EP1603583A2

EP1603583A2 - Use of incense or hydrogenation products for preventing and/or treating a cerebral ischemia and/or cerebral traumatic lesion

Info

Publication number: EP1603583A2
Application number: EP04721524A
Authority: EP
Inventors: Frank Striggow; Werner Schmidt; Till Mack
Original assignee: KeyNeurotek AG
Current assignee: KeyNeurotek AG
Priority date: 2003-03-18
Filing date: 2004-03-18
Publication date: 2005-12-14
Also published as: WO2004082699A3; US20060177467A1; WO2004082699A2; US7645461B2

Abstract

The invention relates to the use of incense hydrogenation products (olibanum), the hydrogenated components thereof, the derivatives thereof, the physiologically tolerable salts thereof and hydrated incense extracts for producing a drug used for preventing and/or treating a cerebral ischemia, cerebral traumatic lesion and/or the Alzheimer's disease. Said invention also relates to the use of the incense, the extracts thereof, the substances contained therein, the physiologically tolerable salts thereof, the derivatives thereof and the physiologically tolerable salts of said derivatives, pure boswellic acids, tirucallic acids and other triterpenes, the physiologically tolerable salts thereof, the derivatives thereof and the physiologically tolerable salts of said derivatives for producing a drug for preventing and/or treating a cerebral ischemia and/or cerebral traumatic lesion.

Description

Use of frankincense or its hydrogenation products for the prophylaxis and / or treatment of cerebral ischemia and / or skull / brain trauma

The invention relates to the use of frankincense or components thereof, which may optionally be hydrogenated, for the prophylaxis and / or treatment of cerebral ischemia and / or skull / brain trauma. In addition, it has been found that the hydrogenation products of frankincense or the components thereof are particularly advantageous in the prophylaxis and / or treatment of Alzheimer's disease.

The invention thus relates in particular to the use of the hydrogenation products of frankincense (olibanum), its hydrogenated ingredients and physiologically acceptable salts and derivatives thereof for the manufacture of a medicament for the prophylaxis and / or treatment of cerebral ischemia, skull / brain trauma and / or Alzheimer's disease. The invention further relates to the use of frankincense or components of the frankincense for the manufacture of a medicament for the prophylaxis and / or treatment of cerebral ischemia and / or traumatic brain injury (TBI).

Ischemia is the interruption of the blood supply to cells, tissues or organs. This situation is particularly critical when a continuous supply of oxygen and / or nutrients (e.g. glucose) is necessary. This applies in particular to the central nervous system (CNS), since nerve cells in particular are extremely sensitive to an interruption in the oxygen and glucose supply. Short-term ischemia, e.g. as a result of a stroke or a heart attack, leads to neuronal cell death in the affected brain areas.

The cellular mechanisms of ischemia-related damage processes are complex and their complexity has so far been poorly understood. Therefore, effective measures for prevention and therapy are problematic.

Skull / brain trauma is a combined injury to the head, skull and brain, although the external covering may remain intact. The general distinction is between open skull / brain trauma and covered skull / brain trauma distinguished, with an open skull / brain trauma, the dura is destroyed, so that CSF and / or brain matter escapes. A distinction is made between blunt or covered brain trauma, in which the dura is not destroyed.

The injuries to the skull and / or the brain associated with a skull / brain trauma lead to an increase in intracranial pressure and thus to damage to various areas of the brain. Neuronal damage processes indexed in this way can influence the patient's cognitive, physical and psychological properties, although the cellular mechanisms of traumatic damage processes are complex and their complexity has so far been poorly understood.

Although various treatment methods for cerebral ischemia or skull / brain trauma are known, there is a considerable need for a treatment method which, in particular, prevents the death of nerve cells and, in the case of skull / brain trauma, in particular also prevents the occurrence of trauma-induced lesions.

Alzheimer's disease is a degenerative disease with morphological and biochemical changes in brain areas. It represents a progressive atrophy of the large cortex with senile plaques, degeneration of neurofibrils and conophilic angiopathy. The symptoms of Alzheimer's disease include disorientation with impaired cognitive abilities, memory loss, total regression to dementia. Biochemically, a disturbance of the cortical cholinergic system with a decrease in the choline acetylase (reduced acetylcholine synthesis) can be demonstrated.

The causes of the development of Alzheimer's disease are unclear. Genetic, metabolic or even "slow virus infections" are the main topics discussed. So far, no targeted therapeutic agents are available. The therapeutic options extend above all to the relief of illness-related symptoms. For example, the cholinesterase inhibitor tacrine is used to treat Alzheimer's disease, which is said to improve cognitive performance. Therapy with this active ingredient is unsatisfactory due to its low response rate and its strong side effects during long-term therapy. There is therefore a strong need for a treatment method that at least progresses in the atrophy of the brain in Alzheimer's Patient delayed. There is also a need for a drug whose active ingredient has a high availability at the target organ (brain) and is well tolerated, especially in long-term therapy.

The use of frankincense is already known in folk medicine for the treatment of various diseases, especially inflammation and rheumatism, especially in Chinese and Indian folk medicine.

Frankincense or olibanum is understood to mean a gum resin that can be obtained from the bark of the trees Boswellia carteri, Boswellia serrata and other species that are native to Arabia and Somalia. The resin typically contains 5 to 9% of the olibanum oil (or frankincense oil), 15 to 16% resin acids, 25 to 30% ether-insoluble compounds and 45 to 55% ether-soluble compounds, especially the triterpenoid boswellic acids, mainly ß-boswellic acid. Boswellic acid is often referred to as boswellic acid in the literature.

A mixture of the resins of the balsam family Boswellia sacra (southern Arabia), Boswellia carteri and Boswellia frereana (both Somalia) is often referred to as frankincense or olibanum. Indian frankincense ("Salai Guggal") is also known, which is obtained from extracts of the resin from Boswellia serrata (India). Salai Guggal is a herbal mixture of many substances. It contains essential oils (various mono-, di- and sesquiterpenes), mucus (e.g. galactose, arabinose,

Mannose, xylose) and, according to the current state of knowledge, pharmacologically active resin substances (pentacyclic and tetracyclic triterpenes, Boswellic acids or Tirucallen acids). After extraction with lipophilic solvents using special processes

(see below) a so-called "standardized Indian frankincense dry extract" is obtained.

Pardhy & Bhattacharyya report in Ind. J. Chem., 16 b: 176-178, 1978 that Boswellia serrata essentially contains the following ingredients: β-boswellic acid, acetyl-β-boswellic acid, acetyl-11-keto-β-boswellic acid , 11-keto-ß-boswellic acid and to a lesser extent α- and ß-boswellic acid as well as the tirucallic acids.

Several medical applications for frankincense or frankincense extract and in particular for boswellic acid and its derivatives have recently been found. For example, WO 90/01937 reports that α-boswellic acid acetate and β-boswellic acid acetate and their analogues inhibit topoisomerase-I and topoisomerase-II. Therefore, this document suggests using the compounds to treat various types of cancer.

DE-A 42 01 903 and the equivalent EP-A 552 657 disclose that pure boswellic acid, physiologically acceptable salts thereof, derivatives thereof and salts of the derivatives or a boswellic acid-containing herbal preparation can combat inflammation processes which are caused by increased leukotriene formation , Therefore, these publications suggest the compounds in particular for the treatment of inflammatory joint diseases, epidermal lesions, allergic and chronic asthma, endotoxin shock, inflammatory bowel diseases and chronic hepatitis.

DE-A 4444 288 and the equivalent EP-B 0 796 103 disclose that frankincense, frankincense extracts, substances contained in frankincense, their physiologically acceptable salts, their derivatives and their physiological salts, pure boswellic acid, a physiologically acceptable salt, a derivative and a salt of the derivative can be used in the treatment of Alzheimer's disease.

DE-A 44 45 728 uses pure boswellic acid, physiologically acceptable salts thereof, derivatives thereof or salts of the derivatives and herbal preparations which contain boswellic acid for the treatment of brain tumors.

WO 97/07796 uses boswellic acid, a physiologically acceptable salt, a derivative, a salt of the derivative or a boswellic acid-containing plant preparation for the prophylaxis and / or combating of diseases which are caused by increased leukocyte elastase or piasmin activity. This publication therefore proposes to use the compounds in the treatment of diseases such as, for example, pulmonary emphysema, acute respiratory distress syndrome, shock lung, cystic fibrosis, chronic bronchitis, glomerulonephritis and rheumatoid arthritis, and also to inhibit the growth and metastasis of many types of cancer.

WO 02/15916 and the priority-establishing DE-A 100 41 217 disclose didydroboswellic acids, physiologically acceptable salts thereof and hydrogenated extracts from Boswellia. They propose to use these compounds for the prophylactic and / or therapeutic treatment of undesirable physical and mental conditions, in particular of somatic, psychosomatic and psychological disorders such as, for example, inflammatory processes which are caused by increased leukotriene formation, leukocyte elastase or piasmin activity. The abovementioned diseases are, for example, inflammatory joint diseases, epidermal lesions, allergic and chronic asthma, endotoxin shock, inflammatory bowel diseases, chronic hepatitis, pulmonary emphysema, acute respiratory distress syndrome, shock lung, cystic fibrosis, chronic bronchitis, glomerulonephritis and rheumatic tumors as well as rheumatic tumors and rheumatoid arthritis.

None of these documents shows that frankincense or hydrogenated frankincense products can be used for the prevention and treatment of cerebral ischemia and / or skull / brain trauma. The excellent suitability of hydrogenated frankincense products for the treatment of Alzheimer's disease cannot be deduced from the literature.

It is therefore an object of the invention to provide a medicament which can be successfully used for the prevention and / or treatment of cerebral ischemia and / or skull / brain trauma.

Another object of the invention is also to provide a medicament which has a high bioavailability at the target organ and which, in addition to an excellent effectiveness in the treatment of cerebral ischemia and head / brain trauma, is used particularly advantageously in the treatment of Alzheimer's disease can be.

These objects are solved by the subject matter of the claims.

The invention thus provides on the one hand the use of frankincense, frankincense extracts, substances contained in frankincense, their physiologically acceptable salts, their derivatives and their physiologically acceptable salts, pure boswellic acid, a physiologically acceptable salt of boswellic acid, a derivative of boswellic acid, a salt of a derivative the boswellic acid or a boswellic acid-containing herbal preparation for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of skull / brain trauma and / or cerebral ischemia for Available, but also the use of the hydrogenation products of frankincense extracts, substances contained in frankincense, their physiologically acceptable salts, their derivatives and their physiologically acceptable salts, pure boswellic acid, a physiologically acceptable salt of boswellic acid, a derivative of boswellic acid, a salt of a derivative of boswellic acid or a herbal preparation containing boswellic acid for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia, skull / brain trauma and / or Alzheimer's disease.

Because of their effectiveness in the prophylaxis and treatment of cerebral ischemia, the medicinal products can advantageously also be used for the prophylaxis and treatment of cerebral damage from stroke, heart attack or after an operation.

Surprisingly, it has been found that frankincense, in particular frankincense extracts and substances contained in frankincense, and their derivatives, in each case optionally in the salt form, and the hydrogenation products of the above compounds and active mixtures are outstandingly suitable for preventing and / or treating cerebral ischemia and head / brain trauma are.

In contrast to the literature, not only are frankincense and frankincense extracts suitable for the treatment of Alzheimer's disease, but also the aforementioned hydrogenation products, which also have good bioavailability.

Although, as described above, frankincense and frankincense extracts are known as traditional natural remedies or as medicinal products for the treatment of various mental and physical conditions, the literature does not provide any information about the availability of the active substances contained in the target organ (place of action). This so-called bioavailability is particularly important in the prophylaxis and / or treatment of diseases that affect the brain. An effective active ingredient should namely be able to penetrate the blood / brain barrier, which can lead to an increase in activity with the same or lower dosage of the drug. In addition, there must also be adequate absorption in the intestine. According to the invention, acetyl-11-keto-β-boswellic acid (AKBA), 11-keto-β-boswellic acid (KBA) and β-boswellic acid are preferably used as boswellic acid. ß-boswellic acid can contain small amounts of α- or γ-boswellic acid, ß-boswellic acid can be obtained in a manner known per se from plants containing boswellic acid, in particular from Boswellia serrata. Other suitable Boswellia species are Boswellia papyrifera, Boswellia frereana, Boswellia carteri, Boswellia thunfera or Boswellia glabra, however other representatives of the Boswellia family can also be used.

Physiologically acceptable salts of boswellic acid are preferably the sodium, potassium, ammonium and calcium salts. Preferred derivatives of boswellic acid are _C. -C ₆ - Alkyl esters in which the carboxyl group of boswellic acid has been esterified with an appropriate alcohol. Methyl esters, ethyl esters, n-propyl esters, / so-propyl esters, n-butyl esters, / so-butyl esters and feit-but esters are particularly preferred. It is also possible that the hydroxyl group of the boswellic acid has been esterified with a physiologically acceptable carboxylic acid, preferably with a C .- to C ₂ o, in particular with a d- C ₆ carboxylic acid, in particular formic acid or acetic acid. Derivatives of boswellic acid which are preferably used according to the invention are β-boswellic acid acetate. ß-boswellic acid formate, ß-boswellic acid methyl ester, acetyl-ß-boswellic acid, acetyl-11-keto-ß-boswellic acid (AKBA) and 11-keto-ß-boswellic acid (KBA).

According to the invention, herbal preparations, in particular frankincense or frankincense extracts, are preferably used for the production of the medicaments for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma. The extracts preferably contain one or more of the aforementioned compounds.

According to the invention, preference is therefore given to the use of frankincense or frankincense extracts which contain boswellic acid, in particular β-boswellic acid, for the production of a medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma.

Boswellic acids, in particular β-boswellic acid, can be obtained in a manner known per se from plants containing boswellic acid, in particular from Boswellia serrata. Other suitable Boswellia species are Boswellia papyrifera, Boswellia frereana, Boswellia carteri, Boswellia thurifera or Boswellia glabra, however other members of the Boswellia family can also be used.

The frankincense used or the frankincense extracts used according to the invention (eg Salai Guggal) preferably contain β-boswellic acid and / or acetyl-β-boswellic acid and / or acetyl-11-keto-β-boswellic acid and / or 11-keto-β-boswellic acid ,

Herbal preparations which according to the invention can preferably be used for the production of the medicaments for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma are commercially available, for example from Ayurmedica, Pöcking, for example under the name H15. This is a lipophilic extract from Boswellia serrata, which contains a dry extract from Olibanum as the active ingredient. The product is available as a tablet or as granules. According to DE-A 44 44 288, one tablet contains 400 mg of dry extract from olibanum (4.2-5.9: 1), extracting agent: chloroform / methanol. 1 g of granules contains 500 mg of dry extract from olibanum (4.2-5.9: 1), extracting agent: chloroform / methanol.

According to the invention, however, other preparations with frankincense extract can also be used. In particular, according to the invention synthetically produced or naturally obtained ingredients of frankincense, in particular acetyl-11-keto-ß-boswellic acid and / or 11-keto-ß-boswellic acid and / or ß-boswellic acid, optionally in a mixture with α- and / or γ-boswellic acid and / or one or more of the derivatives of boswellic acid preferably used according to the invention as described above for the manufacture of the medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or Skull / brain trauma can be used.

The active substances and active substance compositions which are preferred according to the invention and which can be used to prepare the medicaments for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma are described, for example, in DE-A 44 44 288 and DE-A 44 45 728 described, to which extent reference is made. Preferred boswellic acids and Derivatives of boswellic acids are also described in DE-A 42 01 903, to which reference is also made in this respect.

According to the invention, the active substances and active substance compositions which are described in DE-A 4444 288 are preferred.

According to the invention, preference is also given to using a plant extract which has been obtained from frankincense, for example by ethanolic extraction.

According to the invention, the medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma can contain further active substances, in particular further herbal active substances, in addition to the active substances based on frankincense defined here.

According to the invention, it has also been found that the hydrogenation products of the incense are very well absorbed and can penetrate the blood / brain barrier sufficiently so that a sufficient concentration of the active compounds in the target organ can be achieved, the activity of the products being essentially retained, advantageously even being improved ,

The hydrogenation products of frankincense, its ingredients and the physiologically acceptable salts and derivatives of these hydrogenation products, but also hydrogenated frankincense extracts, are suitable for producing a medicament according to the invention for the prophylactic and / or therapeutic treatment of cerebral ischemia, skull / brain trauma and / or Alzheimer's disease.

Also suitable according to the invention are hydrogenation products of boswellic acid-containing plant extracts, boswellic acid, physiologically acceptable salts of boswellic acid, derivatives of boswellic acid, physiologically acceptable salts of these derivatives, boswellic acid-containing vegetable preparations or keto-boswellic acid-containing plant extracts. Also suitable are hydrogenation products of further ingredients in frankincense, such as, for example, tirucallenic acid or other triterpenoid compounds, salts or derivatives thereof, and of vegetable extracts which contain these compounds. Also suitable according to the invention are the hydrogenation products of acetyl-11-keto-β-boswellic acid, 11-keto-β-boswellic acid or β-boswellic acid, the latter being able to contain small amounts of α- or γ-boswellic acid. Also suitable according to the invention are hydrogenation products of ß-boswellic acid acetate, ß-boswellic acid formate, ß-boswellic acid methyl ester, acetyl-ß-boswellic acid, but also of the boswellic acids and derivatives of boswellic acids described in DE-A 42 01 903, to which reference is made in this regard becomes.

Dihydroboswellic acids, their physiologically acceptable salts, derivatives thereof as well as physiological salts of the derivatives, in particular β-dihydroboswellic acid acetate, β-dihydroboswellic acid methyl ester, β-dihydroboswellic acid methyl ester, acetyl-β-dihydroboswellic acid, α-dihydro acid acid, α-dihydrogen acid, α-dihydro acid, α-di-dihydroic acid, α-di-dihydro-well acid, α-di-dihydro-well acid, α-di-dihydro-well acid, α-di-dihydro-well acid, α-di-dihydro-well acid, α-di-dihydro-diacid, α-di-dihydro-well acid Formyl dihydroboswellic acid can be used.

Also suitable according to the invention are keto-dihydroboswellic acids, their physiologically acceptable salts, derivatives thereof and physiological salts of the derivatives, in particular acetyl-11-keto-β-dihydroboswellic acid, 11-keto-β-dihydroboswellic acid or formyl-11-keto-β-dihydroboswellic acid.

The hydrogenation products which can be used according to the invention can be obtained by hydrogenation, preferably by catalytic hydrogenation. The hydrogenation of these compounds is carried out in a manner known to the person skilled in the art, preferably in such a way that the basic structure of the compound is selectively hydrogenated. Such a method is described for example in WO 02/15916.

A hydrogenated plant extract obtained from frankincense, for example by ethanolic extraction, can also be used to produce the medicament according to the invention for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma and / or Alzheimer's disease.

The physiologically acceptable salts of the hydrogenation products according to the invention are understood to be the sodium, potassium, ammonium and calcium salts of the abovementioned compounds. In particular, such C.-C ₆ alkyl esters are the derivatives Understand dihydroboswellic acid in which the carboxyl group of dihydroboswellic acid has been esterified with a corresponding alcohol. Such dihydroboswellic acid alkyl esters are, for example, the methyl ester, ethyl ester, n-propyl ester, / so-propyl ester, π-butyl ester, / so-butyl ester and fe / t-butyl ester. It is also possible for the hydroxyl group of dihydroboswellic acid to be esterified with a physiologically tolerable carboxylic acid, for example with a C to C ₂₀ , in particular with a C.-C _6, carboxylic acid, in particular with formic acid or acetic acid.

Herbal preparations that can be used to produce the hydrogenation products according to the invention are commercially available, for example from Ayurmedica, Pöcking, for example under the name H15.

According to the invention, however, hydrogenation products from other preparations with frankincense extract can also be used; in particular, according to the invention, hydrogenation products of synthetically produced or naturally obtained ingredients of frankincense, in particular acetyl-11-keto-ß-boswellic acid and / or 11-keto-ß- boswellic acid and / or β-boswellic acid, optionally in a mixture with α- and / or γ-boswellic acid and / or one or more of the derivatives of boswellic acid which are preferably used according to the invention, as described above, can be used for the preparation of the medicament.

Active substances and active substance compositions which are suitable according to the invention and which can be used to produce the medicaments according to the invention with the hydrogenation products are described, for example, in WO 02/15916, to which reference is made in this regard.

According to the invention, the medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia and / or skull / brain trauma and / or Alzheimer's disease can contain further active substances, in particular further herbal active substances, in addition to the active substances based on frankincense defined here.

According to the invention, however, hydrogenation products from other preparations with frankincense extract can also be used; in particular, according to the invention, hydrogenation products can also be synthetically produced or in a natural way Incense ingredients obtained, in particular acetyl-11-keto-ß-boswellic acid and / or 11-keto-ß-boswellic acid and / or ß-boswellic acid, optionally in a mixture with α- and / or γ-boswellic acid and / or one or more the boswellic acid derivatives preferably used according to the invention, as described above, can be used for the preparation of the medicament.

Since the above frankincense products and the hydrogenated frankincense products have a very low toxicity, their tolerance is generally good. Depending on the severity of the illness to be treated and other factors such as the duration of the illness, possible known intolerances of the patient, the general condition of the patient, etc., their dosages can easily be selected by the treating doctor. The medicament is preferably formulated according to the invention in such a way that it is present in unit doses which can be administered orally, one or more times a day, in particular one to four times a day, preferably.

According to the invention, the medicaments can be formulated in a manner known per se for customary administration routes, for example as oral, parenteral, rectal, intranasal, intracranial or intrathecal administrations. Oral, parenteral, rectal and intranasal applications are preferred here. It is also possible that the formulations are designed for inhalation or insufflation. Formulations for intracranial or intrathecal administration are also possible.

The pharmaceuticals according to the invention can, for example, be in solid, semi-solid or liquid form. For example, they can be formulated in the form of tablets, granules or capsules which, in addition to the active substance or the active substance, also contain pharmaceutically acceptable additives, such as binders, fillers, lubricants, explosives or, if appropriate, wetting agents, and which can be coated.

According to the invention, preference is given to medicaments which are in the form of tablets or granules or pellets, the granules or pellets generally being in conventional capsules. In addition to the active ingredient or the active ingredient extract, the granules or tablets contain customary pharmaceutically acceptable additives such as binders, for example pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethyl cellulose, fillers such as lactose, sucrose, mannitol, corn starch, microcrystalline cellulose or calcium hydrogenphosphate, lubricants such as stearic acid, polyethylene glycol . Magnesium stearate, talc or silicon dioxide, disintegrants such as potato starch, sodium starch glycolate or sodium carboxymethyl cellulose and in particular the known super disintegrants and optionally wetting agents such as sodium lauryl sulfate. Tablets, pellets or capsules can be coated in a manner known per se (for example with a water-soluble or enteric coating) or they can be present uncoated. Coated tablets are preferred.

Furthermore, in a manner known to those skilled in the art, the medicaments can be in the form of liquid preparations for oral administration. Liquid preparations for oral administration can be present, for example, as aqueous or oily solutions, syrups, elixirs, emulsions or suspensions. It is also possible that formulations are available as a dry product for reconstitution with a suitable solvent, in particular water. The production of such liquid preparations is also known, and conventional additives such as e.g. Suspension agents such as sorbitol, cellulose derivatives, glucose, sugar syrup, gelatin, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, gum arabic or sorbitan monooleate, non-aqueous vehicles such as almond oil, oily esters, ethyl alcohol or fractionated vegetable oils, preservatives or methyl or benzyl para-para Sorbic acid, buffers, flavoring and aroma agents, coloring and sweetening agents are present.

Medicaments according to the invention can also be formulated as preparations for injection in a manner known per se. Preparations for injection, in particular for intravenous, intramuscular, subcutaneous, intrathecal or intracranial injection, which are suitably present in unit dosage form such as ampoules or in multiple dose containers, are preferred according to the invention. If appropriate, the formulations contain a customary preservative and other customary auxiliaries. Furthermore, the medicaments according to the invention can also be prepared as suspensions, solutions or emulsions in oily or aqueous vehicles in a manner known to the person skilled in the art. For example, the preparations can be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and can contain customary auxiliaries such as suspending, stabilizing and / or dispersing agents and / or agents for adjusting the tonicity. Again, it is possible that the agent is present as a dry powder for reconstitution in a suitable carrier. Liquid sprays, nasal drops or snuff powder can be mentioned as intranasal drugs.

If administration is to be by inhalation, the compounds are made available, for example, as an aerosol spray. For example, the compounds or extracts according to the invention can be present in pressurized packs using suitable blowing agents. In this case the package will also contain a suitable dosing device. Capsules or cartridges made of, for example, gelatin for use in an inhalation device or an insufflation device can be prepared in the usual way so that a powder mixture of a compound used according to the invention and a suitable powder base such as lactose or starch is used.

Examples of suitable formulations and processes for their preparation can be found in DE-A 44 44 288 and DE-A 44 45 728, to which full reference is made in this regard. In particular, reference is made to the examples from DE-A 44 44 288. According to the invention, the medicinal products can be formulated in a corresponding manner.

The neuroprotective effect of frankincense extract containing boswellic acid on infarct volume after experimentally induced transient focal cerebral ischemia (stroke) was checked as follows.

Experimental induction of focal ischemia by intracerebral microinjection of endothelin 1 near the middle cerebral artery (eMCAO)

Sprague Dawley rats (250-280g) are clamped into a head stereotaxy under halothane inhalation anesthesia and the skin in the skull area is opened. Using a dentist's drill, a hole (1 mm in diameter) is drilled in the cranial bones according to the coordinates: 0.90 mm anterior bregma, 5.2 mm lateral to the satura sagittalis. A Hamilton syringe is now lowered from the dura mater 7.5 mm deep into the brain and 3 μl (90 pmol) endothelin 1 is injected into the vicinity of the central cerebral artery. Endothelin 1 has a vasoconstructive effect, which closes the vessel and thus induces the stroke. After 5 minutes the syringe is removed and the skin over the Skull bones sewn up. The animals are kept normothermal throughout the operation.

Experimental groups:

Group 1: (n = 8) eMCAO and frankincense extract (10 mg / kg, intraperitoneal ip injection) 2 h before induction of ischemia, 6 h (10 mg / kg, ip) after reperfusion, on day 3 (10 mg / kg, ip) and on the 6th day (10 mg / kg, ip).

Group 2: (n = 8) eMCAO and solvent (0.9% NaCI with 10% ethanol) i.p. Injection as described in group 1.

Group 3: (n = 8) sham operated control group.

Group 4: (n = 8) mechanical lesion induced by the puncture channel of the Hamilton syringe.

Determination of the infarct volume:

After a survival time of 7 days, the animals are perfusion-fixed in deep pentobarbital anesthesia with 4% paraformaldehyde in 0.1 M phosphate buffer. The brains are removed and 1 mm thick coronal sections are made in a rat brain matrix. After cryoprotection in 30% sucrose, 20 μm thick cryostat sections are made, mounted on slides and stained with toluidine Nissl. By using a light microscope (Nikon, Eclipse TE 3000) with image analysis software Lucia version 4.2.1. the cortical and striatal infarct area is determined and the infarct volume is calculated by multiplying by the section thickness. The data are analyzed for statistical significance using Student's t-test.

Results:

The occlusion of the middle cerebral artery leads to the death of nerve cells in the brain regions of the cortex and striatum. 7 days after induction of cerebral ischemia and parallel administration of frankincense extract, a significant and significant reduction in the infarct volume can be observed compared to the untreated control group. This finding is surprising and new.

This proves that the medication produced according to the invention can reduce the damage to cerebral tissue and the resulting neurological abnormalities as a result of ischemia, or that such damage can be prevented. The neuroprotective effect of frankincense extract containing boswellic acid on brain injuries was checked as follows.

Experimental induction of traumatic brain injury

Initially, experimental animals were experimentally induced to suffer a traumatic brain injury using the so-called "fluid percussion" method. For this purpose, Sprague Dawley rats (250 to 280 g) were clamped into a head stereotaxy under halothane inhalation anesthesia and the skin in the skull area was opened. Using a dentist's drill, a 5 mm hole (diameter) is drilled in the skull bones of the right calotte between the bregma and lamda, the dura mater remaining intact. A defined metal weight deflects the pin of the plexiglass cylinder via a plexiglass cylinder filled with isotonic saline solution, which is connected to the trepanation hole. This causes a rapid increase in intracranial pressure and thus injury to cortical and striatal areas of the brain. After induction of the traumatic brain injury, the skin is sewn over the skull bone. The animals were kept normothermal throughout the operation.

Experimental groups:

Four test groups were formed from eight test animals each, with group 1 being administered intraperitoneally with 10 mg / kg of frankincense extract two hours before induction of ischemia, six hours after reperfusion, on the third day after the operation and on the sixth day after the operation , Group 2 received an aqueous solution containing 10% ethanol and 0.9% sodium chloride intraperitoneally instead of frankincense extract, using the same administration regimen as for group 1. Group 3 received no treatment, neither with frankincense extract nor with solvent, and group 4 was a control group in which no ischemia was induced.

Determination of the trauma volume:

After a survival time of seven days, the animals were perfusion-fixed in deep pentobarbital anesthesia with 4% paraformaldehyde in 0.1 M phosphate buffer, and the infarct volume was determined. For this purpose, the brains were removed and 1 mm thick coronal sections were made in a rat brain matrix. After cryoprotection in 30% sucrose, 20 μm thick cryostat sections were made, on one Slides were drawn up and stained with toluidine Nissl. Using a light microscope (Nikon, Eclipse TE 3000) with Lucia version 4.2.1 image analysis software, the cortical and striatal trauma area was determined and the trauma volume was calculated by multiplying by the section thickness. The data were analyzed for statistical significance using Student's t-test.

Results:

It was shown that the experimentally induced brain trauma led to the death of nerve cells in the brain regions of the cortex and striatum. Seven days after induction of brain trauma and administration of frankincense extract, however, a significant and significant reduction in the trauma-induced lesions can be observed in comparison with the untreated control group.

This proves that the medication produced according to the invention can reduce the damage to cerebral tissue and the resulting neurological abnormalities as a result of a skull / brain trauma or that such damage can be prevented.

Claims

claims:

1. Use of frankincense, frankincense extracts, substances contained in frankincense, their physiologically acceptable salts, their derivatives and their physiologically acceptable salts, pure boswellic acid, a physiologically acceptable salt of boswellic acid, a derivative of boswellic acid, a salt of a derivative of boswellic acid or a boswellic acid -containing herbal preparation for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of skull / brain trauma and / or cerebral ischemia.

2. Use according to claim 1, wherein the cerebral ischemia occurs as a result of a stroke, heart attack or a surgical intervention.

3. Use according to claim 1 or 2, characterized in that frankincense or a plant extract containing boswellic acid is used.

4. Use according to claim 1 or 2, characterized in that a keto

Boswellic acid, in particular 3-0-acetyl-11-keto-ß-boswellic acid or 11-keto-ß-boswellic acid, a physiologically acceptable salt of a keto-boswellic acid, a derivative of a keto-boswellic acid, a salt of a derivative of a keto-boswellic acid or a plant extract containing a keto-boswellic acid is used for the manufacture of the medicament.

5. Use according to claim 1 or 2, characterized in that a tirucallenic acid, another triterpene or a salt or derivative thereof or a plant extract containing a tirucallenic acid, another triterpene or a salt or derivative thereof is used for the manufacture of the medicament.

6. Use according to one of claims 1 to 3, characterized in that an extract from the resin of Boswellia serrata is used for the manufacture of the medicament.

7. Use of the hydrogenation products of frankincense extracts, substances contained in frankincense, their physiologically acceptable salts, their derivatives and their physiologically acceptable salts, pure boswellic acid, a physiologically acceptable salt of boswellic acid, a derivative of boswellic acid, a salt of a derivative of boswellic acid or a boswellic acid -containing herbal preparation for the manufacture of a medicament for the prophylactic and / or therapeutic treatment of cerebral ischemia, skull / brain trauma and / or Alzheimer's disease.

8. Use according to claim 7, wherein the medicament is used for the prophylaxis and / or treatment of Alzheimer's disease.

9. Use according to claim 7 or 8, characterized in that the hydrogenation product of a boswellic acid-containing vegetable extract is used.

10. Use according to claim 7 or 8, characterized in that a hydrogenated

Extract from the resin of Boswellia serrata is used to manufacture the drug.

11. Use according to claim 7 or 8, characterized in that the hydrogenation product of boswellic acid, a physiologically acceptable salt of boswellic acid, a derivative thereof, a salt of a derivative of boswellic acid or a plant preparation containing boswellic acid is used.

12. Use according to any one of claims 7 to 11, wherein the hydrogenation product is dihydroboswellic acid.

13. Use according to claim 7 or 8, characterized in that the hydrogenation product is selected from the group consisting of ß-dihydroboswellic acid acetate, ß-dihydroboswellic acid formate, ß-dihydroboswellic acid methyl ester, acetyl- ß-dihydroboswellic acid, α-dihydroboswellic acid, acetyl-α- dihydroboswellic acid and formyl-α-dihydroboswellic acid.

14. Use according to claim 7 or 8, characterized in that a keto-dihydroboswellic acid, in particular acetyl-11-keto-ß-dihydroboswellic acid, 11-keto-ß-dihydroboswellic acid or formyl-11-keto-ß-dihydroboswellic acid, a physiologically acceptable Salt of a keto-dihydroboswellic acid, a derivative of a keto-dihydroboswellic acid, a salt of a derivative of a keto-dihydroboswellic acid or a hydrogenated keto-boswellic acid-containing vegetable extract is used for the preparation of the medicament.

15. Use according to claim 7 or 8, characterized in that a hydrogenation product of tirucallenic acid, its salt or a derivative thereof or a hydrogenated plant extract containing tirucallenic acid is used for the manufacture of the medicament.

16. Use according to one of claims 1 to 15, characterized in that the medicament is designed for intraperitoneal, oral, buccal, rectal, intramuscular, topical, subcutaneous, intra-articular, intravenous, intrathecal or intracranial administration.

17. Use according to one of claims 1 to 16, characterized in that the medicament is in the form of a tablet or solution.