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 the priority of a Chinese patent application filed with the China National Intellectual Property Administration on April 26, 2022, with the application number 202210448842.8 and the invention title "R-Ketamine Liquid Preparation and Its Use", the content of which should be understood to be incorporated herein by reference.

[0002] This application relates to the technical field of pharmaceutical preparations, and more particularly to R-ketamine liquid preparations and their use as antidepressants.

Background Art

[0003] Major depressive disorder (MDD) is a common mental disorder, typically characterized by mood depression, slow thinking, reduced speech and motor activity. Depression seriously affects patients' lives and work, and imposes a heavy burden on families and society. According to statistics, the number of suicides caused by depression is estimated to reach up to 1 million per year. Currently, in clinical practice, antidepressants (such as tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors) are mainly used to treat this mental disorder, but these drugs do not exert a therapeutic effect on all depressed patients. Therefore, it is necessary to develop new antidepressant drugs.

[0004] In recent years, research has shown that ketamine, as an N-methyl-D-aspartic acid (NMDA) receptor antagonist, can improve 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 by the presynaptic membrane. Such special psychiatric drugs have attracted attention.

[0005] To meet the needs of more depressed patients, reduce the treatment cost, and relieve the burden on patients' families, the development of new preparations with clinical application value has become an issue.

Summary of the Invention

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

[0007] In one embodiment, the present application provides an R-ketamine liquid formulation for oral mucosal administration, comprising R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, and water.

[0008] In other embodiments, the present invention provides the use of the above-mentioned R-ketamine liquid formulation in the preparation of a drug for the prevention, remission, or treatment of depression, the drug which may be used for the treatment of major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, and bipolar depression.

[0009] In another embodiment, the present invention provides a method for preventing, relieving, or treating depression in a patient using the above-mentioned R-ketamine liquid formulation, comprising administering a therapeutically effective amount of the R-ketamine liquid formulation to the patient.

[0010] In other embodiments, the present invention provides the above-mentioned R-ketamine liquid formulation for use in the prevention, remission, or treatment of depression in patients, wherein the depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, or bipolar depression.

[0011] In another embodiment, the present application provides a method for preparing the R-ketamine liquid formulation. [Brief explanation of the drawing]

[0012] The drawings are provided to help understand the technical proposal of this application, form part of the specification, and are used together with the embodiments of this application to interpret the technical proposal of this application, and are not intended to limit the technical proposal of this application. [Figure 1] This shows the in vitro diffusion of different R-ketamine preparations according to this application. [Figure 2] This diagram shows the relationship between the administration route and pharmacokinetics of different R-ketamine preparations according to the present invention. [Figure 3] This diagram shows the relationship between different administration routes and AUC for different R-ketamine preparations according to the present invention. [Modes for carrying out the invention]

[0013] A first aspect of the present application provides a liquid formulation of R-ketamine for oral mucosal administration, comprising R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, and water.

[0014] Unless otherwise specified, R-ketamine used in this text refers to (R)-ketamine. , Boketamin, arketamine 、k It is also called etamine, (2R)-2-(2-chlorophenyl)-2(methylamino)cyclohexanone, etc., and refers to the (R)-enantiomer of ketamine.

[0015] In the liquid formulation of this application, whether R-ketamine is used or a pharmaceutically acceptable salt of R-ketamine is used, the active substance content is calculated based on the R-ketamine content in both cases.

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

[0017] Because the R-ketamine liquid formulation described in this application has high bioavailability, it can be prepared as a product with relatively low substance concentrations, which not only meets the preventive or therapeutic needs of clinical patients but also avoids the risk of abuse associated with high-concentration administration. Furthermore, the R-ketamine liquid formulation has good compatibility with saliva, reducing irritation to mucous membranes and minimizing drug side effects.

[0018] In one embodiment, the concentration of R-ketamine in the liquid formulation is 0.7% w / v to 8.4% w / v. In another embodiment, the concentration of R-ketamine in the liquid formulation is 1.4% w / v to 6.3% w / v. In yet another embodiment, the concentration of R-ketamine in the liquid formulation is 1.4% w / v to 5.6% w / v. Furthermore, in one embodiment, the concentrations of R-ketamine in the liquid formulation are 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, and 2.3% 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.

[0019] In other embodiments, acids that can form pharmaceutically 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, glycerophosphate, 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, peroxosulfic 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, pharmaceutically acceptable salts of R-ketamine include hydrochloride, sulfate, phosphate, maleate, acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, bisgluconate, fumarate, glycerophosphate, stearate, heptanoate, caproate, hydrobromide (i.e., HBr) salt, hydroiodide (i.e., HI) salt, lactate, methanesulfonate, nicotinate, oxalate, dihydroxynaphthoate, pectinate, peroxosulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, and mandelate.

[0021] In one embodiment, the concentration of the amphiphilic pharmaceutically acceptable excipient in the liquid formulation is 0.03% w / v to 0.11% w / v. In other embodiments, the concentration of the amphiphilic pharmaceutically acceptable excipient in the liquid formulation is 0.03% w / v to 0.07% w / v. Further, in one embodiment, the concentration of the amphiphilic pharmaceutically 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% w / v, 0.053% 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, 0.083% 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 pharmaceutically acceptable excipient is one of sodium lauryl sulfate, alkyl alcohol amide, alkyl succinic sulfonate, alcohol amine alkyl benzene sulfonate, naphthenate, sulfosuccinate, alkyl phenol sulfonic acid ester, polyoxyethylene monolaurate, sodium heptyl sulfate, sodium deoxycholate, sodium heptyl sulfonate, or a combination thereof, preferably sodium lauryl sulfate and sodium deoxycholate.

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

[0024] In other embodiments, the pH range of the liquid formulation is 3.0 to 5.7. In other embodiments, 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 other embodiments, the liquid formulation 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 formulation is 2.5 to 5.7.

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

[0027] In other embodiments, the thickening agent is xanthan gum, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, carbomer or polyvinyl pyrrolidone, or a combination thereof.

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

[0029] In one embodiment, the combination of thickeners includes, but is not limited to, a composition of 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, sodium carboxymethylcellulose 4000 and xanthan gum, and sodium carboxymethylcellulose 4000 and hypromellose, with the ratio (w / w) of the combination of two thickeners being 1:5 to 5:1.

[0030] In one embodiment, the concentration of the thickener is 0.01% w / v to 3.5% w / v. In another embodiment, the concentration of the thickener is 0.05 to 3.0% w / v. In yet another embodiment, the concentration of the thickener is 0.05 to 2.0% w / v. In a further embodiment, the concentration of the thickener 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 auxiliary agents selected from buffers, flavoring agents, antioxidants, osmotic pressure regulators, and preservatives. In other embodiments, the R-ketamine liquid formulation further comprises one or more auxiliary agents selected from buffers, flavoring agents, antioxidants, osmotic pressure regulators, preservatives, and osmotic pressure enhancers.

[0032] In one embodiment of the R-ketamine liquid formulation described in this application, the buffer 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.

[0033] The buffer described herein can maintain the pH of a liquid formulation within a stable range and contribute to improving the stability of a solution formulation. The concentration of the buffer is 0.1 to 0.3% w / v. In one embodiment, the concentration of the buffer is 0.1 to 0.2% w / v. In another embodiment, the concentration of the buffer is 0.1 to 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 other embodiments, the present application provides an R-ketamine liquid formulation further comprising a flavoring agent. The flavoring agent can mask any off-flavors that the pharmaceutical composition may have, thereby improving 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, sodium cyclamate, saccharin, neohesperidin, thaumatin, stevia, or acesulfame potassium, or a combination thereof.

[0035] In one embodiment, the concentration of the flavoring agent in the R-ketamine liquid formulation according to the present application is 0.01 to 0.05% w / v. In another embodiment, the concentration of the flavoring agent is 0.01 to 0.03% w / v. In yet another embodiment, the concentration of the flavoring agent is 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 a liquid formulation of R-ketamine further comprising an antioxidant. The antioxidant can effectively inhibit or delay the oxidation of the formulation, thereby preventing oxidative deterioration of the drug and its formulation, and preventing problems such as discoloration and precipitation due to oxidation, thereby improving drug stability. In one embodiment, the antioxidant in the liquid formulation is ethylenediaminetetraacetic acid (EDTA) or its sodium 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 concentration of the antioxidant in the R-ketamine liquid formulation according to the present application is 0.010 to 0.020% w / v. In another embodiment, the concentration of the antioxidant is 0.010 to 0.015% w / v. In yet another embodiment, the concentration of the antioxidant in the liquid formulation is 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. In some embodiments, the preservative is selected from one or more of the following: 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 concentration of the preservative in the R-ketamine liquid formulation according to the present application is 0.010 to 0.020% w / v. In another embodiment, the concentration of the preservative is 0.010 to 0.015% w / v. In yet another embodiment, the concentration of the preservative 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 an osmotic regulator. In some embodiments, the osmotic regulator 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. In some embodiments, the penetration enhancer is one or more of the following: propylene glycol, Tween 80, hypromellose, sodium lauryl sulfate, sodium doxate, polysorbate, tetradecyl maltoside, lecithin, hydroxypropyl-β-cyclodextrin, sodium sulfobutyl-β-cyclodextrin, or PEG400.

[0042] A second aspect of the present application specifically provides an R-ketamine liquid formulation comprising R-ketamine hydrochloride, an amphiphilic pharmaceutically acceptable excipient, a thickener, and water, wherein the pH range of the liquid formulation is 4.5 to 5.5, and the R-ketamine content in the liquid formulation is 0.7% w / v to 8.4% w / v.

[0043] In one embodiment, the types of thickeners and the content of amphiphilic pharmaceutically acceptable excipients therein are as described above.

[0044] In other embodiments, the thickening agent is one of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose, or a combination thereof.

[0045] In the R-ketamine liquid formulation according to this application, the simultaneous use of an amphiphilic, pharmaceutically acceptable excipient and a thickener allows for more sufficient in vitro release of the API in the formulation, which in turn promotes the permeability of R-ketamine through the oral mucosa and contributes to improving the bioavailability of the R-ketamine solution formulation.

[0046] In one embodiment of the R-ketamine liquid formulation described herein, 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 thickener is xanthan gum. In another embodiment, the thickener is hypromellose. In another embodiment, the thickener is carboxymethylcellulose sodium 4000 and carboxymethylcellulose sodium 12000. In another embodiment, the thickener is carboxymethylcellulose sodium 4000 and hypromellose.

[0047] A third aspect of the present application specifically provides an R-ketamine liquid formulation comprising R-ketamine hydrochloride, an amphiphilic pharmaceutically acceptable excipient, a thickener, a buffer, and water, wherein the pH range of the liquid formulation is 4.5 to 5.5, and the R-ketamine content in the liquid formulation is 0.7% w / v to 8.4% w / v.

[0048] In one embodiment, the types of the thickener and buffer and the content of the amphiphilic pharmaceutically acceptable excipients therein are as described above.

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

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

[0051] In one embodiment, the types of the thickener, antioxidant, flavoring agent, and buffering agent, and the content of them with amphiphilic pharmaceutically acceptable excipients are as described above.

[0052] In other embodiments, the thickening agent is one of carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, carboxymethylcellulose sodium 12000, xanthan gum, and hypromellose, or a combination thereof.

[0053] In one embodiment of the R-ketamine liquid formulation described in this application, 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 thickeners are carboxymethylcellulose sodium 4000 and carboxymethylcellulose sodium 12000. In another embodiment, the antioxidant is disodium edetate, the flavoring agent is sodium saccharin or maltitol, and the thickeners are carboxymethylcellulose sodium 4000 and hypromellose.

[0054] In one embodiment, the buffering agent in the R-ketamine liquid formulation according to the present application is citric acid.

[0055] A fifth aspect of the present application provides the use of a liquid R-ketamine preparation in the preparation of a drug for the prevention, remission, or treatment of depression, the drug being used for the treatment of major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, and bipolar depression.

[0056] In one embodiment, in the use of the R-ketamine liquid formulation according to the present application in the preparation of a drug for the prevention, remission, or treatment of depression, the liquid formulation is administered to the oral buccal mucosa of the patient.

[0057] A sixth aspect of the present application provides a method for preventing, relieving, or treating depression in a patient using an R-ketamine liquid preparation, comprising administering a therapeutically effective amount of the R-ketamine liquid preparation to the patient.

[0058] In one embodiment, the present application provides a method for preventing, relieving, or treating depression in a patient using an R-ketamine liquid formulation, wherein the depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, or bipolar depression.

[0059] In one embodiment, a method for preventing, relieving, or treating depression in a patient using the R-ketamine liquid formulation according to the present application, wherein the liquid formulation is administered to the oral buccal mucosa of the patient.

[0060] A seventh aspect of the present invention provides an R-ketamine liquid preparation used for the prevention, remission, or treatment of depression in patients, wherein the depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, or bipolar depression.

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

[0062] In the 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 stir thoroughly to dissolve. Then, sequentially add the prescribed amounts of any antioxidant such as disodium edetate, any buffer such as citric acid, any flavoring agent such as sodium saccharin, and any preservative such as benzalkonium chloride, and stir thoroughly to dissolve. b) Add any amphiphilic pharmaceutically acceptable excipient and any thickener in the prescribed amount, and stir thoroughly until dissolved. c) Adjust the pH to the appropriate value using sodium hydroxide. d) Transfer the solution to a flask of a specific volume and add water to fix the volume up to the marked level. e) After volume fixation, the solution passes through a 0.45 μm filtration membrane, and the filtrate is filled into a pre-filled syringe to obtain the finished product.

[0063] The beneficial effects of this application are as follows: (1) The R-ketamine liquid formulation according to this application is rapidly absorbed, takes effect quickly within 3 to 7 minutes, and has an AUC0-240min greater than 7000 ng / mL. The R-ketamine liquid formulation has high bioavailability, does not undergo crystallization, has high stability, and can not only meet the demands of large-scale processing and production but also reduce the risk of drug administration to patients. (2) The R-ketamine liquid formulation according to this application can effectively improve the bioavailability of the active substance by using amphiphilic pharmaceutically acceptable excipients, and by further adding a thickening agent to extend the residence time of the liquid formulation in the oral mucosa, the absorption of R-ketamine can be further improved, thereby contributing to the improvement of the bioavailability of the R-ketamine liquid formulation. (3) The R-ketamine liquid formulation according to this application is easy to administer and significantly improves patient compliance. The dosage is small, the volume is small, and irritation to the mucous membrane is greatly reduced, thereby reducing the risk of abuse.

[0064] Unless otherwise specified, the concentration of all components is expressed in weight / volume % (%w / v). As is commonly understood, the %w / v value refers to the amount of a specific composition or component in a compound. As is well known, equivalent concentrations can 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 a liquid formulation of R-ketamine for oral mucosal administration and its use, which can be realized by those skilled in the art by appropriately improving process parameters in light of the contents of this application. Similar substitutions and modifications will be obvious to those skilled in the art and will be considered included in this application. The methods and applications of this application have been described through preferred embodiments, but those concerned can realize and apply the technology of this application by modifying or appropriately changing and combining the methods and applications described herein without departing from the contents, spirit and scope of this application. All reagents and 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 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. The preparation method includes the following preparation steps. a) Weigh out the prescribed amount of R-ketamine hydrochloride, add 80% of the total weight in purified water, and stir thoroughly to dissolve. Then, sequentially add the prescribed amounts of disodium edetate, citric acid, sodium saccharin, and benzalkonium chloride, and stir thoroughly to dissolve. b) Add the corresponding sodium lauryl sulfate and sodium carboxymethylcellulose 4000 for the different formulations, and stir thoroughly until dissolved. c) Adjust the pH to 4.5-5.5 using sodium hydroxide. d) Transfer the solution to a specific volume flask and add water to fix the volume up to the 10 ml mark. e) After volume fixation, the solution passes through a 0.45 μm filtration membrane, and the filtrate is filled into 1 ml pre-filled syringes (purchased from Shandong Zibo Minkang Pharmaceutical Packing Co., Ltd.) to obtain the finished product at 1 ml / cell.

[0068] Example 2 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 8000 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0069] Example 3 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 12000 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0070] Example 4 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Xanthan gum 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0071] Example 5 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Carboxymethylcellulose sodium 12000 0.8mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0072] Example 6 Prescription: R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Hypromellose 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0073] Example 7 prescription R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Hypromellose 0.8mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0074] Example 8 prescription R-Ketamine Hydrochloride 32.3 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0075] Example 9 prescription R-Ketamine Hydrochloride 16.14 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 1 mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0076] Example 10 prescription R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0077] Example 11 prescription R-Ketamine Hydrochloride 32.3 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0078] Example 12 prescription R-Ketamine Hydrochloride 16.14 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Sodium lauryl sulfate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0079] Example 13 prescription R-Ketamine Hydrochloride 64.6 mg Citric acid 1.5mg Disodium edetate 0.12 mg Saccharin sodium 0.3 mg Carboxymethylcellulose sodium 4000 0.2mg Sodium alkylsuccinate sulfonate 0.66 mg Benzalkonium chloride 0.125 mg Add water up to 1 ml as needed. Refer to Example 1 for the preparation method.

[0080] Example 14: Stability test of oral buccal solution of R-ketamine hydrochloride according to the present invention. Table 1. Impurity information for oral buccal fluid containing R-ketamine hydrochloride. JPEG0007873311000001.jpg51135

[0081] Both of the above impurities can be obtained commercially.

[0082] The inventors conducted long-term stability experiments on the samples prepared in Examples 1 to 13 under conditions of 25°C ± 2°C and RH 60% ± 5%.

[0083] 1. Method for detecting ketamine content Measurements are performed according to high-performance liquid chromatography (General Rule 0512). Chromatography conditions: Octadecylsilane was used as the packing material. 0.95 g of sodium hexanesulfonate was dissolved in 1 L of a mixed solution of acetonitrile and water (acetonitrile:water = 25:75), and 4 ml of glacial acetic acid was added and mixed uniformly to form the mobile phase. The detection wavelength was 215 nm, the flow rate was 1.0 ml per minute, the column temperature was 30 °C, and the injection volume was 20 μl.

[0084] 2. Method for detecting ketamine-related substances Measurements are performed according to high-performance liquid chromatography (General Rule 0512). Chromatography conditions: Octadecylsilane was used as the packing material (Agela MP C18 4.6×150 mm, 5 μm or equivalent to the column efficiency), 25 mM phosphate buffer (3.4 g of potassium dihydrogen phosphate dissolved in 1000 ml of water, pH adjusted to 2.5 with phosphoric acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to the table below, with a detection wavelength of 215 nm, a column temperature of 30 °C, a flow rate of 1.0 ml per minute, and an injection volume of 20 μl.

[0085] Table 2. Sample Test Conditions for Detection of Raw Material and Auxiliary Content JPEG0007873311000002.jpg58103

[0086] Table 3 Long-term test results for Examples 1-13 JPEG0007873311000003.jpg233147

[0087] As can be seen from the long-term test results in Table 4, the drug formulations obtained in this application were stored at room temperature for 6 months, and the total impurities in the oral buccal fluid of R-ketamine hydrochloride were all 0.5% or less, and the maximum single impurity was 0.2% or less in all cases. This indicates that the quality meets the quality standards and is stable.

[0088] Example 15: In vitro permeability test of oral buccal solution of R-ketamine hydrochloride according to the present invention. In this study, the Franz diffusion cell method was employed, and the phospholipid biomimetic barrier PermeaPad® (biomimetic membrane) was selected to simulate oral mucosa. PBS buffer was used as the diffusion medium. When the diffusion cell reached 37°C, 0.5 ml of artificial saliva was first added to the top of the biomimetic membrane, followed by 0.2 ml of the formulation solution. Sampling times were 10 min, 20 min, 30 min, 45 min, 60 min, 180 min, 240 min, 300 min, and 360 min. Waste mode was used, and 1 ml of sample was taken at each time point to detect the content in the liquid phase.

[0089] Table 4 In vitro transmission results for Examples 1-12 JPEG0007873311000004.jpg83147

[0090] Comparative Example 1: Nasal administration preparation of R-ketamine hydrochloride (prepared in 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 Adjust the pH of the sodium hydroxide solution to 4.50. Add water up to 20.00 ml. The preparation method includes the following preparation steps. a) Weigh out the prescribed amounts of R-ketamine hydrochloride, citric acid monohydrate, disodium edetate, benzalkonium chloride, and 14 g of purified water, and dissolve them by stirring thoroughly under 40°C conditions. b) Adjust the pH to 4.5 using 1M sodium hydroxide. c) Transfer the solution to a specific 20 ml volume flask and add water to fix the volume up to the marked level. d) After volume fixation, the solution passes through a 0.45 μm filtration membrane, and the filtrate is filled according to demand.

[0091] Comparative Example 2: Nasal administration preparation of R-ketamine hydrochloride (prepared in 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 Adjust the pH of the sodium hydroxide solution to 4.50. Add water up to 20.00 ml. Refer to Comparative Example 1 for the preparation method.

[0092] Comparative Example 3: Nasal administration preparation of R-ketamine hydrochloride (prepared in 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 Adjust the pH of the sodium hydroxide solution to 4.50. Add water up to 20.00 ml. Refer to Comparative Example 1 for the preparation method.

[0093] Test Example 1: In Vitro Stability Test For details on the experimental method, please refer to Example 14.

[0094] Table 5: Stability test results for Example 1 and Comparative Examples 1-3 JPEG0007873311000005.jpg63143

[0095] As can be seen from the stability test results in Table 5, the drug formulation obtained in this application meets the standards for substance content, impurity content, and pH value after stability testing. The substance content of Comparative Examples 1 to 3 increased abnormally, indicating that the stability of these formulations is not high.

[0096] Test Example 2: In vitro transdermal diffusion experiment In this study, the Franz diffusion cell method was employed, and the phospholipid biomimetic barrier PermeaPad® (biomimetic membrane) was selected to simulate oral mucosa. PBS buffer was used as the diffusion medium. When the diffusion cell reached 37°C, 0.5 ml of artificial saliva was first added to the top of the biomimetic membrane to divide the cells into groups. Then, 0.2 ml of the solutions from Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3 were added to each group. Sampling times were 10 min, 20 min, 30 min, 45 min, 60 min, 180 min, 240 min, 300 min, and 360 min. Waste mode was used, and 1 ml of sample was taken at each time point to detect the content in the liquid phase.

[0097] Table 6 In vitro transmission results for Example 1 and Comparative Examples 1-3 JPEG0007873311000006.jpg52104

[0098] Specifically, the in vitro diffusion data for the four R-ketamine preparations is shown in Figure 1. As can be seen from Table 6 and Figure 3 above, the transmucosal penetration of a unit volume of oral buccal solution of the R-ketamine hydrochloride prepared in the present invention was higher and the release rate was clearly improved compared to the comparative example of the R-ketamine hydrochloride nasal absorption preparation.

[0099] Example 3: In vivo pharmacokinetic experiment 1. Experimental group division Table 7 Animal Grouping Status JPEG0007873311000007.jpg5369

[0100] 2. Experimental Plan In this experiment, New Zealand white rabbits were used, weighing 2.5 kg to 3.0 kg, with 6 rabbits in each group, half male and half female. Four different formulations were administered by administering R-ketamine hydrochloride in an oral buccal solution at a dose of 7 mg / rabbit. In Examples 1 and 10, unilateral oral buccal solution administration was used, with a dose of 0.125 ml / rabbit. In Example 11, unilateral oral buccal solution administration was used, with a dose of 0.250 ml / rabbit. In Example 12, bilateral oral buccal solution administration was used, with a dose of 0.250 ml / side. Before blood collection, the rabbits were placed in a rabbit fixing box, and blood collection was performed using the marginal vein of the ear ala. Blood collection times were 0 min (before administration), 2 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, and 240 min. Approximately 1 mL of whole blood is collected at each time point and placed in a heparin sodium-containing blood collection tube. The blood is then centrifuged at 4000 rpm for 10 minutes to obtain a plasma sample. The supernatant is taken and divided into three parts, each placed in a 0.5 mL EP tube (two parts are placed in 150 μl tubes, and the remaining plasma is placed in a third cryopreservation tube as a backup sample). After processing the plasma samples separately, they are stored at a temperature of -80°C or below.

[0101] 3. Experimental results Table 8 Results of pharmacokinetic experiments in rabbits after sample administration to four groups. JPEG0007873311000008.jpg53158

[0102] As can be seen from Table 8 and Figures 2 and 3, for the four different oral-cheek solutions of R-ketamine hydrochloride, the blood concentration reached its peak within 3.5 to 7.1 minutes after oral-cheek administration. In all cases, the peak blood concentration Cmax exceeded 320 ng / ml, and the AUC0-240min was higher than 5000 min* ng / ml. This indicates that the oral-cheek solutions of different concentrations of R-ketamine hydrochloride administered via the buccal mucosa of this invention were absorbed quickly, resulting in high in vivo blood concentrations and rapid in vivo efficacy.

[0103] The technical solution of this application may also be applied to oral buccal fluid buccal mucosal administration systems for R-ketamine, ketamine, or pharmaceutically acceptable salts. The objectives of this application can be achieved by adjusting or changing the active ingredient content, the types and dosages of pharmaceutically available adjuvants, etc.

[0104] The embodiments presented herein are as described above, but these are embodiments provided for the convenience of understanding the present application and are not intended to limit it. Those skilled in the art may make any modifications and changes to the embodiments and details without departing from the spirit and scope presented herein, but the scope of protection of the present application shall be limited to the claims attached.

Claims

1. A liquid formulation of R-ketamine, which is administered orally via the mucous membrane, and comprises R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient, a thickener, and water, wherein the pH range of the liquid formulation is 2.5 to 5.

7. The aforementioned amphiphilic pharmaceutically acceptable excipients are sodium lauryl sulfate or sodium alkyl succinate sulfonate. The aforementioned thickening agent is one of xanthan gum, sodium carboxymethylcellulose, and hypromellose, or a combination thereof, in an R-ketamine liquid preparation.

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

7.

3. The R-ketamine liquid formulation according to claim 2, wherein the concentration of R-ketamine in the liquid formulation is 0.7% w / v to 8.4% w / v.

4. The R-ketamine liquid formulation according to claim 2, wherein the concentration of the amphiphilic pharmaceutically acceptable excipient in the liquid formulation is 0.01% w / v to 0.11% w / v.

5. The R-ketamine liquid formulation according to claim 2, wherein the pH range of the liquid formulation is 3.0 to 5.

7.

6. The R-ketamine liquid formulation according to claim 1, wherein the carboxymethylcellulose sodium is one of carboxymethylcellulose sodium 800, carboxymethylcellulose sodium 4000, carboxymethylcellulose sodium 8000, or carboxymethylcellulose sodium 12000, or a combination thereof.

7. The R-ketamine liquid formulation according to claim 1, wherein the concentration of the thickening agent is 0.01% w / v to 3.5% w / v.

8. The R-ketamine liquid formulation according to claim 1, wherein the liquid formulation further comprises one or more auxiliary agents selected from buffering agents, flavoring agents, antioxidants, osmotic pressure regulators, and preservatives, or wherein the liquid formulation further comprises one or more auxiliary agents selected from buffering agents, flavoring agents, antioxidants, osmotic pressure regulators, preservatives, and osmotic pressure enhancers.

9. The liquid formulation further comprises a buffer, a flavoring agent, an antioxidant, and a preservative. The buffer 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. The flavoring agent is one of saccharin sodium, fructose, sucralose, stevioside, menthol, maltitol, xylitol, aspartame, sodium cyclamate, saccharin, neohesperidin, thaumatin, stevia, and acesulfame potassium, or a combination thereof. The antioxidant is edetate disodium, vitamin E, gallate, sodium bisulfite, and ascorbyl phosphate. The R-ketamine liquid formulation according to claim 8, wherein the preservative is one of an acid or a salt thereof, butylhydroxyanisole, and tocopherol, or a combination thereof, and the preservative is one of methyl hydroxybenzoate, ethyl p-hydroxybenzoate, propylparaben, butylparaben, sodium methylparaben, sodium 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, or a combination thereof.

10. Use of the R-ketamine liquid preparation according to any one of claims 1 to 9 in the preparation of a drug for the prevention, remission, or treatment of depression.

11. The use according to claim 10, wherein the depression is major depressive disorder, unipolar depression, treatment-resistant depression, treatment-resistant depression, anxiety depression, or bipolar depression.

12. The use according to claim 10, wherein the liquid formulation is administered to the oral buccal mucosa of the patient.

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