Liposome formulation of l-serine and method for preparing same

Abstract

The present invention relates to a composition comprising a liposome that includes a lipid and L-serine or a pharmaceutically acceptable salt thereof. By providing a liposomal formulation capable of maximizing the efficacy of L-serine, the present invention improves the bioavailability, stability, and absorption rate of L-serine, reduces side effects, and thereby maximizes the therapeutic or preventive effect of L-serine on neurological, psychiatric, and cognitive disorders.

Description

Liposomal formulation of L-serine and method for preparing the same

[0001] The present invention relates to a composition comprising a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same for the prevention or treatment of neurological, mental, and cognitive disorders, and a use of the pharmaceutical composition. In addition, the present invention relates to a method for preparing a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof.

[0002] On the one hand, the present invention relates to a liposome formulation comprising lipid and L-serine or a pharmaceutically acceptable salt thereof, and to a liposome powder capable of maximizing the effect of L-serine.

[0003] L-serine is one of the 20 essential amino acids found in the human body and is a non-essential amino acid that plays a crucial role in the synthesis of proteins and neurotransmitters. In particular, L-serine is essential for maintaining nervous system function and is known to have potential efficacy in the prevention or treatment of various neurological, psychiatric, and cognitive disorders.

[0004] However, L-serine is inherently hydrophilic, which means it has a low bioavailability (absorption rate through the digestive system) when administered orally. This is a major limitation, as L-serine is not sufficiently absorbed and is excreted, making it difficult to reach the required blood concentration and ultimately hindering the full therapeutic effect of L-serine. This low bioavailability not only makes it difficult to exert the drug's effects, but also leads to the need for high-dose administration to achieve the target therapeutic effect, which can increase the likelihood of side effects.

[0005] Various studies have been conducted to improve the in vivo delivery efficiency of hydrophilic amino acids, such as L-serine, or water-insoluble amino acids or drugs. Among these, drug delivery systems using liposomes have attracted attention. Liposomes are spherical vesicles composed of a phospholipid bilayer structure similar to biological membranes. They possess a hydrophilic interior that can encapsulate hydrophilic substances, while their lipid bilayers can accommodate hydrophobic substances. Thanks to these characteristics, liposomes can efficiently encapsulate hydrophilic drugs, such as L-serine, preventing their degradation in vivo and enhancing their ability to cross absorption barriers, significantly improving drug stability and absorption rates.

[0006] [Prior Art Literature]

[0007] [Patent Document]

[0008] (Patent Document 1) Korean Patent Publication No. 2022-0131186

[0009] (Patent Document 2) Korean Patent Publication No. 2024-0105361

[0010] (Patent Document 3) Korean Patent Publication No. 2025-0081156

[0011] The purpose of the present invention is to provide a composition comprising a liposome comprising lipids and L-serine or a pharmaceutically acceptable salt thereof, thereby improving the bioavailability of L-serine and maximizing the effect of L-serine in the prevention or treatment of diseases related to the maintenance of the nervous system, such as neurological, mental and cognitive disorders.

[0012] [1] In one aspect of the present invention, the present invention relates to a composition comprising a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof.

[0013] [2] In the above [1], the lipid is lecithin, cholesterol, phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylethanolamine (PE), sphingomyelin (SM), It may be characterized by being selected from the group consisting of dimyristoylphosphatidylcholine (DMPC), dioleoylphosphatidylcholine (DOPC), dierucoylphosphatidylcholine (DEPC), phytosterol, and glycolipid.

[0014] [3] In the above [2], the composition may be a composition containing two or more types of the lipids.

[0015] [4] In the above [1], the content of the lipid is,

[0016] Based on 100 parts by weight of L-serine, it can be 10 parts by weight to 1,000 parts by weight.

[0017] [5] In the above [4], the content of the lipid is

[0018] Based on 100 parts by weight of L-serine, it can be 10 parts by weight to 200 parts by weight.

[0019] [6] In the above [1], the composition may additionally include at least one selected from the group consisting of a surfactant, a pH regulator, and an adsorbent.

[0020] [7] In the above [6], the surfactant may be at least one selected from the group consisting of polysorbate, sorbitan monooleate, polyethylene glycol, poloxamer, sodium lauryl sulfate, polyglyceryl ester, sorbitan ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene alkyl ether.

[0021] [8] In the above [6], the pH adjusting agent may be at least one selected from the group consisting of citric acid, potassium citrate, sodium citrate, phosphoric acid, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium phosphate, and potassium phosphate.

[0022] [9] In the above [6], the adsorbent may be at least one selected from the group consisting of calcium silicate, magnesium aluminate metasilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

[0023]

[0010] In one aspect of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating neurological, mental and cognitive disorders, comprising any one of the compositions [1] to [9].

[0024]

[0011] In the above

[0010] , the neurological, mental and cognitive disorder may be any one selected from the group consisting of autism spectrum, bipolar disorder, Tourette's, tics, Prader-Willi, attention deficit hyperactivity disorder (ADHD), Fragile-X syndrome, dementia, Alzheimer's, Parkinson's disease, Huntington's disease, affective disorder, sleep disorder, schizophrenia, depression, movement disorder, memory disorder, epilepsy, seizure disorders, cerebral palsy, neurodevelopmental delay and mild cognitive impairment (MCI).

[0025]

[0012] In the above

[0010] , the dosage form of the pharmaceutical composition may be selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquids, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, lyophilized preparations, suppositories, injections, and external preparations for skin.

[0026]

[0013] In one aspect of the present invention, the present invention relates to a method for preparing a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0027] a) liposome solution manufacturing step; and

[0028] b) Drying stage.

[0029]

[0014] In the above

[0013] , the step of preparing the liposome solution of a) may include a step of dissolving L-serine or a pharmaceutically acceptable salt thereof in a water-soluble solvent, adding the solution to a solution in which lipid is dissolved in an organic solvent, and stirring the solution.

[0030]

[0015] In the above

[0013] , the liposome solution manufacturing step of a) may include additionally adding a surfactant or a pH regulator.

[0031]

[0016] In the above

[0013] , the drying step of b) may include a step performed using a freeze dryer, a spray dryer, a fluid bed dryer, a vacuum dryer, or a water bath dryer.

[0032]

[0017] In the above

[0013] , the method for manufacturing the liposome may additionally include a liposome liquid adsorption step before the drying step of b).

[0033]

[0018] In the above

[0017] , the liposome liquid adsorption step may include a step of introducing at least one selected from the group consisting of calcium silicate, magnesium aluminate metasilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate as an adsorbent.

[0034]

[0019] In one aspect of the present invention, the present invention relates to a method for preventing or treating neurological, mental and cognitive disorders, comprising a step of administering a therapeutically effective amount of the pharmaceutical composition of

[0010] to a subject.

[0035]

[0020] In one aspect of the present invention, the present invention relates to the use of a therapeutically effective amount of the pharmaceutical composition of

[0010] for preparing a medicament for the prevention or treatment of neurological, mental and cognitive disorders.

[0036]

[0021] In one aspect of the present invention, the present invention relates to the use of the pharmaceutical composition of

[0010] in a therapeutically effective amount for the prevention or treatment of neurological, mental and cognitive disorders.

[0037] The present invention provides a liposomal formulation comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof, thereby improving the bioavailability, stability and absorption rate of L-serine and reducing side effects, thereby maximizing the effect of L-serine, and may be useful for the prevention or treatment of neurological, mental and cognitive disorders.

[0038] Figure 1 shows the results of a test (PK) performed to evaluate the pharmacodynamic characteristics after oral administration of each formulation to evaluate the in vivo absorption rate of liposome powder.

[0039] Hereinafter, the present invention will be described in more detail.

[0040] Each description and embodiment disclosed in this invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention is not limited by the specific descriptions described below.

[0041] Furthermore, those skilled in the art will recognize or be able to ascertain, through routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Furthermore, such equivalents are intended to be encompassed by the present invention.

[0042] definition

[0043] As used herein, the term “consisting of” means that the proportion of a particular component(s) totals 100%. The components or features listed below the term “consisting of” may be essential or mandatory.

[0044] As used herein, the term "comprising" means the presence of a feature, step, or component described below, and does not exclude the presence or addition of one or more features, steps, or components. Components or features described below "comprising" in this specification may be essential or mandatory, but some embodiments may further include other optional or non-essential components or features.

[0045] In this specification, the term “comprising” may, in some implementations, be modified to refer to “consisting essentially of” or “consisting of.”

[0046] In this specification, the term “lipid” refers to all organic compounds that are major components of biological membranes and are insoluble in water but soluble in organic solvents, and includes lipids as liposome-forming components. Specifically, the lipid may be at least one selected from the group consisting of lecithin, cholesterol, phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), and distearoylphosphatidylcholine (DSPC), and may include two or more types, but is not limited thereto.

[0047] As used herein, the term "L-serine" refers to one of the 20 standard amino acids found in the human body, which plays a crucial role in the synthesis of proteins and neurotransmitters, and is a non-essential amino acid. Specifically, in one embodiment of the present invention, L-serine may be encapsulated within liposomes as an active ingredient. L-serine may be a compound represented by the following chemical formula 1, but is not limited thereto.

[0048]

[0049] In this specification, the term “pharmaceutically acceptable salt” refers to all salt forms of an active ingredient (e.g., L-serine), which means a form prepared so that the active ingredient can maintain or even improve the original therapeutic efficacy without causing toxic reactions or serious side effects when administered to the human body. Such salts can be used for the purpose of improving the solubility, stability, absorption rate, bioavailability, and ease of preparation of drugs, and can be formed through various chemical bonds such as inorganic acids, organic acids, inorganic bases, and organic bases.

[0050] In one embodiment of the present invention, the pharmaceutically acceptable salt of L-serine is a salt of L-serine commonly used in the pharmaceutical industry, and may be a compound represented by the following chemical formula 2, but the type of the salt and the source thereof are not limited thereto. Specifically, the pharmaceutically acceptable salt may be an inorganic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, etc. of L-serine. The pharmaceutically acceptable salts of these examples may be used alone or in combination of two or more. More specifically, for example, the inorganic salt may be a metal salt including a calcium salt, a potassium salt, a sodium salt, a magnesium salt, etc., the inorganic acid salt may include a hydrochloride, a nitrate, a bromate, an iodate, a perchlorate, a tartrate, a sulfate, etc., and the organic acid salt may be, but is not limited to, acetate, trifluoroacetate, benzoate, citrate, gluconate, lactate, malate, mandelate, mesylate, fumarate, maleate, succinate, tartrate, glutamate, aspartate, etc.

[0051]

[0052] As used herein, the term "liposome" refers to a spherical vesicle composed of one or more phospholipid bilayers. This structure, similar to the composition of cell membranes, offers the advantages of high biocompatibility and low toxicity. Liposomes are formed by arranging the hydrophilic head and hydrophobic tail of the bilayer, forming an aqueous core capable of encapsulating hydrophilic drugs, while hydrophobic drugs can be encapsulated between the lipid bilayers. This structure can be utilized to enhance drug stability in the body, increase drug delivery efficiency to the target site, improve drug bioavailability, and reduce drug exposure to unnecessary sites, thereby alleviating side effects. The composition, size, and surface properties of liposomes can be varied depending on the type of drug to be encapsulated and the purpose of delivery.

[0053] As used herein, the term "lecithin" refers to a mixture of diglycerides of fatty acids linked to choline esters of phosphoric acid, which may include other compounds by isolation methods. Typically, the lecithin may be a mixture of acetone-insoluble phosphatides. Preferably, the lecithin may be obtained from soybeans, egg yolks, sunflower seeds, rapeseeds (canola oil), nuts, and corn using methods known in the art.

[0054] In this specification, the term "cholesterol" refers to a type of steroid, a basic substance that constitutes the cell membrane of animal cells, and a precursor of various steroid substances. Chemical formula C 27 H 46 It is indicated by O, and is insoluble in water, acids, and alkalis, but dissolves in organic solvents such as ether and chloroform.

[0055] In this specification, the term “neurological, mental, and cognitive disorders” refers to a broad group of diseases caused by any functional or structural abnormality related to the nervous system (brain, spinal cord, and peripheral nerves) of the human body. Neurological disorders are diseases caused by structural or functional damage to the nervous system itself, including the brain, spinal cord, and peripheral nerves, and affect motor, sensory, and cognitive functions: for example, they may include Tourette Syndrome, Tic Disorders, Parkinson's Disease, Huntington's Disease, Movement Disorders, Epilepsy, Seizure Disorders, Cerebral Palsy, and Neurodevelopmental Delay. Mental illness is a condition that involves serious changes in thinking, emotions, and behavior, causing disruption to daily life. It may be related to biochemical imbalances or structural abnormalities in the brain: For example, this may include bipolar disorder, mood disorders, sleep disorders, schizophrenia, and depression. Cognitive disorders are conditions that are characterized by impairment or decline in cognitive functions such as memory, learning ability, reasoning ability, and problem-solving ability: For example, this may include Autism Spectrum Disorder, Prader-Willi Syndrome, Attention Deficit Hyperactivity Disorder (ADHD), Fragile X Syndrome, Dementia, Alzheimer's Disease, Memory Impairment, and Mild Cognitive Impairment (MCI).

[0056] In this specification, the term “dosage form” refers to a pharmaceutical composition processed into a specific form for safely and effectively administering the active ingredient of a drug (e.g., L-serine or a pharmaceutically acceptable salt thereof) to a subject. In other words, it refers to the form of a final product that is physically and chemically stabilized so that the drug can exhibit the intended effect in the subject and designed to be absorbed through a specific route. The dosage form is determined by considering the drug’s solubility, stability, absorption rate, bioavailability, onset time of effect, minimization of side effects, and patient convenience of taking the drug. In addition, the dosage form can be determined by considering the route of administration, physicochemical properties of the drug, onset characteristics of effect, patient compliance, etc. Depending on the dosage, it can be divided into oral administration, parenteral administration, topical administration, etc., and depending on the form, it can be divided into solid preparations (e.g., tablets, pills, powders, granules, capsules, lyophilized preparations, etc.), liquid preparations (suspensions, oral solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solvents, etc.), injections, external preparations for skin, or suppositories.

[0057] In this specification, the term “prevention” means any act of suppressing the onset of clinical symptoms of a disease by administering a pharmaceutical composition according to the present invention.

[0058] In this specification, the term “treatment” means any action by which the clinical symptoms of a disease are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.

[0059] As used herein, the term “therapeutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject’s body weight, sex, age, health status, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0060] In the present invention, the term "administration" refers to introducing a given substance into a subject by any suitable method, and the pharmaceutical composition may be administered via any route as long as it can reach the target tissue. Such administration methods include, but are not limited to, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, topical administration, intranasal administration, intrapulmonary administration, and rectal administration. However, since proteins are digested during oral administration, it may be desirable to formulate oral compositions to coat the active agent or protect it from degradation in the stomach. Furthermore, the pharmaceutical composition may be administered by any device that allows the active agent to travel to target cells.

[0061] liposome composition

[0062] In one aspect of the present invention, the present invention relates to a composition comprising a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof.

[0063] The composition described above can maximize the effects of L-serine as an active ingredient encapsulated in a liposomal formulation of L-serine. According to one embodiment of the invention, the effects of L-serine can be maximized and exhibited in a subject by administering a composition comprising a liposomal formulation encapsulating L-serine.

[0064] In one aspect of the present invention, the lipid is lecithin, cholesterol, phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylethanolamine (PE), sphingomyelin (SM), dimyristoylphosphatidylcholine (DIMYR), It may be at least one selected from the group consisting of dioleoylphosphatidylcholine (DOPC), dierucoylphosphatidylcholine (DEPC), phytosterol, and glycolipid.

[0065] In another aspect of the present invention, the composition may include two or more types of lipids. For example, the composition may include two or more types of lipids, including a combination of lecithin and cholesterol, lecithin and phosphatidylcholine, lecithin and HSPC, lecithin and DPPC, or lecithin and DSPC.

[0066] In another aspect of the present invention, the lecithin may be a naturally occurring or synthetic lecithin that can be suitably purified. Specifically, the lecithin includes, but is not limited to, soybean lecithin or egg yolk lecithin. More specifically, the lecithin includes, but is not limited to, dihexanoyl-L-alpha-lecithin, dioctanoyl-L-alpha-lecithin, didecanoyl-L-alpha-lecithin, didodecanoyl-L-alpha-lecithin, ditetradecanoyl-L-alpha-lecithin, dihexadecanoyl-L-alpha-lecithin, dioctadecanoyl-L-alpha-lecithin, dioleoyl-L-alpha-lecithin, dilinoleoyl-L-alpha-lecithin, and alpha-palmitol.

[0067] In another aspect of the present invention, the cholesterol may include a cholesterol derivative. The cholesterol derivative may be, but is not limited to, sitosterol, ergosterol, stigmasterol, 4,22-stigmasteradien-3-one, stigmasterol acetate, lanosterol, cycloartenol, or combinations thereof. Cholesterol may help strengthen the lipid bilayer and reduce permeability.

[0068] In one aspect of the present invention, the content of the lipid may be 10 parts by weight to 1,000 parts by weight based on 100 parts by weight of L-serine.

[0069] Specifically, the content of the lipid may be 10 parts by weight to 200 parts by weight based on 100 parts by weight of L-serine.

[0070] When the ratio of the lipid including the above lecithin is less than 10 parts by weight, the encapsulation efficiency of L-serine may decrease or the shape of the liposome may become unstable, and when it exceeds 1,000 parts by weight, the production cost may increase and difficulties in the solidification process may occur due to increased viscosity. Therefore, it is preferable to satisfy the above range.

[0071] In another aspect of the present invention, the composition may further comprise at least one selected from the group consisting of a surfactant, a pH regulator, and an adsorbent.

[0072] In another aspect of the present invention, the surfactant may be at least one selected from the group consisting of polysorbate, sorbitan monooleate, polyethylene glycol, poloxamer, sodium lauryl sulfate, polyglyceryl ester, sorbitan ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene alkyl ether, but is not limited thereto, and an appropriate type capable of dissolving cholesterol in an aqueous solvent may be selected. Specifically, the surfactant may reduce the interfacial tension between a hydrophobic lipid and a hydrophilic solvent, thereby promoting self-assembly and stable formation of liposomes, and inducing uniform dispersion of the components, thereby providing physicochemical stability of the formulation.

[0073] Specifically, the polyglyceryl ester may include, but is not limited to, for example, polyglyceryl-3 oleate, polyglyceryl-4 oleate, polyglyceryl-6 oleate, polyglyceryl-10 oleate, polyglyceryl-10 stearate, polyglyceryl-3 stearate, polyglyceryl-4 laurate, polyglyceryl-4 caprate or polyglyceryl-6 caprylate.

[0074] Additionally, specifically, the sorbitan ester may include, but is not limited to, sorbitan monolaurate (or Span 20), sorbitan monostearate (or Span 60), or sorbitan monooleate.

[0075] Specifically, the polyoxyethylene sorbitan fatty acid ester may include, but is not limited to, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monostearate (Tween 60), or polyoxyethylene sorbitan monooleate (Tween 80).

[0076] Additionally, specifically, the polyoxyethylene alkyl ether may include, but is not limited to, polyoxyethylene lauryl ether (Brij 30), polyoxyethylene lauryl ether (Brij 35), or polyoxyethylene steryl ether (Brij 78), for example.

[0077] In another aspect of the present invention, the pH adjusting agent may be at least one selected from the group consisting of citric acid, potassium citrate, sodium citrate, phosphoric acid, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium phosphate, and potassium phosphate. Specifically, the pH adjusting agent can adjust and maintain the pH within a specific range, thereby ensuring the stability of lipids and L-serine, and providing an optimal environment for the formation and maintenance of liposomes.

[0078] In addition, the specific range of the pH may be 4.0 to 7.0 or 4.5 to 6.0. For example, the pH may be 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, etc. The composition according to the present invention can be stably maintained for a long period of time in the above pH range, and can have excellent convenience of administration and compliance with medication.

[0079] In another aspect of the present invention, the adsorbent may be at least one selected from the group consisting of calcium silicate, magnesium aluminosilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate. The adsorbent may be used for the purpose of moisture absorption, fluidity improvement, tablet formability enhancement, or stabilization of a specific component.

[0080] Pharmaceutical composition

[0081] In one aspect of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating neurological, mental and cognitive disorders, comprising a composition comprising the liposome.

[0082] The pharmaceutical composition according to the present invention can be prepared according to conventional methods in the pharmaceutical field. The pharmaceutical composition can be combined with an appropriate pharmaceutically acceptable carrier depending on the dosage form, and, if necessary, can be prepared by further including excipients, diluents, dispersants, emulsifiers, buffers, stabilizers, binders, disintegrants, solvents, etc. The appropriate carriers, etc., which do not inhibit the activity and properties of the pharmaceutical composition according to the present invention, can be selected differently depending on the dosage form and dosage form.

[0083] The pharmaceutical composition of the present invention may be selected from the group consisting of various dosage forms for oral or parenteral administration, such as tablets, pills, powders, granules, capsules, suspensions, oral solutions, emulsions, syrups, sterilized aqueous solutions, non-aqueous solutions, lyophilized preparations, suppositories, injections, and topical preparations for skin. When formulating, the composition may be prepared using diluents or excipients such as commonly used fillers, bulking agents, binders, wetting agents, disintegrants, and surfactants.

[0084] Solid dosage forms for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may be prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid dosage forms for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included.

[0085] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases may include witepsol, macrogol, Tween 61, cocoa butter, laurin butter, and glycerogelatin.

[0086] The pharmaceutical composition according to the present invention may further comprise a stabilizer or gelling agent. Such stabilizers or gelling agents include, but are not limited to, propylene glycol monopalmitostearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, hydrogenated fats, polyvinylpyrrolidone, polyethylene, glycerol, polyoxyethylene stearate, sorbitan fatty acid esters, cholesterol, macrogol-20-glycerol monostearate, poloxamer 124, isopropyl myristate, isopropyl palmitate, colloidal silica, hydrophobic colloidal silica, magnesium stearate, zinc stearate, aluminum stearate, lanolin alcohol, organoclay, petrolatum or polyoxyl 6 stearate.

[0087] The pharmaceutical composition according to the present invention may further comprise a polymer-based carrier. Polymer-based carriers include, but are not limited to, acrylic polymers such as polyacrylic and polymethacrylic acid derivatives, such as cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase, amylopectin, dextran, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), HEMA, carbopol, derivatives thereof, or mixtures thereof.

[0088] The pharmaceutical composition according to the present invention may further comprise an organic cosolvent. Organic cosolvents include, but are not limited to, ethylene glycol, propylene glycol, N-methyl pyrrolidone, 2-pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, dimethylglycol monomethyl ether, diethylene glycol monomethyl ether, solketal, glycerol, polyethylene glycol, or polypropylene glycol.

[0089] The pharmaceutical composition according to the present invention may additionally comprise a pH-active ingredient. Suitable pH-active ingredients, such as buffers or pH-adjusting agents, include, but are not limited to, disodium phosphate, monosodium phosphate, boric acid, sodium borate, sodium citrate, hydrochloric acid, or sodium hydroxide.

[0090] The pharmaceutical composition according to the present invention may additionally comprise an osmotically active ingredient. Examples of osmotically active ingredients include, but are not limited to, sodium chloride, mannitol, or glycerol.

[0091] The pharmaceutical composition according to the present invention may further comprise a preservative. Preservatives include, but are not limited to, benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxethanol, phenylethyl alcohol, sorbic acid, methyl, propyl paraben, chlorhexidine digluconate, EDTA, or mixtures thereof.

[0092] Each component of the pharmaceutical composition according to the present invention may be included in the pharmaceutical composition in an amount suitable for achieving its purpose, and the present invention is not limited thereto.

[0093] In another aspect of the present invention, the neurological, mental and cognitive disorder may be any one selected from the group consisting of autism spectrum, bipolar disorder, Tourette's, tics, Prader-Willi, attention deficit hyperactivity disorder (ADHD), Fragile-X syndrome, dementia, Alzheimer's, Parkinson's disease, Huntington's disease, affective disorder, sleep disorder, schizophrenia, depression, movement disorder, memory disorder, epilepsy, seizure disorders, cerebral palsy, neurodevelopmental delay and mild cognitive impairment (MCI).

[0094] The pharmaceutical composition may be administered in a pharmaceutically effective amount. The pharmaceutically effective amount may vary depending on factors including the intended use, the patient's age, sex, weight, and health status, the type and severity of the disease, the activity and sensitivity of the drug, the method of administration, the time of administration, the route and excretion rate of the drug, the duration of treatment, the combination or concurrent use of drugs, and other factors well known in the medical field. For example, although not fixed, it may be administered once or several times daily at a dose of 1 to 1000 mg / kg, for example, 10 to 400 mg / kg. The above dosage does not limit the scope of the present invention in any way.

[0095] Manufacturing method

[0096] In one aspect of the present invention, the present invention relates to a method for preparing a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0097] a) liposome solution manufacturing step; and

[0098] b) Drying stage.

[0099] In another aspect of the present invention, the step of preparing the liposome solution of a) may include a step of dissolving L-serine or a pharmaceutically acceptable salt thereof in a water-soluble solvent, adding the dissolved solution to a solution of lipid dissolved in an organic solvent, and stirring the solution.

[0100] In another aspect of the present invention, the liposome solution preparation step of a) may include additionally adding a surfactant or pH regulator depending on the composition.

[0101] Furthermore, in the liposome solution manufacturing step of a), the stirring step may be performed at, for example, 15°C to 35°C, preferably at room temperature, and may be performed using a homogenization device, for example, a homogenizer, a high-pressure homogenizer, an ultrasonic homogenizer, a microfluidizer, a membrane extruder, etc., but is not limited thereto.

[0102] Specifically, the water-soluble solvent in the liposome solution manufacturing step of the above a) may be, but is not limited to, ethanol, water, Ringer's solution, purified water, water for injection, phosphate buffered saline (PBS), physiological saline, or a mixture thereof.

[0103] In another aspect of the present invention, the drying step of b) may include a step performed using a dryer.

[0104] Specifically, the drying step may include, but is not limited to, a step performed using a freeze dryer, a spray dryer, a fluid bed dryer, a vacuum dryer, or a water bath dryer as a dryer.

[0105] In another aspect of the present invention, the method for preparing the liposome may additionally include a liposome liquid adsorption step before the drying step of b).

[0106] Specifically, the liposome liquid adsorption step may be performed by, for example, injecting an adsorbent into a high-speed mixer, a ribbon mixer, a paddle mixer, a V-blender, a conical mixer, or a Nauta mixer, and then injecting the liposome liquid of a).

[0107] In addition, the liposome liquid adsorption step may include, but is not limited to, a step of introducing one or more selected from the group consisting of calcium silicate, magnesium aluminate metasilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate as an adsorbent.

[0108] In another aspect of the present invention, the present invention may further include a step of obtaining or separating liposome granules or powder containing L-serine after the drying step of b).

[0109] Furthermore, the obtained or separated granules or powder can be formulated by mixing them with a binder, disintegrant, lubricant, sweetener, flavoring agent, etc.

[0110] Treatment methods and uses

[0111] In one aspect of the present invention, the present invention relates to a method for preventing or treating neurological, mental and cognitive disorders, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition.

[0112] The pharmaceutical composition may be appropriately administered to a subject according to a conventional method, administration route, and dosage used in the art, depending on the purpose or need. Examples of administration routes include oral, parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal administration, and parenteral injection includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In addition, an appropriate dosage and frequency of administration may be selected according to a method known in the art, and the actual amount of the pharmaceutical composition of the present invention to be administered and the frequency of administration may be appropriately determined by various factors, such as the type of symptom to be treated, administration route, sex, health condition, diet, age and weight of the subject, and severity of the disease.

[0113] The pharmaceutical composition may be administered to any subject capable of developing a neurological, mental, or cognitive disorder, including, for example, humans and primates, as well as livestock such as cows, pigs, horses, and dogs. In some embodiments, the animal may be an animal other than a human.

[0114] The above pharmaceutical composition can be administered via an appropriate route of administration depending on the formulation, and can be administered via various routes, either oral or parenteral, as long as it can reach the target tissue. The method of administration is not particularly limited, and can be administered by conventional methods such as oral, rectal, intravenous, intramuscular, transdermal, or respiratory inhalation.

[0115] The pharmaceutically effective amount of each active ingredient used during administration may vary depending on the specific compound or pharmaceutical composition used, the mode of administration, the condition to be treated, the severity of the condition to be treated, the species of the warm-blooded animal, body weight, sex, diet, and age. Therefore, the dosage regimen using the pharmaceutical composition of the present invention is selected based on various factors, including the route of administration and the renal and hepatic function of the patient. A physician, clinician, or veterinarian skilled in the art can readily determine and prescribe the effective amount of the drug required to prevent, counteract, or arrest the progression of the condition. Optimal precision in achieving drug concentrations within the range of efficacy without toxicity requires a regimen based on the dynamics of drug availability at the site of targeting. This includes considering the distribution, equilibrium, and elimination of the drug. Therefore, the dosage regimen, i.e., the dosage level and frequency of administration of any individual component of the present invention, can be adjusted to provide the optimal therapeutic response.

[0116] In one aspect of the present invention, the present invention relates to the use of a therapeutically effective amount of the pharmaceutical composition for preparing a medicament for the prevention or treatment of neurological, psychiatric and cognitive disorders.

[0117] In one aspect of the present invention, the present invention relates to the use of the pharmaceutical composition in a therapeutically effective amount for the prevention or treatment of neurological, mental and cognitive disorders.

[0118] Among the terms or elements mentioned in the above method and use, the same meanings as mentioned in the description of the above composition, pharmaceutical composition and manufacturing method apply to the composition, pharmaceutical composition or manufacturing method.

[0119] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the content of the present invention and are not intended to limit the scope of the present invention to the following examples.

[0120]

[0121] Example

[0122] Example 1. Preparation of liposome powder (1)

[0123] In Experimental Example 1, L-serine was dissolved in purified water, while lecithin was dissolved in ethanol, according to the ingredients and contents described in Table 1 below. The solution of L-serine dissolved in purified water was added to the lecithin solution, and the mixture was stirred at 10,000 rpm using a homogenizer at room temperature to prepare a liposome solution. Thereafter, silicon dioxide was added to the high-speed mixer to adsorb the liposome solution. The solvent was evaporated at 60°C using a hot water dryer to prepare a liposome powder containing L-serine.

[0124] For Experimental Examples 2 to 6, the same process as Experimental Example 1 was followed, except that the ratio of L-serine and lecithin was changed according to the ingredients and contents described in Table 1 below.

[0125] Content (g)Experimental example 1Experimental example 2Experimental example 3Experimental example 4Experimental example 5Experimental example 6Blend purposeIngredient nameActive ingredientL-serine200200200200200200LipidLecithin2050100200300400AdsorbentSilicon dioxide252525252525SolventEthanolq.sq.sq.sq.sq.spurified waterq.sq.sq.sq.sq.sq

[0126] qs quantum sufficit quantity

[0127]

[0128] Example 2. Preparation of liposome powder (2)

[0129] For Experimental Examples 7 to 12, the preparation was carried out in the same manner as Experimental Example 1, except that two or more types of lipids were included, but the types were different, according to the components and contents described in Table 2 below.

[0130] Content (g)Experimental example 7Experimental example 8Experimental example 9Experimental example 10Experimental example 11Experimental example 12Blend purposeIngredient nameActive ingredientL-serine200200200200200200LipidLecithin8080808080160Cholesterol20----40Phosphatidylcholine-20----HSPC--20---DPPC---20--DSPC----20-AdsorbentSilicon dioxide252525252525SolventEthanolq.sq.sq.sq.sq.sPurified waterq.sq.sq.sq.sq.sq

[0131] qs quantum sufficit quantity

[0132]

[0133] Example 3. Preparation of liposome powder (3)

[0134] For Experimental Examples 13 to 18, the same process as Experimental Example 7 was performed, except that microcrystalline cellulose was additionally included as a surfactant and adsorbent according to the ingredients and contents described in Table 3 below, and the surfactant was added to a solution mixed with L-serine and lecithin.

[0135] Content (g)Experimental example 13Experimental example 14Experimental example 15Experimental example 16Experimental example 17Experimental example 18Blend purposeIngredient nameActive ingredientL-serine200200200200200200LipidLecithin80808080808080Cholesterol202020202020SurfactantPolysorbate1.0----5.0Polyethylene glycol-1.0----Poloxamer--1.0---Sodium lauryl sulfate---1.0--Sorbitan monooleate----1.0-AdsorbentSilicon dioxide252525252525Microcrystalline cellulose444444Solventethanolq.sq.sq.sq.sq.spurified waterq.sq.sq.sq.sq.sq

[0136] qs quantum sufficit quantity

[0137]

[0138] Example 4. Preparation of liposome powder (4)

[0139] In Experimental Examples 19 and 20, L-serine was dissolved in purified water, while lecithin and cholesterol were dissolved in ethanol, according to the ingredients and contents described in Table 4 below. The solution of L-serine dissolved in purified water was added to the lecithin and cholesterol solution, and then stirred at 10,000 rpm using a homogenizer at room temperature to prepare a liposome solution. Thereafter, in Experimental Example 19, the solvent was evaporated through a freeze dryer to prepare a liposome powder containing L-serine, and in Experimental Example 20, the solvent was evaporated through a spray dryer to prepare a liposome powder containing L-serine.

[0140] Content (g) Experimental example 19 Experimental example 20 Mixing purpose Ingredient name Active ingredient L-serine 200 200 Lipid Lecithin 80 80 Cholesterol 20 20 Solvent Ethanol q.sq.s Purified water q.sq.s

[0141] qs quantum sufficit quantity

[0142]

[0143] Example 5. Preparation of liposome formulation

[0144] For Experimental Examples 21 to 26, the liposome powder prepared in Experimental Example 13 was mixed with additives according to the ingredients and contents described in Table 5 below to prepare powders, granules, capsules, or tablets. The L-serine content per unit dosage form was 200 mg.

[0145] Content (mg) Experimental example 21 (powder) Experimental example 22 (powder) Experimental example 23 (granules) Experimental example 24 (capsules) Experimental example 25 (tablets) Experimental example 26 (tablets) Blending purpose Ingredient Main ingredient Powder of Experimental example 13 330 330 330 330 330 330 330 Excipient Lactose 60-60 60 60 30 Calcium hydrogen phosphate -60 --- 30 Binder Povidone 10 10 10 10 10 10 Disintegrant Crospovidone 77 777 Lubricant Magnesium stearate 2.65 2.65 2.65 2.65 2.65 2.65 Flavoring Apple mint 0.05 0.05 0.05 0.05 0.05 Sweetener Sucralose 0.3 0.3 0.3 0.3 0.3 0.3 Unit Mass (mg) 410.0410.0410.0410.0410.0410.0

[0146]

[0147] Evaluation Example 1. Evaluation of the encapsulation rate of liposome powder

[0148] 4g of the samples from Experimental Examples 1 to 18 were collected, and their L-serine content and encapsulation rate were measured. The samples were placed in weighed Amicon Ultra-4 tubes, and their weights were measured. Afterwards, the samples were centrifuged for 30 minutes at 4℃ and 3,000 rpm, and the weight of the Amicon Ultra-4 tubes (free Cobamamide and tube) from which the containers were separated was measured, and the encapsulation rate was measured using the following calculation formula. The results of the L-serine content and encapsulation rate in each experimental example are as shown in Table 6 below.

[0149]

[0150] M: Weight (g) of Amicon Ultra-4 tube containing the sample

[0151] N: Weight of Amicon Ultra-4 tube including container (g)

[0152] F: Weight of free Cobamamide and tube (g)

[0153] H: Weight of container in Amicon Ultra-4 tube (g)

[0154] Experimental Example 1 Experimental Example 2 Experimental Example 3 Experimental Example 4 Experimental Example 5 Experimental Example 6 L-serine content (%) 100.999.9 101.2 104.4 97.199.9 Encapsulation rate (%) 75.6 74.9 76.2 76.8 77.179.2 Experimental Example 7 Experimental Example 8 Experimental Example 9 Experimental Example 10 Experimental Example 11 Experimental Example 12 L-serine content (%) 102.3 104.9 101.5 99.798.69 9.3 Encapsulation rate (%) 84.2 79.78 1.78 0.98 4.18 6.3 Experimental Example 13 Experimental Example 14 Experimental Example 15 Experimental Example 16 Experimental Example 17 Experimental Example 18 L-serine Content (%) 104.599.2102.6101.298.799.6 Encapsulation rate (%) 88.586.486.682.485.787.6

[0155] As confirmed in Table 6, all experimental examples met the minimum encapsulation rate criterion of 70% or higher. In particular, it was confirmed that higher encapsulation rates were observed in Experimental Examples 7 to 12, which used two or more types of lipids, and Experimental Examples 13 to 18, which additionally used a surfactant.

[0156] Evaluation Example 2. Stability Evaluation of Liposome Powder

[0157] To evaluate the stability of the liposome powders manufactured in Experimental Examples 1, 7, and 13, the stability was evaluated for 4 weeks under accelerated test conditions (temperature: 40±2℃, humidity: 75±5%). The items evaluated were appearance, loss on drying, and L-serine content, and the results are as shown in Table 7 below.

[0158] Evaluation Item Criteria Experimental Example Experimental Example 1 Experimental Example 7 Experimental Example 13 Starting point Acceleration 4 weeks Starting point Acceleration 4 weeks Appearance Light yellow granules Left Left Left Left Left Left Left Left Drying loss (%) 3% or less 1.7% 2.2% 1.4% 2.2% 1.6% 2.4% L-serine content (%) 90.0~130.0% 100.9% 100.4% 102.3% 101.9% 104.5% 104.2% Judgment Suitable Suitable Suitable Suitable Suitable Suitable

[0159]

[0160] As confirmed in Table 7, it was confirmed that the liposome powders manufactured in Experimental Examples 1, 7, and 13 maintained their properties under the above accelerated test conditions, had a drying loss below the standard, and had an excellent L-serine content, indicating a very stable state.

[0161] Evaluation Example 3. Evaluation of the in vivo absorption kinetics (PK) test of liposome powder

[0162] To evaluate the in vivo absorption rate of the liposome powder manufactured in Experimental Example 7, a pharmacokinetic (PK) test was conducted to evaluate the pharmacodynamic characteristics after oral administration of each formulation. The entire experiment was repeated twice under identical conditions.

[0163] Six-week-old male Sprague-Dawley rats (SPF) were used as experimental animals. They were housed three per cage for approximately one week to acclimatize. After acclimatization, jugular vein catheters were inserted for repeated blood sampling.

[0164] For catheter insertion, heparin was diluted with saline to a final concentration of 20 U / mL and dispensed into 1-mL syringes (100 μL each). The catheter tube was cut to 8 cm in length, and the vascular insertion point was marked approximately 1.5 cm away. Each experimental rat was tagged on the tail for individual identification, and its weight was subsequently measured.

[0165] Anesthesia was induced by intramuscular injection of a mixture of ketamine and Rompun (xylazine) in a 2:1 (v / v) ratio. After induction of anesthesia, the supraclavicular jugular area (ventral side) and the back were shaved and disinfected with alcohol. The jugular area was incised to expose the blood vessel, a suture was passed beneath the blood vessel, and the muscle and skin were dissected from the ventral to dorsal direction using mosquito forceps. A catheter tube with a needle was inserted from the dorsal skin and passed ventrally, and a spatula was inserted beneath the jugular vein and the blood vessel was incised with microscissors. The catheter was then inserted into the blood vessel to a depth of approximately 1.5 cm and a syringe was connected. After confirming that blood was aspirated well, 100 μL of heparin was injected through the catheter. The incised blood vessels and skin were sutured, and the catheter needle was secured with dental cement. To prevent infection, 100 μL of gentamicin was administered intramuscularly. After surgery, each animal was housed individually in a cage to recover.

[0166] Rats that had fully recovered were transferred to a fasting plate the evening before the experiment and fasted, with water provided ad libitum. Fasting continued for at least 12 hours until the day of the experiment. The following morning, each rat's condition was checked and its weight remeasured. Rats with dislodged catheters or poor condition were excluded, and five to six rats were ultimately selected for each group.

[0167] On the day of the experiment, heparin was prepared at the same concentration of 20 U / mL. The required dose was calculated and prepared for each formulation based on the average body weight of each group. Considering losses during the experiment, a surplus of 10 animals was included. The concentrations for each formulation were as follows.

[0168] Syrup (first control group, G1): 100 mg / mL as L-serine

[0169] Liposome formulation (Experimental Example 7, G4): 273 mg / mL as L-serine

[0170] API (stock solution) (second control, G5): 100 mg / mL as L-serine

[0171] Oral administration was administered orally by connecting an oral tube to a 1 mL syringe and accurately measuring the calculated dosage based on the body weight of each individual.

[0172] Since L-serine is an endogenous substance, jugular vein blood samples were collected from animals at -2, -1, and 0 hours before administration, and then at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. The collected blood was collected in heparinized tubes and stored on ice. When all samples from the same time point were pooled, the plasma was separated by centrifugation at 3,000 rpm for 10 minutes. The separated plasma was transferred to a new 1.5 mL tube and stored at -80°C. After all blood samples were collected, the experimental rats were euthanized using a CO2 chamber, and the carcasses were disposed of by cervical dislocation.

[0173] The stored plasma samples were quantified for L-serine concentration using LC-MS / MS. Based on the analyzed concentration data, pharmacokinetic parameters were calculated using non-compartmental analysis (NCA) using WinNonlin software. The results are shown in Table 8 and Figure 1.

[0174] Group(Group) Dosage Formulation Dosage PK Parameter AUC last (h*μg / mL)AUC last _D (h*μg / mL)*(volume-based numerical correction)C max (μg / mL)C max _D (μg / mL)(volume-based numerical correction)T max (h)t 1 / 2 (h)G1L-serine syrup (100 mg / mL)400 mg / kg246.56 ± 28.640.62 ± 0.07113.19 ± 46.730.28 ± 0.120.6 ± 0.22.6 ± 1.5G4Experimental Example 7 (273 mg / mL in DW)546 mg / kg431.43 ± 181.06 * 0.79 ± 0.33149.67 ± 50.630.37 ± 0.130.5 ± 0.33.8 ± 2.7G5API (100 mg / mL in DW)400 mg / kg268.67 ± 103.760.69 ± 0.26130.61 ± 39.330.36 ± 0.100.5 ± 0.32.7 ± 2.8

[0175] AUC last : Area Under the Curve from time 0 to last; Area under the drug concentration-time curve, i.e., the area under the concentration-time curve from administration (time 0) to the last measured concentration

[0176] AUC last _D(h*ug / mL): AUC last (h*ug / mL) / Dose

[0177] C max: Maximum Plasma Concentration; The highest drug concentration reached in the blood after drug administration

[0178] T max : Time to Reach Maximum Plasma Concentration; The maximum drug concentration in the blood (C) after drug administration. max ) time to reach

[0179] T 1 / 2 : Half-life: The time it takes for the blood drug concentration to decrease by half

[0180] *p < 0.05 vs. G1 (One-way ANOVA followed by Dunnett's multiple comparisons test).

[0181]

[0182] As confirmed in the results in Table 8, it was confirmed that a greater amount of L-serine was absorbed from the liposome powder manufactured in Experimental Example 7 than from the L-serine syrup (G1) and API (G5). In addition, as a result of analysis by normalization based on the administered dose, it was confirmed that the bioavailability of the liposome powder increased by approximately 15% compared to the L-serine solution (API, G5), thereby proving that the in vivo absorption rate of L-serine manufactured with the liposome powder increased.

[0183] Evaluation Example 4. Stability Evaluation of Powders and Granules

[0184] In order to evaluate the stability of the powder manufactured in Experimental Example 21 and the granules manufactured in Experimental Example 23, the stability was evaluated for 3 months under accelerated test conditions (temperature: 40±2℃, humidity: 75±5%) and long-term storage test conditions (temperature: 25±2℃, humidity: 60±5%). The items evaluated were appearance, particle size test, L-serine content, and formulation uniformity, and the results are as shown in Table 9 below.

[0185] Evaluation Item Criteria Experimental Example Experimental Example 21 Experimental Example 23 Starting point Acceleration 3 months Long-term 3 months Starting point Acceleration 3 months Long-term 3 months Appearance Light yellow powder or granules Same Same Same Same Same Same Same Same Particle size test Suitable for KP particle size test method Suitable Suitable Suitable Suitable Suitable Suitable L-serine content (%) 90.0~130.0% 102.4% 99.7% 101.2% 100.7% 99.1% 100.2% Uniformity of preparation (%) Judgment value 15% or less 3.2% 4.5% 3.5% 3.6% 4.8% 3.9% Judgment Suitable Suitable Suitable Suitable Suitable Suitable

[0186] As confirmed in Table 9, the powders and granules manufactured in Experimental Examples 21 and 23 maintained their properties under the above-mentioned accelerated test conditions and long-term storage test conditions, were suitable for the particle size test, had excellent L-serine content, and were also excellent in formulation uniformity, showing a very stable state.

[0187] Evaluation Example 5. Stability Evaluation of Capsules and Tablets

[0188] In order to evaluate the stability of the capsules manufactured in Experimental Example 24 and the tablets manufactured in Experimental Example 26, the stability was evaluated for 3 months under accelerated test conditions (temperature: 40±2℃, humidity: 75±5%) and long-term storage test conditions (temperature: 25±2℃, humidity: 60±5%). The items evaluated were disintegration test, dissolution test, L-serine content, and formulation uniformity, and the results are as shown in Table 10 below.

[0189] Evaluation Item Criteria Experimental Example Experimental Example 24 Experimental Example 26 Starting point acceleration 3 months Long-term 3 months Starting point acceleration 3 months Long-term 3 months Disintegration test Capsule: Within 20 minutes, Tablet: Within 30 minutes Within 5 minutes Within 10 minutes Within 5 minutes Within 10 minutes Within 10 minutes Release test (%) 45 minutes, 70 (%, Q) or more 96.0% 93.5% 96.2% 92.4% 91.1% 93.6% L-serine content (%) 90.0~130.0% 99.5% 98.7% 99.2% 102.1% 100.8% 101.3% Preparation uniformity (%) Judgment value 15% or less 6.2% 6.4% 5.8% 8.4% 8.1% 8.3% Judgment Suitable Suitable Suitable Suitable Suitable Suitable

[0190]

[0191] As confirmed in Table 10, the capsules and tablets manufactured in Experimental Examples 24 and 26, respectively, met the criteria for all items under the above-mentioned accelerated test conditions and long-term storage test conditions, and showed no significant change compared to the starting point, confirming that they are stable formulations that can be stored for a long period of time.

Claims

1. A composition comprising a liposome containing lipid and L-serine or a pharmaceutically acceptable salt thereof.

2. In the first paragraph, the lipid is lecithin, cholesterol, phosphatidylcholine, hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC), phosphatidylglycerol (PG), phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidylethanolamine (PE), sphingomyelin (SM), dimyristoylphosphatidylcholine (DIMYR), A composition characterized in that at least one is selected from the group consisting of dioleoylphosphatidylcholine (DOPC), dierucoylphosphatidylcholine (DEPC), phytosterol, and glycolipid.

3. In the second paragraph, the composition comprises two or more types of the lipids.

4. In paragraph 1, the content of the lipid is A composition comprising 10 to 1,000 parts by weight based on 100 parts by weight of L-serine.

5. In paragraph 4, the content of the lipid is A composition comprising 10 to 200 parts by weight based on 100 parts by weight of L-serine.

6. In the first paragraph, the composition further comprises at least one selected from the group consisting of a surfactant, a pH regulator, and an adsorbent.

7. A composition according to claim 6, wherein the surfactant is at least one selected from the group consisting of polysorbate, sorbitan monooleate, polyethylene glycol, poloxamer, sodium lauryl sulfate, polyglyceryl ester, sorbitan ester, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene alkyl ether.

8. In the 6th paragraph, the composition is at least one selected from the group consisting of citric acid, potassium citrate, sodium citrate, phosphoric acid, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium phosphate, and potassium phosphate.

9. In the 6th paragraph, the composition is at least one selected from the group consisting of calcium silicate, magnesium aluminate metasilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate.

10. A pharmaceutical composition for preventing or treating neurological, mental and cognitive disorders, comprising a composition according to any one of claims 1 to 9.

11. A pharmaceutical composition according to claim 10, wherein the neurological, mental and cognitive disorder is any one selected from the group consisting of autism spectrum, bipolar disorder, Tourette's, tics, Prader-Willi, attention deficit hyperactivity disorder (ADHD), Fragile-X syndrome, dementia, Alzheimer's, Parkinson's disease, Huntington's disease, affective disorder, sleep disorder, schizophrenia, depression, movement disorder, memory disorder, epilepsy, seizure disorders, cerebral palsy, neurodevelopmental delay and mild cognitive impairment (MCI).

12. In the 10th paragraph, the pharmaceutical composition is in the form of a tablet, a pill, a powder, a granule, a capsule, a suspension, an oral solution, an emulsion, a syrup, a sterilized aqueous solution, a non-aqueous solution, a lyophilized preparation, a suppository, an injection, and an external preparation for skin.

13. A method for preparing a liposome comprising a lipid and L-serine or a pharmaceutically acceptable salt thereof, comprising the following steps: a) liposome solution manufacturing step; and b) Drying stage.

14. A method for producing a liposome, wherein the step of producing a liposome solution in paragraph 13 comprises the step of dissolving L-serine or a pharmaceutically acceptable salt thereof in a water-soluble solvent, adding the solution to a solution in which lipid is dissolved in an organic solvent, and stirring the solution.

15. A method for producing liposomes, comprising additionally adding a surfactant or pH regulator in the liposome solution production step of paragraph 13.

16. A method for producing a liposome, wherein the drying step of b) in paragraph 13 comprises a step of performing the drying step using a freeze dryer, a spray dryer, a fluid bed dryer, a vacuum dryer, or a water bath dryer.

17. A method for producing liposomes in claim 13, wherein the method for producing liposomes further comprises a step of adsorbing liposome liquid before the drying step of b).

18. A method for producing a liposome, wherein the liposome liquid adsorption step in the 17th paragraph includes a step of introducing at least one selected from the group consisting of calcium silicate, magnesium aluminosilicate metasilicate, hydrous silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, lactose, and calcium hydrogen phosphate as an adsorbent.

19. A method for preventing or treating neurological, mental and cognitive disorders, comprising administering to a subject a therapeutically effective amount of the pharmaceutical composition of Article 10.

20. Use of a pharmaceutical composition of claim 10 in a therapeutically effective amount for the manufacture of a medicament for the prevention or treatment of neurological, mental and cognitive disorders.

21. Use of the pharmaceutical composition of Article 10 in a therapeutically effective amount for the prevention or treatment of neurological, mental and cognitive disorders.

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