JP4938237B2 - 4−ヒドロキシタモキシフェンによる乳房痛の治療 - Google Patents
4−ヒドロキシタモキシフェンによる乳房痛の治療 Download PDFInfo
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- JP4938237B2 JP4938237B2 JP2004560487A JP2004560487A JP4938237B2 JP 4938237 B2 JP4938237 B2 JP 4938237B2 JP 2004560487 A JP2004560487 A JP 2004560487A JP 2004560487 A JP2004560487 A JP 2004560487A JP 4938237 B2 JP4938237 B2 JP 4938237B2
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Description
1987; Graham, 1995)、閉経前女性の大半に影響を与えている。周期性乳房痛は、用量依存的効果で、エストロゲン置換療法を受けている閉経後女性において再発する可能性もある(Callantine,
1975)。最近のある大規模な調査で、年齢18〜54歳の女性の67%が過去6ヶ月中に周期的な乳房の不快感を経験しており、そのうちの17%が毎月7日以上続く疼痛を報告している(Ader,
1997)。「非周期性乳房痛」は、その名称が示唆しているように、月経周期とは関係のない乳房における疼痛を指す。多くの状態が非周期性乳房痛を生じるものであり、それには硬化性腺症、ティーツェ症候群および希に乳癌などがある。最後に、乳房外乳房痛には、例えば患者が乳房の奥にある筋肉または肋骨からの疼痛を感じる場合に起こるような、他の疼痛源から乳房に出てくる乳房疼痛などがある。
et al., 1978; Gorins et al., 1984)。
et al., 1988)。
et al., 1982; Kuiper et al., 1997)。トランス4−ヒドロキシタモキシフェンは、トランス−タモキシフェンと比較して、正常ヒト上皮乳房細胞の培養での増殖を100倍阻害する(Malet
et al., 1988)。
1982)を見よ。それらの各化合物は、各種細胞で多様かつ予測できない生理活性を示し、その一部は各化合物のエストロゲン受容体配座に対する個別的効果によって測定される。すなわち、各化合物のエストロゲン受容体結合により、特有の受容体−リガンド配座が生じ、それが各種補因子を召集することで、異なる化合物では薬理特性が変動することになる(Wijayaratne
et al., 1999; Giambiagi et al., 1988)。
et al., 2001)。対照的に、4−ヒドロキシタモキシフェンは哺乳動物癌細胞系でエストロンスルファターゼ活性に対するかなりの阻害効果を示すが、それに関してタモキシフェンはほとんど効果がない(Chetrite
et al., 1993)。
1982)に由来する合成が記載されている。その合成は、下記の数段階で行われる。
段階2 段階1とは別に、1,2−ジフェニル−1−ブタノンのヒドロキシル化による1−(4−ヒドロキシフェニル)−2−フェニル−1−ブタノンの形成;
段階3−段階1の生成物と段階2の生成物との間の反応による1−(4−ジメチルアミノエトキシフェニル)−1−[p−2−テトラヒドロピラニルオキシ)フェニル]−2−フェニルブタン−1−オールの形成;
段階4 メタノール/塩酸による脱水によるシスおよびトランス異性体の混合物としての1−[p−(β−ジメチルアミノエトキシ)フェニル]−トランス−1−(p−ヒドロキシフェニル)−2−フェニル−1−ブト−1−エン =4−OH−タモキシフェンの生成;
段階5 クロマトグラフィーおよび結晶化によるシスおよびトランス異性体の分離による一定の比活性の実現。
et al., supra)。従って本発明に関して、4−ヒドロキシタモキシフェンはいずれの皮膚表面にも投与可能であるが、好ましくは片方または両方の乳房に投与する。
(Lippincott Williams & Wilkins, 2000), pp.836-58; PERCUTANEOUS ABSORPTION:
DRUGS COSMETICS MECHANISMS METHODOLOGY, Bronaugh and Maibach (Marcel Dekker,
1999))。これらの刊行物が明らかにしているように、医薬分野での当業者は、各種の要素および方法を駆使して、効果的な経皮送達を得ることができる。
乳癌患者4名に、12時間〜7日間の所定の間隔で乳房に直接投与することでアルコール溶液での[3H]−4−ヒドロキシタモキシフェンを投与してから、患部組織の摘出手術を行った。手術後、摘出組織と腫瘍周囲の正常乳房組織の両方に放射能が含まれていた(Kuttennetal.,1985)。
この試験では、タモキシフェンの経口投与後の4−ヒドロキシタモキシフェンの組織濃度および血漿濃度と、水性アルコールゲルでの経皮投与後の4−ヒドロキシタモキシフェンの組織濃度と血漿濃度とを比較した(Pujol et al.)。
乳癌手術の予定がある患者31名を5群中の1群に無作為に割り当てた。その患者に、表3に示したように経口タモキシフェンまたは経皮4−ヒドロキシタモキシフェンのいずれかを投与した。投与は1日1回行い、3〜4週間続けてから手術を行った。この試験では、3つの異なる用量の4−ヒドロキシタモキシフェン(0.5、1または2mg/日)および2種類の投与面積(両方の乳房あるいは両腕、両前腕および両肩などの大面積の皮膚のいずれかに)を評価した。1群の患者には、20mg/日(10mgを1日2回)の経口タモキシフェンの投与を行った(ノルバルデックス(Nolvaldex;登録商標))。
本試験は、年齢18〜45歳の健常閉経前女性における局所投与4−ヒドロキシタモキシフェンゲルの耐容性および薬物動態を示すものである。各参加者には、2月経周期の期間にわたり、1日1回のゲル投与を行った。
本試験は、経皮投与した際に、4−ヒドロキシタモキシフェンが乳房痛を効果的に治療することを示すものである。
Claims (4)
- 乳房痛の治療のための医薬であって、経皮投与に好適な形態のものであり、水性アルコール媒体中に4−ヒドロキシタモキシフェンと浸透促進剤とを含み、前記浸透促進剤がミリスチン酸イソプロピルである医薬。
- 前記4−ヒドロキシタモキシフェンがアルコール溶液に製剤されている請求項1に記載の医薬。
- 前記4−ヒドロキシタモキシフェンが水性アルコールゲルに製剤されている請求項1に記載の医薬。
- 前記水性アルコールゲルがエチルアルコール、ミリスチン酸イソプロピルおよびヒドロキシプロピルセルロースを含む請求項3に記載の医薬。
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EP1579856A1 (en) | 2004-03-22 | 2005-09-28 | Laboratoires Besins International | Treatment and prevention of benign breast disease with 4-hydroxy tamoxifen |
US7507769B2 (en) | 2004-03-22 | 2009-03-24 | Laboratoires Besins International | Treatment and prevention of benign breast disease with 4-hydroxy tamoxifen |
EP1579857A1 (en) | 2004-03-22 | 2005-09-28 | Laboratoires Besins International | Chemically stable compositions of 4-hydroxy tamoxifen |
EP1647271A1 (en) | 2004-10-14 | 2006-04-19 | Laboratoires Besins International | 4-Hydroxy tamoxifen gel formulations |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4919937A (en) * | 1984-01-20 | 1990-04-24 | Mauvais Jarvis Pierre | Percutaneous administration of tamoxifen |
WO2001043775A2 (en) * | 1999-12-16 | 2001-06-21 | Dermatrends, Inc. | Hydroxide-releasing agents as skin permeation enhancers |
Also Published As
Publication number | Publication date |
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NZ540494A (en) | 2007-05-31 |
CY1106131T1 (el) | 2011-06-08 |
EP1572178B1 (en) | 2006-05-03 |
CA2509660A1 (en) | 2004-07-01 |
ES2263072T3 (es) | 2006-12-01 |
EP1572178A2 (en) | 2005-09-14 |
WO2004054557A3 (en) | 2004-08-05 |
CA2509660C (en) | 2011-08-30 |
AU2003303033A1 (en) | 2004-07-09 |
DK1572178T3 (da) | 2006-09-11 |
DE60305068D1 (de) | 2006-06-08 |
ATE324880T1 (de) | 2006-06-15 |
SI1572178T1 (sl) | 2006-10-31 |
WO2004054557A2 (en) | 2004-07-01 |
JP2006514949A (ja) | 2006-05-18 |
AU2003303033B2 (en) | 2009-06-04 |
PT1572178E (pt) | 2006-09-29 |
US20050032909A1 (en) | 2005-02-10 |
HK1075403A1 (en) | 2005-12-16 |
US7786172B2 (en) | 2010-08-31 |
DE60305068T2 (de) | 2007-01-11 |
MXPA05006526A (es) | 2006-02-17 |
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