TW201737916A - 口服溶液 - Google Patents
口服溶液 Download PDFInfo
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- TW201737916A TW201737916A TW106124366A TW106124366A TW201737916A TW 201737916 A TW201737916 A TW 201737916A TW 106124366 A TW106124366 A TW 106124366A TW 106124366 A TW106124366 A TW 106124366A TW 201737916 A TW201737916 A TW 201737916A
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- acid
- solution
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- salt
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 65
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 45
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 40
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 235000014655 lactic acid Nutrition 0.000 claims abstract description 33
- 239000004310 lactic acid Substances 0.000 claims abstract description 33
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 23
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims abstract description 20
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 20
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims abstract description 19
- 239000001630 malic acid Substances 0.000 claims abstract description 19
- 235000011090 malic acid Nutrition 0.000 claims abstract description 19
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 18
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011975 tartaric acid Substances 0.000 claims abstract description 17
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 17
- 235000015165 citric acid Nutrition 0.000 claims abstract description 16
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 59
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- 235000019264 food flavour enhancer Nutrition 0.000 claims description 19
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 9
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- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 abstract 1
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- 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 9
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- HELXLJCILKEWJH-NCGAPWICSA-N rebaudioside A Chemical compound O([C@H]1[C@H](O)[C@@H](CO)O[C@H]([C@@H]1O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HELXLJCILKEWJH-NCGAPWICSA-N 0.000 description 8
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- 235000019658 bitter taste Nutrition 0.000 description 4
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 229910001220 stainless steel Inorganic materials 0.000 description 4
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- 239000004097 EU approved flavor enhancer Substances 0.000 description 3
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Abstract
本發明提供適合用於口服7-[4-(4-苯並[b]噻吩-4-基-六氫吡□-1-基)丁氧基]-1H-喹啉-2-酮(化合物(I))或其鹽之溶液。一種口服溶液,其含有化合物(I)或其鹽,及至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸,且其pH值為2.5-4.5。
Description
本發明關於適合用於口服7-[4-(4-苯並[b]噻吩-4-基-六氫吡-1-基)丁氧基]-1H-喹啉-2-酮或其鹽之溶液。
已知7-[4-(4-苯並[b]噻吩-4-基-六氫吡-1-基)丁氧基]-1H-喹啉-2-酮(以下稱為化合物(I))或其鹽具有多巴胺D2受體部分激動劑作用、血清素5-HT2A受體拮抗劑作用及腎上腺素α1受體拮抗劑作用,除了這些作用外,化合物(I)並進一步具有血清素攝取抑制作用(或血清素再攝取抑制作用)(專利文獻1),且對中樞神經系統疾病(尤其是精神分裂症)具有廣泛之治療範圍。
再者,化合物(I)或其鹽很難溶於水中並具有苦味。
專利文件1:JP-A-2006-316052
可有效用於口服之化合物(I)或其鹽的藥物溶液符合患有中樞神經系統疾病(尤其是患有精神疾病,諸如精神分裂症,等之患者),在吞嚥口服之固體作用劑上有困難之患者的特定需要。此外,口服溶液可協助醫師處理以確定患者之劑量,等。
在配製化合物(I)或其鹽之口服溶液方面,希望能將該難溶於水之藥物增溶。另外,希望能提供方便服用之較無苦味的溶液。
本發明者已進行各種研究以試圖解決上述問題,並且發現化合物(I)或其鹽之口服溶液(其中該藥物係經增溶)可藉由在其中添加至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸,並將其pH值調節至2.5-4.5來取得。此外,本發明者發現可經由在該溶液中添加甘胺酸來取得優越之緩衝能力。此外,本發明者已發現可經由在該溶液中添加至少一種風味增強劑和/或掩蔽劑來取得苦味較少之溶液,此種溶液很容易服用且提供上述效果。本發明已基於這類發現而完成。
因此,本發明關於下列各項。
[1]一種口服溶液,其包含化合物(I)或其鹽,及
至少一種選自下列群組之化合物:乳酸,磷酸,乙醇酸,蘋果酸,酒石酸,檸檬酸,琥珀酸酸及醋酸,且其pH值為2.5-4.5。
[2]如上述[1]之溶液,其進一步包含甘胺酸。
[3]如上述[1]或[2]之溶液,其中至少一種選自由乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸所組成之群組的化合物為乳酸。
[4]如上述[1]-[3]中任一項之溶液,其進一步包含至少一種風味增強劑和/或掩蔽劑。
[5]如上述[1]-[4]中任一項之溶液,其進一步包含增溶劑。
[6]一種口服溶液,其包含化合物(I)或其鹽、至少一種風味增強劑和/或掩蔽劑及至少一種自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸,且其pH值為2.5-4.5。
[7]一種口服溶液,其包含化合物(I)或其鹽、至少一種風味增強劑和/或掩蔽劑及至少一種自下列群組之化合物:乳酸、磷酸、乙醇酸及蘋果酸,且其pH值為2.5-4.5。
[8]如上述[6]或[7]之溶液,其進一步包含增溶劑。
[9]如上述[6]或[7]之溶液,其中該至少一種風味增強劑和/或掩蔽劑為甘胺酸。
此處,本發明之口服溶液為水溶液。
根據本發明可以增強化合物(I)或其鹽之溶解度,可提供含有以所需濃度溶解在溶液中之化合物(I)或其鹽的口服溶液。此外,含有甘胺酸之本發明的口服溶液具有優異之緩衝能力,即使在使用時以飲用水稀釋時其pH值的變化不大,此可防止化合物(I)或其鹽因為pH值改變而沉澱。此外,含有至少一種風味增強劑和/或掩蔽劑之本發明的口服溶液的苦味被壓抑且風味良好,容易飲用。
本發明之口服溶液含有化合物(I)或其鹽作為活性成分。化合物(I)或其鹽可藉由JP-A-2006-316052中所描述之方法,或類似的方法製造。
可用於本發明之化合物(I)的鹽類並無特殊限制,只要其為藥學上可接受之鹽。可提出者有,例如無機酸鹽類,諸如硫酸鹽、硝酸鹽、鹽酸鹽、磷酸鹽、氫溴酸鹽,等,有機酸鹽類,諸如醋酸鹽、磺酸鹽(諸如對甲苯磺酸鹽、甲磺酸鹽、乙磺酸鹽,等)、草酸鹽、馬來酸鹽、富馬酸鹽、蘋果酸鹽、酒石酸鹽、檸檬酸鹽、琥珀酸鹽、苯甲酸鹽,等。
本發明之口服溶液中的化合物(I)或其鹽的含量為化合物(I)之形式時通常為約0.01-約6毫克/毫升,較佳為約0.1-約3毫克/毫升,更佳為約0.5-約1毫克/毫
升。
本發明之口服溶液含有至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸。其中,乳酸、磷酸、乙醇酸或蘋果酸為較佳者,乳酸或磷酸為更佳者,乳酸為特佳者。
乳酸可為D-乳酸,L-乳酸,L-乳酸與D-乳酸之混合物或L-乳酸與D-乳酸之外消旋混合物。
在本發明之口服溶液中,該“至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸”的含量通常為約0.5-約200毫克/毫升,較佳為約1-約50毫克/毫升,更佳為約5-約20毫克/毫升。
由於本發明之口服溶液包含“至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸”,化合物(I)及其鹽之溶解度可被提高且可提供含有以所需濃度溶解在製劑中之化合物(I)或其鹽的口服溶液。
本發明之口服溶液的特徵在於pH值為2.5-4.5。
本發明之口服溶液的pH值較佳為2.5-4.0,更佳為3.0-3.6,特佳為3.0-3.4。
pH值在上述範圍內之本發明的口服溶液可提高化合物(I)及其鹽之溶解度,且可提供含有以所需濃度溶解在溶液中之化合物(I)或其鹽的口服溶液。
較佳地,本發明之口服溶液具有之經緩衝的pH值係
落在上述範圍內。本發明中,該用於調節pH值之方法及緩衝方法並無特別限制,且可使用藥物製劑領域中已知的方法(例如加入緩衝劑、pH值調節劑)。
例如,可經由在本發明之口服溶液中添加適量之酸(例如乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸或醋酸)及適量之鹼(尤其是氫氧化鈉)來將pH值調節至上述範圍內並緩衝。緩衝後之本發明的口服溶液可保持所欲之pH值範圍內,即使在使用時以中性、略酸或略鹼之飲料稀釋時。
本發明中,當所含有之必要組分乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸或醋酸的量能將pH值調整到上述範圍內並緩衝時,則可能不含有其他酸及當量的鹼。
較佳地,本發明之口服溶液含有甘胺酸。
本發明中,添加甘胺酸可促成緩衝能力。
根據患者之偏好,該口服溶液可在投服前以飲用水(諸如礦泉水、自來水,等)稀釋以增加量以便於飲用。在本發明之口服溶液中,化合物(I)係以pH-依賴的方式溶解,因此,當以飲用水(尤其是硬水)稀釋時,該口服溶液之pH值可能改變而使化合物(I)或其鹽沉澱。
含有甘胺酸之本發明的口服溶液具有優異之緩衝能力,因此,即使當以飲用水(尤其是硬水)稀釋時其pH值不會改變很大且保持在上述範圍內,從而可防止化合物(I)或其鹽沉澱。
本發明之口服溶液中之甘胺酸的含量通常為約0.5%-約50毫克/毫升,較佳為約1-約30毫克/毫升,更佳為約5-約20毫克/毫升。
本發明之口服溶液中,特佳為含有組合之甘胺酸及乳酸。經由組合添加甘胺酸及乳酸可提高該溶液之緩衝能力,且即使當以飲用水(尤其是硬水)稀釋該溶液時pH值不會改變很大且保持在上述範圍內,從而可防止化合物(I)或其鹽沉澱。
當本發明之口服溶液包含甘胺酸和乳酸將,甘胺酸與乳酸之重量比(甘胺酸:乳酸)通常為約1:0.1-10,較佳為約1:0.5-5,更佳為約1:0.5-2。
較佳地,本發明之口服溶液含有風味增強劑和/或掩蔽劑。
可提出之用於本發明中以作為風味增強劑和/或掩蔽劑有胺基酸(諸如丙胺酸、蘇胺酸、脯胺酸、絲胺酸,等)、天然甜味劑(諸如蔗糖、果糖、右旋糖、麥芽糖、海藻糖、葡萄糖、甜菊及甘油,等)、半合成之甜味劑(諸如乳糖醇、麥芽糖醇、木糖醇、山梨糖醇及甘露糖醇,等)、合成之甜味劑(諸如三氯蔗糖、糖精、醋磺內酯鉀及阿斯巴甜(aspartame),等)及香料(諸如櫻桃、橙、薄荷、草莓、蘋果、鳳梨、茴香果、桃、覆盆子及香橙奶油,等)。其中,三氯蔗糖及甜菊為較佳之甜味劑。在香料方面,香橙味較佳。可使用這些作用劑中之一或多種。
在本發明之口服溶液中,該風味增強劑和/或掩蔽劑
之含量通常為約0.1%-約800毫克/毫升,較佳為約0.3-約100毫克/毫升,更佳為約0.5-約20毫克/毫升。
由於甘胺酸具有甜味,其亦可作為風味增強劑和/或掩蔽劑。當本發明之口服溶液中含有甘胺酸時,從風味增強劑和/或掩蔽劑之觀點來看,該甘胺酸及其他風味增強劑和/或掩蔽劑的總含量僅需在上述之範圍內。
較佳地,本發明之口服溶液中含有增溶劑。
可提出之用於本發明中作為增溶劑者有與水混溶之溶劑(諸如乙醇、甘油、丙二醇、山梨糖醇、聚乙二醇(例如聚乙二醇400)、聚乙烯吡咯啶酮(聚維酮(povidone))及苄醇,等)、其親水-親油平衡值(HLB)不小於15之醫學上可接受的表面活性劑(諸如脂肪酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯山梨糖醇酐脂肪酸酯(例如、聚山梨酸酯80)、聚氧乙烯單烷基醚、氫化油、聚氧乙烯氫化蓖麻油(例如聚氧乙烯氫化蓖麻油60)及泊洛沙姆(poloxamer),等)、環形低聚醣(諸如α-環糊精、β-環糊精及羥丙基β環糊精(HP β CD),等),等。其中,甘油、丙二醇、聚乙二醇(例如聚乙二醇400)、聚氧乙烯山梨糖醇酐脂肪酸酯(例如聚山梨酸酯80)及HP β CD為較佳者,且甘油,丙二醇及聚乙二醇(例如聚乙二醇400)為更佳者。可使用這些增溶劑中之一或多種。
在本發明之口服溶液中,該增溶劑之含量通常為約10-約500毫克/毫升,較佳為約50-約400毫克/毫升,更佳為約100-約300毫克/毫升。
在用於本發明中以作為增溶劑方面,丙二醇與甘油之組合為特佳者。較佳地,丙二醇與甘油之重量比(丙二醇:甘油)為約1:0.1-10,更佳為約1:1-5,特佳為約1:3。
較佳地,本發明之口服溶液含有穩定劑。
可提出之用於本發明中作為穩定劑者有螯合劑(諸如乙二胺四醋酸鈉鹽(乙二胺四醋酸二鈉(EDTA-2Na)、乙二胺四醋酸四鈉(EDTA-4Na),等),酒石酸,蘋果酸及檸檬酸,等)、抗氧化劑(諸如偏亞硫酸氫鈉、亞硫酸氫鈉、沒食子酸丙酯、抗壞血酸鈉及抗壞血酸,等)。其中,EDTA-2Na為較佳者。可以使用這些穩定劑中的一或多種。由於含有穩定劑(如乙二胺四醋酸之鈉鹽,尤其是EDTA-2Na),本發明之口服溶液可取得長期保存之穩定性。
本發明之口服溶液中,穩定劑的含量通常為約0.001-約2毫克/毫升,較佳為約0.01-約1毫克/毫升,更佳為約0.05-約0.2毫克/毫升。
較佳地,本發明之口服溶液進一步含有防腐劑。
可提出之作為防腐劑者有:苯甲酸、苯甲酸鈉、對羥基苯甲酸甲酯、對羥基苯甲酸乙酯、對羥基苯甲酸丙酯、對羥基苯甲酸丁酯、苄醇、山梨酸及山梨酸鉀、對羥基苯甲酸酯、脫氫醋酸、脫氫醋酸鈉,等,其中,對羥基苯甲酸甲酯及對羥基苯甲酸丙酯是較佳者。可使用這些種類中之一或多種。
本發明之口服溶液中,防腐劑之含量通常為約0.1-約10毫克/毫升,較佳為約0.5-約2毫克/毫升。
在用於本發明中以作為防腐劑方面,對羥基苯甲酸甲酯與對羥基苯甲酸丙酯之組合為特佳者。較佳地,對羥基苯甲酸甲酯與對羥基苯甲酸丙酯之重量比(對羥基苯甲酸甲酯:對羥基苯甲酸丙酯)較佳為約1:0.01-0.5,更佳為約1:0.1-0.2,特佳為約1:0.15。
除了上述組分外,本發明之口服溶液可能包含藥物製劑領域中已知之添加劑。
本發明之口服溶液的較佳實例為含有化合物(I)或其鹽,及至少一種選自下列群組之化合物的溶液:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸,尤其是乳酸,且其pH值為2.5-4.5。
此外,在上述之口服溶液中,可提出者為進一步含有甘胺酸之口服溶液。
此外,在上述之口服溶液中,可提出者為進一步含有至少一種風味增強劑和/或掩蔽劑(例如三氯蔗糖、甜菊、香料)之口服溶液。
此外,在上述之口服溶液中,可提出者為進一步含有增溶劑(例如甘油、丙二醇、聚乙二醇、聚氧乙烯山梨糖醇酐脂肪酸酯、HP β CD、聚氧乙烯氫化蓖麻油,尤其是甘油與丙二醇之組合)之口服溶液。
此外,在上述之口服溶液中,可提出者為進一步含有防腐劑(例如對羥基苯甲酸甲酯,對羥基苯甲酸丙酯,尤
其是對羥基苯甲酸甲酯與對羥基苯甲酸丙酯之組合)和/或穩定劑(例如乙二胺四醋酸之鈉鹽(尤其是EDTA-2Na))之口服溶液。
本發明之口服溶液的製造方法並無特別限制,該溶液可藉由已知方法將上述組分混合,調節pH值,及必要時進行過濾來製造。
例如,本發明之口服溶液可藉由將溶液(a)(此係經由將可選擇地添加之增溶劑(例如甘油、聚乙二醇、丙二醇)、至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及化合物(I)或其鹽混合並溶解在水中來取得)與溶液(b)(此係經由將可選擇地添加之增溶劑(例如甘油、聚乙二醇、丙二醇)、添加劑(例如甘胺酸、風味增強劑和/或掩蔽劑(例如三氯蔗糖、甜菊、香料))、防腐劑(例如對羥基苯甲酸甲酯、對羥基苯甲酸丙酯)、可選擇地添加之穩定劑(例如EDTA-2Na)在水中混合並溶解,調整pH值並將混合物過濾來取得)混合,調節pH值,再進行過濾來製造。在混合溶液(a)與(b)後可加入添加劑(例如甘胺酸、風味增強劑和/或掩蔽劑(例如三氯蔗糖、甜菊、香料))及穩定劑(例如EDTA-2Na)並摻合之。
在上述用於製備溶液(a)的步驟中,各組分之添加順序並無特別限制。例如,將至少一種選自乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸之化合物溶解在增溶劑與水的混合物中,加入化合物(I)或其
鹽並使其溶解在該混合物中,以產生溶液(a)。或者,將化合物(I)或其鹽分散在增溶劑與水的混合物中,將至少一種選自乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸之化合物加入所取得之分散液中以溶解上述之化合物(I)或其鹽,以取得溶液(a)。
在上述用於製備溶液(b)的步驟中,各組分之添加順序並無特別限制。例如,將添加劑(例如甘胺酸、風味增強劑和/或掩蔽劑、防腐劑、穩定劑)溶解在增溶劑與水的混合物中,以取得溶液(b)。當使用對羥基苯甲酸酯(例如對羥基苯甲酸甲酯、對羥基苯甲酸丙酯)作為防腐劑時,亦可將對羥基苯甲酸酯溶解在增溶劑(例如丙二醇,等)與水的混合物中來取得溶液(b),亦可將除了對羥基苯甲酸酯外之增溶劑(例如甘油,等)及添加劑(例如甘胺酸、風味增強劑和/或掩蔽劑、除了對羥基苯甲酸酯外之防腐劑、穩定劑)溶解在水中以取得不同之溶液(b)。這些溶液(b)及溶液(a)可以被直接混合。
可令對羥基苯甲酸酯溶解在增溶劑(例如丙二醇)與水之混合物中的溫度通常為45-70℃,較佳為50-70℃。
本發明之含有化合物(I)或其鹽的口服溶液可用於治療人類患者之精神分裂症及相關疾病(例如躁鬱症及老年癡呆症)。本發明之口服溶液的每日劑量一般為0.1-6毫升(為化合物(I)之形式時為0.05-6毫克),較佳為0.5-4毫升(為化合物(I)之形式時為0.5-4毫克)。
本發明之口服溶液可直接投服或在稀釋後投服。
本發明參考實例更詳細地解釋於下文中,這些實例並不應被理解為用於限制本發明。
在實例中,7-[4-(4-苯並[b]噻吩-4-基-六氫吡-1-基)丁氧基]-1H-喹啉-2-酮被描述為化合物(I)。
(1)將聚乙二醇400與一部分(20-30%)純水混合,並一邊攪拌一邊將DL-乳酸溶解於其中。將化合物(I)添加在此溶液中,並藉由攪拌溶解之。
(2)將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯加入丙二醇與一部分(10-20%)純水的混合物中,混合並溶解之,同時將溫度保持在45-55℃。將容器的溫度降至40-50℃,加入乙二胺四醋酸二鈉、三氯蔗糖、甜菊及甘胺酸,混合並溶解之,再將溶液冷卻至25-30℃並一邊攪拌之。
(3)將上述溶液(2)加入上述溶液(1)並一邊攪拌,以將其混合。進一步加入香料,並混合之。
(4)將1N氫氧化鈉水溶液加入上述溶液(3)中以將pH值調節至3.0-3.2,並以純水稀釋至最終濃度。以不銹鋼篩過濾該混合物以產生具有表1之組成的口服水溶液。
(1)將聚乙二醇400與一部分(20-30%)純水混合,加入化合物(I),並藉由攪拌分散之。一邊攪拌一邊將DL-乳酸加入此溶液中以溶解化合物(I)。
(2)將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯加入丙二醇與一部分(10-20%)純水的混合物中,混合並溶解之,同時將溫度保持在50-70℃。一邊攪拌一邊將溶液
冷卻至25-30℃。
(3)將乙二胺四醋酸二鈉、三氯蔗糖、甜菊及甘胺酸與一部分(10-20%)純水混合並溶解之。
(4)一邊攪拌,一邊將上述溶液(1)及上述溶液(2)加入上述溶液(3)中,以將其混合。進一步加入香料並混合之。
(5)將1N氫氧化鈉水溶液加入上述溶液(4)中以將pH值調節至3.0-3.2,並以純水稀釋至最終濃度。以不銹鋼篩過濾該混合物以產生具有表1之組成的口服水溶液。
以同於實施例1中之方式,但將化合物(I)之添加量減少一半來取得化合物(I)之口服水溶液(0.5毫克/毫升)。
(1)將甘油與一部分(20-30%)純水混合,並一邊攪拌一邊將DL-乳酸溶解於其中。將化合物(I)添加在此溶液中,並藉由攪拌溶解之。
(2)將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯加入丙二醇與一部分(10-20%)純水的混合物中,混合並溶解之,同時將溫度保持在45-55℃。將容器的溫度降至40-50℃,加入乙二胺四醋酸二鈉、三氯蔗糖、甜菊及甘
胺酸,混合並溶解之,再一邊攪拌一邊將溶液冷卻至25-30℃。
(3)一邊攪拌一邊將上述溶液(2)加入上述溶液(1),將其混合。進一步加入香料並混合之。
(4)將1N氫氧化鈉水溶液加入上述溶液(3)中以將pH值調節至3.0-3.2,並以純水稀釋至最終濃度。以不銹鋼篩過濾該混合物以產生具有表2之組成的口服水溶液。
(1)將約一半量之丙二醇與一部分(20-30%)純水混合,加入化合物(I),並藉由攪拌分散之。一邊攪拌一邊將DL-乳酸加入此溶液中以溶解化合物(I)。
(2)將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯加入剩餘之丙二醇與一部分(10-20%)純水的混合物中,混合並溶解之,同時將溫度保持在50-70℃。一邊攪拌一邊將溶液冷卻至25-30℃。
(3)將甘油、乙二胺四醋酸二鈉、三氯蔗糖及甘胺酸加入一部分(10-20%)純水中,並將該混合物溶解。
(4)一邊攪拌,一邊將上述溶液(1)及上述溶液(2)加入上述溶液(3)中以將其混合。進一步加入香料並混合之。
(5)將1N氫氧化鈉水溶液加入上述溶液(4)中以將pH值調節至3.0-3.2,並以純水稀釋至最終濃度。以不銹鋼篩過濾該混合物以產生具有表2之組成的口服水溶液。
以同於實施例3中之方式,但將化合物(I)之添加量減少一半來取得化合物(I)之口服水溶液(0.5毫克/毫升)。
藉由類似於實例1-4之方法製造具有表3-6之組成的實例5-8之口服水溶液。
藉由以下試驗檢查當以飲用水稀釋口服溶液時pH值的變化。
藉由下列方法製造具有表7之組成的實例9-12之溶液。
(1)將甘油與一部分(20-30%)純水混合,一邊攪拌一邊加入化合物(I)並分散之。一邊攪拌一邊將DL-乳酸加入此溶液中以溶解化合物(I)。
(2)將對羥基苯甲酸甲酯及對羥基苯甲酸丙酯加入丙二醇與一部分(10-20%)純水的混合物中,混合並溶解之,同時將溫度保持在50-70℃。一邊攪拌一邊將溶液冷卻至25-30℃。
(3)一邊攪拌一邊將上述溶液(2)加入上述溶液(1)中,將剩餘之添加劑與一部分純水加入其中,藉由攪拌使該混合物溶解。
(4)依需要將1N氫氧化鈉水溶液或磷酸加入上述溶液(3)中以將pH值調節至3.0-3.2,並以純水稀釋至最終濃度。
依上述之相同方式,但未添加化合物(I)來製造具有表7之組成的溶液。
以飲用水(Crystal Geyser(硬度38毫克/升,軟水,由Crystal Geyser水公司生產;進口商和銷售商:大塚食
品有限公司)、Evian(硬度304毫克/升,硬水,由Danone製造;進口商和銷售商:ITO EN有限公司)、Contrex(硬度1468毫克/升,硬水,由雀巢集團製造;進口商和銷售商:Suntoryfoods有限公司)及自來水)和大塚蒸餾水(由大塚製藥廠製造)將對照實例及實例中所得之溶液稀釋50倍並測量稀釋之前和之後的pH值變化。
在稀釋方面,精確地測量對照實例及實例之溶液(4毫升),並使用移液管將其放置在50毫升量筒中,再以各飲用水精確地調整至50毫升。使用稀釋之樣本作為pH測量樣本。
表8中顯示稀釋前之對照實例及實例之溶液的pH值、各飲用水之pH值及稀釋樣本之pH值。
在具有相同之乳酸含量且含有甘胺酸之實例9與具有相同之乳酸含量且不具有甘胺酸之實例10之間比較以每一種飲用水稀釋後的pH值。結果,與實例10相比較,實例9以任何飲用水稀釋後之pH值變化均較溫和,由此表明其緩衝能力增強。在具有相同之乳酸含量且含有甘胺酸之實例11與具有相同之乳酸含量且不具有甘胺酸之實例12之間比較以每一種飲用水稀釋後的pH值。結果,與實例12相比較,實例11以任何飲用水稀釋後之pH值變化均較溫和,由此表明其緩衝能力增強。
上述結果證明添加甘胺酸可增強緩衝能力。
根據本發明可提供適合口服化合物(I)或其鹽之溶液。
本申請案係以美國臨時申請案編號61/548,859為基礎,其內容全部納入本文中。
Claims (9)
- 一種口服溶液,其包含7-[4-(4-苯並[b]噻吩-4-基-六氫吡-1-基)丁氧基]-1H-喹啉-2-酮或其鹽,及至少一種選自下列群組之化合物:乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸,且其pH值為2.5-4.5。
- 如申請專利範圍第1項之溶液,其進一步包含甘胺酸。
- 如申請專利範圍第1或2項之溶液,其中至少一種選自由乳酸、磷酸、乙醇酸、蘋果酸、酒石酸、檸檬酸、琥珀酸及醋酸所組成之群組的化合物為乳酸。
- 如申請專利範圍第1或2項之溶液,其進一步包含至少一種風味增強劑和/或掩蔽劑。
- 如申請專利範圍第3項之溶液,其進一步包含至少一種風味增強劑和/或掩蔽劑。
- 如申請專利範圍第1或2項之溶液,其進一步包含增溶劑。
- 如申請專利範圍第3項之溶液,其進一步包含增溶劑。
- 如申請專利範圍第4項之溶液,其進一步包含增溶劑。
- 如申請專利範圍第5項之溶液,其進一步包含增溶劑。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1420077A (en) * | 1972-04-14 | 1976-01-07 | Unilever Ltd | Process for imparting or enhancing fresh cheese flavour in a food digital transmission systems |
MY129350A (en) * | 2001-04-25 | 2007-03-30 | Bristol Myers Squibb Co | Aripiprazole oral solution |
JP4584706B2 (ja) * | 2002-05-03 | 2010-11-24 | イスラエル インスティチュート フォー バイオロジカル リサーチ | 中枢及び末梢神経系障害を治療するための方法及び組成物、並びにそれらに有用な新規の化合物 |
CA2564180A1 (en) * | 2004-04-22 | 2005-11-03 | Dainippon Sumitomo Pharma Co., Ltd. | Pharmaceutical preparation containing bacterial cell wall skeleton component |
TWI320783B (en) * | 2005-04-14 | 2010-02-21 | Otsuka Pharma Co Ltd | Heterocyclic compound |
JP4315393B2 (ja) | 2005-04-14 | 2009-08-19 | 大塚製薬株式会社 | 複素環化合物 |
WO2006134864A1 (ja) * | 2005-06-13 | 2006-12-21 | Dainippon Sumitomo Pharma Co., Ltd. | 可溶化型製剤 |
WO2007027565A2 (en) * | 2005-09-01 | 2007-03-08 | Baxter International Inc. | Argatroban formulation comprising an acid as solubilizer |
US20100004267A1 (en) * | 2006-07-31 | 2010-01-07 | Asubio Pharma Co., Ltd. | Liquid preparation |
EP2200584A2 (en) * | 2007-09-17 | 2010-06-30 | Schering Corporation | Formulation containing cyclin-dependent kinase inhibiting compound and method of treating tumors using the same |
CA2700263A1 (en) | 2007-09-21 | 2009-03-26 | Forest Laboratories Holdings Limited | Soluble dosage forms containing cephem derivatives suitable for parenteral administration |
US8263652B2 (en) * | 2007-10-31 | 2012-09-11 | Sk Biopharmaceuticals Co., Ltd. | Stabilized pediatric suspension of carisbamate |
ES2685469T3 (es) * | 2010-08-24 | 2018-10-09 | Otsuka Pharmaceutical Co., Ltd. | Suspensión y composición de torta que contienen derivado de carboestirilo y aceite de silicona y/o derivado de aceite de silicona |
CN102119922A (zh) * | 2011-03-03 | 2011-07-13 | 天津市炜杰科技有限公司 | 以酸作为增溶剂的21(s)阿加曲班静脉注射液 |
AR085840A1 (es) * | 2011-04-05 | 2013-10-30 | Otsuka Pharma Co Ltd | Medicamento que contiene un compuesto que es 7-[4-(4-benzo[b]tiofen-4-il-piperazin-1-il)butoxi]-1h-quinolin-2-ona |
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