholesterol and triglycerides among plasma lipids, and little attention has been paid to their effects on Lp(a). . In recent years, the following reports have been made regarding the effects of conventional hyperlipidemia therapeutic agents on Lp(a). Probucol (Maeda, S., et al., Atherosc.
lerosis, volume 79, pages 267-269,
1989), clofibrate (Albers,
J.

ら、Metabolism、  24巻、1047〜1
054頁、  197’年)、コレスチラミン(Ler
en、  T、P、  ら、Atherosclero
sis 、  73巻、135〜141 頁、1988
年)、ブラバスタチン(Jacob、 B、G、ら、A
nn。
et al., Metabolism, vol. 24, 1047-1
054, 197'), cholestyramine (Ler
en, T.P., et al., Atherosclero
sis, vol. 73, pp. 135-141, 1988
), bravastatin (Jacob, B, G, et al., A
nn.

Intern、  Medl、112 巻、713〜7
14 頁、1990年)、ロバスタチン、シンパスタチ
ン(Kostner、  G、M、ら、C1rcula
tion  、 80巻、1313〜1319頁、19
89年)およびエブタスタチン(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(Carlso
n、  L、A、ら、J。
Intern, Medl, vol. 112, 713-7
14, 1990), lovastatin, simpastatin (Kostner, G, M, et al., C1rcula
tion, vol. 80, pp. 1313-1319, 19
1989) and ebtastatin (Atsushi Murai et al., Arteriosclerosis, Vol. 15, pp. 1461-1464, 1987), etc., do not have an effect of lowering serum Lp(a), and in some cases even tend to increase it. Slightly nicotinic acid preparations (Carlso
n, L, A, et al., J.

Intern、 Med、 、 226巻、271〜2
76頁、1989年)、ベザフィプレート(Schwa
rtzkopff、 W。
Intern, Med, 226, 271-2
76 pages, 1989), Bezafi Plate (Schwa
rtzkopff, W.

ら、Muench、  Med、  Wochensc
hr、、 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ロール
(Albers。
et al., Muench, Med, Wochensc.
hr, vol. 130, pp. 422-426, 1988
Only a serum Lp(a)-lowering effect has been observed in patients such as 2010). Also, the steroid drug Stanozolol (Albers).

J、ら、Biochemica  Biophysic
a  Acta、  。
J. et al. Biochemica Biophysics
a 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。
795, pp. 293-296, 1984)
, the antibiotic neomycin (Gurakar, A
, et al., Atherosclerosis, Vol. 57, pp. 293-301, 1985) in serum Lp(a).
Although it has been shown to have a lowering effect, there are problems in terms of side effects, etc.

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しp (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。
There have been reports on the serum Lp(a) lowering effect of health foods such as fish oil or fish liver oil containing icosapentoic acid and docosahexaenoic acid; however, there have been reports that they lower Lp(a) (Gavish).

D、ら、Cl1n、Res、、38巻、250A頁、1
990年)、作用なしとする報告(Gries、  A
、ら、Thrombosis Res、  、  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(Herrmann。
D, et al., Cl1n, Res, vol. 38, p. 250A, 1
990), report of no effect (Gries, A.
, et al., Thrombosis Res, , 58
Vol., pp. 667-668, 1990) and a report that Lp(a) was lowered in some patients when combined with exercise stress (Herrmann et al.).

W、ら、Med、 K11n、、 84巻、429〜4
33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)低下作用をあられすと
しても、これまでの知見では有効成分が何であるのかま
ったくわかつておらず、脂肪酸や他のビタミン等が作用
している可能性もある。
W, et al., Med, K11n, 84, 429-4.
33, 1989), contradictory results have been obtained. Furthermore, even if fish oil were to have an Lp(a)-lowering effect, it is not clear at all what the active ingredient is based on the knowledge to date, and it is possible that fatty acids or other vitamins are at play.

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B
4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(
Re1s、 G、 J、 。
Furthermore, fish oil and health foods both have low icosapent acid content, including thromboxane A2, which has platelet aggregation properties, and leukotriene B, which has leukocyte migration properties.
Arachidonic acid, which is a precursor of No. 4, is also included. Also,
If you increase the dosage of fish oil or health foods to increase their effectiveness, you run the risk of consuming too many calories from fatty acids and taking too much vitamins A and D, and may also cause nausea, vomiting, diarrhea, abdominal pain, and weight loss. There is also a high incidence of side effects such as increased
Re1s, G., J.

Lancet、  Aug 31. 2 巻、8656
号、177〜181頁、1989年)。
Lancet, Aug. 31. Volume 2, 8656
No., pp. 177-181, 1989).

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な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
であるエバゾール■(持出製薬)投与による副作用発現
率は低いことが知られている(0.H,P、学術情報委
員会、0.H,P、news。
Focusing on icosapentoic acid in fish oil, it is known to have a serum total cholesterol and triglyceride lowering effect. Further, a formulation for the treatment or prevention of thrombosis containing highly purified icosapentic acid, its salt, ester or amide is disclosed in Japanese Patent Publication No. 62-57605. Furthermore, it is known that the incidence of side effects is low when administered with Evasol ■ (Kokado Seiyaku), a highly purified ethyl icosapentate preparation (0.H,P, Academic Information Committee, 0.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。
32, pp. 205-208, 1990). However, to date, there is no knowledge regarding the effect of icosapent acid, its salts or esters 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(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 not affected by diet or drugs. Therefore, it has a serum Lp(a) lowering effect and can be administered safely. The development of drugs that can do this is desperately needed.

[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] As a result of intensive research to solve the above problems, the present inventors discovered that icosapentoic acid has a serum Lp(a) lowering effect, and completed 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、そ
の製薬挙上許容しうる塩およびエステルからなる群から
選ばれる少なくとも1つを含有するリポプロテイン(a
)低下剤である。
That is, the present invention provides a lipoprotein (a
) is a depressant.

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 fatty acids other than icosapent acid, and the content of icosapent 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。
Moreover, as an active ingredient, icosapent acid ethyl ester is preferable.

以下に本発明の詳細な説明する。The present invention will be explained in detail below.

本発明のLp (a)低下剤は、有効成分としてイコサ
ペント酸、その製薬挙上許容しうる塩、エステルもしく
はこれらの混合物を含有する。
The Lp(a) lowering agent of the present invention contains icosapent acid, its pharmaceutically acceptable salts, esters or mixtures thereof 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
の製薬挙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挙
上許容される塩を形成することもできる。
The icosapentoic 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 a glyceride. It is also possible to form pharmaceutically acceptable salts with inorganic bases such as sodium salts and potassium salts, organic bases such as benzylamine salts and diethylamine salts, or basic amino acids such as arginine salts and lysine salts.

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、ドコサベンクエン酸、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
−リルン酸、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、アラキシン酸、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 lowering agent of the present invention may further contain fatty acids other than icosapent acid. These fatty acids include docosahexaenoic acid, docosabencitric acid, docosamonoenoic acid, arachidonic acid, eicosatetraenoic acid, eicosatrienoic acid, eicosamonenoic acid, octadecatetraenoic acid, alpha
- Unsaturated fatty acids such as lylunic acid, linoleic acid, oleic acid, palmitoleic acid, hexadecatetraenoic acid, hexadecatrienoic acid and hexadecadienoic acid or behenic acid, alaxic acid, stearic acid, palmitic acid and myristic acid. Examples include saturated fatty acids such as

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。
In addition, unless otherwise specified, fatty acids such as icosapentoic acid as used in the present invention refer to free forms of fatty acids such as those mentioned above, salts thereof with inorganic bases such as sodium salts, or organic bases such as benzylamine salts. and their alkyl esters such as ethyl ester, or esters thereof such as glycerides.

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。
It is desirable that the icosapent acid content in the total fatty acids of the Lp (a) lowering agent of the present invention is 50% by weight or more, preferably 70% by weight or more, more preferably 90% by weight or more, and the arachidonic acid content is low. .

このようなイコサペント酸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1例えば、純度約98%のイコサペント酸、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(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
カバイオケミカ社製)、純度95%以上のイコサペント
酸(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 icosapent acid or its ester can be obtained, for example, from natural fats and oils such as fish oil by continuous distillation, liquid chromatography, and the like. Icosapent acid can also be obtained by hydrolyzing icosapent acid ester by known methods. Or existing commercially available products 1 For example, icosapent acid with a purity of about 98%, icosapent acid sodium salt with a purity of about 98%, purity of about 99%
Icosapentoic acid methyl ester of (manufactured by Tokyo Kasei Kogyo Co., Ltd.) and icosapent acid ethyl ester (manufactured by Tokyo Kasei Kogyo Co., Ltd.) with a purity of 90% can be used.

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 daily therapeutic dose for an adult of the Lp (a) lowering agent of the present invention is 0.5 to 5.0 g as icosapentoic acid, but it can be increased or decreased as appropriate depending on the route of administration or symptoms, and the entire amount can be administered at once. It is also possible to administer separately or in divided doses. As for the route of administration, oral administration is preferred, but in addition to intravenous and rectal administration, it can also be used as an external preparation, 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 effectiveness, safety, and
and methods for producing therapeutic agents.

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、エバゾー
ル■を2.7g/日経口投与し、投与前、投与後4およ
び122週目採血し血清Lp (a)値をバイオブール
社製のプレートを使用した酵素免疫測定法で測定した。
Effect on serum Lp(a) concentration 2.7 g/day of Evazol was orally administered to a total of 6 subjects with dyslipidemia and hyperlipidemia, and blood samples were collected before administration, 4 and 122 weeks after administration, and serum samples were collected. The Lp(a) value was measured by enzyme immunoassay using a plate manufactured by Bioboule.

第1表に結果を示す。Table 1 shows the results.

に及ぼす影響 以上のように、エバゾール■12週間連続経口投与によ
り、特に高いLp (a)値の人を含めて金側で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 mentioned above, continuous oral administration of Evazol ■ for 12 weeks lowers Lp on the gold side, including in people with particularly high Lp(a) values.
A significant reduction in (a) was observed. This effect was observed from the 4th week onwards in most people. Furthermore, no significant side effects were observed during the administration period.

エバゾール■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。渋谷端義ら、
医薬品研究、20巻、801〜844頁、1989年。
Evasol ■ is known to be highly safe, and toxicity tests are described in the following literature. Danyoshi Shibuya et al.
Pharmaceutical Research, Vol. 20, pp. 801-844, 1989.

また、イコサペント酸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。
In addition, icosapent acid and triglyceride type icosapent acid have high safety as well.

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)低下剤は著明な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 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。
As is clear from the above explanation and test results, the Lp(a) lowering agent of the present invention has a remarkable Lp(a) lowering effect and is highly safe, so it is useful as an Lp(a) lowering agent. be. In addition, diseases for which Lp(a) is considered a risk factor, such as ischemic heart disease, restenosis after coronary artery bypass surgery, cerebral infarction, carotid artery sclerosis, abdominal aortic aneurysm, vascular dementia, diabetes, and diabetic retina. In addition, the Lp(a) lowering agent of the present invention can be used with any conventional pharmaceutical carrier, base, or excipient in a conventional manner. ,
It can be prepared into pharmaceutical formulations.

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 formulations will be 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%、アラキドン酸エチル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 (approximately 0.5 ml volume) are sterilized, ethylated and purified fish oil: 90.6% ethyl icosapentate, 2.3% ethyl arachidonate, ethyl octadecatetraenoate. 0.2% of vitamin E and 0.7% of ω-3 ethyl icosatetraenoate.
The solution was added to 2% and filled with 300 mg of ethyl icosapentate, and then sealed.

実施例B  乳剤 イコサペント酸エチル     11 流動パラフイン         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バラオキシ安息香酸プロピル   0.
1精製水            59.5100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 Setanol 5 Sorbitan monostearate 3.8 Polyoxyethylene sorbitan monostearate 6.2 Dibutylhydroxytoluene 0. 2 Methyl paraoxybenzoate 0.2 Propyl paraoxybenzoate 0.
1 Purified water 59.5100% by weight Among the above components, the components other than purified water are dissolved by heating at 80° C., and purified water heated to 80° C. is gradually added to this while stirring, and emulsified for 10 minutes. Thereafter, the mixture is cooled to 35° C. while stirring to obtain a uniform emulsion.

[発明の効果] 本発明Lp (a)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8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(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。
[Effects of the Invention] The Lp(a)-lowering agent of the present invention has a remarkable Lp(a)-lowering effect, and also lowers Lp(a) expressed in triglyceride-rich lipoprotein moieties. Diseases for which these are considered risk factors, such as ischemic heart disease, restenosis after coronary artery bypass surgery, cerebral infarction, carotid artery sclerosis, abdominal aortic aneurysm, vascular dementia, diabetes, diabetic retinopathy, and vasculopathy. It is expected to be used as a preventive and therapeutic agent for Parkinson's disease, etc. On the other hand, the Lp (a) lowering agent of the present invention contains high-purity icosapent acid as an active ingredient, has a low content of impurities such as arachidonic acid, and does not have the side effects observed with fish oil (has high safety). This is actually the first formulation that can be used as an Lp(a) lowering agent.

Claims (4)

【特許請求の範囲】[Claims] (1)有効成分としてイコサペント酸、その製薬学上許
容しうる塩およびエステルからなる群から選ばれる少な
くとも1つを含有するリポプロテイン(a)低下剤。
(1) A lipoprotein (a) lowering agent containing at least one member selected from the group consisting of icosapent acid, its pharmaceutically acceptable salts and esters as an active ingredient.
(2)前記有効成分に、さらにイコサペント酸以外の脂
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 lipoprotein (a) lowering agent according to claim 1, wherein the active ingredient further contains a fatty acid other than icosapent acid, a salt thereof, and an ester.
(3)前記有効成分が、全脂肪酸、その塩およびエステ
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.
(4)前記有効成分がイコサペント酸エチルエステルで
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 any one of claims 1 to 3, wherein the active ingredient is icosapent acid ethyl ester.
JP02312010A 1990-11-16 1990-11-16 Lipoprotein (a) lowering agent Expired - Lifetime JP3103588B2 (en)

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