JP2013538814A - 水溶性抗酸化剤を使用する製剤 - Google Patents
水溶性抗酸化剤を使用する製剤 Download PDFInfo
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- JP2013538814A JP2013538814A JP2013527318A JP2013527318A JP2013538814A JP 2013538814 A JP2013538814 A JP 2013538814A JP 2013527318 A JP2013527318 A JP 2013527318A JP 2013527318 A JP2013527318 A JP 2013527318A JP 2013538814 A JP2013538814 A JP 2013538814A
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- opadry
- layer
- saxagliptin
- soluble antioxidant
- white
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- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 description 1
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- 108020003175 receptors Proteins 0.000 description 1
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- AFNTWHMDBNQQPX-NHKADLRUSA-N saxagliptin hydrate Chemical compound O.C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 AFNTWHMDBNQQPX-NHKADLRUSA-N 0.000 description 1
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- 150000004760 silicates Chemical class 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
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- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- KSAVQLQVUXSOCR-UHFFFAOYSA-M sodium lauroyl sarcosinate Chemical compound [Na+].CCCCCCCCCCCC(=O)N(C)CC([O-])=O KSAVQLQVUXSOCR-UHFFFAOYSA-M 0.000 description 1
- 229940045885 sodium lauroyl sarcosinate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
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- 239000000829 suppository Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
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- 229940095064 tartrate Drugs 0.000 description 1
- FBWNMEQMRUMQSO-UHFFFAOYSA-N tergitol NP-9 Chemical compound CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1 FBWNMEQMRUMQSO-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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Abstract
Description
本発明は、製造工程中および/または有効保存期間中の保存中に、投与形態製剤のギ酸および/またはホルミル種産生を阻止するかまたは減少させる水溶性抗酸化剤を含む固体、半固体または液体製剤に関する。本発明の製剤は、製造工程中および/または有効保存期間の保存中に、N−ホルミル化不純物(およびゼラチン架橋)の形成を阻止するかまたは減少させる。
サクサグリプチンは、現在2型糖尿病の処置に使用され、商品名Onglyza(登録商標)で販売されているジペプチジルペプチダーゼIV(DPP−IV)阻害剤である。
一つの面において、本発明は、少なくとも1種の水溶性抗酸化剤を含む固体、半固体または液体製剤を提供する。本発明の製剤は、製造工程中および/または有効保存期間中の保存中におけるホルムアルデヒド、ギ酸および/またはそれらの誘導体の形成を阻止するかまたは減少させ、それにより、NFAのようなホルミル不純物を阻止するかまたは減少させる。本発明の固体および半固体製剤は、錠剤、保存顆粒(stock granulation)またはカプセル製剤を含むが、これらに限定されない。本発明の液体製剤は、製造工程中、ホルムアルデヒド、ギ酸および/またはそれらの誘導体を形成する傾向にあるかまたはそれらの形成を支持するコーティング製剤を含むが、これらに限定されない。
本発明は、アミン含有活性医薬成分のN−ホルミル化を阻止するかまたは減少させる固体、半固体または液体製剤における水溶性抗酸化剤の使用を開示する。アミン性薬物、例えばサクサグリプチンはギ酸またはその誘導体と反応してNFA不純物を形成し得る。水溶性抗酸化剤はギ酸またはその誘導体と反応して、N−ホルミル化を阻止するかまたは減少させる。あるいは、抗酸化剤はポリエチレングリコール(PEG)および/またはギ酸の形成に至る製剤中の他の添加物の酸化的分解を阻止し得る。
一つの面において、本発明は、場合により少なくとも1種の抗糖尿病剤またはその薬学的に許容される塩を含んでよい錠剤コアを含む錠剤を提供し、ここで、抗糖尿病剤はサクサグリプチン以外である。第一層は錠剤コアを被覆し、コーティング物質および場合により少なくとも1種の水溶性抗酸化剤を含む。第二層は第一層を被覆し、活性医薬成分、コーティング物質および少なくとも1種の水溶性抗酸化剤を含み、ここで、活性医薬成分は1級または2級アミンである。第三層は第二層を被覆し、コーティング物質および場合により水溶性抗酸化剤を含む。
他の面において、本発明は結合剤、湿潤剤、滑沢剤および場合により少なくとも1種の抗糖尿病剤またはその薬学的に許容される塩を含む錠剤コアを含む即時放出錠剤を提供し、ここで、抗糖尿病剤はサクサグリプチン以外である。第一層は錠剤コアを被覆し、コーティング物質および場合により少なくとも1種の水溶性抗酸化剤を含む。第二層は第一層を被覆し、活性医薬成分、コーティング物質および少なくとも1種の水溶性抗酸化剤を含み、ここで、活性医薬成分は1級または2級アミンである。第三層は第二層を被覆し、コーティング物質および場合により水溶性抗酸化剤を含む。
他の面において、本発明は、崩壊剤、放出修飾剤(release modifier)、増量剤、湿潤剤、滑沢剤および場合により少なくとも1種の抗糖尿病剤またはその薬学的に許容される塩を含む錠剤コアを含む徐放型錠剤を提供し、ここで、抗糖尿病剤はサクサグリプチン以外である。第一層は錠剤コアを被覆し、コーティング物質および場合により少なくとも1種の水溶性抗酸化剤を含む。第二層は第一層を被覆し、活性医薬成分、コーティング物質および少なくとも1種の水溶性抗酸化剤を含み、ここで、活性医薬成分は1級または2級アミンである。第三層は第二層を被覆し、コーティング物質および場合により水溶性抗酸化剤を含む。
(2S,3R,4R,5S,6R)−2−(4−クロロ−3−(4−エトキシベンジル)フェニル)−6−(ヒドロキシメチル)テトラヒドロ−2H−ピラン−3,4,5−トリオール
ダパグリフロジンは、米国特許6,515,117または国際公開出願WO03/099836およびWO2008/116179に記載の方法に準じて製造できる。これらの開示は、引用によりそれらの全体をあらゆる目的のために本明細書に包含させる。SGLT2 EC50=1.1nM。
(2S,3R,4R,5S,6R)−2−(4−クロロ−3−(4−エトキシベンジル)フェニル)−6−(ヒドロキシメチル)テトラヒドロ−2H−ピラン−3,4,5−トリオール(S)−プロパン−1,2−ジオール水和物(1:1:1)
ダパグリフロジン(S)−プロピレングリコール水和物(1:1:1)は、公開出願WO08/002824およびWO2008/116179に記載の方法に準じて製造できる。これらの開示は、引用によりそれらの全体をあらゆる目的のために本明細書に包含させる。SGLT2 EC50=1.1nM。
(2S,3R,4R,5S,6R)−2−(4−クロロ−3−(4−エトキシベンジル)フェニル)−6−(ヒドロキシメチル)テトラヒドロ−2H−ピラン−3,4,5−トリオール(R)−プロパン−1,2−ジオール水和物(1:1:1)
ダパグリフロジン(R)プロピレングリコール水和物(1:1:1)は、WO08/002824およびWO2008/116179に記載の方法に準じて製造できる。これらの開示は、引用によりそれらの全体をあらゆる目的のために本明細書に包含させる。SGLT2 EC50=1.1nM。
サクサグリプチン錠2.5mgを1日間60℃/75%RHに曝露し、続いて、乾燥剤を入れ、誘導密封した高密度ポリエチレン容器(HDPE容器)で30℃/65%RHで12ヶ月間保存した。
対照試験において、サクサグリプチン錠を、HDPE容器中、30℃/65%RHで12ヶ月間、予め60℃/75%RHに曝露することなく保存した。
曝露した錠剤のNFAレベルは、曝露していない錠剤より顕著に高かった(〜0.4−0.5%w/w(サクサグリプチン)対<0.05%w/w)。両者のCAレベルは同等であった(〜0.05%w/w(サクサグリプチン))。
サクサグリプチン第二層コーティング懸濁液の製造工程に従って、Opadry(登録商標)II白色の4バッチを使用して、水中17.5%w/w濃度のコーティング懸濁液を調製し、塩酸を使用してpH2.0±0.3に調節した。懸濁液を室温(〜25℃)で8日間または14日間保存した。誘導体化ガスクロマトグラフィー(GC)法により総ホルミル種レベルを分析した。結果を表1に示す。
錠剤中のNFA形成に対するOpadry懸濁液の待機保存の影響
サクサグリプチン第二層コーティング懸濁液の製造工程に従って、Opadry(登録商標)II白色粉末を水に17.5%w/w濃度で分散させ、塩酸を使用してpH2.0±0.3に調節した。このOpadry懸濁液を使用して、上の実施例1に記載した第三層コーティング法を実施してサクサグリプチン錠2.5mgを製造し、その間懸濁液を、1例について各層最大72時間(日常的な製造で許容される最大待機保存)待機させ、他例では最大12時間(日常的な製造で可能な最短保存)待機させた。前の例では、懸濁液を最初のコーティング前に48時間待機させ、懸濁液の総待機保存時間(コーティング終了まで)を最大72時間とした。後の例では、コーティングを懸濁液製造直後に開始し、懸濁液の総保存時間(コーティング終了まで)を最大12時間とした。被覆錠剤を、乾燥剤を入れ、吸引密閉したHDPE容器に包装した。包装医薬品製品を40℃、75%RHで6ヶ月間または50℃で1ヶ月間保存し、不純物を分析した。この試験の結果を表2に示す。
異なる待機時間のバッチ間の%CAおよび総不純物を比較して、NFAは懸濁液の待機時間の関数として増加する主分解産物であることが判明した。これらのデータは、製品製造中の懸濁液の待機時間が、医薬品保存中のNFAの成長に影響することを示した。
Opadryフィルムのホルムアルデヒドおよびギ酸レベル減少における抗酸化剤の相対的効果
Opadry(登録商標)II白色粉末を塩酸含有水に溶解し、pH2.0±0.3に調節した。500μLのコーティング懸濁液を5mLシンチレーションバイアルに分配した。開放バイアルを一夜、40℃に維持して、フィルムを形成させた。バイアルにゴム栓をし、密閉した。密閉バイアルを60℃で5日間維持し、GC法によりホルムアルデヒドおよびギ酸レベルを分析した。
並行実験で、0.2%w/v脂質可溶性抗酸化剤(BHT)または2%w/v 水溶性抗酸化剤(アスコルビン酸または没食子酸プロピル)を含むOpadry懸濁液cを調製し、同様に処理した。これらの濃度は、各抗酸化剤の推奨使用濃度の最大値であり、それらの最大効果を試験するために使用した。この試験の結果を表3に示す。
コア中に薬物が存在する錠剤
本明細書に開示する知見はまた錠剤のコアに薬物が存在する経口固体投与形態にも適用可能である。本発明の製剤を、ギ酸またはホルミル化種、例えばギ酸エステル類または無水物と反応する薬物に使用できる。水溶性抗酸化剤を、種々の残存レベル(5ppm以上の範囲)のギ酸または種々のホルミル化種を含む製剤に添加し得る。製剤は、ホルミル化種を最初から含むおよび/または2日間〜3ヶ月間の期間、高温(例えば40℃〜60℃)および/または多湿(例えば75%RH〜95%RH)条件での保存により形成するものであり得る。本錠剤は被覆されていても、被覆されていなくてもよい。錠剤が被覆されているならば、本発明で提案される抗酸化剤を錠剤のコーティングまたはコアまたは両者に使用できる。
サクサグリプチン錠剤
サクサグリプチン錠剤を、三層コーティング工程でプラセボコア錠剤をポリビニルアルコール(PVA)ベースのOpadryコーティング物質でコーティングして、コーティング物質にサクサグリプチンを混入することにより製造する。本発明によるサクサグリプチン錠剤の製剤組成を表12に記載する。本組成物は、2.5mgsのサクサグリプチン投与量を反映する。種々の投与量のサクサグリプチン錠剤は、有効医薬物質の負荷ならびに添加物組成および総錠剤重量の修飾により製造できる。
サクサグリプチン/メトホルミン即時放出型固定投与量錠剤
サクサグリプチン/塩酸メトホルミン即時放出(Saxa/Met IR)錠剤を、三層コーティング工程でMet IRコア錠剤をPVAベースのOpadryコーティング物質でコーティングして、コーティング物質にサクサグリプチンを混入することにより製造する。Saxa/Met IR錠剤の製剤組成を表13に記載する。本組成物はサクサグリプチン投与量2.5mgおよび塩酸メトホルミン投与量500mgを反映する。他の固定用量組み合わせ製品は、有効医薬物質の負荷ならびに錠剤のコアまたはコーティングにおける添加物の組成および総錠剤重量の修飾により製造できる。
サクサグリプチン/メトホルミン徐放型固定投与量錠剤
サクサグリプチン/塩酸メトホルミン徐放型(Saxa/Met XR)錠剤を、三層コーティング工程でMet XRコア錠剤をPVAベースのOpadryコーティング物質でコーティングして、コーティング物質にサクサグリプチンを混入することにより製造する。Saxa/Met XR錠剤の製剤組成を表14に記載する。本組成物はサクサグリプチン投与量2.5mgおよび塩酸メトホルミン投与量500mgを反映する。他の固定用量組み合わせ製品は、有効医薬物質の負荷ならびに錠剤のコアまたはコーティングにおける添加物の組成および総錠剤重量の修飾により製造できる。
液体および半固体製剤
本発明の製剤はまた経口、外用または非経腸使用を対象とし得る液体製剤にも適用できる。これらの製剤は溶液、懸濁液、エマルジョン、軟膏、ゲル、坐薬、自己乳化系、自己マイクロエマルジョン化系および他の半固体投与形態を含み得る。本発明の液体製剤は、ギ酸またはホルミル化種、例えばギ酸エステル類または無水物と反応する薬物に使用できる。水溶性抗酸化剤を、一定残存レベルのギ酸または種々のホルミル化種(5ppm以上の範囲)を含む製剤に添加し得る。製剤は、ホルミル化種を最初から含むおよび/または2日間〜3ヶ月間の期間、高温(例えば40℃〜60℃)および/または多湿(例えば75%RH〜95%RH)条件での保存により形成するものであり得る。
Claims (38)
- (a) 次のものを含む錠剤コア
(i) 場合により少なくとも1種の抗糖尿病剤または薬学的に許容されるその塩(抗糖尿病剤はサクサグリプチン以外である);
(b) 次のものを含む、錠剤コアを被覆する第一層
(i) コーティング物質;および
(ii) 場合により少なくとも1種の水溶性抗酸化剤;
(c) 次のものを含む、第一層を被覆する第二層
(i) コーティング物質;
(ii) 少なくとも1種の水溶性抗酸化剤;および
(iii) 活性医薬成分または薬学的に許容されるその塩(ここで、活性医薬成分は1級アミンまたは2級アミンである);および
(d) 次のものを含む、第二層を被覆する第三層
(i) コーティング物質;および
(ii) 場合により少なくとも1種の水溶性抗酸化剤
を含む、被覆錠剤。 - 活性医薬成分がサクサグリプチン、シタグリプチン、ビルダグリプチン、リナグリプチン、デュトグリプチンまたはアログリプチンである、請求項1に記載の被覆錠剤。
- 活性医薬成分がサクサグリプチンである、請求項1に記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸、没食子酸プロピル、亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、重亜硫酸ナトリウム、チオグリセロール、チオグリコール酸またはそれらの組み合わせである、請求項1〜3のいずれかに記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸または没食子酸プロピルである、請求項1〜3のいずれかに記載の被覆錠剤。
- 第二コーティング層のコーティング物質が少なくとも約10wt%ポリ(エチレングリコール)、ポリ(ビニルアルコール)またはそれらの組み合わせを含む、請求項1〜5のいずいれかに記載の被覆錠剤。
- 錠剤コアが2種の充填剤、崩壊剤および滑沢剤を含み、コーティング物質がOpadry(登録商標)IIである、請求項1〜5のいずれかに記載の被覆錠剤。
- (a) 錠剤コアが
(i) 約99mgsのラクトース一水和物;
(ii) 約90mgsの微結晶性セルロース;
(iii) 約10mgsのクロスカルメロースナトリウム;および
(iv) 約1mgのステアリン酸マグネシウムを含み;
(b) 第一層が
(i) 約21mgs Opadry(登録商標)II白色を含み;
(c) 第二層が
(i) 約20mgs Opadry(登録商標)II白色;
(ii) 約0.5mgs 没食子酸プロピル;および
(iii) 約2.5mgs サクサグリプチンを含み;そして
(d) 第三層が
(i) 約17mgs Opadry II有色を含む、
請求項1に記載の被覆錠剤。 - 錠剤コアが結合剤、湿潤剤、滑沢剤および少なくとも1種の抗糖尿病剤またはその薬学的に許容される塩を含み、抗糖尿病剤がグリブリド、メトホルミン、グルコバンス(登録商標)、ロシグリタゾン、ピオグリタゾン、シタグリプチン、ビルダグリプチン、ダパグリフロジン、ダパグリフロジン(S)−プロピレングリコール水和物またはそれらの組み合わせである、請求項1に記載の被覆錠剤。
- コーティング中の活性医薬成分がサクサグリプチン、シタグリプチン、ビルダグリプチン、リナグリプチン、デュトグリプチンまたはアログリプチンである、請求項9に記載の被覆錠剤。
- 錠剤コアが結合剤、湿潤剤、滑沢剤および抗糖尿病剤を含み、抗糖尿病剤がメトホルミン、ダパグリフロジン、ダパグリフロジン(S)−プロピレングリコール水和物またはそれらの組み合わせであり、活性医薬成分がサクサグリプチンである、請求項1に記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸、没食子酸プロピル、亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、重亜硫酸ナトリウム、チオグリセロール、チオグリコール酸またはそれらの組み合わせである、請求項11に記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸または没食子酸プロピルであり、コーティング物質がOpadry(登録商標)IIである、請求項11に記載の被覆錠剤。
- (a) 錠剤コアがダパグリフロジンまたはダパグリフロジン(S)−プロピレングリコール水和物、結合剤、湿潤剤および滑沢剤を含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアがダパグリフロジンまたはダパグリフロジン(S)−プロピレングリコール水和物、ポビドン、精製水およびステアリン酸マグネシウムを含み;
(b) 第一層がOpadry(登録商標)II白色を含み
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが塩酸メトホルミン、結合剤、湿潤剤および滑沢剤を含み;
(b) 第一層がOpadry(登録商標)II白色を含み
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが塩酸メトホルミン、ポビドン、精製水およびステアリン酸マグネシウムを含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが
(i) 約500mgsの塩酸メトホルミン;
(ii) 約20mgsのポビドン;
(iii) 約5mgsの精製水;および
(iv) 約1.75mgsのステアリン酸マグネシウムを含み;
(b) 第一層が
(i) 約21mgs Opadry(登録商標)II白色を含み;
(c) 第二層が
(i) 約20mgs Opadry(登録商標)II白色;
(ii) 約0.5mgs 没食子酸プロピル;および
(iii) 約2.5mgs サクサグリプチンを含み;そして
(d) 第三層が
(i) 約17mgs Opadry II有色を含む、
請求項1に記載の被覆錠剤。 - 錠剤コアが崩壊剤、放出修飾剤、増量剤、湿潤剤、滑沢剤および少なくとも1種の抗糖尿病剤またはその薬学的に許容される塩を含み、抗糖尿病剤がグリブリド、メトホルミン、グルコバンス(登録商標)、ロシグリタゾン、ピオグリタゾン、シタグリプチン、ビルダグリプチン、ダパグリフロジン、ダパグリフロジン(S)−プロピレングリコール水和物またはそれらの組み合わせである、請求項1に記載の被覆錠剤。
- 活性医薬成分がサクサグリプチン、シタグリプチン、ビルダグリプチン、リナグリプチン、デュトグリプチンまたはアログリプチンである、請求項18に記載の被覆錠剤。
- 錠剤コアが崩壊剤、放出修飾剤、増量剤、湿潤剤、滑沢剤および抗糖尿病剤を含み、抗糖尿病剤がメトホルミン、ダパグリフロジン、ダパグリフロジン(S)−プロピレングリコール水和物またはそれらの組み合わせであり、活性医薬成分がサクサグリプチンである、請求項1に記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸、没食子酸プロピル、亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、重亜硫酸ナトリウム、チオグリセロール、チオグリコール酸またはそれらの組み合わせである、請求項21に記載の被覆錠剤。
- 水溶性抗酸化剤がアスコルビン酸または没食子酸プロピルであり、コーティング物質がOpadry(登録商標)IIである、請求項1に記載の被覆錠剤。
- (a) 錠剤コアがダパグリフロジンまたはダパグリフロジン(S)−プロピレングリコール水和物、崩壊剤、放出修飾剤、増量剤、湿潤剤および滑沢剤を含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色を含みアスコルビン酸または没食子酸プロピル;
およびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアがダパグリフロジンまたはダパグリフロジン(S)−プロピレングリコール水和物、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロース、微結晶性セルロース、精製水およびステアリン酸マグネシウムを含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが塩酸メトホルミン、崩壊剤、放出修飾剤、増量剤、湿潤剤および滑沢剤を含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが塩酸メトホルミン、カルボキシメチルセルロースナトリウム、ヒドロキシプロピルメチルセルロース、微結晶性セルロース、精製水およびステアリン酸マグネシウムを含み;
(b) 第一層がOpadry(登録商標)II白色を含み;
(c) 第二層がOpadry(登録商標)II白色、アスコルビン酸または没食子酸プロピルおよびサクサグリプチンを含み;そして
(d) 第三層がOpadry II有色を含む、
請求項1に記載の被覆錠剤。 - (a) 錠剤コアが
(i) 約500mgsの塩酸メトホルミン;
(ii) 約50mgsのカルボキシメチルセルロースナトリウム;
(iii) 約370mgsのヒドロキシプロピルメチルセルロース;
(iv) 約100mgsの微結晶性セルロース;
(v) 約5mgsの精製水;および
(vi) 約3.5mgsのステアリン酸マグネシウムを含み;
(b) 第一層が
(i) 約21mgs Opadry(登録商標)II白色を含み;
(c) 第二層が
(i) 約20mgs Opadry(登録商標)II白色;
(ii) 約0.5mgs 没食子酸プロピル;および
(iii) 約2.5mgs サクサグリプチンを含み;そして
(d) 第三層が
(i) 約17mgs Opadry II有色を含む、
請求項1に記載の被覆錠剤。 - 固体、半固体または液体製剤における活性医薬成分のN−ホルミル化を阻止するかまたは減少させる方法であって、少なくとも1種の水溶性抗酸化剤を固体、半固体または液体製剤に添加することを含み、該活性医薬成分が1級アミンまたは2級アミンであり、該固体、半固体または液体製剤がポリエチレングリコールを単独でまたはポリビニルアルコールと組み合わせて含む、方法。
- 固体、半固体または液体製剤がOpadry(登録商標)IIを含む、請求項29に記載の方法。
- 活性医薬成分がサクサグリプチン、シタグリプチン、ビルダグリプチン、リナグリプチン、デュトグリプチンまたはアログリプチンである、請求項29または30に記載の方法。
- 活性医薬成分がサクサグリプチンである、請求項29または30に記載の方法。
- 水溶性抗酸化剤がアスコルビン酸、没食子酸プロピル、亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、重亜硫酸ナトリウム、チオグリセロール、チオグリコール酸またはそれらの組み合わせである、請求項32に記載の方法。
- 水溶性抗酸化剤がアスコルビン酸または没食子酸プロピルである、請求項32に記載の方法。
- 固体、半固体または液体製剤におけるギ酸レベルを阻止するかまたは減少させる方法であって、少なくとも1種の水溶性抗酸化剤を固体、半固体または液体製剤に添加することを含み、該固体、半固体または液体製剤がポリエチレングリコールを単独でまたはポリビニルアルコールと組み合わせて含む、方法。
- 固体、半固体または液体製剤がOpadry(登録商標)IIを含む、請求項35に記載の方法。
- 水溶性抗酸化剤がアスコルビン酸、没食子酸プロピル、亜硫酸ナトリウム、メタ重亜硫酸ナトリウム、重亜硫酸ナトリウム、チオグリセロール、チオグリコール酸またはそれらの組み合わせである、請求項35または36に記載の方法。
- 水溶性抗酸化剤がアスコルビン酸または没食子酸プロピルである、請求項35または36に記載の方法。
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EP (1) | EP2611442B1 (ja) |
JP (1) | JP5837072B2 (ja) |
KR (1) | KR20130137624A (ja) |
CN (1) | CN103370064A (ja) |
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- 2011-09-01 MX MX2013002146A patent/MX2013002146A/es unknown
- 2011-09-01 JP JP2013527318A patent/JP5837072B2/ja active Active
- 2011-09-01 EP EP11758019.1A patent/EP2611442B1/en active Active
- 2011-09-01 AU AU2011295837A patent/AU2011295837B2/en active Active
- 2011-09-01 WO PCT/US2011/050212 patent/WO2012031124A2/en active Application Filing
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2015531763A (ja) * | 2012-08-17 | 2015-11-05 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | コビメチニブ及びメベムラフェニブを投与することを含むメラノーマの併用療法 |
US10946009B2 (en) | 2015-04-02 | 2021-03-16 | Theravance Biopharma R&D Ip, Llc | Combination dosage form of a mu opioid receptor antagonist and an opioid agent |
US11452723B2 (en) | 2015-04-02 | 2022-09-27 | Theravance Biopharma R&D Ip, Llc | Combination dosage form of a mu opioid receptor antagonist and an opioid agent |
JP7423264B2 (ja) | 2019-10-17 | 2024-01-29 | 日本ジェネリック株式会社 | シタグリプチン含有錠剤 |
Also Published As
Publication number | Publication date |
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JP5837072B2 (ja) | 2015-12-24 |
EP2611442B1 (en) | 2018-07-04 |
CN103370064A (zh) | 2013-10-23 |
US20130224296A1 (en) | 2013-08-29 |
AU2011295837B2 (en) | 2015-06-18 |
WO2012031124A2 (en) | 2012-03-08 |
KR20130137624A (ko) | 2013-12-17 |
EP2611442A2 (en) | 2013-07-10 |
AU2011295837A1 (en) | 2013-05-02 |
WO2012031124A3 (en) | 2012-06-21 |
MX2013002146A (es) | 2013-04-03 |
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