JPH054367B2 - - Google Patents
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- Publication number
- JPH054367B2 JPH054367B2 JP2244707A JP24470790A JPH054367B2 JP H054367 B2 JPH054367 B2 JP H054367B2 JP 2244707 A JP2244707 A JP 2244707A JP 24470790 A JP24470790 A JP 24470790A JP H054367 B2 JPH054367 B2 JP H054367B2
- Authority
- JP
- Japan
- Prior art keywords
- hydroxyvitamin
- platelet aggregation
- present
- parts
- vitamin
- 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.)
- Expired - Lifetime
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は、1α−ヒドロキシビタミンD3類を含
有する抗血小板凝集剤に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an antiplatelet aggregation agent containing 1α-hydroxyvitamin D 3 .
近年、デルカ（De Luca）等及びコデイツク
（Kodiek）等の一連の研究の結果、ビタミンD3
の生体内活性物質が1α，25−ジヒドロキシビタ
ミンD3（以下1α，25−（OH）2−D3と略称する）で
あり、また1α位の水酸基の存在がその生物活性
の発現には必須であることが明らかにされた。以
後この活性型の1α，25−（OH）2−D3の類似体、
例えば1α−ヒドロキシビタミンD3（以下1α−
（OH）−D3と略称する）、1α，24−ジヒドロキシ
ビタミンD3（以下1α，24−（OH）2−D3と略称す
る）など多くの1α−ヒドロキシビタミンD3類が
合成され、1α，25−（OH）2−D3とともにそのビ
タミンＤ様生物活性が注目されており、1α−
（OH）−D3は慢性腎不全、副甲状腺機能低下症、
ビタミンＤ抵抗性クル病・骨軟化症におけるビタ
ミンＤ代謝異常を伴う諸症状（低カルシウム血
症、テタニー、骨痛、骨病変等）の改善に適応さ
れている。 In recent years, as a result of a series of studies by De Luca et al. and Kodiek et al., vitamin D3
The active substance in the body is 1α,25-dihydroxyvitamin D 3 (hereinafter abbreviated as 1α,25-(OH) 2 -D 3 ), and the presence of a hydroxyl group at the 1α position is essential for the expression of its biological activity. It was revealed that. Hereafter analogs of this active form of 1α,25-(OH) 2 -D 3 ,
For example, 1α-hydroxyvitamin D 3 (hereinafter 1α-
(OH)-D 3 ), 1α,24-dihydroxyvitamin D 3 (hereinafter abbreviated as 1α,24-(OH) 2 -D 3 ), and many other 1α-hydroxyvitamin D 3 types have been synthesized. Along with 1α,25−(OH) 2 −D 3 , its vitamin D-like biological activity has attracted attention, and 1α−
(OH)-D 3 is chronic renal failure, hypoparathyroidism,
It is indicated for improving various symptoms associated with abnormal vitamin D metabolism (hypocalcemia, tetany, bone pain, bone lesions, etc.) in vitamin D-resistant rickets and osteomalacia.
本発明者等は、その後鋭意研究を続けた結果、
1α−ヒドロキシビタミンD3類に後述の抗血小板
凝集剤作用のあることを見出し、本発明を完成し
た。 As a result of continued intensive research, the inventors found that
The present invention was completed based on the discovery that 1α-hydroxyvitamin D 3 has an antiplatelet aggregation effect as described below.
即ち本発明は、1α−ヒドロキシビタミンD3類
の抗血小板凝集剤に関する。 That is, the present invention relates to antiplatelet aggregation agents of the 1α-hydroxyvitamin D 3 class.
本発明において用いられる1α−ヒドロキシビ
タミンD3とは
1α−（OH）−D3，
1α，25−（OH）2−D3，
1α，24S−（OH）2−D3，
1α，24R−（OH）2−D3，
1α，24S，25−（OH）3−D3，
1α，24R，25−（OH）3−D3，
1α，25S，26−（OH）3−D3，
1α，25R，26−（OH）3−D3，
1α，25−（OH）2−23−OXO−D3，
1α，25−（OH）2−24−OXO−D3，
1α，25S，26−（OH）3−23−OXO−D3，
1α，25R，26−（OH）3−23−OXO−D3，
1α，25S−（OH）2−D3−26，23S−lactone，
1α，25R−（OH）2−D3−26，23S−lactone，
1α−（OH）−24，25，26，27−tetraucr−23−
COOH−C3
などが含まれる。 What is 1α - hydroxyvitamin D 3 used in the present invention ? (OH) 2 −D 3 , 1α, 24S, 25− (OH) 3 −D 3 , 1α, 24R, 25− (OH) 3 −D 3 , 1α, 25S, 26− (OH) 3 −D 3 , 1α, 25R, 26−(OH) 3 −D 3 , 1α, 25−(OH) 2 −23−OXO−D 3 , 1α, 25−(OH) 2 −24−OXO−D 3 , 1α, 25S, 26−(OH) 3 −23−OXO−D 3 , 1α, 25R, 26−(OH) 3 −23−OXO−D 3 , 1α, 25S−(OH) 2 −D 3 −26, 23S−lactone, 1α, 25R−(OH) 2 −D 3 −26, 23S−lactone, 1α−(OH)−24, 25, 26, 27−tetraucr−23−
Includes COOH- C3 , etc.
これらの本物質は例えばU.S.Patent 3697559，
特開昭51−76252，特開昭51−76254，U.S，
Patent3741996，特開昭55−22655，特開昭55−
22656，特開昭56−61351，Arch.Biochem.
Biophys.，204，387（1981），H.F.De Luca，ビ
タミンＤ−［その新しい流れ］，講談社，サイエン
テイフイク（1982）などに開示されている。 These substances are, for example, US Patent 3697559,
JP 51-76252, JP 51-76254, US,
Patent3741996, JP-A-55-22655, JP-A-55-
22656, JP 56-61351, Arch.Biochem.
Biophys., 204 , 387 (1981), HFDe Luca, Vitamin D - [The New Trend], Kodansha, Scientific (1982), etc.
本発明においては光学異性体のいずれを用いて
もよく、又、二種以上を混合して用いてもよい。 In the present invention, any of the optical isomers may be used, or two or more types may be used as a mixture.
本発明の抗血小板凝集剤は活性成分として上記
本物質を含有して、下記に示す種々の製剤形態に
て用いられる。本発明の抗血小板凝集剤は、経口
的、非経口的に投与される。 The antiplatelet aggregation agent of the present invention contains the above-mentioned present substance as an active ingredient and is used in various formulations shown below. The antiplatelet aggregation agent of the present invention is administered orally or parenterally.
投与形態としては例えば、圧縮錠剤、被覆錠
剤、硬又は軟弾性ゼラチンカプセル、エチルアル
コール溶液、油性または水性溶液または懸濁液な
どが用いられる。 Examples of dosage forms that can be used include compressed tablets, coated tablets, hard or soft elastic gelatin capsules, ethyl alcohol solutions, oily or aqueous solutions or suspensions.
油性溶液の溶媒としては、植物油例えばヤシ
油、トウモロコシ油、綿実油、ココナツツ油、落
花生油、魚肝油、油状エステル例えばポリソルベ
ート80などを使用することができる。 As solvents for oily solutions, vegetable oils such as coconut oil, corn oil, cottonseed oil, coconut oil, peanut oil, fish liver oil, oily esters such as polysorbate 80, etc. can be used.
直腸内投与の場合には坐剤ベース例えばカカオ
脂またはそのトリグリセライドなどを含む薬用組
成物とすることができる。 For rectal administration, the pharmaceutical composition may include a suppository base, such as cocoa butter or its triglycerides.
本物質は単位投与形態中、２×10-5乃至１×10
％、好ましくは２×10-4乃至１％を含有する。 The substance may be present in unit dosage form between 2 x 10 -5 and 1 x 10
%, preferably 2×10 −4 to 1%.
又、投与量は0.1乃至104μｇ／日／人、好まし
くは0.5乃至103μｇ／日／人とすることができ
る。そして、上記量的関係が保持されるように、
１日１〜３回の投与回数となるように調製され
る。 Further, the dosage can be 0.1 to 10 4 μg/day/person, preferably 0.5 to 10 3 μg/day/person. Then, so that the above quantitative relationship is maintained,
The drug is prepared so that it can be administered 1 to 3 times a day.
以下、実施例により本発明を詳述する。 Hereinafter, the present invention will be explained in detail with reference to Examples.
実施例 １
抗血小板凝集作用
20週齢正常ウイスター系雄ラツトよりチトラー
ト採血（チトラーチは全血液の1/10量）を行な
い、これを1500rpmで６分間遠心分離し、その上
澄から多血小板血漿（Platelet Rich Plasma；
以下、PRPと略す）を得た。これを用いて
invitroでAdenosine Diphosphate（以下、ADPと
略す）惹起血小板凝集に対する1α−ヒドロキシ
ビタミンD3類の効果を検討した。Example 1 Anti-platelet aggregation effect Chitrach blood was collected from a 20-week-old normal Wistar male rat (chitrach is 1/10 volume of whole blood), centrifuged at 1500 rpm for 6 minutes, and platelet-rich plasma (chitrach) was extracted from the supernatant. Platelet Rich Plasma;
(hereinafter abbreviated as PRP) was obtained. using this
The effects of 1α-hydroxyvitamin D 3 on adenosine diphosphate (hereinafter abbreviated as ADP)-induced platelet aggregation were investigated in vitro.
1α−ヒドロキシビタミンD3類のエタノール溶
液を1.5μｇとり、PRP250ｍ中に添加し、２分
間37℃にてインキユベート後、ADPを30μM入
れ、血小板凝集測定に供した。このときの1α−
ヒドロキシビタミンD3類の最終濃度は0.12μｇ／
ｍ（0.6％エタノールPRP）となる。対照には、
1.5μｇのエタノールを用いた。尚、血小板凝集測
定には、Payton Lumiaggregation Module
Model 1000を用いた。 1.5 μg of an ethanol solution of 1α-hydroxyvitamin D 3 was added to PRP250m, and after incubation at 37° C. for 2 minutes, 30 μM of ADP was added and subjected to platelet aggregation measurement. 1α− at this time
The final concentration of hydroxyvitamin D type 3 is 0.12μg/
m (0.6% ethanol PRP). For comparison,
1.5 μg of ethanol was used. For platelet aggregation measurement, Payton Lumiaggregation Module
Model 1000 was used.
対照に対する血小板凝集阻害率を下記式より求
めた。 The platelet aggregation inhibition rate relative to the control was determined from the following formula.
血小板凝集阻害率
＝対照の最大血小板凝集率−1α−ヒドロキシビタ
ミンD3類添加の最大血小板凝集率／対照の最大血小板凝
集率×100（％）
血小板凝集阻害率は、
1α−（OH）−D3……13％，
1α，25−（OH）2−D3……15％，
1α，25R−（OH）2−D3……13％，
であつた。 Platelet aggregation inhibition rate = maximum platelet aggregation rate of control - 1α-hydroxyvitamin D Maximum platelet aggregation rate with addition of type 3 / maximum platelet aggregation rate of control x 100 (%) Platelet aggregation inhibition rate is: 1α-(OH)-D 3 ...13%, 1α,25−(OH) 2 − D3 ...15%, 1α,25R−(OH) 2 − D3 ...13%.
実施例 ２
1α−（OH）−D3をパナセート800（日本油脂製、
中級脂肪酸のトリグリセライド）に10μｇ／mlの
濃度に溶解し、１カプセル中に1α−（OH）−D3を
1μｇ含有するように下記剤皮成分を加温溶解し、
軟カプセル製造機を用いて常法により軟カプセル
剤を作成した。Example 2 1α-(OH)-D 3 was added to Panacet 800 (NOF Co., Ltd.,
One capsule contains 1α-(OH) -D3 dissolved in triglyceride (intermediate fatty acid) to a concentration of 10μg/ml.
The following skin components were dissolved by heating to contain 1μg,
Soft capsules were prepared by a conventional method using a soft capsule making machine.
剤皮処方例
ゼラチン 10重量部
グリセリン ２重量部
防腐剤（エチルパラベン） 0.05重量部
チタンホワイト 0.2重量部
水 0.2重量部
（最終形態に於ける重量部）
実施例 ３
実施例２の1α−（OH）−D3に代えて、1α，25
−（OH）2−D3を用い、以下同様にして1α，25−
（OH）2−D3を１カプセル当り1μｇを含有する軟
カプセル剤を得た。 Shell formulation example Gelatin 10 parts by weight Glycerin 2 parts by weight Preservative (ethylparaben) 0.05 parts by weight Titanium white 0.2 parts by weight Water 0.2 parts by weight (parts by weight in final form) Example 3 1α-(OH of Example 2) )−D 1α, 25 instead of 3
Using −(OH) 2 −D 3 , 1α, 25−
Soft capsules containing 1 μg of (OH) 2 -D 3 per capsule were obtained.
実施例 ４
実施例２の1α−（OH）−D3に代えて、1α，24R
−（OH）2−D3を用い、以下同様にして1α，24R
−（OH）2−D3を１カプセル当り1μｇを含有する
軟カプセル剤を得た。Example 4 In place of 1α-(OH)-D 3 in Example 2, 1α,24R
Using −(OH) 2 −D 3 , 1α, 24R in the same manner
Soft capsules containing 1 μg of -(OH) 2 -D 3 per capsule were obtained.
Claims (1)
とを特徴とする抗血小板凝集剤。1. An antiplatelet aggregation agent characterized by containing 1α-hydroxyvitamin D 3 .
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP24470790A JPH03169818A (en) | 1983-08-02 | 1990-09-14 | Inhibitor of blood platelet agglutination containing 1alpha-hydroxyvitamin d3 compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14132383A JPS6045516A (en) | 1983-08-02 | 1983-08-02 | Physiologically active agent containing 1alpha- hydroxyvitamin d3 |
| JP24470790A JPH03169818A (en) | 1983-08-02 | 1990-09-14 | Inhibitor of blood platelet agglutination containing 1alpha-hydroxyvitamin d3 compounds |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14132383A Division JPS6045516A (en) | 1983-08-02 | 1983-08-02 | Physiologically active agent containing 1alpha- hydroxyvitamin d3 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH03169818A JPH03169818A (en) | 1991-07-23 |
| JPH054367B2 true JPH054367B2 (en) | 1993-01-19 |
Family
ID=26473578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP24470790A Granted JPH03169818A (en) | 1983-08-02 | 1990-09-14 | Inhibitor of blood platelet agglutination containing 1alpha-hydroxyvitamin d3 compounds |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH03169818A (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6045516A (en) * | 1983-08-02 | 1985-03-12 | Kureha Chem Ind Co Ltd | Physiologically active agent containing 1alpha- hydroxyvitamin d3 |
-
1990
- 1990-09-14 JP JP24470790A patent/JPH03169818A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPH03169818A (en) | 1991-07-23 |
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