Patent Description:
D-amino acid oxidase (DAAO) is a peroxisomal enzyme that oxidizes D-amino acids to the corresponding imino acids. It has been reported that DAAO is involved in the metabolism of brain D-amino acids, including D-serine, and the regulation of the glutamatergic neurotransmission. As such, DAAO is a target for treating central nervous system (CNS) disorders that are associated with D-serine and/or glutamatergic neurotransmission.

The present disclosure is based on the discovery that tannic acids, particularly those having more than three galloyl moieties, effectively inhibited the activity of DAAO. As such, compositions containing such tannic acids would benefit treatment of diseases and disorders associated with DAAO and/or glutamatergic neurotransmission, such as CNS disorders. The Invention is as defined in the appended claims.

Accordingly, one aspect of the present disclosure features a composition (e.g., a pharmaceutical composition, a health food product, or a medical food product), for use in treating a central nervous system (CNS) disorder, wherein the composition comprises (i) a mixture of tannic acids or an acceptable salt thereof, and (ii) a carrier, wherein the composition contains no more than <NUM>% of tannic acids having three or less galloyl moieties, wherein no more than <NUM>% of the tannic acids in the mixture have <NUM>-<NUM> galloyl moieties, and wherein at least <NUM>% of the tannic acids in the mixture have <NUM>-<NUM> galloyl moieties, and wherein the CNS disorder is selected from the group consisting of ADHD, learning disorder, schizophrenia, pain, depression, suicidal ideation and/or behavior, bipolar disorder, tic disorder, post-traumatic stress disorder, anxiety, social anxiety disorder, panic disorder, autism, Asperger's disorder, obsessive-compulsive disorder (OCD), Tourette's syndrome, mild cognitive impairment, dementia, vascular dementia, Alzheimer's disorder, frontotemporal dementia, Parkinson's disorder, Huntington's disease, nocturnal enuresis, blepharospasm, cerebral malaria and non-epileptic seizure. In some examples, the mixture of tannic acids in the composition comprises tannic acids having <NUM>-<NUM> galloyl moieties (e.g., <NUM>-<NUM> galloyl moieties, <NUM>-<NUM> galloyl moieties, or <NUM>-<NUM> galloyl moieties). In some examples, the mixture of tannic acids constitutes at least <NUM>% by weight of the total tannic acid content in the composition. In some examples, the tannic acids described herein are the only tannic acid content in the composition.

The composition for use described herein may comprise no more than <NUM>% (e.g., <<NUM>%, <<NUM>% or <<NUM>%) of tannic acids having <NUM>-<NUM> galloyl moieties. Alternatively or in addition, the composition for use may comprise at least <NUM>% (e.g., ><NUM>%, ><NUM>%, or ><NUM>%) tannic acids having <NUM>-<NUM> galloyl moieties (e.g., <NUM>-<NUM> galloyl moieties).

In some embodiments, the tannic acid described herein is from at least a plant source, including but not limited to, Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, Rhus punjabensis var. sinica (Diels) Rehder & E. Wilson, Camellia sinensis, Berry, Bixa orellana, Vitis vinifera, Punica granatum, Quercus infectoria, Quercus cerris, Acacia mearnsii, Pseudotsuga menziesii, Caesalpinia spinosa, Fagus hayata Palib. ex Hayata, or Machilus thunbergii Sieb.

In some embodiments, the tannic acid described herein is from at least a plant source, which can be Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, Rhus punjabensis var. sinica (Diels) Rehder & E.

In some embodiments, the tannic acid described herein is from at least a plant source requiring a nesting insect including but not limited to Andricus kollari, Andricusfecundatrix, Andricus quercuscalicis, Andricus quercuscalicis, Biorhiza pallida, Neuroterus quercusbaccarum, Neuroterus albipes, Neuroterus numismalis, Cynips quercusfolii, Melaphis chinensis (Bell), Melaphispeitan Tsai et Tang, Nurudea sinica Tsai et Tang, Nurudea shiraii matsumura, Nurudea rosea Matsumura, Meitanaphis elongallis Tsai et Tang, Macrorhinarium ensigallis Tsai et Tang, Macrorhinarium ovagallis Tsai et Tang, Floraphis meitanensis Tsai et Tang, Meitanaphis flavogallis Tang, Kaburagia rhusicola Takagi, Kaburagia ovatihuicola Xiang, Kaburagia ensigallis Tsai et Tang, Kaburagia ovogallis, Kaburagia thusicola Takagi, Meitanaphis microgallis Xiang, or Floraphis choui Xiang.

In some embodiments, the tannic acid described herein is from at least a plant source requiring a nesting insect including but not limited to Melaphis chinensis (Bell), Melaphis peitan Tsai et Tang, Nurudea sinica Tsai et Tang, Nurudea shiraii matsumura, Nurudea rosea Matsumura, Meitanaphis elongallis Tsai et Tang, Macrorhinarium ensigallis Tsai et Tang, Macrorhinarium ovagallis Tsai et Tang, Floraphis meitanensis Tsai et Tang, Meitanaphis flavogallis Tang, Kaburagia rhusicola Takagi, Kaburagia ovatihuicola Xiang, Kaburagia ensigallis Tsai et Tang, Kaburagia ovogallis, Kaburagia thusicola Takagi, Meitanaphis microgallis Xiang, or Floraphis choui Xiang.

In some embodiments, the tannic acid described herein is from the gallnuts selected from Chinese belly-shaped gallnuts, horned gallnuts, hard ensiform gallnuts, egg-hard ensiform gallnuts, and inflorescence gallnuts of at least a plant source requiring nesting insect. Also provided herein are methods for preparing the tannic acid composition as described herein. Such a method comprises (i) providing gallnuts of a plant (e.g., any of the plant sources as described herein); (ii) grinding the gallnuts to form gallnut power; (iii) extracting the gallnut power with a first solvent to produce a first tannic acid extract; and (iv) contacting the tannic acid extract with charcoal, CaSO<NUM>, MgSO<NUM>, or a combination thereof to remove substances absorbed to the charcoal or precipitated by the CaSO<NUM>, or MgSO<NUM>, thereby producing a first tannic acid composition. Optionally, the method may further comprise (v) dissolving the first tannic acid composition in a second solvent to form a solution, (vi) adding methylene chloride (CH<NUM>Cl<NUM>) or dichloroethane to the solution, and (vii) collecting solid substances thus formed, thereby producing a second tannic acid composition. Examples of the first solvent for use in step (iii) include, but are not limited to, acetone, methyl ethyl ketone, ethyl acetate, ethanol, isopropanol, tetrahydrofuran, <NUM>,<NUM>-dioxane, hexane, or a combination thereof. Examples of the second solvent for use in step (v) include, but are not limited to, acetone, acetonitrile, ethyl acetate, methyl ethyl ketone, or a combination thereof. The preparation methods as described herein further comprise a step of removing tannic acids having <NUM>-<NUM> galloyl moieties to form an enriched tannic acid extract. The removing step is performed by mixing a first tannic acid extract with a solvent, which is a combination of (i) any one of acetone, acetonitrile, methyl ethyl ketone, or ethyl acetate, and (ii) any one of pentane, hexane, or heptane, to form two organic layers and collect the oiler layer to produce the enriched tannic acid extract. In some instances, the solvent comprises methyl ethyl ketone/hexane, or ethyl acetate/hexane. The removing step is performed after step (iii) and before step (iv). In some embodiments, any of the preparation methods as described herein may further comprise, prior to step (iii) and after step (ii), passing the gallnut power through a sieve of <NUM>-<NUM>-mesh.

In some embodiments, any of the compositions described herein is a pharmaceutical composition, which comprises a pharmaceutically acceptable carrier. Such a pharmaceutical composition may further comprise a second therapeutic agent.

In some examples, the second therapeutic agent is an anti-obesity agent, which includes, but is not limited to, orlistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, pralintide, phentermine, fenfluramine, dexfenfluramine topiramate, dinitrophenol, bupropion, and zonisamide.

In other examples, the second therapeutic agent is an agent for treating a central nervous system (CNS) disorder. Such an agent can be an antidepressant, an antipsychotic, a psychostimulant, a mood stabilizer, an anxiolytic, an agent for treating attention deficit hyperactivity disorder (ADHD) or an agent for treating Alzheimer's disease (AD).

Examples of antipsychotic drugs include, but are not limited to, butyrophenone, phenothiazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, promazine, triflupromazine, levomepromazine, promethazine, thioxanthene, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, aripiprazole, lamotrigine, memantine, cannabidiol, LY2140023, droperidol, pimozide, butaperazine, carphenazine, remoxipride, piperacetazine, sulpiride, acamprosate, and tetrabenazine.

The antidepressants can be monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), selective serotonin reuptake inhibitors (SSRIs), noradrenergic and specific serotonergic antidepressants (NASSAs), norepinephrine (noradrenaline) reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, or serotonin-norepinephrine reuptake inhibitors (SNRIs). Examples include, but are not limited to, fluoxetine, paroxetine, escitalopram, citalopram, sertraline, fluvoxamine, venlafaxine, milnacipram, duloxetine, mirtazapine, mianserin, reboxetine, bupropion, amitriptyline, nortriptiline, protriptyline, desipramine, trimipramine, amoxapine, bupropion, clomipramine, desipramine, doxepin, isocarboxazid, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valporate, maprotiline, brofaromine, gepirone, moclobemide, isoniazid, and iproniazid.

Any of the pharmaceutical compositions described herein may be formulated for oral administration or for parenteral administration.

In other embodiments, the composition is a health food product (e.g., a nutraceutical composition) or a medical food product, which may comprise an edible carrier. Such compositions may be formulated as a tablet, a capsule, a soft chew, or a gel.

In some embodiments, the composition for use in the treatment method described herein can be any of the pharmaceutical compositions, health food products, and/or medical food products described herein.

In some examples, the subject in need of the treatment is a human patient having or suspected of having the CNS disorder. In other examples, the subject is a human patient who has been subjected to or is on a treatment for treating the CNS disorder.

The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the present invention will be apparent from the following drawings and detailed description of several embodiments, and also from the appended claims.

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

Tannic acids are a subfamily of tannins existing in various plants. Tannic acids extracted from plants are a mixture of polygalloyl glucoses or polygalloyl quinic acid esters containing <NUM>-<NUM> galloyl moieties. Provided below is the structure of an exemplary tannic acid molecule that contains <NUM> galloyl moieties linked to a glucose moiety. <CHM>
Historically, tannic acids have been used as an antidote to soak up poisons, and for treating short-term conditions, such as bleeding, rashes and other conditions of soreness.

The present disclosure is based on the discoveries that tannic acids having four or more galloyl moieties, showed strong inhibitory activity against DAAO, which is known to be involved in various diseases and disorders, such as obesity, hyperlipidemia, diabetes, and CNS disorders. The present studies also showed that tannic acids successfully reduced body weight and improved basic behavioral functioning, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and cognitive behaviors in a mouse model. Further, tannic acids showed rescue and protective effects on mice treated with MK801, an antagonist of the N-methyl-D-aspartate receptor (the NMDA receptor). NMDA receptor is a glutamate receptor and ion channel protein expressed on nerve cells and plays an important role in controlling synaptic plasticity, repair, neurodevelopment, learning and memory function.

Accordingly, the present disclosure provides tannic acid-containing compositions for use in treating CNS disorders and methods for preparing a tannic acid composition.

Disclosed herein are compositions, for example, pharmaceutical compositions, health food product such as nutraceutical compositions, and medical food that comprise one or more tannic acids and a carrier, e.g., a pharmaceutically acceptable carrier and/or an edible carrier. Such carriers, either naturally occurring or non-naturally occurring (synthetic), may confer various benefits to the tannic acids in the composition, for example, improving in vitro and/or in vivo stability of the tannic acids, enhancing bioavailability of the tannic acids, increasing bioactivity of the tannic acids, and/or reducing side effects. Suitable carriers include, but are not limited to, diluents, fillers, salts, buffers, stabilizers, solubilizers, buffering agents, preservatives, or a combination thereof. In some examples, the carrier may comprise benzoate such as sodium benzoate.

The compositions described herein comprise one or more tannic acids or pharmaceutically acceptable salts thereof. The term "pharmaceutically-acceptable salts" refers to the relatively non-toxic, inorganic or organic base addition salts of tannic acids. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the one or more tannic acids with a suitable organic or inorganic base, and isolating the salt thus formed during subsequent purification. Suitable inorganic bases include, but are not limited to, sodium hydroxide, barium hydroxide, iron (ii) hydroxide, iron(III) hydroxide, magnesium hydroxide, calcium hydroxide, aluminium hydroxide, ammonium hydroxide, potassium hydroxide, caesium hydroxide, or lithium hydroxide. Suitable organic bases include, but are not limited to, pyridine, methyl amine, imidazole, benzimidazole, histidine, phosphazene bases, or a hydroxide of an organic cation such as quaternary ammonium hydroxide and phosphonium hydroxide. See, for example, <NPL>.

In some embodiments, the tannic acids contained in the compositions disclosed herein are a mixture of tannic acids having various numbers of galloyl moieties, e.g., <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM>, or pharmaceutically acceptable salts thereof. In some examples, the mixture of tannic acids contains tannic acids having at least <NUM> galloyl moieties (e.g., <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, or <NUM>-<NUM> galloyl moieties) or pharmaceutically acceptable salts thereof. The tannic acids in the composition may be substantially free of tannic acids having <NUM> or less galloyl moieties. As used herein, "substantially free" of tannic acids having <NUM> or less galloyl moieties means that the total amount of such tannic acids in the composition is no more than <NUM>% by weight. In some examples, the total amount of tannic acids having <NUM> or less galloyl moieties in the compositions described herein may be less than <NUM>%, <NUM>%, <NUM>%, <NUM>%, or less. In some examples, the composition is completely free of any tannic acid having <NUM> or less galloyl moieties.

Any of the compositions described herein may contain no more than <NUM>% (e.g., no more than <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or less) tannic acids with <NUM>-<NUM> galloyl moieties. Alternatively or in addition, the composition may contain no less than <NUM>% (e.g., <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or more) of tannic acids with <NUM>-<NUM> galloyl moieties or with <NUM>-<NUM> galloyl moieties. In one particular example, the composition contains no more than <NUM>% of tannic acid having <NUM>-<NUM> galloyl moieties and no less than <NUM>% tannic acids having <NUM>-<NUM> galloyl moieties. In another example, the composition contains no more than <NUM>% of tannic acids with <NUM>-<NUM> galloyl moieties and no less than <NUM>% of tannic acids with <NUM>-<NUM> galloyl moieties. In yet another example, the composition contains no more than <NUM>% of tannic acids with <NUM>-<NUM> galloyl moieties and no less than <NUM>% of tannic acids with <NUM>-<NUM> galloyl moieties. Alternatively, the composition contains no more than <NUM>% of tannic acids having with <NUM>-<NUM> galloyl moieties and no less than <NUM>% of tannic acids with <NUM>-<NUM> galloyl moieties.

The tannic acid or tannic acid mixture for use in making the compositions disclosed herein may be prepared by conventional methods. For example, a mixture of tannic acids may be extracted or isolated from at least a suitable plant source, including but not limited to Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, Rhus punjabensis var. sinica (Diels) Rehder & E. Wilson, Camellia sinensis, Berry, Bixa orellana, Vitis vinifera, Punica granatum, Quercus infectoria, Quercus cerris, Acacia mearnsii, Pseudotsuga menziesii, Caesalpinia spinosa, Fagus hayata Palib. ex Hayata, or Machilus thunbergii Sieb. In some embodiments, the tannic acid or tannic acid mixture contained in the composition herein are extracted from Rhus chinensis, Rhus javanica, Rhus semialata, Rhus coriaria, Rhus potaninii, or Rhus punjabensis var. sinica (Diels) Rehder & E.

The plant source described herein may require a nesting insect including but not limited to Andricus kollari, Andricus fecundatrix, Andricus quercuscalicis, Andricus quercuscalicis, Biorhiza pallida, Neuroterus quercusbaccarum, Neuroterus albipes, Neuroterus numismalis, Cynips quercusfolii, Melaphis chinensis (Bell), Melaphis peitan Tsai et Tang, Nurudea sinica Tsai et Tang, Nurudea shiraii Matsumura, Nurudea rosea Matsumura, Meitanaphis elongallis Tsai et Tang, Macrorhinarium ensigallis Tsai et Tang, Macrorhinarium ovagallis Tsai et Tang, Floraphis meitanensis Tsai et Tang, Meitanaphis flavogallis Tang, Kaburagia rhusicola Takagi, Kaburagia ovatihuicola Xiang, Kaburagia ensigallis Tsai et Tang, Kaburagia ovogallis, Kaburagia thusicola Takagi, Meitanaphis microgallis Xiang, and Floraphis choui Xiang.

In some embodiments, the tannic acid or tannic acid mixture is extracted from the gallnuts including but not limited to Chinese belly-shaped gallnuts, horned gallnuts, hard ensiform gallnuts, egg-hard ensiform gallnuts, and inflorescence gallnuts of at least a plant source and requiring nesting insect described herein.

In other embodiments, the tannic acids contained in the compositions described herein are a substantially homogeneous population. Such a tannic acid population may contain a tannic acid having a defined number of galloyl moieties, for example, any number between <NUM> and <NUM> (including <NUM> and <NUM>), or a pharmaceutically acceptable salt thereof. As used herein, the term "substantially homogenous" means that the tannic acid having the defined number of galloyl moieties constitutes at least <NUM>% by weight (e.g., <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or above) of the total tannic acid content in the composition. In some examples, the substantially homogenous tannic acid population contains tannic acids having <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> galloyl moieties. Such substantially homogeneous tannic acid populations may be isolated from a mixture of tannic acids having varied numbers of gallolyl moieties (e.g., those described herein) via a conventional method, for example, chromatography.

The tannic acid extract may be subjected to one or more purification procedures, for example, gel filtration, fractionation, partition, re-crystallization, and chromatography (e.g., HPLC) or a combination thereof. See, e.g., Examples below. Alternatively, the tannic acid or tannic acid mixture may be prepared by chemical synthesis following routine methodology.

In some embodiments, a tannic acid composition as described herein can be prepared as follows. Gallnuts from a suitable plant source, e.g., those described herein, can be obtained via routine methods. The gallnuts can be grinded to form gallnut powers. In some examples, the gallnut power can be passed through a sieve having a suitable size (e.g., <NUM>-mesh, <NUM>-mesh, <NUM>-mesh, <NUM>-mesh, or <NUM>-mesh) to form fine gallnut powers.

A suitable solvent can then be used to extract the tannic acid content from any of the gallnut powers described herein. As used herein, the term "solvent" refers to a liquid capable of dissolving one or more solutes. A solvent may comprise a pure population of a substance that dissolves a solute of interest. Alternatively, a solvent as used herein may be a mixture of multiple substances for dissolving the solute. A suitable solvent for extracting tannic acids comprise acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, ethanol, isopropanol, tetrahydrofuran, <NUM>,<NUM>-dioxane, pentane, hexane, heptane, or a combination thereof. To extract the tannic acid contents, the gallnut powers can be placed into a suitable volume of the solvent. The mixture thus formed can be stirred at a suitable temperature (e.g., room temperature) for a suitable period (e.g., <NUM>-<NUM> hours, <NUM>-<NUM> hours, <NUM>-<NUM> hours, <NUM>-<NUM> hours). The resultant solution can then be filtered and concentrated by routine practice (e.g., by vacuum evaporation).

The concentrated composition, containing tannic acids, is then mixed with charcoal, CaSO<NUM>, MgSO<NUM>, or a combination thereof to remove undesired substances (e.g., substances that can be absorbed to the charcoal or precipitated by CaSO<NUM> and/or MgSO<NUM>). In some examples, any of the tannic acid-containing compositions obtained from preceding steps can be mixed with charcoal first for a suitable period of time (e.g., stirred at room temperature for <NUM>-<NUM> hours). CaSO<NUM> and/or MgSO<NUM> can then be added to the mixture, which can be stirred under a suitable temperature (e.g., room temperature) for a suitable period (e.g., <NUM> minutes to <NUM> hours). The mixture can then be filtered through, e.g., a bed of Celite, washed with a suitable solvent (e.g., acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, ethanol, or a combination thereof), and concentrated by a routine method to produce a tannic acid composition. In other examples, any of the tannic acid-containing compositions obtained from preceding steps can be mixed with charcoal first for a suitable period of time (e.g., stirred at room temperature for <NUM>-<NUM> hours, for example, <NUM>-<NUM> hours or <NUM>-<NUM> hours). The charcoal can then be removed from the mixture to form a solution. CaSO<NUM> and/or MgSO<NUM> can then added to the solution, which can be stirred under a suitable temperature (e.g., room temperature) for a suitable period (e.g., <NUM> minutes to <NUM> hours, for example, <NUM> minutes to <NUM> hours or to <NUM> hour). The mixture can then be filtered through, e.g., a bed of Celite, washed with a suitable solvent (e.g., acetone, acetonitrile, methyl ethyl ketone, ethyl acetate, ethanol, or a combination thereof), and concentrated by a routine method to produce a tannic acid composition.

A method for preparing the tannic acid composition as described herein further comprises a step of reducing or removing tannic acids having <NUM>-<NUM> galloyl moieties (<NUM>-<NUM>), and may comprise a step of enriching tannic acids having <NUM>-<NUM> galloyl moieties (<NUM>-<NUM>).

To remove tannic acids having <NUM>-<NUM>, a crude tannic acid composition is mixed with a suitable solvent to form a mixture, which can be incubated (e.g., stirred) for a suitable period (e.g., <NUM>-<NUM> hours) under a suitable temperature (e.g., room temperature) to allow for formation of two organic layers. Tannic acids having less than <NUM> would be dissolved in the upper layer. Tannic acids having greater than <NUM> would stay in the oiler layer (lower layer) as solid substances. The oiler layer, enriched with tannic acids having large numbers of galloyl moieties, can be collected. If needed, the oiler layer can be concentrated and the solids thus obtained can be dissolved in a suitable solvent. Suitable solvents for removing tannic acids having less than <NUM> include a mixture of any one of the group (i) solvent and any one of the group (ii) solvent listed below:.

The resultant solution is subject to the charcoal, CaSO<NUM> and/or MgSO<NUM> treatment to remove undesired substances as described herein.

To enrich tannic acids having large numbers of galloyl moieties (e.g., <NUM>-<NUM>), a tannic acid-containing composition can be first dissolved in a suitable solvent such as acetone, acetonitrile, methyl ethyl ketone, or ethyl acetate. The solution thus formed can be stirred and CH<NUM>Cl<NUM> or dichloroethane can be added to the solution slowly dropwise to allow for precipitation of the desired tannic acids. The solids can then be collected by routine practice (e.g., filtration and/or drying) to produce an enriched tannic acid composition.

Some examples follow, which are merely illustrative and by no means limit the present disclosures to these specific examples.

Some examples follow, which are not part of the Invention.

The one or more tannic acids described herein (e.g., a mixture of tannic acids or a substantially homogenous population of tannic acids having a defined number of galloyl moieties as described herein) can be mixed with a pharmaceutically acceptable carrier (excipient) to form a pharmaceutical composition, which can be used for treating any of the target diseases as described herein. In some embodiments, the tannic acid population in the composition is substantially free of condensed tannins and/or phlorotannins. "Acceptable" means that the carrier must be compatible with the active ingredient of the composition (and preferably, capable of stabilizing the active ingredient) and not deleterious to the subject to be treated. Pharmaceutically acceptable excipients (carriers) including buffers, which are well known in the art. See, e.g., <NPL>.

Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers and other material which are well-known in the art. Exemplary pharmaceutically acceptable carriers for tannic acids or salts thereof in particular are described in <CIT>. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the invention. Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from a suitable inorganic base, (e.g., sodium hydroxide, barium hydroxide, iron (ii) hydroxide, iron(III) hydroxide, magnesium hydroxide, calcium hydroxide, aluminium hydroxide, ammonium hydroxide, potassium hydroxide, caesium hydroxide, or lithium hydroxide) or a suitable organic base (e.g., pyridine, methyl amine, imidazole, benzimidazole, histidine, phosphazene bases, or a hydroxide of an organic cation such as quaternary ammonium hydroxide and phosphonium hydroxide). Also, pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as lithium, sodium, potassium or calcium salts.

The tannic acid-containing pharmaceutical compositions as described herein can comprise pharmaceutically acceptable carriers, excipients, or stabilizers in the form of lyophilized formulations or aqueous solutions. Acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations used, and may comprise buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; <NUM>-pentanol; benzoates, sorbate and m-cresol); low molecular weight (less than about <NUM> residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, serine, alanine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrans; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

In other examples, the pharmaceutical composition described herein can be formulated in sustained-release format. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing tannic acids, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(<NUM>-hydroxyethylmethacrylate), or poly(vinylalcohol)), polylactides (<CIT>), copolymers of L-glutamic acid and <NUM> ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-<NUM>-hydroxybutyric acid.

The pharmaceutical compositions to be used for in vivo administration must be sterile. This is readily accomplished by, for example, filtration through sterile filtration membranes. Therapeutic compositions are generally placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

The pharmaceutical compositions described herein can be in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation, or jntrathecal or intracerebral routes.

For preparing solid compositions such as tablets, the principal active ingredient can be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from <NUM> to about <NUM> of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

Suitable surface-active agents include, in particular, non-ionic agents, such as polyoxyethylenesorbitans (e.g., Tween™ <NUM>, <NUM>, <NUM>, <NUM> or <NUM>) and other sorbitans (e.g., Span™ <NUM>, <NUM>, <NUM>, <NUM> or <NUM>). Compositions with a surface-active agent will conveniently comprise between <NUM> and <NUM>% surface-active agent, and can be between <NUM> and <NUM>%. It will be appreciated that other ingredients may be added, for example mannitol or other pharmaceutically acceptable vehicles, if necessary.

Suitable emulsions may be prepared using commercially available fat emulsions, such as Intralipid™, Liposyn™, Infonutrol™, Lipofundin™ and Lipiphysan™. The active ingredient may be either dissolved in a pre-mixed emulsion composition or alternatively it may be dissolved in an oil (e.g., soybean oil, safflower oil, cottonseed oil, sesame oil, corn oil or almond oil) and an emulsion formed upon mixing with a phospholipid (e.g., egg phospholipids, soybean phospholipids or soybean lecithin) and water. It will be appreciated that other ingredients may be added, for example glycerol or glucose, to adjust the tonicity of the emulsion. Suitable emulsions will typically contain up to <NUM>% oil, for example, between <NUM> and <NUM>%.

Pharmaceutical compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect.

Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.

In some embodiments, any of the tannic acid-containing pharmaceutical compositions may further comprise a second therapeutic agent based on the intended therapeutic uses of the composition.

In some examples, the second therapeutic agent is an anti-obesity agent, including, but not limited to, orlistat, lorcaserin, sibutramine, rimonabant, metformin, exenatide, pralintide, phentermine, fenfluramine, dexfenfluramine topiramate, dinitrophenol, bupropion, and zonisamide.

In other examples, the second therapeutic agent is an agent for treating a CNS disease/disorder. Such a therapeutic agent may be an antipsychotic drug. Exemplary antipsychotic drugs include, but are not limited to, butyrophenone (e.g., haloperidol (HALDOL™), phenothiazine (e.g., chlorpromazine (THORAZINE™), fluphenazine (PROLIXIN™), perphenazine (TRILAFON™), prochlorperazine (COMPAZINE™), thioridazine (MELLARIL™), trifluoperazine (STELAZINE™), mesoridazine, promazine, triflupromazine (VESPRIN™), levomepromazine (NOZINAN™), promethazine (PHENERGAN™), thioxanthene (e.g., chlorprothixene, flupenthixol (DEPIXOL™, FLUANXOL™), thiothixene (NAVANE™), zuclopenthixol (CLOPIXOL™, ACUPHASE™), clozapine (CLOZARIL™), olanzapine (ZYPREXA™), risperidone (RISPERDAL™, RISPERDAL CONSTA™), quetiapine (SEROQUEL™), ziprasidone (GEODON™), amisulpride (SOLIAN™), asenapine, paliperidone (INVEGA®), aripiprazole (ABILITY™), dopamine partial agonists (BIFEPRUNOX™, NORCLOZAPINE™ (ACP-<NUM>)), lamotrigine (LAMICTAL™), , tetrabenazine (NITOMAN™, XENAZINE™), cannabidiol, LY2140023, and the like).

Alternatively, the second therapeutic agent can be an antidepressant and/or mood stabilizer. In certain embodiments the antidepressant comprises a monoamine oxidase inhibitor (MAOI), a tricyclic antidepressant (TCA), a tetracyclic antidepressant (TeCA), a selective serotonin reuptake inhibitor (SSRI), a noradrenergic and specific serotonergic antidepressant (NASSA), a norepinephrine (noradrenaline) reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, and/or a serotonin-norepinephrine reuptake inhibitor (SNRI). Exemplary SSRIs include fluoxetine (PROZAC™), paroxetine (PAXIL™, SEROXAT™), escitalopram (LEXAPRO™, ESIPRAM™), citalopram (CELEXA™), sertraline (ZOLOFT™), fluvoxamine (LUVOX™)). Exemplary SNRIs include venlafaxine (EFFEXOR™), milnacipram and duloxetine (CYMBALTA™). Additional antidepressant include a noradrenergic and specific serotonergic antidepressant (NASSA) (e.g., mirtazapine (AVANZA™, ZISPIN™, REMERON™), or mianserin, a norepinephrine (noradrenaline) reuptake inhibitor (NRI) (e.g., reboxetine (EDRONAX™)), a norepinephrine-dopamine reuptake inhibitors (e.g., bupropion (WELLBUTRIN™, ZYBAN™)), amitriptyline, nortriptiline, protriptyline, desipramine, imipramine, trimipramine, amoxapine, bupropion, bupropion SR, clomipramine, doxepin, isocarboxazid, venlafaxine XR, tranylcypromine, trazodone, nefazodone, phenelzine, lamatrogine, lithium, topiramate, gabapentin, carbamazepine, oxacarbazepine, valporate, maprotiline, mirtazapine, brofaromine, gepirone, moclobemide, isoniazid, iproniazid, and the like.

In other examples, the second therapeutic agent can be an agent for the treatment of ADD and/or ADHD. Suitable ADHD medications include, but are not limited to amphetamine, modafinil, desoxyn, methamphetamine, cocaine, arecoline, dexmethylphenidate (focalin, focalin XR), dextroamphetamine (dexedrine, dexedrine spansules, dextroamphetamine ER, dextrostat), methylphenidate (concerta, daytrana, metadate CD, metadate ER, methylin, methylin ER, ritalin, ritalin-LA, ritalin-SR), lisdexamfetamine dimesylate (Vyvanse), mixed salts amphetamine (Adderall, Adderall XR), atomoxetine (Strattera), clonidine hydrochloride (Catapres), guanfacine hydrochloride (Tenex), arecoline, and pemoline.

Further, the second therapeutic agent may be an agent for use in treating a cognitive disorder, and/or a condition characterized by neurodegeneration (e.g., Alzheimer's disease, or Parkinson's disease). Such therapeutic agents include, but are not limited to tacrine, rivastigmine, memantine (AXURA™, AKATINOL™, NAMENDA™, EBIXA™, ABIXA™), donepezil (Aricept™), physostigmine, nicotine, arecoline, huperzine alpha, selegiline, rilutek™ (riluzole), vitamine c, vitamine e, carotenoids, ginkgo biloba, and the like.

In some embodiments, the tannic acid-containing compositions described herein can be a health food product, which can be any kinds of liquid and solid/semi-solid materials that are used for nourishing humans and animals, for improving basic behavioral functioning, hyperactivity, anxiety, depression, suicidal ideation and/or behavior, sensorimotor gating, pain threshold, memory and/or cognitive functioning, or for facilitating treatment of any of the target diseases noted herein (e.g., a CNS disorder, including those described herein). The health food product may be a food product (e.g., tea-based beverages, juice, soft drinks, coffee, milk, jelly, cookies, cereals, chocolates, snack bars, herbal extracts, dairy products (e.g., ice cream, and yogurt)), a food/dietary supplement, or a nutraceutical formulation.

The health food product described herein, containing one or more tannic acids (e.g., the tannic acid mixture described herein or the substantially homogenous population of a tannic acid having a defined number of galloyl moieties as also described herein), may comprise one or more edible carriers, which confer one or more of the benefits to the tannic acids in the product as described herein. Examples of edible carriers include starch, cyclodextrin, maltodextrin, methylcellulose, carbonmethoxy cellulose, xanthan gum, and aqueous solutions thereof. Other examples include solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art. In some examples, the healthy food products described herein may further include neuroprotective foods, such as fish oil, flax seed oil, and/or benzoate.

In some examples, the healthy food product is a nutraceutical composition, which refers to compositions containing components from food sources and conferring extra health benefits in addition to the basic nutritional value found in foods. A nutraceutical composition as described herein comprises the tannic acid content described herein (e.g., the tannic acid mixture or the substantially homogenous tannic acid population as described herein) and additional ingredients and supplements that promote good health and/or enhance stability and bioactivity of the tannic acids.

The actions of nutraceutical compositions may be fast or/and short-term or may help achieve long-term health objectives as those described herein, e.g., improving basic behavioral functioning, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and/or cognitive functioning in, e.g., human subjects who have or are at risk for diseases associated with DAAO such as CNS disorders. The nutraceutical compositions may be contained in an edible material, for example, as a dietary supplement or a pharmaceutical formulation. As a dietary supplement, additional nutrients, such as vitamins, minerals or amino acids may be included. The composition can also be a drink or a food product, e.g., tea, soft drink, juice, milk, coffee, cookie, cereal, chocolate, and snack bar. If desired, the composition can be sweetened by adding a sweetener such as sorbitol, maltitol, hydrogenated glucose syrup and hydrogenated starch hydrolyzate, high fructose corn syrup, cane sugar, beet sugar, pectin, or sucralose.

The nutraceutical composition disclosed herein can be in the form of a solution. For example, the nutraceutical formulation can be provided in a medium, such as a buffer, a solvent, a diluent, an inert carrier, an oil, or a creme. In some examples, the formulation is present in an aqueous solution that optionally contains a non-aqueous co-solvent, such as an alcohol. The nutraceutical composition can also be in the form of powder, paste, jelly, capsule, or tablet. Lactose and corn starch are commonly used as diluents for capsules and as carriers for tablets. Lubricating agents, such as magnesium stearate, are typically added to form tablets.

The health food products may be formulated for a suitable administration route, for example, oral administration. For oral administration, the composition can take the form of, for example, tablets or capsules, prepared by conventional means with acceptable excipients such as binding agents (for example, pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (for example, potato starch or sodium starch glycolate); or wetting agents (for example, sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Also included are bars and other chewable formulations.

In some examples, the health food product can be in a liquid form and the one or more edible carriers can be a solvent or dispersion medium comprising but not limited to, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol), lipids (e.g., triglycerides, vegetable oils, liposomes) or combinations thereof. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropylcellulose; or combinations thereof. In many cases, it will be advisable to include an isotonic agent, such as, for example, sugars, sodium chloride or combinations thereof.

Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. In one embodiment, the liquid preparations can be formulated for administration with fruit juice. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (for example, lecithin or acacia); non-aqueous vehicles (for example, almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (for example, methyl or propyl-p-hydroxybenzoates, benzoate or sorbate).

The health food products described herein may further comprise one or more second therapeutic agents, including those described herein.

The present disclosure also provides compositions of medical food products, use in improving basic behavioral functioning, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory and/or cognitive functioning, and/or for treating a target disease as described herein (e.g., a CNS disorder). A medical food product is a food product formulated to be consumed or administered enterally. Such a food product is usually used under the supervision of a physician for the specific dietary management of a target disease, such as those described herein. In some instances, such a medical food composition is specially formulated and processed (as opposed to a naturally occurring foodstuff used in a natural state) for a patient in need of the treatment (e.g., human patients who suffer from illness or who requires use of the product as a major active agent for alleviating a disease or condition via specific dietary management. ) In some examples, a medical food composition described herein is not one of those that would be simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition.

Any of the medical food compositions described herein, comprising one or more tannic acid molecules or salts thereof and at least one carrier (e.g., those described herein), can be in the form of a liquid solution; powder, bar, wafer, a suspension in an appropriate liquid or in a suitable emulsion, as detailed below. The at least one carrier, which can be either naturally-occurring or synthetic (non-naturally occurring), would confer one or more benefits to the tannic acid content in the composition, for example, stability, bioavailability, and/or bioactivity. Any of the carriers described herein may be used for making the medical food composition. In some embodiments, the medical food composition may further comprise one or more additional ingredients selected from the group including, but not limited to natural flavors, artificial flavors, major trace and ultra-trace minerals, minerals, vitamins, oats, nuts, spices, milk, egg, salt, flour, lecithin, xanthan gum and/or sweetening agents. The medical food composition may be placed in a suitable container, which may further comprise at least an additional therapeutic agent such as those described herein.

Any of the tannic acid-containing compositions described herein may be used to improve basic behavioral functioning, hyperactivity, anxiety, depression, suicidal ideation and/or behavior, sensorimotor gating, pain threshold, memory, and/or cognitive functioning in a subject in need of the treatment. Such compositions may also be used to treating diseases or disorders associated with DAAO such as a central nervous disorder (e.g., those described herein).

As used herein, the term "treating" refers to the application or administration of a composition including one or more active agents to a subject, who is in need of the treatment, for example, having a target disease or disorder, a symptom of the disease/disorder, or a predisposition toward the disease/disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the disorder, the symptom of the disease, or the predisposition toward the disease or disorder.

Alleviating a target disease/disorder includes delaying the development or progression of the disease, or reducing disease severity. Alleviating the disease does not necessarily require curative results. As used therein, "delaying" the development of a target disease or disorder means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated. A method that "delays" or alleviates the development of a disease, or delays the onset of the disease, is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.

"Development" or "progression" of a disease means initial manifestations and/or ensuing progression of the disease. Development of the disease can be detectable and assessed using standard clinical techniques as well known in the art. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. "Development" includes occurrence, recurrence, and onset. As used herein "onset" or "occurrence" of a target disease or disorder includes initial onset and/or recurrence.

To achieve any of the intended therapeutic effects described herein, an effective amount of a tannic acid-containing composition may be administered to a subject in need of the treatment via a suitable route.

The terms "subject," "individual," and "patient" are used interchangeably herein and refer to a mammal being assessed for treatment and/or being treated. Subjects may be human, but also include other mammals, particularly those mammals useful as laboratory models for human disease, e.g. mouse, rat, rabbit, dog, etc..

A human subject who needs the treatment may be a human patient having, at risk for, or suspected of having a target disease/disorder, such as a CNS disorder. A subject having a target disease or disorder can be identified by routine medical examination, e.g., laboratory tests, organ functional tests, and/or behavior tests. A subject suspected of having any of such target disease/disorder might show one or more symptoms of the disease/disorder. A subject at risk for the disease/disorder can be a subject having one or more of the risk factors for that disease/disorder, for example, a genetic factor. In some instances, the human subject is a child who has, is suspected of having, or is at risk for a CNS disorder associated with children, for example, attention deficit/hyperactivity disorder (ADHD), autism, Asperger's disorder, obsessive compulsive disorder, depression, psychosis, chronic pain, and learning disorder.

The methods and compositions described herein may be used to treat a CNS disorder. Exemplary CNS disorders that can be treated by the methods and compositions described herein include attention deficit/hyperactivity disorder (ADHD), schizophrenia, pain, depression, suicidal ideation and/or behavior, bipolar disorder, tic disorder, post-traumatic stress disorder, anxiety, social anxiety disorder, panic disorder, autism, Asperger's disorder, obsessive-compulsive disorder, learning disorder, Tourette's syndrome, mild cognitive impairment, dementia, vascular dementia, a neurodegenerative disorder (e.g., Alzheimer's disorder or Parkinson's disease, frontotemporal dementia, Huntington's disease), nocturnal enuresis, blepharospasm, non-epileptic seizure and cerebral malaria.

As used herein, "an effective amount" refers to the amount of each active agent (e.g., the tannic acid mixture or the substantially homogenous population of tannic acids as described herein) required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents, such as one or more of the second therapeutic agents described herein. In some embodiment, the therapeutic effect is to inhibit the activity of DAAO (e.g., by at least <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, <NUM>%, or higher) in the subject. In some embodiments, the therapeutic effect is improvement of basic behavioral functioning, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory, and/or improvement of cognitive functioning. In some embodiments, the therapeutic effect is alleviating one or more symptoms associated with any of the CNS disorders described herein.

Determination of whether an amount of the composition as described herein achieved the therapeutic effect would be evident to one of skill in the art. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration, genetic factors and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment.

Empirical considerations, such as the half-life, generally will contribute to the determination of the dosage. Frequency of administration may be determined and adjusted over the course of therapy, and is generally, but not necessarily, based on treatment and/or suppression and/or amelioration and/or delay of a target disease/disorder. Alternatively, sustained continuous release formulations of a composition as described herein may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

Generally, for administration of any of the compositions, an exemplary daily dosage might range from about any of <NUM>µg/kg to <NUM>µg/kg to <NUM>µg/kg to <NUM>µg/kg to <NUM>/kg, to <NUM>/kg to <NUM>/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression of symptoms occurs or until sufficient therapeutic levels are achieved to alleviate a target disease or disorder, or a symptom thereof. An exemplary dosing regimen comprises administering one or more initial doses at a suitable interval over a suitable period. If necessary, multiple maintenance doses can be given to the subject at a suitable interval over a suitable period of time. However, other dosage regimens may be useful, depending on the pattern of pharmacokinetic decay that the practitioner wishes to achieve. For example, dosing from one to four times a day or a week is contemplated. In some embodiments, dosing ranging from about <NUM>µg/mg to about <NUM>/kg (such as about <NUM>µg/mg, about <NUM>µg/mg, about <NUM>µg/mg, about <NUM>µg/mg, about <NUM>µg/mg, about <NUM>/kg, and about <NUM>/kg) may be used. In some embodiments, dosing frequency can be three times a day, twice a day, once a day, once every other day, once every week, once every <NUM> weeks, once every <NUM> weeks, once every <NUM> months, or once every <NUM> months. The dosing regimen can vary over time.

In some embodiments, for an adult patient of normal weight, doses ranging from about <NUM> to <NUM>/kg/day (e.g., <NUM> to <NUM>/kg/day, <NUM>-<NUM>/kg/day, <NUM>-<NUM>/kg/day, or <NUM>-<NUM>/kg/day) may be administered. The particular dosage regimen, i.e., dose, timing and repetition, will depend on the particular individual and that individual's medical history, as well as the properties of the individual agents (such as the half-life of the agent, and other considerations well known in the art).

For the purpose of the present disclosure, the appropriate dosage of a tannic acid-composition as described herein will depend on the specific tannic acid or tannic acid mixture, and/or other active ingredient employed, the type and severity of the disease/disorder, whether the composition is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the DAAO inhibitor, and the discretion of the attending physician. Typically the clinician will administer a composition, until a dosage is reached that achieves the desired result.

Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the composition (e.g., a pharmaceutical composition, a health food composition, a nutraceutical composition or a medical food composition) to the subject, depending upon the type of disease to be treated or the site of the disease. This composition can also be administered via other conventional routes, e.g., administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In addition, it can be administered to the subject via injectable depot routes of administration such as using <NUM>-week, half (or two week)-, <NUM>-, <NUM>-, or <NUM>-month depot injectable or biodegradable materials and methods. In some examples, the pharmaceutical composition is administered intraocularlly or intravitreally.

Injectable compositions may contain various carriers such as vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injection, water-soluble antibodies can be administered by the drip method, whereby a pharmaceutical formulation containing tannic acids and a physiologically acceptable excipient is infused. Physiologically acceptable excipients may include, for example, <NUM>% dextrose, <NUM>% saline, Ringer's solution or other suitable excipients. Intramuscular preparations, e.g., a sterile formulation of a suitable soluble salt form of tannic acids, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, <NUM>% saline, or <NUM>% glucose solution.

In one embodiment, a tannic acid-containing composition is administered via a site-specific or targeted local delivery technique. Examples of site-specific or targeted local delivery techniques include various implantable depot sources of the tannic acid-containing compositions or local delivery catheters, such as infusion catheters, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See, e.g., <CIT> and <CIT>.

Treatment efficacy for a target disease/disorder can be assessed by methods well-known in the art.

Also provided herein are combined therapies using any of the tannic acid-containing compositions described herein and a second therapeutic agent, such as those described herein. The term combination therapy, as used herein, embraces administration of these agents (e.g., a tannic acid-containing composition and an anti-CNS disorder agent) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the agents, in a substantially simultaneous manner. Sequential or substantially simultaneous administration of each agent can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues. The agents can be administered by the same route or by different routes. For example, a first agent (e.g., a tannic acid-containing composition) can be administered orally, and a second agent (e.g., an anti-CNS disorder agent) can be administered intravenously.

As used herein, the term "sequential" means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of a tannic acid-containing composition and an anti-CNS disorder agent, a sequential dosage regimen could include administration of the tannic acid-containing composition before, simultaneously, substantially simultaneously, or after administration of the anti-CNS disorder agent, but both agents will be administered in a regular sequence or order. The term "separate" means, unless otherwise specified, to keep apart one from the other. The term "simultaneously" means, unless otherwise specified, happening or done at the same time, i.e., the agents of the invention are administered at the same time. The term "substantially simultaneously" means that the agents are administered within minutes of each other (e.g., within <NUM> minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two compounds separately). As used herein, concurrent administration and substantially simultaneous administration are used interchangeably. Sequential administration refers to temporally separated administration of the agents described herein.

Combination therapy can also embrace the administration of the agents described herein (e.g., a tannic acid-containing composition and an anti-CNS disorder agent) in further combination with other biologically active ingredients (e.g., a different anti-CNS disorder agent) and non-drug therapies (e.g., surgery).

It should be appreciated that any combination of a tannic acid-containing composition and a second therapeutic agent (e.g., an anti-CNS disorder agent) may be used in any sequence for treating a target disease. The combinations described herein may be selected on the basis of a number of factors, which include but are not limited to the effectiveness of inhibiting DAAO, improving basic behavioral functioning, hyperactivity, anxiety, depression, sensorimotor gating, pain threshold, memory or enhancing cognitive functioning, and/or alleviating at least one symptom associated with the target disease, or the effectiveness for mitigating the side effects of another agent of the combination. For example, a combined therapy described herein may reduce any of the side effects associated with each individual members of the combination, for example, a side effect associated with the second therapeutic agent.

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of neuroscience, molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, <NPL>). <NPL>; <NPL>); <NPL>; <NPL>; <NPL>);<NPL>; <NPL>; <NPL>); <NPL>. ); <NPL>); <NPL>);<NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>); <NPL>);<NPL>).

Without further elaboration, it is believed that one skilled in the art can, based on the above description, utilize the present invention to its fullest extent. The specific embodiments provided herein are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

The activity of tannic acids for inhibiting D-amino acid oxidase (DAAO) was determined as follows.

The activity of DAAO was determined in vitro by measuring the inhibition of the catabolism of known substrate, D-proline. The cofactor FAD (<NUM> fM) was added to the DAAO stock solution first. For the assay, potential inhibitors of tannic acid(s) were mixed with reaction mixture containing phosphate buffered saline (<NUM> NaCl, <NUM> KCl, <NUM> Na<NUM>HPO<NUM>, <NUM> NaH<NUM>PO<NUM>, pH <NUM>), horseradish peroxidase (<NUM> U/ml), o-phenylendiamine (OPD, <NUM>%), and <NUM> <IMG>g human-(or porcine-) DAAO, and incubated for about <NUM>. After the pre-incubation period, <NUM> D-proline were added as substrate and the reaction continued for <NUM>. OPD was oxidized to form <NUM>,<NUM>-diaminophenazine (DAP) by horseradish peroxidase. The absorbance of DAP was measured at <NUM> by a spectrophotometry. Assay was done in serial dilutions of the inhibitors to generate IC<NUM> and analyzed by Prism (Graphpad Software). In the analysis, the spectrophotometry readings were fit to a standard equation to determine the concentration of <NUM> % inhibition (IC<NUM>). All enzymatic assays were conducted at room temperature in <NUM>-well plate format.

As shown in <FIG>, tannic acids as a group showed a strong D-amino acid oxidase (DAAO) inhibitory activity with an IC<NUM> value of <NUM>.

The DAAO inhibitory activities of subgroups of tannic acids (having a particular number of galloyl moieties) were determined as follows. Tannic acid fractions having different numbers of galloyl moieties were separated by a reversed-phase column (LiChroprep® RP-<NUM>) with a mobile phase of acetonitrile and distilled water in gradient elution. The DAAO inhibitory activity of each tannic acid fraction at <NUM> (Table <NUM>) and <NUM> (<FIG>, Table <NUM>) was analyzed by the method described above, using distilled water and <NUM>% DMSO aqueous solution as blank controls and sodium benzoate as a positive control.

Table <NUM> shows the anti-DAAO activities of tannic acids with different numbers of galloyl moieties. Tannic acids with four or more <NUM> galloyl moieties showed much higher activity in inhibiting DAAO as compared with tannic acids with less than <NUM> galloyl moieties. All DAAO assays were done with <NUM> µM of tannic acids.

Table <NUM> shows the anti-DAAO activities of tannic acids with different numbers of galloyl moieties at <NUM>. <NUM> galloyl moieties showed weak activity, while the higher numbers of galloyl moieties showed significantly higher inhibition of DAAO activities.

Table <NUM> below shows the IC50 (µM) of anti-DAAO activities of tannic acids with different numbers of galloyl moieties. The IC<NUM> were determined for each tannic acid with different numbers of galloyl moieties, which indicating potent tannic acids with more than <NUM> galloyl moieties. Tannic acids with four or more <NUM> galloyl moieties showed much smaller IC50 and more potent in inhibiting DAAO as compared with tannic acids with less than <NUM> galloyl moieties. (G=number of galloyl group).

Therefore, purification of tannic acids with more than <NUM> galloyl moieties enriches the potency as indicated by the smaller IC<NUM>, as compared to the tannic acid mixture (Table <NUM>). The results show that tannic acids having more than <NUM> galloyl moieties (e.g., <NUM>-<NUM>) exhibited higher DAAO inhibition potency than the tannic acids having <NUM> and less galloyl moieties.

The objective of this study was to verify the effects of multiple doses of tannic acids on basic metabolism, behavioral functioning, and cognitive behaviors. In this experiment, the body weight, spontaneous locomotion activity, anxiety-like behaviors, spatial learning and memory, depressive-like behaviors and sensorimotor gating function of each mouse were examined following the repeated injections or oral administrations of tannic acids. These activities are known to be mediated by the NMDA receptor. (<NPL>);<NPL>]; <NPL>; <NPL>;<NPL>]; <NPL>]; <NPL>]). An exemplary illustration of this study is shown in <FIG>.

C57BL/6J male mice were group housed (<NUM>-<NUM> mice per cage) with food and water available ad libitum in polysulfone ventilated cages (Alternative Design, AR, USA) in the animal rooms. The colony was maintained on a <NUM>/<NUM>-h light/dark cycle at the temperature of <NUM> ± <NUM> and all behavioral studies were performed during the dark cycle. All animals used in this study were adult mice (at least <NUM> months of age).

Tannic acids were purchased from Sigma (Sigma-Aldrich, USA). The adult mice were randomly assigned to three groups: (<NUM>) control, (<NUM>) tannic acid (<NUM>/kg), and (<NUM>) tannic acid (<NUM>/kg), which were treated, respectively, by a vehicle control (PBS), tannic acid at <NUM>/kg, and tannic acid at <NUM>/kg. Two weeks prior to the behavioral tests, all mice were injected intraperitoneally (i. ) with either the vehicle control or tannic acid every other day. The body weight of each mouse, which served as an index of its physical development and metabolism, was recorded on the day of injection.

All mice treated with either the vehicle control or the tannic acids as described above were tested sequentially by <NUM> tasks: (<NUM>) open field task for spontaneous locomotion test, (<NUM>) anxiety-like behaviors test by elevated plus maze, (<NUM>) spatial learning and memory test by Barnes maze, (<NUM>) depressive-like behaviors test by tail suspension, and (<NUM>) sensorimotor function test by prepulse inhibition. At least a <NUM>-week interval was made between different tasks. In order to minimize carryover effects, the tasks were arranged in the sequence to ensure that the more stressful task did not occur prior to a less stressful one. The procedures are described in<NPL>).

During the period of repeated injections, the body weight of the tannic acid (<NUM>/kg) group were increased at a level lower than that of the control group, while the body weight of the tannic acid (<NUM>/kg) was much lighter than the controls.

The open field task is a common measurement of novelty induced exploratory behavior and general activity in both mice and rats. In this study, the mice were placed in a PLEXIGLAS® cage (<NUM> × <NUM> × <NUM>) under <NUM>-<NUM> lux light intensity. Their spontaneous locomotor activities were measured for <NUM> minutes using the EthoVision video tracking system (Noldus Information Technology, the Netherlands). The travel distance of each mouse was measured as an index of locomotion activity. As shown in <FIG>, tannic acids reduced the travel distances of the treated mice in a dose-dependent manner.

A similar experiment was carried out, in which mice were administered orally at <NUM>/kg, <NUM>/kg, <NUM>/kg, <NUM>/kg, and <NUM>/kg for a single dose and their locomotion activities were measured for <NUM> minutes, <NUM> minutes, <NUM> minutes, and <NUM> minutes. Tannic acids at all tested doses reduced the locomotion of the treated mice as compared with the mice treated with the vehicle control. The results are illustrated in <FIG>.

An elevated plus maze consisting of two open arms and two closed arms was used to assess the instinctively anxious behavior. The maze was elevated <NUM> from the floor with two open arms (each <NUM> long × <NUM> wide), two closed arms plus <NUM> high walls without a roof (each <NUM> long × <NUM> wide), and a square shaped central platform (<NUM> × <NUM>). Each mouse was placed in the central platform and faced toward one of the closed arms for observation under <NUM>-<NUM> lux light intensity for <NUM> minutes. The time spent on each part of the maze and travel distance on each part of maze were recorded by the EthoVision tracking system (Noldus Information Technology, the Netherlands).

The aversive duration ratio of each group was shown in <FIG>, Panel A. In comparison to the control group, the tannic acid (<NUM>/kg) group displayed marginal higher aversive duration ratios whereas the tannic acid (<NUM>/kg) group did not. The aversive distance ratio of each group was shown in <FIG>, Panel B. The tannic acid (<NUM>/kg) group displayed significant higher aversive distance ratios as compared with the control group. The number of risk assessments of each group is displayed in <FIG> Panel C. As compared to the control group, both tannic acid groups displayed significant lower risk assessments (all p < <NUM>).

Mice were tested in the Barnes maze to examine their spatial learning and memory as described previously (<NPL>]). The testing apparatus was an elevated (<NUM> above the floor) circular PLEXIGLAS® plate (<NUM> in diameter) with <NUM> holes (<NUM> in diameter, <NUM> between holes) evenly spaced around the perimeter. The mice were trained on the plate to identify an escape box (<NUM> × <NUM> × <NUM>) hidden behind the target hole, which was designated as an analog to the hidden platform in the Morris water maze task. The location of the target hole was selected for each mouse but randomized across mice. Mice were initially placed at the center of the plate covered by an opaque cylinder, and the cylinder was removed <NUM> seconds after the beginning of the trial with both an aversive tone (<NUM>, <NUM> dB) and the lights (<NUM> lux) switched on. The mice were trained to locate the target hole according to surrounding visual cues and escape from the aversive tone for three training trials per day over <NUM> consecutive days. The spatial memory was measured by the "probe test". All of the training trials and the probe trials were videotaped for <NUM> minutes. Then, the escape latency for the training trials and the percentage of time in different quadrants (target, left, right, and opposite) during the probe test were analyzed. In the probe test, the tannic acid (<NUM>/kg) group displayed a significant preference to the target zone whereas the other groups did not, as illustrated in <FIG>.

The basic metabolism, behavior functioning, and cognitive behaviors characteristics of mice treated with tannic acids with multiple injections at various doses were studied in the experiments described in Example <NUM>. In summary, three main findings were noted.

First, the body weight of mice in the tannic acid (<NUM>/kg) group decreased. This group of mice also displayed lower spontaneous locomotion in the open field. The open field tasks were used to test novelty-induced locomotor activity and general motor functions (<NPL>]; <NPL>]). Without being bound by theory, the decreased locomotion activity in mice with repeated tannic acid injections may be resulted from the faster habituation to the novel environment.

Second, the anxiety-like behaviors of mice treated with tannic acid were decreased in the elevated plus maze. The elevated plus maze task is a mouse model for putative anxiolytic or anxiogenic compounds screening (<NPL>]; <NPL>]). The increase in the proportion of time spent in open arms represents lower anxiety in the plus maze. In the experiment, mice with repeated injections displayed not only higher proportion of time spent in open arms but also higher proportion of travel distance in open arms and lower risk assessment. These results support that repeated injections of tannic acid reduced the anxiety-like behaviors in the elevated plus maze.

Third, mice with repeated tannic acid injections displayed the enhancement of spatial memory retrieval in the Barnes maze. The Barnes maze is a task to evaluate the cognitive function in mice, especially the spatial learning and memory (<NPL>]). Based on the advancement of the understanding of specific cognitive functional domains, an increasing amount of clinical research emphasizes the impact of cognitive deficits in many mental illnesses including schizophrenia, dementia, Alzheimer's disease, depression, and obsessive compulsive disorder (OCD) etc. (<NPL>]; <NPL>];<NPL>]; <NPL>];<NPL>]). In the probe test (memory retrieval phase), the tannic acid (<NUM> group) displayed preference to the target zone. This evidence indicated that repeated injections of a high dose tannic acid was able to enhance the cognitive function in normal mice. Furthermore, NMDA receptor signaling is considered as an important role in the learning process and memory consolidation (<NPL>]; <NPL>]). Therefore, repeated injections of tannic acid may enhance the cognitive function through NMDA signaling in mice.

Thus, the results of this study indicate that tannic acids would be effective in weight reduction and improving basic behavioral functioning, hyperactivity, anxiety, memory and/or cognitive behavior. For example, a large percentage of children with ADHD have co-morbid learning disorder that can also be improved by tannic acid, given its effects on learning and memory.

The objective of this experiment was to assess the potential mechanisms of action of tannic acids in treating CNS disorders, using MK801, a well-known NMDA receptor antagonist. Tannic acids and MK801 were administrated in mice by intraperitoneal (i. ) injections before the behavioral tests (i.e., open field and prepulse inhibition), respectively.

This experiment was designed to characterize the mechanism of action of tannic acid. MK801, also known as dizocilpine, is an antagonist of NMDA receptor (<NPL>]). It has been used in many aspects of NMDA hypo-function induced symptoms of central nerve system diseases, including stereotypic behaviors, anhedonia, learning and memory deficits, working memory impairment and sensorimotor function abnormalities (<NPL>]; <NPL>]; <NPL>]; <NPL>]; <NPL>]). The objective of these experiments was to assess the effects of tannic acids on mice with hypo-function NMDA receptor. An exemplary experimental design is illustrated in <FIG>.

C57BL/6J male mice were group housed (<NUM>-<NUM> mice per cage) with food and water available ad libitum in polysulfone ventilated cages (Alternative Design, AR, USA) in the animal rooms. The colony was maintained on a <NUM>/<NUM>-h light/dark cycle at the temperature of <NUM> ± <NUM> and all behavioral studies will be performed during the dark cycle. All animals used in this study were adult mice (at least <NUM> months of age).

The mice were randomly assigned into six groups:.

Each mouse in Groups <NUM>-<NUM> received an acute administration of MK-<NUM> (Sigma-Aldrich, USA) dissolved in normal saline, <NUM>/kg, i. ) <NUM> minutes prior to the behavioral tests. Each mouse in Groups <NUM>-<NUM> received an acute administration of tannic acids (Sigma-Aldrich, USA; dissolved in PBS, <NUM>, <NUM>, <NUM> or <NUM>/kg, i. ) <NUM> minutes prior to the MK801 administration.

All mice in this study were tested with open field task and prepulse inhibition task with at least <NUM>-week interval between two tasks. An additional cohort of mice was used to test the effect of different sources of tannic acid on prepulse inhibition.

Compared to the control group (Group <NUM>), the MK801 group (Group <NUM>) displayed a hyper-locomotion activity. The tannic acid <NUM>, <NUM>, and <NUM> groups (Groups <NUM>, <NUM>, and <NUM>) displayed a lower locomotion activity than the control group as illustrated in <FIG>. In comparison to the MK801 group (Group <NUM>), all tannic acid groups displayed lower locomotion activity, as shown in <FIG>.

Pre-attentive processes tend to be automatic and rapid, and to operate outside of conscious awareness, whereas deliberate attention processes have limited resources, require more efforts, and operate more slowly. A common measure of pre-attentive process is prepulse inhibition. This paradigm has been commonly examined in mouse models of several mental illnesses (e.g., schizophrenia, Alzheimer's disease) because the deficit manifests in a similar manner to the human symptom. (<NPL>]; <NPL>]; <NPL>]).

Prepulse inhibition was used as an index of sensorimotor gating function using SR-LAB startle apparatus (San Diego Instruments, San Diego, CA, USA). Under <NUM> dB background noise, each session was composed of <NUM> minutes accumulation period followed by <NUM> trials in four blocks. The pulse alone (PA) trial was a <NUM>, <NUM> dB white noise burst. In the prepulse (pp) + pulse trials, a <NUM> white noise prepulse stimuli of <NUM> dB (pp6), <NUM> dB (pp10), and <NUM> dB (pp18) were presented <NUM> before a <NUM> <NUM> dB pulse. The non-stimulus (NS) trials presented the background noise only. The initial and the last blocks were composed of six PA trials, respectively. Two middle blocks consisted of PA, pp + pulse, and NS trials. These trials were presented pseudo-randomly and separated by intertribal intervals of <NUM> seconds on average (varying between <NUM> to <NUM>). The percentage of prepulse inhibition was evaluated by the following formula: % PPI = <NUM> × [(PA score) - (pp-P score)] / (PA score), where the PA score was the average of the PA value in the middle blocks. Tannic acid improved the prepulse inhibition as in <FIG> and dose-dependently, as demonstrated in <FIG>.

In <NUM> dB prepulse intensity, no significant difference was found among the <NUM> groups. In <NUM> dB prepulse intensity, MK801 and tannic acid (<NUM>/kg) groups did not show the difference relative to the control group. As compared to the control group, the tannic acid (<NUM>/kg) group displayed a marginally higher percentage of prepulse inhibition, and the tannic acid (<NUM>/kg) and tannic acid (<NUM>/kg) groups displayed significantly higher percentages of prepulse inhibition. In terms of the <NUM> dB prepulse intensity, compared to the control group, the tannic acid (<NUM>/kg), tannic acid (<NUM>/kg) and tannic acid (<NUM>/kg) groups displayed significantly higher percentages of prepulse inhibition as compared with the control group, while no such results was observed in the MK801 and tannic acid (<NUM>/kg) groups, as depicted in <FIG>.

The objective of this experiment was to evaluate the effects of different sources of tannic acids on prepulse inhibition. Tannic acids purchased from Sigma-Aldrich (source A) and from Spectrum, USA (source B) at <NUM>/kg were used in this study.

With respect to the <NUM> dB and <NUM> dB prepulse intensities, no significant difference was observed between the mice treated with tannic acids of the two sources and the control group or the MK801 group. In terms of the <NUM> dB prepulse intensity, both tannic acid groups displayed significantly higher percentages of prepulse inhibition as compared with the control group whereas no such results was observed in the MK801 group. The results obtained from the mice treated with source A tannic acids and source B tannic acids were similar, as shown in <FIG>.

Though psychosis symptoms are challenging to observe and measure in animal models, the psychosis-related behaviors can be tested include psychomotor agitation, excitement symptoms, sensory gating and sensitivity to psychotomimetic drugs, such as MK801 (<NPL>]; <NPL>]). In mice, parameters related to hyper-locomotion activity and alteration of novelty-induced locomotion activity (either impairment of habituation to novelty or increased exploration) in an open field task can be used to measure the psychomotor agitation and excitement symptoms, respectively ( <NPL>]; <NPL>]; <NPL>]). In the present study, the administration of tannic acid, both by i. or per os (p. ) routes, reversed/protected MK801 induced hyper-locomotion activity in the open field. The result indicated that the tannic acids are a potential therapeutic agent for treating psychosis symptoms (e.g., delusions and hallucinations).

In the prepulse inhibition task, <NUM>/kg of tannic acid was sufficient to enhance the sensorimotor gating function in mice treated with MK-<NUM>. In addition, different sources of tannic acid did not affect the enhancement of sensorimotor function in the prepulse inhibition task. Deficits in prepulse inhibition has been commonly considered as a schizophrenic endophenotype in mouse models because the deficit manifests can be identified similarly in humans (<NPL>]; <NPL>];<NPL>]). The deficits of prepulse inhibition were also found in other central nerve system diseases, including autism spectrum disorder (<NPL>]), obsessive compulsive disorder, Huntington's disease, nocturnal enuresis, attention deficit disorder, Tourette's syndrome, blepharospasm, non-epileptic seizures, post-traumatic stress disorder (<NPL>]), panic disorder, bipolar disorder, mild dementia of Alzheimer's, dementia with Lewy bodies, and combined attention-deficit hyperactivity disorder and tic disorder (<NPL>];<NPL>];<NPL>]; <NPL>]).

As such, tannic acids are a promising therapeutic agent for various CNS disorders. Further, tannic acids reduce both spontaneous and MK-<NUM> induced hyperlocomotion, indicating that tannic acids Tannic acid can serve as a therapeutic agent to improve symptoms of ADHD and its related disorders.

Moreover, it was observed that tannic acids could reduce body weights in mice treated thereby, indicating that tannic acids would be effective in control body weight and/or treating obesity and its related disorders.

The objective of this experiment was to assess the potential mechanisms of action of tannic acids in treating CNS disorders, using MK801, a well-known NMDA receptor antagonist. Tannic acids and MK801 were administrated in mice by oral gavage (p. ) and intraperitoneal (i. ) injections respectively before the behavioral tests (i.e., open field, prepulse inhibition, Barnes maze and sucrose preference), respectively.

The mice were randomly assigned into five groups:.

Each mouse in Groups <NUM>-<NUM> received an acute administration of MK-<NUM> (Sigma-Aldrich, USA) dissolved in normal saline, <NUM>/kg for open field and Barnes maze tasks, and <NUM>/kg for prepulse inhibition and sucrose preference tasks by i. injection) <NUM> minutes prior to the behavioral tests. Each mouse in Groups <NUM>-<NUM> received an acute oral administration of tannic acids (Merck Millipore, Germany; dissolved in PBS, <NUM>, <NUM>, or <NUM>/kg, p. ) <NUM> minutes prior to the MK801 administration.

All mice in this study were tested with open field task, prepulse inhibition task, Barnes maze and sucrose preference with at least <NUM>-week interval between tasks.

In this test, tannic acids were administered orally <NUM> minutes before the MK801 (<NUM>/kg) injection. As shown in <FIG>, MK801 induced hyper-locomotion and tannic acids rescued the MK801-induced hyper-locomotion in a dose-dependent manner.

Compare to the control group, MK801 (<NUM>/kg) induced robust prepulse inhibition deficits. In <NUM> dB and <NUM> dB prepulse intensities, tannic acid (<NUM>, <NUM> and <NUM>/kg) did not rescue/protect the MK801-induced prepulse inhibition deficits. In terms of the <NUM> dB prepulse intensity, compared to the MK801 group, the tannic acid (<NUM>/kg), and tannic acid (<NUM>/kg) groups displayed significantly rescue/protective effects on MK801 induced prepulse inhibition deficit. Whereas no such results was observed in the MK801 and tannic acid (<NUM>/kg) groups, as illustrated in <FIG>.

Tannic acid dose-dependently improves the memory retrival of Barnes maze task in the MK-<NUM>-treated mice as shown in <FIG>.

Compare to the control group, mice in MK801 group did not show the preference toward the sucrose solution (<NUM>%). Compare to the MK801 group, mice with tannic acid <NUM>/kg and <NUM>/kg displayed rescue/protective effects on MK801 induced depressive-like behavior (anhedonia) as shown in <FIG>.

The objective of this experiment was to assess the analgesic effects of tannic acid in mice. Tannic acids were administrated in mice by intraperitoneal (i. ) injections before the behavioral tests (i.e., von Frey test).

Another cohort was used for von-Frey test (a typical assay for pain sensation). The paw withdrawal thresholds of each mouse were sampled before drug injection and <NUM>, <NUM>, <NUM> and <NUM> after drug injection as shown in <FIG>.

C57BL/6J male mice were group housed (<NUM> mice per cage) with food and water available ad libitum in polysulfone ventilated cages (Alternative Design, AR, USA) in the animal rooms. The colony was maintained on a <NUM>/<NUM>-h light/dark cycle at the temperature of <NUM> ± <NUM> and all behavioral studies will be performed during the dark cycle. All animals used in this study were adult mice (at least <NUM> weeks of age).

The mice were randomly assigned into two groups:.

Each mouse in Groups <NUM> received an acute administration of PBS as a vehicle control by i. Each mouse in Groups <NUM> received an acute administration of tannic acids (Merck Millipore, Germany; dissolved in PBS <NUM>/kg, i.

At baseline, no difference was found between groups. Compare to the PBS control, the threshold of Group <NUM> was significantly higher at <NUM>, <NUM> and <NUM> after drug injection as shown in <FIG>.

The compositions and inhibitory activities against D-amino acid oxidase (DAAO) of <NUM> commercial tannic acids from different suppliers were compared.

The compositions of <NUM> commercial tannic acids were determined by HPLC and the inhibitory activities against D-AAO were determined by the method illustrated in Example <NUM>.

- Instrument: Agilent <NUM> Column: Atlantis T3 <NUM>*<NUM>, <NUM>
- Mobile phase A: Water + <NUM>% Trifluoroacetic acid
- Mobile Phase B: Methanol : Acetonitrile <NUM> : <NUM> (v/v)
- Column temperature: <NUM>
- Detector: DAD <NUM>
- Flow rate: <NUM>/min
- Sample preparation: <NUM>/mL
- Injection volume: <NUM>µL
- Diluent: water
- Gradient:.

The HPLC chromatograms of <NUM> tannic acids from different plant sources are illustrated in <FIG>.

The inhibitory activities of <NUM> commercial tannic acids against DAAO and their compositions are illustrated in Table <NUM>.

Tannic acids extracted from Rhus chinensis have much higher percentage of <NUM>-<NUM> and much lower <NUM>-<NUM> percentage than tannic acids from Quercus infectoria.

Tannic acids were extracted from gallnuts of different plant sources as indicated and their inhibitory activity against D-amino acid oxidase (DAAO) was investigated.

Tannic acid producing gallnuts from a suitable plant source (see Table <NUM> below) were milled by a mechanical grinder and passed through a <NUM>-mesh sieve to produce fine gallnut powder.

The fine gallnut powder (<NUM>) was placed in <NUM> of a suitable solvent (e.g., acetone, acetonitrile, methyl ethyl ketone (MEK), ethyl acetate (EtOAc), ethanol (EtOH), isopropanol, tetrahydrofuran, or <NUM>,<NUM>-dioxane). The mixture thus formed was stirred at either RT or <NUM> overnight. The resultant solution was filtered, and the filtrate was concentrated in vacuum to generate a composition containing tannic acids.

The inhibitory activities of the tannic acids extracted from gallnuts of different plant sources against DAAO, following the above method, are illustrated in Table <NUM>. The comparison of gallnuts of various diameters and their DAAO IC<NUM>'s is illustrated in <FIG>.

As illustrated in Table <NUM> and <FIG>, either gallnuts from Rhus chinensis or Rhus potaninii have lower IC<NUM>'s against DAAO (stronger inhibition) than those from Quercus infectoria. Moreover, smaller gallnuts from Rhus chinensis (diameters of <NUM>-<NUM>) and Rhus potaninii (diameters of <NUM>-<NUM>) have lower IC<NUM>'s as compared to the larger (diameters of <NUM>-<NUM>) gallnuts from the same plant sources.

Tannic acids extracted from gallnuts of each plant source noted herein were enriched as described below. Their inhibitory activities against DAAO were investigated.

The fine gallnut powder (<NUM>) was placed in <NUM> of a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) and the mixture thus formed was stirred at either RT or <NUM> for <NUM> hr. The resultant solution was filtered, and the filtrate was concentrated in vacuum to form a composition containing tannic acids. The composition was mixed with <NUM> of <NUM> or <NUM>% methyl ethyl ketone/hexane solution (<NUM>% or <NUM>% methyl ethyl ketone in hexane). The mixture thus formed was further stirred at RT for <NUM> hr, and the resulting two organic layers were separated. The oilier layer (the lower layer) was concentrated in vacuum to produce a crude solid. The solid was dissolved in <NUM> of a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol), and the resulting solution was mixed with charcoal (<NUM>). The resulting mixture was stirred at RT for <NUM> hr and CaSO<NUM> or MgSO<NUM> (<NUM>) was added into the mixture. The mixture thus formed was further stirred at RT for <NUM> and filtered through a bed of Celite, washed with a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM> mLx2), and concentrated in vacuum. The resultant solid (containing tannic acids) was dissolved in acetone or ethyl acetate (<NUM>), and then the solution thus formed was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) dropwise. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to produce an enriched tannic acid solid.

The fine gallnut power (<NUM>) was placed in <NUM> of a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, ethanol) was stirred at RT for <NUM> hr. The solution thus formed was filtered, and the filtrate collected was mixed with <NUM> of hexane. The mixture was stirred at RT for <NUM> hr, and the resulting two organic layers were separated. The oiler layer (lower layer) was concentrated in vacuum and the solid thus obtained was dissolved in <NUM> of a suitable solvent (acetone, methyl ethyl ketone, ethyl acetate, ethanol, etc.). The resulting solution was mixed with charcoal (<NUM>) and further stirred at RT for <NUM> hr. The mixture thus obtained was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>. The mixture was filtered through a bed of Celite, washed with (acetone, methyl ethyl ketone, ethyl acetate, ethanol, etc.) (<NUM>×<NUM>), and concentrated in vacuum. The crude residues thus obtained were dissolved in acetone or ethyl acetate (<NUM>), and the solution thus formed was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) slowly. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to produce an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) was stirred at RT for <NUM> hr. The resultant solution was filtered, and the filtrate was collected. The filtrate was then added into <NUM> hexane. The mixture thus formed was stirred at RT for <NUM> hr, and the resulting two organic layers were separated. The oilier layer (lower layer) was collected and mixed with <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) and charcoal (<NUM>) and the resulting mixture was stirred at RT for <NUM> hr. The mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>, filtered through a bed of Celite, and washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM> mLx2). The filtrate thus collected was concentrated in vacuum and the resultant solid substances were dissolved in acetone or ethyl acetate (<NUM>). The solution thus formed was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) dropwise. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to form an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) to form a mixture, which was stirred at RT for <NUM> hr. The mixture was mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The resultant mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>, filtered through a bed of Celite, washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>). The filtrate was concentrated in vacuum, the resultant residue was dissolved in acetone or ethyl acetate (<NUM>), and the solution thus formed was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) slowly. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to produce an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) and the mixture thus formed was stirred RT for <NUM> hr. The mixture was mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>. The mixture was filtered through a bed of Celite, and washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>). The filtrate was concentrated down to about <NUM>-<NUM> and the resulting solution was mixed with CH<NUM>Cl<NUM> (<NUM>~<NUM>) dropwise. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to form an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) and the solution thus formed was stirred at RT for <NUM> hr, and then filtered. The filtrate was collected and mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>. The resulting mixture was then filtered through a bed Celite, washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>), and the combined filtrates were concentrated by vacuum evaporation. The crude solid thus formed was dissolved in acetone or ethyl acetate (<NUM>), and the solution was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) slowly. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to give an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of <NUM>% or <NUM>% methyl ethyl ketone/hexane and was stirred at RT for <NUM> hr. The resultant mixture was filtered and solids were collected. The solids were then mixed with <NUM> solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol). The mixture thus formed was stirred at RT for <NUM> hr, filtered and the filtrate was collected. The filtrate was then mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The resulting mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>, filtered through a bed of Celite, washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>), and the filtrate was concentrated by vacuum evaporation. The residue thus obtained was dissolved in acetone or ethyl acetate (<NUM>), and then the solution was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) dropwise. The solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to produce an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of <NUM> or <NUM>% methyl ethyl ketone/hexane and was stirred at RT for <NUM> hr. The solution was filtered and the solid collected was mixed with <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol). The mixture was stirred at RT for <NUM> hr and filtered, and the filtrate collected was mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The resulting mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>. The mixture was then filtered through a bed of Celite, washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>), and the filtrate was concentrated down about <NUM>~<NUM>. The residual solution was mixed with CH<NUM>Cl<NUM> (<NUM>~<NUM>) slowly and the solid thus formed was collected by filtration and dried under vacuum at <NUM> for <NUM> hr to produce an enriched tannic acid composition.

The fine gallnut power (<NUM>) was placed in <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) and was stirred at <NUM>~<NUM> for <NUM> hr. The solution was filtered and the filtrate collected was placed in <NUM> of hexane. The mixture thus formed was stirred at RT for <NUM> hr, and the two resulting organic layers were separated. The oiler layer (lower layer) was collected and mixed with <NUM> of solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol), and the solution thus formed was mixed with charcoal (<NUM>) and stirred at RT for <NUM> hr. The mixture was further mixed with CaSO<NUM> or MgSO<NUM> (<NUM>) and stirred at RT for <NUM>. The mixture was then filtered through a bed of Celite, washed with solvent (acetone, methyl ethyl ketone, ethyl acetate, or ethanol) (<NUM>×<NUM>), and the filtrate was concentrated under vacuum. The residue thus formed was dissolved in acetone or ethyl acetate (<NUM>), and then the solution was stirred and mixed with CH<NUM>Cl<NUM> (<NUM>) dropwise. The solid thus formed was collected by filtration and dried under vacuum at <NUM>~<NUM> for <NUM> hrs to produce an enriched tannic acid composition.

The inhibitory activities of differently enriched tannic acids extracted from gallnuts of different plant sources against DAAO are illustrated in Tables <NUM> and <NUM>.

As shown in Table <NUM>, all enriched tannic acids by any of the preparation methods described herein showed lower IC<NUM> values (indicating stronger inhibition) than those without being enriched (direct extraction only, no removal of tannic acids with <NUM>-<NUM> galloyl moieties, no treatment with charcoal and CaSO<NUM> or MgSO<NUM>, and/or no further treatment with the second solvent and methylene chloride). Moreover, enrichment methods <NUM> and <NUM> provided the enriched tannic acids with the lowest IC<NUM>'s activities against DAAO, as compared with methods <NUM> and <NUM>, while enrichment method <NUM> afforded the enriched tannic acid with a lower IC<NUM> value than enrichment method <NUM>. Also shown, the tannic acid from extraction with EtOH followed by enrichment method <NUM> showed slightly weaker inhibition than that with MEK followed by the same enrichment method.

As illustrated in Table <NUM>, extraction by ethyl acetate (EtOAc) at the extraction temperature of <NUM> followed by enrichment method <NUM> afforded the enriched tannic acid with a much lower IC<NUM> against DAAO than extraction by MEK at room temperature, extraction by MEK at <NUM>, and extraction by MEK at <NUM> followed by enrichment method <NUM>, respectively. Furthermore, as shown in Tables <NUM> and <NUM>, gallnuts from Rhus chinensis with the diameters of no more than <NUM> showed lower IC50 values than those of more than <NUM>.

Claim 1:
A composition for use in treating a central nervous system (CNS) disorder, wherein the composition comprises (i) a mixture of tannic acids or an acceptable salt thereof, and (ii) a carrier, wherein the composition contains no more than <NUM>% of tannic acids having three or less galloyl moieties, wherein no more than <NUM>% of the tannic acids in the mixture have <NUM>-<NUM> galloyl moieties, and wherein at least <NUM>% of the tannic acids in the mixture have <NUM>-<NUM> galloyl moieties, and
wherein the CNS disorder is selected from the group consisting of ADHD, learning disorder, schizophrenia, pain, depression, suicidal ideation and/or behavior, bipolar disorder, tic disorder, post-traumatic stress disorder, anxiety, social anxiety disorder, panic disorder, autism, Asperger's disorder, obsessive-compulsive disorder (OCD), Tourette's syndrome, mild cognitive impairment, dementia, vascular dementia, Alzheimer's disorder, frontotemporal dementia, Parkinson's disorder, Huntington's disease, nocturnal enuresis, blepharospasm, cerebral malaria and non-epileptic seizure.