JP7448490B2 - オデビキシバットの医薬製剤 - Google Patents
オデビキシバットの医薬製剤 Download PDFInfo
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Description
本出願は、2018年6月20日に出願したスウェーデン特許出願第1850761-6号、及び2018年6月20日に出願したスウェーデン特許出願第1850762-4号(これらの開示は、参照によりそれらの全体が本明細書に組み込まれている)の優先権を主張するものである。
・ PFIC 1型は、「バイラー病」と呼ばれることもあり、胆管内の細胞膜中のリン脂質として知られる脂肪の適正な均衡を維持するのを助けるタンパク質をコードする、ATP8B1遺伝子の変異に起因する胆汁分泌の障害によって引き起こされる。これらのリン脂質の不均衡は、胆汁うっ滞及び肝臓内の胆汁酸の上昇と関連している。PFIC 1型に罹患した対象は、通常、生後1か月で胆汁うっ滞を発症し、外科的治療がなければ、生後10年が過ぎる前に肝硬変及び末期肝疾患に進行する。
・ PFIC 2型は、「バイラー症候群」と呼ばれることもあり、胆汁酸を肝臓外に移動させる胆汁酸塩排出ポンプとして知られるタンパク質をコードする、ABCB11遺伝子の変異に起因する胆汁酸塩分泌の障害によって引き起こされる。PFIC 2型を有する対象は、生後数年以内に肝不全を発症することが多く、肝細胞癌として知られる、ある種の肝臓がんを発症するリスクが高い。
・ PFIC 3型は、典型的には、小児期の最初の数年に進行性胆汁うっ滞と共に現れ、細胞膜を横切ってリン脂質を移動させる輸送体をコードするABCB4遺伝子の変異によって引き起こされる。
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91 U.S. Patent No. 9,295,677
a)ホモジナイザを使用してオデビキシバットを水中で湿らせる工程;及び
b)湿ったオデビキシバットを湿式粉砕によって水中に分散させ、それによってオデビキシバットの均質な水性懸濁液を得る工程
を含む。
本明細書で使用される場合、「治療」、「治療する」、及び「治療すること」という用語は、本明細書に記載する通りの疾患、又は障害、又はそれらの1つ若しくは複数の症状の後退、緩和、それらの発症の遅延、又はそれらの進行の阻害を指す。幾つかの実施形態では、治療は、1つ又は複数の症状が発症した後に施されてもよい。他の実施形態では、治療は、症状の非存在下で施されてもよい。例えば、治療は、罹患しやすい個体に(例えば、症状の病歴を考慮して、及び/又は遺伝的若しくは他の罹患しやすい要因を考慮して)、症状の発症前に施されてもよい。治療は、症状が解消した後でも、例えば、その再発を予防又は遅延させるために継続されてもよい。
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EtOH エタノール
MeOH メタノール
RH 相対湿度
2-PrOH 2-プロパノール
X線粉末回折(XRPD)分析
分析は、CuロングファインフォーカスX線管及びPIXcel検出器を備えたPANalytical X'Pert Pro回折計を用いて22℃で行った。自動発散及び散乱防止スリットを、0.02radのSollerスリット及びNiフィルターと一緒に使用した。乾燥試料を、切り出したシリコンのZero Background Holder(ZBH)上に塗抹し、2~40°(2θ)の間で、17分の分析時間で分析した。すべてのスラリー試料を熱処理した多孔質アルミナフィルター基板上に滴下し、それらが乾くにつれて2回分析し、最初に1分16秒の走査(2~30°(2θ))、次いで7分の走査(2~30°(2θ))を行った。最後の17分の走査は、試料が数時間乾燥したときに行った。
管の張力及び電流:40kV、50mA
波長アルファ1(CuKα1):1.5406Å
波長アルファ2(CuKα2):1.5444Å
波長アルファ1とアルファ2の平均(CuKα):1.5418Å
実験は、TA Instruments社Q2000 Differential Scanning Calorimeterを使用して行った。使用したDCSるつぼは、蓋にピンホール(直径≧0.2mm)を有するTZeroアルミニウムパンであった。測定を通して50mL/分の一定流量での乾燥窒素パージをDSCセル内で維持した。
製剤の調製(小規模)
微結晶性セルロース球を、以下のTable 5(表5)に示す通りの異なる2つのオデビキシバットのコーティング懸濁液のうちの1つでコーティングして、0.5%w/w又は1.5%w/wのオデビキシバットのいずれかを含有する粒子を得た。
オデビキシバット原薬を含有するコーティング懸濁液は、以下の3つの工程で調製した:
a)オデビキシバットの懸濁液:オデビキシバット原薬を0.5mmのふるいを通してふるい分けし、続いてホモジナイザを使用して(Ultra Turrax T25;およそ6600~7000rpmで15分)少量の水中で湿らせた。次いで、得られた湿ったオデビキシバット原薬を、コロイドミルを用いて(IKA社Magic Lab MKO又はMKモジュール、14600rpmで20分間、ギャップサイズ1.5回転)水中に分散させ、凝集粒子のレベルが工程内管理の合格限界を満たすまで行った。
b)ヒプロメロースの分散体:ヒプロメロース(3mPa.s)を熱水中に混合しながら分散させ、得られた分散体を室温まで冷却した。
c)オデビキシバットのコーティング懸濁液:コロイドミル内でヒプロメロースの分散体をオデビキシバットの懸濁液に添加し、この懸濁液を4分間10000rpmで混合した。最終的な混合を低速で磁気撹拌器を使用して継続した。オデビキシバットのコーティング懸濁液は、コーティングプロセスに使用する前に0.5mmのふるいを通してろ過した。
微結晶性セルロース(MCC)球は、ウルスター挿入物を有する流動床コーティング機内で、オデビキシバットのコーティング懸濁液を使用してコーティングした。MCC球上のコーティング懸濁液の量は、秤量によって決定する。微粒子だけでなく二重体を除去するために、コーティング済み粒子は、0.5mm及び1.25mmのふるいをそれぞれ通してふるい分けした。次いで粒子をバルクコンテナに移し、医薬品中間体として取り扱った。
各々の単位用量に必要とされる計算量の粒子を、ハードヒドロキシプロピルメチルセルロース(HPMC)カプセル(サイズ0又はサイズ3)中に自動カプセル充填器を使用して充填して、4つの異なる力価:200、400、600、及び1200μgを得た。
製剤の調製(大規模化)
微結晶性セルロース球を、以下のTable 7(表7)に示す通りの異なる2つのオデビキシバットのコーティング懸濁液のうちの1つでコーティングして、0.5%w/w又は1.5%w/wのオデビキシバットのいずれかを含有する粒子を得た。
オデビキシバット原薬を含有するコーティング懸濁液は、以下の3つの工程で調製した:
a)オデビキシバットの懸濁液:オデビキシバット原薬を、ホモジナイザを使用して(Ultra Turrax T25;およそ6600~7000rpmで15分)少量の水中で湿らせた。次いで、得られた湿ったオデビキシバット原薬を、コロイドミルを用いて(IKA社Magic Lab MKO又はMKモジュール、14600rpmで20分間、ギャップサイズ1.5回転)水中に分散させ、凝集粒子のレベルが工程内管理の合格限界、すなわち、d90<12μm(低角度レーザー光散乱(LALLS)によって決定したとき)を満たすまで行った。
b)ヒプロメロースの分散体:ヒプロメロース(3mPa.s)を熱水中に混合しながら分散させ、得られた分散体を室温まで冷却した。
c)オデビキシバットのコーティング懸濁液:ヒプロメロースの分散体をオデビキシバットの懸濁液に添加し、この懸濁液を混合した。最終的な混合を低速で撹拌器を使用して継続した。オデビキシバットのコーティング懸濁液は、コーティングプロセスに使用する前に0.5mmのふるいを通してろ過した。
得られたオデビキシバットのコーティング懸濁液を、実施例1に記載するコーティングプロセスに従って、微結晶性セルロース(MCC)球をコーティングするのに使用した。
カプセルを、実施例1に従って調製した。様々なカプセルの力価についての充填質量、オデビキシバット及び他の成分の量、並びにカプセルのサイズは、上のTable 5(表5)に提示した。
結晶変態1の調製
無水アルコール(100.42kg)及び粗オデビキシバット(18.16kg)を250LのGLRに窒素雰囲気下で撹拌しながら装入した。精製水(12.71kg)を添加し、反応物を25±5℃で15分間窒素雰囲気下で撹拌した。撹拌を25±5℃で3~60分間、透明な溶液が形成されるまで継続した。溶液を、5.0μのSSカートリッジフィルター、続いて0.2μのPPカートリッジフィルターを通してろ過し、次いで清浄な反応器に移した。精製水(63.56kg)を25±5℃で2~3時間にわたってゆっくり添加し、溶液にオデビキシバットの結晶変態1を種晶添加した。溶液を25±5℃で12時間撹拌した。この時間の間に、溶液は濁りを生じた。析出した固体を、遠心分離機を通してろ過し、材料を30分間遠心脱水した。材料を、その後Nutscheフィルター中で12時間真空乾燥させた。次いで材料を、真空棚段乾燥器中、25±5℃、真空下(550mmHg)で10時間、次いで30±5℃、真空下(550mmHg)で16時間乾燥させた。材料をオフホワイトの結晶性固体として単離した。単離した結晶性材料を粉砕し、LDPEの袋に保存した。
エタノール及び水からの結晶変態2の調製
105.9mgのオデビキシバットを計量して1mLのChromacol容器に入れた。磁気撹拌子及び1.0mLのエタノール:水の70:30%v/v混合物を添加し、容器をクリンプキャップで閉じた。次いで、得られたスラリーを25℃で1週間撹拌したままにした。
示差走査熱量測定による結晶分画の決定
この方法は、部分的に結晶性の試料におけるオデビキシバット原薬の結晶分画を定量化する。定量化は、部分的に結晶性の試料がオデビキシバットの結晶性水和物と非晶相との二成分混合物であるという仮定に基づいている。結晶分画は、無水形の融解エンタルピーに基づいて定量化される。この無水形は、水和物を昇温で乾燥させることによって自発的且つ再現可能に形成する、脱水した水和物である。
サイクル1: 5℃/分の走査速度で20℃から120℃への温度の増加;
サイクル2: 10℃/分の走査速度で120℃から80℃への温度の減少;及び
サイクル3: 10℃/分の走査速度で80℃から200℃への温度の増加。
LALLSによってモニタリングされる均質性
オデビキシバットのコーティング懸濁液の均質性を、低角度レーザー光散乱(LALLS)を使用して試験した。0.5%w/wのオデビキシバットを含有する粒子にするための3つのオデビキシバットのコーティング懸濁液を、オデビキシバット原薬(16g)をUltra Turraxホモジナイザで水(200g)中に7分間分散することによって生成した。原薬が分散したら、ホモジナイザを追加的に8分運転した。次いでホモジナイザを水(216g)ですすぎ、それを懸濁液に添加した。
含量均一性
2つの異なる力価、0.5%w/w及び1.5%w/wのペレットを、実施例1に記載する通りに調製した。カプセル中のオデビキシバットの量を、逆相高速液体クロマトグラフィ(RP-HPLC)を使用して、30個のカプセルについて決定した。移動相:40:60 アセトニトリル:酢酸塩緩衝液pH5.5;流量1.5mL/分;カラム:Zorbax SB-CN(50×4.6mm、3.5μm)。オデビキシバットのアッセイ量及び含量均一性をTable 10(表10)に提示する。
低pHでの安定性試験
0.5%w/wのオデビキシバットを含有する約40mgのコーティング済み粒子(200μgのカプセル1個の含量に相当する)を大さじ1杯の食品上に振りかけ、120分間での回収率を決定することによって、オデビキシバットでコーティングされた粒子と、ヨーグルト、リンゴソース、又は果実ピューレの間の適合性を評価した。オデビキシバットの回収率は、逆相高速液体クロマトグラフィ(RP-HPLC)法を使用して決定した。移動相:40:60 アセトニトリル:酢酸塩緩衝液pH5.5;流量1.5mL/分;カラム:Zorbax SB-CN(50×4.6mm、3.5μm)。
長期安定性試験
実施例1に従って調製したサイズ0及びサイズ3のオデビキシバットのカプセルを、HDPEのキャップを有するHDPEのボトル内に保存し、長期保存条件として25℃及び相対湿度60%で、並びに加速条件として40℃及び相対湿度75%で保持した。オデビキシバット、関連物質、及び水の量を、25℃/60%RHで保存した試料については1、3、6、9、及び12か月後に、40℃/75%RHで保存した試料については1、3、及び6か月後に決定した。力価200μg(サイズ0)のカプセルについての結果をTable 15(表15)に、力価600μg(サイズ0)のカプセルについての結果をTable 16(表16)に、力価400μg(サイズ3)のカプセルについての結果をTable 17(表17)に、そして力価1200μg(サイズ3)のカプセルについての結果をTable 18(表18)に提示する。
ペレットの混合均一性
2つの異なる力価、0.5%w/w及び1.5%w/wの粒子を、実施例2に記載する通りに調製した。ふるい分けしたペレットを、PEバッグで裏打ちされた55Lのドラム内に収集した。ペレットを、ドラムの異なる10箇所から0.25mLの試料採取器先端部でサンプリングした。各々の場所からの平均試料は80mgであり、これは、200μg若しくは600μgのサイズ0のカプセル2個の含量、又は400μg又は1200μgのサイズ3のカプセル1個の含量に相当する。オデビキシバットの含量は、RP-UPLCによって決定した:移動相A:80:20 酢酸アンモニウム緩衝液pH5.7/アセトニトリル;移動相B:20:80 酢酸アンモニウム緩衝液pH5.7/アセトニトリル;流量0.40mL/分;カラム:Waters社Acquity BEH C8 100×2.1mm、1.7mm;勾配:0分:60%A:40%B、12分:20%A:80%B、13.5分:20%A:80%B、13.6分:60%A:40%B、15分:60%A:40%B。オデビキシバットのアッセイ量及び含量均一性をTable 19(表19)に提示する。
Claims (27)
- 複数の粒子を含むオデビキシバットの医薬製剤であって、
各粒子が、
0.1~1.5mmの間のサイズであり、
a) コア、及び、
b) コアを取り囲むコーティング層を含み、
コアがオデビキシバットを含有せず、
コーティング層が、オデビキシバット又は医薬として許容されるその塩を含み、
コーティング層中のオデビキシバットの凝集粒子の粒径分布のD90が15μm未満であり、
各粒子が、
粒子の総質量に対して0.1%w/w~5.0%w/wの量でオデビキシバット又は医薬として許容されるその塩を含有し、同じ量のオデビキシバットを実質的に含有する、医薬製剤。 - 各々の粒子が、粒子の総質量に対して0.5%w/w~2.0%w/wの量でオデビキシバット又は医薬として許容されるその塩を含有する、請求項1に記載の製剤。
- 各々の粒子が、粒子の総質量に対して0.5%w/wの量でオデビキシバット又は医薬として許容されるその塩を含有する、請求項1又は2に記載の製剤。
- 各々の粒子が、粒子の総質量に対して1.5%w/wの量でオデビキシバット又は医薬として許容されるその塩を含有する、請求項1又は2に記載の製剤。
- コアが微結晶性セルロースを含む、請求項1に記載の製剤。
- コーティング層が、皮膜形成ポリマーを更に含む、請求項1から5のいずれか一項に記載の製剤。
- コーティング層が、オデビキシバットの均質な水中懸濁液としてコア上に噴霧されている、請求項1から6のいずれか一項に記載の製剤。
- 均質な懸濁液が、オデビキシバットを湿式粉砕によって水中に分散させることによって調製される、請求項7に記載の製剤。
- 均質な懸濁液が、200μmより大きいオデビキシバットの凝集粒子を含有しない、請求項7又は8に記載の製剤。
- コーティング層が界面活性剤を含有しない、請求項1から9のいずれか一項に記載の製剤。
- 粒子が0.1~1.0mmの間のサイズである、請求項1から10のいずれか一項に記載の製剤。
- オデビキシバットが、オデビキシバットの結晶性水和物として存在する、請求項1から11のいずれか一項に記載の製剤。
- オデビキシバットが、CuKα1線で得られた、°2θ位置5.6±0.2、6.7±0.2及び/又は12.1±0.2に少なくとも特定のピークを有するX線粉末回折(XRPD)パターンを有する、オデビキシバットの結晶変態1として存在する、請求項1から12のいずれか一項に記載の製剤。
- 粒子が、サシェ又はカプセル中に含有される、請求項1から13のいずれか一項に記載の製剤。
- コーティング層中のオデビキシバットの凝集粒子の粒径分布のD90が12μm未満である、請求項1から14のいずれか一項に記載の製剤。
- 小児製剤である、請求項1から15のいずれか一項に記載の製剤。
- 肝疾患の治療又は予防に使用するための、請求項1から16のいずれか一項に記載の製剤。
- 肝疾患が胆汁酸依存性疾患である、請求項17に記載の製剤。
- 肝疾患が進行性家族性肝内胆汁うっ滞(PFIC) 、アラジール症候群(ALGS)、胆道閉鎖又は小児胆汁うっ滞性そう痒である、請求項17に記載の製剤。
- オデビキシバットの均質な水性懸濁液を調製する工程を含む、請求項1から19のいずれか一項に記載の医薬製剤を調製するための方法であって、
前記懸濁液中のオデビキシバットの凝集粒子の粒径分布のD90が15μm未満である、方法。 - コーティング懸濁液が、オデビキシバットを湿式粉砕によって水中に分散させることによって調製される、請求項20に記載の方法。
- コーティング懸濁液が、200μmより大きいオデビキシバットの凝集粒子を含有しない、請求項20又は21に記載の方法。
- コーティング懸濁液が界面活性剤を含有しない、請求項20から22のいずれか一項に記載の方法。
- 請求項1から19のいずれか一項に記載の製剤を調製するための方法であって、
a)ホモジナイザを使用してオデビキシバットを水中で湿らせる工程;及び
b)湿ったオデビキシバットを湿式粉砕によって水中に分散させ、それによってオデビキシバットの均質な水性懸濁液を得る工程
を含む方法。 - 皮膜形成ポリマーが、工程(b)で得られた懸濁液に添加される、請求項24に記載の方法。
- オデビキシバットが、オデビキシバットの結晶性水和物として存在する、請求項20から25のいずれか一項に記載の方法。
- オデビキシバットが、CuKα1線で得られた、°2θ位置5.6±0.2、6.7±0.2、及び/又は12.1±0.2に少なくとも特定のピークを有するX線粉末回折(XRPD)パターンを有する、オデビキシバットの結晶変態1として存在する、請求項26に記載の方法。
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