JP2023134418A - 新規ターポリマー及び医薬剤形におけるそれらの使用 - Google Patents
新規ターポリマー及び医薬剤形におけるそれらの使用 Download PDFInfo
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- methacrylate
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- VNJISVYSDHJQFR-UHFFFAOYSA-N tert-butyl 4,4-dimethylpentaneperoxoate Chemical compound CC(C)(C)CCC(=O)OOC(C)(C)C VNJISVYSDHJQFR-UHFFFAOYSA-N 0.000 description 1
- NMOALOSNPWTWRH-UHFFFAOYSA-N tert-butyl 7,7-dimethyloctaneperoxoate Chemical compound CC(C)(C)CCCCCC(=O)OOC(C)(C)C NMOALOSNPWTWRH-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
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- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
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- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
- C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
- C08F220/10—Esters
- C08F220/12—Esters of monohydric alcohols or phenols
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- C08F226/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen
- C08F226/06—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen by a heterocyclic ring containing nitrogen
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Abstract
Description
VP: N-ビニルピロリドン
HEMA: メタクリル酸2-ヒドロキシエチル
POEA: アクリル酸フェノキシエチル
tBMA: メタクリル酸tert-ブチル
CHMA: メタクリル酸シクロヘキシル
IPMA: メタクリル酸イソプロピル
VC: N-ビニルカプロラクタム
AA: アクリル酸
ポリマーの分子量は、溶離液として1重量%トリフルオロ酢酸及び0.5重量%臭化リチウムを含有するジメチルアセトアミド、狭い分子量分布のポリ(メタクリル酸メチル)標準(PSS Polymer Standard Solutions GmbHから市販され、M=800~M=2,200,000の範囲の分子量を有する)及びDRI Wyatt Optilab DSPからの示差屈折率(DRI)検出器を使用して、35℃でサイズ排除クロマトグラフィー(SEC)によって決定した。
300mgの乾燥ポリマーを、150mLのガラス製ねじ蓋瓶中の100mLのリン酸塩緩衝液(pH6.8)に添加した。混合物を、マグネチックスターラー及び長さ3~5cmのマグネチックスターラーバーを使用して、23℃で15分間、300rpmで撹拌した。その後、混合物を、47mmの直径及び8μmの平均孔径を有する乾燥させて秤量したポリカーボネートフィルター(Whatmanから入手可能)でろ過した。残留物を有するフィルターを、0.02MPaの真空オーブン中で75℃で一晩乾燥させた。フィルター上の残留物の量は、残留物を含有する乾燥フィルターの重量から乾燥フィルターの重量を差し引くことによって決定した。残留物の量は、ポリマーの総量(300mg)のパーセンテージとして示される。
VP、AA及びVCの含有量は、VPについて235nm、AA及びVCについて205nmの吸収波長でのUV検出を使用する逆相液体クロマトグラフィーによって決定した。定量は、外部較正によって実施した。サンプルのアリコートを、メタノールに溶解し、直接注入した。クロマトグラフィー分離を、勾配溶出を使用することによって達成した。
ポリマーA1
メカニカルスターラー、コンデンサー、窒素スイープ、温度計、並びにモノマー及び開始剤を徐々に添加するための注入口を備えた2リットルのガラス製反応器に、240グラムのイソプロパノールを投入した。モノマー溶液を、266グラムのイソプロパノールに75グラムのアクリル酸、165グラムのメタクリル酸tert-ブチル、及び60グラムのN-ビニルピロリドンを溶解することによって調製した。開始剤溶液を、200グラムのイソプロパノールに3.84グラムのtert-ブチルペルオキシピバレート溶液(ミネラルスピリット中で75重量%)を溶解することによって調製した。合計10重量%のモノマー溶液を反応器投入物に添加し、得られた溶液を100rpmで撹拌しながら75℃まで加熱した。その後、合計10重量%の開始剤溶液を添加し、温度を80℃まで上昇させた。次いで、残りの90重量%のモノマー及び開始剤溶液を、それぞれ4時間及び5時間にわたって撹拌反応器投入物に一定の供給速度で別々に添加した。これらの添加の間、反応混合物の温度を、80℃に維持した。添加が完了した後、反応混合物を80℃でさらに1時間撹拌し、次いで、周囲温度まで放冷した。サンプルを混合物から採取し、SEC測定のために乾燥させた。別のサンプルを残留モノマー含有量測定のために採取した。およそ150mlの水を添加し、その後、反応混合物のpHを、25重量%の水酸化ナトリウム水溶液を添加することによって設定した。揮発性物質を除去し、生成物を、0.02MPaで75℃で真空オーブン中で一晩乾燥させた。
メカニカルスターラー、コンデンサー、窒素スイープ、温度計、並びにモノマー及び開始剤を徐々に添加するための注入口を備えた2リットルのガラス製反応器に、150グラムのイソプロパノール中の60グラムのN-ビニルピロリドンの溶液を投入した。モノマー溶液を、152グラムのイソプロパノールに75グラムのアクリル酸及び165グラムのメタクリル酸tert-ブチルを溶解することによって調製し、開始剤溶液を、150グラムのイソプロパノールに4.0グラムのtert-ブチルペルオキシピバレート溶液(ミネラルスピリット中で75重量%)を溶解することによって調製した。合計10重量%のモノマー溶液を反応器投入物に添加し、得られた溶液を100rpmで撹拌しながら70℃まで加熱した。その後、合計10重量%の開始剤溶液を添加し、温度を75℃まで上昇させた。次いで、残りの90重量%のモノマー及び開始剤溶液を、それぞれ4時間及び6時間にわたって撹拌反応器投入物に一定の供給速度で別々に添加した。これらの添加の間、反応混合物の温度を、75℃に維持した。添加が完了した後、反応混合物を75℃でさらに1時間撹拌し、次いで、周囲温度まで放冷した。サンプルを混合物から採取し、SEC測定のために乾燥させた。別のサンプルを残留モノマー含有量測定のために採取した。およそ150mlの水を添加し、その後、反応混合物のpHを、25重量%の水酸化ナトリウム水溶液を添加することによって設定した。反応混合物のpHを、25重量%の水酸化ナトリウム水溶液を添加することによって設定した。揮発性物質を減圧下で除去し、生成物を、0.02MPaで75℃で真空オーブン中で一晩乾燥させた。
セレコキシブ(celecoxib)-ポリマー製剤(10重量%薬物負荷):
固体分散体は、セレコキシブ(celecoxib)及びポリマーA7で構成された。製剤を調製するために、3.0gのセレコキシブ(celecoxib)及び27.0gのポリマーを、570gのメタノールに溶解した(5重量%固形分)。噴霧乾燥は、0.7mmの二流体ノズルを備えたBuchiミニスプレードライヤーB-290で、次の条件下で実施した:
窒素流速 35m3/h
入口温度 85~105℃
出口温度 50~70℃
噴霧圧力 0.7MPa
液体流速 300g/h
薬物含有量(UV分光法) 10.3~10.7重量%
固体状態特性(PXRD) X線非晶質
固体分散体は、セレコキシブ(celecoxib)と、ポリマーA1、ポリマーA2、ポリマーA3、ポリマーA4、ポリマーA5、ポリマーA6、ポリマーA7、ポリマーA8、ポリマーB1、ポリマーC1、ポリマーC2、ポリマーC3、ポリマーC4、ポリマーD1、ポリマーE1、ポリマーF1、HPMCAS-LF、HPMCAS-MF又はHPMCAS-HFとで構成された。製剤を調製するために、2.5gのセレコキシブ(celecoxib)及び7.5gのポリマーを、190gのメタノール、又はメタノール及びテトラヒドロフランの1:1混合物に溶解した(5重量%固形分)。噴霧乾燥は、0.7mmの二流体ノズルを備えたBuchiミニスプレードライヤーB-290で、次の条件下で実施した:
窒素流速 35m3/h
入口温度 85~105℃
出口温度 50~70℃
噴霧圧力 0.7MPa
液体流速 300g/h
薬物含有量(UV分光法) 24.2~27.6重量%
固体状態特性(PXRD) X線非晶質
固体分散体は、ダナゾール(danazol)と、ポリマーA1、ポリマーA2、ポリマーA3、ポリマーA4、ポリマーA5、ポリマーA6、ポリマーA7、ポリマーA8、ポリマーB1、ポリマーC1、ポリマーC3、ポリマーD1、ポリマーE1、ポリマーF1、HPMCAS-LF、HPMCAS-MF又はHPMCAS-HFとで構成された。製剤を調製するために、1.5gのダナゾール(danazol)及び13.5gのポリマーを、285gのメタノール、又はメタノール及びテトラヒドロフランの1:1混合物に溶解した(5重量%固形分)。噴霧乾燥は、0.7mmの二流体ノズルを備えたBuchiミニスプレードライヤーB-290で、次の条件下で実施した:
窒素流速 35m3/h
入口温度 85~105℃
出口温度 50~70℃
噴霧圧力 0.7MPa
液体流速 300g/h
薬物含有量(UV分光法) 9.4~11.7重量%
固体状態特性(PXRD) X線非晶質
リン酸塩緩衝液pH6.8の調製
5Lのリン酸塩緩衝液pH6.8を調製するために、34.025gのリン酸二水素カリウムを、5リットルのメスフラスコに入れ、およそ1Lの水に溶解した。次いで、112mLの1M水酸化ナトリウム溶液を添加した; 溶液を水で5Lに希釈した。必要な場合、溶液のpHを6.8に調整した。
薬物放出を定量化し、過飽和の維持を測定するために、インビトロ(in vitro)溶解試験を行った。この目的のために、100mLのリン酸塩緩衝液pH6.8をエルレンマイヤー(Erlenmeyer)フラスコに入れ、多位置マグネチックスターラー(撹拌速度およそ300rpm)上に配置した。37℃の温度に達した後、規定量の噴霧乾燥製剤(0.14mg/mlの薬物濃度に相当)を添加した。1000μLのサンプルを、5分、15分、30分、60分、90分、120分、180分、240分、300分及び360分後に取り出した。サンプルを、微小遠心管にピペットで入れ、14,680rpmで3分間遠心分離して、沈殿物を除去した。透明な上清をメタノールで希釈した(薬物濃度に応じて1:4又は1:10); 溶液中の薬物の濃度を、メタノール中の純粋な薬物の検量線を使用してUV分光法によって決定した。ポリマーの性能を評価するために、濃度-時間曲線下の面積(AUC)を、次のように計算した:
(付記1)
構造単位の20~35重量%が、アクリル酸に由来し、構造単位の45~60重量%が、メタクリル酸イソプロピル、メタクリル酸tert-ブチル及びメタクリル酸シクロヘキシルからなる群から選択される疎水性メタクリレートに由来し、構造単位の15~40重量%が、N-ビニルラクタム、メタクリル酸ヒドロキシエチル及びアクリル酸フェノキシエチルからなる群から選択される第3のオレフィンモノマーに由来し、但し、3つのモノマー群に由来する構造単位の総量が100重量%になる、ターポリマー。
(付記2)
標準条件下での6.8のpHのリン酸塩緩衝液への溶解度が、ターポリマーの0.3重量%水性調製物が8μmの平均孔径を有する膜フィルターでろ過された場合に、フィルター上に残存する不溶性物質の含有量が水性調製物中のターポリマーの量の25重量%以下であるようなものである、付記1に記載のターポリマー。
(付記3)
疎水性メタクリレートが、メタクリル酸tert-ブチルである、付記1又は2に記載のターポリマー。
(付記4)
N-ビニルラクタムが、N-ビニルピロリドンである、付記1~3のいずれか一項に記載のターポリマー。
(付記5)
N-ビニルラクタムが、N-ビニルカプロラクタムである、付記1~3のいずれか一項に記載のターポリマー。
(付記6)
80~150℃の範囲の計算されたガラス転移温度を有する、付記1~5のいずれか一項に記載のターポリマー。
(付記7)
100~150℃の範囲の計算されたガラス転移温度を有する、付記1~5のいずれか一項に記載のターポリマー。
(付記8)
メタクリル酸tert-ブチル由来の構造単位の量が、45~55重量%の範囲にある、付記1~7のいずれか一項に記載のターポリマー。
(付記9)
アクリル酸由来の構造単位の量が、20~30重量%の範囲にある、付記1~8のいずれか一項に記載のターポリマー。
(付記10)
第3のオレフィンモノマー由来の構造単位の量が、20~35重量%の範囲にある、付記1~9のいずれか一項に記載のターポリマー。
(付記11)
7,000~100,000g/molの範囲の重量平均分子量を有する、付記1~10のいずれか一項に記載のターポリマー。
(付記12)
水に溶解すると5~9の範囲のpHをもたらすように、部分的に中和されている、付記1~11のいずれか一項に記載のターポリマー。
(付記13)
フリーラジカル開始剤の存在下でのモノマーのラジカル重合によって、付記1~12のいずれか一項に記載のターポリマーを製造する方法。
(付記14)
重合が、溶液重合である、付記13に記載の方法。
(付記15)
溶液重合が、有機溶媒中で実施される、付記13又は14に記載の方法。
(付記16)
有機溶媒が、イソプロパノールである、付記15に記載の方法。
(付記17)
ラジカル開始剤が、過酸化物である、付記13~16のいずれか一項に記載の方法。
(付記18)
付記1~17のいずれか一項に記載のターポリマー、及び0.1重量%未満の標準条件での水への溶解度を有する活性医薬成分を含む医薬剤形であって、活性成分が非晶質形態で存在する、医薬剤形。
(付記19)
0.1重量%未満の標準条件での水への溶解度を有する活性成分の、ヒト又は動物の身体の水性環境における再結晶化を阻害するための医薬剤形中の再結晶化阻害剤としての、付記1~17のいずれか一項に記載のターポリマーの使用であって、活性成分が該医薬剤形中に非晶質形態で存在する、使用。
Claims (19)
- 構造単位の20~35重量%が、アクリル酸に由来し、構造単位の45~60重量%が、メタクリル酸イソプロピル、メタクリル酸tert-ブチル及びメタクリル酸シクロヘキシルからなる群から選択される疎水性メタクリレートに由来し、構造単位の15~40重量%が、N-ビニルラクタム、メタクリル酸ヒドロキシエチル及びアクリル酸フェノキシエチルからなる群から選択される第3のオレフィンモノマーに由来し、但し、3つのモノマー群に由来する構造単位の総量が100重量%になる、ターポリマー。
- 標準条件下での6.8のpHのリン酸塩緩衝液への溶解度が、ターポリマーの0.3重量%水性調製物が8μmの平均孔径を有する膜フィルターでろ過された場合に、フィルター上に残存する不溶性物質の含有量が水性調製物中のターポリマーの量の25重量%以下であるようなものである、請求項1に記載のターポリマー。
- 疎水性メタクリレートが、メタクリル酸tert-ブチルである、請求項1又は2に記載のターポリマー。
- N-ビニルラクタムが、N-ビニルピロリドンである、請求項1~3のいずれか一項に記載のターポリマー。
- N-ビニルラクタムが、N-ビニルカプロラクタムである、請求項1~3のいずれか一項に記載のターポリマー。
- 80~150℃の範囲の計算されたガラス転移温度を有する、請求項1~5のいずれか一項に記載のターポリマー。
- 100~150℃の範囲の計算されたガラス転移温度を有する、請求項1~5のいずれか一項に記載のターポリマー。
- メタクリル酸tert-ブチル由来の構造単位の量が、45~55重量%の範囲にある、請求項1~7のいずれか一項に記載のターポリマー。
- アクリル酸由来の構造単位の量が、20~30重量%の範囲にある、請求項1~8のいずれか一項に記載のターポリマー。
- 第3のオレフィンモノマー由来の構造単位の量が、20~35重量%の範囲にある、請求項1~9のいずれか一項に記載のターポリマー。
- 7,000~100,000g/molの範囲の重量平均分子量を有する、請求項1~10のいずれか一項に記載のターポリマー。
- 水に溶解すると5~9の範囲のpHをもたらすように、部分的に中和されている、請求項1~11のいずれか一項に記載のターポリマー。
- フリーラジカル開始剤の存在下でのモノマーのラジカル重合によって、請求項1~12のいずれか一項に記載のターポリマーを製造する方法。
- 重合が、溶液重合である、請求項13に記載の方法。
- 溶液重合が、有機溶媒中で実施される、請求項13又は14に記載の方法。
- 有機溶媒が、イソプロパノールである、請求項15に記載の方法。
- ラジカル開始剤が、過酸化物である、請求項13~16のいずれか一項に記載の方法。
- 請求項1~17のいずれか一項に記載のターポリマー、及び0.1重量%未満の標準条件での水への溶解度を有する活性医薬成分を含む医薬剤形であって、活性成分が非晶質形態で存在する、医薬剤形。
- 0.1重量%未満の標準条件での水への溶解度を有する活性成分の、ヒト又は動物の身体の水性環境における再結晶化を阻害するための医薬剤形中の再結晶化阻害剤としての、請求項1~17のいずれか一項に記載のターポリマーの使用であって、活性成分が該医薬剤形中に非晶質形態で存在する、使用。
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CN104084896B (zh) | 2013-04-01 | 2017-09-19 | 黄种玉 | 研磨布制造方法 |
BR112015027832B1 (pt) | 2013-05-06 | 2020-08-18 | The Regents Of The University Of Minnesota | Polímero tendo uma cadeia principal derivada de acrilato, métodos para fazer o polímero tendo uma cadeia principal derivada de acrilato, formulações farmacêuticas e métodos para aumentar a solubilidade de uma droga |
KR102182889B1 (ko) | 2013-05-06 | 2020-11-25 | 리젠츠 오브 더 유니버시티 오브 미네소타 | 당을 포함하는 양친매성 공중합체 |
CN107920998B (zh) * | 2015-08-21 | 2021-07-27 | 巴斯夫欧洲公司 | 基于n-乙烯基吡咯烷酮和丙烯酸的水溶性聚合物作为药物助剂的用途 |
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2018
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- 2018-12-07 CN CN201880081433.0A patent/CN111479834B/zh active Active
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JP7322028B2 (ja) | 2023-08-07 |
US20210069112A1 (en) | 2021-03-11 |
EP3728353A1 (en) | 2020-10-28 |
EP3728353B1 (en) | 2023-08-02 |
CN111479834B (zh) | 2023-05-16 |
US12016926B2 (en) | 2024-06-25 |
JP2021507048A (ja) | 2021-02-22 |
WO2019121051A1 (en) | 2019-06-27 |
CN111479834A (zh) | 2020-07-31 |
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