JPH0242027A - Transmucosal absorbefacient and pernasal administration agent using said absorbefacient - Google Patents
Transmucosal absorbefacient and pernasal administration agent using said absorbefacientInfo
- Publication number
- JPH0242027A JPH0242027A JP63193649A JP19364988A JPH0242027A JP H0242027 A JPH0242027 A JP H0242027A JP 63193649 A JP63193649 A JP 63193649A JP 19364988 A JP19364988 A JP 19364988A JP H0242027 A JPH0242027 A JP H0242027A
- Authority
- JP
- Japan
- Prior art keywords
- insulin
- absorbefacient
- transmucosal
- administration
- injection
- 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.)
- Pending
Links
- 239000000126 substance Substances 0.000 claims abstract description 16
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 claims abstract description 15
- 239000004378 Glycyrrhizin Substances 0.000 claims abstract description 13
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229960004949 glycyrrhizic acid Drugs 0.000 claims abstract description 13
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000019410 glycyrrhizin Nutrition 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 239000000813 peptide hormone Substances 0.000 claims abstract description 6
- 238000010521 absorption reaction Methods 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000003623 enhancer Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 abstract description 90
- 102000004877 Insulin Human genes 0.000 abstract description 45
- 108090001061 Insulin Proteins 0.000 abstract description 45
- 229940125396 insulin Drugs 0.000 abstract description 45
- 238000002347 injection Methods 0.000 abstract description 10
- 239000007924 injection Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 240000004670 Glycyrrhiza echinata Species 0.000 abstract description 2
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 abstract description 2
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 abstract description 2
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 abstract description 2
- 102000014150 Interferons Human genes 0.000 abstract description 2
- 108010050904 Interferons Proteins 0.000 abstract description 2
- 239000002537 cosmetic Substances 0.000 abstract description 2
- 239000003889 eye drop Substances 0.000 abstract description 2
- 229940012356 eye drops Drugs 0.000 abstract description 2
- 235000013305 food Nutrition 0.000 abstract description 2
- 235000003599 food sweetener Nutrition 0.000 abstract description 2
- 229940010454 licorice Drugs 0.000 abstract description 2
- 239000002674 ointment Substances 0.000 abstract description 2
- 239000003765 sweetening agent Substances 0.000 abstract description 2
- 239000004615 ingredient Substances 0.000 abstract 1
- 229940079322 interferon Drugs 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 28
- 210000004369 blood Anatomy 0.000 description 28
- 239000000243 solution Substances 0.000 description 9
- 230000001737 promoting effect Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000010253 intravenous injection Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000007922 nasal spray Substances 0.000 description 4
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229940097496 nasal spray Drugs 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000001331 nose Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 101001011741 Bos taurus Insulin Proteins 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical compound [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010022086 Injection site pain Diseases 0.000 description 1
- 241001385002 Minota Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- IXIBAKNTJSCKJM-BUBXBXGNSA-N bovine insulin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 IXIBAKNTJSCKJM-BUBXBXGNSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- -1 glycyrrhizin ammonium salt Chemical class 0.000 description 1
- 229940074774 glycyrrhizinate Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 150000004667 medium chain fatty acids Chemical class 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明はグリチルリチン、及びその医薬上許容される塩
を有効成分とする難吸収性物質の経粘膜吸収促進剤、並
びにこれを添加した経鼻投与剤に関する。Detailed Description of the Invention [Industrial Application Field] The present invention relates to a transmucosal absorption enhancer for poorly absorbed substances containing glycyrrhizin and its pharmaceutically acceptable salt as active ingredients, and a nasal transmucosal absorption enhancer containing the same. Concerning administration agents.
［従来の技術及び問題点コ
従来から使用されている医薬品中、ペプチドホルモン等
の難吸収性のもの、例えばインスリンは糖尿病の患者等
に対し、注射によってのみ投与されていた。[Prior Art and Problems] Among conventionally used pharmaceuticals, poorly absorbed drugs such as peptide hormones, such as insulin, were administered only by injection to diabetic patients.
しかし、難吸収性物質であるインスリン等の注射法は注
射時に疼痛があり、また長期間の連続投与により身体の
注射部位の組織肥厚などが生じる欠点があった。However, the injection method for insulin, which is a poorly absorbed substance, has the drawback that it causes pain during injection, and continuous administration over a long period of time causes tissue thickening at the injection site in the body.
一方、最近、これらの事態を回避すると共に、在宅投与
を可能にする製剤として、点鼻剤や生布等の製造につい
て研究がされているが、例えばインスリンは約６．００
０の分子量を有し、その分子量が大きいため鼻粘膜或い
は直腸粘膜等からは極めて吸収されにくいことが、その
開発上の大きな障害となっている。On the other hand, recently, research has been conducted on the production of nasal sprays and cloth, etc., as preparations that can avoid these situations and enable home administration.
It has a molecular weight of 0, and because of its large molecular weight, it is extremely difficult to be absorbed through the nasal mucosa or rectal mucosa, which is a major obstacle in its development.
そこで、近年インスリン等の吸収を促進きせる物質の検
討がなされ、その結果、胆汁酸、中鎖脂肪酸、非イオン
性或いはイオン性合成界面活性剤、及びサポニン類など
の界面活性作用のある物質に吸収促進効果があることが
知られるようになった。Therefore, in recent years, studies have been conducted on substances that can promote the absorption of insulin, etc., and as a result, it has been found that substances with surfactant effects such as bile acids, medium-chain fatty acids, nonionic or ionic synthetic surfactants, and saponins have an effect on absorption. It is now known that it has a promoting effect.
本願発明者等は、かかる事情の下で実用的な物質を種々
探求したところ、界面活性作用があり、内服剤の他に点
眼や軟膏の外用薬として用いられ、更に化粧品や甘味料
として食品に添加されている甘草有効成分であるグリチ
ルリチンとその塩が、インスリン、グルカゴンを含む高
分子量のペプチドホルモン等について、これらの経粘膜
吸収促進に顕著な効果を発揮することを発見し、本発明
を完成したものである。The inventors of the present application searched for various practical substances under these circumstances, and found that they have surfactant properties and are used not only as internal medicines but also as external medicines such as eye drops and ointments, and are also used in cosmetics and foods as sweeteners. The present invention was completed by discovering that glycyrrhizin and its salts, which are added active ingredients in licorice, have a remarkable effect on promoting the transmucosal absorption of high-molecular weight peptide hormones, including insulin and glucagon. This is what I did.
本発明における吸収促進に有用な化合物は式：
で示されるグリチルリチン（グリチルリチン酸）及びそ
の医薬上許容きれる塩である。Compounds useful for promoting absorption in the present invention are glycyrrhizin (glycyrrhizic acid) represented by the formula: and its pharmaceutically acceptable salts.
ここで塩とは、例えば、グリチルリチン酸アンモニウム
、グリチルリチン酸アルカリ塩（−、ニナトリウム、−
、ニカリウム塩等）などである。Here, salts include, for example, ammonium glycyrrhizinate, alkali salt of glycyrrhizinate (-, disodium, -
, dipotassium salt, etc.).
これらの化合物は、顕著な吸収促進作用を有する一方、
生体粘膜に対する副作用は極めて微小である。従って、
本願化合物によりペプチドホルモンやインターフェロン
等の高分子量の芹吸収物質の投与において、従来光んど
薬理効果がなかった経粘膜投与、例えば経鼻投与によっ
ても、従来の注射剤による場合と同様に充分な吸収性が
得られる。その結果、注射以外の方法により所定の治療
効果が期待できることとなる。特にインスリンに関して
は糖尿病の治療に極めて有用な製剤を提供するものとし
て大きな期待がもたれる。While these compounds have a remarkable absorption promoting effect,
The side effects on biological mucous membranes are extremely small. Therefore,
The compound of the present application can be used to administer high-molecular weight absorption substances such as peptide hormones and interferons by transmucosal administration, such as nasal administration, which previously had no pharmacological effects, as well as by conventional injections. Provides absorbency. As a result, the desired therapeutic effect can be expected by methods other than injection. In particular, there are great expectations regarding insulin as it will provide a preparation that is extremely useful for the treatment of diabetes.
本願化合物を吸収促進剤として使用する場合は、これを
適用量の難吸収性物質と共に溶屏した水溶液として投与
することができ、経粘膜吸収が促進される結果、その剤
層は、点鼻剤、噴霧剤等とすることが可能となる。When the compound of the present application is used as an absorption enhancer, it can be administered as a dissolved aqueous solution together with an applied amount of a poorly absorbed substance, and as a result of promoting transmucosal absorption, the drug layer is , a spray, etc.
また本願化合物は、適用量の難吸収性物質に添加して常
法により生布、歌膏剤として局所添付することもできる
。The compound of the present invention can also be added to an applied amount of a poorly absorbable substance and applied topically as a cloth or plaster by a conventional method.
これらの場合、本願化合物は０．０１〜１０％の範囲の
含量で用いるこ七により充分な経粘膜吸収促進効果が期
待できる。In these cases, a sufficient transmucosal absorption promoting effect can be expected by using the compound of the present application in a content in the range of 0.01 to 10%.
以下に製剤実施例及び薬理試験例を掲げるが、本発明が
これらの実施例、試験例に限定されるものでないことは
勿論である。Formulation Examples and Pharmacological Test Examples are listed below, but it goes without saying that the present invention is not limited to these Examples and Test Examples.
［Ｍ剤実施例コ
点鼻剤の製造
グリチルリチン・ジカリウム塩又はグリチルリチン・ア
ンモニウム塩の０．０１〜１０％水溶液に、投与液０．
１ｍｌあたりの適用量の単位のウシインスリンを溶解し
て調製する。[Example of Formulation M Production of nasal spray Add 0.01% to 10% aqueous solution of glycyrrhizin dipotassium salt or glycyrrhizin ammonium salt to the administration solution.
Prepare by dissolving bovine insulin in dosage units per ml.
現在のインスリン注射製剤は４０Ｕ及び１００Ｕの二規
格であり、注射剤と同用量を投与する場合、点鼻での投
与液量は０．４〜１ｍｌとなり、ヒトに対する点鼻剤と
して充分可能な液量である。Current insulin injection preparations come in two specifications: 40U and 100U, and when administering the same dose as the injection, the amount of solution administered through the nose is 0.4 to 1ml, which is sufficient for use as a nasal spray for humans. It is quantity.
また、必要に応じ製剤上許容される等張化剤、安定剤及
び保存剤等を添加する。In addition, tonicity agents, stabilizers, preservatives, etc., which are acceptable for formulation, are added as necessary.
噴霧剤の製造
噴霧用の溶液も上記点鼻剤と同様の方法で調製し、容器
に空気またはプレオンを充填する。Preparation of spray The solution for spray is prepared in the same manner as the nasal spray described above, and the container is filled with air or preon.
この場合、容器または圧縮用の装置を手で押圧する等に
より霧状として投与できる容器を使用する。噴霧量は、
１回０．１〜０．２ｍｌであり、２〜５回の噴霧で治療
量のインスリンを充分に投与することができる。In this case, a container is used that can be administered in the form of a mist by manually pressing the container or compression device. The amount of spray is
Each dose is 0.1-0.2 ml, and 2-5 sprays are enough to administer a therapeutic amount of insulin.
［薬理試験例］
吸収促進作用
（１）インスリン投与液の調製
ウジインスリンを、
■ｐＨ７，４の０． ＯＩＭリン酸緩衝液■グリチルリ
チン・ジカリウム又はグリチルリチン・アンモニウムを
１％含む同緩衝液に溶解し、夫々ｉｏｏ Ｕ／ｍｌずつ
のインスリン溶液を調製した。[Pharmacological test example] Absorption promoting effect (1) Preparation of insulin administration solution Maggot insulin was prepared as follows: ■ pH 7.4 0. OIM phosphate buffer ■Ioo U/ml of each insulin solution was prepared by dissolving it in the same buffer containing 1% glycyrrhizin dipotassium or glycyrrhizin ammonium.
（２）被検動物
ウィスター系ラット（体重２５０ｇ前後）を１群３〜７
匹とし、ベンドパルビタール麻酔下、背位固定し、気管
にカニユーレを挿入して呼吸を確保した。また食道にカ
ニユーレを挿入して投与液の漏出を防いだ。(2) Test animals: 3 to 7 Wistar rats (weighing around 250 g) per group.
The animals were placed in a dorsal position under bendoparbital anesthesia, and a cannula was inserted into the trachea to ensure breathing. A cannula was also inserted into the esophagus to prevent leakage of the administered solution.
（３）血中濃度測定
本実験例においては、インスリンはｌ０Ｕ１０．１ｍｌ
／ｋｇずつ投与し、大腿静脈に挿入したカニュ・−レか
ら血液を採取して、ヘパリン前処理した血液を遠心分難
（３，００Ｏｒｐｍ、１０分間）して血漿を得た。イン
スリンは、酵素免疫法（インスリンＢ−テストワコー、
和光紬薬製）を用いて測定した。血糖値はムタロターゼ
・グルコースオキシダーゼ法（グルコースＣ−テストフ
コ−、和光紬薬製）を用いて測定した。(3) Measurement of blood concentration In this experimental example, the amount of insulin was 10 U10.1 ml.
Blood was collected from a cannula inserted into the femoral vein, and the heparin-pretreated blood was centrifuged (3,00 rpm, 10 minutes) to obtain plasma. Insulin was administered by enzyme immunotherapy (insulin B-test Wako,
(manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.). Blood sugar levels were measured using the mutarotase-glucose oxidase method (Glucose C-Test Fuco, manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.).
（４）箕田法
また、インスリンの吸収率及び血糖値の減少率は下記式
から算出した。(4) Minota method In addition, the absorption rate of insulin and the rate of decrease in blood sugar level were calculated using the following formula.
■インスリンの相対吸収率（％）
経鼻： インスリン経鼻投与時のインスリンの０
〜４時間目までの血中濃度
時間曲線下面積（ｈ・μＵ ／ｍｌ）
コントロール：インスリン非投与時のインスリンのＯ〜
４時間目までの血中濃度時
間曲線下面積（ｈ・μＵ／ｍｌ）
静注： インスリンの静脈注射時のインスリンの
Ｏ〜４時間目までの血中濃
度時間曲線下面積（ｈ・μＵ／ｍｌ）
■血糖値の減少率（ＤＸ）
経鼻： インスリン経鼻投与時の血糖値の０〜４
時間目までの血中濃度時間
曲線下面積（ｈ −ｍｇ／ｄｌ）
コントロール：インスリン非投与時の血糖値の０〜４時
間目までの血中濃度時間面
線下面積（ｈ −ｍｇ／ｄｉ）
静注二 インスリン静脈注射時の血糖値の０〜４
時間目までの血中濃度時間
曲線下面積（ｈ −ｍｇ／ｄｉ）
（５）結果
第１図は、インスリン非投与（コントロール）、インス
リン単独投与（単独、 １０ ｕ／ｋｇ）、１％グリチ
ルリチン・ジカリウム（以下、ＧＬ・２Ｋ）含有インス
リン溶液投与（ＩＯＵ／ｋｇ）後の夫々のインスリンの
血中濃度時間曲線を示している。■Relative absorption rate of insulin (%) Nasal: 0 of insulin during nasal administration of insulin
Area under the blood concentration time curve up to 4 hours (h・μU/ml) Control: Insulin O when no insulin was administered
Area under the blood concentration time curve up to the 4th hour (h・μU/ml) Intravenous injection: Area under the blood concentration time curve of insulin from 0 to the 4th hour during intravenous injection of insulin (h・μU/ml ) ■Decrease rate of blood sugar level (DX) Nasal: 0 to 4 of blood sugar level during nasal administration of insulin
Area under the blood concentration time curve (h - mg/dl) Control: Area under the blood concentration time curve from 0 to 4 hours of blood glucose level without insulin administration (h - mg/di) Intravenous injection 2 Blood sugar level during intravenous insulin injection: 0-4
Area under the blood concentration time curve (h - mg/di) (5) Results Figure 1 shows the results for non-insulin administration (control), insulin administration alone (alone, 10 u/kg), and 1% glycyrrhizin. The blood concentration time curves of each insulin after administration (IOU/kg) of an insulin solution containing dipotassium (hereinafter referred to as GL/2K) are shown.
インスリン単独投与でも血漿インスリン濃度はコントロ
ールに比べ投与後１５分で有意（ｐ＜０．０１）に上昇
し、最高血中濃度到達時間（ｔ ｍａｘ）は１時間であ
った。また、投与後４時間目までの血中濃度時間曲線下
面積（ＡＵＣｏ−４＞はコントロールの約６倍となった
が、血糖値を減少させるまでには至らなかった。Even when insulin was administered alone, the plasma insulin concentration increased significantly (p<0.01) 15 minutes after administration compared to the control, and the time to reach the maximum blood concentration (t max) was 1 hour. Furthermore, the area under the blood concentration time curve (AUCo-4>) up to 4 hours after administration was about 6 times that of the control, but it did not lead to a decrease in blood sugar level.
１％ＧＬ・２に含有インスリン１０ Ｕ／ｋｇ投与にお
いて、インスリンの血中濃度変化は、投与後２時間目で
約１９０μＵ／ｍｌの最高血中１５度が得られた。When 10 U/kg of insulin contained in 1% GL.2 was administered, the change in blood insulin concentration reached a maximum of about 190 μU/ml at 15°C 2 hours after administration.
第２図は、この時の血糖値の時間推移を示している。コ
ントロールと単独投与時には有意差は認められなかった
が、１％ＧＬ・２に添加群では投与後１５分でコントロ
ールに比べ約２０％減少した。この血糖値の減少は投与
後４時間後も持続し、その時の血糖減少率は６５％であ
った。FIG. 2 shows the time course of the blood sugar level at this time. No significant difference was observed between the control and single administration, but in the 1% GL-2 addition group, the amount decreased by about 20% compared to the control 15 minutes after administration. This reduction in blood sugar level continued even 4 hours after administration, and the blood sugar reduction rate at that time was 65%.
また、以下の表１は、ＧＬ・２Ｋ及びグリチルリチン・
アンモニウム（以下、ＧＬ−ＮＨ４）の経鼻吸収につい
て静脈注射や皮下注射と比較したものである。In addition, Table 1 below shows GL・2K and glycyrrhizin・
The nasal absorption of ammonium (hereinafter referred to as GL-NH4) is compared with intravenous injection and subcutaneous injection.
表１ インスリンのラット鼻腔内投与後のインスリンの
経鼻吸収率及び血糖
減少率に対するグリチルリチンの効果
インスリン
ＡＵＣ，−。Table 1 Effect of glycyrrhizin on the nasal absorption rate and blood glucose reduction rate of insulin after intranasal administration of insulin in rats Insulin AUC, -.
ｈ・μ［Ｊ／ｍｌ
コントロール ２８．７±５．１径鼻
単独 １７２±１４．２
ＧＬ・２Ｋ ５４４±５９．４ＧＬ−ＮＨ，２
６８±５４，２
静注 ３５７６±５０７
皮下性 １４５６±２６０
面別
減少率
％
相対
吸収率
％
３．９±１１．０ ２．０２
５１．７±２．３ ７．２６
５３．１±８．２ ３．３７
８１．８±１．０ １００
７６．２＋：４．４ ４０．２
インスリンの経鼻投与量は１００１ｋｇ、静注及び皮下
性は５０１ｋｇである。h・μ [J/ml Control 28.7±5.1 diameter nose alone 172±14.2 GL・2K 544±59.4GL-NH,2
68±54,2 Intravenous injection 3576±507 Subcutaneous 1456±260 Reduction rate by area % Relative absorption rate % 3.9±11.0 2.02 51.7±2.3 7.26 53.1±8. 2 3.37 81.8±1.0 100 76.2+:4.4 40.2 The nasal dose of insulin is 1001 kg, and the intravenous and subcutaneous dose is 501 kg.
６値はラット３匹から７匹の平均値上標準誤差である。6 Values are the standard error above the mean of 3 to 7 rats.
インスリン非投与の場合、インスリンの４時間目までの
ＡＵＧ、、は２８．７ｂ−７１Ｕ／ｍｌであったが、イ
ンスリン単独投与では１７２ｈ・μＵ／ｍｌとなった。In the case of no insulin administration, the AUG of insulin up to the 4th hour was 28.7b-71U/ml, but when insulin was administered alone, it was 172h·μU/ml.
これに対し、１％ＧＬ・２に添加群では、インスリンの
八〇Ｃ０−４は５５４ｈ・μＵ／ｍｌでコントロール値
の約１９倍となり、これは静脈注射の吸収率を１００％
とした場合、７．２６％に相当し、この時の血糖減少率
は５２％であった。また、１％ＧＬ −ＮＨ４添加群で
は、吸収率は３．３７％と低いにもかかわらず、血糖減
少率は５３％となった。On the other hand, in the group added to 1% GL・2, the insulin 80C0-4 was 554 h・μU/ml, which was about 19 times the control value, which decreased the absorption rate of intravenous injection to 100%.
In this case, it corresponds to 7.26%, and the blood sugar reduction rate at this time was 52%. Furthermore, in the 1% GL-NH4 addition group, although the absorption rate was as low as 3.37%, the blood sugar reduction rate was 53%.
本試験例でのインスリンの経鼻投与量をヒトに換箕する
と、１０倍量になるが、上記の血糖減少作用から判断す
ると、これらより低用量の投与でも充分な効果が期待さ
れる。If the intranasal dose of insulin in this test example were compared to humans, it would be 10 times the dose, but judging from the blood sugar-reducing effect described above, sufficient effects are expected even with lower doses than these.
第１図は、１％ＧＬ・２に含有インスリン溶液（１０Ｕ
／に３）のラット鼻腔内投与後の血漿中インスリン非投
与時間曲線を示す図、第２図は、１％ＧＬ・２に含有、
１′ンスリン溶液（１００１ｋｇ）のラット鼻腔内投与
後（１）血糖値の変化を示す図である。
０．５
０．５
語間Figure 1 shows an insulin solution (10 U) containing 1% GL.2.
Figure 2 shows the non-administration time curve of plasma insulin after intranasal administration of 3) in rats.
FIG. 2 is a diagram showing (1) changes in blood glucose level after intranasal administration of 1' insulin solution (1001 kg) to rats. 0.5 0.5 Word spacing
Claims (4)
塩を有効成分とする難吸収性物質の経粘膜吸収促進剤。(1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A transmucosal absorption enhancer for poorly absorbed substances containing glycyrrhizin and its pharmaceutically acceptable salts as active ingredients.
塩を有効成分とするペプチドホルモンの経粘膜吸収促進
剤。(2) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A peptide hormone transmucosal absorption enhancer containing glycyrrhizin and its pharmaceutically acceptable salt as active ingredients.
塩を添加してなることを特徴とする経鼻投与剤。(3) A nasal administration agent characterized by adding glycyrrhizin represented by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ and a pharmaceutically acceptable salt thereof to a poorly absorbed substance.
請求の範囲第３項に記載の経鼻投与剤。(4) The nasal preparation according to claim 3, wherein the poorly absorbed substance is a peptide hormone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63193649A JPH0242027A (en) | 1988-08-02 | 1988-08-02 | Transmucosal absorbefacient and pernasal administration agent using said absorbefacient |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63193649A JPH0242027A (en) | 1988-08-02 | 1988-08-02 | Transmucosal absorbefacient and pernasal administration agent using said absorbefacient |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0242027A true JPH0242027A (en) | 1990-02-13 |
Family
ID=16311457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63193649A Pending JPH0242027A (en) | 1988-08-02 | 1988-08-02 | Transmucosal absorbefacient and pernasal administration agent using said absorbefacient |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0242027A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2666987A1 (en) * | 1990-09-20 | 1992-03-27 | Sandoz Sa | NEW COMPOSITION FOR NASAL ADMINISTRATION. |
| US6620788B1 (en) | 1999-02-26 | 2003-09-16 | Hisamitsu Pharmaceutical Co., Inc. | Enteral sorbefacients |
| JP2006298791A (en) * | 2005-04-18 | 2006-11-02 | Kotobuki Seiyaku Kk | Medicine for oral administration, health food or nutrient chemical composition containing glycosaminoglycan or its salt |
| US8895503B2 (en) | 2008-02-28 | 2014-11-25 | Toray Industries, Inc. | Pharmaceutical composition for transnasal administration of peptide hormones or cytokines |
-
1988
- 1988-08-02 JP JP63193649A patent/JPH0242027A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2666987A1 (en) * | 1990-09-20 | 1992-03-27 | Sandoz Sa | NEW COMPOSITION FOR NASAL ADMINISTRATION. |
| US6620788B1 (en) | 1999-02-26 | 2003-09-16 | Hisamitsu Pharmaceutical Co., Inc. | Enteral sorbefacients |
| JP2006298791A (en) * | 2005-04-18 | 2006-11-02 | Kotobuki Seiyaku Kk | Medicine for oral administration, health food or nutrient chemical composition containing glycosaminoglycan or its salt |
| US8895503B2 (en) | 2008-02-28 | 2014-11-25 | Toray Industries, Inc. | Pharmaceutical composition for transnasal administration of peptide hormones or cytokines |
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