Synergistic medicinal compositions for treating dysfunctional D-serine signaling

Abstract

The invention disclosed herein relates to novel synergistic medicinal compositions for treating dysfunctional D-serine (DSR) signaling. Particularly the invention provides potent synergistic medicinal composition comprising combination of N-acetyl taurinate salt of divalent metal (M.sup.2+AT) as serine racemase enzyme (SR) activator/stimulator and benzoic acid ester salt of monovalent or divalent metals (M.sup.+/2+Bz) as d-amino acid oxidase enzyme (DAAO) inhibitor, which are present in weight ratio of 1:0.001 to 1:1.5 along with pharmaceutically acceptable excipients. Further the present synergistic medicinal composition is useful for treating certain neuropsychiatric disorders, neurological disorders and metabolic disorders.

Claims

1. A synergistic medicinal composition, comprising: therapeutically active, medicinal ingredients and pharmaceutically acceptable excipients, wherein the therapeutically active, medicinal ingredients consisting of magnesium acetyl taurate and sodium benzoate in a weight ratio of 1:0.001 to 1:1.5, wherein the composition is effective for treating dysfunctional D-serine signaling.

2. The potent synergistic medicinal composition according to claim 1, wherein the magnesium acetyl taurate is present in a range of 20% to 98% by weight of the total composition.

3. The potent synergistic medicinal composition according to claim 1, wherein the sodium benzoate is present in a range of 1% to 50% by weight of the total composition.

4. The potent synergistic medicinal composition according to claim 1, wherein the pharmaceutically acceptable excipients are selected from the group consisting of a diluent present in a range of 1 to 30%; a binder present in a range of 0.1 to 25%; a lubricant present in a range of 0.1 to 5.0%; a glidant present in a range of 0.1 to 5.0%; an additive present in a range of 1 to 10%; a surfactant present in a range of 0.1 to 5.0%; a stabilizer present in a range of 0.1 to 5.0%; and a plasticizer present in a range of 0.1 to 5.0%, by weight of the total composition.

5. The potent synergistic medicinal composition according to claim 1, wherein an effective unit dose of the composition for an oral administration is formulated in a range of 10 mg to 1000 mg.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 illustrates schematic presentation of synergistic effect of M.sup.2+AT and M.sup.+/2+Bz on DSR signaling.

(2) FIG. 2 illustrates Pharmacokinetics-Area under the plasma blood concentration time curve (AUC) 2(i): Plasma Normal Control, 2(ii): Disease Control, 2(iii): Reference standard, 2(iv): Test 1 [MgAT], 2(v): Test 2 [NaBz], 2(vi): Test 1+Test 2 [MgAT+NaBz].

(3) FIG. 3 illustrates Pharmacokinetics-Area under the plasma brain tissue concentration time curve (AUC) 3(i): Brain Tissue Normal Control, 3(ii): Disease Control, 3(iii): Reference standard, 3(iv): Test 1 [MgAT], 3(v): Test 2 [NaBz], 3(vi): Test 1+Test 2 [MgAT+NaBz].

(4) FIG. 4 is a representation of magnesium 2-acetamidoethanesulfonate dihydrate (Formula I) having a chemical formula C.sub.8H.sub.20MgN.sub.2O.sub.10S.sub.2.

DETAILED DESCRIPTION OF THE INVENTION

(5) The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully interpreted and comprehended. However, any skilled person or artisan will appreciate the extent to which such embodiments could be generalized in practice.

(6) It is further to be understood that all terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting in any manner or scope.

(7) Unless defined otherwise, all technical and scientific expressions used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the invention pertain. In describing and claiming the embodiments of the present invention, the following terminology will be used in accordance with the definitions set out below which are known in the state of art.

(8) The singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise. Also the term “composition” does not limit the scope of the invention for multiple compositions that can be illustrated for best mode of the invention.

(9) The term “pharmaceutically/nutraceutically acceptable salt”, as use herein, represents those salts which are within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.

(10) Particularly the term “pharmaceutically-acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds, mono or divalent metal salts, as well as solvates, co-crystals, polymorphs and the like of the salts.

(11) As used herein, the term “comprising” is intended to mean that the compositions, methods, indications include the recited elements, but not excluding others.

(12) The term “medicinal composition” refers to compositions used to cure a disease or relieve pain. Moreover, the composition comprising active ingredients pertains to curative, healing, officinal, remedial, restorative and therapeutic behavior.

(13) The term “non-proteinogenic” amino acid refers to amino acids which are not coded for by DNA (not present in genetic code). Some amino acids contain the opposite absolute chirality, chemicals that are not available from normal ribosomal translation/transcription machinery.

(14) In current scenario DSR or D-serine is non-proteinogenic which is not naturally encoded by DNA but it is produced endogenously by racemization of naturally coded proteinogenic amino acids called LSR or L-serine.

(15) Moreover DSR is chiral molecule of serine with dextrorotary, which is endogenously synthesized by pyridoxal 5′-phosphate (PLP) binding serine racemase (SR) enzyme catalyzed racemization of levorotatory enantiomer of serine. The SR enzyme is physiologically stimulated or allosterically activated by divalent metal ions (e.g., magnesium) either in free form or in ATP complex.

(16) D-serine amino acid possesses great significance in health, nutrition, and overall metabolism. The term “co-agonist” defines a chemical entity that does not naturally occur in the body and acts on one or more receptors by structural mimicry of the receptors' natural ligand(s).

(17) It may be an agonist or partial agonist for particular receptor, promoting a receptor mediated biological response often by competing with another substance (usually the natural or native substance) at the same receptor at the same receptor.

(18) A partial agonist produces less than the maximum effect even if in a concentration sufficient to bind with all available receptors. D-serine that to co-agonize the NMDA receptor with even greater potency than glycine. It is produced by serine racemase, and is enriched in the same areas as NMDA receptors. It is an optically active amino acid that can combine with a NMDA receptor on a cell to produce a physiologic reaction typical of a naturally occurring substance. Co-agonist implies it is one of other agonists working in conjunction. D-serine can be released both by neurons and astrocytes to regulate NMDA receptors.

(19) NMDA receptors (NMDARs) support patterning and activity of synapses throughout life and are central to many brain disorders. The NMDAR activation requires the concomitant binding of glutamate and a coagonist glycine or D-serine, when NMDAR is activated it allows positively charged ions to flow through the cell membrane. NMDARs also require the binding of the co-agonist glycine for the efficient opening of the ion channel, which is a part of this receptor.

(20) Further the phrase “allosteric regulation” (or allosteric control) defines the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. The site to which the effector binds is termed the allosteric site or regulatory site.

(21) In preferred embodiment, the invention provides novel synergistic medicinal composition for treating or ameliorating dysfunctional D-serine (DSR) signaling.

(22) In particular embodiment, the invention provides potent medicinal composition comprising combination of generally recognized as safe and effective chemical substances or ingredients for enriching endogenous DSR level with no severe side effects.

(23) In preferred embodiment, the invention provides synergistic combination of N-acetyl taurinate salt of divalent metal (M.sup.2+AT) as serine racemase enzyme (SR) activator/stimulator and benzoic acid ester salt of mono valent or divalent metals (M.sup.+/2+Bz) as d-amino acid oxidase enzyme (DAAO) inhibitor which are present in specific weight ratio along with pharmaceutically acceptable excipients to enhance the concentration of non-proteinogenic amino acid co-agonist at NMDAR.

(24) In another embodiment, the invention provides synergistic medicinal composition that regulates the concentration of D-serine at NMDAR as non-proteinogenic co-agonist through synergistic effect of two potential therapeutic agents, wherein one agent is N-acetyl taurinate salt of divalent metal and benzoic acid ester salt of mono or divalent metals, wherein the divalent metals are selected from the group consisting of magnesium, manganese, calcium, zinc and the monovalent metals are selected from the group consisting of lithium, potassium and sodium.

(25) In yet another embodiment, the invention provides synergistic medicinal composition wherein one active moiety is N-acetyl taurinate salt of divalent metal, wherein the divalent metal is magnesium. Particularly the one active moiety is magnesium acetyl taurate [MgAT].

(26) According to the invention, DSR is “non-proteinogenic” D-isomer amino acid which is synthesized from naturally encoded “proteinogenic” L-isomer amino acid called LSR. Particularly biosynthesis of DSR from LSR is racemization or isomerization reaction which is catalyzed by pyridoxal-5′-phosphate (PLP) dependent enzyme serine racemase (SR).

(27) The activity of SR enzyme depends on binding motifs that control PLP (pyridoxal phosphate) cofactor binding as well as divalent cations and ATP binding.

(28) Interestingly, the divalent metal ion activates allosterically serine racemase where Mn.sup.2+ leads to the highest increase in activity of the enzyme (153% @10 μM), followed by Ca′ (134% @1 mM) and Mg.sup.2+ (112% @10 μM) relative to the purified human SR without divalent cation supplementation [Front Mol Biosci. 2019; 6: 8]. However the purpose of taurinate salt in the present composition is not only to improve the bioavailability of divalent metal ion but also to provide antioxidant that reduces hydrogen peroxide (H.sub.2O.sub.2)-induced oxidative stress.

(29) The present composition provides highly water soluble and bioaviable salt of divalent cation (M.sup.2+AT) i.e acetyl taurinate salt of Mn, Mg or Ca wherein the acetyl taurinate salt provides binding site for serine racemase activity thus enhances the rate of racemization of D-serine from L-serine subsequently regulated DSR concentration improve NMDAR activation.

(30) D-serine is a key regulator of NMDAR activity and important physiological ligand at the coagonist site. D-serine synthesis and release, or its metabolism fine tunes NMDAR activation.

(31) Further oxidation of D-serine occurred with the concomitant production of hydrogen peroxide which is regulated by taurinate present in the salt. Taurinate has potential antioxidant effects that subsequently reduce hydrogen peroxide (H.sub.2O.sub.2)-induced oxidative stress, neurotoxicity, neuroinflammation.

(32) In another preferred embodiment, the N-acetyl taurinate salt of divalent metal (M2.sup.+AT) is magnesium acetyl taurate (MgAT) also known as magnesium acetyl taurinate, ATA-Mg, magnesium acetyl taurinate dehydrate and magnesium 2-acetylamino ethane sulfonic acid.

(33) MgAT is chemically known as magnesium 2-acetamidoethanesulfonate dihydrate. It has a chemical formula C.sub.8H.sub.20MgN.sub.2O.sub.10S.sub.2 represented in FIG. 4 as Formula I. Magnesium acetyl taurate is a white powder that is soluble in water.

(34) In another embodiment, the invention provides synergistic medicinal composition comprising a therapeutically effective amount of N-acetyl taurinate salt of divalent metal, wherein M.sup.2+AT is present in the range of 1-5000 mg containing 1-500 mg of elemental magnesium (M.sup.2+) by the weight of total composition.

(35) In another embodiment, the invention provides synergistic medicinal composition comprising therapeutically effective amount of magnesium acetyl taurate present in the range of 1-1000 mg by the weight of total composition.

(36) In another embodiment, the invention provides synergistic medicinal compositions wherein the magnesium acetyl taurate comprises 6 to 8% w/w of elemental magnesium, particularly 6.7% w/w of elemental magnesium by weight of the magnesium acetyl taurate.

(37) Further, the acetyl taurate is present in the range of 91.0%-95.0% w/w, particularly acetyl taurate is present in an amount 94.7% w/w by weight of the magnesium acetyl taurate.

(38) Particularly 250 to 750 mg magnesium acetyl taurate/day providing 17 to 51 mg magnesium/day and 233 to 699 mg acetyl taurate/day, equal to 3.9 to 11.7 mg/kg bw/day for a 60 kg adult.

(39) ‘Manganese’ (Mn.sup.2+) is an essential trace element; it is needed for good health but is only required in tiny amounts. Further adequate intake of 3 mg/day for all adults while for labeling 2 mg/day is recommended by EFSA.

(40) It is further highlighted that Mn.sup.2+ is more active at divalent metal binding site of human SR on the other hand Mg.sup.2+ and Ca.sup.2+ stimulated/activated SR through divalent metal cation binding as well as ATP binding site. The ATP-Ca.sup.2+ complex produces a 2-fold lower maximal activation in comparison to the ATP-Mg.sup.2+ complex and exhibits a 3-fold higher EC.sub.50 (half maximal effective concentration) [Biochim Biophys Acta Proteins Proteom. 2017 April; 1865(4): 381-387].

(41) Conversely high doses of D-serine have been reported to cause nephrotoxicity resulting from D-serine oxidation catalyzed by DAAO. D-amino acid oxidase (DAAO) also known as OXDA, DAMOX) is an enzyme with the function on a molecular level to oxidize D-amino acids to the corresponding imino acids, producing β-hydroxypyruvate, ammonia and hydrogen peroxide.

(42) Usually hydrogen peroxide is associated with oxidative stress, whereas large amounts of β-hydroxypyruvate have been shown to induce cell death. Consequently, DAAO inhibition provide protection against potential toxic side effects from high doses of D-serine [Neuropsychopharmacology: 41, 1610-1619(2016)]. Further peripheral DAAO inhibition has the potential of reducing the need for high doses of D-serine.

(43) D-serine undergoes oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine stimulator with a DAAO inhibitor is feasible way to lower the D-serine dose required to treat neurological and psychiatric diseases caused due to dysregulation of D-serine.

(44) In another preferred embodiment, the invention provides synergistic medicinal composition, wherein the other active moiety is M.sup.+/2+Bz as d-amino acid oxidase enzyme (DAAO) inhibitor, wherein M.sup.+ is monovalent cation or mono valent metal ion and M.sup.2 is divalent cation or divalent metal ion and Bz denotes benzoic acid ester or benzoate salt.

(45) In another embodiment the invention provides synergistic medicinal composition, wherein the monovalent metal ions are selected from the group consisting of lithium, potassium, sodium; whereas divalent metal ions are selected from the group consisting of calcium, magnesium, zinc, and manganese.

(46) In certain embodiments the benzoic acid, benzoic acid salt, or derivative thereof is selected from the group consisting of benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, 2-aminobenzoate, 3-aminobenzoate, and 4-aminobenzoate.

(47) According to the invention, the DAAO inhibitor not only inhibits the degradation or oxidation of D-serine but also reduces neurotoxicity. Therefore, in the present composition the synergistic effect of tuarine and DAAO inhibitors leads to substantial decrease in oxidative stress, excitotoxicity and neuroinflammation.

(48) In another preferred embodiment the benzoic acid ester salt of metal ion is sodium benzoate. Sodium benzoate is an organic sodium salt resulting from the replacement of the proton from the carboxy group of benzoic acid by a sodium ion. Sodium benzoate is a substance which has the chemical formula C.sub.6H.sub.5COONa represented below as Formula II. It is a widely used food preservative, with an E number of E211. It is the sodium salt of benzoic acid and exists in this form when dissolved in water.

(49) ##STR00001##

(50) In another embodiment, the invention provides synergistic medicinal composition comprising a therapeutically effective amount of benzoate salt of metal ion, wherein M.sup.+/2+Bz is present in the range of 1-3000 mg of total composition. Particularly synergistic medicinal composition comprises therapeutically effective amount of sodium benzoate in the range of 1 to 1500 mg of total composition.

(51) In yet another embodiment, the invention provides synergistic medicinal composition comprising combination of M.sup.2+AT present in the range of 1-5000 mg containing 1-500 mg of elemental M.sup.2+ and M.sup.+/2+Bz present in the range of 1-3000 mg of total composition.

(52) In yet another embodiment, the invention provides synergistic medicinal composition comprising sodium benzoate present in the range of 1-1000 mg by weight of total composition.

(53) In certain embodiment, the invention provides synergistic medicinal composition comprising therapeutically effective combination magnesium acetyl taurate present in the range of 10 to 750 mg and sodium benzoate present in the range of 10-1000 mg of total composition.

(54) Consequently in the present composition one moiety improves the production of D-serine (DSR) from L-serine (LSR); simultaneously the other moiety inhibits further degradation of D-serine, thus maintaining the optimum D-serine at NMDAR and thereby augment DSR mediated NMDAR function.

(55) In one preferred embodiment the invention provides, a potent synergistic medicinal composition comprising therapeutic combinations of an effective amount of N-acetyl taurinate salt of divalent metal (M.sup.2+AT) and benzoic acid ester salt of monovalent or divalent metals (M.sup.+/2+Bz), which are present in the weight ratio of 1:0.001 to 1:1.5 along with pharmaceutically acceptable excipients.

(56) In yet another preferred embodiment, the invention provides novel and stable synergistic medicinal compositions for treating dysfunctional D-serine transmission or signaling comprising synergistic medicinal exogenous blend or combination of N-acetyl taurinate salt of divalent metal (M.sup.2+AT) and benzoic acid ester salt of monovalent or divalent metals (M.sup.+/2+Bz) are present in the weight ratio of 1:0.001 to 1:1.5, along with pharmaceutically acceptable excipients.

(57) In certain embodiment, the invention provides the potent synergistic medicinal compositions, wherein divalent metals are selected from the group consisting of magnesium, calcium, manganese, zinc and mono valent metals are selected from the group consisting of lithium, potassium, sodium. In particular embodiment, the divalent metal is magnesium and monovalent metal is sodium present in effective amount.

(58) In one preferred embodiment, the invention provides the potent synergistic medicinal composition, wherein the composition comprises therapeutic combinations of effective amount of magnesium acetyl taurate and sodium benzoate, which are present in the weight ratio of 1:0.001 to 1:1.5 along with pharmaceutically acceptable excipients.

(59) In another preferred embodiment, the invention provides potent synergistic medicinal compositions for treating neuropsychiatric disorders comprising therapeutically effective combination of bioavailable magnesium acetyl taurate and sodium benzoate, which are present in the weight ratio ranging from 1:0.001 to 1:1.5.

(60) In one more embodiment, the invention provides potent and stable synergistic medicinal composition comprising N-acetyl taurinate salt of divalent metal present in a range of 20% to 98% by weight of the total composition.

(61) In another embodiment, the invention provides potent and stable synergistic medicinal composition comprising benzoic acid ester salt of mono or divalent metals which is present in a range of 1% to 50% by weight of the total composition.

(62) In particular embodiment, the invention provides potent and stable synergistic medicinal composition comprising therapeutically effective combination of magnesium acetyl taurate (MgAT) present in a range of 20% to 98% and sodium benzoate present in a range of 1% to 50% by weight of the total composition.

(63) In another preferred embodiment, the invention provides stable, orally active antineuropsychiatric medicinal compositions with enhanced bioavailability comprising synergistic combination of therapeutically effective amount of magnesium acetyl taurate and sodium benzoate which are present in the weight ratio of 1:0.001 to 1:1.5, along with pharmaceutically acceptable excipients.

(64) In another preferred embodiment, the invention provides stable, orally active antineuropsychiatric medicinal composition with enhanced bioavailability, wherein the magnesium acetyl taurate is present in the rage of 20% to 98% and sodium benzoate is present in the range of 1% to 50% by weight of the total composition.

(65) As used herein, the term “therapeutically effective amount” is intended to mean that, ‘the amount of active compounds or chemical substances used in the present invention is significantly more effective for regulating D-serine signaling.

(66) Further the regulated D-serine ameliorates NMDAR signaling pathways in brain, pancreas, liver, adipose tissue, and kidney. In another embodiment, the invention provides synergistic medicinal composition, wherein the composition is useful for treating certain neuropsychiatric disorders, neurological disorders and metabolic disorders or specific pathological conditions related to N-methyl-D-aspartate receptors over- or down-regulation.

(67) The term “neuropsychiatric disorder” relates to medical term that encompasses a broad range of medical conditions that involve both neurology and psychiatry. Neuropsychiatry is concerned with disorders of affect, cognition, and behaviour that arise from overt disorder in cerebral function, or from indirect effects of extracerebral disease. It is mental disorders attributable to diseases of the nervous system.

(68) In another embodiment, the invention discloses potent medicinal synergistic composition which is useful for treating neuropsychiatric disorders including but not limited to neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD), seizures, autism spectrum disorder, and learning disorders, schizophrenia spectrum and other psychotic disorders, bipolar and related disorders, depressive disorders premenstrual dysphoric disorder (pmdd), anxiety disorders, generalized anxiety disorder (gad), cognitive deficit disorders, palsies, uncontrolled anger, migraine headaches. Addictions, hallucination, panic disorder, and phobias (extreme or irrational fears of specific things, such as heights), obsessive-compulsive disorder (OCD), hoarding disorder, and hair-pulling disorder (trichotillomania), trauma and stressor-related disorders, post-traumatic stress disorder (PTSD), acute stress disorder, dissociative identity disorder and dissociative amnesia, illness anxiety disorder, somatic symptom disorder (previously known as hypochondriasis), factitious disorder, feeding and eating disorders, elimination disorders, sleep-wake disorders, sexual dysfunctions, gender dysphoria, disruptive, impulse-control, and conduct disorders, substance-related, addictive disorders, neurocognitive disorders, personality disorders, paraphilic disorders and other mental disorders.

(69) Generally neuropsychiatric disorder include but are not limited to schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, schizotypal personality disorder, major depressive disorder, bipolar disorder, chronic hallucinatory psychosis, dissociative disorders, obsessive-compulsive disorder, induced delusional disorder, posttraumatic stress disorder, menstrual psychosis, cycloid psychosis depression, mania, bipolar disorder, visual hallucination, auditory hallucination, eating disorder, attention deficit hyperactivity disorder, Tourette's syndrome, other movement disorders, substance dependence (alcohol, cocaine), bipolar affective disorders, or unipolar affective disorder, and adolescent conduct disorder.

(70) Further the term neurological disorders relates to any disorder of the nervous system (central and peripheral nervous system). Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves like cranial nerves, peripheral nerves, nerve roots, autonomic nervous system, neuromuscular junction, and muscles can result in a range of symptoms.

(71) These disorders include epilepsy, Alzheimer disease, dementias, cerebrovascular diseases including stroke, migraine and other headache disorders, multiple sclerosis, Parkinson's disease, neuroinfections, brain tumours, traumatic disorders of the nervous system due to head trauma.

(72) Additionally, the term metabolic disorder discloses any disorder occurs when abnormal chemical reactions in human body disrupt the metabolic process. There are different groups of disorders. Some affect the breakdown of amino acids, carbohydrates, or lipids. Another group, mitochondrial diseases, affects the parts of the cells that produce the energy. Metabolic syndrome is a cluster of conditions that occur together, increasing risk of heart disease, stroke, type 2 diabetes, high blood pressure, high blood sugar, overweight, abdominal obesity, excess body fat around the waist, and abnormal cholesterol or triglyceride levels.

(73) In additional embodiment, the invention provides an additional bioenhancer to improve the bioavailability of the present composition by enhancing the absorption of active ingredients inside the body.

(74) In some embodiment, the invention provides synergistic combination of serine ravemase enzyme activator and D-amino-acid oxidase inhibitor present in weight ratio of 1:0.001 to 1:1.5 along with pharmaceutically acceptable excipients augments brain D-serine levels, for the treatment of schizophrenia.

(75) The term “therapeutically effective amount” denotes an amount that reduces the risk, potential, possibility or occurrence of a disease or disorder, or provides advanced alleviation, mitigation, and/or reduction or restoration or modulation, regulation of at least one indicator/biomarker (e.g., blood or serum CRP level), and/or minimize at least one clinical symptom related to dysfunctional DSR signaling.

(76) The term “subject in need thereof” pertains to subject preferably mammal, more preferably human suffering or suspected with neuropsychiatric disorders, neurological and metabolic disorders related to dysregulation of NMDAR and Serine racemase.

(77) The “subject in need thereof” pertains to subject preferably mammal, more preferably human with pre-existing symptoms of neuropsychiatric disorders or in a subject to prevent occurrence of neuropsychiatric disorders or subject with antineuropsychiatric drug intolerance or neuroleptic intolerance or antipsychotic/antineuropsychiatric medication side effects.

(78) In the context of the present invention, the terms “treatment” and the like refer to alleviating, mitigating, prophylaxis, attenuating, managing, regulating, modulating, controlling, minimizing, lessening, decreasing, down regulating, up regulating, moderating, inhibiting, suppressing, limiting, blocking, decreasing, preventing, inhibiting, stabilizing, ameliorating, curing, or healing the neuropsychiatric disorders like schizophrenia.

(79) Notably, the present synergistic composition is water-soluble, non-hazardous, non-toxic and generally recognized as safe for human consumption without any side effects, therefore the present medicinal composition can also be used under preventive therapy/adjuvant therapy/add-on therapy/combination therapy in a subject in need thereof.

(80) In another embodiment, the synergistic composition of the present invention is non-toxic, cost effective, enriched with nutrients or biomolecules and provides safeguard against neural dysfunction from harmful toxins, without any adverse effect.

(81) Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms (“polymorphs”). In general, all physical forms are of use in the methods contemplated by the present invention and are intended to be within the scope of the present invention. Compound or a pharmaceutically acceptable salt, hydrate, polymorph or solvate of a compound” intends the inclusive meaning of “or”, in that materials meeting more than one of the stated criteria are included, e.g., a material that is both a salt and a solvate is encompassed.

(82) Compounds of the invention can exist in particular geometric or stereoisomeric forms. The invention contemplates all such compounds, including dextrorotatory and levorotatory-isomers. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

(83) As used herein, the term “pharmaceutically acceptable carriers, diluents or excipients” is intended to mean, without limitation, any adjuvant, carrier, excipient, sweetening agent, diluents, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or encapsulating agent, encapsulating polymeric delivery systems or polyethyleneglycol matrix, which is acceptable for use in the subject, preferably humans. Excipients may also include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, fragrances, glidants (flow enhancers), lubricants, preservatives, sorbents, suspending or dispersing agents, sweeteners, surfactant, anticaking agent, food additives, or waters of hydration, salts.

(84) In another embodiment, the invention relates to synergistic medicinal composition, which can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. The preferable route of administration includes but not limited to sublingual, rectal, topical, parenteral, nasal or oral.

(85) In some embodiment, the present synergistic medicinal composition can be administered to the subject in need thereof, in the form which is suitable for oral use, such as a tablet, capsule (in the form of delayed release, extended release, sustained release, enteric coated release); hard gelatin capsules, soft gelatin capsules in an oily vehicle, veg capsule, hard or soft cellulose capsule, granulate for sublingual use, effervescent or carbon tablets, aqueous or oily solution, suspension or emulsion, encapsulate, matrix, coat, beadlets, nanoparticles, caplet, granule, particulate, agglomerate, spansule, chewable tablet, lozenge, troche, solution, suspension, rapidly dissolving film, elixir, gel, tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, sprays or reconstituted dry powdered form with a liquid medium or syrup; for topical use including transmucosal and transdermal use, such as a cream, ointment, gel, aqueous or oil solution or suspension, salve, parch or plaster; for nasal use, such as a snuff nasal spray or nasal drops; for vaginal or rectal use, such as a suppository; for administration by inhalation, such as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, such as a tablet, capsule, film, spray. Further the composition can be formulated for parenteral use including intravenous, subcutaneous, intramuscular, intravascular, infusion, intraperitoneal, intracerebral, intracerebroventricular, or intradermal.

(86) Formulations of the present invention suitable for oral administration can be presented as discrete units such as capsules (e.g., soft-gel capsules), cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, syrup; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredients can also be presented in the form of a a bolus, electuary or paste, nutritional bar, energy bars (candy bars), powder, granule sachet.

(87) Further, the present composition can be formulated in the form of age-appropriate pediatric oral dosage forms such as syrup, minitablets, chewable formulations, orodispersible films orodispersible tablets. It can also be prepared in the form of snack, chocolate bars or other confectionery food products.

(88) Notably, the present synergistic composition is stable, non-hazardous, non-toxic and safe for human consumption without any side effects, therefore the present nutritional composition can also be used under preventive therapy/adjuvant therapy/add-on therapy/combination therapy in a subject in need thereof.

(89) In another embodiment, the synergistic composition of the present invention is non-toxic, cost effective, enriched with nutrients or biomolecules and provides safeguard against problems associated with neurotransmission without any adverse effect.

(90) In another embodiment of the invention, the diluents are selected from starches, hydrolyzed starches, partially pregelatinized starches, anhydrous lactose, cellulose powder, lactose monohydrate, sugar alcohols such as sorbitol, xylitol and mannitol, silicified microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium lactate, dibasic calcium phosphate (anhydrous/dibasic dehydrate/tribasic), calcium silicate, calcium sulphate, cellulose acetate, corn starch, pregelatinized starch, dextrin, β-cyclodextrin, dextrates, dextrose, erythritol, ethyl cellulose, fructose, fumaric acid, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium-chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sterilizable maize, sucrose, sugar spheres, talc, trehalose, xylitol, vehicles like petrolatum, dimethyl sulfoxide and mineral oil or the like.

(91) In some embodiment of the invention, the diluent in the composition/formulation is present in a range of 1% to 30% by weight of the total composition/formulation.

(92) In yet another embodiment of the invention, the binder is selected from disaccharides such as sucrose, lactose, polysaccharides and their derivatives like starches, cellulose, or modified cellulose such as microcrystalline cellulose and cellulose ethers such as hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); sugar alcohols such as xylitol, sorbitol, or mannitol; protein like gelatin; synthetic polymers such as polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), starch, acacia, agar, alginic acid, calcium carbonate, calcium lactate, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, co-povidone, corn starch, pregelatinized starch, cottonseed oil, dextrates, dextrin, dextrose, ethyl cellulose, guar gum, hydrogenated vegetable oil, mineral oil, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxyl ethyl methyl cellulose, hydroxypropyl cellulose, inulin, cellulose, methyl cellulose, polyvinylpyrrolidone and polyethylene glycol, lactose, liquid glucose, hypromellose, magnesium aluminum silicate, maltodextrin, maltose, methyl-cellulose, microcrystalline cellulose, pectin, poloxamer, polydextrose, polymethacrylates, povidone, sodium alginate, stearic acid, sucrose, sunflower oil, various animal vegetable oils, and white soft paraffin, paraffin, flavorants, colorants and wax.

(93) In further embodiment of the invention, the binder in the composition/formulation is present in a range of 0.1 to 40% by weight of the composition/formulation.

(94) In another embodiment of the invention, the lubricant is selected from magnesium stearate, zinc stearate, calcium stearate, glycerin monostearate, glyceryl behenate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulphate, medium-chain triglycerides, mineral oil, myristic acid, palmitic acid, poloxamer, polyethylene glycol, sodium benzoate, sodium chloride, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc, potassium, or sodium benzoate or the like.

(95) In some embodiment of the invention, the lubricant in the composition/formulation is present in a range of 0.1% to 10.0% by weight of the total composition/formulation.

(96) In another embodiment of the invention, the solubilizing agent is selected from polysorbate 80, sodium lauryl sulphate, anionic emulsifying wax, nonionic emulsifying wax, glyceryl monooleate, phospholipids, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, polyoxylglycerides, sorbitan esters, triethyl citrate, vitamin E, polyethylene glycol succinate, microcrystalline cellulose, carboxymethyl cellulose sodium, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, hypromellose, hypromellose, acetate succinate, lecithin, polyethylene alkyl ethers, aluminum oxide, poly(methylvinyl ether/maleic anhydride), calcium carbonate, crospovidone, cyclodextrins, fructose, hydroxpropyl betadex, oleyl alcohol, povidone, benzalkonium chloride, benzethonium chloride, benzyl alcohol, benzyl benzoate, cetylpyridinium chloride, inulin, meglumine, poloxamer, pyrrolidone, sodium bicarbonate, starch, stearic acid, sulfobutylether beta cyclodextrin, tricaprylin, triolein, docusate sodium, glycine, alcohol, self-emulsifying glyceryl monooleate, cationic benzethonium chloride, cetrimide, xanthan gum, lauric acid, myristyl alcohol, butylparaben, ethylparaben, methylparaben, propylparaben, sorbic acid or the like.

(97) In another embodiment of the invention, the amount of solubilizing agent or surfactant in the composition/formulation ranges from 0.1% to 10% by weight of the composition/formulation.

(98) In a preferred embodiment of the invention, the solubilizing agent or surfactant is present in a range of 0.1% to 5.0% by weight of the composition/formulation.

(99) In some embodiment of the invention, the glidant is selected from colloidal silicon dioxide, magnesium stearate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, cellulose powdered, hydrophobic colloidal silica, magnesium oxide, zinc stearate, magnesium silicate, magnesium trisilicate, silicon dioxide or the like.

(100) In another embodiment of the invention, the glidant in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/formulation.

(101) In some embodiment of the invention, the stabilizers are selected from the group consisting of alginate, agar, carrageen, gelatin, guar gum, gum arabic, locust bean gum, pectin, starch, xanthan gum, trehalose and likewise.

(102) In some embodiment of the invention, the stabilizer in the composition/formulation is present in a range of 0.1% to 8.0% by weight of the total composition/formulation. In some embodiment of the invention, the plasticizers are added to coating formulations selected from the group propylene glycol, glycerol, glyceryl triacetate (triacetin), triethyl citrate, acetyl triethyl citrate, diethyl phthalate, actetylated monoglycerides, castor oil, mineral oil and like thereof.

(103) In some embodiment of the invention, the plasticizer in the composition/formulation is present in a range of 0.1% to 5.0% by weight of the total composition/formulation.

(104) In some embodiment of the invention, the solvent is selected from water, alcohol, isopropyl alcohol, propylene glycol, mineral oil, benzyl alcohol, benzyl benzoate, flavored glycol, carbon dioxide, castor oil, corn oil (maize), cottonseed oil, dimethyl ether, albumin, dimethylacetamide, ethyl acetate, ethyl lactate, medium-chain triglycerides, methyl lactate, olive oil, peanut oil, polyethylene glycol, polyoxyl, castor oil, propylene carbonate, pyrrolidone, safflower oil, sesame oil, soybean oil, sunflower oil, water-miscible solvents, organic polar or non-polar solvents or mixtures thereof.

(105) In a preferred embodiment of the invention, the solvent in the composition/formulation is used in a quantity sufficient to make the weight of the composition/formulation 100% by weight.

(106) The additional additives include a polymer, a plasticizer, a sweetener, and a powdered flavor, a preservative, a colorant, a surfactant, and other excipients. The powdered flavor composition includes a flavourant associated with a solid carrier. Coating materials such as synthetic polymers, shellac, corn protein (zein) or other polysaccharides, gelatin, fatty acids, waxes, shellac, plastics, and plant fibers and like thereof are used.

(107) In a preferred embodiment of the invention, the additives are used in a range of 1 to 20% w/w of unit dose.

(108) In yet another embodiment, the invention provides a synergistic nutritional composition comprising a therapeutic blend of a biotin-manganese complex and a stabilized oxaloacetate along with pharmaceutical excipients, wherein the pharmaceutical excipients are selected from a diluent, a binder, a lubricant, a glidant, an additive, a surfactant, a stabilizer or mixtures thereof.

(109) In a preferred embodiment, the diluent is present in a range of 1 to 30%; the binder present is present in a range of 0.1 to 25%; the lubricant is present in a range of 0.1 to 10.0%; the glidant is present in a range of 0.1 to 5.0%; the additive is present in a range of 1 to 10%; the surfactant is present in a range of 0.1 to 5.0%; the stabilizer is present in a range of 0.1 to 5.0%; and the plasticizer is present in a range of 0.1 to 5.0%; by weight of total composition.

(110) In a preferred embodiment, the present medicinal composition/formulation is formulated for oral administration. Specifically, the solid medicinal compositions, are in the form of tablets, capsules, pills, hard capsules filled with liquids or solids, soft capsules, sachets, powders, granules, suspensions, solutions, or modified release formulations. Formulations of the present invention suitable for oral administration are presented as discrete units such as capsules (e.g., soft-gel capsules, hard-gel capsule), cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, syrup; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

(111) In further embodiment compositions containing compounds of the invention, M.sup.2+AT and M.sup.+/2+Bz, can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient, or a pharmaceutically acceptable salt thereof.

(112) The magnitude of a prophylactic or therapeutic dose typically varies with the nature and severity of the condition to be treated and the route of administration. The dose, and perhaps the dose frequency, will also vary according to the age, body weight and response of the individual patient. In general, the total daily dose (in single or divided doses) ranges from about 1 mg per day to about 2500 mg per day, preferably about 10 mg per day to about 1000 mg per day. In some embodiments, the total daily dose can range from about 5 mg to about 4000 mg per day, and preferably about 5 mg to about 2000 mg per day.

(113) In another embodiment, the present invention provides a method for treating neuropsychiatric disorders in a subject in need thereof. The method comprises administering an oral dose of a therapeutically effective amount of a medicinal composition comprising an exogenous synergistic combination of magnesium acetyl taurate and sodium benzoate, wherein the magnesium acetyl taurate and sodium benzoate which are present in the a weight ratio of 1:0.001 to 1:1.5, along with pharmaceutically acceptable excipients.

(114) In certain embodiments, the invention provides the potent synergistic medicinal composition wherein the effective unit dose for an oral administration is formulated in a range of 10 to 1000 mg.

(115) It is further recommended that children, patients over 60 years old, initially receive low doses and that the dosage be titrated based on individual physiological responses and/or pharmacokinetics. It can be necessary to use dosages outside these ranges in some cases, as will be apparent to those in the art. The present composition can be used as infant formula as well as adult formula by varying the concentration of active ingredients. Further, it is noted that the dietician or nutritionist or certified physician knows how and when to interrupt, adjust or terminate therapy in conjunction with an individual patient's response.

(116) The use of any and all examples, or exemplary language (e.g., such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.

(117) While in the foregoing specification this invention has been described in relation to certain embodiments thereof, and many details have been put forth for the purpose of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein can be varied considerably without departing from the basic principles of the invention.

(118) The invention may be further illustrated by the following examples, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in anyway. The present invention is not to be limited in terms of the particular embodiments described in this application, which are intended as single illustrations of individual aspects of the invention. Functionally equivalent compositions and treatments within the scope of the invention, in addition to those enumerated herein, will be apparent to those skilled in the art from the foregoing description and examples. Such modifications and variations are intended to fall within the scope of the appended claims. The contents of each reference, patent and patent application cited in this application is hereby incorporated by reference in its entirety.

EXAMPLES

(119) Having described the basic aspects of the present invention, the following non-limiting examples illustrate specific embodiments thereof. Those skilled in the art will appreciate that many modifications may be made in the invention without changing the essence of invention.

Example 1

(120) i. Composition 1: Synergistic blend

(121) TABLE-US-00001 Ingredient w/w % Magnesium Acetyl Taurate 20 to 98% containing 6.7% w/w elemental Mg Sodium Benzoate  1 to 50%

(122) ii. Composition 2: Tablet/Capsule

(123) TABLE-US-00002 Ingredient w/w % unit dose Magnesium Acetyl 20 to 98% Taurate containing 6.7% w/w elemental Mg Sodium Benzoate  1 to 50% Excipient 5-20% Average Weight 100% Average weight in mg 300-500 mg

(124) iii. Composition 3: Tablet/Capsule

(125) TABLE-US-00003 Ingredient w/w % unit dose Magnesium Acetyl Taurate  20-75% Sodium Benzoate   1-40% Diluents   1-10% Binders  0.5-5% Glidants  0.5-5% Lubricants  0.5-5% Stabilizers 0.1-10% Additives   1-10% Solvents QS

(126) iv. Composition 4: Tablet/Capsule

(127) TABLE-US-00004 Ingredient mg per unit dose Magnesium Acetyl Taurate 50-75 Sodium Benzoate  1-10 Silicon dioxide  1-10 Hydroxypropyl Methylcellulose  1-10 Microcrystalline Cellulose  1-20 Zinc Stearate  1-10 PVP K-30  5-10 methylated-β-cyclodextrin  1-10 Polysorbate 80  1-10 Manitol  1-20 Propylene Glycol QS Water QS Average weight 100-150 mg

(128) v. Composition 5: Tablet/Capsule

(129) TABLE-US-00005 Ingredient mg per unit dose Magnesium Acetyl Taurate 350 Sodium Benzoate 300 Sodium ascorbate 1-10 Microcrystalline Cellulose 2-20 Silicon dioxide 5-15 Hydroxypropyl Methylcellulose 2-10 Magnesium citrate 2-10 PVP K-30 5-10 Talc 1-10 Tween 80 1-10 Manitol 5-20 Alcohol QS Water QS Average weight 700-800 mg

(130) vi. Composition 6: Tablet/Capsule

(131) TABLE-US-00006 Ingredient mg per unit dose Magnesium Acetyl Taurate 250 Sodium Benzoate 100 Sodium ascorbate 1-10 Microcrystalline Cellulose 2-20 Silicon dioxide 5-15 Hydroxypropyl Methylcellulose 2-10 Magnesium citrate 2-10 Dibasic calcium phosphate 1-20 PVP K-30 5-10 Talc 1-10 Tween 80 1-10 Manitol 5-20 Alcohol QS Water QS Average weight 370-450 mg

(132) vii. Composition 7: Tablet/Capsule

(133) TABLE-US-00007 Ingredient mg per unit dose Magnesium Acetyl Taurate 150 Sodium Benzoate 50 Microcrystalline Cellulose 1-10 Silicon dioxide 1-10 Hydroxypropyl Methylcellulose 1-10 Magnesium Stearate 2-10 Polyvinylpyrrolidone 1-10 Talc 1-10 Polysorbate 20 1-10 Manitol 1-10 IPA QS Water QS Average weight 200-250 mg

(134) viii. Composition 8: Tablet/Capsule

(135) TABLE-US-00008 Ingredient mg per unit dose Magnesium Acetyl Taurate 50 Sodium Benzoate 5 Silicon Dioxide 1-10 Microcrystalline Cellulose 2-20 Dibasic Calcium Phosphate 2-20 Magnesium Stearate 2-10 Croscarmellose sodium 2-10 Polyvinylpyrrolidone 1-20 Talc 1-10 Sodium ascorbate 1-10 Propylene glycol 1-10 Water QS Average weight 75-100 mg

(136) ix. Composition 9: Tablet/Capsule/Syrup

(137) TABLE-US-00009 Ingredient mg per unit dose Magnesium Acetyl Taurate 200 Sodium Benzoate 5 Microcrystalline Cellulose 1-10 Silicon dioxide 1-10 Hydroxypropyl Methylcellulose 1-10 Magnesium Stearate 2-10 Polyvinylpyrrolidone 1-10 2-Hydroxypropyl-β-cyclodextrin 1-10 Ascorbic Acid 1-10 Polysorbate 20 1-10 Sucrose 1-10 Manitol 1-10 Water QS Average weight 225-250 mg

Example 2: Animal Study

(138) To assess and compare the pharmacokinetics profile of D-serine in rat model.

(139) Test System and Animal Husbandry

(140) Species: Rats

(141) Strain: Sprague Dawley

(142) Sex: Male and Female

(143) No. of animals: 72 Animals (n=6 per group)

(144) Age: 8-12 weeks

(145) Body weight: 230-280 g

(146) Animal House Conditions

(147) Lighting: 12/12 hour light-dark cycle

(148) Temperature: 22±3° C.

(149) Relative Humidity: 30 to 70%

(150) Animals had continuous access to fresh, potable, uncontaminated drinking water.

(151) Feed: Normal chow diet

(152) Group, Designation and Dose Levels:

(153) Six groups were divided into 4 sets of 3 rats each/subset for bleeding and organ (brain) collection—Total 72 rats

(154) TABLE-US-00010 TABLE 1 Animal grouping and treatment details Animal dose (rat) No. of Groups Group Description mg/kg animals Group 1 Control—Normal  0.00 (3 × 4) 12 Group 2 Disease Control [L-Serine O-sulfate]  1.86 mg/kg (3 × 4) 12 Group 3 Standard [Olanzapine] [10 mg human  1.03 mg/kg (3 × 4) 12 dose] Group 4 Magnesium acetyltaurate-[ 350 mg 36.17 mg/kg (3 × 4) 12 human dose ] Group 5 Sodium benzoate -[300 mg human 31.01 mg/kg (3 × 4) 12 dose] Group 6 Magnesium acetyltaurate + Sodium 67.17 mg/kg (3 × 4) 12 benzoate- [650 mg human dose]

(155) TABLE-US-00011 TABLE 2 Sample details Time points/dose For Plasma sampling Set 1 (3 rat) - 0 (Pre-dose) Set 2 (3 rat) - 2 hr  Set 3 (3 rat) - 6 hr  Set 4 (3 rat) - 10 hr For Brain sampling Set 1 (3 rat) - 0 (Pre-dose) Set 2 (3 rat) - 2 hr  Set 3 (3 rat) - 6 hr  Set 4 (3 rat) - 10 hr Total Samples - 72 plasma samples + 72 brain samples.

(156) Blood samples: ˜5004, of blood was collected in tube containing 15% K3-EDTA through retro-orbital bleeding. Plasma was separated using refrigerated centrifuge & stored in −80° C. before analysis. Blood was collected at time point 0, 2, 6 and 10 hrs at least from 3 rats/group/time point.

(157) Organ (Brain) collection: Rats were sacrificed each time point (3 rats/group/time point) by decapitation at 0, 2, 6 or 10 hr post dose. Brain was removed and cerebellum dissected on ice. Tissue samples were frozen on dry ice and stored at −80° C. until analysis.

(158) After concentration step, the extract was commonly re-suspended in a solvent with 75% methanol followed by centrifugation at 12,000 rpm for 10 min at 4° C. Supernatant was filtered with 0.2 micron amicon syringe filter (Millipore, Hessen, Germany), then directly transferred into auto sampler vials

(159) An Accela™ ultra-high performance liquid chromatography (UHPLC) system (Thermo Fisher, Waltham, USA), coupled online via heated electrospray ionization source (HESI) with a Q-Exactive-Orbitrap mass spectrometer (Thermo Fisher), was employed for global metabolomics profiling with 1 μL sample injection volume. The metabolites were profiled using a C18 Hypersil Gold column (1.9 μm, 2.1×150 mm, Thermo).

(160) The temperature of column oven was set at 35° C. and the sample manager was maintained at 4° C. The eluents acetonitrile and water containing 0.1% formic acid were employed in the electrospray ionization-positive (ESI+) mode.

(161) Mobile Phase for Metabolites—

(162) Phase A solvent: Acetonitrile (ACN)

(163) Phase B solvent: Water containing 0.1% formic acid

(164) The flow rate was adjusted at 0.35 mL/min with a linear gradient elution over 20 min. From the start to 3 min, eluent CAN was held at 2%, linearly increased to 25% till 4 min, to 55% during next 4 min, and then to 98% in 15 min. Subsequently, eluent ACN was returned to 50% in 18 min then linearly decreased to 2% (initial conditions) till 20 min.

(165) Fundamental pharmacokinetic parameters such as Area under the plasma concentration-time curve [AUC], Area under the plasma concentration-time curve from time zero to time t [AUC.sub.t], Area under the plasma concentration-time curve from time zero to time of last measurable concentration [AUC.sub.last], Area under the first moment of the plasma concentration-time curve from time zero to infinity [AUMC.sub.t], Area under the first moment of the plasma concentration-time curve from time zero to time t [AUMC.sub.t], Elimination half-life [t½], Lag time [T.sub.lag], Time to reach maximum (peak) plasma concentration following drug administration [T.sub.max], Apparent total body clearance of the drug from plasma [CL], Maximum (peak) plasma drug concentration [Cmax] Apparent total clearance of the drug from plasma after oral administration [CL/F], Last measurable plasma concentration [C.sub.last], Apparent volume of distribution during terminal phase [Vz], Apparent volume of distribution during terminal phase after non-intravenous administration [Vz/F], Terminal disposition rate constant/terminal rate constant [λz], Mean residence time [MRT] were obtained from the non-compartmental analysis of the plasma/blood data using WinNonlin. The area under the plasma concentration time curve (AUC) value was calculated to the last quantifiable sample (AUClast) by using the log-linear trapezoidal rule.

(166) Results:

(167) TABLE-US-00012 TABLE 3 AUC value at different time interval [Blood Plasma Concentration] Plasma Concentration Time Conc ln(C) AUC AUMC R R_adj Normal 0 0.15553 −1.86092 0 0 −0.95065 0.855609 control 2 0.15448 −1.86769 0.31001 0.30896 −0.9104 0.65764 6 0.15431 −1.86879 0.92759 2.7786 10 0.15289 −1.87804 1.54199 7.68812 Diseased 0 0.037876 −3.27344 0 0 −0.94043 0.826618 Control 2 0.027781 −3.5834 0.065657 0.055562 −0.97455 0.899503 6 0.025459 −3.67069 0.172137 0.472194 10 0.020784 −3.87357 0.264623 1.193382 Reference 0 0.907876 −0.09665 0 0 −0.96882 0.907929 standard 2 0.857781 −0.15341 1.765657 1.715562 −0.94192 0.77443 (Olanzapine) 6 0.69459 −0.36443 4.870399 13.48177 10 0.660784 −0.41433 7.581147 35.03253 Test I (MgAT) 0 0.6786 −0.38772 0 0 −0.99917 0.997525 2 0.6074 −0.49857 1.286 1.2148 −0.99983 0.999311 6 0.5124 −0.66865 3.5256 9.7932 10 0.4274 −0.85003 3.4052 14.490 Test II (NaBz) 0 0.6386 −0.44848 0 0 −0.98399 0.952348 2 0.6174 −0.48224 1.256 1.2348 −0.99344 0.973834 6 0.52265 −0.64884 3.5361 9.9762 10 0.4072 −0.89845 3.3958 16.392 Test I + Test II 0 0.994232 −0.00578 0 0 −0.9994 0.998187 (MgAT + NaBz) 2 0.91585 −0.0879 1.910082 1.8317 −1 0.999992 6 0.799569 −0.22368 5.34092 15.08993 10 0.69872 −0.35851 8.337498 38.65916

(168) TABLE-US-00013 TABLE 4 Non-Compartmental Analysis of Plasma Data after Extravascular Input Normal Diseased Reference Test I + Control Control standard Test I Test II Test II Parameter Unit (Group 1) (Group 2 (Group 3) (Group 4) (Group 5) (Group 6) Lambda_z l/h 0.001509106 0.036271109 0.03401739 0.0439334 0.05202658 0.033825313 t1/2 h 459.3099544 19.11017323 20.37625986 15.7772256 13.3229432 20.49196633 Tmax h 0 0 0 0 0 0 Cmax μg/ml 0.15553 0.037876 0.907876 0.6786 0.6386 0.994232 Tlag h 0 0 0 0 0 0 Clast_obs/ 0.983025783 0.548737987 0.727835079 0.62982611 0.63764485 0.702773598 Cmax AUC 0-t μg/ml*h 1.54199 0.264623 7.581147 3.4052 3.3958 8.337498 AUC μg/ml*h 102.8536607 0.837641042 27.00603521 11.1335613 10.2225684 28.99421726 0-inf_obs AUC 0-t/ 0.014992077 0.315914558 0.280720474 0.35716643 0.40807503 0.287557271 0-inf_obs AUMC μg/ml*h{circumflex over ( )}2 68154.39516 22.72175702 800.3095839 343.207898 253.097562 855.9145367 0-inf_obs MRT h 662.634608 27.12588792 29.63447161 22.6785944 19.1413313 29.52018083 0-inf_obs Vz/F_obs (mg)/(μg/ml) 6.44259E−05 61.22011746 1.124808214 54.3966959 45.0630503 68.48580764 Cl/F_obs (mg)/(μg/ml)/h 9.72255E−08 2.220521568 0.03826304 2.38983186 2.34447643 2.316553897

(169) TABLE-US-00014 TABLE 5 AUC value at different time interval [Brain Tissue Sample] Plasma Concentration Time Conc ln(C) AUC AUMC R R_adj Normal 0 0.096006 −2.34334 0 0 −0.95065 0.855609 control 2 0.095358 −2.35012 0.191364 0.190716 −0.9104 0.65764 6 0.095253 −2.35122 0.572586 1.715185 10 0.094377 −2.36046 0.951846 4.745753 Diseased 0 0.02338 −3.75586 0 0 −0.94043 0.826618 Control 2 0.017149 −4.06583 0.040529 0.034298 −0.97455 0.899503 6 0.015715 −4.15311 0.106257 0.291478 10 0.01283 −4.356 0.163348 0.736656 Reference 0 0.560417 −0.57907 0 0 −0.96882 0.907929 standard 2 0.529494 −0.63583 1.089912 1.058989 −0.94192 0.77443 (Olanzapine) 6 0.428759 −0.84686 3.006419 8.322078 10 0.407891 −0.89675 4.67972 21.62502 Test I (P19A) 0 0.418889 −0.87015 0 0 −0.99917 0.997525 2 0.374938 −0.98099 0.793827 0.749877 −0.99983 0.999311 6 0.316296 −1.15108 2.176296 6.045185 10 0.263827 −1.33246 2.136543 9.11728 Test II (P19B) 0 0.394198 −0.9309 0 0 −0.98399 0.952348 2 0.381111 −0.96466 0.775309 0.762222 −0.99344 0.973834 6 0.322623 −1.13127 2.182778 6.158148 10 0.251358 −1.38088 2.230741 10.05679 Test I + Test II 0 0.613723 −0.48821 0 0 −0.9994 0.998187 (P19A + P19B) 2 0.56534 −0.57033 1.179063 1.130679 −1 0.999992 6 0.493561 −0.70611 3.296864 9.31477 10 0.431309 −0.84093 5.146604 23.86368

(170) TABLE-US-00015 TABLE 6 Non-Compartmental Analysis of Brain Tissue Sample after Extravascular Input Normal Diseased Reference Test I + Control Control standard Test I Test II Test II Parameter Unit (Group 1) (Group 2 (Group 3) (Group 4) (Group 5) (Group 6) Lambda_z l/h 0.001509106 0.036271109 0.03401739 0.043933401 0.052026581 0.033825313 t1/2 h 459.3099544 19.11017323 20.37625986 15.77722556 13.32294318 20.49196633 Tmax h 0 0 0 0 0 0 Cmax μg/ml 0.096006173 0.023380247 0.560417284 0.418888889 0.394197531 0.613723457 Tlag h 0 0 0 0 0 0 Clast_obs/Cmax 0.983025783 0.548737987 0.727835079 0.629826113 0.637644848 0.702773598 AUC 0-t μg/ml*h 0.951845679 0.163347531 4.67972037 2.13654321 2.230740741 5.146603704 AUC 0-inf_obs μg/ml*h 63.48991403 0.517062372 16.67039211 7.341704504 6.162079271 17.89766498 AUC 0-t/0-inf_obs 0.014992077 0.315914558 0.280720474 0.357166426 0.40807503 0.287557271 AUMC 0-inf_obs μg/ml*h{circumflex over ( )}2 42070.6143 14.02577594 494.0182617 211.8567273 156.233063 528.3423066 MRT 0-inf_obs h 662.634608 27.12588792 29.63447161 22.67859438 19.14133125 29.52018083 Vz/F_obs (mg)/(μg/ml) 0.104369994 99.17659028 1.822189306 88.12248404 73.00214148 110.9470084 Cl/F_obs (mg)/(μg/ml)/h 0.000157505 3.597244939 0.061986124 3.871520447 3.798051816 3.752817314
Discussion

(171) D-serine concentration-time profiles in plasma after oral administration of D-serine were shown in FIGS. 2 and 3, and the pharmacokinetic parameters were summarized in Table 4 and 6. D-Serine was substantially reduced when treated with serine racemase inhibitor i.e., L-Serine 0-sulfate over control. When composition G6 was given the C.sub.max and AUC were increased as compared to individual test samples G4 and G5.

(172) AUC values of D-serine were increased in a G4 and G5 dose-dependent manner in plasma and brain tissue samples. The increase in the AUC values of test sample with serine racemaze enzyme activator i.e Group 4 and test sample with DAAO inhibitor i.e., Group 5 were observed at dose 36.17 mg/kg and 31.01 mg/kg respectively.

(173) When G6 was administered with dose 67.17 mg/kg, it has shown significant increase in the AUC of plasma D-serine in MgAT+NaBz dose-dependent manner. The combination product further showed improved or enhanced D-serine level as compared to reference or marketed sample olazapine at dose 1.03 mg/kg.

(174) The oral administration of effective dose of present composition increases the plasma D-serine level by 5 to 8 folds over control.

(175) The oral administration of effective dose of present composition increase the plasma D-serine level by more than 55% as compared to individual active ingredient.

(176) According to the pharmacokinetics profile serine racimase (SR) enzyme activator and DAAO inhibitor are concurrently effective in enhancing plasma d-serine levels in a subject. In a concluding manner AUC of plasma concentration of combination of test samples in appropriate ratio gives synergistic effect with significant increase in plasma D-serine level.