JP2011507808A - 使用 - Google Patents
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- JP2011507808A JP2011507808A JP2010537516A JP2010537516A JP2011507808A JP 2011507808 A JP2011507808 A JP 2011507808A JP 2010537516 A JP2010537516 A JP 2010537516A JP 2010537516 A JP2010537516 A JP 2010537516A JP 2011507808 A JP2011507808 A JP 2011507808A
- Authority
- JP
- Japan
- Prior art keywords
- ala
- ala ester
- ester
- cancer
- use according
- 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.)
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Abstract
【解決手段】本発明は、癌、癌に伴って発生する感染症の光動力学的治療もしくは診断または非癌性症状の治療もしくは診断に用いられる医薬品の製造における、5−ALAまたはその前駆体もしくは誘導体(例えば、ALAエステル)である光増感剤の使用であって、前記医薬品は、固形であることを特徴とする使用に関する。本発明はまた、5−ALAまたはその前駆体もしくは誘導体(例えば、ALAエステル)と、少なくとも1つの薬学的に許容可能な担体または賦形剤とを含む、このような方法において用いられる固形医薬品、例えば、坐剤、膣坐剤、錠剤、ペレット剤およびカプセル剤に関する。このような製品は、下部消化器系または女性生殖器系における癌性または非癌性症状の光動力学的治療または診断、例えば、結腸癌または子宮頸癌の治療または診断に用いられるのに特に適している。
【選択図】なし
Description
式中、R1は、置換または非置換、好ましくは置換直鎖状、分岐状または環状アルキル基(例えば、置換直鎖状アルキル基)であり、各R2は、独立して、水素原子または任意に置換されたアルキル基(例えば、R1基)である。
各坐剤(2g)は、以下を含む:
へキシル5−アミノレブリン酸塩酸塩(HAL HCl)100mg、10mgまたは0.8mg
エデト酸ナトリウム(EDTA)40mg
ウイテプゾールS55またはS58十分量
坐剤は、HAL HClおよびエデト酸ナトリウムを液状ウイテプゾール中に懸濁させて調製した。その混合物を坐剤型に充填して冷却した。
へキシル5−アミノレブリン酸塩酸塩(HAL HCl)を含む坐剤は、実施例1に記載したように調製した。ウイテプゾールS55ベースの坐剤におけるHAL HClの安定性は、HPLC分析により調査した。室温(25℃)および冷蔵温度(2〜8℃)の両方における安定性を検査した。その結果を以下の表1に示す。
へキシル5−アミノレブリン酸塩酸塩(HAL HCl)を含む坐剤は、実施例1に記載したように調製した。ウイテプゾールS58ベースの坐剤におけるHAL HClの安定性は、HPLC分析により調査した。室温(25℃)および冷蔵温度(2〜8℃)の両方における安定性を検査した。その結果を以下の表2に示す。
メチル5−アミノレブリン酸(MAL)160mg/gを含む含水クリームのバッチを4つ、室温(25℃)で3ヶ月間設置し、それらのMALの含有量を異なる時点において分析した。3ヶ月で27±4%(平均±SD)の損失が確認された。
HAL HClを含む錠剤コアは、以下に記載する成分を混合した後、直接打錠により調製した。
錠剤コアは、実施例4に記載したように調製した。コアに以下の溶液を噴霧する:
エチルセルロース(2%)
フタル酸ジブチル(1%)
アルコール(エチルアルコールおよびイソプロピルアルコール)(97%)。
HAL HClは、ラクトースと混合して微粉砕する。粒径は、約2〜10ミクロンである。活性材料の量は、約4重量%である(HAL HCl)。この組成物を吸入装置で用いられるカプセル剤に充填する。各カプセル剤は、HAL HClを10mg含む。1回分の用量は、1〜10カプセル剤である。
錠剤コアは、以下から調製する:
コア、半透過層および腸溶コーティングを含む錠剤は、従来の錠剤調製方法を用い、以下に記載する材料から調製する。
錠剤コア:
以下の組成物をそれらの融点を超える温度で混合した。その混合物をカプセル剤に注入して結合した。そして、カプセル剤を2階級のオイドラギット(SおよびN)の混合物でコーティングし、pH感受性膜を得る。
2つの異なるペレット製剤を以下のように調製した。
ペレット製剤Aの組成:
[実施例14− ペレット剤に5−ALAへキシルエステルHClを含むコーティングされていな錠剤]
[実施例15− コーティングされた錠剤(2%CAP)]
錠剤は、実施例14により調製した。錠剤は、アセトン中の酢酸フタル酸セルロース(CAP)(2重量%)の溶液で2回および3回コーティングした。錠剤は、30分間空気乾燥させ、5分間80℃で乾燥させた。
ペレット剤(製剤B、実施例13)は、アセトン中のCAP(2重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
ペレット剤(製剤A、実施例13)は、アセトン中のCAP(2重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
ペレット剤(製剤A、実施例13)は、アセトン中のCAP(4重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
ペレット剤(製剤A、実施例13)は、アセトン中のCAP(6重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
ペレット剤(製剤A、実施例13)は、アセトン中のCAP(8重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
ペレット剤(製剤A、実施例13)は、アセトン中のCAP(10重量%)の溶液で入念に洗浄した。余分な溶剤を除去した。ペレット剤は、30分間室温で乾燥させた後、5分間80℃で乾燥させた。
各錠剤は、以下を含む:
各錠剤は、以下を含む:
コーティングされていないペレット剤(製剤実施例13A)(273mg)を硬質ゼラチンカプセルに充填した。カプセル剤の大きさは17mmで、直径は6mmであった。ゼラチンカプセル剤は、CAP(アセトン中で4%溶液)で2回入念にコーティングした。カプセル製品は、30分間空気乾燥させた後、5分間80℃で乾燥させた。
5−ALAへキシルエステルHCl(237mg)を硬質ゼラチンカプセル剤に充填した。カプセル剤は、CAP(アセトン中で10%溶液)で2回入念にコーティングし、実施例24に記載したように乾燥させた。
錠剤は、実施例27により調製した。錠剤は、オイドラギット(登録商標)(オイドラギット(登録商標)RS30D)の分散液で2回コーティングした。錠剤は、30分間空気乾燥させた後、5分間80℃で乾燥させた。
錠剤は、実施例28により調製した。錠剤は、CAP(アセトン中で6重量%)で2回コーティングした。錠剤は、30分間空気乾燥させ、5分間80℃で乾燥させた。
ペレット剤(実施例13Bより)は、オイドラギット(登録商標)(オイドラギットRS30D分散液)でコーティングした。ペレット剤は、30分間空気乾燥させ、15分間80℃で乾燥させた。
ペレット剤(実施例13Bより)は、オイドラギット(登録商標)(オイドラギット(登録商標)S100、アセトン中で1.0重量%)でコーティングした。ペレット剤は、30分間空気乾燥させ、15分間80℃で乾燥させた。
ペレット剤(実施例13Bより)は、オイドラギット(登録商標)(オイドラギット(登録商標)S100、アセトン中で2.5重量%)でコーティングした。ペレット剤は、30分間空気乾燥させ、15分間80℃で乾燥させた。
ペレット剤(実施例13Bより)は、オイドラギット(登録商標)(オイドラギット(登録商標)S100、アセトン中で2.5重量%)でコーティングした。ペレット剤は、30分間空気乾燥させ、15分間80℃で乾燥させた。
各錠剤は、以下を含む:
錠剤は、実施例35により調製した。錠剤は、オイドラギットS−100(アセトン中でオイドラギット(登録商標)3重量%およびクエン酸トリエチル1%)でコーティングした。錠剤は、30分間空気乾燥させ、5分間80℃で乾燥させた。
サイズ1号のHPMCカプセル剤は、オイドラギットL30D−55、オイドラギットFS30Dおよびクエン酸トリエチルでコーティングした。カプセル剤は、へキシル5−アミノレブリン酸HCl(HAL−HCl)100mgと、賦形剤300mgとを含んでいた。これらには、ポロキサマー188、ゲルシレ44/14、ゲルシレ混合物(44/14:50/02=50:50w/w)およびミグリオール812Nが含まれた。賦形剤は、カプセル剤の溶解後、結腸への薬剤放出に影響を及ぼすよう含められた。カプセル剤は、腸溶コーティングでコーティングされた。
様々な賦形剤の存在下におけるHALの安定性の表示を得るため、80℃での応力研究を行った。HAL HCl(100mg)+賦形剤(300mg)(ポロキサマー188、ゲルシレ44/14、ゲルシレ混合物(44/14:50/02=50:50w/w)およびミグリオール812N)を混合し、20時間後の結果をHPLCで分析した。各不純物のレベルは、ピラジンを基準として計算した。その結果を以下の表に示す。ミグリオールを賦形剤として用いた場合、不純物はほとんど検出不可能であったが、その他の賦形剤は、多数かつ高レベルの不純物をもたらしたことが分かる。ミグリオールを含む試料は、HAL HCl試料自体よりも、含まれる不純物のレベルが低かった。
HAL HCl(100mg)+賦形剤(300mg)(ゲルシレ混合物(44/14:50/02=50:50w/w)またはミグリオール812N)を含むカプセル剤は、実施37に記載したように調製し、25℃/相対湿度60%で安定性をモニターした。安定性のモニタリングのため、(HALの加水分解により形成された)5−アミノレブリン酸(5−ALA)の濃度を安定性の指標として用いた。その結果を図1に示す。加水分解の結果、5−ALAがHALから遊離することが示されている。ミグリオール812Nは、5−ALA値がほとんど増加することなく、最も安定した製品を提供するものであると判明したことが分かる。ゲルシレ混合物に関しては、25℃/相対湿度60%で3ヵ月後に5−ALAの増加が見られた。相応する5−ALAの増加は、ポロキサマー188(図示せず)にも見られた。また、この賦形剤により、2つの未知のピラジン不純物が相当量形成された。
カプセル剤は、実施例37に記載したようにコーティングし、HAL HCl(100mg)と賦形剤(300mg)(ミグリオールまたは混合ゲルシレ(44/14:50/02=50:50w/w))とを混合したものを充填して結合した。これらは、欧州薬局方2.9.3に基づき、タイプ2のUSP溶解装置(パドル付)を用いたインビトロ溶解研究において使用した。カプセル剤は、(胃内における酸性条件を反映させるため)まず0.1MのHClに1時間浸漬させ、その後リン酸緩衝液(pH6.5)に移動させた。初期研究により、両製剤は共に脂肪性かつ疎水性材料に基づくものであるため、溶出溶媒に2%のラウリル硫酸ナトリウムを添加する必要があることが示された。試料を取り出し、HALを異なる時点において分析した。
硬質脂肪を有する多数の坐剤バッチ−ウイテプゾールH32(融点31〜33℃)、H35(融点33.5〜35.5℃)およびH37(融点36〜38℃)−は、溶融した脂肪1.8gにHAL−HCl200mgを溶解させた後、成形することにより製造した(実施例1参照)。
錠剤は、実施例42により調製した。錠剤は、オイドラギットS−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
錠剤は、実施例44により調製した。錠剤は、オイドラギットS−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
錠剤は、実施例46により調製した。錠剤は、オイドラギットS−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
5−ALAメチルエステルHCl(90mg)を硬質ゼラチンカプセル剤に充填し、ゼラチンカプセル剤を、オイドラギット(登録商標)S−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
カプセル剤の大きさ:長さ:17mm、直径:6mm
[実施例49− 5−ALAへキシルエステルを含むペレット剤の安定性]
5−ALAへキシルエステルを含むペレット剤(実施例13より、製剤AおよびB)は、40℃および相対湿度70%で約3週間、気候キャビネット内の開封容器に保存した。
HPLC分析により、高温および高湿度のため5−ALAへキシルエステルの崩壊が増加することは示されなかった。
5−ALAへキシルエステルを含むペレット剤(実施例13より、製剤AおよびB)(1.0グラム)は、水(10ml)中に懸濁させ、37℃で数時間保存した。時間経過に伴う5−ALAへキシルエステルに関し、この水溶液を分析した。5−ALAへキシルエステルの放出は、数時間にわたり、10%未満であった。
DMSO(200mg)を微結晶性セルロース(500mg)と混合して粉末剤(DMSO/MCC粉末剤)を得た。
錠剤は、実施例51により調製した。錠剤は、オイドラギットS−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
DMSO(19mg)を微結晶性セルロース(72mg)および5−ALA HCl(9mg)と混合して粉末剤を得た。粉末剤は、ゼラチンカプセル剤に充填した。
カプセル剤は、実施例53により調製した。カプセル剤は、オイドラギットS−100(6%)およびクエン酸トリエチル(1%)のアセトン溶液でコーティングし、乾燥させた。
Claims (31)
- 癌、癌に伴って発生する感染症の光動力学的治療もしくは診断(例えば、治療)または非癌性症状の治療もしくは診断に用いられる医薬品の製造における、5−ALAまたはその前駆体もしくは誘導体(例えば、ALAエステル)である光増感剤の使用であって、前記医薬品は、固形であることを特徴とする使用。
- 前記製品は、下部消化器系における癌性または非癌性症状の光動力学的治療または診断、例えば、結腸癌の治療または診断に用いられる請求項1に記載の使用。
- 前記製品は、女性生殖器系における癌性または非癌性症状の光動力学的治療または診断、例えば、子宮頸癌の治療または診断に用いられる請求項1に記載の使用。
- 前記光増感剤は、5−ALAエステルまたは薬学的に許容可能なその塩である請求項1〜3のいずれか1項に記載の使用。
- 前記光増感剤は、一般式Iの化合物または薬学的に許容可能なその塩である先行する請求項のいずれかに記載の使用。
R2 2N−CH2COCH2−CH2CO−OR1 (I)
式中、R1は、置換または非置換、好ましくは置換直鎖状、分岐状または環状アルキル基であり、各R2は、独立して、水素原子もしくは任意に置換されたアルキル基(例えば、R1基)である。 - 式Iにおいて、各R2は、水素原子である請求項5に記載の使用。
- 式Iにおいて、R1は、非置換アルキル基(好ましくは、C1-8アルキル、例えば、C1-6アルキル)またはアリール基で置換されたアルキル基(例えば、C1-2アルキル、特に、C1アルキル)である請求項5または6に記載の使用。
- 式Iにおいて、R1は、アリール基で任意に置換されたC1-2アルキル基(好ましくは、C1アルキル基)である請求項5または6に記載の使用。
- 前記化合物は、メチルALAエステル、ベンジルALAエステルまたは置換ベンジルALAエステルから選択される請求項8に記載の使用。
- 式Iにおいて、R1は、アリール基(例えば、フェニル)で置換されたアルキル基(例えば、C1-2アルキル、特に、C1)である請求項5〜7のいずれか1項に記載の使用。
- 前記化合物は、ベンジルALAエステル、4−イソプロピルベンジルALAエステル、4−メチルベンジルALAエステル、2−メチルベンジルALAエステル、3−メチルベンジルALAエステル、4−[t−ブチル]ベンジルALAエステル、4−[トリフルオロメチル]ベンジルALAエステル、4−メトキシベンジルALAエステル、3,4−[ジ−クロロ]ベンジルALAエステル、4−クロロベンジルALAエステル、4−フルオロベンジルALAエステル、2−フルオロベンジルALAエステル、3−フルオロベンジルALAエステル、2,3,4,5,6−ペンタフルオロベンジルALAエステル、3−ニトロベンジルALAエステル、4−ニトロベンジルALAエステル、2−フェニルエチルALAエステル、4−フェニルブチルALAエステル、3−ピリジニル−メチルALAエステル、4−ジフェニル−メチルALAエステルおよびベンジル−5−[(1−アセチルオキシエトキシ)−カルボニル]アミノレブリネートから選択される請求項5に記載の使用。
- 前記化合物は、ベンジルALAエステルである請求項5に記載の使用。
- 式Iにおいて、R1は、非置換アルキル基(好ましくは、C1-8アルキル、例えば、C1-6アルキル)である請求項5〜7のいずれか1項に記載の使用。
- 前記化合物は、メチルALAエステル、エチルALAエステル、プロピルALAエステル、ブチルALAエステル、ペンチルALAエステル、ヘキシルALAエステル、オクチルALAエステル、2−メチルペンチルALAエステル、4−メチルペンチルALAエステル、1−エチルブチルALAエステル、3,3−ジメチル−1−ブチルALAエステルから選択される請求項5に記載の使用。
- 前記化合物は、メチルALAエステル、ヘキシルALAエステルおよび4−メチルペンチルALAエステル(好ましくは、メチルALAエステル)から選択される請求項5に記載の使用。
- 前記化合物は、ヘキシルALAエステルまたは薬学的に許容可能なその塩、例えば、塩酸塩である請求項5に記載の使用。
- 前記固形医薬品は、経口投与される先行する請求項のいずれかに記載の使用。
- 前記固形医薬品は、錠剤の形態で提供される先行する請求項のいずれかに記載の使用。
- 前記固形医薬品は、局所投与される請求項1〜16のいずれか1項に記載の使用。
- 前記固形医薬品は、坐剤または膣坐剤の形態で提供される請求項1〜16または19のいずれか1項に記載の使用。
- 前記医薬品は、子宮、子宮頸部、膣、直腸または結腸の癌を治療または診断するためのものである先行する請求項のいずれかに記載の使用。
- 前記癌に伴って発生する感染症は、ヒトパピローマウイルスにより生じる請求項1〜20のいずれか1項に記載の使用。
- 癌または癌に伴って発生する感染症の光動力学的治療に用いられる医薬品の製造における、5−ALAまたはその前駆体もしくは誘導体である光増感剤の抗癌剤との組み合わせによる使用であって、前記医薬品は、固形であることを特徴とする使用。
- 癌または癌に伴って発生する感染症を治療する光動力学的方法において同時、別個または連続的に用いられる、請求項1〜20のいずれか1項に記載の医薬品および、別個に、抗癌剤を含むキットまたはパック。
- 癌または癌に伴って発生する感染症を治療または診断する光動力学的方法であって、
(a)請求項1〜20のいずれか1項に記載の医薬品を動物に投与する工程と、
(b)光増感剤が所望の部位において有効な組織濃度を得るのに必要な期間、任意に待機する工程と、
(c)前記光増感剤を光活性化する工程とを含むことを特徴とする方法。 - 請求項1〜20のいずれか1項に記載の医薬品を用いて予め投与された動物における癌または癌に伴って発生する感染症を診断する光動力学的方法であって、
(i)光増感剤が所望の部位において有効な組織濃度を得るのに必要な期間、任意に待機する工程と、
(ii)前記光増感剤を光活性化する工程とを含むことを特徴とする方法。 - 手術方法に用いられる医薬品の製造における、5−ALAまたはその前駆体もしくは誘導体(例えば、ALAエステル)である光増感剤の使用であって、前記医薬品は、固形であることを特徴とする使用。
- 5−ALAまたはその前駆体もしくは誘導体(例えば、5−ALAエステル)である光増感剤と、少なくとも1つの薬学的に許容可能な担体または賦形剤とを含む固形医薬品であって、前記医薬品は、坐剤、膣坐剤、錠剤、ペレット剤またはカプセル剤の形態で提供されることを特徴とする固形医薬品。
- 前記光増感剤は、錠剤またはカプセル剤内に設けられた複数のペレット剤、顆粒剤、丸剤または小型錠剤に組み込まれている請求項28に記載の製品。
- 前記光増感剤の遅延放出が可能なカプセル剤、錠剤またはペレット剤の形態で提供される請求項28または29に記載の製品。
- 医学、好ましくは癌、癌に伴って発生する感染症の光動力学的治療もしくは診断(例えば、治療)または非癌性症状の治療もしくは診断に用いられる請求項27〜30のいずれか1項に記載の固形医薬品。
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Also Published As
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EP2684573A2 (en) | 2014-01-15 |
WO2009074811A3 (en) | 2009-08-06 |
CN104306968A (zh) | 2015-01-28 |
CN101896203A (zh) | 2010-11-24 |
BRPI0821668A2 (pt) | 2015-06-16 |
NZ585977A (en) | 2012-06-29 |
US20150031761A1 (en) | 2015-01-29 |
EP2684573A3 (en) | 2014-09-24 |
RU2521228C2 (ru) | 2014-06-27 |
CA2708137A1 (en) | 2009-06-18 |
KR20100095443A (ko) | 2010-08-30 |
EP2231188A2 (en) | 2010-09-29 |
WO2009074811A2 (en) | 2009-06-18 |
AU2008334426A1 (en) | 2009-06-18 |
JP2014012725A (ja) | 2014-01-23 |
RU2010123086A (ru) | 2012-01-20 |
GB0724279D0 (en) | 2008-01-23 |
CA2708137C (en) | 2016-11-22 |
NZ600028A (en) | 2013-08-30 |
JP5686603B2 (ja) | 2015-03-18 |
AU2008334426B2 (en) | 2014-03-27 |
RU2014112548A (ru) | 2015-10-10 |
JP5863735B2 (ja) | 2016-02-17 |
US20110020441A1 (en) | 2011-01-27 |
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