WO2022001889A1 - 去甲曲马多的盐及其用途 - Google Patents

去甲曲马多的盐及其用途 Download PDF

Info

Publication number
WO2022001889A1
WO2022001889A1 PCT/CN2021/102494 CN2021102494W WO2022001889A1 WO 2022001889 A1 WO2022001889 A1 WO 2022001889A1 CN 2021102494 W CN2021102494 W CN 2021102494W WO 2022001889 A1 WO2022001889 A1 WO 2022001889A1
Authority
WO
WIPO (PCT)
Prior art keywords
nortramadol
salt
solvate
pharmaceutical composition
formula
Prior art date
Application number
PCT/CN2021/102494
Other languages
English (en)
French (fr)
Inventor
刘飞
吴刚
王晓波
徐晔海
王琳
郑民强
Original Assignee
南京诺瑞特医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京诺瑞特医药科技有限公司 filed Critical 南京诺瑞特医药科技有限公司
Priority to US18/003,947 priority Critical patent/US20230265044A1/en
Publication of WO2022001889A1 publication Critical patent/WO2022001889A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • 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
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
    • C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the field of medicinal chemistry. Specifically, the present invention relates to a poorly soluble salt of nortramadol, a preparation method of the poorly soluble salt, a pharmaceutical composition comprising the poorly soluble salt, and the medicinal use of the poorly soluble salt or the pharmaceutical composition.
  • Tramadol is a centrally acting synthetic opioid analgesic that is structurally related to codeine and morphine. Tramadol is generally considered a low-risk opioid for moderate-to-severe pain because of its low short-term addiction and low risk of respiratory depression, which is well tolerated. Tramadol is effective for a variety of pain types, including neuropathic pain, postoperative pain, fibromyalgia, osteoarthritis, and cancer-related pain. According to the Chinese Pharmacopoeia, the chemical name of tramadol hydrochloride is ( ⁇ )-(1RS,2RS)-2-[(N,N dimethylamino)methylene]-1-(3-methoxyphenyl) Cyclohexanol hydrochloride.
  • the object of the present invention is to provide a poorly soluble pamoate salt of nortramadol or a solvate thereof.
  • Another object of the present invention is to provide a pharmaceutical composition comprising this poorly soluble salt or a solvate thereof.
  • the poorly soluble pamoate salt of nortramadol or its solvate and the pharmaceutical composition of the present invention can continuously release the active nortramadol in the body, thereby maintaining the drug effect concentration for a long time, and can achieve long-term analgesic effect.
  • the present invention provides a compound represented by formula (I) or a solvate thereof
  • n is an integer of 1 to 4.
  • n 1 or 2.
  • n is 2.
  • the solvate is a solvate formed by the compound represented by formula (I) and methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone or water.
  • the compound represented by formula (I) or a solvate thereof has a D50 value in the range of 0.1 to 100 ⁇ m.
  • the compound represented by formula (I) is the pamoate salt of racemic nortramadol, and the chemical name of racemic nortramadol is ( ⁇ )-(1RS, 2RS )-2-[(N,N-dimethylamino)methylene]-1-hydroxy-cyclohexyl-phenol.
  • the compound shown in (I) is the pamoate salt of dextronortramadol or the pamoate salt of levnortramadol or the pamoate salt of mesonortramadol acid salt.
  • the compound of (I) is the pamoate salt of dextronortrama.
  • the solubility of the compound represented by formula (I) in water is not higher than 0.8 mg/mL; preferably not higher than 0.7 mg/mL; more preferably not higher than 0.5 mg/mL.
  • the hygroscopicity of the compound represented by formula (I) is not higher than 7%; preferably not higher than 4%; more preferably not higher than 3%.
  • the single impurity content of the compound represented by formula (I) placed under light conditions (4500lux ⁇ 500lux) for 10 days is not higher than 0.1%, preferably not higher than 0.06%, more preferably not higher than 0.04% ;
  • the total impurity content is not higher than 0.20%, preferably not higher than 0.10%, more preferably not higher than 0.04%;
  • the single impurity content placed under light conditions (4500lux ⁇ 500lux) for 30 days is not higher than 0.15%, preferably not higher than 0.10%, more preferably not higher than 0.05%; the total impurity content is not higher than 0.40%, preferably not higher than 0.20%, more preferably not higher than 0.05%.
  • the single impurity content of the compound represented by formula (I) placed under high temperature and high humidity conditions (40°C, 75% humidity) for 10 days is not higher than 0.08%, preferably not higher than 0.06%, more preferably not higher than 0.05%; the total impurity content is not higher than 0.20%, preferably not higher than 0.10%, more preferably not higher than 0.05%;
  • the single impurity content placed under high temperature and high humidity conditions (40°C, 75% humidity) for 30 days is not higher than 0.10%, preferably not higher than 0.06%, more preferably not higher than 0.05%; the total impurity content is not higher than 0.30% , preferably not higher than 0.20%, more preferably not higher than 0.05%.
  • the compound of formula (I) has a plasma half-life (t 1/2 ) of at least 16 hours; preferably at least 17 hours.
  • the maximum blood concentration (C max ) of the compound represented by formula (I) is not higher than 500 ng/mL; preferably not higher than 270 ng/mL.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of formula (I) or a solvate thereof described in the first aspect, and optional pharmaceutically acceptable excipients agent.
  • the pharmaceutically acceptable excipients include, but are not limited to, one or more of the following: suspending agents, surfactants, fillers, preservatives, isotonicity regulators, pH regulators , buffer and water.
  • the surfactant is selected from polysorbate 20 (Tween-20).
  • the buffer is selected from sodium dihydrogen phosphate.
  • the compound represented by formula (I) or a solvate thereof is a solid particle having a D50 value in the range of 0.1 to 100 ⁇ m.
  • the pharmaceutical composition is in a dosage form suitable for subcutaneous, intradermal or intramuscular injection.
  • the pharmaceutical composition is in the form of a long-acting preparation; preferably a long-acting solid particulate suspension injection.
  • the pharmaceutical composition contains 10 to 1000 mg; preferably 50 to 200 mg of the compound or a solvate thereof in 1 mL of the suspension injection.
  • the present invention provides the compound represented by the formula (I) or a solvate thereof described in the first aspect, or the use of the pharmaceutical composition described in the second aspect in the preparation of a medicine for preventing, treating or relieving pain .
  • the analgesic drug is a drug for moderate to severe pain.
  • the moderate to severe pain is postoperative pain.
  • the postoperative pain is acute postoperative pain or chronic postoperative pain.
  • the analgesic drug is a safe and effective narcotic drug with long-term stable release of the active ingredient in the body.
  • the medicament is in a dosage form suitable for subcutaneous, intradermal or intramuscular injection.
  • the drug is in the form of a long-acting formulation; preferably a long-acting solid particulate suspension injection.
  • the present invention provides a method for preventing, treating or relieving pain, the method comprising adding a therapeutically effective amount of the compound represented by the formula (I) or a solvate thereof described in the first aspect, or a second
  • the pharmaceutical compositions of the aspects are administered to a subject in need thereof.
  • the pain is moderate to severe pain.
  • the moderate to severe pain is postoperative pain.
  • the postoperative pain is acute postoperative pain or chronic postoperative pain.
  • Figure 1 Concentration-time curves of nortramadol in plasma after administration of different nortramadol formulations in rats.
  • the inventor unexpectedly found that the preparation of O-nortramadol into a specific pamoic acid salt, especially pamoic acid half-salt, can significantly reduce the amount of O-nortramadol. Solubility, thereby achieving a sustainable release of active O-desmethyltramadol.
  • the specific O-nortramadol pamoate salt of the present invention also possesses excellent pharmacokinetic parameters, thereby enabling safe and effective administration. The present invention has been completed on this basis.
  • O-desmethyltramadol Although the solubility of O-desmethyltramadol has been relatively low, there are still various deficiencies. For example, O-nortramadol is still insufficient to achieve sustainable release of active nortramadol, and other properties, especially pharmacokinetic parameters, such as Cmax, are poor.
  • compounds with analgesic activity are often prepared into low-solubility salts, such as specific salt forms, in the prior art.
  • low-solubility salts such as specific salt forms
  • the technical effects of different compounds prepared into different salt forms are often inconsistent.
  • a specific salt form suitable for some compounds is not necessarily effective for other compounds; in addition, some compounds, after being prepared into a specific salt form, although the solubility is reduced, the pharmacokinetic parameters are not significantly improved.
  • the inventors prepared a salt formed by O-nortramadol and pamoic acid.
  • the solubility of this salt was further reduced and its pharmacokinetic properties, such as the Cmax parameter, were significantly improved. Therefore, the insoluble salt or its solvate can sustainably release the active drug in the body and maintain the effective concentration for a long time, thereby not only achieving long-term analgesic effect, but also higher safety.
  • the compound of the present invention is a salt represented by formula (I) or a solvate thereof:
  • n is an integer from 1 to 4.
  • the compound of the present invention is the pamoic acid hemi- or mono-salt of nortramadol; ie, n is 1 or 2; preferably 2.
  • nortramadol is a chiral compound with levoretramadol, dextronortramadol and 2 meso nortramadols, for a total of 4 stereoisomers body.
  • the specific chiral structure of nortramadol is not particularly limited, that is, the racemates of nortramadol (L-nortramadol and D-nortramadol) that can be used The molar ratio is 1:1), or it can be a mixture of any one or more of L-nortramadol and D-nortramadol in any ratio.
  • L-nortramadol is (-)-(1S,2S)-2-[(N,N dimethylamino)methylene]-1-hydroxy-cyclohexyl-phenol, dextrorotation
  • nortramadol is (+)-(1R,2R)-2-[(N,N-dimethylamino)methylene]-1-hydroxy-cyclohexyl-phenol.
  • the hygroscopicity of the compound represented by formula (I) is not higher than 7%; preferably not higher than 4%; more preferably not higher than 3%.
  • the hygroscopicity can be detected by routine experiments known to those skilled in the art.
  • a sample of the compound represented by formula (I) can be taken and placed in a desiccator filled with an 80% RH saturated solution, equilibrated for 24 hours, taken out, and weighed as m 1 ; About 1 mm, weighed as m 2 ; put it into a desiccator filled with 80% RH saturated solution, equilibrated for 24 hours, and weighed as m 3 .
  • the single impurity content of the compound represented by formula (I) placed under light conditions (4500lux ⁇ 500lux) for 10 days is not higher than 0.1%, preferably not higher than 0.06%, more preferably not higher than 0.04% ;
  • the total impurity content is not higher than 0.20%, preferably not higher than 0.10%, more preferably not higher than 0.04%;
  • the single impurity content placed under light conditions (4500lux ⁇ 500lux) for 30 days is not higher than 0.15%, preferably not higher than
  • the total impurity content is not higher than 0.40%, preferably not higher than 0.20%, more preferably not higher than 0.05%.
  • the single impurity content of the compound represented by formula (I) placed under high temperature and high humidity conditions (40°C, 75% humidity) for 10 days is not higher than 0.08%, preferably not higher than 0.06%, more preferably Not higher than 0.05%; total impurity content not higher than 0.20%, preferably not higher than 0.10%, more preferably not higher than 0.05%; single impurity placed under high temperature and high humidity conditions (40°C, 75% humidity) for 30 days
  • the content is not higher than 0.10%, preferably not higher than 0.06%, more preferably not higher than 0.05%; the total impurity content is not higher than 0.30%, preferably not higher than 0.20%, more preferably not higher than 0.05%.
  • the compounds of the present invention also exhibit excellent pharmacokinetic properties.
  • compounds of formula (I) have a plasma half-life (t 1/2 ) of at least 16 hours; preferably at least 17 hours.
  • the maximum plasma concentration (C max ) of the compound represented by formula (I) is not higher than 500 ng/mL; preferably not higher than 270 ng/mL.
  • the compound of the present invention can further form a solvate, for example, a solvate formed by the compound represented by formula (I) with methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone or water thing.
  • a solvate formed by the compound represented by formula (I) with methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetone or water thing.
  • the compound represented by formula (I) of the present invention or a solvate thereof may be in the form of solid particles having a D50 value in the range of 0.1-100 ⁇ m.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound or a solvate thereof and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipients include one or more of the following: suspending agents, surfactants, fillers, preservatives, isotonicity regulators, pH regulators, buffers and water.
  • the surfactant is selected from polysorbate 20 (Tween-20).
  • the buffer is selected from sodium dihydrogen phosphate.
  • the pharmaceutical composition is suitable for subcutaneous, intradermal or intramuscular injection.
  • the pharmaceutical composition is in the form of a long-acting preparation, preferably a long-acting solid particulate suspension injection. 10 to 1000 mg; preferably 50 to 200 mg of the salt or its solvate is contained in 1 mL of the suspension injection.
  • the salts or solvates and pharmaceutical compositions of the present invention can be used to prevent or treat pain, for example, by subcutaneous, intradermal or intramuscular injection to prevent, treat or relieve pain.
  • the pain is moderate to severe pain, such as postoperative pain.
  • the postoperative pain is acute postoperative pain or chronic postoperative pain.
  • the term "effective amount” or “therapeutically effective amount” refers to a dose or amount that results in an improvement in any parameter or clinical condition. Actual doses may vary with each patient and do not necessarily refer to the total elimination of all disease symptoms.
  • D50 refers to the particle size corresponding to a sample whose cumulative particle size distribution percentage reaches 50%. Its physical meaning is that the particles with a particle size larger than it account for 50%, and the particles smaller than it also account for 50%. D50 is also called the median particle size or median particle size.
  • dissolution refers to 1g (mL) of solute Can be dissolved in solvent 10 to less than 30mL; slightly soluble means that 1g (mL) of solute can be dissolved in solvent of 30 to less than 100mL; slightly soluble means that 1g (mL) of solute can be dissolved in solvent of 100 to less than 1000mL ; Slightly soluble means that 1 g (mL) of solute can be dissolved in a solvent of 1000 to less than 10000 mL.
  • the compound of the present invention or its solvate has excellent effects in multiple aspects such as biological activity, safety, bioavailability, stability, solubility, etc.;
  • the compound of the present invention or its solvate has good stability, low hygroscopicity, and is very slightly soluble in water, which is beneficial to the delayed release of the drug, and has a good prospect for finished medicine;
  • the present invention provides a medicine with a simple production process that can stably release local anesthetics in the body for a long time, which can be released continuously for a long time, which can not only prolong the analgesic effect of postoperative pain, but also be convenient for doctors and patients to use, Has good medication compliance.
  • a 500 mL reaction flask was added with racemic nortramadol (28.5 g, 100 mol) and 86 mL of purified water, and the solution was stirred at room temperature to dissolve.
  • Pamoic acid disodium salt monohydrate (22.5 g, 50 mol) was dissolved with 270 mL of purified water and transferred to a constant pressure dropping funnel, and then dropwise addition was started, during which a pale yellow solid was precipitated. After adding about 40min, continue stirring at room temperature for 30min and at 0°C for 25min. After filtration, the filter cake was washed with 50 mL of pre-cooled purified water. Vacuum dried at 50°C for 6h to obtain 43.2g of pale yellow solid.
  • solubility of the sample of Example 1 is 0.5 mg/mL, and the approximate solubility can be expressed as: 1 g of the sample of Example 1 needs to be dissolved in 2000 mL of water.
  • the solubility of the sample of Example 2 is 0.7 mg/mL, and the approximate solubility can be expressed as: 1 g of the sample of Example 2 needs to be dissolved in 1428.6 mL of water.
  • the solubility of racemic nortramadol hydrochloride is greater than 200 mg/mL, and the approximate solubility can be expressed as: 1 g of racemic nortramadol hydrochloride requires 5 mL or less of water to dissolve.
  • the solubility of racemic nortramadol acetate is greater than 50 mg/mL, and the approximate solubility can be expressed as: 1 g of racemic nortramadol acetate needs 20 mL or less of water to dissolve.
  • the solubility of racemic nortramadol free base is 1.4 mg/mL, and the approximate solubility can be expressed as: 1 g of racemic nortramadol free base needs to be dissolved in 714.3 mL of water.
  • the pamoate salt of nortramadol is very slightly soluble in water, which is beneficial to the delayed release of the drug, and has a good prospect for finished medicine.
  • Test process take a weighing bottle, put it in a desiccator filled with 80% RH saturated solution, equilibrate for 24 hours, take it out, weigh it as m 1 , take a sample, spread it in a weighing bottle, with a thickness of about 1 mm, weigh as m 2 , and then put it into a desiccator filled with 80% RH saturated solution, equilibrated for 24 hours, and weighed as m 3 .
  • Example 1 and Example 2 of the present invention Take an appropriate amount of the sample of Example 1 and Example 2 of the present invention, put them in a glass plate, and place them under light conditions (4500lux ⁇ 500lux) and high temperature and high humidity conditions (40°C, 75% humidity) for 30 days, respectively. Samples were taken at 10 and 30 days, and the single impurity and total impurity contents of the three samples under different conditions were investigated respectively. The results are shown in Table 1 and Table 2.
  • Chromatographic column Agilent Pursuit C18, 3um, 4.6*150mm;
  • Mobile phase 0.1% trifluoroacetic acid (mobile phase A): acetonitrile (mobile phase B);
  • the pamoate of nortramadol has good stability under the conditions of light and high temperature and high humidity, which is conducive to long-term storage;
  • the stability under high humidity conditions is particularly excellent.
  • composition of racemic nortramadol, the sample of Example 1 (dinortramadol pamoate), and the sample of Example 2 (nortramadol pamoate monosalt) as shown in Table 3 Preparation of formulations.
  • Test process 15 animals were randomly divided into 3 groups, respectively intramuscular injection of nortramadol preparation, bisnortramadol pamoic acid and nortramadol pamoic acid monosalt preparation (according to Example 6 of the present invention).
  • Method to prepare preparations respectively obtain preparation 1, preparation 2, preparation 3), the administration dose is 50mg/kg (calculated as nortramadol free base), about 0.5, 1, 2, 4, 6, 10 after administration , 24, 48 and 72h, blood samples were collected in K2EDTA anticoagulant tubes in turn, and temporarily stored on ice. Centrifugation was completed within 60min (2-8°C, 8000rpm for 5min), and the plasma was collected and transferred to a centrifuge tube. Store at 15°C.
  • Sample detection and data processing The developed LC-MS/MS method is used to detect plasma samples, obtain blood drug concentration data and calculate pharmacokinetic parameters, including but not limited to Tmax, Cmax, AUC, etc. Details are shown in the table below.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供去甲曲马多的盐，即式(I)所示化合物或其溶剂合物、包含式(I)所示化合物或其溶剂合物的药物组合物以及式(I)所示化合物或其溶剂合物或所述药物组合物在治疗中度至重度疼痛中的用途。本发明的化合物或药物组合物能够在体内长时间稳定地释放出镇痛活性的药物，发挥药效的同时方便医生和患者使用，具有良好的用药依从性。

Description

去甲曲马多的盐及其用途 技术领域
本发明涉及药物化学领域。具体地说，本发明涉及去甲曲马多的难溶性盐、所述难溶性盐的制备方法、包含所述难溶性盐的药物组合物以及所述难溶性盐或药物组合物的医药用途。
背景技术
术后疼痛是手术后即刻发生的急性疼痛，其性质为急性伤害性疼痛，也是临床最常见和最需要紧急处理的急性疼痛。若在初始状态下未被充分控制，容易演变成为术后慢性痛。临床上常用阿片类药物治疗术后疼痛，但其具有呼吸抑制和成瘾性等不良反应。局麻药也是临床上最重要的镇痛药物，包括利多卡因、布比卡因、罗哌卡因等。现有的局麻药物有效作用时间相对较短，需要反复给药。因此临床急需开发出副作用小，且能长时间发挥药效的止痛、麻醉药。
曲马多是一种中枢性合成阿片类镇痛药，在结构上与可待因和吗啡有关。因其短期成瘾性较低、呼吸抑制风险也较低等良好的耐受性，曲马多通常被认为是中度至重度疼痛的低风险阿片类药物。曲马多对多种疼痛类型有效，包括神经性疼痛，术后疼痛，纤维肌痛，骨关节炎和癌症等相关的疼痛。中国药典记载，盐酸曲马多的化学名称为(±)-(1RS,2RS)-2-[(N,N二甲基氨基)亚甲基]-1-(3-甲氧基苯基)环已醇盐酸盐。
曲马多进入人体后的主要代谢途径包括两种，经由CYP2D6催化的O-去甲基化生成O-去甲曲马多，和经由CYP3A4催化的N-去甲基化生成N-去甲基曲马多。但不同患者服用曲马多后，会表现出有差异的药代动力学特征，这归因于CYP2D6基因内的多态性，进而影响了CYP2D6的酶促活性。CYP2D6酶活性强的患者，其体内会代谢生成高浓度的活性代谢产物O-去甲曲马多，产生曲马多中毒的危险。CYP2D6酶活性弱的患者，曲马多的活性代谢产物浓度低，会导致镇痛作用降低。开发曲马多的长效制剂有可能造成个体差异疗效不一，甚至中毒风险。O-去甲曲马多作为曲马多的活性代谢产物，其活性高于曲马多。
因此，临床急需一种生产工艺简单，可在体内长时间稳定释放出麻醉药物的安全且有效的药物。该药物既能维持长时间持续释放，延长镇痛作用，也方便医生和患者用药，具有良好的用药依从性。
发明内容
本发明的目的在于提供一种去甲曲马多的难溶性帕莫酸盐或其溶剂合物。
本发明的另一目的在于提供包括这种难溶性盐或其溶剂合物的药物组合物。
本发明的去甲曲马多的难溶性帕莫酸盐或其溶剂合物和药物组合物能够在体 内可持续释放出活性去甲曲马多，从而维持药效浓度时间较长，能达到长期的镇痛效果。
在第一方面，本发明提供式(I)所示化合物或其溶剂合物
Figure PCTCN2021102494-appb-000001
式中，n为1至4的整数。
在具体的实施方式中，n为1或2。
在具体的实施方式中，n为2。
在优选的实施方式中，所述的溶剂合物为式(I)所示化合物与甲醇、乙醇、正丙醇、异丙醇、乙酸乙酯、丙酮或水形成的溶剂合物。
在优选的实施方式中，式(I)所示化合物或其溶剂合物的D50值在0.1至100μm的范围内。
在优选的实施方式中，式(I)所示化合物是外消旋的去甲曲马多的帕莫酸盐，外消旋的去甲曲马多化学名称为(±)-(1RS,2RS)-2-[(N,N二甲基氨基)亚甲基]-1-羟基-环已基-苯酚。
在优选的实施方式中，(I)所示化合物是右旋去甲曲马多的帕莫酸盐或左旋去甲曲马多的帕莫酸盐或内消旋去甲曲马多的帕莫酸盐。
在优选的实施方式中，(I)所示化合物是右旋去甲曲马的帕莫酸盐。
在优选的实施方式中，式(I)所示化合物在水中的溶解度不高于0.8mg/mL；优选不高于0.7mg/mL；更优选不高于0.5mg/mL。
在优选的实施方式中，式(I)所示化合物的引湿性不高于7％；优选不高于4％；更优选不高于3％。
在优选的实施方式中，式(I)所示化合物在光照条件(4500lux±500lux)下放置10天的单一杂质含量不高于0.1％，优选不高于0.06％，更优选不高于0.04％；总杂质含量不高于0.20％，优选不高于0.10％，更优选不高于0.04％；
在光照条件(4500lux±500lux)下放置30天的单一杂质含量不高于0.15％，优选不高于0.10％，更优选不高于0.05％；总杂质含量不高于0.40％，优选不高于0.20％，更优选不高于0.05％。
在优选的实施方式中，式(I)所示化合物在高温高湿条件(40℃、75％湿度)下放置10天的单一杂质含量不高于0.08％，优选不高于0.06％，更优选不高于0.05％；总杂质含量不高于0.20％，优选不高于0.10％，更优选不高于0.05％；
在高温高湿条件(40℃、75％湿度)下放置30天的单一杂质含量不高于0.10％，优选不高于0.06％，更优选不高于0.05％；总杂质含量不高于0.30％，优选不高于0.20％，更优选不高于0.05％。
在优选的实施方式中，式(I)所示化合物的血浆半衰期(t 1/2)为至少16小时；优选至少17小时。
在优选的实施方式中，式(I)所示化合物的最大血药浓度(C max)不高于500ng/mL；优选不高于270ng/mL。
在第二方面，本发明提供一种药物组合物，所述药物组合物包含第一方面所述的式(I)所示化合物或其溶剂合物，以及任选的药学上可接受的赋形剂。
在优选的实施方式中，所述药学上可接受的赋形剂包括但不限于以下一种或多种：助悬剂、表面活性剂、填充剂、防腐剂、等渗调节剂、pH调节剂、缓冲剂和水。
在优选的实施方式中，所述表面活性剂选自聚山梨酯20(吐温-20)。
在优选的实施方式中，所述缓冲剂选自磷酸二氢钠。
在优选的实施方式中，式(I)所示化合物或其溶剂合物是D50值在0.1至100μm的范围内的固体颗粒。
在具体的实施方式中，所述药物组合物是适于皮下、皮内或肌肉注射的剂型。
在具体的实施方式中，所述药物组合物是长效制剂的形式；优选长效固体微粒悬浮注射剂。
在优选的实施方式中，所述药物组合物在l mL所述悬浮注射剂中包含10至1000mg；优选50至200mg的所述化合物或其溶剂合物。
在第三方面，本发明提供第一方面所述的式(I)所示化合物或其溶剂合物，或第二方面所述的药物组合物在制备预防、治疗或缓解疼痛的药物中的用途。
在优选的实施方式中，所述镇痛药物是用于中度至重度疼痛的药物。
在优选的实施方式中，所述中度至重度疼痛是术后疼痛。
在优选的实施方式中，所述术后疼痛是术后急性疼痛或术后慢性疼痛。
在优选的实施方式中，所述镇痛药物是在体内长期稳定释放活性成分的安全且有效的麻醉药物。
在具体的实施方式中，所述药物是适于皮下、皮内或肌肉注射的剂型。
在具体的实施方式中，所述药物是长效制剂的形式；优选长效固体微粒悬浮注射剂。
在第四方面，本发明提供一种预防、治疗或缓解疼痛的方法，所述方法包括将治疗有效量的第一方面所述的式(I)所示化合物或其溶剂合物，或第二方面所述的 药物组合物给予有此需要的对象。
在优选的实施方式中，所述疼痛是中度至重度疼痛。
在优选的实施方式中，所述中度至重度疼痛是术后疼痛。
在优选的实施方式中，所述术后疼痛是术后急性疼痛或术后慢性疼痛。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1大鼠给予不同去甲曲马多制剂后血浆中去甲曲马多的浓度-时间曲线。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现将O-去甲曲马多制成特定的帕莫酸盐，特别是帕莫酸半盐，能够显著降低O-去甲曲马多的溶解度，从而实现活性O-去甲曲马多的可持续释放。此外，本发明的特定O-去甲曲马多帕莫酸盐还具备优异的药代动力学参数，从而能够实现安全而有效地给药。在此基础上完成了本发明。
本发明的化合物和药物组合物
在本文中，“本发明的化合物”、“本发明的盐”、“去甲曲马多的帕莫酸盐”具有相同含义，并且在本文中可以互换使用。上述术语均是指O-去甲曲马多与帕莫酸形成的盐。本发明中所使用的术语“去甲曲马多”均是指O-去甲曲马多。曲马多是中度至重度疼痛的低风险阿片类药物，而O-去甲曲马多作为曲马多的活性代谢产物，其活性高于曲马多。
本发明人在研究中发现，虽然O-去甲曲马多的溶解度已经比较低，但仍存在种种不足。例如，O-去甲曲马多仍然不足以实现活性去甲曲马多的可持续释放，并且其它特性，特别是药代动力学参数，例如C max不佳。
为获得能长时间发挥药效的镇痛药，在现有技术中常采用将具备镇痛活性的化合物制备成低溶解度的盐，例如特定的盐型。然而，不同的化合物制备成不同的盐型产生的技术效果往往不一致。适用于某些化合物的特定盐型对于其它化合物不一定有效；此外，某些化合物在制备成特定盐型后，虽然溶解度有降低，但药代动力学参数并没有明显改善。
为实现去甲曲马多的可持续释放，并且改善其药代动力学性能，本发明人制备得到了O-去甲曲马多与帕莫酸形成的盐。这种盐的溶解度进一步降低，并且其药代动力学特性，例如C max参数显著改善。因此，这种难溶性盐或其溶剂合物可以在体内可持续地释放活性药物，维持药效浓度时间较长，从而不仅能达到长期 的镇痛效果，并且安全性也更高。
在具体的实施方式中，本发明的化合物是式(I)所示的盐或其溶剂合物：
Figure PCTCN2021102494-appb-000002
其中：n为1至4的整数。
在优选的实施方式中，本发明的化合物是去甲曲马多的帕莫酸半盐或单盐；即，n为1或2；优选为2。
本领域中已知，去甲曲马多是手性化合物，其具有左旋去甲曲马多、右旋去甲曲马多和2种内消旋去甲曲马多，共4种立体异构体。根据本发明的技术方案对去甲曲马多的具体手性构造没有特别限制，即可以采用的去甲曲马多的外消旋体(左旋去甲曲马多和右旋去甲曲马多的摩尔比为1：1的混合物)，也可以是采用左旋去甲曲马多和右旋去甲曲马多中的任一种或者多种的任意比例的混合物。其中，左旋去甲曲马多化学名称为(-)-(1S,2S)-2-[(N,N二甲基氨基)亚甲基]-1-羟基-环已基-苯酚，右旋去甲曲马多化学名称为(+)-(1R,2R)-2-[(N,N二甲基氨基)亚甲基]-1-羟基-环已基-苯酚。
本发明的化合物在诸多方面表现出优异的性能。例如，就引湿性而言，式(I)所示化合物的引湿性不高于7％；优选不高于4％；更优选不高于3％。所述引湿性可以通过本领域技术人员已知的常规实验检测。例如，可以取式(I)所示化合物的样品并置于装有80％RH饱和溶液的干燥器中，平衡24h，取出，称重为m 1；取样品，铺于称量瓶中，厚度约1mm，称重为m 2；再放入装有80％RH饱和溶液的干燥器中，平衡24h，称重为m 3。随后根据公式计算引湿性：引湿性＝(m 3-m 2)/(m 2-m 1)*100％。
就光稳定性而言，式(I)所示化合物在光照条件(4500lux±500lux)下放置10天的单一杂质含量不高于0.1％，优选不高于0.06％，更优选不高于0.04％；总杂质含量不高于0.20％，优选不高于0.10％，更优选不高于0.04％；在光照条件(4500lux±500lux)下放置30天的单一杂质含量不高于0.15％，优选不高于0.10％，更优选不高于0.05％；总杂质含量不高于0.40％，优选不高于0.20％，更优选不高于0.05％。
就热稳定性而言，式(I)所示化合物在高温高湿条件(40℃、75％湿度)下放置10天的单一杂质含量不高于0.08％，优选不高于0.06％，更优选不高于0.05％；总杂质含量不高于0.20％，优选不高于0.10％，更优选不高于0.05％；在高温高湿条件(40℃、75％湿度)下放置30天的单一杂质含量不高于0.10％，优选不高于 0.06％，更优选不高于0.05％；总杂质含量不高于0.30％，优选不高于0.20％，更优选不高于0.05％。
除上述理化性质外，本发明的化合物还表现出优异的药代动力学特性。例如式(I)所示化合物的血浆半衰期(t 1/2)为至少16小时；优选至少17小时。式(I)所示化合物的最大血药浓度(C max)不高于500ng/mL；优选不高于270ng/mL。
在具体的实施方式中，本发明的化合物可以进一步形成溶剂合物，例如式(I)所示化合物与甲醇、乙醇、正丙醇、异丙醇、乙酸乙酯、丙酮或水形成的溶剂合物。
本发明的式(I)所示化合物或其溶剂合物可以是D50值在0.1-100μm范围内的固体颗粒的形式。
在本发明的化合物的基础上，本发明还提供一种药物组合物，所述药物组合物包含治疗有效量的上述化合物或其溶剂合物以及药学上可接受的赋形剂。所述药学上可接受的赋形剂包括以下的一种或多种：助悬剂、表面活性剂、填充剂、防腐剂、等渗调节剂、pH调节剂、缓冲剂和水。
在具体实施方式中，所述表面活性剂选自聚山梨酯20(吐温-20)。
在具体实施方式中，所述缓冲剂选自磷酸二氢钠。
在具体的实施方式中，所述药物组合物适于皮下、皮内或肌肉注射。例如所述药物组合物是长效制剂的形式，优选长效固体微粒悬浮注射剂。在1mL所述悬浮注射剂中包含10至1000mg；优选50至200mg的所述盐或其溶剂合物。
本发明的盐或其溶剂合物、药物组合物可用于预防或治疗疼痛，例如经皮下、皮内或肌肉注射的方式给药来预防、治疗或缓解疼痛。在具体的实施方式中，所述疼痛是中度至重度疼痛，例如术后疼痛。在优选的实施方式中，所述术后疼痛是术后急性疼痛或术后慢性疼痛。
本发明中所使用的术语“有效量”或“治疗有效量”指导致任何参数或者临床症状改进的剂量或用量。实际的剂量可能随着每个患者的不同而变化，并且不一定指消除所有疾病症状的总量。
本发明中所使用的术语“不高于”指小于等于，应理解为包含本数。
本发明所使用的术语“D50”指一个样品的累计粒度分布百分数达到50％时所对应的粒径。它的物理意义是粒径大于它的颗粒占50％，小于它的颗粒也占50％，D50也叫中位粒径或中值粒径。
本发明中所使用的描述近似溶解度的术语定义如下(参见罗明生、高天惠，《药剂辅料大全》[M].成都：四川科学技术出版社，1982，P4):溶解是指1g(mL)溶质能在溶剂10～不到30mL中溶解；略溶是指1g(mL)溶质能在溶剂30～不到100mL中溶解；微溶是指1g(mL)溶质能在溶剂100～不到1000mL中溶解；极微溶解是指1g(mL)溶质能在溶剂1000～不到10000mL中溶解。
本发明的原料和试剂多可以购自商业，或者可以根据已知的方法制备。
本发明的优点：
1.本发明的化合物或其溶剂合物在生物活性、安全性、生物利用度、稳定性、溶解度等多个方面同时具有优异的效果；
2.本发明的化合物或其溶剂合物稳定性好、吸湿性小、极微溶于水，有利于药物的延缓释放，成药前景好；和
3.本发明提供了一种生产工艺简单、可在体内长时间稳定释放出局麻药的药物，其能够持续长时间释放，既能延长手术后疼痛的镇痛作用，也能方便医生和患者使用，具有良好的用药依从性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例.
实施例1.双去甲曲马多帕莫酸盐的制备
Figure PCTCN2021102494-appb-000003
500mL反应瓶中加入外消旋去甲曲马多(28.5g，100mol)和86mL纯化水，室温下搅拌溶清。用270mL纯化水将帕莫酸二钠盐一水合物(22.5g，50mol)溶解并转移至恒压滴液漏斗中，随后开始滴加，滴加过程中析出淡黄色固体。约40min加完，继续在室温下搅拌30min，0℃下搅拌25min。过滤，滤饼用50mL预冷纯化水洗。50℃真空干燥6h，得43.2g淡黄色固体。将固体转移至500mL茄形瓶中，加入250mL正丙醇，90℃加热搅拌转晶4h，随后室温搅拌过夜。过滤，60℃真空干燥5h，得淡黄色固体41.2g，收率93.2％。
1H NMR(400MHz,DMSO-d6)δ9.36(brs,2H),8.27–8.08(m,2H),7.73–7.55(m,1H),7.22–7.07(m,2H),7.05–6.84(m,3H),6.67–6.60(m,1H),5.03(brs,1H),4.68(s,1H),2.92–2.78(m,1H),2.72–2.26(m,1H),2.54(s,3H),2.52(s,3H),2.20–2.06(m,1H),1.94–1.29(m,8H).
实施例2.去甲曲马多帕莫酸单盐
Figure PCTCN2021102494-appb-000004
100mL反应瓶中加入帕莫酸(3.28g，8.46mol.)和DMSO(13mL)，加热溶清。室温搅拌滴加外消旋去甲曲马多(2.11g，8.46mol.)的DMSO(6.3mL)溶液，加完继续搅拌30min，将反应液滴加到100mL纯化水中，析出黄色固体。室温搅拌10min，0℃搅拌20min。过滤，滤饼用10mL预冷纯化水洗。60℃真空干燥4h，得黄色固体4.82g，收率89.4％。
1H NMR(400MHz,DMSO-d6)δ9.32(brs,1H),8.91(brs,1H),8.30(s,2H),8.22–8.06(m,1H),7.85–7.62(m,1H),7.36–7.01(m,5H),6.99–6.80(m,2H),6.67–6.57(m,1H),5.04(brs,1H),4.73(s,1H),2.94–2.81(m,1H),2.66(s,3H),2.58–2.05(m,2H),2.52(s,3H),1.88–1.27(m,8H).
实施例3.去甲曲马多可药用盐的溶解度测定
测定方法：
1、色谱柱：Agilent Pursuit C18,3um,4.6*150mm
2、流动相：0.1％三氟乙酸:乙腈＝20:80，流速：1.0mL/min，波长：215nm，柱温：35℃，进样量：10μl；
3、流动相配制过程：
取1000mL水，加入1.0mL三氟乙酸，混合均匀，超声，即得；
4、样品配制过程：
称取待测样品约10mg，加1mL水，搅拌24h，离心，取上清液作为溶解度供试品，再称取与待测样品相同结构的去甲曲马多帕莫酸盐10mg，置100mL量瓶，加80％甲醇水溶液溶解稀释至刻度，作为相应的对照品溶液。
经试验测定：实施例1样品的溶解度为0.5mg/mL，换算成近似溶解度可表达为：1g实施例1样品需要在2000mL水中溶解。实施例2样品的溶解度为0.7mg/mL，换算成近似溶解度可表达为：1g实施例2样品需要在1428.6mL水中溶解。外消旋去甲曲马多盐酸盐的溶解度大于200mg/mL，换算成近似溶解度可表达为：1g外消旋去甲曲马多盐酸盐需5mL或者更少体积的水即可溶解。外消旋去甲曲马多醋酸盐的溶解度大于50mg/mL，换算成近似溶解度可表达为：1g外消旋去甲曲马多醋酸盐需20mL或者更少体积的水即可溶解。外消旋去甲曲马多游离碱的溶解度为1.4mg/mL，换算成近似溶解度可表达为：1g外消旋去甲曲马多游离碱需714.3mL水中溶解。
综上，可以看出去甲曲马多的帕莫酸盐极微溶于水，有利于药物的延缓释放，成药前景好。
实施例4.去甲曲马多可药用盐的吸湿性测定
试验过程：取称量瓶，放入装有80％RH饱和溶液的干燥器中，平衡24h，取出，称重为m 1，取样品，铺于称量瓶中，厚度约1mm，称重为m 2，再放入装有80％RH饱和溶液的干燥器中，平衡24h，称重为m 3。
计算公式：引湿性＝(m 3-m 2)/(m 2-m 1)*100％
试验结果：实施例1样品的引湿性为2.9％，实施例2样品的引湿性为6.3％。
实施例5.稳定性研究
取本发明实施例1样品、实施例2样品适量，置玻璃平皿中，分别于光照条件(4500lux±500lux)和高温高湿条件(40℃、75％湿度)下放置30天，分别于0、10、30天取样，分别考察3个样品在不同条件下的单杂和总杂含量，结果见表1、表2。
纯度测定实验条件如下：
1、色谱柱：Agilent Pursuit C18,3um,4.6*150mm；
2、流动相：0.1％三氟乙酸(流动相A):乙腈(流动相B)；
3、流速：1.0ml/min，波长：215nm，柱温：35℃，进样量：10μl；
并按如下梯度进行洗脱：
时间(min) A％ B％
0 90 10
20 15 85
表1.光照稳定性考察结果
Figure PCTCN2021102494-appb-000005
表2.高温高湿条件(40℃、75％湿度)稳定性考察结果
Figure PCTCN2021102494-appb-000006
注：上表1、表2中ND表示未检出杂质。
通过以上实验结果可以发现，去甲曲马多的帕莫酸盐在光照和高温高湿条件下稳定性好，有利于长期储存；特别是双去甲曲马多帕莫酸盐在光照和高温高湿条件下稳定性尤其优异。
实施例6.制剂的制备
将外消旋去甲曲马多、实施例1样品(双去甲曲马多帕莫酸盐)、实施例2样 品(去甲曲马多帕莫酸单盐)按照表3所示的组成制备制剂。
表3
Figure PCTCN2021102494-appb-000007
制备方法：
1)将处方量的NaH 2PO 4·H 2O和Tween 20溶解于总重80％的水中，1N NaOH溶液调节pH至7.00；
2)将上述去甲曲马多/双去甲曲马多帕莫酸盐/去甲曲马多帕莫酸单盐原料加入至上述体系中，分散均匀；
3)将上述溶液采用高剪切机剪切约2min；
4)将高剪切后溶液采用高压均质机均质，400～900bar压力下，均质15min得混悬液。
实施例7.药代动力学研究
1.去甲曲马多/去甲曲马多帕莫酸盐单次肌肉注射SD大鼠药代动力学研究
动物种属及等级：SD大鼠，SPF级
性别和数量：雄性，15只
体重：200～220g
来源：浙江维通利华实验动物技术有限公司
许可证号：SCXK(浙)2019-0001
质量合格证号：2004030063
试验过程：15只动物随机分为3组，分别肌肉注射去甲曲马多制剂、双去甲曲马多帕莫酸和去甲曲马多帕莫酸单盐制剂(按本发明实施例6方法制备制剂，分别得到制剂1、制剂2、制剂3)，给药剂量为50mg/kg(以去甲曲马多游离碱计)，给药后大约0.5、1、2、4、6、10、24、48和72h依次采集血样至K2EDTA抗凝管中，并于冰上暂存，60min内完成离心(2-8℃，8000rpm离心5min)，收集血浆转移至离心管中，并于≤-15℃条件下保存。
样品检测与数据处理：采用已开发的LC-MS/MS方法对血浆样品进行检测，获得血药浓度数据并计算药代动力学参数，包括但不限于Tmax，Cmax，AUC等等。详细数据见下表所示。
表4.SD大鼠给药后血浆中去甲曲马多的药代动力学参数
参数 单位 制剂1 制剂2. 制剂3
t 1/2 h 5.59 17.22 16.50
T max h 2.00 6.00 6.00
C max ng/mL 3162 268.7 480.76
AUC last h*ng/mL 14129.56 8986.57 8347.28
AUC inf h*ng/mL 16525.64 9544.66 8930.59
通过上述的SD大鼠给药后血浆中去甲曲马多的药代动力学参数分析，我们发现去甲曲马多的帕莫酸盐较去甲曲马多游离碱的半衰期(t 1/2)长，能够持续长时间释放，制备成缓释药物的成药前景好；最大血药浓度(C max)相对较低，能够有效避免药物的突释及药物突释相关的毒副作用，有着更好的安全性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种去甲曲马多的盐或其溶剂合物，所述去甲曲马多的盐是式(I)所示化合物
    Figure PCTCN2021102494-appb-100001
    式中，n为1至4的整数。
  2. 如权利要求1所述的去甲曲马多的盐或其溶剂合物，其特征在于，n为1或2。
  3. 如权利要求2所述的去甲曲马多的盐或其溶剂合物，其特征在于，n为2。
  4. 一种药物组合物，所述药物组合物包含权利要求1-3中任一项所述的去甲曲马多的盐或其溶剂合物，以及任选的药学上可接受的赋形剂。
  5. 如权利要求4所述的药物组合物，其特征在于，所述药物组合物是适于皮下、皮内或肌肉注射的剂型。
  6. 如权利要求5所述的药物组合物，其特征在于，所述药物组合物是长效制剂的形式；优选长效固体微粒悬浮注射剂。
  7. 权利要求1-3中任一项所述的去甲曲马多的盐或其溶剂合物，或权利要求4-6中任一项所述的药物组合物在制备预防、治疗或缓解疼痛的药物中的用途。
  8. 如权利要求7所述的用途，其特征在于，所述药物是适于皮下、皮内或肌肉注射的剂型。
  9. 如权利要求8所述的用途，其特征在于，所述药物是长效制剂的形式；优选长效固体微粒悬浮注射剂。
  10. 一种预防、治疗或缓解疼痛的方法，所述方法包括将治疗有效量的权利要求1-3中任一项所述的去甲曲马多的盐或其溶剂合物，或权利要求4-6中任一项所述的药物组合物给予有此需要的对象。
PCT/CN2021/102494 2020-06-30 2021-06-25 去甲曲马多的盐及其用途 WO2022001889A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US18/003,947 US20230265044A1 (en) 2020-06-30 2021-06-25 Salt of demethyl tramadol and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010622340.3 2020-06-30
CN202010622340.3A CN113861048A (zh) 2020-06-30 2020-06-30 去甲曲马多的盐及其用途

Publications (1)

Publication Number Publication Date
WO2022001889A1 true WO2022001889A1 (zh) 2022-01-06

Family

ID=78981968

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/102494 WO2022001889A1 (zh) 2020-06-30 2021-06-25 去甲曲马多的盐及其用途

Country Status (3)

Country Link
US (1) US20230265044A1 (zh)
CN (1) CN113861048A (zh)
WO (1) WO2022001889A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030171440A1 (en) * 2001-11-30 2003-09-11 Sepracor Inc. Tramadol analogs and uses thereof
US20110251286A1 (en) * 2010-03-10 2011-10-13 Gruenenthal Gmbh Crystalline salts and/or co-crystals of O-desmethyltramadol
DE102013009114A1 (de) * 2013-05-29 2014-12-04 Franz Gerstheimer Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen
US20170319511A1 (en) * 2011-07-09 2017-11-09 Syntrix Biosystems Inc. Compositions for overcoming resistance to tramadol

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030171440A1 (en) * 2001-11-30 2003-09-11 Sepracor Inc. Tramadol analogs and uses thereof
US20110251286A1 (en) * 2010-03-10 2011-10-13 Gruenenthal Gmbh Crystalline salts and/or co-crystals of O-desmethyltramadol
US20170319511A1 (en) * 2011-07-09 2017-11-09 Syntrix Biosystems Inc. Compositions for overcoming resistance to tramadol
DE102013009114A1 (de) * 2013-05-29 2014-12-04 Franz Gerstheimer Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen

Also Published As

Publication number Publication date
US20230265044A1 (en) 2023-08-24
CN113861048A (zh) 2021-12-31

Similar Documents

Publication Publication Date Title
ES2731601T3 (es) Composiciones de dosificación oral de liberación retardada que contienen CDDO-Me amorfo
RU2685236C2 (ru) Вдыхаемые частицы, содержащие тиотропий
Lim et al. Development of novel sibutramine base-loaded solid dispersion with gelatin and HPMC: physicochemical characterization and pharmacokinetics in beagle dogs
CN108451909B (zh) 一种酮咯酸氨丁三醇片剂
WO2021023099A1 (zh) 一种马钱子碱凝胶制剂及其制备方法
WO2018177232A1 (zh) 难溶性复合物或其溶剂合物、药物组合物及其应用
AU2017314560B2 (en) Crystals of cyclic amine derivative and pharmaceutical use thereof
WO2022001889A1 (zh) 去甲曲马多的盐及其用途
KR102081176B1 (ko) 타크로리무스를 포함하는 서방형 약제학적 제제
CN115141161B (zh) 一种普拉克索昔萘酸盐的晶型a及其制备方法
AU2018404329B2 (en) Antitumor agent for biliary tract cancer and method for treating biliary tract cancer
CN111346078B (zh) 一种他喷他多或其药学上可接受的盐经鼻粘膜给药的药物组合物及其制备方法和应用
CN115124532B (zh) 大黄酸与苦参碱共晶物及制备方法和其组合物与用途
RU2768482C1 (ru) Фармацевтическая композиция агониста каппа-опиоидного рецептора
CN111440086A (zh) 曲尼司特的盐
BRPI0713647A2 (pt) formulações farmacêuticas e composições de um antagonista seletivo cxcr2 ou cxcr1 e métodos para o uso do mesmo visando o tratamento de distúrbios inflamatórios
WO2022241983A1 (zh) 一种左酮咯酸的药物组合物及其制备方法
WO2019246479A1 (en) Form of ponatinib
TWI814468B (zh) 藥用組合物、其製備方法及用途
US20170348252A1 (en) Preparation and Use of Ketamine Derivatives and Ketamine Modifiers in the Treatment of Pain
CN116270587A (zh) 一种局部麻醉药物
CN111346058B (zh) 一种苯二氮䓬类化合物经鼻粘膜给药的药物组合物及其制备方法和用途
CN112999176B (zh) 一种阿昔替尼片剂
WO2017000270A1 (zh) 枸橼酸舍曲林的2种晶型及其制备方法
BR122014004636B1 (pt) Forma cristalina i de [cloridrato de 4-metilbenzoato de 4-[2-dimetilamino-1-(1-hidroxiciclohexil)etil]fenila], seu uso e seus métodos de preparação, bem como composição farmacêutica

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21834041

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21834041

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 21834041

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 05/07/2023)