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WO2002034275A1 - Preparation pharmaceutique a base de chardon marie et de terpenes - Google Patents

Preparation pharmaceutique a base de chardon marie et de terpenes Download PDF

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Publication number
WO2002034275A1
WO2002034275A1 PCT/EP2001/012050 EP0112050W WO0234275A1 WO 2002034275 A1 WO2002034275 A1 WO 2002034275A1 EP 0112050 W EP0112050 W EP 0112050W WO 0234275 A1 WO0234275 A1 WO 0234275A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical preparation
preparation according
milk thistle
thistle extract
pharmaceutical
Prior art date
Application number
PCT/EP2001/012050
Other languages
German (de)
English (en)
Inventor
Walter Schwankl
Reinhard MÄRZ
Heinz-Walter Joseph
Original Assignee
Bionorica Ag
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 Bionorica Ag filed Critical Bionorica Ag
Priority to AU2002212327A priority Critical patent/AU2002212327A1/en
Publication of WO2002034275A1 publication Critical patent/WO2002034275A1/fr

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Classifications

    • 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
    • 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)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • 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)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a pharmaceutical preparation containing a milk thistle extract (extract from Carduus mananum syn. Silybum mananum) or an active ingredient thereof and one or more terpene (s).
  • the terpenes contained in the preparation act as resorption enhancers and thus improve the systemic availability of the poorly soluble active ingredients of the milk thistle extract.
  • the preparations according to the invention are particularly suitable for the prophylaxis and therapy of liver damage and diseases, in particular liver cirrhosis.
  • Liver cirrhosis is pathologically anatomically a progressive scar-connective tissue transformation of the liver as a result of parenchymatization or a progressive fibrotization of the liver. After reshaping, normal liver tissue can no longer regress or restore. Aetiologically, liver cirrhosis distinguishes between alcohol cirrhosis, various metabolic disorders and liver cirrhosis as a result of chronic hepatitis.
  • Extracts obtained from milk thistle (Carduum mananum syn. Silybum marianum), in particular the fruits of milk thistle and the silymarin contained therein, have been known for a long time and have been used for a long time for the prophylaxis and therapy of liver diseases.
  • the extracts are generally used for toxic liver applied damage and recommended for supportive treatment of inflammatory liver diseases and cirrhosis.
  • the active ingredient in milk thistle extract is silymarin.
  • Silymarin consists of a mixture of flavanol derivatives.
  • the main constituents are the dimeric diastomeric pairs silbinin A and silibinin B, isosilibin A and B as well as silichristin, silidianin and small amounts of other ingredients of the same type as siliandrin, silimonin, 2,3-dehydrosilibinin and 2,3-dehydrosilichristin.
  • Silibinin is considered the most pharmacologically active isomer.
  • Pharmaceutical preparations of milk thistle fruit extracts are used in acute and chronic viral, metabolic or toxic liver damage due to the cytoprotective, antioxidative and antifibrotic effects of silymarin and especially of silibinin.
  • the silymarin or its isomers are almost insoluble or at least sparingly soluble in water.
  • the solubility of silibinin under the conditions of gastric juice (37 ° C, pH 3.0) is about 20 mg / L.
  • the dissolution or dissolution of a drug in molecularly dispersed form is a prerequisite for its resorption and thus its effectiveness.
  • the extent and speed of dissolution can become the determining factor for release and resorption and thus the decisive criterion for bioavailability at all for poorly soluble active ingredients.
  • the acidity of a drug which has a quantitative expression in the pKa value, largely determines its behavior in the organism.
  • the solubility and z On the other hand, the rate of dissolution is also determined by the degree of dissociation in the aqueous environment, because ions are hydrophilic and water-soluble.
  • the pKn value is therefore equally important for the release, pharmacokinetics and pharmacodynamics of the active substance.
  • derivatives of silymarin or the compounds mentioned below have been described in the prior art, which are intended to ensure better solubility in water.
  • the derivatives formed in this way include adducts such. B. with cyclodextrin, complex compounds, for example with phosphatidylcholine or certain amino sugars, esters in particular with dicarboxylic acids such as succinic acid, inclusion compounds and salts of all these derivatives.
  • Milk thistle extracts and the pure active ingredients can be produced according to known processes (see for example DE 19 23 082).
  • DE 29 14 330 discloses a process for the production of pure silymarin and a medicament containing the same.
  • the process described in DE 19 23 082 leads to a product which contains 80 to 85 mol% of the active ingredient silymarin.
  • DE 35 37 656 describes a process for obtaining isosilybin-free silybinin and a medicament containing the same.
  • various pharmaceutical preparations which contain the silymarin or one or more of the isomers addressed under this collective term.
  • the object of the invention is therefore to provide a pharmaceutical preparation of the milk thistle extract which allows an improved absorption of the active substance (s).
  • the object of the invention is achieved by a pharmaceutical preparation containing a milk thistle extract or an active ingredient therefrom and one or more particles and optionally conventional pharmaceutical excipients and carriers.
  • Te ⁇ ens as a reso ⁇ tions enhancer improves both the resupposition prerequisites and the resorption processes and thus the resorption overall.
  • the milk thistle extract to be used according to the invention can be any milk thistle extract produced by a known method.
  • the active ingredient of the extract can be individual compounds purified from such an extract or synthetically produced, as described above, and mixtures and derivatives thereof.
  • the extract / active ingredient may contain one or more of the isomers silylbinin, isosilybin, silydianine and silylchristine mentioned under the collective name silymarin, but also derivatives and salts of these compounds, all individually or in a mixture.
  • an extract from milk thistle fruits produced according to conventional methods is particularly preferred.
  • the one or more terpenes also contained in the preparation according to the invention are natural or synthetic essential oils and / or their te ⁇ enoid components in the form of the pure substances or mixtures or derivatives of these pure substances, which may not occur as an essential oil. These oils or substances can be present individually or in a mixture.
  • the essential oils include, in particular, thyme oil, eucalyptus oil, pine needle oil, tea tree oil, Cajeput oil, cardamon oil, peppermint oil, sage oil and rosemary oil, preferably thyme oil.
  • the degree of purity of the essential oils does not play an important role.
  • the Hemite ⁇ ene such as. B. isoprene, tiglinic acid, angelica acid, isovaleric acid; the Monote ⁇ ene, including the acyclic Monote ⁇ ene such. B.
  • the above-mentioned substances can be used as pure substances, including their derivatives such as the glycosides (eg from lemon balm), but also theirs (Any) mixtures, such as those found in essential oils, natural or synthetic.
  • the pharmaceutical preparation according to the invention based on the milk thistle extract mentioned or its active ingredient and the terpenes is usually suitable for systemic application. Preparations which can be administered orally are particularly preferred. Such oral formulations are particularly preferred according to the invention, which allow the active substances to be released and thus resorbed in the intestine.
  • the preparation can be in the form of solutions, drops, tinctures, dragees, pellets, tablets or capsules, in particular hard or soft gelatin capsules, very particularly preferably hardened, enteric soft gelatin capsules.
  • the pharmaceutical preparation of the present invention may also contain suitable pharmaceutical auxiliaries and carriers, such as, for example, acrylic and methacrylic derivatives, alginic acid, sorbic acid derivatives such as alpha-octadecyl-omega-hydroxy-poly- (oxyethylene) -5-sorbic acid, amino acids and their derivatives , in particular A compounds, such as choline, lecithin and phosphatidylcholine, gum arabic, flavorings, ascorbic acid, carbonates such as, for example, sodium, potassium, magnesium and calcium carbonate and hydrogen carbonate, hydrogen phosphates and phosphates of sodium, potassium, calcium and magnesium , Carmellose sodium, Dimeticon, colorants, flavors, preservatives, thickeners, plasticizers, gelatin, glucose syrups, highly disperse silicon dioxide, hydromellose, benzoates, in particular sodium and potassium benzoate, macrogol, magnesium oxide, fatty acids and their derivatives and salts such as stearic acid and stearates
  • the pharmaceutical preparations according to the invention can be provided with one or more coatings.
  • the oral dosage forms are preferably provided with an enteric coating or are in the form of an enteric, hardened soft gelatin capsule.
  • the pharmaceutical preparations of the invention contain the milk thistle extract / its active ingredient (s) and terpene (s) in a weight ratio of 1000: 1 to 1:50.
  • the ratio is preferably in a range from 500: 1 to 1:50, whole particularly preferably from 100: 1 to 1:10.
  • the preparations thus contain 250 to 700 mg of milk thistle extract and 0.25 to 7000 mg of thyme oil.
  • the preparations according to the invention can be administered in a dosage of the milk thistle extract of 50 to 5000 mg, preferably 100 to 1000 mg per day and depending on the therapeutic requirement.
  • Te ⁇ ens as a resuscitation enhancer, the dosage can be reduced compared to the conventional dosage or an improved effect can be achieved with the same dosage.
  • a hardened soft gelatin capsule is made from the following substances:
  • Thyme oil (30 mg / capsule),
  • Gelatin shell gelatin
  • the capsule is manufactured and filled in a manner known per se.
  • the total mass of the finished hardened soft gelatin capsule is approximately 1370 mg with an active substance content of 478 mg or 30 mg.

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Biotechnology (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Botany (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des préparations pharmaceutiques contenant un extrait de chardon marie (Carduus marianum syn. Silybium marianum) ou un principe actif qui en est issu et un ou plusieurs terpènes, de préférence de l'essence de thym. Ces préparations s'utilisent dans la prophylaxie et le traitement de maladies hépatiques, notamment la cirrhose du foie. La présence du ou des terpènes qui agissent comme des activateurs de résorption permet auxdites préparations de mieux résorber les principes actifs.
PCT/EP2001/012050 2000-10-27 2001-10-18 Preparation pharmaceutique a base de chardon marie et de terpenes WO2002034275A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002212327A AU2002212327A1 (en) 2000-10-27 2001-10-18 Pharmaceutical preparation comprised of milk-thistle and terpenes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10053384A DE10053384A1 (de) 2000-10-27 2000-10-27 Pharmazeutische Zubereitung aus Mariendistel und Terpenen
DE10053384.1 2000-10-27

Publications (1)

Publication Number Publication Date
WO2002034275A1 true WO2002034275A1 (fr) 2002-05-02

Family

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Family Applications (1)

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PCT/EP2001/012050 WO2002034275A1 (fr) 2000-10-27 2001-10-18 Preparation pharmaceutique a base de chardon marie et de terpenes

Country Status (3)

Country Link
AU (1) AU2002212327A1 (fr)
DE (1) DE10053384A1 (fr)
WO (1) WO2002034275A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6913769B2 (en) 2003-02-18 2005-07-05 Brian Douglas Oslick Compositions for prevention and treatment of symptoms associated with ethyl alcohol consumption
CN100402023C (zh) * 2003-06-21 2008-07-16 山东绿叶天然药物研究开发有限公司 一种水飞蓟素软胶囊及其制备方法
FR2916637A1 (fr) * 2007-06-04 2008-12-05 Martine Walther Traitement naturel de desintoxication d'alcool, sevrage progressif, a l'abstinence totale a long terme. prevention des cancers du a ses mefaits, de l'hepatite c, cirrhose et cardiovasculaire, diabete
EP2184069A1 (fr) * 2008-11-10 2010-05-12 Martine Walther Traitement naturel de désintoxication d'alcool, sevrage progressif à l'abstinence totale à long terme.
CN111841501A (zh) * 2020-06-23 2020-10-30 五邑大学 一种治疗炎症性疾病的药物组合物及其应用
CN117919256A (zh) * 2024-03-25 2024-04-26 潍坊众邦制药有限公司 一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10256774A1 (de) * 2002-12-05 2004-06-24 Lts Lohmann Therapie-Systeme Ag Transmucosale und transdermale Arzneimittel mit verbesserter Wirkstoffresorption

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3864484A (en) * 1972-05-27 1975-02-04 Madaus & Co Dr Therapeutic compositions and methods using silymarin comprising poly-hydroxyphenyl chromanones
DE2450177A1 (de) * 1973-10-22 1975-04-30 Geb Doll Edith Margot Cobb Antineoplastisches mittel

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3537656A1 (de) * 1984-11-22 1986-05-22 Dr. Madaus GmbH & Co, 5000 Köln Verfahren zur herstellung von isosilybinfreiem silibinin und arzneimittel, enthaltend silibinin
DE19756677A1 (de) * 1997-12-19 1999-06-24 Krewel Meuselbach Gmbh Arzneipflanzentrockenextrakte

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3864484A (en) * 1972-05-27 1975-02-04 Madaus & Co Dr Therapeutic compositions and methods using silymarin comprising poly-hydroxyphenyl chromanones
DE2450177A1 (de) * 1973-10-22 1975-04-30 Geb Doll Edith Margot Cobb Antineoplastisches mittel

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BIOLOGICAL & PHARMACEUTICAL BULLETIN, vol. 17, no. 3, 1994, pages 443 - 445, ISSN: 0918-6158 *
CARCINOGENESIS (OXFORD), vol. 20, no. 11, November 1999 (1999-11-01), pages 2101 - 2108, ISSN: 0143-3334 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; 1994, KIM DONG-HYUN ET AL: "Silymarin and its components are inhibitors of beta-glucuronidase.", XP002188733, Database accession no. PREV199497330651 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; November 1999 (1999-11-01), ZHAO JIFU ET AL: "Tissue distribution of silibinin, the major active constituent of silymarin, in mice and its association with enhancement of phase II enzymes: Implications in cancer chemoprevention.", XP002188731, Database accession no. PREV200000060885 *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; November 2000 (2000-11-01), ANGULO PAUL ET AL: "Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.", XP002188732, Database accession no. PREV200100008584 *
HEPATOLOGY, vol. 32, no. 5, November 2000 (2000-11-01), pages 897 - 900, ISSN: 0270-9139 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6913769B2 (en) 2003-02-18 2005-07-05 Brian Douglas Oslick Compositions for prevention and treatment of symptoms associated with ethyl alcohol consumption
US6967031B1 (en) 2003-02-18 2005-11-22 Brian Douglas Oslick Compositions for prevention and treatment of symptoms associated with ethyl alcohol consumption
CN100402023C (zh) * 2003-06-21 2008-07-16 山东绿叶天然药物研究开发有限公司 一种水飞蓟素软胶囊及其制备方法
FR2916637A1 (fr) * 2007-06-04 2008-12-05 Martine Walther Traitement naturel de desintoxication d'alcool, sevrage progressif, a l'abstinence totale a long terme. prevention des cancers du a ses mefaits, de l'hepatite c, cirrhose et cardiovasculaire, diabete
EP2184069A1 (fr) * 2008-11-10 2010-05-12 Martine Walther Traitement naturel de désintoxication d'alcool, sevrage progressif à l'abstinence totale à long terme.
CN111841501A (zh) * 2020-06-23 2020-10-30 五邑大学 一种治疗炎症性疾病的药物组合物及其应用
CN117919256A (zh) * 2024-03-25 2024-04-26 潍坊众邦制药有限公司 一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途
CN117919256B (zh) * 2024-03-25 2024-05-24 潍坊众邦制药有限公司 一种含有药用甾醇活性物质组合物在制备治疗肝炎的用途

Also Published As

Publication number Publication date
DE10053384A1 (de) 2002-05-08
AU2002212327A1 (en) 2002-05-06

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