Esketamine preparations, and methods for preparing and storing the same.

Abstract

Providing a process for preparing a stable pharmaceutical composition containing esketamine. [Solution] A process for preparing a pharmaceutical composition comprising 0.2% (HPLC area) or less of 6-(2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof relative to the amount of esketamine, or 0.2 w / w or less of 6-(2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof relative to the weight of esketamine, the process comprising: exposing the pharmaceutical composition to light for about 6 hours or less during the preparation of the composition; filling the pharmaceutical composition into a container in the absence of light; and then storing the pharmaceutical composition in a container having an opacity that, as measured using an opacity meter, allows 10% or less of the light passing through the container.

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the priority of U.S. Provisional Patent Application No. 62 / 947,38 7, filed on December 12, 2019, the disclosure of which is incorporated herein by reference.

[0002] (Field of the Invention) The present invention relates to a pharmaceutical composition containing esketamine, and a method for preparing and storing the same.

[0003] (Background) Major Depressive Disorder (MDD) affects approximately 7 - 15% of the general population. MDD is associated with significant morbidity and mortality and is a major debilitating cause worldwide. Approximately one - third of patients are unable to achieve remission despite treatment with multiple antidepressants and are considered to have Treatment Resistant Depression (TRD). Such patients who do not benefit from oral antidepressants also have a high recurrence rate while continuing treatment.

[0004] The impact of TRD on patients' lives is difficult to adequately describe. Many patients have depressive episodes that last for years. Severe depressed patients lose the will to continue their lives, and the rate of suicide attempts increases seven - fold. The average life expectancy is shortened by 10 years. In extreme cases, they are unable to even manage basic self - care such as bathing, eating, or taking care of themselves, and leave all of their care to parents, spouses, etc. This affects not only the patients themselves, ​Losing the ability to feel joy deprives people of the essence of life and its driving force. In reality, their lives are being taken away from them by TRD.

[0005] Currently, pharmaceutical compositions containing esketamine are approved for the treatment of TRD. This composition is designed for administration to humans, thereby ensuring safe and effective treatment. A precise amount of esketamine is needed to ensure the treatment is effective.

[0006] Therefore, while being limited by impurities and / or degradation products, during or after formulation, The need to ensure an accurate dosage of esketamine remains.

[0007] (overview) In some embodiments, the Disclosure relates to esketamine or its pharmaceutically acceptable salts. The present invention provides a pharmaceutical composition comprising an oxidative decomposition product. In a particular embodiment, the oxidative decomposition product is 6 -(2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. In other embodiments, the pharmaceutical composition is (i) 0.2% (HPLC) relative to the amount of esketamine. 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable amount (area) or less (ii) Salts that are added, (ii) 6-(2-chlorohydrate) at a concentration of 0.2% w / w or less relative to the weight of esketamine. (iii) 6-oxohexanoic acid or a pharmaceutically acceptable salt thereof, or 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable concentration of 120 ppm or less Includes salts that are permissible in some embodiments. In some embodiments, esketamine is in the form of a salt, for example If it is a salt of the (S)-enantiomer of ketamine, and an oxidative decomposition product, particularly 6-(2 The amount of -chlorophenyl)-6-oxohexanoic acid is defined relative to the amount of esketamine. In this case, this is the acid relative to the total amount of the salt of the (S)-enantiomer of ketamine on an absolute basis. Amount of decomposition products (i.e., the total amount of the decomposition agent relative to the salt of the (S)-enantiomer of ketamine) It is intended to be interpreted as referring to the quantity of [something].

[0008] In other embodiments, the disclosure includes esketamine or a pharmaceutically acceptable salt thereof. A method for preventing the formation of oxidative decomposition products in a pharmaceutical composition, wherein the pharmaceutical composition is exposed to light. Prepare in the absence of light, store the pharmaceutical composition in the absence of light, and allow the pharmaceutical composition to be used for about 6 Exposure to light for less than an hour, or filling a pharmaceutical composition into a container in the absence of light. The present invention provides a method comprising one or more of the following: a pharmaceutical composition The composition is exposed to light for approximately 6 hours or less during the combined preparation and storage period. More preferably, the pharmaceutical composition, during the combined period of the composition preparation period and storage period, The device is exposed to light for approximately one hour or less, and more preferably for approximately 30 minutes or less.

[0009] In further embodiments, the disclosure relates to esketamine or a pharmaceutically acceptable salt thereof, (i) 6-(2-chlorophosphate) less than 0.2% (HPLC area) of the amount of esketamine (ii) phenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof, (ii) esketamine 6-(2-chlorophenyl)-6-oxohexa (iii) 6-(2-) acid or a pharmaceutically acceptable salt thereof, or (iii) 6-(2-) acid at approximately 120 ppm or less. Pharmaceutical composition comprising lolophenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. A process for preparing a substance, comprising mixing esketamine or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients, and exposing the esketamine to light for about 6 hours or less, provides a process.

Brief Description of the Drawings

[0010] [Figure 1] It is a superposition of full wavelength chromatograms (210 - 500 nm; μAU vs. time), showing the results of light / heat stress (A) and heat stress (B) samples compared with discolored (C) and non-discolored vials from the same batch (batch 1) (D). [Figure 2] It is a bar graph comparing the color tone changes observed in vials of different esketamine batches continuously exposed to D50 light (the same esketamine hydrochloride batch was used for vials without stoppers and batch 6). The numbers in parentheses indicate the number of vials used to calculate the average value. [Figure 3] It is a line graph comparing the color tone changes of stoppered vials of batch 7 stored in the dark at room temperature when continuously exposed to D50 light, when exposed to D50 light for 15 days, and after ICH exposure twice (16 hours). [Figure 4] It is a line graph comparing the color tone changes of stoppered vials of batch 5 (top) and batch 1 (bottom) when exposed to ICH light twice and then stored in the dark at room temperature or 70°C. [Figure 5] It shows a line graph (top) showing the case where the orientation of the vials of batch 6 is different, and a line graph (bottom) showing the comparison of vials of the same esketamine hydrochloride batch with and without stoppers (both upward).

[0011] (Detailed Description of Embodiments) Some of the quantitative expressions given herein are not modified by the term "about". The term "about" Whether or not explicitly used, all quantities given herein This refers to the actual given value, and also to the experimental and / or measurement conditions of such a given value. This includes approximations, and can be reasonably estimated based on the usual skill in the relevant technical field. It is understood that this can also mean referring to an approximation of a given value.

[0012] The present inventors attempted to provide an esketamine preparation free of impurities, but esketamine We found that a solution containing tamine decomposes under certain conditions. In some embodiments... Upon contact with the esketamine solution, a change in color, the formation of solid matter, and / or previously recognized By-products that were not anticipated were generated. Such changes are now, in particular, breakdown products. It has been confirmed that these degradation products and patients This addresses the need for a product containing a similarly acceptable amount for administration to [the target population].

[0013] As used herein, unless otherwise specified, the term "esketamine" refers to ketamine. (S)-enantiomer, i.e., formula (I):

[0014] [ka] This refers to the compound (S)-2-(2-chlorophenyl)-2-(methyl Also known as minocyclohexanone. "Esketamine" is also a salt, for example, Chloride salts such as the hydrochloride of the (S)-enantiomer of ketamine, i.e., formula (II):

[0015] [ka] This refers to the compound (S)-2-(2-chlorophenyl)-2-(methyl Also known as minocyclohexanone hydrochloride. Preferably, esketamine is ( Form of S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride It is a state.

[0016] In some embodiments, esketamine is the (R)-enantiomer of ketamine, that is, Wachi, equation (III):

[0017] [ka] It is substantially free of the compound.

[0018] In other embodiments, esketamine is approximately 10 based on the weight of the esketamine sample. It contains less than % by weight of the (R)-enantiomer of ketamine. In further embodiments, Esketamine is less than approximately 10% by weight, based on the weight of the esketamine sample, and approximately 9% by weight. Less than %, less than approximately 8% by weight, less than approximately 7% by weight, less than approximately 6% by weight, less than approximately 5% by weight, approximately 4% by weight Less than %, less than approximately 3% by weight, less than approximately 2% by weight, less than approximately 1% by weight, less than approximately 0.5% by weight, approximately 0 Ketamine in amounts less than 0.1% by weight, less than approximately 0.005% by weight, or less than approximately 0.001% by weight. It contains the R)-enantiomer. In yet another embodiment, esketamine is esketamine Based on the weight of the sample, approximately 0.001 to 10% by weight of ketamine (R)-enan It contains thiomer. In further embodiments, esketamine is esketamine sa Based on the sample weight, approximately 0.001 to approximately 10% by weight, approximately 0.001 to approximately 5% by weight, approximately 0.001 to about 1% by weight, about 0.001 to about 0.5% by weight, about 0.001 to about 0.1% by weight %, approximately 0.1 to approximately 5% by weight, approximately 0.1 to approximately 1% by weight, approximately 0.1 to approximately 5% by weight, or approximately 0. It contains 5 to approximately 5% by weight of ketamine (R)-enantiomer. Preferably, the pharmaceutical composition The substance is approximately 10 times the total weight of the (S)-enantiomer of ketamine in the pharmaceutical composition. Less than % by weight, more preferably less than about 1% by weight, and even more preferably less than about 0.1% by weight. It contains the (R)-enantiomer of tamin.

[0019] The term "esketamine" also refers to other pharmaceutically acceptable substances that can be readily selected by those skilled in the art. It may also include the salts that are toxic. "Medically acceptable salts" are non-toxic and biologically tolerable. This refers to salts of esketamine that are, in some respect, or otherwise, biologically suitable for administration to the subject. It is intended to be. Generally, see GSPaulekuhn, "Trends in Active Pharmaceutical Ingredient Salt S election based on Analysis of the Orange Book Database”, J.Med.Chem.,2007,50:6665 -72, SMBerge, "Pharmaceutical Salts", JP harm Sci., 1977, 66:1-19, and Handbook of Pha rmaceutical Salts,Properties,Selection,a nd Use,Stahl and Wermuth,Eds.,Wiley-VCH See and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts. It is pharmacologically effective and can be administered to patients without excessive toxicity, irritation, or allergic reactions. This salt is suitable for administration to [the patient].

[0020] Other examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, and sulfites. , bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyro Phosphates, bromides (such as hydrobromides), iodides (such as hydroiodides), acetates, pr Ropionate, decantate, caprylate, acrylate, formate, isobutyrate, capro Salts, heptanes, propiolates, oxalates, malons, succinates, sucroses Phosphates, sebacinates, fumarates, maleates, butin-1,4-diates, hex Syn-1,6-diote, benzoate, chlorobenzoate, methylbenzoate, dinitro Benzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, Xylene sulfonate, phenyl acetate, phenylpropionate, phenyl butyrate, Ethanol, lactate, γ-hydroxybutyrate, glycolate, tartrate, methanesulfone Salts, propane sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates Examples include esterates and mandelates. In particular, the salts of esketamine are hydrochlorides.

[0021] Esketamine composition This disclosure relates to a pharmaceutical combination comprising esketamine or a pharmaceutically acceptable salt thereof and an oxidative degradation product. Provides a product. As used herein, the term "composition" means a product containing specific components in specific amounts. Products containing, as well as those resulting directly or indirectly from specific combinations of amounts of specific components. It shall include any generated products.

[0022] As used herein, the term “oxidative decomposition product” refers to the result of the oxidation of esketamine. This refers to the compounds that are formed, thereby causing the breakdown of esketamine. The chemical reaction is thought to be caused by external factors unrelated to the components of the composition. Factors include exposure to light such as visible light, ultraviolet light, or combinations thereof. These are possible, but are not limited to these. Therefore, oxidative decomposition products can be photooxidative decomposition products. Furthermore, the inventors have found that other external factors such as oxygen and heat promote the oxidation of esketamine. We found that this could be helpful in determining the form of the oxidative decomposition products, regardless of the source of the oxidative decomposition products. Formation may occur via an autocatalytic cycle. Therefore, esketamine is It is desirable to prevent or minimize exposure to such external factors.

[0023] Therefore, in some embodiments, the oxidative decomposition product is 6-(2-chlorophenyl )-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. In other embodiments, The oxidative decomposition product is 6-(2-chlorophenyl)-6-oxohexanoic acid. Further results In the application method, the oxidative decomposition product is 6-(2-chlorophenyl)-6-oxohexanoic acid. It is salt.

[0024] "6-(2-chlorophenyl)-6-oxohexanoic acid" is a chemical compound having the following structure. It refers to a combination of ingredients.

[0025] [ka]

[0026] The presence and amount of oxidative decomposition products in a pharmaceutical composition can be determined by those skilled in the art. Appropriate analytical procedures that may be used to detect catalytic decomposition products include, but are not limited to, thin-layer analysis. Chromatography (TLC), liquid chromatography (LC), high-performance liquid chromatography Raffie (HPLC), mass spectrometry (MS), LC-MS; nuclear magnetic resonance spectroscopy ( NMR; 1 H and 13 C) or elemental analysis, or a combination thereof. Preferably, the oxidative decomposition products are detected and measured using HPLC or LC-MS. As those familiar with the subject will understand, in HPLC analysis of pharmaceutical compositions, each component in the mixture is analyzed by 1 A spectrum with 1 peak is obtained. The ratio of each component is the area of ​​each peak, and each peak It is proportional to the height of the components in the pharmaceutical composition, or the ratio of their combinations. Preferably, the components in the pharmaceutical composition The ratio is calculated by the peak area. Therefore, HPLC is used to detect esketamine in medicines. It is particularly useful when measuring the purity of all pharmaceutical compositions, including drug compositions.

[0027] In the case of a pharmaceutical composition containing esketamine, the presence and amount of oxidative decomposition products are present in the pharmaceutical composition. It can be measured relative to the amount of esketamine present and expressed as a weight percentage.

[0028] In other embodiments, the presence and amount of oxidative decomposition products are defined as the esketamine compound containing the oxidative decomposition products. This can be measured by comparing the LC peaks (such as HPLC peaks) of the product. Thus, the peaks corresponding to the oxidative decomposition products and the peaks corresponding to esketamine present in the pharmaceutical composition are observed. The corresponding peaks are compared and their ratio is calculated. In some embodiments, the pharmaceutical composition The substance contains esketamine base, and the area of ​​the HPLC peak corresponding to the oxidative decomposition product is esketamine. The ratio of the area of ​​the HPLC peak corresponding to the thamin base is calculated. The pharmaceutical composition contains an esketamine salt, and the HPLC peaks corresponding to the oxidative decomposition products are... The ratio of the product to the area of ​​the HPLC peak corresponding to the esketamine salt is calculated. Regardless of the form of esketamine in the pharmaceutical composition, HPLC can be used to analyze the oxidative decomposition of sea urchin. It is possible to calculate the quantity.

[0029] In a further embodiment, the amount of oxidative decomposition products, no matter how small, can be measured and quantified. This is possible. Typically, the amount of oxidative decomposition products is measured in parts per million (ppm) concentration. The eel concentration can be measured using conventional techniques known in the art. The concentration of oxidative decomposition products is calculated in milligrams per liter. Therefore, The ppm of oxidative decomposition products in a pharmaceutical composition is expressed as mg of oxidative decomposition products per liter of solution. It can be adjusted based on the volume of the pharmaceutical composition.

[0030] The pharmaceutical compositions of esketamine described herein are preferably free of impurities. However, the ability to maintain the impurity content in a pharmaceutical composition at 0% is particularly important for such compositions. Storing for a fixed period of time is often impractical. Therefore, it is preferable to have existing and Impurities that may form during and / or storage are kept to a minimum. In some embodiments In this disclosure, the esketamine pharmaceutical composition is approximately 0.2% (H) relative to the amount of esketamine. It contains impurities such as oxidative decomposition products with a PLC area of ​​less than or equal to (NMT). Preferably, pharmaceutical The composition contains 6-(2-chloroform) at a concentration of 0.2% (HPLC area) or less relative to the amount of esketamine. Contains hydroxyphenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. Furthermore, the pharmaceutical composition is 0.1% (HPLC area) or less relative to the amount of esketamine. More preferably, 0.05% (HPLC area) or less of 6-(2-chlorophenyl)-6 -Contains oxohexanoic acid or a pharmaceutically acceptable salt thereof. In other embodiments, The pharmaceutical composition contains no oxidative decomposition products or other undesirable substances at a concentration of 0.2% w / w or less relative to the weight of esketamine. It contains a pure substance. Preferably, the pharmaceutical composition contains 0.2% w of esketamine by weight. / w or less 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable It contains a salt. More preferably, the pharmaceutical composition contains 0. 6-(2-chlorophenyl) 1% w / w or less, more preferably 0.05% w / w or less It contains )-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. Further embodiments In this case, the pharmaceutical composition contains impurities such as oxidative decomposition products at a concentration of approximately 120 ppm or less. Furthermore, the pharmaceutical composition contains approximately 120 ppm or less of 6-(2-chlorophenyl)-6-oxygen It contains sohexanoic acid or a pharmaceutically acceptable salt thereof. More preferably, the pharmaceutical composition , approximately 60 ppm or less, more preferably approximately 30 ppm or less of 6-(2-chlorophenyl It contains )-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the pharmaceutical composition contains about 0.00 of the amount of esketamine. 1%, 0.0015%, 0.002%, 0.0025%, 0.003%, 0.0035% , 0.0040%, 0.0045%, 0.0050%, 0.0055%, 0.0060% , 0.0065%, 0.0070%, 0.0075%, 0.0080%, 0.0085% , 0.0090%, 0.0095%, 0.010%, 0.015%, 0.02%, 0.0 25%, 0.03%, 0.035%, 0.040%, 0.045%, 0.050%, 0. 0.55%, 0.060%, 0.065%, 0.070%, 0.075%, 0.080%, 0.085%, 0.090%, 0.095%, 0.1%, or 0.15% (HPLC area) ) Contains the following oxidative decomposition products. In other embodiments, the pharmaceutical composition contains esketamine It contains approximately 0.001% to 0.2% (HPLC area) of oxidative decomposition products relative to the volume. In one embodiment, the pharmaceutical composition is approximately 0.001% to approximately esketamine. 0.2%, 0.0015%~approximately 0.2%, 0.002%~approximately 0.2%, 0.0025%~ Approximately 0.2%, 0.003% to approximately 0.2%, 0.0035% to approximately 0.2%, 0.0040% ~approximately 0.2%, 0.0045%~approximately 0.2%, 0.0050%~approximately 0.2%, 0.005 5% to approximately 0.2%, 0.0060% to approximately 0.2%, 0.0065% to approximately 0.2%, 0.0 0.70%~approximately 0.2%, 0.0075%~approximately 0.2%, 0.0080%~approximately 0.2%, 0 0.0085%~approximately 0.2%, 0.0090%~approximately 0.2%, 0.0095%~approximately 0.2% , 0.010%~approximately 0.2%, 0.015%~approximately 0.2%, 0.02%~approximately 0.2%, 0 0.025%~approximately 0.2%, 0.03%~approximately 0.2%, 0.035%~approximately 0.2%, 0.0 40% to approximately 0.2%, 0.045% to approximately 0.2%, 0.050%, 0.055% to approximately 0. 2%, 0.060% to approximately 0.2%, 0.065% to approximately 0.2%, 0.070% to approximately 0.2% %, 0.075%~approximately 0.2%, 0.080%~approximately 0.2%, 0.085%~approximately 0.2% , 0.090% to approximately 0.2%, 0.095% to approximately 0.2%, 0.1% to approximately 0.2%, or It contains oxidative decomposition products at a concentration of 0.15% to approximately 0.2% (HPLC area). Furthermore, in other embodiments... In this case, the pharmaceutical composition is approximately 0.001% to approximately 0.15% relative to the amount of esketamine. 0.001% to approximately 0.1%, approximately 0.001% to approximately 0.095%, approximately 0.001% to approximately 0. 0.90%, approximately 0.001% to approximately 0.085%, approximately 0.001% to approximately 0.080%, approximately 0. 0.001% to approximately 0.075%, approximately 0.001% to approximately 0.070%, approximately 0.001% to approximately 0. 0.65%, approximately 0.001% to approximately 0.060%, approximately 0.001% to approximately 0.055%, approximately 0. 0.001% to approximately 0.050%, approximately 0.001% to approximately 0.045%, approximately 0.001% to approximately 0. 0.40%, approximately 0.001% to approximately 0.035%, approximately 0.001% to approximately 0.03%, approximately 0.0 0.01% to approximately 0.025%, approximately 0.001% to approximately 0.02%, approximately 0.001% to approximately 0.01% 5%, approximately 0.001% to approximately 0.010%, approximately 0.001% to approximately 0.0095%, approximately 0.0 0.01% to approximately 0.0090%, approximately 0.001% to approximately 0.0085%, approximately 0.001% to approximately 0 0.0080%, approximately 0.001% to approximately 0.0075%, approximately 0.001% to approximately 0.0070% Approximately 0.001% to approximately 0.0065%, approximately 0.001% to approximately 0.0060%, approximately 0.00 1% to approximately 0.0055%, approximately 0.001% to approximately 0.0050%, approximately 0.001% to approximately 0. 0.0045%, approximately 0.001% to approximately 0.0040%, approximately 0.001% to approximately 0.0035%, Approximately 0.001% to approximately 0.003%, approximately 0.001% to approximately 0.0025%, approximately 0.001% Oxidative decomposition products of approximately 0.002%, 0.001%, and 0.0015% (HPLC area) Contains.

[0032] In another embodiment, the pharmaceutical composition is approximately 0.001% by weight of esketamine. , 0.0015%, 0.002%, 0.0025%, 0.003%, 0.0035%, 0 0.0040%, 0.0045%, 0.0050%, 0.0055%, 0.0060%, 0 0.0065%, 0.0070%, 0.0075%, 0.0080%, 0.0085%, 0 0.0090%, 0.0095%, 0.010%, 0.015%, 0.02%, 0.025 %, 0.03%, 0.035%, 0.040%, 0.045%, 0.050%, 0.05 5%, 0.060%, 0.065%, 0.070%, 0.075%, 0.080%, 0. Oxidation content of 0.85%, 0.090%, 0.095%, 0.1%, or 0.15% w / w or less It contains a solution. In other embodiments, the pharmaceutical composition is, relative to the weight of esketamine, It contains approximately 0.001% to approximately 0.2% w / w of oxidative decomposition products. In further embodiments, The pharmaceutical composition is approximately 0.001% to 0.2% of the weight of esketamine, and 0.001 5% to approximately 0.2%, 0.002% to approximately 0.2%, 0.0025% to approximately 0.2%, 0.00 3% to approximately 0.2%, 0.0035% to approximately 0.2%, 0.0040% to approximately 0.2%, 0.0 0.45%~approximately 0.2%, 0.0050%~approximately 0.2%, 0.0055%~approximately 0.2%, 0 0.0060%~approximately 0.2%, 0.0065%~approximately 0.2%, 0.0070%~approximately 0.2% , 0.0075%~approximately 0.2%, 0.0080%~approximately 0.2%, 0.0085%~approximately 0. 2%, 0.0090%~approximately 0.2%, 0.0095%~approximately 0.2%, 0.010%~approximately 0 0.2%, 0.015%~approximately 0.2%, 0.02%~approximately 0.2%, 0.025%~approximately 0.2 %, 0.03% to approximately 0.2%, 0.035% to approximately 0.2%, 0.040% to approximately 0.2%, 0.045%~approximately 0.2%, 0.050%, 0.055%~approximately 0.2%, 0.060%~ Approximately 0.2%, 0.065% to approximately 0.2%, 0.070% to approximately 0.2%, 0.075% to approximately 0.2%, 0.080%~approximately 0.2%, 0.085%~approximately 0.2%, 0.090%~approximately 0 0.2%, 0.095% to approximately 0.2%, 0.1% to approximately 0.2%, or 0.15% to approximately 0.2% It contains %w / w oxidative decomposition products. In yet another embodiment, the pharmaceutical composition is esketa Approximately 0.001% to 0.15% of the min's weight, approximately 0.001% to 0.1%, approximately 0.001% to approximately 0.095%, approximately 0.001% to approximately 0.090%, approximately 0.001% to approximately 0.085%, approximately 0.001% to approximately 0.080%, approximately 0.001% to approximately 0.075%, approximately 0.001% to approximately 0.070%, approximately 0.001% to approximately 0.065%, approximately 0.001% to approximately 0.060%, approximately 0.001% to approximately 0.055%, approximately 0.001% to approximately 0.050%, approximately 0.001% to approximately 0.045%, approximately 0.001% to approximately 0.040%, approximately 0.001% to approximately 0.035%, approximately 0.001% to approximately 0.03%, approximately 0.001% to approximately 0.025%, approximately 0 0.001% to approximately 0.02%, approximately 0.001% to approximately 0.015%, approximately 0.001% to approximately 0. 0.10%, approximately 0.001% to approximately 0.0095%, approximately 0.001% to approximately 0.0090%, approximately 0.001% to approximately 0.0085%, approximately 0.001% to approximately 0.0080%, approximately 0.001% ~approximately 0.0075%, approximately 0.001%~approximately 0.0070%, approximately 0.001%~approximately 0.00 65%, approximately 0.001% to approximately 0.0060%, approximately 0.001% to approximately 0.0055%, approximately 0 0.001% to approximately 0.0050%, approximately 0.001% to approximately 0.0045%, approximately 0.001% to Approximately 0.0040%, approximately 0.001% to approximately 0.0035%, approximately 0.001% to approximately 0.003 %, approximately 0.001% to 0.0025%, approximately 0.001% to 0.002%, or approximately 0. It contains approximately 0.0015% w / w of oxidative decomposition products.

[0033] In a further embodiment, the pharmaceutical composition contains approximately 120 ppm, approximately 110 ppm, and approximately 100 ppm. ppm, approx. 90ppm, approx. 80ppm, approx. 70ppm, approx. 60ppm, approx. 50ppm, approx. 40 ppm, approximately 30 ppm, approximately 20 ppm, approximately 10 ppm, approximately 5 ppm, or approximately 1 ppm The following impurities, such as oxidative decomposition products, are present in some embodiments of the pharmaceutical composition. These ranges from approximately 1 to 120 ppm, approximately 10 to 110 ppm, approximately 10 to 100 ppm, and approximately 10 ~90 ppm, approximately 10~80 ppm, approximately 10~70 ppm, approximately 10~60 ppm Approximately 10-50 ppm, approximately 10-40 ppm, approximately 10-30 ppm, or approximately 10- It contains approximately 20 ppm of oxidative decomposition products. In other embodiments, the pharmaceutical composition contains approximately 5 to approximately 120 ppm, approximately 10 to approximately 120 ppm, approximately 20 to approximately 120 ppm, approximately 30 to approximately 120 ppm pm, about 40 to about 120ppm, about 50 to about 120ppm, about 60 to about 120ppm, about 70-120 ppm, 80-120 ppm, 90-120 ppm, 100- It contains approximately 120 ppm, or approximately 110 to 120 ppm or less, of oxidative decomposition products.

[0034] Furthermore, the amount of oxidizing impurities present in the solution can be measured according to the color of the pharmaceutical composition. Yes, it is possible. For example, it is possible to visually inspect a pharmaceutical composition and determine its color. This determines the yellow hue of the pharmaceutical composition. In some embodiments, the degree of decomposition is A color scale can be used to make a judgment. For example, a color scale from 1 to 9 Kale can be used, where 1 = colorless, 9 = yellow / brown. Values ​​between them are, for example, 2 = 3 = very slight yellow, 4 = bright yellow, 5 = yellow, 6 = slightly dark yellow 7 = dark yellow, 8 = very dark yellow, and so on, corresponding to progressively increasing yellow intensities. The degree of discoloration or yellowing of the solution is as follows: European Pharmacopoeia, 7th Edition, Chapter 2, Section 2.2.1, and This can be determined as described in Section 2.2.1, pages 21-24, and this is relevant. This is incorporated herein by reference. For example, the degree of coloring can be determined by the following procedure: (i (ii) Use a colorless, transparent, neutral glass tube with a flat bottom and an inner diameter of 15mm to 25mm. (iii) Add the test solution to one tube, and add water to the other tube, or add a solution containing esketamine. (iv) Add a solution containing EDTA, citric acid, and water at pH 4, and under diffuse daylight, the white Compare the colors of each tube by viewing them perpendicular to the background.

[0035] Oxidative decomposition products may be formed at any point during the preparation or storage of the pharmaceutical composition. In some embodiments, oxidative decomposition products are formed during the preparation of the pharmaceutical composition. In this embodiment, the oxidative decomposition product is formed during storage of the pharmaceutical composition. In other embodiments... Furthermore, oxidative decomposition products are formed during preparation and continue to increase even after storage in the absence of light.

[0036] As those skilled in the art will understand, once prepared, a pharmaceutical composition is determined by those skilled in the art. During the period in which it is used, it may be packaged and optionally stored. In some embodiments, medical The drug composition is stored for at least about one week. In other embodiments, the pharmaceutical composition is less At least about 1 month, at least about 3 months, at least about 6 months, at least about 12 months, It will be stored for at least approximately 18 months, or at least approximately 24 months. However, preferably, The pharmaceutical composition, before, during, and / or after storage, (i) in relation to the amount of esketamine , 6-(2-chlorophenyl)-6-oxohexanoic acid at a concentration of 0.2% (HPLC area) or less or a pharmaceutically acceptable salt thereof, (ii) 0.2% w / w of esketamine by weight The following 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable form Salt, or (iii) 6-(2-chlorophenyl)-6-oxohexyl phosphate at approximately 120 ppm or less It contains sanic acid or a pharmaceutically acceptable salt thereof. Preferably, the pharmaceutical composition is stored in a container. At the time of filling the container, (i) 0.2% (HPLC area) of the amount of esketamine Below, more preferably 0.1% (HPLC area) or less, and even more preferably 0.05% (H 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable properties (PLC area) (ii) Salts that are permissible, (ii) less than 0.2% w / w of the weight of esketamine, more preferably Or 0.1% w / w or less, more preferably 0.05% w / w or less of 6-(2-chloromethylcellulose (iii) 6-oxohexanoic acid or a pharmaceutically acceptable salt thereof, or 120 ppm or less, more preferably about 60 ppm or less, and even more preferably about 30 ppm The following 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable form Contains salt.

[0037] According to this disclosure, the pharmaceutical composition is prepared in the absence of light in order to prevent or minimize oxidative degradation. It is preferable that it be stored or prepared in [a specific location]. The term "light" as used herein refers to visible light. This refers to light or light having a wavelength of approximately 380 nm to approximately 750 nm. The term "light" also refers to, This may include light with wavelengths outside this range. For example, the light may be ultraviolet light.

[0038] Storage in the absence of light is preferable, as measured using an opacity meter, when the container passes through. Approximately 10% or less of the light passing through, more preferably approximately 5% or less of the light passing through the container. This refers to the storage of pharmaceutical compositions in containers having an opacity that allows less than approximately 1% of light to pass through. Furthermore, the container containing the pharmaceutical composition should have an ambient light level of less than approximately 10 lux, more preferably about 1 lux. Less than 0.1 lux, more preferably less than about 0.1 lux, and most preferably less than 0.01 lux. It is preferable to store it under these conditions.

[0039] Exposure to light is preferably at least 0.1 lux, more preferably at least 1 lux This refers to the exposure of a pharmaceutical composition to light of a certain intensity.

[0040] Typically, the exposure time of a pharmaceutical composition to light is controlled to prevent or minimize oxidative degradation. It is limited. In some embodiments, exposure of the pharmaceutical composition to light is less than about 1 hour. In some embodiments, exposure of the pharmaceutical composition to light is less than about 30 minutes, or about 25 minutes. Less than, approximately less than 20 minutes, approximately less than 15 minutes, approximately less than 10 minutes, approximately less than 5 minutes, approximately less than 1 minute, approximately 30 seconds The time to light of the pharmaceutical composition is less than, less than approximately 15 seconds, or less than approximately 5 seconds. In other embodiments, the time to light of the pharmaceutical composition is less than, less than, approximately 15 seconds or less than, approximately 5 seconds. Exposure times range from approximately 1 second to 1 hour, approximately 10 seconds to 1 hour, approximately 15 seconds to 1 hour, and approximately 30 seconds to 1 hour. 1 hour, approximately 1 minute to approximately 1 hour, approximately 5 minutes to approximately 1 hour, approximately 10 minutes to approximately 1 hour, approximately 15 minutes to approximately 1 hour The intervals are approximately 20 minutes to 1 hour, 25 minutes to 1 hour, 30 minutes to 1 hour, or 45 minutes to 1 hour. This is 1 hour. In a further embodiment, the exposure of the pharmaceutical composition to light is approximately 1 second to approximately 45 minutes. , about 1 second to about 30 minutes, about 1 second to about 15 minutes, about 1 second to about 10 minutes, about 1 second to about 5 minutes, about 1 second to about 5 minutes Approximately 1 minute, approximately 10 seconds to approximately 45 minutes, approximately 10 seconds to approximately 30 minutes, approximately 10 seconds to approximately 15 minutes, approximately 10 seconds to approximately 10 minutes, about 10 seconds to about 5 minutes, about 10 seconds to about 1 minute, about 30 seconds to about 45 minutes, about 30 seconds to about 30 minutes, about 30 seconds to about 15 minutes, about 3 seconds to about 10 minutes, about 30 seconds to about 5 minutes, about 30 seconds to about 1 minute, about 1 minute to approximately 45 minutes, approximately 1 minute to approximately 30 minutes, approximately 1 minute to approximately 15 minutes, approximately 1 minute to approximately 10 minutes, or approximately 1 minute This takes approximately 5 minutes. Furthermore, exposure of the pharmaceutical composition to light during preparation or storage may be zero. The exposure of the pharmaceutical composition to light during preparation is preferably less than about 1 hour, more preferably about 30 minutes. Less than, and more preferably less than about 5 minutes. Exposure of the pharmaceutical composition to light during storage is about 1 It may be less than an hour, more preferably less than about 30 minutes, and even more preferably less than about 5 minutes. More preferably, the total exposure of the pharmaceutical composition to light during preparation and storage should be less than about 1 hour. The ideal duration is less than approximately 30 minutes, and more preferably less than approximately 5 minutes.

[0041] In some preferred embodiments, the pharmaceutical composition is stored in the absence of light and then... The amount of sketamine should be 0.2% or less (HPLC area), more preferably 0.1% (H 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable properties (PLC area) It is desirable to contain a salt that is permissible. In other preferred embodiments, the pharmaceutical composition After being stored in the absence of light for at least 6 months, esketamine or its pharmaceutically acceptable The amount of salt and esketamine is preferably 0.2% or less (HPLC area) relative to the amount of salt and esketamine. 6-(2-chlorophenyl)-6-oxohexanoic acid is present in a concentration of 0.1% (HPLC area) or less. or a pharmaceutically acceptable salt thereof. In a further preferred embodiment, the pharmaceutical composition After storage in the absence of light, the amount of esketamine was less than 0.2% w / w relative to its weight. Preferably 6-(2-chlorophenyl)-6-oxohexanoic acid at a concentration of 0.1% w / w or less. It is desirable that it contains a pharmaceutically acceptable salt thereof. In other preferred embodiments, Furthermore, the pharmaceutical composition, after being stored in the absence of light for at least 6 months, contains esketamine or The pharmaceutically acceptable salt, and a concentration of 0.2% w / w or less relative to the weight of esketamine, is preferable. Or 6-(2-chlorophenyl)-6-oxohexanoic acid or less at a concentration of 0.1% w / w or It contains a pharmaceutically acceptable salt thereof. In a more preferred embodiment, the pharmaceutical composition is light After storage in the absence of [unclear], 6-(2-chlorophenyl)-6-oxygenated chlorophenyl (6-(2-chlorophenyl)-6-oxygenated chlorophenyl) was stored at a concentration of approximately 120 ppm or less. It is desirable that it contains soxanoic acid or a pharmaceutically acceptable salt thereof. A more preferable substance In the application form, the pharmaceutical composition is stored in the absence of light for at least 6 months, and then approximately 12 6-(2-chlorophenyl)-6-oxygen 0 ppm or less, more preferably 60 ppm or less It is desirable that it contains soxohexanoic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition comprises esketamine or a pharmaceutically acceptable salt thereof, and about 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable concentration of 120 ppm or less It contains salts that are permissible. Preferably, the pharmaceutical composition is suitable for a relative humidity of about 25% to about 80%. In an atmosphere containing, at a temperature in the range of about 20°C to about 75°C, more preferably about 25% to about 3 It is stored in an atmosphere with 0% relative humidity at a temperature ranging from approximately 20°C to approximately 30°C.

[0042] Store the pharmaceutical composition in the absence of light (for example, when measured using an opacity meter, In a substantially opaque container having an opacity that allows less than approximately 10% of the light passing through the container. By storing the pharmaceutical composition under such conditions, the same pharmaceutical composition that was not stored under such conditions will be affected. In comparison, oxidative decomposition products, particularly 6-(2-chlorophenyl)-6-oxohexanoic acid or so The pharmaceutically acceptable salt concentration becomes lower. Similarly, the preparation of the pharmaceutical composition in the absence of light. Manufacturing and filling into containers (for example, when preparing a composition and filling the composition into a container, medical By exposing the drug composition to light for a total of 1 hour or less, preferably 30 minutes or less, the composition can be adjusted. Compared to the same pharmaceutical composition that is exposed to more light during the manufacturing and filling process, oxidative degradation The concentration of the substance decreases.

[0043] In a preferred embodiment, the pharmaceutical composition is stored for 6 months in the absence of light, and then... Ketamine or a pharmaceutically acceptable salt thereof, and 0.2% (HPL) relative to the amount of esketamine. 6-(2-chlorophenyl)-6-oxohexa (C area) or less or 0.2% w / w or less It contains nic acid or a pharmaceutically acceptable salt thereof. More preferably, the pharmaceutical composition is light-free. After being stored under normal conditions for 6 months, the amount of esketamine was 0.1% or less (HPLC area). This is 6-(2-chlorophenyl)-6-oxohexanoic acid or its medicinal properties at a concentration of 0.1% w / w or less. Contains pharmaceutically acceptable salts. Preferably, the pharmaceutical composition is fermented for 12 months in the absence of light, 18 After storage for 1 month or 24 months, 0.2% (HPLC area) of the amount of esketamine 6-(2-chlorophenyl)-6-oxohexanoic acid or so below 0.2% w / w It contains a pharmaceutically acceptable salt of . More preferably, the pharmaceutical composition is 1 in the absence of light. After storage for 2 months, 18 months, or 24 months, add 0.1% (H) of the amount of esketamine. 6-(2-chlorophenyl)-6-oxohexyl phosphate (PLC area) or less or 0.1% w / w or less Contains xanoic acid or a pharmaceutically acceptable salt thereof.

[0044] Preferably, the pharmaceutical composition is stored in a substantially opaque container. Preferably, substantially A truly opaque container, when measured using an opacity meter, allows approximately 10% of the light to pass through it. It has the following acceptable levels of opacity:

[0045] Pharmaceutical compositions may be stored under any conditions that do not impair the integrity of the components or the pharmaceutical composition. Yes, it is possible. Therefore, the pharmaceutical composition can be stored at a temperature in the range of approximately 20°C to approximately 75°C. Yes, it is possible. In some embodiments, the pharmaceutical composition is suitable for temperatures of approximately 20°C to approximately 70°C, and approximately 20°C to Approximately 65°C, approximately 20°C to approximately 60°C, approximately 20°C to approximately 55°C, approximately 20°C to approximately 50°C, approximately 20°C to Approximately 45°C, approximately 20°C to 40°C, approximately 20°C to 35°C, approximately 20°C to 30°C, approximately 25°C to Approximately 75°C, approximately 30°C to approximately 75°C, approximately 35°C to approximately 75°C, approximately 40°C to approximately 75°C, approximately 45°C to Approximately 75°C, approximately 50°C to approximately 75°C, approximately 55°C to approximately 75°C, approximately 60°C to approximately 75°C, or approximately 65°C It is stored at a temperature in the range of ℃ to approximately 75℃. In other embodiments, the pharmaceutical composition is approximately 20 ℃~approx. 40℃, approx. 20℃~approx. 35℃, approx. 20℃~approx. 30℃, approx. 20℃~approx. 25℃, approx. 25 Within the range of ℃ to approximately 40℃, approximately 25℃ to approximately 35℃, approximately 25℃ to approximately 30℃, or approximately 30℃ to approximately 40℃. It is stored at ambient temperature. Preferably, the pharmaceutical composition is stored under ambient conditions such as room temperature. Preferably, the room temperature corresponds to a temperature of approximately 20°C to 30°C.

[0046] Furthermore, it is desirable that the pharmaceutical composition be stored in a facility under conditions where the relative humidity is less than approximately 80%. i. In some embodiments, the pharmaceutical composition is about 25-80%, about 30-80% Approximately 35-80%, approximately 40-80%, approximately 45-80%, approximately 50-80%, approximately 55 ~80%, 60~80%, 65~80%, 70~80%, 75~80 %, approximately 25-75%, approximately 25-70%, approximately 25-65%, approximately 25-60%, approximately 2 5-55%, 25-50%, 25-45%, 25-40%, 25-3 It is stored in a facility with a relative humidity of 5%, or about 25-30%. Preferably, the pharmaceutical compound The finished product is stored in the facility under conditions of a relative humidity of approximately 25-30%.

[0047] To maintain the optimal performance and integrity of the pharmaceutical composition, the pharmaceutical composition is contained in a sealed container. The product is sealed or contained in a container. The container is made of any material that does not react with one or more components of the pharmaceutical composition. It can be composed of, which can be determined by those skilled in the art. Suitable for use as a container. Examples of materials used include, but are not limited to, glass, plastic, or metal. Preferably, the sealed container is made of glass, for example, a glass vial. Preferably, As described above, the container is substantially opaque to light. In some embodiments The container is amber-colored.

[0048] As used herein, the term “substantially opaque” means not transparent, i.e., that This refers to an object that does not allow light to pass through. Therefore, substantially opaque means a container. This refers to an object with opacity that allows approximately 10% or less of the light passing through it to pass through. The amount of light reflected from an object is measured using a light meter, preferably using the contrast ratio method. By determining this, it can be measured by those skilled in the art. In some embodiments, Qualitatively opaque means that approximately 9%, 8%, 7%, 6%, 5%, 4%, and 4% of the light is transmitted. Allowing 3%, approximately 2%, approximately 1%, approximately 0.5%, approximately 0.1% or less of light, or approximately 0% of light. Refers to. Preferably, "substantially opaque" means allowing about 5% or less of light to pass through the container. Having opacity, more preferably an opacity that allows about 1% or less of the light passing through the container. It refers to an object that possesses this property. Therefore, substantially opaque means that it reflects more than 90% of light. This refers to objects such as containers used in the specification. In some embodiments, used herein For containers and other substantially opaque objects used, the percentages are approximately 91%, 92%, 93%, and 94%. Reflects approximately 95%, 96%, 97%, 98%, 99% or more of light, or approximately 100% of light. do.

[0049] The container holding the pharmaceutical composition of esketamine is suitable for any device suitable for such purposes. It can be sealed or airtight using a seal. Examples of such devices are limited to While not the same thing, examples include lids, caps, and stoppers. The device is Preferably, it is composed of a material that does not react or interact with the components of the pharmaceutical composition. The container is sealed. Examples of materials that are not very suitable for this purpose include rubber, silicone, or combinations thereof. Examples include: Preferably, a container and / or a device for sealing or sealing a container, Free from rubber or silicone. Preferably, the container and / or the container is tightly sealed or airtight. The device for this purpose does not contain silicone. Thus, the device for sealing the container In particular, plastic, glass, or combinations thereof, for example, plastic Plastic lid, glass lid, plastic stopper, glass stopper, plus The cap may be made of plastic or glass. Preferably, the device It is made of plastic. Alternatively, heat can be used to seal the container, and as a result, it is airtight. Glass vials, that is, vials with optional notches to allow them to be easily opened. A sample can be obtained.

[0050] A sealed container containing the pharmaceutical composition of esketamine is a second container, preferably one that is protected from light. It can then be placed in a container that is practically opaque. In this way, the esketamine composition Further prevents the possibility of the object being exposed to light. In some embodiments, the second container is These include bags, sacks, etc. Preferably, the second container is suitable for transport. The container may be designed to hold a single container containing the esketamine composition. Alternatively, it may be designed to hold several containers of esketamine composition. In that embodiment, the second container is an amber-colored low-density polyethylene (LDPE) bag. Yes, optionally in a third container such as a carton box, or in an aluminum resealable bag. It will be contained inside the Umbag.

[0051] In some embodiments, the pharmaceutical composition is stored in a substantially opaque, sealed container for about 20 minutes. Temperatures of ℃ to approximately 75℃ and relative humidity of less than 80%, more preferably temperatures of approximately 20℃ to approximately 30℃. It is stored at a temperature of approximately 25°C to 30°C with a relative humidity. Preferably in a substantially opaque container. When measured using an opacity meter, it allows less than approximately 10% of the light passing through the container. It has transparency.

[0052] In some embodiments, the pharmaceutical composition is stored in a sealed container at a temperature of approximately 20°C to approximately 75°C. And after being stored in the absence of light for 6 months at a relative humidity of less than 80%, the amount of esketamine In contrast, 6-(2-chlorophenyl)-6-oxohexa It is desirable that it contains nic acid or a pharmaceutically acceptable salt thereof. Preferably, a sealed container is , having an opacity that allows approximately 10% or less, more preferably 5% or less, of the light passing through the container. More preferably, the pharmaceutical composition is stored under those conditions for 12 months, 18 months, or 24 months. After filtration, 6-(2-chlorophenyl)-6-oxohexyl phosphate is reduced to 0.2% (HPLC area). It contains xanoic acid or a pharmaceutically acceptable salt thereof.

[0053] Furthermore, the pharmaceutical composition may contain other impurities besides oxidative decomposition products. In some embodiments... In this context, the pharmaceutical composition may contain one or more esketamine metabolites, such as noresketamine. In other embodiments, the pharmaceutical composition is approximately 0.2% (HP) relative to the amount of esketamine. It may contain noresketamine or a pharmaceutically acceptable salt thereof with an LC area of ​​less than or equal to the following:

[0054] In a preferred pharmaceutical composition, esketamine free base or esketamine hydrochloride, etc. The sketamine salt is thoroughly mixed with a pharmaceutical carrier, preferably water, according to conventional pharmaceutical formulation techniques. Although combined, this carrier can take on a wide variety of forms depending on the desired form of the drug to be administered. This is possible. Suitable pharmaceutically acceptable carriers are well known in the art. Some descriptions of pharmaceutically acceptable carriers are provided by the American Pharmaceutical Association and the British Pharmaceutical Association. The Handbook of Pharmaceutical Exci was published. It can be found in pients.

[0055] A suitable aqueous formulation of esketamine is a mixture of water, esketamine, and (i) an amount of esketamine. In contrast, oxidative decomposition products or their pharmaceutically acceptable salts, which make up approximately 0.2% (HPLC area) or less, ii) Oxidative decomposition products of esketamine at a concentration of approximately 0.2% w / w or less relative to the weight of esketamine, or the pharmaceutically effective products thereof. (iii) an acceptable salt, or an oxidative decomposition product of about 120 ppm or less, or a pharmaceutically acceptable salt thereof. It contains a salt. In such a composition, esketamine is based on the total volume of the pharmaceutical composition. Therefore, a concentration in the range of approximately 100 mg / mL to approximately 250 mg / mL, or any within that range. It is present in a concentration or range of approximately 125 mg / ml to approximately It is present at concentrations within the range of 180 mg / mL, or at any concentration or range within that range. Preferably, the esketamine is administered at a concentration in the range of approximately 140 mg / mL to approximately 160 mg / mL. Or present at any concentration or range within that range, for example, at a concentration of approximately 140 mg / mL. The concentration refers to the equivalent concentration of the esketamine base.

[0056] The pharmaceutical compositions preferred for use in this specification are preferably aqueous formulations. When used, unless otherwise specified, the term "aqueous" refers to a formulation in which the main liquid component is water. This shall mean the following. Preferably, water shall be more than about 80% by weight of the liquid component of the pharmaceutical composition. More preferably over approximately 90% by weight, more preferably over approximately 95% by weight, more preferably approximately 98% Constitutes a weight %. In a pharmaceutical composition suitable for use in this specification, the water content of the composition Based on the total weight of the composition, this is 85±14% by weight, more preferably 85±12% by weight. A more preferable 85±10% by weight, most preferably 85±7.5% by weight, and especially 85± It is within the range of 5% by weight. In other pharmaceutical compositions used herein, preferably The water content of the composition is 90 ± 14% by weight, more preferably, based on the total weight of the composition. 90±12% by weight, more preferably 90±10% by weight, and most preferably 80±7.5% by weight. The weight percentage is, in particular, within the range of 90 ± 5% by weight. Further pharmaceutical compositions for use in this specification. In a substance, the water content of the composition is 95 ± 4.75% by weight, based on the total weight of the composition. Preferably 95±4.5% by weight, even more preferably 95±4% by weight, and even more preferably Or 95±3.5% by weight, most preferably 95±3% by weight, and especially 95±2.5% by weight. It is within the range. In yet another pharmaceutical composition for use in this specification, the water content of the composition This is based on the total weight of the composition, and is 75-99.99% by weight, more preferably 80-99%. 98% by weight, more preferably 85-99.95% by weight, even more preferably 90-9 9.9% by weight, most preferably 95-99.7% by weight, particularly 96.5-99.5% by weight It is within the range.

[0057] In a preferred embodiment, the aqueous formulation is stored in a sealed container at a temperature of approximately 20°C to approximately 75°C and After being stored for 6 months in the absence of light at a relative humidity of less than 80%, the amount of esketamine was compared to 6-(2-chlorophenyl)-6-oxohexanoic acid at a concentration of 0.2% (HPLC area) or less. It is preferable that the container contains either or a pharmaceutically acceptable salt thereof. Preferably, the container is airtight. The container has an opacity that allows approximately 10% or less, more preferably 5% or less, of the light passing through it. More preferably, the aqueous formulation is stored under those conditions for 12 months, 18 months, or 24 months. , 6-(2-chlorophenyl)-6-oxohexanoic acid at a concentration of 0.2% (HPLC area) or less It contains either a pharmaceutically acceptable salt thereof.

[0058] Other pharmaceutical compositions used herein include one or more buffering agents and / or It further includes a buffer system (i.e., a conjugate acid-base pair). When used herein, the term "buffer" is used. "Agent" is any solid or liquid composition that adjusts the pH of an aqueous formulation when added to it. This refers to a substance (preferably an aqueous liquid composition). Those skilled in the art will know that the buffering agent is water Adjust the pH of the formulation in any direction (towards a more acidic, more basic, or more neutral pH). They will recognize that it can be adjusted. Preferably, the buffer is pharmaceutically acceptable. A suitable example of a buffering agent that can be used in aqueous formulations is sodium hydroxide (NaOH). Citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate Examples include thorium, succinic acid, tartaric acid, malic acid, lactic acid, and fumaric acid, but these include Not limited. Preferably, the buffer or buffering system is NaOH, citric acid, sodium dihydrogen phosphate. Selected from the group consisting of thorium and disodium hydrogen phosphate. In one embodiment, The buffer adjusts the pH of the esketamine pharmaceutical composition (e.g., the aqueous formulation described herein). Adjust the pH to a range of approximately pH 3.5 to approximately pH 6.5, or any amount or range within that range. It is selected to do so. Preferably, the buffer adjusts the pH of the esketamine composition to about pH 4. A range of 0.0 to approximately pH 5.5, or any amount or range within that range, more preferably approximately pH 4. Select to adjust to a pH range of approximately 5.0, or any amount or range within that range. Preferably, the concentrations of the buffer and buffer system, preferably NaOH, are sufficient. It is adjusted to provide sufficient buffering capacity.

[0059] In some embodiments, the present disclosure may include esketamine, water, a buffer or buffering system, preferably Alternatively, the amount of NaOH and (i) esketamine should be approximately 0.2% or less (HPLC area). (ii) an oxidative decomposition product of or a pharmaceutically acceptable salt thereof, (ii) about 0 by weight of esketamine (iii) about 120 This relates to a pharmaceutical composition containing an oxidative decomposition product or a pharmaceutically acceptable salt thereof at a concentration of ppm or less. In compositions such as the above, the buffering agent or buffering system has a pH in the range of approximately pH 4.0 to approximately pH 6.0. It is present in an amount sufficient to obtain a formulation having a pH within or any amount or range within that range. In other embodiments, the present disclosure includes one or more citric acid monohydrates and disodium edetate. (i) about 0.2% (H) of the amount of esketamine. (ii) Oxidative decomposition products of PLC area or less, approximately 0.2% w / of the weight of esketamine (iii) an oxidative decomposition product of w or less or a pharmaceutically acceptable salt thereof, or (iii) approximately 120 ppm or less This relates to a pharmaceutical composition containing an oxidative decomposition product or a pharmaceutically acceptable salt thereof.

[0060] The pharmaceutical composition may optionally contain a preservative. When used herein, Unless otherwise specified, the terms "antimicrobial preservative" and "preservative" refer to the decomposition by microorganisms or the action of microorganisms. This refers to any substance that is typically added to a pharmaceutical composition to protect it from proliferation. In this regard, the growth of microorganisms typically plays an essential role, namely, preservation. The agent serves the primary purpose of avoiding microbial contamination. In one embodiment, the active ingredients and Furthermore, to avoid any microbial influence on the excipients, that is, to avoid microbial degradation. In some cases, it is desirable to do so. Typical examples of preservatives include benzalkonium chloride and salt. Benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol , cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, Lorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, he Xetidine, imidourea, phenol, phenoxyethanol, phenylethyl alcohol Phenymercury nitrate, propylene glycol, sodium propionate, thimerosal Methylparaben, ethylparaben, propylparaben, butylparaben, isobutylparaben Examples include lavender, benzylparaben, sorbic acid, and potassium sorbate, but It is not limited to them.

[0061] Due to its preservative properties, the desired shelf life or stability during use is affected by the presence of the drug itself. If the esketamine content is sufficiently high to achieve the desired result, the pharmaceuticals used herein Preferably, the composition contains no preservatives at all. Preferably, under these circumstances, The concentration of esketamine should be at least 120 mg / mL, preferably about 120 mg / mL. A range of approximately 175 mg / mL, or any concentration or range thereof, more preferably about 125 A range of mg / mL to approximately 150 mg / mL, or any concentration or range thereof, for example, approximately 1 The concentration is 26 mg / mL or approximately 140 mg / mL. The concentration is the equivalent of the esketamine base. It means concentration.

[0062] As used herein, the terms "penetration agent" and "penetration enhancer" are used. And "penetrant" is used to absorb the active ingredient (e.g., esketamine) of a pharmaceutical composition. This refers to any substance that increases or promotes yield and / or bioavailability. Preferably, a penetrating agent. This refers to the absorption and / or production of the active ingredient (e.g., esketamine) of the pharmaceutical composition after nasal administration. To increase or promote the physical availability (i.e., absorption and / or production of active ingredients through mucous membranes) (Increases or promotes the physical usability). Suitable examples include tetradecyl maltoside, glycerides. Sodium corcolate, tauroursodeoxycholic acid , TUDCA), lecithin, etc.; and chitosan (and its salts), as well as benzalkonium chloride , sodium dodecyl sulfate, sodium dodecylate, polysorbate, laureth-9, o Surface active ingredients such as xythoxyl, sodium deoxycholate, and polyarginine These are some examples, but are not limited to them. Preferably, the penetrating agent is tauroursodeoxycholic acid. It is túric acid (TUDCA). Penetrating agents, for example, increase membrane fluidity and epithelial cells. To form transient hydrophilic pores inside, reduce the viscosity of the mucus layer, or tightly bonded areas It can act through any mechanism, including opening up several osmotic agents (e.g., bile salts). (and fusidic acid derivatives) also inhibit enzyme activity in the membrane, thereby inhibiting the active ingredient The bioavailability can be improved. Preferably, the penetrating agent has the following general requirements One or more of these are selected, more preferably all of them. (a) Absorption of the active ingredient (preferably nasal absorption), preferably temporary and / or reversible It is effective in increasing the number of cases. (b) It is pharmacologically inactive. (c) Non-allergenic, non-toxic, and / or non-irritating. (d) It is very potent (effective in small amounts). (e) Compatible with other components of the pharmaceutical composition. (f) It is odorless, colorless, and / or tasteless. (g) It is permitted by the regulatory authorities. (h) It is inexpensive and available in high purity.

[0063] In one embodiment, the penetrating agent penetrates without nasal irritation (absorption of esketamine and / or Selected to increase bioavailability. In another embodiment, the penetrating agent is selected to increase bioavailability. Selected to improve the absorption and / or bioavailability of tamine, and furthermore, to ensure uniform dosing. Selected to enhance efficacy.

[0064] In one embodiment, the present disclosure relates to (i) the amount of esketamine, water, and (i) the amount of esketamine. and an oxidative decomposition product or its pharmaceutically acceptable salt of approximately 0.2% (HPLC area) or less, (i i) Oxidative decomposition products of esketamine at a concentration of approximately 0.2% w / w or less relative to its weight, or their pharmaceutically acceptable properties. (iii) an acceptable salt, or an oxidative decomposition product of about 120 ppm or less, or the pharmaceutically acceptable salt thereof A pharmaceutical composition containing a salt, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition is immersed in This invention relates to a pharmaceutical composition further containing a filtration enhancer, preferably TUDCA.

[0065] In another embodiment, the present disclosure relates to (i) esketamine, water, and (i) an amount of esketamine. In contrast, oxidative decomposition products or their pharmaceutically acceptable salts, which make up approximately 0.2% (HPLC area) or less, ii) Oxidative decomposition products of esketamine at a concentration of approximately 0.2% w / w or less relative to the weight of esketamine, or the pharmaceutically effective products thereof. (iii) an acceptable salt, or an oxidative decomposition product of about 120 ppm or less, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition containing a salt, wherein the pharmaceutical composition does not contain an antimicrobial preservative, and the pharmaceutical composition is It also contains uroursodeoxycholic acid (TUDCA), with TUDCA at approximately 1.0 mg / A concentration in the range of mL to approximately 25.0 mg / mL, or any range thereof, preferably approximately 2.5 mg Concentrations in the range of g / mL to approximately 15 mg / mL, or any range within that range, preferably approximately 5 mg / A pharmaceutical composition containing a concentration in the range of mL to approximately 10 mg / mL, or any range thereof. Regarding another embodiment, the disclosure relates to the presence of TUDCA at a concentration of about 5 mg / mL. This disclosure relates to a pharmaceutical composition. In another embodiment, this disclosure relates to a composition in which TUDCA is approximately 10 mg / This relates to pharmaceutical compositions present in a concentration of mL. For example, incorporated herein by reference Refer to the pharmaceutical composition disclosed in U.S. Patent Application Publication No. 2019 / 0117591. I want to.

[0066] Pharmaceutical compositions for use herein, one or more additional excipients, e.g., wetting agents, saturates It may also contain surfactants, solubilizers, thickeners, colorants, antioxidants, etc. stomach.

[0067] Examples of suitable antioxidant components, when used, include the following: namely, sulfurous acid. Salt; ascorbic acid; sodium ascorbate, calcium ascorbate, or as Potassium corbate and other ascorbic acid salts; ascorbyl palmitate; fumaric acid; e ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salts; tocopherol Gallate salts such as propyl gallate, octyl gallate, or dodecyl gallate. Examples include, but are not limited to, one or more of the following: vitamin E and mixtures thereof. No. Antioxidant components provide long-term stability to liquid compositions. The addition of antioxidant components is This can help enhance and guarantee the stability of the composition, even after 6 months at 40°C. To stabilize. A suitable amount of antioxidant component, if present, is about 0.0 of the total weight of the composition. The amount is 1% by weight to about 3% by weight, preferably about 0.05% by weight to about 2% by weight.

[0068] Solubilizers and emulsifiers are generally less soluble in liquid carriers than active ingredients or other excipients. It may be included to promote uniform dispersion. Examples of suitable emulsifiers, when used, For example, gelatin, cholesterol, acacia, tragacanth, pectin, methylcellulose Examples include, but are not limited to, carbomers, carbomers, and mixtures thereof. Examples of solubilizers include polyethylene glycol, glycerin, D-mannitol, and tre Halos, benzyl benzoate, ethanol, trisaminomethane, cholesterol, trie Thanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate Examples include thorium and mixtures thereof.

[0069] Preferably, the solubilizer contains glycerin. The solubilizer or emulsifier is generally contained in the carrier. It is present in an amount sufficient to dissolve or disperse the active ingredient, namely esketamine. If a chemical or emulsifier is included, the typical amount is about 1% by weight to about 80% by weight of the total weight of the composition. %, preferably about 20% to about 65% by weight, more preferably about 25% to about 55% by weight It is a percentage.

[0070] Suitable isotonic agents, when used, include sodium chloride, glycerin, and D-mannine. Examples include thor, D-sorbitol, glucose, and mixtures thereof. The preferred amount of the isotonic agent is typically about 0.01% by weight to about 15% by weight of the total weight of the composition. Amount %, more preferably about 0.3% by weight to about 4% by weight, more preferably about 0.5% by weight to about It is 3% by weight.

[0071] For example, to increase the retention time in the nasal cavity, a suspension or thickener may be added to the pharmaceutical composition. This may also be used. Preferred examples include hydroxypropyl methylcellulose, carmellose sodium Lilium, microcrystalline cellulose, carbomer, pectin, sodium alginate, chitosan salt Examples include gellan gum, poloxamer, polyvinylpyrrolidone, and xanthan gum. However, it is not limited to these.

[0072] The method for formulating pharmaceutical compositions was published by Marcel Dekker, Inc. Pharmaceutical Dosage For ms:Tablets,Second Edition,Revised and Ex panded, Volumes 1-3; Pharmaceutical, edited by Avis et al. Dosage Forms:Parental Medications,Vol. Umes 1-2; and Pharmaceutical Do (edited by Lieberman et al.) sage Forms:Disperse Systems,Volumes 1-2 It is mentioned in many publications.

[0073] Preparation method The formation of oxidative decomposition products is involved in the preparation of pharmaceutical compositions, filling of pharmaceutical compositions into containers, and the input of pharmaceutical compositions. The packaging of the container, the storage of the pharmaceutical composition, the handling of the pharmaceutical composition by the patient before administration, or These combinations can be reduced or eliminated by taking appropriate measures.

[0074] In some embodiments, the present disclosure relates to the preparation of pharmaceutical compositions containing esketamine. The present invention provides a method for reducing or preventing the formation of oxidative decomposition products. Exposure to pharmaceutical compositions containing ketamine is minimized. In some embodiments, The pharmaceutical composition is prepared in the absence of light as described herein. The above step reduces or eliminates the amount of light that comes into contact with one or more components of the esketamine composition. It can be modified as follows: The reaction process may include a mixing process, a transfer process, a filtration process, or This includes a purification process, or any combination thereof. Preferably, esketamine or so (i) 0.2% (HPLC area) relative to the amount of esketamine The following 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable form (ii) Salt, (ii) Oxidative decomposition products or their medicinal properties of esketamine at a concentration of approximately 0.2% w / w or less relative to the weight of the esketamine. (iii) pharmaceutically acceptable salts, or (iii) oxidative decomposition products of about 120 ppm or less or the pharmaceutically acceptable salt thereof A pharmaceutical composition comprising an acceptable salt and esketamine or a pharmaceutically acceptable salt thereof and 1 Mix the above pharmaceutically acceptable excipients and expose esketamine to light for approximately 6 hours or less. It can be prepared by doing so. More preferably, esketamine is used in the preparation of the composition. During preparation, the product is exposed to light for approximately 1 hour or less, more preferably for approximately 30 minutes or less. To avoid or minimize the presence of light, opaque equipment covers, glass containers, etc. The use of metal or ceramic containers, or a combination thereof, instead of vessels, is already known to those skilled in the art. Known techniques can be applied. For example, a substantially opaque mixture substrate such as a light protection foil can be used for mixing. However, it is particularly desirable to minimize light exposure to the esketamine pharmaceutical composition immediately after its preparation. Therefore, it is contemplated that the exposure of the esketamine pharmaceutical composition will be monitored from the time of its preparation to the final packaging step. Preferably, monitoring is continuous, but such monitoring corrections can be made by those skilled in the art. By recording, appropriate measurement of light exposure is possible. In a preferred embodiment, the preparation of the pharmaceutical composition comprises mixing esketamine or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients in a container surrounded by a light protection foil or in a container protected by an opaque equipment cover. In another preferred embodiment, the mixing can be carried out in a metal or ceramic container. The ambient light level during the preparation of the composition is preferably less than about 10 lux, more preferably less than about 1 lux, even more preferably less than about 0.1 lux, and most preferably less than about 0.01 lux. More preferably, the ambient light level during the preparation of the composition is less than about 10 lux, even more preferably less than about 1 lux or less than about 0.1 lux or less than about 0.01 lux, and the container in which esketamine or a pharmaceutically acceptable salt thereof is mixed with one or more pharmaceutically acceptable excipients is protected from light exposure, for example, by surrounding the container with a light protection foil or using an opaque equipment cover. In other embodiments, the present disclosure provides a method for reducing or preventing the formation of oxidative decomposition products when filling a pharmaceutical composition into a container. Thus, the container is in the absence of light.

[0075] ​​​​​​​​​​​​​​​​The container is then filled with a pharmaceutical composition. The container is filled using instruments such as a funnel or manifold. Light-blocking technology can be used, and this is not limited to, but includes filling stations Opaque shields to cover the station, opaque shields to cover the stopping station, metal or ceramic This includes a filler material, or a combination thereof. For example, the filler material may be stainless steel. It may be a manifold and / or the black silicone sheet covers the entire filling unit or It can be used to cover part of it. The ambient light level when filling the pharmaceutical composition into the container is about 10 Below lux, more comfortably below approximately 1 lux, even more comfortably below approximately 0.1 lux. Most preferably, the brightness is 0.01 lux or less.

[0076] In a preferred embodiment, the pharmaceutical composition, when measured using an opacity meter, is in a container Approximately 10% or less of the light passing through, more preferably approximately 5% or less of the light, or even more preferably The container is filled into a container with an opacity that allows less than approximately 1% of the light passing through to it.

[0077] In a preferred embodiment, the pharmaceutical composition is prepared and filled into a container. During this time, they are exposed to light for approximately 6 hours or less.

[0078] Select a container that is substantially opaque to light for storing the composition. As a result, oxidative decomposition products, particularly 6-(2-chlorophenyl)-6-oxohexanoic acid or the It has been found that the formation of pharmaceutically acceptable salts can be prevented. Therefore, one embodiment In a pharmaceutical composition containing esketamine or a pharmaceutically acceptable salt thereof, oxidation Decomposition products, particularly 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable properties. A method for preventing the formation of salts, wherein when measured using an opacity meter, For storing pharmaceutical compositions, the container has an opacity that allows approximately 10% or less of the light passing through it. A method is provided, including the selection of a container.

[0079] In preferred embodiments, a pharmaceutical combination comprising esketamine or a pharmaceutically acceptable salt thereof Methods for preventing the formation of oxidative decomposition products in the finished product are: a) Exposing the pharmaceutical composition to light for 6 hours or less during the preparation of the composition, b) When measured using an opacity meter, the container should allow approximately 10% or less of light to pass through. Select a container that has opacity, c) Filling the container with the pharmaceutical composition, preferably in the absence of light.

[0080] Preferably, the method further involves storing the pharmaceutical composition in the container in the absence of light. include.

[0081] In a further embodiment, the present disclosure relates to the packaging of a container containing a pharmaceutical composition, including the oxidation of The present invention provides a method for reducing or preventing the formation of lysis material. Preferably, the filled and sealed The container is packaged in a second container which is itself opaque to light. The second container is foil They may be appropriately coated or lined with such materials, and / or opaque to light. It may be made of material. In some embodiments, the second container is made of aluminum. It is.

[0082] In further embodiments, the present disclosure relates to the formation of oxidative decomposition products when storing pharmaceutical compositions. The present invention provides a method for reducing or preventing the following: packaging in a single container or within a second container. The container being used is stored in the absence of light as described herein.

[0083] In still further embodiments, the present disclosure provides a method for reducing or preventing the formation of oxidative degradation products when handling the pharmaceutical composition prior to administration.

[0084] Method of Use Unless otherwise specified, the amounts of ketamine described herein are typically expressed based on the ketamine free base. That is, the amount represents the amount of administered ketamine molecules excluding, for example, counterions (such as pharmaceutically acceptable salts).

[0085] In certain embodiments, ketamine is administered intranasally. In further embodiments, ketamine is administered intranasally as its corresponding hydrochloride. In other embodiments, ketamine is administered intranasally as the corresponding hydrochloride of a 16.14% weight / volume solution (corresponding to 14% weight / volume of ketamine base).

[0086] In still other embodiments, ketamine is a solution containing 161.4 mg / mL of ketamine hydrochloride (corresponding to 140 mg / mL of ketamine base), 0.12 mg / mL of ethylenediaminetetraacetic acid (EDTA), 1.5 mg / mL of citric acid (pH 4.5 in water), and (i) oxidative degradation products or pharmaceutically acceptable salts thereof at about 0.2% (HPLC area) or less relative to the amount of ketamine, (ii) oxidative degradation products or pharmaceutically acceptable salts thereof at about 0.2% w / w or less relative to the weight of ketamine, or (iii) oxidative degradation products or pharmaceutically acceptable salts thereof at about 120 ppm or less, and is administered intranasally. In still further embodiments In terms of form, esketamine is administered intranasally, with intranasal delivery at a dose of 161.4 mg / mL. Esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg / m² L of EDTA, 1.5 mg / mL of citric acid (pH 4.5 in water), and (i) Esketa Oxidative decomposition products or their pharmaceutically acceptable content are approximately 0.2% (HPLC area) or less relative to the amount of mine. (ii) Salts, (ii) Oxidative decomposition products or so that are less than 0.2% w / w of the weight of esketamine (iii) a pharmaceutically acceptable salt of, or (iii) an oxidative decomposition product of or thereof at a concentration of approximately 120 ppm or less. Administer 100 μL of a solution containing a suitably acceptable salt. In other embodiments, Tamin is delivered into the nasal cavity using a nasal spray pump, with the pump delivering 161.4 mg / m². L-grade esketamine hydrochloride (equivalent to 140 mg / mL of esketamine base), 0.12 mg EDTA at 1 / mL, 1.5 mg / mL of citric acid (pH 4.5 in water), and (i) S Oxidative decomposition products of ketamine at a concentration of approximately 0.2% (HPLC area) or less, or their pharmaceutically acceptable properties. (ii) Salts to be used, (ii) Oxidative decomposition products of less than 0.2% w / w relative to the weight of esketamine or (iii) a pharmaceutically acceptable salt thereof, or an oxidative decomposition product of about 120 ppm or less, or the A 100 μL solution containing a pharmaceutically acceptable salt is delivered.

[0087] Generally, one pump from a nasal spray device dispenses approximately 50 μL to 200 μL. 60 μL, approximately 70 μL, approximately 80 μL, approximately 90 μL, approximately 100 μL, approximately 110 μL, approximately 12 0 μL, approximately 130 μL, approximately 140 μL, approximately 150 μL, approximately 160 μL, approximately 170 μL, approximately Deliver the esketamine solution (containing 180 μL and approximately 200 μL) into the target nostril. It may be configured as follows. Therefore, the two pumps will target approximately 100 μL to approximately 400 μL. It will be delivered to [destination].

[0088] The present invention relates to a method for treating depression, preferably resistant depression or treatment-refractory depression. Therefore, to the subject requiring it, any of the pharmaceutical compositions described herein in a therapeutically effective amount. In a method that includes administering a pharmaceutical composition, further utilizing the pharmaceutical composition described herein is possible. Regarding this matter, administration is preferably intranasal.

[0089] In embodiments, the present invention relates to depression, preferably resistant depression or treatment-refractory depression. A method for the treatment of a subject requiring the treatment, as described herein. The present invention relates to a method comprising administering a pharmaceutical composition intranasally.

[0090] As used herein, the term “depression” refers to major depressive disorder, unipolar depression, and treatment. Treatment-resistant depression, treatment-resistant depression, anxiety depression, bipolar depression and (dysthymia) Depression shall be defined to include mood disorders (also known as major depression). Preferably, depression is defined as major depression. Pathological disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, or bipolar disorder I have depression.

[0091] When used herein, the terms “refractory or treatment-resistant depression” and their abbreviations are used. TRD is a suitable set of at least two antidepressants, preferably two or more. It is defined as major depressive disorder that does not respond to antidepressants, more preferably two to three types of antidepressants. It shall be assumed that...

[0092] As used herein, the term “bipolar depression” refers to the characteristics or symptoms of bipolar disorder. This refers to depression. Therefore, the present invention's method for treating bipolar depression The purpose is to provide a method for treating depression and / or the depressive phase of bipolar disorder.

[0093] Unresponsiveness to a given set of appropriate antidepressants can be determined retrospectively or anticipatoryly. Those skilled in the art will recognize this. In the embodiment, the unresponsiveness to a suitable set of antidepressants At least one is determined anticipatoryly. In another embodiment, a suitable set of antidepressants At least two of the unresponsive ones are determined in advance. In another embodiment, a suitable series At least one of the non-responses to antidepressants is determined retrospectively. In another embodiment, At least two of the unresponsiveness cases to an appropriate set of antidepressants are determined retrospectively.

[0094] In one embodiment, the present invention relates to a method for treating depression in patients with suicidal tendencies. The term "depression in patients with suicidal tendencies" refers to at least one symptom of suicidal tendencies, for example. For example, patients may also exhibit suicidal thoughts and / or suicidal behavior (e.g., intentions, attempts, etc.). When diagnosed in this context, including any type of depression as defined herein. Those skilled in the art will understand that this is the case. Therefore, in patients with suicidal tendencies "Depression" includes major depressive disorder in patients with suicidal tendencies, and in patients with suicidal tendencies. Unipolar depression, treatment-resistant depression in patients with suicidal tendencies, in patients with suicidal tendencies Depression accompanied by anxiety and distress, bipolar depression in patients with suicidal tendencies, and suicidal tendencies Examples include, but are not limited to, mood disturbances in patients with certain conditions. Preferably, "self "Depression in patients with suicidal tendencies" refers to major depressive disorder in patients with suicidal tendencies. Unipolar depression in patients with homicidal tendencies, and treatment-resistant depression in patients with suicidal tendencies. Selected from the group consisting of depression. More preferably, "depression in patients with suicidal tendencies." This refers to treatment-resistant depression in patients with suicidal tendencies.

[0095] As used herein, “suicide” means “the act of taking one’s own life.” / en.wikipedia.org / wiki / Suicide-cite_note See -7. Suicide includes attempted suicide or non-lethal suicidal behavior, which is the act of taking one's own life. It is self-inflicted with a desire to end things, but does not result in death. A suicide attempt begins with a series of actions. Sequence of self-initiated actions by individuals that are expected to lead to their own death It is S.

[0096] As used herein, "suicidal ideation" refers to thoughts about suicide or an abnormality related to suicide. This refers to an obsession, or the thought of wanting to end one's own life or no longer wanting to live. However, this does not necessarily mean that they are actively attempting to commit suicide. The range of suicidal ideation The scope ranges from transient to chronic and detailed planning, role-playing, and failed These range from attempts to progress to other approaches, and these are intentionally designed to fail or be discovered. It can be configured to, or may be sufficiently intended to bring about death.

[0097] When used herein, unless otherwise specified, terms such as "to treat" and "treatment" are used. This includes the management and care of human patients for the purpose of combating disease, condition, or disorder. Prevention of the onset of one or more symptoms or complications, or one or more of the symptoms or complications To alleviate or eliminate a disease, condition, or disorder, administer the pharmaceutical composition of this disclosure. This includes.

[0098] The term "therapeutic dose" as used herein refers to the effective dose for the symptoms of the disease or disorder being treated. Human groups requested by researchers, physicians, or other clinicians, including one or more of the following: This refers to the amount of active compounds or pharmaceuticals that induce a biological or pharmaceutical response in the tissue system.

[0099] The optimal dose to be administered can be easily determined by those skilled in the art, and the specific dose used can be determined. The compound, method of administration, strength of the preparation, method of administration, within a limited time (e.g., a maximum of 60 minutes) The number of consecutive doses and the progression of the disease can vary considerably. In addition, the patient's age, Factors specific to the patient receiving treatment, including weight, diet, and number of doses, As a result, dosage adjustments become necessary.

[0100] When used in this specification, the terms "concurrent therapy," "combination therapy," "adjunctive therapy," and "adjunctive treatment" are used. The terms "method," "combination therapy," and "simultaneous administration" refer to combining esketamine with one or more antidepressants. This refers to the treatment of patients who require it by administering it together, and Esketa Min and the antidepressant are administered by any preferred means. In some embodiments, Esketamine drug compositions are administered in regimens using 1 to 5 antidepressants. In terms of administration, the esketamine pharmaceutical composition uses 1, 2, 3, 4, or 5 types of antidepressants. It is administered in a regimen. In other embodiments, the esketamine pharmaceutical composition is one or two types It is administered as part of an antidepressant regimen. In a further embodiment, an esketamine pharmaceutical composition It is administered in a regimen using the antidepressant currently being administered to the patient. In other embodiments The esketamine drug composition is administered in regimens using different antidepressants. In a further embodiment, the esketamine pharmaceutical composition is an antidepressant that has not been previously administered to a patient. It is administered in a drug regimen. In yet another embodiment, the esketamine pharmaceutical composition is It is administered as part of a regimen using antidepressants previously administered to the patient. Esketamine drug composition When substances and antidepressants are administered in separate dosage forms, the daily dose for each compound is... The number of doses can be the same or different, and more typically, they are different. Antidepressants should be prescribed by your doctor. Therefore, it may be administered as prescribed by and / or by its label, and esketami The pharmaceutical composition is administered as described herein. Typically, the patient is receiving antidepressants. This is concurrent treatment with both the drug and esketamine, and both are administered according to their prescribed dosages. It is administered according to the regimen.

[0101] Esketamine pharmaceutical compositions and antidepressants are administered via the same or different routes of administration. This is also acceptable. Examples of preferred methods of administration include oral, intravenous (IV), intranasal (IN), and intramuscular. This includes, but is not limited to, internal (im), subcutaneous (sc), percutaneous, oral, or rectal methods. No. In some embodiments, esketamine is administered intranasally. Unless otherwise specified, the term "antidepressant" can be used to treat depression. This refers to any pharmaceutical product. A preferred example is a monoamine oxidase inhibitor. Drugs, tricyclic antidepressants, serotonin reuptake inhibitors, serotonin-noradrenergic drugs Reuptake inhibitors, noradrenergic / specific serotonergic drugs, or atypical anticoagulants Psychotic drugs are an example, but are not limited to these. Other examples include phenelzine. Monoamine oxidase inhibitors such as tranylcypromine and moclobemide; imipramine, Mitriptyline, desipramine, nortriptyline, doxepin, protriptyline, Tricyclic antidepressants such as limipramine, clomipramine, and amoxapine; maprotiline, etc. Tetracyclic antidepressants; acyclic antidepressants such as nomifensin; triazolopyridines such as trazodone. ;Fluoxetine, sertraline, paroxetine, citalopram, citalopram, esci Serotonin reuptake inhibitors such as talopram and fluvoxamine; serotonin reuptake inhibitors such as nefazadone Rotonin receptor antagonists; venlafaxine, milnacipran, desvenlafaxine Serotonin-noradrenergic regeneration agents such as diuretic, duloxetine, levomilu, and nacipran Reuptake inhibitors; noradrenergic and specific serotonergic drugs such as mirtazapine Drugs; norepinephrine reuptake inhibitors such as reboxetine and edivocketine; bupro Atypical antipsychotics such as Pion; natural products such as kava kava and St. John's wort; s - Nutritional supplements such as adenosylmethionine, and thyroid-stimulating hormone-releasing hormone, etc. Neuropeptides; targeting neuropeptide receptors such as neurokinin receptor antagonists. Examples include compounds such as triiodothyronine and hormones, but are not limited to these. Not done. In some embodiments, the antidepressant is imipramine, amitriptyline, and Cipramine, nortriptyline, doxepin, protriptyline, trimipramine, map Rotiline, Amoxapine, Trazodone, Bupropion, Clomipramine, Fluoxetine Duloxetine, escitalopram, citalopram, sertraline, paroxetine, Fluvoxamine, nefazadone, venlafaxine, milnacipran, reboxetine, mi Rutazapine, phenelzine, tranylcypromine, moclobemide, kava kava, seiyo St. John's wort, s-adenosylmethionine, thyroid hormone-releasing hormone, neurox The antidepressant is a nin receptor antagonist or triiodothyronine. Preferably, the antidepressant is Fluoxetine, imipramine, bupropion, venlafaxine, and sertraline Selected from the following group.

[0102] Antidepressants (e.g., monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors) Serotonin reuptake inhibitors, serotonin-noradrenergic reuptake inhibitors, noradrenergic Sex-specific serotonergic drugs, norepinephrine reuptake inhibitors, natural products, nutritional supplements Foods, neuropeptides, compounds targeting neuropeptide receptors, hormones, and the foregoing The therapeutic effective dose / dosage level and drug regimen of the pharmaceuticals listed can be easily determined by those skilled in the art. It may be determined by, for example, the therapeutic dosage and regimen of a drug approved for sale. These are generally available, for example, on packaging labels, standard medication guidelines, and Phys ician's Desk Reference(Medical Economics You can contact the company or visit http: / / www.pdrel.com online. It is listed in standard medication references such as ( ) or other sources.

[0103] A therapeutically effective dose of esketamine and / or an antidepressant is incorporated herein by reference. U.S. Patent Application Publication No. 2016 / 0338977 and International Publication No. 2019 / 126108 As described in the issue, it may be administered in the initial and / or subsequent stages. In some embodiments The therapeutically effective dose of esketamine is approximately 20 to 100 mg. In other embodiments, The therapeutically effective dose of sketamine is approximately 30 to 90 mg. In further embodiments, sketamine The therapeutically effective dose of esketamine is approximately 40 to 80 mg. In further embodiments, esketamine is used. The effective therapeutic dose is approximately 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2 4, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 ,38,39,40,41,42,43,44,45,46,47,48,49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 6 4, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 , 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, The dosage is 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg. In this embodiment, the therapeutically effective dose is approximately 28 mg, approximately 56 mg, or approximately 84 mg. In this embodiment, the therapeutically effective dose is approximately 56 mg or approximately 84 mg. Further embodiments Therefore, the therapeutically effective dose of esketamine is approximately 28 mg. In other embodiments, esketamine The effective therapeutic dose of n is approximately 56 mg. In a further embodiment, the effective therapeutic dose is approximately 8 It is 4 mg of esketamine.

[0104] abbreviation SEM: Scanning Electron Microscopy EDX: Energy-dispersive X-ray spectroscopy IR-ATR: Infrared Attenuated Total Reflectance LC-MS: Liquid Chromatography-Mass Spectrometry THF: Tetrahydrofuran UV-VIS: Ultraviolet-Visible SPE: solid phase extraction MS: Mass spectrometry RT: retention time STD: Standard CCT: Collision Cell Technology ATR: Total reflectance measurement method IR: Infrared LC-DAD-MS: Liquid chromatography-diode array detector-mass spectrometry ICH: International Conference on Harmonisation of Regulation of Pharmaceuticals for Human Use D50: Standard light source with a color temperature of 5000K; approximate intensity of about 210fc AU: Absorbance unit ICP-MS: Inductively coupled plasma mass spectrometry Lux-hour: Unit of illuminance per hour [Examples]

[0105] Esketamine nasal spray preparation contains 0.12 mg / mL of ethylenediaminetetraacetic acid (ED) in water. TA) and 161.4 mg / m³ of citric acid (pH 4.5) are combined with 1.5 mg / mL of citric acid. It consisted of L-type esketamine hydrochloride (equivalent to 140 mg of esketamine base).

[0106] The following samples were used in the embodiments described later.

[0107] Sample 1: Esketamine nasal spray vial, drug batch 1, yellow / brown discoloration To indicate color. (i) A bag containing vials labeled "less discoloration". (ii) A bag containing a vial labeled "severe discoloration".

[0108] Sample 2: Esketamine nasal spray vial, drug batch 1, no discoloration - vial Al was removed from a nasal spray device.

[0109] Sample 3: Esketamine nasal spray vial, medication batch 2, no discoloration.

[0110] Sample 4: Esketamine nasal spray vial, drug batch 3, no discoloration.

[0111] Sample 5: Esketamine nasal spray vial, drug batch 4, no discoloration.

[0112] Sample 6: Two types of grip seal bags used for storing (holding) the samples. (i) A grip seal bag with a blue zone at the grip seal location. (ii) A grip seal bag that does not have a blue zone in the grip seal area.

[0113] Qualitative investigations include using vials of esketamine from the same lot (batch 1) that have discolored (e.g., Sun Only pull 1 (both bags) and vials that had not discolored (e.g., sample 2) were used.

[0114] Example 1: Glass peeling The possibility of glass delamination in glass vials containing discolored samples was tested, and the discolored sample It was compared to a reference vial that did not contain pull. For this purpose, Batch 1 vials showing discoloration were used. From Al (Sample 1) and a vial from the same batch that did not show discoloration (Sample 2), Ketamine solution and plunger stopper were extracted. Both vials were filled with 0.1M HCl. The vial was rinsed with ethanol and pure water. It is known that the detached glass is adsorbed onto the vial. Fill with 1.25 mg / mL methylene blue solution. Shake and leave for 5 minutes. After incubation, the vial was emptied and rinsed with distilled water to remove all of the methylene blue. Visually inspect the vial and check that the methylene blue has adhered to the glass and that no glass delamination has occurred. We verified whether it was possible or not.

[0115] When vials treated with methylene blue were visually inspected, some samples showed discoloration and others showed discoloration. No difference was observed between the samples that were not treated. Both vials had high stoppers. Very small ring-shaped structures were observed at the bottom, but not at the solution level.

[0116] In the glass peel test, between the sample that discolored with esketamine and the sample that did not discolor, No visual differences were observed. Therefore, the degree of glass delamination is considered to be the same.

[0117] Example 2: Integrity test of stopper I removed the stoppers from the four discolored vials (i.e., sample 1) with a needle tool. Care was taken not to damage the thin central part of the stopper. The stopper was then observed under a microscope. And, the integrity of the stopper was confirmed.

[0118] Upon examining the stopper of the discolored vial (i.e., sample 1), the stopper There were no signs of holes or any other damage.

[0119] Stereomicroscope images of vials in batch 1 of esketamine (those with little discoloration and those with heavy discoloration) Based on both degrees, it is partially formed with many brown suspended particles and small bubbles. Sediment was observed on the inner wall of the vial. Additionally, the rubber stopper had a surface that came into contact with the liquid. Yellow / brown discoloration was observed.

[0120] Based on microscopic analysis, the particles appear as irregular, thin films with varying degrees of yellow / brown coloration. .

[0121] Based on IR microscopy analysis, the particles were identified as being silicone-based. Although we were unable to identify additional features of the clef, we were able to identify the clef in a specific spectral region. Some similarities were observed between the spectrum of tamin and that of tamin.

[0122] The yellow / brown substance was observed to be insoluble in dichloromethane but soluble in THF. Even after washing with dichloromethane, the outlines of the particles were still visible, but they had become slightly fainter. It remains unchanged in color. Based on IR analysis of the remaining yellow / brown substance, it is silicone. The band was gone, but it was not identifiable. The brown substance was very small. It is thought to be composed of particles.

[0123] Based on microscopic and IR analysis, the silicone particles are found in the silicone rubber stopper surface. Due to its high affinity to surfaces, it adheres to the stopper surface of vials, which are most prone to discoloration, and ethanol It has been shown that it can be partially removed by washing with a detergent.

[0124] Example 3: Transmittance Profile of Plastic Grip Seal Bag Three from each bag of Sample 6, Unicam UV 500 (Thermo S UV-Vis spectra were recorded using a pectronic UV-Vis spectrometer.

[0125] Two types of grip-seal bags are used for sample storage. Only slight differences could be observed in the rate profiles.

[0126] Example 4: Analysis of discoloration Optical photographs were taken using a Leica MZ16 stereomicroscope and / or a Leica DMLM microscope. SEM imaging and energy-dispersive X-ray (EDX) analysis are performed by Bruke. Hitachi TM3000 scanning electron microscope equipped with a Quantax 70 EDX detector. The tests were conducted using 5kV and 15kV charge reduction modes (with an EDX reporting threshold of 0.2%). ). Using a Quorum SC7620 sputter coater, the sample was coated with Au / Pd. It was sputter coated.

[0127] Infrared (IR) analysis is performed using a Bruker Hyperion 3000 infrared microscope. The procedure was performed using a SOR27 spectrometer. A 20x ATR objective was used for recording the IR spectrum. A lens was used.

[0128] A. Analysis of the contents of the vial The contents of the selected vial are filtered through a 0.1 μm Whatman Anodisc filter. After filtering using a vacuum filtration unit, it was washed with 0.1M HCl and water. After rinsing and drying the discolored vial of esketamine, use a needle tool to remove the contents from the inside. The substance was collected. A small amount of the substance was transferred to a gold-plated mirror for IR analysis.

[0129] In the discolored vial of Sample 1, many floating brown particles were observed, Small, partially formed air bubbles were also observed in the deposits on the inner wall. Additionally, a rubber stopper... Some yellow / brown discoloration was observed in the wetted parts (the vias were described as having "little discoloration"). (There are few stoppers.) No discoloration or particle suspension was observed in the standard stopper.

[0130] Microscopic images of the particles selected and separated on the filter (Sample 1) show that some of the particles You can see that it appears smoother and less brown.

[0131] The particles separated on the filter look like a curled, thin film of brownish material. The particles appear smoother and less brown.

[0132] SEM (backscattered electron) images of the selected particles were obtained. All the particles had an irregular shape. The particles are flat, with slight irregularities at the edges. When imaged at 15kV, the contrast is... The quality decreases. The particles appear "translucent," and this is despite the Au / Pd coating. This means that the electron beam is partially passing through the particle, which is a very thin particle. This indicates that.

[0133] Whatman Anodisc filter after filtering the contents of a vial that shows discoloration. The IR-ATR of the separated particles shown above and the separated particles scraped off from the inside of the discolored vial. The spectrum was recorded for identification purposes. The brown particles could be identified as silicone-based. Ta.

[0134] B. Stopper Analysis The stopper was examined under a microscope. Two reference vials (Sample 2) were taken from the sample bag. Two severely discolored vials (Sample 1) were selected. Using a needle tool, the vials were opened. The stoppers were removed. Each stopper was washed with 0.1M HCl and particle-free water. One standard stopper and one severely discolored stopper were cleaned with ethanol. The part of the pper that is in contact with the liquid inside the vial is cut out with a scalpel, and the aluminum SE It was attached to an adhesive carbon pad mounted on an M stub. After IR analysis, 4 pieces Au / Pd is coated with a sputter coater onto an SEM sample holder equipped with a stopper. The images were then scanned and captured using a scanning electron microscope (SEM).

[0135] Images of the discolored stopper (separated from Sample 1 vial) and its cross-section were obtained. Specifically, the stopper of the vial in batch 1 of esketamine nasal spray (A (B) The discolored side that is in contact with the esketamine solution, (A) The side that is not in contact with the esketamine solution (C) The opposite side of the stopper (normal color), (D) The stopper that has separated and discolored, An image of the cross-section was obtained. No color transfer to the stopper was observed.

[0136] The discoloration of the stopper extends to the initial peripheral area, which is the part that comes into contact with the drug inside the vial. Observed. No clear discoloration is seen in the cross-section, and the discoloration is a surface effect (brown discoloration on the stopper surface). This suggests that it is highly likely that only the adsorption of substances is occurring.

[0137] Reference stoppers and water washed from batch 1 of esketamine nasal spray. Images of the discolored stopper were obtained. Additionally, the reference stopper and the discolored stopper were also used. Images were also taken after additional cleaning with ethanol. The discolored stopper was compared to the reference stopper. A clear difference was observed when comparing them. However, the material of the stopper was changed by ethanol cleaning. It is clear that parts have been removed.

[0138] The IR-ATR spectra of each stopper were collected from three different points and recorded for identification. In all spectra except for the rubber stopper material, IR microscopy analysis was performed. Based on this, the contribution of silicone was further confirmed. The presence of silicone is in the stopper It can be associated with silicone coating. Reference stopper (HCl and water, or (Wash with HCl, water, and ethanol), discoloration stopper (with HCl, water, and ethanol) In the spectrum of the cleaning process, the contribution of silicone was minimal. Discolored stopper (salt The IR spectrum from the cleaning (using only acid and water) is mainly for silicone and stopper rubber. The contribution of the material was limited. However, when the stopper was further cleaned with ethanol, The contribution of ricone is reduced, and the rubber becomes more distinct. This is the same as the discoloration of the vial. This indicates that silicone particles are adsorbed onto the upper surface. (Sputter coating) Based on SEM analysis of the treated stoppers, a similarly treated discolored stopper and a reference stopper were compared. No differences were observed between the tops.

[0139] C. Solubility Test A small amount of CH2Cl2 was added to one discolored vial (Sample 1), and the same sample... Tetrahydrofuran (THF) was added to another vial. Both vials were re-stopped and shaken. The cow was observed visually. As an additional experiment, using a Whatman Anodisc filter... A portion of the separated particles (Sample 1) was washed with dichloromethane (CH2Cl2) and THF. The solubility was evaluated.

[0140] When CH2Cl2 is added to the discolored solution (Sample 1), the yellow / brown color is due to CH2Cl2. It was found that the phase had transitioned. Visual and microscopic (stereomicroscope) examination revealed that CH2 No particles were observed in the Cl2 solution. When the same test was repeated with THF, the solution It remained yellow / brown, and upon visual inspection and microscopic (stereomicroscope) examination, No particles were observed in the solution.

[0141] Separated particles before and after CH2Cl2 washing (on a Whatman Anodisc filter) Images were obtained (separated from vial 1). Washing with CH2Cl2 revealed the appearance of the particles. A slight difference can be seen (the particle outlines are still visible, but slightly fainter). No removal of the brown color was observed. However, the separated particles (from the vial of sample 1) When the filter containing the stain was rinsed with THF, the brown color almost completely disappeared.

[0142] The IR-ATR spectra of CH2Cl2-washed particles were recorded and identified. The main band disappears, and only the additional band (which was also present initially) remains. The ricone portion is removed, leaving only the brown substance.

[0143] This experiment demonstrated that the silicone portion of the particles dissolves in CH2Cl2. The colored substance does not dissolve in CH2Cl2 but dissolves in THF. Add C to the discolored vial. After adding H2Cl2, no particles were observed, and the brown color was not removed from the filter even after washing. stomach.

[0144] D. Samples subjected to stress (ICH light) One vial of esketamine batch 1 that has not discolored, 700 W / m 2 ICH light After exposure for 2 cycles of 8 hours (total 16 hours), store in a 70°C oven for 3 months (in the dark). The second vial was kept under the same oven conditions without exposure to light, as a reference. The vial was retained. The photograph of the vial was taken with a Leica MZ16 stereomicroscope. Furthermore, degradation products were also observed. To evaluate the pattern, samples were subjected to LC-DAD-MS analysis.

[0145] Stressed and unstressed vials of Esketamine Batch 1 Both images show (A) esketamine batch 1 subjected to stress after exposure to ICH light. (B) vials that were not exposed to light were obtained. They were also kept under the same oven conditions (70°C, 3 months).

[0146] Solution from a vial of esketamine that has been exposed to light (and stored at 70°C for 3 months). It has turned yellow / brown and suspended particles are visible. The appearance is similar to the discolored vials from batch 1. It is visually similar to what was observed in Lu.

[0147] Esketamine that was not exposed to light (but was held under the same oven conditions for the same period of time). No discoloration was observed in the vial solution, and no suspended particles were found.

[0148] For comparison, the esketamine vial from batch 1 (i.e., sample 1) showed less discoloration. Images of both the mild and severe cases were obtained. Furthermore, the contents of all four vials were collected using LC-DA. Analysis was performed using D-MS. In the light / heat stress vials and heat stress vials of batch 1... Based on LC-DAD-MS analysis and the appearance of particulate matter in light / thermal stress vials Therefore, we conclude that light exposure may be the underlying cause of the observed yellow / brown discoloration. It is possible.

[0149] E. Liquid chromatography-diode array detection-mass spectrometry (LC-DAD-MS) ) Liquid chromatography-mass spectrometry (LC-MS) analysis involves comparing the retained sample after dilution with the stock sample. The procedure was performed on the sample that received the response and the solid-phase extract. In the case of dilution, the sample was treated with The sample was diluted 50-fold with cetonitrile before analysis.

[0150] In the solid-phase extraction experiment, the samples were prepared as follows: Three samples that showed yellow / brown discoloration. The contents of the selected vial (Sample 1) are transferred to the SEP-PAK C18 cartridge (W The sample was subjected to solid-phase extraction using aters. A step gradient was used to increase the solvent strength, and the electrode The analytes were eluted according to the difference in sex. The same procedure was used for the reference samples in three vials. I also ran it on (Sample 2).

[0151] The empty vial from Sample 1 was rinsed with 0.1M HCl and water. The colored residue on the inside of the vial remained. It was dissolved in a small amount of tetrahydrofuran (THF).

[0152] LC-MS analysis is performed using Thermo Q Exactive Plus orbit traps. Dionex Ultimat with diode array detector connected to quantitative analyzer The procedure was performed using an e 3000 HPLC system.

[0153] Chromatographic separation was performed using a 150mm x 3.0mm ID Waters XBri. The procedure was performed using a dge C18 3.5 μm column. The column heater was maintained at 45°C, and the flow rate was 0. The flow rate was set to 0.6 mL / min. Eluent A consisted of 10 mM ammonium acetate, and eluent B was acetone. It was a nitrile. Gradient elution consisted of a linear gradient of eluent B from 10% to 100% over 12 minutes. It was then held at 100% B for 5 minutes.

[0154] Using an electrospray ionization source, high performance is achieved in both positive and negative ion modes. High-resolution, precise mass data was obtained. Identification was performed by manually interpreting the spectrum and comparing it to the reference material. This was done by comparing it with the vector.

[0155] After solid-phase extraction, the yellow / brown colored species were concentrated mainly into one fraction. LC of this concentrated fraction. -DAD-MS analysis and analysis of the residue dissolved in THF revealed absorbance at 380-430 nm. The existence of several compounds with UV-Vis spectra exhibiting banding has been demonstrated. Long-range absorption causes materials to appear yellow / brown, so wavelengths of 380-430 nm were selected for chromatography. In the matogram, the analyte colored yellow becomes selectively visible.

[0156] In the chromatogram of the concentrated SPE fraction, several peaks were observed between 3.5 and 6.5 minutes. These peaks were observed. These peaks were not present in the SPE fraction of the uncolored reference sample. The chromatogram of the residue shows two peaks at RT 9.35 min and 11.19 min.

[0157] The mass spectra of all but one of the colored analytes show isotopic patterns of chlorine. Furthermore, by examining the fragmentation pattern of the obtained MS / MS spectrum... The ability to associate the structural information of impurities with the structural information of esketamine, the active ingredient in the pharmaceutical, is possible. can.

[0158] When the total impurity profile of the discolored sample was evaluated, the retention time (RT) was 4.9. A peak is predominantly present at 7 minutes, and this peak is in the chromatogram of the uncolored reference sample. It does not exist (see Figure 1). Furthermore, from the full-wavelength chromatogram, the yellow-colored analyte This represents only a small portion of the analytes present in the concentrated fraction, and other uncolored analytes are also concentrated. You can tell they are there.

[0159] The impurities in RT4.97 have a precise mass of m / z 239.04750 Da [MH]. It was measured, and this is formula C 12 H 12 This corresponds to O3Cl. To obtain structural information about this impurity, A product ion scan was performed on a product with a molecular weight of 239.05. The resulting mass spectrum was obtained. Based on the data, the analyte is 6-(2-chlorophenyl)-6-oxohexanoic acid. This was suggested. Commercially available 6-(2-chlorophenyl purchased from Rieke Metals. )-6-oxohexanoic acid was analyzed, and based on the agreement of both retention time and mass spectrometry data, They confirmed their identity.

[0160] In forced decomposition tests in the presence of hydrogen peroxide and a radical initiator, 6-(2-chloromethyl chloride) The formation of lophenyl)-6-oxohexanoic acid had been reported previously.

[0161] Yellow / brown light / heat stress samples (ICH light) and colorless heat stress samples L C / MS analysis was performed. Samples subjected to light stress showed discoloration, as did the vias in batch 1. Compared to the previous sample, it mainly shows a similar resolution profile. The main degradation product is shown to be 6-(2-chlorophenyl)-6-oxohexanoic acid. It was done. In addition, the presence of several oxidative decomposition products and noresketamine was also confirmed. 6-( 2-chlorophenyl)-6-oxohexanoic acid was used in samples that had not been subjected to light stress. It was also included, but in very small quantities. Figure 1 shows an overlay diagram of different samples. show.

[0162] In addition to yellow / brown colored varieties, the main impurity is 6-(2-chlorophenyl)-6-oxohe It was identified as xanoic acid.

[0163] Example 4: Quantitative Investigation ICP-MS quantitative analysis was performed using a Thermo XSeries2 quadrupole ICP-MS. The measuring instrument operates in Standard (STD) mode and Collision Cell Technology (CCT) mode. It was made to produce Rh (STD mode measurement) or Rh (STD mode measurement) and Y (CCT mode). The combination of measurements was used as the internal standard. For calibration, the Merck ICP multi-element standard was used. IV(Li, B, Na, Mg, Al, K, Ca, Cr, Mn, Fe, Co, Ni, Cu (containing Zn, Ga, Sr, Ag, Cd, In, Ba, Ti, Pb, Bi) or multi-elemental standards It was used in combination with the Merck IV and Sn standard. The calibrated elements were fully quantified. The elements were measured by analytical analysis, and the remaining elements were measured by semi-quantitative analysis.

[0164] A. Concentration of metals present in pharmaceutical solutions To assess the extent to which the observed yellow / brown discoloration is due to the presence of elemental impurities. The contents of the vial taken from the batch that showed discoloration (batch 1, i.e., sample 1) , batches that did not show discoloration (batch 1 / sample 2, batch 2 / sample 3, batch 3) The contents of the vials from sample 4 (batch 4 / sample 5) were analyzed by ICP-MS. The contents of each vial were dispensed using a stainless steel needle attached to a plastic syringe. (All samples were pre-rinsed with ultrapure water) and collected by [method name]. Approximately 0.2 mL of sample was collected by [method name]. 0.1 mL of concentrated HNO3 (69%) was mixed and sonicated at 50°C for 5 minutes. After processing, the sample was diluted to 5 mL with ultrapure water and subjected to ICP-MS analysis.

[0165] ICP-MS performed total elemental analysis. The contents of the vials that showed discoloration (medium or high) were analyzed. (Sample from Batch 1) and vial contents that did not show discoloration (Samples from Batches 1-4) No difference in metal concentration was observed between the two samples. Measured in at least one batch. This table outlines the metals present in esketamine samples with an average concentration exceeding 0.01 μg / mL. As shown in 1A-1B, the average Na concentration of vials from different batches was greater than 200 μg / mL. However, the measured average B concentration was 1.5–2.5 μg / mL. Compared to Al (0.58~0.82 μg / mL), vials that show discoloration (1.1~1. At 5 μg / mL, the average Mg concentration was slightly higher. However, samples that did not show discoloration and When comparing the individual Mg values ​​of the samples showing discoloration, these differences were not significant. The average concentration of l was 0.62-0.75 μg / mL, and the average concentration of Fe was 0.13-0.32 μg / mL. The concentration was g / mL. The average concentrations of Cr, Ni, Zn, Ga, As, Zr, and Ba differed. The level was less than 0.06 μg / mL. Si was measured only by semi-quantitative analysis. Because interference is known, the exact concentration is not shown. However, the uncolored sample The Si concentration was very similar in the discolored and uncolored samples.

[0166] [Table 1]

[0167] [Table 2]

[0168] ICP-MS analysis of the esketamine solution revealed discoloration in the contents of the vial (Batch 1). Metal is detected between the sample and the contents of the vial that do not show discoloration (samples from batches 1-4). No observable differences in concentration were found.

[0169] B. Metal concentrations present in pharmaceuticals from batches 5-7 To evaluate whether there is a relationship between metal concentration and discoloration under light stress, The metal concentrations of the same batch (batch 5-7) used in the Tress test were measured by ICP-MS. The analysis was performed using the following method: Collection of sample contents from vials, sample processing, and sample dilution. This was done using the same method as described in the previous section.

[0170] All elements were analyzed using ICP-MS. The main elements of interest are shown in Table 2. This table includes... The measured concentrations at steps 5-7 are shown. For screening results, three replicate samples are available. Based on the sample preparation (one esketamine vial / sample preparation) and the measurement, the average The concentration and standard deviation were calculated. The average Fe concentration in batch 7 was higher than 1 μg / mL. In contrast, batches 5 and 6 were lower than 1 μg / mL. The average Cr concentration was lower in batch 6 than in batch 6. In batch 7, the concentration was 0.4-0.9 μg / mL, but in batch 5, it was less than 0.1 μg / mL. The average concentrations of Ni and Cu were less than 0.1 μg / mL in different batches. The average measured concentrations of B, Na, mg, Si, and Ca in the sample were greater than 1 μg / mL.

[0171] [Table 3]

[0172] C. Light stress test To compare the effects of light on different batches of esketamine medication, a light stress test was conducted. It began.

[0173] The following batches were included in the test. (i) Pharmaceutical batch 1 from sample 2. (ii) Pharmaceutical batch 5 (containing esketamine hydrochloride). (iii) Pharmaceutical batch 6 (containing esketamine hydrochloride), this is a trial without stopper It was also used in the preparation of experimental drug solutions. (iv) Pharmaceutical batch bulk 7 (containing esketamine hydrochloride), vials of this batch The samples were in a stable state before the actual test and had been stored at different temperatures and humidity levels.

[0174] Three vials were used from each batch. (i) In the optical cabinet, one is facing upwards (stopper at the top) and the other is facing downwards ( One topper is at the bottom, and the other is positioned horizontally. (ii) For ICH light exposure and 70°C storage, the samples were placed adjacent to each other, facing sideways. (iii) In the test without stoppers, all were placed facing upwards (with paraffin facing upwards). (Closed).

[0175] The samples were arranged under different conditions, as shown in Table 3.

[0176] [Table 4]

[0177] The vials are visually inspected at regular time intervals, and the color scale (Janssen Phar) is used. maceutica,Appearance Guide for Solids,ye llowish-brown grades,scale from 1 to 9,2 The color was compared with 015) and a placebo vial (uncolored).

[0178] In data evaluation, the results of vials from the same batch exposed under the same light exposure conditions / duration were compared. It was equalized.

[0179] Contents of all four batches of vials that were continuously exposed to D50 light in a horizontal position after the light exposure period ended. Using a vacuum filtration unit, a 0.1 μm Whatman Anodisc filter was used. It was filtered through a filter and washed with water.

[0180] Optical photographs were taken with a Leica MZ16 stereo microscope and a Leica DMLM microscope. Infrared ( IR) analysis was performed using a Bruker Hyperion 3000 infrared microscope with Tensor27 The experiment was conducted using a spectrometer. A 20x ATR objective lens was used to record the IR spectrum. At the end of the study, LC-DAD-MS was performed on a selected number of vials. Ta.

[0181] (i) Continuous light stress Most vials (with stoppers) discolor, and a color card is used to evaluate the discoloration. The photostress test was stopped after 49 days because it exceeded the scale. In some vials, Discoloration was already outside the scale by the 6th week of the trial (lateral vials of batches 1, 5, or 6). (L) Because it is outside the color card scale, the display data in Figure 2 will be limited by the 35th day. It is limited.

[0182] Before the start of the test, the vials were checked for discoloration (time 0). In all cases, no discoloration occurred. No color was observed (similar to the placebo). As shown in Figure 2, all subjects exposed to continuous light In batch 1, a clear color change was already observed after one week. In batch 1, further testing was conducted daily. The procedure was performed, and it was observed that discoloration had already begun two days later. Furthermore, D50 light was continuously applied. In the exposed vials with stoppers, a cloudy band appeared on the glass vial surface after 2 weeks. Yellow discoloration and particles were clearly visible on the top surface. After 2 weeks of D50 light exposure, Yellow discoloration and particles are clearly visible on the stopper surface inside the vial (batch 6 in this case). Done.

[0183] The particles were observed to be visually similar to those observed previously (Batch 1). In vials stored in a dark place at room temperature and 70°C as a reference, no color changes or particles were observed. It wasn't there.

[0184] (ii) Effects of initial light exposure and subsequent storage in the dark As shown in Figure 3, vials exposed to D50 light for 15 days are continuously exposed to D50 light. The vials discolored similarly, but the color change was significantly slower when placed in the dark (Batch 6). (This showed very similar behavior to batch 7).

[0185] Similar observations are possible for exposure to ICH light. After exposure to ICH light, the vial was It has changed color slightly (it is more colored than the placebo vial, but less than scale 1 on the color card). (Small). These ICH-stressed samples, when stored in the dark, gradually... The discoloration continued.

[0186] (iii) The effect of temperature when stored in the dark As shown in Figure 4, after exposure to ICH light, vials stored at room temperature in the dark slowly The discoloration continued at a steady pace, and the vials stored in a dark place at 70°C also continued to discolor in a similar manner. The speed increased.

[0187] (iv) Effects of light intensity The result was 2 × I, despite the fact that the amount of lux time received was much larger. The discoloration after CH is not as pronounced as after 7 days of continuous exposure to D50 light. Two cycles of ICH light (2 x 8 hours) is equivalent to 2 x 1.2 million lux hours, but over 7 days... D50 light (approximately 210 fc) is equivalent to only about 400,000 lux-hours. However, light intensity does not seem to be more important than duration.

[0188] (v) Influence of vial orientation and the presence of stopper As a result, compared to vials positioned upwards or downwards, horizontally positioned vials are higher Discoloration was observed (see example graph of batch 6 in Figure 5 (first graph), etc.). (The batch showed similar behavior.) This is related to the difference in the surface area of ​​the products exposed to light. It might be because when the vial is laid on its side, the entire side of the vial is exposed. It can be turned downwards, and when turned downwards, only the top part is exposed. When turned upwards, the stopper is at the bottom. It can cast a shadow on a liquid and partially block out light.

[0189] Vials without stoppers showed slower discoloration (from different batches, but the same escape route) Comparison of identically oriented vials prepared from a batch of tamin hydrochloride (Figure 5, second graph). (See reference). No particles were observed even in vials without stoppers. From this, it can be concluded that particles The generation of this substance is strongly related to the contact between the stopper and the esketamine solution in the vial. It is suggested.

[0190] D. Identification of discoloration Microscopic images of particles separated by the Anodisc filter in the entire batch were obtained. Upon evaluation, it was found that the stressed batch contained numerous small brown particles. It was discovered that there were clusters of some larger brown particles, or in some cases, smaller particles. Aggregates were also observed. The appearance of these particles was found in the discolored retaining vials of batch 1. It is similar to a separated particle.

[0191] Furthermore, the particles were analyzed using an IR microscope. Unfortunately, it was not possible to definitively identify the brown particles. This was not possible. However, the IR spectra collected this time showed the discolored retention biomass of batch 1. The brown particles found in Al show a significant similarity to previously obtained IR spectra. Observed. Similar to previous investigations, the possibility of a silicone-like material contributing to certain compounds. Numerous additional bands that could not be assigned were observed to be present in the IR spectrum. It was suspected. However, the spectrum of the particles separated from the vial in the photostress test showed that silicone The relative contribution of the cone-like material is smaller than the spectrum of the particles separated from the retaining vial. It appeared that way (Batch 1).

[0192] To evaluate the impurity profile, different esketamine batches were exposed to light conditions. Samples (1 and 5-7) were analyzed by LC-DAD-MS. Different batches were exposed under the same conditions. No significant difference was observed when comparing the chromatograms.

[0193] E. Conclusions of the light stress test Based on the results of the light stress test, the following considerations can be made regarding discoloration.

[0194] The behavior of different esketamine drug batches, including batch 1, under the same light stress conditions. They are similar (they do not depend on the metal concentration within the test range).

[0195] The appearance of vials subjected to light stress is similar to that of discolored vials. The appearance of the aluminum (presence of brown particles, deposits on the vial walls and stopper), and the outside of the particles. (They have similar appearances and chemical compositions.)

[0196] The duration of light exposure appears to be more important than the actual intensity of the light.

[0197] After initial light exposure (which leads to discoloration), the discoloration continues slowly even in the absence of light.

[0198] The yellow / brown discoloration of the Esketamine Nasal Spray 1 vial is due to silicone particles and yellow It has been shown to be caused by a combination with brown substances. Yellow / brown The substance appears to be adsorbed onto silicone particles and is related to the active ingredient in the pharmaceutical product esketamine. It seems that...

[0199] Embodiments of the present invention 1. A pharmaceutical composition comprising esketamine or a pharmaceutically acceptable salt thereof, and an oxidative decomposition product thereof. thing. 2. The oxidative decomposition product is 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutical product. A pharmaceutical composition according to embodiment 1, wherein the salt is generally acceptable. 3. 6-(2-chlorophosphate) at a concentration of 0.2% (HPLC area) or less relative to the amount of esketamine. The embodiment of Embodiment 2, comprising hexyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. Pharmaceutical composition. 4. For at least 6 months, at least 12 months, at least 18 months, or less After storage for 24 months, the amount of esketamine was less than 0.2% (HPLC area). Contains 6-(2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition described in embodiment 2. 5. In the absence of light for at least 6 months, at least 12 months, and at least 18 months After storage for at least 24 months, add 0.2% (HPL) relative to the amount of esketamine. C area) 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable form A pharmaceutical composition according to embodiment 2, comprising a salt. 6. 6-(2-chlorophenyl) at a concentration of 0.2% w / w or less relative to the weight of esketamine. The pharmaceutical composition according to embodiment 2, comprising -6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. thing. 7. For at least 6 months, at least 12 months, at least 18 months, or less After storage for 24 months, 6-(2) was found to be less than 0.2% w / w of the weight of esketamine. A form comprising chlorophenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition described in 2. 8. In the absence of light for at least 12 months, at least 18 months, or at least 24 months After storage for a month, 6-(2-chlorophenate) is stored at a concentration of 0.2% w / w or less relative to the weight of esketamine. The medical device according to embodiment 2, comprising (nyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. A pharmaceutical composition. 9. 6-(2-chlorophenyl)-6-oxohexanoic acid or so at a concentration of approximately 120 ppm or less. A pharmaceutical composition according to embodiment 2, comprising a pharmaceutically acceptable salt of the same. 10. For at least 6 months, at least 12 months, at least 18 months, or less After storage for at least 24 months, the concentration of 6-(2-chlorophenyl)-6- is approximately 120 ppm or less. A pharmaceutical composition according to embodiment 2, comprising oxohexanoic acid or a pharmaceutically acceptable salt thereof. 11. In the absence of light for at least 12 months, at least 18 months, or at least After 24 months of storage, the concentration of 6-(2-chlorophenyl)-6-oxo was approximately 120 ppm or less. A pharmaceutical composition according to embodiment 2, comprising hexanoic acid or a pharmaceutically acceptable salt thereof. 12. Storage temperature is in the range of approximately 20°C to approximately 75°C, as in aspects 4, 5, 7, 8, and 10. A pharmaceutical composition according to any one of the following 11. 13. Storage in an atmosphere with a relative humidity of approximately 25-80%, as in aspects 4 and 5. A pharmaceutical composition as described in 7, 8, 10, or 11. 14. The pharmaceutical composition is absorbed in less than approximately 1 hour, less than approximately 30 minutes, less than approximately 10 minutes, or less than approximately 1 minute. A pharmaceutical composition according to any one of embodiments 3, 6, or 9, which is exposed to light. 15. The pharmaceutical composition according to any one of embodiments 1 to 14, wherein the pharmaceutical composition is contained in a sealed container. thing. 16. The pharmaceutical composition according to embodiment 15, wherein the sealed container is a sealed glass vial. 17. The pharmaceutical composition according to 15 or 16, wherein the sealed container is substantially opaque to light. . 18. The pharmaceutical composition according to embodiment 17, wherein the sealed container is an amber-colored container. 19. The sealed container includes a plastic stopper, in any one of embodiments 15 to 18. The pharmaceutical composition described. 20. The sealed container is located inside a second container that is substantially opaque to light, embodiment 15~ A pharmaceutical composition as described in any one of the 19. 21. After storing in the absence of light for at least 6 months, esketamine or its pharmaceutically acceptable substances Acceptable salts and 6-(2-) at a concentration of 0.2% (HPLC area) or less relative to the amount of esketamine. A medically acceptable salt thereof, comprising chlorophenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. A pharmaceutical composition. 22. After storing in the absence of light for at least 6 months, esketamine or its pharmaceutically acceptable substances Allowable salts and 6-(2-chlorophosphate) less than 0.2% w / w relative to the weight of esketamine. A pharmaceutical composition comprising hexaenoic acid (hexyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. . 23. After storing in the absence of light for at least 6 months, esketamine or its pharmaceutically acceptable substances Acceptable salts and 6-(2-chlorophenyl)-6-oxohexa at concentrations of approximately 120 ppm or less A pharmaceutical composition comprising nic acid or a pharmaceutically acceptable salt thereof. 24. A pharmaceutical composition according to any one of embodiments 1 to 23, which is an intranasal pharmaceutical composition. 25. Of the following: citric acid monohydrate, disodium edetate, sodium hydroxide, and water A pharmaceutical composition according to any one of embodiments 1 to 24, further comprising one or more of the above. 26. Nore esketamine at a concentration of approximately 0.2% (HPLC area) or less relative to the amount of esketamine. A pharmaceutical according to any one of embodiments 1 to 25, further comprising n or a pharmaceutically acceptable salt thereof. composition. 27. Oxidative decomposition in pharmaceutical compositions containing esketamine or a pharmaceutically acceptable salt thereof. A method for preventing the formation of an object, (a) preparing a pharmaceutical composition in the absence of light, (b) storing the pharmaceutical composition in the absence of light, (c) Exposing the pharmaceutical composition to light for approximately 6 hours or less, (d) Filling a container with a pharmaceutical composition in the absence of light, including one or more of the above, method. 28. Esketamine or a pharmaceutically acceptable salt thereof, and 0. 6-(2-chlorophenyl)-6-oxohexanoic acid or less in an HPLC area of ​​2% or less A process for preparing a pharmaceutical composition comprising a pharmaceutically acceptable salt of esketamine or This involves mixing the pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients, A process that includes exposing esketamine to light for approximately 6 hours or less. 29. Esketamine or a pharmaceutically acceptable salt thereof, and 0 by weight of esketamine 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable content of 0.2% w / w or less A process for preparing a pharmaceutical composition comprising a salt that is permissible for esketamine or its medicinal Mixing a pharmaceutically acceptable salt with one or more pharmaceutically acceptable excipients, and Esketa A process that includes exposing Min to light for approximately 6 hours or less. 30. Esketamine or a pharmaceutically acceptable salt thereof, and 6-(2) at a concentration of approximately 120 ppm or less. A medical A process for preparing a pharmaceutical composition, comprising esketamine or one or more pharmaceutically acceptable salts thereof. Mixing with pharmaceutically acceptable excipients and exposing esketamine to light for approximately 6 hours or less A process that includes exposing something. 31. Embodiment 28, in which the mixing is carried out using a mixed substrate that is substantially opaque to light. The process described in any one of the following 30 items. 32. The process according to any one of embodiments 28 to 30, wherein the mixed substrate includes a light-protective foil. 33. Any one of embodiments 28 to 32 further comprises filling a container with a pharmaceutical composition. The process described. 34. Embodiment 33 in which the filling is carried out using a filling substrate that is substantially opaque to light. The process described above. 35. The filling material includes a black silicone sheet or stainless steel, as described in Embodiment 34. The loading process. 36. An embodiment further comprising covering the container with a second container that is substantially opaque to light. The process described in 34 or 35. 37. The process according to embodiment 36, wherein the second container is an aluminum bag.

[0200] The above specification, along with the examples given for illustrative purposes, teaches the principles of the present invention. However, the implementation of this invention is included within the scope of the following claims and equivalents. It will be understood that this includes all common variations, adaptations, and / or modifications.

Claims

1. A pharmaceutical composition comprising esketamine or a pharmaceutically acceptable salt thereof, and an oxidative decomposition product.

2. The oxidative decomposition product is 6-(2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutical product thereof. The pharmaceutical composition according to claim 1, wherein the salt is generally acceptable.

3. (i) 6-(2-c) at a concentration of 0.2% (HPLC area) or less relative to the amount of esketamine. (ii) P-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof, or (ii) The amount of 6-(2-chlorophenyl)-6- (0.2 w / w or less) relative to the weight of the esketamine. The pharmaceutical composition according to claim 2, comprising oxohexanoic acid or a pharmaceutically acceptable salt thereof.

4. For at least six months, at least twelve months, at least eighteen months, or at least After selective storage in the absence of light for 24 months, (i) the amount of esketamine 6-(2-chlorophenyl)-6-oxohexanoic acid or less at a concentration of 0.2% (HPLC area) or less (ii) 0.2 w / of the weight of the esketamine 6-(2-chlorophenyl)-6-oxohexanoic acid or its pharmaceutically acceptable equivalents below w A pharmaceutical composition according to claim 2, comprising a salt.

5. For at least six months, at least twelve months, at least eighteen months, or at least After being stored in the absence of light for 24 months in an optional manner, the amount of esketamine was 0.1 6-(2-chlorophenyl)-6-O % (HPLC area) or less or 0.1% w / w or less The pharmaceutical composition according to claim 4, comprising xohexanoic acid or a pharmaceutically acceptable salt thereof.

6. 6-(2-chlorophenyl)-6-oxohexanoic acid or its medicinal properties at a concentration of approximately 120 ppm or less The pharmaceutical composition according to claim 2, comprising a pharmaceutically acceptable salt.

7. For at least six months, at least twelve months, at least eighteen months, or at least After being selectively stored in the absence of light for 24 months, the concentration of 6-(2-) was reduced to approximately 120 ppm or less. A claim comprising chlorophenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition described in 2.

8. The storage temperature is in the range of approximately 20°C to approximately 75°C, any one of claims 4, 5, or 7. The pharmaceutical composition described in item one.

9. The storage is in an atmosphere having a relative humidity of approximately 25% to approximately 80%, claims 4, 5 A pharmaceutical composition according to any one of items 7 or 8.

10. The pharmaceutical composition is contained in a sealed container, preferably the sealed container is a sealed glass vial. A pharmaceutical composition according to any one of claims 1 to 9.

11. The sealed container is substantially opaque to light, preferably the sealed container is opaque. When measured using a light meter, the container is opaque, allowing approximately 10% or less of the light passing through it. A pharmaceutical composition according to claim 10, having a degree.

12. The sealed container is located inside a second container that is substantially opaque to light, preferably, When the second container is measured using an opacity meter, approximately 10% of the light passing through the container is measured. A pharmaceutical composition according to any one of claims 10 to 11, having an opacity that allows for an opacity of % or less. thing.

13. In an atmosphere with a temperature range of 20°C to approximately 75°C and a relative humidity of approximately 25% to approximately 80% When measured using an opacity meter, the container is opaque, allowing approximately 10% or less of light to pass through. After being stored for 6 months in the aforementioned sealed container with brightness, the amount / weight of esketamine is as follows: Each of the following: 0.2% (HPLC area) or less, or 0.2% w / w or less, 6-(2-chlorophenate The claim 2 comprises (nyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. Pharmaceutical composition.

14. After storing under the above conditions for 12 months, 18 months, or 24 months, the amount of esketamine / 6-( Contains 2-chlorophenyl)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. The pharmaceutical composition described in item 13.

15. A pharmaceutical composition according to any one of claims 1 to 14, which is an intranasal pharmaceutical composition.

16. One of the following: citric acid monohydrate, disodium edetate, sodium hydroxide, and water A pharmaceutical composition according to any one of claims 1 to 15, further comprising the above.

17. Forms of oxidative decomposition products in pharmaceutical compositions containing esketamine or its pharmaceutically acceptable salts. A method to prevent the occurrence, (e) Preparing the pharmaceutical composition in the absence of light, (f) Store the pharmaceutical composition in the absence of light. (g) Exposing the pharmaceutical composition to light for about 6 hours or less, (h) filling a container with the pharmaceutical composition in the absence of light, including one or more of the above. ,method.

18. During the preparation of the composition and the filling of the composition into the container, the pharmaceutical composition is left for 6 hours or less. Exposure to light, and then, when measured using an opacity meter, the amount passing through the container The pharmaceutical composition is stored in a container having an opacity that allows approximately 10% or less of light to pass through. The method according to claim 17, including,

19. During the preparation of the composition and the filling of the composition into the container, the pharmaceutical composition is left for 1 hour or less. The method according to claim 18, comprising exposure to light, preferably for 30 minutes or less.

20. When measured using an opacity meter, the container allows approximately 10% or less of the light passing through it. A claim comprising selecting a container having opacity for storing the pharmaceutical composition. Method 17.

21. a) Exposing the pharmaceutical composition to light for 6 hours or less during the preparation of the composition, b) When measured using an opacity meter, an allowable percentage of light passing through the container is approximately 10% or less. Select a container that has the desired opacity, c) Filling the container with the pharmaceutical composition, preferably in the absence of light, The method according to claim 17.

22. Claim 21 further includes storing the pharmaceutical composition in the container in the absence of light. Method of description.

23. Esketamine or a pharmaceutically acceptable salt thereof, and in proportion to the amount / weight of esketamine, Each of the following is 0.2% (HPLC area) or less or 0.2% w / w or less 6-(2-chlorophenic acid Preparation of a pharmaceutical composition containing (L)-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. A process comprising the esketamine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable Mixing with an acceptable excipient and exposing the esketamine to light for about 6 hours or less. A process that includes the act of doing something.

24. Esketamine or a pharmaceutically acceptable salt thereof, and 6-(2-chloroform) at a concentration of approximately 120 ppm or less. A pharmaceutical composition comprising lophenyl-6-oxohexanoic acid or a pharmaceutically acceptable salt thereof. A process for preparing a substance, comprising the esketamine or a pharmaceutically acceptable salt thereof and one or more Mixing with a pharmaceutically acceptable excipient and exposing the esketamine to light for approximately 6 hours or less. A process that includes exposure.

25. The mixing is carried out using a mixed substrate that is substantially opaque to light, preferably, When measured using an opacity meter, the mixed substrate allows approximately 10% of the light passing through the container to pass through. The process according to claim 23 or 24, having an opacity that allows the following:

26. The process according to claim 25, wherein the mixed substrate includes a light-protective foil.

27. Any one of claims 23 to 26 further comprises filling a container with the pharmaceutical composition. The process described.

28. The filling is carried out using a filling substrate that is substantially opaque to light, preferably, When measured using an opacity meter, the filling substrate allows approximately 10% of the light passing through the container to pass through. The process according to claim 27, having an opacity that allows the following:

29. The filling substrate comprises a black silicone sheet or stainless steel, as described in claim 28. The loading process.

30. The method further includes, preferably, covering the container with a second container that is substantially opaque to light. The process according to claim 28 or 29, wherein the second container is an aluminum bag. vinegar.

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