WO2021143745A1 - 一种长效罗哌卡因药物组合物及其制备方法和用途 - Google Patents

一种长效罗哌卡因药物组合物及其制备方法和用途 Download PDF

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WO2021143745A1
WO2021143745A1 PCT/CN2021/071647 CN2021071647W WO2021143745A1 WO 2021143745 A1 WO2021143745 A1 WO 2021143745A1 CN 2021071647 W CN2021071647 W CN 2021071647W WO 2021143745 A1 WO2021143745 A1 WO 2021143745A1
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ropivacaine
acid
oil
composition
pharmaceutical composition
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PCT/CN2021/071647
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English (en)
French (fr)
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甘勇
郭仕艳
孙银银
朱全垒
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中国科学院上海药物研究所
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Priority to CN202180008982.7A priority Critical patent/CN114980893B/zh
Priority to EP21741682.5A priority patent/EP4091612A4/en
Priority to US17/792,474 priority patent/US20230080811A1/en
Publication of WO2021143745A1 publication Critical patent/WO2021143745A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—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

Definitions

  • the invention belongs to the technical field of medicine, and in particular, relates to a long-acting ropivacaine pharmaceutical composition, a preparation method thereof, and use thereof for preparing a medicine for treating postoperative pain.
  • the pharmaceutical composition has a controllable release behavior and a sustained-release effect, can significantly reduce the peak plasma concentration of the drug, maintain a stable blood concentration in the body, prolong the effective treatment time, reduce the effective therapeutic dose, increase the utilization rate of the drug, and reduce nerves Toxic risk, long-acting analgesic effect, can be used to treat postoperative pain.
  • Postoperative pain is a comprehensive response to soft tissue trauma during hypersensitivity surgery that stimulates the central nervous system. It is acute pain, which will have a significant impact on the function of the patient’s various organs, causing changes in a series of pathophysiological parameters, and This leads to various complications, which seriously affects the patient's postoperative recovery and affects the patient's life and health.
  • Postoperative analgesia can not only reduce postoperative pain in patients, but also stabilize various physiological indicators of patients, reduce the probability of complications during surgery, improve prognosis and shorten the length of hospital stay.
  • Local anesthetics can reversibly block the occurrence and conduction of nerve impulses by inhibiting the sodium ion channel of nerve cells. They are often used clinically for analgesia.
  • Ropivacaine is a newly synthesized amide local anesthetic in recent years, and it is the result of further optimization of bupivacaine. Compared with traditional local anesthetics, ropivacaine has the advantages of long curative effect time, accurate pain treatment effect, and less cardiotoxicity, which indicates that its clinical application will be more extensive in the future.
  • ropivacaine is the levorotatory isomer of 1-propyl-2,6-piperidinamide hydrochloride, the pH is 7.4, the pKa is 8.1, the fat solubility is low, and the dissociation constant is high. Therefore, its sensitivity to C fiber is significantly higher than that of A fiber, and it has obvious characteristics of separation of motor nerve block and sensory nerve block, that is, only sensory nerve block is produced at low concentration, and it has an impact on motor block. Very small and non-progressive, high concentrations can produce sensory nerve block and motor nerve block.
  • Modern anesthesia theory believes that while adequate postoperative analgesia, maintaining a certain degree of exercise capacity (that is, reducing the occurrence of motor block) is conducive to early getting out of bed, promoting gastrointestinal peristalsis and functional recovery, and shortening hospitalization time. More importantly, the higher drug concentration accompanying exercise block may cause chronic neurotoxicity (Acute Med Surg. 2017 Apr; 4(2): 152-160). Therefore, increasing sensory nerve block while avoiding motor block as much as possible has important clinical significance.
  • ropivacaine is relatively single, only ordinary hydrochloride or methanesulfonate aqueous solution, and the action time is short, which is difficult to meet the treatment requirements of postoperative pain, and multiple administrations will not only lead to poor patient compliance , It can also cause the peak-to-valley effect of blood drug concentration and produce toxic reactions. Therefore, the development of a safe and long-acting ropivacaine pharmaceutical composition has important clinical application value.
  • CN103142458B provides a ropivacaine oil solution preparation composition, which has a simple prescription process and a certain slow-release effect.
  • the pharmaceutical composition involved in the examples is that ropivacaine is dissolved in a system consisting of benzyl alcohol, benzyl benzoate, soybean oil or castor oil.
  • the composition can cause inflammatory reactions at the injection site and may cause Brings the risk of neuroinflammation, and has a certain risk of local irritation, and there is a safety risk.
  • CN104427977B provides a proliposome preparation of ropivacaine hydrochloride and a preparation method thereof.
  • the prescription adopts natural phospholipid, non-aqueous carrier and viscosity modifier ethanol, and the obtained proliposome preparation increases the drug loading capacity , Extending the duration of the drug effect.
  • the preparation has high viscosity and poor needle penetration, which brings inconvenience to clinical use. At the same time, the effective bioavailability of the medicine is low, which will lead to waste of medicine.
  • CN109316602A provides a compound sustained-release drug delivery system composed of local anesthetics, non-steroidal anti-inflammatory drugs, solvents and slow-release materials. Although it has a certain slow-release analgesic effect and the function of promoting wound healing, it is non-steroidal Body anti-inflammatory drugs have a capping effect and have the disadvantages of causing adverse gastrointestinal reactions, nervous system and cardiovascular system toxicity. At the same time, the proportion of organic solvents is large, reaching 30-40%, which is easy to cause irritation at the injection site and poses safety risks.
  • CN108743952A provides a phospholipid-mixed solvent-oil as a carrier local anesthetic sustained-release preparation and preparation method, which uses benzyl benzoate, ethanol and benzyl alcohol as solvents, the total amount of solvents is as high as 40-50%, which is easy to cause injection The irritation of the site and systemic adverse reactions pose safety hazards.
  • WO2019046293A1 provides a sustained-release anesthetic composition, comprising a local anesthetic and one or more lipid mixtures (such as phospholipids or cholesterol), prepared into a lipid matrix by a one-step freeze-drying method, and then hydrated with a buffer Formation;
  • US2015250724A1 provides a liposome formulation of a long-acting controlled-release local anesthetic, by mixing water and organic phase, adding phospholipids and cholesterol to form an emulsion, so that the emulsion and the second aqueous phase solution are exchanged externally to form lipids
  • the preparation processes of the above two patents are relatively complicated and have stability problems during long-term storage.
  • CN106535886A provides a drug delivery system composed of amide-type local anesthetics, enol acid non-steroidal anti-inflammatory drugs and delivery carriers for the treatment of acute or chronic pain.
  • non-steroidal anti-inflammatory drugs have a capping effect and have the disadvantages of easily causing adverse gastrointestinal reactions, nervous system and cardiovascular system toxicity.
  • the delivery carrier is composed of polyorthoesters, polar aprotic solvents and viscosity-lowering agents triglycerides, and the resulting composition has a relatively high viscosity, poor needle penetration, and poor clinical administration convenience.
  • the obtained composition has a certain sustained-release effect, it has low effective drug availability, high irritation at the injection site, high potential safety hazards, poor needle penetration, and complex technology. , Poor stability and other shortcomings.
  • the composition of the present invention is improved on the basis of the existing research technology, adding an appropriate amount of medicinal effect enhancer, not only can maintain the slow-release effect and good stability characteristics of the composition, but also extend the conventional sustained-release preparation at the same dose It can reduce the effective therapeutic dose under the same analgesic effect, improve the motor nerve block, and improve the safety of medication, which has not been reported in the field.
  • An object of the present invention is to provide a long-acting ropivacaine pharmaceutical composition.
  • Another object of the present invention is to provide a method for preparing the above-mentioned long-acting ropivacaine pharmaceutical composition.
  • Another object of the present invention is to provide the use of the aforementioned long-acting ropivacaine pharmaceutical composition.
  • ropivacaine salts have low solubility in oils and fats, which cannot meet the needs of clinical high-dose administration.
  • the inventors added an appropriate amount of medicinal phospholipids to the composition, and after a suitable preparation process, it can dissolve ropivacaine salts and ropivacaine free alkali, and the solution is stable and injectable. Good penetration.
  • the inventors prepared compositions containing different proportions of medicinal phospholipids, and conducted pharmacodynamic investigations in rats. As a result, the inventors unexpectedly found that the proportions of phospholipids were different, and the obtained compositions were in rats.
  • the duration of drug effect is different, but compared with ropivacaine hydrochloride injection (trade name: Nilepin), it can significantly extend the duration of drug effect. Therefore, in drug development, the corresponding composition can be designed according to different clinical treatment needs to achieve the purpose of precise treatment.
  • the inventors found that the drug in the composition is not completely released in the rat body, resulting in bioavailability Especially the effective bioavailability is low. Drugs that have not exerted their medicinal effects will stay in the body, which will not only cause waste of drugs, but may also cause chronic toxicity of nerve fibers. At the same time, during the entire drug efficacy measurement period, the rats have the phenomenon of curling up and not touching the ground for a long time (that is, motor block), so the development of the composition needs to be improved.
  • the effective therapeutic dose R is calculated by the following formula:
  • A is the administration dose of ropivacaine drug
  • T t is the effective treatment time of the drug in the body.
  • the effective treatment time of the drug in the body refers to the duration of the drug effect, which is determined by the drug effect experiment. The smaller the R value, the smaller the dose of the drug required to achieve the unit efficacy duration, that is, the longer the effective treatment time of the drug under the same dose.
  • the inventors unexpectedly discovered that after adding the drug effect enhancer of the present invention, the drug effect duration of the pharmaceutical composition is significantly prolonged, the effective bioavailability is improved, the analgesic effect is enhanced, and the effective therapeutic dose R value is significant Decrease, the irritation at the injection site is significantly reduced. With the same analgesic effect, the motor block condition is significantly improved.
  • the present invention provides a long-acting ropivacaine pharmaceutical composition.
  • the composition has obvious advantages over ropivacaine hydrochloride injection and other reported related preparations in terms of safety, sustained-release effect and maintenance time, drug utilization, improvement of motor blockage, and the like.
  • the present invention provides a long-acting ropivacaine pharmaceutical composition, the pharmaceutical composition comprising: ropivacaine; a medicinal solvent; a medicinal phospholipid; a medicinal oil; a medicinal effect enhancer, optional Antioxidants and optional acid-base regulators, wherein the drug effect enhancer can significantly prolong the duration of the drug effect of the composition, and can significantly reduce the effective therapeutic dose of the drug compared with conventional sustained-release preparations at the same dose.
  • the drug effect enhancer is selected from one or a combination of two or more of omega-3 fatty acids and their metabolites, substances rich in omega-3 fatty acids or their metabolites, and more preferably, the drug effect is enhanced
  • the dosage of the agent in the composition ranges from 0.5% to 10%.
  • the pharmaceutical composition of the present invention comprises, based on the total weight of the composition, in percentage by weight,
  • the ropivacaine mainly includes ropivacaine free base and its salts, which may be a combination of one, two or more of them.
  • the salt may be, for example, hydrochloride, methanesulfonate, hydrobromide, hydroiodide, sulfate, citrate, tartrate, lactate, citrate, horse Lyric acid salt, fumarate salt, etc.
  • the pharmaceutical solvent may be a single organic solvent or a mixture of multiple organic solvents.
  • the pharmaceutical solvent include, but are not limited to, benzyl alcohol, ethanol, propylene glycol, glycerin, isopropanol, N-methylpyrrolidone, dimethyl sulfoxide, liquid polyethylene glycol, dimethylacetamide, glycerol monoacetate Ester, polyethylene glycol monomethyl ether, diethylene glycol monoethyl ether, ethyl lactate, ethyl acetate, propylene glycol diethyl, diethyl malonate, tetrahydrofuran polyethylene glycol ether, benzyl benzoate , Or a mixture of two or more thereof, more preferably, the pharmaceutical solvent is one or more selected from benzyl alcohol, propylene glycol, and ethanol.
  • the antioxidant is used to prevent or slow down the oxidative degradation of the composition, and it can be any antioxidant that can be used in the pharmaceutical composition system of the present invention in the art, as long as it is effective for ropiva.
  • the drug activity of caine does not have any obvious adverse effects.
  • it may be selected from cysteine, ⁇ -tocopherol, ⁇ -tocopherol acetate, N-acetyl-L-cysteine, and butylated hydroxyanisole.
  • the acid-base regulator is used to adjust the pH of the composition.
  • It can be any acid-base regulator that can be used in the pharmaceutical composition system of the present invention in the art, as long as it is effective for The drug activity of pivacaine does not have any obvious adverse effects.
  • it can be selected from arginine, lysine, histidine, glycine, tromethamine, diethanolamine, ethylenediamine, meglumine, and hydrochloric acid.
  • acetic acid anhydrous citric acid, ascorbic acid, lactic acid, tartaric acid, methanesulfonic acid, methionine, sodium hydroxide, and triethanolamine; preferably selected from tromethamine, diethanolamine, ethylenediamine One or more of meglumine.
  • the medicinal oil can be selected from one or a combination of two or more of the following: natural vegetable oils (such as castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil) Oil, olive oil, cottonseed oil) or semi-natural oils artificially modified from natural vegetable oils (such as hydrogenated castor oil), purified oils and corresponding derivatives; synthetic oils, mainly including medium-chain triglycerides (e.g. caprylic acid) Triglycerides, capric triglycerides or a mixture of the two), long-chain triglycerides, triacetin or other corresponding derivatives, ethyl oleate.
  • natural vegetable oils such as castor oil, sesame oil, soybean oil, sunflower oil, peanut oil, corn oil, rapeseed oil
  • Oil olive oil, cottonseed oil
  • semi-natural oils artificially modified from natural vegetable oils such as hydrogenated castor oil
  • synthetic oils mainly including medium-chain triglycerides (e
  • the pharmaceutical phospholipid can be selected from one or more combinations of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids.
  • natural phospholipids include, but are not limited to, egg yolk lecithin, soybean phospholipids, or combinations thereof;
  • semi-synthetic phospholipids include, but are not limited to, hydrogenated egg yolk lecithin, hydrogenated soybean phospholipids, or combinations thereof;
  • Examples include, but are not limited to, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, One or more combinations of myristoylphosphatidylcholine, etc.
  • the pharmaceutical phospholipids include, but are not limited
  • the drug effect enhancer can significantly prolong the duration of the drug effect of the composition, and can significantly reduce the effective therapeutic dose of the drug at the same dose compared with conventional sustained-release preparations.
  • the drug effect enhancer of the present invention can be selected from one or a combination of two or more of omega-3 fatty acids and their metabolites, and substances rich in omega-3 fatty acids or their metabolites.
  • omega-3 fatty acids and their metabolites mainly refer to omega-3 polyunsaturated fatty acids and their metabolites, such as alpha-linolenic acid and its metabolites eicosapentaenoic acid (EPA) and arachis Dicahexaenoic acid (DHA) or a combination thereof.
  • the alpha-linolenic acid involved is alpha-linolenic acid (ALA) derived from plants, and the substance rich in alpha-linolenic acid can be linseed oil, perilla seed oil, walnut oil, argan oil and other vegetable oils; rich in EPA And DHA and other ⁇ -linolenic acid metabolites can be fish oil, laver oil, algae oil.
  • the substances rich in omega-3 fatty acids or their metabolites include substances rich in ⁇ -linolenic acid, substances rich in ⁇ -linolenic acid metabolites eicosapentaenoic acid and docosahexaenoic acid or substances
  • the substance rich in ⁇ -linolenic acid includes linseed oil, perilla seed oil, walnut oil, argan oil or a combination thereof; the metabolite of ⁇ -linolenic acid is rich in eicosapentaenoic acid
  • Substances with docosahexaenoic acid include fish oil, laver oil and algae oil or a combination thereof.
  • the drug effect enhancer is one or more selected from substances rich in omega-3 fatty acids or their metabolites, and more preferably, the drug effect enhancer It is selected from substances rich in omega-3 fatty acids or their metabolites, the content of eicosapentaenoic acid (EPA) is not less than 15%, and the content of docosahexaenoic acid (DHA) is not less than 10%
  • the efficacy enhancer is selected from substances rich in omega-3 fatty acids or their metabolites, and the content of eicosapentaenoic acid (EPA) is not less than 20%
  • one or more of the substances whose docosahexaenoic acid (DHA) content is not less than 10% is more particularly preferably one or more selected from fish oil and laver oil.
  • the long-acting ropivacaine pharmaceutical composition of the present invention can reduce the peak plasma concentration of the drug by more than 30% compared with the same dose of ropivacaine hydrochloride injection, preferably by more than 50%, more preferably by more than 60%;
  • the duration is more than 12h, more than 24h, or even more than 48h, for example, it can be 12-24h, 24-48h, 12-48h, etc.;
  • the effective therapeutic dose of the composition can be reduced by more than 10% compared with conventional sustained-release preparations, preferably reduced 20% or more, more preferably 30% or more;
  • the composition and the conventional sustained-release preparation can improve the motor block by 20%, preferably 30%, and more preferably 60% while achieving the same analgesic effect.
  • the present invention provides a method for preparing the above-mentioned long-acting ropivacaine pharmaceutical composition, and the method includes the following steps:
  • the prescription amount of ropivacaine, prescription amount of medicinal oil, prescription amount of medicinal phospholipid, prescription amount of medicinal effect enhancer and optional, prescription amount of antioxidant and optional, prescription amount of acid and alkali The regulator and prescription amount of pharmaceutical solvent are evenly dispersed in the excess volatile organic solvent;
  • the drug effect enhancer and the acid-base regulator can be added at the same time or sequentially with ropivacaine, antioxidants, drug solvents, medicinal oils and phospholipids, or added in the final step.
  • examples of the volatile organic solvent include, but are not limited to, ethanol, dichloromethane, chloroform, methanol, etc., for example.
  • the present invention provides a method for preparing the aforementioned long-acting ropivacaine pharmaceutical composition, the method comprising the following steps:
  • the antioxidants and acid-base regulators can be added in any step of the above process.
  • the present invention provides a method for preparing the aforementioned long-acting ropivacaine pharmaceutical composition, the method comprising the following steps:
  • the antioxidants and acid-base regulators can be added in any step of the above process.
  • the composition is a clear solution.
  • the above method may also include the steps of sub-packaging and optional sterilization or sterilization.
  • the sterilization is, for example, filtration sterilization.
  • the sterilization is, for example, moist heat sterilization.
  • the present invention provides the use of the long-acting ropivacaine pharmaceutical composition in the preparation of pain relief drugs.
  • the composition can controllably adjust the time for treating pain, and can provide long-term analgesic effects.
  • the pain relief drug may be in various dosage forms for local administration or in the form of packaging kits, for example, suitable for local injection, such as subcutaneous or intramuscular injection, or directly instilled into the incision for administration, or incision infiltration administration, or Administration at the nerve plexus or through joint cavity injection, preferably by subcutaneous injection, more preferably in the form of a dosage form or packaged kit for subcutaneous infiltration administration.
  • the pain is post-operative pain.
  • the pharmaceutical composition provides pain relief of at least about 12 hours. In some embodiments, the pharmaceutical composition provides pain relief between 12 and 24 hours. In some embodiments, the pharmaceutical composition provides pain relief for at least about 24 hours. In some embodiments, the pharmaceutical composition provides pain relief between 24 and 48 hours. In some embodiments, the pharmaceutical composition provides pain relief of at least about 48 hours. In some embodiments, the pharmaceutical composition provides pain relief between 48 and 72 hours. In some embodiments, the pharmaceutical composition provides pain relief of at least about 72 hours.
  • the composition has a significant advantage over the pain relief time of the composition without the drug effect enhancer and the amount of the drug effect enhancer outside the scope of the present invention.
  • the long-acting ropivacaine pharmaceutical composition provided by the present invention can be injected locally, such as subcutaneously or intramuscularly, or directly instilled into the incision for administration, or incision infiltration administration, or administered at the nerve plexus, or through Joint cavity injection is preferably subcutaneous injection administration, more preferably subcutaneous infiltration administration.
  • the expected total amount of the long-acting ropivacaine pharmaceutical composition provided by the present invention that needs to be taken daily is 5-1000 mg, preferably 10-500 mg, based on the active drug.
  • ropivacaine refers to ropivacaine free base or a pharmaceutically acceptable salt of ropivacaine, where ropivacaine free base may be in the form of a solvate of ropivacaine free base, And the pharmaceutically acceptable salt of ropivacaine may be in the form of a solvate of the pharmaceutically acceptable salt of ropivacaine, unless otherwise explained according to the context.
  • sensor nerve block means that the nerve endings of any sensory site are blocked in the process of transmitting impulses to the center, resulting in loss of perception, which can be understood as sensory block.
  • the present invention specifically refers to loss of pain.
  • Analgesia in the present invention refers to the blocking of sensory nerves, and the drug effect refers to the effect of blocking the sensory nerves.
  • motor nerve block refers to that the process of nerve fibers sending nerve impulses to the surroundings and producing movement is blocked, which is manifested as impaired motor function and limited activity, which can be understood as motor block.
  • the term "effective treatment time” can be understood as the duration of the drug's pharmacological effects, and can be understood as the pharmacological duration.
  • effective therapeutic dose refers to the required drug dose when the unit effective therapeutic time is reached.
  • compositions that has a prescription similar to the present invention but does not contain a drug effect enhancer, such as the proliposome preparation disclosed in CN104427977B.
  • composition can be understood as a pharmaceutical composition, a pharmaceutical prescription, a pharmaceutical prescription, a formula or a pharmaceutical preparation.
  • bioavailability refers to the speed and extent at which the drug is absorbed into the human circulation.
  • AUC blood drug concentration-time curve
  • the term "effective concentration” refers to the minimum blood drug concentration that exerts a drug effect. When the blood drug concentration is greater than this value, the drug can exert its drug effect. It can be understood as the minimum effective concentration and the minimum effective concentration.
  • effective bioavailability refers to the area under the plasma concentration-time curve that is greater than the effective concentration.
  • the present invention provides a long-acting ropivacaine pharmaceutical composition through creative research.
  • the composition has good solubility to ropivacaine free base and salt-type drugs, and has good injection traversability and controllable release rate.
  • the composition significantly reduces C max and improves safety.
  • the most important thing is that the composition of the present invention can prolong the effective treatment time, reduce the effective treatment dose, and can improve the bioavailability and effective bioavailability, ensuring that the drug meets the clinical analgesic time requirement while fully exposing the drug to avoid Drug waste reduces the potential risk of neurotoxicity.
  • the composition of the present invention can solve the problems of clinical treatment and safety requirements of local anesthetics, and has good application prospects.
  • the present invention Compared with the previously studied ropivacaine pharmaceutical preparations, the present invention has the following advantages:
  • the present invention can reduce the peak plasma concentration by at least 30%, preferably by at least 50%, and more preferably by at least 60%.
  • the peak concentration improves the safety of clinical medication.
  • the pharmaceutical composition of the present invention has a duration of drug effect of more than 12 hours, preferably more than 24 hours, which reduces the number of repeated administrations, increases patient compliance, and reduces treatment costs.
  • the pharmaceutical composition of the present invention can release drugs more completely, significantly improve bioavailability and effective bioavailability, avoid long-term retention of ineffective drugs, and reduce the risk of nerve fiber damage.
  • the pharmaceutical composition of the present invention can significantly prolong the efficacy time and reduce the treatment cost compared with conventional sustained-release preparations at the same dosage.
  • the pharmaceutical composition of the present invention can improve motor blockade, reduce neurotoxicity, and facilitate pain recovery.
  • the pharmaceutical composition of the present invention can reduce the effective therapeutic dose, and can reduce the dosage of the drug when the duration of the same drug effect is reached, improve the utilization rate of the drug, avoid the waste of the drug, and reduce the risk of toxic reactions. .
  • the pharmaceutical composition of the present invention has a controllable duration of drug effect, and provides the beneficial value of on-demand selection for the development and clinical use of ropivacaine drugs.
  • the pharmaceutical composition of the present invention has low local irritation, good biocompatibility and safety.
  • the present invention has the advantages of good safety, high bioavailability, controllable slow-release effect, high drug utilization, low neurotoxicity, and good injection puncture.
  • Figure 1 shows the results of the inspection of the animal mechanical leg shrinkage threshold of Comparative Example 3.
  • Figure 2 shows the comparative study results of the animal mechanical leg shrinkage threshold of Comparative Example 4 and the ropivacaine pharmaceutical composition (composition 6, 7, 9, 16, 17, 22); and the mechanical leg shrinkage before administration of each group of animals Compared with the threshold, ***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 3 shows the comparative study results of the animal mechanical leg shrinkage threshold of Comparative Example 4 and the ropivacaine pharmaceutical composition (composition 6, 7, 9, 16, 17, 22); compared with the mechanical leg shrinkage threshold of Comparative Example 4 , ###P ⁇ 0.001, ##P ⁇ 0.01, #P ⁇ 0.05.
  • Figure 4 shows the results of comparing the nerve block scores of placebo with normal saline, comparative example 4 and ropivacaine compositions (compositions 6, 7, 9, 16, 17, 22); the nerve block scores of the placebo group with normal saline Compared with block score, ***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 5 shows the results of comparative investigation of the animal mechanical leg shrinkage threshold of the ropivacaine pharmaceutical composition of the present invention (compositions 9-1, 9-2 and 9-3); and the mechanical leg shrinkage threshold before administration of each group of animals In comparison, ***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figure 6 shows the comparative study results of animal mechanical leg shrinkage thresholds of Comparative Examples 8, 9 and ropivacaine pharmaceutical compositions (compositions 23, 24 and 25); compared with the mechanical leg shrinkage threshold of each group of animals before administration, ***P ⁇ 0.001, **P ⁇ 0.01, *P ⁇ 0.05.
  • Figures 7 and 8 show the results of in vivo pharmacokinetics (PK) investigations of the ropivacaine pharmaceutical composition of the present invention (compositions 7, 9, 17) and comparative examples 3 and 4.
  • PK pharmacokinetics
  • Figure 9 shows the relationship between the efficacy and pharmacokinetics of the ropivacaine pharmaceutical composition 7 of the present invention.
  • Figure 10 shows the results of the irritation investigation of the composition 8 of the present invention and the comparative example 7 at the injection site.
  • Figure 11 shows the histopathological observation results of the injection site of the non-injected group, Comparative Example 3, Comparative Example 5, and the ropivacaine composition of the present invention (compositions 7, 9).
  • Comparative example 4 CN104427977B proliposomal preparation (conventional sustained-release preparation)
  • composition in Table 8 add the prescription amount of ropivacaine to the pharmaceutical solvent, stir until dissolved to obtain the pharmaceutical solution; add the medicinal phospholipid to the corresponding medicinal oil, high-speed shearing to the medicinal phospholipid Completely dissolve; add the drug solution to it, stir evenly, then add the drug effect enhancer, stir to obtain the drug-containing solution, filter and pack, fill with nitrogen, seal, and then sterilize with moist heat to obtain a clear and transparent liquid.
  • compositions prepared after adding an appropriate amount of medicinal phospholipids are all clear and transparent, achieving the purpose of improving the solubility of the drug in the composition system.
  • Table 9 Preparation process of the composition: Dissolve the prescription amount of ropivacaine in the drug solvent to obtain the drug solution; add the medicinal phospholipid and stir until the medicinal phospholipid is completely dissolved; then add the medicinal oil and the medicinal effect enhancer, Stir until uniform to obtain a drug-containing solution, filter and distribute, fill with nitrogen, seal, and then sterilize with moist heat to obtain a clear and transparent liquid.
  • the preparation process of the composition in Table 10 Weigh the prescription amount of ropivacaine medicine, medicinal oil, medicinal phospholipid, medicinal solvent, and medicinal effect enhancer into a pre-weighed round bottom flask, weigh, and add excess Then place the flask in a water bath ultrasonic wave.
  • the ultrasonic wave makes the phospholipids completely dispersed and the components are completely dissolved.
  • the obtained liquid medicine is filtered and packed, filled with nitrogen and sealed to obtain a clear and transparent liquid.
  • the preparation process of the composition in Table 11 Weigh the prescription amount of ropivacaine drug, medicinal oil, medicinal phospholipid, medicinal solvent, antioxidant, medicinal effect enhancer and acid-base regulator to a pre-weighed circle The bottom flask was weighed, and an excess of absolute ethanol was added, and then the flask was placed in a water bath ultrasonic wave. The ultrasonic wave made the phospholipids completely dispersed and the components were completely dissolved. At this time, connect the round-bottomed flask to a suitable rotary evaporator, and evaporate under reduced pressure until the weight change of the round-bottomed flask indicates that the absolute ethanol has been removed. The obtained medicinal solution is filtered and divided, filled with nitrogen, sealed, and then sterilized by moist heat to obtain a clear and transparent liquid.
  • the preparation process of the composition in Table 12 Weigh the prescription amount of ropivacaine drug, medicinal oil, medicinal phospholipid, medicinal solvent, medicinal effect enhancer and acid-base regulator into a pre-weighed round bottom flask, Weigh, add an excess of absolute ethanol, and place the flask in a water bath ultrasonic wave.
  • the ultrasonic wave makes the phospholipids completely dispersed and the components are completely dissolved.
  • the obtained medicinal solution is filtered and divided, filled with nitrogen, sealed, and then sterilized by moist heat to obtain a clear and transparent liquid.
  • the pharmaceutical composition of Preparation Example 1 was placed to observe its appearance to determine its stability. If there is no visible precipitate, it can be considered that the shelf stability of the composition is good.
  • composition 7 Clear and transparent No significant changes Composition 8 Clear and transparent No significant changes Composition 9 Clear and transparent No significant changes Composition 10 Clear and transparent No significant changes Composition 11 Clear and transparent No significant changes Composition 12 Clear and transparent No significant changes Composition 13 Clear and transparent No significant changes Composition 14 Clear and transparent No significant changes Composition 15 Clear and transparent No significant changes Composition 16 Clear and transparent No significant changes Composition 17 Clear and transparent No significant changes Composition 22 Clear and transparent No significant changes Composition 23 Clear and transparent No significant changes Composition 24 Clear and transparent No significant changes
  • Test product solution accurately weigh an appropriate amount of the test product into a measuring flask, add methanol to dissolve and dilute to the mark, vortex and sonicate to obtain the test product solution;
  • Content reference substance solution Weigh an appropriate amount of ropivacaine drug reference substance in a volumetric flask, accurately weigh it, dissolve in methanol and dilute to the mark to obtain the content reference substance solution.
  • Related substance reference substance solution accurately transfer 1ml of the test substance solution to a 100ml measuring flask, add methanol and dilute to the mark to obtain the related substance determination reference substance solution.
  • a 21G needle was used to determine the penetration of the composition, and the results are shown in Table 15.
  • composition of the present invention has suitable injection traversability; while in Comparative Example 4, bolus injection is difficult and the injection traversability is extremely poor.
  • the administered dose refers to the dose calculated according to the amount of hydrochloride of the active ingredient in the preparation (that is, when free base is used, it is converted to hydrochloride).
  • mice Male SD rats, 200-300g, were bred adaptively for 3 days, and the basic threshold was measured every day.
  • Experimental grouping and dosage randomly grouped according to the basic threshold, 6 animals in each group. Different compositions (or comparative compositions) were respectively injected into the subcutaneous tissue of the rat foot plantar (administration volume ranged from 0.10 to 0.35 ml). The von Frey fiber-filament pain meter was used to measure the pain threshold and investigate the motor block.
  • Detection method von Frey acupuncture-foot-lifting method: Rats move freely in a cage, fix the moving space, and after they are quiet, von Frey filaments are used to stimulate the rat's soles, and the rat's mechanical leg withdrawal threshold is measured. The higher the mechanical retraction threshold, the better the effect of sensory nerve block.
  • Evaluation method Use paired t-test to compare the mechanical leg shrinkage threshold of each group of animals with the pre-dose, and use unpaired t-test to compare the mechanical leg shrinkage threshold of each group of animals with Comparative Example 4.
  • P ⁇ 0.05 indicates a statistical difference
  • P ⁇ 0.01 and P ⁇ 0.001 indicate significant statistical differences.
  • Figures 1 to 2 show that, compared with the mechanical leg withdrawal threshold before administration, the sensory nerve block duration of Comparative Examples 3 and 4 in rats is 2h and about 30h, respectively.
  • Compositions 6, 7, and 9 of the present invention The sensory nerve block maintenance time of 16, 17, and 22 were 48h, 48h, 72h, 54h, 72h and 54h, respectively. It can be seen that, compared with Comparative Example 4, the composition of the present invention can extend the duration of sensory block by at least 60% at the same dosage.
  • Figure 3 shows that, compared with Comparative Example 4, composition 6 is at 36-48h, composition 7 is at 36-48h, composition 9 is at 36-72h, composition 16 is at 36-54h, and composition 17 is at 36-72h.
  • Composition 22 has a significant difference in the mechanical leg shrinkage threshold between 36 and 54 hours, indicating that the composition of the present invention has a significant increase in potency compared with Comparative Example 4, and the composition has a significant advantage in duration of potency compared with Comparative Example 4.
  • R A/T t , where A is the administered dose of ropivacaine, T t is the effective treatment time of the drug in the body, and R is the effective treatment dose.
  • the effective therapeutic dose R of the compositions 6, 7, 9, 16, 17 and 22 can be reduced by at least 40% compared with the comparative examples 3 and 4, indicating that the same effective treatment time is achieved, and the composition of the present invention consumes a smaller drug dose It can avoid the waste of clinical drugs and the toxicity caused by excessive drugs.
  • the pharmaceutical composition of the present invention has a controllable pain relief time, and provides the beneficial value of on-demand selection for drug development.
  • Grade 1 (representing no motor block, represented by a value of 1): The rat's paw can land normally, and the weight is normal, and there is no weakness;
  • Grade 2 (representing a slight motor block, represented by a value of 2): The rat's paw can land normally, but there is slight weakness;
  • Grade 3 (representing complete motor block, represented by a value of 3): The rat's paw occasionally touches the ground and there is weakness;
  • Grade 4 (representing complete motor block, represented by a value of 4): The rat's paw does not touch the ground at all and has severe weakness.
  • Evaluation method Use unpaired t-test to compare the motor nerve block scores of each group of animals with the normal saline placebo group. P ⁇ 0.05 indicates statistical difference, P ⁇ 0.01 and P ⁇ 0.001 indicate significant statistical difference. The results are shown in Figure 4.
  • the duration of the motor block of the composition can be shortened by at least 20% compared with Comparative Example 4. . It is shown that the composition of the present invention improves the motor nerve block compared with Comparative Example 4, which means that the composition of the present invention does not increase the risk of nerve damage while meeting the clinical analgesia requirements, and has higher safety.
  • composition 9 On the basis of composition 9, the drug concentration and dosage were changed, and the method of pharmacodynamic investigation (1) was used to determine the sensory nerve block of the corresponding composition.
  • the composition and dosage information are shown in Table 19, and the sensory nerve block results are shown in Figure 5.
  • compositions 9-1, 9-2, and 9-3 in the body were 24h, 36h and 48h, respectively. It can be seen that different medicinal doses can achieve different pain relief time, which provides convenience for clinical on-demand selection.
  • the effective therapeutic doses R of compositions 9-1, 9-2, and 9-3 are 0.6, 0.7, and 0.7, respectively, which are all significantly lower than the conventional sustained-release preparation of Comparative Example 4, indicating that the composition of the present invention improves the drug Utilization rate.
  • the ratio and type of the drug effect enhancer in the composition were changed, and the method of drug effect investigation (1) was used to determine the sensory nerve block of the corresponding composition on the animal.
  • the composition and dosage information are shown in Table 20, and the sensory nerve block results are shown in Figure 6 and Table 21.
  • Figure 6 shows that the sensory nerve block duration of Comparative Examples 8, 9 and Compositions 23, 24, and 25 in rats were 30h, 30h, 72h, 54h and 48h, respectively. It can be seen that, at the same dosage, compositions 23-25 (containing 5% drug effect enhancer) have a higher sensory resistance than Comparative Example 8 (without drug effect enhancer) and Comparative Example 9 (containing 15% drug effect enhancer). The duration can be extended by at least 60%.
  • Fish oil type 3322 contains eicosapentaenoic acid and docosahexaenoic acid at about 33% and about 22%, respectively.
  • Fish oil type 1812 contains eicosapentaenoic acid and docosahexaenoic acid.
  • the content is about 18% and about 12%, respectively.
  • the content of docosahexaenoic acid in the algae oil is about 35%, without eicosapentaenoic acid.
  • the sensory nerve block duration of compositions 23, 24 and 25 were shortened in turn, indicating that the content of eicosapentaenoic acid and docosahexaenoic acid in the composition would be reduced. Affect the duration of the drug effect, and the pharmacodynamic results of two fatty acids containing eicosapentaenoic acid and docosahexaenoic acid are better.
  • Time/h Composition 23 Composition 24 Composition 25 Before administration 12 ⁇ 3 13 ⁇ 3 13 ⁇ 3 3 300 ⁇ 0#& 300 ⁇ 0#& 300 ⁇ 0#& 6 240 ⁇ 66# 260 ⁇ 42# 240 ⁇ 66#
  • R A/T t , where A is the administered dose of ropivacaine, T t is the effective treatment time of the drug in the body, and R is the effective treatment dose.
  • the effective therapeutic dose of the composition of the present invention is at least 40% lower than that of Comparative Examples 8 and 9, indicating that the composition of the present invention can improve the utilization of drugs.
  • the administered dose refers to the dose calculated according to the amount of hydrochloride of the active ingredient in the preparation (that is, when free base is used, it is converted to hydrochloride).
  • the obtained pharmaceutical composition was injected subcutaneously into male SD rats, and blood was taken regularly, and the content of the drug in the plasma was determined by the LC-MS method to investigate the pharmacokinetics in the body.
  • mice male SD rats, 200 ⁇ 300g, source: Shanghai Institute of Materia Medica, Chinese Academy of Sciences;
  • mice were randomly divided into groups according to the following table, 6 in each group;
  • PK pharmacokinetic
  • AUC is bioavailability
  • AUC t is effective bioavailability
  • the fitting graph is shown in Figure 9, which shows that the blood concentration and pharmacodynamics of the composition of the present invention have a good correlation in the body, which means that the composition of the present invention has a good effect in drug research and clinical use. Strong controllability.
  • the efficacy durations of the combined compositions 7, 9, and 17 are 48h, 72h, and 72h, respectively, it is inferred
  • the effective concentration of ropivacaine hydrochloride in rats is about 20ng/ml (Comparative Example 3 After being injected into the body, the drug quickly enters the blood, resulting in poor correlation between the blood concentration and the local drug effect, so 20ng/ml The effective concentration of ml is not applicable to Comparative Example 3).
  • the drug below the effective concentration is the ineffective drug concentration
  • the blood drug concentration of Comparative Example 4 reaches the ineffective concentration at about 30h, and its overall bioavailability and effective bioavailability are low, indicating that some drugs Failure to effectively exert the drug effect and stay in the body at a low concentration for a long time will undoubtedly bring a higher risk of neurotoxicity.
  • Compositions 7, 9 and 17 fully exposed the drug within the time required for analgesia (for example, 48h or 72h), reducing the duration of the drug staying in the body in an ineffective form.
  • compositions 7, 9 and 17 are improved, indicating that the composition of the present invention is relatively released in the body, can give full play to the efficacy, increase the utilization rate of the drug, and reduce the risk of neurotoxicity. Improve the safety of medication.
  • the composition of the present invention can reduce C max by at least 70% compared with Comparative Example 3 (ropivacaine hydrochloride injection) at the same dose.
  • the composition of the present invention has more complete drug release, significantly improved bioavailability and effective bioavailability, can reduce the duration of drug retention in the body in an ineffective form, and improve drug utilization. Reduce the risk of toxicity caused by long-term exposure of nerve fibers to lower drug concentrations.
  • the composition of the present invention can improve motor blockage and reduce neurotoxicity compared with conventional sustained-release preparations, which is of great significance in clinical use.
  • the medicinal effect enhancer in the present invention can exert unexpected effects in a certain proportion.
  • the administered dose refers to the dose calculated according to the amount of hydrochloride of the active ingredient in the preparation (that is, when free base is used, it is converted to hydrochloride).
  • Composition 8 and Comparative Example 7 were injected into the subcutaneous tissue of the rat foot and plantar respectively, and the irritation at the injection site was observed 24 hours after the administration.
  • the dosage information is shown in Table 25, and the results are shown in Figure 10.
  • the administered dose refers to the dose calculated according to the amount of hydrochloride of the active ingredient in the preparation (that is, when free base is used, it is converted to hydrochloride).
  • the rats were injected subcutaneously with 13 mg/kg Comparative Example 3, 45 mg/kg Comparative Example 5, Composition 7 and Composition 9 to the rats, and the rats were euthanized 48 hours after the administration, and the tissue samples at the injection site were dissociated with a scalpel.
  • the sample size needs to cover the size of the tissue at the administration site.
  • the sample is fixed in buffered formalin.
  • dehydration treatment with dehydrating agent xylene the tissue sample was embedded in paraffin, and the tissue sample was cut into thin slices (5 ⁇ m tissue section) using a cryostat, and placed on a glass slide. Tissue sections were obtained after staining with hematoxylin-eosin. Observe the tissue morphology and immunohistology with a microscope. The results are shown in Figure 11.

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Abstract

提供了一种长效罗呱卡因药物组合物及其制备方法和用途。所述药物组合物包含：罗哌卡因；药物溶剂；药用磷脂；药用油脂；药效增强剂，非必需的抗氧剂及非必需的酸碱调节剂。所述药物组合物具有可控的释放行为和缓释效果，可显著降低药物的血浆峰浓度，维持稳定的体内血药浓度，延长有效治疗时间，降低有效治疗剂量，提高药物利用率，降低神经毒性风险，具有长效镇痛作用，可用于疼痛治疗。

Description

一种长效罗哌卡因药物组合物及其制备方法和用途 技术领域
本发明属于医药技术领域，具体而言，涉及一种长效罗哌卡因药物组合物，及其制备方法，以及其用于制备治疗术后疼痛的药物的用途。所述药物组合物具有可控的释放行为和缓释效果，可显著降低药物的血浆峰浓度，维持稳定的体内血药浓度，延长有效治疗时间，降低有效治疗剂量，提高药物利用率，降低神经毒性风险，具有长效镇痛作用，可用于治疗术后疼痛。
背景技术
术后疼痛，是在刺激中枢神经系统的超敏性手术过程中对软组织创伤的综合响应，属于急性疼痛，会对患者的各器官功能产生重大影响，引起一系列的病理生理参数发生改变，并导致各种并发症，严重影响了患者的术后康复，使患者的生命健康受到影响。
术后镇痛不仅可以减轻患者术后疼痛，还能稳定患者各项生理指标，可降低手术期并发症的产生几率，可改善预后并对缩短住院时间有着显著影响。
局部麻醉药通过抑制神经细胞钠离子通道，能在用药局部可逆性地阻断神经冲动的发生与传导，临床上常用于镇痛。
罗哌卡因是近几年新合成的一类酰胺类局部麻醉药，是布比卡因进一步优化的成果。与传统的局部麻醉药相比，罗哌卡因具有疗效作用时间长，疼痛治疗效果确切，心脏毒性小等优点，提示其在今后的临床应用将更加广泛。
罗哌卡因基本结构为1-丙基-2,6-盐酸哌啶酰胺类的左旋异构体，pH为7.4，pKa为8.1，脂溶性低，解离常数高。因而，它对C纤维的敏感性明显高于A纤维，具有明显的运动神经阻滞和感觉神经阻滞相分离的特点，即低浓度时只产生感觉神经阻滞，而对运动阻滞的影响极小并且是非进行性的，高浓度可产生感觉神经阻滞和运动神经阻滞。现代麻醉理论认为，术后充分镇痛的同时，保持患者一定的运动能力(即减少运动阻滞的发生)有利于其早期下床活动，促进胃肠道的蠕动和功能的恢复，可缩短住院时间。更重要的是，运动阻滞时伴随的较高的药物浓度可能会引起神经慢性毒性(Acute Med Surg.2017 Apr；4(2):152-160)。因此，增加感觉神经阻滞而又尽量避免运动阻滞具有重要的临床意义。
目前罗哌卡因的临床制剂较单一，只有普通的盐酸盐或甲磺酸盐水溶液，且作用时间较短，难以满足术后疼痛的治疗要求，而多次给药不仅会导致患者顺应性差，还会引起血药浓度的峰谷效应，产生毒性反应。因此，开发一种安全、长效的罗哌卡因药物组合物具有重要的临床应用价值。
CN103142458B提供了一种罗哌卡因油溶液制剂组合物，其处方工艺简单，具有一定的缓释作用。实施例中涉及的药物组合物为罗哌卡因溶于由苯甲醇、苯甲酸苄酯、大豆油或蓖麻油组成的系统，但经考察，该组合物会导致注射部位的炎症反应，可能会带来神经炎症风险，且具有一定的局部刺激性风险，存在安全隐患。
CN104427977B提供了一种盐酸罗哌卡因的前体脂质体制剂及其制备方法，处方采 用天然磷脂、非水载体及粘度调节剂乙醇，所得的前体脂质体制剂，提高了载药量，延长了药效持续时间。但该制剂粘度大，通针性差，给临床使用带来不便。同时，其药物有效生物利用度较低，会导致药物的浪费。
CN109316602A提供了一种由局部麻醉药、非甾体抗炎药、溶媒和缓释材料组成的复方缓释递药系统，虽具有一定的缓释镇痛效果和促进伤口愈合的功能，但非甾体抗炎药具有封顶效应，且存在容易引起胃肠道不良反应、神经系统和心血管系统毒性的缺点。同时，其有机溶剂比例较大，达30～40％，易引起注射部位的刺激性，存在安全隐患。
CN108743952A提供了一种磷脂-混溶剂-油为载体的局部麻醉药缓释制剂与制备方法，其采用苯甲酸苄酯、乙醇和苯甲醇为溶剂，溶剂总量高达40～50％，易引起注射部位的刺激性和全身不良反应，存在安全隐患。
WO2019046293A1提供了一种麻醉剂的缓释组合物，包括一种局部麻醉剂和一种或多种脂质混合物(如磷脂或胆固醇)，采用一步冻干法制备成脂质基质，再用缓冲液水化形成；US2015250724A1提供了一种长效控释局部麻醉剂的脂质体制剂，通过将水和有机相混溶，加入磷脂和胆固醇形成乳液，使乳液与第二水相溶液进行外部溶液交换形成脂质体，上述2个专利制备工艺均较复杂且长期放置时存在稳定性问题。
CN106535886A提供了一种由酰胺型局部麻醉剂、烯醇酸非甾体抗炎药和输送载体组成的递药系统，用于治疗急性或慢性疼痛。同样，非甾体抗炎药具有封顶效应，且存在容易引起胃肠道不良反应、神经系统和心血管系统毒性的缺点。另外，输送载体由聚原酸酯、极性非质子溶剂和粘度降低剂甘油三酸酯组成，所得组合物的粘度较大，通针性较差，临床给药便利性差。
另外，据文献Anesth Analg.2006 Sep；103(3):608-14报道，当神经纤维长时间暴露较低浓度的局部麻醉药时，会导致神经突的生长显著延迟，肌动蛋白的轴突运输受到破坏，对神经纤维造成损伤，会产生例如神经炎症或神经纤维化等症状。
目前，以上专利文献中均采用本领域常用的辅料，所得组合物虽具有一定的缓释效果，但存在药物有效利用度低、注射部位刺激性大、安全性隐患大、通针性差、工艺复杂、稳定性差等缺点。本发明的组合物在已有研究技术的基础上进行改进，加入适量的药效增强剂，不仅能保持组合物的缓释效果和良好稳定性的特点，还能延长同剂量下常规缓释制剂的药效持续时间，并能降低相同镇痛药效下的有效治疗剂量，改善运动神经阻滞情况，提高用药安全性，这在本领域中未见报道。
发明内容
本发明的一个目的是提供一种长效罗哌卡因药物组合物。
本发明的另一个目的是提供上述长效罗哌卡因药物组合物的制备方法。
本发明的再一个目的是提供上述长效罗哌卡因药物组合物的用途。
经调研，本发明人得知油性溶液能够提供改善的缓释效果。但罗哌卡因的盐类，在油脂中的溶解度较低，不能满足临床高剂量给药的需求。经尝试，本发明人在组合物中加入适量的药用磷脂，经过适宜的配制过程后，既能溶解罗哌卡因盐类，又能溶解罗哌卡因游离碱，且溶液稳定性和注射通针性良好。
基于此，本发明人制备了含有不同比例的药用磷脂的组合物，并在大鼠体内进行药 效学考察，结果本发明人意外地发现，磷脂比例不同，得到的组合物在大鼠体内的药效持续时间有所不同，但相对于盐酸罗哌卡因注射液(商品名：耐乐品)均能显著延长药效持续时间。因此，在药物开发中，可根据临床上不同的治疗需求，设计相应的组合物，达到精准治疗的目的。
上述组合物虽较盐酸罗哌卡因注射液显著降低了血浆峰浓度，具有一定的缓释效果，但本发明人发现，组合物中的药物在大鼠体内的释放不完全，导致生物利用度尤其是有效生物利用度较低。未发挥药效作用的药物会滞留体内，这不仅会造成药物的浪费，还可能会引起神经纤维的慢性毒性。同时，在整个药效测定期间内，大鼠长时间存在脚部蜷缩且不着地(即运动阻滞)的现象，故该组合物的研发有待改进。
本发明中，有效治疗剂量R通过下式计算：
R＝A/T t
其中，A为罗哌卡因药物的给药剂量，T t为药物在体内的有效治疗时间。这里，药物在体内的有效治疗时间是指药效持续时间，通过药效实验测定。R值越小表明达到单位药效持续时间所需的药物剂量越小，即同等剂量下的药物的有效治疗时间越长。
通过研究，本发明人意外地发现，加入本发明所述的药效增强剂后药物组合物的药效持续时间显著延长，有效生物利用度提高，镇痛药效增强，有效治疗剂量R值显著减小，注射部位的刺激性明显减弱。达到相同的镇痛效果下，运动阻滞情况明显改善。
根据上述研究，本发明提供了一种长效罗哌卡因药物组合物。所述组合物在安全性、缓释效果及维持时间、药物利用率、运动阻滞情况改善等方面较盐酸罗哌卡因注射液和已报道的其他相关制剂均具有明显优势。
一方面，本发明提供了一种长效罗哌卡因药物组合物，所述药物组合物包含：罗哌卡因；药物溶剂；药用磷脂；药用油脂；药效增强剂，非必需的抗氧剂及非必需的酸碱调节剂，其中，所述药效增强剂可显著延长组合物的药效持续时间，同剂量下较常规缓释制剂可显著降低药物有效治疗剂量，优选地，所述药效增强剂选自ω-3脂肪酸及其代谢产物、富含ω-3脂肪酸或其代谢产物的物质等中的一种或两种以上的组合，更优选地，所述药效增强剂在组合物中的用量范围为0.5％-10％。
优选地，本发明的药物组合物包含，基于组合物的总重，以重量百分比计，
约0.5％至约10％，优选约1％至约8％，更优选约1％至约5％的罗哌卡因；
约2％至约25％，优选约3％至约23％，更优选约5％至约20％的药物溶剂；
约8％至约55％，优选约10％至约50％，更优选约15％至约45％的药用磷脂；
约15％至约89％，优选约20％至约76％，更优选约22％至约60％的药用油脂；
约0.5％至约10％，优选约1％至约9％，更优选约2％至约8％的药效增强剂；
约0％至约1％，优选约0％至约0.5％，更优选约0％至约0.3％的抗氧剂；
约0％至约8％，优选约0％至约5％，更优选约0％至约3％的酸碱调节剂。
本发明的药物组合物中，所述罗哌卡因主要包括罗哌卡因游离碱及其盐类，可以是它们中的一种、两种或两种以上的组合物。优选地，所述的盐类可以是例如盐酸盐、甲磺酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、柠檬酸盐、酒石酸盐、乳酸盐、枸橼酸盐、马来酸盐、富马酸盐等。
本发明的药物组合物中，优选地，所述药物溶剂可为单一有机溶剂或多种有机溶剂 的混合物。所述药物溶剂的实例包括但不限于苯甲醇、乙醇、丙二醇、甘油、异丙醇、N-甲基吡咯烷酮、二甲基亚砜、液态聚乙二醇、二甲基乙酰胺、单乙酸甘油酯、聚乙二醇单甲醚、二乙二醇单乙基醚、乳酸乙酯、乙酸乙酯、丙二醇二乙酯、丙二酸二乙酯、四氢呋喃聚乙二醇醚、苯甲酸苄酯，或其两者以上的混合物，更优选地，所述药物溶剂为选自苯甲醇、丙二醇、乙醇中的一种或多种。
本发明的药物组合物中，所述抗氧剂用于防止或减缓组合物的氧化降解，其可以是本领域中可以用于本发明药物组合物体系的任何抗氧剂，只要其对于罗哌卡因的药物活性没有明显不利影响即可，例如其可以为选自半胱氨酸、a-生育酚、a-生育酚醋酸酯、N-乙酰基-L-半胱氨酸、丁羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、硫辛酸、茶多酚、L-抗坏血酸棕榈酸酯、谷胱甘肽中的一种或多种；优选为选自a-生育酚、L-抗坏血酸棕榈酸酯中的一种或多种。
本发明的药物组合物中，所述酸碱调节剂用于调节组合物的酸碱性，其可以是本领域中可以用于本发明药物组合物体系的任何酸碱调节剂，只要其对于罗哌卡因的药物活性没有明显不利影响即可，例如其可以为选自精氨酸、赖氨酸、组氨酸、甘氨酸、氨丁三醇、二乙醇胺、乙二胺、葡甲胺、盐酸、乙酸、无水枸橼酸、抗坏血酸、乳酸、酒石酸、甲磺酸、蛋氨酸、氢氧化钠、三乙醇胺中的一种或多种；优选为选自氨丁三醇、二乙醇胺、乙二胺、葡甲胺中的一种或多种。
本发明的药物组合物中，所述药用油脂可选自以下的一种或两种以上的组合：天然植物油(如蓖麻油、芝麻油、大豆油、葵花籽油、花生油、玉米油、菜籽油、橄榄油、棉籽油)或者天然植物油经人工改进的半天然油脂(如：氢化蓖麻油)、油脂纯化物及相应衍生物；人工合成油脂，主要包括中链甘油三酸酯(例：辛酸甘油三酸酯、癸酸甘油三酸酯之一或二者混合物)、长链甘油三酸酯、三乙酸甘油酯或其他相应衍生物、油酸乙酯。
本发明的药物组合物中，所述药用磷脂可选自：天然磷脂、半合成磷脂、合成磷脂中一种或多种的组合。所述天然磷脂的实例包括但不限于蛋黄卵磷脂、大豆磷脂或其组合等；所述半合成磷脂的实例包括但不限于氢化蛋黄卵磷脂、氢化大豆磷脂或其组合等；所述合成磷脂的实例包括但不限于二棕酰磷脂酰乙醇胺、二棕酰磷脂酸、二棕酰磷脂酰甘油、二油酰磷脂酰乙醇胺、二棕酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱中的一种或多种组合等。所述药用磷脂优选天然磷脂。
本发明的药物组合物中，所述药效增强剂可显著延长组合物的药效持续时间，同剂量下较常规缓释制剂可显著降低药物有效治疗剂量。优选地，本发明所述药效增强剂可选自ω-3脂肪酸及其代谢产物、富含ω-3脂肪酸或其代谢产物的物质中的一种或两种以上的组合。
具体地，所述的ω-3脂肪酸及其代谢产物，主要指ω-3多不饱和脂肪酸及其代谢产物，如α-亚麻酸及其代谢产物二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)或其组合。所涉及的α-亚麻酸为来源于植物的α-亚麻酸(ALA)，富含α-亚麻酸的物质可以是亚麻籽油、紫苏籽油、核桃油、阿甘油等植物油；富含EPA和DHA等α-亚麻酸代谢产物的物质可以是鱼油、紫菜油、藻油。所述富含ω-3脂肪酸或其代谢产物的物质包括富含α-亚麻酸的物质、富含α-亚麻酸代谢产物二十碳五烯酸和二十二碳六烯酸的物质或其组 合，优选地，所述富含α-亚麻酸的物质包括亚麻籽油、紫苏籽油、核桃油、阿甘油或其组合；所述富含α-亚麻酸代谢产物二十碳五烯酸和二十二碳六烯酸的物质包括鱼油、紫菜油和藻油或其组合。
本发明的药物组合物中，优选地，所述药效增强剂为选自富含ω-3脂肪酸或其代谢产物的物质中的一种或多种，更优选地，所述药效增强剂为选自富含ω-3脂肪酸或其代谢产物的物质中的二十碳五烯酸(EPA)含量不小于15％，且二十二碳六烯酸(DHA)含量不小于10％的物质中的一种或多种；特别优选地，所述药效增强剂为选自富含ω-3脂肪酸或其代谢产物的物质中的二十碳五烯酸(EPA)含量不小于20％，且二十二碳六烯酸(DHA)含量不小于10％的物质中的一种或多种，还更特别优选为选自鱼油和紫菜油中的一种或多种。
本发明的长效罗哌卡因药物组合物，可使药物的血浆峰浓度较同剂量盐酸罗哌卡因注射液降低30％以上，优选降低50％以上，更优选降低60％以上；药效持续时间为12h以上，24h以上，甚至48h以上，例如可以是12-24h，24-48h，12-48h等；所述组合物的有效治疗剂量较常规缓释制剂可降低10％以上，优选降低20％以上，更优选降低30％以上；所述组合物和常规缓释制剂在达到相同的镇痛效果下，运动阻滞情况可改善20％，优选改善30％，更优选改善60％。
另一方面，本发明提供了上述长效罗哌卡因药物组合物的制备方法，该方法包括以下步骤：
处方量的罗哌卡因、处方量的药用油脂、处方量的药用磷脂和处方量的药效增强剂和非必需地，处方量的抗氧剂以及非必需地，处方量的酸碱调节剂、处方量的药物溶剂在过量的挥发性有机溶剂中分散均匀；
去除过量的挥发性有机溶剂，例如通过蒸发和/或真空泵干燥；
如果需要，补加药物溶剂至处方量，混匀。
在该方法中，药效增强剂、酸碱调节剂可以与罗哌卡因、抗氧剂、药物溶剂、药用油脂和药用磷脂同时加入或者先后加入，或者最后步骤加入。
本发明中，所述挥发性有机溶剂的实例，例如，包括但不限于，乙醇、二氯甲烷、三氯甲烷、甲醇等。
还一方面，本发明提供了上述长效罗哌卡因药物组合物的制备方法，该方法包括以下步骤：
将罗哌卡因加入药物溶剂，使罗哌卡因充分溶解，得到罗哌卡因溶液；
将药用磷脂与药用油脂充分混合均匀(氮气保护)，加入罗哌卡因溶液，混合均匀；
再将药效增强剂加入其中，混合均匀，过滤，即得。
非必需地，所述的抗氧剂和酸碱调节剂可在以上过程中任一步骤加入。
还一方面，本发明提供了上述长效罗哌卡因药物组合物的制备方法，该方法包括以下步骤：
将罗哌卡因溶于药物溶剂，得到罗哌卡因溶液；
加入药用磷脂，使其溶解均匀；
加入药用油脂与药效增强剂，混合均匀，过滤，即得。
非必需地，所述的抗氧剂和酸碱调节剂可在以上过程中任一步骤加入。
在一些实施方式中，所述组合物为澄清的溶液。
根据实际需要，在上述方法中还可以包括分装以及非必需的除菌或灭菌的步骤。所述除菌例如是过滤除菌。所述灭菌例如是湿热灭菌。
再一方面，本发明提供了上述长效罗哌卡因药物组合物在制备疼痛缓解药物中的用途。该组合物能可控地调节治疗疼痛的时间，可提供长效的镇痛效果。所述疼痛缓解药物可以为局部给药的各种剂型或包装试剂盒的形式，例如适合局部注射，如皮下或肌肉注射给药、或在切口直接滴入给药、或切口浸润给药、或在神经丛处给药、或通过关节腔注射，优选皮下注射给药，更优选皮下浸润给药的剂型或包装试剂盒的形式。
在一些实施方式中，所述疼痛为手术后疼痛。
在一些实施方式中，所述药物组合物提供了至少约12h的疼痛缓解。在一些实施方式中，所述药物组合物提供了12和24h之间的疼痛缓解。在一些实施方式中，所述药物组合物提供了至少约24h的疼痛缓解。在一些实施方式中，所述药物组合物提供了24和48h之间的疼痛缓解。在一些实施方式中，所述药物组合物提供了至少约48h的疼痛缓解。在一些实施方式中，所述药物组合物提供了48和72h之间的疼痛缓解。在一些实施方式中，所述药物组合物提供了至少约72h的疼痛缓解。
在一些实施方式中，所述组合物较未加药效增强剂和本发明范围外药效增强剂用量的组合物疼痛缓解时间具有显著优势。
本发明提供的长效罗哌卡因药物组合物可局部注射，如皮下或肌肉注射给药、或在切口直接滴入给药、或切口浸润给药、或在神经丛处给药、或通过关节腔注射，优选皮下注射给药，更优选皮下浸润给药。
本发明提供的长效罗哌卡因药物组合物每天需要服用的预期总量按活性药物计为5～1000mg，优选10～500mg。
术语解释
术语“罗哌卡因”是指罗哌卡因游离碱或罗哌卡因的药学上可接受的盐，这里，罗哌卡因游离碱可以是罗哌卡因游离碱的溶剂化物的形式，以及罗哌卡因的药学上可接受的盐可以是罗哌卡因的药学上可接受的盐的溶剂化物的形式，除非根据上下文另有解释。
术语“感觉神经阻滞”，是指任一感觉部位的神经末梢向中枢传导冲动的这一过程被阻滞，导致知觉丧失，可理解为感觉阻滞。本发明中特指痛觉丧失，本发明中的镇痛是指感觉神经被阻滞，药效指感觉神经被阻滞的效果。
术语“运动神经阻滞”，是指神经纤维向周围传出神经冲动并产生运动的这一过程被阻滞，表现为运动功能受损，活动受限，可理解为运动阻滞。
术语“有效治疗时间”，可理解为药物可发挥药效作用的持续时间，可理解为药效持续时间。
术语“有效治疗剂量”，是指达到单位有效治疗时间时，所需的药物剂量。
术语“常规缓释制剂”，可理解为和本发明有类似处方但不含药效增强剂的组合物，例如在CN104427977B中公开的前体脂质体制剂。
术语“组合物”，可理解为药物组合物、药物处方、药物组方、配方或药物制剂。
术语“生物利用度”，是指药物被吸收进入人体循环的速度与程度，本发明中是以 血药浓度-时间曲线下面积(AUC)进行比较。
术语“起效浓度”，是指发挥药效作用的最小血药浓度，血药浓度大于该数值时，药物才可发挥药效，可理解为最小有效浓度、最低有效浓度。
术语“有效生物利用度”，是指大于起效浓度的血药浓度-时间曲线下面积。
本发明通过创造性地研究，提供了一种长效罗哌卡因药物组合物。该组合物对罗哌卡因游离碱和盐型药物均具有较好的溶解度，具有良好的注射通针性和可控的释放速率。和市售盐酸罗哌卡因注射液相比，该组合物显著降低了C max，提高了安全性。最关键的是，本发明的组合物可延长有效治疗时间，降低有效治疗剂量，且能提高生物利用度和有效生物利用度，确保药物在满足临床镇痛时间需求的同时，充分暴露药物，避免药物浪费，降低神经毒性的潜在风险。本发明的组合物能解决局部麻醉制剂临床治疗和安全性需求的问题，具有良好的应用前景。
与已有研究的罗哌卡因药物制剂相比，本发明具有如下优点：
1.本发明与同剂量的市售盐酸罗哌卡因注射液相比，可降低至少30％的血浆峰浓度，优选可降低至少50％的血浆峰浓度，更优选可降低至少60％的血浆峰浓度，提高了临床用药的安全性。
2.本发明的药物组合物，药效持续时间可达12h以上，优选可达24h以上，减少了重复给药次数，增加了患者的顺应性，降低了治疗成本。
3.本发明的药物组合物较常规缓释制剂可使药物释放更加完全，显著提高生物利用度和有效生物利用度，避免无效药物的长时间滞留，降低神经纤维受损的风险。
4.本发明的药物组合物，同剂量下较常规缓释制剂可显著延长药效时间，降低治疗成本。
5.在相同镇痛效果下，本发明的药物组合物较常规缓释制剂可改善运动阻滞情况，降低神经毒性，利于疼痛恢复。
6.本发明的药物组合物较常规缓释制剂可降低有效治疗剂量，在达到相同药效持续时间的情况下可降低药物使用剂量，提高药物利用率，避免药物浪费，降低毒性反应的发生风险。
7.本发明的药物组合物具有可控的药效持续时间，为罗哌卡因药物的开发和临床使用提供了按需选择的有益价值。
8.本发明的药物组合物的局部刺激性小，具有良好的生物相容性和安全性。
9.本发明与已研究的局部麻醉制剂相比，具有安全性好、生物利用度高、缓释效果可控、药物利用率高、神经毒性小、注射通针性良好的优点。
附图说明
图1显示对比例3的动物机械缩腿阈值考察结果。
图2显示对比例4和罗哌卡因药物组合物(组合物6、7、9、16、17、22)的动物机械缩腿阈值对比考察结果；与每组动物给药前的机械缩腿阈值相比，***P＜0.001，**P＜0.01，*P＜0.05。
图3显示对比例4和罗哌卡因药物组合物(组合物6、7、9、16、17、22)的动物机械缩腿阈值对比考察结果；与对比例4的机械缩腿阈值相比，###P＜0.001，##P＜0.01， #P＜0.05。
图4显示生理盐水安慰剂、对比例4和罗哌卡因组合物(组合物6、7、9、16、17、22)的神经阻滞评分对比考察结果；与生理盐水安慰剂组的神经阻滞评分相比，***P＜0.001，**P＜0.01，*P＜0.05。
图5显示本发明的罗哌卡因药物组合物(组合物9-1、9-2和9-3)的动物机械缩腿阈值对比考察结果；与每组动物给药前的机械缩腿阈值相比，***P＜0.001，**P＜0.01，*P＜0.05。
图6显示对比例8、9和罗哌卡因药物组合物(组合物23、24和25)的动物机械缩腿阈值对比考察结果；与每组动物给药前的机械缩腿阈值相比，***P＜0.001，**P＜0.01，*P＜0.05。
图7和图8显示本发明的罗哌卡因药物组合物(组合物7、9、17)和对比例3、4的体内药代(PK)考察结果。
图9显示本发明的罗哌卡因药物组合物7的药效和药代的关系图。
图10显示本发明组合物8和对比例7在注射部位的刺激性考察结果。
图11显示未注射组、对比例3、对比例5和本发明罗哌卡因组合物(组合物7、9)的注射部位组织病理学观察结果。
具体实施方式
通过下列实施例和实验例进一步对本发明组方、制备方法、用途进行说明，但不作为对本发明的限制。下面参照实施例进一步详细阐述本发明，但本领域技术人员应当理解，本发明并不限于这些实施例以及使用的制备方法。而且，本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰，但这些都将包括本发明的范围内。
实施例
对比例1和2：
按照表1所列处方，将药用油脂和药物溶剂混合均一，加入罗哌卡因药物，涡旋、超声，得到浑浊不透明的液体；
尝试将罗哌卡因药物先溶解于药物溶剂中，此时溶解过程较迅速，再加入处方量的药用油脂，涡旋，立刻呈现白色浑浊现象。
表1.药物组合物处方
Figure PCTCN2021071647-appb-000001
对比例3：盐酸罗哌卡因注射液
称取处方量的盐酸罗哌卡因原料药、氯化钠至西林瓶中，加入纯化水，涡旋并超声，溶解澄清后得到均一的溶液，调节pH值为4.0～6.0，即为盐酸罗哌卡因注射液。
表2.对比例3处方
处方 比例
盐酸罗哌卡因 10mg/ml
氯化钠 7.1mg/ml
纯化水 适量
对比例4：CN104427977B的前体脂质体制剂(常规缓释制剂)
将处方量的盐酸罗哌卡因一水合物、卵磷脂PL-90G、蓖麻油、盐酸半胱氨酸加至预称重的圆底烧瓶中，称重，加入过量的无水乙醇，将烧瓶放置水浴超声波中，超声使磷脂完全分散，且各组分完全溶解，且保证无水乙醇的量超过需要的最终量。此时将圆底烧瓶接到合适的旋转蒸发器上，减压蒸发至圆底烧瓶重量变化表明无水乙醇的量小于或等于6％。使烧瓶冷却至室温，如果必要，再加入无水乙醇直至达到6％，混匀，将内容物转移至玻璃小瓶中，室温保存。
表3.对比例4处方
处方 比例(w/w)
盐酸罗哌卡因一水合物 4.78％
卵磷脂PL-90G 53.91％
蓖麻油 35.21％
无水乙醇 6.0％
盐酸半胱氨酸 0.1％
对比例5：CN103142458B的油溶液制剂
称取处方量的罗哌卡因游离碱至西林瓶中，加入苯甲醇和苯甲酸苄酯，搅拌使药物完全溶解，然后加入大豆油，搅拌均匀得到澄清的油性溶液。
表4.对比例5处方
处方 比例
罗哌卡因游离碱 30mg/ml
大豆油 75％(v/v)
苯甲酸苄酯 15％(v/v)
苯甲醇 10％(v/v)
对比例6：CN109316602A提供的制剂
称取处方量的罗哌卡因游离碱和帕瑞昔布，依次加入处方量的苯甲醇、苯甲酸苄酯和乙醇，振摇搅拌至完全溶解，再加入处方量的卵磷脂E80，搅拌振摇至完全溶解，加入适量的蓖麻油，摇匀。分别在2～8℃和室温条件下放置5h，两种条件下均观察到明显的针状物析出现象。
表5.对比例6处方
处方 比例(w/w)
罗哌卡因游离碱 8％
帕瑞昔布 3％
卵磷脂E80 26％
苯甲酸苄酯 15％
苯甲醇 10％
乙醇 10％
蓖麻油 28％
对比例7：CN109316602A提供的制剂
称取处方量的罗哌卡因游离碱和帕瑞昔布，依次加入处方量的苯甲醇、苯甲酸苄酯和乙醇，盖塞，搅拌至完全溶解，再加入处方量的蛋黄卵磷脂PC-98T，搅拌至完全溶解，加入适量的大豆油至处方量，搅拌混匀。
表6.对比例7处方
处方 用量
罗哌卡因游离碱 3％w/v
帕瑞昔布 1.5％w/v
乙醇 10％v/v
苯甲酸苄酯 20％v/v
苯甲醇 10％v/v
蛋黄卵磷脂PC-98T 20％w/v
大豆油 加至100％v/v
对比例8和9：
将处方量的盐酸罗哌卡因、丙二醇、大豆卵磷脂S100、蓖麻油、葡甲胺加至预称重的圆底烧瓶中，称重，加入过量的无水乙醇，将烧瓶放置水浴超声波中，超声使各组分完全溶解。此时将圆底烧瓶接到合适的旋转蒸发器上，减压蒸发至圆底烧瓶重量变化表明无水乙醇已被除尽。使烧瓶冷却至室温，加入处方量的鱼油，混匀，将内容物转移至玻璃小瓶中，室温保存。
表7.对比例8和9的处方信息
处方 对比例8比例(w/w) 对比例9比例(w/w)
盐酸罗哌卡因 4.5％ 4.5％
大豆卵磷脂S100 42％ 42％
蓖麻油 38.2％ 23.2％
丙二醇 15％ 15％
鱼油3322型 / 15％
葡甲胺 0.3％ 0.3％
实施例1
制备长效药物组合物
表8的组合物的制备过程：将处方量的罗哌卡因加入药物溶剂中，搅拌至溶解，得到药物溶液；将药用磷脂加入至相应的药用油脂中，高速剪切至药用磷脂完全溶解；在其中加入药物溶液，搅拌均匀，再加入药效增强剂，搅拌，得到含药溶液，过滤分装，充氮，密封，然后湿热灭菌，得到澄清透明的液体。
表8.药物组合物处方
Figure PCTCN2021071647-appb-000002
结果显示，加入适量的药用磷脂后制备所得组合物均澄清透明，达到了改善药物在组合物体系中溶解度的目的。
表9组合物的制备过程：将处方量的罗哌卡因溶于药物溶剂中，得到药物溶液；加入药用磷脂，搅拌至药用磷脂完全溶解；再加入药用油脂与药效增强剂，搅拌至均匀，得到含药溶液，过滤分装，充氮，密封，然后湿热灭菌，得到澄清透明的液体。
表9.药物组合物处方
Figure PCTCN2021071647-appb-000003
表10的组合物的制备过程：称取处方量的罗哌卡因药物、药用油脂、药用磷脂、药物溶剂、药效增强剂至预称重的圆底烧瓶中，称重，加入过量的无水乙醇，后将烧瓶放置水浴超声波中，超声使磷脂完全分散，且各组分完全溶解。此时将圆底烧瓶接到合 适的旋转蒸发器上，减压蒸发至圆底烧瓶重量变化表明无水乙醇已被除尽。若有需要，补加乙醇至处方量，并混匀。所得药液过滤分装，充氮，密封，得到澄清透明的液体。
表10.药物组合物处方
Figure PCTCN2021071647-appb-000004
表11的组合物的制备过程：称取处方量的罗哌卡因药物、药用油脂、药用磷脂、药物溶剂、抗氧剂、药效增强剂和酸碱调节剂至预称重的圆底烧瓶中，称重，加入过量的无水乙醇，后将烧瓶放置水浴超声波中，超声使磷脂完全分散，且各组分完全溶解。此时将圆底烧瓶接到合适的旋转蒸发器上，减压蒸发至圆底烧瓶重量变化表明无水乙醇已被除尽。所得药液过滤分装，充氮，密封，然后湿热灭菌，得到澄清透明的液体。
表11.药物组合物处方
Figure PCTCN2021071647-appb-000005
Figure PCTCN2021071647-appb-000006
表12的组合物的制备过程：称取处方量的罗哌卡因药物、药用油脂、药用磷脂、药物溶剂、药效增强剂和酸碱调节剂至预称重的圆底烧瓶中，称重，加入过量的无水乙醇，后将烧瓶放置水浴超声波中，超声使磷脂完全分散，且各组分完全溶解。此时将圆底烧瓶接到合适的旋转蒸发器上，减压蒸发至圆底烧瓶重量变化表明无水乙醇已被除尽。所得药液过滤分装，充氮，密封，然后湿热灭菌，得到澄清透明的液体。
表12.药物组合物处方
Figure PCTCN2021071647-appb-000007
实验例
实验例1 稳定性考察
将制备实施例1的药物组合物放置观察外观，以判断其稳定性情况。若无可见的析出物，则可认为组合物的放置稳定性良好。
表13.药物组合物的稳定性考察结果
组合物编号 外观 放置1月外观稳定性
对比例1 浑浊不透明 /
对比例2 浑浊不透明 /
组合物3 澄清透明 无明显变化
组合物4 澄清透明 无明显变化
组合物5 澄清透明 无明显变化
组合物6 澄清透明 无明显变化
组合物7 澄清透明 无明显变化
组合物8 澄清透明 无明显变化
组合物9 澄清透明 无明显变化
组合物10 澄清透明 无明显变化
组合物11 澄清透明 无明显变化
组合物12 澄清透明 无明显变化
组合物13 澄清透明 无明显变化
组合物14 澄清透明 无明显变化
组合物15 澄清透明 无明显变化
组合物16 澄清透明 无明显变化
组合物17 澄清透明 无明显变化
组合物22 澄清透明 无明显变化
组合物23 澄清透明 无明显变化
组合物24 澄清透明 无明显变化
结果显示，所制备的组合物均呈现澄清透明，说明其放置稳定性良好。而CN109316602A提供的制剂(即对比例6)放置5h即有明显析出现象，显示稳定性不佳。
选择部分所述组合物放置相应条件，按照如下方法检测含量和有关物质总量变化。
检测仪器：
高效液相色谱仪1260，美国安捷伦技术有限公司。
检测条件：
色谱柱：十八烷基硅烷键合硅胶柱(4.6mm×150mm,5μm，美国安捷伦技术有限公司)；流动相为乙腈-磷酸氢二钠缓冲液(磷酸调节pH＝8.0)的溶液，流速为1ml/min，柱温为30℃，检测波长为240nm。
配制方法：
供试品溶液：精密称取供试品适量至量瓶中，加入甲醇溶解并定容至刻度线，涡旋超声得到供试品溶液；
含量对照品溶液：称取适量的罗哌卡因药物对照品于容量瓶中，精密称定，甲醇溶解并定容至刻度线，即得含量对照品溶液。
有关物质对照品溶液：精密移取供试品溶液1ml至100ml量瓶中，加入甲醇稀释至刻度线，即得有关物质测定对照品溶液。
精密取上述溶液注入液相色谱仪，以外标法计算含量，自身稀释对照法计算有关物质，并计算有关物质总量。结果见表14。
表14.组合物的含量和有关物质测定结果
Figure PCTCN2021071647-appb-000008
Figure PCTCN2021071647-appb-000009
结果显示，本发明的组合物在加速和长期条件下放置6月后，含量和有关物质未发生显著变化。
以上研究结果表明，本发明的组合物的稳定性良好。
实验例2  药物组合物的通针性测定
采用21G针头测定组合物的通针性，测定结果见表15。
表15.药物组合物的粘度测定结果
组合物 注射通针性
组合物3至组合物25 粘度适中，能顺利通过21G针头
对比例4 推注困难，粘度大，注射通针性差
对比例5 粘度较小，能顺利通过21G针头
结果显示，本发明涉及的组合物具有适宜的注射通针性；而对比例4推注困难，注射通针性极差。
实验例3
在下面的实验描述中，给药剂量均是指按照制剂中的活性成分的盐酸盐的量(即，在使用游离碱的情况下，折算为盐酸盐)计算的剂量。
长效药物组合物的体内药效考察(1)
实验动物：雄性SD大鼠，200-300g，适应性饲养3天，并每天测定基础阈值。
实验分组与给药剂量：依照基础阈值随机分组，每组6只。将不同的组合物(或对比例组合物)分别注射入大鼠足跖皮下组织(给药体积范围为0.10～0.35ml)。采用von Frey纤维丝测痛仪测定疼痛阈值并考察运动阻滞情况。
药效实验给药剂量见表16。
表16.药物组合物体内药效学考察的给药剂量信息
组合物 剂量/mg/kg
生理盐水安慰剂 /
对比例3 13 *1
对比例4 45
组合物6 45
组合物7 45
组合物9 45
组合物16 45
组合物17 45
组合物22 45
*1：本发明在实施药效试验时，曾尝试将对比例3的剂量设置更高，结果发现大鼠在注射15mg/kg对比例3后立刻出现惊厥和抽搐现象，随后发生死亡。此现象的直接原因是血药浓度过高出现的中毒反应。而本发明组合物中的大鼠未出现中毒现象，说明本发明组合物较对比例3能提高安全性。
感觉神经阻滞：
检测方法，von Frey针刺-抬足法：大鼠在笼中自由活动，固定活动空间，待其安静后，采用von Frey纤维丝刺激大鼠脚掌，测定大鼠的机械缩腿阈值。机械缩腿阈值越高，表明感觉神经阻滞的效果越好。
评价方法：使用配对t检验将每组动物的机械缩腿阈值与给药前比较，采用非配对t检验将每组动物的机械缩腿阈值与对比例4比较，P＜0.05表示具有统计学差异，P＜0.01及P＜0.001表示具有显著统计学差异。
测定时间：由于在实验过程中发现对比例3的感觉神经阻滞维持时间较短，最多维持至3h左右，故对比例3的测定时间为0.5h、1h、2h、2.5h、3h。而长效组合物的测定时间若按照此设置，则会导致时间点过于密集，可能会对大鼠的行为产生影响。故长效组合物的时间点设置较对比例3更稀疏。结果见图1～3。
图1～2显示，和给药前的机械缩腿阈值相比，对比例3和4在大鼠体内的感觉神经阻滞持续时间分别为2h和约30h，本发明的组合物6、7、9、16、17和22的感觉神经阻滞维持时间分别为48h、48h、72h、54h、72h和54h。可见，在相同剂量下，本发明的组合物和对比例4相比，感觉阻滞持续时间可至少延长60％。
图3显示，和对比例4相比，组合物6在36～48h、组合物7在36～48h、组合物9在36～72h、组合物16在36～54h、组合物17在36～72h、组合物22在36～54h的机械缩腿阈值均有显著差异，表明本发明组合物较对比例4的药效强度显著增加，组合物的药效持续时间较对比例4具有显著优势。
根据组合物的感觉神经阻滞持续时间，计算各组合物的有效治疗剂量，结果见表17。
表17.药物的有效治疗剂量计算结果
参数 对比例3 对比例4 组合物6 组合物7 组合物9 组合物16 组合物17 组合物22
R 6.5 1.5 0.9 0.9 0.6 0.8 0.6 0.8
备注：R＝A/T t，其中，A为罗哌卡因药物的给药剂量，T t为药物在体内的有效治疗时间，R为有效治疗剂量。
可见，组合物6、7、9、16、17和22的有效治疗剂量R较对比例3、4可至少降低40％，表明达到同样的有效治疗时间，本发明的组合物消耗药物剂量更小，可避免临床上药物的浪费和过多药物导致的毒性反应。另外，本发明的药物组合物具有可控的疼痛缓解时间，为药物开发提供了按需选择的有益价值。
运动神经阻滞：
在测定感觉神经阻滞的同时，采用四级评分法对各组大鼠的运动神经阻滞情况进行评价。得分越高，表明运动神经阻滞的情况越严重。
1级(代表无运动阻滞，以数值1表示)：大鼠爪子可正常着地、且负重正常，未有无力的情况；
2级(代表发生轻微运动阻滞，以数值2表示)：大鼠爪子可正常着地，但有轻微无力的情况；
3级(代表发生完全运动阻滞，以数值3表示)：大鼠爪子偶尔着地且有无力情况；
4级(代表发生完全运动阻滞，以数值4表示)：大鼠爪子完全不着地且有严重的无力情况。
评价方法：使用非配对t检验将每组动物的运动神经阻滞得分情况与生理盐水安慰剂组比较，P＜0.05表示具有统计学差异，P＜0.01及P＜0.001表示具有显著统计学差异，结果见图4。
运动神经阻滞和感觉神经阻滞的持续时间对比结果见表18。
表18.组合物的感觉神经阻滞和运动神经阻滞比较结果
组合物 运动阻滞持续时间/感觉神经阻滞持续时间
对比例4 1.60
组合物6 1.17
组合物7 0.88
组合物9 0.67
组合物16 0.89
组合物17 0.67
组合物22 0.89
基于组合物的运动神经阻滞持续时间/感觉神经阻滞持续时间的比值结果，表明若达到相同的感觉神经阻滞持续时间，组合物的运动阻滞持续时间较对比例4可缩短至少20％。显示本发明组合物较对比例4改善了运动神经阻滞情况，意味着本发明组合物在满足临床镇痛需求的情况下，不会增加神经受损的风险，具有更高的安全性。
长效药物组合物的体内药效考察(2)
在组合物9的基础上，变化药物浓度和给药剂量，采用药效考察(1)的方法测定相应组合物的感觉神经阻滞情况。组合物及给药剂量信息见表19，感觉神经阻滞结果见图5。
表19.组合物的处方和给药剂量信息
Figure PCTCN2021071647-appb-000010
组合物9-1、9-2、9-3在体内的感觉阻滞持续时间分别为24h，36h和48h。可见，不同的药用剂量可达到不同的疼痛缓解时间，为临床的按需选择提供便利。
经计算，组合物9-1、9-2、9-3的有效治疗剂量R分别为0.6、0.7和0.7，均显著低于对比例4的常规缓释制剂，说明本发明组合物提高了药物的利用率。
长效药物组合物的体内药效考察(3)
变化组合物中药效增强剂的比例和型号，采用药效考察(1)的方法测定相应组合物对动物的感觉神经阻滞情况。组合物及给药剂量信息见表20，感觉神经阻滞结果见图6和表21。
表20.组合物的处方和给药剂量信息
组合物 剂量mg/kg
对比例8 45
对比例9 45
组合物23 45
组合物24 45
组合物25 45
图6显示，对比例8、9和组合物23、24、25在大鼠体内的感觉神经阻滞持续时间分别为30h、30h、72h、54h和48h。可见，在相同剂量下，组合物23～25(含5％药效增强剂)较对比例8(不含药效增强剂)及对比例9(含15％药效增强剂)的感觉阻滞持续时间可至少延长60％。鱼油3322型中包含二十碳五烯酸和二十二碳六烯酸的含量分别为约33％和约22％，鱼油1812型中包含二十碳五烯酸和二十二碳六烯酸的含量分别为约18％和约12％，藻油中的二十二碳六烯酸的含量为约35％，不含二十碳五烯酸。在含有相同比例的药效增强剂下，组合物23、24和25的感觉神经阻滞持续时间依次缩短，说明组合物中的二十碳五烯酸和二十二碳六烯酸的含量会影响药效持续时间，同时含有二十碳五烯酸和二十二碳六烯酸两种脂肪酸的药效学结果更优。
表21.组合物的机械阈值结果
时间/h 组合物23 组合物24 组合物25
给药前 12±3 13±3 13±3
3 300±0#& 300±0#& 300±0#&
6 240±66# 260±42# 240±66#
24 153±41#&& 200±49###&&& 127±41
30 113±33##&& 180±0###&&& 67±16#
36 68±28##&& 140±44###&&& 49±18##&&
48 54±14###&&& 68±28##&& 37±18&
54 47±21##&& 36±19#& 14±2
72 30±15#& 18±7 18±7
备注：#p<0.05,##p<0.01,###p<0.001v.s.对比例8；&p<0.05,&&p<0.01,&&&p<0.001v.s.对比例9
表21结果显示，和对比例8及9相比，组合物23～25在24h或24h后的不同时间点的机械缩腿阈值具有显著差异，表明组合物的药效持续时间较对比例8、9具有显著优势。表明药效增强剂通过一定的机制达到了预料不到的效果。
根据组合物的感觉神经阻滞持续时间，计算各组合物的有效治疗剂量，结果见表22。
表22.药物的有效治疗剂量计算结果
参数 对比例8 对比例9 组合物23 组合物24 组合物25
R 1.5 1.5 0.6 0.8 0.9
备注：R＝A/T t，其中，A为罗哌卡因药物的给药剂量，T t为药物在体内的有效治疗时间，R为有效治疗剂量。
可见，本发明的组合物的有效治疗剂量较对比例8和9至少降低了40％，说明本发明组合物可提高药物利用率。
实验例4
在下面的实验描述中，给药剂量均是指按照制剂中的活性成分的盐酸盐的量(即，在使用游离碱的情况下，折算为盐酸盐)计算的剂量。
长效药物组合物的体内药代动力学考察
将所得的药物组合物，皮下注射至雄性SD大鼠，定时取血，采用LC-MS法测定血浆中药物的含量，考察体内的药代动力学情况。
实验动物：雄性SD大鼠，200～300g，来源：中国科学院上海药物研究所；
实验分组：将大鼠按照下表随机分组，每组6只；
给药制剂与剂量信息见表23。
表23.药物组合物的体内药代动力学实验的给药剂量信息
组合物 剂量/mg/kg
对比例3 13
对比例4 45
组合物7 45
组合物9 45
组合物17 45
实验过程：皮下注射，在预定的时间点，通过大鼠眼眶取血0.5ml置于肝素钠抗凝的离心管中，3000rpm离心10min，分离血浆，经LC-MS法检测血药浓度。
计算组合物的药代动力学(PK)参数，采用t检验对结果进行统计分析，结果见表24及图7～8。
表24.药物组合物的PK参数
Figure PCTCN2021071647-appb-000011
备注：AUC为生物利用度，AUC t为有效生物利用度。
备注：*p<0.05**p<0.01***P＜0.001v.s.对比例4。
表24结果显示，组合物7、9和17较同剂量的对比例3的C max降低了至少70％，和对比例4相比，组合物7和9生物利用度和有效生物利用度均显著提高。
结合药效考察结果和PK曲线，拟合做图得到图9，显示出本发明组合物在体内的血药浓度和药效关联性良好，意味着本发明组合物在药物研究和临床使用中具有较强的可控性。
根据实验例3的药效实验结果，且由于本发明组合物具有良好的血药浓度-药效关联性，结合组合物7、9、17的药效持续时间分别为48h、72h和72h，推断盐酸罗哌卡因在大鼠体内的起效浓度约为20ng/ml(对比例3注射至体内后，药物快速入血，导致其血药浓度与局部药效的关联性不佳，故20ng/ml的起效浓度对于对比例3不适用)。如图7显示，在起效浓度以下的药物即为无效药物浓度，对比例4在30h左右的血药浓度即到达无效浓度，且其总体生物利用度和有效生物利用度较低，说明部分药物未能有效发挥药效，在体内以低浓度滞留较长时间，这无疑会带来较高的神经毒性风险。而组合物7、9和17较对比例4在镇痛的需求时间内(例如48h或72h)，将药物充分暴露，减少了药物以无效形式滞留体内的持续时间。同时，组合物7、9和17的生物利用度和有效生物利用度均有提高，说明本发明组合物在体内释放较完全，能充分发挥药效，提高药物利用率，并降低神经毒性风险，提高用药安全性。
综上，本发明组合物较同剂量的对比例3(盐酸罗哌卡因注射液)能降低至少70％C max。和常规缓释制剂相比，本发明的组合物的药物释放更加完全，生物利用度和有效生物利用度均有显著提高，可减小药物以无效形式滞留体内的持续时间，提高药物利用率，降低由神经纤维长时间暴露于较低药物浓度中所带来的毒性风险。另外，在具有相同镇痛效果的情况下，本发明组合物较常规缓释制剂能改善运动阻滞情况，降低神经毒性，在临床使用中具有重要意义。本发明中的药效增强剂在一定比例情况下，可发挥意想不到的效果。
实验例5
在下面的实验描述中，给药剂量均是指按照制剂中的活性成分的盐酸盐的量(即，在使用游离碱的情况下，折算为盐酸盐)计算的剂量。
注射部位的刺激性考察
将组合物8和对比例7分别注射入大鼠足跖皮下组织，在给药后24h，观察注射部位的刺激性情况。给药剂量信息见表25，结果见图10。
表25.组合物给药剂量信息
组合物 剂量
组合物8 45mg/kg
对比例7 45mg/kg
结果显示，给药后24h，对比例7的注射部位皮肤出现明显的发黑甚至轻微溃烂的现象，显示刺激性较大，而本发明组合物注射部位除有轻微红肿外，其他无明显异常，表明本发明组合物较对比例7具有更好的注射部位耐受性和安全性。
实验例6
在下面的实验描述中，给药剂量均是指按照制剂中的活性成分的盐酸盐的量(即，在使用游离碱的情况下，折算为盐酸盐)计算的剂量。
注射部位的组织病理学观察
皮下注射13mg/kg对比例3，45mg/kg对比例5、组合物7和组合物9至大鼠，于给药后的48h，将大鼠安乐死，使用解剖刀解离注射部位的组织样品。取样大小需覆盖给药部位组织大小，用生理盐水冲洗样品后，将样品固定在缓冲的福尔马林中。用脱水剂二甲苯进行脱水处理，后将组织样品包埋在石蜡中，使用冷冻切片机将组织样品切成薄片(5μm组织切片)，置于载玻片。用苏木精-伊红染色后获得组织切片。用显微镜观察组织形态学和免疫组织学情况。结果见图11。
结果显示，组合物7、组合物9，未注射组及对比例3的组织切片无明显异样，而对比例5中出现了明显的炎症细胞浸润，注射部位的刺激情况较严重。说明本发明的组合物安全性良好，较常规缓释剂能减轻注射部位的刺激情况。
据文献Acute Med Surg.2017 Apr；4(2):152-160报道，神经毒性一般会在给药部位附近的神经纤维周围观察到炎症以及反应性纤维化，在组织病理学评估中，主要为浸润细胞(包括巨噬细胞、异物巨细胞、淋巴细胞和浆细胞)的浸润。本发明的组合物较对比例5显著减弱了注射部位的刺激性反应，表明本发明组合物对于降低神经毒性具有积极的作用。

Claims (10)

  1. 一种长效罗哌卡因药物组合物，所述药物组合物包含：罗哌卡因；药物溶剂；药用磷脂；药用油脂；药效增强剂；非必需的抗氧剂及非必需的酸碱调节剂，
    其中，所述药效增强剂选自ω-3脂肪酸及其代谢产物、富含ω-3脂肪酸或其代谢产物的物质中的一种或两种以上的组合。
  2. 根据权利要求1所述的长效罗哌卡因药物组合物，其中，所述药物组合物使药物的血浆峰浓度较同剂量盐酸罗哌卡因注射液降低30％以上，优选降低50％以上，更优选降低60％以上；药效持续时间达12h以上，24h以上，甚至48h以上。
  3. 根据权利要求1或2所述的长效罗哌卡因药物组合物，其中，所述药物组合物包含，基于组合物的总重，以重量百分比计，
    0.5％至10％，优选1％至8％，更优选1％至5％的罗哌卡因；
    2％至25％，优选3％至23％，更优选5％至20％的药物溶剂；
    8％至55％，优选10％至50％，更优选15％至45％的药用磷脂；
    15％至89％，优选20％至76％，更优选22％至60％的药用油脂；
    0.5％至10％，优选1％至9％，更优选2％至8％的药效增强剂；
    约0％至1％，优选0％至0.5％，更优选0％至0.3％的抗氧剂；
    约0％至8％，优选0％至5％，更优选0％至3％的酸碱调节剂。
  4. 根据权利要求1-3中任一项所述的长效罗哌卡因药物组合物，其中，
    所述ω-3脂肪酸及其代谢产物包括ω-3多不饱和脂肪酸及其代谢产物，如α-亚麻酸及其代谢产物二十碳五烯酸和二十二碳六烯酸或其组合；
    所述富含ω-3脂肪酸或其代谢产物的物质包括富含α-亚麻酸的物质、富含α-亚麻酸代谢产物二十碳五烯酸和二十二碳六烯酸的物质或其组合，优选地，所述富含α-亚麻酸的物质包括亚麻籽油、紫苏籽油、核桃油、阿甘油或其组合；所述富含α-亚麻酸代谢产物二十碳五烯酸和二十二碳六烯酸的物质包括鱼油、紫菜油和藻油或其组合；
    所述药效增强剂为选自富含ω-3脂肪酸或其代谢产物的物质中的一种或多种，优选为选自富含ω-3脂肪酸或其代谢产物的物质中的二十碳五烯酸含量不小于15％且二十二碳六烯酸含量不小于10％的物质中的一种或多种，特别优选为选自富含ω-3脂肪酸或其代谢产物的物质中的二十碳五烯酸含量不小于20％且二十二碳六烯酸含量不小于10％的物质中的一种或多种，还更特别优选为选自鱼油和紫菜油中的一种或多种。
  5. 根据权利要求1-4中任一项所述的长效罗哌卡因组合物，其中，
    所述罗哌卡因包括罗哌卡因游离碱及其盐类；和/或
    所述药物溶剂为选自苯甲醇、乙醇、丙二醇、甘油、异丙醇、N-甲基吡咯烷酮、二甲基亚砜、液态聚乙二醇、二甲基乙酰胺、单乙酸甘油酯、聚乙二醇单甲醚、二乙二醇单乙基醚、乳酸乙酯、乙酸乙酯、丙二醇二乙酯、丙二酸二乙酯、四氢呋喃聚乙二醇醚、苯甲酸苄酯中的一种或多种，更优选地，所述药物溶剂为选自苯甲醇、丙二醇、乙醇中 的一种或多种；和/或
    所述抗氧剂为选自半胱氨酸、a-生育酚、a-生育酚醋酸酯、N-乙酰基-L-半胱氨酸、丁羟基茴香醚、二丁羟基甲苯、没食子酸丙酯、叔丁基对苯二酚、硫辛酸、茶多酚、L-抗坏血酸棕榈酸酯、谷胱甘肽中的一种或多种；优选为选自a-生育酚、L-抗坏血酸棕榈酸酯、半胱氨酸中的一种或多种；和/或
    所述酸碱调节剂为选自精氨酸、赖氨酸、组氨酸、甘氨酸、氨丁三醇、二乙醇胺、乙二胺、葡甲胺、盐酸、乙酸、无水枸橼酸、抗坏血酸、乳酸、酒石酸、甲磺酸、蛋氨酸、氢氧化钠、三乙醇胺中的一种或多种；优选为选自氨丁三醇、二乙醇胺、乙二胺、葡甲胺中的一种或多种。
  6. 根据权利要求1-5中任一项所述的长效罗哌卡因组合物，其中，所述药用油脂为选自天然植物油(如蓖麻油、芝麻油、大豆油、葵花籽油、花生油、玉米油、菜籽油、橄榄油、棉籽油)或者天然植物油经人工改进的半天然油脂(如：氢化蓖麻油)、油脂纯化物及相应衍生物；人工合成油脂，主要包括中链甘油三酸酯(如：辛酸甘油三酸酯、癸酸甘油三酸酯之一或二者混合物)、长链甘油三酸酯、三乙酸甘油酯或其他相应衍生物、油酸乙酯中的一种或多种。
  7. 根据权利要求1-6中任一项所述的长效罗哌卡因组合物，其中，所述药用磷脂为选自：天然磷脂、半合成磷脂、合成磷脂中的一种或多种，优选地，所述天然磷脂选自蛋黄卵磷脂、大豆磷脂及其组合；所述半合成磷脂选自氢化蛋黄卵磷脂、氢化大豆磷脂或其组合；所述合成磷脂为选自二棕酰磷脂酰乙醇胺、二棕酰磷脂酸、二棕酰磷脂酰甘油、二油酰磷脂酰乙醇胺、二棕酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱中的一种或多种。
  8. 根据权利要求1-7中任一项所述的长效罗哌卡因药物组合物在制备疼痛缓解药物，特别是用于治疗术后疼痛的药物中的用途。
  9. 根据权利要求8所述的用途，其中，所述疼痛缓解药物通过局部注射，如皮下或肌肉注射给药、或在切口直接滴入给药、或切口浸润给药、或在神经丛处给药、或通过关节腔注射，优选皮下注射给药，更优选皮下浸润给药来施用。
  10. 根据权利要求8或9所述的用途，其中，所述长效罗哌卡因药物组合物每天需要服用的预期总量按活性药物计为5～1000mg，优选10～500mg。
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113941002A (zh) * 2021-08-27 2022-01-18 南京清普生物科技有限公司 一种小分子药物缓释递药系统

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11992483B2 (en) 2021-03-31 2024-05-28 Cali Biosciences Us, Llc Emulsions for local anesthetics
CN113941004B (zh) * 2021-07-26 2022-10-21 南京清普生物科技有限公司 一种高浓度局麻药的缓释组合物
CN114344299A (zh) * 2021-12-17 2022-04-15 佐建锋 一种具有长效缓释作用的脂质释药系统及其制备方法
CN115006533B (zh) * 2021-12-28 2023-07-14 南京清普生物科技有限公司 一种含局麻药的均相水性组合物

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102370619A (zh) * 2010-08-18 2012-03-14 罗和国 脂肪乳乳化局麻药
CN103142458A (zh) 2013-01-22 2013-06-12 莱普德制药有限公司 无成瘾性镇痛缓释递药系统的组方与制备方法
WO2013168172A1 (en) * 2012-05-10 2013-11-14 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
US20150250724A1 (en) 2012-09-21 2015-09-10 Kansai Medical University Educational Corporation Long-lasting, controlled-release local anesthetic liposome preparation
US20150359738A1 (en) * 2014-06-16 2015-12-17 Loewi LLC Methods of Anesthetizing Nerve Tissue in the Trigeminal Nerve Pathway and Medical Uses Thereof
CN106535886A (zh) 2014-04-21 2017-03-22 赫伦治疗有限公司 长效聚合物输送系统
CN108159055A (zh) * 2018-01-04 2018-06-15 西安力邦医药科技有限责任公司 治疗乳腺癌的长效递药系统、其制备方法及应用
CN108743952A (zh) 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法
CN109316602A (zh) 2018-11-13 2019-02-12 西安力邦医药科技有限责任公司 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用
WO2019046293A1 (en) 2017-08-28 2019-03-07 Tlc Biopharmaceuticals, Inc. EXTENDED RELEASE ANESTHETIC COMPOSITIONS AND METHODS OF PREPARATION THEREOF

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5814659A (en) * 1996-04-23 1998-09-29 Dtr Dermal Therapy (Barbados) Inc. Topical analgesic composition
WO2004067563A1 (en) * 2003-01-28 2004-08-12 Academisch Ziekenhuis Leiden Peptide inhibitors of toxins derived from ll-37
CN111542325A (zh) * 2017-05-03 2020-08-14 梧桐树健康科学公司 用于治疗恶性肿瘤和癌前病症的组合物及其使用方法和制备药剂的方法
EP3743072B1 (en) * 2018-01-22 2023-10-25 Foresee Pharmaceuticals Co., Ltd. Pharmaceutical composition for sustained release delivery of buprenorphine

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102370619A (zh) * 2010-08-18 2012-03-14 罗和国 脂肪乳乳化局麻药
WO2013168172A1 (en) * 2012-05-10 2013-11-14 Painreform Ltd. Depot formulations of a local anesthetic and methods for preparation thereof
CN104427977A (zh) 2012-05-10 2015-03-18 佩因拉佛姆有限公司 局部麻醉剂的储库制剂及其制备方法
US20150250724A1 (en) 2012-09-21 2015-09-10 Kansai Medical University Educational Corporation Long-lasting, controlled-release local anesthetic liposome preparation
CN103142458A (zh) 2013-01-22 2013-06-12 莱普德制药有限公司 无成瘾性镇痛缓释递药系统的组方与制备方法
CN106535886A (zh) 2014-04-21 2017-03-22 赫伦治疗有限公司 长效聚合物输送系统
US20150359738A1 (en) * 2014-06-16 2015-12-17 Loewi LLC Methods of Anesthetizing Nerve Tissue in the Trigeminal Nerve Pathway and Medical Uses Thereof
WO2019046293A1 (en) 2017-08-28 2019-03-07 Tlc Biopharmaceuticals, Inc. EXTENDED RELEASE ANESTHETIC COMPOSITIONS AND METHODS OF PREPARATION THEREOF
CN108159055A (zh) * 2018-01-04 2018-06-15 西安力邦医药科技有限责任公司 治疗乳腺癌的长效递药系统、其制备方法及应用
CN108743952A (zh) 2018-06-11 2018-11-06 西安力邦医药科技有限责任公司 局部麻醉药的磷脂-混溶剂-油缓释递药系统组方与制备方法
CN109316602A (zh) 2018-11-13 2019-02-12 西安力邦医药科技有限责任公司 一种长效镇痛并促进伤口愈合的复方缓释递药系统的组方与应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ACUTE MED SURG., vol. 4, no. 2, April 2017 (2017-04-01), pages 152 - 160
ANESTH ANALG., vol. 103, no. 3, September 2006 (2006-09-01), pages 608 - 14
See also references of EP4091612A4

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113941002A (zh) * 2021-08-27 2022-01-18 南京清普生物科技有限公司 一种小分子药物缓释递药系统

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