JPH06192107A - Glycyrrhizin oral agent - Google Patents
Glycyrrhizin oral agentInfo
- Publication number
- JPH06192107A JPH06192107A JP34715892A JP34715892A JPH06192107A JP H06192107 A JPH06192107 A JP H06192107A JP 34715892 A JP34715892 A JP 34715892A JP 34715892 A JP34715892 A JP 34715892A JP H06192107 A JPH06192107 A JP H06192107A
- Authority
- JP
- Japan
- Prior art keywords
- glycyrrhizin
- preparation
- water
- acid
- glycyrrhizic acid
- 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
- 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 title claims abstract description 59
- 229960004949 glycyrrhizic acid Drugs 0.000 title claims abstract description 58
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 58
- 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 title claims abstract description 55
- 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 title claims abstract description 55
- 239000004378 Glycyrrhizin Substances 0.000 title claims abstract description 30
- 239000003795 chemical substances by application Substances 0.000 title abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 150000002632 lipids Chemical class 0.000 claims abstract description 11
- 238000010521 absorption reaction Methods 0.000 claims abstract description 10
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000002960 lipid emulsion Substances 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 8
- 210000000813 small intestine Anatomy 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 30
- 239000003623 enhancer Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 6
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 6
- 239000002736 nonionic surfactant Substances 0.000 claims description 4
- 229940124532 absorption promoter Drugs 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 239000002075 main ingredient Substances 0.000 claims 2
- 238000007796 conventional method Methods 0.000 abstract description 6
- 239000011248 coating agent Substances 0.000 abstract description 2
- 238000000576 coating method Methods 0.000 abstract description 2
- 238000002156 mixing Methods 0.000 abstract description 2
- MPDGHEJMBKOTSU-YKLVYJNSSA-N 18beta-glycyrrhetic acid Chemical compound C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H](O)C1(C)C MPDGHEJMBKOTSU-YKLVYJNSSA-N 0.000 abstract 2
- MPDGHEJMBKOTSU-UHFFFAOYSA-N Glycyrrhetinsaeure Natural products C12C(=O)C=C3C4CC(C)(C(O)=O)CCC4(C)CCC3(C)C1(C)CCC1C2(C)CCC(O)C1(C)C MPDGHEJMBKOTSU-UHFFFAOYSA-N 0.000 abstract 1
- 229960003720 enoxolone Drugs 0.000 abstract 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 25
- 239000001685 glycyrrhizic acid Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 description 16
- 239000008280 blood Substances 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 14
- -1 alkali metal salt Chemical class 0.000 description 12
- FIWQZURFGYXCEO-UHFFFAOYSA-M sodium;decanoate Chemical compound [Na+].CCCCCCCCCC([O-])=O FIWQZURFGYXCEO-UHFFFAOYSA-M 0.000 description 10
- 239000003549 soybean oil Substances 0.000 description 10
- 235000012424 soybean oil Nutrition 0.000 description 10
- 210000001198 duodenum Anatomy 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 241000700159 Rattus Species 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 239000002702 enteric coating Substances 0.000 description 6
- 238000009505 enteric coating Methods 0.000 description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000001015 abdomen Anatomy 0.000 description 5
- 230000002183 duodenal effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 210000004731 jugular vein Anatomy 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 3
- 206010002091 Anaesthesia Diseases 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- ACXGEQOZKSSXKV-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O.CCCCCCCC(O)=O ACXGEQOZKSSXKV-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 2
- 208000019423 liver disease Diseases 0.000 description 2
- 229960002446 octanoic acid Drugs 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229960005480 sodium caprylate Drugs 0.000 description 2
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 description 2
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、グリチルリチン及びそ
の塩の血中への移行性を大幅に高め、生体内利用率を大
きく向上させた経口剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oral preparation which has a greatly improved transferability of glycyrrhizin and its salts into the blood and a greatly improved bioavailability.
【０００２】[0002]
【従来の技術及びその課題】グリチルリチン及びその塩
は、単独もしくはアミノ酸などと配合され、各種の薬理
作用例えば抗コルチゾン作用、脱コレステロール作用、
抗アレルギー作用、抗炎症作用、解毒作用、胃潰瘍修復
作用等を有していることが知られている。グリチルリチ
ン又はその塩（以下、グリチルリチン）を主薬とするグ
リチルリチン製剤は、主として肝疾患治療用の医薬品と
して実用に供せられている。BACKGROUND OF THE INVENTION Glycyrrhizin and its salts are used alone or in combination with amino acids, and have various pharmacological actions such as anticortisone action and decholesterolization action.
It is known to have antiallergic action, antiinflammatory action, detoxification action, gastric ulcer repair action and the like. A glycyrrhizin preparation containing glycyrrhizin or a salt thereof (hereinafter referred to as glycyrrhizin) as a main drug is put to practical use mainly as a drug for treating liver diseases.
【０００３】一般に、急性及び慢性のいかんを問わず肝
疾患治療用の医薬品は、比較的長期にわたって薬剤を連
続投与することが必要とされる。そして、グリチルリチ
ン経口剤は、患者の通院頻度を減少させ、通院負担を軽
減するために開発され使用されているが、市販されてい
る全身作用期待のグリチルリチン経口投与の場合、胃酸
による分解や肝臓での初回通過効果による代謝のため、
血中への移行性に問題があることが報告（治療学、VOL.
7,No.5,p.703（1981年））されている。そのため、経口
剤に代わる剤形として坐剤が検討（特開平1-294619号）
されている。しかし、患者の立場からすれば、効果が確
実であれば、坐剤よりも使用しやすい経口剤が望まれて
いる。そして、血中への移行性を改善した経口剤として
は、脂肪酸グリセリドの配合及び腸溶性被膜での被覆を
施した製剤の報告（特開平3-255037号）がされている。
しかし、この製剤は、効果が確定している注射剤の血中
濃度に比べ、まだまだ十分な血中移行性を示していると
は考えられない。In general, pharmaceuticals for treating liver diseases, whether acute or chronic, require continuous administration of the agents for a relatively long period of time. Glycyrrhizin oral agents have been developed and used to reduce the frequency of patient visits to hospitals and to reduce the burden of hospital visits.However, in the case of oral administration of glycyrrhizin, which is expected to have a systemic effect on the market, it is decomposed by gastric acid or in the liver. Metabolism due to the first-pass effect of
Reported a problem with transferability to blood (Therapeutics, VOL.
7, No. 5, p. 703 (1981)). Therefore, suppositories are being examined as an alternative form to oral agents (Japanese Patent Laid-Open No. 1-294619).
Has been done. However, from the standpoint of the patient, an oral preparation that is easier to use than a suppository is desired if the effect is certain. As an oral preparation having improved transferability into blood, there is a report on a preparation containing a fatty acid glyceride and an enteric coating (Japanese Patent Laid-Open No. 3-255037).
However, it cannot be considered that this preparation shows a sufficient blood transfer property as compared with the blood concentration of an injection for which the effect is confirmed.
【０００４】[0004]
【課題を解決するための手段および作用】そこで、本発
明者らは、グリチルリチン及びその塩の経口投与に於け
る血中への移行性を改善する方法について鋭意検討した
結果、グリチルリチン及びその塩を脂肪乳剤又は複合脂
質混合体、又はそれらの乾燥粉末とし、吸収促進剤とし
て中鎖脂肪酸及びその塩類及びそのグリセリド又は非イ
オン系界面活性剤の少なくとも１つを含有させ、常法に
より製剤成型し、更に、製剤を腸溶性被膜で被覆する。
即ち、主薬及び吸収促進剤の製剤からの放出を、小腸上
部にて行えば、従来の経口剤より極めて優れた吸収性を
示すことを見い出した。[Means and Actions for Solving the Problems] Therefore, as a result of diligent studies on the method of improving the transmissibility of glycyrrhizin and its salts into blood upon oral administration, the present inventors have found that glycyrrhizin and its salts A fat emulsion or complex lipid mixture, or a dry powder thereof, containing at least one of medium chain fatty acid and its salts and its glyceride or nonionic surfactant as an absorption promoter, and molded into a formulation by a conventional method, In addition, the formulation is coated with an enteric coating.
That is, it was found that when the release of the main drug and the absorption enhancer from the preparation is carried out in the upper small intestine, it exhibits extremely excellent absorbability as compared with the conventional oral preparation.
【０００５】グリチルリチンの塩としては、医薬として
許容されるものであればよく、カリウム、ナトリウム、
アンモニウム塩などが挙げられる。グリチルリチン及び
その塩を脂肪乳剤又は複合脂質混合体、又はそれらの乾
燥粉末とすることにより、グリチルリチン及びその塩の
存在状態が変化したものと考えられる。The glycyrrhizin salt may be any pharmaceutically acceptable salt, such as potassium, sodium,
Examples thereof include ammonium salts. It is considered that the presence state of glycyrrhizin and its salt was changed by making glycyrrhizin and its salt into a fat emulsion, a complex lipid mixture, or their dry powder.
【０００６】脂肪乳剤は、従来知られている任意の処
方、方法により製造される。例えば、全体の50％（W/V
）までの油脂（例えば単純脂質）と油脂に対し重量比
で 2〜70％（W/V ）の乳化剤（例えばリン脂質）及び必
要に応じて乳化補助剤、安定化剤等を加熱或いは溶媒留
去するなどしてグリチルリチンと均一に混合し、適当量
の水を加え、通常のホモジナイザー等により均質化する
ことにより製造される。 複合脂質混合体は、従来知ら
れている任意の処方、方法により製造される。例えば、
複合脂質（例えばリン脂質）及び必要に応じて安定化剤
等を加熱或いは溶媒留去するなどしてグリチルリチンと
均一に混合し、適当量の水を加え、均質化することによ
り製造される。The fat emulsion is produced by any conventionally known method and method. For example, 50% (W / V
) Up to 2) to 70% (W / V) emulsifier (eg phospholipid) in weight ratio to fats and oils (eg simple lipids) and, if necessary, heating or solvent distillation of emulsifying aids, stabilizers, etc. It is produced by uniformly mixing it with glycyrrhizin by removing it, adding an appropriate amount of water, and homogenizing with an ordinary homogenizer. The complex lipid mixture is produced by any conventionally known formulation and method. For example,
The complex lipid (for example, phospholipid) and, if necessary, a stabilizer and the like are heated or mixed with the glycyrrhizin to uniformly mix them with water, and an appropriate amount of water is added for homogenization.
【０００７】吸収促進剤として、中鎖脂肪酸及びその塩
類としては、例えば、カプリン酸カプリル酸やカプロン
酸などの中鎖の脂肪酸のアルカリ金属塩やアルカリ土類
金属塩を使用することができる。また、中鎖脂肪酸グリ
セリドとしては、カプリン酸、カプリル酸、カプロン酸
などのモノ、ジ、トリグリセリド等を使用することがで
きる。更に、非イオン系界面活性剤としては、例えば、
ポリオキシエチレンアルキルエーテル等、ポリオキシエ
チレンアルキルフェニルエーテル等、ポリオキシエチレ
ンソルビタン脂肪酸エステル等、ポリオキシエチレン硬
化ヒマシ油等、ポリエチレングリコール脂肪酸エステル
等、蔗糖脂肪酸エステル等を例示することができ、これ
らは単独で、又は適宜組み合わせて使用することができ
る。As the medium-chain fatty acid and its salt as the absorption promoter, for example, an alkali metal salt or an alkaline earth metal salt of a medium chain fatty acid such as caprylic acid caprylic acid or caproic acid can be used. As the medium chain fatty acid glyceride, mono-, di-, triglycerides such as capric acid, caprylic acid and caproic acid can be used. Further, as the nonionic surfactant, for example,
Examples thereof include polyoxyethylene alkyl ether, etc., polyoxyethylene alkylphenyl ether, etc., polyoxyethylene sorbitan fatty acid ester, etc., polyoxyethylene hydrogenated castor oil, etc., polyethylene glycol fatty acid ester, etc., sucrose fatty acid ester, etc. They can be used alone or in appropriate combination.
【０００８】腸溶性被膜は、薬剤に通常用いられるもの
であればよく、例えば、ヒドロキシプロピルメチルセル
ロースフタレート、セルロースアセテートなどを使用す
ることができる。The enteric coating may be any one commonly used in medicine, and for example, hydroxypropylmethyl cellulose phthalate, cellulose acetate and the like can be used.
【０００９】主薬及び吸収促進剤の製剤からの放出は、
消化管中、胃より下部であればどこでもよいのではな
く、小腸上部にて選択的に行う。The release of the main drug and absorption enhancer from the formulation is
The digestive tract may be selected anywhere in the upper small intestine rather than anywhere below the stomach.
【００１０】グリチルリチン及びその塩を、脂肪乳剤又
は複合脂質混合体、又はそれらの乾燥粉末とし、吸収促
進剤として中鎖脂肪酸及びその塩類又は非イオン系界面
活性剤の少なくとも１つを含有させ、更に、各種の腸溶
性被膜で被覆することにより、小腸上部においての吸収
に最適な放出制御できる経口製剤が創製できたものと考
えられる。Glycyrrhizin and a salt thereof are made into a fat emulsion or a complex lipid mixture, or a dry powder thereof, and at least one of a medium-chain fatty acid and a salt thereof or a nonionic surfactant is added as an absorption enhancer. It is considered that, by coating with various enteric coatings, an oral preparation capable of controlled release optimal for absorption in the upper small intestine could be created.
【００１１】経口剤の剤形としては、通常の錠剤、カプ
セル剤、顆粒剤、散剤などが挙げられ、製剤化に際し必
要に応じて賦型剤、結合剤、滑沢剤、安定化剤、着色剤
等を配合することができる。本発明製剤は、特開平3-25
5037号よりもグリチルリチン及びその塩の血中への移行
性を大幅に高めうる。グリチルリチン含量は薬効が期待
できる量であればとくに制限はなく、好ましくは１回量
が50〜250mg で、１日１〜３回投与することができる。Examples of the dosage form of the oral preparation include ordinary tablets, capsules, granules, powders and the like. A excipient, a binder, a lubricant, a stabilizer, a coloring agent may be added as necessary during formulation. Agents and the like can be added. The preparation of the present invention is disclosed in JP-A-3-25
The transferability of glycyrrhizin and its salts into the blood can be significantly increased compared to No. 5037. The glycyrrhizin content is not particularly limited as long as it is expected to have a medicinal effect, and a single dose is preferably 50 to 250 mg, which can be administered 1 to 3 times a day.
【００１２】[0012]
【実施例等】次に参考例、製造例及び試験例により本発
明を更に詳細に且つ具体的に説明する。製剤の評価試験
は、ラットを用いておこなった。EXAMPLES The present invention will be described in more detail and specifically with reference to Reference Examples, Production Examples and Test Examples. The evaluation test of the preparation was carried out using rats.
【００１３】参考例１ 成分 グリチルリチン酸 0.5 g水 99.5 g 合計 100.0 g グリチルリチン酸を水に溶解させて、グリチルリチン水
溶液（以下、ＧＬ水溶液）を得た。 Reference Example 1 Component Glycyrrhizic acid 0.5 g Water 99.5 g Total 100.0 g Glycyrrhizic acid was dissolved in water to obtain a glycyrrhizin aqueous solution (hereinafter, GL aqueous solution).
【００１４】参考例２ 成分 グリチルリチン酸 1 g 精製卵黄レシチン 4 g 大豆油 16 g水 179 g 合計 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去する。次に大豆油を加え混合し、水を加
えて乳化して製した。 Reference Example 2 Component Glycyrrhizic acid 1 g Purified egg yolk lecithin 4 g Soybean oil 16 g Water 179 g Total 200 g Glycyrrhizic acid and purified egg yolk lecithin are uniformly mixed and dissolved, and the solvent is distilled off. Next, soybean oil was added and mixed, and water was added to emulsify the mixture.
【００１５】参考例３ 成分 グリチルリチン酸 10 g 精製卵黄レシチン 10 g水 180 g 合計 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去する。次に水を加えて製した。 Reference Example 3 Component Glycyrrhizic acid 10 g Purified egg yolk lecithin 10 g Water 180 g Total 200 g Glycyrrhizic acid and purified egg yolk lecithin are uniformly mixed and dissolved, and the solvent is distilled off. Next, it was made by adding water.
【００１６】参考例４ 成分 グリチルリチン酸 0.5 g カプリン酸ナトリウム 4.0 g水 95.5 g 合計 100.0 g グリチルリチン酸を水に溶解させて、更にカプリン酸ナ
トリウムを加えて製した。 Reference Example 4 Component Glycyrrhizic acid 0.5 g Sodium caprate 4.0 g Water 95.5 g Total 100.0 g Glycyrrhizic acid was dissolved in water, and sodium caprate was further added.
【００１７】製造例１ 成分 ［処方−１］ ［処方−２］ グリチルリチン酸 1 g 1 g カプリン酸ナトリウム 8 g 4 g 精製卵黄レシチン 4 g 4 g 大豆油 16 g 16 g 水 171 g 175 g 合計 200 g 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去する。次に大豆油を加え混合し、水を加
えて乳化する。更にカプリン酸ナトリウムを加えて製し
た。 Production Example 1 Component [Formulation-1] [Formulation-2] Glycyrrhizic acid 1 g 1 g Sodium caprate 8 g 4 g Purified egg yolk lecithin 4 g 4 g Soybean oil 16 g 16 g Water 171 g 175 g Total 200 g 200 g Glycyrrhizic acid and purified egg yolk lecithin are uniformly mixed and dissolved, and the solvent is distilled off. Next, soybean oil is added and mixed, and water is added to emulsify. Furthermore, it manufactured by adding sodium caprate.
【００１８】製造例２ 成分 グリチルリチン酸 1 g カプロン酸ナトリウム 8 g 精製卵黄レシチン 4 g 大豆油 16 g水 171 g 合計 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去する。次に大豆油を加え混合し、水を加
えて乳化する。更にカプロン酸ナトリウムを加えて製し
た。 Production Example 2 components Glycyrrhizic acid 1 g Sodium caproate 8 g Purified egg yolk lecithin 4 g Soybean oil 16 g Water 171 g Total 200 g Glycyrrhizic acid and purified egg yolk lecithin are uniformly mixed and dissolved, and the solvent is distilled off. Next, soybean oil is added and mixed, and water is added to emulsify. Furthermore, it manufactured by adding sodium caproate.
【００１９】製造例３ 成分 グリチルリチン酸 1 g カプリル酸ナトリウム 8 g 精製卵黄レシチン 4 g 大豆油 16 g水 171 g 合計 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去する。次に大豆油を加え混合し、水を加
えて乳化する。更にカプリル酸ナトリウムを加えて製し
た。 Production Example 3 components Glycyrrhizic acid 1 g Sodium caprylate 8 g Purified egg yolk lecithin 4 g Soybean oil 16 g Water 171 g Total 200 g Glycyrrhizic acid and purified egg yolk lecithin are uniformly mixed and dissolved, and the solvent is distilled off. Next, soybean oil is added and mixed, and water is added to emulsify. Furthermore, it manufactured by adding sodium caprylate.
【００２０】製造例４ 成分 ［処方−１］ ［処方−２］ グリチルリチン酸 10 g 10 g カプリン酸ナトリウム 8 g 4 g 精製卵黄レシチン 10 g 10 g 水 172 g 176 g 合計 200 g 200 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去し、次に水を加え、更にカプリン酸ナト
リウムを加えて製した。 Production Example 4 components [Formulation-1] [Formulation-2] Glycyrrhizic acid 10 g 10 g Sodium caprate 8 g 4 g Purified egg yolk lecithin 10 g 10 g Water 172 g 176 g Total 200 g 200 g Glycyrrhizic acid Purified egg yolk lecithin was uniformly mixed and dissolved, the solvent was distilled off, water was then added, and sodium caprate was further added.
【００２１】製造例５ 成分 グリチルリチン酸 1 g カプリン酸ナトリウム 8 g 精製卵黄レシチン 4 g 大豆油 16 g マンニト−ル 50 g水 171 g 合計 250 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去し、次に大豆油を加え混和し、水を加え
て乳化する。更にカプリン酸ナトリウム及びマンニト−
ルを加えて溶かした後、乾燥する。次に、常法により顆
粒を製し、腸溶性被膜を施し経口製剤とした。 Production Example 5 components Glycyrrhizic acid 1 g Sodium caprate 8 g Purified egg yolk lecithin 4 g Soybean oil 16 g Mannitol 50 g Water 171 g Total 250 g Glycyrrhizic acid and purified egg yolk lecithin were uniformly mixed and dissolved, and the solvent was added. After distilling off, soybean oil is added and mixed, and water is added to emulsify. In addition, sodium caprate and mannito
And melted, and dried. Next, granules were manufactured by an ordinary method and an enteric coating was applied to give an oral preparation.
【００２２】製造例６ 成分 グリチルリチン酸 10 g カプリン酸ナトリウム 8 g 精製卵黄レシチン 10 g マンニト−ル 50 g水 172 g 合計 250 g グリチルリチン酸と精製卵黄レシチンを均一混合溶解
し、溶媒を留去し、次に水を加え、更にカプリン酸ナト
リウム及びマンニト−ルを加えて溶かした後、乾燥す
る。次に、常法により顆粒を製し、腸溶性被膜を施し経
口製剤とした。 Production Example 6 ingredients Glycyrrhizic acid 10 g Sodium caprate 8 g Purified egg yolk lecithin 10 g Mannitol 50 g Water 172 g Total 250 g Glycyrrhizic acid and purified egg yolk lecithin were uniformly mixed and dissolved, and the solvent was distilled off, Next, water is added, and sodium caprate and mannitol are further added and dissolved, followed by drying. Next, granules were manufactured by an ordinary method and an enteric coating was applied to give an oral preparation.
【００２３】試験例１ 24時間絶食させたラットに参考例１をＧＬＨ2 （グリチ
ルリチン酸）として20mg/Kg 、胃内投与又はエーテル麻
酔下で腹部を開復し十二指腸投与後、腹部を縫合し、経
時的に頸静脈より採血し、常法により血漿を得た。この
血漿中のグリチルリチン酸濃度を高速液体クロマトグラ
フ法により測定し、得られた血漿中濃度からＡＵＣ0-8
［曲線下面積（Area under the curve）（μｇ・hr/ml
）］を求めた。そして、注射剤との比較で利用率を算
出した。 Test Example 1 20 mg / Kg of GLH 2 (glycyrrhizic acid) as reference example 1 was given to a rat fasted for 24 hours, and the abdomen was opened by intragastric administration or under ether anesthesia, and after duodenum administration, the abdomen was sutured, Blood was collected from the jugular vein over time, and plasma was obtained by a conventional method. The glycyrrhizic acid concentration in this plasma was measured by a high performance liquid chromatographic method, and AUC 0-8 was determined from the obtained plasma concentration.
[Area under the curve (μg · hr / ml
)] Was asked. Then, the utilization rate was calculated by comparison with the injection.
【００２４】結果は、下記に示される通りであり、ＧＬ
水溶液は、経口投与および十二指腸投与に於いてほんの
わずかしか吸収されないことが判明した。 The results are as shown below, GL
The aqueous solution was found to be only poorly absorbed upon oral and duodenal administration.
【００２５】試験例２ 24時間絶食させたラットに参考例２，３をＧＬＨ2 （グ
リチルリチン酸）として20mg/Kg 、エーテル麻酔下で腹
部を開復し十二指腸投与後、腹部を縫合し、経時的に頸
静脈より採血し、常法により血漿を得た。この血漿中の
グリチルリチン酸濃度を高速液体クロマトグラフ法によ
り測定し、ＡＵＣ0-8 を求めた。そして、注射剤との比
較で利用率を算出した。 Test Example 2 Rats fasted for 24 hours were treated with Reference Examples 2 and 3 as GLH 2 (glycyrrhizinic acid) at 20 mg / Kg, and the abdomen was reopened under ether anesthesia. Blood was collected from the jugular vein and plasma was obtained by a conventional method. The glycyrrhizic acid concentration in this plasma was measured by high performance liquid chromatography to determine AUC 0-8 . Then, the utilization rate was calculated by comparison with the injection.
【００２６】結果は、下記に示される通りであり、グリ
チルリチン脂肪乳剤及びグリチルリチン複合脂質混合体
は、十二指腸投与に於いてわずかしか吸収されないこと
が判明した。 The results are shown below, and it was found that the glycyrrhizin fat emulsion and the glycyrrhizin complex lipid mixture were poorly absorbed upon duodenal administration.
【００２７】試験例３ 24時間絶食させたラットに参考例１又は実施例１〜４を
ＧＬＨ2 （グリチルリチン酸）として20mg/Kg 、胃内投
与又はエーテル麻酔下で腹部を開復し十二指腸投与後、
腹部を縫合し、経時的に頸静脈より採血し、常法により
血漿を得た。この血漿中のグリチルリチン酸濃度を高速
液体クロマトグラフ法により測定し、ＡＵＣ0-8 を求め
た。そして、注射剤との比較で利用率を算出した。 Test Example 3 Rats fasted for 24 hours were treated with Reference Example 1 or Examples 1 to 4 as GLH 2 (glycyrrhizinic acid) at 20 mg / Kg, intragastrically administered or after abdominal resection under ether anesthesia and duodenal administration. ,
The abdomen was sutured, blood was collected from the jugular vein over time, and plasma was obtained by a conventional method. The glycyrrhizic acid concentration in this plasma was measured by high performance liquid chromatography to determine AUC 0-8 . Then, the utilization rate was calculated by comparison with the injection.
【００２８】結果は、下記に示される通りであり、グリ
チルリチンはその水溶液、脂肪乳剤又は複合脂質混合体
に吸収促進剤を分散させた製剤を胃内に投与しても血中
にグリチルリチンをほとんど検出されなかった。また吸
収促進剤の効果も認めなかった。グリチルリチンを脂肪
乳剤又は複合脂質混合体とし吸収促進剤を分散させた製
剤を十二指腸内投与したものは他と比較して非常に高い
血漿中グリチルリチンを検出され、吸収が著しく改善さ
れた。その改善効果は脂肪乳剤において特に顕著であっ
た。中鎖脂肪酸の吸収促進効果はカプリン酸＞カプリル
酸＞カプロン酸の順で、また吸収改善の効果はその配合
量に依存していた。 検 体 投与部位 ＡＵＣ（利用率） 製造例−１、処方−２ 胃 0.9 （ 0.4％） 製造例−４、処方−１ 胃 0.7 （ 0.3％） 参考例−４ 十二指腸 23.5 （10.0％） 製造例−１、処方−２ 十二指腸 138.7 （58.8％） 製造例−１、処方−１ 十二指腸 224.1 （95.0％） 製造例−４、処方−２ 十二指腸 34.9 （15.5％） 製造例−４、処方−１ 十二指腸 58.2 （24.7％） 製造例−２ 十二指腸 28.0 （11.9％） 製造例−３ 十二指腸 91.9 （38.9％）The results are as shown below. Glycyrrhizin was almost detected in the blood even when the glycyrrhizin was administered into the stomach as an aqueous solution, a fat emulsion, or a preparation in which an absorption enhancer was dispersed in a complex lipid mixture. Was not done. Moreover, the effect of the absorption enhancer was not recognized. In the duodenal administration of a preparation in which glycyrrhizin was used as a fat emulsion or a complex lipid mixture and an absorption enhancer was dispersed, extremely high plasma glycyrrhizin was detected, and absorption was remarkably improved. The improving effect was particularly remarkable in the fat emulsion. The absorption-promoting effect of medium-chain fatty acids was in the order of capric acid> caprylic acid> caproic acid, and the absorption-improving effect was dependent on the compounding amount thereof. Test body administration site AUC (utilization) Preparation -1, formulated -2 stomach 0.9 (0.4%) Preparation -4 formulated -1 stomach 0.7 (0.3%) Reference Example -4 duodenum 23.5 (10.0%) Preparation - 1. Prescription-2 Duodenum 138.7 (58.8%) Production Example-1, Prescription-1 Duodenum 224.1 (95.0%) Production Example-4, Prescription-2 Duodenum 34.9 (15.5%) Production Example-4, Prescription-1 Duodenum 58.2 ( 24.7%) Production Example-2 Duodenum 28.0 (11.9%) Production Example-3 Duodenum 91.9 (38.9%)
【００２９】試験例４ 24時間絶食させたラットにＧＬＨ2 （グリチルリチン
酸）として20mg/Kg 、実施例５，６を経口投与及び実施
例１をエーテル麻酔下で腹部を開復し十二指腸投与後、
腹部を縫合し、経時的に頸静脈より採血し常法により血
漿を得た。この血漿中のグリチルリチン酸濃度を高速液
体クロマトグラフ法により測定し、ＡＵＣ0-8 を求め
た。そして、注射剤との比較で利用率を算出した。 Test Example 4 20 mg / Kg of GLH 2 (glycyrrhizinic acid) was orally administered to rats that had been fasted for 24 hours, and Examples 5 and 6 were orally administered.
The abdomen was sutured, blood was collected from the jugular vein over time, and plasma was obtained by a conventional method. The glycyrrhizic acid concentration in this plasma was measured by high performance liquid chromatography to determine AUC 0-8 . Then, the utilization rate was calculated by comparison with the injection.
【００３０】結果は、下記に示される通りであり、本発
明品は、優れた吸収性を示した。 検 体 投与部位 ＡＵＣ（利用率） 製造例−５ 経口 157.6（ 66.8 ％） 製造例−６ 経口 135.5（ 57.4 ％） 製造例−１、処方−１ 十二指腸 224.1（ 95.0 ％）The results are shown below, and the product of the present invention showed excellent absorbency. Test body administration site AUC (utilization) Preparation -5 oral 157.6 (66.8%) Preparation -6 oral 135.5 (57.4%) Preparation Example -1, formulated -1 duodenum 224.1 (95.0%)
【００３１】[0031]
【発明の効果】本発明によるグリチルリチン経口剤は、
きわめて優れた利用率を示し、従来の経口剤の有してい
た課題、薬効発現の不確実性及びそれに伴う投与量の増
加に起因する副作用の発現を回避することができる。The oral preparation of glycyrrhizin according to the present invention is
It has an extremely high utilization rate, and can avoid the problems that conventional oral agents have, the uncertainty of the onset of drug efficacy, and the occurrence of side effects due to the accompanying increase in the dose.
【００３２】[0032]
【図１】製造例１・処方１，製造例２及び３をラットに
十二指腸投与し、経時的に採血して血漿中におけるグリ
チルリチンの濃度推移を調べた結果を示すグラフであ
る。FIG. 1 is a graph showing the results of examining the transition of the concentration of glycyrrhizin in plasma by intraperitoneally administering duodenal administration to rats of Preparation Example 1 / Preparation 1 and Preparation Examples 2 and 3, and collecting blood over time.
【図２】製造例１・処方１及び２，参考例４をラットに
胃内投与または十二指腸投与し、経時的に採血して血漿
中におけるグリチルリチンの濃度推移を調べた結果を示
すグラフである。FIG. 2 is a graph showing the results of examining the time course of glycyrrhizin concentration in plasma obtained by intragastrically or duodenally administering rats of Production Example 1 / Prescription 1 and 2, and Reference Example 4 and collecting blood over time.
【図３】製造例４・処方１，参考例４をラットに胃内投
与または十二指腸投与し、経時的に採血して血漿中にお
けるグリチルリチンの濃度推移を調べた結果を示すグラ
フである。FIG. 3 is a graph showing the results of investigating the concentration transition of glycyrrhizin in plasma by intragastrically or duodenally administering to Production Example 4, Prescription 1, and Reference Example 4 and collecting blood over time.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 粟 谷 寿 一 名古屋市東区東外堀町35番地 株式会社三 和化学研究所内 (72)発明者 平 出 欽 也 名古屋市東区東外堀町35番地 株式会社三 和化学研究所内 (72)発明者 澤 井 喜 一 名古屋市東区東外堀町35番地 株式会社三 和化学研究所内 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor, Juichi Awaya, 35, Higashi Sotobori-cho, Higashi-ku, Nagoya City, Sanwa Chemical Research Institute Co., Ltd. Sanwa Chemical Research Institute (72) Inventor Kiichi Sawai 35 Higashi Sotobori-cho, Higashi-ku, Nagoya-shi Sanwa Chemical Research Institute Co., Ltd.
Claims (4)
た少なくとも１種を主薬とする経口剤。1. An oral preparation containing at least one selected from glycyrrhizin and salts thereof as a main ingredient.
はそれらの乾燥粉末とすることを特徴とする、請求項１
に記載の経口剤。2. The main ingredient is a fat emulsion or a complex lipid mixture, or a dry powder thereof, characterized in that
Oral preparation according to.
塩類及びそのグリセリド又は非イオン系界面活性剤の少
なくとも１つを含有させることを特徴とする、請求項１
又は２に記載の経口剤。3. An absorption promoter containing at least one of a medium-chain fatty acid, a salt thereof, a glyceride thereof, and a nonionic surfactant.
Or the oral preparation according to 2.
を、小腸上部にて行うことを特徴とする、請求項１−３
のいずれか１つに記載の経口剤。4. The release of the main drug and the absorption enhancer from the formulation is performed in the upper part of the small intestine.
The oral preparation according to any one of 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34715892A JPH06192107A (en) | 1992-12-25 | 1992-12-25 | Glycyrrhizin oral agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34715892A JPH06192107A (en) | 1992-12-25 | 1992-12-25 | Glycyrrhizin oral agent |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06192107A true JPH06192107A (en) | 1994-07-12 |
Family
ID=18388312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP34715892A Pending JPH06192107A (en) | 1992-12-25 | 1992-12-25 | Glycyrrhizin oral agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH06192107A (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999045934A1 (en) * | 1998-03-11 | 1999-09-16 | Grelan Pharmaceutical Co., Ltd. | Bubbling enteric coated preparations |
| WO2000016784A1 (en) * | 1998-09-21 | 2000-03-30 | Amato Pharmaceutical Products, Ltd. | Oral drug delivery system for enhancing the bioavailability of activated glycyrrhetin |
| JP2002537321A (en) | 1999-02-22 | 2002-11-05 | エラン コーポレイション ピーエルスィー | Solid oral dosage form containing enhancer |
| JP2003073262A (en) * | 2001-08-30 | 2003-03-12 | Gotoo Corporation:Kk | Inclusion coating agent for solid preparation, solid preparation, method for producing the same, and foods |
| WO2004047846A1 (en) * | 2002-11-27 | 2004-06-10 | Minophagen Pharmaceutical Co., Ltd. | Oil/glycyrrhizin-containing surfactant phase type gel composition |
| EP1059091A4 (en) * | 1998-03-02 | 2005-12-21 | Hisamitsu Pharmaceutical Co | Transmucous sorbefacients |
| EP2609922A4 (en) * | 2010-08-26 | 2014-04-02 | Shuguang Hospital Affiliated To Shanghai University Of Traditional Chinese Medicine | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CHRONIC LIVER DISEASE AND USE THEREOF |
| US8883201B2 (en) | 2006-04-07 | 2014-11-11 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| US8999383B2 (en) | 2008-05-07 | 2015-04-07 | Merrion Research Iii Limited | Compositions of GnRH related compounds and processes of preparation |
| US9089484B2 (en) | 2010-03-26 | 2015-07-28 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor Xa inhibitors for oral administration |
| JP2016516442A (en) * | 2013-04-29 | 2016-06-09 | チグルパティ テクノロジーズ プライベート リミテッド | Toxicity reduction of alcoholic beverages |
| US10265384B2 (en) | 2015-01-29 | 2019-04-23 | Novo Nordisk A/S | Tablets comprising GLP-1 agonist and enteric coating |
-
1992
- 1992-12-25 JP JP34715892A patent/JPH06192107A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1059091A4 (en) * | 1998-03-02 | 2005-12-21 | Hisamitsu Pharmaceutical Co | Transmucous sorbefacients |
| US6326360B1 (en) | 1998-03-11 | 2001-12-04 | Grelan Pharmaceuticals Co., Ltd. | Bubbling enteric coated preparations |
| WO1999045934A1 (en) * | 1998-03-11 | 1999-09-16 | Grelan Pharmaceutical Co., Ltd. | Bubbling enteric coated preparations |
| WO2000016784A1 (en) * | 1998-09-21 | 2000-03-30 | Amato Pharmaceutical Products, Ltd. | Oral drug delivery system for enhancing the bioavailability of activated glycyrrhetin |
| JP2002537321A (en) | 1999-02-22 | 2002-11-05 | エラン コーポレイション ピーエルスィー | Solid oral dosage form containing enhancer |
| JP2003073262A (en) * | 2001-08-30 | 2003-03-12 | Gotoo Corporation:Kk | Inclusion coating agent for solid preparation, solid preparation, method for producing the same, and foods |
| WO2004047846A1 (en) * | 2002-11-27 | 2004-06-10 | Minophagen Pharmaceutical Co., Ltd. | Oil/glycyrrhizin-containing surfactant phase type gel composition |
| US8883201B2 (en) | 2006-04-07 | 2014-11-11 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| US8883203B2 (en) | 2006-04-07 | 2014-11-11 | Merrion Research Iii Limited | Solid oral dosage form containing an enhancer |
| US8999383B2 (en) | 2008-05-07 | 2015-04-07 | Merrion Research Iii Limited | Compositions of GnRH related compounds and processes of preparation |
| US9089484B2 (en) | 2010-03-26 | 2015-07-28 | Merrion Research Iii Limited | Pharmaceutical compositions of selective factor Xa inhibitors for oral administration |
| EP2609922A4 (en) * | 2010-08-26 | 2014-04-02 | Shuguang Hospital Affiliated To Shanghai University Of Traditional Chinese Medicine | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CHRONIC LIVER DISEASE AND USE THEREOF |
| JP2016516442A (en) * | 2013-04-29 | 2016-06-09 | チグルパティ テクノロジーズ プライベート リミテッド | Toxicity reduction of alcoholic beverages |
| US10265384B2 (en) | 2015-01-29 | 2019-04-23 | Novo Nordisk A/S | Tablets comprising GLP-1 agonist and enteric coating |
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