JPWO2019136451A5

JPWO2019136451A5 -

Info

Publication number: JPWO2019136451A5
Application number: JP2020537622A
Authority: JP
Publication date: 2023-02-08

Description

「剤形（dosage form）」は、有効薬剤の投与単位を意味する。剤形の例としては、錠剤、カプセル剤、注射剤、懸濁液、液体、エマルション、インプラント、粒剤、スフィア、クリーム、軟膏、坐剤、吸入形態、経皮形態、口内剤、舌下剤、局所剤、ゲル、粘膜剤などが含まれる。
"Dosage form " means a dosage unit of active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalation forms, transdermal forms, oral formulations, sublingual formulations, Includes topical agents, gels, mucosal agents, and the like.

「医薬組成物」は、少なくとも１種類の有効薬剤、および少なくとも１種類の担体などの他の物質を含んでなる組成物である。「医薬組合せ」は、単一の剤形に組み合わせることができる少なくとも２種類の有効薬剤の組合せ、またはそれらの有効薬剤が本明細書に記載のいずれかの障害を治療するために一緒に使用されるべきであるという説明書を添えて別個の剤形で一緒に提供され得る少なくとも２種類の有効薬剤の組合せである。
A "pharmaceutical composition" is a composition comprising at least one active agent and other substances, such as at least one carrier. A "pharmaceutical combination" is a combination of at least two active agents that can be combined in a single dosage form or when those active agents are used together to treat any of the disorders described herein. A combination of at least two active agents that may be provided together in separate dosage forms with instructions that they should be.

温度、冷却手順、および単離手順を変更することによるいくつかの結晶化およびスラリー実験を行った（実施例１０、表９７～１００）。これらの実験から、化合物ＩＩの１１のユニークな形態が見出されたが、形態Ａ、形態Ｂ、および形態Ｄのみが評価に適当であった。他の形態は弱い結晶形、溶媒和物、不安定な水和物、または無水物となった。これら３つの固体形のうち形態Ｂは、治療剤形として予期されないほど優れた高い結晶性の安定な材料であることが判明した。動的水蒸気吸着実験では、化合物ＩＩは、９０％相対湿度に曝された後も形態Ｂのままであった（実施例１１）。
Several crystallization and slurry experiments were performed by varying the temperature, cooling procedure, and isolation procedure (Example 10, Tables 97-100). From these experiments, 11 unique forms of Compound II were found, but only Forms A, B, and D were suitable for evaluation. Other forms were weakly crystalline, solvates, unstable hydrates, or anhydrous. Of these three solid forms, Form B was found to be a highly crystalline, stable material that was unexpectedly superior as a therapeutic dosage form . In dynamic water vapor sorption experiments, compound II remained in Form B after exposure to 90% relative humidity (Example 11).

形態Ｂは、固体剤形で有効医薬成分として使用するのに有利な特性を有し、このような処方物中で有効性の増強を示し得る。一つの実施形態において、形態Ｂは、以下により詳細に記載されるように、ＨＣｌおよびアセトンからの再結晶化によって生産される。一つの実施形態において、形態Ｂは、図１５に示されるものと実質的に同様のＸＲＰＤパターンを特徴とする。一つの実施形態において、形態Ｂは、６．５°±０．２、９．５±０．２°、１４．０±０．２°、１４．４±０．２°、１８．１±０．２°、１９．７±０．２°、および２２．４±０．２°から選択される少なくとも３つの２θ値を含んでなるＸＲＰＤパターンを特徴とする。一つの実施形態において、形態Ｂは、９．５±０．２°の２θ値を少なくとも含んでなるＸＲＰＤパターンを特徴とする。いくつかの実施形態において、単離された化合物ＩＩ形態Ｂは、４．６±０．２° ２θにおける少なくとも１つのピークが存在しないことを特徴とする。いくつかの実施形態において、単離された化合物ＩＩ形態Ｂは、５．０±０．２° ２θにおけるピークが存在しないことを特徴とする。一つの実施形態において、単離された形態Ｂは、熱重量測定赤外線（ＴＧ－ＩＲ）分析において、３１～１２０℃で７．５％の重量損失を有することを特徴とする。一つの実施形態において、単離された形態Ｂは、約１０５±２０℃、約２２０±２０℃、および約３５０±２０℃、例えば、１０５℃、２２０℃、および３５０℃または９２℃、２１９℃、および３４１℃に示差走査熱量測定（ＤＳＣ）オンセット吸熱を有することを特徴とする。
Form B has advantageous properties for use as an active pharmaceutical ingredient in solid dosage forms and may exhibit enhanced efficacy in such formulations. In one embodiment, Form B is produced by recrystallization from HCl and acetone, as described in more detail below. In one embodiment, Form B is characterized by an XRPD pattern substantially similar to that shown in FIG. In one embodiment, Form B is 6.5°±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1°± characterized by an XRPD pattern comprising at least three 2-theta values selected from 0.2°, 19.7±0.2°, and 22.4±0.2°. In one embodiment, Form B is characterized by an XRPD pattern comprising at least a 2-theta value of 9.5±0.2 degrees. In some embodiments, the isolated Compound II Form B is characterized by the absence of at least one peak at 4.6±0.2 degrees 2-theta. In some embodiments, the isolated Compound II Form B is characterized by the absence of a peak at 5.0±0.2 degrees 2-theta. In one embodiment, isolated Form B is characterized by having a weight loss of 7.5% between 31-120° C. in thermogravimetric infrared (TG-IR) analysis. In one embodiment, isolated Form B is at about 105±20°C, about 220±20°C, and about 350±20°C, such as 105°C, 220°C, and 350°C or 92°C, 219°C. , and a differential scanning calorimetry (DSC) onset endotherm at 341°C.

Ｇ１Ｔ３８、またはその薬学上許容可能な塩は、経口剤形で投与される。
G1T38, or a pharmaceutically acceptable salt thereof, is administered in oral dosage form .

Ｇ１Ｔ３８、またはその薬学上許容可能な塩は、単独でまたは本明細書に記載されるような障害を有するヒトを治療するための別の化合物もしくは別の生物活性薬剤と組み合わせて、経口剤形で投与される。
G1T38, or a pharmaceutically acceptable salt thereof, in an oral dosage form , alone or in combination with another compound or another bioactive agent for treating humans with disorders as described herein administered.

本明細書で企図されるように、Ｇ１Ｔ３８、またはその薬学上許容可能な塩は、経口剤形で投与され、免疫チェックポイント阻害剤とさらに組み合わせて、任意の標準的な化学療法薬治療モダリティーと組み合わせることができる。
As contemplated herein, G1T38, or a pharmaceutically acceptable salt thereof, is administered in an oral dosage form , further combined with an immune checkpoint inhibitor, and any standard chemotherapeutic drug treatment modality. Can be combined.

一つの実施形態において、Ｇ１Ｔ３８、またその医薬的塩は、経口剤形で投与され、限定されるものではないが、顆粒球コロニー刺激因子（Ｇ－ＣＳＦ、例えば、ニューポゲン（フィルグラスチム）、ニューラスタ（ｐｅｇ－フィルグラスチム）、またはレノグラスチムとして販売）、顆粒球－マクロファージコロニー刺激因子（ＧＭ－ＣＳＦ、例えば、モルグラモスチムおよびサルグラモスチム（リューカイン）として販売）、Ｍ－ＣＳＦ（マクロファージコロニー刺激因子）、トロンボポエチン（巨核球増殖分化因子（ＭＧＤＦ）、例えば、ロミプロスチムおよびエルトロンボパグとして販売）インターロイキン（ＩＬ）－１２、インターロイキン－３、インターロイキン－１１（脂肪生成阻害因子またはオプレルベキン）、ＳＣＦ（幹細胞因子、スティール因子、ｋｉｔ－リガンド、またはＫＬ）およびエリスロポエチン（ＥＰＯ）、およびそれらの誘導体（例えば、ダルベポエチン、エポセプト(Epocept)、ナノカイン、エポフィット(Epofit)、エポジェン、エプレックス、およびプロクリットとしてのエポエチン－α；例えば、ネオレコルモン、レコルモンおよびミセラ(Micera)として販売されるエポエチン－β）、エポエチン－δ（例えば、ディネポとして販売）、エポエチン－ω（例えば、エポマックスとして販売）、エポエチンζ（例えば、シラポおよびレタクリットとして販売）ならびに例えば、エポセプト(Epocept)、エポトルスト(Epotrust)、エリプロセーフ(Erypro Safe)、レポイチン(Repoitin)、Vintor(ヴィントール)、エポフィット(Epofit)、エリカイン(Erykine)、ウェポックス、エスポゲン(Espogen)、レリポエチン(Relipoietin)、シャンポエチン(Shanpoietin)、ジロップ(Zyrop)およびＥＰＩＡＯとして販売）を含む造血系増殖因子の使用とさらに組み合わせられる。
In one embodiment, G1T38, or a pharmaceutical salt thereof, is administered in an oral dosage form , including but not limited to granulocyte colony stimulating factor (G-CSF, eg, neupogen (filgrastim), Rasta (sold as peg-filgrastim), or lenograstim), granulocyte-macrophage colony-stimulating factor (GM-CSF, for example sold as molgramostim and sargramostim (leukine)), M-CSF (macrophage colony-stimulating factor), thrombopoietin (sold as megakaryocyte growth differentiation factor (MGDF), e.g. romiplostim and eltrombopag) interleukin (IL)-12, interleukin-3, interleukin-11 (adipogenesis inhibitor or oprelvekin), SCF (stem cell factor, Steele factor, kit-ligand, or KL) and erythropoietin (EPO), and their derivatives (e.g., Darbepoetin, Epocept, Nanokine, Epofit, Epogen, Eplex, and Procrit). epoetin-α; e.g. epoetin-β sold as Neorecormone, Recormone and Micera), epoetin-δ (e.g. sold as Dinepo), epoetin-ω (e.g. sold as Epomax), epoetin ζ ( marketed as e.g. Cilapo and Retacrit) and e.g. Epocept, Epotrust, Erypro Safe, Repoitin, Vintor, Epofit, Erykine, Wepox , Espogen, Relipoietin, Shanpoietin, Zyrop and EPIAO) are further combined with the use of hematopoietic growth factors.

一つの実施形態において、Ｇ１Ｔ３８、またはその医薬的塩は、経口剤形で投与され、ＣＤＫ７阻害剤とさらに組み合わせられる。
In one embodiment, G1T38, or a pharmaceutical salt thereof, is administered in an oral dosage form and is further combined with a CDK7 inhibitor.

Claims

The structure below:

A pharmaceutical composition comprising a solid dosage form comprising crystalline Form B of
The crystalline form B of compound II was 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0. characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2-theta values selected from 2°, 19.7±0.2° and 22.4±0.2°;
of oral delivery of crystalline Form B of Compound II , wherein said pharmaceutical composition provides a (mean AUC _{(0-24) ss} (h ^* ng/mL))/(dose (mg)) ratio of less than 5 in humans. administered using a dosing regimen for
Said pharmaceutical composition, wherein said solid dosage form is administered at a dose of crystalline Form B of Compound II selected from the group consisting of 100 mg, 150 mg and 200 mg twice daily.

2. The pharmaceutical composition of claim 1, wherein said solid dosage form provides a (mean AUC _(0-24)ss (h ^* ng/mL))/(dose (mg)) ratio of less than 3.

3. The pharmaceutical composition of claim 1 or 2 , wherein the solid dosage form provides a (mean AUC _(0-24)ss (h ^* ng/mL))/(dose (mg)) ratio of less than 2.25. thing.

The structure below:

A pharmaceutical composition comprising a solid dosage form comprising crystalline Form B of
The crystalline form B of compound II was 6.5±0.2°, 9.5±0.2°, 14.0±0.2°, 14.4±0.2°, 18.1±0. characterized by an X-ray powder diffraction (XRPD) pattern comprising at least three 2-theta values selected from 2°, 19.7±0.2° and 22.4±0.2°;
wherein the pharmaceutical composition exhibits a (mean AUC _(0-24)ss (h ^* ng/mL))/(absolute neutrophil count (cells/mm ³ )) ratio of less than 1.25 on day 22 of administration in humans and administered using a dosing regimen for oral delivery of crystalline Form B of Compound II , which provides
Said pharmaceutical composition, wherein said solid dosage form is administered at a dose of crystalline Form B of Compound II selected from the group consisting of 100 mg, 150 mg and 200 mg twice daily.

5. The solid dosage form of claim 4, wherein the solid dosage form provides a (mean AUC _(0-24)ss (h ^* ng/mL))/(absolute neutrophil count (cells/mm ³ )) ratio of less than 1.0. The pharmaceutical composition according to .

5. The pharmaceutical composition according to claim 1 or 4 , wherein 100 mg of Compound II crystalline Form B is administered twice daily with an interval of 12 hours.

5. The pharmaceutical composition according to claim 1 or 4 , wherein 1 50 mg of compound II crystalline form B is administered twice daily with an interval of 12 hours.

5. The pharmaceutical composition according to claim 1 or 4 , wherein 200 mg of Compound II crystalline Form B is administered twice daily with an interval of 12 hours.

The pharmaceutical composition according to any one of claims 1 to 8 , which is a pharmaceutical composition for treating CDK4/6 replication-dependent cancers in humans.

said cancer is HR+/HER2- breast cancer, HR-/HER2+ breast cancer, EGFR-mutated non-small cell carcinoma, KRAS-mutated non-small cell lung cancer, castration-resistant prostate cancer, mantle cell lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, BRAF-mutant melanoma, RAS-mutant colorectal cancer, RAS-mutant pancreatic cancer, RAS-mutant cholangiocarcinoma, endometrial cancer, and intergastrointestinal 10. The pharmaceutical composition according to claim 9 , which is selected from cytoplasmic tumors (GIST).

11. The pharmaceutical composition according to claim 9 or 10 , wherein said dosing regimen is administered for at least 24 days .

12. The pharmaceutical composition of any one of claims 9-11 , wherein the human is administered one or more additional therapeutic agents.

5. The pharmaceutical composition according to claim 1 or 4, wherein the crystalline Form B of Compound II is characterized by an XRPD pattern comprising at least a 2[Theta] value of 9.5±0.2[deg.].

5. The pharmaceutical composition according to claim 1 or 4, wherein the crystalline Form B of compound II is characterized by an XRPD pattern in which 2[Theta] values of 5.0±0.2[deg.] are absent.

5. The pharmaceutical composition according to claim 1 or 4, wherein the crystalline form B of compound II is characterized by differential scanning calorimetry (DSC) onset endotherms of 105±20°C, 220±20°C and 350±20°C.

9. The cancer is selected from the group consisting of breast cancer, non-small cell carcinoma, liver cancer, prostate cancer, hematopoietic cancer, melanoma, colon cancer, pancreatic cancer, endometrial cancer, sarcoma and liposarcoma. The pharmaceutical composition according to .

10. The pharmaceutical composition of claim 9, wherein said dosing regimen is administered for at least 28 days.

13. The pharmaceutical composition of claim 12, wherein said cancer is HR+/HER2- breast cancer and said additional therapeutic agent is an anti-estrogenic compound.

19. The pharmaceutical composition according to claim 18, wherein said antiestrogenic compound is selected from the group consisting of tamoxifen, raloxifene, fulvestrant, letrozole, anastrozole and exemestane.