JP7482532B2 - サイクロセリン化合物の製剤およびそれらの用途 - Google Patents
サイクロセリン化合物の製剤およびそれらの用途 Download PDFInfo
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- JP7482532B2 JP7482532B2 JP2021513838A JP2021513838A JP7482532B2 JP 7482532 B2 JP7482532 B2 JP 7482532B2 JP 2021513838 A JP2021513838 A JP 2021513838A JP 2021513838 A JP2021513838 A JP 2021513838A JP 7482532 B2 JP7482532 B2 JP 7482532B2
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- 125000005017 substituted alkenyl group Chemical group 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000004426 substituted alkynyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 235000012751 sunset yellow FCF Nutrition 0.000 description 1
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- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 235000012756 tartrazine Nutrition 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- 229960000943 tartrazine Drugs 0.000 description 1
- UJMBCXLDXJUMFB-GLCFPVLVSA-K tartrazine Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1\N=N\C1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-GLCFPVLVSA-K 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960005333 tetrabenazine Drugs 0.000 description 1
- 229960003231 thioacetazone Drugs 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 229960005013 tiotixene Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229960005196 titanium dioxide Drugs 0.000 description 1
- 235000010215 titanium dioxide Nutrition 0.000 description 1
- 229960004394 topiramate Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960003741 tranylcypromine Drugs 0.000 description 1
- 229960003991 trazodone Drugs 0.000 description 1
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
- ZEWQUBUPAILYHI-UHFFFAOYSA-N trifluoperazine Chemical compound C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 ZEWQUBUPAILYHI-UHFFFAOYSA-N 0.000 description 1
- 229960002324 trifluoperazine Drugs 0.000 description 1
- XSCGXQMFQXDFCW-UHFFFAOYSA-N triflupromazine Chemical compound C1=C(C(F)(F)F)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 XSCGXQMFQXDFCW-UHFFFAOYSA-N 0.000 description 1
- 229960003904 triflupromazine Drugs 0.000 description 1
- 229960002431 trimipramine Drugs 0.000 description 1
- ZSCDBOWYZJWBIY-UHFFFAOYSA-N trimipramine Chemical compound C1CC2=CC=CC=C2N(CC(CN(C)C)C)C2=CC=CC=C21 ZSCDBOWYZJWBIY-UHFFFAOYSA-N 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229940102566 valproate Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- PJDFLNIOAUIZSL-UHFFFAOYSA-N vigabatrin Chemical compound C=CC(N)CCC(O)=O PJDFLNIOAUIZSL-UHFFFAOYSA-N 0.000 description 1
- 229960005318 vigabatrin Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229950001272 viomycin Drugs 0.000 description 1
- GXFAIFRPOKBQRV-GHXCTMGLSA-N viomycin Chemical compound N1C(=O)\C(=C\NC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)C[C@@H](N)CCCN)CNC(=O)[C@@H]1[C@@H]1NC(=N)N[C@@H](O)C1 GXFAIFRPOKBQRV-GHXCTMGLSA-N 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
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- 229940046008 vitamin d Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000013618 yogurt Nutrition 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- WFPIAZLQTJBIFN-DVZOWYKESA-N zuclopenthixol Chemical compound C1CN(CCO)CCN1CC\C=C\1C2=CC(Cl)=CC=C2SC2=CC=CC=C2/1 WFPIAZLQTJBIFN-DVZOWYKESA-N 0.000 description 1
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Description
本出願は、2018年9月13日に出願された「Formulations of Cycloserine Compounds and Applications Thereof」と題する米国特許出願第16/130,747号の利益を主張し、その内容は参照によりその全体が本明細書に組み込まれる。
本明細書に開示されるサイクロセリン化合物の製剤(例えば、固体製剤)は、サイクロセリン化合物(有効成分)を含有する内部コア、および内部コアに直接または間接的に付着され得る外層を含み得る。場合によっては、製剤は、内部コアと外層との間に位置し得る単離層をさらに含み得る。
いくつかの例において、サイクロセリン化合物の塩は、式[A][B]を有し、式中、[A]は、サイクロセリン化合物のカチオン形態であり、[B]は、式(I)の化合物のアニオン形態である。
Xは、-NH2または-OHであり、
L1およびL2の各々は、独立して、C1~6アルキレン、C2~6アルケニレン、もしくはC2~6アルキニレンであるか、または原子価が許すように、L1およびL2の一方が、N、O、もしくはSであり、他方が、C1~6アルキレン、C2~6アルケニレン、もしくはC2~6アルキニレンであり、
塩中の[A]と[B]との比が、10:1~1:10の範囲である。
式中、AおよびBの各々は、独立して、-NH2、-OH、または-Hであり、
C1
式中、AおよびBの各々は、独立して、-OHまたは-Hである。いくつかの実施形態において、AおよびBの少なくとも一方は、-OHである。いくつかの実施形態において、AおよびBの両方が-OHである。
式中、AおよびBの各々は、独立して、-OHまたは-Hである。いくつかの実施形態において、AおよびBの少なくとも一方は、-OHである。いくつかの実施形態において、AおよびBの両方が-OHである。
また、本明細書に記載される固体剤形などの薬学的組成物、および組成物を配置するための容器(例えば、バイアル、アンプル、ボトル、注射器、および/またはディスペンサーパッケージ、または他の好適な容器)を含み得るキット(例えば、医薬品パック)も本開示に包含される。そのようなキットは、神経精神障害または結核を治療する、および/またはそのリスクを低減することを必要とする対象において、それを行うのに有用であり得る。
サイクロセリン化合物を含む組成物(例えば、固体剤形)のいずれも、例えば、神経精神障害を有するか、またはそのリスクがあるヒト対象における基本的な行動機能、多動性、不安、うつ病、自殺念慮および/または行動、感覚運動ゲーティング、疼痛閾値、記憶および/または認知機能を改善した患者における短期または長期健康目的を達成するのを助け得る。
1.D-サイクロセリンの安定性試験のストレス試験は、Macleods Pharmaから市販されているD-サイクロセリン500mgを用いて行い、開封して室温で高湿度(>90%RHまたは75%RH)、高温(40℃もしくは60℃)、または光条件で10日間保存した。結果は、表1に示されるように、D-サイクロセリンが高湿度に敏感であり、光に比較的敏感であり、40℃および60℃で比較的安定していることを示す。以下の実験では、D-サイクロセリンの安定性を確認するために総不純物を設定した。
湿度はD-サイクロセリンの安定性に影響を与える主要な事実であるため、ストレス条件下(75%RHおよび40℃)での安定性への影響を試験するために、いくつかの添加剤を選択した。結果を以下の表2に示す。ラクトースおよび微結晶性セルロースpH-102(MCC pH-102、別名Avicel pH-102、3~5%の含水量を有する微結晶性セルロース)(試料1)またはマンニトールおよび微結晶性セルロースpH-102(試料2)、微結晶性セルロースpH-102単独(試料3)は、組成物中のD-サイクロセリンを安定化するのにより良い効果を有する。調査結果は、試料2および3が安定性試験でより良いパフォーマンスを示すことを明らかにする。
腸溶性コーティング錠の調製には3つのステップがある。最初のステップは、S250スマートタブレットプレス機で圧縮されたコア錠を調製することである。第2のステップは、P MINI LABコーティング機によって単離層材料でコーティングされたコア錠を調製することである。最後のステップは、P MINI LABコーティング機によって腸溶層材料でコーティングされた単離層錠剤を調製することである。
有効成分(例えば、D-サイクロセリン化合物のうちのいずれか)を60メッシュスクリーンによってふるいにかけ、賦形剤を30メッシュのスクリーンによって別々にふるいにかけた。ふるいにかけた粉末をブレンディング機で5分間混合して混合物1を形成した。次いで、混合物1を潤滑剤としてのステアリン酸マグネシウムとおよそ5分間ブレンドし、そのブレンドをS250スマートタブレットプレス機によって圧縮して錠剤にした。得られたコア錠と呼ばれる錠剤を秤量し、それらの硬度、破砕性、および崩壊時間を試験した。溶解放出時間は、腸溶性コーティングプロセス後に試験される。
2.1.単離層コーティング材料溶液の調製
7493.2gの精製水および9894.8gの95%エタノールを秤量し、容器に入れて52.47%のエタノール溶液を得た。次いで、単離層コーティング材料(Shanghai Colorcon Coating Technology Ltd.から購入したOpadry(登録商標)295K680002)を、52.47%のエタノール溶液にゆっくり添加し、室温で45分間撹拌して、8%の固形分を有する単離コーティング溶液を得た。単離コーティング溶液は、コーティングプロセス中に継続的に撹拌する必要があった。
P MINI LABコーティング機は、入口空気温度を40℃~60℃に設定し、パン速度を2rpmに設定することによって予熱した。次いで、コア錠を、排気温度が約42℃に達するまでコーティング機に入れ、次いで、表3に示されるパラメータの下で、単離コーティング溶液をコア錠にスプレーした。コーティングの重量増加が3.0±0.5%の目標範囲に達したとき、スプレーおよび加熱プロセスを停止した。
スプレーおよび加熱プロセスを停止した後、コーティングパン速度を5rpmに調整し、入口空気流を200~500m3/hに調整して5分間冷却し、次いで単離層でコーティングされた錠剤を排出した。
3.1腸溶層コーティング材料溶液の準備
腸溶性コーティング材料(Shanghai Colorcon Coating Technology Ltd.から購入したAcryl-EZE(登録商標)93O640017)を精製水に溶解し、腸溶性コーティング溶液を得るために、室温で少なくとも45分間継続して撹拌した。腸溶性コーティング溶液の最終濃度は、20重量%である。腸溶性コーティング溶液は、コーティングプロセス中にデジタルオーバーヘッド撹拌機で継続して撹拌する必要があった。
P MINI LABコーティング機は、入口空気温度を40℃~60℃に設定し、パン速度を2rpmに設定することによって予熱した。次いで、単離層でコーティングされた錠剤を、排気温度が約35℃に達するまでコーティング機に入れ、次いで、表3に示されるパラメータの下で、腸溶性コーティング溶液を、単離層でコーティングされた錠剤にさらにスプレーした。コーティングプロセスを注意深く監視して、パンの温度およびスプレーの品質が十分であり、付着する錠剤が観察されないことを確認する必要がある。コーティングの重量増加が12.36±0.5%の目標範囲に達したときに、スプレーおよび加熱プロセスを停止した。
スプレーおよび加熱プロセスを停止した後、コーティングパン速度を5rpmに調整し、入口空気流を200~500m3/hに調整して、5分間冷却した後、腸溶性コーティング錠を排出した。
得られた錠剤を硬度試験に供し、試験した錠剤を破壊するのに必要な力(N)を記録した。錠剤の硬度は、120~160Nの間で制御された。
10個の錠剤を錠剤破砕装置に入れ、25±1rpmで100回転させた。試験した錠剤のうちのいずれかが壊れた場合、試験は失敗したと判断された。錠剤が壊れなかった場合は、秤量して重量減少(%)を計算した。重量減少(%)は、1%未満である必要がある。
6個の錠剤を37±2℃の水に入れた。これらの錠剤が30分以内に崩壊しなかった場合、試験は失敗したと判断された。これらの錠剤の崩壊時間(分)を記録した。
溶解試験は、酸段階および緩衝液段階を含む遅延放出剤形の溶解のためのUSP法に基づいて実施した。酸段階では、6個の錠剤を容器内の最初の溶解媒体(0.1N塩酸、pH2.0)に加え、溶解試験に供した。溶解媒体の容量は900mLであり、回転速度は100rpmであった。腸溶性コーティングは、胃の酸性環境に抵抗するため、これらの錠剤が120分以内に溶解した場合、試験は失敗したと判断された。酸段階でのこれらの錠剤の溶解時間(分)を記録した。
表4に示されるように、いくつかの製剤を使用してコア錠剤を調製した。微結晶性セルロースpH-102(MCC pH-102)、微結晶性セルロースpH-112(MCC pH-112、別名Avicel pH-112、1.5%未満の含水量を有する微結晶性セルロース)、デンプン 1500、およびアルファ化デンプンを、製剤中の希釈剤として使用した。MCC pH-112およびデンプン1500を含む製剤2、ならびにMCC pH-112およびアルファ化デンプンを含む製剤3は、製剤1よりも低い硬度およびより大きな破砕性を示した。
腸溶性錠剤は、実施例2に従って調製した。単離層および腸溶層は、胃の酸性環境から薬学的有効成分を保護した。したがって、表6に示されるように、単離層材料および腸溶層材料の量を調査した。
1.ナノ結晶D-サイクロセリンの調製
プロセスA:
100mgの粗D-サイクロセリン粉末(Stride Shasunから購入)を1mLの脱イオン水に溶解して、飽和D-サイクロセリン水溶液を調製した。10mLの飽和D-サイクロセリン溶液を、20mLのtert-ブタノールまたはエタノール中の70%メチルエチルケトン(MEK)またはエタノール中の90% MEKにゆっくりと添加し、40Hzで1分間の超音波処理によって同時に粉砕した。溶液を、0.2μmフィルター膜を使用した吸引濾過によって濾過した。濾過した溶液を、10,000rpmで10分間遠心分離した。収集物を真空乾燥させて、ナノ結晶D-サイクロセリンを得た(平均収率:40.9%)。プロセスAによって調製したナノ結晶D-サイクロセリンを、以下の実験および試験に使用した。
D-サイクロセリンの飽和水溶液を、スプレー乾燥機によって乾燥させ、スプレー乾燥したD-サイクロセリン粉末を、遊星ボールミルによって粉砕した。粉砕したD-サイクロセリン粉末の直径は、0.2μm未満であった。
D-サイクロセリンの飽和水溶液をスプレー乾燥機によって乾燥させ、スプレー乾燥したD-サイクロセリン粉末を、プロセスAに示したのと同じステップでD-サイクロセリンの第2の飽和水溶液に調製した。D-サイクロセリンの第2飽和水溶液10mLを、エタノール中の70%メチルエチルケトン50mLにゆっくりと添加し、プロペラ撹拌機によって150rpmで10分間撹拌し、D-サイクロセリンを沈殿させた。沈殿したD-サイクロセリンを真空濾過によって収集し、真空乾燥オーブンによって70℃で一晩乾燥させた。得られたD-サイクロセリンを、遊星ボールミルによって粉砕した。粉砕したD-サイクロセリン粉末の直径は、0.2μm未満であった。
カプセル製剤の調製:
(1)製剤A:サイズ9の社内腸溶性カプセルのナノ結晶D-サイクロセリン。5.66gのKollicoat(登録商標)腸溶性コーティング材料を、開いたサイズ9の空のブタ硬質ゼラチンカプセル(Torpac)の表面に均一にブラッシングした後、コーティングされたカプセルが硬く乾燥するまで空気乾燥させた。コーティングステップおよび乾燥ステップを5回繰り返した後、開いたカプセルをそのまま閉じて使用できるようにした。各カプセルにおよそ10mgのナノ結晶D-サイクロセリンを充填した。
2μLの各血漿試料を、96ウェルプレートのウェルに移した。アセトニトリル中の0.1ng/μLのIS(Piracetam)100μLを各ウェルに添加して、タンパク質を沈殿させた。96ウェルプレートを1分間ボルテックスした後、3000rpmで5分間遠心分離した。上清を、LC-MS/MSによって分析する。
腸溶性コーティングされたkangke 0# HPMCカプセルは、Shaoxing Comco capsule Co.Ltdから入手した。最初に、API(サイクロセリン)およびすべての他の賦形剤を、40メッシュのふるいに通した。第2に、API、微結晶性セルロース、マンニトールまたはラクトース、およびクロスカルメロースナトリウムをそれぞれビニール袋に量り入れ、手動で3分間混合して混合物1を得た。第3に、ステアリン酸マグネシウムを秤量し、混合物1と複合し、手動で1分間混合して混合物2を得た。最後に、混合物2を腸溶性コーティングされたカプセルに直接充填し、耐酸性溶解試験を行った。
1.パッチ製剤の調製
(1)パッチ製剤C:最初に、10mgのポビドンを、0.05mLのNaOH溶液に添加した。次いで、ポビドン溶液に、0.5mLのジプロピレングリコール、0.6mLのPEG400、および0.2mLのコーン油を添加して、ボルテックスおよび超音波処理によってエマルジョン溶液を形成した。15mgのナノ結晶D-サイクロセリンを、1.35mLのエマルジョン溶液に撹拌条件で添加した。ナノ結晶D-サイクロセリンがエマルジョン溶液に十分に懸濁されると、最終製剤が得られ、次いで経皮送達試験のためにフランツ拡散セルシステムのドナーコンパートメントに添加された。製剤および試験結果を表11に示す。
450nmの細孔サイズを有するSTART-M(登録商標)膜(Merckから購入)を、フランツ拡散セル(PermeGear,Riegelsville,PA,USAから購入)に装着した。受容体コンパートメントには、8mLのDI水が含まれていた。1~1.35mLの上述の製剤を、それぞれドナーコンパートメントを横切って1cm2の領域の面積にわたって膜に適用した。ドナーコンパートメントを周囲温度に曝露し、蒸発を防ぐためにパラフィルムで覆った後、膜に適用した製剤が受容体コンパートメントの脱イオン水に拡散した。受容体コンパートメント内の溶液(すなわち、放出媒体)を、テフロンコーティングされた磁気棒を用いて32°Cで継続して撹拌した。6、24、48、72、96、120、および144時間後に、試料(0.2mL)を製剤C~Gの放出媒体から取り出し、等量のDI水で置き換えて浸漬状態を維持した。別の試料セット(0.2mL)を取り出し、メタノールで希釈した後、LC-MS/MSによって分析した。
D-サイクロセリンの分析は、LC-MS/MS法によって開発されている。LC-MS/MS分析に使用したクロマトグラフィーカラムは、Thermo Fisher ScientificからのC18カラムであった。移動相は、(A)アセトニトリル中の0.1%トリフルオロ酢酸および(B)DI水中の0.1%トリフルオロ酢酸で構成され、勾配条件は、表10に示される通りであった。流量は、0.5mL/分であった。オートサンプラーの温度は、4℃で維持し、注入量は、5μLで維持した。総LC実行時間は、20分であった。分析物のイオン化および検出は、三連四重極型質量分析計、API-2000で正イオンモードで実行した。プロトン化した前駆体から生成物イオン(m/z 103.1から75.0)への遷移を監視するために、MRMモードを使用して定量を行った。
各製剤の長期経皮放出動態をシミュレートし、非線形方程式によって計算した。各製剤の理想的な最大放出量およびT1/2(受容体コンパートメントに放出される最大半量D-サイクロセリンでの時間)を表11に示し、各製剤の放出動態を図2に示す。
特許請求の範囲において、「a」、「an」、および「the」などの冠詞は、反対に示されない限り、または文脈から明らかでない限り、1つまたは2つ以上を意味し得る。グループの1つ以上のメンバー間に「または」を含む特許請求の範囲または説明は、グループメンバーのうちの1つ、2つ以上、もしくはすべては、反対に示されない限り、または文脈から明らかでない限り、所与の生成物もしくはプロセスに存在する、用いられる、またはそうでなければ関連する場合に満たされているとみなされる。本発明は、グループの正確に1つのメンバーが、所与の生成物もしくはプロセスに存在する、用いられる、またはそうでなければ関連する実施形態を含む。本発明は、2つ以上またはすべてのグループメンバーが、所与の生成物もしくはプロセスに存在する、用いられる、またはそうでなければ関連する実施形態を含む。
Claims (21)
- 固体剤形であって、
(i)サイクロセリン化合物および薬学的に許容される賦形剤を含む、内部コア、ここで、前記薬学的に許容される賦形剤が、充填剤、結合剤、崩壊剤、潤滑剤、担体、分散試薬、抗沈降試薬、増強剤、徐放性試薬、またはそれらの混合物を含み、前記内部コアはマンニトールを含まず、pH調整剤を含まない、
(ii)前記内部コアに付着した、ポリメタクリレート、フタル酸塩、セルロースエステル、シェラック、アルギン酸塩、またはそれらの混合物を含む腸溶層、
を含み、
前記固体剤形が、約10mg~約1500mgの前記サイクロセリン化合物を含有し、
前記固体剤形において、前記腸溶層の含量が、前記内部コアの含量の10%~14%(w/w)である、固体剤形。 - (iii)前記内部コアと前記腸溶層との間の単離層をさらに含み、前記単離層が、セルロースポリマーを含む、請求項1に記載の固体剤形。
- 前記内部コアにおいて、
(a)前記充填剤が、デンプン、ラクトース、スクロース、グルコース、リン酸カルシウム、微結晶性セルロース、およびそれらの混合物からなる群から選択され、
(b)前記結合剤が、カルボキシメチルセルロース、微結晶性セルロース(MCC)、ヒドロキシプロピルセルロース、アルギン酸塩、ゼラチン、ポリビニルピロリジノン、アカシア、およびそれらの混合物からなる群から選択され、
(c)前記崩壊剤が、寒天、炭酸カルシウム、ジャガイモまたはタピオカデンプン、アルギン酸、特定のケイ酸塩、デンプングリコール酸ナトリウム(SSG)、クロスカルメロース、クロスポビドン、炭酸ナトリウム、およびそれらの混合物からなる群から選択され、ならびに/または
(d)前記潤滑剤が、ステアリン酸マグネシウム、コロイド状二酸化ケイ素、タルク、ステアリン酸カルシウム、固体ポリエチレングリコール、ラウリル硫酸ナトリウム、およびそれらの混合物からなる群から選択される、請求項1または請求項2に記載の固体剤形。 - 前記内部コア中の前記薬学的に許容される賦形剤が、約50~500mgの前記充填剤、約10~100mgの前記結合剤、約10~200mgの前記崩壊剤、および約5~100mgの前記潤滑剤を含む、請求項1~3のいずれか一項に記載の固体剤形。
- 前記充填剤が、微結晶性セルロース(MCC)pH102を含み、前記結合剤が、ヒドロキシルプロピルセルロース(HPC)を含み、前記崩壊剤が、クロスカルメロースを含み、前記潤滑剤が、ステアリン酸マグネシウムを含む、請求項1~4のいずれか一項に記載の固体剤形。
- 前記腸溶層が、
(a)モル比1:1のポリ(メタクリル酸-co-エチルアクリレート)、モル比1:1のポリ(メタクリル酸-co-メチルメタクリレート)、モル比1:2のポリ(メタクリル酸-co-メチルメタクリレート)、およびモル比7:3:1のポリ(メチルアクリレート-co-メチルメタクリレート-co-メタクリル酸)からなる群から選択される、ポリメタクリレート、
(b)ポリ酢酸ビニルフタレート、ヒドロキシプロピルメチルセルロースフタレート、フタル酸ジエチル、および酢酸フタル酸セルロースからなる群から選択される、フタレート、ならびに/または
(c)酢酸トリメリト酸セルロース、酢酸コハク酸セルロース、および酢酸コハク酸ヒドロキシプロピルメチルセルロースからなる群から選択される、セルロースエステルを含む、請求項1~5のいずれか一項に記載の固体剤形。 - 前記腸溶層が、1:1の比の90.5重量%~98.49重量%のポリ(メタクリル酸-co-エチルアクリレート)、0.5重量%~2重量%のラウリル硫酸ナトリウム、0.01重量%~2.5重量%のクエン酸トリエチル、0.5重量%~2.5重量%のコロイド状二酸化ケイ素、および0.5重量%~2.5重量%のタルクを含む、請求項1~6のいずれか一項に記載の固体剤形。
- 前記セルロースポリマーが、ヒドロキシプロピルメチルセルロース(HPMC)である、請求項1~7のいずれか一項に記載の固体剤形。
- 前記HPMCが、50,000~125,000ダルトンの平均分子量を有する、請求項8に記載の固体剤形。
- 前記単離層が、95.5重量%~99.49重量%のヒドロキシプロピルメチルセルロース、0.5重量%~2.5重量%のタルク、および0.01重量%~2重量%のトリアセチンを含む、請求項2~9のいずれか一項に記載の固体剤形。
- 約10mg~約300mgの前記腸溶層および/または約10mg~約100mgの前記単離層を含む、請求項2~10のいずれか一項に記載の固体剤形。
- 前記薬学的に許容される賦形剤が、MCC pH102、クロスカルメロース、ヒドロキシプロピルセルロース(HPC)、およびステアリン酸マグネシウムを含み、前記腸溶層が、ポリメタクリレートを含み、前記単離層が、50,000~125,000ダルトンの分子量を有するHPMCを含む、請求項2~11のいずれか一項に記載の固体剤形。
- 前記サイクロセリン化合物が、ナノ結晶形態である、請求項1~12のいずれか一項に記載の固体剤形。
- 前記サイクロセリン化合物が、約0.05μm~約500μmの範囲のD90値を有する粒子形態である、請求項1~13のいずれか一項に記載の固体剤形。
- 前記サイクロセリン化合物が、D-サイクロセリンもしくはL-サイクロセリン、またはそれらの薬学的に許容される塩である、請求項1~14のいずれか一項に記載の固体剤形。
- 薬学的組成物、栄養補助食品組成物、健康食品、または医療食品である、請求項1~14のいずれか一項に記載の固体剤形。
- 神経精神疾患または結核に関連する症状を緩和するための請求項1~16のいずれか一項に記載の固体剤形。
- 前記神経精神障害が、統合失調症、精神病性障害、アルツハイマー病、前頭側頭型認知症、血管性認知症、レヴィー小体型認知症、老年性認知症、軽度認知障害、良性健忘症、運動失調症状、脊髄小脳変性症、閉鎖性頭部損傷、自閉症スペクトラム障害、アスペルガー障害、特定不能の広汎性発達障害(PDD-NOS)、脆弱性X症候群、注意欠陥多動性障害、注意欠陥障害、強迫性障害、チック障害、小児期学習障害、月経前症候群、うつ病、大うつ病性障害、無快感症、自殺念慮および/または行動、双極性障害、不安障害、パニック障害、神経性食欲不振症、恐怖症、広場恐怖症、閉所恐怖症、心的外傷後ストレス障害、慢性軽度および予測不可能なストレス、摂食障害、嗜癖障害、人格障害、パーキンソン障害、ハンチントン障害、多発性硬化症、筋萎縮性側索硬化症、トゥレット症候群、夜尿症、非てんかん発作、眼瞼けいれん、デュシェンヌ型筋ジストロフィー、脳卒中、慢性疼痛、痛覚過敏および異痛症を含む神経因性疼痛、糖尿病性多発神経障害、ならびに慢性疼痛症候群からなる群から選択される、請求項17に記載の固体剤形。
- 前記固体剤形が、前記対象に1日3回~3ヶ月に1回投与される、請求項17または18に記載の固体剤形。
- 前記対象が、前記神経精神障害の追加の治療を受けているか、または前記対象が、結核の追加の治療を受けている、請求項17~19のいずれか一項に記載の固体剤形。
- 前記神経精神障害または結核を治療するための追加の治療薬を、前記対象に投与することをさらに含む、請求項17~20のいずれか一項に記載の固体剤形。
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