WO2022017300A1 - 一种药物组合物及其应用 - Google Patents
一种药物组合物及其应用 Download PDFInfo
- Publication number
- WO2022017300A1 WO2022017300A1 PCT/CN2021/106973 CN2021106973W WO2022017300A1 WO 2022017300 A1 WO2022017300 A1 WO 2022017300A1 CN 2021106973 W CN2021106973 W CN 2021106973W WO 2022017300 A1 WO2022017300 A1 WO 2022017300A1
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- WO
- WIPO (PCT)
- Prior art keywords
- salt
- bupropion
- deuterated dextromethorphan
- dextromethorphan
- mass ratio
- Prior art date
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Classifications
-
- 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
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
Definitions
- the present invention provides the technical field of pharmaceutical combination application, in particular to a pharmaceutical composition and its application.
- Dextromethorphan (CAS: 125-71-3), English name: Dextromethorphan, its chemical name is (+)-3-methoxy-17-methyl-(9 ⁇ , 13 ⁇ , 14 ⁇ )-morphinane, clinical Shangduo uses its hydrobromide (CAS: 125-69-9) as a medicine, and its deuterated compounds can be obtained by prior art CN101687868A etc., for example, the chemical structure of a deuterated dextromethorphan is as follows:
- Bupropion (CAS: 34911-55-2), English name: Bupropion, its chemical name is 1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino] -1-acetone is used clinically with its hydrochloride (CAS: 31677-93-7) as a drug.
- the chemical structure of bupropion is as follows:
- CN106163522A discloses a composition and method comprising bupropion or a related compound and dextromethorphan, which is used for anti-depression and other neurological disorders, and the related drug is currently in the clinical stage. There are also extensive unaddressed clinical needs in this area.
- the primary object of the present invention is to provide a pharmaceutical composition containing deuterated dextromethorphan or a salt thereof, and a bupropion drug or a salt thereof.
- the bupropion drug of the present invention is selected from bupropion, S-bupropion, R-bupropion, hydroxybupropion, erythro-hydroxybupropion, threo-hydroxybupropion One or a combination of two or more ketones.
- deuterated dextromethorphan or its salt and bupropion or its salt can be used in combination in any ratio, especially the mass ratio is 1-10:1-10, including but Not limited to: 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 2:1, 3:1 , 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1.
- the pharmaceutical composition is selected from: a combination of deuterated dextromethorphan or its salt and bupropion or its salt, deuterated dextromethorphan or its salt and S-amphetamine combination of other ketone or its salt, combination of deuterated dextromethorphan or its salt and R-bupropion or its salt, combination of deuterated dextromethorphan or its salt and hydroxybupropion or its salt, deuterium Combination of dextromethorphan or its salt and erythro-hydroxybupropion or its salt, combination of deuterated dextromethorphan or its salt and threo-hydroxybupropion or its salt.
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- bupropion or its salt is calculated as bupropion, and the two The mass ratio is 1:1-10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- S-bupropion or its salt is calculated as S-bupropion, and the mass ratio of the two is 1:1-10;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan, and R-bupropion or its salt is counted as R-bupropion, and the mass ratio of the two is 1:1-10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan, and hydroxybupropion or its salt is calculated as hydroxybupropion, and the mass ratio of the two is 1:1-10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan, and erythro-hydroxybupropion or its salt is calculated as erythro-hydroxybupropion, and the mass ratio of the two is 1:1-10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- threo-hydroxybupropion or its salt is calculated as threo-hydroxybupropion, and the mass ratio of the two is 1:1-10.
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- bupropion or its salt is calculated as bupropion, and the two The mass ratio is 1:1-8;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan, and S-bupropion or its salt is counted as S-bupropion, and the mass ratio of the two is 1:1-8;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan
- R-bupropion or its salt is counted as R-bupropion, and the mass ratio of the two is 1:1-8;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan, and hydroxybupropion or its salt is calculated as hydroxybupropion, and the mass ratio of the two is 1:1-8;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan, and erythro-hydroxybupropion or its salt is counted as erythro-hydroxybupropion, and the mass ratio of the two is 1:1-8;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- threo-hydroxybupropion or its salt is calculated as threo-hydroxybupropion, and the mass ratio of the two is 1:1-8.
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- bupropion or its salt is calculated as bupropion, and the two The mass ratio is 1:1-6;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- S-bupropion or its salt is calculated as S-bupropion, and the mass ratio of the two is 1:1-6;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan
- R-bupropion or its salt is counted as R-bupropion, and the mass ratio of the two is 1:1-6;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan, and hydroxybupropion or its salt is calculated as hydroxybupropion, and the mass ratio of the two is 1:1-6;
- deuterated dextromethorphan or its salt is counted as deuterated dextromethorphan, and erythro-hydroxybupropion or its salt is counted as erythro-hydroxybupropion, and the mass ratio of the two is 1:1-6;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- threo-hydroxybupropion or its salt is calculated as threo-hydroxybupropion, and the mass ratio of the two is 1:1-6.
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- bupropion or its salt is calculated as bupropion
- the two Mass ratios are 1:1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.5, 1:3.75 , 1:4, 1:4.25, 1:4.5, 1:4.75, 1:4.88, 1:4.91, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25, 1 : 6.5, 1: 6.75, 1: 7, 1: 7.25, 1: 7.5, 1: 7.75, 1: 8, 1: 8.25, 1: 8.5, 1: 8.75, 1: 9, 1: 9.25, 1: 9.5 , 1:9.75, 1:10.
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- S-bupropion or its salt is calculated as S-bupropion
- the mass ratio of the two is 1:1, 1:1.25, 1 : 1.5, 1: 1.75, 1: 2, 1: 2.25, 1: 2.5, 1: 2.75, 1: 3, 1: 3.25, 1: 3.27, 1: 3.5, 1: 3.75, 1: 3.93, 1: 4 , 1:4.25, 1:4.5, 1:4.75, 1:4.88, 1:4.91, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:5.89, 1:6, 1:6.25, 1 : 6.5, 1: 6.75, 1: 7, 1: 7.25, 1: 7.5, 1: 7.75, 1: 8, 1: 8.25, 1: 8.5, 1: 8.75, 1: 9, 1: 9.25, 1: 9.5 , 1:9.75, 1:10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- R-bupropion or its salt is calculated as R-bupropion
- the mass ratio of the two is 1:1, 1:1.25, 1 : 1.5, 1: 1.75, 1: 2, 1: 2.25, 1: 2.5, 1: 2.75, 1: 3, 1: 3.25, 1: 3.27, 1: 3.5, 1: 3.75, 1: 3.93, 1: 4 , 1:4.25, 1:4.5, 1:4.75, 1:4.88, 1:4.91, 1:5, 1:5.25, 1:5.5, 1:5.75, 1:5.89, 1:6, 1:6.25, 1 : 6.5, 1: 6.75, 1: 7, 1: 7.25, 1: 7.5, 1: 7.75, 1: 8, 1: 8.25, 1: 8.5, 1: 8.75, 1: 9, 1: 9.25, 1: 9.5 , 1:9.75, 1:10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- hydroxybupropion or its salt is calculated as hydroxybupropion, and the mass ratio of the two is 1:1, 1:1.25, 1:1.5 , 1: 1.75, 1: 2, 1: 2.25, 1: 2.5, 1: 2.75, 1: 3, 1: 3.25, 1: 3.27, 1: 3.5, 1: 3.75, 1: 3.93, 1: 4, 1 : 4.25, 1: 4.5, 1: 4.75, 1: 4.88, 1: 4.91, 1: 5, 1: 5.25, 1: 5.5, 1: 5.75, 1: 5.89, 1: 6, 1: 6.25, 1: 6.5 , 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1:9.5, 1 : 9.75, 1:10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- erythro-hydroxybupropion or its salt is calculated as erythro-hydroxybupropion
- the mass ratio of the two is 1:1, 1:1.25 , 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.27, 1:3.5, 1:3.75, 1:3.93, 1 : 4, 1: 4.25, 1: 4.5, 1: 4.75, 1: 4.88, 1: 4.91, 1: 5, 1: 5.25, 1: 5.5, 1: 5.75, 1: 5.89, 1: 6, 1: 6.25 , 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1 : 9.5, 1: 9.75, 1: 10;
- deuterated dextromethorphan or its salt is calculated as deuterated dextromethorphan
- threo-hydroxybupropion or its salt is calculated as threo-hydroxybupropion
- the mass ratio of the two is 1:1, 1:1.25 , 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.27, 1:3.5, 1:3.75, 1:3.93, 1 : 4, 1: 4.25, 1: 4.5, 1: 4.75, 1: 4.88, 1: 4.91, 1: 5, 1: 5.25, 1: 5.5, 1: 5.75, 1: 5.89, 1: 6, 1: 6.25 , 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1 : 9.5, 1: 9.75, 1: 10.
- the mass ratio of the salt of the aforementioned deuterated dextromethorphan and the salt of bupropion is 10-18:50, and the preferred specific mass ratio is 10:50, 12:50, 15:50, 18:50.
- the pharmaceutical composition contains 10 mg to 500 mg, 20 mg to 200 mg, 25 mg to 100 mg, and 30 mg to 80 mg of deuterated dextromethorphan; and the mass ratio is 1:1, 1:1.25 , 1:1.5, 1:1.75, 1:2, 1:2.25, 1:2.5, 1:2.75, 1:3, 1:3.25, 1:3.27, 1:3.5, 1:3.75, 1:3.93, 1 : 4, 1: 4.25, 1: 4.5, 1: 4.75, 1: 4.88, 1: 4.91, 1: 5, 1: 5.25, 1: 5.5, 1: 5.75, 1: 5.89, 1: 6, 1: 6.25 , 1:6.5, 1:6.75, 1:7, 1:7.25, 1:7.5, 1:7.75, 1:8, 1:8.25, 1:8.5, 1:8.75, 1:9, 1:9.25, 1 : 9.5, 1:9.75, 1:10 respectively with bupropion, S-bupropion, R-bupropion, hydroxybupro
- the pharmaceutical composition contains 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80 mg of deuterated dextromethorphan; and according to the mass ratio of 1: 1, 1: 1.25, 1: 1.5, 1: 1.75, 1: 2, 1: 2.25, 1: 2.5, 1 : 2.75, 1:3, 1:3.25, 1:3.27, 1:3.5, 1:3.75, 1:3.93, 1:4, 1:4.25, 1:4.5, 1:4.75, 1:4.88, 1:4.91 , 1:5, 1:5.25, 1:5.5, 1:5.75, 1:5.89, 1:6, 1:6.25, 1
- the pharmaceutical composition contains 10 mg to 500 mg, 20 mg to 200 mg, 25 mg to 100 mg, 30 mg to 80 mg of a salt of deuterated dextromethorphan.
- the pharmaceutical composition contains 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 , 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74 , 75, 76, 77, 78, 79, 80 mg of deuterated dextromethorphan salts.
- the pharmaceutical composition contains 10 mg to 500 mg, 50 mg to 300 mg, 100 mg to 200 mg of a salt of bupropion.
- the pharmaceutical composition contains 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 , 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145 , 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170 , 171, 172, 173, 174
- the salt of deuterated dextromethorphan is preferably and the salt of bupropion is preferably
- Threohydroxybupropion 92264-82-9
- the active compounds in the pharmaceutical compositions of the present invention also include any salts, solvates or hydrates thereof.
- Salts of compounds of the present invention are formed from acids with basic groups of the compounds (such as amino functional groups) or from bases with acidic groups of the compounds (such as carboxyl functional groups).
- the compound is a pharmaceutically acceptable acid addition salt.
- Various pharmaceutically acceptable salts are usually selected.
- pharmaceutically acceptable means that a component is suitable, within the scope of sound medical judgment, for use in contact with human and other mammalian tissues without undue toxicity, irritation, allergic reaction, etc., and is compatible with reasonable The benefit/risk ratio is commensurate.
- Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogenbisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, Tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid acid, lactic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid; and related inorganic and organic acids.
- inorganic acids such as hydrogenbisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric
- the pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate , metaphosphate, pyrophosphate, hydrochloride, bromate, iodate, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyric acid Salt, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate , butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxyl Benzoate, Methoxybenzoate, Phthalate, Terephthalate, Sulfonate, Xylene Sulfonate, Phenyl Acetate, Phenyl
- pharmaceutically acceptable acid addition salts include salts formed with inorganic acids such as bupropion hydrochloride and dextromethorphan hydrobromide.
- hydrate as used in the present invention is meant to further include stoichiometric or non-stoichiometric amounts of water bound by non-covalent intermolecular forces.
- solvate as used herein is meant to further include stoichiometric or non-stoichiometric amounts of solvents (such as water, acetone, ethanol, methanol, dichloromethane, 2-propane) bound by non-covalent intermolecular forces alcohol, etc.) compounds.
- solvents such as water, acetone, ethanol, methanol, dichloromethane, 2-propane
- D refers to deuterium
- compositions of the present invention include pharmaceutical compositions suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
- the methods of preparation include the step of bringing into association the molecule to be administered with ingredients such as carriers that constitute one or more accessory ingredients.
- ingredients such as carriers that constitute one or more accessory ingredients.
- the compositions are prepared by uniformly intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers, or both, followed by shaping the product, if necessary.
- compositions of the present invention suitable for oral administration may be provided in the following forms: individual units (such as capsules, cachets or tablets) each containing a predetermined amount of the active ingredient; powders or granules; solutions in aqueous or non-aqueous liquids or suspension; oil-in-water liquid emulsion; water-in-oil liquid emulsion; filled in liposomes; or bolus and the like.
- Soft gelatin capsules are suitable for containing the suspension, which advantageously increases the rate of absorption of the compound.
- common carriers include lactose and corn starch.
- Lubricants such as magnesium stearate are also often added.
- suitable diluents include lactose and dried cornstarch.
- compositions suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, bacteriostatic agents, and solutes that render the formulation isotonic with the blood of the intended recipient; and may include suspensions Aqueous and non-aqueous sterile suspensions of agents and thickening agents.
- the formulations can be presented in unit-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) state simply before use with the addition of a sterile liquid carrier, such as water for injection.
- a sterile liquid carrier such as water for injection.
- Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
- the injectable solutions may take the form of, for example, sterile injectable aqueous or oily suspensions.
- compositions of the present invention may be administered by nasal aerosol or inhalation.
- the present invention further provides a pharmaceutical use of the aforementioned pharmaceutical composition for preventing and/or treating neurological disorders.
- Such neurological disorders include, but are not limited to, depression, major depression, treatment-resistant depression, and treatment-resistant bipolar depression.
- depression includes bipolar disorder of cyclothymia, seasonal affective disorder, mania, anxiety, attention deficit disorder (ADD), attention deficit disorder with hyperactivity (ADDH), attention deficit disorder Deficit/Hyperactivity Disorder (AD/HD), bipolar and manic disorders, obsessive-compulsive disorder, bulimia, obesity or weight gain, narcolepsy, chronic fatigue syndrome, premenstrual syndrome, substance addiction or Abuse, nicotine addiction, psychosexual dysfunction, pseudobulbar mood, and mood lability.
- ADD attention deficit disorder
- ADH attention deficit disorder with hyperactivity
- AD/HD attention deficit disorder Deficit/Hyperactivity Disorder
- the pharmaceutical composition of the present invention has more excellent metabolic effect with respect to the prior art, and ensures the suitable drug concentration and effect of medication;
- the specific ratio of the pharmaceutical composition of the present invention has excellent synergistic effect, preferably the mass ratio of deuterated dextromethorphan and bupropion is 1:1-10; more preferably deuterated dextromethorphan and bupropion
- the mass ratio of ketones is 1:1-8; the mass ratio of deuterated dextromethorphan to bupropion is particularly preferably 1:1-6.
- the pharmaceutical composition of the present invention can be widely used in cough and various neurological symptom diseases, and has a broad-spectrum application effect.
- the raw materials used in the embodiment of the present invention are dextromethorphan hydrobromide, deuterated dextromethorphan, and bupropion hydrochloride, and the quality of each substance used in the experiment is calculated by free concentration, that is, dextromethorphan hydrobromide is dextromethorphan hydrobromide.
- bupropion hydrochloride is calculated in terms of bupropion.
- deuterated dextromethorphan and bupropion are respectively as follows:
- the raw material adopted by deuterated dextromethorphan in the embodiment is deuterated dextromethorphan hydrobromide monohydrate
- the raw material adopted by bupropion is bupropion hydrochloride, deuterated dextromethorphan
- the structures of hydrobromide monohydrate and bupropion hydrochloride are as follows:
- the molecular weight of deuterated dextromethorphan hydrobromide monohydrate is 376.37, the molecular weight of deuterated dextromethorphan is 277.44; the molecular weight of bupropion hydrochloride is 276.20, and the molecular weight of bupropion is 276.20. 239.74 meter.
- Buffer A Weigh 680.5 mg of potassium dihydrogen phosphate and 20.23 mg of EDTA into a blue cap bottle, add 50 mL of purified water to prepare 0.1 M potassium dihydrogen phosphate buffer (13.61 mg/mL, containing 1.0 mM EDTA, 0.4 mg/mL) mL).
- Buffer B Weigh 4564.4 mg of dipotassium hydrogen phosphate trihydrate and 80.9 mg of EDTA into a blue-cap bottle, add 200 mL of purified water to prepare 0.1 M dipotassium hydrogen phosphate buffer (17.42 mg/mL, containing 1.0 mM EDTA, 0.4 mg/mL).
- Buffer C Buffer B was added to Buffer A, and the pH was adjusted to 7.4 with a pH meter to obtain 0.1M potassium phosphate buffer (containing 1.0mM EDTA, pH 7.4).
- Working solution Take 60 ⁇ L of mixed stock solution 1 obtained in step 1 and dilute with 140 ⁇ L potassium phosphate buffer to obtain working solution (30 ⁇ M).
- stop solution 150 ⁇ L/well
- purified water 100 ⁇ L purified water (including T0)
- the analyte (dextromethorphan or deuterated dextromethorphan)/internal standard peak area ratio was converted to percentage remaining (% remaining) with the following formula:
- the half-life of deuterated dextromethorphan and bupropion in the mass ratio of 1:1-1:14 is significantly longer than that of deuterated dextromethorphan alone (the ratio of 1:0), which is well reflected in this ratio. synergistic effect with bupropion.
- the half-life of deuterated dextromethorphan and bupropion at a ratio of 1:0.5 is comparable to that of deuterated dextromethorphan (1:0 ratio), which fails to reflect the effect of bupropion. synergistic effect.
- the combination of 1:1-1:4 dextromethorphan and bupropion has the same effect in each ratio.
- the combined half-life of deuterated dextromethorphan and bupropion in the same ratio is significantly higher than that of dextromethorphan and bupropion.
- mice Thirty-five male C57BL/6 mice, weighing 20-22 g, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
- deuterated dextromethorphan/bupropion group (12mg/kg+24mg/kg), deuterated dextromethorphan/bupropion group (12mg/kg+48mg/kg), Deuterated dextromethorphan/bupropion group (12mg/kg+72mg/kg), deuterated dextromethorphan/bupropion group (12mg/kg+96mg/kg), deuterated dextromethorphan/amphetamine ketone group (12mg/kg+120mg/kg), deuterated dextromethorphan/bupropion group (12mg/kg+144mg/kg), deuterated dextromethorphan/bupropion group (12mg/kg+ 168 mg/kg).
- deuterated dextromethorphan/bupropion (1.2mg/ml+2.4mg/ml), deuterated dextromethorphan/bupropion Ketone (1.2mg/ml+4.8mg/ml), Dextromethorphan/Bupropion (1.2mg/ml+7.2mg/ml), Dextromethorphan/Bupropion (1.2mg/ml) +9.6mg/ml), Dextromethorphan/Bupropion (1.2mg/ml+12mg/ml), Dextromethorphan/Bupropion (1.2mg/ml+14.4mg/ml), Deuterated Dextromethorphan/Bupropion (1.2mg/ml+16.8mg/ml).
- mice Male C57BL/6 mice were randomly divided into 7 groups according to their body weight, with 5 mice in each group, namely the deuterated dextromethorphan/bupropion group (12mg/kg+24mg/kg, 1:2), the deuterated dextromethorphan/bupropion group (1:2), the deuterated dextromethorphan and bupropion group.
- dextromethorphan/bupropion (12 mg/kg + 144 mg/kg) group had a stiff tail, motor rigidity, tremors, and convulsions
- dextromethorphan/bupropion (12 mg/kg) /kg+168mg/kg) group had 4 animals' toxicity manifestations of posterior rigidity, irregular movement rigidity, tremor and convulsion.
- mice When the deuterated dextromethorphan/bupropion dose was equal to or greater than 12 mg/kg + 144 mg/kg, the mice showed significant neurotoxicity. Therefore, the tolerable dose ratio in mice was less than or equal to 1: 10.
- dextromethorphan hydrobromide or deuterated dextromethorphan the structure is shown in formula I
- bupropion hydrochloride add in normal saline and vortex to dissolve, respectively, to make dextromethorphan (free concentration) or deuterated dextromethorphan.
- Methorphan was at 4 mg/mL and bupropion (free) at 24 and 32 mg/mL.
- dextromethorphan or deuterated dextromethorphan Take an equal volume of dextromethorphan or deuterated dextromethorphan and mix them with 24 and 32 mg/mL bupropion solution respectively to obtain a deuterated dextromethorphan + amphetamine with a drug concentration of 2+12 mg/mL dextromethorphan
- the deuterated dextromethorphan solution or the 24 mg/mL bupropion solution was diluted 2 times with normal saline, respectively, so that the concentration of the deuterated dextromethorphan solution was 2 mg/mL.
- mice of 20-22 g were randomly divided into 3 groups, namely dextromethorphan + bupropion (20 + 120 mg/kg, drug concentration 2 + 12 mg/mL), deuterated dextromethorphan Methorphan + bupropion (20+120mg/kg, drug concentration of 2+12mg/mL) and deuterated dextromethorphan (20mg/kg, drug concentration of 2mg/mL), administered by intragastric administration at 10mL/kg respectively the above drugs.
- Mice in each group are numbered 1-9, 3 mice at each time point, and blood was collected 2-3 times for each mouse.
- mice 1-3 were 0.25, 1.5, and 7h, and the time points for blood collection were 0.25, 1.5, and 7 h.
- the blood collection time points of mice were 0.5, 2 and 24 h, and the blood collection time points of mice No. 7-9 were 1 and 5 h.
- 100 ⁇ L of whole blood was collected from the retro-orbital venous plexus in heparinized EP tubes, and centrifuged at 10,000 rpm for 2 min to separate plasma. Dextromethorphan or deuterated dextromethorphan concentration was detected by LC-MS.
- WinNonlin calculates the pharmacokinetic parameters of dextromethorphan or deuterated dextromethorphan.
- the exposure of the deuterated dextromethorphan single-agent group was 387h*ng/ml, and the Cmax was 269ng/mL.
- the deuterated dextromethorphan and bupropion were administered in combination (the ratio was 1:6) the deuterated dextromethorphan The exposure was 940h*ng/ml, and the Cmax was 438ng/mL. Compared with the single drug group, the exposure and Cmax were significantly increased.
- the combination of deuterated dextromethorphan and bupropion showed a good synergistic effect.
- mice Thirty male C57BL/6 mice, weighing 20-22 g, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
- the design groups are blank vehicle group, dextromethorphan (free concentration)/bupropion (free concentration) group (12mg/kg+30mg/kg), deuterated dextromethorphan/an Fetadone (free concentration) group (12mg/kg+30mg/kg)
- mice Male C57BL/6 mice were randomly divided into 3 groups according to the initial screening cough times, 10 mice in each group, namely blank vehicle group, dextromethorphan/bupropion group and deuterated dextromethorphan/bupropion group , the mice in each group were given one time according to the corresponding test article, and the dosage volume was 10ml/kg. After 30min of administration, the mice were put into an inverted 600ml beaker filled with saturated steam of concentrated ammonia water, and the time was immediately for 10s, and then the mice were taken out. The mice were put into another inverted 600ml beaker to start timing, the coughs of the mice were observed, and the total number of coughs within 5min was recorded.
- mice 88 male C57BL/6J mice, weighing 20-22 g, were purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
- mice Male C57BL/6J mice were randomly divided into 8 groups with 11 mice in each group, namely blank vehicle group, deuterated dextromethorphan (free concentration) 3, 12 mg/kg group, bupropion (free concentration) 30 mg/kg kg group, deuterated dextromethorphan/bupropion group (3/30, 4/30, 5/30, 6/30, 7.5/30, 9/30 mg/kg).
- the test product was administered once, and the administration volume was 10ml/kg.
- the mice were put into an inverted 600ml beaker filled with concentrated ammonia saturated steam, and the time was immediately for 10s, and then the mice were taken out and placed in another inverted 600ml beaker. Start timing in the beaker, observe the mice cough, and record the total number of coughs within 5 min.
- deuterated dextromethorphan/bupropion after 60 minutes of administration, compared with deuterated dextromethorphan and bupropion alone, deuterated dextromethorphan/bupropion at doses of 3+30mg/kg to 12+30mg/kg within the range, the antitussive effect on mice was significantly enhanced, reflecting the synergistic effect, and deuterated dextromethorphan/bupropion was significantly better than dextromethorphan/bupropion.
- Buffer A Weigh about 680.5 mg of potassium dihydrogen phosphate and 20.23 mg of EDTA into a glass bottle, add a certain volume of purified water to prepare 0.1 M potassium dihydrogen phosphate buffer (13.61 mg/mL, containing 1.0 mM EDTA, 0.4 mg/mL).
- Buffer B Weigh about 4564.4 mg of dipotassium hydrogen phosphate trihydrate and 80.9 mg of EDTA into a glass bottle, add a certain volume of purified water to prepare 0.1 M dipotassium hydrogen phosphate buffer (17.42 mg/mL, containing 1.0 mM EDTA, 0.4 mg/mL).
- Buffer C Buffer B was added to Buffer A, and the pH was adjusted to 7.4 with a pH meter to obtain 0.1M potassium phosphate buffer (containing 1.0mM EDTA, pH 7.4).
- 1Stock solution 1 Accurately weigh deuterated dextromethorphan (d3), deuterated dextromethorphan (d6), and appropriate amount of bupropion hydrochloride powder, add DMSO to dissolve, and then press deuterated dextromethorphan: bupropion The mass ratios are 1:10, 1:6, 1:4, 1:3.3, 1:3 and 1:0 to prepare different ratios of deuterated dextromethorphan (d3) + bupropion, deuterated dextromethorphan (d6) + Bupropion mixed stock solution. Take 5 ⁇ L of the mixed stock solution and dilute with 495 ⁇ L of 50% ACN/H 2 O to obtain stock solution 1.
- Working solution Take 60 ⁇ L of the stock solution 1 obtained in step 1 and dilute it with 140 ⁇ L potassium phosphate buffer to obtain the working solution.
- stop solution 150 ⁇ L/well
- purified water 100 ⁇ L purified water (including T0)
- deuterated dextromethorphan (d3) and deuterated dextromethorphan (d6) are as follows:
- mice were randomized according to body weight the day before dosing.
- deuterated dextromethorphan hydrobromide monohydrate referred to as "deDM”
- deuterated dextromethorphan hydrobromide monohydrate Abbreviated as “deDM”
- Bup deuterated dextromethorphan hydrobromide monohydrate
- the administration volume is 10 mL/kg
- the specific administration dosage is shown in the dosage recorded in Table 7.3.
- the time to start dosing was defined as 0 min.
- the 2 cm tail end of the mouse was attached to a horizontal metal rod, so that the animal was in a suspended state, and the immobility time of the mouse within 6 min was observed and recorded, and the immobility time of the last 4 min was recorded by a timer, which was used for data analysis. .
- deDM+Bup combination group (calculated as 1:3-1:6 according to deuterated dextromethorphan:bupropion) can significantly reduce the immobility time in the tail suspension.
- deDM, and Bup have a synergistic effect.
- Reagents sodium chloride injection, EDTA-K2, acetonitrile, and formic acid are all commercially available.
- deuterated dextromethorphan hydrobromide monohydrate dextromethorphan hydrobromide monohydrate (DM), bupropion hydrochloride (BUP);
- the test sample Accurately weigh the test sample into a suitable container, add the target volume of sodium chloride injection, and configure it into 2.8+11.6 mg/mL for the deuterated dextromethorphan hydrobromide monohydrate + bupropion hydrochloride group, respectively.
- the dextromethorphan hydrobromide monohydrate + bupropion hydrochloride group was 2.8+11.6 mg/mL
- the deuterated dextromethorphan hydrobromide monohydrate group was 2.8 mg/mL administration solution.
- Deuterated dextromethorphan and dextromethorphan in beagle dog plasma were determined using a validated bioanalytical method.
- the standard curve concentrations of deuterated dextromethorphan in plasma were 2, 4, 20, 80, 400, 600, 1000 and 2000 ng/mL, and the QC concentrations were 6, 100, 800 and 1600 ng/mL.
- the standard curve concentrations of dextromethorphan in plasma were 1, 2, 10, 50, 200, 400, 600 and 1000 ng/mL, and the QC concentrations were 3, 30, 500 and 800 ng/mL.
- No. 0 capsules were filled with deuterated dextromethorphan and bupropion hydrochloride (calculated as bupropion) according to the following mass ratio, and the total amount of deuterated dextromethorphan and bupropion in each unit capsule was 100 mg.
- Embodiment 10 The preparation method of deuterated dextromethorphan hydrobromide monohydrate
- YMSF-D6 was obtained according to the prior art.
- Embodiment 11 The preparation method of deuterated dextromethorphan hydrobromide
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Abstract
提供了药物组合应用技术领域,具体涉及一种药物组合物及其应用。
Description
本发明提供了药物组合应用技术领域,具体涉及一种药物组合物及其应用。
右美沙芬(CAS:125-71-3),英文名为:Dextromethorphan,其化学名称为(+)-3-甲氧基-17-甲基-(9α,13α,14α)-吗啡烷,临床上多以其氢溴酸盐(CAS:125-69-9)作为药物使用,其氘代化合物可以通过现有技术CN101687868A等获得,例如一种氘代右美沙芬的化学结构如下:
安非他酮(CAS:34911-55-2),英文名为:Bupropion,其化学名称为1-(3-氯苯基)-2-[(1,1-二甲基乙基)氨基]-1-丙酮,临床上多以其盐酸盐(CAS:31677-93-7)作为药物使用,安非他酮化学结构如下:
CN106163522A公开了一种包含安非他酮或相关化合物和右美沙芬的组合物和方法,用于抗抑郁等神经病症,目前相关药物处于临床阶段。该领域还有广泛的未被解决的临床需求。
发明内容
鉴于现有技术的临床需求,本发明的首要目的是提供了一种药物组合物,所述药物组合物含有氘代右美沙芬或其盐,和安非他酮类药物或其盐。
本发明所述安非他酮类药物选自安非他酮、S-安非他酮、R-安非他酮、羟基安非他酮、赤式羟基安非他酮、苏式羟基安非他酮中的一种或者两种以上的组合。
本发明所述药物组合物中,氘代右美沙芬或其盐和安非他酮类药物或其盐可以以任意比例进行组合使用,特别是质量比为1-10:1-10,包括但不限于:1:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1、2:1、3:1、4:1、5:1、6:1、7:1、8:1、9:1、10:1。
作为本发明的一种优选技术方案,所述药物组合物选自:氘代右美沙芬或其盐与安非他酮或其盐的组合、氘代右美沙芬或其盐与S-安非他酮或其盐的组合、氘代右美沙芬或其盐与R-安非他酮或其盐的组合、氘代右美沙芬或其盐与羟基安非他酮或其盐的组合、氘代右美沙芬或其盐与赤式羟基安非他酮或其盐的组合、氘代右美沙芬或其盐与苏式羟基安非他酮或其盐的组合。
作为本发明的一种优选技术方案,所述药物组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1-10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1-10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1-10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1-10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1-10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏式羟基安非他酮计,二者的质量比为1:1-10。
作为本发明的一种优选技术方案,所述药物组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1-8;
或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1-8;
或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1-8;
或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1-8;
或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1-8;
或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏式羟基安非他酮计,二者的质量比为1:1-8。
作为本发明的一种优选技术方案,所述药物组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1-6;
或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1-6;
或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1-6;
或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1-6;
或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1-6;
或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏式羟基安非他酮计,二者的质量比为1:1-6。
作为本发明的一种优选技术方案,所述药物组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.5、1:3.75、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10。
或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1: 2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;
或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏式羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10。
作为本发明的一种优选技术方案,前述氘代右美沙芬的盐和安非他酮的盐二 者的质量比为10-18:50,优选具体质量比为10:50、12:50、15:50、18:50。
在本发明的一种实施方案中,所述药物组合物含有10mg至500mg、20mg至200mg、25mg至100mg、30mg至80mg的氘代右美沙芬;并按照质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10分别与安非他酮、S-安非他酮、R-安非他酮、羟基安非他酮、赤式羟基安非他酮、苏式羟基安非他酮中的一种组合。
例如:所述药物组合物含有30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80mg的氘代右美沙芬;并按照质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10分别与安非他酮、S-安非他酮、R-安非他酮、羟基安非他酮、赤式羟基安非他酮、苏式羟基安非他酮中的一种组合。
在本发明的一种实施方案中,所述药物组合物含有10mg至500mg、20mg至200mg、25mg至100mg、30mg至80mg的氘代右美沙芬的盐。具体地,例如:所述药物组合物含有30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59、60、61、62、63、64、65、66、67、68、69、70、71、72、73、74、75、76、77、78、79、80mg的氘代右美沙芬的盐。
在本发明的一种实施方案中,所述药物组合物含有10mg至500mg、50mg至300mg、100mg至200mg的安非他酮的盐。具体地,例如:所述药物组合物含有100、101、102、103、104、105、106、107、108、109、110、111、112、113、114、115、116、117、118、119、120、121、122、123、124、125、126、 127、128、129、130、132、133、134、135、136、137、138、139、140、141、142、143、144、145、146、147、148、149、150、151、152、153、154、155、156、157、158、159、160、161、162、163、164、165、166、167、168、169、170、171、172、173、174、175、176、177、178、179、180mg、181、182、183、18、185、186、187、188、189、190、191、192、193、194、195、196、197、198、199、200的安非他酮的盐。
部分所述化合物的结构、英文名,CAS号如下:
如本发明药物组合物中活性化合物还包括其任何盐、溶剂化物或水合物。
本发明化合物的盐是由酸与所述化合物的碱性基团(诸如氨基官能团)或由碱与所述化合物的酸性基团(诸如羧基官能团)形成。根据另一个实施例,所述化合物是药学上可接受的酸加成盐。通常选择各种药学上可接受的盐。
如本发明所用的术语“药学上可接受”是指组分在合理医学判断的范围内适合用于与人类和其它哺乳动物的组织接触而无过度毒性、刺激、过敏反应等,且与合理的益处/风险比相称。
常用于形成药学上可接受的盐的酸包括无机酸,诸如氢硫酸(hydrogenbisulfide)、盐酸、氢溴酸、氢碘酸、硫酸和磷酸;以及有机酸,诸如对甲苯磺酸、水杨酸、酒石酸、重酒石酸(bitartaricacid)、抗坏血酸、马来酸、苯磺酸(besylicacid)、富马酸、葡萄糖酸、葡糖醛酸、甲酸、谷氨酸、甲烷磺酸、乙烷磺酸、苯磺酸、乳酸、草酸、对溴苯基磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸和乙酸;以及相关的无机酸和有机酸。
因此,所述医药学上可接受的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐(monohydrogenphosphate)、磷酸二氢盐(dihydrogenphosphate)、偏磷酸盐、焦磷酸盐、盐酸盐、溴酸盐、碘酸盐、乙酸盐、丙酸盐、癸酸盐(decanoate)、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐(caprate)、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、羟乙酸盐、马来酸盐、酒石酸盐、甲烷磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃 酸盐和其它盐。
在一个实施例中,药学上可接受的酸加成盐包括与诸如盐酸安非他酮和氢溴酸氘代右美沙芬等无机酸形成的盐。
如本发明所用的术语“水合物”意指更包括化学计算量或非化学计算量的通过非共价分子间力结合的水的化合物。
如本发明所用的术语“溶剂化物”意指更包括化学计算量或非化学计算量的通过非共价分子间力结合的溶剂(诸如水、丙酮、乙醇、甲醇、二氯甲烷、2-丙醇等)的化合物。
“D”是指氘。
本发明的药物组合物包括适合经口、直肠、经鼻、局部(包括经颊和舌下)、阴道或非经肠(包括皮下、肌肉内、静脉内和皮内)投药的药物组合物。
所述制备方法包括使待投与的分子与诸如载剂等构成一种或一种以上辅助成分的成分结合的步骤。一般来说,通过使活性成分与液体载剂、脂质体或细粉状固体载剂或两者均匀地密切结合,接着必要时使产物成形来制备所述组合物。
在某些实施例中,经口投与所述化合物。适合经口投药的本发明组合物可以如下形式提供:各含预定量的活性成分的独立单元(诸如胶囊、扁囊剂或片剂);粉剂或颗粒剂;水性液体或非水性液体中的溶液或悬浮液;水包油型液体乳液;油包水型液体乳液;填充于脂质体中;或大丸剂(bolus)等。软明胶胶囊可适用于含有所述悬浮液,这可有利地增加化合物的吸收速率。
在口服片剂的情况下,常用载剂包括乳糖和玉米淀粉。通常还加入诸如硬脂酸镁等润滑剂。对于以胶囊形式经口投药,适用的稀释剂包括乳糖和干燥玉米淀粉。当经口投与水性悬浮液时,使活性成分与乳化剂和悬浮剂组合。必要时,可加入某些甜味剂和/或调味剂和/或着色剂。
适合非经肠投药的组合物包括可含有抗氧化剂、缓冲剂、抑菌剂和使调配物变得与预定接受者的血液等渗的溶质的水性和非水性无菌注射溶液;和可包括悬浮剂和增稠剂的水性和非水性无菌悬浮液。调配物可在例如密封安瓿和小瓶等单位剂量或多剂量容器中提供,且可以仅需在使用前即刻加入例如注射用水等无菌液体载剂的冷冻干燥(冻干)状态贮存。临时注射溶液和悬浮液可由无菌粉剂、颗粒剂和片剂制备。
所述注射溶液可呈例如无菌可注射水性或油性悬浮液的形式。
另外,本发明的药物组合物可用鼻气雾剂或吸入剂投与。
本发明进一步提供了前述一种药物组合物在制备预防和/或治疗神经类病症的药物用途。
所述神经类病症包括但不限于,抑郁、重度抑郁、难治性抑郁和难治性双相型抑郁。
更为具体的所述抑郁包括循环性情感精神病的双相型病症、季节性情感障碍、躁狂、焦虑症、注意力缺失症(ADD)、注意力缺陷障碍伴多动(ADDH)、注意力缺陷/多动障碍(AD/HD)、双相和狂躁病症、强迫性神经失调、贪食症、肥胖或重量增加、发作性睡病、慢性疲劳综合征、经前期综合征、物质成瘾或滥用、尼古丁成瘾、心理性性功能障碍、假性延髓情绪以及情绪不稳。
本发明相对于现有技术的有益效果包括:
(1)本发明的药物组合物相对于现有技术有更为优异的代谢效果,保证用药适宜的药物浓度和效果;
(2)本发明的药物组合物的特定比例具有优异的协同增效效果,优选氘代右美沙芬与安非他酮质量比1:1-10;进一步优选氘代右美沙芬与安非他酮质量比1:1-8;特别优选氘代右美沙芬与安非他酮质量比1:1-6。
(3)本发明的药物组合物的特定比例的效果优于非氘代右美沙芬和安非他酮组合的效果。
(4)本发明的药物组合物可以广泛应用咳嗽及各种神经类症状疾病,具有广谱的应用的效果。
下面结合实施例对本发明作进一步详细的描述,但发明的实施方式不限于此。
本发明实施例采用原料为氢溴酸右美沙芬、氘代右美沙芬、盐酸安非他酮,而各物质用于实验的质量均以游离浓度计算,即氢溴酸右美沙芬以右美沙芬计,盐酸安非他酮以安非他酮计。
本发明实施例除另有说明外,氘代右美沙芬和安非他酮结构式分别如下:
其中,氘代右美沙芬氢溴酸盐一水合物的分子量以376.37计,氘代右美沙芬的的分子量以277.44计;盐酸安非他酮的分子量以276.20计,安非他酮的分子量以239.74计。
实施例1肝微粒体稳定性实验
1.1实验步骤:
1. 0.1M磷酸钾缓冲液(pH7.4)的配制
Buffer A:称取680.5mg磷酸二氢钾和20.23mg EDTA于蓝盖瓶中,加入50mL纯化水,制得0.1M磷酸二氢钾缓冲液(13.61mg/mL,含1.0mM EDTA,0.4mg/mL)。
Buffer B:称取4564.4mg磷酸氢二钾三水合物和80.9mg EDTA于蓝盖瓶中,加入200mL纯化水,制得0.1M磷酸氢二钾缓冲液(17.42mg/mL,含1.0mM EDTA,0.4mg/mL)。
Buffer C:将Buffer B加入到Buffer A中,用pH计调pH为7.4,得到0.1M磷酸钾缓冲液(含1.0mM EDTA,pH 7.4)。
2.工作溶液的配制
①储备液1:精密称取氢溴酸右美沙芬、氘代右美沙芬氢溴酸盐一水合物、盐酸安非他酮粉末适量,加入甲醇/水(v/v=1:1)溶解,使右美沙芬的浓度为6.0mg/mL(游离浓度)、氘代右美沙芬的浓度为6.0mg/mL、安非他酮的浓度为84.0mg/mL(游离浓度)。按下表所述方法,将84.0mg/mL安非他酮溶液以甲醇/水(v/v=1:1)稀释,取等体积的稀释后安非他酮溶液和右美沙芬溶液,安非他酮溶液和氘代右美沙芬溶液混合,使成不同比例的右美沙芬/氘代右美沙芬+安非他酮混合储备液1。
右美沙芬/氘代右美沙芬+安非他酮混合储备液的配制
②工作溶液:取60μL步骤①所得混合储备液1,用140μL磷酸钾缓冲液稀释,得工作溶液(30μM)。
3.准备96孔板,标记T0,T20,T60孔。
4.将18.8μL(20mg蛋白/mL)肝微粒体加入到456.2μL缓冲液中,然后加入25μL步骤②所得右美沙芬/氘代右美沙芬+安非他酮或阳性对照工作溶液,用移液枪混合均匀。
5.取上述混合液,分装到标记为T0、T20、T60的相应孔中,平行两个复孔,每孔30μL。立即在T0孔中加入50ng/mL普萘洛尔(内标IS)乙腈终止溶液(150μL/孔),然后加入15μL NADPH溶液(5mg/mL),混合均匀。
6.到达设定的时间后,加入终止溶液(150μL/孔)以终止反应,混合均匀,然后在各个时间点的孔中加入100μL纯化水(包括T0),再次混合均匀。
7.将96孔板以4000rpm离心5分钟。
8.取200μL上清液转移到新的96孔板中,用于LC/MS/MS分析。
1.2数据分析:
将分析物(右美沙芬或氘代右美沙芬)/内标峰面积比转换为剩余百分比(剩余率%),公式如下:
剩余率%=各时间点的分析物与IS峰面积比/t=0时分析物与IS峰面积比×100
基于各个时间点剩余率计算斜率,并计算右美沙芬或氘代右美沙芬半衰期。
1.3实验结果:
1.4微粒体实验结论:
氘代右美沙芬与安非他酮在1:1-1:14质量配比时半衰期均明显长于氘代右美沙芬单药(配比1:0),在该配比时很好的体现了与安非他酮的协同作用。而氘代右美沙芬与安非他酮在1:0.5配比时和氘代右美沙芬单药(配比1:0)相比半衰期相当,未能体现安非他酮的作用,未见协同效果。而1:1-1:4右美沙芬与安非他酮的组合后各比例的效果相当,相同配比中氘代右美沙芬与安非他酮的组合半衰期均明显高于右美沙芬与安非他酮的组合。
实施例2小鼠耐受剂量摸索实验
2.1实验动物
雄性C57BL/6小鼠35只,体重20-22g,购于北京维通利华实验动物技术有限公司。
2.2实验药物:氘代右美沙芬、盐酸安非他酮
给药组别(剂量):氘代右美沙芬/安非他酮组(12mg/kg+24mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+48mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+72mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+96mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+120mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+144mg/kg)、氘代右美沙芬/安非他酮组(12mg/kg+168mg/kg)。
2.3制剂配制:
以游离碱计算,称取一定量药物溶于生理盐水中,分别配置成氘代右美沙芬 /安非他酮(1.2mg/ml+2.4mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+4.8mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+7.2mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+9.6mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+12mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+14.4mg/ml)、氘代右美沙芬/安非他酮(1.2mg/ml+16.8mg/ml)。
2.4实验方法:
雄性C57BL/6小鼠,按照体重随机分为7组,每组5只,分别为氘代右美沙芬/安非他酮组(12mg/kg+24mg/kg,1:2)、氘代右美沙芬/安非他酮组(12mg/kg+48mg/kg,1:4)、氘代右美沙芬/安非他酮组(12mg/kg+72mg/kg,1:6)、氘代右美沙芬/安非他酮组(12mg/kg+96mg/kg,1:8)、氘代右美沙芬/安非他酮组(12mg/kg+120mg/kg,1:10)、氘代右美沙芬/安非他酮组(12mg/kg+144mg/kg,1:12)、氘代右美沙芬/安非他酮组(12mg/kg+168mg/kg,1:14),各组小鼠按照对应的受试品给予1次,给药体积为10ml/kg,给药后,观察小鼠安全性。
2.5实验结果
氘代右美沙芬/安非他酮(12mg/kg+24mg/kg)、氘代右美沙芬/安非他酮(12mg/kg+48mg/kg)、氘代右美沙芬/安非他酮(12mg/kg+72mg/kg)、氘代右美沙芬/安非他酮(12mg/kg+96mg/kg)、氘代右美沙芬/安非他酮(12mg/kg+120mg/kg)组小鼠体征无明显改变。
然而,氘代右美沙芬/安非他酮(12mg/kg+144mg/kg)组有1只动物尾巴僵硬、运动僵硬、震颤、倒地抽搐,氘代右美沙芬/安非他酮(12mg/kg+168mg/kg)组有4只动物后置僵硬、运动不规律僵硬、震颤、抽搐的毒性表现。
2.6实验结论
当氘代右美沙芬/安非他酮剂量等于或大于12mg/kg+144mg/kg剂量时,小鼠表现为明显的神经毒性,因此,小鼠可耐受剂量比例范围为小于或者等于1:10。
实施例3C57BL/6小鼠单次口服右美沙芬或氘代右美沙芬+安非他酮药代动 力学研究
3.1给药溶液配制:
精密称取氢溴酸右美沙芬或氘代右美沙芬(结构如式Ⅰ所示)、盐酸安非他酮,分别加入生理盐水涡旋溶解,使右美沙芬(游离浓度)或氘代右美沙芬的浓度为4mg/mL,安非他酮(游离浓度)的浓度为24和32mg/mL。取等体积的右美沙芬或氘代右美沙芬分别与24和32mg/mL的安非他酮溶液混合,得到药物浓度为2+12mg/mL的右美沙芬的氘代右美沙芬+安非他酮溶液,将氘代右美沙芬或24mg/mL安非他酮溶液分别用生理盐水稀释2倍,使得氘代右美沙芬溶液的浓度为2mg/mL。
3.2 C57BL/6小鼠给药及采血:
取20-22g的雄性C57BL/6小鼠27只,随机分为3组,分别为右美沙芬+安非他酮(20+120mg/kg,药物浓度为2+12mg/mL)、氘代右美沙芬+安非他酮(20+120mg/kg,药物浓度为2+12mg/mL)和氘代右美沙芬(20mg/kg,药物浓度为2mg/mL),按10mL/kg分别灌胃给予上述药物。每组小鼠编号为1-9号,每个时间点3只小鼠,每只小鼠采血2-3次,1-3号小鼠采血时间点为0.25、1.5和7h,4-6号小鼠采血时间点为0.5、2和24h,7-9号小鼠采血时间点为1和5h,自眼眶后静脉丛采集全血100μL于肝素化EP管中后,10000rpm离心2min,分离血浆,LC-MS检测右美沙芬或氘代右美沙芬浓度。
3.3数据统计:
以同一时间点三只动物的血药浓度作平均值,WinNonlin计算右美沙芬或氘代右美沙芬药代动力学参数。
3.4实验结果:
3.5小鼠PK实验结论:
氘代右美沙芬单药组暴露量为387h*ng/ml,Cmax为269ng/mL,氘代右美沙芬与安非他酮联合给药时(配比为1:6)氘代右美沙芬暴露量为940h*ng/ml,Cmax为438ng/mL,与单药组相比暴露量和Cmax有明显提升,氘代右美沙芬安非他酮组合后体现出了很好的协同作用。在同样1:6配比下,氘代右美沙芬与安非他酮联合给药时暴露量和Cmax明显高于右美沙芬与安非他酮联合给药,体内小鼠PK实验体现了氘代右美沙芬与安非他酮的组合优于右美沙芬与安非他酮的组合。
实施例4小鼠镇咳实验方案
4.1试剂与仪器
氢氧化铵,ACS试剂,28.0-30.0%NH
3,艾览(上海)化工科技有限公司,批号CEC1070004。超声波雾化器WH-2000,广东粤华医疗器械厂有限公司。
4.2实验动物
雄性C57BL/6小鼠30只,体重20-22g,购于北京维通利华实验动物技术有限公司。
4.3实验药物:
氢溴酸右美沙芬、氘代右美沙芬、盐酸安非他酮
给药组别(剂量):设计组别为空白溶媒组、右美沙芬(游离浓度)/安非他酮(游离浓度)组(12mg/kg+30mg/kg)、氘代右美沙芬/安非他酮(游离浓度)组(12mg/kg+30mg/kg)
4.4制剂配制:
以游离碱计算,称取一定量药物溶于生理盐水中,分别配置成氘代右美沙芬/安非他酮(1.2mg/ml+3mg/ml)和右美沙芬/安非他酮(1.2mg/ml+3mg/ml)。
4.5实验方法:
雄性C57BL/6小鼠,按照初筛咳嗽次数随机分为3组,每组10只,分别为空白溶媒组、右美沙芬/安非他酮组和氘代右美沙芬/安非他酮组,各组小鼠按照对应的受试品给予1次,给药体积为10ml/kg,给药30min后,将小鼠放进倒置600ml充满浓氨水饱和蒸汽的烧杯中,立即计时10s,然后取出小鼠放入另一倒置的600ml烧杯中开始计时,观察小鼠咳嗽,并记录5min内咳嗽的总次数,给药60min后,重复上述操作,评价并记录小鼠在5min内的咳嗽总次数。
4.6统计方法:
所有实验数据用均数表示。采用Graphad Prism 5软件进行统计分析。组间比较采用单因素方差分析(one-way ANOVA)检验,方差齐的组间比较用LSD,方差不齐的组间比较用Dunnett's T3,P<0.05表示有统计学意义。
4.7实验结果:
注:**P<0.05vs空白溶媒组,
#P<0.05vs右美沙芬/安非他酮组
4.8实验结论
给药30min,60min后,氘代右美沙芬/安非他酮对小鼠的镇咳作用均优于 右美沙芬/安非他酮,并且在给药60min时,氘代右美沙芬/安非他酮显著性优于右美沙芬/安非他酮。
实施例5小鼠镇咳实验方案
5.1试剂与仪器
氢氧化铵,ACS试剂,28.0-30.0%NH
3,艾览(上海)化工科技有限公司,批号CEC1070004。超声波雾化器WH-2000,广东粤华医疗器械厂有限公司。
5.2实验动物
雄性C57BL/6J小鼠88只,体重20-22g,购于北京维通利华实验动物技术有限公司。
5.3实验药物:
氢溴酸氘代右美沙芬一水合物、盐酸安非他酮
给药组别(剂量):设计组别为空白溶媒组、氘代右美沙芬(游离浓度)3、12mg/kg组,安非他酮(游离浓度)30mg/kg组,氘代右美沙芬/安非他酮组(3/30、4/30、5/30、6/30、7.5/30、9/30mg/kg)。
5.4制剂配制:
以游离碱计算,称取一定量药物溶于生理盐水中,分别配置成氘代右美沙芬(游离浓度)0.3、1.2mg/ml组,安非他酮(游离浓度)3mg/ml组,氘代右美沙芬/安非他酮组(0.3/3、0.4/3、0.5/3、0.6/3、0.75/3、0.9/3mg/ml)。
5.5实验方法:
雄性C57BL/6J小鼠,随机分为8组,每组11只,分别为空白溶媒组、氘代右美沙芬(游离浓度)3、12mg/kg组,安非他酮(游离浓度)30mg/kg组,氘代右美沙芬/安非他酮组(3/30、4/30、5/30、6/30、7.5/30、9/30mg/kg),各组小鼠按照对应的受试品给予1次,给药体积为10ml/kg,给药60min后,将小鼠放进倒置600ml充满浓氨水饱和蒸汽的烧杯中,立即计时10s,然后取出小鼠 放入另一倒置的600ml烧杯中开始计时,观察小鼠咳嗽,并记录5min内咳嗽的总次数。
5.6统计方法:
所有实验数据用均数表示。采用Graphad Prism 5软件进行统计分析。组间比较采用单因素方差分析(one-way ANOVA)检验,方差齐的组间比较用SNK,方差不齐的组间比较用Dunnett's T3,P<0.05表示有统计学意义。
5.7实验结果:
注:*P<0.05vs空白溶媒组
5.8实验结论
结合实施例4和5,给药60min后,相比单用氘代右美沙芬、安非他酮,氘代右美沙芬/安非他酮在3+30mg/kg至12+30mg/kg剂量范围内,对小鼠的镇咳作用明显增强,体现协同增效的作用,并且氘代右美沙芬/安非他酮显著性优于右美沙芬/安非他酮。
实施例6肝微粒体稳定性实验
6.1、实验步骤
1. 0.1M磷酸钾缓冲液(pH7.4)的配制
Buffer A:称取约680.5mg磷酸二氢钾和20.23mg EDTA于玻璃瓶中,加入一定体积的纯化水,制得0.1M磷酸二氢钾缓冲液(13.61mg/mL,含1.0mM EDTA,0.4mg/mL)。
Buffer B:称取约4564.4mg磷酸氢二钾三水合物和80.9mg EDTA于玻璃瓶中,加入一定体积的纯化水,制得0.1M磷酸氢二钾缓冲液(17.42mg/mL,含1.0mM EDTA,0.4mg/mL)。
Buffer C:将Buffer B加入到Buffer A中,用pH计调pH为7.4,得到0.1M磷酸钾缓冲液(含1.0mM EDTA,pH 7.4)。
2.工作溶液的配制
①储备液1:精密称取氘代右美沙芬(d3)、氘代右美沙芬(d6)、盐酸安非他酮粉末适量,加入DMSO溶解,然后按氘代右美沙芬:安非他酮质量比为1:10、1:6、1:4、1:3.3、1:3和1:0配制成不同比例的氘代右美沙芬(d3)+安非他酮、氘代右美沙芬(d6)+安非他酮混合储备液。取5μL混合储备液,用495μL 50%ACN/H
2O稀释,得储备液1。
②工作溶液:取60μL步骤①所得储备液1,用140μL磷酸钾缓冲液稀释,得工作溶液。
3.准备96孔板,标记T0,T60孔。
4.将18.8μL(20mg蛋白/mL)肝微粒体加入到456.2μL缓冲液中,然后加入25μL步骤②所得工作溶液,用移液枪混合均匀。
5.取上述混合液,分装到标记为T0、T60的相应孔中,平行两个复孔,每孔30μL。立即在T0孔中加入50ng/mL普萘洛尔(内标IS)乙腈终止溶液(150μL/孔),然后加入15μL NADPH溶液(5mg/mL),混合均匀。
6.标记为T60孔的96孔板37℃预孵10min。将15μL NADPH溶液加入到T60孔,开始反应60min,最终反应系统包含约为0.5mg/mL的肝微粒体,2mM的NADPH。
7.到达设定的时间后,加入终止溶液(150μL/孔)以终止反应,混合均匀,然后在各个时间点的孔中加入100μL纯化水(包括T0),再次混合均匀。
8.将96孔板以4000rpm离心5分钟。
9.取200μL上清液转移到新的96孔板中,用于LC/MS/MS分析。
6.2、数据分析
将分析物/内标峰面积比转换为剩余百分比(剩余率%),公式如下:
剩余率%=各时间点的分析物与IS峰面积比/t=0时分析物与IS峰面积比×100
6.3、实验结果
在人肝微粒体中孵育60min后,氘代右美沙芬(d6)与安非他酮各个配比原型剩余量均高于氘代右美沙芬(d3)与安非他酮的组合。
注,氘代右美沙芬(d3)和氘代右美沙芬(d6)结构式如下:
实验7小鼠悬尾模型中的药效研究
7.1实验方法过程
7.1.1适应
110只雄性ICR小鼠测试前,在实验环境中适应3天,其中有10只动物做备用。
7.1.2动物分组
根据实验设计,在给药前一天根据小鼠的体重随机分组。
7.1.3给药
给药当天,称量动物体重,然后根据体重口服给予生理盐水对照、氘代右美沙芬氢溴酸盐一水合物(简称“deDM”)和氘代右美沙芬氢溴酸盐一水合物(简称“deDM”)/盐酸安非他酮(简称“Bup”)混合液,给药体积为10mL/kg,具体给药剂量见7.3表中记载的剂量。开始给药的时间定义为0min。
7.1.4悬尾测试
将小鼠尾端2cm贴在一根水平金属棍上,使动物成悬挂状态,观察和记录小鼠在6min内的不动时间,后4min的不动时间被计时器记录,被用于数据分析。
7.2数据收集和分析
使用Excel软件收集数据。使用Prism(Graphpad software,Inc.)软件进行数据分析,两组之间使用t-test方法进行差异分析,各组动物之间进行单因素方差分析附加Dunnett多重比较检验数据。p<0.05认为是有显著性差异。
7.3实验结果
注:与空白对照组相比,**P<0.01
从上述实验结果可见,deDM+Bup联合用药组(按氘代右美沙芬:安非他酮计为1:3-1:6)能显著减少悬尾中的不动时间,相对于不同剂量的deDM,以及Bup具有协同效果。
实施例8:犬药代动力学实验
8.1实验材料
试剂:氯化钠注射液,EDTA-K2,乙腈,甲酸均为市售可得。
仪器:AB SCIEX 5500三重四级杆质谱)。
8.2实验动物
Beagle犬18只,雌雄各半,体重6kg-10kg,购于江苏亚东实验动物研究院有限公司。
8.3实验药物
氢溴酸氘代右美沙芬一水合物(deDM)、氢溴酸右美沙芬一水合物(DM)、盐酸安非他酮(BUP);
灌胃给药剂量设计氢溴酸氘代右美沙芬一水合物+盐酸安非他酮组为14mg/kg+58mg/kg(按氘代右美沙芬:安非他酮质量比=1:4.88)、氢溴酸右美沙芬一水合物+盐酸安非他酮组为14mg/kg+58mg/kg,氢溴酸氘代右美沙芬一水合物组为14mg/kg。
8.4制剂配制
准确称取供试品于合适容器中,加入目标体积的氯化钠注射液,分别配置成氢溴酸氘代右美沙芬一水合物+盐酸安非他酮组为2.8+11.6mg/mL,氢溴酸右美 沙芬一水合物+盐酸安非他酮组为2.8+11.6mg/mL,氢溴酸氘代右美沙芬一水合物组为2.8mg/mL给药溶液。
8.5血样采集
犬单次灌胃给药后,于0min(给药前)、5min、15min、30min、1h、2h、4h、8h、24h分别用头皮针于前肢或后肢静脉采集血液约1mL置于含EDTA-K2抗凝剂采血管中,4000rpm离心10min分离血浆,≤-65℃保存待测。
8.6生物分析
采用验证过的生物分析方法测定氘代右美沙芬、右美沙芬在比格犬血浆中的浓度。氘代右美沙芬在血浆中的标准曲线浓度为2、4、20、80、400、600、1000和2000ng/mL,QC浓度为6、100、800和1600ng/mL。右美沙芬在血浆中的标准曲线浓度为1、2、10、50、200、400、600和1000ng/mL,QC浓度为3、30、500和800ng/mL。
8.7数据处理
使用Analyst 8.7.0及Watson LIMS 7.4分析测定氘代右美沙芬、右美沙芬在血浆中的浓度后,绘制浓度和时间曲线,并用WinNonlin 8.1至少计算下列参数:C
max、AUC
0-t。
从上述结果可见,氘代右美沙芬与安非他酮联合给药时(配比为1:4.88)与氘代右美沙芬单药组和右美沙芬与安非他酮联合给药相比,暴露量和Cmax有明显提升,氘代右美沙芬安非他酮组合后体现出了很好的协同作用。
实施例9药物组合物
采用氘代右美沙芬和盐酸安非他酮(以安非他酮计)按照以下质量比进行0号胶囊填充,每个单位胶囊中氘代右美沙芬和安非他酮总量为100mg。
实施例10氘代右美沙芬氢溴酸盐一水合物的制备方法
将YMSF-D6(1.0eq)加入到48%HBr(0.42v/w,1.05eq,d=1.5)和水(5v/w)中,升温至65-75℃,搅拌0.5h,缓慢降温至20-30℃,搅拌0.5h以上,过滤,用水洗涤(2v/w),40-50℃,真空干燥10h,得到氘代右美沙芬氢溴酸盐一水合物。其中,YMSF-D6按照现有技术获得。
实施例11氘代右美沙芬氢溴酸盐的制备方法
称实施例10的3.5g氘代右美沙芬氢溴酸盐一水合物,加入10ml甲醇中,搅拌溶解,滴入至200ml甲基叔丁基醚中,搅拌5h,氮气保护下抽滤,固体40℃真空干燥一天,得固体氘代右美沙芬氢溴酸盐。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (13)
- 一种药物组合物,其特征在于,所述药物组合物含有氘代右美沙芬或其盐,和安非他酮类药物或其盐。
- 根据权利要求1所述的一种药物组合物,其特征在于,所述安非他酮类药物选自安非他酮、S-安非他酮、R-安非他酮、羟基安非他酮、赤式羟基安非他酮、苏式羟基安非他酮中的一种或者两种以上的组合。
- 根据权利要求1或2所述的一种药物组合物,其特征在于,所述药物组合物中,氘代右美沙芬或其盐和安非他酮类药物或其盐的质量比为1-10:1-10。
- 根据权利要求1任一项所述的一种药物组合物,其特征在于,所述药物组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6;或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6;或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6;或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6;或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6;或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏式羟基安非他酮计,二者的质量比为1:1-10,优选二者的质量比为1:1-8,更优选二者的质量比为1:1-6,最优选为1:3-1:6。
- 根据权利要求1-4任一项所述的一种药物组合物,其特征在于,所述组合物中:氘代右美沙芬或其盐以氘代右美沙芬计,安非他酮或其盐以安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1: 2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;或者氘代右美沙芬或其盐以氘代右美沙芬计,S-安非他酮或其盐以S-安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;或者氘代右美沙芬或其盐以氘代右美沙芬计,R-安非他酮或其盐以R-安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;或者氘代右美沙芬或其盐以氘代右美沙芬计,羟基安非他酮或其盐以羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;或者氘代右美沙芬或其盐以氘代右美沙芬计,赤式羟基安非他酮或其盐以赤式羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10;或者氘代右美沙芬或其盐以氘代右美沙芬计,苏式羟基安非他酮或其盐以苏 式羟基安非他酮计,二者的质量比为1:1、1:1.25、1:1.5、1:1.75、1:2、1:2.25、1:2.5、1:2.75、1:3、1:3.25、1:3.27、1:3.5、1:3.75、1:3.93、1:4、1:4.25、1:4.5、1:4.75、1:4.88、1:4.91、1:5、1:5.25、1:5.5、1:5.75、1:5.89、1:6、1:6.25、1:6.5、1:6.75、1:7、1:7.25、1:7.5、1:7.75、1:8、1:8.25、1:8.5、1:8.75、1:9、1:9.25、1:9.5、1:9.75、1:10。
- 根据权利要求1-4任一项所述的一种药物组合物,其特征在于,所述盐选自:硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、盐酸盐、溴酸盐、碘酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、羟乙酸盐、马来酸盐、酒石酸盐、甲烷磺酸盐、丙烷磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐。
- 根据权利要求1-4所述的一种药物组合物,其特征在于,氘代右美沙芬的盐和安非他酮的盐二者的质量比为10-18:50,优选具体质量比为10:50、12:50、15:50、18:50。
- 根据权利要求1所述的一种药物组合物,其特征在于,所述药物组合物包括适合经口、直肠、经鼻、局部(包括经颊和舌下)、阴道或非经肠(包括皮下、肌肉内、静脉内和皮内)投药的药物组合物。
- 根据权利要求1-10任意一项所述的一种药物组合物在制备预防和/或治疗咳嗽及各种神经类病症的药物用途。
- 根据权利要求11所述的药物用途,其特征在于:所述神经类病症包括但不限于,抑郁、重度抑郁、难治性抑郁和难治性双相型抑郁。
- 根据权利要求12所述的药物用途,其特征在于:所述抑郁包括循环性情感精神病的双相型病症、季节性情感障碍、躁狂、焦虑症、注意力缺失症(ADD)、注意力缺陷障碍伴多动(ADDH)、注意力缺陷/多动障碍(AD/HD)、双相和狂躁病症、强迫性神经失调、贪食症、肥胖或重量增加、发作性睡病、慢性疲劳综合征、经前期综合征、物质成瘾或滥用、尼古丁成瘾、心理性性功能障碍、假性延髓情绪以及情绪不稳。
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US11844797B1 (en) * | 2023-04-20 | 2023-12-19 | Antecip Bioventures Ii Llc | Combination of dextromethorphan and bupropion for treating depression |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101015519A (zh) * | 2007-02-27 | 2007-08-15 | 重庆医药工业研究院有限责任公司 | 一种氯雷他定口服复方药物组合物 |
CN101254249A (zh) * | 2008-03-20 | 2008-09-03 | 张辉 | 一种治疗咳嗽痰多症的中西药复方制剂及其生产方法 |
CN101687868A (zh) | 2007-05-01 | 2010-03-31 | 康塞特医药品公司 | 吗啡烷化合物 |
CN104195218A (zh) * | 2014-09-03 | 2014-12-10 | 广东中西达一新药开发有限公司 | 一种细胞色素p450酶的特异性探针底物组合物及其应用 |
CN106163522A (zh) | 2013-11-05 | 2016-11-23 | 安泰赛普生物风投二代有限责任公司 | 包含安非他酮或相关化合物和右美沙芬的组合物和方法 |
CN111297860A (zh) * | 2014-11-21 | 2020-06-19 | 安泰赛普生物风投二代有限责任公司 | 使用赤式羟基安非他酮调节药物血浆水平的方法 |
CN111343980A (zh) * | 2017-10-04 | 2020-06-26 | 新凯治疗有限责任公司 | 右美沙芬经皮递送装置 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3090760A1 (en) * | 2008-10-30 | 2016-11-09 | Concert Pharmaceuticals, Inc. | Combination of morphinan compounds and antidepressant for the treatment of pseudobulbar affect, neurological diseases, intractable and chronic pain and brain injury |
JP7061079B2 (ja) * | 2016-07-04 | 2022-04-27 | アヴェニール ファーマシューティカルズ, インコーポレイテッド | 重水素化デキストロメトルファンの合成方法 |
-
2021
- 2021-07-19 WO PCT/CN2021/106973 patent/WO2022017300A1/zh unknown
- 2021-07-19 EP EP21846859.3A patent/EP4183391A4/en active Pending
- 2021-07-19 CN CN202311304808.4A patent/CN117100750A/zh active Pending
- 2021-07-19 CN CN202180005272.9A patent/CN114340608B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101015519A (zh) * | 2007-02-27 | 2007-08-15 | 重庆医药工业研究院有限责任公司 | 一种氯雷他定口服复方药物组合物 |
CN101687868A (zh) | 2007-05-01 | 2010-03-31 | 康塞特医药品公司 | 吗啡烷化合物 |
CN101254249A (zh) * | 2008-03-20 | 2008-09-03 | 张辉 | 一种治疗咳嗽痰多症的中西药复方制剂及其生产方法 |
CN106163522A (zh) | 2013-11-05 | 2016-11-23 | 安泰赛普生物风投二代有限责任公司 | 包含安非他酮或相关化合物和右美沙芬的组合物和方法 |
CN110279682A (zh) * | 2013-11-05 | 2019-09-27 | 安泰赛普生物风投二代有限责任公司 | 包含安非他酮或相关化合物和右美沙芬的组合物和方法 |
CN104195218A (zh) * | 2014-09-03 | 2014-12-10 | 广东中西达一新药开发有限公司 | 一种细胞色素p450酶的特异性探针底物组合物及其应用 |
CN111297860A (zh) * | 2014-11-21 | 2020-06-19 | 安泰赛普生物风投二代有限责任公司 | 使用赤式羟基安非他酮调节药物血浆水平的方法 |
CN111343980A (zh) * | 2017-10-04 | 2020-06-26 | 新凯治疗有限责任公司 | 右美沙芬经皮递送装置 |
Non-Patent Citations (1)
Title |
---|
See also references of EP4183391A4 |
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CN117100750A (zh) | 2023-11-24 |
CN114340608B (zh) | 2023-10-31 |
CN114340608A (zh) | 2022-04-12 |
EP4183391A4 (en) | 2024-04-17 |
EP4183391A1 (en) | 2023-05-24 |
TW202206075A (zh) | 2022-02-16 |
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