WO2014118997A1 - Nouvelle préparation de capsule molle à base de polyol - Google Patents

Nouvelle préparation de capsule molle à base de polyol Download PDF

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Publication number
WO2014118997A1
WO2014118997A1 PCT/JP2013/052640 JP2013052640W WO2014118997A1 WO 2014118997 A1 WO2014118997 A1 WO 2014118997A1 JP 2013052640 W JP2013052640 W JP 2013052640W WO 2014118997 A1 WO2014118997 A1 WO 2014118997A1
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WO
WIPO (PCT)
Prior art keywords
glycyrrhizic acid
soft capsule
mass
oral administration
solvent
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PCT/JP2013/052640
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English (en)
Japanese (ja)
Inventor
健二郎 古閑
展司 吉川
義孝 西原
鈴木　智也
Original Assignee
宏輝システムズ株式会社
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 宏輝システムズ株式会社 filed Critical 宏輝システムズ株式会社
Priority to PCT/JP2013/052640 priority Critical patent/WO2014118997A1/fr
Priority to PCT/JP2014/051939 priority patent/WO2014119614A1/fr
Publication of WO2014118997A1 publication Critical patent/WO2014118997A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A61K9/4825—Proteins, e.g. gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to an oral preparation in which glycyrrhizic acid and its salt or licorice extract have improved gastrointestinal absorbability and transferability to the liver and other organs.
  • the present invention also relates to an oral preparation of extracts for Chinese medicine and the like using a polyhydric alcohol base that is easy to take and dissolves easily in the digestive tract.
  • Glycyrrhizic acid and its derivatives, or salts thereof, alone or in combination with amino acids and the like, have various pharmacological actions such as anti-cortisone action, decholesterol action, anti-allergy action, anti-inflammatory action, detoxification action, gastric ulcer repair action
  • Anti-chronic hepatitis action is known.
  • For the treatment of chronic hepatitis mainly intravenous injections are used. By the way, in the case of chronic hepatitis treatment, a large amount of drugs must be administered over a relatively long period. For this reason, in intravenous administration, several 20 ml ampoules are combined into about 100 ml at a time. In this administration method, not only pain is given to the patient, but also administration has a problem that the tissue at the injection site is thickened every day and for a long time.
  • oral preparations based on glycyrrhizic acid are the best means to solve these problems.
  • currently available oral preparations of glycyrrhizic acid have low absorption from the digestive tract. It has been reported that there is a problem in the transferability into the blood due to enzymatic degradation. Therefore, in the case of chronic hepatitis, the distribution to the liver, which is the site of action of the drug, is estimated to be slight. Therefore, many preparation studies for increasing absorption of glycyrrhizic acid from the digestive tract have been conducted.
  • a dosage form that replaces the oral preparation of glycyrrhizic acid a suppository containing a surfactant such as witebsol or labrasol has been reported.
  • a surfactant such as witebsol or labrasol
  • BA biological effectiveness
  • an object of the present invention is to provide a novel soft capsule preparation for oral administration of glycyrrhizic acid with a polyhydric alcohol base that is excellent in absorbability from the gastrointestinal tract and distribution to the liver, is easy to take and dissolves easily in the gastrointestinal tract Is to provide.
  • Another object of the present invention is to provide an orally administered soft capsule preparation of extracts for Chinese medicine and the like based on a polyhydric alcohol base that is easy to take and dissolves easily in the digestive tract.
  • a polyhydric alcohol such as glycerin / polyethylene glycol or a mixture thereof as a solvent
  • a drug solution dissolved at a higher concentration than usual using water as a solvent in an appropriate ratio with an aqueous gelatin solution
  • Molded as a soft capsule and made into an oral formulation Molded as a soft capsule and made into an oral formulation.
  • Such soft capsules are quickly liquefied in the body at body temperature, and glycyrrhizic acid dissolved in the solvent in the capsules is quickly absorbed from the digestive tract.
  • glycyrrhizic acid improves the absorbability.
  • a high-concentration solution can be obtained by using a polyhydric alcohol such as glycerin / polyethylene glycol or a mixture thereof as a solvent.
  • a polyhydric alcohol such as glycerin / polyethylene glycol or a mixture thereof as a solvent.
  • These polyhydric alcohols are additives commonly used in pharmaceuticals and foods, and do not need to be considered toxic.
  • the gastrointestinal tract is not damaged as in the case of surfactants, it is excellent in that it can be taken with peace of mind even in long-term administration.
  • This mixing ratio is permissible up to 0.5 to 5 volumes of an aqueous gelatin solution with respect to 1 volume of a glycerin solution of glycyrrhizic acid.
  • a desirable ratio is 0.5 to 2 volumes of gelatin aqueous solution with respect to 1 volume of glycerin solution of glycyrrhizic acid.
  • the glycyrrhizic acid high-concentration solution may be gelled under a low pH such as the stomach.
  • a phosphate mixture such as disodium monohydrogen phosphate or potassium dihydrogen phosphate
  • the object can be achieved by adding 5% to 10% of the mixed solution prepared above.
  • the soft capsule quickly liquefies due to body temperature in the digestive tract and is absorbed from the digestive tract. Furthermore, by coating this with an enteric coating and making it an oral formulation, the drug will be delivered to the lower digestive tract (lower intestine or large intestine) by oral administration, and glycyrrhizic acid or its salt at a higher concentration in the body. Can also be absorbed. Moreover, the particle size of the soft capsule can be controlled, and a small particle size product having a diameter of about 1 mm can be manufactured. Such a small particle size product is expected to dissolve quickly in the body and is also effective in preventing dose fluctuation due to product variations sometimes seen in large particle size products.
  • glycyrrhizic acid is soluble in glycerin at a high concentration
  • amino acids such as glycine and methionine, which are subcomponents of oral preparations, are preferably aqueous solutions.
  • a soft capsule composed of a plurality of active ingredients by mixing a glycerin solution of glycyrrhizic acid. Further, by reducing the particle size, it is easy to take, and it is easy to deal with administration tests using small rodent animals.
  • the administration becomes easy and the absorption in the digestive tract can be accelerated.
  • the licorice extract preparation contains glycyrrhizic acid, it is effective in improving the absorbability of glycyrrhizic acid, which is the main component. Structure of the invention
  • (1) at least one main drug selected from glycyrrhizic acid and its salt or licorice extract is made into a high-concentration solution with a polyhydric alcohol such as glycerin / polyethylene glycol or a mixture thereof as a solvent, gelatin
  • the present invention relates to a preparation for oral administration of glycyrrhizic acid, characterized in that a mixture obtained by mixing with an aqueous solution in which is dissolved is softly encapsulated.
  • the soft capsule prepared here is characterized in that the configuration is different from that of a normal soft capsule.
  • ordinary soft capsules include oils and fats containing active ingredients in a film mainly composed of gelatin.
  • the soft capsule concerning this invention can also be coat
  • the salt of glycyrrhizic acid as the active ingredient in the preparation of the present invention is not limited as long as it is provided as a pharmaceutical.
  • Salts of alkali metals potassium, sodium, etc.
  • salts of alkaline earth metals calcium, magnesium, etc.
  • ammonium salts Pharmaceutically acceptable organic amines (tetramethylammonium, triethylammonium, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine , N-methyl-D-glucamine and the like).
  • glycyrrhizic acid disodium salt glycyrrhizic acid dipotassium salt, or glycyrrhizic acid monoammonium salt is preferable.
  • These can be used alone or in combination of two kinds.
  • the present invention can also be applied to the fatty acid esters of glycyrrhizic acid (for example, stearyl glycyrrhizinate and glyceryl glycyrrhizinate).
  • this technique can also be used for extracts for traditional Chinese medicine.
  • any gelatin that is usually used for drugs can be used.
  • another water-soluble medicinal component eg, amino acids
  • stabilizers, surfactants, diluents, additives, lubricants, preservatives may be included as necessary.
  • the glycyrrhizic acid content in the present invention is not particularly limited as long as it is an amount capable of exhibiting a medicinal effect, and varies depending on symptoms, age, etc., but preferably 1 to 500 mg per dose, and administered once to several times a day. it can.
  • FIG. 1 is a graph showing basic experimental results.
  • FIG. 2 is a graph showing Example 1.
  • FIG. 3 is a graph showing one result of Example 2.
  • FIG. 4 is a graph showing another result of Example 2.
  • Preparation was performed by dissolving monoammonium glycyrrhizinate in glycerin so that the glycyrrhizic acid concentration in the formulation was 25 mg / ml and 50 mg / ml.
  • the upper cecum was lightly ligated with a suture, the lower small intestine was taken out, and the glycerin solution was slowly injected using a microsyringe. Thereafter, bile was collected. The liver was collected at the end of the test. The concentration of glycyrrhizic acid in these bile and liver was quantified by HPLC method. The results are shown in FIG.
  • the glycyrrhizic acid excretion rate up to 24 hours was 4.67% of the dose at 2.5 mg / rat and 4.55% of the dose at 5 mg / rat.
  • the bile glycyrrhizic acid concentration is also at a very high level, with a maximum value of 17.1 ⁇ g / ml after 4 hours in the 2.5 mg / rat administration and a maximum value of 62. after 1.5 hours in the 5 mg / rat administration. It showed 0 ⁇ g / ml.
  • the concentration of glycyrrhizic acid in bile does not change rapidly as a whole and is maintained at 10-17 ⁇ g / ml in 2.5 mg / rat administration, and 42.4 ⁇ g / ml in 1 hour after administration in 5 mg / rat administration. Even after 24 hours, a high level of 13.3 ⁇ g / ml was maintained. Although the utilization rate for the dose is about 5%, maintaining a highly practical level of glycyrrhizic acid in bile for more than 24 hours after administration suggests the possibility of a practical formulation that can exert therapeutic effects in humans. To do.
  • part means part by weight.
  • Production Example 1 Glycerin aqueous solution formulation 50 g of glycerin was collected, added to 510 g of water and dissolved by stirring to prepare a glycerin aqueous solution.
  • Production Example 2 Monoammonium glycyrrhizinate, gelatin dispersion formulation 20 g of monoammonium glycyrrhizinate is weighed and mixed with 100 g of gelatin. This is added to the aqueous glycerin solution of Production Example 1 while stirring and dispersing. This was heated to 70 ° C. and dissolved to prepare a soft capsule adjustment solution.
  • Production Example 3 Soft Capsule Production Wet capsules were produced using a dripping type soft capsule production machine.
  • Test example 1 The soft capsules produced in the above production example with only 5 mg per rat as glycyrrhizic acid were orally administered using a sonde. Glycyrrhizic acid excretion from bile was 3.6% by 24 hours after administration. Formulation-2 in FIG. 2 shows the corresponding results. Comparative example
  • a suspension of 7% glucose solution of glycyrrone tablets was prepared so as to be about 5 mg / ml as glycyrrhizic acid, and 1 ml was administered to rats using a sonde.
  • Glycyrrhizic acid excretion from bile was 1.4% by 24 hours after administration. This result is shown in Formulation-1 in FIG.
  • Production Example 4 Glycerin aqueous solution formulation 50 g of glycerin was collected, dissolved in 510 g of water and dissolved by stirring to prepare a glycerin aqueous solution.
  • Production Example 5 Monoammonium glycyrrhizinate, gelatin dispersion formulation 20 g of monoammonium glycyrrhizinate is weighed and mixed with 100 g of gelatin. This is added to the glycerin aqueous solution of Production Example 4 while stirring and dispersing. This was heated to 70 ° C. and dissolved to prepare a soft capsule adjustment solution.
  • Production Example 6 Soft capsule production Wet capsules were produced using a drop type soft capsule production machine.
  • Test example 2 The soft capsule produced in the above Production Example 6 in an amount of 5 mg per rat as glycyrrhizic acid was orally administered using a sonde. The maximum concentration of glycyrrhizic acid excreted from bile was 7 ⁇ g / ml up to 8 hours after administration. Formulation-3 in FIG. 4 shows the corresponding results. In Formulation-2 (Production Example 3 of Example 1) in FIG. 3, the maximum amount remained at 4.5 ⁇ g / ml, indicating the usefulness of L-arginine as an adjuvant.
  • Production Example 7 Glycerin aqueous solution formulation 50 g of glycerin was collected, added to 510 g of water and dissolved by stirring to prepare a glycerin aqueous solution.
  • Production Example 8 Licorice extract powder, gelatin dispersion liquid formulation Licorice extract powder 20 g and L-arginine 8 g are weighed and mixed with 100 g of gelatin. This is added to the aqueous glycerin solution of Production Example 7 while stirring and dispersing. This was heated to 70 ° C. and dissolved to prepare a soft capsule adjustment solution. It was confirmed that this adjusting solution was solidified at room temperature and dissolved at 37 ° C.
  • a soft capsule of a glycyrrhizic acid / glycerin solution can be determined as an optimal dosage form. Moreover, it was confirmed that the addition of L-arginine contributes to the improvement of absorbability.
  • licorice extract powder can be prepared as a main drug instead of glycyrrhizic acid, and this preparation can be applied to a Chinese herbal extract.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
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  • Animal Behavior & Ethology (AREA)
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Abstract

La présente invention concerne une nouvelle préparation de capsule molle administrée par voie orale d'acide glycyrrhizique utilisant une base de polyol. De plus, la présente invention concerne une préparation de capsule molle administrée par voie orale d'un extrait pour la médecine chinoise et similaire utilisant une base de polyol. Un polyol tel que la glycérine ou le polyéthylèneglycol, ou un mélange de ceux-ci est utilisé en tant que solvant. Une solution de médicament dissoute à une concentration plus élevée que le cas usuel dans lequel de l'eau est utilisée en tant que solvant, est formée sous forme de capsules molles après avoir été mélangée avec une solution aqueuse de gélatine à un rapport approprié, pour obtenir une préparation orale. Les capsules molles se liquéfient rapidement dans le corps à température corporelle, et l'acide glycyrrhizique dissous par le solvant dans les capsules est rapidement absorbé à partir du tube digestif. La glycérine est utile pour améliorer l'absorption, et des polyols tels que la glycérine sont stables et n'endommagent pas le tube digestif. En plus du composant actif, l'acide glycyrrhizique, des composants auxiliaires tels que la glycine et la méthionine peuvent être prédissous dans la solution de gélatine à un rapport approprié. La présente invention peut également être utilisée dans un extrait de réglisse contenant de l'acide glycyrrhizique, ou dans des extraits pour la médecine chinoise et similaire.
PCT/JP2013/052640 2013-01-30 2013-01-30 Nouvelle préparation de capsule molle à base de polyol WO2014118997A1 (fr)

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PCT/JP2013/052640 WO2014118997A1 (fr) 2013-01-30 2013-01-30 Nouvelle préparation de capsule molle à base de polyol
PCT/JP2014/051939 WO2014119614A1 (fr) 2013-01-30 2014-01-29 Préparation sous forme de comprimé souple administré par voie orale

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PCT/JP2013/052640 WO2014118997A1 (fr) 2013-01-30 2013-01-30 Nouvelle préparation de capsule molle à base de polyol

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5813511A (ja) * 1981-07-14 1983-01-26 Towa Yakuhin Kk 光不安定性医薬の被包用軟カプセル
JPH0445753A (ja) * 1990-06-11 1992-02-14 Fuji Capsule Kk ゼリー製品とその製法
JPH07258103A (ja) * 1993-09-13 1995-10-09 Hu Kye Sung 抗血栓剤及びその製造方法
JPH10226650A (ja) * 1997-02-18 1998-08-25 Ono Pharmaceut Co Ltd グリチルリチン経口投与製剤
JP2003055263A (ja) * 2001-08-20 2003-02-26 Fuji Capsule Kk 軟カプセル剤充填用組成物
JP2008184430A (ja) * 2007-01-30 2008-08-14 Ss Pharmaceut Co Ltd ソフトカプセル
JP2008189626A (ja) * 2007-02-07 2008-08-21 Minofuaagen Seiyaku:Kk 経口用グリチルリチン可溶化製剤及びその製造方法
JP2012506914A (ja) * 2009-12-07 2012-03-22 ファーマキング カンパニー リミテッド カジノキ抽出物及びニンドウ抽出物を含む抗炎症性薬学的組成物

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JPH03255037A (ja) * 1990-03-02 1991-11-13 Santen Pharmaceut Co Ltd グリチルリチン製剤
DE69910183T2 (de) * 1998-03-11 2004-06-03 Grelan Pharmaceutical Co., Ltd., Hamura Darmlösliche sprudelnde zusammensetzungen
JP4603357B2 (ja) * 2002-08-13 2010-12-22 インターベツト・インターナシヨナル・ベー・ベー 添加剤をデリバリーするための組成物及び方法
JPWO2004047846A1 (ja) * 2002-11-27 2006-03-23 株式会社ミノファーゲン製薬 グリチルリチン含有界面活性剤相中油型ゲル組成物
JP2006298791A (ja) * 2005-04-18 2006-11-02 Kotobuki Seiyaku Kk グリコサミノグリカン又はその塩を含む経口投与用医薬品、健康食品又は栄養薬品組成物。
JP2007045788A (ja) * 2005-08-12 2007-02-22 Kenjiro Koga グリチルリチン酸高濃度水溶液の調製法
JP2007063223A (ja) * 2005-09-01 2007-03-15 Kobayashi Pharmaceut Co Ltd しみ又はそばかす予防又は治療用経口組成物及び食品
US20090060983A1 (en) * 2007-08-30 2009-03-05 Bunick Frank J Method And Composition For Making An Orally Disintegrating Dosage Form
JP2009137872A (ja) * 2007-12-05 2009-06-25 Lion Corp グルクロノラクトン含有経口用固形製剤

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5813511A (ja) * 1981-07-14 1983-01-26 Towa Yakuhin Kk 光不安定性医薬の被包用軟カプセル
JPH0445753A (ja) * 1990-06-11 1992-02-14 Fuji Capsule Kk ゼリー製品とその製法
JPH07258103A (ja) * 1993-09-13 1995-10-09 Hu Kye Sung 抗血栓剤及びその製造方法
JPH10226650A (ja) * 1997-02-18 1998-08-25 Ono Pharmaceut Co Ltd グリチルリチン経口投与製剤
JP2003055263A (ja) * 2001-08-20 2003-02-26 Fuji Capsule Kk 軟カプセル剤充填用組成物
JP2008184430A (ja) * 2007-01-30 2008-08-14 Ss Pharmaceut Co Ltd ソフトカプセル
JP2008189626A (ja) * 2007-02-07 2008-08-21 Minofuaagen Seiyaku:Kk 経口用グリチルリチン可溶化製剤及びその製造方法
JP2012506914A (ja) * 2009-12-07 2012-03-22 ファーマキング カンパニー リミテッド カジノキ抽出物及びニンドウ抽出物を含む抗炎症性薬学的組成物

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