R-Ketamine Liquid Preparation and Its Use

Abstract

The present application discloses an R-ketamine liquid formulation. The R-ketamine liquid formulation is an aqueous solution formulation, which includes R-ketamine or a pharma- ceutical acceptable salt thereof, an amphipathic pharma- ceutical acceptable excipient, 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 fast formulation 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 202210448842.8 and entitled "R-Ketamine Liquid Preparation and Use Thereof," the contents of which are hereby incorporated by reference.

[0002] This application relates to the field of drug formulations, but is not limited thereto, and in particular to liquid formulations of R-ketamine and their use as antidepressants. [Background technology]

[0003] Major depression disorder (MDD) is a common mental disorder, and its typical symptoms are low mood, slow thinking, and reduced and slow speech. Depression seriously interferes with the patient's life and work, and places a heavy burden on the family and society. According to statistics, the number of suicides caused by depression is estimated to reach one million every year. Currently, in clinical practice, antidepressants (e.g., tricyclic antidepressants, selective 5-hydroxytryptamine reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors) are mainly used to treat this mental disorder, but these drugs cannot exert a therapeutic effect on all patients with depression. Therefore, it is necessary to develop a new drug for treating depression.

[0004] In recent years, research has shown that ketamine, as an N-methyl-D-aspartate (NMDA) receptor antagonist, can increase the level of monoamine compounds in the brain and exert an antidepressant effect by increasing the release of monoamines or inhibiting the reuptake of monoamines in the presynaptic membrane. This special psychiatric drug has attracted attention.

[0005] In order to meet the needs of more patients with depression, reduce treatment costs, and ease the burden on patients' families, it is important to develop new formulations that have clinical application value. Summary of the Invention

[0006] The present application provides an R-ketamine liquid formulation for oral mucosal administration, which has high stability, rapid absorption, high bioavailability, simple administration method, and good compliance.

[0007] In one aspect, the present application provides an R-ketamine liquid formulation, the liquid formulation being for oral mucosal administration and comprising R-ketamine or a pharma- ceutical acceptable salt thereof, an amphipathic pharma- ceutical acceptable excipient, and water.

[0008] In another aspect, the present application provides a use of the above-mentioned R-ketamine 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, or bipolar depression.

[0009] In another aspect, the present application provides a method for preventing, ameliorating, or treating depression in a patient with the R-ketamine liquid formulation, comprising administering to the patient a therapeutically effective amount of the R-ketamine liquid formulation.

[0010] In another aspect, the present application provides the above-mentioned R-ketamine liquid formulation 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.

[0011] In another aspect, the present application provides a method for preparing the R-ketamine liquid formulation. [Brief description of the drawings]

[0012] 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 shows the in vitro diffusion profile of different R-ketamine formulations according to the present application. [Diagram 2] FIG. 1 is a diagram showing the relationship between administration route and pharmacokinetics of different R-ketamine formulations according to the present application. [Diagram 3] FIG. 1 is a graph showing the relationship between different administration routes and AUC for different R-ketamine formulations according to the present application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] In a first aspect of the present application, there is provided an R-ketamine liquid formulation, the liquid formulation being for oral mucosal administration and comprising R-ketamine or a pharma- ceutical acceptable salt thereof, an amphipathic pharma- ceutical acceptable excipient, and water.

[0014] Unless otherwise specified, R-ketamine as used herein is also known as (R)-ketamine, arketamine, revocetamine, arketamine, d-ketamine, (2R)-2-(2-chlorophenyl)-2(methylamino)cyclohexanone, etc. and refers to the (R)-enantiomer of ketamine.

[0015] In the liquid formulation of the present application, whether R-ketamine or a pharma- ceutical acceptable salt of R-ketamine is used, the content of the active substance is calculated based on the content of R-ketamine.

[0016] In one embodiment of the R-ketamine liquid formulation described herein, the content of R-ketamine in the liquid formulation is 0.5% w / v to 8.5% w / v.

[0017] The R-ketamine 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 R-ketamine liquid formulation has good compatibility with saliva, reduces irritation to mucous membranes, and reduces the side effects of the drug.

[0018] In one embodiment, the concentration of R-ketamine in the liquid formulation is between 0.7% w / v and 8.4% w / v. In another embodiment, the concentration of R-ketamine in the liquid formulation is between 1.4% w / v and 6.3% w / v. In a further embodiment, the concentration of R-ketamine in the liquid formulation is between 1.4% w / v and 5.6% w / v. Further, in one embodiment, the concentration of R-ketamine 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, 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.

[0019] In other embodiments, acids that may form pharma- ceutically acceptable salts with R-ketamine 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.

[0020] In one embodiment, pharma- ceutically acceptable salts of R-ketamine 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.

[0021] In one embodiment, the concentration of the amphipathic pharma- ceutically acceptable excipient in the liquid formulation is 0.03% w / v to 0.11% w / v. In another embodiment, the concentration of the amphipathic pharma-ceutically acceptable excipient in the liquid formulation is 0.03% w / v to 0.07% w / v. Furthermore, in one embodiment, the concentration of the amphipathic pharma-ceutically acceptable excipient in the liquid formulation is 0.01% w / v, 0.013% w / v, 0.016% w / v, 0.02% w / v, 0.023% w / v, 0.026% w / v, 0.03% w / v, 0.033% w / v, 0.036% w / v, 0.04% w / v, 0.043% w / v, 0.046% w / v, 0.05 ... 3%w / v, 0.056%w / v, 0.06%w / v, 0.063%w / v, 0.066%w / v, 0.07%w / v, 0.073%w / v, 0.076%w / v, 0.08%w / v, 0.0 83%w / v, 0.086%w / v, 0.09%w / v, 0.093%w / v, 0.096%w / v, 0.10%w / v, 0.103%w / v, 0.106%w / v, 0.11%w / v.

[0022] In one embodiment, the amphiphilic pharma- ceutically acceptable excipient is one of sodium lauryl sulfate, alkyl alcohol amides, alkyl succinic acid sulfonates, alcoholamine alkyl benzene sulfonates, naphthenates, sulfosuccinates, alkyl phenol sulfonates, polyoxyethylene monolaurate, sodium heptyl sulfate, sodium deoxycholate, sodium heptyl sulfonate, or a combination thereof, preferably sodium lauryl sulfate, sodium deoxycholate.

[0023] In one embodiment, the liquid formulation has a pH of 2.5 to 5.7.

[0024] In another embodiment, the pH range of the liquid formulation is 3.0 to 5.7. In another embodiment, the pH range of the R-ketamine liquid formulation is 4.0 to 5.7. In a further embodiment, the pH of the liquid formulation is 5.0 to 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.

[0025] In another embodiment, the liquid formulation comprises R-ketamine or a pharma- ceutical acceptable salt thereof in a concentration of 0.5% w / v to 8.5% w / v, an amphipathic pharma- ceutical acceptable excipient in a concentration of 0.01% w / v to 0.11% w / v, and water, and the liquid formulation has a pH range of 2.5 to 5.7.

[0026] In some embodiments of the present application, the R-ketamine liquid formulation may further comprise a viscosity enhancing agent.

[0027] In other embodiments, the viscosity increasing agent is xanthan gum, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyvinyl alcohol, carbomer, or polyvinylpyrrolidone, or a combination thereof.

[0028] In other embodiments, the sodium carboxymethylcellulose is selected from one or more of: sodium carboxymethylcellulose 800, sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, and sodium carboxymethylcellulose 12000.

[0029] 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.

[0030] 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% to 3.0% w / v. In a further embodiment, the concentration of the thickening agent is 0.05% 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.

[0031] In other embodiments, the R-ketamine liquid formulation further comprises one or more of the following auxiliary agents: a buffering agent, a flavoring agent, an antioxidant, an osmolality adjusting agent, a preservative, and, in other embodiments, the R-ketamine liquid formulation further comprises one or more of the following auxiliary agents: a buffering agent, a flavoring agent, an antioxidant, an osmolality adjusting agent, a preservative, and a permeation enhancer.

[0032] In one embodiment of the R-ketamine liquid formulation described herein, the buffering agent can 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.

[0033] 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.

[0034] In another embodiment, the present application provides an R-ketamine liquid formulation further comprising a flavoring agent. The flavoring agent can mask possible off-tastes of the pharmaceutical composition to improve the palatability, which contributes to improving patient compliance. In one embodiment, the flavoring agent of the liquid formulation is sodium saccharin, fructose, sucralose, stevioside, menthol, maltitol, xylitol, aspartame, sodium cyclamate, saccharin, neohesperidin, thaumatin, stevia, or acesulfame potassium, or a combination thereof.

[0035] In one embodiment, the flavoring agent in the R-ketamine 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.

[0036] In one embodiment, the present application provides an R-ketamine liquid formulation further comprising an antioxidant. The antioxidant can effectively prevent or delay the oxidation of the formulation, prevent problems such as oxidative deterioration of the drug and its formulation, and discoloration and precipitation caused by oxidation, and improve 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.

[0037] In one embodiment, the antioxidant in the R-ketamine 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.

[0038] In one embodiment, the R-ketamine 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 sodium ethylenediaminetetraacetate.

[0039] In one embodiment, the preservative concentration in the R-ketamine liquid formulation of the present application is 0.010-0.020% w / v. In another embodiment, the preservative concentration is 0.010-0.015% w / v. In another embodiment, the preservative concentration is 0.010% w / v, 0.0125% w / v, 0.015% w / v, 0.0175% w / v, or 0.02% w / v.

[0040] In one embodiment, the R-ketamine 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 R-ketamine 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 R-ketamine liquid formulation, comprising R-ketamine hydrochloride, an amphiphilic pharma- ceutically acceptable excipient, a thickener, and water, wherein the pH range of the liquid formulation is 4.5-5.5, and the content of R-ketamine in the liquid formulation is 0.7% w / v-8.4% w / v.

[0043] In one embodiment, the types of viscosity enhancing agents and their content of amphiphilic pharma- ceutically acceptable excipients 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 R-ketamine liquid formulation of the present application, the simultaneous use of an amphiphilic pharma- ceutically acceptable excipient and a thickener can provide a more sufficient in vitro release of the API in the formulation, and can effectively promote the permeability of R-ketamine through the oral mucosa, thereby cooperating in improving the bioavailability of the R-ketamine solution formulation.

[0046] In one embodiment of the R-ketamine 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 provided an R-ketamine liquid formulation, comprising R-ketamine hydrochloride, an amphiphilic pharma- ceutically acceptable excipient, a thickener, a buffer, and water, wherein the pH range of the liquid formulation is 4.5 to 5.5, and the content of R-ketamine in the liquid formulation is 0.7% w / v to 8.4% w / v.

[0048] In one embodiment, the types of viscosity enhancing agents and buffering agents and the content of amphiphilic pharma- ceutically acceptable excipients therewith are as described above.

[0049] In one embodiment, in the R-ketamine liquid formulation according to the present application, the buffer is citric acid.

[0050] In a fourth aspect of the present application, there is specifically provided an R-ketamine liquid formulation, comprising R-ketamine hydrochloride, an amphiphilic pharma- ceutically acceptable excipient, a thickener, an antioxidant, a flavoring agent, a buffer, and water, wherein the pH range of the liquid formulation is 4.5 to 5.5, and the content of R-ketamine in the liquid formulation is 0.7% w / v to 8.4% w / v.

[0051] In one embodiment, the types of thickening agents, antioxidants, flavoring agents and buffering agents and the content of amphiphilic pharma- ceutically acceptable excipients therewith 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 R-ketamine 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 R-ketamine liquid formulation according to the present application, the buffer is citric acid.

[0055] A fifth aspect of the present application provides a use of an R-ketamine 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, and bipolar depression.

[0056] In one embodiment, in the use of an R-ketamine 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 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 R-ketamine liquid formulation, comprising administering to the patient a therapeutically effective amount of the R-ketamine liquid formulation.

[0058] In one embodiment, the present application provides a method of preventing, ameliorating, or treating depression in a patient with an R-ketamine 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 the method of preventing, ameliorating, or treating depression in a patient with an R-ketamine liquid formulation according to the present application, 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 R-ketamine 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 R-ketamine 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 R-ketamine liquid formulation, comprising the following preparation steps a) to e): a) Weigh out the prescribed amount of R-ketamine 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, an optional flavoring agent such as sodium saccharin, and an optional preservative such as benzalkonium chloride, and thoroughly stir to dissolve. b) Add the prescribed amounts of any amphiphilic pharma- ceutical acceptable excipients and any thickening agents, and dissolve by stirring thoroughly. 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 R-ketamine liquid formulation of the present application is rapidly absorbed, takes effect within 3-7 minutes, and has an AUC0-240min of greater than 7000ng / mL. The R-ketamine 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 R-ketamine liquid formulation of the present application uses an amphipathic pharma- ceutical acceptable excipient, which can effectively improve the bioavailability of the active substance. The addition of a thickener can further increase the residence time of the liquid formulation in the oral mucosa, thereby further improving the absorption of R-ketamine and cooperating in improving the bioavailability of the R-ketamine liquid formulation. (3) The R-ketamine liquid formulation of the present application has a simple and easy-to-administer method, which significantly improves patient compliance. The small dosage and small volume significantly reduce irritation to the mucous membrane, 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] This application discloses an oral mucosal R-ketamine liquid formulation and its use, and those skilled in the art can realize it by appropriately improving the process parameters in view of the contents of this application. It should be noted that similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this application. The method and application of this 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 this application without departing from the content, spirit and scope of this application. Any reagents or equipment used in this 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: R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml The preparation method includes the following preparation steps. a) Weigh out the prescribed amount of R-ketamine hydrochloride, add 80% of the total weight of purified water, and stir thoroughly to dissolve. Then add the prescribed amounts of disodium edetate, citric acid, sodium saccharin, and benzalkonium chloride in order, and stir thoroughly to dissolve. b) Add the corresponding sodium lauryl sulfate, sodium carboxymethylcellulose 4000 in different formulations and dissolve by stirring thoroughly. 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: R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 8000 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0069] Example 3 Formulation: R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 12000 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0070] Example 4 Formulation: R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Xanthan gum 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0071] Example 5 Formulation: R-Ketamine 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 Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0072] Example 6 Formulation: R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Hypromellose 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0073] Example 7 Prescription R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Hypromellose 0.8mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0074] Example 8 Prescription R-Ketamine hydrochloride 32.3mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0075] Example 9 Prescription R-Ketamine hydrochloride 16.14mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 1mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0076] Example 10 Prescription R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0077] Example 11 Prescription R-Ketamine hydrochloride 32.3mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0078] Example 12 Prescription R-Ketamine hydrochloride 16.14mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Sodium lauryl sulfate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0079] Example 13 Prescription R-Ketamine hydrochloride 64.6mg Citric acid 1.5mg Disodium edetate 0.12mg Sodium saccharin 0.3mg Sodium carboxymethylcellulose 4000 0.2mg Sodium alkylsuccinate sulfonate 0.66mg Benzalkonium chloride 0.125mg Add water up to 1ml See Example 1 for preparation method.

[0080] Example 14 Stability test of the present invention's R-ketamine hydrochloride in buccal fluid Table 1. Information on impurities in oral buccal fluid containing R-ketamine hydrochloride JPEG2025516166000001.jpg51135

[0081] Both of these impurities are commercially available.

[0082] The present inventors carried out 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%.

[0083] 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.

[0084] 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.

[0085] Table 2. Raw materials and auxiliary substance content detection sample test conditions JPEG2025516166000002.jpg58103

[0086] Table 3. Long-term test results for Examples 1 to 13 JPEG2025516166000003.jpg233147

[0087] 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 R-ketamine hydrochloride in the buccal fluid were all less than 0.5%, and the maximum single impurities were all less than 0.2%, so the quality met the quality standard and was stable.

[0088] Example 15 In vitro permeation test of the present invention's R-ketamine 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.

[0089] Table 4. In vitro permeation results for Examples 1 to 12 JPEG2025516166000004.jpg83147

[0090] Comparative Example 1 R-ketamine hydrochloride intranasal preparation (prepared with reference to Patent CN 114306218 A) Prescription ingredients R-Ketamine hydrochloride 3.228g Citric acid monohydrate 0.03g Disodium edetate 0.0036g Benzalkonium chloride 0.0015g Sodium hydroxide to adjust pH to 4.50 Add water until it reaches 20.00ml. The preparation method includes the following preparation steps. a) Weigh out the prescribed amounts of R-ketamine hydrochloride, citric acid monohydrate, edetate disodium, benzalkonium chloride, and 14 g of purified water, and dissolve them by thoroughly stirring at 40°C. b) Adjust the pH to 4.5 with 1M sodium hydroxide. c) Transfer the solution into a specific 20 ml volumetric flask and top 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.

[0091] Comparative Example 2 R-ketamine hydrochloride intranasal preparation (prepared with reference to Patent CN 114306218 A) Prescription ingredients R-Ketamine hydrochloride 3.228g Citric acid monohydrate 0.03g Disodium edetate 0.0036g Benzalkonium chloride 0.003g Sodium hydroxide to adjust pH to 4.50 Add water until it reaches 20.00ml. For the preparation method, refer to Comparative Example 1.

[0092] Comparative Example 3 R-ketamine hydrochloride intranasal preparation (prepared with reference to Patent CN 114306218 A) Prescription ingredients R-Ketamine hydrochloride 3.228g Citric acid monohydrate 0.03g Disodium edetate 0.0036g Benzalkonium chloride 0.006g Sodium hydroxide to adjust pH to 4.50 Add water until it reaches 20.00ml. For the preparation method, refer to Comparative Example 1.

[0093] Test Example 1 In vitro stability test See Example 14 for experimental methods.

[0094] Table 5. Stability test results for Example 1 and Comparative Examples 1 to 3 JPEG2025516166000005.jpg63143

[0095] As can be seen from the stability test results in Table 5, after the drug formulation obtained in the present application has passed the stability test, the substance content, impurity content and pH value all meet the standards. The substance contents of Comparative Examples 1 to 3 are abnormally increased, indicating that the stability of the formulations is not high.

[0096] Test Example 2: In vitro transdermal diffusion experiment 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 above the biomimetic membrane, and the groups were divided, and then 0.2ml of the solutions of Example 1, Comparative Example 1, Comparative Example 2 and Comparative Example 3 were added respectively. The sampling times were 10min, 20min, 30min, 45min, 60min, 180min, 240min, 300min and 360min. The waste mode was adopted, and 1ml samples were taken at each time, and the content was detected in the liquid phase.

[0097] Table 6. In vitro permeation results for Example 1 and Comparative Examples 1 to 3 JPEG2025516166000006.jpg52104

[0098] Specifically, the in vitro diffusion data of the four R-ketamine formulations are shown in FIG. 1. As can be seen from Table 6 and FIG. 3 above, compared with the comparative example R-ketamine hydrochloride nasal formulation, the transmucosal permeability of a unit dose of R-ketamine hydrochloride in oral buccal fluid prepared in the present invention was higher, and the release rate was obviously improved.

[0099] Test Example 3 In vivo pharmacokinetics experiment 1. Experimental group assignment Table 7 Animal grouping status JPEG2025516166000007.jpg5369

[0100] 2. Experimental plan The experiment used New Zealand White rabbits, weighing 2.5kg-3.0kg, with six rabbits in each group, half male and half female. Four different formulations were treated with oral buccal administration of R-ketamine hydrochloride at 7mg / rabbit, with single-sided oral buccal administration in Examples 1 and 10 at a dose of 0.125ml / rabbit, single-sided oral buccal administration in Example 11 at a dose of 0.250ml / rabbit, and bilateral oral buccal administration in Example 12 at a dose of 0.250ml / side. Before blood collection, the rabbits were placed in a rabbit fixing box, and the blood collection method was marginal ear vein blood collection, with blood collection times at 0min (before administration), 2min, 5min, 10min, 15min, 30min, 60min, 120min, and 240min. Approximately 1 mL of whole blood was collected at each time point and placed in a blood collection tube containing sodium heparin, then centrifuged at 4000 rpm for 10 minutes to obtain plasma samples. The supernatant was then divided into three portions and placed in 0.5 mL EP tubes (two portions were placed in 150 μL, and the remaining plasma was placed in a third cryopreservation tube as a backup sample). After dividing and processing the plasma samples, they were stored at a temperature below -80°C.

[0101] 3. Experimental results Table 8. Pharmacokinetics experiment results in rabbits after administration of samples from the four groups JPEG2025516166000008.jpg53158

[0102] As can be seen from Table 8 and Figures 2 and 3, for the four different types of R-ketamine hydrochloride buccal fluid, the blood concentration all reached the maximum within 3.5 to 7.1 minutes after buccal administration, the maximum blood concentration Cmax all exceeded 320 ng / ml, and the AUC0-240min all exceeded 5000 min*ng / ml. This indicates that the buccal administration of different concentrations of R-ketamine hydrochloride from buccal fluid of the present application has a fast absorption rate, a high in vivo blood concentration, and can rapidly exert its medicinal effect in vivo.

[0103] 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. 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.

[0104] 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. An R-ketamine liquid preparation, wherein the liquid preparation is for buccal mucosal administration and contains R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, and water, and the pH value range of the liquid preparation is 2.5 to 5.

7.

2. The R-ketamine liquid preparation according to claim 1, wherein the liquid preparation contains R-ketamine or a pharmaceutically acceptable salt thereof at a concentration of 0.5% w / v to 8.5% w / v, an amphiphilic pharmaceutically acceptable excipient at a concentration of 0.01% w / v to 0.11% w / v, and water, and the pH value range of the liquid preparation is 2.5 to 5.

7.

3. The R-ketamine liquid preparation according to claim 2, wherein in the liquid preparation, the concentration of R-ketamine 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. The R-ketamine liquid preparation according to claim 2, wherein in the liquid preparation, the amphiphilic pharmaceutically acceptable excipient is one kind or a combination of sodium lauryl sulfate, alkyl alcohol amide, alkyl succinate sulfonate, alcohol amine alkyl benzene sulfonate, naphthenate, sulfosuccinate, alkylphenol sulfonic acid ester, polyoxyethylene monolaurate, sodium heptyl sulfate, sodium deoxycholate, sodium heptyl sulfonate, and is preferably sodium lauryl sulfate and sodium deoxycholate.

5. The R-ketamine liquid preparation according to claim 2, wherein in the liquid preparation, the concentration of the amphiphilic pharmaceutically acceptable excipient is 0.01% w / v to 0.11% w / v, preferably 0.03% w / v to 0.09% w / v, and more preferably 0.05% w / v to 0.07% w / v.

6. The R-ketamine liquid preparation according to claim 2, wherein the pH range of the liquid preparation is 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 R-ketamine liquid preparation according to any one of claims 1 to 6, wherein the liquid preparation further contains a thickener.

8. The thickener is one kind, or a combination thereof, selected from xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, sodium lauryl sulfate, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, carbomer, and polyvinyl pyrrolidone. The R-ketamine liquid preparation according to claim 7.

9. The sodium carboxymethyl cellulose is one kind, or a combination thereof, selected from sodium carboxymethyl cellulose 800, sodium carboxymethyl cellulose 4000, sodium carboxymethyl cellulose 8000, or sodium carboxymethyl cellulose 12000. The R-ketamine liquid preparation according to claim 8.

10. The concentration of the thickener is 0.01% w / v to 3.5% w / v. The R-ketamine liquid preparation according to claim 7.

11. The liquid preparation further comprises one or more kinds of adjuvants selected from buffer agents, flavoring agents, antioxidants, osmotic pressure regulators, and preservatives. Or, the liquid preparation further comprises one or more kinds of adjuvants selected from buffer agents, flavoring agents, antioxidants, osmotic pressure regulators, preservatives, and penetration enhancers. The R-ketamine liquid preparation according to any one of claims 1 to 10.

12. The liquid preparation further comprises a buffer agent, a flavoring agent, an antioxidant, and a preservative. The R-ketamine liquid preparation according to claim 11.

13. The buffer agent is one kind, or a combination thereof, selected from 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. The R-ketamine liquid preparation according to claim 11 or 12.

14. The flavoring agent is one kind, or a combination thereof, selected from sodium saccharin, fructose, sucralose, stevioside, menthol, maltitol, xylitol, aspartame, sodium cyclamate, saccharin, neohesperidin, thaumatin, stevia, and acesulfame potassium. The R-ketamine liquid preparation according to claim 11 or 12.

15. The antioxidant is one kind, or a combination thereof, selected from disodium edetate, vitamin E, gallate, sodium bisulfite, ascorbic acid or its salts, butylhydroxyanisole, and tocopherol. The R-ketamine liquid preparation according to claim 11 or 12.

16. The preservative is one kind of methyl hydroxybenzoate, ethyl p-hydroxybenzoate, propyl paraben, butyl paraben, sodium methyl paraben, sodium ethyl p-hydroxybenzoate, sodium propyl paraben, sodium butyl paraben, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, benzyl alcohol, benzalkonium bromide, benzalkonium chloride, trichloro-tert-butanol, resorcinol, and sodium ethylenediaminetetraacetate, or a combination thereof. The R-ketamine liquid preparation according to claim 11 or 12.

17. Use of the R-ketamine liquid preparation according to any one of claims 1 to 16 in the preparation of a drug for the prevention, remission or treatment of depression.

18. The depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, or bipolar depression. The use according to claim 17.

19. The liquid preparation is administered to the buccal mucosa of the patient. The use according to claim 17 or 18.

20. A method for preventing, remitting or treating a patient with depression with the R-ketamine liquid preparation according to any one of claims 1 to 16, comprising administering a therapeutically effective amount of the R-ketamine liquid preparation to the buccal mucosa of the patient. The method.

21. The depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression or bipolar depression. The method according to claim 20.

22. Use of the R-ketamine liquid preparation according to any one of claims 1 to 16 in the prevention, remission or treatment of a patient's depression.

23. The depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression or bipolar depression. Use of the R-ketamine liquid preparation according to claim 22 in the prevention, remission or treatment of a patient's depression.

24. The liquid preparation is administered to the buccal mucosa of the patient. Use of the R-ketamine liquid preparation according to claim 22 or 23 in the prevention, remission or treatment of a patient's depression.

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