Quetiapine-fatty acid conjugate nanoparticles using fattigation technology and use thereof as long-acting injection

Abstract

The present invention relates to: quetiapine-fatty acid conjugate nanoparticles using fattigation technology; and use thereof as a long-acting injection. More specifically, the present invention provides self-assembled nanoparticles and a long-acting injectable composition comprising same, the self-assembled nanoparticles comprising a quetiapine-fatty acid conjugate in which one or more fatty acids are conjugated to quetiapine or a pharmaceutically acceptable salt thereof, and being formed by self-assembly according to pH changes. When the composition according to the present invention is administered into the body, the bioavailability, half-life, and the like of quetiapine are improved and the composition exhibits excellent long-acting release characteristics, and thus medication compliance of patients with mental disorders can be improved by using the composition.

Description

Quetiapine-fatty acid conjugate nanoparticles using patching technology and their long-acting injectable use

[0001] The present invention relates to a long-lasting injectable composition, and more particularly, to nanoparticles of a quetiapine-fatty acid conjugate using a fatty acid inclusion technology, a patching platform, and a long-lasting injectable composition using the same.

[0002] The fattigation platform is an innovative technology that combines biopolymers like albumin or gelatin with fatty acids to form amphiphilic structures capable of self-assembling into nanoparticles. Potential applications of this technology include macromolecules like gelatin, albumin, and transferrin; protein / peptide drugs like insulin, calcitonin, semaglutide, and leuprolide; and small active pharmaceutical ingredients like quetiapine and paliperidone.

[0003] Quetiapine is a pharmaceutical compound named 2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol [2-(2-(4-dibenzo[b,f][1,4]thiazepine-11-yl-1-piperazinyl)ethoxy)ethanol]. Quetiapine is a dibenzothiazepine that exhibits antipsychotic effects through antagonism of dopamine D2 receptors and serotonin 5-HT2 receptors, and is an atypical antipsychotic used as adjunctive therapy for major depressive disorders such as schizophrenia and bipolar disorder. However, this drug has low oral bioavailability (9%) and a short half-life (6-7 hours) due to its broad primary effects, necessitating high doses (150-800 mg / day) and frequent dosing (once or twice daily). Therefore, typical quetiapine formulations require daily dosing, which is difficult for approximately 75% of psychiatric patients and contributes to worsening of their condition during treatment.

[0004] Quetiapine is currently widely available in tablet form (Seroquel, Astrazeneca), and an extended-release tablet formulation (Seroquel XR, Astrazeneca) that uses a gel matrix to slow drug absorption and improve medication compliance is also available. However, these tablets and extended-release tablets still have low oral bioavailability and a short half-life, necessitating high doses and frequent administration. Furthermore, patients with schizophrenia may refuse to take tablets, which necessitates improvements in medication compliance. Furthermore, long-acting injections (LAI, Depot) are widely known to be effective in improving medication compliance and therapeutic efficacy compared to other formulations, particularly in patients with schizophrenia, who often resist swallowing and have difficulty predicting when their illness will develop. Therefore, the development of long-acting injectable formulations for these psychiatric medications is critical.

[0005] The purpose of the present invention is to provide a drug formulation and a method for manufacturing the same that can improve medication compliance compared to oral tablets by improving the bioavailability, half-life, and number of administrations of a drug for treating mental illness.

[0006] In order to achieve the above purpose, the present invention provides self-assembling nanoparticles comprising a quetiapine-fatty acid conjugate in which one or more fatty acids are bound to quetiapine or a pharmaceutically acceptable salt thereof, and characterized in that they are formed by self-assembly according to a change in pH.

[0007] The present invention provides a polymer nanoparticle comprising a polymer matrix; and a quetiapine-fatty acid conjugate in which one or more fatty acids are bound to quetiapine or a pharmaceutically acceptable salt thereof, wherein the quetiapine-fatty acid conjugate is loaded into the polymer matrix and formed.

[0008] The present invention provides a long-lasting injectable composition comprising the above nanoparticles.

[0009] The present invention provides a method for producing a quetiapine-fatty acid conjugate, comprising the steps of: neutralizing quetiapine or a pharmaceutically acceptable salt thereof to obtain a quetiapine base; adding the quetiapine base, fatty acid, and activator obtained in the step to an organic solvent for reaction; and evaporating and purifying the solvent after the reaction is completed.

[0010] The present invention provides a method for producing self-assembled nanoparticles comprising a quetiapine-fatty acid conjugate, comprising the steps of dissolving a quetiapine-fatty acid conjugate produced according to the above-described production method in an organic solvent, adding an acidic solution to produce a mixture, and stirring the mixture, and then evaporating the organic solvent.

[0011] In addition, the present invention provides a method for producing polymer nanoparticles in which a quetiapine-fatty acid conjugate is loaded into a polymer matrix, the method comprising the steps of: preparing a mixed solution by dissolving a quetiapine-fatty acid conjugate and a polymer prepared according to the above-described method in an organic solvent; adding the mixed solution to an aqueous solution containing a polymer stabilizer and homogenizing and emulsifying the solution; and evaporating the organic solvent, centrifuging and washing the residue to obtain nanoparticles.

[0012] The long-acting injectable composition according to the present invention provides a nanoformulation by combining quetiapine, a drug for treating mental illness, with various fatty acids using a fattigation platform, thereby improving bioavailability, half-life, etc. when administered into the body and exhibiting excellent long-term sustained release characteristics. By using this, the medication compliance of patients with mental illness can be improved.

[0013] In particular, the self-assembled nanoparticles of the quetiapine-fatty acid conjugate according to the present invention can maximize the therapeutic effect by being converted into a conjugate in the body and continuously converted from the conjugate into an active drug by enzymatic or chemical action.

[0014] Additionally, it has the advantage of reducing the number of injections compared to conventional methods and reducing pain during injection by using a thinner needle.

[0015] FIG. 1 is a diagram illustrating the enzymatic conversion of quetiapine-fatty acid conjugate (QFC) to quetiapine (QTP) in human plasma (A) and human liver S9 fraction (B) according to one embodiment of the present invention.

[0016] FIG. 2 shows particle size distributions of nanoparticles manufactured according to another embodiment of the present invention, wherein (A) is a QTP base-loaded nanoparticle (PLGA-Q NP), (B) is a PLGA nanoparticle loaded with a quetiapine-myristic acid conjugate (QM) (PLGA-QM NP), (C) is a QFC self-assembled nanoparticle (QMN), and (D) is an albumin-coated nanoparticle of QMN (albumin-coated QMN).

[0017] Figure 3 shows scanning electron microscope (SEM) images and transmission electron microscope (TEM) images of the four types of nanoparticles, (A) PLGA-Q NP, (B) PLGA-QM NP, (C) QMN, and (D) albumin-coated QMN.

[0018] Figure 4 shows the injectability tests of four nanoformulations using a 26-G needle.

[0019] Figure 5 shows drug release profiles of four nanoformulations in a medium without esterase.

[0020] Figure 6 shows the drug release profiles of the nanoformulations in a medium supplemented with esterase.

[0021] Figure 7 shows the plasma concentration time profiles of QTP (A) and QM (B) after IM administration to beagle dogs.

[0022] Figure 8 shows the patching technology applied to the development of a long-acting nanoformulation of quetiapine.

[0023] Hereinafter, the present invention will be described in detail.

[0024]

[0025] In order to improve the physicochemical problems of quetiapine and the low medication compliance of tablets, the inventor of the present invention prepared a quetiapine-fatty acid conjugate nanoformulation using the inventor's unique fattigation platform, and confirmed that the nanoformulation was slowly absorbed when injected into the body and exhibited long-term sustained release characteristics in the body, thereby completing the present invention (Fig. 8).

[0026]

[0027] The present invention provides self-assembled nanoparticles comprising a quetiapine-fatty acid conjugate in which one or more fatty acids are bound to quetiapine or a pharmaceutically acceptable salt thereof.

[0028] In this specification, "quetiapine" is one of the first-line antipsychotic drugs for treating mental illness, represented by the following chemical formula 1 (C 21 H 25 N3O2S), has the following properties: molecular weight of 383.5 g / mol, solubility in water of 0.5869 mg / L, Log P value of 2.81, and melting point of 174-176 ℃:

[0029] <Chemical Formula 1>

[0030]

[0031]

[0032] The above quetiapine can be synthesized by a method well known in the art, and a commercially available one can be selected and used, but the method or material is not particularly limited.

[0033] The above quetiapine can be used in the form of a pharmaceutically acceptable salt within the range having the same efficacy.

[0034] As used herein, “pharmaceutically acceptable” means a salt that is non-toxic to cells or humans exposed to the drug and has a safety and efficacy profile suitable for administration to humans.

[0035] The above salt may be used in the form of either a pharmaceutically acceptable basic salt or an acid salt. The basic salt may be used in the form of either an organic basic salt or an inorganic basic salt, and may be selected from the group consisting of sodium salt, potassium salt, calcium salt, lithium salt, magnesium salt, cesium salt, aminium salt, ammonium salt, triethylaminium salt, and pyridinium salt.

[0036] Acid salts are useful as acid addition salts formed by free acids. Inorganic acids and organic acids can be used as free acids, and inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfurous acid, phosphoric acid, diphosphoric acid, nitric acid, etc., and organic acids include citric acid, acetic acid, maleic acid, malic acid, fumaric acid, gluconic acid, methanesulfonic acid, benzenesulfonic acid, camphorsulfonic acid, oxalic acid, malonic acid, glutaric acid, acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid, aspartic acid, stearic acid, etc., but are not limited thereto, and all salts formed using various inorganic acids and organic acids commonly used in the art can be included.

[0037] In addition, the above quetiapine may include not only the above salts, but also all salts, hydrates, solvates, derivatives, etc. that can be prepared by conventional methods. The addition salt may be prepared by conventional methods, and may be prepared by dissolving in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic base, or adding an aqueous base solution of an inorganic base, and then precipitating or crystallizing. Alternatively, the addition salt may be obtained by evaporating the solvent or the excess base from the mixture and then drying, or the precipitated salt may be prepared by suction filtration.

[0038] Preferably, the quetiapine or a pharmaceutically acceptable salt thereof may be quetiapine fumarate represented by the following chemical formula 2, but is not limited thereto.

[0039] <Chemical Formula 2>

[0040]

[0041]

[0042] As used herein, “quetiapine-fatty acid conjugate” means a prodrug of quetiapine, which is formed by conjugating one or more fatty acids to quetiapine or a pharmaceutically acceptable salt thereof using a fattigation platform, and which can be decomposed in vivo into quetiapine and each fatty acid or its metabolite through chemical or enzymatic hydrolysis.

[0043] By using the above-mentioned patching platform, it is possible to induce not only molecular changes such as polarity of drug molecules, secondary structure of proteins, and self-assembly properties, but also changes in physicochemical properties such as solubility, stability, and biomembrane permeability, and biopharmaceutical and therapeutic properties such as bioavailability and toxicity.

[0044]

[0045] In the present invention, the fatty acid may include a natural or synthetic, short-chain or long-chain, saturated or unsaturated, straight-chain or branched, ring-containing or non-ring-containing, substituted or unsubstituted fatty acid. Preferably, the fatty acid may be selected from saturated or unsaturated fatty acids having a chain length of C10 to C18, and may include, for example, fatty acids as shown in Table 1 below, but is not limited thereto.

[0046] Depending on the chain length of the fatty acid, the properties of the quetiapine-fatty acid conjugate and the nanoparticles containing the same may vary.

[0047] Fatty acid chemical structure and physicochemical properties Decanoic acid Chemical formula: C 10 H 20 O2 Characteristics: C10, saturated molecular weight: 172.26 g / mol Melting point: 31.5 ℃ log P: 4.09 Myristic acid Chemical formula: C 14 H 28 O2 Characteristics: C14, saturated molecular weight: 228.37 g / mol Melting point: 53.9 ℃ log P: 6.11 Stearic acid Chemical formula: C 18 H 36 O2 Characteristics: C18, saturated molecular weight: 284.48 g / mol Melting point: 69.3 ℃ log P: 8.23 ​​Oleic acid Chemical formula: C 18 H 34 O2 Characteristics: C18, mono-unsaturated Molecular weight: 282.47 g / mol Melting point: 13.4℃ log P: 7.64

[0048]

[0049] More specifically, the quetiapine-fatty acid conjugate can be formed by reacting the primary hydroxyl group of quetiapine with the carboxyl group of a fatty acid to form an ester conjugate. Upon in vivo injection, the conjugate can be hydrolyzed to convert it into a biologically, pharmacologically, or therapeutically active form, including quetiapine and its active metabolites.

[0050] According to one analysis example of the present invention, it can be confirmed that the form of the quetiapine-fatty acid conjugate can be encapsulated more effectively than the form of general quetiapine.

[0051]

[0052] The above quetiapine-fatty acid conjugate can self-assemble to form nanoparticles depending on changes in pH. Preferably, the quetiapine-fatty acid conjugate can self-assemble by being protonated in an acidic state, more preferably at a pH of 1 to 2.

[0053] The above self-assembled nanoparticles are spherical particles having an average particle diameter of 50 to 400 nm, and preferably, the average particle diameter may be 100 to 200 nm, but is not limited thereto.

[0054] By forming the above quetiapine-fatty acid conjugate into nanoparticles in this way, it is possible to improve solubility by increasing the surface area and facilitating diffusion in the body.

[0055] According to one analysis example of the present invention, it can be confirmed that the self-assembled nanoparticles have a higher drug content, such as quetiapine, than the polymer nanoparticles described below.

[0056] In addition, the self-assembled nanoparticles may have a particle surface coated with one or more selected from albumin, gelatin, collagen, alginic acid, or hyaluronic acid.

[0057] According to another analysis example of the present invention, nanoparticles coated with serum protein components such as albumin can preserve stability and further improve the dissolution rate of lipophilic drugs, and can also exhibit various effects depending on the type of coating protein.

[0058]

[0059] The present invention provides polymer nanoparticles comprising a polymer matrix; and a quetiapine-fatty acid conjugate in which one or more fatty acids are bound to quetiapine or a pharmaceutically acceptable salt thereof.

[0060] The above polymer nanoparticles can be formed by loading the quetiapine-fatty acid conjugate into a polymer matrix.

[0061] The polymer matrix may be a biodegradable or biocompatible polymer, and may be at least one selected from the group consisting of poly(D,L-lactic-co-glycolic acid) [poly(D,L-Lactic-co-glycolic acid, PLGA], polylactic acid (PLA), albumin, gelatin, alginic acid, and hyaluronate sodium, and may preferably be PLGA, but is not limited thereto.

[0062] The ratio of lactic acid to glycolic acid monomers of the PLGA may be (1 to 3): 1, preferably 1: 1. The weight average molecular weight of the PLGA may range from 7000 to 17,000 to 30,000 to 60,000, preferably from 7000 to 17,000, but is not limited thereto. The PLGA may be terminated with a carboxylic acid or capped with an ester group, preferably a carboxyl terminal group.

[0063] The polymer matrix is ​​preferably biodegradable to allow spontaneous decomposition by body metabolic processes, so that it can be easily disposable and does not accumulate in the body.

[0064]

[0065] In the polymer nanoparticles, the quetiapine-fatty acid conjugate may be included in an amount of 20 to 50 parts by weight based on 100 parts by weight of the total polymer nanoparticles, preferably 30 to 40 parts by weight, which may correspond to 20 to 25 parts by weight of quetiapine.

[0066] The above polymer nanoparticles are spherical particles having an average particle diameter of 100 to 500 nm, and preferably, the average particle diameter may be 200 to 300 nm, but is not limited thereto.

[0067]

[0068] The present invention provides a composition for long-acting injection (LAI) comprising the self-assembled nanoparticles or the polymer nanoparticles described above.

[0069] The long-acting injectable composition may be used for the treatment of any one or more mental disorders selected from the group consisting of schizophrenia, bipolar disorder, and depression.

[0070] The above quetiapine drug release can be controlled by a combination of a drug diffusion process and a hydrolysis process of an ester conjugated to the quetiapine. Preferably, when the composition is administered into the body, the quetiapine-fatty acid conjugate is hydrolyzed by plasma esterase to convert to quetiapine, which can then diffuse.

[0071] Preferably, the composition can provide sustained drug release for more than one month.

[0072] The above composition is in the form of a nano-suspension in which the above nanoparticles are dispersed, and can be injected through a 23 to 26 gauge needle, preferably through a 26 gauge needle, to avoid pain and improve patient compliance, but is not limited thereto.

[0073] Long-acting injectable formulations offer several advantages over conventional formulations of the same drug, including significantly improved patient compliance and enhanced bioavailability of quetiapine. Because drug bioavailability can be improved through the injectable route of administration, the long-acting injectable compositions of the present invention can provide a higher level of bioavailability (>75%) after intramuscular or subcutaneous administration than oral administration (9% bioavailability). This means that the total injected dose can be significantly lower than the daily dose required for the same period, thereby reducing toxicity and improving patient compliance. Furthermore, these formulations can offer other benefits, including improved systemic bioavailability, reduced dosing frequency (i.e., fewer injections) without compromising therapeutic efficacy, reduced incidence of adverse effects, and reduced overall healthcare costs.

[0074] The high surface area of ​​the nanoparticles of the present invention allows for a shorter time to reach plasma drug concentrations necessary for therapeutic efficacy and provides a predictable drug release profile, thereby avoiding the long lag phase observed in some long-acting injectable formulations. Furthermore, nanosuspensions with smaller particles elicit less severe inflammatory responses at the injection site than formulations with larger particles, making them more suitable for local tolerability.

[0075] The nanoparticles according to the present invention are converted into lipophilic conjugates in the body, and the subsequent conversion from the conjugate to the active drug by enzymatic or chemical action also affects the release or absorption rate and is necessary to maximize the therapeutic effect.

[0076]

[0077] The present invention provides a method for preparing a quetiapine-fatty acid conjugate.

[0078] The method for producing a quetiapine-fatty acid conjugate according to the present invention may include the steps of: neutralizing quetiapine or a pharmaceutically acceptable salt thereof to obtain a quetiapine base; adding the obtained quetiapine base, fatty acid, and activator to an organic solvent and reacting them; and, after the reaction is completed, removing and purifying the organic solvent.

[0079] The step of obtaining the above quetiapine base can be performed using a liquid-liquid extraction method. According to one embodiment of the present invention, the quetiapine base can be obtained by neutralizing and extracting quetiapine fumarate salt with a saturated ethyl acetate-sodium bicarbonate solution.

[0080] In the above-mentioned reacting step, the organic solvent may be at least one selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, or acetonitrile (ACN).

[0081] The above fatty acid may be selected from saturated or unsaturated fatty acids of C10 to C18, and may preferably be selected from decanoic acid, myristic acid or stearic acid, but is not limited thereto.

[0082] The above activator may be selected from 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl), N,N′-dicyclohexylcarbodiimide (DCC) or N,N′-diisopropylcarbodiimide (DIC), which can induce activation of the carboxyl group of the fatty acid.

[0083] Additionally, the above-mentioned reacting step can be performed by further adding another base such as 4-dimethylaminopyridine (DMAP) or triethylamine (TEA).

[0084] After the above reaction is completed, the organic solvent can be removed and purified to obtain a quetiapine-fatty acid conjugate.

[0085] It can be confirmed that the quetiapine-fatty acid conjugate manufactured by this manufacturing method has lower solubility in water due to the binding of fatty acids, but has higher lipophilicity and a lower conversion rate to quetiapine.

[0086]

[0087] The present invention provides a method for preparing self-assembled nanoparticles comprising a quetiapine-fatty acid conjugate.

[0088] The method for producing self-assembled nanoparticles according to the present invention may include the steps of dissolving the quetiapine-fatty acid conjugate produced according to the method for producing the above quetiapine-fatty acid conjugate in an organic solvent and adding an acidic solution to produce a mixture; and the step of stirring the mixture and then evaporating the organic solvent.

[0089] The above quetiapine-fatty acid conjugate has a concentration range of 10 to 125 mg / mL, which may correspond to a concentration of quetiapine of 5 to 80 mg / mL.

[0090] The organic solvent may be one or more selected from solvents miscible with water, such as tetrahydrofuran (THF), methanol, ethanol, isopropanol, acetone, or acetonitrile (ACN), but is not limited thereto.

[0091] The above acidic solution may be an aqueous solution containing an acidifying agent having a pH of 1 to 2.

[0092] The acidifying agent is used to adjust the pH to a desired value, and may be selected from, for example, hydrochloric acid, phosphoric acid, citric acid, and acetic acid, but hydrochloric acid is preferably selected.

[0093] The concentration of the hydrochloric acid may be such that the molar ratio of proton to quetiapine is in the range of 0.5 to 5, preferably 1.

[0094] The organic solvent and acidic solution may be included in a volume ratio of 1:10 to 10:1, and preferably mixed in a volume ratio of 1:1 to protonate the quetiapine-fatty acid conjugate, and the amphiphilic ionizable conjugate may self-assemble to form nanoparticles.

[0095] The above manufacturing method may further include a step of coating the surface of self-assembled nanoparticles by adding at least one selected from albumin, gelatin, collagen, alginic acid, or hyaluronic acid to the mixture.

[0096]

[0097] In addition, the present invention provides a method for producing polymer nanoparticles in which a quetiapine-fatty acid conjugate is loaded into a polymer matrix.

[0098] The method for producing polymer nanoparticles according to the present invention may include the steps of dissolving the quetiapine-fatty acid conjugate and the polymer produced according to the method for producing the quetiapine-fatty acid conjugate described above in an organic solvent to produce a mixed solution; adding the mixed solution to an aqueous solution containing a polymer stabilizer and homogenizing and emulsifying the solution; and evaporating the organic solvent, centrifuging and washing the residue to obtain nanoparticles.

[0099] The concentration of the above quetiapine-fatty acid conjugate is within the range of 50 to 120 mg / mL, which may correspond to a concentration of quetiapine of 30 to 80 mg / mL.

[0100] The organic solvent may be selected from halogenated hydrocarbons such as chloroform, ethyl chloride, dichloromethane or trichloroethane, ethyl acetate, acetone or a combination thereof.

[0101] The polymer stabilizer may be selected from polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinyl pyrrolidone (PVP), sodium polymethacrylate, or sodium polyacrylate, and is preferably polyvinyl alcohol, but is not limited thereto.

[0102]

[0103] Nanoparticles manufactured according to the manufacturing method of the present invention can be formed into a sterilized powder form. The powder form can be obtained by adding mannitol to an aqueous suspension and then freeze-drying the suspension. In this case, the amount of mannitol added can be 5 to 20 wt%, preferably 10 to 15 wt%.

[0104] The above-mentioned powder-type nanoparticles can be used by suspending the powder in a dispersion solvent before administering the drug to a patient. The dispersion solvent can include a stabilizer, a pH adjuster, an osmotic pressure adjuster, and water for injection. The stabilizer can be selected from a polymer such as albumin or gelatin, or a nonionic surfactant, for example, a polysorbate series such as polysorbate 80 or polysorbate 20, or a poloxamer series such as poloxamer 188. The osmotic pressure adjuster can be one or more selected from sodium chloride, glucose, mannitol, or glucitol.

[0105] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the scope of the present invention and are not intended to limit its scope. These examples are provided to more fully explain the present invention to those of average skill in the art.

[0106]

[0107] Experimental Materials

[0108] Quetiapine (QTP) fumarate (USP) was purchased from Aurobindo Pharma Company, India. Decanoic acid, myristic acid, stearic acid, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl), and 4-dimethylaminopyridine (DMAP) were purchased from Sigma-Aldrich (St. Louise, MO, USA). Poly(D,L-lactic-co-glycolic acid) [poly(D,L-Lactic-co-glycolic acid, PLGA] (Resomer® RG 502H, acid-terminated, molecular weight 7,000–17,000) and poly(vinyl alcohol) [poly(vinyl alcohol), PVA] (87–90% hydrolyzed, average molecular weight 30,000–70,000) were purchased from Sigma-Aldrich (Seoul, Korea). Other chemicals and reagents used in this study were of analytical grade.

[0109]

[0110] <Example 1> Synthesis of quetiapine-fatty acid conjugate (QFC)

[0111] The method for synthesizing QFC from quetiapine (QTP) fumaric acid is as shown in the following reaction scheme 1:

[0112] <Reaction Scheme 1>

[0113]

[0114]

[0115] Referring to the above reaction scheme 1, briefly, first, QTP fumarate salt was neutralized using a liquid-liquid extraction method such as saturated ethyl acetate / sodium bicarbonate solution to obtain QTP base, and then the carboxyl group of fatty acid was activated by other activators such as 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC HCl) or N,N′-dicyclohexylcarbodiimide (DCC) or N,N′-diisopropylcarbodiimide (DIC). The activated fatty acid was added to QTP in the presence of other bases such as 4-dimethylaminopyridine (DMAP) or triethylamine (TEA).

[0116] The solvent used for the synthetic reaction was tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, or other suitable organic solvents such as acetonitrile (ACN).

[0117]

[0118] More specifically, first, by liquid-liquid extraction method, QTP fumaric acid (5 g) was added to a mixture of ethyl acetate (20 mL) and saturated sodium bicarbonate solution (20 mL), QTP fumarate salt was neutralized with sodium bicarbonate, and the obtained QTP base was extracted with ethyl acetate. The organic matter was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain QTP free base. To a solution of QTP base (10 mmol) in THF (5 mL) were added fatty acids (decanoic acid, myristic acid, stearic acid) (11 mmol), EDC HCl (15 mmol), and DMAP (2 mmol). The mixture was stirred at room temperature for 4–6 hours to ensure complete reaction. The solvent was evaporated, and the obtained conjugate was purified using column chromatography using a mixture of ethyl acetate (EtAc) and n-hexane in an appropriate ratio as a solvent. After drying under high vacuum to remove organic solvents, purified conjugates QD (quetiapine-decanoic acid conjugate), QM (quetiapine-myristic acid conjugate), and QS (quetiapine-stearic acid conjugate) were obtained.

[0119] Referring to Table 2 below, the obtained conjugates showed significantly lower water solubility than QTP fumaric acid. The lipophilicity and hydrolysis rate of QFC varied depending on the carbon chain length of the fatty acid. Conjugates with longer fatty acid chains exhibited higher lipophilicity and lower conversion to QTP in human plasma and liver extracts (Figure 1).

[0120] Solubility in water (μg / mL)Solubility in octanol (mg / mL)Log PQuetiapine fumarate 35 33.92 ± 86.5 9 22.11 ± 1.7 5 0.80 ± 0.04Quetiapine-decanoic acid conjugate (QD) 1.90 ± 0.19 46 8.68 ± 43.6 35.39 ± 0.06Quetiapine-myristic acid conjugate (QM) 0.45 ± 0.26 5 38.20 ± 11.0 46.13 ± 0.16Quetiapine-stearic acid conjugate (QS) 0.07 ± 0.03 6 3.12 ± 7.857.00 ± 0.19

[0121]

[0122] <Example 2> Preparation of PLGA nanoparticles loaded with QTP base (PLGA-Q NP)

[0123] The PLGA nanoparticles of the present invention were prepared by an emulsion-solvent evaporation method. The drug and PLGA were dissolved in an appropriate organic solvent, and the organic solvent was added to an aqueous solution containing a polymer stabilizer to perform dispersion and emulsification. After evaporation of the organic solvent, the residue was centrifuged and washed to obtain nanoparticles. The obtained PLGA nanoparticles were spherical particles with a particle size diameter of 200-300 nm. The organic solvent may be selected from halogenated hydrocarbons (e.g., chloroform, ethyl chloride, dichloromethane, or trichloroethane), ethyl acetate, and acetone, or combinations thereof. The polymer stabilizer may be selected from polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinyl pyrrolidone (PVP), sodium polymethacrylate, and sodium polyacrylate, with PVA being preferred. Dispersion emulsification was performed using a high-speed homogenizer (e.g., Homogenizer HG-15D, Daihan, Korea).

[0124] Specifically, 200 mg of PLGA (50 / 50, acid-terminated, molecular weight 7,000–17,000) and QTP were weighed and dissolved in 4 mL of ethyl acetate to obtain a clear solution. The ethyl acetate solution was added to 8 mL of an aqueous solution containing 2% (w / v) polyvinyl alcohol (PVA) as a stabilizer. The mixture was then emulsified using a high-speed homogenizer at 15,000 rpm for 30 min. The resulting pre-emulsion was added to 12 mL of a 2% PVA solution and stirred in a fume hood at room temperature for 24 h to evaporate the organic solvent. The nanoparticles were then purified through three-step centrifugation (15 min, 13,000 rpm, 25°C) and resuspended in deionized water. The final nanosuspension was added with 5% (w / v) mannitol as a cryoprotectant, frozen at -80°C for 24 h, and lyophilized for 48 h to obtain a powder dosage form. The lyophilized powder was reconstituted in water for injection before injection to obtain PLGA-Q NPs.

[0125] Referring to Fig. 2(A), the particle size of QTP-loaded PLGA nanoparticles measured by dynamic light scattering (DLS) using an ELSZ-2000 machine can be confirmed to have an average diameter of 248.2 nm (D10 = 147.30 nm, D50 = 255.30 nm, D90 = 452.50 nm). In addition, as shown in Fig. 3(A), the round shape of PLGA-Q NPs can be observed in SEM and TEM images.

[0126]

[0127] <Example 3> Preparation of PLGA nanoparticles loaded with QFC (QM) (PLGA-QFC (QM) NP)

[0128] 200 mg of PLGA (50 / 50, acid-terminated, molecular weight 7,000–17,000) and QM were weighed and dissolved in 4 mL of ethyl acetate to obtain a clear solution. The ethyl acetate solution was added to 8 mL of an aqueous solution containing 2% (w / v) PVA as a stabilizer. The mixture was then emulsified using a high-speed homogenizer at 15,000 rpm for 30 min. The resulting pre-emulsion was added to 12 mL of a 2% PVA solution and stirred in a fume hood at room temperature for 24 h to evaporate the organic solvent. The nanoparticles were then purified through three stages of centrifugation (15 min, 13,000 rpm, 25°C) and resuspended in deionized water. The final nanosuspension was added with 5% (w / v) mannitol as a cryoprotectant, frozen at -80°C for 24 h, and lyophilized for 48 h to obtain a powder dosage form. The lyophilized powder was reconstituted in water for injection before injection to obtain PLGA-QM NPs.

[0129] Referring to Fig. 2(B), the particle size of PLGA nanoparticles loaded with QM, as measured by dynamic light scattering (DLS) using an ELSZ-2000 machine, was confirmed to have an average diameter of 277.3 nm (D10 = 180.80 nm, D50 = 279.90 nm, D90 = 437.10 nm). In addition, as shown in Fig. 3(B), the round shape of PLGA-QM NPs can be observed in SEM and TEM images.

[0130]

[0131] <Example 4> Preparation of self-assembled nanoparticles (QMN) of QFC

[0132] Self-assembled nanoparticles of QFC were prepared by solvent evaporation. The conjugate was dissolved and protonated in a mixture of water and an organic solvent containing an acidifying agent at a volume ratio of 1:10 to 10:1, preferably 1:1. The organic solvent was evaporated in a hood at room temperature for 24–48 h, and the protonated QFC self-assembled to form spherical nanoparticles with a particle size of 100–200 nm. The organic solvent can be selected from water-miscible solvents such as alcohols (methanol, ethanol, isopropanol), acetone, acetonitrile, and tetrahydrofuran.

[0133] More specifically, quetiapine-myristic acid conjugate (QM) was first dissolved in THF, and a 0.14 N hydrochloric acid solution (5 mL) was added to a 100 mg / mL solution of QM in THF (5 mL). The mixture was stirred at 700 rpm in a hood for 24 h to remove THF and obtain self-assembled QM nanoparticles (QMN). Mannitol was added as a cryoprotectant at 10% (w / v) to the nanoparticle system, and the mixture was frozen at -80°C for 24 h and then lyophilized for 48 h to obtain a powder form for long-term storage. The lyophilized powder was reconstituted in 5 mL of water before injection to obtain QMN.

[0134] Referring to Fig. 2(C), the distribution particle size of QMN can be confirmed by dynamic light scattering (DLS) using an ELSZ-2000 device, with an average diameter of approximately 180 nm (D10 = 94.20 nm, D50 = 182.50 nm, D90 = 378.40 nm). In addition, as shown in Fig. 3(C), the round shape of QMN can be observed in SEM and TEM images.

[0135]

[0136] <Example 5> Preparation of albumin-coated QMN nanoparticles

[0137] QMN (100 mg / mL) was added dropwise to a 0.01 M human serum albumin solution (40 mg / mL) in PBS under stirring at 1,000 rpm. Free albumin was removed by ultracentrifugation (16,000 rpm, 15 min, 25°C), and the collected pellet (albumin-coated QMN) was redispersed in 1 mL of PBS. Mannitol was added as a cryoprotectant at 10% (w / v) to the nanoparticle system, and the solution was frozen at -80°C for 24 h and then lyophilized for 48 h to obtain a powder form for long-term storage. The lyophilized powder was reconstituted in 5 mL of water before injection to obtain albumin-coated QMN.

[0138] The particle size distribution of the albumin-coated QMN can be confirmed in Fig. 2(D), and the round shape of the albumin-coated QMN can be observed in the TEM and SEM images of Fig. 3(D).

[0139]

[0140] <Analysis Example 1> Analysis of drug content (DC) and encapsulation efficiency (EE) of each nanoformulation

[0141] QTP and QM were quantitatively analyzed by the HPLC-UV method using an HPLC system equipped with a UV detector (Agilent 1200, Agilent Technologies, USA).

[0142] HPLC conditions were as follows: isokinetic separation was performed using a Hypersil gold C18 column (250 × 4.6 mm, particle size 5 μm). The mobile phase for QTP quantification consisted of 54% MeOH, 7% ACN, and 39% dibasic ammonium phosphate solution (2.6 g / L). The mobile phase for QM consisted of a mixture of ACN and 0.1% trichloroacetic acid (70:30). The flow rate was 1.3 mL / min, the injection volume was 30 μL, and the detection wavelength was 230 nm.

[0143]

[0144] The drug content (DC) and encapsulation efficiency (EE) of four nanoformulations, including PLGA-Q NPs (F1) prepared according to Example 2, PLGA-QM NPs (F2) prepared according to Example 3, QMNs (F3) prepared according to Example 4, and Albumin-coated QMNs (F4) prepared according to Example 5, were measured using the direct method.

[0145] The freeze-dried sample was accurately weighed and dissolved in 1 mL of ACN. The mixture was then centrifuged at 10,000 rpm for 10 minutes, and the supernatant was diluted with ACN and subjected to HPLC analysis under the conditions described above.

[0146] The drug content (DC) refers to the mass ratio of the QTP base to the solid weight of the nanosuspension, which is calculated by the following equation 1:

[0147] <Formula 1>

[0148] DC = drug mass in nanoparticles / nanoparticle mass × 100 (%)

[0149] Encapsulation efficiency (EE) is the percentage of drug successfully entrapped in nanoparticles and is calculated by Equation 2 below:

[0150] <Formula 2>

[0151] EE = mass of drug in nanoparticles / total mass of drug added × 100 (%)

[0152]

[0153] Table 3 below shows the DC and EE values ​​of the four formulations.

[0154] Drug content (DC, %)Encapsulation efficiency (EE, %)F1PLGA-Q NP20.12 ± 0.8967.18 ± 1.14F2PLGA-QM NP27.92 ± 1.4495.36 ± 0.04F3QMN61.31 ± 0.7199.96 ± 0.02F4albumin-coated QMN58.89 ± 1.6193.12 ± 1.37

[0155] Referring to Table 3 above, the higher EE index of F2 compared to F1 (95.36% vs. 67.18%) indicates that QM was encapsulated more effectively than QTP when the same amount of QTP or QM was initially loaded into PLGA. It can be seen that the formulations prepared by pH-induced self-assembly (F3 and F4) had higher DC ratios of 61.31% and 58.89%, respectively, than the PLGA-based formulation (F2) with a DC ratio of 27.92%.

[0156]

[0157] <Analysis Example 2> Injection Analysis

[0158] To test the injectability of the nanoformulation, a 26G, ½-inch needle (outer diameter 0.464 mm, inner diameter 0.260 mm) provided by Korea Vaccine Co., Ltd. was used. The formulation was considered "injectable" if it could easily pass through the needle without significant force.

[0159] Regarding the injectability of the four nanoformulations (F1-F4), tests were conducted using a thin-gauge (26G) needle, which is significantly smaller than the 21G needle used clinically for PLGA microsphere products (Trelsta, Risperdal). As shown in Figure 4, all nanoformulations were able to pass through the needle without applying high pressure. Injections using a thin needle can reduce patient pain and be more patient-friendly in clinical practice.

[0160]

[0161] <Analysis Example 3> Confirmation of drug release in a test tube

[0162] In vitro drug release studies were performed using a dialysis method in a medium containing 0.01 M phosphate-buffered saline (PBS), pH 7.4, 0.5% sodium dodecyl sulfate (SDS), and 0.1% sodium azide. To mimic in vivo conditions, 5 units / mL of esterase was added to the medium containing 0.5% Tween 80 and 0.1% sodium azide. The sample was accurately weighed, dissolved in 1 mL of PBS buffer, placed in a 3-mL dialysis tube (Pur-A-Lyzer™, molecular weight cut-off (MWCO) 3,500 Da), and then placed in a 50-mL tube containing 40 mL of release medium. The tube was incubated in an incubator shaking at 100 rpm at 37°C. At each time point, 1 mL of medium was withdrawn and 1 mL of fresh buffer was added. QM and QTP concentrations were measured by HPLC-UV method.

[0163]

[0164] 3-1. In vitro drug release assay in esterase-free medium

[0165] Drug release characteristics were evaluated in 0.01 M PBS containing 0.5% sodium dodecyl sulfate and 0.1% sodium azide as an antimicrobial agent to maintain the sink state.

[0166] Referring to Figure 5, F1 showed that more than 80% of quetiapine was released after 1 day. The QM release rate of F2 showed three stages: an initial release (approximately 25%) after 12 hours, a delayed phase (diffusion phase) with less drug release (approximately 30%) after 21 days, and a secondary sustained-release phase (approximately 45%) of about 45% after 28 days. F3 showed slow drug release with less than 20% of QM released even after 1 month. This can be explained by the rapid conversion of QMN to lipophilic QM when the pH changes from acidic to physiological pH. In contrast, when albumin was coated on the QMN surface (F4), about 40% of QM was released after 1 month, showing improved stability and dissolution profile. Overall, the highly lipophilic QM showed a controlled drug release profile for 1 month compared to quetiapine for several days. No QTP was detected in the dissolution solvent of the QM-containing formulations (F2, F3, F4), indicating that the presence of esterase is required for the conversion of QM to QTP.

[0167]

[0168] 3-2. In vitro drug release analysis in esterase-supplemented medium

[0169] 5 U / mL of esterase was added to the release medium to mimic enzyme concentrations in muscle or bloodstream.

[0170] As shown in Figure 6, the release profiles of QTP in F2, F3, and F4 showed a sustained release of quetiapine for one month without a long lag phase. Esterase catalyzed the hydrolysis of QM to QTP, leading to a gradual decrease in QM concentration and an increase in QTP concentration as a function of time. The QM concentration rapidly decreased below the quantifiable level (0.5 μg / mL) after 3 days, while the QTP release rate reached 40–60% over one month in all QM-containing formulations (F2, F3, and F4). Furthermore, the addition of esterase accelerated the biodegradation of the ester bonds in PLGA molecules, allowing for faster diffusion of QM from the polymer matrix compared to tests performed in a medium without esterase.

[0171]

[0172] <Analysis Example 4> Confirmation of the pharmacokinetic profile in beagle dogs

[0173] After receiving approval from the Animal Experiment Ethics Committee of Endic Co., Ltd. (Approval No.: P 233032) based on the Animal Protection Act, the concentration-time profiles of QTP and QM in plasma were evaluated after intravenous injection of the test formulation into normal beagle dogs (Canis familiaris).

[0174] Sixteen male beagles (10±1 kg), aged 2 to 3 years, purchased from Endic Co., Ltd. (located in Gyeonggi-do), were housed in a room with controlled temperature and relative humidity (21±2℃, 50±15%, respectively) under a 12-h light / dark cycle. The dogs were allowed to acclimate to the environment for one week during the acclimation period. During the test period, approximately 250 g of solid food per day was provided from the food box at a specific time every afternoon. The dogs were then randomly divided into four groups (n = 4 per group), and the four formulations (PLGA-Q NP, PLGA-QM NP, QMN, and Albumin-coated QMN) were injected intraperitoneally into one of the dogs' left hind legs using a 26G needle at a QTP concentration of 35 mg / kg.

[0175] To measure drug concentrations in plasma, blood samples (approximately 3 mL) were collected from the jugular vein using a 26G heparin syringe at predetermined times (0 h (before administration), 2, 4, 8, 24, 48, 96, 168, 336, 504, 672, and 840 h). The collected blood was immediately centrifuged at 4,000 rpm for 10 min at 4°C, and the separated supernatant was stored in a -70°C freezer until quantitative analysis. Plasma proteins were precipitated by mixing 20 μL of sample with 180 μL of acetonitrile containing an internal standard (carbamazepine 1 ng / mL), and the mixture was centrifuged to collect the supernatant (150 μL) for quantitative analysis. Plasma QTP and QM concentrations were measured using a validated high-performance liquid chromatography-mass spectrometry (HPLC-MS / MS) method. All experimental results obtained in the experiment are expressed as the mean ± standard deviation. Pharmacokinetic parameters were calculated using the WinNonlin program (Pharsight Co., Inc., USA), and the drug compartment model was applied as a non-compartment model to each parameter.

[0176] As a result of observing the changes in drug concentration and drug-fatty acid conjugate concentration over time after intramuscular (IM) injection of four nano drug formulations in beagle dogs, as shown in Fig. 7, the plasma QM concentration reached the maximum concentration within 24 hours and significantly decreased below the LOQ (0.5 ng / mL) after 7 days for all tested formulations, confirming the continuous conversion of QM to QTP by plasma esterase (Fig. 7B). These results were similar to the in vitro dissolution test including esterase in Analysis Example 3 above.

[0177] Referring to Figure 7(A), the dissolution profile of F1 (PLGA-Q NP) in beagle dogs after IM injection showed a very large burst release at 24 hours after injection. The maximum plasma concentration (C) of PLGA-Q NP was 2 hours after injection. max) reached nearly 3000 ng / mL, which was 10 times higher than the minimum toxic concentration (MTC) of 300 ng / mL. The formulation containing QM was F 2, For F3 and F4, C was approximately 650, 250, and 700 ng / mL, respectively. max The burst-release effect was significantly reduced by recording the release profile. However, PLGA-based formulations (F1 and F2) provided a sustained-release profile for only one week, which was much faster than the one-month in vitro dissolution data. This could be explained by the lack of depot formation or the rapid absorption of PLGA NPs after IM administration.

[0178] In contrast, self-assembled QMN nanoparticles (F3) exhibited a controlled release profile in beagle dogs following IM injection, with plasma concentrations of QTP remaining within the therapeutic window (20–300 ng / mL) for approximately 2 weeks and above the LOQ for 5 weeks. This controlled release profile of the F3 formulation was attributed to the rapid conversion of QMN to a lipophilic QM depot at the neutral pH at the injection site. The sustained release of QM from the injection site after hydrolysis to QTP contributed to the 5-week sustained release profile of QMN.

[0179] Serum proteins (mainly albumin) were a key factor in dissolving lipophilic drugs in blood. Pre-coating QMN with albumin (F4) resulted in rapid drug release over a week, demonstrating the role of the protein corona in drug release from nanosuspensions. In the case of QMN, pre-coating with albumin preserved nanoparticle stability at the injection site, accelerating QMN absorption. Furthermore, albumin can form a complex with QM via its fatty acid binding site, significantly enhancing the dissolution rate.

[0180]

[0181] Table 4 below summarizes the pharmacokinetic parameters.

[0182] Pharmacokinetic parametersF1(PLGA-Q NP)F2(PLGQ-QM NP)F3(QMN)F4(Albumin-coated QMN)QTPQTPQMQTPQMQTPQMT max (h)224192442020C max (h)2770.00±637.86644.50±107.18692.25±336.63249.75±99.93135.80±99.04699.50±94.53444.50±375.06AUC last (ng*h / mL)34067.56±3868.7539153.79±4845.8024664.16±2788.133725 4.96±5559.462558.38±1199.4132069.69±5602.659479.04±4050.18AUC inf (ng*h / mL)34163.69±3867.3639309.36±4915.1924829.43±12851.1037 454.19±5521.172645.29±1137.4932089.64±5603.559620.78±4151.10T 1 / 2 (h)56.69±14.1622.32±5.7111.65±1.25105.44±11.3124.66±7.2714.86±1.389.21±1.57

[0183]

[0184] The four formulations had similar AUC last The values ​​showed equivalent administration doses among the four test formulations. In particular, the target formulation (QMN) manufactured using the patching platform had a C of 249.75 ng / mL, which is higher than the minimum effective concentration (MEC) of the drug of 20 ng / mL and lower than the maximum toxic concentration (MTC) of 300 ng / mL. max . Also, the apparent half-life of the drug (T 1 / 2 ) showed the most prominent pharmacokinetic profile of 105.44 hours, and therefore QMN can be considered as an LAI formulation with excellent injectability using a thin needle and no large burst release or toxicity with a small number of administrations once or twice a month.

[0185]

[0186] While specific aspects of the present invention have been described in detail above, it should be apparent to those skilled in the art that these specific descriptions merely represent preferred embodiments and are not intended to limit the scope of the present invention. In other words, the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A self-assembling nanoparticle comprising a quetiapine-fatty acid conjugate in which one or more fatty acids are bound to quetiapine or a pharmaceutically acceptable salt thereof, and characterized in that the self-assembling nanoparticle is formed by self-assembly according to a change in pH.

2. In paragraph 1, The above fatty acids are, Self-assembling nanoparticles characterized by being selected from saturated fatty acids of C10 to C18.

3. In paragraph 1, The above nanoparticles are, Self-assembled nanoparticles characterized by being spherical particles with an average particle diameter of 50 to 400 nm.

4. In paragraph 1, The above nanoparticles are, A self-assembling nanoparticle characterized by being coated with at least one selected from the group consisting of albumin, gelatin, collagen, alginic acid, and hyaluronic acid.

5. Polymer matrix; and A quetiapine-fatty acid conjugate comprising one or more fatty acids bound to quetiapine or a pharmaceutically acceptable salt thereof, A polymer nanoparticle characterized in that the quetiapine-lipid phase conjugate is loaded into the polymer matrix and formed.

6. In paragraph 5, The above polymer matrix is, A polymer nanoparticle characterized by comprising at least one selected from the group consisting of poly(D, L-lactic-co-glycolic acid) [poly(D, L-Lactic-co-glycolic acid, PLGA], polylactic acid (PLA), albumin, gelatin, alginic acid, and hyaluronate sodium.

7. In paragraph 5, The above quetiapine-fatty acid conjugate is, A polymer nanoparticle characterized in that it is contained in an amount of 20 to 50 parts by weight based on 100 parts by weight of the total polymer nanoparticles.

8. In paragraph 5, The above nanoparticles are, A polymer nanoparticle characterized by being a spherical particle with an average particle diameter of 100 to 500 nm.

9. A long-acting injectable composition comprising a nanoparticle according to any one of claims 1 to 8.

10. In paragraph 9, The above composition, A long-acting injectable composition characterized in that, when administered into the body, a quetiapine-fatty acid conjugate is hydrolyzed by plasma esterase and converted into the quetiapine active ingredient.

11. In paragraph 9, The above composition, A long-acting injectable composition characterized by continuous drug release for more than one month.

12. In paragraph 9, The above composition, A long-acting injectable composition characterized in that it is used for the treatment of any one or more mental disorders selected from the group consisting of schizophrenia, bipolar disorder, and depression.

13. A step of neutralizing quetiapine or a pharmaceutically acceptable salt thereof to obtain quetiapine base; A step of adding the quetiapine base, fatty acid and activator obtained in the above step to an organic solvent and reacting them; and A method for producing a quetiapine-fatty acid conjugate, comprising the step of evaporating and purifying the solvent after the above reaction is completed.

14. A step of dissolving the quetiapine-fatty acid conjugate prepared according to Article 13 in an organic solvent and adding an acidic solution to prepare a mixture; and A method for producing self-assembled nanoparticles comprising a quetiapine-fatty acid conjugate, comprising the step of stirring the above mixture and then evaporating the organic solvent to obtain self-assembled nanoparticles.

15. A step of preparing a mixed solution by dissolving the quetiapine-fatty acid conjugate and polymer prepared according to Article 13 in an organic solvent; A step of adding the above mixed solution to an aqueous solution containing a polymer stabilizer and homogenizing and emulsifying it; and A method for producing polymer nanoparticles loaded with a quetiapine-fatty acid conjugate in a polymer matrix, comprising the step of evaporating the organic solvent, centrifuging the residue, and washing the residue to obtain nanoparticles.

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