Pharmaceutical composition

Abstract

The present invention provides subcutaneous pharmaceutical injectable compositions comprising ketamine or a salt thereof (e.g. Ketamine hydrochloride) equivalent to 50 mg / ml ketamine base and a stabilizer. The invention also provides a method for preparing the composition. The compositions of the present invention describe typical pharmacokinetic properties. The compositions of the present invention are bioequivalent to currently commercially available injectable compositions, but have lower Cmax, similar Tmax, and similar AUC. The composition disclosed by the invention can be used for treating refractory depression and managing pain.

Description

Technical Field

[0001] The present invention relates to subcutaneous injectable compositions comprising ketamine equivalent to 50 mg / ml ketamine base and a stabilizer. The compositions exhibit altered Cmax but similar Tmax and similar area under the curve (AUC). The present invention also relates to methods for preparing subcutaneous injectable compositions comprising ketamine and a stabilizer. Background Art

[0002] Injectable ketamine hydrochloride is used as a general anesthetic to prevent pain and discomfort during medical examinations, procedures, and minor surgeries. Ketamine and its salts are being tested in numerous clinical trials for various applications. It has provided significant relief for patients with complex regional pain syndrome (CRP), a poorly understood condition in which patients experience persistent, severe, and debilitating pain, and for pain management. Pain management specialists rely on ketamine for palliative care, treating chronic pain from tumors and other types of pain. It can also be used to treat refractory depression. This wonder drug has several other applications. However, it is also associated with certain side effects. Common known side effects of ketamine hydrochloride include blurred vision, double vision, dreamlike sensations, dizziness, drowsiness, jerky muscle movements, loss of appetite, nausea, vomiting, and sleep problems (e.g., insomnia). Other side effects include hallucinations, severe confusion, and extremely fearful and unusual thoughts.

[0003] Hospitalized patients and other patients are often prescribed other medications. When these other medications are used, they can interfere with the effects of ketamine or its salts. Ketamine can interact with barbiturates and other anesthetics if administered to a patient. The presence or amount of ketamine in the blood after injection is somewhat unpredictable.

[0004] Ketamine or ketamine hydrochloride is a potent molecule and is administered under the supervision of a physician. Initial doses of ketamine administered intravenously range from 1 mg / kg to 4.5 mg / kg. An average dose of 2 mg / kg produces surgical anesthesia for approximately 5 to 10 minutes. Initial doses of ketamine administered intramuscularly (IM) range from 6.5 mg / kg to 13 mg / kg. A dose of 10 mg / kg typically produces surgical anesthesia for approximately 12 to 25 minutes. Ketamine injection is currently available in strengths of 10 mg base / mL, 50 mg base / mL, and 100 mg base / mL. Ketamine has a solubility of 200 mg / mL in water.

[0005] Ketamine is a racemic mixture of two isomers, and S(+) ketamine has been shown to have a significantly shorter duration of action than racemic ketamine, which allows for faster recovery from S(+) ketamine use as an anesthetic and easier dosage adjustment when used for sedation and / or analgesia. It is also known that a single systemic administration has only a short duration of action. [Pediatric Anesthesia 2005 15:91–97, CHARLES LIN MD AND MARCEL E. DURIEUX MD PhD, Department of Anesthesiology, University of Virginia Health System Charlottesville, Charlottesville, VA, USA]

[0006] A single subanesthetic dose of ketamine alleviates depressive symptoms. However, patients experience transient dissociative, psychotomimetic side effects, and hemodynamic changes, limiting its clinical application.

[0007] Ketamine is known to have a direct effect on free recall and recognition memory. Ketamine is known to produce significant levels of thought disorder and withdrawal-retardation in healthy volunteers. Ketamine is known to cause behavioral and perceptual changes, as well as acute perceptual and cognitive impairment.

[0008] The label for Ketamine Hydrochloride (Ketalar) Injection states that it is formulated as a weakly acidic (pH 3.5-5.5) sterile solution for intravenous or intramuscular injection containing the equivalent of 10 mg, 50 mg, or 100 mg of ketamine base per milliliter and that it contains no more than 0.1 mg / mL of added (benzethonium chloride) as a preservative. The 10 mg / mL solution has been made isotonic with sodium chloride.

[0009] There are special precautions that state that "Special Precautions reactions occur in approximately 12% of patients. The severity of psychological manifestations varies between pleasant dreamlike states, vivid imagery, hallucinations, and emergence delirium. In some cases, these states are accompanied by confusion, agitation, and irrational behavior, and a few patients recall them as unpleasant experiences. They usually last no more than a few hours; however, in a few cases, recurrence occurs up to 24 hours after surgery. Ketamine hydrochloride (Ketalar) is known to have no residual psychological effects. The incidence of these emergence phenomena is lowest in elderly patients (over 65 years of age). In addition, they occur less frequently when the drug is administered intramuscularly and their incidence decreases with experience with the drug. The incidence of psychological manifestations during emergence, particularly dreamlike observations and emergence delirium, can be reduced by using lower recommended doses of ketamine hydrochloride (Ketalar) in combination with intravenous diazepam during induction and maintenance of anesthesia. (See DOSAGE AND ADMINISTRATION section. In addition, these reactions can be reduced if verbal, tactile, and visual stimulation of the patient is minimized during the recovery period. This does not preclude monitoring of vital signs. To terminate severe emergence reactions, a small hypnotic dose of a short-acting or ultra-short-acting barbiturate may be necessary. When ketamine hydrochloride (Ketalar) is used on an outpatient basis, the patient should not be released until recovery from anesthesia is complete and should then be accompanied by a responsible adult.

[0010] WO2020232274 discloses a ketamine formulation for subcutaneous injection, describing a complexation with β-cyclodextrin. WO / 2022 / 109050 also describes a complexation of ketamine with cyclodextrin.

[0011] EP3932393 claims a liquid pharmaceutical formulation comprising i). an active ingredient selected from ketamine and esketamine or a pharmaceutically acceptable salt thereof; ii). a cellulose ether; iii). glycerol; and iv). water.

[0012] Conventional and currently available injectable formulations often exhibit one or more side effects such as blurred vision, double vision, dreamlike sensations, dizziness, drowsiness, jerky muscle movements, loss of appetite, nausea, vomiting, and sleep problems (e.g., insomnia), and therefore the fullest pharmaceutical potential of ketamine or its salt (e.g., hydrochloride) has not been fully realized. These side effects are due to a sudden increase in blood ketamine levels after administration of the injectable composition. Injections of ketamine or its salt (e.g., hydrochloride) that are free of one or more side effects or undesirable effects are not available. Therefore, there is a pressing need to provide injectable compositions of ketamine or its salt (e.g., hydrochloride) that are safe and effective and have predictable blood levels. Simply reducing the amount of ketamine in the injectable composition would result in subtherapeutic concentrations and thus would not induce the desired drug effect while attempting to eliminate undesirable effects. Consequently, there is no subcutaneous injectable composition that does not induce an undesirable sudden increase or spike in ketamine after administration of the injectable composition, but that produces ketamine concentrations that ensure therapeutic efficacy in patients with depression who exhibit concentrations above the Cmax required for therapeutic efficacy.

[0013] There is a need to provide suitable injectable forms, such as subcutaneous injection, for the treatment of refractory depression and the treatment or management of chronic pain.

[0014] Purpose of the Invention

[0015] In view of the above, an object of the present invention is to provide an injectable composition comprising ketamine equivalent to 50 mg / ml ketamine base, which is safer and free from side effects caused by a sudden increase in ketamine concentration in the blood after administration of conventional injectable dosage forms.

[0016] Another object of the present invention is to provide a subcutaneous injectable composition comprising ketamine equivalent to 50 mg / ml ketamine base, which should exhibit a similar AUC to the currently marketed injectable composition, although it may have a different Cmax (preferably a lower Cmax) and a similar Tmax.

[0017] Yet another object of the present invention is to provide a ketamine composition for the treatment of refractory depression and / or pain management.

[0018] Another object of the present invention is to provide a method for preparing a composition comprising ketamine equivalent to 50 mg / ml ketamine base, which is safer and does not have side effects caused by a sudden increase in ketamine concentration in the blood after administration of conventional injectable dosage forms.

[0019] Yet another object of the present invention is to provide an injectable composition comprising ketamine and a stabilizer, said composition exhibiting predictable blood levels.

[0020] Another object of the present invention is to provide a subcutaneously injectable composition comprising ketamine equivalent to 50 mg / ml ketamine base that exhibits a mean Cmax well above the concentration required for therapeutic efficacy in patients with depression (0.5 mg / kg; 40 min infusion; 185 ng / ml), although it exhibits a lower Cmax than currently marketed compositions. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 A graph is provided of ketamine blood concentrations (in nanograms (ng) / ml) from the test and reference compositions on the Y-axis versus time (in hours) on the X-axis. Summary of the Invention

[0022] The present invention provides an injectable composition comprising ketamine equivalent to ketamine base present at 50 mg / ml, wherein the injectable composition exhibits an AUC similar to that exhibited by currently marketed injectable compositions, although the injectable composition may have a different Cmax (preferably a lower Cmax) and a similar Tmax. The composition unexpectedly controls a sudden rise in ketamine in the blood following administration. The composition is an aqueous composition.

[0023] The composition of the present invention does not have the side effects caused by a sudden increase in the concentration of ketamine in the blood after administration of conventional injectable dosage forms. The composition is a subcutaneous injectable composition.

[0024] The composition has a Cmax that is 80% to 100% of the Cmax of a commercially available injectable composition for subcutaneous use and an AUC 0-t 80% to 100% of the commercially available injectable composition, but the Tmax is similar, wherein similar Tmax means 100% ± 10% of the Tmax of the currently commercially available subcutaneous injectable composition.

[0025] The present invention provides a composition comprising a ketamine salt equivalent to 50 mg / ml ketamine base, a stabilizer, and at least one pharmaceutically acceptable excipient. The composition exhibits a lower Cmax than a conventional ketamine injectable composition, but exhibits a similar Tmax and a similar AUC.

[0026] The composition comprises a stabilizer selected from, but not limited to, potassium pyrrolidone (PVPK), diethylene glycol monoethyl ether or an alkyl derivative thereof, polyethylene glycol (PEG), and sodium carboxymethylcellulose. In one embodiment, the stabilizer is PVPK. In another embodiment, the stabilizer is PVPK-12 or PVPK-30.

[0027] In one embodiment, the composition comprises ketamine and a stabilizer in a ratio of 12: 1 to 2: 1. In one embodiment, the ratio of ketamine to stabilizer is 10: 1 to 3: 1. In another embodiment, the ratio of ketamine to stabilizer is 7: 1 to 3: 1.

[0028] In another embodiment, the ratio of ketamine to stabilizer is from 12.5:1 to 2.5:1, preferably from 10:1 to 3.33:1, and more preferably from 7.14:1 to 3.33:1.

[0029] The composition comprises at least one pharmaceutically acceptable excipient selected from, but not limited to, aqueous and / or non-aqueous solvents, co-solvents, solubilizers, antioxidants, buffers / pH adjusters, chelating agents, preservatives, antimicrobial agents, and tonicity adjusters.

[0030] In one embodiment, the composition comprises a chelating agent. The chelating agent is selected from, but not limited to, disodium EDTA, sodium EDTA, calcium disodium EDTA, versetamide, calteridol calcium, and diethylenetriaminepentaacetic acid. In a preferred embodiment, the chelating agent is disodium EDTA.

[0031] The ratio of stabilizer to chelating agent in the composition is preferably from 40: 1 to 250: 1. In one preferred embodiment, the ratio is from 50: 1 to 160: 1. In another preferred embodiment, the ratio is from 50: 1 to 150: 1.

[0032] In yet another embodiment, the composition comprises an isotonic agent. In a preferred embodiment, the isotonic agent is sodium chloride. The ratio of stabilizer to isotonic agent in the composition is preferably 2.5:1 to 14.29:1. In a preferred embodiment, the ratio is 2.94:1 to 9.38:1. In another preferred embodiment, the ratio is 3.68:1 to 9.38:1.

[0033] In another preferred embodiment, the composition further comprises a preservative. The preservative is selected from, but not limited to, benzethonium chloride, benzyl alcohol, benzalkonium chloride, chlorobutanol, m-cresol, methylparaben, propylparaben, and phenol. In a preferred embodiment, the preservative is benzethonium chloride. The amount of the preservative in the composition is 0.1 mg / ml.

[0034] In a preferred embodiment, the present invention provides a composition comprising a ketamine salt equivalent to 50 mg / ml of ketamine base, a stabilizer, a chelating agent, and an isotonic agent. In one embodiment, the composition comprises 4-20 mg / ml of stabilizer, 0.05 mg / ml-0.2 mg / ml of chelating agent, and 1.2-2 mg / ml of isotonic agent. In another embodiment, the stabilizer is selected from povidone K12 and / or povidone K30, the chelating agent is disodium edetate, and the isotonic agent is sodium chloride. In another embodiment, the composition further comprises 0.10 mg / ml of benzethonium chloride.

[0035] In a preferred embodiment, the present invention provides an aqueous injectable composition comprising a ketamine salt equivalent to 50 mg / ml ketamine base, 15 mg / ml povidone K12, 0.10 mg / ml disodium edetate, 1.6 mg / ml sodium chloride, and 0.10 mg / ml benzethonium chloride.

[0036] In another embodiment, the compositions of the present invention are eliminated at a slower rate than currently marketed injectable compositions of ketamine.

[0037] In yet another embodiment, the compositions of the present invention are administered by intramuscular and intravenous routes.

[0038] In another embodiment, the present invention provides for the use of a composition comprising a ketamine salt equivalent to 50 mg / ml ketamine base, a stabilizer, and at least one pharmaceutically acceptable excipient for treatment-resistant depression and pain management.

[0039] In yet another embodiment, the present invention provides a method of treating refractory depression and managing pain, wherein the method comprises administering the composition of any of the preceding claims.

[0040] In yet another embodiment, the composition provided herein is a subcutaneous injectable composition. The composition is provided in a package size of 50 mg ketamine base / ml. The package size is equivalent to package sizes such as 30 mg ketamine base in 0.6 ml, 35 mg ketamine base in 0.7 ml, and 40 mg ketamine base in 0.8 ml.

[0041] Compared to currently marketed compositions, the compositions of the present invention exhibit a smaller or lower Cmax, which indicates that the compositions of the present invention have a smaller risk of concentration-dependent side effects.

[0042] In one embodiment, the composition exhibited a mean Cmax of 454.911 ng / mL, which is well above the concentration required for therapeutic efficacy in patients with depression (0.5 mg / kg; 40 min infusion; 185 ng / ml).

[0043] In another embodiment, the present invention provides a method for preparing a composition as claimed in any preceding claim, wherein the method comprises obtaining a solution of a chelating agent, a stabilizer, an isotonic agent, an optional preservative, and a ketamine salt in water having a dissolved oxygen content of 0.5 mg / ml; and adjusting the pH of the solution to 3.0 to 5.5, preferably 3 to 5.

[0044] In yet another embodiment, the Cmax of the composition is 80% to 100% of the Cmax of a commercially available injectable composition for subcutaneous use, and the AUC 0-t It is 80%-100% of the commercially available injectable composition, wherein the Tmax is 100%±10% of the Tmax of the currently commercially available injectable composition. DETAILED DESCRIPTION

[0045] The present invention relates to a subcutaneously injectable pharmaceutical composition comprising ketamine or a salt thereof (e.g., hydrochloride), a stabilizer, and at least one pharmaceutically acceptable excipient. The compositions of the present invention exhibit blood levels after administration such that the compositions of the present invention do not exhibit at least one undesirable effect. The pharmacokinetic properties of the compositions of the present invention are surprising. The compositions of the present invention were found to have a similar Tmax but a lower Cmax compared to conventional ketamine (50 mg / ml) injectable compositions. However, the AUC of the compositions of the present invention was comparable to the AUC of currently commercially available ketamine injectable compositions.

[0046] By definition, in the present invention, (a) Cmax means the maximum concentration of a drug in the blood after administration, (b) Tmax means the time required for the drug to reach its maximum concentration (Cmax) after administration, and (c) AUC means area under the curve, which means the area under the curve of the blood / plasma concentration of the drug over time after administration. It represents the total drug exposure over time. If the mean bioavailability of the test composition is within (80% to 125%) of the mean bioavailability of the reference composition with a certain degree of confidence, or if the estimated 90% confidence interval of the ratio of the geometric means of the main PK parameters (AUC and Cmax) is completely within the bioequivalence limits of 80% to 125%, then the two compositions are considered bioequivalent.

[0047] λz / terminal elimination rate constant - it describes drug The rate of elimination from the system / body. It is equivalent to the proportion of a substance eliminated per unit time measured at any particular moment. In Example 7, the value for the test formulation was 0.4 compared to 0.5 for the reference formulation, indicating that the test composition was eliminated at a slower rate than the reference formulation, and therefore the test formulation remained in the body for a longer duration.

[0048] MRT INF_obs: (Mean Observed Residence Time) - MRT obs represents the average time a molecule resides in the body. In Example 7, the test composition has a value of 2, while the reference formulation has a value of 1.9, indicating that the test compound resides in the body longer than the reference formulation.

[0049] Mrt Last - MRT represents the average time a molecule stays in the body when observed for 24 hours. In Example 7, the value of the test composition was 2.1, while the value of the reference composition was 2.0, indicating that the test composition stayed in the body longer than the reference composition.

[0050] VSS obs is the apparent volume of distribution at steady state. The volume of distribution (Vd) is a pharmacokinetic parameter that represents the tendency of an individual drug to remain in the plasma or to redistribute to other tissue compartments. Drugs with high Vd tend to leave the plasma and enter the extravascular compartments of the body. Conversely, drugs with low Vd tend to remain in the plasma. Example 7 shows that the test formulation (Vss -0.0018) has more distribution in the body compartments than the reference formulation (Vss -0.0014).

[0051] AUC_%Extrap obs-AUC 0-inf : Area under the concentration-time curve from time 0 to infinity (extrapolated from available concentrations).

[0052] AUC 0-t : The area under the quantifiable concentration-time curve from time 0 to the time of the last quantifiable concentration (here 24 hours).

[0053] The present invention provides a transparent, stable subcutaneous injectable composition comprising ketamine or a salt thereof in an amount equivalent to up to 50 mg / ml ketamine base and a stabilizer and at least one pharmaceutically acceptable excipient selected from, but not limited to, aqueous and / or non-aqueous solvents, co-solvents, solubilizers, antioxidants, buffers / pH adjusters, chelating agents, complexing agents, preservatives, antimicrobial agents, and tonicity adjusters.

[0054] Surprisingly, certain carefully selected pharmaceutically acceptable ingredients can result in compositions exhibiting a reduced Cmax, similar or different Tmax, and similar AUC, thereby eliminating at least one undesirable effect of currently marketed injectable formulations when stabilizers are present with ketamine, without compromising efficacy. These substances, or pharmaceutically acceptable ingredients, are referred to as stabilizers and are essential to the compositions of the present invention and cause beneficial changes in ketamine blood levels when the compositions of the present invention are injected. Incorporation of these substances enables the compositions of the present invention to exhibit an AUC similar to that of currently available compositions, but without exhibiting at least one of the undesirable effects or side effects, because the compositions of the present invention have a lower Cmax and a similar Tmax. This surprising property of the compositions of the present invention enables them to be used by patients and, if permitted by local law, reduces the reliance on strict physician use. It also enables the fullest medicinal potential of the ketamine molecule to be utilized. Various grades of polyethylene glycol, such as PEG 300, PEG 400, or various pharmaceutically acceptable oils, can also be used as stabilizers. The present invention is exemplified using PVPK as a stabilizer. PVPK, or povidone K or polyvinylpyrrolidone (PVP) potassium, commonly known as povidone, is a water-soluble polymer prepared from the monomer N-vinylpyrrolidone. PVPK is available in a range of molecular weights and relevant viscosities. Various grades of PVPK can be used to perform the present invention, and the present invention utilizes PVPK-12 and PVPK30 grades for illustration. Diethylene glycol monoethyl ether or its alkyl derivatives, polyethylene glycol (PEG), and sodium CMC can also be used as stabilizers. The most critical ratio governing the compositions of the present invention is the ketamine:stabilizer ratio. A ketamine:stabilizer ratio of 12.5:1 to 2.5:1, more preferably 10:1 to 3.33:1, and most preferably 7.14:1 to 3.33:1, is necessary to prepare compositions of the present invention in which, despite a lower Cmax, the AUC is similar.

[0055] One such exemplary subcutaneous injectable composition comprising ketamine and a stabilizer having a batch size of 3 liters is described below. For simplicity, the amounts of the ingredients are expressed as mg / ml and the method for preparing it is described:

[0056]

[0057] The amount of ketamine was calculated based on the assay and LOD.

[0058] The method for preparing the composition of the present invention is described as follows:

[0059] 1. Check the weight of all ingredients according to the ingredient list and calculation sheet. Check the material status on the label.

[0060] 2. Confirm SS production cans with in-process labels.

[0061] 3. Collect approximately 4 L of WFI from the recirculation line in the jacketed production tank. Start continuous stirring and perform nitrogen sparging / bubbling and blanketing. Check the dissolved oxygen (DO) content of the WFI using a calibrated dissolved oxygen (DO) meter (DO should be no greater than 0.5 mg / L). After checking the DO, transfer 2 L of WFI from the jacketed production tank to a separate SS container and start nitrogen sparging / bubbling. Set aside for volume adjustment. Cool the WFI in the jacketed production tank and SS container to 50°C to 60°C.

[0062] 4. Add and dissolve the assigned amount of disodium EDTA (chelating agent), followed by the addition and dissolution of povidone K12 (stabilizer) in the jacketed production tank. Rinse the disodium EDTA container twice with water for injection from the SS container and add it to the jacketed production tank. This is the chelating agent solution.

[0063] 5. Add and dissolve the assigned amount of sodium chloride (isotonic agent) in the above jacketed production tank. Rinse the container with water for injection and add it in the jacketed production tank under stirring and nitrogen bubbling / sparging and cover by stirring for 10-15 minutes to prepare an isotonic solution.

[0064] 6. Add and dissolve the assigned amount of benzethonium chloride (preservative) in the jacketed production tank. Rinse the container with water for injection and add it to the jacketed production tank under stirring and nitrogen bubbling / sparging, and cover with stirring until a clear solution is obtained. This is the preservative solution. This step is optional and is not applicable in the case of compositions that do not use a preservative.

[0065] 7. Cool the above isotonic solution obtained in step 5 or the antiseptic solution obtained in step 6 to room temperature by applying cold water and nitrogen purge in the jacket. Check the temperature of the solution. This is the cooled solution.

[0066] 8. In a jacketed production tank, add and dissolve the assigned amount of ketamine hydrochloride in the cooled solution obtained in step 7, while stirring and purging with nitrogen. Rinse the container with water for injection and add it to the jacketed production tank under stirring and nitrogen bubbling / sparging, and cover with stirring to obtain a clear solution. This is the ketamine solution and check the clarity of the solution.

[0067] 9. Make up the volume of the ketamine solution obtained in step 8 to approximately 2.5 L with water for injection. Stir the solution under nitrogen sparging / bubbling for 10 minutes and cover. Check the pH of the solution in the jacketed production tank. Limit the pH to 3.0 to 5.0. This is the pH test solution.

[0068] 10. Make up the final volume of the pH test solution obtained in step 9 to 3 liters with the remaining amount of water for injection from the SS container to prepare an unfiltered solution. Finally, stir the unfiltered solution for 30 minutes under nitrogen bubbling / sparging and blanketing. This is the bulk solution.

[0069] 11. Collect samples of the bulk solution into glass bottles and send them to the Quality Control Department with an in-process testing request for bulk analysis.

[0070] 12. Close all openings of the jacketed production tank and blanket the production tank with nitrogen bubbling and complete filtration.

[0071] The composition is sterilized by filtration through a 0.22μ filter. The solvent in the present invention is water for injection. Other aqueous or non-aqueous solvents such as diethylene glycol monoethyl ether (Transcutol) or its alkyl derivatives or various grades of tetrahydrofuran glycol ether (Glycofurol) can be used in appropriate amounts. Commonly used solvents such as water and ethanol can be used to carry out the present invention. Various types of alcohols can be used as solvents and / or solubilizers. Alcohols selected from monohydric alcohols or polyhydric alcohols can be used. Alcohols other than monohydric alcohols are interpreted as polyhydric alcohols. An example of a monohydric alcohol is any pharmaceutically acceptable single-chain or branched alcohol having only one OH group. Suitable examples are ethanol or benzyl alcohol. Glycerol is an example of a polyhydric alcohol. Many other polyhydric alcohols exist. Polyethylene glycol or some ether derivatives can be used as good solubilizers.

[0072] The terms solvent, cosolvent, or solubilizer are used interchangeably. These can be solid or liquid. When a solid is present in solution in an appropriate solvent, the solid also acts as a solubilizer. The ketamine salts used in the present invention and the other ingredients used in the present invention are water-soluble.

[0073] The solubilizing agent can be selected from, but is not limited to, 2% to 50% diethylene glycol monoethyl ether (Transcutol), up to 50% PEG300, up to 20.30% PEG 400, polysorbate or Tween (e.g., Tween 80). It can also comprise a suitable vegetable oil as a solvent. Alcohol (e.g., ethanol) is a good solubilizing agent. Diethylene glycol monoethyl ether or its alkyl derivatives at a concentration within the range of 0.2%-5% (v / v) are used as solubilizing agents and stabilizers, either alone or in combination with other stabilizers.

[0074] The present invention provides a therapeutically effective amount of ketamine or a salt (eg, hydrochloride) in an aqueous composition suitable for administration by the subcutaneous route.

[0075] The composition of the present invention is a ready-to-use composition of ketamine or its salt for use in managing pain and treating refractory depression.

[0076] In particular, the present invention provides a simple and economical composition comprising ketamine or a salt thereof (e.g., its hydrochloride) equivalent to 50 mg / ml ketamine base, suitable for subcutaneous administration, which is bioequivalent to conventionally available injectable compositions comprising 50 mg / ml ketamine base.

[0077] The composition of the present invention exhibits a viscosity of 1.0 cps to 3.0 cps.

[0078] Various grades of polyglycol ether (eg up to 5% polyglycol ether (Glycofurol 75)) can be used as solvents or co-solvents or solubilizers. Tween (eg Tween 80) is used as a surfactant or solubilizer.

[0079] The present invention optionally uses an antioxidant selected from, but not limited to, monothioglycerol, acetylcysteine, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), ascorbyl ester (salt), ascorbyl palmitate, methylparaben, propylparaben, thimerosal and mixed tocopherol components. In addition, the present invention can also include additional excipients, for example preservatives, such as benzalkonium chloride, benzyl alcohol, metacresol, parabens, phenol, thimerosal. In another embodiment, the composition of the present invention can also include stabilizers, for example polysorbate 80, 1-cysteine, diethanolamine, 1-methionine, sodium gluconate, sodium thioglycolate, triethanolamine and oleic acid. These will be incorporated to the guidelines known to those skilled in the art allowing them to be incorporated in quantity and applicable specifications.

[0080] The isotonicity of compositions is obtained by adding an isotonic agent or a tension regulator of accurately calculated amount, the isotonic agent or tension regulator being selected from sodium chloride, anhydrous dextrose, glycerol, glucose, mannitol, sorbitol, potassium chloride or calcium chloride. Most preferably, the isotonic agent is sodium chloride. The ratio of stabilizer to isotonic agent is 2.5: 1 to 14.29: 1, preferably 2.94: 1 to 9.38: 1, more preferably 3.68: 1 to 9.38: 1. Compositions of the present invention have an osmotic pressure concentration (osmolality) of approximately less than 100mOsm / kg to approximately 800mOsm / kg. It is desirable and obtainable that solution isotonicity (isotony) or isotonic pressure (isotonicity) be 100mOsm / kg to 400mOsm / kg. The techniques and methods for regulating isotonic pressure or osmotic pressure are known in the art, and therefore should regulate isotonic pressure.

[0081] The compositions of the present invention include a chelating agent. Chelating agents that can be used in the formulation to chelate trace amounts of metal impurities can be selected from, but are not limited to, disodium EDTA, sodium EDTA, 0.2% calcium disodium EDTA, 2.54% versetamide, 0.023% calcium calteridol, diethylenetriamine pentaacetic acid, and similar ingredients. In one embodiment, the ratio of stabilizer to chelating agent in the composition is 40:1 to 250:1, preferably 50:1 to 160:1, and more preferably 50:1 to 150:1. The ratio of stabilizer to chelating agent is crucial to the composition.

[0082] In some embodiments, the composition comprises an antimicrobial preservative. In other embodiments, the composition does not have any preservative. When present, the preservative is selected from, but not limited to, 0.01% benzethonium chloride, up to 2% benzyl alcohol, 0.02% benzalkonium chloride, 2.5% to 5% tributyl alcohol (chlorobutanol), 0.1% to 0.3% metacresol, up to 1% paraben (e.g., methyl paraben, propyl paraben), up to 0.45% phenol. Some more excipients such as 2-phenoxyethanol, phenylmercuric nitrate, thimerosal and excipients, etc., or their mixtures. Benzyl alcohol also serves as a solvent. In a preferred embodiment, the preservative used is benzethonium chloride.

[0083] Suitable surfactants (eg, polysorbate / Tween, sorbitan monolaurate, lecithin, povidone or other pharmaceutically acceptable surfactants) can be used alone or in combination to prepare the compositions of the present invention.

[0084] A pH close to physiological pH is recommended to minimize pain, irritation, and tissue damage. Buffers optimize solubility and stability by adjusting pH.

[0085] Examples of pH adjusters or buffers that can be used include, but are not limited to, sodium, potassium, or ammonium salts of weak acids, tris(hydroxymethyl)-aminomethane, or sodium citrate, sodium phosphate, sodium hydroxide, Tris base-65, Tris acetate, Tris HCl-65, or commonly known acetates, citrates, phosphates, or other physiologically active materials that act as buffers, such as sodium hydroxide, hydrochloric acid, boric acid, citric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof. The stable aqueous injectable solution can contain one or more pH adjusters in an amount sufficient to provide a solution pH of about 3 to about 5.5, preferably 3 to 5, during storage.

[0086] Composition is filled, sealed, packaged and is provided in the suitable container of being made (preferably being made by single compartment) by glass or plastics, and described compartment can be made up of low-density polyethylene (LDPE), high-density polyethylene (HDPE), polypropylene (PP) or the mixture of polyethylene and polypropylene.The glass material preferably used is USPI type glass (borosilicate glass) and II type glass.In another embodiment, described composition can be provided with the volume of single compartment less than 1ml or promptly with injection, and it can be diluted according to physiological use.The container that is used to hold composition of the present invention can be plugged by rubber stopper, closure or disc seal, nut or cap-plug combination seal.

[0087] The composition is subjected to a sterilization process to obtain a sterile composition. The formulation is prepared and filled into articles of manufacture and terminally sterilized by electron beam radiation (e.g., gamma radiation, natural light, microwave heat, moist heat sterilization, dry heat sterilization). Autoclave sterilization can preferably be performed after final packaging. A typical cycle for the autoclave to achieve sterilization of the final product is 121° C. for 15 minutes.

[0088] The composition may be autoclaved at a temperature of 110 to 130° C., preferably 115 to 125° C., for a period of 5 to 30 minutes, preferably 10 to 20 minutes. More preferably, the autoclaving is performed at 120 to 122° C. for 15 minutes.

[0089] The sterilized compositions are stored under different stability conditions according to the stability guidelines. The compositions provide the precise dosage of activity.

[0090] In another embodiment, the composition has a pH of 3.00 to 5.00 and a viscosity of 1.0 cps to 3.0 cps.

[0091] The injectable composition of the present invention exhibits a similar AUC to currently available commercial ketamine injectable compositions, although Cmax is lower and Tmax is more or less similar. Despite the similar AUC, the undesirable effects associated with currently available commercial ketamine injectable compositions are unrelated to the composition of the present invention. The composition does not induce the ketamine spikes seen with conventional compositions and is therefore safe and effective. The composition of the present invention is suitable for administration via the subcutaneous route.

[0092] The most critical ratio to control in the composition of the present invention is the ratio of ketamine:stabilizer. The ratio of ketamine:stabilizer is 12.5:1 to 2.5:1, more preferably 10:1 to 3.33:1, and most preferably 7.14:1 to 3.33:1.

[0093] It is more preferable to maintain the ratio of stabilizer to isotonic agent at 2.5:1 to 14.29:1, more preferably at 2.94:1 to 9.38:1, and most preferably at 3.68:1 to 9.38:1.

[0094] It is more preferable to maintain a stabilizer to chelating agent ratio of 40:1 to 250:1, more preferably 50:1 to 160:1, and most preferably 50:1 to 150:1.

[0095] Thus, provided are subcutaneous injectable compositions comprising ketamine equivalent to 50 mg / ml ketamine base and a stabilizer, which exhibit a lower Cmax than currently marketed compositions, indicating that the compositions of the present invention have a lower risk of concentration-dependent side effects.

[0096] Thus, provided are subcutaneous injectable compositions comprising ketamine equivalent to 50 mg / ml ketamine base and a stabilizer, which exhibit a mean Cmax of 454.911 ng / mL, which is well above the concentration required for therapeutic efficacy in patients with depression.

[0097] Thus, provided are subcutaneous injectable compositions comprising ketamine equivalent to 50 mg / ml ketamine base and a stabilizer, which exhibit the same Tmax as currently marketed formulations, meaning that the efficacy of onset is not impaired or delayed, but rather similar to that of the marketed composition.

[0098] Clear solution and immediate-release injectable compositions are considered bioequivalent unless they contain ingredients that affect the release of the active substance and, therefore, bioavailability. The addition of ingredients not present in conventional injectable compositions is highly likely to alter the release of ketamine and, therefore, bioavailability, rendering them no longer bioequivalent. The compositions of the present invention contain stabilizers (ingredients, i.e., PVPK or PEG) and other ingredients listed previously herein that have the potential to render the compositions non-bioequivalent. The present invention also relates to specific amounts of stabilizers that ensure that the compositions of the present invention are bioequivalent without the side effects associated with conventional injectable compositions, as they surprisingly reduce Cmax, do not affect Tmax, and surprisingly maintain a similar AUC.

[0099] It can be noted that the Cmax and AUC of the composition of the present invention (ie the test composition) fall within the 80%-125% norm of the reference composition. Therefore, the composition of the present invention is bioequivalent to the currently marketed composition.

[0100] The above and other objects, features, and advantages of the present invention will now be described in detail with reference to certain exemplary embodiments thereof as illustrated in the accompanying examples, but without limitation thereto. While the present invention will be described in conjunction with the exemplary embodiments, it will be understood that this description is not intended to limit the invention to those exemplary embodiments. On the contrary, the present invention is intended to encompass not only the exemplary embodiments, but also various alternatives, modifications, equivalents, and other embodiments that may be included within the spirit and scope of the present invention as defined by the appended claims. Thus, compositions in which additional active ingredients are present, as well as the claimed % of ketamine and / or ketamine:stabilizer ratios, fall within the scope of the present invention.

[0101] Although the present invention has been described through some specific aspects, based on the teachings and disclosure of the present invention, modifications and equivalents of these specific aspects that are obvious to those skilled in the art should be considered to be included in the scope of protection of the present invention.

[0102] Example:

[0103] Example 1: Ketamine subcutaneous composition For Trials A and G, a batch size of 3 liters was prepared and quantities are expressed in mg / ml.

[0104]

[0105] Example 2: Procedure for preparing the composition of Example 1.

[0106] 1. Check the weight of all ingredients according to the ingredient list and calculation sheet. Check the material status on the label.

[0107] 2. Confirm SS production cans with in-process labels.

[0108] 3. Collect approximately 4 liters of WFI from the recirculation line in the jacketed production tank. Start continuous stirring and perform nitrogen sparging / bubbling and blanketing. Check the dissolved oxygen content of the WFI using a calibrated DO (dissolved oxygen) meter (DO should be no greater than 0.5 mg / L). After checking the DO, transfer 2 liters of WFI from the jacketed production tank to a separate stainless steel (SS) container and start nitrogen sparging / bubbling. Set aside for volume adjustment. Cool the WFI in the jacketed production tank and SS container to 50°C to 60°C.

[0109] 4. Add and dissolve the allotted amount of EDTA disodium followed by Povidone K12 in the jacketed production tank. Rinse the EDTA disodium container twice with water for injection from the SS container and add this to the jacketed production tank. This is the chelating agent solution.

[0110] 5. Add and dissolve the assigned amount of sodium chloride in the above jacketed production tank. Rinse the container with water for injection and add it in the jacketed production tank under stirring and nitrogen bubbling / sparging and cover by stirring for 10-15 minutes to prepare an isotonic solution.

[0111] 6. Add and dissolve the assigned amount of benzethonium chloride (in the case of Test A) in the jacketed production tank. Rinse the container with water for injection and add it to the jacketed production tank under stirring and nitrogen bubbling / sparging, and cover with stirring until a clear solution is obtained. This is the preservative solution. This step is optional and is not applicable in the case of compositions that do not use a preservative (such as Test G).

[0112] 7. The isotonic solution obtained in step 5 or the antiseptic solution obtained in step 6 is cooled to room temperature by applying cold water and nitrogen purge in the jacket to reduce the temperature to 40-45°C. This is the cooled solution.

[0113] 8. In a jacketed production tank, add and dissolve the assigned amount of ketamine hydrochloride in the cooled solution obtained in step 7, stirring continuously and purging with nitrogen. Rinse the container with water for injection and add it to the jacketed production tank under stirring and nitrogen bubbling / sparging, and cover with stirring until a clear solution is obtained. This is the ketamine solution and check the clarity of the solution.

[0114] 9. Make up the volume of the ketamine solution obtained in step 8 to approximately 2.5 L with water for injection and stir for 10 minutes under nitrogen bubbling / sparging and blanketing, and check the pH of the solution. Limit the pH to 3.0 to 5.0. This is the pH test solution.

[0115] 10. Make the final volume of the pH test solution obtained in step 9 up to 3 L using the remaining amount of water for injection from the SS container to prepare an unfiltered solution. Stir the unfiltered solution for 30 minutes under nitrogen bubbling / sparging and blanketing. This is the bulk solution.

[0116] 11. Collect a sample of the bulk solution obtained in step 10 into a glass bottle and send it for bulk analysis.

[0117] 12. Close all openings of the jacketed production tank and blanket the production tank with nitrogen bubbling until filtration is complete.

[0118] 13. Filter to sterilize the composition by filtration through a 0.22 mu filter to prepare a filtered or sterilized solution.

[0119] 14. Aseptically fill and seal the filtered or sterilized solution into ampoules and vials and conduct stability studies.

[0120] Example 3: Compositions with varying stable doses. The amount of each ingredient is expressed as (mg / mL)

[0121]

[0122] Example 4: Analysis and determination of ketamine compositions The analysis method described in IP-2022, volume II, pages 2667-2668 was followed.

[0123] Example 5: Example 1 Composition G - 6 Month Stability at 25°C ± 2°C / 60% ± 5% RH

[0124]

[0125] Example 6: Example 1 Composition G: 6-month stability at 40°C ± 2°C / 75% ± 5% RH

[0126]

[0127]

[0128] Example 7: Pharmacokinetic parameters of ketamine test product and reference commercial formulation (mean ± SD)

[0129] test Reference <![CDATA[C max ]]> 454.9 554.5 <![CDATA[AUC 0-t ]]> 693.0 847.0829846 <![CDATA[AUC 0-inf _obs]]> 699.6813577 851.9259781 AUC_%Extrap obs 6.7 4.843 Lambda_z 0.4 0.5 MRTINF_obs 2 1.9 MRT last 2.1 2 Tlast 24 24 <![CDATA[T max ]]> 0.5 0.5 Vss_obs 0.0018 0.0014

[0130] It can be noted that the Cmax of the test composition is 82.04% of the Cmax of the reference product.

[0131] The Tmax of the test composition and the reference composition were the same. 0-t The Lambda_z value of the test composition was 0.4, compared to 0.5 for the reference composition, indicating that the test composition was eliminated at a slower rate than the reference composition and therefore the test composition remained in the body for a longer duration. The MRTINF_obs value of the test composition was 2, while the MRTINF_obs value of the reference composition was 1.9, indicating that the test composition remained in the body for a longer time than the reference composition. For the test composition, the value of the last MRT was 2.1, while that of the reference composition was 2.0, indicating that the test composition remained in the body for a longer time than the reference composition. The value of Vss_obs indicated that the test composition (Vss-0.0018) had more distribution in the body compartments than the reference composition (Vss-0.0014). Tlast (time of last observed concentration) indicates the concentration of the analyte at 24 hours (the last time point of blood collection).

[0132] Example 8: Compositions containing PEG-400, PVP K-30, and PVP K-12: Compositions containing PEG-400, PVP K-30, and PVP K-12 were prepared using the method of Example 2. In one composition, PEG-400 was incorporated at 0.2 ml / ml of the composition. In another composition, PVP K-30 was incorporated at 5.9 mg / ml of the composition. In yet another composition, PVP K-12 was incorporated at 10 mg / mL. All other ingredients remained the same. The formulations were found to be stable.

[0133] Example 9: Study of blood concentration of ketamine in rats.

[0134] Figure 1 A graph is provided of blood concentrations of ketamine from the test composition and the reference composition (in nanograms (ng) / ml) on the Y-axis versus time (in hours) on the X-axis.

[0135] 24 rats (12 males and 12 females) were randomly assigned to 2 different groups G1 and G2 based on body weight, with 6 animals per sex in each group.After randomization, the selected animals were identified by the animal number written on the tail.

[0136] For Groups G1 and G2, a dosage formulation was prepared to achieve a concentration of 3.1 mg / ml. For example, 1 ml of the composition of the present invention was diluted with 16 ml of normal saline to obtain a concentration of 3.1 mg / ml. The composition of the present invention required for a 200 g rat (3.1 mg / kg dose) was 0.62 mg (3.1*200 / 1000=0.62 mg). To administer 0.62 mg of the composition of the present invention at a concentration of 3.1 mg / ml, a dosage volume of 0.2 ml was required to be administered to the rat. The most commonly used dose in humans is 0.5 mg / kg. The conversion factor for rats is 6.17. Therefore, the rat equivalent dose is 3.1 mg / kg.

[0137] Animals in G1 were administered the composition of the present invention, and animals in G2 were administered Ketamine 50 injection, a commercially available formulation manufactured by Themis Medicare Ltd, at 3.1 mg / kg body weight via subcutaneous route.

[0138] Blood was collected from the retro-orbital sinuses. Ketamine is a dissociative anesthetic, so initial blood collection was performed without any anesthetic, and isoflurane was used at subsequent blood collection time points. Approximately 0.2 ml to 0.3 ml of blood was collected at each time point in a vial containing 1% EDTA as an anticoagulant, and plasma was subsequently separated for analysis. The separated plasma was transferred to pre-labeled polypropylene tubes and stored at -80°C until transferred to the analytical laboratory for bioanalysis using standard procedures.

[0139] The peak plasma concentrations (Cmax) of the test and reference were found to be 454.911 ng / mL and 554.509 ng / mL at 0.50 hours and 0.50 (Tmax) hours, respectively. Figure 1 ]. It was found that the time to reach Cmax for the test and reference was similar, indicating that both test formulations exhibited similar release and absorption profiles. The plasma concentrations observed at 24 hours (C-24 hours) were 0.000 ng / mL and 0.000 ng / mL in the test and reference, respectively.

[0140] The AUC was determined to understand the total exposure to ketamine concentration that will remain in the blood, which will determine the dose of the compound. In this study, the AUC of the test and reference formulations were 0-t They were 692.979 ng / mL and 847.083 ng / mL respectively.

[0141] Example 10: The composition of the present invention was compared with the currently commercially available Ketamine 50 Injection 5 ml vial (manufactured by Themis Medical Co., Ltd. (common name: Ketamine Hydrochloride Injection IP 50 mg / ml)) in a behavioral test.

[0142] A study was conducted to evaluate the effects of the compositions of the present invention on the behavior of Sprague Dawley rats when compared to a commercial formulation of Ketamine 50 Injection when administered by the subcutaneous route.

[0143] The animals were divided into three groups, each consisting of 6 animals. Group G1 served as the control group and was administered with normal saline. The animals in group G2 were administered with the composition of the present invention, and group G3 was administered with a commercially available formulation, administered subcutaneously in increasing amounts on three different days at three doses (i.e., 1.5 mg / kg, 3 mg / kg, and 6 mg / kg).

[0144] The dose volume should not exceed 1 mL / kg. The actual volume administered should be calculated based on the most recent body weight of each animal.

[0145] Animals are evaluated on open field tests, learning and memory tests (eg, Y-maze test), and a functional observation battery test.

[0146] Open field test:

[0147] 1) At 1.5 mg / kg, the number of rearings decreased in the G2 group, but the decrease was greater in the G3 group. This suggests that the composition of the present invention has a smaller inhibitory effect on locomotion and movements, and is superior to currently commercially available formulations in terms of deterioration of locomotor activity in rats at a dose of 1.5 mg / kg.

[0148] Urination: The G3 group had a slightly higher frequency of urination than the G2 group. This suggests that the G2 animals may have better muscle control than the G3 animals. Therefore, at 1.5 mg / kg, the composition of the present invention has fewer side effects or none of the effects found in commercially available compositions.

[0149] 2) At 3 mg / kg, the incidence of ataxic gait (muscle coordination failure) in both males and females in the G3 group was higher than in the G2 group. This means that at a dose of 3 mg / kg, the composition of the present invention group (i.e., G2) caused less muscle coordination disturbance than the commercially available formulation (i.e., G3).

[0150] 3) At 6 mg / kg, the number of standing up times of animals in group G3 decreased more than that of animals in group G2, which means that at a dose of 6 mg / kg, the composition of the present invention group (i.e., G2) caused less disturbance in muscle coordination than the commercially available formulation (i.e., G3).

[0151] At 3 mg / kg and 6 mg / kg, G2 animals had better muscle control than animals in G3, which means that the composition of the present invention can achieve better muscle coordination and control than the commercially available composition.

[0152] Learning and memory tests:

[0153] At 1.5 mg / kg, G2 males showed better spatial reference memory (SRM) than G3. In the G3 group, it decreased significantly. At 3 mg / kg, G2 males showed an increase in same-arm return (%SAR).

[0154] Regarding spatial reference memory (SRM test), the composition of the present invention caused less deterioration of spatial memory compared to low (1.5 mg / kg) and medium (3 mg / kg) doses of the currently marketed formulation.

[0155] Function observation combination:

[0156] At the 1.5 mg / kg dose, there was a significant difference in the paw spacing between animals treated with the commercial formulation of ketamine and animals treated with the composition of the invention, indicating an inability to properly recover the hind paw.

[0157] At 3.0 mg / kg, the incidence of recovery reflex in the G2 group was higher than that in the G3 group.

[0158] At 6.0 mg / kg, G2 and G3 were comparable to controls.

[0159] This suggests that the composition of the present invention has less effect on muscle coordination and balance than lower doses of commercially available ketamine formulations. This also means that the composition of the present invention at a dose of 1.5 mg / kg has less potential for neurotoxicity than commercially available ketamine formulations.

[0160] Summary and Conclusion:

[0161] This indicates that the composition of the present invention is superior to the currently available injectable formulation of ketamine in terms of less deterioration in the following properties:

[0162] 1. Locomotor activity at low doses.

[0163] 2. Spatial Reference Memory (SRM) at Low and Medium Doses

[0164] 3. Muscle coordination and balance at low doses.

[0165] definition:

[0166] Spatial reference memory (SRM) represents long-term memory responsible for spatial recognition (space-related). Spontaneous alteration performance (SAP) indicates retrograde working memory and cognitive function. Same-arm return (SAR) ratio assesses aspects of attentional dysfunction in active working memory performance in the Y-maze.

[0167] SAP indicates that the animal has a good working memory, will remember which arms of the maze it has already visited, and will show a tendency to enter arms that have been visited less recently.

[0168] SRM indicates that spatial reference memory is intact and the animal enters the novel arm and spends more time in the novel arm than in the other arms of the maze. Animals with impaired spatial reference memory will not be able to recognize the novel arm.

Claims

1. A composition comprising a ketamine salt equivalent to 50 mg / ml ketamine base, a stabilizer, and at least one pharmaceutically acceptable excipient; wherein the composition exhibits a lower Cmax than a conventional ketamine injectable composition, but exhibits a similar Tmax and a similar AUC.

2. The composition of claim 1, wherein the composition comprises ketamine and a stabilizer in a ratio of 12:1 to 2:

1.

3. The composition of claim 1, wherein the composition comprises ketamine and a stabilizer in a ratio of 10:1 to 3:

1.

4. The composition of claim 1, wherein the composition comprises ketamine and a stabilizer in a ratio of 7:1 to 3:

1.

5. The composition of claim 1, wherein the stabilizer is selected from potassium pyrrolidone (PVPK), diethylene glycol monoethyl ether or its alkyl derivatives, polyethylene glycol (PEG), sodium carboxymethyl cellulose.

6. The composition of claim 1, wherein the stabilizer is potassium polyvinylpyrrolidone (PVPK), preferably PVPK-12 or PVPK-30.

7. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from aqueous and / or non-aqueous solvents, co-solvents, solubilizers, antioxidants, buffers / pH adjusters, chelating agents, preservatives, antimicrobials and tonicity adjusters.

8. The composition of claim 1, wherein the excipient is a chelating agent selected from the group consisting of disodium EDTA, sodium EDTA, calcium disodium EDTA, veselamide, calcium carteridinol and diethylenetriaminepentaacetic acid, preferably disodium EDTA.

9. The composition of claim 1, wherein the excipient is a preservative selected from the group consisting of benzethonium chloride, benzyl alcohol, benzalkonium chloride, chlorobutanol, m-cresol, methylparaben, propylparaben and phenol, preferably benzethonium chloride.

10. The composition of claim 1, wherein the excipient is an isotonic agent selected from the group consisting of sodium chloride, anhydrous glucose, glycerol, glucose, mannitol, sorbitol, potassium chloride and calcium chloride, preferably sodium chloride.

11. The composition of claim 8, wherein the ratio of stabilizer to chelating agent is from 40:1 to 250:1, preferably from 50:1 to 160:1, and more preferably from 50:1 to 150:

1.

12. The composition of claim 10, wherein the ratio of the stabilizer to the isotonic agent is 2.5:1 to 14.29:1, preferably 2.94:1 to 9.38:1, and more preferably 3.68:1 to 9.38:

1.

13. The composition of claim 9, wherein the preservative is present in an amount of 0.1 mg / ml.

14. A composition according to any preceding claim which is an aqueous subcutaneous injectable composition.

15. The composition of any preceding claim, wherein the composition is administered by intramuscular and intravenous routes.

16. The composition of any preceding claim, wherein the composition is eliminated at a slower rate than currently marketed injectable compositions of ketamine.

17. A composition comprising a ketamine salt equivalent to 50 mg / ml of ketamine base, a stabilizer in an amount of 4-20 mg / ml, a chelating agent in an amount of 0.05 mg / ml-0.2 mg / ml, and an isotonic agent in an amount of 1.2-2 mg / ml.

18. The composition of claim 17, wherein the stabilizer is selected from povidone K12 and povidone K30, the chelating agent is disodium edetate, and the isotonic agent is sodium chloride.

19. The composition of claim 17, wherein the composition further comprises benzethonium chloride in an amount of 0.1 mg / ml.

20. An aqueous injectable composition comprising a ketamine salt equivalent to 50 mg / ml ketamine base, povidone K12 in an amount of 15 mg / ml, disodium edetate in an amount of 0.10 mg / ml, sodium chloride in an amount of 1.6 mg / ml, and benzethonium chloride in an amount of 0.10 mg / ml.

21. The composition of claim 20, wherein the composition exhibits a mean Cmax of 454.91 ng / ml.

22. A composition as claimed in any preceding claim, wherein the composition has a Cmax that is 80-100% of the Cmax of a commercially available injectable composition for subcutaneous use and an AUC0-t that is 80%-100% of the commercially available injectable composition, wherein the Tmax is 100±10% of the Tmax of the currently commercially available injectable composition.

23. A method for preparing a composition as claimed in any preceding claim, wherein the method comprises obtaining a solution of dissolving specific amounts of a chelating agent, a stabilizer, an isotonic agent, an optional preservative, and ketamine or a salt thereof in water having a dissolved oxygen content of 0.5 mg / ml; and adjusting the pH of the solution to between 3.0 and 5.5, preferably between 3 and 5.

24. Use of a composition as claimed in any preceding claim for treatment-resistant depression and management of pain.

25. A method for treating refractory depression and managing pain, wherein the method comprises administering a composition as claimed in any one of the preceding claims.

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