WO2006067796A1 - Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer - Google Patents

Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer Download PDF

Info

Publication number
WO2006067796A1
WO2006067796A1 PCT/IN2004/000402 IN2004000402W WO2006067796A1 WO 2006067796 A1 WO2006067796 A1 WO 2006067796A1 IN 2004000402 W IN2004000402 W IN 2004000402W WO 2006067796 A1 WO2006067796 A1 WO 2006067796A1
Authority
WO
WIPO (PCT)
Prior art keywords
formulation
herbal
herbal formulation
extract
alzheimer
Prior art date
Application number
PCT/IN2004/000402
Other languages
English (en)
Inventor
Palpu Pushpangadan
Chandana Venkateswara Rao
Kamal Kishore
Ramasami Kartik
Yogendra Kumar Gupta
Raghavan Govindarajan
Original Assignee
Council Of Scientific And Industrial Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Council Of Scientific And Industrial Research filed Critical Council Of Scientific And Industrial Research
Priority to PCT/IN2004/000402 priority Critical patent/WO2006067796A1/fr
Publication of WO2006067796A1 publication Critical patent/WO2006067796A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/81—Solanaceae (Potato family), e.g. tobacco, nightshade, tomato, belladonna, capsicum or jimsonweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/59—Menispermaceae (Moonseed family), e.g. hyperbaena or coralbead
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention provides a novel herbal formulation useful as a brain tonic, improves the memory and helps in recalling of thoughts. BACKGROUND AND PRIOR ART OF THE INVENTION
  • a major discovery of the past two decades in the field of neurosciences has been the elucidation of behavioural, neurobiological and cellular basis of learning and memory processes.
  • the brain is an assembly of interrelated neural systems that regulates their owns and each other's activity in a dynamic, complex fashion. Morphological properties of central neurons have been very useful for the description of the functional characteristics. Learning is defined as the acquisition of information and skills, and subsequent retention of that information is called memory.
  • Alzheimer's disease is the term used to describe a dementing disorder marked by certain brain changes, regardless of the age of onset. Accordingly, effect of a wide variety of pharmacological agents or brain lesion on cognitive behaviour have been studied and most validly interpreted as "enhancement or impairment" of learning and memory process.
  • cholinergic hypo function causes dementia with symptoms such as memory loss and disorientation in cerebrovascular or alzheimers disease (Coyle et al 1983).
  • cerebral ischemia a reduction in the cerebral blood flow and blood oxygen occur.
  • hypoxia induces a reduction of memory and judgement that is associated with a decrease in acetylcholine synthesis (Gibson and Duffy, 1981).
  • main characteristic of memory formation in animals, as well as in human being is its progression from a short-lived labile form to a long- lasting stable form.
  • Alzheimer's disease is not a normal part of aging -it is not something that inevitably happens in later life. Rather it is one of the dementing disorders, a group of brain diseases that lead to the loss of mental and physical functions. Alzheimer's disease is an exception, rather than rule, in old age. Alzheimer' s disease or a related dementia afflicts only 5 to 6 percent of older people. Research indicates that 1 percent of the population aged 65-74 has severe dementia, increasing to 7 percent of those aged 75-84 and 25 percent of those 85 or older. The main risk factor for Alzheimer's disease is increased age.
  • Alzheimer's disease The rates of disease increase markedly with advancing age, with 25 percent of people over 85 suffering from Alzheimer's or other severe dementia. Some investigators, describing Alzheimer's may be due to heredity. The onset of Alzheimer's disease is usually very slow and gradual, seldom occurring before age 65. Over time, however, if follows a progressively more serious course. Among the symptoms that typically develop, none is unique to Alzheimer's disease at its various stages. It is therefore essential for suspicious changes to be thoroughly evaluated before they become inappropriately or negligently labelled Alzheimer's disease. Problem of memory, particularly recent or short-term memory, are common early in the course of disease. Microscopic brain tissue changes have been described in Alzheimer's disease since Alios Alzheimer first reported them in 1906.
  • senile or neuritic plaques chemical deposits consisting of degenerating nerve cells combined with a form of protein called ⁇ amyloid
  • neurofibrillary tangles malformation within nerve cells.
  • the plaques found in the brains of people with Alzheimer's disease appear to be made, in part, from protein molecules- amyloid precursor protein (APP)-that normally are essential components of the brain. Plaque are made when an enzyme snips APP apart at a specific place and then leaves the fragments ⁇ amyloid in the brain tissue where they come together in abnormal deposits. It has not as yet been definitely determined how neurofibrillary tangles are formed.
  • APP protein molecules- amyloid precursor protein
  • Alzheimer's disease As research on Alzheimer's disease progresses, scientists are describing other abnormal anatomical and chemical changes associated with the disease. These include nerve cell degeneration in the brain nucleus basal is of Meynert and reduced levels of the neurotransmitter acetylcholine in the brains of Alzheimer's disease victims.
  • the clinical features of Alzheimer's disease, as opposed to the "tissue" changes, are three folds, firstly Dementia- significant loss of intellectual abilities such as memory capacity, severe enough to interfere with social or occupational functioning; secondly, Insidious onset of symptoms- subtly progressive and irreversible course with documented deterioration over time. Thirdly, Exclusion of all other specific causes of dementia by history, physical examination laboratory tests, psychometric and other studies.
  • Alzheimer's Disease Associated Protein ADAP
  • the proteins which seems to appears only in people with Alzheimer' s, is mainly concentrated in the cortex covering the front and side sections of the brain, regions involved in memory function.
  • researchers have found ADAP not only in the brain tissue but also in spinal fluid.
  • Alzheimer's disease is the most over diagnosed and misdiagnosed disorder of mental functioning in older adults.
  • Part of the problem, already alluded to, is that many other disorders show symptoms that resemble those of Alzheimer' s disease.
  • the crucial difference though, is that many of these disorders — unlike Alzheimer's disease — may be stopped, reversed, or cured with appropriate treatment.
  • organic mental disorders condition that affect brain and result in intellectual, behavioural, and psychological dysfunction are referred to as "organic mental disorders". These disorders represent a broad grouping of diseases and include Alzheimer's disease.
  • Alzheimer's disease In addition to organic mental disorders resulting from these diverse causes, other forms of mental dysfunction or mental health problem can also be confused with Alzheimer's disease. These form of condition are referred to as pseudodementia. Because of many other disorders that can be confused with Alzheimer's disease, a comprehensive clinical evaluation is essential to arrive at a correct diagnosis of symptoms that looks like those of Alzheimer's disease. Such an assessment should include at least three major components firstly a through general medical workup; secondly, a neurological examination, and thirdly, a psychiatric evaluation that may include psychological or psychometric testing. Alzheimer's disease has emerged as one of the great developments in modern day medicine, with a growing number of clues but still no answers as to its cause.
  • the main object of the present invention is to provide a novel synergistic herbal formulation used as a brain tonic, cognition and recalling of thoughts in various dosage forms viz; tablets, capsules for easy consumption.
  • Another objective of the present invention is to prepare herbal dosage form that improves the memory and used in treatment of senile dementia.
  • the invention provides a herbal formulation having the property of developing intellectual power as well as in quick grasping of trial been done once that is the sign of improving memory and used in treatment of dementia as a brain tonic and as a central antioxidant.
  • a synergistic herbal formulation(s) comprising the extracts of pharmacologically effective form obtained from Tinospora cordifolia, Centella asiatica, Withania somnifera, Mucuna pruriens and Curcuma longa in pharmaceutically acceptable dosage optionally along with an additive useful as brain tonic and in treatment of senile and presenile dementia
  • the extracts/juice of the plants viz Tinospora cordifolia , Centella asiatica, Withania somnifera, Mucuna pruriens and Curcuma longa are mixed in the ratio ranging from 1 : 0.5 : 1 : 1 : 2 and 1 : 1 : 1 : 1 : 2 by weight balance by conventional additives.
  • the extract of Centella asciatica is obtained from leaves.
  • the extract of Tinospora cordifolia is obtained from stem.
  • the extract of Withania somnifera is obtained from root.
  • the extract of Mucuna pruriens is obtained from seeds
  • the extract of Curcuma longa is obtained from rhizomes.
  • the formulation contains starch, lactose, acacia as additives.
  • the formulation is used in a soft gelatin capsule of oral dosage forms.
  • the formulation has the property of improving the intellectual power of memorising and used in treatment of senile dementia as a brain tonic and as a central antioxidant.
  • the formulation ameliorates the symptoms of disease and to improve the general health of the patient.
  • the formulation is used to cross the blood brain barrier and leads to enhancement in the superoxide dismutase in frontal cortex.
  • the formulation is used to cross the blood brain barrier and leads to enhancement in the catalase in frontal cortex. In yet another embodiment of the invention the formulation is used to cross the blood brain barrier and leads to enhancement in the glutathione peroxidase in frontal cortex.
  • the formulation is used to cross the blood brain barrier and leads to enhance the superoxide dismutase in the striatum.
  • the said formulation is used to cross the blood brain barrier and leads to enhance the catalase in the striatum.
  • the formulation is used to cross the blood brain barrier and leads to enhance the glutathione peroxidase in the striatum. In yet another embodiment of the invention the formulation is used to cure migraine and anaemia.
  • the formulation shows anti-inflammatory activity and pain reduction activity.
  • the formulation is used in the treatment of anticonvulsant activity .
  • the formulation at different dose of 100, 200 and 400 mg/kg did not showed any toxicity in rats as well as no change in organ body weight.
  • the synergistic formulation at a dose ranging from 100-200 mg/kg on passive avoidance test showed significant activity.
  • the present invention also provides a method of treating Alzheimers disease, comprising the step of administering an effective amount to patient of the herbal composition, together with or in combination with therapeutically acceptable additives.
  • the present invention provides a novel herbal formulation useful in the treatment of alzheimers.
  • the herbal dosage form obtained from the fresh leaves extract of Centella asiatica is having a potential memory-enhancing role and also found to be effective in producing tranquilizing effects, stem extract of Tinospora cordifolia, the root extract of
  • the plant used in the invention have following properties as reported.
  • Centella asiatica Family Umbelliferae
  • Botanical description A slender herbaceous creeping; stem long, prostate coming off from theleaf-axils of a vertical rootstock, filiform, often reddish, and with long internodes, rooting at the nodes. Leaves 1.3-6.3 cm in diameter, several from the rootstock which often have much elongated petioles, and 1-3 from each nodes of the stems, orbulicar, reniform, rather broader than long, more or less cupped, entire or shallowly crenate, glabrous on both sides, and with numerous slender nerves from a deeply cordate base; petioles very variable in length 7.5-15 cm long or more, channelled, glabrous or nearly so; stipule short, adnate to the petioles forming a sheating base.
  • Medicinal uses The plant is Acrid, bitter, digestible, laxative, cooling effect, tonic, and antipyretic, improve appetite (Unani), cures leucoderma anaemia, urinary discharge, disease of blood, use in insanity (Ayurveda).
  • the plant has bad taste; soporific, sedatives to the nerves, acts as a cardiotonic clears the voice and the brain; cures hiccough, headache.
  • the plant is considered as a useful alternative and tonic in diseases of skin, nerves. In some part of India, the people are in the habit of taking the powdered dried leaves with milk for improving their general intelligence.
  • the leaves are said to be useful in syphilitic skin diseases, both externally and internally and on the Malabar Coast, the plant is one of the remedies for leprosy. It is also a popular remedy for slight dysenteric derangement of bowls to which children are subject: three or four leaves are given with cumin and sugar, and the pounded leaves are applied to navel. In konkan one or two leaves are given every morning to cure stuttering and the juice is applied (generally as a lep with Cadamba bark and black cumin) to skin eruption supposed to arise from heat of blood.
  • Fhytochemistry The alcoholic extract of herb an essential oil, green in colour and possing the strong odour of the herb, fatty oil, sitosterol and a resinous substance have been obtained.
  • the fatty oil consists of the glyceride, linolic, lignoceric, palmitic and stearic acid.
  • An alkaloid hydrocortylin has been obtained from the dried plant.
  • Vellarine, peptic acids are present in the leaves and roots.
  • the plants also contain ascorbic acid in a cone, of 13.8 mg%.
  • a glycoside asiaticoside has been isolated from the plant.
  • the major component of the triterpine mixture is centoic acid.
  • the usual dose for the oral administration is 5-10 grains of the plant powder thrice daily. In larger doses, the drug is a simplifying narcotic, producing giddiness and some times coma.
  • the alcoholic extract produce tranquillising effect in rats. It was found non-toxic up to a dose of 350-mg/kg i.p.
  • the alcoholic and aqueous extracts antagonise spontaneous contraction and also caused relaxation of musculature of isolated ileum of rat.
  • the alcoholic extract was found to have depressant effect in rat in toxic doses.
  • the glycosidal fractions have a sedative action in rats. It decreases the tone and diminished the amplitude of contractions of isolated ileum of rabbit and albino rat.
  • Botanical description An erect, evergreen, grayish tomentose shrub 0.3- 2 m tall, with fairly long, stout, fleshy, whitish-brown roots. Leaves simple, alternate or subopposite, broadly ovate, glabrous, 5-12 cm long and 2.5 - 7 cm wide, apex subacute, base un equal, margins entire, finely stellate-pubescent beneath; main nerves about 6 pairs; petioles 0.3- 1.7 cm long.
  • the roots are considered alternative, germicidal, aphrodisiac and diuretic; they are used in Ayurveda to treat ulcers, fever, dyspnoea, cough, consumption, dropsy, rheumatism, toxicosis and memory loss.
  • the powdered roots mixed with equal parts of honey and ghee is thought to be beneficial for impotence or seminal debility.
  • the roots as well as the bruised leaves are also used externally to treat ulcers, painful swellings and scabies.
  • the total alkaloids present in the roots produce relaxant and anti spasmodic effects.
  • the fruits and seeds are diuretic.
  • the leaves are considered anthelmintic and bitter, and their infusion is given to relieve fever.
  • Tinospora cordifolia Family Menispermaceae
  • Botanical Descriptions A large glabrous climbing shrub. Stems rather succulent with long filiform, aerial roots arising from branches. Bark; warty, papery thin, creamy white or grey brown. Peels off easily. Wood, soft, perforated. Leaves; membranous, cordate with broad sinus. Pointed at the tip. Flowers; unisexual and greenish, in long clusters. Seeds; curved. Drupes; ovoid, succulent, lustrous, red, pea sized. Fruits; fleshy, one seeded. During the summer flowers and fruits during the winter.
  • Medicinal Uses Useful in bilious fever, rheumatism, general debility, seminal weakness, splenic diseases and urinary affections. Fresh plant is considered more efficacious. It is mostly used for preparing a kind of starch known as Guduchi satva or Sat giloe.
  • Phytochemistry Sesquiterpene tinocordifolin, sesquiterpene glucoside tinocordifolioside, tinosponone, tinocordioside, cordioside, furanoid diterpenes, a new clerodane furano- diterpene viz.
  • Other alkaloids viz., jatrorrhizine, palmatine, berberine, tembeterine, phenylpropene disaccharides cordifolioside A, B and C, choline, tinosporic acid, tinosporal, tinosporon, 20- ⁇ -hydroxyecdysone, palmatoside C and F, cordifolisides D and E, diterpenoid furanolactones.
  • Botanical Description Pantropical in distribution, it is found almost throughout India and in the Andaman and Nicobar Islands in damp habitats, ravines and scrub forests. Occasionally cultivated. A large, pubescent, herbaceous or sometimes woody, annual climber. Leaves trifoliate, leaf rachis 5-12 cm long, appressed silky; stipules linear, about 4mm long; leaflets membranous, 7.5-12.5 cm long and 5-7.5 cm wide, ovate-rhomboid, asymmetrical, apex obtuse or acute,base rounded or truncate.both surfaces grey silky-pubescent.
  • Fruit (pod) S-shaped, thick, turgid,5-10cm long and 1.2-1.8 cm wide, longitudinally ribbed, densely covered with yellow-brown stinging hairs; seeds 4-6,black, ovoid, 1.2 cm long. Flowers and fruits almost throughout the year but mainly between August and January in central Indian deciduous forest regions.
  • M. Pruriens seeds have been reported to be a good source of 3,4- dihydroxyphenylalanine (L-dopa). Damoong and Ramaswamy (1937) have reported the isolation of L-dopa from seeds in a yield of 1.5 percent.
  • the alcoholic extract of M Pruriens seeds gave four alkaloids viz., mucunine, mucunadine, Prurienine and prurieninine .
  • the 80 percent alcoholic extract of seeds showed the presence of 5 indolic compounds, two of which were identified as tryptamine and 5-hydroxytryptamine.
  • Different parts of M. Pruriens except trichomes of pods yielded four indole-3-alkylamines.
  • Botanical discription The genus Curcuma comprising about fifty species, distributed in tropical and subtropical regions of Asia, belongs to the tribe Hedychieae and consists of a rather homogenous group of rhizomatous perennials.
  • the taxonomic status of Curcuma heyneana was discussed by Firman et al; 1988 (Phytochem. 27: 3887-3891) based on essential oil analysis.
  • Tomlinson's (1969) work based on the anatomical evidence, which has much relevance in the classification of the order Zingiberales.
  • Curcuma longa were used predominantly for endoparasites, internal and external injuries and pregnancy related conditions in ethenic community of Trinidad and Tobago. Curcuma longa is used as dietary intake in Nepal (Eigner and Scholz, J Ethnopharmacol 1999, 67(1): 1-6).
  • Essential oils are complex mixtures of odorous and steam-volatile compounds that are deposited in the subcuticular space of glandular hair, cell organelle, idioblasts, excretory cavities and canals or exceptionally in heartwoods. In other words, they are very complex, aromatic, volatile mixture containing many different compounds.
  • the constituents of essential oils belong to numerous classes of chemical substances, such as hydrocarbons, alcohols, aldehydes, ketones, acids, esters, oxides and ether (Thappa et al, J. Essent. Oil Res., 1982,11 :97-103).
  • Essential oils largely comprises of terpenoid compounds, which constitute two or more isoprene units. Based on this, terpenoids are mainly classified into four groups viz.
  • the essential oil forms the basic raw materials for perfume and flavour making industries. They are also used in the cosmetics and pharmaceutical industries. Many natural essential oils are used in aromatherapy to cure and prevent illness due to their therapeutic properties and also because of their fragrance, which can influence human thoughts and emotions. Many of the essential oils are reported to have antimicrobial, insect repellent and insecticidal properties.
  • Curcuma The genus Curcuma is exhibits diverse pharmacological activities against cancer and tumorgensis. Anto et al, Mutation Res., 1996, 370: 127-131, has reported the anticancer and antitumour properties of Curcuma longa. It was demonstrated that the inhibitory effect of curcumin on DNA and RNA synthesis in cultured HeLa cells. Dietary curcumin may inhibit azoxymethanol (40 M) induced colonic neoplasia in mice (Huang et al., Cancer Lett 1992, 64(2): 117-21). The antimicrobial properties are well known and the result reported by many researchers pointed out the antibiotic activities of Curcuma. Banerjee and Nigam (J. Res. Ind. Med.
  • Curcumin inhibited rat liver microsomal delta 5 and delta 6 desaturases (Shimizu et al., Lipids 1992, 27(7): 509-12). Curcuma contains an. active principle(s) other than curcuminoid, which can modify the metabolism of lipid and lipoproteins.
  • Curcumin as well as turmeric increase bile flow. Essential oils of turmeric have also been found to increase the bile flow. However, some investigators have found it to be ulcerogenic (Prasad et al. J. Physiol. Pharmocol, 1976, 20, 92). The gastric secretion was found to be reduced after 3 h in conscious rabbits by aqueous and methanolic extracts of turmeric (Sakai et al.
  • Curcumin and turmeric have been shown to protect liver against a variety of toxicants in vitro as well as in vivo. They include carbon tetrachloride, aflatoxin B- 1, paracetamol iron, and cyclophosphamide in mouse, rat and duckling. Evidence for the hypocholesterolemic and hypolipidemic activities of curcumin has been provided when it was fed with diet to rats for 7 weeks at the concentration of 0.15% (Rao et al. 1970 J. Nutri. 100, 1307). Ethanolic extract of C. longa has been shown to have hypoglycemic activity in normal as well as alloxan - induced diabeties in rats.
  • Curcumin has also isolated a lipopolysaccharide from the root of Curcumin, which is similar to bacterial lipopolysaccharides and is immunostimulant (Inagawa et al. Chem Pharm Bull 1992, 40, 994 ).
  • the wound healing property of turmeric was investigated long back and its local application was found to be effective (Gujral et al., J. bid. Med. Association 22, 273 1958).
  • a sum of approximately 26 compounds has been isolated from different Curcuma sp. having high antioxidant activity. Curcumin did not produce any toxicity either on single administration or on repeated oral administration over a period of 6 months in rat and monkey at doses up to 800 and 1800- mg/kg day, respectively.
  • the novelty of the invention is in a herbal formulation having the property of developing intellectual power as well as in quick grasping of trial been done once that is the sign of improving memory and used in treatment of dementia as a brain tonic and as a central antioxidant.
  • the synergistic herbal formulation comprises extracts of pharmacologically effective form obtained from Tinospora cordifolia, Centella asiatica, Withania somnifera, hducuna pruriens and Curcuma longa in pharmaceutically acceptable dosage optionally along with an additive useful as brain tonic and in treatment of senile and presenile dementia.
  • the extracts/juice of the plants viz Tinospora cordifolia , Centella asiatica, Withania somnifera, Mucuna pruriens and Curcuma longa are mixed in the ratio ranging from 1 : 0.5 : 1 : 1 : 2 and 1 : 1 : 1 : 1 : 2 by weight balance by conventional additives.
  • the extract of Centella asciatica is obtained from leaves.
  • the extract of Tinospora cordifolia is obtained from stem.
  • the extract of Withania somnifera is obtained from root.
  • the extract of Mucuna pruriens is obtained from seeds and the the extract of Curcuma longa is obtained from rhizomes.
  • the said formulation contains starch, lactose, acacia as additives.
  • the said formulation having the property of improving the intellectual power of memorising and used in treatment of senile dementia as a brain tonic and as a central antioxidant.
  • the formulation is known to ameliorate the symptoms of disease and to improve the general health of the patient.
  • the said formulation is used to cross the blood brain barrier and leads to enhancement in the superoxide dismutase in frontal cortex.
  • the said formulation is used to cross the blood brain barrier and leads to enhancement in the catalase in frontal cortex.
  • the formulation is used to cross the blood brain barrier and leads to enhancement in the glutathione peroxidase in frontal cortex.
  • the formulation is used to cross the blood brain barrier and leads to enhance the superoxide dismutase in the striatum.
  • the formulation is used to cross the blood brain barrier and leads to enhance the catalase in the striatum.
  • the formulation is used to cross the blood brain barrier and leads to enhance the glutathione peroxidase in the striatum.
  • the formulation is used to cure migraine and anaemia.
  • the formulation showed the anti-inflammatory activity and pain reduction activity.
  • the formulation is used in the treatment of anticonvulsant activity.
  • the formulation at different dose of 100, 200 and 400 mg/kg did not showed any toxicity in rats as well as no change in organ body weight.
  • the synergistic formulation at a dose ranging from 100-200 mg/kg on passive avoidance test showed significant activity.
  • the method of treating alzheimers comprises the step of administering an effective amount to patient of the herbal composition, together with or in combination with therapeutically acceptable additives.
  • new herbal formulation(s) is having the property of improving the memory and used in treatment of amnesia as a brain tonic and as a central antioxidant.
  • the invention thus meets the need for a new process in which the optimal proportions of long chain fatty acids vitamins, amino acids, and active therapeutic marker compounds are retained in the product and underlies the efficacy of the compound as a brain tonic.
  • the oleaginous edible oil according to the invention can be incorporated into a variety of food products, including, without limitation, butter, margarine, ice cream and mayonnaise- chocolate products, preparation of jaggery, water based brinks such as wines and mineral waters.
  • inventive oil is also suitable for encapsulation in gelatin shells to form soft gels/capsules. Regardless of the particular form in which the inventive oil is prepared, the daily dosage of the oil to experimental animals fall within the ranges set forth above. Depending on the concentration of the inventive oil in the above form, the total amount of the food product per serving or encapsulated oil etc will also vary the desired therapeutic activity.
  • the invention is further illustrated by the following non-limiting examples. Formulation (Fl) Tinospora cordifolia 2wt. %
  • Curcuma longa were collected and dried in shade.
  • the dried material (IKg) is then powdered and extracted with 50 % aqueous alcohol (3 L) for 5 days. At the end of this, the solvent is decanted and filtered if necessary to remove the plant debris.
  • the extract is then concentrated under vacuum at less than 50 0 C. Then the extract is lyophilised to obtain the extract in powder form.
  • the formulation Fl contains the Tinospora cordifolia only
  • the formulation F2 contains the Withania somnifera only
  • the formulation F3 contains the Mucuna pruriens only
  • the formulation F4 contains the Centella asiatica only
  • the formulation F5 contains the Curcuma longa only
  • the formulation F6 contains the Tinospora cordifolia and Withania somnifera only
  • the formulation F7 contains the Tinospora cordifolia , Withania somnifera and
  • the formulation F8 contains the Tinospora cordifolia, Withania somnifera, Mucuna pruriens and Centella asiatica only
  • Behavioral tests Passive avoidance task (step-down test): A step-down passive avoidance was examined using apparatus consisted of a box (25 x 25 x 40 cm), a floor with stainless-steel grid 2mm in diameter at 8-mm intervals, and a rubber platform (4cm diameter, 4cm height) set on the grid in one corner. Electric stimulation was given through the grid connected with a scrambled shock generator.
  • Values are mean ⁇ S.E.M. a P ⁇ 0.01, ⁇ 0.00I compared with i.c.v. STZ- treated rats.
  • ITL initial transfer latency after 13 days of i.c.v. STZ administration.
  • STZ + vehicle STZ+ F6 100 mg/kg; STZ+F7 100mg/kg; STZ+F8 100 mg/kg, STZ+F9 100 mg/kg ITL- the time taken for the rats to move from the open arm. and enter into one of the closed arm was recorded as 'initial transfer latency (ITL).
  • ITL 'initial transfer latency
  • the formulation F6 contains the Tinospora cordifolia and Withania somnifera
  • the formulation F7 contains the Tinospora cordifolia , Withania somnifera and Mucuna pruriens
  • the formulation F8 contains the Tinospora cordifolia, Withania somnifera, Mucuna pruriens andCentella asiatica
  • the formulation F9 contains the Tinospora cordifolia, Withania somnifera, Mucuna pruriens, Centella asiatica and Curcuma longa.
  • Intracerebroventricular administration of streptozotocin Immediately prior to surgery, rats were anaesthetized with chloral hydrate (240mg/kg, i.p., in 4%solution) and positioned in a stereotaxic apparatus. A saggital incision was made in the scalp and twoholes were drilled through the skull for placement of the injection cannula into the lateral cerebral ventricles. Animals received either i.c.v.
  • ACSF artificial cerebrospinal fluid
  • lO ⁇ L/site lO ⁇ L/site
  • i.c.v.STZ 3mg/kg bilaterally using a microsyringe
  • the composition of the ACSF was (in mmol/L): Nacl 147; KcI 2.9; Mgcl 2 1.6; Cacl 2 1.7; dextrose 2.2.
  • the cannula was left in place for a period of 2 min following the injection.
  • the stereotaxic coordinates for i.c.v. injection was 0.8mm posterior to bregma, 1.8mm lateral to the saggital suture and 3.6mm beneath the cortical surface.
  • Elevated plus-maze (Behavioural test) The plus-maze is the simple, fast and less time consuming process. There is no need of prior training or noxious stimuli (sound or light) is required .It is predictable and reliable procedure for studying cognition in Alzheimer's condition and to study the effect of drug response to senile dementia. Exposure of animals to novel maze alley evokes an approach- avoidance conflict, which is stronger in open arm as compared to enclosed arm. Rodents have aversion for high and open space and preferred enclosed arm and, therefore spend greater time in enclosed arm.
  • the plus maze consists of two opposite open arms (50* 10cm), crossed with two closed arms of the same dimensions with 40cm high walls.
  • the arms are connected by a central square (10 ⁇ l ⁇ cm).
  • rats were placed individually at one end of an open arm, facing away from the central square.
  • the time taken for rat to move from open arm and enter into one of the closed arms was recorded as 'initial transfer latency' (ITL).
  • ITL 'initial transfer latency'
  • the animal was allowed to explore the maze for 30s after recording the ITL, the rat was placed similarly on the open arm and the retention latency was noted again and termed as 'first retention transfer latency' (1 st RTL) and 'second retention transfer latency' (2 nd RTL).
  • Table 3 Effect of different formulation on oxidative stress markers in i.cv. Streptozotocin (STZ)-treated rats on day 21.
  • Table 3 represent a significant antioxidant activity by decreasing the level of malondialdehyde in the brain of i.cv. STZ rats treated with F6, F7, F8 and F9 formulation at a dose of lOOmg/kg compared with the vehicle-treated i.cv. STZ rats indicate attenuation of lipid peroxidation.
  • the increase in the gluthathione level in F9 treated i.cv. STZ groups are due the antioxidant property.
  • the formulation F6 contains the Tinospora cordifolia and Withania somnifera only
  • the formulation F7 contains the Tinospora cordifolia , Withania somnifera and Mucuna pruriens only
  • the formulation F8 contains the Tinospora cordifolia, Withania somnifera, Mucuna pruriens andCentella asiatica only
  • the rats were killed on day 21 for estimation of oxidative stress parameter (malondialdehyde(MDA), gluthathione, superoxide dismutase, and catalase in the whole brain upon completion of the behavioral task.
  • MDA oxidative stress parameter
  • animals were decapitated under ether anaesthesia and their brains quickly removed, cleaned with ice-cold saline and stored at -80 0 C.
  • Tissue preparation Brain tissue samples were thawed and homogenized with 10 times (w/v) ice-cold 0.1 mol/1 phosphate buffer (ph 7.4). Aliquots of homogenates from rat brain were separated and used to determine protein, lipid peroxidation and gluthathione. The remaining homogenates were centrifuged at 28 90Og for 60 min and the supernatant was then used for enzyme assays. Catalase activity was determined immediately after sample preparation and SOD was determined within 24h. Protein concentration was determined according to the method of Lowry using purified bovine serum albumin as a standard. Table 4: Effect of formulation (F9) in frontal cortex region in rat brain and the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxide (GPX).
  • SOD superoxide dismutase
  • CAT catalase
  • GPX glutathione peroxide
  • the F9 formulation contains Tinospora cordifolia, Withania somnifera, Mucuna pruriens, Centella asiatica and Curcuma longa only.
  • the F9 formulation shows the effective significant GPX, CAT and SOD compared with the normal. This is because of the presence of Curcuma longa present in the F9 formulation.
  • Table 5 Effect of formulation (F9) on rat brain in stratium of brain region and the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX).
  • SOD superoxide dismutase
  • CAT catalase
  • GPX glutathione peroxidase
  • the F9 formulation contains Tinospora cordifolia, Withania somnifera, Mucuna pruriens, Centella asiatica and Curcuma longa only.
  • the formulation F6 contains the Tinospora cordifolia and Withania somnifera only
  • the formulation F7 contains the Tinospora cordifolia . Withania somnifera and
  • the formulation F8 contains the Tinospora cordifolia, Withania somnifera, Mucuna pruriens and centella asiatica only
  • the formulation FI l contains the Centella asiatica, Mucuna pruriens and Curcuma longa only.
  • the F9 formulation shows the effective significant anti-inflammatory action against control compared with the other formulations. This is because of the presence of Curcuma longa present in the F9 formulation.
  • Indomethacin is a synthetic bioactive molecule used in treatment of inflammation only. The disadvantage of the molecule indomethacin is it causes gastric ulcer.
  • Antiinflammatory activity Carrageenin induced paw edema: Rats were injected with 0.1 ml of 1% ⁇ carrageenin (St.-Louis, MO) into the subplantar side of the left hind paw. The paw was marked with ink at the level of the lateral malleolus and dipped in perspex cell up to this mark. The paw volume was measured with an Ugo Basile Plethysmometer (No: 61402) (7140
  • Formulation (F9) was administered at dose of 100 mg/kg respectively orally by gavage 1 h before the ⁇ carrageenin injection. Significant reductions in the paw volume compared to vehicle treated control animals were considered as anti-inflammatory response. Percentage inhibition of oedema was calculated as follows:
  • Vx Paw volume in drug treated rats
  • V c Paw volume in control group of rats.
  • Kidney g
  • Liver g
  • Spleen g
  • F9 formulation contains mixture of Tinospora cordifolia, Withania somnifera, Mucuna pruriens , Centella asiatica and Curcuma longa only

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Botany (AREA)
  • Epidemiology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente invention concerne une nouvelle formulation galénique utilisée pour améliorer la mémoire et pour traiter la démence sénile et présénile sous forme de stimulateur cérébral. La/les formulation(s) comprend/comprennent de l’extrait alcoolisé de Tinospora cordifolia, Centella asiatica, Withania somnifera, Mucuna pruriens et Curcuma longa. Elle(s) est/sont classiquement utilisée(s) sous forme d’émulsion ou de capsule de gélatine molle pour les formes posologiques orales.
PCT/IN2004/000402 2004-12-24 2004-12-24 Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer WO2006067796A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000402 WO2006067796A1 (fr) 2004-12-24 2004-12-24 Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2004/000402 WO2006067796A1 (fr) 2004-12-24 2004-12-24 Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer

Publications (1)

Publication Number Publication Date
WO2006067796A1 true WO2006067796A1 (fr) 2006-06-29

Family

ID=34960570

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2004/000402 WO2006067796A1 (fr) 2004-12-24 2004-12-24 Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer

Country Status (1)

Country Link
WO (1) WO2006067796A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9517249B2 (en) 2012-11-26 2016-12-13 Access Business Group International Llc Antioxidant dietary supplement and related method

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2134269A (en) * 1983-01-22 1984-08-08 Marconi Instruments Ltd Frequency counting
US6153198A (en) * 1999-07-13 2000-11-28 Natreon Inc. Withania somnifera composition
WO2003006034A2 (fr) * 2001-07-11 2003-01-23 Sahajanand Biotech Private Limited Formulation medicinale
WO2003068251A1 (fr) * 2002-02-14 2003-08-21 Dalmia Centre For Research And Development Formulation a base d'herbes medicinales destinee a traiter des troubles deficitaires de l'attention (dca/thada) et procede de preparation correspondant
WO2003079812A1 (fr) * 2002-03-25 2003-10-02 Council Of Scientific And Industrial Research Aliments fonctionnels d'origine vegetale et procede de preparation correspondant
GB2388539A (en) * 2002-05-15 2003-11-19 Sahajanand Biotech Private Ltd Herbal formulations
US6733797B1 (en) * 2000-11-15 2004-05-11 William K. Summers Neuroceutical for improving memory and cognitive abilities

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2134269A (en) * 1983-01-22 1984-08-08 Marconi Instruments Ltd Frequency counting
US6153198A (en) * 1999-07-13 2000-11-28 Natreon Inc. Withania somnifera composition
US6733797B1 (en) * 2000-11-15 2004-05-11 William K. Summers Neuroceutical for improving memory and cognitive abilities
WO2003006034A2 (fr) * 2001-07-11 2003-01-23 Sahajanand Biotech Private Limited Formulation medicinale
WO2003068251A1 (fr) * 2002-02-14 2003-08-21 Dalmia Centre For Research And Development Formulation a base d'herbes medicinales destinee a traiter des troubles deficitaires de l'attention (dca/thada) et procede de preparation correspondant
WO2003079812A1 (fr) * 2002-03-25 2003-10-02 Council Of Scientific And Industrial Research Aliments fonctionnels d'origine vegetale et procede de preparation correspondant
GB2388539A (en) * 2002-05-15 2003-11-19 Sahajanand Biotech Private Ltd Herbal formulations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VAIDYA A D B: "THE STATUS AND SCOPE OF INDIAN MEDICINAL PLANTS ACTING ON CENTRAL NERVOUS SYSTEM", INDIAN JOURNAL OF PHARMACOLOGY, vol. 29, no. 5, October 1997 (1997-10-01), pages S340 - S343, XP009024718, ISSN: 0253-7613 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9517249B2 (en) 2012-11-26 2016-12-13 Access Business Group International Llc Antioxidant dietary supplement and related method
US10201583B2 (en) 2012-11-26 2019-02-12 Access Business Group International Llc Antioxidant dietary supplement and related method

Similar Documents

Publication Publication Date Title
Akbar Handbook of 200 medicinal plants: a comprehensive review of their traditional medical uses and scientific justifications
Keys Chinese herbs
Dhiman Ayurvedic drug plants
Wiart Ethnopharmacology of medicinal plants: Asia and the Pacific
Galani et al. Argyreia speciosa (Linn. f.) sweet: A comprehensive review
US20080286394A1 (en) Novel herbal formulation as brain tonic
Bhutya Ayurvedic Medicinal Plants of India (Vol. 1)
Selvam Inventory of vegetable crude drug samples housed in botanical survey of India, Howrah
Ansari et al. Therapeutics and pharmacology of Gul-e-Surkh (Rosa damascena Mill): An important Unani drug
Modi et al. Argyreia speciosa Linn. f.: phytochemistry, pharmacognosy and pharmacological studies
Jana et al. Herbal Treatment To Skin Diseases: A Global Approach.
Chaudhry A handbook of common medicinal plants used in Ayurveda
JP4624263B2 (ja) ツボクサとゴマを含む、脳の強壮剤としての薬草製剤
US7429397B2 (en) Herbal formulation as memory enhancer in Alzheimer condition
Shaikh et al. Medicinal Flora of Poona College
WO2006067796A1 (fr) Formulation galenique servant de stimulateur de la memoire dans la maladie d’alzheimer
Rani et al. Ethnomedicinal, Pharmacological and Phytochemical Screening of Supari (Areca catechu Linn.): A Review
US7344739B2 (en) Anti-allergic herbal formulation
Rajashekharan et al. Ethno-medico-bot anical studies of cheriya arayan-and valiya arayan-(Aristolochia indica, Linn; Aristolochia tagala, Cham)
US7658954B2 (en) Synergistic antipyretic formulation
Rao et al. Indian Medicinal Plants: Uses and Propagation Aspects
Dash et al. Potential medicinal plants of centurion university of technology and management, Bhubaneswar and their medicinal uses
Sherin Nisha Standardization and Pharmacological Screening of Anti-Ulcer, Anti-Inflammatory and Anti-Diarrhoeal Activities of Siddha Formulation of Hingastaga Mathirai in Animals
Nandhini Pre Clinical study of Herbo Mineral Drug MANDOORA VADAGAM for its Haematinic, Hepatoprotective and Anti-Oxidant activities
Samroothul Parveen Hepatoprotective activity of Maavilingapattai Chooranam on CCl4, Paracetamol and Ethanol Induced Hepatotoxicity in In-vivo models

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 1261/DELNP/2005

Country of ref document: IN

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 04816656

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 04816656

Country of ref document: EP

Kind code of ref document: A1

WWW Wipo information: withdrawn in national office

Ref document number: 4816656

Country of ref document: EP