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Title:  Method of treating a cognitive memory dysfunction using Gugulipid

United States Patent:  6,896,901

Issued:  May 24, 2005

Inventors:  Pratap; Ram (Lucknow, IN); Pal; Raghwendra (Lucknow, IN); Singh; Satyawan (Lucknow, IN); Shankar; Girja (Lucknow, IN); Nath; Chandeshwar (Lucknow, IN); Singh; Hemant Kumar (Lucknow, IN); Raina; Depak (Lucknow, IN); Srivastava; Arwind Kumar (Lucknow, IN); Rastogi; Anil Kumar (Lucknow, IN); Murthy; Puvvada Sri Ramachandra (Lucknow, IN); Srivastava; Sudhir (Lucknow, IN); Asthana; Onkar Prasad (Lucknow, IN); Singh; Narenda (Lucknow, IN); Nand; Nitya (Lucknow, IN)

Assignee:  Council of Scientific & Industrial Research (IN)

Appl. No.:  742424

Filed:  December 22, 2000

Abstract

The present invention provides new uses of Gugulipid, an ethyl acetate extract of the resin of the plant Comiphora wighitii, for controlling or preventing cognitive dysfunction, hyperglycemia and some infective conditions of the skin and a method of preparing Gugulipid by agitating the resin in shake flask assembly or sonicating assembly and preparing a solid or a creamy dosage forms.

Description of the Invention

FIELD OF INVENTION

The present invention claims some new uses of Gugulipid, an ethyl acetate extract of the resin of the plant Comiphora wighitii, commonly called gum guggulu. These include modifications of the extraction methods and methods for controlling or preventing cognitive dysfunction, hyperglycemia and some infective conditions of the skin.

BACKGROUND OF THE INVENTION

Ayurveda takes a holistic view of human disease. It views any disease as a dysfunction of the whole body rather than of a single organ or physiological process. Most of the Ayurvedic drugs therefore are likely to act on a number of dysfunctions of the body involving a number of organs and functions. Gugulipid, an ethylacetate 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. Chemopharmacological investigation of this extract resulted in the characterization of guggulsterone [cis-and trans-4, 17 (20)-pregnadiene-3, 16-dione] as the major constituent. Apart from guggulsterone, other chemical constituents in the ethyl acetate soluble fraction added to and modulated the total activity. This fraction rather than pure guggulsterone was developed as a hypolipidemic drug and named gugulipid. As a follow up of the holistic view of Ayurveda of human disease, gugulipid was tested for other related and unrelated conditions/dysfunction and found to possess cognitive and anti-hyperglycemic activities and also improved in general dermal dysfunctions. These novel uses of gugulipid are now claimed.

PRIOR ART

Guggul, highly valued in Indian system of medicine Ayurveda, is the gum resin exudate of a small tree Commiphora wighitii belonging to the family Burseraceae. It is specially recommended for the treatment of obesity, lipid disorders and rheumatoid arthritis (Ayurvedic treatise: Sushruta, Vagabhatta). In Tibetan medicine, the plant (C. Wighitii) mixed with other herbs is used for skin diseases, anemia, edema, salivation and heaviness of stomach [Lama, S. and Santra, S. C., Sci. Cult. 45, 262 (1979)]. Modern pharmacological studies on the crude drug and some of its fractions have supported the claims of Ayurveda. The anti-arthritis and anti-inflammatory activities were confirmed by Gujral and co-workers [Gujral, M. L., Sareen, K., Tangri, K. K., Amma, M. K. P. and Roy, A. K. Ind. J. Physiol. Pharmacol. 4, 267 (1960)]. The hypolipidemic and anti-atherosclerotic activities reported by Dwarakanath and Satyawati. [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 of Ayurvedic Medicine), Banaras Hindu University, Varanasi, (1966)]. Later on, its ethyl acetate extract was developed by joint efforts of Malti-Chem Research Center, Baroda and Central Drug Research Institute, Lucknow as hypolipidemic drug [A process for obtaining hypolipidemic and anti-platelet aggregation fraction from guggul resin. Indian Patent No.148265 dated 6.4.79., N. K. Kapoor., Sukh Dev and S. Nityanand]. A mixed type of mechanism has been implicated for lipid lowering effect of gugulipid. The stimulation of plasma LCAT, hepatic lipases, receptor mediated catabolism of LDL and increased faecal bile acid excretion as well as suppression of hepatic cholesterol biosynthesis are the mechanisms responsible for lipid lowering effect of gugulipid [S. Nityanand and N. K. Kapoor, Ind J. Exp. Biol. 11, 395 (1973); N. K. Kapoor and S. Nityanand, Ind. J. Heart Res. Supp-1) 22 (1988)]. With the discovery of hypolipidemic activity of the gum resin, systematic chemical investigations were carried out to characterize compounds of the gum resin responsible for hypolipidemic activity. Mc Cook et al. have recently claimed alcoholic extract of gum guggul for controlling or preventing sebum secretion from sebocytes which is associated with a shiny, undesirable appearance and a disagreeable tactile sensation [J. P. Mc Cook et. al. U.S. Pat. No. 5,690,948 (1997). Antisebum and antioxidant compositions containing gugulipid and alcoholic fractions thereof].

The applicants have earlier obtained a U.S. Pat. No. 6,086,889 for a process for isolation of lipid fraction containing Z and E guggulsterones from the aerial parts of the plant Comiphora wighitii. The said process 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; soaking the material again in polar solvent; filtering and concentrating the extracted material in the polar solvent under reduced pressure and gel filtration or silica gel chromatography to obtain Z and E ketosteroid containing lipid fraction. The present invention introduces non-obvious modifications to the extraction method as described in the earlier prior art and describes new uses of the Gugulipid, which were not known earlier.

GENESIS OF THE INVENTION

With the isolation of variety of compounds of varied structural classes such as lignans, lipids, diterpenoids and steroids, we initiated quite early a program to investigate structure based biological profiles of gugulipid. Earlier, it was revealed that the hypolipidemic and thyroid stimulating actions 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 receptors 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, Oct. 9-12, 1988].

ROLE IN IMPROVING COGNITIVE FUNCTIONS

Recent developments in understanding of neurosteroids, role of free radicals and antioxidants in brain function as well as in hyperglycemia prompted us to explore gugulipid for these activities. Behavioral studies have suggested a potential role of pregnenolone, in particular, for memory enhancement. Intracerebroventricular (i.c.v.) administration of pregnenolone and pregnenolone sulfate leads to an amelioration in various memory task in rodents [Flood, J. F., Morley, J. F., and Robert, E., Memory enhancing effects in male mice of pregnenolone and of steroids metabolically derived from it; Proc. Natl. Acad Sci. USA; 89, 1567 (1992)]. These memory-enhancing effects might be attributed to the N-methyl-D-aspartate (NMDA)-antagonistic properties of pregnenolone sulfate since NMDA agonists have been shown to impair cognitive functions in rodents [Bowlby, M. R., 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 neurosteroid pregnenolone. These findings prompted us to explore memory enhancing properties of gugulipid because of similarity among biogenic precursor of pregnenolone (1) and steroids present in Gugulipid such as guggulsterol-I (2), guggulsterol-II (3) and guggulsterol-III (4) (FIG. 1) [V. D. Patil, U. R. Nayak and Sukh Dev: Chemistry of Ayurvedic Crude Drugs-I, Tetrahedron 28, 2341 (1972)].

ROLE IN IMPROVEMENT OF DIABETIC CONDITION

Recent years have seen increasing interest in the role of free radical oxidative damage in human disease. Free radicals are highly reactive species that have the potential to oxidize biological molecules including proteins, lipids and DNA. To prevent or retard oxidation, rich arrays of natural antioxidant mechanism exist. These antioxidant defense mechanisms have been found defective in many diseases. Increased production of free radicals has been strongly implicated in the pathophysiology of diabetes and atherosclerosis. Glucose combines with serum proteins and lipoproteins in a non-enzymatic glycation reaction and may auto-oxidize in situ generating free radicals and causing local oxidative damage [Hunt, J. V., Wolff, S. P. in "Oxidative glycation and free radical production; a causal mechanism of diabetic complications". Free Radical. Res. Commun. 12-13,115 (1991)]. The free radical scavenging antioxidants react preferentially with free radicals before vital structure can be attacked.

Troglitazone, a hypoglycemic agent has been shown to exhibit strong antioxidant activity. Its 1,4-bis-oxygenated phenyl pattern of chroman skeleton is real pharmacophore responsible for antioxidant property. Gugulipid and gugguisterone are also known to have antioxidant property [Guggulsterone, a potent hypolipidemic, prevents oxidation of low density lipoproteins, K. Singh, R. Chander and N. K. Kapoor, Phytotherapy Research, II, 291 (1997)]. There are several molecules in lignan class where 1,2-or 1,4-bis-oxygenated phenyl pharmacophoric pattern are present (FIG. 2). [Sukh Dev, Proc. Ind. Sci. Acad. 49A, 359 (1983)].

Thus the presence of above biologically potential class of molecules makes gugulipid a good candidate for exploration against diseases associated with dyslipidemia, hyperglycemia and behavior.

OBJECTS OF THE PRESENT INVENTION

An object of the present invention was to develop a method of extraction of Guggul resin by continuous shaking or sonication procedure to obtain improved yields of the extract. Another object of the present invention was to develop cognition enhancing effect of gugulipid orally in any pharmaceutical preparations.

Still another object of the present invention was to develop a method of reducing, preventing or controlling hyperglycemic conditions by consuming gugulipid in any pharmaceutically acceptable formulations.

Another object of the invention is to develop a method of improving conditions of infected skin.

SUMMARY OF THE INVENTION

The present provides process for extraction gugulipid of resin from aerial branches of the plant C. wighitii comprises suspending gum/resin with a non-polar solvent, filtration or decantation, repetition of the process for extraction of fatty acids, extraction of residual matter with ethyl acetate by continuous shaking or sonication procedure, mixing of polar and nonpolar fractions and filtration to remove solid suspension and finally the solvent is removed to get gugulipid.

The invention also provides method for the preparation of pharmaceutically acceptable compositions for controlling hyperglycemic conditions and improving conditions of infected skin.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides process for extraction gugulipid of resin from aerial branches of the plant C. wighitii, said process comprising

  •  
    bulleta) suspending gum/resin of plant C. wighitti in a non-polar solvent for a period of 5 to 8 hours,
    bulletb) filtration or decantation of the soluble portion,
    bulletc) repeating the above steps for the extraction of fatty matter,
    bulletd) extraction of residual matter with ethyl acetate by agitation on shake flask or sonicating assembly.
    bullete) mixing the extracts from steps (a), (c) and (d) and filtering to remove solid suspension, to obtain gugulipid, and if desired,
    bulletf) converting the gugulipid into solid or creamy dosage forms by any known method.



    The term Gugulipid as used herein means an ethyl acetate extract of gum/resin Guggul from the tree C. wighti.

    The term "Ethyl acetate extract" means the non-aqueous fraction of gum/resin.

    In an embodiment, the non-polar solvent is selected from n-hexane, cyclohexane or any other solvents.

    In another embodiment of the invention, the yield of Gugulipid from the said process is in between 45-60%.

    In another embodiment of the invention, the solid dosage form is obtained by maceration of the component gugulipid, starch and microcrystalline cellulose in suitable proportions in a mixer till the mixture becomes flowable powder.

    In another embodiment of the invention, the cream formulations is obtained by dissolving gugulipid alone or with help of solvent in suitable portions of polyethylene glycol by heating on water-bath and pulling off the solvent.

    In another embodiment of the invention, gugulipid in combination with or associated with an additive is used for controlling or preventing cognitive dysfunction, hyperglycemia and some infective conditions of the skin in mammals.

    In another embodiment of the invention, Gugulipid is administered in the form of extracts, solid dosages or cream formulations as may be suitable.

    In another embodiment of the invention, for enhancing cognitional behavior by feeding gugulipid or mixed with other agent of similar property given orally in the form of suitable pharmaceutical preparations and with amount necessary for activity.

    In another embodiment of the invention, for reversal of Atropine induced amnesia in male swiss mice by administrating gugulipid dosage equivalent to 40 mg/kg/day for about 7 days either in the form of extracts or solid dosage.

    In another embodiment of the invention, Gugulipid is used for treatment of patients suffering from human memory dysfunctions like Alzheimers disease and Korsakoff's disease alone or in combination with other treatments.

    In another embodiment of the invention, gugulipid in combination with or associated with an additive is used for reducing, preventing or controlling hyperglycemic conditions by consuming necessary amount of gugulipid for activity in any pharmaceutically acceptable formulations.

    In yet another embodiment gugulipid as a hypoglycemic agent decrease the blood glucose level by 30-60% of streptozotocin induced diabetic rats at 100 mg/kg body weight between 1-7 hrs and evident from first hour post administration of gugulipid either in extract or solid dosage form.

    In yet another embodiment Gugulipid has hypoglycemic effect at 100 mg/kg of body weight per dose and the average lowering of about 45%in blood glucose profile between 3-7 hrs.

    In yet another embodiment, Gugulipid has hypoglycemic effect at 100 mg/kg of body weight dose in glucose-loaded rats and the peak lowering effect is between 30-60 min. post glucose-load.

    The inventive methods of controlling memory dysfunction, hyperglycemic or infectious conditions of skin conditions employ gugulipid or extract of gum/resin in pharmaceutically acceptable dosage forms.

  • Claim 1 of 5 Claims

    1. A method of treating a cognitive memory dysfunction in a mammal, said method comprising administering to said mammal a pharmaceutically acceptable composition consisting essentially of a capsule or a tablet of a memory enhancing effective amount of gugulipid, starch, microcrystalline cellulose at a yield of 45-60%,

    wherein said gugulipid is administered at a dosage level equivalent to 40 mglkgldav for 7 days.

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