WO2023115511A1 - 一种芳基丙酸衍生物及其乳状制剂 - Google Patents

一种芳基丙酸衍生物及其乳状制剂 Download PDF

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WO2023115511A1
WO2023115511A1 PCT/CN2021/141083 CN2021141083W WO2023115511A1 WO 2023115511 A1 WO2023115511 A1 WO 2023115511A1 CN 2021141083 W CN2021141083 W CN 2021141083W WO 2023115511 A1 WO2023115511 A1 WO 2023115511A1
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oil
preparation
compound
injection
acid
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PCT/CN2021/141083
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English (en)
French (fr)
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叶海
周文亮
徐颖
吕田
闵涛
陈星燃
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南京海融医药科技股份有限公司
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Priority to PCT/CN2021/141083 priority Critical patent/WO2023115511A1/zh
Priority to CN202180028459.0A priority patent/CN115836047B/zh
Publication of WO2023115511A1 publication Critical patent/WO2023115511A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • C07C68/00—Preparation of esters of carbonic or haloformic acids
    • C07C68/06—Preparation of esters of carbonic or haloformic acids from organic carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/96—Esters of carbonic or haloformic acids
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the application belongs to the field of pharmaceutical preparations, and relates to an aryl propionic acid derivative and an emulsion preparation thereof.
  • Multimodal analgesia is to reduce peripheral and central sensitization by combining analgesic drugs with different mechanisms of action and various analgesic methods, acting on different targets of pain conduction pathways, exerting an additive or synergistic effect of analgesia, To obtain the best analgesic effect, reduce the dose of a single analgesic drug, and reduce adverse reactions.
  • analgesics it is mainly combined with other analgesics to reduce the dosage of opioids in clinical practice, so as to reduce their adverse reactions.
  • intravenous injection of parecoxib sodium 40 mg and dezocine 5 mg at the same time is used for postoperative analgesia in patients with hepatitis cirrhosis; flunoxicam and fentanyl for injection are combined in intravenous patient-controlled analgesia (PCA) for postoperative analgesia.
  • PCA intravenous patient-controlled analgesia
  • Analgesia etc.
  • morphine As a classic representative of opioid receptor agonists, morphine is widely used in various moderate and severe acute pain due to its long-acting and powerful analgesic effect, but sometimes causes side effects mediated by the central nervous system, such as respiratory depression, sedation And dizziness, etc. In addition, there is also addiction. At the same time, due to the existence of the 3-position phenolic hydroxyl group of morphine, the aqueous solution of morphine and its salts is unstable, and is easily affected by pH and temperature. It is most stable and neutral when the pH value is 4 Easily oxidized under alkaline conditions.
  • Fentanyl citrate injection is a powerful analgesic, suitable for sedation and analgesia before, during and after anesthesia, and the pH value of its solution is 4.0-6.0.
  • the commonly used non-steroidal anti-inflammatory drugs that can be used for intravenous injection such as ibuprofen injection, ketorolac tromethamine injection, parecoxib sodium for injection, etc.
  • the solution pH values are neutral to alkaline.
  • the instructions for diclofenac sodium injection emphasize that it cannot be mixed with other injections in the same infusion container. Therefore, there are few drugs that can be used in the same analgesic pump as opioids such as morphine in clinical practice, which brings great inconvenience to actual clinical operations.
  • Loxoprofen Sodium is the first aryl propionic acid non-steroidal anti-inflammatory drug. It was first developed by Japan's Daiichi Sankyo Co., Ltd. and first listed in Japan in 1986. Loxoprofen sodium is a non-selective cyclooxygenase inhibitor, which produces medicinal effects by inhibiting the synthesis of prostaglandins and unsaturated fatty acids catalyzed by arachidonic acid, so as to achieve the purpose of anti-inflammatory and analgesic. At present, there are mainly two dosage forms of these drugs clinically, oral and external, and there is no injection dosage form.
  • Loxoprofen sodium is a prodrug designed to overcome severe gastrointestinal adverse reactions. It has no activity itself. After oral administration, loxoprofen is absorbed in the form of free acid. In the human body, it needs to undergo the action of carbonyl reductase to reduce its cyclopentanone group stereoselectively. Among its eight metabolites Only (2S,1'R,2'S)-trans-OH has anti-inflammatory activity and exerts its therapeutic effect.
  • loxoprofen sodium solution is on the high side, and the environment of high pH value is easy to cause the opioids represented by morphine hydrochloride to precipitate in the combination of analgesic pump (PCA), thus limiting the realization of its Co-administration with opioids to reduce opioid use.
  • PCA analgesic pump
  • Loxoprofen is a liver-metabolized prodrug, which can be biotransformed in vivo into hydroxyl metabolites with 3 chiral centers, and theoretically generates 8 stereoisomers, of which the main biological activity is 2S, 1'R,2'S-trans-hydroxy active metabolite (compound 1), the structural formula is as follows:
  • the present application further optimizes the structure of the loxoprofen active substance, that is, compound 1, and derivatizes the carboxyl group of the active metabolite to prepare compound N2, which overcomes the defects of poor solubility and poor stability of the active metabolite itself.
  • Loxoprofen sodium reduces the dosage of the drug. And further make it into milky preparation, effectively overcome the problem of compatibility with opioids such as morphine hydrochloride, which is of great significance for effectively controlling the dosage of addictive drugs such as morphine in clinical practice.
  • the application provides an aryl propionic acid derivative and an emulsion preparation thereof.
  • the present application provides an aryl propionic acid derivative, that is, compound N2 represented by structural formula (1), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate, or its Solvates of pharmaceutically acceptable salts,
  • the present application provides a method for preparing a compound represented by structural formula (1), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate or a solvate of a pharmaceutically acceptable salt , which includes the step of compound 1 reacting with the compound shown in structural formula (2):
  • compound 1 is the active metabolite of loxoprofen, that is, the active metabolite of 2S, 1'R, 2'S-trans hydroxyl, and X in the compound shown in structural formula (2) can be chlorine, bromine and iodine.
  • the implementation method of this patent includes the step of reacting compound 1 and the compound represented by structural formula (2) in the presence of an acid-binding agent, and the acid-binding agent used is an inorganic base such as NaOH, KOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3.
  • the acid-binding agent used is an inorganic base such as NaOH, KOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3.
  • NaHCO 3 or organic bases such as triethylamine, pyridine, DMAP, DIEA, DBU;
  • the reaction solvent is acetone, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran , toluene, ethyl acetate, acetonitrile, DMF, DMAc or ether, one, two or more.
  • the preparation of the compound shown in structural formula (1) specifically includes the following steps:
  • the acid-binding agent is one of inorganic bases such as NaOH, KOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 or organic bases such as triethylamine, pyridine, DMAP, DIEA, DBU, Two or more; preferably one of Na 2 CO 3 , NaHCO 3 , triethylamine, pyridine, and DIEA;
  • inorganic bases such as NaOH, KOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3
  • organic bases such as triethylamine, pyridine, DMAP, DIEA, DBU, Two or more; preferably one of Na 2 CO 3 , NaHCO 3 , triethylamine, pyridine, and DIEA;
  • the reaction solvent is one, two or more of acetone, dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, ethyl acetate, acetonitrile, DMF, DMAc or ether; preferably two One of methyl chloride, toluene, ethyl acetate, acetonitrile, and DMF.
  • the compound represented by structural formula (2) is preferably 1-halogenated ethyl ethyl carbonate.
  • the present application provides the compound represented by the above structural formula (1), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate, or a solvate of a pharmaceutically acceptable salt thereof
  • the drug can be used to treat one or more of the following diseases: rheumatoid arthritis, low back pain, migraine, neuralgia, cancer pain, visceral pain, mixed pain, shoulder joint pain Inflammation, osteoarthritis, anti-inflammatory and/or analgesic for cervical, shoulder-wrist syndrome, analgesic and/or anti-inflammatory after surgery, trauma or tooth extraction, antipyretic and/or analgesic for acute upper respiratory inflammation.
  • diseases rheumatoid arthritis, low back pain, migraine, neuralgia, cancer pain, visceral pain, mixed pain, shoulder joint pain Inflammation, osteoarthritis, anti-inflammatory and/or analgesic for cervical, shoulder-wrist syndrome, analgesic and/or anti-inflammatory after surgery, trauma or tooth extraction, antipyretic and/or analgesic for acute upper respiratory inflammation.
  • the drug is a non-steroidal anti-inflammatory drug.
  • the present application also provides a milky preparation containing aryl propionic acid derivatives, which comprises:
  • the emulsion preparation is an emulsion preparation including nanoemulsion or submicroemulsion, and its average particle size is in the range of 10-550nm, preferably in the range of 50-350nm, more preferably in the range of 50-200nm, and then A range of 50-150 nm is further preferred.
  • the total weight of the emulsion preparation is 100%, and the mass percentage of the active ingredient is 0.1-10%, preferably 1-3%.
  • the emulsifier suitable for this application is selected from one or more combinations of lecithin and its derivatives, such as soybean lecithin, egg yolk lecithin, hydrogenated lecithin, and lecithin derivatives.
  • the emulsifier is selected from egg yolk lecithin and/or soybean lecithin, and the mass percentage is 0.5-15%, preferably 1.2-10%.
  • the oil suitable for this application is injectable oily ester, and described oil is selected from long-chain oil for injection or/and medium-chain oil for injection, and described long-chain oil is refined soybean oil, rice oil, castor oil, sunflower oil Kernel oil, tea oil, palm oil, coix seed oil, peanut oil, safflower oil, corn oil, cottonseed oil, olive oil, sesame oil, fish oil, sesame oil or a combination of several; said medium chain oil for injection It is one or a combination of medium-chain monoglycerides, medium-chain diglycerides, and medium-chain triglycerides.
  • the oil is selected from one or more of sesame oil, medium-chain triglyceride, soybean oil, sunflower oil, and peanut oil, and the mass percentage is 0.1-15%, preferably 3-10%.
  • the milky preparation further includes a stabilizer selected from oleic acid or/and sodium oleate, with a mass percentage of 0.01-1%.
  • the milky preparation further includes an isotonic regulator, and the isotonic regulator is selected from one or more of sucrose, glucose, sorbitol, xylitol, sodium chloride, and glycerol, The mass percentage is 0.5-15%, preferably 1-10%.
  • the milky preparation further includes a pH regulator selected from the group consisting of citric acid, hydrochloric acid, citric acid, fumaric acid, lysine, tartaric acid, histidine, citric acid One or more of sodium, sodium hydroxide, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, ascorbic acid, sodium ascorbate, and a pH regulator to adjust the pH to 4.5-6.5.
  • a pH regulator selected from the group consisting of citric acid, hydrochloric acid, citric acid, fumaric acid, lysine, tartaric acid, histidine, citric acid
  • a pH regulator selected from the group consisting of citric acid, hydrochloric acid, citric acid, fumaric acid, lysine, tartaric acid, histidine, citric acid
  • a pH regulator selected from the group consisting of citric acid, hydrochloric acid, citric acid, fumaric acid, lysine, tartaric acid, histidine,
  • the emulsion preparation also includes a co-emulsifier selected from n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, amyl alcohol, Kolliphor HS15, polysorbate 80
  • a co-emulsifier selected from n-butanol, ethylene glycol, ethanol, propylene glycol, glycerol, amyl alcohol, Kolliphor HS15, polysorbate 80
  • the mass percentage is 0.5-30%, preferably 2-10%.
  • the present application also provides a method for preparing a milky preparation containing aryl propionic acid derivatives.
  • milky injections can be divided into nanoemulsions and submicroemulsions according to the size of the emulsions and the differences in preparation methods.
  • Nanoemulsion is composed of oil, water, emulsifier and co-emulsifier, and is a thermodynamically stable system with isotropy and clear appearance. Because nanoemulsions can significantly increase the solubility of drugs in the lipophilic and hydrophilic regions, in order to promote the formation of emulsion droplets with a small radius of curvature, it is necessary to add co-emulsifiers in addition to emulsifiers in the prescription.
  • Submicron emulsion consists of oil phase, water phase, emulsifier and stabilizer.
  • the preparation method comprises the following steps:
  • step (3) Homogenizing the colostrum obtained in step (3) through microfluidics, microfluidics or high pressure to obtain end milk;
  • the dosage of the emulsifier is 1.2-4w/w%, and the dosage of oil for injection is 5-10w/w%.
  • the prepared fat emulsion injection has an average particle diameter in the range of 100-550 nm, more preferably in the range of 150-300 nm.
  • the preparation method comprises the following steps:
  • step (3) Homogenizing the colostrum obtained in step (3) through microfluidics, microfluidics or high pressure to obtain end milk;
  • the dosage of the emulsifier is 4-10w/w%, and the dosage of oil for injection is 3-5w/w%.
  • the prepared nanoemulsion injection has an average particle diameter in the range of 50-200 nm, more preferably in the range of 50-150 nm.
  • the present application also provides an application of an aryl propionic acid derivative and an opioid drug in the preparation of a non-steroidal anti-inflammatory drug.
  • the present application provides the compound represented by the above structural formula (1), its racemate, stereoisomer, pharmaceutically acceptable salt or solvate, or a solvate of a pharmaceutically acceptable salt thereof Co-administration of drugs and opioids in the preparation of drugs.
  • the medicament is used to treat one or more of the following diseases: rheumatoid arthritis, low back pain, migraine, neuralgia, cancer pain, visceral pain, mixed pain, periarthritis of the shoulder , Osteoarthritis, anti-inflammatory and/or analgesic for cervical, shoulder-wrist syndrome, analgesic and/or anti-inflammatory after surgery, trauma or tooth extraction, antipyretic and/or analgesic for acute upper respiratory inflammation.
  • diseases rheumatoid arthritis, low back pain, migraine, neuralgia, cancer pain, visceral pain, mixed pain, periarthritis of the shoulder , Osteoarthritis, anti-inflammatory and/or analgesic for cervical, shoulder-wrist syndrome, analgesic and/or anti-inflammatory after surgery, trauma or tooth extraction, antipyretic and/or analgesic for acute upper respiratory inflammation.
  • the emulsion preparations prepared in the present application are suitable for administration by parenteral administration, including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intracerebroventricular medication.
  • Administration can be parenteral in the form of a bolus, or it can be administered, for example, by means of a continuous infusion pump.
  • Commonly used containers for injections include glass ampoules, vials, plastic ampoules, and prefilled needles.
  • the present application derivatizes the carboxyl group of the active metabolite transformed by loxoprofen sodium into an ester to obtain compound N2, which improves the stability of the active metabolite of loxoprofen sodium, and simultaneously passes
  • the preparation method prepares the emulsion preparation, which improves its stability in the oil solution. After being prepared into an emulsion, it can be used in the same analgesic pump with opioids such as morphine, which solves the problem of the precipitation of opioids such as morphine. It is of great significance to effectively control the dosage of addictive drugs such as morphine in clinical practice.
  • Fig. 1 is the hydrogen spectrum atlas of compound N2 of the present application.
  • Fig. 2 is the mass spectrogram of compound N2 of the present application.
  • Figure 3 shows the degradation of compound N2 of the present application in human plasma.
  • Figure 4 shows the production of compound N2 of the present application in human plasma.
  • Fig. 5 is a semi-logarithmic graph of the average plasma concentration time of the compound N2 emulsion injection of the present application in Beagle dogs.
  • Figure 6A is the particle size distribution diagram of the milky injection of the present application before sterilization
  • Figure 6B is the particle size distribution of the milky injection of the present application after sterilization.
  • Figure 7A is the Zeta potential measurement result of the milky injection of the present application before sterilization
  • Figure 7B is the Zeta potential measurement result of the milky injection of the present application after sterilization.
  • Fig. 8 is a transmission electron microscope (TEM) image of the emulsion injection solution of the present application.
  • TEM transmission electron microscope
  • Fig. 9 is a shaking stability diagram of the emulsion injection solution of the present application.
  • the dynamic light scattering optical particle size analyzer PSS Nicomp Z3000 based on Rayleigh scattering theory is adopted, and the following parameters are used: optical intensity 300KHz; refraction angle 90°; The refractive index is 1.333; the viscosity is 0.933cp; the time is 5 minutes, the particle size and Zeta potential are detected, and the average particle size, PI, Zeta potential and other data are analyzed.
  • Test Example 1 Metabolism Research of Compound N2 of the Application in Human Plasma
  • Test Example 2 Pharmacokinetic study of compound N2 emulsion injection of the present application in Beagle dogs
  • Loxoprofen active metabolite tromethamine salt injection was administered at 0.8 mg/kg, and compound N2 emulsion injection was administered at an equimolar dose of 1.17 mg/kg. 24 hours before the administration, all dogs were transferred to the laboratory where the experiment will be carried out, placed in corresponding experimental cages to adapt the animals to the experimental environment, and reared in single cages. On the day of the experiment, the animals were divided into 2 groups. The feeding method was consistent with the daily feeding during the experiment.
  • the lateral vein of the forelimb or the small saphenous vein of the lateral hind limb was injected, and blood was collected before administration (pre-dose) and 3min, 5min, 10min, 15min, 30min, 1h, 2h, 4h, 6h and 8h after administration, and each blood collection was about 1 mL, add 10 ⁇ L of 2% DDVP saline and 10 ⁇ L of 15% EDTA-K2 solution for anticoagulation, centrifuge at 4°C and 2400 ⁇ g for 5 min, take the supernatant to obtain plasma samples, and freeze at -10°C to -30°C save.
  • concentrations of active metabolites of loxoprofen and compound N2 in plasma were determined by LC-MS/MS analysis.
  • Test Example 3 Screening of types of emulsifiers
  • the emulsifier is selected from egg yolk lecithin (PL-100M), egg yolk lecithin (PC-98T), egg yolk lecithin (E80), soybean lecithin (S100), soybean lecithin (S75), hydrogenated lecithin.
  • the colostrum was homogenized for 6 cycles at a pressure between 850-950 bar to obtain end milk containing different emulsifiers.
  • the obtained final milk is filtered and sterilized by a 0.22 ⁇ m syringe filter to obtain a nanoemulsion preparation.
  • the average particle size, polydispersity index (PI) and Zeta potential of the nanoemulsion preparation are measured in the following table:
  • egg yolk lecithin PL-100M was used as an emulsifier to obtain samples with small particle size, large absolute value of potential, and small PI, so egg yolk lecithin PL-100M was finally determined to be the emulsifier in the following examples.
  • Emulsion injections are prepared with different amounts of emulsifiers.
  • the formulation composition is shown in the table below:
  • emulsifier consumption is selected from 0.5% ⁇ 4.5%
  • Embodiment 15 ⁇ 18 experimental method
  • IKA T10 high-speed disperser shears the oil phase for 10 minutes, and magnetically stirs the water phase to make it evenly mixed.
  • the water phase was kept warm in a water bath at 65°C, and the IKA T25 high-speed disperser was sheared at 15,000 rpm, and the oil phase was added to the water phase.
  • the high-speed shear was continued for 10 minutes to obtain colostrum.
  • Adjust the pH of the colostrum to 4.5-6.5 with an appropriate amount of 0.1mol/L citric acid solution.
  • the colostrum was homogenized for 6 cycles at a pressure between 850-950 bar to obtain end milk with different emulsifier dosages. After the obtained final milk is filled and sealed, it is sterilized at 121° C. for 12 minutes. Determination of its average particle size, Zeta potential and PI is shown in the following table:
  • the dosage of egg yolk lecithin (PL-100M) of the present application is preferably 1.2 to 4%.
  • the prescription composition is shown in the following table:
  • the colostrum was homogenized for 6 cycles at a pressure between 850-950 bar to obtain end milk with different emulsifier dosages.
  • the obtained final milk was filtered and sterilized through a 0.22 ⁇ m syringe filter, and the nanoemulsion was obtained after filling and sealing.
  • the average particle size, polydispersity index (PI) and Zeta potential of the nanoemulsion are measured in the following table:
  • the dosage of egg yolk lecithin (PL-100M) of the present application is preferably 4-10%.
  • Test Example 5 Screening of Oil Types for Injection
  • the oil is selected from one or more of peanut oil, medium chain triglyceride, rice oil, castor oil, sesame oil, sunflower oil, tea oil, corn germ oil, and soybean oil.
  • the colostrum was homogenized for 6 cycles at a pressure between 850 and 950 bar to obtain end milk with different injection oil dosages.
  • the obtained final milk was filtered and sterilized through a 0.22 ⁇ m syringe filter, and the nanoemulsion was obtained after filling and sealing.
  • the average particle size, polydispersity index (PI) and Zeta potential of the nanoemulsion are measured in the following table:
  • the preferred oil phase of the fat emulsion of the present application is one or more of peanut oil, medium chain triglyceride (MCT), sunflower oil, tea oil, corn germ oil, and soybean oil.
  • MCT medium chain triglyceride
  • sunflower oil sunflower oil
  • tea oil corn germ oil
  • soybean oil soybean oil
  • Emulsion injections are prepared with different amounts of soybean oil.
  • the composition of the prescription is shown in the table below:
  • the amount of soybean oil is selected from 0.1% to 15%
  • IKA T10 high-speed disperser shears the oil phase for 10 minutes, and magnetically stirs the water phase to make it evenly mixed.
  • the water phase was kept warm in a water bath at 65°C, and the IKA T25 high-speed disperser was sheared at 15,000 rpm, and the oil phase was added to the water phase.
  • the high-speed shear was continued for 10 minutes to obtain colostrum.
  • Adjust the pH of the colostrum to 4.5-6.5 with an appropriate amount of 0.1mol/L citric acid solution.
  • the colostrum was homogenized for 6 cycles at a pressure between 850-950 bar to obtain end milk with different emulsifier contents. After the obtained final milk was filled and sealed, it was sterilized at 121°C for 12 minutes, and its average particle size, Zeta potential and PI were measured, as shown in the table below:
  • embodiment 41 ⁇ 43 has lower average particle size and lower PI value, so the consumption of soybean oil is preferably 3 ⁇ 10%.
  • the preferred ratio of egg yolk lecithin is 4-10%, and in the emulsion injection formulation, the total proportion of the oil phase is generally At 10% to 20%, too little oil phase can’t completely envelop the fat-soluble compound, and too much oil phase is easy to break after sterilization. Therefore, when preparing nanoemulsion, the preferred amount of oil for injection must be within the range mentioned above. A certain value among the above-mentioned 3-10% will not be studied too much here.
  • Test Example 7 Screening of types and dosages of co-emulsifiers, stabilizers, pH regulators, and osmotic pressure regulators
  • composition of the prescription is shown in the following table:
  • the colostrum was homogenized for 6 cycles at a pressure between 850-950 bar to obtain end milk with different amounts of soybean oil.
  • the obtained final milk is filtered and sterilized by a 0.22 ⁇ m syringe filter to obtain a nanoemulsion preparation. Stability samples were kept at 2-8°C and 25°C to observe the properties of the milky injection.
  • each example maintains a good appearance shape under the condition of retaining the sample.
  • the drug content of the nanoemulsion can be selected from 0.1-10%; in addition, all stabilizers, co-emulsifiers, isotonic regulators, and pH regulators perform well in the prescription.
  • Test Example 9 Dilution stability investigation with opioids such as morphine

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Abstract

本申请涉及一种芳基丙酸衍生物及其乳状制剂。所述芳基丙酸衍生物是对洛索洛芬活性代谢物的羧基进行衍生化，制备得到结构式(1)化合物，增加了化合物在油溶液中的溶解度，并进一步将其制成乳状制剂，有效克服了同盐酸吗啡等阿片类药物配伍的问题，对临床上有效控制吗啡等成瘾性药物的使用剂量具有重要意义。

Description

一种芳基丙酸衍生物及其乳状制剂 技术领域
本申请属于药物制剂领域，涉及一种芳基丙酸衍生物及其乳状制剂。
背景技术
世界卫生组织认为：疼痛本身是一种疾病，如不及时治疗，可转化为慢性疼痛、神经病理性疼痛，甚至引发抑郁症。美国麻醉师协会于2012年更新了《围手术期急性疼痛管理临床实践指南》，提出麻醉医生应多采用多模式镇痛的疼痛管理治疗。多模式镇痛，是通过联合不同作用机制的镇痛药物和多种镇痛方法，通过作用于疼痛传导通路的不同靶点，发挥镇痛的相加或协同作用，减少外周和中枢敏感化，而获得最佳镇痛效果，同时减少单种镇痛药剂量，减少不良反应。
目前临床上主要是通过联合其他镇痛药物减少阿片类药物使用剂量，从而减少其不良反应。比如同时将帕瑞昔布钠静脉注射40mg和地佐辛5mg，用于肝炎肝硬化患者术后镇痛；注射用氟诺昔康和芬太尼在静脉自控镇痛(PCA)联合应用用于术后镇痛等。
作为阿片受体激动药的经典代表，吗啡由于其长效强大的镇痛作用，广泛应用于各种中、重度急性疼痛，但是有时会引起中枢神经系统介导的副作用，例如呼吸抑制、镇静作用和头晕等，此外还存在成瘾性，同时由于吗啡3位酚羟基的存在，使得吗啡及其盐的水溶液不稳定，易受pH和温度的影响，在pH值为4时最稳定，中性和碱性条件下易氧化。枸橼酸芬太尼注射液为强效镇痛药，适用于麻醉前、中、后的镇静与镇痛，其溶液pH值为4.0～6.0。而目前临床上常用的可以用于静脉注射给药的非甾体抗炎药，如布洛芬注射液、酮咯酸氨丁三醇注射液、注射用帕瑞昔布钠等，其溶液的pH值均在中性偏碱性。双氯芬酸钠注射液在说明书中重点强调了其不能与其他注射液在同一输液容器中混合使用。所以临床上鲜有药物能与吗啡等阿片类药物在同一个镇痛泵中使用，这给实际临床操作带来了极大的不便。
洛索洛芬钠(Loxoprofen Sodium)是第一个芳基丙酸类非甾体抗炎药，最早由日本第一三共株式会社首先研制，于1986年在日本首先上市。洛索洛芬钠是非选择性环氧化酶抑制剂，通过抑制花生四烯酸催化前列腺素和不饱和脂肪酸的合成而产生药效，从而达到抗炎镇痛的目的。目前此类药物在临床上主要有口服和外用两种剂型，并无注射剂型。口服给药由于半衰期较短，每天需要给药3-4次，且易造成胃肠道损害及伴有心血管病风险，需长期服药的患者或胃溃疡患者往往不能耐受。洛索洛芬钠是一种前体类药物，其设计初衷是为了克服严重的消化道不良反应。其本身没有活性，口服给药后，洛索洛芬以游离酸的形式被吸收，在人体内需经过羰基还原酶的作用，将其环戊酮基团立体选择性还原，其八种代谢物中只有(2S,1’R,2’S)-trans-OH具有抗炎活性，发挥其治疗作用。考虑到注射液通过静脉注射途径进入人体内并无吸收过程，所以可能将洛索洛芬钠直接做成注射剂并不是一个最合适的选择。除此之外，洛索洛芬钠溶液的酸度值偏高，高pH值的环境易使以盐酸吗啡为代表的阿片类药物在镇痛泵(PCA)联用中析出，故而限制了实现其与阿片类药物联用来减少阿片类药物用量 的作用。
发明内容
洛索洛芬是一种肝脏代谢型的前药，在体内可生物转化具有3个手性中心的羟基代谢物，理论上生成8个立体异构体，其中发挥主要生物活性的的是2S,1’R,2’S-反式羟基活性代谢物(化合物1)，结构式如下：
Figure PCTCN2021141083-appb-000001
本申请通过进一步优化洛索洛芬活性物即化合物1的结构，对活性代谢物的羧基进行衍生化，制备得到化合物N2，克服了活性代谢物本身存在的溶解度差、稳定性差的缺陷，同时相对洛索洛芬钠降低了药物用量。并进一步将其制成乳状制剂，有效克服了同盐酸吗啡等阿片类药物配伍的问题，对临床上有效控制吗啡等成瘾性药物的使用剂量具有重要意义。
本申请提供了一种芳基丙酸衍生物及其乳状制剂。
第一方面，本申请提供一种芳基丙酸衍生物，即结构式(1)所示的化合物N2，其消旋体、立体异构体、药学上可接受的盐或溶剂合物，或者其药学上可接受的盐的溶剂合物，
Figure PCTCN2021141083-appb-000002
第二方面，本申请提供结构式(1)所示的化合物、其消旋体、立体异构体、药学上可接受的盐或溶剂合物或者药学上可接受的盐的溶剂合物的制备方法，其包括化合物1与结构式(2)所示化合物反应的步骤：
Figure PCTCN2021141083-appb-000003
其中，化合物1为洛索洛芬活性代谢物，即2S,1’R,2’S-反式羟基活性代谢物，结构式(2)所示化合物中X可以为氯、溴和碘。
根据本专利实施方法，包括化合物1与结构式(2)所示化合物在缚酸剂存在下反应的步骤，所用缚酸剂为无机碱如NaOH、KOH、K 2CO 3、KHCO 3、Na 2CO 3、NaHCO 3或有机碱如三乙胺、吡啶、DMAP、DIEA、DBU中的一种、两种或更多种；反应溶剂为丙酮、二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、甲苯、乙酸乙酯、乙腈、DMF、DMAc或乙醚中的一种、两种或更多种。
根据本专利实施方法，结构式(1)所示化合物的制备具体包括以下步骤：
(1)将化合物1溶解在溶剂中，然后加入结构式(2)所示化合物，冰浴下搅拌，分批加入缚酸剂，加毕；
(2)将反应容器移至室温搅拌反应过夜，TLC检测反应完全后，向反应容器中加入水、乙酸乙酯，振摇分液；以及
(3)将反应液萃取，洗涤，有机相干燥后浓缩，经柱层析纯化，得到目标化合物。
其中，所述缚酸剂为无机碱如NaOH、KOH、K 2CO 3、KHCO 3、Na 2CO 3、NaHCO 3或有机碱如三乙胺、吡啶、DMAP、DIEA、DBU中的一种、两种或更多种；优选为Na 2CO 3、NaHCO 3、三乙胺、吡啶、DIEA中的一种；
所述反应溶剂为丙酮、二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、甲苯、乙酸乙酯、乙腈、DMF、DMAc或乙醚中的一种、两种或更多种；优选为二氯甲烷、甲苯、乙酸乙酯、乙腈、DMF中的一种。
根据本申请的实施方案，结构式(2)所示化合物优选为1-卤代乙基乙基碳酸酯。
第四方面，本申请提供了上述结构式(1)所示的化合物、其消旋体、立体异构体、药学上可接受的盐或溶剂合物、或其药学上可接受的盐的溶剂合物在制备药物中的应用。
根据本申请的实施方案，所述药物可用于治疗一种或更多种以下的疾病：类风湿关节炎、腰痛症、偏头痛、神经痛、癌症疼痛、内脏疼痛、混合性疼痛、肩关节周围炎、骨性关节炎，颈肩腕综合征的消炎和/或镇痛，手术后、外伤后或拔牙后的镇痛和/或消炎、急性上呼吸道炎解热和/或镇痛。
根据本申请的实施方案，所述药物为非甾体抗炎药物。
第五方面，本申请还提供一种含芳基丙酸衍生物的乳状制剂，其包含：
(a)结构式(1)所示的化合物N2，其消旋体、立体异构体、药学上可接受的盐或溶剂合物，或者其药学上可接受的盐的溶剂合物作为活性成分：
Figure PCTCN2021141083-appb-000004
(b)乳化剂；以及
(c)油。
根据本申请的实施方案，所述乳状制剂为包括纳米乳或亚微乳在内的乳状制剂，其平均粒径大小在10-550nm范围，优选50-350nm范围，进一步优选50-200nm范围，再进一步优选50-150nm范围。
根据本申请的实施方案，所述乳状制剂的总重量计为100％，活性成分的质量百分比为0.1-10％，优选为1-3％。
适合用于本申请的乳化剂选自卵磷脂及其衍生物，如大豆卵磷脂、蛋黄卵磷脂、氢化卵磷脂，及卵磷脂衍生物中的一种或几种的组合。
根据本申请的实施方案，所述乳化剂选自蛋黄卵磷脂和/或大豆卵磷脂，质量百分比为0.5-15％，优选为1.2-10％。
适合用于本申请的油为可注射用油酯，所述油选自注射用长链油或/和注射用中链油，所述长链油为精制大豆油、稻米油、蓖麻油、葵花仁油、茶油、棕榈油、薏米仁油、花生油、红花油、玉米油、棉籽油、橄榄油、麻油、鱼油、芝麻油中的一种或几种的组合；所述注射用中链油为中链甘油单酯、中链甘油双酯、中链甘油三酯中的一种或几种的组合。
根据本申请的实施方案，所述油选自芝麻油、中链甘油三酸酯、大豆油、葵花仁油、花生油的一种或几种，质量百分比为0.1-15％，优选3-10％。
根据本申请的实施方案，所述乳状制剂还包括稳定剂，所述稳定剂选自油酸或/和油酸钠，质量百分比为0.01-1％。
根据本申请的实施方案，所述乳状制剂还包括等渗调节剂，所述等渗调节剂选自蔗糖、葡萄糖、山梨醇、木糖醇、氯化钠、甘油中的一种或几种，质量百分比为0.5-15％，优选为1-10％。
根据本申请的实施方案，所述乳状制剂还包括pH调节剂，所述pH调节剂选自枸橼酸、盐酸、柠檬酸、富马酸、赖氨酸、酒石酸、组氨酸、枸橼酸钠、氢氧化钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、抗坏血酸、抗坏血酸钠中的一种或几种，pH调节剂调节pH至4.5-6.5。
根据本申请的实施方案，所述乳状制剂还包括助乳化剂，所述助乳化剂选自正丁醇、乙二醇、乙醇、丙二醇、丙三醇、戊醇、Kolliphor HS15、聚山梨酯80一种或几种，质量百分比为0.5-30％，优选2-10％。
第六方面，本申请还提供一种含芳基丙酸衍生物的乳状制剂的制备方法。
通常，乳状注射液根据乳粒大小以及制备方法的差异可以分为纳米乳和亚微乳。纳米乳是由油、水、乳化剂和助乳化剂组成的，具各向同性、外观澄清的热力学稳定体系。纳米乳由于在亲油、亲水区域，能显著增大药物的溶解度，为促进曲率半径很小的乳滴的形成，处方中除加入乳化剂外还需要加入助乳化剂。亚微乳由油相、水相、乳化剂和稳定剂组成。
根据本申请的实施方案，所述乳状制剂为亚微乳时，制备方法包括以下步骤：
(1)将注射用油、稳定剂、乳化剂、结构式(1)所示的化合物，混合制备得油相；
(2)向注射用水中加入等渗调节剂；
(3)将油相加入水相中，高速剪切得初乳；调节pH至4.5-6.5；
(4)对步骤(3)所得初乳通过微射流、微流控或高压均质，得终乳；以及
(5)灌装，熔封，灭菌即得。
其中，所述乳化剂用量为1.2-4w/w％，注射用油用量为5-10w/w％。
制备得到的脂肪乳注射剂其平均粒径为100-550nm范围，进一步优选为150-300nm范围。
根据本申请的实施方案，所述乳状制剂为纳米乳时，制备方法包括以下步骤：
(1)将注射用油、稳定剂、乳化剂、助乳化剂加热搅拌溶解，再加入结构式(1)所示的化合物，混合制备得油相；
(2)向注射用水中加入等渗调节剂；
(3)将水相加入油相中，高速剪切得初乳；调节pH至4.5-6.5；
(4)对步骤(3)所得初乳通过微射流、微流控或高压均质，得终乳；以及
(5)过滤除菌，灌装，熔封，即得。
其中，所述乳化剂用量为4-10w/w％，注射用油用量为3-5w/w％。
制备得到的纳米乳注射剂其平均粒径为50-200nm范围，进一步优选为50-150nm范围。
本申请还提供一种芳基丙酸衍生物与阿片类药物协同给药在制备非甾体抗炎药物中的应用。
第七方面，本申请提供了上述结构式(1)所示的化合物、其消旋体、立体异构体、药学上可接受的盐或溶剂合物、或其药学上可接受的盐的溶剂合物与阿片类药物协同给药在制备药物中的应用。
根据本申请的实施方案，所述药物用于治疗一种或更多种以下疾病：类风湿关节炎、腰痛症、偏头痛、神经痛、癌症疼痛、内脏疼痛、混合性疼痛、肩关节周围炎、骨性关节炎，颈肩腕综合征的消炎和/或镇痛，手术后、外伤后或拔牙后的镇痛和/或消炎、急性上呼吸道炎解热和/或镇痛。
本申请制备的乳状制剂适宜于以肠胃外给药方式给药，肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内，例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。注射剂常用容器有玻璃安瓿、西林瓶、塑料安瓿、预充针等。
本申请具有如下有益效果：
与现有技术相比，本申请将洛索洛芬钠在体内转化的活性代谢物的羧基进行衍生化成酯，得到化合物N2，提高了洛索洛芬钠的活性代谢物的稳定性，同时通过制剂手段制备乳状制剂，提高了其在油溶液中的稳定性，制备成乳剂后，可与吗啡等阿片类药物在同一个镇痛泵中使用，解决了吗啡等阿片类药物析出的问题，对临床上有效控制吗啡等成瘾性药物的使用剂量具有重要意义。
附图说明
图1为本申请化合物N2的氢谱图谱。
图2为本申请化合物N2的质谱图谱。
图3为本申请化合物N2在人血浆中降解情况。
图4为本申请化合物N2在人血浆中生成情况。
图5为本申请化合物N2乳状注射液在比格犬中的平均血药浓度时间半对数曲线图。
图6A为本申请乳状注射液灭菌前的粒度分布图,图6B为本申请乳状注射液灭菌后的粒度分布图。
图7A为本申请乳状注射液灭菌前Zeta电位测定结果,图7B为本申请乳状注射液灭菌后Zeta电位测定结果。
图8为本申请乳状注射液透射电镜(TEM)图。
图9为本申请乳状注射液振摇稳定性图。
具体实施方式
下面结合具体实施例和附图对本申请作进一步详述，以下实施例只是描述性的，不是限定性的，不能以此限定本申请的保护范围，如无特别说明，所用原料均可通过市售或自制获得。
本申请中涉及的主要检测方法：
一、pH测定：
参照pH值测定法(中国药典2020版通则0631)测定。
二、粒度、Zeta电位测定：
取本品乳状注射液约25μL稀释于4mL经过滤的纯化水中，振摇使其混合均匀，得检测样品。参照粒度和粒度分布测定法(中国药典2020版通则0982第三法)，采用基于瑞利散射理论的动态光散射光学粒度分析仪PSS Nicomp Z3000，采用下列参数：光学强度300KHz；折射角90°；折射率1.333；粘度0.933cp；时间5min，进行粒度和Zeta电位检测，并对平均粒径、PI、Zeta电位等数据进行分析。
化合物N2的合成：
Figure PCTCN2021141083-appb-000005
实施例1
室温下，称取化合物1(5.0g，20.16mmol)，加入DMF(10mL)搅拌溶解，然后加入1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，碳酸钠(3.2g，30.24mmol)，KI(1g，6.0mmol)和TBAB(0.19g，0.6mmol)。将反应移至60度水浴锅中加热反应6h。TLC检测反应完全后，先浓缩除去DMF溶剂，然后向反应瓶中加入水100mL，乙酸乙酯50mL,振摇分液，有机层在用饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，制砂，经快速柱层析得到无色油状物5g,收率74.9％。
核磁氢谱图谱见附图1；质谱图见附图2。
实施例2
室温下，称取化合物1(5.0g，20.16mmol)，加入丙酮(10mL)搅拌溶解，然后加入1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，碳酸钠(3.2g，30.24mmol)，KI(1g，6.0mmol)和TBAB(0.19g，0.6mmol)。将反应移至60度水浴锅中加热反应6h。TLC检测反应完全后，先浓缩除去DMF溶剂，然后向反应瓶中加入水100mL，乙酸乙酯50mL,振摇分液，有机层在用饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，制砂，经快速柱层析得到无色油状物5.2g,收率71％。
实施例3
室温下，称取化合物1(5.0g，20.16mmol)，加入DMF(10mL)搅拌溶解，然后加入 1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，碳酸钾(4.17g，30.24mmol)，KI(1g，6.0mmol)和TBAB(0.19g，0.6mmol)。将反应移至60度水浴锅中加热反应6h。TLC检测反应完全后，先浓缩除去DMF溶剂，然后向反应瓶中加入水100mL，乙酸乙酯50mL,振摇分液，有机层在用饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，制砂，经快速柱层析得到无色油状物5.8g，收率79％。
实施例4
室温下，称取化合物1(5.0g，20.16mmol)，加入DMF(10mL)搅拌溶解，然后加入1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，碳酸铯(9.83g，30.24mmol)，KI(1g，6.0mmol)和TBAB(0.19g，0.6mmol)。将反应移至60度水浴锅中加热反应6h。TLC检测反应完全后，先浓缩除去DMF溶剂，然后向反应瓶中加入水100mL，乙酸乙酯50mL,振摇分液，有机层在用饱和食盐水洗，无水硫酸钠干燥，抽滤，浓缩，制砂，经快速柱层析得到无色油状物6.2g，收率84.5％。
实施例5
室温下，称取1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，NaI(9.0g，60.48mmol),CaCl 2(2.0g，18.1mmol),TBAB(0.29g，0.91mmol)于乙腈(30mL)中，将反应移至60度条件下加热反应4h，过滤除去固体，浓缩除去溶剂，然后加入乙酸乙酯50mL，再经水洗，5％Na 2S 2O 3洗，盐水洗，无水硫酸钠干燥，浓缩得到1-碘乙基乙基碳酸酯，不经纯化直接进行下一步反应。
将制备得到的1-碘乙基乙基碳酸酯用20mL DMF溶解，加入化合物1(5.0g，20.16mmol)和DIEA(2.6g，20.16mmol)室温搅拌反应6h，过滤除去固体，滤液浓缩至干，加入乙酸乙酯50mL，经水洗，盐水洗，无水硫酸钠干燥，浓缩，制砂，快速柱层析得无色油状物6.5g，总收率为88.6％。
实施例6
室温下，称取1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，NaI(9.0g，60.48mmol),CaCl 2(2.0g，18.1mmol),TBAB(0.29g，0.91mmol)于乙酸乙酯(30mL)中，将反应移至60度条件下加热反应4h，过滤除去固体，滤液经水洗，5％Na 2S 2O 3洗，盐水洗，无水硫酸钠干燥，浓缩得到1-碘乙基乙基碳酸酯，不经纯化直接进行下一步反应。
将制备得到的1-碘乙基乙基碳酸酯用20mL DMF溶解，加入化合物1(5.0g，20.16mmol)和DIEA(2.6g，20.16mmol)室温搅拌反应6h，过滤除去固体，滤液浓缩至干，加入乙酸乙酯50mL，经水洗，盐水洗，无水硫酸钠干燥，浓缩，制砂，快速柱层析得无色油状物6.4g，总收率为87.2％。
实施例7
室温下，称取1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，NaI(9.0g，60.48mmol),CaCl 2(2.0g，18.1mmol),TBAB(0.29g，0.91mmol)于丙酮(30mL)中，加热回流4h，过滤除去固体，过滤除去固体，浓缩除去溶剂，然后加入乙酸乙酯50mL，再经水洗，5％Na 2S 2O 3洗，盐水洗，无水硫酸钠干燥，浓缩得到1-碘乙基乙基碳酸酯，不经纯化直接进行下一步反 应。
将制备得到的1-碘乙基乙基碳酸酯用20mL DMF溶解，加入化合物1(5.0g，20.16mmol)和DIEA(2.6g，20.16mmol)室温搅拌反应6h，过滤除去固体，滤液浓缩至干，加入乙酸乙酯50mL，经水洗，盐水洗，无水硫酸钠干燥，浓缩，制砂，快速柱层析得无色油状物6.7g，总收率为91.3％。
实施例8
室温下，称取1-氯乙基乙基碳酸酯(4.6g，30.24mmol)，NaI(9.0g，60.48mmol)，CaCl 2(2.0g，18.1mmol)，TBAB(0.29g，0.91mmol)于DMF(30mL)中，加热回流4h，过滤除去固体，过滤除去固体，浓缩除去溶剂，然后加入乙酸乙酯50mL，再经水洗，5％Na 2S 2O 3洗，盐水洗，无水硫酸钠干燥，浓缩得到1-碘乙基乙基碳酸酯，不经纯化直接进行下一步反应。
将制备得到的1-碘乙基乙基碳酸酯用20mL DMF溶解，加入化合物1(5.0g，20.16mmol)和DIEA(2.6g，20.16mmol)室温搅拌反应6h，过滤除去固体，滤液浓缩至干，加入乙酸乙酯50mL，经水洗，盐水洗，无水硫酸钠干燥，浓缩，制砂，快速柱层析得无色油状物6.5g，总收率为88.6％。
试验例1：本申请化合物N2在人血浆中的代谢研究
(1)配制40mM的化合物N2，配制40mM的洛索洛芬活性代谢物纯乙腈贮备液；
(2)取25μL洛索洛芬活性代谢物贮备液1mL的人血浆中混合，涡旋30s，取样200μL加入800μL乙腈沉降蛋白，涡旋1min终止反应，作为洛索洛芬活性代谢物对照；40mM的化合物N2贮备液稀释200倍作为前药对照；
(4)取100μL化合物N2纯乙腈贮备液加入4mL的人血浆中混合，涡旋30s，置于37℃恒温振荡水浴加热器中200rpm振荡；
(5)在不同时间点(0、15、30、60和120min)取样200μL，每个时间点取样3次，加入800μL乙腈沉降蛋白，涡旋1min终止反应；并同法做空白血浆对照；
(6)12000rpm，4℃离心10min，取上清液，(过滤膜)进样30μL，记录峰面积变化；
(7)观察并分析化合物N2的水解速率。
实验结果如下表所示：
表1 化合物N2的代谢数据
化合物 前药化合物剩余量(％) 活性代谢物生成量(％)
N2 35.41％±1.83％ 53.40％±3.26％
由试验结果可知：化合物N2在血浆中的水解速率快，在体外人血浆中能够迅速转化为活性代谢物发挥其药理活性作用(见图3图4)。
试验例2：本申请化合物N2乳状注射液在比格犬体内药动学研究
洛索洛芬活性代谢物氨丁三醇盐注射液以0.8mg/kg、化合物N2乳状注射液以等摩尔计量1.17mg/kg剂量给药。给药24小时之前，将所有犬转移至将进行试验的实验室，置于相应实验笼具中使动物适应实验环境，单笼饲养。实验当天，将动物分为2组。实验期间饲喂方 式与日常饲喂保持一致。前肢外侧静脉或后肢外侧的小隐静脉注射，于给药前(pre-dose)和给药后3min、5min、10min、15min、30min、1h、2h、4h、6h和8h采血，每次采血约1mL，加入10μL的2％DDVP生理盐水和10μL的15％EDTA-K2溶液抗凝，于4℃和2400×g条件下离心5min，取上清获得血浆样品，于-10℃～-30℃冷冻保存。用LC-MS/MS分析测定血浆中洛索洛芬活性代谢物以及化合物N2的浓度。
表2 洛索洛芬活性代谢物氨丁三醇盐注射液以及化合物N2乳状注射液药动学参数
Figure PCTCN2021141083-appb-000006
上述试验结果表明：单次静脉给予1.17mg/kg的化合物N2乳状注射液后，比格犬血浆中仅3min的时间点可检测到活性代谢物，提示化合物N2在比格犬血浆中很快转化为活性代谢物；附图5为本申请化合物N2乳状注射液在比格犬中的平均血药浓度时间半对数曲线图，从图中可以看出静脉给予化合物N2乳状注射液体内药代动力学行为与静脉给予0.8mg/kg的洛索洛芬活性代谢物氨丁三醇盐注射液的数据相近，基于血浆中洛索洛芬活性代谢物氨丁三醇盐注射液的AUC 0-t数据，比格犬单次静脉给予化合物N2乳状注射液的相对生物利用度为94.59％。
试验例3：乳化剂种类的筛选
采用不同的乳化剂制备乳状注射液，纳米乳的处方组成见下表：
表3 乳状注射液处方
Figure PCTCN2021141083-appb-000007
其中，乳化剂选自蛋黄卵磷脂(PL-100M)、蛋黄卵磷脂(PC-98T)、蛋黄卵磷脂(E80)、大豆卵磷脂(S100)、大豆卵磷脂(S75)、氢化卵磷脂。
实验方法：
称取处方量的乳化剂、无水乙醇、大豆油、油酸在60℃下搅拌溶解，再加入处方量的化合物，混合搅拌制备得油相。称取处方量的水相，磁力搅拌使其混合均匀。对油相进行60℃水浴保温，高速分散机在20000rpm转速剪切下，将水相加入油相中，加入完全后继续高速剪切3分钟，得初乳。用适量的0.1mol/L枸橼酸溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到含不同乳化剂的终乳。所得终乳经0.22μm注射器过滤器过滤除菌后，得纳米乳制剂。测定纳米乳制剂的平均粒径、多分散指数(PI)以及Zeta电位见下表：
表4 平均粒径、Zeta电位及PI的测定
Figure PCTCN2021141083-appb-000008
上述试验结果表明：当乳化剂选用蛋黄卵磷脂时，所得纳米乳粒径普遍较小，乳化剂为大豆卵磷脂时，纳米乳粒径较大。而且目前广泛应用于临床的载药乳状注射液多采用天然蛋黄卵磷脂作为乳化剂，故后续实施例仅考察天然蛋黄卵磷脂用做乳化剂对乳状注射液对制剂稳定性的影响。同时，蛋黄卵磷脂PL-100M作为乳化剂所得样品粒径小、电位绝对值大、PI小，所以最终确定蛋黄卵磷脂PL-100M为后续实施例中乳化剂。
试验例4：乳化剂用量筛选
采用不同用量的乳化剂制备乳状注射液，当制备亚微乳时，处方组成见下表：
表5 乳状注射液处方
Figure PCTCN2021141083-appb-000009
其中，乳化剂用量选自0.5％～4.5％
实施例15～18实验方法：
分别称取处方量油相和水相，IKA T10高速分散机对油相剪切10分钟，对水相磁力搅拌使其混合均匀。对水相进行65℃水浴保温，IKA T25高速分散机在15000rpm转速剪切下，将油相加入水相中，加入完全后继续高速剪切10分钟，得初乳。用适量的0.1mol/L枸橼酸溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到不同乳化剂用量的终乳。所得终乳灌装熔封后，于121℃灭菌12分钟后。测定其平均粒径、Zeta电位及PI见下表：
表6 平均粒径、Zeta电位及PI的测定
Figure PCTCN2021141083-appb-000010
上述结果表明，蛋黄卵磷脂在处方中的用量越多，制得的样品平均粒径越小，但是同时随着蛋黄卵磷脂用量的增大，溶解在大豆油中以制得澄清的油相的时间越长，磷脂在高速剪 切下被氧化的概率越大。综合上述结果，本申请蛋黄卵磷脂(PL-100M)的用量优选在1.2～4％
当制备纳米乳时，处方组成见下表：
表7 乳状注射液处方
Figure PCTCN2021141083-appb-000011
实施例19～22实验方法：
称取处方量的蛋黄卵磷脂(PL-100M)、无水乙醇、大豆油、油酸在60℃下搅拌溶解，再加入处方量的化合物，混合搅拌制备得油相。称取处方量的水相，磁力搅拌使其混合均匀。对油相进行60℃水浴保温，高速分散机在20000rpm转速剪切下，将水相加入油相中，加入完全后继续高速剪切3分钟，得初乳。用适量的0.1mol/L枸橼酸溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到不同乳化剂用量的终乳。所得终乳经0.22μm注射器过滤器过滤除菌，灌装熔封后得纳米乳。测定纳米乳的平均粒径、多分散指数(PI)以及Zeta电位见下表：
表8 平均粒径、Zeta电位及PI的测定
Figure PCTCN2021141083-appb-000012
上述试验结果表明：在蛋黄卵磷脂用量较大的情况下，可以适当加入少量的助乳化剂以提高乳剂的稳定性。实施例19～21有更低的平均粒径和较高的Zeta电位，综上，本申请蛋黄卵磷脂(PL-100M)的用量优选在4～10％。
试验例5：注射用油种类筛选
采用不同种类的注射用油制备乳状注射液，纳米乳的处方组成见下表：
表9 乳状注射液处方
Figure PCTCN2021141083-appb-000013
其中，油选自花生油、中链甘油三酸酯、稻米油、蓖麻油、芝麻油、葵花仁油、茶油、玉米胚芽油、大豆油中的一种或几种。
实验方法：
称取处方量的蛋黄卵磷脂(PL-100M)、无水乙醇、不同种类的注射用油、油酸在60℃下搅拌溶解，再加入处方量的化合物，混合搅拌制备得油相。称取处方量的水相，磁力搅拌使其混合均匀。对油相进行60℃水浴保温，高速分散机在20000rpm转速剪切下，将水相加入油相中，加入完全后继续高速剪切3分钟，得初乳。用适量的0.1mol/L枸橼酸溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到不同注射用油用量的终乳。所得终乳经0.22μm注射器过滤器过滤除菌，灌装熔封后得纳米乳。测定纳米乳的平均粒径、多分散指数(PI)以及Zeta电位见下表：
表10 平均粒径、Zeta电位及PI的测定
Figure PCTCN2021141083-appb-000014
Figure PCTCN2021141083-appb-000015
上述试验结果表明：本申请脂肪乳剂优选的油相为花生油、中链甘油三酸酯(MCT)、葵花仁油、茶油、玉米胚芽油、大豆油中的一种或几种。考虑到目前广泛应用于临床的载药脂肪乳、纳米乳多采用大豆油作为单一的注射用油，同时MCT的摄入量过大会引起包括恶心，呕吐，腹胀，胃肠道不适，腹痛，渗透性腹泻等不良反应，因此后续实施例仅考察大豆油作为注射用油对制剂稳定性的影响。
试验例6：注射用油用量筛选
采用不同用量的大豆油制备乳状注射液，当制备亚微乳时，处方组成见下表：
表11 乳状注射液处方
Figure PCTCN2021141083-appb-000016
其中，大豆油用量选自0.1％～15％
实验方法：
分别称取处方量油相和水相，IKA T10高速分散机对油相剪切10分钟，对水相磁力搅拌使其混合均匀。对水相进行65℃水浴保温，IKA T25高速分散机在15000rpm转速剪切下，将油相加入水相中，加入完全后继续高速剪切10分钟，得初乳。用适量的0.1mol/L枸橼酸溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到不同乳化剂含量的终乳。所得终乳灌装熔封后，于121℃灭菌12分钟，测定其平均粒径、Zeta电位及PI见下表：
表12 平均粒径、Zeta电位及PI的测定
Figure PCTCN2021141083-appb-000017
上述试验结果表明：实施例41～43有较低的平均粒径和更低的PI值，故大豆油的用量优选为3～10％。
当制备纳米乳时，由于处方中蛋黄卵磷脂的用量较多，上文的实施例中已经表明蛋黄卵磷脂优选比例为4～10％，并且在乳状注射液处方中，油相总占比一般在10～20％，过少的油相无法完成包住脂溶性化合物，过多的油相灭菌后容易破乳，因此当制备纳米乳时，注射用油的的优选用量一定在上文所述的3～10％中的某一数值，在此不过多研究。
试验例7：助乳化剂、稳定剂、pH调节剂、渗透压调节剂的种类及用量筛选
采用不同比例的化合物、稳定剂、助乳化剂、渗透压调节剂、pH调节剂制备乳状注射液，处方组成见下表：
表13 乳状注射液处方
Figure PCTCN2021141083-appb-000018
Figure PCTCN2021141083-appb-000019
Figure PCTCN2021141083-appb-000020
实验方法：
称取处方量的蛋黄卵磷脂(PL-100M)、助乳化剂、大豆油、稳定剂在60℃下搅拌溶解，再加入处方量的化合物，混合搅拌制备得油相。称取处方量的渗透压调节剂和纯化水，磁力搅拌使其混合均匀，得水相。对油相进行60℃水浴保温，高速分散机在20000rpm转速剪切下，将水相加入油相中，加入完全后继续高速剪切3分钟，得初乳。用适量的pH调节剂溶液调节初乳的pH至4.5～6.5。将初乳于850-950bar之间的压力均质6个循环，得到不同大豆油用量的终乳。所得终乳经0.22μm注射器过滤器过滤除菌后，得纳米乳制剂。在2-8℃和25℃下进行稳定性样品留样，观察乳状注射液的性状。
表14 乳状注射液的性状
Figure PCTCN2021141083-appb-000021
Figure PCTCN2021141083-appb-000022
上述试验结果表明：除实施例52、62和63外，各实施例均在留样条件下保持较好的外观形状。由此可见，纳米乳含药量可选自0.1-10％；另外，各稳定剂、助乳化剂、等渗调节剂、pH调节剂在处方中均表现良好。
试验例8：振摇稳定性考察
取乳状注射液于恒温培养振荡器中，设定参数为温度：8℃，转速：100rpm。分别于0h、8h、24h取样，观察外观状态并测定粒径。结果如图9。振摇24h后，粒径几乎没有变化，表明振摇在24h内振摇稳定性良好。
试验例9：与吗啡等阿片类药物稀释稳定性考察
将化合物N2乳状注射液用生理盐水稀释至100mL后，于室温下加入不同类别的阿片类镇痛药，在不同的时间点观察混合溶液的外观、测定其平均粒径、pH见下表：
测定其平均粒径、Zeta电位及PI见下表：
表15 外观、粒径及pH的测定
Figure PCTCN2021141083-appb-000023
Figure PCTCN2021141083-appb-000024
对比例1
同时，将一些NSAIDs注射液，本申请列举了双氯芬酸钠注射液、酮咯酸氨丁三醇注射液用生理盐水稀释至100mL后，与阿片类镇痛药放入同一容器中，观察是否有晶体析出。结果见下表：
表16 NSAIDs注射液与阿片类镇痛药合用的性状观察
Figure PCTCN2021141083-appb-000025
上述试验结果表明：化合物N2乳状注射液与吗啡等阿片类药物在同一容器中合用时，在48小时内稳定性良好，为其在临床上，在镇痛泵中与阿片类药物合用提供了数据支持。

Claims (20)

  1. 一种芳基丙酸衍生物，即结构式(1)所示的化合物，其消旋体、立体异构体、药学上可接受的盐或溶剂合物，或者其药学上可接受的盐的溶剂合物，
    Figure PCTCN2021141083-appb-100001
  2. 一种制备权利要求1所述的芳基丙酸衍生物的方法，其包括化合物1与结构式(2)所示化合物反应的步骤：
    Figure PCTCN2021141083-appb-100002
    其中，化合物1为洛索洛芬活性代谢物，即2S,1’R,2’S-反式羟基活性代谢物，结构式(2)所示化合物中X可以为氯、溴和碘。
  3. 根据权利要求2所述的方法，其中，包括化合物1与结构式(2)所示化合物在缚酸剂存在下反应的步骤，所用缚酸剂为无机碱如NaOH、KOH、K 2CO 3、KHCO 3、Na 2CO 3、NaHCO 3或有机碱如三乙胺、吡啶、DMAP、DIEA、DBU中的一种、两种或更多种；反应溶剂为丙酮、二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、甲苯、乙酸乙酯、乙腈、DMF、DMAc或乙醚中的一种、两种或更多种。
  4. 根据权利要求2所述的方法，其中，包括以下步骤：
    (1)将化合物1溶解在溶剂中，然后加入结构式(2)所示化合物，冰浴下搅拌，分批加入缚酸剂，加毕；
    (2)将反应容器移至室温搅拌反应过夜，TLC检测反应完全后，向反应容器中加入水、乙酸乙酯，振摇分液；以及
    (3)将反应液萃取，洗涤，有机相干燥后浓缩，经柱层析纯化，得到目标化合物；
    其中，所述缚酸剂为无机碱如NaOH、KOH、K 2CO 3、KHCO 3、Na 2CO 3、NaHCO 3或有机碱如三乙胺、吡啶、DMAP、DIEA、DBU中的一种、两种或更多种；优选为Na 2CO 3、NaHCO 3、三乙胺、吡啶、DIEA中的一种；
    所述反应溶剂为丙酮、二氯甲烷、三氯甲烷、四氯化碳、四氢呋喃、甲苯、乙酸乙酯、乙腈、DMF、DMAc或乙醚中的一种、两种或更多种；优选为二氯甲烷、甲苯、乙酸乙酯、乙腈、DMF中的一种。
  5. 根据权利要求4所述的方法，其中，结构式(2)所示化合物为1-卤代乙基乙基碳酸酯。
  6. 如权利要求1所述芳基丙酸衍生物在制备非甾体抗炎药物中的应用；优选地，所述药物用于治疗一种或更多种以下疾病：类风湿关节炎、腰痛症、偏头痛、神经痛、癌症疼痛、内脏疼痛、混合性疼痛、肩关节周围炎、骨性关节炎，颈肩腕综合征的消炎和/或镇痛，手术 后、外伤后或拔牙后的镇痛和/或消炎、急性上呼吸道炎解热和/或镇痛。
  7. 一种含芳基丙酸衍生物的乳状制剂，其包含：
    (a)结构式(1)所示的化合物，其消旋体、立体异构体、药学上可接受的盐或溶剂合物，或者其药学上可接受的盐的溶剂合物作为活性成分：
    Figure PCTCN2021141083-appb-100003
    (b)乳化剂；以及
    (c)油。
  8. 根据权利要求7所述的乳状制剂，其中，所述乳状制剂为包括纳米乳或亚微乳在内的乳状制剂，平均粒径大小在10-550nm范围，优选50-350nm范围，进一步优选50-200nm范围，再进一步优选50-150nm范围。
  9. 根据权利要求7所述的乳状制剂，其中，所述乳状制剂按总重量计为100％，活性成分的质量百分比为0.1-10％，优选为1-3％。
  10. 根据权利要求7所述的乳状制剂，其中，所述乳化剂选自大豆卵磷脂、蛋黄卵磷脂、氢化卵磷脂及卵磷脂衍生物中的一种或几种的组合，优选蛋黄卵磷脂和/或大豆卵磷脂，质量百分比为0.5-15％，优选为1.2-10％。
  11. 根据权利要求7所述的乳状制剂，其中，所述油选自注射用长链油或/和注射用中链油，所述长链油为精制大豆油、稻米油、蓖麻油、葵花仁油、茶油、棕榈油、薏米仁油、花生油、红花油、玉米油、棉籽油、橄榄油、麻油、鱼油、芝麻油中的一种或几种的组合；所述注射用中链油为中链甘油单酯、中链甘油双酯、中链甘油三酯中的一种或几种的组合，质量百分比为0.1-15％，优选3-10％。
  12. 根据权利要求7所述的乳状制剂，其中，所述乳状制剂还包括稳定剂，所述稳定剂选自油酸或/和油酸钠，质量百分比为0.01-1％。
  13. 根据权利要求7所述的乳状制剂，其中，所述乳状制剂还包括等渗调节剂，所述等渗调节剂选自蔗糖、葡萄糖、山梨醇、木糖醇、氯化钠、甘油中的一种或几种，质量百分比为0.5-15％，，优选1-10％。
  14. 根据权利要求7所述的乳状制剂，其中，所述乳状制剂还包括pH调节剂，所述pH调节剂选自枸橼酸、盐酸、柠檬酸、富马酸、赖氨酸、酒石酸、组氨酸、枸橼酸钠、氢氧化钠、柠檬酸钠、磷酸二氢钠、磷酸氢二钠、抗坏血酸、抗坏血酸钠中的一种或几种，pH调节剂调节pH至4.5-6.5。
  15. 根据权利要求8所述的乳状制剂，其中，所述乳状制剂为纳米乳时，还包括助乳化剂，所述助乳化剂选自正丁醇、乙二醇、乙醇、丙二醇、丙三醇、戊醇、Kolliphor HS15、聚山梨酯80中的一种或几种，质量百分比为0.5-30％，优选2-10％。
  16. 一种如权利要求7～15任一项所述的乳状制剂的制备方法，其中，所述乳状制剂为亚 微乳时，制备方法包括以下步骤：
    (1)将注射用油、稳定剂、乳化剂、结构式(1)所示的化合物，混合制备得油相；
    (2)向注射用水中加入等渗调节剂；
    (3)将油相加入水相中，高速剪切得初乳；调节pH至4.5-6.5；
    (4)对步骤(3)所得初乳通过微射流、微流控或高压均质，得终乳；以及
    (5)灌装，熔封，灭菌即得。
  17. 根据权利要求16所述的制备方法，其中，所述乳化剂用量为1.2-4w/w％，注射用油用量为5-10w/w％。
  18. 一种如权利要求7～15任一项所述的乳状制剂的制备方法，其中，所述乳状制剂为纳米乳时，制备方法包括以下步骤：
    (1)将注射用油、稳定剂、乳化剂、助乳化剂加热搅拌溶解，再加入结构式(1)所示的化合物，混合制备得油相；
    (2)向注射用水中加入等渗调节剂；
    (3)将水相加入油相中，高速剪切得初乳；调节pH至4.5-6.5；
    (4)对步骤(3)所得初乳通过微射流、微流控或高压均质，得终乳；以及
    (5)过滤除菌，灌装，熔封，即得。
  19. 据权利要求18所述的制备方法，其中，所述乳化剂用量为4-10w/w％，注射用油用量为3-5w/w％。
  20. 如权利要求1所述芳基丙酸衍生物与阿片类药物协同给药在制备药物中的应用；优选地，所述药物用于治疗一种或更多种以下疾病：类风湿关节炎、腰痛症、偏头痛、神经痛、癌症疼痛、内脏疼痛、混合性疼痛、肩关节周围炎、骨性关节炎，颈肩腕综合征的消炎和/或镇痛，手术后、外伤后或拔牙后的镇痛和/或消炎、急性上呼吸道炎解热和/或镇痛。
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WO2022052936A1 (zh) * 2020-09-09 2022-03-17 南京海融医药科技股份有限公司 一种芳基丙酸衍生物、药物组合物及其制备方法和应用

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