JP2012522763A - ニトロカテコール誘導体を含む医薬製剤及びその製造方法 - Google Patents
ニトロカテコール誘導体を含む医薬製剤及びその製造方法 Download PDFInfo
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- JP2012522763A JP2012522763A JP2012503350A JP2012503350A JP2012522763A JP 2012522763 A JP2012522763 A JP 2012522763A JP 2012503350 A JP2012503350 A JP 2012503350A JP 2012503350 A JP2012503350 A JP 2012503350A JP 2012522763 A JP2012522763 A JP 2012522763A
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
Classifications
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Abstract
【選択図】なし
Description
式中、R1及びR2は独立して水素又は生理的条件下で加水分解性の基から選択され、任意で置換された低級アルカノイル又はアロイルであり、
Xはメチレン基であり、
Yは酸素、窒素又は硫黄の原子であり、
nは0、1、2及び3から選択され、
mは0又は1であり、
R3は、印がついていない結合によって示されるように連結される、式A、B、C、D、E及びF:
Pは中央ユニット、例えば平面ユニットであり、例えば1,3,4−オキサジアゾール−2,5−ジイル、1,2,4−オキサジアゾール−3,5−ジイル、4−メチル−4H−1,2,4−トリアゾール−3,5−ジイル、1,3,5−トリアジン−2,4−ジイル、1,2,4−トリアジン−3,5−ジイル、2H−テトラゾール−2,5−ジイル、1,2,3−チアジアゾール−4,5−ジイル、1−アルキル−3−(アルコキシカルボニル)−1H−ピロール−2,5−ジイル(アルキルは、メチル、エチル、n−プロピル及びn−ブチルで表わされ、またアルコキシはメトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる)、1−アルキル−1H−ピロール−2,5−ジイル(アルキルは、メチル、エチル、n−プロピル及びn−ブチルで表わされる)、チアゾール−2,4−ジイル、1−H−ピラゾール−1,5−ジイル、ピリミジン−2,4−ジイル、オキサゾール−2,4−ジイル、カルボニル、1H−イミダゾール−1,5−ジイル、イソキサゾール−3,5−ジイル、フラン−2,4−ジイル、3−アルコキシカルボニルフラン−2,4−ジイル(アルコキシは、メトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる)、ベンゼン−1,3−ジイル及び(Z)−1−シアノエテン−1,2−ジイルの位置異性体から選択されるものである。生理学的条件下で加水分解性の適切な基は当該分野において周知であり、またO原子と共にエーテル、エステル又は炭酸エステル結合を形成する基を含む。
‐式Iのニトロカテコール誘導体、その塩、エステル、水和物、溶媒和物及びその他の誘導体から選択される少なくとも1種の活性医薬成分を造粒して顆粒を形成し、
‐造粒の前、最中又はその後に、少なくとも1種のホスフェート誘導体をこの少なくとも1種の活性医薬成分と混合し、
‐造粒の前、最中又はその後に、少なくとも1種のポリビニルピロリドン誘導体化合物をこの少なくとも1種の活性医薬成分と混合する工程を含む。
LOD(%)=[(m0−mf)/m0]x100
を使用して計算することができる。
API 0.2〜50.0質量%
ホスフェート誘導体 5.0〜50.0質量%
追加のフィラー 0.0〜85.0質量%
ポビドン誘導体 1.0〜15.0質量%
滑沢剤 1.0〜15.0質量%
崩壊剤 1.0〜15.0質量%
API 0.2〜30.0質量%
ホスフェート誘導体 20.0〜50.0質量%
追加のフィラー 0.0〜85.0質量%
ポビドン誘導体 3.0〜10.0質量%
滑沢剤 1.0〜10.0質量%
崩壊剤 3.0〜10.0質量%
API 20.0〜50.0質量%
ホスフェート誘導体 20.0〜50.0質量%
追加のフィラー 0.0〜55.0質量%
ポビドン誘導体 3.0〜10.0質量%
滑沢剤 1.0〜10.0質量%
崩壊剤 3.0〜10.0質量%
質量220±40gの250mlのメスシリンダ(目盛りは2ml間隔)。
m/V0
を使用してg/mlで求め得る。式中、mは質量(グラム)であり、V0はゆるみ状態での見掛け体積である。
M/V1250
を使用してg/mlで求め得る。式中、mは質量(グラム)であり、V1250は、1250回のハブ後の見掛け体積である。
CI(%)=100x[(V0−Vf)/V0]
を使用して計算し得る。
4種の高用量カプセルを(実験室規模)、まず以下の表1に記載の量のAPI、リン酸二カルシウム及び/又は微結晶セルロース、クロスカルメロース−ナトリウム及び/又はポビドン及び/又はアルファ化デンプンを実験室規模の高せん断ミキサ(Stephan)で混合することによって形成した。これらの実施例で使用したAPIは、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドであった。精製水を各混合物に添加し、混合物を造粒した。
低用量カプセルを調製するために、2種のバッチA製剤を実験室規模で調製した。この2種の低用量カプセルのバッチを、以下の表2に記載の組成物を使用して形成した。まず、以下の表2に記載の量のAPI、リン酸二カルシウム、微結晶セルロース、クロスカルメロース−ナトリウム及びポビドンを、V−ブレンダで混合した。これらの実施例で使用したAPIは2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドであった。精製水を混合物に添加し、混合物を手動で混合し、造粒した。
CI(%)=100x[(V0−Vf)/V0]
を使用して計算した。
様々な用量の3種のカプセル(パイロット規模)のバッチを、以下の表3に記載の組成物を使用して形成した。バッチHは低用量カプセル、バッチJは中用量カプセル、バッチLは高用量カプセルである。
5種の高用量カプセルを、まず表4に記載の量のAPI、第1微結晶セルロース量、第1エチルセルロース量及びとうもろこしデンプンを高せん断ミキサで混合することによって形成した。これらの実施例で使用したAPIは、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドであった。精製水を各混合物に添加し、混合物を造粒した。
Claims (44)
- 式Iのニトロカテコール誘導体、その塩、エステル、水和物、溶媒和物及びその他の誘導体から選択される少なくとも1種の活性医薬成分と、少なくとも1種のホスフェート誘導体と、少なくとも1種のポリビニルピロリドン誘導体化合物とを含む組成物であって、前記少なくとも1種の活性医薬成分が顆粒の形態で存在することを特徴とする組成物。
下式I、
(I)
(式Iにおいて、
R1及びR2は独立して水素又は生理的条件下で加水分解性の基から選択され、任意で置換された低級アルカノイル又はアロイルであり、
Xはメチレン基であり、
Yは酸素、窒素又は硫黄の原子であり、
nは0、1、2及び3から選択され、
mは0又は1であり、
R3は、印がついていない結合によって示されるように連結される、式A、B、C、D、E及びF:
(式中、R4、R5、R6及びR7は独立して水素、C1−C6−アルキル、C1−C6−チオアルキル、C1−C6−アルコキシ、C6−C12−アリールオキシ又はC6−C12−チオアリール基、C1−C6−アルカノイル又はC7−C13−アロイル基、アミノ、C1−C6−アルキルアミノ、C1−C6−ジアルキルアミノ、C3−C12−シクロアルキルアミノ、C3-C12−ヘテロシクロアルキルアミノ、C1−C6−アルキルスルホニル、C6−C12−アリールスルホニル、ハロゲン、C1−C6−ハロアルキル、例えばトリフルオロメチル、シアノ、ニトロ又はヘテロアリール基から選択され、或いは残基R4、R5、R6及びR7の2個以上が一緒になって脂肪族若しくはヘテロ脂肪族環又は芳香族若しくはヘテロ芳香族環を表す)から選択されるピリジン基であり、
Pは中央ユニット、例えば平面ユニットであり、例えば1,3,4−オキサジアゾール−2,5−ジイル、1,2,4−オキサジアゾール−3,5−ジイル、4−メチル−4H−1,2,4−トリアゾール−3,5−ジイル、1,3,5−トリアジン−2,4−ジイル、1,2,4−トリアジン−3,5−ジイル、2H−テトラゾール−2,5−ジイル、1,2,3−チアジアゾール−4,5−ジイル、アルキルがメチル、エチル、n−プロピル及びn−ブチルで表わされ、またアルコキシがメトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる1−アルキル−3−(アルコキシカルボニル)−1H−ピロール−2,5−ジイル、アルキルがメチル、エチル、n−プロピル及びn−ブチルで表わされる1−アルキル−1H−ピロール−2,5−ジイル、チアゾール−2,4−ジイル、1−H−ピラゾール−1,5−ジイル、ピリミジン−2,4−ジイル、オキサゾール−2,4−ジイル、カルボニル、1H−イミダゾール−1,5−ジイル、イソキサゾール−3,5−ジイル、フラン−2,4−ジイル、アルコキシがメトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる3−アルコキシカルボニルフラン−2,4−ジイル、ベンゼン−1,3−ジイル並びに(Z)−1−シアノエテン−1,2−ジイルの位置異性体から選択されるものである。) - 前記活性医薬成分が、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドである、請求項1に記載の組成物。
- 前記活性医薬成分が、5−[3−(2,5−ジクロロ−4,6−ジメチルピリジン−3−イル)−[1,2,4]オキサジアゾール−5−イル]−3−ニトロベンゼン−1,2−ジオールである、請求項1に記載の組成物。
- 前記活性医薬成分が、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドと、5−[3−(2,5−ジクロロ−4,6−ジメチルピリジン−3−イル)−[1,2,4]オキサジアゾール−5−イル]−3−ニトロベンゼン−1,2−ジオールとの組み合わせである、請求項1に記載の組成物。
- 前記活性医薬成分が、0.02〜90質量%を構成する、請求項1〜4のいずれかに記載の組成物。
- 前記活性医薬成分が、0.2〜50質量%を構成する、請求項5に記載の組成物。
- 前記顆粒が、前記少なくとも1種のホスフェート誘導体及び/又は前記少なくとも1種のポリビニルピロリドン誘導体化合物を更に含む、請求項1〜6のいずれかに記載の組成物。
- 前記少なくとも1種のホスフェート誘導体が、二塩基性無水リン酸カルシウム、二塩基性リン酸カルシウム二水和物及び三塩基性リン酸カルシウムから選択される、請求項1〜7のいずれかに記載の組成物。
- 前記少なくとも1種のホスフェート誘導体が、二塩基性リン酸カルシウム二水和物である、請求項8に記載の組成物。
- 前記少なくとも1種のホスフェート誘導体が、0.5〜99.5質量%を構成する、請求項1〜9のいずれかに記載の組成物。
- 前記少なくとも1種のホスフェート誘導体が、10〜80質量%を構成する、請求項10に記載の組成物。
- 前記少なくとも1種のホスフェート誘導体が、20〜60質量%を構成する、請求項11に記載の組成物。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、ポビドン又はコポビドンから選択される、請求項1〜12のいずれかに記載の組成物。
- 前記ポリビニルピロリドン誘導体化合物が、ポビドンである、請求項13に記載の組成物。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、0.1〜40質量%を構成する、請求項1〜14のいずれかに記載の組成物。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、2〜20質量%を構成する、請求項15に記載の組成物。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、3〜10質量%を構成する、請求項16に記載の組成物。
- 少なくとも1種の賦形剤を更に含む、請求項1〜17のいずれかに記載の組成物。
- 嵩密度が0.2g/mlより大きい、請求項1〜18のいずれかに記載の組成物。
- 嵩密度が0.5g/mlより大きい、請求項19に記載の組成物。
- 追加のAPIを更に含む、請求項1〜20のいずれかに記載の組成物。
- 請求項1〜21のいずれかに記載の組成物を含む医薬製剤。
- 錠剤及びカプセルから選択される剤形である、請求項22に記載の医薬製剤。
- 0.5〜1.5g/mLの見掛け密度を示す錠剤である、請求項23に記載の医薬製剤。
- 0.8〜1.2g/mLの見掛け密度を示す錠剤である、請求項24に記載の医薬製剤。
- 組成物又は医薬製剤を製造する方法であって、
式Iのニトロカテコール誘導体、その塩、エステル、水和物、溶媒和物及びその他の誘導体から選択される少なくとも1種の活性医薬成分を造粒して顆粒を形成し、
造粒の前、最中又はその後に、少なくとも1種のホスフェート誘導体を前記少なくとも1種の活性医薬成分と混合し、
造粒の前、最中又はその後に、少なくとも1種のポリビニルピロリドン誘導体化合物を前記少なくとも1種の活性医薬成分と混合することを特徴とする方法。
式I:
(I)
式Iにおいて、
R1及びR2は独立して水素又は生理的条件下で加水分解性の基から選択され、任意で置換される低級アルカノイル又はアロイルであり、
Xはメチレン基であり、
Yは酸素、窒素又は硫黄の原子であり、
nは0、1、2及び3から選択され、
mは0又は1であり、
R3は、印がついていない結合によって示されるように連結される、式A、B、C、D、E及びF:
(式中、R4、R5、R6及びR7は独立して水素、C1−C6−アルキル、C1−C6−チオアルキル、C1−C6−アルコキシ、C6−C12−アリールオキシ又はC6−C12−チオアリール基、C1−C6−アルカノイル又はC7−C13−アロイル基、アミノ、C1−C6−アルキルアミノ、C1−C6−ジアルキルアミノ、C3−C12−シクロアルキルアミノ、C3-C12−ヘテロシクロアルキルアミノ、C1−C6−アルキルスルホニル、C6−C12−アリールスルホニル、ハロゲン、C1−C6−ハロアルキル、トリフルオロメチル、シアノ、ニトロ又はヘテロアリール基から選択され、或いは残基R4、R5、R6及びR7の2個以上が合わさって脂肪族若しくはヘテロ脂肪族環又は芳香族若しくはヘテロ芳香族環を表す)から選択されるピリジン基であり、
Pは中央ユニット、例えば平面ユニットであり、例えば1,3,4−オキサジアゾール−2,5−ジイル、1,2,4−オキサジアゾール−3,5−ジイル、4−メチル−4H−1,2,4−トリアゾール−3,5−ジイル、1,3,5−トリアジン−2,4−ジイル、1,2,4−トリアジン−3,5−ジイル、2H−テトラゾール−2,5−ジイル、1,2,3−チアジアゾール−4,5−ジイル、アルキルがメチル、エチル、n−プロピル及びn−ブチルで表わされ、またアルコキシがメトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる1−アルキル−3−(アルコキシカルボニル)−1H−ピロール−2,5−ジイル、アルキルがメチル、エチル、n−プロピル及びn−ブチルで表わされる1−アルキル−1H−ピロール−2,5−ジイル、チアゾール−2,4−ジイル、1−H−ピラゾール−1,5−ジイル、ピリミジン−2,4−ジイル、オキサゾール−2,4−ジイル、カルボニル、1H−イミダゾール−1,5−ジイル、イソキサゾール−3,5−ジイル、フラン−2,4−ジイル、アルコキシがメトキシ、エトキシ、n−プロポキシ及びイソプロポキシで表わされる3−アルコキシカルボニルフラン−2,4−ジイル、ベンゼン−1,3−ジイル並びに(Z)−1−シアノエテン−1,2−ジイルの位置異性体から選択されるものである。 - 前記少なくとも1種の活性医薬成分が、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドである、請求項26に記載の方法。
- 前記少なくとも1種の活性医薬成分が、5−[3−(2,5−ジクロロ−4,6−ジメチルピリジン−3−イル)−[1,2,4]オキサジアゾール−5−イル]−3−ニトロベンゼン−1,2−ジオールである、請求項26に記載の方法。
- 前記少なくとも1種の活性医薬成分が、2,5−ジクロロ−3−(5−(3,4−ジヒドロキシ−5−ニトロフェニル)−1,2,4−オキサジアゾール−3−イル)−4,6−ジメチルピリジン 1−オキシドと、5−[3−(2,5−ジクロロ−4,6−ジメチルピリジン−3−イル)−[1,2,4]オキサジアゾール−5−イル]−3−ニトロベンゼン−1,2−ジオールとの組み合わせである、請求項26に記載の方法。
- 前記少なくとも1種のホスフェート誘導体が、二塩基性無水リン酸カルシウム、二塩基性リン酸カルシウム二水和物及び三塩基性リン酸カルシウムから選択される、請求項26〜29のいずれかに記載の方法。
- 前記少なくとも1種のホスフェート誘導体が、二塩基性リン酸カルシウム二水和物である、請求項30に記載の方法。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、ポビドン又はコポビドンから選択される、請求項26〜31のいずれかに記載の方法。
- 前記少なくとも1種のポリビニルピロリドン誘導体化合物が、ポビドンである、請求項32に記載の方法。
- 前記造粒工程が、造粒液を使用して行われる、請求項26〜33のいずれかに記載の方法。
- 前記顆粒を乾燥させることを更に含む、請求項34に記載の方法。
- 前記顆粒を篩過することを更に含む、請求項26〜35のいずれかに記載の方法。
- 前記顆粒を少なくとも1種の賦形剤とブレンドすることを更に含む、請求項26〜36のいずれかに記載の方法。
- 造粒後、前記組成物が、0.2g/mLより大きい嵩密度を有する、請求項26〜37のいずれかに記載の方法。
- 造粒後、前記組成物が、0.5g/mLより大きい嵩密度を有する、請求項38に記載の方法。
- 前記医薬製剤を製造する際に、医薬品剤形を形成することを更に含む、請求項26〜39のいずれかに記載の方法。
- 前記医薬品剤形の形成が、前記組成物を錠剤に圧縮する工程を含む、請求項40に記載の方法。
- 前記錠剤が、0.5〜1.5g/mLの見掛け密度を有する、請求項41に記載の方法。
- 前記錠剤が、0.8〜1.2g/mLの見掛け密度を有する、請求項42に記載の方法。
- 前記医薬品剤形の形成が、カプセルに前記組成物を充填する工程を含む、請求項40に記載の方法。
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