JP7417958B2 - Cdk9阻害薬の局所送達のための徐放製剤 - Google Patents
Cdk9阻害薬の局所送達のための徐放製剤 Download PDFInfo
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- JP7417958B2 JP7417958B2 JP2021509951A JP2021509951A JP7417958B2 JP 7417958 B2 JP7417958 B2 JP 7417958B2 JP 2021509951 A JP2021509951 A JP 2021509951A JP 2021509951 A JP2021509951 A JP 2021509951A JP 7417958 B2 JP7417958 B2 JP 7417958B2
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Description
本出願は2018年4月23日に出願された米国特許出願第62/661,599の利益を請求し、その内容は参照によって本明細書に組み込まれる。
[連邦政府が後援する研究又は開発下で行われた発明に対する権利に関する声明]
ある態様において、本発明はCDK9阻害薬の局所送達について新規の徐放製剤を記載し、ここでその阻害薬は生体吸収性ポリマーにカプセル化され、そしてポリマーが分解される時間にわたり放出される。その阻害薬は、全体的な全身投与量を最小限に抑えながら、長期間にわたり治療レベルで局所的に利用可能である。
II.定義
III.組成物及び方法
A.化合物
B.組成物
C.方法
実施例1.乳酸・グリコール酸共重合体及びフラボピリドールを含む粒子の合成
フラボピリドール-乳酸グリコール酸共重合体粒子の調製方法は同一の乳化溶媒蒸発法を用いて実施された。簡潔に、PLGAを塩化メチレン(5%w/v)において溶解し、フラボピリドールを添加し、そしてその溶液を滅菌水中のバルク量のポリビニルアルコールに加えて、さらにホモジナイズし(2分間、35,000rpm)エマルジョンを形成した。それゆえ形成された粒子を24時間撹拌し、残存した塩化メチレンを蒸発させた。MPsを洗浄し、凍結乾燥し、そして-20℃で保存した。サイズ分布をMicrotrac Nanotrac Dynamic Light Scattering Particle Analyzerによって測定し、そして走査型電子顕微鏡によって確認した。
表1:与えられた特性(L/G比、インヘレント粘度、末端基)を有するPLGAカプセル化したフラボピリドールの製剤。製剤1:Lactel(登録商標)B6013-2、LG比50:50、IV:0.55~0.75 dL/g、酸末端;製剤2:Purasorb(登録商標)5004A、LG比50:50、IV0.4dL/g、酸末端;製剤3:Lactel(登録商標)B6012-4、LG比75:25、IV0.7~0.9dL/g、酸末端。
実施例3.PLGA/フラボピリドール粒子はラットの変形性関節症モデルにおいて活性である。
実施例4.変化した放出特性によるPLGA-フラボピリドール粒子の合成の比較
表2:エステル末端化したPLGAからの積載及び粒子サイズ
表3:製剤特徴
実施例6.SNS-32、ボルシクリブ(Voruciclib)、及びディナシクリブの製剤化
Claims (20)
- サイクリン依存性キナーゼ9(CDK9)阻害薬及び酸末端化乳酸・グリコール酸共重合体(PLGA)を含むマイクロパーティクルであって、前記CDK9阻害薬がPLGAによってカプセル化され、かつ前記マイクロパーティクルが約3から約50ミクロンの直径を有し、かつ前記CDK9阻害薬の徐放を担い、
ここで前記CDK9阻害剤は、フラボピリドール、SNS-032、ボルシクリブ(voruciclib)、又はそれらの医薬的に許容可能な塩から選択され、
ここで前記マイクロパーティクルは約0.5重量%~約5重量%のCDK9阻害剤を有し、かつ前記マイクロパーティクルは、投与後30日間に約80%から約95%のCDK9阻害剤を放出する、
マイクロパーティクル。 - 前記CDK9阻害薬がフラボピリドールである請求項1に記載のマイクロパーティクル。
- 前記PLGAが約50:50から約75:25の乳酸とグリコール酸との(L:G)比を有する請求項2に記載のマイクロパーティクル。
- 前記マイクロパーティクルが投与後約60日の期間にわたり前記CDK9阻害薬を放出する請求項1~3のいずれか一項に記載のマイクロパーティクル。
- 前記マイクロパーティクルが投与後24時間にわたり前記CDK9阻害薬の約3%から約30%を放出する請求項1~4のいずれか一項に記載のマイクロパーティクル。
- 前記マイクロパーティクルが投与後24時間にわたり前記CDK9阻害薬の約3%から約20%を放出する請求項1~4のいずれか一項に記載のマイクロパーティクル。
- 前記マイクロパーティクルが投与後60日にわたり前記CDK9阻害薬を放出する、請求項5又は6に記載のマイクロパーティクル。
- 請求項1~7のいずれか一項に記載の複数のマイクロパーティクル及び医薬的に許容可能な担体を含む医薬組成物。
- 前記複数のマイクロパーティクルが約10から約20ミクロンの平均の直径を有する請求項8に記載の医薬組成物。
- 前記複数のマイクロパーティクルの質量の90%(D90)が約30ミクロンより小さい直径を有する請求項8に記載の医薬組成物。
- 前記複数のマイクロパーティクルが前記CDK9阻害薬の質量に基づいて約0.5%から約5%を有する請求項8に記載の医薬組成物。
- 注射による送達のために処方される、請求項8に記載の医薬組成物。
- 請求項1~7のいずれか一項に記載の治療有効量の複数のマイクロパーティクルを含む、医薬組成物であって、前記マイクロパーティクルはCDK9阻害薬及び乳酸・グリコール酸共重合体(PLGA)を含み、ここで前記CDK9阻害薬を前記PLGAによりカプセル化し、かつ前記マイクロパーティクルが前記CDK9阻害薬の徐放を担う、医薬組成物。
- 前記CDK9阻害薬がフラボピリドールである請求項13に記載の医薬組成物。
- 請求項13に記載の医薬組成物を前記対象の炎症部位で投与することを含む、請求項15に記載の医薬組成物。
- 前記対象が関節炎、変形性関節症、外傷性の変形性関節症、及び外傷性疾患より選択される疾病又は状態を有する請求項13~15のいずれか一項の医薬組成物。
- 前記炎症部位が、関節、軟骨、又は外傷の部位である請求項15又は16に記載の医薬組成物。
- 前記医薬組成物が注射によって投与される請求項13~16のいずれか一項に記載の医薬組成物。
- 炎症部位を治療する医薬組成物であって、請求項1~7のいずれか一項に記載の複数のマイクロパーティクルに製剤化されたCDK9阻害薬を含む組成物を前記部位に投与することを含み、ここで前記マイクロパーティクルは少なくとも24時間前記部位で前記CDK9阻害薬の徐放を担い、かつそれによって前記部位での炎症を減少する又は回復する、医薬組成物。
- 前記CDK9阻害薬がフラボピリドールである、請求項19に記載の医薬組成物。
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