DE60115831T2 - Gugulipid for the treatment of cognitive disorders - Google Patents

Description

Territory of invention

The The present invention claims some new uses of gugulipid, an ethyl acetate extract of the resin of the plant Comiphora wightii, which is commonly called gum guggulu. Procedure for control or prevention of cognitive disorders are revealed.

Background of the invention:

Ayurveda stands for a holistic picture of human illness. It looks every Disease rather than a disorder of the entire body as a single organ or physiological process. It is because of that Probably most Ayurvedic medicines are used in one Number of faults of the body, which involve a number of organs and functions. gugulipid an ethyl acetate-soluble fraction of gum guggul, was developed as a hypolipidemic agent, based on the reference to the lipid-lowering effect of Guggul resin in Charak Samhita, a classic text of Ayurveda. A chemopharmacological study of this extract resulted in the characterization of guggulsterone [cis- and trans-4,17- (20) -pregnadiene-3,16-dione] as the main ingredient. In addition to guggulsterone contributed other chemical Ingredients in the ethyl acetate-soluble fraction to the total effect at and modulated these. More this faction than pure guggulsterone was considered a hypolipemic Drug developed and called Gugulipid. As a consequence of the became a holistic picture of Ayurveda of human disease Gugulipid tested on other related and unrelated conditions / disorder and has been found to have cognitive effects. These new uses of gugulipid are now claimed.

State of the art

guggul, which is highly valued in the Indian system of Ayurvedic medicine, is the rubber resin exudate of a small tree Commiphora wightii, which belongs to the family Burseraceae. It will be specially for the treatment of obesity, lipid disorders and rheumatoid arthritis recommended (Ayurvedic treatise: Sushruta, Vagabhatta). In the Tibetan medicine becomes the plant (C. Wighitii) mixed with other herbs, against skin diseases, anemia, edema, salivation and stomach problems used [Lama, S. and Santra, S. C., Sci. Cult. 45, 262 (1979)]. Recent pharmacological studies of bulk drug and some his factions have supported the claims of Ayurveda. The Antiarthritic and antiinflammatory effects were reported by Gujral and employees confirmed [Gujral, M.L., Sareen, K., Tangri, K.K., Amma, M.K.P. and Roy, A.K. Ind. J. Physiol. Pharmacol. 4, 267 (1960)]. About the hypolipidemic and antiatherosclerotic effects has been reported by Dwarakanath and Satyawati reports. [Dwarakanath, C., and Satyawati, G.V. Ayurveda Pradeepika (Ceylon), 1, 69 (1970)]; Satyawati, G.V. in "Effect of an indigenous drug and disorders of lipid metabolism with special reference to atherosclerosis and obesity (Medoroga) ", M.D. Thesis (Doctor Ayurvedic Medicine), Banaras Hindu University, Varanasi, (1966)]. Later became its ethyl acetate extract through joint efforts of Malti-Chem Research Center, Baroda and the Central Drug Research Institute, Lucknow as hypolipidemic Drug developed [A process for obtaining hypolipidemic and anti-platelet aggregation fraction from guggul resin. Indian patent No. 148265, dated 06.04.1979, N.K. Kapoor, Sukh Dev and S. Nityanand]. A mixed mechanism type became with the lipid-lowering effect associated with gugulipid. The stimulation of plasma LCAT, hepatic lipases, receptor mediated catabolism of LDL and increased faecal bile acid excretion as well as the suppression of Hepatic cholesterol biosynthesis are the mechanisms involved for the Lipid-lowering effect of gugulipid are responsible [S. Nityanand and N.K. Kapoor, Ind. J. Exp. Biol. 11, 395 (1973); N.K. Kapoor and S. Nityanand, Ind. J. Heart Res. (Suppl. 1) 22 (1988)]. With the discovery the hypolipidemic Effect of the rubber resin were systematic chemical studies carried out, to characterize compounds of the rubbery resin which for the hypolipidemic Effect are responsible. Recently, Mc Cook et al. one alcoholic extract of gum guggul for control or prevention sebum secretion from sebocytes, what with a shiny, undesirable Appearance and an unpleasant tactile sensation in connection stands claimed [J. P. Mc Cook et al. U.S. Patent 5,690,948 (1997). Antisebum and antioxidant composition containing gugulipid and alcoholic fractions thereof].

Applicants previously received U.S. Patent No. 6,086,889 for a process for isolating a lipid fraction containing Z and E guggulsterones from the aerial parts of the plant Comiphora wighitii. The method comprises the steps of soaking or soxhlet extracting the powdered aerial part of the plant with a non-polar solvent; Filtering or decanting the extract; re-soaking the material in a polar solvent; Filter and concentrate the extracted material in the polar solvent under reduced pressure and gel filtration or silica gel chromatography to obtain a lipid fraction containing Z- and E-Ketosteroid. The present invention introduces non-obvious modifications to the extraction process as described in the prior art and describes new uses of gugulipid which were previously unknown.

formation the invention

With the isolation of a variety of compounds from different Structural classes such as lignans, lipids, diterpenoids and steroids we started pretty early a program for the study of structure-based biological Profiles of Gugulipid. Earlier were the hypolipidemic and thyroid-stimulating effects of guggulsterone [Tripathi, S.N., Gupta, M., Dwivedi, L.D. and Sen, S.P., J. Res. Ind. Med. 10, 11 (1975); Singh, V. and Kapoor, N.K. in "Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats. "In Proceedings of Society of Biological Chemists, India, 57th Annual Meeting, CSIR Center for Biochemicals, New Delhi, October 9-12, 1988].

Role in the improvement of cognitive functions

Newer developments. In the understanding of neurosteroids, the role of free radicals and antioxidants in brain function and hyperglycaemia, gugulipid prompted us to study these effects. Behavioral studies suggested a potential role of pregnenolone, especially for memory improvement. Intracerebroventricular (icv) administration of pregnenolone and pregnenolone sulfate leads to an improvement in various memory tasks in rodents [Flood, JF, Morley, JF and Robert, E., Memory enhancing effects in male mice of pregnenolone and of steroid metabolically derived from it; Proc. Natl. Acad. Sci. USA; 89, 1567 (1992)]. These memory-enhancing effects may be due to the N-methyl-D-aspartate (NMDA) antagonistic properties of pregnenolone sulfate, since it has been shown that NMDA agonists adversely affect cognitive functions in rodents [Bowlby, MR, Pregnenolone sulfate potentiation of N methyl-D-aspartate receptor channels in hippocampal neurons. Mol. Pharmacol., 43, 813 (1993)]. As already stated, cholesterol is the precursor of the neurosteroid pregnenolone. This finding prompted us to study the memory-improving properties of gugulipid, because of the similarity between the biogenic precursor of pregnenolone (1) and the steroids present in the gugulipid, such as guggulsterol-I (2), guggulsterol-II (3 ) and guggulsterol-III (4) ( 1 ) [VD Patil, UR Nayak and Sukh Dev: Chemistry of Ayurvedic Crude Drugs I, Tetrahedron 28, 2341 (1972)].

Tasks of present invention

A The object of the present invention was to improve cognition Effect of gugulipid orally in any pharmaceutical preparations to develop.

Summary the invention

The The present invention provides the use of gugulipid (an ethyl acetate extract of rubber or resin of a tree Comiphora wightii) at Preparation of a means of reduction, control or prevention a cognitive disorder in a mammal ready.

The Gugulipid may be in any form, especially in the form of a Extract, in solid dosage form or in the form of a cream formulation available. The use of Gugulipiden allows an improvement of the cognitive behavior preferred by administering gugulipid as an extract or by mixing with others pharmaceutically acceptable Additives before administration.

The Use of gugulipid is for the production of an agent. The agent may be any further Include additive, wherein suitable additives one or more selected from a protein, carbohydrate, sugar, talc, magnesium stearate, microcrystalline Cellulose, starch, Calcium carbonate and / or any other pharmaceutically acceptable Carrier, are.

In preparing the composition, a solid dosage form may be obtained by macerating the gugulipid compound with starch and microcrystalline cellulose together in a mixture to obtain a free-flowing powder. The solid dosage form can be obtained in the form of a tablet by dissolving gugulipid in ethanol and adding starch and microcrystalline cellulose. This is followed by evaporation of the solvent, passing the material through a 40 mesh screen to give Gra To obtain nula, and pressing the granules to obtain a tablet.

The use according to the invention Gugulipid may be used to treat a human memory dysfunction such as Alzheimer's disease or Korsakov's disease, suffering patients, if necessary in combination with other treatments. The use can for the reversion of atropine-induced amnesia.

The Use may be such that the gugulipid in any form at a dosage level corresponding to 40 mg / kg / day, optionally for 7 days.

The Use may be such that the gugulipid at a dosage level of 100 mg / kg body weight is administered per day.

The Use of gugulipid may be such that the gugulipid is as a cream of gugulipid of 5% in polyethylene glycol (PEG) provided becomes. The cream is for multiple uses, such as twice a day, suitable.

Detailed description the invention:

Accordingly, presents the present invention Gugulipid in combination with or in connection with an additive ready, taking it for control or prevention a cognitive disorder in mammals is used. In another embodiment of the invention Gugulipid is in In the form of extracts, in solid dosage forms or in the Form of cream formulations as they may be administered.

In another embodiment of the invention is used to improve cognitive behavior by feeding gugulipid or a mixture with another agent with similar property orally in the form of suitable pharmaceutical preparations and in a Amount, which for an effect is necessary given.

In another embodiment of the invention becomes the reversion of atropine-induced amnesia in males Switzerland mice Gugulipid in a dosage equivalent to 40 mg / kg / day for about 7 days either in the form of extracts or in solid dosage form administered.

In another embodiment of the invention Gugulipid is used to treat human memory dysfunction, such as Alzheimer's disease and Korsakov's disease, sufferers Patients, alone or in combination with other treatments used.

The inventive method to control memory dysfunction Gugulipid or an extract of the rubber / resin in pharmaceutical acceptable Dosage forms.

Short description of appended Drawings:

1 shows the structure of the cholesterol metabolite and related compounds in gugulipid.

2 shows the structure of the lignans of Commiphora mukul and troglitazone with 1,2- or 1,4-bis-oxidized phenylpharmacophore.

3 shows the effect of gugulipid and ginkobyloba on atropine-induced dementia in the passive avoidance test.

The The following example is given by way of illustration and is not intended to be as limiting the scope of the present invention become.

Example I

This Example reports of cognition-enhancing property of gugulipid in an animal model of Alzheimer's disease.

Comparative study of gugulipid and Ginkgo biloba as a cognition-enhancing agent through the test on passive avoidance.

one the most common Tests in memory research is the inhibition of imitating activities or learned habits. The expression "passive Avoidance " normally used to describe experiments in which the animals learn a harmful Event by suppression to avoid a special behavior. Different forms of human memory dysfunction can occur in the animal through the administration of different centrally acting Drugs can be modeled on normal, healthy recipients. anticholinergics like scopolamine or atropine produce transient labeling effects, which are similar the deficits that are present in patients with Alzheimer's disease (AD) whereas benzodiazepines produce effects similar to those of Anterograde amnesia are typical of patients with Karsakov's disease (KD) is.

Basic principle of the test procedure:

If a mouse or a rat is placed in a closed chamber, the interconnected dark and enlightened departments it prefers to be near walls in the dark, but when in the dark department is given an electric shock, she moves into the enlightened department and stays there until she remembers the danger. A typical example of the Testing of cognitive behavior consists of three phases: Familiarization: the animal is placed in the enlightened department and after 10 seconds The reconnaissance is returned to the home cage. Learning: immediately After the animal came into the dark room, it became inevitable Hit the foot and the animals returned to the illuminated side. Memory Test: 24 hours after the learning attempt, the animal is fed after feeding Test drug is given back to the illuminated side and that Method of learning is repeated. The latency period is measured. Rating: the latency during the learning and memory test phase is being measured. An extension the latency period is defined as learning.

Passive avoidance test:

The Mice were a single attempt of passive avoidance testing as by Brioni et al. [Brioni, J. D .; Hock, F.J. and McGaugh, J.J. in "Drug Effects on Learning and Memory ". H.G. Vogel and W.H. Vogel (ed.). "Drug Discovery and Evaluation: Pharmacological Assays "Springer-Verlag, Berlin, 1997]. The passive avoidance test was equipped with a computer-operated pendulum box (Columbus Instruments, Ohio, USA), which is equipped with the software program PACS 30 was, examined. The pendulum box consists of two compartments. An automated door was used to isolate the compartments. After an exploration period of 30 seconds for Acclimation, the animal was subjected to a test of 270 seconds. Each mouse was placed in the bright (light intensity 10) department and during a transfer to the dark ward, she became an electric Beat (0.5 mA for 5 s) through a grid. The computer-operated door was close by the transfer set to the mouse the full duration of the electric shock suspend. Infrared sensors observe the transfer of one Division in the other, giving as transfer latency (TLZ) in seconds was recorded. TLZ was in a control and an acute Stress group (30 min after immobilization) on day 1 (experiment I) and next Day (trial II) recorded. In the case of the chronic stress group Trial I was 30 min after immobilization (day 5) and trial II 24 hours later carried out. As criterion for improved cognitive activity was an increase in TLZ in trial II compared with trial I have taken.

method

Effect of administration of gugulipid as an extract:

Male Switzerland mice (25 to 30 g) were randomly divided into 4 groups (n = 10). Extracts of gugulipid (40 mg / kg / day) and G. biloba (30 mg / kg / day) were each administered to one group for 7 days, with an equivalent volume of vehicle administered to the other two groups. On the eighth day, atropine (4 mg / kg, imp.) Was administered to each animal of the extract-treated groups and a vehicle group 5 minutes before the passive avoidance test in a computer-operated pendulum box using PACS 30 software. Transfer latency (TLZ) from the illuminated chamber to the dark chamber was recorded for all groups. Mean and standard deviation (SA) of mean was the calculated TLZ (passive avoidance test) of each group. The significance of the difference between the values of two groups was determined by the student "t-test". Gugulipid is as effective as the standard drug G. biloba and the data are in a bar chart ( 3 ). The experiments were carried out according to the following protocol:

Both extract treated groups showed significant reversion the atropine-induced Amnesia.

effect administration of a solid dosage form of gugulipid: A solid gugulipid dosage form equivalent to 40 mg / kg / day was for 7 days to Switzerland mice administered. It was found that they are in the model of the test passive avoidance alike was effective as the standard drug Ginkobiloba.

A solid dosage form was prepared by mixing gugulipid with starch or microcrystalline cellulose produced.

It should be taken for granted that with the illustrated and previously beschrie particular forms of the invention is only intended to be representative. The change including those suggested in this specification, but not limited thereto, may be made in the illustrated embodiments without departing from the clear teaching of the disclosure. Accordingly, reference should be made to the following appended claims in determining the full scope of the invention.

Advantages of the present Invention:

The The present invention adds new uses of gugulipid Improvement of cognition ready.

Claims (10)

Use of gugulipid, an ethyl acetate extract of rubber or resin of a tree Comiphora wightii, at which Preparation of a means of reduction, control or prevention a cognitive disorder in a mammal. Use according to claim 1, wherein gugulipid in the form of an extract, in solid dosage form or in the form of a cream formulation. Use according to claim 1 or claim 2, wherein cognitive behavior is improved and Taking gugulipid as an extract or mixture with other pharamazeutisch acceptable Additives is administered. Use according to one the claims 1 to 3, wherein the agent includes an additive, wherein the Additive one or more selected from protein, carbohydrate, Sugar, talc, magnesium stearate, microcrystalline cellulose, starch, calcium carbonate and / or a pharmaceutically acceptable carrier. Use according to one the claims 1 to 4, wherein the solid dosage form by maceration of the compound Gugulipid, of strength and microcrystalline cellulose in a mixture to free-flowing powder to receive. Use according to one the claims 1 to 4, wherein the solid dosage form in the form of a tablet by dissolving of gugulipid with ethanol and addition of starch and microcrystalline cellulose, Evaporation of the solvent, Passing the material through a sieve with a mesh size of 40, to get granules, and pressing the granules to a tablet to receive. Use according to one the claims 1 to 6 for the treatment of a human memory dysfunction such as Alzheimer's disease or Korsakov's disease, sufferers Patients, if necessary in combination with other treatments. Use according to one the claims 1 to 7 for the reversion of atropine-induced amnesia. Use according to one the claims 1 to 8, wherein the gugulipid at a dosage level corresponding 40 mg / kg / day, optionally for 7 days, administered. Use according to one the claims 1 to 8, wherein the gugulipid at a dosage level corresponding 100 mg / kg body weight is administered.