JP5443763B2 - 製剤 - Google Patents
製剤 Download PDFInfo
- Publication number
- JP5443763B2 JP5443763B2 JP2008546637A JP2008546637A JP5443763B2 JP 5443763 B2 JP5443763 B2 JP 5443763B2 JP 2008546637 A JP2008546637 A JP 2008546637A JP 2008546637 A JP2008546637 A JP 2008546637A JP 5443763 B2 JP5443763 B2 JP 5443763B2
- Authority
- JP
- Japan
- Prior art keywords
- cyano
- deoxy
- capsule
- palmitoyl
- pharmaceutical formulation
- 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.)
- Expired - Fee Related
Links
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Description
(i)結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン及び中鎖トリグリセリドを混合し、懸濁液を形成する工程と;
(ii)工程(i)で形成された混合物を予め形成されたカプセルに移送する工程と;
(iii)該カプセルをシール(seal)する工程と
を含む上記の薬学的製剤を調製する方法に関する。
本発明の薬学的組成物は、液体の核を封入できる外側のカプセル又はシェル(shell)を含む。
上述の通り、本発明の製剤は、2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン(以降、活性剤と呼ぶ)及び液体担体を含む液体又は半液体の核を含む。
本製剤は、2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシンを、活性成分として含む。この化合物は、1−(2−C−シアノ−2−ジオキシ−β−D−アラビノ−ペントフラノシル)−N4−パルミトイルシトシンとしても知られ、下に示す構造を有し、全体を通して「CYC682」と呼ぶ。
上述の通り、本発明のもう1つの様態は、
(i)結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン及び中鎖トリグリセリドを混合する工程と;
(ii)工程(i)で形成された混合物を予め形成されたカプセルに移送する工程と;
(iii)該カプセルをシールする工程と
を含む上記のような薬学的製剤を調製する方法に関する。
[実施例]
1(a) 2’−シアノ−2’−デオキシ−1−β−D−アラビノフラノシルシトシン
50mlの水中に溶解させた8.66g(30mmol)の2’−シアノ−2’−デオキシ−1−β−D−アラビノフラノシルシトシン一塩酸塩の溶液を、90mlのDowex 1X2(商標)イオン交換樹脂(CHCOO−型)を充填したカラムに通し、カラムを300mlの水で洗浄した。流出液及び洗液を混合及び凍結乾燥し、無色の粉体として7.23g(収率95.5%)の表題の化合物を得た。
NMRスペクトル(六重水素化ジメチルスルホキシド,270MHz)δ ppm:
7.28(1H,広幅一重線);
7.23(1H,広幅一重線);
7.83(1H,二重線,J=7.8Hz);
6.17(1H,二重線,J=7.3Hz);
6.17(1H,二重線,J=5.9Hz);
5.77(1H,二重線,J=7.3Hz);
5.12〜5.16(1H,多重線);
4.36〜4.44(1H,多重線);
3.56〜3.80(4H,多重線)。
5.045g(20mmole)の2’−シアノ−2’−デオキシ−1−β−D−アラビノフラノシルシトシン[上の工程(a)で記載したように調製]をピリジンとの共沸蒸留により3回乾燥し、残渣を200mlのピリジン中に懸濁した。6.7ml(21mmole)の1,3−ジクロロ−1,1,3,3−テトライソプロピルジシロキサンを懸濁液に加え、生じる混合物を窒素雰囲気において室温で1時間攪拌した。溶液を、減圧蒸留により、その元の体積のほぼ半分まで濃縮し、濃縮物を200mlの酢酸エチルで希釈した。希釈した溶液を、各200mlの炭酸水素ナトリウム飽和水溶液で2回洗浄した。次いで、それを無水硫酸マグネシウム上で乾燥した。溶媒を減圧蒸留で除去し、生じる残渣をトルエン及びメタノールの混合物と混合した。混合物を共沸蒸留し、11.21gの残渣を得た。これを、5容量%のメタノールを含む塩化メチレンを溶離液として使用し、300gのシリカゲル(230〜400メッシュ)に通してカラムクロマトグラフィーで精製し、発泡体として8.67g(収率87%)の表題の化合物を得た。
NMR(CDCl3,270MHz)δ ppm:
7.69(1H,二重線,J=7.26Hz);
6.31(1H,二重線,J=7.26Hz);
5.74(1H,二重線,J=7.26Hz);
4.64(1H,二重二重線,J=7.26 & 7.26Hz);
4.15〜4.04(2H,多重線);
3.84(1H,三重二重線,J=7.26 & 3.30Hz);
3.67(1H,二重二重線,J=7.26 & 7.26Hz);
1.15〜0.93(28H,多重線)。
1.48g(3mmole)の2’−シアノ−2’−デオキシ−3’,5’−O−(1,1,3,3−テトライソプロピルジシロキサン−1,3−ジイル)−1−β−D−アラビノフラノシルシトシン[上の工程(b)で記載したように調製]及び3.07g(12mmole)のパルミチン酸を50mlのベンゼンを用いる共沸蒸留で乾燥し、残渣を30mlのテトラヒドロフラン中に溶解した。2.47g(12mmole)のジシクロヘキシルカルボジイミド及び120mg(0.9mmole)の4−(N,N−ジメチルアミノ)ピリジンを溶液に加え、生じる混合物を窒素雰囲気において50℃で2.5時間攪拌した。このときの最後に不溶物を濾過して除去し、減圧蒸留によって濾液から溶媒を除去した。残渣を、100mlの酢酸エチル及び50mlの5%重量/容量の炭酸水素ナトリウム水溶液間で分配した。有機層を50mlの塩化ナトリウム飽和水溶液で洗浄し、無水硫酸マグネシウム上で乾燥した。溶媒を減圧下に留去し、残渣を、1%容量/容量のメタノールを含む塩化メチレンを溶離液として使用するシリカゲルに通してカラムクロマトグラフィーで精製し、カラメル状の固体として1.85gの表題の化合物を得た。
NMRスペクトル(六重水素化ジメチルスルホキシド,270MHz)δ ppm:
10.94(1H,一重線);
8.02(1H,二重線,J=7.82Hz);
7.30(1H,二重線,J=7.32Hz);
6.21(1H,二重線,J=7.83Hz);
4.69(1H,一重線);
4.22(2H,多重線);
3.98(1H,二重線,J=2.45Hz);
3.42(1H,二重線,J=3.92Hz);
2.40(2H,三重線,J=7.32Hz);
1.53(2H,一重線);
0.82〜1.23(55H)。
0.31ml(5.45mmole)の酢酸及び2.84g(10.9mmole)のフッ化テトラブチルアンモニウムを、氷冷及び攪拌しながら、60mlのテトラヒドロフラン(モレキュラーシーブ3A上で予め乾燥したもの)中の4.0g(5.45mmol)の2’−シアノ−2’−デオキシ−N4−パルミトイル−3’,5’−O−(1,1,3,3−テトライソプロピルジシロキサン−1,3−ジイル)−1−β−D−アラビノフラノシルシトシン[上の工程(c)で記載したように調製]の溶液に添加し、生じる混合物を窒素雰囲気において40分攪拌した。次いで、反応混合物を減圧下で蒸発させ、乾燥するまで濃縮し、残渣を100mlの塩化メチレン及び50mlの塩化ナトリウム飽和水溶液間で分配した。有機層を50mlの塩化ナトリウム飽和水溶液で洗浄し、無水硫酸マグネシウム上で乾燥した。次いで、溶媒を減圧蒸留で除去し、残渣であるカラメル状の固体を、4%容量/容量のメタノールを含む塩化メチレンを溶離液として使用するシリカゲルに通してカラムクロマトグラフィーで精製し、無色の粉体として2.25gの表題の化合物を得た。
NMRスペクトル(六重水素化ジメチルスルホキシド,270MHz)δ ppm:
10.91(1H,一重線);
8.36(1H,二重線,J=7.8Hz);
7.29(1H,二重線,J=7.8Hz);
6.25(1H,二重線,J=5.4Hz);
6.21(1H,二重線,J=7.3Hz);
5.22(1H,広幅一重線);
4.43(1H,多重線);
3.61〜3.93(4H,多重線);
2.40(2H,三重線,J=7.3Hz);
1.54(2H,三重線,J=6.8Hz);
1.24(24H,一重線);
0.83〜0.88(3H,多重線)。
12.9g(51.1mmole)の2’−シアノ−2’−デオキシ−1−β−D−アラビノフラノシルシトシン[上の実施例1(a)で記載したように調製]及び38.1g(76.7mmole)の無水パルミチン酸を1リットルの丸底フラスコ中に入れ、そこに51mlのジメチルホルムアミドを加えた。生じる混合物を、水分から保護するように注意しながら、100℃に維持された油浴中で20分攪拌した。出発化合物の消失を薄層クロマトグラフィーで確認した(展開溶媒として5%容量/容量のメタノールを含む塩化メチレンを使用)。出発化合物が消失した時点で、513mlのジイソプロピルエーテルを攪拌しながら反応混合物に添加し、混合物を氷冷しながら1時間放置した。このときの最後に、不溶物を濾過して回収した。その不溶物を513mlのプロパノールに加熱して攪拌しながら完全に溶解し、溶液を冷蔵庫中で一晩放置し、上の1(d)の生成物と同一の物理化学的特性を有する無色の粉体として18.0gの表題の化合物を得た。
(a)日本国特許第2569251号の実施例1(1d)及び欧州特許第536936号(実施例1で上に記載された)に記載された化合物である2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン(30g)に2.5容量%(300ml)で水を含む酢酸メチルを添加し、生じる混合物を約55℃まで昇温し、透明な溶液を調製した。続いて、1分あたり約0.5℃の速度で5℃まで溶液を冷却した。冷却の過程で約45℃まで冷却した時点で、板状結晶を溶液より分離した。5℃で20分間さらに攪拌後、分離された結晶を濾過して回収し、2.5容量%(30ml)で水を含む酢酸メチルで洗浄し、所望の結晶B(28.78g、純度97.9%)を96.0%[モル数/モル数]の収率で得た。
2つの異なる強度:25mg及び75mgのCYC682で、カプセルを調製した。それぞれに見合って、より低強度の方を3号カプセルに充填して製剤したのに対し、より高強度の方を1号カプセルに充填して製剤した。全ての材料は、薬局方品質である。
成分 機能 %(重量/重量)
CYC682 活性剤 25
Miglyol 812N欧州薬局方/GRAS 液体担体 75
を含む。
1.CYC682を混合容器に量り入れる。
2.正しい総量が加えられるまで、Miglyol 812Nを徐々に加える。
3.2つの成分を、Silverson社製混合機を使用して高速で5〜8分間、混合する。
4.試料を取り出し、均一性を確かめる。
5.均一であれば、減圧で吸引して混合物を脱気する。
6.Bosch社製1500Lカプセル充填機に3号交換部分を据え付け、25mg投与量用の所望の充填重量が得られるように充填ポンプを調整する。
7.12個のカプセルの平均に対して次の目標、即ち、警告2.5%;処置3.5%;廃棄5.0%を使用し、25mgのカプセルを充填する。それぞれのカプセルの限界は7.5%である。
8.3号交換部分を1号交換部分に交換し、充填重量を再設定して、75mgのカプセル用に繰り返す。全ての他の条件は、同一である。
9.全てのカプセルの充填が完了すれば、透明なゼラチンを使用してカプセルをバンドする。
40℃/75%相対湿度(RH)及び25℃/69%RHのポリプロピレン容器中に、カプセルを配置した。後者は通常の保存条件を構成していると考えられるのに対し、前者は加速保存条件を構成していると考えられる。検討は、6カ月の加速条件下での初期評価と、それに続く通常の保存条件下でのより長期の評価とよりなっていた。6カ月は、加速安定性試験のために認められた期間である。
Claims (24)
- (i)カプセルと、(ii)結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン、並びに、中鎖トリグリセリド油及びポリグリコール化グリセリドから選択される液体担体を含む核とを含む薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシンがB型を含む、請求項1に記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシンがB型からなる、請求項1又は請求項2に記載の薬学的製剤。
- 液体担体が中鎖トリグリセリド油である、請求項1〜3のいずれかに記載の薬学的製剤。
- 中鎖トリグリセリド油がヤシ油又はカプリル酸/カプリン酸トリグリセリドである、請求項1〜4のいずれかに記載の薬学的製剤。
- ポリグリコール化グリセリドがGelucire 44/14である、請求項1〜3のいずれかに記載の薬学的製剤。
- カプセルがゼラチンカプセルである、請求項1〜6のいずれかに記載の薬学的製剤。
- カプセルが硬カプセルである、請求項1〜7のいずれかに記載の薬学的製剤。
- カプセルが1種又は複数の乳白剤及び/又は1種又は複数の顔料を含む、請求項1〜8のいずれかに記載の薬学的製剤。
- 顔料及び/又は乳白剤が0.1〜10%の量でそれぞれ存在している、請求項9に記載の薬学的製剤。
- 乳白剤が二酸化チタンである、請求項9又は請求項10に記載の薬学的製剤。
- 二酸化チタンが2%の量で存在している、請求項11に記載の薬学的製剤。
- カプセルがゼラチンバンドでシールされている、請求項1〜12のいずれかに記載の薬学的製剤。
- 核が結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン及び液体担体からなる、請求項1〜13のいずれかに記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン1重量部に対して、液体担体の量が2〜50重量部である、請求項1〜14のいずれかに記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン1重量部に対して、液体担体の量が2〜10重量部である、請求項1〜15のいずれかに記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン1重量部に対して、液体担体の量が2〜5重量部である、請求項1〜16のいずれかに記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン1重量部に対して、液体担体の量が3重量部である、請求項1〜17のいずれかに記載の薬学的製剤。
- 経口投与のための、請求項1〜18のいずれかに記載の薬学的製剤。
- 結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシンのゼラチンカプセル中の液体担体としての、中鎖トリグリセリドの使用。
- 中鎖トリグリセリドがヤシ油又はカプリル酸/カプリン酸トリグリセリドである、請求項20に記載の使用。
- (i)結晶性2’−シアノ−2’−デオキシ−N4−パルミトイル−1−β−D−アラビノフラノシルシトシン及び中鎖トリグリセリドを混合する工程と;
(ii)工程(i)で形成された混合物を予め形成されたカプセルに移送する工程と;
(iii)該カプセルをシールする工程と
を含む請求項1〜19のいずれかに記載の薬学的製剤を調製する方法。 - 工程(iii)がゼラチンバンドでカプセルをシールすることを含む、請求項22に記載の方法。
- 工程(iii)がマイクロ噴霧によりカプセルをシールすることを含む、請求項22に記載の方法。
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PCT/GB2006/004927 WO2007072061A2 (en) | 2005-12-23 | 2006-12-22 | Crystalline pyrimidine nucleoside derivatives suspensions in capsules |
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CN1302007C (zh) | 2001-04-30 | 2007-02-28 | 葛兰素集团有限公司 | 具有抗炎性的在17.α位上具有环酯基的雄甾烷的17.β.-硫代羧酸酯衍生物 |
GB0625283D0 (en) | 2006-12-19 | 2007-01-24 | Cyclacel Ltd | Combination |
EP2148676B1 (en) * | 2007-04-25 | 2016-05-25 | Cyclacel Limited | Use of sapacitabine to treat proliferative disease |
US8124593B2 (en) | 2007-11-05 | 2012-02-28 | Cyclacel Limited | Methods of treatment using sapacitabine |
GB0808357D0 (en) | 2008-05-08 | 2008-06-18 | Cyclacel Ltd | Process |
CN102088969B (zh) | 2008-06-09 | 2013-06-12 | 西克拉塞尔有限公司 | 沙帕他滨或cndac与dna甲基转移酶抑制剂如地西他滨和普鲁卡因的组合 |
RU2538593C2 (ru) * | 2009-05-15 | 2015-01-10 | Дельта-Флай Фарма, Инк. | НОВЫЕ СТАБИЛЬНЫЕ КРИСТАЛЛЫ МОНОГИДРОХЛОРИДА 1-(2-β-D-АРАБИНОФУРАНОЗИЛ)ЦИТОЗИНА |
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JP5873375B2 (ja) * | 2012-04-03 | 2016-03-01 | 中日本カプセル 株式会社 | ソフトカプセル及びソフトカプセルの製造方法 |
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CN106963742B (zh) * | 2016-11-07 | 2021-02-23 | 澳门大学 | 中药固液胶囊及其制备方法 |
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CA2633308A1 (en) | 2007-06-28 |
IL192348A0 (en) | 2009-08-03 |
DK1962814T3 (en) | 2018-08-06 |
PT1962814T (pt) | 2018-06-22 |
US20090074856A1 (en) | 2009-03-19 |
WO2007072061A2 (en) | 2007-06-28 |
GB0526419D0 (en) | 2006-02-08 |
WO2007072061A3 (en) | 2007-10-25 |
BRPI0620229B1 (pt) | 2020-09-15 |
AU2006327951A1 (en) | 2007-06-28 |
BRPI0620229B8 (pt) | 2021-05-25 |
EP1962814A2 (en) | 2008-09-03 |
CN101346132A (zh) | 2009-01-14 |
JP2013189463A (ja) | 2013-09-26 |
AU2006327951B2 (en) | 2012-09-06 |
HUE039368T2 (hu) | 2018-12-28 |
ES2672106T3 (es) | 2018-06-12 |
JP2009520797A (ja) | 2009-05-28 |
HK1126412A1 (en) | 2009-09-04 |
RU2008130411A (ru) | 2010-01-27 |
IL192348A (en) | 2016-02-29 |
CA2633308C (en) | 2014-06-17 |
CN101346132B (zh) | 2013-01-16 |
EP1962814B1 (en) | 2018-04-25 |
TR201808182T4 (tr) | 2018-07-23 |
RU2428972C2 (ru) | 2011-09-20 |
BRPI0620229A8 (pt) | 2018-01-02 |
US8497291B2 (en) | 2013-07-30 |
BRPI0620229A2 (pt) | 2011-11-01 |
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