(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(19) World Intellectual Property Organization International Bureau

(43) International Publication Date PCT (10) International Publication Number 26 June 2008 (26.06.2008) WO 2008/074896 Al

(51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 36/185 (2006.01) A61P 25/28 (2006.01) kind of national protection available): AE, AG, AL, AM, A61P 25/00 (2006.01) A61P 25/30 (2006.01) AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, A6IP 25/16 (2006.01) CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (21) International Application Number: IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, PCT/EP2007/064523 LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, (22) International Filing Date: PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, 2 1 December 2007 (21.12.2007) TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 2006/0942 2 1 December 2006 (21.12.2006) IE ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 0705001.6 15 March 2007 (15.03.2007) GB European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, 60/923,084 12 April 2007 (12.04.2007) US FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (71) Applicant and GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor: PRENDERGAST, Patrick T. [IE/AU]; Kenil- worth Station, Byrock, New South Wales 2831 (AU). Published: — with international search report (74) Agent: MURGITRO YD & COMPANY; Unit 1, Block 8, — before the expiration of the time limit for amending the Blanchardstown Corporate Park, Cruiserath Road, Dublin claims and to be republished in the event of receipt of 15, Dublin (IE). amendments

(54) Title: COMPOSITIONS AND METHODS FOR TREATMENT OF CHRONIC NEUROLOGICAL DISORDERS

(57) Abstract: The present invention provides a composition comprising at least one extract of magnolia,or an analogue, derivative, metabolite or pro-drug thereof, and lecithin. The extract of magnolia may be selected from the group consisting of magnolol (5,5'- diallyl-2,2'-dihydroxybiphenyl, 1), honokiol (5,5'-diallyl-2,4'-dihydroxybiphenyl, 2), taspine and asimilobine. The invention further provides a method of treatment of a chronic neurological disorder using the composition of the invention. The chronic neurological disorder for treatment may be selected from, but is not limited to, drug dependence, in particular drug cravings, Alzheimer's disease and Parkinson's disease. COMPOSITIONS AND METHODS FOR TREATMENT OF CHRONIC NEUROLOGICAL DISORDERS

Field of the Invention The present invention relates to compositions and methods for the treatment of chronic neurological disorders. In particular, the present invention provides compositions comprising at least one extract derived from the magnolia plant. The invention further extends to the use of

pharmaceutical compositions comprising at least one magnolia extract in the treatment of drug dependency. The compositions of the present invention have further utility in methods of treatment of chronic neurological disorders such as neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.

Background to the Invention Drug or substance dependence is a disorder caused by various types of addictive substances. The number of individuals suffering from drug dependence is estimated to exceed 30 million worldwide. Furthermore, drug dependence has a detrimental effect on society as a whole due to the number of social problems caused by drug dependence and related organic mental disorders. Thus, there is a worldwide demand for an effective treatment for drug dependence.

There are two types of drug or substance dependency, namely psychological dependence and physical dependence. Psychological dependence is a dependency of the mind referring to a condition wherein an individual possesses a heightened desire and compulsion to take a certain drug. Physical dependence refers to a condition wherein an individual experiences withdrawal symptoms when levels of the drug are depleted in the subject or when the pharmacological effect of the drug weakens or stops.

Most addictive drugs can cause dependence after a single use and once the user is addicted, the symptoms can persist long after the use of the drug is terminated. For these reasons, drug dependency is considered to be a chronic neurological disorder. Furthermore, overdose of such drugs may have a deteriorating effect on the living body and may even cause death.

Examples of substances generally known to cause drug dependency include cocaine, opium (heroin, morphine, etc), alcohols, amphetamine (or amphetamine-like substances), , cannabinoids, hallucinogen, inhalants, nicotine, phencyclidine (or phencyclidine-like substances), sedatives, hypnotic agents and anxiolytic agents. Subjects suffering from drug dependency are often found to be dependent on more than one of these substances.

Addictive drugs/substances are classified into the following types according to the symptoms of their use: morphine type, alcohol type, barbiturate type, amphetamine type, cocaine type, cannabinoid type, organic solvent type and hallucinogen type.

Methamphetamine (also known as Deoxyephedrine, Pervertin, Anadrex, Metamfetamine, Methylamphetamine, meth or crystal meth) is a highly addictive stimulant drug which activates certain systems in the brain. Specifically, methamphetamine acts as a dopaminergic and adrenergic

reuptake inhibitor and as a sympathomimetic. It stimulates the mesolimbic

reward pathway resulting in euphoria and excitement for a user. Users are thus prone to addiction and craving. Methamphetamine rapidly enters the brain and triggers a cascading release of dopamine and norepinephrine, and to a lesser extent serotonin. Users may become obsessed or perform repetitive tasks such as cleaning, hand-washing, or assembling and disassembling objects. Withdrawal is characterised by hypersomnia, polyphagia and depression-like symptoms, often accompanied by anxiety and drug-craving.

From the onset of drug dependence, the role of the Central Nervous

System (CNS) reward system in drug dependence has been examined. The reward system has been identified as the site responsible for

intracranial self stimulation related behaviours in animals and plays a role

in eliciting senses of pleasure, motivation and euphoria. Drug dependence is difficult to treat as many addictive substances stimulate the reward system, thereby eliciting senses of pleasure in users. Furthermore, the influence of such stimulation remains even after the drug is depleted from the body. This system is therefore closely related to cravings and addiction.

The regions of the brain that are closely associated with the reward system are the ventral segmental area (VTA), the nucleus accumbes

(NAc), the locus ceruleus and the medical forebrain bundle. In particular, the dopaminergic system projecting from the VTA to the NAc plays a central role in the activation of the reward system. Dopamine derived from the VTA acts on the nerves of the NAc. Cocaine increases the NAc dopamine level through inhibition of dopamine transporters of nerve cells

in the NAc. Therefore, an increase of dopamine levels in the NAc is implicated in the inductive mechanism of drug dependence, cravings and addiction. Research in the treatment of drug dependence has focused on the use of drugs that target dopamine or other neurotransmitters indirectly related to the dopaminergic nervous system, such as serotonin, GABA, glutamine acid, receptors thereof or intracellular signalling cascades associated with dopamine receptors. However, no investigation of this kind has resulted in the development of any substance which is effective in the treatment of drug dependence, cravings and addiction.

Cocaine or amphetamine dependence is currently treated by psychotherapy. However, the results of treatment with psychotherapy are poor and there is no effective medical therapy available. Treatment with dopamine antagonists or agonists may also be used. However, such treatment has little therapeutic effect. Psychotic disorders induced by cocaine or amphetamine are treated by symptomatic treatment with antipsychotic drugs. Opium or nicotine dependence is treated by symptomatic treatment using alternative substances, such as methadone or nicotine patches. Although such therapy may be effective in the treatment of certain symptoms, the dependency and cravings continue.

The inventor has now surprisingly found that a composition comprising an extract of magnolia formulated with lecithin is surprisingly effective in

reducing or abolishing drug dependence, and in particular cravings for the drug methamphetamine. The inventor has further identified that the foregoing composition also exhibits a surprising effectiveness in the treatment of other chronic neurological diseases, such as Parkinson's disease and Alzheimer's disease.

Summary of the Invention According to a first aspect of the present invention there is provided a composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.

According to a second aspect of the present invention there is provided a pharmaceutical composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin along with at least one pharmaceutically acceptable diluent, carrier or excipient.

According to a third aspect of the present invention there is provided a combined medicament comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.

According to a fourth aspect of the present invention there is provided a method for treatment of a chronic neurological disorder, the method comprising the steps of: - providing a therapeutically effective amount of a composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin; and

- administering the composition to a subject in need of such treatment.

According to a fifth aspect of the present invention there is provided a composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin for use in medicine.

According to a sixth aspect of the present invention there is provided the use of a composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin in the preparation of a medicament for treatment of a chronic neurological disorder.

According to a seventh aspect of the present invention there is provided a composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin for use in treatment of a chronic neurological disorder.

According to an eighth aspect of the invention there is provided a kit for the performance of any one of the foregoing methods of the invention, said kit comprising one or more therapeutically effective amounts of the composition of the invention in a pharmaceutically acceptable form along with instructions for use of the same.

Detailed Description of the Invention The present invention provides a combined medicament comprising at least one extract of magnolia and lecithin. The invention further extends to the use of said combined medicament in the treatment of chronic neurological disorders, such as drug dependence, Parkinson's disease and Alzheimer's disease.

While not wishing to be bound by theory, it is hypothesised that the extract of magnolia can act as an inhibitor. inhibitors are used in the treatment of Alzheimer's disease and other related diseases. Without wishing to be bound by theory, it is further

hypothesised that the present invention is based, at least in part, on the formulation of the extract of magnolia with lecithin allowing improved transport of the magnolia extract into the brain. In particular, the inventor theorizes that formulation of the magnolia extract with lecithin enhances the blood brain barrier permeability of the magnolia extract. The inventor has shown that compositions of the present invention result in the magnolia extract being highly effective for the treatment of drug dependency. The inventor has identified particular magnolia extracts and combinations of extracts which have utility in the treatment of drug dependency and therefore which can be used in the treatment of drug addiction. The inventor has thus employed an approach to the treatment of drug dependence which is substantially different to that taken previously by researchers who have addressed this problem. Specifically, the present inventor focused on the relationship between nucleus accumbes (NAc) acetyl (Ach) levels and the onset of drug dependency, cravings and/or addiction.

The inventor has further identified the surprising utility of the compositions of the present invention in the treatment of other chronic neurological disorders, such as Alzheimer's disease and Parkinson's disease, wherein the compositions suppress, inhibit or improve cognitive impairment, muscular impairment or any other such deterioration which causes a

progression of disease pathology. It has previously been shown that chronic methamphetamine users have markedly depleted dopamine in the non-motor portion of the basal ganglia system. Thus, from a physiological point of view, chronic methamphetamine users may resemble patients with

Parkinson's disease when considered in terms of neurochemical similarities. A therapeutic approach which targets depletion of dopamine

in the non-motor portion of the basal ganglia system may therefore provide a treatment not only for drug addiction, but also for neurological conditions which are characterised, or involve, a depletion of dopamine levels in the non-motor portion of the basal ganglia system as part of the disease pathology, such as has been postulated for Parkinson's disease and Alzheimer's disease. In certain embodiments the composition of the invention comprises, on a dry matter basis, from about 0.01 % to about 90% of said at least one magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, by weight of the composition and from about 10% to 99.99% of lecithin.

In certain embodiments the composition of the present invention has a dry matter weight percentage composition of from about 30.0 to 99.9% magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, and about 0.1 % to 70.0% lecithin.

In certain embodiments, the compositions of the present invention has a weight percentage composition of from about 50.0 to 99.9% magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, and about 0.1 % to 50.0% lecithin.

In certain embodiments the chronic neurological disorder is drug dependence. The compositions of the present invention have particular

utility in the treatment of drug dependence, addiction and cravings and, in

particular, in the treatment of drug dependence caused by at least one substance selected from the group consisting of morphine, alcohol, barbiturate, cocaine and cannabinoid, or organic solvents or derivatives thereof.

In certain embodiments the drug dependence is methamphetamine addiction, including associated cravings for methamphetamine.

In certain embodiments, the drug dependence, addiction and/or cravings are caused by at least one substance selected from the group comprising of a substance defined as, or derived from, morphine, alcohol, barbiturate, cocaine and cannabinoid, or organic solvents or derivatives thereof.

In certain embodiments, the chronic neurological disorder is selected from the group comprising, but not limited to, Parkinson's disease, Alzheimer's disease, mild cognitive impairment (MCI), multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS), Huntington's disease, prion diseases such as CJD, AIDS-related dementia, encephalitis, stroke, head trauma and related chronic neurological disorders.

Suitably the extract of magnolia is derived from any part of a magnolia plant (e.g. Magnolia officianalis), such as the leaf, root, bark, natural exudation of the bark, flower, fruit, stem or branch. Typically, however, the extract is derived from the bark, flower bud or leaf of the magnolia plant.

In various embodiments the magnolia extract can be obtained using water or hydrophilic organic solvents, such as alcohol, or mixtures thereof. For example, a magnolia extract for use in the present invention may be derived from the bark of the Magnolia officianalis plant. In certain embodiments, a composition of the invention may comprise extracts derived from two or more parts of the Magnoli officianalis plant. An extract may be obtained by adding water to a magnolia bark, of fragments thereof, followed by the performance of an extraction process at a temperature of around 50 C for a prescribed duration. The extract is then filtered and concentrated as desired. Alternatively, an alcohol-based extraction method may be used wherein 30% by volume of ethanol is added to magnolia bark. Extraction is performed at a temperature of around 60 C for a prescribed duration. The extract is then filtered and concentrated as required. Alternatively, 60% by volume of ethanol can be added to magnolia bark powder and extraction performed at a temperature of around 1000C for a prescribed duration. The extract is then filtered and concentrated as required. The above extraction methods may also be used for the derivation of an extract from the flower buds of the Magnolia plant.

In certain embodiments the extract is derived from magnolia bark and is commercially available, for example, Magnolia bark P.E . (Xiamen Unilogistics Inc. Guangzhou Branch, China) comprising 50% magnolol

having molecular formula C2oH44Oio and a molecular weight of 444 available as a powder).

In certain embodiments the magnolia extract may be, but is not limited to, at least one of the extracts selected from the group consisting of: magnolol

( '-diallyl^^'-dihydroxybiphenyl, 1), honokiol (5,5'-diallyl-2,4'- dihydroxybiphenyl, 2), taspine and/or asimilobine.

Taspine is an obtainable as an extract from the leaf of magnolia. Asimilobine is also an alkaloid, similar to, for example, Irinidine, which is also obtainable as an extract from the leaf of magnolia and which is a serotonergic receptor.

In certain embodiments the extract of magnolia is taspine or an analogue or synthetic version thereof. In certain embodiments the extract of

magnolia is asimilobine or an analogue or synthetic version thereof. In certain embodiments the extract of magnolia is honokiol or an analogue or synthetic version thereof. In certain embodiments the extract of magnolia is magnolol or an analogue or synthetic version thereof. In certain embodiments of the present invention the composition comprises two or more of magnolol, honokiol, taspine and asimilobine or functionally equivalent analogues or synthetic versions thereof.

Magnolia extract (or extract of magnolia) refers to the magnolia extract on a dry basis without the solvent used in the extraction process. In certain embodiments the total content of magnolia extract present in the compositions is preferably about 0.001 -30 weight (wt) %, more preferably about 0.01 -5 wt%, of the total composition. In certain embodiments the content of each magnolia extract present within the compositions is preferably about 0.001 -50 wt%, more preferably about 0.001 -30 wt%, more preferably about 0.01 -5 wt%, of the total composition.

Typically the magnolia extract is provided in the form of an oil or powder or a mixture thereof. Suitably the composition of the invention may be administered orally. Accordingly in certain embodiments the magnolia extract is provided at around 0.001-50 wt% of the total composition, the compositions further comprising a suitable base which is provided at a suitable wt% to allow oral administration. Typically the composition is oil based.

In certain embodiments the extract of magnolia is chemically

manufactured in order to produce a synthetic version of an extract of magnolia, or a synthetic analogue or derivative thereof which is functionally equivalent to the naturally derived extract.

In various further embodiments the compositions of the invention may further comprise at least one of dihydroxydihdromagnolol and dihydrohonokiol. In a certain embodiments the compositions of the invention may further comprise at least one acetylcholinesterase inhibitor, wherein the acetylcholinesterase inhibitor is selected from the group consisting of, but not limited to, galanthamine, epigalanthanmine norgalanthamine, , hvastigmine and and analogues, salts and derivatives thereof.

As defined herein the term "lecithin" is a synonym for pure phosphatidylcholine, a phospholipid which is the major component of a phosphatide fraction which may be isolated from either egg yolk or soy beans or from mammalian brain tissue from which it is mechanically or chemically extracted using hexane. Lecithin is probably the most common phospholipid. Lecithin may be extracted from soy beans for use as an emulsifying agent in foods. Lecithin is an emulsifier because it has both polar and non-polar properties, which enable it to cause mixing of other fats and oils with water components. Lecithin is also a major component

in the lipid bilayers of cell membranes. Lecithin contains the ammonium salt of choline joined to the phosphate by an ester linkage. The nitrogen

has a positive charge, just as in the ammonium ion. In choline, the nitrogen has the positive charge and four methyl groups attached.

In certain embodiments the composition may comprise olive oil and/or at least one bioflavonoid.

The invention further extends to compositions comprising metabolites, mimetics, derivatives, analogues, solvate forms, pharmaceutically acceptable salts and/or pro-drugs of the magnolia extract. The invention further extends to compositions comprising metabolites, mimetics, derivatives, analogues, solvate forms, pharmaceutically acceptable salts and/or pro-drugs of lecithin. Furthermore, the magnolia extract and/or lecithin may be in the form of an enantiomer or diasterioisomers, wherein the desired functional activity of the compound is maintained. The terms used in the claims encompass all these forms.

Examples of pro-drugs include entities that have certain protected group(s) and which may not possess pharmacological activity as such, but

may, in certain instances, be administered (e.g. orally or parenterally) and thereafter metabolised in the body to form the compounds of the present invention which are pharmacologically active.

As defined herein the term "metabolite" means any substance which results from, or is produced by, or digestion by a subject of a compound administered to said subject. In pharmaceutical terms, the term relates to the product which remains after digestion or metabolism, particularly by the liver, has occurred.

As used herein the term "mimetic" relates to any compound which includes, but is not limited to, a peptide, polypeptide, antibody or other organic chemical which has the same qualitative activity or effect as the magnolia extract and/or lecithin compounds of the invention.

The term "derivative" as used herein includes chemical modified forms of the magnolia extract and/or lecithin, said derivatives retaining the desired chemical activity of these compounds.

Analogues may be provided in a salt, in particular a pharmaceutical salt. As herein defined the expression "pharmaceutically salt" extends to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. A "pharmaceutically acceptable cationic salt" includes, but is not limited to, cationic salts such as the alkali metal salts, for example, sodium or potassium, as well as alkaline earth metal salts, for example magnesium, ammonium salts and the like. A "pharmaceutically acceptable acid addition salt" includes, but is not limited to, salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts.

Pharmaceutically-acceptable salts are well known to those skilled in the art, and for example include those mentioned by Berge et al, in J. Pharm.

Sci. 66,1-1 9 ( 1977). Suitable acid addition salts are formed from acids which form non-toxic salts and include the hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate, bisulphate, phosphate, hydrogenphosphate, acetate, trifluoroacetate, gluconate, lactate, salicylate, citrate, tartrate, ascorbate, succinate, maleate/fumarate, gluconate, formate, benzoate, methanesulphonate, ethanesulphonate, benzenesulphonate and p- toluenesulphonate salts.

The compounds and/or agents of the invention may be prepared by chemical synthesis techniques. It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound and/or agent of the invention. This may be achieved by conventional techniques, for example as described in "Protective Groups in Organic Synthesis" by T W Greene and

P G M Wuts, John Wiley and Sons lnc.(1 991 ), and by P.J. Kocienski, in

"Protecting Groups", Georg Thieme Verlag ( 1 994).

It is possible during some of the reactions that any stereocentres present could, under certain conditions, be epimerised, for example if a base is used in a reaction with a substrate having an optical centre comprising a

base-sensitive group. It should be possible to circumvent potential problems such as this by choice of reaction sequence, conditions, reagents, protection/deprotection regimes and the like as these are well known in the art.

In certain embodiments the composition is a combined medicament comprising extract of magnolia and lecithin.

The term "combined medicament" as used herein defines a "kit of parts" in the sense that the combination partners, i.e. (a) a magnolia extract and (b) lecithin, can be dosed independently either simultaneously or at different time points or can be used together as different fixed combinations with distinguished amounts of each of the combination partners (a) and (b). The parts of the kit of parts can therefore be administered simultaneously, sequentially or separately, for example chronologically staggered at different time points with equal or different time intervals for any part of the kit of parts.

Typically the time intervals of the administration and the dosage forms are chosen such that the effect on the treated disorder is larger than the effect which would be obtained by use of only any one of the combination partners (a) and (b). The ratio of the total amounts of the combination partner (a) to the combination partner (b) in the combined medicament can

be varied, for example, in order to cope with the needs of a subject to be treated.

Typically the amount of the magnolia extract and lecithin is selected such that a synergism results from the administration of both parts, the synergism being an effect which is more than an additive effect resulting from use of each of the magnolia extract and lecithin individually. Further advantages may be the reduction in side effects or reduction in effective dosage of one or both parts.

In various further aspects, the present invention further extends to a pharmaceutical pack comprising one or more compartments wherein at least one compartment comprises one or more of the compounds as defined herein, or a composition, combined medicament or medicament as defined herein.

The present invention further extends to compositions of the present invention which further comprise at least one or of galanthamine, epigalanthanmine norgalanthamine, donepezil, and tacrine, and analogues, salts and derivates thereof. Methods for the administration of such compositions are further provided by the present invention. Such methods may comprise the simultaneous or sequential administration of the compositions of the present invention with at least one or more compounds selected from the group consisting of galanthamine, epigalanthanmine norgalanthamine, donepezil, rivastigmine and tacrine, and analogues, salts and derivates thereof.

In certain embodiments the pharmaceutical composition of the invention is an orally administrable formulation. Suitably the pharmaceutically acceptable diluent, carrier or excipient is selected depending upon the intended route of administration. The pharmaceutically acceptable diluent, carrier or excipient should be non-toxic and should not interfere with the efficacy of the magnolia extract.

When administered by means of the oral route, the composition may assume a variety of suitable dosage forms which include, but are not limited to a tablet, capsule, liquid, microemulsion, powder, gel capsule, soft gel capsule, sustained release formula, enema or syrup. A tablet may comprise a solid carrier such as gelatine. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included.

Alternatively the composition may be administered parenterally (including subcutaneous, intramuscular, intravenous routes), or by other suitable routes of administration which may include, but which are not limited to, rectal, topical (including buccal and sublingual), vaginal, intradermal or administration via oral or nasal inhalation, by means of, for example a nebuliser or inhaler. The dosage form of the composition will be provided

in a form suitable for the intended route of administration and appropriate pharmaceutically acceptable carriers and diluents can further be selected according to the dosage form when formulating the product.

In certain embodiments the composition may be formulated with specific lipids which enhance brain delivery of the magnolia extract. The composition may also be administered via microspheres, liposomes, other microparticulate delivery systems or sustained release formulations.

Examples of the techniques and protocols mentioned above and other techniques and protocols which may be used in accordance with the

invention can be found in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A.R., Lippincott Williams & Wilkins; 20th edition (December 15, 2000) ISBN 0-91 2734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, H .C. et al. 7th Edition ISBN 0- 683305-72-7 the entire disclosures of which are herein incorporated by reference. The composition is preferably provided to a subject in a "therapeutically effective amount", this being sufficient to show benefit to the subject. The

benefit may be in the form of amelioration or reduction of drug dependence, for example a reduction in frequency and/or severity of cravings.

The actual amount administered, and rate and time-course of administration will depend on, and can be determined with due reference to, the nature and severity of the condition which is being treated, as well as factors such as the age, sex and weight of the patient to be treated and the route of administration.

Dosage regimens can include a single administration of the composition of the invention, or multiple administrative doses of the composition. The compositions can further be administered sequentially or separately with other therapeutics and medicaments which are used for the treatment of chronic neurological disorders, such as drug dependence.

As herein defined, the term "drug dependence", or associated terms such as "drug dependency" or "drug dependent", means that a subject has a chronic neurological disorder which manifests itself as the subject being a compulsive user of a substance which results in negative consequences. These terms encompass drug addiction, wherein a subject desires or craves a regular intake of a drug. Typically use of the drug upon which the subject is dependent results in drug abuse, that is excessive use of a drug, or use of a drug for a purpose other than that for which it was prescribed and/or medically intended. Physical dependence on a substance, for example where a therapeutic drug is required by a subject for treatment of a defined medical need or condition, is not necessarily sufficient to define an addiction or drug dependence as used herein. Further, the term "drug dependence" also encompasses further associated conditions, such as cravings caused by addiction to drugs or related or associated substances. The term "drug dependence" further encompasses "substance related disorders" based on the criterion of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) of the American Psychiatric Association, including substance use disorders and substance induced disorders.

The term "cravings", or associated terms such as "craves" and "craving", refers to a subject's desire for intake of a drug or substance.

The term "addiction" refers to a state of physiological and/or psychological dependence on a drug. Addiction encompasses cravings for the drug.

The term "treatment" is used herein to refer to any regime that can benefit a human or non-human animal. The treatment may be in respect of an existing condition or may be prophylactic (preventative treatment). Treatment may include curative, alleviative or prophylactic effects.

Unless otherwise defined, all technical and scientific terms used herein

have the meaning commonly understood by a person who is skilled in the art in the field of the present invention.

Throughout the specification, unless the context demands otherwise, the terms "comprise" or "include", or variations such as "comprises" or "comprising", "includes" or "including" will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers. As used herein, the term "subject" refers to an animal, preferably a mammal and in particular a human. The term "subject" is interchangeable with the term "patient" as used herein.

As used herein terms such as "a", "an" and "the" include singular and plural referents unless the context clearly demands otherwise. Thus, for example, reference to "a composition" includes a single composition as well as two or more different compositions in combination.

The present invention will now be described with reference to the following examples, which are provided for the purpose of illustration and are not intended to be construed as being limiting on the present invention.

EXAMPLES Example 1 - Exemplification of technique for obtaining magnolia extract The form of the compositions of the present invention will depend upon the intended route of administration of the composition. The extraction

method used to obtain the magnolia extract for use in the composition of the present invention is determined by the plant tissue from which the extract is obtained. Suitable extraction methods will be well known to those skilled in the art and include any conventional methods used in the field. These include, but are not limited to, solvent extraction, steam or dry distillation, cold pressing and hyperbaric extraction. Details of these

procedures are well known in the art and outlines of the procedures involved are provided below.

(a) Solvent extraction Solvents, such as chloroform-methanol, hot ethanol, hexane, petroleum ether, propanone, ethyl ethanoate or perchloric acid, are used to dissolve components of a sample of plant tissue. The solvents are then evaporated, leaving a residue which contains the plant extracts. The

residue can then be dissolved in alcohol which, when removed, leaves the extracts.

Non-limiting examples of suitable solvents for use in solvent-based extraction include, but are not limited to, aqueous solvents (e.g. water, acidic or basic aqueous solvents, etc.), alcohols (e.g. lower alcohols, such as methanol, absolute ethanol, ethanol, or polyhydric alcohols, such as propylene glycol, 1,3-butylene glycol, etc.), ketones such as acetone, diethyl ether, dioxane, acetonithle, esters, such as ethyl acetate, and organic solvents, such as xylene, benzene and chloroform. These may be

used either singly or in the form of a mixture of two or more. In certain embodiments water, methanol, ethanol and 50% ethanol are preferred.

Two or more solvent extracts may be used in combination in the compositions of the present invention.

Examples of suitable methodology for solvent-based extraction has been provided herein-before. A further suitable method, and a variation to the methods provided hereinbefore, includes the steps of (i) finely grounding magnolia bark, (ii) adding 5 to 10 times (by weight) of an extracting solution, for example water, alcohol, organic solvent or a mixture thereof, (iii) allowing the mixture to stand at room temperature for at least one week, (iv) filtering the extract, (v) lyophilizing the extract and (vi) using the

lyophilised product in a composition of the present invention. Alternatively, an extracting solvent (such as water or an organic solvent) is added to the magnolia material and, after a certain period of digestion or heating at the refluxing temperature of the solvent, the mixture is filtered and the filtrate is concentrated to dryness. In formulating the compositions of the invention, the magnolia extract(s) may be used as such, or may be admixed with compositions such as diluents, excipients or carrier which permits for oral administration.

(b) Steam distillation Typically steam (often superheated at high pressures) is passed through a sample of plant tissue. The components to be extracted are drawn into the steam, which is then condensed to precipitate out the extract and the distilled water. Aqueous extracts may also be contained in the distilled water phase. When lower heats are used, larger molecules can be extracted from the plant tissue.

(c) Dry distillation This method is generally used to extract high boiling point components from wood. A sample of plant tissue is heated to release the desired extracts by evaporation from the tissue. The evaporated extracts are then obtained by condensation.

(d) Cold pressing A sample of plant tissue is cut and then ground. Pressing of the ground tissue releases components of the tissue, thus releasing the extracts.

(e) Hyperbaric extraction This method uses high-pressure carbon dioxide. The high pressure causes the carbon dioxide to liquefy. Volatile components of a sample of plant tissue form a solution with the liquefied carbon dioxide. The extracts are obtained when the carbon dioxide is de-pressurised such that the gas evaporates leaving a mixture of plant extracts. The magnolia extract used in the present invention can be obtained by adding water to thinly sliced magnolia and extracting at 50 C for a prescribed duration, filtering the extract and concentrating it as desired. Alternatively, 30 vol % ethanol can be added to thinly sliced magnolia and extraction carried out at 60 C for a prescribed duration. The extract is then filtered and concentrated as desired. Also, 60 vol% ethanol can be added to magnolia powder and extraction carried out at 100°C for a prescribed duration, before filtering the extract and concentrating it as desired.

Example 2 - Exemplification of technique for preparation of compositions The first step in the preparation of the compositions of the present invention involves a process for making the plant material suitable for mixing with lecithin and optionally incorporating into a base, wherein the base is appropriate to the intended route of administration.

The specified portion of the plant is collected and dried under shade at

room temperature in an enclosed room for 72 hours or more until the material is dry. A specified amount of material is then extracted with solvents, such as n-hexane, chloroform, ethanol, methanol and/or water,

in cold/hot conditions. The choice of the solvent depends upon the type of material expected at the end of extraction process.

The extraction process is carried out in a closed container immersing specified amounts of the plant material in respective solvents for 72 hours. At the end of this stage, the solvent is decanted and filtered if necessary to remove any plant debris. The solvent is then concentrated by evaporating under vacuum at room temperature. If the solvent used is water, the concentrated solution is freeze-dhed to obtain the final product in powder form. If the solvent used is a non-polar solvent, the final product is an oily and viscous substance with specific physico-chemical properties.

This final product is made into a formulation intended for oral use by using it as an ingredient for making a tablet, powder, liquid or gel capsule.

More specifically, the magnolia extract(s) may be used as such or may be admixed with inter alia known medicinally acceptable bases or additives suitable for oral administration, including for example, water, alcohols, oleaginous substances, surfactants, preservatives, perfumes, colorants, humectants, thickening agents, water-soluble polymers, antioxidants, chelating agents, pH adjusting agents, vitamins, amino acids, antimicrobial agents, algae extracts, various drugs, additives and so forth.

As discussed above, techniques for formulating extracts into compositions suitable for oral administration are well known to persons skilled in the art.

Further guidance can be found in Remington's Pharmaceutical Sciences, 18th edition, Gennaro, A .R., Lippincott Williams & Wilkins; 20th edition (December 15, 2000) ISBN 0-91 2734-04-3 and Pharmaceutical Dosage Forms and Drug Delivery Systems; Ansel, H.C. et al. 7th Edition ISBN 0- 683305-72-7 the entire disclosures of which are herein incorporated by reference.

Example 3 - Administration of compositions of the present invention to subjects with drug dependence Magnolia extract comprising magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl,

1), honokiol (5,5'-diallyl-2,4'-dihydroxybiphenyl, 2), taspine or asimilobine formulated along with lecithin was administered to methamphetamine addicts. It was found that administration completely freed the addicts from cravings for methamphetamine within 20 to 30 minutes of administration. Taspine and asimilobine alone in lecithin proved more effective than magnolol or

honokiol in lecithin. The order of effectiveness at reducing cravings was taspine, followed by asimilobine, followed by honokiol, followed by magnolol.

The compositions of the present invention are effective in the treatment of symptoms of both psychological and/or physical drug dependence and sensitisation (reverse tolerance), and hence have utility in a wide range of treatments.

All documents referred to in this specification are herein incorporated by reference. Various modifications and variations to the described embodiments of the inventions will be apparent to those skilled in the art without departing from the scope of the invention. Although the invention

has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes of carrying out the invention which are obvious to those skilled in the art are intended to be covered by the present invention. Claims 1. A composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.

2 . A composition as claimed in claim 1 wherein the composition comprises, on a dry matter basis, from about 0.01 % to 90% of said at least one magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, by weight of the composition and from about 10% to 99.99% of lecithin.

3 . A composition as claimed in claim 1 wherein the composition comprises dry matter weight percentage composition of from 30.0 to 99.9% magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, and 0.1 % to 70.0% lecithin.

4 . A composition as claimed in claim 1 wherein the composition comprises a weight percentage composition of from about 50.0 to 99.9% magnolia extract, or analogue, derivative, metabolite or pro-drug thereof, and about 0.1 % to 50.0% lecithin.

5 . A composition as claimed in any one of claims 1 to 4 wherein the extract of magnolia is selected from at least one of the group consisting of: magnolol, honokiol, taspine and asimilobine.

6 . A composition as claimed in any preceding claim wherein the extract of magnolia, or analogue, derivative, metabolite or pro-drug thereof is chemically manufactured.

7 . A composition as claimed in any preceding claim wherein the composition comprises dihydroxydihdromagnolol and/or dihydrohonokiol. 8 . A composition as claimed in any preceding claim wherein the composition further comprises olive oil.

9 . A composition as claimed in any preceding claim wherein the composition further comprises at least one bioflavonoid.

10 . A composition as claimed in any preceding claim wherein the composition comprises an acetylcholinesterase inhibitor selected from the group consisting of galanthamine, epigalanthanmine norgalanthamine, donepezil, rivastigmine and tacrine.

11. A composition as claimed in any preceding claim wherein the composition is a pharmaceutical composition and further comprises at least one pharmaceutically acceptable diluent, carrier or excipient.

12 . A method for treatment of a chronic neurological disorder, the method comprising the steps of: - providing a therapeutically effective amount of a composition according to any of claims 1 to 11; and

- administering the composition to a subject in need of treatment.

13 . A method as claimed in claim 12 wherein the chronic neurological disorder is selected from the group consisting of drug dependence, Parkinson's disease, Alzheimer's disease, mild cognitive impairment, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's disease, prion diseases, AIDS-related dementia, encephalitis, stroke and head trauma. 14. A method as claimed in claim 13 wherein the chronic neurological disorder is drug dependency.

15 . A method as claimed in claim 14 wherein the drug dependency is

manifested in a subject as craving for a particular drug compound.

16 . A method as claimed in claim 14 or 15 wherein the drug is methamphetamine.

17 . A method as claimed in claim 13 wherein the chronic neurological disorder is Alzheimer's disease or Parkinson's disease.

18 . A composition according to any one of claims 1 to 11 for use in medicine.

19 . A composition according to any one of claims 1 to 11 for use in the treatment of a chronic neurological disorder.

20. A composition as claimed in claim 19 wherein the chronic neurological disorder is selected from the group consisting of drug dependence, Parkinson's disease, Alzheimer's disease, mild cognitive impairment, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's disease, prion diseases, AIDS-related dementia, encephalitis, stroke and head trauma.

2 1 . A composition as claimed in claim 20 wherein the chronic neurological disorder is drug dependence.

22. A composition as claimed in claim 2 1 wherein the drug dependence

is manifested in a subject as craving for a particular drug compound. 23. A composition as claimed in claim 2 1 or 22 wherein the drug is methamphetamine.

24. A composition as claimed in claim 19 wherein the chronic neurological disorder is Alzheimer's disease or Parkinson's disease.

25. Use of a composition according to any one of claims 1 to 11 in the preparation of a medicament for treatment of a chronic neurological disorder.

26. Use as claimed in claim 25 wherein the chronic neurological disorder is selected from the group consisting of drug dependence, Parkinson's disease, Alzheimer's disease, mild cognitive impairment, multiple sclerosis, Amyotrophic lateral sclerosis, Huntington's disease, prion diseases, AIDS-related dementia, encephalitis, stroke and head trauma.

27. Use as claimed in claim 25 wherein the chronic neurological disorder is drug dependence.

28. Use as claimed in claim 27 wherein the drug dependence is manifested in a subject as craving for a particular drug compound.

29. Use as claimed in claim 27 or 28 wherein the drug is methamphetamine.

30. Use as claimed in claim 25 wherein the chronic neurological disorder is Alzheimer's disease or Parkinson's disease. 3 1 . A combined medicament comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.

32. A combined medicament as claimed in claim 3 1 wherein the extract of magnolia, or analogue, derivative, metabolite or pro-drug thereof, is chemically manufactured.

33. A combined medicament as claimed in claim 3 1 or 32 wherein the extract of magnolia is selected from at least one of the group consisting of magnolol, honokiol, taspine and asimilobine.

34. A combined medicament as claimed in any one of claims 3 1 to 33 wherein the composition comprises dihydroxydihdromagnolol and/or dihydrohonokiol.

35. A combined medicament as claimed in any one of claims 3 1 to 34 wherein the composition comprises olive oil.

36. A combined medicament as claimed in any one of claims 3 1 to 35 wherein the composition comprises at least one bioflavonoid.

37. A combined medicament as claimed in any one of claims 3 1 to 36 wherein the composition comprises at least one acetylcholinesterase inhibitor wherein the acetylcholinesterase inhibitor is selected from the group consisting of galanthamine, epigalanthanmine norgalanthamine, donepezil, rivastigmine and tacrine. A. CLASSIFICATION OF SUBJECT MATTER INV. A61K36/185 A61P25/00 A61P25/16 A61P25/28 A61P25/30

According Io International Patent Classification (IPC) or to both national classification and IPC

B FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K

Documentation searched other than minimum documentation to the extent that such documents are included in lhe fields searched

Electronic data base consulted during the international search (name of data base and where practical search terms used) EPO-Internal, WPI Data, BIOSIS, CHEM ABS Data, PAJ

C DOCUMENTS CONSIDERED TO BE RELEVANT

Category' Citalion of document with indication where appropriate of the relevant passages Relevant Io claim No

WO 2004/000235 A (WRIGLEY W M JUN CO [US]; 1,5,31, MAXWELL JAMES ROY [US]; GREENBERG MICHAEL 33 J [ ) 3 1 December 2003 (2003-12-31) claims 1,18-20,30,31,41 page 7 , paragraph 4 1

US 2005/147631 A l (GOLDSTEIN MINDY S [US] 1,31 ET AL) 7 July 2005 (2005-07-07) claims 1,4 page 4 ; example 1 page 3 , paragraph 35

WO 2005/089803 A (BOEHRINGER INGELHEIM INT 1,31 [DE]; BOEHRINGER INGELHEIM PHARMA [DE]; HAYAS) 29 September 2005 (2005-09-29) claims 1,3,21

-/--

Further documents are listed in lhe continuation of Box C See patent family annex

Special categories of αled documents 'T' later document published after the international filing dale 1 or priority dale and not in conflict with the application bul "A document defining the general state of the art which is not cited to understand the principle or theory underlying the considered Io be of particular relevance invention 1 E earlier document bul published on or after the international • X# document of particular relevance the claimed invention filing date cannol be considered novel or cannol be considered to ' L1 document which may throw doubts on pπoπly claιm(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another "Y" document of particular relevance lhe claimed invention cilation or other special reason (as specified) cannol be considered to involve an inventive step when the 1O" documenl referring to an oral disclosure use exhibition or document is combined with one or more other such docu¬ other means ments such combination being obvious Io a person skilled 'P" document published prior Io the inlernational filing dale but in lhe art later than the priority dale claimed • &• document member of lhe same patent family

Dale of the actual completion of the international search Dale of mailing of the international search report

19 May 2008 04/06/2008

Name and mailing address of the ISA/ Authorized officer European Patent Office P B 5818 Palentlaan 2 NL - 2280 HV Ri|swi|k TeI (+31 -70) 340-2040 Tx 3 1 651 epo nl Fax (+31-70) 340-3016 Rodri go-Si mόn , Ana

Form PCT/ISA/210 (second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category * Citation of document with indication, where appropriate, of the relevant passages Relevant Io claim No

X US 2004/081713 Al (MAXWELL JAMES ROY -[US] 1 ,5 , 7 , ET AL) 29 Apri l 2004 (2004-04-29) 3 1 , 33 c l aims 1 , 18-20,30, 3 1 , 4 1 page 7 , paragraph 4 1

X US 2006/045896 Al (MORARIU MARIUS [US] ) 1 , 5 , 2 March 2006 ( 2006-03-02) 9-11 , 3 1 , 33 page 8 , paragraph 67 c l aims 1 , 5 page 10, paragraph 78 c l aims 14 , 15 page 13, paragraph 105 page 13, paragraph 106 page 13, paragraph 18

Y US 2006/074108 Al (GUPTA SHYAM K [US] ) 2-4 ,6-8, 6 Apri l 2006 (2006-04-06) 12-30, 32 , 34, 35 c l aims 1 ,22 page 19, paragraphs 236, 241 page 2 , paragraph 46 page 12, paragraph 182

Y US 5 916 919 A (XU HONG-XI [CA] ET AL) 2-4 ,6-8, 29 June 1999 ( 1999-06-29) 12-30, 32 , 34, 35 col umn 1 , l i nes 5,6 col umn 3 , l i ne 37 col umn 7 , l i ne 29

Y US 2005/129783 Al (MCCLEARY EDWARD L [US] 2-4 ,6-8, ET AL ) 16 June 2005 (2005-06-16) 12-30, 32 , 34, 35 c l aims 1 , 13 page 1 , paragraph 6

A , P WO 2007/011504 A (WRIGLEY W M JUN CO [US] ; 1-37 DODDS MICHAEL WILLIAM JAMES [US] ; MAXWELL JAM) 25 January 2007 (2007-01-25) the whole document

A , P WO 2007/011674 A (BAKER DONALD J [US] ) 1-37 25 January 2007 (2007-01-25) the whole document

A , P WO 2007/067340 A (GIC INNOVATIONS COMPANY 1-37 [US] ; DODDS MICHAEL [US] ; MAXWELL JAMES [US] ; ) 14 June 2007 (2007-06-14) the whole document

Y US 3 694 557 A (PERSINOS GEORGIA J ) 2-4,6-8, 26 September 1972 ( 1972-09-26) 12-30, 32 , 34, 35 c l aim 1

-/--

Form PCT/ISA/210 (oonlinualion of second sheet) (April 2005) C(Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT

Category' Citation ot document, with indication, where appropriate, of the relevant passages Relevant Io claim No

Y US 5 156 847 A ( LEWIS WALTER H [US] ET AL) 2-4 ,6-8, 20 October 1992 ( 1992-10-20) 12-30, 32, 34, 35 cl aim 1

Y HASRAT JA ET AL: "Isoqui nol i ne 2-4 ,6-8, deri vati ves i sol ated from the fruit of 12-30, Annona muricata as 5-HTergic 5-HT1A 32 , 34, 35 receptor agoni sts i n rats : unexpl oited antidepressi ( lead ) products" JOURNAL OF PHARMACY AND PHARMACOLOGY , LONDON, vol . 49, no . 11 , 1 January 1997 ( 1997-01-01 ) , pages 1145-1149, XP009099939 ISSN : 0022-3573 Abstract , 3 the whole document

Y KIM YK ET AL: "Cytotoxic components from 2-4,6-8, stem bark o f Magnol i a obovata" 12-30, PLANTA MEDICA, THIEME , STUTTGART , DE , 32, 34, 35 vol . 65, no. 3 , 1 Apri l 1999 ( 1999-04-01 ) , pages 291-292 , XP009099954 ISSN: 0032-0943 page 1 , col umn 2 , paragraph 3

Y DATABASE WPI Week 199731 2-4,6-8, Derwent Publ icati ons Ltd . , London , GB ; AN 12-30, 1997-333303 32, 34, 35 XP002480658 & CN 1 106 267 A ( LUO G) 9 August 1995 ( 1995-08-09 ) abstract

Y DATABASE WPI Week 199745 2-4,6-8, Derwent Publ icati ons Ltd . , London , GB ; AN 12-30, 1997-480904 32, 34, 35 XP002480659 & CN 1 120 449 A ( LUO G) 17 Apri l 1996 ( 1996-04-17) abstract

Y DATABASE WPI Week 199528 2-4,6-8, Derwent Publ icati ons Ltd . , London , GB; AN 12-30, 1995-207358 32 , 34, 35 XP002480660 & CN 1 084 070 A (WANG G) 23 March 1994 ( 1994-03-23) abstract

Form PCT/ISA/210 (coπtinualion Ol second she βl ) (April 200S) C(Cont ιnuatcon) DOCUMENTS CONSIDERED TO B E RELEVANT

Category' Citation of document with indication where appropriate of the relevant passages Relevant Io claim No

A , P DATABASE WPI Week 200751 1, 5 , 31 . Derwent Publ ications Ltd . , London , GB ; AN 33 2007-514355 XP002480661 & CN 1 895 237 A (UNIV SICHUAN) 17 January 2007 (2007-01-17) abstract

Y DATABASE WPI Week 200676 2-4 ,6-8, Derwent Publ i cati ons Ltd . , London , GB; AN 12-30, 2006-737416 32, 34, 35 XP002480662 & KR 2005 111 256 A ( REPUBLIC KOREA) 24 November 2005 (2005-11-24 ) abstract

Y DATABASE WPI Week 199101 2-4 ,6-8, Derwent Publ i cati ons Ltd . , London , GB ; AN 12-30, 1991-003143 32 , 34, 35 XP002480663 & J P 02 279650 A (OTSUKA PHARM CO LTD) 15 November 1990 ( 1990-11-15) abstract

Y DATABASE WPI Week 199817 2-4 ,6-8, Derwent Publ icati ons Ltd. , London , GB ; AN 12-30, 1998-189153 32 , 34 , 35 XP002480664 & J P 10 045573 A (KUREHA CHEM IND CO LTD) 17 February 1998 ( 1998-02-17) abstract

Y DATABASE WPI Week 199127 2-4 ,6-8, Derwent Publ ications Ltd . , London , GB ; AN 12-30, 1991-196394 32 , 34, 35 XP002480665 & J P 03 120214 A (KURARAY CO LTD) 22 May 1991 ( 1991-05-22) abstract

X DATABASE WPI Week 200301 1, 3 1 Derwent Publ ications Ltd . , London , GB; AN 2003-003776 XP002480666 & J P 2002 226322 A (KINOSHITA M) 14 August 2002 (2002-08-14) abstract

X DATABASE WPI Week 199545 1, 3 1 Derwent Publ icati ons Ltd . , London , GB ; AN 1995-345074 XP002480667 & CN 1 094 895 A (HUAXING MATERIA MEDICA INST) 16 November 1994 ( 1994-11-16) abstract

Form PCT/ISA/210 (oontinualion ol second sheet) (April 2005) C(Contιnuatιon) DOCUMENTS CONSIDERED TO BE RELEVANT

Category' Citation of document with indication where appropriate of lhe relevant passages Relevant to claim No

SHOJI NOBURU ET AL.: "Asimi lobine and 2-4,6-8, liniridine, serotonergic receptor 12-30, antagonists from NeI umbo nucifera" 32,34,35 JOURNAL OF NATURAL PRODUCTS, 1987, page 773, XP002480657 the whole document

Form PCT/ISA/210 (oonlinualion ol second sheet) (April 2005) Patent document Publication Patent family Publication cited in search report date member(s) date

WO 2004000235 A 31-12-2003 AU 2003279300 Al 06-01-2004 AU 2003279301 Al 06-01-2004 CA 2489949 Al 31-12-2003 CA 2493839 Al 31-12-2003 CN 1662220 A 31-08-2005 EP 1551367 A2 13-07-2005 EP 1515690 A2 23-03-2005 WO 2004000234 A2 31-12-2003

US 2005147631 Al 07-07-2005 NONE

WO 2005089803 A 29-09-2005 A R 049876 Al 13-09-2006 J P 2007530481 T 01-11-2007

US 2004081713 Al 29-04-2004 US 2006013779 Al 19-01-2006 US 2008107610 Al 08-05-2008

US 2006045896 Al 02-03-2006 NONE

US 2006074108 Al 06-04-2006 NONE

US 5916919 A 29-06-1999 NONE

US 2005129783 Al 16-06-2005 NONE

WO 2007011504 A 25-01-2007 AU 2006270385 Al 25-01-2007 CA 2614988 Al 25-01-2007 EP 1901704 Al 26-03-2008

WO 2007011674 A 25-01-2007 CA 2615444 Al 25-01-2007

WO 2007067340 A 14-06-2007 NONE

US 3694557 A 26-09-1972 NONE

US 5156847 A 20-10-1992 NONE

CN 1106267 A 09-08-1995 NONE

CN 1120449 A 17-04-1996 NONE

CN 1084070 A 23-03-1994 NONE

CN 1895237 A 17-01-2007 NONE

K R 2005111256 A NONE

J P 2279650 A 15-11-1990 NONE

J P 10045573 A 17-02-1998 NONE

J P 3120214 A 22-05-1991 NONE

J P 2002226322 A 14-08-2002 NONE

CN 1094895 A 16-11-1994 NONE

Form PCT/ISA/210 (pal βnl lamily annex) (April 2005)