JP2008525316A - 4‐ヒドロキシタモキシフェン系ゲル製剤 - Google Patents
4‐ヒドロキシタモキシフェン系ゲル製剤 Download PDFInfo
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- JP2008525316A JP2008525316A JP2007536126A JP2007536126A JP2008525316A JP 2008525316 A JP2008525316 A JP 2008525316A JP 2007536126 A JP2007536126 A JP 2007536126A JP 2007536126 A JP2007536126 A JP 2007536126A JP 2008525316 A JP2008525316 A JP 2008525316A
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
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- 210000003780 hair follicle Anatomy 0.000 description 1
- 150000001261 hydroxy acids Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000030776 invasive breast carcinoma Diseases 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
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- 238000012261 overproduction Methods 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
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Abstract
【解決手段】0.105−0.950%の4−ヒドロキシタモキシフェンと、50−75%の少なくとも1種類のC2−C6アルコールと、0.1−5.0%の少なくとも1種類のゲル化剤と、0.1−5.0%の少なくとも1種類の浸透促進剤と、20−50%の水性媒体とを含み、パーセンテージ(%)は組成物の重量に対する重量である医薬組成物。
【選択図】なし
Description
所望量の4OHT及び混合する工程と、
少なくとも1種類のゲル化剤を加えて及び再び混合する工程と、
少なくとも1種類の水性媒体を加えて再び混合する工程を含む。
様々な医薬組成物を調製した。
EP:ヨーロッパ薬局方、USP:米国薬局方
1000gのpH7のリン酸塩緩衝水溶液を得るため、0.85gのKH2PO4及び3.46gのNaHPO4を秤量し、1000gの純水で希釈した。この溶液をポータブルミキサーで少なくとも10分間混合した。
第1ミキサータンクをチェックし、適切な洗浄処理が行われたことを確認した。
800ミリバールの減圧下で、混合せずに、アルコールをミキサータンクに添加した。 このタンクにミリスチン酸イソプロピルを添加した。賦形剤の容器をアルコールで洗浄した。
安全光を点灯し、室内光を消灯した。4−OHTをミキサータンクに装填し、容器をアルコールで洗浄した。
この溶液を、タービンを2000rpm、スクレーパを40rpmで、20分間にわたって混合した。
800ミリバールの減圧下で、タービンを2000rpmで、ミキサータンクに、ヒドロキシプロピルセルロース(Klucel HF)を充填した。操作の最後にタービンを停止した。
800ミリバールの減圧下で、スクレーパを40rpm/分で、リン酸塩緩衝液を、ミキサータンクに移した。他の方法、即ち、タービンを2000rpmで20秒間及び600rpmで20秒間、スクレーパを40rpm/分で生成物を20分間混合した。操作の最後にタービンを停止した。
ミキサータンクを、徐々に100ミリバールまで減圧し、即ち、第1工程で250ミリバール、第2工程で150ミリバール、第3工程で100ミリバールにした。スクレーパを40rpm/分で100ミリバールの減圧下で2分間保持した。
スクレーパを40rpm/分で生成物を10分間混合した。操作の最後にスクレーパを停止した。
余分な空気の混入を避けるため、抽出タービンを経て、カバーを備えたステンレス鋼タンクの中にゲルを移した。ゲルを移しながら、サンプリングをした。
インビトロの吸収検討
材料と方法
4−OHTゲル
放射標識の4−OHT(3H)を、上記の医薬組成物の調製に使用した。
0.057%、0.114%、及び0.228%の4−OHT濃度に組成物(ゲル)を調製した。
原理
皮膚への吸収によって投与される生存液(レセプター液)に真皮が接触するように、静置型フランツ拡散セル(フランツセル)に配置して、ヒトの腹部皮膚分節の生検によるインビトロの経皮吸収を定量的に検討した。
皮膚生検標本はセルの2つの部分との間に水平に設置され、2つの区画を区切る:
−一方の表皮側の区画は、ガラス製のシリンダー(正確な1.77cm2の領域を有し、皮膚の上側に配置される);
−他方は真皮側であり、外皮の下部面に位置し、横方向の収集ポートを有する一定体積の貯蔵ポートを含む。
この2要素は、クランプを用いて組み立てた。
下部区画(真皮)には、15g/Lのウシ血清アルブミン添加した9g/Lの塩化ナトリウムからなるレセプター液体を満たす。各時点で、側部収集部から生存液を全体的に抽出し、新鮮な液体に置換した。
セルの下部を37℃に温度調節した。受容体の流体の温度と内容物の均一性は、撹拌(磁気スターラー)によって維持した。上部(上皮区画)は、外側に曝されているため、上皮表面が実験室の空気に曝された。
これらは、ヒトの腹部皮膚から、形成外科による白人ドナーからのサンプルであった。使用前に、皮膚を−20℃で保存した。付着した皮下脂肪を小刀で除去し、デルマトームを用いて皮膚を約0.5mmの厚さにした。検査される各々の製剤及び各々の容量に対して12セルのフランツセルを用意し、3種類の異なるドナーの皮膚サンプルを12セルの間に均等に分配した。
フランツセルを、検査される製剤を添加する前日に、通常どおり設置した。
上皮区画を、実験室の空気に接触させ、真皮区画を37℃に温度調節し、皮膚を、アルブミネート入り生理学的血清に約17時間にわたって接触させた。
所望量のゲルを(5μL、10μL、又は20μL)、ガラスシリンダーで区切られた表皮の表面全体に、マイクロピペットを用いて塗布した。真皮区画に含有される液体のサンプリングは、24時間目に、側部収集ポートから行った。
粒子カウンターのPackard−tricarb 2900TRを用い、液体シンチレーションにより検出した。
拡散セルの下部区画からサンプリングした受容体の液体を、15mLの液体シンチレーションカクテル(Picofluor 4OR、Packard)に直接入れ、放射能測定を行った。
各サンプルの真の活性を示す1分間あたりの崩壊度(dpm)を得るため、クエンチングを考慮しながら、外部較正の方法により測定速度を較正した。バックグラウンドを減算し、各サンプルのcpmを求めた。各シンチレーション液体に関する特定のクエンチング曲線を作成した。結果を、適切に較正した測定希釈速度から求め、投与量に対するサンプル中の物質の重量又は百分率で表す。
組成物中の4−OHTの所与の濃度と、皮膚に塗布された組成物の所与の容量について、11〜12の実験測定の平均値と併せて標準偏差(Sd)で表す。
フランツセルにおけるインビトロの4−OHT調製
24時間におけるレセプター液体中の4−OHT量の平均値±Sd
インビボ吸収検査
プロトコル
本検査は、規則的な月経周期である32人の女性の種々の4−OHTの用量レベルでの非盲検であった。女性らに対して、用量を無作為選択し(4−OHTの日用量は、群Aと群Bに対して1mg、群Cには2mg群Dに対して4mg)、21日間毎朝、女性らの乳房に塗布した。
4−OHTの用量、1mg、2mg、及び4mg各々を複数回投与後、第14日と第20日との間は安定状態となった。
ゲル0.228%=0.228%の4−OHTを含むゲル
Claims (15)
- 4−ヒドロキシタモキシフェン0.105−0.950%と、
少なくとも1種類のC2−C6アルコール50−75%と、
少なくとも1種類のゲル化剤0.1−5.0%と、
少なくとも1種類の浸透促進剤0.1−5.0%と、
水性媒体20−50%と、を含み、
パーセンテージ(%)が、前記医薬組成物の重量に対する重量である医薬組成物。 - 4−ヒドロキシタモキシフェン0.205−0.950%と、
少なくとも1種類のC2−C6アルコール50−75%と、
少なくとも1種類のゲル化剤0.1−5.0%と、
少なくとも1種類の浸透促進剤0.1−5.0%と、
水性媒体20−50%と、を含み、
パーセンテージ(%)が、前記医薬組成物の重量に対する重量である、請求項1に記載の医薬組成物。 - 4−ヒドロキシタモキシフェン0.220−0.350%、好ましくは、約0.228%と、
エタノール60−75%と、
ヒドロキシプロピルセルロース0.5−1.5%と、
ミリスチン酸イソプロピル0.4−2.0%と、
リン酸塩緩衝液20−40%と、を含み、
パーセンテージ(%)が、前記医薬組成物の重量に対する重量である、請求項1乃至2のいずれか一項に記載の医薬組成物。 - 前記C2−C6アルコールが、エタノール、プロパン−1−オール、及びプロパン−2−オール、並びにそれらの混合物からなる群から選択される、請求項1乃至3のいずれかに一項記載の医薬組成物。
- 前記ゲル化剤が、アクリル酸系のポリマー、セルロース化合物、及びそれらの混合物からなる群から選択される、請求項1乃至4のいずれか一項に記載の医薬組成物。
- 前記ゲル化剤が、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシエチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルメチルセルロース、及びそれらの混合物からなる群から選択される少なくとも1種類のゲル化剤を含む、請求項1乃至5のいずれか一項に記載の医薬組成物。
- ミリスチン酸イソプロピルを含む、請求項1乃至6のいずれか一項に記載の医薬組成物。
- 前記水性媒体が、少なくとも1種類の塩基、好ましくは、トリエタノールアミン、水酸化ナトリウム、水酸化アンモニウム、水酸化カリウム、アルギニン、アミノメチルプロパノール、トロメタミン、及びそれらの混合物からなる群から選択される塩基を含む、請求項1乃至7のいずれか一項に記載の医薬組成物。
- 前記水性媒体が、少なくとも1種類の緩衝液、好ましくは、クエン酸塩、トリスマレイン酸塩、リン酸緩衝液、及びそれらの混合物からなる群から選択される、請求項1乃至8のいずれか一項に記載の医薬組成物。
- pHが、7.5−10.0である、請求項1乃至9のいずれか一項に記載の医薬組成物。
- 経皮性又は経皮的送達に有用なゲルであって、請求項1乃至10のいずれか一項に記載の医薬組成物を含むゲル。
- 請求項1乃至10のいずれか一項に記載の医薬組成物又は請求項11に記載のゲルを含有する、投与パケット、単回投与パケット又は複数回投与パケット。
- 請求項1乃至10のいずれか一項に記載の医薬組成物又は請求項11に記載のゲルを含有する、例えば手動ポンプを備えたディスペンサー。
- 請求項1乃至10のいずれか一項に記載の医薬組成物又は請求項11に記載のゲルを調製する方法であって、
少なくとも1種類のC2−C6アルコール及び少なくとも1種類の浸透促進剤を含有する混合物を調製する工程と、
所望量の4−ヒドロキシタモキシフェンを添加し混合する工程と、
少なくとも1種類のゲル化剤を添加し及び再び混合する工程と、
少なくとも1種類の水性媒体を添加し再び混合する工程を含む方法。 - 良性の乳房疾患、瘢痕及びケロイド、女性化乳房症、乳癌、乳房痛、及び高密度の胸部組織が関与する症状の治療及び/又は予防において使用するための、請求項1乃至10のいずれか一項に記載の医薬組成物又は請求項11に記載のゲル。
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EP04292447.2 | 2004-10-14 | ||
EP04292447A EP1647271A1 (en) | 2004-10-14 | 2004-10-14 | 4-Hydroxy tamoxifen gel formulations |
US63835904P | 2004-12-23 | 2004-12-23 | |
US60/638,359 | 2004-12-23 | ||
PCT/EP2005/011654 WO2006040196A1 (en) | 2004-10-14 | 2005-10-13 | 4-hydroxy tamoxifen gel formulations |
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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 |
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JP2006514967A (ja) * | 2003-04-01 | 2006-05-18 | ラボラトワール ブザン アンテルナスィヨナル | 4−ヒドロキシタモキシフェンによる乳癌の予防および治療 |
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WO2006040196A1 (en) | 2006-04-20 |
ES2318563T3 (es) | 2009-05-01 |
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PT1799201E (pt) | 2009-02-26 |
DK1799201T3 (da) | 2009-03-30 |
MA28927B1 (fr) | 2007-10-01 |
BRPI0518139B1 (pt) | 2021-10-13 |
AU2005293712A1 (en) | 2006-04-20 |
HK1103027A1 (en) | 2007-12-14 |
CA2582174C (en) | 2013-01-29 |
PL1799201T3 (pl) | 2009-05-29 |
EP1799201A1 (en) | 2007-06-27 |
ATE415156T1 (de) | 2008-12-15 |
JP5047800B2 (ja) | 2012-10-10 |
KR20070068366A (ko) | 2007-06-29 |
NO338755B1 (no) | 2016-10-17 |
EA200700834A1 (ru) | 2007-10-26 |
EA011295B1 (ru) | 2009-02-27 |
IL182298A (en) | 2013-01-31 |
HRP20090239T1 (en) | 2009-06-30 |
IL182298A0 (en) | 2007-07-24 |
EP1799201B1 (en) | 2008-11-26 |
SI1799201T1 (sl) | 2009-06-30 |
KR101294947B1 (ko) | 2013-08-09 |
AU2005293712B2 (en) | 2011-04-21 |
MX2007004371A (es) | 2007-06-07 |
DE602005011314D1 (de) | 2009-01-08 |
CA2582174A1 (en) | 2006-04-20 |
CY1110499T1 (el) | 2015-04-29 |
GEP20104889B (en) | 2010-02-10 |
TNSN07139A1 (en) | 2008-11-21 |
BRPI0518139A (pt) | 2008-10-28 |
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