CN102791282A - 可口服给予的含有胰岛素的药物制剂 - Google Patents
可口服给予的含有胰岛素的药物制剂 Download PDFInfo
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- CN102791282A CN102791282A CN201080038764XA CN201080038764A CN102791282A CN 102791282 A CN102791282 A CN 102791282A CN 201080038764X A CN201080038764X A CN 201080038764XA CN 201080038764 A CN201080038764 A CN 201080038764A CN 102791282 A CN102791282 A CN 102791282A
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Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A—HUMAN NECESSITIES
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Abstract
本发明的主题是可口服给予的药物制剂，其含有生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物，蛋白酶抑制剂和高分子量(天然)蛋白质的组合。本发明也涉及用于制备药物制剂的方法。本发明的主题也包括药物制剂的用途和用于在哺乳动物中治疗糖尿病的方法。
Description
本发明的主题是可口服给予的药物制剂，所述制剂含有如下物质的组合：生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物，蛋白酶抑制剂和高分子量(天然)蛋白质。本发明也涉及用于制备药物制剂的方法。本发明的主题也包括药物制剂的用途和在哺乳动物中用于治疗糖尿病的方法。
在可口服给予的胰岛素制剂的发展中，2个基本问题需要解决：抑制天然肽的胰岛素的降解，和使其通过肠屏障。
根据文献，已有很多发展可口服给予的含有胰岛素的药物制剂的尝试。实质上，这些制剂彼此不同的是：它们含有除胰岛素外的不同物质，以抑制酶促失活，进而促进胰岛素的吸收和再吸收。
第EP1454631号文件描述了在水悬浮液中含有治疗有效量的胰岛素和晶体右旋糖酐微粒的药物制剂。该制剂提供了可以是单相或多相的胰岛素的控释。
第US1993005970号文件公开了含有共价连接至寡聚物的胰岛素的药物制剂。
在第WO0033866号国际公开文本中公开的药物制剂包含在非水性亲水介质中的胰岛素，所述胰岛素与长链PEG物质混合，以悬浮液的形式存在。
第WO9636352号国际公开文本描述了一种适宜口服或经鼻给予的胰岛素制剂，所述制剂含有至少两种促进吸收的化合物，所述化合物例如水杨酸钠、月桂基硫酸钠、油酸、亚油酸、卵磷脂(lecitin)等。
美国专利第US5438040号的主题是可口服给予的含有缀合胰岛素络合物的药物制剂，其中胰岛素共价键合于生理兼容的聚亚烷基二醇衍生物，所述制剂是稳定的和水溶性的，并且同时在消化***中不降解。
在日本专利申请第JP54028807号中公开的制剂包含作为添加剂的粘蛋白和胰岛素酶抑制剂。
描述于国际公开文本第WO0166085号的药物制剂包含胰岛素、碱金属(C8至C22烷基)硫酸盐、作为溶剂的水或乙醇、酚类化合物、抗氧化剂和蛋白酶抑制剂-所述抑制剂例如杆菌肽或其衍生物、大豆胰蛋白酶或抑肽酶。
国际公开文本第WO9310767号提供了在胃肠道中酶促失活的任何肽类活性成分口服施用的问题的解决方法。就胰岛素而言，通过将胰岛素掺入明胶基质实现该目的。明胶使得活性成分在小肠和大肠中被吸收以至于其不长时间暴露于肽酶的降解作用。
在第EP0127535号文件中公开的药物制剂包含胰岛素、胆酸和蛋白酶抑制剂。胆酸促进吸收，蛋白酶抑制剂防止胰岛素被蛋白酶解。口服给予的制剂快速通过胃，并在肠中被释放和快速吸收。
欧洲专利申请第EP0351651号公开了适于口服和含服给药的制剂，除胰岛素外，所述制剂包含作为促进吸收的物质的聚氧化亚乙基二醇-羧酸-甘油酯，和载体物质。
在美国专利第US3172814号中公开的制剂包含胰岛素和脱水-甲醛苯胺，以防止胰岛素作用的减弱。
根据国际公开文本第WO2007121318号的制剂包含胰岛素和作为载体物质的4-CNAB的钠盐，将其共同冻干，然后将所得粉末做成片剂或填充进明胶胶囊。
根据国际公开文本第WO9843615号，使用可膨胀的水凝胶基质，所述基质是甲基丙烯酸和聚亚烷基二醇的共聚物，可使胰岛素仅当其到达小肠时释放。在肠道中聚合物也抑制蛋白水解酶的活性，并帮助胰岛素在吸收之前长时间保持活性。
目前已知的制剂通常由如下事实来表征：胰岛素的生物利用度低，仅仅少量从胃肠道吸收，降解迅速，不能影响血糖水平。
本发明的目的是发展含有胰岛素的可口服给予的药物制剂，所述制剂比目前已知的那些生物利用度更好。
通过组合胰岛素、抑制蛋白酶的物质和高分子量天然蛋白质实现所设定的目的。重要的是抑制蛋白酶的物质和蛋白质均应该具有肠用载体，以使其均可以通过肠壁，并且采用适当的载体分子也可以使天然肽的胰岛素通过肠壁。
本发明涉及可口服给予的药物制剂，所述制剂含有生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物、蛋白酶抑制剂和高分子量(天然)蛋白质的组合。
人胰岛素是在位点B28具有Asp、Lys、Leu、Val或Ala，且在位点B29具有Lys或Pro的类似物；或des(B28-B30)，des(B27)或des(B30)人胰岛素。
根据本发明的优选实施方案，蛋白酶抑制剂是ε-氨基-己酸，高分子量天然蛋白质是酪蛋白。
根据本发明的药物制剂包含40-100IU的人重组胰岛素、100-1000mg的ε-氨基-己酸和1-100mg的酪蛋白，和药学上可接受的载体和添加剂物质。
根据本发明的药物制剂可以在哺乳动物中用于(1型和2型)糖尿病的治疗。
根据本发明的药物制剂也可以方便地用于妊娠中的糖尿病的治疗。
本发明也涉及治疗有效量的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物、ε-氨基-己酸和酪蛋白的组合用于制备适用于在哺乳动物中治疗(1型和2型)糖尿病的可口服给予的药物制剂的用途。
本发明的主题也包含用于制备可口服给予的药物制剂的方法，根据该方法将40-100IU的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物、100-1000mg的ε-氨基-己酸和1-100mg的酪蛋白与药学上可接受的载体和添加剂物质混合，并配制成可口服给予的剂型。
可口服给予的药物制剂可以是胶囊、片剂或膜包衣片剂。
本发明也涉及在哺乳动物中用于治疗(1型和2型)糖尿病的方法，根据该方法，给予患者可口服给予的药物制剂，所述制剂含有治疗有效量的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物、ε-氨基-己酸和酪蛋白。更确切地说，给予患者含有40-100IU人重组胰岛素、100-1000mg的ε-氨基-己酸和1-100mg酪蛋白的药物制剂。
根据本发明的药物制剂由超过30％的生物利用度来表征。
通过图1-3更详细地描述我们的发明，测定结果如实施例所示。
图1：在含有α-糜蛋白酶(1.5μg/10μl)的溶液中在等量的胰岛素/ε-氨基-己酸(氨基己酸，Sigma，MO)存在下的胰岛素(100μM；天然的)的稳定性。
图2：在链脲霉素(50mg/kg静脉内(i.v.))诱导的糖尿病中，口服单剂量的胰岛素(10IU/kg)对血糖水平的作用。与皮下注射胰岛素(10IU/kg)相比。＊与对照相比的显著性差异(p＜0.05)。每组n＝8。缩略语：insac1(口服胰岛素，采用1mg/kg的ε-氨基-己酸；insac10：口服胰岛素，采用10mg/kg的ε-氨基-己酸；insac100：口服胰岛素，采用100mg/kg的ε-氨基-己酸；ins s.c：皮下注射胰岛素。
图3：口服单剂量的胰岛素(10IU/kg)在链脲霉素(50mg/kg静脉内注射(i.v.))诱导的糖尿病中对血浆胰岛素免疫反应性的作用。与皮下注射胰岛素(10IU/kg)相比。＊与对照相比的显著性差异。(p＜0.05)。每组n＝8。
图1的数据显示，在120分钟之后，60％的配制的胰岛素未受损，而大于80％的天然胰岛素已降解。
图2和3的数据证明配制的口服胰岛素提高血浆胰岛素水平，并在胰岛素缺乏性糖尿病中有效减少血糖水平。以试验为基础，采用相同的标准胰岛素(10IU/kg)，与10mg/kg相比，含量为100mg/kg的ε-氨基-己酸不具有优势。皮下注射胰岛素的“60分钟”值可能已降低血浆浓度值。
实施例：
实施例1：通过ε-氨基-己酸载体分子使用口服胰岛素的可能性
将雄性Wistar大鼠(Charles-River实验室，布达佩斯，匈牙利)用于试验。在试验之前，将动物断食16个小时。试验在早晨8点至9点间开始。以随机方式形成2x6组，每组4只动物。通过饲喂探针根据下列方案对动物进行预处理：第1组：采用1g/kg的ε-氨基-己酸；第2组：采用0.1U/kg的胰岛素；第3组：采用0.1U/kg的胰岛素和1g/kg的ε-氨基-己酸；第4组：采用1.0U/kg的胰岛素；第5组：采用1.0U/kg的胰岛素和1g/kg的ε-氨基-己酸；以及第6组：采用溶剂。在第一次6组处理15分钟之后和第二次6组处理60分钟之后，取动脉血测定血糖和血浆胰岛素水平。所得结果总结于表1：
表1
15分钟的值
60分钟的值
实施例2：采用标准酪蛋白的氨基己酸对胰岛素的吸收的作用。
将ε-氨基-己酸-人重组胰岛素混合物与标准酪蛋白经十二指肠给予健康雄性Wistar大鼠(230-250g)。测量终点是采用葡萄糖氧化酶法测得的血糖，在给予胰岛素-氨基己酸制剂(水性悬浮液)15和60分钟之后，采用放射免疫测定法测量血浆胰岛素免疫反应性。
试验结果如表2所示：
数据：平均值±S.D.，每组n＝8。统计：在ANOVA之后用Bonferroni校正进行t检验。
表2
实施例3：“体外”稳定性
体外稳定性意指，在蛋白降解酶的存在下，与天然的胰岛素相比，胰岛素-氨基己酸混合物的原始制剂的生物降解(反向HPLC测定的结果)。
实施例4：在实验性糖尿病中的生物利用度和有效性
在Sprague-Dawley雄性大鼠(230-250g)中用静脉内单剂量的链脲霉素导致实验性糖尿病。在10天之后，采用禁食(在断食12小时之后)血糖水平比15mmol/1更高的动物继续试验。口服或胃肠外(s.c.)给予动物胰岛素(10IU/kg)，然后测量血糖水平(在表2中的数据)和血浆胰岛素免疫反应性(在表3中的数据)。
在降低血糖的作用方面，根据本发明的药物制剂与皮下给予胰岛素几乎等效，其适于降低异常的高血糖水平，以用于治疗糖尿病的哺乳动物。
该药物制剂对皮下给予胰岛素具有胰岛素增敏作用。
该药物制剂在大鼠中的消除半衰期大约是40分钟。
药物制剂不显示亚慢性毒性。
Claims (12)
1.可口服给予的药物制剂，其中所述药物制剂包含生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物，蛋白酶抑制剂和高分子量天然蛋白质的组合。
2.根据权利要求1的药物制剂，其中人胰岛素是在位点B28具有Asp、Lys、Leu、Val或Ala，且在位点B29具有Lys或Pro的类似物；或des(B28-B30)、des(B27)或des(B30)人胰岛素。
3.根据权利要求1的药物制剂，其中蛋白酶抑制剂是ε-氨基-己酸。
4.根据权利要求1或2的药物制剂，其中高分子量天然蛋白质是酪蛋白。
5.根据权利要求1-4任一项的药物制剂，其中所述药物制剂包含40-100IU的人重组胰岛素、100-1000mg的ε-氨基-己酸和1-100mg的酪蛋白。
6.治疗有效量的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物，ε-氨基-己酸和酪蛋白的组合制备在哺乳动物中适于治疗(1型和2型)糖尿病的可口服给予的药物制剂中的用途。
7.用于制备可口服给予的药物制剂的方法，其中将40-100IU的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物、100-1000mg的ε-氨基-己酸和1-100mg的酪蛋白与药学上可接受的载体和添加剂物质混合，并配制成可口服给予的剂型。
8.根据权利要求1-5任一项的药物制剂的用途，所述药物制剂用于在哺乳动物中治疗(1型和2型)糖尿病。
9.根据权利要求1-5任一项的药物制剂的用途，所述药物制剂用于治疗妊娠中的糖尿病。
10.在哺乳动物中用于治疗(1型和2型)糖尿病的方法，其中给予患者可口服给予的药物制剂，所述制剂含有治疗有效量的生物技术制备的人重组胰岛素和/或修饰的胰岛素或其类似物和/或衍生物，ε-氨基-己酸和酪蛋白。
11.在哺乳动物中用于治疗1型糖尿病的方法，其中给予患者含有40-100IU的人重组胰岛素、100-1000mg的ε-氨基-己酸和1-100mg的酪蛋白的药物制剂。
12.根据权利要求1-5任一项的药物制剂，其中所述药物制剂的生物利用度超过30％。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP0900482 | 2009-08-03 | ||
| HU0900482A HUP0900482A2 (en) | 2009-08-03 | 2009-08-03 | Pharmaceutical formulation for oral administration |
| PCT/IB2010/053499 WO2011015984A1 (en) | 2009-08-03 | 2010-08-02 | Orally administerable pharmaceutical preparation containing insulin |
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| CN102791282A true CN102791282A (zh) | 2012-11-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201080038764XA Pending CN102791282A (zh) | 2009-08-03 | 2010-08-02 | 可口服给予的含有胰岛素的药物制剂 |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US20120129769A1 (zh) |
| EP (1) | EP2461820A1 (zh) |
| JP (1) | JP2013501043A (zh) |
| KR (1) | KR20120088660A (zh) |
| CN (1) | CN102791282A (zh) |
| AU (1) | AU2010280418B2 (zh) |
| BR (1) | BR112012002413A2 (zh) |
| CA (1) | CA2769620A1 (zh) |
| HU (1) | HUP0900482A2 (zh) |
| IL (1) | IL217856A0 (zh) |
| MX (1) | MX2012001461A (zh) |
| RU (1) | RU2012109006A (zh) |
| UA (1) | UA106506C2 (zh) |
| WO (1) | WO2011015984A1 (zh) |
| ZA (1) | ZA201201519B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111065749A (zh) * | 2017-06-28 | 2020-04-24 | 德国亥姆霍兹慕尼黑中心健康与环境研究中心（有限公司） | 用于确定发展1型糖尿病的风险的方法 |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK2726091T3 (da) * | 2011-06-29 | 2020-03-09 | Rani Therapeutics Llc | Præparater med terapeutisk middel til fremføring i et lumen i tarmkanalen ved hjælp af en synkbar anordning til lægemiddelfremføring |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0127535A2 (en) * | 1983-05-23 | 1984-12-05 | Hadassah Medical Organization | Pharmaceutical compositions containing insulin |
| JPH06172199A (ja) * | 1992-12-07 | 1994-06-21 | Tsumura & Co | ペプチド類経鼻投与用組成物 |
| CN1116629A (zh) * | 1994-06-16 | 1996-02-14 | 伊莱利利公司 | 单体胰岛素类似物制剂 |
| CN101062408A (zh) * | 2006-04-27 | 2007-10-31 | 深圳市隆阳生物科技有限公司 | 口服胰岛素复合制剂及其制备方法 |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3172814A (en) | 1962-04-06 | 1965-03-09 | Jr Edgar A Ferguson | Oral blood sugar lowering compositions |
| JPS5428807A (en) | 1977-08-09 | 1979-03-03 | Hiroyuki Sumi | Oral insulin |
| DE68909135T2 (de) | 1988-07-21 | 1994-04-07 | Hoffmann La Roche | Insulinzubereitung. |
| WO1993010767A1 (de) | 1991-12-05 | 1993-06-10 | Alfatec-Pharma Gmbh | Perorale applikationsform für peptidarzneistoffe, insbesondere insulin |
| US5359030A (en) | 1993-05-10 | 1994-10-25 | Protein Delivery, Inc. | Conjugation-stabilized polypeptide compositions, therapeutic delivery and diagnostic formulations comprising same, and method of making and using the same |
| US5968899A (en) * | 1994-06-03 | 1999-10-19 | Tsumura & Co. | Medicinal compositions of peptides with EACA or tranexamic acid for enhanced mucosal absorption |
| US5653987A (en) | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
| US5970193A (en) | 1996-10-24 | 1999-10-19 | Nortel Networks Corporation | Data communications structures relating to data shelf configurations |
| WO1998043615A1 (en) | 1997-04-02 | 1998-10-08 | Purdue Research Foundation | Method for oral delivery of proteins |
| WO2000033866A1 (en) | 1998-12-04 | 2000-06-15 | Provalis Uk Limited | Pharmaceutical compositions containing insulin |
| US6375975B1 (en) | 1998-12-21 | 2002-04-23 | Generex Pharmaceuticals Incorporated | Pharmaceutical compositions for buccal and pulmonary application |
| CA2518136A1 (en) | 2003-03-04 | 2004-09-16 | The Technology Development Company Ltd. | Oral insulin composition and methods of making and using thereof |
| JP5103748B2 (ja) * | 2005-02-16 | 2012-12-19 | 東レ株式会社 | 医薬組成物 |
| JP5222727B2 (ja) * | 2005-09-06 | 2013-06-26 | オーラメッド・ファーマスーティカルズ・インコーポレイテッド | タンパク質を経口投与するための方法及び組成物 |
| US8927015B2 (en) | 2006-04-12 | 2015-01-06 | Emisphere Technologies, Inc. | Formulations for delivering insulin |
| JP2008266179A (ja) * | 2007-04-19 | 2008-11-06 | Fujifilm Corp | 経肺用組成物 |
| US20110144010A1 (en) * | 2007-06-01 | 2011-06-16 | Novo Nordisk A/S | Spontaneously Dispersible Preconcentrates Including a Peptide Drug in a Solid or Semisolid Carrier |
| AU2009283821B2 (en) * | 2008-08-18 | 2014-05-29 | Entera Bio Ltd. | Methods and compositions for oral administration of proteins |
-
2009
- 2009-08-03 HU HU0900482A patent/HUP0900482A2/hu unknown
-
2010
- 2010-08-02 CN CN201080038764XA patent/CN102791282A/zh active Pending
- 2010-08-02 UA UAA201202346A patent/UA106506C2/uk unknown
- 2010-08-02 JP JP2012523416A patent/JP2013501043A/ja active Pending
- 2010-08-02 KR KR1020127005524A patent/KR20120088660A/ko not_active Application Discontinuation
- 2010-08-02 RU RU2012109006/15A patent/RU2012109006A/ru unknown
- 2010-08-02 EP EP10757272A patent/EP2461820A1/en not_active Withdrawn
- 2010-08-02 WO PCT/IB2010/053499 patent/WO2011015984A1/en active Application Filing
- 2010-08-02 CA CA2769620A patent/CA2769620A1/en not_active Abandoned
- 2010-08-02 MX MX2012001461A patent/MX2012001461A/es not_active Application Discontinuation
- 2010-08-02 AU AU2010280418A patent/AU2010280418B2/en not_active Expired - Fee Related
- 2010-08-02 BR BR112012002413A patent/BR112012002413A2/pt not_active IP Right Cessation
- 2010-08-02 US US13/387,212 patent/US20120129769A1/en not_active Abandoned
-
2012
- 2012-01-31 IL IL217856A patent/IL217856A0/en unknown
- 2012-02-29 ZA ZA2012/01519A patent/ZA201201519B/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0127535A2 (en) * | 1983-05-23 | 1984-12-05 | Hadassah Medical Organization | Pharmaceutical compositions containing insulin |
| JPH06172199A (ja) * | 1992-12-07 | 1994-06-21 | Tsumura & Co | ペプチド類経鼻投与用組成物 |
| CN1116629A (zh) * | 1994-06-16 | 1996-02-14 | 伊莱利利公司 | 单体胰岛素类似物制剂 |
| CN101062408A (zh) * | 2006-04-27 | 2007-10-31 | 深圳市隆阳生物科技有限公司 | 口服胰岛素复合制剂及其制备方法 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111065749A (zh) * | 2017-06-28 | 2020-04-24 | 德国亥姆霍兹慕尼黑中心健康与环境研究中心（有限公司） | 用于确定发展1型糖尿病的风险的方法 |
| CN111065749B (zh) * | 2017-06-28 | 2024-06-28 | 德国亥姆霍兹慕尼黑中心健康与环境研究中心（有限公司） | 用于确定发展1型糖尿病的风险的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2011015984A1 (en) | 2011-02-10 |
| EP2461820A1 (en) | 2012-06-13 |
| AU2010280418A1 (en) | 2012-03-22 |
| BR112012002413A2 (pt) | 2016-03-01 |
| HUP0900482A2 (en) | 2011-03-28 |
| KR20120088660A (ko) | 2012-08-08 |
| CA2769620A1 (en) | 2011-02-10 |
| UA106506C2 (uk) | 2014-09-10 |
| IL217856A0 (en) | 2012-03-29 |
| MX2012001461A (es) | 2012-05-22 |
| AU2010280418B2 (en) | 2015-04-09 |
| HU0900482D0 (en) | 2009-10-28 |
| ZA201201519B (en) | 2013-05-29 |
| US20120129769A1 (en) | 2012-05-24 |
| RU2012109006A (ru) | 2013-09-10 |
| JP2013501043A (ja) | 2013-01-10 |
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Application publication date: 20121121 |