WO2004071516A1 - Preparation percutanee contenant de la glycyrrhizine - Google Patents

Preparation percutanee contenant de la glycyrrhizine Download PDF

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Publication number
WO2004071516A1
WO2004071516A1 PCT/JP2004/001647 JP2004001647W WO2004071516A1 WO 2004071516 A1 WO2004071516 A1 WO 2004071516A1 JP 2004001647 W JP2004001647 W JP 2004001647W WO 2004071516 A1 WO2004071516 A1 WO 2004071516A1
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WO
WIPO (PCT)
Prior art keywords
water
glycyrrhizin
aqueous solution
treatment
transdermal
Prior art date
Application number
PCT/JP2004/001647
Other languages
English (en)
Japanese (ja)
Inventor
Masao Yoshida
Tetsuo Nakamura
Original Assignee
Immuno Japan Inc.
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 Immuno Japan Inc. filed Critical Immuno Japan Inc.
Publication of WO2004071516A1 publication Critical patent/WO2004071516A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a glycyrrhizin-containing transdermal preparation, and more particularly, the present invention relates to a glycyrrhizin-containing transdermal preparation that is effective for treating bruises, burns or pressure sores.
  • Glycyrrhizin the main component of licorice, is a conjugate of glycyrrhetin and two molecules of glucuronic acid.
  • Daritinoleritic acid and its salts eg, dipotassium glycyrrhizinate, tricalidium glycyrrhizinate, disodium glycyrrhizinate, trisodium dalycyrrhizinate, monoammonium glycyrrhizinate, niammonium glycyrrhizinate, etc.
  • sweeteners eg, dipotassium glycyrrhizinate, tricalidium glycyrrhizinate, disodium glycyrrhizinate, trisodium dalycyrrhizinate, monoammonium glycyrrhizinate, niammonium gly
  • Glycyrrhizin also has an anti-inflammatory effect (Inoue, H., et al., Chemi. Pharm. Bull., 35, 3883-3889, 1987; and Inoue, H., et al., Chem. Pharm. Bull., 34, 897-901, 1986), Improving the innate immunity of living organisms (Hiroshi Seino: Innate immunity in mucosal immunity, Molecular Medicine, 36 (5), 520-526, 1999; Oizaki Katsuo: Overview, Innate immunity Single copy: Inflammation and immunity, September 2001), with the ability to enhance the ability of substances to pass through mucous membranes and skin (Motohiro Mishima et al., Biol. Pharma.
  • An object of the present invention is to solve the above-mentioned problems of the conventional technology. That is, an object of the present invention is to provide a transdermal preparation which is effective for treating and / or sometimes preventing skin diseases such as bruises, burns or pressure sores.
  • the inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, it was found that spraying an aqueous solution containing glycyrrhizin as an active ingredient onto the trunk of a patient suffering from bruises, burns or pressure sores caused these symptoms. And found that the present invention was completed.
  • transdermal preparation comprising an aqueous solution containing dalityrrhizin as an active ingredient.
  • the aqueous solution is an aqueous solution containing ammonia water.
  • the aqueous solution is a hydrophobically converted aqueous solution containing a solvent.
  • the solvent is glycerin and ethanol.
  • the concentration of glycyrrhizin in the aqueous solution is between 0.01 and 5% by weight.
  • glycyrrhizin is obtained by purifying licorice extract by HPLC.
  • the transdermal formulation of the present invention can be used for treatment and / or prevention of bruises, burns or pressure sores.
  • a method for treating and preventing or preventing bruises, burns or pressure sores which comprises transdermally administering a transdermal preparation comprising an aqueous solution containing glycyrrhizin as an active ingredient to the skin.
  • FIG. 1 shows the results of an example in which the ulcer was healed with GL water.
  • Treatment 4 days Treatment with GL water twice a day, 4 days after treatment
  • Treatment 150 The surrounding granulation layer area was enlarged and the wound surface was dry.
  • Treatment 2 2nd day The whole treatment process It was healed rapidly in less than 1 month. Spraying of the GL water was stopped 25 days later. The healing was completed and the need for treatment was eliminated.
  • Figure 2 shows the therapeutic effect of GL water on burn edema in rats (total of 2 experiments, 6 rats per group).
  • the transdermal preparation of the present invention is characterized by comprising an aqueous solution containing glycyrrhizin as an active ingredient.
  • Glycyrrhizin used in the present invention can be obtained, for example, by purifying licorice extract by HPLC (National Institute of Health Sciences, Glycyrrhizic Acid Standard (Control 991). Hiroyuki Saito et al., Bull. Natl. Sci. 117, 195-198, 1999).
  • Glycyrrhizic acid and its salts for example, glycyrrhizic acid diuretic
  • Glycyrrhizinate, trisodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, and the like can be used.
  • the concentration of glycyrrhizin in the aqueous solution is not particularly limited as long as the desired medicinal effect can be achieved, but is generally from 0.01 to 5% by weight, preferably from 0.05 to 1% by weight. If the concentration is too low, it is difficult to sufficiently exert the efficacy of the active ingredient glycyrrhizin.On the other hand, if the concentration is too high, it is difficult to achieve the effect corresponding to the increase in the compounding amount. Become.
  • the water used for preparing the transdermal formulation of the present invention is not particularly limited, as long as it is water used in the field of ordinary pharmaceuticals.
  • Water can be mixed in the remaining amount of the total amount of other essential components and optional components contained in the transdermal formulation of the present invention.
  • about 70 to 99% by weight is preferable, and particularly about 75 to 99% by weight.
  • a small amount of aqueous ammonia can be added to the transdermal formulation of the present invention for solubilizing glycyrrhizin in water.
  • the amount of ammonium water added may be such that glycyrrhizin can be solubilized in water, and is generally about 0 to 1.0% by weight based on the total amount of the aqueous solution.
  • a solvent can be added to the aqueous glycyrrhizin solution to convert the aqueous glycyrrhizin solution to hydrophobic in order to enhance the skin permeability of the glycyrrhizin aqueous solution.
  • Alcohol can be used as the solvent used here.
  • polyhydric alcohols such as glycerin and monohydric lower alcohols (for example, methanol, ethanol, normanolepropanol, isopropanol, normanole butanol, t- Butyl alcohol, etc.) can be used. They are
  • glycerin and ethanol can be used in combination.
  • the content of the solvent such as alcohol is not particularly limited, but is preferably about 1 to 30% by weight, and is particularly preferable. Or about 10 to 30% by weight.
  • a pH buffer In the external preparation for skin of the present invention, a pH buffer, a surfactant, a saccharide, a dissolution aid, a chelate, which are usually added in the formulation, in addition to the above components, unless the effects of the present invention are hindered.
  • Additives such as preservatives, preservatives, fresheners, thickeners or gelling agents can be added.
  • pH buffers include, for example, boric acid, sodium hydrogen phosphate, glacial acetic acid, citric acid, sodium hydroxide, triethanolamine, ascorbic acid, glycine, L-arginine, benzoic acid, benzoic acid Sodium, sodium chloride, glucose and the like can be used.
  • polyoxyethylene hydrogenated castor oil 60 self-emulsifying glyceryl monostearate, etc.
  • a saccharide mannitol or the like can be used.
  • ⁇ -Cyclodextrins such as cyclodextrin, propylene glycol and the like can be used, and sodium edetate and the like can be used as a chelating agent.
  • ethanol benzalkonium chloride, sorbic acid, etc.
  • a preservative d-camphor, keich oil, 1-menthol, etc.
  • a thickener or As a gelling agent, carboxyvinyl polymer, glycerin monooleate and the like can be used.
  • the dosage form of the skin external preparation of the present invention is not particularly limited, and can be prepared as an oily preparation, an emulsion preparation, an aerosol preparation, or the like, but is preferably prepared as an aqueous preparation.
  • it is effective to prepare it as a gel, lotion, poultice, etc.
  • transdermal preparation of the present invention using the above essential and optional components, a conventional method may be used.For example, these components may be weighed and heated and stirred as necessary. After dissolving in water, the percutaneous preparation of the present invention is produced by an operation such as cooling. Can be built.
  • the dosage form of the transdermal formulation of the present invention is not particularly limited as long as it is a form suitable for transdermal administration, and can be formulated into any form.
  • the transdermal formulation of the present invention can be prepared into, for example, a spray, a gel, a lotion, a poultice and the like, and a preparation method thereof can be prepared by a conventional method of each preparation.
  • a propellant can be prepared into an aerosol form such as a spray by combining with a propellant.
  • propellants include chlorofluorocarbons such as chlorofluorocarbons, chlorofluorocarbons, chlorofluorocarbons, chlorofluorocarbons, propane, butane, isobutane, nonolemanolebutane, and isopentane.
  • a hydrocarbon gas such as normal pentane, a liquefied gas such as dimethyl ether, a carbon dioxide gas, a nitrogen gas, or the like can be used.
  • glycyrrhizin and other optional components are sequentially added to and dissolved in purified water, and further purified water is added to the obtained solution to adjust each component to a desired concentration.
  • a gelling agent can be obtained by adding a gelling agent to cause gelation.
  • glycyrrhizin and other optional components are sequentially added to purified water and dissolved, and purified water is further added to the obtained solution to adjust each component to a desired concentration.
  • a lotion can be obtained by finally adjusting the pH of the preparation to a desired pH with a pH buffer.
  • poultices for example, glycyrrhizin and other optional components are sequentially added to purified water, melting angle is advanced, kneading is carried out for an appropriate time, pH is adjusted as needed, and then spread using a spreader or the like.
  • a method to obtain a poultice by spreading it on a support such as a nonwoven fabric so that it has a certain thickness, covering the surface with a plastic film or the like as necessary, and cutting it to an appropriate size as necessary. be able to.
  • the amount and use of the transdermal formulation of the present invention are not particularly limited, and may be appropriate depending on various factors including the type and severity of the disease, the administration form, and the age and weight of the patient. Can be set appropriately.
  • the dose of glycyrrhizin as an active ingredient is about 10 to 50 xg / kg per day, preferably about 10 to 20 ⁇ g / kg, but a slight increase is acceptable. It is preferable to administer the above dose of the drug in 1 to 4 divided doses per day.
  • the transdermal preparation of the present invention can be used, for example, for treating and preventing or preventing bruises, burns or pressure sores, and bites caused by snakes (particularly when the type of snake is unknown and antiserum cannot be selected). ) As well as bee stings.
  • Glycyrrhizin (GL) water used in the following examples was prepared as follows.
  • Example 1 A case where a bruise was treated with glycyrrhizin (GL) water
  • the PBS solution (buffer solution) was sprayed and applied as a control drug instead of the administration of GL water. Pain and swelling in the control were not completely absent within a short time of 30 minutes, were still inflammatory after 2 days, and were healed on the 5th day, with evidence of subcutaneous bleeding. In the comparison between the GL water group and the PBS group as a control, the time required for complete recovery of the GL group was 35 minutes, while that in the control group was 120 hours, and the difference was clear. . That is, GL water was proved to be effective for bruises.
  • Example 2 A case where a second-degree burn (burn blister) was cured with GL water
  • the wound surface is washed with physiological saline, and GL water is sprayed widely, and then a small GL water droplet on the wound surface is spread with sterile gauze and applied to the wound surface so that the spray becomes a coating. Then, the wound surface was covered with the gauze, and the treatment was completed. Twice daily for 25 days (50 times in total), GL water was sprayed and applied.
  • Example 3 A past situation in which GL water was not used in the same patient as in Example 3 is described as a comparative example.
  • immediate treatment such as application of aznol or ertasin ointment
  • Example 4 Therapeutic effect of GL water on burn edema in rats
  • the right hind paw of the rat was immersed in boiling water at 70 ° C for 5 seconds, and the volume of swelling of the foot edema that appeared was measured. Specifically, a certain area of the rat's right hind limb was marked using an oil-based black felt pen, immersed in a small water tank up to the mark, and the amount of water (weight) that had risen was measured. Measurements were made before and 1, 3, and 5 hours after inflammation. The result is shown in figure 2. As a result, a clear decrease was observed in the GL water group compared with the control group (PBS group) at 5 hours, which is considered to be the peak of inflammation. The same experiment was repeated twice using three rats at each measurement point, so in Figure 2, six rats were used at each point.
  • Example 5 Therapeutic effect of GL water on lip health
  • glycyrrhizin is known to cross the mucosa.
  • various antigenic substances present on the surface of the mucous membrane together with glycyrrhizin also stimulate and activate some nonspecific defense mechanisms of the living body as foreign substances entering the body, and nonspecifically prevent pathogens such as invading viruses and bacteria. You may be attacking.
  • the transdermal preparation of the present invention is useful as a drug for treating and / or preventing bruises, burns or pressure sores, and particularly useful as an aqueous transdermal preparation such as a spray, a gel, a lotion, and a poultice. is there.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une préparation percutanée efficace pour traiter et/ou prévenir des maladies de la peau telles que les ecchymoses, les brûlures et les escarres de décubitus. L'invention concerne, en particulier, une préparation percutanée comprenant une solution aqueuse qui contient de la glycyrrhizine comme ingrédient actif.
PCT/JP2004/001647 2003-02-17 2004-02-16 Preparation percutanee contenant de la glycyrrhizine WO2004071516A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003-037553 2003-02-17
JP2003037553A JP2004262772A (ja) 2003-02-17 2003-02-17 グリチルリチン含有経皮製剤

Publications (1)

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WO2004071516A1 true WO2004071516A1 (fr) 2004-08-26

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TW (1) TW200418528A (fr)
WO (1) WO2004071516A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004910A1 (fr) * 2009-07-09 2011-01-13 Minophagen Pharmaceutical Co., Ltd. Glycyrrhizine en tant qu'agent de restauration pour la capacité de production de peptides antimicrobiens

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5126644B2 (ja) * 2006-05-31 2013-01-23 独立行政法人産業技術総合研究所 遺伝子発現プロファイルを用いた漢方薬の評価法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09169652A (ja) * 1995-12-18 1997-06-30 Lion Corp 水性液状組成物
JPH11147826A (ja) * 1997-11-13 1999-06-02 Lion Corp 経皮吸収性の向上方法及び皮膚外用剤
JP2000109416A (ja) * 1998-10-02 2000-04-18 Pola Chem Ind Inc 抗肥満作用を有する化粧料組成物
JP2001097888A (ja) * 1999-09-28 2001-04-10 Hiroshi Ikeno 外用組成物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09169652A (ja) * 1995-12-18 1997-06-30 Lion Corp 水性液状組成物
JPH11147826A (ja) * 1997-11-13 1999-06-02 Lion Corp 経皮吸収性の向上方法及び皮膚外用剤
JP2000109416A (ja) * 1998-10-02 2000-04-18 Pola Chem Ind Inc 抗肥満作用を有する化粧料組成物
JP2001097888A (ja) * 1999-09-28 2001-04-10 Hiroshi Ikeno 外用組成物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011004910A1 (fr) * 2009-07-09 2011-01-13 Minophagen Pharmaceutical Co., Ltd. Glycyrrhizine en tant qu'agent de restauration pour la capacité de production de peptides antimicrobiens

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JP2004262772A (ja) 2004-09-24
TW200418528A (en) 2004-10-01

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