JP2019515024A - ボルチオキセチンのパモ酸塩及びその結晶形 - Google Patents
ボルチオキセチンのパモ酸塩及びその結晶形 Download PDFInfo
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- 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
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Abstract
Description
本発明に係る結晶形は基本的に純粋であり、前記基本的に純粋であるとは、前記結晶形の純度が少なくとも60%、又は少なくとも70%、又は少なくとも80%、又は少なくとも85%、又は少なくとも90%、又は少なくとも93%、又は少なくとも95%、又は少なくとも98%、又は少なくとも99%であることを意味する。
本発明に係る医薬組成物の単回投与量は、患者の体重、投与方法、及び疾患又は疼痛の重症度に応じて変化する。本発明の塩又はその結晶体の単回投与量は、5〜1500mg又は10〜1000mgで、好ましくは10mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、100mg、120mg、140mg、150mg、160mg、180mg、200mg、220mg、240mg、260mg、280mg、300mg、320mg、340mg、350mg、360mg、380mg、400mg、420mg、450mg、460mg、480mg、500mg、520mg、540mg、550mg、570mg、580mg、600mg、620mg、640mg、650mg、680mg、700mg、720mg、740mg、750mg、780mg、800mg、820mg、840mg、850mg、860mg、880mg、900mg、920mg、940mg、950mg又は980mgである。
2.本発明に係るボルチオキセチン・パモ酸塩を用いて安定する長時間作用型製剤に製造すると、2週間ごと又は4週間ごとに患者に薬物を1回投与することができ、これは患者にとって、大幅に薬物の使用効率を高め、薬物の治療効果を向上させ、患者のコンプライアンスを改善し、副作用の発生を低減することができる。
実施例1 ボルチオキセチンのパモ酸塩(r=1)の製造
常温下で、ボルチオキセチン(84.3g、283mmol)、氷酢酸(17g、283mmol)を900mlの水に溶解し、パモ酸(109.9g、283mmol)と水酸化ナトリウム(11.3g、283mmol)とをそれぞれ900mlの水に添加し、撹拌して溶解し、上記調製されたボルシアセチン酢酸水溶液をパモ酸のNaOH水溶液に滴下して中和反応させ、滴下終了後に2時間撹拌し、濾過し、濾過ケーキを3回水洗い、50℃で通風乾燥させて、黄色固体を取得し、生成物を核磁気共鳴プロトンスペクトログラム及び質量スペクトルによって検証する。1H NMR(400MHz,DMSO)δ:8.90(s,2H),8.37(s,2H),8.15(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.35-7.24(m,5H),7.17-7.09(m,4H),6.42(d,J=8.0Hz,2H),4.75(s,2H),3.30-3.15(m,8H),2.32(s,3H),2.23(s,3H);LC−MS:m/z(ES+)for C18H22N2S 298[M+1]+ and m/z(ES−)for C23H16O6 388[M−1]。
方法1:常温下でパモ酸(194mg、0.5mmol)及びボルチオキセチン(298mg、1mmol)を0.7mlのDMSOに溶解し、3mlの蒸留水(DMSO:水=1:4.5)を添加し、浅黄色の粉末生成物が析出するまで静置し、生成物を核磁気共鳴プロトンスペクトログラム及び質量スペクトルによって検証する。1H NMR(400MHz,DMSO)δ:8.20(d,J=8.8Hz,2H),8.16(s,2H),7.63(d,J=8.0Hz,2H),7.34(d,J=7.6Hz,2H),7.24(s,2H),7.17-7.10(m,8H),7.01-6.92(m,4H),6.42(d,J=7.2Hz,2H),4.67(s,2H),3.20-3.10(m,16H),2.32(s,6H),2.24(s,6H);LC−MS:m/z(ES+)for C18H22N2S 298[M+1]+ and m/z(ES−)for C23H16O6 388[M−1]−
方法1:実施例1により製造されたボルチオキセチンのヘミパモ酸塩の生成物(1.0g、1mmol)を150mlのメタノールに添加し、温度を55℃に上昇させて1h撹拌し、固体が析出するまで静置した後に濾過し、得られた濾過ケーキを乾燥させて浅黄色の固体を取得し、粉末X線回折(XRD)で検出することによりA型結晶体と同定する。
実施例4 ボルチオキセチンのヘミパモ酸塩の結晶形Bの製造
ボルチオキセチンのヘミパモ酸塩(133mg、0.13mmol)を常温下で0.5mlのDMSOに溶解し、次に10mlのアセトニトリルを添加し、
又はボルチオキセチンのヘミパモ酸塩(133mg、0.13mmol)を常温下で0.5mlのTHFに溶解し、次に7.5mlのアセトニトリル酢酸エチルを添加して、15日間静置し、
又はボルチオキセチンのヘミパモ酸塩(133mg、0.13mmol)を常温下で0.5mlのTHFに溶解し、次に1mlのアセトンと1mlのn−ヘプタンを添加して、4日間静置し、
上記混合溶液を膨潤で結晶化した後に、得られた結晶体をX線回折(XRD)で検出することによりB型結晶体と同定する。
ボルチオキセチンのヘミパモ酸塩(1.0g、1mmol)を150mlのアセトニトリルに添加し、室温下で3日間撹拌し、又は150mlのアセトンに添加し、室温下で5日間撹拌し、析出した結晶体をX線回折(XRD)で検出することによりD型結晶体と同定する。
実施例3、実施例4及び実施例5により製造された結晶形試料をそれぞれ粉末X線回折(XRD)、示差走査熱量分析(DSC)及び熱重量分析(TGA)によって検出し、各方法の検出条件は以下のとおりである。
機器:ドイツBrukerD8−Advance型X線多結晶粉末回折装置、パワー:3KW、走査範囲2θ:10〜90度、ステップ幅:0.02°、走査速度:5°/min、CuターゲットKα1線を用いる。
熱重量分析計−示差走査熱量計:MettlerYoledo、TGA/DSC3+、SNRB608136702、FNR30139250、
検出条件:温度上昇速度:10℃/min、温度上昇範囲:25〜300℃、天秤での窒素流量:40mL/min、試料窒素流量:60ml/min。
ボルチオキセチンのパモ酸結晶体の媒体における安定性の研究
ボルチオキセチン・ヘミパモ酸塩のA型結晶体、B型結晶体及びD型結晶体をそれぞれ65℃で3日間維持し、100℃で18時間維持し、150℃で2時間維持し、XRDにより試料の結晶形が変化したかどうかを検出し、また、150℃で2時間維持された試料に対して、1H−NMRにより結晶形に不純物が生成されたかどうかを検出する。
比較後に、以上の三種類の結晶体をそれぞれ65℃の条件で3日間維持し、100℃の条件で18時間維持し、150℃の条件で2時間維持すると、XRDが変化せず、150℃の条件で2時間維持すると、1H−NMRが基本的に変化しないことを確認できた。以上の結果は、この三種類の結晶形は150℃以下で化学的・熱的安定性が高いことを示す。
1、試料の製造
それぞれ75.1mgのボルチオキセチンのヘミパモ酸塩結晶形A、B、Dに1mLの希釈剤(1%のCMC−Na、5%のマンニトールを含有する注射用水)を添加し、2minボルテックスし、それぞれ濃度が45.6mg/mLの三種類の結晶形の懸濁液(pH〜7)を得る。
体重範囲が183.0〜186.3gの9匹の雄性Wistarクリーンラット(上海西普爾−必凱実験動物有限公司)に対して、表4に従って投薬する。
頸静脈を穿刺して採血し、試料ごとに約0.2mL採取し、ヘパリンナトリウムを用いて抗凝固し、採取した後に氷上に載置し、採血時間点は、投薬前、投薬30min後、1hrs後、2hrs後、4hrs後、8hrs後、24hrs後、48hrs後、72hrs後、120hrs後、168hrs後、216hrs後、264hrs後、312hrs後、360hrs後、504hrs後、672hrs後にする。血液試料を採取した後に氷上に載置し、血漿を遠心分離する(遠心分離条件:8000回転/分、6分間、2〜8℃)。採取された血漿を、分析する前に−70℃で保存する。
薬物の血中濃度データに基づいて、薬物動態学計算ソフトウェアWinNonlin5.2の非コンパートメントモデルを用いて、それぞれ試験物質の薬物動態学パラメータAUC0−t、AUC0−∞、MRT0−∞、Cmax、Tmax、T1/2などのパラメータを計算する。濃度が定量下限よりも低い試料に対して、薬物動態学パラメータを計算するときに、Cmaxに達する前にサンプリングされた試料をゼロで計算し、Cmaxに達した後にサンプリングされた試料を定量不能(BLQ)として計算する。
Wistarラットにボルチオキセチン・ヘミパモ酸塩を筋肉内注射投与した後に、各動物の異なる時間での血漿濃度測定結果は表5に示され、対応する血漿薬物濃度−時間曲線は図9に示される。
薬物の血中濃度データに基づいて、薬物動態学計算ソフトウェアWinNonlin5.2の非コンパートメントモデルを用いて、それぞれ化合物A及びBの薬物動態学パラメータを計算し、結果は表6に示される。
Claims (25)
- ボルチオキセチン・パモ酸塩であり、構造式が(C18H22N2S)r・C23H16O6・nH2Oであり、但し、rは1又は2で、n=0〜10である化合物。
- 前記nは0、1、2、3、4、5又は6であることを特徴とする請求項1に記載の化合物。
- 前記ボルチオキセチン・パモ酸塩は結晶形物質、溶媒和物又は非晶質物質であることを特徴とする請求項1又は2に記載の化合物。
- 前記ボルチオキセチン・パモ酸塩の結晶形物質は結晶形Aであり、前記結晶形Aの粉末X線回折図において、2θが12.96±0.2、13.56±0.2、16.67±0.2、17.26±0.2及び18.28±0.2度の位置にピークを有する、ことを特徴とする請求項3に記載の化合物。
- 前記結晶形Aの粉末X線回折図において、2θが14.77±0.2、18.28±0.2、18.77±0.2、19.98±0.2、22.08±0.2、23.03±0.2度の一つ以上の位置にピークを有する、ことを特徴とする請求項4に記載の化合物。
- 前記結晶形Aの粉末X線回折図において、2θが11.71±0.2、12.41±0.2、14.77±0.2、18.28±0.2、18.77±0.2、19.98±0.2、21.02±0.2、22.08±0.2、23.03±0.2、24.03±0.2、24.99±0.2、25.94±0.2、27.33±0.2、27.99±0.2、29.80±0.2、30.59±0.2、31.09±0.2、32.70±0.2、35.46±0.2、39.21±0.2、42.81±0.2、46.98±0.2度の一つ以上の位置にピークを有し、又は結晶形Aの粉末X線回折図が図3に示される、ことを特徴とする請求項4に記載の化合物。
- 前記ボルチオキセチン・パモ酸塩の結晶形物質は結晶形Bであり、前記結晶形Bの粉末X線回折図において、2θが15.23±0.2、19.37±0.2及び22.24±0.2度の位置にピークを有する、ことを特徴とする請求項3に記載の化合物。
- 前記結晶形Bの粉末X線回折図において、2θが12.50±0.2、14.93±0.2、23.25±0.2、24.49±0.2、28.28±0.2、30.58±0.2度の一つ以上の位置にピークを有する、ことを特徴とする請求項7に記載の化合物。
- 前記結晶形Bの粉末X線回折図において、2θが11.89±0.2、12.50±0.2、14.93±0.2、18.63±0.2、20.15±0.2、23.25±0.2、24.49±0.2、24.82±0.2、28.28±0.2、30.58±0.2、36.97±0.2、37.58±0.2、38.73±0.2、40.67±0.2、41.81±0.2度の一つ以上の位置にピークを有し、又は結晶形Bの粉末X線回折図が図5に示される、ことを特徴とする請求項7に記載の化合物。
- 前記ボルチオキセチン・パモ酸塩の結晶形物質は結晶形Dであり、前記結晶形Dの粉末X線回折図において、2θが12.34±0.2、16.16±0.2及び18.05±0.2度の位置にピークを有する、ことを特徴とする請求項3に記載の化合物。
- 前記結晶形Dの粉末X線回折図において、2θが11.51±0.2、16.48±0.2、17.69±0.2、19.36±0.2、21.50±0.2、22.50±0.2、24.01±0.2、27.65±0.2度の一つ以上の位置にピークを有する、ことを特徴とする請求項10に記載の化合物。
- 前記結晶形Dの粉末X線回折図において、2θが11.51±0.2、13.66±0.2、14.56±0.2、16.48±0.2、17.69±0.2、18.83±0.2、19.36±0.2、20.09±0.2、21.20±0.2、21.50±0.2、22.50±0.2、24.01±0.2、24.96±0.2、26.40±0.2、26.94±0.2、27.62±0.2、28.46±0.2、29.59±0.2、30.58±0.2、31.08±0.2、31.28±0.2、35.81±0.2、41.45±0.2、41.51±0.2、43.38±0.2、48.23±0.2度の一つ以上の位置にピークを有し、又は結晶形Dの粉末X線回折図が図7に示される、ことを特徴とする請求項10に記載の化合物。
- 神経系疾患を予防治療する薬物の製造における請求項1〜12のいずれかに記載の化合物の結晶形又は非晶質形態の用途であって、
前記疾患は、うつ病、産後うつ病、治療抵抗性うつ病、双極性障害に関連するうつ病、不安障害、強迫性障害、パニック障害、薬物乱用、アルコール依存症、ニコチン依存症、炭水化物依存症、アルツハイマー病、認知障害、慢性疼痛、侵害受容性疼痛、炎症性疼痛、内臓痛、神経因性疼痛、片頭痛又は癌に関連する疼痛である用途。 - 前記疾患は、うつ病、産後うつ病、治療抵抗性うつ病、双極性障害に関連するうつ病、慢性疼痛、侵害受容性疼痛、炎症性疼痛、内臓痛、神経因性疼痛、片頭痛又は癌に関連する疼痛である請求項13に記載の用途。
- 活性成分とする請求項1〜12のいずれかに記載の化合物の結晶形、溶媒和物又は非晶質形態、及び薬学的に許容可能な担体を含む医薬組成物。
- 前記担体は粘性を有する水性又は非水性担体であることを特徴とする請求項15に記載の医薬組成物。
- 前記担体は懸濁化剤、張力剤及び湿潤剤を含むことを特徴とする請求項15に記載の医薬組成物。
- 前記活性成分は人体内で薬効を少なくとも48時間発揮することを特徴とする請求項15に記載の医薬組成物。
- 前記活性成分は人体内で薬効を少なくとも7日間発揮することを特徴とする請求項15に記載の医薬組成物。
- 前記活性成分は人体内で薬効を少なくとも2週間発揮することを特徴とする請求項15に記載の医薬組成物。
- 前記活性成分は人体内で薬効を少なくとも1ヶ月間発揮することを特徴とする請求項15に記載の医薬組成物。
- 請求項15に記載の医薬組成物を患者に投与することを含む、うつ病又は疼痛を治療する方法。
- 前記組成物を注射によって投与する請求項22に記載の方法。
- 前記組成物を筋肉又は皮下に投与する請求項22に記載の方法。
- 投与した後に1日あたりに5〜50mgの用量で体内に放出することができることを特徴とする請求項22に記載の方法。
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