JP6537538B2 - 医薬組成物およびこれを安定化させる方法 - Google Patents
医薬組成物およびこれを安定化させる方法 Download PDFInfo
- Publication number
- JP6537538B2 JP6537538B2 JP2017002785A JP2017002785A JP6537538B2 JP 6537538 B2 JP6537538 B2 JP 6537538B2 JP 2017002785 A JP2017002785 A JP 2017002785A JP 2017002785 A JP2017002785 A JP 2017002785A JP 6537538 B2 JP6537538 B2 JP 6537538B2
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- JP
- Japan
- Prior art keywords
- clevidipine
- pharmaceutical composition
- emulsion
- soybean oil
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 47
- 230000000087 stabilizing effect Effects 0.000 title description 4
- KPBZROQVTHLCDU-GOSISDBHSA-N clevidipine Chemical compound CCCC(=O)OCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC(Cl)=C1Cl KPBZROQVTHLCDU-GOSISDBHSA-N 0.000 claims description 111
- 229960003597 clevidipine Drugs 0.000 claims description 111
- 239000000839 emulsion Substances 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
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- 239000012071 phase Substances 0.000 claims description 13
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- 238000007254 oxidation reaction Methods 0.000 claims description 12
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- 231100000419 toxicity Toxicity 0.000 description 2
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
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- LHAOQTPGTBGTIG-UHFFFAOYSA-N 4-(2,3-dichlorophenyl)-5-methoxycarbonyl-2,6-dimethyl-1,4-dihydropyridine-3-carboxylic acid Chemical group COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC(Cl)=C1Cl LHAOQTPGTBGTIG-UHFFFAOYSA-N 0.000 description 1
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- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Chemical class CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical class NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
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- 239000004472 Lysine Chemical class 0.000 description 1
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- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
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- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 239000002866 dihydropyridine calcium channel blocker Substances 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
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- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Chemical class OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
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- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Description
最初の試験において、0.5mg/mlのクレビジピンエマルションは、100mlのII型ボトルに梱包された後、黒色臭化ブチル栓で密封した。
第2の光安定性の試験において、2つの群の20個の0.5mg/mlのクレビジピンエマルションが、50mlのI型ボトルに梱包された後、黒色臭化ブチル栓で密封された。
実施例1:HPLC操作
クレビジピンアッセイおよび関連する物質は、安定性指示法により、各時点で試験した。
この方法は、波長200nmにおけるピーク検出による、アイソクラティック順相HPLC法である。
カラム温度:35〜40℃
注入体積:20μl
流速:1.0ml/分
実行時間:約25分
ヘプタン:エタノール(90:10)移動相が採用され、物質24を除くクレビジピンおよび分解産物のアッセイに使用した。
1.0ml/分で4時間、カラムとクレビジピン移動相で調整する。
新しいカラムは、0.2ml/分で一晩調整すべきである。
分解産物が溶出したら、カラムは濾過したエタノールで1.0ml/分、約2時間洗浄後、平衡状態にすることができる。
カラムの例:PVAシリカカラム4.6mm×150mm、5ミクロン PV12s051546WT、またはその等価物。
この方法は、波長200nmにおけるピーク検出による、アイソクラティック順相HPLC法である。
カラム温度:35〜40℃
注入体積:20μl〜100μl
実行時間:約60分
ヘプタン:エタノール(95:5)移動相が、物質24のアッセイに採用される。
カラムを、ブランク注入ベースラインが安定になるまで、ヘプタン:エタノール(95:5)移動相を1.0ml/分で流して調整する。
新しいカラムは、0.2ml/分で一晩調整すべきである。
カラムの例:PVAシリカカラム4.6mm×150mm、5ミクロン PV12s051546WT、またはその等価物。
流速:1.0ml/分
(不純物ピーク面積(100))/(分解産物の全ピーク面積+H324/38ピーク面積(クレビジピンピーク面積))
H168/79を不純物の例とした、全ピーク面積に基づく不純物のパーセントの計算:
(H324/78ピーク面積(100))/(分解産物の全ピーク面積+H324/38ピーク面積(クレビジピンピーク面積))
Claims (10)
- 酸化に対して安定化される、静脈投与用のエマルションである医薬組成物の製造方法であって、前記医薬組成物が、
0.5 mg/mLのクレビジピンまたはその薬学的に許容される塩、
20%の大豆油、
グリセリン、
精製卵黄リン脂質、
水、および
水酸化ナトリウム
を含み、
前記製造方法が、
(a)注入用の水を、74℃〜78℃で、混合タンクに注入するステップと;
(b)注入用の水にグリセリンを加え、得られた水相を60℃〜70℃に冷却するステップと;
(c)大豆油を溶解槽に注入して、油相を作製するステップと;
(d)大豆油を混合し、および70℃〜82℃に加熱するステップと;
(e)大豆油混合物にクレビジピンまたはその薬学的に許容される塩を添加し、78℃〜82℃に加熱するステップと;
(f)クレビジピンまたはその薬学的に許容される塩と大豆油との混合物に、卵黄リン脂質を添加するステップと;
(g)水相および油相を混合してエマルションを作製するステップと;
(h)1N水酸化ナトリウムを用いて、pHを6.0〜8.8に調節するステップと;
(i)エマルションを、500〜8000psiの圧力、および50℃〜55℃の温度で均質化するステップ
とを含み、
製造中において、光曝露の量を低減することにより、前記医薬組成物の酸化分解を最小限にして、下記式:
製造方法。 - クレビジピンまたはその薬学的に許容される塩の含量とH324/78の含量との比が重量基準で500:1以上である、請求項1に記載の製造方法。
- 前記医薬組成物は、高血圧の治療または予防に使用される、請求項1〜2のいずれか1項に記載の製造方法。
- 前記不活性ガスは窒素である、請求項1〜3のいずれか1項に記載の製造方法。
- 酸化に対して安定化される、静脈投与用のエマルションである医薬組成物の製造および保存の方法であって、前記医薬組成物が、
0.5mg/mLのクレビジピンまたはその薬学的に許容される塩、
20%の大豆油、
グリセリン、
精製卵黄リン脂質、
水、および
水酸化ナトリウム
を含み、
前記方法が、
(a)注入用の水を、74℃〜78℃で、混合タンクに注入するステップと;
(b)注入用の水にグリセリンを加え、得られた水相を60℃〜70℃に冷却するステップと;
(c)大豆油を溶解槽に注入して、油相を作製するステップと;
(d)大豆油を混合し、および70℃〜82℃に加熱するステップと;
(e)大豆油混合物にクレビジピンまたはその薬学的に許容される塩を添加し、78℃〜82℃に加熱するステップと;
(f)クレビジピンまたはその薬学的に許容される塩と大豆油との混合物に、卵黄リン脂質を添加するステップと;
(g)水相および油相を混合してエマルションを作製するステップと;
(h)1N水酸化ナトリウムを用いて、pHを6.0〜8.8に調節するステップと;
(i)エマルションを、500〜8000psiの圧力、および50℃〜55℃の温度で均質化するステップ
とを含み、
製造中および保存中において、光曝露の量を低減することにより、前記医薬組成物の酸化分解を最小限にして、下記式:
方法。 - クレビジピンまたはその薬学的に許容される塩の含量とH324/78の含量との比が重量基準で500:1以上である、請求項5に記載の方法。
- 前記医薬組成物が、前記医薬組成物の光への曝露を低減するための遮光容器内に保存されることにより安定化される、請求項5または6に記載の方法。
- 前記遮光容器は二次包装によって少なくとも部分的に覆われている、請求項7に記載の方法。
- 前記医薬組成物は、高血圧の治療または予防に使用される、請求項5〜8のいずれか1項に記載の方法。
- 前記不活性ガスは窒素である、請求項5〜9のいずれか1項に記載の方法。
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