WO2017036408A1 - S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof - Google Patents

S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal and sustained release preparation thereof Download PDF

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WO2017036408A1
WO2017036408A1 PCT/CN2016/097784 CN2016097784W WO2017036408A1 WO 2017036408 A1 WO2017036408 A1 WO 2017036408A1 CN 2016097784 W CN2016097784 W CN 2016097784W WO 2017036408 A1 WO2017036408 A1 WO 2017036408A1
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propyl
sterile
ropivacaine
formulation
suspension
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PCT/CN2016/097784
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French (fr)
Chinese (zh)
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叶强
严庞科
冯卫
万华
张轩邈
汪东海
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四川海思科制药有限公司
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Priority to CN201680037141.8A priority Critical patent/CN107848973A/en
Publication of WO2017036408A1 publication Critical patent/WO2017036408A1/en

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    • 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine crystal suitable for industrial production and a sustained release preparation thereof, and a preparation method thereof, belonging to medical technology field.
  • Ropivacaine is a novel long-acting amide local anesthetic that acts in the same way as other local anesthetics and blocks nerve excitation and conduction by inhibiting neuronal sodium channels. Compared with bupivacaine, ropivacaine has the advantages of short onset time, strong degree of separation and blockage, and low toxicity. At present, ropivacaine hydrochloride or ropivacaine mesylate injection is often used clinically, mainly for surgical anesthesia and postoperative pain treatment. However, the in vivo biological half-life of ropivacaine injections is short, resulting in a short duration of topical anesthesia.
  • the existing ropivacaine long-acting injection preparations all use a corresponding sustained-release carrier to control the release of the drug, such as a phospholipid matrix and an oily solution.
  • sustained-release preparations use a large amount of oily base and organic solvent in the prescription, and there are certain safety hazards.
  • WO2013168172A1 discloses a sustained release preparation of ropivacaine, which is disclosed in Example 2, which comprises a formulation containing ropivacaine hydrochloride, phospholipid, castor oil, cysteine and ethanol.
  • the preparation is a paste which is not clear and transparent, and the amount of the phospholipid in the preparation is large, reaching 50% or more, resulting in a large viscosity of the preparation and difficulty in injection.
  • a large amount of castor oil and ethanol are used in the prescription, wherein the concentration of castor oil is as high as 35%, and the concentration of ethanol is 6%, which has certain safety hazards.
  • CN103142458A discloses an oily solution sustained release injection of ropivacaine, which is disclosed in Example 21 as a formulation of ropivacaine free base, benzyl benzoate, benzyl alcohol and castor oil.
  • the formulation contains a high concentration of oil phase and organic solvent, wherein the concentration of castor oil is as high as 75%, and the concentrations of organic solvent benzyl benzoate and benzyl alcohol reach 15% and 10%, respectively, which have certain safety risks.
  • the present invention provides a novel ropivacaine compound crystal (or ropivacaine crystal) having a powder X-ray diffraction pattern having a 2 ⁇ value of 10.5 ⁇ 0.2°, 13.0 ⁇ 0.2°, and 16.4 ⁇ 0.2°. 19.0 ⁇ 0.2°, 21.6 ⁇ 0.2°, 23.4 ⁇ 0.2°, 25.9 ⁇ 0.2°, 26.3 ⁇ 0.2°, and 31.8 ⁇ 0.2° characteristic diffraction peaks.
  • the crystal physicochemical properties of the present invention are stable.
  • the above compound crystal has a powder X-ray diffraction pattern further having a characteristic diffraction peak at 24.3 ⁇ 0.2°.
  • the above compound crystals have a powder X-ray diffraction pattern similar to that of Fig. 1 (substantially the same).
  • the above compound crystal has a DSC chart similar to that of FIG. 2.
  • the ropivacaine crystal of the present invention comprises ropivacaine base crystals or ropivacaine pharmaceutically acceptable water-insoluble salt crystals.
  • Another object of the present invention is to provide a process for producing a crystal of the above compound.
  • the present invention provides a method for preparing a crystal of the above compound, which comprises: from about 0.02 g/mL to about 0.5 g/mL of S-(-)-1- at a temperature of from about -5 ° C to about 70 ° C C1-C4 alcohol of propyl-2',6'-dimethylformylpiperidine, ester of acetonitrile, formic acid C1-C4 alcohol, ester of C1-C4 alcohol, tetrahydrofuran, acetone, methyl isobutyl ketone Crystallization of one or more solvents in dichloromethane, dichloroethane solution gives crystals of the above compounds.
  • the present invention also provides another method for preparing crystals of the above compounds, which comprises: from about 0.02 to about 0.5 g/mL of S-(-)-1 at a temperature of from about -5 ° C to about 70 ° C.
  • At least one of -propyl-2',6'-dimethylformylformylpiperidine is selected from the group consisting of C1-C4 alcohols, acetonitrile, esters of C1-C4 alcohols, esters of C1-C4 alcohols, tetrahydrofuran, acetone, a solution of methyl isobutyl ketone, dichloromethane or dichloroethane, which is selected from C 5-8 alkane, C 5-6 ether, petroleum ether, water or one or more solvents, and then crystallized to obtain the above compound Crystal.
  • the C 5-8 alkane in the above method is selected from one or more of pentane, hexane, heptane or octane.
  • the C 5-6 ether in the above method is isopropyl ether or methyl tert-butyl ether.
  • Another object of the present invention is to provide a sustained release injection preparation of S-(-)-1-propyl-2',6'-dimethylformylpiperidine (ie, ropivacaine) and a preparation method thereof .
  • the inventors have found that by simply using the physical properties of the ropivacaine crystal of the present invention (including ropivacaine free base crystal or its poorly water-soluble salt), it can be effectively suspended in a suitable medium. 72 hours of local analgesic effect. After the preparation was injected into the body, the drug was slowly released as the drug particles were slowly dissolved, and based on these findings, further studies were conducted to complete a novel ropivacaine sustained-release injection preparation.
  • the present invention provides a controlled release injection formulation in the form of a sterile suspension of ropivacaine crystals of the invention which, after injection, releases S-(-)-1-propyl- during a period of at least 12 h 2',6'-xylyleneformyl piperidine, the formulation comprising:
  • a controlled release injectable preparation in the form of a sterile suspension of the present invention wherein the carrier comprises one or more surfactants.
  • the carrier may further comprise a suspending agent.
  • the invention also provides a ropivacaine sustained release suspension formulation, the formulation comprising the following ingredients:
  • the component (a) is the ropivacaine crystal of the present invention, and includes ropivacaine base crystal or ropivacaine pharmaceutically acceptable. Accepted water insoluble salt crystals.
  • the formulation of the invention is an injectable pharmaceutical suspension which, after injection, preferably after intramuscular or subcutaneous injection, is at least about 8 hours, preferably at least 12 hours, more preferably at A therapeutic amount of ropivacaine is released during 48 hours, 72 hours or longer.
  • the ropivacaine suspension of the present invention can be administered as an aqueous ready-to-use suspension, or the suspension can be lyophilized and used in combination with water when ready for use. injection.
  • a suspension formulation according to the present invention wherein ropivacaine is present in the formulation in the form of suspended drug particles, including micron-sized ropivacaine and nano-sized ropivacaine.
  • the suspension preparation according to the present invention wherein the ropivacaine weight percentage is preferably from 1 to 40%, further preferably from 2 to 20%, still more preferably from 2 to 8%.
  • a suspension formulation according to the present invention wherein ropivacaine (including ropivacaine free base or a pharmaceutically acceptable water-insoluble salt thereof) can be averaged by pulverization such as jet milling or mechanical milling
  • the diameter is as small as micron or nanometer.
  • the present invention also provides a method of preparing a poorly water-soluble salt of ropivacaine, comprising the steps of:
  • reaction product is purified by a method such as recrystallization to obtain a poorly water-soluble salt of ropivacaine.
  • the suspension percentage by weight is preferably 0.05%. 20%, further preferably 0.1% to 5%, still more preferably 0.1 to 2%.
  • suspending agents suitable for use include, but are not limited to, one, two or more of the following: sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, Hydroxypropyl methylcellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose and polyvinylpyrrolidone.
  • suspending agents suitable for use in the ropivacaine carrier include various polymers, low molecular weight oligomers, natural products, and surfactants, including nonionic surfactants and ionic surfactants such as gelatin and cheese. Protein, phospholipid, dextran, polyvinyl alcohol, glycerin, acacia, cholesterol, tragacanth, stearic acid.
  • the surfactant weight percentage is preferably from 0.01% to 20%, more preferably from 0.02% to 5%, still more preferably from 0.02% to 2%.
  • suitable surfactants include, but are not limited to, one, two or more of the following: polyoxyethylene derivatives of sorbitan esters, such as polysorbate 20 (Tween-20), poly Sorbate 40 (Tween-40), Polysorbate 60 (Tween-60), Polysorbate 65 (Tween-65), Polysorbate 80 (Tween-80) and Polysorbate 85 (Tween) -85), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188 and poloxamer 407 Et.), 15-hydroxystearate (solutol HS15), preferably Tween-20, Twe
  • the content of the filler is preferably 0.05% to 20%, further preferably 1% to 10%, Still more preferably 3 to 8%.
  • fillers suitable for use herein include, but are not limited to, one, two or more of the following: mannitol, trehalose, sucrose, lactose, maltose, xylitol, glucose, starch, glycine, rings Dextrin, sorbitol and the like, preferably mannitol and sucrose.
  • the buffer is used to stabilize the pH of the ropivacaine suspension preparation at 6 to 8.5, preferably 7 to 8.
  • the amount of the buffer salt used in the buffer is from about 0.02 to about 2%, preferably from 0.03 to 1%, further preferably from 0.1 to 1%, based on the type of the buffer. This is based on the total weight of the sterile injectables.
  • buffers suitable for this purpose include, but are not limited to, one, two or more of the following: phosphate, acetate, citrate or TRIS buffer, preferably phosphate buffer.
  • the pH of the buffered salt solution is preferably 6 to 8.5, more preferably 6.5 to 7.5, still more preferably 7.0 to 7.5.
  • the ropivacaine suspension formulation of the present invention may optionally comprise a pH adjusting agent in an amount to adjust the pH of the suspension in the range of from about 6 to 8.5, preferably from 7 to 8, depending on the pH of the suspension. Whether the value needs to be raised or lowered to achieve the desired pH of 7-8, the pH adjusting agent can be acidic or basic. Therefore, when it is desired to lower the pH, an acidic pH adjusting agent such as hydrochloric acid or acetic acid, preferably hydrochloric acid, can be applied. When it is desired to raise the pH, an alkaline pH adjusting agent such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide or magnesium hydroxide, preferably sodium hydroxide, will be employed.
  • a pH adjusting agent in an amount to adjust the pH of the suspension in the range of from about 6 to 8.5, preferably from 7 to 8, depending on the pH of the suspension.
  • the pH adjusting agent can be acidic or basic. Therefore, when it is desired to lower the pH, an acid
  • the preservative is an antimicrobial agent and an antioxidant, which can Selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxytoluene ether, butylated hydroxytoluene, chlorobutanol, gallic acid ester, hydroxybenzoate, EDTA, phenol, chlorocresol, m-cresol, chlorination Benzyl ethoxylated ammonium, chlorinated myristyl-gamma-methylpyridine, phenylacetic acid mercury and thimerosal, preferably benzyl alcohol and hydroxybenzoic acid ester.
  • the content of the preservative by weight is preferably from 0.05% to 5%, more preferably from 0.1% to 1%, still more preferably from 0.2% to 0.5%.
  • the content of the isotonicity adjusting agent is preferably 0.05% to 20% by weight, more preferably 0.05% to 10%, still more preferably 0.4% to 5%.
  • isotonicity adjusting agents suitable for use include, but are not limited to, one, two or more of the following: mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose, lactose, preferably mannitol, chlorine Sodium and glucose.
  • the invention also provides a preparation method of the suspension preparation, the preparation method comprising the following steps:
  • a carrier for the preparation of a sterile ropivacaine suspension comprising a surfactant, an optional suspending agent, an optional filler, an optional buffer, an optional pH adjusting agent and water
  • the sterilization method used may be filtration sterilization or autoclaving.
  • sterile ropivacaine can be prepared directly by aseptic manufacturing process, or ropivacaine can be dry heat sterilized, autoclaved or irradiated.
  • a sterile suspension of ropivacaine is prepared by mixing sterile ropivacaine with a sterile carrier under sterile conditions to form a sterile preliminary suspension.
  • sterile controlled crystallization and high shear homogenization can also be applied to reduce the particle size of the drug particles to produce particles having an average particle size ranging from 0.1 to 50 microns.
  • ball mills such as Dyno mills
  • other low energy and high energy mills such as roller mills can be used, and high energy mills such as Netzsch mills, DC mills and Planetary mills can be used.
  • the applied milling methods and equipment must be capable of producing a sterile ropivacaine suspension formulation having the desired average particle size. This is preferably carried out using sterile wet milling, microfluidization or sterile high pressure homogenization.
  • the ropivacaine suspension can be lyophilized (lyophilized) to form a lyophilized formulation.
  • the lyophilized formulation when combined with water, forms an injectable suspension for injection.
  • the resulting final ropivacaine suspension can be aseptically filled into a sterile vial and aseptically loaded into a sterile lyophilizer.
  • Freeze drying should include cooling the formulation to about -40 ° C at a suitable cooling rate. More specifically, freeze drying should include three stages: freezing, preliminary drying, and secondary drying. The freezing stage should include cooling the formulation to about -40 ° C at a suitable cooling rate. Preliminary drying should be carried out at less than about 0 ° C and a suitable vacuum and duration. Secondary drying should be carried out above about 0 ° C and a suitable vacuum and duration.
  • the bottle with the resulting lyophilized ropivacaine suspension was aseptically stoppered and sealed under atmospheric pressure or partial vacuum.
  • the invention also provides the use of the suspension formulation for the preparation of an analgesic drug.
  • the analgesic is administered before and after the medical treatment.
  • the suspension preparation is administered by subcutaneous, intradermal or intramuscular injection.
  • w/w for expressing the content of each component forming the suspension preparation of the present invention means “weight (g) of each component / weight (g) of the suspension preparation”.
  • Similar maps refer to substantially identical maps.
  • Rovacaine is a pharmaceutically acceptable water-insoluble salt of ropivacaine base or ropivacaine.
  • Rovacaine base is ropivacaine free base, including the crystalline form of the invention.
  • “Pharmaceutically acceptable water-insoluble salt” means a poorly soluble salt which is safe, non-toxic and which is pharmaceutically acceptable for veterinary use or human pharmaceutical use and which has the desired pharmacological activity, such salts include, However, it is not limited to long-chain fatty acids with organic acids such as C8-C22 (such as caprylic acid (C8), citric acid (C10), myristic acid (C14), palmitic acid (C16), stearic acid (C18), and oleic acid ( C18) etc.), a poorly soluble salt formed by cholic acid, deoxycholic acid, benzoic acid, diclofenac, and palmitic acid.
  • organic acids such as C8-C22 (such as caprylic acid (C8), citric acid (C10), myristic acid (C14), palmitic acid (C16), stearic acid (C18), and oleic acid ( C18) etc.
  • C8-C22 such as caprylic acid (C8)
  • the poorly water-soluble salt of ropivacaine of the present invention means that the solubility in water is less than 2 mg/ml under the conditions of pH 7-8.
  • the solubility of ropivacaine in water-soluble salts in water at pH 7-8 is slightly soluble, very slightly soluble or almost insoluble (Definition of slightly soluble in the Chinese Pharmacopoeia of 2010) : means that 1g (ml) of solute can be dissolved in solvent 100 ⁇ less than 1000ml; the definition of very slightly dissolved in Chinese Pharmacopoeia of 2010 means that solute 1g (ml) can be dissolved in solvent 1000 ⁇ less than 10000ml; 2010 edition The definition of almost insoluble in the Chinese Pharmacopoeia means that 1 g (ml) of solute can not be completely dissolved in 10000 ml of solvent).
  • “Micron-sized ropivacaine” is an average particle size of ropivacaine of less than 100 microns.
  • the average particle size of ropivacaine should range from about 1 to about 100 microns, preferably from about 1 to about 50 microns, more preferably from about 1 to about 10 to 20 microns.
  • Ne-sized ropivacaine is an average particle size of ropivacaine of less than 1 micron.
  • the average particle size of ropivacaine should be in the range of from about 0.1 to about 1 micron.
  • mean particle size refers to a volume mean diameter as determined by a Laser Light Scattering (LLS) method.
  • LLS Laser Light Scattering
  • the present invention provides a crystalline form of ropivacaine and thereby developed a novel class of sustained release injection formulations of ropivacaine.
  • the carrier of the preparation of the present invention is water, and the active ingredient ropivacaine free base crystal or a water-insoluble salt thereof is suspended therein, and the additional agent used is a surfactant and a suspending agent which are commonly used in injections.
  • the preparation of the present invention utilizes the solubility characteristics of ropivacaine free base or its poorly water-soluble salt itself to control drug release. There is no need to add other drug delivery vehicles to control the release of the drug.
  • the preparation can also be used in combination with a suitable drug delivery carrier to further enhance its sustained release effect.
  • the preparation not only has a simple production process, but also the auxiliary materials selected are commonly used auxiliary materials for injection, and have good safety.
  • the sustained release system is a long-acting ropivacaine sustained release system suitable for post-surgical analgesia for providing initial anesthesia and is expected to provide a local anesthetic effect of about 8 to 72 hours or longer at the site of administration.
  • Figure 1 is a powder X-ray diffraction pattern of the compound S-(-)-1-propyl-2',6'-dimethylformylpiperidine.
  • Figure 2 is a DSC chart of the compound S-(-)-1-propyl-2',6'-dimethylformylpiperidine.
  • Figure 3 is a plot of the drug time for different ropivacaine formulations in rats.
  • Figure 4 is a powder X-ray diffraction pattern of ropivacaine stearate.
  • Figure 5 is a powder X-ray diffraction pattern of ropivacaine pamoate.
  • the initial dissolution temperature in the preparation of the crystal of the present invention can be carried out in the range of -5 to 70 °C.
  • Examples 1-3 are the same crystal form, each having a 2 ⁇ value of 10.5 ⁇ 0.2°, 13.0 ⁇ 0.2°, 16.4 ⁇ 0.2°, 19.0 ⁇ 0.2°, 21.6 ⁇ 0.2°, 23.4 ⁇ 0.2°, 25.9 ⁇ 0.2. °, 26.3 ⁇ 0.2°, 31.8 ⁇ 0.2° characteristic diffraction peak, the powder X-ray diffraction pattern is shown in Fig. 1, and the DSC chart is shown in Fig. 2.
  • the ropivacaine base drug substance (prepared in Example 1) was subjected to air flow micronization using a jet mill (Model J-20-LE, Tecnologia Meccanica, Italy) to prepare a micron-sized ropivacaine base.
  • the particle size distribution of the ropivacaine base after micronization of the gas stream was measured by a dry method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK).
  • the micron-sized ropivacaine base was determined to have an average particle size of 3.2 microns and the following particle size distribution: 10% ⁇ 1.27 ⁇ m, 50% ⁇ 2.75 ⁇ m and 90% ⁇ 5.67 ⁇ m.
  • Example 4 25 mg of the micronized ropivacaine base powder prepared in Example 4 was placed in a 5 mL vial and placed in a dry heat sterilization cabinet (100-grade purification door-opening sterilization oven, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.) to 140 Dry heat sterilization at °C for 3 hours.
  • a dry heat sterilization cabinet 100-grade purification door-opening sterilization oven, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.
  • Ropivacaine base (Example 5) 5g Sodium carboxymethyl cellulose 0.55g Tween 80 0.1g 50 mM phosphate buffer (pH 7.2) 94.35g Total 100g
  • Ropivacaine base (Example 5) 20g Tween 80 5g Water for Injection 975g Total 1000g
  • the homogenization pressure is 600 bar) to obtain a suspension having a suitable drug particle size, which is obtained by dispensing.
  • the particle size distribution of the homogenized ropivacaine base suspension was determined by a wet method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK). The drug particles in the ropivacaine base suspension were determined to have an average particle size of 6.3 microns and the following particle size distribution: 10% ⁇ 2.39 ⁇ m, 50% ⁇ 4.72 ⁇ m and 90% ⁇ 8.54 ⁇ m.
  • Ropivacaine base (Example 5) 2g Sodium carboxymethyl cellulose 0.5g Tween 80 0.1g 50 mM phosphate buffer (pH 7.2) 97.4g Total 100g
  • Ropivacaine base (Example 5) 4g Sodium carboxymethyl cellulose 0.5g Tween 80 0.1g 50 mM phosphate buffer (pH 7.2) 95.4g Total 100g
  • Ropivacaine base (Example 5) 8g Sodium carboxymethyl cellulose 0.5g Tween 80 0.1g 50 mM phosphate buffer (pH 7.2) 91.4g Total 100g
  • Ropivacaine base (Example 5) 4g Tween 80 0.4g sucrose 5g Water for Injection 90.6g Total 100g
  • Ropivacaine base (Example 5) 4g Tween 80 0.6g Sodium chloride 1g Water for Injection 94.4g Total 100g
  • Ropivacaine base (Example 5) 4g Sodium carboxymethyl cellulose 0.8g Tween 80 0.4g benzoic acid 0.5g 10 mM phosphate buffer (pH 7.2) 94.3g Total 100g
  • Ropivacaine base (Example 5) 4g Tween 20 0.4g Methylparaben 0.2g 50 mM phosphate buffer (pH 7.2) 95.4g Total 100g
  • Ropivacaine base (Example 5) 6g Sodium carboxymethyl cellulose 1g Tween 80 1g Mannitol 8g 10 mM phosphate buffer (pH 7.4) 184g Total 200g
  • Ropivacaine base (Example 5) 20g Sodium carboxymethyl cellulose 2g Tween 80 1g sucrose 5g Water for Injection 72g Total 100g
  • Ropivacaine base (Example 5) 4g Sodium carboxymethyl cellulose 0.55g Tween 20 0.08g Mannitol 4g 50 mM phosphate buffer (pH 7.2) 91.37g Total 100g
  • Ropivacaine base (2.74 g; 10 mmol) and palmitic acid (2.56 g; 10 mmol) were added to dry acetone (100 mL) and stirred at 40 ° C for 6 hours. The reaction droplets were then added to 2 L of purified water, white crystals were precipitated, filtered and dried in vacuo to give ropivacaine palmitate.
  • Ropivacaine base (2.74 g; 10 mmol) and stearic acid (2.84 g; 10 mmol) were added to absolute ethanol (100 mL) and stirred at 50 ° C for 3 hours.
  • the reaction droplets were then added to 1 L of purified water, white crystals were precipitated, filtered and dried in vacuo to give ropivacaine stearate.
  • the X-ray powder diffraction pattern is shown in Fig. 4.
  • Ropivacaine base (10 g; 36.44 mmol) and palmitic acid (7.08 g; 18.22 mmol) were added to tetrahydrofuran (200 mL) and stirred at 40 ° C for 2 hours.
  • the reaction droplets were then added to 2 L of n-hexane to precipitate a pale yellow solid which was filtered and dried in vacuo to give ropivacaine pamoate.
  • the X-ray powder diffraction pattern is shown in Fig. 5.
  • Example 21 A 3% ropivacaine palmate suspension injection was prepared:
  • Preparation process take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly add the prescribed amount of ropivacaine free base, heat and stir to fully dissolve, to obtain a drug solution; then slowly add castor oil to the drug solution To 100ml, stir and mix, filter and sterilize, dispense into a vial, seal and package.
  • a ropivacaine phospholipid sustained release preparation was prepared in accordance with Example 2 of WO2013168172A1.
  • Preparation method Weigh the prescribed amount of ropivacaine hydrochloride, cysteine, castor oil and soybean phospholipid, add the prescribed amount of ethanol, and obtain a clear solution by ultrasonic bath at 50 degrees Celsius.
  • Example 9 The ropivacaine base sustained-release preparation prepared in Example 8, Example 9 and Example 10 was subjected to animal test, and the test animals were SD rats (6-8 weeks old), 6 rats in each group, and the injection method was neck. Subcutaneous injection in the back, the dosing scheme is shown in the table below. About 0.2 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h after administration for content analysis.
  • Example 8 The test results showed that the sustained release preparation of ropivacaine base prepared in Example 8, Example 9 and Example 10 showed a good sustained release effect compared with the commercially available ropivacaine hydrochloride injection.
  • the peak concentration was significantly reduced and the half-life was significantly prolonged.
  • the 8% ropivacaine base suspension is administered 16 times as much as 0.5% ropivacaine hydrochloride injection, but its peak concentration is only 0.5% ropiva hydrochloride. 1.4 times of the Cain's regular release injection, indicating that the ropivacaine base suspension can effectively control the burst release of the drug. In addition, no central toxicity associated with administration was found in each experimental group, indicating that the ropivacaine base suspension has a wide safety window.
  • OBJECTIVE To evaluate the local analgesic effect (analgesic duration) of different sustained-release formulations of ropivacaine and its effect on wound healing.
  • Test animals Guangxi Bama miniature pig, male, 6 to 7 weeks old, weighing 3 to 5 kg. The postoperative pain model was established after 5 to 7 days of adaptive feeding.
  • Postoperative pain model establishment method anesthesia with isoflurane inhalation anesthesia.
  • the incision was positioned 3 cm from the midline of the left back, parallel to the midline of the back, and the incision was 3 cm.
  • the small pig enters the anesthesia state, the prone/side is placed, and the left back area is prepared for skin preparation.
  • the operation area is disinfected (75% alcohol, iodophor, 75% alcohol), and the predetermined incision is cut, and the skin and fascia are cut, without damaging the muscle.
  • Test group 6 rats in each group, divided into positive control group (0.5% ropivacaine injection), vehicle control group (normal saline), similar control group (1.3% bupivacaine liposome injection suspension) ), ropivacaine base sustained-release suspension preparation group (2), ropivacaine oily solution, ropivacaine phospholipid sustained-release preparation a total of 7 groups, as shown in the following table.
  • Mode of administration and dose subcutaneous injection at the incision, each group of animals were infiltrated and injected corresponding test preparations, the dosage volume was: 1ml/cm, a total of 3ml, and the injection was evenly injected at 3 points on both sides of the incision, a total of 6 points Injection, 0.5 mL / point, the injection points on both sides are about 1 cm apart, suture the incision.
  • Analgesic effect test The tactile measurement kit (Von Frey) was used to detect the postoperative analgesia effect.
  • the Von Frey needle was used to stimulate the skin 0.5 cm away from the incision, and the pain was measured (evasion response: 90-180 degrees torsion, leaving the tester to avoid the stimulus), and the measurement time points were 1 d before surgery (as the base value).
  • each time point was measured 6 times, each interval 5 ⁇ 10S.
  • the pain threshold after acupuncture changes, the time interval of the detection time point is shortened in the subsequent measurement period to more accurately determine the specific failure time. Finally, the time point at which the pain threshold of 6 measurements was restored to the pre-operative baseline value was used as the failure time.
  • Postoperative incision recovery observation and pathological examination 1 day before surgery (basal value) and postoperative, the wound healing was observed and scored every day.
  • test group and the control group are close to the tactile measurement results, that is, on the day when all the animals are restored, all the animals are euthanized, and the local tissues are administered by necropsy, and the main site is observed, and the administration site and the surrounding skin and subcutaneous fascia and muscle are taken. Tissue (take the fixed section (middle of the incision).
  • the site is also taken for fixation, embedding, sectioning, hematoxylin-eosin staining, and observation under the microscope.
  • the anesthetic effect of 0.5% ropivacaine hydrochloride injection (if the dose is the same as that of the sustained-release preparation, causing serious toxicity or even death of the animal) lasted only about 6 hours, 1.3% bupika
  • the anesthesia time of the liposome injection suspension was only about 9 hours.
  • the local anesthesia duration of the four ropivacaine sustained-release preparations was significantly longer than 0.5% ropivacaine hydrochloride injection and 1.3% bupivacaine.
  • the liposome injection suspension in which the 4% ropivacaine base suspension has the longest local anesthesia time, reaching more than 30 hours, the efficacy duration is significantly better than 4% ropivacaine oily solution and 4 % ropivacaine phospholipid sustained release preparation.
  • the ropivacaine phospholipid sustained-release preparation group had high viscosity and was difficult to inject, and the ropivacaine oily solution also had a high viscosity and was difficult to inject.
  • the ropivacaine base suspension has a very low viscosity and the injection operation is easy to carry out.
  • the time of pharmacodynamic action of the same anesthetic drug in animals and human body is mostly different.
  • the anesthetic effect of 1.3% bupivacaine liposome on small pigs is about 9 hours.
  • the corresponding human body action time is at least 24 hours (Skolnik A, Gan TJ. New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine. Expert Opin Pharmacother. 2014 Aug; 15 (11) : 1535-42), that is, 2 to 3 times, from which it is estimated that the anesthesia effect of the 4% ropivacaine base suspension in the human body can reach 48 to 72 hours.
  • the concentration of ropivacaine base has a significant effect on the duration of anesthesia of the ropivacaine suspension, so local anesthesia can be adjusted by adjusting the drug concentration in the drug suspension. The purpose of duration.
  • OBJECTIVE To evaluate the local analgesic effect (analgesic duration) of ropivacaine pamoate sustained release injection and nanosized ropivacaine sustained release injection and its effect on wound healing.
  • Test animals Guangxi Bama miniature pig, male, 6 to 7 weeks old, weighing 3 to 5 kg. The postoperative pain model was established after 5 to 7 days of adaptive feeding.
  • Postoperative pain model establishment method anesthesia with isoflurane inhalation anesthesia.
  • the incision was positioned 3 cm from the midline of the left back, parallel to the midline of the back, and the incision was 3 cm.
  • the small pig enters the anesthesia state, the prone/side is placed, and the left back area is prepared for skin preparation.
  • the operation area is disinfected (75% alcohol, iodophor, 75% alcohol), and the predetermined incision is cut, and the skin and fascia are cut, without damaging the muscle.
  • Test group 6 rats in each group, divided into positive control group (0.5% ropivacaine injection), vehicle control group (normal saline), nano-sized ropivacaine base sustained-release injection (1), Luo Pi***e hydrochloride release sustained-release injection group (1), a total of 3 groups, as shown in the following table.
  • Mode of administration and dose subcutaneous injection at the incision, each group of animals were infiltrated and injected corresponding test preparations, the dosage volume was: 1ml/cm, a total of 3ml, and the injection was evenly injected at 3 points on both sides of the incision, a total of 6 points Injection, 0.5 ml / point, the injection points on both sides are about 1 cm apart, suture the incision. Three days after surgery, intramuscular injection of penicillin daily prevented infection.
  • Analgesic effect test The tactile measurement kit (Von Frey) was used to detect the postoperative analgesia effect.
  • the Von Frey needle was used to stimulate the skin 0.5 cm away from the incision, and the pain was measured (evasion response: 90-180 degrees torsion, leaving the tester to avoid the stimulus), and the measurement time points were 1 d before surgery (as the base value).
  • each time point was measured 6 times, each interval 5 ⁇ 10S.
  • the pain threshold after acupuncture changes, the time interval of the detection time point is shortened in the subsequent measurement period to more accurately determine the specific failure time. Finally, the time point at which the pain threshold of 6 measurements was restored to the pre-operative baseline value was used as the failure time.
  • Postoperative incision recovery observation and pathological examination 1 day before surgery (basal value) and postoperative, the wound healing was observed and scored every day.
  • test group and the control group are close to the tactile measurement results, that is, on the day when all the animals are restored, all the animals are euthanized, and the local tissues are administered by necropsy, and the main site is observed, and the administration site and the surrounding skin and subcutaneous fascia and muscle are taken. Tissue (take the fixed section (middle of the incision).
  • the site is also taken for fixation, embedding, sectioning, hematoxylin-eosin staining, and observation under the microscope.
  • Test sample Duration of drug efficacy 0.5% ropivacaine hydrochloride injection 5.76 ⁇ 0.73 3% nanosized ropivacaine base sustained release injection (Example 15) 29.32 ⁇ 2.54 3% ropivacaine pamoate sustained release injection group (Example 21) 12.67 ⁇ 3.16
  • the anesthetic effect of 0.5% ropivacaine hydrochloride injection (the dose of the drug can cause severe toxicity or even death in animals as the sustained-release preparation) lasts only about 6 hours, while 3% ropera
  • the anesthesia maintenance time of the kaempaol hydrochloride sustained-release injection and the 3% nanosized ropivacaine base sustained-release injection was significantly longer than 0.5% ropivacaine hydrochloride injection.
  • no central toxicity associated with administration was found in each experimental group during the test.

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Abstract

Provided are a long-effective amide local anesthetic: S-(-)-1-propyl-2',6'-aminoxyleneformylpiperidine crystal, a sustained release preparation thereof, and their preparation method. Compared with an existing hydrochloride preparation, the preparation made from the crystal has a particularly good property of continuously and slowly releasing drug and maintaining an effective blood drug concentration, and shows an excellent long-term local analgesic effect.

Description

S-(-)-1-丙基-2′,6′-二甲苯胺甲酰基哌啶晶体及其缓释制剂S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine crystal and sustained release preparation thereof 技术领域Technical field
本发明涉及一种适用于工业化生产的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶晶体及其缓释制剂，以及它们的制备方法，属于医药技术领域。The invention relates to S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine crystal suitable for industrial production and a sustained release preparation thereof, and a preparation method thereof, belonging to medical technology field.
背景技术Background technique
S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，即罗哌卡因，CAS号：84057-95-4，其外观为白色或类白色。S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine, ropivacaine, CAS No.: 84057-95-4, which is white or off-white in appearance.
罗哌卡因是一种新型的长效酰胺类局麻药，其作用机制与其它局麻药相同，通过抑制神经细胞钠离子通道，阻断神经兴奋与传导。同布比卡因等相比，罗哌卡因具有起效时间短、分离阻滞的程度强、毒性小等优点。目前临床常使用盐酸罗哌卡因或甲磺酸盐罗哌卡因注射液，主要用于外科手术麻醉以及术后疼痛的治疗。但是罗哌卡因常释注射液的体内生物半衰期短，使得一次性给药局部麻醉持续时间短。目前，进行临床局部麻醉时需小剂量频繁给药以维持有效治疗浓度，医护费用相对较高。剂量较大时，有效治疗浓度的维持时间长，但最大血药浓度Cmax超出治疗窗，导致副反应。因此，开发罗哌卡因的长效注射制剂，可在较长时间内维持药物的有效治疗浓度，大大降低副作用的发生，使病人免受多次给药的痛苦，从而降低医护成本，提高患者的顺应性，突显出很好的临床开发前景。Ropivacaine is a novel long-acting amide local anesthetic that acts in the same way as other local anesthetics and blocks nerve excitation and conduction by inhibiting neuronal sodium channels. Compared with bupivacaine, ropivacaine has the advantages of short onset time, strong degree of separation and blockage, and low toxicity. At present, ropivacaine hydrochloride or ropivacaine mesylate injection is often used clinically, mainly for surgical anesthesia and postoperative pain treatment. However, the in vivo biological half-life of ropivacaine injections is short, resulting in a short duration of topical anesthesia. At present, small doses of frequent administration are required for clinical local anesthesia to maintain an effective therapeutic concentration, and the medical expenses are relatively high. When the dose is large, the effective treatment concentration is maintained for a long time, but the maximum blood concentration Cmax exceeds the treatment window, resulting in a side reaction. Therefore, the development of long-acting injection preparation of ropivacaine can maintain the effective therapeutic concentration of the drug for a long time, greatly reduce the occurrence of side effects, and protect the patient from the pain of multiple administration, thereby reducing the cost of medical care and improving the patient. The compliance shows a good clinical development prospect.
现有的罗哌卡因长效注射制剂，其均使用了相应的缓释载体来控制药物的释放，比如磷脂基质和油性溶液等。但这些缓释制剂在处方中都使用了大量的油性基质以及有机溶剂，存在一定的安全隐患。The existing ropivacaine long-acting injection preparations all use a corresponding sustained-release carrier to control the release of the drug, such as a phospholipid matrix and an oily solution. However, these sustained-release preparations use a large amount of oily base and organic solvent in the prescription, and there are certain safety hazards.
WO2013168172A1公开了一种罗哌卡因的缓释制剂，其实施例2中公开了其处方含有盐酸罗哌卡因、磷脂、蓖麻油、半胱氨酸和乙醇。该制剂为不澄清透明的糊剂，制剂中磷脂的用量很大，达到了50％以上，导致制剂的粘度很大，注射困难。而且处方中使用了大量的蓖麻油和乙醇，其中蓖麻油的浓度高达35％，乙醇的浓度达到了6％，存在一定的安全性隐患。WO2013168172A1 discloses a sustained release preparation of ropivacaine, which is disclosed in Example 2, which comprises a formulation containing ropivacaine hydrochloride, phospholipid, castor oil, cysteine and ethanol. The preparation is a paste which is not clear and transparent, and the amount of the phospholipid in the preparation is large, reaching 50% or more, resulting in a large viscosity of the preparation and difficulty in injection. Moreover, a large amount of castor oil and ethanol are used in the prescription, wherein the concentration of castor oil is as high as 35%, and the concentration of ethanol is 6%, which has certain safety hazards.
CN103142458A公开了一种罗哌卡因的油性溶液缓释注射剂，其实施例21中公开了其处方为罗哌卡因游离碱，苯甲酸苄酯、苯甲醇和蓖麻油。该制剂处方中含有高浓度的油相和有机溶剂，其中蓖麻油浓度高达75％，有机溶剂苯甲酸苄酯和苯甲醇的浓度分别达到了15％和10％，有一定的安全性风险。CN103142458A discloses an oily solution sustained release injection of ropivacaine, which is disclosed in Example 21 as a formulation of ropivacaine free base, benzyl benzoate, benzyl alcohol and castor oil. The formulation contains a high concentration of oil phase and organic solvent, wherein the concentration of castor oil is as high as 75%, and the concentrations of organic solvent benzyl benzoate and benzyl alcohol reach 15% and 10%, respectively, which have certain safety risks.
因此，有必要开发一种更为安全有效的罗哌卡因缓释注射制剂。 Therefore, it is necessary to develop a safer and more effective ropivacaine sustained-release injection preparation.
发明内容Summary of the invention
本发明的一个目的在于提供一种新的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶(即罗哌卡因)化合物晶体。It is an object of the present invention to provide a novel crystal of S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine (i.e., ropivacaine) compound.
本发明提供了一种新的罗哌卡因化合物晶体(或称罗哌卡因晶体)，其粉末X-射线衍射图谱在2θ值为10.5±0.2°，13.0±0.2°，16.4±0.2°，19.0±0.2°，21.6±0.2°，23.4±0.2°，25.9±0.2°，26.3±0.2°，31.8±0.2°处有特征衍射峰。本发明的晶体理化性质稳定。The present invention provides a novel ropivacaine compound crystal (or ropivacaine crystal) having a powder X-ray diffraction pattern having a 2θ value of 10.5±0.2°, 13.0±0.2°, and 16.4±0.2°. 19.0±0.2°, 21.6±0.2°, 23.4±0.2°, 25.9±0.2°, 26.3±0.2°, and 31.8±0.2° characteristic diffraction peaks. The crystal physicochemical properties of the present invention are stable.
具体地，上述的化合物晶体，其粉末X-射线衍射图谱进一步在24.3±0.2°处有特征衍射峰。Specifically, the above compound crystal has a powder X-ray diffraction pattern further having a characteristic diffraction peak at 24.3±0.2°.
具体地，上述的化合物晶体，其粉末X-射线衍射图谱具有与图1类似(基本相同)图谱。Specifically, the above compound crystals have a powder X-ray diffraction pattern similar to that of Fig. 1 (substantially the same).
具体地，上述的化合物晶体，其DSC图具有与图2类似图谱。Specifically, the above compound crystal has a DSC chart similar to that of FIG. 2.
本发明的罗哌卡因晶体包括罗哌卡因碱晶体或者罗哌卡因药学可接受的水难溶性盐晶体。The ropivacaine crystal of the present invention comprises ropivacaine base crystals or ropivacaine pharmaceutically acceptable water-insoluble salt crystals.
本发明的另一目的在于提供一种上述化合物晶体的制备方法。Another object of the present invention is to provide a process for producing a crystal of the above compound.
本发明提供了一种上述化合物晶体的制备方法，其包括：在约-5℃～约70℃温度下，从包含约0.02g/mL～约0.5g/mL的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的C1～C4醇、乙腈、甲酸C1～C4醇的酯、乙酸C1～C4醇的酯、四氢呋喃、丙酮、甲基异丁基酮、二氯甲烷、二氯乙烷溶液中一种或多种溶剂中结晶得到上述化合物晶体。The present invention provides a method for preparing a crystal of the above compound, which comprises: from about 0.02 g/mL to about 0.5 g/mL of S-(-)-1- at a temperature of from about -5 ° C to about 70 ° C C1-C4 alcohol of propyl-2',6'-dimethylformylpiperidine, ester of acetonitrile, formic acid C1-C4 alcohol, ester of C1-C4 alcohol, tetrahydrofuran, acetone, methyl isobutyl ketone Crystallization of one or more solvents in dichloromethane, dichloroethane solution gives crystals of the above compounds.
本发明还提供上述化合物晶体的另一种制备方法，其包括：在约-5℃～约70℃温度下，向包含约0.02g/mL～约0.5g/mL的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的至少一种选自C1～C4醇、乙腈、甲酸C1～C4醇的酯、乙酸C1～C4醇的酯、四氢呋喃、丙酮、甲基异丁基酮、二氯甲烷、二氯乙烷的溶液中，滴加选自C5-8烷烃、C5-6醚、石油醚、水中一种或多种溶剂后结晶得到上述化合物晶体。The present invention also provides another method for preparing crystals of the above compounds, which comprises: from about 0.02 to about 0.5 g/mL of S-(-)-1 at a temperature of from about -5 ° C to about 70 ° C. At least one of -propyl-2',6'-dimethylformylformylpiperidine is selected from the group consisting of C1-C4 alcohols, acetonitrile, esters of C1-C4 alcohols, esters of C1-C4 alcohols, tetrahydrofuran, acetone, a solution of methyl isobutyl ketone, dichloromethane or dichloroethane, which is selected from C 5-8 alkane, C 5-6 ether, petroleum ether, water or one or more solvents, and then crystallized to obtain the above compound Crystal.
具体地，上述方法中所述C5-8烷烃选自戊烷、己烷、庚烷或辛烷中的一种或多种。Specifically, the C 5-8 alkane in the above method is selected from one or more of pentane, hexane, heptane or octane.
具体地，上述方法中所述C5-6醚为异丙醚或甲基叔丁基醚。Specifically, the C 5-6 ether in the above method is isopropyl ether or methyl tert-butyl ether.
本发明的另一目的在于提供一种S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶(即罗哌卡因)的缓释注射制剂及其制备方法。Another object of the present invention is to provide a sustained release injection preparation of S-(-)-1-propyl-2',6'-dimethylformylpiperidine (ie, ropivacaine) and a preparation method thereof .
发明人发现单纯利用本发明的罗哌卡因晶体(包括罗哌卡因游离碱晶体或其水难溶性盐)自身的物理特性，将其混悬于适宜的介质中则可以有效地达到8～72小时的局部镇痛效果。所述制剂在注射到体内后，随着药物颗粒的缓慢溶解而将药物缓慢释放出来，基于这些发现进行进一步研究而完成了一种新的罗哌卡因缓释注射制剂的发明。The inventors have found that by simply using the physical properties of the ropivacaine crystal of the present invention (including ropivacaine free base crystal or its poorly water-soluble salt), it can be effectively suspended in a suitable medium. 72 hours of local analgesic effect. After the preparation was injected into the body, the drug was slowly released as the drug particles were slowly dissolved, and based on these findings, further studies were conducted to complete a novel ropivacaine sustained-release injection preparation.
本发明提供一种本发明所述罗哌卡因晶体的无菌混悬液形式的控释注射制剂，其在注射后，在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，该制剂包括： The present invention provides a controlled release injection formulation in the form of a sterile suspension of ropivacaine crystals of the invention which, after injection, releases S-(-)-1-propyl- during a period of at least 12 h 2',6'-xylyleneformyl piperidine, the formulation comprising:
(a)罗哌卡因，(a) ropivacaine,
(b)载体，和(b) a carrier, and
(c)用于注射的水。(c) Water for injection.
具体地，本发明的无菌混悬液形式的控释注射制剂，其中所述载体包括一种或多种表面活性剂。所述载体还可进一步包括助悬剂。Specifically, a controlled release injectable preparation in the form of a sterile suspension of the present invention, wherein the carrier comprises one or more surfactants. The carrier may further comprise a suspending agent.
本发明还提供一种罗哌卡因缓释混悬液制剂，所述制剂包括如下成分：The invention also provides a ropivacaine sustained release suspension formulation, the formulation comprising the following ingredients:
(a)罗哌卡因，(a) ropivacaine,
(b)载体，所述载体包括：(b) a carrier comprising:
(1)一种或多种表面活性剂，(1) one or more surfactants,
(2)任选地，一种或多种助悬剂，(2) optionally, one or more suspending agents,
(3)任选地，一种或多种填充剂，(3) optionally, one or more fillers,
(4)任选地，一种或多种防腐剂，(4) optionally, one or more preservatives,
(5)任选地，一种或多种等渗调节剂(5) optionally, one or more isotonicity adjusting agents
(6)任选地，一种或多种缓冲剂，以及(6) optionally, one or more buffers, and
(c)用于注射的水。(c) Water for injection.
具体地，本发明的罗哌卡因缓释混悬液制剂中，所述成分(a)为本发明所述的罗哌卡因晶体，包括罗哌卡因碱晶体或者罗哌卡因药学可接受的水难溶性盐晶体。Specifically, in the ropivacaine sustained-release suspension preparation of the present invention, the component (a) is the ropivacaine crystal of the present invention, and includes ropivacaine base crystal or ropivacaine pharmaceutically acceptable. Accepted water insoluble salt crystals.
具体地，本发明的制剂为可注射的药物混悬液，在注射后，优选地肌肉内或者皮下注射后，所述药物混悬液在至少大约8小时，优选至少12小时，更优选地在48小时、72小时或更长的时间期间释放出治疗量的罗哌卡因。In particular, the formulation of the invention is an injectable pharmaceutical suspension which, after injection, preferably after intramuscular or subcutaneous injection, is at least about 8 hours, preferably at least 12 hours, more preferably at A therapeutic amount of ropivacaine is released during 48 hours, 72 hours or longer.
本发明的罗哌卡因混悬液可以作为含水的可直接应用(ready-to-use)的混悬液而被给予，也可以将此混悬液冻干，在临用时与水组合用于注射。The ropivacaine suspension of the present invention can be administered as an aqueous ready-to-use suspension, or the suspension can be lyophilized and used in combination with water when ready for use. injection.
根据本发明所述的混悬液制剂，其中，罗哌卡因以混悬的药物颗粒(包括微米尺寸的罗哌卡因和纳米尺寸的罗哌卡因)形式存在于制剂中。A suspension formulation according to the present invention, wherein ropivacaine is present in the formulation in the form of suspended drug particles, including micron-sized ropivacaine and nano-sized ropivacaine.
根据本发明所述的混悬液制剂，其中罗哌卡因重量百分比含量优选为1～40％，进一步优选2～20％，更进一步优选2～8％。The suspension preparation according to the present invention, wherein the ropivacaine weight percentage is preferably from 1 to 40%, further preferably from 2 to 20%, still more preferably from 2 to 8%.
根据本发明所述的混悬液制剂，其中罗哌卡因(包括罗哌卡因游离碱或者其药学上可接受的水难溶性盐)可通过气流粉碎和机械研磨等粉碎方式使其平均粒径小至微米或纳米级。A suspension formulation according to the present invention, wherein ropivacaine (including ropivacaine free base or a pharmaceutically acceptable water-insoluble salt thereof) can be averaged by pulverization such as jet milling or mechanical milling The diameter is as small as micron or nanometer.
本发明还提供了一种制备罗哌卡因的水难溶性盐的方法，包括以下步骤：The present invention also provides a method of preparing a poorly water-soluble salt of ropivacaine, comprising the steps of:
(a)将罗哌卡因游离碱与相应的有机酸溶解于适宜的溶剂中搅拌反应成盐。(a) The ropivacaine free base and the corresponding organic acid are dissolved in a suitable solvent and stirred to form a salt.
(b)将反应产物通过重结晶等方法进行纯化得到罗哌卡因的水难溶性盐。(b) The reaction product is purified by a method such as recrystallization to obtain a poorly water-soluble salt of ropivacaine.
具体地，本发明的罗哌卡因缓释混悬液制剂中，助悬剂重量百分比含量优选为0.05％～ 20％，进一步优选0.1％～5％，更进一步优选0.1～2％。适于应用的助悬剂的例子包括但不限于下列中的一种、两种或更多种：羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、透明质酸钠和聚乙烯吡咯烷酮，优选羧甲基纤维素钠和聚乙烯基吡咯烷酮。适于在罗哌卡因载体中使用的其它助悬剂包括各种聚合物、低分子量寡聚物、天然产物和表面活性剂，包括非离子表面活性剂和离子表面活性剂，如明胶、酪蛋白、磷脂、葡聚糖、聚乙烯醇、甘油、***胶、胆固醇、黄蓍胶、硬脂酸。Specifically, in the ropivacaine sustained release suspension preparation of the present invention, the suspension percentage by weight is preferably 0.05%. 20%, further preferably 0.1% to 5%, still more preferably 0.1 to 2%. Examples of suspending agents suitable for use include, but are not limited to, one, two or more of the following: sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, Hydroxypropyl methylcellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose and polyvinylpyrrolidone. Other suspending agents suitable for use in the ropivacaine carrier include various polymers, low molecular weight oligomers, natural products, and surfactants, including nonionic surfactants and ionic surfactants such as gelatin and cheese. Protein, phospholipid, dextran, polyvinyl alcohol, glycerin, acacia, cholesterol, tragacanth, stearic acid.
具体地，本发明的罗哌卡因缓释混悬液制剂中，表面活性剂重量百分比含量优选为0.01％～20％，进一步优选0.02％～5％，更进一步优选0.02～2％。适于应用的表面活性剂的例子包括但不限于下列中的一种、两种或更多种：脱水山梨醇酯的聚氧乙烯衍生物，例如聚山梨酯20(吐温-20)、聚山梨酯40(吐温-40)、聚山梨酯60(吐温-60)、聚山梨酯65(吐温-65)、聚山梨酯80(吐温-80)与聚山梨酯85(吐温-85)、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、卵磷脂、聚乙烯吡咯烷酮、聚乙二醇类、聚氧乙烯与聚氧丙烯醚类(泊洛沙姆188和泊洛沙姆407等)、15-羟基硬脂酸聚乙二醇酯(solutol HS15)，优选吐温-20、吐温-80、15-羟基硬脂酸聚乙二醇酯和泊洛沙姆188。适于在罗哌卡因混悬液载体中使用的其它表面活性剂包括聚氧乙烯脂肪酸酯类表面活性剂(商品名卖泽(Myrij))和聚氧乙烯脂肪醇醚类表面活性剂(商品名苄泽(Brij))等。Specifically, in the ropivacaine sustained release suspension preparation of the present invention, the surfactant weight percentage is preferably from 0.01% to 20%, more preferably from 0.02% to 5%, still more preferably from 0.02% to 2%. Examples of suitable surfactants include, but are not limited to, one, two or more of the following: polyoxyethylene derivatives of sorbitan esters, such as polysorbate 20 (Tween-20), poly Sorbate 40 (Tween-40), Polysorbate 60 (Tween-60), Polysorbate 65 (Tween-65), Polysorbate 80 (Tween-80) and Polysorbate 85 (Tween) -85), polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188 and poloxamer 407 Et.), 15-hydroxystearate (solutol HS15), preferably Tween-20, Tween-80, 15-hydroxystearate polyethylene glycol ester and poloxamer 188. Other surfactants suitable for use in the ropivacaine suspension vehicle include polyoxyethylene fatty acid ester surfactants (trade name Myrij) and polyoxyethylene fatty alcohol ether surfactants (commodities) Named Briz, etc.
具体地，本发明的罗哌卡因缓释混悬液制剂中，填充剂(也称为低温/冻干保护剂)重量百分比含量优选为0.05％～20％，进一步优选1％～10％，更进一步优选3～8％。适于此处用途的填充剂的例子包括但不限于下列中的一种、两种或更多种：甘露醇、海藻糖、蔗糖、乳糖、麦芽糖、木糖醇、葡萄糖、淀粉、甘氨酸、环糊精、山梨醇和类似物，优选甘露醇和蔗糖。Specifically, in the ropivacaine sustained release suspension preparation of the present invention, the content of the filler (also referred to as low temperature/lyophilization inhibitor) is preferably 0.05% to 20%, further preferably 1% to 10%, Still more preferably 3 to 8%. Examples of fillers suitable for use herein include, but are not limited to, one, two or more of the following: mannitol, trehalose, sucrose, lactose, maltose, xylitol, glucose, starch, glycine, rings Dextrin, sorbitol and the like, preferably mannitol and sucrose.
具体地，本发明的罗哌卡因缓释混悬液制剂中，缓冲剂的使用是将罗哌卡因混悬液制剂的pH值稳定在6至8.5，优选7～8。为了达到所述pH，通常地，根据缓冲液的类型，缓冲液中缓冲盐的使用量的范围按重量计是从大约0.02至大约2％，优选0.03～1％，进一步优选0.1～1％，这是基于无菌注射剂的总重量而言的。适于此用途的缓冲液的例子包括但不限于下列中的一种、两种或多种：磷酸盐、醋酸盐、枸橼酸盐或TRIS缓冲液，优选磷酸盐缓冲液。缓冲盐溶液的pH优选为6～8.5，进一步优选6.5～7.5，更进一步优选为7.0～7.5。Specifically, in the ropivacaine sustained-release suspension preparation of the present invention, the buffer is used to stabilize the pH of the ropivacaine suspension preparation at 6 to 8.5, preferably 7 to 8. In order to achieve the pH, generally, the amount of the buffer salt used in the buffer is from about 0.02 to about 2%, preferably from 0.03 to 1%, further preferably from 0.1 to 1%, based on the type of the buffer. This is based on the total weight of the sterile injectables. Examples of buffers suitable for this purpose include, but are not limited to, one, two or more of the following: phosphate, acetate, citrate or TRIS buffer, preferably phosphate buffer. The pH of the buffered salt solution is preferably 6 to 8.5, more preferably 6.5 to 7.5, still more preferably 7.0 to 7.5.
本发明的罗哌卡因混悬液制剂可以任选地包括pH调节剂，其使用量可以调节混悬液的pH值在大约6至8.5的范围，优选7～8，根据混悬液的pH值是否需要升高或降低以达到所需的7～8的pH，pH调节剂可以是酸性的或碱性的。因此，当需要降低pH时，可以应用酸性pH调节剂如盐酸或醋酸，优选盐酸。当需要升高pH时，将应用碱性pH调节剂如氢氧化钠、氢氧化钾、碳酸钙、氧化镁或氢氧化镁，优选氢氧化钠。The ropivacaine suspension formulation of the present invention may optionally comprise a pH adjusting agent in an amount to adjust the pH of the suspension in the range of from about 6 to 8.5, preferably from 7 to 8, depending on the pH of the suspension. Whether the value needs to be raised or lowered to achieve the desired pH of 7-8, the pH adjusting agent can be acidic or basic. Therefore, when it is desired to lower the pH, an acidic pH adjusting agent such as hydrochloric acid or acetic acid, preferably hydrochloric acid, can be applied. When it is desired to raise the pH, an alkaline pH adjusting agent such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide or magnesium hydroxide, preferably sodium hydroxide, will be employed.
具体地，本发明的罗哌卡因缓释混悬液制剂中，防腐剂为抗微生物剂与抗氧化剂，其可 选自包括苯甲酸、苯甲醇、丁基化羟基甲苯醚、丁基化羟基甲苯、氯丁醇、没食子酸酯、羟基苯甲酸酯、EDTA、酚、氯甲酚、间甲酚、氯化苄乙氧铵、氯化肉豆蔻基-γ-甲基吡啶、苯基乙酸汞及硫柳汞，优选苯甲醇和羟基苯甲酸酯。防腐剂重量百分比含量优选为0.05％～5％，进一步优选0.1％～1％，更进一步优选0.2～0.5％。Specifically, in the ropivacaine sustained-release suspension preparation of the present invention, the preservative is an antimicrobial agent and an antioxidant, which can Selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxytoluene ether, butylated hydroxytoluene, chlorobutanol, gallic acid ester, hydroxybenzoate, EDTA, phenol, chlorocresol, m-cresol, chlorination Benzyl ethoxylated ammonium, chlorinated myristyl-gamma-methylpyridine, phenylacetic acid mercury and thimerosal, preferably benzyl alcohol and hydroxybenzoic acid ester. The content of the preservative by weight is preferably from 0.05% to 5%, more preferably from 0.1% to 1%, still more preferably from 0.2% to 0.5%.
具体地，本发明的罗哌卡因缓释混悬液制剂中，等渗调节剂的重量百分比含量优选为0.05％～20％，进一步优选0.05％～10％，更进一步优选0.4～5％。适于应用的等渗调节剂的例子包括但不限于下列中的一种、两种或更多种：甘露醇、山梨醇、氯化钠、葡萄糖、蔗糖、果糖、乳糖，优选甘露醇、氯化钠和葡萄糖。Specifically, in the ropivacaine sustained-release suspension preparation of the present invention, the content of the isotonicity adjusting agent is preferably 0.05% to 20% by weight, more preferably 0.05% to 10%, still more preferably 0.4% to 5%. Examples of isotonicity adjusting agents suitable for use include, but are not limited to, one, two or more of the following: mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose, lactose, preferably mannitol, chlorine Sodium and glucose.
本发明还提供了所述的混悬液制剂的制备方法，所述制备方法包括如下步骤：The invention also provides a preparation method of the suspension preparation, the preparation method comprising the following steps:
(1)制备无菌的罗哌卡因混悬液的载体，其包括表面活性剂、任选的助悬剂、任选的填充剂、任选的缓冲剂、任选的pH调节剂和水，并使之无菌，使用的灭菌方法可以是过滤除菌或者高压蒸汽灭菌。(1) A carrier for the preparation of a sterile ropivacaine suspension comprising a surfactant, an optional suspending agent, an optional filler, an optional buffer, an optional pH adjusting agent and water And sterilizing, the sterilization method used may be filtration sterilization or autoclaving.
(2)制备无菌的罗哌卡因，可以采用无菌生产工艺直接制备无菌的罗哌卡因，或者将罗哌卡因进行干热灭菌，高压蒸汽灭菌或者辐照灭菌。(2) Preparation of sterile ropivacaine, sterile ropivacaine can be prepared directly by aseptic manufacturing process, or ropivacaine can be dry heat sterilized, autoclaved or irradiated.
(3)制备无菌的罗哌卡因初步混悬液，将无菌的罗哌卡因与无菌的载体于无菌条件下混合，形成无菌的初步混悬液。(3) A sterile suspension of ropivacaine is prepared by mixing sterile ropivacaine with a sterile carrier under sterile conditions to form a sterile preliminary suspension.
(4)将罗哌卡因的无菌初步混悬液进行机械研磨或高压均质，使罗哌卡因的粒度降低至所需水平，比如0.1至50微米。制备得到具有所需平均粒度的无菌罗哌卡因混悬液制剂。(4) Mechanically ground or high pressure homogenize the sterile suspension of ropivacaine to reduce the particle size of ropivacaine to the desired level, such as 0.1 to 50 microns. A sterile ropivacaine suspension formulation having the desired average particle size is prepared.
对于减小药物颗粒的粒度，也可以应用其它降低粒度的技术，包括无菌的受控结晶和高剪切匀浆(high shear homogenization)，以产生平均粒度范围为0.1至50微米的颗粒。除了球磨机例如Dyno研磨机(mills)之外，可以应用其它低能和高能研磨机如辊磨机(roller mill)，可以用高能研磨机如Netzsch研磨机、DC研磨机和Planetary研磨机。然而，应用的研磨方法和设备必须能够产生具有所需平均粒度的无菌罗哌卡因混悬液制剂。这优选应用无菌湿磨法、微射流法(microfluidization)或无菌高压均质法进行。Other techniques for reducing particle size, including sterile controlled crystallization and high shear homogenization, can also be applied to reduce the particle size of the drug particles to produce particles having an average particle size ranging from 0.1 to 50 microns. In addition to ball mills such as Dyno mills, other low energy and high energy mills such as roller mills can be used, and high energy mills such as Netzsch mills, DC mills and Planetary mills can be used. However, the applied milling methods and equipment must be capable of producing a sterile ropivacaine suspension formulation having the desired average particle size. This is preferably carried out using sterile wet milling, microfluidization or sterile high pressure homogenization.
此外，还可以将罗哌卡因混悬液进行冻干(冷冻干燥)，制成冻干制剂。该冻干制剂在与水组合后，形成可注射的混悬液用于注射。Alternatively, the ropivacaine suspension can be lyophilized (lyophilized) to form a lyophilized formulation. The lyophilized formulation, when combined with water, forms an injectable suspension for injection.
具体地，可将得到的最终罗哌卡因混悬液无菌填充入无菌瓶内并无菌加载入无菌冻干器。冷冻干燥应该包括，以合适的冷却速度将制剂冷却至大约-40℃。更具体地，冷冻干燥应该包括三个阶段：冷冻、初步干燥和二次干燥。冷冻阶段应该包括以合适的冷却速度将制剂冷却至大约-40℃。初步干燥应该在低于大约0℃和合适的真空及持续时间下实施。二次干燥应该在高于大约0℃和合适的真空及持续时间下实施。在大气压或部分真空下，将带有得到的冻干罗哌卡因混悬液的瓶无菌塞住并密封。 Specifically, the resulting final ropivacaine suspension can be aseptically filled into a sterile vial and aseptically loaded into a sterile lyophilizer. Freeze drying should include cooling the formulation to about -40 ° C at a suitable cooling rate. More specifically, freeze drying should include three stages: freezing, preliminary drying, and secondary drying. The freezing stage should include cooling the formulation to about -40 ° C at a suitable cooling rate. Preliminary drying should be carried out at less than about 0 ° C and a suitable vacuum and duration. Secondary drying should be carried out above about 0 ° C and a suitable vacuum and duration. The bottle with the resulting lyophilized ropivacaine suspension was aseptically stoppered and sealed under atmospheric pressure or partial vacuum.
本发明还提供了所述混悬液制剂在制备镇痛药物中的应用。The invention also provides the use of the suspension formulation for the preparation of an analgesic drug.
根据本发明所述的应用，其中优选所述镇痛药为医疗手术前及手术后给药。According to the application of the present invention, it is preferred that the analgesic is administered before and after the medical treatment.
根据本发明所述的应用，所述混悬液制剂通过皮下，皮内或肌肉注射给药。According to the use according to the invention, the suspension preparation is administered by subcutaneous, intradermal or intramuscular injection.
除有特别说明外，在说明书和权利要求书中使用的术语具有下述含义：Terms used in the specification and claims have the following meanings unless otherwise stated:
在本说明书中，用于表达形成本发明混悬液制剂的各组分含量的“w/w”是指“各组分的重量(g)/混悬液制剂的重量(g)”。In the present specification, "w/w" for expressing the content of each component forming the suspension preparation of the present invention means "weight (g) of each component / weight (g) of the suspension preparation".
“类似图谱”是指基本相同的图谱。"Similar maps" refer to substantially identical maps.
“罗哌卡因”是罗哌卡因碱或者罗哌卡因药学可接受的水难溶性盐。"Ropivacaine" is a pharmaceutically acceptable water-insoluble salt of ropivacaine base or ropivacaine.
“罗哌卡因碱”是罗哌卡因游离碱，包括本发明的晶体形式。"Ropivacaine base" is ropivacaine free base, including the crystalline form of the invention.
“药学上可接受的水难溶性盐”是指安全、无毒并且其对于兽医使用或者人类药物使用上药学可接受的，并且具有所期望的药理学活性的难溶性盐，这样的盐包括，但不限于与有机酸如C8-C22的长链脂肪酸(如辛酸(C8)、癸酸(C10)、肉豆蔻酸(C14)、棕榈酸(C16)、硬脂酸(C18)和油酸(C18)等)、胆酸、脱氧胆酸、苯甲酸、双氯芬酸和帕莫酸等形成的难溶性盐。"Pharmaceutically acceptable water-insoluble salt" means a poorly soluble salt which is safe, non-toxic and which is pharmaceutically acceptable for veterinary use or human pharmaceutical use and which has the desired pharmacological activity, such salts include, However, it is not limited to long-chain fatty acids with organic acids such as C8-C22 (such as caprylic acid (C8), citric acid (C10), myristic acid (C14), palmitic acid (C16), stearic acid (C18), and oleic acid ( C18) etc.), a poorly soluble salt formed by cholic acid, deoxycholic acid, benzoic acid, diclofenac, and palmitic acid.
本发明罗哌卡因的水难溶性盐是指在pH7-8的条件下在水中的溶解度低于2mg/ml。按照2010版中国药典凡例中的定义，罗哌卡因的水难溶性盐在pH7-8的条件下在水中的溶解度属于微溶，极微溶解或几乎不溶(2010版中国药典对微溶的定义：系指溶质1g(ml)能在溶剂100～不到1000ml中溶解；2010版中国药典对极微溶解的定义：系指溶质1g(ml)能在溶剂1000～不到10000ml中溶解；2010版中国药典对几乎不溶的定义：系指溶质1g(ml)能在溶剂10000ml中不能完全溶解)。The poorly water-soluble salt of ropivacaine of the present invention means that the solubility in water is less than 2 mg/ml under the conditions of pH 7-8. According to the definition in the 2010 edition of the Chinese Pharmacopoeia, the solubility of ropivacaine in water-soluble salts in water at pH 7-8 is slightly soluble, very slightly soluble or almost insoluble (Definition of slightly soluble in the Chinese Pharmacopoeia of 2010) : means that 1g (ml) of solute can be dissolved in solvent 100~ less than 1000ml; the definition of very slightly dissolved in Chinese Pharmacopoeia of 2010 means that solute 1g (ml) can be dissolved in solvent 1000~ less than 10000ml; 2010 edition The definition of almost insoluble in the Chinese Pharmacopoeia means that 1 g (ml) of solute can not be completely dissolved in 10000 ml of solvent).
“微米尺寸的罗哌卡因”是罗哌卡因平均粒径小于100微米。罗哌卡因的平均粒度应该在大约1至大约100微米范围内，优选地大约1至大约50微米范围，更优选地大约1至大约10至20微米范围。"Micron-sized ropivacaine" is an average particle size of ropivacaine of less than 100 microns. The average particle size of ropivacaine should range from about 1 to about 100 microns, preferably from about 1 to about 50 microns, more preferably from about 1 to about 10 to 20 microns.
“纳米尺寸的罗哌卡因”是罗哌卡因平均粒径小于1微米。罗哌卡因的平均粒度应该在大约0.1至大约1微米范围内。"Nano-sized ropivacaine" is an average particle size of ropivacaine of less than 1 micron. The average particle size of ropivacaine should be in the range of from about 0.1 to about 1 micron.
术语“平均粒度(mean particle size)”，是指，如激光光散射(Laser Light Scattering,LLS)方法所测定的体积平均径(volume mean diameter)。粒度分布(particle size distribution)是LLS方法测定的，平均粒度是从粒度分布计算出来的。The term "mean particle size" refers to a volume mean diameter as determined by a Laser Light Scattering (LLS) method. The particle size distribution is determined by the LLS method and the average particle size is calculated from the particle size distribution.
综上，本发明提供了一种罗哌卡因晶型并由此开发出一类新型罗哌卡因缓释注射制剂。本发明制剂的载剂为水，活性成分罗哌卡因游离碱晶体或其水难溶性盐混悬于其中，所用到的附加剂为注射剂中常用的表面活性剂和助悬剂等。与以往报道的罗哌卡因缓释制剂不同，本发明的制剂是利用罗哌卡因游离碱或其水难溶性盐本身的溶解特性来控制药物的释放，而 不需要加入其它的药物缓释载体来控制药物的释放。当然，该制剂也可以与适宜的药物缓释载体联合使用以进一步提高其缓释效果。该制剂不仅生产工艺简单，而且选用的辅料为注射剂中常用的辅料，具有良好的安全性。该缓释***是一种适合用于医疗手术后镇痛的罗哌卡因长效缓释***，用于提供初始麻醉并且预计在施用部位提供大约8～72小时或更长的局部麻醉作用。In summary, the present invention provides a crystalline form of ropivacaine and thereby developed a novel class of sustained release injection formulations of ropivacaine. The carrier of the preparation of the present invention is water, and the active ingredient ropivacaine free base crystal or a water-insoluble salt thereof is suspended therein, and the additional agent used is a surfactant and a suspending agent which are commonly used in injections. Unlike the previously reported sustained-release preparation of ropivacaine, the preparation of the present invention utilizes the solubility characteristics of ropivacaine free base or its poorly water-soluble salt itself to control drug release. There is no need to add other drug delivery vehicles to control the release of the drug. Of course, the preparation can also be used in combination with a suitable drug delivery carrier to further enhance its sustained release effect. The preparation not only has a simple production process, but also the auxiliary materials selected are commonly used auxiliary materials for injection, and have good safety. The sustained release system is a long-acting ropivacaine sustained release system suitable for post-surgical analgesia for providing initial anesthesia and is expected to provide a local anesthetic effect of about 8 to 72 hours or longer at the site of administration.
附图说明DRAWINGS
图1是化合物S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的粉末X射线衍射图。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a powder X-ray diffraction pattern of the compound S-(-)-1-propyl-2',6'-dimethylformylpiperidine.
图2是化合物S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的DSC图。Figure 2 is a DSC chart of the compound S-(-)-1-propyl-2',6'-dimethylformylpiperidine.
图3是不同罗哌卡因制剂在大鼠体内的药时曲线。Figure 3 is a plot of the drug time for different ropivacaine formulations in rats.
图4罗哌卡因硬脂酸盐的粉末X射线衍射图。Figure 4 is a powder X-ray diffraction pattern of ropivacaine stearate.
图5罗哌卡因帕莫酸盐的粉末X射线衍射图。Figure 5 is a powder X-ray diffraction pattern of ropivacaine pamoate.
具体实施方式detailed description
以下结合具体实施例和实验例对本发明作进一步的详细说明，但不应被理解为对本发明保护范围的限制。本发明晶体制备中起始溶解温度的区间为-5～70℃之内均可实施。The invention is further described in detail below with reference to specific examples and experimental examples, but should not be construed as limiting the scope of the invention. The initial dissolution temperature in the preparation of the crystal of the present invention can be carried out in the range of -5 to 70 °C.
实施例1  罗哌卡因碱晶体的制备Example 1 Preparation of ropivacaine base crystals
S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶(即罗哌卡因，100g，0.36mol)，在约60℃下溶解于乙醇1000ml中，溶液在约0℃下搅拌约3小时。分离出沉淀的晶体，用乙醇-庚烷(乙醇：庚烷＝1：5，200ml)洗涤，干燥，得到目标化合物(65g，产率65％)。产品外观为白色。所得化合物S-(-)-1-丙基-2’，6’-二甲苯胺甲酰基哌啶晶体的粉末X射线衍射图如图1。晶体的熔解起始温度为145～146℃(熔点仪测定)。S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine (ie ropivacaine, 100 g, 0.36 mol), dissolved in 1000 ml of ethanol at about 60 ° C, the solution is in Stir at about 0 ° C for about 3 hours. The crystals precipitated were separated, washed with ethanol-heptane (ethanol: heptane = 1: 5, 200 ml) and dried to give the title compound (65 g, yield: 65%). The appearance of the product is white. The powder X-ray diffraction pattern of the obtained compound S-(-)-1-propyl-2',6'-dimethylformylpiperidine crystal was as shown in Fig. 1. The melting initiation temperature of the crystal was 145 to 146 ° C (measured by a melting point meter).
实施例2  罗哌卡因碱晶体的制备Example 2 Preparation of Ropivacaine Base Crystals
S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶(100g，0.36mol)，溶解于甲基异丁基酮(2000ml)中，在外温约60℃下，减压浓缩至400ml。在约25℃下搅拌约5小时。分离出沉淀的晶体，干燥，得到目标化合物(73g，产率73％)，产品外观为白色。晶体的熔点为144～146℃(熔点仪测定)。S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine (100 g, 0.36 mol), dissolved in methyl isobutyl ketone (2000 ml) at an external temperature of about 60 ° C It was concentrated to 400 ml under reduced pressure. Stir at about 25 ° C for about 5 hours. The precipitated crystals were separated and dried to give the title compound (73 g, yield 73%). The melting point of the crystal is 144 to 146 ° C (measured by a melting point meter).
实施例3  罗哌卡因碱晶体的制备Example 3 Preparation of Ropivacaine Base Crystals
S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶(100g，0.36mol)，在约60℃下溶解于四氢呋喃(500ml)中，搅拌约0.5小时，用约15分钟滴加水(4500ml)，搅拌5小试。分离出沉淀的晶体，用四氢呋喃-水(四氢呋喃：水＝1：5，100ml)洗涤，干燥，得到目标化合物(93g，产率93％)，产品外观为白色。晶体的熔解起始温度为145～147℃(熔点仪测定)。 S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine (100 g, 0.36 mol), dissolved in tetrahydrofuran (500 ml) at about 60 ° C, stirred for about 0.5 hour, with Water (4,500 ml) was added dropwise over about 15 minutes, and 5 small tests were stirred. The crystals precipitated were separated, washed with tetrahydrofuran-water (tetrahydrofuran: water = 1:5, 100 ml) and dried to give the title compound (93 g, yield 93%). The melting initiation temperature of the crystal was 145 to 147 ° C (measured by a melting point meter).
经鉴定实施例1-3为同一晶型，均具有2θ值为10.5±0.2°，13.0±0.2°，16.4±0.2°，19.0±0.2°，21.6±0.2°，23.4±0.2°，25.9±0.2°，26.3±0.2°，31.8±0.2°的特征衍射峰，其粉末X射线衍射图见图1，DSC图见图2。The identified Examples 1-3 are the same crystal form, each having a 2θ value of 10.5±0.2°, 13.0±0.2°, 16.4±0.2°, 19.0±0.2°, 21.6±0.2°, 23.4±0.2°, 25.9±0.2. °, 26.3±0.2°, 31.8±0.2° characteristic diffraction peak, the powder X-ray diffraction pattern is shown in Fig. 1, and the DSC chart is shown in Fig. 2.
实施例4  制备微米尺寸的罗哌卡因碱Example 4 Preparation of micron-sized ropivacaine base
使用气流粉碎机(型号J-20-LE,Tecnologia Meccanica，Italy)对罗哌卡因碱原料药(实施例1制备)进行气流微粉化，制备微米尺寸的罗哌卡因碱。使用Mastersizer 2000激光散射粒度分布仪(Malvern Instrument,UK)通过干法测定气流微粉化后的罗哌卡因碱的粒径分布。确定微米尺寸的罗哌卡因碱具有3.2微米的平均粒度和下列粒度分布：10％<1.27μm，50％<2.75μm和90％<5.67μm。The ropivacaine base drug substance (prepared in Example 1) was subjected to air flow micronization using a jet mill (Model J-20-LE, Tecnologia Meccanica, Italy) to prepare a micron-sized ropivacaine base. The particle size distribution of the ropivacaine base after micronization of the gas stream was measured by a dry method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK). The micron-sized ropivacaine base was determined to have an average particle size of 3.2 microns and the following particle size distribution: 10% < 1.27 μm, 50% < 2.75 μm and 90% < 5.67 μm.
实施例5  对罗哌卡因碱进行干热灭菌Example 5 Dry heat sterilization of ropivacaine base
将25mg实施例4制备的微粉化的罗哌卡因碱粉末装入5mL西林瓶中，放置于干热灭菌柜(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)中以140℃干热灭菌3小时。25 mg of the micronized ropivacaine base powder prepared in Example 4 was placed in a 5 mL vial and placed in a dry heat sterilization cabinet (100-grade purification door-opening sterilization oven, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.) to 140 Dry heat sterilization at °C for 3 hours.
使用Waters公司的Xbridge C18色谱柱(5μm，250×4.6mm)，使用乙腈-磷酸盐缓冲液(取1mol/L磷酸二氢钠溶液1.3ml，0.5mol/L磷酸氢二钠溶液32.5mL，加水至1000mL，调节pH至8.0)(50：50)为流动相，检测波长为240nm，进行HPLC分析。将干热灭菌的药物粉末溶解于流动相中并进行分析。HPLC分析表明干热灭菌后的罗哌卡因碱的纯度为99％以上，有关物质在中国药典要求的限度范围内。Using Waters Xbridge C18 column (5 μm, 250 × 4.6 mm), using acetonitrile-phosphate buffer (take 1 mol/L sodium dihydrogen phosphate solution 1.3 ml, 0.5 mol/L disodium hydrogen phosphate solution 32.5 mL, add water To 1000 mL, the pH was adjusted to 8.0) (50:50) as a mobile phase, and the detection wavelength was 240 nm, and HPLC analysis was performed. The dry heat sterilized drug powder was dissolved in the mobile phase and analyzed. HPLC analysis showed that the purity of ropivacaine base after dry heat sterilization was 99% or more, and the relevant substances were within the limits required by the Chinese Pharmacopoeia.
实施例6  对罗哌卡因碱缓释混悬液进行湿热灭菌Example 6 Hydrothermal sterilization of ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 5g5g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.55g0.55g
吐温80Tween 80 0.1g0.1g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 94.35g94.35g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，再加入罗哌卡因碱，搅拌分散均匀，将样品以2ml/瓶的量分装至5ml安瓿中并密封。将安瓿瓶置于高压蒸汽灭菌器(不锈钢立式压力蒸汽灭菌器，上海申安医疗器械厂)中以121℃灭菌15分钟。高压蒸汽灭菌处理后，冷却样品置室温，然后置于4℃冷藏。Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, slowly add sodium carboxymethylcellulose while stirring, and then add ropivacaine after sodium carboxymethylcellulose is completely dissolved. The base was stirred and dispersed uniformly, and the sample was dispensed into a 5 ml ampoule in an amount of 2 ml/bottle and sealed. The ampoule was placed in a high pressure steam sterilizer (stainless steel vertical pressure steam sterilizer, Shanghai Shen'an Medical Instrument Factory) and sterilized at 121 ° C for 15 minutes. After autoclaving, the sample was cooled to room temperature and then refrigerated at 4 °C.
在高压蒸汽灭菌处理之后，未观察到混悬液样品有明显的颜色变化。使用Waters公司的Xbridge C18色谱柱(5μm，250×4.6mm)，使用乙腈-磷酸盐缓冲液(取1mol/L磷酸二氢钠溶液1.3mL，0.5mol/L磷酸氢二钠溶液32.5mL，加水至1000mL，调节pH至8.0)(50：50)为流动相，检测波长为240nm，进行HPLC分析。将灭菌后的混悬液样品溶解于流动相 中并进行分析。HPLC分析表明混悬液样品中罗哌卡因碱降解产物少于1％，有关物质在中国药典要求的限度范围内。以上结果说明罗哌卡因碱混悬液可以耐受高压蒸汽灭菌处理。No significant color change was observed in the suspension samples after autoclaving. Using Waters Xbridge C18 column (5 μm, 250 × 4.6 mm), using acetonitrile-phosphate buffer (take 1 mol/L sodium dihydrogen phosphate solution 1.3 mL, 0.5 mol/L disodium hydrogen phosphate solution 32.5 mL, add water To 1000 mL, the pH was adjusted to 8.0) (50:50) as a mobile phase, and the detection wavelength was 240 nm, and HPLC analysis was performed. Dissolve the sterilized suspension sample in the mobile phase And analyze it. HPLC analysis indicated that the ropivacaine base degradation product in the suspension sample was less than 1%, and the relevant substances were within the limits required by the Chinese Pharmacopoeia. The above results indicate that the ropivacaine base suspension can withstand autoclaving.
实施例7  制备浓度为2％的罗哌卡因碱缓释混悬液Example 7 Preparation of a 2% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 20g20g
吐温80Tween 80 5g5g
注射用水Water for Injection 975g975g
共Total 1000g1000g
称取注射用水，室温下加入处方量的吐温80，搅拌溶解，再加入罗哌卡因碱，搅拌分散均匀，121℃，15min高压蒸汽灭菌，在无菌条件下高压均质(Niro Savino，均质压力600bar)得到具有适宜药物粒径的混悬液，分装即得。使用Mastersizer 2000激光散射粒度分布仪(Malvern Instrument,UK)通过湿法测定均质后的罗哌卡因碱混悬液的粒径分布。确定罗哌卡因碱混悬液中的药物颗粒具有6.3微米的平均粒度和下列粒度分布：10％<2.39μm，50％<4.72μm和90％<8.54μm。Weigh the water for injection, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, add ropivacaine base, stir and disperse evenly, autoclave at 121 ° C, 15 min, and homogenize under high pressure (Niro Savino) The homogenization pressure is 600 bar) to obtain a suspension having a suitable drug particle size, which is obtained by dispensing. The particle size distribution of the homogenized ropivacaine base suspension was determined by a wet method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK). The drug particles in the ropivacaine base suspension were determined to have an average particle size of 6.3 microns and the following particle size distribution: 10% < 2.39 μm, 50% < 4.72 μm and 90% < 8.54 μm.
实施例8  制备浓度为2％的罗哌卡因碱缓释混悬液Example 8 Preparation of a 2% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 2g2g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.5g0.5g
吐温80Tween 80 0.1g0.1g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 97.4g97.4g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，121℃，15min高压蒸汽灭菌，再加入经微粉化的无菌罗哌卡因碱(实施例4中制备)，无菌条件下高速剪切(F22Z高速剪切机，Fluko公司制造，剪切速度10000rpm)分散均匀，分装即得。Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, slowly add sodium carboxymethyl cellulose while stirring, after the sodium carboxymethyl cellulose is completely dissolved, 121 ° C, 15 min high pressure steam Sterilize, and then add micronized sterile ropivacaine base (prepared in Example 4), and disperse uniformly under high-speed shearing (F22Z high-speed shearing machine, manufactured by Fluko, cutting speed 10000 rpm) under aseptic conditions. Pack and sell.
实施例9  制备浓度为4％的罗哌卡因碱缓释混悬液Example 9 Preparation of a 4% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g4g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.5g0.5g
吐温80Tween 80 0.1g0.1g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 95.4g95.4g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，121℃，15min高压蒸汽灭菌，再加入经微粉化的无菌罗哌卡因碱(实施例4中制备)，无菌条件下高速剪切(F22Z高速剪切机，Fluko公司制造，剪切速度10000rpm)分散均匀，分装即得。 Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, slowly add sodium carboxymethyl cellulose while stirring, after the sodium carboxymethyl cellulose is completely dissolved, 121 ° C, 15 min high pressure steam Sterilize, and then add micronized sterile ropivacaine base (prepared in Example 4), and disperse uniformly under high-speed shearing (F22Z high-speed shearing machine, manufactured by Fluko, cutting speed 10000 rpm) under aseptic conditions. Pack and sell.
实施例10  制备浓度为8％的罗哌卡因碱缓释混悬液Example 10 Preparation of a 8% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 8g8g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.5g0.5g
吐温80Tween 80 0.1g0.1g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 91.4g91.4g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，121℃，15min高压蒸汽灭菌，再加入经微粉化的无菌罗哌卡因碱(实施例4中制备)，无菌条件下高速剪切(F22Z高速剪切机，Fluko公司制造，剪切速度10000rpm)分散均匀，分装即得。Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, slowly add sodium carboxymethyl cellulose while stirring, after the sodium carboxymethyl cellulose is completely dissolved, 121 ° C, 15 min high pressure steam Sterilize, and then add micronized sterile ropivacaine base (prepared in Example 4), and disperse uniformly under high-speed shearing (F22Z high-speed shearing machine, manufactured by Fluko, cutting speed 10000 rpm) under aseptic conditions. Pack and sell.
实施例11  制备浓度为4％的罗哌卡因碱缓释混悬液Example 11 Preparation of a 4% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g4g
吐温80Tween 80 0.4g0.4g
蔗糖sucrose 5g5g
注射用水Water for Injection 90.6g90.6g
共Total 100g100g
称取注射用水，室温下加入处方量的吐温80、蔗糖，搅拌溶解，121℃，15min高压蒸汽灭菌，再加入经过辐照灭菌的罗哌卡因碱，高速剪切分散均匀，将混悬液使用微射流仪(Nano DeBEE45，均化压力10000psi)进行均化。Weigh the water for injection, add the prescribed amount of Tween 80, sucrose at room temperature, stir and dissolve, autoclave at 121 ° C for 15 minutes, add radiation-sterilized ropivacaine base, and shear and disperse at high speed. The suspension was homogenized using a microfluidizer (Nano DeBEE 45, homogenization pressure 10,000 psi).
实施例12  制备浓度为4％的罗哌卡因碱缓释混悬液Example 12 Preparation of a 4% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g4g
吐温80Tween 80 0.6g0.6g
氯化钠Sodium chloride 1g1g
注射用水Water for Injection 94.4g94.4g
共Total 100g100g
称取注射用水，室温下加入处方量的吐温80、氯化钠，搅拌溶解，121℃，15min高压蒸汽灭菌，再加入经过辐照灭菌的罗哌卡因碱，高速剪切分散均匀，将混悬液使用微射流仪(Nano DeBEE45，均化压力10000psi)进行均化。Weigh the water for injection, add the prescribed amount of Tween 80, sodium chloride at room temperature, stir to dissolve, autoclave at 121 ° C for 15 minutes, add radiation-sterilized ropivacaine base, and spread at high speed. The suspension was homogenized using a microfluidizer (Nano DeBEE 45, homogenization pressure 10,000 psi).
实施例13  制备浓度为4％的罗哌卡因碱缓释混悬液Example 13 Preparation of a 4% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g4g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.8g0.8g
吐温80Tween 80 0.4g0.4g
苯甲酸benzoic acid 0.5g0.5g
10mM磷酸盐缓冲液(pH7.2)10 mM phosphate buffer (pH 7.2) 94.3g94.3g
共Total 100g100g
称取10mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，再加入苯甲酸和罗哌卡因碱，搅拌分散均匀，121℃，15min高压蒸汽灭菌，于无菌条件湿法研磨(DYNO MILL research lab，瑞士WAB公司)得到合适的药物粒径，分装即得。使用Mastersizer 2000激光散射粒度分布仪(Malvern Instrument,UK)通过湿法测定研磨后的罗哌卡因碱混悬液的粒径分布。确定罗哌卡因碱混悬液中的药物颗粒具有0.23微米的平均粒度和下列粒度分布：10％<0.16μm，50％<0.29μm和90％<0.46μm。Weigh 10 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, slowly add sodium carboxymethyl cellulose while stirring, after the sodium carboxymethyl cellulose is completely dissolved, then add benzoic acid and Luo Pepcaine base, stirred and dispersed evenly, autoclaved at 121 ° C, 15 min, autoclaved, and sterilized by wet conditions (DYNO MILL research lab, WAB, Switzerland) to obtain the appropriate drug particle size, and dispensed. The particle size distribution of the ground ropivacaine base suspension after the grinding was measured by a wet method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK). The drug particles in the ropivacaine base suspension were determined to have an average particle size of 0.23 microns and the following particle size distribution: 10% < 0.16 μm, 50% < 0.29 μm and 90% < 0.46 μm.
实施例14  制备浓度为4％的罗哌卡因碱缓释混悬液Example 14 Preparation of a 4% concentration of ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g 4g
吐温20Tween 20 0.4g0.4g
对羟基苯甲酸甲酯Methylparaben 0.2g0.2g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 95.4g95.4g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温20和对羟基苯甲酸甲酯，搅拌溶解，经0.22微米的滤膜过滤除菌，再加入经过辐照灭菌的罗哌卡因碱，高速剪切分散均匀，将混悬液使用微射流仪(Nano DeBEE45，均化压力10000psi)进行均化。确定罗哌卡因碱混悬液中的药物颗粒具有15.4微米的平均粒度和下列粒度分布：10％<5.92μm，50％<12.3μm和90％<20.6μm。Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 20 and methylparaben at room temperature, stir to dissolve, filter and sterilize through 0.22 μm filter, and then add radiation-sterilized ropivacaine. The base was homogenized by high speed shear dispersion and the suspension was homogenized using a microfluidizer (Nano DeBEE 45, homogenization pressure 10,000 psi). The drug particles in the ropivacaine base suspension were determined to have an average particle size of 15.4 microns and the following particle size distribution: 10% < 5.92 μm, 50% < 12.3 μm and 90% < 20.6 μm.
实施例15  制备浓度为3％的纳米尺寸化的罗哌卡因碱缓释混悬液Example 15 Preparation of a Nanosized ropivacaine base sustained release suspension at a concentration of 3%
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 6g6g
羧甲基纤维素钠Sodium carboxymethyl cellulose 1g1g
吐温80Tween 80 1g 1g
甘露醇Mannitol
8g8g
10mM磷酸盐缓冲液(pH7.4)10 mM phosphate buffer (pH 7.4) 184g184g
共Total 200g200g
称取磷酸盐缓冲液，室温下加入处方量的吐温80和甘露醇，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，121℃，15min高压蒸汽灭菌，再加入经辐照灭菌的微粉化罗哌卡因碱，于无菌条件下高速剪切分散均匀，随后于无菌条件下湿法研磨(DYNO MILL research lab，瑞士WAB公司)。使用Mastersizer 2000激光散射粒度分布仪(Malvern Instrument,UK)通过湿法测定湿法研磨后的混悬液的粒径分布。确定研磨后的混悬液具有0.52微米的平均粒度和下列粒度分布：10％<0.21μm，50％<0.43μm和90％<0.79μm。 Weigh phosphate buffer, add the prescribed amount of Tween 80 and mannitol at room temperature, stir to dissolve, slowly add sodium carboxymethyl cellulose while stirring, after the sodium carboxymethyl cellulose is completely dissolved, 121 ° C, 15 min Autoclave sterilization, addition of radiation-sterilized micronized ropivacaine base, high-speed shear dispersion under sterile conditions, and then wet grinding under sterile conditions (DYNO MILL research lab, WAB, Switzerland) ). The particle size distribution of the wet-milled suspension was measured by a wet method using a Mastersizer 2000 laser scattering particle size distribution analyzer (Malvern Instrument, UK). It was confirmed that the milled suspension had an average particle size of 0.52 μm and the following particle size distribution: 10% < 0.21 μm, 50% < 0.43 μm, and 90% < 0.79 μm.
实施例16  制备浓度为20％的罗哌卡因碱缓释混悬液Example 16 Preparation of a 20% ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 20g20g
羧甲基纤维素钠Sodium carboxymethyl cellulose 2g2g
吐温80Tween 80 1g1g
蔗糖sucrose 5g5g
注射用水Water for Injection 72g72g
共Total 100g100g
称取注射用水，室温下加入处方量的吐温80和蔗糖，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，利用0.22μm的滤膜进行过滤除菌，再加入经微粉化的罗哌卡因碱，高速剪切分散均匀后进行高压均质(Avestin，均质压力400psi)，分装即得。Weigh the water for injection, add the prescribed amount of Tween 80 and sucrose at room temperature, stir to dissolve, and slowly add sodium carboxymethylcellulose while stirring. After the sodium carboxymethylcellulose is completely dissolved, use a 0.22 μm filter. Filtration and sterilization, and then added micronized ropivacaine base, high-speed shear dispersion and uniformity, high pressure homogenization (Avestin, homogenization pressure 400psi), ready to dispense.
实施例17  制备罗哌卡因碱缓释混悬液的冻干制剂Example 17 Preparation of lyophilized preparation of ropivacaine base sustained-release suspension
处方：prescription:
罗哌卡因碱(实施例5)Ropivacaine base (Example 5) 4g4g
羧甲基纤维素钠Sodium carboxymethyl cellulose 0.55g0.55g
吐温20Tween 20 0.08g0.08g
甘露醇Mannitol
4g4g
50mM磷酸盐缓冲液(pH7.2)50 mM phosphate buffer (pH 7.2) 91.37g91.37g
共Total 100g100g
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80和甘露醇，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠，待羧甲基纤维素钠溶解完全后，用0.22μm的滤膜进行过滤除菌，再加入经160摄氏度干热灭菌2小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化罗哌卡因碱，高速剪切分散均匀。将5ml的上述悬浮液无菌填充入无菌瓶中，随后用无菌塞子在无菌条件下将其部分塞住。将瓶无菌转移至冷冻干燥器并按下列循环进行冻干：Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 and mannitol at room temperature, stir to dissolve, slowly add sodium carboxymethylcellulose while stirring, after the sodium carboxymethylcellulose is dissolved completely, use 0.22 μm The filter membrane is filtered and sterilized, and then added to the micronized ropivacaine base which is sterilized by dry heat at 160 ° C for 2 hours (100-grade purification on the door sterilization sterilizer, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.), and the high-speed shear is evenly dispersed. . 5 ml of the above suspension was aseptically filled into a sterile vial, which was then partially stoppered under sterile conditions using a sterile stopper. The vials were aseptically transferred to a freeze dryer and lyophilized as follows:
(a)热处理：于-40℃冷冻产物0.1～1小时，置于-40℃至少3小时，(a) Heat treatment: the product is frozen at -40 ° C for 0.1 to 1 hour, and placed at -40 ° C for at least 3 hours.
(b)冷却冷凝器至-50℃或更低，(b) Cool the condenser to -50 ° C or lower,
(c)初步干燥：在大约2小时期间，降低舱压至大约100微米汞柱并升高产物温度至-5℃；于-5℃和100微米汞柱下持续初步干燥至少48小时，(c) preliminary drying: during about 2 hours, reduce the tank pressure to approximately 100 micron mercury and raise the product temperature to -5 ° C; continue preliminary drying at -5 ° C and 100 micron mercury for at least 48 hours,
(d)应用无菌氮或空气，在大气压或部分真空下塞住瓶并从冷冻干燥器中移出，(d) applying sterile nitrogen or air, plugging the bottle under atmospheric pressure or partial vacuum and removing it from the freeze dryer,
(e)用合适的封口物密封瓶并加上标签。(e) Seal the bottle with a suitable seal and label it.
实施例18  罗哌卡因棕榈酸盐的制备：Example 18 Preparation of ropivacaine palmitate:
将罗哌卡因碱(2.74克；10毫摩尔)和棕榈酸(2.56克；10毫摩尔)加入到无水丙酮(100mL)中，并在40摄氏度下搅拌6小时。随后将反应液滴加到2L纯化水中，析出白色晶体，过滤并真空干燥，即得到罗哌卡因棕榈酸盐。 Ropivacaine base (2.74 g; 10 mmol) and palmitic acid (2.56 g; 10 mmol) were added to dry acetone (100 mL) and stirred at 40 ° C for 6 hours. The reaction droplets were then added to 2 L of purified water, white crystals were precipitated, filtered and dried in vacuo to give ropivacaine palmitate.
实施例19  罗哌卡因硬脂酸盐的制备：Example 19 Preparation of ropivacaine stearate:
将罗哌卡因碱(2.74克；10毫摩尔)和硬脂酸(2.84克；10毫摩尔)加入到无水乙醇(100mL)中，并在50摄氏度下搅拌3小时。随后将反应液滴加到1L纯化水中，析出白色晶体，过滤并真空干燥，即得到罗哌卡因硬脂酸盐，X射线粉末衍射图谱见图4。Ropivacaine base (2.74 g; 10 mmol) and stearic acid (2.84 g; 10 mmol) were added to absolute ethanol (100 mL) and stirred at 50 ° C for 3 hours. The reaction droplets were then added to 1 L of purified water, white crystals were precipitated, filtered and dried in vacuo to give ropivacaine stearate. The X-ray powder diffraction pattern is shown in Fig. 4.
实施例20  罗哌卡因帕莫酸盐(罗哌卡因：帕莫酸＝2：1(摩尔比))的制备：Example 20 Preparation of ropivacaine palmate (ropivacaine: palmitic acid = 2:1 (molar ratio)):
将罗哌卡因碱(10克；36.44毫摩尔)和帕莫酸(7.08克；18.22毫摩尔)加入到四氢呋喃(200mL)中，并在40摄氏度下搅拌2小时。随后将反应液滴加到2L正己烷中，析出淡黄色固体，过滤并真空干燥，即得到罗哌卡因帕莫酸盐，X射线粉末衍射图谱见图5。Ropivacaine base (10 g; 36.44 mmol) and palmitic acid (7.08 g; 18.22 mmol) were added to tetrahydrofuran (200 mL) and stirred at 40 ° C for 2 hours. The reaction droplets were then added to 2 L of n-hexane to precipitate a pale yellow solid which was filtered and dried in vacuo to give ropivacaine pamoate. The X-ray powder diffraction pattern is shown in Fig. 5.
实施例21  制备浓度为3％的罗哌卡因帕莫酸盐混悬型注射液：Example 21 A 3% ropivacaine palmate suspension injection was prepared:
处方：prescription:
Figure PCTCN2016097784-appb-000001
Figure PCTCN2016097784-appb-000001
称取50mM磷酸盐缓冲液，室温下加入处方量的吐温80，搅拌溶解，边搅拌边缓慢加入羧甲基纤维素钠(安徽山河药用辅料股份有限公司)，待羧甲基纤维素钠溶解完全后，121℃，15min高压蒸汽灭菌，再加入微粉化的罗哌卡因帕莫酸盐，高速剪切分散均匀，分装即得。Weigh 50 mM phosphate buffer, add the prescribed amount of Tween 80 at room temperature, stir to dissolve, and slowly add sodium carboxymethyl cellulose (Anhui Shanhe Pharmaceutical Excipient Co., Ltd.) to the sodium carboxymethyl cellulose while stirring. After the dissolution is complete, autoclave sterilization at 121 ° C for 15 minutes, and then add micronized ropivacaine pamoate, which is evenly dispersed at high speed and dispensed.
实施例22～32  罗哌卡因缓释混悬液的制备Examples 22 to 32 Preparation of ropivacaine sustained release suspension
处方：prescription:
Figure PCTCN2016097784-appb-000002
Figure PCTCN2016097784-appb-000002
Figure PCTCN2016097784-appb-000003
Figure PCTCN2016097784-appb-000003
称取处方量的水或缓冲液，边搅拌边缓慢加入处方量的表面活性剂和其他辅料，待溶解完全后，利用0.22μm的滤膜进行过滤除菌，再加入处方量的经140摄氏度干热灭菌4小时(百级净化对开门灭菌烘箱，南京飞龙制药设备有限公司)的微粉化原料药，高速剪切分散均匀，分装即得。Weigh the prescribed amount of water or buffer, and slowly add the prescribed amount of surfactant and other excipients while stirring. After the solution is completely dissolved, filter and sterilize with a 0.22 μm filter, and then add the prescribed amount of 140 ° C. Heat sterilization 4 hours (100-level purification on the door sterilization oven, Nanjing Feilong Pharmaceutical Equipment Co., Ltd.) micronized raw materials, high-speed shear dispersion and uniform, ready to get.
实施例33  制备罗哌卡因油性溶液Example 33 Preparation of ropivacaine oily solution
参照CN103142458A中实施例21制备罗哌卡因的油性溶液。An oily solution of ropivacaine was prepared as described in Example 21 of CN103142458A.
处方：prescription:
罗哌卡因游离碱Ropivacaine free base 4.5g4.5g
苯甲醇Benzyl alcohol 10ml10ml
苯甲酸苄酯Benzyl benzoate 15ml15ml
蓖麻油加至Castor oil is added to 100ml100ml
制备工艺：取处方量的苯甲醇、苯甲酸苄酯，缓慢加入处方量的罗哌卡因游离碱，加热并搅拌，使其充分溶解，得到药物溶液；再将蓖麻油缓慢加到药物溶液中至100ml，搅拌混匀，膜过滤除菌，分装至西林瓶中，密封并包装。Preparation process: take the prescribed amount of benzyl alcohol, benzyl benzoate, slowly add the prescribed amount of ropivacaine free base, heat and stir to fully dissolve, to obtain a drug solution; then slowly add castor oil to the drug solution To 100ml, stir and mix, filter and sterilize, dispense into a vial, seal and package.
实施例34  制备罗哌卡因磷脂缓释制剂Example 34 Preparation of ropivacaine phospholipid sustained release preparation
参照WO2013168172A1中实施例2制备罗哌卡因磷脂缓释制剂。A ropivacaine phospholipid sustained release preparation was prepared in accordance with Example 2 of WO2013168172A1.
处方：prescription:
一水合盐酸罗哌卡因Ropivacaine hydrochloride monohydrate 4.78g(相当于罗哌卡因碱4g)4.78g (equivalent to ropivacaine base 4g)
大豆磷脂Soy lecithin 53.91g53.91g
蓖麻油castor oil 35.21g35.21g
半胱氨酸Cysteine 0.1g0.1g
乙醇Ethanol 6.0g6.0g
制备方法：称取处方量的盐酸罗哌卡因，半胱氨酸，蓖麻油和大豆磷脂，加入处方量的乙醇，于50摄氏度下水浴超声得到澄清的溶液，趁热分装即得。Preparation method: Weigh the prescribed amount of ropivacaine hydrochloride, cysteine, castor oil and soybean phospholipid, add the prescribed amount of ethanol, and obtain a clear solution by ultrasonic bath at 50 degrees Celsius.
实施例35  进行动物体内释放试验Example 35 In vivo release test in animals
将实施例8、实施例9和实施例10中制备的罗哌卡因碱缓释制剂进行动物试验，试验动物为SD大鼠(6～8周龄)，每组6只，注射方式为颈背部皮下注射，给药方案参见下表。给药后5min、15min、30min、1h、2h、4h、8h、12h、24h、48h每只采血约0.2mL，用于含量分析。 The ropivacaine base sustained-release preparation prepared in Example 8, Example 9 and Example 10 was subjected to animal test, and the test animals were SD rats (6-8 weeks old), 6 rats in each group, and the injection method was neck. Subcutaneous injection in the back, the dosing scheme is shown in the table below. About 0.2 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h after administration for content analysis.
Figure PCTCN2016097784-appb-000004
Figure PCTCN2016097784-appb-000004
各个样品给药后的药时曲线如图3所示，药动学参数如下表所示。The drug time curve after administration of each sample is shown in Fig. 3, and the pharmacokinetic parameters are shown in the following table.
不同罗哌卡因制剂的药动学参数(mean±SD，n＝6)Pharmacokinetic parameters of different ropivacaine preparations (mean±SD, n=6)
样品sample T1/2(h)T 1/2 (h) Tmax(h)T max (h) Cmax(ng/ml)C max (ng/ml) AUClast(ng/ml*h)AUC last (ng/ml*h)
2％混悬液(实施例8)2% suspension (Example 8) 7.2±1.47.2±1.4 2.3±0.92.3±0.9 990±394990±394 8793±15088793±1508
4％混悬液(实施例9)4% suspension (Example 9) 14.2±2.314.2±2.3 3.3±1.23.3±1.2 1229±3351229±335 20183±431020183±4310
8％混悬液(实施例10)8% suspension (Example 10) 23.5±5.223.5±5.2 1.1±0.31.1±0.3 2463±5162463±516 32084±361132084±3611
0.5％盐酸罗哌卡因注射液0.5% ropivacaine hydrochloride injection 0.7±0.10.7±0.1 0.3±0.10.3±0.1 1776±3481776±348 2425±6322425±632
试验结果显示，实施例8、实施例9和实施例10中制备的罗哌卡因碱缓释制剂与市售的盐酸罗哌卡因注射液相比均显示出良好的缓释效果，药物的达峰浓度显著降低，半衰期显著延长。The test results showed that the sustained release preparation of ropivacaine base prepared in Example 8, Example 9 and Example 10 showed a good sustained release effect compared with the commercially available ropivacaine hydrochloride injection. The peak concentration was significantly reduced and the half-life was significantly prolonged.
值得一提的是，8％罗哌卡因碱混悬液的给药剂量是0.5％盐酸罗哌卡因常释注射液的16倍之多，但其达峰浓度仅为0.5％盐酸罗哌卡因常释注射液的1.4倍，说明罗哌卡因碱混悬液可以有效控制药物的突释。此外，各实验组未发现与给药相关的中枢毒性，表明罗哌卡因碱混悬液具有很宽的安全窗。It is worth mentioning that the 8% ropivacaine base suspension is administered 16 times as much as 0.5% ropivacaine hydrochloride injection, but its peak concentration is only 0.5% ropiva hydrochloride. 1.4 times of the Cain's regular release injection, indicating that the ropivacaine base suspension can effectively control the burst release of the drug. In addition, no central toxicity associated with administration was found in each experimental group, indicating that the ropivacaine base suspension has a wide safety window.
实施例36  不同罗哌卡因缓释制剂的药效学研究(小型猪术后痛模型)Example 36 Pharmacodynamic Study of Different Ropivacaine Sustained Release Preparations (Small Pig Postoperative Pain Model)
试验目的：评价不同罗哌卡因碱缓释制剂的局部镇痛效果(镇痛持续时间)以及对伤口愈合的影响。OBJECTIVE: To evaluate the local analgesic effect (analgesic duration) of different sustained-release formulations of ropivacaine and its effect on wound healing.
试验动物：广西巴马小型猪，雄性，6～7周龄，体重3～5Kg。适应性饲养5～7天后进行术后痛模型的建立。Test animals: Guangxi Bama miniature pig, male, 6 to 7 weeks old, weighing 3 to 5 kg. The postoperative pain model was established after 5 to 7 days of adaptive feeding.
术后痛模型建立方法：麻醉选用异氟烷吸入麻醉。切口定位于左后背距背中线3cm，平行于背中线，切口3cm。待小型猪进入麻醉状态后俯卧/侧卧，择左后背区域备皮。备皮完成后进行术区消毒(75％酒精，碘伏，75％酒精)，并切开预定切口，切开皮肤及筋膜，不损伤肌肉。Postoperative pain model establishment method: anesthesia with isoflurane inhalation anesthesia. The incision was positioned 3 cm from the midline of the left back, parallel to the midline of the back, and the incision was 3 cm. After the small pig enters the anesthesia state, the prone/side is placed, and the left back area is prepared for skin preparation. After the skin preparation is completed, the operation area is disinfected (75% alcohol, iodophor, 75% alcohol), and the predetermined incision is cut, and the skin and fascia are cut, without damaging the muscle.
试验分组：每组6只，分阳性对照组(0.5％罗哌卡因注射液)、溶媒对照组(生理盐水)、同类对照药组(1.3％布比卡因脂质体注射用混悬液)、罗哌卡因碱缓释混悬液制剂组(2个)，罗哌卡因油性溶液，罗哌卡因磷脂缓释制剂共7组，如下表所示。Test group: 6 rats in each group, divided into positive control group (0.5% ropivacaine injection), vehicle control group (normal saline), similar control group (1.3% bupivacaine liposome injection suspension) ), ropivacaine base sustained-release suspension preparation group (2), ropivacaine oily solution, ropivacaine phospholipid sustained-release preparation a total of 7 groups, as shown in the following table.
序号Serial number 受试样品Test sample
11 生理盐水 Saline
22 0.5％罗哌卡因注射液0.5% ropivacaine injection
33 1.3％布比卡因脂质体注射用混悬液(Exparel，美国Pacira公司)1.3% bupivacaine liposome injection suspension (Exparel, Pacira, USA)
44 2％罗哌卡因碱混悬液(实施例8)2% ropivacaine base suspension (Example 8)
55 4％罗哌卡因碱混悬液(实施例9)4% ropivacaine base suspension (Example 9)
66 4％罗哌卡因油性溶液(实施例33)4% ropivacaine oily solution (Example 33)
77 4％罗哌卡因磷脂缓释制剂(实施例34)4% ropivacaine phospholipid sustained release preparation (Example 34)
给药方式和给药剂量：切口处皮下注射，各组动物分别浸润注射对应的受试制剂，给药体积为：1ml/cm，共3ml，切口两侧各分3点均匀注射，共6点注射，0.5mL/点，两侧注射点相距约1cm，缝合切口。术后3天，每天肌肉注射青霉素预防感染。Mode of administration and dose: subcutaneous injection at the incision, each group of animals were infiltrated and injected corresponding test preparations, the dosage volume was: 1ml/cm, a total of 3ml, and the injection was evenly injected at 3 points on both sides of the incision, a total of 6 points Injection, 0.5 mL / point, the injection points on both sides are about 1 cm apart, suture the incision. Three days after surgery, intramuscular injection of penicillin daily prevented infection.
镇痛效果检测：选用触觉测量套件(Von Frey)检测术后切口镇痛效果。先采用Von Frey针刺激距切口0.5cm处皮肤，测量其痛觉(逃避反应：扭转90～180度，离开测试者以避开刺激)，测量时间点分别为术前1d(作为基础值)，术后15min、30min、1h、3h、6h、9h、12h、24h、36h、48h、72h每个时间点测量6次，每次间隔5～10S。当针刺后的痛阈值发生变化时，在后续的测定周期中缩短检测时间点的时间间隔，以便较为准确地测定具体的失效时间。最后以6次测定的痛阈值中有3次恢复到手术前基础值水平的时间点作为失效时间。Analgesic effect test: The tactile measurement kit (Von Frey) was used to detect the postoperative analgesia effect. The Von Frey needle was used to stimulate the skin 0.5 cm away from the incision, and the pain was measured (evasion response: 90-180 degrees torsion, leaving the tester to avoid the stimulus), and the measurement time points were 1 d before surgery (as the base value). After 15 min, 30 min, 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, each time point was measured 6 times, each interval 5 ~ 10S. When the pain threshold after acupuncture changes, the time interval of the detection time point is shortened in the subsequent measurement period to more accurately determine the specific failure time. Finally, the time point at which the pain threshold of 6 measurements was restored to the pre-operative baseline value was used as the failure time.
术后切口恢复情况观察和病理学检查：术前1d(基础值)及术后，每天观察切口愈合情况并评分。当供试品组与对照组触觉测量结果接近时，即所有动物药效恢复当天，安乐死所有动物，剖检给药局部组织，大体观察，并取给药部位及周围皮肤及皮下筋膜、肌肉组织(取固定切面(切口中部)另外，当大体观察发现明显病变时，也取该部位病检)进行固定，包埋，切片，苏木精-伊红染色，显微镜下观察。Postoperative incision recovery observation and pathological examination: 1 day before surgery (basal value) and postoperative, the wound healing was observed and scored every day. When the test group and the control group are close to the tactile measurement results, that is, on the day when all the animals are restored, all the animals are euthanized, and the local tissues are administered by necropsy, and the main site is observed, and the administration site and the surrounding skin and subcutaneous fascia and muscle are taken. Tissue (take the fixed section (middle of the incision). In addition, when the obvious lesion is found in the general observation, the site is also taken for fixation, embedding, sectioning, hematoxylin-eosin staining, and observation under the microscope.
实验结果如下表所示：The experimental results are shown in the following table:
不同罗哌卡因碱缓释制剂在小型猪术后镇痛模型中的药效持续时间(mean±SD，n＝6)Duration of efficacy of different ropivacaine base sustained-release preparations in postoperative analgesia model of miniature pigs (mean±SD, n=6)
试验样品Test sample 药效持续时间(h)Duration of drug efficacy (h)
0.5％盐酸罗哌卡因注射液0.5% ropivacaine hydrochloride injection 6.17±1.156.17±1.15
1.3％布比卡因脂质体注射用混悬液1.3% bupivacaine liposome injection suspension 8.83±0.758.83±0.75
2％罗哌卡因碱混悬液(实施例8)2% ropivacaine base suspension (Example 8) 23.72±2.0423.72±2.04
4％罗哌卡因碱混悬液(实施例9)4% ropivacaine base suspension (Example 9) 34.52±4.4134.52±4.41
4％罗哌卡因油性溶液(实施例33)4% ropivacaine oily solution (Example 33) 21.17±3.5921.17±3.59
4％罗哌卡因磷脂缓释制剂(实施例34)4% ropivacaine phospholipid sustained release preparation (Example 34) 26.68±5.2426.68±5.24
如上表所示，0.5％盐酸罗哌卡因注射液(给药剂量若与缓释制剂一样则会引起动物的严重毒性反应甚至死亡)的麻醉效果只持续了约6小时，1.3％布比卡因脂质体注射用混悬液的麻醉时间也只有约9小时，4种罗哌卡因缓释制剂的局部麻醉持续时间显著长于0.5％盐酸罗哌卡因注射液和1.3％布比卡因脂质体注射用混悬液，其中4％罗哌卡因碱混悬液的局部麻醉时间最长，达到了30小时以上，药效持续时间明显优于4％罗哌卡因油性溶液和4％罗哌卡因磷脂缓释制剂。在给药过程中发现，罗哌卡因磷脂缓释制剂组的粘度很高，注射时难度很大，罗哌卡因油性溶液也具有较高的粘度，注射困难。而罗哌卡因碱混悬液粘度很低，注射操作很容易进行。 As shown in the above table, the anesthetic effect of 0.5% ropivacaine hydrochloride injection (if the dose is the same as that of the sustained-release preparation, causing serious toxicity or even death of the animal) lasted only about 6 hours, 1.3% bupika The anesthesia time of the liposome injection suspension was only about 9 hours. The local anesthesia duration of the four ropivacaine sustained-release preparations was significantly longer than 0.5% ropivacaine hydrochloride injection and 1.3% bupivacaine. The liposome injection suspension, in which the 4% ropivacaine base suspension has the longest local anesthesia time, reaching more than 30 hours, the efficacy duration is significantly better than 4% ropivacaine oily solution and 4 % ropivacaine phospholipid sustained release preparation. During the administration, it was found that the ropivacaine phospholipid sustained-release preparation group had high viscosity and was difficult to inject, and the ropivacaine oily solution also had a high viscosity and was difficult to inject. The ropivacaine base suspension has a very low viscosity and the injection operation is easy to carry out.
值得一提的是，同一***物在动物体和人体里的药效作用时间大多情况下是有差别的，例如1.3％布比卡因脂质体在小型猪上的麻醉作用时间为9小时左右，但在相对应的人体作用时间则为至少24小时(Skolnik A，Gan TJ.New formulations of bupivacaine for the treatment of postoperative pain：liposomal bupivacaine and SABER-Bupivacaine.Expert Opin Pharmacother.2014 Aug；15(11)：1535-42)，即2～3倍，由此推算，4％罗哌卡因碱混悬液在人体内的麻醉作用时间可达48～72小时。从图3中可还以看出，罗哌卡因碱的浓度对罗哌卡因混悬液的麻醉持续时间有显著影响，因此可以通过调整药物混悬液中的药物浓度来达到调整局部麻醉持续时间的目的。It is worth mentioning that the time of pharmacodynamic action of the same anesthetic drug in animals and human body is mostly different. For example, the anesthetic effect of 1.3% bupivacaine liposome on small pigs is about 9 hours. , but at the corresponding human body action time is at least 24 hours (Skolnik A, Gan TJ. New formulations of bupivacaine for the treatment of postoperative pain: liposomal bupivacaine and SABER-Bupivacaine. Expert Opin Pharmacother. 2014 Aug; 15 (11) : 1535-42), that is, 2 to 3 times, from which it is estimated that the anesthesia effect of the 4% ropivacaine base suspension in the human body can reach 48 to 72 hours. It can be seen from Figure 3 that the concentration of ropivacaine base has a significant effect on the duration of anesthesia of the ropivacaine suspension, so local anesthesia can be adjusted by adjusting the drug concentration in the drug suspension. The purpose of duration.
此外，在试验过程中，各实验组都未发现与给药相关的中枢毒性。对动物手术切口的肉眼观察和病理学检查表明，2％和4％罗哌卡因碱混悬液组中动物手术切口仅有一定程度的炎症变化且与生理盐水组相当，表明罗哌卡因碱混悬液具有很低的局部组织毒性，而且不会影响伤口的愈合。而4％罗哌卡因油性溶液和4％罗哌卡因磷脂缓释制剂组伤口缝合处炎症反应明显，创面有大量的炎性渗出物(以中性粒细胞为主)，可见脓球形成；皮下组织水肿出血明显，有大量密集的炎性细胞浸润；肌肉组织有明显的炎细胞浸润，且伴有变性/坏死现象。表明这两种制剂有明显的局部组织毒性。In addition, no central toxicity associated with administration was found in each experimental group during the test. Visual observation and pathological examination of the surgical incision of the animals showed that the surgical incision in the 2% and 4% ropivacaine base suspensions had only a certain degree of inflammatory changes and was comparable to the saline group, indicating ropivacaine. Alkali suspensions have very low local tissue toxicity and do not affect wound healing. The 4% ropivacaine oily solution and the 4% ropivacaine phospholipid sustained-release preparation group had obvious inflammation in the wound suture, and the wound had a large amount of inflammatory exudate (mainly neutrophils), and the pus was seen. Formation; subcutaneous tissue edema bleeding, a large number of dense inflammatory cell infiltration; muscle tissue has obvious inflammatory cell infiltration, accompanied by degeneration / necrosis. These two formulations showed significant local tissue toxicity.
实施例37  罗哌卡因帕莫酸盐缓释注射液和纳米尺寸化的罗哌卡因碱缓释注射液的药效学研究(小型猪术后痛模型)Example 37 Pharmacodynamic study of ropivacaine pamoate sustained release injection and nanosized ropivacaine base sustained release injection (small pig postoperative pain model)
试验目的：评价罗哌卡因帕莫酸盐缓释注射液和纳米尺寸化的罗哌卡因碱缓释注射液的局部镇痛效果(镇痛持续时间)以及对伤口愈合的影响。OBJECTIVE: To evaluate the local analgesic effect (analgesic duration) of ropivacaine pamoate sustained release injection and nanosized ropivacaine sustained release injection and its effect on wound healing.
试验动物：广西巴马小型猪，雄性，6～7周龄，体重3～5Kg。适应性饲养5～7天后进行术后痛模型的建立。Test animals: Guangxi Bama miniature pig, male, 6 to 7 weeks old, weighing 3 to 5 kg. The postoperative pain model was established after 5 to 7 days of adaptive feeding.
术后痛模型建立方法：麻醉选用异氟烷吸入麻醉。切口定位于左后背距背中线3cm，平行于背中线，切口3cm。待小型猪进入麻醉状态后俯卧/侧卧，择左后背区域备皮。备皮完成后进行术区消毒(75％酒精，碘伏，75％酒精)，并切开预定切口，切开皮肤及筋膜，不损伤肌肉。Postoperative pain model establishment method: anesthesia with isoflurane inhalation anesthesia. The incision was positioned 3 cm from the midline of the left back, parallel to the midline of the back, and the incision was 3 cm. After the small pig enters the anesthesia state, the prone/side is placed, and the left back area is prepared for skin preparation. After the skin preparation is completed, the operation area is disinfected (75% alcohol, iodophor, 75% alcohol), and the predetermined incision is cut, and the skin and fascia are cut, without damaging the muscle.
试验分组：每组6只，分阳性对照组(0.5％罗哌卡因注射液)、溶媒对照组(生理盐水)、纳米尺寸化的罗哌卡因碱缓释注射液(1个)、罗哌卡因帕莫酸盐缓释注射液组(1个)，共3组，如下表所示。Test group: 6 rats in each group, divided into positive control group (0.5% ropivacaine injection), vehicle control group (normal saline), nano-sized ropivacaine base sustained-release injection (1), Luo Pi***e hydrochloride release sustained-release injection group (1), a total of 3 groups, as shown in the following table.
序号Serial number 受试样品Test sample
11 生理盐水 Saline
22 0.5％罗哌卡因注射液0.5% ropivacaine injection
33 3％纳米尺寸化的罗哌卡因碱缓释注射液(实施例15)3% nanosized ropivacaine base sustained release injection (Example 15)
44 3％罗哌卡因帕莫酸盐缓释注射液组(实施例21)3% ropivacaine pamoate sustained release injection group (Example 21)
给药方式和给药剂量：切口处皮下注射，各组动物分别浸润注射对应的受试制剂，给药体积为：1ml/cm，共3ml，切口两侧各分3点均匀注射，共6点注射，0.5ml/点，两侧注射点相距约1cm，缝合切口。术后3天，每天肌肉注射青霉素预防感染。Mode of administration and dose: subcutaneous injection at the incision, each group of animals were infiltrated and injected corresponding test preparations, the dosage volume was: 1ml/cm, a total of 3ml, and the injection was evenly injected at 3 points on both sides of the incision, a total of 6 points Injection, 0.5 ml / point, the injection points on both sides are about 1 cm apart, suture the incision. Three days after surgery, intramuscular injection of penicillin daily prevented infection.
镇痛效果检测：选用触觉测量套件(Von Frey)检测术后切口镇痛效果。先采用Von Frey针刺激距切口0.5cm处皮肤，测量其痛觉(逃避反应：扭转90～180度，离开测试者以避开刺激)，测量时间点分别为术前1d(作为基础值)，术后15min、30min、1h、3h、6h、9h、12h、24h、36h、48h、72h每个时间点测量6次，每次间隔5～10S。当针刺后的痛阈值发生变化时，在后续的测定周期中缩短检测时间点的时间间隔，以便较为准确地测定具体的失效时间。最后以6次测定的痛阈值中有3次恢复到手术前基础值水平的时间点作为失效时间。Analgesic effect test: The tactile measurement kit (Von Frey) was used to detect the postoperative analgesia effect. The Von Frey needle was used to stimulate the skin 0.5 cm away from the incision, and the pain was measured (evasion response: 90-180 degrees torsion, leaving the tester to avoid the stimulus), and the measurement time points were 1 d before surgery (as the base value). After 15 min, 30 min, 1 h, 3 h, 6 h, 9 h, 12 h, 24 h, 36 h, 48 h, 72 h, each time point was measured 6 times, each interval 5 ~ 10S. When the pain threshold after acupuncture changes, the time interval of the detection time point is shortened in the subsequent measurement period to more accurately determine the specific failure time. Finally, the time point at which the pain threshold of 6 measurements was restored to the pre-operative baseline value was used as the failure time.
术后切口恢复情况观察和病理学检查：术前1d(基础值)及术后，每天观察切口愈合情况并评分。当供试品组与对照组触觉测量结果接近时，即所有动物药效恢复当天，安乐死所有动物，剖检给药局部组织，大体观察，并取给药部位及周围皮肤及皮下筋膜、肌肉组织(取固定切面(切口中部)另外，当大体观察发现明显病变时，也取该部位病检)进行固定，包埋，切片，苏木精-伊红染色，显微镜下观察。Postoperative incision recovery observation and pathological examination: 1 day before surgery (basal value) and postoperative, the wound healing was observed and scored every day. When the test group and the control group are close to the tactile measurement results, that is, on the day when all the animals are restored, all the animals are euthanized, and the local tissues are administered by necropsy, and the main site is observed, and the administration site and the surrounding skin and subcutaneous fascia and muscle are taken. Tissue (take the fixed section (middle of the incision). In addition, when the obvious lesion is found in the general observation, the site is also taken for fixation, embedding, sectioning, hematoxylin-eosin staining, and observation under the microscope.
实验结果如下表所示：The experimental results are shown in the following table:
不同罗哌卡因制剂在小型猪术后镇痛模型中的药效持续时间(mean±SD,n＝6)Duration of efficacy of different ropivacaine preparations in postoperative analgesia model of miniature pigs (mean±SD, n=6)
试验样品Test sample 药效持续时间(h)Duration of drug efficacy (h)
0.5％盐酸罗哌卡因注射液0.5% ropivacaine hydrochloride injection 5.76±0.735.76±0.73
3％纳米尺寸化的罗哌卡因碱缓释注射液(实施例15)3% nanosized ropivacaine base sustained release injection (Example 15) 29.32±2.5429.32±2.54
3％罗哌卡因帕莫酸盐缓释注射液组(实施例21)3% ropivacaine pamoate sustained release injection group (Example 21) 12.67±3.1612.67±3.16
如上表所示，0.5％盐酸罗哌卡因注射液(给药剂量若与缓释制剂一样则会引起动物的严重毒性反应甚至死亡)的麻醉效果只持续了约6小时，而3％罗哌卡因帕莫酸盐缓释注射液和3％纳米尺寸化的罗哌卡因碱缓释注射液的麻醉维持时间显著长于0.5％盐酸罗哌卡因注射液。此外，在试验过程中，各实验组都未发现与给药相关的中枢毒性。对动物手术切口的肉眼观察和病理学检查表明，3个罗哌卡因受试药物组中动物手术切口仅有一定程度的炎症变化且与生理盐水组相当，表明罗哌卡因帕莫酸盐缓释注射液和纳米尺寸化的罗哌卡因碱缓释注射液具有很低的局部组织毒性，而且不会影响伤口的愈合。As shown in the above table, the anesthetic effect of 0.5% ropivacaine hydrochloride injection (the dose of the drug can cause severe toxicity or even death in animals as the sustained-release preparation) lasts only about 6 hours, while 3% ropera The anesthesia maintenance time of the kaempaol hydrochloride sustained-release injection and the 3% nanosized ropivacaine base sustained-release injection was significantly longer than 0.5% ropivacaine hydrochloride injection. In addition, no central toxicity associated with administration was found in each experimental group during the test. Visual observation and pathological examination of the surgical incision of the animals showed that the surgical incision of the three ropivacaine test groups had only a certain degree of inflammatory changes and was comparable to the saline group, indicating that ropivacaine pamoate Sustained-release injections and nanosized ropivacaine base sustained-release injections have low local tissue toxicity and do not affect wound healing.
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本领域技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明和范围的前提下本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。 The basic principles and main features of the present invention and the advantages of the present invention are shown and described above. It should be understood by those skilled in the art that the present invention is not limited by the foregoing embodiments, and that the present invention is described in the foregoing description and the description of the present invention. And improvements, such variations and modifications are intended to fall within the scope of the invention as claimed.

Claims (42)

  1. 一种S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶化合物晶体，其特征在于其粉末X-射线衍射图谱在2θ值为10.5±0.2°，13.0±0.2°，16.4±0.2°，19.0±0.2°，21.6±0.2°，23.4±0.2°，25.9±0.2°，26.3±0.2°，31.8±0.2°处有特征衍射峰。A crystal of S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine compound characterized by a powder X-ray diffraction pattern having a 2θ value of 10.5±0.2°, 13.0± Characteristic diffraction peaks at 0.2°, 16.4±0.2°, 19.0±0.2°, 21.6±0.2°, 23.4±0.2°, 25.9±0.2°, 26.3±0.2°, and 31.8±0.2°.
  2. 根据权利要求1所述的化合物晶体，其特征在于其粉末X-射线衍射图具有与图1类似图谱。The compound crystal according to claim 1, wherein the powder X-ray diffraction pattern has a map similar to that of FIG.
  3. 根据权利要求1所述的化合物晶体，其特征在于其DSC图具有与图2类似图谱。The compound crystal according to claim 1, wherein the DSC pattern has a map similar to that of FIG.
  4. 权利要求1～3任一项所述化合物晶体的制备方法，其包括：在约-5℃～约70℃温度下，从包含约0.02g/mL～约0.5g/mL的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的至少一种选自C1～C4醇、乙腈、甲酸C1～C4醇的酯、乙酸C1～C4醇的酯、四氢呋喃、丙酮、甲基异丁基酮、二氯甲烷、二氯乙烷的溶液中结晶得到所述晶体。A process for the preparation of a crystal of a compound according to any one of claims 1 to 3, which comprises from about 0.02 g/mL to about 0.5 g/mL of S-(-) at a temperature of from about -5 ° C to about 70 ° C. At least one of 1-propyl-2',6'-dimethylformylformylpiperidine is selected from the group consisting of C1-C4 alcohols, acetonitrile, esters of C1-C4 alcohols, esters of C1-C4 alcohols, tetrahydrofuran, The crystal is obtained by crystallization from a solution of acetone, methyl isobutyl ketone, dichloromethane or dichloroethane.
  5. 权利要求1～3任一项所述化合物晶体的制备方法，其包括：在约-5℃～约70℃温度下，向包含约0.02g/mL～约0.5g/mL的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的至少一种选自C1～C4醇、乙腈、甲酸C1～C4醇的酯、乙酸C1～C4醇的酯、四氢呋喃、丙酮、甲基异丁基酮、二氯甲烷、二氯乙烷的溶液中，滴加选自C5-8烷烃、C5-6醚、石油醚、水中一种或多种溶剂后结晶得到所述晶体。A process for the preparation of a crystal of a compound according to any one of claims 1 to 3, which comprises, at a temperature of from about -5 ° C to about 70 ° C, to an S-(-) comprising from about 0.02 g/mL to about 0.5 g/mL. At least one of 1-propyl-2',6'-dimethylformylformylpiperidine is selected from the group consisting of C1-C4 alcohols, acetonitrile, esters of C1-C4 alcohols, esters of C1-C4 alcohols, tetrahydrofuran, In a solution of acetone, methyl isobutyl ketone, dichloromethane, or dichloroethane, one or more solvents selected from the group consisting of C 5-8 alkane, C 5-6 ether, petroleum ether, and water are added dropwise and crystallized. The crystal.
  6. 根据权利要求4或5所述的方法，其特征在于所述C5-8烷烃选自戊烷、己烷、庚烷或辛烷中的一种或多种。Process according to claim 4 or 5, characterized in that the C 5-8 alkane is selected from one or more of pentane, hexane, heptane or octane.
  7. 根据权利要求4或5所述的方法，其特征在于所述C5-6醚为异丙醚或甲基叔丁基醚。Process according to claim 4 or 5, characterized in that the C 5-6 ether is isopropyl ether or methyl tert-butyl ether.
  8. 权利要求1～3任一项所述化合物的无菌混悬液形式的控释注射制剂，其在注射后，在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，该制剂包括：A controlled release injection formulation in the form of a sterile suspension of a compound according to any one of claims 1 to 3 which, after injection, releases S-(-)-1-propyl-2' over a period of at least 12 h, 6'-Dimethylformylpiperidine, the formulation comprising:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，(a) S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (b)载体，和(b) a carrier, and
    (c)用于注射的水。(c) Water for injection.
  9. 权利要求8所述的制剂，其中所述载体包括一种或多种表面活性剂。The formulation of claim 8 wherein the carrier comprises one or more surfactants.
  10. 权利要求9所述的制剂，其中所述载体还包括助悬剂。The formulation of claim 9 wherein the carrier further comprises a suspending agent.
  11. 无菌混悬液形式的控释S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶注射制剂，其在注射后，在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，该制剂包括：A controlled release S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine injection formulation in the form of a sterile suspension which, after injection, releases S- during a period of at least 12 h (-)-1-propyl-2',6'-dimethylformylpiperidine, the formulation comprising:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，(a) S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (b)载体，所述载体包括： (b) a carrier comprising:
    (1)一种或多种表面活性剂，(1) one or more surfactants,
    (2)任选地，一种或多种助悬剂，(2) optionally, one or more suspending agents,
    (3)任选地，一种或多种填充剂，(3) optionally, one or more fillers,
    (4)任选地，一种或多种防腐剂，(4) optionally, one or more preservatives,
    (5)任选地，一种或多种等渗调节剂(5) optionally, one or more isotonicity adjusting agents
    (6)任选地，一种或多种缓冲剂，以及(6) optionally, one or more buffers, and
    (c)用于注射的水。(c) Water for injection.
  12. 权利要求11所述的制剂，进一步包括pH调节剂。The formulation of claim 11 further comprising a pH adjusting agent.
  13. 权利要求11所述的制剂，所述混悬液含有平均粒度在0.1至100微米范围内的固体。The formulation of claim 11 which contains a solid having an average particle size in the range of from 0.1 to 100 microns.
  14. 权利要求13所述的制剂，其为无菌混悬液形式，所述混悬液含有平均粒度在0.1至50微米范围内的固体。The formulation of claim 13 in the form of a sterile suspension comprising a solid having an average particle size in the range of from 0.1 to 50 microns.
  15. 权利要求14所述的制剂，其中所述固体的平均粒度为0.1至20微米。The formulation of claim 14 wherein said solid has an average particle size of from 0.1 to 20 microns.
  16. 权利要求11～15任一项所述的制剂，其被设计为在8h至72h的时间期间，以被控制的速率释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶。A formulation according to any one of claims 11 to 15 which is designed to release S-(-)-1-propyl-2',6'-dimethyl at a controlled rate over a period of from 8 h to 72 h. Benziyl piperidine.
  17. 权利要求11-15任一项所述的制剂，其为混悬液形式，其中各组份的重量百分含量为：A formulation according to any one of claims 11 to 15 in the form of a suspension wherein the weight percent of each component is:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶1％～40％，优选2％～20％，进一步优选2％～8％；(a) S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine 1% to 40%, preferably 2% to 20%, more preferably 2% to 8%;
    (b)助悬剂0.05％～20％，优选0.1％～5％，进一步优选0.1～2％；(b) a suspending agent of 0.05% to 20%, preferably 0.1% to 5%, further preferably 0.1 to 2%;
    (c)表面活性剂0.01％～20％，优选0.02％～5％，进一步优选0.02～2％；(c) a surfactant of 0.01% to 20%, preferably 0.02% to 5%, further preferably 0.02 to 2%;
    (d)缓冲剂0.02％～2％，优选0.03％～1％，进一步优选0.1～1％，以调节混悬液的pH值在6至8.5的范围内。(d) The buffer is 0.02% to 2%, preferably 0.03% to 1%, more preferably 0.1% to 1%, to adjust the pH of the suspension to be in the range of 6 to 8.5.
  18. 权利要求11～15任一项所述的制剂，其中所述助悬剂选自羧甲基纤维素或其钠盐、羟丙基纤维素、甲基纤维素、羟乙基纤维素、羟丙基甲基纤维素、透明质酸钠和聚乙烯吡咯烷酮，优选羧甲基纤维素钠和聚乙烯基吡咯烷酮；所述表面活性剂选自聚山梨酯20(吐温-20)、聚山梨酯40(吐温-40)、聚山梨酯60(吐温-60)、聚山梨酯65(吐温-65)、聚山梨酯80(吐温-80)、聚山梨酯85(吐温-85)、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、卵磷脂、聚乙烯吡咯烷酮、聚乙二醇类、聚氧乙烯与聚氧丙烯醚类(泊洛沙姆188和泊洛沙姆407等)、15-羟基硬脂酸聚乙二醇酯，优选吐温-20、吐温-80、15-羟基硬脂酸聚乙二醇酯和泊洛沙姆188；所述填充剂选自甘露醇、蔗糖、麦芽糖、木糖醇、乳糖、葡萄糖、 淀粉、山梨醇或其类似物，优选甘露醇和蔗糖；所述防腐剂选自苯甲酸、苯甲醇、丁基化羟基甲苯醚、丁基化羟基甲苯、氯丁醇、没食子酸酯、羟基苯甲酸酯、EDTA、酚、氯甲酚、间甲酚、氯化苄乙氧铵、氯化肉豆蔻基-γ-甲基吡啶、苯基乙酸汞、硫柳汞，优选苯甲醇和羟基苯甲酸酯；所述等渗调节剂选自甘露醇、山梨醇、氯化钠、葡萄糖、蔗糖、果糖、乳糖，优选甘露醇、氯化钠和葡萄糖；所述缓冲剂选自磷酸盐、醋酸盐、枸橼酸盐或TRIS缓冲液，优选磷酸盐。The preparation according to any one of claims 11 to 15, wherein the suspending agent is selected from the group consisting of carboxymethylcellulose or a sodium salt thereof, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl Methylcellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose and polyvinylpyrrolidone; the surfactant is selected from the group consisting of polysorbate 20 (Tween-20), polysorbate 40 (Tween-40), Polysorbate 60 (Tween-60), Polysorbate 65 (Tween-65), Polysorbate 80 (Tween-80), Polysorbate 85 (Tween-85) , polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188 and poloxamer 407, etc.), Polyethylene glycol 15-hydroxystearate, preferably Tween-20, Tween-80, 15-hydroxystearate polyethylene glycol ester and poloxamer 188; the filler is selected from the group consisting of mannitol and sucrose , maltose, xylitol, lactose, glucose, Starch, sorbitol or the like, preferably mannitol and sucrose; the preservative is selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxytoluene ether, butylated hydroxytoluene, chlorobutanol, gallic acid ester, hydroxybenzoic acid Acid ester, EDTA, phenol, chlorocresol, m-cresol, benzethonium chloride, chlorinated myristyl-gamma-methylpyridine, phenylacetic acid mercury, thimerosal, preferably benzyl alcohol and hydroxybenzoate The isotonicity adjusting agent is selected from the group consisting of mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose, lactose, preferably mannitol, sodium chloride and glucose; the buffer is selected from the group consisting of phosphates, acetates, A citrate or TRIS buffer, preferably a phosphate.
  19. 权利要求11～15任一项所述的制剂，其在注射后，在12h至72h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，该制剂包括：A formulation according to any one of claims 11 to 15 which, after injection, releases S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine during a period of from 12 h to 72 h , the formulation includes:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，(a) S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (b)羧甲基纤维素或其钠盐，(b) carboxymethylcellulose or a sodium salt thereof,
    (c)吐温80，(c) Tween 80,
    (d)磷酸盐，以调节pH为6～8.5，(d) Phosphate to adjust the pH to 6-8.5,
    (e)任选地，氢氧化钠，以调节pH为6～8.5，和(e) optionally, sodium hydroxide to adjust the pH to 6 to 8.5, and
    (f)用于注射的水。(f) Water for injection.
  20. 权利要求19所述的制剂，包括以下比例的组分：The formulation of claim 19 comprising the following proportions of components:
    Figure PCTCN2016097784-appb-100001
    Figure PCTCN2016097784-appb-100001
  21. 权利要求11～15任一项所述的制剂，其每1ml混悬液含10至400mg以游离碱计的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶。The preparation according to any one of claims 11 to 15, which contains 10 to 400 mg of S-(-)-1-propyl-2',6'-dimethylaminoformyl group as a free base per 1 ml of the suspension. Piperidine.
  22. 权利要求8～21所述的制剂，其活性组分是S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的水难溶性盐。The preparation according to any one of claims 8 to 21, wherein the active ingredient is a water-insoluble salt of S-(-)-1-propyl-2',6'-dimethylaminoformyl piperidine.
  23. 权利要求22所述的制剂，其中所述水难溶性盐是S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶与有机酸所形成的难溶性化合物，优选与C8～C22的长链脂肪酸、胆酸、脱氧胆酸、苯甲酸、双氯芬酸和帕莫酸等形成的水难溶性盐，所述长链脂肪酸进一步优选自辛酸、癸酸、肉豆蔻酸、棕榈酸、硬脂酸和油酸。The preparation according to claim 22, wherein said poorly water-soluble salt is a poorly soluble compound formed by S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine and an organic acid. It is preferably a poorly water-soluble salt formed with a long-chain fatty acid of C8 to C22, cholic acid, deoxycholic acid, benzoic acid, diclofenac, and palmitic acid, and the long-chain fatty acid is further preferably derived from caprylic acid, capric acid, myristic acid, Palmitic acid, stearic acid and oleic acid.
  24. 权利要求23所述的水难溶性盐的制备方法，其包括以下步骤：A method of producing a poorly water-soluble salt according to claim 23, which comprises the steps of:
    (a)将S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶与相应的有机酸溶解于适宜的溶剂中搅 拌反应成盐，(a) dissolving S-(-)-1-propyl-2',6'-dimethylformylpiperidine and the corresponding organic acid in a suitable solvent Mix and react into salt,
    (b)将反应产物通过重结晶进行纯化得到S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的水难溶性盐。(b) The reaction product is purified by recrystallization to obtain a water-insoluble salt of S-(-)-1-propyl-2',6'-dimethylformyl-piperidine.
  25. 权利要求1～3任一项所述化合物晶体的无菌冻干控释制剂，其包括：A sterile lyophilized controlled release formulation of a compound according to any one of claims 1 to 3, which comprises:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，和(a) S-(-)-1-propyl-2',6'-dimethylformylpiperidine, and
    (b)载体，(b) carrier,
    其中所述制剂在与水组合后，形成无菌注射制剂，在注射后，所述无菌注射制剂在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶。Wherein the formulation, when combined with water, forms a sterile injectable preparation which, after injection, releases S-(-)-1-propyl-2',6'- during a period of at least 12 h. Xylylformyl piperidine.
  26. 权利要求25所述的冻干控释制剂，其平均粒度在0.1至20微米范围内，当与水组合用于注射后，在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶。The lyophilized controlled release formulation of claim 25 having an average particle size in the range of from 0.1 to 20 microns and which, when combined with water for injection, releases S-(-)-1-propyl- during a period of at least 12 hours. 2',6'-xylyleneformyl piperidine.
  27. 权利要求26所述的冻干控释制剂，其平均粒度是0.2-20微米。The lyophilized controlled release formulation of claim 26 having an average particle size of from 0.2 to 20 microns.
  28. 权利要求25所述的冻干控释制剂，其中所述载体包括：The lyophilized controlled release preparation of claim 25, wherein the carrier comprises:
    (1)一种或多种助悬剂，(1) one or more suspending agents,
    (2)一种或多种表面活性剂，和(2) one or more surfactants, and
    (3)一种或多种填充剂。(3) One or more fillers.
    (4)一种或多种缓冲剂。(4) One or more buffers.
  29. 权利要求28所述的冻干控释制剂，进一步包括pH调节剂。The lyophilized controlled release formulation of claim 28, further comprising a pH adjusting agent.
  30. 权利要求28所述的冻干控释制剂，当与水组合并注射后，在至少12h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，该制剂包括：The lyophilized controlled release formulation of claim 28, when combined with water and injected, releases S-(-)-1-propyl-2',6'-dimethylaminoformylperidine over a period of at least 12 hours Pyridine, the formulation includes:
    (a)S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，(a) S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (b)羧甲基纤维素或其钠盐，(b) carboxymethylcellulose or a sodium salt thereof,
    (c)吐温80，(c) Tween 80,
    (d)甘露醇，(d) mannitol,
    (e)磷酸盐以调节pH为6～8.5，和(e) phosphate to adjust the pH to 6 to 8.5, and
    (f)任选地，氢氧化钠以调节pH为6～8.5。(f) Optionally, sodium hydroxide is adjusted to a pH of from 6 to 8.5.
  31. 权利要求30所述的冻干控释制剂，当与水重新组合并注射后，在12～72h的时间期间释放S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶。The lyophilized controlled release preparation of claim 30 which, when recombined with water and injected, releases S-(-)-1-propyl-2',6'-dimethylaniline during a period of from 12 to 72 hours Acyl piperidine.
  32. 权利要求25～31所述的冻干控释制剂，其活性组分是S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶或其水难溶性盐。The lyophilized controlled release preparation according to Claims 25 to 31, wherein the active ingredient is S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine or a poorly water-soluble salt thereof.
  33. 制备权利要求25～32所述的无菌冻干控释制剂的方法，该方法包括下列步骤： A method of preparing the sterile lyophilized controlled release formulation of claims 25-32, the method comprising the steps of:
    (a)制备无菌的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶，(a) Preparation of sterile S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (b)制备用于该无菌S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的无菌载体，(b) preparing a sterile carrier for the sterile S-(-)-1-propyl-2',6'-dimethylformylpiperidine,
    (c)使所述无菌S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶和所述无菌载体组合，形成包括无菌的固体混合物的无菌初步混悬液，(c) combining the sterile S-(-)-1-propyl-2',6'-dimethylformylformylpiperidine and the sterile carrier to form a sterile comprising a sterile solid mixture Preliminary suspension,
    (d)使所述无菌初步混悬液中的所述无菌固体混合物的平均粒度降低到0.1至10～20微米范围内，形成无菌最终混悬液，和(d) reducing the average particle size of the sterile solid mixture in the sterile preliminary suspension to a range of from 0.1 to 10 to 20 microns to form a sterile final suspension, and
    (e)冻干所述无菌最终混悬液，形成冻干制剂。(e) lyophilizing the sterile final suspension to form a lyophilized formulation.
  34. 权利要求33所述的方法，其中制备无菌的S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的步骤是用无菌生产工艺、干热灭菌、高压蒸汽灭菌或者辐照灭菌实施的。The method of claim 33, wherein the step of preparing sterile S-(-)-1-propyl-2',6'-dimethylformylpiperidine is performed by an aseptic manufacturing process, dry heat sterilization , autoclaved or irradiated sterilization.
  35. 权利要求33所述的方法，其中制备无菌S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶的无菌载体的步骤是用过滤除菌或高压蒸汽灭菌实施的。The method of claim 33, wherein the step of preparing a sterile carrier of sterile S-(-)-1-propyl-2',6'-dimethylformylpiperidine is by filtration sterilization or high pressure steam Sterilized implementation.
  36. 权利要求33所述的方法，其中降低所述无菌初步悬浮液中的无菌固体混合物的平均粒度的步骤是用湿磨法、微射流法或高压均质法实施的。The method of claim 33 wherein the step of reducing the average particle size of the sterile solid mixture in the sterile preliminary suspension is carried out by wet milling, microfluidization or high pressure homogenization.
  37. 权利要求36所述的方法，其中所述湿磨法包括湿球磨，其中所述的高压均质法包括高压均质机。The method of claim 36 wherein said wet milling comprises wet ball milling, and wherein said high pressure homogenizing process comprises a high pressure homogenizer.
  38. 权利要求33所述的方法，其中所述冻干步骤是通过冷却所述无菌最终混悬液至大约-40℃并在低于大约0℃干燥所述冷却的无菌最终混悬液来实施的，从而形成S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶冻干制剂。The method of claim 33, wherein said lyophilizing step is carried out by cooling said sterile final suspension to about -40 ° C and drying said cooled sterile final suspension below about 0 ° C. To form a lyophilized formulation of S-(-)-1-propyl-2',6'-dimethylformylformyl piperidine.
  39. 权利要求33所述的方法，其中所述无菌最终混悬液的冻干步骤是以三个阶段实施的：(1)冷冻阶段，包括在大约-40℃冷却无菌最终混悬液，(2)初步干燥阶段，在低于大约0℃进行，和(3)二次干燥阶段，在高于大约0℃进行，从而形成S-(-)-1-丙基-2',6'-二甲苯胺甲酰基哌啶混悬液的冻干形式。30. The method of claim 33, wherein the lyophilization step of the sterile final suspension is carried out in three stages: (1) a freezing stage comprising cooling the sterile final suspension at about -40 ° C, ( 2) preliminary drying stage, carried out below about 0 ° C, and (3) secondary drying stage, above about 0 ° C, to form S-(-)-1-propyl-2',6'- A lyophilized form of a xylylformylpiperidine suspension.
  40. 权利要求8～32任一项所述制剂在制备镇痛药物中的用途。Use of a formulation according to any one of claims 8 to 32 for the preparation of an analgesic medicament.
  41. 权利要求40所述的用途，所述镇痛药物为医疗手术前、后或手术中施用的镇痛药物。The use according to claim 40, wherein the analgesic drug is an analgesic drug administered before, after or during a medical operation.
  42. 权利要求40所述的用途，所述镇痛药物为经皮下、皮内或肌肉注射给予的药物。 The use according to claim 40, wherein the analgesic drug is a drug administered subcutaneously, intradermally or intramuscularly.
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CN114522145A (en) * 2021-11-02 2022-05-24 浙江仙琚萃泽医药科技有限公司 Method for producing ropivacaine powder formulations and ropivacaine powder formulations obtained thereby

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