Esketamine liquid formulations and uses thereof

Abstract

The present application discloses an esketamine liquid formulation. The esketamine liquid formulation is an aqueous solution, and includes esketamine or a pharma- ceutically acceptable salt thereof, a polyol or a derivative thereof, and water, and the pH value of the liquid formulation is 2.5 to 5.7. The liquid formulation of the present application is administered via the oral mucosa, and has high formulation stability, rapid absorption, high bioavailability, a simple administration method, and good compliance. The formulation of the present application can be used for the prevention, amelioration, or treatment of major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, or bipolar depression.

Description

[Technical field]

[0001] This application claims priority to a Chinese patent application filed with the China Patent Office on April 26, 2022, bearing application number 202210448847.0 and entitled "Esketamine liquid formulation and use thereof", the contents of which are hereby incorporated by reference.

[0002] TECHNICAL FIELD This application relates to the field of drug formulations, but is not limited thereto, and in particular to liquid formulations of esketamine and their use as an antidepressant. [Background technology]

[0003] Depression is a type of manic-depressive illness, and its typical symptoms are low mood, slow thinking, and reduced and slow speech and movement. Depression seriously impairs the life and work of patients, placing a heavy burden on families and society, and about 15% of depressed patients die by suicide. According to a joint study by the World Health Organization, the World Bank, and Harvard University, depression is the second largest disease burden in China.

[0004] In recent years, ketamine has attracted attention as a psychiatric drug for the treatment of depression, and its antidepressant effects have been proven in numerous reports. Ketamine is a fast-acting antidepressant, and its mechanism is presumed to be to increase the levels of monoamine compounds in the brain by increasing monoamine release or inhibiting presynaptic monoamine reuptake, thereby exerting its antidepressant effects.

[0005] Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist, and most ketamine currently used in clinical practice is racemic, containing two enantiomers: dextroketamine and levo-ketamine. Research has shown that dextroketamine, or esketamine, has a higher affinity for NMDA, opioid receptors, and M cholinergic receptors than levo-ketamine, and its inhibitory effect on 5-HT is only 50% of that of levo-ketamine. In addition, side effects such as hallucinations and dreams caused by the administration of ketamine are mainly due to the levo-type isomer. Therefore, esketamine has better therapeutic effects and fewer side effects such as hallucinations and addiction.

[0006] The new antidepressant, developed and manufactured by Johnson & Johnson, is a nasal spray containing esketamine hydrochloride as the main drug, which has a rapid, long-lasting and powerful therapeutic effect on patients with treatment-resistant depression and suicidal tendencies, and was first approved for sale in the United States in March 2019. The product also received Breakthrough Drug Designation (BTD) for the treatment of treatment-resistant depression and Major Depressive Disorder with Imminent Suicide Risk, both of which were awarded by the FDA in 2013 and 2016, respectively.

[0007] Although esketamine achieves good antidepressant effects by intranasal administration, for patients with nasal inflammation or poor nasal mucosal tolerance, nasal administration cannot meet the drug use needs of such patients.In addition, for the nasal spray formulation of esketamine hydrochloride that has been released, the volume of nasal administration is relatively small, and in order to reach a therapeutic dose, the concentration of esketamine hydrochloride in the formulation is relatively high, close to the water saturation of esketamine.Such a high concentration esketamine hydrochloride solution increases the risk of ketamine abuse to a certain extent.In addition, according to pharmacokinetic studies, although the drug absorption rate is fast by nasal spray administration of esketamine, the in vivo drug absorption is poor due to nasal spray administration, and the bioavailability is not high.Therefore, in order to better expand the clinical application scope of ketamine antidepressant, meet the needs of more patients with depression, reduce treatment costs, and ease the burden on patients' families, other effective administration routes should be considered. Summary of the Invention

[0008] The present application provides a liquid formulation of esketamine for oral mucosal administration, which has high stability, rapid absorption, high bioavailability, simple administration method, and good compliance.

[0009] In one aspect, the present application provides an esketamine liquid formulation, the liquid formulation being for oral mucosal administration, comprising esketamine or a pharma- ceutically acceptable salt thereof in a concentration of 0.500% w / v to 8.500% w / v, a polyol or a derivative thereof, and water.

[0010] In another aspect, the present application provides a use of the above-mentioned esketamine liquid formulation in the preparation of a medicament for the prevention, amelioration or treatment of depression, which may be used to treat major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, bipolar depression.

[0011] In another aspect, the present application provides a method for preventing, ameliorating, or treating depression in a patient with the above-mentioned esketamine liquid formulation, comprising administering to the patient a therapeutically effective amount of the esketamine liquid formulation.

[0012] In another aspect, the present application provides the above liquid formulation of esketamine for use in preventing, ameliorating or treating depression in a patient, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression or bipolar depression.

[0013] In another aspect, the present application provides a method for preparing the esketamine liquid formulation. [Brief description of the drawings]

[0014] The drawings are intended to provide an understanding of the technical solution of the present application, are a part of the specification, and are used to interpret the technical solution of the present application together with the embodiments of the present application, and are not intended to limit the technical solution of the present application. [Figure 1]FIG. 1 is a diagram showing the relationship between administration route and pharmacokinetics of different esketamine formulations according to the present application. [Diagram 2] FIG. 1 shows the relationship between different administration routes and AUC for different esketamine formulations according to the present application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] A first aspect of the present application provides an esketamine liquid formulation, the liquid formulation being for oral mucosal administration and comprising esketamine or a pharma- ceutical acceptable salt thereof at a concentration of 0.5% w / v to 8.5% w / v, a polyol or a derivative thereof, and water.

[0016] Unless otherwise specified, esketamine as used herein is also known as S-ketamine, esketamine, (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride, etc., and refers to the (S)-enantiomer of ketamine.

[0017] In the liquid formulation of the present invention, whether esketamine or a pharma- ceutically acceptable salt of esketamine is used, the content of the active substance is calculated based on the content of esketamine.

[0018] In one embodiment of the esketamine liquid formulation described herein, the liquid formulation contains esketamine in an amount ranging from 0.5% w / v to 8.5% w / v.

[0019] The esketamine liquid formulation described in the present application has high bioavailability, so that the liquid formulation can be prepared as a product with a relatively low substance concentration, which can not only meet the preventive or therapeutic needs of clinical patients, but also avoid the risk of abuse caused by administration of high concentrations.In addition, the esketamine liquid formulation has good compatibility with saliva, reduces irritation to mucous membranes, and reduces the side effects of the drug.

[0020] In one embodiment, the concentration of esketamine in the liquid formulation is 0.7% w / v to 8.4% w / v. In another embodiment, the concentration of esketamine in the liquid formulation is 1.4% w / v to 6.3% w / v. In a further embodiment, the concentration of esketamine in the liquid formulation is 1.4% w / v to 5.6% w / v. Furthermore, in one embodiment, the concentration of esketamine in the liquid formulation is 0.7% w / v, 0.8% w / v, 0.9% w / v, 1.0% w / v, 1.1% w / v, 1.2% w / v, 1.3% w / v, 1.4% w / v, 1.5% w / v, 1.6% w / v, 1.7% w / v, 1.8% w / v, 1.9% w / v, 2.0% w / v, 2.1% w / v, 2.2% w / v, 2.3% w / v, 2.4% w / v, 2.5% w / v, 2.6% w / v, 2.7% w / v, 2.8% w / v, 2.9% w / v, 3.0% w / v, 3.1% w / v, 3.2% w / v, 3.3% w / v, 3.4% w / v, 3.5% w / v, 3.6% w / v, 3.7% w / v, 3.8% w / v, 3.9% w / v, 3.9% w / v, 3.0% w / v, 3.1% w / v, 3.2% w / v, 3.3% w / v, 3.4% w / v, 3.5% w / v, 3.6% w / v, 3.7% w / v, 3.8% w / v w / v, 2.4%w / v, 2.5%w / v, 2.6%w / v, 2.7%w / v, 2.8%w / v, 2.9%w / v, 3.0%w / v, 3.1%w / v, 3.2%w / v, 3.3%w / v, 3.4%w / v, 3.5%w / v, 3.6%w / v, 3.7%w / v, 3.8%w / v, 3.9%w / v, 4.0%w / v, 4.1%w / v, 4.2%w / v, 4.3%w / v, 4 .4%w / v, 4.5%w / v, 4.6%w / v, 4.7%w / v, 4.8%w / v, 4.9%w / v, 5.0%w / v, 5.1%w / v, 5.2%w / v, 5.3%w / v, 5.4 %w / v, 5.5%w / v, 5.6%w / v, 5.7%w / v, 5.8%w / v, 5.9%w / v, 6.0%w / v, 6.1%w / v, 6.2%w / v, 6.3%w / v, 6.4%w / v, 6.5%w / v, 6.6%w / v, 6.7%w / v, 6.8%w / v, 6.9%w / v, 7.0%w / v, 7.1%w / v, 7.2%w / v, 7.3%w / v, 7.4%w / v, 7 .5%w / v, 7.6%w / v, 7.7%w / v, 7.8%w / v, 7.9%w / v, 8.0%w / v, 8.1%w / v, 8.2%w / v, 8.3%w / v or 8.4%w / v.

[0021] In one embodiment, acids that may form pharma- ceutically acceptable salts with esketamine include hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, acetic acid, adipic acid, alginic acid, citric acid, aspartic acid, benzoic acid, benzenesulfonic acid, hydrogen sulfate, butyric acid, camphoric acid, camphorsulfonic acid, bisgluconic acid, fumaric acid, glycerophosphoric acid, stearic acid, heptanoic acid, caproic acid, hydrobromic acid (i.e., HBr), hydroiodic acid (i.e., HI), lactic acid, methanesulfonic acid, nicotinic acid, oxalic acid, dihydroxynaphthoic acid, pectinic acid, peroxosulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, thiocyanic acid, glutamic acid, p-toluenesulfonic acid, undecanoic acid, and mandelic acid.

[0022] In one embodiment, pharma- ceutically acceptable salts of esketamine include hydrochloride, sulfate, phosphate, maleate, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, bisgluconate, fumarate, glycerophosphate, stearate, heptanoate, caproate, hydrobromide (i.e., HBr), hydroiodide (i.e., HI), lactate, methanesulfonate, nicotinate, oxalate, dihydroxynaphthoate, pectinate, peroxosulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, and mandelate salts.

[0023] In a further embodiment, the concentration of the polyol or derivative thereof in the liquid formulation is between 1% w / v and 30% w / v.

[0024] In one embodiment, the polyol or derivative thereof is present in the liquid formulation at a concentration of 4% w / v to 25% w / v. In another embodiment, the polyol or derivative thereof is present in the liquid formulation at a concentration of 5% w / v to 20% w / v. In a further embodiment, the polyol or derivative thereof is present in the liquid formulation at a concentration of 1% w / v, 1.5% w / v, 2% w / v, 2.5% w / v, 3% w / v, 3.5% w / v, 4% w / v, 4.5% w / v, 5% w / v, 5.5% w / v, 6% w / v, 6.5% w / v, 7% w / v, 7.5% w / v, 8% w / v, 8.5% w / v, 9% w / v, 9.5% w / v, 10% w / v, 10.5% w / v, 11% w / v. , 11.5%w / v, 12%w / v, 12.5%w / v, 13%w / v, 13.5%w / v, 14%w / v, 14.5%w / v, 15%w / v, 15.5%w / v, 16%w / v, 16.5%w / v, 17 %w / v, 17.5%w / v, 18%w / v, 18.5%w / v, 19%w / v, 19.5%w / v, 20%w / v, 21%w / v, 22%w / v, 23%w / v, 24%w / v or 25%w / v.

[0025] In one embodiment, the polyol or derivative thereof is one of ethylene glycol, propylene glycol, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, menthol, a polysorbate (e.g., Tween 80, Tween 60, or Tween 20), or a combination thereof.

[0026] In one embodiment, the pH of the liquid formulation is 2.5-5.7. In another embodiment, the pH of the liquid formulation is in the range of 3.0-5.7. In another embodiment, the pH of the esketamine liquid formulation is in the range of 4.0-5.7. In a further embodiment, the pH of the liquid formulation is 5.0-5.5. In another embodiment, the pH of the liquid formulation is 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, or 5.7.

[0027] In one embodiment, the liquid formulation comprises esketamine or a pharma- ceutically acceptable salt thereof in a concentration of 0.5% w / v to 8.5% w / v, a polyol or a derivative thereof in a concentration of 1% w / v to 30% w / v, and water, and the liquid formulation has a pH range of 2.5 to 5.7.

[0028] In some embodiments of the present application, the esketamine liquid formulation may further comprise a viscosity enhancing agent.

[0029] In one embodiment, the viscosity increasing agent is xanthan gum, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, carbomer, or polyvinylpyrrolidone, or a combination thereof.

[0030] In one embodiment, the viscosity increasing agent sodium carboxymethylcellulose is selected from one or more of sodium carboxymethylcellulose 800, sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000.

[0031] In one embodiment, the combination of thickeners includes, but is not limited to, sodium carboxymethylcellulose 4000 and sodium carboxymethylcellulose 12000, sodium carboxymethylcellulose 800 and sodium carboxymethylcellulose 12000, sodium carboxymethylcellulose 4000 and xanthan gum, sodium carboxymethylcellulose 4000 and hypromellose, a composition of sodium carboxymethylcellulose 4000 and xanthan gum, and a composition of sodium carboxymethylcellulose 4000 and hypromellose, and the ratio (w / w) of the combination of two types of thickeners is 1:5 to 5:1.

[0032] In one embodiment, the concentration of the thickening agent is 0.01% w / v to 3.5% w / v. In another embodiment, the concentration of the thickening agent is 0.05% w / v to 3.0% w / v. In yet another embodiment, the concentration of the thickening agent is 0.05% w / v to 2.0% w / v. In further embodiments, the concentration of the thickening agent is 0.01% w / v, 0.05% w / v, 0.1% w / v, 0.15% w / v, 0.2% w / v, 0.25% w / v, 0.30% w / v, 0.35% w / v, 0.40% w / v, 0.45% w / v, 0.50% w / v, 0.55% w / v, 0.60% w / v, 0.65% w / v, 0.70% w / v, 0.75% w / v, 0.80% w / v, 0.85% w / v, 0.90% w / v, 0.95% w / v or 1.00% w / v.

[0033] In other embodiments, the esketamine liquid formulation further comprises one or more of the following auxiliary agents: a buffering agent, a flavoring agent, an antioxidant, a osmolality adjusting agent, a preservative, and, in other embodiments, the esketamine liquid formulation further comprises one or more of the following auxiliary agents: a buffering agent, a flavoring agent, an antioxidant, a osmolality adjusting agent, a preservative, and a permeation enhancer.

[0034] In one embodiment of the esketamine liquid formulation described herein, the buffering agent may be citric acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, acetic acid, boric acid, sodium borate, succinic acid, tartaric acid, lactic acid, fumaric acid, trisodium phosphate (trisodium phosphate dodecahydrate or TSP), sodium benzoate, benzoic acid, sodium hydroxide, potassium hydroxide, alkali metal carbonate, sodium carbonate, imidazole, pyrophosphate, sodium gluconate, sodium lactate, phosphoric acid, borate, bicarbonate, Tris-HCl, citrate, or a combination thereof.

[0035] The buffering agent described herein can maintain the pH of the liquid formulation within a stable range, and contributes to improving the stability of the solution formulation. The concentration of the buffering agent is 0.1-0.3% w / v. In one embodiment, the concentration of the buffering agent is 0.1-0.2% w / v. In another embodiment, the concentration of the buffering agent is 0.1-0.15% w / v. In other embodiments, the concentration of the buffer is 0.1% w / v, 0.11% w / v, 0.12% w / v, 0.13% w / v, 0.14% w / v, 0.15% w / v, 0.16% w / v, 0.17% w / v, 0.18% w / v, 0.19% w / v, 0.2% w / v, 0.21% w / v, 0.22% w / v, 0.23% w / v, 0.24% w / v, 0.25% w / v, 0.26% w / v, 0.27% w / v, 0.28% w / v, 0.29% w / v or 0.3% w / v.

[0036] In another embodiment, the present application provides an esketamine liquid formulation further comprising a flavoring agent. The flavoring agent can mask possible off-tastes of the pharmaceutical composition, improving the palatability and contributing to improved patient compliance. In one embodiment, the flavoring agent of the liquid formulation is sodium saccharin, fructose, sucralose, stevioside, menthol, maltitol, xylitol, aspartame, cyclamate, saccharin, neohesperidin, thaumatin, stevia, or acesulfame potassium, or a combination thereof. In one embodiment, the flavoring agent in the esketamine liquid formulation of the present application has a concentration of 0.01-0.05% w / v. In another embodiment, the flavoring agent has a concentration of 0.01-0.03% w / v. In another embodiment, the flavoring agent has a concentration of 0.01% w / v, 0.02% w / v, 0.03% w / v, 0.04% w / v, or 0.05% w / v.

[0037] In another embodiment, the present application provides an esketamine liquid formulation further comprising an antioxidant. The antioxidant can effectively prevent or delay the oxidation of the formulation, and can prevent problems such as oxidative deterioration of the drug and its formulation, and discoloration and precipitation caused by oxidation, thereby improving drug stability. In one embodiment, the antioxidant of the liquid formulation is ethylenediaminetetraacetic acid (EDTA) or its sodium salt or calcium salt, vitamin E, gallate, sodium bisulfite, ascorbic acid or its salt, butylhydroxyanisole or tocopherol, or a combination thereof.

[0038] In one embodiment, the antioxidant in the esketamine liquid formulation of the present application is present at a concentration of 0.010-0.020% w / v. In another embodiment, the antioxidant in the liquid formulation is present at a concentration of 0.010-0.015% w / v. In another embodiment, the antioxidant in the liquid formulation is present at a concentration of 0.010% w / v, 0.011% w / v, 0.012% w / v, 0.013% w / v, 0.014% w / v, 0.015% w / v, 0.016% w / v, 0.017% w / v, 0.018% w / v, 0.019% w / v, or 0.02% w / v.

[0039] In one embodiment, the esketamine liquid formulation further comprises a preservative, hi some embodiments, the preservative is selected from one or more of methylparaben, ethyl p-hydroxybenzoate, propylparaben, butylparaben, sodium methylparaben, sodium ethyl p-hydroxybenzoate, sodium propylparaben, sodium butylparaben, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, benzyl alcohol, benzalkonium bromide, benzalkonium chloride, trichloro-tert-butanol, resorcinol, and disodium ethylenediaminetetraacetate (disodium edetate).

[0040] In one embodiment, the esketamine liquid formulation further comprises a osmolality modifier, hi some embodiments, the osmolality modifier is selected from one or more of sodium chloride, potassium nitrate, boric acid, and glucose.

[0041] In one embodiment, the esketamine liquid formulation further comprises a penetration enhancer, hi some embodiments, the penetration enhancer is one or more of propylene glycol, Tween 80, hypromellose, sodium lauryl sulfate, sodium docusate, polysorbate, tetradecyl maltoside, lecithin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin sodium, or PEG 400.

[0042] In a second aspect of the present application, there is provided an esketamine liquid formulation, comprising esketamine hydrochloride, a polyol or a derivative thereof, a thickener and water, wherein the pH range of the liquid formulation is 4.5-5.5, and the content of esketamine in the liquid formulation is 0.7% w / v-8.4% w / v.

[0043] In one embodiment, the types of thickeners and their content of polyol or its derivatives are as described above.

[0044] In another embodiment, the viscosity increasing agent is one or a combination of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose.

[0045] In the esketamine liquid formulation of the present application, the simultaneous use of polyol or its derivative and a thickener can provide a more sufficient in vitro release of the API in the formulation, and can effectively promote the permeability of esketamine through the oral mucosa, thereby cooperating in improving the bioavailability of the esketamine solution formulation.

[0046] In one embodiment of the esketamine liquid formulation described herein, the thickening agent is one of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose, or a combination thereof. In one embodiment, the thickening agent is xanthan gum. In another embodiment, the thickening agent is hypromellose. In another embodiment, the thickening agent is carboxymethylcellulose sodium 4000 and carboxymethylcellulose sodium 12000. In another embodiment, the thickening agent is carboxymethylcellulose sodium 4000 and hypromellose.

[0047] In a third aspect of the present application, there is specifically provided an esketamine liquid formulation, comprising esketamine hydrochloride, a polyol or a derivative thereof, a thickener, a buffer and water, wherein the pH range of the liquid formulation is 4.5-5.5, and the content of esketamine in the liquid formulation is 0.7% w / v-8.4% w / v.

[0048] In one embodiment, the types of thickening agents and buffering agents and their content of polyol or its derivatives are as described above.

[0049] In one embodiment, in the esketamine liquid formulation of the present application, the buffering agent is citric acid.

[0050] In a fourth aspect of the present application, there is specifically provided an esketamine liquid formulation, comprising esketamine hydrochloride, a polyol or a derivative thereof, a thickener, an antioxidant, a flavoring agent, a buffer and water, wherein the pH range of the liquid formulation is 4.5-5.5, and the content of esketamine in the liquid formulation is 0.7% w / v-8.4% w / v.

[0051] In one embodiment, the types of thickeners, antioxidants, flavoring agents and buffering agents and the content of polyol or its derivatives are as described above.

[0052] In another embodiment, the viscosity increasing agent is one or a combination of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose.

[0053] In one embodiment of the esketamine liquid formulation described herein, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickener is one of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose, or a combination thereof. In one embodiment, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickener is xanthan gum. In another embodiment, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickener is hypromellose. In another embodiment, the thickener is sodium carboxymethylcellulose sodium 4000 and sodium carboxymethylcellulose sodium 12000. In another embodiment, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickener is sodium carboxymethylcellulose sodium 4000 and hypromellose.

[0054] In one embodiment, in the esketamine liquid formulation of the present application, the buffering agent is citric acid.

[0055] In a fifth aspect of the present application, there is provided a use of an esketamine liquid formulation in the preparation of a medicament for the prevention, amelioration or treatment of depression, which may be used for the treatment of major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, bipolar depression.

[0056] In one embodiment, in the use of an esketamine liquid formulation according to the present application in the preparation of a medicament for the prevention, amelioration or treatment of depression, the liquid formulation is administered to the oral buccal mucosa of a patient.

[0057] In a sixth aspect of the present application, there is provided a method for preventing, ameliorating or treating depression in a patient with an esketamine liquid formulation, comprising administering to the patient a therapeutically effective amount of the esketamine liquid formulation.

[0058] In one embodiment, the present application provides a method of preventing, ameliorating, or treating depression in a patient with an esketamine liquid formulation, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, or bipolar depression.

[0059] In one embodiment, in a method of preventing, ameliorating, or treating depression in a patient with an esketamine liquid formulation according to the present disclosure, the liquid formulation is administered to the patient's oral buccal mucosa.

[0060] In a seventh aspect of the present application, there is provided an esketamine liquid formulation for use in the prevention, amelioration or treatment of depression in a patient, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression or bipolar depression.

[0061] In one embodiment, an esketamine liquid formulation is used to prevent, ameliorate, or treat depression in a patient, and the liquid formulation is administered to the oral buccal mucosa of the mammal.

[0062] In an eighth aspect, the present application provides a method for preparing the esketamine liquid formulation, comprising the following preparation steps a) to e): a) Weigh out the prescribed amount of esketamine hydrochloride, add purified water, and thoroughly stir to dissolve. Then, sequentially add the prescribed amounts of an optional antioxidant such as disodium edetate, an optional buffer such as citric acid, and an optional flavoring agent such as sodium saccharin, and thoroughly stir to dissolve. b) Add the polyol or its derivative and any thickener in the formulation and stir thoroughly to dissolve. c) Adjust the pH to the corresponding value with sodium hydroxide. d) The solution is transferred to a specific volumetric flask and topped up with water to fix the volume up to the mark. e) After the volume is fixed, the solution is passed through a 0.45 μm filtration membrane, and the filtrate is filled into a prefilled syringe to obtain the finished formulation.

[0063] The beneficial effects of the present invention are as follows: (1) The esketamine liquid formulation of the present application is rapidly absorbed, takes effect within 4-7 minutes, and has an AUC0-240min of greater than 7000ng / mL. The esketamine liquid formulation has high bioavailability, no crystallization, and high stability, which not only meets the demands of large-scale processing and production, but also reduces the medication risk for patients. (2) The esketamine liquid formulation of the present application can effectively improve the bioavailability of the active substance by using a polyol or its derivative, and the addition of a thickener can further increase the residence time of the liquid formulation in the oral mucosa, thereby further improving the absorption amount of esketamine and cooperating in improving the bioavailability of the esketamine liquid formulation. (3) The administration method of the liquid formulation of esketamine according to the present invention is simple and easy, which greatly improves patient compliance. The small administration dose and small volume significantly reduce irritation to mucous membranes, thereby reducing the risk of abuse.

[0064] Unless otherwise noted, all component concentrations are in percent by weight / volume (%w / v). As is commonly understood, the %w / v value refers to the amount of a particular composition or ingredient in a formulation. As is well known, equivalent concentrations may be expressed in different units. For example, a concentration of 0.1%w / v may be expressed as a 1mg / ml solution.

[0065] The present application discloses an esketamine liquid formulation for oral mucosal administration and its use, and those skilled in the art can realize it by appropriately improving the process parameters in view of the contents of the present application. In addition, similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present application. The method and application of the present application have been described through the preferred embodiments, but those skilled in the art can make modifications or suitable changes and combinations to the methods and applications described herein to realize and apply the technology of the present application without departing from the content, spirit and scope of the present application. Any reagents or equipment used in the present application are commercially available.

[0066] device: S220-K pH meter, SHJ-6AB magnetic stirring water bath, ME204T / 02 electronic balance, ME3002T / 02 electronic balance, DSC-800T fully automatic transdermal diffusion meter, DIONEX U300 high-performance liquid chromatograph.

[0067] Example 1 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Propylene glycol 100mg Add water up to 1ml The preparation method includes the following preparation steps. a) Weigh out the prescribed amount of esketamine hydrochloride, add 80% of the total mass of purified water, and stir thoroughly to dissolve. Then add the prescribed amounts of disodium edetate, citric acid, and sodium saccharin in order, and stir thoroughly to dissolve. b) Add the corresponding propylene glycol, sodium carboxymethylcellulose 4000 in different formulations and stir thoroughly to dissolve. c) Adjust the pH to 4.5-5.5 with sodium hydroxide. d) The solution is transferred into a specific volumetric flask and the volume is fixed to the 10 ml mark by topping up with water. e) After the volume is fixed, the solution is passed through a 0.45 μm filtration membrane, and the filtrate is filled into a 1 ml prefilled syringe (purchased from Shandong Zibo Minkang Pharmaceutical Packing Co., Ltd.) to obtain a finished formulation at 1 ml per syringe.

[0068] Example 2 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 8000 1mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0069] Example 3 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 12000 10mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0070] Example 4 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Xanthan gum 1mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0071] Example 5 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Sodium carboxymethylcellulose 12000 0.8mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0072] Example 6 Formulation: Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Hypromellose 1mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0073] Example 7 Prescription Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Hypromellose 0.8mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0074] Example 8 Prescription Esketamine hydrochloride 32.3mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0075] Example 9 Prescription Esketamine hydrochloride 16.14mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0076] Example 10 Prescription Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0077] Example 11 Prescription Esketamine hydrochloride 32.3mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0078] Example 12 Prescription Esketamine hydrochloride 16.14mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Propylene glycol 100mg Add water up to 1ml See Example 1 for preparation method.

[0079] Example 13 Prescription Esketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate 100mg Add water up to 1ml See Example 1 for preparation method.

[0080] Example 14: Stability test of esketamine hydrochloride in oral fluid During the preparation and storage of esketamine hydrochloride buccal solution, the following two impurities are likely to be produced: [Table 1] Both of these impurities are commercially available. The present inventors conducted long-term stability experiments on the samples prepared in Examples 1 to 13 in an environment of 25° C.±2° C. and RH 60%±5%.

[0081] 1. How to detect ketamine content Measure according to high performance liquid chromatography (General Rule 0512). Chromatographic conditions: octadecylsilane is used as the packing material, 0.95 g of sodium hexanesulfonate is dissolved in 1 L of a mixture of acetonitrile and water (acetonitrile:water=25:75), 4 ml of glacial acetic acid is added and mixed uniformly to obtain the mobile phase, the detection wavelength is 215 nm, the flow rate is 1.0 ml per minute, the column temperature is 30°C, and the injection volume is 20 μl.

[0082] 2. Methods for detecting ketamine-related substances Measure according to high performance liquid chromatography (General Rule 0512). Chromatographic conditions: octadecylsilane is used as the packing material (Agela MP C18 4.6×150 mm, 5 μm or equivalent to the column efficiency), 25 mM phosphate buffer (take 3.4 g of potassium dihydrogen phosphate, add 1000 ml of water to dissolve, and adjust the pH to 2.5 with phosphoric acid) is used as the mobile phase A, and acetonitrile is used as the mobile phase B. Gradient elution is performed according to the table below, the detection wavelength is 215 nm, the column temperature is 30° C., the flow rate is 1.0 ml per minute, and the injection volume is 20 μl.

[0083] [Table 2]

[0084] Table 4. Long-term test results for Examples 1 to 13 [Table 3]

[0085] As can be seen from the long-term test results in Table 4, after the drug formulation obtained in this application was left at room temperature for 6 months, the total impurities of esketamine hydrochloride in the buccal fluid were all less than 0.5%, and the maximum single impurities were all less than 0.2%, so that the quality meets the quality standard and is stable.

[0086] Example 15 In vitro permeation test of the present invention's esketamine hydrochloride through buccal fluid In this study, the Franz diffusion cell method was adopted, and the phospholipid biomimetic barrier PermeaPad (registered trademark) (biomimetic membrane) was selected to simulate the oral mucosa, and PBS buffer solution was used as the diffusion medium. When the diffusion cell reached 37°C, 0.5ml of artificial saliva was first added to the top of the biomimetic membrane, and then 0.2ml of the formulation solution was added. The sampling times were 10min, 20min, 30min, 45min, 60min, 180min, 240min, 300min, and 360min. The waste mode was adopted to take 1ml samples at each time and detect the content in the liquid phase.

[0087] Table 5. In vitro permeation results for Examples 1 to 13 [Table 4]

[0088] Comparative Example 1 Esketamine hydrochloride nasal spray (prepared with reference to patent CN 111297803 A) Prescription ingredients Esketamine hydrochloride 161.4mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium hydroxide to adjust pH to 4.52 Add water up to 1ml Product specifications: A single spray contains 7.00mg of esketamine The preparation method includes the following preparation steps. a) Weigh out the prescribed amount of dextroketamine hydrochloride, add a certain amount of purified water, and thoroughly stir to dissolve. Then add the prescribed amounts of disodium edetate and citric acid in order, and thoroughly stir to dissolve. b) Adjust the pH to 4.5 with sodium hydroxide. c) The solution is transferred into a specific volumetric flask and topped up with water to fix the volume up to the mark. d) After the volume is fixed, the solution is passed through a 0.45 μm filtration membrane, and the filtrate is filled according to demand.

[0089] Comparative Example 2 Esketamine hydrochloride oral dissolving film 1 (prepared with reference to patent CN 111447920 A) Prescription ingredients Esketamine hydrochloride 4.3232g Hypromellose 9.00g Hydroxypropyl cellulose 3.00g PEG400 300g Carbomer 974P 0.01g Hydroxypropylmethyl-β-cyclodextrin 0.37g The preparation method includes the following preparation steps. a) Weigh out the prescribed amount of esketamine hydrochloride, add a certain amount of purified water, and thoroughly stir to dissolve. Then, add the prescribed amounts of hypromellose, hydroxypropyl cellulose, and PEG400 in turn, and thoroughly stir to dissolve. b) Add the corresponding Carbomer 974P, Hydroxypropylmethyl-β-cyclodextrin in different formulations and dissolve by stirring thoroughly. c) After leaving it to degas, it is applied and dried, and then hammered into a mold to the desired specifications.

[0090] Comparative Example 3 Esketamine hydrochloride oral dissolving film 2 (prepared with reference to patent CN 111447920 A) Prescription ingredients Esketamine hydrochloride 4.3232g Hypromellose 9.00g Hydroxypropyl cellulose 3.00g PEG400 300g Sodium deoxycholate 0.003g For the preparation method, refer to Comparative Example 2, using sodium deoxycholate instead of Carbomer 974P and hydroxypropylmethyl-β-cyclodextrin.

[0091] Test Example 1 In vivo pharmacokinetics experiment 1. Experimental group assignment Table 6 Animal grouping status [Table 5]

[0092] 2. Experimental plan The experiment used New Zealand White rabbits, weighing 2.5kg to 3.0kg, with six rabbits in each group, half male and half female. Comparative Example 1 used unilateral nasal administration, with a dose of 0.05ml / rabbit (one spray). Examples 1 and 10 used unilateral oral buccal administration, with a dose of 0.125ml / rabbit (total dose 7mg). Example 11 used unilateral oral buccal administration, with a dose of 0.250ml / rabbit (total dose 7mg). Example 12 used bilateral oral buccal administration, with a dose of 0.250ml / side (total dose 7mg). Comparative Examples 2 and 3 used unilateral oral buccal administration, with a dose of 1 tablet / rabbit (7mg). Comparative Examples 2 and 3 used sublingual administration, with a dose of 1 tablet / rabbit (7mg). Before blood sampling, rabbits were placed in a rabbit restrainer, and blood was collected from the marginal ear vein at 0 min (before administration), 2 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, and 240 min. At each time, about 1 ml of whole blood was collected and put into a blood collection tube containing sodium heparin, and centrifuged at 4000 rpm for 10 min to obtain plasma samples. The supernatant was taken and divided into three parts into 0.5 ml EP tubes (two parts were put into 150 μl, and the remaining plasma was put into the third cryopreservation tube as a backup sample). After dividing and processing the plasma samples, the samples were stored at a temperature below -80 ° C.

[0093] 3. Experimental results Table 7. Pharmacokinetic study results of 9 groups of samples administered via different routes in rabbits [Table 6]

[0094] As can be seen from Table 7 and Figure 1, in the rabbits administered esketamine hydrochloride via different routes, the Tmax of the oral buccal fluid administration group (Example 1) is close to that of the nasal administration group (Comparative Example 1), within about 4 to 7 minutes, while the Tmax of the orally dissolving film groups (Comparative Examples 2 and 3) is within the range of 20 to 60 minutes. This indicates that the onset of effect of the oral buccal fluid administration of esketamine hydrochloride of the present application and the nasal administration of its nasal spray are similar, while the onset of effect of the orally dissolving film is slower than that of the oral buccal fluid administration of the present application.

[0095] As can be seen from the data on average Cmax, the Cmax of the oral buccal fluid administration group (Example 1) was significantly increased, improving by about 1-fold, compared to the nasal administration group (Comparative Example 1), while the Cmax of the orally dissolving film group (Comparative Examples 2 and 3) was lower than that of the nasal administration group, decreasing by about 1-2-fold. This indicates that the drug absorption of esketamine hydrochloride of the present application by buccal mucosal administration of oral buccal fluid is higher than that by nasal administration.

[0096] As can be seen from Table 7 and Figure 2, the AUC0-240min of the oral buccal fluid administration group (Example 1) was significantly increased (p<0.05), improving by about 1-fold, compared with the nasal administration group (Comparative Example 1), while the AUC0-240min of the orally dissolving film groups (Comparative Examples 2 and 3) was not significantly different from the nasal administration group (p>0.05). This result is consistent with the Cmax result, and further indicates that the in vivo drug absorption of esketamine hydrochloride of the present application by buccal mucosal administration of oral buccal fluid is higher than that by nasal administration and orally dissolving film administration.

[0097] As can be seen from Table 7 and Figure 1, in the different administration routes of esketamine hydrochloride in rabbits, the Tmax of the oral buccal administration group (Examples 10, 11, and 12) at different concentrations was close to that of the nasal administration group (Comparative Example 1), within about 5 to 7 minutes, and the onset speed was faster than that of the orally dissolving film group. The Cmax of the oral buccal administration group (Examples 10, 11, and 12) at different concentrations was significantly increased, improving by about 1-fold, while the Cmax of the orally dissolving film group (Comparative Example 2, Comparative Example 3) was lower than that of the nasal administration group, decreasing by about 1 to 2-fold. This indicates that the drug absorption of the oral buccal fluid administration of esketamine hydrochloride at different concentrations of the present application is higher than that of nasal administration.

[0098] As can be seen from Table 7 and Figure 2, compared with the nasal administration group (Comparative Example 1), the AUC0-240min of the oral buccal administration groups (Examples 10, 11, and 12) administered at different concentrations significantly increased (p<0.05), improving by about 1-fold, while the AUC0-240min of the orally dissolving film groups (Comparative Examples 2 and 3) did not differ significantly from the nasal administration group (p>0.05). This result is consistent with the Cmax result, further demonstrating that the in vivo drug absorption after administration of esketamine hydrochloride at different concentrations of the present application to the buccal mucosa is higher than that of nasal administration and oral dissolving film administration.

[0099] As described above, the in vivo drug absorption of esketamine hydrochloride via buccal mucosal administration in the oral cavity was significantly higher than that via nasal administration and oral dissolving film administration, being approximately one-fold higher. Furthermore, the onset times of the two routes were similar, approximately 4 to 7 minutes, and the onset rate was faster than that via oral dissolving film administration.

[0100] The technical solution of the present application can also be applied to an oral / buccal fluid delivery system for R-ketamine, ketamine or a pharma- ceutical acceptable salt thereof. The objective of the present application can be achieved by adjusting or modifying the content of the active ingredient, the type of pharma- ceutical adjuvants, the dosage, etc.

[0101] The examples given in the present application are as above, but the above contents are merely examples for the convenience of understanding the present application, and are not intended to limit the present application. Those skilled in the art may make any modifications and changes to the embodiments and details without departing from the spirit and scope of the present application, but the scope of protection of the present application is based on the scope of the appended claims.

Claims

1. 1. An esketamine liquid formulation, the liquid formulation being for oral mucosal administration, comprising esketamine or a pharma- ceutical acceptable salt thereof at a concentration of 0.5% w / v to 8.5% w / v, a polyol or a derivative thereof, and water, and the liquid formulation has a pH value ranging from 2.5 to 5.

7.

2. 2. The esketamine liquid formulation of claim 1, wherein the liquid formulation comprises esketamine or a pharma- ceutical acceptable salt thereof in a concentration of 0.5% w / v to 8.5% w / v, a polyol or a derivative thereof in a concentration of 1% w / v to 30% w / v, and water, and the liquid formulation has a pH value in the range of 2.5 to 5.

7.

3. 3. The esketamine liquid formulation of claim 2, wherein the concentration of esketamine in the liquid formulation is 0.7% w / v to 8.4% w / v, preferably 1.4% w / v to 6.3% w / v, and more preferably 1.4% w / v to 5.6% w / v.

4. 3. The esketamine liquid formulation of claim 2, wherein the polyol or its derivative is selected from one of ethylene glycol, propylene glycol, 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate, menthol, polysorbate, or a combination thereof, preferably propylene glycol or ethylene glycol.

5. 3. The esketamine liquid formulation of claim 2, wherein the concentration of the polyol or its derivative is from 1% w / v to 30% w / v, preferably from 4% w / v to 25% w / v, and more preferably from 5% w / v to 20% w / v.

6. 3. The esketamine liquid formulation of claim 2, wherein the liquid formulation has a pH range of 3.0 to 5.7, preferably 4.0 to 5.7, more preferably 4.5 to 5.5, and particularly preferably 5.0 to 5.

5.

7. The esketamine liquid formulation of any one of claims 1 to 6, wherein the liquid formulation further comprises a viscosity enhancing agent.

8. 8. The esketamine liquid formulation of claim 7, wherein the viscosity enhancing agent is one of xanthan gum, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, carbomer, and polyvinylpyrrolidone, or a combination thereof.

9. 9. The esketamine liquid formulation of claim 8, wherein the sodium carboxymethylcellulose is sodium carboxymethylcellulose 800, sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, or sodium carboxymethylcellulose 12000, or a combination thereof.

10. 8. The esketamine liquid formulation of claim 7, wherein the viscosity enhancing agent is present in a concentration of 0.01% to 3.5% w / v.

11. The esketamine liquid formulation of any one of claims 1 to 10, wherein the liquid formulation further comprises one or more auxiliary agents selected from the group consisting of buffering agents, flavoring agents, antioxidants, osmolality adjusting agents, preservatives, and permeation enhancers.

12. 12. The esketamine liquid formulation of claim 11, wherein the liquid formulation further comprises a buffer, a flavoring agent, and an antioxidant, or wherein the liquid formulation further comprises a buffer, a flavoring agent, an antioxidant, and a permeation enhancer.

13. 13. The esketamine liquid formulation of claim 11 or 12, wherein the buffering agent is one of citric acid, sodium citrate, acetic acid, sodium acetate, lactic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, succinic acid, boric acid, sodium borate, tartaric acid and fumaric acid, or a combination thereof.

14. 13. The esketamine liquid formulation of claim 11 or 12, wherein the flavoring agent is one of sodium saccharin, fructose, sucralose, stevioside, menthol, maltitol, xylitol, aspartame, cyclamate, saccharin, neohesperidin, thaumatin, stevia, and acesulfame potassium, or a combination thereof.

15. 13. The esketamine liquid formulation of claim 11 or 12, wherein the antioxidant is one of edetate disodium, vitamin E, gallate, sodium bisulfite, ascorbic acid or its salts, butylated hydroxyanisole, and tocopherol, or a combination thereof.

16. Use of the esketamine liquid formulation according to any one of claims 1 to 15 in the preparation of a medicament for the prevention, amelioration or treatment of depression.

17. 17. The use of claim 16, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression, or bipolar depression.

18. 18. The use according to claim 16 or 17, wherein the liquid formulation is administered to the oral buccal mucosa of a patient.

19. A method for preventing, ameliorating or treating depression in a patient with an esketamine liquid formulation described in any one of claims 1 to 15, comprising administering a therapeutically effective amount of the esketamine liquid formulation to the patient's oral buccal mucosa.

20. 20. The method of claim 19, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression or bipolar depression.

21. 16. Use of an esketamine liquid formulation according to any one of claims 1 to 15 in the prevention, amelioration or treatment of depression in a patient.

22. 22. The use of an esketamine liquid formulation as described in claim 21 in preventing, ameliorating or treating depression in a patient, wherein the depression is major depressive disorder, unipolar depression, treatment-refractory depression, treatment-resistant depression, anxiety depression or bipolar depression.

23. 23. The use of an esketamine liquid formulation as described in claim 21 or 22 in preventing, ameliorating or treating depression in a patient, wherein the liquid formulation is administered to the patient's oral buccal mucosa.

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