WO2022160970A1 - Solution concentrée de médicament insoluble ne contenant pas d'éthanol, et solution micellaire préparée à partir de celle-ci - Google Patents

Solution concentrée de médicament insoluble ne contenant pas d'éthanol, et solution micellaire préparée à partir de celle-ci Download PDF

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WO2022160970A1
WO2022160970A1 PCT/CN2021/137169 CN2021137169W WO2022160970A1 WO 2022160970 A1 WO2022160970 A1 WO 2022160970A1 CN 2021137169 W CN2021137169 W CN 2021137169W WO 2022160970 A1 WO2022160970 A1 WO 2022160970A1
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weight percentage
weight
phospholipid
cosolvent
emulsifier
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English (en)
Chinese (zh)
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吴翠栓
程晓波
张丹
侯继祥
赵博册
张强
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北京德立福瑞医药科技有限公司
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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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K9/0012—Galenical forms characterised by the site of application
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    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention belongs to the field of pharmaceutical preparations. Specifically, the present invention relates to an ethanol-free insoluble drug concentrate and a preparation method thereof, and also relates to a micelle solution prepared from the concentrate.
  • ethanol is widely used in injections.
  • docetaxel injection contains 13% absolute ethanol
  • hydrocortisone injection contains 50% ethanol
  • hydrocortisone acetate injection (alcohol type) contains 50% ethanol
  • a cardiovascular and cerebrovascular drug 10% ethanol in deacetyl elixir injection, 10% (V/V) ethanol in digoxigenin injection, and 20% (V/V) in nimodipine injection ) ethanol, nitroglycerin injection, diazepam injection, pyrithione hydrochloride injection, and Shuxuening injection also all use 95% ethanol as an excipient
  • antibacterial drugs azithromycin injection, azithromycin sodium chloride injection
  • Amphotericin B liposome for injection and voriconazole for injection also contain ethanol
  • an immunosuppressive drug tacrolimus injection contains 638 mg of ethanol per milli
  • ethanol is also widely used in preparations for oral administration of poorly soluble drugs.
  • Huoxiangzhengqi Shui contains 40%-50% ethanol; Ten Drops of Water contains 60%-70% ethanol; Compound Licorice Oral Solution contains Licorice Liquid Extract and Compound Camphor tincture; Cold Cough Syrup contains Licorice Liquid Extract and Orange Skin tincture; cyclosporine oral solution and levocarnitine oral solution contain a small amount of ethanol; digoxin oral solution contains 9%-11% ethanol; ergocryptine caffeine oral solution contains 5.8% (v/v) ethanol .
  • the following medicines also contain ethanol: ketorolac tromethamine tablets/capsules, nitroglycerin aerosol, albuterol aerosol, clenbuterol hydrochloride aerosol, musk pain reliever aerosol (the amount of ethanol is 47%-57%), wide chest aerosol (27% (ml/g)-42% (ml/g) of ethanol), isosorbide nitrate spray (containing 90% ethanol), Gutongling tincture (The amount of ethanol is 45%-55%), the swelling and pain-relieving tincture (the amount of ethanol is 47%-57%), the tincture of eliminating wounds and swelling (the amount of ethanol is 50%-60%), the burning spirit tincture (the amount of ethanol is 70%) %-75%), Jintongxiao tincture (50%-60% ethanol), compound camphor tincture (52%-60% ethanol), belladonna tincture (60%-70% ethanol), ginger Tincture (80%-88% ethanol), Polygala tincture (5
  • ethanol-containing preparations in prescriptions especially injections, often have adverse effects after administration. For example, they have strong vascular irritants, and are likely to cause pain at the injection site when injected into blood vessels, and repeated injections are also likely to cause Phlebitis; in addition, ethanol has an impact on the nervous system, resulting in muscle incoordination, unresponsiveness, inattention, decreased self-control, memory loss, mental decline, etc. Ethanol can also damage the liver and stimulate the stomach. .
  • the preparations containing ethanol in prescriptions cannot be used for patients with ethanol allergy, resulting in limited medication for these patients.
  • One of the objectives of the present invention is to provide an ethanol-free insoluble drug concentrate, which avoids the above-mentioned side effects caused by ethanol, and provides a safer choice for the clinical application of insoluble drugs.
  • a clinically applicable dose of poorly soluble drugs can be prepared into a stable composition by using a specific compound emulsifier and a co-emulsifier, and the composition can achieve good performance on poorly soluble drugs.
  • Dissolved which is a concentrate, is a uniform and transparent solution, and the preparation process is extremely simple.
  • the composition of the present invention can be diluted with an aqueous solvent to form a micellar solution immediately before use, and the formed micellar solution can be directly used for administration to patients, which is convenient for administration and has excellent stability.
  • the aqueous vehicle may be an aqueous vehicle suitable for injection (eg, water for injection, 5% dextrose injection, 0.9% sodium chloride injection, etc.) or an aqueous vehicle suitable for oral administration (eg, purified water, etc.).
  • an aqueous vehicle suitable for injection eg, water for injection, 5% dextrose injection, 0.9% sodium chloride injection, etc.
  • an aqueous vehicle suitable for oral administration eg, purified water, etc.
  • the micellar solution obtained by diluting the composition of the present invention fully meets the requirements of intravenous injection and can be administered by intravenous injection.
  • the concentrated solution of the present invention not only has excellent stability, but also contains fewer kinds of excipients, has a simple preparation process, and is suitable for various insoluble drugs.
  • the micellar solution obtained by diluting the concentrated solution of the present invention can smoothly realize the administration of poorly soluble drugs, especially the injection administration, and satisfies the currently unmet clinical needs.
  • the purpose of the present invention is to provide an ethanol-free insoluble drug concentrate, and to provide a simple, environmentally friendly and easy-to-industrial method for preparing the concentrate.
  • the purpose of the present invention is to provide a micellar solution, which can smoothly realize the administration of poorly soluble drugs, especially the injection administration.
  • the present invention provides an ethanol-free insoluble drug concentrate, characterized in that the concentrate contains a poorly soluble drug and a carrier that helps to form micelles, and the carrier is emulsified by complex agent and cosolvent, wherein the composite emulsifier is composed of phospholipid and non-phospholipid emulsifier, and the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixtures, more preferably selected from propylene glycol, PEG200, PEG300 , PEG400 and their mixtures, and the concentrate is oil-free.
  • the phospholipid is preferably selected from soybean lecithin, egg yolk lecithin and mixtures thereof, more preferably egg yolk lecithin.
  • Described non-phospholipid emulsifier is preferably selected from polyoxyethylene castor oil (for example, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (for example, polyoxyethylene 40 hydrogenated castor oil). , polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate (such as polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof.
  • polyoxyethylene castor oil for example, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil
  • polyoxyethylene hydrogenated castor oil for example, polyoxyethylene 40 hydrogenated castor oil
  • polyoxyethylene 60 hydrogenated castor oil polyoxyethylene 60 hydrogenated castor oil
  • polyethylene glycol 15-hydroxystearate for example, vitamin E polyethylene glycol 1000 succinate (TPGS)
  • TPGS vitamin E polyethylene glycol 1000 succinate
  • described non-phospholipid emulsifier is selected from polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, 15-hydroxystearate polyethylene glycol ester, polyoxyethylene 35 castor oil Sorbitan 80 and their mixtures.
  • the weight percentage of the poorly soluble drug is 0.1% to 100% by weight. 20%, preferably 0.5% to 15%, such as 0.5%, 1%, 1.5%, 2%, 5%, 6%, 10%, 15%; the weight percentage of the phospholipid is 0.1% to 20%, preferably 0.5% % ⁇ 10%, such as 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%; the weight percentage of the non-phospholipid emulsifier is 20% ⁇ 80%, preferably 30% ⁇ 70%, such as 30%, 35%, 40%, 43%, 46%, 48%, 50%, 70%; the balance is cosolvent.
  • the concentrated solution of the present invention can only be composed of a poorly soluble drug and a carrier that helps to form micelles
  • the carrier is composed of a complex emulsifier and a cosolvent, wherein the complex emulsifier is composed of a phospholipid and a non-phospholipid emulsifier, so
  • the co-solvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and mixtures thereof, preferably selected from propylene glycol, PEG200, PEG300, PEG400 and mixtures thereof, and the concentrate is oil-free.
  • the concentrates of the present invention may further contain pH adjusters and/or antioxidants.
  • pH adjusters and/or antioxidants can be selected from citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, One or more of phosphates such as sodium monohydrogen phosphate, sodium dihydrogen phosphate or sodium phosphate.
  • the antioxidant can be selected from ⁇ -tocopherol succinate ( ⁇ -tocopherol succinate), ascorbyl palmitate (ascorbyl palmitate), butylated hydroxyanisole (BHA), butylated hydroxytoluene ( one or more of butylated hydroxytoluene, BHT).
  • oil is for example: vegetable oil, such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, sunflower oil, cottonseed oil, camellia oil, etc.; animal oil, such as fish oil, Egg yolk oil, lanolin, etc.; Mineral oils, such as liquid paraffin, etc.; Natural or synthetic triglycerides, such as medium-chain triglycerides (MCT), long-chain triglycerides (LCT), structured oils, etc.; and others known grease.
  • MCT medium-chain triglycerides
  • LCT long-chain triglycerides
  • the present invention provides a method for preparing the ethanol-free insoluble drug concentrate, characterized in that the method comprises the steps of: mixing the insoluble drug, phospholipids, non-phospholipid emulsifiers and auxiliary substances Solvents are mixed in any order, stirred well, filtered, and sealed in aliquots.
  • the present invention provides a micellar solution obtained by diluting the ethanol-free poorly soluble drug concentrate described above with an aqueous vehicle.
  • the obtained micellar solution is uniform and transparent in appearance, and can be used for injection administration.
  • the present invention provides the use of the ethanol-free, poorly soluble drug concentrate described above in the preparation of a micellar solution.
  • the micellar solution is especially useful for intravenous injection.
  • FIG. 1 is a microscopic observation of a representative HE-stained section of a rabbit ear of a rabbit administered 5% glucose injection.
  • Figure 2 shows the results of microscope observation of representative HE-stained sections of rabbit ears of rabbits administered with commercially available nimodipine injection.
  • FIG. 3 is a microscope observation result of a representative HE-stained section of a rabbit ear of a rabbit administered the nimodipine injection of the present invention.
  • Embodiment 1 An ethanol-free insoluble drug concentrate, characterized in that the concentrate comprises a poorly soluble drug and a carrier that helps to form micelles, wherein:
  • the carrier is composed of a composite emulsifier and a cosolvent
  • the complex emulsifier is composed of phospholipids and non-phospholipid emulsifiers, and the phospholipids are selected from soybean lecithin, egg yolk lecithin and their mixtures,
  • Described cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixtures, preferably is selected from propylene glycol, PEG200, PEG300, PEG400 and their mixtures,
  • Embodiment 2 The concentrate of embodiment 1, wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene castor oil (eg, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil), polyoxyethylene castor oil Ethylene hydrogenated castor oil (eg polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), poly Sorbates (eg polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof.
  • polyoxyethylene castor oil eg, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil
  • polyoxyethylene castor oil Ethylene hydrogenated castor oil eg polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil
  • polyethylene glycol 15-hydroxystearate vitamin E polyethylene glycol 1000 succinate (TPGS)
  • Embodiment 3 The concentrate according to Embodiment 2, wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, 15- Polyethylene glycol hydroxystearate, polysorbate 80 and mixtures thereof.
  • the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, 15- Polyethylene glycol hydroxystearate, polysorbate 80 and mixtures thereof.
  • Embodiment 4 The concentrate of any one of Embodiments 1 to 3, wherein the co-solvent is selected from the group consisting of propylene glycol, PEG300, PEG400, and mixtures thereof.
  • Embodiment 5 The concentrate according to any one of Embodiments 1 to 4, wherein when the weight of the poorly soluble drug, the complex emulsifier, and the co-solvent is summed to 100 wt %, the wt % of the poorly soluble drug is 0.1% to 20%, preferably 0.5% to 15%; the weight percentage of the phospholipid is 0.1% to 20%, preferably 0.5% to 10%; the weight percentage of the non-phospholipid emulsifier is 20% to 80%, It is preferably 30% to 70%; the balance is cosolvent.
  • Embodiment 6 The composition of any one of embodiments 1 to 5, wherein the poorly soluble drug is selected from the group consisting of celecoxib, valdecoxib, etocoxib , ibuprofen, dexibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate , dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporin, tacrolimus tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole (itraconazole), voriconazole, miconazole, ketoconazole, progesterone, Coenzyme Q10, clopidogrel, paclitaxel, docetaxel docetaxel, cabazitax
  • Embodiment 7 The concentrate of any one of Embodiments 1 to 6, further comprising a pH adjuster, an antioxidant, or both.
  • Embodiment 8 The composition of any one of Embodiments 1 to 6, wherein:
  • the insoluble drug is nimodipine
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of nimodipine is 1%
  • the weight percentage of egg yolk lecithin is 2%
  • the 15-hydroxystearic acid polyethylene glycol is The weight percentage of ester is 46%
  • the weight percentage of propylene glycol is 51%;
  • the insoluble drug is posaconazole
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is PEG300
  • the weight percentage of posaconazole is 1%
  • the weight percentage of egg yolk lecithin is 3%
  • the 15-hydroxystearic acid polymer The weight percent of ethylene glycol ester is 50%
  • the weight percent of PEG300 is 46%;
  • the insoluble drug is docetaxel
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of docetaxel is 1%
  • the weight percentage of egg yolk lecithin is 3%
  • the 15-hydroxystearic acid poly The weight percent of ethylene glycol ester is 48%
  • the weight percent of propylene glycol is 48%;
  • the insoluble drug is clopidogrel
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the insoluble drug is levosimendan
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of levosimendan is 0.5%
  • the weight percentage of egg yolk lecithin is 2%
  • the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 50%, and the weight percentage of propylene glycol is 47.5%;
  • the insoluble drug is tacrolimus
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the insoluble drug is cyclosporine
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of cyclosporine is 10%
  • the weight percentage of egg yolk lecithin is 2%
  • the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%.
  • the weight percentage of alcohol ester is 43%
  • the weight percentage of propylene glycol is 45%;
  • the insoluble drug is paclitaxel
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of paclitaxel is 1%
  • the weight percentage of egg yolk lecithin is 2%
  • the weight of 15-hydroxystearic acid polyethylene glycol ester The percentage is 46%
  • the weight percentage of propylene glycol is 51%;
  • the insoluble drug is ibuprofen
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is PEG300
  • the weight percentage of ibuprofen is 10%
  • the weight percentage of egg yolk lecithin is 2%
  • the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%.
  • the weight percentage of alcohol ester is 40%
  • the weight percentage of PEG300 is 48%;
  • the insoluble drug is coenzyme Q10
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of coenzyme Q10 is 5%
  • the weight percentage of egg yolk lecithin is 10%
  • the weight percentage of 15-hydroxystearate polyethylene glycol is The weight percentage of propylene glycol is 30%, and the weight percentage of propylene glycol is 55%;
  • the insoluble drug is cabazitaxel
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is Tween 80
  • the cosolvent is propylene glycol
  • the insoluble drug, compound emulsifier is When the total weight of the cosolvent is 100% by weight, the weight percentage of cabazitaxel is 1%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of Tween 80 is 46%, and the weight percentage of propylene glycol is 51% ;
  • the insoluble drug is celecoxib
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of celecoxib is 6%
  • the weight percentage of egg yolk lecithin is 0.5%
  • the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 70%
  • the weight percentage of propylene glycol is 23.5%;
  • the insoluble drug is etoricoxib
  • the phospholipid is egg yolk lecithin
  • the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate
  • the cosolvent is propylene glycol
  • the weight percentage of etoricoxib is 5%
  • the weight percentage of egg yolk lecithin is 5%
  • the weight percentage of 15-hydroxystearic acid polyethylene glycol is 5%.
  • the weight percent of alcohol ester is 35%
  • the weight percent of propylene glycol is 55%.
  • Embodiment 9 Use of the concentrate of any one of Embodiments 1 to 8 in the preparation of a micellar solution for intravenous injection, in particular intravenous drip.
  • Embodiment 10 The method for preparing the concentrated solution described in any of Embodiments 1 to 8, the method comprising the steps of: mixing the poorly soluble drug, phospholipid, non-phospholipid emulsifier and cosolvent in any order, stirring uniformly, filtering , sub-pack gland seal.
  • Embodiment 11 A micellar solution obtained by diluting the concentrate of any one of Embodiments 1 to 8 with an aqueous vehicle.
  • Embodiment 12 The micellar solution of Embodiment 11, wherein the aqueous vehicle is water for injection, 5% dextrose injection, or 0.9% sodium chloride injection.
  • Embodiment 13 The micellar solution according to Embodiment 12 for intravenous injection, in particular intravenous drip.
  • composition of the present invention and its preparation method
  • micellar solution can be used directly for administration by injection, such as intravenous administration.
  • the present invention provides an ethanol-free, poorly soluble drug concentrate, characterized in that the concentrate contains a poorly soluble drug and a carrier that helps to form micelles, wherein the carrier It is composed of a composite emulsifier and a cosolvent, the composite emulsifier is composed of a phospholipid and a non-phospholipid emulsifier, and the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixtures, preferably selected from propylene glycol, PEG200, PEG300 or PEG400, and the concentrate is oil-free.
  • the carrier is composed of a composite emulsifier and a cosolvent
  • the composite emulsifier is composed of a phospholipid and a non-phospholipid emulsifier
  • the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixtures, preferably selected from propylene glycol,
  • the phospholipid is preferably selected from soybean lecithin, egg yolk lecithin and mixtures thereof, more preferably egg yolk lecithin.
  • Described non-phospholipid emulsifier is selected from polyoxyethylene castor oil (such as polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, oxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbates (e.g. polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof.
  • polyoxyethylene castor oil such as polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil
  • polyoxyethylene hydrogenated castor oil such as polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, oxyethylene 60 hydrogenated castor oil
  • polyethylene glycol 15-hydroxystearate such as vitamin E polyethylene glycol 1000 succinate (TPGS)
  • TPGS vitamin E polyethylene glycol 1000
  • the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate Esters 80 and their mixtures.
  • compositions of the present invention are oil-free.
  • the "oil” is for example: vegetable oil, such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, sunflower oil, cottonseed oil, camellia oil, etc.; animal oil, such as fish oil, Egg yolk oil, lanolin, etc.; Mineral oils, such as liquid paraffin, etc.; Natural or synthetic triglycerides, such as medium-chain triglycerides (MCT), long-chain triglycerides (LCT), structured oils, etc.; and others known grease.
  • MCT medium-chain triglycerides
  • LCT long-chain triglycerides
  • the weight percentage of the poorly soluble drug is 0.1 % ⁇ 20%, preferably 0.5% ⁇ 15%, such as 0.5%, 1%, 1.5%, 2%, 5%, 6%, 10%, 15%;
  • the weight percentage of the phospholipid is 0.1% ⁇ 20%, Preferably 0.5% ⁇ 10%, such as 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%;
  • the weight percentage of the non-phospholipid emulsifier is 20% ⁇ 80%, preferably 30% % ⁇ 70%, such as 30%, 35%, 40%, 43%, 46%, 48%, 50%, 70%; the balance is cosolvent.
  • the concentrated solution of the present invention is a uniform and transparent solution with good physical and chemical stability. For example, after being placed at room temperature for 12 months or at 40° C. for 30 days, the concentrated solution in Example 5 of the present invention has always been a transparent and uniform solution, no stratification, and no drug precipitation. The content and related substances have not changed significantly, which meets the requirements of drug quality control standards.
  • the concentrates of the present invention can be diluted with an aqueous vehicle to form a micellar solution.
  • the aqueous vehicle may be an aqueous vehicle suitable for injection (eg, water for injection, 5% dextrose injection, 0.9% sodium chloride injection, etc.) or an aqueous vehicle suitable for oral administration (eg, purified water, etc.).
  • an aqueous vehicle suitable for injection such as 5% glucose injection
  • the micellar solution formed by the concentrated solution of the present invention meets the requirements of intravenous injection or even intravenous drip injection. Therefore, the micellar solution can be Directly used for subcutaneous injection, intradermal injection, intraperitoneal injection, intravenous injection, including intravenous bolus and intravenous drip.
  • the concentrated solution of the present invention not only has good stability itself, but also the micellar solution obtained by its dilution also has good stability.
  • the solution formed by diluting the concentrated solution of the present invention with 5% glucose injection was placed at room temperature for 24 hours, and no drug precipitation or layering was observed.
  • the “poorly soluble drug” in the present invention refers to a known drug that can be applied in the field of medicine, and its solubility in water is relatively low relative to its effective dosage. More specifically, the “insoluble drug” in the present invention refers to the solubility of "slightly soluble” (1g (ml) of the solute can be dissolved in 100 to less than 1000ml of solvent), “ “Slightly soluble” (1g (ml) of solute can be dissolved in 1000 to less than 10,000ml of solvent) or "barely insoluble or insoluble” (1g (ml) of solute cannot be completely dissolved in 10,000ml of solvent) drugs.
  • Examples of the poorly soluble drugs described in the present invention include, but are not limited to: celecoxib, valdecoxib, etoricoxib, ibuprofen, dextroibuprofen, propofol, flurbiprofen axetil, Alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefo Divir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, miconazole, ketoconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, carbachol Taxet, etoposide, teniposide, hydroxycamptothecin,
  • the poorly soluble drug is selected from celecoxib, ibuprofen, dextro-ibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate Ester, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posacon azole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide, and etoricoxib.
  • the insoluble drug is selected from nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
  • the inventors screened the emulsifiers used in the concentrated solution of the present invention, and the phospholipid emulsifier examined soybean lecithin, egg yolk lecithin, and hydrogenated soybean lecithin; the non-phospholipid emulsifier examined polyoxyethylene 40 hydrogenated castor oil (such as kolliphor RH40). ), polyoxyethylene 35 castor oil (eg kolliphor EL), polyethylene glycol 15-hydroxystearate (eg kolliphor HS15), vitamin E polyethylene glycol succinate (TPGS), polysorbate 80 (eg Tween 80).
  • polyoxyethylene 40 hydrogenated castor oil such as kolliphor RH40
  • polyoxyethylene 35 castor oil eg kolliphor EL
  • polyethylene glycol 15-hydroxystearate eg kolliphor HS15
  • vitamin E polyethylene glycol succinate TPGS
  • polysorbate 80 eg Tween 80.
  • the experimental results show that the solution stability of the concentrated solution prepared by using a single phospholipid emulsifier or a non-phospholipid emulsifier is poor after dilution, and it will be layered about 1 hour after the solution is formed; only the phospholipid and non-phospholipid When the two emulsifiers are used in combination, the obtained concentrated solution is stable and uniform, and the obtained solution has good stability after being diluted to meet all the requirements of intravenous injection preparations.
  • the inventors also screened co-solvents, including propylene glycol, glycerol, PEG200, PEG300, PEG400, etc., all of which can form a concentrated solution in the form of a uniform and transparent solution, and the concentrated solution has good physical and chemical stability.
  • co-solvents including propylene glycol, glycerol, PEG200, PEG300, PEG400, etc., all of which can form a concentrated solution in the form of a uniform and transparent solution, and the concentrated solution has good physical and chemical stability.
  • the concentrates prepared with glycerol were more viscous than several other co-solvents.
  • the most preferred concentrates of the present invention are those having the components and proportions given in Example 5 of this application.
  • the ethanol-free poorly soluble drug concentrate of the present invention described above may be composed of only the poorly soluble drug and a carrier that helps to form micelles, the carrier is composed of a complex emulsifier and a cosolvent, wherein the complex
  • the emulsifier is composed of phospholipids and non-phospholipid emulsifiers
  • the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixtures, preferably selected from propylene glycol, PEG200, PEG300, PEG400 and their mixtures
  • the concentrated Fluid does not contain oil.
  • the ethanol-free poorly soluble drug concentrate of the present invention described above may also contain other components, such as pH adjusters and/or antioxidants.
  • pH adjusters and/or antioxidants can be selected from citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, One or more of phosphates such as sodium monohydrogen phosphate, sodium dihydrogen phosphate or sodium phosphate.
  • the antioxidant may be selected from one or more of ⁇ -tocopheryl succinate, ascorbyl palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).
  • the present invention provides a method for preparing the ethanol-free insoluble drug concentrate, characterized in that, the method comprises the following steps: mixing the insoluble drug, phospholipids, non-phospholipid emulsifiers and auxiliary substances Solvents are mixed in any order, stirred evenly, filtered, and sealed with a lid.
  • the invention adopts an extremely simple prescription process to prepare an ethanol-free insoluble drug concentrate with good stability, which can be diluted with an aqueous solvent to obtain a micelle solution that can be directly used for intravenous administration.
  • the concentrated solution of the present invention has a simplified formula and a simple preparation process, and can be obtained by simply mixing, stirring, filtering and packaging. There is no need for homogenizers, microfluidizers and complex liquid dispensing systems; general enterprises can implement this process.
  • the physical and chemical stability of the concentrated solution of the present invention is significantly improved; storage and transportation do not require a cold chain, which greatly reduces the cost of production, transportation, storage and use, and provides great convenience for clinical medication.
  • the present invention provides a micellar solution obtained by diluting the ethanol-free poorly soluble drug concentrate described above with an aqueous vehicle.
  • the obtained micellar solution is uniform and transparent in appearance, and can be used for injection administration.
  • micellar solution was uniform and transparent, neither cloudy nor present any precipitate. After preliminary inspection, it is estimated that micelles with a particle size of about 10 nm or less are formed in the solution, so the formed solution is called “micellar solution”, and the micelle solution is close to the true solution.
  • the micellar solution is stable at room temperature for at least 24 hours.
  • micellar solution avoids the side effects associated with ethanol because it does not contain ethanol, eg, has greatly reduced vascular irritation compared to the corresponding injection solution containing ethanol.
  • micellar solution can be administered to a patient to treat a disease that the poorly soluble drug contained therein can treat.
  • nimodipine-containing concentrates and micellar solutions can be used to improve blood circulation in the recovery period of acute cerebrovascular disease, treat cerebral vasospasm after subarachnoid hemorrhage of various causes, and the ischemic neurological effects caused by it.
  • celecoxib-containing concentrates and micellar solutions can be used to treat acute pain and inflammatory diseases such as osteoarthritis and rheumatoid arthritis ;
  • Concentrates and micellar solutions containing paclitaxel or docetaxel may be used to treat cancers such as solid tumors such as breast, ovarian, head and neck, lung (including non-small cell and small cell lung), pancreatic, Gastric cancer, melanoma, soft tissue sarcoma; concentrates and micellar solutions containing ibuprofen or dextroibuprofen may be used to treat pain such as headache, arthralgia, migraine, toothache, muscle pain, neuralgia, dysmenorrhea.
  • the poorly soluble drugs described herein and their uses are known in the art, and prior art documents describing the use of these poorly soluble drugs are considered part of this application.
  • the present invention provides the use of the above-mentioned ethanol-free insoluble drug concentrate in preparing a micellar solution.
  • the micellar solutions are especially useful for intravenous injections, such as intravenous boluses and intravenous drips.
  • the inventors took various drugs such as nimodipine as a model of poorly soluble drugs, and investigated in detail the effects on the formation, physical and chemical stability of ethanol-free, poorly soluble drug concentrates, and micelles obtained after dilution.
  • the main factor for the physical stability of the solution is to obtain the concentrate of the present invention.
  • the concentrated solution can be widely used in insoluble drugs, realizes the injection and administration of insoluble drugs, and provides a new treatment possibility for clinical application.
  • carrier that aids in micelle formation refers to a pharmaceutically acceptable carrier that aids in the formation of micellar solutions when the concentrates of the present invention are diluted with an aqueous vehicle.
  • the carrier that facilitates the formation of micelles consists of a co-emulsifier and a co-solvent, which means that other than the co-emulsifier and co-solvent as defined herein, no significant amounts of other Substances that help to form micelles.
  • ethanol refers to a substance of formula CH3CH2OH .
  • medium chain triglycerides refers to the non-volatile vegetable oils extracted from the firm dried endosperm of coconut or the dried endosperm of oleifera, which is a mixture of saturated fatty acid triglycerides.
  • Medium-chain triglycerides can be obtained commercially, for example, from Liaoning Xinxing Pharmaceutical, Germany IOI Oleo GmbH, etc.
  • polyoxyethylene castor oil refers to materials obtained by reacting various amounts of ethylene oxide with castor oil.
  • examples of polyoxyethylene castor oil include, but are not limited to, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil.
  • polyoxyethylene 35 castor oil refers to a substance obtained by the reaction of 1 mol of glycerol ricinoleate with 35 mol of ethylene oxide, which in addition to polyoxyethylene glycerol triricinoleate, also contains a small amount of Polyethylene Glycol Ricinoleate and Free Glycol.
  • Polyoxyethylene 35 castor oil is commercially available, for example, from BASF and the like under the trade names kolliphor EL and kolliphor ELP.
  • pure polyoxyethylene 35 castor oil refers to purified polyoxyethylene glycerol triricinoleate substantially free of polyethylene glycol ricinoleate and free glycol.
  • polyoxyethylene hydrogenated castor oil refers to materials obtained by reacting varying amounts of ethylene oxide with hydrogenated castor oil.
  • examples of polyoxyethylene hydrogenated castor oil include, but are not limited to, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil.
  • polyoxyethylene 40 hydrogenated castor oil refers to a substance obtained by reacting 1 mol of glycerol trihydroxystearic acid with 40-45 mol of ethylene oxide, in which, except for polyoxyethylene glycerol trihydroxystearate In addition, it also contains a small amount of polyethylene glycol trihydroxystearic acid and free polyethylene glycol.
  • Polyoxyethylene 40 hydrogenated castor oil is commercially available, for example, under the tradename kolliphor RH40 from BASF and the like.
  • polyoxyethylene 60 hydrogenated castor oil refers to a substance obtained by reacting 1 mol of glycerol trihydroxystearic acid with 60 mol of ethylene oxide, wherein, in addition to polyoxyethylene glycerol trihydroxystearate, Also contains a small amount of polyethylene glycol trihydroxystearic acid, free polyethylene glycol.
  • polyethylene glycol 15-hydroxystearate as used herein is commercially available, for example, from BASF or Sigma-Aldrich under the trade names kolliphor HS15 or Solutol HS-15.
  • vitamin E polyethylene glycol succinate TPGS
  • TPGS vitamin E polyethylene glycol succinate
  • polysorbate refers to a series of partial fatty acid esters of polyoxyethylene sorbitan copolymerized in a ratio of about 20.5 or 4 moles of ethylene oxide per mole of sorbitol.
  • polysorbates include, but are not limited to, for example, polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80.
  • Polysorbate can be obtained commercially, for example, from Nanjing Weir Pharmaceutical Co., Ltd. under the trade names of Tween 20, Tween 40, and Tween 80.
  • the terms “about”, “approximately” and “around” mean that the numerical value given thereafter may be extended up or down by 20%.
  • “about 100” means 80% to 120%.
  • nimodipine concentrates obtained from prescriptions 1-5 are light yellow clear and transparent solutions
  • the nimodipine concentrates obtained from prescriptions 6-8 are turbid liquids
  • EPC, SPC and HSPC are insoluble in the system, and solutions cannot be obtained, so No further investigation after dilution.
  • Example 2 Screening of composite emulsifiers
  • nimodipine concentrates obtained in formulations 9-10 were all clear and transparent pale yellow solutions, and it was observed that these concentrates did not delaminate after being placed at 25°C for 12 months.
  • the nimodipine concentrate obtained in recipe 11 is a turbid liquid, and HSPC is insoluble in the system and cannot form a solution, so no further investigation after dilution is done.
  • nimodipine concentrate in the form of a transparent solution cannot be prepared with the composite emulsifier composed of HS15 and HSPC, but the nimodipine concentrate prepared with the composite emulsifier composed of HS15 and EPC and SPC respectively is uniform. Clear solutions, and none of these concentrates were observed to separate after 12 months at 25°C.
  • the concentrates of formulations 9 and 10 were diluted with 5% glucose injection at a volume ratio of 1:100 to form clear and transparent solutions. As shown in Table 5, these solutions were placed at 25° C. for 24 hours, and no precipitate was observed, which met the needs of intravenous administration.
  • a formulation containing a phospholipid and a non-phospholipid complex emulsifier should be used, and the phospholipid should not be HSPC, because not all phospholipid emulsifiers can produce clear and transparent solutions.
  • the inventor has investigated a variety of pharmaceutically acceptable non-ethanol cosolvents, and the specific experimental design is as follows:
  • the nimodipine concentrate prepared according to recipes 22-26 was diluted 100-fold with 5% dextrose injection at a volume ratio of 1:100. After standing at 25°C for 24 hours, the formation of a solution was observed and the stability of the resulting solution was examined.
  • the experimental results are shown in Table 9.
  • the concentrated solution prepared with the investigated cosolvent is light yellow clear and transparent solution, and the concentrated solution of prescription 22-25 has good fluidity, and by contrast, the concentrated solution of prescription 26 is relatively sticky. Thick and less fluid than formula 22-25 concentrates.
  • the solutions obtained after diluting with these concentrated solutions all had good stability, and no precipitate was found to be precipitated after standing at 25° C. for 24 hours.
  • Example 5 Preparation of a poorly soluble pharmaceutical composition without ethanol (* the total amount of the poorly soluble drug, compound emulsifier, and cosolvent is regarded as 100%)
  • EPC and docetaxel weigh the prescribed amount of EPC and docetaxel, put them into a 20 ml vial, add the prescribed amount of propylene glycol, and stir at 2000 rpm for 10 min in a water bath at 60°C. Then add the prescribed amount of HS15 to it, and stir at 2000 rpm for 5 min in a water bath at 60° C. to obtain a uniform and transparent solution.
  • Example 5 According to the "Chinese Pharmacopoeia” 2015 edition of the four general rules 9001 on the stability test guidelines for raw materials and pharmaceutical preparations, the concentrated solution 1 in Example 5 was placed at a temperature of 25 ° C ⁇ 2 ° C and a relative humidity of 60% ⁇ 5%, Samples were taken at the end of the 0th, 3rd, 6th and 12th months to investigate the corresponding indicators.
  • Inspection method Visual inspection.
  • Chromatographic column C18 column (Model: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, particle size 5.0 ⁇ m)
  • UV detector detection wavelength 235nm
  • System suitability In system suitability solution chromatography, nimodipine peak and impurity I(2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyl group
  • the resolution of the ethyl isopropyl ester) peak should be greater than 3.0.
  • nimodipine Take the concentrated solution 1 placed at each specified time point, accurately weigh it, add methanol to dissolve and quantitatively dilute to make a solution containing about 0.2 mg of nimodipine per 1 mL, as the test solution; accurately measure the nimodipine
  • An appropriate amount of the standard substance was diluted with methanol into a solution containing about 2 ⁇ g of nimodipine per 1 mL as a reference solution.
  • Another appropriate amount of nimodipine standard and impurity I standard was taken, dissolved in methanol and diluted to make a mixed solution containing about 200 ⁇ g of nimodipine and 1 ⁇ g of impurity I per 1 mL, as a system adaptability solution.
  • Chromatographic column C18 column (Model: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, particle size 5.0 ⁇ m)
  • UV detector detection wavelength 235nm
  • the number of theoretical plates calculated by the main peak of nimodipine should not be less than 8000, the resolution of nimodipine and adjacent impurity peaks should meet the requirements, and the relative standard deviation of repeated injection should not exceed 2.0%.
  • nimodipine and impurity I peak should be greater than 3.0.
  • Example 5 The above experimental results show that the concentrated solution 1 in Example 5 is placed for 12 months under the conditions of a temperature of 25 °C ⁇ 2 ° C and a relative humidity of 60% ⁇ 5%, and all indicators meet the requirements, physical stability and chemical stability good.
  • the inventor also carried out the stability investigation of the concentrated solution 2-13 of Example 5 under the conditions of temperature 40 °C ⁇ 2 °C, relative humidity 60% ⁇ 5%, sampling time was 0, 5, 10, 30 days.
  • the index is the content of poorly soluble drugs, and the results are shown in Table 11.
  • micellar solutions that were stable for at least 24 hours.
  • the daily dose of commercially available nimodipine injection for human administration is 10 mg, which is 0.47 mg/kg when converted into rabbits according to the average body weight of a human being 60 kg.
  • the nimodipine injection of the present invention, the commercially available nimodipine injection, and the 5% glucose injection were respectively administered to the rabbits by instillation of the marginal ear vein, once a day, for 7 consecutive days. Visual inspection was performed before daily administration and 48 hours after the last administration.
  • the animals were euthanized, and the rabbit ears at the injection site and the vicinity were cut for hematoxylin-eosin staining (HE staining for short), and the sections were observed under a light microscope to determine whether there were any Vasodilation, congestion, hemorrhage, thrombosis, vessel wall hyperplasia, inflammatory cell infiltration, endothelial cell degeneration and necrosis, surrounding tissue edema and other pathological changes, and each animal was evaluated according to the "vascular autopsy scoring criteria" shown in Table 12. score.
  • Vascular stimulation response score No obvious reaction 0 mild congestion 1 Mild to moderate congestion, swelling 2 Moderate to severe congestion, swelling, ear droop 3 Mild to moderate hyperemia, swelling, and mild to moderate necrosis 4 Mild to moderate hyperemia, swelling, and moderate to severe extensive necrosis 5
  • the scores of animals in the same group were averaged, and the stimulation level was determined according to the following criteria.
  • Nimodipine concentrate of the present invention concentrate 1 of Example 5 with the batch number of DME-009 2020121701 is diluted with 5% glucose injection to a nimodipine concentration of 0.2 mg/ml
  • Nimodipine injection (trade name: Nimotong, containing 23.7% (v/v) ethanol), specification: 50ml:10mg. It was diluted with 5% Dextrose Injection to a nimodipine concentration of 0.2 mg/ml prior to administration
  • Grouping The rabbits were randomly divided into 3 groups, 6 in each group. The three groups were respectively given commercial nimodipine injection (group A), nimodipine injection of the present invention (group B) and 5% glucose injection (group C). See Table 13 for details.
  • Mode of administration Instillation in the marginal ear vein using a syringe pump.
  • Sections prepared with HE staining as described in Section 1.1 were observed with a light microscope. The result is as follows:
  • the rabbit ears on the administration side of animals in group B were intact, with only a small amount of mild congestion and swelling. Observation under the light microscope showed that the rabbit ears were slightly loose and edema, and no other obvious abnormality was found.
  • the results show that the nimodipine injection of the present invention has little irritation, and the irritation is significantly improved compared with the commercially available nimodipine injection.
  • Representative HE staining (20 ⁇ and 200 ⁇ ) results of rabbits in group B are shown in Figure 3 .
  • the nimodipine injection of the present invention is significantly less irritating to blood vessels than the commercially available nimodipine injection, and has very obvious advantages.

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Abstract

La présente invention concerne une solution concentrée d'un médicament insoluble ne contenant pas d'éthanol, la solution concentrée comprenant un médicament insoluble et un support, qui aide à former une micelle, le support étant composé d'un émulsifiant composite et d'un co-solvant. L'émulsifiant composite est composé d'un phospholipide et d'un émulsifiant non phospholipide, le phospholipide étant choisi parmi le phospholipide de soja, la lécithine du jaune d'œuf et un mélange de ceux-ci. Le co-solvant est choisi parmi le propylène glycol, le glycérol, le PEG200, le PEG300, le PEG400 et un mélange de ceux-ci. De plus, la solution concentrée ne contient pas d'huile. La solution concentrée peut être utilisée pour préparer une solution micellaire pour injection intraveineuse.
PCT/CN2021/137169 2021-01-28 2021-12-10 Solution concentrée de médicament insoluble ne contenant pas d'éthanol, et solution micellaire préparée à partir de celle-ci WO2022160970A1 (fr)

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