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WO2008074896A1 - Compositions et procédés de traitement de troubles neurologiques chroniques - Google Patents

Compositions et procédés de traitement de troubles neurologiques chroniques Download PDF

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Publication number
WO2008074896A1
WO2008074896A1 PCT/EP2007/064523 EP2007064523W WO2008074896A1 WO 2008074896 A1 WO2008074896 A1 WO 2008074896A1 EP 2007064523 W EP2007064523 W EP 2007064523W WO 2008074896 A1 WO2008074896 A1 WO 2008074896A1
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Prior art keywords
composition
drug
disease
magnolia
extract
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Ceased
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PCT/EP2007/064523
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English (en)
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Patrick T. Prendergast
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Individual
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Priority claimed from IE20060942A external-priority patent/IE20060942A1/en
Priority claimed from GB0705001A external-priority patent/GB0705001D0/en
Application filed by Individual filed Critical Individual
Publication of WO2008074896A1 publication Critical patent/WO2008074896A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A61K36/575—Magnolia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence

Definitions

  • the present invention relates to compositions and methods for the treatment of chronic neurological disorders.
  • 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.
  • 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.
  • 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.
  • 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.
  • Examples of substances generally known to cause drug dependency include cocaine, opium (heroin, morphine, etc), alcohols, amphetamine (or amphetamine-like substances), caffeine, 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 overwhelmed 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.
  • the central Nervous 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.
  • VTA ventral segmental area
  • NAc the locus ceruleus and the medical forebrain bundle.
  • 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.
  • 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.
  • compositions 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.
  • composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.
  • 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.
  • a combined medicament comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin.
  • a method for treatment of a chronic neurological disorder comprising the steps of:
  • composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin;
  • composition a subject in need of such treatment.
  • composition comprising at least one extract of magnolia, or an analogue, derivative, metabolite or pro-drug thereof, and lecithin for use in medicine.
  • 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.
  • 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.
  • kits for the performance of any one of the foregoing methods of the invention 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.
  • 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.
  • the extract of magnolia can act as an acetylcholinesterase inhibitor. Acetylcholine inhibitors are used in the treatment of Alzheimer's disease and other related diseases.
  • 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.
  • the inventor theorizes that formulation of the magnolia extract with lecithin enhances the blood brain barrier permeability of the magnolia extract.
  • 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.
  • the present inventor focused on the relationship between nucleus accumbes (NAc) acetyl choline (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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the drug dependence is methamphetamine addiction, including associated cravings for methamphetamine.
  • 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.
  • 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.
  • MCI mild cognitive impairment
  • MS multiple sclerosis
  • ALS Amyotrophic lateral sclerosis
  • Huntington's disease prion diseases such as CJD, AIDS-related dementia, encephalitis, stroke, head trauma and related chronic neurological disorders.
  • 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.
  • a magnolia plant e.g. Magnolia officianalis
  • the extract is derived from the bark, flower bud or leaf of the magnolia plant.
  • the magnolia extract can be obtained using water or hydrophilic organic solvents, such as alcohol, or mixtures thereof.
  • a magnolia extract for use in the present invention may be derived from the bark of the Magnolia officianalis plant.
  • 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 0 C for a prescribed duration. The extract is then filtered and concentrated as desired.
  • 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 0 C for a prescribed duration.
  • the extract is then filtered and concentrated as required.
  • 60% by volume of ethanol can be added to magnolia bark powder and extraction performed at a temperature of around 100 0 C 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.
  • 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 C2oH 44 Oio and a molecular weight of 444 available as a powder).
  • 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 alkaloid 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.
  • 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 refers to the magnolia extract on a dry basis without the solvent used in the extraction process.
  • 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.
  • 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.
  • magnolia extract is provided in the form of an oil or powder or a mixture thereof.
  • the composition of the invention may be administered orally.
  • 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.
  • the composition is oil based.
  • 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.
  • compositions of the invention may further comprise at least one of dihydroxydihdromagnolol and dihydrohonokiol.
  • 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, donepezil, hvastigmine and tacrine and analogues, salts and derivatives thereof.
  • 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.
  • the nitrogen In choline, the nitrogen has the positive charge and four methyl groups attached.
  • 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.
  • 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.
  • 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.
  • the term "metabolite” means any substance which results from, or is produced by, metabolism or digestion by a subject of a compound administered to said subject.
  • the term relates to the product which remains after digestion or metabolism, particularly by the liver, has occurred.
  • magnolia extract and/or lecithin compounds of the invention 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.
  • 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.
  • pharmaceutically salt extends to both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • 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.
  • 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.(1991 ), and by P.J. Kocienski, in “Protecting Groups", Georg Thieme Verlag (1994).
  • 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.
  • composition is a combined medicament comprising extract of magnolia and lecithin.
  • kits 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.
  • 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.
  • 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.
  • 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.
  • compositions of the present invention which further comprise at least one or of galanthamine, epigalanthanmine norgalanthamine, donepezil, rivastigmine 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.
  • the pharmaceutical composition of the invention is an orally administrable formulation.
  • 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.
  • the composition 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.
  • 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.
  • 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.
  • 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.
  • compositions are 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.
  • drug dependence 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.
  • drug addiction wherein a subject desires or craves a regular intake of a drug.
  • 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.
  • drug dependence also encompasses further associated conditions, such as cravings caused by addiction to drugs or related or associated substances.
  • 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
  • cravings or associated terms such as “craves” and “craving”, refers to a subject's desire for intake of a drug or substance.
  • Addiction refers to a state of physiological and/or psychological dependence on a drug. Addiction encompasses cravings for the drug.
  • 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.
  • 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.
  • 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.
  • composition includes a single composition as well as two or more different compositions in combination.
  • 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.
  • 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.
  • aqueous solvents e.g. water, acidic or basic aqueous solvents, etc.
  • 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.
  • an extracting solution for example water, alcohol, organic solvent or a mixture thereof
  • an extracting solvent such as water or an organic solvent
  • 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.
  • 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.
  • 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.
  • 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 0 C for a prescribed duration, filtering the extract and concentrating it as desired.
  • 30 vol % ethanol can be added to thinly sliced magnolia and extraction carried out at 60 0 C for a prescribed duration.
  • the extract is then filtered and concentrated as desired.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention concerne une composition comprenant au moins un extrait de magnolia, ou un analogue, dérivé, métabolite ou pro-médicament à base de celui-ci, et de lécithine. L'extrait de magnolia peut être choisi dans le groupe comprenant le magnolol (5,5'-diallyl-2,2'-dihydroxybiphényl, 1), l'honokiol (5,5'-diallyl-2,4'-dihydroxybiphényl, 2), la taspine et l'asimilobine. L'invention concerne en outre un procédé de traitement d'un trouble neurologique chronique utilisant la composition de l'invention. Le trouble neurologique chronique à traiter peut être choisi, de manière non restrictive, parmi la toxicomanie, en particulier, l'état de besoin de drogues, la maladie d'Alzheimer et la maladie de Parkinson.
PCT/EP2007/064523 2006-12-21 2007-12-21 Compositions et procédés de traitement de troubles neurologiques chroniques Ceased WO2008074896A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IE2006/0942 2006-12-21
IE20060942A IE20060942A1 (en) 2006-12-21 2006-12-21 Pharmaceutical composition for treatment of drug dependence and parkinson's disease and alzheimers disease
GB0705001.6 2007-03-15
GB0705001A GB0705001D0 (en) 2007-03-15 2007-03-15 Composition and method for treatment of drug dependence and disease
US92308407P 2007-04-12 2007-04-12
US60/923,084 2007-04-12

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WO2010075594A3 (fr) * 2008-12-19 2010-08-19 Henderson, Roy, Walter Extraction de molécules spécifiques d'une matière organique par la technologie de l'éclatement cellulaire hyperbare
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2012024616A1 (fr) * 2010-08-19 2012-02-23 Buck Institute For Age Research Méthodes de traitement de troubles cognitifs légers (mci) et de troubles associés
US20120178719A1 (en) * 2009-05-29 2012-07-12 The Trustees Of Columbia University In The City Of New York Modulation of phospholipase d for the treatment of neurodegenerative disorders
EP2327402A4 (fr) * 2008-09-25 2013-08-07 Bioland Ltd Composition contenant 4-o-méthylhonokiol pour traiter ou prévenir des maladies liées aux amyloïdes
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
WO2021026285A1 (fr) * 2019-08-06 2021-02-11 Kirkland Justin Formulations comprenant du dihydrohonokiol
WO2022160065A1 (fr) * 2021-01-31 2022-08-04 Betterlife Pharma Inc. Formulations comprenant du dihydrohonokiol

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EP2327402A4 (fr) * 2008-09-25 2013-08-07 Bioland Ltd Composition contenant 4-o-méthylhonokiol pour traiter ou prévenir des maladies liées aux amyloïdes
WO2010075594A3 (fr) * 2008-12-19 2010-08-19 Henderson, Roy, Walter Extraction de molécules spécifiques d'une matière organique par la technologie de l'éclatement cellulaire hyperbare
US20120178719A1 (en) * 2009-05-29 2012-07-12 The Trustees Of Columbia University In The City Of New York Modulation of phospholipase d for the treatment of neurodegenerative disorders
US9267122B2 (en) * 2009-05-29 2016-02-23 The Trustees Of Columbia University In The City Of New York Modulation of phospholipase D for the treatment of neurodegenerative disorders
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2012024616A1 (fr) * 2010-08-19 2012-02-23 Buck Institute For Age Research Méthodes de traitement de troubles cognitifs légers (mci) et de troubles associés
US10449177B2 (en) 2010-08-19 2019-10-22 Buck Institute For Research On Aging Methods of treating mild cognitive impairment (MCI) and related disorders
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10624875B2 (en) 2012-11-14 2020-04-21 The Johns Hopkins University Methods and compositions for treating schizophrenia
US11160785B2 (en) 2013-03-15 2021-11-02 Agenebio Inc. Methods and compositions for improving cognitive function
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10925834B2 (en) 2015-05-22 2021-02-23 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
WO2021026285A1 (fr) * 2019-08-06 2021-02-11 Kirkland Justin Formulations comprenant du dihydrohonokiol
CN114206365A (zh) * 2019-08-06 2022-03-18 J·柯克兰 包含二氢和厚朴酚的制剂
WO2022160065A1 (fr) * 2021-01-31 2022-08-04 Betterlife Pharma Inc. Formulations comprenant du dihydrohonokiol

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