CN102006860A - 含全甲基化环糊精的药物组合物 - Google Patents
含全甲基化环糊精的药物组合物 Download PDFInfo
- Publication number
- CN102006860A CN102006860A CN2009801128584A CN200980112858A CN102006860A CN 102006860 A CN102006860 A CN 102006860A CN 2009801128584 A CN2009801128584 A CN 2009801128584A CN 200980112858 A CN200980112858 A CN 200980112858A CN 102006860 A CN102006860 A CN 102006860A
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- China
- Prior art keywords
- pharmaceutical composition
- active substances
- cyclodextrin
- pharmaceutically active
- described pharmaceutical
- Prior art date
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 239000013543 active substance Substances 0.000 claims description 53
- 239000000203 mixture Substances 0.000 claims description 27
- 229920000858 Cyclodextrin Polymers 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 229960003793 midazolam Drugs 0.000 claims description 19
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 claims description 19
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 17
- 229960004134 propofol Drugs 0.000 claims description 13
- 208000019901 Anxiety disease Diseases 0.000 claims description 10
- 230000036506 anxiety Effects 0.000 claims description 10
- 229940049706 benzodiazepine Drugs 0.000 claims description 10
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 8
- 238000010253 intravenous injection Methods 0.000 claims description 7
- 230000003444 anaesthetic effect Effects 0.000 claims description 6
- 229960002640 nordazepam Drugs 0.000 claims description 6
- AKPLHCDWDRPJGD-UHFFFAOYSA-N nordazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 AKPLHCDWDRPJGD-UHFFFAOYSA-N 0.000 claims description 6
- UMSGKTJDUHERQW-UHFFFAOYSA-N Brotizolam Chemical compound C1=2C=C(Br)SC=2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl UMSGKTJDUHERQW-UHFFFAOYSA-N 0.000 claims description 4
- WYCLKVQLVUQKNZ-UHFFFAOYSA-N Halazepam Chemical compound N=1CC(=O)N(CC(F)(F)F)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 WYCLKVQLVUQKNZ-UHFFFAOYSA-N 0.000 claims description 4
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N Medazepam Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 claims description 4
- MWQCHHACWWAQLJ-UHFFFAOYSA-N Prazepam Chemical compound O=C1CN=C(C=2C=CC=CC=2)C2=CC(Cl)=CC=C2N1CC1CC1 MWQCHHACWWAQLJ-UHFFFAOYSA-N 0.000 claims description 4
- IKMPWMZBZSAONZ-UHFFFAOYSA-N Quazepam Chemical compound FC1=CC=CC=C1C1=NCC(=S)N(CC(F)(F)F)C2=CC=C(Cl)C=C12 IKMPWMZBZSAONZ-UHFFFAOYSA-N 0.000 claims description 4
- SEQDDYPDSLOBDC-UHFFFAOYSA-N Temazepam Chemical compound N=1C(O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 SEQDDYPDSLOBDC-UHFFFAOYSA-N 0.000 claims description 4
- 229960004538 alprazolam Drugs 0.000 claims description 4
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 claims description 4
- 229960003051 brotizolam Drugs 0.000 claims description 4
- 229960004782 chlordiazepoxide Drugs 0.000 claims description 4
- ANTSCNMPPGJYLG-UHFFFAOYSA-N chlordiazepoxide Chemical compound O=N=1CC(NC)=NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 ANTSCNMPPGJYLG-UHFFFAOYSA-N 0.000 claims description 4
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 claims description 4
- 229960003120 clonazepam Drugs 0.000 claims description 4
- GGRWZBVSUZZMKS-UHFFFAOYSA-N demoxepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C[N+]([O-])=C1C1=CC=CC=C1 GGRWZBVSUZZMKS-UHFFFAOYSA-N 0.000 claims description 4
- 229950010734 demoxepam Drugs 0.000 claims description 4
- 229960003529 diazepam Drugs 0.000 claims description 4
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 4
- 229960004381 flumazenil Drugs 0.000 claims description 4
- OFBIFZUFASYYRE-UHFFFAOYSA-N flumazenil Chemical compound C1N(C)C(=O)C2=CC(F)=CC=C2N2C=NC(C(=O)OCC)=C21 OFBIFZUFASYYRE-UHFFFAOYSA-N 0.000 claims description 4
- 229960003528 flurazepam Drugs 0.000 claims description 4
- SAADBVWGJQAEFS-UHFFFAOYSA-N flurazepam Chemical compound N=1CC(=O)N(CCN(CC)CC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1F SAADBVWGJQAEFS-UHFFFAOYSA-N 0.000 claims description 4
- 229960002158 halazepam Drugs 0.000 claims description 4
- 229960003019 loprazolam Drugs 0.000 claims description 4
- UTEFBSAVJNEPTR-RGEXLXHISA-N loprazolam Chemical compound C1CN(C)CCN1\C=C/1C(=O)N2C3=CC=C([N+]([O-])=O)C=C3C(C=3C(=CC=CC=3)Cl)=NCC2=N\1 UTEFBSAVJNEPTR-RGEXLXHISA-N 0.000 claims description 4
- 229960002225 medazepam Drugs 0.000 claims description 4
- 229960001454 nitrazepam Drugs 0.000 claims description 4
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 claims description 4
- 229960004535 oxazepam Drugs 0.000 claims description 4
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 claims description 4
- 229960004856 prazepam Drugs 0.000 claims description 4
- 229960001964 quazepam Drugs 0.000 claims description 4
- 229960003188 temazepam Drugs 0.000 claims description 4
- 229960003386 triazolam Drugs 0.000 claims description 4
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 claims description 4
- DIWRORZWFLOCLC-HNNXBMFYSA-N (3s)-7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound N([C@H](C(NC1=CC=C(Cl)C=C11)=O)O)=C1C1=CC=CC=C1Cl DIWRORZWFLOCLC-HNNXBMFYSA-N 0.000 claims description 3
- -1 Midazepam Chemical compound 0.000 claims description 3
- 238000010668 complexation reaction Methods 0.000 claims description 3
- 229960004391 lorazepam Drugs 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- WFMXPQMXLSHZAR-UHFFFAOYSA-O [Cl].[N+](=O)([O-])[O-].[NH4+] Chemical compound [Cl].[N+](=O)([O-])[O-].[NH4+] WFMXPQMXLSHZAR-UHFFFAOYSA-O 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229960001403 clobazam Drugs 0.000 claims description 2
- CXOXHMZGEKVPMT-UHFFFAOYSA-N clobazam Chemical compound O=C1CC(=O)N(C)C2=CC=C(Cl)C=C2N1C1=CC=CC=C1 CXOXHMZGEKVPMT-UHFFFAOYSA-N 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- 230000000968 intestinal effect Effects 0.000 claims description 2
- 239000008177 pharmaceutical agent Substances 0.000 abstract 3
- 230000009471 action Effects 0.000 description 14
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- 206010002091 Anaesthesia Diseases 0.000 description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
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- 239000000839 emulsion Substances 0.000 description 8
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 210000004877 mucosa Anatomy 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
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- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
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- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 2
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- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
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- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
本发明涉及一种用于药物活性物质给药的药物组合物。依据本发明，所述药物组合物包含：a)一种药学活性物质，其含有芳香基团或芳香部分，分子的大小不超过2nm；b)一种全甲基化的环糊精，其取代度为每个吡喃葡萄糖单元的3个甲基；全甲基化的环糊精和药学活性物质形成复合物。
Description
技术领域
本发明涉及一种药物组合物，如用于术前抗焦虑或麻醉的组合物。
背景技术
将药学活性物质制成制剂后，通过一定的给药形式使其能到达拟定的作用位置获得期望的浓度和可能的效果，这是药学上常见的问题。所以为了血液中能达到预定的全身浓度，用于静脉注射的拟定的活性物质在某种程度上必须是水溶的。另一方面为了能达到作用部位或透过细胞膜，活性物质原则上应有一定的亲脂性。例如一种具有良好水溶性的活性物质静脉注射后血液中能达到高的全身浓度，然而由于活性物质的低亲脂性，但却表现为差的生物利用度，这可能是由于在拟定的作用位置它不能透过细胞膜造成的。
对于一定的给药形式，如透粘膜给药，若药学活性物质透过粘膜速度太慢或滞后，活性物质不能达到或过慢达到足够的全身浓度，其生物利用度可能会受影响。这个问题会通过所称的术前抗焦虑为例在下面说明。
病人在麻醉前或术前通常会给予术前用药。主要的目的是通过所谓的术前抗焦虑减少或避免精神压力。依据有关调查病人术前的心理状况对手术中的循环系统状态和术后止痛剂需求有很大的影响。不足的术前抗焦虑会引起诸如过高的胃酸分泌，在麻醉时被吸入。这可能会危及生命的。
依据现有技术抗焦虑通常采用苯并二氮杂卓类药物。
手术当日的术前用药，原则上在麻醉开始前45到60分钟口服可快速分布的苯并二氮杂卓，特别是咪达唑仑。
口服使用的生物利用度是非常不一样的，因此很难计算。不能排除可能达不到抗焦虑的剂量不正确的情况。
此外口服给药时获得必要的足够的血浆浓度的分布时间45至60min和医院的时间安排要求是不可协调的。为使手术设施高负载运行，一般是在术前15分钟通知病人进行准备，这么短的准备时间内通过口服苯并二氮杂卓是不能达到有效的术前抗焦虑。
WO-A-01/30391建议将咪达唑仑Midazolam和β-环糊精配制成一种透粘膜给药的溶液制剂。
发明内容
因此本发明的目的是获得前面提及的一种类型的药物组合物，它能够提供一种安全可靠的活性物质给药形式，具有足够可靠和可预测的作用特性。
本发明包括：
a)一种药学活性物质，其含有芳香基团或芳香部分，分子的大小不超过2nm；b)一种全甲基化的环糊精，其取代度为每个吡喃葡萄糖单元的3个甲基；所述全甲基化的环糊精和药学活性物质形成复合物。
现有技术(WO-A-01/30391)已建议采用环糊精作为助剂，将药学活性物质复合，应能在水溶液中稳定或溶解，提高膜穿透性。
本发明已知特定环糊精的惊奇特点，即一种取代度为每个吡喃葡萄糖单元3个甲基的全甲基化的环糊精，一方面在水溶液中具有良好的稳定性并可复合亲脂性药学活性物质，另一方面可使活性物质易于透膜。
环糊精通常为环形，含有相应的环形孔穴。本发明使用的全甲基化的环糊精具有一系列的优点特性，一方面可与权利要求1中定义的药学活性物质形成复合物，另一方面可使药学活性物质在作用部位的靶向释放更加准确。由于全甲基化环糊精不再含有OH基团，这使得疏水的药学活性物质(芳香基团或芳香部分)可进入到环糊精的孔穴中形成复合物。在未全甲基化情况下，由于环糊精上残余的羟基使得孔穴的入口或周边仍是亲水的，这样不容易复合疏水药学活性物质。
此外本发明还发现未全甲基化残余的羟基，在水溶液中由于氢键作用会导致不希望的环糊精分子的凝聚和聚集。使用全甲基化环糊精能避免这点。
依据本发明，用于复合的药学活性物质(客体分子)的分子大小最大不超过2nm或更小，并含有芳香基团或芳香部分。这意味着客体分子的至少一部分具有芳香化特征的电子离域。客体分子因此具有疏水性和进入环糊精孔穴的合适大小。客体分子优选无末端亲水基团，更优选无末端羟基。
依据本发明，一种水溶性的或在水溶液中稳定的，不凝聚/不聚集的复合物会形成，该复合物能快速可靠地将药学活性物质传送至作用部位。对于全甲基化环糊精惊奇的改善性能的可能解释是，全甲基化环糊精亲脂性提高，这使它易于和膜相互作用以及使环糊精复合的活性物质的吸收变得容易。
本发明使用的环糊精的高亲脂性体现为高的LogP值，LogP值为相应物质在溶剂体系辛烷醇/水中的分配系数。根据本发明，该LogP值优选最小为5，更优选最小为7。全甲基化β-环糊精的LogP值为9。
环糊精含六个(α-环糊精)，七个(β-环糊精)或八个(γ-环糊精)吡喃葡萄糖单元。每个吡喃葡萄糖单元含三个羟基。一定条件下羟基能被甲基取代。全甲基化环糊精为完全取代，取代度为3。
环糊精中优选β-环糊精。
本发明使用的环糊精具有孔状外表和疏水孔穴内部(空腔)，它优选和亲脂性药学活性物质复合，使其能在水相中溶解。在药理作用部位复合物中的活性物质释放(可能是通过环糊精和膜的“对接”)，使得膜通过变得容易。
药物在目标细胞中的吸收通常是被动的，因为通常无转运系统通过细胞膜。药物通过生物膜的被动扩散通量是由药物的亲脂性和膜处的浓度梯度所决定的。然而，这两者通常是相反的。高的亲脂性(在作用部位被动通过细胞膜的能力较高)通常意味着差的水溶性，由于相应的药物在细胞膜外的水相中溶解较少，以致在作为屏障的膜处不能形成大的浓度梯度。
本发明的药物组合物是将环糊精和优选的亲脂性药学活性物质复合，形成易溶于水的复合物，可在膜处达到更高的浓度。一旦转运到膜处，活性物质以一种方式明显释放，其亲脂性在跨膜时起主导作用。本发明的组合物由于它的水溶性能在膜屏障处形成高的浓度梯度，同时药学活性物质的亲脂性可以提高通过膜屏障的透过速度。现有技术中在药学作用部位对通过细胞膜的透过速率起相反作用的两个因素在本发明里表现为令人意外的协同作用。
环糊精和药学活性物质形成复合物适宜的络合常数K值介于10至70l/Mol之间，优选15至65l/Mol，更优选20至55l/Mol，最优选30至40l/Mol。这个范围内的络合常数确保了水性体系中复合物足够的稳定性，且药学活性物质能够在拟定作用部位释放。
本发明组合物的pH值优选为4至7，特别优选5.5至6.5。这一值对应着粘膜的pH值，因此如果透粘膜给药可不产生刺激或其它的不好的副作用。
本发明的组合物可包含各种药学活性物质。首选logP值至少为3的药学活性物质。这表示此活性物质在辛烷醇/水中平衡分配的十进制对数值至少为3。这对应着药学活性物质的亲脂性高低。依本发明可适用的药学活性物质logP值可更高，如所提到的亲脂性物质，例如氟烷halothane的logP值约为200。
全甲基化β-环糊精有可结合药学活性物质的孔穴，孔穴直径为0.6-0.65nm，高度为约2nm，适合接受药学活性物质。因此优选适合孔穴大小的活性物质。
如前所述，本发明的组合物适用于提高药学活性物质在拟定作用部位的生物利用度。在这种作用方式中，组合物的复合物通过一作用方式到达药学作用部位(例如通过血液循环系统)，活性物质从复合物中释放并通过细胞膜。环糊精本身不能通过细胞膜。
本发明的另一方面表明，使用本发明的组合物不仅仅是为了能确保通过血液循环系统转运到作用部位的活性物质的生物利用度(借助环糊精)，还是为了在特定给药方式下能确保获得足够的和在一时间域内足够的可预见的全身浓度。依据本发明这点，组合物里的复合物不但在作用部位释放活性物质，还改善了活性物质透过粘膜的性能，如透粘膜给药，于是可快速和可预测地达到确定的全身浓度。依据本发明这点，在透过粘膜时，活性物质已从环糊精复合物中释放。
本发明的组合物也适用于配制透粘膜给药制剂。
透粘膜给药的药物组合物是将一种药学活性物质(可能多种药学活性物质)与助剂配制成制剂，使药物能全部或主要部分透过粘膜(特别是鼻粘膜和/或口腔粘膜)，被全身吸收。透粘膜给药的优点在于，可快速，可靠和更容易地计量药学活性物质的全身分布，因为相应的血清浓度不会受胃肠道的特殊性和不可测性影响(首过效应为肠吸收后的肝代谢)。本发明组合物特别适合于制成经鼻，舌内，肠或口腔前庭(orovestibulare)给药制剂。本组合物也能提高肠吸收。
药学活性物质特别优选苯并二氮杂卓，可从包括如下物质的组中选取，如阿普唑仑Alprazolam，溴替唑仑Brotizolam，氯氮卓Chlordiazepoxid，氯巴扎姆Clobazam，氯硝西泮Clonazepam，氯硝安Clorazepam，去甲氧安定地莫西泮Demoxazepam，氟马西尼Flumazenil，氟西泮Flurazepam，哈拉西泮Halazepam，咪达唑仑Midazolam，去甲西泮Nordazepam，美达西泮Medazepam，地西泮Diazepam，硝西泮Nitrazepam，奥沙西泮Oxazepam，Midazepam，劳拉西泮Lorayepam，普拉西泮Prazepam，夸西泮Quazepam，三唑仑triazolam，替马西泮Temazepam和氯普唑仑Loprazolam。苯并二氮杂卓中的咪达唑仑为特别优选。
组合物中的苯并二氮杂卓的量在优选剂型里用量为0.5％-2％(重量百分比)，特别优选为1％(重量百分比)。组合物优选为水溶液。
此外本发明使用取代度为每个吡喃葡萄糖单元3个甲基的全甲基化环糊精制备药物复合物，例如用于透粘膜给药。此外依本发明制备的药物用于术前抗焦虑为优选。
另据本发明，应用本发明的组合物是为了难溶于水的活性物质能以静脉注射方式使用。丙泊酚的实例会加以说明。
1977年首先在临床中试用丙泊酚作为静脉注射麻醉药物。使用此麻醉药物的脂肪乳液(商品名Diprivan)可减少经常观察到的静脉注射时伴随的疼痛，因此1989年丙泊酚被引入临床中使用。
所述丙泊酚脂肪乳液含大豆油，甘油，蛋磷脂。注射时的血管疼痛一直是一常见问题，其甚至可能会引起严重的过敏反应。由于脂肪乳液作为制剂有利于微生物生长，所以短时间存放后的乳液污染会在给药后引起败血症。依本发明，具有上述定义的甲基化度的环糊精和丙泊酚复合成一种药学活性物没有所提及的缺点。
如实验部分所述的，依本发明制备的丙泊酚制剂与现有技术的脂肪乳液相比，只需低的等效剂量用量。由于不使用脂肪乳液中的助剂，也就不存在微生物污染引起败血症的上述问题。
附图说明
图1依赖于给药方式和给药形式的咪达唑仑血清浓度时间变化平均值高斯曲线拟合图(n＝5/组)。
具体实施方式
本发明的具体实施例描述如下。附图为咪达唑仑的本发明实施例剂型和比较例剂型的血清浓度变化。
实施例1
透粘膜给药的咪达唑仑组合物。
透粘膜给药的1％咪达唑仑组合物如下配制
咪达唑仑 10mg
全甲基化β-环糊精(甲基化度3) 150mg
Hypromellose 400(羟丙甲纤维素) 1mg
浓磷酸 2.6mg
NaOH 10％： 适量，调节pH值为4.2
山梨酸钾 1.4mg
水加至 1ml
Hypromellose 400是一种羟丙甲基纤维素，分子量约为400，作为粘膜润湿剂。制备的溶液pH值调为4.2。本实施例中环糊精和药学活性物质的质量比为15∶1，本发明的环糊精和药学活性物质的质量比优选为50∶1至10∶1，更优选40∶1至12∶1，进一步优选20∶1至12∶1。
一组五个试验者，每人给予0.75ml所述溶液(含7.5mg咪达唑仑)透粘膜给药。
为了与现有技术比较，另三组，每组五个试验者给予同样剂量7.5mg咪达唑仑，以下述方式给药。
比较例1：羟丙基-β-环糊精取代本发明实施例中的全甲基化β-环糊精
比较例2：7.5mg咪达唑仑溶于覆盆子汁口服
比较例3：7.5mg咪达唑仑片剂口服
比较例1中除了环糊精被替换外，其余与实施例1的配方完全一样。
图1中列出相应咪达唑仑给药后时间与血清浓度平均值的关系，从附图可看出本发明的组合物具有最快的分布并达到最高血清浓度和最长持续作用。
开头已提到在医院里一般是在术前15分钟传呼病人进行准备，因此抗焦虑术前给药仅存在这个时间窗，无把握给予快速起效的苯并二氮杂卓如咪达唑仑，这使得无法知道实际上什么时候该实施手术。
附图还显示本发明的组合物在15分钟后已达到了名义血清浓度，已有抗焦虑效果。现有技术中的制剂(包括使用β-羟丙基环糊精作为复合剂的透粘膜制剂)都是在15分钟后才开始有血清分布。在实践中，这意味着现有技术的抗焦虑术前给药在15分钟后并没起作用，所以没达到用药的目的。
实施例2
静脉注射异丙酚组合物
两种1％的异丙酚制剂供使用。一种是现有技术的制剂，商业名为Diprivan的脂肪乳液，乳液基质由大豆油，甘油，蛋磷脂组成，乳液基质中含有1％的异丙酚。
本发明配方：
异丙酚 10mg
全甲基化β-环糊精 80.2mg
浓磷酸 2.mg
NaOH 10％： 适量，调节pH值为6.8
水加至 1ml
下面称本配方为CD-Prppofol(CD异丙酚)。
十二只体重在48至53kg间的歌廷根迷你猪中的每一只被随机地用Diprivan和CD-Prppofol(CD异丙酚)进行麻醉。通过外周静脉导管进行注射。
麻醉深度通过麻醉深度监护仪CSM(cerebral state monitoring)和相应的麻醉深度指数CSI(cerebral state index)进行监控。所期望的麻醉深度的CSI值设为40至60。此外还通过心电图(ECG)，脉搏血氧仪(测定血氧饱和度(SaO2 value))和二氧化碳侦测仪(检测二氧化碳分压(pCO2 value))监控麻醉深度。
获得上述麻醉深度的等效剂量，本发明制剂的剂量为87.5±12.5mg，现有技术的制剂(Diprivan)的剂量为225±12.5mg。
本发明的制剂表现了快速的导入分布和导出性能。注射本发明的组合物1分钟后即起作用，而现有技术的制剂2分钟才后起作用。本发明的制剂的麻醉作用在19分钟后结束，而现有技术的制剂的麻醉作用在25.5分钟结束。与现有技术的组合物相比，本发明的组合物不会产生乳液化(Emulyse)。
Claims (13)
1.一种用于药学活性物质给药的药物组合物，其特征在于，所述药物组合物包括：a)一种药学活性物质，其含有芳香基团或芳香部分，分子的大小不超过2nm；b)一种全甲基化的环糊精，其取代度为每个吡喃葡萄糖单元的3个甲基；所述全甲基化的环糊精和药学活性物质形成复合物。
2.如权利要求1中所述的药物组合物，其特征在于，所述环糊精为一种β-环糊精。
3.如权利要求1或2中所述的药物组合物，其特征在于，所述的组合物pH值为4至7，优选为5.5至6.5。
4.如权利要求1~3中任一所述的药物组合物，其特征在于，所述环糊精和药学活性物质形成的复合物的络合常数K值介于10至70l/M，优选为15至65l/M，更优选为20至55l/M，更进一步优选为30至40l/M。
5.如权利要求1~4中任一所述的药物组合物，其特征在于，所述药学活性物质的logP值至少为3。
6.如权利要求1~5中任一所述的药物组合物，其特征在于，所述药物组合物被制成用于透粘膜给药制剂。
7.如权利要求6中所述的药物组合物，其特征在于，所述药物组合物被制成经鼻，舌内，肠或口腔前庭给药制剂。
8.如权利要求1~7中任一所述的药物组合物，其特征在于，所述药学活性物质包括苯并二氮杂卓。
9.如权利要求8中所述的药物组合物，其特征在于，所述苯并二氮杂卓从下组选择：阿普唑仑Alprazolam，溴替唑仑Brotizolam，氯氮卓Chlordiazepoxid，氯巴扎姆Clobazam，氯硝西泮Clonazepam，氯硝安Clorazepam，去甲氧安定地莫西泮Demoxazepam，氟马西尼Flumazenil，氟西泮Flurazepam，哈拉西泮Halazepam，咪达唑仑Midazolam，去甲西泮Nordazepam，美达西泮Medazepam，地西泮Diazepam，硝西泮Nitrazepam，奥沙西泮Oxazepam，Midazepam，劳拉西泮Lorazepam，普拉西泮Prazepam，夸西泮Quazepam，三唑仑triazolam，替马西泮Temazepam和氯普唑仑Loprazolam。
10.如权利要求8或9中任一所述的药物组合物，其特征在于，所述苯并二氮杂卓的重量百分比为0.5％至2％。
11.如权利要求1~5中任一所述的药物组合物，其特征在于，所述药物组合物是一种静脉注射用的麻醉药物制剂。
12.如权利要求11所述的药物组合物，其特征在于，所述药物组合物含有丙泊酚。
13.如权利要求1~12中任一所述的药物组合物用于制备一种静脉注射用的术前抗焦虑或麻醉药物。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08006866.1 | 2008-04-04 | ||
| EP08006866A EP2106786A1 (de) | 2008-04-04 | 2008-04-04 | Pharmazeutische Zubereitung mit permethyliertem Cyclodextrin |
| PCT/EP2009/002381 WO2009121585A1 (de) | 2008-04-04 | 2009-04-01 | Pharmazeutische zubereitung mit permethyliertem cyclodextrin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102006860A true CN102006860A (zh) | 2011-04-06 |
| CN102006860B CN102006860B (zh) | 2012-12-19 |
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| CN2009801128584A Active CN102006860B (zh) | 2008-04-04 | 2009-04-01 | 含全甲基化环糊精的药物组合物 |
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| Country | Link |
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| US (1) | US8980882B2 (zh) |
| EP (2) | EP2106786A1 (zh) |
| JP (1) | JP5635490B2 (zh) |
| KR (1) | KR101516846B1 (zh) |
| CN (1) | CN102006860B (zh) |
| CA (1) | CA2720480C (zh) |
| DK (1) | DK2299973T3 (zh) |
| WO (1) | WO2009121585A1 (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107080736A (zh) * | 2017-03-22 | 2017-08-22 | 山东信谊制药有限公司 | 一种劳拉西泮片的制备方法 |
| CN111330019A (zh) * | 2018-12-18 | 2020-06-26 | 中国人民解放军第二军医大学 | 氟马西尼包合物及其制备方法和应用 |
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| EP1579862A1 (en) | 2004-03-25 | 2005-09-28 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the reduction of heart size in mammals suffering from heart failure |
| US8980894B2 (en) | 2004-03-25 | 2015-03-17 | Boehringer Ingelheim Vetmedica Gmbh | Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure |
| EP1920785A1 (en) | 2006-11-07 | 2008-05-14 | Boehringer Ingelheim Vetmedica Gmbh | Liquid preparation comprising a complex of pimobendan and cyclodextrin |
| EP2484350B1 (de) * | 2011-02-04 | 2016-04-20 | Roewer, Norbert, Univ.-Prof. Dr. med. | Pharmazeutische Zubereitung, enthaltend einen Komplex eines Propofolsalzes mit einem Cyclodextrin |
| HUE060093T2 (hu) | 2012-03-15 | 2023-01-28 | Boehringer Ingelheim Vetmedica Gmbh | Gyógyszerészeti tablettakészítmény az állatgyógyászati ágazat számára, eljárás annak elõállítására és annak alkalmazása |
| EP2919791B1 (de) | 2012-11-15 | 2017-03-22 | SapioTec GmbH | Delphinidinkomplex als antiphlogistischer oder immunsuppressiver wirkstoff |
| US9511047B2 (en) | 2012-12-11 | 2016-12-06 | Sapiotec Gmbh | Delphinidin for combating melanoma cells |
| EP3021832B9 (en) | 2013-07-19 | 2023-03-15 | Boehringer Ingelheim Vetmedica GmbH | Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition |
| EP3106150B1 (en) | 2013-12-04 | 2021-07-28 | Boehringer Ingelheim Vetmedica GmbH | Improved pharmaceutical compositions of pimobendan |
| US10537570B2 (en) | 2016-04-06 | 2020-01-21 | Boehringer Ingelheim Vetmedica Gmbh | Use of pimobendan for the reduction of heart size and/or the delay of onset of clinical symptoms in patients with asymptomatic heart failure due to mitral valve disease |
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| JPS5946228A (ja) * | 1982-09-08 | 1984-03-15 | Zeria Shinyaku Kogyo Kk | 生物学的に活性な有機化合物の水溶性及びリンパ移行性薬剤の製造方法 |
| HU199444B (en) * | 1985-09-10 | 1990-02-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing 7-isopropoxy-isoflavone-cyclodextrene inclusion complex and pharmaceutical compositions therefrom |
| HUP9701945A3 (en) * | 1997-11-10 | 2000-04-28 | Hexal Ag | Pharmaceutical composition for injection containing cyclodextrin and taxoids |
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| AU759280C (en) * | 1998-02-23 | 2004-01-22 | Cyclops, Ehf | High-energy cyclodextrin complexes |
| US6699849B1 (en) * | 1998-02-23 | 2004-03-02 | Cyclops, Ehf. | Cyclodextrin complexes of benzodiazepines |
| CA2381846A1 (en) * | 1999-08-11 | 2001-02-15 | Josef Pitha | Potentiation of inclusion complex formation of cyclodextrin derivatives |
| AU7937500A (en) | 1999-10-27 | 2001-05-08 | Farmarc Nederland Bv | Pharmaceutical composition containing midazolam |
| US20030113367A1 (en) * | 2000-03-28 | 2003-06-19 | Penkler Lawrence John | Alprazolam inclusion complexes and pharmaceutical compositions thereof |
| DE10064219B9 (de) * | 2000-12-22 | 2009-02-12 | Nasalis Pain Relief International Gmbh | Neue Fentanyl und/oder dessen Derivate enthaltende pharmazeutische Zusammensetzung zur nasalen Anwendung |
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| MXPA04007328A (es) * | 2002-02-01 | 2005-07-05 | Shimoda Biotech Pty Ltd | Composicion farmaceutica. |
| CA2520522C (en) * | 2003-03-28 | 2012-05-29 | Ivax Corporation | Cladribine formulations for improved oral and transmucosal delivery |
| EP1704858A4 (en) * | 2004-01-14 | 2008-06-04 | Otsuka Pharma Co Ltd | PROPOFOL-CONTAINING FAT-EMULSION PREPARATION |
| DE102005017775A1 (de) * | 2005-04-13 | 2006-10-19 | Schering Ag | Komplexe aus Vitamin D-Verbindungen oder deren Analoga mit einem 5Z,7E,10(19)-Trien-System und methlierten Derivaten des ß-Cyclodextrins |
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- 2008-04-04 EP EP08006866A patent/EP2106786A1/de not_active Withdrawn
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- 2009-04-01 CA CA2720480A patent/CA2720480C/en active Active
- 2009-04-01 JP JP2011502290A patent/JP5635490B2/ja active Active
- 2009-04-01 KR KR1020107024701A patent/KR101516846B1/ko active IP Right Grant
- 2009-04-01 DK DK09728128.1T patent/DK2299973T3/da active
- 2009-04-01 CN CN2009801128584A patent/CN102006860B/zh active Active
- 2009-04-01 EP EP09728128.1A patent/EP2299973B1/de active Active
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107080736A (zh) * | 2017-03-22 | 2017-08-22 | 山东信谊制药有限公司 | 一种劳拉西泮片的制备方法 |
| CN111330019A (zh) * | 2018-12-18 | 2020-06-26 | 中国人民解放军第二军医大学 | 氟马西尼包合物及其制备方法和应用 |
| CN111330019B (zh) * | 2018-12-18 | 2022-03-15 | 中国人民解放军第二军医大学 | 氟马西尼包合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101516846B1 (ko) | 2015-05-07 |
| WO2009121585A1 (de) | 2009-10-08 |
| EP2106786A1 (de) | 2009-10-07 |
| US20110028457A1 (en) | 2011-02-03 |
| CA2720480A1 (en) | 2009-10-08 |
| CN102006860B (zh) | 2012-12-19 |
| KR20110020763A (ko) | 2011-03-03 |
| EP2299973B1 (de) | 2017-02-15 |
| CA2720480C (en) | 2015-07-21 |
| DK2299973T3 (da) | 2017-05-22 |
| JP2011516441A (ja) | 2011-05-26 |
| EP2299973A1 (de) | 2011-03-30 |
| US8980882B2 (en) | 2015-03-17 |
| JP5635490B2 (ja) | 2014-12-03 |
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