Long-acting injectable formulation of ketamine pamoate salt

Abstract

Sustained-release pharmaceutical compositions comprising ketamine pamoate salt and a pharmaceutically acceptable carrier thereof are provided, including aqueous suspensions, solutions, and matrix delivery systems, which can provide sustained release for anesthesia, analgesia, or the treatment of central nervous system disorders and anti-inflammatory disorders.

Description

[Technical Field]

[0001] The present disclosure relates generally to formulations of ketamine pamoate salts. In particular, the present disclosure relates to sustained-release pharmaceutical compositions comprising R,S-ketamine pamoate salts, S-ketamine pamoate salts, or R-ketamine pamoate salts, and their use for the treatment of anesthesia, analgesia, or anti-inflammatory disorders and central nervous system disorders. [Background technology]

[0002] Ketamine, i.e., 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one, is an arylcyclohexylamine derivative and a racemic mixture containing equal amounts of S-ketamine and R-ketamine. The molecular weight (MW) of ketamine is 237.73, and that of ketamine hydrochloride (HCl) is 274.19. Human clinical studies have shown that the initial distribution phase of intravenous ketamine from the central compartment (plasma) to peripheral tissue compartments occurs with a half-life of 7–11 minutes, and the elimination phase occurs with a half-life of 2–3 hours (Way et al., 1982). Ketamine is rapidly distributed and has a short duration of action. Therefore, ketamine is typically administered as an immediate-release dosage form.

[0003] As an N-methyl D-aspartate (NMDA) receptor antagonist, ketamine is indicated for use as an anesthetic; for example, ketamine hydrochloride has been sold as Ketaller injection (intravenously or intramuscularly) since 1970. Furthermore, S-ketamine hydrochloride is used in the antidepressant Spravato (nasal spray), which was approved by the FDA in 2019, for the treatment of treatment-resistant depression (TRD).

[0004] Commercially available ketamine preparations have two limitations. First, ketamine preparations generally exhibit a short half-life in clinical trials. Specifically, the ketamine elimination half-life of Ketalar is 2.5 hours. Furthermore, esketamine concentrations in Spravato decline rapidly, with a mean terminal half-life ranging from 7 to 12 hours. Second, adverse events, such as dissociation, dizziness, nausea, sedation, vertigo, hypoesthesia, anxiety, lethargy, elevated blood pressure, vomiting, and intoxication, may occur after administration of ketamine preparations, requiring patients to be observed for several hours during the recovery period. Therefore, long-acting ketamine preparations are being developed.

[0005] PCT Patent Publication Nos. WO2018 / 122626A1 and WO2019 / 186357A1 to Cellix Bio Ltd. disclose ketamine salts (ketamine and -RH), where RH represents pamoic acid, in a 1:1 ratio of ketamine to pamoic acid.

[0006] PCT Patent Publication No. WO 2005 / 016261 A2 to Alkermes Controlled Therapeutics Inc. discloses a pharmaceutical composition comprising a pamoate salt of an active agent selected from the group consisting of haloperidol and aripiprazole, the composition releasing an effective amount of the active agent over a period of at least about 48 hours.

[0007] In a previous study, Han et al. (Int. J. Pharm. (2020), 581, 119291) disclosed sustained-release ketamine nanoparticles containing poly(ethylene glycol) (PEG)-block-poly(lactic-co-glycolic acid) (PLGA). The formulation showed a sustained-release profile for over 5 days after intravenous injection in mice, demonstrating the C value of ketamine. max is 1000 to 10,000 ng / mL.

[0008] PCT Patent Publication No. WO2017 / 003935A1 to Shenox Pharmaceuticals LLC. describes a transdermal delivery device containing ketamine, SHX-001, for the treatment of major depressive disorder (MDD) and pain. The transdermal delivery device provides ketamine plasma concentrations of less than 100 ng / mL for 8 hours to 7 days, reducing ketamine's adverse side effects. Pharmacokinetic profiles are predicted by known convolution methods using in vitro transdermal permeation data and in vivo intravenous plasma concentration data.

[0009] PCT Patent Publication No. WO2019 / 073408A1 to Douglas Pharmaceuticals Ltd. describes oral sustained-release ketamine hydrochloride tablets containing polyethylene oxide (PEO) for the treatment of treatment-resistant depression (TRD), treatment-resistant anxiety, and phobia. Plasma concentrations of ketamine demonstrated a 2-day sustained-release profile following single dose administration of 60 mg, 120 mg, and 240 mg ketamine tablets in clinical trials, demonstrating a significant improvement in ketamine C. max The oral formulation has no dissociative side effects after doses of 60 mg to 120 mg and minimal dissociative side effects at 240 mg. Summary of the Invention

[0010] In view of the above, the present disclosure relates to various sustained-release pharmaceutical compositions of ketamine pamoate salts, which may be crystalline or amorphous forms of ketamine pamoate salts having a 2:1 ketamine to pamoate stoichiometry, crystalline or amorphous forms of ketamine pamoate salts having a 1:1 ketamine to pamoate stoichiometry, or combinations thereof.

[0011] According to embodiments of the present disclosure, the ketamine pamoate salt may be R,S-ketamine pamoate salt having a 2:1 stoichiometry of ketamine to pamoate (Formula I), S-ketamine pamoate salt having a 2:1 stoichiometry of ketamine to pamoate (Formula II), R-ketamine pamoate salt having a 2:1 stoichiometry of ketamine to pamoate (Formula III), R- or S-ketamine pamoate salt having a 1:1 stoichiometry of ketamine to pamoate (Formula IV), or any combination thereof.

[0012] [ka]

[0013] Formula I (R,S-ketamine pamoate salt, 2:1 ratio),

[0014] [ka]

[0015] Formula II (S-ketamine pamoate salt, 2:1 ratio),

[0016] [ka]

[0017] Formula III (R-ketamine pamoate salt, 2:1 ratio),

[0018] [ka]

[0019] Formula IV (R- or S-ketamine pamoate salt, 1:1 ratio).

[0020] According to embodiments of the present disclosure, the crystalline form of ketamine pamoate salt is represented by an X-ray powder diffraction (XRPD) pattern comprising one or more 2θ values ​​selected from 6.0, 10.7, 11.6, 12.0, 13.0, 14.7, 15.0, 22.2, 25.2, and 30.3 (±0.2 2θ).

[0021] In some embodiments of the present disclosure, the ketamine pamoate salt is R,S-ketamine pamoate salt (2:1 ratio) in a crystalline form represented by an XRPD pattern comprising one or more 2θ values ​​selected from 6.0, 8.6, 10.7, 11.6, 12.0, 13.0, 14.7, 15.0, 15.3, 17.9, 18.6, 19.6, 20.0, 21.1, 21.6, 22.2, 23.3, 24.4, 25.2, 25.9, 26.9, 28.6, 29.7, 30.3, 32.4, 34.0, and 36.6 (±0.2 2θ).

[0022] In some embodiments of the present disclosure, the ketamine pamoate salt is S-ketamine pamoate salt (2:1 ratio) in a crystalline form represented by an XRPD pattern comprising one or more 2θ values ​​selected from 6.0, 10.8, 11.7, 12.0, 12.6, 13.1, 14.6, 15.1, 18.2, 19.2, 19.7, 20.1, 22.0, 22.8, 23.3, 23.7, 24.1, 24.7, 25.2, 27.3, 30.1, 31.6, 45.4, 56.4, and 75.2 (±0.2 2θ).

[0023] In some embodiments of the present disclosure, the ketamine pamoate salt is R-ketamine pamoate salt (2:1 ratio) in a crystalline form represented by an XRPD pattern comprising one or more 2θ values ​​selected from 6.0, 10.8, 11.7, 12.0, 12.6, 13.1, 14.6, 15.0, 18.2, 19.3, 19.7, 20.6, 22.0, 22.9, 23.6, 24.1, 24.7, 25.2, 25.9, 27.3, 30.1, 31.6, 45.4, 56.4, and 75.2 (±0.2 2θ).

[0024] In some embodiments of the present disclosure, the ketamine pamoate salt is R- or S-ketamine pamoate salt (1:1 ratio) in a crystalline form represented by an XRPD pattern comprising one or more 2θ values ​​selected from 6.0, 7.5, 8.6, 9.4, 10.7, 11.1, 11.6, 12.1, 13.0, 14.7, 15.0, 15.5, 17.9, 18.6, 19.3, 20.0, 20.7, 21.1, 21.6, 22.3, 23.1, 23.4, 24.3, 25.0, 26.2, 26.9, 28.6, 29.8, 30.3, 31.1, 32.4, 33.3, 33.9, 36.6, and 37.4 (±0.2 2θ).

[0025] In some embodiments of the present disclosure, the pamoate salt of ketamine is in a crystalline form represented by an XRPD pattern substantially corresponding to the pattern shown in FIG. 1, FIG. 2, FIG. 3, or FIG.

[0026] According to some embodiments of the present disclosure, the sustained-release pharmaceutical composition comprises ketamine pamoate salt and a pharmaceutically acceptable carrier thereof. In some embodiments of the present disclosure, the pharmaceutically acceptable carrier is selected from the group consisting of palmitic acid, oleic acid, stearic acid, decanoic acid, linoleic acid, N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, polyethylene glycol 4000 (PEG 4000), polysorbate 80 (Tween 80), sodium carboxymethylcellulose, sodium chloride, polylactic acid, poly(lactic-co-glycolic acid), and any combination thereof.

[0027] According to embodiments of the present disclosure, the sustained release pharmaceutical composition may be an injectable aqueous suspension, an injectable solution, or an injectable matrix delivery system.

[0028] In some embodiments of the present disclosure, the sustained release pharmaceutical composition is an injectable aqueous suspension comprising ketamine pamoate salt and a pharmaceutically acceptable carrier thereof selected from the group consisting of polyethylene glycol 4000 (PEG 4000), polysorbate 80 (Tween 80), carboxymethylcellulose sodium, sodium chloride, or any combination thereof. In some embodiments, the injectable aqueous suspension of the present disclosure has a mean particle size (d50) of less than 20 μm and a mean particle size (d50) of less than 300 μm. 2 / g.

[0029] In some embodiments of the present disclosure, the sustained-release pharmaceutical composition is an injectable solution comprising ketamine pamoate salt and a pharmaceutically acceptable carrier thereof selected from the group consisting of N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, or any combination thereof. In some embodiments, the injectable solution of the present disclosure may further comprise at least one of palmitic acid, oleic acid, stearic acid, decanoic acid, and linoleic acid.

[0030] In some embodiments of the present disclosure, the sustained-release pharmaceutical composition is an injectable matrix delivery system comprising ketamine pamoate salt and a pharmaceutically acceptable carrier selected from the group consisting of polylactic acid, poly(lactic-co-glycolic acid), or any combination thereof. In some embodiments, the injectable matrix delivery system of the present disclosure may further comprise at least one of N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, and benzyl alcohol.

[0031] According to embodiments of the present disclosure, in the sustained release pharmaceutical composition, ketamine pamoate salt is present in a concentration of 1% to 99%, 5% to 90%, 5% to 60%, 10% to 60%, or 15% to 40% (w / w).

[0032] According to embodiments of the present disclosure, the sustained release pharmaceutical composition is an injectable formulation. In some embodiments, the sustained release pharmaceutical composition is prepared for subcutaneous, intramuscular, or intradermal injection.

[0033] According to embodiments of the present disclosure, the sustained release pharmaceutical composition is resistant to heat.

[0034] According to embodiments of the present disclosure, the sustained release pharmaceutical composition may further comprise one or more additional agents, hi some embodiments, the additional agents are selected from the group consisting of wetting agents, suspending agents, tonicity adjusting agents, pH adjusting agents, buffering agents, antioxidants, preservatives, and any combination thereof.

[0035] The present disclosure also provides a method for treating a disease or condition by using the sustained release pharmaceutical composition described above. According to an embodiment of the present disclosure, the method comprises administering the sustained release pharmaceutical composition to a subject in need thereof.

[0036] According to embodiments of the present disclosure, the disease or condition is selected from the group consisting of a central nervous system disorder, depression, inflammation, pain, and any combination thereof. In some embodiments, the disease or condition is selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, tinnitus, refractory chronic migraine, asthma, anxiety, substance use disorder, alcohol use disorder, eating disorder, refractory status epilepticus, cerebral ischemia, Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, multiple sclerosis, and any combination thereof.

[0037] The present disclosure also provides a method for anesthetizing a subject in need thereof by using the sustained release pharmaceutical composition described above. According to an embodiment of the present disclosure, the method comprises administering the sustained release pharmaceutical composition to the subject.

[0038] According to embodiments of the present disclosure, the sustained release pharmaceutical composition exhibits a steady release profile that lasts for 72 hours, for example, 1 week, 2 weeks, 3 weeks, or 1 month after administration. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of R,S-ketamine pamoate salt (crystalline form, ratio 2:1). [Figure 2] FIG. 2 shows the X-ray powder diffraction pattern of S-ketamine pamoate salt (crystalline form, ratio 2:1). [Figure 3] FIG. 3 shows the X-ray powder diffraction pattern of R-ketamine pamoate salt (crystalline form, ratio 2:1). [Figure 4] FIG. 4 shows the X-ray powder diffraction pattern of R,S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 5] FIG. 5 shows the X-ray powder diffraction pattern of S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 6] FIG. 6 shows the X-ray powder diffraction pattern of R-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 7] FIG. 7 shows the X-ray powder diffraction patterns of R- or S-ketamine pamoate salts (crystalline forms, 1:1 ratio). [Figure 8] FIG. 8 shows the 1H nuclear magnetic resonance (NMR) spectrum of R,S-ketamine pamoate salt (crystalline form, ratio 2:1). [Figure 9] FIG. 9 shows the 1H nuclear magnetic resonance (NMR) spectrum of S-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 10] FIG. 10 shows the 1H nuclear magnetic resonance (NMR) spectrum of R-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 11] FIG. 11 shows the 1H nuclear magnetic resonance (NMR) spectrum of R- or S-ketamine pamoate salt (crystalline form, 1:1 ratio). [Figure 12] FIG. 12 shows the 13C nuclear magnetic resonance (NMR) spectrum of S-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 13] FIG. 13 shows the 13C nuclear magnetic resonance (NMR) spectrum of R-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 14] FIG. 14 shows the Fourier transform infrared (FTIR) spectrum of S-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 15] FIG. 15 shows the FTIR spectrum of R-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 16] FIG. 16 shows the FTIR spectrum of S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 17] FIG. 17 shows the FTIR spectrum of R-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 18] FIG. 18 shows the FTIR spectrum of R,S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 19] FIG. 19 shows the FTIR spectrum of R- or S-ketamine pamoate salt (amorphous form, 1:1 ratio). [Figure 20] FIG. 20 shows the differential scanning calorimetry (DSC) pattern of R,S-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 21] FIG. 21 shows the DSC pattern of S-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 22] FIG. 22 shows the DSC pattern of R-ketamine pamoate salt (crystalline form, 2:1 ratio). [Figure 23] FIG. 23 shows the DSC patterns of R- or S-ketamine pamoate salts (crystalline forms, 1:1 ratio). [Figure 24] FIG. 24 shows the DSC pattern of S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 25] FIG. 25 shows the DSC pattern of R-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 26] FIG. 26 shows the DSC pattern of R,S-ketamine pamoate salt (amorphous form, 2:1 ratio). [Figure 27] FIG. 27 shows the intrinsic dissolution rate of R,S-ketamine pamoate salt (crystalline form) in media with different pH values. [Figure 28] FIG. 28 shows the intrinsic dissolution rate of R,S-ketamine hydrochloride in media with different pH values. [Figure 29] FIG. 29 shows the intrinsic dissolution rates of crystalline and amorphous forms of S-ketamine pamoate salt, R-ketamine pamoate salt, and R,S-ketamine pamoate salt in pH 7.4 medium. [Figure 30] FIG. 30 shows the X-ray powder diffraction pattern of ketamine pamoate salt after heating (121° C.) for 4 hours. [Figure 31] FIG. 31 shows the DSC patterns of ketamine pamoate salt before and after heating (121° C.) for 4 hours. [Figure 32] FIG. 32 shows the mean plasma levels of ketamine following subcutaneous injection of formulation SL01 at a dose of 60 mg ketamine / kg in rats. [Figure 33] FIG. 33 shows the mean plasma levels of ketamine following subcutaneous injection of formulation SL02 at a dose of 60 mg ketamine / kg in rats. [Figure 34] FIG. 34 shows the mean plasma levels of ketamine following subcutaneous injection of formulation SL03 at a dose of 60 mg ketamine / kg in rats. [Figure 35] FIG. 35 shows the mean plasma levels of ketamine following subcutaneous injection of formulation AS01 at a dose of 60 mg ketamine / kg in rats. [Figure 36] FIG. 36 shows the mean plasma levels of ketamine following subcutaneous injection of formulation SL02 at a dose of 3 mg ketamine / kg in minipigs. [Figure 37]FIG. 37 shows the mean plasma levels of ketamine following subcutaneous injection of formulation SL04 at a dose of 6 mg ketamine / kg in minipigs. [Figure 38] FIG. 38 shows the mean plasma levels of ketamine following subcutaneous injection of formulation AS02 at a dose of 6 mg ketamine / kg in minipigs. [Figure 39] FIG. 39 shows the mean plasma levels of ketamine following intramuscular injection of formulation AS03 at a dose of 10.3 mg ketamine / kg in minipigs. [Figure 40] FIG. 40 shows the mean plasma levels of ketamine following subcutaneous injection of formulation AS05 at a dose of 3 mg ketamine / kg in minipigs. [Figure 41] FIG. 41 shows the mean ketamine release profiles following subcutaneous injection of formulations SL01, SL02, SL03 and AS01 at a dose of 60 mg ketamine / kg in rats. [Figure 42] FIG. 42 shows the mean ketamine release profile following subcutaneous injection of formulations SL02 and AS05 at a dose of 3 mg ketamine / kg, the mean ketamine release profile following subcutaneous injection of formulations AS02 and SL04 at a dose of 6 mg ketamine / kg, and the mean ketamine release profile following intramuscular injection of formulation AS03 at a dose of 10.3 mg ketamine / kg in minipigs. [Figure 43] Figure 43 shows the protocol for a dexamethasone (DEX)-induced depression-like animal model to evaluate the antidepressant effects of ketamine hydrochloride (KET), R,S-ketamine pamoate (KEP), S-ketamine pamoate (S-KEP), and R-ketamine pamoate (R-KEP). ICR mice were intraperitoneally injected with saline or decreasing doses of DEX (0.5 mg / kg, 0.3 mg / kg, and 0.1 mg / kg) on ​​postnatal days 1 to 3 (P1–P3), respectively. Drugs or saline were administered subcutaneously on day 35 (P35, i.e., day 0, D0), and forced swim tests (FSTs) were performed every 10 days from day 1 (D1, P36) to day 98. Sedative behavior was also assessed using a sedation rating scale from immediately after injection until day 28 (P49) after drug administration. [Figure 44] Figure 44 is a graph showing the antidepressant effects of ketamine hydrochloride (KET), R,S-ketamine pamoate (KEP), S-ketamine pamoate (S-KEP), and R-ketamine pamoate (R-KEP) in the forced swimming test (FST) from day 1 to day 63 after drug administration. Results are expressed as mean ± SEM. Student's t-test was used to analyze the saline group compared with other groups at each time point. *p<0.05, **p<0.01, and ***p<0.001 indicate significant differences compared to the saline group. [Figure 45] Figure 45 is a graph showing the sedation assessment scores of mice treated with saline (Saline group), ketamine hydrochloride (KET), R,S-ketamine pamoate (KEP), S-ketamine pamoate (S-KEP), and R-ketamine pamoate (R-KEP) from immediately after injection to day 28. DETAILED DESCRIPTION OF THE INVENTION

[0040] The following examples are used to illustrate the present disclosure. Those skilled in the art can easily imagine other advantages and effects of the present disclosure based on the disclosure herein. The present disclosure can also be implemented or applied as described in different examples. The above examples can be modified or changed to implement the present disclosure for different aspects and applications without violating its scope.

[0041] Additionally, it should be noted that, as used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent. The term "or" is used interchangeably with the term "and / or" unless the context clearly dictates otherwise.

[0042] The present disclosure relates to a formulation of ketamine pamoate salt that provides a sustained release profile after a single administration and minimizes the initial burst. According to embodiments of the present disclosure, the ketamine pamoate salt formulation is useful for treating central nervous system disorders, depression, pain, or inflammation. In some embodiments of the present disclosure, the ketamine pamoate salt is a crystalline or amorphous form of R,S-ketamine pamoate salt, S-ketamine pamoate salt, or R-ketamine pamoate salt. In some embodiments of the present disclosure, the ketamine pamoate salt is a ketamine pamoate salt with a 2:1 stoichiometry of ketamine to pamoate, a ketamine pamoate salt with a 1:1 stoichiometry of ketamine to pamoate, or a combination thereof.

[0043] According to an embodiment of the present disclosure, the formulation of ketamine pamoate salt is a sustained release pharmaceutical composition comprising a crystalline or amorphous form of said ketamine pamoate salt and a pharmaceutically acceptable carrier thereof.

[0044] According to embodiments of the present disclosure, the sustained release pharmaceutical composition may comprise ketamine pamoate salt in any suitable concentration, for example, 1% to 99%, 1% to 90%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 10% to 70%, 10% to 60%, 15% to 50%, and 15% to 40% (w / w). Note that when numerical ranges are disclosed in this disclosure, it is intended to include all values ​​within the range as if each of these values ​​were individually disclosed.

[0045] According to embodiments of the present disclosure, the sustained-release pharmaceutical composition may be formulated in an aqueous solution containing a biocompatible solvent as a pharmaceutically acceptable carrier, which may include, but is not limited to, organic solvents such as N-methyl-2-pyrrolidone, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, dimethyl sulfoxide, N,N-dimethylacetamide, propylene glycol, dimethyl glycol, benzyl alcohol, or any combination thereof.

[0046] According to an embodiment of the present disclosure, the sustained release pharmaceutical composition may be formulated in an aqueous suspension containing at least one of PEG4000, Tween 80, sodium carboxymethylcellulose, sodium chloride, or any combination thereof.

[0047] According to embodiments of the present disclosure, the sustained release pharmaceutical composition may be formulated in a matrix delivery system comprising a pharmaceutically acceptable carrier and a controlled release matrix, which may comprise polylactic acid, poly(lactic-co-glycolic acid), or a combination thereof.

[0048] The sustained release pharmaceutical compositions of the present disclosure may further comprise wetting agents, suspending agents, tonicity adjusting agents, pH adjusting agents, buffering agents, antioxidants, preservatives, and any combination thereof.

[0049] The various formulations disclosed herein lack an undesirable initial burst and can exhibit sustained profiles of 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, or more. Ketamine pamoate salt formulations without significant burst release not only reduce the risk of certain systemic side effects, such as pinprick pupils, sedation, hypotension, and respiratory depression, but also reduce the burden on physicians of frequently monitoring patients. Furthermore, ketamine pamoate salt formulations exhibit high bioavailability, pharmaceutically effective plasma concentrations for at least 1 week, and minimal risk of local site reactions.

[0050] Different examples were used to illustrate the present disclosure. The following examples should not be considered as limiting the scope of the present disclosure. [Example]

[0051] The preparation flow of S-ketamine pamoate salt and R-ketamine pamoate salt is shown in Scheme 1 below.

[0052] Scheme 1

[0053] [ka]

[0054] R-Ketamine Pamoate Salt (6) S-Ketamine Pamoate Salt (7) A: Di-p-toluoyl-L-tartaric acid / EtOH, EtOH / H2O (3:2) B: Di-p-toluoyl-L-tartaric acid / EtOH, EtOH / H2O (2:3) C: HCl / THF D: Disodium pamoate / H2O

[0055] Example 1: Preparation of R,S-ketamine free base (1) 10 g of R,S-ketamine hydrochloride was dissolved in 100 mL of water, and then 150 mL of saturated aqueous sodium bicarbonate solution was added with stirring for 10 minutes. The reaction mixture was extracted with dichloromethane (100 mL × 2). The separated organic layers were combined and distilled under reduced pressure to obtain R,S-ketamine free base (1).

[0056] Example 2: Preparation of (-)-O,O'-di-p-toluoyl-L-tartrate of R-ketamine (2) Di-p-toluoyl-L-tartaric acid (13 g, 33.6 mmol) and R,S-ketamine free base (8 g, 33.6 mmol) were dissolved in ethanol (EtOH, 160 mL) with stirring for 5 minutes. 10 mL of water was added dropwise to the solution at room temperature, followed by stirring for 1 hour, resulting in a precipitate. The filtrate was collected by suction filtration and dried under vacuum. The residue was dissolved in 100 mL of 60% ethanol solution (i.e., EtOH:HO = 3:2) at 60 °C and cooled to room temperature for 1 hour to obtain a solid, which was then dried under vacuum. The resulting powder was analyzed by high-performance liquid chromatography (HPLC), differential scanning calorimetry (DSC), optical rotation, nuclear magnetic resonance (NMR) spectroscopy, and literature references. The (-)-O,O'-di-p-toluoyl-L-tartrate salt of R-ketamine (2) was characterized by specific rotation, melting point (mp), and HPLC chiral purity as shown below. mp=133.5-141.3℃,

[0057]

number

[0058] c=1.0, dimethylformamide, chiral purity=98.4%. 1 H-NMR(DMSO-d6):7.87(d,4H,J=8.0Hz),7.68(d,1H,J=6.8Hz),7.44(m,3H),7.36(d,4H, J=8.0Hz), 5.74(s, 2H), 2.66-2.32(m, 2H), 2.39(s, 6H), 2.04(s, 3H), 1.90-1.58(m, 6H).

[0059] Example 3: Preparation of (-)-O,O'-di-p-toluoyl-L-tartrate of S-ketamine (3) The precipitate from Example 2 was dried under reduced pressure. The solid was dissolved in 100 mL of 40% ethanol solution (i.e., EtOH:HO = 2:3) at 60 °C and cooled to room temperature for 1 hour to obtain a solid, which was then dried under vacuum. The resulting powder was analyzed by HPLC, DSC, optical rotation, NMR spectroscopy, and literature information. The (-)-O,O'-di-p-toluoyl-L-tartrate salt of S-ketamine (3) was characterized by specific rotation, melting point, and HPLC chiral purity, as shown below. mp=157.1-163.3℃,

[0060]

number

[0061] c=1.0, dimethylformamide, chiral purity=100%. 1 H-NMR(DMSO-d6):7.87(d,4H,J=7.6Hz),7.67(d,1H,J=7.6Hz),7.44(m,3H),7.36(d,4H, J=8.0Hz),5.74(s,2H),2.64-2.31(m,2H),2.39(s,6H),2.03(s,3H),1.91-1.59(m,6H).

[0062] Example 4: Preparation of R-ketamine pamoate salt (6) (crystalline, 2:1 ratio) R-ketamine di-p-toluoyl-L-tartrate (2) was dissolved in 10 volumes of tetrahydrofuran (THF) by stirring at 2°C to 10°C. Hydrochloric acid (37%) was added to the solution to obtain a precipitate, which was collected by suction filtration to obtain R-ketamine hydrochloride (4). R-ketamine hydrochloride (4) and disodium pamoate were each dissolved in 10 volumes of water. Water was then distilled from the reaction mixture under reduced pressure. The residue was dissolved in ethanol with stirring at 60°C and recrystallized by lowering the temperature. The resulting powder was analyzed by HPLC, DSC, infrared (IR), X-ray diffraction pattern (XRD), and NMR spectroscopy. The crystalline form of R-ketamine pamoate (6) was characterized by the analytical results and the corresponding chromatographic properties.

[0063]

number

[0064] This was confirmed by the specific rotation of the R-ketamine pamoate salt (6).

[0065] Example 5: Preparation of S-ketamine pamoate salt (7) (crystalline, 2:1 ratio) S-ketamine di-p-toluoyl-L-tartrate (3) was dissolved in 10 volumes of tetrahydrofuran (THF) by stirring at 2°C to 10°C. Hydrochloric acid (37%) was added to the solution to obtain a precipitate, which was collected by suction filtration to obtain S-ketamine hydrochloride (5). S-ketamine hydrochloride (5) and disodium pamoate were each dissolved in 10 volumes of water. Water was then distilled from the reaction mixture under reduced pressure. The residue was recrystallized in ethanol with stirring at 60°C and isolated by vacuum filtration. The resulting powder was analyzed by HPLC, DSC, optical rotation, IR, XRD, and NMR spectroscopy. The crystalline form of S-ketamine pamoate (7) was characterized by the analytical results and the

[0066]

number

[0067] This was confirmed by the specific rotation of the S-ketamine pamoate salt (7).

[0068] Example 6: Preparation of R-ketamine pamoate salt (amorphous, 2:1 ratio) R-ketamine pamoate salt (6) was dissolved in methanol and the solvent was removed under reduced pressure to obtain an amorphous form of R-ketamine pamoate salt. The resulting powder was analyzed by HPLC, DSC, optical rotation, IR, XRD, and NMR spectroscopy. The amorphous form of R-ketamine pamoate salt was characterized by the analytical results and

[0069]

number

[0070] This was confirmed by the specific rotation of the R-ketamine pamoate salt.

[0071] Example 7: Preparation of S-ketamine pamoate salt (amorphous, 2:1 ratio) S-ketamine pamoate salt (7) was dissolved in methanol and the solvent was removed under reduced pressure to obtain the amorphous form of S-ketamine pamoate salt (amorphous). The resulting powder was analyzed by HPLC, DSC, optical rotation, IR, XRD, and NMR spectroscopy. The amorphous form of S-ketamine pamoate salt was characterized by the analytical results and

[0072]

number

[0073] This was confirmed by the specific rotation of the S-ketamine pamoate salt.

[0074] Example 8: Preparation of R,S-ketamine pamoate salt (crystalline, 2:1 ratio) Ketamine hydrochloride (20 g, 72.9 mmol) and disodium pamoate monohydrate (15 g, 33.3 mmol) were dissolved in 65% aqueous ethanol (350 mL) in a round-bottom flask. The mixture was stirred constantly at 70 °C for 30 minutes. The mixture was then gradually cooled to ambient temperature in an ice bath. The mixture was then stirred overnight at ambient temperature. The reaction mixture was filtered, and the powder was collected and dried under reduced pressure. The resulting powder was analyzed by DSC, IR, XRD, and NMR spectroscopy.

[0075] Example 9: Preparation of R,S-ketamine pamoate salt (amorphous, 2:1 ratio) The powder collected from Example 8 was dissolved in methanol. The solvent was then removed under reduced pressure and dried to obtain amorphous R,S-ketamine pamoate salt. The resulting powder was analyzed by DSC, IR, XRD, and NMR spectroscopy.

[0076] Example 10: Preparation of R- or S-ketamine pamoate salt (crystalline, 1:1 ratio) Ketamine free base (10 g, 42.1 mmol) and pamoic acid (16 g, 41.2 mmol) were dissolved in acetonitrile (2300 mL) and dimethyl sulfoxide (100 mL) in a round-bottom flask. The mixture was stirred overnight at ambient temperature. The reaction mixture was filtered, and the powder was collected and dried under reduced pressure. The resulting powder was analyzed by DSC, IR, XRD, and NMR spectroscopy.

[0077] Example 11: XRPD analysis X-ray powder diffraction (XRPD) patterns were obtained on a Bruker D8 Discover X-ray powder diffractometer equipped with a CuKα radiation source operated at 40 kV and 40 mA.

[0078] Each sample was scanned between 2° and 80° in 2θ with a step size of 0.02° and a scan rate of 0.6 s / step. The 2θ angular peak positions and I / I data corresponding to all crystalline forms of ketamine pamoate salt peaks with intensities greater than 10% of the maximum peak are shown in Table 1 below.

[0079] The crystalline forms of R- or S-ketamine pamoate salt (1:1 ratio), R,S-ketamine pamoate salt (2:1 ratio), S-ketamine pamoate salt (2:1 ratio), and R-ketamine pamoate salt (2:1 ratio) were characterized by X-ray diffraction patterns (XRD), and the results are shown in Figures 1 to 7.

[0080] [Table 1-1]

[0081] [Table 1-2]

[0082] Example 12: NMR analysis The crystalline form of ketamine pamoate salt was dissolved in a deuterated solvent (DMSO) and nuclear magnetic resonance (NMR) spectra were obtained using a Bruker Ascend™ 400 MHz NMR spectrometer.

[0083] The properties of the crystalline forms of R- or S-ketamine pamoate salt (1:1 ratio), R,S-ketamine pamoate salt (2:1 ratio), S-ketamine pamoate salt (2:1 ratio), and R-ketamine pamoate salt (2:1 ratio) are: 1 This was confirmed by H-NMR spectroscopy (as shown in Table 2 and Figures 8 to 11). Furthermore, S-ketamine pamoate salt (2:1 ratio) and R-ketamine pamoate salt (2:1 ratio) were 13 C-NMR spectroscopy was performed and chemical shifts were reported in ppm (as shown in Table 3 and Figures 12 and 13).

[0084] [Table 2]

[0085] [Table 3]

[0086] Example 13: Fourier transform infrared (FT-IR) spectroscopy The polymorphs of ketamine pamoate salt were further characterized by infrared (IR) spectroscopy measurements obtained on disk using a Bruker FPA-FTIR Vertex 70V, Hyperion 3000 system, and the results are shown in Figures 14-19. The IR absorbance (wavenumbers, cm) was sufficient to identify the crystalline and amorphous forms of S-ketamine pamoate salt, R-ketamine pamoate salt, and R,S-ketamine pamoate salt. -1 ) reported in Table 4 below.

[0087] [Table 4]

[0088] Example 14: DSC analysis Differential scanning calorimetry (DSC) analysis of samples of R,S-ketamine pamoate salt (2:1 ratio), S-ketamine pamoate salt (2:1 ratio), R-ketamine pamoate salt (2:1 ratio), and R- or S-ketamine pamoate salt (1:1 ratio) showed glass transitions at approximately 234°C, 212°C, 214°C, and 230°C, respectively, indicating that the samples were crystalline (Figures 20-23). ​​DSC analysis of samples of S-ketamine pamoate salt (2:1 ratio) and R-ketamine pamoate salt (2:1 ratio) showed glass transitions at approximately 210°C and 193°C, indicating that the samples were amorphous (Figures 24 and 25). DSC analysis of a sample of R,S-ketamine pamoate salt (2:1 ratio) showed a glass transition at about 213° C., indicating that the sample was amorphous (FIG. 26).

[0089] DSC analysis was performed using a Mettler Toledo DSC3 under standard conditions. The DSC analysis of the crystalline forms of ketamine pamoate salt is summarized in Table 5 below.

[0090] [Table 5]

[0091] Example 15: Solubility Test The solubility of ketamine pamoate salt was measured based on the guidance of the United States Pharmacopeia (USP) and is summarized in Table 6 below. The results showed that ketamine pamoate salt had low solubility in different pH media. The highest solubility was observed for R,S-ketamine pamoate salt at pH 1.2 (1.68 mg / mL), and the lowest solubility was observed for R,S-ketamine pamoate salt at pH 6.8 (0.16 mg / mL). R- or S-ketamine pamoate salt (1:1 ratio) had similar solubility characteristics to R,S-ketamine pamoate salt (2:1 ratio). Here, the highest solubility was observed for R- or S-ketamine pamoate salt (1:1 ratio) at pH 1.2 (0.72 mg / mL), and the lowest solubility was observed for R- or S-ketamine pamoate salt (1:1 ratio) at pH 6.8 (0.07 mg / mL).

[0092] We also found that ketamine pamoate salt is less soluble in aqueous solutions than ketamine hydrochloride (solubility: >200 mg / mL in water).

[0093] [Table 6]

[0094] Example 16: Dissolution Rate Studies The intrinsic dissolution rates of the crystalline and amorphous forms of ketamine pamoate salt were determined using the intrinsic dissolution rotating disk method described in Chapter 1087 of the United States Pharmacopoeia, where the media pH was 1.2, 4.5, 6.8, or 7.4, the media volume was 900 mL, the rotation speed was 50 rpm, the media temperature was 37° C., and the detection wavelength was 210 nm. The results are shown in Tables 7 and 8 and Figures 27 to 29.

[0095] As shown in Table 7 and Figures 29 and 30, the intrinsic dissolution rate of the crystalline form of R,S-ketamine pamoate salt (2:1 ratio) decreased as the pH increased, and compared to R,S-ketamine hydrochloride, R,S-ketamine pamoate salt (2:1 ratio) exhibited substantially lower dissolution rates in different pH media.

[0096] The dissolution rates of the crystalline and amorphous forms of S-ketamine pamoate salt (2:1 ratio), R-ketamine pamoate salt (2:1 ratio), and R,S-ketamine pamoate salt (2:1 ratio) in a pH 7.4 medium are also shown in Table 8 and Figure 29, and the solubility classification of these ketamine pamoate salts based on the Biopharmaceutical Classification System (BCS) is also shown in Table 8. The intrinsic dissolution rate of ketamine pamoate salt was observed to be more than 80 times lower than that of ketamine hydrochloride.

[0097] [Table 7]

[0098] [Table 8]

[0099] Example 17: Preparation of Ketamine Pamoate Salt Solution R,S-Ketamine pamoate salt (crystalline, 2:1 ratio) and excipients were added to a glass vial and dissolved in a biocompatible organic solvent such as N-methyl-2-pyrrolidone (NMP) or N,N-dimethylacetamide (DMAc). The mixture was stirred at ambient temperature or slightly heated until all components were dissolved. The composition of the resulting pharmaceutical solution is shown in Table 9 below.

[0100] [Table 9]

[0101] Example 18: Preparation of an aqueous suspension of ketamine pamoate salt R,S-ketamine pamoate salt (crystalline, 2:1 ratio), S-ketamine pamoate salt (crystalline, 2:1 ratio), and R-ketamine pamoate salt (crystalline, 2:1 ratio) were individually added to flasks and suspended in excipients consisting of polyethylene glycol 4000 (PEG 4000), polysorbate 80 (Tween 80), sodium carboxymethylcellulose (NaCMC), and / or sodium chloride (NaCl) dissolved in dd-HO.

[0102] The aqueous suspension was mixed uniformly by ultrasonic treatment and then milled. The composition of the aqueous suspension and the milling process used are shown in Table 10. The aqueous suspension was added to a glass vial and the particle size distribution was analyzed using a Bettersizer S2-E laser particle size distribution analyzer. The particle size distribution results are shown in Table 11.

[0103] [Table 10]

[0104] [Table 11]

[0105] Example 19: Preparation of a matrix delivery system of ketamine pamoate salt R,S-ketamine pamoate salt (crystalline, 2:1 ratio), polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA), and a biocompatible solvent were added to a glass vial and placed in a 50°C water bath with constant stirring until all components were dissolved. The mixture was removed from the water bath and stirred at room temperature to form a solution (i.e., a matrix delivery system). The composition of the matrix delivery system is shown in Table 12 below.

[0106] [Table 12]

[0107] Example 20: Stability study of pharmaceutical formulations of ketamine pamoate salt To evaluate the stability of ketamine pamoate salt formulations at elevated temperatures (121 °C), pharmaceutical Type I glass vials (3 mL), rubber closures, and aluminum and polypropylene flip-off seals were used. Additionally, formulation AS11, prepared in Example 18, was heated in an oven at 121 °C for 1 to 4 hours.

[0108] Subsequently, the analysis of ketamine and total related substances was analyzed using HPLC, and the results are shown in Table 13. In addition, the particle size distribution of the formulation was further measured, and the results are shown in Table 14.

[0109] After heating for 4 hours, the formulation was dried under vacuum, and the powder was characterized by XRD and DSC. The XRD of the heated ketamine pamoate salt is shown in Table 15 and Figure 1. The DSC of the heated ketamine pamoate salt is shown in Figure 31. By comparing with the results obtained in Example 14, it was found that the R,S-ketamine pamoate salt before and after heating for 4 hours exhibited onset temperatures of 231.3°C and 231.6°C, respectively.

[0110] HPLC results indicated that the ketamine assay was between 99.7% and 100.8%, and no related substances were produced. Furthermore, particle size distribution, XRD, and DSC results indicated no significant differences between the formulations before and after heating. These results suggested that the ketamine pamoate suspension had excellent heat resistance.

[0111] [Table 13]

[0112] [Table 14]

[0113] [Table 15-1]

[0114] [Table 15-2]

[0115] Example 21: Pharmacokinetic profile of pharmaceutical formulations of ketamine pamoate salt in rats Formulations SL01, SL02, SL03, and AS01 prepared in Examples 17 and 18 were subcutaneously injected into male CD(SD)IGS rats at a dose of 60 mg ketamine / kg. Blood samples were collected from the external jugular vein at specific time points. Plasma samples were separated by centrifugation and stored frozen for later analysis. LC-MS / MS was used to analyze the ketamine concentration in the plasma samples.

[0116] The pharmacokinetic profiles of Formulations SL01, SL02, SL03, and AS01 are shown in Tables 16-19 and Figures 32-35. The results showed that Formulation SL01 maintained its release profile of ketamine over 10 days, Formulation SL02 maintained its release profile of ketamine over 14 days, Formulation SL03 maintained its release profile of ketamine over 10 days, and Formulation AS01 maintained its release profile of ketamine over 14 days.

[0117] [Table 16]

[0118] [Table 17]

[0119] [Table 18]

[0120] [Table 19]

[0121] Example 22: Pharmacokinetic profile of pharmaceutical formulations of ketamine pamoate salt in minipigs Formulations SL02, SL04, AS02, AS03 and AS05 prepared in Examples 17 and 18 were injected subcutaneously (SC) or intramuscularly (IM) into male Lanyu minipigs (provided by PigModel Animal Technology Co., Ltd.). The details of the administration record of the minipigs animal study are shown in Table 20 below.

[0122] Blood samples were collected from the external jugular vein at specific time points. Plasma samples were separated by centrifugation and stored frozen for later analysis. LC-MS / MS was used to analyze the naltrexone concentration in the plasma samples. The pharmacokinetic profiles of formulations SL02, SL04, AS02, AS03, and AS05 are shown in Tables 21-25 and Figures 36-40. The results showed that formulation AS03 maintained its ketamine release profile over 21 days. Plasma concentrations of ketamine after injection of formulation AS02 were below 10 ng / mL from 2 hours to 28 days.

[0123] [Table 20]

[0124] [Table 21]

[0125] [Table 22]

[0126] [Table 23]

[0127] [Table 24]

[0128] [Table 25]

[0129] Example 23: In vivo release profile of injectable pharmaceutical formulations in rats and minipigs Based on the pharmacokinetic profile in rats and minipigs, the area under the curve (AUC 0-t ) and the area under the plasma concentration-time curve (AUC) extrapolated from time 0 to infinity 0-∞ The percentage of naltrexone released in the release profile was calculated using the following formula:

[0130]

number

[0131] The in vivo release profiles of formulations SL01, SL02, SL03, and AS01 in rats are shown in Table 26 and Figure 41. The in vivo release profiles of formulations SL02, SL04, AS02, AS03, and AS05 in minipigs are shown in Table 27 and Figure 42. The release profiles in two different animal models showed that the ketamine pamoate salt formulations could consistently release ketamine for various periods ranging from 10 to 28 days.

[0132] [Table 26]

[0133] [Table 27]

[0134] Example 24: Antidepressant effects in vivo Using a dexamethasone (DEX)-induced depression-like animal model, we evaluated the antidepressant effects of ketamine hydrochloride (KET), R,S-ketamine pamoate (KEP), S-ketamine pamoate (S-KEP), and R-ketamine pamoate (R-KEP) at equivalent doses (120 mg / kg ketamine free base). According to literature, depressive-like behaviors have been observed in juvenile and adult mice exposed to DEX during the neonatal period. The protocol for this study is shown in Figure 43 and described below.

[0135] Neonatal ICR mice were intraperitoneally injected with saline or DEX at doses of 0.5 mg / kg, 0.3 mg / kg, and 0.1 mg / kg on postnatal days 1, 2, and 3 (P1–P3), respectively. Mice administered with saline served as the control group, while mice administered with DEX were divided into KET, KEP, S-KEP, R-KEP, and saline groups (n = 10–14 mice per group). On postnatal day 35, mice in the KET, KEP, S-KEP, and R-KEP groups were subcutaneously injected with a KET formulation, formulation AS04 containing KEP, formulation AS06 containing S-KEP, and formulation AS07 containing R-KEP. The KET formulation was 20% (w / w) ketamine hydrochloride dissolved in 0.9% saline. Formulations AS04, AS06, and AS07 were prepared as described in Example 18. Mice in the control and saline groups were injected with equal volumes of 0.9% saline.

[0136] The antidepressant effect was evaluated by a forced swimming test (FST) performed from day 1 (P36) to day 63 (P98) after drug administration. Mice in all groups underwent swimming training before drug administration. During the FST, mice were placed in a 5-L glass cylinder (27 cm high, 18 cm diameter) filled with 4 L of water (23 ± 1°C). The total duration of immobility during the FST was observed for 5 min. Results were expressed as mean ± SEM. Student's t-test was used to analyze the saline group (DEX-treated mice injected with saline) and other groups at each time point. * p<0.05, ** p<0.01, and ***p<0.001 indicates a significant difference compared to the saline group.

[0137] Mice exposed to DEX neonatally showed a significant increase in immobility time in the FST compared with the control group. The results of the FST are shown in Figure 44. Both KET and KEP were observed to reduce the increased immobility time in DEX-treated mice 1 day after administration. Furthermore, KEP sustained a reduction in immobility time for at least 52 days after administration, and this effect became more pronounced. In contrast, KET only reduced immobility time from 1 to 10 days after injection, and this effect failed to persist between 11 and 21 days after injection.

[0138] In addition, sedative behavior was also assessed by the Rodent Sedation Rating Scale (Table 28) immediately after drug administration for 28 days. As shown in Figure 45, mice in the KET group exhibited strong sedation-related behaviors immediately after injection, and this effect was fully reversible by 2 hours after administration. Mice treated with KEP, S-KEP, and R-KEP exhibited normal behavior from 0 to 28 days after injection.

[0139] [Table 28]

[0140] As a result, KET, KEP, S-KEP, and R-KEP all showed rapid antidepressant effects in the FST after a single injection at equivalent doses (120 mg / kg of ketamine free base), and this effect persisted for at least 10 days in DEX-treated mice. Surprisingly, in the KEP, S-KEP, and R-KEP groups, sedation or other ketamine-related psychotomimetic effects and nervous system disorders did not occur after administration, indicating that S-KEP and R-KEP have additional beneficial properties for use as antidepressants compared to KEP and KET.

[0141] Although several embodiments of the present disclosure have been described in detail above, those skilled in the art may make various modifications and changes to the specific embodiments shown without substantially departing from the teachings and advantages of the present disclosure. Such modifications and changes are within the scope of the present disclosure, as set forth in the appended claims.

[0142] References 1. Han, Felicity Y., et al. “Sustained-release ketamine-loaded nanoparticles fabricated by sequential nanoprecipitation.” International Journal of Pharmaceutics(2020) :119291. 2. Way, Walter L. “ketamine -its pharmacology and therapeutic uses.” Anesthesiology: The Journal of the American Society of Anesthesiologists 56.2(1982) :119-136.

Claims

1. 1. A sustained release pharmaceutical composition comprising a crystalline or amorphous form of ketamine pamoate salt and a pharmaceutically acceptable carrier thereof, the ketamine pamoate salt is selected from the group consisting of R,S-ketamine pamoate salt, S-ketamine pamoate salt, R-ketamine pamoate salt, and any combination thereof, wherein the ketamine pamoate salt is a ketamine pamoate salt having a 2:1 stoichiometry of ketamine to pamoate, a ketamine pamoate salt having a 1:1 stoichiometry of ketamine to pamoate, or a combination thereof; and The pharmaceutically acceptable carrier is selected from the group consisting of N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, polyethylene glycol 4000 (PEG 4000), polysorbate 80 (Tween 80), sodium carboxymethylcellulose, sodium chloride, polylactic acid, poly(lactic-co-glycolic acid), and any combination thereof. Sustained release pharmaceutical compositions.

2. 2. The sustained release pharmaceutical composition of claim 1, wherein the sustained release pharmaceutical composition is an injectable aqueous suspension and the pharmaceutically acceptable carrier is polyethylene glycol 4000 (PEG 4000), polysorbate 80 (Tween 80), sodium carboxymethylcellulose, sodium chloride, or any combination thereof.

3. 3. The sustained release pharmaceutical composition of claim 2, having an average particle size (d50) of less than 20 μm and a specific surface area of ​​more than 300 m2 / g.

4. 2. The sustained release pharmaceutical composition of claim 1, wherein the sustained release pharmaceutical composition is an injectable solution and the pharmaceutically acceptable carrier is N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, or any combination thereof.

5. 5. The sustained release pharmaceutical composition of claim 4, further comprising at least one of palmitic acid, oleic acid, stearic acid, decanoic acid, linoleic acid, ethyl acetate, ethanol, butanol, 2-butanol, isobutanol, isopropanol, glycerin, benzyl benzoate, propylene glycol, dimethyl glycol, and benzyl alcohol.

6. 2. The sustained release pharmaceutical composition of claim 1, wherein the sustained release pharmaceutical composition is an injectable matrix delivery system and the pharmaceutically acceptable carrier is polylactic acid, poly(lactic-co-glycolic acid), or a combination thereof.

7. 7. The sustained release pharmaceutical composition of claim 6, further comprising at least one of N-methyl-2-pyrrolidone, dimethyl sulfoxide, N,N-dimethylacetamide, or any combination thereof.

8. 10. The sustained release pharmaceutical composition of claim 1, further comprising one or more additives selected from the group consisting of wetting agents, suspending agents, tonicity adjusting agents, pH adjusting agents, buffering agents, antioxidants, and preservatives.

9. 2. The sustained release pharmaceutical composition of claim 1, wherein said ketamine pamoate salt is present in a concentration of 1% to 99% w / w.

10. 10. The sustained release pharmaceutical composition of claim 9, wherein the ketamine pamoate salt is present in a concentration of 5% to 60% w / w.

11. 10. The sustained release pharmaceutical composition of claim 1, which is prepared for subcutaneous, intramuscular or intradermal injection.

12. The sustained release pharmaceutical composition of claim 1, which is heat resistant.

13. The sustained-release pharmaceutical composition of claim 1, administered to a subject in need thereof, for treating a disease or condition selected from the group consisting of central nervous system diseases, depression, inflammation, pain, and any combination thereof.

14. 14. The sustained release pharmaceutical composition of claim 13, wherein the disease or condition is selected from the group consisting of major depressive disorder (MDD), treatment-resistant depression (TRD), suicidal ideation, bipolar disorder, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, tinnitus, refractory chronic migraine, asthma, anxiety, substance use disorder, alcohol use disorder, eating disorder, refractory status epilepticus, cerebral ischemia, Alzheimer's disease, Parkinson's disease, stroke, traumatic brain injury, multiple sclerosis, and any combination thereof.

15. The sustained-release pharmaceutical composition of claim 1, administered to a subject in need thereof for anesthetizing the subject in need thereof.

16. 16. The sustained release pharmaceutical composition of any one of claims 13 to 15, wherein the sustained release pharmaceutical composition exhibits a steady release profile for 72 hours after administration.

17. 16. The sustained release pharmaceutical composition of any one of claims 13 to 15, wherein the sustained release pharmaceutical composition exhibits a stable release profile for one week after administration.

18. 16. The sustained release pharmaceutical composition of any one of claims 13 to 15, wherein the sustained release pharmaceutical composition exhibits a stable release profile for two weeks after administration.

19. 16. The sustained release pharmaceutical composition of claim 13, wherein the sustained release pharmaceutical composition exhibits a stable release profile for one month after administration.

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