JP2014510795A - 経口投与用の単位用量形態物 - Google Patents
経口投与用の単位用量形態物 Download PDFInfo
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- JP2014510795A JP2014510795A JP2014505380A JP2014505380A JP2014510795A JP 2014510795 A JP2014510795 A JP 2014510795A JP 2014505380 A JP2014505380 A JP 2014505380A JP 2014505380 A JP2014505380 A JP 2014505380A JP 2014510795 A JP2014510795 A JP 2014510795A
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- JAJWGJBVLPIOOH-IZYKLYLVSA-M sodium taurocholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 JAJWGJBVLPIOOH-IZYKLYLVSA-M 0.000 description 1
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- ABTZKZVAJTXGNN-UHFFFAOYSA-N stearyl heptanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCCCCC ABTZKZVAJTXGNN-UHFFFAOYSA-N 0.000 description 1
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- 210000000130 stem cell Anatomy 0.000 description 1
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- 229920001909 styrene-acrylic polymer Polymers 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 235000019327 succinylated monoglyceride Nutrition 0.000 description 1
- 229960004291 sucralfate Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013269 sustained drug release Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003899 tartaric acid esters Chemical class 0.000 description 1
- 206010043207 temporal arteritis Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 125000005887 tetrahydrobenzofuranyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229920000428 triblock copolymer Polymers 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
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- SFLBDBJLRVHQLY-UHFFFAOYSA-M trimethyl(2-prop-2-enoyloxypropyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(C)OC(=O)C=C SFLBDBJLRVHQLY-UHFFFAOYSA-M 0.000 description 1
- USFMMZYROHDWPJ-UHFFFAOYSA-N trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium Chemical compound CC(=C)C(=O)OCC[N+](C)(C)C USFMMZYROHDWPJ-UHFFFAOYSA-N 0.000 description 1
- RRHXZLALVWBDKH-UHFFFAOYSA-M trimethyl-[2-(2-methylprop-2-enoyloxy)ethyl]azanium;chloride Chemical compound [Cl-].CC(=C)C(=O)OCC[N+](C)(C)C RRHXZLALVWBDKH-UHFFFAOYSA-M 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
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- 239000005019 zein Substances 0.000 description 1
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Abstract
【解決手段】経口投与に好適な、TH−302および他の低酸素活性化プロドラッグの製剤および単位用量形態物を調製する。
【選択図】図1
Description
本出願は、米国仮特許出願第61/475,844号(2011年4月15日出願)の米国特許法第119条(e)による優先権を主張する(その内容は参照によって本明細書中に組み込まれる)。
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
R6は、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリールまたはヘテロアリールであり;
R3およびR4は独立して、2−ハロアルキル、2−アルキルスルホニルオキシアルキル、2−ヘテロアルキルスルホニルオキシアルキル、2−アリールスルホニルオキシアルキルおよび2−ヘテロアルキルスルホニルオキシアルキルからなる群から選択され;
R1は式L−Z3を有し、
LはC(Z1)2であり、
それぞれのZ1は独立して、水素、ハロゲン、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリール、ヘテロアリール、C3〜C8シクロアルキル、ヘテロシクリル、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルであり、
または、Lは、
Z3は、下記式からなる群から選択される式を有する生体内還元基:
X2は、NR7、SまたはOであり、
それぞれのR7は独立して、C1〜C6アルキル、C1〜C6ヘテロアルキル、C3〜C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、
かつ、R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1〜C6アルキル、C1〜C6ヘテロアルキル、C1〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6アルキルアミノ、C1〜C6ジアルキルアミノ、アリール、CON(R7)2、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルである)である)。様々な実施態様において、本発明の経口製剤および方法に利用される化合物は、TH−281、TH−302、およびTH−308からなる群より選択される式1の化合物である(構造は、下記に示される)。
すべての数値表示(例えば、pH、温度、時間、濃度および重量)は、範囲を含めて、典型的には、0.1、1.0、10.0または100.0の刻みによる(+)または(−)の変動を適宜伴う場合がある概数である。必ずしも明示的に述べられるとは限らないが、すべての数値表示には、用語「約」が先行することを理解されたい。
オスのSD(Sprague−Dawley)ラットに、100mg/kgのTH−302の単回経口用量が通常生理食塩水において投与されたとき、TH−302が迅速に吸収され、平均ピーク血漿中濃度(15.8μg/mL)が最初(0.25時間)のサンプリング時点までに達成された。対応する平均濃度曲線下面積(AUC)および半減期は13.1μg−h/mLおよび1.6hであった。同じ量(100mg/kg)を30分の静脈内(IV)注入によって投与した後では、注入終了時の平均ピーク血漿中濃度が30.9μg/mLであり、平均AUCおよび半減期がそれぞれ、17.1μg−h/mLおよび0.27hであった。これら2つの試験に基づいて、TH−302の絶対的生物学的利用能が、およそ77%であると求められた。このことは、TH−302が経口投与に好適であることを示している。
1つの実施形態において、本発明の製剤は、TH−302または式Iの別の低酸素活性化プロドラッグを含むか、あるいは、TH−302または式Iの別の低酸素活性化プロドラッグから本質的になる即時放出製剤である。1つの実施形態において、即時放出製剤は非被覆の通常マトリックス製剤である。1つの実施形態において、即時放出製剤は、TH−302または式Iの別の低酸素活性化プロドラッグを含有するゼラチンカプセルまたは錠剤である。ゼラチンカプセルに含有されるTH−302または他の低酸素活性化プロドラッグは、様々な実施形態において、粉末、顆粒状物質、または、実質的に球状のマイクロ粒子である。本発明のゼラチンカプセルは、ゼラチンカプセルを異なるタイプの抗ガンアルキル化薬(イホスファミド)のために調製することについて報告される方法を適合化することによって製造することができる。Manegold他、Ann Oncol.1996;7(6):637〜9(これは参照によって本明細書中に組み込まれる)を参照のこと。即時放出製剤は一般に、薬物放出の速い速度および/または大きいCmaxを提供する。本明細書中の開示を考慮して本発明の即時放出製剤の作製に適用することができる、他の即時放出製剤を作製する様々な方法が当業者に広く知られており、これらの方法は、本発明の製剤および投薬形態物を作製するために用いることができ、または適合化することができる。
1つの実施形態において、本発明の製剤は放出調節製剤である。1つの実施形態において、放出調節製剤はモノリシック製剤である。本明細書中で使用される場合、モノリシック製剤は、多粒子製剤とは対照的に、単一ユニット物または錠剤を示す。1つの実施形態において、放出調節製剤は多粒子製剤である。放出調節製剤の様々な例が、米国特許第5、591、452号および同第5、965、161号に開示されており、そのような例は、本発明の放出調節製剤を調製するために本開示に従って変更することができる。1つの実施形態において、放出調節製剤は被覆される。1つの実施形態において、被覆は機能的な被覆である。1つの実施形態において、機能的な被覆は下記の1つまたは複数を含む:ポリマー被覆、水分バリア被覆、腸溶性ポリマー被覆、および、これらの混合物。別の実施形態において、被覆は非機能的な被覆である。非機能的な被覆は、TH−302または式Iの別の低酸素活性化プロドラッグの放出に実質的な影響を及ぼさないかもしれないが、代わりに、製剤または投薬形態物の化学的安定性、生物学的安定性または物理的安定性を高めること(これらに限定されない)を含めて、製剤の他の性質に影響を与えるかもしれない。
1つの実施形態において、機能的な被覆はポリマー被覆である。一般に、反応性アミンを含有するポリマーは、TH−302に使用されるポリマー被覆において避けられる。1つの実施形態において、ポリマー被覆は制御放出性被覆である。1つの実施形態において、制御放出性被覆はアクリルポリマーを含む。好適なアクリルポリマーには、アクリル酸コポリマーおよびメタクリル酸コポリマー、メタクリル酸シアノエチル、メタクリル酸エトキシエチル、メタクリル酸グリシジルコポリマー、メタクリル酸メチルコポリマー、ポリ(アクリル酸)、ポリアクリルアミド、ポリ(メタクリル酸)、ポリ(メタクリル酸メチル)、ならびに、ポリ(無水メタクリル酸)が含まれるが、これらに限定されない。
1つの実施形態において、TH−302または式Iの別の低酸素活性化プロドラッグの放出調節製剤が錠剤としての単位服用形態で提供される。1つの実施形態において、錠剤は、TH−302または式Iの別の低酸素活性化プロドラッグと、賦形剤とを含むコアを含む。そのような賦形剤と混合されたとき、コアは即時放出製剤である場合がある。1つの実施形態において、コアは、TH−302または式Iの別の低酸素活性化プロドラッグの放出を制御する制御放出性被膜によって取り囲まれる。様々な実施形態において、水分バリアが制御放出性被膜を取り囲む。存在する場合、水分バリア被膜は、水分がTH−302または式Iの他の低酸素活性化プロドラッグと接触することを遅らせる。必要に応じて、このような錠剤はさらに、コア、水分バリアおよび/または制御放出性被膜を取り囲む1つまたは複数のさらなる機能的な被覆または非機能的な被覆を含む場合があり、あるいは、コア、水分バリアおよび/または制御放出被膜を取り囲む1つまたは複数のさらなる機能的な被覆または非機能的な被覆から本質的になる場合がある。
1つの実施形態において、本発明によって提供される錠剤は延長放出錠剤である。1つの実施形態において、錠剤は、TH−302または式Iの別の低酸素活性化プロドラッグと、1つまたは複数の賦形剤とを含むコアを含む。1つの実施形態において、コアは、TH−302または式Iの他の低酸素活性化プロドラッグの放出を制御する制御放出性被膜によって取り囲まれる。錠剤は必要に応じて、コアまたは制御放出性被膜を取り囲む1つまたは複数のさらなる機能的な被膜または非機能的な被膜を含む場合がある。
1つの実施形態において、錠剤コアは、延長放出の制御放出性被覆により被覆される。1つの実施形態において、錠剤コアは、官能基を何ら有しない中性エステルコポリマーの水性分散物を含むか、または、官能基を何ら有しない中性エステルコポリマーの水性分散物から本質的になる水性の制御放出性被覆により被覆される。1つの実施形態において、錠剤はさらに、水分バリアを含む。制御放出性被膜および水分バリアは2段階で塗布することができる。制御放出性被覆を錠剤コアの表面に直接に塗布することができ、この被覆は、主にTH−302または式Iの別の低酸素活性化プロドラッグの放出を制御するために機能する。水分バリアを、錠剤による水分の吸収を妨げるために、または遅らせるために制御放出性被膜の表面に直接に塗布することができる。
1つの実施形態において、錠剤は、延長放出の制御放出性被膜を含む。延長放出の制御放出性被膜は、水不溶性かつ水浸透性の皮膜形成ポリマー、必要な場合には水溶性ポリマー、および、さらに必要な場合には可塑剤を含む半透過性被膜である。延長放出の制御放出性被膜のために有用である水不溶性かつ水浸透性の皮膜形成ポリマーの非限定的な例には、セルロースエーテル、セルロースエステルおよびポリビニルアルコールが含まれる。延長放出の制御放出性被膜のために有用である水溶性ポリマーの他の非限定的な例には、限定されないが、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースおよびポリビニルピロリドンが含まれる。
いくつかの実施形態において、水分バリアが、本発明の単位用量形態物の制御放出性被膜と直接に接触している。様々な実施形態において、好適なバリアは、腸溶性ポリマー、浸透強化剤、および、必要な場合には可塑剤を含む。いくつかの実施形態において、腸溶性ポリマーはアクリルポリマーである。例えば、限定されないが、アクリルポリマーは、約1:1のポリメタクリル酸−メタクリル酸メチルを含むメタクリル酸コポリマーであり得る。
1つの実施形態において、錠剤は強化吸収錠剤である。1つの実施形態において、強化吸収錠剤は、TH−302または式Iの別の低酸素活性化プロドラッグと、1つまたは複数の医薬的に許容される賦形剤とを含むコアを含む。1つの実施形態において、コアは、TH−302または式Iの他の低酸素活性化プロドラッグの放出を制御する強化吸収被覆によって取り囲まれる。いくつかの実施形態において、強化吸収被覆は1つの被膜からなる。強化吸収錠剤の利点としては、特定の他のタイプの錠剤または投薬形態物と比較して、組成物において要求される薬物の量を少なくすることが挙げられ、これにより、副作用の軽減および/または製造費用の低減をもたらすことができる。
1つの実施形態において、本発明によって提供される製剤は、TH−302または式Iの別の低酸素活性化プロドラッグを含む制御放出マトリックスである。マトリックスコアからの薬物放出の動態は、少なくとも部分的には製剤内の賦形剤の拡散特性および/または侵食特性に依存する。そのような制御放出マトリックスにおける使用のための好適な賦形剤材料には、例として、放出抵抗性物質または制御放出物質、例えば、疎水性ポリマー、親水性ポリマー、親油性物質、および、それらの混合物などが含まれる。
1つの実施形態において、TH−302または式Iの別の低酸素活性化プロドラッグの製剤は、TH−302または式Iの別の低酸素活性化プロドラッグと、1つまたは複数の医薬的に許容される賦形剤とを含有する多数のマイクロ粒子を含有する多粒子系である。マイクロ粒子はカプセルに含有され得るか、あるいは、摂取されたとき、多数のサブユニット物に分解するマトリックスまたは錠剤に圧縮成形することができる(ただし、この場合、サブユニット物またはペレットが製剤の所望される制御放出特性を有する)。多粒子体または多ユニット製剤は1つまたは複数の被覆によって取り囲まれ得る。そのような被覆の例には、限定されないが、ポリマーの制御放出被覆、遅延放出被覆、腸溶性被覆、即時放出被覆、矯味性(taste−masking)被覆、延長放出被覆および非機能的な被覆が含まれる。賦形剤には、限定されないが、消泡剤、バインダー、化学的安定剤、着色剤、希釈剤、崩壊剤、乳化剤、フィラー、矯味矯臭剤、流動促進剤、滑剤、pH調節剤、球形化助剤、溶解性増強剤および懸濁化剤の1つまたは複数が含まれる。
1つの実施形態において、マイクロ粒子製剤は層状のマイクロ粒子を含む。そのような層状マイクロ粒子は、粒子またはコア(例えば、糖の球体など)をTH−302または式Iの別の低酸素活性化プロドラッグおよび必要な場合にはポリマーバインダーにより被覆することによって作製することができる。様々な実施形態において、粒子またはコアがTH−302または式Iの別の低酸素活性化プロドラッグを含有するか、あるいは、不活性である(プロドラッグを何ら含有しない)かのどちらかである。いくつかの実施形態において、不活性コアが水不溶性物質(例えば、セルロース球体または二酸化ケイ素など)を含むか、または、水不溶性物質(例えば、セルロース球体または二酸化ケイ素など)から構成される。他の実施形態において、不活性コアが水溶性物質(例えば、デンプン、塩または糖球体など)を含むか、または、水溶性物質(例えば、デンプン、塩または糖球体など)から構成される。
1つの実施形態において、TH−302または式Iの別の低酸素活性化プロドラッグの製剤はナノ粒子を含む。ナノ粒子は、本明細書中で使用される場合、サブミクロン(例えば、限定されないが、1μm未満)の粒子である(例えば、コロイド粒子など)。これには、薬物が粒子または球体の全体に吸着されるか、あるいは溶解されるか、そうでなければ含まれるナノ粒子またはナノ球体、および、薬物が、殻様の壁によって取り囲まれる水性コアまたは油性コアに閉じ込められるナノカプセルが含まれる。
1つの実施形態において、本発明の製剤はTH−302または式Iの別の低酸素活性化プロドラッグのパルス性放出を提供する。パルス性放出は、1つまたは複数の時間間隔での薬物放出、例えば、薬物の最初の急速放出、それに続く、遅い放出での薬物放出、または、最初の急速放出、それに続く、ある期間後、通常は1時間〜4時間後の、別の急速放出での薬物放出を示す。例えば、米国特許第5、011、692号および同第5、980、508号を参照のこと(これらのそれぞれが参照によって本明細書中に組み込まれる)。例えば、限定されないが、被覆されていない矯味マイクロ粒子または腸溶性被覆マイクロ粒子を遅延放出型または持続放出型の被覆されたマイクロ粒子と組み合わせることによって、パルス性薬物放出プロファイルまたは時間療法的プロファイルを達成することができる。例えば、限定されないが、本発明のパルス性放出製剤に好適な賦形剤には、コラーゲン、アテロコラーゲンが含まれる。
1つの実施形態において、本発明は、本明細書中に提供されるTH−302または式Iの別の低酸素活性化プロドラッグの経口製剤の単位用量形態物を提供する。様々な実施形態において、単位用量形態物は、約25mg〜約1000mg、約50mg〜約900mg、約75mg〜約700mg、約100mg〜約600mg、約25mg〜約100mg、または、約700mg〜約1000mgのTH−302または式Iの別の低酸素活性化プロドラッグを含有する。
本実施例は、TH−302の驚くほどに高い経口生物学的利用能を実証する。純度が高速液体クロマトグラフィー(HPLC)分析に基づいて約96%であったTH−302(1−メチル−2−ニトロ−1H−イミダゾール−5−イル)N,N’−ビス(2−ブロモエチル)ジアミドホスファート、m.w.=449)を使用した。オスのSD(Sprague−Dawley)ラット(n=3、各時点あたり)に、100mg/kgのTH−302の単回経口用量を投与した(表1および図1を参照のこと)。TH−302が迅速かつ十分に吸収され、平均ピーク血漿中濃度が15分の最初のサンプル採取時点で達成され、絶対的経口生物学的利用能が77.3%であった。対応する平均曲線下面積(AUC)および半減期がそれぞれ、13.1μg−h/mLおよび1.6hであった。30分のIV注入による100mg/kgの同じ用量の後では(表2)、注入終了時の平均ピーク血漿中濃度が30.9μg/mLであり、平均AUCおよび半減期がそれぞれ、17.1μg−h/mLおよび0.27hであった。本実施例では、TH−302およびそのような他の薬物が経口製剤としての投与に好適であることが示される。
表1.ラットにおけるTH−302の薬物動態(平均±標準偏差(S.D.))
bn=2
AUC:ゼロから無限までの濃度時間曲線下総面積;IV:静脈内;PO:経口
表2.ラットaにおけるTH−302の30分の静脈内注入の後でのTH−302の単回服用の薬物動態的パラメーター
bn=2
活性薬剤の結晶形態物(約100mg〜約500mg)が、活性薬剤の即時放出製剤を様々な単位用量形態物で提供するためにゼラチンカプセルに入れられる。あるいは、約100mg〜約500mgの活性薬剤と、ラクトース、スクロースまたは別の糖とを含有するマイクロ粒子製剤が、活性薬剤の急速放出製剤を様々な単位用量形態物で提供するためにゼラチンカプセルに入れられる。
約500gの活性薬剤、約600gの、約100,000の分子量を有するポリ(エチレンオキシド)、および、約50gの、平均分子量が約40,000であるポリビニルピロリドンを混合ボールに加え、これらの成分を10分間にわたって乾式混合する。その後、約300gの無水エタノールを、10分間にわたって絶え間ない混和を行いながらゆっくり加えて、造粒混合物を調製する。この新しく調製された造粒混合物を20メッシュの篩いに通し、25℃で約20時間乾燥させ、その後、16メッシュの篩いに通す。次に、造粒混合物をミキサーに移し、約10gのステアリン酸マグネシウムを滑剤として加えて、本発明の経口製剤を製造する。製剤を圧力下で圧縮成形して、例えば、約100mg〜約500mgの活性薬剤を含む錠剤にする。
本発明の経口製剤を実施例3の手順に従って製造し、下記のものを含む単位用量形態物を提供する:(i)活性薬剤を約50mg〜約500mg、(ii)分子量が約100,000〜約500,000であるポリ(アルキレンオキシド)ポリマー(例えば、ポリ(エチレンオキシド)、ポリ(プロピレンオキシド)、ポリ(イソプロピレンオキシド)およびポリ(ブチレンオキシド))を約10mg〜約500mg、または、アルカリカルボキシメチルセルロースおよびアルカリ土類カルボキシメチルセルロースから選択される、分子量が約7,500〜325,000であるポリマーを約10mg〜約500mg、(iii)分子量が約5,000〜約300,000のポリ(ビニル)ポリマー(例えば、ポリビニルピロリドン;ビニルピロリドンと、酢酸ビニル、塩化ビニル、フッ化ビニル、酪酸ビニル、ラウリン酸ビニルおよびステアリン酸ビニルの1つまたは複数とのコポリマー)を約0.5mg〜約50mg、ならびに、(iv)ポリエチレングリコール、ステアリン酸マグネシウム、ステアリン酸カルシウム、オレイン酸カリウム、ステアリン酸ナトリウム、ステアリン酸およびパルミチン酸ナトリウムから選択される滑剤を最大で約7.5mg。本発明の他の経口製剤は、他の賦形剤、例えば、着色剤、圧縮成形助剤(例えば、微結晶セルロースなど)およびバインダー(例えば、デンプンなど)を含有する場合がある。製剤は、経口投与可能な錠剤を得るために、1/8トン〜3トンの力で圧縮成形される。
実施例3および実施例4の錠剤を被覆して、下記のような本発明の単位用量形態物を提供する。最初に、被覆溶液(これは親水性または疎水性であり得る)を調製する。分子量が約220,000であり、エトキシル含有量が約50重量%であるエチルセルロース(約154g)と、分子量が約80,000であり、モル置換が3である約112gのヒドロキシプロピルセルロースと、約15gのポリオキシエチレン(40)ステアラートとを、撹拌を行いながら、約3,700gの無水エタノールに溶解する。生じた溶液を、撹拌することなく、3日間放置して、被覆組成物−1を得る。
活性薬剤を一定の期間ゆっくり放出することができる緩和放出型マイクロ粒子製剤を下記のように調製する。微結晶セルロース(約160g)、ラクトース(約75g)、クエン酸(約40gまで)および活性薬剤(約100g)を混合し、遊星形ミキサーにて水を使用して混練し、湿塊を形成する。湿塊を、Nica E140押出し機に通して、押出し物(約1mmの直径)を形成する。その後、押出し物を、Nica球状化装置に通して、マイクロ粒子を形成し、その後、マイクロ粒子を棚型乾燥オーブンまたは流動床乾燥機で乾燥して、本発明のマイクロ粒子製剤を得る。これらは、本発明の他の経口製剤を提供するために本明細書中に記載されるように、硬い殻の医薬用カプセルに詰められるか、または被覆されるか、または層状化される。
本実施例では、上記のように調製されるマイクロ粒子が下記のように2工程プロセスにより被覆される。ヒドロキシプロピルメチルセルロース(約7.5重量%)およびポリエチレングリコール(約2.5重量%)の水溶液を調製し、マイクロ粒子に噴霧して、封止被膜を形成する。その後、封止被覆されたマイクロ粒子を、アセチル化モノグリセリド(約9.5重量%)と混合したエチルセルロースの市販の水性分散物(例えば、Aquacoat(登録商標)、30重量%)を使用してバリア被膜により被覆する。被覆されたマイクロ粒子は、本発明の他の経口製剤を提供するために本明細書中に記載されるように、硬い殻の医薬用カプセルに詰められる場合があるか、または層状化される場合がある。
約15mgのアテロコラーゲンおよび1mgの活性薬剤の混合物を打錠機(400kg/cm2)で圧縮成形し、35mgのアテロコラーゲンを再び打錠機で圧縮成形する。このようにして、活性薬剤含有コラーゲン層および活性薬剤非含有コラーゲン層が製造される。上記手順をさらに3回繰り返し、その結果、各層の4つの層が形成される。厚さが約1.5mmであり、直径が約10mmであり、重量が約200mgである円筒状ペレットがこのようにして製造される。別途、約10gのSilastic(登録商標)382シリコーン基剤および約2滴のオクタン酸第一スズを素早く一緒に混合する。混合物を、直径が15mmであり、深さが5mmである容器に入れる。上記の積層化された円筒状ペレットを、上部(活性薬剤含有コラーゲン層)を空気と接触させたままで前記混合物に浸す。シリコーンポリマーを、ペレットが浸された混合物を室温で24時間放置することによって硬化させる。その後、製剤を容器から取り出す。このようにして得られる被覆された医薬調製物からの活性薬剤の溶解度を、生理食塩水を室温で使用し、一定の時間間隔で生理食塩水をサンプリングすることによって求めて、単位時間内に放出される活性薬剤の量を高速液体クロマトグラフィーによって求める。
Claims (19)
- 下記の式Iの低酸素活性化プロドラッグ:
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
R6は、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリールまたはヘテロアリールであり;
R3およびR4は独立して、2−ハロアルキル、2−アルキルスルホニルオキシアルキル、2−ヘテロアルキルスルホニルオキシアルキル、2−アリールスルホニルオキシアルキルおよび2−ヘテロアルキルスルホニルオキシアルキルからなる群から選択され;
R1は式L−Z3を有し、
LはC(Z1)2であり、
それぞれのZ1は独立して、水素、ハロゲン、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリール、ヘテロアリール、C3〜C8シクロアルキル、ヘテロシクリル、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルであり、
または、Lは、
Z3は、下記式からなる群から選択される式を有する生体内還元基:
X2は、NR7、SまたはOであり、
それぞれのR7は独立して、C1〜C6アルキル、C1〜C6ヘテロアルキル、C3〜C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、
かつ、R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1〜C6アルキル、C1〜C6ヘテロアルキル、C1〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6アルキルアミノ、C1〜C6ジアルキルアミノ、アリール、CON(R7)2、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルである)
である)
または、その医薬的に許容される塩
を含む経口製剤であって、
放出調節製剤である経口製剤。 - 錠剤である、請求項1に記載の放出調節製剤。
- マイクロ粒子を含む、請求項1に記載の放出調節製剤。
- 制御放出マトリックスを含む、請求項1に記載の放出調節製剤。
- さらにコアを含む、請求項1に記載の放出調節製剤。
- さらに被膜を含む、請求項1に記載の放出調節製剤。
- 前記被膜が制御放出被膜である、請求項6に記載の放出調節製剤。
- 前記被膜が水分バリア被膜である、請求項6に記載の放出調節製剤。
- ナノ粒子を含む、請求項1に記載の放出調節製剤。
- 添加物、消泡剤、バインダー、化学的安定剤、着色剤、希釈剤、崩壊剤、乳化剤、フィラー、矯味矯臭剤、流動促進剤、滑剤、pH調節剤、可塑剤、可溶化剤、膨潤強化剤、球形化助剤、溶解性増強剤および懸濁化剤の1つまたは複数をさらに含む、請求項1〜9のいずれか一項に記載の放出調節製剤。
- 前記低酸素活性化プロドラッグのパルス性放出プロファイルを示す、請求項1〜10のいずれか一項に記載の放出調節製剤。
- 下記の式Iの低酸素活性化プロドラッグ:
Y2は、O、S、NR6、NCOR6またはNSO2R6であり、
R6は、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリールまたはヘテロアリールであり;
R3およびR4は独立して、2−ハロアルキル、2−アルキルスルホニルオキシアルキル、2−ヘテロアルキルスルホニルオキシアルキル、2−アリールスルホニルオキシアルキルおよび2−ヘテロアルキルスルホニルオキシアルキルからなる群から選択され;
R1は式L−Z3を有し、
LはC(Z1)2であり、
それぞれのZ1は独立して、水素、ハロゲン、C1〜C6アルキル、C1〜C6ヘテロアルキル、アリール、ヘテロアリール、C3〜C8シクロアルキル、ヘテロシクリル、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルであり、
または、Lは、
Z3は、下記式からなる群から選択される式を有する生体内還元基:
X2は、NR7、SまたはOであり、
それぞれのR7は独立して、C1〜C6アルキル、C1〜C6ヘテロアルキル、C3〜C8シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールであり、
かつ、R8は独立して、水素、ハロゲン、シアノ、CHF2、CF3、CO2H、アミノ、C1〜C6アルキル、C1〜C6ヘテロアルキル、C1〜C6シクロアルキル、C1〜C6アルコキシ、C1〜C6アルキルアミノ、C1〜C6ジアルキルアミノ、アリール、CON(R7)2、C1〜C6アシル、C1〜C6ヘテロアシル、アロイルまたはヘテロアロイルである)
である)
または、その医薬的に許容される塩と、
1つまたは複数の医薬的に許容される賦形剤と
を含む、経口用即時放出型の、マイクロ粒子またはナノ粒子の経口製剤。 - 請求項12に記載される即時放出製剤を含むゼラチンカプセル製剤または錠剤製剤。
- 前記低酸素活性化プロドラッグがTH−302である、請求項1〜13のいずれか一項に記載の経口製剤。
- 請求項1〜14のいずれか一項に記載される経口製剤の単位服用物。
- 約25mg〜約1000mgのTH−302を含む、請求項15に記載の単位服用物。
- 約50mg〜約500mgのTH−302を含む、請求項16に記載の単位服用物。
- 約75mgのTH−302を含む、請求項17に記載の単位服用物。
- ガンを処置する方法であって、請求項1〜14のいずれか一項に記載される製剤または請求項15〜18のいずれか一項に記載される単位服用物の治療効果的な量を、そのような処置を必要としている患者に投与することを含む、方法。
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Also Published As
Publication number | Publication date |
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WO2012142520A3 (en) | 2013-01-03 |
BR112013025969A2 (pt) | 2016-12-20 |
IL228709A0 (en) | 2013-12-31 |
CN103458880A (zh) | 2013-12-18 |
EP2696858A4 (en) | 2014-09-03 |
AU2012242514A1 (en) | 2013-10-24 |
CA2832203A1 (en) | 2012-10-18 |
WO2012142520A2 (en) | 2012-10-18 |
US20140072624A1 (en) | 2014-03-13 |
EP2696858A2 (en) | 2014-02-19 |
RU2013147744A (ru) | 2015-05-20 |
KR20140045931A (ko) | 2014-04-17 |
MX2013011655A (es) | 2013-11-01 |
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