Liquid preparation of L-serine or a pharmaceutically acceptable salt thereof and preparation method thereof

Abstract

The present invention discloses a liquid formulation of L-serine or a pharmaceutically acceptable salt thereof and a method for preparing the same. Specifically, the present invention relates to a liquid formulation and a method for preparing the same, wherein the liquid formulation comprises a high concentration of L-serine or a pharmaceutically acceptable salt thereof, has excellent stability and safety, and exhibits excellent pharmacological effects.

Description

[0001] The present invention is a divisional application of the Chinese patent application with application number 202280034814.X, application date March 17, 2022, and invention name “Liquid preparation of L-serine or its pharmaceutically acceptable salt and preparation method thereof”. Technical Field

[0002] The present invention relates to a liquid preparation of L-serine or a pharmaceutically acceptable salt thereof and a method for preparing the liquid preparation. Background Art

[0003] Amino acids are the basic units that make up proteins in living organisms and are roughly divided into two categories: essential amino acids that are not synthesized by the body and non-essential amino acids that are synthesized by the body.

[0004] The 20 different amino acids discovered so far can be divided into two groups based on their solubility in water: hydrophilic amino acids (such as serine, threonine, tyrosine, and cysteine) and hydrophobic amino acids (such as glycine, alanine, valine, leucine, and isoleucine).

[0005] In particular, the L-form of serine (hereinafter referred to as L-serine), one of the non-essential amino acids synthesized by the body, has a molecular weight of approximately 105.1 g / mol. L-serine, a hydrophilic amino acid, has a solubility limit of approximately 250 mg / ml in water at 20°C. However, high doses of L-serine in solution can cause discoloration and precipitation over time.

[0006] Although L-serine is a non-essential amino acid synthesized by the body, L-serine deficiency can be caused by a variety of factors, including inborn errors of serine biosynthesis, hypoxic-ischemic brain injury, and traumatic brain injury. Disorders of L-serine biosynthesis in the brain may specifically reduce the production of glutathione, which protects against damage caused by reactive oxygen species (ROS), leading to fatal diseases.

[0007] Therefore, for patients who have low concentrations of serine in the blood due to reduced or interrupted biosynthesis of L-serine, it is crucial to directly provide them with L-serine rather than other amino acids for treatment.

[0008] However, it is challenging to develop a single formulation that can provide L-serine alone, as well as a formulation containing a high dose or high concentration of L-serine sufficient to normalize L-serine deficiency.

[0009] For this reason, a method has been proposed of applying a large amount of an amino acid complex solution containing low-concentration L-serine to patients who previously had to receive L-serine.

[0010] In addition, a method of directly administering a powdered or solid raw material has been proposed, but in this case, medication compliance drops sharply, thereby reducing the therapeutic effect.

[0011] Therefore, there is still a need to develop a liquid preparation containing high concentration of L-serine and which can be used for oral administration.

[0012] [Related technical literature]

[0013] Patent Document 1: Korean Patent No. 10-2091620

[0014] Patent Document 2: Korean Patent No. 10-1672347

[0015] Non-patent document 1: “Effect of sample pretreatment in amino acid analysis,” Korean Journal of Clinical Pathology 2001; 21(1): 34-39 (Kim Moon-hee and Moon Hae-ran). Summary of the Invention

[0016] Technical issues

[0017] The object of the present invention is to provide a liquid preparation comprising a high concentration of L-serine or a pharmaceutically acceptable salt thereof.

[0018] The liquid preparation according to the present invention can allow for rapid administration and long-term use of L-serine, and can contain a high concentration of L-serine. Therefore, the total dose of the drug required for treatment can be reduced to improve the convenience of medication. As a liquid, it can be used for oral administration, and patients have high medication compliance, thereby producing a good therapeutic effect.

[0019] The liquid preparation according to the present invention can contain a high concentration of L-serine or a pharmaceutically acceptable salt thereof, wherein no solid matter is separated out or precipitated for a long time, thereby having excellent stability in storage stability and long-term storage, and the liquid preparation can improve the solubility properties of L-serine to prevent discoloration and recrystallization, thereby resulting in improved safety.

[0020] The liquid preparation according to the present invention can keep L-serine or a pharmaceutically acceptable salt thereof in a completely dissolved state for a long time, can have a pH ranging from slightly acidic to neutral, does not contain strong acids such as hydrochloric acid groups and sulfuric acid groups, can significantly reduce the total dosage, and can be highly stable and safe for long-term safe use by patients suffering from diseases including central nervous system diseases, thereby resulting in very high medication convenience and medication compliance.

[0021] The liquid formulation according to the present invention has improved bioavailability when administered orally and is highly stable to have an improved ability to maintain formulation quality during long-term storage and / or use, thereby ensuring excellent therapeutic effects for a long time, and the liquid formulation provides improved pharmacoeconomics based on physical appearance, improved drug usability, ease of formulation, and high formulation stability.

[0022] Another object of the present invention is to provide a method for preparing a liquid preparation containing a high concentration of L-serine or a pharmaceutically acceptable salt thereof.

[0023] Solution to the problem

[0024] 1) The present invention relates to a liquid preparation comprising L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, and a thickener, wherein the preparation has a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 50 mg / mL or more.

[0025] 2) In the embodiment according to 1) of the present invention, the liquid preparation may have a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 50 mg / mL to about 500 mg / mL.

[0026] 3) In at least one embodiment according to 1) or 2) of the present invention, the liquid formulation may have a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 70 mg / mL to about 300 mg / mL.

[0027] 4) In at least one embodiment of 1) to 3) according to the present invention, the thickener contained in the liquid preparation may be agar, bentonite, carbomer, sodium carboxymethylcellulose, carrageenan, microcrystalline sodium carboxymethylcellulose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, pectin, polyethylene oxide, povidone, corn starch, potato starch, wheat starch, xanthan gum, gelatin or a mixture thereof.

[0028] 5) In at least one embodiment of 1) to 4) according to the present invention, the thickener contained in the liquid preparation may be sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, or a mixture thereof.

[0029] 6) In at least one embodiment according to 1) to 5) of the present invention, the liquid formulation may have a thickening agent at a concentration of about 0.5 mg / mL to about 100 mg / mL.

[0030] 7) In at least one embodiment according to 1) to 6) of the present invention, the liquid formulation has a pH of about 4.0 to about 7.0.

[0031] 8) In at least one embodiment of 1) to 7) according to the present invention, the liquid preparation may further include a buffer.

[0032] 9) In at least one embodiment of 1) to 8) according to the present invention, the buffering agent may be borate, acetate, carbonate, citrate, lactate and hydrates thereof (hydrates of borate, acetate, carbonate, citrate or lactate), or a mixture thereof.

[0033] 10) In at least one embodiment of 1) to 9) according to the present invention, the buffering agent may be at least one selected from ammonium carbonate, sodium acetate, potassium acetate, calcium carbonate, calcium lactate, potassium citrate, sodium citrate, sodium bicarbonate, sodium lactate and hydrates thereof.

[0034] 11) In at least one embodiment of 1) to 10) according to the present invention, the buffer may be a pharmaceutically acceptable citrate or a hydrate thereof.

[0035] 12) In at least one embodiment of 1) to 11) according to the present invention, the liquid preparation may further comprise a solvent.

[0036] 13) In at least one embodiment of 1) to 12) according to the present invention, the liquid preparation may be in the form of a syrup.

[0037] 14) In at least one embodiment of 1) to 13) according to the present invention, the liquid preparation may further contain a sweetener.

[0038] 15) In at least one embodiment of 1) to 14) according to the present invention, the sweetener may be one selected from acesulfame potassium, aspartame, dextrates, dextrose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevioside, steviol glycoside, enzyme-modified stevioside, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, white sugar (e.g., refined white sugar), syrup, simple syrup, honey, and mixtures thereof.

[0039] 16) In at least one embodiment of 1) to 15) according to the present invention, the liquid preparation may further comprise a diluent, a solubilizer, a flavoring agent, a preservative, a sweetener, an acidulant, a buffer, or a mixture thereof.

[0040] 17) In at least one embodiment of 1) to 16) according to the present invention, the preservative may be benzoic acid, sodium benzoate, methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol or a mixture thereof.

[0041] 18) The present invention relates to a liquid preparation comprising: L-serine or a pharmaceutically acceptable salt thereof in an amount of about 50 mg / mL to about 500 mg / mL, at least one thickener selected from sodium carboxymethylcellulose, povidone, hydroxyethylcellulose and carbomer, a buffer, and a solvent.

[0042] 19) In at least one embodiment according to 1) to 18) of the present invention, the liquid formulation may have a pH of about 4.0 to about 7.0.

[0043] 20) In at least one embodiment of 1) to 19) according to the present invention, the buffer may be a borate, acetate, carbonate, citrate, lactate, a hydrate of borate, acetate, carbonate, citrate or lactate, or a mixture thereof.

[0044] 21) In at least one embodiment of 1) to 20) according to the present invention, the liquid preparation may further comprise a diluent, an acidulant, a preservative, a sweetener, or a mixture thereof.

[0045] 22) The present invention relates to a liquid preparation comprising L-serine or a pharmaceutically acceptable salt thereof, a thickener, a buffer and a solvent, wherein the amount of L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL to about 500 mg / mL, the thickener is selected from sodium carboxymethylcellulose, povidone or a mixture thereof, the buffer is citrate, and the solvent is one selected from water, purified water, water for injection, Ringer's solution, physiological saline and a mixture thereof.

[0046] 23) In at least one embodiment according to 1) to 22) of the present invention, the liquid formulation may have a pH of about 4.5 to about 7.0.

[0047] 24) In at least one embodiment of 1) to 23) according to the present invention, the liquid preparation may be for oral administration, and in particular may be a liquid for internal use.

[0048] 25) In at least one embodiment of 1) to 24) according to the present invention, the liquid preparation may be a solution.

[0049] 26) In at least one embodiment of 1) to 25) according to the present invention, the liquid preparation can be used for preventing or treating central nervous system diseases.

[0050] 27) In at least one embodiment of 1) to 26) according to the present invention, the central nervous system disease can be at least one selected from autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, mood disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder and memory disorder.

[0051] 28) In at least one embodiment of 1) to 27) according to the present invention, the liquid formulation can be used to prevent or treat autism spectrum disorders.

[0052] 29) The present invention relates to a method for preparing the above-mentioned liquid preparation containing L-serine or a pharmaceutically acceptable salt thereof.

[0053] 30) The present invention relates to a method for preparing the liquid preparation of the present invention according to at least one of 1) to 29) above, wherein the method comprises:

[0054] (1) dissolving a thickener in a solvent to prepare a first solution;

[0055] (2) adding a pharmaceutically acceptable first additive to the first solution, and heating the mixture at about 50° C. or higher to prepare a second solution having a pH of about 4.0 to about 7.0; and

[0056] (3) Cooling the second solution, and then dissolving L-serine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable second additive in the cooled second solution to prepare a third solution.

[0057] 31) At least one liquid preparation of 1) to 30) above has a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 50 mg / mL or higher.

[0058] 32) In at least one embodiment of 1) to 31) according to the present invention, the first additive may include an acidifier, a buffer, a solubilizer, a preservative, or a mixture thereof.

[0059] 33) In at least one embodiment of 1) to 32) according to the present invention, the second additive may include a diluent, a sweetener, a flavoring, a coloring agent, or a mixture thereof.

[0060] 34) The present invention provides a method for treating a central nervous system disease using the liquid preparation according to 1) to 33) described above, wherein the central nervous system disease can be at least one selected from autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, mood disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder and memory disorder.

[0061] 35) The present invention provides the use of the liquid preparation according to 1) to 33) described above for treating central nervous system diseases, wherein the central nervous system diseases can be at least one selected from autism spectrum disorders, Alzheimer's disease, Parkinson's disease, intellectual disabilities, learning disabilities, language disorders, attention deficit hyperactivity disorder, mood disorders, movement disorders, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory diseases, cerebrovascular diseases, attention disorders and memory disorders.

[0062] 36) The present invention provides the use of the liquid preparation according to 1) to 33) described above in the preparation of a medicament for treating a central nervous system disease, wherein the central nervous system disease can be at least one selected from autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, mood disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder and memory disorder.

[0063] Advantageous Effects of the Invention

[0064] The liquid preparation according to the present invention can allow for rapid administration and long-term use of L-serine, and can contain a high concentration of L-serine. Therefore, the total dose of the drug required for treatment can be reduced to improve the convenience of medication. As a liquid preparation, it can be used for oral administration, and the patient's medication compliance is high, thereby producing a good therapeutic effect.

[0065] The liquid preparation according to the present invention can contain a high concentration of L-serine or a pharmaceutically acceptable salt thereof, wherein no solid matter is separated out or precipitated for a long time, thereby having excellent stability in storage stability and long-term storage, and the liquid preparation can improve the solubility properties of L-serine to prevent discoloration and recrystallization, thereby resulting in improved safety.

[0066] The liquid preparation according to the present invention can keep L-serine or a pharmaceutically acceptable salt thereof in a completely dissolved state for a long time, can have a pH ranging from slightly acidic to neutral, does not contain strong acids such as hydrochloric acid groups and sulfuric acid groups, can significantly reduce the total dosage, and can be highly stable and safe for long-term safe use by patients suffering from diseases including central nervous system diseases, thereby resulting in very high medication convenience and medication compliance.

[0067] The liquid formulation according to the present invention has improved bioavailability when administered orally and is highly stable to have an improved ability to maintain formulation quality during long-term storage and / or use, thereby ensuring excellent therapeutic effects for a long time, and the liquid formulation provides improved pharmacoeconomics based on physical appearance, improved drug usability, ease of formulation, and high formulation stability.

[0068] The liquid formulation according to the present invention can be used for large-scale production and is economically feasible. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 is a graph showing the results of appearance stability tests on liquid preparations according to Examples and Comparative Examples of the present invention.

[0070] Figure 2 This is a graph showing the concentration curves of the example preparations according to the present invention and the control preparation in beagle dog plasma after administration. DETAILED DESCRIPTION

[0071] The term "oral preparation" used herein refers to a medicine that can be taken, including liquids for oral administration and solids for oral administration.

[0072] As used herein, the term "oral liquid" refers to a liquid preparation in a formulation for oral administration that can be taken.

[0073] The term "oral solid" as used herein refers to a solid preparation in an internal preparation for oral administration that can be taken.

[0074] The terms “first”, “second”, etc. used herein are only used to distinguish between multiple components or multiple steps, but do not indicate priority.

[0075] The present invention relates to a liquid preparation containing L-serine or a pharmaceutically acceptable salt thereof as an active ingredient at a high concentration and a preparation method thereof.

[0076] An embodiment of the present invention relates to a liquid formulation comprising L-serine or a pharmaceutically acceptable salt thereof.

[0077] In an embodiment of the present invention, the liquid preparation comprises L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, and a thickener.

[0078] In an embodiment of the present invention, the present invention relates to a liquid preparation comprising L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, and a thickener, wherein the liquid preparation may have a concentration of about 50 mg / mL or more of L-serine or a pharmaceutically acceptable salt thereof.

[0079] L-serine or a pharmaceutically acceptable salt thereof is a material having high solubility in water, but liquid preparations in which L-serine is dissolved at a high concentration of about 50 mg / mL or higher have limitations in terms of drug stability (e.g., discoloration and precipitation during storage), and therefore liquid preparations containing L-serine in an amount of about 50 mg / mL or higher have not been developed.

[0080] The liquid formulation according to the present invention can contain a high concentration of L-serine or a pharmaceutically acceptable salt thereof as the active ingredient, making it suitable for oral administration and offering significantly improved convenience. Specifically, a method has been proposed in which a large amount of an amino acid complex solution containing a low concentration of L-serine is administered to patients who previously had to receive L-serine. However, this amino acid complex solution contains low concentrations of L-serine along with a variety of other amino acids. This amino acid complex solution is used as a parenteral nutrition solution for supplying amino acids for hypoproteinemia, hyponutrition, and pre- and post-operative conditions, and contains a low concentration of approximately 5 mg / mL of L-serine along with various other amino acids. When L-serine is administered at high doses of 10 g or more using conventional amino acid complex solutions, the solution volume exceeds 2 L, and administering this amount to the patient requires a significant amount of time. This increases treatment costs, significantly hinders convenient drug administration, and can lead to the administration of other amino acids that the patient does not need. Furthermore, the long-term, multiple administration of the solution makes it difficult to accurately calculate the amount to be administered to the patient, and oral administration is not practical, resulting in significantly low patient compliance.

[0081] The liquid preparation according to the present invention can allow for rapid administration and long-term use of L-serine, and can contain a high concentration of L-serine. Therefore, the total dose of the drug required for treatment can be reduced to improve the convenience of medication. As a liquid preparation, it can be used for oral administration, thereby producing a good therapeutic effect with high patient compliance.

[0082] Furthermore, the liquid preparation can maintain stability as described above for a long period of time while using water as a solvent, and is therefore very safe.

[0083] The liquid preparation according to the present invention can contain a high concentration of L-serine or a pharmaceutically acceptable salt thereof, wherein no solid matter is separated out or precipitated for a long time, thereby having excellent stability in storage stability and long-term storage, and the liquid preparation can improve the solubility properties of L-serine or its salt to prevent discoloration and recrystallization of L-serine or its salt, thereby resulting in improved safety.

[0084] The liquid preparation according to the present invention can keep L-serine or a pharmaceutically acceptable salt thereof in a completely dissolved state for a long time, can have a pH ranging from slightly acidic to neutral, does not contain strong acids such as hydrochloric acid groups and sulfuric acid groups, can significantly reduce the total dose, and can be highly safe for long-term safe use by patients suffering from diseases including central nervous system diseases.

[0085] The liquid preparation according to the present invention has improved bioavailability and is highly stable and safe with an improved ability to maintain preparation quality during long-term storage and / or use, thereby ensuring long-term excellent therapeutic effects. The liquid preparation maintains a stable liquid state for a long time, thereby significantly improving medication compliance, and the liquid preparation provides improved pharmacoeconomics based on physical appearance, improved drug usability, ease of preparation and high preparation stability.

[0086] In an embodiment of the present invention, L-serine is a compound represented by the following Formula 1, and its source is not particularly limited as long as the compound can be used in liquid preparations.

[0087] [Formula 1]

[0088]

[0089] In an 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 is not particularly limited as long as the salt can be used in liquid preparations.

[0090] In embodiments of the present invention, pharmaceutically acceptable salt can be an inorganic salt, inorganic acid salt, organic acid salt, sulfonate etc. of L-serine.These exemplary pharmaceutically acceptable salts can be used alone, or two or more of them can be mixed and used.For example, inorganic salt can be a metal salt comprising calcium salt, potassium salt, sodium salt, magnesium salt etc., inorganic acid salt can comprise hydrochloride, nitrate, bromate, iodate, perchlorate, tartrate, sulfate etc., organic acid salt can comprise acetate, trifluoroacetate, citrate, maleate, succinate, oxalate, benzoate, tartrate, fumarate, mandelate, propionate, lactate, glycolate, gluconate, galacturonate, glutamate, glutarate, glucuronate, aspartate, ascorbate, carbonate, vanillate, hydroiodic acid etc., and sulfonate can comprise methanesulfonate, ethanesulfonate, benzenesulfonate, tosyl ether, naphthalenesulfonate etc.

[0091] In one embodiment, the pharmaceutically acceptable salt of L-serine may be a metal salt of L-serine, specifically at least one of a calcium salt, a potassium salt, a sodium salt or a magnesium salt, and the pharmaceutically acceptable salt of L-serine may be a magnesium salt.

[0092] In an embodiment of the present invention, the liquid preparation may contain a high concentration of L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, and may specifically contain L-serine or a pharmaceutically acceptable salt thereof in an amount of about 50 mg / mL or more.

[0093] In one embodiment, the liquid formulation may contain L-serine or a pharmaceutically acceptable salt thereof as the active ingredient at a concentration of about 50 mg / mL to about 500 mg / mL.

[0094] In one embodiment, the liquid formulation may contain L-serine or a pharmaceutically acceptable salt thereof as an active ingredient at a concentration of about 70 mg / mL to about 300 mg / mL.

[0095] In one embodiment, the liquid formulation may contain L-serine or a pharmaceutically acceptable salt thereof as an active ingredient at a concentration of about 100 mg / mL to about 200 mg / mL.

[0096] For example, the liquid formulation can contain a concentration of about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about In some embodiments, the present invention can be used in an amount of L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, such as about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, about 500 mg / mL, etc.

[0097] In an embodiment of the present invention, the liquid preparation may include a thickener, which is a pharmaceutically acceptable additive. In this case, the liquid preparation of the present invention may exhibit excellent stability while including high concentrations of L-serine or a pharmaceutically acceptable salt thereof.

[0098] In an embodiment of the present invention, the thickener is a material that resists liquid-like flow and may be agar, bentonite, carbomer, sodium carboxymethylcellulose, carrageenan, sodium microcrystalline carboxymethylcellulose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, pectin, polyethylene oxide, povidone, corn starch, potato starch, wheat starch, xanthan gum, gelatin, etc. These exemplary thickeners may be used alone, or two or more thereof may be mixed and used.

[0099] In an embodiment of the present invention, the carbomer can be carbomer 971P, carbomer 910, carbomer 934, carbomer 934p, carbomer 940, carbomer 941, carbomer 1342, a carbomer copolymer, a carbomer homopolymer, a carbomer interpolymer, etc., but is not limited thereto.

[0100] For example, the thickening agent may be sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, or a mixture thereof.

[0101] In embodiments of the present invention, the liquid formulation may have a thickening agent concentration of about 0.5 mg / mL to about 150 mg / mL, particularly about 0.5 mg / mL to about 100 mg / mL, more particularly about 1 mg / mL to about 100 mg / mL.

[0102] In an embodiment of the present invention, the liquid preparation may further include a solvent. The solvent is a material that can dissolve the molecules or ions of the active ingredient L-serine or its pharmaceutically acceptable salt to form a uniformly dispersed mixture (solution), and is not particularly limited, as long as the solvent can be used for liquid preparations.

[0103] In an embodiment of the present invention, the solvent can be water, purified water, water for injection, Ringer's solution, ethanol, ether, alcohol, white wine, fruit wine, glycerol, peanut oil, physiological saline, etc., and these exemplary solvents can be used alone, or two or more of them can be mixed and used.

[0104] In an embodiment of the present invention, the solvent may be an aqueous solvent, for example, the solvent may be water, Ringer's solution, purified water, water for injection, physiological saline, or a mixture thereof.

[0105] In an embodiment of the present invention, the liquid preparation may have a pH ranging from slightly acidic to neutral, particularly a pH of about 4.0 to about 7.0. The liquid preparation according to the present invention may remain stable for a long time within the above pH range, may be highly stable, and may provide significantly superior medication convenience and medication compliance. For example, the liquid formulations of the present invention can have a pH of about 4.5 to about 7.0, can specifically have a pH of about 4.5 to about 6.0, and can more specifically have a pH of about 5.0 to about 6.0, for example, the liquid formulations can have a pH of about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, etc.

[0106] In embodiments of the present invention, liquid preparation can further comprise buffer.In this case, can keep stable for a long time when having the pH that is suitable for using according to the liquid preparation that comprises L-serine or its pharmaceutically acceptable salt of the present invention, can be highly safe, and can provide significantly excellent administration convenience and medication compliance.

[0107] A buffer is a material added to a solution to prevent a significant change in the hydrogen ion index. It can generally be a mixture of a weak acid and a salt thereof or a salt of an acid. There are no particular limitations as long as the material can function as a buffer. For example, the buffer can be a borate, acetate, carbonate, citrate, lactate, or the like, and can be a hydrate of each of the above salts, or a mixture thereof. The buffer can include one of acetate, carbonate, citrate, lactate, and hydrates thereof, or a mixture of two or more thereof.

[0108] For example, the buffer can be ammonium carbonate, sodium acetate, potassium acetate, calcium carbonate, calcium lactate, potassium citrate, sodium citrate, sodium bicarbonate, sodium lactate and hydrates thereof. These exemplary buffers can be used alone, or two or more thereof can be mixed and used.

[0109] According to an embodiment of the present invention, the liquid preparation may not contain phosphoric acid or phosphate. Phosphoric acid or phosphate can cause diarrhea, so patients with illness or reduced endurance or frail and elderly people (e.g., children or the elderly) may experience side effects such as diarrhea when taking large doses for a long time. Therefore, if necessary, the liquid preparation according to an embodiment of the present invention may not contain phosphoric acid or phosphate.

[0110] In an embodiment of the present invention, the amount of the buffer included may have a concentration suitable for maintaining pH, and the concentration of the buffer included may specifically be about 0.5 mg / mL to about 50 mg / mL, but the concentration may be appropriately adjusted depending on the type of the buffer.

[0111] In an embodiment of the present invention, the liquid preparation may further contain a sweetener, and the liquid preparation containing L-serine or a pharmaceutically acceptable salt thereof according to the present invention can maintain a stable liquid state for a long time while containing a sweetener, and is therefore highly safe and provides significantly excellent administration convenience and medication compliance, thereby allowing even patients who have difficulty taking oral medications (e.g., children and the elderly) to easily take the medication.

[0112] Sweetener is a material for providing sweet taste, and is not particularly limited as long as the material can be used for liquid preparations. For example, sweetener can be acesulfame potassium, aspartame, dextrose, dextrose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevioside, steviol glycoside, enzyme-modified stevioside, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, white sugar (such as refined white sugar), syrup, simple syrup, honey etc. These exemplary sweeteners can be used alone, or two or more of them can be mixed and used.

[0113] The taste of the liquid preparation according to an embodiment of the present invention can be improved by adding a sweetener, thereby significantly increasing the convenience of medication for children. In addition, adding such a sweetener can provide excellent stability, safety and therapeutic effects.

[0114] In an embodiment of the present invention, the liquid preparation may further comprise, in addition to the thickener, buffer and / or sweetener, additional additives, which may be diluents, acidulants, preservatives or mixtures thereof.

[0115] In an embodiment of the present invention, in addition to thickeners, buffers and / or sweeteners, the liquid preparation may further comprise additional additives, which may be diluents, solubilizers, stabilizers, flavoring agents, coloring agents, preservatives, foaming agents, refreshing agents, antibacterial agents, flavor enhancers or mixtures thereof.

[0116] Diluent is a material other than a solvent that is used to increase the capacity of a liquid preparation, and is not particularly limited as long as the material can be used for a liquid preparation. For example, the diluent can be a sugar, a sugar alcohol, a glycol or a mixture thereof, and can particularly be hexylene glycol, propylene glycol, sorbitol, sorbitan, sorbitol solution, mannitol, lactose, etc. These exemplary diluents can be used alone, or two or more thereof can be mixed and used.

[0117] Solubilizing agent is the liquid material for increasing the solubility of all components, and is not particularly limited, as long as this material can be used for liquid preparation.For example, solubilizing agent can be sucrose monostearate, polyoxyethylene sorbitol fatty acid ester (diester), polyoxyethylene monoalkyl ether, lanolin ether, lanolin ester etc., for example, can be polysorbate.These exemplary solubilizing agents can be used separately, or can use two or more of them in mixed use.

[0118] Stabilizers are materials added to prevent flavor degradation and delay oxidation, or to prevent volatile flavors from evaporating and degrading, and are not particularly limited as long as they can be used in liquid preparations. The liquid preparations of the present invention exhibit sufficient stability for a long period of time without the addition of stabilizers, but stabilizers may optionally be added to maintain flavor or taste.

[0119] The stabilizer may be an alkalizing agent including aqueous ammonia, potassium hydroxide, sodium hydroxide, prolamin, etc. These exemplary stabilizers may be used alone, or two or more thereof may be mixed and used.

[0120] Flavoring agent is the material for adding specific flavor, and is not particularly limited, as long as the material can be used for liquid preparation.For example, flavoring agent can be almond oil, anethole, benzaldehyde, ethyl acetate, ethyl vanillin, lactitol, maltol, menthol, methyl salicylate, monosodium glutamate, peppermint, peppermint oil, menthol, rose oil and concentrated rose water, thymol, vanillin etc.These exemplary flavoring agents can be used alone, or two or more of them can be mixed and used.

[0121] Coloring agent is the material for imparting color, and is not particularly limited, as long as this material can be used for liquid preparation.For example, coloring agent can be caramel, iron oxide (red, yellow, mixed type) etc.In addition, for example, can use the tar pigment that is used for medicine, quasi-drug and cosmetics according to Food and Drug Administration 2000-66 announcement.These exemplary coloring agents can be used alone, or can use two or more of them in mixed use.

[0122] Antiseptic is to be used for protecting all components from deterioration, discoloration, corrosion etc. or for delaying or preventing the material of microorganism or chemical deterioration, and is not particularly limited, as long as this material can be used for liquid preparation.For example, antiseptic can be benzoic acid, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol etc.These exemplary antiseptics can be used alone, or can use two or more of them in combination.

[0123] The foaming agent is a material used to increase the amount of air in the preparation and is not particularly limited as long as the material can be used in liquid preparations. For example, the foaming agent can be sodium bicarbonate, sodium carbonate, magnesium carbonate, ammonium bicarbonate, ammonium carbonate, potassium carbonate, calcium carbonate, etc. These exemplary foaming agents can be used alone or in combination of two or more.

[0124] A refreshing agent is a material for providing a refreshing feeling and is not particularly limited as long as the material can be used in a liquid preparation. For example, the refreshing agent can be d-camphor, dl-camphor, l-menthol, dl-menthol, peppermint oil, eucalyptus oil, etc. These exemplary refreshing agents can be used alone, or two or more of them can be mixed and used.

[0125] Flavor enhancers are materials for maximizing or adjusting the original taste and flavor without changing the original flavor, and are not particularly limited as long as the material can be used in liquid preparations. For example, flavor enhancers can be white sugar, citric acid, monosodium glutamate, peppermint oil, etc. These exemplary flavor enhancers can be used alone, or two or more of them can be mixed and used.

[0126] In an embodiment of the present invention, the liquid preparation may comprise L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, and a solvent, wherein the amount of L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL or higher.

[0127] In an embodiment of the present invention, the liquid preparation may comprise L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, and a sweetener, wherein the amount of L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL or higher.

[0128] In an embodiment of the present invention, the liquid preparation may comprise L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, a sweetener, and a solvent, wherein the amount of the L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL or higher.

[0129] In an embodiment of the present invention, in addition to L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, a sweetener and a solvent, the liquid preparation may further comprise at least one of a diluent, a flavoring agent, a preservative, a sweetener and an acidulant, wherein the amount of the L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL or higher.

[0130] In an embodiment of the present invention, in addition to L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, a sweetener and a solvent, the liquid preparation may further comprise at least one selected from a diluent, a flavoring agent, a preservative, a sweetener, an acidulant and a solubilizing agent, wherein the amount of the L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL or higher.

[0131] In an embodiment of the present invention, in addition to L-serine or a pharmaceutically acceptable salt thereof as an active ingredient, a thickener, a buffer, a sweetener and a solvent, the liquid preparation may further comprise at least one selected from a diluent, a flavoring agent, a preservative, a sweetener, an acidulant, a solubilizer, a cosolvent and a stabilizer, wherein the amount of the L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL to about 500 mg / mL.

[0132] In embodiments of the present invention, liquid preparation can comprise: the L-serine or its pharmaceutically acceptable salt of the amount of approximately 50mg / mL to approximately 500mg / mL, be selected from at least one thickening agent among sodium carboxymethylcellulose, polyvidone, hydroxyethyl cellulose and carbomer, buffer, and solvent.Liquid preparation can have approximately 4.0 to approximately 7.0 pH. In this case, the type of buffer and solvent is identical with previously described. In addition, if necessary, liquid preparation can further comprise at least one in diluent, acidulant, preservative, sweetener and their mixture.

[0133] In an embodiment of the present invention, the liquid preparation can include L-serine or a pharmaceutically acceptable salt thereof, a thickening agent, a buffer and a solvent, wherein the amount of the L-serine or a pharmaceutically acceptable salt thereof is from about 50 mg / mL to about 500 mg / mL, the thickening agent is selected from sodium carboxymethylcellulose, povidone or a mixture thereof, the buffer is a citrate, and the solvent is selected from one of water, purified water, water for injection, Ringer's solution, normal saline and a mixture thereof. The liquid preparation can have a pH of from about 4.0 to about 7.0.

[0134] In an embodiment of the present invention, the liquid preparation may comprise L-serine or a pharmaceutically acceptable salt thereof, a thickener, a buffer and a solvent, wherein the amount of L-serine or a pharmaceutically acceptable salt thereof is about 50 mg / mL to about 300 mg / mL, the thickener is sodium carboxymethylcellulose, the buffer is citrate, and the solvent is one selected from water, purified water, water for injection, Ringer's solution, physiological saline and a mixture thereof, and the liquid preparation may have a pH of about 4.0 to about 7.0.

[0135] In one embodiment, the liquid formulation can include additives such as thickeners, buffers, sweeteners, diluents, flavorings, preservatives, sweeteners, acidulants, and solubilizers, each independently at a concentration of about 0.001 mg / mL or higher or about 0.01 mg / mL to about 150 mg / mL. For example, the liquid formulation can include additives, each independently at a concentration of about 0.001 mg / mL, about 0.01 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, about 30 mg / mL, about 40 mg / mL, about 50 mg / mL, about 60 mg / mL, about 70 mg / mL, about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, etc.

[0136] In an embodiment of the present invention, the liquid formulation may be for oral use or parenteral use.The liquid formulation may be particularly for oral use or oral administration, and more particularly may be an oral solution, such as an oral liquid.

[0137] In an embodiment of the present invention, the liquid preparation may be a syrup, an elixir, a spirit, medicated water, or lemonade, particularly a syrup or lemonade, and more particularly a syrup.

[0138] In an embodiment of the present invention, the liquid preparation may be in a solution state, and in particular may be a clear solution.

[0139] The liquid preparation according to the present invention is highly stable and shows significantly excellent appearance stability and content stability in a stability test under accelerated test conditions (temperature: 40±2°C, relative humidity: 75±5%) for 3 months (Experimental Examples 1 and Figure 1 ; and Experimental Example 2).

[0140] The liquid preparation according to the present invention exhibits a high blood concentration when orally administered, thereby providing an excellent therapeutic effect, and when administered to beagle dogs, the liquid preparation exhibits excellent PK properties compared to a control preparation in which powdered L-serine at the same concentration was added to water (Experimental Examples 3 and Figure 2 ).

[0141] The liquid preparation comprising L-serine or a pharmaceutically acceptable salt thereof according to the present invention can be used for preventing or treating central nervous system diseases.

[0142] In an embodiment of the present invention, the central nervous system disease can be at least one selected from autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, mood disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder and memory disorder, in particular it can be autism spectrum disorder, Alzheimer's disease and / or Parkinson's disease, and more in particular it can be autism spectrum disorder.

[0143] In an embodiment of the present invention, the liquid formulation can be used to prevent or treat autism spectrum disorders.

[0144] Another embodiment of the present invention relates to a method for preparing the above-mentioned liquid formulation.

[0145] The present invention relates to a method for preparing a liquid preparation containing a high concentration of L-serine or a pharmaceutically acceptable salt thereof, wherein the liquid preparation has a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 50 mg / mL or higher.

[0146] In an embodiment of the present invention, a method for preparing a liquid preparation of L-serine or a pharmaceutically acceptable salt thereof may include dissolving an active ingredient, an additive, or a combination thereof in a solvent.

[0147] The method for preparing the liquid formulation according to the present invention may comprise:

[0148] (1) dissolving a thickener in a solvent to prepare a first solution;

[0149] (2) adding a pharmaceutically acceptable first additive to the first solution, and heating the mixture at 50° C. or higher to prepare a second solution having a pH of about 4.0 to about 7.0; and

[0150] (3) Cooling the second solution, and then dissolving L-serine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable second additive in the cooled second solution to prepare a third solution.

[0151] The liquid preparation has a concentration of L-serine or a pharmaceutically acceptable salt thereof of about 50 mg / mL or more.

[0152] The preparation method of the present invention can mass-produce a highly stable liquid preparation containing L-serine or a pharmaceutically acceptable salt thereof at a high concentration by a simple method, and is therefore economically and commercially excellent.

[0153] In the above-mentioned preparation method, when the active ingredient, additives, etc. are each more than one type as needed, the order of addition can be adjusted according to the characteristics of the components contained in the liquid preparation.

[0154] In an embodiment of the present invention, the pharmaceutically acceptable first additive may be one or a mixture of two or more selected from the group consisting of an acidifier, a buffer, a preservative, and a solubilizer.

[0155] In an embodiment of the present invention, the pharmaceutically acceptable second additive may be a diluent, a sweetener, a flavoring agent, a coloring agent, or a mixture thereof.

[0156] In an embodiment of the present invention, in the preparation method, when necessary, in addition to the first additive and the second additive, an additional pharmaceutically acceptable third additive can be further added. In particular, the method for preparing the liquid preparation can further include adding a pharmaceutically acceptable third additive to the third solution.

[0157] In an embodiment of the present invention, the pharmaceutically acceptable third additive may be the same as or different from the first additive and / or the second additive, and in particular, the third additive may be different from the first additive or the second additive. For example, the third additive may be a thickener, a buffer, a sweetener, a diluent, an acidulant, a preservative, a solubilizer, a stabilizer, a flavoring agent, a colorant, a foaming agent, a refreshing agent, an antibacterial agent, a flavor enhancer, or a mixture thereof.

[0158] In an embodiment of the present invention, the heating temperature in step (1) may be about 50°C to about 80°C.

[0159] In an embodiment of the present invention, the cooling temperature in step (2) may be lower than about 50°C or in the range of about 4°C to about 50°C.

[0160] In the preparation method, the temperature for dissolving the active component, additives, etc. in the solvent can be adjusted according to the characteristics of each component.

[0161] In the preparation method according to the present invention, various physical properties including the active components in the liquid preparation and their concentrations, the types of additives and their concentrations, and the pH of the liquid preparation may be substantially the same as those described in the liquid preparation according to the present invention, as long as the physical properties do not contradict each other.

[0162] With respect to the descriptions of the liquid formulations and methods for preparing the liquid formulations described herein, any one of the descriptions shown is equally applicable to the other as long as the descriptions do not contradict each other.

[0163] Modes of the Invention

[0164] Hereinafter, the present invention is explained in detail by way of examples. The following examples are intended to further illustrate the present invention without limiting its scope.

[0165] Example

[0166] Hereinafter, preferred embodiments according to the present invention are provided to help understand the present invention. However, the following embodiments are provided only to make the present invention easier to understand, and the content of the present invention is not limited by the embodiments.

[0167] Regarding the components used in the examples, products such as L-serine (Tianjin Tianyao, China), D-sorbitol solution (Baikwang Industrial Co., Ltd., South Korea), carbomer 971P (Lubrizol, USA), hydroxyethylcellulose (Ashland, USA), povidone K-30 (BASF, Germany), sodium carboxymethylcellulose (Patel Chem, India), Tween 20 (Samjeon Pure Chemicals, South Korea), apple mint flavor SJ-G (22005221) (Mitsui Flavors, South Korea), methylparaben (SAN Fu Chemical, Taiwan, China), propylparaben (SAN Fu Chemical, Taiwan, China), refined white sugar (Nexpharm Korea, South Korea), citric acid hydrate (Samjeon Pure Chemicals, South Korea), potassium citrate hydrate (Samjeon Pure Chemicals, South Korea), sodium citrate hydrate (Samjeon Pure Chemicals, South Korea), sucralose (WHAWON PHARM, South Korea), aspartame (Daishin Pharmaceutical, South Korea), enzyme-modified stevia (Wako pure chemical, Japan) and acesulfame potassium (WHAWONPHARM, South Korea).

[0168] Example 1: Preparation of liquid preparation 1 (Examples 1-1 to 1-6)

[0169] A liquid preparation containing L-serine at a concentration of 100 mg / mL was prepared according to the components and contents listed in the following Table 1. The contents listed in Table 1 represent the amount (mg) contained per 1 mL of the liquid.

[0170] First, the thickener is swollen in purified water and then dissolved. The preservative, acidifier, buffer, and solubilizer are completely dissolved at a heating temperature of 50°C or higher, and the pH is adjusted to 4.0 to 7.0. Thereafter, the solution is cooled to below 50°C, and L-serine, a diluent, a sweetener, and the like are added and dissolved. Once all substances have dissolved, a colorant or flavoring is added, and the volume is adjusted with purified water to produce an oral syrup containing L-serine.

[0171] [Table 1]

[0172]

[0173]

[0174] Example 2: Preparation of liquid preparation 2 (Examples 2-1 to 2-6)

[0175] According to the components and contents listed in Table 2 below, liquid preparations containing L-serine at different concentrations were prepared in substantially the same manner as the preparation method described in Example 1 (Examples 2-1 to 2-6).

[0176] The contents listed in Table 2 represent the amounts (mg) contained per 1 mL of the liquid preparation.

[0177] [Table 2]

[0178]

[0179] Example 3: Preparation of liquid preparation 3 (Examples 3-1 to 3-6)

[0180] According to the component and content listed in the following table 3, the liquid preparation (embodiment 3-1 to 3-6) containing the L-serine of 100mg / mL concentration was prepared in a manner substantially identical to the preparation method described in Example 1. The content listed in the table 3 represents the amount (mg) contained in every 1mL liquid preparation.

[0181] [Table 3]

[0182]

[0183] Example 4: Preparation of Liquid Preparation 4 (Examples 4-1 to 4-6)

[0184] According to the components and contents listed in Table 4 below, liquid preparations containing L-serine (Examples 4-1 to 4-6) were prepared in substantially the same manner as described in Example 1. The contents listed in Table 4 represent the amount (mg) contained per 1 mL of the liquid preparation.

[0185] [Table 4]

[0186]

[0187]

[0188] Comparative Examples 1-3

[0189] According to the components and contents listed in Table 5 below, liquid preparations containing L-serine (Comparative Examples 1 to 3) were prepared in substantially the same manner as described in Example 1. The contents listed in Table 5 represent the amount (mg) contained per 1 mL of the liquid preparation.

[0190] [Table 5]

[0191]

[0192] Experimental Example 1: Appearance Stability Test

[0193] The liquid preparations prepared in Examples and Comparative Examples were subjected to a stability test for 3 months under accelerated test conditions (temperature: 40±2° C., relative humidity: 75±5%).

[0194] The stability test results of Example 1 above are shown in Table 6 below.

[0195] In addition, the stability test results of Examples 1-6, 2-1, 2-6, and 3-4 according to the present invention and Comparative Examples 1 to 3 are shown in Tables 7 and Figure 1 below.

[0196] [Table 6]

[0197]

[0198] [Table 7]

[0199]

[0200] As can be seen from Tables 6, 7, and Figure 1 [End]]below, the liquid preparations prepared according to the examples of the present invention remained in a transparent state, indicating that the appearance was stable under accelerated test conditions.

[0201] On the other hand, it was found that the preparation containing only the main component in Comparative Example 1 showed precipitation in the form of solid particles; the preparation without a thickener in Comparative Example 2 changed color to yellow and showed precipitation in the form of solid particles; the preparation with a pH of 2.2 in Comparative Example 3 changed color to brown and dark brown and showed precipitation in the form of solid particles, resulting in poor stability.

[0202] Experimental Example 2: Content Stability Test

[0203] The preparations prepared by the examples and comparative examples were stored for 3 months under long-term storage test conditions (temperature: 25 ± 2 °C, relative humidity: 60 ± 5 %), and then the content (%) was evaluated using the following analytical method. The results are shown in Table 8.

[0204] [L-Serine Content Test Method]

[0205] In the liquid preparations prepared in the examples and comparative examples, 100 mg of an equal amount of L-serine was placed in a 100 mL volumetric flask, and purified water was added to make 100 mL so that the mixture was used as a sample solution. Separately, 100 mg of L-serine standard (Sigma, USA) was placed in a 100 mL volumetric flask, and then purified water was added to make 100 mL so that the mixture was used as a standard solution. The amount of L-serine was calculated by testing 10 μL of the standard solution and the sample solution according to liquid chromatography under the following conditions.

[0206] <HPLC Operating Conditions>

[0207] · Column: SIELC Primesep 100 (4.6X 150 mm, 5 μm)

[0208] Detector: Ultraviolet absorption measurement method (reference wavelength: 200nm)

[0209] Flow rate: 1.0 mL / min

[0210] Column temperature: constant at about 30°C

[0211] Mobile phase: Add phosphoric acid to 1 L of purified water and adjust the pH to 2.2.

[0212] Holding time: 60 minutes.

[0213] [Table 8]

[0214]

[0215] As shown in Table 8, even after 3 months, the liquid preparations of Examples (Examples 1-6, 2-1, 2-6, and 3-4) containing L-serine in an amount of 50 mg / mL to 300 mg / mL remained within the standard content range, showing excellent content stability.

[0216] On the other hand, the liquid preparations according to Comparative Examples 1, 2, and 3 showed a significant decrease in content (below the standard) after 3 months, resulting in poor appearance and content stability. In particular, it was found that Comparative Example 1, which contained only the active ingredient without additives, and Comparative Example 3, which had a strongly acidic pH, showed very severe content reduction.

[0217] Experimental Example 3: Animal PK Test

[0218] Prepared the liquid preparation (syrup) among embodiment 1-6 and before using, prepared control preparation by L-serine powder quick dissolving in purified water.In this case, the concentration of the L-serine in the control preparation is identical with the concentration in the liquid preparation of embodiment 1-6.

[0219] The liquid preparations of Examples 1-6 (administered to the experimental group) and the control preparation (administered to the control group) were each orally administered to a total of 12 beagle dogs in a crossover manner in 2 groups (6 dogs in each group) over 2 phases; then, the College of Pharmacy at Kyungpook National University measured the blood L-serine concentration profile and evaluated the pharmacokinetics.

[0220] Since L-serine is an endogenous drug present in the body, blood was collected within a certain period of time before administration and after administration. Beagle dogs weighing approximately 10 kg were fasted for a certain period of time before administration, and blood was collected at 0, 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4, 6, 9, 12, and 24 hours. Each experimental agent was then orally administered at a dose of 40 mL / 4 g / head, and blood was then collected at the same time points.

[0221] The PK test results for beagle dogs are shown in Tables 9 and Figure 2 middle.

[0222] Analysis of L-serine in the samples was performed using LC-MS / MS after pre-treating the plasma samples via a protein precipitation method by partially modifying the analytical method reported in "The Effect of Sample Pretreatment in Amino Acid Analysis" (Korean Journal of Clinical Pathology 2001; 21(1): 34-39 (Kim Moon-hee and Moon Hae-ran)).

[0223] [Table 9]

[0224]

[0225] As shown in Table 9 and Figure 2 As can be seen from the figure, Examples 1-6 according to the present invention showed higher blood concentrations (C max ) and the area under the blood concentration curve (AUC), indicating that Examples 1 to 6 have relatively high bioavailability. Examples 1 to 6 showed a smaller CV (coefficient of variation, which indicates deviation due to oral administration) than the control formulation, confirming that the test formulation showed a certain effect by reducing the deviation between individuals.

Claims

1. A liquid preparation comprising: 50 mg / mL to 300 mg / mL of L-serine or a pharmaceutically acceptable salt thereof; One or more thickening agents selected from sodium carboxymethylcellulose, povidone, hydroxyethylcellulose and carbomer; a buffer which is citrate; and acidifiers, wherein the liquid preparation has a pH of 4.0 to 7.0, and the preparation is used for preventing or treating autism spectrum disorder.

2. The liquid preparation according to claim 1, wherein L-serine or a pharmaceutically acceptable salt thereof is present at a concentration of 70 mg / mL to 300 mg / mL.

3. The liquid preparation according to claim 1, wherein The liquid formulation contains a thickening agent at a concentration of 0.5 mg / mL to 100 mg / mL.

4. The liquid preparation according to claim 1, wherein The liquid formulation further comprises a solvent.

5. The liquid preparation according to claim 1, wherein The liquid preparation is a syrup.

6. The liquid preparation according to claim 1, wherein The liquid formulation further comprises a sweetener.

7. The liquid preparation according to claim 6, wherein The sweetener is one selected from acesulfame potassium, aspartame, dextrose, dextrose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevioside, steviol glycoside, enzyme-modified stevioside, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, white sugar, syrup, simple syrup, honey and a mixture thereof.

8. The liquid preparation according to claim 1, wherein The liquid preparation further comprises an additive selected from the group consisting of a diluent, a solubilizer, a flavoring agent, a preservative, a sweetener, and a mixture thereof.

9. The liquid preparation according to claim 8, wherein The preservative is one selected from benzoic acid, sodium benzoate, methyl hydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol and a mixture thereof.

10. A liquid preparation comprising: 50 mg / mL to 300 mg / mL of L-serine or a pharmaceutically acceptable salt thereof; a thickening agent selected from sodium carboxymethylcellulose, povidone or a mixture thereof; a buffer which is citrate; acidifiers; and The solvent is selected from water, purified water, water for injection, Ringer's solution, physiological saline and a mixture thereof, wherein the liquid preparation has a pH of 4.0 to 7.0, and the preparation is used for preventing or treating autism spectrum disorder.

11. The liquid preparation according to any one of claims 1 to 10, wherein The liquid preparation is an oral preparation.

12. The liquid preparation according to any one of claims 1 to 10, wherein The liquid preparation is a solution.

13. A method for preparing the liquid preparation according to claim 1, comprising: (1) dissolving a thickener in a solvent to prepare a first solution; (2) adding a pharmaceutically acceptable first additive to the first solution, and heating the mixture to 50° C. or higher to prepare a second solution having a pH of 4.0 to 7.0; as well as (3) Cooling the second solution, and then dissolving L-serine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable second additive in the cooled second solution to prepare a third solution.

14. The method according to claim 13, wherein The pharmaceutically acceptable first additive comprises one or more selected from the group consisting of an acidifier, a buffer, a solubilizer, and a preservative.

15. The method according to claim 13, wherein The pharmaceutically acceptable second additive comprises one or more selected from the group consisting of a diluent, a sweetener, a flavoring agent, and a coloring agent.

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