Pharmaceutical formulations of R-ketamine

Abstract

The present disclosure is directed to R-ketamine formulations for subcutaneous administration. In some embodiments, the formulations described herein are optionally substantially free of S-ketamine and its pharma- ceutically acceptable salts. In some embodiments, the formulations described herein include R-ketamine at a concentration of about 90 mg / mL to about 110 mg / mL at a suitable pH.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 319,504, filed March 14, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] R-ketamine has been shown to be active in treating various neurological conditions and relieving corresponding symptoms.To optimize the effect of administration of R-ketamine, the development of new, stable and useful formulations is required.The present disclosure helps to solve the clinical need for administration of R-ketamine using a composition formulated for subcutaneous administration. Summary of the Invention

[0003] In one aspect, the present disclosure is directed to a formulation comprising R-ketamine or a pharma- ceutically acceptable salt thereof for subcutaneous administration.

[0004] In some embodiments, a formulation for subcutaneous administration comprising R-ketamine or a pharma- ceutically acceptable salt thereof is substantially free of S-ketamine and / or a pharma-ceutically acceptable salt thereof.

[0005] In some embodiments, a formulation for subcutaneous administration comprising R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 110 mg / mL.

[0006] In some embodiments, a formulation for subcutaneous administration comprising R-ketamine contains R-ketamine at a concentration of about 95 mg / mL to about 110 mg / mL.

[0007] In some embodiments, a formulation for subcutaneous administration containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 105 mg / mL.

[0008] In some embodiments, a formulation for subcutaneous administration comprising R-ketamine contains R-ketamine at a concentration of about 95 mg / mL to about 105 mg / mL.

[0009] In some embodiments, formulations for subcutaneous administration comprising R-ketamine contain R-ketamine at a concentration of about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, or about 110 mg / mL.

[0010] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is about 6.0 or less.

[0011] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is about 5.8 or less.

[0012] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is about 5.70 to about 5.80.

[0013] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is below a pH of about 5.75.

[0014] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.8.

[0015] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.75.

[0016] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine further comprises a buffer.

[0017] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine further comprises a buffer selected from one or more of a succinate buffer, a tartrate buffer, a maleate buffer, a fumarate buffer, a citrate buffer, and an acetate buffer.

[0018] In some embodiments, the formulation for subcutaneous administration includes a pharma- ceutically acceptable salt of R-ketamine.

[0019] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: a) about 90 mg / mL to about 110 mg / mL of R-ketamine; b) a buffering agent; and The pH of the formulation is below 5.8, and the formulation is substantially free of S-ketamine.

[0020] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.7 or less.

[0021] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.7.

[0022] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.6 or less.

[0023] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.6.

[0024] In some embodiments, the pH of a formulation for subcutaneous administration containing R-ketamine is a pH of about 5.5.

[0025] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffer selected from one or more of a succinate buffer, a tartrate buffer, a maleate buffer, a fumarate buffer, a citrate buffer, and an acetate buffer.

[0026] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffering agent, wherein the buffering agent is a succinate buffer.

[0027] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffering agent, wherein the buffering agent is a tartrate buffer.

[0028] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffering agent, wherein the buffering agent is a maleate buffer.

[0029] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffering agent, wherein the buffering agent is a fumarate buffer.

[0030] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffer, wherein the buffer is a citrate buffer.

[0031] In some embodiments, the formulation for subcutaneous administration comprising R-ketamine comprises a buffering agent, wherein the buffering agent is an acetate buffer.

[0032] In one aspect, the present disclosure is directed to a process for preparing a formulation for subcutaneous administration comprising R-ketamine.

[0033] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a dilute acid.

[0034] In some embodiments, the process for preparing a formulation for subcutaneous administration comprising R-ketamine includes adjusting the pH using an acidic solution having a concentration of less than 1N.

[0035] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a dilute HCl solution.

[0036] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a diluent base.

[0037] In some embodiments, the process for preparing a formulation for subcutaneous administration comprising R-ketamine includes adjusting the pH using a basic solution having a concentration of less than 1N.

[0038] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using either a dilute KOH solution or a dilute NaOH solution.

[0039] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a dilute NaOH solution.

[0040] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a dilute KOH solution.

[0041] In some embodiments, the process for preparing a formulation for subcutaneous administration comprising R-ketamine includes adjusting the pH using a basic solution less than 1N.

[0042] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using either a KOH solution at a concentration of 1 N or less or a NaOH solution at a concentration of 1 N or less.

[0043] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 1 N NaOH solution.

[0044] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 1 N KOH solution.

[0045] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 0.5 N NaOH solution.

[0046] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 0.5 N KOH solution.

[0047] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 0.15 N NaOH solution.

[0048] In some embodiments, the process for preparing a formulation containing R-ketamine for subcutaneous administration includes adjusting the pH using a 0.15 N KOH solution.

[0049] In some embodiments, the process discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitates an increase in the solubility of R-ketamine. In some embodiments, the pH is adjusted slowly. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base. In some embodiments, the pH is adjusted in such a manner as to minimize local variations in pH. In some embodiments, the pH is adjusted to minimize minute changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base, which minimizes minute changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base, which minimizes minute changes in pH in the solution, which improves the solubility of R-ketamine in the formulation.

[0050] In some embodiments, the processes discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitate increasing the solubility of R-ketamine at a pH of about 5.6 to about 5.8.

[0051] In some embodiments, the processes discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitate increasing the solubility of R-ketamine at a pH of about 5.8.

[0052] In some embodiments, the processes discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitate increasing the solubility of R-ketamine at a pH of about 5.75.

[0053] In some embodiments, the processes discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitate increasing the solubility of R-ketamine at a pH of about 5.7.

[0054] In some embodiments, the processes discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitate increasing the solubility of R-ketamine at a pH of about 5.6.

[0055] In one aspect, the present disclosure is directed to an injection device comprising a needle suitable for subcutaneous administration, the device further comprising an R-ketamine formulation for subcutaneous administration.

[0056] In one aspect, the present disclosure is directed to an injection device comprising a needle suitable for subcutaneous administration, the device further comprising an R-ketamine formulation for subcutaneous administration, the formulation being substantially free of S-ketamine.

[0057] In one aspect, the present disclosure is directed to an injection device comprising a needle suitable for subcutaneous administration, the device comprising: a) about 90 mg / mL to about 110 mg / mL of R-ketamine; b) a buffer; and The pH of the formulation is below 5.8, and the formulation is substantially free of S-ketamine.

[0058] In one aspect, the present disclosure is directed to a kit comprising an R-ketamine formulation for subcutaneous administration and instructions for its use.

[0059] In one aspect, the present disclosure is directed to a method of treating a patient in need thereof comprising administering an R-ketamine formulation discussed herein.

[0060] In one aspect, the present disclosure is directed to a method of treating a patient in need thereof comprising administering an R-ketamine formulation via subcutaneous administration.

[0061] In one aspect, the present disclosure is directed to the use of the R-ketamine formulations discussed herein for the treatment of a neurological condition. [Brief description of the drawings]

[0062] [Figure 1] Figure 1 shows the Henderson-Hasselbalch representation of R-ketamine over a range of pH. The text under the bottom bracket reads "Free base concentrations follow Henderson-Hasselbalch" and the text in the top left reads "Prevalent alkene species as a function of pH." [Diagram 2] FIG. 2 illustrates the concentration (mg / mL) of R-ketamine in 50% propylene glycol and the pH value of the final solution, showing an increase in R-ketamine concentration to 46.5 mg / mL compared to approximately 20 mg / mL at pH 6. [Diagram 3] FIG. 3 illustrates the precipitation of 60 mg / mL R-ketamine in phosphate buffer (pH 5.8) after two weeks of storage. [Figure 4] Figure 4 shows the solubility of R-ketamine in the pH range of 5.5 to 5.7. [Diagram 5] Figure 5 shows the 4-week stability of various concentrations of R-ketamine at pH 5.5-5.7. [Figure 6] FIG. 6 shows impurities of R-ketamine in water for injection (WFI) after 4 weeks of storage at room temperature (RT) at pH 5.5-5.7. [Figure 7] Figure 7 shows the solubility of R-ketamine within the pH range of 5.5 to 5.7. [Figure 8] FIG. 8 shows the 4-week stability of various concentrations of R-ketamine at pH 5.5-5.7. [Figure 9] FIG. 9 shows impurities in maleic acid buffered R-ketamine after 4 weeks of storage at room temperature (RT) at pH 5.5-5.7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] All publications, patents, and patent applications mentioned within this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0064] As used herein, "R-ketamine" refers to the R-(-) enantiomer of ketamine (R-ketamine IUPAC name: (2R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one).

[0065] As used herein, "about" or "approximately," when used in connection with a numerical variable, generally refers to the value of the variable and all values ​​of the variable that are within experimental error of the stated numerical value (e.g., within a 95% confidence interval for the mean) or within plus or minus 10%, whichever is greater.

[0066] As used herein, the terms "a" or "an" refer to one or more of that entity. In addition, reference to an "agent" by the indefinite article "a" or "an" does not necessarily exclude the possibility that there is more than one agent present.

[0067] As used herein, the verb "comprise" and its conjugations as used in the specification and claims are used in their open-ended sense to mean that the items following the word are included but not excluding items not specifically mentioned. The present disclosure may suitably "comprise," "consist," or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0068] As used herein, the term "subject" is used interchangeably with the term "patient" and preferably refers to a human patient. In some embodiments, the subject can be any animal, including non-human mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, or primates.

[0069] As used herein, the terms "formulation" and "composition" are used interchangeably unless otherwise clearly intended to have a different meaning.

[0070] As used herein, the term "dosage form" refers to a parenteral composition (e.g., subcutaneous administration) in which a single dose is delivered to a subject in a single administration. The term "effective amount" is interchangeable with "therapeutically effective dose" or "therapeutically effective amount" and refers to an amount sufficient to produce a desired effect. An effective amount is sufficient to cause an improvement in the subject's condition.

[0071] As used herein, the term "parenteral or injectable" refers to administration of a drug by injection beneath one or more layers of the skin or mucosa, and can include, for example, subcutaneous, intravenous, intraperitoneal, or intramuscular injection.

[0072] As used herein, the term "subcutaneous administration" as used herein refers to any type of administration method used to deliver a medicament into the layer of fat between the skin and muscle, including, but not limited to, a patch or needle, among others. This type of administration can be given by a medical professional or can be self-injected.

[0073] As used herein, the term "subcutaneous injection" as used herein refers to a shot that delivers a medication into the layer of fat between the skin and muscle. This type of injection usually involves a needle and can be given by a medical professional or can be self-injected. In some embodiments, the formulation can be self-injected at home.

[0074] As used herein, "treatment," "treatment," and the like, describe the administration of a pharmaceutical composition of the invention to a subject or patient for the purpose of combating a disease, condition, or disorder, including reducing, alleviating, or eliminating one or more symptoms or complications of a disease, condition, or disorder, or reducing, alleviating, or eliminating the disease, condition, or disorder.

[0075] As used herein, "prevention," "preventing," and the like, describe halting the onset of a disease, condition, or disorder, or one or more symptoms or complications thereof.

[0076] Formulations of the Disclosure In some embodiments, the formulations may include pre-filled syringes, vials, powders for injection for reconstitution, concentrates for injection (ready to dilute) or solutions (ready to use) that are diluted prior to delivery.

[0077] In some embodiments, any of the salts or salt forms described in International Application No. PCT / US2022 / 046412 are contemplated in each aspect and / or embodiment as described herein. International Application No. PCT / US2022 / 046412 is incorporated herein by reference in its entirety.

[0078] In some embodiments, the formulation may be an isotonic aqueous solution or suspension.

[0079] For subcutaneous use, sterile solutions may be employed. In some embodiments, the total concentration of solutes should be controlled to render the formulation isotonic.

[0080] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 150 mg / mL.

[0081] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 150 mg / mL.

[0082] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 150 mg / mL.

[0083] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 150 mg / mL.

[0084] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL to about 150 mg / mL.

[0085] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 110 mg / mL to about 150 mg / mL.

[0086] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 120 mg / mL to about 150 mg / mL.

[0087] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 130 mg / mL to about 150 mg / mL.

[0088] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 140 mg / mL to about 150 mg / mL.

[0089] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 140 mg / mL.

[0090] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 140 mg / mL.

[0091] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 140 mg / mL.

[0092] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 140 mg / mL.

[0093] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL to about 140 mg / mL.

[0094] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 110 mg / mL to about 140 mg / mL.

[0095] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 120 mg / mL to about 140 mg / mL.

[0096] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 130 mg / mL to about 140 mg / mL.

[0097] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 130 mg / mL.

[0098] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 130 mg / mL.

[0099] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 130 mg / mL.

[0100] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 130 mg / mL.

[0101] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL to about 130 mg / mL.

[0102] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 110 mg / mL to about 130 mg / mL.

[0103] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 120 mg / mL to about 130 mg / mL.

[0104] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 120 mg / mL.

[0105] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 120 mg / mL.

[0106] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 120 mg / mL.

[0107] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 120 mg / mL.

[0108] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL to about 120 mg / mL.

[0109] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 110 mg / mL to about 120 mg / mL.

[0110] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 110 mg / mL.

[0111] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 110 mg / mL.

[0112] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 110 mg / mL.

[0113] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 110 mg / mL.

[0114] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL to about 110 mg / mL.

[0115] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 100 mg / mL.

[0116] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 100 mg / mL.

[0117] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 100 mg / mL.

[0118] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 100 mg / mL.

[0119] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 90 mg / mL.

[0120] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 90 mg / mL.

[0121] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL to about 90 mg / mL.

[0122] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 80 mg / mL.

[0123] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL to about 80 mg / mL.

[0124] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL to about 70 mg / mL.

[0125] In some embodiments, the subcutaneous injection formulation containing R-ketamine contains R-ketamine at a concentration of about 95 mg / mL to about 110 mg / mL.

[0126] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL to about 105 mg / mL.

[0127] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 95 mg / mL to about 105 mg / mL.

[0128] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 105 mg / mL, or about 110 mg / mL.

[0129] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 60 mg / mL.

[0130] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 65 mg / mL.

[0131] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 70 mg / mL.

[0132] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 75 mg / mL.

[0133] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 80 mg / mL.

[0134] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 85 mg / mL.

[0135] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 90 mg / mL.

[0136] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 95 mg / mL.

[0137] In some embodiments, the formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 100 mg / mL.

[0138] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 105 mg / mL.

[0139] In some embodiments, a formulation for subcutaneous injection containing R-ketamine contains R-ketamine at a concentration of about 110 mg / mL.

[0140] In some embodiments, the formulation comprises substantially pure R-ketamine. In some embodiments, the formulation is substantially free of S-ketamine. In some embodiments, more than 90%, more than 95%, more than 96%, more than 97%, more than 98%, or more than 99% of the ketamine is R-ketamine. Alternatively or additionally, R-ketamine substantially free of S-ketamine refers to R-ketamine in which S-ketamine is below the limit of detection using methods conventional in the art. A further alternative R-ketamine substantially free of S-ketamine refers to R-ketamine in which the amount of S-ketamine is such that when the composition is administered to a subject, side effects associated with S(+)-ketamine are substantially reduced or absent. Exemplary side effects include, but are not limited to, psychotomimetic effects such as changes in perception, mood, thinking, or mental state, e.g., anhedonia or negative affect. Additional side effects include somnolence, dizziness, headache, dysarthria, paresthesia, imbalance, hypoesthesia, coma, memory impairment, sedation, paresthesia, slurred speech, derealization, confusion, aversion, bruxism, dissociation, euphoria, speech loss, and changes in time perception.

[0141] In some embodiments, greater than 90% of the ketamine is R-ketamine. In some embodiments, greater than 95% of the ketamine is R-ketamine. In some embodiments, greater than 96% of the ketamine is R-ketamine. In some embodiments, greater than 97% of the ketamine is R-ketamine. In some embodiments, greater than 98% of the ketamine is R-ketamine. In some embodiments, greater than 99% of the ketamine is R-ketamine. In some embodiments, greater than 99.5% of the ketamine is R-ketamine. In some embodiments, greater than 99.9% of the ketamine is R-ketamine.

[0142] In some embodiments, the formulation is a liquid formulation for subcutaneous administration that includes R-ketamine. In some embodiments, the formulation is a liquid formulation for subcutaneous administration that includes non-ionized R-ketamine (i.e., free base). In some embodiments, the formulation is a liquid formulation for subcutaneous administration that includes R-ketamine in a mixture of ionized and non-ionized forms (free base). In some embodiments, the formulation is a liquid formulation for subcutaneous administration that includes R-ketamine in ionized form. In some embodiments, the formulation is a liquid formulation for subcutaneous administration that includes R-ketamine in salt form.

[0143] In some embodiments, the pH of the injectable formulation of the present disclosure may be adjusted to a suitable pH. In some embodiments, the formulation pH is adjusted using a weak base. In some embodiments, the formulation pH is adjusted using a dilute base. In some embodiments, the formulation pH is adjusted using a strong base. In some embodiments, the formulation pH is adjusted using a dilute base of a weak base. In some embodiments, the formulation pH is adjusted using a dilute base of a strong base. In some embodiments, the formulation pH is adjusted using NaOH. In some embodiments, the formulation pH is adjusted using KOH. In some embodiments, the formulation pH is adjusted using 1N NaOH. In some embodiments, the formulation pH is adjusted using 1N KOH. In some embodiments, the formulation pH is adjusted using 0.5N NaOH. In some embodiments, the formulation pH is adjusted using 0.5N KOH.

[0144] In some embodiments, the formulation pH is adjusted using a weak acid. In some embodiments, the formulation pH is adjusted using a dilute acid. In some embodiments, the formulation pH is adjusted using a strong acid. In some embodiments, the formulation pH is adjusted using a dilute acid of a weak acid. In some embodiments, the formulation pH is adjusted using a dilute acid of a strong acid.

[0145] In some embodiments, the method further comprises adjusting the pH of the pharmaceutical composition. In some embodiments, only minimal adjustment of the pH is required. In some embodiments, the pH is adjusted using a strong base. In some embodiments, the pH is adjusted using sodium hydroxide, potassium hydroxide, barium hydroxide, cesium hydroxide, strontium hydroxide magnesium hydroxide, calcium hydroxide, lithium hydroxide, or rubidium hydroxide.

[0146] In some embodiments, the pH is adjusted with sodium hydroxide. In some embodiments, the pH is adjusted to a desired pH. In some embodiments, the formulation is adjusted to a pH of about 5.0. In some embodiments, the formulation is adjusted to a pH of about 5.1. In some embodiments, the formulation is adjusted to a pH of about 5.2. In some embodiments, the formulation is adjusted to a pH of about 5.3. In some embodiments, the formulation is adjusted to a pH of about 5.4. In some embodiments, the formulation is adjusted to a pH of about 5.5. In some embodiments, the formulation is adjusted to a pH of about 5.6. In some embodiments, the formulation is adjusted to a pH of about 5.70. In some embodiments, the formulation is adjusted to a pH of about 5.71. In some embodiments, the formulation is adjusted to a pH of about 5.72. In some embodiments, the formulation is adjusted to a pH of about 5.73. In some embodiments, the formulation is adjusted to a pH of about 5.74. In some embodiments, the formulation is adjusted to a pH of about 5.75. In some embodiments, the formulation is adjusted to a pH of about 5.76. In some embodiments, the formulation is adjusted to a pH of about 5.77. In some embodiments, the formulation is adjusted to a pH of about 5.78. In some embodiments, the formulation is adjusted to a pH of about 5.79. In some embodiments, the formulation is adjusted to a pH of about 5.8. In some embodiments, the formulation is adjusted to a pH of about 5.9. In some embodiments, the formulation is adjusted to a pH of about 6.0. In some embodiments, the formulation is adjusted to a pH of 5.0-6.0.

[0147] In some embodiments, the pH of the formulation is about 5.0 to about 6.0. In some embodiments, the pH of the formulation is about 5.1 to about 6.0. In some embodiments, the pH of the formulation is about 5.2 to about 6.0. In some embodiments, the pH of the formulation is about 5.3 to about 6.0. In some embodiments, the pH of the formulation is about 5.4 to about 6.0. In some embodiments, the pH of the formulation is about 5.5 to about 6.0. In some embodiments, the pH of the formulation is about 5.6 to about 6.0. In some embodiments, the pH of the formulation is about 5.7 to about 6.0. In some embodiments, the pH of the formulation is about 5.8 to about 6.0. In some embodiments, the pH of the formulation is about 5.9 to about 6.0.

[0148] In some embodiments, the pH of the formulation is about 5.0 to about 5.9. In some embodiments, the pH of the formulation is about 5.1 to about 5.9. In some embodiments, the pH of the formulation is about 5.2 to about 5.9. In some embodiments, the pH of the formulation is about 5.3 to about 5.9. In some embodiments, the pH of the formulation is about 5.4 to about 5.9. In some embodiments, the pH of the formulation is about 5.5 to about 5.9. In some embodiments, the pH of the formulation is about 5.6 to about 5.9. In some embodiments, the pH of the formulation is about 5.7 to about 5.9. In some embodiments, the pH of the formulation is about 5.8 to about 5.9.

[0149] In some embodiments, the pH of the formulation is about 5.0 to about 5.8. In some embodiments, the pH of the formulation is about 5.1 to about 5.8. In some embodiments, the pH of the formulation is about 5.2 to about 5.8. In some embodiments, the pH of the formulation is about 5.3 to about 5.8. In some embodiments, the pH of the formulation is about 5.4 to about 5.8. In some embodiments, the pH of the formulation is about 5.5 to about 5.8. In some embodiments, the pH of the formulation is about 5.6 to about 5.8. In some embodiments, the pH of the formulation is about 5.7 to about 5.8.

[0150] In some embodiments, the pH of the formulation is about 5.0 to about 5.7. In some embodiments, the pH of the formulation is about 5.1 to about 5.7. In some embodiments, the pH of the formulation is about 5.2 to about 5.7. In some embodiments, the pH of the formulation is about 5.3 to about 5.7. In some embodiments, the pH of the formulation is about 5.4 to about 5.7. In some embodiments, the pH of the formulation is about 5.5 to about 5.7. In some embodiments, the pH of the formulation is about 5.6 to about 5.7.

[0151] In some embodiments, the pH of the formulation is about 5.0 to about 5.6. In some embodiments, the pH of the formulation is about 5.1 to about 5.6. In some embodiments, the pH of the formulation is about 5.2 to about 5.6. In some embodiments, the pH of the formulation is about 5.3 to about 5.6. In some embodiments, the pH of the formulation is about 5.4 to about 5.6. In some embodiments, the pH of the formulation is about 5.5 to about 5.6.

[0152] In some embodiments, the pH of the formulation is about 5.0 to about 5.5. In some embodiments, the pH of the formulation is about 5.1 to about 5.5. In some embodiments, the pH of the formulation is about 5.2 to about 5.5. In some embodiments, the pH of the formulation is about 5.3 to about 5.5. In some embodiments, the pH of the formulation is about 5.4 to about 5.5.

[0153] In some embodiments, the pH of the formulation is about 5.0 to about 5.4. In some embodiments, the pH of the formulation is about 5.1 to about 5.4. In some embodiments, the pH of the formulation is about 5.2 to about 5.4. In some embodiments, the pH of the formulation is about 5.3 to about 5.4.

[0154] In some embodiments, the pH of the formulation is about 5.0 to about 5.3. In some embodiments, the pH of the formulation is about 5.1 to about 5.3. In some embodiments, the pH of the formulation is about 5.2 to about 5.3.

[0155] In some embodiments, the pH of the formulation is about 5.0 to about 5.2. In some embodiments, the pH of the formulation is about 5.1 to about 5.2.

[0156] In some embodiments, the pH of the formulation is about 5.0 to about 5.1.

[0157] In some embodiments, the pH of the formulation is about 5.0. In some embodiments, the pH of the formulation is about 5.1. In some embodiments, the pH of the formulation is about 5.2. In some embodiments, the pH of the formulation is about 5.3. In some embodiments, the pH of the formulation is about 5.4. In some embodiments, the pH of the formulation is about 5.5. In some embodiments, the pH of the formulation is about 5.6. In some embodiments, the pH of the formulation is about 5.70. In some embodiments, the pH of the formulation is about 5.71. In some embodiments, the pH of the formulation is about 5.72. In some embodiments, the pH of the formulation is about 5.73. In some embodiments, the pH of the formulation is about 5.74. In some embodiments, the pH of the formulation is about 5.75. In some embodiments, the pH of the formulation is about 5.76. In some embodiments, the pH of the formulation is about 5.77. In some embodiments, the pH of the formulation is about 5.78. In some embodiments, the pH of the formulation is about 5.79. In some embodiments, the pH of the formulation is about 5.8. In some embodiments, the pH of the formulation is about 5.9. In some embodiments, the pH of the formulation is about 6.0.

[0158] In some embodiments, the R-ketamine formulation does not include cyclodextrin. In some embodiments, the R-ketamine formulation does not include cyclodextrin or a cyclodextrin derivative.

[0159] Injectable compositions may be supplied in a variety of delivery forms, for example, in ampoules, prefilled syringes, auto-injectors with or without needles, as small volume injections, or in multi-dose containers with added preservatives.

[0160] In some embodiments of the present disclosure, the parenteral composition is formulated as a subcutaneous injection.

[0161] Each of the injectable formulations (eg, subcutaneous injectable formulations) of the present disclosure also includes water, which may be present as saline, to further dilute the formulation to an appropriate volume suitable for injection.

[0162] Suitable volumes of the R-ketamine formulations of the present disclosure for use in an injection device (e.g., for subcutaneous administration) are in the range of about 0.1 mL to about 10 mL. Suitable volumes may include, for example, 0.1 mL, 0.2 mL, 0.3 mL, 0.4 mL, 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 2.0 mL, 3.0 mL, 4.0 mL, 5.0 mL, 6.0 mL, 7.0 mL, 8.0 mL, 9.0 mL, and 10.0 mL, and all amounts therebetween.

[0163] In some embodiments, the formulation has an osmolality of about 150 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 175 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 200 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 225 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 250 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 275 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 325 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 350 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 375 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 400 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of about 475 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 500 mOsm / kg to about 850 mOsm / kg.

[0164] In some embodiments, the formulation has an osmolality of at least about 150 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 175 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 200 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 225 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 250 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 275 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 300 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 325 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 350 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 375 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 400 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 425 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 475 mOsm / kg. In some embodiments, the formulation has an osmolality of at least about 500 mOsm / kg.

[0165] In some embodiments, the formulation has an osmolality of less than about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 825 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 800 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 775 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 750 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 725 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 700 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 675 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 650 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 625 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 600 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 575 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 550 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 525 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 500 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 450 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 400 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 350 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 300 mOsm / kg. In some embodiments, the formulation has an osmolality of less than about 250 mOsm / kg.

[0166] In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg to about 350 mOsm / kg, about 300 mOsm / kg to about 400 mOsm / kg, about 300 mOsm / kg to about 450 mOsm / kg, about 300 mOsm / kg to about 500 mOsm / kg, about 300 mOsm / kg to about 550 mOsm / kg, about 300 mOsm / kg to about 600 mOsm / kg, about 300 mOsm / kg to about 650 mOsm / kg, about 300 mOsm / kg to about 700 mOsm / kg, about 300 mOsm / kg to about 750 mOsm / kg, about 300 mOsm / kg to about 850 mOsm / kg, about 300 mOsm / kg to about 900 mOsm / kg, about 300 mOsm / kg to about 1000 mOsm / kg, about 300 mOsm / kg to about 1100 mOsm / kg, about 300 mOsm / kg to about 1200 mOsm / kg, about 300 mOsm / kg to about 1300 mOsm / kg, about 300 mOsm / kg to about 1400 mOsm / kg, about 300 mOsm / kg to about 1500 mOsm / kg, about 300 mOsm / kg to about 1600 mOsm / kg, about 300 mOsm / kg to about 1700 mOsm m / kg~about 800mOsm / kg, about 300mOsm / kg~about 850mOsm / kg, about 350mOsm / kg~about 400mOsm / kg, about 350mOsm / kg~about 450mOsm / kg, about 350mOsm / kg~about 500mOsm / kg, about 350mO sm / kg~about 550mOsm / kg, about 350mOsm / kg~about 600mOsm / kg, about 350mOsm / kg~about 650mOsm / kg, about 350mOsm / kg~about 700mOsm / kg, about 350mOsm / kg~about 750mOsm / kg, about 350m Osm / kg~about 800mOsm / kg, about 350mOsm / kg~about 850mOsm / kg, about 400mOsm / kg~about 450mOsm / kg, about 400mOsm / kg~about 500mOsm / kg, about 400mOsm / kg~about 550mOsm / kg, about 40 0mOsm / kg~about 600mOsm / kg, about 400mOsm / kg~about 650mOsm / kg, about 400mOsm / kg~about 700mOsm / kg, about 400mOsm / kg~about 750mOsm / kg, about 400mOsm / kg~about 800mOsm / kg, about 4 00mOsm / kg~Approx. 850mOsm / kg, Approx. 450mOsm / kg~Approx. 500mOsm / kg, Approx. 450mOsm / kg~Approx. 550mOsm / kg, Approx. 450mOsm / kg~Approx. 600mOsm / kg, Approx. 450mOsm / kg~Approx. 650mOsm / kg, Approx. 450mOsm / kg to about 700mOsm / kg, about 450mOsm / kg to about 750mOsm / kg, about 450mOsm / kg to about 800mOsm / kg, about 450mOsm / kg to about 850mOsm / kg, about 500mOsm / kg to about 550mOsm / kg,Approx. 500mOsm / kg~Approx. 600mOsm / kg, Approx. 500mOsm / kg~Approx. 650mOsm / kg, Approx. 500mOsm / kg~Approx. 700mOsm / kg, Approx. 500mOsm / k g ~ approx. 750mOsm / kg, approx. 500mOsm / kg ~ approx. 800mOsm / kg, approx. 500mOsm / kg ~ approx. 850mOsm / kg, approx. 550mOsm / kg ~ approx. 600mOsm / kg, about 550mOsm / kg to about 650mOsm / kg, about 550mOsm / kg to about 700mOsm / kg, about 550mOsm / kg to about 750mOsm / kg, about 550mOsm / kg ~ approx. 800mOsm / kg, approx. 550mOsm / kg ~ approx. 850mOsm / kg, approx. 600mOsm / kg ~ approx. 650mOsm / kg, approx. 600mOsm / kg ~ approx. 700mOs m / kg, about 600mOsm / kg to about 750mOsm / kg, about 600mOsm / kg to about 800mOsm / kg, about 600mOsm / kg to about 850mOsm / kg, about 650m Osm / kg ~ approx. 700mOsm / kg, approx. 650mOsm / kg ~ approx. 750mOsm / kg, approx. 650mOsm / kg ~ approx. 800mOsm / kg, approx. 650mOsm / kg ~ approx. 850 mOsm / kg, about 700 mOsm / kg to about 750 mOsm / kg, about 700 mOsm / kg to about 800 mOsm / kg, about 700 mOsm / kg to about 850 mOsm / kg, about 750 mOsm / kg to about 800 mOsm / kg, about 750 mOsm / kg to about 850 mOsm / kg, or about 800 mOsm / kg to about 850 mOsm / kg. In some embodiments, the formulation has an osmolality of about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg. In some embodiments, the formulation comprises at least about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg,or about 800 mOsm / kg. In some embodiments, the formulation has an osmolality of up to about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm / kg, about 500 mOsm / kg, about 550 mOsm / kg, about 600 mOsm / kg, about 650 mOsm / kg, about 700 mOsm / kg, about 750 mOsm / kg, about 800 mOsm / kg, or about 850 mOsm / kg.

[0167] In some embodiments, the formulation is isotonic.

[0168] In some embodiments, the formulation has an osmolality of about 500 mOsm / kg. stability

[0169] In some embodiments, the formulation remains stable for more than about 4 weeks, more than about 5 weeks, more than about 6 weeks, more than about 7 weeks, more than about 8 weeks, more than about 9 weeks, more than about 10 weeks, more than about 11 weeks, more than about 12 weeks, more than about 13 weeks, more than about 14 weeks, or more than about 15 weeks.

[0170] In some embodiments, the formulation remains stable for more than about 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than about 12 months, more than 13 months, more than 14 months, more than 15 months, more than 16 months, more than 17 months, more than 18 months, more than 19 months, more than 20 months, more than 21 months, more than 22 months, more than 23 months, or more than 24 months.

[0171] In some embodiments, the concentration of R-ketamine in the formulation is stable for more than about 4 weeks, more than about 5 weeks, more than about 6 weeks, more than about 7 weeks, more than about 8 weeks, more than about 9 weeks, more than about 10 weeks, more than about 11 weeks, more than about 12 weeks, more than about 13 weeks, more than about 14 weeks, or more than about 15 weeks.

[0172] In some embodiments, the concentration of R-ketamine in the formulation is stable for greater than about 1 month, greater than 2 months, greater than 3 months, greater than 4 months, greater than 5 months, greater than 6 months, greater than 7 months, greater than 8 months, greater than 9 months, greater than 10 months, greater than 11 months, greater than about 12 months, greater than 13 months, greater than 14 months, greater than 15 months, greater than 16 months, greater than 17 months, greater than 18 months, greater than 19 months, greater than 20 months, greater than 21 months, greater than 22 months, greater than 23 months, or greater than 24 months.

[0173] In some embodiments, the impurities in the formulation are stable for more than about 4 weeks, more than about 5 weeks, more than about 6 weeks, more than about 7 weeks, more than about 8 weeks, more than about 9 weeks, more than about 10 weeks, more than about 11 weeks, more than about 12 weeks, more than about 13 weeks, more than about 14 weeks, or more than about 15 weeks.

[0174] In some embodiments, the impurities in the formulation are stable for more than about 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than about 12 months, more than 13 months, more than 14 months, more than 15 months, more than 16 months, more than 17 months, more than 18 months, more than 19 months, more than 20 months, more than 21 months, more than 22 months, more than 23 months, or more than 24 months.

[0175] In some embodiments, the osmolality in the formulation is stable for more than about 4 weeks, more than about 5 weeks, more than about 6 weeks, more than about 7 weeks, more than about 8 weeks, more than about 9 weeks, more than about 10 weeks, more than about 11 weeks, more than about 12 weeks, more than about 13 weeks, more than about 14 weeks, or more than about 15 weeks.

[0176] In some embodiments, the osmolality in the formulation is stable for more than about 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than about 12 months, more than 13 months, more than 14 months, more than 15 months, more than 16 months, more than 17 months, more than 18 months, more than 19 months, more than 20 months, more than 21 months, more than 22 months, more than 23 months, or more than 24 months.

[0177] In some embodiments, the pH of the formulation is stable for more than about 4 weeks, more than about 5 weeks, more than about 6 weeks, more than about 7 weeks, more than about 8 weeks, more than about 9 weeks, more than about 10 weeks, more than about 11 weeks, more than about 12 weeks, more than about 13 weeks, more than about 14 weeks, or more than about 15 weeks.

[0178] In some embodiments, the pH of the formulation is stable for more than about 1 month, more than 2 months, more than 3 months, more than 4 months, more than 5 months, more than 6 months, more than 7 months, more than 8 months, more than 9 months, more than 10 months, more than 11 months, more than about 12 months, more than 13 months, more than 14 months, more than 15 months, more than 16 months, more than 17 months, more than 18 months, more than 19 months, more than 20 months, more than 21 months, more than 22 months, more than 23 months, or more than 24 months.

[0179] In some embodiments, the formulation is stable in the presence of light. In some embodiments, the formulation is stable in the presence of heat. In some embodiments, the formulation is stable at room temperature. In some embodiments, the formulation is stable in the presence of heat.

[0180] In some embodiments, the term stable means that the percentage, volume, or concentration of impurities, pH, R-ketamine, osmolality, and the like does not change by more than about 0.1%, more than about 0.2%, more than about 0.3%, more than about 0.4%, more than about 0.5%, more than about 0.6%, more than about 0.7%, more than about 0.8%, more than about 0.9%, more than about 1%, more than about 2%, more than about 3%, more than about 4%, more than about 5%, more than about 6%, more than about 7%, more than about 8%, more than about 9%, or more than about 10% from the original percentage, volume, or concentration. Carrier Fluid

[0181] In some embodiments, the R-ketamine subcutaneous formulation comprises a carrier liquid. In some embodiments, the R-ketamine subcutaneous formulation comprises a carrier liquid, and the carrier fluid is water. In some embodiments, the R-ketamine subcutaneous formulation comprises a carrier liquid, and the carrier fluid is water for injection (WFI). In some embodiments, the R-ketamine subcutaneous formulation comprises a carrier liquid, and the carrier fluid is a buffer.

[0182] In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection. In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection and a buffer. In some embodiments, the R-ketamine subcutaneous formulation comprises a buffer.

[0183] In some embodiments, the R-ketamine subcutaneous formulation comprises a succinate buffer.

[0184] In some embodiments, the R-ketamine subcutaneous formulation comprises a tartrate buffer.

[0185] In some embodiments, the R-ketamine subcutaneous formulation comprises a maleate buffer.

[0186] In some embodiments, the R-ketamine subcutaneous formulation comprises a fumarate buffer.

[0187] In some embodiments, the R-ketamine subcutaneous formulation comprises a citrate buffer.

[0188] In some embodiments, the R-ketamine subcutaneous formulation comprises an acetate buffer.

[0189] In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection and maleate buffer.

[0190] In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection and fumarate buffer.

[0191] In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection and citrate buffer.

[0192] In some embodiments, the R-ketamine subcutaneous formulation comprises water for injection and acetate buffer.

[0193] Process for preparing the formulation In some embodiments, R-ketamine or a pharma- ceutically acceptable salt thereof is added to water for injection and the pH is slowly adjusted using a diluent base to obtain a final concentration of R-ketamine of about 60 mg / mL to about 110 mg / mL. In some embodiments, the R-ketamine used to prepare the formulation is selected from any of the salts or salt forms described in International Application No. PCT / US2022 / 046412. In some embodiments, a specific amount of R-ketamine, R-ketamine salt, or R-ketamine salt form is added to obtain a free base equivalent as disclosed herein.

[0194] In some embodiments, the pH of the R-ketamine formulation is increased using an inorganic base. In some embodiments, the pH of the R-ketamine formulation is increased using an inorganic base at a concentration of 1 N. In some embodiments, the pH of the R-ketamine formulation is increased using an inorganic base at a concentration of 0.5 N. In some embodiments, the pH of the R-ketamine formulation is increased using an inorganic base at a concentration of 0.15 N. In some embodiments, the pH of the R-ketamine formulation is titrated.

[0195] In some embodiments, the process discussed herein for preparing a formulation for subcutaneous administration comprising R-ketamine facilitates an increase in the solubility of R-ketamine. In some embodiments, the pH is adjusted slowly. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base. In some embodiments, the pH is adjusted in such a manner as to minimize local variations in pH. In some embodiments, the pH is adjusted to minimize minute changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base, which minimizes minute changes in pH in the solution. In some embodiments, the pH is adjusted slowly using a dilute acid or a dilute base, which minimizes minute changes in pH in the solution, which improves the solubility of R-ketamine in the formulation.

[0196] The injectable composition of the present disclosure can be prepared by those skilled in the art by using standard methods and conventional techniques appropriate for the desired formulation.The formulation for intramuscular or subcutaneous administration of the present disclosure can be packaged and / or stored in a suitable container, including, but not limited to, syringes, ampoules, vials, including sealed vials such as vials whose openings are sealed with syringe-puncturable septa or Sure-seal caps, and the like.In some embodiments, the formulation is pre-filled into a disposable syringe for self-administration by the patient, with or without an auto-injector.Each container can contain R-ketamine or a pharma-ceutically acceptable salt thereof at a desired dose.

[0197] To further minimize oxidative degradation of the active ingredient, the container may be filled with an inert gas, such as nitrogen and / or carbon dioxide, which is otherwise oxygen-free. It is further contemplated that the container may be enclosed in a sealed package from which oxygen is excluded. This may be accomplished by vacuum packaging or by replacing oxygen with a blanket or purge of nitrogen, carbon dioxide, or other oxygen-free inert gas. After sealing the seal, the packaging material itself should be relatively impermeable to oxygen diffusion. The package should also be impermeable to normal light, since light may induce degradation of R-ketamine. Standard methods for sealing and packaging the various containers described herein are well known in the art and can be used in conjunction with packaging and / or storing the dosage forms of the present disclosure.

[0198] In some embodiments, the R-ketamine formulation is contained within a "unit dosage form." The phrase "unit dosage form" refers to a physically discrete unit, each unit containing a predetermined amount of R-ketamine sufficient to produce a desired effect. Of course, the parameters of the unit dosage form depend on the concentration of R-ketamine in the formulation and the effect to be achieved.

[0199] How to use The R-ketamine formulations of the present disclosure are useful in the prevention and / or treatment of a variety of diseases or conditions.

[0200] The R-ketamine formulations described herein are useful as neuroprotective, preventive, or therapeutic agents for diseases or conditions associated with glutamate transmission, specifically glutamate neurotransmission via N-methyl-D-aspartate (hereinafter abbreviated as NMDA) receptors. Growing evidence suggests that abnormal glutamate transmission, for example, via NMDA receptors, is associated with the pathophysiology of mood disorders, and that NMDA receptors also play an important role in neurobiology.

[0201] The R-ketamine formulations described herein are useful as neuroprotective, prophylactic, or therapeutic agents for cognitive dysfunction, such as mood disorders, bipolar disorder, major depressive disorder, generalized anxiety disorder, panic disorder, obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), eating disorders, and substance use disorders (drug dependence).

[0202] The R-ketamine formulations described herein are also useful for treating neurodegenerative diseases and numerous medical diseases, including but not limited to cardiovascular disease, cancer (also called malignant tumors), inflammatory diseases, bone diseases, and the like. Exemplary inflammatory and bone diseases include ulcerative colitis, Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, insulin-dependent diabetes mellitus, Addison's disease, Goodpasture's syndrome, IgA nephropathy, interstitial nephritis, Sjogren's syndrome, autoimmune pancreatitis, psoriasis, atopic dermatitis, pneumonia, chronic bronchitis, bronchial asthma, systemic lupus erythematosus (SLE), scleroderma, or delirium, and bone diseases are osteoporosis, osteolytic bone metastasis, and Paget's disease of bone. Inflammatory diseases are chronic diseases that progress over a long period of time (several years), so initiating treatment early may prevent the progression of symptoms. Moreover, the R-ketamine formulations described herein may also be used to prevent the onset of inflammatory or bone diseases by administering the R-ketamine formulations described herein to patients with genetic backgrounds that may predispose them to inflammatory diseases prior to the onset of symptoms.

[0203] The R-ketamine formulations described herein are also useful in treating neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, dementia with Lewy bodies, and the like. In some embodiments, the R-ketamine formulations described herein treat one or more symptoms of a neurodegenerative disease.

[0204] The R-ketamine formulations described herein are also useful in treating neurodevelopmental conditions or disorders, such as pediatric or fetal neurodevelopmental disorders. Exemplary neurodevelopmental disorders include schizophrenia, autism spectrum disorder, attention deficit / hyperactivity disorder, autism spectrum disorder, and other learning disorders. Symptoms include cognitive impairments, such as attention deficit, reduced verbal fluency, reduced learning and retention of verbal information, reduced processing speed, reduced declarative memory, working memory deficits, reduced executive function, or combinations thereof. In some embodiments, the R-ketamine formulations described herein treat one or more symptoms of a neurodevelopmental disorder. The R-ketamine formulations described herein are useful as neuroprotective, prophylactic, or therapeutic agents for diseases or conditions associated with brain dopamine loss. The R-ketamine formulations described herein may be used to prevent or treat diseases or conditions associated with a decrease in dopamine transporter (DAT). Specifically, examples of dysfunctions or conditions of the brain dopamine nervous system include substance use disorders (drug dependence) known in stimulant or cocaine abusers, and R-ketamine is considered to be effective as a preventive or therapeutic drug for substance use disorders (drug dependence). It has been reported that dopamine transporters (DAT) are reduced in the brains of cocaine abusers and stimulant drug (methamphetamine) users, and it has been pointed out that the reduction in DAT is associated with cognitive dysfunction. In addition, the reduction in DAT in patients with substance use disorders is similar to the reduction in DAT seen in some neurodegenerative diseases, such as Parkinson's disease patients.

[0205] In addition, the R-ketamine formulations described herein may be involved in the signal mediated by brain-derived neurotrophic factor (BDNF), which leads to having neuroprotective effects.Due to these neuroprotective effects, the R-ketamine formulations described herein may be used not only for the prevention or treatment of depressive symptoms and neurodegenerative diseases, but also for the prevention or treatment of cognitive dysfunction as described above under the term "cognitive dysfunction".

[0206] As a result, the present disclosure provides compositions comprising the R-ketamine formulations described herein for use in the prevention or treatment of a neurodevelopmental disorder, a neurodegenerative disease, an inflammatory or bone disease, or a cognitive dysfunction.

[0207] The present disclosure provides a composition comprising an R-ketamine formulation described herein for use in the manufacture of a medicament for the prevention or treatment of a neurodevelopmental disorder, a neurodegenerative disease, an inflammatory or bone disease, or a cognitive dysfunction.

[0208] The present disclosure provides a method for preventing or treating a neurodevelopmental disorder, a neurodegenerative disease, an inflammatory or bone disease, or a cognitive impairment, comprising administering a therapeutically effective amount of a composition comprising an R-ketamine formulation described herein.

[0209] By using the R-ketamine formulations described herein as prophylactic or therapeutic agents for neurodevelopmental disorders, neurodegenerative diseases, inflammatory or bone diseases, or cognitive dysfunction, it is possible to prevent the onset of the disease or disorder and exert therapeutic effects such as alleviation and improvement of symptoms in patients suffering from neurodevelopmental disorders, neurodegenerative diseases, inflammatory or bone diseases, or cognitive dysfunction. Because many of the disorders, diseases, and dysfunctions described herein progress over a long period of time (measured in years), early treatment may also prevent progression of symptoms or reduce severity.

[0210] In addition, it may also be used in patients with genetic backgrounds that potentially predispose them to neurodevelopmental, neurodegenerative, inflammatory or bone diseases, or cognitive impairment, to prevent the onset of a disorder, disease, or dysfunction by administration prior to the onset of symptoms.

[0211] In the present disclosure, the R-ketamine formulations described herein are used to prevent or treat a neurodevelopmental disorder, a neurodegenerative disease, an inflammatory or bone disease, or a cognitive impairment, and administration of the drug is scheduled for an extended period of time.

[0212] Thus, the R-ketamine formulations described herein may be used to administer the drug for extended periods of time without adding side effects, and therefore may be used as prophylactic or therapeutic agents for neurodevelopmental disorders, neurodegenerative diseases, inflammatory or bone diseases, or cognitive dysfunction.

[0213] The R-ketamine formulations described herein are useful as prophylactic agents for neurodevelopmental disorders, neurodegenerative disorders, inflammatory or bone diseases, or cognitive dysfunction by preventing the onset of the disorder, disease, or dysfunction, or as agents for preventing the progression of the symptoms of the disorder, disease, or dysfunction.In addition, the therapeutic agent may have a therapeutic effect of preventing the progression of the symptoms and reducing or improving the symptoms.

[0214] The process for the R-ketamine formulation described herein is useful for the prevention and / or treatment of one or more symptoms associated with any of the disorders, diseases, or dysfunctions described herein, such as depressive symptoms.In some embodiments, depressive symptoms include, but are not limited to, lack of interest in activities, changes in sleep patterns, changes in appetite, feelings of guilt, hopelessness, lack of energy, lack of concentration, stress, depressed or depressed mood, impaired motivation, impaired cognitive function, reduced thinking ability, anxiety, insomnia, anhedonia and negative emotions, loss of appetite, fatigue, and suicidal thoughts.The process for preparing the R-ketamine formulation of the present disclosure is useful in preparing a medicament for the prevention and / or treatment of depression.

[0215] The R-ketamine formulations described herein are useful for preventing and / or treating a substance use disorder in a subject. In some embodiments, the substance use disorder includes abuse of alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleep aids, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyrate (GHB), N,N-dimethyltryptamine (DMT), ayahuasca, mescaline, salvia divinorum, or nicotine.

[0216] The R-ketamine formulations described herein are useful for preventing and / or treating substance use withdrawal symptoms in a subject. In some embodiments, substance use withdrawal symptoms include symptoms of withdrawal from alcohol, marijuana, synthetic cannabinoids, opioids, stimulants, barbiturates, benzodiazepines, dextromethorphan (DXM), sleep aids, khat, synthetic cathinones, cocaine, 3,4-methylenedioxymethamphetamine (MDMA), phencyclidine (PCP), lysergic acid diethylamide (LSD), psilocybin, inhalants, rohypnol, gamma-hydroxybutyrate (GHB), N,N-dimethyltryptamine (DMT), ayahuasca, mescaline, salvia divinorum, or nicotine.

[0217] Additional disorders and symptoms thereof that can be treated by the R-ketamine formulations described herein are described in International Publication Nos. WO 2015 / 037248 (PCT / JP2014 / 004730), WO 2019 / 213551 (PCT / US2019 / 030644), WO 2019 / 065900 (PCT / JP2018 / 036079), WO 2019 / 160057 (PCT / JP2019 / 005415), and WO 2020 / 138491 (PCT / JP2019 / 051605), which are incorporated by reference in their entireties.

[0218] All percentages and ratios used herein are by weight unless otherwise indicated.Other features and advantages of the present disclosure are apparent from different examples.The examples provided illustrate different components and methodologies useful in carrying out the present disclosure.The examples do not limit the disclosure claimed.Based on the present disclosure, those skilled in the art can identify and adopt other components and methodologies useful for carrying out the present disclosure.

[0219] All patents, patent applications, and publications mentioned herein are incorporated herein by reference in their entirety. However, when a patent, patent application, or publication containing express definitions is incorporated by reference, it should be understood that those express definitions apply to the incorporated patent, patent application, or publication in which they are found, and not to the remainder of the text of this application, particularly the claims of this application.

[0220] kit The present disclosure provides kits that include the R-ketamine formulations and pharmaceutical compositions described herein.

[0221] In some embodiments, the R-ketamine formulation or pharmaceutical composition is stored in a reservoir of a drug delivery device. In some embodiments, the formulation is stored in a cartridge that is insertable and / or attachable to the drug delivery device. In some embodiments, the R-ketamine formulation is stored in a reservoir of a drug delivery device that includes a needle configured for subcutaneous injection. In some embodiments, the cartridge and / or drug delivery device comprises a product label for subcutaneous injection. In some embodiments, a kit comprising a product label for subcutaneous injection is disclosed herein. EXAMPLES

[0222] R-ketamine is the R-(-) enantiomer of ketamine (IUPAC name: 2-(2-chlorophenyl)-2-(methylamino)cyclohexan-1-one). R-ketamine is being investigated for the treatment of several neurological conditions. Due to the poor solubility of the free base in water, it is usually used as the hydrochloride salt, which exhibits a solubility of greater than 140 mg / mL in water at pH>5. R-ketamine properties as used herein: Molecular weight: 274.18 g / mol as hydrochloride salt; Molecular weight as free base: 237.75 g / mol; Molecular formula: C 13 H 17 Cl2NO. [Table 1] [Table 2]

[0223] In water, R-ketamine exhibits buffering properties according to Henderson-Hasselbalch at pH 5.5-9.5, as illustrated in Figure 1. From pH 5.5 onwards, the free base will precipitate as a result, if this is not prevented by the addition of suitable excipients.

[0224] A suitable R-ketamine formulation for subcutaneous injection at a concentration of 60 mg / ml (100 mg / ml) was developed. In addition to the concentration, a pH of 5-6 and a tonicity as close as possible to physiological values ​​were achieved.

[0225] The formation of inclusion complexes between R-ketamine free base and supplemented cyclodextrins, the addition of co-solvents, or buffering of the formulation at suitable pH values ​​were investigated. The interactions between the free base and beta-cyclodextrins presenting pH values ​​greater than 5.5 were investigated using a statistical design of experiments. Promising candidates for co-solvent screening were tested for applicability. For the investigation of suitable buffer systems, two compendial buffer systems were employed, and their suitability was tested at pH 5.2-5.8.

[0226] Example 1. Cyclodextrin-containing The effect of hydroxypropyl β-cyclodextrin (HPB) on the solubility of R-ketamine at different pH values ​​was investigated. The factors varied were the pH of the solution and the concentration of HPB. The response factors were the tonicity of the filtered (0.22 μm) solution, determined by freezing point depression, and the API content, measured by HPLC. [Table 3] [Table 4]

[0227] Using the above specifications, the following full factorial designs were prepared and tested. [Table 5]

[0228] Experimental procedure After dissolving the active ingredient (100 mg / ml, 86.96 mg / ml free base), a defined amount of HPB was added. After complete dissolution of the two components, the target pH was adjusted using sodium hydroxide solution (1 M). The resulting solution was filtered through a syringe filter (0.22 μm) and analyzed by HPLC and freezing point depression. A separate protocol was prepared for each individual experiment.

[0229] result The results (Table 6) confirm the pronounced pH dependence of R-ketamine solubility in water, which is apparently not significantly affected by the addition of HPB. The lack of correlation between tonicity and drug content at higher pH values ​​is notable. While initially attributed to an error in the control strategy, this phenomenon can now be understood to be due to the amount of sodium hydroxide used for pH adjustment. [Table 6]

[0230] Example 2. Co-solvent screening For co-solvent screening, a set of potential candidates was identified. Specifically, 5% sulfobutyl ether β-cyclodextrin (SBE7), polyethylene glycol 400 (PEG400), glycerol, propylene glycol, and 5% polysorbate 80 were screened at pH 5 and 6. Unless otherwise specified, co-solvents were screened at 20% and 50% (m / V). As a control, the solubility of R-ketamine in water was studied at pH 5 and 6.

[0231] Experimental procedure Test solutions consisted of water for injection. Each co-solvent was prepared and the active substance was dissolved to a nominal concentration of 100 mg / ml (equivalent to 86.96 mg / ml of free base). The pH was then adjusted to pH 5 using 1N NaOH and a sample was obtained under filtration (0.22 μm). Afterwards, the pH was further increased to pH 6 and another sample was taken (also filtered). Both samples were analyzed for assay and tonicity by HPLC and freezing point depression.

[0232] result Batch size: 90g / pH set at end of blend (1N NaOH / 1N HCl) [Table 7]

[0233] The use of co-solvents did not lead to the desired effect to reach a solution containing 60 mg / mL of R-ketamine hydrochloride. The interaction between the pH optima below 5 could not be overcome by the different co-solvents at different concentrations as described above. Only the concentration of 50% propylene glycol showed an increase in the level to 46.5 mg / ml instead of a value of approximately 20 mg / mL at pH 6 (shown in Figure 2). Due to the severe freezing point depression, the osmolality could not be tested.

[0234] Example 3. Buffer One observation from the previous example was that there is a range between pH 5 and pH 6 in which 60 mg / ml of API can be dissolved. Strong precipitation of the free base occurs only at pHs above 5.9, as observed. Based on this observation, it was decided to investigate two compendial buffer systems (citrate buffer and phosphate buffer) for their ability to keep 60 mg / ml of R-ketamine in solution and stabilize the formulation against pH shifts. Another change was that the pH adjustment was made with 0.15 N NaOH instead of 1 N NaOH in the following experiments. This change was not made completely because there was concern that the very alkaline microenvironment around the sodium hydroxide solution droplets would lead to the formation of flakes that would be difficult to dissolve.

[0235] Citrate Buffer [Table 8]

[0236] Experimental procedure The components of 20 mM buffer solution and the appropriate amount of R-ketamine HCl (60 mg / ml, equivalent to 52.2 mg / ml free base) were weighed together and diluted in water for injection. The pH was then adjusted to, for example, 5.2. After filling to the target volume, the mixture was stirred for a defined time and a sample was obtained under filtration (0.22 μm). The sample was analyzed for content by HPLC and for tonicity by freezing point depression.

[0237] result [Table 9]

[0238] The results for citrate buffer (Table 9) show an almost constant content and tonicity within the pH range of 5.2-5.8. The observable trend towards higher content at higher pH is within the measurement precision of the method. No precipitation could be visually detected, only a content of approximately 46.5 mg / ml was found.

[0239] A series of experiments using 60 mg / ml R-ketamine was supplemented with a single study of 70 mg / ml R-ketamine (60.9 mg / ml free base) at pH 5.8 (Table 10), where precipitation was observed after pH adjustment. [Table 10]

[0240] Phosphate buffer Based on previous results from the citrate buffer series experiments, experiments with phosphate buffers were likely to be limited to pH 5.8. Nominal concentrations of 60 and 70 mg / ml were investigated.

[0241] Experimental procedure Solutions were prepared and tested as described for the citrate buffer.

[0242] result [Table 11]

[0243] After pH adjustment and filtration, both tests showed a slightly reduced active ingredient content compared to the original concentration, but no visible precipitation occurred. Starting from a nominal 70 mg / ml R-ketamine (corresponding to 60.9 mg / ml of free base), a content of 59.7 mg / ml was found in the filtered solution at pH 5.8. As a result, the targeted 60 mg / ml can be dissolved in water for injection under phosphate buffer with acceptable values ​​for pH and tonicity. The pH properties of the phosphate buffer are also slightly dependent on temperature, thus allowing terminal sterilization of the formulation.

[0244] Orientational Stability Test Subsequent storage of the successfully tested phosphate buffered formulation at room temperature (pH 5.8) revealed a limited shelf life, as a microcrystalline precipitate was observed after two weeks.

[0245] Maleic acid buffer Due to its ability to act as a buffer in the acidic to neutral range, 0.02 M maleic acid in water was proposed as the base formulation. The objective was to investigate the solubility capacity for R-ketamine in the concentration ranges of 60, 80, and 100 mg / ml at pH 5.5 and 5.7 (after a feasibility study with pH 5.8 was deemed unsuccessful) and the stability of the formulation in a 4-week study.

[0246] The variables observed were visual appearance, assay, and pH. A portion of the 4 week samples were examined for purity in addition to assay. As a standard for comparison, solution behavior in Water for Injection (WFI) was observed at the same pH values.

[0247] Initial studies with maleic acid buffer In an initial feasibility study, the dissolution behavior of R-ketamine in the presence of maleic acid was investigated. Pure water was used as a comparison. In an unbuffered aqueous solution of 60 mg / ml R-ketamine, a pH of 4.65 was obtained. When the same amount of R-ketamine was dissolved in a 0.02 M maleic acid buffer adjusted to pH 5.75, the pH decreased to a value of 5.38.

[0248] In initial tests, the pH could then be raised to 5.8 with 0.15 M NaOH without precipitation of the active ingredient.

[0249] Results (water for injection) In addition to the experimental parameters mentioned above, the possible influence of the alkali used for pH adjustment was also investigated (Figure 4). KOH and NaOH were compared and no differences were observed. At both pH 5.5 and pH 5.7 it was possible to prepare clear solutions in the concentration range of 60-100 mg / ml of API. The preparation of each sample was carried out separately. - 4-week stability assay - The stability study showed a satisfactory stability after 4 weeks of storage at room temperature (Figure 5). Visually, the sample presented as a clear solution without any signs of precipitation. - 4 week impurity assay Impurity determinations were performed on 4 week samples and showed extensive stability. - 4 week stability: pH Regardless of whether the pH was set at 5.5 or 5.7, all samples showed a trend towards a decrease in pH over the duration of the study. On average, the change was 0.2 pH units, but in one case it reached 0.4 units. These changes are reasonable, since the solutions were not buffered.

[0250] Results (0.02M maleic acid) In addition to the experimental parameters mentioned above, the possible influence of the alkali used for pH adjustment was also investigated. KOH and NaOH were compared and no differences were observed. - pH dependence of solubility It was possible to prepare clear solutions at concentrations ranging from 60 to 100 mg / ml of API at both pH 5.5 and pH 5.7. The preparation of each sample was carried out separately. - 4-week stability assay Stability studies showed satisfactory stability after 4 weeks of storage at room temperature. Visually, the samples presented as clear solutions without signs of precipitation. Deviations from the nominal concentration were most pronounced at the highest dose. - 4 week impurity assay Impurity determinations were performed only on 4 week samples and showed extensive stability. - 4 week stability: pH In the maleic acid stabilized systems, the pH proved to be stable and in many cases no changes could be detected during storage.

[0251] overview The solubility of R-ketamine is strongly dependent on pH. In the acidic pH range, the active ingredient is easily soluble, while precipitation occurs at pH values ​​above 5.7-5.9. A careful selection of the formulation parameters makes it possible to match the requirements of the application route with the dissolution behavior of the active ingredient. The way in which the pH is adjusted also has a large impact. By using low concentrations of alkali, the formation of a highly alkaline microenvironment around the instillation point can be avoided. This prevents the formation of a floccule of the active ingredient that is difficult to dissolve again.

[0252] Example 4. R-Ketamine Formulation in Maleate Buffer R-ketamine formulations at various pH values ​​were prepared in maleate buffer.

[0253] Maleate Buffer Components: Maleic acid, C4H4O4, mw 116.07 · NaOH, 1N aqueous solution Distilled H2O

[0254] Maleate buffer (100 mL at 20 mM) was prepared, for example, by adding 0.232 g maleic acid, 2 mL NaOH, and adding H2O to 100 mL.

[0255] R-ketamine formulation (40 mg / mL) at pH 5.0 in 20 mM maleate buffer, and R-ketamine formulation (40 mg / mL) at pH 5.7 in 20 mM maleate buffer

[0256] Formulations are prepared, for example, by adding the equivalent of 40 mg / ml R-ketamine free base (46 mg / ml R-ketamine HCl salt) in 20 mM maleate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0257] R-ketamine formulation (80 mg / mL) at pH 5.0 in 20 mM maleate buffer, and R-ketamine formulation (80 mg / mL) at pH 5.7 in 20 mM maleate buffer

[0258] Formulations are prepared, for example, by adding the equivalent of 80 mg / ml of R-ketamine free base (92 mg / ml of R-ketamine HCl salt) in 20 mM maleate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0259] Example 5. R-Ketamine Formulations in Fumarate Buffer R-ketamine formulations at various pH values ​​were prepared in fumarate buffer.

[0260] Fumarate Buffer Components: Fumaric acid, C4H4O4, mw 116.07 · NaOH, 1N aqueous solution Distilled H2O

[0261] Fumarate buffer (100 mL at 20 mM) was prepared, for example, by adding 0.232 g fumaric acid, 2 mL NaOH, and adding H2O to 100 mL.

[0262] R-ketamine formulation (40 mg / mL) at pH 5.0 in 20 mM fumarate buffer, and R-ketamine formulation (40 mg / mL) at pH 5.7 in 20 mM fumarate buffer

[0263] Formulations are prepared, for example, by adding the equivalent of 40 mg / ml R-ketamine free base (46 mg / ml R-ketamine HCl salt) in 20 mM fumarate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0264] R-ketamine formulation (80 mg / mL) at pH 5.0 in 20 mM fumarate buffer, and R-ketamine formulation (80 mg / mL) at pH 5.7 in 20 mM fumarate buffer

[0265] Formulations are prepared, for example, by adding the equivalent of 80 mg / ml of R-ketamine free base (92 mg / ml of R-ketamine HCl salt) in 20 mM fumarate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0266] Example 6. R-Ketamine Formulation in Citrate Buffer R-ketamine formulations at various pH values ​​were prepared in citrate buffer, and the citrate buffer was prepared accordingly.

[0267] Prepare 1 liter of citrate buffer 20 mM pH 5 [Table 12] 1. Prepare 800 mL of distilled water in a suitable container. 2. Add 3.42 g of sodium citrate dihydrate to the solution. 3. Add 1.608g of citric acid to the solution. 4. Adjust the solution to the final desired pH using HCl or NaOH. 5. Add distilled water until the volume is 1 L.

[0268] Prepare 1 liter of citrate buffer at pH 5.7 [Table 13] 1. Prepare 800 mL of distilled water in a suitable container. 2. Add 4.424 g of sodium citrate dihydrate to the solution. 3. Add 0.953 g of citric acid to the solution. 4. Adjust the solution to the final desired pH using HCl or NaOH. 5. Add distilled water until the volume is 1 L.

[0269] R-ketamine formulation (40 mg / mL) at pH 5.0 in 20 mM citrate buffer, and R-ketamine formulation (40 mg / mL) at pH 5.7 in 20 mM citrate buffer

[0270] Formulations are prepared, for example, by adding the equivalent of 40 mg / ml of R-ketamine free base (46 mg / ml of R-ketamine HCl salt) in 20 mM citrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0271] R-ketamine formulation (80 mg / mL) at pH 5.0 in 20 mM citrate buffer, and R-ketamine formulation (80 mg / mL) at pH 5.7 in 20 mM citrate buffer

[0272] Formulations are prepared, for example, by adding the equivalent of 80 mg / ml of R-ketamine free base (92 mg / ml of R-ketamine HCl salt) in 20 mM citrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0273] Example 7. R-Ketamine Formulation in Succinate Buffer R-ketamine formulations at various pH values ​​were prepared in succinate buffer. Succinate Buffer Components: Succinic acid, C4H4O4, mw 118.09 · NaOH, 1N aqueous solution Distilled H2O

[0274] Fumarate buffer (100 mL at 20 mM) was prepared, for example, by adding 0.236 g succinic acid, 2 mL NaOH, and adding H2O to 100 mL.

[0275] R-ketamine formulation (40 mg / mL) at pH 5.0 in 20 mM succinate buffer, and R-ketamine formulation (40 mg / mL) at pH 5.7 in 20 mM succinate buffer

[0276] Formulations are prepared, for example, by adding the equivalent of 40 mg / ml R-ketamine free base (46 mg / ml R-ketamine HCl salt) in 20 mM succinate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0277] R-ketamine formulation (80 mg / mL) at pH 5.0 in 20 mM succinate buffer, and R-ketamine formulation (80 mg / mL) at pH 5.7 in 20 mM succinate buffer

[0278] Formulations are prepared, for example, by adding the equivalent of 80 mg / ml of R-ketamine free base (92 mg / ml of R-ketamine HCl salt) in 20 mM succinate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0279] Example 8. R-Ketamine Formulation in Tartrate Buffer R-ketamine formulations at various pH values ​​were prepared in tartrate buffer.

[0280] Tartrate Buffer Components: · Tartaric acid, C4H6O6, mw 150.09 Sodium tartrate dihydrate, mw 230.08 · NaOH, 1N aqueous solution Distilled H2O

[0281] Tartrate buffer (1 L at 5 mM) is prepared, for example, by adding 0.75 g tartaric acid, 2 mL NaOH, and adding HO to 1 L. Tartrate buffer (1 L at 15 mM) is prepared, for example, by adding 3.425 g sodium tartrate dihydrate, 2 mL dilute acid, and adding HO to 1 L. Tartrate buffer (1 L at 20 mM) is prepared, for example, by adding 4.6 g sodium tartrate dihydrate, 2 mL dilute acid, and adding HO to 1 L.

[0282] R-ketamine formulation (40 mg / mL) at pH 5.0 in 20 mM tartrate buffer, and R-ketamine formulation (40 mg / mL) at pH 5.7 in 20 mM tartrate buffer

[0283] Formulations are prepared, for example, by adding the equivalent of 40 mg / ml R-ketamine free base (46 mg / ml R-ketamine HCl salt) in 20 mM tartrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0284] R-ketamine formulation (80 mg / mL) at pH 5.0 in 20 mM tartrate buffer, and R-ketamine formulation (80 mg / mL) at pH 5.7 in 20 mM tartrate buffer

[0285] Formulations are prepared, for example, by adding 80 mg / ml of R-ketamine free base equivalent (92 mg / ml of R-ketamine HCl salt) in 20 mM tartrate buffer, and the pH of the final formulation is adjusted to a pH of 5.0 or equivalent to a pH of 5.7 using HCl or NaOH (less than 0.2 M or 0.15 M).

[0286] Equivalent While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications, and other variations thereof will be apparent to those skilled in the art, and all such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present invention.

Claims

1. A subcutaneous formulation containing R-ketamine, substantially free of S-ketamine, wherein the R-ketamine is present at a concentration of 60 mg / mL to 150 mg / mL.

2. The formulation according to claim 1, wherein the R-ketamine is present at concentrations of 70 mg / mL to 120 mg / mL, 70 mg / mL to 100 mg / mL, and 75 mg / mL to 100 mg / mL.

3. The formulation according to claim 1, wherein the R-ketamine is present at a concentration of 60 mg / mL, 65 mg / mL, 70 mg / mL, 75 mg / mL, 80 mg / mL, 85 mg / mL, 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, or 110 mg / mL.

4. The formulation according to claim 1, wherein the pH of the formulation is 6.0 or less.

5. The formulation according to claim 1, wherein the pH of the formulation is 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.

0.

6. The formulation according to claim 1, wherein the pH of the formulation is 5.70 to 5.

80.

7. The formulation according to claim 1, wherein the subcutaneous formulation has a pH below 5.

8.

8. The formulation according to claim 1, wherein the subcutaneous formulation has a pH of 5.8 or 5.

75.

9. The formulation according to claim 1, wherein the subcutaneous formulation further comprises a buffer, wherein the buffer is optionally selected from one or more of succinate buffer, tartrate buffer, phosphate buffer, maleate buffer, fumarate buffer, citrate buffer, and acetate buffer.

10. A subcutaneous injection preparation of R-ketamine according to Claim 1, a) R-ketamine in a concentration of 90 mg / mL to 110 mg / mL, b) Including a buffering agent, A formulation wherein the pH of the formulation is 5.8 or less, and the formulation substantially does not contain S-ketamine.

11. The formulation according to claim 10, wherein the R-ketamine is present at a concentration of 90 mg / mL, 95 mg / mL, 100 mg / mL, 105 mg / mL, or 110 mg / mL.

12. The formulation according to claim 10, wherein the pH of the formulation is 5.8, 5.75, or 5.

7.

13. The formulation according to any one of claims 9 to 12, wherein the buffering agent is selected from one or more of phosphate buffer, maleate buffer, fumarate buffer, citrate buffer, and acetate buffer.

14. A process for preparing the formulation according to claim 1, comprising adjusting the pH using a diluting acid or a diluting base.

15. A formulation according to claim 1 for the treatment of a disease or condition, wherein the disease or condition is optionally depression or depressive symptoms.

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