EP1802320A1

EP1802320A1 - Pharmaceutical canscora diffusa-containing composition

Info

Publication number: EP1802320A1
Application number: EP05794094A
Authority: EP
Inventors: Michael Barthel
Original assignee: Individual
Current assignee: Individual
Priority date: 2004-10-21
Filing date: 2005-10-21
Publication date: 2007-07-04
Also published as: US20080193567A1; WO2006042440A1; JP2008516997A; CH699169B1; WO2006042440A8

Abstract

The invention relates to a pharmaceutical composition containing an active substance obtainable from a Canscora-type plant of a Gentianaceae family, in particular a substance obtainable from a plant of Canscora diffusa species. The inventive canscora-containing composition is administratable for treating several central nervous system disturbances, in particular concentration and learning disturbances, school difficulties, school refusal, dyslexia, memory retardation, development retardation, language development retardation, confusion states, dementia and age-related dementia, Morbus Alzheimer, memory disturbances, fragile (X)-syndrome, psychosis, depressive disorders, schizophrenic disorders, affective psychosis, mania, afraid and panic states, children and adult hyperkinetic behaviours, hallucinations, compulsive acts, for example washing compulsion, unusual behaviours, nervous anorexia, lack of drive, borderline syndrome, autismus, bipolar affective disorders, intellectual handicaps, fright state, nightmares, tics and self confidence fault.

Description

Pharmaceutical composition containing Canscora diffusa

The present invention relates to a pharmaceutical composition containing the plant Canscora diffusa, in the family Gentianaceae, a dosage form containing the composition and the use of the pharmaceutical composition.

It is known that the tropical climate Canscora diffusa is used in the Philippines in the form of an absinthe of Pflance as a tonic and as a remedy for stomach pain (Lemmens, RHMJ: Canscora diffusa (VaIh) R. Br. Ex Roemer & Schultes Canscora decussata is used as a laxative, as a means of general health improvement, and as a general, unspecified nerve tonic.Canscora lucidissima is reportedly used as a medicinal plant in China and Vietnam, but it does not specify what it is for diffusa, there is only one scientific work, in which the isolation of the active ingredient Diffutin, a Glycosyloxyflavan, is listed.The active ingredient diffutin is assigned an "adaptogenic" effect. This is an effect against stress and against anxiety. Canscora decussata contains xanthones C-glycosides, one of which, Magniferin, has anti-inflammatory and "CNS-lowering" effects, but it is not clear what the latter indication means, and it has a fungicidal and a weak effect It also has an anti-Mycobacterium tuberculosis effect and also spermicide in animal studies.

Ghosal, S. et al. describe the isolation of the active ingredient diffutin from the plant Canscora diffusa (Ghosal, S. et al .: "Diffutin, a novel adaptogenic glucosyloxyflavan from Canscora diffusa in Journal of Chemical Research, Synopses, 1983, page 330). Also referred to in this article is the "adaptogenic" (anti-stress and anti-anxiety) effect of this plant, which is called the main active ingredient of Canscora.

The same author (Ghosal, S.) describes in an article (Ghosal, S. et al., "Dichotosin and Dichotosinin, 2 Adaptogenic Glucosyloxyflavans from Hoppea-Dichotoma", Photochemistry (Oxford), Vol. 24, No. 4, 1985, Pages 831-833) show the "adaptogenic" effect of 2-glycosyloxyflavans, the dichotosin and dichotosinin, obtained from the root of the plant Hoppea dichotoma. It also applies to the earlier writing of the same author (Ghosal) on diffutin in Canscora diffusa. Concerning Canscora diffusa no new findings are revealed.

Object of the present invention is to propose new uses of substances or extracts of the plant of the genus Canscora diffusa, (family Gentianaceae).

There is a great need for the enrichment of the therapy, in particular the treatment of disorders in the intellectual field to provide drugs that have not only good efficacy, but also a wide range of indications and little or no side effects.

This object has surprisingly been achieved by providing the Canscora diffusa-containing pharmaceutical compositions described below. It has been found that extracts from the plant Canscora diffusa can be used for the treatment of mental and intellectual diseases. In the mental field it concerns the treatment of psychoses such as schizophrenia and depression, in the intellectual field the treatment of disorders of learning and memory, e.g. the attention deficit syndrome (ADS), the students' unwillingness to pick up the subject matter, the loss of memory, e.g. in dementia, Alzheimer's.

The therapeutic use of the plant Capscora diffusa in the mental and intellectual field is not yet known.

In the light of this prior art, the finding that the plant species Canscora diffusa has the pharmacological activity described below, which makes it particularly suitable for the treatment of diseases of the central nervous system, is unexpected.

The pharmacological test results, from which these conclusions had to be drawn, as well as the concrete indications in the mental and intellectual area are explained and explained in detail in the description.

Canscora diffusa is from the Gentianaceae family. It is a narrow, four-leaved annual plant that grows to a normal size of 15 to 60 cm. The stems are quadrangular. The leaves are arranged opposite, the lower ones are elliptical 4x1 cm in size, the upper ones are wider 2.5x1, 6 cm in size. They are dreinervig, The flowers are purple-colored, numerous, two-sexed. The petals are up to 1, 5 cm long. It can bloom all year round. (For more detailed botanical description, see attached copy of botanical books.) It grows well on moist rocks. It has a very wide distribution in tropical Africa, in the tropical areas of Asia, especially in Nepal, India, Sri Lanka, Vietnam, Laos, Thailand, Java, Philippines and tropical Australia.

For the drugs according to the invention, preferably the whole above-ground plant with stalk, leaf and flower without the root is used. However, it is also conceivable to extract the plant with an alcoholic or aqueous / alcoholic solution (mono-, di- or trihydric alcohols having 1 to 5 C atoms) and to use the extract.

In order to be suitable for the production of the drug, the plant should be obtained from their natural occurrence. Alternatively, it can also be grown and then obtained.

For the preparation of the plant, the usual methods such. Cleaning, crushing and drying and stabilization method used. Among the drying methods, lyophilization should be mentioned in particular. Among the stabilization methods, the preservation with 96% ethanol should be mentioned.

Since the drug is not stable on prolonged transport, either the above-mentioned preservation with 96% ethanol is particularly recommended, or even better the trituration with milk sugar, e.g. in a porcelain roughened grate, which is performed as follows. 1 part by weight of the fresh plant is triturated for one hour with 100 parts by weight lactose (lactose) until a dry powdery greenish colored substance has formed.

The alcoholic extract or the trituration with lactose is preferably used at a concentration of 1 nanogram per single dose.

The dosage is given as a single dose at intervals of 1 to 12 months, preferably 2-4 months, according to stopping the improvement in the symptoms. Therapeutic dosage forms

The preparation of pharmaceutical compositions containing Canscora diffusa or their use in the use according to the invention is carried out in the usual way by means of common pharmaceutical and technological processes. For this purpose, the extract or the trituration with milk sugar is processed together with suitable pharmaceutically acceptable excipients and carriers to the drug forms suitable for the various indications and application sites.

An important systemic administration form is peroral administration as tablets, hard or soft gelatin capsules, dragees, powders, pellets, microcapsules, oblong compresses, granules, chewing gums. Lozenges, chewing gum, sachets or globules.

As adjuvants for the preparation of pharmaceutical compositions for peroral administration, for example, counter sticking and lubricating and release agents, dispersants, such as flame-dispersed silica, disintegrants, such as various types of starch, PVP, cellulose esters as granulating agents, such as waxy and or polymeric substances on Euthragit ^® , cellulose or Cremophor ^® base used.

Antioxidants, sweeteners, such as sucrose, xylitol or mannitol, flavoring agents, flavorings, preservatives, ingredients, buffering agents, directing agents; such as microcrystalline cellulose, starch and starch hydrolysates (for example Celutab ^®), lactose, polyethylene glycols, polyvinylpyrrolidone and Dicalcimphosphat, lubricants, fillers, such as Lactαse or starch, binders in the form of lactose. Starches such as wheat or corn or rice starch, cellulose derivatives such as methylcellulose, hydroxypropylcellulose or silica, talc, stearates such as magnesium stearate, aluminum stearate, calcium stearate, talc, siliconized talc, stearic acid, cetyl alcohol, hydrogenated fats, may also be used.

For conventional application on the skin, the usual emulsions, gels, ointments, creams or mixed-phase or amphiphilic emulsion systems (oil / water-water / oil-mixed phase) and liposomes and Transfersomen be mentioned.

Ais Hiifs- or carriers are recordable as sodium alginate as gelling agent for the preparation of a suitable basis or cellulose derivatives, such as guar or xanthan gum, inorganic gelling agents, such as aluminum hydroxides or bentonites (so-called thixotropic gel-forming agent), polyacrylic acid derivatives, such as Carbopol ^®, polyvinylpyrrolidone, microcrystalline cellulose or carboxymethyl cellulose. Furthermore, amphiphilic lower and higher molecular weight compounds such as phospholipids come into consideration. The gels can be present either as water-based hydrogels or as hydrophobic organelles, for example based on mixtures of low and high molecular weight paraffin hydrocarbons and vaseline.

Suitable emulsifiers are anionic, cationic or neutral surfactants, for example alkali soaps, metal soaps, amine soaps, sulfurized and sulfonated compounds, invert soaps, high coat alcohols, partial fatty acid esters of sorbitan and polyoxyethylene abitans, wool wax, lanolin or other syndthetic products for the preparation of the oil / water and / or or water / oil emulsions.

The hydrophilic organogels can be prepared, for example, based on high molecular weight polyethylene glycols. These gel-like shapes are washable. As lipids in the form of fatty and / or oil and / or waxy components for the preparation of ointments, creams or emulsions are vaseline, natural or synthetic waxes, fatty acids, fatty alcohols, fatty acid esters, for example as mono-, di- or triglydeides, paraffin oil or vegetable oils, hydrogenated castor oil or coconut oil, lard, synthetic fat, eg based on caprylic, capric, lauric and stearic acid, or triglyceride mixtures such as Miglycol® used.

To adjust the pH, osmatically effective acids and alkalis, e.g. Hydrochloric acid, citric acid, caustic soda, potassium hydroxide, sodium hydrogen carbonate, and also buffer systems, e.g. Citrate, phosphate, Tris buffer or triethanolamine.

To enhance stability, preservatives, e.g. Methyl or Popylbenzoat- (parabens) or sorbic acid are added.

Other topically administrable forms include pastes, powders or solutions. The pastes often contain lyophilic and hydrophilic excipients with a very high proportion of fat as the basis for consistency. The powders or topically applied powders may be used to increase the dispersity and the flow and lubricity and to prevent agglomerates, such as starches, such as wheat or rice starch, flame-dispersed silica or silica, which also serve as a diluent. Particularly suitable as traπsdermale systems are patches which, based on various layers and / or mixtures of suitable excipients and carriers, are capable of delivering the active ingredient in a controlled manner over longer or shorter periods of time. In the production of such transdermal systems come for the purpose of improved and / or accelerated penetration, the membrane permeation enhancing substances or permeation promoters, such as oleic acid, Arzone®, adipic acid derivatives, ethanol, urea, popyl glycol in addition to suitable auxiliaries and carriers, such as solvents, polymeric components , such as based on Eutragit®, into consideration.

The patches are preferably applied to the inside of the forearm.

Furthermore, injectables can also be administered. These are either in the form of ampoules or as so-called ready-to-use Injektabilia, e.g. as pre-filled syringes or disposable syringes, besides also in vials for multiple removal, prepared. Administration of the injectables may be in the form of subcutaneous (s.c.), intramuscular (i.m.), intravenous (Lv.) Or intracutaneous (i. E.) Administration. The respectively suitable injection forms can be used in particular as solutions, crystal suspensions, nanoparticulate or colloidally disperse systems, such as e.g. Hydrosols.

The injectable preparations can also be prepared as concentrates, which can be adjusted with aqueous isotonic diluents to the desired active ingredient dosage. Furthermore, they may also be used as powders, e.g. Lyophilisates are prepared, which are then preferably dissolved or dispersed immediately before administration with suitable diluents.

Suitable excipients and carriers in the preparation of the injectable preparations are acqua steήlisata, the pH-influencing substances, such as organic and inorganic acids and bases, and their salts, buffer substances for adjusting the pH, isotonizing, such as sodium chloride, sodium bicarbonate , Glucose and fructose, surfactants or surface-active substances and emulsifiers, such as partial fatty acid esters of polyoxyethylene sorbitan (Tween®), or fatty acid esters of polyoxyethylene (Cremophor®), fatty oils, such as peanut oil, soybean oil and castor oil, synthetic fatty acid esters, such as ethyl oleate , Isopropyl myristate and neutral oil (Miglycol®), as well as polymeric auxiliaries, such as, for example, gelatin, dextran, polyvinylpyrrolidone, the solubility-increasing additives of organic solvents, such as, for example, propylene glycol, ethanol, N ₁ N- Dimethylacetamide or complexing agents such as citrates and urea, preservatives such as Benzolsäurehydroxypopyl- and methyl ester, Benzylakohol, antioxidants such as sodium sulfite and stabilizers such as EDTA into consideration.

Administration may also be perlingual.

Delayed release dosage forms may also be used.

One skilled in the art can readily identify and prepare the appropriate dosage forms in accordance with pharmaceutical prescriptions and procedures based on pharmaceutical and physical principles.

indications

The composition of the present invention containing Canscora diffusa can be found in many disorders of the central nervous system (CNS), especially in impaired concentration, disturbed nerves, school impairments, school refusal, dyslexia, mental retardation and developmental retardation, speech development delay, confusion states, mental dementia and senile dementia , Alzheimer's disease, in memory impairment, in fragile (X) syndrome, in psychosis, depression, schizophrenia, in affective psychoses, in mania, in hyperkinetic behavioral disorders in children and adults, in hemucinations, in compulsive acts such as Compulsory washing, behavioral abnormalities, anorexia nervosa, listlessness, borderline syndrome, autism, bipolar mood disorders, mental disability, test lamp fever, nightmares, tics, lack of self-confidence.

Pharmacologically experimental part

The pharmaceutical composition according to the invention with an extract of the plant Canscora diffusa was applied in 274 patients within about 6 to 7 years, of which 106 were female. Among these 274 patients, a clear subjective and objective improvement of the symptoms occurred at 183. For each of the 274 patients, one single dose was used. In the period of the effect of the single dose no other drugs (either internally or externally eg as ointments) were administered, no vitamins, trace elements, minerals, phytotherapeutics, etc., so that the effect alone is attributable to the drug used by Canscora diffusa.

The amount of active ingredient was always in the nanogram range or even lower, in the picogram range.

In most patients, the improvement of the symptoms occurred without a previous exacerbation of the existing symptoms. In about 5% of the cases a slight aggravation of the symptoms lasting for a maximum of 5 to 14 days was observed. In 10% to 20% of cases, somatic symptoms that were not related to the existing symptoms appeared in the short term (for a few days), which was often interpreted by most patients as a solution to unresolved problems or previous suppression. In about 25% of cases, in the third week after the first ingestion, the original symptoms reappeared again in a significantly reduced form. However, after several hours or a few days, it stopped again without another dose of medication.

With regard to the frequency of dosing, it should be noted that in these 183 patients who experienced significant improvement or recovery, a single dose should be given no sooner than 7 weeks. The longest duration of effect was 11 months, that is to say that the symptoms that led to the indication for Canscora diffusa did not return until after 11 months in these patients, so that only then was a single dose necessary. The average duration of a single dose is two to three months. The duration of action of a single dose depends on the severity of the disease. The need for repetition exists only with recurrence of the complaints.

None of the 274 patients studied using Canscora diffusa had any side effects, probably due to the careful dosage. In the 91 patients who were unable to improve with Canscora diffusa, no adverse effects or side effects were observed or reported by the patients. Comparison with other therapeutics in terms of effect, side effect, duration of action and costs

Compared to the Canscora diffusa-containing pharmaceutical composition according to the invention, no other psychotropic drug has such a range of indications and thus its range of action.

Due to the fact that the administration takes place only in the practice and afterwards no further ingestion is necessary at home, until the complaints reappear after 2 to 3 months at the earliest and the patient in the repetition consultation in the practice a new drug dose In the case of no other psychopharmaceutical, the compliance is as high as in the case of the Canscora diffusa-containing pharmaceutical compositions according to the invention.

No other psychotropic drug has such a long duration of action.

No other psychotropic drug is so side effects.

Based on a minimum average duration of action of 2 months and assumed costs for a single dose of 40, - €, the costs of the treatment according to the invention Canscora diffusa ^: containing pharmaceutical composition are significantly lower than comparable psychotropic drugs, such as Ritalin ^® (is about 4 to 6 times as expensive), Captagon ^® (is about 4 times more expensive), Dogmatil ^® (is about 5 times more expensive), Fluctin ^® (is about 10 times as expensive), Ludiomil ^® (is about 2 times as expensive).

Due to the usual multimorbidity associated with anxiety in psychiatric patients, the cost of other conditions that are treated with other therapies should be added to conventional medicines. In the Canscora diffusa containing pharmaceutical composition of the present invention, this drug was the only one given to the patient. (It should be noted that patients consistently, including those who did not recover, had very happily welcomed monotherapy.) This adds further costs to other therapeutics, making the cost comparison even more significant in favor of the inventive Canscora diffusa. containing pharmaceutical composition fails. The invention relates to a pharmaceutical composition containing an active substance obtained from a plant of the genus Canscora in the family Gentianaceae, particularly obtained an active ingredient from a plant ^"of the type Canscora diffusa. The composition of the invention with a content of Canscora can in many disorders in central nervous system, in particular in case of impaired concentration, learning disabilities, at school performance weakness, Schulleistungsverweigemng, dyslexia, mental retardation and developmental retardation, speech development delay, Verwirmngszuständen, mental dementia and senile dementia, Alzheimer's disease, memory impairment, fragile (X) syndrome, psychosis , Depression, schizophrenia, affective psychoses, mania, anxiety and panic states, hyperkinetic behavioral disorders in children and adults, hallucinations, obsessional behavior such as washing compulsion, behavior sauffälligkeiten be administered in anorexia nervosa, with listlessness in borderline syndrome, autism, ^"in bipolar affective disorders, mental disabilities, in fright, in nightmares, with tics, with lack of self-confidence.

Claims

claims

1. A pharmaceutical composition containing a plant of the species Canscora diffusa.

2. Pharmaceutical composition according to claim 1, characterized in that the composition contains at least one content or constituents of the whole above-ground plant.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the components of the plant Canscora diffusa contained in the composition or the content thereof contained in the composition thereof only those of the above-ground plant, in particular both of the stem and the leaf, and the Flowering, are.

_**

4. Pharmaceutical composition according to one of claims 1 to 3, characterized in that the constituents of the plant are obtained by extraction with a preferably polar solvent from the fresh or dried plant.

5. Pharmaceutical composition according to claim 4, characterized in that as the solvent! Water, an alcohol having 1 to 5 carbon atoms, acetone, tetrahydrofuran, dimethyl sulfoxide or mixtures of two or more of the aforementioned solvents are used.

6. A pharmaceutical composition according to claim 4 or 5, characterized in that a water / alcohol mixture is used as the solvent.

7. A pharmaceutical composition according to any one of claims 1 to 3, characterized in that the components contained in the plant are obtained by a trituration of parts of plants with lactose.

8. Dosage form of a pharmaceutical composition according to any one of claims 1 to 7, characterized by its suitability for peroral administration or perlingual administration.

9. Dosage form of a pharmaceutical composition according to one of

Claims 1 to 8, characterized by their suitability for transdermal administration.

10. Darreichurigsform according to claim 9, characterized by a plaster containing the composition.

11. Dosage form of a pharmaceutical composition according to one of

Claims 1 to 10, characterized by their suitability for injection.

12. Dosage form of a pharmaceutical composition according to one of. Claims 1 to 11, characterized in that a single dose 0.1 to 1000 ng, preferably 0.5 to 100 and particularly preferably 1 to 10 nanograms of the alcoholic extract or the trituration with lactose contains.

13. Use of the pharmaceutical composition according to one of

Claims 1 to 12 for the manufacture of a medicament for the medicament treatment of disorders of the central nervous system.

14. Use according to claim 13, for the treatment of one or more of the following

Central Nervous System Disorders: Concentration disorders, memory deficits, learning disabilities, school performance deficits, school denial, dyslexia, mental retardation, mental retardation, developmental retardation, speech development delay.

15. Use according to claim 13 or 14, for the treatment of one or more of the following disorders of the central nervous system: confusion, mental dementia and senile dementia, Alzheimer's disease, fragile (X) syndrome.

16. Use according to claim 15, for the treatment of one or more of the following

Central nervous system disorders: psychosis, depression, bipolar mood disorders, schizophrenia, mood disorders, obsessive-compulsive disorder Washing compulsion, mania, hallucinations, anorexia nervosa, autism, borderline syndrome.

17. Use according to claim 15 or 16, for the treatment of one or more of the following disorders of the central nervous system: behavioral problems, Hyperkinetic behavioral problems in children and adults, listlessness, stage fright, nightmares, tics, lack of self-confidence.

18. Pharmaceutically active composition obtainable by extraction of the plant Canscora diffusa in the family Gentianaceae.