WO2023207730A1 - R-氯胺酮液体制剂及其用途 - Google Patents

R-氯胺酮液体制剂及其用途 Download PDF

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Publication number
WO2023207730A1
WO2023207730A1 PCT/CN2023/089329 CN2023089329W WO2023207730A1 WO 2023207730 A1 WO2023207730 A1 WO 2023207730A1 CN 2023089329 W CN2023089329 W CN 2023089329W WO 2023207730 A1 WO2023207730 A1 WO 2023207730A1
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Prior art keywords
ketamine
liquid preparation
depression
sodium
acid
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Ceased
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PCT/CN2023/089329
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English (en)
French (fr)
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WO2023207730A9 (zh
Inventor
吴有斌
黄志勇
吴继宏
邵良玉
田峦鸢
周师孟
林霞
向永曜
李小妹
吕金良
李莉娥
屈钦
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Yichang Humanwell Pharmaceutical Co Ltd
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Yichang Humanwell Pharmaceutical Co Ltd
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Priority to US18/859,689 priority Critical patent/US20250281426A1/en
Priority to EP23795163.7A priority patent/EP4501314A4/en
Priority to JP2024562836A priority patent/JP2025516166A/ja
Priority to TW112115546A priority patent/TW202345781A/zh
Publication of WO2023207730A1 publication Critical patent/WO2023207730A1/zh
Anticipated expiration legal-status Critical
Publication of WO2023207730A9 publication Critical patent/WO2023207730A9/zh
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose

Definitions

  • the present application relates to but is not limited to the technical field of pharmaceutical preparations, and in particular to R-ketamine liquid preparations and their use as antidepressant drugs.
  • depression Major depression disorder, MDD
  • MDD Major depression disorder
  • depression is a common mental illness with typical symptoms of low mood, slow thinking, reduced speech and movement, and slowness. Depression seriously disrupts patients' lives and work, placing a heavy burden on families and society. According to statistics, the number of suicide deaths due to depression is estimated to be as high as 1 million every year.
  • antidepressants such as tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors
  • These medications do not work for all people with depression. Therefore, there is a need to develop new drugs to treat depression.
  • ketamine as an N-methyl-D-aspartate (NMDA) receptor antagonist, can improve brain function by increasing the release of monoamines or inhibiting the reuptake of monoamines in the presynaptic membrane. levels of monoamine compounds that exert antidepressant effects. This particular psychiatric drug has also attracted much attention.
  • NMDA N-methyl-D-aspartate
  • This application provides an R-ketamine liquid preparation, which is administered through the oral mucosa.
  • the preparation of this application has high stability, fast absorption, high bioavailability, simple administration method and good compliance.
  • the present application provides an R-ketamine liquid preparation, which is administered through the oral mucosa, and includes R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient and water.
  • this application provides the use of the above-mentioned R-ketamine liquid preparation in the preparation of drugs for preventing, alleviating or treating depression.
  • the drugs can be used to treat major depression, unipolar depression, refractory depression, Resistant depression, anxious depression, bipolar depression.
  • the present application provides a method of using the above-mentioned R-ketamine liquid preparation to prevent, alleviate or treat depression in a patient, including administering a therapeutically effective amount of R-ketamine liquid preparation to the patient.
  • the present application provides the above-mentioned R-ketamine liquid preparation for preventing, alleviating or treating depression in patients, and the depression is major depression, unipolar depression, refractory depression, and refractory depression. Depression, anxious depression, bipolar depression.
  • the present application provides a method for preparing the aforementioned R-ketamine liquid preparation.
  • Figure 1 shows the diffusion situation of different R-ketamine preparations proposed in this application in vitro.
  • Figure 2 is a diagram showing the relationship between administration routes and pharmacokinetics of different R-ketamine preparations proposed in this application;
  • Figure 3 is a diagram showing the relationship between different administration routes and AUC of different R-ketamine preparations proposed in this application.
  • the first aspect of the application provides an R-ketamine liquid preparation, which is administered through the oral mucosa, and includes R-ketamine or a pharmaceutically acceptable salt thereof, an amphiphilic pharmaceutically acceptable excipient and water.
  • R-ketamine as used herein is also known as (R)-ketamine, arkketamine, levketamine, arketamine, d-ketamine, (2R)-2-(2-chlorophenyl)-2( Methylamino) cyclohexanone, etc., which refers to the (R)-enantiomer of ketamine.
  • the content of R-ketamine in the liquid preparation is 0.5% w/v to 8.5% w/v.
  • the R-ketamine liquid preparation described in this application has high bioavailability. Therefore, the liquid preparation can be prepared as a product with a lower substance concentration, which can not only meet the prevention or treatment needs of clinical patients, but also avoid the complications caused by high-concentration administration. risks of abuse. At the same time, R-ketamine liquid preparation has good compatibility with saliva, reducing irritation to mucous membranes and reducing drug side effects.
  • the concentration of R-ketamine in the liquid preparation is 0.7% w/v to 8.4% w/v; in another embodiment, the concentration of R-ketamine in the liquid preparation is 1.4% w /v ⁇ 6.3% w/v; in another embodiment, the concentration of R-ketamine in the liquid preparation is 1.4% w/v ⁇ 5.6% w/v.
  • 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, 0.8%
  • 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, benzene Formic acid, benzenesulfonic acid, hydrogen sulfate, butyric acid, camphoric acid, camphorsulfonic acid, digluconic acid, fumaric acid, glyceryl phosphate, stearic acid, heptanoic acid, hexanoic acid, hydrobromic acid (HBr), hydroiodic acid (i.e.
  • HI lactic acid, methanesulfonic acid, nicotinic acid, oxalic acid, dihydroxynaphthoic acid, pectic acid, persulfate, 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.
  • pharmaceutically acceptable salts of R-ketamine include hydrochloride, sulfate, phosphate, maleate, acetate, adipate, alginate, citrate, Aspartate, benzoate, benzenesulfonate, sulfuric acid Hydrogen salt, butyrate, camphorate, camphorsulfonate, digluconate, fumarate, glycerophosphate, stearate, enanthate, hexanoate, hydrobromide (HBr) salt , hydroiodic acid (ie HI) salt, lactate, methanesulfonate, nicotinate, oxalate, dihydroxynaphthoate, pectate, persulfate, 3-phenylpropionate, Picrate, pivalate, propionate, succinate, tartrate, thiocyanate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate and mandelate.
  • the concentration of amphiphilic pharmaceutically acceptable excipients in the liquid formulation is 0.03% w/v to 0.11% w/v. In another embodiment, the concentration of amphiphilic pharmaceutically acceptable excipients in the liquid preparation is 0.03% w/v to 0.07% w/v; in another embodiment, the liquid preparation in The concentrations of amphipathic pharmaceutically acceptable excipients are 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.
  • the amphiphilic pharmaceutically acceptable excipient is sodium lauryl sulfate, alkyl alcoholamide, alkyl succinate sulfonate, alcoholamine alkyl benzene sulfonate, Naphthenate, sulfosuccinate, alkylphenol sulfonate, polyoxyethylene monolaurate, sodium heptyl sulfate, sodium deoxycholate, sodium heptyl sulfonate, or a combination thereof, Sodium lauryl sulfate and sodium deoxycholate are preferred.
  • the pH of the liquid formulation is 2.5 to 5.7.
  • the pH range of the liquid preparation is 3.0-5.7; in yet another embodiment, the pH range of the R-ketamine liquid preparation is 4.0-5.7; in yet another embodiment, the The pH of the liquid preparation is 5.0-5.5; in another embodiment, the pH of the liquid preparation 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.
  • the liquid preparation includes R-ketamine or a pharmaceutically acceptable salt thereof at a concentration of 0.5% w/v to 8.5% w/v, and a concentration of 0.01% w/v to 0.11% w/ v Amphiphilic pharmaceutically acceptable excipients and water, the pH value of the liquid preparation ranges from 2.5 to 5.7.
  • the R-ketamine liquid formulation may further include a viscosifier.
  • the tackifier is xanthan gum, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene Alcohol, carbomer or polyvinylpyrrolidone, or combinations thereof.
  • the sodium carboxymethylcellulose is selected from the group consisting of sodium carboxymethylcellulose 800, sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, and sodium carboxymethylcellulose 12000. one or more.
  • the combination of tackifiers includes, without limitation: carboxymethylcellulose sodium 4000 and carboxymethylcellulose sodium 12000, carboxymethylcellulose sodium 800 and carboxymethylcellulose sodium 12000 , sodium carboxymethylcellulose 4000 and xanthan gum, sodium carboxymethylcellulose 4000 and hypromellose, sodium carboxymethylcellulose 4000 and xanthan gum composition, sodium carboxymethylcellulose 4000 and hydroxypropyl methylcellulose
  • the ratio (w/w) of the two tackifier combinations ranges from 1:5 to 5:1.
  • the concentration of the tackifier is 0.01% w/v ⁇ 3.5% w/v; in another embodiment, the concentration of the tackifier is 0.05 ⁇ 3.0% w/v; in another embodiment, the concentration of the tackifier is 0.05-2.0% w/v; in yet another embodiment, the concentration of the tackifier 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.
  • the R-ketamine liquid formulation further includes one or more of the following auxiliary materials: buffers, flavoring agents, antioxidants, osmotic pressure regulators and preservatives. In another embodiment, the R-ketamine liquid formulation further includes one or more of the following auxiliary materials: buffers, flavoring agents, antioxidants, osmotic pressure regulators, preservatives and penetration enhancers.
  • the buffer 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 carbonates, sodium carbonate, imidazole, pyrophosphate, glucose Sodium acid, sodium lactate, phosphoric acid, borate, bicarbonate, Tris-HCl, citrate, or combinations thereof.
  • the buffer described in this application can maintain the pH of the liquid preparation within a stable range, which is beneficial to improving the stability of the solution preparation.
  • the concentration of the buffer is 0.1-0.3% w/v; in one embodiment, the concentration of the buffer is 0.1-0.2% w/v; in another embodiment, the concentration of the buffer is 0.1 ⁇ 0.15% w/v; in another embodiment, 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/
  • the present application provides an R-ketamine liquid formulation further comprising a flavoring agent.
  • Flavoring agents can mask the possible peculiar smell of the pharmaceutical composition and improve its palatability, which is beneficial to improving patient compliance.
  • the flavoring agent of the liquid preparation is sodium saccharin, fructose, sucralose, stevia, menthol, maltitol, xylitol, aspartame, cyclamate, saccharin, orange peel Glycosides, thaumatin, stevia or acesulfame potassium, or combinations thereof.
  • the application provides an R-ketamine liquid preparation, and the concentration of the flavoring agent is 0.01 to 0.05% w/v; in another embodiment, the concentration of the flavoring agent is 0.01 ⁇ 0.03% w/v; in 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.
  • the present application provides a liquid formulation of R-ketamine, which formulation further includes an antioxidant.
  • Antioxidants can effectively prevent or delay the oxidation of preparations, prevent oxidative deterioration of drugs and their preparations, as well as discoloration, precipitation and other problems caused by oxidation, and increase drug stability.
  • the antioxidant of the liquid preparation is ethylenediaminetetraacetic acid (EDTA) or its sodium or calcium salt, vitamin E, gallate, sodium bisulfite, ascorbic acid or its salt, butylated hydroxyanisole. ether or tocopherol, or combinations thereof.
  • the application provides an R-ketamine liquid preparation, and the concentration of the antioxidant is 0.010-0.020% w/v; in another embodiment, the concentration of the antioxidant is 0.010-0.015 % w/v; in 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.
  • the R-ketamine liquid formulation further includes a preservative.
  • the preservative is selected from the group consisting of methyl paraben, ethyl paraben, propyl paraben, butyl paraben, sodium methyl paraben, sodium paraben, Sodium ethyl benzoate, sodium propylparaben, sodium butylparaben, sorbic acid, potassium sorbate, sodium sorbate, benzoic acid, sodium benzoate, benzyl alcohol, benzalkonium bromide, benzalkonium chloride One or more of ammonium, chlorobutanol, resorcinol and sodium edetate.
  • the application provides an R-ketamine liquid preparation, and the concentration of the preservative is 0.010-0.020% w/v; in another embodiment, the concentration of the preservative is 0.010-0.015 %w/v; in another real world In the embodiment, the concentration of the preservative in the liquid preparation is 0.010% w/v, 0.0125% w/v, 0.015% w/v, 0.0175% w/v or 0.02% w/v.
  • the R-ketamine liquid formulation further includes an osmolality regulator.
  • the viscosonic pressure regulator is selected from one or more of sodium chloride, potassium nitrate, boric acid, and glucose.
  • the R-ketamine liquid formulation further includes a penetration enhancer.
  • the penetration enhancer is propylene glycol, Tween 80, hypromellose, sodium lauryl sulfate, sodium docusate, polysorbate, myristyl maltoside, lecithin , one or more of hydroxypropyl- ⁇ -cyclodextrin, sodium sulfobutyl- ⁇ -cyclodextrin or PEG400.
  • the second aspect of this application specifically provides an R-ketamine liquid preparation, which includes R-ketamine hydrochloride, an amphiphilic pharmaceutically acceptable excipient, a thickener and water; the pH range of the liquid preparation is 4.5 ⁇ 5.5, and the content of R-ketamine in the liquid preparation is 0.7% w/v ⁇ 8.4% w/v.
  • the types of tackifiers and their contents with amphipathic pharmaceutically acceptable excipients are as described above.
  • the tackifier is one of sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and hypromellose , or a combination thereof.
  • the simultaneous use of amphiphilic pharmaceutically acceptable excipients and thickeners can make the API in the prescription more fully released in vitro, and can better promote the passage of R-ketamine through the oral cavity. mucosal permeability, synergistically improving the bioavailability of R-ketamine solution formulations.
  • the thickener is sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and One of hypromellose, or a combination thereof.
  • the tackifier is xanthan gum; in another embodiment, the tackifier is hypromellose; in another embodiment, the tackifier is carboxymethyl Sodium cellulose 4000 and sodium carboxymethylcellulose 12000; in another embodiment, the tackifier is sodium carboxymethylcellulose 4000 and hypromellose.
  • the third aspect of this application specifically provides an R-ketamine liquid preparation, which includes R-ketamine hydrochloride, an amphiphilic pharmaceutically acceptable excipient, a tackifier, a buffer and water; the pH of the liquid preparation The range is 4.5 to 5.5, and the content of R-ketamine in the liquid preparation is 0.7% w/v to 8.4% w/v.
  • the types of the viscosity-increasing agent and the buffering agent and their content with the amphipathic pharmaceutically acceptable excipients are as described above.
  • the application provides an R-ketamine liquid preparation
  • the buffer is citric acid
  • the fourth aspect of this application specifically provides an R-ketamine liquid preparation, which includes R-ketamine hydrochloride, amphiphilic pharmaceutically acceptable excipients, thickeners, antioxidants, flavoring agents, buffers and water. ;
  • the pH range of the liquid preparation is 4.5 to 5.5, and the content of R-ketamine in the liquid preparation is 0.7% w/v to 8.4% w/v.
  • the types of viscosifiers, antioxidants, flavoring agents and buffers as well as their contents with amphipathic pharmaceutically acceptable excipients are as described above.
  • the tackifier is one of sodium carboxymethylcellulose 4000, sodium carboxymethylcellulose 8000, sodium carboxymethylcellulose 12000, xanthan gum and hypromellose , or a combination thereof.
  • the antioxidant is disodium edetate
  • the flavoring agent is sodium saccharin or maltitol
  • the thickening agent is carboxymethylcellulose.
  • the antioxidant is disodium edetate
  • the flavoring agent is sodium saccharin or maltitol
  • the thickening agent is xanthan gum
  • the antioxidant It is disodium edetate
  • the flavoring agent is sodium saccharin or maltitol
  • the flavoring agent is sodium saccharin or maltitol.
  • Viscosifier hypromellose in another embodiment, the tackifier is sodium carboxymethylcellulose 4000 and sodium carboxymethylcellulose 12000; in another embodiment, the antioxidant is Disodium terate, the flavoring agent is sodium saccharin or maltitol, and the thickening agent is sodium carboxymethylcellulose 4000 and hypromellose.
  • the application provides an R-ketamine liquid preparation
  • the buffer is citric acid
  • the fifth aspect of this application provides the use of an R-ketamine liquid preparation in the preparation of drugs to prevent, alleviate or treat depression.
  • the drugs can be used to treat major depression, unipolar depression, refractory depression, Resistant depression, anxious depression, bipolar depression.
  • the application provides a use of an R-ketamine liquid formulation in the preparation of a drug for preventing, alleviating or treating depression, and the liquid formulation is applied to the oral buccal membrane of a patient.
  • the sixth aspect of the present application provides a method of using R-ketamine liquid preparation to prevent, alleviate or treat depression in a patient, including administering a therapeutically effective amount of R-ketamine liquid preparation to the patient.
  • the present application provides a method for preventing, alleviating or treating depression in a patient using R-ketamine liquid formulation, the depression being major depression, unipolar depression, treatment-resistant depression, refractory depression Sexual depression, anxious depression, bipolar depression.
  • the application provides a method of preventing, alleviating or treating depression in a patient using an R-ketamine liquid formulation, which is applied to the buccal membrane of the patient's oral cavity.
  • the seventh aspect of this application provides an R-ketamine liquid preparation for preventing, alleviating or treating depression in patients, where the depression is major depression, unipolar depression, treatment-resistant depression, and refractory depression disorders, anxiety depression, and bipolar depression.
  • a liquid formulation of R-ketamine for preventing, alleviating, or treating depression in a patient is administered to the buccal membrane of the oral cavity of a mammal.
  • this application provides a preparation method for the aforementioned R-ketamine liquid preparation, including the following preparation steps:
  • the solution passes through a 0.45 ⁇ m filter membrane, and the filtrate is filled into a prefilled syringe to obtain the finished product.
  • the R-ketamine liquid preparation provided in this application is rapidly absorbed and takes effect quickly within 3 to 7 minutes, and its AUC0-240min can be greater than 7000ng/mL.
  • the R-ketamine liquid preparation has high bioavailability, no crystallization phenomenon, and high stability. It can not only meet the needs of large-scale processing and production, but also reduce the risk of medication for patients.
  • the R-ketamine liquid preparation provided in this application can effectively improve the bioavailability of the active substance by using amphiphilic pharmaceutically acceptable excipients; by further adding a viscosity-increasing agent, the liquid preparation can be increased in the oral mucosa.
  • the residence time can further increase the absorption of R-ketamine and synergistically improve the bioavailability of R-ketamine liquid preparations.
  • R-ketamine liquid preparation provided in this application is simple and easy to administer, greatly increasing patient compliance. Due to the small dosage and small volume, it can greatly reduce irritation to mucous membranes and reduce the risk of abuse.
  • concentrations of all ingredients are in percent weight/volume (%w/v). as commonly understood
  • %w/v value refers to the amount of a specific component or ingredient in the formulation. It is known that equivalent concentrations can be expressed in different units. For example, a concentration of 0.1% w/v can also be expressed as a 1 mg/ml solution.
  • the preparation method includes the following preparation steps:
  • the solution passes through a 0.45 ⁇ m filter membrane, and the filtrate is filled into a 1 ml prefilled syringe (purchased from Shandong Zibo Minkang Pharmaceutical Packaging Co., Ltd.), 1 ml/tube to obtain the finished preparation.
  • Both of the above two impurities can be purchased through commercial channels.
  • the inventor conducted long-term stability experiments on the samples prepared in Examples 1-13 in an environment of 25°C ⁇ 2°C and RH 60% ⁇ 5%.
  • the mobile phase is uniform; the detection wavelength is 215nm; the flow rate is 1.0ml per minute; the column temperature is 30°C; the injection volume is 20 ⁇ l.
  • Chromatographic conditions Use octadecylsilane bonded silica gel as filler (Agela MP C18 4.6 ⁇ 150mm, 5 ⁇ m or equivalent column efficiency); use 25mM phosphate buffer (take 3.4g of potassium dihydrogen phosphate, add 1000ml of water to dissolve, Use phosphoric acid to adjust the pH to 2.5) as mobile phase A, and acetonitrile as mobile phase B. Carry out gradient elution according to the table, the detection wavelength is 215nm; the column temperature is 30°C; the flow rate is 1.0ml per minute; the injection volume is 20 ⁇ l.
  • the Franz diffusion cell method was used and a phospholipid biomimetic barrier was used.
  • Bionic membrane simulates oral mucosa, and the diffusion medium uses PBS buffer; after the diffusion pool reaches 37°C, first add 0.5ml of artificial saliva above the bionic membrane, and then add 0.2ml of prescription solution.
  • the sampling time points are 10min, 20min, and 30min. , 45min, 60min, 180min, 240min, 300min, 360min, using waste mode, take 1ml sample at each time point, and detect the content with liquid phase.
  • the preparation method includes the following preparation steps:
  • the preparation method refers to Comparative Example 1.
  • the preparation method refers to Comparative Example 1.
  • the Franz diffusion cell method was used and a phospholipid biomimetic barrier was used.
  • Bionic membrane simulates oral mucosa, and the diffusion medium uses PBS buffer; after the diffusion pool reaches 37°C, first add 0.5 ml of artificial saliva above the bionic membrane, group them, and then add 0.2 ml of Example 1, Comparative Example 1, and Comparative Example respectively.
  • the sampling time points are 10min, 20min, 30min, 45min, 60min, 180min, 240min, 300min, and 360min. Waste mode is used. 1ml sample is taken at each time point and the content is detected by liquid phase.
  • the in vitro diffusion data of four R-ketamine preparations are shown in Figure 1. From the above Table 6 and Figure 3, it can be seen that compared with the preparation of R-ketamine hydrochloride for nasal absorption in the comparative example, the R hydrochloride prepared by the present invention -The unit amount of ketamine buccal solution has a high transmucosal permeability and a significantly increased release speed.
  • This experiment used New Zealand white rabbits, 2.5kg to 3.0kg, 6 in each group, half male and half female.
  • Four different preparations were administered with R-ketamine hydrochloride buccal liquid at a dosage of 7 mg/animal.
  • Examples 1 and 10 used unilateral buccal liquid administration, and the dosage was 0.125 ml/animal;
  • Example 11 used The buccal fluid was administered on one side, and the dosage was 0.250 ml/animal; in Example 12, buccal fluid was administered on both sides, and the dosage was 0.250 ml/side.
  • the blood collection method is ear vein blood collection.
  • the blood collection time points are: 0min (before administration), 2min, 5min, 10min, 15min, 30min, 60min, 120min, and 240min.
  • the plasma concentrations of four different R-ketamine hydrochloride buccal solutions can reach the highest value within 3.5 to 7.1 minutes after buccal administration; the highest plasma concentrations Cmax are all More than 320ng/ml; AUC0-240min are all higher than 5000min*ng/ml. It shows that the R-ketamine hydrochloride buccal solution of different concentrations in the present application has a fast absorption rate when administered through the buccal membrane, has a high blood concentration in the body, and can quickly exert its medicinal effect in the body.
  • the technical solution of this application can also be used for buccal liquid and buccal film delivery systems of R-ketamine, ketamine or pharmaceutically acceptable salts, by adjusting or changing the content of active ingredients, the types and dosage of pharmaceutical excipients, etc. to achieve this goal.

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Abstract

本申请公开了一种R-氯胺酮液体制剂。所述的R-氯胺酮液体制剂为水性溶液剂，包含R-氯胺酮或其药学上可接受的盐、两亲型药学上可接受的赋形剂和水，而且，所述液体制剂的pH值为2.5-5.7。本申请的液体制剂经口腔黏膜给药，制剂吸收快、生物利用度高，施用方式简单、依从性好。本申请的制剂可用于重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症的预防、缓解或治疗。

Description

R-氯胺酮液体制剂及其用途
本申请要求于2022年4月26日提交中国专利局、申请号为202210448842.8、发明名称为“R-氯胺酮液体制剂及其用途”的中国专利申请的优先权，其内容应理解为通过引用的方式并入本申请中。
技术领域
本申请涉及但不限于药物制剂技术领域，特别涉及R-氯胺酮液体制剂及其作为抗抑郁药物的用途。
背景技术
抑郁症(Major depression disorder，MDD)是一种常见的精神疾病，以情感低落、思维迟缓、以及言语动作减少，迟缓为典型症状。抑郁症严重困扰患者的生活和工作，给家庭和社会带来沉重的负担。据统计，每年因抑郁症自杀死亡人数估计高达100万人。目前，临床上主要是使用抗抑郁药(例如：三环类抗抑郁药，选择性5-羟色胺再摄取抑制剂，血清素和去甲肾上腺素再摄取抑制剂)治疗这种精神疾病，然而，这些药物并不能针对所有的抑郁症患者发挥治疗作用。因此，需要开发新型的抑郁症治疗药物。
近年来，研究证明表明：氯胺酮作为N-甲基-D-天门冬氨酸(NMDA)受体拮抗剂，能够通过增加单胺的释放或者抑制突触前膜对单胺的再摄取，提高大脑单胺化合物的水平，从而发挥抗抑郁作用。这种特殊的精神科药物也因此颇受关注。
为了满足更多抑郁症患者的需求，降低治疗成本，减轻患者家庭负担，亟需开发新型的具有临床应用价值的制剂。
发明内容
本申请提供了一种R-氯胺酮液体制剂，其经口腔黏膜给药，本申请的制剂稳定性高、吸收快、生物利用度高，施用方式简单、依从性好。
一方面，本申请提供了一种R-氯胺酮液体制剂，该液体制剂经口腔黏膜给药，其包括R-氯胺酮或其药学上可接受的盐、两亲型药学上可接受的赋形剂和水。
另一方面，本申请提供了上述R-氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途，所述药物可用于治疗重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
又一方面，本申请提供了一种使用上述R-氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法，包括向患者施用治疗有效量的R-氯胺酮液体制剂。
又一方面，本申请提供了上述R-氯胺酮液体制剂，用于预防、缓解或治疗患者的抑郁症，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
又一方面，本申请提供了前述R-氯胺酮液体制剂的制备方法。
附图概述
附图用来提供对本申请技术方案的理解，并且构成说明书的一部分，与本申请的实施例一起用于解释本申请的技术方案，并不构成对本申请技术方案的限制。
图1为本申请提出不同R-氯胺酮制剂在体外的扩散情况。
图2为本申请提出不同R-氯胺酮制剂给药途径与药代的关系图；
图3为本申请提出不同R-氯胺酮制剂不同给药途径与AUC的关系图。
详述
本申请第一方面提供了一种R-氯胺酮液体制剂，该液体制剂经口腔黏膜给药，其包括R-氯胺酮或其药学上可接受的盐、两亲型药学上可接受的赋形剂和水。
除非另外说明，本文所用的R-氯胺酮，也被称为(R)-氯胺酮、阿克氯胺酮、左氯胺酮、arketamine、d-ketamine、(2R)-2-(2-氯苯基)-2(甲氨基)环己酮等，其指的是氯胺酮的(R)-对映体。
在本申请的液体制剂中，无论使用的是R-氯胺酮，还是R-氯胺酮药学上可接受的盐，在计算活性物质含量时，均以R-氯胺酮的含量来进行计算。
在本申请所述R-氯胺酮液体制剂的一实施方案中，所述液体制剂中R-氯胺酮的含量为0.5％w/v～8.5％w/v。
本申请所述R-氯胺酮液体制剂生物利用度高，因此，该液体制剂可以被制备为较低物质浓度的产品，既能满足临床患者的预防或治疗需求，又可以避免因高浓度给药带来的滥用风险。同时，R-氯胺酮液体制剂与唾液相容性良好，减少对粘膜的刺激性，降低药物副作用。
在一实施方案中，所述液体制剂中R-氯胺酮的浓度为0.7％w/v～8.4％w/v；在另一实施方案中，所述液体制剂中R-氯胺酮的浓度为1.4％w/v～6.3％w/v；在又一实施方案中，所述液体制剂中R-氯胺酮的浓度为1.4％w/v～5.6％w/v。还在一实施方案中，所述液体制剂中R-氯胺酮的浓度为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或8.4％w/v。
在另一实施方案中，可以与R-氯胺酮形成药学上可接受盐的酸包括盐酸、硫酸、磷酸、马来酸、乙酸、己二酸、藻酸、枸橼酸、天冬氨酸、苯甲酸、苯磺酸、硫酸氢、丁酸、樟脑酸、樟脑磺酸、双葡糖酸、延胡索酸、甘油磷酸、硬脂酸、庚酸、己酸、氢溴酸(即HBr)、氢碘酸(即HI)、乳酸、甲磺酸、烟酸、草酸、双羟基萘酸、果胶酸、过硫酸、3-苯基丙酸、苦味酸、新戊酸、丙酸、琥珀酸、酒石酸、硫氰酸、谷氨酸、对甲苯磺酸、十一酸和扁桃酸。
在一实施方案中，R-氯胺酮药学上可接受的盐，包括盐酸盐、硫酸盐、磷酸盐、马来酸盐、乙酸盐、己二酸盐、藻酸盐、枸橼酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸 氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、双葡糖酸盐、延胡索酸盐、甘油磷酸盐、硬脂酸盐、庚酸盐、己酸盐、氢溴酸(即HBr)盐、氢碘酸(即HI)盐、乳酸盐、甲磺酸盐、烟酸盐、草酸盐、双羟基萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一酸盐和扁桃酸盐。
在一实施方案中，所述液体制剂中两亲型药学上可接受的赋形剂的浓度为0.03％w/v～0.11％w/v。在另一实施方案中，所述液体制剂中两亲型药学上可接受的赋形剂的浓度为0.03％w/v～0.07％w/v；还在一实施方案中，所述液体制剂中两亲型药学上可接受的赋形剂的浓度为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。
在一实施方案中，所述两亲型药学上可接受的赋形剂为十二烷基硫酸钠、烷基醇酰胺、烷基琥珀酸酯磺酸盐、醇胺烷基苯磺酸盐、环烷酸盐、磺基琥珀酸盐、烷基酚磺酸酯、聚氧乙烯单月桂酸酯，庚基硫酸钠、脱氧胆酸钠、庚基磺酸钠中的一种，或其组合，优选十二烷基硫酸钠、脱氧胆酸钠。
在一实施方案中，所述液体制剂的pH为2.5～5.7。
在另一实施方案中，所述液体制剂的pH范围为3.0～5.7；在又一实施方案中，所述R-氯胺酮液体制剂的pH范围为4.0～5.7；在又一实施方案中，所述液体制剂的pH为5.0～5.5；还在一实施方案中，所述液体制剂的pH为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或5.7。
在另一实施方案中，所述液体制剂包括浓度为0.5％w/v～8.5％w/v的R-氯胺酮或其药学上可接受的盐、浓度为0.01％w/v～0.11％w/v两亲型药学上可接受的赋形剂和水，所述液体制剂的pH值范围为2.5～5.7。
在本申请的某一些实施方案中，所述R-氯胺酮液体制剂还可以包含增粘剂。
在另一实施方案中，所述增粘剂为黄原胶、羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙烯醇、卡波姆或聚乙烯吡咯烷酮，或其组合。
在另一实施方案中，所述羧甲基纤维素钠选自羧甲基纤维素钠800、羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000中的一种或多种。
在一实施方案中，所述增粘剂的组合非限制性地包括：羧甲基纤维素钠4000与羧甲基纤维素钠12000、羧甲基纤维素钠800与羧甲基纤维素钠12000、羧甲基纤维素钠4000与黄原胶、羧甲基纤维素钠4000与羟丙甲纤维素、羧甲基纤维素钠4000与黄原胶组合物、羧甲基纤维素钠4000与羟丙甲纤维素组合物，两种增粘剂组合的配比(w/w)范围为1∶5～5∶1。
在一实施方案中，所述增粘剂的浓度为0.01％w/v～3.5％w/v；在另一实施方案中，所述增粘剂的浓度为0.05～3.0％w/v；在又一实施方案中，所述增粘剂的浓度为0.05～2.0％w/v；还在一实施方案中，所述增粘剂的浓度为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或1.00％w/v。
在另一实施方案中，所述R-氯胺酮液体制剂还包含下列辅料中一种或多种：缓冲剂、矫味剂、抗氧化剂、渗透压调节剂和防腐剂。在另一实施方案中，所述R-氯胺酮液体制剂还包含下列辅料中一种或多种：缓冲剂、矫味剂、抗氧化剂、渗透压调节剂、防腐剂和促渗剂。
在本申请所述R-氯胺酮液体制剂的一实施方案中，所述缓冲剂可以为枸橼酸、磷酸二氢钠、磷酸氢二钠、乙酸、硼酸、硼酸钠、琥珀酸、酒石酸、乳酸、富马酸、磷酸三钠(磷酸三钠十二水合物或TSP)、苯甲酸钠、苯甲酸、氢氧化钠、氢氧化钾、碱金属碳酸盐、碳酸钠、咪唑、焦磷酸盐、葡糖酸钠、乳酸钠、磷酸、硼酸盐、碳酸氢盐、Tris-HCl、枸橼酸盐，或其组合。
本申请所述缓冲剂能够维持液体制剂pH在一个稳定的范围内，有利于提高溶液制剂的稳定性。所述缓冲剂的浓度为0.1～0.3％w/v；在一实施方案中，所述缓冲剂的浓度为0.1～0.2％w/v；在另一实施方案中，所述缓冲剂的浓度为0.1～0.15％w/v；在另一实施方案中，所述缓冲剂的浓度为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或0.3％w/v。
在另一实施方案中，本申请提供一种R-氯胺酮液体制剂，该制剂还包括矫味剂。矫味剂能够掩蔽药物组合物可能具有的异味而改善其适口性，有利于提高患者的依从性。在一实施方案中，所述液体制剂的矫味剂为糖精钠、果糖、三氯蔗糖、甜菊素、薄荷脑、麦芽糖醇、木糖醇、阿斯巴甜、甜蜜素、糖精、新橙皮苷，奇异果甜蛋白、甜叶菊或安赛蜜，或其组合。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂，所述矫味剂的浓度为0.01～0.05％w/v；在另一实施方案中，所述矫味剂的浓度为0.01～0.03％w/v；在另一实施方案中，所述矫味剂的浓度为0.01％w/v、0.02％w/v、0.03％w/v、0.04％w/v或0.05％w/v。
在一实施方案中，本申请提供一种R-氯胺酮液体制剂，该制剂还包括抗氧化剂。抗氧化剂能够有效阻止或延缓制剂的氧化，可以防止药物及其制剂的氧化变质，以及由氧化所导致的变色、产生沉淀等问题，增加药物稳定性。在一实施方案中，所述液体制剂的抗氧化剂为乙二胺四乙酸(EDTA)或其钠盐或钙盐、维生素E、没食子酸盐、亚硫酸氢钠、抗坏血酸或其盐、丁羟茴醚或生育酚，或其组合。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂，所述抗氧化剂的浓度为0.010～0.020％w/v；在另一实施方案中，所述抗氧化剂的浓度为0.010～0.015％w/v；在另一实施方案中，所述液体制剂的抗氧化剂的浓度为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或0.02％w/v。
在一实施方案中，所述R-氯胺酮液体制剂还包含防腐剂。在一些实施方案中，所述防腐剂选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、对羟基苯甲酸丙酯钠、对羟基苯甲酸丁酯钠、山梨酸、山梨酸钾、山梨酸钠、苯甲酸、苯甲酸钠、苯甲醇、苯扎溴铵、苯扎氯铵、三氯叔丁醇、间苯二酚和乙二胺四乙酸钠中的一种或者多种。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂，所述防腐剂的浓度为0.010～0.020％w/v；在另一实施例中，所述防腐剂的浓度为0.010～0.015％w/v；在另一实 施例中，所述液体制剂的防腐剂的浓度为0.010％w/v、0.0125％w/v、0.015％w/v、0.0175％w/v或0.02％w/v。
在一实施方案中，所述R-氯胺酮液体制剂还包含渗透压调节剂。在一些实施方案中，所述粘渗透压调节剂选自氯化钠、硝酸钾、硼酸和葡萄糖中的一种或者多种。
在一实施方案中，所述R-氯胺酮液体制剂还包含促渗剂。在一些实施方案中，所述促渗剂为丙二醇、吐温80、羟丙甲纤维素、十二烷基硫酸钠、多库酯钠、聚山梨醇酯、十四烷基麦芽糖苷、卵磷脂、羟丙基-β-环糊精、磺丁基-β-环糊基钠或PEG400中的一种或多种。
本申请第二方面具体提供了一种R-氯胺酮液体制剂，其包括盐酸R-氯胺酮，两亲型药学上可接受的赋形剂，增粘剂和水；所述液体制剂的pH范围为4.5～5.5，所述液体制剂中R-氯胺酮的含量为0.7％w/v～8.4％w/v。
在一实施方案中，所述增粘剂的种类以及它们与两亲型药学上可接受的赋形剂的含量如前所述。
在另一实施方案中，所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种，或其组合。
在本申请所提供的R-氯胺酮液体制剂中，同时使用两亲型药学上可接受的赋形剂和增粘剂可以使处方中API体外释放更充分，能够更好的促进R-氯胺酮通过口腔粘膜的渗透性，协同提高R-氯胺酮溶液制剂的生物利用度。
在本申请所述R-氯胺酮液体制剂的一实施方案中，所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种，或其组合。在一实施方案中，所述增粘剂为黄原胶；在另一实施方案中，所述增粘剂羟丙甲纤维素；在另一实施方案中，所述增粘剂为羧甲基纤维素钠4000和羧甲基纤维素钠12000；在另一实施方案中，所述增粘剂为羧甲基纤维素钠4000及羟丙甲纤维素。
本申请第三方面具体提供了一种R-氯胺酮液体制剂，其包括盐酸R-氯胺酮，两亲型药学上可接受的赋形剂，增粘剂，缓冲剂和水；所述液体制剂的pH范围为4.5～5.5，所述液体制剂中R-氯胺酮的含量为0.7％w/v～8.4％w/v。
在一实施方案中，所述增粘剂和缓冲剂的种类以及它们与两亲型药学上可接受的赋形剂的含量如前所述。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂，所述缓冲剂为枸橼酸。
本申请第四方面具体提供了一种R-氯胺酮液体制剂，其包括盐酸R-氯胺酮、两亲型药学上可接受的赋形剂，增粘剂，抗氧化剂，矫味剂，缓冲剂和水；所述液体制剂的pH范围为4.5～5.5，所述液体制剂中R-氯胺酮的含量为0.7％w/v～8.4％w/v。
在一实施方案中，所述增粘剂、抗氧化剂、矫味剂和缓冲剂的种类以及它们与两亲型药学上可接受的赋形剂的含量如前所述。
在另一实施方案中，所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种，或其组合。
在本申请所述R-氯胺酮液体制剂的一实施方案中，所述抗氧化剂为依地酸二钠，所述矫味剂为糖精钠或麦芽糖醇，所述增粘剂为羧甲基纤维素钠4000、羧甲基纤维素钠8000、羧甲基纤维素钠12000、黄原胶和羟丙甲纤维素中的一种，或其组合。在一实施方案中，所述抗氧化剂为依地酸二钠，所述矫味剂为糖精钠或麦芽糖醇，所述增粘剂为黄原胶；在另一实施方案中，所述抗氧化剂为依地酸二钠，所述矫味剂为糖精钠或麦芽糖醇，所述增 粘剂羟丙甲纤维素；在另一实施方案中，所述增粘剂为羧甲基纤维素钠4000和羧甲基纤维素钠12000；在另一实施方案中，所述抗氧化剂为依地酸二钠，所述矫味剂为糖精钠或麦芽糖醇，所述增粘剂为羧甲基纤维素钠4000及羟丙甲纤维素。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂，所述缓冲剂为枸橼酸。
本申请第五方面提供了一种R-氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途，所述药物可用于治疗重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中，本申请提供的一种R-氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途，所述液体制剂被施用于患者的口腔颊膜。
本申请第六方面提供了一种使用R-氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法，包括向患者施用治疗有效量的R-氯胺酮液体制剂。
在一实施方案中，本申请提供一种使用R-氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中，本申请提供的一种使用R-氯胺酮液体制剂预防、缓解或治疗患者抑郁症的方法，所述液体制剂被施用于患者的口腔颊膜。
本申请第七方面提供了一种R-氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、双相抑郁症。
在一实施方案中，一种R-氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症，所述液体制剂被施用于哺乳动物的口腔颊膜。
第八方面，本申请提供了前述R-氯胺酮液体制剂的制备方法，包括以下制备步骤：
a)称取处方量盐酸R-氯胺酮、加入纯化水，充分搅拌溶解后，再依次加入处方量的任选的抗氧化剂如依地酸二钠、任选的缓冲剂如枸橼酸、任选的矫味剂如糖精钠、任选的防腐剂如苯扎氯铵充分搅拌溶解；
b)加入处方量的任选的两亲型药学上可接受的赋形剂、任选的增粘剂，充分搅拌溶解
c)用氢氧化钠调节pH至相应值；
d)将溶液转移至特定的容量瓶中，补水定容至刻度；
e)定容后溶液过0.45μm的滤膜，滤液灌装至预灌封注射器内，即得制剂成品。
本申请的有益效果如下：
(1)本申请所提供的R-氯胺酮液体制剂吸收迅速，在3～7min内快速起效，其AUC0-240min可大于7000ng/mL。该R-氯胺酮液体制剂的生物利用度高，同时不会出现析晶现象，稳定性高，既能满足规模化加工生产的需要，又降低了患者的用药风险。
(2)本申请所提供R-氯胺酮液体制剂通过使用两亲型药学上可接受的赋形剂，可有效提高活性物质的生物利用度；通过进一步加入增粘剂，增加液体制剂在口腔黏膜的滞留时间，可进一步提高R-氯胺酮吸收量，协同提高R-氯胺酮液体制剂的生物利用度。
(3)本申请所提供的R-氯胺酮液体制剂给药方式简便易行，患者依从性大大增加，由于给药剂量小、体积小，可大大减少对粘膜的刺激，同时降低滥用风险。
除非另有说明，否则所有成分的浓度均以重量/体积％(％w/v)为单位。如通常所理解 的，％w/v值是指配制品中特定组分或成分的量。众所周知，能以不同单位表示等效浓度。例如，0.1％w/v的浓度也可以表示为1mg/ml溶液。
本申请公开了经口腔黏膜给药的R-氯胺酮液体制剂及其用途，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本申请。本申请的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本申请内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本申请技术。本申请中所用试剂或仪器均可由市场购得。
仪器：
S220-KpH计、SHJ-6AB磁力搅拌水浴锅、ME204T/02电子天平、ME3002T/02电子天平、DSC-800T全自动透皮扩散仪、戴安U300高效液相色谱仪。
实施例1
处方：
制备方法，包括以下制备步骤：
a)称取处方量盐酸R-氯胺酮、加入总重量80％的纯化水，充分搅拌溶解后，再依次加入处方量的依地酸二钠、枸橼酸、糖精钠、苯扎氯铵充分搅拌溶解；
b)加入不同处方中相对应的十二烷基硫酸钠、羧甲基纤维素钠4000，充分搅拌溶解；
c)用氢氧化钠调节pH至4.5～5.5；
d)将溶液转移至特定的容量瓶中，补水定容至刻度10ml；
e)定容后溶液过0.45μm的滤膜，滤液灌装至1ml预灌封注射器内(购于山东淄博民康药业包装有限公司)，1ml/支即得制剂成品。
实施例2
处方：

制备方法参照实施例1。
实施例3
处方：
制备方法参照实施例1。
实施例4
处方：
制备方法参照实施例1。
实施例5
处方：

制备方法参照实施例1。
实施例6
处方：
制备方法参照实施例1。
实施例7
处方
制备方法参照实施例1。
实施例8
处方
制备方法参照实施例1。
实施例9
处方
制备方法参照实施例1。
实施例10
处方
制备方法参照实施例1。
实施例11
处方
制备方法参照实施例1。
实施例12
处方
制备方法参照实施例1。
实施例13
处方
制备方法参照实施例1。
实施例14本申请的盐酸R-氯胺酮口颊液的稳定性测试
表1盐酸R-氯胺酮口颊液杂质信息：
上述2个杂质均可通过商业渠道购买获得。
本发明人对实施例1-13，制备得到的样品在25℃±2℃和RH60％±5％的环境中进行了长期稳定性实验。
1.氯胺酮含量检测的方法：
照高效液相色谱法(通则0512)测定
色谱条件：用十八烷基硅烷键合硅胶为填充剂；取0.95g己烷磺酸钠溶于1L的乙腈和水的混合溶液(乙腈∶水＝25∶75)，再加4ml冰醋酸混匀为流动相；检测波长为215nm；流速为每分钟1.0ml；柱温为30℃；进样体积20μl。
2.氯胺酮有关物质检测的方法：
照高效液相色谱法(通则0512)测定。
色谱条件：用十八烷基硅烷键合硅胶为填充剂(Agela MP C18 4.6×150mm，5μm或柱效相当)；以25mM磷酸盐缓冲液(取磷酸二氢钾3.4g，加水1000ml使溶解，用磷酸调pH值至2.5)为流动相A，以乙腈为流动相B。按下表进行梯度洗脱，检测波长为215nm；柱温为30℃；流速为每分钟1.0ml；进样体积20μl。
表2原辅料含量检测样品试验条件
表3：实施例1-13的长期试验结果


通过表4长期试验的结果可见，本申请所得的药物制剂在室温下放置长达6个月，盐酸R-氯胺酮口颊液的总杂均不超过0.5％，最大单杂也均不超过0.2％，其质量仍符合质量标准，质量稳定。
实施例15本申请的盐酸R-氯胺酮口颊液的体外渗透试验
本研究采用Franz扩散池法，选用磷脂仿生屏障(仿生膜)模拟口腔黏膜，扩散介质采用PBS缓冲液；待扩散池达37℃后，在仿生膜上方先加入0.5ml人工唾液，然后加入0.2ml处方溶液，取样时间点为10min、20min、30min、45min、60min、180min、240min、300min、360min，采用waste模式，每个时间点取1ml样品，液相检测含量。
表4：实施例1-12的体外渗透结果
对比例1盐酸R-氯胺酮经鼻给药制剂(参照专利CN 114306218 A制备)
处方组分

制备方法，包括以下制备步骤：
a)称取处方量盐酸R-氯胺酮、一水枸橼酸、依地酸二钠、苯扎氯铵和14g纯化水，40℃条件下充分搅拌溶解后；
b)用1M氢氧化钠调节pH至4.5；
c)将溶液转移至特定的20ml容量瓶中，补水定容至刻度；
d)定容后溶液过0.45μm的滤膜，滤液按需求灌装。
对比例2盐酸R-氯胺酮经鼻给药制剂(参照专利CN 114306218 A制备)
处方组分
制备方法参照对比例1。
对比例3盐酸R-氯胺酮经鼻给药制剂(参照专利CN 114306218 A制备)
处方组分
制备方法参照对比例1。
试验例1体外稳定性试验
实验方法参照实施例14。
表5：实施例1、对比例1-3的稳定性试验结果
通过表5稳定性试验的结果可见，本申请所得的药物制剂经稳定性试验后，物质含量、杂质含量、pH值均符合标准。对比例1-3的物质含量异常增加，表明该制剂稳定性不高。
试验例2体外透皮扩散实验
本研究采用Franz扩散池法，选用磷脂仿生屏障(仿生膜)模拟口腔黏膜，扩散介质采用PBS缓冲液；待扩散池达37℃后，在仿生膜上方先加入0.5ml人工唾液，分组，然后分别加入0.2ml实施例1、对比例1、对比例2和对比例3溶液，取样时间点为10min、20min、30min、45min、60min、180min、240min、300min、360min，采用waste模式，每个时间点取1ml样品，液相检测含量。
表6：实施例1、对比例1-3的体外渗透结果
具体地，四种R-氯胺酮制剂在体外的扩散数据如图1所示，由上表6和图3可知，与对比例盐酸R-氯胺酮经鼻吸收的制剂相比，本发明制备的盐酸R-氯胺酮口颊液的单位量经黏膜渗透率高，释放速度明显提高。
试验例3体内药代实验
1、实验分组
表7：动物分组情况

2、实验方案
本实验采用新西兰白兔，2.5kg～3.0kg，每组6只，雌雄各半。四种不同制剂，按照7mg/只的量给予盐酸R-氯胺酮口颊液处理，实施例1、实施例10采用单侧口颊液给药，给药量为0.125ml/只；实施例11采用单侧口颊液给药，给药量为0.250ml/只；实施例12采用双侧口颊液给药，给药量为0.250ml/侧。采血前将家兔置于兔固定盒中，采血方式为耳缘静脉采血，采集血液时间点为：0min(给药前)，2min、5min、10min、15min、30min、60min、120min、240min。每个时间点取约1mL全血至含肝素钠的采血管中，4000rpm离心10min，离心得血浆样品，取上清液分装3份至0.5ml EP管中(前2份装150μl，多余血浆装于第3个冻存管中作为备份样)，血浆样品分装处理后置于≤-80℃保存样本。
3、实验结果
表8：四组样品给药后兔子药代实验结果
由表8和图2、图3可知，四种不同的盐酸R-氯胺酮口颊液，在口颊给药后3.5～7.1min内，血药浓度均能到达最高值；最高血药浓度Cmax均超过320ng/ml；AUC0-240min均高于5000min*ng/ml。说明本申请不同浓度的盐酸R-氯胺酮口颊液经颊膜给药的吸收速率快，体内血药浓度高，能够在体内快速发挥药效。
本申请技术方案也可用于R-氯胺酮、氯胺酮或药学上可接受的盐的口颊液颊膜给药系统，通过调整或改变活性成分含量、可用于药学上的辅料种类、用量等手段达到本申请目的。
虽然本申请所揭露的实施方式如上，但所述的内容仅为便于理解本申请而采用的实施方式，并非用以限定本申请。任何本申请所属领域内的技术人员，在不脱离本申请所揭露的精神和范围的前提下，可以在实施的形式及细节上进行任何的修改与变化，但本申请的保护范围，仍须以所附的权利要求书所界定的范围为准。

Claims (24)

  1. 一种R-氯胺酮液体制剂，该液体制剂经口腔黏膜给药，其包括R-氯胺酮或其药学上可接受的盐、两亲型药学上可接受的赋形剂和水，所述液体制剂的pH值范围为2.5～5.7。
  2. 根据权利要求1所述的R-氯胺酮液体制剂，其中，所述液体制剂包括浓度为0.5％w/v～8.5％w/v的R-氯胺酮或其药学上可接受的盐、浓度为0.01％w/v～0.11％w/v两亲型药学上可接受的赋形剂和水，所述液体制剂的pH值范围为2.5～5.7。
  3. 根据权利要求2所述的R-氯胺酮液体制剂，其中，在所述液体制剂中R-氯胺酮的浓度为0.7％w/v～8.4％w/v；优选地，为1.4％w/v～6.3％w/v；更优选地，为1.4％w/v～5.6％w/v。
  4. 根据权利要求2所述的R-氯胺酮液体制剂，其中，在所述液体制剂中两亲型药学上可接受的赋形剂为十二烷基硫酸钠、烷基醇酰胺、烷基琥珀酸酯磺酸盐、醇胺烷基苯磺酸盐、环烷酸盐、磺基琥珀酸盐、烷基酚磺酸酯、聚氧乙烯单月桂酸酯，庚基硫酸钠、脱氧胆酸钠、庚基磺酸钠中的一种，或其组合，优选十二烷基硫酸钠、脱氧胆酸钠。
  5. 根据权利要求2所述的R-氯胺酮液体制剂，其中，在所述液体制剂中两亲型药学上可接受的赋形剂的浓度为0.01％w/v～0.11％w/v；优选地，为0.03％w/v～0.09％w/v；更优选地，为0.05％w/v～0.07％w/v。
  6. 根据权利要求2所述的R-氯胺酮液体制剂，其中，所述液体制剂的pH范围为3.0～5.7；优选地，为4.0～5.7；更优选地，为4.5～5.5；特别优选地，为5.0～5.5。
  7. 根据权利要求1至6中任一项所述的R-氯胺酮液体制剂，所述的液体制剂还包含增粘剂。
  8. 根据权利要求7所述的R-氯胺酮液体制剂，其中，所述增粘剂为黄原胶、羧甲基纤维素钠、羟丙基甲基纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、聚乙烯醇、卡波姆和聚乙烯吡咯烷酮中的一种，或其组合。
  9. 根据权利要求8所述的R-氯胺酮液体制剂，其中，所述羧甲基纤维素钠为羧甲基纤维素钠800、羧甲基纤维素钠4000、羧甲基纤维素钠8000或羧甲基纤维素钠12000中的一种，或其组合。
  10. 根据权利要求7所述的R-氯胺酮液体制剂，其中，所述增粘剂的浓度为0.01％w/v～3.5％w/v。
  11. 根据权利要求1至10中任一项所述的R-氯胺酮液体制剂，所述的液体制剂还包含下列辅料中一种或多种：缓冲剂、矫味剂、抗氧化剂、渗透压调节剂和防腐剂；或者所述的液体制剂还包含下列辅料中一种或多种：缓冲剂、矫味剂、抗氧化剂、渗透压调节剂、防腐剂和促渗剂。
  12. 根据权利要求11所述的R-氯胺酮液体制剂，其中，所述的液体制剂还包含缓冲剂、矫味剂、抗氧化剂和防腐剂。
  13. 根据权利要求11或12所述的R-氯胺酮液体制剂，其中，所述的缓冲剂为枸橼酸、枸橼酸钠、乙酸、乙酸钠、乳酸、磷酸二氢钠、磷酸氢二钠、琥珀酸、硼酸、硼酸钠、酒石酸和富马酸中的一种，或其组合。
  14. 根据权利要求11或12所述的R-氯胺酮液体制剂，其中，所述的矫味剂为糖精钠、果糖、三氯蔗糖、甜菊素、薄荷脑、麦芽糖醇、木糖醇、阿斯巴甜、甜蜜素、糖精、新橙皮苷、奇异果甜蛋白、甜叶菊和安赛蜜中的一种，或其组合。
  15. 根据权利要求11或12所述的R-氯胺酮液体制剂，其中，所述的抗氧化剂为依地酸二钠、维生素E、没食子酸盐、亚硫酸氢钠、抗坏血酸或其盐、丁羟茴醚和生育酚中的一种，或其组合物。
  16. 根据权利要求11或12所述的R-氯胺酮液体制剂，其中，所述的防腐剂为羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、对羟基苯甲酸丁酯、对羟基苯甲酸甲酯钠、对羟基苯甲酸乙酯钠、对羟基苯甲酸丙酯钠、对羟基苯甲酸丁酯钠、山梨酸、山梨酸钾、山梨酸钠、苯甲酸、苯甲酸钠、苯甲醇、苯扎溴铵、苯扎氯铵、三氯叔丁醇、间苯二酚和乙二胺四乙酸钠中的一种，或其组合物。
  17. 权利要求1～16中任一项所述R-氯胺酮液体制剂在制备预防、缓解或治疗抑郁症药物中的用途。
  18. 根据权利要求17所述的用途，其中，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症、或双相抑郁症。
  19. 根据权利要求17或18所述的用途，其中，所述液体制剂被施用于患者的口腔颊膜。
  20. 一种使用权利要求1～16中任一项所述R-氯胺酮液体制剂预防、缓解或治疗抑郁症患者的方法，包括向患者口腔颊膜施用治疗有效量的所述R-氯胺酮液体制剂。
  21. 根据权利要求20所述的方法，其中，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症或双相抑郁症。
  22. 根据权利要求1～16中任一项所述R-氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症。
  23. 根据权利要求22所述R-氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症，其中，所述抑郁症为重性抑郁症、单相抑郁症、难治性抑郁症、顽固性抑郁症、焦虑性抑郁症或双相抑郁症。
  24. 根据权利要求22或23所述R-氯胺酮液体制剂用于预防、缓解或治疗患者的抑郁症，其中，所述液体制剂被施用于患者的口腔颊膜。
PCT/CN2023/089329 2022-04-26 2023-04-19 R-氯胺酮液体制剂及其用途 Ceased WO2023207730A1 (zh)

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