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WO2017036408A1 - Cristal de s-(-)-1-propyl-2',6'-aminoxylèneformylpipéridine et préparation à libération prolongée associée - Google Patents

Cristal de s-(-)-1-propyl-2',6'-aminoxylèneformylpipéridine et préparation à libération prolongée associée Download PDF

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Publication number
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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Prior art keywords
propyl
sterile
ropivacaine
formulation
suspension
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English (en)
Chinese (zh)
Inventor
叶强
严庞科
冯卫
万华
张轩邈
汪东海
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN201680037141.8A priority Critical patent/CN107848973A/zh
Publication of WO2017036408A1 publication Critical patent/WO2017036408A1/fr
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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 Picocaine 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

L'invention concerne un anesthésique local du type amidique à efficacité durable, le cristal de S-(-)-1-propyl-2',6'-aminoxylèneformylpipéridine, une préparation à libération prolongée associée, et leur procédé de préparation. Par rapport à une préparation de chlorhydrate existante, la préparation réalisée avec le cristal permet une libération continue et lente du médicament particulièrement bonne, le maintien d'une concentration du médicament dans le sang efficace, et présente un effet antalgique local durable excellent.
PCT/CN2016/097784 2015-09-01 2016-09-01 Cristal de s-(-)-1-propyl-2',6'-aminoxylèneformylpipéridine et préparation à libération prolongée associée Ceased WO2017036408A1 (fr)

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CN109134352A (zh) * 2018-09-21 2019-01-04 合肥锐思生物医药有限公司 一种制备难溶性复合物或其溶剂合物的方法
EP3331516A4 (fr) * 2015-07-13 2019-06-26 Neon Laboratories Ltd. Solution d'injection hyperbare de chlorhydrate de ropivacaïne et procédé pour la préparation de celle-ci
CN109996787A (zh) * 2017-03-27 2019-07-09 合肥合源药业有限公司 难溶性复合物或其溶剂合物、药物组合物及其应用
CN110935024A (zh) * 2018-09-21 2020-03-31 合肥合源药业有限公司 长效组合物
CN110934868A (zh) * 2018-09-21 2020-03-31 合肥合源药业有限公司 难溶性复合物、药物组合物及其应用
CN114504552A (zh) * 2021-11-02 2022-05-17 浙江仙琚萃泽医药科技有限公司 制备罗哌卡因混悬注射液和粉末制剂的方法以及由此获得的罗哌卡因混悬注射液和粉末制剂
CN114522141A (zh) * 2021-04-08 2022-05-24 浙江仙琚萃泽医药科技有限公司 一种罗哌卡因混悬注射液及其制备方法
CN114522145A (zh) * 2021-11-02 2022-05-24 浙江仙琚萃泽医药科技有限公司 制备罗哌卡因粉末制剂的方法以及由此获得的罗哌卡因粉末制剂
CN117959252A (zh) * 2023-07-27 2024-05-03 南京清普生物科技有限公司 罗哌卡因或其药学上可接受的盐的组合物及其用途

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EP3331516A4 (fr) * 2015-07-13 2019-06-26 Neon Laboratories Ltd. Solution d'injection hyperbare de chlorhydrate de ropivacaïne et procédé pour la préparation de celle-ci
JP2020515513A (ja) * 2017-03-27 2020-05-28 フルーティー ホールディングス リミテッドＦｒｕｉｔｈｙ Ｈｏｌｄｉｎｇｓ Ｌｉｍｉｔｅｄ 難溶性複合物又はその溶媒和物、薬物組成物及びその応用
KR102248445B1 (ko) 2017-03-27 2021-05-04 프루티 홀딩스 리미티드 불용성 착물 또는 이의 용매화물, 약제학적 조성물 및 이의 용도
KR20190101980A (ko) * 2017-03-27 2019-09-02 프루티 홀딩스 리미티드 불용성 착물 또는 이의 용매화물, 약제학적 조성물 및 이의 용도
CN109996787B (zh) * 2017-03-27 2022-07-05 合肥合源药业有限公司 难溶性复合物或其溶剂合物、药物组合物及其应用
CN109996787A (zh) * 2017-03-27 2019-07-09 合肥合源药业有限公司 难溶性复合物或其溶剂合物、药物组合物及其应用
CN110934868A (zh) * 2018-09-21 2020-03-31 合肥合源药业有限公司 难溶性复合物、药物组合物及其应用
CN109134352A (zh) * 2018-09-21 2019-01-04 合肥锐思生物医药有限公司 一种制备难溶性复合物或其溶剂合物的方法
CN110935024A (zh) * 2018-09-21 2020-03-31 合肥合源药业有限公司 长效组合物
CN110935024B (zh) * 2018-09-21 2023-08-08 合肥合源药业有限公司 长效组合物
CN114522141A (zh) * 2021-04-08 2022-05-24 浙江仙琚萃泽医药科技有限公司 一种罗哌卡因混悬注射液及其制备方法
CN114504552A (zh) * 2021-11-02 2022-05-17 浙江仙琚萃泽医药科技有限公司 制备罗哌卡因混悬注射液和粉末制剂的方法以及由此获得的罗哌卡因混悬注射液和粉末制剂
CN114522145A (zh) * 2021-11-02 2022-05-24 浙江仙琚萃泽医药科技有限公司 制备罗哌卡因粉末制剂的方法以及由此获得的罗哌卡因粉末制剂
CN117959252A (zh) * 2023-07-27 2024-05-03 南京清普生物科技有限公司 罗哌卡因或其药学上可接受的盐的组合物及其用途
WO2025021176A1 (fr) * 2023-07-27 2025-01-30 南京清普生物科技有限公司 Composition de ropivacaïne ou de sel pharmaceutiquement acceptable de ropivacaïne, et utilisation de la composition

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