JP2008540439A - 安定なナノ粒子処方物 - Google Patents
安定なナノ粒子処方物 Download PDFInfo
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- JP2008540439A JP2008540439A JP2008510185A JP2008510185A JP2008540439A JP 2008540439 A JP2008540439 A JP 2008540439A JP 2008510185 A JP2008510185 A JP 2008510185A JP 2008510185 A JP2008510185 A JP 2008510185A JP 2008540439 A JP2008540439 A JP 2008540439A
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- 235000013311 vegetables Nutrition 0.000 description 1
- 229910001928 zirconium oxide Inorganic materials 0.000 description 1
- GFQYVLUOOAAOGM-UHFFFAOYSA-N zirconium(iv) silicate Chemical compound [Zr+4].[O-][Si]([O-])([O-])[O-] GFQYVLUOOAAOGM-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明はまた、本発明の安定なナノ粒子処方物の製造法及びその使用法も提供する。
硬化植物油中の化合物A
まず最初に、候補の分散媒Wecobee(R)S(植物油から誘導のトリグリセリド、融点約44℃)における化合物Aの溶解度を以下の方法により測定した。硬化植物油5グラムを秤量してシンチレーションバイアルに入れ、50℃に加熱した。化合物A 5gを追加し、水浴中で磁気スターラーにより撹拌した。原薬が溶解しなかったので、硬化植物油の総量が10gになるまで追加の硬化植物油を徐々に加えた。この混合物を60℃の水浴中で一晩撹拌した。この混合物を同じ温度で濾過し(濾過組立品をオーブンで60℃まで加熱した)、60℃の硬化植物油中の化合物Aの濾液溶解度を0.48mg/gと測定した。
ブランド)を用い、50℃で溶融させたWecobee(R)S 700gに化合物A 150gを分散させることによって調製した。ミル処理設備から洗浄媒体を引き抜いた後、DynoMillTMを3200rpmで撹拌させながら原薬懸濁物を400ml/分で循環させた。沈降を避けるためにミキサーを用いて懸濁物の撹拌を続けたが、ミル処理の間は加熱しなかった。循環水浴温度及び循環水道水温度をさらに下げて、その温度を55℃付近まで冷却して維持し、製品温度を45℃〜50℃まで冷却し維持した。これらの温度をミル処理期間を通じて維持した。懸濁物は計5時間ミルに供した。ミル処理終了後、懸濁物を貯蔵容器に移動させ、室温に冷却するにまかせた。
固脂中の化合物B
まず、ダイズ油中の化合物Bの溶解度を、ダイズ油が(目視で)ほぼ透明になるまで、秤量した原薬量にダイズ油を徐々に加えていくことによって視覚的に概算した。油中の原薬の概算値は、追加した総油量から算出した。ダイズ油中の化合物Bの溶解度は1mg/ml未満であり、従って、ダイズ油中での化合物Bの溶解度の低さは同様に固脂中での溶解度の低さにつながると判断された。
硬化ココグリセリド中の化合物C
媒体(硬化ココグリセリド、Softisan(R)142として販売、約42〜44℃の融点範囲)をホットプレート上で50℃に加熱した。油中での溶解度の低さが一般的に知られている化合物C 2.5gを秤量して50ml遠心チューブに入れ、このチューブを対流式オーブンで50℃に加熱した。1mm超高密度ジルコニウムビーズ20mlを別のチューブで同じ温度に加熱した。このビーズを原薬に追加した後、Softisan(R)142を10mlさらに追加した。チューブの上部付近を加熱テープで包み、温度コントロールを低に設定した。縦型ミルのインペラーをチューブに挿入し、この処方物を2000rpmで3時間混合した。溶融させたSoftisan(R)142をさらに10ml追加し、ガラス棒で混合した。次いでこの溶融懸濁物を予備加熱した濾過組立品を用いて55℃でスクリーンにかけてミル処理用ビーズを除去した。
実施例1〜3の粒子径の分析
実施例1〜3の粒子径の分析を、Horiba LA−920レーザ回折式粒度分布測定装置を用いて行った。サンプルの200mg部を最初に50℃の水浴中で加熱し、Aerosol(R)OT−100分散剤(Cytec Industries Inc.から販売されているジオクチルスルホコハク酸ナトリウム)を含有するダイズ油25mlを追加し、次いでサンプルを撹拌した。このサンプルをこの装置に移し、撹拌し、超音波処理し、そして分析した。実施例1〜3の粒子径の分析結果を以下の表1A、1B、及び1Cに示す。
実施例1の物理的安定性
実施例1で調製したナノ粒子懸濁物の物理的安定性を測定するために、40℃/75%相対湿度(RH)で3月間、この懸濁物に負荷をかけた。このサンプルを3月の各月の終点で粒子径の安定性について分析した。
実施例2の物理的安定性
実施例2で調製した組成物の物理的安定性を測定するために、加熱及び冷却を交互に行うことによりこの懸濁物に負荷をかけた;サンプルを1週目は50℃で、2週目は5℃で、3週目は50℃で保存した。このサンプルを3週の終点での粒子径の安定性について分析した。
Claims (32)
- 約1000nm未満の平均粒子径を有する難溶性の原薬、固体又は半固体の分散媒、及び場合により非表面改質性の添加剤を含む、薬学的ナノ粒子処方物。
- 難溶性の原薬が約750nm未満の平均粒子径を有する、請求項1に記載の処方物。
- 難溶性の原薬が約600nm未満の平均粒子径を有する、請求項1に記載の処方物。
- 難溶性の原薬の少なくとも95%が、約1000nm未満の粒子径を有する、請求項1に記載の処方物。
- 処方物中の難溶性の原薬の量が約0.01質量%〜約30質量%の範囲である、請求項1に記載の処方物。
- 処方物中の難溶性の原薬の量が約1質量%〜約20質量%の範囲である、請求項5に記載の処方物。
- 非表面改質性の添加剤が非表面修飾性の薬学的に許容できる固体賦形剤である、請求項1に記載の処方物。
- 難溶性の原薬が、蛋白質、ペプチド、機能性食品、抗炎症薬、NSAID、COX−2阻害薬、鎮痛薬、抗ムスカリン薬、ムスカリン様作用薬、コルチコステロイド、エラスターゼ阻害薬、腫瘍療法薬、抗嘔吐薬、神経保護薬、心血管薬、抗血小板薬、脂質調節薬、抗凝固薬、駆虫薬、抗不整脈薬、心臓変力薬、降圧薬、利尿薬、診断薬、画像診断薬、抗ウイルス薬、抗真菌薬、抗生物質、抗ミコバクテリア薬、抗痙攣薬、抗糖尿病薬、抗てんかん薬、抗腫瘍薬、免疫活性薬、免疫抑制薬、抗甲状腺薬、甲状腺用薬、抗うつ薬、麻酔薬、抗不安薬、睡眠薬、神経弛緩薬、収れん薬、ベータアドレナリン受容体遮断薬、ドパミン作用薬、止血薬、免疫薬、筋弛緩薬、副交感神経作用薬、副甲状腺カルシトニン、ビスホスホネート、プロスタグランジン、放射性医薬品、性ホルモン、ステロイド、刺激薬、食欲抑制薬、交感神経作用薬、抗アレルギー薬、抗ヒスタミン薬、鎮咳薬、血管拡張薬、及びキサンチン類からなる群より選択される1つ又はそれ以上である、請求項1に記載の処方物。
- 難溶性の原薬が、神経保護薬、抗不整脈薬、抗痙攣薬、及び抗不安薬からなる群より選択される1つ又はそれ以上である、請求項8に記載の処方物。
- 難溶性の原薬が、7−クロロ−N,N,5−トリメチル−4−オキソ−3−フェニル−3,5−ジヒドロ−4H−ピリダジノ[4,5−b]インドール−1−アセトアミド、6−フルオロ−9−メチル−2−フェニル−4−(ピロリジン−1−イルカルボニル)−2,9−ジヒドロ−1H−ピリド[3,4−b]インドール−1−オン、及び2−ブチル−3−[4−[3−(ジブチルアミノ)プロピル]ベンゾイル]−1−ベンゾフラン−5−カルボン酸イソプロピルフマル酸塩からなる群より選択される、請求項1に記載の処方物。
- 難溶性の原薬が、7−クロロ−N,N,5−トリメチル−4−オキソ−3−フェニル−3,5−ジヒドロ−4H−ピリダジノ[4,5−b]インドール−1−アセトアミドである、請求項10に記載の処方物。
- 難溶性の原薬が、6−フルオロ−9−メチル−2−フェニル−4−(ピロリジン−1−イルカルボニル)−2,9−ジヒドロ−1H−ピリド[3,4−b]インドール−1−オンである、請求項10に記載の処方物。
- 難溶性の原薬が、2−ブチル−3−[4−[3−(ジブチルアミノ)プロピル]ベンゾイル]−1−ベンゾフラン−5−カルボン酸イソプロピルフマル酸塩である、請求項10に記載の処方物。
- 分散媒が、硬化植物油、トリグリセリド、硬化ココグリセリド、混合グリセリド、硬化グリセリド、合成グリセリド、分別脂肪酸のグリセリンエステル、脂肪酸の非表面活性エステル、脂肪酸、ココアバター、ココアバター代用物、ハード脂、天然ろう及び合成ろう、並びにワセリンからなる群より選択される1つ又はそれ以上の物質である、請求項1に記載の処方物。
- 分散媒が、硬化植物油、トリグリセリド、硬化ココグリセリド、混合グリセリド、硬化グリセリド、合成グリセリド、分別脂肪酸のグリセリンエステル、脂肪酸のプロピレングリコールジエステル、その他の脂肪酸の非表面活性エステル、脂肪酸、ココアバター、ココアバター代用物、ハード脂、天然ろう及び合成ろう、並びにワセリンからなる群より選択される1つ又はそれ以上の物質である、請求項10に記載の処方物。
- 分散媒が硬化植物油、ハード脂、及び硬化ココグリセリドからなる群より選択される1つ又はそれ以上の物質である、請求項15に記載の処方物。
- 分散媒が1つ又はそれ以上の硬化植物油である、請求項11に記載の処方物。
- 分散媒が1つ又はそれ以上のハード脂である、請求項12に記載の処方物。
- 分散媒が1つ又はそれ以上の硬化ココグリセリドである、請求項13に記載の処方物。
- 固体又は半固体の分散媒が2つ又はそれ以上の物質の混合物である、請求項1に記載の処方物。
- 治療有効量の請求項1に記載の薬学的ナノ粒子処方物を患者に投与することからなる、患者の治療方法。
- 治療有効量の請求項10に記載の薬学的ナノ粒子処方物を患者に投与することからなる、患者の治療方法。
- 神経変性疾患又はがんを治療する方法であって、治療有効量の請求項11に記載の薬学的ナノ粒子処方物をそのような治療が必要な患者に投与することからなる、方法。
- 不安、てんかん、痙縮、若しくは筋拘縮を治療又は予防する方法であって、治療有効量の請求項12に記載の薬学的ナノ粒子処方物をそのような治療又は予防が必要な患者に投与することからなる、方法。
- 不整脈を治療又は予防する方法であって、治療有効量の請求項13に記載の薬学的ナノ粒子処方物をそのような治療又は予防が必要な患者に投与することからなる、方法。
- 神経変性疾患又はがんの治療のための医薬の製造における、請求項11に記載の薬学的ナノ粒子処方物の使用。
- 不安、てんかん、痙縮、又は筋拘縮の治療のための医薬の製造における、請求項12に記載の薬学的ナノ粒子処方物の使用。
- 不整脈の治療のための医薬の製造における、請求項13に記載の薬学的ナノ粒子処方物の使用。
- (a)1つ又はそれ以上の難溶性の原薬と、室温で固体又は半固体の溶融分散媒を混合する工程、及び
(b)混合物をメディアミルに供してナノ粒子処方物を形成する工程、
を含む、請求項1に記載のナノ粒子処方物の調製法。 - (a)固体又は半固体の分散媒を固体又は半固体の分散媒の融点又はそれ以上の第一の温度範囲に加熱して溶融分散媒を形成する工程、
(b)1つ又はそれ以上の難溶性の原薬と溶融分散媒を混合して混合物を形成する工程、
(c)混合物を複数の粉砕メディアと共にメディアミルに供してナノ懸濁物を形成する工程、及び
(d)固体又は半固体の分散媒の融点未満の第二の温度範囲にナノ懸濁物を冷却してナノ粒子処方物を形成する工程、
を含む、請求項28に記載の方法。 - (a)固体又は半固体の分散媒を固体又は半固体の分散媒の融点又はそれ以上の第一の温度範囲に加熱して溶融分散媒を形成する工程、
(b)1つ又はそれ以上の難溶性の原薬と溶融分散媒を混合して混合物を形成する工程、
(c)混合物を複数の粉砕メディアと共にメディアミルに供してナノ懸濁物を形成する工程、
(d)ナノ懸濁物をカプセルに充填する工程、及び
(e)固体又は半固体の分散媒の融点未満の第二の温度範囲にカプセルを冷却してナノ粒子処方物を形成する工程、
を含む、請求項28に記載の方法。 - (a)固体又は半固体の分散媒を固体又は半固体の分散媒の融点又はそれ以上の第一の温度範囲に加熱して溶融分散媒を形成する工程、
(b)1つ又はそれ以上の難溶性の原薬と溶融分散媒を混合して混合物を形成する工程、
(c)混合物を複数の粉砕メディアと共にメディアミルに供してナノ懸濁物を形成する工程、及び
(d)非表面改質性の固体添加剤を用いてナノ懸濁物を造粒処理して固体処方物を形成する工程、
を含む、請求項28に記載の方法。
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US8343498B2 (en) * | 2008-10-12 | 2013-01-01 | Massachusetts Institute Of Technology | Adjuvant incorporation in immunonanotherapeutics |
WO2013041944A1 (en) | 2011-09-19 | 2013-03-28 | Ranbaxy Laboratories Limited | Process for the preparation of micronized candesartan cilexetil |
CN104174468B (zh) * | 2014-08-27 | 2016-06-15 | 上海延安药业有限公司 | 粘稠性药物锆珠研磨方法 |
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JP2019513778A (ja) * | 2016-04-15 | 2019-05-30 | エピザイム,インコーポレイティド | Ehmt1およびehmt2阻害剤としてのアミン置換アリールまたはヘテロアリール化合物 |
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JP2022081606A (ja) * | 2016-04-15 | 2022-05-31 | エピザイム,インコーポレイティド | Ehmt1およびehmt2阻害剤としてのアミン置換アリールまたはヘテロアリール化合物 |
JP7420847B2 (ja) | 2016-04-15 | 2024-01-23 | エピザイム,インコーポレイティド | Ehmt1およびehmt2阻害剤としてのアミン置換アリールまたはヘテロアリール化合物 |
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MA29492B1 (fr) | 2008-05-02 |
ZA200708633B (en) | 2009-01-28 |
US20080038359A1 (en) | 2008-02-14 |
WO2007086911A3 (en) | 2008-04-17 |
HK1120417A1 (en) | 2009-04-03 |
WO2007086911A2 (en) | 2007-08-02 |
AU2006336414A1 (en) | 2007-08-02 |
AU2010241245A1 (en) | 2010-11-25 |
CA2606861A1 (en) | 2007-08-02 |
BRPI0611433A2 (pt) | 2010-09-08 |
IL187128A0 (en) | 2008-06-05 |
KR20080015077A (ko) | 2008-02-18 |
RU2409352C2 (ru) | 2011-01-20 |
JP5483874B2 (ja) | 2014-05-07 |
CN101252914A (zh) | 2008-08-27 |
EP1895982A2 (en) | 2008-03-12 |
CA2606861C (en) | 2012-08-07 |
NO20076120L (no) | 2007-11-27 |
NZ562559A (en) | 2011-03-31 |
CN101252914B (zh) | 2013-03-27 |
AU2006336414B2 (en) | 2011-11-24 |
RU2007145055A (ru) | 2009-06-10 |
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