DE102006045762A1 - Green tea drug extract, in particular for the prophylaxis and treatment of diseases of the central nervous system, its use for the production of a medicament and process for its preparation - Google Patents

Abstract

A green tea extract, in particular for the prophylaxis and treatment of neurological and psychiatric disorders of the central nervous system, in particular mental concentration disorders, pain, depression and dementia, has an enriched portion of theanine and theogallin and is decaffeinated.

Description

The The invention relates to a green tea drug extract for the prophylaxis and treatment of neurological and psychiatric Diseases of the central nervous system, especially mental Concentration power disturbances Pain, depression and dementia, and its use in manufacture a medicine and a method for producing such Green tea extract medicines.

It can be stated in the prior art that for theanine as a pure substance, on the one hand soothing (see JP 2005 289 948 A1 . JP 2005 232 045 A1 or JP 901 2454 A1 ), on the other hand stimulating properties (see JP 9100230 A1 ) to be discribed. This is especially true for theanine mixed with caffeine, arginine, rice bran extract (see JP 2002 3220 53 A1 . KR 10 2005 121 535 A1 or US 2005 0020 627 A1 ).

From the DE 10 106 216 A1 For example, a green tea extract is known that is decaffeinated, low in tanning but enriched in L-theanine. It is made by first decaffeinating green tea leaves, green tea blanc or green tea powder and then extracting it in water. The extract is then contacted with polystyrene and then concentrated. The extract is used as an ingredient in beverages or beverage concentrates.

From the EP 10 57 483 A1 For example, a pharmaceutically active composition is known for treating various symptoms, such as obesity, premenstrual symptoms, or hypersensitivity, which includes theanine.

From the EP 10 74 252 B1 For example, a theanine-containing composition for suppressing behavioral problems in pets is known.

The currently common Medicaments for the treatment of diseases of the central nervous system, especially from dementia, depression and concentration disorder a broad spectrum of side effects. There is therefore a great need after a prophylaxis or an improved drug with a good therapeutic efficacy with the lowest possible rate of side effects. In particular, this also applies and especially for prophylaxis.

Of the Invention is therefore the object of a drug for Treatment of diseases of the central nervous system as well Specify a method for its production based on green tea as natural Starting material a good therapeutic effect at low Has side effect rate and thereby easy to produce and to a drug is configurable.

These Task is by a green tea drug extract (hereinafter referred to as SGTE = "special green tea extract") specified in claim 1 type in product technical terms solved. Accordingly contains the SGTE next to an enriched portion of Theanin further one enriched portion of theogallin and is decaffeinated.

When preferred enrichment levels for Theanin and Theogallin have at least six percent and at least three percent, with caffeine content at maximum 0.03 percent should be.

A biological or pharmacological effect of said SGTE not yet described. Based on the previously known Literature was an effect of SGTE in pathological disorders of the central nervous system, especially neurological and psychiatric Diseases and concentration disorders were not expected. Only the application of the completely "bias" -free examination in the rat telestereo EEG yielded in experiments other objective, the indication of the existence of such CNS Effect. The effect was further confirmed by in vitro experiments on Hippocampal slice preparation in direct interaction between the active substance and its target organ, the brain, underpinned.

Of the SGTE according to the invention can for the preparation of a corresponding medicament for prophylaxis and treatment of neurological and psychiatric disorders of the central nervous system, in particular of mental concentration disorder, Pain, depression and dementia are used. In this context are also disturbances Can be treated with such a drug, as in children Attention deficit hyperactivity syndrome. details Information on this is the description of the embodiment removable.

In procedural aspects, the invention provides a method to

• a) wässrige Extraktion von Grüntee-Blättern,
• b) Flüssig-Flüssig-Extraktion des in Schritt a) erhaltenen wässrigen Grün tee-Extraktes,
• c) absorptive Anreicherung des in Schritt b) gewonnenen Extraktes in einem Absorber,
• d) Elution des Absorbers,
• e) Aufkonzentrieren des Eluats zu einem entkoffeinierten, mit Theanin und Theogallin angereicherten Grüntee-Extrakt mit einem Trockensub stanz-Gehalt von vorzugsweise mind. 50%.

Production of a SGTE, which has the following method steps:

• a) aqueous extraction of green tea leaves,
• b) liquid-liquid extraction of the aqueous green tea extract obtained in step a),
• c) absorptive enrichment of the extract obtained in step b) in an absorber,
• d) elution of the absorber,
• e) concentrating the eluate to a decaffeinated, enriched with theanine and theogallin green tea extract with a Trockensub punch content of preferably min. 50%.

On the basis of this fundamental Method steps that further specify in the further dependent claims are, can the ones mentioned above Shares of theanine, theogallin and caffeine can be achieved.

Further Features, details and advantages of the invention will become apparent from the following description in which the nature of the SGTE, whose Mechanisms of action and the experiments made using the attached diagrams be explained in more detail. Show it:

1 a comparison chart showing the effect of SGTE on EEG frequencies during the first hour after drug administration (mean of n = 4 animals);

2 a diagram showing the concentration-dependent increase in the amplitude of the population spike (activity of pyramidal cells) in the presence of SGTE in the hippocampal slice preparation in vitro (mean of 4 sections with average error of the mean); and

3 a graph of the behavior behavior of the amplitude behavior of the population spike in the hippocampal slice after theta-burst stimulation in the presence of SGTE.

to Preparation of the SGTE according to the invention becomes green tea used as raw material. This becomes in a first step one aqueous Subjected to extraction - step a) the manufacturing process.

Of the thus obtained aqueous Green tea extract becomes in a second step a liquid-liquid extraction - step b) - by Subjected to ethyl acetate. Here are caffeine and part of Polyphenols removed, resulting in an enrichment to the desired Substances Theanin and Theogallin leads.

A further, adsorptive enrichment takes place in a third process stage - step c) - over one adsorber filled with functionalized divinylbenzene. The resulting, aqueous Pass is to be rejected. The elution - step d) - takes place with demineralized water, with two separate sub-fractions to be obtained. In particular, the second sub-fraction is rich Theanine, Theogallin and Green Tea contained amino acids.

In another step - step e) - will the fraction in question to a dry matter content of approx. 50% concentrated and can already be used as such. Of the thus containing concentrated Theanin- and Theogallin- enriched Green tea extract can in a further process step spray dried.

The SGTE produced as described above has essentially the following composition based on dry substance: water content 3.2% ash content 24.1% Total amino acids 3.52% caffeine ≤ 0.01% L-theanine 9.71% theogallin 4.65%

Of the Rest consists of a variety of substances. Analyzes have as Residual tannins 2.5% as well as carbohydrates, acids and acid derivatives to 52.3%.

In studies of changes in the EEG frequencies of the rat after administration of SGTE and In the direct interaction of SGTE and brain matter in the rat hippocampal slice preparation in vitro, it has surprisingly been found that the preparation has an effect in the brain which is useful in the treatment of neurological and psychiatric disorders of the brain, especially dementia, depression, pain and concentration performance disorders is useful.

SGTE surprisingly shows in the tele-stereo-EEG model in rats changes in EEG frequencies as measured after administration of classical drugs for the treatment of dementias (example galanthamine), depression (example paroxetine) as well as mental dysfunctions (eg amphetamine). The changes seen after administration of classical drugs and after administration of a dose of SGTE (75 mg / kg) and measured according to Test Procedure 1 are in 1 shown.

From the finding that SGTE produces the same characteristic changes in EEG frequencies as commonly used in the treatment of dementias, depression and concentration disorders, it can be concluded that SGTE is effective in treating the same indications. The fact that drugs used in the same indication also cause similar EEG changes was demonstrated by Dimpfel using more than 40 reference substances for 8 different indications ( Dimpfel W .: "Preclinical data base of pharmaco-specific rat EEG fingerprints (Tele-Stereo-EEG)" in Eur J Med Res (2003) 8: 199-207 ).

In addition, studies on the hippocampal slice preparation were performed in vitro. In these studies it was surprisingly found that SGTE causes both an increase in pyramidal cell activity following single challenge and an increase in long-term potentiation (see 2 and 3 ). This phenomenon has already been reported in the literature for other stimulating and anti-dementing drugs such as memantine ( Dimpfel W .: "Effects of memantine on synaptic transmission in the hippocampus in vitro" in Arzneim.-Forsch / Drug Res (1995) 45: 1-5 ).

The SGTE according to the invention As a drug containing drug are preferably administered orally.

to Administration can be the drug of the invention, as the active ingredient Contains SGTE, e.g. in the form of powders, tablets, capsules, pills, dragees, granules, Pellets, solutions, Syrups, dispersions can be formulated, with the active ingredient optional be combined with pharmaceutically acceptable excipients and carriers can.

The medicaments of the invention, containing the SGTE as an active ingredient, are usually in accordance with conventional Methods are prepared and in a pharmaceutically suitable form administered.

To the Example can the solid oral forms together with the active ingredient diluents, e.g. Lactose, dextrose, sucrose, cellulose, cornstarch or Potato starch; Lubricant, e.g. Silicate, talc, stearic acid, magnesium or calcine stearate and / or polyethylene glycols; Binders, e.g. Starches, rubber arabic, gelatin, methylcellulose, carboxymethylcellulose or Polyvinylpyrrolidone: Anesthetic, e.g. Starch, alginic acid, alginates or sodium starch glycolates, foaming mixtures thereof; dyes; sweeteners; Wetting agents such as lecithin, polysorbates, laurylsulfates and im general non-toxic and pharmacologically inactive substances, which are used in pharmaceutical formulations contain.

The pharmaceutical preparations can in a known manner, e.g. by mixing, granulating, Tabletting, sugar coating or coating coating processes.

The liquid Dispersions for oral administration may be e.g. Syrups, emulsions and suspensions.

syrups can as a carrier e.g. Sucrose or sucrose with glycerol and / or mannitol and / or sorbitol contain.

The Suspensions and the emulsions may be used as carriers e.g. a natural one Resin, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The dosage unit of the drug may contain, for example, from 1720 to 4300 mg, preferably from 1935 to 2580 mg of SGTE per daily dose in the case of oral dosage forms. For example, the daily dose can be in 1 to 3 single doses, preferably in two divided doses, daily.

Test Method 1 (Tele-Stereo EEG)

The changes The EEG frequencies were after administration of saline (control) or oral determined by SGTE 75 mg / kg.

The investigations were carried out analogously to the method described by W. Dimpfel ( Dimpfel W .: "Preclinical data base of pharmaco-specific rat EEG fingerprints (Tele-Stereo-EEG)" in Eur J Med Res (2003) 8: 199-207 ) carried out as follows:
Four male adult Fischer-344 rats (day-night converted) were implanted with 4 bipolar concentric electrodes at the age of 6 months along with a microplug on a common baseplate. The plug was used to record a 4-channel transmitter for telemetric transmission of the field potentials derived from the frontal cortex, hippocampus, striatum and formatio reticularis. The signals were subjected to Fast Fourier Transformation in real time on a computer system ("EEG Analysis" software, OS Science operating system, "LabTeam" lab computer from MediSyst, Linden, DE), and the power density spectra were each averaged over 60 minutes. The subdivision of the spectra into 6 different frequency ranges allowed the detection of pharmaco-specific changes with respect to the pre-values measured before each application within these frequency bands.

To the Application protocol of the substance is to record that the substance Orally 45 minutes after the start of the measurements (pre-value) was applied. Five minutes later the measurements were restarted, at least over the next 5 hours continuously analyzed and in 60-minute periods summarized. The test substance was administered in a dosage of 75 mg / kg (SGTE).

The statistical comparison of the experiments with the results obtained after administration of saline solution was carried out by means of a multivariate analysis according to Ahrens and Läuter (see H. Ahrens, J. Läuter: "Multidimensional Analysis of Variance" (1974), Akademie Verlag, Berlin ) on the basis of the changes within the individual frequency bands in all Himregionen as variables.

The administration of saline hardly resulted in changes in electrical activity (μV ² / Ω) compared to the pre-phase values.

Administration of SGTE resulted in significant changes in power density in the frontal cortex. (please refer 1 ). Note the similarity to drugs used to treat depression, dementia, and concentration disorders.

Test method 2 (long term potentiation in the hippocampal slice preparation in vitro)

effects of SGTE on the excitability of the pyramidal cells were in the hippocampal slice preparation of Rat determined. The analysis of the effects took place on two levels. First the normal excitability was checked by the application of single stimuli and then after a so-called "theta-burst stimulation" the effects measured on the long-term potentiation.

For the implementation of this Studies were nine adult male CD rats used. The isolation of the hippocampus was performed on anaesthetized patients and subsequently exsanguineous animals in phosphate buffered saline (NaCl: 124 mM; KCl: 5mM; CaCl 2 mM; MgSO4: 2mM; NaH 2 PO 4: 1.25 mM; NaHCO3: 26 mM: glucose: 10 mM; Control Solution: Artificial Cerebral Spinal Fluid (ACSF). The SGTE was produced by Plantextrakt, Vestenbergsgreuth, to disposal posed.

The middle part of the hippocampus was then blocked with the aid of a rapid adhesive and cut with a vibratome into 400 μm thick slices. These sections were stored for at least one hour before the start of the experiment (see SJ Schiff, GG Somjen: "The effects of temperature on synaptic transmission in hippocampal tissue slices" in Brain Research (1985), 345: 279-284 ) in a carcass-bubbled incubation chamber.

The Experiment itself was in a so-called "base unit" with "Haas Top" (Medical Systems Corp., USA) performed at 35 degrees Celsius.

The with the help of peristaltic pumps (Infusomat B. Braun Melsungen AG) superfused hippokam pus cut lay on a piece of gauze. Introduced carbogen maintained the required oxygen supply to the solution. The flow rate was 200 ml / h.

The Stimulation of the CA2 region (Schaffer collaterals) occurred under Use of a stimulus generator (lab computer Labteam Fa. Medi-Syst GmbH, Linden, DE) an insulation unit using a bipolar concentric steel electrode (Rhodes Medical Systems, USA). The pulse width was 200 μs, the current constant 200 μA. The stimulus generator released at intervals of 20 seconds each 4 individual irritations in the Cut a total of 4 population spikes evoked. The derivative the answer was in the CA3 region. The system averaged the Responses of the 4 spike amplitudes.

The effect of SGTE on the evoked potential was investigated after single stimulation as well as after induction of long-term potentiation by a short duration (1 s) tetanic stimulus (90 Hz) (see KG Reymann, HK Mattkies, U. Frey, VS Voborbyev, H. Mattkies: "Calcium-induced long-term potentiation in the hippocampal slice. Characterization of the time course and conditions "in Brain Bulletin (1986), 17: 291-296 ). The cut was first superfused with control solution. After finding a suitable signal and registering this output signal for several times instead of the control solution was switched to SGTE solution. Each cut was only used for one experiment at a time. Values are given for n = 4 cuts.

The Derivation of the evoked response was done every 10 minutes extracellular with a drawn glass capillary (electrodepuller, Rhema Labortechnik, DE). The response signal was amplified (amplifier "LMI", List Electronics, Darmstadt, DE) with a laboratory computer system "Labteam" (Software NeuroTool, MediSyst GmbH, Linden DE) analog-digital conversion (resolution 12 Bit) and evaluated. After finding a suitable signal (amplitude height approx 1 mV) became the amplitude level of the population spike (SAP = sum action potential, popspike) as Output size set. This reference value was the average of the last three measured amplitude levels while Superfusion with the ACSF solution (Baseline). This was followed by superfusion with test substance with the same procedure. In subsequent experiments, a short-term tetanic stimulation (theta burst stimulus = TBS) for the induction of Long-term potentiation. Resulting amplitude changes were given in% of this initial value (n = 4). Values in the presence the test substance are given in% reduction of this reference value.

The results of these investigations are in the 2 and 3 shown. The first experimental set-up shows a concentration-dependent increase in the amplitude of the population spike in the presence of 0 to 13 mg / l SGTE in single challenge (see 2 ). The initiation of long-term potentiation by TBS was also increased in a concentration-dependent manner at the same concentration (see 3 ), as known from anti-dementia tests. From this result it can be concluded that SGTE - as can be seen from the EEG examinations - positively influences depression and dementia.

Claims (13)

Green tea drug extract for the prophylaxis and treatment of neurological and psychiatric disorders of the central nervous system, in particular mental concentration disorders, pain, depression and dementia, with an enriched portion of theanine, characterized in that the extract also contains an enriched portion of theogallin, and decaffeinated. Green tea-drug extract according to claim 1, characterized by the following proportions based on the dry substance: - Theanine at least 6.0% - Theogallin at least 3.0% - Caffeine maximum 0.03%. Green tea extract according to claim 1 or 2, characterized by the following proportions based on the dry matter: - water content 2.0% to 5.0% - ashes 20.0% to 30.0% - Amino acids 2.0% to 10.0% - Caffeine below 0.03% - Theanine 6.0% to 40.0% and - Theogallin 3.0% to 20.0%. Green tea medicine extract according to claim 1 or 2, characterized in that the extract additionally pharmaceutically acceptable carriers, Auxiliaries and / or diluents contains. Green tea medicine extract according to one of the preceding claims, characterized that it is prepared for oral administration. Green tea-drug extract according to one of the preceding claims, characterized by the following composition based on the dry matter: - water content 2.5% to 4.0%, in particular 3.2% - ashes 23.0% to 25.0%, in particular 24.1% - Amino acids 3.0% to 4.0%, especially 3.52% - Caffeine below 0.01 - Theanine 9.0% to 10.5%, especially 9.71 and - Theogallin 4.0% to 5.5%, especially 4.65%. Use of green tea drug extract according to any one of the preceding claims for the manufacture of a medicament for the prophylaxis and treatment of neurological and psychiatric Diseases of the central nervous system, especially mental Concentration power disturbances Pain, depression and dementia. Process for the preparation of a green tea-drug extract according to one of the claims 1 to 6, characterized by the following method steps: a) aqueous Extraction of green tea leaves, b) Liquid-liquid extraction of the aqueous obtained in step a) Green tea extract medicines, c) absorptive enrichment of the extract obtained in step b) an absorber, d) elution of the absorber, e) Concentrate of the eluate to a decaffeinated, with theanine and theogallin enriched green tea extract with a dry matter content of preferably at least 50%. Method according to claim 8, characterized in that that the liquid-liquid extraction according to step b) carried out by ethyl acetate becomes. Method according to claim 8 or 9, characterized that the absorptive enrichment in step c) over a functionalized Filled divinylbenzene Absorber takes place. Method according to one of claims 8 to 10, characterized that the elution of the absorber according to step d) with demineralized Water takes place. Method according to one of claims 8 to 11, characterized that in the elution of the absorber according to step d) two separate Partial fractions are obtained, of which the second, to Theanin, Theogallin and green tea-specific amino acids rich fraction fraction is subjected to the further process steps. Method according to one of claims 8 to 12, characterized the green tea-drug extract obtained in step e) is spray-dried becomes.