CN1065141C - 通过鼻粘膜给药的药物制剂 - Google Patents
通过鼻粘膜给药的药物制剂 Download PDFInfo
- Publication number
- CN1065141C CN1065141C CN98108852A CN98108852A CN1065141C CN 1065141 C CN1065141 C CN 1065141C CN 98108852 A CN98108852 A CN 98108852A CN 98108852 A CN98108852 A CN 98108852A CN 1065141 C CN1065141 C CN 1065141C
- Authority
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- China
- Prior art keywords
- pharmaceutical preparation
- insulin
- alkali metal
- nasal mucosa
- metal salt
- 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.)
- Expired - Lifetime
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims description 31
- 229940079593 drug Drugs 0.000 title description 5
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims abstract description 29
- -1 alkali metal salts Chemical class 0.000 claims abstract description 26
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- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 25
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 25
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 23
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Abstract
本发明涉及通过鼻粘膜给药的药物制剂，更具体讲，本发明涉及的是通过鼻粘膜给药的药物制剂，所述药物制剂包括作为活性成份的多肽类化合物，选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和/或其它适于药用的添加剂或赋形剂。
Description
本发明涉及通过鼻粘膜给药的药物制剂，更具体讲，本发明涉及的是通过鼻粘膜给药的药物制剂，所述药物制剂包括作为活性成份的多肽类化合物，选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或其它适于药用的添加剂或赋形剂。
多肽类化合物由于易受肠胃道酶的降解和在肝脏中易被代谢而难于在患者体内产生应有的药效，因此，多肽类药物通常是以注射剂形式给药的，如皮下，肌内或静脉等。但长期以注射形式使用多肽类药物也给患者带来诸多不便，如一般需要到医院去注射，注射器械要消毒，由注射引起的痛苦和刺激，因长期注射可能引起的组织损伤和坏死以及潜在的传染其它疾病的危险。因此近年来多肽类化合物的通过粘膜，如通过鼻腔给药的研究引起人们极大的关注。中国专利申请号88106763．6，发明题目为“通过粘膜给药的配方及其制备方法”披露了通过粘膜给药的配方，其中该配方中所用的吸收促进剂为糖或其衍生物，如选自D-赤藓糖、D-核糖、D-核酮糖、D-木糖、D-来苏糖、L-阿拉伯糖、D-甘露糖、L-山梨糖或D-景天庚酮糖的单糖，选自α-环糊精，β-环糊精、γ-环糊精和支链环糊精的寡糖；中国专利申请号：95119260．4的发明专利披露了多肽类药物粘膜吸收剂型的促进剂，其中所述促进剂包括：月桂氮酮、皂苷、甘草酸、甘草酸酯、甘草酸盐、甘草亭酸及钠盐、二羟基黄木酸及其衍生物、羧酸酯类，且该专利唯一给出的实例是舌下含片。更进一步讲，目前还没有一个通过鼻粘膜给药的多肽类药物制剂上市，因此，开发通过鼻粘膜给药的多肽类化合物仍是十分迫切和需要的。
本发明的目的是提供通过鼻粘膜给药的含多肽类化合物的药物制剂。
本发明人经广泛深入的研究，现已发现具有与注射给药基本相同的药物活性且无刺激性的经鼻粘膜给药的含多肽类化合物的药物制剂。更具体讲，本发明经鼻粘膜给药的药物制剂包括作为活性成份的多肽类化合物，选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或适宜的其它药用添加剂或赋形剂，本发明基于上述发现得以完成。
本发明第一方面涉及的是经鼻粘膜给药的含多肽类化合物的药物制剂，该药物制剂包括作为活性成份的多肽类化合物，选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或其它适于药用的赋形剂或添加剂。
本发明第二方面涉及的是经鼻粘膜给药用于治疗糖尿病的药物制剂，该药物制剂包括作为活性成份的胰岛素，选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或其它适于药用的赋形剂或添加剂。
本发明再一方面涉及的是制备经鼻粘膜给药的含多肽类化合物的药物制剂的方法。其包括将作为活性成份的多肽类化合物与选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或其它适于药用的赋形剂或添加剂混合。
本发明再一方面涉及的是制备经鼻粘膜给药的含胰岛素的药物制剂的方法，其包括将作为活性成份的胰岛素选自牛磺酸或其碱金属盐或其C1-6烷基酯，透明质酸或其碱金属盐，或它们的混合物的吸收促进剂，和／或其它适于药用的赋形剂或添加剂混合。
根据本发明，本发明中所用术语“多肽类化合物”是例如选自牛、猪或人工合成的胰岛素，降钙素、水蛭素、胰高血糖素、后叶加压素、催乳激素、生长激素、促甲状腺激素、促肾上腺皮质激素、干扰素等的多肽化合物。
在本发明的吸收促进剂中所用的术语“牛磺酸碱金属盐”是如钠、钾盐等；本发明吸收促进剂中出现的术语“透明质酸碱金属盐”是如钠、钾盐等。
在本发明中使用的术语“胰岛素”包括来自动物(如牛、猪等)的天然胰岛素或人工合成的胰岛素，其中人工合成胰岛素指人工合成的胰岛素和通过重组DNA技术产生的重组人体基因胰岛素。
在本发明中使用的术语“糖尿病”是指Ⅰ型和Ⅱ型糖尿病。
根据本发明，本发明的经鼻粘膜给药的含多肽类化合物的药物制剂或经鼻粘膜给药的含胰岛素的药物制剂是以液体滴剂或液体喷雾剂形式使用的。
根据本发明，本发明的经鼻粘膜给药的含多肽化合物的药物制剂或经鼻粘膜给药的含胰岛素的药物制剂的施用对象是人类。
进一步讲，本发明的经鼻粘膜给药的含多肽类化合物的药物制剂的特征为：本发明的药物制剂包括0．01～20w／v％牛磺酸或其碱金属盐或其C1-6烷基酯，或0．01～10w／v％透明质酸或其碱金属盐，或它们的混合物，作为吸收促进剂。
根据本发明，本发明经鼻粘膜给药的含多肽类化合物的药物制剂的施用剂量取决于患者的年龄、体重、身体状况及疾病的严重程度等。根据本发明，本发明的经鼻粘膜给药的含多肽类化合物的药物制剂可以单剂量或多剂量形式使用
根据本发明，本发明药物制剂显示出良好的药物活性并且对鼻粘膜未发现刺激性或其它不良反应，因此，本发明的药物制剂是一种优良的通过粘膜系统给药的药物制剂。
下面实验例及制备例是本发明的进一步详细说明，它们不意味着对本发明的任何限制。
实验例
以滴鼻剂形式使用的本发明含胰岛素的经鼻给药制剂对因注射四氧嘧啶所引起的大鼠高血糖的血糖影响
材料
动物：Wistar大鼠，雄性，体重200-220g，购自军事医学科学院动物中心，合格证号：京动管质字(1994)第052号
本发明含胰岛素的药物制剂；剂量分别为10IU胰岛素／kg，5IU胰岛素／kg和2．5IU胰岛素／kg
试剂及仪器：
四氧嘧啶：批号：FL0610021153，市售，香港生产。
UV 265紫外-可见光分光光度计：日本
方法：
取上述健康大鼠禁食，(自由饮水24)小时后，静脉注射四氧嘧啶盐溶液40mg／Kg，注射后36小时再次禁食(自由饮水)，12小时后开始试验，开始试验时，每只大鼠按30mg／Kg腹腔注射戊巴比妥钠麻醉后取血，测定血糖，随机分为空白对照组，模型组和给药组。空白对照组为未注射四氧嘧啶的组。空白组及模型对照组于鼻腔滴入不含胰岛素的本发明受试药物制剂，剂量为：10μl／100g；给药组以等体积(10μl／100g)向鼻腔滴入剂量分别为10IU胰岛素／kg，5IU胰岛素／kg和2．5IU胰岛素／kg的本发明受试药物制剂。各组均于给药后1、2、3、4小时取血测定血糖值，进行比较，结果见下面表1
表1：经鼻粘膜给药的含胰岛素滴鼻剂对四氧嘧啶引起的大鼠高血糖的作用
给药后1小时组别 给药剂量 动物数 降糖 降糖值 降糖百分率
(只) 动物(％) (mg／dl) (％)空白组 10μl／100g 10 60 5．9±3．1 8．5±5．1模型组 10μl／100g 10 60 27．1±16．9 11．3±8．7给药组 10IU／Kg 10 100 53．3±17．5 18．8±7．3给药组 5IU／Kg 10 100 46．0±20．7 17．1±7．8给药组 2．5IU／Kg 10 100 36．7±17．0 13．2±6．3表1(续)给药后2小时组别 给药剂量 动物数降糖 降糖值 降糖百分率
(只) 动物(％) (mg／d1) (％)空白组 10μl／100g 10 60 8．1±4．6 11．0±6．3模型组 10μl／100g 10 30 6．2±5．5 1．9±1．6给药组 10IU／Kg 10 100 89．2±44．2 29．6±10．9给药组 5IU／Kg 10 100 59．3±32．0 21．4±10．0给药组 2．5IU／Kg 10 100 48．6±37．6 16．8±11．2表1(续)给药物3小时组别 给药剂量 动物数(只)降糖 降糖值 降糖百分
动物(％) (mg／dl) 率(％)空白组 10μ1／100g 10 30 5．1±2．1 7．2±3．0模型组 10μl／100g 10 20 9．8±9．7 2．6±1．8给药组 10IU／Kg 10 100 75．6±51．8 24．3±13．9给药组 5IU／Kg 10 90 46．1±22．6 16．6±6．8给药组 2．5IU／Kg 10 80 43．8±35．9 14．9±11．6表(续)给药后4小时组别 给药剂量 动物数(只) 降糖 降糖值 降糖百分
动物(％) (mg／dl) 率(％)空白组 10μl／100g 10 0 0 0模型组 10μl／100g 10 0 0 0给药组 10IU／Kg 10 100 56．3±53．6 16．8±15．9给药组 5IU／Kg 10 80 19．3±10．8 6．8±3．5给药组 2．5IU／Kg 10 80 31．2±29．8 10．4±9．3
注：IU指国际单位。
由表1中数据表明本发明的含胰岛素的药物制剂可通过鼻粘膜被有效吸收并产生理想的降血糖效果。
制备实施例1：通过鼻粘膜给药的药物制剂
配方：
成份 用量
胰岛素 20000IU
牛磺酸 2g
0．1N盐酸或0．1N氢氧化钠 适量
尼泊金乙酯 0．03g
蒸馏水 加至100ml
向上述牛磺酸、尼泊金乙酯中加入适量蒸馏水，加热使其溶解，冷却后，用0．1N盐酸或0．1N氢氧化钠调pH至7，然后加入上述胰岛素，溶解后，过滤灭菌，所得溶液分装于灭菌的特制西林瓶中。
制备实施例2：通过鼻粘膜给药的药物制剂
配方：
成份 用量
胰岛素 20000IU
透明质酸 0．5g
0．1N盐酸或0．1N氢氧化钠 适量
尼泊金乙酯 0．03g
蒸馏水 加至100ml
向上述透明质酸、尼泊金乙酯中加入适量蒸馏水，加热使其溶解，冷却后，用0．1N盐酸或0．1N氢氧化钠调pH至7，然后加入上述胰岛素，溶解后，过滤灭菌，所得溶液分装于灭菌的特制西林瓶中。
制备实施例3：通过鼻粘膜给药的药物制剂
配方：
成份 用量
胰岛素 20000IU
牛磺酸 2g
透明质酸 1g
0．1N盐酸或0．1N氢氧化钠 适量
尼泊金乙酯 0．03g
蒸馏水 加至100ml
向上述牛磺酸、透明质酸、尼泊金乙酯中加入适量蒸馏水，加热使其溶解，冷却后，用0．1N盐酸或0．1N氢氧化钠调pH至7，然后加入上述胰岛素，溶解后，过滤灭菌，所得溶液分装于灭菌的特制西林瓶中。
Claims (6)
1．通过鼻粘膜给药的药物制剂，其包括作为活性成份的选自胰岛素，降钙素，水蛭素，胰高血糖素、后叶加压素、催乳激素、生长激素、促甲状腺激素、促肾上腺皮质激素或干扰素的多肽类化合物，含有牛磺酸或其碱金属盐或其C1-6烷基酯和透明质酸或其碱金属盐的吸收促进剂，及适于药用的其它赋形剂或添加剂。
2．权利要求1的药物制剂，其中所述多肽化合物为胰岛素。
3．权利要求2的药物制剂，其中所述胰岛素包括来自猪，牛，人工合成或基因工程得到的胰岛素。
4．权利要求1-3之任一的药物制剂，其中该药物制剂是以滴剂或喷雾剂形式使用的。
5．权利要求1-3任一的药物制剂，其特征在于该制剂含0．01-20w／v％牛磺酸或其碱金属盐或其C1-6烷基酯，和0．01-10w／v％的透明质酸或其碱金属盐。
6．权利要求1-3任一的药物制剂，其中所述碱金属盐为钠或钾盐。
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98108852A CN1065141C (zh) | 1998-05-20 | 1998-05-20 | 通过鼻粘膜给药的药物制剂 |
| US09/674,519 US6623732B1 (en) | 1998-05-20 | 1999-04-01 | Pharmaceutical formulation for nasal administration |
| AU30550/99A AU3055099A (en) | 1998-05-20 | 1999-04-01 | A pharmaceutical formulation for nasal administration |
| EP99912088A EP1079801A1 (en) | 1998-05-20 | 1999-04-01 | A pharmaceutical formulation for nasal administration |
| JP2000549208A JP2002515416A (ja) | 1998-05-20 | 1999-04-01 | 経鼻投与用医薬製剤 |
| PCT/JP1999/001704 WO1999059543A1 (en) | 1998-05-20 | 1999-04-01 | A pharmaceutical formulation for nasal administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN98108852A CN1065141C (zh) | 1998-05-20 | 1998-05-20 | 通过鼻粘膜给药的药物制剂 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1235846A CN1235846A (zh) | 1999-11-24 |
| CN1065141C true CN1065141C (zh) | 2001-05-02 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98108852A Expired - Lifetime CN1065141C (zh) | 1998-05-20 | 1998-05-20 | 通过鼻粘膜给药的药物制剂 |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP2002515416A (zh) |
| CN (1) | CN1065141C (zh) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1285382C (zh) * | 2004-12-20 | 2006-11-22 | 凌沛学 | 含海藻糖和玻璃酸的鼻腔用药传递系统及其制备方法 |
| CN112353789B (zh) * | 2015-12-25 | 2022-05-17 | 北京乳凝创智生物技术研发中心（有限合伙） | 一种化妆品 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418642A1 (en) * | 1989-09-11 | 1991-03-27 | Teikoku Seiyaku Kabushiki Kaisha | High-absorbable transvaginal preparation containing biologically active peptides |
| JPH03246233A (ja) * | 1990-02-23 | 1991-11-01 | Shiseido Co Ltd | 経粘膜投与用薬剤組成物 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2671381B2 (ja) * | 1988-05-23 | 1997-10-29 | 藤沢薬品工業株式会社 | 点眼剤 |
| JPH02104531A (ja) * | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド組成物 |
| GB9020544D0 (en) * | 1990-09-20 | 1990-10-31 | Sandoz Ltd | Improvements in or relating to organic compounds |
-
1998
- 1998-05-20 CN CN98108852A patent/CN1065141C/zh not_active Expired - Lifetime
-
1999
- 1999-04-01 JP JP2000549208A patent/JP2002515416A/ja active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418642A1 (en) * | 1989-09-11 | 1991-03-27 | Teikoku Seiyaku Kabushiki Kaisha | High-absorbable transvaginal preparation containing biologically active peptides |
| JPH03246233A (ja) * | 1990-02-23 | 1991-11-01 | Shiseido Co Ltd | 経粘膜投与用薬剤組成物 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1235846A (zh) | 1999-11-24 |
| JP2002515416A (ja) | 2002-05-28 |
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