WO2002034275A1

WO2002034275A1 - Pharmaceutical preparation comprised of milk-thistle and terpenes

Info

Publication number: WO2002034275A1
Application number: PCT/EP2001/012050
Authority: WO
Inventors: Walter Schwankl; Reinhard MÄRZ; Heinz-Walter Joseph
Original assignee: Bionorica Ag
Priority date: 2000-10-27
Filing date: 2001-10-18
Publication date: 2002-05-02
Also published as: AU2002212327A1; DE10053384A1

Abstract

The invention relates to pharmaceutical preparations containing a milk-thistle extract (Carduus marianum syn. Silybum marianum) or an active agent therefrom and containing one or more terpene(s), preferably thyme oil, for the prevention and treatment of liver diseases, especially cirrhosis of the liver. The inventive preparations enable an improved resorption of active substances due to the presence of the terpene(s) that act(s) as a resorption enhancer.

Description

Pharmaceutical preparation made from milk thistle and terpenes

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. However, 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. Depending on the pH of the aqueous environment (stomach and intestinal contents etc.) and the pKa value of the substance, an equilibrium is established between undissociated (neutral) and dissociated (ionized) molecules. Only the neutral drug molecules are capable of membrane permeation (= resorption) (non-ionic diffusion). 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. The pKa value of 6.4 (pKphenoi = 9.9), which is unusually low for phenolic bodies such as silymarin, corresponds to a relatively high acidity. This acidity is also the reason why silymarin forms stable salts with organic bases in aqueous solutions, which are suitable for parenteral administration. At the same time, this high acidity is the reason for its poor absorption in vivo, which occurs to a small extent according to the absorption observed in vivo after oral administration of silymarin in the small intestine.

As described above, good solubility in water is a prerequisite for the parenteral use of a pharmaceutical, as well as for pharmacological and biochemical studies. Drugs whose solubility is below 0.3% (FDA regulations on bioavailability indicate 0.5%) are considered problematic drugs. In such ^"substances is accelerated must be attempted, that the dissolution of the drug in the gastrointestinal tract and by suitable measures such as micronization, salt formation, derivatization. Like..

Accordingly, various 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. Furthermore, DE 35 37 656 describes a process for obtaining isosilybin-free silybinin and a medicament containing the same. Also known according to the prior art are various pharmaceutical preparations which contain the silymarin or one or more of the isomers addressed under this collective term. To improve water solubility, pharmaceutical preparations have been described in which the active ingredients are dissolved with pharmaceutically acceptable carriers and wetting agents and then co-precipitated (EP-A-0 722 719) or in which the silymarin is dissolved in polyethylene glycol as the only carrier (see DE 197 44 459).

All of these preparations are used as for the therapy and prophylaxis of liver diseases in general, for the therapy of liver cirrhosis and of poisoning. However, they have in common that the absorption of the poorly water-soluble active ingredient is still too low. 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. The effect of Teφens as a resoφtions 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. For example, 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. However, 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 teφenoid 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.

For the Teφene as substances that should also include terpenoid substances, the Hemiteφene such as. B. isoprene, tiglinic acid, angelica acid, isovaleric acid; the Monoteφene, including the acyclic Monoteφene such. B. 2,6-dimethylococtane, α-myrcene, (E) -ß-ocimene, Perillen, Linalool, Geranial, (S) - (+) citronellal and the monocyclic monoterpenes such as cyclopropane and ^' cyclobutane monoteφene such as Chrysanthemic acid or Junionon, cyclopentane monotopes such as iridoids or nepetalactones or (-) - secologanin and (-) - oleuropein, cyclohexane monotopes such as o-menthan, eis- or trans-p-menthan, (R) - (+) - Limonene, Teφinolen- (-) - menthol, (+) - perillaaldehyde, (-) - menthone or (+) - carvone, bicyclic monoteφenes such as the oxygen-bridged terpenes 1,4-cineol, 1, 8-cineol, or ascaridol ; the cyclopropane bicycles caran and thujan, the cyclobutane bicyclus pinan, and the bicycloheptanes camphane and fenchane; the sesquiterpenes such as farnesane, bisabolane, germacrane and elemane, as well as humulans. Particularly preferred particles are thymol, menthol, cineol, borneol, carvone, limenone and pinene, most preferably thymol.

According to the patent, 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.

For oral administration, 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, in particular Magnesium and calcium stearate, Fatty acid esters and mono- and diglycerides of fatty acids, natural and artificial waxes such as beeswax, yellow wax and montanglycol wax, chlorides, in particular sodium chloride, polyvidone, polyethylene glycols, polyvinylpyrrolidone, povidone, oils such as castor oil, soybean oil, coconut oil, palm kernel oil, especially sugar and sugar derivatives - No- and disaccharides such as glucose, fructose, mannose, galactose, lactose, maltose, xylose, sucrose, dextrose and cellulose and their derivatives, shellac, starch and starch derivatives, in particular maize starch, talc, titanium dioxide, tartaric acid, sugar alcohols such as mannitol, sorbitol and xylitol and their derivatives, and mixtures thereof. Lipophilic and amphiphilic auxiliaries such as oils, waxes, polyethylene glycol and lecithin are preferred.

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 preparations according to the invention are produced in a manner known to the person skilled in the art.

The combination according to the invention of milk thistle extract or its active ingredient (s) with Teφen (s) enables an improvement of the absorption (absorption) or permeation of the poorly soluble active substances. That or the Teφen (e) contained in the formulation causes here as Resoφtionsenhancer a higher bioavailability of the active ingredient. Despite the poor water solubility of the silymarin, a satisfactory resection with all therapeutic consequences can thus be achieved via this effect of the teφens.

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. According to a preferred embodiment, 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. However, due to the effect of Teφens 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.

Preparation example

In the usual way, a hardened soft gelatin capsule is made from the following substances:

Contents: milk thistle extract (478 mg / capsule),

Thyme oil (30 mg / capsule),

lecithin,

Soybean oil,

coconut oil,

Palm kernel oil, yellow wax

Hard film: hypromellose phthalate,

dibutyl phthalate,

Water,

ethanol,

acetone

Gelatin shell: gelatin,

glycerin,

sorbitol,

Water,

Red iron oxide and black iron oxide

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.

Claims

claims

1. Pharmaceutical preparation containing a milk thistle extract or an active ingredient therefrom and one or more terpene (s) and optionally conventional pharmaceutical excipients and excipients.

2. Pharmaceutical preparation according to claim 1 for oral administration.

3. Pharmaceutical preparation according to claim 1 or 2, characterized in that its absorption takes place in the intestine.

4. Pharmaceutical preparation according to one of the preceding claims, characterized in that it is in the form of a solution, tincture, tablet,

, dragees, granules, pellets or capsules.

5. Pharmaceutical preparation according to claim 4, characterized in that the preparation is in the form of hard or soft gelatin capsules, in particular hardened, enteric soft gelatin capsules.

6. Pharmaceutical preparation according to one of the preceding claims, characterized in that the active ingredient of the milk thistle extract is silymarin, one of its isomers, selected from silibinin, isosilybin, silydianin and silychristine, derivatives and salts thereof and mixtures thereof ,

7. Pharmaceutical preparation according to one of the preceding claims, characterized in that the one or more terpenes are natural or synthetic essential oils or their active substances in pure form, individually or in a mixture.

8. Pharmaceutical preparation according to claim 7, characterized in that the terpene is thyme oil or thymol.

9. Pharmaceutical preparation according to one of the preceding claims, characterized in that the preparation contains milk thistle extract (silymarin) and Teφen (e) in a weight ratio of 1000: 1 to 1:50.

10. Pharmaceutical preparation according to claim 9, characterized in that the preparation contains 250 to 700 mg milk thistle extract and 0.25 to 7000 mg thyme oil.

11. Use of the pharmaceutical preparation according to one of claims 1 to 10 for the prevention and treatment of liver diseases.

12. Use according to claim 12 for the prevention and treatment of cirrhosis of the liver.