DE4221879C2 - Pharmaceutical preparation with the effect of the Gingko biloba extract - Google Patents

Description

The present invention relates to a pharmaceutical Preparation with the effect of the Gingko biloba extract. The The invention further relates to a method of manufacture of such a pharmaceutical preparation.

Rutin has been at odds with knowledge for many years shaft as a vitamin-like substance (vitamin P). The original The role of rutin in the treatment of peripheral her circulatory disorders had to give way to the realization that Rutin as a pure substance after oral administration in so little Extent is absorbed that with the applied doses it has hardly any clinically relevant effects can. His u. a. circulation-promoting effect could up to be observed only when it comes to biological Structures was bound and so as food in the body per came.

All attempts to get a re for the isolated rutin Failed to develop sorption-improving formulation so far their goal. Modern galenic processes of the Her Provision of inclusion compounds with cyclic oligo saccharides such as cyclodextrins have no resorption ver result in improvements. The solubility properties of rutin  do not allow solubilization in aqueous systems as the most important prerequisite for improved enteral Absorption.

So liquid pharmaceutical preparations such. B. drops to Oral or injection solutions special auxiliaries (Lö agent) and cannot contain water as al contain solvent. It would always be in water a tiny fraction of Rutin or his agly Kon quercetin soluble.

In the case of acidic or basic poorly water-soluble substances can e.g. B. trying to find a stable, water soluble Find salt form. If this is not possible, can by Addition of suitable, water-miscible organic solutions tel, for example ethanol, 1,2-propylene glycol, glycerol or polyethylene glycols the solubility of lipophilic Substances in water can be increased. Following this principle are commercial, liquid, rutin or other flavonoids ent medicinal preparations for oral or oral use name built up.

It would be fundamentally wrong of these technological ones Measures ago or from the presence of rutin in solution in egg ner liquid drug preparation conclusions on the resorp want to carry out in the organism.

According to the theory of passive diffusion, drugs only absorbed in dissolved form in the gastrointestinal tract. Around therefore ensure absorption of rutin in vivo and thus an optimal pharmacological or therapeutic To achieve an effect, at least the dissolved state of the Rutins - not only in the preparation, but also in vivo - to be guaranteed.  

However, this is in the case of a pharmaceutical preparation that is organic Contains solvents or salts of rutin, not the case, as you can easily imagine. Through physiological Influences (dilution effects or pH shifts) in the Ma gene tract becomes the forced in vitro solubilizer undone and as a result there is imminent failure felling or coarse flocculation.

The production of rutin derivatives, e.g. B. rutin sulfur acid ester, although led to an improvement in solubility in aqueous systems, the stability against hydrolysis of this However, esters in the gastrointestinal tract are so low that their ver soaping immediately with no chance of an improved absorption tion occurs. The only successful improvement so far absorption was achieved by producing hydroxyethyl Links. The group of the rutin-hydroxy-ethyl-ether (e.g. Tris, di, and mono-hydroxy-ethyl-rutin) is usually as a different mixture of the different derivatives (e.g. troxerutin) are no longer pure substances. The improved absorption of these compounds led to a substantial loss of valuable pharmacological Properties of rutin or its aglycon as the egg gene carrier of the pharmacological effect.

Troxerutin and other rutin conjugates, however, have the ur Original role of isolated rutin, in the therapy of peripheral circulatory disorders. The still no evidence of enteral absorption of rutin as a pure substance has even led to its status as an approved drug. The one here reporting pharmaceutical preparations, as well as procedures The solubilization of rutin would take into account a lot In vain attempts, a barely expected IN novation mean. Soluble in gastric juice-stable form made and thus made absorbable rutin could be one extraordinary economic importance as best ver  inert natural remedy for a number of indications gain.

In clinical studies on the absorption of rutin, the moleku lardispers in gelatin distributed by the test subjects had been found, it was now surprisingly found that Ru tin in vivo the metabolites quercetin, kämpol and iso rhamnetin forms. The metabolites of rutin are therefore identical table with the most important ingredients of the Gingko biloba-Ex tracts.

The present invention is therefore based on the object the active ingredients of Gingko biloba from a raw material source, which is more accessible than a gingko biloba extract in one that is adequate for the patient and sufficient dosage form that can be absorbed put.

This object is achieved by a pharmaceutical dissolved preparation, the rutin in molecular disperse Distribution in a base substance derived from collagen with a molecular weight above 100 D, selected from the Group consisting of gelatin, fractionated gelatin, Gelatin derivatives, collagen hydrolyzates and their Mixtures, optionally in addition to the usual pharmaceutical ones  Carriers and auxiliaries in addition to the usual pharmaceuticals Contains carriers and auxiliaries.

Taking a pharmaceutical preparation in the sense of the Erfin Both pharmaceutical preparations and dietary food preparations (health care) understand the.

Rutin is a glycoside of quercetin with rutinose that is found in occurs in many plant species and is therefore much lighter  is available as the extract from Gingko biloba. Such Plant species come from genera such as Fagopyrum, Sophora, Viola, Ruta, Solidago, Verbascum etc.  

The above object is further achieved by a method for Manufacture of a pharmaceutical preparation with the effect of the Gingko biloba extract, which is known is that you put rutin in solution and this Solution with an aqueous solution of a base substance from egg a hydrophilic peptide with a molecular weight above 100 D mixed and the solvent or solvents removed, whereby one obtains a molecularly disperse distribution of rutin where given one in the first or after the second stage if pharmaceutically customary excipients and auxiliaries puts.

According to the invention not only the advantage is achieved that the Active ingredients of the Gingko biloba extract are much lighter than are available in the prior art. Likewise be it is significant that the effectiveness or bioavailability of the Active ingredients of the Gingko biloba extract according to the invention is improved and thus an effective therapeutic use the active ingredients of the Gingko biloba extract is achieved.

A rutin preparation according to the invention thus becomes an In dication spectrum accessible, as it was previously for the preparation Gingko biloba extract is known. Under gingko biloba extract in the sense of the invention are commercially available, Medicinal products containing Gingko biloba extract or trade Common Gingko biloba extracts understood.

Indication or efficacy of gingko biloba extract, ins particular the flavon contained in Gingko biloba extract glycoside fraction, can be present for example with:

• - ischemic diseases
• - central and peripheral arterial circulatory disorders stanchions  
• - Vascular disorders of various origins
• - neuropathies  
• - encephalopathies
• - myelopathy
• - tendency to platelet aggregation
• - Hypoxia damage
• - radical-induced, pathological changes
• - brain disorders
• - cerebral edema Etc.

According to the present invention, one is derived from collagen Base substance made of a hydrophilic peptide with a Sufficient molecular weight over 100 D, rutin in solution Stabilize form so that no organic solvents or surfactants etc. are more necessary as solubilizers are.

Such systems according to the invention can be liquid, aqueous solutions are available, but it can also be done by appropriate The solvent is removed (e.g. spray or freeze drying). Leave the products so dried by adding water or in a physiological environment such as which dissolve (redisperse) to its original state.

The term "base substance derived from collagen a hydrophilic peptide with a molecular weight above 100 D " here means a substance derived from collagen, selected from the group consisting of: gelatin, fractionated Gelatin, collagen hydrolyzates, gelatin derivatives; such as their mixtures.

Gelatin is a scleroprotein obtained from collagen-containing material, which has different properties depending on the manufacturing process. It essentially consists of four molecular weight fractions that influence the physicochemical properties as a function of molecular weight and percentage weight. The higher z. B. the part of microgel (10 ⁷ to 10 ⁸ D), the higher the viscosity of the aqueous solution. Commercial varieties contain up to 15 percent by weight. The fractions of al pha-gelatin and its oligomers (9.5 x 10 ^{4/10 5} to 10 ⁶ D) are crucial for the gel strength and are übli cherweise between 10 and 40 weight percent. Molecular weights below the alpha gelatin are referred to as peptides and can be up to 80 percent by weight in conventional gelatin qualities (low bloom).

Gelatin is temperature and concentration dependent ges sol-gel conversion behavior that of the molecular Composition is dependent. As a convention method for that The Bloom number is given as the gelation capacity. Low Commercial qualities start at 50 bloom, high bloom varieties are around 300 bloom.

Fractionated gelatin is the special case of gelatin and is made by special manufacturing techniques such as. B. Ultrafiltration obtained from conventional gelatin. The composition can, for. B. by removal of peptides (MW <9.5 × 10 ⁴ D) or by mixtures of individual fractions such as. B. alpha chains, dimeric and trimeric chains or microgel can be varied.

Gelatin derivatives are chemically modified gelatins, such as e.g. B. succinylated gelatin, which can also be used as a plasma expander are known.

Collagen hydrolyzate is understood to mean a product obtained from collagen or gelatin by pressure hydrolysis or enzymatically, without the ability to form a gel. The molecular weight composition can be between a few hundred D to below 9.5 × 10 ⁴ D due to the manufacturing process. Collagen hydrolyzates are soluble in cold water.

It has also been shown that the use of one of Collagen-derived substance from the group mentioned above not only as a solution-imparting base substance for rutin the advantage of stabilizing such substances in aqueous Solution, but more extensive Benefits.

Rutin is in a preparation according to the invention protected from external influences such as B. light, air oxygen etc. Is the preparation according to the invention in solid, re-resolvable form, is also a Protection of sensitive ingredients from moisture or Moisture access guaranteed. So that's sensitive che rutin in its galenical preparation at the same time effective against loss of activity due to decomposition processes preserved.

Furthermore, substances derived from collagen can be present geous an unpleasant, e.g. T. bitter taste of rutin in a preparation according to the invention.

With regard to absorption or bioavailability of rutin have a pharmaceutical preparation according to the invention own investigations showed that an increased Re sorption and associated a significant increase in Bioavailability compared to conventional preparations the application can be achieved in vivo.

The presence of substances derived from collagen, such as B. gelatin as a macromolecule of primary biogenic origin provides the greatest possible tolerance of the drug preparation in the organism safely. Undesirable side effects of other auxiliary substances, e.g. B. Irritation of mucus skin, such as by organic solvents or Surfactants can be caused to drop out completely or can at least be significantly reduced.  

Thus, the present invention is extremely worthwhile full contribution to sensible therapeutic use and Use of phytopharmaceuticals containing rutin.

The content of the "Solid and liquid solutions of flavonoids" titled patent application P 42 21 834.4 of ALFATEC Pharma GmbH and GGU mbH & Co. KG from the same day also becomes Subject of the disclosure of the present patent application made.

In the following the method for producing an invented pharmaceutical preparation according to the invention with the effect of the gingko biloba extract.

In the simplest case, the method according to the invention can be for the production of such pharmaceutical preparations describe the following process steps:

• a) The rutin is transferred into solution and mixed this solution with an aqueous solution of the base substance.
• b) This solution becomes or will become the solution medium removed, resulting in rutin in molecular disks Persian distribution in the basic substance is preserved.

The ratio of rutin to Ba is usually Sissubstance 1: 0.5 to 1: 1000, but especially 1: 2 to 1:50, stated in parts by weight of dry substance.

This system according to the invention can be additional hydrophilic macromolecules that the solubilizing we strengthen the base substance, u. May even potentiate can, such as B. agar, gum arabic, pectins, tra  ganth, xanthan, natural and modified starches, Dex trane, dextrins, maltodextrin, chitosan, alginates, cellulo derivative derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene Lingglycols, polyacrylic acid, and polymers of methacrylic acid and methacrylic acid esters; as well as their mixtures added become.

The weight ratio of these hydrophilic macromolecules to Base substance can be up to 1: 1.

The according to the inventive method described provided system can possibly further for the corresponding Use suitable carriers and auxiliary substances added the. Such can e.g. B. pharmaceutically common carrier and Excipients from the following groups:

• 1. additional scaffolders, e.g. B. dextrans, sucrose, glycine, lactose, polyvinyl pyrrolidone, sorbitol, mannitol and mixtures thereof.
• 2. Fillers, e.g. B. Strength.
• 3. surfactants, such as B. Polysorbates;
• 4. pH correctives, e.g. B. disodium citrate, disodium phosphate Etc.
• 5. dyes, e.g. B. curcumin,
• 6. flavoring additives or flavoring agents, e.g. B. fruit extracts, fruit juice concentrates etc.

In one embodiment of the method described under a) the rutin can be mixed in water-miscible orga African solvents can be solved. Water can already be present, but is not absolutely necessary.  

Those can be selected as solvents for rutin from the group consisting of: water-miscible organi chemical solvent systems; water miscible organic Solvents such as lower alcohols such as methanol, ethanol, Isopropanol; lower ketones such as acetone; lower ether; never their esters; as well as their mixtures.

The stable solids obtained with this simple process Solutions of rutin can already be used as medicinal accessories horse riding viewed and used as such.

The stability of the aqueous / organic system is below in in vitro as well as in vivo conditions but not to the application senheit of the organic solubilizer such. B. alcohol bound, as one might suspect at first. this fact can be removed by removing the alcohol, e.g. B. by Evapora tion easy to show, in contrast to commercially available medication preparations (drops) of the prior art.

The organic additive in the products according to the invention should therefore have a vehicle function, for example reject that of collagen by changing the hydration shell directed substance such as gelatin whose lipophilic areas ak be activated. In this way, interactions can be preferred between gelatin and lipophilic parts of the molecule of the Rutins.

Another embodiment of the Ver described under a) step for the production of liquid, aqueous and stable, molecularly disperse distributions of rutin in the sense The invention can be applied because rutin in basic medium is soluble with salt formation. At this Process variant can be based on organic solvents Mostly partially, but surprisingly also entirely without be tested.  

Rutin is usually used in an aqueous-ammoniacal medium dissolved at pH values above 7 and with the base sub punch, or aqueous solutions thereof homogeneously mixed, so that a clear solution is created. It is advantageous under Inert gas atmosphere (e.g. nitrogen or argon gas) works to decompose rutin in the basic environment to avoid by accessing carbon dioxide.

The salt formation can then be reversed with the addition of acid be made, or the ammonia by those described below benen process step of drying (b) specified metho the, e.g. B. by simple evaporation or freeze drying, be removed.

The procedure according to the invention according to the previously specified molecularly disperse distributions can concentrate before the now following process step b) or organic solvent can be removed be, e.g. B. by evaporation.

In the process step specified under b) or the solvents from a preparation according to the invention tion removed. This can be done, for example, by drying happen, with different process variants ben.

option A

The preparation is freeze-dried in the transferred to dry, solid condition.

The freezing of the preparation can take place in the freeze drying system itself, e.g. B. in the range of -10 ° C to -40 ° C. The complete freezing can easily be determined by a sudden change in the conductivity in the sample to be frozen. The actual drying is carried out at temperatures of 15 ° C below the sublimation point of water at a pressure of 0.1 Pa to 10 ² Pa (0.001 mbar to 1.03 mbar). The drying process, which can take place in a conventional freeze dryer (condenser temperature: approx. -40 ° C) at -25 ° C and 33 Pa (0.33 mbar) in primary drying with sublimation of the frozen water, leads to secondary drying (desorption ) to a freeze-dried product.

Variant B

By usual spray drying water or a volatile total organic solvent or the ammonia removed. In conventional spray drying systems, norma is used air as a process gas with an inlet temperature between 100 ° C and 300 ° C, with an average tempera difference between process gas and material from 50 ° C to 100 ° C can result. As a process gas, if there is special oxidation sensitive substances also an inert gas, such as e.g. B. nitrogen can be used.

A dry powder is obtained.

Variant C

In one embodiment of the method according to the invention step (b) can be done, for example, by simple air drying and then grinding a gelatin granulate with it properties according to the invention can be obtained. In the Drying can speed up the drying process and to maintain low temperatures under vacuum (approx. 3000 to 5000 Pa (approx. 30 to 50 mbar)), for example at Drying temperatures of up to 50 ° C can be worked.

Suitable for the preparations of rutin according to the invention for example as the basic substances of collagen guided substances selected from the group consisting of  from: gelatin, fractionated gelatin, collagen hydrolysa ten, gelatin derivatives; as well as their mixtures.

Depending on the molecular composition of the use The collagen-derived substance arises Different forms of training of the Ver driving.

When using collagen hydrolyzates, the Ver step a) without the application of heat, e.g. B. in space perform temperature. In combination with subsequent Freeze drying thus becomes a thermal load Stung a preparation according to the invention during the ge effectively avoided the entire manufacturing process.

In the case of gelatin, process step a) is corresponding to modify. To put the gelatin in an aqueous solution transfer, the use of heat (e.g. 30-45 ° C) is required Lich.

From gelatin it is also known that depending on the Manufacture of the gelatin in question its ash content, d. H. the degree of desalination varies. With commercially available gelatin grades can be up to 2% by weight. At however, the residual ash content is of good quality due to the solution at values below 0.2% by weight.

The knowledge of this fact can be broad Ren embodiment of the method according to the invention Zen:

Rutin is known to be calcium or Ma can form magnesium ions complexes. These additions from two Interactions with the polar cause valuable ions Groups of rutin form a conjugate (complex formation) of the two Components. The preferred coordination points of the Calci  um or magnesium can have a hydroxyl group on the Koh lenstoffatom 3, a hydroxyl group on the carbon atom 5 to together with the neighboring keto group (carbon atom 4) on the flavonoid skeleton of rutin. The education such complexes is visualized by a bathochromic ver shift of the absorption maxima is displayed.

Interactions of such complexes from rutin with calcium or magnesium salts with the functional groups of the gela tin molecule lead to an effective stabilization in the sense of the invention, which would not be possible without gelatin and therefore to the precipitation of rutin in the physiological medium would lead.

Therefore, in this embodiment of the invention Process now, for example, a commercially available gelatin with a higher ash content (salinity). Ande On the other hand, a desalinated Gela tine variety a defined amount of calcium or magnesium salt (e.g. 1 to 2% by weight calcium chloride or magnesium chloride) can be added in a controlled manner.

Preparations according to the invention in powder form can be obtained by Packing in suitable containers (e.g. bags) for Production of liquid, aqueous, ingestible medicinal oil serve. The powder can also be used in common hard gelati necapsules can be filled into classic pellets or gra nulates are further processed and then in hard gelatin capsules are filled. Compression according to the usual metho to tablets, production of coated tablets, etc., if necessary under Use of conventional tableting aids, such as. B. FST comm plex, is also possible.

Preparations lyophilized according to the invention, particularly in the case of Use of low molecular weight gelatin varieties, collagen hydro Lysates or gelatin derivatives can be found in cold water  accelerated redissolution. Such preparations can be used as Basis for parenterals, such as B. serve injection solutions.

Also transdermal preparations or processing of an er Preparation according to the invention with conventional auxiliaries to egg A transdermal preparation is possible.

In the case of the photosensitive substance rutin, the processing must principally under light protection.

Within the framework of his specialist knowledge, the specialist can easily do the same constantly work out further process variants. The following Examples are intended to explain the invention in more detail:

example 1

150 g of a collagen hydrolyzate with an ash content below half 0.2% by weight are distilled in 5 l at room temperature dissolved water.

30 g of rutin are dissolved in 2 l of ethanol and with the Kolla gene hydrolyzate solution mixed homogeneously until a clear solution arises.

By spray drying, at which the inlet temperature of the Process gas is 180 ° C and the outlet temperature is 80 ° C, the solvent is removed and a dry one is obtained Powder. Nitrogen is used as the process gas.

150 mg of the powder (corresponding to 25 mg of rutin) are in 25 ml of artificial gastric juice redissolved at 37 ° C. It results a clear solution.

The powder obtained is after dry granulation with übli Chen tabletting aids (FST complex) mixed and on  a tablet machine into tablets with a content of 25 mg of rutin pressed.

Example 2

150 g of a fractionated gelatin with a peptide content below 1% are placed in 3 l of distilled water and swollen 45 minutes. The gelatin is then completely dissolved at 40 ° C.

30 g of rutin are dissolved in 2 l of ethanol and with the Gelati mixed solution. The clear solution is then, as in Bei Game 1 specified, spray dried.

The powder obtained is in opaque hard gelatin capsules filled with 25 mg of rutin.

Example 3

300 g of a commercially available collagen hydrolyzate with a Ash content below 0.6 wt.% Are in at room temperature Dissolved 1.5 l of distilled water. Suspen in this solution 90 g of rutin are added. This is done under a nitrogen atmosphere long ammonia solution (25%) added with stirring until one clear solution arises.

This solution is in a freeze dryer at -35 ° C deep-frozen and by primary drying at -25 ° C and 5 Pa (0.05 mbar) and a secondary drying at 20 ° C.

The product obtained completely dissolves in cold water and clear on and can prepare for oral intake the solutions are used.  

Example 4

300 g of a fully desalinated gelatin powder (100 Bloom) with an ash content below 0.2% by weight are distilled in 6 l water and swollen for 45 minutes. The Ge latine is then completely dissolved at 45 ° C.

6 g of calcium chloride and 90 g are added to the gelatin solution Rutin. As long as ammonia solution under nitrogen atmosphere (25%) while stirring until a clear solution is formed. The solution is then spray dried (entry temp temperature 200 ° C outlet temperature 90 ° C, process gas is stick material).

An intensely yellow colored powder is obtained which is opaque Hard gelatin capsules, each containing 40 mg rutin is filled.

Example 5

300 g of a commercially available gelatin powder (60 Bloom) with an ash content below 2% by weight are distilled in 6 l water and swollen for 45 minutes. The Ge latine is then completely dissolved at 40 ° C.

75 g of rutin are added to the gelatin solution. Under nitrogen As long as the atmosphere becomes ammonia solution (25%) while stirring given until a clear solution arises.

This solution is in a freeze dryer at -30 ° C deep-frozen and by primary drying at -20 ° C and 10 Pa (0.1 mbar) and a secondary drying at 25 ° C.  250 mg of the powder (corresponding to 50 mg of rutin) are in 25 ml of artificial gastric juice redissolved at 37 ° C. It results a clear, intensely yellow colored solution.

Example 6

Clinical studies on the bioavailability of rutin have been un under the following conditions:

In a group of 4 healthy subjects, over 24 hours the renal excretion of quercetin, fighter oil and Isorhamnetin after administration of 600 mg rutin as an accessory riding with gelatin (compared to a commercially available Ready-made rutin drugs (as a control) of the same dosage) measured. The food-related flavon excretion was there taken into account and through appropriate dietary regulations kept as low as possible.

The analysis and identification of the flavon excretions can e.g. B. can be carried out as follows:

• 1. Acidic cleavage (1 M hydrochloric acid) in biological Liquids (urine) contain flavone conjugates.
• 2. Solid phase extraction with methanol to enrich the released flavones (e.g. Extrelut®, Merck).
• 3. HPLC analysis with diode array detection and identification tion of individual flavones, additionally electrochemical Identification (anodic oxidation potential).

The sensitivity of the analysis mentioned is <10 ng flavon per ml.  

The renal flavon excretions were:

Related to the excretion profile of quercetin the net excretion of total flavones in a resorp tion rate of 5.9 ± 2.3%.

The values obtained are shown in FIGS . 1 to 4 Darge. Show:

Fig. 1 shows the urinary excretion of Gesamtflavonen,

Fig. 2 shows the urinary excretion of quercetin,

Fig. 3, the urinary excretion of kaempferol,

Fig. 4 shows the renal excretion of isorhamnetin.

As you can see from the figures, it was not just the familiar one Rutin metabolite quercetin, but also as metabolites of the rutin compounds identified for the first time in vivo Kämpol and Isorhamnetin qualitatively and quantitatively in the renal excretions demonstrated.

This gave a metabolite spectrum of rutin, the essentially the range of active ingredients of the Gingko biloba-Ex tracts corresponds.

Claims (7)

1. Pharmaceutical preparation with the effects of gingko biloba extract containing rutin in molecular disperser Distribution in a base substance derived from collagen with a molecular weight over 100 D, selected from the group consisting of gelatin, fractionated Gelatin, gelatin derivatives, collagen hydrolyzates and their mixtures, optionally in addition to pharmaceutical usual carriers and auxiliaries. 2. Pharmaceutical preparation according to claim 1, characterized characterized in that the weight ratio of rutin to the base substance is from 1: 0.5 to 1: 1000. 3. Pharmaceutical preparation according to claims 1 and 2, additionally comprising hydrophilic macromolecules the group: agar-agar, gum arabic, pectins, tragacanth, Xanthan, natural and modified starches, Dextrans, dextrins, maltodextrin, chitosan, alginates, Cellulose derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, Polyethylene glycols, polyacrylic acid and polymers from methacrylic acid and methacrylic acid esters; As well as their Mixtures, in a weight ratio to the base substance up to 1: 1. 4. A process for the preparation of a pharmaceutical preparation having the effect of the Gingko biloba extract, according to claims 1-3, characterized in that

• a) converting rutin into solution and mixing this solution with an aqueous solution of a base substance made of a hydrophilic peptide with a molecular weight above 100 D, and
• b) the solvent or solvents are removed, as a result of which a molecularly disperse distribution of the rutin in the base substance is obtained,

where appropriate in stage a) or after stage b) Adds pharmaceutically customary carriers and auxiliaries. 5. The method according to claim 4, characterized in that a basic substance with an ash content below of 2%, especially below 0.2%. 6. The method according to claim 5, characterized in that the basic substance is controlled by calcium or magnesium salt adds.