CN1160122C - 一种制备口服胰岛素油相制剂的方法 - Google Patents
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Abstract
本发明属于生物药物的制备领域，涉及一种制备口服胰岛素油相制剂的方法。包括将一定量的胰岛素溶解在酸性水相缓冲溶液中(A)，再加入到亲水亲油平衡值为10≤HLB＜20的液态的非离子型表面活性剂溶液中，进行搅拌均匀混合成为溶液(B)；再加入到亲水亲油平衡值为0＜HLB＜10的液态的亲油性乳化剂中搅拌混合，成为油相制剂；本发明具有制备工艺简单，所需成本低等特点，并在口服时，能比较好的抵抗胃肠道酶的降解作用，容易吸收，发挥更好的降糖药效。
Description
技术领域 本发明属于生物药物的制备技术领域，特别涉及制备口服多肽蛋白质药物制剂的新工艺。
背景技术 许多生物药物，如胰岛素、人生长激素、降钙素、溶栓酶等都是以注射的途径给药。特别是有的药物，如胰岛素需要每天注射，多者一天要注射3-4次，给病人造成极大的痛苦与不便，因此将其制成口服制剂便成为人们追求的目标。如果在此方面有所突破，将会产生巨大的社会和经济效益，据美国《New Scientists》报估计，其年经济效益可达60亿美元。但直接将这些生物药物口服，由于胃肠道内酶的降解消化及肠道的吸收屏障，使其利用度很低，小于0.5％，为此有人将胰岛素用脂质体包裹起来，以抵抗酶的降解作用，但由于其吸收性差，大大影响了口服时的药效；也有人将胰岛素用α-氰基丙烯酸酯做成微囊，希望胰岛素包在疏水的囊腔中。实验证明，胰岛素并不在微囊的囊腔，而是分布在微囊的表面。尽管这种微囊在一定程度上具有抗酶水解的作用，但由于动物的个体差异使得其重复性较差，还不能作为真正的药物制剂应用。还有的研究者将胰岛素溶解在疏水溶剂中或油相中，制成口服制剂。但总的来说制备工艺都比较复杂。如英国专利(专利号：WO 95/13795，WO 97/34581)中在把胰岛素溶入油相制剂中时，要采用旋转蒸发，喷雾干燥，或者在低于零下40℃的冷凝器温度及小于0.1毫巴的真空下冷冻干燥两夜等方法去除亲水性溶剂，这一方面限制了生产的规模，另一方面也增大了成本。
发明内容 本发明的目的是为克服已有技术的不足之处，提出一种制备口服胰岛素油相制剂的方法，具有制备工艺简单，容易实现，所需成本低等优点，采用本发明制备的口服胰岛素油相制剂在口服时，能比较好的抵抗胃肠道酶的降解作用，且容易吸收，发挥更好的降糖药效。
本发明提出的一种制备口服胰岛素油相制剂的方法，其特征在于，包括以下步骤：
(1)将一定量的胰岛素溶解在水相缓冲溶液中，该溶液(A)的PH值为3-5，胰岛素的含量为0.01-0.5克/毫升；
(2)将上述含胰岛素的酸性溶液(A)加入到亲水亲油平衡值(HLB：Hydrophile-Lipophile Balance)为10≤HLB＜20的液态的非离子型表面活性剂或表面活性混合液中；所述溶液(A)与这些表面活性剂或他们的混合液的的比例为1∶5至1∶50；该两种溶液在温度5-30℃下进行搅拌，使其均匀的混合在一起，成为一种透明的溶液(B)；
(3)将溶液(B)加入到亲水亲油平衡值为0＜HLB＜10的液态亲油性乳化剂或其混合液中，溶液(B)与其的比例为1∶1至1∶10，使该两种溶液在温度5-30℃下搅拌混合，最终成为一种透明的油相制剂(C)，在4～10℃下保存；
(4)为了保持溶液的稳定，加入一定量的抗氧化剂，若抗氧化剂为脂溶性的，可直接加入所述的第三步骤中的溶液中；若抗氧化剂为水溶性的，可在所述的制备第一步骤溶液中加入。
所述的第二步骤中的表面活性剂可为：十甘油单油酸酯(HLB＝12.9)、六甘油单月桂酸酯(HLB＝13.5)、十甘油单辛酸酯(HLB＝16)、聚乙二醇-8-甘油辛酸/癸酸酯(HLB＝14)、聚甘油-6-二油酸酯(HLB＝10)、吐温80(HLB＝15.4)
所述第二步的搅拌速度可为200-2000转/分，搅拌时间可为0.5-5小时。
所说的第三步骤中的亲油性乳化剂可为：三甘油辛酸/癸酸酯(HLB＝1)、甘油辛酸/癸酸酯(HLB＝3)、甘油油酸酯(HLB＝3)、甘油亚油酸酯(HLB＝3)、聚甘油-3-油酸酯(HLB＝6)、聚乙二醇-6-甘油单油酸酯(HLB＝4)、聚乙二醇-6-甘油亚油酸酯(HLB＝4)、司盘80(HLB＝4.3)、聚乙二醇4-甘油辛酸/癸酸脂(HLB＝5)。
所说的第三步的搅拌温度可为5-30℃，搅拌速度可为200～2000转/分，搅拌时间可为0.5～5小时。
所说的抗氧化剂的加入量可为最终溶液的0.01％～0.1％；所说的抗氧化剂可为VE，VC，半胱氨酸，没食子酸酯，叔丁基对苯二酚。
所说的油相制剂可以直接用来口服，也可以将其装入胶囊中，制成液体的胶囊制剂(此胶囊可为软胶囊，也可以为液体硬胶囊)。也可以与一些固体的赋形剂混合。如淀粉，糊精，乙基纤维素，单硬脂酸酯等，制成固体片剂或固体颗粒胶囊制剂口服。
本发明还可用于其它多肽蛋白质药物的油相制剂的制作。
本发明所述方法具有制备工艺简单，容易实现，所需成本低等特点，该方法采用毒性小，口服安全的分散剂及油相等材料，使胰岛素均匀的分散溶解到油相中，最终成为一种透明的胰岛素油相制剂。采用该方法制成的油相制剂体外实验表明，它在不同的pH(2-11)溶液中，都能发生乳化作用，并且胰岛素基本上仍然包裹在油中而不进入水相。因此在口服时，能比较好的抵抗胃肠道酶的降解作用，且容易吸收，发挥更好的降糖药效。
附图说明
图1为糖尿病大鼠口服本发明所制备的胰岛素油相制剂后的降糖效应曲线图。
具体实施方式
实施例1：
1.在5ml pH＝4的溶液中加入胰岛素0.5g，使其溶解(溶液A)；
2.取吐温80 2ml，十甘油单辛酸酯23ml，混合均匀，然后将溶液A加入混合，搅拌均匀。搅拌速度：800转/分；时间：2小时；温度：20℃(溶液B)；
3.取甘油油酸酯70ml，将上述B溶液加入混合成100ml。搅拌速度：800转/分；时间：3小时；温度：20℃(C溶液)；
4.在C溶液中加入没食子酸丙酯60μl，混合均匀，存放于冰箱中冷藏。
实施例2：
1.在5ml pH＝4的溶液中加入1g胰岛素，50mg Vc使其溶解(A溶液)；
2.取聚乙二醇-8-甘油辛酸/癸酸酯40ml，将A溶液加入混合成45ml左右。搅拌速度：1500转/分；时间：2小时；温度：24℃(B溶液)；
3.取聚甘油3油酸酯27.5 ml，聚乙二醇-6-甘油单油酸脂27.5ml，混合成55ml溶液，然后将B溶液与该混合液在下列条件下混合，搅拌速度：1500转/分；时间：2小时；温度：24℃(C溶液)，存放于冰箱中冷藏。
实施例3：
1.在4ml pH＝4的溶液中加入0.8g胰岛素，使其溶解(A溶液)；
2.取聚乙二醇-8-甘油辛酸/癸酸酯20ml，将A溶液加入搅拌混合成24ml。搅拌速度：500转/分；时间：2.5小时；温度：18℃(B溶液)；
3.取聚甘油-3-油酸酯76ml，将B溶液加入搅拌混合成100ml，500转/分；时间：3小时；温度：18℃(C溶液)；
4.在C溶液加入80μl VE并混合均匀，存放于冰箱中冷藏。
上述实施例的方法制备的口服胰岛素油相制剂经过动物实验：糖尿病大鼠(n＝10)口服(25IU/Kg体重)后的降糖效应如图1所示。
Claims (6)
1、一种制备口服胰岛素油相制剂的方法，其特征在于，包括以下步骤：
1)将一定量的胰岛素溶解在水相缓冲溶液中，该溶液(A)的PH值为3-5，胰岛素的含量为0.01-0.5克/毫升；
2)将上述含胰岛素的酸性溶液(A)加入到亲水亲油平衡值为10≤HLB＜20的液态的非离子型表面活性剂或其混合液中；所述溶液(A)与这些表面活性剂他们的混合液的比例可为1∶5至1∶50；该两种溶液在温度5-30℃下进行搅拌，使其均匀的混合在一起，成为一种透明的溶液(B)；
3)将溶液(B)加入到亲水亲油平衡值为0＜HLB＜10的液态的亲油性乳化剂或其混合液中，使溶液(B)与其的比例为1∶1至1∶10，该两种溶液在5-30℃下搅拌混合，最终成为一种透明的油相制剂(C)，在4～10℃下保存；
4)为了保持溶液的稳定，加入一定量的抗氧化剂，若抗氧化剂为脂溶性的，可直接加入到所述的第三步骤中的溶液中；若抗氧化剂为水溶性的，可在所述的制备第一步骤溶液中加入。
2、如权利要求1所述的方法，其特征在于，所述的第二步骤中的表面活性剂可为：十甘油单油酸酯、六甘油单月桂酸酯、十甘油单辛酸酯、聚乙二醇-8-甘油辛酸/癸酸酯、聚甘油-6-二油酸酯、吐温80。
3、如权利要求1所述的方法，其特征在于，所述第二步的搅拌速度可为200～2000转/分，搅拌时间可为0.5-5小时。
4、如权利要求1所述的方法，其特征在于，所说的第3步骤中的亲油性乳化剂可为：三甘油辛酸/癸酸酯、甘油辛酸/癸酸酯、甘油油酸酯、甘油亚油酸酯、聚甘油-3-油酸酯、聚乙二醇-6-甘油单油酸酯、聚乙二醇-6-甘油亚油酸酯、司盘80、聚乙二醇4-甘油辛酸/癸酸脂。
5、如权利要求1所述的方法，其特征在于，所说的第三步的搅拌温度可为5-30℃，搅拌速度可为200～2000转/分，搅拌时间可为0.5～5小时。
6、如权利要求1所述的方法，其特征在于，所说的抗氧化剂的加入量可为0.01％～0.1％；所说的抗氧化剂可为VE，VC，半胱氨酸，没食子酸酯，叔丁基对苯二酚。
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| CNB01115327XA CN1160122C (zh) | 2001-04-20 | 2001-04-20 | 一种制备口服胰岛素油相制剂的方法 |
| PCT/CN2002/000258 WO2002085408A1 (fr) | 2001-04-20 | 2002-04-12 | Procede de production d'une preparation a base d'huile contenant de l'insuline pour administration orale |
| US10/474,474 US7018980B2 (en) | 2001-04-20 | 2002-04-12 | Method for preparation of orally administrated insulin formulation |
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| CNB01115327XA CN1160122C (zh) | 2001-04-20 | 2001-04-20 | 一种制备口服胰岛素油相制剂的方法 |
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Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE10114178A1 (de) | 2001-03-23 | 2002-10-10 | Aventis Pharma Gmbh | Zinkfreie und zinkarme Insulinzubereitungen mit verbesserter Stabilität |
| DE10227232A1 (de) * | 2002-06-18 | 2004-01-15 | Aventis Pharma Deutschland Gmbh | Saure Insulinzubereitungen mit verbesserter Stabilität |
| CA2873524C (en) | 2006-05-04 | 2018-02-20 | Boehringer Ingelheim International Gmbh | A polymeric form of 1-((4-methyl-quinazolin-2-yl)methyl)-3-7-(2-butyn-1-yl)-8-(3-(r)-aminopiperidin-1-yl)xanthine |
| PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
| WO2008015099A2 (en) | 2006-07-31 | 2008-02-07 | Novo Nordisk A/S | Pegylated, extended insulins |
| EP1891935A1 (de) * | 2006-08-14 | 2008-02-27 | Cognis IP Management GmbH | Emulsionskonzentrat |
| DK2074141T3 (en) * | 2006-09-22 | 2016-11-28 | Novo Nordisk As | The protease resistant insulin analogues. |
| WO2008132224A2 (en) * | 2007-04-30 | 2008-11-06 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
| EP2164458A1 (en) * | 2007-06-01 | 2010-03-24 | Novo Nordisk A/S | Stable non-aqueous pharmaceutical compositions |
| WO2008145728A1 (en) * | 2007-06-01 | 2008-12-04 | Novo Nordisk A/S | Spontaneously dispersible preconcentrates including a peptide drug in a solid or semisolid carrier |
| US9260502B2 (en) * | 2008-03-14 | 2016-02-16 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| PL2910570T3 (pl) | 2008-03-18 | 2017-06-30 | Novo Nordisk A/S | Stabilizowane względem proteaz, acylowane analogi insuliny |
| JP5395160B2 (ja) | 2008-03-26 | 2014-01-22 | オラムド エルティーディー． | タンパク質の経口投与方法及び組成物 |
| BRPI0908292B1 (pt) | 2008-05-05 | 2022-09-20 | Oramed Ltd | Métodos e composições para administração oral de exenatida |
| US20200155558A1 (en) | 2018-11-20 | 2020-05-21 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral antidiabetic drug |
| KR101820024B1 (ko) | 2008-10-17 | 2018-01-18 | 사노피-아벤티스 도이칠란트 게엠베하 | 인슐린과 ｇｌｐ－1 효능제의 병용물 |
| WO2010113177A2 (en) | 2009-03-31 | 2010-10-07 | Reliance Life Sciences Pvt. Ltd. | Oral insulin delivery systems for controlling diabetes |
| TW201105346A (en) * | 2009-07-06 | 2011-02-16 | Sanofi Aventis Deutschland | Heat-stable and vibration-stable insulin preparations |
| EP2477644A1 (en) * | 2009-09-16 | 2012-07-25 | Novo Nordisk A/S | Stable non-aqueous liquid pharmaceutical compositions comprising an insulin |
| ES2667069T3 (es) | 2009-11-13 | 2018-05-09 | Sanofi-Aventis Deutschland Gmbh | Composición farmacéutica que comprende desPro36exendina-4(1-39)-Lys6-NH2 y metionina |
| TR201809460T4 (tr) | 2009-11-13 | 2018-07-23 | Sanofi Aventis Deutschland | Bir GLP- 1-agonisti, bir insülin ve metiyonin içeren farmasötik bileşim. |
| JP5908847B2 (ja) | 2010-01-12 | 2016-04-26 | ノヴォ ノルディスク アー／エス | インスリンペプチドを経口投与するための医薬組成物 |
| AU2010360116B2 (en) | 2010-08-30 | 2014-06-26 | Sanofi-Aventis Deutschland Gmbh | Use of AVE0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2 |
| CN102397535B (zh) * | 2010-09-15 | 2013-08-28 | 中国科学院生物物理研究所 | 胰岛素结晶微球、其混悬剂、以及制备方法 |
| AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
| WO2012090124A2 (en) | 2010-12-29 | 2012-07-05 | Ecolab Usa Inc. | IN SITU GENERATION OF PEROXYCARBOXYLIC ACIDS AT ALKALINE pH, AND METHODS OF USE THEREOF |
| CN102125520A (zh) * | 2011-02-24 | 2011-07-20 | 美迪思生物科技(北京)有限公司 | 含亲水性生物大分子的乳剂、其制备方法及用途 |
| US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
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| EP2800579B1 (en) | 2012-01-03 | 2017-08-30 | Oramed Ltd. | Capsules containing oil-based liquid compositions of combined therapeutic agents for treating diabetes |
| DK4082530T5 (da) | 2012-02-01 | 2024-07-22 | Oramed Ltd | Proteasehæmmerholdige sammensætninger, sammensætninger omfattende samme og fremgangsmåder til fremstilling og anvendelse af samme |
| CA2870313A1 (en) | 2012-04-11 | 2013-10-17 | Novo Nordisk A/S | Insulin formulations |
| CN103861090B (zh) * | 2012-12-18 | 2017-06-13 | 美迪思生物科技(北京)有限公司 | 含蛋白或多肽的疏水溶液、其制备方法及用途 |
| EP2941267B1 (en) | 2013-01-03 | 2022-11-16 | Oramed Ltd. | Compositions for use in treating nafld |
| JP6499184B2 (ja) | 2013-10-07 | 2019-04-10 | ノヴォ ノルディスク アー／エス | インスリン類似体の新規な誘導体 |
| EP2946788A1 (en) | 2014-05-23 | 2015-11-25 | Immundiagnostik AG | Method and composition for treating heart failure with preserved ejection fraction |
| CN107205928B (zh) * | 2014-11-04 | 2021-05-11 | 因华生技制药股份有限公司 | 不稳定或难溶药物的口服投予 |
| US9950039B2 (en) | 2014-12-12 | 2018-04-24 | Sanofi-Aventis Deutschland Gmbh | Insulin glargine/lixisenatide fixed ratio formulation |
| US9845290B2 (en) | 2014-12-18 | 2017-12-19 | Ecolab Usa Inc. | Methods for forming peroxyformic acid and uses thereof |
| KR102701093B1 (ko) | 2014-12-18 | 2024-08-29 | 에코랍 유에스에이 인코퍼레이티드 | 다가 알콜 폼에이트를 통한 퍼옥시폼산의 생성 |
| US11040902B2 (en) | 2014-12-18 | 2021-06-22 | Ecolab Usa Inc. | Use of percarboxylic acids for scale prevention in treatment systems |
| TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患治療 |
| TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患之治療 |
| BR112019011761A2 (pt) | 2016-12-16 | 2019-11-05 | Novo Nordisk As | composições farmacêuticas contendo insulina |
| WO2019241635A1 (en) | 2018-06-15 | 2019-12-19 | Ecolab Usa Inc. | On site generated performic acid compositions for teat treatment |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH08502492A (ja) * | 1992-10-16 | 1996-03-19 | スミスクライン・ビーチャム・コーポレイション | 治療用ミクロエマルジョン |
| GB9323588D0 (en) * | 1993-11-16 | 1994-01-05 | Cortecs Ltd | Hydrophobic preparation |
| US5824638A (en) * | 1995-05-22 | 1998-10-20 | Shire Laboratories, Inc. | Oral insulin delivery |
| GB9613858D0 (en) | 1996-07-02 | 1996-09-04 | Cortecs Ltd | Hydrophobic preparations |
| CN1224360A (zh) * | 1996-07-02 | 1999-07-28 | 科特克斯(英国)有限公司 | 包含中链单酸甘油酯的疏水性制剂 |
| CN1141974C (zh) * | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
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- 2001-04-20 CN CNB01115327XA patent/CN1160122C/zh not_active Expired - Lifetime
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- 2002-04-12 WO PCT/CN2002/000258 patent/WO2002085408A1/zh not_active Application Discontinuation
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| US7018980B2 (en) | 2006-03-28 |
| WO2002085408A1 (fr) | 2002-10-31 |
| CN1318416A (zh) | 2001-10-24 |
| US20040097410A1 (en) | 2004-05-20 |
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