Liquid formulations of L-serine or its pharma-ceutically acceptable salts and methods for preparing same

Abstract

The present invention relates to a liquid formulation containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof, having excellent stability and safety, and exhibiting excellent pharmacological action, and a method for preparing the same.

Description

[Technical field]

[0001] The present invention relates to a liquid formulation of L-serine or a pharma- ceutically acceptable salt thereof, and a method for preparing said liquid formulation.

[0002] [Background technology] Amino acids are the building blocks of proteins that make up living systems and tend to be classified into two types: essential amino acids, which cannot be synthesized by the body, and non-essential amino acids, which can be synthesized by the body.

[0003] A total of 20 different amino acids have been discovered so far, which can be classified 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.

[0004] In particular, the L-form of serine (hereinafter referred to as L-serine), a type of non-essential amino acid synthesized by the body, has a molecular weight of about 105.1 g / mol. As a hydrophilic amino acid, L-serine exhibits a water solubility limit of about 250 mg / ml at 20° C., but high doses of L-serine in solution cause discoloration and precipitation over time.

[0005] L-serine is a non-essential amino acid synthesized by the body, but L-serine deficiency can occur due to multiple causes, including congenital genetic defects in the serine biosynthetic metabolic pathway, hypoxic-ischemic brain injury, and traumatic brain injury. In particular, impaired L-serine biosynthesis in the brain can cause fatal damage by reducing the production of glutathione, which prevents damage caused by reactive oxygen species (ROS).

[0006] It is therefore very important that patients who have low blood serine levels due to a reduction or interruption of L-serine biosynthesis are given L-serine directly for treatment instead of other amino acids.

[0007] However, it is difficult to develop a formulation that can provide only L-serine and that contains a high enough dose or concentration of L-serine to bring the L-serine deficiency to normal levels.

[0008] For this reason, it has been proposed to administer large amounts of amino acid complex solutions containing low concentrations of L-serine to patients who would otherwise have already received L-serine.

[0009] Furthermore, a method of directly ingesting powdered or solid raw materials has also been suggested, but in this case, compliance with medication drops sharply, thereby reducing the therapeutic effect.

[0010] Therefore, there remains a need to develop a liquid formulation containing L-serine at a high concentration and available for oral administration.

[0011] [Prior art document] [Patent Document 1] Korean Patent No. 10-2091620 [Patent Document 2] Korean Patent No. 10-1672347 [Non-Patent Document 1] "Effect of Sample Pretreatment on Amino Acid Analysis" Korean Journal of Clinical Pathology, 2001;21(1):34-39 (Moon-Hee Kim and Hae-Ran Moon)

[0012] [Disclosure of the Invention] [Technical issues] An object of the present invention is to provide a liquid formulation containing L-serine or a pharma- ceutically acceptable salt thereof at a high concentration.

[0013] The liquid formulations of the present invention can allow for rapid administration and long-term intake of L-serine, can contain L-serine in high concentrations, and therefore can improve convenience of administration by reducing the total dose of medicine required for treatment, can be made available as a liquid formulation for oral administration, and can increase patient compliance, thereby increasing the therapeutic effect.

[0014] The liquid formulation of the present invention can have excellent storage stability and long-term storage life due to the high concentration of L-serine or a pharma- ceutically acceptable salt thereof without showing precipitation or settling of solid materials for an extended period of time, and can prevent discoloration and recrystallization by improving the solubility of L-serine, thereby improving safety.

[0015] The liquid preparation according to the present invention can maintain L-serine or a pharma- ceutically acceptable salt thereof in a completely dissolved state for a long period of time, can exhibit a pH in the range of slightly acidic to neutral without containing strong acids such as hydrochloric acid and sulfuric acid, can significantly reduce the total dose, and can be so stable and safe that it can be safely used for a long period of time by patients with diseases including central nervous system diseases, thereby significantly increasing the convenience of taking the medicine and the compliance rate.

[0016] The liquid formulations of the present invention are highly stable, exhibiting improved bioavailability when administered orally and an improved ability to maintain formulation quality over extended storage and / or use, thereby ensuring superior therapeutic efficacy over extended periods of time, and also providing improved pharmaceutical economics based on physical appearance, improved drug utility, ease of formulation, and a high degree of formulation stability.

[0017] Another object of the present invention is to provide a method for preparing a liquid formulation containing L-serine or a pharma- ceutically acceptable salt thereof at a high concentration.

[0018] [Solution to the problem] 1) The present invention relates to a liquid formulation comprising L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient and a thickening agent, the liquid formulation having L-serine or a pharma- ceutically acceptable salt thereof at a concentration of about 50 mg / mL or more.

[0019] 2) In embodiment 1) of the present invention, the liquid formulation may have L-serine or a pharma- ceutically acceptable salt thereof at a concentration of about 50 mg / mL to about 500 mg / mL.

[0020] 3) In at least one embodiment of 1) or 2) according to the present invention, the liquid formulation may have L-serine or a pharma- ceutically acceptable salt thereof at a concentration of about 70 mg / mL to about 300 mg / mL.

[0021] 4) In at least one embodiment of 1) to 3) according to the present invention, the thickener contained in the liquid formulation may be agar, bentonite, carbomer, sodium carboxymethylcellulose, carrageenan, microcrystalline sodium carboxymethylcellulose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, pectin, polyethylene oxide, povidone, corn starch, potato starch, wheat starch, xanthan gum, gelatin, or a mixture thereof.

[0022] 5) In at least one embodiment of 1) to 4) according to the present invention, the viscosity enhancer contained in the liquid formulation may be sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, or a mixture thereof.

[0023] 6) In at least one embodiment of 1) to 5) according to the present invention, the liquid formulation may have a viscosity enhancing agent at a concentration of about 0.5 mg / mL to about 100 mg / mL.

[0024] 7) In at least one embodiment of 1) to 6) according to the present invention, the liquid preparation has a pH of about 4.0 to about 7.0.

[0025] 8) In at least one of the embodiments 1) to 7) according to the present invention, the liquid formulation may further contain a buffering agent.

[0026] 9) In at least one embodiment of 1) to 8) according to the present invention, the buffer may be a borate, an acetate, a carbonate, a citrate, a lactate, or a hydrate thereof (a hydrate of the borate, acetate, carbonate, citrate, or lactate), or a mixture thereof.

[0027] 10) In at least one of the embodiments 1) to 9) according to the present invention, the buffer may be at least one selected from the group consisting of ammonium carbonate, sodium acetate, potassium acetate, calcium carbonate, calcium lactate, potassium citrate, sodium citrate, sodium bicarbonate, sodium lactate, and hydrates thereof.

[0028] 11) In at least one embodiment of 1) to 10) according to the present invention, the buffering agent may be a pharma- ceutically acceptable salt of citric acid or a hydrate thereof.

[0029] 12) In at least one of the embodiments 1) to 11) according to the present invention, the liquid formulation may further contain a solvent.

[0030] 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.

[0031] 14) In at least one embodiment of 1) to 13) according to the present invention, the liquid formulation may further contain a sweetener.

[0032] 15) In at least one embodiment of 1) to 14) according to the present invention, the sweetener may be one selected from the group consisting of acesulfame potassium, aspartame, dextrates, glucose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevia, steviol glycoside, enzyme-modified stevia, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, white sugar such as refined white sugar, syrup, simple syrup, honey, and mixtures thereof.

[0033] 16) In at least one embodiment of 1) to 15) according to the present invention, the liquid formulation may further comprise a diluent, a solubilizer, a flavoring agent, a preservative, a sweetener, an acidifier, a buffer, or a mixture thereof.

[0034] 17) In at least one embodiment of 1) to 16) according to the present invention, the preservative may be benzoic acid, sodium benzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol, or a mixture thereof.

[0035] 18) The present invention relates to a liquid formulation comprising L-serine or a pharma- ceutically acceptable salt thereof in an amount of about 50 mg / mL to about 500 mg / mL, at least one thickening agent selected from the group consisting of sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, and carbomer, a buffer, and a solvent.

[0036] 19) In at least one embodiment of 1) to 18) according to the present invention, the liquid preparation may have a pH of about 4.0 to about 7.0.

[0037] 20) In at least one embodiment of 1) to 19) according to the present invention, the buffer may be a borate, an acetate, a carbonate, a citrate, a lactate, a hydrate of the borate, acetate, carbonate, citrate, or lactate, or a mixture thereof.

[0038] 21) In at least one embodiment of 1) to 20) according to the present invention, the liquid formulation may further comprise a diluent, an acidifier, a preservative, a sweetener, or a mixture thereof.

[0039] 22) The present invention relates to a liquid formulation comprising L-serine or a pharma- ceutically acceptable salt thereof in an amount of about 50 mg / mL to about 500 mg / mL, a thickening agent selected from sodium carboxymethylcellulose, povidone, or a mixture thereof, a buffer which is a salt of citric acid, and a solvent which is one selected from the group consisting of water, purified water, water for injection, Ringer's solution, physiological saline, and a mixture thereof.

[0040] 23) In at least one embodiment of 1) to 22) according to the present invention, the liquid formulation may have a pH of about 4.5 to about 7.0.

[0041] 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 preparation for internal use.

[0042] 25) In at least one embodiment of 1) to 24) according to the present invention, the liquid preparation may be a solution.

[0043] 26) In at least one embodiment of 1) to 25) according to the present invention, the liquid preparation may be a preparation for preventing or treating a central nervous system disease.

[0044] 27) In at least one embodiment of 1) to 26) according to the present invention, the central nervous system disease may be at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder.

[0045] 28) In at least one embodiment of 1) to 27) according to the present invention, the liquid preparation may be for preventing or treating an autism spectrum disorder.

[0046] 29) The present invention relates to a method for preparing the above-mentioned liquid formulation containing L-serine or a pharma- ceutically acceptable salt thereof.

[0047] 30) The present invention relates to a method for preparing the liquid formulation of the present invention according to at least one of 1) to 29), (1) dissolving a thickening agent in a solvent to prepare a first solution; (2) adding a first pharma- ceutically acceptable excipient to the first solution and heating the mixture to prepare a second solution having a pH of about 4.0 to about 7.0 at about 50° C. or higher; and (3) cooling the second solution, and then dissolving L-serine or a pharma- ceutically acceptable salt thereof and a second pharma-ceutically acceptable excipient in the cooled second solution to prepare a third solution. The present invention relates to a method comprising the steps of:

[0048] 31) At least one of the liquid preparations 1) to 30) above has L-serine or a pharma- ceutically acceptable salt thereof at a concentration of about 50 mg / mL or more.

[0049] 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.

[0050] 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 agent, a coloring agent, or a mixture thereof.

[0051] 34) The present invention provides a method for treating a central nervous system disease using the liquid preparation according to 1) to 33) above, wherein the central nervous system disease may be at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder.

[0052] 35) The present invention provides use of the liquid preparation according to 1) to 33) above for treating a central nervous system disease, wherein the central nervous system disease may be at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder.

[0053] 36) The present invention provides use of the liquid preparation according to any one of 1) to 33) above for preparing a medicament for treating a central nervous system disease, wherein the central nervous system disease may be at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder.

[0054] [Advantageous Effects of the Invention] The liquid formulations of the present invention can allow for rapid administration and long-term intake of L-serine, can contain L-serine in high concentrations, thus improving convenience of administration by reducing the total dose of drug required for treatment, and can be made available as liquid formulations for oral administration, increasing patient compliance and thereby improving therapeutic efficacy.

[0055] The liquid formulation of the present invention can exhibit excellent storage stability and long-term storage life by containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof without showing precipitation or settling of solid materials for an extended period of time, and can prevent discoloration and recrystallization by improving the solubility of L-serine, thereby improving safety.

[0056] The liquid preparation according to the present invention can maintain L-serine or a pharma- ceutically acceptable salt thereof in a completely dissolved state for a long period of time, can exhibit a pH in the range of slightly acidic to neutral without containing strong acids such as hydrochloride and sulfate groups, can significantly reduce the total dose, and can be so stable and safe that it can be safely used for a long period of time by patients with diseases including central nervous system diseases, thereby significantly increasing the convenience of taking the medicine and the compliance rate.

[0057] The liquid formulations of the present invention exhibit improved bioavailability when administered orally and are highly stable with an improved ability to maintain formulation quality over extended storage and / or use, thereby ensuring superior therapeutic efficacy over extended periods of time, and also providing improved pharmaceutical economics based on physical appearance, improved drug utility, ease of formulation, and a high degree of formulation stability.

[0058] The liquid formulations of the present invention may be amenable to large scale production and may be economically viable. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 shows the results of an appearance stability test of liquid preparations according to examples and comparative examples of the present invention. [Diagram 2] FIG. 2 is a graph showing plasma concentration curves in beagle dogs administered an example formulation of the present invention and a control formulation.

[0060] [Best Mode for Carrying Out the Invention] As used herein, the term "oral formulation" means an ingestible drug, and includes both liquid formulations for oral administration and solid formulations for oral administration.

[0061] The term "oral liquid formulation" as used herein means a liquid formulation among ingestible formulations for oral administration.

[0062] The term "oral solid preparation" as used herein means a solid preparation among ingestible internal preparations for oral administration.

[0063] As used herein, the terms "first", "second", etc. are used only to distinguish between multiple components or multiple steps and do not denote a priority order.

[0064] The present invention relates to a liquid formulation containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient, and a method for preparing the same.

[0065] One embodiment of the present invention relates to a liquid formulation comprising L-serine or a pharma- ceutically acceptable salt thereof.

[0066] In embodiments of the present invention, the liquid formulation comprises L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient and a viscosity enhancing agent.

[0067] In embodiments of the present invention, the present invention relates to a liquid formulation comprising L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient and a viscosity enhancing agent, wherein the liquid formulation may have a concentration of L-serine or a pharma- ceutically acceptable salt thereof of about 50 mg / mL or greater.

[0068] Although L-serine or a pharma- ceutically acceptable salt thereof is a material having high solubility in water, liquid formulations in which L-serine is dissolved at a high concentration of about 50 mg / mL or more have limitations in drug stability, such as discoloration and precipitation caused during storage, and therefore, liquid formulations containing L-serine in an amount of about 50 mg / mL or more have not been successfully developed.

[0069] The liquid formulation according to the present invention can contain a high concentration of L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient, and is therefore suitable for oral administration and has a remarkably excellent convenience of administration. 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 a patient who has already received L-serine. However, the amino acid complex solution contains a low concentration of L-serine as well as a number of other amino acids. This amino acid complex solution is used as a parenteral nutrition solution that serves to supply amino acids in hypoproteinemia, malnutrition, and pre- and post-operative conditions, and contains L-serine at a low concentration of about 5 mg / mL together with various other amino acids. When L-serine is administered at a high dose of 10 g or more through a typical amino acid complex solution, the amount of the solution may exceed 2 L, and it takes a long time to administer the amount to the patient. This increases the cost of treatment and excessively impedes the convenience of drug administration to the patient, and other amino acids that the patient does not need are also administered together. Furthermore, when the solution is administered multiple times over a long period of time, it is not easy to accurately calculate the amount administered to the patient, making oral administration inapplicable and thus significantly reducing patient compliance.

[0070] The liquid formulations of the present invention can allow for rapid administration and long-term intake of L-serine, can contain L-serine in high concentrations, thus improving convenience of administration by reducing the total dose of drug required for treatment, and can be made available as liquid formulations for oral administration, thereby increasing therapeutic efficacy and patient compliance.

[0071] Furthermore, the liquid formulation is capable of maintaining the above-mentioned stability for long periods of time while using water as a solvent, and is therefore significantly safer.

[0072] The liquid formulation of the present invention can exhibit excellent storage stability and long-term storage life by containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof without showing precipitation or settling of solid materials for an extended period of time, and can prevent discoloration and recrystallization of L-serine or a salt thereof by improving the solubility of L-serine or a salt thereof, thereby improving safety.

[0073] The liquid formulation according to the present invention can maintain L-serine or a pharma- ceutically acceptable salt thereof in a completely dissolved state for a long period of time, can exhibit a pH in the range of slightly acidic to neutral without containing strong acids such as hydrochloric acid and sulfuric acid, can significantly reduce the total dose, and can be so safe that it can be used safely for a long period of time by patients with diseases including central nervous system diseases.

[0074] The liquid formulations of the present invention are highly stable and safe, exhibiting improved bioavailability, and an improved ability to maintain formulation quality over extended storage and / or use, thereby ensuring superior therapeutic efficacy over extended periods of time, maintaining a stable liquid state over extended periods of time, thereby significantly improving compliance, and also providing improved pharmaceutical economics based on physical appearance, improved drug utility, ease of formulation, and a high degree of formulation stabilization.

[0075] In several embodiments of the present invention, L-serine is a compound represented by the following formula 1, and the source of the compound is not particularly limited, so long as the compound can be used in a liquid formulation.

[0076] [ka]

[0077] In several embodiments of the present invention, the pharma- ceutically 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 a liquid formulation.

[0078] In some embodiments of the present invention, the pharma- ceutically acceptable salt may be an inorganic salt, an inorganic acid salt, an organic acid salt, a sulfonic acid salt, etc. of L-serine. These exemplary pharma- ceutically acceptable salts may be used alone or in combination of two or more of them. For example, inorganic salts may be metal salts including calcium salts, potassium salts, sodium salts, magnesium salts, and the like; inorganic acid salts may include hydrochlorides, nitrates, bromates, iodates, perchlorates, tartrates, sulfates, and the like; organic acid salts may include acetates, trifluoroacetates, citrates, maleates, succinates, oxalates, benzoates, tartrates, fumarates, mandelates, propionates, lactates, glycolates, gluconates, galacturonates, glutamates, glutarates, glucuronates, aspartates, ascorbates, carbonates, vanillates, hydroiodic acid salts, and the like; sulfonates may include methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, naphthalenesulfonates, and the like.

[0079] In one embodiment, the pharma- ceutically acceptable salt of L-serine may be a metal salt of L-serine, particularly at least one of a calcium salt, a potassium salt, a sodium salt, or a magnesium salt, and the pharma- ceutically acceptable salt of L-serine may be a magnesium salt.

[0080] In some embodiments of the present invention, the liquid formulation may contain high concentrations of L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient, particularly in an amount of about 50 mg / mL or greater.

[0081] In one embodiment, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient at a concentration of about 50 mg / mL to about 500 mg / mL.

[0082] In one embodiment, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient at a concentration of about 70 mg / mL to about 300 mg / mL.

[0083] In one embodiment, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient at a concentration of about 100 mg / mL to about 200 mg / mL.

[0084] For example, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient at 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 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, and the like.

[0085] In some embodiments of the present invention, the liquid formulation may contain a pharma- ceutically acceptable additive, a thickening agent, and in this case, the liquid formulation according to the present invention may exhibit excellent stability while containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof.

[0086] In embodiments of the present invention, the thickening agent is a material that resists liquid-like flow and can be agar, bentonite, carbomer, sodium carboxymethylcellulose, carrageenan, microcrystalline sodium carboxymethylcellulose, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, pectin, polyethylene oxide, povidone, corn starch, potato starch, wheat starch, xanthan gum, gelatin, etc. These exemplary thickening agents can be used alone or in combination of two or more of them.

[0087] In embodiments of the present invention, the carbomer can be, but is not limited to, carbomer 971P, carbomer 910, carbomer 934, carbomer 934p, carbomer 940, carbomer 941, carbomer 1342, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, and the like.

[0088] For example, the viscosity increasing agent can be sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, or mixtures thereof.

[0089] In embodiments of the present invention, the liquid formulation may have a viscosity agent in a concentration of from about 0.5 mg / mL to about 150 mg / mL, specifically from about 0.5 mg / mL to about 100 mg / mL, and more specifically from about 1 mg / mL to about 100 mg / mL.

[0090] In some embodiments of the present invention, the liquid formulation may further include a solvent. The solvent is a material that can dissolve the active ingredient L-serine or a pharma- ceutically acceptable salt thereof to form a homogeneously dispersed mixture (solution), and is not particularly limited as long as the solvent can be used in the liquid formulation.

[0091] In several embodiments of the present invention, the solvent may be water, purified water, water for injection, Ringer's solution, ethanol, ether, alcohol, white wine, fruit wine, glycerin, peanut oil, saline, etc., and these exemplary solvents may be used alone or in combination of two or more thereof.

[0092] In embodiments 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, saline, or a mixture thereof.

[0093] In embodiments of the invention, the liquid formulations may have a pH in the slightly acidic to neutral range, and in particular, the liquid formulations may have a pH of about 4.0 to about 7.0. The liquid formulations of the present invention may remain stable, or may be highly stable, over extended periods of time in the above pH ranges, and may provide significantly improved medication convenience and compliance. For example, the liquid formulation of the present invention may have a pH of about 4.5 to about 7.0, particularly about 4.5 to about 6.0, and more particularly about 5.0 to about 6.0, e.g., the liquid formulation may 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.

[0094] In embodiments of the invention, the liquid formulation may further comprise a buffering agent, in which case the liquid formulation of the invention comprising L-serine or a pharma- ceutically acceptable salt thereof may remain stable over an extended period of time while exhibiting a suitable pH for administration, and may be highly stable, providing significantly improved administration convenience and compliance.

[0095] A buffer is a material added to a solution to prevent significant changes in pH, and generally may be a mixture of a weak acid and its associated salt or acid salt, and is not particularly limited as long as the material can be used as a buffer. For example, the buffer may be borate, acetate, carbonate, citrate, lactate, etc., or may be a hydrate form of each of the above salts, or a mixture thereof. The buffer solution may include one of acetate, carbonate, citrate, lactate, and their hydrates, or may include a mixture of two or more of them.

[0096] For example, the buffering agent may be ammonium carbonate, sodium acetate, potassium acetate, calcium carbonate, calcium lactate, potassium citrate, sodium citrate, sodium bicarbonate, sodium lactate, and hydrates thereof. These exemplary buffering agents may be used alone or in combination of two or more thereof.

[0097] According to some embodiments of the present invention, the liquid formulation may not contain phosphoric acid or phosphate salts. Phosphoric acid or phosphate salts may cause diarrhea, and thus patients with disease or reduced stamina, or weak and elderly people, such as children or seniors, may experience side effects such as diarrhea when taking large doses for a long period of time. Therefore, according to one embodiment of the present invention, the liquid formulation may not contain phosphoric acid or phosphate salts if necessary.

[0098] In some embodiments of the present invention, the buffer may be included in an amount that provides a suitable concentration for maintaining the pH, and in particular in a concentration of about 0.5 mg / mL to about 50 mg / mL, although the concentration may be adjusted appropriately depending on the type of buffer.

[0099] In several embodiments of the present invention, the liquid formulation may further comprise a sweetener, and the liquid formulation of the present invention comprising L-serine or a pharma- ceutically acceptable salt thereof may remain stable in a liquid state for a long period of time while containing a sweetener, and is therefore very safe and exhibits remarkably excellent convenience of administration and compliance, such that even patients who have difficulty in taking drugs orally, such as children and the elderly, can easily take the drug.

[0100] Sweetener is a material for giving sweetness, and is not particularly limited as long as the material can be used in liquid preparations.For example, sweetener can be acesulfame potassium, aspartame, dextrate, glucose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevia, steviol glycoside, enzyme-modified stevia, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, refined white sugar, syrup, simple syrup, honey, etc. These exemplary sweeteners may be used alone, or two or more of them may be mixed and used.

[0101] The taste of the liquid formulation according to one embodiment of the present invention can be improved by adding sweeteners, thereby significantly increasing the convenience of children to take the medicine. Moreover, the addition of these sweeteners can provide superior stability, safety, and therapeutic effect.

[0102] In embodiments of the present invention, the liquid formulation may further comprise additional additives other than a thickening agent, a buffering agent, and / or a sweetener, which may be a diluent, an acidifier, a preservative, or a mixture thereof.

[0103] In embodiments of the present invention, the liquid formulation may further comprise further additives other than a thickening agent, a buffering agent, and / or a sweetener, which further additives may be a diluent, a solubilizer, a stabilizer, a flavoring agent, a coloring agent, a preservative, an effervescent agent, a freshening agent, a preservative, a flavor synergist, or mixtures thereof.

[0104] The diluent is a material other than a solvent for increasing the volume of a liquid formulation, and is not particularly limited as long as the material can be used in a liquid formulation.For example, the diluent may be a sugar, a sugar alcohol, a glycol, or a mixture thereof, and may be specifically hexylene glycol, propylene glycol, sorbitol, sorbitan, sorbitol solution, mannitol, lactose, etc. These exemplary diluents may be used alone, or two or more of them may be mixed together.

[0105] Solubilizer is a liquid material for increasing the solubility of all components, and is not particularly limited as long as the material can be used in liquid preparations.For example, the solubilizer can be sucrose monostearate, polyoxyethylene sorbitol fatty acid ester (twin ester), polyoxyethylene monoalkyl ether, lanolin ether, lanolin ester, etc., and can be, for example, polysorbate.These exemplary solubilizers can be used alone, or two or more of them can be mixed and used.

[0106] The stabilizer is a material added to prevent flavor deterioration and retard oxidation, or to prevent evaporation and deterioration of volatile flavors, and is not particularly limited as long as the material can be used in a liquid formulation. The liquid formulation of the present invention can exhibit sufficient stability for a long period of time without the addition of a stabilizer, but a stabilizer may be added to maintain the flavor or taste.

[0107] The stabilizer may be an alkalizing agent including aqueous ammonia, potassium hydroxide, sodium hydroxide, prolamin, etc. These exemplary stabilizers may be used alone or in combination of two or more of them.

[0108] Flavoring agents are materials for adding a specific flavor, and are not particularly limited as long as the materials can be used in liquid preparations. For example, flavoring agents can be almond oil, anethole, benzaldehyde, ethyl acetate, ethyl vanillin, lactitol, maltol, menthol, methyl salicylate, monosodium glutamate, peppermint, peppermint oil, peppermint alcohol, rose oil, high-concentration rose water, thymol, vanillin, etc. These exemplary flavoring agents may be used alone, or two or more of them may be mixed together.

[0109] The coloring agent is a material for imparting color, and is not particularly limited as long as the material can be used in a liquid formulation. For example, the coloring agent may be caramel, iron oxide (red, yellow, mixed), etc. In addition, tar dyes for drugs, quasi-drugs, and cosmetics according to Food and Drug Administration Notification No. 2000-66 may be used. These exemplary coloring agents may be used alone, or two or more of them may be mixed and used.

[0110] The preservative is a material used to protect all ingredients from spoilage, discoloration, corrosion, etc., or to delay or prevent spoilage caused by microorganisms or chemicals, and is not particularly limited as long as the material can be used in a liquid formulation. For example, the preservative can be benzoic acid, sodium benzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol, etc. These exemplary preservatives may be used alone or in combination of two or more of them.

[0111] The effervescent agent is a material for increasing the amount of air in the formulation, and is not particularly limited as long as the material can be used in a liquid formulation. For example, the effervescent agent may be sodium bicarbonate, sodium carbonate, magnesium carbonate, ammonium bicarbonate, ammonium carbonate, potassium carbonate, calcium carbonate, etc. These exemplary effervescent agents may be used alone, or two or more of them may be mixed and used.

[0112] The refreshing agent is a material for giving 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 may be used alone, or two or more of them may be mixed and used.

[0113] The flavor synergist is a material for maximizing or adjusting the initial taste sensation and flavor without changing the initial flavor, and is not particularly limited as long as the material can be used in liquid formulations.For example, the flavor synergist can be sucrose, citric acid, monosodium glutamate, peppermint oil, etc. These exemplary flavor synergists can be used alone or in combination of two or more of them.

[0114] In embodiments of the present invention, the liquid formulation may comprise L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL or greater, a viscosity enhancing agent, a buffer, and a solvent.

[0115] In embodiments of the present invention, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL or greater, a thickening agent, a buffer, and a sweetener.

[0116] In embodiments of the present invention, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL or more, a viscosity enhancer, a buffer, a sweetener, and a solvent.

[0117] In several embodiments of the present invention, the liquid formulation may further comprise at least one of a diluent, a flavoring agent, a preservative, a sweetener, and an acidifier, in addition to L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL or more, a thickener, a buffer, a sweetener, and a solvent.

[0118] In several embodiments of the present invention, the liquid formulation may further comprise at least one selected from the group consisting of a diluent, a flavoring agent, a preservative, a sweetener, an acidifier, and a solubilizer, in addition to L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL or more, a thickener, a buffer, a sweetener, and a solvent.

[0119] In several embodiments of the present invention, the liquid formulation may further contain at least one selected from the group consisting of a diluent, a flavoring, a preservative, a sweetener, an acidifier, a solubilizing agent, a solubilizer, and a stabilizer, in addition to L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient in an amount of about 50 mg / mL to about 500 mg / mL, a thickener, a buffer, a sweetener, and a solvent.

[0120] In some embodiments of the present invention, the liquid formulation may contain L-serine or a pharma- ceutically acceptable salt thereof in an amount of about 50 mg / mL to about 500 mg / mL, at least one thickening agent selected from the group consisting of sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, and carbomer, a buffer, and a solvent. The liquid formulation may have a pH of about 4.0 to about 7.0. In this case, the types of the buffer and the solvent are the same as those already described. In addition, the liquid formulation may further contain at least one of a diluent, an acidifier, a preservative, a sweetener, and a mixture thereof, if necessary.

[0121] In embodiments of the present invention, the liquid formulation may include L-serine or a pharma- ceutically acceptable salt thereof in an amount of about 50 mg / mL to about 500 mg / mL, a thickening agent selected from sodium carboxymethylcellulose, povidone, or a mixture thereof, a buffering agent which is a salt of citric acid, and a solvent which is one selected from the group consisting of water, purified water, water for injection, Ringer's solution, saline, and mixtures thereof. The liquid formulation may have a pH of about 4.0 to about 7.0.

[0122] In embodiments of the present invention, the liquid formulation may comprise L-serine or a pharma- ceutically acceptable salt thereof in an amount of about 50 mg / mL to about 300 mg / mL, a thickening agent which is sodium carboxymethylcellulose, a buffer which is a salt of citric acid, and a solvent which is one selected from the group consisting of water, purified water, water for injection, Ringer's solution, saline, and mixtures thereof, and the liquid formulation may have a pH of about 4.0 to about 7.0.

[0123] In one embodiment, the liquid formulation may contain additives such as thickeners, buffers, sweeteners, diluents, flavorings, preservatives, sweeteners, acidifiers, and solubilizers, each independently at a concentration of about 0.001 mg / mL or more, or from about 0.01 mg / mL to about 150 mg / mL. For example, the liquid formulation may contain additives 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.

[0124] In embodiments of the invention, the liquid formulation may be an oral or parenteral formulation. The liquid formulation may in particular be an oral or oral administration formulation, more in particular an oral solution, e.g. an oral solution.

[0125] In embodiments of the invention, the liquid formulation may be a syrup, elixir, spirit, medicinal water, or lemonade, particularly a syrup or lemonade, and more particularly a syrup.

[0126] In embodiments of the present invention, the liquid formulation may be in the form of a solution, in particular a clear solution.

[0127] The liquid formulation of the present invention is very stable, and a 3-month stability test under accelerated test conditions (temperature: 40±2°C, relative humidity: 75±5%) showed significantly excellent appearance and content stability (Experimental Example 1 and FIG. 1; and Experimental Example 2).

[0128] The liquid formulation of the present invention exhibited high blood concentrations when administered orally, thereby resulting in good therapeutic efficacy, and when administered to beagle dogs, the liquid formulation exhibited a superior PK profile compared to a control formulation in which the same concentration of powdered L-serine was added to water (Experimental Example 3 and FIG. 2).

[0129] The liquid preparation of the present invention containing L-serine or a pharma- ceutically acceptable salt thereof can be used to prevent or treat central nervous system diseases.

[0130] In embodiments of the present invention, the central nervous system disease may be at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder, in particular autism spectrum disorder, Alzheimer's disease, and / or Parkinson's disease, more in particular autism spectrum disorder.

[0131] In embodiments of the invention, the liquid formulation may be used to prevent or treat autism spectrum disorders.

[0132] Another embodiment of the present invention relates to a method for preparing the above liquid formulation.

[0133] The present invention relates to a method for preparing a liquid formulation containing a high concentration of L-serine or a pharma- ceutically acceptable salt thereof, the liquid formulation having a concentration of L-serine or a pharma- ceutically acceptable salt thereof of about 50 mg / mL or more.

[0134] In embodiments of the present invention, a method for preparing a liquid formulation of L-serine or a pharma- ceutically acceptable salt thereof may include dissolving an active ingredient, an excipient, or a combination thereof in a solvent. The method for preparing the liquid formulation according to the present invention comprises the steps of: (1) dissolving a thickening agent in a solvent to prepare a first solution; (2) adding a first pharma- ceutically acceptable excipient to the first solution and heating the mixture to prepare a second solution having a temperature of 50° C. or higher and a pH of about 4.0 to about 7.0; and (3) cooling the second solution, and then dissolving L-serine or a pharma- ceutically acceptable salt thereof and a second pharma-ceutically acceptable excipient in the cooled second solution to prepare a third solution. may include.

[0135] The liquid formulation has L-serine or a pharma- ceutically acceptable salt thereof at a concentration of about 50 mg / mL or greater.

[0136] The preparation method of the present invention enables the mass production of highly stable liquid formulations containing high concentrations of L-serine or a pharma- ceutically acceptable salt thereof through a simple method, and is therefore economical and commercially advantageous.

[0137] In the above preparation method, when the active ingredient, additive, etc. each contain two or more kinds as necessary, the order of addition can be adjusted according to the properties of the ingredients contained in the liquid preparation.

[0138] In some embodiments of the present invention, the first pharma- ceutically acceptable excipient may be one or a mixture of two or more selected from the group consisting of an acidifier, a buffering agent, a preservative, and a solubilizing agent.

[0139] In embodiments of the present invention, the second pharma- ceutically acceptable excipient may be a diluent, a sweetener, a flavoring agent, a coloring agent, or a mixture thereof.

[0140] In some embodiments of the present invention, in addition to the first and second additives, a further pharma- ceutically acceptable third additive may be added in the preparation method, if necessary. Specifically, the method for preparing a liquid formulation may further include adding a pharma-ceutically acceptable third additive to the third solution.

[0141] In embodiments of the present invention, the pharma- ceutically acceptable third additive may be the same as or different from the first additive and / or the second additive, in particular, the third additive may be different from the first additive and / or the second additive. For example, the third additive may be a thickening agent, a buffering agent, a sweetener, a diluent, an acidifying agent, a preservative, a solubilizing agent, a stabilizer, a flavoring agent, a coloring agent, an effervescent agent, a freshening agent, a preservative, a flavor synergist, or a mixture thereof.

[0142] In embodiments of the present invention, the heating temperature in step (1) can be from about 50°C to about 80°C.

[0143] In embodiments of the present invention, the cooling temperature in step (2) can be less than about 50°C, or from about 4°C to about 50°C.

[0144] In this preparation method, the temperature at which the active ingredient, additives, etc. are dissolved in the solvent can be adjusted depending on the properties of each ingredient.

[0145] In the preparation method of the present invention, various physical properties, including the active ingredient and its concentration in the liquid formulation, the type and concentration of additives, and the pH of the liquid formulation, may be substantially the same as the physical properties described in the liquid formulation of the present invention, as long as the physical properties are not inconsistent with each other.

[0146] With respect to the descriptions of the liquid formulations and methods for preparing the liquid formulations described herein, a description given in either one may be equally applicable to the other, unless the descriptions are inconsistent with each other.

[0147] [Form for the invention] The present invention will now be described in detail with reference to examples. The following examples are intended to further illustrate the present invention without limiting the scope of the present invention.

[0148] [Example] In order to facilitate understanding of the present invention, preferred examples of the present invention are described below. However, the following examples are provided only to facilitate understanding of the present invention, and the contents of the present invention are not limited to the examples.

[0149] Regarding the ingredients used in the examples, L-serine (Tianjin Tianyao, China), D-sorbitol solution (PAIK KWANG INDUSTRIAL CO.,LTD, Korea), Carbomer 971P (Lubrizol, USA), Hydroxyethylcellulose (Ashland, USA), Povidone K-30 (BASF, Germany), Sodium Carboxymethylcellulose (Patel chem, India), Tween 20 (SAMCHUN PURE CHEMICAL, Korea), Apple Mint Flavor SJ-G (22005221) (SAMJUNG FLAVOR, Korea), Methyl p-oxybenzoate (SAN Fu chemical, Taiwan), Propyl p-oxybenzoate (SAN Fu chemical, Taiwan), Sucrose (Nexpharm Korea, Korea), Citric Acid Hydrate (SAMCHUN PURE CHEMICAL, Korea), Potassium Citrate Hydrate (SAMCHUN PURE The following products were purchased and used: sodium citrate hydrate (SAMCHUN PURE CHEMICAL, Korea), sucralose (WHAWON PHARM, Korea), aspartame (DAESHIN PHARM, Korea), enzyme-modified stevia (Wako pure chemical, Japan), and acesulfame potassium (WHAWON PHARM, Korea).

[0150] Example 1: Preparation of Liquid Formulation 1 (Examples 1-1 to 1-6) A liquid formulation containing L-serine at a concentration of 100 mg / mL was prepared according to the ingredients and contents listed in Table 1 below. The contents listed in Table 1 indicate the amount (mg) contained per 1 mL of the liquid formulation.

[0151] First, the thickener was swelled in purified water and then dissolved. The preservative, acidifier, buffer, and solubilizer were completely dissolved at a heating temperature of 50°C or higher to adjust the pH to 4.0-7.0. The solution was then cooled to below 50°C, and L-serine, diluent, sweetener, etc. were then added and dissolved. After everything was dissolved, a colorant or flavoring was added and the volume was adjusted with purified water to prepare a syrup for oral administration containing L-serine.

[0152] [Table 1]

[0153] Example 2: Preparation of Liquid Formulation 2 (Examples 2-1 to 2-6) Liquid preparations (Examples 2-1 to 2-6) containing L-serine at various concentrations according to the components and contents listed in Table 2 below were prepared in a manner substantially similar to that described in Example 1.

[0154] The contents listed in Table 2 indicate the amount (mg) contained per mL of the liquid formulation.

[0155] [Table 2]

[0156] Example 3: Preparation of Liquid Formulation 3 (Examples 3-1 to 3-6) According to the components and contents listed in Table 3 below, liquid preparations (Examples 3-1 to 3-6) containing L-serine at a concentration of 100 mg / mL were prepared in a manner substantially similar to the preparation method described in Example 1. The contents listed in Table 3 indicate the amount (mg) contained per 1 mL of the liquid preparation.

[0157] [Table 3]

[0158] Example 4: Preparation of Liquid Formulation 4 (Examples 4-1 to 4-6) According to the ingredients 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 in Example 1. The contents listed in Table 4 indicate the amount (mg) contained per 1 mL of the liquid preparation.

[0159] [Table 4]

[0160] Comparative Examples 1 to 3 Liquid formulations containing L-serine (Comparative Examples 1 to 3) were prepared in substantially the same manner as in Example 1, according to the ingredients and contents listed in Table 5 below. The contents listed in Table 5 indicate the amount (mg) contained per 1 mL of the liquid formulation.

[0161] [Table 5]

[0162] Experimental Example 1: Appearance stability test The liquid formulations prepared through the Examples and Comparative Examples were tested for stability for 3 months under accelerated test conditions (temperature: 40±2° C., relative humidity: 75±5%).

[0163] The stability test results for Example 1 above are shown in Table 6 below.

[0164] Furthermore, the stability test results for Examples 1-6, 2-1, 2-6, and 3-4 of the present invention and Comparative Examples 1 to 3 are shown in Table 7 below and FIG.

[0165] [Table 6]

[0166] [Table 7]

[0167] As can be seen in Tables 6, 7, and Figure 1, the liquid formulations prepared according to the examples of the present invention remained clear, indicating that both appearances were found to be stable under the accelerated testing conditions.

[0168] On the other hand, for the formulation of Comparative Example 1 in which only the main component was dissolved, precipitation in the form of solid particles was shown; the formulation of Comparative Example 2 without a thickening agent changed color to yellow and showed precipitation in the form of solid particles; the formulation of Comparative Example 3 showing a pH of 2.2 changed color to brown and dark brown and showed precipitation in the form of solid particles, indicating a decrease in stability.

[0169] Experimental Example 2: Content stability test The formulations prepared through 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 analysis method. The results are shown in Table 8.

[0170] [L-Serine content test method] In the formulations prepared in the Examples and Comparative Examples, 100 mg of L-serine in equal amounts was placed in a 100 mL flask, purified water was added to make 100 mL, and this mixture was used as the sample solution.

[0171] Separately, 100 mg of L-serine standard substance (Sigma, USA) was placed in a 100 mL flask, then purified water was added to make 100 mL, and this mixture was used as the standard solution. By testing 10 μL of the standard solution and the sample solution according to the liquid chromatography method under the following conditions, the amount of L-serine was calculated.

[0172] <HPLC operating conditions> Column: SIELC Primesep 100 (4.6 × 150 mm, 5 μm) Detector: Ultraviolet absorption photometer (reference wavelength: 200 nm) Flow rate: 1.0 mL / min Column temperature: Constant temperature of about 30°C Mobile phase: Phosphoric acid is added to 1 L of purified water and the pH is adjusted to 2.2. Retention time: 60 minutes

[0173] [Table 8]

[0174] As shown in Table 8, the liquid formulations of the examples (Examples 1-6, 2-1, 2-6, and 3-4) containing L-serine in amounts of 50 mg / mL to 300 mg / mL remained in the standard content range even after 3 months, demonstrating excellent content stability.

[0175] On the other hand, the liquid formulations of Comparative Examples 1, 2, and 3 showed a significant decrease in content (below standard) after 3 months, which resulted in a decrease in the stability of appearance and content. In particular, Comparative Example 1, which contains only the active ingredient and no additives, and Comparative Example 3, which has a strong acidic pH, were found to show a very significant decrease in content.

[0176] Experimental example 3: Animal PK study The liquid preparations (syrups) prepared in Examples 1-6 and a control preparation prepared by dissolving L-serine powder in purified water immediately before administration were prepared. In this case, the concentration of L-serine in the control preparation was the same as that in the liquid preparations of Examples 1-6.

[0177] The liquid formulations of Examples 1-6 (administered to the experimental group) and the control formulation (administered to the control group) were orally administered to a total of 12 beagle dogs in two groups (6 dogs in each group) in a two-stage crossover administration format, and then the blood L-serine concentration profile was measured and the pharmacokinetics was evaluated by Kyungpook National University College of Pharmacy.

[0178] Since L-serine is an endogenous drug present in the body, blood samples were taken for a certain period before administration and blood samples were taken after administration. Beagle dogs weighing approximately 10 kg were deprived of food for a certain period before administration, and blood samples were taken 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 / dog, and blood samples were taken at the same time points.

[0179] The results of the PK test in beagle dogs are shown in Table 9 below and FIG.

[0180] The analytical method reported in "Effect of sample pretreatment on amino acid analysis," Korean Journal of Clinical Pathology 2001, 21(1):34-39 (Moon-Hee Kim, Hae-Ran Moon) was modified to pretreat plasma samples through protein precipitation, and then L-serine in the samples was analyzed using LC-MS / MS.

[0181] [Table 9]

[0182] As can be seen in Table 9 and FIG. 2, Examples 1-6 of the present invention achieved higher blood concentrations (C ) than the control formulation administered by dissolving the L-serine powder immediately before administration. max ) and a wide area under the blood concentration curve (AUC). This indicates that Examples 1-6 have relatively high bioavailability. Examples 1-6 showed that the CV (coefficient of variation), which indicates the deviation due to oral administration, was smaller than that of the control formulation. This confirms that the test formulation will show a certain effect by reducing the deviation between individuals.

Claims

1. L-serine or a pharma- ceutically acceptable salt thereof as an active ingredient; and Thickeners and buffers A liquid formulation comprising: the thickening agent is one selected from the group consisting of sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, agar, hydroxypropylcellulose, hypromellose, xanthan gum, gelatin, carrageenan, guar gum, corn starch, potato starch, wheat starch, and mixtures thereof; the liquid formulation having a concentration of L-serine or a pharma- ceutically acceptable salt thereof from about 50 mg / mL to about 300 mg / mL; The liquid formulation has a pH of about 4.0 to about 7.

0.

2. 2. The liquid formulation of claim 1, wherein L-serine or a pharma- ceutically acceptable salt thereof is present in a concentration of about 70 mg / mL to about 300 mg / mL.

3. 3. The liquid formulation according to claim 1 or 2, wherein the viscosity increasing agent is one selected from the group consisting of sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, carbomer, and mixtures thereof.

4. The liquid formulation of any one of claims 1 to 3, wherein the viscosity enhancing agent is at a concentration of about 0.5 mg / mL to about 100 mg / mL.

5. The liquid preparation according to any one of claims 1 to 4, wherein the buffer is at least one selected from the group consisting of borate, acetate, carbonate, citrate, lactate, and hydrates thereof.

6. The liquid preparation according to any one of claims 1 to 5, wherein the buffer is at least one selected from the group consisting of ammonium carbonate, sodium acetate, potassium acetate, calcium carbonate, calcium lactate, potassium citrate, sodium citrate, sodium bicarbonate, sodium lactate, and hydrates thereof.

7. The liquid formulation according to any one of claims 1 to 6, wherein the buffering agent is a pharma- ceutically acceptable salt of citric acid, or a hydrate thereof.

8. The liquid formulation according to any one of claims 1 to 7, further comprising a solvent.

9. The liquid preparation according to any one of claims 1 to 8, which is a syrup.

10. The liquid formulation according to any one of claims 1 to 9, further comprising a sweetener.

11. 11. The liquid formulation of claim 10, wherein the sweetener is one selected from the group consisting of acesulfame potassium, aspartame, dextrates, glucose, fructose, high fructose, galactose, maltose, mannitol, maltitol, xylitol, stevia, steviol glycosides, enzyme-modified stevia, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, sucralose, sucrose, white sugar, syrup, simple syrup, honey, and mixtures thereof.

12. 12. The liquid formulation of any one of claims 1 to 11, further comprising an additive selected from the group consisting of diluents, solubilizers, flavorings, preservatives, sweeteners, acidifiers, and mixtures thereof.

13. 13. The liquid formulation of claim 12, wherein the preservative is one selected from the group consisting of benzoic acid, sodium benzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, sorbic acid, potassium sorbate, sodium sorbate, chlorobutanol, cresol, chlorocresol, and mixtures thereof.

14. L-serine or a pharma- ceutically acceptable salt thereof in an amount from about 50 mg / mL to about 300 mg / mL; at least one thickening agent selected from the group consisting of sodium carboxymethylcellulose, povidone, hydroxyethylcellulose, and carbomer; Buffering agents; and solvent A liquid formulation comprising: The liquid formulation has a pH of about 4.0 to about 7.

0.

15. 15. The liquid formulation of claim 14, further comprising one selected from the group consisting of diluents, acidifiers, preservatives, sweeteners, and mixtures thereof.

16. L-serine or a pharma- ceutically acceptable salt thereof in an amount from about 50 mg / mL to about 300 mg / mL; a viscosity enhancing agent selected from sodium carboxymethylcellulose, povidone, or a mixture thereof; A buffer which is a salt of citric acid; and A solvent selected from the group consisting of water, purified water, water for injection, Ringer's solution, physiological saline, and mixtures thereof. A liquid formulation comprising: The liquid formulation has a pH of about 4.0 to about 7.

0.

17. The liquid formulation according to any one of claims 1 to 16, which is for oral administration.

18. The liquid formulation according to any one of claims 1 to 17, which is a solution.

19. The liquid formulation according to any one of claims 1 to 18 for preventing or treating a central nervous system disease.

20. 20. The liquid formulation of claim 19, wherein the central nervous system disease is at least one selected from the group consisting of autism spectrum disorder, Alzheimer's disease, Parkinson's disease, intellectual disability, learning disability, language disorder, attention deficit hyperactivity disorder, emotional disorder, movement disorder, hypoxic-ischemic brain injury, traumatic brain injury, neuroinflammatory disease, cerebrovascular disease, attention disorder, and memory disorder.

21. 20. The liquid formulation of claim 19 for preventing or treating an autism spectrum disorder.

22. A method for preparing a liquid formulation according to any one of claims 1 to 21, comprising the steps of: (1) dissolving the thickening agent in a solvent to prepare a first solution; (2) adding a first pharma- ceutically acceptable excipient to the first solution and heating the mixture to prepare a second solution having a pH of about 4.0 to about 7.0 at about 50° C. or higher; and (3) cooling the second solution, and then dissolving L-serine or a pharma- ceutically acceptable salt thereof and a second pharma- ceutically acceptable excipient in the cooled second solution to prepare a third solution. A method comprising:

23. 23. The method of claim 22, wherein the first pharma- ceutically acceptable excipient comprises at least one selected from the group consisting of an acidifier, a buffer, a solubilizer, and a preservative.

24. 24. The method of claim 22 or 23, wherein the pharma- ceutically acceptable second additive comprises at least one selected from the group consisting of diluents, sweeteners, flavoring agents, and coloring agents.

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